@article {pmid40275359, year = {2025}, author = {Grima, N and Smith, AN and Shepherd, CE and Henden, L and Zaw, T and Carroll, L and Rowe, DB and Kiernan, MC and Blair, IP and Williams, KL}, title = {Multi-region brain transcriptomic analysis of amyotrophic lateral sclerosis reveals widespread RNA alterations and substantial cerebellum involvement.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {40}, pmid = {40275359}, issn = {1750-1326}, support = {Ideas Grant 2011120//National Health and Medical Research Council/ ; Investigator Grant 1176913//National Health and Medical Research Council/ ; Angie Cunningham PhD Scholarship and Project Grant-In-Aid Award//FightMND/ ; Discovery Grant//FightMND/ ; Grant-in-Aid//Motor Neurone Disease Research Australia/ ; R28AA012725/AA/NIAAA NIH HHS/United States ; Not applicable//Neuroscience Research Australia/ ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the motor neurons, causing progressive muscle weakness and paralysis. While research has focused on understanding pathological mechanisms in the motor cortex and spinal cord, there is growing evidence that extra-motor brain regions may also play a role in the pathogenesis or progression of ALS.

METHODS: We generated 165 sample-matched post-mortem brain transcriptomes from 22 sporadic ALS patients with pTDP-43 pathological staging and 11 non-neurological controls. For each individual, five brain regions underwent mRNA sequencing: motor cortex (pTDP-43 inclusions always present), prefrontal cortex and hippocampus (pTDP-43 inclusions sometimes present), and occipital cortex and cerebellum (pTDP-43 inclusions rarely present). We examined gene expression, cell-type composition, transcript usage (% contribution of a transcript to total gene expression) and alternative splicing, comparing ALS-specific changes between brain regions. We also considered whether post-mortem pTDP-43 pathological stage classification defined ALS subgroups with distinct gene expression profiles.

RESULTS: Significant gene expression changes were observed in ALS cases for all five brain regions, with the cerebellum demonstrating the largest number of total (> 3,000) and unique (60%) differentially expressed genes. Pathway enrichment and predicted activity were largely concordant across brain regions, suggesting that ALS-linked mechanisms, including inflammation, mitochondrial dysfunction and oxidative stress, are also dysregulated in non-motor brain regions. Switches in transcript usage were identified for a small set of genes including increased usage of a POLDIP3 transcript, associated with TDP-43 loss-of-function, in the cerebellum and a XBP1 transcript, indicative of unfolded protein response activity, in the motor cortex. Extensive variation in RNA splicing was identified in the ALS brain, with 26-41% of alternatively spliced genes unique to a given brain region. This included detection of TDP-43-associated cryptic splicing events such as the STMN2 cryptic exon which was shown to have a pTDP-43 pathology-specific expression pattern. Finally, ALS patients with stage 4 pTDP-43 pathology demonstrated distinct gene and protein expression changes in the cerebellum.

CONCLUSIONS: Together our findings highlighted widespread transcriptome alterations in ALS post-mortem brain and showed that, despite the absence of pTDP-43 pathology in the cerebellum, extensive and pTDP-43 pathological stage-specific RNA changes are evident in this brain region.}, } @article {pmid40273110, year = {2025}, author = {Souza, AA and Silva, STD and Régis, AMP and Aires, DN and Pondofe, KM and Melo, LP and Valentim, RAM and Lindquist, ARR and Macedo, LRD and Ribeiro, TS}, title = {Muscle strengthening in individuals with Amyotrophic Lateral Sclerosis: a systematic review with meta-analyses.}, journal = {PloS one}, volume = {20}, number = {4}, pages = {e0320788}, doi = {10.1371/journal.pone.0320788}, pmid = {40273110}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation/therapy ; *Muscle Strength/physiology ; *Resistance Training/methods ; *Exercise Therapy/methods ; }, abstract = {Despite the observed benefits of properly prescribed exercises for people with Amyotrophic Lateral Sclerosis (ALS), the scarcity of studies and lack of consensus on the effects of muscle-strengthening exercises on this population has a negative impact on their rehabilitation. This study aimed to evaluate the effects of muscle-strengthening interventions in individuals with ALS. This systematic review of intervention studies included clinical trials that performed non-respiratory muscle strengthening in people with ALS compared to non-strengthening interventions, usual care, or placebo. Such studies were obtained from the MEDLINE, EMBASE, Cochrane Library, SPORTDiscus, and Physiotherapy Evidence Database databases, with no language or publication date restrictions. The outcomes considered were peripheral muscle strength, functionality, fatigue, and adverse events. The Physiotherapy Evidence Database scale was used to analyze the risk of bias, while the Grading of Recommendations Assessment, Development and Evaluation system was used to evaluate the quality of the evidence. Searches were conducted in October 2023 and eight studies were included, totaling 296 individuals. Seven of the eight studies showed superiority of the experimental intervention over the control, but this was not supported in the meta-analyses. Small sample size and high heterogeneity in the primary studies contributed significantly to the low quality of the evidence. There was no evidence of the superiority of interventions for muscle strengthening compared to interventions not aimed at strengthening, usual care, or placebo in terms of the outcomes analyzed immediately after the intervention. The quality of the evidence ranged from low to very low. Five of the studies evaluated adverse events, without reporting serious events. Interventions for muscle strengthening did not prove to be more effective when compared to the control group in the short term nor seem to produce serious adverse events. The low quality of the evidence indicates the need for studies with greater methodological rigor in this population, to more assertively assess the impacts of this intervention over the short, medium, and long term.}, } @article {pmid40272376, year = {2025}, author = {Nguyen, THV and Ferron, F and Murakami, K}, title = {Neurotoxic Implications of Human Coronaviruses in Neurodegenerative Diseases: A Perspective from Amyloid Aggregation.}, journal = {ACS chemical biology}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschembio.5c00153}, pmid = {40272376}, issn = {1554-8937}, abstract = {Human coronaviruses (HCoVs) include seven species: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1, and SARS-CoV-2. The last three, classified as Betacoronaviruses, are highly transmissible and have caused severe pandemics. HCoV infections primarily affect the respiratory system, leading to symptoms such as dry cough, fever, and breath shortness, which can progress to acute respiratory failure and death. Beyond respiratory effects, increasing evidence links HCoVs to neurological dysfunction. However, distinguishing direct neural complications from preexisting disorders, particularly in the elderly, remains challenging. This study examines the association between HCoVs and neurodegenerative diseases like Alzheimer disease, Parkinson disease, Lewy body dementia, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease. It also presents the long-term neurological effects of HCoV infections and their differential impact across age groups and sexes. A key aspect of this study is the investigation of the sequence and structural similarities between amyloidogenic and HCoV spike proteins, which can provide insights into potential neuropathomechanisms.}, } @article {pmid40271431, year = {2025}, author = {Rana, A and Katiyar, A and Arun, A and Berrios, JN and Kumar, G}, title = {Natural sulfur compounds in mental health and neurological disorders: insights from observational and intervention studies.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1534000}, doi = {10.3389/fnut.2025.1534000}, pmid = {40271431}, issn = {2296-861X}, abstract = {Over the years, the global disease burden of neurological disorders (NDs) and mental disorders (MDs) has significantly increased, making them one of the most critical concerns and challenges to human health. In pursuit of novel therapies against MD and ND, there has been a growing focus on nutrition and health. Dietary sulfur, primarily derived from various natural sources, plays a crucial role in numerous physiological processes, including brain function. This review offers an overview of the chemical composition of several natural sources of the sulfur-rich substances such as isothiocyanates, sulforaphane, glutathione, taurine, sulfated polysaccharides, allyl sulfides, and sulfur-containing amino acids, all of which have neuroprotective properties. A multitude of studies have documented that consuming foods that are high in sulfur enhances brain function by improving cognitive parameters and reduces the severity of neuropathology by exhibiting antioxidant and anti-inflammatory properties at the molecular level. In addition, the growing role of natural sulfur compounds in repairing endothelial dysfunction, compromising blood-brain barrier and improving cerebral blood flow, are documented here. Furthermore, this review covers the encouraging results of supplementing sulfur-rich diets in many animal models and clinical investigations, along with their molecular targets in MD, such as schizophrenia, depression, anxiety, bipolar disorder, and autism spectrum disorder, and ND, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS). The prospects of natural sulfur compounds show great promise as they have potential applications in nutraceuticals, medicines, and functional foods to enhance brain function and prevent diseases. However, additional research is required to clarify the mechanisms by which it works, enhance its bioavailability, and evaluate its long-term safety for broad use.}, } @article {pmid40271315, year = {2025}, author = {Honda, N and Watanabe, Y and Honda, H and Uemoto, M and Fukuhara, H and Hanajima, R}, title = {Implications of Mutant SOD1 on RNA Processing and Interferon Responses in Amyotrophic Lateral Sclerosis: Omics Data Analysis.}, journal = {Cureus}, volume = {17}, number = {3}, pages = {e81045}, doi = {10.7759/cureus.81045}, pmid = {40271315}, issn = {2168-8184}, abstract = {INTRODUCTION: Cytoplasmic inclusions are observed in motor neurons in amyotrophic lateral sclerosis (ALS) associated with the Cu/Zn superoxide dismutase mutation (mtSOD1). Although these inclusions are a hallmark of the disorder, degeneration is not necessarily initiated in the cytoplasm, nor are these structures the culprit of ALS. The nucleus stores genetic material and acts as the cell's control center, and a small fraction of mtSOD1 is reported to be distributed in the nucleus. We hypothesized that mtSOD1 in the nucleus contributes to motor neuron degeneration.

METHODS: We explored the roles of mtSOD1 in relation to nuclear proteins, chromosomal DNA, and mRNA expression. An immortalized cell line derived from a transgenic ALS mouse model expressing mtSOD1-L126delTT with a FLAG was used for stable immunoprecipitation of mtSOD1-binding molecules using shotgun proteomics and chromatin immunoprecipitation-sequencing (ChIP-seq). We also examined mRNA expression by silencing whole SOD1 (innate mouse Sod1 and mtSOD1) or mtSOD1 alone and compared these patterns against those in non-silenced counterparts.

RESULTS: We identified 392 mtSOD1-interacting proteins in the nucleus. Gene ontology (GO) revealed these proteins to be enriched for "mRNA processing." Notably, more than 11% of mtSOD1-interacting proteins were expressed concurrently with previously reported wild-type TAR DNA-binding protein 43 (TDP-43)-interacting proteins. ChIP-seq revealed that mtSOD1-interacting DNA portions showed a preference for zinc finger protein-binding motifs. GO analysis of the ChIP-seq data revealed that "mRNA processing" was again enriched among the genes harboring mtSOD1-binding domains. RNA expression analyses revealed that the presence of mouse Sod1 and mtSOD1 induced the overexpression of molecules related to "type 1 IFN responses."

CONCLUSIONS: We revealed that mtSOD1 interacted with nuclear proteins and specific DNA segments and that RNA expression was notably altered when mouse Sod1 and mtSOD1 were silenced. These interactions could play a pivotal role in motor neuron degeneration.}, } @article {pmid40271071, year = {2025}, author = {Luo, H and Wei, S and Fu, S and Han, L}, title = {Role of Achyranthes aspera in neurodegenerative diseases: current evidence and future directions.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1511011}, doi = {10.3389/fphar.2025.1511011}, pmid = {40271071}, issn = {1663-9812}, abstract = {Neurodegenerative diseases are caused by the progressive degeneration of neurons and/or their myelin sheaths, ultimately leading to cognitive and motor dysfunction. Due to their complex pathogenesis and the limited efficacy of therapeutic drugs, these diseases have attracted significant attention. Achyranthes aspera, belongs to family Amaranthaceae, has been extensively used in the traditional and folk medicines for the treatment of various ailments. Modern research has revealed that Achyranthes aspera possesses various pharmacological effects, including cardiocerebrovascular protection, immune regulation, antioxidation, and anti-aging. Furthermore, the neuroprotective effects of Achyranthes aspera have been confirmed by numerous scientific studies. This review focuses on the primary pharmacological effects and mechanisms of Achyranthes aspera in the prevention and treatment of neurodegenerative diseases, as well as their potential application prospects. This review aims to provide insights into the potential clinical applications and research directions of Achyranthes aspera in neurodegenerative diseases.}, } @article {pmid40268233, year = {2025}, author = {Basak, B and Holzbaur, ELF}, title = {Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis.}, journal = {Journal of molecular biology}, volume = {}, number = {}, pages = {169161}, doi = {10.1016/j.jmb.2025.169161}, pmid = {40268233}, issn = {1089-8638}, abstract = {Mitochondrial quality control is instrumental in regulating neuronal health and survival. The receptor-mediated clearance of damaged mitochondria by autophagy, known as mitophagy, plays a key role in controlling mitochondrial homeostasis. Mutations in genes that regulate mitophagy are causative for familial forms of neurological disorders including Parkinson's disease (PD) and Amyotrophic lateral sclerosis(ALS). PINK1/Parkin-dependent mitophagy is the best studied mitophagy pathway, while more recent work has brought to light additional mitochondrial quality control mechanisms that operate either in parallel to or independent of PINK1/Parkin mitophagy. Here, we discuss our current understanding of mitophagy mechanisms operating in neurons to govern mitochondrial homeostasis. We also summarize progress in our understanding of the links between mitophagic dysfunction and neurodegeneration and highlight the potential for therapeutic interventions to maintain mitochondrial health and neuronal function.}, } @article {pmid40267658, year = {2025}, author = {Orsucci, D and Vista, M and Santorelli, FM}, title = {Conversational AI in neurogenetics. The example of FUS gene.}, journal = {Journal of the neurological sciences}, volume = {473}, number = {}, pages = {123511}, doi = {10.1016/j.jns.2025.123511}, pmid = {40267658}, issn = {1878-5883}, } @article {pmid40267619, year = {2025}, author = {Garnés-Camarena, O and Mahíllo-Fernández, I and Martínez-Ulloa, P and Mandeville, R and Lorenzo, O and Stashuk, DW}, title = {Towards early diagnosis of amyotrophic lateral sclerosis using near fibre EMG.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {174}, number = {}, pages = {114-122}, doi = {10.1016/j.clinph.2025.04.006}, pmid = {40267619}, issn = {1872-8952}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons and diagnosis is usually delayed several months. The continuous denervation and reinnervation associated with ALS are manifest in EMG signals as changes in motor unit potential (MUP) size, temporal dispersion and instability. Near Fibre EMG is a novel method to assess early changes in MUP temporal dispersion and instability using routinely recorded EMG signals in a semi-automated manner.

METHODS: Near Fibre EMG values from 2318 MUs, retrospectively sampled at the time of ALS diagnosis, from 96 muscles of 15 patients were compared with values from 3954 MUs sampled from 109 muscles of 84 reference subjects.

RESULTS: 30.1% and 46.1% of ALS MUs had MUPs with increased complexity or instability, respectively, and 17.4% had both. The potential importance and heightened sensitivity of NFEMG was highlighted when analyzing normal-sized motor units; as many as 24% of the normal-sized MUPs actually had significant instability, while 14% had increased complexity, and 7.4% had both.

CONCLUSIONS: Near Fibre EMG can characterize motor unit electrophysiological status and hence help quantify the degree, and course of denervation and reinnervation.

SIGNIFICANCE: Near-Fiber EMG offers the potential to facilitate earlier ALS diagnosis, which, as promising therapies become available, can be consequential.}, } @article {pmid40267236, year = {2025}, author = {Zhong, H and Zhu, J and Liu, S and Zhou, D and Long, Q and Wu, C and Zhao, B and Cheng, C and Yang, Y and Wu, Q and Wu, Y and Li, C and Wang, Z and Wu, J and Guo, X and Zhi, D and Deng, Y and Wu, L}, title = {Linking DNA methylation in brain regions to Alzheimer's disease risk: a Mendelian randomization study.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddaf053}, pmid = {40267236}, issn = {1460-2083}, support = {//University of Hawai'i Cancer Center/ ; }, abstract = {AIM: DNA methylation in brain regions represents a potential mechanism linking genetic variation to Alzheimer's disease (ad) risk, yet most studies have focused on blood-derived methylation markers. In this study, we conducted a systematic Mendelian randomization (MR) study to evaluate associations between predicted brain region-specific DNA methylation levels and ad risk, using methylation quantitative trait loci (mQTL) as genetic instruments.

METHODS: We analyzed mQTLs from five human brain regions: cerebellum (CRBLM), frontal cortex (FCTX), causal pons (PONS), and temporal cortex (TCTX) from 600 individuals in Gibbs et al's study, as well as mQTLs from dorsolateral prefrontal cortex (DLPFC) of 543 participants in the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). In our MR analyses, we integrated these mQTLs with single nucleotide polymorphisms (SNP)-ad risk summary statistics derived from 85 934 ad-related cases and 401 577 normal controls.

RESULTS: Among 62 554 cytosine-guanine dinucleotide (CpG) sites, we identified 597 CpG sites (CpGs) significantly associated with ad risk (false discovery rate (FDR) < 0.05). Of these, 289 were confirmed through colocalization and summary-based MR (SMR) analyses, including one CpG site in CRBLM, 285 in DLPFC, one in FCTX, two in PONS, and one in TCTX. By integrating gene expression data, we identified 19 CpG sites with consistent associations across methylation levels, expression of eight target genes, and ad risk, including novel regulatory mechanisms involving RITA1's modulation of cg11558705 and PCGF3's regulation of cg10009224.

CONCLUSION: Our findings highlight brain region-specific DNA methylation as a mediator of genetic risk for ad, offering insights into ad pathogenesis and identifying potential therapeutic targets.}, } @article {pmid40267187, year = {2025}, author = {Guillaud, L and Garanzini, A and Zakhia, S and De la Fuente, S and Dimitrov, D and Boerner, S and Terenzio, M}, title = {Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons.}, journal = {Science advances}, volume = {11}, number = {17}, pages = {eadq6077}, doi = {10.1126/sciadv.adq6077}, pmid = {40267187}, issn = {2375-2548}, mesh = {*Adenosine Triphosphate/metabolism ; Humans ; Animals ; *Protein Aggregation, Pathological/metabolism/pathology ; Mice ; *Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Axons/metabolism ; Viscosity ; Mitochondria/metabolism ; Protein Aggregates ; Parkinson Disease/metabolism/pathology ; DNA-Binding Proteins/metabolism ; Alzheimer Disease/metabolism/pathology ; }, abstract = {Neurodegenerative diseases display synaptic deficits, mitochondrial defects, and protein aggregation. We show that intracellular adenosine triphosphate (ATP) regulates axoplasmic viscosity and protein aggregation in mammalian neurons. Decreased intracellular ATP upon mitochondrial inhibition leads to axoterminal cytosol, synaptic vesicles, and active zone component condensation, modulating the functional organization of mouse glutamatergic synapses. Proteins involved in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) condensed and underwent ATP-dependent liquid phase separation in vitro. Human inducible pluripotent stem cell-derived neurons from patients with PD and ALS displayed reduced axoplasmic fluidity and decreased intracellular ATP. Last, nicotinamide mononucleotide treatment successfully rescued intracellular ATP levels and axoplasmic viscosity in neurons from patients with PD and ALS and reduced TAR DNA-binding protein 43 (TDP-43) aggregation in human motor neurons derived from a patient with ALS. Thus, our data suggest that the hydrotropic activity of ATP contributes to the regulation of neuronal homeostasis under both physiological and pathological conditions.}, } @article {pmid40265300, year = {2025}, author = {Xu, IQ and Guo, L and Xu, J and Setiawan, S and Deng, X and Lo, YL and Chai, JYH and Simmons, Z and Ramasamy, S and Yeo, CJJ}, title = {Predictive Analysis of Amyotrophic Lateral Sclerosis Progression and Mortality in a Clinic Cohort From Singapore.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28416}, pmid = {40265300}, issn = {1097-4598}, support = {C210112024//Agency for Science, Technology and Research/ ; IRNMR21CPGJJ//National Neuroscience Institute/ ; }, abstract = {INTRODUCTION: There is currently no comprehensive Amyotrophic Lateral Sclerosis (ALS) patient database in Singapore comparable to those available in Europe and the United States. We established the Singapore ALS registry (SingALS) to draw meaningful inferences about the ALS population in Singapore through developing statistical and machine learning-based predictive models.

METHODS: The SingALS registry was established through the retrospective collection of demographic, clinical, and laboratory data from 72 ALS patients at Tan Tock Seng Hospital (TTSH) and combining it with demographic and clinical data from 71 patients at Singapore General Hospital (SGH). The SingALS was compared against international ALS registries. Using comparative studies including survival and temporal feature analysis, we identified key factors influencing ALS survival and developed a machine learning model to predict survival outcomes.

RESULTS: Compared to Caucasian-dominant registries, such as the German Swabia registry, SingALS patients had longer average survival (50.51 vs. 31.0 months), younger age of onset (56.18 vs. 66.6 years), and lower bulbar onset prevalence (20.98% vs. 34.10%). Singaporean males had poorer outcomes compared to females, with a hazard ratio (HR) of 3.12 (p = 0.008). Patients who died within 24 months had an earlier need for being bedbound (p < 0.004), percutaneous endoscopic gastrostomy (PEG) insertion (p = 0.004) and non-invasive ventilation (NIV) (p < 0.001). Machine learning and statistical analysis indicated that a steeper ALSFRS-R slope, higher alkaline phosphatase (ALP), white blood cell (WBC), absolute neutrophil counts, and creatinine levels are associated with worse mortality.

DISCUSSION: We developed a comprehensive Singaporean ALS registry and identified key factors influencing survival.}, } @article {pmid40265276, year = {2025}, author = {Mendonça, IP and Peixoto, CA}, title = {The Double-Edged Sword: The Complex Function of Enteric Glial Cells in Neurodegenerative Diseases.}, journal = {Journal of neurochemistry}, volume = {169}, number = {4}, pages = {e70069}, doi = {10.1111/jnc.70069}, pmid = {40265276}, issn = {1471-4159}, support = {CNPq;#301891/2022-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; IAM-PROEP# 005-FIO-22//Instituto Aggeu Magalhães/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism ; *Neuroglia/metabolism/pathology/physiology ; Animals ; *Enteric Nervous System/pathology/metabolism ; }, abstract = {Over the past two decades, a growing number of studies have been conducted on the role of bidirectional communication through the gut-brain axis in the development of neurodegenerative diseases. These studies were driven by the curious fact that all of these diseases present varying degrees of intestinal involvement included in their wide range of symptoms. A population of cells belonging to the ENS, called enteric glial cells (EGCs), appears to actively participate in this communication between the intestine and the brain, but acting in a dualistic manner, sometimes in reactive gliosis releasing inflammatory mediators, sometimes promoting homeostasis and resilience in the face of inflammatory injuries. To date, the intracellular mechanisms that define the transcriptional profile expressed in EGCs in each situation have not yet been elucidated. This review proposes a discussion on: (1) the complex role of distinct phenotypes of enteric glial cells involved in neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and multiple sclerosis (MS); and (2) innovative strategies such as IDO/TDO inhibitors, Brazil nuts, caffeic acid, polyphenols, among others, that act on EGCs and have the potential to treat neurodegenerative diseases.}, } @article {pmid40264898, year = {2024}, author = {Kumar, J and Varela-Ramirez, A and Narayan, M}, title = {Development of novel carbon-based biomedical platforms for intervention in xenotoxicant-induced Parkinson's disease onset.}, journal = {BMEmat}, volume = {2}, number = {4}, pages = {}, pmid = {40264898}, issn = {2751-7446}, abstract = {Chronic exposure to herbicides, weedicides, and pesticides is associated with the onset and progress of neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we have investigated whether quinic- and chlorogenic-acid-derived Carbon Quantum Dots (QACQDs and ChACQDs, respectively) protect against a (pesticide) paraquat-insult model of PD. Our results indicated that both types of CQDs intervened in the soluble-to-toxic transformation of the amyloid-forming model protein Hen Egg White Lysozyme (HEWL). Furthermore, QACQDs and ChACQDs demonstrated antioxidant activity while remaining biocompatible in a human neuroblastoma-derived cell line (SH-SY5Y) up to 5 mg/ml and protected the cell line from the environmental neurotoxicant (paraquat). Importantly, both CQDs were found to protect dopaminergic neuronal ablation in a paraquat model of Parkinson's disease using the nematode C. elegans. Our results are significant because both plant-derived organic acids cross the blood-brain barrier, making them attractive for developing CQD architectures. Furthermore, since the synthesis of these CQDs was performed using green chemistry methods from precursor acids that cross the BBB, these engineered bionanomaterial platforms are tantalizing candidates for preventing neurodegenerative disorders associated with exposure to environmental neurotoxicants.}, } @article {pmid40263468, year = {2025}, author = {Su, Y and Schwartz, M and Fayad, I and García, M and Zavala, MA and Tijerín-Triviño, J and Astigarraga, J and Cruz-Alonso, V and Liu, S and Zhang, X and Chen, S and Ritter, F and Besic, N and d'Aspremont, A and Ciais, P}, title = {Canopy height and biomass distribution across the forests of Iberian Peninsula.}, journal = {Scientific data}, volume = {12}, number = {1}, pages = {678}, pmid = {40263468}, issn = {2052-4463}, support = {ANR-22-FAI1-0002//Agence Nationale de la Recherche (French National Research Agency)/ ; ANR-22-FAI1-0002//Agence Nationale de la Recherche (French National Research Agency)/ ; ANR-22-FAI1-0002//Agence Nationale de la Recherche (French National Research Agency)/ ; ANR-22-FAI1-0002//Agence Nationale de la Recherche (French National Research Agency)/ ; }, abstract = {Accurate mapping of vegetation canopy height and biomass distribution is essential for effective forest monitoring, climate change mitigation, and sustainable forestry. Here we present high-resolution remote sensing-based canopy height (10 m resolution) and above ground biomass (AGB, 50 m resolution) maps for the forests of the Iberian Peninsula from 2017 to 2021, using a deep learning framework that integrates Sentinel-1, Sentinel-2, and LiDAR data. Two UNET models were developed: one trained on Airborne Laser Scanning (ALS) data (MAE: 1.22 m), while another using Global Ecosystem Dynamics Investigation (GEDI) footprints (MAE: 3.24 m). External validation with 6,308 Spanish National Forest Inventory (NFI) plots (2017-2019) confirmed canopy height reliability, showing MAEs of 2-3 m in tree-covered areas. AGB estimates were obtained through Random Forest models that linked UNET derived height predictions to NFI AGB data, achieves an MAE of ~29 Mg/ha. The creation of high-resolution maps of canopy height and biomass across various forest landscapes in the Iberian Peninsula provides a valuable new tool for environmental researchers, policy makers, and forest management professionals, offering detailed insights that can inform conservation strategies, carbon sequestration efforts, and sustainable forest management practices.}, } @article {pmid40262868, year = {2025}, author = {Shi, Y and Wu, Z and Cheng, R and Zhang, L and Guo, X and Li, X and Bi, Y}, title = {The Trp-574-Leu mutations together with enhanced metabolism contribute to cross-resistance to ALS inhibiting herbicides in Fimbristylis littoralis.}, journal = {Pesticide biochemistry and physiology}, volume = {210}, number = {}, pages = {106385}, doi = {10.1016/j.pestbp.2025.106385}, pmid = {40262868}, issn = {1095-9939}, abstract = {Fimbristylis littoralis Gaudich., an important weed in Chinese paddy fields, has caused significant yield losses in rice and other crops. Acetolactate synthase (ALS) inhibitors, such as halosulfuron-methyl, are widely used for weed control. This study identified a highly resistant population (R23-1) of F. littoralis to halosulfuron-methyl, with an exceptionally high resistance index (RI) of 3441.66. The resistant mechanisms of F. littoralis to ALS inhibitors have not been reported previously. We employed a comprehensive approach to address this, including whole-plant bioassay, ALS target gene sequencing, molecular docking, synergistic tests with metabolic enzyme inhibitors, glutathione S-transferases (GSTs) activity assays, and cross-resistance testing. The results revealed the first report of a Trp-574-Leu mutation in the ALS gene of the R23-1 population, which significantly increased binding energy, as shown by molecular docking analysis. Synergistic tests demonstrated that the cytochrome P450 monooxygenase (P450) inhibitor piperonyl butoxide (PBO) and the GSTs inhibitor 4-chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) markedly enhanced the sensitivity of the R23-1 population to halosulfuron-methyl, with synergistic ratios of 4.11 and 8.15, respectively, while malathion had no effect. GST activity decreased in both populations after halosulfuron-methyl treatment, with the R23-1 population consistently showing significantly higher levels, peaking on day five. Furthermore, the R23-1 population demonstrated cross-resistance to multiple ALS inhibitors. These findings provide novel insights into the resistance mechanisms of F. littoralis and lay a theoretical foundation for developing effective strategies to mitigate or delay the evolution of resistance.}, } @article {pmid40262704, year = {2025}, author = {Kim, HB and Ehsan, MF and Alshawabkeh, AN and Kim, JG}, title = {Electrochemical activation of alum sludge for the adsorption of lead (Pb(II)) and arsenic (As): Mechanistic insights and machine learning (ML) analysis.}, journal = {Bioresource technology}, volume = {}, number = {}, pages = {132563}, doi = {10.1016/j.biortech.2025.132563}, pmid = {40262704}, issn = {1873-2976}, abstract = {Alum sludge (AlS) has emerged as an effective adsorbent for anionic contaminants, with traditional activation methods like acid/base treatments and calcination employed to enhance its adsorption capacity. However, these approaches encounter significant drawbacks, including excessive waste generation, structural degradation, and limited efficacy for cationic contaminants. To overcome these challenges, this study proposes electrochemical activation as a sustainable method to enhance alum sludge adsorption performance by generating oxygen-containing functional groups (O-FGs) on its surface. In particular, cathodic activated AlS (E-AlS) leads to the formation of hydroxyl (-OH) and carboxyl (-COOH) groups, which served as key active sites for Pb(II) adsorption through complexation mechanisms. E-AlS effectively removed both Pb(II) and As within 4 h, showcasing its dual functionality for cationic and anionic contaminants. While HCl- and KOH-activated AlS also achieved 100 % Pb(II) removal, they caused substantial aluminum (Al) leaching, exceeding 1,000 mg/L, due to structural instability. In contrast, E-AlS minimized Al leaching, preserved structural integrity, and exhibited a 6.5-fold higher Pb(II) adsorption capacity than raw AlS. X-ray photoelectron spectroscopy (XPS) and machine learning (ML) validated the enhanced adsorption performance of E-AlS. These findings highlight electrochemical activation as a cost-effective and environmentally friendly remediation.}, } @article {pmid40262277, year = {2025}, author = {Turner, N and Palmer, J and Faull, C and Davidson, S and Turner, MR and Wilson, E}, title = {Tracheostomy ventilation in ALS: healthcare practitioner perspectives on quality of life and implications for decision-making.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2025.2495014}, pmid = {40262277}, issn = {2167-9223}, abstract = {Objectives: This qualitative study aimed to increase understanding of how healthcare practitioners (HCPs) perceive quality of life for people with ALS who use tracheostomy ventilation (TV) and the extent to which such views inform discussions regarding future treatment and care. Methods: A thematic analysis was applied to data derived from online semi-structured interviews with a professionally diverse group of 24 HCPs with experience of supporting people with ALS to use TV. Results: Four main themes relating to TV use emerged: i) Positive benefits; ii) Risks and challenges; iii) Factors influencing HCP perspectives; iv) Concepts informing HCP discussions. HCPs acknowledged that TV has the potential to extend life but were concerned with prolonging a serious decline in physical and cognitive functioning. HCPs tried to identify the 'tipping point' between quantity and quality of life for the individual and their family, taking into account the likelihood of a higher burden of care. HCPs drew on prior experience to assess anticipated quality of life, yet most HCPs in the UK have limited experience of TV for this group. HCPs also drew on principles of person-centered care, patient autonomy and value for money to guide their approach to discussing TV. Conclusions: HCP experience of positive outcomes of TV can foster a more proactive approach to initiating conversations about its potential use. Sharing best practice and improving guidance for HCPs may support early and on-going future care planning and enable people with ALS to make choices which are informed and in their best interests.}, } @article {pmid40261626, year = {2025}, author = {Lum, JS and Brown, ML and Suters, SC and Yerbury, JJ and McAlary, L}, title = {In-Gel Zymography of Amyotrophic Lateral Sclerosis-Associated Variants of Superoxide Dismutase-1.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2918}, number = {}, pages = {221-228}, pmid = {40261626}, issn = {1940-6029}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/enzymology/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; Humans ; *Enzyme Assays/methods ; *Electrophoresis, Polyacrylamide Gel/methods ; }, abstract = {In-gel zymography allows the separation of protein via electrophoresis and subsequent measurement of enzymatic activity of enzymes from biological mixtures. The antioxidant enzyme superoxide dismutase 1 (SOD1) is an important cytosolic oxygen radical scavenging enzyme that has been implicated in a range of pathologies, including cancer, metabolic and neurodegenerative diseases, most notably amyotrophic lateral sclerosis (ALS). Here, we describe a method to detect and compare SOD1 activity from both cell and tissue samples. This method can be utilized to compare differences between ALS-associated SOD1 genetic variants and pharmacologically treated biological samples.}, } @article {pmid40261116, year = {2025}, author = {Shneider, NA and Nesta, AV and Rifai, OM and Yasek, J and Elyaman, W and Aziz-Zaman, S and Lyu, MA and Levy, SHS and Hoover, BN and Vlad, G and Huang, M and Zeng, K and Sadeghi, T and Reddy, A and Flowers, CR and Parmar, S}, title = {Clinical Safety and Preliminary Efficacy of Regulatory T Cells for ALS.}, journal = {NEJM evidence}, volume = {4}, number = {5}, pages = {EVIDoa2400249}, doi = {10.1056/EVIDoa2400249}, pmid = {40261116}, issn = {2766-5526}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Middle Aged ; *T-Lymphocytes, Regulatory/transplantation ; Female ; Male ; Aged ; Adult ; Biomarkers/blood ; Treatment Outcome ; Neurofilament Proteins/blood ; }, abstract = {BACKGROUND: Peripheral and neuroinflammation have been previously associated with progression in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease involving progressive loss of motor neurons. We hypothesize that regulatory T cell (Treg) therapy can resolve inflammation and preserve function in those patients with ALS.

METHODS: Participants with ALS received infusions of a fixed dose (100×10[6] cells) of umbilical cord blood-derived, allogeneic, nonhuman leukocyte antigen-matched, cryopreserved Treg product (TREG), administered as four weekly infusions followed by six monthly infusions. No lymphodepletion, immunosuppression, or interleukin 2 was administered. The primary outcome was dose-limiting toxicity, including infusion reaction within 24 hours (as graded by National Cancer Institute - Common Terminology Criteria for Adverse Events, Version 4.0) and/or regimen-related death, or grade 3 or 4 cytokine release syndrome within 14 days postinfusion. We measured clinical response using the Revised ALS Functional Rating Scale (ALSFRS-R; range 0 to 48, with lower numbers indicating lower functional ability). Exploratory analyses measured serum and plasma neurofilament light (NfL) and inflammatory biomarkers.

RESULTS: Six participants with a median age of 48.5 years (range 27 to 66 years) and baseline ALSFRS-R score of 31.5 (range 23 to 43) were treated with a median of 11 (range 6 to 22) TREG infusions in an ambulatory setting. No dose-limiting toxicity was observed. In participants with sufficient data points (n=4), the mean ALSFRS-R slope of decline was -1.66±1.03 points/month before treatment, -0.41±0.45/month during treatment, and -0.60±0.59/month posttreatment. Biomarkers including NfL and inflammatory markers MIP-1δ (macrophage inflammatory protein-1 delta), CTACK (cutaneous T cell-attracting chemokine), and GROα (growth-regulated oncogene alpha) exhibited different relationships with ALSFRS-R score between participants.

CONCLUSIONS: This study demonstrates the preliminary safety of "off-the-shelf", allogeneic Treg-cell therapy.}, } @article {pmid40261114, year = {2025}, author = {Abati, E}, title = {Regulatory T Cell-Based Therapies - A New Piece of the ALS Therapeutic Puzzle?.}, journal = {NEJM evidence}, volume = {4}, number = {5}, pages = {EVIDe2500078}, doi = {10.1056/EVIDe2500078}, pmid = {40261114}, issn = {2766-5526}, } @article {pmid40260525, year = {2025}, author = {Ganapule, A and Garg, D and Agarwal, A and Gupta, A and Rajan, R and Desai, S and Chandarana, M and Sidharth, S and Tripathi, M and Garg, A and Radhakrishnan, DM and Srivastava, AK}, title = {The Expanding Spectrum of Anti-IgLON5 Disease: A Case Series from an Indian Cohort.}, journal = {Annals of Indian Academy of Neurology}, volume = {}, number = {}, pages = {}, doi = {10.4103/aian.aian_1073_24}, pmid = {40260525}, issn = {0972-2327}, abstract = {Anti-IgLON5 disease is an evolving entity that lies at the confluence of autoimmunity and neurodegeneration. Reports from India remain sparse. In this series, we describe seven Indian patients with anti-IgLON5-related disease. Patients presented across the fifth to eighth decades with a mean duration of illness of 16 months. All had movement disorders, which included gait ataxia, parkinsonism, and chorea. Six patients had sleep disturbances. Five had a frontal dysexecutive dementia phenotype. Two had epilepsy. Bulbar involvement was present in four, and one had amyotrophic lateral sclerosis (ALS)-like features. Magnetic resonance imaging was abnormal in two cases. Positron emission tomography of the brain also contributed to diagnosis. Combination immunotherapies were used in most of the patients, with three showing a sustained response and two deaths reported due to sepsis-related complications. It is important to recognize the increasing spectrum of IgLON5-related disease to enable timely initiation of immunotherapy before marked degeneration occurs.}, } @article {pmid40260387, year = {2025}, author = {Guo, N and Huang, W and Huang, J and Liu, Y and Zhu, K and Gao, W}, title = {Global research trends in biomarkers, therapeutic targets, and drugs for amyotrophic lateral sclerosis: a bibliometric and visualization analysis.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1588968}, pmid = {40260387}, issn = {1663-9812}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons, marked by complex pathological mechanisms and a lack of effective treatments. Despite substantial global research efforts, no comprehensive bibliometric analysis has systematically mapped the evolution of ALS biomarkers, therapeutic targets, and pharmacological advancements.

METHODS: This study, based on 4,250 publications retrieved from the Web of Science Core Collection (2005-2025), employs bibliometric tools such as CiteSpace and VOSviewer to conduct the first multidimensional analysis of global trends in ALS biomarkers, therapeutic targets, and drug research.

RESULTS: The results revealed contributions from 20,168 authors across 92 countries, with annual publications growing at an average rate of 16.5%. The United States dominated research output, accounting for 34.07% (n=1,448, TLCS=7,100), while the United Kingdom achieved the highest research impact with an average of 68 citations per article. Leading institutions, including the University of Oxford and the University of Milan, consistently produced high-impact studies. Pioneering scholars such as Turner MR and Kiernan MC made significant contributions to advancing therapeutic targets and drug discovery. The interdisciplinary integration of molecular biology and genetics emerged as a core driver of progress in ALS research. Neurofilament light chain (NfL), antisense oligonucleotide (ASO) drugs, transcranial magnetic stimulation (TMS), oxygen free radicals (oxidative stress), and gene therapy have consistently remained central research focuses in the ALS therapeutic field. Looking ahead, stem cell therapy, blood-brain barrier (BBB) penetration technologies, and skeletal muscle targeting are poised to emerge as prominent research directions.

CONCLUSION: The United States dominates ALS research productivity, whereas the United Kingdom demonstrates superior citation influence. Despite China's substantial publication volume, its limited citation impact underscores the necessity for enhanced methodological rigor and strategic international collaboration. Current research priorities encompass NfL, TMS, and ASO therapies, with emerging innovations in stem cell therapy, BBB penetration technologies and skeletal muscle targeting showing therapeutic promise. Future directions should prioritize biomarker standardization, optimization of drug delivery systems, and Clinical Translation.}, } @article {pmid40259632, year = {2025}, author = {García-Casanova, PH and Pérez-Martínez, P and Sevilla, T and Doménech, R and León, M and Vázquez-Costa, JF}, title = {In Response to "Homogeneous ALS Cohorts in Terms of Etiology, Onset Type and Vaccination Status Are Required to Assess the Outcome of Their COVID Infection".}, journal = {European journal of neurology}, volume = {32}, number = {4}, pages = {e70162}, doi = {10.1111/ene.70162}, pmid = {40259632}, issn = {1468-1331}, } @article {pmid40259624, year = {2025}, author = {Finsterer, J}, title = {Homogeneous ALS Cohorts in Terms of Etiology, onset type, and Vaccination Status Are Required to Assess the Outcome of Their COVID Infection.}, journal = {European journal of neurology}, volume = {32}, number = {4}, pages = {e70161}, doi = {10.1111/ene.70161}, pmid = {40259624}, issn = {1468-1331}, } @article {pmid40258293, year = {2025}, author = {Elsayyid, M and Tanis, JE and Yu, Y}, title = {Simple In-Cell Processing Enables Deep Proteome Analysis of Low-Input Caenorhabditis elegans.}, journal = {Analytical chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.analchem.4c05003}, pmid = {40258293}, issn = {1520-6882}, abstract = {Caenorhabditis elegans is a widely used genetic model organism; however, the worm cuticle complicates extraction of intracellular proteins, a prerequisite for typical bottom-up proteomics. Conventional physical disruption procedures are not only time-consuming but can also cause significant sample loss, making it difficult to perform proteomics with low-input samples. Here, for the first time, we present an on-filter in-cell (OFIC) processing approach that can digest C. elegans proteins directly in the cells of the organism after methanol fixation. With OFIC processing and single-shot LC-MS analysis, we identified over 9400 proteins from a sample of only 200 worms, the largest C. elegans proteome reported to date that did not require fractionation or enrichment. We systematically evaluated the performance of the OFIC approach by comparing it to conventional lysis-based methods. Our data suggest superior performance of OFIC processing for C. elegans proteome identification and quantitation. We further evaluated the OFIC approach with even lower-input samples, including single worms. Then, we used this method to determine how the proteome is impacted by loss of superoxide dismutase sod-1, the ortholog of human SOD1, a gene associated with amyotrophic lateral sclerosis. Analysis of 8800 proteins from only 50 worms as the initial input showed that loss of sod-1 affects the abundance of proteins required for stress response, ribosome biogenesis, and metabolism. In conclusion, our streamlined OFIC approach, which can be broadly applied to other systems, minimizes sample loss while offering the simplest workflow reported to date for C. elegans proteomics.}, } @article {pmid40256588, year = {2024}, author = {Ahmady, H and Afrand, M and Motaqi, M and Meftahi, GH}, title = {Utilizing Sertoli Cell Transplantation as a Therapeutic Technique for the Management of Neurodegenerative Diseases.}, journal = {Archives of Razi Institute}, volume = {79}, number = {4}, pages = {701-710}, pmid = {40256588}, issn = {2008-9872}, mesh = {*Neurodegenerative Diseases/therapy ; Humans ; Male ; Animals ; *Sertoli Cells/transplantation ; }, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are defined by aberrant protein accumulation, brain atrophy, and gradual decline of neuronal function. Despite the considerable endeavors devoted to discovering treatments for NDs in recent decades, the demand for efficient therapeutic agents persists. Sertoli cells (SCs) play a crucial role in providing a supportive structure and environment for the development of germ cells. SCs, whether transplanted as xenogeneic or allogeneic cells, present a viable choice for enhancing graft persistence via the release of immunomodulatory and trophic factors, including neurturin (NTN), platelet-derived growth factor, Fas (CD95) ligand (FasL), glial-derived neurotrophic factor, interleukin 1 (IL1), brain-derived neurotrophic factor, interleukin 6 (IL6), transforming growth factors, and vascular growth factor, that protect replaced cells and tissues from the immune system. However, there is currently no cohesive evidence regarding the neuroprotective influence of the transplantation of SCs on NDs. Therefore, this review focuses on assessing stem cells' neuroprotective impact on neurodegenerative diseases in pre-clinical settings and presenting cohesive information. A comprehensive search was conducted between 2000 and 2022. In the identification stage, after a comprehensive search across databases, including Web of Science, Scopus, and PubMed/Medline, 103 papers were obtained. The search conducted in the present study yielded a total of nine relevant papers on the therapeutic effect of the transplantation of SCs on NDs. It was found that the transplantation of SCs exhibits a promising impact on enhancing the symptoms of neurological diseases in rats. The findings highlight the need for multiple standardized pre-clinical trials to find reliable information to confirm the utilization of the transplantation of SCs and the reduction of the symptoms of neurodegenerative diseases.}, } @article {pmid40255098, year = {2025}, author = {Regnault, R and Kouach, M and Goossens, L and Thuru, X and Bailly, C and Goossens, JF}, title = {HR-MS Analysis of the Covalent Binding of Edaravone to 5-Formylpyrimidine Bases and a DNA Oligonucleotide Containing a 5-Formylcytidine Residue.}, journal = {Rapid communications in mass spectrometry : RCM}, volume = {39}, number = {14}, pages = {e10050}, doi = {10.1002/rcm.10050}, pmid = {40255098}, issn = {1097-0231}, support = {//Comité de l'Oise de la Ligue Contre le Cancer/ ; //French Ligue Against Cancer/ ; }, mesh = {Edaravone/chemistry ; *Mass Spectrometry/methods ; *Oligonucleotides/chemistry/metabolism ; *Pyrimidines/chemistry ; *DNA/chemistry ; *Cytidine/chemistry/analogs & derivatives ; Cytosine/analogs & derivatives ; }, abstract = {RATIONALE: Edaravone (EDA) is a radical scavenger and an antioxidant drug approved to treat amyotrophic lateral sclerosis and used as a research tool to explore treatment of neurodegenerative diseases and cancers. It is also a reactive agent, known as PMP (1-phenyl-3-methyl-5-pyrazolone), used for the analysis of polysaccharides composition. EDA can react with sugars and aromatic aldehydes. In this context, we have investigated the reactivity of EDA toward the biologically relevant formylated nucleobases, nucleosides, and an oligonucleotide containing a formylated residue.

METHODS: The formation of both mono- and bis-adducts between EDA and the formylated nucleobases (5-formyluracil (5fU) and 5-formylcytosine (5fC)) or the corresponding nucleosides 5-fdU and 5-fdC was characterized using high-resolution mass spectrometry (HR-MS). Similarly, the covalent binding of EDA to an 8-mer palindromic oligonucleotide d (TATG[*C]ATA) containing a single 5-fdC residue [*C] under physiological conditions was investigated using mass spectrometry.

RESULTS: For the first time, EDA is shown to react with formylated pyrimidines. Covalent and stable adducts were identified. EDA was found to react efficiently with the formylated oligonucleotide to generate mono- and bis-adducts. The rate of formation of the mono-adduct was five times higher than that of the bis-adduct. The reaction of EDA with aldehydic DNA modifications such as 5fU/5fC may have important consequences in terms of gene expression.

CONCLUSIONS: These observations raise implications for an epigenetic contribution to the mechanism of action of EDA. The biological implications of our in vitro results are discussed, notably in the frame of neurodegenerative diseases and cancers.}, } @article {pmid40254405, year = {2025}, author = {Shevchuk, DV and Tukhvatulin, AI and Dzharullaeva, AS and Berdalina, IA and Zakharova, MN}, title = {Molecular Biomarkers of Neurodegeneration in Amyotrophic Lateral Sclerosis.}, journal = {Biochemistry. Biokhimiia}, volume = {90}, number = {2}, pages = {276-288}, doi = {10.1134/S0006297924604039}, pmid = {40254405}, issn = {1608-3040}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnosis/pathology/blood ; Biomarkers/metabolism/blood ; Male ; Female ; Middle Aged ; Aged ; Amyloid beta-Peptides/metabolism/blood ; Adult ; tau Proteins/metabolism/blood ; Clusterin ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disease. However, definitive diagnosis could be delayed by up to 12 months due to the lack of specific and sensitive biomarkers for ALS. In our study, conducted for the first time on a large cohort of ALS patients (n = 100) within the Russian population, we assessed key biomarkers of neurodegenerative pathology, including β-amyloids (Aβ40 and Aβ42) and tau proteins (Tau-total and Tau-p181), as well as other pathogenetically relevant, promising biomarkers such as FGF-21, Kallikrein-6 (KLK-6), NCAM-1, Neurogranin (NRGN), TDP-43, Apolipoprotein E4, Clusterin (Apo J), Complement Factor H, Fetuin-A, α2-Macroglobulin, Apo AI, Apo CIII, Apo E, Complement C3, GDNF, sRAGE, and S100B protein. Significant differences between the ALS patients and the control group were observed for Aβ40 (p = 0.044), Aβ42 (p < 0.001), FGF-21 (p < 0.001), Tau-total (p = 0.001), Tau-p181 (p = 0.014), Clusterin (p < 0.001), Complement C3 (p = 0.001), and S100B (p = 0.024). A significant direct correlation was found between the ALSFRS-R score and concentrations of Aβ40 and Aβ42. Changes in the complement system (Complement C3 and Complement Factor H) were identified, highlighting critical role of neuroinflammatory processes in ALS pathogenesis. Additionally, increased levels of FGF-21 were observed in the patients with the bulbar onset of ALS. Significant increase in the concentration of the chaperone protein clusterin in the patients with rapid disease progression suggests its potential as a prognostic biomarker for motor neuron disease. Furthermore, its role in maintaining proteostasis could provide novel therapeutic targets.}, } @article {pmid40254295, year = {2025}, author = {Epel, ES and White, KE and Brownell, KD and Rodin, J and Hollis, AL and Diefenbach, MA and Alegria, KE and Fromer, E and Czajkowski, SM and Bacon, SL and Revenson, TA and Ruiz, J and Maibach, E and , }, title = {Transforming Health Psychology and Behavioral Medicine to Address the Climate Crisis: A Call for Strategic Research and Advocacy.}, journal = {Annals of behavioral medicine : a publication of the Society of Behavioral Medicine}, volume = {59}, number = {1}, pages = {}, doi = {10.1093/abm/kaae088}, pmid = {40254295}, issn = {1532-4796}, mesh = {Humans ; *Climate Change ; *Behavioral Medicine ; *Health Behavior ; Social Change ; }, abstract = {OBJECTIVE: The climate crisis poses the largest threat to human health and survival and has been a public health emergency for many years. It is causing harmful consequences for physical and mental health and is amplifying existing health inequities. In this call to action, we highlight the relevance of the health psychology and behavioral medicine communities in addressing the health impacts of climate change.

METHOD: We identify mitigation and adaptation climate health behaviors and social changes needed that underlie the three essential objectives to address climate change and its associated health consequences: (a) rapid decarbonization, (b) drawdown of atmospheric heat-trapping gases (sequestration), and (c) adap- tation.

RESULTS: To advance the behavioral and systemic changes necessary to protect health, we propose a 1-2-3 Transformational Model in which the larger field of health psychology and behavioral medicine promotes (1) One Health, human and planetary health by (2) targeting climate health behaviors, and (3) social change across major professional areas, including research, interventions, and education/advo- cacy. We urge the adoption of the social quantum change paradigm, a systems approach to understanding the process of social change, where systemic change is viewed as local to global, and the individual has an influential role.

DISCUSSION: These shifts in views, priorities, and methods will bolster hope, collective efficacy, and action to support the next generation of health psychology and behavioral medicine profession- als. With these changes, the health psychology and behavioral medicine communities can have a more immediate and meaningful impact on the climate crisis and its associated health consequences.}, } @article {pmid40254133, year = {2025}, author = {Turner-Ivey, B and Jenkins, DP and Carroll, SL}, title = {Multiple Roles for Neuregulins and their ERBB Receptors in Neurodegenerative Disease Pathogenesis and Therapy.}, journal = {The American journal of pathology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajpath.2025.03.012}, pmid = {40254133}, issn = {1525-2191}, abstract = {The role that neurotrophins such as nerve growth factor play in the pathogenesis of neurodegenerative diseases has long been appreciated. However, the neuregulin (NRG) family of growth factors and/or their ERBB receptors have also been implicated in the pathogenesis of conditions such as Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). In this review, we consider (1) the structural variability of NRG isoforms generated by alternative RNA splicing, the use of multiple promoters and proteolysis and the impact that this structural variability has on neuronal and glial physiology during development and adulthood. We discuss (2) the NRG receptors ERBB2, ERBB3 and ERBB4, how activation of each of these receptors further diversifies NRG actions in the central nervous system and how dementia-related proteins such as γ-secretase modulate the action of NRGs and their ERBB receptors. We then (3) turn to the abnormalities in NRG and ERBB expression and function evident in human AD and mouse AD models, how these abnormalities affect brain function, and attempts to use NRGs to treat AD. Finally, (4) we discuss NRG effects on the survival and function of neurons relevant to FTLD and ALS, alterations in NRG/ERBB signaling identified in these conditions and the recent discovery of multiple human pedigrees in which autosomal dominant FTLD/ALS potentially results from point mutations in ERBB4.}, } @article {pmid40253599, year = {2025}, author = {Malik, M and Bhatti, T and Hodson-Tole, E and Onambele-Pearson, G and Chaouch, A}, title = {Physical activity in amyotrophic lateral sclerosis: a systematic review of the methodologies used to assess a possible association.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-18}, doi = {10.1080/21678421.2025.2488298}, pmid = {40253599}, issn = {2167-9223}, abstract = {Growing evidence suggests that strenuous physical activity (PA) may be associated with an increased risk of developing Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease. However, there are inconsistent findings across studies that may reduce our understanding of any potential associations. We propose that these differences may reflect the tools used to record historical PA. We conducted a systematic review evaluating the risk of developing ALS due to PA. The inclusion criteria were met by 22/113 studies, and an association between increasing PA and ALS was found in 15 studies. Studies that found a positive association were more likely to have longer recall periods and convert data into Metabolic Equivalent of Task values. Studies that did not find an association with increasing PA were more likely to use questionnaires with no validity or reliability data. Questionnaires with validity data all showed at least a moderate correlation of PA compared to objective measures, with reliability ranging from poor to good. Study designs included prospective cohort and case-control, which may also contribute to heterogeneity in findings. This work highlights the need for consensus on the type of questionnaire to use to assess potential associations between PA and ALS.}, } @article {pmid40252901, year = {2025}, author = {Baidya, AT and Dante, D and Das, B and Wang, L and Darreh-Shori, T and Kumar, R}, title = {Discovery and characterization of novel pyridone and furan substituted ligands of choline acetyltransferase.}, journal = {European journal of pharmacology}, volume = {}, number = {}, pages = {177638}, doi = {10.1016/j.ejphar.2025.177638}, pmid = {40252901}, issn = {1879-0712}, abstract = {The key to the management of two devastating diseases, namely Alzheimer's Disease (AD) and Amyotrophic Lateral Sclerosis (ALS) lies in an early diagnosis, which is difficult due to its multifactorial nature. However, a common hallmark of AD and ALS is degeneration of cholinergic system. Choline acetyltransferase (ChAT) has been proposed as a potential target for development of cholinergic-specific biomarker. However, lack of selective, potent, brain permeable molecular probes of ChAT hinder development of ChAT biomarkers. In this study, we have successfully utilised structure-based virtual screening approach and identified two ChAT inhibitors from a database of 1.4 million compounds. The compounds were then subjected to rigorous in vitro characterization. Compound V6 showed Ki value of 11 μM and IC50 value of 21.73 μM, while V15 showed Ki and IC50 values of 4.5 and 9.42 μM, respectively for ChAT enzyme. V6 and V15 showed good solubility of 0.21 mg/ml and 0.17 mg/ml respectively and cytotoxicity analysis indicated no toxicity. We also performed a 200 ns molecular dynamics simulation, which revealed the intricate interaction dynamics for V6 and V15 with ChAT binding pocket. Moreover, the Tanimoto similarity analysis indicated the novelty and structural diversity of the hits. In conclusion, these validated hits provide a platform to develop potent, selective, blood-brain barrier permeable small molecules as chemical probes of ChAT or as Positron Emission Tomography tracer for early diagnosis and/or in vivo monitoring of the effect of new therapeutic candidates in spectrum of neurodegenerative disorders, in which cholinergic deficit is one of the hallmarks.}, } @article {pmid40252666, year = {2025}, author = {Balendra, R and Sreedharan, J and Hallegger, M and Luisier, R and Lashuel, HA and Gregory, JM and Patani, R}, title = {Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy.}, journal = {The Lancet. Neurology}, volume = {24}, number = {5}, pages = {456-470}, doi = {10.1016/S1474-4422(25)00109-7}, pmid = {40252666}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *TDP-43 Proteinopathies/genetics/pathology ; *Mutation/genetics ; }, abstract = {Mutations in the TARDBP gene, which encodes the TDP-43 protein, account for only 3-5% of familial cases of amyotrophic lateral sclerosis and less than 1% of cases that are apparently idiopathic. However, the discovery of neuronal inclusions of TDP-43 as the neuropathological hallmark in the majority of cases of amyotrophic lateral sclerosis has transformed our understanding of the pathomechanisms underlying neurodegeneration. An individual TARDBP mutation can cause phenotypic heterogeneity. Most mutations lie within the C-terminus of the TDP-43 protein. In pathological conditions, TDP-43 is mislocalised from the nucleus to the cytoplasm, where it can be phosphorylated, cleaved, and form insoluble aggregates. This mislocalisation leads to dysfunction of downstream pathways of RNA metabolism, proteostasis, mitochondrial function, oxidative stress, axonal transport, and local translation. Biomarkers for TDP-43 dysfunction and targeted therapies are being developed, justifying cautious optimism for personalised medicine approaches that could rescue the downstream effects of TDP-43 pathology.}, } @article {pmid40252655, year = {2025}, author = {Dame, PS}, title = {The four most common genetic subtypes of amyotrophic lateral sclerosis: state of the art and future directions.}, journal = {The Lancet. Neurology}, volume = {24}, number = {5}, pages = {380-381}, doi = {10.1016/S1474-4422(25)00117-6}, pmid = {40252655}, issn = {1474-4465}, } @article {pmid40251832, year = {2025}, author = {Bresque, M and Esteve, D and Balmer, G and Hamilton, HL and Stephany, JS and Pehar, M and Vargas, MR}, title = {FABP7 Expression Modulates the Response of Astrocytes to Induced Endotoxemia.}, journal = {Glia}, volume = {}, number = {}, pages = {}, doi = {10.1002/glia.70023}, pmid = {40251832}, issn = {1098-1136}, support = {R01NS122973/NH/NIH HHS/United States ; R01NS132760/NH/NIH HHS/United States ; }, abstract = {Fatty acid binding proteins (FABPs) are a family of small proteins involved in fatty acid (FA) subcellular trafficking. In the adult central nervous system, FABP7, one of the members of this family, is highly expressed in astrocytes and participates in lipid metabolism, regulation of gene expression, and energy homeostasis. Reactive astrocytes in Alzheimer's disease and amyotrophic lateral sclerosis animal models upregulate FABP7 expression. This upregulation may contribute to the pro-inflammatory phenotype that astrocytes display during neurodegeneration and is detrimental for co-cultured neurons. Here, we explore how FABP7 expression modulates astrocyte response to inflammatory stimuli. Our results showed that silencing FABP7 expression in astrocyte cultures before treatment with different inflammatory stimuli decreases the expression of a luciferase reporter expressed under the control of NF-κB -response elements. Correspondingly, FABP7-silenced astrocytes display decreased nuclear translocation of the NF-κB-p65 subunit in response to these stimuli. Moreover, silencing FABP7 decreases the toxicity of stimulated astrocytes toward co-cultured motor neurons. Similar results were obtained after silencing FABP7 in human astrocytes differentiated from induced pluripotent stem cells. Finally, knockdown of astrocytic FABP7 expression in vivo reduces glial activation in the cerebral cortex of mice after systemic bacterial lipopolysaccharide (LPS) administration. In addition, whole transcriptome RNA sequencing analysis from the cerebral cortex of LPS-treated mice showed a differential inflammatory transcriptional profile, with attenuation of NF-κB-dependent transcriptional response after FABP7 knockdown. Together, our results highlight the potential of FABP7 as a target to modulate neuroinflammation in the central nervous system.}, } @article {pmid40251218, year = {2025}, author = {Abid, MN and Siming, L and Chao, H and Amin, M and Sarwer, S}, title = {Enhancing faculty teaching performance through constructive leadership with a mediating role of job satisfaction.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {13454}, pmid = {40251218}, issn = {2045-2322}, mesh = {*Job Satisfaction ; *Leadership ; Humans ; Male ; Female ; Cross-Sectional Studies ; *Teaching ; Adult ; *Faculty/psychology ; Universities ; Pakistan ; Middle Aged ; Surveys and Questionnaires ; }, abstract = {This study explored the impact of constructive leadership styles including transformational leadership (TLS), authentic leadership (ALS), and servant leadership (SLS) on faculty teaching performance (FTP), with job satisfaction (JS) acting as a critical mediator. Using a cross-sectional design and convenience sampling, data were collected from 346 faculty members across six universities in Lahore, Pakistan. Structural equation modeling (SEM) and regression analysis revealed that all three leadership styles significantly enhanced FTP, with transformational leadership showing the strongest influence. Authentic and servant leadership also demonstrated robust positive effects. Job satisfaction emerged as a pivotal mediator, strengthening the relationship between CLS and FTP.These findings highlight the transformative potential of constructive leadership in improving teaching performance and emphasize the critical role of department heads in fostering such practices. By prioritizing strategies to enhance employee motivation and satisfaction, institutions can improve retention, productivity, and overall academic excellence. This study reinforces existing literature on leadership and teaching performance while providing novel insights into the mediating role of job satisfaction, offering actionable implications for academic leadership and organizational development.}, } @article {pmid40250284, year = {2025}, author = {Calma, AD and Pavey, N and Silva, CS and van den Bos, MAJ and Yiannikas, C and Farrar, MA and Kiernan, MC and Menon, P and Vucic, S}, title = {Diagnostic utility of threshold tracking TMS paradigms in early amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {174}, number = {}, pages = {105-113}, doi = {10.1016/j.clinph.2025.03.044}, pmid = {40250284}, issn = {1872-8952}, abstract = {OBJECTIVE: Threshold tracking transcranial magnetic stimulation (TMS) has exhibited utility as a diagnostic technique in Amyotrophic Lateral Sclerosis (ALS). Different threshold tracking paradigms have recently been proposed. The present study assessed the diagnostic utility of serial ascending and parallel threshold tracking TMS in ALS.

METHODS: Threshold tracking TMS was undertaken on 90 prospectively recruited participants suspected of ALS. Short interval intracortical inhibition (SICI) was recorded with serial ascending and parallel threshold tracking paradigms between Interstimulus Interval (ISI) 1-to-7 ms. The primary outcome measure was differences in diagnostic utility of the paradigms in differentiating ALS from ALS mimicking disorders using receiver operating characteristic (ROC) analysis (DeLong statistical method).

RESULTS: Reduction in SICI reliably differentiated ALS from mimic disorders, irrespective of the threshold tracking paradigm. Comparison of area under the curve (AUC) established a significantly higher value for mean SICI (1-7 ms) with the serial ascending SICI paradigm (0.81, 95 % confidence interval 0.72-0.91) compared to the parallel paradigm (SICI 0.72, 95 % confidence interval 0.61-0.83, p = 0.0065). The better diagnostic utility of serial ascending paradigm was evident for SICI recorded between 1-to-5 ms, and was maintained irrespective of disease onset site, degree of functional impairment, and the degree of lower motor neuron dysfunction. A comparable diagnostic utility across threshold tracking paradigms was evident in ALS participants who presented with a relative paucity of upper motor neuron signs.

CONCLUSION: While threshold tracking TMS reliably differentiated ALS from mimic disorders, the present study established better diagnostic utility with the serial ascending threshold tracking TMS paradigm.

SIGNIFICANCE: The serial ascending threshold tracking TMS should be used in a clinical setting as a diagnostic tool for ALS.}, } @article {pmid40250093, year = {2025}, author = {Casiraghi, V and Pellegrini, E and Brusati, A and Peverelli, S and Invernizzi, S and Santangelo, S and Colombrita, C and Verde, F and Ticozzi, N and Silani, V and Ratti, A}, title = {Characterization of human healthy i[3] lower motor neurons exposed to CSF from ALS patients stratified by UNC13A and C9ORF72 genotype.}, journal = {Journal of the neurological sciences}, volume = {473}, number = {}, pages = {123508}, doi = {10.1016/j.jns.2025.123508}, pmid = {40250093}, issn = {1878-5883}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons. Neurodegeneration in ALS might be driven by proteotoxicity or neuroinflammation, which have also been proposed to be promoted by toxic components of the cerebrospinal fluid (CSF). We investigated the possible toxicity of ALS CSF on healthy induced pluripotent stem cells (iPSC)-derived integrated, inducible, and isogenic lower motor neurons (i[3]LMNs). CSFs were obtained from ALS patients homozygous for the risk UNC13A rs12608932 single nucleotide polymorphism (CC) and for the corresponding major allele (AA), ALS patients with C9ORF72 hexanucleotide repeat expansion, and individuals affected by normal pressure hydrocephalus as non-disease controls (ND). A chronic and low-dose sodium arsenite (ARS) treatment was used as positive control of oxidative stress. We found that 10 % ALS CSF treatment for 48 h was not sufficient to induce significant alterations in viability, autophagic flux, axonal degeneration, DNA damage, and Golgi apparatus integrity in healthy i[3]LMNs, in contrast to ARS treatment. Only UNC13A CC CSF significantly increased protein aggregation and Golgi apparatus fragments dimension. RNA-sequencing revealed that all ALS and ND CSFs induced expression changes of few genes, while chronic ARS deregulated the expression of thousands of genes, mostly involved in inflammation and synapse biology. In this work, we demonstrated that in our experimental settings only CSF from UNC13A CC patients induced some ALS-associated pathological features in healthy i[3]LMNs. Further studies will be required to elucidate the mechanistic link between the risk UNC13A genotype and CSF composition and toxicity.}, } @article {pmid40249897, year = {2025}, author = {Siegler, JE and Galetta, SL}, title = {Editors' Note: Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis: A Prospective Cohort Study.}, journal = {Neurology}, volume = {104}, number = {9}, pages = {e213609}, doi = {10.1212/WNL.0000000000213609}, pmid = {40249897}, issn = {1526-632X}, } @article {pmid40249896, year = {2025}, author = {Kawada, T}, title = {Reader Response: Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis: A Prospective Cohort Study.}, journal = {Neurology}, volume = {104}, number = {9}, pages = {e209943}, doi = {10.1212/WNL.0000000000209943}, pmid = {40249896}, issn = {1526-632X}, } @article {pmid40249895, year = {2025}, author = {Vaage, AM and Nakken, O}, title = {Author Response: Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis: A Prospective Cohort Study.}, journal = {Neurology}, volume = {104}, number = {9}, pages = {e209962}, doi = {10.1212/WNL.0000000000209962}, pmid = {40249895}, issn = {1526-632X}, } @article {pmid40248372, year = {2025}, author = {Dai, ZS and Zhang, M and Deng, YY and Zhou, N and Tian, Y}, title = {Efficacy of a novel artificial liver versatile plasma purification system in patients with acute-on-chronic liver failure.}, journal = {World journal of gastroenterology}, volume = {31}, number = {14}, pages = {103892}, pmid = {40248372}, issn = {2219-2840}, mesh = {Humans ; *Acute-On-Chronic Liver Failure/mortality/therapy/blood ; Female ; Male ; Middle Aged ; Prospective Studies ; *Liver, Artificial ; Treatment Outcome ; Aged ; Patient Readmission/statistics & numerical data ; Adult ; Length of Stay/statistics & numerical data ; Kaplan-Meier Estimate ; Follow-Up Studies ; Peritonitis/epidemiology/etiology ; China/epidemiology ; }, abstract = {BACKGROUND: We have innovatively amalgamated membrane blood purification and centrifugal blood cell separation technologies to address the limitations of current artificial liver support (ALS) models, and develop a versatile plasma purification system (VPPS) through centrifugal plasma separation.

AIM: To investigate the influence of VPPS on long-term rehospitalization and mortality rates among patients with acute-on-chronic liver failure (ACLF).

METHODS: This real-world, prospective study recruited inpatients diagnosed with ACLF from the Second Xiangya Hospital of Central South University between October 2021 and March 2024. Patients were categorized into the VPPS and non-VPPS groups based on the distinct ALS models administered to them. Self-administered questionnaires, clinical records, and self-reported data served as the primary methods for data collection. The laboratory results were evaluated at six distinct time points. All patients were subjected to follow-up assessments for > 12 months. Kaplan-Meier survival analyses and Cox proportional hazards models were used to evaluate the risks of hospitalization and mortality during the follow-up period.

RESULTS: A cohort of 502 patients diagnosed with ACLF was recruited, with 260 assigned to the VPPS group. On comparing baseline characteristics, the VPPS group exhibited a significantly shorter length of stay, higher incidence of spontaneous peritonitis and pulmonary aspergillosis compared to the non-VPPS group (P < 0.05). Age [hazard ratio (HR) = 1.142, 95%CI: 1.01-1.23, P = 0.018), peritonitis (HR = 2.825, 95%CI: 1.07-6.382, P = 0.026), albumin (HR = 0.67, 95%CI: 0.46-0.942, P = 0.023), total bilirubin (HR = 1.26, 95%CI: 1.01-3.25, P = 0.021), international normalized ratio (HR = 1.97, 95%CI: 1.21-2.908, P = 0.014), and VPPS/non-VPPS (HR = 3.24, 95%CI: 2.152-4.76, P < 0.001) were identified as significant independent predictors of mortality in both univariate and multivariate analyses throughout the follow-up period. Kaplan-Meier survival analyses demonstrated significantly higher rehospitalization and mortality rates in the non-VPPS group compared to the VPPS group during follow-up of ≥ 2 years (log-rank test, P < 0.001).

CONCLUSION: These findings suggest that VPPS is safe and has a positive influence on prognostic outcomes in patients with ACLF.}, } @article {pmid40247237, year = {2025}, author = {Pehlivanidis, A and Kouklari, EC and Kalantzi, E and Korobili, K and Tagkouli, E and Papanikolaou, K}, title = {Self-reported symptoms of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and affective lability in discriminating adult ADHD, ASD and their co-occurrence.}, journal = {BMC psychiatry}, volume = {25}, number = {1}, pages = {391}, pmid = {40247237}, issn = {1471-244X}, abstract = {BACKGROUND: To diagnose and manage adults with Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), or their co-occurrence (ADHD + ASD), clinicians must identify specific features that differentiate these diagnostic categories. Self-report questionnaires targeting specific features are widely used and, together with clinical assessments, provide reliable diagnoses. Although affective lability is present in various psychiatric disorders, it lacks specificity when screening for ADHD in the general population, and its discriminant value for ADHD, ASD, and ADHD + ASD has not been studied.

METHODS: This study involved 300 adults without intellectual developmental disorder (188 male) who received an ADHD (n = 174), ASD (n = 68), or ADHD + ASD (n = 58) diagnosis after a multidisciplinary consensus decision according to DSM-5 criteria. Before clinical assessment, all patients requesting evaluation for one of these diagnoses completed questionnaires on an online platform. The assessment instruments included a modified version of the Barkley Adult ADHD Rating Scale (BAARS IV) for ADHD, the Autism Spectrum Quotient (AQ) and the Empathy Quotient (EQ) for ASD features, and the Affective Lability Scale (ALS) for affective lability. Total scores and sub-scores of the instruments were compared among the three groups. Additionally, stepwise logistic regression analyses were conducted to identify specific measures that contribute to group discrimination.

RESULTS: Results revealed distinct patterns in symptomatology as expected. The ADHD and the ADHD + ASD groups presented significantly higher ALS total score compared to ASD. Stepwise logistic regression analyses identified specific measures contributing to group differentiation. ASD vs. ADHD + ASD discrimination included BAARS IV current total score and EQ total score. The subscale anger from ALS in addition with BAARS IV past total score and AQ total score were the factors that discriminated ADHD diagnosis from the co-occurrence of ADHD and ASD. Finally, BAARS IV past total score, BAARS IV current inattention, AQ total score, and EQ total score were found to differentiate ADHD from ASD.

CONCLUSIONS: The study highlights the significance of incorporating emotional dimensions in diagnostic frameworks and may contribute valuable insights for clinicians differentiating neurodevelopmental conditions.}, } @article {pmid40247229, year = {2025}, author = {Samudi Raju, C and Kono, M and Looi, KW and Ong, JX and Tan, CA and Ang, CS and Tan, PHY and Shamnugam, H and Sekaran, SDKC and Syed Omar, SF and Lum, LCS}, title = {Low atypical lymphocyte score as a predictor of non-severe dengue.}, journal = {BMC infectious diseases}, volume = {25}, number = {1}, pages = {551}, pmid = {40247229}, issn = {1471-2334}, abstract = {BACKGROUND: Severe dengue has been linked to the presence of atypical lymphocytes, which can be quantified using the Q-flag parameter on a hematology analyzer. A higher atypical lymphocyte count has previously been associated with severe dengue. We aimed to evaluate the feasibility of the atypical lymphocyte score to provide an early prognosis for dengue severity.

METHOD: A prospective observational study enrolled adult patients admitted to the Infectious Disease ward with a febrile illness of less than 7 days. Blood samples obtained daily until discharge, were processed with XN-20 hematology analyzer with specific attention given to atypical lymphocyte score. Severe dengue cases were classified according to the 2009 World Health Organization Classification.

RESULTS: A total of 287 cases of laboratory-confirmed dengue, including 25 severe cases, were included. Dengue fever compared to non-dengue patients manifested increased lymphocytes within the high fluorescent zone on Day 6, The atypical lymphocyte score (ALS) of severe dengue showed an early rise, reaching a saturation point of 300 and remaining stable within the timeframe of days 4 to 8 post-fever onset. All but one severe dengue patient had a score exceeding 100 on day 4 post fever onset.

CONCLUSION: An atypical lymphocyte score below 100 on day 4 post fever onset, may serve as a predictive indicator that severe dengue is less likely to develop, potentially allowing for a lower level of medical intervention. These findings may contribute to more efficient resource allocation during outbreaks.

TRIAL REGISTRATION: The study was registered under National Medical Research Registration of Malaysia, (NMRR-18-3347-45473, 1 Sept 2019).}, } @article {pmid40245393, year = {2025}, author = {Musson, LS and Mitic, N and Leigh-Valero, V and Onambele-Pearson, G and Knox, L and Steyn, FJ and Holdom, CJ and Dick, TJ and van Eijk, RP and van Unnik, JW and Botman, LC and Beswick, E and Murray, D and Griffiths, A and McDermott, C and Hobson, E and Chaouch, A and Hodson-Tole, E}, title = {The Use of Digital Devices to Monitor Physical Behavior in Motor Neuron Disease: Systematic Review.}, journal = {Journal of medical Internet research}, volume = {27}, number = {}, pages = {e68479}, doi = {10.2196/68479}, pmid = {40245393}, issn = {1438-8871}, mesh = {Humans ; *Motor Neuron Disease/physiopathology ; *Exercise ; *Wearable Electronic Devices ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a progressive and incurable neurodegenerative disease. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is the primary clinical tool for assessing disease severity and progression in MND. However, despite its widespread use, it does not adequately capture the extent of physical function decline. There is an urgent need for sensitive measures of disease progression that can be used to robustly evaluate new treatments. Measures of physical function derived from digital devices are beginning to be used to assess disease progression. There is value in establishing a consensus approach to standardizing the use of such devices.

OBJECTIVE: We aimed to explore how digital devices are being used to quantify free-living physical behavior in MND. We evaluated the feasibility and assessed the implications for monitoring physical behavior for future clinical trials and clinical practice.

METHODS: Systematic searches of 4 databases were performed in October 2023 and June 2024. Peer-reviewed English-language articles (including preprints) that examined how people living with MND used digital devices to assess their free-living physical behavior were included. Study reporting quality was assessed using a 22-item checklist (maximum possible score=44 points).

RESULTS: In total, 12 articles met the inclusion criteria for data extraction. All studies were longitudinal and observational in design, but data collection, analysis, and reporting protocols varied. Quality assessment scores ranged between 19 and 40 points. Sample sizes ranged between 10 and 376 people living with MND at baseline, declining over the course of the study. Most studies used an accelerometer device worn on the wrist, chest, hip, or ankle. Participants were typically asked to continuously wear devices for 1 to 8 days at 1- to 4-month intervals, with studies running for 12 weeks to 24 months. Some studies asked participants to wear the device continuously for the full duration. Studies derived traditional end points focusing on duration, intensity, and frequency of physical activity or nontraditional end points focusing on features of an individual's movement patterns. The correlation coefficients (r) between physical behavior end points and ALSFRS-R ranged from 0.31 to 0.78. Greater monitoring frequencies and improved end point sensitivity were shown to provide smaller sample size requirements and shorter durations for hypothetical clinical trials. People living with MND found using devices acceptable and reported a low burden. Adherence assessed in 8 (67%) studies was good, ranging from approximately 86% to 96%, with differences evident between wear locations. The perspectives of other end users and implications on clinical practice were not explored.

CONCLUSIONS: Remote monitoring of free-living physical behavior in MND is in its infancy but has the potential to quantify physical function. It is essential to develop a consensus statement, working toward agreed and standardized methods for data collection, analysis, and reporting.}, } @article {pmid40244212, year = {2025}, author = {Zhang, M and Zhou, H and Pan, Y and Wei, L}, title = {A pregnant woman with a 5-year history of amyotrophic lateral sclerosis: A case report.}, journal = {International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijgo.70173}, pmid = {40244212}, issn = {1879-3479}, support = {202414030736//Medical and Health Science and Technology Project of Shandong Province/ ; ZHKY202423//Chinese Nursing Association Scientific Research Project/ ; QDFY+X 2023125//the Clinical Medicine +X Project of the Affiliated Hospital of Qingdao University/ ; }, } @article {pmid40244186, year = {2025}, author = {Hu, C and Jiang, Y and Ma, C and Xu, F and Cui, C and Du, X and Chen, J and Zhu, L and Yu, S and He, X and Yu, W and Wang, Y and Xu, X}, title = {Decreased Cdk2 Activity Hindered Embryonic Development and Parthenogenesis Induction in Silkworm, Bombyx mori L.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26073341}, pmid = {40244186}, issn = {1422-0067}, support = {2021C02072//Technological Grant of Zhejiang for Breeding New Agricultural Varieties/ ; 32100377//National Natural Science Foundation of China/ ; CARS-18//Key Scientific and the China Agriculture Research System of MOF and MARA/ ; }, mesh = {Animals ; *Bombyx/embryology/genetics/enzymology ; *Parthenogenesis/drug effects ; *Cyclin-Dependent Kinase 2/metabolism/antagonists & inhibitors/genetics ; *Embryonic Development/drug effects ; *Insect Proteins/metabolism/genetics/antagonists & inhibitors ; Female ; }, abstract = {Cyclin-dependent protein kinase 2 (Cdk2), an important member of the serine/threonine-specific protein kinase family, plays a critical regulatory role in biological processes. Previous studies have demonstrated that Cdk2 is involved in the arrest and resumption of meiosis in mammalian oocytes. In this study, we explored the function of Cdk2 through parthenogenetic lines (PLs) and corresponding amphigonic lines (ALs) in a model lepidopteran insect silkworm, Bombyx mori L. Our findings revealed a positive correlation between Cdk2 activity and the parthenogenesis induction rate. The pharmacological inhibition of Cdk2 using the specific inhibitor AUZ454 not only significantly reduced the parthenogenesis induction rate but also caused developmental delays in embryos. These results demonstrate that Cdk2 is essential for parthenogenesis success and is a potential target gene for biological reproductive regulation.}, } @article {pmid40244061, year = {2025}, author = {Tseriotis, VS and Liampas, A and Lazaridou, IZ and Karachrysafi, S and Vavougios, GD and Hadjigeorgiou, GM and Papamitsou, T and Kouvelas, D and Arnaoutoglou, M and Pourzitaki, C and Mavridis, T}, title = {Repulsive Guidance Molecule-A as a Therapeutic Target Across Neurological Disorders: An Update.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26073221}, pmid = {40244061}, issn = {1422-0067}, mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy ; *Nerve Tissue Proteins/metabolism/antagonists & inhibitors/genetics ; *GPI-Linked Proteins/metabolism/antagonists & inhibitors/genetics ; Molecular Targeted Therapy ; Neurodegenerative Diseases/metabolism/drug therapy ; }, abstract = {Repulsive guidance molecule-a (RGMa) has emerged as a significant therapeutic target in a variety of neurological disorders, including neurodegenerative diseases and acute conditions. This review comprehensively examines the multifaceted role of RGMa in central nervous system (CNS) pathologies such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuromyelitis optica spectrum disorder, spinal cord injury, stroke, vascular dementia, auditory neuropathy, and epilepsy. The mechanisms through which RGMa contributes to neuroinflammation, neuronal degeneration, and impaired axonal regeneration are herein discussed. Evidence from preclinical studies associate RGMa overexpression with negative outcomes, such as increased neuroinflammation and synaptic loss, while RGMa inhibition, particularly the use of agents like elezanumab, has shown promise in enhancing neuronal survival and functional recovery. RGMa's responses concerning immunomodulation and neurogenesis highlight its potential as a therapeutic avenue. We emphasize RGMa's critical role in CNS pathology and its potential to pave the way for innovative treatment strategies in neurological disorders. While preclinical findings are encouraging so far, further clinical trials are needed to validate the safety and efficacy of RGMa-targeted therapies.}, } @article {pmid40243827, year = {2025}, author = {Carvalho, MCR}, title = {Reviewed article: Almeida ALS, Sousa TMS, Caldeira TCM, Claro RM. Association between adherence to the Food Guide golden rule and health characteristics among adult Brazilian women: a cross-sectional study with VIGITEL data, 2018-2021. Epidemiol Serv Saude. 2025:34;20240232.}, journal = {Epidemiologia e servicos de saude : revista do Sistema Unico de Saude do Brasil}, volume = {34}, number = {}, pages = {e20240232.b}, doi = {10.1590/S2237-96222025v34e20240232.b}, pmid = {40243827}, issn = {2237-9622}, } @article {pmid40243826, year = {2025}, author = {Tramontt, C}, title = {Reviewed article: Almeida ALS, Sousa TMS, Caldeira TCM, Claro RM. Association between adherence to the Food Guide golden rule and health characteristics among adult Brazilian women: a cross-sectional study with VIGITEL data, 2018-2021. Epidemiol Serv Saude. 2025:34;20240232.}, journal = {Epidemiologia e servicos de saude : revista do Sistema Unico de Saude do Brasil}, volume = {34}, number = {}, pages = {e20240232.a}, doi = {10.1590/S2237-96222025v34e20240232.a}, pmid = {40243826}, issn = {2237-9622}, } @article {pmid40243810, year = {2025}, author = {Flores, SV and Lillo, P and Levi-Monsalve, A and Roco-Videla, Á and Montaña, R}, title = {Genetic ancestry and risk allele C9orf72 rs3849942 T for amyotrophic lateral sclerosis in Latin American populations.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {379-381}, doi = {10.1080/21678421.2024.2447459}, pmid = {40243810}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/ethnology ; *C9orf72 Protein/genetics ; *Genetic Predisposition to Disease/genetics ; Latin America/epidemiology ; Alleles ; Female ; Male ; *Polymorphism, Single Nucleotide/genetics ; White People/genetics ; Middle Aged ; White ; }, abstract = {This study examines the relationship between genetic ancestry and the rs3849942 T allele, linked to ALS, in 347 Latin American individuals from the 1000 Genomes Project. Ancestry proportions were estimated using 446 AIMs, and associations were analyzed via logistic regression. Higher Native American ancestry significantly reduced the likelihood of carrying the T allele, while European ancestry increased it. These findings emphasize the importance of incorporating genetic diversity into ALS research.}, } @article {pmid40243699, year = {2025}, author = {Xu, R and Kang, Q and Yang, X and Yi, P and Zhang, R}, title = {Unraveling Molecular Targets for Neurodegenerative Diseases Through Caenorhabditis elegans Models.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26073030}, pmid = {40243699}, issn = {1422-0067}, support = {32270739//National Natural Science Foundation of China/ ; }, mesh = {*Caenorhabditis elegans/genetics/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/genetics/drug therapy/pathology ; *Disease Models, Animal ; Humans ; Caenorhabditis elegans Proteins/metabolism/genetics ; }, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and prion disease, represent a group of age-related disorders that pose a growing and formidable challenge to global health. Despite decades of extensive research that has uncovered key genetic factors and biochemical pathways, the precise molecular mechanisms underlying these diseases and effective therapeutic strategies remain elusive. Caenorhabditis elegans (C. elegans) has emerged as a powerful model organism for studying NDDs due to its unique biological features such as genetic tractability, conserved molecular pathways, and ease of high-throughput screening. This model provides an exceptional platform for identifying molecular targets associated with NDDs and developing novel therapeutic interventions. This review highlights the critical role of C. elegans in elucidating the complex molecular mechanisms of human NDDs, with a particular focus on recent advancements and its indispensable contributions to the discovery of molecular targets and therapeutic strategies for these NDDs.}, } @article {pmid40243477, year = {2025}, author = {Romano, R and Del Fiore, VS and Ruotolo, G and Mazzoni, M and Rosati, J and Conforti, FL and Bucci, C}, title = {Lysosomal Dysfunction in Amyotrophic Lateral Sclerosis: A Familial Case Linked to the p.G376D TARDBP Mutation.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26072867}, pmid = {40243477}, issn = {1422-0067}, support = {PRIN2022 N. 2022XTM2S3//Ministero dell'università e della ricerca/ ; PRIN2022 PNRR N. P2022FBZXY//Ministero dell'università e della ricerca/ ; D.M. n. 737 of 25.06.2021//Ministero dell'università e della ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Lysosomes/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; Motor Neurons/metabolism/pathology ; *Mutation ; Fibroblasts/metabolism/pathology ; Male ; Female ; Induced Pluripotent Stem Cells/metabolism ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Consequent to the loss of these cells, neuromuscular functions decline, causing progressive weakness, muscle wasting, and paralysis, leading to death in 2 to 5 years. More than 90% of ALS cases are sporadic, while the remaining 10% of cases are familial, due to mutations in 40 different genes. One of the most common genes to be mutated in ALS is TARDBP (transactive response DNA binding protein 43), which encodes TDP-43 (TAR DNA-binding protein 43). A mutation in exon 6 of TARDBP causes the aminoacidic substitution G376D in the C-terminal region of TDP-43, leading to its cytoplasmic mislocalization and aggregation. In fibroblasts derived from patients carrying this mutation, we found a strong increase in lysosome number, with overexpression and higher nuclear translocation of the transcription factor TFEB. In contrast, lysosomal functionality was deeply compromised. Interestingly, lysosomal activity was unaffected at an early stage of the disease, worsening in more advanced stages. Moreover, we observed the same pathological phenotype in iPSC (induced pluripotent stem cells)-derived patient motor neurons carrying the G376D mutation. Therefore, this mutation compromises the functionality of lysosomes, possibly contributing to neurodegeneration.}, } @article {pmid40243463, year = {2025}, author = {Fan, X and Diao, W and Wang, H and Yin, X and Qian, W}, title = {Interferon Regulatory Factors as a Potential Therapeutic Target for Neuroinflammation: A Focus on Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26072906}, pmid = {40243463}, issn = {1422-0067}, support = {82473926//National Natural Science Foundation of China/ ; 81872875//National Natural Science Foundation of China/ ; 81170317//National Natural Science Foundation of China/ ; 81473218//National Natural Science Foundation of China/ ; 81503077//National Natural Science Foundation of China/ ; JC2023042//the project of Nantong Natural Science Foundation/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Animals ; *Interferon Regulatory Factors/metabolism/genetics ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Signal Transduction ; Inflammation/metabolism ; }, abstract = {Interferon Regulatory Factors (IRFs) are critical modulators of immune and inflammatory responses, yet their roles in Alzheimer's disease (AD) and other neurodegenerative disorders remain incompletely understood. While IRFs are recognized for their regulatory functions in neuroinflammation, microglial activation, and neuronal survival, their dual roles as both drivers of pathological inflammation and mediators of neuroprotective pathways underscore a sophisticated regulatory paradox in neurodegenerative disorders. This review aims to synthesize current evidence on IRF-mediated neuroinflammation in AD and related diseases, focusing on the multifaceted functions of key IRF family members, including IRF1, IRF3, and IRF7. We critically evaluate their divergent roles: IRF1 and IRF3, for instance, exacerbate neuroinflammatory cascades and amyloid-beta (Aβ) pathology in AD, whereas IRF7 may paradoxically suppress inflammation under specific conditions. Additionally, we explore IRF dysregulation in Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease, emphasizing shared and distinct mechanisms across neurodegenerative disorders. Restoring IRF balance through genetic manipulation, small-molecule inhibitors, or microbiome-derived modulators could attenuate neuroinflammation, enhance Aβ clearance, and protect neuronal integrity. Ultimately, this work provides a framework for future research to harness IRF signaling pathways in the development of precision therapies for AD and other neurodegenerative diseases.}, } @article {pmid40241787, year = {2025}, author = {Wölfel, SM and Widmann, CN and Castro-Gomez, S and Weydt, P and Tacik, P and Heneka, MT}, title = {Cognitive capacity in amyotrophic lateral sclerosis: the value of diagnostic markers in cerebrospinal fluid and the influence of nutrition and pulmonary function.}, journal = {Brain communications}, volume = {7}, number = {2}, pages = {fcaf137}, pmid = {40241787}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is an incurable neurodegenerative disease that is fatal with a median of 3-4 years. It is characterized by degeneration of the first and second motor neurons. In addition to physical limitations, neuropsychological abnormalities occur in more than 50% of cases. This leads to a rapid loss of autonomy and increases the need for care. An individual prognosis for the course of the disease, in particular the development of cognitive and behavioural abnormalities, is not yet possible As part of our investigations, we focused on cognitive performance and behavioural abnormalities measured by the Edinburgh Cognitive and Behavioural ALS Screen in patients with amyotrophic lateral sclerosis and investigated possible prognostic biomarkers in cerebrospinal fluid as well as modifiable factors such as nutrition and lung function. A retrospective data analysis of 99 patients with amyotrophic lateral sclerosis cases examined between 2018 and 2021 at the Department for Neurodegenerative Diseases and Gerontopsychiatry at the University Hospital of Bonn, using Edinburgh Cognitive and Behavioural ALS Screen, revealed that elevated levels of total tau and phospho-tau 181 were associated with diminished performance of patients with amyotrophic lateral sclerosis on the Edinburgh Cognitive and Behavioural ALS Screen. Additionally, weight loss during the course of the disease has been observed to have a deleterious impact on cognitive performance. Moreover, we were able to demonstrate a previously insufficiently described correlation between abnormalities in the Edinburgh Cognitive and Behavioural ALS Screen and low-normal thiamine levels in serum. The hypothesis that reduced lung function has a negative effect on cognitive performance was not supported by our findings. The initial onset of amyotrophic lateral sclerosis, whether bulbar or spinal, does not appear to affect cognition and behaviour measured using Edinburgh Cognitive and Behavioural ALS Screen. Furthermore, our findings confirm the utility of the Edinburgh Cognitive and Behavioural ALS Screen in identifying a behavioural variant frontotemporal dementia in amyotrophic lateral sclerosis patients who have been previously diagnosed by experienced neurologists using the Rascovsky criteria. This development facilitates a more precise utilization of complex diagnostic instruments. Our results provide insight into the prognosis of patients with amyotrophic lateral sclerosis in terms of cognitive performance and behavioural abnormalities as the disease progresses, as well as potential therapeutic approaches to stabilize and support neuropsychological abnormalities. The importance of total tau as a widely available prognostic marker should be emphasized. Additionally, new avenues of research are emerging, particularly regarding the role of thiamine in amyotrophic lateral sclerosis.}, } @article {pmid40241786, year = {2025}, author = {Hernández-Gloria, JJ and Jaramillo-Gonzalez, A and Savić, AM and Mrachacz-Kersting, N}, title = {Toward brain-computer interface speller with movement-related cortical potentials as control signals.}, journal = {Frontiers in human neuroscience}, volume = {19}, number = {}, pages = {1539081}, pmid = {40241786}, issn = {1662-5161}, abstract = {Brain Computer Interface spellers offer a promising alternative for individuals with Amyotrophic Lateral Sclerosis (ALS) by facilitating communication without relying on muscle activity. This study assessed the feasibility of using movement related cortical potentials (MRCPs) as a control signal for a Brain-Computer Interface speller in an offline setting. Unlike motor imagery-based BCIs, this study focused on executed movements. Fifteen healthy subjects performed three spelling tasks that involved choosing specific letters displayed on a computer screen by performing a ballistic dorsiflexion of the dominant foot. Electroencephalographic signals were recorded from 10 sites centered around Cz. Three conditions were tested to evaluate MRCP performance under varying task demands: a control condition using repeated selections of the letter "O" to isolate movement-related brain activity; a phrase spelling condition with structured text ("HELLO IM FINE") to simulate a meaningful spelling task with moderate cognitive load; and a random condition using a randomized sequence of letters to introduce higher task complexity by removing linguistic or semantic context. The success rate, defined as the presence of an MRCP, was manually determined. It was approximately 69% for both the control and phrase conditions, with a slight decrease in the random condition, likely due to increased task complexity. Significant differences in MRCP features were observed between conditions with Laplacian filtering, whereas no significant differences were found in single-site Cz recordings. These results contribute to the development of MRCP-based BCI spellers by demonstrating their feasibility in a spelling task. However, further research is required to implement and validate real-time applications.}, } @article {pmid40180127, year = {2025}, author = {Kaltchenko, M and Kim, E and Radtke, S and Wan, J}, title = {Response to Li et al's "Comments on 'Dupilumab and neuropsychiatric outcomes in pediatric atopic dermatitis: A real-world cohort analysis'".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.03.081}, pmid = {40180127}, issn = {1097-6787}, } @article {pmid40240969, year = {2025}, author = {Xia, H and Wang, ZH and Wang, XB and Gao, MR and Jiang, S and Du, XY and Yang, XL}, title = {Investigating the genetic association of mitochondrial DNA copy number with neurodegenerative diseases.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {160}, pmid = {40240969}, issn = {1471-2377}, support = {2023B03003//Autonomous Region Key Research and Development Project/ ; 2022TSYCLJ0066//the Tian-Shan Talent Program/ ; 82371258//the National Natural Science Foundation of China/ ; ZYYD2022C17//the Central Guiding Local Science and Technology Development Special Fund Project/ ; }, abstract = {OBJECTIVE: This study aims to investigate the causal relationship between Mitochondrial DNA (mtDNA) copy number and several common neurodegenerative diseases (NDs).

METHODS: We conducted a bidirectional two-sample Mendelian randomization (MR) analysis using data from genome-wide association studies (GWAS) as instrumental variables (IVs). After screening for relevance and potential confounders, we estimated the association between mtDNA copy number and NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Multiple sclerosis (MS). Additionally, we validated our findings using GWAS data on mtDNA copy number from Longchamps et al., sourced from the Genetics Epidemiology Consortium and the UK Biobank (UKB) aging study cohort.

RESULTS: A GWAS analysis of 395,718 UKB participants found no significant association between mtDNA copy number and the risk of NDs, including AD (OR = 0.956, P = 0.708), PD (OR = 1.223, P = 0.179), ALS (OR = 0.972, P = 0.374), and MS (OR = 0.932, P = 0.789). Similarly, reverse MR analysis revealed no significant relationship between genetic predictions of NDs and mtDNA copy number: AD (OR = 0.987, P = 0.062), PD (OR = 0.997, P = 0.514), ALS (OR = 0.974, P = 0.706), and MS (OR = 1.003, P = 0.181).

CONCLUSION: Although mitochondrial dysfunction is implicated in the pathogenesis of NDs, no clear evidence supports a causal role for mtDNA copy number. The relationship between mtDNA copy number and NDs is likely mediated by more complex molecular regulatory mechanisms. Further research is required to elucidate these intricate interactions.}, } @article {pmid40238886, year = {2025}, author = {Cheemala, A and Kimble, AL and Burrage, EN and Helming, SB and Tyburski, JD and Leclair, NK and Omar, OM and Zuberi, AR and Murphy, M and Jellison, ER and Reese, B and Hu, X and Lutz, CM and Yan, R and Murphy, PA}, title = {Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects.}, journal = {Science advances}, volume = {11}, number = {16}, pages = {eads0505}, doi = {10.1126/sciadv.ads0505}, pmid = {40238886}, issn = {2375-2548}, mesh = {*Blood-Brain Barrier/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Mice ; *Mutation ; Humans ; *Endothelial Cells/metabolism/pathology ; Disease Models, Animal ; Brain/metabolism/pathology ; }, abstract = {Mutations in the TARDBP gene encoding TDP-43 protein are linked to loss of function in neurons and familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We recently identified reduced nuclear TDP-43 in capillary endothelial cells (ECs) of donors with ALS-FTD. Because blood-brain barrier (BBB) permeability increases in ALS-FTD, we postulated that reduced nuclear TDP-43 in ECs might contribute. Here, we show that nuclear TDP-43 is reduced in ECs of mice with an ALS-FTD-associated mutation in TDP-43 (Tardbp[G348C]) and that this leads to cell-autonomous loss of junctional complexes and BBB integrity. Targeted excision of TDP-43 in brain ECs recapitulates BBB defects and loss of junctional complexes and ultimately leads to fibrin deposition, gliosis, phospho-Tau accumulation, and impaired memory and social interaction. Transcriptional changes in TDP-43-deficient ECs resemble diseased brain ECs. These data show that nuclear loss of TDP-43 in brain ECs disrupts the BBB and causes hallmarks of FTD.}, } @article {pmid40237254, year = {2025}, author = {Russek, M and Peltner, J and Haenisch, B}, title = {Supplementing Single-Arm Trials with External Control Arms-Evaluation of German Real-World Data.}, journal = {Clinical pharmacology and therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1002/cpt.3684}, pmid = {40237254}, issn = {1532-6535}, abstract = {As single-arm trials (SATs) are increasingly used in pharmaceutical research, the validity of such study designs needs to be critically assessed. We characterize the feasibility of supplementing SATs with real-world data (RWD)-derived external control arms by determining the proportion of SATs on breast cancer and amyotrophic lateral sclerosis (ALS) for which an external control arm based on RWD can be constructed. The main outcome measure is the number and percentage of trials for which all important eligibility criteria and at least one primary endpoint could be identified in one of five German RWD sources. We surveyed all SATs concerning breast cancer or ALS treatment registered in the European Union's clinical trial registers between 2004 and 2023. Ten out of 379 breast cancer SATs and 2 of 11 ALS SATs could feasibly be supplemented with RWD-derived external control arms, if all important eligibility criteria and a primary endpoint have to be identifiable in the RWD source. Ninety-three breast cancer trials had at least one outcome ascertainable in a RWD source, and 35 trials had all important eligibility criteria recorded in a RWD source. Nine ALS trials had at least one primary endpoint ascertainable in RWD sources, and 2 had all important eligibility criteria recorded in a RWD source. Our study shows that SATs with RWD-derived external control arms will rarely be suitable to establish treatment effects of medicines in the current setting for the investigated phenotypes and that SATs should be designed with limitations of the source of external controls in mind.}, } @article {pmid40237114, year = {2025}, author = {Thompson, OL and Russell, JA and Stockman, SK and Swall, JL and Simmons, T}, title = {Assessing the effectiveness of alternate light sources in the search for skeletal remains.}, journal = {Journal of forensic sciences}, volume = {}, number = {}, pages = {}, doi = {10.1111/1556-4029.70049}, pmid = {40237114}, issn = {1556-4029}, abstract = {Many search and recovery operations for human skeletal remains are unsuccessful due to difficulties recognizing bones in outdoor environments even when evidence indicates the last known whereabouts of missing individuals. Though the collagen component of bone is known to emit fluorescence, this property has not been leveraged consistently during skeletal remains searches. Thirty-six mock searches were completed in 5000 ft[2] zones of eastern deciduous forest by volunteers associated with the Virginia Department of Emergency Management. Pig and deer bones were scattered and partially concealed under brush and leaf cover. Pairs of volunteers were allowed up to 1 h to conduct searches in their usual pattern. Nighttime searches were conducted with handheld alternate light source (ALS) devices (uvBeast™, Crime-lite[®], ForenScope, and Labino AB), which produced ultraviolet (385-395 nm), violet (395-425 nm), blue (~455 nm), cyan (~510 nm), or green (~530 nm) lights. Filtered safety glasses were paired with appropriate ALS. Daytime searches were conducted under the same parameters, without ALS. Results indicated that (1) nighttime searches with ALS produced a recovery rate more than triple that of daytime searches (p < 0.0001) and that they were often completed more quickly, and (2) the violet Crime-lite[®], due to breadth of illumination and strength of fluorescent response, consistently produced the highest recovery rate (95%). Data suggest that nighttime searches with ALS can be used both as the primary search method for locating and recovering human skeletal remains, and as a secondary method for recovering any bones expected to be present but not found during daylight searches.}, } @article {pmid40236412, year = {2025}, author = {Jude, JJ and Levi-Aharoni, H and Acosta, AJ and Allcroft, SB and Nicolas, C and Lacayo, BE and Card, NS and Wairagkar, M and Brandman, DM and Stavisky, SD and Willett, FR and Williams, ZM and Simeral, JD and Hochberg, LR and Rubin, DB}, title = {An intuitive, bimanual, high-throughput QWERTY touch typing neuroprosthesis for people with tetraplegia.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.04.01.25324990}, pmid = {40236412}, abstract = {Recognizing keyboard typing as a familiar, high information rate communication paradigm, we developed an intracortical brain computer interface (iBCI) typing neuroprosthesis providing bimanual QWERTY keyboard functionality for people with paralysis. Typing with this iBCI involves only attempted finger movements, which are decoded accurately with as few as 30 calibration sentences. Sentence decoding is improved using a 5-gram language model. This typing neuroprosthesis performed well for two iBCI clinical trial participants with tetraplegia - one with ALS and one with spinal cord injury. Typing speed is user-regulated, reaching 110 characters per minute, resulting in 22 words per minute with a word error rate of 1.6%. This resembles able-bodied typing accuracy and provides higher throughput than current state-of-the-art hand motor iBCI decoding. In summary, a typing neuroprosthesis decoding finger movements, provides an intuitive, familiar, and easy-to-learn paradigm for individuals with impaired communication due to paralysis.}, } @article {pmid40236149, year = {2025}, author = {Strell, P and Waldron, MA and Johnson, S and Shetty, A and Crane, AT and Steer, CJ and Low, WC}, title = {Characterization of the intraspecies chimeric mouse brain at embryonic day 12.5.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.03.31.646380}, pmid = {40236149}, issn = {2692-8205}, abstract = {Incidence of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis have increased dramatically as life expectancy at birth has risen year-over-year and the population ages. Neurological changes within the central nervous system, specifically the brain, include cell loss and deterioration that impact motor function, memory, executive function, and mood. Available treatments are limited and often only address symptomatic manifestations of the disease rather than disease progression. Cell transplantation therapy has shown promise for treating neurodegenerative diseases, but a source of autologous cells is required. Blastocyst complementation provides an innovative method for generating those autologous neural cells. By injecting mouse induced pluripotent stem cells (iPSCs) into a wild type (WT) mouse blastocyst, we generated a chimeric mouse brain derived of both donor and host neuronal and non-neuronal cells. An embryonic day 12.5 (E12.5), automated image analysis of mouse-mouse chimeric brains showed the presence of GFP-labeled donor-derived dopaminergic and serotonergic neuronal precursors. GFP-labeled donor-derived cholinergic precursor neurons and non-neuronal microglia-like and macrophage-like cells were also observed using more conventional imaging analysis software. This work demonstrates that the generation of mouse-mouse chimeric neural cells is possible; and that characterization of early neuronal and non-neuronal precursors provides a first step towards utilizing these cells for cell transplantation therapies for neurodegenerative diseases.}, } @article {pmid40235960, year = {2025}, author = {Basgaran, A and Lymberopoulos, E and Burchill, E and Reis-Dehabadi, M and Sharma, N}, title = {Machine learning determines the incidence of Alzheimer's disease based on population gut microbiome profile.}, journal = {Brain communications}, volume = {7}, number = {2}, pages = {fcaf059}, pmid = {40235960}, issn = {2632-1297}, abstract = {The human microbiome is a complex and dynamic community of microbes, thought to have symbiotic benefit to its host. Influences of the gut microbiome on brain microglia have been identified as a potential mechanism contributing to neurodegenerative diseases, such as Alzheimer's disease, motor neurone disease and Parkinson's disease (Boddy SL, Giovannelli I, Sassani M, et al. The gut microbiome: A key player in the complexity of amyotrophic lateral sclerosis (ALS). BMC Med. 2021;19(1):13). We hypothesize that population level differences in the gut microbiome will predict the incidence of Alzheimer's disease using machine learning methods. Cross-sectional analyses were performed in R, using two large, open-access microbiome datasets (n = 959 and n = 2012). Countries in these datasets were grouped based on Alzheimer's disease incidence and the gut microbiome profiles compared. In countries with a high incidence of Alzheimer's disease, there is a significantly lower diversity of the gut microbiome (P < 0.05). A permutational analysis of variance test (P < 0.05) revealed significant differences in the microbiome profile between countries with high versus low incidence of Alzheimer's disease with several contributing taxa identified: at a species level Escherichia coli, and at a genus level Haemophilus and Akkermansia were found to be reproducibly protective in both datasets. Additionally, using machine learning, we were able to predict the incidence of Alzheimer's disease within a country based on the microbiome profile (mean area under the curve 0.889 and 0.927). We conclude that differences in the microbiome can predict the varying incidence of Alzheimer's disease between countries. Our results support a key role of the gut microbiome in neurodegeneration at a population level.}, } @article {pmid40235867, year = {2025}, author = {Sundararaju, U and Rajakumar, HK}, title = {Prognostic value of neutrophil-to-lymphocyte ratio in gastric cancer: Enhancing clinical relevance.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {4}, pages = {103128}, pmid = {40235867}, issn = {1948-5204}, abstract = {Gastric cancer (GC) is a leading cause of cancer-related deaths, highlighting the need for reliable prognostic biomarkers to guide treatment. Wei et al's systematic review and meta-analysis evaluates the neutrophil-to-lymphocyte ratio (NLR) as a potential biomarker for GC patients undergoing neoadjuvant chemotherapy. NLR is a simple and cost-effective measure of systemic inflammation that shows promise in predicting treatment response and survival outcomes, including overall survival and progression-free survival. However, variations in NLR thresholds and timing of measurements affect its accuracy and clinical utility. Moreover, the studies reviewed primarily involved Asian populations, which may limit the generalizability of the findings. To improve NLR's clinical relevance, future research should focus on standardizing NLR thresholds, refining measurement timing, and incorporating additional inflammatory markers like platelet-to-lymphocyte ratio and Glasgow prognostic score. Addressing confounders and including diverse patient populations will help improve NLR's reliability as a prognostic marker for GC.}, } @article {pmid40235786, year = {2025}, author = {Wang, LP and Yang, C and Fu, JY and Zhang, XY and Shen, XM and Shi, NL and Wu, HL and Gao, XR}, title = {A preliminary study of steady-state visually-evoked potential-based non-invasive brain-computer interface technology as a communication aid for patients with amyotrophic lateral sclerosis.}, journal = {Quantitative imaging in medicine and surgery}, volume = {15}, number = {4}, pages = {3469-3479}, pmid = {40235786}, issn = {2223-4292}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, leading to severe disability and ultimately death. Communication difficulties are common in ALS patients as the disease progresses; thus, alternative communication aids need to be explored. This study sought to examine the use and effect of steady-state visually-evoked potential (SSVEP)-based non-invasive brain-computer interface (BCI) technology as a communication aid for patients with ALS and to examine possible influencing factors.

METHODS: In total, 12 patients with ALS were selected, and a 40-character target selection was performed using SSVEP-based non-invasive BCI technology. The patients were presented with specific visual stimuli, and nine-lead electroencephalogram (EEG) signals in the occipital region were acquired when the patients were looking at the target. Using the feature recognition analysis method, the final output was the characters recognized by the patients. The basic clinical data of the patients (e.g., age, gender, course of disease, affected area, and ALS functional scale score) were collected, and the BCI accuracy rate, information transmission rate, and average SSVEP recognition time were calculated.

RESULTS: The results revealed that the recognition efficiency of the ALS patients varied. The accuracy potential increased as the stimulus duration extended, highlighting the possibility for improvement via further optimization. The results also showed that the experimental design schedules typically used for healthy individuals may not be entirely suitable for ALS patients, which presents an exciting opportunity to tailor future studies to better meet the unique needs of ASL patients. Further, the results revealed the necessity of using customized experimental schedules in future studies, which could lead to more relevant and effective data collection for ALS patients.

CONCLUSIONS: The study found that SSVEP-based non-invasive BCI technology has promising potential as a communication aid for ALS patients. While further algorithm optimization and comprehensive studies with larger sample sizes are necessary, the initial findings are encouraging, and could lead to the development of more effective communication solutions that are specifically tailored to address the challenges faced by ALS patients.}, } @article {pmid40235752, year = {2025}, author = {Huang, NX and Zeng, JY and Huang, HW and Fang, SY and Chen, S and Li, JQ and Chen, HJ and Zou, ZY}, title = {Association of glymphatic system disturbance with neural dysfunction in amyotrophic lateral sclerosis.}, journal = {Quantitative imaging in medicine and surgery}, volume = {15}, number = {4}, pages = {3445-3457}, pmid = {40235752}, issn = {2223-4292}, abstract = {BACKGROUND: Formation and aggregation of pathological proteins in the brain constitutes a critical hallmark of amyotrophic lateral sclerosis (ALS). However, the role of the glymphatic system in the clearance of pathological proteins in ALS remains unclear. The purpose of this cross-sectional study was to evaluate glymphatic system disturbance in ALS and its relation to neural function.

METHODS: This study included 38 healthy controls (HCs) and 30 patients with ALS who underwent diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rs-fMRI). The disease severity, duration, and progression rate of ALS were recorded. Glymphatic system function was indirectly evaluated by DTI analysis along the perivascular space (ALPS) surrounding the deep medullary vein. Neural activity was examined in sensorimotor-related brain areas by measuring amplitude of low-frequency fluctuation (ALFF) based on rs-fMRI. A two-sample t-test or Mann-Whitney test was used to examine between-group differences in ALPS, diffusivities measured along the x-, y-, and z-axis in the association (Dxx_association, Dyy_association, Dzz_association) and projection (Dxx_projection, Dyy_projection, Dzz_projection) fiber areas, and ALFF indices. The associations between ALPS, diffusivities, ALFF, and clinical assessments were determined via Spearman correlation analysis, and diagnostic performance was evaluated with receiver operating characteristic curve analysis.

RESULTS: Patients with ALS exhibited significantly decreased ALPS and increased diffusivities (Dyy_association and Dyy_projection) as compared to HCs (all P values <0.05). Patients with ALS showed decreased ALFF in sensorimotor-related regions, including the bilateral primary motor and somatosensory areas (all P values <0.001) and left supplementary motor area (P=0.031). ALPS and diffusivities were correlated with ALFF in the sensorimotor-motor regions (all P values <0.05), and ALPS and ALFF correlated with disease severity and duration (all P values <0.05). ALPS, diffusivities, and ALFF showed moderate ability to diagnose ALS.

CONCLUSIONS: The glymphatic system function was impaired in ALS. This may contribute to spontaneous neural activity disturbance and could represent a mechanism for the development of sensorimotor deficits frequently observed in patients with ALS.}, } @article {pmid40235273, year = {2025}, author = {Scelsa, SN and MacGowan, DJL}, title = {Disease Modification in SOD1-ALS With Tofersen May Result in Serious CNS Inflammation.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28413}, pmid = {40235273}, issn = {1097-4598}, } @article {pmid40234983, year = {2025}, author = {Xie, Q and Li, K and Chen, Y and Li, Y and Jiang, W and Cao, W and Yu, H and Fan, D and Deng, B}, title = {Gene therapy breakthroughs in ALS: a beacon of hope for 20% of ALS patients.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {19}, pmid = {40234983}, issn = {2047-9158}, support = {81901273//National Natural Science Foundation of China/ ; ZCLY24H0903//Natural Science Foundation of Zhejiang Province/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that remains incurable. Although the etiologies of ALS are diverse and the precise pathogenic mechanisms are not fully understood, approximately 20% of ALS cases are caused by genetic factors. Therefore, advancing targeted gene therapies holds significant promise, at least for the 20% of ALS patients with genetic etiologies. In this review, we summarize the main strategies and techniques of current ALS gene therapies based on ALS risk genes, and review recent findings from animal studies and clinical trials. Additionally, we highlight ALS-related genes with well-understood pathogenic mechanisms and the potential of numerous emerging gene-targeted therapeutic approaches for ALS.}, } @article {pmid40234916, year = {2025}, author = {Park, KH and Yu, E and Choi, S and Kim, S and Park, C and Lee, JE and Kim, KW}, title = {Optogenetic induction of TDP-43 aggregation impairs neuronal integrity and behavior in Caenorhabditis elegans.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {20}, pmid = {40234916}, issn = {2047-9158}, support = {NRF-2022R1A2C1003766//Ministry of Education, Science and Technology/ ; RS-2024-00331685//Ministry of Food and Drug Safety/ ; }, abstract = {BACKGROUND: Cytoplasmic aggregation of TAR DNA binding protein 43 (TDP-43) in neurons is one of the hallmarks of TDP-43 proteinopathy. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are closely associated with TDP-43 proteinopathy; however, it remains uncertain whether TDP-43 aggregation initiates the pathology or is a consequence of it.

METHODS: To demonstrate the pathology of TDP-43 aggregation, we applied the optoDroplet technique in Caenorhabditis elegans (C. elegans), which allows spatiotemporal modulation of TDP-43 phase separation and assembly.

RESULTS: We demonstrate that optogenetically induced TDP-43 aggregates exhibited insolubility similar to that observed in TDP-43 proteinopathy. These aggregates increased the severity of neurodegeneration, particularly in GABAergic motor neurons, and exacerbated sensorimotor dysfunction in C. elegans.

CONCLUSIONS: We present an optogenetic C. elegans model of TDP-43 proteinopathy that provides insight into the neuropathological mechanisms of TDP-43 aggregates. Our model serves as a promising tool for identifying therapeutic targets for TDP-43 proteinopathy.}, } @article {pmid40234116, year = {2025}, author = {McHale-Owen, H and Faller, KME and Chaytow, H and Gillingwater, TH}, title = {Phosphoglycerate kinase 1 as a therapeutic target in neurological disease.}, journal = {Trends in molecular medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.molmed.2025.03.008}, pmid = {40234116}, issn = {1471-499X}, abstract = {Phosphoglycerate kinase 1 (PGK1) is a highly conserved enzyme that catalyzes the initial ATP-producing step in glycolysis. Improving cellular energy production by increasing PGK1 activity may be beneficial in multiple neurological conditions where cell metabolism is dysregulated, including Parkinson's disease (PD) and motor neuron disease (MND). This review examines recent evidence that suggests increasing PGK1 activity may be beneficial in multiple neurological conditions and discusses the current challenges surrounding the development of PGK1-focused therapies. PGK1 has considerable therapeutic potential, but novel PGK1 activators are needed to maximize the benefit for patients.}, } @article {pmid40232694, year = {2024}, author = {Ichikawa, Y and Sato, B and Hirano, SI and Takefuji, Y and Satoh, F}, title = {Hydrogen inhalation therapy may ameliorate amyotrophic lateral sclerosis.}, journal = {Medical gas research}, volume = {14}, number = {3}, pages = {149-150}, doi = {10.4103/2045-9912.390249}, pmid = {40232694}, issn = {2045-9912}, } @article {pmid40232582, year = {2025}, author = {Mehrnoosh, F and Rezaei, D and Pakmehr, SA and Nataj, PG and Sattar, M and Shadi, M and Ali-Khiavi, P and Zare, F and Hjazi, A and Al-Aouadi, RFA and Sapayev, V and Zargari, F and Alkhathami, AG and Ahmadzadeh, R and Khedmatgozar, M and Hamzehzadeh, S}, title = {The role of Panax ginseng in neurodegenerative disorders: mechanisms, benefits, and future directions.}, journal = {Metabolic brain disease}, volume = {40}, number = {4}, pages = {183}, pmid = {40232582}, issn = {1573-7365}, mesh = {Humans ; *Panax ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Ginsenosides/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Plant Extracts/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Multiple sclerosis (MS), and Huntington's disease (HD) represent a growing global health challenge, especially with aging populations. Characterized by progressive neuronal loss, these diseases lead to cognitive, motor, and behavioral impairments, significantly impacting patients' quality of life. Current therapies largely address symptoms without halting disease progression, underscoring the need for innovative, disease-modifying treatments. Ginseng, a traditional herbal medicine with well-known adaptogenic and neuroprotective properties, has gained attention as a potential therapeutic agent for neurodegeneration. Rich in bioactive compounds called ginsenosides, ginseng exhibits antioxidant, anti-inflammatory, and anti-apoptotic effects, making it a promising candidate for addressing the complex pathology of neurodegenerative diseases. Recent studies demonstrate that ginsenosides modulate disease-related processes such as oxidative stress, protein aggregation, mitochondrial dysfunction, and inflammation. In AD models, ginsenosides have been shown to reduce amyloid-beta accumulation and tau hyperphosphorylation, while in PD, they help protect dopaminergic neurons and mitigate motor symptoms. Ginseng's effects in ALS, MS, and HD models include improving motor function, extending neuronal survival, and reducing cellular toxicity. This review provides a comprehensive overview of the neuroprotective mechanisms of ginseng, emphasizing its therapeutic potential across various neurodegenerative diseases and discussing future research directions for its integration into clinical practice.}, } @article {pmid40232308, year = {2025}, author = {Wu, J and Xu, Y and Yin, T and Zhang, N and Fan, D and Ye, S}, title = {Unveiling structural damage of the corpus callosum in amyotrophic lateral sclerosis through diffusion tensor imaging and spread direction perspectives.}, journal = {Annals of medicine}, volume = {57}, number = {1}, pages = {2490822}, doi = {10.1080/07853890.2025.2490822}, pmid = {40232308}, issn = {1365-2060}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/physiopathology ; *Corpus Callosum/pathology/diagnostic imaging ; *Diffusion Tensor Imaging/methods ; Male ; Female ; Middle Aged ; Aged ; Adult ; Motor Cortex/pathology/diagnostic imaging ; }, abstract = {OBJECTIVE: Damage to the corpus callosum (CC) in amyotrophic lateral sclerosis (ALS) patients has been confirmed via electrophysiological, neuroimaging, and autopsy studies. Additionally, the CC is hypothesized to serve as a pathway for the spread of pathological information. This study aimed to investigate whether the CC plays a mediating role in the symptomatic spread of ALS.

METHODS: In this observational study, diffusion tensor imaging (DTI) data were acquired from 45 individuals with the upper motor neuron-dominant (UMN-D) phenotype of ALS. The UMN-D ALS patients were categorized into two groups based on the direction of symptom spread, including 25 patients with horizontal spread (group H) and 20 patients with vertical spread (group V). Diffusivity indices were derived through whole-brain analysis and probabilistic fiber tracking.

RESULTS: According to the voxel-based analysis and tract-based spatial statistics, differences in axial diffusivity (AD) in the CC were observed between disease subgroups, with patients in group H showing higher AD values than those in group V. Fiber tracking analysis revealed persistent differences in the AD indices of CC-primary motor cortex (PMC) fibers between the two disease subgroups.

CONCLUSION: In UMN-D ALS patients, the direction of symptom spread may be related to the degree of CC involvement. The AD metric may be a more specific indicator of CC damage.}, } @article {pmid40231507, year = {2025}, author = {Tecalco-Cruz, AC and Ramírez-Jarquín, JO and Medina Abreu, KH and Palacios-Serrato, EG and López-Cánovas, L and Zepeda-Cervantes, J and Oropeza-Martínez, E}, title = {Molecular Interplay of ISG15/ISGylation in Neuropathologies.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273378149250322050004}, pmid = {40231507}, issn = {1996-3181}, abstract = {ISG15 is a 15 kDa ubiquitin-like protein that covalently associates with its target proteins by a sequential enzymatic process known as ISGylation. Research on protein ISGylation has increased in recent years, and some studies have suggested that ISG15 is involved in neuroprotection and neurodegeneration mechanisms. This review outlines the current state of research on the implications of ISG15/ISGylation in other neuropathies such as malignant tumors, ataxia telangiectasia, ischemia, depression, and neurodegenerative diseases such as Alzheimer´s, Parkinson's diseases, multiple sclerosis, and amyotrophic lateral sclerosis. Based on the studies reported to date, ISG15/ ISGylation promotes the progression of brain tumors such as glioblastoma. Moreover, ISG15/ ISGylation seems to play a dual role in neuropathies, demonstrating a neuroprotective effect when there is acute brain damage, but ISG15/ISGylation is associated with reduced neuroprotection when there is chronic damage, such as in neurodegenerative diseases.}, } @article {pmid40231293, year = {2025}, author = {Smyth, BR and Patwardhan, S and Turner, EL and McLintock, S}, title = {Using Functional Resonance Analysis Method (FRAM) Modelling to Assess the Factors That Slow or Prevent Clinicians in Performing Advanced Life Support (ALS) During Crash Calls to Park House Mental Health Hospital.}, journal = {Cureus}, volume = {17}, number = {4}, pages = {e82231}, pmid = {40231293}, issn = {2168-8184}, abstract = {This Quality Improvement Project (QIP) aimed to improve the response system for crash calls at Park House Mental Health Hospital, supported by the North Manchester General Hospital Crash Team. Using a functional resonance analysis method (FRAM), the team identified inefficiencies in the Advanced Life Support (ALS) process, with delayed responses increasing patient mortality risks. Interviews with staff helped create "work-as-imagined" (WAI) and "work-as-done" (WAD) models, highlighting the underperformed functions like ward entry protocols, and fully stocked crash trolleys. Recommendations, including access cards, stock changes, and live simulations, were implemented, in an aim to improve ALS provision.}, } @article {pmid40230758, year = {2025}, author = {Bossei, AA and Al Zahrani, HA and Bossei, FA and Saadi, SM and Alsaedi, AS and Al Sulami, AQ and Al Asmari, EH and Aalam, AA and Khojah, IM}, title = {Emergency Physicians' Perceptions, Knowledge, and Attitudes Toward Family Presence During Resuscitation in the Emergency Department: A Multicenter Survey-Based Cross-Sectional Study.}, journal = {Cureus}, volume = {17}, number = {3}, pages = {e80612}, pmid = {40230758}, issn = {2168-8184}, abstract = {BACKGROUND: Cardiac arrest remains a significant public health issue, with high incidence rates in both in-hospital and out-of-hospital settings. The practice of family presence during resuscitation (FPDR) has gained attention for its potential benefits to patients and their families. This study evaluates the perceptions, knowledge, and attitudes of emergency physicians (EPs) regarding FPDR in the emergency department (ED) and aims to inform policy development at King Abdulaziz University Hospital in Jeddah, Saudi Arabia.

METHODS:  A multicenter cross-sectional study was conducted from January to April 2023, surveying EPs from multiple EDs across the western region of Saudi Arabia. Participants, certified in basic (BLS) or advanced life support (ALS), completed an anonymous online survey adapted from previous studies.

RESULTS: Our study surveyed 122 EPs, with 112 completing the survey. Of the participants, 49.1% were aged 25-29 years, 61.6% were men, and 58.9% had 1-4 years of work experience. Awareness of FPDR was reported by 67.9% (n = 76) of participants. Only 3.6% (n = 4) had a policy allowing FPDR, while 6.3% (n = 7) had a policy prohibiting it. Additionally, 49.1% (n = 55) supported implementing an FPDR policy. Awareness of FPDR was significantly higher among younger, male, and more experienced physicians (p < 0.05). Higher perception and practice scores were observed among those aware of FPDR, those who had participated in CPR with a family member, and those without a prohibiting policy (p < 0.05).

CONCLUSION: EPs in the western region of Saudi Arabia generally support FPDR, recognizing its potential benefits. However, concerns about its impact on performance and medicolegal issues warrant further exploration. To implement effective FPDR policies, these concerns must be addressed, along with efforts to promote awareness and training. Future research should expand to include broader healthcare settings and multidisciplinary teams to develop comprehensive, evidence-based guidelines.}, } @article {pmid40229738, year = {2025}, author = {Abdoalsadig, E and Hamid, M and Peck, A and Johar, L and Kimonis, V}, title = {Utilization of CoRDS registry to monitor quality of life in patients with VCP multisystem proteinopathy.}, journal = {Orphanet journal of rare diseases}, volume = {20}, number = {1}, pages = {178}, pmid = {40229738}, issn = {1750-1172}, mesh = {Humans ; Registries ; *Quality of Life ; Female ; Male ; *Valosin Containing Protein/genetics/metabolism ; Middle Aged ; Aged ; Myositis, Inclusion Body/genetics ; Adult ; Amyotrophic Lateral Sclerosis/genetics ; Osteitis Deformans/genetics ; Frontotemporal Dementia/genetics ; }, abstract = {BACKGROUND: VCP disease, also known as multisystem proteinopathy, is a rare, autosomal dominant, adult-onset, neuromuscular disease that is caused by variants in the valosin-containing protein (VCP) gene. VCP disease may exhibit one or more of the following primary features: inclusion body myopathy, Paget's disease of bone (PDB), Frontotemporal dementia, and amyotrophic lateral sclerosis. Due to its progressive nature, death normally occurs in their sixties due to respiratory and cardiac failure. The purpose of this study is to utilize the Cure VCP Disease patient registry hosted by the Coordination of Rare Diseases at Sanford (CoRDS) to conduct a prospective natural history study.

METHODS: Seventy-nine participants enrolled in the patient registry and answered demographic, VCP variant type, Patient-reported outcome measures (PROMs), and quality of life (QOL) questionnaires over the course of 3 years. We additionally investigated if any sex differences existed and if genotype-phenotype correlations affected the rate of progression of the varying clinical manifestations.

RESULTS: Overall, participants' mobility declined significantly as the disease progressed. Participants reported a 0.6% decline in upper extremity function, 1.2% decline in lower extremity function, and 0.3% decline in cognitive function per year of age. Furthermore, participants reported a 1.6% decline in upper and lower extremity function and a 0.1% decline in cognitive function per year of disease duration. The highest PROMs correlations were noted between overall health and lower extremity function, upper extremity function, fatigue, and the ability to perform vigorous activities. Genotype-phenotype correlations revealed no significant differences except for the absence of PDB in the p.Arg159Cys group.

CONCLUSION: The VCP CoRDS Registry was found to be a valuable tool for monitoring the QOL in patients with VCP disease and capturing patient perspectives for future clinical trials.}, } @article {pmid40229540, year = {2025}, author = {Ghimire, S and Kreilaus, F and Rosa Porto, R and Anderson, LL and Yerbury, JJ and Arnold, JC and Karl, T}, title = {Behavioural effects of oral cannabidiol (CBD) treatment in the superoxide dismutase 1 G93 A (SOD1[G93 A]) mouse model of amyotrophic lateral sclerosis.}, journal = {Psychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {40229540}, issn = {1432-2072}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting voluntary muscle movement as well as cognitive and other behavioural domains at later disease stages. No effective treatment for ALS is currently available. Elevated neuroinflammation, oxidative stress and alterations to the endocannabinoid system are evident in ALS. The phytocannabinoid cannabidiol (CBD) has anti-inflammatory and anti-oxidant properties. Thus, we evaluated the remedial effects of chronic oral cannabidiol (CBD) treatment on ALS-relevant behavioural domains in the copper-zinc superoxide dismutase 1 (SOD1) mouse model of ALS that carries a G93A mutation (SOD1[G93A]).

METHODS: Male and female SOD1[G93A] and wild type-like (WT) littermates were fed either a control (CHOW) or CBD-enriched chow diet (equivalent to a dose of 36 mg/kg per day) beginning from 10 weeks of age. Bodyweight and motor performance were recorded weekly from 11 to 19 weeks and open field behaviours at 12 and 18 weeks. Mice were also tested for prepulse inhibition (PPI), social behaviours, as well as fear-associated memory.

RESULTS: CBD treatment ameliorated the bodyweight loss in female SOD1[G93A] mice, tended to reinstate sociability in SOD1[G93A] males, strengthened social recognition memory in SOD1[G93A] females, and improved the PPI response in younger SOD1[G93A] females at higher prepulse intensities. CBD had no effect on motor impairments but instead reversed the anxiolytic-like phenotype of 12-week-old male SOD1[G93A] mice and decreased the acoustic startle response and strengthened cue freezing in male mice.

CONCLUSION: Thus, the current remedial oral dose of CBD delayed disease progression (inferred by bodyweight) in both male and female mice and improve specific cognitive deficits of SOD1[G93A] mice in a sex specific manner without altering the motor phenotype.}, } @article {pmid40229296, year = {2025}, author = {Kumar, P and Bishnoi, R and Priyadarshini, P and Chhuneja, P and Singla, D}, title = {Understanding the structural basis of ALS mutations associated with resistance to sulfonylurea in wheat.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {12855}, pmid = {40229296}, issn = {2045-2322}, mesh = {*Acetolactate Synthase/genetics/chemistry/metabolism ; *Triticum/genetics/enzymology/drug effects ; *Sulfonylurea Compounds/pharmacology/chemistry ; *Herbicide Resistance/genetics ; Molecular Docking Simulation ; Herbicides/pharmacology ; *Plant Proteins/genetics/chemistry/metabolism ; Molecular Dynamics Simulation ; *Mutation ; Pyridines/pharmacology/chemistry ; }, abstract = {Developing herbicide-tolerant wheat varieties is highly desirable for effective weed management and improved crop yield. The enzyme acetolactate synthase (ALS) is the target enzyme for the sulfonylurea class of herbicides. The structural analysis of mutable sites in ALS is crucial for the generation of herbicide-resistant crops. Previous studies indicated that mutant lines of Triticum aestivum ALS (TaALS) with amino acid substitutions at P174, G631, and G632 residues provided resistance to sulfonylurea herbicide, nicosulfuron. The present study aimed to provide structural insights into mutable residues causing sulfonylurea herbicide resistance to TaALS enzyme through in-silico molecular docking and simulation approaches. The molecular docking analysis suggested a single point mutation at TaALS-P174S, its double mutant conformations (TaALS-G632S/P174S and TaALS-G631D/G632S) and associated triple mutant conformation (TaALS-G631D/G632S/P174S) to have the lowest binding affinity with nicosulfuron than the wild-type conformation of TaALS. Furthermore, the molecular dynamic simulation study confirms the weakest and more stable binding of the triple mutant conformation with nicosulfuron. Our computational study identifies a triple mutant conformation (TaALS-G631D/G632S/P174S) to be more effective in developing sulfonylurea herbicide-resistant wheat crops.}, } @article {pmid40226510, year = {2025}, author = {Ufarry Alvarado, AJ and Zaidi Pons, MA and Plaza Hernández, J and Torres Ortiz, C}, title = {Improvements of Paraquat Treatment in Liquid Media for Behavior and Neurodegenerative Tests.}, journal = {microPublication biology}, volume = {2025}, number = {}, pages = {}, pmid = {40226510}, issn = {2578-9430}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a disease characterized by misfolded and aggregated proteins that have toxic effects on motor neurons. The missense mutation, G85R, of the sod-1 gene associated with ALS displays locomotor impairments in Caenorhadbitis elegans (C. elegans). We treated the sod-1 (G85R) strain with 0 and 2.5 mM Paraquat treatments in a liquid M9 buffer for 4 hours and in solid NGM media for 18 hours. In both methodologies, the locomotion defects and neurodegeneration were significantly increased with 2.5 mM Paraquat. Our work provides evidence of methodology that is more cost effective, rapid and reproducible to perform behavior and neurodegenerative assay in worms.}, } @article {pmid40225153, year = {2023}, author = {Fiorini, MR and Dilliott, AA and Farhan, SMK}, title = {Evaluating the Utility of REVEL and CADD for Interpreting Variants in Amyotrophic Lateral Sclerosis Genes.}, journal = {Human mutation}, volume = {2023}, number = {}, pages = {8620557}, pmid = {40225153}, issn = {1098-1004}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Computational Biology/methods ; *Genetic Predisposition to Disease ; *Genetic Variation ; *Software ; Genetic Association Studies ; Mutation ; Databases, Genetic ; Genetic Testing ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease affecting approximately two per 100,000 individuals globally. While there are many benefits to offering early genetic testing to people with ALS, this has also led to an increase in the yield of novel variants of uncertain significance in ALS-associated genes. Computational (in silico) predictors, including REVEL and CADD, are widely employed to provide supporting evidence of pathogenicity for variants in conjunction with clinical, molecular, and other genetic evidence. However, in silico predictors are developed to be broadly applied across the human genome; thus, their ability to evaluate the consequences of variation in ALS-associated genes remains unclear. To resolve this ambiguity, we surveyed 20 definitive and moderate ClinGen-defined ALS-associated genes from two large, open-access ALS sequencing datasets (total people with ALS = 8,230; controls = 9,671) to investigate REVEL and CADD's ability to predict which variants are most likely to be disease-causing in ALS. While our results indicate a predetermined pathogenicity threshold for REVEL that could be of clinical value for classifying variants in ALS-associated genes, an accurate threshold was not evident for CADD, and both in silico predictors were of limited value for resolving which variants of uncertain significance (VUS) may be likely pathogenic in ALS. Our findings allow us to provide important recommendations for the use of REVEL and CADD scores for variants and indicate that both tools should be used with caution when attempting to evaluate the pathogenicity of VUSs in ALS genetic testing.}, } @article {pmid40222791, year = {2025}, author = {Bhardwaj, I and Singh, S and Ansari, AH and Rai, SP and Singh, D}, title = {Effect of stress on neuronal cell: Morphological to molecular approach.}, journal = {Progress in brain research}, volume = {291}, number = {}, pages = {469-502}, doi = {10.1016/bs.pbr.2025.01.010}, pmid = {40222791}, issn = {1875-7855}, mesh = {Humans ; Animals ; *Neurons/pathology/metabolism/physiology ; *Stress, Psychological/pathology/metabolism ; *Brain/pathology ; }, abstract = {Stress can be characterized as any perceived or actual threat that necessitates compensatory actions to maintain homeostasis. It can alter an organism's behavior over time by permanently altering the composition and functionality of brain circuitry. The amygdala and prefrontal cortex are two interrelated brain regions that have been the focus of initial research on stress and brain structural and functional plasticity, with the hippocampus serving as the entry point for most of this knowledge. Prolonged stress causes significant morphological alterations in important brain regions such as the hippocampus, amygdala, and prefrontal cortex. Memory, learning, and emotional regulation are among the cognitive functions that are adversely affected by these changes, including neuronal shrinkage, dendritic retraction, and synaptic malfunction. Stress perturbs the equilibrium of neurotransmitters, neuronal plasticity, and mitochondrial function at the molecular level. On the other hand, chronic stress negatively impacts physiology and can result in neuropsychiatric diseases. Recent molecular research has linked various epigenetic processes, such as DNA methylation, histone modifications, and noncoding RNAs, to the dysregulation of genes in the impacted brain circuits responsible for the pathophysiology of chronic stress. Numerous disorders, including neurodegenerative diseases (NDDs) including Alzheimer's, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, multiple sclerosis, and Parkinson's disease, have been linked to oxidative stress as a possible cause.}, } @article {pmid40222103, year = {2025}, author = {Lum, JS and Brown, ML and Farrawell, NE and Bartlett, R and Chisholm, CG and Gorman, J and Dosseto, A and Dux, F and McInnes, LE and Ecroyd, H and McAlary, L and Crouch, PJ and Donnelly, PS and Yerbury, JJ}, title = {A polytherapy approach demonstrates therapeutic efficacy for the treatment of SOD1 associated amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {115}, number = {}, pages = {105692}, doi = {10.1016/j.ebiom.2025.105692}, pmid = {40222103}, issn = {2352-3964}, abstract = {BACKGROUND: SOD1 mutations are a significant contributor of familial amyotrophic lateral sclerosis (ALS) cases. SOD1 mutations increase the propensity for the protein to misfold and aggregate into insoluble proteinaceous deposits within motor neurons and neighbouring cells. The small molecule, CuATSM, has repeatedly shown in mouse models to be a promising therapeutic treatment for SOD1-associated ALS and is currently in Phase II/III clinical trials for the treatment of ALS. We have previously shown CuATSM stabilises various ALS-associated variants of the SOD1 protein, reducing misfolding and toxicity. Two additional FDA-approved small molecules, ebselen and telbivudine, have also been identified to reduce mutant SOD1 toxicity, providing additional potential therapeutic candidates that could be used in combination with CuATSM. Here, we aimed to investigate if CuATSM, ebselen and telbivudine (CET) polytherapy could improve on the therapeutic efficacy of CuATSM monotherapy for the treatment of SOD1-associated ALS.

METHODS: We utilised a 3D checkerboard approach to investigate whether a matrix of different concentrations CuATSM, ebselen and telbivudine could provide therapeutic improvements on cell survival, SOD1 folding and aggregation in SOD1[G93A]-transfected NSC-34 cells, compared to CuATSM alone. To progress the preclinical development of CET polytherapy, we evaluated the bioavailability and safety of in vivo polytherapy administration. Furthermore, we assessed and compared the effects of CET- and CuATSM-treatment on disease onset, motor function, survival and neuropathological features in SOD1[G93A] mice.

FINDINGS: CET polytherapy reduced inclusion formation and increased cell survival of NSC-34 cells overexpressing SOD1[G93A] compared to higher concentrations of CuATSM monotherapy. In addition, CET administration was bioavailable and tolerable in mice. CET treatment in SOD1[G93A] mice delayed disease onset, reduced motor impairments, and increased survival compared to vehicle- and CuATSM-treated mice. In line with these findings, biochemical analysis of lumbar spinal cords showed CET administration improved SOD1 folding, decreased misfolded SOD1 accumulation, and reduced motor neuron loss.

INTERPRETATION: These findings support CET polytherapy as an advantageous alternative compared to CuATSM monotherapy and highlight the potential of utilising small molecules targeting SOD1 as a polytherapy avenue for the treatment of SOD1-associated ALS.

FUNDING: This work was supported by a FightMND Drug Development Grant, an Australian National Health and Medical Research Council (NHMRC) Investigator Grant (No. 1194872) and a Motor Neuron Disease Research Institute of Australia Bill Gole Postdoctoral Fellowship.}, } @article {pmid40222004, year = {2025}, author = {Oliveri, F and Bicaj, M and Cillerai, M and Cabona, C and Gemelli, C and Uccelli, A and Schenone, A and Ferraro, PM}, title = {Prevalence of cognitive impairment in motor neuron diseases: alternative norming methods lead to considerably diverse estimates.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/21678421.2025.2488294}, pmid = {40222004}, issn = {2167-9223}, abstract = {Objectives: Cognitive impairment (CI) is frequently observed in motor neuron diseases (MNDs), and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) represents the most widely used measure to evaluate it. For the Italian ECAS, two norming approaches are currently available: the "regression-based" (R) and the "2 standard deviation-based" (2SD). In this study, we therefore aimed at comparing those two methods for the detection of CI in MNDs. Methods: Raw ECAS scores from 160 MND patients were corrected using both the R and the 2SD methods. According to Strong's criteria, patients were then categorized as either cognitively normal (CN), with CI (ALSci), with behavioral impairment (ALSbi), or both (ALScbi). Results: Using the R approach, the frequency of below-cutoff performances was 3.12% for the ECAS total, 4.37% for the ALS specific, and 3.75% for the ALS nonspecific score. Using the 2SD method, the prevalence increased to 25.62% for the ECAS total, 21.25% for the ALS specific, and 23.12% for the ALS nonspecific score. The same increase was observed across all single tasks except for the digit span backward. The R-based frequency of Strong's diagnoses was 7.50% for ALSci, 15.62% for ALSbi, and 3.14% for ALScbi, which became 24.38% for ALSci, 8.75% for ALSbi and 10% for ALScbi with the 2SD method. Conclusions: The norming approach has a significant impact on the estimated prevalence of CI in MNDs, with the R method representing the most conservative one. These findings highlight the need for harmonized protocols in future studies evaluating CI in MNDs.}, } @article {pmid40220918, year = {2025}, author = {Key, J and Almaguer-Mederos, LE and Kandi, AR and Sen, NE and Gispert, S and Köpf, G and Meierhofer, D and Auburger, G}, title = {ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {106903}, doi = {10.1016/j.nbd.2025.106903}, pmid = {40220918}, issn = {1095-953X}, abstract = {The cytoplasmic Ataxin-2 (ATXN2) protein associates with TDP-43 in stress granules (SG) where RNA quality control occurs. Mutations in this pathway underlie Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis. In contrast, Ataxin-2-like (ATXN2L) is predominantly perinuclear, more abundant, and essential for embryonic life. Its sequestration into ATXN2 aggregates may contribute to disease. In this study, we utilized two approaches to clarify the roles of ATXN2L. First, we identified interactors through co-immunoprecipitation in both wild-type and ATXN2L-null murine embryonic fibroblasts. Second, we assessed the proteome profile effects using mass spectrometry in these cells. Additionally, we examined the accumulation of ATXN2L interactors in the SCA2 mouse model, Atxn2-CAG100-KnockIn (KIN). We observed that RNA-binding proteins, including PABPN1, NUFIP2, MCRIP2, RBMS1, LARP1, PTBP1, FMR1, RPS20, FUBP3, MBNL2, ZMAT3, SFPQ, CSDE1, HNRNPK, and HNRNPDL, exhibit a stronger association with ATXN2L compared to established interactors like ATXN2, PABPC1, LSM12, and G3BP2. Additionally, ATXN2L interacted with components of the actin complex, such as SYNE2, LMOD1, ACTA2, FYB, and GOLGA3. We noted that oxidative stress increased HNRNPK but decreased SYNE2 association, which likely reflects the relocalization of SG. Proteome profiling revealed that NUFIP2 and SYNE2 are depleted in ATXN2L-null fibroblasts. Furthermore, NUFIP2 homodimers and SYNE1 accumulate during the ATXN2 aggregation process in KIN 14-month-old spinal cord tissues. The functions of ATXN2L and its interactors are therefore critical in RNA granule trafficking and surveillance, particularly for the maintenance of differentiated neurons.}, } @article {pmid40220686, year = {2025}, author = {Coloma, L and Aramendia, J and Amigo, JM and Población, I and Alberquilla, F and Gorla, G and Huidobro, J and Torre-Fdez, I and Arana, G and Madariaga, JM}, title = {Analysis and interpretation of organic compounds in Martian meteorites with Raman imaging and chemometrics.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {338}, number = {}, pages = {126194}, doi = {10.1016/j.saa.2025.126194}, pmid = {40220686}, issn = {1873-3557}, abstract = {One of the focuses of the research being developed on Mars (and consequently in samples from Mars) is the detection and study of organic compounds. Perseverance rover, currently analysing the Martian surface, is equipped with top-level instrumentation to detect mostly organic molecules. One of the techniques being used is Raman spectroscopy, due to its capability to analyse both inorganic and organic compounds simultaneously and its non-destructive and non-invasive properties. Unfortunately, it becomes cumbersome to determine the belonging of specific Raman bands in complex mixtures composed of an undetermined number of organic and inorganic molecules. Therefore, the study of this mixed information must be carried out with dedicated Chemometrics methods in order to understand the number of compounds present in a mixture (using Principal Component Analysis - PCA) and to obtain the pure spectra and the relative intensity of each compound (using spectral unmixing methods like Multivariate Curve Resolution - MCR). This manuscript presents an analysis of specific areas from the NWA 6148 Martian Nakhlite using Raman imaging, coupled with principal component analysis (PCA) and multivariate curve resolution (MCR), to determine the spatial distribution and spectral signatures of all organic and inorganic molecules present in these areas. The proposed methodology could be applied to the laboratory study of the future Mars-returned samples and other extraterrestrial samples returned to Earth.}, } @article {pmid40219902, year = {2025}, author = {Lapp, HS and Günther, R}, title = {SOD1-ALS mimicking an inflammatory neuropathy: a case report.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2025.2488296}, pmid = {40219902}, issn = {2167-9223}, abstract = {We present the case of a 36-year-old patient with a rapidly progressing SOD1-ALS, who was initially diagnosed as inflammatory acute motor axonal neuropathy due to contrast-enhancement of the lumbar spinal cord and a pure secondary motor neuron phenotype. Since the initiation of tofersen, disease progression and neurofilament levels impressively declined.}, } @article {pmid40218232, year = {2025}, author = {Iglesias, M and Cascón, JA and Maimó, A and Albaladejo, A and Andreo, F and Fernández, AS and Palazón, MM and González-Posada, IM and García, RG and Cordovilla, R}, title = {Evaluation of Diaphragmatic Ultrasound in Respiratory Functional Assessment in Patients with ALS.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {15}, number = {7}, pages = {}, doi = {10.3390/diagnostics15070884}, pmid = {40218232}, issn = {2075-4418}, support = {becaPII2019//SOCIEDAD ESPAÑOLA DE NEUMOLOGÍA Y CIRUGÍA TORÁCICA (SEPAR)/ ; }, abstract = {Background: Diaphragmatic ultrasound emerges as a valuable non-invasive method for assessing diaphragm functionality in patients with amyotrophic lateral sclerosis (ALS). This study aimed to evaluate diaphragmatic ultrasound parameters in ALS, compare them with respiratory function tests, and determine whether they are associated with the need for non-invasive ventilation (NIV). Methods: This was a prospective, descriptive, and multicenter study across five centers, enrolling patients with recent diagnoses of ALS. At three-monthly visits, participants underwent both diaphragmatic ultrasound and pulmonary function testing. The following variables were analyzed: withdrawal from this study due to NIV or death, excursion, velocity, thickness, thickening fraction, and spirometric and respiratory muscle function values. Results: A total of 41 patients were included. A total of 24 (61.5%) patients left this study before the final year: 17 due to initiation of NIV, 4 due to clinical deterioration without NIV, and 3 due to death. Statistically significant moderate correlations were observed between diaphragmatic excursion and velocity and FVC and supine FVC (p < 0.001) and with MIP and the SNIP test (p < 0.05). No correlation was observed with thickening fraction. Additionally, lower baseline values in excursion were significantly associated with study withdrawal, along with reduced lung function (FVC, supine FVC, and MEP (p < 0.001). Conclusions: assessing diaphragmatic excursion by ultrasonography may serve as a useful tool for monitoring patients with ALS.}, } @article {pmid40217081, year = {2025}, author = {Baek, SH and Tae, WS and Auer, D and Kim, BJ}, title = {Brain diffusion tensor imaging changes linked to the split hand phenomenon in amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {12450}, pmid = {40217081}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/pathology ; Male ; *Diffusion Tensor Imaging/methods ; Female ; Aged ; Middle Aged ; *Brain/diagnostic imaging/pathology/physiopathology ; Pyramidal Tracts/diagnostic imaging/pathology/physiopathology ; Anisotropy ; White Matter/diagnostic imaging/pathology ; }, abstract = {The split-hand phenomenon is an early and specific feature of amyotrophic lateral sclerosis (ALS). This study aimed to investigate whether the split-hand phenomenon in ALS is associated with the white matter degeneration of the brain. Patients diagnosed with clinically definite or probable ALS were prospectively recruited and underwent both nerve conduction studies to assess the split-hand index (SHI) and brain diffusion tensor imaging (DTI). Demographic, clinical, and electrophysiological data were all collected. A total of 35 patients with ALS (18 male; median age, 66.0 years) were enrolled in this study. The axial diffusivity (AD) and mode of anisotropy (MO) values of DTI in the corticospinal tract (CST) positively correlated with the SHI. However, there were no significant correlations between the SHI and the fraction anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) scalars. In addition, patients having ALS with bilateral split-hand phenomenon showed reduced AD values in the left CST and reduced MO values in the bilateral CST compared with those without the split-hand phenomenon. However, there were no significant differences in FA, MD, and RD scalars. Our findings suggest that the split-hand phenomenon is associated with degenerative brain changes, particularly in the CST.}, } @article {pmid40216746, year = {2025}, author = {Rezaei, A and Kocsis-Jutka, V and Gunes, ZI and Zeng, Q and Kislinger, G and Bauernschmitt, F and Isilgan, HB and Parisi, LR and Kaya, T and Franzenburg, S and Koppenbrink, J and Knogler, J and Arzberger, T and Farny, D and Nuscher, B and Katona, E and Dhingra, A and Yang, C and Gouna, G and LaClair, KD and Janjic, A and Enard, W and Zhou, Q and Hagan, N and Ofengeim, D and Beltrán, E and Gokce, O and Simons, M and Liebscher, S and Edbauer, D}, title = {Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {3442}, pmid = {40216746}, issn = {2041-1723}, support = {390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 407495230//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 423957469//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 101057649//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; 101117710//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; }, mesh = {Animals ; Female ; Mice ; *Oligodendroglia/metabolism/drug effects ; *Lipid Metabolism/drug effects/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/drug therapy/pathology ; *C9orf72 Protein/genetics/metabolism ; Disease Models, Animal ; Male ; Cholesterol/metabolism ; Humans ; *2-Hydroxypropyl-beta-cyclodextrin/pharmacology ; Mice, Transgenic ; Myelin Sheath/metabolism ; Spinal Cord/metabolism/pathology ; Longevity/drug effects/genetics ; }, abstract = {Clinical and genetic research links altered cholesterol metabolism with ALS development and progression, yet pinpointing specific pathomechanisms remain challenging. We investigated how cholesterol dysmetabolism interacts with protein aggregation, demyelination, and neuronal loss in ALS. Bulk RNAseq transcriptomics showed decreased cholesterol biosynthesis and increased cholesterol export in ALS mouse models (GA-Nes, GA-Camk2a GA-CFP, rNLS8) and patient samples (spinal cord), suggesting an adaptive response to cholesterol overload. Consequently, we assessed the efficacy of the cholesterol-binding drug 2-hydroxypropyl-β-cyclodextrin (CD) in a fast-progressing C9orf72 ALS mouse model with extensive poly-GA expression and myelination deficits. CD treatment normalized cholesteryl ester levels, lowered neurofilament light chain levels, and prolonged lifespan in female but not male GA-Nes mice, without impacting poly-GA aggregates. Single nucleus transcriptomics indicated that CD primarily affected oligodendrocytes, significantly restored myelin gene expression, increased density of myelinated axons, inhibited the disease-associated oligodendrocyte response, and downregulated the lipid-associated genes Plin4 and ApoD. These results suggest that reducing excess free cholesterol in the CNS could be a viable ALS treatment strategy.}, } @article {pmid40216201, year = {2025}, author = {Cagalinec, M and Adnan, M and Borecka, S and Bultynck, G and Choubey, V and Yanovsky-Dagan, S and Ezer, S and Gasperikova, D and Harel, T and Jurkovicova, D and Kaasik, A and Liévens, JC and Maurice, T and Peviani, M and Richard, EM and Skoda, J and Skopkova, M and Tarot, P and Van Gorp, R and Zvejniece, L and Delprat, B}, title = {Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer.}, journal = {Biochimica et biophysica acta. Molecular cell research}, volume = {}, number = {}, pages = {119954}, doi = {10.1016/j.bbamcr.2025.119954}, pmid = {40216201}, issn = {1879-2596}, abstract = {Membrane contact sites harbor a distinct set of proteins with varying biological functions, thereby emerging as hubs for localized signaling nanodomains underlying adequate cell function. Here, we will focus on mitochondria-associated endoplasmic reticulum membranes (MAMs), which serve as hotspots for Ca[2+] signaling, redox regulation, lipid exchange, mitochondrial quality and unfolded protein response pathway. A network of MAM-resident proteins contributes to the structural integrity and adequate function of MAMs. Beyond endoplasmic reticulum (ER)-mitochondrial tethering proteins, MAMs contain several multi-protein complexes that mediate the transfer of or are influenced by Ca[2+], reactive oxygen species and lipids. Particularly, IP3 receptors, intracellular Ca[2+]-release channels, and Sigma-1 receptors (S1Rs), ligand-operated chaperones, serve as important platforms that recruit different accessory proteins and intersect with these local signaling processes. Furthermore, many of these proteins are directly implicated in pathophysiological conditions, where their dysregulation or mutation is not only causing diseases such as cancer and neurodegeneration, but also rare genetic diseases, for example familial Parkinson's disease (PINK1, Parkin, DJ-1), familial Amyotrophic lateral sclerosis (TDP43), Wolfram syndrome1/2 (WFS1 and CISD2), Harel-Yoon syndrome (ATAD3A). In this review, we will discuss the current state-of-the-art regarding the molecular components, protein platforms and signaling networks underlying MAM integrity and function in cell function and how their dysregulation impacts MAMs, thereby driving pathogenesis and/or impacting disease burden. We will highlight how these insights can generate novel, potentially therapeutically relevant, strategies to tackle disease outcomes by improving the integrity of MAMs and the signaling processes occurring at these membrane contact sites.}, } @article {pmid40215589, year = {2025}, author = {Yaguchi, H and Miyagawa, S and Nakada, R and Yamamoto, S and Sakuta, K}, title = {Speech-swallow dissociation in velopharyngeal closure for differentiating amyotrophic lateral sclerosis and myasthenia gravis.}, journal = {Auris, nasus, larynx}, volume = {52}, number = {3}, pages = {239-242}, doi = {10.1016/j.anl.2025.03.003}, pmid = {40215589}, issn = {1879-1476}, abstract = {OBJECTIVE: Speech-swallow dissociation (SSD) in velopharyngeal closure on laryngoscopy is a sign of pseudobulbar palsy. We hypothesized that this finding could differentiate amyotrophic lateral sclerosis (ALS) from myasthenia gravis (MG). This study aimed to identify laryngoscopic findings useful in differentiating these two diseases.

METHODS: ALS and MG patients with bulbar symptoms who underwent fiberoptic laryngoscopy in our hospital were retrospectively examined. The following laryngoscopic items were evaluated: velopharyngeal incompetence (VPI) in phonation and swallowing, pharyngeal constriction, vocal cord movement, and salivary status.

RESULTS: One hundred seven patients (70 with ALS and 37 with MG) were included for analysis. The prevalence of VPI in phonation was significantly higher in the ALS group (40 % vs. 19 %; P = 0.027). The prevalence of SSD in velopharyngeal closure was also significantly higher in the ALS group (33 % vs. 3 %; P < 0.001). The other laryngoscopic findings did not differ between the groups. Multivariate logistic regression showed that SSD in velopharyngeal closure was independently associated with ALS (odds ratio, 26.64; 95 % confidence interval, 2.24-317.58; P = 0.009).

CONCLUSION: SSD in velopharyngeal closure is useful for differentiating ALS from MG.}, } @article {pmid40214652, year = {2025}, author = {Yu, G and Liu, X and Huang, W and Wang, S and Zhan, J and Ma, L and Li, H and Lin, X and Liu, T and Amine, K and Li, H}, title = {Ferromagnetic Atomic d-p Orbital Hybridization for Promoting Al-S Batteries.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {}, number = {}, pages = {e2418784}, doi = {10.1002/adma.202418784}, pmid = {40214652}, issn = {1521-4095}, support = {tsqn202211118//Taishan Scholar Program of Shandong Province/ ; ZR2023YQ008//Excellent Youth Science Fund Project of Shandong China/ ; 2021KJ020//Outstanding Youth Innovation Team of Universities in Shandong Province/ ; 51804173//National Natural Science Foundation (NSFC) of China/ ; DE-SC0012704//Brookhaven National Laboratory under contract/ ; }, abstract = {Rechargeable aluminum-sulfur batteries (Al-S) are emerging as a promising alternative energy storage system beyond lithium-ion batteries due to their high energy density, abundant material resources, and economic efficiency. However, their practical application remains challenged by sluggish conversion kinetics, polysulfide shuttling, and low sulfur cathode utilization. While extensive studies have focused on enhancing polysulfide adsorption through catalytic strategies, the roles of electronic structure in dictating catalytic performance remain underexplored. Here, this work unveils the critical effect of unpaired electronic structure on the catalytic performance of single atom ferromagnetic transition metals through a systematic evaluation of three typical atomically dispersed ferromagnetic single atoms-Fe, Co, and Ni-supported on porous carbon (denoted as PC-SAFAs). Comprehensive characterizations and density functional theory (DFT) calculations reveal that the PC-SAFe catalysts, exhibiting the highest spin polarization arising from unpaired electrons, demonstrate the strongest interactions with polysulfide, thereby facilitating rapid and reversible polysulfide conversion reactions. Consequently, Al-S batteries incorporating the optimized PC-SAFe cathode achieve an impressive specific capacity of 508.8 mAh g[-1] at 1.0 A g[-1] after 500 cycles, along with much improved rate capability. This work provides a deeper understanding of the role of electronic structure in catalytic chemistry, and offers new insights for developing high-performance Al-S batteries.}, } @article {pmid40214138, year = {2025}, author = {Reus, LM and Willemse, SW and de Boer, SCM and De Houwer, J and Hartog, WL and Mol, MO and van Rooij, JGJ and Tesi, N and Donker Kaat, L and Hulsman, M and Vijverberg, EGB and Holstege, H and van Rheenen, W and Veldink, JH and van den Berg, LH and van Swieten, JC and Seelaar, H and van der Lee, SJ and van Es, MA and Pijnenburg, YAL}, title = {UNC13A Polymorphism Influences Survival in Patients with Frontotemporal Dementia.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27245}, pmid = {40214138}, issn = {1531-8249}, abstract = {UNC13A (rs12608932-CC) is associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and shortens survival in ALS. We aim to describe the association for UNC13A and survival in FTD. We included 626 patients with FTD from Dutch memory clinics, including a subcohort of 150 patients with TDP-43 pathology. Survival analyses were performed using Cox proportional hazard models in a recessive manner. Homozygosity for rs12608932-C in UNC13A was associated with a shorter survival compared with other genotypes (hazard ratio [HR] = 1.28, 95% confidence interval [CI] = 1.02-1.60, p = 0.033), which has implications for patient counselling and trial design. ANN NEUROL 2025.}, } @article {pmid40213728, year = {2025}, author = {Grigore, A and Goebel, LJ}, title = {Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: A Case Report and Clinical Insights.}, journal = {Cureus}, volume = {17}, number = {3}, pages = {e80329}, pmid = {40213728}, issn = {2168-8184}, abstract = {Primary care providers are often the first contact for patients with neurodegenerative illnesses, however, they may not be aware of the relationship of certain diseases that may have an impact on their patients' longevity. This case report reminds clinicians of the association between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Physicians should be aware of the association, because FTD commonly occurs first and may prepare clinicians to be alert to the signs of ALS in these patients, leading to earlier detection of ALS and the prescription of disease-modifying medication that may extend the lifespan of people with these diseases. We describe the case of a 61-year-old female patient initially presenting with cognitive decline most likely due to FTD who subsequently developed ALS.}, } @article {pmid40213632, year = {2025}, author = {Dezawa, M}, title = {Macrophage- and pluripotent-like reparative Muse cells are unique endogenous stem cells distinct from other somatic stem cells.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {13}, number = {}, pages = {1553382}, pmid = {40213632}, issn = {2296-4185}, abstract = {Muse cells are endogenous reparative stem cells with dual characteristics: pluripotent-like and macrophage-like. They can be identified by the pluripotent surface marker stage-specific embryonic antigen-3-positive (SSEA-3 (+)) cells in the bone marrow, peripheral blood, and various organs, including the umbilical cord and amnion. Muse cells can differentiate into ectodermal, endodermal, and mesodermal lineage cells, self-renew, and selectively migrate to damaged sites by sensing one of the universal tissue damage signals, sphingosine-1-phosphate (S1P). At these sites, they phagocytose damaged/apoptotic cells and differentiate into the same cell type as the phagocytosed cells. In this manner, Muse cells replace damaged/apoptotic cells with healthy, functioning cells, thereby repairing tissues. Due to their specific immunosuppressive and immunotolerant mechanism, clinical trials have been conducted for acute myocardial infarction (AMI), subacute ischemic stroke, epidermolysis bullosa, amyotrophic lateral sclerosis (ALS), cervical spinal cord injury, neonatal hypoxic-ischemic encephalopathy (HIE), and COVID-19 acute respiratory distress syndrome. These trials involved the intravenous injection of ∼1.5 × 10[7] donor Muse cells without human leukocyte antigen (HLA) matching or immunosuppressant treatment, and they demonstrated safety and therapeutic efficacy. Thus, donor Muse cell treatment does not require gene manipulation, differentiation induction, or surgical intervention. These unique characteristics distinguish Muse cells from other somatic stem cells, such as mesenchymal stem cells, VSEL stem cells, and marrow-isolated adult multi-lineage inducible (MIAMI) cells.}, } @article {pmid40212206, year = {2025}, author = {Basnet, P and Singh, PR and Pudasaini, KR and Shrestha, S and Kc, A}, title = {A rare case of symmetric quadriplegia in a patient with Japanese encephalitis: a case report.}, journal = {Annals of medicine and surgery (2012)}, volume = {87}, number = {4}, pages = {2430-2433}, pmid = {40212206}, issn = {2049-0801}, abstract = {INTRODUCTION AND IMPORTANCE: Acute flaccid paralysis is a rare neurological complication of Japanese encephalitis (JE) infection, which may involve one or multiple limbs. Symmetric involvement of upper and lower limbs such as in this case is rarely reported.

PRESENTATION OF CASE: We present a case of a 30-year-old male from Terai region of Nepal who presented with fever, altered level of consciousness, and symmetrical quadriplegia. Based on these clinical findings, cerebrospinal fluid (CSF) analysis was done which came back negative. And based on results, polymerase chain reaction for herpes simplex virus types I and II was done which came out negative. Other neurological conditions such as amyotrophic lateral sclerosis and spinal dystrophy were ruled out because of the presence of fever and altered mental status. He was eventually diagnosed with JE based on his CSF analysis and positive result for JE serology/IgM Antibody Capture Enzyme-Linked Immunosorbent Assay test.

CLINICAL DISCUSSION: The patient presented with fever, altered mental status, and symmetrical flaccid paralysis of the bilateral upper and lower limb. Symmetrical involvement of the upper and the lower limbs is unusual in most cases of JE.

CONCLUSION: This case highlights the importance of awareness on the part of the clinician about the possibilities of atypical presentation in JE. It also emphasizes that Japanese encephalitis should be a part of the differential in patients with atypical neurological presentation in endemic areas.}, } @article {pmid40212027, year = {2025}, author = {Menezes, AT and Nagasse, HY and Lopes, HRM and Coltri, PP}, title = {Design of a GFP reporter for splicing analysis in mammalian cells.}, journal = {Biotechnology reports (Amsterdam, Netherlands)}, volume = {46}, number = {}, pages = {e00887}, pmid = {40212027}, issn = {2215-017X}, abstract = {Eukaryotic genes are formed by exons and introns. Pre-mRNA splicing promotes exon ligation and intron removal and is performed by a specialized macromolecular machinery named spliceosome, composed of five small ribonucleoprotein particles (snRNPs) and more than one hundred proteins. The activity of this complex is highly accurate due to the coordinated activity of its components. Altered splicing has been related to the development of several diseases, including neurodegenerative disorders, such as amyotrophic lateral sclerosis, and different types of cancer. Detailed understanding of splicing regulation in eukaryotic cells can be achieved using splicing reporter systems. We designed a reporter plasmid suitable for splicing analysis in cultured mammalian cells. Our reporter is based on GFP expression, and the splicing outcome can be easily visualized by fluorescence microscopy. We quantified splicing activity in two human cell lines, HEK-293T and MDA-MB-231, confirming its suitability for use in live cells in culture.}, } @article {pmid40139318, year = {2025}, author = {Lai, IC and Wei, JC}, title = {Comment on Vera et al's "Interleukin-23 inhibition associates with lower incidence of cardiovascular risk factor type diseases compared to biologic naïve patients with psoriasis: A retrospective cohort study.".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.12.054}, pmid = {40139318}, issn = {1097-6787}, } @article {pmid40210846, year = {2025}, author = {Joyce, EE and Yin, W and Löf, M and Wirdefeldt, K and Sandin, S and Fang, F}, title = {Mediterranean dietary pattern and risk of neurodegenerative diseases in a cohort of Swedish women.}, journal = {NPJ Parkinson's disease}, volume = {11}, number = {1}, pages = {71}, pmid = {40210846}, issn = {2373-8057}, support = {802091/ERC_/European Research Council/International ; R01TS000324-01-00/CC/CDC HHS/United States ; 2019-01088//Vetenskapsrådet/ ; }, abstract = {Mediterranean dietary patterns (MDP) may be neuroprotective. Using a large population-based cohort of 42,582 Swedish women, this study examined the association between MDP adherence and the risk of Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). During 1991-1992, women in the Women's Lifestyle and Health Study reported dietary intake, and MDP adherence was calculated. Incident neurodegenerative diseases were identified using the Swedish National Patient Register through 2022. Women who reported high MDP adherence had a lower risk of PD (HR: 0.69, 95% CI: 0.49-0.95), primarily over age 60 (HR: 0.68, 95% CI: 0.47-0.97). A moderate-high MDP adherence was associated with a lower risk of ALS before age 60 (HR: 0.44, 95% CI: 0.19-0.99), but not overall. We observed no association between MDP adherence and AD. Our findings suggest higher adherence to a MDP may be protective against PD above age 60, and ALS before age 60.}, } @article {pmid40210682, year = {2025}, author = {Perciballi, E and Bovio, F and Ferro, S and Forcella, M and Rosati, J and Carletti, RM and D'Anzi, A and Gelati, M and La Bella, V and Innocenti, M and Spataro, R and Pecoraro, M and Lombardi, I and Vulcano, E and Ruotolo, G and Mercurio, S and Sabatelli, M and Lattante, S and Malm, T and Ohtonen, S and Vescovi, AL and Fusi, P and Ferrari, D}, title = {Mitochondrial and energy metabolism dysfunctions are hallmarks of TDP-43[G376D] fibroblasts from members of an Amyotrophic Lateral Sclerosis family.}, journal = {Cell death & disease}, volume = {16}, number = {1}, pages = {272}, pmid = {40210682}, issn = {2041-4889}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Fibroblasts/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; *Mitochondria/metabolism/pathology/genetics ; *Energy Metabolism/genetics ; Male ; Female ; Middle Aged ; Mutation/genetics ; Glycolysis ; Pedigree ; Adult ; Cell Proliferation ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease, causing degeneration of motor neurons, paralysis, and death. About 5-10% of cases are associated with gene mutations inherited from a family member (fALS). Among them, mutations in the transactive-response (TAR)-DNA-binding protein (TARDBP), which encodes for the TAR DNA binding protein 43 (TDP-43) are responsible for 4-5% of fALS but the molecular mechanisms that initiate and sustain the neurodegenerative process are largely unknown. Metabolic impairments might be involved in the pathogenesis of ALS and are currently under investigation. In order to correlate biochemical and metabolic alterations with disease progression, here, we established the metabolic fingerprint of dermal fibroblasts derived from symptomatic and asymptomatic members of a family with fALS cases carrying to the p.G376D mutation in TDP-43. We found that increased proliferation, unbalanced oxidative homeostasis and higher ATP production rate coupled with enhanced metabolic activity are underlying traits of this family. Fibroblasts from carrier individuals deploy several mechanisms to increase mitochondrial respiration to meet increasing energy demands. This is accompanied by an upregulation of glycolysis corresponding to a metabolic reprograming towards a glycolytic phenotype for ATP production during ALS progression, particularly in late disease stages. In summary, we uncover alterations in energy metabolism in TDP43[G376D] patient-derived primary fibroblasts that may be used as risk biomarkers and/or to monitor ALS progression.}, } @article {pmid40209696, year = {2025}, author = {Hawas, Y and Hamad, AA and Meshref, M and Elbehary, M and Mohamed, RG and Elshahat, A and Mabrouk, MA and Nashwan, AJ and Fouda, BH}, title = {Clinical Features, Diagnostic Implications, And Outcomes of Amyotrophic Lateral Sclerosis and Myasthenia Gravis Overlap Syndrome: A Systematic Review.}, journal = {Medical principles and practice : international journal of the Kuwait University, Health Science Centre}, volume = {}, number = {}, pages = {1-18}, doi = {10.1159/000545806}, pmid = {40209696}, issn = {1423-0151}, abstract = {OBJECTIVE: This review aims to summarize the current evidence of reported myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) overlap syndrome regarding clinical and laboratory features, diagnostic implications, management, outcomes, and comorbid conditions to raise awareness among healthcare providers and aid in proper care provision.

METHODS: Recently, a few cases of an unusual association between both diseases have been reported. PubMed, Scopus, and Web of Science were searched from inception until May 2024 to identify eligible studies. After the screening and data extraction, 20 studies with 42 cases suffering from ALS and MG were included.

RESULTS: 42 cases were categorized into four groups as follows: The first group had 26 cases with MG onset (range 26-82 years) preceding ALS (range 46-83 years). The second group had 9 cases with ALS (range 34-89) preceding MG (range 40-89 years). The third group comprised 5 cases of ALS with positive acetylcholine receptor antibodies but without clinical manifestations of MG. The fourth group involved 2 cases of ALS with initial ocular symptoms that were unresponsive to MG treatments.

CONCLUSION: The onset of new ptosis or diplopia in ALS patients should prompt clinicians to consider the possibility of a coexisting condition or alternative diagnosis. Additionally, positive acetylcholine receptor antibodies alone are insufficient to diagnose MG if ALS coexists. In patients with ALS, repetitive nerve stimulation tests may be less sensitive for detecting MG. Thus, diagnosing MG in ALS patients should rely on clinical presentation and response to empirical treatment.}, } @article {pmid40209306, year = {2025}, author = {Meanti, R and Bresciani, E and Rizzi, L and Molteni, L and Coco, S and Omeljaniuk, RJ and Torsello, A}, title = {Cannabinoid Receptor 2 (CB2R) as potential target for the pharmacological treatment of neurodegenerative diseases.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {186}, number = {}, pages = {118044}, doi = {10.1016/j.biopha.2025.118044}, pmid = {40209306}, issn = {1950-6007}, abstract = {The endocannabinoid system (ECS) is a ubiquitous physiological system that plays a crucial role in maintaining CNS homeostasis and regulating its functions. It includes cannabinoid receptors (CBRs), endogenous cannabinoids (eCBs), and the enzymes responsible for their synthesis and degradation. In recent years, growing evidence has highlighted the therapeutic potential of the ECS and CBRs, in a wide range of severe diseases and pathological conditions, including Alzheimer's and Parkinson's diseases, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Huntington's Disease, HIV-1 associated neurocognitive disorders, neuropathic pain and migraine. Targeting the cannabinoid type 2 receptor (CB2R) has gained attention due to its ability to (i) mitigate neuroinflammatory responses, (ii) regulate mitochondrial function and (iii) provide trophic support, all without eliciting the psychotropic actions associated with CB1R activation. This review aims to explore the potential of CB2R modulation as a strategy for the prevention and treatment of neurologic disorders, exploring both preclinical and clinical findings.}, } @article {pmid40207633, year = {2025}, author = {Luteijn, MJ and Bhaskar, V and Trojer, D and Schürz, M and Mahboubi, H and Handl, C and Pizzato, N and Pfeifer, M and Dafinca, R and Voshol, H and Giorgetti, E and Manneville, C and Garnier, IPM and Müller, M and Zeng, F and Buntin, K and Markwalder, R and Schröder, H and Weiler, J and Khar, D and Schuhmann, T and Groot-Kormelink, PJ and Keller, CG and Farmer, P and MacKay, A and Beibel, M and Roma, G and D'Ario, G and Merkl, C and Schebesta, M and Hild, M and Elwood, F and Vahsen, BF and Ripin, N and Clery, A and Allain, F and Labow, M and Gabriel, D and Chao, JA and Talbot, K and Nash, M and Hunziker, J and Meisner-Kober, NC}, title = {High-throughput screen of 100 000 small molecules in C9ORF72 ALS neurons identifies spliceosome modulators that mobilize G4C2 repeat RNA into nuclear export and repeat associated non-canonical translation.}, journal = {Nucleic acids research}, volume = {53}, number = {7}, pages = {}, doi = {10.1093/nar/gkaf253}, pmid = {40207633}, issn = {1362-4962}, support = {EFRE/IWB 20102-F1900731-KZP//European Funds for Regional Development/ ; WISS2025 F2200397-KZP//Salzburger Landesregierung/ ; }, mesh = {Humans ; *Spliceosomes/drug effects/metabolism/genetics ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Protein Biosynthesis/drug effects ; Active Transport, Cell Nucleus/drug effects ; Serine-Arginine Splicing Factors/metabolism ; *Neurons/metabolism/drug effects ; High-Throughput Screening Assays ; *Small Molecule Libraries/pharmacology ; DNA Repeat Expansion ; RNA/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Cell Nucleus/metabolism ; }, abstract = {An intronic G4C2 repeat expansion in the C9ORF72 gene is the major known cause for Amyotrophic Lateral Sclerosis (ALS), with current evidence for both, loss of function and pathological gain of function disease mechanisms. We screened 96 200 small molecules in C9ORF72 patient iPS neurons for modulation of nuclear G4C2 RNA foci and identified 82 validated hits, including the Brd4 inhibitor JQ1 as well as novel analogs of Spliceostatin-A, a known modulator of SF3B1, the branch point binding protein of the U2-snRNP. Spliceosome modulation by these SF3B1 targeted compounds recruits SRSF1 to nuclear G4C2 RNA, mobilizing it from RNA foci into nucleocytoplasmic export. This leads to increased repeat-associated non-canonical (RAN) translation and ultimately, enhanced cell toxicity. Our data (i) provide a new pharmacological entry point with novel as well as known, publicly available tool compounds for dissection of C9ORF72 pathobiology in C9ORF72 ALS models, (ii) allowing to differentially modulate RNA foci versus RAN translation, and (iii) suggest that therapeutic RNA foci elimination strategies warrant caution due to a potential storage function, counteracting translation into toxic dipeptide repeat polyproteins. Instead, our data support modulation of nuclear export via SRSF1 or SR protein kinases as possible targets for future pharmacological drug discovery.}, } @article {pmid40205152, year = {2025}, author = {Mohan, M and Mannan, A and Singh, TG}, title = {Unravelling the role of protein kinase R (PKR) in neurodegenerative disease: a review.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {377}, pmid = {40205152}, issn = {1573-4978}, mesh = {Humans ; *eIF-2 Kinase/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics ; Animals ; Parkinson Disease/metabolism/genetics ; Huntington Disease/genetics/metabolism ; Alzheimer Disease/metabolism/genetics ; Mitochondria/metabolism ; }, abstract = {Protein Kinase R is an essential regulator of many cell activities and belongs to one of the largest and most functionally complex gene families. These are found all over the body, and by adding phosphate groups to the substrate proteins, they regulate their activity and coordinate the action of almost all cellular processes. Recent research has illuminated the involvement of PKR in the pathogenesis of neurodegenerative disorders (NDs), thereby expanding our understanding of intricate molecular mechanisms underlying disease progression. Through their inhibition or activation, they hold potential therapeutic targets for the pathogenesis or protection of NDs. In the case of AD (AD), PKR contributes to the protection or elevation of Aβ accumulation, neuroinflammation, synaptic plasticity alterations, and neuronal excitability. Similarly, in Parkinson's disease (PD), PKR again has a dual role in dopaminergic neuronal loss, gene mutations, and mitochondrial dysfunction via various pathways. Notably, neuronal excitotoxicity, as well as genetic mutations, have been linked to ALS. In Huntington's disease (HD), PKR is associated with decreased or increased mutated genes, striatal neuron degeneration, neuroinflammation, and excitotoxicity. This review emphasizes strategies that target PKR for the treatment of neurodegenerative disorders. Doing so offers valuable insights that can guide future research endeavors and the development of innovative therapeutic approaches.}, } @article {pmid40204975, year = {2025}, author = {Wolmer, PS and de Borba, FC and de Rezende, TJR and González-Salazar, C and Pedroso, JL and Barsottini, OGP and Kleinerova, J and Bede, P and Marques, W and França, MC}, title = {Distinct patterns of cerebral and spinal pathology along the spectrum of ATXN2-related disorders.}, journal = {Journal of neurology}, volume = {272}, number = {5}, pages = {330}, pmid = {40204975}, issn = {1432-1459}, support = {2013/07559-3//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; }, mesh = {Humans ; Male ; *Ataxin-2/genetics ; Female ; Middle Aged ; *Spinocerebellar Ataxias/pathology/genetics/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/pathology/genetics/diagnostic imaging ; Adult ; Magnetic Resonance Imaging ; Aged ; *Spinal Cord/pathology/diagnostic imaging ; *Brain/pathology/diagnostic imaging ; Neuroimaging ; }, abstract = {BACKGROUND: The ATXN2 gene contains a polymorphic CAG-rich region encoding a polyglutamine tract in ataxin- 2. Normal alleles have fewer than 27 CAG repeats, 27-34 repeats pose a risk for ALS (ATXN2-ALS), and > 34 repeats cause spinocerebellar ataxia type 2 (SCA2). The striking phenotypic differences between these two ATXN2-related conditions are not yet fully understood.

OBJECTIVE: To characterize and compare the distinguishing radiological signatures of ATXN2-ALS, SCA2, sporadic ALS (sALS) and healthy controls in vivo using quantitative computational neuroimaging techniques.

METHODS: Four groups were defined: healthy controls (n = 34), sALS (n = 17), ATXN2-ALS (n = 16), and SCA2 (n = 17). Cortical, subcortical, brainstem, cerebellar and spinal regions were segmented based on T1-weighted data using validated segmentation tools and their volumes estimated. Group-specific morphometric data were correlated with cerebral ATXN2 expression maps from the Allen Human Brain Atlas.

RESULTS: Study groups were age and sex-matched. sALS, ATXN2-ALS and SCA2 have distinct structural CNS signatures, with disease burden restricted to the precentral gyri in the sALS group, to the spinal cord and brainstem in the ATXN2-ALS group and more diffusely distributed in the subcortical structures in the SCA2 group. Brain ATXN2 expression correlated with the structural signature of SCA2, but not with that of ATXN2-ALS.

CONCLUSIONS: Neuroimaging signatures differ in ATXN2-ALS and SCA2, indicating distinct mechanisms of ATXN2-mediated neurodegeneration. sALS and ATXN2-ALS also exhibit distinct patterns of CNS involvement. The unique imaging signatures and clinical profiles along the spectrum of ATXN2-related disorders raise important questions regarding the pathophysiology of the disease and have practical clinical ramifications.}, } @article {pmid40204667, year = {2025}, author = {Parajuli, S and McDonald, MR and Adhikari, L and Wolyn, DJ}, title = {Genetic architecture of anthocyanin pigment traits and purple spot (Stemphylium vesicarium) resistance in an F1 pseudo-testcross population of asparagus.}, journal = {The plant genome}, volume = {18}, number = {2}, pages = {e70028}, doi = {10.1002/tpg2.70028}, pmid = {40204667}, issn = {1940-3372}, support = {ASC-18/19//Canadian Agri-Science Cluster for Horticulture 3/ ; //Asparagus Farmers of Ontario/ ; //Agriculture and Agri-Food Canada/ ; UofGT2-2019-27360//Ontario Ministry of Agriculture Food and Rural Affairs/ ; }, mesh = {*Anthocyanins/genetics/metabolism ; Quantitative Trait Loci ; *Plant Diseases/microbiology/genetics ; *Disease Resistance/genetics ; *Asparagus Plant/genetics/microbiology/metabolism ; *Ascomycota/pathogenicity/physiology ; Phenotype ; Crosses, Genetic ; Plant Leaves/genetics/microbiology ; }, abstract = {Stemphylium vesicarium (Wallr.) Simmons is a plant pathogenic fungus causing purple spot in both fern and spears of asparagus (Asparagus officinalis L.). Although the fern can be sprayed with fungicides to control the disease, pesticide applications during spear harvest are restricted. Infected spears can develop prominent pigmentation at lesion sites, reducing marketable yield. Breeding resistant asparagus cultivars with decreased lesion numbers and reduced purpling at the site of infection is considered the most economical and sustainable approach to combat this disease. The objectives of this study were to determine the genetic architectures of, and relationships among, anthocyanin pigment expression in spear scale leaves (ALS) and spear lesions (APS) and purple spot levels in spears (NPS) and fern (PSF). Traits were phenotyped over 2 years under natural conditions in an F1 pseudo-testcross population, and quantitative trait loci (QTL) were mapped. ALS, APS, NPS, and PSF were not correlated, suggesting independent regulation of the anthocyanin pathway in scale leaves and lesions and no relationship between pigment and disease. Segregation, 3 red:1 purple and 3 red:13 purple, was observed in scale leaves and lesions, respectively. Two stable QTL for each of ASL, APS, and NPS, one tentative QTL for ASL, four tentative QTL for APS, two tentative QTL for NPS, and three tentative QTL for PSF were identified. Candidate genes were found for four loci. This study advances the genetic understanding of anthocyanin pigmentation at a tissue-specific level, and purple spot disease severity in spears and fern, supporting future breeding efforts.}, } @article {pmid40203833, year = {2025}, author = {Shen, D and Vincent, A and Udine, E and Buhidma, Y and Anoar, S and Tsintzas, E and Maeland, M and Xu, D and Carcolé, M and Osumi-Sutherland, D and Aleyakpo, B and Hull, A and Martínez Corrales, G and Woodling, N and Rademakers, R and Isaacs, AM and Frigerio, C and van Blitterswijk, M and Lashley, T and Niccoli, T}, title = {Differential neuronal vulnerability to C9orf72 repeat expansion driven by Xbp1-induced endoplasmic reticulum-associated degradation.}, journal = {Cell reports}, volume = {}, number = {}, pages = {115459}, doi = {10.1016/j.celrep.2025.115459}, pmid = {40203833}, issn = {2211-1247}, abstract = {Neurodegenerative diseases are characterized by the localized loss of neurons. Why cell death is triggered only in specific neuronal populations and whether it is the response to toxic insults or the initial cellular state that determines their vulnerability is unknown. To understand individual cell responses to disease, we profiled their transcriptional signatures throughout disease development in a Drosophila model of C9orf72 (G4C2) repeat expansion (C9), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. We identified neuronal populations specifically vulnerable or resistant to C9 expression and found an upregulation of protein homeostasis pathways in resistant neurons at baseline. Overexpression of Xbp1s, a key regulator of the unfolded protein response and a central node in the resistance network, rescues C9 toxicity. This study shows that neuronal vulnerability depends on the intrinsic transcriptional state of neurons and that leveraging resistant neurons' properties can boost resistance in vulnerable neurons.}, } @article {pmid40203806, year = {2025}, author = {Johnson, AM and Lukens, JR}, title = {Glia get RIPped in ALS.}, journal = {Immunity}, volume = {58}, number = {4}, pages = {778-780}, doi = {10.1016/j.immuni.2025.03.013}, pmid = {40203806}, issn = {1097-4180}, mesh = {*Amyotrophic Lateral Sclerosis/immunology/pathology/metabolism ; Humans ; Animals ; *Neuroglia/immunology/metabolism ; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/immunology ; *Microglia/immunology/metabolism ; *Astrocytes/immunology/metabolism ; Mice ; Neuroinflammatory Diseases/immunology ; Disease Models, Animal ; }, abstract = {While neuroinflammatory responses driven by microglia and astrocytes have been extensively linked to neurodegenerative disease progression in amyotrophic lateral sclerosis (ALS), the specific pathways that coordinate glial cell-dependent neuroinflammation in ALS remain poorly defined. In this issue of Immunity, Zelic et al.[1] identified RIPK1 as a pivotal regulator of glial cell-driven neuroinflammation in multiple ALS models.}, } @article {pmid40202986, year = {2025}, author = {Askarova, A and Yaa, RM and Marzi, SJ and Nott, A}, title = {Genetic risk for neurodegenerative conditions is linked to disease-specific microglial pathways.}, journal = {PLoS genetics}, volume = {21}, number = {4}, pages = {e1011407}, doi = {10.1371/journal.pgen.1011407}, pmid = {40202986}, issn = {1553-7404}, abstract = {Genome-wide association studies have identified thousands of common variants associated with an increased risk of neurodegenerative disorders. However, the noncoding localization of these variants has made the assignment of target genes for brain cell types challenging. Genomic approaches that infer chromosomal 3D architecture can link noncoding risk variants and distal gene regulatory elements such as enhancers to gene promoters. By using enhancer-to-promoter interactome maps for human microglia, neurons, and oligodendrocytes, we identified cell-type-specific enrichment of genetic heritability for brain disorders through stratified linkage disequilibrium score regression. Our analysis suggests that genetic heritability for multiple neurodegenerative disorders is enriched at microglial chromatin contact sites, while schizophrenia heritability is predominantly enriched at chromatin contact sites in neurons followed by oligodendrocytes. Through Hi-C coupled multimarker analysis of genomic annotation (H-MAGMA), we identified disease risk genes for Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and schizophrenia. We found that disease-risk genes were overrepresented in microglia compared to other brain cell types across neurodegenerative conditions and within neurons for schizophrenia. Notably, the microglial risk genes and pathways identified were largely specific to each disease. Our findings reinforce microglia as an important, genetically informed cell type for therapeutic interventions in neurodegenerative conditions and highlight potentially targetable disease-relevant pathways.}, } @article {pmid40202704, year = {2025}, author = {Oyovwi, MO and Chijiokwu, EA and Ben-Azu, B and Atere, AD and Joseph, UG and Ogbutor, UG and Udi, OA}, title = {Potential Roles of Natural Antioxidants in Modulating Neurodegenerative Disease Pathways.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40202704}, issn = {1559-1182}, abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, are increasingly prevalent among aging populations. Oxidative stress contributes to these diseases, leading to cellular damage and neuronal death. Natural antioxidants are being explored as preventive measures. This study aims to assess the effectiveness of natural antioxidants in delaying the onset or progression of neurodegenerative diseases by identifying their specific mechanisms of action. A comprehensive review of existing literature was conducted, focusing on studies that examine the role of natural antioxidants in neuroprotection. Key natural antioxidants, including flavonoids, polyphenls, vitamins C and E, and omega-3 fatty acids, were reviewed and analyzed for their bioavailability, mechanisms of action, and outcomes in both in vitro and in vivo studies. Additionally, clinical trials involving human subjects were considered to provide insights into the translational implications of antioxidant consumption. The findings suggest that several natural antioxidants exhibit neuroprotective properties by modulating oxidative stress, reducing inflammation, and promoting neuronal survival. For instance, flavonoids such as quercetin and resveratrol have shown promise in enhancing cognitive function and mitigating the pathophysiological alterations associated with neurodegeneration. In clinical studies, higher intakes of dietary antioxidants were correlated with a reduced risk of developing neurodegenerative disorders. Natural antioxidants offer potential for preventing neurodegenerative diseases by counteracting oxidative stress and maintaining cellular integrity. Overall, our report recommends that further research is needed to optimize dosages and understand their long-term benefits.}, } @article {pmid40202498, year = {2025}, author = {Gu, J and Yang, M and Zhang, L and Liu, Y and Yan, R and Pan, D and Qian, X and Hu, H and Chu, D and Hu, C and Liu, F and Cui, H}, title = {Rhythmic TDP-43 affects RNA splicing of USP13, resulting in alteration of BMAL1 ubiquitination.}, journal = {The Journal of cell biology}, volume = {224}, number = {5}, pages = {}, doi = {10.1083/jcb.202405142}, pmid = {40202498}, issn = {1540-8140}, support = {32171258//National Natural Science Foundation of China/ ; BK20211329//Natural Science Foundation of Jiangsu Province/ ; //Co-Innovation Center of Neuroregeneration/ ; //Nantong University/ ; }, mesh = {Animals ; *ARNTL Transcription Factors/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Ubiquitination ; *Circadian Rhythm/genetics ; Humans ; Mice ; *RNA Splicing/genetics ; *Ubiquitin-Specific Proteases/genetics/metabolism ; Mice, Inbred C57BL ; Male ; HEK293 Cells ; }, abstract = {Circadian rhythm disorders are common characteristics of neurodegenerative diseases. The pathological aggregation of transactive response DNA-binding protein 43 (TDP-43) is associated with multiple neurodegenerative diseases, such as amyotrophic lateral sclerosis. However, the relationship between TDP-43 and circadian rhythm remains unknown. Here, we found that TDP-43 is rhythmically expressed both in vivo and in vitro. TDP-43 knockdown affected the expression of circadian genes, including BMAL1, CLOCK, CRY1, and PER2, and impaired autonomous circadian wheel behavior, cognitive functions, and balance abilities in mice. Furthermore, TDP-43 knockdown induced aberrant splicing of ubiquitin-specific peptidase 13 (USP13) and blocked USP13 rhythmic expression, enhancing the ubiquitination of BMAL1. Meanwhile, TDP-43 knockdown altered the rhythmic expression of phospho-AMPKα (Thr172) and platelet-type phosphofructokinase (PFKP), which may change cellular glucose uptake and ATP production. Our findings further the understanding of the role of TDP-43 dysfunction in circadian rhythm disruption in neurodegenerative diseases and provide new mechanistic evidence supporting the interaction between circadian rhythm disruption and neurodegeneration.}, } @article {pmid40200760, year = {2025}, author = {Herrmann, C and Uzelac, Z and Michels, S and Weber, A and Richter, L and Elmas, Z and Jagodzinski, L and Wurster, C and Schuster, J and Dreyhaupt, J and Dorst, J}, title = {Alterations of Fat and Ketone Body Metabolism in ALS and SMA-A Prospective Observational Study.}, journal = {European journal of neurology}, volume = {32}, number = {4}, pages = {e70132}, doi = {10.1111/ene.70132}, pmid = {40200760}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Ketone Bodies/metabolism ; Male ; Female ; Middle Aged ; Prospective Studies ; *Muscular Atrophy, Spinal/metabolism ; Aged ; Adult ; Energy Metabolism/physiology ; *Adipose Tissue/metabolism ; Fatty Acids, Nonesterified/metabolism/blood ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerdosis (ALS) and spinal muscular atrophy (SMA) are motor neuron diseases associated with distinct metabolic alterations. ALS patients feature an increased resting energy expenditure (REE) causing weight loss and cachexia. In SMA, a disturbed utilization of free fatty acids has been described. These metabolic alterations negatively affect prognosis in both diseases. The objective of this study was to further characterize these changes to identify potential therapeutic targets.

METHODS: Between 11/2020 and 08/2022, 112 ALS patients, 77 SMA patients, and 50 controls were recruited in the Department of Neurology of Ulm University. Standardized blood and urinary samples were collected to analyze fat and ketone metabolism.

RESULTS: Ketone body levels were higher in ALS and SMA compared to controls. In both diseases, patients with higher BMI featured higher ketone bodies and free fatty acids compared to those with lower BMI, while in controls we found the opposite phenomenon. In SMA, more severe disease types were associated with higher ketone body levels. Compared to ALS, SMA patients featured higher ketone body and free fatty acid levels.

CONCLUSIONS: Our data suggest that already during early disease stages, ALS patients produce ketone bodies to compensate for the energy deficit. In SMA, on the other hand, the persistence of ketogenesis may indicate an upregulation of all available metabolic pathways for energy production due to the disturbance of fatty acid utilization. Therefore, the application of additional sources of energy, such as ketone bodies, might constitute a promising therapeutic option in both diseases.}, } @article {pmid40200577, year = {2025}, author = {Winkelsas, A and Apfel, A and Johnson, B and Harmison, G and Perez, KD and Li, D and Cheung, VG and Grunseich, C}, title = {Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4.}, journal = {HGG advances}, volume = {}, number = {}, pages = {100435}, doi = {10.1016/j.xhgg.2025.100435}, pmid = {40200577}, issn = {2666-2477}, abstract = {Amyotrophic lateral sclerosis 4 (ALS4) is an autosomal dominant motor neuron disease that is molecularly characterized by reduced R-loop levels and caused by pathogenic variants in senataxin (SETX). SETX encodes an RNA/DNA helicase that resolves three-stranded nucleic acid structures called R-loops. Currently, there are no disease-modifying therapies available for ALS4. Given that SETX is haplosufficient, removing the product of the mutated allele presents a potential therapeutic strategy. We designed a series of siRNAs to selectively target the RNA transcript from the ALS4 allele containing the c.1166T>C mutation (p.Leu389Ser). Transfection of HEK293 cells with siRNA and plasmids encoding either wild-type or mutant (Leu389Ser) epitope-tagged SETX revealed that three siRNAs specifically reduced mutant SETX protein levels while having minimal effect on the wild-type SETX protein. In ALS4 primary fibroblasts, siRNA treatment silenced the endogenous mutant SETX allele, while sparing the wild-type allele, and restored R-loop levels in patient cells. Our findings demonstrate that mutant SETX, differing from wild-type by a single nucleotide, can be effectively and specifically silenced by RNA interference.}, } @article {pmid40200520, year = {2025}, author = {Nikiema, SLW and Barro, SG and Kantagba, YMK and Kouraogo, BAJ and Staccini, P}, title = {Design and Development of a Virtual Reality Tool for Adult Basic Life Support Training.}, journal = {Studies in health technology and informatics}, volume = {323}, number = {}, pages = {414-418}, doi = {10.3233/SHTI250123}, pmid = {40200520}, issn = {1879-8365}, mesh = {*Virtual Reality ; Humans ; *Cardiopulmonary Resuscitation/education/instrumentation ; Adult ; *User-Computer Interface ; }, abstract = {The research introduces a Virtual Reality (VR) instrument for Adult Basic Life Support (ABLS) training, employing Blender for 3D modeling, Unity3D for VR environment creation, XChart for data visualization, and the Oculus Quest 2 as the principal VR headset. The device replicates authentic emergency situations, offering immediate feedback on CPR execution. Preliminary findings indicate enhancements in technical proficiency and user engagement; nonetheless, issues like as motion sickness and scalability remain unresolved. Future improvements will concentrate on sophisticated haptic feedback and ALS scenarios.}, } @article {pmid40200352, year = {2025}, author = {Li, J and Tang, S and Li, J and Huang, X and Liu, Y and Zeng, J and Fan, Y}, title = {Incidence and health burden of 20 rare neurological diseases in South China from 2016 to 2022: a hospital-based observational study.}, journal = {Orphanet journal of rare diseases}, volume = {20}, number = {1}, pages = {163}, pmid = {40200352}, issn = {1750-1172}, support = {202007030010//Guangzhou Science and Technology Program Key Projects/ ; 2020B1212060017//Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases/ ; 2020B1111170002//Guangdong Provincial Clinical Research Center for Neurological Diseases/ ; }, mesh = {Humans ; China/epidemiology ; Male ; Female ; *Nervous System Diseases/epidemiology ; Incidence ; Adult ; Middle Aged ; *Rare Diseases/epidemiology ; Adolescent ; Child ; Aged ; Young Adult ; Hospitals ; }, abstract = {BACKGROUND: Rare neurological diseases (RNDs) result in severe health burdens worldwide. Data from China are limited. We aimed to investigate the health burden of 20 RNDs in Guangdong Province (GD), which contains two-thirds of the population of South China.

METHODS: The hospitalization data of 20 RNDs were described using hospital-based front sheet data from 3,037 hospitals of GD from 2016 to 2022. The 20 RNDs included amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth Disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, congenital myotonia, congenital myasthenic syndrome, Dravet syndrome, Fabry disease, hereditary spastic paraplegia, Huntington disease, Leber hereditary optic neuropathy, mitochondrial encephalopathy (ME), multi-focal motor neuropathy, myotonic dystrophy, primary hereditary dystonia, progressive muscular dystrophy (PMD), spinal and bulbar muscular atrophy, spinal muscular atrophy (SMA), spinocerebellar ataxia, Wilson disease (WD) and X-linked adrenoleukodystrophy. Age were presented as mean and standard deviation while length of hospital stay as median and interquartile range (25th and 75th percentiles). The other variables were described as number and percentage. The data were analyzed by Joinpoint regression.

RESULTS: There were 9,351 cases, including 330 ICU and 155 death cases. The average age was 33.7 ± 22.0 y, and 63.8% of patients were male. From 2016 to 2022, the number of RND (and juvenile RND) cases were 1034 (184), 1174 (293), 1443 (374), 1422 (320), 1331 (337), 1432 (409) to 1515 (515). ICU (and juvenile ICU) cases rose from 28 (3), 34 (6), 24 (4), 38 (11), 46 (13), 54 (24) to 106 (56). Joinpoint regression showed significant upward trend in percentages of juvenile and juvenile ICU cases (APC = 8.13, P< 0.05; APC = 28.42, P< 0.05). The fop five RNDs were WD, ASL, PMD, ME, and SMA, which accounted for 79.7% of all, 99.1% of ICU, and 94.8% of death cases.

CONCLUSIONS: We demonstrated that the increase in health burden of RNDs was mainly evident in juveniles in South China from 2016 to 2022. The top 5 RNDs accounted for majority of the critical patients.}, } @article {pmid40199586, year = {2025}, author = {Fyrberg, E and Learnard, H and Lee, S and Jun, YW and Gao, FB}, title = {New Mouse Lines that Drive Tetracycline-Controlled Gene Expression in a Small Subset of Spinal Cord Dorsal Horn Neurons.}, journal = {eNeuro}, volume = {}, number = {}, pages = {}, doi = {10.1523/ENEURO.0441-24.2025}, pmid = {40199586}, issn = {2373-2822}, abstract = {Mouse lines with tetracycline-controlled gene expression in specific neuronal populations provide valuable tools for studying their development, function, connectivity and pathology in vivo. Our initial goal was to generate a mouse model that could express amyotrophic lateral sclerosis (ALS)-associated genes specifically in spinal cord motor neurons under the control of the HB9 promoter. However, HB9-tTA mice unexpectedly direct target gene expression in a small subset of dorsal horn neurons. These mice represent a new tool for scientists who are interested in studying these spinal cord neurons.Significance Statement We have generated new mouse lines that can manipulate gene expression in a small subset of dorsal horn neurons in the spinal cord. These new tools will be useful for scientists who are interested in studying the development, function, and connectivity of this small subset of spinal neurons in vivo.}, } @article {pmid40198794, year = {2025}, author = {Corucci, G and Vadukul, DM and Paracini, N and Laux, V and Batchu, KC and Aprile, FA and Pastore, A}, title = {Membrane Charge Drives the Aggregation of TDP-43 Pathological Fragments.}, journal = {Journal of the American Chemical Society}, volume = {}, number = {}, pages = {}, doi = {10.1021/jacs.5c00594}, pmid = {40198794}, issn = {1520-5126}, abstract = {TDP-43 protein is an RNA-binding protein linked to amyotrophic lateral sclerosis, frontotemporal dementia, and Alzheimer disease. While normally a protein that shuttles between the nucleus and cytoplasm, TDP-43 has recently been found also in extracellular vesicles. These are an important medium for cell-cell communication that allows the transfer of lipids, proteins, and genetic material among cells. An increasing concern in neurodegenerative diseases, however, is the possibility that extracellular vesicles can also provide an effective way to spread misfolded proteins that could "infect" other cells according to a "prion-like" mechanism. To characterize the interaction of TDP-43 with lipid membranes, we carried out a systematic biophysical study using a TDP-43 fragment lacking the first 84 N-terminal residues, called M85, and synthetic model phospholipid membranes. We utilized standard techniques, such as fluorescence and microscopy, complemented by neutron reflectivity measurements. Our results show that lipid charge affects the modality by which M85 interacts with membranes: a higher negative charge induces the protein to bind to the bilayer surface, promoting protein aggregation and decreasing lipid bilayer damage that this interaction causes. Thus, we speculate that the M85-lipid membrane interaction could play an important and previously undefined role in TDP-43-related neurodegenerative diseases.}, } @article {pmid40198473, year = {2025}, author = {Seok, HY}, title = {Critical issues in the use of edaravone for the treatment of amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {40198473}, issn = {1590-3478}, abstract = {Edaravone, along with riluzole, is a key treatment for amyotrophic lateral sclerosis (ALS), with evidence supporting its efficacy in slowing disease progression, particularly in patients with early-stage ALS. Despite its approval and increasing clinical use, several critical questions about its use remain unanswered: Can edaravone be effective as monotherapy? Is it beneficial for patients who fall outside the inclusion criteria of pivotal trials? What is the optimal duration of treatment as ALS progresses? In addition, does edaravone provide clinical benefit to patients with familial ALS? Answering these questions is essential to optimize the use of edaravone in clinical practice and to further our understanding of its role in the treatment of ALS. This review synthesizes the current evidence to address these questions and identifies areas that require further investigation.}, } @article {pmid40196899, year = {2025}, author = {Li, S and Pandat, T and Chi, B and Moon, D and Mas, M}, title = {Management Approaches to Spastic Gait Disorders.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28402}, pmid = {40196899}, issn = {1097-4598}, abstract = {Spastic gait presents clinically as the net mechanical consequence of neurological impairments of spasticity, weakness, and abnormal synergies and their interactions with the ground reaction force in patients with upper motor neuron syndromes and with some neuromuscular diseases. It is critical to differentiate whether the primary problem is weakness or spasticity, thus better understanding different phenotypes of spastic gait disorders. Pelvic girdle abnormality plays a pivotal role in determining the clinical presentation of gait disorders, since it determines the body vector and compensatory kinetic chain reactions in the knee and ankle joints. Knee joint abnormality can be a mechanical compensation for hip and/or ankle and foot abnormality. Diagnostic nerve blocks and instrumented gait analysis may be needed for diagnosing the underlying problems and developing an individualized plan of care. A wide spectrum of treatment options has been used to manage spastic gait disorders. Some are in early and investigational stages, such as neuromodulation modalities, while others are well-developed, such as therapeutic exercise, ankle-foot orthoses, botulinum toxin treatment, and surgical interventions. Physicians and other healthcare providers who manage spastic gait disorders should be familiar with these treatment options and should employ appropriate interventions concurrently rather than serially. The most effective treatments can be selected based on careful evaluation, inputs from patients, family, and therapists, along with appropriate goal setting. Treatment plans need to be re-evaluated for effectiveness, relevance, and in concordance with disease progress. This is particularly important for patients with progressive neuromuscular diseases such as amyotrophic lateral sclerosis.}, } @article {pmid40196659, year = {2025}, author = {Ramesh, N and Evans, A and Wojta, K and Yang, Z and Boks, MM and Kahn, RS and de Boer, SCM and van der Lee, SJ and Pijnenburg, YAL and Reus, LM and Ophoff, RA}, title = {Accurate DNA Methylation Predictor for C9orf72 Repeat Expansion Alleles in the Pathogenic Range.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.03.20.643775}, pmid = {40196659}, issn = {2692-8205}, abstract = {The hexanucleotide (G 4 C 2) repeat expansion in the promoter region of C9orf72 is the most frequent genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this study, we conducted a genome-wide DNA methylation (DNAm) analysis using EPIC version 2 (EPICv2) arrays on an FTD cohort comprising 27 carriers and 250 non-carriers of the pathogenic C9orf72 repeat expansion from the Amsterdam Dementia Cohort. We identified differentially methylated CpGs probes associated with the pathogenic C9orf72 expansion and used these findings to create a DNAm Least Absolute Shrinkage and Selection Operator (LASSO) predictor to identify repeat expansion carriers. Eight CpG sites at the C9orf72 locus were significantly differentially hypermethylated in repeat expansion carriers compared to non-carriers. The LASSO model predicted repeat expansion status with an average accuracy of 98.6%. The LASSO predictor was further validated in an independent cohort of 2,548 subjects with available EPICv2 data, identifying four C9orf72 repeat expansion carriers, subsequently confirmed by repeat-primed PCR. This result not only illustrates the accuracy of the DNAm predictor of C9orf72 repeat expansion carriers but also suggests that repeat expansion carriers may be more prevalent than expected. The identification of a highly accurate DNAm biomarker for a repeat expansion locus associated with neurodegenerative disorders may provide great value for studying this locus. The approach holds significant promise for investigating this and other repeat expansion loci, particularly given the growing interest in epigenetic epidemiological studies involving large cohorts with available DNAm data.}, } @article {pmid40196013, year = {2025}, author = {Viteri, JA and Kerr, NR and Brennan, CD and Kick, GR and Wang, M and Ketabforoush, A and Snyder, HK and Moore, PJ and Darvishi, FB and Dashtmian, AR and Ayyagari, SN and Rich, K and Zhu, Y and Arnold, WD}, title = {Targeting senescence in Amyotrophic Lateral Sclerosis: senolytic treatment improves neuromuscular function and preserves cortical excitability in a TDP-43Q331K mouse model.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-6081213/v1}, pmid = {40196013}, issn = {2693-5015}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron degeneration in the primary motor cortex (PMC) and spinal cord. Aging is a key factor in ALS onset and progression, with evidence suggesting that biological aging-a process involving cellular decline- far outpaces chronological aging in ALS. This promotes senescent cell accumulation-marked by irreversible cell-cycle arrest, impaired apoptosis, and chronic inflammation-disrupting tissue homeostasis and impairing neuronal support functions. Thus, targeting senescence presents a novel therapeutic strategy for ALS. Here, we investigated the senolytic combination Dasatinib and Quercetin (D&Q) in TDP-43 [Q331K] ALS mice. D&Q improved neuromuscular function and reduced plasma neurofilament light chain, a biomarker of axonal damage. The most pronounced improvement was the improved cortical excitability, accompanied by reductions in senescence and TDP-43 in the PMC. These findings highlight the potential of senolytics to mitigate ALS-related dysfunction, supporting their viability as a therapeutic strategy. *Jose A. Viteriab, Nathan R. Kerrab, and Charles D. Brennana are co-first authors.}, } @article {pmid40192904, year = {2025}, author = {Kodirov, SA}, title = {Comparison of Superoxide Dismutase Activity at the Cell, Organ, and Whole-Body Levels.}, journal = {Cell biochemistry and biophysics}, volume = {}, number = {}, pages = {}, pmid = {40192904}, issn = {1559-0283}, abstract = {Superoxide dismutase (SOD) can be considered an antitoxic metalloenzyme that facilitates the production of oxygen and hydrogen peroxide from superoxide anions. Four classes have been identified depending on selective binding of metals, namely Cu,Zn-SOD, Fe-SOD, Mn-SOD, and Ni-SOD. The established isoforms are SOD1, SOD2, and SOD3 in various cells and tissues of eukaryotes. The relatively newer type Ni-SOD binds nickel and is observed in bacteria, including the genus Streptomyces. The Fe-SOD and Mn-SOD are also present in bacteria. Cu,Zn superoxide dismutase (SOD1) activity correlates with various pathophysiological states of organs. SOD2 binds manganese (Mn) and is located in the mitochondria. The SOD3, similar to the SOD1, binds copper and zinc, which are also expressed in the brain. The assay relies on several methods, including the enzyme activities, expression, field potential, and patch-clamp electrophysiology. The effects of SOD activity are emphasized at organ and whole-body levels depending on animal models. The antioxidant properties and behavior of SOD are compared based on responses among females and males to diet and toxic substances. However, in humans with amyotrophic lateral sclerosis (ALS), the mean SOD activity in both erythrocytes and muscles was comparable to controls. The detailed comparisons between the catalase and SOD activities are one of the aspects of this review. Also, modulation of excitability and synaptic plasticity in neurons by SOD is highlighted.}, } @article {pmid40192272, year = {2025}, author = {Kurashige, T and Murao, T and Kanaya, Y and Dodo, Y and Sugiura, T and Kuraoka, K and Ohshita, T}, title = {Intramuscular Nerve Bundles Reflect TDP-43 Pathology in the Medulla and Spinal Cord of ALS Patients.}, journal = {Neuropathology and applied neurobiology}, volume = {51}, number = {2}, pages = {e70016}, pmid = {40192272}, issn = {1365-2990}, support = {//SENSHIN Medical Research Foundation/ ; //ALS foundation by Japan ALS Association/ ; //Tsuchiya Foundation/ ; //Takeda Science Foundation/ ; //Japan ALS Association/ ; //Daiichi Sankyo Foundation of Life Science/ ; //Kato Memorial Trust for Nanbyo Research/ ; //Kurozumi Medical Foundation/ ; //Okinaka Memorial Institute for Medical Research/ ; //Takeda Science Foundation, and Tsuchiya Foundation/ ; }, } @article {pmid40189941, year = {2025}, author = {Padigos, J and Murray, L and Bredhauer, O and Jaspers, J and Bethune, S}, title = {Extending the interval for changing flushing solutions for central venous and arterial line systems in the intensive care unit: An evidence-based quality improvement project.}, journal = {Nursing in critical care}, volume = {30}, number = {3}, pages = {e70034}, pmid = {40189941}, issn = {1478-5153}, mesh = {Humans ; *Quality Improvement ; *Intensive Care Units/organization & administration ; Queensland ; *Catheterization, Central Venous/methods ; Time Factors ; Catheter-Related Infections/prevention & control ; }, abstract = {BACKGROUND: Central venous lines (CVLs) and arterial lines (ALs) are commonly used for patients in the intensive care units (ICUs) to facilitate the administration of medications and haemodynamic monitoring. In an ICU in Queensland, Australia (AU), saline (sodium chloride 0.9%) flush bags used for these lines were routinely changed every 24 h following organizational policy that all intravenous fluid bags are to be changed within a 24-h period.

AIM: This quality improvement (QI) project aimed to evaluate current practice guided by the Plan-Do-Study-Act (PDSA) model of QI and implementation science. Benchmarking practices with other ICUs was conducted.

STUDY DESIGN: A narrative literature review focused on evaluating the safe interval for changing flush solutions every 24 h was performed using EBSCO Medline, CINAHL, Cochrane Library, Embase and Google Scholar databases for citations up to November 2022. Bloodstream infection rates attributed to CVLs and/or ALs were monitored. Economic analysis was performed. End-user feedback was sought. A change of practice was implemented for a 1-year study period (March 2023 - March 2024) to extend dwell times of flushing solutions for CVLs and ALs from every 24 h to every 96 h.

RESULTS: One-year post-implementation, no bloodstream infections were linked to CVLs or ALs. A simplified economic analysis was performed based on costs of 0.9% sodium chloride 500-mL fluid bags, which revealed that changing the fluid bags once every 96 h resulted in a per patient saving of AU$3.21 for any individual AL or CVL and up to AU$6.42 per patient where both an AL and CVL are in situ, based on fluid bag cost at AU$1.07 per bag. This saving excludes potential savings from reduced nursing time, infection-related costs and recycling costs.

CONCLUSION: A sustainable practice change based on evidence was implemented in the local ICU. The use of the PDSA model of the QI process and the principles of implementation science strengthened the buy-in and implementation of the project.

This practice change was examined through lenses of evidence-based practice, environmental sustainability (minimizing environmental footprint by limiting plastic bag usage), patient safety, cost minimization, and reduced nursing workload.}, } @article {pmid40189519, year = {2025}, author = {Tseng, PT and Zeng, BY and Hsu, CW and Hung, CM and Carvalho, AF and Stubbs, B and Chen, YW and Chen, TY and Lei, WT and Chen, JJ and Su, KP and Shiue, YL and Liang, CS}, title = {The pharmacodynamics-based prophylactic benefits of GLP-1 receptor agonists and SGLT2 inhibitors on neurodegenerative diseases: evidence from a network meta-analysis.}, journal = {BMC medicine}, volume = {23}, number = {1}, pages = {197}, pmid = {40189519}, issn = {1741-7015}, mesh = {Humans ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology ; *Neurodegenerative Diseases/prevention & control/drug therapy ; *Glucagon-Like Peptide-1 Receptor Agonists ; Network Meta-Analysis as Topic ; Randomized Controlled Trials as Topic ; Hypoglycemic Agents/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a new generation of antihyperglycemic agents that operate through mechanisms distinct from conventional diabetes treatments. Beyond their metabolic effects, these medications have demonstrated neuroprotective properties in preclinical studies. While clinical trials have explored their therapeutic potential in established neurodegenerative conditions, their role in disease prevention remains unclear. We conducted a network meta-analysis (NMA) to comprehensively evaluate the prophylactic benefits of these agents across multiple neurodegenerative diseases and identify the most promising preventive strategies.

METHODS: We systematically searched PubMed, Embase, ClinicalKey, Cochrane CENTRAL, ProQuest, ScienceDirect, Web of Science, and ClinicalTrials.gov through October 24th, 2024, for randomized controlled trials (RCTs) of GLP-1 receptor agonists or SGLT2 inhibitors. Our primary outcome was the incidence of seven major neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, Lewy body dementia, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington's disease. Secondary outcomes included safety profiles assessed through dropout rates. We performed a frequentist-based NMA and evaluated risk of bias with Risk of Bias tool. The main result of the primary outcome in the current study would be re-affirmed via sensitivity test with Bayesian-based NMA.

RESULTS: Our analysis encompassed 22 RCTs involving 138,282 participants (mean age 64.8 years, 36.4% female). Among all investigated medications, only dapagliflozin demonstrated significant prophylactic benefits, specifically in preventing Parkinson's disease (odds ratio = 0.28, 95% confidence intervals = 0.09 to 0.93) compared to controls. Neither GLP-1 receptor agonists nor other SGLT2 inhibitors showed significant preventive effects for any of the investigated neurodegenerative conditions. Drop-out rates were comparable across all treatments.

CONCLUSIONS: This comprehensive NMA reveals a novel and specific prophylactic effect of dapagliflozin against Parkinson's disease, representing a potential breakthrough in preventive neurology. The specificity of dapagliflozin's protective effect to Parkinson's disease might rely on its highly selective inhibition to SGLT2. These findings provide important direction for future research and could inform preventive strategies for populations at risk of Parkinson's disease.

TRIAL REGISTRATION: PROSPERO CRD42021252381.}, } @article {pmid40188980, year = {2025}, author = {Chong, ZZ and Souayah, N}, title = {Pathogenic TDP-43 in amyotrophic lateral sclerosis.}, journal = {Drug discovery today}, volume = {}, number = {}, pages = {104351}, doi = {10.1016/j.drudis.2025.104351}, pmid = {40188980}, issn = {1878-5832}, abstract = {The aberrant expression of the trans-active response DNA-binding protein of 43 kDa (TDP-43) has been closely associated with amyotrophic lateral sclerosis (ALS). Cytoplasmic inclusions containing TDP-43 can be found in the brain and spinal cord in up to 97% of ALS cases. Mutations in the TARDBP gene promote the nuclear export of TDP-43, increase cytoplasmic aggregation, and predispose TDP-43 to post-translational modifications. Cleavage of TDP-43 and the resulting C- and N-terminal fragments also contribute to the development of ALS. Cellularly, the resulting impairment of autophagy and mitochondria aggravates cellular damage and neurodegeneration. Given the contribution of pathogenic TDP-43 to the development of ALS, elucidating the mechanisms related to TDP-43 will facilitate finding therapeutic targets for the disease.}, } @article {pmid40188806, year = {2025}, author = {Saller, R and Schwabl, H and Rostock, M and Dal Cero, M}, title = {[Vom Spezifischen zum Systemischen - am Beispiel Tormentill / Blutwurz, der Heilpflanze des Jahres 2024].}, journal = {Complementary medicine research}, volume = {}, number = {}, pages = {1-8}, doi = {10.1159/000545128}, pmid = {40188806}, issn = {2504-2106}, abstract = {Am Beispiel des in verschiedenen lokalen Traditionen genutzten Blutwurz, Tormentill (Potentilla erecta) wird exemplarisch eine offensichtliche Kluft zwischen üblichen indikationsgetriebenen Zulassungsverfahren und der empirischen Realität sowie dem Potential vieler Heilpflanzen aufgezeigt. Für Tormentillae rhizoma ist ein breites Spektrum an Inhaltsstoffen und das mit dem Vielstoffgemisch einhergehende Wirkprofil einer u.a. vielfältig antiinflammatorisch wirkenden, systemischen Droge experimentell belegt. Die traditionelle Empirie der dämpfenden Effekte im Entzündungsgeschehen wird dadurch plausibilisiert. Die moderne Forschung liefert also Daten für einen sinnvollen Einsatz einer gut verträglichen Heilpflanze mit vielfältigen Anwendungsmöglichkeiten für Haut und Schleimhaut (innerlich und äusserlich). Auf dem Markt gibt es aber, abgesehen von vereinzelten topischen Spezialitäten und Arzneitees, kaum Zubereitungen als zugelassene Arzneispezialität. Denn die derzeitige Praxis der Arzneimittelzulassung bevorzugt die spezifischen und organbezogenen Wirkungen und übersieht dabei das systemische Potential, die Modulationsfähigkeit dieser natürlichen Stoffgemische, wie sie durch traditionelle und empirische Belege angezeigt wird. Systemische Wirkungen zeigen ihre Stärke gerade im Zusammenspiel mit anderen Therapien insbesondere beim additiven Einsatz mit Spezifika, indem sie bestimmte Wirkungen verstärken bzw. abschwächen oder die Verträglichkeit der Spezifika erhöhen bzw. deren Nebenwirkungen abmildern. Die Kombination von spezifisch wirkenden Arzneimitteln mit solchen Systemmitteln (wie z.B. Blutwurz, Tormentill) stellt damit eine weitere Therapieoption dar, die als sinnvolle Ergänzung, wenn nicht sogar als Grundlage bei Prävention, Therapie und Lebensgestaltung zu werten ist.}, } @article {pmid40188740, year = {2025}, author = {Kuo, YC and Yang, CC and Tsai, LK}, title = {Exploring CSF biomarkers in amyotrophic lateral sclerosis: Highlighting the significance of TDP-43.}, journal = {Journal of the neurological sciences}, volume = {472}, number = {}, pages = {123479}, doi = {10.1016/j.jns.2025.123479}, pmid = {40188740}, issn = {1878-5883}, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the existence of the TAR DNA-binding protein 43 (TDP-43) aggregates in motor neurons. This study investigated specific cerebrospinal fluid (CSF) biomarkers, including TDP-43, as diagnostic or prognostic biomarkers for ALS.

METHODS: The study included a hospital-based cohort of sporadic ALS patients (N = 30) and age-matched controls (N = 19). Using immunomagnetic reduction technology, CSF levels of TDP-43, neurofilament light chain (NfL), phosphorylated tau 181 (p-tau181), and total tau (t-tau) were assessed. Plasma levels of TDP-43 were also measured. The association of the different biomarkers with disease severity was investigated using ALS Functional Rating Scale-Revised (ALSFRS-R) scores, forced vital capacity (FVC), and compound muscle action potential (CMAP) amplitudes. The rate of disease progression was evaluated by measuring decline in ALSFRS-R over time.

RESULTS: ALS patients had higher CSF NfL and lower ratio of p-tau181/t-tau than control subjects. No significant difference between groups was observed in CSF TDP-43. In ALS patients, CSF levels of any biomarker, including TDP-43, were not associated with ALSFRS-R scores, FVC, or mean CMAP amplitudes. However, CSF TDP-43 positively correlated with the rate of decline in ALSFRS-R (p = 0.042). ALS patients with high CSF TDP-43 levels (>5 pg/mL) showed larger decline in ALSFRS-R (14.0 ± 11.90 vs. 8.8 ± 5.48 per year; p = 0.045) than those with lower TDP-43. Plasma TDP-43 levels did not correlate with CSF TDP-43 or any clinical parameter.

CONCLUSION: CSF TDP-43 is associated with the rate of disease progression and may be a prognostic biomarker in patients with sporadic ALS.}, } @article {pmid40188375, year = {2025}, author = {Prajapati, JL and Dhurandhar, Y and Singh, AP and Gupta, DK and Baghel, VS and Kushwaha, U and Namdeo, KP}, title = {Redox chemical delivery system: an innovative strategy for the treatment of neurodegenerative diseases.}, journal = {Expert opinion on drug delivery}, volume = {}, number = {}, pages = {}, doi = {10.1080/17425247.2025.2489558}, pmid = {40188375}, issn = {1744-7593}, abstract = {INTRODUCTION: It is anticipated that the prevalence of illnesses affecting the central nervous system (CNS) will rise significantly due to longer lifespans and changing demography. Age-related decline in brain function and neuronal death are features of neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, which provide formidable treatment challenges. Because most therapeutic drugs cannot pass across the blood-brain barrier (BBB) to reach the brain, there are still few treatment alternatives available despite a great deal of research.

AREAS COVERED: This study explores the role of redox chemical delivery systems in CNS drug delivery and addresses challenges associated with neurodegenerative disease (ND). Redox Chemical Delivery System offers a promising approach to enhancing leveraging redox reactions that facilitate the transport of therapeutic agents across the BBB. Through the optimization of medication delivery pathways to the brain, this technology has the potential to greatly improve the treatment of ND.

EXPERT OPINION: As our understanding of the biological underpinnings of ND deepens, the potential for effective interventions increases. Refining drug delivery strategies, such as RCDS, is essential for advancing CNS therapies from research to clinical practice. These advancements could transform the management of ND, improving both treatment efficacy and patient outcomes.}, } @article {pmid40187044, year = {2025}, author = {Fu, Y and Zhang, J and Qin, R and Ren, Y and Zhou, T and Han, B and Liu, B}, title = {Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases.}, journal = {Pharmacological reviews}, volume = {77}, number = {3}, pages = {100053}, doi = {10.1016/j.pharmr.2025.100053}, pmid = {40187044}, issn = {1521-0081}, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due to their intricate pathogenesis and substantial variability among patients, including differences in environmental exposures and genetic predispositions. One of the defining characteristics of NDs is widely reported to be the buildup of misfolded proteins. For example, Alzheimer disease is marked by amyloid beta and hyperphosphorylated Tau aggregates, whereas Parkinson disease exhibits α-synuclein aggregates. Amyotrophic lateral sclerosis and frontotemporal dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, and fused-in sarcoma protein aggregates, and Huntington disease involves mutant huntingtin and polyglutamine aggregates. These misfolded proteins are the key biomarkers of NDs and also serve as potential therapeutic targets, as they can be addressed through autophagy, a process that removes excess cellular inclusions to maintain homeostasis. Various forms of autophagy, including macroautophagy, chaperone-mediated autophagy, and microautophagy, hold a promise in eliminating toxic proteins implicated in NDs. In this review, we focus on elucidating the regulatory connections between autophagy and toxic proteins in NDs, summarizing the cause of the aggregates, exploring their impact on autophagy mechanisms, and discussing how autophagy can regulate toxic protein aggregation. Moreover, we underscore the activation of autophagy as a potential therapeutic strategy across different NDs and small molecules capable of activating autophagy pathways, such as rapamycin targeting the mTOR pathway to clear α-synuclein and Sertraline targeting the AMPK/mTOR/RPS6KB1 pathway to clear Tau, to further illustrate their potential in NDs' therapeutic intervention. Together, these findings would provide new insights into current research trends and propose small-molecule drugs targeting autophagy as promising potential strategies for the future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview of the potential of activating autophagy to eliminate toxic protein aggregates in the treatment of neurodegenerative diseases. It also elucidates the fascinating interrelationships between toxic proteins and the process of autophagy of "chasing and escaping" phenomenon. Moreover, the review further discusses the progress utilizing small molecules to activate autophagy to improve the efficacy of therapies for neurodegenerative diseases by removing toxic protein aggregates.}, } @article {pmid40186067, year = {2025}, author = {Maranzano, A and Gentile, F and Passaretti, M and Doretti, A and Colombo, E and Wall, AK and Treddenti, M and Patisso, V and De Lorenzo, A and Gendarini, C and Cocuzza, A and Maio, AD and Pierro, S and Poletti, B and Cinnante, CM and Morelli, C and Messina, S and Pereira, JB and Hardiman, O and Silani, V and Verde, F and Ticozzi, N}, title = {Rate of change in upper and lower motor neuron burden is associated with survival in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {315}, pmid = {40186067}, issn = {1432-1459}, support = {2022-12375731//Ministero della Salute/ ; E3-2022-23683266//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/pathology/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; *Motor Neurons/pathology ; Retrospective Studies ; Aged ; Disease Progression ; Adult ; Severity of Illness Index ; Cohort Studies ; ROC Curve ; }, abstract = {BACKGROUND: We hypothesize that the rate of change in upper (ΔUMN) and lower (ΔLMN) motor neuron signs from symptom onset to first clinical assessment represent best predictors of survival and disease progression in amyotrophic lateral sclerosis (ALS) compared to singular quantification of UMN and LMN involvement.

METHODS: A retrospective inpatient cohort of 1000 ALS patients was evaluated. The burden of UMN and LMN signs was assessed using the Penn Upper Motor Neuron Score and Lower Motor Neuron Score, respectively. For 421 patients, we compute the ENCALS survival model. Univariate and regularized Cox regressions were conducted to estimate the effect of the aforementioned variables on survival. The ROC curve analysis was then employed to a training sub-cohort to identify a ΔLMN cut-off value discriminating ALS patients with prolonged vs short survival. This cut-off value was then cross validated on a test sub-cohort. A multinomial regression model was used to compare different ΔUMN and ΔLMN scores among ENCALS groups.

RESULTS: ΔUMN and ΔLMN showed a negative association with survival (ΔUMN: HR = 1.30; ΔLMN: HR = 4.22). A cut-off value of 0.22 for ΔLMN was identified to predict patients with estimated short vs prolonged survival. ENCALS groups characterized by shorter survival presented significantly higher ΔUMN and ΔLMN scores compared to those with longer survival. No significant association of PUMNS or LMNS gross scores with the above-mentioned variables was observed.

CONCLUSION: By reflecting the progressing degeneration of the two distinct motor neuron subpopulations, ΔUMN and ΔLMN might represent reliable and easily measurable clinical indexes to estimate survival in ALS.}, } @article {pmid40185982, year = {2025}, author = {Cummings, JL and Teunissen, CE and Fiske, BK and Le Ber, I and Wildsmith, KR and Schöll, M and Dunn, B and Scheltens, P}, title = {Biomarker-guided decision making in clinical drug development for neurodegenerative disorders.}, journal = {Nature reviews. Drug discovery}, volume = {}, number = {}, pages = {}, pmid = {40185982}, issn = {1474-1784}, abstract = {Neurodegenerative disorders are characterized by complex neurobiological changes that are reflected in biomarker alterations detectable in blood, cerebrospinal fluid (CSF) and with brain imaging. As accessible proxies for processes that are difficult to measure, biomarkers are tools that hold increasingly important roles in drug development and clinical trial decision making. In the past few years, biomarkers have been the basis for accelerated approval of new therapies for Alzheimer disease and amyotrophic lateral sclerosis as surrogate end points reasonably likely to predict clinical benefit.Blood-based biomarkers are emerging for Alzheimer disease and other neurodegenerative disorders (for example, Parkinson disease, frontotemporal dementia), and some biomarkers may be informative across multiple disease states. Collection of CSF provides access to biomarkers not available in plasma, including markers of synaptic dysfunction and neuroinflammation. Molecular imaging is identifying an increasing array of targets, including amyloid plaques, neurofibrillary tangles, inflammation, mitochondrial dysfunction and synaptic density. In this Review, we consider how biomarkers can be implemented in clinical trials depending on their context of use, including providing information on disease risk and/or susceptibility, diagnosis, prognosis, pharmacodynamic outcomes, monitoring, prediction of response to therapy and safety. Informed choice of increasingly available biomarkers and rational deployment in clinical trials support drug development decision making and de-risk the drug development process for neurodegenerative disorders.}, } @article {pmid40185700, year = {2025}, author = {Yang, T and Pang, D and Huang, J and Xiao, Y and Li, C and Wei, Q and Ou, R and Cheng, Y and Lin, J and Che, N and Fu, J and Jiang, Q and Wang, S and Liu, J and Zhang, S and Shang, H}, title = {Association between sleep and ALS-FTSD: A Prospective Cohort Study based on 396,918 UK biobank participants.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {123}, pmid = {40185700}, issn = {2158-3188}, support = {82371430//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; United Kingdom/epidemiology ; Prospective Studies ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Sleep Wake Disorders/epidemiology/complications ; Aged ; Risk Factors ; Biological Specimen Banks ; *Sleep/physiology ; Incidence ; Adult ; Proportional Hazards Models ; *Frontotemporal Dementia/epidemiology ; UK Biobank ; }, abstract = {Amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) is a fatal neurodegenerative condition, and identifying its modifiable risk factors is a critical public health issue. This large-scale prospective cohort study investigated the role of sleep-related factors in ALS-FTSD risk using data from 396,918 UK Biobank participants. Eight sleep-related exposures were assessed, and Cox proportional hazards regression was employed to evaluate their associations with ALS-FTSD incidence. Subgroup and sensitivity analyses were conducted to validate the robustness of our findings. At baseline, participants had a mean age of 56.31 ± 8.12 years, with 47.5% being male. In the fully adjusted Cox model, organic sleep disorders (G47) (HR: 1.81, 95% CI: 1.21, 2.72, P = 0.004), hypersomnia (G47.1) (HR: 36.53, 95% CI: 9.04, 147.55, P < 0.001), and extreme short sleep (<5 h per day) (HR: 2.09, 95% CI: 1.09, 3.99, P = 0.046) were significantly associated with increased ALS-FTSD risk. In conclusions, these findings revealed the relationship between sleep and the risk of ALS-FTSD, identifying new modifiable risk factors and potential preventive possibilities for ALS-FTSD. Further research is warranted to elucidate the mechanistic links between sleep disturbances and ALS-FTSD pathogenesis.}, } @article {pmid40185615, year = {2025}, author = {Dawson, M}, title = {Marxism on Musk: reflections on Baum et al's 'Twenty-First Century Alienation and Health'.}, journal = {Journal of epidemiology and community health}, volume = {}, number = {}, pages = {}, doi = {10.1136/jech-2025-223762}, pmid = {40185615}, issn = {1470-2738}, } @article {pmid40185536, year = {2025}, author = {Uzgiris, AJ and Ladic, LA and Pfister, SX}, title = {Advances in neurofilament light chain analysis.}, journal = {Advances in clinical chemistry}, volume = {126}, number = {}, pages = {31-71}, doi = {10.1016/bs.acc.2025.01.006}, pmid = {40185536}, issn = {2162-9471}, mesh = {*Neurofilament Proteins/analysis ; Humans ; Biomarkers/analysis ; *Nervous System Diseases/diagnosis/metabolism ; }, abstract = {This chapter provides a comprehensive summary of clinical laboratory testing for neurofilament light chain (NfL) in neurologic disease. A primer on the NfL structure and function is presented with its potential use as a biomarker. The most widely utilized methods for NfL in biologic samples are highlighted and examined. Limitations of current knowledge are considered, as are outstanding questions related to dissemination and standardization of testing. Herein we focus on methods available today and those in development for clinical use. In the final section, a broad vision is presented of how NfL may be utilized in the future to improve diagnosis and treatment of neurologic diseases as well as for maintaining health.}, } @article {pmid40185386, year = {2025}, author = {Lei, S and Liu, Y}, title = {Identifying blood mitochondrial DNA copy number as a biomarker for development of neurodegenerative diseases: Evidence from Mendelian randomization analysis.}, journal = {Neuroscience}, volume = {573}, number = {}, pages = {421-429}, doi = {10.1016/j.neuroscience.2025.04.003}, pmid = {40185386}, issn = {1873-7544}, abstract = {Mitochondrial dysfunction has been associated with neurodegenerative diseases (NDDs). This study aimed to explore the association between blood mitochondrial DNA copy number (mtDNA-CN) and development of NDDs. This study was based on two-sample Mendelian randomization (MR) analysis. The genome wide association study (GWAS) data of NDDs including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), age-related macular degeneration (AMD), multiple sclerosis (MS), Parkinson's disease (PD), primary open-angle glaucoma (POAG), and vascular dementia (VD) was obtained from FinnGen consortium. Inverse-variance weighted (IVW) was applied as the primary approach for MR estimation. MR results revealed that blood mtDNA-CN exhibited a significant relationship with the incidence of AD (IVW-P = 0.011, odds ratio [OR] = 0.65) and AMD (IVW-P = 0.038, OR = 0.64). However, there was no significant association observed between blood mtDNA-CN and other NDDs (IVW-P > 0.05). Our findings supported the relationship between mitochondrial dysfunction and development of AD and AMD, and that blood mtDNA-CN may serve as a potential biomarker for the incidence of these two NDDs.}, } @article {pmid40185066, year = {2025}, author = {Fujii, T and Honda, H and Yoshidomi, S and Kashu, KY and Yamasaki, R and Yoshimura, M and Sasagasako, N and Iwaki, T and Isobe, N}, title = {Plexin D1 accumulation in the spinal motor neurons of patients with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {472}, number = {}, pages = {123483}, doi = {10.1016/j.jns.2025.123483}, pmid = {40185066}, issn = {1878-5883}, abstract = {BACKGROUND: Plexin D1 in endothelial cells (ECs) in the spinal cord (SC) has emerged as a key protein in spinal motor neuron (MN) maturation. Here, we pathologically investigated plexin D1 expression in the SCs of patients with sporadic amyotrophic lateral sclerosis (sALS) to clarify the association between plexin D1 expression in ECs and MN degeneration.

METHODS: We measured plexin D1 expression in the ECs of lumbar SC tissue samples from 11 patients with sALS and 8 age- and sex-matched patients with other non-inflammatory neurological diseases (OND) by immunohistochemistry. Additionally, the number and percentage of plexin D1-positive MNs in lumbar MNs were assessed in each case. We also evaluated the immunoreactivity of TAR DNA binding protein (TARDBP) in plexin D1-positive MNs.

RESULTS: Immunohistochemistry showed that there was no obvious difference in plexin D1 expression in ECs between sALS and OND cases. Unexpectedly, plexin D1 accumulation was greater in MNs of patients with sALS compared with those with OND. The number and percentage of plexin D1-positive MNs in patients with sALS were significantly greater than in patients with OND (median [interquartile range], 6 (Brown and Al-Chalabi, 2017; Mackenzie et al., 2007; Suk and Rousseaux, n.d.; Vieira et al., 2022; Oda et al., 1995; Tateno et al., 2009; Brandon et al., 2003; Brooks et al., 2000; Fujii et al., 2018; Honda et al., 2015; Oiwa et al., 2023 [1-3, 5-12]) vs. 1 [0-3.3], p = 0.0349; and 12.9 % [5.5-15.5] vs. 1.1 % [0-3.5], p = 0.0032, respectively). Plexin D1-positive MNs showed TARDBP cytoplasmic mislocalization and aggregation.

CONCLUSIONS: Plexin D1 was similarly expressed in ECs between sALS and OND cases, but accumulated in the degenerated MNs of patients with sALS. Plexin D1 accumulation in MNs may provide new insights into the mechanism of MN degeneration in ALS.}, } @article {pmid40184864, year = {2025}, author = {Deloncle, R and Guillard, O and Pineau, A}, title = {Copper in human health: From COVID 19 to neurodegenerative diseases.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {89}, number = {}, pages = {127636}, doi = {10.1016/j.jtemb.2025.127636}, pmid = {40184864}, issn = {1878-3252}, abstract = {Copper (Cu) exists in two oxidation states Cu+I and Cu+II yielding formation of enzymes involved in biological processes. In higher concentrations, by oxidative process and ROS production, Cu is toxic towards plants, humans and animals livers as observed in Wilson disease or sheep scrapie. Fighting according to the Fenton reaction against bacteria and viruses, has been proposed as a mean of combatting nosocomial diseases and complementary to COVID19 vaccination. In humans, Cu is stocked in liver, muscle or bound to brain protein as ß-APP, tau-protein, α-synuclein, ubiquitin or prion which present antioxidant properties when Cu-bonded. In abnormal ß-sheet conformation, they can trigger neurodegenerative diseases such as Alzheimer(AD), Parkinson(PD) and ALS. In these diseases, blood copper increase correlated with brain copper decrease has been described. In AD, abnormal D-serine has been detected in blood and cerebrospinal fluid. D-glutamate and D-alanine blood levels have been found in AD and could also be controlled with Cu and ceruloplasmin in a possible disease screening test. This abnormal D-conformation might result from epimerization of physiologically L-conformation brain peptides into protease-resistant D-enantiomers. This has previously been experimentally demonstrated for Bovine Spongiform Encephalopathy in a free Cu reductive medium with UV-induced free radicals. The Cu brain protective effect against free radicals was restored with cupric addition in oxidizing medium. Cupric supplementation in the brain, might restore Cu protection and slow down neurodegenerative processes. To lower side effects, Cu amino-acid complexes able to cross the blood brain barrier might be suggested for a Cu transfer to the brain.}, } @article {pmid40184012, year = {2025}, author = {Chowdhury, MR and Reddy, RVS and Nampoothiri, NK and Erva, RR and Vijaykumar, SD}, title = {Exploring bioactive natural products for treating neurodegenerative diseases: a computational network medicine approach targeting the estrogen signaling pathway in amyotrophic lateral sclerosis and Parkinson's disease.}, journal = {Metabolic brain disease}, volume = {40}, number = {4}, pages = {169}, doi = {10.1007/s11011-025-01585-y}, pmid = {40184012}, issn = {1573-7365}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; *Parkinson Disease/drug therapy/metabolism/genetics ; *Signal Transduction/drug effects/physiology ; Computational Biology/methods ; *Estrogens/metabolism ; *Biological Products/therapeutic use/pharmacology ; Protein Interaction Maps/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Gene Regulatory Networks/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) share overlapping molecular mechanisms, including estrogen signaling dysregulation, oxidative stress, and neuroinflammation. Standard treatments often lead to adverse effects due to unintended cross-talk with the estrogen signaling pathway. Identifying key regulatory genes and bioactive plant-derived compounds that modulate estrogen signaling without interfering with standard therapies offers a promising neuroprotective strategy. A network medicine and systems biology approach was used, beginning with the screening of 29 medicinal plants for ALS and 49 for PD, identifying 12 shared plants with neuroprotective potential. Bioactive compounds were screened for gene, protein, and pathway interactions, leading to target prediction (846 ALS-related and 690 PD-related targets) and disease association mining, which identified 93 overlapping genes (OGs). Protein-protein interaction (PPI) network analysis and MCODE clustering revealed ESR1, EGFR, and SRC as key hub-bottleneck (HB) genes, further validated via differential gene expression analysis. Gene ontology (GO) and pathway enrichment analyses revealed significant enrichment in estrogen signaling confirming the involvement of HB genes in neurodegenerative disease progression. Differential expression analysis confirmed ESR1 upregulation in ALS but downregulation in PD, suggesting a converse disease-specific regulatory pattern. Gene regulatory network (GRN) analysis identified hsa-miR-145-5p (ALS) and hsa-miR-181a-5p (PD) as key regulators, while FOXC1, GATA2, and TP53 emerged as crucial transcription factors (TFs) influencing disease progression. Molecular docking and MD simulations validated strong and stable interactions of Eupalitin (CYP19A1, -9.0 kcal/mol), Hesperetin (ESR1, -8.1 kcal/mol), and Sumatrol (PIK3CA, -8.9 kcal/mol). These phytochemicals, derived from Rosmarinus officinalis, Artemisia scoparia, Ocimum tenuiflorum, and Indigofera tinctoria, maintained stable hydrogen bonding and hydrophobic interactions for over 30% of a 25 ns simulation, supporting their therapeutic potential. The identification of ESR1, EGFR, and SRC as key targets, alongside estrogen signaling involvement, highlights the need for targeted nutraceutical interventions. These findings pave the way for safer, plant-based therapies that mitigate neurodegeneration while preserving estrogen signaling integrity, offering a promising adjuvant strategy alongside existing treatments.}, } @article {pmid40183526, year = {2025}, author = {Dorst, J and Dreyhaupt, J and Wernecke, D and Weiland, U and Parlak, Ö and Wiesenfarth, M and Elmas, Z and Herrmann, C and Bäzner, H and Boertlein, A and Dempewolf, S and Foerch, C and Hecht, M and Kohler, A and Opherk, C and Althaus, K and Clauer-Bredt, M and Lindner, A and Ruf, W and Brenner, D and Witzel, S and Peter, RS and Schuster, J and Ludolph, AC and Rosenbohm, A and Nagel, G}, title = {Population-Based Versus Hospital-Based Data in Amyotrophic Lateral Sclerosis-A Factor to Consider?.}, journal = {European journal of neurology}, volume = {32}, number = {4}, pages = {e70137}, pmid = {40183526}, issn = {1468-1331}, support = {577631//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis/therapy ; Male ; Female ; Middle Aged ; Aged ; *Registries ; Selection Bias ; *Hospitals/statistics & numerical data ; }, abstract = {BACKGROUND: Over the past years, some studies in amyotrophic lateral sclerosis (ALS) have provided heterogeneous findings regarding demographic and clinical data as well as the impact of various prognostic factors. It is well known that these inconsistencies might be caused by a selection bias in hospital-based data sets. In this study, we sought to further characterize this selection bias.

METHODS: We compared hospital-based data from the ALS center at Ulm University (UC; n = 3833; 1997-2021) with the population-based ALS registry Swabia (SR; n = 852; 2010-2020).

RESULTS: Patients from UC were younger (age of onset 60.9 [IQR 52.4-68.9] vs. 65.0 [57.0-72.7]), had a higher share of males (60.5% vs. 56.3%), a longer diagnostic delay (10.5 [IQR 6.4-18.4] months vs. 6.9 [IQR 3.4-12.1] months), a higher prevalence of the "definite" category according to El Escorial diagnostic criteria (60.9% vs. 11.2%), a higher share of familial cases (12.9% vs. 6.3%), a slower progression rate (points of ALS functional rating scale revised lost per month -0.54 [IQR -1.02 to -0.28] vs. -0.79 [IQR -1.47 to -0.43]), and (among all deceased patients) a higher share of percutaneous endoscopic gastrostomy (26.7% vs. 17.7%) and non-invasive ventilation (34.3% vs. 25.3%).

CONCLUSIONS: The observed differences likely indicate a selection bias in hospital-based data, which may be attributed, among others, to the willingness to travel large distances to a specialized center, the desire to participate in clinical studies, and the attitude toward life-prolonging measures. These differences must be considered when interpreting and generalizing study results from hospital-based populations.}, } @article {pmid40183433, year = {2025}, author = {Jiang, J and Li, X and Mi, Y and Wang, Y and Heng, Y and Li, Z and Deng, M}, title = {Real-world evidence of riluzole on survival and ALSFRS change in a Chinese ALS cohort.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/17582024.2025.2488235}, pmid = {40183433}, issn = {1758-2032}, abstract = {AIMS: This study aimed to evaluate the effects of riluzole on survival and changes in ALS Functional Rating Scale (ALSFRS) among Chinese patients with Amyotrophic Lateral Sclerosis (ALS).

PATIENTS & METHODS: Propensity score matching was used to balance baseline variables between the riluzole group (n = 238) and control group (n = 454). Survival was analyzed using Kaplan - Meier curves and Cox regression, while multivariable linear regression assessed ALSFRS changes at 6 and 12 months. Subgroup analyses were conducted to identify potential responders.

RESULTS: Riluzole did not significantly improve survival (p = 0.478) or ALSFRS changes at 6 months (p = 0.380) or 12 months (p = 0.175). Subgroup analyses revealed no survival benefit in any subgroup, and further stratification showed inconsistent adverse effects on ALSFRS scores.

CONCLUSIONS: Riluzole neither prolonged survival nor slowed functional decline in Chinese ALS patients, with no subgroup demonstrating a better response.}, } @article {pmid40183173, year = {2025}, author = {Zulueta, A and Piras, R and Azzolino, D and Mariani, P and Sideri, R and Garrè, C and Federico, G and Lucchi, T and Magni, P and Parati, EA and Lunetta, C}, title = {Neurofilament Light Chain Levels, Skeletal Muscle Loss, and Nutritional Decline: Key Prognostic Factors in Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28407}, pmid = {40183173}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Hypermetabolism and weight loss are established negative prognostic factors in amyotrophic lateral sclerosis (ALS). However, the role of individualized body composition parameters in predicting ALS progression has been underexplored. This study aimed to investigate the correlation between nutritional parameters, neurofilament light chain (NfL) levels, and disease progression in ALS patients.

METHODS: The Global Leadership Initiative on Malnutrition criteria were used to define malnutrition in this study. Nutritional status was assessed using body mass index and bioelectrical impedance analysis. The rate of disease progression was defined by the change in the Revised ALS Functional Rating Scale score (ΔFRS). NfL was quantified using single molecule array technology. Spearman's analyses were used to assess correlations.

RESULTS: Sixty of 110 ALS patients were classified as malnourished. There was a strong positive correlation between NfL and ΔFRS (r = 0.71), and a moderate negative correlation with disease duration (r = -0.55). The correlations between NfL and body composition parameters were statistically significant, although weak. NfL levels were significantly higher in fast progressors (p < 0.0001 compared to slow progressors) and in malnourished patients (p = 0.0001). Of the 34 fast progressor patients, 28 (82%) exhibited some degree of malnutrition.

DISCUSSION: Our findings indicate that poor nutritional status, particularly reduced skeletal muscle mass-both independently and in combination with fat mass loss-is associated with elevated NfL levels and faster ALS progression. NfL, combined with nutritional parameters, could serve as a valuable biomarker for disease severity. Further research is warranted to clarify the role of skeletal muscle abnormalities in ALS progression.}, } @article {pmid40182859, year = {2025}, author = {Kobayakawa, Y and Ko, S and Tashiro, T and Maimaitijiang, G and Kira, JI and Kishimoto, J and Yamasaki, R and Isobe, N}, title = {FVC-DiP correlates with neurofilament light chain levels in serum and cerebrospinal fluid in patients with ALS.}, journal = {BMJ neurology open}, volume = {7}, number = {1}, pages = {e001012}, pmid = {40182859}, issn = {2632-6140}, abstract = {BACKGROUND: We previously reported a scale to assess the disease progression rate in patients with amyotrophic lateral sclerosis (ALS), the forced vital capacity decline pattern scale (FVC-DiP). In this study, we investigated the association between FVC-DiP scores and neurofilament light chain (NfL) in the serum and cerebrospinal fluid (CSF) in patients with ALS.

METHODS: We performed a retrospective study to examine the association between NfL levels and the rate of disease progression (N=41). The disease progression rate was assessed using three methods: the FVC-DiP score determined using the percentage of predicted FVC (%FVC) and disease duration at the %FVC measurement, the rate of decline in the ALS Functional Rating Scale Revised (ALSFRS-R) score (ΔFS) and the rate of decline in the %FVC (Δ%FVC).

RESULTS: The FVC-DiP scores were significantly correlated with NfL levels in both the serum and CSF (serum, R[2]=0.274, p<0.001; CSF, R[2]=0.274, p=0.001). Patients assessed as rapidly progressing by the FVC-DiP had high NfL levels, and patients assessed as slowly progressing had low NfL levels. In the group with a low ΔFS and/or Δ%FVC, although the disease progression rate assessed by the FVC-DiP may have differed from the assessments obtained using the ALSFRS-R and/or %FVC, the correlation between FVC-DiP scores and serum NfL levels remained consistent.

CONCLUSIONS: The FVC-DiP was significantly associated with NfL levels in the serum and CSF, suggesting that the FVC-DiP is a reasonable scale to assess the rate of ALS progression.}, } @article {pmid40181571, year = {2025}, author = {Yoganathan, K and Dharmadasa, T and Northall, A and Talbot, K and Thompson, AG and Turner, MR}, title = {Asymmetry in amyotrophic lateral sclerosis: clinical, neuroimaging and histological observations.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf121}, pmid = {40181571}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of the motor system marked by significant phenotypic heterogeneity. Motor symptoms in the limbs consistently emerge focally and asymmetrically and, whilst variable, the pattern of regional progression related to the balance of clinical upper and lower motor neuron signs, upper versus lower limb onset and hand dominance to some extent. The neurobiological mechanisms and pathological correlates for this lateralised onset and non-random progression are uncertain. Cerebral neuroimaging studies have commonly reported structural and functional asymmetries in ALS, but the limited analysis of the pre-symptomatic phase has limited their implications. Post-mortem study of spinal cord provided strong evidence for focal pathology at symptom onset in ALS. Histopathological staging of molecular pathology in post mortem tissue lacks clinical correlation and an ordered, sequential temporal progression in life cannot be assumed. The development of integrated brain and cord MRI holds the hope of deepening understanding of the relationship between focal symptomatology and histopathological progression. This review considers the nature and implications of asymmetry in ALS across clinical, neuroimaging and post mortem histopathology, highlighting the current gaps in knowledge and the need for a broader investigative framework.}, } @article {pmid40181198, year = {2025}, author = {Manolopoulos, A and Yao, PJ and Kapogiannis, D}, title = {Extracellular vesicles: translational research and applications in neurology.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {40181198}, issn = {1759-4766}, abstract = {Over the past few decades, extensive basic, translational and clinical research has been devoted to deciphering the physiological and pathogenic roles of extracellular vesicles (EVs) in the nervous system. The presence of brain cell-derived EVs in the blood, carrying diverse cargoes, has enabled the development of predictive, diagnostic, prognostic, disease-monitoring and treatment-response biomarkers for various neurological disorders. In this Review, we consider how EV biomarkers can bring us closer to understanding the complex pathogenesis of neurological disorders such as Alzheimer disease, Parkinson disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis and multiple sclerosis. We describe how translational research on EVs might unfold bidirectionally, proceeding from basic to clinical studies but also in the opposite direction, with biomarker findings in the clinic leading to novel hypotheses that can be tested in the laboratory. We demonstrate the potential value of EVs across all stages of the therapeutic development pipeline, from identifying therapeutic targets to the use of EVs as reporters in model systems and biomarkers in clinical research. Finally, we discuss how the cargo and physicochemical properties of naturally occurring and custom-engineered EVs can be leveraged as novel treatments and vehicles for drug delivery, potentially revolutionizing neurotherapeutics.}, } @article {pmid40180875, year = {2025}, author = {Li, H and Cheng, M and Zhang, N and Wang, S and Ye, C and Li, H and Wang, S and Wang, Z and Yang, X and Liu, Z and Zhang, X and Xu, J and Xu, Q and Wang, J}, title = {The role of serum vitamins in mediating the effect of neurodegenerative diseases on subcortical brain volume.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100155}, doi = {10.1016/j.tjpad.2025.100155}, pmid = {40180875}, issn = {2426-0266}, abstract = {BACKGROUND: Neurodegenerative diseases (NDs) lead to a progressive loss of neuronal cells and link to atrophy of subcortical brain structures, but the causal intermediates are not known. To test whether major NDs (Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis) causally affects subcortical atrophy, and whether serum vitamin level play a mediating role in this process.

METHODS: Using large-scale genome-wide association study (GWAS) summary data, we performed two-sample Mendelian randomization (MR) to assess the causal effect of NDs on the volume of seven subcortical structures, and then adopted two-step multivariable MR approach to quantify the proportion of the effect of NDs on the volume of subcortical regions mediated by serum vitamin level. Finally, we utilized animal experiments to validate results and explored the potential molecular mechanisms.

RESULTS: Genetically predicted AD was associated with atrophy of the nucleus accumbens (NAc) (β = -0.09; p = 5.13 × 10[-5]), amygdala (β = -0.07; p = 8.44 × 10[-4]), and hippocampus (β = -0.07; p = 0.001), as well as with low serum vitamin D level (β = -0.02; p = 6.84 × 10[-6]). Specifically, decreased serum vitamin D level mediated 3.99 % (95 % CI: -0.006 to -5.82 × 10[-5]) and 3.97 % (95 % CI: -0.007 to -2.94 × 10[-4]) of the total effect of AD on hippocampal and NAc atrophy, respectively. Animal experiments further confirmed significant delays in hippocampal and NAc atrophy, a significant reduction of β-amyloid deposits and an increase of vitamin D receptor expression in hippocampus in AD mice with high-dose vitamin D diet.

CONCLUSIONS: These findings provide important insights into the effect sizes of vitamin D-mediated roles in AD and atrophy of subcortical structures. Interventions to increase serum vitamin D levels at a population level might attenuate damage to hippocampus in patients with AD.}, } @article {pmid40180687, year = {2025}, author = {Ms, S and Banerjee, S and D'Mello, SR and Dastidar, SG}, title = {Amyotrophic Lateral Sclerosis: Focus on Cytoplasmic Trafficking and Proteostasis.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40180687}, issn = {1559-1182}, support = {SAN No: 102/IFD/SAN/2549/2019-20//DBT RLS/ ; SAN No: 102/IFD/SAN/2549/2019-20//DBT RLS/ ; CRG/2022/005004//Science and Engineering Research Board/ ; CRG/2022/005004//Science and Engineering Research Board/ ; LBRN//Louisiana Biomedical Research Network/ ; IIRPIG-2023-0001508//Indian Council of Medical Research/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease characterized by the pathological loss of upper and lower motor neurons. Whereas most ALS cases are caused by a combination of environmental factors and genetic susceptibility, in a relatively small proportion of cases, the disorder results from mutations in genes that are inherited. Defects in several different cellular mechanisms and processes contribute to the selective loss of motor neurons (MNs) in ALS. Prominent among these is the accumulation of aggregates of misfolded proteins or peptides which are toxic to motor neurons. These accumulating aggregates stress the ability of the endoplasmic reticulum (ER) to function normally, cause defects in the transport of proteins between the ER and Golgi, and impair the transport of RNA, proteins, and organelles, such as mitochondria, within axons and dendrites, all of which contribute to the degeneration of MNs. Although dysfunction of a variety of cellular processes combines towards the pathogenesis of ALS, in this review, we focus on recent advances concerning the involvement of defective ER stress, vesicular transport between the ER and Golgi, and axonal transport.}, } @article {pmid40180646, year = {2025}, author = {Temiz, K and Gul, A and Gov, E}, title = {5-Repurposed Drug Candidates Identified in Motor Neurons and Muscle Tissues with Amyotrophic Lateral Sclerosis by Network Biology and Machine Learning Based on Gene Expression.}, journal = {Neuromolecular medicine}, volume = {27}, number = {1}, pages = {24}, pmid = {40180646}, issn = {1559-1174}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Humans ; *Machine Learning ; *Motor Neurons/metabolism/drug effects ; *Drug Repositioning/methods ; Transcriptome ; Gene Expression Profiling ; *Muscle, Skeletal/metabolism ; Gene Regulatory Networks ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that leads to motor neuron degeneration, muscle weakness, and respiratory failure. Despite ongoing research, effective treatments for ALS are limited. This study aimed to apply network biology and machine learning (ML) techniques to identify novel repurposed drug candidates for ALS. In this study, we conducted a meta-analysis using 4 transcriptome data in ALS patients (including motor neuron and muscle tissue) and healthy controls. Through this analysis, we uncovered common shared differentially expressed genes (DEGs) separately for motor neurons and muscle tissue. Using common DEGs as proxies, we identified two distinct clusters of highly clustered differential co-expressed cluster genes: the 'Muscle Tissue Cluster' for muscle tissue and the 'Motor Neuron Cluster' for motor neurons. We then evaluated the performance of the nodes of these two modules to distinguish between diseased and healthy states with ML algorithms: KNN, SVM, and Random Forest. Furthermore, we performed drug repurposing analysis and text-mining analyses, employing the nodes of clusters as drug targets to identify novel drug candidates for ALS. The potential impact of the drug candidates on the expression of cluster genes was predicted using linear regression, SVR, Random Forest, Gradient Boosting, and neural network algorithms. As a result, we identified five novel drug candidates for the treatment of ALS: Nilotinib, Trovafloxacin, Apratoxin A, Carboplatin, and Clinafloxacin. These findings highlight the potential of drug repurposing in ALS treatment and suggest that further validation through experimental studies could lead to new therapeutic avenues.}, } @article {pmid40179811, year = {2025}, author = {Li, B and Mu, H and Shan, D and Yang, Y and Wang, Y and Li, J and Wang, H and Sun, X and Ji, X and Zhan, Z and Jiao, Y and Tang, Y and Kong, B and Gao, B and Wang, Y and Sun, P and Liu, F}, title = {Generation of an induced pluripotent stem cell (iPSC) line (INNDSUi009-A) from a patient with amyotrophic lateral sclerosis due to SOD1 mutation.}, journal = {Stem cell research}, volume = {85}, number = {}, pages = {103704}, doi = {10.1016/j.scr.2025.103704}, pmid = {40179811}, issn = {1876-7753}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive degeneration of nerve cells in the spinal cord and brain. We generated and characterized a human induced pluripotent stem cell (iPSC) line from skin fibroblasts of a patient with ALS due to SOD1 Mutation. The pluripotency of these iPSCs was verified by the expression of several pluripotency markers at both RNA and protein levels, as well as their capability to differentiate into all three germ layers.}, } @article {pmid40179249, year = {2025}, author = {Traynor, BJ}, title = {The interneuron hypothesis of amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {4}, pages = {1045-1046}, pmid = {40179249}, issn = {1460-2156}, support = {/NH/NIH HHS/United States ; 1ZIAAG000933/AG/NIA NIH HHS/United States ; }, } @article {pmid40178484, year = {2025}, author = {Gao, Y and Lu, Y and Chen, R and Zhao, S and Liu, J and Zhang, S and Bai, X and Zhang, J}, title = {Skin pathology in ALS: Diagnostic implications and biomarker potential.}, journal = {Biomolecules & biomedicine}, volume = {}, number = {}, pages = {}, doi = {10.17305/bb.2025.12100}, pmid = {40178484}, issn = {2831-090X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons in the spinal cord and brain, resulting in motor deficits and muscle atrophy. Approximately 5-10% of ALS patients are familial (fALS), while the rest are sporadic (sALS). Currently, early diagnosis of ALS cannot be achieved based on clinical manifestations and electromyography due to the lack of effective and easily available biomarkers. The skin and central nervous system (CNS) share the same embryonic origin. Several skin biomarkers have been found in many neurodegenerative diseases, such as abnormal deposition of pathological α-synuclein (α-Syn) in Parkinson's disease. Thus, molecular changes in the skin associated with ALS-specific pathological events could readily be detected and become biomarkers for ALS through skin testing. Here, we summarize the literature on pathological changes in the skin of ALS patients and animal models, including structural abnormalities of the skin, reduced density of skin nerve fibers, abnormal protein aggregation, altered mitochondrial morphology and function, and dysregulation of skin inflammation, which may be useful for early diagnosis and monitoring of ALS progression.}, } @article {pmid40178078, year = {2025}, author = {Castro, J and de Carvalho, M}, title = {Synaptic dynamics linked to widespread elevation of H-reflex before peripheral denervation in amyotrophic lateral sclerosis.}, journal = {Journal of neurophysiology}, volume = {133}, number = {4}, pages = {1146-1147}, doi = {10.1152/jn.00582.2024}, pmid = {40178078}, issn = {1522-1598}, } @article {pmid40177728, year = {2025}, author = {Liu, S and Lun, J and Zhan, Y and Li, Z and Tian, J and Zhang, C and Pan, L}, title = {CRISPR/Cas12a Combined with RAA for On-Site Detection of ALS W574L Mutation in Three Alopecurus Species: A Visual Approach for Herbicide Resistance Monitoring.}, journal = {Journal of agricultural and food chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jafc.5c02188}, pmid = {40177728}, issn = {1520-5118}, abstract = {The genus Alopecurus encompasses several weed species, including Alopecurus japonicus, Alopecurus aequalis, and Alopecurus myosuroides, which represent significant threats to agricultural productivity, particularly in wheat and oilseed rape fields. ALS-inhibiting herbicides have been extensively used for controlling Alopecurus weeds. However, the widespread use of these herbicides has led to the rapid emergence of resistance in Alopecurus populations with the Trp-574-Leu (W574L) mutation in the ALS gene being one of the most common resistance mechanisms. This study aims to develop a novel molecular detection method combining recombinase-aided amplification (RAA) with CRISPR/Cas12a technology to detect the W574L mutation in Alopecurus species. The method was optimized for key parameters, balancing efficiency with experimental costs, and was evaluated for specificity, sensitivity, and field applicability. This approach offers a rapid, accurate, and visual tool for identifying W574L target-site resistance in A. japonicus, A. aequalis, and A. myosuroides, with significant potential for monitoring resistance and enhancing weed management strategies.}, } @article {pmid40176466, year = {2025}, author = {Zhang, Y and Robinson, K and Xia, Y and Sun, J}, title = {Synergistic Effects of Riluzole and Sodium Butyrate on Barrier Function and Disease Progression of Amyotrophic Lateral Sclerosis Through the Gut-Neuron Axis.}, journal = {Comprehensive Physiology}, volume = {15}, number = {2}, pages = {e70009}, pmid = {40176466}, issn = {2040-4603}, support = {R01DK114126/NH/NIH HHS/United States ; R01DK105118/NH/NIH HHS/United States ; R01DK134343/NH/NIH HHS/United States ; I01BX004824-06//U.S. Department of Veterans Affairs/ ; }, mesh = {Animals ; *Riluzole/pharmacology/therapeutic use/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology ; Mice ; *Butyric Acid/pharmacology/therapeutic use ; Disease Progression ; *Neuroprotective Agents/pharmacology ; Male ; Mice, Transgenic ; Drug Synergism ; Disease Models, Animal ; *Neurons/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Emerging evidence has shown that gut-brain barrier dysfunction occurs at the early stages of ALS. Previous studies demonstrated that sodium butyrate significantly prolonged the life span of ALS mice. Riluzole is the first FDA-approved drug for ALS treatment. We hypothesize that Riluzole and sodium butyrate combined treatment further decreases aggregation of the h-SOD1[G93A], restores the gut-brain barrier function, and delays ALS progression. SOD1[G93A] mice (9-10-week-old) were treated with Riluzole (10 mg/kg, I.P. daily), sodium butyrate (2% in drinking water), or Riluzole and sodium butyrate combination for 6 weeks. The Riluzole/butyrate combination showed a significantly longer rotarod time, increased grip strength, and enhanced intestinal barrier, as compared with Riluzole or sodium butyrate-only treatment. More reduction of h-SOD1[G93A] aggregation was observed in the colon, spinal cord lumbar, and brain cortex with Riluzole and sodium butyrate combination, compared with Riluzole or sodium butyrate-only treatment. Tight junction proteins (ZO-1 and Claudin-5) significantly increased in the colon, spinal cord lumbar, and brain cortex of mice with Riluzole and sodium butyrate treatment. The Riluzole and sodium butyrate combination reduced serum lipopolysaccharides and h-SOD1[G93A] aggregation, and inflammatory cytokines more than those in Riluzole or sodium butyrate-only treatment. Overall, Riluzole and sodium butyrate treatment is more effective than either Riluzole or sodium butyrate-only in delaying ALS progress. It provides a potential therapeutic strategy and mechanism by restoring barrier function through the gut-brain axis for ALS.}, } @article {pmid40174325, year = {2025}, author = {Farndale, L and Insall, R and Yuan, K}, title = {TriDeNT : Triple deep network training for privileged knowledge distillation in histopathology.}, journal = {Medical image analysis}, volume = {102}, number = {}, pages = {103479}, doi = {10.1016/j.media.2025.103479}, pmid = {40174325}, issn = {1361-8423}, abstract = {Computational pathology models rarely utilise data that will not be available for inference. This means most models cannot learn from highly informative data such as additional immunohistochemical (IHC) stains and spatial transcriptomics. We present TriDeNT , a novel self-supervised method for utilising privileged data that is not available during inference to improve performance. We demonstrate the efficacy of this method for a range of different paired data including immunohistochemistry, spatial transcriptomics and expert nuclei annotations. In all settings, TriDeNT outperforms other state-of-the-art methods in downstream tasks, with observed improvements of up to 101%. Furthermore, we provide qualitative and quantitative measurements of the features learned by these models and how they differ from baselines. TriDeNT offers a novel method to distil knowledge from scarce or costly data during training, to create significantly better models for routine inputs.}, } @article {pmid40172690, year = {2025}, author = {Mathis, S and Beauvais, D and Duval, F and Barnay, M and Strub, V and Géfard-Gontier, E and Solé, G and Le Masson, G}, title = {When neuromuscular disorders become stars.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {305}, pmid = {40172690}, issn = {1432-1459}, mesh = {Humans ; *Neuromuscular Diseases/diagnosis ; Retrospective Studies ; History, 20th Century ; Motion Pictures ; Television ; }, abstract = {This retrospective study identified 125 audio-visual works from cinema and television, including films, TV series, and documentaries, depicting neuromuscular disorders since 1910. Motor neuron disorders, including amyotrophic lateral sclerosis (ALS), had the highest representation (69.3%), followed by myopathies (20%). The predominant genre was documentary (48%), which offered more factual representation than fictional works. ALS was overrepresented due to its dramatic nature and association with notable figures, including the American baseball player Lou Gehrig and British theoretical physicist Stephen Hawking; other neuromuscular disorders, such as Duchenne muscular dystrophy, were depicted less frequently. Despite inaccuracies in some portrayals, these works raise public awareness and contribute to a greater understanding of rare diseases, such as neuromuscular disorders, among the general public.}, } @article {pmid40171862, year = {2025}, author = {Bierowski, AE and Comber, PC and Kuc, A and Shah, A and Carroll, G}, title = {The Effect of Prehospital Protocol Modification during COVID-19 on First-Pass Intubation Success Rates.}, journal = {Prehospital and disaster medicine}, volume = {}, number = {}, pages = {1-4}, doi = {10.1017/S1049023X25000238}, pmid = {40171862}, issn = {1945-1938}, abstract = {INTRODUCTION: Many Emergency Medical Services (EMS) agencies modified their protocols during the height of the COVID-19 pandemic, particularly those involving procedures that lead to an increased risk of airborne exposure, such as intubation. In 2020, local Advanced Life Support (ALS) providers' first-line airway management device was the supraglottic airway (SGA), and tracheal intubations (TIs) were rarely performed.

OBJECTIVE: This study's aim was to investigate the potential clinical effect of this pandemic-related protocol change on first-pass TI success rates and on overall initial advanced airway placement success.

METHODS: This study was a retrospective prehospital chart review for all ALS encounters from a single urban EMS agency that resulted in the out-of-hospital placement of at least one advanced airway per encounter from January 1, 2019 through June 30, 2021 (n = 452). Descriptive statistics and chi square tests were used to evaluate data. Statistical significance was defined at P < .05.

RESULTS: Significantly fewer TIs were attempted in 2020 (n = 16) compared to 2019 (n = 80; P < .001), and first-pass TI success rates significantly decreased in 2021 (n = 22; 61.1%) compared to 2019 (n = 63; 78.8%; P = .047). Also, SGA placement constituted 91.2% of all initial airway management attempts in 2020 (n = 165), more than both 2019 (n = 114; 58.8%; P < .001) and 2021 (n = 87; 70.7%; P < .001). Overall first-attempt advanced airway placement success, encompassing both supraglottic and TI, increased from 2019 (n = 169; 87.1%) to 2020 (n = 170; 93.9%; P = .025). Conversely, overall first attempt advanced airway placement success decreased from 2020 to 2021 (n = 104; 84.6%; P = .0072).

CONCLUSIONS: Lack of exposure to TI during the COVID-19 pandemic likely contributed to this local agency's decreased first-pass TI success in 2021. Moving forward, agencies should utilize simulation labs and other continuing education efforts to help maintain prehospital providers' proficiency in performing this critical procedure, particularly when protocol changes temporarily hinder or prohibit field-based psychomotor skill development.}, } @article {pmid40171534, year = {2025}, author = {Burg, T and Tzeplaeff, L and Cassel, R and Lingor, P}, title = {Editorial: Innovative approaches to catalyze preclinical and clinical research on amyotrophic lateral sclerosis (ALS) and related disorders.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1582539}, pmid = {40171534}, issn = {1662-4548}, } @article {pmid40171495, year = {2024}, author = {Oviedo, BJ and Arroyo-Hernandez, J and Gutiérrez-Bolaños, MJ and Alvarado-Pérez, H and Mora-Monestel, E and Rojas-Alvarado, A and Álvarez-Valverde, V and Jiménez-Bonilla, P}, title = {Assesment of chemometric analysis utilizing Multivariate Curve Resolution Alternating Least Squares (MCRALS) for examination of thermal and photodegradation of fern extracts.}, journal = {BioInspired Processing (BIP), IEEE International Conference on}, volume = {2024}, number = {}, pages = {}, pmid = {40171495}, support = {D43 TW011403/TW/FIC NIH HHS/United States ; }, abstract = {This study focuses on refining Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) for chromatographic profiling to analyze chemical changes in Serpocaulon sessilifolium extracts from the Costa Rican rainforest. High-Performance Liquid Chromatography (HPLC) with a diode array detector (DAD) and Mass Detector were employed, where traditional analyses often discard valuable spectral data beyond the maximum absorption wavelength. To optimize the analysis, Principal Component Analysis (PCA) were used to select the optimal number of components for MCR-ALS. Fern extracts, stored under varying conditions -refrigeration, warm temperatures, and UV light exposure- are analyzed over time to study their chemical stability. The decomposition identifies key chemical constituents, revealing that warmer conditions and UV exposure accelerate degradation, with significant shifts in chemical composition observed over time. MCR-ALS analysis allows detailed tracking of chemical changes, showing emerging peaks and shifts in concentration, particularly in the more reactive compounds, enhancing resolution and overcoming challenges such as peak interference and co-elution. The study highlights the differences between UV-absorption data and mass spectrometry, where mass spectrometry offers more detailed resolution but requiring greater computational resources. The use of both methods provides a comprehensive understanding of the chemical dynamics of the extracts. This research demonstrates the potential of MCR-ALS, combined with advanced statistical tools, for improving chromatographic analysis and contributing to botanical and natural product research.}, } @article {pmid40171058, year = {2025}, author = {Husted, C and Tubman, G}, title = {Case Study: The Benefits of the Neubie Direct Current Electrical Stimulation Device for Pain, Spasticity, and Movement in Amyotrophic Lateral Sclerosis.}, journal = {Integrative medicine (Encinitas, Calif.)}, volume = {24}, number = {2}, pages = {25-29}, pmid = {40171058}, issn = {1546-993X}, abstract = {This case study reports the impact of the Neubie direct current electrical stimulation device in helping restore nerve conduction and function in a 65-year-old woman with sporadic ALS. Use of the Neubie began 12 months after her sudden onset of symptoms. By then, she could not move her fingers or toes, had drop foot, had lost considerable weight and muscle mass, and was in pain. After her first Neubie session, she could wiggle her toes and that movement persisted. After two months she had no hip pain and was moving her fingers, toes, hands, and feet. The Master Reset protocol was used to facilitate the calming of the nervous system and required a sequential increase of settings. She then developed tight, painful shoulders from being in a wheelchair and Neubie treatments on her shoulders ultimately allowed her to become pain-free and regain some range of motion to increase her shoulder flexibility. Her voice then became soft due to a weak diaphragm. After two months she could feel the Neubie treatments increase the innervation of her diaphragm. At the time of this data collection and work, she was pain-free, had increased movement and range of motion, and had more energy. She showed improvements in muscle activation and strength in her legs and was able to stand with assistance. The results of this case study support the need to further study the impact of the Neubie in ALS, especially early in the course of the disease.}, } @article {pmid40170896, year = {2025}, author = {Wang, Y and Mi, Y and Wang, H and Jiang, J and Mao, L and Heng, Y and Li, X and Deng, M}, title = {Combined impact of CHCHD10 p.Gly66Val and three other variants suggests oligogenic contributions to ALS.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1438207}, pmid = {40170896}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by a progressive loss of motor neurons and muscle atrophy. Genetic factors are known to play important roles in ALS and concomitant presence of rare variants in ALS patients have been increasingly reported.

METHODS: In order to explore the genetic variants in ALS patients within the context of oligogenic inheritance and to elucidate the clinical heterogeneity observed in these patients, we conducted whole-genome sequencing on 34 familial ALS (FALS) probands.

RESULTS: In one proband, we identified a CHCHD10 p.Gly66Val variant, along with three additional variants: UNC13A p.Leu1034Val, SUSD1 p.Trp704Ser, and SQSTM1 p.His359del. This patient exhibited a slow disease progression and a prolonged survival duration, consistent with the clinical features of ALS patients with CHCHD10 variants. This suggests that the CHCHD10 p.Gly66Val variant may play a predominant role in shaping the patient's phenotype, while the other variants may primarily contribute to ALS occurrence.

DISCUSSION: Variants in CHCHD10 have been found in ALS and other neurodegenerative diseases, exhibiting significant clinical variability. However, the combinatorial effect of CHCHD10 and other ALS-related gene variants has not been fully studied. Our findings suggest that the combined impact of these four variants contributes to this patient's ALS phenotype, distinguishing it from other, less severe neuromuscular disorders associated with CHCHD10 mutations. Overall, this study further supports the oligogenic pathogenic basis of ALS and offers new insights into understanding the intricate clinical presentations associated with CHCHD10 variants.}, } @article {pmid40170672, year = {2025}, author = {Schneck, D and Arguedas, A and Xenopoulos-Oddsson, A and Arcila-Londono, X and Lunetta, C and Wymer, J and Olney, N and Gwathmey, K and Ajroud-Driss, S and Hayat, G and Heiman-Patterson, T and Cerri, F and Fournier, C and Glass, J and Sherman, A and Fiecas, M and Walk, D}, title = {Time-to-event prediction in ALS using a landmark modeling approach, using the ALS Natural History Consortium dataset.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2025.2482943}, pmid = {40170672}, issn = {2167-9223}, abstract = {BACKGROUND AND OBJECTIVES: Times to clinically relevant events are a valuable outcome in observational and interventional studies, complementing linear outcomes such as functional rating scales and biomarkers. In ALS, there are several clinically relevant events. We developed dynamic prediction models for several of these times to events that can be used for clinical trial modeling and personal planning.

METHODS: Landmark time-to-event analysis was implemented to determine the effect of patient characteristics on disease progression. Longitudinal data from 1557 participants in the ALS Natural History Consortium dataset were used. Five outcomes in the ALS disease progression were considered: loss of ambulation, loss of speech, gastrostomy, noninvasive ventilation (NIV) use, and continuous NIV use. Covariates in our models include age at diagnosis, sex, onset location, riluzole use, diagnostic delay, ALSFRS-R scores at the landmark time, and ALSFRS-R rates of change from baseline. Internal and external validation techniques were used.

RESULTS: For each of our models and landmark times, we present risk prediction intervals for random sets of patient characteristics. We demonstrate our models' application for an individual's personal predicted time-to-event. Our internal and external validation metrics indicate good concordance and overall performance. The time to loss of speech models perform the best for each metric in terms of both internal and external validation.

DISCUSSION: Landmarking is an efficient, individualized risk prediction model that is intuitive for both clinicians and patients. Importantly, landmarking can be used for clinical trial modeling, personal planning, and development of real-world evidence of the impacts of treatment interventions.}, } @article {pmid40169784, year = {2025}, author = {Simonini, C and Zucchi, E and Martinelli, I and Gianferrari, G and Lunetta, C and Sorarù, G and Trojsi, F and Pepe, R and Piras, R and Giacchino, M and Banchelli, F and Mandrioli, J}, title = {Neurodegenerative and neuroinflammatory changes in SOD1-ALS patients receiving tofersen.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {11034}, pmid = {40169784}, issn = {2045-2322}, support = {Ricerca Corrente funding scheme of the Italian Ministry of Health//Ministero della Salute/ ; Ricerca Finalizzata bando 2021 (RF-2021-12373036)//Ministero della Salute/ ; bando FAR 2021, Progetti di ricerca Interdisciplinari Mission Oriented, NEURALS project)//Università Degli Studi di Modena e Reggio Emila/ ; Neurobiobanca di Modena//Fondazione Cassa di Risparmio di Modena/ ; }, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy/cerebrospinal fluid ; Middle Aged ; *Neurofilament Proteins/cerebrospinal fluid/blood ; *Biomarkers/blood/cerebrospinal fluid ; *Superoxide Dismutase-1 ; *alpha 1-Antitrypsin/blood ; Disease Progression ; Aged ; Adult ; Chitinase-3-Like Protein 1/blood/cerebrospinal fluid ; Neuroinflammatory Diseases/drug therapy ; }, abstract = {The initiation of tofersen, a new specific antisense oligonucleotide (ASO) for SOD1 pathology, marked a significant turning point for SOD1-ALS patients. While clinical trials and early access program studies reported a significant reduction in plasma and cerebrospinal fluid (CSF) neurofilament levels, neuroinflammation following prolonged treatment was never assessed. In this multicenter study, we evaluated a cohort of 18 SOD1-ALS patients treated with tofersen, analyzing correlations between biomarkers of neurodegeneration/neuroinflammation and clinical variables indicative of disease progression. NfL, NfH, CHI3L1, and Serpina1 levels in serum and CSF were determined by semi-automated immunoassays (Ella™ technology). Generalized linear mixed models were employed to investigate longitudinal trends of these biomarkers. Our data highlighted a progressive decrease in CSF neurofilament levels during tofersen treatment (MR = 0.97, 95% CI 0.94-0.99, p = 0.006 and MR = 0.98, 95% CI 0.95-1.00, p = 0.076 for NfL and NfH in CSF, respectively). Conversely, CSF levels of SerpinA1 and CHI3L1 increased over time (MR = 1.12, 95% CI 1.08-1.16, p < 0.0001 and MR = 1.039, 95% CI 1.015-1.062, p = 0.001 for SerpinA1 and CHI3L1 in CSF, respectively), but these modifications were most apparent after six and twelve months of therapy, respectively. Disease progression rate did not correlate with these biomarker trends. We observed a significant decrease in neurofilament levels during Tofersen treatment, alongside an increase in neuroinflammatory markers, potentially linked to an immune response triggered by ASO treatment. Given the limited data on tofersen's long-term efficacy in ALS due to its recent introduction, identifying biomarkers that predict clinical outcomes such as diminished therapeutic response or adverse effects is crucial. These biomarkers may help to better understand the underlying pathomechanisms of ALS and tofersen's role in modulating disease progression.}, } @article {pmid40169635, year = {2025}, author = {D'Amico, A and Cucunato, R and Salemi, G and Bella, V and Aridon, P}, title = {A population based study to analyse amyotrophic lateral sclerosis as a multi-step process.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {11189}, pmid = {40169635}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/epidemiology ; Humans ; Female ; Male ; Middle Aged ; Aged ; Disease Progression ; Adult ; Sicily/epidemiology ; Incidence ; Aged, 80 and over ; }, abstract = {Recent studies suggest that Amyotrophic Lateral Sclerosis (ALS) follows a multistep process. We evaluated this hypothesis in a well-defined ALS population in Palermo, Sicily, almost entirely followed by our ALS Clinical Center. Incident data from the ALS Center (2014-2023) were analyzed, including both sporadic and familial ALS forms of the disease. To evaluate the multistep process, we regressed the natural log of age-specific incidence against the natural log of patient age We identified 216 ALS patients. We obtained a slope of 5 (r[2] = 0.93); the 95% CI ranged from 2.51 to 7.60, remaining relatively wide due to the small sample size, with a p-value of 0.008. The slope estimate was consistent with a 6-step process. In the Palermo ALS population, the multistep analysis confirms a process consistent with a 6-step model. This data, obtained in a relatively homogeneous population, further highlights the probability of strict interaction between environmental and genetic variables in the disease. Our data offer insights into the complexity of the mechanisms involved in the pathogenesis of the disease, particularly during its asymptomatic phase. This study supports the hypothesis that a single therapeutic silver bullet would probably be insufficient to arrest or slow the disease's progression.}, } @article {pmid40169538, year = {2025}, author = {Iyer, KA and Tenchov, R and Sasso, JM and Ralhan, K and Jotshi, J and Polshakov, D and Maind, A and Zhou, QA}, title = {Rare Diseases, Spotlighting Amyotrophic Lateral Sclerosis, Huntington's Disease, and Myasthenia Gravis: Insights from Landscape Analysis of Current Research.}, journal = {Biochemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.biochem.4c00722}, pmid = {40169538}, issn = {1520-4995}, abstract = {Rare diseases are a diverse group of disorders that, despite each individual condition's rarity, collectively affect a significant portion of the global population. Currently approximately 10,000 rare diseases exist globally, with 80% of these diseases being identified as having genetic origins. In this Review, we examine data from the CAS Content Collection to summarize scientific progress in the area of rare diseases. We examine the publication landscape in the area in an effort to provide insights into current advances and developments. We then discuss the evolution of key concepts in the field, genetic associations, as well as the major technologies and development pipelines of rare disease treatments. We focus our attention on three specific rare diseases: (i) amyotrophic lateral sclerosis, a terminal neurodegenerative disease affecting the central nervous system resulting in progressive loss of motor neurons that control voluntary muscles; (ii) Huntington's disease, another terminal neurodegenerative disease that causes progressive degeneration of nerve cells in the brain, with a wide impact on a person's functional abilities; and (iii) myasthenia gravis, a chronic autoimmune synaptopathy leading to skeletal muscle weakness. While the pathogenesis of these rare diseases is being elucidated, there is neither a cure nor preventative treatment available, only symptomatic treatment. The objective of the paper is to provide a broad overview of the evolving landscape of current knowledge on rare diseases and specifically on the biology and genetics of the three spotlighted diseases, to outline challenges and evaluate growth opportunities, an aim to further efforts in solving the remaining challenges.}, } @article {pmid40169452, year = {2025}, author = {Hou, X and Jiang, J and Deng, M}, title = {Exploring epigenetic modifications as potential biomarkers and therapeutic targets in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {304}, pmid = {40169452}, issn = {1432-1459}, support = {82273915//National Natural Science Foundation of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Humans ; *Epigenesis, Genetic ; *Biomarkers/metabolism ; DNA Methylation ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. Whole-genome sequencing has identified many novel ALS-associated genes, but genetics alone cannot fully explain the onset of ALS and an effective treatment is still lacking. Moreover, we need more biomarkers for accurate diagnosis and assessment of disease prognosis. Epigenetics, which includes DNA methylation and hydroxymethylation, histone modifications, chromatin remodeling, and non-coding RNAs, influences gene transcription and expression by affecting chromatin accessibility and transcription factor binding without altering genetic information. These processes play a role in the onset and progression of ALS. Epigenetic targets can serve as potential biomarkers and more importantly, the reversibility of epigenetic changes supports their potential role as versatile therapeutic targets in ALS. This review summarized the alterations in different epigenetic modulations in ALS. Additionally, given the close association between aberrant metabolic profiles characterized by hypoxia and high glycolytic metabolism in ALS and epigenetic changes, we also integrate epigenetics with metabolomics. Finally, we discuss the application of therapies based on epigenetic mechanisms in ALS. Our data integration helps to identify potential diagnostic and prognostic biomarkers and support the development of new effective therapies.}, } @article {pmid40167598, year = {2025}, author = {Shi, Y and Wan, Y and Wang, Y and Fang, K and Yang, J and Lu, Y and Xie, X and Pan, J and Gao, D and Wang, H and Qu, H}, title = {Quantitative [1]H NMR optimization for high-throughput metabolite analysis in industrial bioprocess monitoring.}, journal = {Analytical and bioanalytical chemistry}, volume = {}, number = {}, pages = {}, pmid = {40167598}, issn = {1618-2650}, support = {2023C03116//Key Research and Development Program of Zhejiang Province/ ; }, abstract = {Quantitative [1]H NMR ([1]H qNMR) is an ideal tool for bioprocess monitoring because it can comprehensively detect and quantify diverse metabolites that significantly influence bioprocess performance. However, the long experiment time associated with the [1]H qNMR, due to the long longitudinal relaxation time (T1) of some metabolites, does not meet the requirements for high-throughput analysis. We developed a high-throughput [1]H qNMR method for bioprocess analysis using a short relaxation delay (D1) to reduce analytical time and a correction factor (k) to compensate for incomplete relaxation. A total of 27 metabolites were quantified using spectral deconvolution via a peak fitting algorithm and MCR-ALS. Methodological validation results indicated that the precision and accuracy of the developed qNMR method were consistently high across different D1 values, with LOQs ranging from 0.008 to 0.13 mM and LODs ranging from 0.024 to 0.38 mM. Notably, a longer D1 value generally resulted in lower LODs and LOQs for most metabolites. A D1 value of 4 s was optimal for balancing analysis time and performance. The method is broadly applicable for bioprocess monitoring and control, offering valuable guidance for optimizing CHO cell culture processes and improving yield.}, } @article {pmid40166719, year = {2025}, author = {Xiong, J and Chen, X and Huang, K and Pan, Y}, title = {Successful Guselkumab Treatment in a Patient with Comorbid Psoriasis and Amyotrophic Lateral Sclerosis: A Case Study and Literature Review.}, journal = {Clinical, cosmetic and investigational dermatology}, volume = {18}, number = {}, pages = {735-741}, pmid = {40166719}, issn = {1178-7015}, abstract = {Psoriasis is genetically influenced and can be triggered by factors such as infections, stress, and lifestyle. Chronic plaque psoriasis, the most prevalent form, involves key roles for IL-17 and IL-23 in its pathogenesis. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons, resulting in muscle weakness and atrophy. Currently, there is no cure for ALS, and treatment is symptomatic, aimed at improving quality of life. The combination of psoriasis and ALS is relatively rare. Although biologic agents have shown remarkable efficacy in the treatment of chronic plaque psoriasis, we have not found any case reports regarding the use of biologic agents for treating psoriasis accompanied by ALS. Our study presents a patient with severe plaque psoriasis and ALS who exhibited a positive response to Guselkumab, without worsening of ALS symptoms, suggesting a promising therapeutic strategy. This could provide a treatment option for patients with psoriasis combined with ALS.We conducted a comprehensive review of the literature on the comorbidity of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and ALS, with plaque psoriasis. This review highlights the differential impact of treatment modalities. Specifically, we found that TNF-α inhibitors may have adverse effects in MS but could provide protective benefits in AD and PD. In ALS patients with psoriasis, IL-17A and IL-23 inhibitors, exemplified by Guselkumab, are suggested as a more suitable alternative due to their lower risk of worsening ALS symptoms.}, } @article {pmid40166606, year = {2025}, author = {de-Winton Cummings, PJ and Gonzalez Bravo, C and Dukes, KC and Wilks, AD and Ahlers, CD and Casado Castillo, FE and Courtney, A and Elliott-Wherry, AN and Knobbe, JE and Pineiro-Falcon, NM and Schaeffer, SE and Tillinghast, S and Tovar, EF and Villa, AT and Carvour, ML}, title = {Modifiable social and structural factors influence COVID-19 vaccine intention among frontline workers in the Midwestern USA: a community-engaged survey study.}, journal = {BMJ public health}, volume = {3}, number = {1}, pages = {e000859}, pmid = {40166606}, issn = {2753-4294}, abstract = {INTRODUCTION: COVID-19 vaccines have been a crucial measure in the pandemic response, yet vaccine uptake has been variable across the population. We sought to identify social and structural factors associated with COVID-19 vaccine intention among adults in the Midwestern USA who worked in one or more frontline industries during the COVID-19 pandemic.

METHODS: A community-engaged, cross-sectional online survey study was conducted between May and July 2022 among 889 workers. Guided by Thomas and Penchasky's 5As theory of access and Thomson et al's 5As taxonomy of vaccine uptake, we assessed modifiable social and structural factors related to access (transportation and convenient locations), affordability (time and incentives), activation (reminders), acceptability (experiences in a healthcare setting, political confidence and vaccine confidence) and accommodation (language inclusion and flexible appointments). Multinomial logistic regression was used to identify potentially modifiable factors that may influence vaccine intention among more than 200 surveyed workers who had not yet been vaccinated.

RESULTS: Workers who intended not to receive the vaccine were at least three times more likely to report transportation challenges, limited time off work and inflexible vaccine appointments compared with those who intended to vaccinate. Interest in financial incentives was strongly endorsed among workers who did not intend to vaccinate and among those who were undecided. Concerns about vaccine safety or side effects did not influence intention, whereas concerns about vaccine effectiveness were more common among workers who did not intend to vaccinate. Mistrust in government leaders was associated with positive vaccine intention.

CONCLUSIONS: Vaccine intention among frontline workers is strongly influenced by social and structural factors and not solely by hesitancy about the vaccine itself.}, } @article {pmid40166559, year = {2025}, author = {Lorincz-Comi, N and Cheng, F}, title = {Bayesian estimation of shared polygenicity identifies drug targets and repurposable medicines for human complex diseases.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.03.17.25324106}, pmid = {40166559}, abstract = {BACKGROUND: Complex diseases may share portions of their polygenic architectures which can be leveraged to identify drug targets with low off-target potential or repurposable candidates. However, the literature lacks methods which can make these inferences at scale using publicly available data.

METHODS: We introduce a Bayesian model to estimate the polygenic structure of a trait using only gene-based association test statistics from GWAS summary data and returns gene-level posterior risk probabilities (PRPs). PRPs were used to infer shared polygenicity between 496 trait pairs and we introduce measures that can prioritize drug targets with low off-target effects or drug repurposing potential.

RESULTS: Across 32 traits, we estimated that 69.5 to 97.5% of disease-associated genes are shared between multiple traits, and the estimated number of druggable genes that were only associated with a single disease ranged from 1 (multiple sclerosis) to 59 (schizophrenia). Estimating the shared genetic architecture of ALS with all other traits identified the KIT gene as a potentially harmful drug target because of its deleterious association with triglycerides, but also identified TBK1 and SCN11B as putatively safer because of their non-association with any of the other 31 traits. We additionally found 21 genes which are candidate repourposable targets for Alzheimer's disease (AD) (e.g., PLEKHA1, PPIB) and 5 for ALS (e.g., GAK, DGKQ).

CONCLUSIONS: The sets of candidate drug targets which have limited off-target potential are generally smaller compared to the sets of pleiotropic and putatively repurposable drug targets, but both represent promising directions for future experimental studies.}, } @article {pmid40165742, year = {2025}, author = {Fernández Soberón, S and Gómez Escobar, T and Caravaca Puchades, A and Andrés-Benito, P and Vázquez-Costa, JF and Mora Pardina, J and Juntas Morales, R and Povedano, M}, title = {Yentl syndrome, a real phenomenon in amyotrophic lateral sclerosis (ALS)?.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2024.2432030}, pmid = {40165742}, issn = {2167-9223}, abstract = {Introduction: ALS, a neurodegenerative disorder, exhibits variable incidence and prevalence across various databases consulted. Among these, PRO-ACT stands out as the most extensive publicly accessible repository of aggregated ALS clinical trial information. The estimated male-female ratio is greater for men at younger ages, which tends to equalize with aging. If specific measures are not taken to address this, this higher male prevalence could result in a higher inclusion of men in clinical trials, which could lead to biases in the observed results, preventing the proper assessment of differences between sexes. Our aim was to describe the demographic dates of the population included in ALS clinical trials in the last 8 years at Spanish national reference centers, with special interest in female participation. Methodology: Retrospective and descriptive observational study using databases of national reference centers. Results: We analyzed the databases of 4 neurological Spanish reference centers during a period of 8 years. A total number of 426 subjects were included. A greater participation of the male sex was evident in all the studies evaluated, representing 64.55% of the subjects included. This predominance has not varied significantly over the last 8 years. Our results correlate with the data published in PRO-ACT to date, where men represent 60% of the total number of participants. Conclusion: The predominance of the male sex in ALS clinical trials is a consistent and invariable finding and is known as Yentl's syndrome. This phenomenon prevents the principle of neutrality of medicine, allowing for purely partial knowledge.}, } @article {pmid40164574, year = {2025}, author = {Gómez-Gálvez, P and Navarro, V and Castro, AM and Paradas, C and Escudero, LM}, title = {Computational Analysis of SOD1-G93A Mouse Muscle Biomarkers for Comprehensive Assessment of ALS Progression.}, journal = {Neuropathology and applied neurobiology}, volume = {51}, number = {2}, pages = {e70014}, doi = {10.1111/nan.70014}, pmid = {40164574}, issn = {1365-2990}, support = {//Margarita Salas Fellowship - NextGenerationEU/ ; CB18/05/00028//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; PI13/01347//National Institute of Health Carlos III/ ; PI23/01892//National Institute of Health Carlos III/ ; FORT23/00008//National Institute of Health Carlos III/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/genetics ; Animals ; *Disease Progression ; *Muscle, Skeletal/pathology ; Mice ; *Disease Models, Animal ; *Mice, Transgenic ; *Biomarkers/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {AIMS: To identify potential image biomarkers of neuromuscular disease by analysing morphological and network-derived features in skeletal muscle biopsies from a murine model of amyotrophic lateral sclerosis (ALS), the SOD1[G93A] mouse and wild-type (WT) controls at distinct stages of disease progression.

METHODS: Using the NDICIA computational framework, we quantitatively evaluated histological differences between skeletal muscle biopsies from SOD1[G93A] and WT mice. The process involved the selection of a subset of features revealing these differences. A subset of discriminative features was selected to characterise these differences, and their temporal dynamics were assessed across disease stages.

RESULTS: Our findings demonstrate that muscle pathology in the mutant model evolves from early alterations in muscle fibre arrangement, detectable at the presymptomatic stage through graph theory features, to the subsequent development of the typical morphological pattern of neurogenic atrophy at more advanced disease stages.

CONCLUSIONS: Our assay identifies a neurogenic signature in mutant muscle biopsies, even when the disease is phenotypically imperceptible.}, } @article {pmid40163151, year = {2025}, author = {Wadan, AS and Shaaban, AH and El-Sadek, MZ and Mostafa, SA and Moshref, AS and El-Hussein, A and Ellakwa, DE and Mehanny, SS}, title = {Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {40163151}, issn = {1432-1912}, abstract = {Neurodegenerative disorders present significant challenges to modern medicine because of their complex etiology, pathogenesis, and progressive nature, which complicate practical treatment approaches. Mitochondrial dysfunction is an important contributor to the pathophysiology of various neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review paper examines the current literature highlighting the multifaceted functions of mitochondria, including energy production, calcium signaling, apoptosis regulation, mitochondrial biogenesis, mitochondrial dynamics, axonal transport, endoplasmic reticulum-mitochondrial interactions, mitophagy, mitochondrial proteostasis, and their crucial involvement in neuronal health. The literature emphasizes the increasing recognition of mitochondrial dysfunction as a critical factor in the progression of neurodegenerative disorders, marking a shift from traditional symptom management to innovative mitochondrial-based therapies. By discussing mitochondrial mechanisms, including mitochondrial quality control (MQC) processes and the impact of oxidative stress, this review highlights the need for novel therapeutic strategies to restore mitochondrial function, protect neuronal connections and integrity, and slow disease progression. This comprehensive review aims to provide insights into potential interventions that could transform the treatment landscape for neurodegenerative diseases, addressing symptoms and underlying pathophysiological changes.}, } @article {pmid40162390, year = {2025}, author = {Xie, Y and Xie, H and Wang, RL}, title = {Enhancing palliative care in malignant obstructive jaundice: A critical care perspective on endoscopic biliary stenting.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {3}, pages = {103431}, pmid = {40162390}, issn = {1948-9366}, abstract = {This letter responds to Wang et al's recent publication on endoscopic biliary stenting for malignant obstructive jaundice (MOJ) by offering constructive feedback and suggestions for future research. We commend the authors for their comprehensive study design and execution, which included a clear delineation of study groups and a robust set of outcome measures. We suggest that future studies incorporate additional biomarkers, such as serum levels of liver enzymes and bilirubin, to provide a more nuanced understanding of liver function changes post-intervention. The study's focus on short-term survival rates is appreciated, but we recommend exploring longer-term follow-up periods to capture the full spectrum of survival outcomes. Additionally, the inclusion of quality of life assessments using validated instruments could offer a more holistic view of patient outcomes. From a critical care perspective, we advocate for the integration of advanced imaging techniques to better characterize biliary anatomy and potentially predict treatment response or complications. We believe that incorporating these suggestions could enhance the understanding of endoscopic biliary stenting's role in MOJ management and its impact on patient outcomes, influencing future clinical guidelines and practice.}, } @article {pmid40161216, year = {2025}, author = {Scarcella, S and Brambilla, L and Quetti, L and Rizzuti, M and Melzi, V and Galli, N and Sali, L and Costamagna, G and Comi, GP and Corti, S and Gagliardi, D}, title = {Unveiling amyotrophic lateral sclerosis complexity: insights from proteomics, metabolomics and microbiomics.}, journal = {Brain communications}, volume = {7}, number = {2}, pages = {fcaf114}, pmid = {40161216}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is the most common motor neuron disease and manifests as a clinically and genetically heterogeneous neurodegenerative disorder mainly affecting the motor systems. To date, despite promising results and accumulating knowledge on the pathomechanisms of amyotrophic lateral sclerosis, a specific disease-modifying treatment is still not available. In vitro and in vivo disease models coupled with multiomics techniques have helped elucidate the pathomechanisms underlying this disease. In particular, omics approaches are powerful tools for identifying new potential disease biomarkers that may be particularly useful for diagnosis, prognosis and assessment of treatment response. In turn, these findings could support physicians in stratifying patients into clinically relevant subgroups for the identification of the best therapeutic targets. Here, we provide a comprehensive review of the most relevant literature highlighting the importance of proteomics approaches in determining the role of pathogenic misfolded/aggregated proteins and the molecular mechanisms involved in the pathogenesis and progression of amyotrophic lateral sclerosis. In addition, we explored new findings arising from metabolomic and lipidomic studies, which can aid to elucidate the intricate metabolic alterations underlying amyotrophic lateral sclerosis pathology. Moreover, we integrated these insights with microbiomics data, providing a thorough understanding of the interplay between metabolic dysregulation and microbial dynamics in disease progression. Indeed, a greater integration of these multiomics data could lead to a deeper understanding of disease mechanisms, supporting the development of specific therapies for amyotrophic lateral sclerosis.}, } @article {pmid40159068, year = {2025}, author = {Wang, HF and Wang, HR and Lin, YC and Bai, JM and Li, M and Huang, XS}, title = {[Analysis of serum 25-hydroxyvitamin D3 levels and prognosis in patients with amyotrophic lateral sclerosis].}, journal = {Zhonghua nei ke za zhi}, volume = {64}, number = {4}, pages = {325-332}, doi = {10.3760/cma.j.cn112138-20240728-00481}, pmid = {40159068}, issn = {0578-1426}, support = {2023124//Tianjin Municipal Health and Health Commission Traditional Chinese Medicine and Integrative Medicine Research Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; Prognosis ; Prospective Studies ; *Calcifediol/blood ; Cross-Sectional Studies ; Risk Factors ; Male ; Biomarkers/blood ; Female ; Middle Aged ; }, abstract = {Objective: To evaluate serum 25-hydroxyvitamin D3 [25(OH)D3] as a potential biomarker for amyotrophic lateral sclerosis (ALS) severity and to identify risk factors influencing ALS prognosis. Methods: This study included 217 ALS patients hospitalized at the Department of Neurology, First Medical Center, Chinese PLA General Hospital, between October 2018 and October 2021, who met the revised El Escorial diagnostic criteria. A cross-sectional analysis assessed differences in clinical indicators-including the ALS Functional Rating Scale-Revised (ALSFRS-R) and forced vital capacity percentage (FVC%)-across different serum 25(OH)D3 levels. The correlation between 25(OH)D3 levels and individual ALSFRS-R components was also examined. Conduct a prospective cohort study to identify independent risk factors affecting the survival time of ALS patients. Results: Among three groups categorized by serum 25(OH)D3 levels, there were significant differences in the proportion of males (χ[2]=10.51, P<0.05). Serum 25(OH)D3 levels correlated positively with lower limb function scores in the ALSFRS-R (r=0.05, P<0.05), but they were not identified as an independent risk factor for survival (HR=0.98, 95%CI 0.93-1.04, P>0.05). In contrast, delayed diagnosis(HR=0.94, 95%CI 0.89-0.99, P<0.05) and reduced FVC%(HR=0.94, 95%CI 0.97-0.99, P<0.05) were independent predictors of shorter survival. Conclusion: Serum 25(OH)D3 levels differ by gender distribution and may be linked to better lower limb function in ALS patients. However, their role in prolonging survival remains uncertain.}, } @article {pmid40157939, year = {2025}, author = {Rossi, S and Milani, M and Della Valle, I and Bisegna, S and Durante, V and Addesse, M and D'Avorio, E and Di Salvio, M and Serafino, A and Cestra, G and Apolloni, S and D'Ambrosi, N and Cozzolino, M}, title = {Cytoplasmic accumulation of a splice variant of hnRNPA2/B1 contributes to FUS-associated toxicity in a mouse model of ALS.}, journal = {Cell death & disease}, volume = {16}, number = {1}, pages = {219}, pmid = {40157939}, issn = {2041-4889}, support = {Nutrage, IFT DBA.AD005.225//Consiglio Nazionale delle Ricerche (National Research Council)/ ; SpliceALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; SwitchALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; SpliceALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; SpliceALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; SwitchALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism/genetics ; *RNA-Binding Protein FUS/metabolism/genetics ; Mice ; *Disease Models, Animal ; *Cytoplasm/metabolism ; *Alternative Splicing/genetics ; *Motor Neurons/metabolism/pathology ; Humans ; Exons/genetics ; Mice, Transgenic ; }, abstract = {Genetic and experimental findings point to a crucial role of RNA dysfunction in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). Evidence suggests that mutations in RNA binding proteins (RBPs) such as FUS, a gene associated with ALS, affect the regulation of alternative splicing. We have previously shown that the overexpression of wild-type FUS in mice, a condition that induces ALS-like phenotypes, impacts the splicing of hnRNP A2/B1, a protein with key roles in RNA metabolism, suggesting that a pathological connection between FUS and hnRNP A2/B1 might promote FUS-associated toxicity. Here we report that the expression and distribution of different hnRNP A2/B1 splice variants are modified in the affected tissues of mice overexpressing wild-type FUS. Notably, degenerating motor neurons are characterized by the cytoplasmic accumulation of splice variants of hnRNP A2/B1 lacking exon 9 (hnRNP A2b/B1b). In vitro studies show that exon 9 skipping affects the nucleocytoplasmic distribution of hnRNP A2/B1, promoting its localization into stress granules (SGs), and demonstrate that cytoplasmic localization is the primary driver of hnRNP A2b recruitment into SGs and cell toxicity. Finally, boosting exon 9 skipping using splicing switching oligonucleotides exacerbates disease phenotypes in wild-type FUS mice. Altogether, these findings reveal that alterations of the nucleocytoplasmic distribution of hnRNP A2/B1, driven by FUS-induced splicing changes, likely contribute to motor neuron degeneration in ALS.}, } @article {pmid40157684, year = {2025}, author = {Yu, T and Li, M and Li, M and Zhang, Q and Zhang, H and Jiang, Z and Wang, S and Mao, H and Li, D and Fan, L and Hu, C and Xu, X}, title = {Zebrafish TDP43 positively regulates p65-mediated apoptotic pathway.}, journal = {International journal of biological macromolecules}, volume = {308}, number = {Pt 3}, pages = {142599}, doi = {10.1016/j.ijbiomac.2025.142599}, pmid = {40157684}, issn = {1879-0003}, abstract = {TAR DNA-binding protein 43 (TDP43) is a multifunctional RNA/DNA binding protein that serves as a hallmark of neurodegeneration in amyotrophic lateral sclerosis (ALS) and is associated with the inflammatory response related to nuclear factor κB (NF-κB) pathway. However, the relationship between TDP43 and NF-κB is not well known. In this study, zebrafish TDP43 (DrTDP43) can be induced by grass carp reovirus (GCRV) or spring viremia of carp virus (SVCV). DrTDP43 enhances the nuclear factor-kappaB (NF-κB) activity and the expression of p65 and TNFα, as well as promotes the phosphorylation of p65 in response to stimulation of GCRV and SVCV. Further assays indicate that DrTDP43 primarily resides in the nucleus and interacts with p65 via its RRM1. DrTDP43 is required for p65 to induce pro-inflammatory cytokine production (IL-6, IL-10, TNFα, IL-1β). It disrupts mitochondrial membrane potential and exacerbates apoptosis via downregulating Bcl2 and upregulating Bax, caspase3, and eIF2α. Moreover, knockdown of TDP43 decreases the content of reactive oxygen species (ROS) and the number of apoptotic cells in zebrafish larvae, which is attributed to the lower lever of p65 phosphorylation and expression of TNFα, Bax and cleaved-caspase3. In a word, these results establish TDP43 as a critical activator of the NF-κB-mediated apoptotic pathway during antiviral responses, which reveals a previously unrecognized host defense mechanism.}, } @article {pmid40157434, year = {2025}, author = {Pu, L and Steele, JR and Phillips, CR and Violi, JP and Rodgers, KJ}, title = {The cyanobacterial toxins BMAA and 2,4-DAB perturb the l-serine biosynthesis pathway and induce systemic changes in energy metabolism in human neuroblastoma cells: A proteomic study.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {106}, number = {}, pages = {106058}, doi = {10.1016/j.tiv.2025.106058}, pmid = {40157434}, issn = {1879-3177}, abstract = {Blue-green algae (cyanobacteria), an ancient phylum of bacteria, produce a wide array of secondary metabolites that are toxic to humans. Rapid growth of cyanobacteria in an aquatic environment can result in algal blooms capable of turning waterways green and increasing toxin levels in the environment. Cyanobacterial toxins were first linked to the high incidence of a complex neurodegenerative disorder reported on the island of Guam in the 1940s but more recently have been linked to clusters of sporadic amyotrophic lateral sclerosis (sALS) worldwide. The non-protein amino acid β-N-methylamino-L-alanine (BMAA) and its isomer L-2,4-diaminobutyric acid (2,4-DAB) are produced concurrently by most cyanobacterial species. We carried out proteomic analysis on human neuroblastoma cells treated with BMAA and 2,4-DAB to determine the underlying mechanisms of toxicity resulting from exposure to these cyanotoxins and identified significant changes in the l-serine biosynthesis pathway as well as pathways associated with energy production in the cell such as fatty acid ß-oxidation and glycolysis. The impact on the serine biosynthetic pathway was supported by demonstrating a significant decrease in both mRNA and protein levels of the enzyme 3-phosphoglycerate dehydrogenase (PHGDH) the first committed step in serine biosynthesis. PHGDH uses 3-phospho-D-glycerate (3PG) an intermediate in the glycolytic pathway as a substrate, and co-incubation of cells with l-serine restored expression levels of PHGDH as did cell pre-treatment with the glycolytic product pyruvate. This is the first study to link exposure to BMAA and 2,4-DAB to impairments in the l-serine biosynthesis pathway and broad disturbances in energy metabolism.}, } @article {pmid40157356, year = {2025}, author = {Rummens, J and Khalil, B and Yıldırım, G and Silva, P and Zorzini, V and Peredo, N and Wojno, M and Ramakers, M and Van Den Bosch, L and Van Damme, P and Davie, K and Hendrix, J and Rousseau, F and Schymkowitz, J and Da Cruz, S}, title = {TDP-43 seeding induces cytoplasmic aggregation heterogeneity and nuclear loss of function of TDP-43.}, journal = {Neuron}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuron.2025.03.004}, pmid = {40157356}, issn = {1097-4199}, abstract = {Cytoplasmic aggregation and nuclear depletion of TAR DNA-binding protein 43 (TDP-43) are hallmarks of several neurodegenerative disorders. Yet, recapitulating both features in cellular systems has been challenging. Here, we produced amyloid-like fibrils from recombinant TDP-43 low-complexity domain and demonstrate that sonicated fibrils trigger TDP-43 pathology in human cells, including induced pluripotent stem cell (iPSC)-derived neurons. Fibril-induced cytoplasmic TDP-43 inclusions acquire distinct biophysical properties, recapitulate pathological hallmarks such as phosphorylation, ubiquitin, and p62 accumulation, and recruit nuclear endogenous TDP-43, leading to its loss of function. A transcriptomic signature linked to both aggregation and nuclear loss of TDP-43, including disease-specific cryptic splicing, is identified. Cytoplasmic TDP-43 aggregates exhibit time-dependent heterogeneous morphologies as observed in patients-including compacted, filamentous, or fragmented-which involve upregulation/recruitment of protein clearance pathways. Ultimately, cell-specific progressive toxicity is provoked by seeded TDP-43 pathology in human neurons. These findings identify TDP-43-templated aggregation as a key mechanism driving both cytoplasmic gain of function and nuclear loss of function, offering a valuable approach to identify modifiers of sporadic TDP-43 proteinopathies.}, } @article {pmid40157355, year = {2025}, author = {Scialò, C and Zhong, W and Jagannath, S and Wilkins, O and Caredio, D and Hruska-Plochan, M and Lurati, F and Peter, M and De Cecco, E and Celauro, L and Aguzzi, A and Legname, G and Fratta, P and Polymenidou, M}, title = {Seeded aggregation of TDP-43 induces its loss of function and reveals early pathological signatures.}, journal = {Neuron}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuron.2025.03.008}, pmid = {40157355}, issn = {1097-4199}, abstract = {Neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) results from both gain of toxicity and loss of normal function of the RNA-binding protein TDP-43, but their mechanistic connection remains unclear. Increasing evidence suggests that TDP-43 aggregates act as self-templating seeds, propagating pathology through the central nervous system via a prion-like cascade. We developed a robust TDP-43-seeding platform for quantitative assessment of TDP-43 aggregate uptake, cell-to-cell spreading, and loss of function within living cells, while they progress toward pathology. We show that both patient-derived and recombinant TDP-43 pathological aggregates were abundantly internalized by human neuron-like cells, efficiently recruited endogenous TDP-43, and formed cytoplasmic inclusions reminiscent of ALS/FTD pathology. Combining a fluorescent reporter of TDP-43 function with RNA sequencing and proteomics, we demonstrated aberrant cryptic splicing and a loss-of-function profile resulting from TDP-43-templated aggregation. Our data highlight known and novel pathological signatures in the context of seed-induced TDP-43 loss of function.}, } @article {pmid40157354, year = {2025}, author = {Klickstein, JA and Johnson, MA and Antonoudiou, P and Maguire, J and Paulo, JA and Gygi, SP and Weihl, C and Raman, M}, title = {ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons.}, journal = {Stem cell reports}, volume = {}, number = {}, pages = {102478}, doi = {10.1016/j.stemcr.2025.102478}, pmid = {40157354}, issn = {2213-6711}, } @article {pmid40156516, year = {2025}, author = {Gorgich, EA and Heidari, Z and Mahmoudzadeh-Sagheb, H and Rustamzadeh, A and Shabani, A and Amirzadeh, A and Haghi Ashtiani, B}, title = {Brain Metabolite Profiles are Associated with Selective Neuronal Vulnerability and Underlying Mechanisms in Amyotrophic Lateral Sclerosis.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.4c00593}, pmid = {40156516}, issn = {1948-7193}, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurological syndrome accompanied by selective degeneration of somatic motor neurons and neurochemistry alterations. Nevertheless, eye movement's nuclei are relatively spared from ALS damage. This survey was to probe metabolite changes in the primary motor cortex (PMC) and interstitial nucleus of Cajal (INC) of ALS patients using proton magnetic resonance spectroscopy ([1]H-MRS). In this case-control study, 20 patients with ALS and 20 healthy controls underwent 1.5 T MRI and multivoxel [1]H-MRS. [1]H-MRS spectra to determine metabolite profiles including tNAA, mIns, tCr, tCho, and also tNAA/tCr, tNAA/tCho, and mIns/tNAA metabolite ratios from the PMC and INC were quantified via a point resolved spectroscopy pulse (PRESS) sequence in two groups. Further, the associations between [1]H-MRS markers with forced vital capacity (FVC), ALS functional rating scale (ALSFRS-R), and disease progression rate (ΔFS) were investigated. In the PMC, tNAA and tNAA/tCr were significantly lower in ALS patients than the healthy controls, but mIns and mIns/tNAA were significantly greater in these patients (p < 0.05). In the INC, tCho and mIns concentrations, and mIns/tNAA ratio were significantly increased (p < 0.05) in ALS patients, while tNAA and tNAA/tCr ratio did not show significant discriminations between the two groups (p > 0.05). The PMC tNAA/Cr ratio is associated with ALSFRS-R (p = 0.001, r = 0.71), FVC (p = 0.03, r = 0.58), and ΔFS (p = 0.01, r = -0.33). The mIns/tNAA ratio in PMC is also associated with ΔFS (p = 0.02, r = 0.41). In the INC, tCho concentrations (p = 0.04, r = -0.54) and mIns/tNAA ratio (p = 0.02, r = -0.38) were negatively associated with ALSFRS-R and positively correlated with ΔFS (p = 0.01, r = 0.33) and (p = 0.001, r = 0.61), respectively. The study suggests that neurochemistry changes in ALS patients' brains are linked to selective neuronal vulnerability and the underlying pathophysiology of the disease.}, } @article {pmid40155688, year = {2025}, author = {Fan, X and Zeng, Y and Zhang, F and Xu, Y and Duan, Q and Long, S and Lin, Y and Wang, K and Jiang, L}, title = {Genetic effects of circulating hormone and proteome on amyotrophic lateral sclerosis identified by Mendelian randomization.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {10782}, pmid = {40155688}, issn = {2045-2322}, support = {82201242//National Natural Science Foundation of China/ ; 82470903//National Natural Science Foundation of China/ ; LY24C110001//Natural Science Foundation of Zhejiang Province/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics ; *Mendelian Randomization Analysis ; *Proteome ; Testosterone/blood ; Sex Hormone-Binding Globulin/metabolism/genetics ; Proteomics/methods ; Risk Factors ; Polymorphism, Single Nucleotide ; Insulin-Like Growth Factor I/metabolism/genetics ; Male ; Biomarkers/blood ; Female ; Genetic Predisposition to Disease ; Hormones/blood ; }, abstract = {Altered circulating hormones in ALS patients have been widely reported by previous observational studies, but whether these relationships are causal is unclear. Moreover, the potential therapeutic targets for ALS and the effects of plasma protein fluctuation on ALS progression are not fully understood. Therefore, we conducted a Mendelian randomization (MR) study to evaluate the causal role of 5 hormonal risk factors (insulin-like growth factor-1, IGF-1; sex hormone-binding globulin, SHBG; free testosterone, FT; total testosterone, TT; and estradiol) in ALS risk. Furthermore, we screened up to 90 circulating proteins including cytokines, chemokines, growth factors, and interferons, to identify potential therapeutic targets for ALS. Our MR analysis found genetically predicted higher level of FT was associated with a 23% lowered risk of ALS. Further screening of proteomic traits found that 12 plasma proteins were causally associated with ALS. These findings suggest that higher FT potentially exerts a protective effect on ALS risk. Several proteins may act as potential circulating biomarkers and therapeutic targets for ALS. In the future, high-throughput proteomic analyses and experimental explorations are likely needed to clarify the regulated role and mechanistic pathways.}, } @article {pmid40155564, year = {2025}, author = {Tang, J and Zhao, Y and Chen, Y and Yang, Y and Gong, Z and Li, Z and Zhang, M and Zhang, J}, title = {White matter integrity mediated the effect of plasma uric acid levels on cognitive function in ALS patients.}, journal = {Brain imaging and behavior}, volume = {}, number = {}, pages = {}, pmid = {40155564}, issn = {1931-7565}, support = {82271478//National Natural Science Foundation of China/ ; 2024AOXIANG05//the Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital/ ; }, abstract = {OBJECTIVE: To investigate the association between plasma uric acid levels and white matter microstructural alterations in amyotrophic lateral sclerosis (ALS) patients and to explore the potential mediating role of white matter microstructural alterations in the protective effect of plasma uric acid on cognitive function in ALS patients.

METHODS: 73 right-handed ALS patients were recruited for this study. Plasma uric acid levels were measured, diffusion tensor imaging scans were performed to assess white matter integrity, and cognition was evaluated using the Edinburgh Cognitive and Behavioral Screen. The relationships among plasma uric acid, white matter integrity, and cognitive function were examined through multivariate linear regression analysis. Additionally, mediation analysis was performed to investigate whether white matter integrity mediated the relationship between uric acid levels and cognitive function.

RESULTS: The findings revealed a positive correlation between plasma uric acid levels and extensive preservation of white matter microstructure in various regions, including the fornix, cerebellar, internal capsule, frontotemporal and frontooccipital lobe bundles among ALS patients. Mediation analysis indicated that fractional anisotropy in the hippocampal portion of the cingulum fully mediated the effects of plasma uric acid levels on executive function in ALS patients.

INTERPRETATION: Our results suggested that elevated plasma uric acid may preserve the integrity of white matter microstructure in ALS patients. Furthermore, we have identified evidence supporting the mediating influence of the hippocampal portion of the cingulum in linking plasma uric acid levels to cognitive function among ALS patients.}, } @article {pmid40153582, year = {2025}, author = {Norata, D and Capone, F and Motolese, F and Marano, M and Rossi, M and Calandrelli, R and Sacchetti, M and Mantelli, F and Di Lazzaro, V and Pilato, F}, title = {1953-2023. Seventy Years of the Nerve Growth Factor: A Potential Novel Treatment in Neurological Diseases?.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.0573}, pmid = {40153582}, issn = {2152-5250}, abstract = {Rita Levi-Montalcini's 1953 discovery of nerve growth factor (NGF) in mouse sarcoma tumors marked a groundbreaking moment in neuroscience. NGF, a key signaling molecule, became the first identified neurotrophic factor, influencing the growth, differentiation, and survival of neurons in both peripheral and central nervous systems. NGF and related neurotrophic factors hold therapeutic potential for various neurological disorders, such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, amyotrophic lateral sclerosis, spinal cord injuries, neuropathies, traumatic brain injuries, and stroke. However, despite promising in vitro studies and animal models findings, NGF efficacy in patients remains unproven. Indeed, its use as a therapeutic agent faces challenges in delivery and clinical translation. This review delves into these challenges, exploring ongoing research on refined delivery methods, dosages, and safety profiles. Innovative strategies, including molecular mimicking, combination therapies, gene therapy, and coupling with neuromodulation techniques like transcranial magnetic stimulation and vagal nerve stimulation, are discussed. Incorporating nerve growth factor (NGF) into a comprehensive strategy may prove beneficial, particularly in non-neurodegenerative conditions such as stroke, trauma, and neuropathies. In these instances, NGF holds promise for promoting tissue regeneration and repair. Challenges persist in addressing the complexity of neurodegenerative pathologies for a combined therapeutic approach.}, } @article {pmid40152938, year = {2025}, author = {Yu, L and Yang, Z and Ming, Z and Zhou, Q and Zeng, S}, title = {Impaired Aortic Biomechanical Properties in Patients With Severe Obstructive Sleep Apnea Syndrome.}, journal = {Echocardiography (Mount Kisco, N.Y.)}, volume = {42}, number = {4}, pages = {e70135}, doi = {10.1111/echo.70135}, pmid = {40152938}, issn = {1540-8175}, support = {kq2208343//Natural Science Foundation of Changsha City/ ; 2024JJ8122//Natural Science Foundation of Hunan Province/ ; }, mesh = {Humans ; *Sleep Apnea, Obstructive/physiopathology/complications ; Male ; Female ; Middle Aged ; *Aorta/physiopathology/diagnostic imaging ; Biomechanical Phenomena ; Severity of Illness Index ; Adult ; Echocardiography/methods ; }, abstract = {PURPOSE: Evaluating the biomechanical properties of the aorta is crucial for assessing cardiovascular risk and preventing disease progression. The aim of this study was to evaluate the biomechanical properties of the ascending aorta (AA) in severe obstructive sleep apnea syndrome (OSAS) patients with or without hypertension (HT) via velocity vector imaging (VVI).

METHODS: A total of 68 patients with severe OSAS were selected, 35 of whom were included in the simple OSAS group and 33 of whom were included in the OSAS + HT group, and 40 volunteers without these two disorders who were taken as the control group. AA biomechanical properties, that is, AA longitudinal strain (ALS), AA circumferential strain (ACS), and fractional area change (FAC), were evaluated via VVI. Pulsed Doppler early transmitral peak flow velocity (E), early diastolic mitral annular velocity (e'), left ventricular (LV) global longitudinal strain (GLS), and the AA dimension (AD) were also measured.

RESULTS: ALS (mean ± SD; 32.8% ± 11.9% and 19.7% ± 7.6% vs. 40.6% ± 15.6%, p = 0.006), ACS (mean ± SD; 11.8% ± 3.5% and 8.6% ± 2.7% vs. 16.5% ± 5.8%, p = 0.02), and FAC (mean ± SD; 21.0% ± 5.3% and 12.4% ± 3.8% vs. 32.8% ± 9.7%, p = 0.004) were significantly lower in the patient groups (OSAS and OSAS + HT, respectively) than in the control group. LV systolic and diastolic functions were also impaired in the patient groups. Compared with volunteers without OSAS and HT, these patients had a greater AD and E/e' ratio and a lower GLS (p < 0.01). The aortic biomechanical properties were strongly correlated with the LV function and sleep parameters.

CONCLUSION: AA biomechanical properties are impaired in patients with severe OSAS, especially those with HT. Impairments in these aortic biomechanical properties are associated with diminished LV function and abnormal sleep parameters. This discovery may help clinicians identify and manage potential cardiovascular risks in OSAS patients. Further large-scale longitudinal studies are needed to confirm the potential predictive value of aortic events (e.g., aortic aneurysm or dissection) in patients with OSAS.}, } @article {pmid40152605, year = {2025}, author = {Yuan, C and Dong, H and Wu, C and Liu, J and Wang, Z and Wang, X and Ren, H and Wang, Z and Lu, Q}, title = {EPG-5 regulates TGFB/TGF-β and WNT signalling by modulating retrograde endocytic trafficking.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/15548627.2025.2485420}, pmid = {40152605}, issn = {1554-8635}, abstract = {The Vici syndrome protein EPG5 acts as a tethering factor determining the fusion specificity of autophagosomes with late endosomes/lysosomes. Here we demonstrated that during C. elegans development, EPG-5 modulates SMA and MAB TGFB/TGF-β signaling in controlling body size and also WNT signaling in regulating cell migration. EPG-5 is required for retrograde trafficking of the TGFB receptor SMA-6 and WLS/Wntless homolog MIG-14. In epg-5 mutants, SMA-6 and MIG-14 are trapped within hybrid endosomal structures, which colocalize with SNX-1- and SNX-3-labeled vesicles, respectively. Basolateral recycling processes of transmembrane cargos H.s.TFR/hTfR and H.s.IL2RA/hTAC are also defective in epg-5 mutants. Depletion of EPG-5 causes defective RAB-5 and RAB-7, and RAB-5 and RAB-10 conversion, leading to the formation of these hybrid vesicles. The defects in endocytic trafficking and autophagy in epg-5 mutants are ameliorated by knocking down components of the HOPS complex. Our study demonstrates the intersection between the autophagy pathway and the endocytic pathway, providing insights into the pathogenesis of amyotrophic lateral sclerosis (ALS) and Vici syndrome.Abbreviations: ALM: anterior lateral microtubule; ATG: autophagy related; AVM: anterior ventral microtubule; CORVET: class C core vacuole/endosome tethering; DAF-4: abnormal dauer formation 4; DIC: differential interference contrast; EPG: ectopic PGL granules; EPG-5: ectopic P granules 5; GAP: GTPase activating protein; GFP: green fluorescent protein; HOPS: homotypic fusion and vacuole protein sorting; H.s.IL2RA/hTAC: human interleukin 2 receptor subunit alpha; H.s.TFR/hTfR: human transferrin receptor; L1/L4: the first/fourth larval; mCh: mCherry; MIG-14: abnormal cell migration 14; PLM: posterior lateral microtubule; PVM: posterior ventral microtubule; RAB: ras-related protein; RFP: red fluorescent protein; RME-1: receptor mediated endocytosis 1; SMA-6: small 6; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SNX: sorting nexin; TBC-2: TBC1 (Tre-2/Bub2/Cdc16) domain family 2; TGFB/TGF-β: transforming growth factor beta; TGN: trans-Golgi network; VPS: related to yeast vacuolar protein sorting factor; WT: wild type.}, } @article {pmid40152389, year = {2025}, author = {Belosludtseva, NV and Ilzorkina, AI and Dubinin, MV and Mikheeva, IB and Belosludtsev, KN}, title = {Comparative Study of Structural and Functional Rearrangements in Skeletal Muscle Mitochondria of SOD1-G93A Transgenic Mice at Pre-, Early-, and Late-Symptomatic Stages of ALS Progression.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {30}, number = {3}, pages = {28260}, doi = {10.31083/FBL28260}, pmid = {40152389}, issn = {2768-6698}, support = {23-25-00286//Russian Science Foundation/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/physiopathology/pathology ; *Mice, Transgenic ; *Disease Progression ; Male ; *Mitochondria, Muscle/metabolism/ultrastructure/pathology ; Mice ; Muscle, Skeletal/metabolism/ultrastructure/pathology/physiopathology ; Disease Models, Animal ; Superoxide Dismutase/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Lipid Peroxidation ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive multisystem disease characterized by limb and trunk muscle weakness that is attributed, in part, to abnormalities in mitochondrial ultrastructure and impaired mitochondrial functions. This study investigated the time course of structural and functional rearrangements in skeletal muscle mitochondria in combination with motor impairments in Tg (copper-zinc superoxide dismutase enzyme (SOD1) G93A) dl1/GurJ (referred to as SOD1-G93A/low) male mice, a familial ALS model, as compared with non-transgenic littermates.

METHODS: The neurological status and motor functions were assessed weekly using the paw grip endurance method and the grid suspension test with two-limb and four-limb suspension tasks. Transmission electron microscopy followed by quantitative analysis was performed to study ultrastructural alterations in the quadriceps femoris. Functional analysis of skeletal muscle mitochondria was performed using high-resolution Oxygraph-2k (O2K) respirometry and methods for assessing the calcium retention capacity index and the content of lipid peroxidation products in freshly isolated preparations.

RESULTS: Based on the behavioral phenotyping data, specific age groups were identified: postnatal day 56 (P56) (n = 10-11), 84 (P84) (n = 10-11), and 156 (P154) (n = 10-12), representing the pre-symptomatic, early-symptomatic and late-symptomatic stages of ALS progression in SOD1-G93A/low mice, respectively. Electron microscopy showed mosaic destructive changes in subsarcolemmal mitochondria in fibers of the quadriceps femoris from 84-day-old SOD1-G93A/low mice. Morphometric analysis revealed an elevation in the mean size of the mitochondria in SOD1-G93A mice at P84 and P154. In addition, the P154 transgenic group demonstrated a decrease in sarcomere width and the number of mitochondria per unit area. At the symptomatic stage, SOD1-G93A mice exhibited a decreased respiratory control ratio, ADP-stimulated, and uncoupled respiration rates of mitochondria isolated from the quadriceps femoris muscle, as measured by high-resolution respirometry. In parallel, the mitochondria showed lower calcium retention capacity and increased levels of lipid peroxidation products compared with the control.

CONCLUSIONS: Taken together, these results indicate stage-dependent changes in skeletal muscle mitochondrial ultrastructure and functions associated with defective oxidative phosphorylation, impaired calcium homeostasis, and oxidative damage in the SOD1-G93A/low mouse model, which appears to be a promising direction for the development of combination therapies for ALS.}, } @article {pmid40151753, year = {2025}, author = {Carqueja, I and Montenegro Sá, F and Monteiro, S}, title = {Ventricular Arrhythmias Caused by Left Main Coronary Artery Vasospasm: A Diagnostic Challenge in a Cardiac Arrest Victim.}, journal = {Cureus}, volume = {17}, number = {2}, pages = {e79554}, pmid = {40151753}, issn = {2168-8184}, abstract = {Sudden cardiac death (SCD) is a common cause of cardiovascular deaths. It may be caused by primary electrical diseases, cardiomyopathies, myocarditis, valvular heart diseases, or coronary artery disease (including acute coronary syndrome). Coronary artery vasospasm is defined as a transient total or subtotal coronary artery obstruction, associated with angina symptoms and ischemic findings on electrocardiogram (ECG). It is a cause of myocardial infarction, life-threatening arrhythmias, atrioventricular block, and SCD. A 55-year-old man presented to the hospital after an out-of-hospital cardiac arrest (OHCA). He had a previous history of cardiovascular risk factors, excessive alcohol intake, non-obstructive coronary artery disease, and paroxysmic atrial fibrillation. On the day of the OHCA, he had a sudden collapse while exercising, with ventricular fibrillation and return of spontaneous circulation (ROSC) after advanced life support (ALS). No ECG or echocardiographic anomalies were identified on hospital admission. The patient suffered three more episodes of cardiac arrest during the hospital stay, with atypical arrhythmic presentations. No ECG or echocardiographic abnormalities were observed after ROSC. The fourth cardiac arrest had concomitant segmental ST changes and de novoechocardiographic segmental motility abnormalities suggestive of left main coronary artery occlusion. These findings were transient, with a normal ECG and echocardiogram obtained one hour after ROSC. No electrolyte abnormalities or other causes of cardiac arrest were identified. The hypothesis of left main coronary vasospasm was raised as the likely diagnosis. Coronary artery vasospasm is a possible cause of major cardiac events. Diagnosis can be challenging due to the transient findings and varied manifestations, often in patients with normal coronary arteries. The correct diagnosis and treatment of coronary artery vasospasm can have a determinant effect on prognosis and mortality, as appropriate treatment can lead to prolonged event-free survival. Provocative coronary vasospasm tests performed in patients with atypical cardiovascular manifestations can allow for the timely diagnosis of vasospasm and avoid critical events. The authors aim to raise awareness of the different clinical presentations of coronary artery vasospasm and its consequences. The performance of provocative tests in selected patients should be considered to promote early diagnosis and potentially avoid major events.}, } @article {pmid40151693, year = {2025}, author = {Tariq, D and Madhusudan, R and Guntupalli, Y and Karumanchi Anantha Venkata Sai, S and Vejandla, B and Lnu, M}, title = {A Cross-Sectional Study Comparing Patient Information Guides for Amyotrophic Lateral Sclerosis, Myasthenia Gravis, and Guillain-Barré Syndrome Produced by ChatGPT-4 and Google Gemini 1.5.}, journal = {Cureus}, volume = {17}, number = {2}, pages = {e79646}, pmid = {40151693}, issn = {2168-8184}, abstract = {INTRODUCTION: Patient education for amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG), and Guillain-Barré syndrome (GBS) is essential for effective symptom management, improving quality of life, and enabling informed care decisions. AI tools enhance healthcare and patient education through personalized care and improved diagnostics.

METHODS:  In this study, ChatGPT (OpenAI, San Francisco, CA, USA) and Google Gemini (Mountain View, CA, USA) generated patient education guides for ALS, MG, and GBS. Variables included word count, sentence count, average words and syllables per sentence, grade level, ease score using the Flesch-Kincaid calculator, similarity score using QuillBot, and reliability using a modified DISCERN score. Statistical analysis was done using R version 4.3.2 (2023; R Foundation for Statistical Computing, Vienna, Austria).

RESULTS: ChatGPT-generated brochures for patient education on ALS, MG, and GBS had a higher grade level and lower ease score compared to those generated by Google Gemini. Although both models had similar reliability and similarity percentages, ChatGPT produced more content with greater complexity and slightly higher reliability.

CONCLUSION:  This study found no significant difference in the average ease, grade, and reliability scores between the two AI tools when generating patient information brochures on ALS, MG and GBS. However, a statistically significant difference was observed in the mean word counts generated by the tools.}, } @article {pmid40151398, year = {2025}, author = {Roy, SM and Acquarone, E and Argyrousi, EK and Zhang, H and Staniszewski, A and Inoue, A and Ziarek, JJ and Arancio, O and Watterson, DM}, title = {Optimized 5-HT2b inhibitors for neuropsychiatric syndromes with cognitive dysfunction.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70073}, pmid = {40151398}, issn = {2352-8737}, abstract = {INTRODUCTION: Neuropsychiatric syndromes such as anxiety and agitation are clinical presentations common to diverse neurodegenerative diseases and brain injury sequelae. They are a concern due to the impact on cognition, social interactions, and non-pharmacological treatments. Cognitive or behavioral disturbances occur at early disease stages and increase with disease progression. Coincident pathologies include the loss of serotonin (5-HT) neurons and appearance of neurofibrillary tangles in the raphe nucleus. Brain 5-HT2b receptor (5-HT2bR) levels are increased in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and post-stroke morbidity. HTR2B gene variants are implicated in psychiatric disorders. 5-HTRs are associated with atypical neurotropic drug mechanisms and behavioral dysfunction in drug abuse. The accumulating body of evidence suggests that selective 5-HT2bR inhibition might mitigate neuropsychiatric syndromes and the associated cognitive dysfunction. Atypical neurotropic drugs interact with a variety of monoamine receptors and outcomes are viewed as a combination of 5-HT and dopamine D2 receptor mediated actions. Clearly, there is a need for insight into precision 5-HT2bR inhibition as a potential pharmacological mechanism for treatment of neuropsychiatric syndromes and cognitive dysfunction associated with dementia.

METHODS: Strategic optimization of an atypical neurotropic drug was used to develop MW073, a highly selective and orally bioavailable inhibitor of 5-HT2bR activity and β-arrestin-1 recruitment that is devoid of dopamine receptor recognition and risk of 5-HT2bR agonist activity.

RESULTS: MW073 ameliorates amyloid and tau induction of behavioral dysfunction in preventive or disease stage intervention paradigms. Using MW073 as a standard of comparison, risperidone was shown to be a dose-dependent inhibitor 5-HT2bR activity and β-arrestin-1 recruitment.

DISCUSSION: Selective inhibition of 5-HT2bR activity is a viable mechanism for the treatment of neuropsychiatric syndromes with synaptic dysfunction as a root cause and is a previously unrealized pharmacodynamic mechanism potentially embedded in current neurotherapeutics.

HIGHLIGHTS: A new highly selective 5-HT2bR antagonist, MW073, is described and used as a reference standard.MW073 attenuates synaptic and behavioral dysfunctions an animal models of neuropsychatric syndromes.Risperidone is a dose dependent inhibitor of 5-HT2bR activity and arrestin recruitment.}, } @article {pmid40150989, year = {2025}, author = {Matsumoto, S and Tateishi-Karimata, H and Ohyama, T and Sugimoto, N}, title = {Controlling the Local Conformation of RNA G-Quadruplex Results in Reduced RNA/Peptide Cytotoxic Accumulation Associated with C9orf72 ALS/FTD.}, journal = {Small methods}, volume = {}, number = {}, pages = {e2401630}, doi = {10.1002/smtd.202401630}, pmid = {40150989}, issn = {2366-9608}, abstract = {Repeat expansion of d(G4C2) in the noncoding region of the C9orf72 gene contributes to neurodegenerative diseases. The repeat expansion transcript r(G4C2) induces RNA/peptide accumulation, which, in turn, induces cytotoxicity and accelerates the development of neurodegenerative diseases. Such cytotoxic accumulation is triggered by peptide aggregation. Here, a technique is developed to prevent accumulation by regulating RNA interactions, assuming that RNA structure is important for peptide interactions. A screening method is used to identify compounds that suppress RNA accumulation of r(G4C2) repeats. The four compounds are identified with wide π-planes containing hydroxyl, methoxy, and cyclic ether groups that suppressed RNA accumulation. Interestingly, these compounds also suppressed RNA/peptide accumulation in neuroblastoma cells, indicating that RNA accumulation is a key regulator of RNA/peptide cytotoxic aggregate formation. In vitro and in silico physicochemical analyses reveal that these compounds bind to the loop region of the G-quadruplex via hydrogen bonds or CH-π interactions, resulting in an altered loop conformation. Importantly, these conformational changes inhibited RNA G-quadruplex associations. These results show that conformational changes are promising for controlling the interactions between G-quadruplexes and further RNA accumulation. These findings may be useful in the development of therapeutic strategies for the treatment of neurodegenerative diseases.}, } @article {pmid40149779, year = {2025}, author = {Ginanneschi, F and Casali, S and Cioni, C and Righi, D and Emmanuello, E and Toccaceli, C and Plantone, D and De Stefano, N}, title = {Does Lumbar Puncture Still Have Clinical Value for Patients with Amyotrophic Lateral Sclerosis?.}, journal = {Brain sciences}, volume = {15}, number = {3}, pages = {}, pmid = {40149779}, issn = {2076-3425}, abstract = {Background: The relationship between routine cerebrospinal fluid (CSF) testing and clinical and prognostic data in amyotrophic lateral sclerosis (ALS) remains unclear. Additionally, biochemical data have never been correlated with markers of neurodegeneration. The purpose of this study is to determine whether lumbar puncture may still have clinical utility in ALS. Methods: We collected the CSF profiles of 140 ALS subjects. CSF protein, albumin, IgG, IgG index, albumin quotient (QAlb), t-tau, p-tau, and Aβ42 were analyzed. Results: Approximately one-quarter of ALS patients had elevated levels of protein, albumin, and QAlb in the CSF, but these were not associated with clinical or survival data. Among the neurodegeneration markers, the percentage of patients with abnormal values ranged from 26.3% to 35.4%. The p-tau/t-tau ratio and Aβ42 were correlated with both the ALS progression rate and the time from diagnosis to death. Aβ42 was the prognostic marker most strongly associated with survival. Conclusions: The lack of correlation between biochemical CSF findings and the clinical and/or prognostic status of ALS suggests that these markers have no clinical value. However, neurodegeneration markers that are easily measurable in clinical laboratories, particularly Aβ42, may be useful at the time of diagnosis for predicting ALS survival and progression rate.}, } @article {pmid40149599, year = {2025}, author = {Yang, W and Xiao, W and Liu, X and Li, H and Huang, T and Fan, D}, title = {Testosterone Supplementation: A Potential Therapeutic Strategy for Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {13}, number = {3}, pages = {}, pmid = {40149599}, issn = {2227-9059}, support = {82071426//National Natural Science Foundation of China/ ; }, abstract = {Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterized by the degeneration of spinal cord and brain neurons. Proteomics combined with Mendelian randomization (MR) is an effective method for finding disease treatment targets. Methods: We aimed to seek new therapeutic targets for ALS. A large-scale GWAS on proteomics (4907 circulatory protein) with 35,559 individuals was included as the exposure data; a GWAS with 138,086 ALS patients was used as the outcome data; we found that a high level of sex hormone-binding globulin (SHBG) is a risk factor by MR analysis. Colocalization analyses were used to validate the causality between SHBG and ALS further. Functional enrichment found a high level of SHBG was associated with a low level of bioavailable testosterone. Two-sample MR confirmed the association of SHBG (400,210 samples), bioavailable testosterone (367,289 samples), and ALS. Results: A high level of SHBG, and a low level of bioavailable testosterone are risk factors for ALS. Conclusions: A low level of bioavailable testosterone is a risk factor for ALS. Although our study is relatively limited and cannot fully confirm that testosterone supplementation has a therapeutic effect on ALS, it offers a promising direction for ALS therapy.}, } @article {pmid40149536, year = {2025}, author = {Kleinerova, J and Chipika, RH and Tan, EL and Yunusova, Y and Marchand-Pauvert, V and Kassubek, J and Pradat, PF and Bede, P}, title = {Sensory Dysfunction in ALS and Other Motor Neuron Diseases: Clinical Relevance, Histopathology, Neurophysiology, and Insights from Neuroimaging.}, journal = {Biomedicines}, volume = {13}, number = {3}, pages = {}, pmid = {40149536}, issn = {2227-9059}, support = {JPND-Cofund-2-2019-1 & HRB EIA-2017-019//HRB/ ; }, abstract = {Background: The clinical profiles of MNDs are dominated by inexorable motor decline, but subclinical proprioceptive, nociceptive and somatosensory deficits may also exacerbate mobility, dexterity, and bulbar function. While extra-motor pathology and frontotemporal involvement are widely recognised in motor neuron diseases (MNDs), reports of sensory involvement are conflicting. The potential contribution of sensory deficits to clinical disability is not firmly established and the spectrum of sensory manifestations is poorly characterised. Methods: A systematic review was conducted to examine the clinical, neuroimaging, electrophysiology and neuropathology evidence for sensory dysfunction in MND phenotypes. Results: In ALS, paraesthesia, pain, proprioceptive deficits and taste alterations are sporadically reported and there is also compelling electrophysiological, histological and imaging evidence of sensory network alterations. Gait impairment, impaired dexterity, and poor balance in ALS are likely to be multifactorial, with extrapyramidal, cerebellar, proprioceptive and vestibular deficits at play. Human imaging studies and animal models also confirm dorsal column-medial lemniscus pathway involvement as part of the disease process. Sensory symptoms are relatively common in spinal and bulbar muscular atrophy (SBMA) and Hereditary Spastic Paraplegia (HSP), but are inconsistently reported in primary lateral sclerosis (PLS) and in post-poliomyelitis syndrome (PPS). Conclusions: Establishing the prevalence and nature of sensory dysfunction across the spectrum of MNDs has a dual clinical and academic relevance. From a clinical perspective, subtle sensory deficits are likely to impact the disability profile and care needs of patients with MND. From an academic standpoint, sensory networks may be ideally suited to evaluate propagation patterns and the involvement of subcortical grey matter structures. Our review suggests that sensory dysfunction is an important albeit under-recognised facet of MND.}, } @article {pmid40149460, year = {2025}, author = {Ghezzi, A and Gianferrari, G and Baldassarri, E and Zucchi, E and Martinelli, I and Vacchiano, V and Bonan, L and Zinno, L and Nuredini, A and Canali, E and Gizzi, M and Terlizzi, E and Medici, D and Sette, E and Currò Dossi, M and Morresi, S and Santangelo, M and Patuelli, A and Longoni, M and De Massis, P and Ferro, S and Fini, N and Simonini, C and Carra, S and Zamboni, G and Mandrioli, J}, title = {Phenotypical Characterization of C9ALS Patients from the Emilia Romagna Registry of ALS: A Retrospective Case-Control Study.}, journal = {Genes}, volume = {16}, number = {3}, pages = {}, pmid = {40149460}, issn = {2073-4425}, support = {00000000//Emilia Romagna Regional Health Authority/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/epidemiology ; Male ; Female ; *C9orf72 Protein/genetics ; Middle Aged ; *Registries ; Aged ; *Phenotype ; Case-Control Studies ; Disease Progression ; Retrospective Studies ; Adult ; Prognosis ; }, abstract = {BACKGROUND/OBJECTIVES: C9ORF72 expansion is associated with significant phenotypic heterogeneity. This study aimed to characterize the clinical features of C9ALS patients from the Emilia Romagna ALS registry (ERRALS) and compare them with non-mutated ALS (nmALS) patients matched for sex, age at onset, and diagnostic delay, sourced from the same register.

METHODS: In total, 67 C9ALS patients were compared to 201 nmALS. Clinical data, phenotype, and prognostic factors were analyzed in the two groups and within the C9ALS group after stratification by sex.

RESULTS: C9ALS patients displayed a higher disease progression rate and shorter times to gastrostomy and invasive ventilation, despite no differences in overall survival. Female C9ALS had a more severe bulbar and upper motor neuron involvement compared to males. Cognitive and behavioral symptoms were more common in the C9ALS group, and the former was an independent prognostic factor. Prevalences of, autoimmune diseases, and dyslipidemia were significantly higher among C9ALS patients.

CONCLUSIONS: In our dataset, we show an overall increased disease progression rate in C9ALS patients and hint at sex-specific discrepancies in some phenotypical characteristics. We also suggest a possible clinically relevant involvement of C9ORF72 expansion in metabolism and autoimmunity.}, } @article {pmid40149017, year = {2025}, author = {Suk, TR and Part, CE and Zhang, JL and Nguyen, TT and Heer, MM and Caballero-Gómez, A and Grybas, VS and McKeever, PM and Nguyen, B and Ali, T and Callaghan, SM and Woulfe, JM and Robertson, J and Rousseaux, MWC}, title = {A stress-dependent TDP-43 SUMOylation program preserves neuronal function.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {38}, pmid = {40149017}, issn = {1750-1326}, support = {PJT-195691//CIHR/ ; }, mesh = {*Sumoylation/physiology ; *DNA-Binding Proteins/metabolism/genetics ; Humans ; Animals ; *Neurons/metabolism ; Mice ; Male ; Female ; Frontotemporal Dementia/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Aging/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are overwhelmingly linked to TDP-43 dysfunction. Mutations in TDP-43 are rare, indicating that the progressive accumulation of exogenous factors - such as cellular stressors - converge on TDP-43 to play a key role in disease pathogenesis. Post translational modifications such as SUMOylation play essential roles in response to such exogenous stressors. We therefore set out to understand how SUMOylation may regulate TDP-43 in health and disease. We find that TDP-43 is regulated dynamically via SUMOylation in response to cellular stressors. When this process is blocked in vivo, we note age-dependent TDP-43 pathology and sex-specific behavioral deficits linking TDP-43 SUMOylation with aging and disease. We further find that SUMOylation is correlated with human aging and disease states. Collectively, this work presents TDP-43 SUMOylation as an early physiological response to cellular stress, disruption of which may confer a risk for TDP-43 proteinopathy.}, } @article {pmid40148124, year = {2025}, author = {Beckers, D and Kretz, F and Glandorf, K and Abdassalam, S and Amer, M and Breyer, DRH and Kaymak, H and Klabe, K and Beckers, L}, title = {Automated Comprehensive Analysis of Preoperative Biometric Parameters in Cataract Patients: A Retrospective Study of over 6 000 Eyes.}, journal = {Klinische Monatsblatter fur Augenheilkunde}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2541-4942}, pmid = {40148124}, issn = {1439-3999}, abstract = {Cataract surgery is one of the most successful surgical procedures, improving vision and quality of life for millions globally. An accurate preoperative measurement is crucial for predicting outcomes, particularly in minimizing postoperative refractive errors through precise intraocular lens (IOL) selection. This study aimed to analyze preoperative biometric data in cataract patients to identify key parameters relevant for clinical decision-making. The study also sought to understand patient demographics and biometrics in a representative population. An automated retrospective analysis was conducted on the preoperative biometric data of 6 163 eyes from 3 118 patients who underwent cataract or clear lens extraction (CLE) surgery in a German clinic over the past 2 years. All measurements were taken using the IOL Master 700 (Carl Zeiss Meditec, Jena, Germany), and data were automatically transferred for analysis using a dedicated software tool. Biometric parameters assessed included axial length (AL), keratometry values (K, TK), anterior chamber depth (ACD), lens thickness (LT), and vitreous length (VL). The age and gender distribution of the cohort was also considered. The biometric data from this large patient cohort largely aligns with published norms for cataract patients. The majority of eyes exhibited ALs and corneal curvatures within expected ranges, supporting accurate IOL power calculations. The study also confirmed a high prevalence of mild astigmatism, suggesting that toric IOLs could address residual astigmatism for better visual outcomes. This study's large sample size adds valuable insights into preoperative cataract patient data and shows the value of an automated analysis.}, } @article {pmid40148057, year = {2025}, author = {De Marchi, F and Spinelli, EG and Bendotti, C}, title = {Neuroglia in neurodegeneration: Amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Handbook of clinical neurology}, volume = {210}, number = {}, pages = {45-67}, doi = {10.1016/B978-0-443-19102-2.00004-1}, pmid = {40148057}, issn = {0072-9752}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Frontotemporal Dementia/pathology ; *Neuroglia/pathology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases sharing significant pathologic and genetic overlap, leading to consider these diseases as a continuum in the spectrum of their pathologic features. Although FTD compromises only specific brain districts, while ALS involves both the nervous system and the skeletal muscles, several neurocentric mechanisms are in common between ALS and FTD. Also, recent research has revealed the significant involvement of nonneuronal cells, particularly glial cells such as astrocytes, oligodendrocytes, microglia, and peripheral immune cells, in disease pathology. This chapter aims to provide an extensive overview of the current understanding of the role of glia in the onset and advancement of ALS and FTD, highlighting the recent implications in terms of prognosis and future treatment options.}, } @article {pmid40147067, year = {2025}, author = {Jiang, T and Ding, W and Li, X}, title = {Serum creatine kinase dynamics in amyotrophic lateral sclerosis: Predictive role of male sex, limb onset, and intermediate disease duration for stratified monitoring.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {135}, number = {}, pages = {111203}, doi = {10.1016/j.jocn.2025.111203}, pmid = {40147067}, issn = {1532-2653}, abstract = {OBJECTIVE: To investigate serum creatine kinase (CK) levels in amyotrophic lateral sclerosis (ALS) patients and their associations with disease characteristics, exploring its utility as a biomarker for disease progression.

METHODS: This retrospective study included 81 definitive ALS patients and 99 matched controls. Serum CK levels were analyzed against sex, age, onset site, disease duration, and ALSFRS-R scores using Mann-Whitney U tests, Kruskal-Wallis tests, and multivariate regression.

RESULTS: ALS patients exhibited significantly elevated CK levels compared to controls (233.92 ± 216.91 vs. 101.81 ± 34.28 IU/L, P < 0.05), with 65.43 % exceeding gender-specific ranges. Multivariate analysis identified male sex (β = 0.32, 95 % CI: 0.21-0.43; P < 0.05), limb onset (vs. bulbar: β = 0.41, 95 % CI: 0.29-0.53; P < 0.05), and intermediate disease duration (1-3 years: β = 0.32, P < 0.05) as independent predictors. CK levels peaked in limb-onset patients (lower limb: 342.40 ± 283.53 IU/L vs. bulbar: 96.20 ± 49.39 IU/L; P < 0.05). Higher CK was associated with moderate disease severity (ALSFRS-R 36-40 vs. ≤ 35: P < 0.05).

CONCLUSION: Serum CK elevation in ALS is strongly linked to male sex, limb onset, and intermediate disease duration (1-3 years), though long-duration cases (>3 years) were underrepresented (n = 4). These findings highlight CK's potential as a cost-effective biomarker for personalized monitoring, particularly in limb-onset males with moderate functional impairment. Further validation in larger cohorts is warranted.}, } @article {pmid40145977, year = {2025}, author = {Zhao, W and Liu, Z and Wu, J and Liu, A and Yan, J}, title = {Potential targets of microglia in the treatment of neurodegenerative diseases: mechanism and therapeutic implications.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-01343}, pmid = {40145977}, issn = {1673-5374}, abstract = {For diverse neurodegenerative disorders, microglial cells are activated. Furthermore, dysfunctional and hyperactivated microglia initiate mitochondrial autophagy, oxidative stress, and pathological protein accumulation, ending with neuroinflammation that exacerbates damage to dopaminergic neurons and contributes significantly to the pathology of neurodegenerative disorder. Microglial overactivation is closely associated with the secretion of pro-inflammatory cytokines, the phagocytosis of injured neurons, and the modulation of neurotoxic environments. This review summarizes the role of microglia neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, cortical degeneration, Lewy body dementia, and Huntington's disease. It also discusses novel forms of cell death such as ferroptosis, cuproptosis, disulfidptosis, and parthanatos (poly(adenosine diphosphate ribose) polymerase 1-dependent cell death), as well as the impact of regulatory factors related to microglial inflammation on microglial activation and neuroinflammation. The aim is to identify potential targets for microglial cell therapy in neurodegenerative diseases.}, } @article {pmid40145976, year = {2025}, author = {Wang, Z and Cao, W and Chen, L and Zhang, S and Tang, L and Cui, W and Kong, M and Yu, L and Fan, D and Zheng, W}, title = {The role of the peripheral immune system in mediating axonal dysfunction in early-stage amyotrophic lateral sclerosis: an age- and sex-based analysis.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-01081}, pmid = {40145976}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons. Early-stage axonal dysfunction, rather than central nervous system injury, plays a key role in the disease process. However, the molecular mechanisms underlying this dysfunction remain unclear. To investigate the relationship between peripheral immune dysregulation and axonal dysfunction in amyotrophic lateral sclerosis, we recruited 372 patients within the first 12 months of sporadic amyotrophic lateral sclerosis onset between January 2018 and May 2024. We collected peripheral immune markers at baseline, including total leukocytes, lymphocytes, monocytes, neutrophils, basophils, eosinophils, and platelets. We also calculated four derived ratios: neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and systemic immune inflammation index. Multivariate analysis, adjusted for confounding factors, revealed that higher counts of total leukocytes and neutrophils, as well as higher neutrophil-related ratios, including the neutrophil to lymphocyte ratio and the systemic immune inflammation index, were significantly correlated with higher compound muscle action potential scores. Stratified analyses revealed that these associations varied by age and sex. Furthermore, mediation analysis demonstrated that axonal dysfunction plays a significant role in the relationship between immune markers and disease progression. These findings emphasize the critical role that peripheral immune dysregulation plays in amyotrophic lateral sclerosis progression by mediating peripheral nerve injury, particularly in the early stages of the disease. This study highlights the importance of the peripheral nervous system in the early stages of amyotrophic lateral sclerosis and provides new insights into disease mechanisms and potential therapeutic targets.}, } @article {pmid40143847, year = {2025}, author = {Meyer, J and Gaur, N and von der Gablentz, J and Friedrich, B and Roediger, A and Grosskreutz, J and Steinbach, R}, title = {Phosphorylated neurofilament heavy chain (pNfH) concentration in cerebrospinal fluid predicts overall disease aggressiveness (D50) in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1536818}, pmid = {40143847}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, characterized by tremendous clinical heterogeneity that necessitates reliable biomarkers for the trajectory of the disease. The potential of phosphorylated Neurofilament-Heavy-chain (pNfH) measured in cerebrospinal fluid (CSF) to mirror disease progressiveness has repeatedly been suggested but is not applicable as outcome on an individual patient-level. This potential was probably obfuscated before due to imprecise clinical measures of disease progression that assumed a linear decline of motoric function over time. The primary objective was therefore to study if disease aggressiveness, as quantified via the D50 model, would reveal more stable correlations with pNfH.

METHODS: ELISA-quantified pNfH CSF levels of 108 patients with ALS were comparatively analyzed in relation to three different measures of disease progression speed via analyses of covariance, linear and non-linear regressions, respectively. These were (a) the D50, depicting a patient's overall disease aggressiveness, (b) cFL, the calculated functional loss-rate as locally derived parameter of progression speed, and (c) DPR, the disease progression-rate as more commonly used linear approximation of points lost per month in the ALS functional rating scale since symptom onset.

RESULTS: All analyses of covariance showed a significant main impact of the respective disease progression-speed parameter on pNfH, independent of disease phase, presence of frontotemporal dementia, analyzing laboratory, sex or clinical onset type, while only age revealed borderline additional influence. Notably, CSF pNfH concentration was independent of how far the disease had progressed, as neither disease phase nor a direct regression with the quantified disease accumulation at the time of lumbar puncture revealed a significant correlation. However, the parameter D50 quantifying aggressiveness showed the most significant impact on pNfH-levels, as compared to the cFL and even more evident in contrast to the DPR. This superiority of D50 was confirmed in direct linear and most evident in non-linear regressions with pNfH.

CONCLUSION: Overall disease aggressiveness in ALS, as quantified by D50, most robustly correlated with CSF pNfH-levels, independent of the time of collection during symptomatic disease. This opens perspectives to use CSF pNfH as a prognostic outcome measure for future therapeutic interventions in the sense of precision medicine.}, } @article {pmid40143800, year = {2025}, author = {Heylen, A and Vermeiren, Y and De Deyn, PP and Van Dam, D}, title = {Monoaminergic Alterations at the Subregional Cervical and Thoracic Spinal Cord Level of Patients Within the FTD-ALS Continuum and Early-Onset AD: Low Thoracic Dopaminergic Activity in ALS.}, journal = {Journal of neurochemistry}, volume = {169}, number = {3}, pages = {e70046}, doi = {10.1111/jnc.70046}, pmid = {40143800}, issn = {1471-4159}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Female ; Male ; *Frontotemporal Dementia/metabolism/pathology ; Aged ; Middle Aged ; *Alzheimer Disease/metabolism/pathology ; *Dopamine/metabolism ; Spinal Cord/metabolism ; Biogenic Monoamines/metabolism ; Thoracic Vertebrae ; Cervical Cord/metabolism ; }, abstract = {Early-onset neurodegeneration leads to cognitive and behavioral symptoms in frontotemporal dementia (FTD) and motor disturbances in amyotrophic lateral sclerosis (ALS). Despite distinct clinical profiles, more than half of FTD patients experience ALS-related symptoms and vice versa. Spinal cord monoamine neurotransmitter alterations were reported in ALS, but not yet in FTD. Therefore, we compared monoaminergic turnover across the FTD-ALS continuum. Reversed-phase, ultra-high-performance liquid chromatography with electrochemical detection was used to measure levels of the monoamines (nor)adrenaline ((N)A), dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) and their metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in five cervical and thoracic spinal cord regions in 10 FTD, 14 ALS, 6 mixed FTD-ALS, 14 early-onset Alzheimer's disease (EOAD), and 7 control (CONTR) individuals. At the cervical level, NA levels were lower in FTD-ALS versus CONTR, whereas the HVA/5-HIAA ratio was higher in ALS versus EOAD in the lateral funiculus. In the dorsal horn-intermediate gray matter, DA levels were decreased in FTD-ALS compared to FTD. At the thoracic level, DOPAC was lower in ALS than in FTD-ALS patients in the ventral and lateral funiculus, ventral horn, and dorsal horn-intermediate gray matter, as was the DOPAC/DA ratio in the lateral funiculus and dorsal horn-intermediate gray matter. Contrarily, HVA/DA turnover was lower in FTD-ALS than in FTD in the dorsal and ventral funiculus. We observed lower NA levels in FTD-ALS than in FTD in the ventral funiculus, and lower MHPG/NA turnover in the dorsal horn-intermediate gray matter. A levels were lower in ALS versus FTD. This study indicates differences in monoaminergic turnover across the FTD-ALS continuum, at the cervical and thoracic levels, with primarily a decrease in dopaminergic activity in ALS. Characterizing disease-specific neurochemical profiles for FTD, ALS, or FTD-ALS could contribute to the identification of novel interesting pharmacological targets.}, } @article {pmid40143051, year = {2025}, author = {Zou, Y and Zhang, J and Chen, L and Xu, Q and Yao, S and Chen, H}, title = {Targeting Neuroinflammation in Central Nervous System Diseases by Oral Delivery of Lipid Nanoparticles.}, journal = {Pharmaceutics}, volume = {17}, number = {3}, pages = {}, pmid = {40143051}, issn = {1999-4923}, support = {82100892//Hong Chen/ ; 82300929//Jing Zhang/ ; }, abstract = {Neuroinflammation within the central nervous system (CNS) is a primary characteristic of CNS diseases, such as Parkinson's disease, Alzheimer's disease (AD), amyotrophic lateral sclerosis, and mental disorders. The excessive activation of immune cells results in the massive release of pro-inflammatory cytokines, which subsequently induce neuronal death and accelerate the progression of neurodegeneration. Therefore, mitigating excessive neuroinflammation has emerged as a promising strategy for the treatment of CNS diseases. Despite advancements in drug discovery and the development of novel therapeutics, the effective delivery of these agents to the CNS remains a serious challenge due to the restrictive nature of the blood-brain barrier (BBB). This underscores the need to develop a novel drug delivery system. Recent studies have identified oral lipid nanoparticles (LNPs) as a promising approach to efficiently deliver drugs across the BBB and treat neurological diseases. This review aims to comprehensively summarize the recent advancements in the development of LNPs designed for the controlled delivery and therapeutic modulation of CNS diseases through oral administration. Furthermore, this review addresses the mechanisms by which these LNPs overcome biological barriers and evaluate their clinical implications and therapeutic efficacy in the context of oral drug delivery systems. Specifically, it focuses on LNP formulations that facilitate oral administration, exploring their potential to enhance bioavailability, improve targeting precision, and alleviate or manage the symptoms associated with a range of CNS diseases.}, } @article {pmid40141996, year = {2025}, author = {Kodama, TS and Furuita, K and Kojima, C}, title = {Beyond Static Tethering at Membrane Contact Sites: Structural Dynamics and Functional Implications of VAP Proteins.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {6}, pages = {}, pmid = {40141996}, issn = {1420-3049}, support = {JP22H05536, JP22K19184, JP23H02416, and JP23K18030//Ministry of Education, Culture, Sports, Science and Technology/ ; NMR Platform//Ministry of Education, Culture, Sports, Science and Technology/ ; CR-24-05//Institute for Protein Research, Osaka University/ ; JP24ama121001//Japan Agency for Medical Research and Development/ ; }, mesh = {Humans ; *Vesicular Transport Proteins/chemistry/metabolism ; Cell Membrane/metabolism/chemistry ; Animals ; Protein Conformation ; Phylogeny ; }, abstract = {The membranes surrounding the eukaryotic cell and its organelles are continuously invaginating, budding, and undergoing membrane fusion-fission events, which enable them to perform functions not found in prokaryotic cells. In addition, organelles come into close contact with each other at membrane contact sites (MCSs), which involve many types of proteins, and which regulate the signaling and transport of various molecules. Vesicle-associated membrane protein (VAMP)-associated protein (VAP) is an important factor involved in the tethering and contact of various organelles at MCSs in almost all eukaryotes and has attracted attention for its association with various diseases, mainly neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, the detailed mechanism of its functional expression remains unclear. In this review, we quantitatively discuss the structural dynamics of the entire molecule, including intrinsically disordered regions and intramolecular and intermolecular interactions, focusing on the vertebrate VAP paralogs VAPA and VAPB. Molecular phylogenetic and biophysical considerations are the basis of the work.}, } @article {pmid40141987, year = {2025}, author = {Russo, A and Putaggio, S and Tellone, E and Calderaro, A and Cirmi, S and Laganà, G and Ficarra, S and Barreca, D and Patanè, GT}, title = {Emerging Ferroptosis Involvement in Amyotrophic Lateral Sclerosis Pathogenesis: Neuroprotective Activity of Polyphenols.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {6}, pages = {}, pmid = {40141987}, issn = {1420-3049}, mesh = {*Ferroptosis/drug effects ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy/genetics ; *Polyphenols/pharmacology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; Reactive Oxygen Species/metabolism ; Lipid Peroxidation/drug effects ; Oxidative Stress/drug effects ; Mitochondria/metabolism/drug effects ; Iron/metabolism ; }, abstract = {Neurodegenerative diseases are a group of diseases that share common features, such as the generation of misfolded protein deposits and increased oxidative stress. Among them, amyotrophic lateral sclerosis (ALS), whose pathogenesis is still not entirely clear, is a complex neurodegenerative disease linked both to gene mutations affecting different proteins, such as superoxide dismutase 1, Tar DNA binding protein 43, Chromosome 9 open frame 72, and Fused in Sarcoma, and to altered iron homeostasis, mitochondrial dysfunction, oxidative stress, and impaired glutamate metabolism. The purpose of this review is to highlight the molecular targets common to ALS and ferroptosis. Indeed, many pathways implicated in the disease are hallmarks of ferroptosis, a recently discovered type of iron-dependent programmed cell death characterized by increased reactive oxygen species (ROS) and lipid peroxidation. Iron accumulation results in mitochondrial dysfunction and increased levels of ROS, lipid peroxidation, and ferroptosis triggers; in addition, the inhibition of the Xc[-] system results in reduced cystine levels and glutamate accumulation, leading to excitotoxicity and the inhibition of GPx4 synthesis. These results highlight the potential involvement of ferroptosis in ALS, providing new molecular and biochemical targets that could be exploited in the treatment of the disease using polyphenols.}, } @article {pmid40141149, year = {2025}, author = {Zheng, MY and Luo, LZ}, title = {The Role of IL-17A in Mediating Inflammatory Responses and Progression of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {6}, pages = {}, pmid = {40141149}, issn = {1422-0067}, support = {No. 2023D022//the Fujian Provincial Natural Science Foundation/ ; No. 3502Z202473076//the Science and Technology Program of Xiamen City/ ; No. 2019-WJ-30//the Fujian Province Health Education Joint Research Project/ ; }, mesh = {Humans ; *Interleukin-17/metabolism/immunology ; *Neurodegenerative Diseases/metabolism/immunology/pathology ; Animals ; Inflammation/metabolism/immunology/pathology ; Receptors, Interleukin-17/metabolism ; Signal Transduction ; Disease Progression ; Blood-Brain Barrier/metabolism/immunology ; }, abstract = {IL-17A has been implicated as a critical pro-inflammatory cytokine in the pathogenesis of autoimmune and neurodegenerative disorders. Emerging evidence indicates its capacity to activate microglial cells and astrocytes, subsequently inducing the production of inflammatory mediators that exacerbate neuronal injury and functional impairment. Clinical observations have revealed a demonstrated association between IL-17A concentrations and blood-brain barrier (BBB) dysfunction, creating a pathological feedback loop that amplifies neuro-inflammatory responses. Recent advances highlight the cytokine's critical involvement in neurodegenerative disorders through multiple molecular pathways. Therapeutic interventions utilizing monoclonal antibodies (mAbs) against IL-17A or its cognate receptor (IL-17R) have shown promising clinical potential. This review systematically examines the IL-17A-mediated neuro-inflammatory cascades; the mechanistic contributions to neurodegenerative pathology in the established disease models including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis; and current therapeutic strategies targeting the IL-17A signaling pathways. The analysis provides novel perspectives on optimizing cytokine-directed therapies while identifying the key challenges and research priorities for translational applications in neurodegeneration.}, } @article {pmid40140966, year = {2025}, author = {Balaban, E and Köse, TE and Günaçar, DN and Naralan, ME and Gonca, M}, title = {Comparison of methods for detecting mandibular lingula and can antilingula be used in lingula mandibula detection?.}, journal = {BMC oral health}, volume = {25}, number = {1}, pages = {430}, pmid = {40140966}, issn = {1472-6831}, support = {02025001021255//Recep Tayyip Erdoğan University Development Foundation/ ; 02025001021255//Recep Tayyip Erdoğan University Development Foundation/ ; 02025001021255//Recep Tayyip Erdoğan University Development Foundation/ ; 02025001021255//Recep Tayyip Erdoğan University Development Foundation/ ; }, mesh = {Humans ; *Cone-Beam Computed Tomography ; Female ; Male ; Retrospective Studies ; Middle Aged ; Adult ; *Mandible/diagnostic imaging ; Aged ; Adolescent ; Aged, 80 and over ; Young Adult ; Orthognathic Surgical Procedures ; Anatomic Landmarks/diagnostic imaging ; Mandibular Nerve/diagnostic imaging/anatomy & histology ; }, abstract = {OBJECTIVE: The aim of this study is to evaluate the relationship between anatomical reference points used during orthognathic surgery and to minimize the risks of iatrogenic neurovascular damage.

MATERIALS AND METHODS: This retrospective study included cone-beam computed tomography (CBCT) images involving the mandible from patients who visited Recep Tayyip Erdoğan University Faculty of Dentistry between January 2018 and September 2023. The age range of the included individuals was set between 18 and 80 years. Horizontal and vertical distances between mandibular anatomical structures, such as the lingula mandibula (LM), mandibular foramen (MF), antilingula (AL), and surrounding structures were measured using CBCT software. Individuals with intraosseous pathology, insufficient image quality, or a history of surgical/orthodontic treatment were excluded from the study.

RESULTS: A total of 240 hemimandibles from 120 patients were analyzed (55.83% female, 44.17% male; mean age: 46.78 ± 15.30 years). Significant differences were identified in LM positions according to different AL types. The LM was found to be more inferior and posterior relative to hill and ridge type ALs, while it was more anterior relative to plateau type ALs. In 26.25% of mandibular rami, AL was not detected.

CONCLUSION: The position of the AL can serve as a guide in determining the osteotomy line during inferior vertical ramus osteotomy (IVRO). However, relying solely on AL as a reference point may increase the risk of inferior alveolar nerve (IAN) injury. Preoperative tomographic evaluations to determine the relationships among LM, MF, and AL can provide a safer approach in surgical planning, reduce complications, and help protect neurovascular structures.}, } @article {pmid40140908, year = {2025}, author = {Wang, KS and Smeyers, J and Eggan, K and Budnik, B and Mordes, DA}, title = {C9ORF72 poly-PR disrupts expression of ALS/FTD-implicated STMN2 through SRSF7.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {67}, pmid = {40140908}, issn = {2051-5960}, support = {K08 NS104270/NS/NINDS NIH HHS/United States ; K08NS104270/NS/NINDS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Serine-Arginine Splicing Factors/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Stathmin/genetics/metabolism ; DNA Repeat Expansion/genetics ; Neurons/metabolism/drug effects ; }, abstract = {A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and combined ALS/FTD. The repeat is transcribed in the sense and the antisense directions to produce several dipeptide repeat proteins (DPRs) that have toxic gain-of-function effects; however, the mechanisms by which DPRs lead to neural dysfunction remain unresolved. Here, we observed that poly-proline-arginine (poly-PR) was sufficient to inhibit axonal regeneration of human induced pluripotent stem cell (iPSC)-derived neurons. Global phospho-proteomics revealed that poly-PR selectively perturbs nuclear RNA binding proteins (RBPs). In neurons, we found that depletion of one of these RBPs, SRSF7 (serine/arginine-rich splicing factor 7), resulted in decreased abundance of STMN2 (stathmin-2), though not TDP-43. STMN2 supports axon maintenance and repair and has been recently implicated in the pathogenesis of ALS/FTD. We observed that depletion of SRSF7 impaired axonal regeneration, a phenotype that could be rescued by exogenous STMN2. We propose that antisense repeat-encoded poly-PR perturbs RBPs, particularly SRSF7, resulting in reduced STMN2 and axonal repair defects in neurons. Hence, we provide a potential link between DPRs gain-of-function effects and STMN2 loss-of-function phenotypes in neurodegeneration.}, } @article {pmid40140666, year = {2025}, author = {de Bernardo, N and de la Rubia Ortí, JE and Villarón-Casales, C and Privado, J and Maset-Roig, R and Cañabate, M and Sancho-Cantus, D and Sanz, IO and Fernández, RF and Proaño, B and Tvarijonaviciute, A and Rubio, CP and Benlloch, M and Menargues-Ramírez, R and Alarcón-Jiménez, J}, title = {Autonomic nervous system and mediating role of respiratory function in patients with ALS.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {10513}, pmid = {40140666}, issn = {2045-2322}, support = {2021-203-003//Universidad Católica de Valencia San Vicente Màrtir/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Autonomic Nervous System/physiopathology ; Cross-Sectional Studies ; Aged ; Antioxidants/metabolism ; Cognition/physiology ; Respiration ; Oxidative Stress ; Heart Rate/physiology ; Adult ; }, abstract = {Patients with Amyotrophic Lateral Sclerosis (ALS) exhibit altered patterns of respiratory rate and heart rhythm that are directly related to autonomic nervous system (ANS) activity. This study aimed to analyze the role of the ANS in respiratory function, cognition, functionality, and antioxidant capacity in patients with ALS through a predictive model that assesses the mediating activity of respiration. This quantitative, observational, analytical, and cross-sectional clinical study was conducted using a sample of 75 patients diagnosed with ALS. ANS activity, respiratory function, cognition, functionality, and antioxidant capacity were also measured. Using these values, a structural equation model was developed using AMOS V.23 software. The mediational predictive model showed that increased sympathetic nervous system (SNS) activity, in turn, increased respiratory function, whereas the role of the parasympathetic nervous system in respiration was very weak and had the opposite effect. Furthermore, SNS activity increased respiratory function values, which, in turn, improved functional capacity, cognition, and antioxidant power in patients with ALS, with respiratory function playing a mediating role. The mediating effect of respiratory function was observed primarily between ANS and functional disability. For oxidative stress, respiratory function showed a high mediating effect, such that greater respiratory function corresponded to greater antioxidant capacity. Additionally, for cognitive activity, a moderate direct effect of the ANS was observed; however, it was greatly enhanced by respiratory disability. Finally, differences were only found based on sex, with respiratory capacity and antioxidant power being higher in men.}, } @article {pmid40140608, year = {2025}, author = {Dubey, SK and Bellen, HJ}, title = {A neuroprotective role of polyunsaturated fatty acids in C9orf72-ALS/FTD.}, journal = {Nature neuroscience}, volume = {28}, number = {4}, pages = {710-712}, pmid = {40140608}, issn = {1546-1726}, } @article {pmid40140376, year = {2025}, author = {Megat, S and Marques, C and Hernán-Godoy, M and Sellier, C and Stuart-Lopez, G and Dirrig-Grosch, S and Gorin, C and Brunet, A and Fischer, M and Keime, C and Kessler, P and Mendoza-Parra, MA and Zwamborn, RAJ and Veldink, JH and Scholz, SW and Ferrucci, L and Ludolph, A and Traynor, B and Chio, A and Dupuis, L and Rouaux, C}, title = {CREB3 gain of function variants protect against ALS.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {2942}, pmid = {40140376}, issn = {2041-1723}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; Humans ; *Cyclic AMP Response Element-Binding Protein/metabolism/genetics ; Male ; Mice ; *Motor Neurons/metabolism/pathology ; Mice, Transgenic ; Gain of Function Mutation ; Endoplasmic Reticulum Stress/genetics ; Female ; Motor Cortex/metabolism/pathology ; Disease Models, Animal ; Middle Aged ; Superoxide Dismutase-1/genetics/metabolism ; Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly evolving neurodegenerative disease arising from the loss of glutamatergic corticospinal neurons (CSN) and cholinergic motoneurons (MN). Here, we performed comparative cross-species transcriptomics of CSN using published snRNA-seq data from the motor cortex of ALS and control postmortem tissues, and performed longitudinal RNA-seq on CSN purified from male Sod1[G86R] mice. We report that CSN undergo ER stress and altered mRNA translation, and identify the transcription factor CREB3 and its regulatory network as a resilience marker of ALS, not only amongst vulnerable neuronal populations, but across all neuronal populations as well as other cell types. Using genetic and epidemiologic analyses we further identify the rare variant CREB3[R119G] (rs11538707) as a positive disease modifier in ALS. Through gain of function, CREB3[R119G] decreases the risk of developing ALS and the motor progression rate of ALS patients.}, } @article {pmid40139174, year = {2025}, author = {Toraih, EA and Siddiqui, S and Siddiqui, S and Shirini, K and Elfezzani, N and Abdelmaksoud, A and Elshazli, RM and Hussein, MH and Elmorsy, EM and Fawzy, MS}, title = {Thyroid Disorders as a Risk Factor for Neurodegenerative Proteinopathies: A Large-Scale Propensity Score-Matched Analysis.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-19}, doi = {10.1159/000545369}, pmid = {40139174}, issn = {1423-0208}, abstract = {INTRODUCTION: The relationship between thyroid disorders and neurodegenerative diseases remains poorly understood. This large-scale retrospective cohort study aimed to investigate the association between thyroid disorders and various neurodegenerative diseases, as well as the potential impact of thyroidectomy.

METHODS: We analyzed data from 3,719,666 patients with thyroid disorders and 2,945,438 controls from 120 healthcare organizations. After propensity score matching, each group included 2,033,096 patients. We compared the risk of neurodegenerative diseases between these groups and examined the effect of thyroidectomy in a subgroup analysis of 31,753 matched pairs.

RESULTS: Patients with thyroid disorders showed significantly higher risks of Alzheimer's disease (RR=1.15, 95%CI: 1.110-1.195), Parkinson's disease (RR=1.25, 95%CI: 1.187-1.318), amyotrophic lateral sclerosis (RR=1.35, 95%CI: 1.131-1.622), frontotemporal dementia (RR=1.44, 95%CI: 1.219-1.702), Lewy body dementia (RR=1.15, 95%CI: 1.107-1.186), progressive supranuclear palsy (RR=1.41, 95%CI: 1.095-1.819), vascular dementia (RR=1.32, 95%CI: 1.266-1.369), Niemann-Pick disease type C (RR=1.34, 95%CI: 1.092-1.638), and Wilson's disease (RR=1.26, 95%CI: 1.056-1.507). Interestingly, the risk of multiple sclerosis was lower (RR=0.80, 95%CI: 0.738-0.862). Thyroidectomy was associated with a 44.2% lower risk of Lewy body dementia (RR=0.558, 95%CI: 0.339-0.919, p=0.020).

CONCLUSION: Thyroid disorders are significantly associated with an increased risk of several neurodegenerative diseases. Thyroidectomy may have a protective effect against Lewy body dementia. These findings suggest a complex relationship between thyroid function and neurodegeneration, emphasizing the need for neurological monitoring in patients with thyroid disorders and further research into thyroid-brain interactions.}, } @article {pmid40138872, year = {2025}, author = {Liang, T and Jiang, T and Liang, Z and Li, L and Chen, Y and Chen, T and Yang, L and Zhang, N and Dong, B and Xie, X and Gu, B and Wu, Q}, title = {Gut microbiota-driven BCAA biosynthesis via Staphylococcus aureus -expressed acetolactate synthase impairs glycemic control in type 2 diabetes in South China.}, journal = {Microbiological research}, volume = {296}, number = {}, pages = {128145}, doi = {10.1016/j.micres.2025.128145}, pmid = {40138872}, issn = {1618-0623}, mesh = {*Diabetes Mellitus, Type 2/microbiology/metabolism ; *Gastrointestinal Microbiome/physiology ; *Staphylococcus aureus/enzymology/genetics/metabolism ; *Amino Acids, Branched-Chain/biosynthesis ; *Acetolactate Synthase/metabolism/genetics ; Humans ; Animals ; Mice ; China ; Male ; Insulin Resistance ; Female ; Middle Aged ; *Glycemic Control ; Blood Glucose ; Feces/microbiology ; Staphylococcal Infections/microbiology ; Metagenomics ; Prediabetic State/microbiology ; Metabolomics ; Insulin ; }, abstract = {An increase in branched-chain amino acid (BCAA) levels can result in insulin resistance at different stages of type 2 diabetes (T2D), however, the causes of this increase are unclear. We performed metagenomics and metabolomics profiling in patients with prediabetes (PDM), newly diagnosed diabetes (NDDM), and post-medication type 2 diabetes (P2DM) to investigate whether altered gut microbes and metabolites could explain the specific clinical characteristics of different disease stages of T2D. Here we identify acetolactate synthase (ALS) a BCAA biosynthesis enzyme in Staphylococcus aureus as a cause of T2D insulin resistance. Compared with healthy peoples, patients with PDM, NDDM, and P2DM groups, especially in P2DM group, have increased faecal numbers of S. aureus. We also demonstrated that insulin administration may be a risk factor for S. aureus infection in T2D. The presence of ALS-positive S. aureus correlated with the levels of BCAAs and was associated with an increased fasting blood glucose (FBG) and insulin resistance. Humanized microbiota transplantation experiment indicated that ALS contributes to disordered insulin resistance mediated by S. aureus. We also found that S. aureus phage can reduced the FBG levels and insulin resistance in db/db mice. The ALS-positive S. aureus are associated with insulin resistance in T2D, opening a new therapeutic avenue for the prevention or treatment of diabetes.}, } @article {pmid40138119, year = {2025}, author = {Ali, N and Sayeed, U and Shahid, SMA and Akhtar, S and Khan, MKA}, title = {Molecular mechanisms and biomarkers in neurodegenerative disorders: a comprehensive review.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {337}, pmid = {40138119}, issn = {1573-4978}, mesh = {Humans ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/diagnosis/metabolism/cerebrospinal fluid ; Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; tau Proteins/metabolism/cerebrospinal fluid ; Parkinson Disease/diagnosis/metabolism/genetics/cerebrospinal fluid ; alpha-Synuclein/metabolism ; Alzheimer Disease/diagnosis/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/diagnosis/genetics/cerebrospinal fluid ; Huntington Disease/diagnosis/metabolism/genetics ; Positron-Emission Tomography/methods ; }, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD), are significant global health challenges, owing to their profound impact on cognitive, motor, and behavioral functions. The etiology and progression of these disorders are influenced by a complex interplay of environmental factors and genetic predispositions with specific genetic markers, such as mutations in the APOE and HTT genes, which play pivotal roles. Current therapeutic interventions predominantly focus on symptom management; however, emerging strategies, including gene therapies, anti-amyloid agents, and neuroprotective approaches, are designed to directly target the underlying disease mechanisms. Advances in biomarker discovery and imaging methodologies have emerged as essential tools for early diagnosis and monitoring of therapeutic efficacy in these disorders. In the context of AD, cerebrospinal fluid (CSF) amyloid-beta (Aβ) and tau levels, along with positron emission tomography (PET) imaging, are well-established biomarkers. Similarly, CSF alpha-synuclein and dopamine transporter (DAT) imaging have been employed as diagnostic tools for PD. Moreover, emerging biomarkers, such as blood-based tau and the Aβ42/40 ratio for AD, as well as the neurofilament light chain (NfL) for ALS and PD, hold promise for enhancing early diagnostic accuracy and facilitating the longitudinal assessment of disease progression. This study comprehensively examined the molecular mechanisms underlying these neurodegenerative disorders, focusing on amyloid-beta plaque deposition and tau protein aggregation in AD, alpha-synuclein misfolding in PD, and aberrant protein aggregation in ALS and HD, thereby contributing to a deeper understanding of the pathophysiological basis of these disorders.}, } @article {pmid40138021, year = {2025}, author = {Vaughan, DP and Real, R and Jensen, MT and Fumi, RG and Hodgson, M and Jabbari, E and Lux, D and Wu, L and , and , and Warner, TT and Jaunmuktane, Z and Revesz, T and Rowe, JB and Rohrer, J and Morris, HR}, title = {Analysis of C9orf72 repeat length in progressive supranuclear palsy, corticobasal syndrome, corticobasal degeneration, and atypical parkinsonism.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {293}, pmid = {40138021}, issn = {1432-1459}, support = {PROSPECT2//Progressive Supranuclear Palsy Association/ ; T033371/1/MRC_/Medical Research Council/United Kingdom ; 220258/WT_/Wellcome Trust/United Kingdom ; MC_UU_00030/14//Cambridge Centre for Parkinson-Plus/ ; NIHR203312//NIHR Cambridge Biomedical Research Centre/ ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *Supranuclear Palsy, Progressive/genetics ; Male ; Female ; Aged ; *Parkinsonian Disorders/genetics ; *DNA Repeat Expansion/genetics ; Middle Aged ; *Corticobasal Degeneration/genetics ; Aged, 80 and over ; Cohort Studies ; Prospective Studies ; }, abstract = {BACKGROUND: Pathogenic hexanucleotide repeat expansions in C9orf72 are the commonest genetic cause of frontotemporal dementia and/or amyotrophic lateral sclerosis. There is growing interest in intermediate repeat expansions in C9orf72 and their relationship to a wide range of neurological presentations, including Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, corticobasal degeneration, and corticobasal syndromes.

AIMS: To assess the prevalence of intermediate C9orf72 repeat expansions in a large cohort of prospectively-recruited patients clinically diagnosed with progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and atypical parkinsonism (APS), compared with healthy controls. We also sought to replicate the association between C9orf72 repeat length and CBD in neuropathologically confirmed cases.

METHODS: 626 cases, including PSP (n = 366), CBS (n = 130), and APS (n = 53) from the PROSPECT study, and 77 cases with pathologically confirmed CBD were screened for intermediate repeat expansions in C9orf72 using repeat-primed PCR. These were compared to controls from the PROSPECT-M-UK study and from the 1958 Birth Cohort.

RESULTS: There was no difference in the mean or largest allele size in any affected patient group compared with controls. A higher proportion of our affected cohort had large C9orf72 repeat expansions compared to controls, but there was no difference when comparing the frequency of intermediate expansions between affected patients and controls. There was no relationship between repeat length and age at onset, level of disability, or survival.

CONCLUSIONS: Intermediate expansions in C9orf72 do not appear to be a genetic risk factor for PSP, CBS, CBD, or atypical parkinsonism. They are not associated with age at onset, disability, or survival in our study.}, } @article {pmid40137505, year = {2025}, author = {Calderón-Garcidueñas, L and González-Maciel, A and Reynoso-Robles, R and Cejudo-Ruiz, FR and Silva-Pereyra, HG and Gorzalski, A and Torres-Jardón, R}, title = {Alzheimer's, Parkinson's, Frontotemporal Lobar Degeneration, and Amyotrophic Lateral Sclerosis Start in Pediatric Ages: Ultrafine Particulate Matter and Industrial Nanoparticles Are Key in the Early-Onset Neurodegeneration: Time to Invest in Preventive Medicine.}, journal = {Toxics}, volume = {13}, number = {3}, pages = {}, pmid = {40137505}, issn = {2305-6304}, abstract = {Billions of people are exposed to fine particulate matter (PM2.5) levels above the USEPA's annual standard of 9 μg/m[3]. Common emission sources are anthropogenic, producing complex aerosolized toxins. Ultrafine particulate matter (UFPM) and industrial nanoparticles (NPs) have major detrimental effects on the brain, but the USA does not measure UFPM on a routine basis. This review focuses on the development and progression of common neurodegenerative diseases, as diagnosed through neuropathology, among young residents in Metropolitan Mexico City (MMC). MMC is one of the most polluted megacities in the world, with a population of 22 million residents, many of whom are unaware of the brain effects caused by their polluted atmosphere. Fatal neurodegenerative diseases (such as Alzheimer's and Parkinson's) that begin in childhood in populations living in air polluted environments are preventable. We conclude that UFPM/NPs are capable of disrupting neural homeostasis and give rise to relentless neurodegenerative processes throughout the entire life of the highly exposed population in MMC. The paradigm of reaching old age to have neurodegeneration is no longer supported. Neurodegenerative changes start early in pediatric ages and are irreversible. It is time to invest in preventive medicine.}, } @article {pmid40137226, year = {2025}, author = {Stella, R and Bertoli, A and Lopreiato, R and Peggion, C}, title = {A Twist in Yeast: New Perspectives for Studying TDP-43 Proteinopathies in S. cerevisiae.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {11}, number = {3}, pages = {}, pmid = {40137226}, issn = {2309-608X}, abstract = {TAR DNA-binding protein 43 kDa (TDP-43) proteinopathies are a group of neurodegenerative diseases (NDs) characterized by the abnormal accumulation of the TDP-43 protein in neurons and glial cells. These proteinopathies are associated with several NDs, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and some forms of Alzheimer's disease. Yeast models have proven valuable in ND research due to their simplicity, genetic tractability, and the conservation of many cellular processes shared with higher eukaryotes. For several decades, Saccharomyces cerevisiae has been used as a model organism to study the behavior and toxicity of TDP-43, facilitating the identification of genes and pathways that either exacerbate or mitigate its toxic effects. This review will discuss evidence showing that yeast models of TDP-43 exhibit defects in proteostasis, mitochondrial function, autophagy, and RNA metabolism, which are key features of TDP-43-related NDs. Additionally, we will explore how modulating proteins involved in these processes reduce TDP-43 toxicity, aiding in restoring normal TDP-43 function or preventing its pathological aggregation. These findings highlight potential therapeutic targets for the treatment of TDP-43-related diseases.}, } @article {pmid40136713, year = {2025}, author = {Gao, J and Sikal, A and Hankin, R and Zheng, Y and Sterling, E and Chan, K and Yao, Y}, title = {Extracellular Vesicles from Regenerating Skeletal Muscle Mitigate Muscle Atrophy in an Amyotrophic Lateral Sclerosis Mouse Model.}, journal = {Cells}, volume = {14}, number = {6}, pages = {}, pmid = {40136713}, issn = {2073-4409}, support = {startup//University of Georgia/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Extracellular Vesicles/metabolism/transplantation ; *Muscular Atrophy/pathology/metabolism ; *Muscle, Skeletal/pathology/metabolism ; *Disease Models, Animal ; Mice ; *Regeneration ; NF-kappa B/metabolism ; Mice, Inbred C57BL ; Signal Transduction ; Cell Differentiation ; Macrophages/metabolism ; Male ; Myoblasts/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterized by progressive motor neuron degeneration and muscle atrophy, with no effective treatments available. Chronic inflammation, which impairs muscle regeneration and promotes proteolysis, is a key contributor to ALS-related muscle atrophy and a promising therapeutic target. Here, we applied extracellular vesicles (EVs) derived from regenerating skeletal muscles 14 days post-acute injury (CTXD14SkM-EVs), which possess a unique anti-inflammatory profile, to target muscle defects in ALS. We found that CTXD14SkM-EVs enhanced myoblast differentiation and fusion in a cellular muscle-wasting model induced by pro-inflammatory cytokine tumor necrosis factor alpha. Intramuscular administration of these EVs into an ALS mouse model mitigated muscle atrophy by promoting muscle regeneration, shifting macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 state, and suppressing the aberrant Nuclear Factor Kappa B (NF-κB) signaling, a key driver of muscle protein degradation. These results underscore the therapeutic potential of regenerating muscle-derived EVs for combating muscle atrophy in ALS.}, } @article {pmid40136670, year = {2025}, author = {Bond, S and Saxena, S and Sierra-Delgado, JA}, title = {Microglia in ALS: Insights into Mechanisms and Therapeutic Potential.}, journal = {Cells}, volume = {14}, number = {6}, pages = {}, pmid = {40136670}, issn = {2073-4409}, support = {//Rare Village/ ; //Radala Foundation/ ; //University of Missouri- Columbia, School of Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/pathology/immunology ; Humans ; *Microglia/pathology/metabolism ; Animals ; Motor Neurons/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons, leading to escalating muscle weakness, atrophy, and eventually paralysis. While neurons are the most visibly affected, emerging data highlight microglia-the brain's resident immune cells-as key contributors to disease onset and progression. Rather than existing in a simple beneficial or harmful duality, microglia can adopt multiple functional states shaped by internal and external factors, including those in ALS. Collectively, these disease-specific forms are called disease-associated microglia (DAM). Research using rodent models, patient-derived cells, and human postmortem tissue shows that microglia can transition into DAM phenotypes, driving inflammation and neuronal injury. However, these cells can also fulfill protective roles under certain conditions, revealing their adaptable nature. This review explores recent discoveries regarding the multifaceted behavior of microglia in ALS, highlights important findings that link these immune cells to motor neuron deterioration, and discusses emerging therapies-some already used in clinical trials-that aim to recalibrate microglial functions and potentially slow disease progression.}, } @article {pmid40136528, year = {2025}, author = {Chen, X and Wang, Y and Zhang, Y and Li, X and Zhang, L and Gao, S and Zhang, C}, title = {Neural Excitatory/Inhibitory Imbalance in Motor Aging: From Genetic Mechanisms to Therapeutic Challenges.}, journal = {Biology}, volume = {14}, number = {3}, pages = {}, pmid = {40136528}, issn = {2079-7737}, support = {C2406001//the Shenzhen Medical Research Fund/ ; 2024TJCR023//the Tongji Hospital High Quality Clinical Research Fund/ ; 32020103007//the Major International (Regional) Joint Research Project/ ; 2022YFA1206000//the National Key Research and Development Program of China/ ; 32371189, 32300984//the National Natural Science Foundation of China/ ; }, abstract = {Neural excitatory/inhibitory (E/I) imbalance plays a pivotal role in the aging process. However, despite its significant impact, the role of E/I imbalance in motor dysfunction and neurodegenerative diseases has not received sufficient attention. This review explores the mechanisms underlying motor aging through the lens of E/I balance, emphasizing genetic and molecular factors that contribute to this imbalance (such as SCN2A, CACNA1C, GABRB3, GRIN2A, SYT, BDNF…). Key regulatory genes, including REST, vps-34, and STXBP1, are examined for their roles in modulating synaptic activity and neuronal function during aging. With insights drawn from ALS, we discuss how disruptions in E/I balance contribute to the pathophysiology of age-related motor dysfunction. The genes discussed above exhibit a certain association with age-related motor neuron diseases (like ALS), a relationship that had not been previously recognized. Innovative genetic therapies, such as gene editing technology and optogenetic manipulation, are emerging as promising tools for restoring E/I balance, offering hope for ameliorating motor deficits in aging. This review explores the potential of these technologies to intervene in aging-related motor diseases, despite challenges in their direct application to human conditions.}, } @article {pmid40135721, year = {2025}, author = {Fayaz, MU and Wang, Q and Xu, M and Chen, D and Pan, F and Song, C}, title = {Compressive Strain-Induced Uphill Hydrogen Distribution in Strontium Ferrite Films.}, journal = {ACS applied materials & interfaces}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsami.4c21825}, pmid = {40135721}, issn = {1944-8252}, abstract = {Hydrogen incorporation into metal oxides enhances their electrochemical properties, making them highly suitable for various energy conversion applications. The controlled distribution of hydrogen ions in material systems and their conduction at elevated temperatures have garnered significant attention for various energy storage and environmental monitoring applications, including fuel cells, smart windows, and sensor technologies. In this work, cost-effective, high-concentration hydrogen-doped SrFeO3-δ (HSrFeO3-δ) films were prepared under ambient conditions by treating Al(s)|SrFeO3-δ(s) films with KOH(aq), utilizing electron-proton codoping to investigate hydrogen distribution. The uphill hydrogen distributions in SrFeO3-δ films with compressive strain, in contrast to the density gradient behavior under tensile strain, suggest the fundamental role of the strain states in the hydrogen accommodation. Compressively strained films with a rich Al source follow an anomalous uphill feature of hydrogen distribution, highlighting their potential use as electrolyte for fuel cells. The strain significantly influences the structure, chemical lattice coupling, and consequently the ionic transport in SrFeO3-δ. Ionic conductivity measurements reveal that compressively strained HSrFeO3-δ films with uphill hydrogen distributions exhibit a significant ionic conductivity of 0.189 S/cm at 413 K, with an activation energy of approximately 0.29 eV, making them suitable for low-temperature electrochemical applications. These findings provide a promising approach for tuning material properties and valuable insights for building iontronic devices.}, } @article {pmid40135631, year = {2024}, author = {Novy, C and Tysnes, OB and Busk, ØL and Jaioun, K and Holmøy, T and Holla, ØL and Høyer, H}, title = {Association of UNC13A with increased amyotrophic lateral sclerosis risk, bulbar onset, and lower motor neuron involvement in a Norwegian ALS cohort.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2024.2447922}, pmid = {40135631}, issn = {2167-9223}, abstract = {Objective: Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by the loss of motor neurons, has limited treatment options available. Treatments targeting specific ALS genes, including UNC13A, have attracted considerable attention. The UNC13A rs12608932 variant has been associated with an increased risk of ALS, shorter survival, and more frequent bulbar onset. Methods: In this study, we investigated the allele frequency of rs12608932 among 500 Norwegian ALS patients, divided into three groups: patients with a genetic cause, patients without a genetic cause, and the entire ALS population. The three groups were compared to two independent control groups. The patients carrying UNC13A genotypes AA, AC, and CC were further clinically characterized and compared using additive, recessive, and dominant models. Results: The frequency of the rs12608932 C allele was higher in the patients with ALS (0.438) than in the controls (0.365; p < 0.001). Among ALS patients without a known genetic cause, individuals with the CC genotype exhibited higher frequencies of bulbar onset (p = 0.015) and prominent lower motor neuron involvement (p = 0.007) than those with the AA and AC genotypes. Conclusions: The CC genotype of rs12608932 is associated with an increased risk of ALS. Additionally, it acts as a modifier of the ALS phenotype, increasing the risk of bulbar onset and dominant lower motor neuron involvement, specifically in patients without a genetic cause in known ALS genes.}, } @article {pmid40135564, year = {2025}, author = {Liang, W and Zhang, C and Wang, D and Su, X and Tan, X and Yang, Y and Cong, C and Wang, Y and Huo, D and Wang, H and Wang, S and Wang, X and Feng, H}, title = {Inhibition of Salt-Inducible Kinase 2 Protects Motor Neurons From Degeneration in ALS by Activating Autophagic Flux and Enhancing mTORC1 Activity.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {3}, pages = {e70341}, pmid = {40135564}, issn = {1755-5949}, support = {2023-KYYWF-0195//Innovative Scientific Research Fund of Harbin Medical University/ ; 82271450//National Natural Science Foundation of China/ ; 82301599//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Autophagy/physiology ; Mice ; *Mice, Transgenic ; *Protein Serine-Threonine Kinases/metabolism/genetics ; *Mechanistic Target of Rapamycin Complex 1/metabolism ; Humans ; Mice, Inbred C57BL ; Male ; Nerve Degeneration/pathology/metabolism ; }, abstract = {OBJECTIVES: Autophagic impairment has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Salt-inducible kinase 2 (SIK2), a member of the AMP-activated protein kinase (AMPK) family widely expressed in the central nervous system, plays critical roles in neuronal survival, neurogenesis, and the regulation of autophagy. This study aims to investigate the effects and underlying mechanisms of SIK2 in the pathogenesis of ALS.

METHODS: In our work, we used both in vivo and in vitro models of ALS to study the effect of SIK2. Protein and RNA levels were assessed by Western blot, RT-qPCR, immunofluorescence, and immunohistochemistry. Cell viability and apoptosis were evaluated using CCK-8 assay and flow cytometry. Transmission electron microscopy was employed to examine autophagic vacuoles. Additionally, lentivirus particles carrying shRNA targeting SIK2 (sh-SIK2) were injected into the lateral ventricle of ALS mice at 60 days of age. Motor performance was evaluated by the rotarod test.

RESULTS: We observed that increased expression of SIK2 significantly contributed to the degeneration of motor neurons in both the cellular model and the hSOD1[G93A] transgenic mice model of ALS. SIK2 knockdown enhanced neuronal survival and restored mTORC1 activity. Furthermore, SIK2 suppression facilitated the clearance of mutant SOD1 accumulation by activating autophagic flux and enhancing lysosomal acidification. Conversely, SIK2 overexpression impaired mTORC1 activity, exacerbating autophagy dysfunction by inhibiting lysosomal function, and ultimately led to motor neuron degeneration. In vivo, SIK2 deficiency delayed disease onset and extended the lifespan of ALS mice by enhancing autophagy-mediated clearance of mutant SOD1 aggregates.

CONCLUSIONS: Our findings reveal that SIK2 regulates autophagic flux by modulating lysosomal acidification, thereby influencing the degradation of mutant SOD1 aggregates. SIK2 suppression enhances autophagy-mediated clearance of toxic protein aggregates and protects motor neurons, highlighting its potential as a therapeutic target for ALS.}, } @article {pmid40135522, year = {2025}, author = {Bai, D and Fang, Y and Tian, J and Liao, Y and Liu, M and Pan, L}, title = {Tribenuron-methyl resistance in Capsella bursa-pastoris: the co-existence of ALS target enzyme mutation (Pro-197-Ser) and overexpression of GSTF12 and ADP/ATP carrier protein.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.8794}, pmid = {40135522}, issn = {1526-4998}, support = {//Scientific Research Fund of Hunan Provincial Education Department/ ; //National Natural Science Foundation of China/ ; //National Key Research and Development Program of China/ ; //China Agriculture Research System/ ; //Modern Agricultural Industrial Technology System of Hunan Province/ ; }, abstract = {BACKGROUND: Capsella bursa-pastoris, a prevalent wheat-field weed in China, demonstrates substantial resistance to tribenuron-methyl, a herbicide-targeting acetolactate synthase (ALS). Understanding weed herbicide-resistance mechanisms is crucial for managing resistant weed populations. However, the genes potentially involved in nontarget-site resistance (NTSR) in herbicide-resistant C. bursa-pastoris remain poorly understood and require further investigation. This research aimed to elucidate the resistance level and underlying mechanisms of a field population (R) from Shandong Province, China, to tribenuron-methyl.

RESULTS: Whole-plant bioassays revealed that the relative resistance index (RI) of the R population was 54-fold greater than that of the tribenuron-methyl-sensitive population (S). Additionally, treatment with the cytochrome P450 (CYP450) inhibitor malathion or the glutathione S-transferase (GST) inhibitor 4-Chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) partially mitigated the resistance of the R population to tribenuron-methyl. Sequencing of the ALS target enzyme identified a substitution of proline (CCT) at position 197 with serine (TCT). RNA sequencing combined with quantitative reverse transcription polymerase chain reaction (qRT-PCR) verification identified upregulation of a candidate GST gene (GSTF12) and an ADP/ATP carrier protein in the R population. Heterologous expression of the two candidate genes in yeast cells demonstrated enhanced growth in the presence of tribenuron-methyl.

CONCLUSION: We first identified that, in tribenuron-methyl-resistant C. bursa-pastoris, the Pro-197-Ser mutation in the ALS gene, along with GSTF12 and ADP/ATP carrier protein overexpression, jointly mediate its resistance. This enhances our understanding of herbicide-resistance mechanisms and offers a novel perspective for managing tribenuron-methyl-resistant weeds in agricultural practices. © 2025 Society of Chemical Industry.}, } @article {pmid40134643, year = {2025}, author = {Guo, YX and Yan, X and Liu, XC and Liu, YX and Liu, C}, title = {Artificial intelligence-driven strategies for managing renal and urinary complications in inflammatory bowel disease.}, journal = {World journal of nephrology}, volume = {14}, number = {1}, pages = {100825}, pmid = {40134643}, issn = {2220-6124}, abstract = {In this editorial, we discuss the article by Singh et al published in World Journal of Nephrology, stating the need for timely adjustments in inflammatory bowel disease (IBD) patients' long-term management plans. IBD is chronic and lifelong, with recurrence and remission cycles, including ulcerative colitis and Crohn's disease. It's exact etiology is unknown but likely multifactorial. Related to gut flora and immune issues. Besides intestinal symptoms, IBD can also affect various extraintestinal manifestations such as those involving the skin, joints, eyes and urinary system. The anatomical proximity of urinary system waste disposal to that of the alimentary canal makes early detection and the differentiation of such symptoms very difficult. Various studies show that IBD and it's first-line drugs have nephrotoxicity, impacting the patients' life quality. Existing guidelines give very few references for kidney lesion monitoring. Singh et al's plan aims to improve treatment management for IBD patients with glomerular filtration rate decline, specifically those at risk. Most of IBD patients are young and they need lifelong therapy. So early therapy cessation, taking into account drug side effects, can be helpful. Artificial intelligence-driven diagnosis and treatment has a big potential for management improvements in IBD and other chronic diseases.}, } @article {pmid40133903, year = {2025}, author = {Mitchell, G and Siwela, P and Goldstein, S and Diedericks, AM}, title = {Alcohol industry involvement in the delayed South Africa Draft Liquor Amendment Bill 2016: a case study based on freedom of information requests.}, journal = {Globalization and health}, volume = {21}, number = {1}, pages = {11}, pmid = {40133903}, issn = {1744-8603}, support = {N/A//FORUT/ ; N/A//FORUT/ ; N/A//FORUT/ ; N/A//FORUT/ ; }, mesh = {South Africa ; Humans ; *Alcoholic Beverages/economics/legislation & jurisprudence ; Alcohol Drinking/legislation & jurisprudence ; Industry/legislation & jurisprudence ; Advertising/legislation & jurisprudence ; Food Industry/legislation & jurisprudence ; }, abstract = {BACKGROUND: South Africa is reported to have one of the highest per capita rates of alcohol consumption among drinkers globally, with alcohol harms exacerbating socio-economic inequalities in the country. The Draft Liquor Amendment Bill 2016 proposed new restrictions on alcohol advertising, availability, and liability of retailers and manufacturers for harm related to any contravention of the regulations. To date, the Bill has not progressed through the legislative process. The alcohol industry is known to use a diverse set of strategies to delay evidence-based policies globally.

METHODS: We aimed to explore Bill-related activity by industry within the National Economic and Development Labour Council, a multi-stakeholder forum that assesses socio-economic policies before they reach parliament. On 06 July 2023 we made a Request for Access to Record, using form two of the Promotion of Access to Information Act (PAIA), no. 2 of 2000 to the National Economic and Development Labour Council for access to minutes of all meetings, reports, and any other publications related to the Bill between January 2016 and December 2022. Informed by Ulucanlar et al's (2023) model and taxonomies of corporate political activity, we extracted data on industry Bill-related activity and thematically analysed key events, presented here as a narrative synthesis.

RESULTS: We identified activity by 14 alcohol industry organisations related to the Bill between 2016 and 2022. Industry representation on five National Economic and Development Labour Council-related committees identified between 2017 and 2021 facilitated their involvement in Bill-related discussions and supported access to other government departments. Community representation was low in all committees compared to industry, labour, and government. Industry funded two socio-economic assessments of the Bill in 2017 and 2022, despite an independent socio-economic impact assessment having already been completed. The 2017 report delayed progress of the Bill, and the 2022 're-evaluation' was more critical of the proposed measures, with the differing conclusions attributed to different methodologies. During the covid-19 pandemic, industry used a 'carrot and stick' approach of legal threats and donations to attempt to move towards self-regulation via a social compact. The National Economic and Development Labour Council confirmed in 2023 that the social compact was unsuccessful.

CONCLUSIONS: Early 'regulatory capture' gave the alcohol industry the opportunity to shape assessment of the Bill within the National Economic and Development Labour Council. Our findings are in line with previous studies on corporate influence on policy globally, and support calls for a reassessment of the role and proportion of industry representation within the National Economic and Development Labour Council locally.}, } @article {pmid40133096, year = {2025}, author = {Shenouda, M and McKeever, PM and Robertson, J}, title = {The long and the short of TDP-43.}, journal = {Trends in neurosciences}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tins.2025.03.003}, pmid = {40133096}, issn = {1878-108X}, abstract = {In a recent study, Dykstra and colleagues show that shortened TAR DNA Binding Protein 43 (sTDP-43) isoforms are generated as by-products of TDP-43 autoregulation. sTDP-43 levels are regulated through nonsense-mediated decay and proteasomal and autophagic degradation, and elicit toxicity through dominant negative effects on TDP-43 splicing activity. These results identify mechanisms contributing to sTDP-43 accumulation and toxicity in disease.}, } @article {pmid40132878, year = {2025}, author = {Klickovic, U and Zampedri, L and Zafeiropoulos, N and Ziff, OJ and Sinclair, CD and Wastling, S and Dudziec, M and Allen, J and Trimmel, K and Howard, RS and Malaspina, A and Sharma, N and Sidle, KC and Shah, S and Nasel, C and Yousry, TA and Greensmith, L and Morrow, JM and Thornton, JS and Fratta, P}, title = {Muscle MRI quantifies disease progression in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-335571}, pmid = {40132878}, issn = {1468-330X}, abstract = {BACKGROUND AND OBJECTIVES: Quantitative and operator-independent biomarkers of disease progression are urgently needed in amyotrophic lateral sclerosis (ALS) research. We assess the potential of skeletal muscle MRI as a sensitive and reliable outcome measure for future ALS clinical trials.

METHODS: In this longitudinal cohort study, muscle MRI of head-neck, upper and lower limb regions, alongside clinical and functional assessments, were acquired at three time points over the individual maximum observation period (iMOP) of 1 year in 20 patients with ALS and 16 healthy controls. Quantitative MRI parameters cross-sectional area (CSA), volume (VOL), fat fraction, functional rest muscle area and water T2 (T2m) were correlated with changes in clinical disease severity (functional rating scales and myometry).

RESULTS: Among 20 patients with ALS, 17 completed follow-up. Progressive muscle atrophy (CSA, VOL) was observed at hand (rs=0.66), head-neck (partial η²=0.47) and lower-limb level (thighs: η²=0.56, calves: η²=0.54) over iMOP. MRI changes correlated with leg muscle strength (knee extension: r=0.77; plantar flexion: r=0.78), hand grip strength (r=0.71) and functional rating scales (r=0.68).

INTERPRETATION: Our findings demonstrate the effectiveness of muscle MRI as a sensitive neuroimaging biomarker of disease progression in ALS, highlighting its potential application in clinical trials.}, } @article {pmid40132681, year = {2025}, author = {Wang, Z and Yang, C and Wang, X and Lyu, W and Liao, H and Liu, X and Liu, H and Zhang, J and Shen, H and Zhang, L and Wang, H}, title = {Decoding stress granules dynamics: Implications for neurodegenerative disease.}, journal = {Progress in neurobiology}, volume = {248}, number = {}, pages = {102758}, doi = {10.1016/j.pneurobio.2025.102758}, pmid = {40132681}, issn = {1873-5118}, abstract = {Stress granules (SGs) are membrane-less cytoplasmic structures formed by cells in response to external stress, primarily composed of mRNA and proteins. The dynamic properties of their assembly, maintenance, and disassembly play crucial roles in cellular homeostasis. Recent studies have increasingly revealed that aberrations in SGs dynamics are closely related to the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review summarizes the latest research progress on SGs dynamics in neurodegenerative diseases. It begins with an overview of the basic biological characteristics of SGs and their functions in neurons, followed by an in-depth exploration of the mechanisms and regulatory pathways of SGs dynamics. The review then summarizes potential therapeutic strategies targeting SGs dynamics abnormalities, particularly through small molecule drugs to modulate SGs formation and disassembly, aiming to delay or halt the progression of neurodegenerative diseases. The review also highlights the application prospects of these interventions in treating neurodegenerative diseases. Finally, the review introduces current techniques used to study SGs dynamics, discussing their advantages, limitations, and future development possibilities. This review aims to provide researchers with a comprehensive perspective to advance the understanding and clinical application of SGs dynamics in the field of neurodegenerative diseases.}, } @article {pmid40132594, year = {2025}, author = {Zelic, M and Blazier, A and Pontarelli, F and LaMorte, M and Huang, J and Tasdemir-Yilmaz, OE and Ren, Y and Ryan, SK and Shapiro, C and Morel, C and Krishnaswami, P and Levit, M and Sood, D and Chen, Y and Gans, J and Tang, X and Hsiao-Nakamoto, J and Huang, F and Zhang, B and Berry, JD and Bangari, DS and Gaglia, G and Ofengeim, D and Hammond, TR}, title = {Single-cell transcriptomic and functional studies identify glial state changes and a role for inflammatory RIPK1 signaling in ALS pathogenesis.}, journal = {Immunity}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.immuni.2025.02.024}, pmid = {40132594}, issn = {1097-4180}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss. Microglia and astrocyte-driven neuroinflammation is prominent in ALS, but the cell state dynamics and pathways driving disease remain unclear. We performed single-nucleus RNA sequencing of ALS spinal cords and identified altered glial cell states, including increased expression of inflammatory and glial activation markers. Many of these signals converged on the inflammation and cell death regulator receptor-interacting protein kinase 1 (RIPK1) and the necroptotic cell death pathway. In superoxide dismutase 1 (SOD1)[G93A] mice, blocking RIPK1 kinase activity delayed symptom onset and motor impairment and modulated glial responses. We used human induced pluripotent stem cell (iPSC)-derived motor neuron, astrocyte, and microglia tri-cultures to identify potential biomarkers that are secreted upon RIPK1 activation in vitro and modulated by RIPK1 inhibition in the cerebrospinal fluid (CSF) of people with ALS. These data reveal ALS-enriched glial populations associated with inflammation and suggest a deleterious role for neuroinflammatory signaling in ALS pathogenesis.}, } @article {pmid40131525, year = {2025}, author = {Kleinerova, J and Tahedl, M and McKenna, MC and Garcia-Gallardo, A and Hutchinson, S and Hardiman, O and Raoul, C and Ango, F and Schneider, B and Pradat, PF and Tan, EL and Bede, P}, title = {Cerebellar dysfunction in frontotemporal dementia: intra-cerebellar pathology and cerebellar network degeneration.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {289}, pmid = {40131525}, issn = {1432-1459}, support = {JPND-Cofund-2-2019-1/HRBI_/Health Research Board/Ireland ; HRB EIA-2017-019/HRBI_/Health Research Board/Ireland ; ANR France 2022-CEREBRALS//Agence Nationale de la Recherche/ ; }, mesh = {Humans ; *Frontotemporal Dementia/pathology/diagnostic imaging/physiopathology ; Male ; Female ; Middle Aged ; Aged ; *Cerebellum/pathology/diagnostic imaging/physiopathology ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/complications/physiopathology ; Magnetic Resonance Imaging ; Diffusion Tensor Imaging ; Neural Pathways/diagnostic imaging/pathology/physiopathology ; Nerve Net/diagnostic imaging/pathology/physiopathology ; Cerebellar Diseases/diagnostic imaging/pathology/physiopathology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share overlapping clinical, genetic, and neuroimaging features; a spectrum of conditions commonly referred to as the ALS-FTD continuum. The majority of imaging studies focus on supratentorial pathology, and phenotype-defining motor, cognitive, and behavioural profiles are often exclusively attributed to supratentorial degeneration overlooking the contribution of cerebellar pathology.

METHODS: A multimodal neuroimaging study was conducted to evaluate phenotype-associated cerebello-cerebral connectivity profiles in ALS-FTD, behavioural variant frontotemporal dementia (bvFTD), non-fluent variant (nfvPPA), and semantic variant primary progressive aphasia (svPPA). Structural connectivity, functional connectivity, and volumetric analyses were conducted.

RESULTS: Radial diffusivity analyses detected impaired bilateral cerebello-frontal, cerebello-parietal, and cerebello-temporal connectivity in all study groups along the ALS-FTD spectrum. Cerebello-occipital disconnection was captured in ALS-FTD and nfvPPA. Spinocerebellar disconnection was detected in C9orf72 negative ALS-FTD and nfvPPA. C9orf72 positive ALS-FTD patients exhibited both anterior and posterior lobe cerebellar volume loss, while bvFTD and nfvPPA patients showed posterior cerebellar atrophy. Flocculonodular degeneration was observed in nfvPPA and cerebellar crura atrophy in bvFTD. Bilateral corticospinal tract and corpus callosum degeneration was detected in ALS-FTD, bvFTD, and nfvPPA. Primary motor cortex volume reductions were captured in both ALS-FTD and nfvPPA.

CONCLUSIONS: Our analyses capture significant cerebro-cerebellar disconnection in frontotemporal dementia. Corticospinal tract and motor cortex degeneration can be readily detected in non-ALS phenotypes. Intra-cerebellar pathology, coupled with the degeneration of cerebellar projections and the ensuing dysfunction of cerebro-cerebellar networks likely contribute to phenotype-defining clinical profiles in frontotemporal dementia. Infratentorial disease burden and cerebellar network dysfunction should, therefore, be carefully considered in FTD, and phenotype-defining neuropsychological profiles should not be solely attributed to supratentorial degeneration.}, } @article {pmid40131291, year = {2025}, author = {Penn, J and McAleer, R and Ziegler, C and Cheskes, S and Nolan, B and von Vopelius-Feldt, J}, title = {Effectiveness of Prehospital Critical Care Scene Response for Major Trauma: A Systematic Review.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/10903127.2025.2483978}, pmid = {40131291}, issn = {1545-0066}, abstract = {OBJECTIVES: Major trauma is a leading cause of morbidity and mortality worldwide. It is unclear if the addition of a critical care response unit (CCRU) with capabilities comparable to hospital emergency departments might improve outcomes following major trauma, when added to Basic or Advanced Life Support (BLS/ALS) prehospital care. This systematic review describes the evidence for a CCRU scene response model for major trauma.

METHODS: We searched Medline (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (Ovid), CINAHL (EBSCOhost), Science Citation Index Expanded (Web of Science), Conference Proceedings Citation Index - Science (Web of Science), LILACS (Latin American and Caribbean Health Sciences Literature) for relevant publications from 2003 to 2024. We included any study that compared CCRU and BLS/ALS care at the scene of major trauma, reported patient-focused outcomes, and utilized statistical methods to reduce bias and confounding. The risk of bias was assessed by two independent reviewers, using the ROBINS-I tool. Based on our a priori knowledge of the literature, a narrative analysis was chosen. The review was prospectively registered (PROSPERO ID CRD42023490668).

RESULTS: The search yielded 5243 unique records, of which 26 retrospective cohort studies and one randomized controlled trial met inclusion criteria. Sample sizes ranged from 308 to 153,729 patients. Eighteen of the 27 included studies showed associations between CCRUs and improved survival following trauma, which appear to be more consistently found in more critically injured and adult patients, as well as those suffering traumatic cardiac arrest. The remaining nine studies showed no significant difference in outcomes between CCRU and BLS/ALS care. Most studies demonstrated critical or severe risks of bias.

CONCLUSIONS: Current evidence examining CCRU scene response for major trauma suggests potential benefits in severely injury patients but is limited by overall low quality. Further high-quality research is required to confirm the benefits from CCRU scene response for major trauma.}, } @article {pmid40130694, year = {2025}, author = {Burke, KM and Arulanandam, V and Scirocco, E and Royse, T and Hall, S and Weber, H and Arnold, J and Pathak, P and Walsh, C and Paganoni, S}, title = {Assistive Technology in ALS: A Scoping Review of Devices for Limb, Trunk, and Neck Weakness.}, journal = {American journal of physical medicine & rehabilitation}, volume = {}, number = {}, pages = {}, doi = {10.1097/PHM.0000000000002742}, pmid = {40130694}, issn = {1537-7385}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting upper and lower motor neurons that control voluntary muscles. With no known cure, clinical care is focused on symptom management to maximize function and quality of life. Assistive technology plays a crucial role and enables some restoration of movement and function despite disease progression. This scoping review assesses the effectiveness of assistive technologies tested in people living with ALS, specifically those designed to compensate for upper and lower extremity, trunk, and cervical muscle weakness. A comprehensive search was conducted across PubMed, CINAHL, ERIC, Google Scholar, and through citation chasing. We included 26 articles that tested an assistive device on at least one person living with ALS and evaluated the device's effectiveness in restoring movement or providing stabilization to support functional mobility or activities of daily living. Most studies were pilot feasibility or usability trials, with small numbers of ALS participants. The devices showed various benefits, including improved range of motion, function, and participation in daily activities. This review highlights the potential for assistive devices to enhance function in people living with ALS and underscores the need for comprehensive studies involving larger cohorts of individuals at different stages of ALS.}, } @article {pmid40129929, year = {2025}, author = {Liang, F and Sun, Y and Yang, J and Shen, Z and Wang, G and Zhu, J and Zhou, C and Xia, Y}, title = {Gut microbiome is associated with radiotherapy response in lung cancer patients with brain metastases.}, journal = {Frontiers in cellular and infection microbiology}, volume = {15}, number = {}, pages = {1562831}, pmid = {40129929}, issn = {2235-2988}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Lung Neoplasms/radiotherapy/pathology/microbiology ; Male ; Female ; Middle Aged ; *Brain Neoplasms/secondary/radiotherapy ; Aged ; *RNA, Ribosomal, 16S/genetics ; *Feces/microbiology ; *Bacteria/classification/isolation & purification/genetics ; Treatment Outcome ; Adult ; }, abstract = {PURPOSE: To investigate the gut microbiome of lung cancer patients with brain metastases undergoing radiotherapy, identify key microorganisms associated with radiotherapy response, and evaluate their potential as biomarkers.

METHODS AND MATERIALS: This study enrolled 55 newly diagnosed lung cancer patients with brain metastases. Fecal samples were collected before radiotherapy and analyzed by 16S rRNA sequencing to assess the gut microbiome's composition and function. Patients were categorized into response (n=28) and non-response (n=27) groups based on treatment efficacy, and α-diversity, β-diversity, and functional pathways were compared between them. Linear Discriminant Analysis Effect Size was used to identify microbial features associated with treatment efficacy. Logistic regression analyses were performed to evaluate the predictive capacity of clinical and microbial factors for treatment outcomes.

RESULTS: No significant difference in α-diversity was observed between the groups (P > 0.05), but β-diversity differed significantly (P = 0.036). Twelve characteristic microorganisms were identified in the response group, including g_ Oscillibacter and g_ Blautia, and nine in the non-response group, such as f_ Desulfovibrionaceae and g_ Megamonas. Metabolic pathways associated with treatment response included ketone body metabolism and pathways related to amyotrophic lateral sclerosis. Multivariate analysis identified g_Flavonifractor (odds ratio [OR] = 6.680, P = 0.004), g_Negativibacillus (OR = 3.862, P = 0.014), C-reactive protein (OR = 1.054, P = 0.017), and systemic inflammation response index (OR = 1.367, P = 0.043) as independent predictors of radiotherapy response. The nomogram and microbiome models achieved area under the curve (AUC) values of 0.935 and 0.866, respectively, demonstrating excellent predictive performance. Decision curve analysis further confirmed these models provided significant net benefits across risk thresholds.

CONCLUSIONS: The composition and functional characteristics of the gut microbiome in lung cancer patients with brain metastases prior to radiotherapy are associated with therapeutic response and possess potential as predictive biomarkers. Further studies are warranted to validate these findings.}, } @article {pmid40129635, year = {2025}, author = {Galaz-Araya, C and Zuñiga-Núñez, D and Salas-Sepúlveda, F and Herrera-Morande, A and Aspée, A and Poblete, H and Zamora, RA}, title = {Theoretical evaluation of a bulky ortho-thioalkyl-azobenzene as an alternative to photocontrol structural cytotoxic effects of metal-free and disulfide oxidized hSOD1 in pathogenesis of ALS.}, journal = {RSC advances}, volume = {15}, number = {12}, pages = {9018-9026}, pmid = {40129635}, issn = {2046-2069}, abstract = {This study presents a novel photopharmacological strategy to mitigate the cytotoxic effects of apo-hSOD1[S-S], a misfolded protein implicated in neurodegenerative diseases. Using quantum chemical calculations and molecular dynamics simulations, we demonstrate that ortho-thio-substituted azobenzene photoswitches (ortho-TABPs) can be employed to precisely modulate the dynamics of the crucial electrostatic loop (EL) in apo-hSOD1[S-S]. We establish that larger ortho-S-alkyl substituents on the ortho-TABP enhance its redox stability, favouring the cis conformation through the modulation of the position of the n → π* transition. This stability is crucial for operation within the reducing cellular environment. Furthermore, we demonstrate the successful and consistent photomodulation of EL conformational dynamics in apo-hSOD1[S-S] through covalent tethering of an ortho-TABP. This control is achieved by leveraging the thermodynamically stable trans conformation of the photoswitch, which allosterically influences the EL and consequently, the geometry of the Zn-binding site, a critical determinant of apo-hSOD1[S-S] cytotoxicity. This work paves the way for developing targeted therapies for neurodegenerative diseases by demonstrating the precise and effective photomodulation of apo-hSOD1[S-S] via rationally designed ortho-TABPs.}, } @article {pmid40128927, year = {2025}, author = {Aikawa, M and Ando, T and Shibayama, H and Kubota, M and Sonoo, M and Fukutake, T}, title = {[A case of amyotrophic lateral sclerosis complicated by syringomyelia associated with Chiari type I malformation].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {}, number = {}, pages = {}, doi = {10.5692/clinicalneurol.cn-002045}, pmid = {40128927}, issn = {1882-0654}, abstract = {The patient was a 78-year-old woman. She underwent foramen magnum decompression for syringomyelia associated with Chiari type I malformation, which had developed with difficulty in raising the left upper limb and muscle weakness in both upper limbs. One year after surgery, weight loss of 20 ‍kg, progressive muscle atrophy and weakness in the extremities, paralytic dysarthria, and fasciculation in the bilateral anterior thighs were observed, and needle electromyography showed acute denervation and chronic denervation in the medial vastus muscle. The rapid postoperative progression of symptoms and lower motor neuron symptoms in the lower extremities could not be explained by syringomyelia associated with Chiari type I malformation and were considered a possible complication of amyotrophic lateral sclerosis (ALS). It is possible that the surgery may have caused ALS progression, and attention to the rate of progression of neurologic symptoms may be important in the diagnosis of ALS complications.}, } @article {pmid40128823, year = {2025}, author = {Zhang, W and Huang, C and Yao, H and Yang, S and Jiapaer, Z and Song, J and Wang, X}, title = {Retrotransposon: an insight into neurological disorders from perspectives of neurodevelopment and aging.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {14}, pmid = {40128823}, issn = {2047-9158}, support = {2023TSYCCX0051//Tianshan Talent Training Program/ ; }, mesh = {Humans ; *Retroelements/genetics ; *Aging/genetics ; *Nervous System Diseases/genetics ; Animals ; }, abstract = {Neurological disorders present considerable challenges in diagnosis and treatment due to their complex and diverse etiology. Retrotransposons are a type of mobile genetic element that are increasingly revealed to play a role in these diseases. This review provides a detailed overview of recent developments in the study of retrotransposons in neurodevelopment, neuroaging, and neurological diseases. Retrotransposons, including long interspersed nuclear elements-1, Alu, SINE-VNTR-Alu, and endogenous retrovirus, play important regulatory roles in the development and aging of the nervous system. They have also been implicated in the pathological processes of several neurological diseases, including Alzheimer's disease, X-linked dystonia-parkinsonism, amyotrophic lateral sclerosis, autism spectrum disorder, and schizophrenia. Retrotransposons provide a new perspective for understanding the molecular mechanisms underlying neurological diseases and provide insights into diagnostic and therapeutic strategies of these diseases.}, } @article {pmid40128246, year = {2025}, author = {Hu, X and Wei, M and Zhang, H and Yu, M and Wang, M and Zhou, B and Luo, Y and Li, B}, title = {The experience of pain symptoms in patients with amyotrophic lateral sclerosis: a qualitative study.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {10183}, pmid = {40128246}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology ; Middle Aged ; Male ; Female ; *Pain/psychology/etiology ; *Qualitative Research ; Aged ; Adult ; Adaptation, Psychological ; Pain Management/methods ; }, abstract = {ALS is a progressive neurodegenerative disease that has a serious impact on patients and their caregivers. For a long time in the past, ALS was considered a painless disease that was largely ignored by clinicians. Describing the complexity and needs of pain symptoms from the perspective of patients can provide the most intuitive direction for future research. The purpose of our research is to explore the experience of pain symptoms in patients with amyotrophic lateral sclerosis (ALS), provide reference for better understanding of pain symptoms in ALS patients. From April 2023 to May 2023, 27 patients experiencing pain symptoms in Peking University Third Hospital who met the diagnostic criteria of "Chinese Guidelines for the Diagnosis and Treatment of amyotrophic lateral sclerosis" were interviewed by means of objective sampling. The content analysis method was used to describe the pain changes since the disease (amyotrophic lateral sclerosis), the factors that aggravate the pain, the measures to cope with the pain and the needs. The interview results included 3 themes and 11 subthemes. (1) Pain is diverse: the type of pain, the time when pain occurs, the change in pain intensity, and the factors that aggravate pain; (2) Individualized pain coping measures: posture adjustment, medication, physical therapy, warmth, emotional regulation; (3) Patients lack of understanding of pain: insufficient source of knowledge, the single orientation of the solution. The nature, location and aggravating factors of pain in amyotrophic lateral sclerosis patients in China are complicated, which should be paid attention to by clinical staff and scientific researchers. The situation of pain management is not optimistic, and the pain of the vast majority of patients has not been effectively alleviated. It is necessary to realize the importance of self-management and care of others in coping with pain, and conduct further research in the future to find a breakthrough in pain relief, so as to strengthen pain intervention in clinical practice.}, } @article {pmid40127736, year = {2025}, author = {Maetani, Y and Kurashige, T and Tada, Y and Kume, K and Watanabe, T and Sotomaru, Y and Yamanaka, K and Maruyama, H and Kawakami, H}, title = {Optineurin knock-out forms TDP-43 aggregates to regulate TDP-43 protein levels despite autophagic up-regulation and aberrant TDP-43 expression.}, journal = {Neuroscience research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neures.2025.03.005}, pmid = {40127736}, issn = {1872-8111}, abstract = {Optineurin is a causative gene of amyotrophic lateral sclerosis (ALS) and has many roles in processes such as autophagy and inflammation. However, it is unclear how optineurin causes ALS. Optineurin knock-out (Optn-KO) mice, which have been generated by several researchers, exhibit motor neuron degeneration and TDP-43 aggregates, but no motor deficits. Motor dysfunction in ALS model mice is associated with TDP-43 in the spinal cord. We bred Optn-KO mice with TDP-43 overexpression transgenic mice and evaluated whether increased TDP-43 protein causes motor deficits and whether Optn-KO affects TDP-43 protein level. Optn-KO mice had spinal TDP-43 protein levels and motor function comparable to wild-type mice, and TDP-43-transgenic (TDP-43-tg) mice resulted in motor dysfunction and early death. However, double-mutant TDP-43-tg / Optn-KO mice had lower TDP-43 protein levels than TDP-43-tg mice at 18 months age, and showed inhibition of the TBK1-optinerurin autophagic pathway with aging. Furthermore, Optn-KO caused TDP-43-positive cytoplasmic aggregates. TDP-43 overexpression by itself induced spinal microgliosis, but Optn-KO suppressed that microgliosis. Finally, we showed that Optn-KO mice could not exhibit behavioral dysfunction because TDP-43 protein levels were not elevated despite autophagy inhibition. Thus, downregulation of Optn may suppress TDP-43 toxicity by regulating its abundance through aggregate formation.}, } @article {pmid40127392, year = {2025}, author = {Vasta, R and De Mattei, F and Tafaro, S and Canosa, A and Manera, U and Grassano, M and Palumbo, F and Cabras, S and Matteoni, E and Di Pede, F and Zocco, G and Pellegrino, G and Minerva, E and Pascariu, D and Iazzolino, B and Callegaro, S and Fuda, G and Salamone, P and De Marchi, F and Mazzini, L and Moglia, C and Calvo, A and Chiò, A}, title = {Changes to Average Survival of Patients With Amyotrophic Lateral Sclerosis (1995-2018): Results From the Piemonte and Valle d'Aosta Registry.}, journal = {Neurology}, volume = {104}, number = {8}, pages = {e213467}, doi = {10.1212/WNL.0000000000213467}, pmid = {40127392}, issn = {1526-632X}, mesh = {*Amyotrophic Lateral Sclerosis/mortality/therapy/diagnosis ; Humans ; Male ; *Registries ; Female ; Middle Aged ; Aged ; Proportional Hazards Models ; Cohort Studies ; Survival Rate ; Italy/epidemiology ; Adult ; }, abstract = {BACKGROUND AND OBJECTIVES: The average survival of patients with amyotrophic lateral sclerosis (ALS) ranges from 2 to 5 years from symptom onset. However, it remains unclear whether this estimate has improved over time. The objective of this study was to analyze the survival trend of a large population-based cohort of patients with ALS over a 24-year period.

METHODS: Patients from the Piemonte and Valle d'Aosta registry for ALS (PARALS) were categorized into the first (1995-2002), second (2003-2010), or third (2011-2018) epoch based on their diagnosis date. Survival was defined as the time from diagnosis to death, tracheostomy, or censoring date. A Cox proportional hazard model was developed with diagnosis epoch as the primary variable of interest, adjusted for sex, site of onset, age at onset, diagnostic delay, forced vital capacity at diagnosis, Δbody mass index from onset to diagnosis, noninvasive mechanical ventilation use, gastrostomy use, and site of follow-up. A subset analysis comparing the 2007-2012 and 2013-2018 cohorts was conducted, incorporating riluzole prescription, genetics, and preslope category as additional covariates.

RESULTS: A total of 3,134 patients were included, evenly distributed across the 3 epochs (990, 1,023, and 1,121, respectively). The median survival remained stable during the first and second epoch (18.6 months vs 18.3 months) but improved during the third epoch (20.1 months; p = 0.0041), with a hazard ratio (HR) of 0.76 (95% CI 0.67-0.87, p = 0.00003). In the subset analysis, the most recent epoch (2013-2018) showed a continued survival advantage (HR 0.77, 95% CI 0.65-0.90). Of interest, the survival benefit was only evident among intermediate progressors (HR 0.60, 95% CI 0.45-0.80).

DISCUSSION: In the PARALS, ALS survival increased over time. In a subset analysis, the beneficial effect of the epoch was only evident among intermediate progressors. The improvement in multidisciplinary care provided by tertiary centers may be one possible explanation for this finding, although further dedicated studies are needed to confirm this hypothesis.}, } @article {pmid40126464, year = {2025}, author = {Shefner, JM and Cudkowicz, ME and Genge, A and Hardiman, O and Al-Chalabi, A and Andrews, JA and Chio, A and Corcia, P and Couratier, P and de Carvalho, M and Heiman-Patterson, T and Henderson, RD and Ingre, C and Johnston, W and Ludolph, A and Maragakis, NJ and Miller, TM and Mora, JS and Petri, S and Simmons, Z and van den Berg, LH and Zinman, L and Kupfer, S and Malik, FI and Meng, L and Simkins, TJ and Wei, J and Wolff, AA and Rudnicki, SA and , }, title = {Reldesemtiv in Amyotrophic Lateral Sclerosis: Results From the COURAGE-ALS Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {40126464}, issn = {2168-6157}, abstract = {IMPORTANCE: Treatment options for amyotrophic lateral sclerosis (ALS) remain suboptimal. Results from a phase 2 study of reldesemtiv in ALS suggested that it may slow disease progression.

OBJECTIVE: To assess the effect of reldesemtiv vs placebo on functional outcomes in ALS.

A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (COURAGE-ALS) was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted at 83 ALS centers in 16 countries from August 2021 to July 2023. The first 24-week period was placebo controlled vs reldesemtiv. All participants received reldesemtiv during the second 24-week period with a 4-week follow-up. Two interim analyses were planned, the first for futility and the second for futility and possible resizing. This was a hybrid decentralized trial with approximately half the trial visits performed remotely and the remaining visits in the clinic. Eligible participants met criteria for definite, probable, or possible ALS with lower motor neuron signs by modified El Escorial Criteria, ALS symptoms for 24 months or less, ALS Functional Rating Scale-Revised (ALSFRS-R) total score of 44 or less, and forced vital capacity of greater than or equal to 65% of predicted.

INTERVENTIONS: Oral reldesemtiv, 300 mg, or placebo twice daily.

MAIN OUTCOMES AND MEASURES: The primary end point was change in ALSFRS-R total score from baseline to week 24.

RESULTS: Of the 696 participants screened, 207 were screen failures. A total of 486 participants (mean [SD] age, 59.4 [10.9] years; 309 male [63.6%]) were randomized to reldesemtiv (n = 325) or placebo (n = 161); 3 randomized patients were not dosed. The second interim analysis at 24 weeks after randomization included 256 participants. The data monitoring committee recommended that the trial should end due to futility, and the sponsor agreed. The mean (SE) group difference in the ALSFRS-R score from baseline to week 24 was -1.1 (0.53; 95% CI, -2.17 to -0.08; P = .04, favoring placebo). Given excess missing data from early termination, the combined assessment assumed greater importance; it, too, failed to show a benefit from treatment with reldesemtiv (win probability was 0.44 for reldesemtiv and 0.49 for placebo, with a win ratio of 0.91; 95% CI of win ratio, 0.77-1.10; P = .11).

CONCLUSIONS AND RELEVANCE: This randomized clinical trial failed to demonstrate efficacy for reldesemtiv in slowing functional decline in ALS.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04944784.}, } @article {pmid40126385, year = {2025}, author = {Yarlagadda, S and Hazboun, M and Vilke, G and Farah, J and Donofrio-Odmann, JJ}, title = {Epidemiology of Neonate Prehospital Care at the San Diego (US) - Tijuana (Mexico) International Border.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/10903127.2025.2476196}, pmid = {40126385}, issn = {1545-0066}, abstract = {OBJECTIVES: Neonates, infants 30 days of age or younger are understudied in prehospital emergencies. Our objective was to describe prehospital assessment and care for patients <30 days of age at the San Diego-Tijuana Point of Entry (POE). Additional objectives included describing assessments, care, frequency, and level of care for newborns brought to the border by Mexican ambulances.

METHODS: This was a retrospective analysis from January 1, 2014, to January 01, 2020, of all 9-1-1 calls involving patients <30 days of age at the San Diego POEs. The 9-1-1 responses to newly delivered patients were "newborns". Patients who were not immediately post-delivery were "neonates." Patient demographics, response intervals, clinician interventions, and dispositional data were collected from electronic patient records. Descriptive statistics were applied.

RESULTS: A total of 57 patients <30 days of age were included. With 27 newborn patients, 15 were delivered by emergency medical services (EMS) personnel (27, 55.6%). Initial appearance, pulse, grimace, activity, and respiration (APGAR) scores were 8-10 in 44.4% and 5-7 in 29.6%. Procedures included newborn care (88.9%), advanced life support (ALS) assessment (63.0%), and warming (59.3%). There were five patients that had stimulation, 7 received oxygen, and 3 received Bag-Valve-Mask (BVM) ventilation. No serial heart rates were documented. Regarding 30 neonates, the predominant method of transport to the POE was Mexican ambulance (n 16, 53.3%). Medications administered included oxygen (n 16, 53.3%) and albuterol/ipratropium (n 1, 3.3%). Procedures included ALS assessment (n 19, 63.3%), pulse oximetry (n 22, 73.3%), and 3-lead electrocardiogram (n 8, 26.7%). Three patients (10%) received BVM. Mexican Ambulances brought 16 neonates. A physician or nurse was present in 37.5% of transfers, 50% were incubated, 25% intubated, 37.5% on supplemental oxygen, and 71% had preexisting intravenous access. These were not interfacility transfers but were 9-1-1 activations by U.S. border agents; and 14 neonates did not arrive via Mexican ambulance. Their complaints were respiratory distress (n 7, 50%) and Brief Resolved Unexplained Episode (n 4, 28.6%).

CONCLUSIONS: We found that 9-1-1 transports at the San Diego-Tijuana POE for patients <30 days were few and involved resuscitation, neonates in Mexican ambulances with specialized equipment, physicians, and unfamiliar medications. Neonates arriving via private transport had respiratory distress and BRUE.}, } @article {pmid40125959, year = {2025}, author = {Gupta, U and Kumar, A and Alam, MI and Balaji, PG and Sharma, A and Yadav, AK}, title = {Synthesis and characterization of protein nanohybrid systems for the brain delivery of Riluzole.}, journal = {Therapeutic delivery}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/20415990.2025.2478805}, pmid = {40125959}, issn = {2041-6008}, abstract = {AIMS: Synthesis and Characterization of Protein NanoHybrid Systems for the Brain Delivery of Riluzole.

METHODS/MATERIALS: Fullerene is converted into carboxylated fullerene (CF) and then, prepared RZU-loaded BSA nanoparticles conjugated with CF.

RESULTS: The particle size and zeta potential of RZU-PNH were found to be 210 ± 1.15 nm and -18.5 ± 0.615 mV respectively, and entrapment efficiency and loading efficiency of RZU-PNH were found to be 98.8 ± 0.53% and 11.6 ± 0.43%, respectively. The XRD of the RZU-PNH shows the amorphism behavior and CD revealed that secondary structure of the protein mainly consists of α-helix andβ-sheet. The MTT assay showed 88.60% and 90.84% cell viability in both SH-SY5Yand N2a cell lines at a concentration of 20 μg/ml and also, no significant nasal ciliotoxicity was observed after incubation with RZU-PNH.

CONCLUSIONS: Obtained results indicated RZU-PNH formulation to treat amyotrophic lateral sclerosis.}, } @article {pmid40125702, year = {2025}, author = {Madhavan, S and Deshmukh, S and Cummings, M and Doshi, A and Rezania, K and Freels, S and Sawa, G}, title = {Home-Based Tele-tDCS in Amyotrophic Lateral Sclerosis: Feasibility, Safety, and Preliminary Efficacy.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70038}, pmid = {40125702}, issn = {2328-9503}, support = {R21HD102722//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Transcranial direct current stimulation (tDCS) shows promise as a neuromodulatory intervention in various neurological disorders, but its application in ALS, particularly in a remote, home-based format, remains underexplored. This study investigates the feasibility, safety, and preliminary efficacy of remotely supervised tele-tDCS in ALS patients.

METHODS: This double-blinded pilot study included 14 spinal-onset ALS participants randomized into two groups: the intervention group received 72 tele-tDCS sessions over 24 weeks, and the delayed-start group received 36 sham sessions followed by 36 tele-tDCS sessions. Stimulation was delivered at 2 mA for 20 min 3 times a week. Primary outcomes included feasibility, safety, and disease progression measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Adherence and adverse effects were monitored throughout.

RESULTS: Ten participants completed the study, with an overall compliance rate of 98.3%. No serious adverse events were reported, and mild side effects, like itching and tingling, were consistent with tDCS literature. The intervention group demonstrated a significantly slower decline in ALSFRS-R scores than the delayed-start group. At 24 weeks, the intervention group had a mean ALSFRS-R change of -1.7, compared to -13.6 in the delayed-start group (p = 0.0018). Additionally, the change in ALSFRS-R between pre- and mid-intervention significantly differed between groups (p = 0.0071).

INTERPRETATION: Tele-tDCS was feasible, safe, and well-tolerated in individuals with ALS. Preliminary efficacy results suggest that tele-tDCS may slow disease progression, underscoring the potential of tele-tDCS as a promising home-based neuromodulatory intervention in ALS management.

TRIAL REGISTRATION: Clinical trial registration: NCT04866771.}, } @article {pmid40125691, year = {2025}, author = {Ono, D and Kawai, H and Kuwahara, H and Yokota, T}, title = {Refining Muscle Morphometry Through Machine Learning and Spatial Analysis.}, journal = {Neuropathology and applied neurobiology}, volume = {51}, number = {2}, pages = {e70012}, doi = {10.1111/nan.70012}, pmid = {40125691}, issn = {1365-2990}, mesh = {Humans ; *Machine Learning ; Retrospective Studies ; Spatial Analysis ; Neuromuscular Diseases/pathology/diagnosis ; Muscle, Skeletal/pathology ; Male ; Female ; Middle Aged ; Muscular Diseases/pathology/diagnosis ; Adult ; Aged ; }, abstract = {AIMS: Muscle morphology provides important information in differentiating disease aetiology, but its measurement remains challenging because of the lack of an efficient and objective method. This study aimed to quantitatively refine the morphological features of muscle fibres in neuromuscular diseases using machine learning.

METHODS: In this retrospective study, we analysed muscle biopsy specimens on haematoxylin and eosin-staining. Machine learning-based software was developed to segment muscle fibre contours and perform automated muscle morphometry and subsequent graph theory-based spatial analysis of atrophied fibre grouping. A decision tree-based framework, LightGBM, was trained to predict underlying aetiologies based on morphometric and spatial variables.

RESULTS: The study included 100 muscle samples, including 20 normal muscles, 49 myopathies and 19 neuropathies. The fine-tuned segmentation model, YOLOv8, achieved a mask average precision of 0.819. The muscle morphometry revealed the significance of fibre circularity. The mean circularity was higher in the myopathy group, and the SD of circularity was elevated in the neuropathy group. Although most cases were consistent with textbook findings, atypical presentations, such as dermatomyositis with angular atrophy and amyotrophic lateral sclerosis with round atrophy, were objectively documented. Spatial analysis quantified grouped atrophy, showing the potential to feature specific atrophy patterns. The LightGBM model successfully predicted the final clinical diagnosis of the myopathies and neuropathies with an accuracy of 0.852, which exceeded that of 0.808 by human annotation.

CONCLUSION: Automated muscle morphometry and spatial analysis provide quantification of muscle morphology and patterns of atrophy, which will facilitate objective and efficient investigation of neuromuscular diseases.}, } @article {pmid40124885, year = {2025}, author = {Dethier, C and Azirar, S and Verluyten, L and Boonen, H and Grosber, M and Gutermuth, J}, title = {Response to Fässler et al's "Successful treatment of refractory folliculitis decalvans with apremilast".}, journal = {JAAD case reports}, volume = {57}, number = {}, pages = {122-123}, pmid = {40124885}, issn = {2352-5126}, } @article {pmid40124731, year = {2025}, author = {Liu, QZ and Sun, NZ}, title = {Investigation on the quality of life after anterior minimally invasive total hip arthroplasty: Commentary on recent findings.}, journal = {World journal of orthopedics}, volume = {16}, number = {3}, pages = {105318}, pmid = {40124731}, issn = {2218-5836}, abstract = {This editorial critically evaluated the recent study by Ishikura et al, which examined the impact of anterior minimally invasive total hip arthroplasty (MIS-THA) on postoperative quality of life, with a specific focus on the timeline and influencing factors for return to work and resumption of driving. Ishikura et al's research demonstrated that anterior MIS-THA could shorten recovery time, reduce postoperative pain, and significantly enhance patients' quality of life and productivity. Their findings identified occupational type and work intensity as key determinants of postoperative recovery. By synthesizing evidence from multiple studies, this analysis systematically evaluated the clinical advantages of anterior MIS-THA-including reduced soft tissue trauma and accelerated functional recovery-while acknowledging its limitations, such as a steep surgical learning curve and early postoperative complication risks. The discussion emphasized the necessity of designing personalized rehabilitation protocols that accounted for patients' occupational demands. Notably, while current findings primarily derived from retrospective analyses, the article highlighted the need for prospective cohort studies to validate these observations. The commentary also addressed ongoing debates in the field, particularly the elevated complication rates associated with the direct anterior approach compared to posterior techniques, thereby underscoring the critical role of surgeon expertise in optimizing procedural safety. Collectively, this evaluation advanced our understanding of postoperative recovery dynamics in anterior MIS-THA and provides evidence-based insights to refine clinical rehabilitation frameworks.}, } @article {pmid40122623, year = {2025}, author = {Ghanizada, H and Nedergaard, M}, title = {The glymphatic system.}, journal = {Handbook of clinical neurology}, volume = {209}, number = {}, pages = {161-170}, doi = {10.1016/B978-0-443-19104-6.00006-1}, pmid = {40122623}, issn = {0072-9752}, mesh = {Humans ; *Glymphatic System ; Neurodegenerative Diseases/therapy ; Animals ; Brain ; }, abstract = {The glymphatic system, a brain-wide network-supporting cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange, is essential for removing metabolic waste from the brain. This system's proper functioning is crucial for maintaining neural health and preventing the accumulation of harmful substances that can lead to neurodegenerative diseases. This chapter explores the glymphatic system's mechanisms, its dysfunction in various neurologic disorders, and potential therapeutic strategies. Recent discoveries reveal the glymphatic system's involvement in aging, sleep, cerebral edema, and conditions, such as Alzheimer, Parkinson, Huntington diseases, amyotrophic lateral sclerosis, small vessel disease, hydrocephalus, migraine, stroke, traumatic brain injury, and psychiatric disorders, where impaired waste clearance contributes to disease pathogenesis. Moreover, therapeutic interventions targeting glymphatic dysfunction present promising avenues for mitigating the effects of neurodegenerative diseases. The chapter underscores the potential of integrating glymphatic research into broader clinical practices, offering new strategies for disease management and prevention.}, } @article {pmid40122396, year = {2025}, author = {Cao, Y and Xu, Y and Cao, M and Chen, N and Zeng, Q and Lai, MKP and Fan, D and Sethi, G and Cao, Y}, title = {Fluid-based biomarkers for neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {108}, number = {}, pages = {102739}, doi = {10.1016/j.arr.2025.102739}, pmid = {40122396}, issn = {1872-9649}, abstract = {Neurodegenerative diseases, such as Alzheimer's Disease (AD), Multiple Sclerosis (MS), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are increasingly prevalent as global populations age. Fluid biomarkers, derived from cerebrospinal fluid (CSF), blood, saliva, urine, and exosomes, offer a promising solution for early diagnosis, prognosis, and disease monitoring. These biomarkers can reflect critical pathological processes like amyloid-beta (Aβ) deposition, tau protein hyperphosphorylation, α-syn misfolding, TDP-43 mislocalization and aggregation, and neuronal damage, enabling detection long before clinical symptoms emerge. Recent advances in blood-based biomarkers, particularly plasma Aβ, phosphorylated tau, and TDP-43, have shown diagnostic accuracy equivalent to CSF biomarkers, offering more accessible testing options. This review discusses the current challenges in fluid biomarker research, including variability, standardization, and sensitivity issues, and explores how combining multiple biomarkers with clinical symptoms improves diagnostic reliability. Ethical considerations, future directions involving extracellular vehicles (EVs), and the integration of artificial intelligence (AI) are also highlighted. Continued research efforts will be key to overcoming these obstacles, enabling fluid biomarkers to become crucial tools in personalized medicine for neurodegenerative diseases.}, } @article {pmid40120962, year = {2025}, author = {Zhang, X and Wang, J and Zhang, J and Jiang, C and Liu, X and Wang, S and Zhang, Z and Rastegar-Kashkooli, Y and Dialameh, F and Peng, Q and Tao, J and Ding, R and Wang, J and Cheng, N and Wang, M and Wang, F and Li, N and Xing, N and Chen, X and Fan, X and Wang, J and Wang, J}, title = {Humanized rodent models of neurodegenerative diseases and other brain disorders.}, journal = {Neuroscience and biobehavioral reviews}, volume = {172}, number = {}, pages = {106112}, doi = {10.1016/j.neubiorev.2025.106112}, pmid = {40120962}, issn = {1873-7528}, abstract = {Central Nervous System (CNS) diseases significantly affect human health. However, replicating the onset, progression, and pathology of these diseases in rodents is challenging. To address this issue, researchers have developed humanized animal models. These models introduce human genes or cells into rodents. As a result, rodents become more suitable for studying human CNS diseases and their therapies in vivo. This review explores the preparation protocols, pathological and behavioral characteristics, benefits, significance, and limitations of humanized rodent models in researching various CNS diseases, particularly Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, glial cells-related CNS diseases, N-methyl-D-aspartic acid receptor encephalitis, and others. Humanized rodent models have expanded the opportunities for in vivo exploration of human neurodegenerative diseases, other brain disorders, and their treatments. We can enhance translational research on CNS disorders by developing, investigating, and utilizing these models.}, } @article {pmid40119776, year = {2025}, author = {Pesti, B and Langa, X and Kumpesa, N and Valdeolivas, A and Sultan, M and Rottenberg, S and Hahn, K}, title = {Mini Review: Spatial Transcriptomics to Decode the Central Nervous System.}, journal = {Toxicologic pathology}, volume = {}, number = {}, pages = {1926233251325204}, doi = {10.1177/01926233251325204}, pmid = {40119776}, issn = {1533-1601}, abstract = {Spatial transcriptomics (ST) is revolutionizing our understanding of the central nervous system (CNS) by providing spatially resolved gene expression data. This mini review explores the impact of ST on CNS research, particularly in neurodegenerative diseases like Alzheimer's, Parkinson's, multiple sclerosis, and amyotrophic lateral sclerosis. We describe two foundational ST methods: sequencing-based and imaging-based. Key studies are reviewed highlighting the power of ST data sets to map transcriptomes to disease-specific histomorphology, elucidate molecular mechanisms of regional and cellular vulnerability, integrate single-cell data with tissue mapping, and reveal receptor-ligand interactions. Despite current challenges like data interpretation and resolution limits, ST holds promise for identifying novel drug targets, evaluating their therapeutic potential, and bridging gaps between animal models and human studies to advance development of CNS-targeting compounds.}, } @article {pmid40119207, year = {2025}, author = {Cheng, M and Lu, D and Li, K and Wang, Y and Tong, X and Qi, X and Yan, C and Ji, K and Wang, J and Wang, W and Lv, H and Zhang, X and Kong, W and Zhang, J and Ma, J and Li, K and Wang, Y and Feng, J and Wei, P and Li, Q and Shen, C and Fu, XD and Ma, Y and Zhang, X}, title = {Author Correction: Mitochondrial respiratory complex IV deficiency recapitulates amyotrophic lateral sclerosis.}, journal = {Nature neuroscience}, volume = {28}, number = {4}, pages = {913}, doi = {10.1038/s41593-025-01941-2}, pmid = {40119207}, issn = {1546-1726}, } @article {pmid40118328, year = {2025}, author = {Mansour, HM and El-Khatib, AS}, title = {Oligonucleotide-based therapeutics for neurodegenerative disorders: Focus on antisense oligonucleotides.}, journal = {European journal of pharmacology}, volume = {998}, number = {}, pages = {177529}, doi = {10.1016/j.ejphar.2025.177529}, pmid = {40118328}, issn = {1879-0712}, abstract = {Antisense oligonucleotides (ASOs) specifically bind to target RNA sequences and regulate protein expression through various mechanisms. ASOs are a promising therapeutic approach for treating neurodegenerative diseases. The ASO field is a growing area of drug development that focuses on targeting the root cause of diseases at the RNA level, providing a promising alternative to therapies that target downstream processes. Addressing challenges related to off-target effects and inadequate biological activity is essential to successfully develop ASO-based therapies. Researchers have investigated various chemical modifications and delivery strategies to overcome these challenges. This review discusses oligonucleotide-based therapies, particularly ASOs. We discuss the chemical modifications and mechanisms of action of ASOs. Additionally, we recap the results of preclinical and clinical studies testing different ASOs in various neurodegenerative disorders, including spinal muscular atrophy, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. In conclusion, ASO drugs show promise as a therapeutic option for treating neurodegenerative diseases.}, } @article {pmid40117902, year = {2025}, author = {Wi, JH and Lee, H and Park, JM and Heo, Y and Jo, S and Lee, J and Kim, Y and Jung, C and Kim, NJ and Song, GY and Kim, P and Kim, H and Lee, S}, title = {Development of a TBK1 and ALK dual inhibitor for alleviating depressive behavior via anti-inflammatory effects.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {186}, number = {}, pages = {117991}, doi = {10.1016/j.biopha.2025.117991}, pmid = {40117902}, issn = {1950-6007}, abstract = {Polypharmacology offers innovative strategies for treating immune and inflammatory dysregulation in complex diseases. Here, we identified ALS-04, a dual inhibitor of TANK-binding kinase 1 (TBK1) and anaplastic lymphoma kinase (ALK), which are closely linked to stimulator of interferon genes (STING)-mediated immune responses. ALS-04 effectively suppressed 2'3'-cyclic GMP-AMP (cGAMP)- and lipopolysaccharide (LPS)-induced type I interferon and pro-inflammatory responses by targeting the STING-TBK1 and STING-ALK pathways. Furthermore, ALS-04 significantly alleviated depressive symptoms, including anhedonia and behavioral despair, in an LPS-induced mouse model of depression. These findings highlight the therapeutic potential of dual TBK1 and ALK inhibition in depression by modulating immune and inflammatory pathways.}, } @article {pmid40117341, year = {2025}, author = {Koehn, LM and Steele, JR and Schittenhelm, RB and Nicolazzo, JA}, title = {Sex-Specific Markers of Neuroinflammation and Neurodegeneration in the Spinal Cord Proteome of the SOD1[G93A] Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Journal of proteome research}, volume = {24}, number = {4}, pages = {1956-1970}, doi = {10.1021/acs.jproteome.4c00990}, pmid = {40117341}, issn = {1535-3907}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Female ; *Spinal Cord/metabolism/pathology ; Mice ; Male ; Disease Models, Animal ; *Proteome/genetics/metabolism ; *Superoxide Dismutase-1/genetics ; Proteomics/methods ; Biomarkers/metabolism ; Mice, Transgenic ; *Neuroinflammatory Diseases/metabolism/pathology/genetics ; Sex Factors ; Sex Characteristics ; Superoxide Dismutase/genetics ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that has no cure. The underlying mechanistic details of sex differences in the ALS spinal cord, the site of disease onset, are not understood to an extent that could guide novel drug development. To address this, the spinal cords of 120-day-old wild-type (WT) and SOD1[G93A] (familial mouse model of ALS with mutant superoxide dismutase 1) mice were subjected to untargeted, quantitative proteomics using tandem mass tag acquisition on high-resolution mass spectrometric instrumentation. Compared to WT, both male and female SOD1[G93A] spinal cords exhibited an upregulation of neuroinflammatory cascades of both peripheral and central origins, as well as a downregulation of proteins reflective of death and dysfunction of cells within the spinal cord. However, female and male SOD1[G93A] mouse spinal cords exhibited sex-specific differences in proteins compared to respective WT that related to immune response, as well as cellular structure, function, and homeostasis. The proteomic datasets presented provide entire cohort and sex-specific spinal cord drug targets and disease biomarkers in the SOD1[G93A] mouse model of ALS that may guide future drug development and sex selection in preclinical study designs utilizing the SOD1[G93A] model.}, } @article {pmid40116411, year = {2025}, author = {Albrethsen, J and Drici, L and Slot Vilmann, LM and Holmboe, SA and Thomsen, CE and Rogaczewska Groendahl, VL and Ottenheijm, ME and Nielsen, AB and Christoffersen, C and Aksglaede, L and Hagen, CP and Wewer Albrechtsen, NJ and Juul, A}, title = {Targeted proteomics of serum IGF-I, -II, IGFBP-2, -3, -4, -5, -6 and ALS.}, journal = {Clinical chemistry and laboratory medicine}, volume = {}, number = {}, pages = {}, pmid = {40116411}, issn = {1437-4331}, abstract = {OBJECTIVES: The insulin-like growth factors (IGFs) regulate growth in humans. IGF-I and IGF binding protein (IGFBP)-3 are biomarkers in children with growth disorders. We investigate a targeted proteomics method for absolute quantitation of eight IGF protein family members in human serum, including the peptide hormones IGF-I and -II, and the six binding proteins IGFBP-2, -3, -4, -5, -6 and acid labile subunit (ALS).

METHODS: Serum preparation was optimized for targeted proteomics of IGF related proteins on a clinical LC-MS/MS platform (UHPLC coupled with Triple-Q MS). We created quality controls, standards and internal standards and 289 serum samples from healthy children and adolescents were measured in ten batches over two months. The method was compared to WHO reference standards, clinical and research immunoassays, and relative proteomics profiling.

RESULTS: The sensitivity and reproducibility were sufficient for most but not all IGF protein family members. Targeted proteomics correlated well with clinical immunoassays for IGF-I (R[2]=0.88) and for IGFBP-3 (R[2]=0.46), (p<0.001). The correlation between targeted proteomics and non-clinical immunoassays for IGF-II, IGFBP-2, -4, -5, -6 and ALS varied between proteins.

CONCLUSIONS: We present a method for parallel quantification of IGF-I, IGFBP-3, 5 and ALS for clinical verification studies, whereas targeted proteomics of the five remaining IGF related proteins (IGF-II, IGFBP-2, -4, and -6) require further examination. The sensitivity of our new IGF-I method suggests a possible diagnostic role for targeted proteomics of IGF-I in the management of children with extremely low levels of circulating IGF-I.}, } @article {pmid40116377, year = {2025}, author = {Zhu, Y and Li, M and Zhou, M and Hong, D}, title = {Letter on Wine Glass Sign in Bulbar-Onset Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27239}, pmid = {40116377}, issn = {1531-8249}, } @article {pmid40116361, year = {2025}, author = {Li, C and Noonan, AM and Hays, J and Roychowdhury, S and Malalur, P and Elkhatib, R and Manne, A and Mittra, A and Rahman, S and Yan, L and Hill, K and Abbott, N and Phelps, M and Na, JY and Liang, B and Storts, H and Khan, M and Zhang, EH and Miles, W and Yildiz, V and Wei, L and Wang, JJ and Jin, N}, title = {Riluzole in Combination with mFOLFOX6 and Bevacizumab in Treating Patients with Metastatic Colorectal Cancer: A Phase 1 Clinical Trial.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-3964}, pmid = {40116361}, issn = {1557-3265}, abstract = {BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the US. 5-fluorouracil (5-FU)-based chemotherapies in combination with targeted agents remain the standard of care in patients with metastatic or locally advanced disease. New treatment strategies are needed for metastatic CRC patients with microsatellite stable disease. Preclinical studies showed that riluzole, an oral medicine for amyotrophic lateral sclerosis, inhibits glutamate release and synergizes with 5-FU to reduce cell viability in CRC cell lines.

METHODS: In this single-arm, phase 1 trial of riluzole in combination with mFOLFOX6/bevacizumab for patients with metastatic CRC, the riluzole dose started at 50 mg twice daily, escalating to 100 mg twice daily or de-escalating to 50 mg once daily. Patients received riluzole for 16 weeks in combination with mFOLOFX6/bevacizumab for 8 cycles. Patients then either continued mFOLFOX6/bevacizumab or switched therapy.

RESULTS: Twelve of the 14 patients enrolled were evaluable. All patients previously received FOLFOX, and 5 patients (41.7%) showed disease resistance to it. Two patients obtained partial responses, 9 had stable disease, and 1 had progressive disease. The objective response rate was 16.7%, and the disease control rate was 91.7%. The median duration of response was 4.9 months (95% CI 1.6-9.8). Median progression-free survival and overall survival were 4.89 and 12.98 months, respectively.

CONCLUSION: Our study showed that riluzole plus mFOLFOX6/bevacizumab is well tolerated in patients with metastatic CRC and may have clinical activity in patients whose disease is resistant to FOLFOX.}, } @article {pmid40116017, year = {2025}, author = {Addy, G and Scirocco, E and Gelevski, D and Rohrer, M and Roderick, A and McCormack, M and Weiss Sadan, A and Scalia, J and Parikh, N and Giacomelli, E and Locatelli, M and Neel, DV and D'Agostino, D and Leite, A and Yu, H and Sherman, AV and Mock, J and Kalmes, A and Luppino, S and Babu, S and Berry, J and Cudkowicz, M and Paganoni, S}, title = {An Expanded Access Protocol of RNS60 in Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28398}, pmid = {40116017}, issn = {1097-4598}, support = {//The study drug was provided at no cost by Revalesio, and program costs were covered by philanthropic donations to the Sean M. Healey & AMG Center for ALS/ ; }, abstract = {AIMS: RNS60 is an investigational product in clinical development for amyotrophic lateral sclerosis (ALS). RNS60 slowed disease progression in the ALS SOD1[G93A] mouse model and was safe and well tolerated both in an open-label pilot study and a randomized, placebo-controlled, multicenter phase 2 trial in people living with ALS. The objective of this ongoing expanded access protocol (EAP) was to provide RNS60 to people living with ALS who are ineligible for controlled clinical trials and to collect data on the safety and tolerability of dosing RNS60 via twice-daily nebulization rather than the previously studied daily nebulization with weekly intravenous administration.

METHODS: Eligible participants (≥ 18 years old, diagnosed with ALS per investigator assessment, and ineligible for an ALS clinical trial testing RNS60) were treated with twice-daily nebulization of RNS60 at home. Safety was evaluated by the assessment of adverse events and routine safety labs.

RESULTS: A total of 84 participants have been treated with RNS60 via nebulization twice daily for up to 48 months so far. The most common treatment-related adverse event was increased secretions [N = 27 (32%)]. Serious adverse events (SAEs) [69 occurrences; N = 38 (45%) with at least one SAE] and deaths [N = 24 (28%)] were deemed not related to RNS60.

DISCUSSION: This EAP supports the benign side effect profile of RNS60 when administered via twice-daily nebulization and demonstrates the feasibility of long-term EAPs as a complementary approach to controlled trials in people with advanced ALS.}, } @article {pmid40113485, year = {2025}, author = {Anzilotti, S and Franco, C and Valsecchi, V and Cuomo, O and Lombardi, G and Di Muraglia, N and De Iesu, N and Laudati, G and Annunziato, L and Canzoniero, LMT and Giuseppe, P}, title = {Modulation of ZnT-1 by Let7a unveils a therapeutic potential in amyotrophic lateral sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {}, number = {}, pages = {e00571}, doi = {10.1016/j.neurot.2025.e00571}, pmid = {40113485}, issn = {1878-7479}, abstract = {The imbalance in cellular ionic homeostasis represents a hallmark of several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS). Zinc Transporter 1 (ZnT1), the first described member of the ZnT family, stands out as the sole member of the SLC30 family responsible for exporting cytosolic zinc to the extracellular space. While ZnT1 is expressed across all tissues and cell types studied, it exhibits the highest prominence within the central nervous system. In ALS SOD1[G93A] mice, a reduction in ZnT1 expression consistent with disease progression has been observed, prompting our investigation into its role in ALS pathophysiology. Remarkably, through the use of a sequence complementary to the microRNA let-7a (anti-Let-7a) able to modulate ZnT1 expression, we demonstrated in ALS mice its capability to: (1) prevent the reduction in ZnT1 levels in the spinal cord; (2) preserve motor neuron survival in the ventral spinal horn; (3) decrease astroglial and microglial activation while sparing resident microglial cells in the spinal cord; and (4) improve the lifespan and alleviate motor symptoms.}, } @article {pmid40109661, year = {2025}, author = {Hong, Y and Shi, JQ and Feng, S and Huang, SQ and Yuan, ZH and Liu, S and Zhang, XH and Zhou, JS and Jiang, T and Zhao, HD and Zhang, YD}, title = {The systemic inflammation markers as potential predictors of disease progression and survival time in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1552949}, pmid = {40109661}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal and untreatable neurodegenerative disease with only 3-5 years' survival time after diagnosis. Inflammation has been proven to play important roles in ALS progression. However, the relationship between systemic inflammation markers and ALS has not been well established, especially in Chinese ALS patients. The present study aimed to assess the predictive value of systemic inflammation markers including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and systemic immune-inflammation index (SII) for Chinese amyotrophic lateral sclerosis (ALS).

METHODS: Seventy-two Chinese ALS patients and 73 controls were included in this study. The rate of disease progression was calculated as the change of Revised ALS Functional Rating Scale (ALSFRS-R) score per month. Patients were classified into fast progressors if the progression rate > 1.0 point/month and slow progressors if progression rate ≤ 1.0 point/month. The value of NLR, PLR, LMR, and SII were measured based on blood cell counts. The association between systemic inflammation markers and disease progression rate was confirmed by logistic regression analysis. Kaplan-Meier curve and Cox regression models were used to evaluate factors affecting the survival outcome of ALS patients.

RESULTS: For Chinese ALS patients, NLR, PLR and SII were higher, LMR was lower when compared with controls. All these four markers were proved to be independent correlated with fast progression of ALS. Both Kaplan-Meier curve and Cox regression analysis indicated that higher NLR and lower LMR were associated with shorter survival time in the ALS patients.

DISCUSSION: In conclusion, the systemic inflammation markers, especially NLR and LMR might be independent markers for rapid progression and shorter survival time in Chinese ALS patients.}, } @article {pmid40109277, year = {2025}, author = {Ding, XY and Habimana, JD and Li, ZY}, title = {The role of DPP6 dysregulation in neuropathology: from synaptic regulation to disease mechanisms.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1547495}, pmid = {40109277}, issn = {1662-5102}, abstract = {As a transmembrane protein, DPP6 modulates the function and properties of ion channels, playing a crucial role in various tissues, particularly in the brain. DPP6 interacts with potassium channel Kv4.2 (KCND2), enhancing its membrane expression and channel kinetics. Potassium ion channels are critical in progressing action potential formation and synaptic plasticity. Therefore, dysfunction of DPP6 can lead to significant health consequences. Abnormal DPP6 expression has been identified in several diseases, such as amyotrophic lateral sclerosis (ALS), autism spectrum disorder (ASD), spinal bulbar muscular atrophy (SBMA), and idiopathic ventricular fibrillation. Recent research has indicated a connection between DPP6 and Alzheimer's disease as well. The most common symptoms resulting from DPP6 dysregulation are mental deficiency and muscle wastage. Notably, these symptoms do not always occur at the same time. Besides genetic factors, environmental factors also undoubtedly play a role in diseases related to DPP6 dysregulation. However, it remains unclear how the expression of DPP6 gets regulated. This review aims to summarize the associations between DPP6 and neurological diseases, offering insights as well as proposing hypotheses to elucidate the underlying mechanisms of DPP6 dysregulation.}, } @article {pmid40108302, year = {2025}, author = {Ma, W and Polgár, E and Dickie, AC and Hajer, MA and Quillet, R and Gutierrez-Mecinas, M and Yadav, M and Hachisuka, J and Todd, AJ and Bell, AM}, title = {Anatomical characterisation of somatostatin-expressing neurons belonging to the anterolateral system.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {9549}, pmid = {40108302}, issn = {2045-2322}, support = {MR/S002987/1/MRC_/Medical Research Council/United Kingdom ; MR/S002987/1/MRC_/Medical Research Council/United Kingdom ; 219433/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; 304005/Z/23/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; *Somatostatin/metabolism/genetics ; Mice ; *Neurons/metabolism ; *Spinal Cord/metabolism/cytology ; Axons/metabolism ; Male ; Pain/metabolism/genetics ; }, abstract = {Anterolateral system (ALS) spinal projection neurons are essential for pain perception. However, these cells are heterogeneous, and there has been extensive debate about the roles of ALS populations in the different pain dimensions. We recently performed single-nucleus RNA sequencing on a developmentally-defined subset of ALS neurons, and identified 5 transcriptomic populations. One of these, ALS4, consists of cells that express Sst, the gene coding for somatostatin, and we reported that these were located in the lateral part of lamina V. Here we use a Sst[Cre] mouse line to characterise these cells and define their axonal projections. We find that their axons ascend mainly on the ipsilateral side, giving off collaterals throughout their course in the spinal cord. They target various brainstem nuclei, including the parabrachial internal lateral nucleus, and the posterior triangular and medial dorsal thalamic nuclei. We also show that in the L4 segment Sst is expressed by ~ 75% of ALS neurons in lateral lamina V and that there are around 120 Sst-positive lateral lamina V cells on each side. Our findings indicate that this is a relatively large population, and based on projection targets we conclude that they are likely to contribute to the affective-motivational dimension of pain.}, } @article {pmid40106466, year = {2025}, author = {Lemmers, SAM and Le Luyer, M and Stoll, SJ and Hoffnagle, AG and Ferrell, RJ and Gamble, JA and Guatelli-Steinberg, D and Gurian, KN and McGrath, K and O'Hara, MC and Smith, ADAC and Dunn, EC}, title = {Inter-rater reliability of stress signatures in exfoliated primary dentition - Improving scientific rigor and reproducibility in histological data collection.}, journal = {PloS one}, volume = {20}, number = {3}, pages = {e0318700}, pmid = {40106466}, issn = {1932-6203}, mesh = {Humans ; *Dental Enamel ; Reproducibility of Results ; *Tooth, Deciduous ; Stress, Physiological ; Observer Variation ; Female ; Child ; Male ; Stress, Psychological ; Data Collection/methods ; }, abstract = {Accentuated Lines (ALs) in tooth enamel can reflect metabolic disruptions from physiological or psychological stresses during development. They can therefore serve as a retrospective biomarker of generalized stress exposure in archaeological and clinical research. However, little consensus exists on when ALs are identified and inter-rater reliability is poorly quantified across studies. Here, we sought to address this gap by examining the reliability of accentuated (AL) markings across raters, in terms of both the presence versus absence of ALs and their intensity (HAL= Highly Accentuated, MAL= Mildly Accentuated, RL= Retzius Line). Ratings were made and compared across observers (with different levels of experience) and pairs of raters (who agreed on AL coding through consensus meetings) (N = 15 teeth, eight observers). Results indicated that more experience in AL assessment does not necessarily produce higher reliability between raters. Most disagreements in intensity ratings occurred in categories other than HAL. Furthermore, when AL assessment was performed by pairs of raters, reliability was significantly higher than individual assessments (Gwet's AC1 = 0.28 to 0.56 for line presence assessment; Gwet's AC1 = 0.48 to 0.64 for line intensity assessment). Based on these results, we recommend a workflow called IRRISS (Improving Reliability and Reporting In Scoring of Stress-markers) to increase rigor and reproducibility in histological analysis of dental collections. The introduction of IRRISS is well-timed, given the surge in studies of teeth occurring across anthropological, epidemiological, medical, forensic, and climate research fields.}, } @article {pmid40105438, year = {2025}, author = {Ueha, R and Dealino, MA and Koyama, M and Yamakawa, K and Matsumoto, N and Sato, T and Goto, T and Mizukami, A and Kondo, K}, title = {Improved Pharyngeal Contraction and Oral Intake Status After Modified Central-Part Laryngectomy for Late-Stage ALS.}, journal = {Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery}, volume = {}, number = {}, pages = {}, doi = {10.1002/ohn.1229}, pmid = {40105438}, issn = {1097-6817}, abstract = {OBJECTIVE: To investigate the effects of modified central-part laryngectomy with pharyngeal space reduction (CPL-PR) on patients with weak deglutitive pharyngeal contraction, as seen in late-stage amyotrophic lateral sclerosis (ALS).

STUDY DESIGN: Retrospective case series.

SETTING: Single-institution academic center.

METHODS: Patients with late-stage ALS confined at The University of Tokyo Hospital between 2019 and March 2024 in whom CPL-PR had been performed were identified. Patients who had undergone simultaneous pharyngeal flap surgery or had no preoperative high-resolution manofluorography done were excluded. Preoperatively, penetration-aspiration scale (PAS) scores were determined via videofluoroscopic swallowing study. Functional oral intake scale (FOIS) scores and high-resolution manometric parameters were measured and compared preoperatively and postoperatively.

RESULTS: Eighteen patients were identified with a median age of 66.5 (interquartile range [IQR]: 58.0-74.8). The median preoperative PAS score was 7.5 (IQR: 5.5-8.0), indicating severe dysphagia. There was significant improvement in oral intake status with FOIS scores increasing from 1 (IQR: 1-1) to 3 (IQR: 2-3) at 3 months postoperatively (P = .0002). Significant increases in velopharyngeal closure integral (P = .024) and mesohypopharyngeal contractile integral (P = .0001) were observed. Upper esophageal sphincter (UES) resting pressure was reduced (P = .0002), and UES relaxation time was prolonged during swallowing (P < .0001).

CONCLUSION: There were tangible improvements in pharyngeal contraction, UES bolus passage, and oral intake status following CPL-PR, which contribute to regaining oral intake in late-stage ALS. CPL-PR is an option for patients requiring tracheostomy who wish to prevent aspiration and regain their ability to take food orally.}, } @article {pmid40105291, year = {2025}, author = {Ozeki-Hayashi, R and Wilkinson, DJC}, title = {'An Unimaginable Challenge': A Cross-Cultural Qualitative Study of Ethics and Decision-Making Around Tracheostomy Ventilation in Patients with Amyotrophic Lateral Sclerosis.}, journal = {AJOB empirical bioethics}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/23294515.2025.2474928}, pmid = {40105291}, issn = {2329-4523}, abstract = {BACKGROUND: The rate of tracheostomy with invasive ventilation (TIV) for patients with Amyotrophic Lateral Sclerosis (ALS) varies widely. Previous studies have shown that doctors' values may affect decision-making. There have been no previous international qualitative comparisons of medical decision-making process for TIV or why practice varies.

METHODS: We conducted semi-structured in-depth interviews with 16 doctors actively involved in the management of ALS patients from Japan (n = 7), the UK (n = 5), and the US (n = 4). We used three hypothetical cases to explore decision-making. Conversations were transcribed and thematically analyzed.

RESULTS: Our data reveals similarities but also marked differences in views between the US, the UK and Japan. Almost all participants stated that they ought to respect patient autonomy. However, their approaches varied. British participants wanted to (and felt that they should) respect patient autonomy, but they also believed that TIV was not a realistic option. US participants were likely to prioritize patient autonomy over other ethical principles, and Japanese participants were likely to limit patient autonomy indirectly. The option of TIV appeared to be heavily influenced by the availability of healthcare resources in all three countries. The high cost, limited availability and difficulty of treatment meant that particularly in the UK and the US, it is challenging to receive TIV even if patients wanted this.

CONCLUSIONS: Our study illustrates how the emphasis on autonomy varies along with variations in the way care is organized in the setting of highly resource intensive treatment and progressive severe disabling illness. There is a need to review elements of the decision-making process in all three countries. This includes the need for transparent, ideally centralized, decision-making guidelines about the provision of TIV. Although we investigated a rare neuromuscular disease, our results will be relevant to other diseases requiring highly resource-intensive treatment toward the end of life.}, } @article {pmid40105198, year = {2025}, author = {Gotkine, M and Schoenfeld, DA and Cohen, I and Shefner, JM and Lerner, Y and Cohen, IR and Klein, C and Ovadia, E and Cudkowicz, ME and , }, title = {Akt Activation With IPL344 Treatment for Amyotrophic Lateral Sclerosis: First in Human, Open-Label Study.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28393}, pmid = {40105198}, issn = {1097-4598}, support = {//Immunity Pharma/ ; }, abstract = {INTRODUCTION/AIMS: Akt intracellular signal transduction pathway dysfunction has been reported in people with amyotrophic lateral sclerosis (ALS) providing a novel target for intervention in this devastating progressive disease. This first-in-human study evaluated the safety, tolerability, and preliminary efficacy of the Akt pathway activator, IPL344, in people with ALS.

METHODS: Nine participants with ALS and a progression rate > 0.55 points/month on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) received open-label IPL344 treatment (once-daily) for up to 36 months. Safety was assessed through adverse event (AE) reporting. Plasma neurofilament light chain (NfL) concentrations were measured before and after treatment. Clinical outcomes were compared to historical data.

RESULTS: The mean ± SD duration of IPL344 follow-up was 14.0 ± 12.5 months. One participant developed drug hypersensitivity, two had central venous catheter-related AEs, and two had serious pneumonia AEs. The unadjusted mean ± SE slope of decline in ALSFRS-R was -0.53 ± 0.15 (48% slower progression vs. historical controls, p = 0.028). Adjustment for disease stage and rate-indicating covariates indicated a 64% slower ALSFRS-R progression (p = 0.034), with increased rather than reduced body weight (p = 0.02). Eight of nine IPL344-treated participants had a significantly improved slope compared to the median slope of a matched control group (p = 0.04). Plasma NfL concentrations were lowered by 27% (n = 6). Unadjusted median survival for participants in the IPL344 group was 43.4 months [95% CI: 20.5, NA] compared with 19.1 months [17.4, 23.0] in the historical control group.

DISCUSSION: These preliminary data indicate that IPL344 was safe and well-tolerated, and possibly effective. Our findings may merit further investigation in a larger placebo-controlled clinical trial.}, } @article {pmid40103545, year = {2025}, author = {Sonaglioni, A and Torretta, P and Nicolosi, GL and Lombardo, M}, title = {Left ventricular mechanics assessment in amyloidosis patients: a systematic review and meta-analysis.}, journal = {Minerva cardiology and angiology}, volume = {}, number = {}, pages = {}, doi = {10.23736/S2724-5683.24.06683-3}, pmid = {40103545}, issn = {2724-5772}, abstract = {BACKGROUND: Over the last decade, a small number of studies have used speckle tracking echocardiography (STE) or cardiac magnetic resonance (CMR) for measuring left ventricular (LV) mechanics in patients with amyloidosis. This systematic review and meta-analysis aimed at assessing the overall influence of amyloidosis on LV global longitudinal strain (GLS) and regional longitudinal strain at basal (BLS), mid (MLS) and apical (ALS) level, respectively.

METHODS: All imaging studies assessing LV-GLS, LV-BLS, LV-MLS and LV-ALS in amyloidosis patients versus healthy controls, selected from PubMed and EMBASE databases, were included. The risk of bias was assessed by using the National Institutes of Health (NIH) Quality Assessment of Case-Control Studies. Continuous data (LV-GLS, LV-BLS, LV-MLS and LV-ALS) were pooled as a standardized mean differences (SMDs) comparing amyloidosis group with healthy controls. The overall SMDs of LV-GLS, LV-BLS, LV-MLS and LV-ALS were calculated using the random-effect model.

RESULTS: The full-texts of 13 studies with 553 amyloidosis patients and 575 healthy controls were analyzed. STE (53.8%) and CMR (46.2%) studies were separately analyzed. Average LV-GLS magnitude was significantly impaired in amyloidosis patients vs. controls in both STE (13.8±3.9 vs. 19.8±2.7%) and CMR (12.3±4 vs. 17.9±3.5%) studies. The impairment of segmental strain detected in amyloidosis patients was prevalent at basal and mid level, with relative "apical sparing." SMDs obtained for LV-GLS (SMD -1.80, 95% CI: -2.35, -1.24, P <0.001), LV-BLS (-1.98; 95% CI: -2.51, -1.45, P <0.001) and LV-MLS (-1.84; 95% CI: -2.46, -1.23, P <0.001) assessment were significantly larger than that obtained for LV-ALS (-0.72; 95% CI: -1.31, -0.13, P=0.02) measurement. Substantial heterogeneity was found among the studies assessing LV-GLS (I[2]=92.5%), LV-BLS (I[2]=91.4%), LV-MLS (I[2]=94.3%) and LV-ALS (I[2]=94.6%). Egger's test yielded a P value of 0.10, 0.20, 0.09 and 0.55 for LV-GLS, LV-BLS, LV-MLS and LV-ALS assessment respectively, indicating no publication bias. On meta-regression analysis, none of the moderators was significantly associated with effect modification for LV-GLS, LV-BLS, LV-MLS and LV-ALS (all P<0.05).

CONCLUSIONS: Amyloidosis has a large negative effect on LV-GLS, primarily related to the deterioration of segmental longitudinal strain at the basal and mid level, with relative apical sparing.}, } @article {pmid40102416, year = {2025}, author = {Rivas-Fernández, JP and Vuillemin, M and Pilgaard, B and Klau, LJ and Fredslund, F and Lund-Hanssen, C and Welner, DH and Meyer, AS and Morth, JP and Meilleur, F and Aachmann, FL and Rovira, C and Wilkens, C}, title = {Unraveling the molecular mechanism of polysaccharide lyases for efficient alginate degradation.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {2670}, pmid = {40102416}, issn = {2041-1723}, support = {315385//Norges Forskningsråd (Research Council of Norway)/ ; 226244//Norges Forskningsråd (Research Council of Norway)/ ; 294946//Norges Forskningsråd (Research Council of Norway)/ ; DFF170746//Det Frie Forskningsråd (Danish Council for Independent Research)/ ; 2021-SGR-00680//Government of Catalonia | Agència de Gestió d'Ajuts Universitaris i de Recerca (Agency for Management of University and Research Grants)/ ; NNF10CC1016517//Novo Nordisk Fonden (Novo Nordisk Foundation)/ ; }, mesh = {*Polysaccharide-Lyases/metabolism/chemistry ; *Alginates/chemistry/metabolism ; *Catalytic Domain ; Crystallography, X-Ray ; Kinetics ; Magnetic Resonance Spectroscopy ; Models, Molecular ; }, abstract = {Alginate lyases (ALs) catalyze the depolymerization of brown macroalgae alginates, widely used naturally occurring polysaccharides. Their molecular reaction mechanism remains elusive due to the lack of catalytically competent Michaelis-Menten-like complex structures. Here, we provide structural snapshots and dissect the mechanism of mannuronan-specific ALs from family 7 polysaccharide lyases (PL7), employing time-resolved NMR, X-ray, neutron crystallography, and QM/MM simulations. We reveal the protonation state of critical active site residues, enabling atomic-level analysis of the reaction coordinate. Our approach reveals an endolytic and asynchronous syn β-elimination reaction, with Tyr serving as both Brønsted base and acid, involving a carbanion-type transition state. This study not only reconciles previous structural and kinetic discrepancies, but also establishes a comprehensive PL reaction mechanism which is most likely applicable across all enzymes of the PL7 family as well as other PL families.}, } @article {pmid40102061, year = {2025}, author = {Tran, K and Hayes, HA and Bromberg, M}, title = {A prospective observational study of decision-making by patients with amyotrophic lateral sclerosis upon recommendation for PEG enteral feeding tubes.}, journal = {Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1002/ncp.11290}, pmid = {40102061}, issn = {1941-2452}, abstract = {OBJECTIVE: To understand challenges surrounding acceptance of a percutaneous endoscopic gastroscopic enteral feeding tube by patients with amyotrophic lateral sclerosis: a prospective observational study.

METHODS: This was a prospective observational study of 41 patients and care partners attending a multidisciplinary Motor Neuron Disease clinic. Surveys were administered pregastrostomy tube placement (N = 23) and postplacement (N = 41). Some were not available both pre- and postplacement). For preplacement, we queried barriers affecting their decision for receiving a gastrostomy tube at the time of recommendation. For postplacement, we queried factors that influenced their decision as well as perceived benefit and satisfaction with use.

RESULTS: Patient concerns about receiving a gastrostomy tube centered on the procedure, possible pain/infection (48%), limitations on activities (44%), impact on body image, and possible extension of life. For patients who received a gastrostomy tube, satisfaction was very high (93%), and there was reduced patient (59%) and care partners (54%) stress. The average BMI was 28.6 kg/m[2] at diagnosis, and there was no net gain in weight. The average time until placement of a gastrostomy tube following recommendation was 145 days (range 13-824 days).

CONCLUSIONS: Despite counseling at multiple time points, the decision to obtain a feeding tube is often challenging for patients and care partners. Gastrostomy tube placement was perceived as a substantial benefit. Addressing these barriers may reduce concerns and promote earlier decision-making to maximize the benefits of placing a gastrostomy tube sooner.}, } @article {pmid40101794, year = {2025}, author = {Krüger, DR and Jeschke, E and Gehrke, T and Günster, C and Halder, AM and Leicht, H and Malzahn, J and Schräder, P and Wirtz, DC and Zacher, J and Heller, KD}, title = {Impact of Hospital Case Volume on the Complication Rate in Hip Arthroplasty: An Analysis of Nationwide AOK Data.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2538-6446}, pmid = {40101794}, issn = {1864-6743}, abstract = {Aufgrund des demografischen Wandels und damit verbundener erwarteter Steigerungen der Fallzahlen von primärer Hüftendoprothetik und Revisionseingriffen ist es wichtig, Faktoren zu identifizieren, die Komplikationen und Revisionen reduzieren können. Ein solcher Faktor ist die Fallzahl eines Krankenhauses. Studien haben gezeigt, dass Krankenhäuser mit höheren Fallzahlen niedrigere Morbiditäts- und Komplikationsraten aufweisen. Die meisten Studien basieren dabei auf Registerdaten, die oft unvollständig sind und keine patientenspezifischen Faktoren beinhalten.In dieser Studie wurden bundesweite pseudonymisierte stationäre Abrechnungsdaten und Versichertenstammdaten der Allgemeinen Ortskrankenkassen (AOK) im Zeitraum von 2017 bis 2019 bei Patienten mit primärer Hüftendoprothese analysiert. Zur Analyse des Einflusses der Fallzahl auf das Outcome wurden 5 Fallzahlkategorien gebildet (I: 1-49, II: 50-99, III: 100-199, IV: 200-399, V: ≥ 400 Operationen pro Jahr). Als Endpunkte wurden 90-Tage-Sterblichkeit, 1-Jahres-Revisionsoperationen, chirurgische Komplikationen (90 Tage bzw. 365 Tage), periprothetische Femurfrakturen (90 Tage) und schwere Allgemeinkomplikationen im Krankenhausaufenthalt betrachtet. Der Einfluss der Fallzahl auf das Outcome wurde mittels multipler logistischer Regression unter Berücksichtigung patientenspezifischer Faktoren bestimmt.Die Analyse von 137494 Fällen aus 993 Kliniken zeigt einen statistisch signifikanten Zusammenhang zwischen der Fallzahlgruppe und der Häufigkeit von Revisionsoperationen, chirurgischen Komplikationen, periprothetischen Femurfrakturen und allgemeinen Komplikationen. Bei Kliniken mit einer Fallzahl von weniger als 50 pro Jahr zeigte sich eine Risikoerhöhung um 65%-88% für diese Endpunkte gegenüber der fallzahlstärksten Gruppe. Für den Endpunkt Sterblichkeit ergibt eine dichotome Betrachtung der Fallkategorien ebenfalls einen signifikanten Einfluss der Fallzahlen.Die Studie zeigt, dass, auch unter Berücksichtigung patientenspezifischer Faktoren, höhere Fallzahlen bei primärer Hüftendoprothetik in Krankenhäusern mit niedrigeren Komplikationsraten verbunden sind. Diese Erkenntnisse unterstreichen die Bedeutung der Fallzahl als Faktor zur Verbesserung der Versorgungsqualität in der Hüftendoprothetik.}, } @article {pmid40100917, year = {2025}, author = {Thau-Habermann, N and Gschwendtberger, T and Bodemer, C and Petri, S}, title = {Parthenolide regulates microglial and astrocyte function in primary cultures from ALS mice and has neuroprotective effects on primary motor neurons.}, journal = {PloS one}, volume = {20}, number = {3}, pages = {e0319866}, pmid = {40100917}, issn = {1932-6203}, mesh = {Animals ; *Microglia/drug effects/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Sesquiterpenes/pharmacology ; *Motor Neurons/drug effects/metabolism/pathology ; *Neuroprotective Agents/pharmacology ; Mice ; *Astrocytes/drug effects/metabolism ; Cells, Cultured ; Mice, Transgenic ; Superoxide Dismutase/metabolism ; }, abstract = {Over the last twenty years, the role of microgliosis and astrocytosis in the pathophysiology of neurodegenerative diseases has increasingly been recognized. Dysregulation of microglial and astrocyte properties and function has been described also in the fatal degenerative motor neuron disease amyotrophic lateral sclerosis (ALS). Microglia cells, the immune cells of the nervous system, can either have an immunonegative neurotoxic or immunopositive neuroprotective phenotype. The feverfew plant (Tanacetum parthenium) derived compound parthenolide has been found to be capable of interfering with microglial phenotype and properties. Positive treatment effects were shown in animal models of neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. Now we were able to show that PTL has a modulating effect on primary mouse microglia cells, both wild type and SOD1, causing them to adopt a more neuroprotective potential. Furthermore, we were able to show that PTL, through its positive effect on microglia, also has an indirect positive impact on motor neurons, although PTL itself has no direct effect on these primary motor neurons. The results of our study give reason to consider PTL as a drug candidate for ALS.}, } @article {pmid40100796, year = {2025}, author = {Giroud, M and Kuhn, B and Steiner, S and Westwood, P and Mendel, M and Mani, A and Pinard, E and Haap, W and Grether, U and Caramenti, P and Rombach, D and Zambaldo, C and Ritter, M and Schmid, P and Gasser, C and Aregger, N and Séchet, N and Topp, A and Bilyard, M and Malnight-Alvarez, A and Plitzko, I and Hilbert, M and Kalayil, S and Burger, D and Bonardi, C and Saal, W and Haider, A and Wittwer, MB and Brigo, A and Benz, J and Keaney, J}, title = {Discovery of a Potent SARM1 Base-Exchange Inhibitor with In Vivo Efficacy.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {6}, pages = {6558-6575}, doi = {10.1021/acs.jmedchem.4c03127}, pmid = {40100796}, issn = {1520-4804}, mesh = {Animals ; *Armadillo Domain Proteins/antagonists & inhibitors/metabolism ; Mice ; *Cytoskeletal Proteins/antagonists & inhibitors/metabolism ; Humans ; Structure-Activity Relationship ; Drug Discovery ; Male ; }, abstract = {Sterile alpha and TIR Motif Containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD[+]) hydrolase that plays a central role in programmed axonal degeneration. Axonal degeneration has been linked to neurodegenerative and neurological disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and peripheral neuropathies. Therefore, developing potent and selective SARM1 inhibitors could be an effective strategy to treat these disorders. We present herein the structure-guided discovery of two novel SARM1 inhibitors, 7 and 35. Compounds 7 and 35 are potent inhibitors across assays and possess favorable ADMET properties. When tested in vivo, compound 7 showed efficacy after oral dosing in a mouse model of peripheral nerve injury by decreasing plasma neurofilament light (NfL) levels at 50 mg/kg compared with vehicle-treated control mice, holding promise for the treatment of neurodegenerative and neurological disorders.}, } @article {pmid40100285, year = {2025}, author = {De Bertier, S and Lautrette, G and Amador, MD and Miki, T and Boillée, S and Lobsiger, CS and Bohl, D and Darios, F and Machat, S and Duchesne, M and Vourc'h, P and Fauret-Amsellem, AL and Corcia, P and Guy, N and Couratier, P and Seilhean, D and Millecamps, S}, title = {MAPT mutations in amyotrophic lateral sclerosis: clinical, neuropathological and functional insights.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {272}, pmid = {40100285}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; *tau Proteins/genetics ; Male ; Female ; Middle Aged ; Mutation ; Pedigree ; Adult ; Aged ; Brain/pathology ; Animals ; Mutation, Missense ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a well-established disease continuum, underpinned by TDP43-pathology. In contrast, the clinical manifestations of Tau-linked disorders are typically limited to cognitive phenotypes or atypical parkinsonism, although few reports describe motor neuron involvement associated with MAPT (microtubule-associated protein Tau) mutations. This study aimed to investigate the contribution of MAPT to the ALS phenotype.

METHODS: We analyzed a whole-exome sequencing database comprising 470 ALS patients and explored the pathogenicity of the identified variants through familial, clinical, neuropathological, and cellular studies.

RESULTS: We identified two missense variants in the Tau repeat domains: the novel p.I308T variant, in a patient with early-onset ALS, and the p.P364S mutation in three families with spinal- or respiratory-onset ALS. Segregation of this mutation with disease could be confirmed in two affected cousins. The observation of p.P364S patient's tissue showed accumulations of hyperphosphorylated Tau in various brain regions, prominent in the motor cortex with Lewy body-like inclusions, along with a C-terminal cleaved form of Tau in muscle. In NSC-34 motor neuron cells expressing p.I308T or p.P364S mutants, Tau was discontinuous along the neurites, with clusters of mitochondria resulting from impaired mitochondrial motility.

CONCLUSION: These findings expand the molecular understanding of ALS to include MAPT mutations. MAPT analysis should be incorporated into ALS genetic screening, particularly in patients with a familial history of the disease. Recognizing the full spectrum of MAPT-linked neurodegenerative diseases is of considerable interest, given the ongoing efforts to develop MAPT-targeted therapies.}, } @article {pmid40099869, year = {2025}, author = {Kim, SB and Lee, JS and Lan, X and Huang, W and Taylor, DJ and Kwon, YT and Zhang, Y and Ji, CH}, title = {The structure-function relationship of ATE1 R-transferase of the autophagic Arg/N-degron pathway.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/15548627.2025.2473393}, pmid = {40099869}, issn = {1554-8635}, abstract = {ATE1 (arginyltransferase 1; EC 2.3.2) transfers the amino acid arginine (Arg) from Arg-tRNA[Arg] to the N-terminal (Nt) residues of proteins, such as aspartate (Asp), glutamate (Glu), and oxidized cysteine (Cys). The resulting Nt-Arg acts as an N-degron that regulates the degradation of various biomaterials via the ubiquitin/Ub-proteasome system (UPS) or the autophagy-lysosome system (ALS). In the UPS, Arg/N-degrons are recognized by cognate N-recognins, leading to substrate ubiquitination and proteasomal degradation. In the ALS, the same degrons bind the macroautophagy/autophagy receptor SQSTM1/p62 (sequestosome 1) to facilitate self-polymerization of SQSTM1 associated with cargoes and SQSTM1 interaction with LC3-II on phagophores. A key unresolved question is why only a small subset of proteins acquires Arg/N-degrons, given the rather weak binding affinity of ATE1 for Nt-substrates. In this study, we determined the cryo-EM structures of human ATE1 in complex with Arg-tRNA[Arg] and an Nt-Asp peptide. ATE1 harbors two adjacent pockets that each bind an Nt-substrate or Arg-tRNA[Arg], the latter being wrapped by a long, unstructured loop. In the apo state, two ATE1 monomers form a homodimer. ATE1 achieves the selectivity for its peptidyl-ligands through these multivalent interactions, with Kd values in the micro-molar range. These results reveal the structural principle of Nt-arginylation at the crossroads of the UPS and ALS.Abbreviations: ALS: autophagy-lysosome system; Arg: arginine; Asp: aspartate; ATE1: arginyltransferase 1; Cys: cysteine; CysO2(H): Cys sulfinic acid; Glu: glutamate; Nt: N-terminal; UBR: ubiquitin protein ligase E3 component n-recognin; UPS: ubiquitin-proteasome system; ZZ: ZZ-type zinc finger.}, } @article {pmid40099804, year = {2025}, author = {Zheng, W and Zhang, X and Chen, J and Luan, X and Wang, J and Zhang, L and Liu, K and Zhao, Y and Xu, Z}, title = {The Effect of Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex on the Amyotrophic Lateral Sclerosis Patients With Cognitive Impairment: A Double-Blinded, Randomized, and Sham Control Trial.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {3}, pages = {e70316}, pmid = {40099804}, issn = {1755-5949}, support = {20YF1436400//Shanghai Sailing program/ ; 23DZ2291500//Shanghai Science and Technology Innovation Action Plan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications/psychology ; *Transcranial Magnetic Stimulation/methods ; Double-Blind Method ; Male ; Female ; Middle Aged ; Aged ; *Cognitive Dysfunction/therapy/etiology/psychology ; *Dorsolateral Prefrontal Cortex/physiology ; Treatment Outcome ; Prefrontal Cortex ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. A large number of ALS patients have cognitive impairment. In this double-blinded, randomized, and sham-controlled study, we aimed to investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on ALS patients with cognitive impairment.

METHODS: A total of 90 ALS patients with cognitive impairment were recruited from two cohorts; 80 participants were randomly assigned in a 1:1 ratio to receive 10 Hz rTMS or sham treatment on the bilateral dorsolateral prefrontal cortices (DLPFC) for 4 consecutive weeks. The patients were assessed by ECAS and ALSFRS-R scales. The Zarit care burden scale was administered to caregivers of ALS patients. The primary outcome measured was the rate of decline in the total ECAS score between pretreatment, 6 months post-treatment, and 12 months post-treatment. Secondary outcomes included the group difference in the slope of the Zarit score, ALSFRS-R total score, and the neurofilament light chain plasma levels.

RESULTS: The ECAS total score in the intention-to-treat population significantly changed from 79.74 ± 6.39 to 81.98 ± 6.51 and 79.22 ± 6.50 with rTMS intervention at the 6-month and 12-month follow-ups, respectively (p = 0.031, p = 0.042). The Zarit score also significantly decreased from 57.65 ± 3.42 to 52.24 ± 3.34 and 56.42 ± 3.41 at the 3-month and 6-month post-treatment time points, respectively (p = 0.003, p = 0.014). No significant differences were observed between the groups for other secondary endpoints. However, there was a trend of decreasing NF-L level rates in the treatment group over the first 6 months' follow-up.

CONCLUSIONS: rTMS could yield short-term positive effects on the ALS patients subgroup with cognitive impairment and alleviate caregivers' burden. No improvement was observed in the severity of ALS and ALS plasma biomarkers.}, } @article {pmid40099353, year = {2025}, author = {Giorgio, CM and Tancredi, V and Licata, G and Moscarella, E and Argenziano, G and Fulgione, E and Babino, G and Franzese, P and Di Brizzi, EV}, title = {Cutting-edge insights: LC-OCT and 5% cyclosporine for early lichen sclerosus treatment.}, journal = {Dermatology reports}, volume = {}, number = {}, pages = {}, doi = {10.4081/dr.2025.10279}, pmid = {40099353}, issn = {2036-7392}, abstract = {Dear Editor, Atrophic lichen sclerosus (ALS) is a chronic inflammatory dermatosis with significant morbidity, primarily affecting genital areas. The disease is often misdiagnosed or underdiagnosed, resulting in delayed treatment and progression to atrophic stages and permanent scars. While corticosteroids remain the first-line treatment, their long-term use may lead to adverse effects such as skin atrophy, prompting the need for alternative therapies. Cyclosporine, a calcineurin inhibitor, has shown efficacy in managing immune-mediated skin diseases and is delivered effectively through the Pentravan® vehicle. [...].}, } @article {pmid40099231, year = {2025}, author = {Hwang, DW and Ser, J and Ziabrev, K and Park, GK and Jo, MJ and Yokomizo, S and Bao, K and Yamashita, A and Cho, H and Henary, M and Kashiwagi, S and Choi, HS}, title = {Image-Guided Monitoring of Mitochondria and Blood-Brain Barrier Dysfunction in Amyotrophic Lateral Sclerosis Mice.}, journal = {Biomaterials research}, volume = {29}, number = {}, pages = {0162}, pmid = {40099231}, issn = {1226-4601}, abstract = {Early detection of amyotrophic lateral sclerosis (ALS) progression is critical for improving disease management and therapeutic outcomes. However, the clinical heterogeneity and variability in ALS symptoms often lead to delayed diagnosis and suboptimal therapeutic interventions. Since mitochondrial dysfunction is a hallmark of ALS, we hypothesized that monitoring mitochondrial function could serve as a reliable strategy for early diagnosis and therapeutic monitoring of ALS. To address this, we synthesized and characterized 2 novel near-infrared fluorophores, ALS04 and ALS05, designed to target mitochondria and lysosomes. Their physicochemical properties, serum protein binding, fluorescence characteristics, photostability, and pharmacokinetics were systematically evaluated. We found that benzothiazole-based fluorophores exhibit excellent mitochondrial targeting, optimal optical properties, biocompatibility, and favorable biodistribution in vivo. Interestingly, ALS04 showed superior mitochondrial accumulation compared to ALS05, despite their similar physicochemical properties. This enhanced accumulation can be attributed to the lower molecular weight and higher lipophilicity of ALS04. Real-time fluorescence imaging revealed a substantial reduction in ALS04 signals in mitochondrial-rich tissues such as brown fat, highlighting its potential for monitoring mitochondrial dysfunction in early-stage ALS. Furthermore, the detection of ALS04 in the mouse brain suggests its ability to monitor blood-brain barrier hyperpermeability, another key feature of ALS pathology. These findings establish ALS04 as a promising noninvasive imaging tool for monitoring biomarkers associated with ALS progression. Its ability to detect early-stage pathophysiological changes in an ALS mouse model highlights its potential for advancing our understanding of ALS mechanisms and facilitating the identification of novel therapeutic targets.}, } @article {pmid40097890, year = {2025}, author = {Dezfouli, MA and Shalilahmadi, D and Shamsaei, G and Esmaeili, A and Majdinasab, N and Rashidi, SK}, title = {Circulating miR-223/NLRP3 axis and IL-1β level in functional disease progression of amyotrophic lateral sclerosis.}, journal = {Acta neurologica Belgica}, volume = {}, number = {}, pages = {}, pmid = {40097890}, issn = {2240-2993}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease identified by progressive motor neuron loss. NLRP3 inflammasomes induce inflammation and pyroptosis, which can lead to neurodegeneration, muscle atrophy, and respiratory decline. miR-223 targets NLRP3 and suppresses inflammasome formation. Here, miR-223, NLRP3 and IL-1β levels were evaluated as plasma biomarkers in the incidence and progression of ALS.

METHODS: 32 ALS patients and 32 healthy subjects were assessed. In all patients, the functional disability was determined by Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and the respiratory dysfunction was assessed by the percent predicted forced vital capacity (ppFVC) index in spirometry examination. Plasma levels of miR-223, NLRP3 and IL-1β were assessed in ALS and control groups.

RESULTS: Compared to the healthy controls, ALS patients showed decreased miR-223 expression (P < 0.0001), increased NLRP3 expression (P = 0.0002) and increased IL-1β level (P = 0.0003). The areas under the ROC curves for miR-223, NLRP3 and IL-1β were 0.82, 0.76 and 0.75 respectively. The ALSFRS-R and ppFVC values were positively correlated with miR-223 and negatively correlated with NLRP3 and IL-1β levels.

CONCLUSION: Our results indicated that changes in miR-223, NLRP3 and IL-1β levels may correlate with the occurrence and functional progression of ALS. Additionally, therapeutic approaches based on miR-223 and inflammatory mediators can be proposed as effective strategies against disease progression.}, } @article {pmid40097762, year = {2025}, author = {Nabakhteh, S and Lotfi, A and Afsartaha, A and Khodadadi, ES and Abdolghaderi, S and Mohammadpour, M and Shokri, Y and Kiani, P and Ehtiati, S and Khakshournia, S and Khatami, SH}, title = {Nutritional Interventions in Amyotrophic Lateral Sclerosis: From Ketogenic Diet and Neuroprotective Nutrients to the Microbiota-Gut-Brain Axis Regulation.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40097762}, issn = {1559-1182}, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with significant challenges in diagnosis and treatment. Recent research has highlighted the complex nature of ALS, encompassing behavioral impairments in addition to its neurological manifestations. While several medications have been approved to slow disease progression, ongoing research is focused on identifying new therapeutic targets. The current review focuses on emerging therapeutic strategies and personalized approaches aimed at improving patient outcomes. Recent advancements highlight the importance of targeting additional pathways such as mitochondrial dysfunction and neuroinflammation to develop more effective treatments. Personalized medicine, including genetic testing and biomarkers, is proving valuable in stratifying patients and tailoring treatment options. Complementary therapies, such as nutritional interventions like the ketogenic diet and microbiome modulation, also show promise. This review emphasizes the need for a multidisciplinary approach that integrates early diagnosis, targeted treatments, and supportive care to address the multisystemic nature of ALS and improve the quality of life for patients.}, } @article {pmid40097438, year = {2025}, author = {Ayyadurai, VAS and Deonikar, P and Kamm, RD}, title = {A molecular systems architecture of neuromuscular junction in amyotrophic lateral sclerosis.}, journal = {NPJ systems biology and applications}, volume = {11}, number = {1}, pages = {27}, pmid = {40097438}, issn = {2056-7189}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; *Neuromuscular Junction/metabolism/pathology ; Humans ; *Motor Neurons/pathology/metabolism ; Animals ; Systems Biology/methods ; }, abstract = {A molecular systems architecture is presented for the neuromuscular junction (NMJ) in order to provide a framework for organizing complexity of biomolecular interactions in amyotrophic lateral sclerosis (ALS) using a systematic literature review process. ALS is a fatal motor neuron disease characterized by progressive degeneration of the upper and lower motor neurons that supply voluntary muscles. The neuromuscular junction contains cells such as upper and lower motor neurons, skeletal muscle cells, astrocytes, microglia, Schwann cells, and endothelial cells, which are implicated in pathogenesis of ALS. This molecular systems architecture provides a multi-layered understanding of the intra- and inter-cellular interactions in the ALS neuromuscular junction microenvironment, and may be utilized for target identification, discovery of single and combination therapeutics, and clinical strategies to treat ALS.}, } @article {pmid40097075, year = {2025}, author = {Cuevas, EP and Madruga, E and Valenzuela-Martínez, I and Ramírez, D and Gil, C and Nagaraj, S and Martin-Requero, A and Martinez, A}, title = {MicroRNA signature of lymphoblasts from amyotrophic lateral sclerosis patients as potential clinical biomarkers.}, journal = {Neurobiology of disease}, volume = {208}, number = {}, pages = {106871}, doi = {10.1016/j.nbd.2025.106871}, pmid = {40097075}, issn = {1095-953X}, abstract = {MicroRNAs (miRNAs) are a class of small, non-coding RNAs involved in different cellular functions that have emerged as key regulators of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). ALS is a fatal disease that lacks of not only effective treatments, but also presents delays in its diagnosis, since reliable clinical biomarkers are unavailable. In recent years, advancements in high-throughput sequencing strategies have led to the identification of novel ALS biomarkers, facilitating earlier diagnosis and assessment of treatment efficacy. Since immortalized lymphocytes obtained from peripheral blood are a suitable model to study pathological features of ALS, we employed these samples with the aim of characterize the dysregulated miRNAs in ALS patients. Next-generation sequencing (NGS) was utilized in order to analyze the expression profiles of miRNAs in immortalized lymphocytes from healthy controls, sporadic ALS (sALS), and familial ALS with mutations in superoxide dismutase 1 (SOD1-ALS). The screening analysis of the NGS data identified a set of dysregulated miRNAs, of which nine candidates were selected for qRT-PCR validation, identifying for the first time the possible importance of hsa-miR-6821-5p as a potential ALS biomarker. Furthermore, the up-regulated miRNAs identified are predicted to have direct or indirect interactions with genes closely related to ALS, such as SIGMAR1, HNRNPA1 and TARDBP. Additionally, by Metascape enrichment analysis, we found the VEGFA/VEGFR2 signaling pathway, previously implicated in neuroprotective effects in ALS, as a candidate pathway for further analyses.}, } @article {pmid40095345, year = {2025}, author = {Dehghani, S and Ocakcı, O and Hatipoglu, PT and Özalp, VC and Tevlek, A}, title = {Exosomes as Biomarkers and Therapeutic Agents in Neurodegenerative Diseases: Current Insights and Future Directions.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40095345}, issn = {1559-1182}, abstract = {Neurodegenerative diseases (NDs) like Alzheimer's, Parkinson's, and ALS rank among the most challenging global health issues, marked by substantial obstacles in early diagnosis and effective treatment. Current diagnostic techniques frequently demonstrate inadequate sensitivity and specificity, whilst conventional treatment strategies encounter challenges related to restricted bioavailability and insufficient blood-brain barrier (BBB) permeability. Recently, exosomes-nanoscale vesicles packed with proteins, RNAs, and lipids-have emerged as promising agents with the potential to reshape diagnostic and therapeutic approaches to these diseases. Unlike conventional drug carriers, they naturally traverse the BBB and can deliver bioactive molecules to affected neural cells. Their molecular cargo can influence cell signaling, reduce neuroinflammation, and potentially slow neurodegenerative progression. Moreover, exosomes serve as non-invasive biomarkers, enabling early and precise diagnosis while allowing real-time disease monitoring. Additionally, engineered exosomes, loaded with therapeutic molecules, enhance this capability by targeting diseased neurons and overcoming conventional treatment barriers. By offering enhanced specificity, reduced immunogenicity, and an ability to bypass physiological limitations, exosome-based strategies present a transformative advantage over existing diagnostic and therapeutic approaches. This review examines the multifaceted role of exosomes in NDDs, emphasizing their diagnostic capabilities, intrinsic therapeutic functions, and transformative potential as advanced treatment vehicles.}, } @article {pmid40094392, year = {2025}, author = {Resch, M and Frickel, JS and Dischinger, K and Wen, RCS and Hell, K and Harner, ME}, title = {The Mia40 substrate Mix17 exposes its N-terminus to the cytosolic side of the mitochondrial outer membrane.}, journal = {Journal of cell science}, volume = {}, number = {}, pages = {}, doi = {10.1242/jcs.263661}, pmid = {40094392}, issn = {1477-9137}, support = {413985647//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Mitochondrial architecture and the contacts between the outer and the inner mitochondrial membrane depend on the mitochondrial contact site and cristae organizing system (MICOS) that is highly conserved from yeast to human. Mutations in the mammalian MICOS subunit Mic14/CHCHD10 have been linked to amyotrophic lateral sclerosis and frontotemporal dementia, indicating the importance of this protein. Mic14/CHCHD10 has a yeast ortholog, Mix17, a protein of unknown function, which has not been shown to interact with MICOS so far. As a first step to elucidate the function of Mix17 and its orthologs, we analyzed its interactions, biogenesis and mitochondrial sublocation. We report that Mix17 is no stable MICOS subunit in yeast. Our data suggest that Mix17 is the first Mia40 substrate in the mitochondrial outer membrane. Unlike all other Mia40 substrates, Mix17 spans the outer membrane and exposes its N-terminus to the cytosol. The insertion of Mix17 is likely to be mediated by its interaction with Tom40, the pore of the TOM complex. Moreover, we show that the exposure of Mix17 to the cytosolic side of the membrane depends on its N-terminus.}, } @article {pmid40093130, year = {2025}, author = {Zhou, Z and Luquette, LJ and Dong, G and Kim, J and Ku, J and Kim, K and Bae, M and Shao, DD and Sahile, B and Miller, MB and Huang, AY and Nathan, WJ and Nussenzweig, A and Park, PJ and Lagier-Tourenne, C and Lee, EA and Walsh, CA}, title = {Recurrent patterns of widespread neuronal genomic damage shared by major neurodegenerative disorders.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40093130}, issn = {2692-8205}, support = {R01 HG012573/HG/NHGRI NIH HHS/United States ; R56 AG079857/AG/NIA NIH HHS/United States ; DP2 AG072437/AG/NIA NIH HHS/United States ; R01 AG082346/AG/NIA NIH HHS/United States ; K01 AG051791/AG/NIA NIH HHS/United States ; R01 NS032457/NS/NINDS NIH HHS/United States ; DP2 AG086138/AG/NIA NIH HHS/United States ; R01 AG070921/AG/NIA NIH HHS/United States ; R01 AG088082/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) are common neurodegenerative disorders for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 429 neurons from three C9ORF72 ALS, six C9ORF72 FTD, seven AD, and twenty-three neurotypical control brains revealed significantly increased burdens in somatic single nucleotide variant (sSNV) and insertion/deletion (sIndel) in all three disease conditions. Mutational signature analysis identified a disease-associated sSNV signature suggestive of oxidative damage and an sIndel process, affecting 28% of ALS, 79% of FTD, and 65% of AD neurons but only 5% of control neurons (diseased vs. control: OR=31.20, p = 2.35×10[-10]). Disease-associated sIndels were primarily two-basepair deletions resembling signature ID4, which was previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Duplex sequencing confirmed the presence of sIndels and identified similar single-strand events as potential precursor lesions. TOP1-associated sIndel mutagenesis and resulting genome instability may thus represent a common mechanism of neurodegeneration.}, } @article {pmid40092960, year = {2025}, author = {Liu, Y and Li, XF}, title = {Characteristics and therapeutic strategies for familial gastrointestinal stromal tumors.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {3}, pages = {100463}, pmid = {40092960}, issn = {1948-5204}, abstract = {This editorial discusses Wang et al's article on familial gastrointestinal stromal tumors (GISTs). We read with great interest this article concerning the diagnosis, treatment, and post-treatment management of patients with familial GISTs. The actual incidence of GISTs may be underestimated due to diagnostic limitations and the long-term low-risk behavior of some GISTs. The molecular landscape of GISTs is primarily driven by mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. A subset of GISTs without these mutations known as wild-type GISTs, may harbor other rare mutations, impacting their response to targeted therapies. Clinically, patients with GISTs present with non-specific symptoms, often leading to delayed diagnosis. Genetic predispositions in familial GISTs provide insights into the genetic architecture and extragastrointestinal manifestations of GISTs. Management has evolved from surgical interventions to molecular-based therapies using tyrosine kinase inhibitors. The management of GISTs, especially in familial cases, requires a multidisciplinary approach. Cases of different gene mutations were reported in the same family, suggesting that incorporating genetic testing into routine clinical practice is crucial for the early identification of high-risk individuals and the implementation of tailored surveillance programs.}, } @article {pmid40092497, year = {2025}, author = {Fujii, Y and Kanbayashi, T and Takahashi, K and Hamada, Y and Kobayashi, S and Sonoo, M}, title = {Correlation between decremental responses in repetitive nerve stimulation and disease progression rate in patients with amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology practice}, volume = {10}, number = {}, pages = {40-46}, pmid = {40092497}, issn = {2467-981X}, abstract = {OBJECTIVE: Decrement responses in repetitive nerve stimulation (RNS) are theoretically expected to correlate with the disease progression speed in amyotrophic lateral sclerosis (ALS). However, actual results have been controversial. We investigated this issue using ΔFS calculated from the ALS functional rating scale revised version (ALSFRS-R) and the duration of illness.

METHODS: RNS results of the abductor pollicis brevis, trapezius, and deltoid muscles in our previous study were reviewed. We investigated correlations and multiple regressions regarding decremental percentage (Decr%), the amplitude of the initial compound muscle action potential (Amp), and progression speed parameters, i.e. ΔFS or ΔUL-FS, the latter being the ΔFS for the upper-limb questions in ALSFRS-R.

RESULTS: Included subjects were 124 patients with ALS, 47 of whom were upper-limb onset. Multiple regression analyses revealed that Decr% is largely determined by Amp and that Δ FS or ΔUL-FS showed no or little contributions to Decr%.

CONCLUSIONS: Decremental responses in RNS does not predict the speed of progression of the functional impairment in patients with ALS.

SIGNIFICANCE: This study suggests that the decremental responses in RNS in ALS are contributed by the impaired neuromuscular transmission in chronic sprouts following extensive reinnervation, as well as by the immature sprouts.}, } @article {pmid40092496, year = {2025}, author = {Theuriet, J and Bohic, A and Bonjour, M and Bernard, E and Cluse, F and Svahn, J and Jomir, L and Vallet, AE and Demia, M and Roux, L and Bârsan, IC and Alves, L and Dion, M and Meens, L and Moussy, M and Bouhour, F and Péréon, Y and Pegat, A}, title = {Contralateral R1 response in blink reflex in patients with amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology practice}, volume = {10}, number = {}, pages = {47-51}, pmid = {40092496}, issn = {2467-981X}, abstract = {OBJECTIVE: This study aimed to compare the frequency of blink reflex's contralateral R1 responses (R1') between patients with amyotrophic lateral sclerosis (ALS), non-ALS motor deficit patients, and healthy volunteers.

METHODS: A total of 120 participants were prospectively recruited: 40 with ALS, 40 with a non-ALS motor deficit, and 40 healthy volunteers. Blink reflexes were recorded from orbicularis oculi muscles following supraorbital nerve stimulation.

RESULTS: R1' was more frequent in the ALS group (42.5 %) compared to healthy volunteers (12.5 %, p = 0.00588), and compared to non-ALS patients (7.5 %, p = 0.000789). Bilateral R1' was observed only in ALS patients (22.5 %). No clinically significant difference was found in the latencies or amplitudes of the R1, R2, or R1' responses among groups. R1' was more frequent in ALS patients with pseudobulbar affect (71.4 %) compared to those without (36.4 %).

CONCLUSIONS: The higher frequency of R1' in ALS highlights its potential role in distinguishing ALS from other motor disorders. Its sensitivity was low, but bilateral R1' was specific to ALS. The higher frequency of R1' among ALS patients with pseudobulbar affect potentially reflects corticobulbar neuron degeneration.

SIGNIFICANCE: The R1', especially when bilateral, could serve as an additional diagnostic biomarker for ALS, although its clinical relevance should be considered within the broader diagnostic context.}, } @article {pmid40091916, year = {2025}, author = {Ansari, U and Wen, J and Karabala, M and Syed, B and Abed, I and Razick, DI and Lui, F}, title = {Analysis of Respiratory Muscle Strength Training in Amyotrophic Lateral Sclerosis (ALS) Patients: A Systematic Review.}, journal = {Cureus}, volume = {17}, number = {2}, pages = {e78903}, pmid = {40091916}, issn = {2168-8184}, abstract = {Respiratory muscle weakness is a significant contributor to morbidity and mortality in amyotrophic lateral sclerosis (ALS) patients. Respiratory muscle strength training (RMST) has emerged as a potential therapeutic approach to mitigate respiratory muscle weakness in ALS. Still, its efficacy and safety remain unclear due to conflicting evidence and methodological heterogeneity in existing studies. A systematic review was conducted across three databases (PubMed (United States National Library of Medicine, Bethesda, MD, USA), Embase (Elsevier, Amsterdam, Netherlands), and Cochrane Library (Cochrane, Alberta, Canada)) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to assess the effectiveness of RMST in ALS patients. Eligible studies included comparative studies for RMST, focusing on outcomes such as maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC), and ALS Functional Rating Scale (ALSFRS-R). Quality assessment was performed using the Cochrane Risk of Bias tool. This study included six studies, including 183 patients with a mean age of 58.0 years (49.6 to 63.2) and a mean follow-up time of 21.2 weeks (eight to 52). The average mean difference for ALSFRS-R (three studies), MIP (three studies), MEP (three studies), and FVC (two studies) were 2.062 (0.04 to 5.3), 2.285 (-8.145 to 10.8), 19.435 (10.86 to 21.7), and 7.23 (3.6 to 10.86), respectively. Complications related to RMST were poorly reported across studies. Secondary outcomes, such as depression scores, blood oxygen levels, and heart rate variability, showed promising trends but lacked consistency. Despite positive findings on respiratory muscle strength, RMST's efficacy in ALS management remains inconclusive. Challenges include methodological heterogeneity, limited sample sizes, and inadequate reporting of complications. Future research should focus on standardized protocols, larger sample sizes, longer follow-ups, and comprehensive assessment of adverse effects to clarify the role of RMST in ALS treatment.}, } @article {pmid40091372, year = {2025}, author = {Jaspers Focks, RJ and Helleman, J and van den Berg, LH and Visser-Meily, JM and Gaytant, MA and Wijkstra, PJ and Beelen, A}, title = {Initiating non-invasive ventilation in patients with Amyotrophic Lateral Sclerosis in The Netherlands: A centralised approach to respiratory care.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602251319167}, doi = {10.1177/22143602251319167}, pmid = {40091372}, issn = {2214-3602}, abstract = {BACKGROUND: In the Netherlands a centralised approach to respiratory care for patients with Amyotrophic Lateral Sclerosis is used based on national guidelines. Patients with Amyotrophic Lateral Sclerosis are referred to one of 4 centres for Home Mechanical Ventilation.

OBJECTIVE: Our aim was to evaluate the respiratory care according to the Dutch guideline by evaluation of reasons for starting non-invasive ventilation, timing of initiating and survival in patients with Amyotrophic Lateral Sclerosis using non-invasive ventilation.

METHOD: A retrospective chart-review was performed of 323 patients, who had been referred to centres for Home Mechanical Ventilation in 2016-2018. Data collected included symptoms of hypoventilation, forced vital capacity, blood gasses, criteria for (not) initiating non-invasive ventilation, and survival. Kaplan-Meyer curves and Multivariate Cox proportional hazard regression were used in the analysis.

RESULTS: The main criteria used for initiating non-invasive ventilation were hypercapnia (77%) and the presence of orthopnea and/or dyspnoea (25%). Median survival after starting non-invasive ventilation was 11 months, and was shorter for patients with bulbar disease onset and older age. The proportion of the total disease duration that was spent on non-invasive ventilation was not significantly affected by age, sex or site of disease. Seventy nine percent of the patients who didn't start non-invasive ventilation had reached a joint decision with their caregivers and/or physicians.

CONCLUSION: Key outcomes of the Dutch centralised respiratory care approach have shown that most patients were initiated on non-invasive ventilation due to presence of hypercapnia and/or dyspnoea/orthopnea, which is according to the Dutch guidelines. Half of patients spent at least 33% of their disease duration on non-invasive ventilation. To help find the optimal criteria and timing for non-invasive ventilation it would be useful for other countries to share their key outcomes as well.}, } @article {pmid40090808, year = {2025}, author = {Rosina, M and Scaricamazza, S and Fenili, G and Nesci, V and Valle, C and Ferri, A and Paronetto, MP}, title = {Hidden players in the metabolic vulnerabilities of amyotrophic lateral sclerosis.}, journal = {Trends in endocrinology and metabolism: TEM}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tem.2025.02.004}, pmid = {40090808}, issn = {1879-3061}, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex and rapidly progressive motor neuron disorder with a fatal outcome. Despite the remarkable progress in understanding ALS pathophysiology, which has significantly contributed to clinical trial design, ALS remains a rapidly disabling and life-shortening condition. The non-motor neuron features of ALS, including nutritional status, energy expenditure, and metabolic imbalance, are increasingly gaining attention. Indeed, the bioenergetic failure and mitochondrial dysfunction of patients with ALS impact not only the high energy-demanding motor neurons but also organs and brain areas long considered irrelevant to the disease. As such, here we discuss how considering energy balance in ALS is reshaping research on this disease, opening the path to novel targetable opportunities for its treatment.}, } @article {pmid40089090, year = {2025}, author = {Men, J and Wang, X and Zhou, Y and Huang, Y and Zheng, Y and Wang, Y and Yang, S and Chen, N and Yan, N and Duan, X}, title = {Neurodegenerative diseases: Epigenetic regulatory mechanisms and therapeutic potential.}, journal = {Cellular signalling}, volume = {131}, number = {}, pages = {111715}, doi = {10.1016/j.cellsig.2025.111715}, pmid = {40089090}, issn = {1873-3913}, abstract = {Neurodegenerative diseases (NDDs) are a class of diseases in which the progressive loss of subtype-specific neurons leads to dysfunction. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), among others. Previous studies have demonstrated that the pathogenesis of NDDs involves various mechanisms, including genetic factors, oxidative stress, apoptosis, and the immune response. Recent studies have shown that epigenetic regulation mediates the interactions between DNA methylation, chromatin remodeling, histone modification, and non-coding RNAs, thus affecting gene transcription. A growing body of research links epigenetic modifications to crucial pathways involved in the occurrence and development of NDDs. Epigenetics has also been found to regulate and maintain nervous system function, and its imbalance is closely related to the occurrence and development of NDDs. The present review summarizes focuses on the role of epigenetic modifications in the pathogenesis of NDDs and provides an overview of the key genes regulated by DNA methylation, histone modification, and non-coding RNAs in NDDs. Further, the current research status of epigenetics in NDDs is summarized and the potential application of epigenetics in the clinical diagnosis and treatment of NDDs is discussed.}, } @article {pmid40087396, year = {2025}, author = {Omar, OMF and Kimble, AL and Cheemala, A and Tyburski, JD and Pandey, S and Wu, Q and Reese, B and Jellison, ER and Hao, B and Li, Y and Yan, R and Murphy, PA}, title = {Endothelial TDP-43 depletion disrupts core blood-brain barrier pathways in neurodegeneration.}, journal = {Nature neuroscience}, volume = {}, number = {}, pages = {}, pmid = {40087396}, issn = {1546-1726}, support = {19IPLOI34770151//American Heart Association (American Heart Association, Inc.)/ ; 23PRE1027078//American Heart Association (American Heart Association, Inc.)/ ; R00-HL125727//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; RF1-NS117449//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS074256//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; GM135592//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; AG046929//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; }, abstract = {Endothelial cells (ECs) help maintain the blood-brain barrier but deteriorate in many neurodegenerative disorders. Here we show, using a specialized method to isolate EC and microglial nuclei from postmortem human cortex (92 donors, 50 male and 42 female, aged 20-98 years), that intranuclear cellular indexing of transcriptomes and epitopes enables simultaneous profiling of nuclear proteins and RNA transcripts at a single-nucleus resolution. We identify a disease-associated subset of capillary ECs in Alzheimer's disease, amyotrophic lateral sclerosis and frontotemporal degeneration. These capillaries exhibit reduced nuclear β-catenin and β-catenin-downstream genes, along with elevated TNF/NF-κB markers. Notably, these transcriptional changes correlate with the loss of nuclear TDP-43, an RNA-binding protein also depleted in neuronal nuclei. TDP-43 disruption in human and mouse ECs replicates these alterations, suggesting that TDP-43 deficiency in ECs is an important factor contributing to blood-brain barrier breakdown in neurodegenerative diseases.}, } @article {pmid40086112, year = {2025}, author = {Liampas, I and Veltsista, D and Germeni, A and Batzikosta, P and Michou, E and Kefalopoulou, Z and Chroni, E}, title = {F waves in amyotrophic lateral sclerosis: A systematic review and meta-analysis.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {55}, number = {4}, pages = {103061}, doi = {10.1016/j.neucli.2025.103061}, pmid = {40086112}, issn = {1769-7131}, abstract = {OBJECTIVE: This systematic review and meta-analysis aimed to determine the pattern of F-wave abnormalities and their potential utility in the early diagnosis of amyotrophic lateral sclerosis (ALS).

METHODS: Medline and Embase were thoroughly searched. We primarily emphasized F-wave recordings from the abductor digiti minimi, following stimulation of the ulnar nerve at the wrist. Data from case-control studies involving individuals with ALS versus healthy controls (HC) or other well-defined patient groups were reviewed and -if appropriate- quantitatively synthesized.

RESULTS: Twenty-nine studies were included in this systematic review and 17 of them in the analytic part. The pattern of F-abnormalities in ALS compared to HC was as follows: decreased persistence (MD=20.25 %,15.67-24.84 %), mildly prolonged minimum latency (MD=1.59msec,1.11-2.06msec), increased maximum amplitude (MD=196μV,106-287μV) and elevated Index total Freps (MD=33.9 %,26.0-41.8 %). Affected limbs (with substantial weakness in clinical examination and/or muscle wasting and/or abnormal nerve conduction studies) exhibited more marked abnormalities in persistence, minimum latency, and Index total Freps, whereas abnormalities in these parameters were very mild in clinically unaffected limbs. More prominent increases in maximum amplitude accompanied pyramidal dysfunction. Of note, isolated upper motor neuron (UMN) disorders exhibited a comparable increase in Index total Freps without a decrease in persistence.

CONCLUSIONS: The pattern of F wave abnormalities may raise suspicion of involvement of the under-study lower motor neuron (LMN) pool in ALS. These findings may identify LMN dysfunction even at a preclinical stage and prompt extensive electromyographic investigations. UMN involvement may to some extent differentiate the profile of F wave abnormalities in ALS.}, } @article {pmid40085521, year = {2025}, author = {Mercan, M and Seyhan, S and Yayla, V}, title = {The phenotyping dilemma in VRK1-related motor neuron disease: a Turkish family with young-onset amyotrophic lateral sclerosis caused by a novel mutation.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-18}, doi = {10.1080/21678421.2025.2477732}, pmid = {40085521}, issn = {2167-9223}, abstract = {Objective: Vaccinia-related kinase 1 (VRK1)-related disease is an extremely rare autosomal recessive disorder primarily affecting the peripheral and/or central nervous system. In this report, we describe the genetic and clinical features of two siblings from a Turkish family presenting with an amyotrophic lateral sclerosis (ALS) phenotype due to a novel homozygous VRK1 mutation, and discuss the broad phenotypic spectrum associated with pathogenic variants in this gene. Methods: We analyzed the demographic data, clinical histories, neurological examinations, laboratory findings, and genetic results of 53 patients, including our cases, derived from 27 different reports. Results: Whole-exome sequencing identified a novel homozygous missense mutation, c.700A > G (p.Asn234Asp), in the VRK1 gene in two affected siblings. The characteristic features of the ALS phenotype included a recessive inheritance pattern, motor deficits with onset in the lower limbs, pyramidal tract signs, and a muscle magnetic resonance imaging (MRI) pattern demonstrating preferential involvement of the posterior compartments of the leg and thigh. The most common phenotypes associated with VRK1 mutations were ALS (18/53, 34%) and distal hereditary motor neuropathy (dHMN) (14/53, 26.4%), followed by pontocerebellar hypoplasia type 1 (7/53, 13.2%), hereditary motor and sensory neuropathy (5/53, 9.4%), autosomal recessive primary microcephaly with brain malformations (4/53, 7.5%), and spastic paraplegia (2/53, 3.8%). The ALS phenotype exhibited a significantly earlier mean age of onset compared to the dHMN phenotype (p = 0.015; 15.3 ± 11.5 and 27 ± 15.5 years, respectively). Conclusion: Our findings highlight the importance of investigating VRK1 mutations in patients with young-onset familial ALS. Furthermore, this report provides a systematic classification of the phenotype definitions associated with VRK1 mutations.}, } @article {pmid40084393, year = {2025}, author = {Helmold, B and Nathaniel, G and Barkhaus, P and Bertorini, T and Bromberg, M and Brown, A and Carter, GT and Chang, V and Crayle, J and Denson, K and Glass, J and Heiman-Patterson, T and Hobson, E and Jackson, C and Jhooty, S and Mallon, E and Maragakis, N and Cadavid, JM and Mcdermott, C and Pattee, G and Pierce, K and Wang, O and Wicks, P and Bedlack, R}, title = {ALSUntangled #78: Zinc.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/21678421.2025.2476688}, pmid = {40084393}, issn = {2167-9223}, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). In this review, we assess the utilization of dietary zinc supplements for modulating ALS pathology and progression. Studies in mouse models of ALS have demonstrated that high-dose zinc supplementation may be harmful, but moderate doses could potentially be beneficial. Clinical data is limited, and only one trial has explored zinc supplementation within PALS. This study reported potential benefits in slowing ALS progression but lacked statistical analyses and failed to report quantitative evidence. Numerous case reports from individual patients at varying doses have demonstrated no benefit. Zinc supplements at moderate doses are generally low cost and not associated with severe complications, but further research is required to determine the safety and efficacy of zinc supplementation within PALS. Therefore, we cannot at this time, endorse zinc supplementation to slow ALS progression.}, } @article {pmid40080233, year = {2025}, author = {Aydın, Ş and Özdemir, S and Adıgüzel, A}, title = {The Potential of cfDNA as Biomarker: Opportunities and Challenges for Neurodegenerative Diseases.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {1}, pages = {34}, pmid = {40080233}, issn = {1559-1166}, mesh = {Humans ; *Biomarkers/blood ; *Cell-Free Nucleic Acids/blood ; *Neurodegenerative Diseases/blood/diagnosis/genetics ; Animals ; }, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), are characterized by the progressive and gradual degeneration of neurons. The prevalence and rates of these disorders rise significantly with age. As life spans continue to increase in many countries, the number of cases is expected to grow in the foreseeable future. Early and precise diagnosis, along with appropriate surveillance, continues to pose a challenge. The high heterogeneity of neurodegenerative diseases calls for more accurate and definitive biomarkers to improve clinical therapy. Cell-free DNA (cfDNA), including fragmented DNA released into bodily fluids via apoptosis, necrosis, or active secretion, has emerged as a promising non-invasive diagnostic tool for various disorders including neurodegenerative diseases. cfDNA can serve as an indicator of ongoing cellular damage and mortality, including neuronal loss, and may provide valuable insights into disease processes, progression, and therapeutic responses. This review will first cover the key aspects of cfDNA and then examine recent advances in its potential use as a biomarker for neurodegenerative disorders.}, } @article {pmid40077653, year = {2025}, author = {de Carvalho Vilar, MD and Coutinho, KMD and de Lima Vale, SH and Dourado Junior, MET and de Medeiros, GCBS and Piuvezam, G and Brandao-Neto, J and Leite-Lais, L}, title = {Evidence-Based Nutritional Recommendations for Maintaining or Restoring Nutritional Status in Patients with Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Nutrients}, volume = {17}, number = {5}, pages = {}, pmid = {40077653}, issn = {2072-6643}, support = {grant number 302298/2017-7 (Jose Brandao-Neto)//National Council for Scientific and Technological Development/ ; TED 132/2018//Ministry of Health (Brazil) - Laboratory of Technological Innovation in Health from the Federal University of Rio Grande do Norte - LAIS/UFRN/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diet therapy/therapy/complications ; Humans ; *Nutritional Status ; *Nutrition Assessment ; Evidence-Based Medicine ; Quality of Life ; Nutritional Support/methods ; Dietary Supplements ; Deglutition Disorders/diet therapy/therapy ; Gastrostomy ; Nutrition Therapy/methods ; }, abstract = {Background/Objectives: This study is a systematic review of guidelines that aims to synthesize evidence-based recommendations to support appropriate nutritional management for patients with amyotrophic lateral sclerosis (ALS). Methods: PubMed/MEDLINE, Embase, Scopus, SciELO, Web of Science, LILACS, ScienceDirect, and Google Scholar were searched for records published up to July 2024. Clinical practice guidelines addressing any aspect of nutritional intervention in ALS were included. No language or country of publication restrictions were applied. Data extraction was performed by two independent reviewers. The methodological quality of the reports was assessed using the AGREE II instrument. Discrepancies were resolved by consensus. Results: The findings and main recommendations were summarized narratively. A total of 837 records were identified, and 11 were included in this review. The overall AGREE II scores for the included studies ranged from 3 to 7. The summary of nutritional recommendations was organized into topics: (1) dysphagia, (2) nutritional assessment, (3) energy, (4) protein, (5) supplementation, and (6) percutaneous endoscopic gastrostomy (PEG). This review summarizes relevant and updated nutritional recommendations to maintain or restore the nutritional status of patients with ALS, contributing to their quality of life and survival time. Conclusions: These nutritional recommendations will help health professionals and caregivers to implement and standardize nutritional care according to evidence-based practice in ALS. PROSPERO registration number CRD42021233088.}, } @article {pmid40076771, year = {2025}, author = {Aguiar, B and Alfenim, AR and Machado, CS and Moreira, J and Pinto, M and Otero-Espinar, FJ and Borges, F and Fernandes, C}, title = {Exploring Nano-Delivery Systems to Enhance the Edaravone Performance in Amyotrophic Lateral Sclerosis Treatment.}, journal = {International journal of molecular sciences}, volume = {26}, number = {5}, pages = {}, pmid = {40076771}, issn = {1422-0067}, support = {2023.13291.PEX//Foundation for Science and tecnhology/ ; UIDB/00081/2020 (CIQUP)//Foundation for Science and Technology/ ; LA/P/0056/2020(IMS)//Foundation for Science and Technology/ ; 2021.04016.CEECIND/CP1655/CT0004//Foundation for Science and Technology/ ; IMPULSE: IMproving User experience, Long-term sustainability, and Services//EU-OPENSCREEN HORIZON-INFRA-2023-DEV-0/ ; 2020.08731.BD//Foundation for Science and Technology/ ; 2023.01250.BD//Foundation for Science and Technology/ ; 2024.00809.BD//Foundation for Science and Technology/ ; SFRH/BD/145637/2019//Foundation for Science and Technology/ ; }, mesh = {*Edaravone/pharmacology/chemistry/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Nanoparticles/chemistry ; Drug Delivery Systems/methods ; Free Radical Scavengers/chemistry/pharmacology ; Drug Carriers/chemistry ; Nanoparticle Drug Delivery System/chemistry ; Polyethylene Glycols/chemistry ; }, abstract = {Edaravone is one of the treatment options for Amyotrophic Lateral Sclerosis, but its therapeutic efficacy is limited due to the incapacity to cross the blood-brain barrier, as well as its short life span and poor stability, which is ultimately caused by its tautomerism in physiological condions. This work presents an overview about the use of several nanoformulations based on polymeric, protein, lipidic, or hybrid structure as suitable and stable drug delivery systems for encapsulating edaravone. We also evaluated the functionalization of nanoparticles with pegylated chains using the polyethylene glycol or tocopherol polyethylene glycol succinate and the possibility of preparing polymeric nanoparticles at different pH (7.4, 9, and 11). Edaravone was sucessfully encapsulated in polymeric, lipid-polymer hybrid, and lipidic nanoparticles. The use of higher pH values in the synthesis of polymeric nanoparticles has led to a decrease in nanoparticle size and an increase in the percentage of encapsulation efficiency. However, the resulting nanoformulations are not stable. Only polymeric and hybrid nanoparticles showed good stability over 80 days of storage, mainly at 4 °C. Overall, the nanoformulations tested did not show cytotoxicity in the SH-SY5Y cell line except the nanostructured lipid carrier formulations that showed some cytotoxicity possibly due to lipidic peroxidation. In conclusion, this work shows that edaravone can be encapsulated in different nanocarriers that could act as an interesting alternative for the treatment of Amyotrophic Lateral Sclerosis.}, } @article {pmid40075757, year = {2025}, author = {Rizzo, GEM and Coluccio, C and Forti, E and Fugazza, A and Binda, C and Vanella, G and Di Matteo, FM and Crinò, SF and Lisotti, A and Maida, MF and Aragona, G and Mauro, A and Repici, A and Anderloni, A and Fabbri, C and Tarantino, I and On Behalf Of The I-Eus Group, }, title = {Endoscopic Ultrasound-Guided Anastomoses of the Gastrointestinal Tract: A Multicentric Experience.}, journal = {Cancers}, volume = {17}, number = {5}, pages = {}, pmid = {40075757}, issn = {2072-6694}, support = {N/A//I-EUS working group/ ; }, abstract = {This multicenter retrospective study included patients undergoing EUS-guided GI anastomoses from 2016 to 2023. Indications for EUS-guided anastomosis were GOO, ALS or patients with altered anatomy needing endoscopic interventions. The primary outcome was technical success, while secondary outcomes included clinical success, safety, lumen-apposing metal stent (LAMS) patency, and the need for reinterventions. A total of 216 patients (mean age 64.5 [±13.94] years; 49.1% males) were included. In total, 149 cases (69%) were GOO, 44 (20.4%) cases were bilioenteric anastomotic strictures or lithiasis in altered anatomy, 14 cases (6.5%) were ALS, and 9 patients (4.2%) were for ERCP in altered anatomy after EUS-GG. Overall, EUS-GE was performed in 181 patients (83.8%), EUS-JJ in 44 cases (20.4%), and EUS-GG in 10 (4.6%). Technical success was 94.91%, and clinical success was 93.66%. The adverse event (AE) rate was 11.1%. The reintervention rate was 7.69%. The median follow-up was 85 days. In conclusions, EUS-guided GI anastomoses are technically feasible and safe in both malignant and benign diseases.}, } @article {pmid40075315, year = {2025}, author = {Soliman, R and Fahmy, N and Swelam, MS}, title = {Headache types and characteristics in patients with Amyotrophic Lateral Sclerosis.}, journal = {The journal of headache and pain}, volume = {26}, number = {1}, pages = {53}, pmid = {40075315}, issn = {1129-2377}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/physiopathology ; Female ; Male ; Middle Aged ; Cross-Sectional Studies ; Adult ; Headache/etiology/epidemiology/diagnosis ; Aged ; Tension-Type Headache/diagnosis ; Severity of Illness Index ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive loss of motor neurons, this result in muscle denervation, atrophy and consequently death takes place due to respiratory failure within 3-5 years of onset of symptoms.

OUR AIM: Was to investigate types and frequency of headache in ALS patients.

METHODS: This is cross sectional hospital based study. Clinically definite 100 ALS Patients (diagnosed according to El Escorial revised criteria) were recruited out of 137 ALS patients presented to the Neuromuscular Clinic in Ain Shams university Hospital from February 2022 to June 2024. Patients were screened for headache types and symptoms diagnosed according to International Headache Society criteria (IHS). Headache severity and impact were assessed using Arabic versions of Headache Impact Test (HIT) and Migraine Disability Assessment (MIDAS). Depression was also assessed via Arabic version of Beck's Depression Inventory (BDI). ALS symptoms severity was assessed via Arabic version of Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). Cognitive functions were assessed via the Egyptian version of the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS‑EG). Demographic data and ALS related parameters were collected.

RESULTS: Among 100 patients with clinically definite ALS, 79 patients reported headaches, 62 of them had primary headaches; with tension-type headache being the most commonly reported in 46 patients, Migraine in 16 patients. Fifteen ALS patients had secondary headaches; among them 12 had headache secondary to respiratory insufficiency and 3 patients developed headache after the initiation of Riluzole therapy. Two patients had non specific headache. Mean age for the patients at ALS presentation was 43.9 ± 13.8, Mean ALSFRS-R score 33.3 ± 9.04. The relationships between headache and clinical features of ALS were also investigated.

IN CONCLUSION: ALS patients should be evaluated for Headache; Not only headache secondary to respiratory compromise and hypercapnea, but also primary headaches which can be overlooked in patients with ALS.}, } @article {pmid40075110, year = {2025}, author = {Raas, Q and Haouy, G and de Calbiac, H and Pasho, E and Marian, A and Guerrera, IC and Rosello, M and Oeckl, P and Del Bene, F and Catanese, A and Ciura, S and Kabashi, E}, title = {TBK1 is involved in programmed cell death and ALS-related pathways in novel zebrafish models.}, journal = {Cell death discovery}, volume = {11}, number = {1}, pages = {98}, pmid = {40075110}, issn = {2058-7716}, support = {682622//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; }, abstract = {Pathogenic mutations within the TBK1 gene leading to haploinsufficiency are causative of amyotrophic lateral sclerosis (ALS). This gene is linked to autophagy and inflammation, two cellular mechanisms reported to be dysregulated in ALS patients, although its functional role in the pathogenesis could involve other players. We targeted the TBK1 ortholog in zebrafish, an optimal vertebrate model for investigating genetic defects in neurological disorders. We generated zebrafish models with invalidating tbk1 mutations using CRISPR-Cas9 or tbk1 knockdown models using antisense morpholino oligonucleotide (AMO). The early motor phenotype of zebrafish injected with tbk1 AMO beginning at 2 days post fertilization (dpf) is associated with the degeneration of motor neurons. In parallel, CRISPR-induced tbk1 mutants exhibit impaired motor function beginning at 5 dpf and increased lethality beginning at 9 dpf. A metabolomic analysis showed an association between tbk1 loss and severe dysregulation of nicotinamide metabolism, and incubation with nicotinamide riboside rescued the motor behavior of tbk1 mutant zebrafish. Furthermore, a proteomic analysis revealed increased levels of inflammatory markers and dysregulation of programmed cell death pathways. Necroptosis appeared to be strongly activated in TBK1 fish, and larvae treated with the necroptosis inhibitor necrosulfonamide exhibited improved survival. Finally, a combined analysis of mutant zebrafish and TBK1-mutant human motor neurons revealed dysregulation of the KEGG pathway "ALS", with disrupted nuclear-cytoplasmic transport and increased expression of STAT1. These findings point toward a major role for necroptosis in the degenerative features and premature lethality observed in tbk1 mutant zebrafish. Overall, the novel tbk1-deficient zebrafish models offer a great opportunity to better understand the cascade of events leading from the loss of tbk1 expression to the onset of motor deficits, with involvement of a metabolic defect and increased cell death, and for the development of novel therapeutic avenues for ALS and related neuromuscular diseases.}, } @article {pmid40074931, year = {2025}, author = {Michielsen, A and van Veenhuijzen, K and Hiemstra, F and Jansen, IM and Kalkhoven, B and Veldink, JH and Kruitwagen, ET and van Es, M and van Zandvoort, MJE and van den Berg, LH and Westeneng, HJ}, title = {Cognitive impairment within and beyond the FTD spectrum in ALS: development of a complementary cognitive screen.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {268}, pmid = {40074931}, issn = {1432-1459}, support = {grant agreement no 772376- EScORIAL//H2020 European Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/physiopathology ; Male ; Female ; *Frontotemporal Dementia/complications/diagnosis/physiopathology ; *Cognitive Dysfunction/etiology/diagnosis/physiopathology ; Middle Aged ; Aged ; *Neuropsychological Tests ; }, abstract = {OBJECTIVE: To investigate cognitive impairments in amyotrophic lateral sclerosis (ALS), extending both within and beyond the established frontotemporal dementia (FTD) spectrum, using the Complementary Cognitive ALS Screen (C-CAS).

METHODS: The C-CAS, designed to complement the Edinburgh cognitive and behavioural ALS screen (ECAS), explores cognitive (sub)domains not investigated by the ECAS. Normative data were collected, and models adjusted for age, sex, and education level were developed. Item scores below the 5th percentile in controls were considered abnormal. A sum score was constructed, and C-CAS impairments were compared between ALS patients and controls, and to ECAS impairments.

RESULTS: Data from 314 controls and 184 ALS patients were analyzed. The C-CAS is feasible, well-tolerated, and takes 15-20 min to complete. ALS patients performed worse across all 12 items. Within the FTD spectrum, impairments in social cognition, inhibition, and cognitive flexibility were identified in up to 16%, 14%, and 12% of ALS patients, respectively, with minimal overlap with ECAS impairments. Beyond the FTD spectrum, impairments were found in visuoconstruction, incidental non-verbal memory and body orientation (13% each), with minimal overlap with ECAS memory or visuospatial impairments. Overall, 24% of the ALS patients obtained an abnormal C-CAS sum score. Compared to the ECAS, the C-CAS detected additional impairments in 15% of ALS patients. Item-specific and sum score results based on normative data can be accessed at (https://apps4mnd.com/ccas/).

INTERPRETATION: We identified cognitive impairments in ALS within and beyond the FTD spectrum not captured by existing screening tools. The C-CAS complements the ECAS, improving personalized counseling and research stratification in ALS.}, } @article {pmid40074537, year = {2025}, author = {Mkhize, L and Marimani, M and Duze, ST}, title = {Characterization of Vibrio cholerae from the Jukskei River in Johannesburg, South Africa.}, journal = {Letters in applied microbiology}, volume = {78}, number = {3}, pages = {}, doi = {10.1093/lambio/ovaf036}, pmid = {40074537}, issn = {1472-765X}, support = {138279//National Research Foundation/ ; RKSST23//Carnegie DTA/ ; }, mesh = {South Africa ; *Vibrio cholerae/genetics/isolation & purification/classification ; *Rivers/microbiology ; *Cholera/microbiology/epidemiology ; Humans ; Cholera Toxin/genetics ; Genome, Bacterial ; Virulence Factors/genetics ; Bacterial Proteins/genetics ; }, abstract = {The current study aimed to isolate and characterize Vibrio cholerae isolated from the Jukskei River, one of the largest Rivers in Johannesburg, South Africa. Water samples collected from the Jukskei River were subjected to culture-based methods for the detection and isolation of V. cholerae. Twenty-four V. cholerae were isolated, confirmed using real-time PCR, and sequenced using the MInION portable nanopore-sequencing device. Reference-based genome assemblies were constructed from the raw reads using the EPI2ME software followed by bioinformatics analysis using the Centre for Genomic Epidemiology website. All the V. cholerae isolates isolated from the Jukskei River were classified as non-O1/non-O139 and none of the isolates harbored the cholera toxin gene, ctxA. All 24 V. cholerae isolates belonged to sequence type 741, virulent genes including toxR, vspD, als, hlyA, makA, and rtxA as well as the Vibrio pathogenicity island 2 were detected amongst the isolates. Antimicrobial resistance genes (parC, varG, and gyrA) were detected in 83% of isolates. Although V. cholerae non-O1/non-O139 are not associated with epidemic cholera they can still cause mild to life-threatening illnesses. Therefore, increased surveillance should be considered to better understand the public health risks to the local community.}, } @article {pmid40074390, year = {2025}, author = {Cappa, SF}, title = {Hemispheric asymmetry in neurodegenerative diseases.}, journal = {Handbook of clinical neurology}, volume = {208}, number = {}, pages = {101-112}, doi = {10.1016/B978-0-443-15646-5.00009-9}, pmid = {40074390}, issn = {0072-9752}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/physiopathology ; *Functional Laterality/physiology ; Brain/pathology/physiopathology ; }, abstract = {Hemispheric asymmetry in pathologic involvement is frequently observed in neurodegenerative disorders (NDD) and is responsible for differences in cognitive and motor clinical manifestations in individual patients. While asymmetry is modest in typical Alzheimer disease (AD), atypical AD presentations with prominent language impairment [logopenic/phonologic variant of primary progressive aphasia (L/Phv-PPA)] are associated with prevalent involvement of the language-dominant hemisphere. Similarly, in the frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) spectrum, the semantic (Sv) and nonfluent/agrammatic (Nf/Av) variants of PPA are due to asymmetric pathology involving the language-dominant hemisphere. A reversed (typically right-sided) pattern of asymmetry is often found in conditions associated with prominent disorders of behavior and social cognition (i.e., behavioral variant of frontotemporal degeneration-Bv FTD). Asymmetry is generally modest and less consistent in NDD with prevalent motor manifestations, such as Parkinson disease (PD). Overall, the pattern of hemispheric involvement reflects the network-specific selectivity of NDD and is compatible with the spreading of pathology along connection pathways.}, } @article {pmid40073860, year = {2025}, author = {Zhang, Z and Fu, X and Wright, N and Wang, W and Ye, Y and Asbury, J and Li, Y and Zhu, C and Wu, R and Wang, S and Sun, S}, title = {PTPσ-mediated PI3P regulation modulates neurodegeneration in C9ORF72-ALS/FTD.}, journal = {Neuron}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuron.2025.02.005}, pmid = {40073860}, issn = {1097-4199}, support = {RF1 NS113820/NS/NINDS NIH HHS/United States ; }, abstract = {The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the repeat expansion in C9ORF72. Dipeptide repeat (DPR) proteins translated from both sense and antisense repeats, especially arginine-rich DPRs (R-DPRs), contribute to neurodegeneration. Through CRISPR interference (CRISPRi) screening in human-derived neurons, we identified receptor-type tyrosine-protein phosphatase S (PTPσ) as a strong modifier of poly-GR-mediated toxicity. We showed that reducing PTPσ promotes the survival of both poly-GR- and poly-PR-expressing neurons by elevating phosphatidylinositol 3-phosphate (PI3P), accompanied by restored early endosomes and lysosomes. Remarkably, PTPσ knockdown or inhibition substantially rescues the PI3P-endolysosomal defects and improves the survival of C9ORF72-ALS/FTD patient-derived neurons. Furthermore, the PTPσ inhibitor diminishes GR toxicity and rescues pathological and behavioral phenotypes in mice. Overall, these findings emphasize the critical role of PI3P-mediated endolysosomal deficits induced by R-DPRs in disease pathogenesis and reveal the therapeutic potential of targeting PTPσ in C9ORF72-ALS/FTD.}, } @article {pmid40073394, year = {2025}, author = {Janes, WE and Marchal, N and Song, X and Popescu, M and Mosa, ASM and Earwood, JH and Jones, V and Skubic, M}, title = {Integrating Ambient In-Home Sensor Data and Electronic Health Record Data for the Prediction of Outcomes in Amyotrophic Lateral Sclerosis: Protocol for an Exploratory Feasibility Study.}, journal = {JMIR research protocols}, volume = {14}, number = {}, pages = {e60437}, pmid = {40073394}, issn = {1929-0748}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/diagnosis ; *Electronic Health Records ; *Feasibility Studies ; Machine Learning ; Male ; Female ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) leads to rapid physiological and functional decline before causing untimely death. Current best-practice approaches to interdisciplinary care are unable to provide adequate monitoring of patients' health. Passive in-home sensor systems enable 24×7 health monitoring. Combining sensor data with outcomes extracted from the electronic health record (EHR) through a supervised machine learning algorithm may enable health care providers to predict and ultimately slow decline among people living with ALS.

OBJECTIVE: This study aims to describe a federated approach to assimilating sensor and EHR data in a machine learning algorithm to predict decline among people living with ALS.

METHODS: Sensor systems have been continuously deployed in the homes of 4 participants for up to 330 days. Sensors include bed, gait, and motion sensors. Sensor data are subjected to a multidimensional streaming clustering algorithm to detect changes in health status. Specific health outcomes are identified in the EHR and extracted via the REDCap (Research Electronic Data Capture; Vanderbilt University) Fast Healthcare Interoperability Resource directly into a secure database.

RESULTS: As of this writing (fall 2024), machine learning algorithms are currently in development to predict those health outcomes from sensor-detected changes in health status. This methodology paper presents preliminary results from one participant as a proof of concept. The participant experienced several notable changes in activity, fluctuations in heart rate and respiration rate, and reductions in gait speed. Data collection will continue through 2025 with a growing sample.

CONCLUSIONS: The system described in this paper enables tracking the health status of people living with ALS at unprecedented levels of granularity. Combined with tightly integrated EHR data, we anticipate building predictive models that can identify opportunities for health care services before adverse events occur. We anticipate that this system will improve and extend the lives of people living with ALS.

DERR1-10.2196/60437.}, } @article {pmid40072375, year = {2025}, author = {Gong, Z and Ba, L and Li, Z and Hou, H and Zhang, M}, title = {CD16[-]CD56[bright] NK Cells: A Protective NK Cell Subset for Progression and Prognosis in Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.1597}, pmid = {40072375}, issn = {2152-5250}, abstract = {Amyotrophic lateral sclerosis (ALS) is a non-neuron-autonomous disease where peripheral immune dysregulation significantly impacts disease progression. However, the immunopathological mechanisms of natural killer (NK) cells in ALS remain largely unexplored. This study enrolled 241 ALS patients and 102 healthy controls (HC), analyzing lymphocyte subsets, including T cells, B cells, and NK cells. A sub-cohort of 81 ALS patients was followed up for one year at three-month intervals. Linear mixed and Cox proportional hazards models were used to evaluate the association between lymphocyte subsets and ALS progression and prognosis. Our results revealed significant reductions in total T cells, helper T cells (Th), and NK cells in ALS patients compared to HC (P &;lt 0.05). Slow-progressing ALS patients exhibited higher counts of total T cells, Th, CD16-CD56[bright] NK cells, and CD16[+]CD56[bright] NK cells, while showing lower counts of CD16[+]CD56[dim] NK cells compared to fast-progressing ALS patients (P &;lt 0.05). ALS patients with lower CD16[-]CD56[bright] NK cell counts experienced a faster decline in motor function than those with higher counts (P &;lt 0.05). Elevated CD16[-]CD56[bright] NK cell counts were associated with improved ALS prognosis (HR, 0.73; 95% CI: 0.60-0.90; P &;lt 0.05). This study suggests that CD16[-]CD56[bright] NK cells play a protective role in ALS progression and prognosis, offering a potential therapeutic target for ALS.}, } @article {pmid40072076, year = {2025}, author = {Calvo, B and Schembri-Wismayer, P and Durán-Alonso, MB}, title = {Age-Related Neurodegenerative Diseases: A Stem Cell's Perspective.}, journal = {Cells}, volume = {14}, number = {5}, pages = {}, pmid = {40072076}, issn = {2073-4409}, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Aging/pathology ; Animals ; Stem Cells/metabolism ; Neurogenesis ; }, abstract = {Neurodegenerative diseases encompass a number of very heterogeneous disorders, primarily characterized by neuronal loss and a concomitant decline in neurological function. Examples of this type of clinical condition are Alzheimer's Disease, Parkinson's Disease, Huntington's Disease and Amyotrophic Lateral Sclerosis. Age has been identified as a major risk in the etiology of these disorders, which explains their increased incidence in developed countries. Unfortunately, despite continued and intensive efforts, no cure has yet been found for any of these diseases; reliable markers that allow for an early diagnosis of the disease and the identification of key molecular events leading to disease onset and progression are lacking. Altered adult neurogenesis appears to precede the appearance of severe symptoms. Given the scarcity of human samples and the considerable differences with model species, increasingly complex human stem-cell-based models are being developed. These are shedding light on the molecular alterations that contribute to disease development, facilitating the identification of new clinical targets and providing a screening platform for the testing of candidate drugs. Moreover, the secretome and other promising features of these cell types are being explored, to use them as replacement cells of high plasticity or as co-adjuvant therapy in combinatorial treatments.}, } @article {pmid40070688, year = {2025}, author = {Hosseini Faradonbeh, SM and Seyedalipour, B and Keivan Behjou, N and Rezaei, K and Baziyar, P and Hosseinkhani, S}, title = {Structural insights into SOD1: from in silico and molecular dynamics to experimental analyses of ALS-associated E49K and R115G mutants.}, journal = {Frontiers in molecular biosciences}, volume = {12}, number = {}, pages = {1532375}, pmid = {40070688}, issn = {2296-889X}, abstract = {Protein stability is a crucial characteristic that influences both protein activity and structure and plays a significant role in several diseases. Cu/Zn superoxide dismutase 1 (SOD1) mutations serve as a model for elucidating the destabilizing effects on protein folding and misfolding linked to the lethal neurological disease, amyotrophic lateral sclerosis (ALS). In the present study, we have examined the structure and dynamics of the SOD1 protein upon two ALS-associated point mutations at the surface (namely, E49K and R115G), which are located in metal-binding loop IV and Greek key loop VI, respectively. Our analysis was performed through multiple algorithms on the structural characterization of the hSOD1 protein using computational predictions, molecular dynamics (MD) simulations, and experimental studies to understand the effects of amino acid substitutions. Predictive results of computational analysis predicted the deleterious and destabilizing effect of mutants on hSOD1 function and stability. MD outcomes also indicate that the mutations result in structural destabilization by affecting the increased content of β-sheet structures and loss of hydrogen bonds. Moreover, comparative intrinsic and extrinsic fluorescence results of WT-hSOD1 and mutants indicated structural alterations and increased hydrophobic surface pockets, respectively. As well, the existence of β-sheet-dominated structures was observed under amyloidogenic conditions using FTIR spectroscopy. Overall, our findings suggest that mutations in the metal-binding loop IV and Greek key loop VI lead to significant structural and conformational changes that could affect the structure and stability of the hSOD1 molecule, resulting in the formation of toxic intermediate species that cause ALS.}, } @article {pmid40069959, year = {2025}, author = {Chiò, A and Foucher, J and Gwathmey, KG and Ingre, C}, title = {Minimum clinically important difference for drug effectiveness in an area of patient-oriented therapeutic goals in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2475893}, pmid = {40069959}, issn = {2167-9223}, abstract = {Objective: In this review, we will examine the more common endpoints incorporated in randomized controlled trials (RCTs) and their strength of evidence, focusing on the definition of what constitutes a clinically meaningful change. We will also reflect on the perspective of patients and their families regarding the design of RCTs in amyotrophic lateral sclerosis (ALS). Methods: Authors performed a scoping review of the literature around clinical meaningfulness in the ALS field and the minimum clinically important difference to deem a treatment effective. Results: The use of survival as an RCT endpoint, as well as the ALS functional rating scale-revised slope, has been criticized, and their relevance for patients remains debated. Biomarkers are promising alternatives as surrogate endpoints, but currently, only cerebrospinal fluid and plasma neurofilaments have emerged as reliable and sensitive biomarkers of disease progression. Incorporating patients' preferences and priorities for their care when treatments are selected is important to minimize the burden of care and limit the potential harms of overtreatment. Patients' interest in and acceptance of a new therapy is also determined by its impact on their quality of life. Discussion and conclusion: While scientifically sound trials must be conducted, this must be balanced with patient expectations of limiting trial burden, duration and placebo usage. An important approach in uniting these diverging needs is the inclusion of people with ALS and their organizations to advise in the design and execution of clinical trials, facilitating the design of RCTs more focused on patients' expectations while retaining a high scientific rigor.}, } @article {pmid40069809, year = {2025}, author = {Jonsdottir, G and Vilhjalmsson, R and Sigurdardottir, V and Hjaltason, H and Klinke, ME and Jonsdottir, H}, title = {Nursing contribution to end-of-life care decision-making in patients with neurological diseases on an acute hospital ward: documentation of signs and symptoms.}, journal = {BMC nursing}, volume = {24}, number = {1}, pages = {271}, pmid = {40069809}, issn = {1472-6955}, support = {71545//Icelandic Nurses Association/ ; }, abstract = {BACKGROUND: Recognizing impending death in patients with neurological diseases presents challenges for nurses and other healthcare professionals. This study aimed to identify nursing contribution to end-of-life (EOL) care decision-making for patients with neurological diseases in an acute hospital ward and to compare signs and symptoms among subgroups of patients.

METHODS: In this retrospective study, we analyzed data from 209 patient health records using the Neurological End-Of-Life Care Assessment Tool to evaluate the care in the last 3 to 7 days of life. Key aspects included the need for EOL care, EOL care decision-making, signs and symptoms of imminent death, and communication with relatives. The patient records pertain to patients who died in an acute neurological ward between January 2011 and August 2020; 123 with ischemic stroke, 48 with hemorrhagic stroke, 27 with amyotrophic lateral sclerosis [ALS], and 11 with Parkinson's disease or extrapyramidal and movement disorders [PDoed]. Both descriptive and inferential statistical analyses were performed to analyze the data.

RESULTS: Nurses identified the need for EOL care in 36% of cases and contributed to EOL decision-making as information brokers (15%), advocates (6%), and supporters (6%). They identified disease progression in 44% of the cases. The mean number of signs and symptoms in both the acute and progressive disease groups was 6.5 and ranged from 1 to 14. Patients with stroke without a documented EOL decision had more severe symptoms, including respiratory congestion (68%) and dyspnea (37%), than those with EOL decision. A higher frequency of no food intake was documented in patients with stroke receiving EOL care (p = 0.007) compared to those without. Among patients with ALS or PDoed, those with EOL decision showed a trend toward a higher frequency of unconsciousness or limited consciousness than those without EOL decision (p = 0.067). For all groups of patients, conversations with relatives occurred in 85% instances and family meetings in 93%.

CONCLUSIONS: Nurses made substantial contributions to EOL care decision-making for patients with neurological diseases. To improve early identification of imminent death in patients with neurological diseases in acute hospital wards, healthcare professionals must investigate barriers contributing to delayed recognition.

CLINICAL TRIAL NUMBER: Not applicable.}, } @article {pmid40069360, year = {2025}, author = {Cheng, M and Lu, D and Li, K and Wang, Y and Tong, X and Qi, X and Yan, C and Ji, K and Wang, J and Wang, W and Lv, H and Zhang, X and Kong, W and Zhang, J and Ma, J and Li, K and Wang, Y and Feng, J and Wei, P and Li, Q and Shen, C and Fu, XD and Ma, Y and Zhang, X}, title = {Mitochondrial respiratory complex IV deficiency recapitulates amyotrophic lateral sclerosis.}, journal = {Nature neuroscience}, volume = {28}, number = {4}, pages = {748-756}, pmid = {40069360}, issn = {1546-1726}, support = {2019YFA0508701//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; 2022YFA1303300//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Animals ; Rats ; Motor Neurons/metabolism/pathology ; *Electron Transport Complex IV/genetics ; *Mitochondria/metabolism/genetics ; Humans ; Disease Models, Animal ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is categorized into ~10% familial and ~90% sporadic cases. While familial ALS is caused by mutations in many genes of diverse functions, the underlying pathogenic mechanisms of ALS, especially in sporadic ALS (sALS), are largely unknown. Notably, about half of the cases with sALS showed defects in mitochondrial respiratory complex IV (CIV). To determine the causal role of this defect in ALS, we used transcription activator-like effector-based mitochondrial genome editing to introduce mutations in CIV subunits in rat neurons. Our results demonstrate that neuronal CIV deficiency is sufficient to cause a number of ALS-like phenotypes, including cytosolic TAR DNA-binding protein 43 redistribution, selective motor neuron loss and paralysis. These results highlight CIV deficiency as a potential cause of sALS and shed light on the specific vulnerability of motor neurons, marking an important advance in understanding and therapeutic development of sALS.}, } @article {pmid40067829, year = {2025}, author = {O'Neill, K and Shaw, R and Bolger, I and , and Tam, OH and Phatnani, H and Gale Hammell, M}, title = {ALS molecular subtypes are a combination of cellular and pathological features learned by deep multiomics classifiers.}, journal = {Cell reports}, volume = {44}, number = {3}, pages = {115402}, doi = {10.1016/j.celrep.2025.115402}, pmid = {40067829}, issn = {2211-1247}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/classification ; Humans ; Neuroglia/pathology/metabolism ; Transcriptome/genetics ; Spinal Cord/pathology/metabolism ; Neurons/metabolism/pathology ; Deep Learning ; Microglia/pathology/metabolism ; Male ; DNA-Binding Proteins/metabolism/genetics ; Oxidative Stress ; Female ; Multiomics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex syndrome with multiple genetic causes and wide variation in disease presentation. Despite this heterogeneity, large-scale genomics studies revealed that ALS postmortem samples can be grouped into a small number of subtypes, defined by transcriptomic signatures of mitochondrial dysfunction and oxidative stress (ALS-Ox), microglial activation and neuroinflammation (ALS-Glia), or TDP-43 pathology and associated transposable elements (ALS-TE). In this study, we present a deep ALS neural net classifier (DANCer) for ALS molecular subtypes. Applying DANCer to an expanded cohort from the NYGC ALS Consortium highlights two subtypes that strongly correlate with disease duration: ALS-TE in cortex and ALS-Glia in spinal cord. Finally, single-nucleus transcriptomes demonstrate that ALS subtypes are recapitulated in neurons and glia, with both ALS-wide and subtype-specific alterations in all cell types. In summary, ALS molecular subtypes represent a combination of cellular and pathological features that correlate with clinical features of ALS.}, } @article {pmid40067821, year = {2025}, author = {, and Berry, JD and Maragakis, NJ and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Stommel, EW and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, A and Shefner, J and Hall, M and Kittle, G and Babu, S and Andrews, J and D'Agostino, D and Tustison, E and Scirocco, E and Giacomelli, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Ajroud-Driss, S and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, KJ and Simmons, Z and Miller, T and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, L and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, C and Ladha, S and Heiman-Patterson, T and Caress, J and Swenson, A and Peltier, A and Lewis, R and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, CE and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Glass, J and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Rynders, A and Evan, J and Evan, J and Hartford, A and Sepassi, M and Ho, KS and Glanzman, R and Greenberg, B and Hotchkin, MT and Paganoni, S and Cudkowicz, ME and , }, title = {CNM-Au8 in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.}, journal = {JAMA}, volume = {333}, number = {13}, pages = {1138-1149}, pmid = {40067821}, issn = {1538-3598}, abstract = {IMPORTANCE: Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD+, resulting in an increase of cellular adenosine triphosphate production.

OBJECTIVE: To determine the effects of CNM-Au8 on ALS disease progression.

CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses.

INTERVENTIONS: Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation.

RESULTS: Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]).

CONCLUSIONS AND RELEVANCE: No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks.

TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04414345.}, } @article {pmid40067755, year = {2025}, author = {, and Shefner, JM and Oskarsson, B and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Heiman-Patterson, T and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, AV and Hall, M and Kittle, G and Berry, JD and Babu, S and Andrews, J and D'Agostino, D and Tustison, E and Scirocco, E and Giacomelli, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Ajroud-Driss, S and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, K and Maragakis, NJ and Simmons, Z and Miller, TM and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, LA and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, CE and Ladha, S and Caress, JB and Swenson, A and Peltier, A and Lewis, RA and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, C and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Leitner, ML and Chen, K and Goldberg, YP and Cohen, Y and Geva, M and Hayden, MR and Paganoni, S and Cudkowicz, ME and , }, title = {Pridopidine in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.}, journal = {JAMA}, volume = {333}, number = {13}, pages = {1128-1137}, pmid = {40067755}, issn = {1538-3598}, abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.

OBJECTIVE: To determine the effects of pridopidine, a σ1-receptor agonist, in ALS.

Pridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.

INTERVENTIONS: Eligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.

RESULTS: Among 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR <1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).

CONCLUSIONS AND RELEVANCE: In this 24-week study, pridopidine did not impact the progression of ALS.

TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04615923.}, } @article {pmid40067754, year = {2025}, author = {, and Andrews, J and Paganoni, S and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Young, E and Chase, M and Pothier, L and Harkey, B and Yu, H and Sherman, A and Shefner, J and Hall, M and Kittle, G and Connolly, MR and Berry, JD and D'Agostino, D and Tustison, E and Giacomelli, E and Scirocco, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Heitzman, D and Ajroud-Driss, S and Appel, SH and Shroff, S and Katz, J and Felice, K and Maragakis, NJ and Simmons, Z and Goutman, SA and Olney, N and Miller, T and Fernandes, JA and Ilieva, H and Jawdat, O and Weiss, MD and Foster, L and Vu, T and Ladha, S and Owegi, MA and Newman, DS and Arcila-Londono, X and Jackson, CE and Swenson, A and Heiman-Patterson, T and Caress, J and Fee, D and Peltier, A and Lewis, R and Rosenfeld, J and Walk, D and Johnson, K and Elliott, M and Kasarskis, EJ and Rutkove, S and McIlduff, CE and Bedlack, R and Elman, L and Goyal, NA and Rezania, K and Twydell, P and Benatar, M and Glass, J and Cohen, JA and Jones, V and Zilliox, L and Wymer, JP and Beydoun, SR and Shah, J and Pattee, GL and Martinez-Thompson, J and Nayar, S and Granit, V and Donohue, M and Grossman, K and Campbell, DJ and Qureshi, IA and Cudkowicz, ME and Babu, S and , }, title = {Verdiperstat in Amyotrophic Lateral Sclerosis: Results From the Randomized HEALEY ALS Platform Trial.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {40067754}, issn = {2168-6157}, abstract = {IMPORTANCE: Myeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.

OBJECTIVE: To determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.

Verdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.

INTERVENTIONS: Eligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale-Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.

RESULTS: A total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, -23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.

CONCLUSIONS AND RELEVANCE: Results demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.

TRIAL REGISTRATION: Clinical Trial Identifiers: NCT04297683 and NCT04436510.}, } @article {pmid40066150, year = {2025}, author = {Stains, EL and Kennalley, AL and Tian, M and Boehnke, KF and Kraus, CK and Piper, BJ}, title = {Medical Cannabis in the United States: Comparing 2017 and 2024 State Qualifying Conditions to the 2017 National Academies of Sciences Report.}, journal = {Mayo Clinic proceedings. Innovations, quality & outcomes}, volume = {9}, number = {2}, pages = {100590}, pmid = {40066150}, issn = {2542-4548}, abstract = {OBJECTIVE: To compare the 2017 National Academies of Sciences, Engineering, and Medicine cannabis report to state medical cannabis (MC) laws defining approved qualifying conditions (QC) from 2017 and 2024 and to determine the evidence level of the QCs approved in each state.

PATIENTS AND METHODS: The 2017 National Academies of Sciences (NAS) report assessed therapeutic evidence for over 20 medical conditions treated with MC. We identified the QCs of 38 states (including Washington DC) where MC was legal in 2024 and compared them to the QCs listed by these states in 2017. The QCs were then categorized on the basis of NAS-established levels of evidence: limited, moderate, or substantial/conclusive evidence of effectiveness, limited evidence of ineffectiveness, or no/insufficient evidence to support or refute effectiveness. This study was completed from January 31, 2023 to June 20, 2024.

RESULTS: Most states listed at least one QC with substantial evidence-80.0% in 2017 and 97.0% in 2024. However, in 2024 only 8.3% of the QCs on states' QC lists met the standard of substantial/conclusive evidence. Of the 20 most popular QCs in the country in 2017 and 2024, one only (long-term pain) was categorized by the NAS as having substantial evidence for effectiveness. However, 7 were rated as either ineffective (eg, glaucoma) or insufficient evidence.

CONCLUSION: Most QCs lack evidence for use on the basis of the 2017 NAS report. Many states recommend QCs with little evidence (amyotrophic lateral sclerosis) or even those for which MC is ineffective (depression). These findings highlight a disparity between state-level MC recommendations and the evidence to support them.}, } @article {pmid40065593, year = {2025}, author = {Chen, S and Carter, D and Prier, J and Bingham, J and Patel, S and Kotay, M and Brockenbrough, PB and Gwathmey, K}, title = {Racial Disparities in ALS Progression: Time to Clinical Events Observed in a Single Center.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28390}, pmid = {40065593}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Studies examining racial differences in ALS have previously focused on diagnostic delay and disease severity. Time to critical clinical events has rarely been investigated, despite its importance in revealing differences in ALS patients' disease courses. This study explores racial disparities in time to specific clinical events in Black and non-Hispanic White ALS patients at a single center.

METHODS: We performed a retrospective analysis of 33 Black and 170 non-Hispanic White ALS patients examined at Virginia Commonwealth University between 2017 and 2023. Diagnosis dates, referral dates for wheelchair, noninvasive ventilation (NIV), augmentative and alternative communication (AAC) and hospice, along with demographic and clinical factors, were collected. We analyzed the racial difference for events occurring before or on the day of diagnosis using logistic regression models, and for events occurring after diagnosis using Cox proportional hazard models, adjusting for relevant demographic and clinical factors.

RESULTS: Black patients had significantly higher odds of acquiring a wheelchair (odds ratio = 4.06, p = 0.015) and NIV before diagnosis (odds ratio = 2.93, p = 0.017). Following diagnosis, Black patients had 1.72 times the hazards for wheelchair referral (p = 0.051), 2.17 times the hazard for NIV referral (p < 0.001), 1.84 times the hazard for AAC referral (p = 0.034), and 1.59 times the hazard for hospice referral (p = 0.24).

DISCUSSION: Our single-center findings demonstrate a large racial difference in time to clinical events for Black versus White ALS patients referred for NIV, AAC, hospice, and wheelchair, suggesting more advanced disease at the time of presentation or more rapid progression.}, } @article {pmid40065553, year = {2025}, author = {Boddy, SL and Simpson, RM and Walters, SJ and Walsh, T and McDermott, CJ and , and , }, title = {Further development of a patient-reported outcome measure to assess the impact of oral secretion problems in people living with MND.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2025.2469721}, pmid = {40065553}, issn = {2167-9223}, abstract = {Objective: Oral secretion problems are common yet poorly managed in people living with MND (plwMND). A validated patient-reported outcome for measuring saliva symptoms in this patient group would facilitate better monitoring of individuals. This study aimed to assess the validity, reliability and sensitivity to change of a revised version of the clinical saliva score for MND (CSS-MNDr). Methods: Data were collected as part of a longitudinal, observational saliva management study. The CSS-MNDr, ALS Functional Rating Scale, a Global Rating of Change questionnaire and saliva-specific modified Likert scale were completed at each study visit, each of which probed the severity of saliva symptoms. Construct validity, test-retest reliability and sensitivity of the CSS-MNDr were assessed and the minimal important difference of the instrument was estimated. Results: The CSS-MNDr showed excellent test-retest reliability (intraclass correlation coefficient >0.9). Construct validity showed the CSS-MNDr performed as expected, with bulbar-onset participants scoring significantly higher than those who reported limb-onset across all visits (group mean scores). Strong correlation of total scores with the ALSFRS-R saliva question was demonstrated (-0.8), with the thick subscore correlating less well (-0.5). A minimal important difference in the range of -2.5 to -3.6 over 3 months was estimated for worsening symptoms. Conclusions: The CSS-MNDr has been validated as a reliable patient reported outcome for measuring saliva problems in plwMND. With separate scores for thick and thin secretion problems, the CSS-MNDr is the most comprehensive tool for assessing salivary problems in plwMND reported to date.}, } @article {pmid40065552, year = {2025}, author = {Shibata, N and Kataoka, I and Okamura, Y and Murakami, K and Kato, Y and Yamamoto, T and Masui, K}, title = {Implications for soluble iron accumulation, oxidative stress, and glial glutamate release in motor neuron death associated with sporadic amyotrophic lateral sclerosis.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {}, number = {}, pages = {}, doi = {10.1111/neup.13033}, pmid = {40065552}, issn = {1440-1789}, abstract = {Oxidative stress in sporadic amyotrophic lateral sclerosis (ALS) has been evidenced by accumulation of oxidatively modified products of nucleic acids, lipids, sugars, and proteins in the motor neuron system of brains and spinal cords obtained at autopsy from the patients. We recently demonstrated soluble iron accumulation in activated microglia of sporadic ALS spinal cords. This finding could indicate that iron-mediated Fenton reaction is most likely to be responsible for oxidative stress associated with this disease. The excitatory amino acid neurotoxicity hypothesis for sporadic ALS has been proposed based on increased glutamate and aspartate concentrations in cerebrospinal fluid from the patients. Initially, the increase in extracellular excitatory amino acid levels was considered to reflect excessive release from the axon terminal of upper motor neurons. However, it is a question of whether the damaged upper motor neurons continue releasing glutamate even in advanced stage of this disease. To address this issue, we hypothesized that glial cells might be a glutamate release source. Our immunohistochemical analysis on autopsied human spinal cords revealed that ferritin, hepcidin, ferroportin, aconitase 1, tumor necrosis factor-α (TNF-α), TNF-α-converting enzyme (TACE), and glutaminase-C (GAC) were expressed mainly in microglia and that cystine/glutamate antiporter (xCT) was expressed mainly in astrocytes. We next performed cell culture experiments. Cultured microglia treated with soluble iron over-released glutamate and TNF-α via aconitase 1 and TACE, respectively. Cultured microglia treated with TNF-α over-released glutamate via GAC. Cultured microglia treated with hepcidin, of which expression is known to be upregulated by TNF-α, showed downregulated expression of ferroportin. Cultured astrocytes treated with hydrogen peroxide over-released glutamate via xCT. These observations provide in vivo and in vitro evidence that microglia and astrocytes are glutamate suppliers in response to soluble iron overload and oxidative stress, respectively, in sporadic ALS.}, } @article {pmid40064496, year = {2025}, author = {Su, Y and Yang, F and Xie, JC and Zhang, C and Luo, RX and Li, WS and Liu, BL and Su, MZ}, title = {Electroacupuncture Neural Stimulation Mitigates Bladder Dysfunction and Mechanical Allodynia in Cyclophosphamide Induced Cystitis through Downregulation of the BDNF-TrkB Signaling Pathway.}, journal = {eNeuro}, volume = {12}, number = {3}, pages = {}, pmid = {40064496}, issn = {2373-2822}, abstract = {Central sensitization plays a critical role in bladder pain syndrome/interstitial cystitis (BPS/IC). Electroacupuncture (EA) nerve stimulation therapy has been broadly acknowledged as an effective means of alleviating chronic pathological pain. However, it remains to be explored whether EA is effective in mitigating pain-sensitive symptoms of BPS/IC and the mechanisms involved. This study aims to investigate the analgesic effect and mechanism of EA therapy. To achieve this goal, we employed several techniques: mechanical pain threshold tests to assess pain sensitivity, urodynamic studies to evaluate bladder function, Western blotting (WB) for protein analysis, immunofluorescence for visualizing, and transcriptomics. A rat cystitis model was established through a systemic intraperitoneal injection with cyclophosphamide (CYP). EA therapy was executed by stimulating the deep part of the hypochondriac point, where the 2nd-4th sacral nerves traverse. EA treatment was observed to effectively reduce mechanical allodynia, enhance urinary function, suppress the activation of microglial cells, and alleviate neuroinflammation. Additionally, EA demonstrated the capability to downregulate BDNF-TrkB signal transduction in the spinal dorsal horn. Transcriptome sequencing has indicated that EA therapy potentially inhibits excitatory neural transmission and modulates several pathways related to longevity. Furthermore, EA therapy has shown efficacy in treating conditions such as Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. In conclusion, by regulating the BDNF-TrkB signaling, EA nerve stimulation can effectively alleviate bladder dysfunction and mechanical allodynia in cyclophosphamide-induced cystitis model. Our research elucidates the underlying mechanisms of EA therapy in treating bladder dysfunction and offers new theoretical insights for addressing painful sensitization in BPS.Significance Statement Central sensitization is a major factor in bladder pain syndrome/interstitial cystitis (BPS/IC), making effective pain management crucial. This study explores the potential of electroacupuncture (EA) as a therapeutic approach to alleviate pain and improve bladder function in a rat model of BPS/IC induced by cyclophosphamide. Our findings demonstrate that EA therapy significantly reduces mechanical allodynia, enhances urinary function, and decreases neuroinflammation by modulating BDNF-TrkB signaling in the spinal dorsal horn. The research highlights EA's capability to inhibit excitatory neural transmission and provide relief in chronic pain conditions. These results offer new insights into the mechanisms of EA therapy, potentially improving treatment strategies for BPS/IC and similar pain syndromes.}, } @article {pmid40064491, year = {2025}, author = {Izumi, Y and Nakayama, Y}, title = {[Communicating the Diagnosis of Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {3}, pages = {259-263}, doi = {10.11477/mf.188160960770030259}, pmid = {40064491}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; *Communication ; Patient Care Team ; }, abstract = {When explaining amyotrophic lateral sclerosis, family members, caregivers, and other professionals are encouraged to be present with the patient's consent. Patients' perceptions vary considerably depending on their condition, personality, and home environment; therefore, the content of the explanation should be carefully considered. If the patient did not fully understand or provide consent to participate, the explanation was repeated. Depending on the patient's level of understanding and acceptance, we provided step-by-step explanations. The patients were informed that the decision could change later, even after the treatment plan had been decided. In explanations involving a multidisciplinary team, each professional explains; however, it is also important for the team leader to understand the patient's perceptions.}, } @article {pmid40063887, year = {2025}, author = {Hayden, CD and Murphy, BP and Gilsenan, D and Nasseroleslami, B and Hardiman, O and Murray, D}, title = {Clinical validation of a novel hand dexterity measurement device.}, journal = {PLOS digital health}, volume = {4}, number = {3}, pages = {e0000744}, pmid = {40063887}, issn = {2767-3170}, abstract = {The lack of sensitive objective outcome measures for hand dexterity is a barrier for clinical assessment of neurological conditions and has negatively affected clinical trials. Here, we clinically validate a new method for measuring hand dexterity, a novel hand worn sensor that digitises the Finger Tapping Test. The device was assessed in a cohort of 180 healthy controls and 51 people with Amyotrophic Lateral Sclerosis (ALS) and compared against rating scales and traditional measures (Nine Hole Peg test and grip dynamometry). 14 features were extracted from the device and using a logistic regression algorithm, a 0-100 dexterity performance score was generated for each participant, which accounted for age/sex differences. The device returned objective ratings of a participant's hand dexterity (dominant, non-dominant and overall score). The average overall dexterity performance score in all healthy participants was 88 ± 17 (mean ± standard deviation). The overall dexterity score was statistically significantly worse in participants with ALS (age/sex matched healthy subset: 80 ± 20, ALS: 45 ± 32, p-value < 0.0001). The device also had a higher completion rate, (94% dominant hand) compared to the traditional measures (82% dominant hand). This test and scoring system have been validated and the regression model was developed using a framework that is potentially applicable to any relevant condition. This device could act as an objective outcome measure in clinical trials and may be useful in improving patient care.}, } @article {pmid40063831, year = {2025}, author = {Kubinski, S and Claus, L and Schüning, T and Zeug, A and Kalmbach, N and Staege, S and Gschwendtberger, T and Petri, S and Wegner, F and Claus, P and Hensel, N}, title = {Aggregates associated with amyotrophic lateral sclerosis sequester the actin-binding protein profilin 2.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddaf020}, pmid = {40063831}, issn = {1460-2083}, support = {ZE994//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of upper and lower motoneurons. The four most frequently mutated genes causing familial ALS (fALS) are C9orf72, FUS, SOD1, and TARDBP. Some of the related wild-type proteins comprise intrinsically disordered regions (IDRs) which favor their assembly in liquid droplets-the biophysical mechanism behind the formation of physiological granules such as stress granules (SGs). SGs assemble and dissolve dependent on the cellular condition. However, it has been suggested that transition from reversible SGs to irreversible aggregates contributes to the toxic properties of ALS-related mutated proteins. Sequestration of additional proteins within these aggregates may then result in downstream toxicity. While the exact downstream mechanisms remain elusive, rare ALS-causing mutations in the actin binding protein profilin 1 suggest an involvement of the actin cytoskeleton. Here, we hypothesize that profilin isoforms become sequestered in aggregates of ALS-associated proteins which induce subsequent dysregulation of the actin cytoskeleton. Interestingly, localization of neuronal profilin 2 in SGs was more pronounced compared with the ubiquitously expressed profilin 1. Accordingly, FUS and C9orf72 aggregates prominently sequestered profilin 2 but not profilin 1. Moreover, we observed a distinct sequestration of profilin 2 and G-actin to C9orf72 aggregates in different cellular models. On the functional level, we identified dysregulated actin dynamics in cells with profilin 2-sequestering aggregates. In summary, our results suggest a more common involvement of profilins in ALS pathomechanisms than indicated from the rarely occurring profilin mutations.}, } @article {pmid40061974, year = {2025}, author = {Zhang, ZN and Hao, L and Han, S and Li, SS and Lin, SX and Miao, YD}, title = {Harnessing the prognostic power of preoperative systemic immune-inflammation index/albumin ratio in hepatocellular carcinoma resection.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {2}, pages = {102261}, pmid = {40061974}, issn = {1948-9366}, abstract = {The recent study by Chen et al, published in the World Journal of Gastroenterology, introduces a groundbreaking assessment tool-the preoperative systemic immune-inflammation index/albumin (SII/ALB) ratio-for patients with hepatocellular carcinoma (HCC) undergoing curative resection. This study not only establishes the independent prognostic significance of the SII/ALB ratio but also incorporates it into a predictive nomogram, enhancing its utility for clinical decision-making. The SII/ALB ratio, by integrating inflammatory and nutritional biomarkers, offers a novel lens through which the prognosis of HCC patients can be viewed, suggesting a more tailored approach to patient management. The development of the nomogram, validated for its accuracy in predicting patient outcomes, marks a pivotal advance, potentially guiding surgical decisions and postoperative care. However, the study's focus on a single-center cohort prompts the need for validation in a broader, more diverse patient population to ensure its applicability across various clinical settings. Moreover, longitudinal studies could elucidate the dynamic changes in SII/ALB post-surgery, offering insights into its potential as a continuous monitor for recurrence and long-term survival. This abstract aim to underscore the critical findings of Chen et al's study while calling for further research to explore the full potential of the SII/ALB ratio in the global management of hepatocellular carcinoma.}, } @article {pmid40061972, year = {2025}, author = {Yi, XM and Cai, HQ and Jiao, Y}, title = {Programmed cell death receptor 1 inhibitor Pembrolizumab in the treatment of advanced gastric cancer.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {2}, pages = {100257}, pmid = {40061972}, issn = {1948-9366}, abstract = {This editorial discusses Christodoulidis et al's article, which appeared in the most recent edition. The clinical trials have demonstrated the programmed cell death receptor 1 (PD-1) inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer (AGC). Pembrolizumab combined with chemotherapy can enhance its sensitivity, and further eliminate tumor cells that develop resistance to chemotherapy. The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis. The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy, and the safety is controllable. PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.}, } @article {pmid40061966, year = {2025}, author = {Wang, H and Jiao, Y and Ma, Q and Liu, YH}, title = {Overview of endoscopic biliary stenting in malignant obstructive jaundice.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {2}, pages = {103378}, pmid = {40061966}, issn = {1948-9366}, abstract = {This article discusses Wang et al's essay. Endoscopic biliary stenting, a less invasive alternative to surgery, is effective for malignant obstructive jaundice. This article summarizes the pathophysiology of biliary obstruction, the technical aspects of stenting, and the clinical outcomes. By comparison of endoscopic stenting with percutaneous biliary drainage, improvements and complications are focused on. Additionally, patient selection for stenting and future advancements in stent technology are important. Overall, endoscopic biliary stenting is a valuable palliative option for patients with malignant jaundice, especially those ineligibles for surgery.}, } @article {pmid40060668, year = {2025}, author = {Axakova, A and Ding, M and Cote, AG and Subramaniam, R and Senguttuvan, V and Zhang, H and Weile, J and Douville, SV and Gebbia, M and Al-Chalabi, A and Wahl, A and Reuter, J and Hurt, J and Mitchell, A and Fradette, S and Andersen, PM and van Loggerenberg, W and Roth, FP}, title = {Landscapes of missense variant impact for human superoxide dismutase 1.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40060668}, issn = {2692-8205}, support = {RM1 HG010461/HG/NHGRI NIH HHS/United States ; UM1 HG011989/HG/NHGRI NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease for which important subtypes are caused by variation in the Superoxide Dismutase 1 gene SOD1. Diagnosis based on SOD1 sequencing can not only be definitive but also indicate specific therapies available for SOD1-associated ALS (SOD1-ALS). Unfortunately, SOD1-ALS diagnosis is limited by the fact that a substantial fraction (currently 26%) of ClinVar SOD1 missense variants are classified as "variants of uncertain significance" (VUS). Although functional assays can provide strong evidence for clinical variant interpretation, SOD1 assay validation is challenging, given the current incomplete and controversial understanding of SOD1-ALS disease mechanism. Using saturation mutagenesis and multiplexed cell-based assays, we measured the functional impact of over two thousand SOD1 amino acid substitutions on both enzymatic function and protein abundance. The resulting 'missense variant effect maps' not only reflect prior biochemical knowledge of SOD1 but also provide sequence-structure-function insights. Importantly, our variant abundance assay can discriminate pathogenic missense variation and provides new evidence for 41% of missense variants that had been previously reported as VUS, offering the potential to identify additional patients who would benefit from therapy approved for SOD1-ALS.}, } @article {pmid40060539, year = {2025}, author = {Petrescu, J and Roque, CG and Jackson, CA and Daly, A and Kang, K and Casel, O and Leung, M and Reilly, L and Eschbach, J and McDade, K and Gregory, JM and Smith, C and Phatnani, H}, title = {Differential Cellular Mechanisms Underlie Language and Executive Decline in Amyotrophic Lateral Sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.02.26.640433}, pmid = {40060539}, issn = {2692-8205}, abstract = {Half of all amyotrophic lateral sclerosis (ALS) patients demonstrate a spectrum of cognitive and behavioral changes over the course of the disease, but the mechanisms underlying this heterogeneity remain unclear. We assemble a high-resolution cellular map of prefrontal cortex regions of the ALS brain by integrating spatial and single-nucleus transcriptomic profiles of a cognitively stratified ALS patient cohort that includes non-neuropathological controls. We find cellular programs characteristic of ALS, including a frequent gliotic response. We also find that executive and language cognitive impairments differ from ALS without cognitive impairment, and from each other, in the extent and pattern of neuronal dysregulation and neuron-glial interactions across different brain regions. These findings reveal a relationship between cognitive phenotype and prefrontal cortex dysfunction in ALS.}, } @article {pmid40060442, year = {2025}, author = {Deng, X and Bradshaw, G and Kalocsay, M and Mitchison, T}, title = {Tubulin Regulates the Stability and Localization of STMN2 by Binding Preferentially to Its Soluble Form.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40060442}, issn = {2692-8205}, support = {R35 GM131753/GM/NIGMS NIH HHS/United States ; }, abstract = {Loss of the tubulin-binding protein STMN2 is implicated in amyotrophic lateral sclerosis (ALS) but how it protects neurons is not known. STMN2 is known to turn over rapidly and accumulate at axotomy sites. We confirmed fast turnover of STMN2 in U2OS cells and iPSC-derived neurons and showed that degradation occurs mainly by the ubiquitin-proteasome system. The membrane targeting N-terminal domain of STMN2 promoted fast turnover, whereas its tubulin binding stathmin-like domain (SLD) promoted stabilization. Proximity labeling and imaging showed that STMN2 localizes to trans-Golgi network membranes and that tubulin binding reduces this localization. Pull-down assays showed that tubulin prefers to bind to soluble over membrane-bound STMN2. Our data suggest that STMN2 interconverts between a soluble form that is rapidly degraded unless bound to tubulin and a membrane-bound form that does not bind tubulin. We propose that STMN2 is sequestered and stabilized by tubulin binding, while its neuroprotective function depends on an unknown molecular activity of its membrane-bound form.}, } @article {pmid40060160, year = {2025}, author = {Mangalindan, KE and Wyatt, TR and Brown, KR and Shapiro, M and Maggio, LA}, title = {Investigating the Road to Equity: A Scoping Review of Solutions to Mitigate Implicit Bias in Assessment within Medical Education.}, journal = {Perspectives on medical education}, volume = {14}, number = {1}, pages = {92-106}, pmid = {40060160}, issn = {2212-277X}, mesh = {Humans ; *Education, Medical/methods ; Bias ; Educational Measurement/methods ; }, abstract = {INTRODUCTION: In medical education, assessments have high-stakes implications. Yet, assessments are rife with unconscious bias, which contributes to inequitable social structures. Implicit bias in assessment must be addressed because medical educators use assessments to guide learning and promote development of physicians' careers. In this scoping review, the authors map the literature on implicit bias in assessment, as it applies to: 1) the types of implicit bias addressed, 2) the targets and types of interventions studied or proposed, and 3) how publications describe intervention efficacy.

METHODS: The authors conducted a scoping review of the literature on interventions to mitigate implicit bias that was published between January 2010 and August 2023. Author pairs independently screened articles for inclusion and extracted data. Discrepancies were resolved with discussion and consensus. Qualitative and quantitative analysis was informed by Anderson et al's three assessment orientations: fairness, assessment for inclusion (AfI), and justice.

RESULTS: 7,831 articles were identified; 54 articles were included. The majority (n = 37; 69%) of articles focus on implicit bias toward those underrepresented in medicine. Interventions to mitigate implicit bias were targeted toward admissions and applications, faculty training, recruitment, summative assessments, and evaluation templates. Interventions had fairness (n = 43; 96%) and AfI (n = 22; 49%) orientations; no articles used a justice-orientation. For the sub-set of research studies (n = 40), almost all (n = 34; 85%) examined a single program/institution.

DISCUSSION: This scoping review showed that more work is necessary to address different types of implicit biases, move scholarship beyond single-institution studies, refine existing interventions, and evaluate how efficacy is defined.}, } @article {pmid40059194, year = {2025}, author = {Shang, Q and Zhou, J and Ye, J and Chen, M}, title = {Adverse events reporting of edaravone: a real-world analysis from FAERS database.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {8148}, pmid = {40059194}, issn = {2045-2322}, mesh = {*Edaravone/adverse effects/therapeutic use ; Humans ; *Adverse Drug Reaction Reporting Systems ; *Databases, Factual ; United States ; United States Food and Drug Administration ; Amyotrophic Lateral Sclerosis/drug therapy ; Bayes Theorem ; Drug-Related Side Effects and Adverse Reactions ; Female ; Male ; }, abstract = {For individuals with amyotrophic lateral sclerosis (ALS), intravenous edaravone is approved as a disease-modifying medication; yet, there have been many reports of adverse events (AEs). We examined the AEs associated with edaravone in this study using actual data from the FDA's (Food and Drug Administration) adverse event reporting system (FAERS). By extracting large-scale data from the FAERS database, this study used the signals of edaravone-associated AEs were quantified using the multiitem gamma Poisson shrinker (MGPS) method based on disproportionality, the Bayesian confidence propagation neural network (BCPNN), the reporting odds ratio (ROR), and the proportional reporting ratio (PRR). In the FAERS database, this study extracted data between April 2017 and March 2024, and edaravone was identified as the "primary suspect (PS)" in 2,986 AE reports. AEs associated with edaravone specifically targeted 27 system organ types (SOCs). Unexpectedly serious AEs that weren't mentioned in the drug insert, include abnormal hepatic function, catheter site thrombosis, pain, cerebral hemorrhage, infection, cerebral infarction, poor venous access, disseminated intravascular coagulation, vein collapse and cerebral venous sinus thrombosis. Our research found possible signals of new AEs that may offer substantial backing for clinical surveillance and edaravone risk assessment, but further research and validation are needed, especially for those AE that may occur in actual usage scenarios but are not yet explicitly described in the instruction.}, } @article {pmid40030015, year = {2025}, author = {Johnson, EA and Nowar, R and Viola, KL and Huang, W and Zhou, S and Bicca, MA and Zhu, W and Kranz, DL and Klein, WL and Silverman, RB}, title = {Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {10}, pages = {e2402117122}, pmid = {40030015}, issn = {1091-6490}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; R56 AG050492/AG/NIA NIH HHS/United States ; AG061708//HHS | National Institutes of Health (NIH)/ ; AG050492//HHS | National Institutes of Health (NIH)/ ; }, mesh = {*Amyloid beta-Peptides/metabolism ; Animals ; Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; Neurons/metabolism/drug effects ; Mice ; Hippocampus/metabolism/pathology ; Alzheimer Disease/metabolism/drug therapy/pathology ; Lysosomes/metabolism ; Protein Aggregation, Pathological/metabolism/drug therapy ; Autophagy/drug effects ; }, abstract = {Protein aggregation is a hallmark of neurodegenerative diseases, which connects these neuropathologies by a common phenotype. Various proteins and peptides form aggregates that are poorly degraded, and their ensuing pathological accumulation underlies these neurodegenerative diseases. Similarities may exist in the mechanisms responsible for the buildup of these aggregates. Therefore, therapeutics designed to treat one neurodegenerative disease may be beneficial to others. In ALS models, the compound NU-9 was previously shown to block neurodegeneration produced by aggregation-inducing mutations of SOD-1 and TDP-43 [B. Genç et al., Clin. Transl. Med. 11, e336 (2021)]. Here, we report that NU-9 also prevents the accumulation of amyloid beta oligomers (AβOs), small peptide aggregates that are instigators of Alzheimer's disease neurodegeneration [M. Tolar et al., Int. J. Mol. Sci. 22, 6355 (2021)]. AβO buildup was measured by immunofluorescence imaging of cultured hippocampal neurons exposed to exogenous monomeric Aβ. In this model, AβO buildup occurs via cathepsin L- and dynamin-dependent trafficking. This is prevented by NU-9 through a cellular mechanism that is cathepsin B- and lysosome-dependent, suggesting that NU-9 enhances the ability of endolysosomal trafficking to protect against AβO buildup. This possibility is strongly supported by a quantitative assay for autophagosomes that shows robust stimulation by NU-9. These results contribute additional understanding to the mechanisms of protein aggregation and suggest that multiple neurodegenerative diseases might be treatable by targeting common pathogenic mechanisms responsible for protein aggregation.}, } @article {pmid40057796, year = {2025}, author = {Mitra, J and Kodavati, M and Dharmalingam, P and Guerrero, EN and Rao, KS and Garruto, RM and Hegde, ML}, title = {Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {54}, pmid = {40057796}, issn = {2051-5960}, support = {R03AG064266/AG/NIA NIH HHS/United States ; R03AG064266/AG/NIA NIH HHS/United States ; RF1NS112719/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; *Disease Models, Animal ; *DNA Repair ; *Gene Knock-In Techniques ; *Cellular Senescence/physiology ; Motor Neurons/metabolism/pathology ; Mice, Transgenic ; Inflammation/metabolism/pathology/genetics ; DNA Ligase ATP/metabolism/genetics ; }, abstract = {TDP-43 mislocalization and aggregation are key pathological features of amyotrophic lateral sclerosis (ALS)- and frontotemporal dementia (FTD). However, existing transgenic hTDP-43 WT or ∆NLS-overexpression animal models primarily focus on late-stage TDP-43 proteinopathy. To complement these models and to study the early-stage motor neuron-specific pathology during pre-symptomatic phases of disease progression, we generated a new endogenous knock-in (KI) mouse model using a combination of CRISPR/Cas9 and FLEX Cre-switch strategy for the conditional expression of a mislocalized Tdp-43∆NLS variant of mouse Tdp-43. This variant is expressed either in the whole body (WB) or specifically in the motor neurons (MNs) in two distinct models. These mice exhibit loss of nuclear Tdp-43, with concomitant cytosolic accumulation and aggregation in targeted cells, leading to increased DNA double-strand breaks (DSBs), signs of inflammation, and associated cellular senescence. Notably, unlike WT Tdp-43, which functionally interacts with Xrcc4 and DNA Ligase 4, the key DSB repair proteins in the non-homologous end-joining (NHEJ) pathway, the Tdp-43∆NLS mutant sequesters them into cytosolic aggregates, exacerbating neuronal damage in mouse brain. The mutant mice also exhibit myogenic degeneration in hindlimb soleus muscles and distinct motor deficits, consistent with the characteristics of motor neuron disease (MND). Our findings reveal progressive degenerative mechanisms in motor neurons expressing endogenous Tdp-43∆NLS mutant, independent of Tdp-43 overexpression or other confounding factors. Thus, this unique Tdp-43 KI mouse model, which displays key molecular and phenotypic features of Tdp-43 proteinopathy, offers a significant opportunity to characterize the early-stage progression of MND further and also opens avenues for developing DNA repair-targeted approaches for treating TDP-43 pathology-linked neurodegenerative diseases.}, } @article {pmid40057753, year = {2025}, author = {Sharbafshaaer, M and Siciliano, M and Passaniti, C and Sant'Elia, V and Silvestro, M and Russo, A and Esposito, S and Tedeschi, G and Trojano, L and Trojsi, F}, title = {Screening of visuospatial abilities in amyotrophic lateral sclerosis (ALS): a pilot study using the battery for visuospatial abilities (BVA).}, journal = {Orphanet journal of rare diseases}, volume = {20}, number = {1}, pages = {110}, pmid = {40057753}, issn = {1750-1172}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Pilot Projects ; Middle Aged ; Aged ; *Neuropsychological Tests ; Visual Perception/physiology ; }, abstract = {BACKGROUND: Cognitive deficits related to frontotemporal dysfunction are common in Amyotrophic Lateral Sclerosis (ALS). Visuospatial deficits, related to posterior cerebral regions, are often underestimated in ALS, though they play a crucial role in attending daily living activities. Our pilot study aims at assessing visuospatial abilities using a domain-specific tool in ALS patients compared to healthy controls (HC).

METHODS: Twenty-three patients with early ALS and 23 age- and education-matched HC underwent the Battery for Visuospatial Abilities (BVA), including 4 visuo-perceptual and 4 visuo-representational subtests.

RESULTS: When compared to HC, ALS scored worse in 2 visuo-perceptual subtests (i.e., Line Length Judgment and Line Orientation Judgment) and 1 visuo-representational tasks (i.e., Hidden Figure Identification, HFI) (p < 0.01). No correlations arose between ALS clinical features and BVA performance. More than 80% of the ALS cohort obtained abnormal scores in the HFI subtest.

CONCLUSIONS: Our findings revealed that patients with ALS scored worse (compared to HC) on selective tests tapping "perceptual" and "representational" visuospatial abilities, since the early stages of disease. In clinical practice, our findings highlight the need for multi-domain neuropsychological assessment, for monitoring disease courses and properly organizing care management of patients with ALS.}, } @article {pmid40057669, year = {2025}, author = {Hatcher, H and Stankeviciute, S and Learn, C and Qu, AX}, title = {Regulatory, Translational, and Operational Considerations for the Incorporation of Biomarkers in Drug Development.}, journal = {Therapeutic innovation & regulatory science}, volume = {}, number = {}, pages = {}, pmid = {40057669}, issn = {2168-4804}, abstract = {BACKGROUND: Biomarkers are an integral component in the drug development paradigm. According to the US Food and Drug Administration (FDA), a biomarker is "a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic intervention" (FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring (MD): Food and Drug Administration (US); 2016-. Glossary. 2016 [Updated 2021 Nov 29, cited 2024 Apr 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK338448/ Co-published by National Institutes of Health (US), Bethesda (MD)). The European Medicines Agency (EMA) defines a biomarker as "an objective and quantifiable measure of a physiological process, pathological process or response to a treatment (excluding measurements of how an individual feels or functions" European Medicines Agency (EMA). Biomaker. 2020a. Available from: https://www.ema.europa.eu/en/glossary-terms/biomarker#:~:text=Biomarker-,Biomarker,an%20individual%20feels%20or%20functions . Several clinical biomarkers are well-documented and have been used routinely for decades in health care settings and have long been accepted as valid endpoints for drug approval (for example, blood pressure measurement as a biomarker for cardiovascular health) (European Medicines Agency (EMA). Assessment report, TAGRISSO. 2016. Available from: https://www.ema.europa.eu/en/documents/assessment-report/tagrisso-epar-public-assessment-report_en.pdf . Accessed 15 Apr 2024). Recently, novel biomarkers have been identified and validated to accelerate developing innovative therapies indicated for serious human diseases, for example targeted/immune therapies of cancer (Chen in Med Drug Discov 21:100174, 2024). As indicators of the efficacy of new pharmacological treatments or therapeutic interventions, biomarkers can improve clinical trial efficacy and reduce uncertainty in regulatory decision making (Bakker et al. in Clin Pharmacol Ther 112:69-80, 2022; Califf in Exp Biol Med 243:213-221, 2018; Parker et al. in Cancer Med 10:1955-1963, 2021).

METHODOLOGY: This article describes case studies of recent drug approvals that successfully leveraged validated and non-validated biomarkers (i.e., tofersen for the neurodegenerative disease amyotrophic lateral sclerosis (ALS) in adults; and osimertinib for treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC)).

CONCLUSIONS: Best practices for biomarker selection and strategies for health authority biomarker qualification programs are presented along with an overview of current limitations and challenges to optimizing biomarker applications along the drug development continuum from regulatory, translational, and operational perspectives.}, } @article {pmid40056685, year = {2025}, author = {Jakhar, M and Barone, V}, title = {Single atom catalysts adsorbed on reduced monolayers for enhanced kinetics in Al-S batteries.}, journal = {Journal of colloid and interface science}, volume = {689}, number = {}, pages = {137226}, doi = {10.1016/j.jcis.2025.03.015}, pmid = {40056685}, issn = {1095-7103}, abstract = {Rechargeable aluminum-sulfur (Al-S) batteries have attracted significant attention as potential next-generation energy storage devices due to their safety, the natural abundance of the elemental components, and high theoretical energy density. However, their utilization is hindered by sluggish reaction kinetics and poor reversibility. Introducing single-atom catalysts (SACs) can promote redox processes at the cathode and help in mitigating the shuttle effect of Al polysulfides (Al2Sx). While the electrochemical, thermodynamic, and thermal stabilities of SACs (Co, Fe, Ir, Ni, Pt, and Rh) have been explored in previous studies, this work focuses on their potential role in enhancing reaction kinetics in Al-S batteries. Our calculations indicate that SACs-based substrates exhibit more robust binding energies for capturing Al2Sx than the bare surfaces. Additionally, SACs lower the free energies associated with the rate-determining step during discharging and exhibit lower decomposition barriers during charging. Moreover, the interaction of soluble Al2Sx with the electrolyte reveals that SAC supported polysulfides are less likely to dissolve in the electrolyte than their pristine counterparts. The analysis of the underlying mechanisms of the interaction of molecules and the Co@ substrate reveals the ability of this substrate to accommodate large volume changes and support a sulfur loading up to 53.37 wt% during the charging and discharging cycles, without causing fractures. The mechanism driving this enhanced performance is extensively investigated through charge transfer, bond strength, and d-band center analyses. Our findings present an effective strategy for designing SACs substrates to improve the electrochemical performance of Al-S cathodes.}, } @article {pmid40056552, year = {2025}, author = {Newell, ME and Babbrah, A and Aravindan, A and Kulkarni, S and Ellershaw, A and Dupati, A and Rathnam, R and Shaffer, G and Estrada, L and Curtis, C and Leneaux, J and Driver, EM and Halden, RU}, title = {Wastewater-borne markers of neurodegenerative disease: β-methylamino-L-alanine and aminomethylphosphonic acid.}, journal = {The Science of the total environment}, volume = {970}, number = {}, pages = {179032}, doi = {10.1016/j.scitotenv.2025.179032}, pmid = {40056552}, issn = {1879-1026}, mesh = {*Wastewater/chemistry ; *Amino Acids, Diamino/analysis ; *Biomarkers/analysis ; *Water Pollutants, Chemical/analysis ; *Neurodegenerative Diseases/epidemiology ; Cyanobacteria Toxins ; Glycine/analogs & derivatives/analysis ; Organophosphonates/analysis ; Tandem Mass Spectrometry ; Humans ; Environmental Monitoring ; Chromatography, Liquid ; Glyphosate ; }, abstract = {Exposure to toxic organic chemicals such as β-methylamino-L-alanine (BMAA) and glyphosate has been associated with neurodegenerative diseases (NDDs), including amyotrophic lateral sclerosis (ALS), Parkinson's Disease (PD), and Alzheimer's Disease (AD). We explored the utility of BMAA and glyphosate's metabolite aminomethylphosphonic acid (AMPA) for serving as potential markers of NDDs by comparing levels of wastewater-borne BMAA and AMPA with regional U.S. rates of NDD prevalence. Newly developed liquid chromatography tandem mass spectrometry (LC-MS/MS) methods were applied to U.S. wastewater samples (n = 87) and resultant concentrations of putative biomarkers were statistically compared to NDD prevalence rates in conjunction with environmental data on algal blooms and agricultural glyphosate use. Locations of algal blooms were found to be significantly associated (p = 0.01) with ALS prevalence rates per 100,000 people. BMAA levels in wastewater were highly correlated (p < 0.0001) with ALS prevalence rates by region. BMAA in wastewater typically peaked in summer months. We conclude that NDD biomarker detection in wastewater holds potential value, with BMAA outperforming AMPA. Furthermore, prevalence data for NDDs may have to be reported to the Centers for Disease Control and Prevention at a higher geospatial resolution to further enhance the value for the present type of analysis. Further method development is needed for AMPA to be quantified using LC-MS/MS. Future method developments focusing on metabolites (e.g., AMPA) may enable epidemiologists to determine human exposure levels rather than the mere occurrence of toxic organic chemicals in the environment.}, } @article {pmid40056503, year = {2025}, author = {Zhan, A and Zhong, K and Zhang, K}, title = {Novel subcellular regulatory mechanisms of protein homeostasis and its implications in amyotrophic lateral sclerosis.}, journal = {Biochemical and biophysical research communications}, volume = {756}, number = {}, pages = {151582}, doi = {10.1016/j.bbrc.2025.151582}, pmid = {40056503}, issn = {1090-2104}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Proteostasis ; Animals ; Mitochondria/metabolism ; Protein Aggregates ; Homeostasis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disorder. Protein aggregates induce various forms of neuronal dysfunction and represent pathological hallmarks in ALS patients. Reducing protein aggregates could be a promising therapeutic strategy for ALS. While most studies have focused on cytoplasmic protein homeostasis, neurons adaptively reduce aggregates across subcellular compartments during stress through previously uncharacterized mechanisms. Here, we summarize novel compartment-specific proteostatic mechanisms: (1) the ERAD/RESET pathways, (2) HSPs-mediated nuclear sequestration, (3) mitochondrial aggregate import (MAGIC), (4) neurite-localized UPS/autophagosome and NMP, and (5) exopher-mediated extracellular disposal. These mechanisms collectively ensure cellular stress adaptation and provide novel therapeutic targets for ALS treatment.}, } @article {pmid40056413, year = {2025}, author = {Kahn, OI and Dominguez, SL and Glock, C and Hayne, M and Vito, S and Sengupta Ghosh, A and Adrian, M and Burgess, BL and Meilandt, WJ and Friedman, BA and Hoogenraad, CC}, title = {Secreted neurofilament light chain after neuronal damage induces myeloid cell activation and neuroinflammation.}, journal = {Cell reports}, volume = {44}, number = {3}, pages = {115382}, doi = {10.1016/j.celrep.2025.115382}, pmid = {40056413}, issn = {2211-1247}, mesh = {Animals ; *Neurofilament Proteins/metabolism ; *Neurons/metabolism/pathology ; Mice ; *Myeloid Cells/metabolism ; *Mice, Knockout ; Microglia/metabolism/pathology ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; Neuroinflammatory Diseases/metabolism/pathology ; Mice, Inbred C57BL ; Humans ; Hippocampus/metabolism/pathology ; Disease Models, Animal ; Macrophages/metabolism ; Calpain/metabolism ; }, abstract = {Neurofilament light chain (NfL) is a neuron-specific cytoskeletal protein that provides structural support for axons and is released into the extracellular space following neuronal injury. While NfL has been extensively studied as a disease biomarker, the underlying release mechanisms and role in neurodegeneration remain poorly understood. Here, we find that neurons secrete low baseline levels of NfL, while neuronal damage triggers calpain-driven proteolysis and release of fragmented NfL. Secreted NfL activates microglial cells, which can be blocked with anti-NfL antibodies. We utilize in vivo single-cell RNA sequencing to profile brain cells after injection of recombinant NfL into the mouse hippocampus and find robust macrophage and microglial responses. Consistently, NfL knockout mice ameliorate microgliosis and delay symptom onset in the SOD1 mouse model of amyotrophic lateral sclerosis (ALS). Our results show that released NfL can activate myeloid cells in the brain and is, thus, a potential therapeutic target for neurodegenerative diseases.}, } @article {pmid40056296, year = {2025}, author = {Li, Z and Fan, J and Gong, Z and Tang, J and Yang, Y and Liu, M and Zhang, M}, title = {Association between cardiac autonomic dysfunction, cognitive impairment, and survival in patients with amyotrophic lateral sclerosis.}, journal = {Clinical autonomic research : official journal of the Clinical Autonomic Research Society}, volume = {}, number = {}, pages = {}, pmid = {40056296}, issn = {1619-1560}, support = {82271478//the National Natural Science Foundation of China/ ; 2024AOXIANG05//the Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital/ ; }, abstract = {PURPOSE: The aim of this study was to investigate the relationship between cardiac autonomic dysfunction, cognitive impairment, and survival in patients with amyotrophic lateral sclerosis (ALS).

METHODS: The heart activity of 65 patients with ALS (28 with normal cognition [ALS-CN]; 37 with impaired cognition [ALS-CI]) and 38 healthy controls (HCs) was measured by 24-h Holter monitoring. Heart rate (HR) measures and heart rate variability (HRV) parameters were compared between the three study groups and, additionally, correlated with five Edinburgh Cognitive and Behavioral ALS Screen (ECAS) domains in the ALS subgroups. Age, gender, and educational level were adjusted. Factors associated with cognitive status were assessed using logistic regression. Survival predictors in patients with ALS were analyzed using the Kaplan-Meier estimator and Cox regression.

RESULTS: Compared to the HCs, patients with ALS-CI exhibited lower RRI (R-R-interval; P = 0.017), SDNN (standard deviation of all normal RR intervals; P = 0.013), SDNN Index (P = 0.044), and VLF power (very low-frequency power; P = 0.012). Total power was reduced in the ALS-CI group compared to the HCs (P = 0.036) and ALS-CN group (P = 0.048). In patients with ALS-CN, language negatively correlated with mean HR (P = 0.001) and positively with the RRI (P = 0.003), SDNN (P = 0.001), SDANN (standard deviation of the average NN intervals; P = 0.005), total power (P = 0.006), VLF power (P = 0.011), and low-frequency power (P = 0.026). Visuospatial function correlated positively with the SDNN Index (P = 0.041). In patients with ALS-CI, executive function (P = 0.015) and ECAS total score (P = 0.009) negatively correlated with the RMSSD (square root of mean sum-of-squares of differences between adjacent NN intervals), while visuospatial function correlated positively with normalized LF value (LFnu; P = 0.049). No associations were observed between the other cognitive domains and any of the 14 HRV/HR measures in patients with either ALS-CI or ALS-CN. SDNN ≤ 100 ms was linked to cognitive impairment (P = 0.039) and also showed a borderline association (P = 0.066) with poorer survival, while cognitive impairment (P = 0.010) was significantly linked to worse outcomes.

CONCLUSIONS: Patients with ALS with cognitive impairment demonstrated reduced cardiac autonomic modulations and altered cognitive autonomic associations. Cognitive impairment was linked to reduced survival, with baseline SDNN ≤ 100 ms identified as a potential marker.}, } @article {pmid40056187, year = {2025}, author = {Wiesenfarth, M and Forouhideh-Wiesenfarth, Y and Elmas, Z and Parlak, Ö and Weiland, U and Herrmann, C and Schuster, J and Freischmidt, A and Müller, K and Siebert, R and Günther, K and Fröhlich, E and Knehr, A and Simak, T and Bachhuber, F and Regensburger, M and Petri, S and Klopstock, T and Reilich, P and Schöberl, F and Schumann, P and Körtvélyessy, P and Meyer, T and Ruf, WP and Witzel, S and Tumani, H and Brenner, D and Dorst, J and Ludolph, AC}, title = {Correction: Clinical characterization of common pathogenic variants of SOD1-ALS in Germany.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {259}, doi = {10.1007/s00415-025-12952-1}, pmid = {40056187}, issn = {1432-1459}, } @article {pmid40055545, year = {2025}, author = {Giblin, A and Cammack, AJ and Blomberg, N and Anoar, S and Mikheenko, A and Carcolé, M and Atilano, ML and Hull, A and Shen, D and Wei, X and Coneys, R and Zhou, L and Mohammed, Y and Olivier-Jimenez, D and Wang, LY and Kinghorn, KJ and Niccoli, T and Coyne, AN and van der Kant, R and Lashley, T and Giera, M and Partridge, L and Isaacs, AM}, title = {Author Correction: Neuronal polyunsaturated fatty acids are protective in ALS/FTD.}, journal = {Nature neuroscience}, volume = {28}, number = {4}, pages = {913}, doi = {10.1038/s41593-025-01926-1}, pmid = {40055545}, issn = {1546-1726}, } @article {pmid40054065, year = {2025}, author = {Tserennadmid, B and Nam, MK and Park, JH and Rhim, H and Kang, S}, title = {HAP/ClpP-mediated disaggregation and degradation of Mutant SOD1 aggregates: A potential therapeutic strategy for Amyotrophic lateral sclerosis (ALS).}, journal = {Biochemical and biophysical research communications}, volume = {756}, number = {}, pages = {151533}, doi = {10.1016/j.bbrc.2025.151533}, pmid = {40054065}, issn = {1090-2104}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; Humans ; *Protein Aggregates ; *Proteolysis ; *Mutation ; Fluorescence Resonance Energy Transfer ; Heat-Shock Proteins/metabolism/genetics/chemistry ; Protein Folding ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by the accumulation of misfolded Cu/Zn superoxide dismutase (SOD1) protein aggregates in motor neurons, leading to progressive motor dysfunction and ultimately death. While the molecular chaperone heat shock protein 104 (Hsp104) has been shown to reduce protein misfolding by disaggregating protein aggregates, fully degrading these disaggregated proteins remains a significant challenge. In this study, we have investigated the effects of Hsp104 and its hyperactive variant, HAP, in combination with caseinolytic protease P (CIpP), on the disaggregation and degradation of SOD1 aggregates. Using laser confocal microscopy, fluorescence loss in photobleaching (FLIP), and biomolecular fluorescence complementation (BiFC)-fluorescence resonance energy transfer (FRET) assays, we demonstrate that Hsp104 effectively disaggregates SOD1 aggregates across 14 different G93 mutants, classified based on the properties of substituted amino acids, thus restoring protein mobility. Notably, the HAP/CIpP system not only disaggregates ALS-associated SOD1[G93A] aggregates but also promotes their proteolytic degradation, as evidenced by a significant reduction in high-order oligomers observed through BiFC and FRET assays. This dual mechanism of action presents. the HAP/CIpP system holds significant therapeutic potential for ALS and other neurodegenerative diseases characterized by protein aggregates, as it enables both effective disaggregation and degradation of toxic protein aggregates, thereby maintaining protein homeostasis.}, } @article {pmid40053600, year = {2025}, author = {Nie, Y and Szebényi, K and Wenger, LMD and Lakatos, A and Chinnery, PF}, title = {Origin and cell type specificity of mitochondrial DNA mutations in C9ORF72 ALS-FTLD human brain organoids.}, journal = {Science advances}, volume = {11}, number = {10}, pages = {eadr0690}, pmid = {40053600}, issn = {2375-2548}, mesh = {Humans ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *DNA, Mitochondrial/genetics ; *Organoids/metabolism/pathology ; *Mutation ; *Brain/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; Frontotemporal Lobar Degeneration/genetics/pathology/metabolism ; Astrocytes/metabolism/pathology ; Mitochondria/genetics/metabolism ; DNA Repeat Expansion/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are primarily genetic in ~20% of patients. Mutations in C9ORF72 are the most frequent cause, but it is not understood why there is notable regional pathology. An increased burden of mitochondrial DNA (mtDNA) mutations in ALS-FTLD brains implicates mitochondrial mechanisms; however, it remains unclear how and when these mutations arise. To address this, we generated cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) of patients with ALS-FTLD harboring the C9ORF72 hexanucleotide repeat expansion alongside CRISPR-corrected isogenic and healthy controls. Here, we show a higher mtDNA single-nucleotide variant (mtSNV) burden in astroglia derived from C9ORF72-mutant organoids, with some de novo mtSNVs likely due to the C9ORF72 repeat and others evading selection to reach higher heteroplasmy levels. Thus, the functional consequences of the regional accumulation of mtSNVs in C9ORF72 ALS-FTLD brains are likely to manifest through astroglial mitochondrial dysfunction.}, } @article {pmid40053462, year = {2025}, author = {Fazzini, L and Martis, A and Pateri, MI and Maccabeo, A and Borghero, G and Puligheddu, M and Montisci, R and Marchetti, MF}, title = {Long-term outcomes and worse clinical course in Takotsubo syndrome patients with amyotrophic lateral sclerosis.}, journal = {Journal of cardiovascular medicine (Hagerstown, Md.)}, volume = {26}, number = {4}, pages = {184-190}, doi = {10.2459/JCM.0000000000001711}, pmid = {40053462}, issn = {1558-2035}, mesh = {Humans ; *Takotsubo Cardiomyopathy/mortality/epidemiology/complications/physiopathology/diagnosis/therapy ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis/complications/epidemiology/therapy/physiopathology ; Female ; Male ; Aged ; Retrospective Studies ; Middle Aged ; Time Factors ; Prevalence ; Aged, 80 and over ; Hospital Mortality ; Risk Factors ; Prognosis ; Cause of Death ; Risk Assessment ; Respiration, Artificial/statistics & numerical data ; Shock, Cardiogenic/mortality/epidemiology/etiology/therapy/diagnosis ; }, abstract = {AIMS: Takotsubo syndrome (TTS) is usually triggered by either physical/psychological stressors or comorbidities, neurological among others. The prevalence of amyotrophic lateral sclerosis (ALS) among TTS and whether it has a worse clinical course is not known. We aim to describe ALS prevalence and its impact on clinical presentation, clinical course, and long-term mortality.

METHODS: We retrospectively screened the overall TTS population admitted and followed up at our institution between 2007 and 2020. Clinical, electrocardiographic, and echocardiographic data were collected. Kaplan-Meier method was applied for time-to-event analysis to assess the outcome of interest of all-cause death.

RESULTS: Eighty-five patients with TTS were included in our study. Overall, the mean age was 70 ± 12 years, 86% were females. Six patients (7% prevalence) were affected by ALS. At admission, patients with ALS were more likely to present left ventricular systolic dysfunction (P = 0.007). The clinical course of ALS patients was more likely complicated by cardiogenic shock (P = 0.003) which required catecholamines infusion (P = 0.001) and mechanical ventilation (P = 0.009). Despite similar in-hospital mortality rates, ALS patients exhibited significantly elevated all-cause mortality during a median 6-year follow-up (hazard ratio, 19.189, 95% confidence interval 5.639-65.296, log-rank test P < 0.001) with significantly shorter hospitalization to death time (P = 0.039).

CONCLUSIONS: Our findings highlight a notable prevalence of ALS among TTS patients, with worse clinical presentation and in-hospital course in ALS-affected individuals. While in-hospital mortality rates were comparable, highlighting the reversible nature of TTS in both groups, long-term follow-up revealed significantly heightened all-cause mortality in ALS patients, emphasizing the impact of ALS on patient prognosis.}, } @article {pmid40051750, year = {2025}, author = {Dib, A and Salem, J and Fares, M}, title = {Recurrent Spontaneous Pneumothorax in the Setting of Amyotrophic Lateral Sclerosis.}, journal = {European journal of case reports in internal medicine}, volume = {12}, number = {3}, pages = {005151}, pmid = {40051750}, issn = {2284-2594}, abstract = {UNLABELLED: Spontaneous pneumothorax (SP) occurrence in amyotrophic lateral sclerosis (ALS) patients is relatively rare and may thus be under-recognised. This latter is a progressive neurodegenerative disorder, leading to muscle weakness and such respiratory complications. This article reports a case manifesting such a rare association.

LEARNING POINTS: The presence of spontaneous pneumothorax in amyotrophic lateral sclerosis patients can exacerbate respiratory insufficiency, leading to acute respiratory failure.Given the under-recognition of this latter complication, clinicians should maintain a high index of suspicion, especially in patients with amyotrophic lateral sclerosis presenting with sudden onset of dyspnoea or chest pain.Early detection and appropriate management are crucial to prevent further respiratory compromise.}, } @article {pmid40051509, year = {2025}, author = {Syed, SA and Singh, J and Elkholy, H and Rojnić Palavra, I and Tomicevic, M and Eric, AP and Pinto da Costa, M and Guloksuz, S and Radhakrishnan, R}, title = {International perspectives on physician knowledge, attitudes, and practices related to medical cannabis.}, journal = {Frontiers in public health}, volume = {13}, number = {}, pages = {1463871}, pmid = {40051509}, issn = {2296-2565}, support = {UL1 TR001863/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Medical Marijuana/therapeutic use ; Female ; Cross-Sectional Studies ; Male ; Adult ; *Health Knowledge, Attitudes, Practice ; *Physicians/psychology/statistics & numerical data ; Surveys and Questionnaires ; *Attitude of Health Personnel ; Middle Aged ; Internationality ; Practice Patterns, Physicians'/statistics & numerical data ; }, abstract = {BACKGROUND: The trends of recreational use of cannabis and the use of cannabis for medical indications (i.e., "medical cannabis") have grown in recent years. Despite that, there is still limited scientific evidence to guide clinical decision-making, and the strength of evidence for the medical use of cannabis is currently considered to be low. In contrast, there is growing evidence of negative health outcomes related to the use of cannabis. In this rapidly shifting landscape, the role of physician attitudes regarding the therapeutic value of cannabis has become essential. This study aimed to characterize knowledge/experience, attitudes, and potential predictors of clinical practice regarding medical cannabis.

METHODS: We conducted a cross-sectional survey of physicians from 17 countries between 2016 and 2018. The survey consisted of questions designed to explore physician knowledge, attitude, and practices regarding the use of medical cannabis. Descriptive statistics were used to examine willingness to recommend medical cannabis for medical and psychiatric indications, followed by regression analysis to identify the predictors of physician willingness to recommend medical cannabis.

RESULTS: A total of 323 physicians responded to the survey, among which 53% were women. The mean age was 35.4 ± 9.5 years, with 10.04 ± 8.6 years of clinical experience. Clinical experience with medical cannabis was overall limited (51.4% noted never having recommended medical cannabis and 33% noted inadequate knowledge regarding medical cannabis). The majority of respondents (84%) recognized the risk of psychosis with cannabis use, while only 23% correctly identified the risk of addiction with daily cannabis use. Overall, willingness to recommend medical cannabis was the highest for chemotherapy-induced nausea (67%), refractory chronic neuropathic pain (52%), and spasticity in amyotrophic lateral sclerosis (ALS; 51%).

CONCLUSION: This international study examining physician knowledge, attitudes, and practices related to medical cannabis revealed that there are significant gaps in domain-specific knowledge related to medical cannabis. There is a wide variability in willingness to recommend medical cannabis, which is not consistent with the current strength of evidence. This study thus highlights the need for greater education related to domain-specific knowledge about medical cannabis.}, } @article {pmid40050936, year = {2025}, author = {Jeejan, J and Rao, L and Sadasivan, S and Lopes, R and Dsouza, N}, title = {Impact of cysteine mutations on the structural dynamics and functional impairment of SOD1: insights into the pathogenicity of amyotrophic lateral sclerosis.}, journal = {Genomics & informatics}, volume = {23}, number = {1}, pages = {7}, pmid = {40050936}, issn = {1598-866X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease prevalent in American and European populations, with its onset and progression significantly influenced by mutations in the superoxide dismutase 1 (SOD1) protein. While previous studies have highlighted the effects of mutations in the metal-binding region and catalytic region and dimerisation of SOD1, the impact of mutations involving the Cysteine residue at the N-terminal end remains unexplored. This study investigates the effects of Cysteine-to-Trp, Phe, Ser, and Gly mutations at the 6th position of SOD1's N-terminal end on its structural dynamics and functional impairment. Our computational analysis using PolyPhen-2, PROVEAN, Meta-SNP, and PhD-SNP predicted mutations to be deleterious, with their negative impacts likely contributing to disease development. Furthermore, stability studies and bonding pattern changes due to the mutations, analysed by mCSM, SDM, DUET, Dynamut2, and PremPS revealed changes in free energy and disruption in intramolecular interactions. The molecular dynamics studies revealed distinct changes in stability patterns among the mutations, particularly in Cys6Trp and Cys6Phe. All the mutations primarily altered the catalytic region of the protein; additionally, Cys6Phe and Cys6Gly caused disruption in the metal-binding region. The impact of mutations on the dimerisation of SOD1, analysed using MM/PBSA showed destabilisation due to Cys6Phe mutation. These findings provide molecular insights into the clinical symptoms observed in patients, highlighting the critical impact of the Cys6Phe mutation on the metal-binding and catalytic loops of SOD1 along with destabilisation of dimer formation. Overall, our analysis offers valuable insights into the molecular mechanisms driving structural changes in SOD1 due to mutations, contributing to a deeper understanding of their role in ALS pathogenicity.}, } @article {pmid40050651, year = {2025}, author = {Gregorio-Sanz, MÁ and Marzo-Campos, JC and Segura-Heras, JV}, title = {Effects of nursing music intervention on cardiovascular patients transferred in advanced life support ambulances.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {7919}, pmid = {40050651}, issn = {2045-2322}, support = {PROMETEO/2021/063//Generalitat Valenciana/ ; }, mesh = {Humans ; Male ; Female ; Aged ; *Ambulances ; *Music Therapy/methods ; *Cardiovascular Diseases/therapy/prevention & control ; Middle Aged ; Case-Control Studies ; Aged, 80 and over ; Advanced Cardiac Life Support/methods ; Blood Pressure ; }, abstract = {Patients with acute cardiovascular disease require out-of-hospital care during the most critical and vulnerable periods of their illness. This study aims to evaluate the influence of musical intervention in patients with acute cardiovascular disease during transfer in Advanced Life Support (ALS) ambulances using an analytical randomized controlled case-control experimental study conducted according to CONSORT guidelines. Forty-one subjects took part in the study. The patients required the administration of nitrates/antiarrhythmics (n = 11, 26.8%), (n = 5, 12.2%) antiemetics, and (n = 7, 17.1%) opioids. Statistically significant differences were found for blood pressure and the variable cardiovascular drugs between groups. The use of music therapy to complement other health measures in ALS ambulances lowers blood pressure values and reduces the need to administrate cardiovascular drugs, thus avoiding their possible side effects. It is easy to implement, has a low cost and should be monitored and controlled as a specific nursing intervention, included in the care of patients transferred by ambulances on a routine basis.}, } @article {pmid40050016, year = {2025}, author = {Martin, J and Johnson, R and Yemane, L and Unaka, N and Ebo, C and Hippolyte, J and Jones, M and Quinn, M and Barber, A and Floyd, B and Blankenburg, R and Hilgenberg, SL}, title = {Multi-institutional exploration of pediatric residents' perspectives on anti-racism curricula: a qualitative study.}, journal = {Medical education online}, volume = {30}, number = {1}, pages = {2474134}, pmid = {40050016}, issn = {1087-2981}, mesh = {Humans ; *Internship and Residency ; *Curriculum ; *Qualitative Research ; *Focus Groups ; *Pediatrics/education ; *Racism/psychology ; United States ; Male ; Female ; Attitude of Health Personnel ; Antiracism ; }, abstract = {BACKGROUND: Anti-racism curricula are increasingly being recognized as an integral component of medical education. To our knowledge, there has not yet been a publication exploring resident perspectives from multiple institutions and explicitly representing both underrepresented in medicine (UIM) and non-UIM perspectives.

OBJECTIVE: To explore and compare UIM and non-UIM pediatric residents' perspectives on the content and qualities of meaningful anti-racism curricula.

METHODS: We performed an IRB-approved multi-institutional, qualitative study that incorporated Sotto-Santiago et al's conceptual framework for anti-racism education. Between February and May 2021, we conducted focus groups of UIM and non-UIM pediatric residents at three large residency programs in the United States. We developed focus group guides using literature review, expert consensus, feedback from study team racial equity experts, and piloting. Focus groups were conducted virtually, audio-recorded, and transcribed verbatim. We employed thematic analysis to code transcripts, create categories, and develop themes until we reached thematic sufficiency. We completed member checking to ensure trustworthiness of themes.

RESULTS: Forty residents participated (19 UIM and 21 non-UIM) in a total of six focus groups. We identified 7 themes, summarized as: 1) racism in medicine is pervasive, therefore (2) anti-racism education is critical to the development of competent physicians, and 3) education should extend to all healthcare providers. 4) Residents desired education focused on action-oriented strategies to advance anti-racism, 5) taught by those with both learned and lived experiences with racism, 6) in a psychologically safe space for UIM residents, and 7) with adequate time and financial resources for successful implementation and engagement.

CONCLUSION: Our multi-institutional study affirms the need for pediatric resident anti-racism education, promotes co-creation as a method to affect culture change, and provides practical strategies for curricular design and implementation.}, } @article {pmid40050010, year = {2025}, author = {Sun, J and De Vocht, J and Stam, D and Lien, CH and Huang, YA and Lamaire, N and Laroy, M and Vansteelandt, K and D'Hondt, A and Van Den Bossche, MJA and Vandenberghe, R and Peeters, RR and Sunaert, S and van Damme, P and Vandenbulcke, M and Van den Stock, J}, title = {Neural correlates of memory deficits in premanifest C9orf72-repeat expansions.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-335169}, pmid = {40050010}, issn = {1468-330X}, abstract = {BACKGROUND: The premanifest stage in carriers of hexanucleotide repeat expansions in the C9orf72 gene (C9RE) is associated with memory impairment. The present study examines whether the impairment is general across domains or disproportionately affects specific stimulus categories such as socioemotional events, and its underlying functional neuroanatomy.

METHODS: This task-based fMRI-study included 21 premanifest C9RE (preC9RE) carriers and 24 controls. Participants encoded stimuli of (emotional and neutral) faces and houses, followed by a recognition task. Using univariate and multivoxel pattern analyses at whole-brain level and region-of-interest level, we investigated the neural change during encoding and retrieval processes, as well as the neural pattern similarity between encoding and retrieval.

RESULTS: Compared with controls, the preC9RE group demonstrated poorer performance in memorising faces (U=104, p=0.002), while their ability to memorise houses remained intact. The preC9RE group exhibited distinct neural patterns in the anterior insula during face encoding compared with the controls (accuracy>0.765, p<0.05). During face retrieval, the preC9RE group showed an increased neural response to encoded faces versus new faces in the right anterior insula (U=394, p=0.015). Individuals with preC9RE exhibited reduced encoding-retrieval neural similarity in the salience network specifically related to face stimuli (U=120, p=0.023).

CONCLUSIONS: The findings reveal functional changes in the salience network related to impaired social memory at the premanifest stage of C9RE. The findings further underscore the high potential of multidimensional neural response patterns as a sensitive biomarker for neurodegenerative functional changes, and the salience network as biomarker for C9RE disease staging.}, } @article {pmid40049531, year = {2025}, author = {Zhang, N and Dong, X}, title = {Causal relationship between gut microbiota, lipids, and neuropsychiatric disorders: A Mendelian randomization mediation study.}, journal = {Journal of affective disorders}, volume = {379}, number = {}, pages = {19-35}, doi = {10.1016/j.jad.2025.02.091}, pmid = {40049531}, issn = {1573-2517}, abstract = {BACKGROUND: Numerous studies have shown an interconnection between the gut microbiota and the brain via the "gut-brain" axis. However, the causal relationships between gut microbiota, lipids, and neuropsychiatric disorders remain unclear. This study aimed to analyze potential associations among gut microbiota, lipids, and neuropsychiatric disorders-including AD, PD, ALS, MS, SCZ, MDD, and BD-using summary data from large-scale GWAS.

METHODS: Bidirectional Mendelian randomization (MR) with inverse variance weighting (IVW) was the primary method. Supplementary analyses included sensitivity analyses, Steiger tests, and Bayesian weighted MR (BWMR). Mediation analyses used two-step MR (TSMR) and multivariable MR (MVMR).

RESULTS: The analyses revealed 51 positive correlations (risk factors) (β > 0, P < 0.05) and 47 negative correlations (protective factors) (β < 0, P < 0.05) between gut microbiota and neuropsychiatric disorders. In addition, 35 positive correlations (β > 0, P < 0.05) and 22 negative correlations (β < 0, P < 0.05) between lipids and neuropsychiatric disorders were observed. Assessment of reverse causality with the seven neuropsychiatric disorders as exposures and the identified gut microbiota and lipids as outcomes revealed no evidence of reverse causality (P > 0.05). Mediation analysis indicated that the effect of the species Bacteroides plebeius on MDD is partially mediated through the regulation of phosphatidylcholine (16:0_20:4) levels (mediation proportion = 10.9 % [95 % CI = 0.0110-0.2073]).

CONCLUSION: This study provides evidence of a causal relationship between gut microbiota and neuropsychiatric disorders, suggesting lipids as mediators. These findings offer new insights into the mechanisms by which gut microbiota may influence neuropsychiatric disorders.}, } @article {pmid40049292, year = {2025}, author = {Faure-de Baets, J and Besnard, J and Banville, F and Cassereau, J and Allain, P}, title = {Effects of virtual reality mindfulness on cognition and well-being in ALS: A randomized trial protocol.}, journal = {Contemporary clinical trials}, volume = {152}, number = {}, pages = {107876}, doi = {10.1016/j.cct.2025.107876}, pmid = {40049292}, issn = {1559-2030}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease primarily affecting motor neurons but also leading to significant non-motor symptoms, including cognitive impairments, anxiety, depression, and behavioral changes, which severely impact quality of life. While mindfulness-based interventions (MBIs) have shown promise in alleviating psychological distress, their accessibility is often limited due to patients' physical impairments. Virtual reality (VR) could enhance engagement and immersion, offering a novel, more inclusive therapeutic approach. This randomized controlled trial (RCT) aims to evaluate the efficacy of a VR-based MBI compared to traditional mindfulness for ALS patients. Forty-six participants will be randomly assigned to an eight-week mindfulness program delivered either via VR or in a conventional format. The primary outcome is quality of life, assessed using the ALS-Specific Quality of Life Scale (ALSSQOL-R). Secondary outcomes include cognitive function, anxiety, depression, behavioral changes, and mindfulness propensity, evaluated at baseline, post-intervention, and three-month follow-up. The study will also examine VR usability and potential accessibility challenges for ALS patients. By addressing a critical gap in non-pharmacological psychological care, this study will provide key insights into the feasibility and benefits of VR-based MBIs. If effective, VR mindfulness could offer an innovative, scalable solution to improve emotional well-being and quality of life in ALS, making psychological support more accessible for patients with severe physical limitations.}, } @article {pmid40049153, year = {2025}, author = {Cho, HW and Jung, S and Park, KH and Choi, JW and Heo, JS and Kim, J and Yun, H and Yu, D and Son, J and Choi, BM}, title = {Deep Learning-based Multi-class Classification for Neonatal Respiratory Diseases on Chest Radiographs in Neonatal Intensive Care Units.}, journal = {Neonatology}, volume = {}, number = {}, pages = {1-19}, doi = {10.1159/000545107}, pmid = {40049153}, issn = {1661-7819}, abstract = {Objective Accurate and timely interpretation of chest radiographs is essential for assessing respiratory distress and guiding clinical management to improve outcomes of critically ill newborns. This study aimed to introduce a deep learning-based automated algorithm designed to classify various neonatal respiratory diseases and healthy lungs using a large dataset of high-quality, multi-class labeled chest X-ray images from neonatal intensive care units (NICUs). Methods Portable supine chest X-ray images for six common conditions (healthy lung, respiratory distress syndrome (RDS), transient tachypnea of the newborn (TTN), air leak syndrome (ALS), atelectasis, and bronchopulmonary dysplasia (BPD)) and demographic variables (gestational age and birth weight) were retrospectively collected from 10 university hospitals in Korea. Ground truth for manual classification of these conditions was generated by 20 neonatologists and validated by others from different hospitals. The dataset, consisting 34,598 for training, 4,370 for validation, and 4,370 for testing, was used to train a modified ResNet50-based deep-learning model for automatic classification. Results The automatic classification algorithm showed high concordance with human-annotated classifications, achieving an overall testing accuracy of 83.96% and an F1-score of 83.68%. The F1-score for each condition was 87.38% for "healthy lung", and 92.19% for "BPD", 90.65% for "ALS", 90.30% for "RDS", 86.56% for "atelectasis", and 70.84% for "TTN". Conclusion We introduced a deep learning-based automated algorithm to classify neonatal respiratory diseases using a large dataset of high-quality, multi-class labeled chest X-ray images, incorporating non-imaging data, which could support neonatologists in making timely and accurate decisions for critically ill newborns.}, } @article {pmid40048825, year = {2025}, author = {Kacker, K and Chetty, N and Feldman, AK and Bennett, J and Yoo, PE and Fry, A and Lacomis, D and Harel, NY and Nogueira, RG and Majidi, S and Opie, NL and Collinger, JL and Oxley, TJ and Putrino, DF and Weber, DJ}, title = {Motor activity in gamma and high gamma bands recorded with a Stentrode from the human motor cortex in two people with ALS.}, journal = {Journal of neural engineering}, volume = {22}, number = {2}, pages = {}, pmid = {40048825}, issn = {1741-2552}, support = {UH3 NS120191/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Motor Cortex/physiopathology/physiology ; Male ; *Brain-Computer Interfaces ; *Gamma Rhythm/physiology ; *Electrocorticography/methods/instrumentation ; Middle Aged ; Female ; Stents ; Electrodes, Implanted ; Motor Activity/physiology ; Movement/physiology ; Aged ; }, abstract = {Objective.This study examined the strength and stability of motor signals in low gamma and high gamma bands of vascular electrocorticograms (vECoG) recorded with endovascular stent-electrode arrays (Stentrodes) implanted in the superior sagittal sinus of two participants with severe paralysis due to amyotrophic lateral sclerosis.Approach.vECoG signals were recorded from two participants in the COMMAND trial, an Early Feasibility Study of the Stentrode brain-computer interface (BCI) (NCT05035823). The participants performed attempted movements of their ankles or hands. The signals were band-pass filtered to isolate low gamma (30-70 Hz) and high gamma (70-200 Hz) components. The strength of vECoG motor activity was measured as signal-to-noise ratio (SNR) and the percentage change in signal amplitude between the rest and attempted movement epochs, which we termed depth of modulation (DoM). We trained and tested classifiers to evaluate the accuracy and stability of detecting motor intent.Main results.Both low gamma and high gamma were modulated during attempted movements. For Participant 1, the average DoM across channels and sessions was 125.41 ± 17.53% for low gamma and 54.23 ± 4.52% for high gamma, with corresponding SNR values of 6.75 ± 0.37 dB and 3.69 ± 0.28 dB. For Participant 2, the average DoM was 22.77 ± 4.09% for low gamma and 22.53 ± 2.04% for high gamma, with corresponding SNR values of 1.72 ± 0.25 dB and 1.73 ± 0.13 dB. vECoG amplitudes remained significantly different between rest and move periods over the 3 month testing period, with >90% accuracy in discriminating attempted movement from rest epochs for both participants. For Participant 1, the average DoM was strongest during attempted movements of both ankles, while for Participant 2, the DoM was greatest for attempted movement of the right hand. The overall classification accuracy was 91.43% for Participant 1 and 70.37% for Participant 2 in offline decoding of multiple attempted movements and rest conditions.Significance.By eliminating the need for open brain surgery, the Stentrode offers a promising BCI alternative, potentially enhancing access to BCIs for individuals with severe motor impairments. This study provides preliminary evidence that the Stentrode can detect discriminable signals indicating motor intent, with motor signal modulation observed over the 3 month testing period reported here.}, } @article {pmid40048117, year = {2025}, author = {Kwon, S and Kim, B and Han, KD and Jung, W and Cho, EB and Shin, DW and Min, JH}, title = {Increased risk of ischemic stroke in amyotrophic lateral sclerosis: a nationwide cohort study in South Korea.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {40048117}, issn = {1590-3478}, support = {HI20C1073//Ministry of Health and Welfare/ ; }, abstract = {BACKGROUND: We investigated the risk of ischemic stroke in ALS and analyzed the effect of ALS-related physical disability using the Korean National Health Insurance Service database.

METHODS: A total of 2,251 ALS patients diagnosed between January 1, 2012, and December 31, 2015, and 1:10 age- and sex-matched control populations were included. Cases that participated in the national health check-up programs were selected. A Cox hazard regression model was used to examine the hazard ratios (HRs) for ischemic stroke in ALS after adjusting for potential confounders.

RESULTS: A total of 681 ALS patients and 10,934 non-ALS participants were selected. ALS patients were slightly younger than the control group (60.3 ± 10.1 years vs. 61.0 ± 10.5 years, p = 0.105), and the proportion of male patients was similar between the two groups (61.6% vs. 60.9%, p = 0.722). ALS patients were more likely to have a lower body mass index (23.1 ± 2.92 vs. 24.0 ± 3.1, p < 0.001) and obstructive sleep apnea syndrome (0.59% vs. 0.06%, p < 0.001) than the controls. In ALS patients, the incidence rate of ischemic stroke was 6.32 per 1,000 person-years, and the adjusted HR of ischemic stroke was 2.58 (95% confidence interval 1.38 - 4.82) compared with the matched group. The risk of ischemic stroke did not differ by the presence of disability in ALS patients.

CONCLUSIONS: Our findings suggest that ALS patients have an increased risk of ischemic stroke compared with controls, but the risk did not differ by the presence of disability in ALS.}, } @article {pmid40047927, year = {2025}, author = {Ludolph, A and Klose, V and Dreyhaupt, J and Del Tredici, K and Braak, H}, title = {The deltoid muscle and the pattern of paresis in ALS.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {253}, pmid = {40047927}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; *Deltoid Muscle/physiopathology/pathology ; Male ; Female ; Middle Aged ; Aged ; *Paresis/etiology/physiopathology ; Adult ; Prospective Studies ; Muscle, Skeletal/physiopathology ; Pyramidal Tracts/physiopathology/pathology ; Electromyography ; Aged, 80 and over ; }, abstract = {There is neuroanatomical and clinical evidence that the corticospinal tract governs the patterns of pareses in sporadic ALS. These patterns are mirrored by phylogenetically young monosynaptic corticomotor neuronal connections. It is well known that, clinically, dysfunction of the deltoid muscle contributes considerably to the early disability of the ALS patient. In this study, we prospectively compared the degree of pareses of the deltoid muscle with the triceps and biceps brachii in N = 71 patients (426 muscles). We could show that the extent of involvement of the deltoid muscle early in the disease process resembles that of the biceps rather than the triceps brachii. This pattern is consistent with functional data of the corticospinal monosynaptic connectivity of all three muscles.}, } @article {pmid40047382, year = {2025}, author = {Murray, D and Rooney, J and Meldrum, D and Al-Chalabi, A and Bunte, TM and Chiwera, T and Choudhury, M and Chio, A and Fenton, L and Fortune, J and Maidment, L and Manera, U and McDermott, CJ and Meyjes, M and Tattersall, R and Torrieri, MC and Van Damme, P and Vanderlinden, E and Wood, C and Van Den Berg, LH and Hardiman, O}, title = {Respiratory measurements, respiratory symptoms, and quality of life in ALS: results from the REVEALS study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2025.2471421}, pmid = {40047382}, issn = {2167-9223}, abstract = {Objective: Progressing respiratory weakness throughout the course of amyotrophic lateral sclerosis (ALS) is clinically associated with distressing symptoms, including dyspnea, orthopnea, and difficulty clearing secretions. Fatigue, poor sleep, and reduced quality of life are also considered to be associated with declining respiratory function. Respiratory measurements guide prescription of interventions, which aim to alleviate symptoms. The relationships between respiratory measurements and patient reported symptoms are currently unclear. Method: The REVEALS study was a longitudinal, observational, multisite study of decline in respiratory function in people with ALS attending six European centers. Respiratory measures (forced and slow vital capacity (F/SVC), sniff nasal inspiratory pressure (SNIP), and peak cough flow) were collected, as were the presence of respiratory symptoms and simple quality of life, fatigue and sleep measures. We used Bayesian's multivariate models to explore the associations of the respiratory measures with outcome variables. Results: Two hundred and eighty participants completed in-person assessments over a median of 8 (IQR 2.3, 14.1) months, with 974 data collection timepoints. The probability of reporting symptoms including dyspnea, orthopnea, and difficulty clearing secretions increased with decreasing respiratory measurement scores. The probability of reporting moderately low quality of life and moderate fatigue also increased with decreasing test scores, but reported sleep quality was not associated with respiratory scores. Conclusion: Respiratory weakness in people with ALS was associated with symptoms including dyspnea, orthopnea, and difficulty clearing secretions. The probability of reporting symptoms increased incrementally as respiratory weakness increased, supporting the use of both respiratory measurements and the presence of symptoms in making decisions about clinical interventions.}, } @article {pmid40046336, year = {2025}, author = {Öztürk, MM and Emgård, J and García-Revilla, J and Fernández-Calle, R and Yang, Y and Deierborg, T and Roos, TT}, title = {The role of microglia in the prion-like transmission of protein aggregates in neurodegeneration.}, journal = {Brain communications}, volume = {7}, number = {2}, pages = {fcaf087}, pmid = {40046336}, issn = {2632-1297}, abstract = {Numerous neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis share a neuropathological hallmark: aberrant protein aggregation in the CNS. Microglia, the brain's innate immune cells, also play a pivotal role in the pathogenesis of these disorders. Multiple studies indicate that these pathological aggregates can propagate throughout the brain in a prion-like manner. A protein/peptide that adopts a prion-like conformation can induce homologous proteins to misfold into a prion-like conformation through templated seeding, enabling cell-to-cell spread and accelerating protein aggregation throughout the brain. Two important questions in the prion-like paradigm are where the prion-like misfolding occurs and how the prion-like aggregates are spread throughout the CNS. Here, we review the role of microglia and associated inflammation in the prion-like spread of pathologically aggregated proteins/peptides in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. A growing body of evidence suggests that microglia can internalize prion-like proteins and transport them to neighbouring neurons and other glial cells. Microglia may also influence the potential seeding of proteins in neurons and induce inflammatory pathways in their microenvironment. This review aims to broaden the understanding of the role of microglia in the prion-like spread of protein aggregation.}, } @article {pmid40045432, year = {2025}, author = {Blair, K and Martinez-Serra, R and Gosset, P and Martín-Guerrero, SM and Mórotz, GM and Atherton, J and Mitchell, JC and Markovinovic, A and Miller, CCJ}, title = {Structural and functional studies of the VAPB-PTPIP51 ER-mitochondria tethering proteins in neurodegenerative diseases.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {49}, pmid = {40045432}, issn = {2051-5960}, support = {MR/X021858/1//UK Research and Innovation/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Endoplasmic Reticulum/metabolism ; *Vesicular Transport Proteins/metabolism ; Animals ; *Mitochondria/metabolism ; Mitochondrial Proteins/metabolism ; Protein Tyrosine Phosphatases/metabolism ; }, abstract = {Signaling between the endoplasmic reticulum (ER) and mitochondria regulates many of the seemingly disparate physiological functions that are damaged in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). A number of studies have now demonstrated that ER-mitochondria signaling is perturbed in these diseases and there is evidence that this may be a driving mechanism in disease onset and progression. VAPB and PTPIP51 are ER-mitochondria tethering proteins; VAPB is an ER protein and PTPIP51 is an outer mitochondrial membrane protein and the two proteins interact to enable inter-organelle signaling. The VAPB-PTPIP51 interaction is disrupted in Alzheimer's disease, Parkinson's disease, FTD and ALS. Here we review the roles of VAPB and PTPIP51 in ER-mitochondria signaling and the mechanisms by which neurodegenerative disease insults may disrupt the VAPB-PTPIP51 interaction.}, } @article {pmid40044663, year = {2025}, author = {Abu-Rumeileh, S and Scholle, L and Mensch, A and Großkopf, H and Ratti, A and Kölsch, A and Stoltenburg-Didinger, G and Conrad, J and De Gobbi, A and Barba, L and Steinacker, P and Klafki, HW and Oeckl, P and Halbgebauer, S and Stapf, C and Posa, A and Kendzierski, T and Silani, V and Hausner, L and Ticozzi, N and Froelich, L and Weishaupt, JH and Verde, F and Otto, M}, title = {Phosphorylated tau 181 and 217 are elevated in serum and muscle of patients with amyotrophic lateral sclerosis.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {2019}, pmid = {40044663}, issn = {2041-1723}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/metabolism/pathology ; *tau Proteins/metabolism/blood ; Male ; Female ; Middle Aged ; Aged ; Phosphorylation ; *Biomarkers/blood ; *Alzheimer Disease/blood/metabolism/pathology/diagnosis ; Muscle, Skeletal/metabolism/pathology ; Case-Control Studies ; Biopsy ; Aged, 80 and over ; Adult ; Cohort Studies ; }, abstract = {Blood phosphorylated (p)-tau 181 and p-tau 217 have been proposed as accurate biomarkers of Alzheimer's disease (AD) pathology. However, blood p-tau 181 is also elevated in amyotrophic lateral sclerosis (ALS) without a clearly identified source. We measured serum p-tau 181 and p-tau 217 in a multicentre cohort of ALS (n = 152), AD (n = 111) cases and disease controls (n = 99) recruited from four different centres. Further, we investigated the existence of both p-tau species using immunohistochemistry (IHC) and mass spectrometry (MS) in muscle biopsies of ALS cases (IHC: n = 13, MS: n = 5) and disease controls (IHC: n = 14, MS: n = 5) from one cohort. Serum p-tau 181 and p-tau 217 were higher in AD and ALS patients compared to disease controls. IHC and MS analyses revealed the presence of p-tau 181 and 217 in muscle biopsies from both ALS cases and disease controls, with ALS samples showing increased p-tau reactivity in atrophic muscle fibres. Blood p-tau species could potentially be used to diagnose both ALS and AD.}, } @article {pmid40044193, year = {2025}, author = {Ross, WT and Buday, S and Yakel, E and Khabele, D and Balls-Berry, J and As-Sanie, S and Colditz, G and Baumann, AA}, title = {Does interdisciplinary group care for the treatment of endometriosis improve pain interference: protocol for a pilot randomised controlled trial at an urban academic medical centre.}, journal = {BMJ open}, volume = {15}, number = {3}, pages = {e097372}, pmid = {40044193}, issn = {2044-6055}, support = {K23 HD110710/HD/NICHD NIH HHS/United States ; KL2 TR002346/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; Female ; Pilot Projects ; *Endometriosis/complications/therapy ; *Quality of Life ; *Pelvic Pain/therapy/etiology ; Academic Medical Centers ; Pain Management/methods ; Adult ; Randomized Controlled Trials as Topic ; Patient Care Team/organization & administration ; Pain Measurement ; }, abstract = {INTRODUCTION: Endometriosis affects 10-15% of people assigned female at birth and can cause chronic pelvic pain and impair many domains of quality of life, such as fertility, mood and bladder, bowel and sexual function. Current treatments often fail, leading to recurrent pain and the need for reintervention. As endometriosis negatively affects many domains of life, a variety of non-pharmacological treatments modestly improve symptoms. To bundle these interventions into accessible packaging, our interdisciplinary team developed a novel endometriosis intervention titled 'Peer-Empowered Endometriosis Pain Support (PEEPS)', an 8-week integrative group care intervention. Here, we present the protocol for a pilot randomised controlled trial (RCT) to evaluate the effectiveness and implementation of PEEPS for people with endometriosis-associated pain refractory to surgical management. We hypothesise that patients who complete the PEEPS programme will show a greater decrease in pain interference in daily activities at intervention completion as compared with baseline than those in the education arm.

METHODS AND ANALYSIS: This is a hybrid type 1 effectiveness-implementation mixed-methods RCT in which 60 participants will be randomised using computer-generated random numbers stratified by group in the ratio 1:1 to PEEPS plus usual versus educational handout plus usual care. The primary outcome is change in pain interference from baseline to intervention completion. Secondary outcomes include change in pain interference from baseline to 6 months and 12 months postintervention, as well as change in other quality-of-life measures as measured by nine validated questionnaires from baseline to completion, 6 months and 12 months. Proctor et al's Implementation Outcomes Framework will be used to evaluate acceptability, appropriateness and feasibility of PEEPS implementation, and the Consolidated Framework for Implementation Research will be used to guide the evaluation of barriers and facilitators of PEEPS at the patient and provider levels. Primary data analyses will follow the intention-to-treat principle. Descriptive statistics and two-sample t-tests for normally distributed values and Wilcoxon Rank-Sum test were performed for non-normally distributed values. Frequency analysis and Fisher's exact or χ[2] tests will be used for categoric variables as appropriate. Longitudinal analysis of the primary and secondary outcomes will be conducted with a mixed-effects model to investigate the effect of PEEPS compared with education. Least square means (LSMs) and the corresponding 95% CIs at each timepoint, as well as LSM differences and 95% CIs between any post-baseline and baseline will be provided for the outcomes. ORs and 95% CIs will be calculated for categorical outcomes. Qualitative data will be collected in the form of open-ended feedback, focus groups with programme completers and semistructured interviews with participants who complete two or fewer sessions. The analysis will use an embedded design-experimental model in which quantitative and qualitative outcomes will occur concurrently with weight priority given to quantitative data.

ETHICS AND DISSEMINATION: This trial was approved by the Washington University in St. Louis Institutional Review Board (protocol 202402082) on 27 March 2024 and has low risk of harm to participants. All deidentified data from this project will be shared via Digital Commons@Becker. The findings of this study will be disseminated via scientific meetings and peer-reviewed journals. The results and conclusions will be summarised for patients and the public in common language using infographics to make the findings accessible. This pilot RCT will yield the effect size for PEEPS and generate implementation context and outcomes data to guide PEEPS application to real-world practice. If PEEPS proves to be effective, this study will inform adaptation and scaling to improve the lives of people with endometriosis through a non-hormonal, fertility-preserving approach.

TRIAL REGISTRATION NUMBER: ClinicalTrials.gov; NCT06549985.}, } @article {pmid40042459, year = {2025}, author = {Lee, SM and Yoon, SJ and Park, KW and Kim, A and Kim, HJ and Jung, NY and Jang, H and Seeley, WW and Kim, YE and Moon, SY and Kim, EJ and , }, title = {Semantic variant primary progressive aphasia with ANXA11 p.D40G.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {3}, pages = {e14566}, pmid = {40042459}, issn = {1552-5279}, support = {2021-ER1004-01//Korea National Institute of Health/ ; 2024-ER1001-00//Korea National Institute of Health/ ; RS-2024-00337993//Korea Dementia Research Project through the Korea Dementia Research Center, funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; }, mesh = {Humans ; *Aphasia, Primary Progressive/genetics/pathology ; Male ; Female ; Aged ; Middle Aged ; *Annexins/genetics ; *DNA-Binding Proteins/genetics ; Frontotemporal Dementia/genetics/pathology ; Republic of Korea ; Cohort Studies ; High-Throughput Nucleotide Sequencing ; }, abstract = {INTRODUCTION: Pathogenic variants of annexin A11 (ANXA11) have been identified in patients with amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). We explored ANXA11 pathogenic variants in a Korean FTD cohort to investigate the prevalence and the role of ANXA11 variation in FTD.

METHODS: We used next-generation sequencing (NGS) to search for pathogenic variants in ANXA11 in two nationwide FTD cohorts in Korea.

RESULTS: We identified a pathogenic variant in ANXA11, c.119A > G (p.D40G), in six patients with semantic variant primary progressive aphasia (svPPA), representing 5.5% of the svPPA cohort (6/109), and representing 2.3% of the FTD cohort overall (6/259). Only one patient later developed features suggestive of ALS.

DISCUSSION: This study links a rare variant in ANXA11 to a sporadic clinical syndrome in which specific TAR DNA-binding protein-43 (TDP-43) forms an obligate co-fibril with annexin A11. The variant, p.D40G, lies within the N-terminal portion of annexin A11's TDP-43 type C interacting domain, suggesting that genetic variation in that region may promote co-fibrillization.

HIGHLIGHTS: The pathogenic variant of annexin A11 (ANXA11I) is linked to frontotemporal dementia (FTD) syndrome. ANXA11 (p.D40G) may be one of the possible genetic causes of semantic variant primary progressive aphasia (svPPA). ANXA11 (p.D40G) may enhance heteromeric amyloid filaments of annexin A11 and TDP-43, promoting frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) type C.}, } @article {pmid40041912, year = {2025}, author = {Dash, UC and Bhol, NK and Swain, SK and Samal, RR and Nayak, PK and Raina, V and Panda, SK and Kerry, RG and Duttaroy, AK and Jena, AB}, title = {Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {1}, pages = {15-34}, pmid = {40041912}, issn = {2211-3835}, abstract = {Neuroprotection is a proactive approach to safeguarding the nervous system, including the brain, spinal cord, and peripheral nerves, by preventing or limiting damage to nerve cells and other components. It primarily defends the central nervous system against injury from acute and progressive neurodegenerative disorders. Oxidative stress, an imbalance between the body's natural defense mechanisms and the generation of reactive oxygen species, is crucial in developing neurological disorders. Due to its high metabolic rate and oxygen consumption, the brain is particularly vulnerable to oxidative stress. Excessive ROS damages the essential biomolecules, leading to cellular malfunction and neurodegeneration. Several neurological disorders, including Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, multiple sclerosis, and ischemic stroke, are associated with oxidative stress. Understanding the impact of oxidative stress in these conditions is crucial for developing new treatment methods. Researchers are exploring using antioxidants and other molecules to mitigate oxidative stress, aiming to prevent or slow down the progression of brain diseases. By understanding the intricate interplay between oxidative stress and neurological disorders, scientists hope to pave the way for innovative therapeutic and preventive approaches, ultimately improving individuals' living standards.}, } @article {pmid40039939, year = {2024}, author = {Udhayakumar, R and Gopakumar, S and Rahman, S and Karmakar, C}, title = {Nonlinear Assessment of Gait Signal Complexity in Neurodegenerative Disorders.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10781711}, pmid = {40039939}, issn = {2694-0604}, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology ; *Algorithms ; *Gait/physiology ; Nonlinear Dynamics ; Entropy ; Signal Processing, Computer-Assisted ; Male ; Female ; Middle Aged ; Aged ; }, abstract = {The human gait cycle undergoes discernible alterations upon the onset of neurodegenerative diseases (NDD) such as Parkinson's, Huntington's, and Amyotrophic lateral sclerosis. Each specific neurodegenerative disorder imparts a distinct influence on human gait dynamics, and precise quantification of these changes holds the potential for accurate methods of NDD detection.Nonlinear entropy algorithms, such as sample entropy (SampEn), find widespread use in physiological signal analysis. SampEn gauges signal complexity by identifying pattern matches within windowed sub-segments of the signal. However, traditional SampEn is notably dependent on user-defined parameters, particularly the tolerance parameter r, leading to inaccuracies in complexity information.SampEn profiling emerges as an alternative concept, eliminating the need for an input r parameter. This data-driven algorithm autonomously generates a set of 'r' values based on the signal's dynamics, yielding a comprehensive SampEn profile. The SampEn profile, containing extensive information about the signal's complexity, serves as a valuable resource for extracting secondary entropy features.In this study, we have contrasted the efficacy of traditional SampEn with SampEn profile-based secondary features such as Total SampEn (TSE) and Median SampEn (MSE), in identifying neurological states. Our findings consistently reveal that secondary features derived from the reduced-parametric SampEn profiling method outperform the traditional parametric SE in distinguishing control cohorts from specific Neurodegenerative Disease (NDD) cohorts.}, } @article {pmid40039399, year = {2024}, author = {Rechichi, I and Amprimo, G and Cicolin, A and Olmo, G}, title = {Predicting Amyotrophic Lateral Sclerosis Progression: an EMG-based Survival Analysis.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10782485}, pmid = {40039399}, issn = {2694-0604}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/mortality ; Humans ; *Electromyography/methods ; *Disease Progression ; Male ; Female ; Middle Aged ; Survival Analysis ; Aged ; Sleep, REM ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease, ultimately leading to muscle inefficiency and death. A vast majority of people with ALS also suffer from sleep disorders. Previous studies highlighted the presence of REM Sleep Without Atonia (RSWA) in an ALS cohort, and suggested its strong correlation with the disease severity. This study investigates the ability of electromyography (EMG) parameters recorded during Rapid-eye Movement (REM) sleep to predict disease progress and outcome rapidity in ALS. Survival models trained on a cohort of 45 ALS patients undergoing a longitudinal study, revealed a promising predictive power for the proposed EMG-derived metrics (c-index ≥ 0.65) and encouraging goodness of fit (through c-index and χ[2]). These results suggest the possibility of employing the trained model in follow-up procedures, based on non-invasive, lightweight EMG metrics, which would significantly ease disease monitoring and help personalized symptomatic care.}, } @article {pmid40039278, year = {2024}, author = {Murphy, EK and Doussan, A and Verga, S and Stommel, EW and McIlduff, C and Halter, RJ and Rutkove, SB}, title = {Assessing Pulmonary Function in ALS using Electrical Impedance Tomography.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10781742}, pmid = {40039278}, issn = {2694-0604}, mesh = {Humans ; *Electric Impedance ; *Tomography/methods ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; *Respiratory Function Tests/methods ; Male ; Female ; Middle Aged ; Lung/diagnostic imaging/physiopathology ; Algorithms ; Case-Control Studies ; Aged ; Adult ; }, abstract = {This study aimed to determine an optimal model involving thoracic electrical impedance tomography (EIT) metrics and patient geometric information to best correlate to standard pulmonary function test (PFT) measures in a cohort of 32 ALS patients and 32 age-matched healthy controls. Thoracic EIT is a non-invasive technology in which an electrode belt chest allows for real-time impedance imaging of respiratory function. The optimal form of the model was determined via a genetic algorithm a novel technique for model generation in EIT applications. Combining multiple metrics yielded optimal r[2] values of 0.62 and 0.66 for 1- and 2-term regression models optimized. The results appear very promising and further refinement of the technology appears warranted.}, } @article {pmid40038221, year = {2025}, author = {Mustafa, F and Mittal, S and Garg, D and Agarwal, A and Garg, A and Gupta, BK and Soneja, M and Srivastava, AK}, title = {HIV associated motor neuron disease (MND): A case series with systematic review of literature.}, journal = {Journal of neurovirology}, volume = {31}, number = {1}, pages = {1-15}, pmid = {40038221}, issn = {1538-2443}, mesh = {Humans ; *HIV Infections/drug therapy/complications/virology ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/virology/drug therapy/diagnostic imaging/pathology ; Female ; Adult ; *Motor Neuron Disease/virology/drug therapy ; Viral Load ; CD4 Lymphocyte Count ; Anti-HIV Agents/therapeutic use ; }, abstract = {Human immunodeficiency virus (HIV) associated motor neuron disease (MND) is very rare. HIV infection can cause an MND-like syndrome due to central nervous system (CNS) involvement de novo or during antiretroviral therapy (ART) due to CNS escape. We present two cases: one with a classic amyotrophic lateral sclerosis (ALS) phenotype, which was the manifestation of symptomatic CNS escape from ART, and the second with a primary lateral sclerosis (PLS) phenotype associated with underlying HIV infection. A systematic review of published literature of people living with HIV (PLHIV) who developed ALS/ MND was conducted using the PubMed, Embase, and Lilacs databases. A total of 91 cases were found, 89 of which were obtained from 37 articles, and two were included from our own case series. In patients with HIV-associated MND, 63 patients reviewed had a classic ALS phenotype followed by progressive muscular atrophy variant (12), progressive bulbar palsy (8), PLS (7) and bulbar onset ALS (1). Neuroimaging, electrophysiology, cerebrospinal fluid (CSF) analysis, CSF and serum HIV viral load, and CD4 count investigations were used for diagnosis. Following the initiation or modification of antiretroviral therapy (ART), approximately 70% exhibited an improvement or a stable disease course. HIV-associated MND is a rare condition that can occur in both ART-naive individuals and those on treatment. A proportion of cases (~ 70%) show improvement with ART. Accurate diagnosis requires the exclusion of opportunistic infections, which remains a critical yet challenging aspect of managing this condition.}, } @article {pmid40037468, year = {2025}, author = {Peck, A and Dadi, A and Yavarow, Z and Alfano, LN and Anderson, D and Arkin, MR and Chou, TF and D'Ambrosio, ES and Diaz-Manera, J and Dudley, JP and Elder, AG and Ghoshal, N and Hart, CE and Hart, MM and Huryn, DM and Johnson, AE and Jones, KB and Kimonis, V and Kiskinis, E and Lee, EB and Lloyd, TE and Mapstone, M and Martin, A and Meyer, H and Mozaffar, T and Onyike, CU and Pfeffer, G and Pindon, A and Raman, M and Richard, I and Rubinsztein, DC and Schiava, M and Schütz, AK and Shen, PS and Southworth, DR and Staffaroni, AM and Taralio-Gravovac, M and Weihl, CC and Yao, Q and Ye, Y and Peck, N}, title = {2024 VCP International Conference: Exploring multi-disciplinary approaches from basic science of valosin containing protein, an AAA+ ATPase protein, to the therapeutic advancement for VCP-associated multisystem proteinopathy.}, journal = {Neurobiology of disease}, volume = {207}, number = {}, pages = {106861}, pmid = {40037468}, issn = {1095-953X}, support = {R01 CA293084/CA/NCI NIH HHS/United States ; Z99 DK999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {*Valosin Containing Protein/genetics/metabolism ; Humans ; Animals ; Myositis, Inclusion Body/genetics/therapy/metabolism ; Frontotemporal Dementia/genetics/therapy ; }, abstract = {Valosin-containing protein (VCP/p97) is a ubiquitously expressed AAA+ ATPase associated with numerous protein-protein interactions and critical cellular functions including protein degradation and clearance, mitochondrial homeostasis, DNA repair and replication, cell cycle regulation, endoplasmic reticulum-associated degradation, and lysosomal functions including autophagy and apoptosis. Autosomal-dominant missense mutations in the VCP gene may result in VCP-associated multisystem proteinopathy (VCP-MSP), a rare degenerative disorder linked to heterogeneous phenotypes including inclusion body myopathy (IBM) with Paget's disease of bone (PDB) and frontotemporal dementia (FTD) or IBMPFD, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), parkinsonism, Charcot-Marie Tooth disease (CMT), and spastic paraplegia. The complexity of VCP-MSP makes collaboration among stakeholders essential and necessitates a multi-disciplinary approach. The 2024 VCP International Conference was hosted at Caltech between February 22 and 25. Co-organized by Cure VCP Disease and Dr. Tsui-Fen Chou, the meeting aimed to center the patient as a research partner, harmonize diverse stakeholder engagement, and bridge the gap between basic and clinical neuroscience as it relates to VCP-MSP. Over 100 multi-disciplinary experts attended, ranging from basic scientists to clinicians to patient advocates. Attendees discussed genetics and clinical presentation, cellular and molecular mechanisms underlying disease, therapeutic approaches, and strategies for future VCP research. The conference included three roundtable discussions, 29 scientific presentations, 32 scientific posters, nine patient and caregiver posters, and a closing discussion forum. The following conference proceedings summarize these sessions, highlighting both the identified gaps in knowledge and the significant strides made towards understanding and treating VCP diseases.}, } @article {pmid40037332, year = {2025}, author = {Belbasis, L and Morris, S and van Duijn, C and Bennett, D and Walters, R}, title = {Mendelian randomization identifies proteins involved in neurodegenerative diseases.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf018}, pmid = {40037332}, issn = {1460-2156}, support = {203141/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; //NIHR/ ; //NHS/ ; /DH_/Department of Health/United Kingdom ; }, abstract = {Proteins are involved in multiple biological functions. High-throughput technologies have allowed the measurement of thousands of proteins in population biobanks. In this study, we aimed to identify proteins related to Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis by leveraging large-scale genetic and proteomic data. We performed a two-sample cis Mendelian randomization study by selecting instrumental variables for the abundance of >2700 proteins measured by either Olink or SomaScan platforms in plasma from the UK Biobank and the deCODE Health Study. We also used the latest publicly available genome-wide association studies for the neurodegenerative diseases of interest. The potentially causal effect of proteins on neurodegenerative diseases was estimated based on the Wald ratio. We tested 13 377 protein-disease associations, identifying 169 associations that were statistically significant (5% false discovery rate). Evidence of co-localization between plasma protein abundance and disease risk (posterior probability > 0.80) was identified for 61 protein-disease pairs, leading to 50 unique protein-disease associations. Notably, 23 of 50 protein-disease associations corresponded to genetic loci not previously reported by genome-wide association studies. The two-sample Mendelian randomization and co-localization analysis also showed that APOE abundance in plasma was associated with three subcortical volumes (hippocampus, amygdala and nucleus accumbens) and white matter hyper-intensities, whereas PILRA and PILRB abundance in plasma was associated with caudate nucleus volume. Our study provided a comprehensive assessment of the effect of the human proteome that is currently measurable through two different platforms on neurodegenerative diseases. The newly associated proteins indicated the involvement of complement (C1S and C1R), microglia (SIRPA, SIGLEC9 and PRSS8) and lysosomes (CLN5) in Alzheimer's disease; the interleukin-6 pathway (CTF1) in Parkinson's disease; lysosomes (TPP1), blood-brain barrier integrity (MFAP2) and astrocytes (TNFSF13) in amyotrophic lateral sclerosis; and blood-brain barrier integrity (VEGFB), oligodendrocytes (PARP1), node of Ranvier and dorsal root ganglion (NCS1, FLRT3 and CDH15) and the innate immune system (CR1, AHSG and WARS) in multiple sclerosis. Our study demonstrates how harnessing large-scale genomic and proteomic data can yield new insights into the role of the plasma proteome in the pathogenesis of neurodegenerative diseases.}, } @article {pmid40036711, year = {2025}, author = {Nguyen, ML and Haddad, A and Law-Ye, B and Hesters, A}, title = {Uncommon Spinal Cord MRI Findings in a Patient With Early-Onset Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Neurology}, volume = {104}, number = {7}, pages = {e213503}, doi = {10.1212/WNL.0000000000213503}, pmid = {40036711}, issn = {1526-632X}, } @article {pmid40036368, year = {2025}, author = {Ervilha Pereira, P and De Bleecker, JL and Bogaert, E and Dermaut, B}, title = {Myopathic aggregation-prone variants in the TDP-43 prion-like domain: genetics paving the way.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf076}, pmid = {40036368}, issn = {1460-2156}, abstract = {While neuropathological and genetic studies have established the crucial involvement of TDP-43 proteinopathy in the pathogenesis of ALS (Amyotrophic Lateral Sclerosis), FTD (Frontotemporal Dementia) and related neurodegenerative disorders, multiple studies have described the presence of TDP-43 inclusions in muscular disorders, including inclusion body myositis but also other related rimmed vacuole myopathies. In addition, TDP-43 has been reported to be essential in normal muscle physiology as it is implicated in the formation of so-called amyloid-like myogranules during normal muscle regeneration after injury. However, genetic evidence supporting a primary role for TDP-43 proteinopathy in muscle disease has been missing. In the present review we highlight recent landmark discoveries linking novel pathogenic TDP-43 variants [p.(W385IfsX10) and p.(G376V)] within the prion-like domain with unusual aggregation-propensity and muscle rather than neuronal pathology. We discuss these studies in the context of known TDP-43-related pathways in ALS/FTD pathogenesis and show how they challenge some widely accepted views such as ALS as a pure neurogenic presynaptic neuromuscular disease and the direct correlation between TDP-43 aggregation-propensity and neurotoxicity. Finally, we discuss TDP-43 as part of a growing list of RNA-binding proteins including hnRNPA2B1 and hnRNPA1 as genetic causes of myopathies and relate this to the idea of 'multisystem proteinopathy'.}, } @article {pmid40034872, year = {2025}, author = {Wagner, H and Mlček, M and Krupičková, P and Popkova, M and Mejstrik, A and Boucek, T and Michálek, P and Kittnar, O and Belohlavek, J}, title = {Adrenaline has a limited effect on myocardial microvascular blood flow: A randomised experimental study in a porcine cardiac arrest model.}, journal = {Resuscitation plus}, volume = {22}, number = {}, pages = {100893}, pmid = {40034872}, issn = {2666-5204}, abstract = {BACKGROUND: Adrenaline (ADR) is a cornerstone of advanced life support (ALS) in cardiac arrest (CA), although its neurologically favourable survival outcomes remain unclear. ADR increases coronary perfusion pressure (CPP), with levels >15 mmHg associated with successful defibrillation. This study aimed to elucidate the relationship between ADR, myocardial microvascular blood flow, and resuscitation outcomes using a porcine CA model simulating refractory ventricular fibrillation (VF).

METHODS: This study involved 24 domestic pigs. After instrumentation, intubation, and baseline measurements, the animals were randomised into the ADR or control (saline) groups. VF was induced, and cardiopulmonary resuscitation was initiated using continuous mechanical chest compressions and ventilation. ADR or saline was administered following ALS guidelines. After 21 min of ALS, defibrillation was performed. Continuous measurements of arterial and venous blood pressures using an electrocardiogram and index of myocardial resistance (IMR) and transit mean time (Tmn) 1 min before and after each injection or peak blood pressure were recorded and compared between the groups. CPP-IMR, amplitude spectrum area (AMSA)-IMR, CPP-Tmn, and AMSA-Tmn correlations were assessed.

RESULTS: Compared with six animals in the control group, three in the ADR group achieved a return of spontaneous circulation. No difference was observed in IMR or AMSA; however, significant increases in CPP and arterial end-diastolic blood pressure were observed at several time points. Tmn differed between groups only at two time points.

CONCLUSION: Repeated ADR doses during prolonged ALS simulating refractory VF did not improve myocardial microvascular blood flow, as measured using IMR, despite leading to an increase in CPP.}, } @article {pmid40034089, year = {2025}, author = {Vaage, AM and Holmøy, T and Dahl, J and Stigum, H and Meyer, HE and Nakken, O}, title = {Statin Use and Amyotrophic Lateral Sclerosis Survival: A Population-Based Cohort Study.}, journal = {European journal of neurology}, volume = {32}, number = {3}, pages = {e70095}, pmid = {40034089}, issn = {1468-1331}, support = {//ALS Norway/ ; 2022050//Helse Sør-Øst RHF/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/epidemiology/drug therapy ; Female ; Male ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Middle Aged ; Cohort Studies ; Aged ; Norway/epidemiology ; Registries ; Adult ; }, abstract = {BACKGROUND: Dyslipidemia is common in amyotrophic lateral sclerosis (ALS). Statin use has been associated with both favorable and poor prognoses. We assessed whether statin use affects ALS survival.

METHODS: We linked four Norwegian health surveys (1972-2003) with mandatory national registries to obtain information on premorbid health, ALS diagnosis, and death. Using the Norwegian Prescribed Drug Registry, we identified participants who had dispensed statins pre- and post-diagnosis. We first compared pre-diagnosis statin discontinuation rates between ALS patients and matched controls. Flexible parametric models were then fitted to estimate the relationship between statin use and survival time in ALS, using restricted mean survival time and hazard ratio (HR) as effect measures.

RESULTS: A total of 524 patients (43% female) with ALS were included. Mean time from ALS diagnosis to death or end of study was 2.0 (SD 2.1) years. A substantial proportion of statin users (21%) discontinued statins during the year leading up to diagnosis. This group was characterized by poorer ALS prognosis compared to those adhering to statins and were included as statin users in our analysis. After adjusting for sex, age, birth year, riluzole use and premorbid smoking status, body mass index, and total cholesterol levels, statin use was not associated with ALS survival. The estimated mean survival difference comparing statin users to non-users was 0.74 (95% CI -5.98 to 7.47) months, corresponding to a HR of 0.97 (95% CI 0.77-1.23).

CONCLUSION: Statin use was not associated with ALS survival, suggesting that statins should not routinely be discontinued in ALS.}, } @article {pmid40033997, year = {2025}, author = {Poulsen, NS and Kraglund, LR and Vissing, J}, title = {Physical training of wheelchair users with neuromuscular disorders: A systematic review.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602241313114}, doi = {10.1177/22143602241313114}, pmid = {40033997}, issn = {2214-3602}, abstract = {OBJECTIVE: Wheelchair users with neuromuscular disorders have symptoms related to the disease and complications to the sedentary lifestyle, such as constipation and lower back pain. Physical training might be beneficial. This systematic review investigates the potential benefits and harms of physical training for wheelchair users with neuromuscular disorders.

METHODS: We systematically searched PubMed including studies published until July 2024. Inclusion criteria: 1) participants with a neuromuscular disorder, 2) at least 60% of participants in a study were wheelchair users, 3) physical training and its effects were investigated, 4) studies were prospective, and 5) English language was used. Non-peer-reviewed articles were excluded. Search results were screened by title, abstract, and full text. Two independent authors assessed the quality with the Downs and Black Quality Index.

RESULTS: We included 14 studies of 140 patients from 5 types of neuromuscular disorders (Duchenne muscular atrophy, spinal muscular atrophy, limb-girdle muscular atrophy, facioscapulohumeral muscular dystrophy, and amyotrophic lateral sclerosis). The mean quality was low (16/32) due to flaws in study design, selection bias, and power. Even though many were of low quality and lacked descriptions of adverse events, they all showed positive effects. Most studies investigated physical training of mastication or respiration with improvements in both. Other findings were improvements in endurance, extremity strength, and range of motion.

CONCLUSIONS: Physical training of wheelchair users with neuromuscular disorders is not well investigated. Physical training seems safe and beneficial, but training of respiratory and masticatory muscles is the only well-documented exercise modality that can be advised in patients with Duchenne Muscular Dystrophy or Duchenne Muscular Dystrophy/Spinal Muscular Atrophy, respectively. Larger, high-quality trials, including other neuromuscular disorders, are needed to assess the effects and adverse events of physical training.}, } @article {pmid40033457, year = {2025}, author = {Kallambettu, V and York, JD and Vasilopolous, T and Hutcheson, K and Plowman, E}, title = {Validation of the Dynamic Imaging Grade of Swallowing Toxicity for Amyotrophic Lateral Sclerosis.}, journal = {Neurogastroenterology and motility}, volume = {}, number = {}, pages = {e70008}, doi = {10.1111/nmo.70008}, pmid = {40033457}, issn = {1365-2982}, support = {/NS/NINDS NIH HHS/United States ; /CA/NCI NIH HHS/United States ; }, abstract = {INTRODUCTION: Although dysphagia is prevalent in persons with amyotrophic lateral sclerosis (pALS) and is associated with morbidity and mortality, no validated outcomes currently exist for the gold standard videofluoroscopy (VF) exam. We therefore sought to psychometrically validate the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale in pALS.

METHODS: One hundred pALS attended a research evaluation and underwent a standardized VF and validated clinical outcomes of oral intake (FOIS), perceived swallowing impairment (EAT-10), and ALS disease progression (ALSFRS-Revised). Duplicate, independent, and blinded VF ratings were completed using the DIGEST and MBSImP scales. Weighted kappa, ANOVAs (Tukey's HSD, Welch's correction), and Chi-square analyses were performed to determine intra- and inter-rater reliability, criterion validity, and construct validity of the DIGEST scale for use in pALS.

RESULTS: The mean age was 64.4(SD = 10.4), 50% were male, and the average ALS duration was 28.2 months (SD = 22.2). Excellent intra-rater (kappa = 0.92-1.0) and inter-rater (kappa = 0.94) reliability were noted for DIGEST ratings. DIGEST grades significantly discriminated pharyngeal pathophysiology (MBSImP, F(3,96) = 24.7, p < 0.0001), perceived dysphagia (EAT-10, F(3,40) = 20.8, p < 0.0001), oral intake (FOIS, X[2]:25.4, df = 3, p < 0.0001), ALS bulbar disease progression (ALSFRS-bulbar, F(3,93) = 20.8, p < 0.0001) with main effects noted for all analyses. Post hoc pairwise comparisons noted differences across all DIGEST grades with the exception of DIGEST 2 versus 3 (moderate vs. severe dysphagia), p > 0.05.

CONCLUSIONS: These data confirm that the DIGEST scale is a reliable and valid VF outcome for use in pALS to distinguish normal versus impaired swallowing and mild versus moderate or severe dysphagia for use in clinical practice and as a clinical trial endpoint marker.}, } @article {pmid40033250, year = {2025}, author = {Lu, C and Huang, XX and Huang, M and Liu, C and Xu, J}, title = {Mendelian randomization of plasma proteomics identifies novel ALS-associated proteins and their GO enrichment and KEGG pathway analyses.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {82}, pmid = {40033250}, issn = {1471-2377}, mesh = {Humans ; *Mendelian Randomization Analysis/methods ; *Amyotrophic Lateral Sclerosis/genetics/blood ; *Proteomics/methods ; *Genome-Wide Association Study/methods ; *Biomarkers/blood ; Blood Proteins/genetics/analysis/metabolism ; Quantitative Trait Loci ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder with an increasing incidence rate. Despite advances in ALS research over the years, the precise etiology and pathogenic mechanisms remain largely elusive.

OBJECTIVE: To identify novel plasma proteins associated with ALS through Mendelian randomization methods in large-scale plasma proteomics and to provide potential biomarkers and therapeutic targets for ALS treatment.

METHODS: This study employed a large-scale plasma proteomic Mendelian randomization approach using genetic data from 80,610 individuals of European ancestry (including 20,806 ALS patients and 59,804 controls) derived from a genome-wide association study (GWAS). Protein quantitative trait loci (pQTLs) data were obtained from Ferkingstad et al. (2021), which measured 4,907 proteins in 35,559 Icelandic individuals. Multiple Mendelian randomization (MR) techniques were utilized, including weighted median, MR-Egger, Wald ratio, inverse-variance weighting (IVW), basic model, and weighted model. Heterogeneity was evaluated using Cochran's Q test. Horizontal pleiotropy was assessed through the MR-Egger intercept test and MR-PRESSO outlier detection. Sensitivity analysis was performed via leave-one-out analysis.

RESULTS: MR analysis revealed potential causal associations between 491 plasma proteins and ALS, identifying 19 novel plasma proteins significantly linked to the disease. Proteins such as C1QC, UMOD, SLITRK5, ASAP2, TREML2, DAPK2, ARHGEF10, POLM, SST, and SIGLEC1 showed positive correlations with ALS risk, whereas ADPGK, BTNL9, COLEC12, ADGRF5, FAIM, CRTAM, PRSS3, BAG5, and PSMD11 exhibited negative correlations. Reverse MR analyses confirmed that ALS negatively correlates with ADPGK and ADGRF5 expression. Enrichment analyses, including Gene Ontology (GO) functional analysis, indicated involvement in critical biological processes such as external encapsulating structure organization, extracellular matrix organization, chemotaxis, and taxis. KEGG pathway analysis highlighted significant enrichment in the PI3K-Akt signaling pathway, cytokine-cytokine receptor interactions, and axon guidance.

CONCLUSION: This study enhances the understanding of ALS pathophysiology and proposes potential biomarkers and mechanistic insights for therapeutic development. Future research should explore the clinical translation of these findings to improve ALS patient outcomes and quality of life.}, } @article {pmid40032505, year = {2025}, author = {Callegaro, S and Manera, U and Canosa, A and Grassano, M and Palumbo, F and Cabras, S and Matteoni, E and Di Pede, F and De Mattei, F and De Marchi, F and Mazzini, L and Moglia, C and Calvo, A and Chiò, A and Vasta, R}, title = {Another brick in our knowledge of ALS causes: a population-based study of residential clustering.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-335670}, pmid = {40032505}, issn = {1468-330X}, } @article {pmid40032118, year = {2025}, author = {Dang, M and Wu, L and Zhang, X}, title = {Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances.}, journal = {International journal of biological macromolecules}, volume = {306}, number = {Pt 3}, pages = {141677}, doi = {10.1016/j.ijbiomac.2025.141677}, pmid = {40032118}, issn = {1879-0003}, abstract = {Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a critical RNA/DNA-binding protein involved in various cellular processes, including RNA splicing, transcription regulation, and RNA stability. Mislocalization and aggregation of TDP-43 in the cytoplasm are key features of the pathogenesis of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). This review provides a comprehensive retrospective and prospective analysis of TDP-43 research, highlighting structural insights, significant milestones, and the evolving understanding of its physiological and pathological functions. We delineate five major stages in TDP-43 research, from its initial discovery as a pathological hallmark in neurodegeneration to the recent advances in understanding its liquid-liquid phase separation (LLPS) behavior and interactions with cellular processes. Furthermore, we assess therapeutic strategies targeting TDP-43 pathology, categorizing approaches into direct and indirect interventions, alongside modulating aberrant TDP-43 LLPS. We propose that future research will focus on three critical areas: targeting TDP-43 structural polymorphisms for disease-specific therapeutics, exploring dual temporal-spatial modulation of TDP-43, and advancing nano-therapy. More importantly, we emphasize the importance of understanding TDP-43's functional repertoire at the mesoscale, which bridges its molecular functions with broader cellular processes. This review offers a foundational framework for advancing TDP-43 research and therapeutic development.}, } @article {pmid40031506, year = {2024}, author = {Guo, J and Chen, D and Zeng, X and Liu, X and Wang, X and Teng, S and Ye, K and Sun, X and Zhang, S and He, J and Fan, D and Liu, Y}, title = {A Multi-branch Attention-based Deep Learning Method for ALS Identification with sMRI Data.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10782847}, pmid = {40031506}, issn = {2694-0604}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/diagnosis ; *Deep Learning ; Humans ; *Spinal Cord/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Algorithms ; Image Processing, Computer-Assisted/methods ; }, abstract = {The structural Magnetic resonance imaging (sMRI) of spinal cord plays a significant role in the clinical diagnosis of Amyotrophic Lateral Sclerosis (ALS). But due to small cross-sectional area in the axial plane and long sagittal/coronal expansion of spinal cord, the diagnosis of ALS using sMRI of spinal cord has remained largely at the stage of morphological observation. In this study, a Multi-branch attention-based deep learning method is proposed to solve this problem. Multi-branch framework is utilized to extract general features of all levels of spinal cord for challenging of long sagittal and coronal expansion of spinal cord, and attention module coupled with multi-scale module in each branch is applied to extract multi-scale features and pay more attention to the important regions of the spinal cord in the axial plane. Experiments show that the proposed method obtains better performance in ALS identification, which implies that the proposed method can extract features of important region in the spinal cord and could be helpful to find more regions sensitive for ALS disease identification.}, } @article {pmid40030850, year = {2025}, author = {Hong, Z and Yi, S and Deng, M and Zhong, Y and Zhao, Y and Li, L and Zhou, H and Xiao, Y and Hu, X and Niu, L}, title = {Transcranial Focused Ultrasound Modifies Disease Progression in SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {IEEE transactions on ultrasonics, ferroelectrics, and frequency control}, volume = {72}, number = {2}, pages = {191-201}, doi = {10.1109/TUFFC.2024.3525143}, pmid = {40030850}, issn = {1525-8955}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/diagnostic imaging/genetics ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Ultrasonic Therapy/methods ; Superoxide Dismutase-1/genetics ; Disease Progression ; Muscle, Skeletal/physiopathology ; Male ; Motor Cortex ; Humans ; Elasticity Imaging Techniques ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressively worsening neurodegenerative condition with very few treatment options available. Ultrasound neuromodulation offers promising benefits for treating neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. However, the effects and underlying mechanisms of ultrasound neuromodulation on ALS remain unclear. A head-mounted ultrasound neuromodulation system was developed to noninvasively stimulate the motor cortex of symptomatic mice carrying the G93A human SOD1 mutation (SOD $1^{\text {G93A} } $) for four weeks. Motor performance was assessed through the rotarod locomotor test, grip strength test, and open field test. In addition, the effect of ultrasound stimulation on the elastic modulus of gastrocnemius muscle atrophy was measured using real-time shear wave elastography (SWE). Subsequently, the brain tissues of the mice were harvested. Gastrocnemius morphology was examined using hematoxylin-eosin and Gomori aldehyde-fuchsin (GAF) staining. The number of neurons and the phenotype of microglia in the motor cortex were observed by immunohistochemical analysis. Ultrasound therapy delayed disease onset by 10.7% and increased the lifespan by 6.7% in SOD $1^{\text {G93A} } $ mice by reduction of neuronal loss and enhancement of M2 microglia in the motor cortex. Furthermore, we found significant improvements in motor function for ultrasound-treated mice. More importantly, ultrasound stimulation ameliorated gastrocnemius muscle atrophy in the SOD $1^{\text {G93A} } $ mice. These results revealed the neuroprotective effects of ultrasound against the disease pathogenesis of SOD $1^{\text {G93A} } $ mice. Transcranial ultrasound neuromodulation provides an innovative tool for the intervention and treatment of neurodegenerative diseases.}, } @article {pmid40030617, year = {2024}, author = {Jiang, Y and Li, K and Liang, Y and Chen, D and Tan, M and Li, Y}, title = {Daily Assistance for Amyotrophic Lateral Sclerosis Patients Based on a Wearable Multimodal Brain-Computer Interface Mouse.}, journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TNSRE.2024.3520984}, pmid = {40030617}, issn = {1558-0210}, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic, progressive neurodegenerative disease that mainly causes damage to upper and lower motor neurons. This leads to a progressive deterioration in the voluntary mobility of the upper and lower extremities in ALS patients, which underscores the pressing need for an assistance system to facilitate communication and body movement without relying on neuromuscular function. In this paper, we developed a daily assistance system for ALS patients based on a wearable multimodal brain-computer interface (BCI) mouse. The system comprises two subsystems: a mouse system assisting the upper extremity and a wheelchair system based on the mouse system assisting the lower extremity. By wearing a BCI headband, ALS patients can control a computer cursor on the screen with slight head rotation and eye blinking, and further operate a computer and drive a wheelchair with specially designed graphical user interfaces (GUIs). We designed operating tasks that simulate daily needs and invited ALS patients to perform the tasks. In total, 15 patients with upper extremity limitations performed the mouse system task and 9 patients with lower extremity mobility issues performed the wheelchair system task. To our satisfaction, all the participants fully accomplished the tasks and average accuracies of 83.9% and 87.0% for the two tasks were achieved. Furthermore, workload evaluation using NASA Task Load Index (NASA-TLX) revealed that the participants experienced a low workload when using the system. The experimental results demonstrate that the proposed system provides ALS patients with effective daily assistance and shows promising long-term application prospects.}, } @article {pmid40030616, year = {2024}, author = {Bista, S and Coffey, A and Mitchell, M and Fasano, A and Dukic, S and Buxo, T and Giglia, E and Heverin, M and Muthuraman, M and Carson, RG and Lowery, M and Manus, LM and Hardiman, O and Nasseroleslami, B}, title = {Abnormal EEG spectral power and coherence measures during pre-motor stage in Amyotrophic Lateral Sclerosis.}, journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TNSRE.2024.3523109}, pmid = {40030616}, issn = {1558-0210}, abstract = {Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder characterized by progressive motor decline. Studies of electroencephalographic (EEG) activity during rest and motor execution have captured network changes in ALS. However, the nature of network-level impairment in the pre-motor activity in ALS remains unclear. Assessing the (dys)function of motor networks engaged prior to motor output is essential for understanding the motor pathophysiology in ALS. We recorded EEG in 22 people with ALS (PwALS) and 16 age-matched healthy controls during rest and isometric pincer-grip tasks. EEG spectral power and coherence were calculated during rest, pre-motor stage, and motor execution. In PwALS, significantly higher event-related spectral perturbations were observed compared to controls over electrodes representing a) contralateral prefrontal and parietal regions in theta band during pre-motor stage, b) contralateral parietal and ipsilateral motor regions in high-beta band during motor execution. Similarly, spectral coherence revealed abnormal EEG connectivity within 1) sensorimotor network during rest in theta band, 2) (pre)motor networks during pre-motor stage in low-alpha and high-beta bands, 3) Fronto-parietal networks during execution in high-beta band. Furthermore, the abnormal EEG connectivity during rest and execution (but not during pre-motor stage) showed significant negative correlation with clinical ALS-functional-rating-scale scores. Combining abnormal EEG connectivity from rest, pre-motor, and execution stages provided more powerful discrimination between patients and controls with a uniquely higher contribution of measures pertaining to the pre-motor stage. The results indicate that pre-motor functional activity reflects a different and unique aspect of network impairment, with potential for inclusion as biomarker candidates in ALS.}, } @article {pmid40030411, year = {2024}, author = {Mishra, S and Chatterjee, D and Kanekar, N}, title = {Topological Gait Analysis: A New Framework and Its Application to the Study of Human Gait.}, journal = {IEEE journal of biomedical and health informatics}, volume = {28}, number = {12}, pages = {7040-7053}, doi = {10.1109/JBHI.2024.3427700}, pmid = {40030411}, issn = {2168-2208}, mesh = {Humans ; *Gait Analysis/methods ; Adult ; Male ; Middle Aged ; Female ; Gait/physiology ; Aged ; Parkinson Disease/physiopathology ; Amyotrophic Lateral Sclerosis/physiopathology ; Signal Processing, Computer-Assisted ; Huntington Disease/physiopathology ; Algorithms ; }, abstract = {OBJECTIVE: This study introduces a physiologically driven topological gait analysis (TGA) framework to gain insights into pathological gait.

METHODS: A publicly available gait dataset consisting of four groups: healthy adults, people with Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) was used. The topological properties of the configuration space of three gait parameters were studied by approximating the underlying distribution through a Gaussian kernel-based density estimation technique. Thereafter, sublevel sets of the density estimate were analyzed using cubical persistence homology.

RESULTS: Three new features were constructed: 1. Probability density estimates (PDEs) that characterize the distribution of gait parameters over their configuration space. Healthy adults exhibited a unimodal distribution, while people with neurodegenerative disorders displayed a multi-modal distribution. 2. Persistence entropy plots that summarize changes in the PDEs and characterize the uncertainty in the underlying distribution. Gait of healthy adults was concentrated at higher entropy values as opposed to neurodegenerative gait. 3. A number that captures disease severity trends.

CONCLUSIONS: Topological features in PD and HD indicate a 'bias' to a certain set of gait configurations. This lack of exploration may reflect poor planning of the underlying topology, resulting in outward manifestations of impaired gait. The lower variegations in PDEs in ALS compared to PD and HD suggest that the planning of the topology of gait may occur at higher levels of the neural architecture.

SIGNIFICANCE: TGA offers characterization of gait at a hitherto uncharted level, potentially serving neuromotor markers for early diagnosis and personalized rehabilitation protocols.}, } @article {pmid40029926, year = {2025}, author = {Panda, P and Mohanty, S and Gouda, SR and Baral, TC and Mohanty, A and Nayak, J and Mohapatra, R}, title = {Advanced strategies for enhancing the neuroprotective potential of curcumin: delivery systems and mechanistic insights in neurodegenerative disorders.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-26}, doi = {10.1080/1028415X.2025.2472773}, pmid = {40029926}, issn = {1476-8305}, abstract = {Background: Curcumin, a polyphenolic compound derived from Curcuma longa, exhibits significant neuroprotective potential due to its diverse pharmacological properties.Objective: This review explores curcumin's role in modulating key pathological mechanisms underlying neurodegenerative disorders such as Alzheimer's, Parkinson's diseases, Amyotrophic Lateral Sclerosis, Huntington's Disease and Prion Disease.Methods: A comprehensive analysis of curcumin's molecular interactions, including its effects on amyloid-beta (Aβ) aggregation, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal-induced neurotoxicity, was conducted. Additionally, strategies to overcome its low bioavailability and blood-brain barrier (BBB) permeability were evaluated.Results: Curcumin inhibits Aβ aggregation and promotes disaggregation, reducing amyloid plaque formation in Alzheimer's disease. It modulates glial cell activity, attenuating neuroinflammation and fostering a neuroprotective environment. By interacting with tau proteins, curcumin prevents hyperphosphorylation and neurofibrillary tangle formation. As a potent antioxidant, it scavenges reactive oxygen species, mitigating oxidative stress-related neuronal damage. Its metal-chelating properties further diminish neurotoxicity by sequestering iron and copper ions. Despite its limited bioavailability and BBB permeability, curcumin's therapeutic efficacy can be enhanced using nanocarriers such as nanoparticles, liposomes, and micelles, which improve solubility, stability, and brain penetration.Conclusion: Curcumin's multifaceted neuroprotective mechanisms make it a promising candidate for preventing or slowing neurodegenerative disease progression. Advanced drug delivery systems hold potential for overcoming its pharmacokinetic limitations, paving the way for future clinical applications.}, } @article {pmid40029669, year = {2025}, author = {Carroll, E and Scaber, J and Huber, KVM and Brennan, PE and Thompson, AG and Turner, MR and Talbot, K}, title = {Drug repurposing in amyotrophic lateral sclerosis (ALS).}, journal = {Expert opinion on drug discovery}, volume = {20}, number = {4}, pages = {447-464}, pmid = {40029669}, issn = {1746-045X}, mesh = {*Drug Repositioning ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; *Drug Discovery/methods ; Translational Research, Biomedical/methods ; }, abstract = {INTRODUCTION: Identifying treatments that can alter the natural history of amyotrophic lateral sclerosis (ALS) is challenging. For years, drug discovery in ALS has relied upon traditional approaches with limited success. Drug repurposing, where clinically approved drugs are reevaluated for other indications, offers an alternative strategy that overcomes some of the challenges associated with de novo drug discovery.

AREAS COVERED: In this review, the authors discuss the challenge of drug discovery in ALS and examine the potential of drug repurposing for the identification of new effective treatments. The authors consider a range of approaches, from screening in experimental models to computational approaches, and outline some general principles for preclinical and clinical research to help bridge the translational gap. Literature was reviewed from original publications, press releases and clinical trials.

EXPERT OPINION: Despite remaining challenges, drug repurposing offers the opportunity to improve therapeutic options for ALS patients. Nevertheless, stringent preclinical research will be necessary to identify the most promising compounds together with innovative experimental medicine studies to bridge the translational gap. The authors further highlight the importance of combining expertise across academia, industry and wider stakeholders, which will be key in the successful delivery of repurposed therapies to the clinic.}, } @article {pmid40029136, year = {2025}, author = {Revi, N and Nandeshwar, M and Harijan, D and Sankaranarayanan, SA and Joshi, M and Prabusankar, G and Rengan, AK}, title = {Acridine Benzimidazolium Derivatives Induced Protective Microglia Polarization and In Silico TDP-43 Interaction─Potential Implications for Amyotrophic Lateral Sclerosis.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {6}, pages = {1103-1116}, doi = {10.1021/acschemneuro.4c00791}, pmid = {40029136}, issn = {1948-7193}, mesh = {*Microglia/drug effects/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Animals ; *DNA-Binding Proteins/metabolism ; Benzimidazoles/pharmacology ; Neuroprotective Agents/pharmacology ; Mice ; Acridines/pharmacology ; Humans ; Molecular Docking Simulation ; }, abstract = {Abnormal protein aggregation and associated neuronal-glial cell cytotoxicity lead to a plethora of neurodegenerative disorders. Most of the earlier investigations on understanding neurodegenerative disease progression and cure focused on neuronal damage and restoration potential. With increased evidence on the role of glial cells like microglia and astrocytes in mediating these disorders, more studies are dedicated to understanding the role of inflammatory responses mediated by glial cells and how they lead to neuroinflammation. Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder caused by TDP-43 aggregation that affects motor neurons. Pro-inflammatory microglia are considered to aggravate the disorder condition. In the current study, a previously reported molecule with TDP-43 inhibition, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)imidazol-3-ium) dibromide salt (AIM4), is analyzed for its microglia polarization properties along with two other derivatives, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (ABE) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)benzoimidazol-3-ium) dibromide salt (ABA). The 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (ABE) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl) benzimidazol-3-ium) dibromide salt (ABA) display the increased ability to maintain microglial cells to anti-inflammatory state and TDP-43 binding as compared to 3,3'-(acridine-4,5-diylbis(methylene)) bis(carboxymethyl)imidazolium dibromide salt (AIM4). This was confirmed from total nitrite levels, mitochondria membrane potential analysis, and molecular docking studies. The selected pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) displayed decreased levels, and anti-inflammatory cytokines IL-4 and IL-10 displayed increased levels, however not very significantly, upon treatment with all acridine derivatives. The compounds were investigated on lipopolysaccharides (LPS)-triggered mouse microglial cells and Danio rerio embryos displaying no significant cytotoxicity and physiological changes (cardiac rhythm), respectively. In molecular docking studies, alanine at 315 mutated to glutamate of TDP-43 directly interacts with AIM4. However, π-σ interactions of the aromatic backbone of acridine in ABE and ABA with 313 phenylalanine of TDP-43 along with hydrogen bonds formed between 309, 310 glycine amino acids and imidazolium bromide side chains rendered a stronger binding of these acridine derivatives with the protein potentially inhibiting fibrillation. Conclusion: ABA, ABE, and AIM4 maintain microglia in an anti-inflammatory state. However, more studies are required to understand its interaction with TDP-43 and the mechanism of its anti-inflammatory nature.}, } @article {pmid40028680, year = {2025}, author = {Khosravi, S and Amini, E and Emamikhah, M and Alavi, A and Lang, AE and Rohani, M}, title = {Motor Neuron Involvement in Two ATP13A2-Related Families: ALS And HSP-Like Phenotypes.}, journal = {Movement disorders clinical practice}, volume = {}, number = {}, pages = {}, doi = {10.1002/mdc3.70027}, pmid = {40028680}, issn = {2330-1619}, abstract = {BACKGROUND: Mutations in the ATP13A2 gene have been implicated in various neurodegenerative disorders, including Kufor-Rakeb syndrome (KRS), neuronal ceroid lipofuscinosis (NCL), hereditary spastic paraplegia (HSP), and amyotrophic lateral sclerosis (ALS). This report presents two Iranian families with ATP13A2 variants exhibiting atypical features of KRS.

CASES: We highlight four patients from two consanguineous Iranian families with mutations in the ATP13A2 gene presenting with variable features of motor neuron disease as well as juvenile-onset parkinsonism, and cognitive decline. The onset of symptoms ranged from 11 to 29 years, with initial manifestations including gait disturbance, postural instability, and cognitive impairment. As the disease progressed, patients developed a range of neurological signs, such as dystonia, spasticity, and dysarthria.

CONCLUSION: This report expands the phenotypic spectrum of ATP13A2-related disorders, highlighting the potential overlap of symptoms associated with KRS, ALS, and HSP.}, } @article {pmid40027730, year = {2025}, author = {Pant, DC and Lone, MA and Parameswaran, J and Ma, F and Dutta, P and Wang, Z and Park, J and Verma, S and Hornemann, T and Jiang, J}, title = {Lack of motor defects and ALS-like neuropathology in heterozygous Sptlc1 Exon 2 deletion mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40027730}, issn = {2692-8205}, support = {R01 AG068247/AG/NIA NIH HHS/United States ; UL1 TR000454/TR/NCATS NIH HHS/United States ; }, abstract = {Mutations in the human SPTLC1 gene have recently been linked to early onset amyotrophic lateral sclerosis (ALS), characterized by global atrophy, motor impairments, and symptoms such as tongue fasciculations. All known ALS-linked SPTLC1 mutations cluster within exon 2 and a specific variant, c.58G>T, results in exon 2 skipping. However, it is unclear how the exon 2 deletion affects SPTLC1 function in vivo and contributes to ALS pathogenesis. Leveraging the high genomic sequence similarity between mouse and human SPTLC1, we created a novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in the endogenous murine Sptlc1 locus. While heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely. These findings indicate that Sptlc1 ΔExon2 heterozygous mice do not replicate the disease phenotype but provide valuable insights into SPTLC1 biology and serve as a useful resource for future mechanistic studies.}, } @article {pmid40027671, year = {2025}, author = {Woo, E and Tasnim, F and Kawamata, H and Manfredi, G and Konrad, C}, title = {Investigation of mitochondrial phenotypes in motor neurons derived by direct conversion of fibroblasts from familial ALS subjects.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40027671}, issn = {2692-8205}, support = {R01 NS139141/NS/NINDS NIH HHS/United States ; R35 NS122209/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons, leading to fatal muscle paralysis. Familial forms of ALS (fALS) account for approximately 10% of cases and are associated with mutations in numerous genes. Alterations of mitochondrial functions have been proposed to contribute to disease pathogenesis. Here, we employed a direct conversion (DC) technique to generate induced motor neurons (iMN) from skin fibroblasts to investigate mitochondrial phenotypes in a patient-derived disease relevant cell culture system. We converted 7 control fibroblast lines and 17 lines harboring the following fALS mutations, SOD1[A4V], TDP-43[N352S], FUS[R521G], CHCHD10[R15L], and C9orf72 repeat expansion. We developed new machine learning approaches to identify iMN, analyze their mitochondrial function, and follow their fate longitudinally. Mitochondrial and energetic abnormalities were observed, but not all fALS iMN lines exhibited the same alterations. SOD1[A4V], C9orf72, and TDP-43[N352S] iMN had increased mitochondrial membrane potential, while in CHCHD10[R15L] cells membrane potential was decreased. TDP-43[N352S] iMN displayed changes in mitochondrial morphology and increased motility. SOD1[A4V], TDP-43[N352S], and CHCHD10[R15L] iMN had increased oxygen consumption rates and altered extracellular acidification rates, reflecting a hypermetabolic state similar to the one described in sporadic ALS fibroblasts. FUS[R521G] mutants had decreased ATP/ADP ratio, suggesting impaired energy metabolism. We then tested the viability of iMN and found decreases in survival in SOD1[A4V], C9orf72, and FUS[R521G], which were corrected by small molecules that target mitochondrial stress. Together, our findings reinforce the role of mitochondrial dysfunction in ALS and indicate that fibroblast-derived iMN may be useful to study fALS metabolic alterations. Strengths of the DC iMN approach include low cost, speed of transformation, and the preservation of epigenetic modifications. However, further refinement of the fibroblasts DC iMN technique is still needed to improve transformation efficiency, reproducibility, the relatively short lifespan of iMN, and the senescence of the parental fibroblasts.}, } @article {pmid40027590, year = {2025}, author = {Untalan, LGV and Malanog, JPD and Jamora, RDG}, title = {Evaluating YouTube as a source of information on amyotrophic lateral sclerosis.}, journal = {Digital health}, volume = {11}, number = {}, pages = {20552076251324439}, pmid = {40027590}, issn = {2055-2076}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that leads to progressive motor weakness and eventual death. Recent years have seen an increase in online information on ALS, with the popular video platform YouTube becoming a prominent source. We aimed to evaluate the quality, reliability, actionability, and understandability of ALS videos on YouTube.

METHODS: A search was performed using the keyword "Amyotrophic Lateral Sclerosis" on YouTube. A total of 240 videos were viewed and assessed by two independent raters. Video characteristics such as type of uploader, views, likes, comments, and Video Power Index were also collected.

RESULTS: Videos had moderate to low quality and reliability (Global Quality Scale [GQS] and modified DISCERN [mDISCERN] median 2.5), and poor understandability and actionability (PEMAT total median 8.5). Among the general video characteristics, only length of video showed a significant positive correlation across the tools (with mDISCERN [p < 0.001]; with GQS [p < 0.001]; with PEMAT [p < 0.001]). Videos from physicians (p = 0.024, sig <0.05), other healthcare professionals (p = 0.017, sig <0.05), and educational channels (p = 0.001, sig <0.05) had better quality when compared to others.

CONCLUSION: YouTube videos are a poor source of information for ALS as videos tend to have moderate to low quality and reliability and are poorly understandable and actionable. Longer videos, and videos uploaded by those in the healthcare and educational fields, were found to perform relatively better. Thus, when using YouTube, caution and careful attention to the video characteristics are recommended.}, } @article {pmid40027570, year = {2025}, author = {Giorgio, A and Ciracì, E and De Luca, M and Stella, G and Giorgio, V}, title = {Hepatic abscess and hydatid liver cyst: European infectious disease point of view.}, journal = {World journal of hepatology}, volume = {17}, number = {2}, pages = {103325}, pmid = {40027570}, issn = {1948-5182}, abstract = {This manuscript is based on a recent study by Pillay et al that was published in recently. Liver abscesses can be caused by rare potentially life-threatening infections of either bacterial or parasitic origin. The incidence rate in Europe is lower than in developing countries, but it is a major complication with high morbidity, particularly in immunocompromised patients. They are most frequently caused by Enterobacterales infections, but hypervirulent Klebsiella strains are an emerging problem in Western countries. Amoebiasis has been a public health problem in Europe, primarily imported from other endemic foci. At the same time, this infection is becoming an emerging disease, as the number of infected patients who have not traveled to endemic areas is rising. Treatment options for hydatid liver cyst include chemotherapy, open or laparoscopic surgery, percutaneous treatment (percutaneous aspiration, re-aspiration and injection and its modification) and ''wait and watch'' strategy. Most hydatid liver cyst patients in Pillay et al's study received surgical treatment, but several studies have confirmed the safety and efficacy of percutaneous aspiration, re-aspiration and injection.}, } @article {pmid40025671, year = {2025}, author = {Wang, Y and Li, C and Yang, Y and Ma, C and Zhao, X and Li, J and Wei, L and Li, Y}, title = {A Surface-Enhanced Raman Spectroscopy Platform Integrating Dual Signal Enhancement and Machine Learning for Rapid Detection of Veterinary Drug Residues in Meat Products.}, journal = {ACS applied materials & interfaces}, volume = {17}, number = {10}, pages = {16202-16212}, doi = {10.1021/acsami.4c21938}, pmid = {40025671}, issn = {1944-8252}, mesh = {*Spectrum Analysis, Raman/methods ; *Veterinary Drugs/analysis ; *Machine Learning ; *Drug Residues/analysis ; *Meat Products/analysis ; Animals ; Metal Nanoparticles/chemistry ; Food Contamination/analysis ; }, abstract = {The detection and quantification of veterinary drug residues in meat remain a significant challenge due to the complex background interference inherent to the meat matrix, which compromises the stability and accuracy of spectroscopic analysis. This study introduces an advanced label-free surface-enhanced Raman spectroscopy (SERS) platform for the precise identification and quantification of veterinary drugs. By employing a dual enhancement strategy involving sodium borohydride activation and calcium ion-deuterium oxide guidance, this platform achieves the efficient capture and signal amplification of drug molecules on highly active nanoparticles. High-quality SERS spectra were obtained for carprofen, doxycycline hydrochloride, chloramphenicol, and penicillin G sodium salt, enabling accurate classification and interference suppression. In addition, the application of machine learning algorithms, including PCA-LDA, heatmap, and decision tree modeling, allows for accurate differentiation of mixed drug samples. Quantitative analyses in meat samples were achieved through Raman intensity ratios and multivariate curve resolution-alternate least-squares (MCR-ALS) analysis, with results showing high consistency with high-performance liquid chromatography (HPLC) measurements. These findings highlight the potential of this SERS-based platform for accurate and rapid detection of multicomponent veterinary drug residues in complex food matrices.}, } @article {pmid40025240, year = {2025}, author = {Maier, A and Kettemann, D and Weyen, U and Grehl, T and Schulte, PC and Steinbach, R and Rödiger, A and Weydt, P and Petri, S and Wolf, J and Grosskreutz, J and Koch, JC and Weishaupt, JH and Rosseau, S and Norden, J and Körtvélyessy, P and Koch, B and Holm, T and Hildebrandt, B and Schumann, P and Walter, B and Riitano, A and Münch, C and Meyer, T and Spittel, S}, title = {Provision, cough efficacy and treatment satisfaction of mechanical insufflation-exsufflation in a large multicenter cohort of patients with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {7360}, pmid = {40025240}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications ; *Cough ; Male ; Female ; *Insufflation/methods ; Middle Aged ; Aged ; *Patient Satisfaction ; Longitudinal Studies ; Treatment Outcome ; Germany ; }, abstract = {In patients with amyotrophic lateral sclerosis (ALS), mechanical insufflation-exsufflation (MI-E) addresses cough deficiency to achieve major therapeutic goals: improving costal muscle and joint function, reducing atelectasis through insufflation, and clearing bronchial secretions via exsufflation. Despite its perceived benefits, there is limited systematic research on MI-E provision, symptom alleviation, or patient satisfaction. The research platform Ambulanzpartner coordinated this longitudinal observational study conducted in 12 German ALS centers from July 2018 to September 2023. Patients were enrolled based on ALS-related cough deficiency requiring MI-E therapy. The study recorded provision, reasons for withholding MI-E, clinical parameters, therapy frequency, subjective cough deficiency, and symptomatic relief. Satisfaction with MI-E therapy was determined by the likelihood of recommendation. Out of 694 ALS patients indicated for MI-E, 527 (75.9%) received the therapy. The primary reason for non-provision was that the patient had died before provision (n = 66 of 167; 39.5%). These patients were significantly more affected as represented by higher progression rates and lower cough peak flows (CPF) at the time of MI-E indication (p < 0.05). Most patients who received MI-E used it daily (n = 290 of 370; 78.4%). Self-assessed cough deficiency correlated with clinical measurements, especially for patients with higher deficits. At follow-up visits, patients reported reduced cough deficiency (p < 0.001). Frequent MI-E use was linked to greater symptom relief and higher likelihood of recommending the therapy. This study highlights the symptomatic and palliative potential of MI-E therapy for ALS patients.}, } @article {pmid40025162, year = {2025}, author = {Hiew, JY and Lim, YS and Liu, H and Ng, CS}, title = {Integrated transcriptomic profiling reveals a STING-mediated Type II Interferon signature in SOD1-mutant amyotrophic lateral sclerosis models.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {347}, pmid = {40025162}, issn = {2399-3642}, support = {#SED000125//Monash University Malaysia (Monash Malaysia)/ ; #PM010CNI000148//International Brain Research Organization (IBRO)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/immunology ; Animals ; Humans ; Mice ; *Membrane Proteins/genetics/metabolism ; *Gene Expression Profiling ; *Disease Models, Animal ; *Superoxide Dismutase-1/genetics/metabolism ; Mutation ; Transcriptome ; Interferon-gamma/metabolism/genetics ; }, abstract = {Inflammation is a hallmark of amyotrophic lateral sclerosis (ALS), particularly in cases with SOD1 mutations. Using integrative transcriptomics, we analyzed gene expression changes in mouse models throughout progression, human induced-pluripotent stem cells (hiPSCs), and post-mortem spinal cord tissue from ALS patients. We identified a conserved upregulation of interferon (IFN) genes and IFN-stimulating genes (ISGs) in both mouse models and human ALS, with a predominance Type I IFNs (IFN-α/β) in mice and Type II IFNs (IFN-γ) in humans. In mouse models, we observed robust and sustained upregulation of Type I and II ISGs, including ATF3, beginning at disease onset stage and persisting throughout disease progression. Single-cell transcriptomics further pinpointed vascular endothelial cells as a major source of ISGs. Furthermore, we found that the STING-TBK1 axis is essential for the induction of Type II ISGs in ALS, as its deletion impaired their expression. Our study uncovers a conserved ISGs signature across ALS models and patients, highlighting the potential role of innate immune activation in ALS pathogenesis. These findings suggest that ISGs may serve as potential biomarkers and therapeutic targets for ALS.}, } @article {pmid40024955, year = {2025}, author = {Masood, S and Almas, MS and Hassan, SSU and Tahira, S and Fiaz, MH and Minhas, UEA and Zafar, HMQ and Masood, M}, title = {Safety and efficacy of arimoclomol in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {40024955}, issn = {1590-3478}, abstract = {OBJECTIVES: Amyotrophic Lateral Sclerosis (ALS) is a debilitating motor neuron disorder characterized by muscle weakness, atrophy, and spasticity. This meta-analysis aims to assess the safety and efficacy of Arimoclomol in patients with ALS.

METHOD: A comprehensive literature search was conducted on 3 databases to discover articles published up to August 2024. Included studies were randomized controlled trials (RCTs). Data was analysed using Review Manager (v5.4). Cochrane Risk of Bias-2 (RoB-2) was adopted to assess the quality of RCTs.

RESULTS: A total of 359 patients were analysed, with 239 individuals in the Arimoclomol group and 120 individuals in the placebo group. The pooled analysis of the primary outcome, change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score from baseline, did not demonstrate a statistically significant difference favoring the Arimoclomol group (MD = 0.4495; 95% CI: -0.39, 1.27; p = 0.30). Similarly, secondary outcomes, including the Combined Assessment of Function and Survival (CAFS) rank score (MD = 1.00; 95% CI: -2.68, 4.67; p = 0.60), increase in transaminases (RR = 1.05; 95% CI: 0.19, 5.70; p = 0.95), mortality rate (RR = 0.86; 95% CI: 0.55, 1.34; p = 0.50), and adverse events (RR = 0.86; 95% CI: 0.55, 1.34; p = 0.50), showed no statistically significant differences between the groups.

CONCLUSION: This study does not conclusively demonstrate that Arimoclomol has beneficial effects on ALS patients' physical functionality but shows promise for safety. Further clinical trials are needed to explore the neuroprotective effects of Arimoclomol in the treatment of ALS.}, } @article {pmid40024058, year = {2025}, author = {Baumgarten, BR and Freye, CE}, title = {Use of Fisher's Ratio assisted multivariate curve resolution- alternating least squares for discovery-based analysis using ultrahigh pressure liquid chromatography-high resolution mass spectrometry.}, journal = {Journal of chromatography. A}, volume = {1747}, number = {}, pages = {465812}, doi = {10.1016/j.chroma.2025.465812}, pmid = {40024058}, issn = {1873-3778}, mesh = {Chromatography, High Pressure Liquid/methods ; Least-Squares Analysis ; Multivariate Analysis ; *Mass Spectrometry/methods ; Pharmaceutical Preparations/analysis/chemistry ; }, abstract = {Non-targeted analysis of complex chemical mixtures can be difficult considering the convoluted nature of the matrix and the potential unknown chemical differences between samples or classes of samples. Ultrahigh pressure liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-QTOF) is an ideal technique to probe chemical differences for a wide variety of samples. While UHPLC-QTOF can discover minute chemical differences down to low part per billion (ppb) concentrations with a high degree of confidence, the application of high-resolution mass spectrometry can yield massive amounts of information (∼ 10 gb per sample) that cannot be analyzed manually. Therefore, the application of chemometric techniques is mandatory for the interrogation of complex samples. Fisher's ratio (FR) assisted multivariate curve resolution-alternating least squares (MCR-ALS) was used to the discover and identify the chemical differences between two classes of materials: 1) a pond water matrix and 2) the matrix spiked with a pharmaceutical standard mix containing 17 compounds. Thirteen of the seventeen spiked compounds were discovered using FR analysis, and then five were successfully deconvoluted using MCR-ALS wherein the number of curves chosen were automatically determined using singular value decomposition (SVD). The use of an automated FR assisted MCR-ALS will aid in discovering trace levels of chemical components without the need for the researcher to provide potentially biased input which will aid in non-targeted workflow.}, } @article {pmid40022663, year = {2025}, author = {Buckett, LE and Holdom, CJ and Howe, SL and McCombe, PA and Henderson, RD and Al-Chalabi, A and Steyn, FJ and Ngo, ST}, title = {Persistent high levels of perceived fatigue are not associated with hypermetabolism in patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2471429}, pmid = {40022663}, issn = {2167-9223}, abstract = {Objective: Fatigue is a common symptom in amyotrophic lateral sclerosis (ALS). Little is known about factors that contribute to fatigue, and whether levels of fatigue change throughout disease course. We aimed to determine associations between self-reported perceived fatigue and metabolic and clinical features of ALS, and perceived fatigue over the course of disease. Methods: This prospective study was conducted between July 2017 and March 2024. Baseline measures of self-reported perceived fatigue, metabolic rate, and clinical measures of disease were assessed in 117 participants with clinically definite or probable ALS. For comparison, fatigue and metabolic rate were collected from 107 control participants. Perceived fatigue was determined using the Fatigue Severity Scale (FSS). Metabolic rate was assessed using indirect calorimetry. Functional capacity and clinical progression were assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R). Results: Baseline levels of perceived fatigue were greater in people living with ALS (plwALS) when compared to controls (5.44 vs. 2.55; p < 0.01). Perceived fatigue was higher in plwALS with lower ALSFRS-R scores and was not associated with measures of metabolism. For most plwALS, perceived fatigue remained high as functional capacity worsened. Conclusion: Our findings confirm higher prevalence of perceived fatigue in plwALS, with persistently high FSS scores reported by most patients during follow-up. High levels of fatigue were not associated with hypermetabolism, suggesting that metabolic rate is unlikely to be a primary contributor. Results highlight a need for further research to identify factors that contribute to fatigue in ALS, and options for improved fatigue management.}, } @article {pmid40022581, year = {2025}, author = {Galvin, M and Heverin, M and Mac Domhnaill, É and Mcfarlane, R and Meldrum, D and Murray, D and Bolger, A and Connelly, J and Flynn, K and Fox, E and Gibbons, F and Hederman, L and Impey, S and O'Keefe, I and O'Meara, C and McKibben, D and Nicholson, M and Stephens, G and Van Dijk, J and Van Den Berg, L and Hardiman, O}, title = {Challenges and solutions to complex data governance issues in cross-national, cross-sectoral, multidisciplinary real world health research: a descriptive overview.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2024.2428927}, pmid = {40022581}, issn = {2167-9223}, abstract = {Real-world clinical data is generated during clinical engagements. The collection and further processing and mining of clinical information requires consents and navigation of necessary and important data governance processes. PRECISION ALS is an academic industry programme that collects, collates and analyses clinical and para-clinical data from patients with ALS across 10 European sites. The infrastructure of PRECISION ALS represents a complex interplay of the clinical, governance, and technical frameworks. Incorporation of infrastructural and operational measures enables sophisticated cross-national, cross-sectoral and cross disciplinary health research. PRECISION ALS has established a range of domain expertise, technologies, governance and clinical data management practices that can be applied throughout the life cycle of patient data from generation, collation, delivery and secure storage for advanced analytics. PRECISION ALS is designed to move the field of ALS research to a true Precision Medicine based approach toward new and more effective therapeutics.}, } @article {pmid40021952, year = {2025}, author = {Hao, Y and Li, Z and Du, X and Xie, Q and Li, D and Lei, S and Guo, Y}, title = {Characterization and chemoproteomic profiling of protein O-GlcNAcylation in SOD1-G93A mouse model.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {31}, number = {1}, pages = {82}, pmid = {40021952}, issn = {1528-3658}, support = {92478109//National Natural Science Foundation of China/ ; 82471451//National Natural Science Foundation of China/ ; ZR2024QB108//Shandong Provincial Natural Science Foundation/ ; 7222082//Beijing Municipal Natural Science Foundation，China/ ; }, mesh = {Animals ; *Disease Models, Animal ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Mice ; *Mice, Transgenic ; *Proteomics/methods ; *Acetylglucosamine/metabolism ; *Spinal Cord/metabolism ; Glycosylation ; Superoxide Dismutase-1/metabolism/genetics ; Protein Processing, Post-Translational ; Humans ; Proteome/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. Protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification has been found to affect the processing of several important proteins implicated in ALS. However, the overall level and cellular localization of O-GlcNAc during ALS progression are incompletely understood, and large-scale profiling of O-GlcNAcylation sites in this context remains unexplored.

METHODS: By using immunostaining analysis and chemoenzymatic labeling-based quantitative chemoproteomics, we assayed O-GlcNAcylation dynamics of lumbar spinal cords from SOD-G93A mice and their non-transgenic (NTG) littermates, the most widely used animal model for studying ALS pathogenesis.

RESULTS: We discovered that the global O-GlcNAcylation was significantly reduced at the disease end stage. Correlatively, a great increase of OGA was observed. Immunohistochemistry and immunofluorescence analysis showed a higher proportion of O-GlcNAc-positive neurons in the NTG group, while O-GlcNAc colocalization with astrocytes/microglia was elevated in SOD1-G93A mice. Moreover, we reported the identification of 568 high-confidence O-GlcNAc sites from end-stage SOD1-G93A and NTG mice. Of the 568 sites, 226-many of which occurred on neuronal function and structure-related proteins-were found to be dynamically regulated.

CONCLUSION: These data provide a valuable resource for dissecting the functional role of O-GlcNAcylation in ALS and shed light on promising therapeutic avenues for ALS. The chemoenzymatic labeling-based chemoproteomic approach is applicable for probing O-GlcNAc dynamics in various pathological processes.}, } @article {pmid40020551, year = {2025}, author = {Tafuri, B and Giugno, A and Nigro, S and Zoccolella, S and Barone, R and Tamburrino, L and Gnoni, V and Urso, D and Rollo, E and De Blasi, R and Logroscino, G}, title = {Radiomic alterations and clinical correlates of hypothalamic nuclei in ALS.}, journal = {Computers in biology and medicine}, volume = {189}, number = {}, pages = {109906}, doi = {10.1016/j.compbiomed.2025.109906}, pmid = {40020551}, issn = {1879-0534}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology ; Male ; Female ; Middle Aged ; *Hypothalamus/diagnostic imaging ; Aged ; *Magnetic Resonance Imaging ; Retrospective Studies ; Body Mass Index ; Adult ; Image Processing, Computer-Assisted/methods ; Radiomics ; }, abstract = {OBJECTIVE: The aim of this study is to analyze hypothalamic changes and clinical/metabolic correlates with a radiomic approach in Amyotrophic Lateral Sclerosis (ALS).

METHODS: We retrospectively identified 54 sporadic ALS patients and 53 matched controls. We compared radiomics features over hypothalamic subunits in T1-weighted. Semi-partial correlation (Spearman's correlation) assessed the relationship between Body Mass Index (BMI) and clinical scores with radiomics features. We considered only moderate correlations (rho>|0.4|).

RESULTS: Compared to HC, individuals with ALS showed significantly higher values of radiomic measures in the left Anterior-Inferior, Posterior and Inferior-Tubular hypothalamic subunits. Similarly, right hypothalamic nuclei reported significant differences in Anterior-Superior, Posterior and Inferior-Tubular nuclei. Two radiomics measures of randomness of the intensities in left Anterior-Inferior subunit showed highly significant correlation with greater BMI values. Higher local homogeneity of the right Inferior-Tubular subunit corresponded to higher ALS Functional Rating Scale-Revised (ALSFRS-r), while finer textures of the left Anterior-Superior subunit were negatively related with disease progression rate.

CONCLUSIONS: These results support the hypothesis that a degenerative process affecting hypothalamus in ALS extends beyond the atrophy process. Intriguingly, the close relationship between the entropy of left Anterior-Inferior nucleus and the higher BMI may further demonstrate the critical role of hypothalamus in eating abnormalities. Furthermore, the inhomogeneity of the right Inferior-Tubular subunit reflects a more severe clinical condition by ALSFRS-R. This work represents a significant advancement in the study of ALS and its association with hypothalamic changes through a novel radiological approach, uncovering new associations between sub-hypothalamic radiomic changes, anthropometric measures, and disease outcomes.}, } @article {pmid40019593, year = {2025}, author = {Dobroniak, CC and Lesche, V and Olgemöller, U and Beck, P and Lehmann, W and Spering, C}, title = {Surgical strategy for chest wall reconstruction secondary to cardiopulmonary resuscitation versus post-traumatic.}, journal = {European journal of trauma and emergency surgery : official publication of the European Trauma Society}, volume = {51}, number = {1}, pages = {122}, pmid = {40019593}, issn = {1863-9941}, mesh = {Humans ; *Cardiopulmonary Resuscitation/methods ; Male ; Female ; Retrospective Studies ; Middle Aged ; *Thoracic Wall/injuries/surgery ; *Flail Chest/surgery/etiology ; *Rib Fractures/surgery ; *Sternum/injuries/surgery ; Germany ; Plastic Surgery Procedures/methods ; Aged ; Fracture Fixation, Internal/methods ; Adult ; Length of Stay/statistics & numerical data ; Bone Plates ; }, abstract = {PURPOSE: In mechanically cardiopulmonary resuscitated (CPR) patients, chest compressions at the level of the 3rd to 5th rib on the sternum result in reproducibly similar injury patterns: parasternal osteochondral dissociation (OCS) on both sides in combination with a sternal fracture with or without an additional serial rib fracture in the anterolateral column (ALS). This injury biomechanically impairs physiological breathing, resulting in an inverse breathing pattern. Trauma patients, on the other hand, often show a mixed pattern depending on the location of the main energy. The aim of the study was to evaluate the surgical technique of chest wall reconstruction (CWR) using transsternal refixation of the 5th rib on both sides in combination with plate osteosynthesis of the sternum and to analyze its success in comparison to the surgical strategy of CWR in the context of a traumatic genesis.

METHOD: Data acquisition was performed using medical records of a Level I Trauma Centre in Germany and compare patients with radiologically or clinically diagnosed flail chest as a result of cardiopulmonary mechanical resuscitation (CPR). The retrospective study included patients in the period 2018-2023 after surgical CWR. The patients were either post-CPR (n = 29; CPR) or trauma patients (n = 36; trauma). The collective was described and analyzed using the digital patient file, as well as data on ICU stay and duration of ventilation or conversion to assisted ventilation modes, reason for chest wall instability, time of surgery, length of stay and mortality. As a long-term follow-up, body plethysmography was analyzed comparatively. Primary endpoints were mean length of stay in ICU, time to surgery, ventilator dependency and mortality rate. Secondary endpoints were time to transfer to rehabilitation, ventilation disorders and long term outcome.

RESULTS: In the period 65 patients (48 m, 17w) were included, 29 of whom had been mechanically resuscitated (CPR), 36 formed to post-traumatic cohort (trauma). The CPR were significantly older (69 vs. 58 years; p-value 0.003). The duration from CPR to surgery was on average significantly longer than trauma to surgery (16.76 vs. 4.11 days). The mean length of stay in ICU were 30 days (trauma) and 45 days for CPR (significantly longer, p-value 0.0008). The mean duration of ventilation was 188 h for trauma and 593 h for CPR. Extubation or conversion to assisted, relevant de-escalating ventilation modes was possible in both groups after a mean of 38 h post-OP. Among the CPR patients, 4 died in hospital (hospital mortality: CPR 20.7% vs. trauma 5.6%), 7 (30%) were transferred to an early clinical rehabilitation and 10 were discharged to home or follow-up treatment. In the case of trauma, 5 (14.7%) were transferred to an early clinical rehabilitation and 20 were discharged to home or follow-up treatment. Bodyplethysmography 6 months after CPR / trauma showed no differences in both collectives with regard to ventilation disorders. Diffusion was prolonged in both groups, presumably due to the healing process of lungs contusion. Both showed no restriction disorders.

CONCLUSION: Chest wall reconstruction, including plate osteosynthesis of the sternum in combination with transsternal fixation of the 5th rib on both sides can largely restore physiological respiratory mechanics immediately after surgery and accelerate the weaning success. In the management of patients after CPR, the initial diagnosis which had indicated resuscitation, is the main focus and can often be an obstacle to extubation. Nevertheless, independent breathing can be accelerated by restoring the biomechanics through early surgical treatment using CWR and saves long-term ICU stays with the potential for further complication and resource consumption. CWR forms the essential basis for early rehabilitation of the underlying cause of resuscitation. Ventilation disorders do not occur after surgical CWR, even during the course of the procedure.}, } @article {pmid40019589, year = {2025}, author = {Shaw, SK and Sravani, N and Sharma, A and Anand, J}, title = {Assessment of probable zones of agricultural land suitability based on MCDM, probabilistic, and data-driven approach in Krishna District, India.}, journal = {Environmental monitoring and assessment}, volume = {197}, number = {3}, pages = {339}, pmid = {40019589}, issn = {1573-2959}, mesh = {*Agriculture/statistics & numerical data ; Conservation of Natural Resources/methods ; Decision Making ; *Decision Support Techniques ; Ecosystem ; Geographic Information Systems ; India ; Meteorological Concepts ; Remote Sensing Technology ; }, abstract = {Agricultural land evaluation is essential for crop cultivation for fostering a sustainable and productive agricultural system. To address this issue, this current study implements geographic information system (GIS)-based analytical hierarchy process (AHP), frequency ratio (FR), Shannon entropy (SE), and evidential belief function (EBF) models for possible identification of agricultural land in Krishna district, India. Eight thematic layers viz. rainfall, temperature, soil texture, slope, soil moisture index, organic matter content, groundwater level, and land use/land cover (LULC) exhibit their relative contribution toward the agricultural land suitability (ALS) assessment. A total of 56 groundwater wells are considered to prepare well inventory map. Then, 70% (40) and 30% (16) wells are taken to perform accuracy assessment of the proposed methods in training and validation phase respectively by receiver operating characteristics (ROC) curve and Seed Cell Area Index (SCAI) method. Four distinct classes of ALS have been delineated by each model viz. poor, moderate, high, and very high. AHP (79.05%) and SE (89.94%) showcases their effectiveness in delineating highly suitable agricultural land constituting higher area. Whereas EBF and FR model identifies 33.35% and 27% area of this district as moderate to poor ALS respectively. AUC value reveals that AHP (AUC = 0.701) method can be highly convenient in training phase, whereas EBF (AUC = 0.626) model evaluates average predictive strength for ALS assessment in validation phase for this study area. Outcomes of SCAI method demonstrate higher classification accuracy of SE model indicating higher suitability of bivariate approaches in accurate prediction. Results of this research significantly develop useful perception for the sustainable use and management of agricultural land of Krishna district with higher crop production. This will also help the Agricultural and Irrigation department of this district to build applicative plan for effective utilization of agricultural land with optimized use of available water resources.}, } @article {pmid40019378, year = {2025}, author = {Li, X and Jin, S and Wang, D and Wu, Y and Tang, X and Liu, Y and Yao, T and Han, S and Sun, L and Wang, Y and Hou, SX}, title = {Accumulation of Damaging Lipids in the Arf1-Ablated Neurons Promotes Neurodegeneration through Releasing mtDNA and Activating Inflammatory Pathways in Microglia.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e2414260}, doi = {10.1002/advs.202414260}, pmid = {40019378}, issn = {2198-3844}, support = {2023YFA1800202//National Key Research and Development Program of China/ ; 82450108//National Natural Science Foundation of China/ ; 82203511//National Natural Science Foundation of China/ ; 82472817//National Natural Science Foundation of China/ ; }, abstract = {Lipid metabolism disorders in both neurons and glial cells have been found in neurodegenerative (ND) patients and animal models. However, the pathological connection between lipid droplets and NDs remains poorly understood. The recent work has highlighted the utility of a neuron-specific Arf1-knockout mouse model and corresponding cells for elucidating the nexus between lipid metabolism disorders and amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). In this study, it is found that Arf1 deficiency first induced surplus fatty acid synthesis through the AKT-mTORC1-SREBP1-FASN axis, which further triggered endoplasmic reticulum (ER)-mitochondrial stress cascade via calcium flux. The organelle stress cascade further caused mitochondrial DNA (mtDNA) to be released into cytoplasm. Concurrently, the FASN-driven fatty acid synthesis in the Arf1-deficient neurons might also induce accumulation of sphingolipids in lysosomes that caused dysfunction of autophagy and lysosomes, which further promoted lysosomal stress and mitochondria-derived extracellular vesicles (MDEVs) release. The released MDEVs carried mtDNA into microglia to activate the inflammatory pathways and neurodegeneration. The studies on neuronal lipid droplets (LDs) and recent studies of microglial LDs suggest a unified pathological function of LDs in NDs: activating the inflammatory pathways in microglia. This finding potentially provides new therapeutic strategies for NDs.}, } @article {pmid40017821, year = {2025}, author = {Dierksen, F and Geibel, JS and Albrecht, J and Hofer, S and Dechent, P and Hesse, AC and Frahm, J and Bähr, M and Koch, JC and Liman, J and Maier, IL}, title = {T1-relaxation times along the corticospinal tract as a diagnostic marker in patients with amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroimaging}, volume = {4}, number = {}, pages = {1549727}, pmid = {40017821}, issn = {2813-1193}, abstract = {BACKGROUND AND PURPOSE: In the differential diagnostic workup of amyotrophic lateral sclerosis (ALS), magnetic resonance imaging (MRI) is primarily used to rule out significant differential diagnoses. So far, whole-brain T1-mapping has not been assessed as a diagnostic tool in this patient population.

METHODS: We investigated the diagnostic potential of a novel T1-mapping method based on real-time MRI with 0.5 mm in-plane resolution and 4s acquisition time per slice. The study included patients aged 18 to 90 years who met the revised El Escorial criteria for at least possible ALS. T1-relaxation times were measured along the corticospinal tract in predefined regions of interest.

RESULTS: Twenty-nine ALS-patients and 43 control group patients (CG) were included in the study. Median ALS Functional Rating Scale revised (ALSFRS-R) was 37 (IQR, 35-44) points and the mean duration from symptom onset to MRI was 21 ± 17 (SD) months. ALS patients showed significantly higher T1-relaxation times in all ROIs compared to CG with mean differences in the hand knob of 50 ms (p < 0.001), corona radiata 24 ms (p = 0.034), internal capsule 27 ms (p = 0.002) and midbrain peduncles 48 ms (p < 0.001). There was a consistent negative correlation between the ALSFRS-R and T1-relaxation times in all ROIs.

CONCLUSIONS: T1-relaxation times along the corticospinal tract are significantly elevated in ALS patients compared to CG and associated with lower ALSFRS-R. These results imply the analysis of T1-relaxation times as a promising diagnostic tool that can distinguish ALS patients from the control group. Ongoing longitudinal studies may provide deeper insights into disease progression and the effects of therapeutic interventions.}, } @article {pmid40017539, year = {2025}, author = {Mengistu, DY and Terribili, M and Pellacani, C and Ciapponi, L and Marzullo, M}, title = {Epigenetic regulation of TDP-43: potential implications for amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular medicine}, volume = {5}, number = {}, pages = {1530719}, pmid = {40017539}, issn = {2674-0095}, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by the progressive degeneration of motor neurons. One of the key pathogenic factors implicated in ALS is TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein encoded by the TARDBP gene. Under normal physiological conditions, TDP-43 predominantly resides in the nucleus, where it plays a critical role in regulating gene expression, alternative splicing, RNA transport, and stability. In ALS, TDP-43 undergoes pathological mislocalization from the nucleus to the cytoplasm, disrupting its normal function and contributing to disease progression. The nuclear loss of TDP-43 leads to widespread dysregulation of RNA metabolism. Moreover, mislocalized TDP-43 aggregates in the cytoplasm, acquires toxic properties that sequester essential RNA molecules and proteins. Importantly, deviations in TDP-43 levels, whether excessive or reduced, can lead to cellular dysfunction, and contribute to disease progression, highlighting the delicate balance required for neuronal health. Emerging evidence suggests that epigenetic mechanisms may play a crucial role in regulating TARDBP expression and, consequently, TDP-43 cellular levels. Epigenetic modifications such as DNA methylation, histone modifications, and non-coding RNAs are increasingly recognized as modulators of gene expression and cellular function in neurodegenerative diseases, including ALS. Dysregulation of these processes could contribute to aberrant TARDBP expression, amplifying TDP-43-associated pathologies. This review explores and summarizes the recent findings on how specific epigenetic modifications influence TDP-43 expression and discusses their possible implications for disease progression.}, } @article {pmid40017137, year = {2025}, author = {Lovett, A and Chary, S and Babu, S and Bruneteau, G and Glass, JD and Karlsborg, M and Ladha, S and Mayl, K and McDermott, C and Bucelli, RC and Chiò, A and Ferguson, TA and Cochrane, T and Fradette, S and Smirnakis, K and Inra, J and Malek, S and Fanning, L}, title = {Serious Neurologic Adverse Events in Tofersen Clinical Trials for Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28372}, pmid = {40017137}, issn = {1097-4598}, support = {//Biogen/ ; }, abstract = {INTRODUCTION/AIMS: Tofersen is approved for the treatment of amyotrophic lateral sclerosis (ALS) due to superoxide dismutase 1 mutations (SOD1-ALS). Here we report serious neurologic adverse events (AEs) that occurred in the tofersen clinical trials in people with SOD1-ALS.

METHODS: Serious neurologic AEs of myelitis, radiculitis, aseptic meningitis, and papilledema reported in the tofersen clinical trials are described. Serious AEs were defined according to International Conference for Harmonization guidelines, and neurologic AEs in clinical trials were diagnosed by investigators based on symptoms, clinical examination findings, and diagnostic workup.

RESULTS: Ten participants (approximately 7% of tofersen 100-mg-treated trial participants) experienced a total of 12 serious neurologic AEs-4 of myelitis, 2 of radiculitis, 2 of aseptic meningitis, and 4 of intracranial hypertension (ICH) and/or papilledema. All events but one resolved either spontaneously, with dosing interruption/modification, or with concomitant therapies. One event was ongoing but improved as of December 2022. While 3 events led to tofersen treatment discontinuation, all other participants were able to remain on treatment. No event was life-threatening or fatal.

DISCUSSION: Some antisense oligonucleotides (ASOs) have been described as having pro-inflammatory properties. Aseptic meningitis has been reported with nusinersen; however, myelitis, radiculitis, increased intracranial pressure, and papilledema have not been reported with ASO treatment. These neurologic AEs should be considered when assessing the overall benefit/risk of tofersen treatment for SOD1-ALS. Safety data from the open-label extension and expanded access program will continue to characterize these events and further inform the safety profile of tofersen in SOD1-ALS.}, } @article {pmid40016300, year = {2025}, author = {Xia, Y and Gregory, JM and Waldron, FM and Spence, H and Vallejo, M}, title = {Improving ALS detection and cognitive impairment stratification with attention-enhanced deep learning models.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {7045}, pmid = {40016300}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/complications ; *Deep Learning ; *Cognitive Dysfunction/diagnosis ; Female ; Male ; Aged ; Middle Aged ; Attention ; Neural Networks, Computer ; Brain/diagnostic imaging/pathology ; Neuroimaging/methods ; Frontotemporal Dementia/diagnosis/diagnostic imaging/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease marked by motor deterioration and cognitive decline. Early diagnosis is challenging due to the complexity of sporadic ALS and the lack of a defined risk population. In this study, we developed Miniset-DenseSENet, a convolutional neural network combining DenseNet121 with a Squeeze-and-Excitation attention mechanism, using 190 autopsy brain images from the Gregory Laboratory at the University of Aberdeen. The model distinguishes controls, ALS patients with no cognitive impairment, and ALS patients with cognitive impairment (ALS-frontotemporal dementia) with 97.37% accuracy, addressing a significant challenge in overlapping neurodegenerative disorders involving TDP-43 proteinopathy. Miniset-DenseSENet outperformed other transfer learning models, achieving a sensitivity of 1 and specificity of 0.95. These findings suggest that integrating transfer learning and attention mechanisms into neuroimaging can enhance diagnostic accuracy, enabling earlier ALS detection and improving patient stratification. This model has the potential to guide clinical decisions and support personalied therapeutic strategies.}, } @article {pmid40015858, year = {2025}, author = {Vijayarajan, VBA and Torra, J and Runge, F and de Jong, H and van de Belt, J and Hennessy, M and Forristal, PD}, title = {Confirmation and characterisation of ALS inhibitor resistant Poa trivialis from Ireland.}, journal = {Pesticide biochemistry and physiology}, volume = {208}, number = {}, pages = {106266}, doi = {10.1016/j.pestbp.2024.106266}, pmid = {40015858}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/antagonists & inhibitors/genetics/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Ireland ; *Sulfonylurea Compounds/pharmacology ; Mutation ; Sulfonamides/pharmacology ; Plant Proteins/genetics/antagonists & inhibitors ; Plant Weeds/drug effects ; Poaceae/drug effects ; Isoxazoles ; Sulfones ; }, abstract = {Relying on one broad-spectrum product to control grass weeds has resulted in cases of resistance to acetolactate synthase (ALS) inhibitors in species that were not the primary target such as Poa trivialis (POATR), in wheat fields in Ireland. In this study, we have characterised ALS inhibitor resistance in two populations of POATR-R, suspected of being resistant, to (i) sulfonylurea (SUs)-mesosulfuron + iodosulfuron (the selecting agent), (ii) SU + sulfonylamino‑carbonyl-triazolinone (SCT)-mesosulfuron + propoxycarbazone, and (iii) triazolopyrimidine (TP)-pyroxsulam ALS chemistries. Resistant POATR-R populations showed ALS inhibitor cross-resistance associated with target-site resistance (TSR) mutations. Combined mutations (Pro-197 and Trp-574) were found in POATR-R plants; Trp-574-Leu in POATR-R1 conferring greater SUs, SU + SCT and TP (resistance index, RI >214) resistance, while Pro-197-Thr in POATR-R2 (RI >37) was associated with less resistance. The high levels of ALS inhibitor cross-resistance in POATR-R populations caused by TSR mutations are consistent with the ploidy status, as cytogenetic tests revealed that both the R and S populations were diploid (2n = 2× = 14). Cytochrome P450 inhibitor assays did not detect metabolism-based ALS resistance in POATR-R. Alternative herbicide modes of action, including acetyl-CoA carboxylase (pinoxaden, fenoxaprop, propaquizafop, cycloxydim or clethodim) and 5-enolpyruvylshikimate-3-phosphate synthase (glyphosate) inhibitors applied at the recommended label rate were highly effective on these resistant populations. Residual herbicides and cultural methods, as well as the judicious use of alternative in-crop herbicide options, should be prioritized as sustainable options for managing these ALS-resistant populations. This is first worldwide characterisation of resistance mechanisms in P. trivialis to ALS inhibitor chemistries.}, } @article {pmid40015855, year = {2025}, author = {Xu, Y and Xu, F and Li, Y and Wang, X and Han, Y and Zheng, M}, title = {Effects of Pro197 resistance mutations occurring in different acetolactate synthase (ALS) isozymes on Descurainia sophia L. resistance to tribenuron-methyl.}, journal = {Pesticide biochemistry and physiology}, volume = {208}, number = {}, pages = {106263}, doi = {10.1016/j.pestbp.2024.106263}, pmid = {40015855}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Arylsulfonates/pharmacology ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Isoenzymes/genetics ; *Mutation ; Plant Proteins/genetics/metabolism ; Plant Weeds/drug effects/genetics ; }, abstract = {Descurainia sophia L. is one of the most problematic broad-leaf weed infesting winter wheat in China, and have evolved resistance to acetolactate synthase (ALS)-inhibiting herbicide of tribenuron-methyl. At least four ALS isozymes (ALS1 ∼ ALS4) exist in D. sophia, but these four ALS isozymes are not present in all D. sophia. In addition, amino acid mutations in ALS are mainly responsible for D. sophia resistance to tribenuron-methyl. In this study, D. sophia populations carrying homozygous mutation of Pro197Ser/Thr/Leu/Ala/His in ALS1 or in ALS2 were purified, respectively. Resistant D. sophia populations carrying mutant ALS exhibited 17 ∼ 694 folds resistance to tribenuorn-methyl. In addition, tribenuron-methyl resistance in D. sophia carrying ALS1 mutation was about 2.3 ∼ 11.4 folds higher than D. sophia with the same mutation in ALS2. The reduced binding affinity of ALS to tribenuron-methyl was mainly responsible for D. sophia resistance to tribenuron-methyl. However, the increase in resistance of D. sophia was not linear with the decrease of binding affinity of ALS to tribenuron-methyl. These results indicate that the effects of resistance mutations on ALS1 and ALS2 isozymes are not the same, and the ALS1 and ALS2 function differently in resistance evolution of D. sophia to tribenuron-methyl.}, } @article {pmid40015643, year = {2025}, author = {Hasumi, M and Ito, H and Machida, K and Niwa, T and Taminato, T and Nagai, Y and Imataka, H and Taguchi, H}, title = {Dissecting the mechanism of NOP56 GGCCUG repeat-associated non-AUG translation using cell-free translation systems.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {4}, pages = {108360}, doi = {10.1016/j.jbc.2025.108360}, pmid = {40015643}, issn = {1083-351X}, abstract = {The repeat expansion in the human genome contributes to neurodegenerative disorders such as spinocerebellar ataxia (SCA) and amyotrophic lateral sclerosis. Transcripts with repeat expansions undergo noncanonical translation called repeat-associated non-AUG (RAN) translation. The NOP56 gene, implicated in SCA36, contains a GGCCTG repeat in its first intron. In tissues of patients with SCA36, poly (Gly-Pro) and poly (Pro-Arg) peptides, likely produced through NOP56 RAN translation in (NOP56-RAN), have been detected. However, the detailed mechanism underlying NOP56-RAN remains unclear. To address this, we used cell-free translation systems to investigate the mechanism of NOP56-RAN and identified the following features. (i) Translation occurs in all reading frames of the sense strand of NOP56 intron 1. (ii) Translation is initiated in a 5' cap-dependent manner from near-cognate start codons upstream of the GGCCUG repeat in each frame. (iii) Longer GGCCUG repeats enhance NOP56-RAN. (iv) A frameshift occurs within the GGCCUG repeat. These findings provide insights into the similarities between NOP56-RAN and other types of RAN translation.}, } @article {pmid40015332, year = {2025}, author = {Tavares de Sousa, M and Hergert, B and Crispi, F and Gomez, O and Hecher, K}, title = {Imaging the fetal aortic arch and its branching pattern in a midtrimester screening population.}, journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2548-2411}, pmid = {40015332}, issn = {1438-8782}, abstract = {UNLABELLED: Purpose Variants of the aortic arch branching have recently been found to have an impact for neonates undergoing surgical interventions of the thoracic aorta such as repair of aortic coarctation. They have been described prenatally in 6%, whereas they occur in up to 26% postnatally. To explore whether the branching variations might have been under-diagnosed in utero, we comprehensively assessed the aortic arch and its branching patterns in a low-risk population between 19 and 22 weeks of gestation. Material and Methods This prospective cohort study included 139 low-risk singleton pregnancies. During a standardized fetal echocardiography we investigated the aortic arch in a sagittal view according to predefined landmarks. Based on video clips, its branching pattern was categorized in normal branching or branching variants by two operators who were blinded to each other. Results Classification of the aortic arch branching was achieved in 127/139 (91.4%) cases. 103 cases (81.1%) showed a normal pattern and 24 cases (18.9%) a branching variant. Both operators agreed on 18 brachiobicephalic trunks "(THE SO CALLED BOVINE ARCH)": , 4 aberrant left vertebral arteries, one aortic arch with five branching vessels and in one case there was disagreement on the type of the variant. Conclusion Prenatal targeted echocardiography could identify a 18.9% prevalence of aortic arch branching variants in a low-risk population. Future studies are warranted to assess the clinical impact of our findings on neonates with congenital heart defects.

HINTERGRUND: Gefäßvarianten der thorakalen Aortenabgänge wurden als Risikofaktoren für Neugeborene identifiziert, die eine Intervention der Aorta, zum Beispiel bei Aortenisthmusstenose, vor sich haben. Pränatal wurde die Häufigkeit mit bis zu 6% beschrieben, während sie postnatal in bis zu 26% gefunden wurden. Um zu untersuchen, ob die Varianten bisher in utero unterdiagnostiziert wurden, untersuchten wir den Aortenbogen und die Abgänge in einer Niedrigrisikogruppe zwischen 19 und 22 Schwangerschaftswochen.

MATERIAL UND METHODEN: Diese prospektive Kohortenstudie umfasste 139 Einlingsschwangerschaften mit niedrigem Risiko. Während einer standardisierten fetalen Echokardiografie untersuchten wir den Aortenbogen in sagittaler Ebene. Anhand von Videoclips wurden die Abgänge des Aorta von zwei Untersuchenden, die zueinander verblindet waren, entweder als normales Abgangsmuster oder als Variante klassifiziert.

ERGEBNISSE: Die Klassifizierung des Abgänge der fetalen Aorta gelang in 127/139 (91,4 %) der Fälle. In 103 Fällen (81,1 %) wurde ein normales Abgangsmuster beobachtet, während in 24 Fällen (18,9 %) eine Variante vorlag. In 18 Fällen wurde ein Truncus brachiocephalicus (SOGENANNTER BOVINER AORTENBOGEN),: in 4 Fällen eine aberrante linke Vertebralarterie und in einem Fall ein Aortenbogen mit fünf abgehenden Gefäßen gefunden. In einem Fall waren die Untersuchenden bezüglich der Variante uneinig.

SCHLUSSFOLGERUNG: Die gezielte pränatale Echokardiografie konnte in einer Niedrigrisikopopulation eine Prävalenz von 18,9 % für Varianten der Abgänge des Aortenbogen identifizieren. Zukünftige Studien sind erforderlich, um die klinischen Auswirkungen unserer Ergebnisse auf Neugeborene mit angeborenen Herzfehlern zu bewerten.}, } @article {pmid40014834, year = {2025}, author = {Gusovsky Chevalier, AV and Lin, CC and Kerber, K and Reynolds, EL and Callaghan, BC and Burke, JF}, title = {Cost Trends of New-To-Market Neurologic Medications: An Insurance Claims Database Analysis.}, journal = {Neurology}, volume = {104}, number = {6}, pages = {e213428}, pmid = {40014834}, issn = {1526-632X}, support = {T32 HS029590/HS/AHRQ HHS/United States ; }, mesh = {Humans ; Male ; Female ; United States ; Middle Aged ; *Databases, Factual ; Aged ; Adult ; Nervous System Diseases/drug therapy/economics ; Insurance Claim Review/trends ; Drug Costs/trends ; Young Adult ; }, abstract = {BACKGROUND AND OBJECTIVES: Costs for neurologic medications have increased considerably in recent years. Since 2014, more than 30 neurologic medications have been approved by the US Food and Drug Administration (FDA) for neurologic conditions. This study aims to characterize recent trends in annual costs and aggregate spending from 2012 to 2021 for new-to-market (NTM) medications for 9 neurologic conditions.

METHODS: We used the Merative MarketScan commercial and Medicare supplemental databases to observe patients seen by a neurologist with neurologic diseases with newly FDA-approved medications from 2014 to 2021: amyotrophic lateral sclerosis (ALS), transthyretin amyloidosis (ATTR), Duchenne muscular dystrophy (DMD), Huntington disease (HD), myasthenia gravis (MG), migraine, orthostatic hypotension (OH), tardive dyskinesia (TD), and spinal muscular atrophy (SMA). Patients were included if they had ≥1 disease-related prescription medication fill from 2012 to 2021. NTM (medications approved from 2014 to 2021) and older evidence-based guideline-supported medications were observed annually. Outcomes examined were annual and aggregate out-of-pocket (OOP) and total medication costs.

RESULTS: We identified 2,687 unique individuals with ALS, 38 with ATTR, 69 with DMD, 884 with HD, 9,984 with MG, 441,099 with migraine, 4,723 with OH, 1,266 with TD, and 17 with SMA. The youngest population was DMD (mean = 25 years [SD = 7]), and the oldest was TD (mean = 66 years [SD = 14]). For DMD, the population was 99% male and for migraine, the population was 84% female, and the other conditions had more relatively even sex divides. Collectively, migraine medications had the largest increase in aggregate costs (1993%) and had a substantial increase in OOP costs on average by 234% ($86-$288). Eculizumab for MG was an extreme outlier, with OOP costs increasing by 4,099% ($413-$17,359) and aggregate OOP costs by 7,005% ($5,375-$381,894). OOP costs of edaravone ($304-$5,707) and deutetrabenazine ($670-$7,170) sharply increased by 1,775% and 971%, respectively.

DISCUSSION: NTM medications for neurologic conditions have substantial and increasing individual and societal costs, which was not observed for older generic medications. These data suggest a need for policies to limit the financial burden of NTM medications on patients with neurologic conditions.}, } @article {pmid40013906, year = {2025}, author = {Howard, J and Bekker, HL and McDermott, CJ and McNeill, A}, title = {Exploring the needs and preferences of people with amyotrophic lateral sclerosis (ALS) when making genomic testing decisions: an interview study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2025.2469727}, pmid = {40013906}, issn = {2167-9223}, abstract = {Objective: Whole Genome Sequencing (WGS) for amyotrophic lateral sclerosis (ALS) (also known as motor neuron disease, MND) raises multiple considerations and has a range of implications for individuals and their family. However, it is unclear what needs people with ALS have when making genomic testing decisions. This study explores the experiences, needs and preferences of these individuals when considering WGS and going through the process. Methods: A semi-structured interview study was carried out with 14 people with ALS from across the UK who had, or were considering, WGS. Participants were recruited from a local ALS care center and MND Association/MND Scotland channels. Data were analyzed using framework analysis. Results: Findings indicate variation in (a) how WGS and access to pretest genetic counseling is provided, (b) the perceived adequacy of information to support decision-making and prepare people with ALS for their test result and its consequences, and (c) preferences for making decisions with family and health professionals that best meets their clinical and life needs along the care pathway. Conclusions: There is an urgent need for people with ALS to have relevant, accurate and accessible information that supports proactively their decision-making around WGS, particularly in the context of genetically-targeted treatments and clinical trials. These findings will contribute to the development of a shared decision-making intervention supporting people with ALS to make genomic testing decisions with their family and neurology services.}, } @article {pmid40012994, year = {2025}, author = {Sabetta, E and Ferrari, D and Massimo, L and Kõks, S}, title = {Tandem repeat expansions and copy number variations as risk factors and diagnostic tools for amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1522445}, pmid = {40012994}, issn = {1664-2295}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder leading to upper and lower motoneurons degeneration. Although several mechanisms potentially involved in disease development have been identified, its pathogenesis is not fully understood. From the patient side, ALS diagnosis, still based on clinical criteria, can be difficult and may take up to 1 year. More than 30 genes have been associated to genetically inherited ALS, among which four (C9ORF72, SOD1, TARDBP and FUS) would explain around 60-70% of cases. However, familial ALS represents only 5-10% of ALS cases while the remaining are sporadic, with genetics explaining 6-10% of such cases only. In this context, short tandem repeats (STRs) expansions, have recently been found in clinically diagnosed ALS patients. In this review, we discuss the recent discoveries on ALS associated STRs and their potential as biomarkers as well as prognosis and therapy targets.}, } @article {pmid40012862, year = {2024}, author = {Tang, MB and Liu, YX and Hu, ZW and Luo, HY and Zhang, S and Shi, CH and Xu, YM}, title = {Study insights in the role of PGC-1α in neurological diseases: mechanisms and therapeutic potential.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1454735}, pmid = {40012862}, issn = {1663-4365}, abstract = {Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which is highly expressed in the central nervous system, is known to be involved in the regulation of mitochondrial biosynthesis, metabolic regulation, neuroinflammation, autophagy, and oxidative stress. This knowledge indicates a potential role of PGC-1α in a wide range of functions associated with neurological diseases. There is emerging evidence indicating a protective role of PGC-1α in the pathogenesis of several neurological diseases. As such, a deeper and broader understanding of PGC-1α and its role in neurological diseases is urgently needed. The present review provides a relatively complete overview of the current knowledge on PGC-1α, including its functions in different types of neurons, basic structural characteristics, and its interacting transcription factors. Furthermore, we present the role of PGC-1α in the pathogenesis of various neurological diseases, such as intracerebral hemorrhage, ischemic stroke, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and other PolyQ diseases. Importantly, we discuss some compounds or drug-targeting strategies that have been studied to ameliorate the pathology of these neurological diseases and introduce the possible mechanistic pathways. Based on the available studies, we propose that targeting PGC-1α could serve as a promising novel therapeutic strategy for one or more neurological diseases.}, } @article {pmid40012679, year = {2025}, author = {Glashutter, M and Wijesinghe, P and Matsubara, JA}, title = {TDP-43 as a potential retinal biomarker for neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1533045}, pmid = {40012679}, issn = {1662-4548}, abstract = {TDP-43 proteinopathies are a spectrum of neurodegenerative diseases (NDDs) characterized by the pathological cytoplasmic aggregation of the TDP-43 protein. These include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and others. TDP-43 in the eye shows promise as a biomarker for these NDDs. Several studies have identified cytoplasmic TDP-43 inclusions in retinal layers of donors with ALS, FTLD, AD, CTE, and other conditions using immunohistochemistry. Our findings suggest that pathological aggregates of TDP-43 in the human retina are most prevalent in FTLD-TDP, ALS, and CTE, suggesting these diseases may provide the most reliable context for studying the potential of TDP-43 as a retinal biomarker. Animal model studies have been pivotal in exploring TDP-43's roles in the retina, including its nuclear and cytoplasmic localization, RNA binding properties, and interactions with other proteins. Despite these advances, more research is needed to develop therapeutic strategies. A major limitation of human autopsy studies is the lack of corresponding brain pathology assessments to confirm TDP-43 proteinopathy diagnosis and staging. Other limitations include small sample sizes, lack of antemortem eye pathology and clinical histories, and limited comparisons across multiple NDDs. Future directions for the TDP-43 as a retinal biomarker for NDDs include retinal tracers, hyperspectral imaging, oculomics, and machine learning development.}, } @article {pmid40012394, year = {2025}, author = {Kumar, P and Kumar, A and Keerthipriya, M and H, C and Nalini, A and Vengalil, S and Sitani, K and Nagaraj, C and Dey, S and Debnath, M and K, V and Satyaprabha, TN}, title = {A New Approach to Synthesizing Carbon-11-PBR28 and its Clinical Validation in ALS Patients.}, journal = {Current radiopharmaceuticals}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118744710341203250220042349}, pmid = {40012394}, issn = {1874-4729}, abstract = {BACKGROUND: Many studies have reported Translocator Protein (TSPO) overexpression in many neurological disorders. Carbon-11[11C]PBR28 is a widely used TSPO Positron Emission Tomography (PET) radiopharmaceutical. We have compared HPLC-based purification with cartridge-based purification and performed PET-MR imaging in ALS patients.

METHODS: [11C]PBR28 has been synthesized using an HPLC-based and cartridge-based purification technique in the FX2C chemistry module. All necessary quality controls were performed and compared. We injected 350 ± 20 MBq of the [11C]PBR28 intravenously into human patients (n = 6) diagnosed with amyotrophic lateral syndrome (ALS) and performed simultaneous PETMR dynamic imaging.

RESULTS: The radiochemical purity was greater than 95% with both methods. The radiochemical yield was 11.8 ± 3.3%, and molar activity was 253 ± 20.9 GBq/μmol with a total synthesis time of 25 ± 2 min in the HPLC-based purification method. Whereas the radiochemical yield was 53.0 ± 3.6%, and molar activity was 885 ± 17.7 GBq/μmol with a total synthesis time of 12 ± 2 min in the cartridge-based purification method. We have compared PET-MR imaging of ALS limb onset (n =3) with ALS bulbar and limb onset (n =3), and there was a difference in time activity curves. The activity was higher in the precentral gyrus and cerebellum at 2.5 ± 0.5 min in bulbar cases with an SUV of 2.3 ± 0.3, whereas ALS limb onset showed the highest uptake at 0.5 ± 0.2 min with an SUV of 1.5 ± 0.2.

CONCLUSION: The cartridge-based method provided higher radiochemical yield and molar activity.}, } @article {pmid40012174, year = {2025}, author = {Rajamanickam, G and Hu, Z and Liao, P}, title = {Targeting the TRPM4 Channel for Neurologic Diseases: Opportunity and Challenge.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {}, number = {}, pages = {10738584251318979}, doi = {10.1177/10738584251318979}, pmid = {40012174}, issn = {1089-4098}, abstract = {As a monovalent cation channel, the transient receptor potential melastatin 4 (TRPM4) channel is a unique member of the transient receptor potential family. Abnormal TRPM4 activity has been identified in various neurologic disorders, such as stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, amyotrophic lateral sclerosis, pathologic pain, and epilepsy. Following brain hypoxia/ischemia and inflammation, TRPM4 up-regulation and enhanced activity contribute to the cell death of neurons, vascular endothelial cells, and astrocytes. Enhanced ionic influx via TRPM4 leads to cell volume increase and oncosis. Depolarization of membrane potential following TRPM4 activation and interaction between TRPM4 and N-methyl-d-aspartate receptors exacerbate excitotoxicity during hypoxia. Importantly, TRPM4 expression and activity remain low in healthy neurons, making it an ideal drug target. Current approaches to inhibit or modulate the TRPM4 channel have various limitations that hamper the interpretation of TRPM4 physiology in the nervous system and potentially hinder their translation into therapy. In this review, we discuss the pathophysiologic roles of TRPM4 and the different inhibitors that modulate TRPM4 activity for potential treatment of neurologic diseases.}, } @article {pmid40011745, year = {2025}, author = {Rödström, KEJ and Eymsh, B and Proks, P and Hayre, MS and Cordeiro, S and Mendez-Otalvaro, E and Madry, C and Rowland, A and Kopec, W and Newstead, S and Baukrowitz, T and Schewe, M and Tucker, SJ}, title = {Cryo-EM structure of the human THIK-1 K2P K[+] channel reveals a lower Y gate regulated by lipids and anesthetics.}, journal = {Nature structural & molecular biology}, volume = {}, number = {}, pages = {}, pmid = {40011745}, issn = {1545-9985}, abstract = {THIK-1 (KCNK13) is a halothane-inhibited and anionic-lipid-activated two-pore domain (K2P) K[+] channel implicated in microglial activation and neuroinflammation, and a current target for the treatment of neurodegenerative disorders, for example Alzheimer's disease and amyothropic lateral sclerosis (ALS). However, compared to other K2P channels, little is known about the structural and functional properties of THIK-1. Here we present a 3.16-Å-resolution cryo-EM structure of human THIK-1 that reveals several distinct features, in particular, a tyrosine in M4 that contributes to a lower 'Y gate' that opens upon activation by physiologically relevant G-protein-coupled receptor and lipid signaling pathways. We demonstrate that linoleic acid bound within a modulatory pocket adjacent to the filter influences channel activity, and that halothane inhibition involves a binding site within the inner cavity, both resulting in conformational changes to the Y gate. Finally, the extracellular cap domain contains positively charged residues that line the ion exit pathway and contribute to the distinct biophysical properties of this channel. Overall, our results provide structural insights into THIK-1 function and identify distinct regulatory sites that expand its potential as a drug target for the modulation of microglial function.}, } @article {pmid40011708, year = {2025}, author = {Yang, C and Lee, GB and Hao, L and Hu, F}, title = {TMEM106B deficiency leads to alterations in lipid metabolism and obesity in the TDP-43[Q331K] knock-in mouse model.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {315}, pmid = {40011708}, issn = {2399-3642}, support = {R01 NS088448/NS/NINDS NIH HHS/United States ; R21 AG078741/AG/NIA NIH HHS/United States ; R01NS088448//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS121608/NS/NINDS NIH HHS/United States ; R21AG078741//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01NS121608//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; Mice ; *Membrane Proteins/genetics/metabolism ; *Lipid Metabolism/genetics ; *Nerve Tissue Proteins/genetics/metabolism ; *Disease Models, Animal ; *Obesity/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism/deficiency ; Gene Knock-In Techniques ; Male ; Mice, Inbred C57BL ; }, abstract = {The TMEM106B gene, encoding a lysosomal membrane protein, is closely linked with brain aging and neurodegeneration. TMEM106B has been identified as a risk factor for several neurodegenerative diseases characterized by aggregation of the RNA-binding protein TDP-43, including frontotemporal lobar degeneration (FTLD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). To investigate the role of TMEM106B in TDP-43 proteinopathy, we ablated TMEM106B in the TDP-43[Q331K] knock-in mouse line, which expresses an ALS-linked TDP-43 mutation at endogenous levels. We found that TMEM106B deficiency leads to glial activation, Purkinje cell loss, and behavioral deficits in TDP-43[Q331K] mice without inducing typical TDP-43 pathology. Interestingly, ablation of TMEM106B results in significant body weight gain, increased fat deposition, and hepatic triglyceride (TG) accumulation in TDP-43[Q331K] mice. In addition, lipidomic and transcriptome analysis shows a profound alteration in lipid metabolism in the liver of TDP-43[Q331K]Tmem106b[-/-] mice. Our studies reveal a novel function of TMEM106B and TDP-43 in lipid metabolism and provide new insights into their roles in neurodegeneration.}, } @article {pmid40011434, year = {2025}, author = {Gao, G and Shi, Y and Deng, HX and Krainc, D}, title = {Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1982}, pmid = {40011434}, issn = {2041-1723}, support = {R21 NS114765/NS/NINDS NIH HHS/United States ; NS114765//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS099623/NS/NINDS NIH HHS/United States ; R35 NS122257/NS/NINDS NIH HHS/United States ; NS122257//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS099623//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; *Lipid Peroxidation ; *Ketoglutarate Dehydrogenase Complex/metabolism/genetics ; Humans ; *Mitochondria/metabolism ; *Parkinson Disease/metabolism/genetics ; Male ; Mice ; *alpha-Synuclein/metabolism/genetics ; *Disease Models, Animal ; *DNA-Binding Proteins/metabolism/genetics ; *Dopaminergic Neurons/metabolism/pathology ; Thioctic Acid/metabolism ; Transcription Factors/metabolism/genetics ; Mitochondrial Proteins/metabolism/genetics ; Mice, Knockout ; Ketoglutaric Acids/metabolism ; Brain/metabolism ; }, abstract = {Dysregulation of mitochondrial function has been implicated in Parkinson's disease (PD), but the role of mitochondrial metabolism in disease pathogenesis remains to be elucidated. Using an unbiased metabolomic analysis of purified mitochondria, we identified alterations in α-ketoglutarate dehydrogenase (KGDH) pathway upon loss of PD-linked CHCHD2 protein. KGDH, a rate-limiting enzyme complex in the tricarboxylic acid cycle, was decreased in CHCHD2-deficient male mouse brains and human dopaminergic neurons. This deficiency of KGDH led to elevated α-ketoglutarate and increased lipid peroxidation. Treatment of CHCHD2-deficient dopaminergic neurons with lipoic acid, a KGDH cofactor and antioxidant agent, resulted in decreased levels of lipid peroxidation and phosphorylated α-synuclein. CHCHD10, a close homolog of CHCHD2 that is primarily linked to amyotrophic lateral sclerosis/frontotemporal dementia, did not affect the KGDH pathway or lipid peroxidation. Together, these results identify KGDH metabolic pathway as a targetable mitochondrial mechanism for correction of increased lipid peroxidation and α-synuclein in Parkinson's disease.}, } @article {pmid40010009, year = {2025}, author = {Mikuriya, S and Takegawa-Araki, T and Tamura, M}, title = {Edaravone mitigates TDP-43 mislocalization in human amyotrophic lateral sclerosis neurons with potential implication of the SIRT1-XBP1 pathway.}, journal = {Free radical biology & medicine}, volume = {230}, number = {}, pages = {283-293}, doi = {10.1016/j.freeradbiomed.2025.01.012}, pmid = {40010009}, issn = {1873-4596}, mesh = {Humans ; *Edaravone/pharmacology ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *X-Box Binding Protein 1/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism/drug effects ; *Motor Neurons/metabolism/drug effects/pathology ; *Sirtuin 1/metabolism/genetics ; Signal Transduction/drug effects ; Free Radical Scavengers/pharmacology ; Neuroprotective Agents/pharmacology ; Endoplasmic Reticulum Stress/drug effects ; Gene Expression Regulation/drug effects ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss along with pathological mislocalization of TAR DNA-binding protein 43 (TDP-43), a protein implicated in RNA metabolism. Although edaravone, a free-radical scavenger, has been approved for ALS treatment, its precise mechanism of action is not fully understood, particularly in relation to TDP-43 pathology. Here, we investigated the effects of edaravone on induced pluripotent stem cell (iPSC)-derived motor neurons in a patient with ALS harboring a TDP-43 mutation. Our results demonstrated that edaravone significantly attenuated neurodegeneration, as evidenced by neurite preservation, neuronal cell death reduction, and correction of aberrant cytoplasmic localization of TDP-43. These neuroprotective effects were not observed with vitamin C, indicating a unique mechanism of action for edaravone, distinct from its antioxidative properties. RNA sequencing revealed that edaravone rapidly modulated gene expression, including protein quality control pathway, such as the ubiquitin-proteasome system. Further analysis identified X-box binding protein (XBP1), a key regulator of the endoplasmic reticulum stress response, as a critical factor in the therapeutic effects of edaravone. This study suggests that edaravone may offer a multifaceted therapeutic approach for ALS by targeting oxidative stress and TDP-43 mislocalization through distinct molecular pathways.}, } @article {pmid40009859, year = {2025}, author = {Chung, J and Lim, F}, title = {Effect of Nurse Residency Programs on New Graduate Nurses Entering the Critical Care Setting: An Integrative Review.}, journal = {Critical care nursing quarterly}, volume = {48}, number = {2}, pages = {120-142}, pmid = {40009859}, issn = {1550-5111}, mesh = {Humans ; *Clinical Competence ; *Critical Care Nursing/education ; *Preceptorship ; Education, Nursing, Baccalaureate ; Critical Care ; Internship, Nonmedical/organization & administration ; }, abstract = {The transition period from undergraduate nursing education to professional practice is a time of uncertainty and great difficulty for new graduate nurses (NGNs). Nurse residency programs (NRPs) provide structured education, simulation-based learning, and preceptorship to ease the transition. Although its effect on improving retention of NGNs is well established in the literature, the effect on clinical competency has not been documented as well. The purpose of this integrative review is to appraise the available literature and synthesize the evidence that demonstrates the effect of NRPs on clinical competency of NGNs entering the critical care setting. Inclusion criteria were quantitative and qualitative studies, peer-reviewed studies published after 2004 and in English, identified through a systematic literature search using the CINAHL database. Critical appraisal of the articles was completed using Law et al's Critical Review Form. Eight articles (4 quantitative, 3 mixed method, and 1 qualitative study) met the inclusion criteria. The themes identified were common tools used to assess the efficacy of NRPs, improved clinical competency of NGNs, improved self-confidence, improved retention rates, and peer support among NGNs. Implications for nursing education and practice include applying evidence-based NRPs, incorporating simulation, enhancing sustainability, and reducing NRP variability through accreditation.}, } @article {pmid40009787, year = {2025}, author = {Mondesert, E and Delaby, C and De La Cruz, E and Kuhle, J and Benkert, P and Pradeilles, N and Duchiron, M and Morchikh, M and Camu, W and Cristol, JP and Hirtz, C and Esselin, F and Lehmann, S}, title = {Comparative Performances of 4 Serum NfL Assays, pTau181, and GFAP in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {104}, number = {6}, pages = {e213400}, pmid = {40009787}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; Female ; *Glial Fibrillary Acidic Protein/blood ; Male ; *Neurofilament Proteins/blood ; Aged ; *tau Proteins/blood ; Middle Aged ; *Biomarkers/blood ; Phosphorylation ; Cohort Studies ; Prognosis ; }, abstract = {BACKGROUND AND OBJECTIVES: Selecting the most appropriate blood tests is crucial for the management of patients with amyotrophic lateral sclerosis (ALS). This study evaluates the diagnostic and prognostic performance of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau 181 (pTau181) biomarkers in ALS to establish their clinical relevance and cutoff values.

METHODS: In a cohort of patients from the ALS center in Montpellier, we conducted a head-to-head comparison of 4 different technologies and 3 distinct serum analytes: NfL was tested using the ultrasensitive Simoa and the microfluidic Ella platforms, along with 2 assays recently set up on clinical-grade platforms: Lumipulse and Elecsys. We also used Elecsys to assess serum GFAP and pTau181.

RESULTS: Our cohort included 139 patients with ALS and 70 non-ALS patients, with a mean age of 66.1 ± 11.4 years and 47.4% of women. The mean follow-up was 42 ± 26.3 months for patients with ALS and 141.6 ± 106.3 months for non-ALS patients, with a mortality rate of 85.5% vs 7.7%. There was a high correlation between all methods tested for serum NfL quantification (R[2] = 0.939 to 0.963). The area under the curve (AUC) for ALS diagnosis was 0.889 (0.827-0.932) for NfL Simoa, 0.906 (0.847-0.944) for Ella, 0.912 (0.853-0.948) for Lumipulse, and 0.910 (0.851-0.946) for Elecsys. Serum pTau181 and GFAP showed poor diagnostic performance with AUCs of 0.565 (0.472-0.649) and 0.546 (0.461-0.636), respectively. Kaplan-Meier survival analysis revealed significant hazard ratios (4.4-5.4) for blood NfL. Patients with ALS had a 40%-50% chance of surviving 50 weeks below the prognostic cutoff values while survival rates dropped to near zero above. NfL and GFAP levels were associated with age and body mass index, considered confounding factors. pTau181 levels varied significantly in patients with ALS depending on the site of onset.

DISCUSSION: This study demonstrates the consistent performance of 4 immunoassays for serum NfL quantification in ALS. NfL showed high diagnostic and prognostic accuracy, making it suitable for individual assessment, unlike GFAP or pTau181. We propose diagnostic and prognostic cutoff values for serum NfL, providing a basis for wider implementation, especially with the clinically accredited Lumipulse and Elecsys platforms, which are becoming standard practice.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that serum NfL levels are useful in identifying over 80% of patients with ALS and predicting survival in patients with ALS compared with pTau181 and GFAP levels.}, } @article {pmid40009417, year = {2025}, author = {Oliveira Santos, M and Pinto, S and Silveira, F and Gromicho, M and Alves, I and Castro, J and Castro, I and de Carvalho, M}, title = {Amyotrophic Lateral Sclerosis Associated With Severe Sensory Neuronopathy: Case Series.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {3}, pages = {133-139}, doi = {10.1097/CND.0000000000000520}, pmid = {40009417}, issn = {1537-1611}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Male ; Middle Aged ; Female ; Aged ; Disease Progression ; Sensation Disorders/etiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily the motor system. However, an association with sensory neuronopathy has been scarcely described. We described 3 unrelated patients (2 males) with sporadic spinal-onset ALS and sensory neuronopathy. Mean onset age was 63.7 years and mean Revised Amyotrophic Lateral Sclerosis Functional Rating Scale at diagnosis was 42. Sensory disturbances emerged before or overlap with motor symptoms in the same onset region and followed the same pattern of lower motor neuron involvement over disease progression. Two patients have also bilateral trigeminal sensory fibers affection. None had cognitive abnormalities. Genetic testing for the most common ALS-associated genes was unrevealing. Mean disease duration and ALS functional rating scale-revised at last visit was 47 months and 27, respectively. One patient is still alive, dependent on nocturnal noninvasive ventilation. Motor neuron disease is now considered a multisystem neurodegenerative disorder, and sensory neuronopathy, although very rare, should not be neglected as a possible part of the disease spectrum.}, } @article {pmid40009414, year = {2025}, author = {Hamad, AA}, title = {Tofersen for Amyotrophic Lateral Sclerosis: Genetic Treatment With Precision Medicine: The Future of ALS Treatment.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {3}, pages = {117-119}, doi = {10.1097/CND.0000000000000517}, pmid = {40009414}, issn = {1537-1611}, } @article {pmid40009412, year = {2025}, author = {Finsterer, J}, title = {Before Trapezius RNS Can Be Recommended as an Additional Tool for the Diagnosis of ALS, Well-Powered Prospective Studies Are Required.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {3}, pages = {114-115}, doi = {10.1097/CND.0000000000000515}, pmid = {40009412}, issn = {1537-1611}, } @article {pmid40009238, year = {2025}, author = {Ruffo, P and Traynor, BJ and Conforti, FL}, title = {Advancements in genetic research and RNA therapy strategies for amyotrophic lateral sclerosis (ALS): current progress and future prospects.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {233}, pmid = {40009238}, issn = {1432-1459}, support = {ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/diagnosis ; Humans ; Genetic Therapy/methods ; }, abstract = {This review explores the intricate landscape of neurodegenerative disease research, focusing on Amyotrophic Lateral Sclerosis (ALS) and the intersection of genetics and RNA biology to investigate the causative pathogenetic basis of this fatal disease. ALS is a severe neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness and paralysis. Despite significant research advances, the exact cause of ALS remains largely unknown. Thanks to the application of next-generation sequencing (NGS) approaches, it was possible to highlight the fundamental role of rare variants with large effect sizes and involvement of portions of non-coding RNA, providing valuable information on risk prediction, diagnosis, and treatment of age-related diseases, such as ALS. Genetic research has provided valuable insights into the pathophysiology of ALS, leading to the development of targeted therapies such as antisense oligonucleotides (ASOs). Regulatory agencies in several countries are evaluating the commercialization of Qalsody (Tofersen) for SOD1-associated ALS, highlighting the potential of gene-targeted therapies. Furthermore, the emerging significance of microRNAs (miRNAs) and long RNAs are of great interest. MiRNAs have emerged as promising biomarkers for diagnosing ALS and monitoring disease progression. Understanding the role of lncRNAs in the pathogenesis of ALS opens new avenues for therapeutic intervention. However, challenges remain in delivering RNA-based therapeutics to the central nervous system. Advances in genetic screening and personalized medicine hold promise for improving the management of ALS. Ongoing clinical trials use genomic approaches for patient stratification and drug targeting. Further research into the role of non-coding RNAs in the pathogenesis of ALS and their potential as therapeutic targets is crucial to the development of effective treatments for this devastating disease.}, } @article {pmid40008462, year = {2025}, author = {Huertas-Alonso, AJ and González-Serrano, DJ and Salgado-Ramos, M and Hadidi, M and Sánchez-Verdú, P and Cabañas, B and Chuck, CJ and Clark, JH and Moreno, A}, title = {Sustainable Microwave-Assisted Synthesis of Medium- and Long-Chain Alkyl Levulinates from Biomass-Derived Levulinic Acid.}, journal = {ChemSusChem}, volume = {}, number = {}, pages = {e202402508}, doi = {10.1002/cssc.202402508}, pmid = {40008462}, issn = {1864-564X}, support = {SBPLY/17/180501/000522//Junta de Comunidades de Castilla-La Mancha/ ; RTI2018-099503-B-I00//Ministerio de Ciencia, Innovación y Universidades/ ; }, abstract = {Alkyl levulinates (ALs) represent a family of bio-compounds derived from levulinic acid (LA), a platform chemical obtained from lignocellulosic biomass. Medium- and long-chain ALs (pentyl levulinate or longer) have shown potential as biofuel and fuel additives due to their relatively low oxygen content and resemblance to biodiesel. This study reports a fast and environmentally friendly method for synthesizing ALs via microwave (MW)-assisted LA esterification, laying emphasis on medium- and long-chain ALs. By combining p-toluenesulfonic acid (5 wt % loading) as catalyst and MW radiation as heating source for a short time (5 minutes), excellent yields of ALs (≥89 mol %) were achieved for a wide range of primary and secondary alcohols (2-10 carbons), overcoming the expected lower reactivity of long chain alcohols. Additionally, formation of undesired side products, such as dialkyl ethers or LA aldol condensation products, was significantly minimized. The feasibility of recovering the unreacted alcohol was successfully proved by simple distillation (88 wt % recovery). The green chemistry metrics assessment proved that this approach aligns with the green chemistry principles and the United Nations Sustainable Development Goals, offering a more sustainable pathway for biofuel and fuel additive production.}, } @article {pmid40008327, year = {2025}, author = {van Eijk, RPA and Steyn, FJ and Janse van Mantgem, MR and Schmidt, A and Meyjes, M and Allen, S and Daygon, DV and Loeffler, JP and Al-Chalabi, A and van den Berg, LH and Henderson, RD and Ngo, ST}, title = {An open-label Phase 2a study to assess the safety and tolerability of trimetazidine in patients with amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {1}, pages = {fcaf063}, pmid = {40008327}, issn = {2632-1297}, abstract = {Metabolic imbalance is associated with amyotrophic lateral sclerosis progression. Impaired glucose oxidation and increased reliance on fatty acid oxidation contribute to reduced metabolic flexibility and faster disease progression in amyotrophic lateral sclerosis. We sought to evaluate the safety and tolerability, and explore the pharmacodynamic response of trimetazidine, a partial fatty acid oxidation inhibitor, on oxidative stress markers and energy expenditure in amyotrophic lateral sclerosis. The study was conducted between June 29, 2021 and May 24, 2023. People living with amyotrophic lateral sclerosis, recruited in Australia and the Netherlands, received open-label oral trimetazidine for 12 weeks after an initial 4-week lead-in period. The primary outcome measures were safety and tolerability, as well as the change from baseline in oxidative stress markers malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Secondary outcome measures were change from baseline in energy expenditure, amyotrophic lateral sclerosis functional rating scale-revised, and slow vital capacity (SVC). Linear mixed effects were used to estimate the mean difference in MDA and 8-OHdG between the on- and off-treatment periods. This trial is registered under ClinicalTrial.gov National Clinical Trial (NCT) number NCT04788745 and European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2020-005018-17. Twenty-one participants received trimetazidine; 19 (90%) completed the treatment period. Trimetazidine was well tolerated; there were 57 adverse events reported, of which 7 (11%) were deemed potentially drug-related, including hot flushes (2), nausea (2), paraesthesia (2) and fatigue (1). MDA was numerically lower during treatment [-0.29 uM; 95% confidence interval (CI) -0.90 to 0.33, P = 0.36]; 8-OHdG was significantly lower during treatment (-0.12 nM; 95% CI -0.23 to -0.01, P = 0.0245). The decrease in oxidative stress markers was accompanied by a reduction in resting energy expenditure (95 kcal, 95% CI 36.8-154, P = 0.0014). The absence of a placebo group prevented the interpretation of the clinical parameters. Oral trimetazidine was safe and well tolerated among patients with amyotrophic lateral sclerosis. This, combined with the significant reduction in markers of oxidative stress and resting energy expenditure, warrants a larger double-blind placebo-controlled efficacy study.}, } @article {pmid40008320, year = {2025}, author = {Wulterkens, D and Coumou, F and Slagt, C and Waalewijn, RA and Mommers, L}, title = {Defibrillation pad placement accuracy among Advanced Life Support instructors: A manikin-based observational study examining experience, self-evaluation, and actual performance.}, journal = {Resuscitation plus}, volume = {22}, number = {}, pages = {100886}, pmid = {40008320}, issn = {2666-5204}, abstract = {BACKGROUND: Ventricular fibrillation is common in patients with out-of-hospital cardiac arrest. Early and effective defibrillation is important for their survival. Effective defibrillation depends highly on correct positioning of the defibrillation pads. Teaching this correctly by ALS instructors is therefore crucial.

METHODS: Fifty certified advanced life support instructors were recruited from a large training institute. Participants were asked to place defibrillation pads on an anatomically and real-weight (90 kg) manikin. Primary outcome was the placement of defibrillation pads placed in the sternal-apical and anterior-posterior positions. Secondary outcomes were performance self-assessment, defibrillation experience, self-perceived competence and self-efficacy in teaching defibrillation. These measures were evaluated using an 11-point Likert scale.

RESULTS: A total of 31 medical doctors and 19 registered nurses were enrolled in this study. Defibrillation pads were placed (mean ± SD) 42 ± 21 mm, 38 ± 23 mm, 35 ± 19 mm and 61 ± 48 mm from the reference point for the sternal, apical, anterior and posterior pads respectively, resulting in a respectively correct placement of 18%, 20%, 32% and 28%. The average number of correctly applied pads per instructor was 0.98 ± 0.74 out of four.Self-assessment of defibrillation pads placed by the participants were 8.56 ± 1.33 and 7.88 ± 1.64 for the sternal-apical and anterior-posterior positions respectively. Personal defibrillation experience showed that the majority had applied over 20 standard defibrillations. Experience with anterior-posterior pad placement was less and experience with bi-axillary and double sequential external defibrillation positions were absent in most participants. Self-perceived competence for the sternal-apical, anterior-posterior, bi-axillary and dual external synchronized positions were 8.68 ± 1.06, 8.08 ± 1.37, 5.57 ± 2.95 and 5.11 ± 2.67 respectively. Self-efficacy score for teaching defibrillation was 8.59 ± 0.81. No association was found between the number of correctly applied pads and any of the participants' variables.

CONCLUSION: This study corroborates and expands upon existing knowledge regarding the challenges of defibrillator pad placement, revealing substantial variation in placement accuracy among instructors. Our novel analysis of pad angles and anterior-posterior analysis demonstrates that a significant portion of pads are incorrectly placed. These findings highlight the need for standardized approaches and improved training methodologies in defibrillator pad placement.}, } @article {pmid40008198, year = {2025}, author = {Garetto, B and Cao, N and Finelli, V and Aunan, E and Signorile, M and Olsbye, U and Bordiga, S and Nova, A and Borfecchia, E}, title = {Pinpointing Cu-Coordination Motifs in Bio-Inspired MOFs by Combining DFT-Assisted XAS Analysis and Multivariate Curve Resolution.}, journal = {The journal of physical chemistry. C, Nanomaterials and interfaces}, volume = {129}, number = {7}, pages = {3570-3582}, pmid = {40008198}, issn = {1932-7447}, abstract = {In recent years, X-ray absorption spectroscopy (XAS) has emerged as an essential technique for investigating the structure and composition of heterogeneous catalysts, providing valuable insights into the nature of active sites within these systems. However, the average nature of the XAS signal, inherently merged over all the absorber-containing species forming during in situ/operando experiments, often complicates the interpretation of the data. Nonetheless, advanced analysis methods have been developed to address this problem. In particular, herein we employed in situ XAS spectroscopy together with multivariate curve resolution-alternating least squares (MCR-ALS) and wavelet transform (WT) analysis to monitor the evolution of distinct Cu species in histidine-modified Cu-UiO-66 MOFs and to obtain detailed structural insights about the Cu sites. A novel approach adopted in this work was the application of density functional theory (DFT)-assisted extended X-ray absorption fine structure (EXAFS) fitting to quantitatively refine the local structure of the MCR-derived pure Cu species. This approach revealed the preferential redox activity of Cu[II] ions coordinated within the defective Zr clusters of the MOF, compared to Cu[II] ions bound to both the histidine molecule and the defective site during a standard redox reaction protocol.}, } @article {pmid40007904, year = {2025}, author = {Esteruelas, G and Ettcheto, M and Haro, I and Herrando-Grabulosa, M and Gaja-Capdevila, N and Gomara, MJ and Navarro, X and Espina, M and Souto, EB and Camins, A and García, ML and Sánchez-López, E}, title = {Novel Tissue-Specific Multifunctionalized Nanotechnological Platform Encapsulating Riluzole Against Motor Neuron Diseases.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {2273-2288}, pmid = {40007904}, issn = {1178-2013}, mesh = {*Riluzole/pharmacokinetics/pharmacology/chemistry/administration & dosage ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Motor Neuron Disease/drug therapy ; Neuroprotective Agents/chemistry/pharmacokinetics/pharmacology/administration & dosage ; Motor Neurons/drug effects ; Humans ; Nanoparticles/chemistry ; Polyethylene Glycols/chemistry/pharmacokinetics ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Mice ; Drug Carriers/chemistry/pharmacokinetics ; Blood-Brain Barrier/drug effects/metabolism ; Drug Delivery Systems/methods ; Tissue Distribution ; Peptides/chemistry/pharmacokinetics/administration & dosage ; }, abstract = {BACKGROUND: Motor neuron diseases are neurological disorders characterized by progressive degeneration of upper and/or lower motor neurons. Amyotrophic Lateral Sclerosis (ALS) is the most common form of motor neuron diseases, where patients suffer progressive paralysis, muscle atrophy and finally death. Despite ALS severity, no treatment is safe and fully effective. In this area, Riluzole was the first drug approved and it constitutes the gold-standard for this pathology. However, to obtain suitable therapeutic efficacy, Riluzole requires high doses that are associated with severe adverse effects in other tissues. To attain Riluzole therapeutic efficacy avoiding other organs side-effects, new therapeutic strategies to enhance the delivery of Riluzole specifically to motor neurons constitute an unmet medical need. In this area, we have developed a novel multifunctional nanostructurated carrier to selectively deliver Riluzole to motor neurons.

RESULTS: This work develops and characterizes at in vitro and in vivo levels a tissue-targeted formulation of peptide and PEG-labelled PLGA nanoparticles encapsulating Riluzole. For this purpose, pVEC, a cell penetrating peptide able to increase transport through the blood-brain barrier, was attached to the nanoparticles surface. The multifunctionalized nanoparticles show suitable characteristics for the release of Riluzole in the central nervous system and were detected in motor neurons within 1 h after administration while significantly reducing the concentration of Riluzole in non-therapeutic organs responsible of side effects.

CONCLUSION: A novel drug delivery system has been developed and characterized, demonstrating enhanced CNS biodistribution of riluzole, which shows promise as efficient therapeutic tool for motor neuron diseases, including amyotrophic lateral sclerosis.}, } @article {pmid40006958, year = {2025}, author = {Mielcarska, MB and Rouse, BT}, title = {Viruses and the Brain-A Relationship Prone to Trouble.}, journal = {Viruses}, volume = {17}, number = {2}, pages = {}, pmid = {40006958}, issn = {1999-4915}, mesh = {Humans ; *Brain/virology ; Animals ; Viruses/pathogenicity/genetics ; Antiviral Agents/therapeutic use/pharmacology ; Virus Diseases/virology ; Neurodegenerative Diseases/virology ; }, abstract = {Neurological disorders, some of which are associated with viral infections, are growing due to the aging and expanding population. Despite strong defenses of the central nervous system, some viruses have evolved ways to breach them, which often result in dire consequences. In this review, we recount the various ways by which different viruses can enter the CNS, and we describe the consequences of such invasions. Consequences may manifest as acute disease, such as encephalitis, meningitis, or result in long-term effects, such as neuromuscular dysfunction, as occurs in poliomyelitis. We discuss evidence for viral involvement in the causation of well-known chronic neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, as well as vascular dementia in the elderly. We also describe the approaches currently available to control a few of the neural viral infections. These include antivirals that are effective against human immunodeficiency virus and herpes simplex virus, as well as vaccines valuable for controlling rabies virus, poliomyelitis virus, and some flavivirus infections. There is an urgent need to better understand, at a molecular level, how viruses contribute to acute and, especially, chronic neurological diseases and to develop more precise and effective vaccines and therapies.}, } @article {pmid40006784, year = {2025}, author = {Ji, M and Yu, H and Cui, H and Chen, J and Yu, J and Li, X}, title = {A New Pro-197-Ile Mutation in Amaranthus palmeri Associated with Acetolactate Synthase-Inhibiting Herbicide Resistance.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {4}, pages = {}, pmid = {40006784}, issn = {2223-7747}, support = {CARS25//China Agriculture Research System/ ; }, abstract = {Palmer amaranth (Amaranthus palmeri S. Watson), native to North America, is one of the most prominent invasive weed species on agricultural land. Acetolactate synthase (ALS)-resistant A. palmeri (Amaranthus palmeri) is widespread, while the research focus on resistance pattern and molecular basis of A. palmeri to imazethapyr is seldom documented in China. An A. palmeri population that survived the recommended rate of imazethapyr was collected in Shandong Province, China. The resistant mechanism and pattern of A. palmeri to imazethapyr was investigated. Dose-response assay showed that the resistant (R) population displayed a high resistance level (292.5-fold) to imazethapyr compared with the susceptible (S) population. Sequence analysis of the ALS gene revealed that nucleotide mutations resulted in three resistance-conferring amino acid substitutions, Pro-197-Ile, Trp-574-Leu, and Ser-653-Asp, in the individual plants of the R population. An in vitro enzyme assay indicated that the ALS was relatively unsusceptible to imazethapyr in the R population, showing a resistance index of 88.6-fold. ALS gene expression and copy number did not confer resistance to imazethapyr in the R population. Pro-197-Ile is the first reported amino acid substitution conferring ALS resistance to A. palmeri. This is the first case of an imazethapyr-resistant A. palmeri biotype in China.}, } @article {pmid40004464, year = {2025}, author = {Liu, Z and Song, SY}, title = {Genomic and Transcriptomic Approaches Advance the Diagnosis and Prognosis of Neurodegenerative Diseases.}, journal = {Genes}, volume = {16}, number = {2}, pages = {}, pmid = {40004464}, issn = {2073-4425}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/diagnosis ; *Transcriptome/genetics ; Prognosis ; *Genome-Wide Association Study/methods ; Genomics/methods ; Gene Expression Profiling/methods ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Genetic Predisposition to Disease ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a growing societal challenge due to their irreversible progression and significant impact on patients, caregivers, and healthcare systems. Despite advances in clinical and imaging-based diagnostics, these diseases are often detected at advanced stages, limiting the effectiveness of therapeutic interventions. Recent breakthroughs in genomic and transcriptomic technologies, including whole-genome sequencing, single-cell RNA sequencing (scRNA-seq), and CRISPR-based screens, have revolutionized the field, offering new avenues for early diagnosis and personalized prognosis. Genomic approaches have elucidated disease-specific genetic risk factors and molecular pathways, while transcriptomic studies have identified stage-specific biomarkers that correlate with disease progression and severity. Furthermore, genome-wide association studies (GWAS), polygenic risk scores (PRS), and spatial transcriptomics are enabling the stratification of patients based on their risk profiles and prognostic trajectories. Advances in functional genomics have uncovered actionable targets, such as ATXN2 in ALS and TREM2 in AD, paving the way for tailored therapeutic strategies. Despite these achievements, challenges remain in translating genomic discoveries into clinical practice due to disease heterogeneity and the complexity of neurodegenerative pathophysiology. Future integration of genetic technologies holds promise for transforming diagnostic and prognostic paradigms, offering hope for improved patient outcomes and precision medicine approaches.}, } @article {pmid40004056, year = {2025}, author = {Yan, B and Suen, MC and Xu, N and Lu, C and Liu, C and Zhu, G}, title = {G-Quadruplex Structures Formed by Human Telomere and C9orf72 GGGGCC Repeats.}, journal = {International journal of molecular sciences}, volume = {26}, number = {4}, pages = {}, pmid = {40004056}, issn = {1422-0067}, support = {32071188//National Scientific Foundation of China/ ; 16101120, 161011121, AoE/M-403-16, AoE/M-401/20//Research Grants Council of the Hong Kong Special Administrative Region, China/ ; BGF.2023.019//Hong Kong University of Science and Technology, China/ ; 2021A1515220104//Guangdong Basic and Applied Basic Research Foundation, China/ ; 32301012//Young Scientists Fund of the National Natural Science Foundation of China/ ; }, mesh = {*G-Quadruplexes ; Humans ; *Telomere/genetics ; *C9orf72 Protein/genetics ; *DNA Repeat Expansion/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia/genetics/pathology ; }, abstract = {G-quadruplexes (G4s) are unique nucleic acid structures composed of guanine-rich (G-rich) sequences that can form diverse topologies based on the arrangement of their four strands. G4s have attracted attention for their potential roles in various biological processes and human diseases. In this review, we focus on the G4 structures formed by human telomeric sequences, (GGGTTA)n, and the hexanucleotide repeat expansion, (GGGGCC)n, in the first intron region of the chromosome 9 open reading frame 72 (C9orf72) gene, highlighting their structural diversity and biological significance. Human telomeric G4s play crucial roles in telomere retention and gene regulation. In particular, we provide an in-depth summary of known telomeric G4s and focus on our recently discovered chair-type conformation, which exhibits distinct folding patterns. The chair-type G4s represent a novel folding pattern with unique characteristics, expanding our knowledge of telomeric G4 structural diversity and potential biological functions. Specifically, we emphasize the G4s formed by the (GGGGCC)n sequence of the C9orf72 gene, which represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The thorough structural analysis in this review advances our comprehension of the disease mechanism and provides valuable insights into developing targeted therapeutic strategies in ALS/FTD.}, } @article {pmid40002740, year = {2025}, author = {Meng, K and Jia, H and Hou, X and Zhu, Z and Lu, Y and Feng, Y and Feng, J and Xia, Y and Tan, R and Cui, F and Yuan, J}, title = {Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies.}, journal = {Biomedicines}, volume = {13}, number = {2}, pages = {}, pmid = {40002740}, issn = {2227-9059}, support = {600791001//the Research Start-up Fund of Jining Medical University/ ; JYHL2021MS13//Research Fund for Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University/ ; 81700055//the National Natural Science Foundation of China/ ; Grant No. D2016021//Outstanding Talent Research Funding of Xuzhou Medical University/ ; BK20160229//Natural Science Foundation of Jiangsu Province/ ; tsqn201909147//Taishan Scholars Program of Shandong Province/ ; G2Y-kJS-SD-2023-097//Co-construction of Science and Technology Projects by the Science and Technology Department of the State Administration of Traditional Chinese Medicine/ ; }, abstract = {Neurodegenerative disease (ND) refers to the progressive loss and morphological abnormalities of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Recent studies have shown that mitochondria play a broad role in cell signaling, immune response, and metabolic regulation. For example, mitochondrial dysfunction is closely associated with the onset and progression of a variety of diseases, including ND, cardiovascular diseases, diabetes, and cancer. The dysfunction of energy metabolism, imbalance of mitochondrial dynamics, or abnormal mitophagy can lead to the imbalance of mitochondrial homeostasis, which can induce pathological reactions such as oxidative stress, apoptosis, and inflammation, damage the nervous system, and participate in the occurrence and development of degenerative nervous system diseases such as AD, PD, and ALS. In this paper, the latest research progress of this subject is detailed. The mechanisms of oxidative stress, mitochondrial homeostasis, and mitophagy-mediated ND are reviewed from the perspectives of β-amyloid (Aβ) accumulation, dopamine neuron damage, and superoxide dismutase 1 (SOD1) mutation. Based on the mechanism research, new ideas and methods for the treatment and prevention of ND are proposed.}, } @article {pmid40002527, year = {2025}, author = {Eisen, A and Kiernan, MC}, title = {The Neonatal Microbiome: Implications for Amyotrophic Lateral Sclerosis and Other Neurodegenerations.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, pmid = {40002527}, issn = {2076-3425}, abstract = {Most brain development occurs in the "first 1000 days", a critical period from conception to a child's second birthday. Critical brain processes that occur during this time include synaptogenesis, myelination, neural pruning, and the formation of functioning neuronal circuits. Perturbations during the first 1000 days likely contribute to later-life neurodegenerative disease, including sporadic amyotrophic lateral sclerosis (ALS). Neurodevelopment is determined by many events, including the maturation and colonization of the infant microbiome and its metabolites, specifically neurotransmitters, immune modulators, vitamins, and short-chain fatty acids. Successful microbiome maturation and gut-brain axis function depend on maternal factors (stress and exposure to toxins during pregnancy), mode of delivery, quality of the postnatal environment, diet after weaning from breast milk, and nutritional deficiencies. While the neonatal microbiome is highly plastic, it remains prone to dysbiosis which, once established, may persist into adulthood, thereby inducing the development of chronic inflammation and abnormal excitatory/inhibitory balance, resulting in neural excitation. Both are recognized as key pathophysiological processes in the development of ALS.}, } @article {pmid40002476, year = {2025}, author = {Raymond, J and Howard, IM and Berry, J and Larson, T and Horton, DK and Mehta, P}, title = {Head Injury and Amyotrophic Lateral Sclerosis: Population-Based Study from the National ALS Registry.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, pmid = {40002476}, issn = {2076-3425}, support = {n/a/CC/CDC HHS/United States ; }, abstract = {Background/Objectives: To examine if head injury (HI) is associated with age at ALS diagnosis in the United States. Methods: In this cross-sectional populationf-based analysis, we identified patients with ALS who were registered from 2015 to 2023 who completed the Registry's head trauma survey module. The association between HI and age at ALS diagnosis was assessed using multivariate analysis. Results: Of the 3424 respondents, 56.6% had experienced a HI. The adjusted odds ratio (aOR) for an ALS diagnosis before age 60 years for patients with a HI was 1.24 (95% CI, 1.07-1.45). One or two HIs had an aOR of 1.15 (95% CI, 0.97-1.36), and five or more HIs had an aOR of 1.58 (95% CI, 1.19-2.09). HI before age 18 years yielded an aOR of 2.03 (95% CI, 1.53-2.70) as well as HI between the ages of 18 and 30 years (aOR = 1.48, 95% CI: 1.06-2.06)). When narrowing the analysis to patients with HI before age 18 compared with patients with no HI, we found an association with HI that led to an emergency department or hospital visit (aOR = 1.50 (95% CI: 1.21-1.86)). Conclusions: In this cross-sectional analysis of ALS patients, HIs occurring in childhood and early adulthood and the number of HIs increased the odds of being diagnosed before age 60 years. These results suggest that HI continues to be a risk factor for ALS and could be associated with a younger age of diagnosis.}, } @article {pmid40002468, year = {2025}, author = {Dawoody Nejad, L and Pioro, EP}, title = {Modeling ALS with Patient-Derived iPSCs: Recent Advances and Future Potentials.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, pmid = {40002468}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a terminal complex neurodegenerative disease, with 10-15% of cases being familial and the majority being sporadic with no known cause. There are no animal models for the 85-90% of sporadic ALS cases. More creative, sophisticated models of ALS disease are required to unravel the mysteries of this complicated disease. While ALS patients urgently require new medications and treatments, suitable preclinical in vitro models for drug screening are lacking. Therefore, human-derived induced pluripotent stem cell (hiPSC) technology offers the opportunity to model diverse and unreachable cell types in a culture dish. In this review, we focus on recent hiPSC-derived ALS neuronal and non-neuronal models to examine the research progress of current ALS 2D monocultures, co-cultures, and more complex 3D-model organoids. Despite the challenges inherent to hiPSC-based models, their application to preclinical drug studies is enormous.}, } @article {pmid40002444, year = {2025}, author = {Okoh, C and Mayall, L and Makin, SM and Chen, C and Zarotti, N}, title = {Non-Pharmacological Interventions for Caregivers of People with Motor Neurone Disease: A Scoping Review of Psychosocial Outcomes.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, pmid = {40002444}, issn = {2076-3425}, abstract = {Objective: Caregivers of individuals with motor neurone disease (MND) face a wide range of psychosocial difficulties. To address these, non-pharmacological interventions have been trialled, showing promising results. However, no clear characterisation of the breadth of psychosocial constructs examined by the interventions is currently available, resulting in the lack of a core outcome set (COS). The present review explored the types of psychosocial outcomes investigated in studies that adopted non-pharmacological interventions with caregivers of people with MND. Methods: A scoping review was conducted across four major databases (Academic Search Ultimate, CINAHL, PsycINFO, and MEDLINE) from inception to the 1 March 2024. Results: From an initial return of 4802 citations, 10 were considered eligible for inclusion. A total of 10 main psychosocial outcomes were identified: anxiety and depression, psychological distress, resilience, caregiver burden, caregiver preparedness, self-efficacy, quality of life, spiritual wellbeing, and mindfulness. Conclusions: Caregiver burden and symptoms of anxiety and depression represent pivotal outcomes, but caution is advised with regard to caregiver burden's potential multidimensional structure. Psychological distress and quality of life are also commonly investigated, but clearer consensus is needed on their conceptualisation. There is a paucity of studies characterising important psychosocial outcomes such as resilience, problem-solving, self-efficacy, and mindfulness, while no investigations are available for relevant outcomes such as coping, isolation, and loneliness. Further research is warranted to address these gaps to improve our insight into non-pharmacological support for MND caregivers and ultimately lead to the development of a core psychosocial outcome set in this population.}, } @article {pmid40001624, year = {2025}, author = {Ma, B and Ren, J and Qian, X}, title = {Study on the Polarization of Astrocytes in the Optic Nerve Head of Rats Under High Intraocular Pressure: In Vitro.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {12}, number = {2}, pages = {}, pmid = {40001624}, issn = {2306-5354}, support = {12472309 12072210//National Natural Science Foundation of China/ ; }, abstract = {Astrocytes, the most common glial cells in the optic nerve head (ONH), provide support and nutrition to retinal ganglion cells. This study aims to investigate the polarization types of astrocytes in the ONH of rats under high intraocular pressure (IOP) and explore signaling pathways potentially associated with different types of polarized astrocytes. The rat models with chronic high IOP were established. High IOP lasted for 2, 4, 6, and 8 weeks. Astrocytes were extracted from the ONH of rats using the tissue block cultivation method. Western blot was used to detect the expression of proteins associated with astrocyte polarization. Proteomics was employed to identify differential proteins associated with astrocyte polarization. Astrocytes polarized into A2 astrocytes after 2, 4, 6, and 8 weeks of high IOP, while polarization into A1 astrocytes began only after 8 weeks of high IOP. The differential proteins associated with A1 astrocyte polarization are primarily enriched in pathways of neurodegeneration with respect to multiple diseases, while the differential proteins associated with A2 astrocyte polarization are primarily enriched in pathways of spliceosome in amyotrophic lateral sclerosis. Our findings could provide a better understanding of the role of ONH astrocytes in the pathogenesis of glaucoma and offer new perspectives for glaucoma treatment.}, } @article {pmid40001529, year = {2025}, author = {Onu, CJ and Adu, M and Chakkour, M and Kumar, V and Greenberg, ML}, title = {Inositol Phosphates and Synthesizing Enzymes: Implications in Neurodegenerative Disorders.}, journal = {Biomolecules}, volume = {15}, number = {2}, pages = {}, pmid = {40001529}, issn = {2218-273X}, support = {R01 GM125082/GM/NIGMS NIH HHS/United States ; R35 GM149271/GM/NIGMS NIH HHS/United States ; GM149271/GF/NIH HHS/United States ; GM125082/GF/NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Inositol Phosphates/metabolism ; Animals ; Parkinson Disease/metabolism ; Alzheimer Disease/metabolism ; Signal Transduction ; Inositol/metabolism ; }, abstract = {Inositol is a vital sugar molecule involved in numerous signaling pathways required for cellular homeostasis and cell survival. Myo-inositol and its phospho-derivatives, inositol phosphates (IPs), are the most prevalent forms of inositol found in living cells. They are involved in regulating ion channels, metabolic flux, stress response, and other key biological processes. While emerging research has highlighted the significant roles of inositol phosphates in immunity, cancer, and metabolic diseases, there is a lack of comprehensive reviews on their roles in psychiatric and neurological disorders. This review aims to fill that gap by analyzing the existing literature on the importance of inositol phosphates in severe psychiatric and neurological conditions such as Parkinson's disease, Alzheimer's disease, bipolar disorder, amyotrophic lateral sclerosis, schizophrenia, and Huntington's disease, underscoring the potential to pave the way for new treatment regimens for these debilitating disorders targeting inositol pathways.}, } @article {pmid40001370, year = {2025}, author = {Silva Ortíz, YL and de Sousa, TC and Kruklis, NE and Galeano García, P and Brango-Vanegas, J and Soller Ramada, MH and Franco, OL}, title = {The Role of Amphibian AMPs Against Oxidative Stress and Related Diseases.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {14}, number = {2}, pages = {}, pmid = {40001370}, issn = {2079-6382}, abstract = {Amphibians use their skin as an effective defense mechanism against predators and microorganisms. Specialized glands produce antimicrobial peptides (AMPs) that possess antioxidant properties, effectively reducing reactive oxygen species (ROS) levels. These peptides are promising candidates for treating diseases associated with oxidative stress (OS) and redox imbalance, including neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), as well as age-related conditions, like cardiovascular diseases and cancer. This review highlights the multifaceted roles of AMPs and antioxidant peptides (AOPs) in amphibians, emphasizing their protective capabilities against oxidative damage. They scavenge ROS, activate antioxidant enzyme systems, and inhibit cellular damage. AOPs often share structural characteristics with AMPs, suggesting a potential evolutionary connection and similar biosynthetic pathways. Peptides such as brevinin-1FL and Cath-KP demonstrate neuroprotective effects, indicating their therapeutic potential in managing oxidative stress-related diseases. The antioxidant properties of amphibian-derived peptides pave the way for novel therapeutic developments. However, a deeper understanding of the molecular mechanisms underlying these peptides and their interactions with oxidative stress is essential to addressing ROS-related diseases and advancing therapeutic strategies in clinical practice.}, } @article {pmid40000803, year = {2025}, author = {Giblin, A and Cammack, AJ and Blomberg, N and Anoar, S and Mikheenko, A and Carcolé, M and Atilano, ML and Hull, A and Shen, D and Wei, X and Coneys, R and Zhou, L and Mohammed, Y and Olivier-Jimenez, D and Wang, LY and Kinghorn, KJ and Niccoli, T and Coyne, AN and van der Kant, R and Lashley, T and Giera, M and Partridge, L and Isaacs, AM}, title = {Neuronal polyunsaturated fatty acids are protective in ALS/FTD.}, journal = {Nature neuroscience}, volume = {28}, number = {4}, pages = {737-747}, pmid = {40000803}, issn = {1546-1726}, support = {NS132836//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS123242//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *Fatty Acids, Unsaturated/metabolism ; Humans ; *Frontotemporal Dementia/metabolism/genetics/pathology ; *Neurons/metabolism ; C9orf72 Protein/genetics ; Induced Pluripotent Stem Cells/metabolism ; Drosophila ; Disease Models, Animal ; Fatty Acid Desaturases/metabolism/genetics ; Animals, Genetically Modified ; Male ; Brain/metabolism ; }, abstract = {Here we report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in a Drosophila model of C9orf72 repeat expansion, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), and in human postmortem ALS spinal cord. We performed lipidomics on C9 ALS/FTD Drosophila, induced pluripotent stem (iPS) cell neurons and postmortem FTD brain tissue. This revealed a common and specific reduction in phospholipid species containing polyunsaturated fatty acids (PUFAs). Feeding C9 ALS/FTD flies PUFAs yielded a modest increase in survival. However, increasing PUFA levels specifically in neurons of C9 ALS/FTD flies, by overexpressing fatty acid desaturase enzymes, led to a substantial extension of lifespan. Neuronal overexpression of fatty acid desaturases also suppressed stressor-induced neuronal death in iPS cell neurons of patients with both C9 and TDP-43 ALS/FTD. These data implicate neuronal fatty acid saturation in the pathogenesis of ALS/FTD and suggest that interventions to increase neuronal PUFA levels may be beneficial.}, } @article {pmid40000618, year = {2025}, author = {Ru, Q and Li, Y and Zhang, X and Chen, L and Wu, Y and Min, J and Wang, F}, title = {Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects.}, journal = {Bone research}, volume = {13}, number = {1}, pages = {27}, pmid = {40000618}, issn = {2095-4700}, support = {82071970//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82072506//National Natural Science Foundation of China (National Science Foundation of China)/ ; 31970689//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32330047//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2024AFB971//Natural Science Foundation of Hubei Province (Hubei Provincial Natural Science Foundation)/ ; }, mesh = {*Ferroptosis/physiology ; Humans ; *Homeostasis ; *Iron/metabolism ; *Muscular Diseases/metabolism/therapy/pathology/physiopathology ; Animals ; }, abstract = {The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.}, } @article {pmid39999835, year = {2025}, author = {Saxena, S and Liebscher, S}, title = {Boosting the X factor: Increasing XBP1s-mediated ER stress signaling protects motor neurons in ALS/FTD.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {3}, pages = {844-846}, pmid = {39999835}, issn = {1525-0024}, } @article {pmid39999167, year = {2025}, author = {Wang, HV and Xiang, JF and Yuan, C and Veire, AM and Gendron, TF and Murray, ME and Tansey, MG and Hu, J and Gearing, M and Glass, JD and Jin, P and Corces, VG and McEachin, ZT}, title = {pTDP-43 levels correlate with cell type-specific molecular alterations in the prefrontal cortex of C9orf72 ALS/FTD patients.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {9}, pages = {e2419818122}, pmid = {39999167}, issn = {1091-6490}, support = {F32 ES031827/ES/NIEHS NIH HHS/United States ; RM1 HG008935/HG/NHGRI NIH HHS/United States ; U01 MH116441/MH/NIMH NIH HHS/United States ; R35 NS111602/NS/NINDS NIH HHS/United States ; R35 GM139408/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Prefrontal Cortex/metabolism/pathology ; *Microglia/metabolism/pathology ; Male ; *DNA-Binding Proteins/metabolism/genetics ; Female ; Middle Aged ; Aged ; DNA Repeat Expansion/genetics ; Neurons/metabolism/pathology ; Phosphorylation ; }, abstract = {Repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and familial frontotemporal dementia (ALS/FTD). To identify molecular defects that take place in the dorsolateral frontal cortex of patients with C9orf72 ALS/FTD, we compared healthy controls with C9orf72 ALS/FTD donor samples staged based on the levels of cortical phosphorylated TAR DNA binding protein (pTDP-43), a neuropathological hallmark of disease progression. We identified distinct molecular changes in different cell types that take place during FTD development. Loss of neurosurveillance microglia and activation of the complement cascade take place early, when pTDP-43 aggregates are absent or very low, and become more pronounced in late stages, suggesting an initial involvement of microglia in disease progression. Reduction of layer 2-3 cortical projection neurons with high expression of CUX2/LAMP5 also occurs early, and the reduction becomes more pronounced as pTDP-43 accumulates. Several unique features were observed only in samples with high levels of pTDP-43, including global alteration of chromatin accessibility in oligodendrocytes, microglia, and astrocytes; higher ratios of premature oligodendrocytes; increased levels of the noncoding RNA NEAT1 in astrocytes and neurons, and higher amount of phosphorylated ribosomal protein S6. Our findings reveal progressive functional changes in major cell types found in the prefrontal cortex of C9orf72 ALS/FTD patients that shed light on the mechanisms underlying the pathology of this disease.}, } @article {pmid39998997, year = {2025}, author = {García-Casanova, PH and Vázquez-Costa, JF}, title = {Advances in the early diagnosis of amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {4}, pages = {415-425}, doi = {10.1080/14737175.2025.2471556}, pmid = {39998997}, issn = {1744-8360}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; *Early Diagnosis ; *Biomarkers ; Disease Progression ; Delayed Diagnosis ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease. Despite rapid disease progression, diagnostic delay of 10-16 months persists, influenced by disease-specific factors and healthcare systems. Reducing it is crucial for early intervention, multidisciplinary care planning, and patient participation in clinical trials.

AREAS COVERED: The authors review relevant studies identified through PubMed from 1990 to 2024. The article explores factors contributing to diagnostic delay, the importance of early diagnosis, and strategies for improvement, including the role of diagnostic criteria and biomarkers.

EXPERT OPINION: Diagnosis of ALS remains clinical, with clinical expertise as the main modifiable factor in the diagnostic delay. Some biomarkers may be useful to speed up diagnosis at an earlier stage of the disease and in patients with atypical presentations or co-morbidities. However, the use of biomarkers for ALS diagnosis in clinical practice is far from being established and poses considerable challenges, including the lack of disease-specific biomarkers and the potential for delayed results. Until disease-specific biomarkers become available, early referral to ALS specialists, together with physician education programs, will remain the main tools to reduce diagnostic delay in the next years.}, } @article {pmid39998694, year = {2025}, author = {Paramasivan, NK and Sarker, P and Zekeridou, A and Staff, NP and Klein, CJ and McKeon, A and Pittock, SJ and Dubey, D}, title = {Upper motor neuron-predominant motor neuron disease: a novel immunotherapy-responsive association of GAD65 autoimmunity.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {230}, pmid = {39998694}, issn = {1432-1459}, support = {MN OHE#15//Minnesota Office of Higher Education/ ; }, mesh = {Humans ; *Glutamate Decarboxylase/immunology ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; *Motor Neuron Disease/immunology/physiopathology/therapy ; *Immunotherapy/methods ; Autoantibodies/blood/cerebrospinal fluid ; Adult ; Autoimmunity ; Amyotrophic Lateral Sclerosis/immunology/therapy/physiopathology ; }, abstract = {BACKGROUND: Autoimmune disorders can present as motor neuronopathies and need to be excluded prior to the diagnosis of amyotrophic lateral sclerosis (ALS). We aimed to characterize the clinical phenotypes of patients with motor neuron disease (MND) in the context of high-titer serum/CSF GAD65 antibodies (radioimmunoassay).

METHODS: A retrospective review of all Mayo patients (between 1/1/2003 and 12/31/2023) with motor neuronopathy and co-existing high-titer GAD65 antibodies (≥ 20 nmol/L in serum [equivalent to > 10,000 IU, ELISA] or detection in CSF) was performed. Clinical phenotypes and outcomes were compared with ALS patients diagnosed in the last 5 years (1/1/2019-12/31/2023) who tested negative for GAD65 IgG.

RESULTS: We identified 12 patients with high-titer GAD65 IgG and motor neuronopathy, who often had lower back spasms, history of an exaggerated startle response with immunotherapy responsiveness as compared to ALS patients. On further analysis, a subgroup of these patients with neurogenic changes on EMG, had an upper motor neuron (UMN) predominant syndrome (58%), with history of exaggerated startle (57%), lower back spasms (43%), tandem gait impairment (86%) and UMN bladder symptoms (71%) that were significantly different from the ALS controls. The UMN predominant GAD65 MN responded favorably to immunotherapy with stable electromyography; significantly lesser worsening in mRS and mortality on long-term follow-up.

DISCUSSION: An upper motor neuron predominant motor neuronopathy is a distinct manifestation of GAD65 autoimmunity. Co-existing symptoms like exaggerated startle response, lower back spasms, impaired tandem gait, and UMN bladder signs might warrant consideration of an immunotherapy trial, which could yield favorable results.}, } @article {pmid39998031, year = {2025}, author = {Burke, KM and Shea, C and Arulanandam, V and Sullivan, S and Ellrodt, AS and MacAdam, C and Carney, K and Casagrande, G and Christiansen, E and Paganoni, S}, title = {Cervical Collar Satisfaction and Functional Impact in Amyotrophic Lateral Sclerosis: A Survey Study.}, journal = {American journal of physical medicine & rehabilitation}, volume = {}, number = {}, pages = {}, doi = {10.1097/PHM.0000000000002716}, pmid = {39998031}, issn = {1537-7385}, abstract = {OBJECTIVES: Many people with amyotrophic lateral sclerosis (ALS) develop cervical muscle weakness, often managed with cervical collars. Finding supportive and comfortable collars can be challenging. This study aimed to evaluate satisfaction with various collars and their impact on activities of daily living.

DESIGN: This electronic survey study collected demographic information, clinical status, and participant experiences with commonly used cervical collars.

RESULTS: Thirty-four participants (33 with ALS, 1 with primary lateral sclerosis) completed the survey, with 79% reporting neck weakness and 38% experiencing neck pain. Among those who tried cervical collars (65%), many had tried multiple options. The mean satisfaction across all collar types was 5.03 (SD = 2.92) out of 10.

CONCLUSION: These findings suggest current collars do not fully meet the needs of people living with ALS, emphasizing the importance of improved treatment options. Future research should explore innovative technologies to improve cervical support, function, and quality of life.}, } @article {pmid39997929, year = {2025}, author = {Newell, ME and Aravindan, A and Babbrah, A and Halden, RU}, title = {Epigenetic Biomarkers Driven by Environmental Toxins Associated with Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis in the United States: A Systematic Review.}, journal = {Toxics}, volume = {13}, number = {2}, pages = {}, pmid = {39997929}, issn = {2305-6304}, support = {GF000000002135//Glen Swette Memorial Fund/ ; }, abstract = {Environmental toxins and epigenetic changes have been linked to neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), and amyotrophic lateral sclerosis (ALS). This paper aimed to (i) identify environmental toxins associated with AD, PD, and ALS, (ii) locate potential industrial sources of toxins in the United States (U.S.), and (iii) assess epigenetic changes driven by exposure to toxins reported by patients. Environmental factors and epigenetic biomarkers of neurodegeneration were compiled from 69 studies in the literature using Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) and geographic information system approaches. Some 127 environmental toxins have been associated or putatively associated with AD, PD, or ALS, with four toxic metals (As, Cd, Mn, and Hg) common to all three of these neurodegenerative diseases. Environmental toxins associated with epigenetic changes (e.g., DNA methylation) in patients include air pollutants, metals, and organic chemicals (e.g., pesticides, mycotoxins, and cyanotoxins). Geographic analysis showed that study locations (e.g., U.S., Europe, and East Asia) were selected by researchers based on convenience of access rather than exposure risk and disease prevalence. We conclude that several toxins and epigenetic markers shared among neurodegenerative diseases could serve as attractive future targets guiding environmental quality improvements and aiding in early disease detection.}, } @article {pmid39996748, year = {2025}, author = {Yang, HM}, title = {Mitochondrial Dysfunction in Neurodegenerative Diseases.}, journal = {Cells}, volume = {14}, number = {4}, pages = {}, pmid = {39996748}, issn = {2073-4409}, support = {2020R1A2C1011311//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; Oxidative Stress ; Mitochondrial Dynamics ; Mitophagy ; Reactive Oxygen Species/metabolism ; }, abstract = {Mitochondrial dysfunction represents a pivotal characteristic of numerous neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These conditions, distinguished by unique clinical and pathological features, exhibit shared pathways leading to neuronal damage, all of which are closely associated with mitochondrial dysfunction. The high metabolic requirements of neurons make even minor mitochondrial deficiencies highly impactful, driving oxidative stress, energy deficits, and aberrant protein processing. Growing evidence from genetic, biochemical, and cellular investigations associates impaired electron transport chain activity and disrupted quality-control mechanisms, such as mitophagy, with the initial phases of disease progression. Furthermore, the overproduction of reactive oxygen species and persistent neuroinflammation can establish feedforward cycles that exacerbate neuronal deterioration. Recent clinical research has increasingly focused on interventions aimed at enhancing mitochondrial resilience-through antioxidants, small molecules that modulate the balance of mitochondrial fusion and fission, or gene-based therapeutic strategies. Concurrently, initiatives to identify dependable mitochondrial biomarkers seek to detect pathological changes prior to the manifestation of overt symptoms. By integrating the current body of knowledge, this review emphasizes the critical role of preserving mitochondrial homeostasis as a viable therapeutic approach. It also addresses the complexities of translating these findings into clinical practice and underscores the potential of innovative strategies designed to delay or potentially halt neurodegenerative processes.}, } @article {pmid39996723, year = {2025}, author = {Deecke, L and Ohlei, O and Goldeck, D and Homann, J and Toepfer, S and Demuth, I and Bertram, L and Pawelec, G and Lill, CM}, title = {Peripheral Immune Profiles in Individuals at Genetic Risk of Amyotrophic Lateral Sclerosis and Alzheimer's Disease.}, journal = {Cells}, volume = {14}, number = {4}, pages = {}, pmid = {39996723}, issn = {2073-4409}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; LI 2654/4-1//German Research Foundation/ ; #16SV5536K, #16SV5537, #16SV5538, #16SV5837, #01UW0808,01GL1716A, and 01GL1716B//Bundesministerium für Bildung und Forschung/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/immunology ; *Alzheimer Disease/genetics/immunology ; Male ; Female ; *Genetic Predisposition to Disease ; Middle Aged ; Aged ; Genome-Wide Association Study ; Risk Factors ; Polymorphism, Single Nucleotide/genetics ; Multifactorial Inheritance/genetics ; CD8-Positive T-Lymphocytes/immunology ; }, abstract = {The immune system plays a crucial role in the pathogenesis of neurodegenerative diseases. Here, we explored whether blood immune cell profiles are already altered in healthy individuals with a genetic predisposition to amyotrophic lateral sclerosis (ALS) or Alzheimer's disease (AD). Using multicolor flow cytometry, we analyzed 92 immune cell phenotypes in the blood of 448 healthy participants from the Berlin Aging Study II. We calculated polygenic risk scores (PGSs) using genome-wide significant SNPs from recent large genome-wide association studies on ALS and AD. Linear regression analyses were then performed of the immune cell types on the PGSs in both the overall sample and a subgroup of older participants (>60 years). While we did not find any significant associations between immune cell subtypes and ALS and AD PGSs when controlling for the false discovery rate (FDR = 0.05), we observed several nominally significant results (p < 0.05) with consistent effect directions across strata. The strongest association was observed with CD57+ CD8+ early-memory T cells and ALS risk (p = 0.006). Other immune cell subtypes associated with ALS risk included PD-1+ CD8+ and CD57+ CD4+ early-memory T cells, non-classical monocytes, and myeloid dendritic cells. For AD, naïve CD57+ CD8+ T cells and mature NKG2A+ natural killer cells showed nominally significant associations. We did not observe major immune cell changes in individuals at high genetic risk of ALS or AD, suggesting they may arise later in disease progression. Additional studies are required to validate our nominally significant findings.}, } @article {pmid39996599, year = {2025}, author = {Chowdhury, RN and Azam, MA and Azam, SA and Lana, S and Culver, EN and Garruto, RM and Wander, K}, title = {Elevated Serum MCP-2 and TARC Associated With Increased Risk of Death in Guamanian ALS Patients.}, journal = {European journal of neurology}, volume = {32}, number = {3}, pages = {e70088}, pmid = {39996599}, issn = {1468-1331}, support = {//Sigma Xia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality ; Female ; Male ; Middle Aged ; Aged ; Guam/epidemiology ; Biomarkers/blood ; Adult ; Chemokine CCL2/blood ; }, abstract = {BACKGROUND: This study explores the relationship between inflammation and longevity in a high-incidence focus of amyotrophic lateral sclerosis (ALS) in post-WWII Guam. Characteristics of this focus include the sudden appearance of the disease in high numbers and the unusually long lifespan (without medical interventions) seen in some cases. We used bio-banked specimens to evaluate the relationship between serum immunoregulators and survival time.

METHODS: We evaluated sera from 69 Guam ALS cases collected within 2 years of symptom onset by NIH researchers from 1950 to 1983 for 11 immunoregulators via ELISA (CRP, eotaxin-1, RANTES, IL-6, IL-8, IL-10, IFN-γ, IP-10, MCP-1, MCP-2 and TARC). Factor analysis identified two factors responsible for ~68% of the variation in the data. We estimated Cox proportional hazards models to identify immunoregulators associated with time to death.

RESULTS: Each 10-unit increase in factor 2 cytokines (MCP-2 and TARC) was associated with a 38% increase in the risk of death (HR: 1.38; 95% CI: 1.19, 1.65; p: 0.00).

DISCUSSION: Like sporadic ALS cases worldwide, inflammation is associated with a shortened lifespan in Guamanian ALS; more specifically, our findings suggest serum levels of MCP-2 and TARC at onset may predict disease duration. Further investigation is needed to determine the role of these immunoregulators in disease prognosis and as targets for diagnostic and therapeutic interventions.}, } @article {pmid39996130, year = {2025}, author = {Dilliott, AA and Costanzo, MC and Bandres-Ciga, S and Blauwendraat, C and Casey, B and Hoang, Q and Iwaki, H and Jang, D and Kim, JJ and Leonard, HL and Levine, KS and Makarious, M and Nguyen, TT and Rouleau, GA and Singleton, AB and Smadbeck, P and Solle, J and Vitale, D and Nalls, M and Flannick, J and Burtt, NP and Farhan, SMK}, title = {The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.}, journal = {Neurology. Genetics}, volume = {11}, number = {2}, pages = {e200246}, pmid = {39996130}, issn = {2376-7839}, abstract = {Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathologic mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across 10 different phenotypic groups, including neurologic conditions such as Alzheimer disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively use the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for patients with neurodegenerative disease.}, } @article {pmid39995927, year = {2025}, author = {McDonald, TS and Cui, CS and Lerskiatiphanich, T and Marallag, J and Lee, JD}, title = {Metabolic rate and insulin-independent glucose uptake increase in a TDP-43[Q331K] mouse model of amyotrophic lateral sclerosis.}, journal = {Heliyon}, volume = {11}, number = {3}, pages = {e42482}, pmid = {39995927}, issn = {2405-8440}, abstract = {Impaired glucose regulation is increasingly recognised in amyotrophic lateral sclerosis (ALS), yet the precise mechanisms remain unclear. Here, we investigated energy balance and glucose control in TAR DNA-binding protein 43 (TDP-43)[Q331K] mice, a model of ALS, at both the early and late symptomatic stages of disease. Mutant TDP-43[Q331K] mice and non-transgenic controls underwent indirect calorimetry, as well as intraperitoneal glucose, insulin, and glucagon tolerance testing. We also examined plasma hormone levels and quantified α- and β-cell areas in pancreatic islets. Throughout disease progression, TDP-43[Q331K] mice exhibited elevated metabolic rates, with a transient increase in food intake at the early stages. At the later stages of disease, heightened glucose uptake was observed despite unchanged insulin secretion or tolerance, indicating mechanisms independent of insulin. Notably, TDP-43[Q331K] mice maintained fasting blood glucose levels even when circulating glucagon levels were reduced, suggesting that alternative pathways contribute to preserving euglycemia. These findings reveal a distinct metabolic profile in TDP-43[Q331K] mice, underscoring the complexity of glucose dyshomeostasis in ALS.}, } @article {pmid39995125, year = {2025}, author = {Kalinin, AP and Zubkova, ES and Menshikov, MY and Parfyonova, YV}, title = {ISR Modulators in Neurological Diseases.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X361653250213114821}, pmid = {39995125}, issn = {1875-6190}, abstract = {The dysfunction of different cells lies in the pathogenesis of neurological diseases and is usually associated with cellular stress. Various stressors trigger the integrated stress response (ISR) signaling, whose highly conserved mechanism is primarily aimed at protecting a stress-exposed cell to cope as safely as possible with such stressful conditions. On the contrary, if a cell is unable to cope with excessive stress, the ISR can induce apoptosis. The ISR mechanism, whose main stage is the inhibition of translation machinery in favor of the synthesis of specific proteins, including the transcription factors ATF3, ATF4, CEBPA, and CEBPB, which function only as dimers and determine the uniqueness of the ISR response in each individual case, thus ensures different outcomes of the ISR. Inhibition of global protein synthesis is achieved through phosphorylation of eIF2α by PERK, HRI, PKR, or GCN2. To date, a number of compounds have been developed that modulate the ISR, including activators and inhibitors of the abovementioned ISR kinases as well as modulators of p-eIF2α dephosphorylation. They target different ISR stages, allowing a broad ISR modulation strategy. At the same time, there are no drugs that are both exceptionally safe and effective for the treatment of several neurological diseases, so there is an urgent need for new approaches to the treatment of these disorders. In this review, we represent ISR signaling as an important participant in the pathogenesis of neurological diseases. We also describe how various ISR modulators may become a part of future therapies for these diseases.}, } @article {pmid39995102, year = {2025}, author = {Perdikakis, M and Papadimitrakis, D and Floros, N and Tzavellas, E and Piperi, C and Gargalionis, AN and Papavassiliou, AG}, title = {Diagnostic role of circulating cell-free DNA in schizophrenia and neuro-degenerative disorders.}, journal = {Biomarkers in medicine}, volume = {19}, number = {5}, pages = {165-176}, pmid = {39995102}, issn = {1752-0371}, mesh = {Humans ; *Cell-Free Nucleic Acids/blood ; *Schizophrenia/diagnosis/blood/genetics ; *Neurodegenerative Diseases/diagnosis/blood/cerebrospinal fluid/genetics ; *Biomarkers/blood/cerebrospinal fluid ; Amyotrophic Lateral Sclerosis/diagnosis/blood/genetics/cerebrospinal fluid ; Huntington Disease/diagnosis/blood/genetics/cerebrospinal fluid ; Parkinson Disease/diagnosis/blood/genetics/cerebrospinal fluid ; Alzheimer Disease/diagnosis/blood/cerebrospinal fluid/genetics ; Multiple Sclerosis/diagnosis/blood/cerebrospinal fluid/genetics ; }, abstract = {Over the past few years, circulating cell-free DNA (cfDNA) research has grown exponentially. Several studies have associated the release of cfDNA in the bloodstream, cerebrospinal fluid, and other body fluids with increased apoptosis and cell death. Therefore, their possible use as biomarkers for cancer and other diseases has emerged. The diagnosis of pathological entities such as schizophrenia and neurodegenerative diseases involves many challenges and requires ruling out conditions with similar symptoms. In this context, cfDNA could serve as a valuable diagnostic biomarker. This study encompasses the recent bibliography and research regarding the utilization of circulating cfDNA for diagnostic purposes in schizophrenia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. This minimally invasive method has provided important evidence regarding the diagnosis of the aforementioned diseases although further research is necessary.}, } @article {pmid39995075, year = {2025}, author = {Manco, C and Righi, D and Primiano, G and Romano, A and Luigetti, M and Leonardi, L and De Stefano, N and Plantone, D}, title = {Peripherin, A New Promising Biomarker in Neurological Disorders.}, journal = {The European journal of neuroscience}, volume = {61}, number = {4}, pages = {e70030}, pmid = {39995075}, issn = {1460-9568}, mesh = {Humans ; *Peripherins/metabolism/genetics ; *Biomarkers/metabolism ; Animals ; *Nervous System Diseases/metabolism ; }, abstract = {Peripherin is a class III intermediate filament protein that has recently gained attention as a potential biomarker for axonal damage in the peripheral nervous system. This review examines peripherin gene expression, protein structure, and its functions in both healthy and diseased states. Peripherin is predominantly expressed in the peripheral nervous system, especially in motor and sensory neurons, and plays a critical role in neurite growth, stability, and axonal transport during myelination. Its expression is regulated by various cytokines and undergoes several post-transcriptional modifications. Peripherin interacts with multiple proteins, including neurofilaments and kinases, influencing cytoskeletal dynamics and neuronal functions. The review also explores peripherin involvement in several neurological disorders, such as Amyotrophic Lateral Sclerosis, where its abnormal expression and aggregation contribute to disease pathology. Additionally, peripherin has been linked to polyneuropathies, traumatic axonal injury, and diabetic neuropathy, suggesting its broader relevance as a biomarker in these conditions. The potential of peripherin as a biomarker is further supported by recent studies using ultrasensitive detection methods, which have identified elevated peripherin levels in the serum of patients with neurological diseases. Despite the promising findings, the application of peripherin as a biomarker in clinical settings remains limited, primarily due to challenges in its detection and the need for further validation in diverse patient populations. Future research directions include the development of more sensitive assays and the exploration of peripherin's role in non-neuronal tissues, which may expand its diagnostic and therapeutic potential.}, } @article {pmid39994742, year = {2025}, author = {Djukic, S and Zhao, Z and Jørgensen, LMH and Bak, AN and Jensen, DB and Meehan, CF}, title = {TDP-43 pathology is sufficient to drive axon initial segment plasticity and hyperexcitability of spinal motoneurones in vivo in the TDP43-ΔNLS model of Amyotrophic Lateral Sclerosis.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {42}, pmid = {39994742}, issn = {2051-5960}, support = {R370-2021-1109//The Lundbeck Foundation/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism/physiopathology/genetics ; Animals ; *Motor Neurons/pathology/metabolism/physiology ; *DNA-Binding Proteins/metabolism/genetics ; *Mice, Transgenic ; *Disease Models, Animal ; *Neuronal Plasticity/physiology ; *Axon Initial Segment/metabolism/physiology ; Spinal Cord/pathology/metabolism ; Mice ; Male ; Humans ; Female ; Action Potentials/physiology ; Mice, Inbred C57BL ; }, abstract = {A hyperexcitability of the motor system is consistently observed in Amyotrophic Lateral Sclerosis (ALS) and has been implicated in the disease pathogenesis. What drives this hyperexcitability in the vast majority of patients is unknown. This is important to know as existing treatments simply reduce all neuronal excitability and fail to distinguish between pathological changes and important homeostatic changes. Understanding what drives the initial pathological changes could therefore provide better treatments. One challenge is that patients represent a heterogeneous population and the vast majority of cases are sporadic. One pathological feature that almost all (~97%) cases (familial and sporadic) have in common are cytoplasmic aggregates of the protein TDP-43 which is normally located in the nucleus. In our experiments we investigated whether this pathology was sufficient to increase neuronal excitability and the mechanisms by which this occurs. We used the TDP-43(ΔNLS) mouse model which successfully recapitulates this pathology in a controllable way. We used in vivo intracellular recordings in this model to demonstrate that TDP-43 pathology is sufficient to drive a severe hyper-excitability of spinal motoneurones. Reductions in soma size and a lengthening and constriction of axon initial segments were observed, which would contribute to enhanced excitability. Resuppression of the transgene resulted in a return to normal excitability parameters by 6-8 weeks. We therefore conclude that TDP-43 pathology itself is sufficient to drive a severe but reversible hyperexcitability of spinal motoneurones.}, } @article {pmid39994160, year = {2025}, author = {Dubey, PR and Kaur, G and Shukla, R}, title = {Nano-mediated Management of Metal Toxicity-induced Neurodegeneration: A Critical Review.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39994160}, issn = {1559-1182}, abstract = {Heavy metals, omnipresent in the environment, though imperative in trace quantities for human physiology, become a serious health hazard due to their toxicity. Copper, arsenic, lead, iron, and mercury are some examples of the heavy metals responsible for oxidative stress, which is one of the primary factors behind neurodegenerative diseases like Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Neurodegeneration is caused by toxicity due to environmental exposure to these toxic substances or genetic variation. Conventional therapies, relying on chelation and antioxidants, suffer from the broader perspective of metal removal in a non-selective manner and poor targeting of the brain. In this respect, treatments based on nanotechnology that employ nanoparticles such as dendrimers, micelles, and liposomes constitute a promising interest in enhancing drug delivery with minimal neurotoxicity. The present review outlines the heavy metals responsible for neurodegenerative diseases, their pathophysiology, management strategies available at present, and the scope of nanotechnology intervention in overcoming shortcomings of conventional therapies. The genetic influence of heavy metals on neurological health is also part of this article.}, } @article {pmid39993605, year = {2025}, author = {David Wu, CH and Whelan, TJ and Swaminath, A}, title = {Response to: Comment on Wu et al's article on toxicity in patients receiving radiotherapy for ultracentral stage I non-small cell lung cancer.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {206}, number = {}, pages = {110804}, doi = {10.1016/j.radonc.2025.110804}, pmid = {39993605}, issn = {1879-0887}, } @article {pmid39993604, year = {2025}, author = {Huertas, A and Moghanaki, D and Siva, S}, title = {Comment on Wu et al's article on toxicity in patients receiving radiotherapy for ultracentral stage I non-small cell lung cancer.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {206}, number = {}, pages = {110805}, doi = {10.1016/j.radonc.2025.110805}, pmid = {39993604}, issn = {1879-0887}, } @article {pmid39992908, year = {2025}, author = {Nemeth, T and Zarnocki, A and Ladanyi, A and Papp, C and Ayaydin, F and Szebeni, GJ and Gacser, A}, title = {PCR-based CRISPR/Cas9 system for fluorescent tagging: A tool for studying Candida parapsilosis virulence.}, journal = {PloS one}, volume = {20}, number = {2}, pages = {e0312948}, doi = {10.1371/journal.pone.0312948}, pmid = {39992908}, issn = {1932-6203}, mesh = {*CRISPR-Cas Systems ; Mice ; *Candida parapsilosis/genetics/pathogenicity ; Animals ; Virulence/genetics ; Polymerase Chain Reaction/methods ; Macrophages/microbiology ; Humans ; }, abstract = {Candida parapsilosis is persistent in a hospital environment hence it is often associated with nosocomial infections especially amongst low-birth weight neonates. Genetic modification is therefore important to characterise the physiological and virulence related properties of this fungus. A PCR-based CRISPR/Cas9 system has been adopted to facilitate the generation of fluorescent tagged prototroph isolates. We examined a total of eight fluorescent protein coding genes, out of which three were found to be applicable for simultaneous utilisation. We investigated three clinical isolates of C. parapsilosis in terms of their adherence to silicone and their uptake by J774.2 murine macrophages in competition assays. Interestingly, we found significant differences between them in both experiments where GA1 isolate was significantly less resistant to macrophage uptake and CDC317 was significantly more adherent to silicone material. In silico analysis of the agglutinin-like sequences (Als) exposed remarkable diversity in this protein family and additionally, the thorough analysis of the ALS genes revealed evidence of formation of a new gene by intrachromosomal recombination in the GA1 isolate. Finally, we provide a step by step protocol for the application of the PCR-based CRISPR/Cas9 system for fluorescently labelling C. parapsilosis isolates.}, } @article {pmid39992655, year = {2025}, author = {Liu, X and Shang, H and Wei, Q and Yao, X and Lian, L and Dang, J and Jia, R and Wu, Z and Li, H and Niu, Q and Cheng, X and Zou, Z and Chen, S and Zhang, M and Liu, Y and Liu, Y and Liu, Q and Huang, X and Wang, H and Feng, H and Wang, S and Fan, D and , }, title = {Tetramethylpyrazine Nitrone in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {8}, number = {2}, pages = {e2461055}, pmid = {39992655}, issn = {2574-3805}, mesh = {Humans ; Male ; Middle Aged ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Pyrazines/therapeutic use/adverse effects ; Double-Blind Method ; Aged ; Treatment Outcome ; China ; Nitrogen Oxides ; }, abstract = {IMPORTANCE: Tetramethylpyrazine nitrone has exhibited promising results in improving motor dysfunction in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).

OBJECTIVE: To evaluate the safety and efficacy of orally administered tetramethylpyrazine nitrone in patients with ALS.

This phase 2, multicenter, double-masked, placebo-controlled, randomized clinical trial was conducted from December 24, 2020, through July 14, 2023, in 11 centers in China, with a 180-day follow-up. Patients aged 45 to 70 years, with ALS onset within 2 years, ALS Functional Rating Scale-Revised (ALSFRS-R) scores of at least 2 points on each item, and forced vital capacity (FVC) of at least 80% were included. Patients experienced a 1- to 4-point decrease in ALSFRS-R score during a 3-month screening period.

INTERVENTIONS: Patients were randomly assigned 1:1:1 to receive low-dose tetramethylpyrazine nitrone (600 mg twice daily), high-dose tetramethylpyrazine nitrone (1200 mg twice daily), or placebo (twice daily) for 180 days.

MAIN OUTCOMES AND MEASURES: The primary outcome was change in ALSFRS-R score (range of 0-48, with lower scores indicating worse function) from baseline to 180 days. The secondary outcomes were changes in FVC, grip strength, ALS Assessment Questionnaire-40 (ALSAQ-40) score, and end point events. Safety outcomes included adverse events.

RESULTS: A total of 155 patients (mean [SD] age, 55.0 [6.5] years; 115 men [74.2%]) were randomized (51 [32.9%] to the low-dose tetramethylpyrazine nitrone group, 52 [33.6%] to the high-dose tetramethylpyrazine nitrone group, and 52 [33.6%] to the placebo group). No significant differences were observed in ALSFRS-R score changes between low-dose tetramethylpyrazine nitrone (least squares [LS] mean difference, -0.89 points; 95% CI -3.25 to 1.48 points) and high-dose tetramethylpyrazine nitrone (LS mean difference, -0.20 points; 95% CI -2.48 to 2.07 points) compared with placebo. High-dose tetramethylpyrazine nitrone showed a significantly slower decline in grip strength at day 180 (LS mean difference, 2.46 kg; 95% CI, 0.15-4.76 kg). In a subgroup of patients younger than 65 years with slower disease progression, tetramethylpyrazine nitrone significantly attenuated the decline in grip strength (LS mean difference, 3.63 kg; 95% CI, 0.84-6.41 kg), bulbar scores (LS mean difference, 0.66 points; 95% CI, 0.03-1.29 points), and respiratory scores (LS mean difference, 0.54 points; 95% CI, 0.03-1.06 points). Adverse events were mostly mild or moderate, with no severe treatment-related adverse events or deaths.

CONCLUSIONS AND RELEVANCE: This randomized clinical trial demonstrates that tetramethylpyrazine nitrone is safe and well-tolerated in patients with ALS. There was no difference in the primary end point across the low-dose, high-dose, and placebo groups, with significant benefits in a subgroup of younger patients with slower disease progression.

TRIAL REGISTRATION: ChiCTR Identifier: ChiCTR2000039689.}, } @article {pmid39991082, year = {2025}, author = {Chen, G and Cao, Y and Du, X and Cui, J and Zeng, X and Yang, H and Ren, Z and Xu, K}, title = {The Clinical Research Landscape of Intracranial Nicardipine for Aneurysmal Subarachnoid Hemorrhage: Insights From Bibliometric Analysis.}, journal = {Drug design, development and therapy}, volume = {19}, number = {}, pages = {1129-1146}, pmid = {39991082}, issn = {1177-8881}, mesh = {Humans ; *Bibliometrics ; *Nicardipine/administration & dosage/therapeutic use ; *Subarachnoid Hemorrhage/drug therapy ; Biomedical Research ; }, abstract = {BACKGROUND: The 2023 American Heart Association/American Stroke Association guideline and Wessels et al's 2024 randomized controlled trial highlight the potential benefits of intracranial nicardipine for aneurysmal subarachnoid hemorrhage (aSAH). This study aims to systematically identify the publication trends and research hotspots in this field through bibliometric analysis.

METHODS: Relevant publications were sourced from the Web of Science Core Collection (WoSCC). Bibliometric and visualization analyses were conducted using the online tools of the WoSCC database and CiteSpace 6.2.R6.

RESULTS: Analysis of 28 articles published by 158 researchers from 55 institutions across 8 countries revealed an intermittent small-scale growth in annual publication volume from 1994 to 2024, with a continuous rise in annual citation volume since 2005, indicating growing interest in the field. Japan, Germany, and the United States of America (USA) were the most prolific and influential countries. Institutions such as Tokyo Women's Medical University showed particularly significant contributions. Kasuya Hidetoshi was the most prolific author. There was little global collaboration among countries, institutions, and authors, with distinct regional research characteristics: Japan and Germany focused on intracranial implants, while the USA concentrated on intrathecal injections. Major publishing and co-cited journals included Neurocritical Care, Acta Neurochirurgica, Journal of Neurosurgery, and Stroke. Popular keywords in 2024 included "preventing cerebral vasospasm", "delayed cerebral ischemia", "outcome events", and "clinical trials", revealing current research hotspots.

CONCLUSION: This study maps the global clinical research landscape of intracranial application of nicardipine for aSAH from 1994 to 2024, providing valuable references and guidance for future research.}, } @article {pmid39990425, year = {2025}, author = {Chakraborty, A and Mitra, J and Malojirao, VH and Kodavati, M and Mandal, SM and Gill, SK and Sreenivasmurthy, SG and Vasquez, V and Mankevich, M and Krishnan, B and Ghosh, G and Hegde, M and Hazra, T}, title = {Fructose-2,6-bisphosphate restores TDP-43 pathology-driven genome repair deficiency in motor neuron diseases.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.13.623464}, pmid = {39990425}, issn = {2692-8205}, abstract = {TAR DNA-binding protein 43 (TDP-43) proteinopathy plays a critical role in neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia (FTD). In our recent discovery, we identified that TDP-43 plays an essential role in DNA double-strand break (DSB) repair via the non-homologous end joining (NHEJ) pathway. Here, we found persistent DNA damage in the brains of ALS/FTD patients, primarily in the transcribed regions of the genome. We further investigated the underlying mechanism and found that polynucleotide kinase 3'-phosphatase (PNKP) activity was severely impaired in the nuclear extracts of both patient brains and TDP-43-depleted cells. PNKP is a key player in DSB repair within the transcribed genome, where its 3'-P termini processing activity is crucial for preventing persistent DNA damage and neuronal death. The inactivation of PNKP in ALS/FTD was due to reduced levels of its interacting partner, phosphofructo-2-kinase fructose 2,6 bisphosphatase (PFKFB3), and its biosynthetic product, fructose-2,6-bisphosphate (F2,6BP), an allosteric modulator of glycolysis. Recent work from our group has shown that F2,6BP acts as a positive modulator of PNKP activity in vivo. Notably, exogenous supplementation with F2,6BP restored PNKP activity in nuclear extracts from ALS/FTD brain samples and patient-derived induced pluripotent stem (iPS) cells harboring pathological mutations. Furthermore, we demonstrate that supplementation of F2,6BP restores genome integrity and partially rescues motor phenotype in a Drosophila model of ALS. Our findings underscore the possibility of exploring the therapeutic potential of F2,6BP or its analogs in TDP-43 pathology-associated motor neuron diseases.}, } @article {pmid39990107, year = {2025}, author = {Zhao, S and Chen, R and An, Y and Zhang, Y and Ma, C and Gao, Y and Lu, Y and Yang, F and Bai, X and Zhang, J}, title = {Optineurin overexpression ameliorates neurodegeneration through regulating neuroinflammation and mitochondrial quality in a murine model of amyotrophic lateral sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1522073}, pmid = {39990107}, issn = {1663-4365}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neurons (MNs). Genetic mutations in Optineurin (OPTN) and Superoxide Dismutase 1 (SOD1) have been identified as causal factors for ALS. OPTN immunopositive inclusions have been confirmed in the cases of ALS with SOD1 mutations. However, the role of the OPTN gene in ALS caused by SOD1 mutations is ambiguous.

METHODS: The murine Optn lentivirus and empty vector lentivirus were injected into SOD1 [G93A] mice after discovering variations in Optn expression over time. The phenotype onset date, life span, locomotor activity, and pathological changes in the spinal cord were determined and recorded subsequently. In addition, the influences on cellular apoptosis, mitochondrial dynamics, mitophagy, and neuroinflammation were further investigated.

RESULTS: Optn expression was increased in the spinal cord of SOD1 [G93A] mice at the pre-symptomatic phase, but decreased after disease onset. Optn overexpression led to a 9.7% delay in the onset of disease and improved motor performance in SOD1 [G93A] mice. Optn overexpression also ameliorated the MNs loss by 46.8%. Moreover, all these ameliorating effects induced by Optn overexpression might be due to the inhibition of cellular apoptosis, improvement of mitochondrial quality, regulation of mitochondrial dynamics, promotion of mitophagy, and anti-inflammatory properties.

CONCLUSION: Our data demonstrate that Optn overexpression protects MNs, inhibites cellular apoptosis, improves mitochondrial quality and regulates neuroinflamation in SOD1 [G93A] mice at the pre-symptomatic stage.}, } @article {pmid39989851, year = {2025}, author = {Rea, D and Tham, C and Tham, TC}, title = {Endoscopic calabash technique for gastric mesenchymal tumours: A low hanging fruit or a novel endoscopic technique?.}, journal = {World journal of gastrointestinal endoscopy}, volume = {17}, number = {2}, pages = {101676}, pmid = {39989851}, issn = {1948-5190}, abstract = {The term subepithelial lesions encompasses a wide array of pathology of which numerous benign and malignant pathologies are grouped. A subset of these lesions are termed gastric mesenchymal tumours of which some have innate malignant potential. Currently there is various guidance on the recommended approach to the investigation and management of these lesions and there exists multiple methods of resection. Lin et al have developed and proposed a new method of resection of these gastric mesenchymal tumours within the field of endoscopy, a procedure they have termed endoscopic calabash ligation and resection. This editorial aims to outlay the current landscape for gastric mesenchymal tumours with regards to the various guidelines and resection techniques while comparing Lin et al's new technique to those that are already established in the field of endoscopy. Advancements in endoscopy that maintain or improve patient outcomes compared to the gold standard approach are exciting developments. Lin et al's study suggests that their technique is comparable in regard to patient outcomes while simultaneously being more efficient in its use of hospital resources including procedural time. Whilst the data and analysis proposed in the study is promising, there are areas that need to be addressed before advocating the procedure for widespread use. However, with further studies and analysis this may be foreseeable in the future.}, } @article {pmid39989811, year = {2025}, author = {Marzi, I and Pieraccini, G and Bemporad, F and Chiti, F}, title = {Detection of an Intermediate in the Unfolding Process of the N-Terminal Domain of TDP-43.}, journal = {ACS omega}, volume = {10}, number = {6}, pages = {5616-5633}, pmid = {39989811}, issn = {2470-1343}, abstract = {TAR DNA-binding protein 43 (TDP-43) is a nuclear protein accumulating in intraneuronal cytoplasmic inclusions associated with amyotrophic lateral sclerosis, frontotemporal lobar degeneration with tau-negative/ubiquitin-positive inclusions, and limbic-predominant age-related TDP-43 encephalopathy. Oligomerization of full-length TDP-43, driven by its N-terminal domain (NTD), is essential for its function, but aberrant self-assembly also promotes liquid-liquid phase separation and formation of solid inclusions. Building on recent all-atom molecular dynamics simulations and using various biophysical approaches, we identified a partially unfolded state accumulating during unfolding of TDP-43 NTD, before the major energy barrier of unfolding is crossed. Intrinsic fluorescence spectroscopy coupled to a stopped-flow device at high urea concentration reveals that the intermediate state has a fluorescence emission distinct from those of the native and unfolded states and forms within the 14 ms dead time. Conventional fluorescence spectroscopy shows it still accumulates at moderate urea concentration. Circular dichroism and H/D exchange results show a species with an intermediate content of secondary structure and a distorted β-sheet, whereas SYPRO orange fluorescence indicates an open conformation with more exposed hydrophobic regions compared to the native state. Importantly, this intermediate is observed even at low protein concentration, when TDP-43 NTD is largely monomeric, indicating that its formation is independent of the initial TDP-43 NTD oligomeric state. Dynamic light scattering at high protein concentration shows that the intermediate is a partially folded dimer. The intermediate forms upon chemical denaturation and does not occur under thermal unfolding. Overall, the findings highlight the presence of one more partially folded state for TDP-43 NTD, underlining its high structural plasticity and suggesting that its distinct unfolding pathway may play a critical role in both its functional and pathological behaviors.}, } @article {pmid39989203, year = {2025}, author = {Wu, J and Sun, C and Xu, Y and Fan, D and Ye, S}, title = {The contralateral co-movement test in a Chinese population with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2467959}, pmid = {39989203}, issn = {2167-9223}, abstract = {INTRODUCTION: Mirror movements (MMs) are often overlooked in patients with amyotrophic lateral sclerosis (ALS). Although the contralateral co-movement (COMO) test can be used to evaluate MMs in patients with ALS, it lacks a systematic evaluation. The aim of this study was to validate the effectiveness of the Chinese version of the COMO test in a Chinese ALS population.

METHODS: We prospectively enrolled 173 patients with ALS as the disease group and 28 healthy individuals as controls. All participants were evaluated using the Chinese version of the COMO test. Univariate analysis and multiple linear regression were used to compare differences between groups. Subgroup analysis of the COMO scores was performed based on different disease characteristics.

RESULTS: The COMO score in the ALS group was significantly greater (5.00% [1.67-10.00]) than that in the healthy control group (1.67% [0.00-3.33]). After adjusting for confounders, this difference remained significant. Multivariate linear analysis suggested that the upper motor neuron (UMN) score independently predicted the COMO score (P < 0.001). The COMO score was not affected by different onset regions or lateralizations. Propensity score matching revealed no significant difference in COMO scores between uninvolved limb segments and the corresponding limb segments in other patients. The Cronbach's α of the Chinese COMO test was 0.621.

CONCLUSION: The Chinese COMO test can serve as a potential tool for assessing MMs in Chinese patients with ALS. The UMN score is a factor influencing the COMO score. The COMO test can provide objective evidence for ALS characteristics and the severity of UMN damage.}, } @article {pmid39987720, year = {2025}, author = {Ohnari, K and Mafune, K and Adachi, H}, title = {Usefulness of the Gold Coast criteria in diagnosing fast-progressing amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {471}, number = {}, pages = {123418}, doi = {10.1016/j.jns.2025.123418}, pmid = {39987720}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; *Disease Progression ; Retrospective Studies ; Aged ; *Electromyography/methods ; Sensitivity and Specificity ; Adult ; }, abstract = {The Gold Coast criteria are reportedly more sensitive for diagnosing amyotrophic lateral sclerosis (ALS) than the previously used criteria; however, the sensitivity of these sets of criteria among groups classified according to their prognosis has not been compared. In this study, we examined the difference in the sensitivity for ALS diagnosis among these criteria, especially in patients with fast-progression ALS. We enrolled 95 patients diagnosed with ALS and retrospectively classified them into three groups based on the interval between disease onset and death or tracheostomy. We retrospectively examined the number of patients meeting the Gold Coast, Awaji, or revised El Escorial criteria (rEEC) (definite/probable/possible) at initial clinical examination and electromyography and compared the rates of diagnosis according to each set of criteria among the three groups. The sensitivity of the Gold Coast criteria was significantly higher than that of the Awaji and rEEC criteria (sensitivity, 92.6 % vs. 71.8 % vs. 71.7 %, p < 0.001). The sensitivity of the Gold Coast criteria in patients with fast progression (n = 30) was significantly higher than that of the Awaji and rEEC criteria (sensitivity, 100 % vs. 73.3 % vs. 73.3 %, p = 0.001). Most patients diagnosed only based on the Gold Coast criteria had lower motor signs. Hence, the Gold Coast criteria are particularly useful for diagnosing fast-progression ALS.}, } @article {pmid39987392, year = {2025}, author = {Liu, Y and Xiang, J and Gong, H and Yu, T and Gao, M and Huang, Y}, title = {The Regulation of TDP-43 Structure and Phase Transitions: A Review.}, journal = {The protein journal}, volume = {44}, number = {2}, pages = {113-132}, pmid = {39987392}, issn = {1875-8355}, support = {22477022//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *DNA-Binding Proteins/chemistry/metabolism/genetics ; Phase Transition ; Protein Processing, Post-Translational ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Mutation ; Frontotemporal Dementia/metabolism/genetics/pathology ; }, abstract = {The transactive response DNA binding protein 43 (TDP-43) is an RNA/DNA-binding protein that is involved in a number of cellular functions, including RNA processing and alternative splicing, RNA transport and translation, and stress granule assembly. It has attracted significant attention for being the primary component of cytoplasmic inclusions in patients with amyotrophic lateral sclerosis or frontotemporal dementia. Mounting evidence suggests that both cytoplasmic aggregation of TDP-43 and loss of nuclear TDP-43 function contribute to TDP-43 pathology. Furthermore, recent studies have demonstrated that TDP-43 is an important component of many constitutive or stress-induced biomolecular condensates. Dysregulation or liquid-to-gel transition of TDP-43 condensates can lead to alterations in TDP-43 function and the formation of TDP-43 amyloid fibrils. In this review, we summarize recent research progress on the structural characterization of TDP-43 and the TDP-43 phase transition. In particular, the roles that disease-associated genetic mutations, post-translational modifications, and extrinsic stressors play in the transitions among TDP-43 monomers, liquid condensates, solid condensates, and fibrils are discussed. Finally, we discuss the effectiveness of available regulators of TDP-43 phase separation and aggregation. Understanding the underlying mechanisms that drive the pathological transformation of TDP-43 could help develop therapeutic strategies for TDP-43 pathology.}, } @article {pmid39987285, year = {2025}, author = {Fang, M and Zhou, Y and He, K and Lu, Y and Tao, F and Huang, H}, title = {Glucose Metabolic Reprogramming in Microglia: Implications for Neurodegenerative Diseases and Targeted Therapy.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39987285}, issn = {1559-1182}, support = {82204651//National Natural Science Foundation of China/ ; }, abstract = {As intrinsic immune cells in the central nervous system, microglia play a crucial role in maintaining brain homeostasis. Microglia can transition from homeostasis to various responsive states in reaction to different external stimuli, undergoing corresponding alterations in glucose metabolism. In neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), microglial glucose metabolic reprogramming is widespread. This reprogramming leads to changes in microglial function, exacerbating neuroinflammation and the accumulation of pathological products, thereby driving the progression of neurodegeneration. This review summarizes the specific alterations in glucose metabolism within microglia in AD, PD, ALS, and MS, as well as the corresponding treatments aimed at reprogramming glucose metabolism. Compounds that inhibit key glycolytic enzymes like hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2), or activate regulators of energy metabolism such as AMP-activated protein kinase (AMPK), have shown significant potential in the treatment of various neurodegenerative diseases. However, current research faces numerous challenges, including side effects and blood-brain barrier (BBB) penetration of compounds. Screening relevant drugs from natural products, especially flavonoids, is a reliable approach. On the one hand, longtime herbal medical practices provide a certain degree of assurance regarding clinical safety, and their chemical properties contribute to effective BBB permeability. On the other hand, the concurrent anti-tumor and anti-neuroinflammatory activities of flavonoids suggest that regulation of glucose metabolism reprogramming might be a potential common mechanism of action. Notably, considering the dynamic nature of microglial metabolism, there is an urgent need to develop technologies for real-time monitoring of glucose metabolism processes, which would significantly advance research in this field.}, } @article {pmid39987111, year = {2025}, author = {Zeng, L and Yang, F and Xu, D and Zhou, J and Qiao, G and Wu, M and Li, C and Yu, Y and Qiu, Y and Liu, J}, title = {Actual needs of patients with amyotrophic lateral sclerosis: a qualitative study from Wuhan, China.}, journal = {BMC palliative care}, volume = {24}, number = {1}, pages = {50}, pmid = {39987111}, issn = {1472-684X}, support = {2023AFD160//Hubei Provincial Natural Science Foundation and Traditional Chinese Medicine Innovation and Development Joint/ ; 2024AFD279//Department of Science and Technology, Hubei Province, China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; China ; *Qualitative Research ; Male ; Middle Aged ; Female ; Aged ; Adult ; Needs Assessment ; Health Services Needs and Demand ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disorder that significantly impacts individuals and families. Previous research on ALS has predominantly focused on its pathophysiology, genetic factors, and potential therapeutic interventions. While these aspects are essential for understanding and treating the disease, there has been a growing recognition of the importance of studying patients' actual needs. Understanding these needs is vital for developing patient-centered care models that can enhance the well-being of ALS patients. However, existing studies on patients' needs are often limited in scope. Many are conducted in Western countries, and the results may not be directly applicable to patients in other cultural and socioeconomic contexts. China, with its large population and diverse cultural, economic, and healthcare landscapes, presents a unique setting for studying ALS patients' needs. At the same time, traditional Chinese medicine (TCM) practices are deeply ingrained in their healthcare system and may affect the way people with ALS seek treatment and manage their condition. Therefore, these differences may lead to differences in the actual needs of ALS patients in China. In conclusion, this qualitative study on the actual needs of ALS patients in China aims to bridge the gap in the existing research. By exploring these needs, it can provide valuable insights for healthcare providers, policymakers, and researchers, ultimately contributing to the improvement of care and quality of life for ALS patients in China.

METHOD: We carried out a qualitative study using an empirical phenomenological approach. Individual in-depth interviews were performed among 22 people with ALS from the motor neuron disease rehabilitation center of a tertiary Chinese medicine hospital in China, and the interview content was analyzed qualitatively. Interview recordings were converted to text content by NVivo 11.0 software and analyzed using Colaizzi's phenomenological method.

RESULT: Three main themes were identified in this study: (1) Demand for healthcare services, (2) Emotional requirements, (3) Functional requirements. In addition, 8 sub-themes were extracted as the actual needs of ALS patients.

CONCLUSION: This study is based on the real experience of ALS patients after diagnosis, and a deep understanding of these experiences can explore the actual needs of patients from many aspects and give reasonable advice and help. Given the particularity of the disease and the uncertainty of treatment, patients will have practical needs for relevant medical support, emotional requirements, physical functions, and other aspects during the period of illness, and the corresponding support is an effective measure to reduce the burden on patients.}, } @article {pmid39986312, year = {2025}, author = {Mizielinska, S and Hautbergue, GM and Gendron, TF and van Blitterswijk, M and Hardiman, O and Ravits, J and Isaacs, AM and Rademakers, R}, title = {Amyotrophic lateral sclerosis caused by hexanucleotide repeat expansions in C9orf72: from genetics to therapeutics.}, journal = {The Lancet. Neurology}, volume = {24}, number = {3}, pages = {261-274}, doi = {10.1016/S1474-4422(25)00026-2}, pmid = {39986312}, issn = {1474-4465}, support = {R01 NS121125/NS/NINDS NIH HHS/United States ; RF1 NS123052/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *DNA Repeat Expansion/genetics ; }, abstract = {GGGGCC repeat expansions in C9orf72 are a common genetic cause of amyotrophic lateral sclerosis in people of European ancestry; however, substantial variability in the penetrance of the mutation, age at disease onset, and clinical presentation can complicate diagnosis and prognosis. The repeat expansion is bidirectionally transcribed in the sense and antisense directions into repetitive RNAs and translated into dipeptide repeat proteins, and both accumulate in the cortex, cerebellum, and the spinal cord. Furthermore, neuropathological aggregates of phosphorylated TDP-43 are observed in motor cortex and other cortical regions, and in the spinal cord of patients at autopsy. C9orf72 repeat expansions can also cause frontotemporal dementia. The GGGGCC repeat induces a complex interplay of loss-of-function and gain-of-function pathological mechanisms. Clinical trials using antisense oligonucleotides to target the GGGGCC repeat RNA have not been successful, potentially because they only target a single gain-of-function mechanism. Novel therapeutic approaches targeting the DNA repeat expansion, multiple repeat-derived RNA species, or downstream targets of TDP-43 dysfunction are, however, on the horizon, together with the development of diagnostic and prognostic biomarkers.}, } @article {pmid39985864, year = {2025}, author = {Wilk, LS and Hoveling, RJM and van Velthoven, MFAM and Nijs, HGT and Aalders, MCG}, title = {Optimizing the detection and characterization of bruises using multispectral imaging.}, journal = {Journal of forensic and legal medicine}, volume = {111}, number = {}, pages = {102811}, doi = {10.1016/j.jflm.2025.102811}, pmid = {39985864}, issn = {1878-7487}, mesh = {Humans ; *Contusions/pathology/diagnostic imaging ; Algorithms ; Photography ; *Hematoma/diagnostic imaging/pathology ; }, abstract = {The detection and visualization of sub-dermal hematoma (bruises) plays a key role in suspected physical abuse cases, as it aids in the evaluation of both victim and suspect statements. Current methods rely on visual inspection, frequently aided by alternate light sources (ALS). Ideally, ALS increase visual contrast by exploiting differences in light absorption (due to the formation and clearance of chromophores within the bruise). However, in practice the achievable contrast is often limited by light-scattering: the short-wavelength region of the spectrum (comprising most of the chromophore-specific absorption peaks), is also strongly scattered by the dermal tissue. This, in turn, limits achievable penetration depths, effectively obscuring deep-lying bruises. ALS-based contrast enhancement is further complicated by bruise healing; diffusion and enzymatic activity alter the chromophore concentrations as well as their 3D-distribution within the tissue. To overcome these critical limitations, we employ a multi-spectral camera (8 wavelengths simultaneously) in conjunction with both observer-based scoring and a contrast-quantification algorithm to determine the optimal wavelength for the detection and characterization of bruises over time. We show that (i) bruise contrast significantly increases at 480 nm, 620 nm and 850 nm and (ii) the wavelength achieving optimal contrast gradually changes from 850 nm to 578 nm-480 nm as the bruise heals.}, } @article {pmid39985812, year = {2025}, author = {Filippi, M and Ghirelli, A and Spinelli, EG and Agosta, F}, title = {A comprehensive update on neuroimaging endpoints in amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {4}, pages = {397-413}, doi = {10.1080/14737175.2025.2470324}, pmid = {39985812}, issn = {1744-8360}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging ; Humans ; *Neuroimaging/methods ; *Magnetic Resonance Imaging/methods ; *Disease Progression ; *Positron-Emission Tomography/methods ; Biomarkers ; }, abstract = {INTRODUCTION: There are currently few treatments approved for amyotrophic lateral sclerosis (ALS). Additionally, there remains a significant unmet need for reliable, standardized biomarkers to assess endpoints in clinical trials. Magnetic resonance imaging (MRI)- and positron emission tomography (PET)-derived metrics could help in patient selection and stratification, shortening trial duration and reducing costs.

AREAS COVERED: This review focuses on the potential use of neuroimaging endpoints in the context of ALS therapeutic trials, providing insights on structural and functional neuroimaging, plexus and muscle alterations, glial involvement and neuroinflammation, envisioning how these surrogates of disease progression could be implemented in clinical trials. A PubMed search covering the past 15 years was performed.

EXPERT OPINION: Neuroimaging is essential in understanding ALS pathophysiology, aiding in disease progression tracking and evaluating therapeutic interventions. High costs, limited accessibility, lack of standardization, and patient tolerability limit their use in routine ALS care. Addressing these obstacles is essential for fully harnessing neuroimaging potential in improving diagnostics and treatment in ALS.}, } @article {pmid39985309, year = {2025}, author = {Lajoie, I and , and Kalra, S and Dadar, M}, title = {Regional Cerebral Atrophy Contributes to Personalized Survival Prediction in Amyotrophic Lateral Sclerosis: A Multicentre, Machine Learning, Deformation-Based Morphometry Study.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27196}, pmid = {39985309}, issn = {1531-8249}, support = {//Fondation Brain Canada/ ; //ALS Society of Canada/ ; }, abstract = {OBJECTIVE: Accurate personalized survival prediction in amyotrophic lateral sclerosis is essential for effective patient care planning. This study investigates whether grey and white matter changes measured by magnetic resonance imaging can improve individual survival predictions.

METHODS: We analyzed data from 178 patients with amyotrophic lateral sclerosis and 166 healthy controls in the Canadian Amyotrophic Lateral Sclerosis Neuroimaging Consortium study. A voxel-wise linear mixed-effects model assessed disease-related and survival-related atrophy detected through deformation-based morphometry, controlling for age, sex, and scanner variations. Additional linear mixed-effects models explored associations between regional imaging and clinical measurements, and their associations with time to the composite outcome of death, tracheostomy, or permanent assisted ventilation. We evaluated whether incorporating imaging features alongside clinical data could improve the performance of an individual survival distribution model.

RESULTS: Deformation-based morphometry uncovered distinct voxel-wise atrophy patterns linked to disease progression and survival, with many of these regional atrophies significantly associated with clinical manifestations of the disease. By integrating regional imaging features with clinical data, we observed a substantial enhancement in the performance of survival models across key metrics. Our analysis identified specific brain regions, such as the corpus callosum, rostral middle frontal gyrus, and thalamus, where atrophy predicted an increased risk of mortality.

INTERPRETATION: This study suggests that brain atrophy patterns measured by deformation-based morphometry provide valuable insights beyond clinical assessments for prognosis. It offers a more comprehensive approach to prognosis and highlights brain regions involved in disease progression and survival, potentially leading to a better understanding of amyotrophic lateral sclerosis. ANN NEUROL 2025.}, } @article {pmid39985291, year = {2025}, author = {Steinfurth, L and Grehl, T and Weyen, U and Kettemann, D and Steinbach, R and Rödiger, A and Grosskreutz, J and Petri, S and Boentert, M and Weydt, P and Bernsen, S and Walter, B and GüNTHER, R and Lingor, P and Koch, JC and Baum, P and Weishaupt, JH and Dorst, J and Koc, Y and Cordts, I and Vidovic, M and Norden, J and Schumann, P and Körtvélyessy, P and Spittel, S and Münch, C and Maier, A and Meyer, T}, title = {Self-assessment of amyotrophic lateral sclerosis functional rating scale on the patient's smartphone proves to be non-inferior to clinic data capture.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/21678421.2025.2468404}, pmid = {39985291}, issn = {2167-9223}, abstract = {OBJECTIVE: To investigate self-assessment of the amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) using the patient's smartphone and to analyze non-inferiority to clinic assessment.

METHODS: In an observational study, ALSFRS-R data being remotely collected on a mobile application (App-ALSFRS-R) were compared to ALSFRS-R captured during clinic visits (clinic-ALSFRS-R). ALS progression rate (ALSPR)-as calculated by the monthly decline of ALSFRS-R-and its intrasubject variability (ALSPR-ISV) between ratings were used to compare both cohorts. To investigate non-inferiority of App-ALSFRS-R data, a non-inferiority margin was determined.

RESULTS: A total of 691 ALS patients using the ALS-App and 1895 patients with clinic assessments were included. Clinical characteristics for the App-ALSFRS-R and clinic-ALSFRS-R cohorts were as follows: Mean age 60.45 (SD 10.43) and 63.69 (SD 11.30) years (p < 0.001), disease duration 38.7 (SD 37.68) and 56.75 (SD 54.34) months (p < 0.001) and ALSPR 0.72 and 0.59 (p < 0.001), respectively. A paired sample analysis of ALSPR-ISV was applicable for 398 patients with clinic as well as app assessments and did not show a significant difference (IQR 0.12 [CI 0.11, 0.14] vs 0.12 [CI 0.11, 0.14], p = 0.24; Cohen's d = 0.06). CI of IQR for App-ALSFRS-R was below the predefined non-inferiority margin of 0.15 IQR, demonstrating non-inferiority.

CONCLUSIONS: Patients using a mobile application for remote digital self-assessment of the ALSFRS-R revealed younger age, earlier disease course, and faster ALS progression. The finding of non-inferiority of App-ALSFRS-R assessments underscores, that data collection using the ALS-App on the patient's smartphone can serve as additional source of ALSFRS-R in ALS research and clinical practice.}, } @article {pmid39985110, year = {2025}, author = {Swanson, MEV and Mrkela, M and Turner, C and Curtis, MA and Faull, RLM and Walker, AK and Scotter, EL}, title = {Neuronal TDP-43 aggregation drives changes in microglial morphology prior to immunophenotype in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {39}, pmid = {39985110}, issn = {2051-5960}, mesh = {*Microglia/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Humans ; Animals ; Mice ; Male ; Female ; Middle Aged ; Aged ; Immunophenotyping ; Mice, Transgenic ; Motor Cortex/pathology/metabolism ; Aged, 80 and over ; Microfilament Proteins/metabolism ; Antigens, CD/metabolism ; Calcium-Binding Proteins/metabolism ; }, abstract = {Microglia are the innate immune cells of the brain with the capacity to react to damage or disease. Microglial reactions can be characterised in post-mortem tissues by assessing their pattern of protein expression, or immunophenotypes, and cell morphologies. We recently demonstrated that microglia have a phagocytic immunophenotype in early-stage ALS but transition to a dysfunctional immunophenotype by end stage, and that these states are driven by TAR DNA-binding protein 43 (TDP-43) aggregation in the human brain. However, it remains unclear how microglial morphologies are changed in ALS. Here we examine the relationship between microglial immunophenotypes and morphologies, and TDP-43 pathology in motor cortex tissue from people with ALS and from a TDP-43-driven ALS mouse model. Post-mortem human brain tissue from 10 control and 10 ALS cases was analysed alongside brain tissue from the bigenic NEFH-tTA/tetO-hTDP-43∆NLS (rNLS) mouse model of ALS at distinct disease stages. Sections were immunohistochemically labelled for microglial markers (HLA-DR, CD68, and Iba1) and phosphorylated TDP-43 (pTDP-43). Single-cell microglial HLA-DR, CD68, and Iba1 average intensities, and morphological features (cell body area, process number, total outgrowth, and branch number) were measured using custom image analysis pipelines. In human ALS motor cortex, we identified a significant change in microglial morphologies from ramified to hypertrophic, which was associated with increased Iba1 and CD68 levels. In the rNLS mouse motor cortex, the microglial morphologies changed from ramified to hypertrophic and increased Iba1 levels occurred in parallel with pTDP-43 aggregation, prior to increases in CD68 levels. Overall, the evidence presented in this study demonstrates that microglia change their morphologies prior to immunophenotype changes. These morphological changes may prime microglia near neurons with pTDP-43 aggregation for phagocytosis, in turn triggering immunophenotype changes; first, to a phagocytic state then to a dysfunctional one.}, } @article {pmid39984353, year = {2025}, author = {Comini, L and Pietro, DAD and Olivares, A and Bertella, E and Vitacca, M}, title = {Gut dysbiosis and leaky gut syndrome in moderately impaired amyotrophic lateral sclerosis patients.}, journal = {European journal of internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ejim.2025.02.019}, pmid = {39984353}, issn = {1879-0828}, } @article {pmid39982984, year = {2025}, author = {Verde, EM and Antoniani, F and Mediani, L and Secco, V and Crotti, S and Ferrara, MC and Vinet, J and Sergeeva, A and Yan, X and Hoege, C and Stuani, C and Paron, F and Kao, TT and Shrivastava, R and Polanowska, J and Bailly, A and Rosa, A and Aronica, E and Goswami, A and Shneider, N and Hyman, AA and Buratti, E and Xirodimas, D and Franzmann, TM and Alberti, S and Carra, S}, title = {SUMO2/3 conjugation of TDP-43 protects against aggregation.}, journal = {Science advances}, volume = {11}, number = {8}, pages = {eadq2475}, pmid = {39982984}, issn = {2375-2548}, mesh = {Humans ; *Small Ubiquitin-Related Modifier Proteins/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; *Protein Inhibitors of Activated STAT/metabolism/genetics ; Oxidative Stress ; Protein Aggregates ; Ubiquitins/metabolism ; Sumoylation ; Stress Granules/metabolism ; Protein Binding ; Protein Aggregation, Pathological/metabolism ; Poly-ADP-Ribose Binding Proteins ; }, abstract = {Cytosolic aggregation of the RNA binding protein TDP-43 (transactive response DNA-binding protein 43) is a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. Here, we report that during oxidative stress, TDP-43 becomes SUMO2/3-ylated by the SUMO E3 ligase protein PIAS4 (protein inhibitor of activated STAT 4) and enriches in cytoplasmic stress granules (SGs). Upon pharmacological inhibition of TDP-43 SUMO2/3-ylation or PIAS4 depletion, TDP-43 enrichment in SGs is accompanied by irreversible aggregation. In cells that are unable to assemble SGs, SUMO2/3-ylation of TDP-43 is strongly impaired, supporting the notion that SGs are compartments that promote TDP-43 SUMO2/3-ylation during oxidative stress. Binding of TDP-43 to UG-rich RNA antagonizes PIAS4-mediated SUMO2/3-ylation, while RNA dissociation promotes TDP-43 SUMO2/3-ylation. We conclude that SUMO2/3 protein conjugation is a cellular mechanism to stabilize cytosolic RNA-free TDP-43 against aggregation.}, } @article {pmid39982687, year = {2025}, author = {Loher, P and Londin, E and Ilieva, H and Pasinelli, P and Rigoutsos, I}, title = {Re-Analyses of Samples From Amyotrophic Lateral Sclerosis Patients and Controls Identify Many Novel Small RNAs With Diagnostic And Prognostic Potential.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39982687}, issn = {1559-1182}, abstract = {Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease for which accurate diagnostic and prognostic biomarkers are needed. Toward this goal, we reanalyzed two published collections of datasets generated from the plasma and serum of ALS patients and controls. We profiled these datasets for isoforms of microRNAs (miRNAs) known as isomiRs, transfer RNA-derived fragments (tRFs), and ribosomal RNA-derived fragments (rRFs), placing all remaining reads into a group labeled "not-itrs." We found that plasma and serum are rich in isomiRs (canonical, non-canonical, and non-templated), tRFs, rRFs, and members of an emerging class of small RNAs known as Y RNA-derived fragments (yRFs). In both analyzed collections, we found many isomiRs, tRFs, rRFs, and yRFs that are differentially abundant between patients and controls. We also performed a survival analysis that considered Riluzole treatment status, demographics (age at onset, age at enrollment, sex), and disease characteristics (ALSFRS, rD50, onset type) and found many of the differentially abundant small RNAs to be associated with survival time, with some of these associations being independent of Riluzole treatment. Unexpectedly, many not-itrs that did not map to the human genome mapped exactly to sequences from the SILVA database of ribosomal DNAs (rDNAs). Not-itrs from the plasma datasets mapped primarily to rDNAs from the order of Burkholderiales, and several of them were associated with patient survival. Not-itrs from the serum datasets also showed support for rDNA from Burkholderiales but a stronger support for rDNAs from the fungi group of the Nucletmycea taxon. The findings suggest that many previously unexplored small non-coding RNAs, including human isomiRs, tRFs, rRFs, and yRFs, could potentially serve as novel diagnostic and prognostic biomarkers for ALS.}, } @article {pmid39982214, year = {2025}, author = {Peng, T and Hu, N and Huang, L and Kang, Y and Yan, Y and Zhang, H and Wan, D and Jin, X and Yang, Y}, title = {Safety of edaravone in real-world use: analysis based on FDA adverse event reporting system.}, journal = {Expert opinion on drug safety}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/14740338.2025.2470874}, pmid = {39982214}, issn = {1744-764X}, abstract = {BACKGROUND: Edaravone is a novel free radical scavenger utilized to treat amyotrophic lateral sclerosis (ALS). However, long-term safety data remain limited.

RESEARCH DESIGN AND METHODS: Adverse event reports related to edaravone from the second quarter of 2017 to the second quarter of 2024 were extracted from the US Food and Drug Administration (FDA) Adverse Event Reporting System database (FAERS). Disproportionality analysis was conducted utilizing the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms.

RESULTS: A total of 3,149 adverse event reports related to edaravone were analyzed. The most common adverse reactions included systemic disorders and administration site reactions, nervous system disorders, respiratory system disorders, and surgical and medical procedures. New adverse reaction signals included disseminated intravascular coagulation, gastric fistula, sputum retention, excessive salivation, fractures, elevated cystatin C. The median onset time for adverse events was 43 days (interquartile range: 7-173 days).

CONCLUSION: This study confirmed previously reported adverse events and identified several new ones associated with edaravone. These findings provide valuable insights for optimizing ALS patient management and highlight the need for further research into the mechanisms of these adverse reactions.}, } @article {pmid39981400, year = {2025}, author = {Yang, EJ and Lee, SH}, title = {Herbal Medicine Extracts Improve Motor Function by Anti-Inflammatory Activity in hSOD1[G93A] Animal Model.}, journal = {Mediators of inflammation}, volume = {2025}, number = {}, pages = {1999953}, pmid = {39981400}, issn = {1466-1861}, mesh = {Animals ; Mice ; *Mice, Transgenic ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; *Disease Models, Animal ; *Plant Extracts/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Muscle, Skeletal/drug effects/metabolism ; Paeonia/chemistry ; Male ; Oxidative Stress/drug effects ; Herbal Medicine ; Superoxide Dismutase/metabolism ; Motor Neurons/drug effects/metabolism ; Inflammation/drug therapy/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multicomplex neurodegenerative disorder characterized by motor neuron death, muscle atrophy, and respiratory failure. Owing to its multicomplex mechanisms and multifactorial nature in the skeletal muscle and spinal cord (SC), no effective therapy has been developed. However, herbal medicines, known for their multitarget properties, have demonstrated promising efficacy with limited side effects in treating various diseases. Specifically, Paeonia lactiflora Pallas has been demonstrated to exhibit analgesic, antidepressant, anti-inflammatory, and neuroprotective effects. However, the pharmacological mechanisms underlying the beneficial effects of P. lactiflora in hSOD1[G93A] animal models remain unexplored. Therefore, this study was conducted to investigate the multitarget effects of P. lactiflora in hSOD1[G93A] transgenic mice, an ALS model. Footprint tests, western blot assays, and immunohistochemical analysis were used to assess the effect of P. lactiflora on the tibia anterior (TA), gastrocnemius (GC), and SC. The results revealed that P. lactiflora augmented motor function and decreased motor neuron loss in hSOD1[G93A] mice. Furthermore, P. lactiflora significantly lowered the expression of proteins associated with inflammation and oxidative stress in the skeletal muscle (TA and GC) and SC. P. lactiflora also regulated autophagy function by reducing the levels of key markers, such as P62/sequestosome 1 (SQSTM1), microtubule-associated proteins 1A/1B light chain 3B, and SMAD family member 2, in the muscle and SC. Overall, P. lactiflora treatment improved motor function, prevented motor neuron death, and exhibited anti-inflammatory and antioxidative effects in the skeletal muscle and SC of ALS mouse models. These results suggest that P. lactiflora could serve as a promising multitarget therapeutic agent for systemic and multipathological diseases.}, } @article {pmid39981199, year = {2025}, author = {Kiernan, MC}, title = {Recent developments in consensus diagnostic criteria for amyotrophic lateral sclerosis.}, journal = {eNeurologicalSci}, volume = {38}, number = {}, pages = {100559}, pmid = {39981199}, issn = {2405-6502}, } @article {pmid39980944, year = {2025}, author = {Ji, J}, title = {To the Editor: In Response to Park et al's Perspective on the Resignation of South Korean Residents: A Medical Student View.}, journal = {Journal of graduate medical education}, volume = {17}, number = {1}, pages = {113-114}, pmid = {39980944}, issn = {1949-8357}, } @article {pmid39980027, year = {2025}, author = {Jin, Y and Conneely, KN and Ma, W and Naviaux, RK and Siddique, T and Allen, EG and Guingrich, S and Pascuzzi, RM and Jin, P}, title = {Whole-genome bisulfite sequencing of cell-free DNA unveils age-dependent and ALS-associated methylation alterations.}, journal = {Cell & bioscience}, volume = {15}, number = {1}, pages = {26}, pmid = {39980027}, issn = {2045-3701}, support = {P50 HD104458/HD/NICHD NIH HHS/United States ; R35 NS111602/NS/NINDS NIH HHS/United States ; NS111602/NS/NINDS NIH HHS/United States ; HD104458//National Institute of Child Health and Human Development/ ; }, abstract = {BACKGROUND: Cell-free DNA (cfDNA) in plasma carries epigenetic signatures specific to tissue or cell of origin. Aberrant methylation patterns in circulating cfDNA have emerged as valuable tools for noninvasive cancer detection, prenatal diagnostics, and organ transplant assessment. Such epigenetic changes also hold significant promise for the diagnosis of neurodegenerative diseases, which often progresses slowly and has a lengthy asymptomatic period. However, genome-wide cfDNA methylation changes in neurodegenerative diseases remain poorly understood.

RESULTS: We used whole-genome bisulfite sequencing (WGBS) to profile age-dependent and ALS-associated methylation signatures in cfDNA from 30 individuals, including young and middle-aged controls, as well as ALS patients with matched controls. We identified 5,223 age-related differentially methylated loci (DMLs) (FDR < 0.05), with 51.6% showing hypomethylation in older individuals. Our results significantly overlapped with age-associated CpGs identified in a large blood-based epigenome-wide association study (EWAS). Comparing ALS patients to controls, we detected 1,045 differentially methylated regions (DMRs) in gene bodies, promoters, and intergenic regions. Notably, these DMRs were linked to key ALS-associated pathways, including endocytosis and cell adhesion. Integration with spinal cord transcriptomics revealed that 31% of DMR-associated genes exhibited differential expression in ALS patients compared to controls, with over 20 genes significantly correlating with disease duration. Furthermore, comparison with published single-nucleus RNA sequencing (snRNA-Seq) data of ALS demonstrated that cfDNA methylation changes reflects cell-type-specific gene dysregulation in the brain of ALS patients, particularly in excitatory neurons and astrocytes. Deconvolution of cfDNA methylation profiles suggested altered proportions of immune and liver-derived cfDNA in ALS patients.

CONCLUSIONS: cfDNA methylation is a powerful tool for assessing age-related changes and ALS-specific molecular dysregulation by revealing perturbed locus, genes, and the proportional contributions of different tissues/cells to the plasma. This technique holds promise for clinical application in biomarker discovery across a broad spectrum of neurodegenerative disorders.}, } @article {pmid39979261, year = {2025}, author = {Liu, D and Webber, HC and Bian, F and Xu, Y and Prakash, M and Feng, X and Yang, M and Yang, H and You, IJ and Li, L and Liu, L and Liu, P and Huang, H and Chang, CY and Liu, L and Shah, SH and La Torre, A and Welsbie, DS and Sun, Y and Duan, X and Goldberg, JL and Braun, M and Lansky, Z and Hu, Y}, title = {Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1789}, pmid = {39979261}, issn = {2041-1723}, support = {R01 EY034353/EY/NEI NIH HHS/United States ; P30 EY026877/EY/NEI NIH HHS/United States ; 1F32EY029567//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; EY026877//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; EY034353//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; S10 OD025091/OD/NIH HHS/United States ; R01 EY032518/EY/NEI NIH HHS/United States ; EY032518//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; R01 EY023295/EY/NEI NIH HHS/United States ; EY023295//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; F32 EY029567/EY/NEI NIH HHS/United States ; R01 EY032159/EY/NEI NIH HHS/United States ; R01 EY024932/EY/NEI NIH HHS/United States ; EY024932//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; R01 EY025295/EY/NEI NIH HHS/United States ; S10 OD030452/OD/NIH HHS/United States ; }, mesh = {Animals ; *Cell Cycle Proteins/metabolism/genetics ; *Membrane Transport Proteins/metabolism/genetics ; *Mitochondria/metabolism ; *Axons/metabolism ; *Retinal Ganglion Cells/metabolism/pathology ; Mice ; Humans ; *Microtubules/metabolism ; Nerve Regeneration ; Optic Nerve/metabolism/pathology ; Neuroprotection ; Disease Models, Animal ; Axonal Transport ; Kinesins/metabolism/genetics ; Mice, Inbred C57BL ; Transcription Factor TFIIIA/metabolism/genetics ; Low Tension Glaucoma/metabolism/genetics/pathology ; Male ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; }, abstract = {Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We find that OPTN C-terminus truncation (OPTN∆C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a decrease of axonal mitochondria in mice. We discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C-terminus dependent manner. Furthermore, overexpressing OPTN/TRAK1/KIF5B prevents not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes robust ON regeneration. Therefore, in addition to generating animal models for NTG and ALS, our results establish OPTN as a facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.}, } @article {pmid39978484, year = {2025}, author = {Hülsmeier, AJ}, title = {Glycosphingolipids in neurodegeneration - Molecular mechanisms, cellular roles, and therapeutic perspectives.}, journal = {Neurobiology of disease}, volume = {207}, number = {}, pages = {106851}, doi = {10.1016/j.nbd.2025.106851}, pmid = {39978484}, issn = {1095-953X}, mesh = {Humans ; *Glycosphingolipids/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; }, abstract = {Neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neuronal loss and pose significant global health challenges. Glycosphingolipids (GSLs), critical components of neuronal membranes, regulate signal transduction, membrane organization, neuroinflammation, and lipid raft functionality. This review explores GSL roles in neural development, differentiation, and neurogenesis, along with their dysregulation in neurodegenerative diseases. Aberrations in GSL metabolism drive key pathological features such as protein aggregation, neuroinflammation, and impaired signaling. Specific GSLs, such as GM1, GD3, and GM3, influence amyloid-beta aggregation in AD, α-synuclein stability in PD, and mutant huntingtin toxicity in HD. Therapeutic strategies targeting GSL metabolism, such as GM1 supplementation and enzyme modulation, have demonstrated potential to mitigate disease progression. Further studies using advanced lipidomics and glycomics may support biomarker identification and therapeutic advancements. This work aims to highlight the translational potential of GSL research for diagnosing and managing devastating neurodegenerative conditions.}, } @article {pmid39977838, year = {2025}, author = {Chang, JH and Tschannen, D}, title = {An Integrative Review of Quality Improvement Competence and Engagement Among Frontline Nurses.}, journal = {Journal of nursing care quality}, volume = {40}, number = {2}, pages = {173-180}, pmid = {39977838}, issn = {1550-5065}, mesh = {Humans ; *Quality Improvement ; *Leadership ; Clinical Competence/standards ; }, abstract = {BACKGROUND: Nurses providing direct care have firsthand knowledge of gaps in practice and thus must actively engage in quality improvement (QI) to enhance patient outcomes.

PURPOSE: This integrative review evaluated QI competence and engagement among frontline nurses.

METHODS: Using Souza et al's 6-step framework, literature on QI engagement and competence was synthesized using a rigorous search strategy and quality assessment.

RESULTS: Sixteen studies revealed generally low QI engagement and competence. Factors such as education, experience, and role influenced engagement, with higher levels of education and experience linked to higher QI involvement. Nurse leaders had higher engagement, underscoring the need for strong leadership in creating a culture of improvement.

CONCLUSIONS: Successful and sustainable QI programs and supportive environments enhance QI engagement and competence among frontline nurses.}, } @article {pmid39976286, year = {2025}, author = {Guo, K and Savelieff, MG and Jang, DG and Teener, SJ and Zhao, L and Hur, J and Goutman, SA and Feldman, EL}, title = {Longitudinal Metabolomics in Amyotrophic Lateral Sclerosis Implicates Impaired Lipid Metabolism.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27208}, pmid = {39976286}, issn = {1531-8249}, support = {UL1 TR000433/TR/NCATS NIH HHS/United States ; //the Scott L. Pranger ALS Clinic Fund/ ; //the Peter R. Clark Fund for ALS Research/ ; //the Dr. Randall Whitcomb Fund for ALS Genetics/ ; K23 ES027221/ES/NIEHS NIH HHS/United States ; //the Coleman Therapeutic Discovery Fund/ ; R01ES030049/ES/NIEHS NIH HHS/United States ; UL1TR002240//National Center for Advancing Translational Sciences at the National Institutes of Health/ ; R01TS000289/CC/CDC HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; K23ES027221/ES/NIEHS NIH HHS/United States ; R01NS127188/NS/NINDS NIH HHS/United States ; R01 TS000289/TS/ATSDR CDC HHS/United States ; UL1TR000433//Michigan Institute for Clinical and Health Research/ ; //the Robert A. Epstein and Joan M. Chernoff-Epstein Emerging Scholar Fund/ ; UL1 TR002240/TR/NCATS NIH HHS/United States ; //the Sinai Medical Staff Foundation/ ; //the A. Alfred Taubman Medical Research Institute/ ; //the NeuroNetwork for Emerging Therapies, University of Michigan/ ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by altered metabolome and energy homeostasis, manifesting with body mass index changes and hypermetabolism-both prognostic of disease progression and survival. The cross-sectional ALS metabolome has been characterized, but longitudinal correlations to functional decline are lacking.

METHODS: We longitudinally evaluated metabolomes from ALS plasma and terminal postmortem spinal cord and brain motor cortex tissue. We constructed 3 plasma models. A linear mixed effects model correlated all metabolite levels across all timepoints to their corresponding functional scores. An interaction model predicted a longitudinal change in function from baseline metabolites, whereas a progression model identified metabolites linked to a 20% or 50% drop in function. In postmortem samples, differential metabolites in onset versus second spinal cord segments served as a surrogate of disease progression. Mendelian randomization assessed potential causality from metabolites.

RESULTS: In plasma, all models primarily selected lipid metabolites and sub-pathways, in addition to amino acids, xenobiotics, and various less frequently selected pathways. Among lipids, fatty acids and sphingomyelins were predominant, along with plasmalogens, phosphatidylcholines, and lysophospholipids. Sex interaction findings were nominal. In the spinal cord, sphingomyelin and long-chain saturated and monounsaturated fatty acids were more abundant in the onset segment tissue, whereas phosphatidylcholines and phosphatidylethanolamines were less abundant. Mendelian randomization suggested that impaired carnitine and short chain acylcarnitine metabolism may be genetically determined in ALS, along with various antioxidant derivatives.

INTERPRETATION: Our findings suggest metabolomic changes primarily involving different lipid classes and carnitine metabolism may underscore ALS severity and progression. ANN NEUROL 2025.}, } @article {pmid39976261, year = {2025}, author = {Menendez-Gonzalez, M}, title = {Implementing a tridimensional diagnostic framework for personalized medicine in neurodegenerative diseases.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14591}, pmid = {39976261}, issn = {1552-5279}, support = {PI21/00467//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/diagnosis/genetics ; *Biomarkers ; Neuroimaging/methods ; }, abstract = {Neurodegenerative diseases (NDDs) pose a significant challenge in modern medicine due to their clinical heterogeneity, multifactorial etiologies, and frequent co-pathologies. Traditional diagnostic systems, based on clinical symptoms and post mortem findings, are limited in capturing the complex interactions among genetic, molecular, and neuroanatomical factors. This manuscript introduces a novel tridimensional diagnostic framework that integrates these factors across three key axes: etiology (genetic and environmental influences), molecular markers (primary and secondary biomarkers), and neuroanatomoclinical correlations. Through case studies, we demonstrate the framework's ability to synthesize incomplete datasets, stratify patients, and guide precision medicine. By incorporating omics technologies, neuroimaging, and AI-driven probabilistic modeling, the framework enhances diagnostic accuracy and clinical relevance. This approach may contribute to overcoming the limitations of traditional nosologies, offering a scalable and adaptable tool for both clinical practice and research and advancing the field of precision medicine in NDD management. HIGHLIGHTS: Tridimensional diagnostic system: We propose a new framework that incorporates three axes - etiology, molecular markers, and neuroanatomical-clinical correlations - to enhance diagnostic accuracy for NDDs. Personalized medicine: The tridimensional system enables the integration of genetic, molecular, and clinical data, allowing for highly personalized treatment strategies tailored to individual patients. Proteinopathies as key biomarkers: This diagnostic system emphasizes the use of primary proteinopathies (amyloid, tau, synuclein) and secondary biomarkers (eg, NfL, GFAP) to monitor disease progression and treatment efficacy. Addressing clinical heterogeneity: The framework accommodates the complexity and heterogeneity of NDDs, offering an adaptable diagnostic approach for classical conditions like Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and ALS. Case studies and real-world application: Practical case studies illustrate how this system can be implemented in clinical practice, enabling the combination of DMTs with symptomatic treatments.}, } @article {pmid39976178, year = {2025}, author = {Canosa, A and Manera, U and Vasta, R and Zocco, G and Di Pede, F and Cabras, S and De Mattei, F and Palumbo, F and Iazzolino, B and Minerva, E and Sbaiz, L and Brunetti, M and Gallone, S and Grassano, M and Matteoni, E and Polverari, G and Fuda, G and Casale, F and Salamone, P and De Marco, G and Marchese, G and Moglia, C and Calvo, A and Pagani, M and Chiò, A}, title = {Brain Metabolic Features of FUS-ALS: A 2-[[18]F]FDG-PET Study.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27201}, pmid = {39976178}, issn = {1531-8249}, support = {//A.S.D. Polisportiva U.I.C.I Torino Onlus (Oltre la Vista, Oltre la SLA)/ ; PRIN 2017//Ministero dell'Università e della Ricerca/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; //Fondation Thierry Latran (INSPIRED)/ ; RF-2016- 02362405//Ministero della Salute (The Italian Ministry of Health [Ricerca Sanitaria Finalizzata])/ ; 259867//European Commission's Health Seventh Framework Programme (FP7/2007-2013)/ ; GA101017598//Horizon 2020 Framework Programme (BRAINTEASER [Bringing Artificial Intelligence Home for a Better Care of Amyotrophic Lateral Sclerosis and Multiple Sclerosis])/ ; 101137074//Horizon 2020 Framework Programme/ ; }, abstract = {OBJECTIVE: We aimed at evaluating the brain metabolic features of fused in sarcoma amyotrophic lateral sclerosis (FUS-ALS) compared with sporadic ALS (sALS), using 2-[fluorine-18] fluoro-2-deoxy-D-glucose positron emission tomography (2-[[18]F]FDG-PET).

METHODS: We employed the 2-sample t-test model of SPM12, implemented in MATLAB, to compare 12 FUS-ALS cases with 40 healthy controls (HC) and 48 sALS, randomly collected from the series of patients who underwent brain 2-[[18]F]FDG-PET at the ALS Center of Turin (Italy) at diagnosis from 2009 to 2019. In the comparisons between cases and HC, we included age at PET and sex as covariates. Because FUS-ALS usually shows early onset in spinal regions, in the comparison between FUS-ALS and sALS, we included singularly the following covariates in a second step, to evaluate the determinants of eventual metabolic differences: age at PET, sex, and onset (spinal/bulbar).

RESULTS: sALS patients showed significant relative hypometabolism in bilateral fronto-temporo-occipital cortex and right insula as compared with FUS-ALS. After adjusting for age, the relative hypometabolism remained in the bilateral precentral gyrus and in the right middle and inferior temporal gyrus. As compared with HC, FUS patients displayed a significant relative hypermetabolism in the pontobulbar region and right cerebellar tonsil, dentate nucleus, and uvula, while sALS showed relative hypometabolism in bilateral frontal and occipital cortices and in left temporal and parietal regions.

INTERPRETATION: Patients with FUS-ALS show relative preservation of motor cortex metabolism compared with those with sALS, possibly reflecting the prevalence of lower motor neuron impairment in their phenotype. Prospective studies are necessary to investigate the possible role of 2-[[18]F]FDG-PET as a biomarker to track disease spreading in clinical trials. ANN NEUROL 2025.}, } @article {pmid39975337, year = {2025}, author = {Zinn, KM and McLaren, MW and Imai, MT and Jayaram, MM and Rothstein, JD and Elrick, MJ}, title = {Enterovirus D68 2A protease causes nuclear pore complex dysfunction and motor neuron toxicity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.01.23.632178}, pmid = {39975337}, issn = {2692-8205}, abstract = {The picornavirus Enterovirus D68 (EV-D68) is an important pathogen associated with acute flaccid myelitis (AFM). The pathogenesis of AFM involves infection of spinal motor neurons and motor neuron death, however the mechanisms linking EV-D68 infection to selective neurotoxicity are not well understood. Dysfunction of the nuclear pore complex (NPC) has been implicated in motor neuron injury in neurodegenerative diseases such as amyotrophic lateral sclerosis, and the NPC is also modified by picornavirus proteases during the course of infection. We therefore sought to determine the impact of EV-D68 proteases on NPC structure and function and their role in motor neuron toxicity. We demonstrate widespread disruption of NPC composition by EV-D68 2A and 3C proteases via the direct cleavage of a relatively small number of nucleoporins, notably Nup98 and POM121 by 2A [pro] . Using reporter systems, we demonstrate that 2A [pro] inhibits nuclear import and export of protein cargoes and also disrupts the permeability barrier of the NPC, while having no apparent effect on RNA export. We further show that 2A [pro] is toxic to induced pluripotent stem cell derived motor neurons by demonstrating a rescue of toxicity with 2A [pro] inhibitor telaprevir at concentrations that are insufficient to inhibit viral replication. This study expands our understanding of EV-D68 neuropathogenesis and provides a rationale for targeting the NPC or 2A [pro] therapeutically in AFM.}, } @article {pmid39975323, year = {2025}, author = {Bekier, ME and Pinarbasi, E and Mesojedec, JJ and Ghaffari, L and de Majo, M and Ullian, E and Koontz, M and Coleman, S and Li, X and Tank, EMH and Waksmacki, J and Barmada, S}, title = {Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39975323}, issn = {2692-8205}, support = {UL1 TR000433/TR/NCATS NIH HHS/United States ; R44 NS124457/NS/NINDS NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; }, abstract = {Cytoplasmic TDP43 mislocalization and aggregation are pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the initial cellular insults that lead to TDP43 mislocalization remain unclear. In this study, we demonstrate that Nemo-like kinase (NLK)-a proline-directed serine/threonine kinase-promotes the mislocalization of TDP43 and other RNA-binding proteins by disrupting nuclear import. NLK levels are selectively elevated in neurons exhibiting TDP43 mislocalization in ALS patient tissues, while genetic reduction of NLK reduces toxicity in human neuron models of ALS. Our findings suggest that NLK is a promising therapeutic target for neurodegenerative diseases.}, } @article {pmid39975241, year = {2025}, author = {Ghaffari, LT and Welebob, E and Boehringer, A and Cyliax, K and Pasinelli, P and Trotti, D and Haeusler, AR}, title = {Neuronal Activity-Dependent Gene Dysregulation in C9orf72 i[3]Neuronal Models of ALS/FTD Pathogenesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39975241}, issn = {2692-8205}, support = {R01 NS109150/NS/NINDS NIH HHS/United States ; R01 NS114128/NS/NINDS NIH HHS/United States ; RF1 NS114128/NS/NINDS NIH HHS/United States ; }, abstract = {The GGGGCC nucleotide repeat expansion (NRE) mutation in the C9orf72 (C9) gene is the most common cause of ALS and FTD. Neuronal activity plays an essential role in shaping biological processes within both healthy and neurodegenerative disease scenarios. Here, we show that at baseline conditions, C9-NRE iPSC-cortical neurons display aberrations in several pathways, including synaptic signaling and transcriptional machinery, potentially priming diseased neurons for an altered response to neuronal stimulation. Indeed, exposure to two pathophysiologically relevant stimulation modes, prolonged membrane depolarization, or a blockade of K[+] channels, followed by RNA sequencing, induces a temporally divergent activity-dependent transcriptome of C9-NRE cortical neurons compared to healthy controls. This study provides new insights into how neuronal activity influences the ALS/FTD-associated transcriptome, offering a dataset that enables further exploration of pathways necessary for conferring neuronal resilience or degeneration.}, } @article {pmid39973992, year = {2025}, author = {Nassan, M and Ayala, IA and Sloan, J and Bonfitto, A and Stark, B and Song, S and Naymik, M and Geula, C and Gefen, T and Barbieri, E and Piras, IS and Mesulam, MM and Huentelman, MJ}, title = {The genetics of TDP43-Type-C neurodegeneration: a whole genome sequencing study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.01.25.25320561}, pmid = {39973992}, abstract = {Frontotemporal lobar degeneration-TDP Type C (TDP-C) is a unique neurodegenerative disease that starts by attacking the anterior temporal lobe leading to language and/or behavioral syndromes. Current literature on the genetic associations of TDP-C, which we have reviewed here, is uneven and lacks a discernible corpus of robust findings. In our study, we completed genome wide hypothesis-free analyses utilizing artificial Intelligence (AI) to identify rare and common variants associated with TDP-C. We then investigated ANXA11 and TARDBP in a hypothesis-driven analysis, since it was recently shown that TDP-43 and Annexin A11 co-aggregate in all TDP-C cases. 1) Whole genome sequencing was completed to identify pathogenic rare variants prioritized with Illumina's AI-based Emedgene software on 37 confirmed or probable TDP-C cases from the Northwestern-University Cohort. 2) A genome wide association study was then completed to identify common variants associated with TDP-C cases vs 290 controls. 3) Next, common and rare variants in TARDBP, and ANXA11 were investigated in TDP-C vs controls. These analyses identified novel genetic associations between FIG4 , UBQLN2 , INPP5A , and ANXA11 with TDP-C. Of these FIG4, UBQLN2 and ANXA11 have been associated previously with Amyotrophic lateral sclerosis (ALS). To further assess the observed potential genetic overlap between ALS and TDP-C, we leveraged Mendelian randomization (MR) to assess if the ALS genetic load is associated with TDP-C risk, and found evidence supporting this association. The genetic association of ANXA11 with TDP-C is particularly interesting in view of the recently discovered role of Annexin A11 in forming heterodimers with TDP-43 in all abnormal precipitates, a feature not found in TDP-A or TDP-B, which have no similar predilection for the anterior temporal lobe. In addition to the observed overlap between ALS genetics/ genetic load and TDP-C, it is worth mentioning that FIG4, INPP5A and ANXA11 have been implicated in the inositol metabolism pathway, a feature that remains to be elucidated mechanistically. Our TDP-C genetic literature review identified a surprising paucity of neuropathologically confirmed cases in published investigations. Nonetheless, the literature offers support for some of our findings and reemphasizes the absence of dominant or major pathogenic genes for TDP-C, another feature that sets this neuropathologic entity apart from TDP-A and TDP-B.}, } @article {pmid39973136, year = {2025}, author = {Deng, FY and Zhu, GL and Ou, KL and Zhu, LH and Jia, QQ and Wang, X and Guo, MW and Li, B and Li, SH and Li, XJ and Yin, P}, title = {Ribosome-associated pathological TDP-43 alters the expression of multiple mRNAs in the monkey brain.}, journal = {Zoological research}, volume = {46}, number = {2}, pages = {263-276}, doi = {10.24272/j.issn.2095-8137.2024.286}, pmid = {39973136}, issn = {2095-8137}, mesh = {Animals ; *RNA, Messenger/metabolism/genetics ; *Brain/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *Ribosomes/metabolism/genetics ; *Macaca fascicularis/genetics ; Gene Expression Regulation ; }, abstract = {Cytoplasmic accumulation of TDP-43 is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. While current studies have primarily focused on gene regulation mediated by full-length nuclear TDP-43, the potential effects of cytoplasmic TDP-43 fragments remain less explored. Our previous findings demonstrated that primate-specific cleavage of TDP-43 contributes to its cytoplasmic localization, prompting further investigation into its pathological effects. In the cynomolgus monkey brain, we observed that mutant or truncated TDP-43 was transported onto the ribosome organelle. Ribosome-associated transcriptomic analysis revealed dysregulation of apoptosis- and lysosome-related genes, indicating that cytoplasmic TDP-43 induces neurotoxicity by binding to ribosomes and disrupting mRNA expression. These findings provide mechanistic insights into the gain-of-function effects of pathological TDP-43.}, } @article {pmid39971904, year = {2025}, author = {Hossain, MA and Brahme, RR and Miller, BC and Amin, J and de Barros, M and Schneider, JL and Auclair, JR and Mattos, C and Wang, Q and Agar, NYR and Greenblatt, DJ and Manetsch, R and Agar, JN}, title = {Mass spectrometry methods and mathematical PK/PD model for decision tree-guided covalent drug development.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1777}, pmid = {39971904}, issn = {2041-1723}, support = {R01 NS065263/NS/NINDS NIH HHS/United States ; R01NS065263//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 18-IIA-420//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; }, mesh = {Humans ; *Drug Development/methods ; *Mass Spectrometry/methods ; *Drug Discovery/methods ; *Decision Trees ; Superoxide Dismutase-1/metabolism/genetics ; Models, Theoretical ; Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors/metabolism ; }, abstract = {Covalent drug discovery efforts are growing rapidly but have major unaddressed limitations. These include high false positive rates during hit-to-lead identification; the inherent uncoupling of covalent drug concentration and effect [i.e., uncoupling of pharmacokinetics (PK) and pharmacodynamics (PD)]; and a lack of bioanalytical and modeling methods for determining PK and PD parameters. We present a covalent drug discovery workflow that addresses these limitations. Our bioanalytical methods are based upon a mass spectrometry (MS) assay that can measure the percentage of drug-target protein conjugation (% target engagement) in biological matrices. Further we develop an intact protein PK/PD model (iPK/PD) that outputs PK parameters (absorption and distribution) as well as PD parameters (mechanism of action, protein metabolic half-lives, dose, regimen, effect) based on time-dependent target engagement data. Notably, the iPK/PD model is applicable to any measurement (e.g., bottom-up MS and other drug binding studies) that yields % of target engaged. A Decision Tree is presented to guide researchers through the covalent drug development process. Our bioanalytical methods and the Decision Tree are applied to two approved drugs (ibrutinib and sotorasib); the most common plasma off-target, human serum albumin; three protein targets (KRAS, BTK, SOD1), and to a promising SOD1-targeting ALS drug candidates.}, } @article {pmid39971261, year = {2025}, author = {Álvarez-Aznar, A and Desai, M and Orlich, MM and Vázquez-Liébanas, E and Adams, RH and Brakebusch, C and Gaengel, K}, title = {Cdc42 is crucial for mural cell migration, proliferation and patterning of the retinal vasculature.}, journal = {Vascular pharmacology}, volume = {159}, number = {}, pages = {107472}, doi = {10.1016/j.vph.2025.107472}, pmid = {39971261}, issn = {1879-3649}, abstract = {AIMS: Mural cells constitute the outer lining of blood vessels and are essential for vascular development and function. Mural cell loss or malfunction has been associated with numerous diseases including diabetic retinopathy, stroke and amyotrophic lateral sclerosis. In this work, we investigate the role of CDC42 in mural cells in vivo, using the developing mouse retina as a model.

METHODS: In this study, we generated a mouse model for Cdc42 deletion in mural cells by crossing Pdgfrb-CreER[T2] mice with Cdc42flox/flox mice. This model (Cdc42[iΔMC]) allowed us to investigate the role of CDC42 in pericytes and smooth muscle cells in the developing and adult retinal vasculature.

RESULTS: We find that, during postnatal development, CDC42 is required in both, pericytes and smooth muscle cells to maintain proper cell morphology, mural cell coverage and distribution. During retinal angiogenesis, Cdc42-depleted pericytes lag behind the sprouting front and exhibit decreased proliferation. Consequently, capillaries at the sprouting front remain pericyte deprived, become dilated and are prone to increased vascular leakage. In addition, arteries and arterioles deviate from their normal growth directions and trajectory. While in the adult retina, mural cell coverage normalizes and pericytes adopt a normal morphology, smooth muscle cell morphologies remain abnormal and arteriolar branching angles are markedly reduced.

CONCLUSIONS: Our findings demonstrate that CDC42 is required for mural cell migration and proliferation and suggest that mural cells are essential for normal morphogenesis and patterning of the developing retinal vasculature.}, } @article {pmid39971247, year = {2025}, author = {Zhang, H and Sun, Y}, title = {Response to Chen et al's "Incorporating regional variability and demographic insights into melanoma public health strategies".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.02.029}, pmid = {39971247}, issn = {1097-6787}, } @article {pmid39971210, year = {2025}, author = {Brandstötter, C and Büssing, A and Eham, M and Littger, B and Lorenzl, S and Memmel, M and Paal, P and Bublitz, SK}, title = {Assessment of the Spiritual Needs of People With Amyotrophic Lateral Sclerosis and Their Caregivers.}, journal = {Journal of pain and symptom management}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jpainsymman.2025.02.012}, pmid = {39971210}, issn = {1873-6513}, abstract = {CONTEXT: Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disorder which poses multidimensional burden to patients and caregivers.

OBJECTIVES: This study aimed to investigate spiritual needs in people with Amyotrophic Lateral Sclerosis (pALS) and their closest caregivers, and to identify factors which may contribute to these needs.

METHODS: Spiritual needs were assessed based on the Spiritual Needs Questionnaire (SpNQ) as part of a longitudinal cohort study in pALS and their closest caregivers who were included in a multiprofessional pilot project for ALS in Southern Germany with a focus on neuropalliative care.

RESULTS: About 61 pALS and 52 caregivers were assessed for their spiritual needs. We show that both pALS and their caregivers maintain stable and distinct spiritual needs over time, irrespective of age, gender, care setting, or perceived level of loneliness. While pALS emphasize generativity and inner peace needs, caregivers primarily focus on finding inner peace, which they value even more than pALS.

CONCLUSIONS: Both pALS and their caregivers have strong unmet spiritual, and particularly nonreligious needs, which should be regularly assessed by the interprofessional team. Documenting these needs is the initial step in the spiritual care process, which requires a collaborative response from the interprofessional team. All healthcare professionals involved in ALS care should be attuned to the potential for unmet spiritual needs in patients and their caregivers. Early identification of these needs can facilitate the initiation of appropriate support processes.}, } @article {pmid39969752, year = {2025}, author = {Liao, D and Zhang, Y and Li, S and Tang, H and Bai, X}, title = {miRNAs in neurodegenerative diseases: from target screening to precision therapy.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {39969752}, issn = {1590-3478}, support = {NO.2022-CXTD-05//Sichuan Province Science and Technology Support Program/ ; }, abstract = {miRNAs are critical for different disease development processes, including cell growth, signaling, apoptosis, cancer and neurodegenerative diseases. It has been shown that altered miRNA levels are associated with reactive oxygen species (ROS) formation and mitochondrial dysfunction. While mitochondrial dysfunction and ROS formation occur in many neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, amyotrophic lateral sclerosis, miRNAs have the potential to be diagnostic biomarkers and therapeutic targets with a high degree of specificity, which is highly relevant in neurodegenerative pathologies.This paper gives a general summary of the current expression of miRNAs in neurodegenerative diseases, including miRNAs up-regulated or down-regulated in a variety of diseases, as well as the associated factors of influence. miRNAs are more like a double-edged sword, their multi-targeted role has brought light to many diseases for which there are currently no clear therapeutic options, but at the same time, their low specificity and possible side effects on the whole body should not be ignored, therefore However, at the same time, its low specificity and possible side effects on the whole body should not be ignored, therefore, more attention should be paid to the development of miRNA therapy in terms of its high efficiency, the use of carriers, and the clarification of side effects.}, } @article {pmid39969750, year = {2025}, author = {de Alcântara, C and Cruzeiro, MM and França, MC and Alencar, MA and de Araújo, CM and Camargos, ST and de Souza, LC}, title = {Cognitive and behavioral follow-up of patients with amyotrophic lateral sclerosis type 8.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {39969750}, issn = {1590-3478}, support = {APQ-02980-17//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; Bolsa de Produtividade//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, abstract = {BACKGROUND AND OBJECTIVE: Amyotrophic Lateral Sclerosis type 8 (ALS8) is a familial motor neuron disease caused by the VAPB p.P56S mutation. There is a lack of longitudinal studies to elucidate the cognitive and behavioral progression of this disease. We aimed to investigate the progression of cognitive performance and behavioral symptoms of ALS8 patients over time.

METHODS: The cohort was composed of 23 ALS8 patients (12 men). They underwent neuropsychological assessments in two periods of time, ranging from 24 to 48 months (mean follow-up: 33 ± 10).

RESULTS: There was mild motor and functional decline during the follow-up. There were no significant differences between the first and the second evaluation on tests of verbal fluency, executive functions, episodic memory, and facial emotion recognition. There was a decline in the Language subdomain from the Addenbrooke's Cognitive Examination-revised. Behavioural measures indicated decreasing stereotypic behaviours. Anxiety and depression symptoms remained stable. No patient developed dementia.

CONCLUSION: Cognitive decline parallels motor degeneration in ALS8, with a slow pattern of progression.}, } @article {pmid39969664, year = {2025}, author = {Irdianto, SA and Dwiranti, A and Bowolaksono, A}, title = {Extrachromosomal circular DNA: a double-edged sword in cancer progression and age-related diseases.}, journal = {Human cell}, volume = {38}, number = {2}, pages = {58}, pmid = {39969664}, issn = {1749-0774}, support = {NKB-888/UN2.RST/HKP.05.00/2024//Kementerian Riset Teknologi Dan Pendidikan Tinggi Republik Indonesia/ ; }, mesh = {Humans ; *Neoplasms/genetics/pathology/therapy/etiology ; *Disease Progression ; *DNA, Circular/genetics ; *Genomic Instability/genetics ; Werner Syndrome/genetics ; Diabetes Mellitus, Type 2/genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology/therapy ; Aging/genetics ; }, abstract = {Extrachromosomal circular DNA (eccDNA) is a fascinating form of genetic material found outside the usual chromosomal DNA in eukaryotic cells, including humans. Since its discovery in the 1960s, eccDNA has been linked to critical roles in cancer progression and age-related diseases. This review thoroughly explores eccDNA, covering its types, how it forms, and its significant impact on diseases, particularly cancer. EccDNA, especially in its extrachromosomal DNA (ecDNA) form, contributes to the genetic diversity of tumour cells, helping them evolve quickly and resist treatments. Beyond cancer, eccDNA is also connected to age-related conditions like Werner syndrome, amyotrophic lateral sclerosis (ALS), and type 2 diabetes mellitus (T2DM), where it may affect genomic stability and disease development. The potential of eccDNA as a biomarker for predicting disease outcomes and as a target for new treatments is also highlighted. This review aims to deepen our understanding of eccDNA and inspire further research into its roles in human health and disease, paving the way for innovative diagnostic and therapeutic approaches.}, } @article {pmid39969638, year = {2025}, author = {Almgren, H and Mahoney, CJ and Huynh, W and D'Souza, A and Berte, S and Lv, J and Wang, C and Kiernan, MC and Calamante, F and Tu, S}, title = {Quantifying neurodegeneration within subdivisions of core motor pathways in amyotrophic lateral sclerosis using diffusion MRI.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {215}, pmid = {39969638}, issn = {1432-1459}, support = {APP2029871//NHMRC/ ; 1156093//NHMRC Practitioner Fellowship/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; Aged ; *Corpus Callosum/diagnostic imaging/pathology ; *Pyramidal Tracts/diagnostic imaging/pathology ; *Diffusion Magnetic Resonance Imaging ; *White Matter/diagnostic imaging/pathology ; Adult ; Disease Progression ; Efferent Pathways/diagnostic imaging/pathology ; }, abstract = {BACKGROUND: Diffusion MRI is sensitive to white matter changes in amyotrophic lateral sclerosis (ALS). The current study aimed to establish disease profiles across core motor pathways, and their relevance to clinical progression in ALS.

METHODS: Sixty-five participants (ALS = 47; Control = 18) were recruited for the study. White matter integrity of motor, somatosensory, and premotor subdivisions within the corticospinal tract and corpus callosum were quantified by fibre density, fibre-bundle cross-section, structural connectivity, and fractional anisotropy. Analyses focused on identifying diffusion metrics and tract profiles sensitive to ALS pathology, and their association with clinical progression.

RESULTS: Reduced fibre density of the motor subdivision of the corpus callosum (CC) and corticospinal tract (CST) demonstrated best performance in classifying ALS from controls (area-under-curve: CCmotor = 0.81, CSTmotor = 0.76). Significant reductions in fibre density (CCmotor: p < 0.001; CSTmotor: p = 0.016), and structural connectivity (CCmotor: p = 0.008; CSTsomatosensory: p = 0.012) indicated presence of ALS pathology. Reduced fibre density & cross-section significantly correlated with severity of functional impairment (ALSFRS-R; CCmotor: r = 0.52, p = 0.019; CSTmotor: r = 0.59, p = 0.016). The largest effect sizes were generally found for motor and somatosensory subdivisions across both major white matter bundles.

CONCLUSION: Current findings suggest that ALS does not uniformly impact the corticospinal tract and corpus callosum. There is a preferential disease profile of neurodegeneration mainly impacting primary motor fibres. Microstructural white matter abnormality indicated presence of ALS pathology while macrostructural white matter abnormality was associated with severity of functional impairment. Quantification of white matter abnormality in corticospinal tract and callosal subdivisions holds translational potential as an imaging biomarker for neurodegeneration in ALS.}, } @article {pmid39969486, year = {2025}, author = {Alder, J and Chukwuma, C and Farragher, T and Holden Smith, S and Morris, R and Ealing, J and Hamdalla, H and Bentley, A and Bokhari, S and Freeman, D and Al-Chalabi, A and Rog, D and Das, J and Chaouch, A}, title = {Impact of relative deprivation and ethnicity on the incidence rate of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2025.2465609}, pmid = {39969486}, issn = {2167-9223}, abstract = {Objective: This study assessed a sizable cohort of patients with amyotrophic lateral sclerosis (ALS) in a relatively deprived and ethnically diverse area in the northwest of England. We aimed to evaluate the interaction of relative deprivation and ethnicity with the incidence of ALS. Methods: Six hundred and ninety-three adults from Greater Manchester who were diagnosed with ALS between 1 January 2011 and 31 December 2021 were included in this study. Data were collected from electronic patient records. Relative deprivation was estimated using the Index of Multiple Deprivation 2019 and patients were divided into quartiles of deprivation in England. Ethnicity was sub-grouped into White, Southeast Asian, Black, and Other. Poisson's regression analysis was used to calculate the incidence rate and its interactions with deprivation and ethnicity. Results: 55.4% of patients were male, 95.4% were White, 57.4% were in the two most deprived quartiles, and 87.2% had died by the end of the observation period. The crude incidence rate was 2.21 cases per 100,000 (95% CI 2.00-2.40) per year. There was no difference in the adjusted incidence rates among the quartiles of deprivation, even when considering ethnicity as a confounding variable. The risk of ALS in the White population was 2.08 (95% CI 1.47-3.04) times greater than that in the non-White population. Conclusion: In our cohort, relative deprivation was not an independent risk factor for ALS. A stronger association between White ethnicity and ALS was noted. The reason for this association remains unclear, highlighting the need for more research in this field.}, } @article {pmid39967643, year = {2025}, author = {Abdel-Magid, AF}, title = {Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors as Potential Treatment for Several Inflammatory and Neurodegenerative Diseases.}, journal = {ACS medicinal chemistry letters}, volume = {16}, number = {2}, pages = {204-206}, pmid = {39967643}, issn = {1948-5875}, abstract = {The invention in this patent application relates to 2-amino-[1,2,4]triazolo[1,5-a]pyridin derivatives represented generally herein as formula 1. These compounds have activities as receptor-interacting protein kinase 1 (RIPK1) inhibitors and may potentially provide treatment and/or prophylaxis of inflammatory and neurodegenerative diseases associated with aberrant RIPK1 activity such as ulcerative colitis, Crohn's disease, psoriasis, NASH, heart failure, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease.}, } @article {pmid39965449, year = {2025}, author = {Awasthi, S and Tiwari, PC and Awasthi, S and Dwivedi, A and Srivastava, S}, title = {Mechanistic role of proteins and peptides in Management of Neurodegenerative Disorders.}, journal = {Neuropeptides}, volume = {110}, number = {}, pages = {102505}, doi = {10.1016/j.npep.2025.102505}, pmid = {39965449}, issn = {1532-2785}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Peptides/therapeutic use ; Proteins/metabolism/therapeutic use ; }, abstract = {Proteins and peptides have emerged as significant contributors in the management of neurodegenerative disorders due to their diverse biological functions. These biomolecules influence various cellular processes, including cellular repair, inflammation reduction, and neuronal survival, which are crucial for mitigating the effects of diseases such as Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis (ALS). By interacting with specific cellular receptors, proteins and peptides like neurotrophic factors, cytokines, and enzyme inhibitors promote neurogenesis, reduce oxidative stress, and enhance synaptic plasticity. Nevertheless, till certain limitations and challenges do exist to deliver these fragile therapeutic bioactives. Moreover, targeted delivery systems, such as nanoparticles and biomolecular carriers, are being developed to improve the bioavailability and specificity of these protein-based therapeutics, ensuring efficient crossing of the blood-brain barrier. This review explores the mechanistic pathways through which these biomolecules act, emphasizing their potential to modify disease progression and improve the quality of life in patients with neurodegenerative conditions. Overall, proteins and peptides are not only seen as promising therapeutic agents but also as foundational tools in advancing personalized medicine in the field of neurodegenerative disorders.}, } @article {pmid39965330, year = {2025}, author = {Petro, TM and Esmael, A and Pattee, GL and Al-Sarmi, F and Chiodo, F and Agarkova, IV and Dunigan, DD and Van Etten, JL}, title = {Expression of human superoxide dismutase (SOD) 1 G93A and chlorovirus ATCV-1 SOD increases the response of macrophages to inflammatory stimulants, including ATCV-1 major capsid protein glycans.}, journal = {Immunobiology}, volume = {230}, number = {2}, pages = {152881}, doi = {10.1016/j.imbio.2025.152881}, pmid = {39965330}, issn = {1878-3279}, mesh = {Animals ; Humans ; Mice ; *Macrophages/immunology ; *Superoxide Dismutase-1/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/immunology/genetics ; RAW 264.7 Cells ; *Capsid Proteins/immunology/genetics ; Polysaccharides ; Cytokines/metabolism ; Phycodnaviridae/immunology ; Female ; Interleukin-6/metabolism ; Interferon-gamma/metabolism ; Mice, Transgenic ; Male ; Inflammation Mediators/metabolism ; }, abstract = {One cause of familial Amyotrophic Lateral Sclerosis (ALS) is a mutation in Super Oxide Dismutase 1 (SOD1) whereby amino acid 93 is alanine instead of glycine (SOD1-G93A). Transgenic mice expressing human SOD1-G93A pathogenic variant develop motor neuron disease (MND), similar to ALS. Humans with ALS and SOD1-G93A mice have elevated production of inflammatory cytokines, such as IL-6, which may promote MND. We previously showed that infection with the Chlorovirus Acanthocystis turfacea chlorella virus 1 (ATCV-1), which encodes a SOD1, accelerates onset of MND in these mice and induces macrophages to produce high levels of IL-6. We confirm here that ALS patients compared with healthy controls have significantly elevated levels of plasma IL-6 and Interferon-gamma (IFN-γ), but not IL-17. To determine if expression of ATCV-1 SOD1 or SOD1-G93A in mouse macrophages elevates expression of inflammatory cytokines, we transfected the RAW264.7 mouse macrophage cell line with plasmids encoding ATCV-1 SOD1, wild-type human SOD1, SOD1-G93A, or an empty vector. RAW264.7 cells stably expressing wtSOD1 or G93A-SOD1 were stimulated with poly I:C and Interferon-gamma, alone, or in combination to induce inflammatory factors, such as IL-6 and Nitric Oxide (NO), anti-inflammatory factors, such as IL-10, or activation of Interferon Stimulated Response Elements (ISRE) promoters. After stimulation, production of IL-6 and NO, but not IL-10 or ISRE promoter activity was significantly higher in RAW264.7 cells expressing SOD1-G93A compared with wt SOD1. Moreover, RAW264.7 cells expressing SOD1-G93A compared with wt SOD1 produced higher levels of IL-6 and NO in response to ATCV-1 glycoproteins. Finally, transfection of plasmid encoding ATCV-1 SOD1 into RAW264.7 cells significantly increased expression of inflammatory factors in responses to poly I:C and IFN-γ, primarily in an Interferon regulatory factor 3 (IRF3) dependent fashion. These data clearly show that expression of G93A-SOD1 or ATCV-1 SOD1 in macrophages significantly elevates expression of inflammatory factors following stimulations that mimic virus infection, viral components, or T cell cytokines, thereby suggesting one mechanism by which atypical SOD1 in macrophages can contribute to ALS-MND.}, } @article {pmid39963928, year = {2025}, author = {Lomas, C and Dubey, RC and Perez-Alvarez, G and Lopez Hernandez, Y and Atmar, A and Arias, AY and Vashist, A and Aggarwal, S and Manickam, P and Lakshmana, MK and Vashist, A}, title = {Recent advances in nanotherapeutics for HIV-associated neurocognitive disorders and substance use disorders.}, journal = {Nanomedicine (London, England)}, volume = {20}, number = {6}, pages = {603-619}, pmid = {39963928}, issn = {1748-6963}, support = {R01 DA049657/DA/NIDA NIH HHS/United States ; R03 AG087475/AG/NIA NIH HHS/United States ; U01 ES033265/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/complications/drug therapy ; *Substance-Related Disorders ; *Blood-Brain Barrier/metabolism/drug effects ; Nanoparticles/chemistry ; Animals ; Neurocognitive Disorders/drug therapy/etiology ; Nanomedicine/methods ; AIDS Dementia Complex/drug therapy ; }, abstract = {Substance use disorders (SUD) and HIV-associated neurocognitive disorders (HAND) work synergistically as a significant cause of cognitive decline in adults and adolescents globally. Current therapies continue to be limited due to difficulties crossing the blood-brain barrier (BBB) leading to limited precision and effectiveness, neurotoxicity, and lack of co-treatment options for both HAND and SUD. Nanoparticle-based therapeutics have several advantages over conventional therapies including more precise targeting, the ability to cross the BBB, and high biocompatibility which decreases toxicity and optimizes sustainability. These advantages extend to other neurological disorders such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). This review summarizes recent advances in nanotechnology for application to HAND, SUD, and co-treatment, as well as other neurological disorders. This review also highlights the potential challenges these therapies face in clinical translation and long-term safety.}, } @article {pmid39962920, year = {2025}, author = {}, title = {Correction to "Early Nuclear Phenotypes and Reactive Transformation in Human iPSC-Derived Astrocytes From ALS Patients With SOD1 Mutations".}, journal = {Glia}, volume = {73}, number = {5}, pages = {1107}, doi = {10.1002/glia.70003}, pmid = {39962920}, issn = {1098-1136}, } @article {pmid39962623, year = {2025}, author = {Caratelli, S and De Paolis, F and Silvestris, DA and Baldari, S and Salvatori, I and Tullo, A and Lanzilli, G and Gurtner, A and Ferri, A and Valle, C and Padovani, S and Cesarini, V and Sconocchia, T and Cifaldi, L and Arriga, R and Spagnoli, GC and Ferrone, S and Venditti, A and Rossi, P and Pesole, G and Toietta, G and Sconocchia, G}, title = {The CD64/CD28/CD3ζ chimeric receptor reprograms T-cell metabolism and promotes T-cell persistence and immune functions while triggering antibody-independent and antibody-dependent cytotoxicity.}, journal = {Experimental hematology & oncology}, volume = {14}, number = {1}, pages = {17}, pmid = {39962623}, issn = {2162-3619}, support = {TITAN 2021- ARS01_00906//European Union, European Fund for Regional Development/ ; TITAN 2021- ARS01_00906//European Union, European Fund for Regional Development/ ; Investigator Grants 2020-24440//Italian Association for Cancer Research (AIRC) Foundation/ ; }, abstract = {BACKGROUND: Recent studies have shown that CD32/CD8a/CD28/CD3ζ chimeric receptor cells directly kill breast cancer cells, suggesting the existence of cell surface myeloid FcγR alternative ligands (ALs). Here, we investigated the metabolism, ALs, cytotoxicity, and immunoregulatory functions of CD64/CD28/CD3ζ in colorectal cancer (CRC) and squamous cell carcinoma of the head and neck.

METHODS: The CD64/CD28/CD3ζ -SFG retroviral vector was used to produce viruses for T-cell transduction. T-cell expansion and differentiation were monitored via flow cytometry. Gene expression was assessed by RNA-seq. Bioenergetics were documented on a Seahorse extracellular flux analyzer. CD64/CD28/CD3ζ polarization was identified via confocal microscopy. Cytotoxicity was determined by MTT assay and bioluminescent imaging, and flow cytometry. Tridimensional antitumor activity of CD64/CD28/CD3ζ T cells was achieved by utilizing HCT116-GFP 3D spheroids via the IncuCyte S3 Live-Cell Analysis system. The intraperitoneal distribution and antitumor activity of NIR-CD64/CD28/CD3ζ and NIR-nontransduced T cells were investigated in CB17-SCID mice bearing subcutaneous FaDu Luc + cells by bioluminescent and fluorescent imaging. IFNγ was assessed by ELISA.

RESULTS: Compared to CD16/CD8a/CD28/CD3ζ T cells, CD32/CD8a/CD28/CD3ζ T cells, and non-transduced T cells, CD64/CD28/CD3ζ T cells exhibited the highest levels of cell expansion and persistence capacity. A total of 235 genes linked to cell division and 52 genes related to glycolysis were overexpressed. The glycolytic phenotype was confirmed by functional in vitro studies accompanied by preferential T-cell effector memory differentiation. Interestingly, oxamic acid was found to inhibit CD64-CR T cell proliferation, indicating the involvement of lactate. Upon CD64/CD28/CD3ζ T-cell conjugation with CRC cells, CD64/CD28/CD3ζ cells polarize at immunological synapses, leading to CRC cell death. CD64/CD28/CD3ζ T cells kill SCCHN cells, and in combination with the anti-B7-H3 mAb (376.96) or anti-EGFR mAb, these cells trigger antibody-dependent cellular cytotoxicity (ADCC) in vitro under 2D and 3D conditions. The 376.96 mAb combined with CD64/CD28/CD3ζ T cells had anti-SCCHN activity in vivo. In addition, they induce the upregulation of PD-L1 and HLA-DR expression in cancer cells via IFNγ. PD-L1 positive SCCHN cells in combination with anti-PD-L1 mAb and CD64-CR T cells were killed by ADCC, which enhanced direct cytotoxicity. These findings indicate that the glycolytic phenotype is involved in CD64-CR T cell proliferation/expansion. These cells mediate long-lasting HLA-independent cytotoxicity and ADCC in CRC and SCCHN cells.

CONCLUSIONS: CD64/CD28/CD3ζ T cells could significantly impact the rational design of personalized studies to treat CRC and SCCHN and the identification of novel FcγR ALs in cancer and healthy cells.}, } @article {pmid39961705, year = {2025}, author = {Shah, NM and Kaltsakas, G and Madden-Scott, S and Apps, C and Sheridan, S and Ramsay, M and Srivastava, S and Suh, ES and D'Cruz, R and Mackie, M and Weston, N and Hart, N and Murphy, P}, title = {Mechanical insufflation-exsufflation use in neuromuscular disease: a single centre cohort study.}, journal = {BMJ open respiratory research}, volume = {12}, number = {1}, pages = {}, pmid = {39961705}, issn = {2052-4439}, mesh = {Humans ; *Insufflation/methods ; *Neuromuscular Diseases/complications ; Middle Aged ; Female ; Retrospective Studies ; Male ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/therapy ; Cohort Studies ; }, abstract = {INTRODUCTION: Mechanical insufflation-exsufflation (MIE) is a commonly used therapy to augment secretion clearance in individuals with neuromuscular disease. There are no clear evidence-based guidelines on the settings that should be used in different diagnostic groups and how they should be titrated. We report on the settings used in the largest cohort of individuals using domiciliary MIE in the literature.

METHODS: A retrospective observational study reporting on all individuals initiated on MIE for long-term domiciliary use at our centre, 2013-2019.

RESULTS: This study reports on 359 adults established on domiciliary MIE. The most common diagnostic groups were congenital neuromuscular disease (26%), spinal cord injury (23%) and amyotrophic lateral sclerosis (23%). Median age at initiation was 55 years. Median (IQR) insufflation pressure was 35 (30-40) cm H2O and exsufflation pressure was 45 (40-50) cm H2O. Inspiratory time was 2.5 (2.3-2.8) s, expiratory time was 2.7 (2.3-2.8) s, and pause between expiration and inspiration was 2.0 (1.2-2.0) s. Median (IQR) survival following the initiation of MIE was 66 (54-78) months. Increasing age and amyotrophic lateral sclerosis were significantly associated with shorter life expectancy, while the delivery of MIE via oronasal interface compared with tracheostomy was associated with longer life expectancy.

CONCLUSION: This is the largest reported cohort of adults using domiciliary MIE. The most common groups using MIE were congenital neuromuscular disease, spinal cord injury patients and amyotrophic lateral sclerosis. The range of prescribed settings is narrow, reflecting the limited evidence base in this field and the need to better understand optimal targets for titration of different MIE settings.}, } @article {pmid39961673, year = {2025}, author = {Aryapadi, V and Trivedi, J}, title = {Atypical presentation of amyotrophic lateral sclerosis with SOD1-H47R mutation.}, journal = {BMJ case reports}, volume = {18}, number = {2}, pages = {}, doi = {10.1136/bcr-2024-263293}, pmid = {39961673}, issn = {1757-790X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Superoxide Dismutase-1/genetics ; Male ; *Mutation ; Middle Aged ; }, abstract = {Traditionally, amyotrophic lateral sclerosis (ALS) is recognised as a fatal neurodegenerative disease that typically emerges in the later decades of life, with a life expectancy of 2-5 years after symptom onset. We now understand that ALS exhibits a wide phenotypic clinical spectrum, significantly influenced by genetic factors. Here, we describe a patient with familial ALS carrying a heterozygous pathogenic H47R mutation of the superoxide dismutase 1 (SOD1) gene. His clinical presentation is atypical, with a slow progressive course, lower extremity weakness, and sparing of bulbar and respiratory function, consistent with the flail leg variant of ALS. The objective of this report is to increase awareness of atypical presentations of ALS and the diagnostic challenges they pose to clinicians. In addition to a description of the clinical case, we briefly discuss the new role of gene therapy in the treatment of familial ALS with SOD1 mutations.}, } @article {pmid39961464, year = {2025}, author = {Soumya, BS and Gamit, N and Patil, M and Shreenidhi, VP and Dharmarajan, A and Warrier, S}, title = {Modeling amyotrophic lateral sclerosis with amniotic membrane-derived mesenchymal stem cells: A novel approach for disease modeling.}, journal = {Experimental cell research}, volume = {446}, number = {1}, pages = {114449}, doi = {10.1016/j.yexcr.2025.114449}, pmid = {39961464}, issn = {1090-2422}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism/therapy ; *Mesenchymal Stem Cells/metabolism ; Humans ; *Amnion/cytology/metabolism ; *Cell Differentiation ; *Motor Neurons/metabolism/pathology ; Animals ; Oxidative Stress ; Superoxide Dismutase/metabolism/genetics ; Basic Helix-Loop-Helix Transcription Factors/genetics/metabolism ; Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism/genetics ; Oligodendrocyte Transcription Factor 2/metabolism/genetics ; Nerve Tissue Proteins/metabolism/genetics ; Cells, Cultured ; Disease Models, Animal ; Homeodomain Proteins/genetics/metabolism ; Transcription Factors/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Advancement of therapeutics for neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) has been predominantly hampered by the dearth of relevant disease models. Despite numerous animal models, significant challenges remain in correlating these with human disease complexities. In this study, the ALS model was created using amniotic membrane-derived mesenchymal stem cells (AM-MSCs) which were differentiated into motor neurons (MN) with specific MN induction media and transiently transfected with mutated human SOD1 G93A plasmid to induce ALS-like condition. Characterization included gene expression analysis, immunocytochemistry, flow cytometry, and Western blot. Functional assays assessed the extent of degeneration and model efficiency. AM-MSCs demonstrated multipotency and were positive for MSC markers. Upon differentiation, the expression of MN markers like MNX1, Olig2, and ChAT were found to be elevated. SOD1 G93A overexpression, downregulated MN markers, upregulated NURR1 gene, reduced acetylcholine (ACh), reduced glutathione, and elevated oxidative stress markers. This robust in-vitro ALS model derived from AM-MSCs offers an alternative to animal models to provide an efficient and cost-effective platform to conduct rapid drug screening.}, } @article {pmid39961396, year = {2025}, author = {Ferraro, PM and Mollar, E and Melissari, L and Buscema, M and Bagnoli, E and Cabona, C and Gemelli, C and Vignolo, M and Maranzana, C and Marogna, M and Ferrera, L and Beronio, A and De Michelis, C and Bergamaschi, V and Bragadin, MM and Brichetto, G and Braido, F and Rao, F}, title = {Longitudinal respiratory trajectories in motor neuron disease phenotypes: Multiparametric characterization and clinical management.}, journal = {Respiratory medicine}, volume = {239}, number = {}, pages = {108003}, doi = {10.1016/j.rmed.2025.108003}, pmid = {39961396}, issn = {1532-3064}, mesh = {Humans ; *Phenotype ; *Motor Neuron Disease/physiopathology ; Male ; Female ; Middle Aged ; Aged ; Longitudinal Studies ; *Respiratory Function Tests/methods ; *Noninvasive Ventilation/methods ; Disease Progression ; Amyotrophic Lateral Sclerosis/physiopathology/therapy ; Oximetry ; Blood Gas Analysis ; Spirometry/methods ; }, abstract = {BACKGROUND: Motor neuron diseases (MNDs) encompass amyotrophic lateral sclerosis (ALS), pure/predominant upper (pUMN) and lower motor neuron (pLMN) phenotypes. However respiratory studies have mainly focused on bulbar (B-ALS) and spinal (S-ALS) onset ALS, while little is known in other MNDs. In this study we therefore aimed at characterizing baseline and longitudinal patterns of respiratory involvement and their clinical management in MND patients stratified by their clinical phenotype.

METHODS: Serial pulmonary function tests (PFTs) (spirometry, arterial blood gas analysis, overnight pulse oximetry and peak cough expiratory flow) records of the MND patients hospitalized between 2020 and 2024 were reviewed. Using longitudinal examinations, deltas of variation in respiratory measures were generated and frequency and timings of non-invasive ventilation (NIV) adaptation were evaluated. Data were compared between phenotypes using the Kruskal-Wallis test with Bonferroni adjustment.

RESULTS: 42 S-ALS, 105 B-ALS, 42 pLMN and 31 pUMN patients were included. Both at baseline and longitudinally, B-ALS showed the worst respiratory parameters, followed by pLMN, S-ALS and pUMN. NIV adaptation was equally frequent between groups, but earlier in B-ALS compared to pUMN (p = 0.01). At baseline, B-ALS showed worse spirometry and PCEF only, but compared to all the other phenotypes (p from <0.0001 to 0.03). Longitudinally, they conversely exhibited more severe decline in all PFTs, but only relative to pUMN (p from 0.0009 to 0.04), with deltas of variation comparable to the ones observed in S-ALS and pLMN. Among NIV users, more severe PCEF and spirometry impairment further emerged in S-ALS compared to pUMN (p from 0.01 to 0.04).

CONCLUSIONS: We evidenced convergent trajectories of respiratory decline across B-ALS, S-ALS and pLMN, highlighting the utility of multimodal assessments for tracking progressing respiratory disturbances. These findings have potential to accelerate earlier and more tailored respiratory management across diverse MND phenotypes.}, } @article {pmid39960747, year = {2025}, author = {Turnbull, J}, title = {Platform Trials in ALS.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2025.0100}, pmid = {39960747}, issn = {1538-3598}, } @article {pmid39960672, year = {2025}, author = {Paganoni, S and Fournier, CN and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Ajroud-Driss, S and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, AV and Shefner, JM and Hall, M and Kittle, G and Berry, JD and Babu, S and Andrews, J and Dagostino, D and Tustison, E and Giacomelli, E and Scirocco, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, K and Maragakis, NJ and Simmons, Z and Miller, TM and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, LA and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, CE and Ladha, S and Heiman-Patterson, T and Caress, JB and Swenson, A and Peltier, A and Lewis, R and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, C and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Glass, J and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Harvey, B and Patel, S and Mahoney, P and Duda, PW and Cudkowicz, ME and , }, title = {Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {8}, number = {2}, pages = {e2459058}, pmid = {39960672}, issn = {2574-3805}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Double-Blind Method ; Aged ; Treatment Outcome ; Edaravone/therapeutic use ; }, abstract = {IMPORTANCE: The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression.

OBJECTIVE: To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS.

Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens.

INTERVENTIONS: Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing.

MAIN OUTCOMES AND MEASURES: The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; <1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164).

RESULTS: Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04297683.}, } @article {pmid39959987, year = {2025}, author = {Lee, D and Shin, Y and Roh, JS and Ahn, J and Jeoong, S and Shin, SS and Yoon, M}, title = {RETRACTED: Lee et al. Lemon Balm Extract ALS-L1023 Regulates Obesity and Improves Insulin Sensitivity via Activation of Hepatic PPARα in High-Fat Diet-Fed Obese C57BL/6J Mice. Int. J. Mol. Sci. 2020, 21, 4256.}, journal = {International journal of molecular sciences}, volume = {26}, number = {4}, pages = {}, pmid = {39959987}, issn = {1422-0067}, abstract = {The journal retracts the article titled "Lemon Balm Extract ALS-L1023 Regulates Obesity and Improves Insulin Sensitivity via Activation of Hepatic PPARα in High-Fat Diet-Fed Obese C57BL/6J Mice" [...].}, } @article {pmid39958595, year = {2025}, author = {Arnold, WD and Majithia, K}, title = {Triumphs, Trials, and Future Considerations in Genetic Therapies for Hereditary Neuromuscular Diseases.}, journal = {Missouri medicine}, volume = {122}, number = {1}, pages = {46-52}, pmid = {39958595}, issn = {0026-6620}, mesh = {Humans ; *Genetic Therapy/methods/trends ; *Neuromuscular Diseases/genetics/therapy ; *Muscular Dystrophy, Duchenne/genetics/therapy ; Amyotrophic Lateral Sclerosis/genetics/therapy ; Muscular Atrophy, Spinal/genetics/therapy ; Precision Medicine/methods/trends ; }, abstract = {Neuromuscular diseases include conditions that affect the spinal motor neurons, peripheral nerves, neuromuscular junctions, and muscles, and they can result from acquired and inherited causes. The number of genetic therapies targeting the inherited causes of neuromuscular diseases has surged in the last decade. This review aims to highlight the current state of genetic therapies within the framework of precision medicine, focusing on the achievements and the gaps that remain. A major emphasis is on spinal muscular atrophy, Duchenne muscular dystrophy, and amyotrophic lateral sclerosis, as these neuromuscular diseases have seen tremendous recent advancements. We will also discuss the future considerations necessary to accelerate the development of next-generation genetic therapies and enhance therapeutic outcomes for patients with neuromuscular diseases.}, } @article {pmid39958549, year = {2025}, author = {Zhang, Y}, title = {Enhancing rectal cancer liver metastasis prediction: Magnetic resonance imaging-based radiomics, bias mitigation, and regulatory considerations.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {2}, pages = {102151}, pmid = {39958549}, issn = {1948-5204}, abstract = {In this article, we comment on the article by Long et al published in the recent issue of the World Journal of Gastrointestinal Oncology. Rectal cancer patients are at risk for developing metachronous liver metastasis (MLM), yet early prediction remains challenging due to variations in tumor heterogeneity and the limitations of traditional diagnostic methods. Therefore, there is an urgent need for non-invasive techniques to improve patient outcomes. Long et al's study introduces an innovative magnetic resonance imaging (MRI)-based radiomics model that integrates high-throughput imaging data with clinical variables to predict MLM. The study employed a 7:3 split to generate training and validation datasets. The MLM prediction model was constructed using the training set and subsequently validated on the validation set using area under the curve (AUC) and dollar-cost averaging metrics to assess performance, robustness, and generalizability. By employing advanced algorithms, the model provides a non-invasive solution to assess tumor heterogeneity for better metastasis prediction, enabling early intervention and personalized treatment planning. However, variations in MRI parameters, such as differences in scanning resolutions and protocols across facilities, patient heterogeneity (e.g., age, comorbidities), and external factors like carcinoembryonic antigen levels introduce biases. Additionally, confounding factors such as diagnostic staging methods and patient comorbidities require further validation and adjustment to ensure accuracy and generalizability. With evolving Food and Drug Administration regulations on machine learning models in healthcare, compliance and careful consideration of these regulatory requirements are essential to ensuring safe and effective implementation of this approach in clinical practice. In the future, clinicians may be able to utilize data-driven, patient-centric artificial intelligence (AI)-enhanced imaging tools integrated with clinical data, which would help improve early detection of MLM and optimize personalized treatment strategies. Combining radiomics, genomics, histological data, and demographic information can significantly enhance the accuracy and precision of predictive models.}, } @article {pmid39958442, year = {2025}, author = {Ozbey, D and Saribas, S and Kocazeybek, B}, title = {Gut microbiota in Crohn's disease pathogenesis.}, journal = {World journal of gastroenterology}, volume = {31}, number = {6}, pages = {101266}, pmid = {39958442}, issn = {2219-2840}, mesh = {Humans ; *Crohn Disease/microbiology/immunology/therapy ; *Gastrointestinal Microbiome ; *Fecal Microbiota Transplantation ; Treatment Outcome ; Intestinal Mucosa/microbiology/immunology/pathology ; Feces/microbiology ; Colon/microbiology/pathology/immunology ; Dysbiosis ; Ileum/microbiology/pathology/immunology ; Animals ; Colitis, Ulcerative/microbiology/therapy/immunology ; }, abstract = {Inflammatory bowel diseases (IBDs) are classified into two distinct types based on the area and severity of inflammation: Crohn's disease (CD) and ulcerative colitis. In CD, gut bacteria can infiltrate mesenteric fat, causing expansion known as creeping fat, which may limit bacterial spread and inflammation but can promote fibrosis. The gut bacteria composition varies depending on whether the colon or ileum is affected. Fecal microbiota transplantation (FMT) transfers feces from a healthy donor to restore gut microbiota balance, often used in IBD patients to reduce inflammation and promote mucosal repair. The use of FMT for CD remains uncertain, with insufficient evidence to fully endorse it as a definitive treatment. While some studies suggest it may improve symptoms, questions about the duration of these improvements and the need for repeated treatments persist. There is a pressing need for methods that provide long-term benefits, as highlighted by Wu et al's research.}, } @article {pmid39957655, year = {2025}, author = {Mombaur, B and Dias, K}, title = {Patient Navigation in Amyotrophic Lateral Sclerosis (ALS): A Potential Approach to Timely Diagnosis.}, journal = {Journal of health care for the poor and underserved}, volume = {36}, number = {1}, pages = {361-374}, doi = {10.1353/hpu.2025.a951602}, pmid = {39957655}, issn = {1548-6869}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Patient Navigation/organization & administration ; Healthcare Disparities ; Delayed Diagnosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) poses challenges for timely diagnosis due to its protean early manifestations and lack of definitive tests. This article explores how patient navigation interventions can expedite diagnosis, particularly for underserved patients who face disproportionately longer delays. Patient navigation has proven effective in reducing disparities in various diseases by providing guidance and support to patients and caregivers. It enhances awareness, facilitates communication with health care providers, and streamlines diagnosis. Drawing from literature on patient navigation in other diseases, this article proposes tailored adaptations for ALS diagnosis and addresses potential implementation barriers and strategies to overcome them. Integrating patient navigation into the ALS diagnostic pathway holds promise for improving efficiency, optimizing outcomes, and reducing health care disparities among underserved populations.}, } @article {pmid39957101, year = {2025}, author = {Kikuchi, K and Yamazaki, Y and Kanekura, K and Hayamizu, Y}, title = {Graphene Biosensor Differentiating Sensitive Interactions between Ribonucleic Acid and Dipeptide Repeats in Liquid-Liquid Phase Separation.}, journal = {ACS applied materials & interfaces}, volume = {17}, number = {8}, pages = {12765-12771}, pmid = {39957101}, issn = {1944-8252}, mesh = {*Dipeptides/chemistry ; *Graphite/chemistry ; *Biosensing Techniques/methods ; Humans ; RNA/chemistry ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Transistors, Electronic ; Liquid-Liquid Extraction/methods ; Phase Separation ; }, abstract = {Liquid-Liquid Phase Separation (LLPS) plays a crucial role in cell biology and is closely associated with neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Recent studies connect mutations in the C9ORF72 gene to the production of arginine-rich dipeptide repeat proteins (R-DPRs), such as poly(PR) and poly(GR). These R-DPRs disrupt LLPS in membrane-less organelles (MLOs) and contribute to disease pathology. While traditional analysis techniques like nuclear magnetic resonance (NMR), fluorescence recovery after photobleaching (FRAP), and Förster resonance energy transfer (FRET) provide insights into LLPS's role in these diseases, their ability is limited in detecting weak intermolecular interactions within LLPS droplets. This study employs graphene field-effect transistors (GFETs) for their superior sensitivity in detecting these molecular interactions. We immobilized RNA (poly-A) on GFETs and measured the electrical conductivity of GFETs to characterize shifts in the voltage of the charge neutral point in GFETs, allowing for the detection of dipeptide repeat peptides, such as (PR)12, (GR)12, and R12. Our results show that interactions between peptides and RNA require a specific peptide concentration threshold and vary between peptide types. Notably, the minimal conductivity shift suggests that peptides containing proline residues exhibit a nonuniform spatial distribution during interactions with RNA on graphene surfaces. This finding indicates that peptide rigidity induced by prolines plays a vital role in these molecular interactions and their multivalent contacts with RNA, which agrees with findings reported in other recent works. The capability of GFETs to detect these interactions at nanomolar concentrations marks a significant advancement in sensitivity over existing methods. This research sheds light on the mechanisms of LLPS involving R-DPRs and opens avenues for further understanding of related neurodegenerative diseases.}, } @article {pmid39956874, year = {2025}, author = {Demaegd, KC and Kernan, A and Cooper-Knock, J and van Vugt, JJFA and Harvey, C and Moll, T and O'Brien, D and Gornall, S and Drury, L and Farhan, SMK and Dion, PA and Rouleau, GA and Western, A and Parsons, PJ and Mclean, B and Benatar, M and van den Berg, LH and Van Damme, P and Willem Dankbaar, J and Hendrikse, J and Koole, W and de Bie, C and Hobson, E and Veldink, JH and van de Warrenburg, B and Pasterkamp, RJ and van Rheenen, W and Kirby, J and Shaw, PJ and van Es, MA}, title = {An observational study of pleiotropy and penetrance of amyotrophic lateral sclerosis associated with CAG-repeat expansion of ATXN2.}, journal = {European journal of human genetics : EJHG}, volume = {}, number = {}, pages = {}, pmid = {39956874}, issn = {1476-5438}, support = {216596/Z/19/Z//Wellcome Trust (Wellcome)/ ; 899-792//Motor Neurone Disease Association (MNDA)/ ; 974-797//Motor Neurone Disease Association (MNDA)/ ; 972-797//Motor Neurone Disease Association (MNDA)/ ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, abstract = {Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are both associated with a CAG-repeat expansion in ATXN2 and with TDP-43-positive neuronal cytoplasmic inclusions. The two disorders have been viewed as distinct entities, where an intermediate length expansion of 31-33 CAG-repeats is associated with sporadic ALS and a full length expansion of ≥34 CAG-repeats is associated with SCA2. We report the clinical phenotype of ATXN2-positive patients and their relatives, identified in three specialist ALS clinics, which force a reconsideration of this dichotomy. We also report the frequency of ATXN2 expansions in two large cohorts of ALS patients and in a population-matched cohort of controls. We report ten cases of familial ALS in which disease is associated with either an intermediate or a full-length ATXN2 CAG-repeat expansion. Pedigrees and patients feature additional phenotypes including parkinsonism, dementia and essential tremor (ET). We conclude that CAG-repeat expansions in ATXN2 exhibit pleiotropy and are associated with a disease spectrum that includes ALS, SCA2, and parkinsonism; to recognise this complexity we propose the new term 'ATXN2-related neurodegeneration'. We also observed sporadic ALS associated with full-length expansions. We conclude that ATXN2 CAG-repeat expansions, irrespective of length, should be considered a risk factor for ALS. Interrupted CAG-repeats were associated with an ALS phenotype in our data but we also identified ALS cases with uninterrupted expansions. Our findings have relevance for researchers, patients and families linked to CAG-repeat expansions in ATXN2.}, } @article {pmid39956201, year = {2025}, author = {Potestio, L and Martora, F and Megna, M}, title = {Response to Sood et al's "Real-world experience of bimekizumab for plaque psoriasis in adult patients with prior exposure to interleukin-17 inhibitors: A 16-week multicenter retrospective review".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.10.129}, pmid = {39956201}, issn = {1097-6787}, } @article {pmid39956001, year = {2025}, author = {Romero-Gavilán, F and Cerqueira, A and García-Arnáez, I and Scalschi, L and Vicedo, B and Azkargorta, M and Elortza, F and Izquierdo, R and Gurruchaga, M and Goñi, I and Suay, J}, title = {Proteomic evaluation of borosilicate hybrid sol-gel coatings with osteogenic, immunomodulatory and antibacterial properties.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {250}, number = {}, pages = {114561}, doi = {10.1016/j.colsurfb.2025.114561}, pmid = {39956001}, issn = {1873-4367}, mesh = {Humans ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Staphylococcus aureus/drug effects ; *Osteogenesis/drug effects ; *Proteomics ; *Coated Materials, Biocompatible/chemistry/pharmacology ; *Escherichia coli/drug effects ; Silicates/chemistry/pharmacology ; Surface Properties ; Microbial Sensitivity Tests ; Osteoblasts/drug effects/metabolism/cytology ; Immunologic Factors/pharmacology/chemistry ; Gels/chemistry/pharmacology ; }, abstract = {Silica hybrid sol-gel coatings represent an interesting approach to bioactivate dental implants. Boron is known for its osteogenic, angiogenic and antibacterial functions in biomedical applications. This study describes the synthesis of a novel borosilicate hybrid sol-gel coating using a mixture of methyltrimethoxysilane, tetraethyl orthosilicate and trimethyl borate (TMB). Coatings with different amounts of boron were obtained, and their physiochemical properties were examined; in vitro tests with human osteoblasts and macrophages (THP-1) were carried out. The effects of these materials on bacteria viability were evaluated using Escherichia coli and Staphylococcus aureus. The human serum proteins adsorbed onto the coatings were analysed employing proteomic techniques. To synthesise the new materials, the appropriate sol-gel reactions were developed; boron was integrated into the silica network, and well-adhering coatings were obtained. These borosilicate coatings were non-cytotoxic, displayed osteogenic potential, and upregulated adsorption of proteins related to bone regeneration (IGF2, ALS and APOE). Boron upregulated the expression of TNF-α, INFg and TGF-β and increased the TNF-α and TGF-β cytokine production in THP-1. Moreover, the addition of boron caused downregulation of NOX2 expression. Proteomic analysis revealed that boron-doping reduced the adsorption of immunoglobulins and complement system proteins. It also caused an increase in the levels of apolipoproteins, antioxidant proteins and serum amyloid A proteins, which was in agreement with in vitro results. The coatings with 10 and 20 % TMB displayed antibacterial effect against S. aureus. The results of this study will enhance our comprehension of interactions between boron-containing biomaterials and biological systems.}, } @article {pmid39955058, year = {2025}, author = {Paul, S and Dansithong, W and Figueroa, KP and Gandelman, M and Hivare, P and Scoles, DR and Pulst, SM}, title = {Staufen2 dysregulation in neurodegenerative disease.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {3}, pages = {108316}, pmid = {39955058}, issn = {1083-351X}, mesh = {Humans ; Animals ; MicroRNAs/genetics/metabolism ; *RNA-Binding Proteins/genetics/metabolism ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; HEK293 Cells ; TOR Serine-Threonine Kinases/metabolism/genetics ; Frontotemporal Dementia/metabolism/genetics/pathology ; Spinocerebellar Ataxias/metabolism/genetics/pathology ; 3' Untranslated Regions ; *Neurodegenerative Diseases/metabolism/genetics ; *Cytoskeletal Proteins/genetics/metabolism ; Disease Models, Animal ; Stress Granules/metabolism/genetics ; }, abstract = {Staufen2 (STAU2) is an RNA-binding protein that controls mRNA trafficking and expression. Previously, we showed that its paralog, Staufen1 (STAU1), was overabundant in cellular and mouse models of neurodegenerative diseases and amyotrophic lateral sclerosis (ALS) patient spinal cord. Here, we investigated features of STAU2 that might parallel STAU1. STAU2 protein, but not mRNA, was overabundant in spinocerebellar ataxia type 2 (SCA2), ALS/frontotemporal dementia patient fibroblasts, ALS patient spinal cord tissues, and in central nervous system tissues from SCA2 and ALS animal models. Exogenous expression of STAU2 in human embryonic kidney 293 cells activated mechanistic target of rapamycin (mTOR) and stress granule formation. Targeting STAU2 by RNAi normalized mTOR in SCA2 and C9ORF72 cellular models. The microRNA miR-217, previously identified as downregulated in SCA2 mice, targets the STAU2 3'-UTR. We now demonstrate that exogenous expression of miR-217 significantly reduced STAU2 and mTOR levels in cellular models of neurodegenerative disease. These results suggest a functional link between STAU2 and mTOR signaling and identify a major role for miR-217 that could be exploited in therapeutic development.}, } @article {pmid39954969, year = {2025}, author = {Utami, KH and Morimoto, S and Mitsukura, Y and Okano, H}, title = {The roles of intrinsically disordered proteins in neurodegeneration.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {1869}, number = {4}, pages = {130772}, doi = {10.1016/j.bbagen.2025.130772}, pmid = {39954969}, issn = {1872-8006}, mesh = {Humans ; *Intrinsically Disordered Proteins/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Proteostasis ; Proteasome Endopeptidase Complex/metabolism ; Animals ; Autophagy ; Protein Folding ; Protein Aggregation, Pathological/metabolism ; }, abstract = {Neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease share a common pathological hallmark: the accumulation of misfolded proteins, particularly involving intrinsically disordered proteins (IDPs) like TDP-43, FUS, Tau, α-synuclein, and Huntingtin. These proteins undergo pathological aggregation, forming toxic inclusions that disrupt cellular function. The dysregulation of proteostasis mechanisms, including the ubiquitin-proteasome system (UPS), ubiquitin-independent proteasome system (UIPS), autophagy, and molecular chaperones, exacerbates these proteinopathies by failing to clear misfolded proteins effectively. Emerging therapeutic strategies aim to restore proteostasis through proteasome activators, autophagy enhancers, and chaperone-based interventions to prevent the toxic accumulation of IDPs. Additionally, understanding liquid-liquid phase separation (LLPS) and its role in stress granule dynamics offers novel insights into how aberrant phase transitions contribute to neurodegeneration. By targeting the molecular pathways involved in IDP aggregation and proteostasis regulation, and better understanding the specificity of each component, research in this area will pave the way for innovative therapeutic approaches to combat these neurodegenerative diseases. This review discusses the molecular mechanisms underpinning IDP pathology, highlights recent advancements in drug discovery, and explores the potential of targeting proteostasis machinery to develop effective therapies.}, } @article {pmid39954940, year = {2025}, author = {Satao, KS and Doshi, GM}, title = {Intercellular communication via exosomes: A new paradigm in the pathophysiology of neurodegenerative disorders.}, journal = {Life sciences}, volume = {365}, number = {}, pages = {123468}, doi = {10.1016/j.lfs.2025.123468}, pmid = {39954940}, issn = {1879-0631}, mesh = {*Exosomes/metabolism/physiology ; Humans ; *Neurodegenerative Diseases/metabolism/physiopathology/pathology ; *Cell Communication/physiology ; Animals ; }, abstract = {Neurodegenerative disorders are one of the leading causes of death and disability and pose a great economic burden on healthcare systems. Generally, these neurodegenerative disorders have a progressive deterioration in neural function and structure, and deposition of misfolded proteins commonly occurs, such as amyloid-β in AD and α-synuclein in PD. However, there exists a special class of exosomes, which acts like a transmitter and enhances communication between cells. The present review discusses the significant role of exosomes in neurodegenerative diseases, with a focus on Amyotrophic lateral Sclerosis (ALS), AD, PD, and Huntington's disease (HD). In this review, the biogenesis of exosomes is discussed from multivesicular bodies and onwards to their release into the extracellular environment. The present review focuses on recent data concerning the possible use of modified exosomes as ND therapy. Indeed, future work is needed to explain the processes driving exosome biogenesis and cargo selection, while opening new routes by the use of exosome-based therapeutics in neurodegenerative disease diagnosis and treatment.}, } @article {pmid39954710, year = {2025}, author = {Nadeem, ZA and Ahmed, S}, title = {Amyotrophic lateral sclerosis and lovastatin: a promising treatment perspective.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-2}, doi = {10.1080/21678421.2025.2463943}, pmid = {39954710}, issn = {2167-9223}, } @article {pmid39954573, year = {2025}, author = {Kiernan, MC and Timmins, HC}, title = {Utility of the Gold Coast criteria for amyotrophic lateral sclerosis: Experience with fast progressors.}, journal = {Journal of the neurological sciences}, volume = {470}, number = {}, pages = {123417}, doi = {10.1016/j.jns.2025.123417}, pmid = {39954573}, issn = {1878-5883}, } @article {pmid39954119, year = {2025}, author = {Jacobsen, AB and Fanella, G and de Carvalho, M and Koltzenburg, M and Oliveira Santos, M and Cengiz, B and Blicher, J and Obál, I and Heintzelmann, MB and Nix, W and Camdessanché, JP and Fuglsang-Frederiksen, A and Tankisi, H}, title = {Variability of the Penn upper motor neuron score in amyotrophic lateral sclerosis: need for a revised score.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {208}, pmid = {39954119}, issn = {1432-1459}, support = {R346-2020-1946//Lundbeck Foundation/ ; R392-2022-699//Lundbeck Foundation/ ; J.nr.23-2B-12533//Aage og Johanne Louis-Hansens Fond/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Aged ; Middle Aged ; Reproducibility of Results ; Aged, 80 and over ; *Severity of Illness Index ; Observer Variation ; Motor Neurons/pathology/physiology ; }, abstract = {There is a need for a consensus on a clinical scale for evaluating upper motor neuron (UMN) burden in amyotrophic lateral sclerosis (ALS) to improve consistency in clinical diagnosis, research and monitoring of disease progression. The Penn upper motor neuron score (PUMNS) is the most commonly published scale, however, the reliability of the scale has only been evaluated in a single study involving two raters. The objective of this study was to evaluate the inter-rater reliability of the PUMNS in ALS patients among multiple raters, and to discuss an updated UMN score including the signs with the highest inter-rater reliability. This study included seven ALS patients (mean age: 71 ± 11.5, six males, one female). Each patient was evaluated with the PUMNS by eight raters from different centers blinded to previous observations. The intra-class correlation coefficient (ICC) was calculated to assess the inter-rater reliability of the total PUMNS. The inter-rater reliability of the binary subscores was assessed with Gwet's AC1 coefficient. The inter-rater agreement for the total PUMNS yielded an ICC of 0.81 (95% CI 0.56;0.96). Items with the highest inter-rater reliability included Hoffman's sign, Babinski's sign, clonus and deep tendon reflexes, while the facial reflex (Gwet's AC1 -0.038 (95% CI -0.25,0.18)) and crossed adduction (0.18 (95% CI (-0.32,0.67)) had the lowest inter-rater reliability. In conclusion, PUMNS demonstrated good inter-rater reliability overall, while some of the subscores had poor inter-rater reliability. Based on this, we call for an updated UMN score to enhance diagnostic accuracy and research consistency in ALS.}, } @article {pmid39954028, year = {2025}, author = {Al Ojaimi, Y and Vallet, N and Dangoumau, A and Lanznaster, D and Bruno, C and Lefevre, A and Osman, S and Dupuy, C and Emond, P and Vourc'h, P and Corcia, P and Krupova, Z and Veyrat-Durebex, C and Blasco, H}, title = {Metabolomic and Proteomic Profiling of Serum-Derived Extracellular Vesicles from Early-Stage Amyotrophic Lateral Sclerosis Patients.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {1}, pages = {21}, pmid = {39954028}, issn = {1559-1166}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/blood ; Male ; Middle Aged ; Female ; Aged ; Biomarkers/blood ; Extracellular Vesicles/metabolism ; Proteome/metabolism ; Metabolome ; Adult ; Proteomics/methods ; Case-Control Studies ; Lipid Metabolism ; Exosomes/metabolism ; }, abstract = {The identification of reliable biomarkers for amyotrophic lateral sclerosis (ALS) is an unmet medical need for the development of diagnostic and therapeutic strategies. Brain-derived extracellular vesicles (EVs) have been described in peripheral blood serum and used as a direct readout of the status of the central nervous system. Here, we aimed to explore exosome-enriched EVs (referred to simply as EVs) from ALS patients via omics analysis at an early disease stage. Serum EVs were obtained from 9 healthy controls and 9 ALS patients. After EV purification, proteomic (LC‒MS/MS followed by TimsTOF Pro Mass Spectrometry) and metabolomic (Q Exactive mass spectrometer) analyses were performed. No differences in the size or concentration of EVs were observed between the controls and ALS patients. Proteomic analysis revealed 45 proteins differentially expressed in the EVs of ALS patients compared with those of controls. Metabolomic analysis revealed several distinctly represented metabolites involved in the citrate cycle and complex lipid metabolism between patients and controls. Interomics correlation analysis revealed 2 modules that were strongly associated with ALS and included several lipid metabolism-related proteins and metabolites. This study is the first to evaluate EVs by integrated proteomics and metabolomics in early-stage ALS patients, highlighting the technological progress in global inter-omics explorations of small biological samples. The differences observed in the levels of several exosomal proteins and metabolites, including phospholipids, could be used to identify serum biomarkers and novel players involved in ALS pathogenesis.}, } @article {pmid39953725, year = {2025}, author = {Nishida, K and Sakashita, K and Futamura, N}, title = {Decision-making trends in therapeutic interventions for multiple system atrophy: a 24-year retrospective study.}, journal = {Movement disorders clinical practice}, volume = {}, number = {}, pages = {}, doi = {10.1002/mdc3.70000}, pmid = {39953725}, issn = {2330-1619}, support = {JPMH23FC1010//the Ministry of Health, Labour and Welfare, Japan/ ; }, abstract = {BACKGROUND: Managing multiple system atrophy (MSA) is challenging. While invasive interventions for amyotrophic lateral sclerosis are well-studied, those for MSA remain less explored.

OBJECTIVES: To explore factors influencing treatment choices and trends in advanced-stage MSA.

METHODS: A retrospective cohort study analyzed 128 MSA patients at Hyogo Chuo National Hospital, Japan, from 2000 to 2024, focusing on treatment period and age at onset.

RESULTS: Tracheostomy invasive ventilation (TIV) decreased after 2014 (26.9% vs. 9.2%; P = 0.023). TIV-treated patients remained similarly young before and after 2014 (age at onset 52.7 vs. 54.5 years; P = 0.659) and tracheostomy was chosen by younger patients after 2014 (58.3 vs. 51.5 years; P < 0.001). Conversely, enteral nutrition increased in older patients (57.4 vs. 62.9 years; P = 0.011).

CONCLUSIONS: In Japanese MSA, preferences for invasive treatments shifted, with younger patients favoring TIV and tracheostomy, while older patients preferred less invasive options, emphasizing personalized care.}, } @article {pmid39952435, year = {2025}, author = {Truel, JS and Novice, M and Shapiro, J and Lo Sicco, KI}, title = {Response to Folliat et al's "Characteristics of pruritus in lichen planopilaris and frontal fibrosing alopecia: A cohort study in a French hospital".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.11.084}, pmid = {39952435}, issn = {1097-6787}, } @article {pmid39952329, year = {2025}, author = {Ji, Y and Jiang, Q and Chen, B and Chen, X and Li, A and Shen, D and Shen, Y and Liu, H and Qian, X and Yao, X and Sun, H}, title = {Endoplasmic reticulum stress and unfolded protein response: Roles in skeletal muscle atrophy.}, journal = {Biochemical pharmacology}, volume = {234}, number = {}, pages = {116799}, doi = {10.1016/j.bcp.2025.116799}, pmid = {39952329}, issn = {1873-2968}, mesh = {Humans ; *Unfolded Protein Response/physiology ; *Endoplasmic Reticulum Stress/physiology ; *Muscular Atrophy/metabolism/pathology ; Animals ; *Muscle, Skeletal/metabolism/pathology ; }, abstract = {Skeletal muscle atrophy is commonly present in various pathological states, posing a huge burden on society and patients. Increased protein hydrolysis, decreased protein synthesis, inflammatory response, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) are all important molecular mechanisms involved in the occurrence and development of skeletal muscle atrophy. The potential mechanisms of ERS and UPR in skeletal muscle atrophy are extremely complex and have not yet been fully elucidated. This article elucidates the molecular mechanisms of ERS and UPR, and discusses their effects on different types of muscle atrophy (muscle atrophy caused by disuse, cachexia, chronic kidney disease (CKD), diabetes mellitus (DM), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), aging, sarcopenia, obesity, and starvation), and explores the preventive and therapeutic strategies targeting ERS and UPR in skeletal muscle atrophy, including inhibitor therapy and drug therapy. This review aims to emphasize the importance of endoplasmic reticulum (ER) in maintaining skeletal muscle homeostasis, which helps us further understand the molecular mechanisms of skeletal muscle atrophy and provides new ideas and insights for the development of effective therapeutic drugs and preventive measures for skeletal muscle atrophy.}, } @article {pmid39950184, year = {2025}, author = {Høj, A and Holm-Yildiz, S and Krag, T and Dejanovic, D and van Overeem Hansen, T and Dunø, M and Ørngreen, MC and Vissing, J and Løkken, N}, title = {2-[[18]F] FDG PET/CT in Rapid Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency: A Case Report.}, journal = {JIMD reports}, volume = {66}, number = {2}, pages = {e12469}, pmid = {39950184}, issn = {2192-8304}, abstract = {Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn metabolic myopathy affecting fat and protein metabolism. Patients with late-onset MADD typically present with exercise intolerance and muscle weakness. We present a patient with an acute, very late-onset symptom debut at 52 years of age. Over 5 months, the patient deteriorated from asymptomatic to almost complete loss of ambulation. He had a substantial weight loss, head-drop, progressive proximal limb and chewing weakness. Due to the rapid progression, amyotrophic lateral sclerosis, myositis, myasthenia gravis and a paraneoplastic syndrome in relation to underlying malignancy were considered first. A 2-[[18]F] FDG PET/CT scan was performed to exclude a paraneoplastic syndrome. The scan revealed diffuse and symmetric, pathologically high 2-[[18]F] FDG-uptake in the patient's neck, shoulder, and paravertebral muscles, which was later suggested as a sign of a metabolic myopathy. Muscle biopsy (Oil Red O staining) and acylcarnitine profile (elevated C5-C18 acylcarnitines) findings suggested MADD, which was confirmed by genetic analysis showing biallelic variants in the ETFDH gene (c.1763A>G, p.(His588Arg); c.897G>A, p.(Leu299=)). After 1 month of dietary intervention and daily diet supplements (riboflavin 400 mg TID, levocarnitine 1 g TID, Q10 150 mg qD in two doses), the patient had almost recovered to his habitual level. A posttreatment muscle biopsy showed less disrupted ultrastructure of the myofibers. We learned from this case of rapid and late-onset MADD that 2-[[18]F] FDG PET/CT, with diffuse and symmetric 2-[[18]F] FDG-uptake in skeletal muscle, can be valuable in clarifying this rare diagnosis.}, } @article {pmid39949668, year = {2025}, author = {Xu, J and Yu, Y and Wang, Y and Zhang, S and Liu, E and Wang, W and Zhu, C and Li, J}, title = {Postoperative Axial Length Prediction Model in Children With Congenital Cataract and Intraocular Lens Implantation.}, journal = {Journal of ophthalmology}, volume = {2025}, number = {}, pages = {9948890}, pmid = {39949668}, issn = {2090-004X}, abstract = {Purpose: To develop a prediction model for postoperative axial length (AL) in Asian children with congenital cataracts undergoing primary/secondary intraocular lens (IOL) implantation. Design: Retrospective observational study. Methods: Data were collected from children who underwent cataract surgery for congenital cataracts at the Eye Hospital of Wenzhou Medical University between 2006 and 2020. All participants completed preoperative and at least 1-year of postoperative follow-up. SPSS 26.0 software was used to analyze the variable factors affecting AL growth and the interactions among these factors. A generalized estimating equation (GEE) was employed to assess the correlation between the AL and related univariates over time. The univariate model was applied to build a multivariate model to predict the postoperative AL. Two validation sets were used to verify the accuracy of the formula. Results: The study involved 86 children, accounting for 148 eyes. The median age at the time of surgery was 3.00 years, with a median age of 9.50 years at the final follow-up visit. The median duration of follow-up was 5.00 years. The preoperative and final follow-up mean ALs were 21.79 ± 1.77 and 23.36 ± 1.90 mm, respectively. Taking the predicted AL (Y) as the dependent variable and the age at surgery (X 1), age at review (X 2), and preoperative AL (X 3) as the independent variables, the prediction model was established as Y = 0.20 - 0.473 × X 1 + 0.446 × X 2 + 0.993 × X 3 - 0.014 × (X 2 - X 1)∗X 2. Conclusions: This model predicts AL growth in children following congenital cataract surgery and IOL implantation, helping ophthalmologists select appropriate IOL power.}, } @article {pmid39948244, year = {2025}, author = {Picard, F and Nonaka, T and Belotti, E and Osseni, A and Errazuriz-Cerda, E and Jost-Mousseau, C and Bernard, E and Conjard-Duplany, A and Bohl, D and Hasegawa, M and Raoul, C and Galli, T and Schaeffer, L and Leblanc, P}, title = {Enhanced secretion of the amyotrophic lateral sclerosis ALS-associated misfolded TDP-43 mediated by the ER-ubiquitin specific peptidase USP19.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {82}, number = {1}, pages = {76}, pmid = {39948244}, issn = {1420-9071}, support = {MyoNeurALP strategic grants//AFM-Téléthon/ ; MyoNeurALP strategic grants//AFM-Téléthon/ ; SPREADALS//Agence Nationale de la Recherche/ ; SPREADALS//Agence Nationale de la Recherche/ ; SPREADALS//Agence Nationale de la Recherche/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Endoplasmic Reticulum/metabolism ; *Protein Folding ; *Endopeptidases/metabolism/genetics ; HEK293 Cells ; Autophagy ; }, abstract = {Proteinopathies, such as amyotrophic lateral sclerosis (ALS), are marked by the accumulation of misfolded proteins that disrupt cellular processes. Eukaryotic cells have developed protein quality control systems to eliminate these aberrant proteins, but these systems often fail to differentiate between normal and misfolded proteins. In ALS, pathological inclusions primarily composed of misfolded TDP-43 are a hallmark of the disease. Recently, a novel unconventional secretion process called misfolding-associated protein secretion (MAPS) has been discovered to selectively export misfolded proteins. USP19, an Endoplasmic Reticulum-associated ubiquitin peptidase, plays a crucial role in this process. In this study, we investigated the impact of ER-anchored USP19 on the secretion of misfolded TDP-43. Here we found that USP19 overexpression significantly promotes the secretion of soluble and aggregated misfolded TDP-43, requiring both ER anchoring and ubiquitin peptidase activity. Characterization of the cellular and molecular mechanisms involved in this process highlighted the importance of early autophagosomal and late endosomal/amphisomal compartments, while lysosomes did not play a key role. By using dominant-negative mutants and small interfering RNAs, we identified that USP19-mediated secretion of misfolded TDP-43 is modulated by key factors involved in cellular trafficking and secretion pathways, such as ATG7, the ESCRT-O HGS/HRS, the Rab GTPases RAB11A, RAB8A, and RAB27A, and the v-SNARE VAMP7. We also confirmed the crucial role of the DNAJC5/CSPα cochaperone. Overall, this study provides new insights into how cells manage the secretion of misfolded TDP-43 proteins and potentially opens new avenues for therapeutic interventions in ALS and related disorders.}, } @article {pmid39947885, year = {2025}, author = {Iacoangeli, A and Dilliott, AA and Al Khleifat, A and Andersen, PM and Başak, NA and Cooper-Knock, J and Corcia, P and Couratier, P and deCarvalho, M and Drory, VE and Glass, JD and Gotkine, M and Lerner, YM and Hardiman, O and Landers, JE and McLaughlin, RL and Pardina, JSM and Morrison, K and Pinto, S and Povedano, M and Shaw, CE and Shaw, PJ and Silani, V and Ticozzi, N and van Damme, P and van den Berg, LH and Vourc'h, P and Weber, M and Veldink, JH and , and Dobson, R and Rouleau, GA and Al-Chalabi, A and Farhan, SMK}, title = {Oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling and therapeutic implications.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-335364}, pmid = {39947885}, issn = {1468-330X}, abstract = {BACKGROUND: Despite several studies suggesting a potential oligogenic risk model in amyotrophic lateral sclerosis (ALS), case-control statistical evidence implicating oligogenicity with disease risk or clinical outcomes is limited. Considering its direct clinical and therapeutic implications, we aim to perform a large-scale robust investigation of oligogenicity in ALS risk and in the disease clinical course.

METHODS: We leveraged Project MinE genome sequencing datasets (6711 cases and 2391 controls) to identify associations between oligogenicity in known ALS genes and disease risk, as well as clinical outcomes.

RESULTS: In both the discovery and replication cohorts, we observed that the risk imparted from carrying multiple ALS rare variants was significantly greater than the risk associated with carrying only a single rare variant, both in the presence and absence of variants in the most well-established ALS genes. However, in contrast to risk, the relationships between oligogenicity and ALS clinical outcomes, such as age of onset and survival, did not follow the same pattern.

CONCLUSIONS: Our findings represent the first large-scale, case-control assessment of oligogenicity in ALS and show that oligogenic events involving known ALS risk genes are relevant for disease risk in ~6% of ALS but not necessarily for disease onset and survival. This must be considered in genetic counselling and testing by ensuring to use comprehensive gene panels even when a pathogenic variant has already been identified. Moreover, in the age of stratified medication and gene therapy, it supports the need for a complete genetic profile for the correct choice of therapy in all ALS patients.}, } @article {pmid39947630, year = {2025}, author = {Moreno-Martinez, L and Gaja-Capdevila, N and Mosqueira-Martín, L and Herrando-Grabulosa, M and Rodriguez-Gomez, L and Gonzalez-Imaz, K and Calvo, AC and Sagartzazu-Aizpurua, M and Moreno-García, L and Fuentes, JM and Acevedo-Arozena, A and Aizpurua, JM and Miranda, JI and López de Munain, A and Vallejo-Illarramendi, A and Navarro, X and Osta, R and Gil-Bea, FJ}, title = {Novel FKBP prolyl isomerase 1A (FKBP12) ligand promotes functional improvement in SOD1[G93A] amyotrophic lateral sclerosis (ALS) mice.}, journal = {British journal of pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bph.17448}, pmid = {39947630}, issn = {1476-5381}, support = {PID2022-140354OB-I00//Agencia Estatal de Investigación/ ; PID2020-119780RB-100//Agencia Estatal de Investigación/ ; IKERBASQUE/PP/2022/003//Ikerbasque, Basque Foundation for Science/ ; PIF19/184//Euskal Herriko Unibertsitatea/ ; PI2020/08-1//CIBER-CALS/ ; CB06/05/1105//Instituto de Salud Carlos III of Spain/ ; CB06/05/0041//Instituto de Salud Carlos III of Spain/ ; BIO19/ROCHE/017/BD//Roche Stop Fuga de Cerebros/ ; IT1732-22//Basque Government/ ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment options. ALS pathogenesis involves intricate processes within motor neurons, characterized by dysregulated Ca[2+] influx and buffering in early ALS-affected motor neurones. This study proposes the modulation of ryanodine receptors (RyRs), key mediators of intracellular Ca[2+], as a therapeutic target.

EXPERIMENTAL APPROACH: A novel class of novel FKBP12 ligands that show activity as cytosolic calcium modulators through stabilizing RyR channel activity, were tested in the superoxide dismutase 1 (SOD1)[G93A] mouse model of ALS. Different outcomes were used to assess treatment efficacy, including electrophysiology, histopathology, neuromuscular function and survival.

KEY RESULTS: Among the novel FKBP12 ligands, MP-010 was chosen for its central nervous system availability and favourable in vitro pharmaco-toxicological profile. Chronic administration of MP-010 to SOD1[G93A] mice produced preservation of motor nerve conduction, with the 61-mg·kg[-1] dose significantly delaying the onset of motor impairment. This was accompanied by improved motor coordination, increased innervated endplates and significant preservation of motor neurones in the spinal cord of treated mice. Notably, MP-010 treatment significantly extended lifespan by an average of 10 days compared to vehicle.

CONCLUSIONS AND IMPLICATIONS: FKBP12 ligands, particularly MP-010, exhibit promising neuroprotective effects in ALS, highlighting their potential as novel therapeutic agents. Further investigations into the molecular mechanisms and clinical translatability of these compounds are needed for their application in ALS treatment.}, } @article {pmid39947279, year = {2025}, author = {Gelbenegger, G and Cheskes, S and Jilma, B and Zeitlinger, M and Lin, S and Drennan, IR and Jorda, A}, title = {Amiodarone dose in patients with shockable out-of-hospital cardiac arrest.}, journal = {Resuscitation}, volume = {}, number = {}, pages = {110534}, doi = {10.1016/j.resuscitation.2025.110534}, pmid = {39947279}, issn = {1873-1570}, abstract = {BACKGROUND: Amiodarone is used in shockable out-of-hospital cardiac arrest (OHCA), but the ideal dose is unknown.

METHODS: This was an analysis from the Resuscitation Outcomes Consortium Cardiac Epidemiologic Registry (2011-2015). Patients with shockable OHCA who received 5 or more defibrillation attempts and treatment with 300 or 450 mg of amiodarone were included. Outcomes were ROSC at ED arrival, survival at hospital discharge, and favorable neurologic function at discharge. Group-differences were adjusted for using inverse probability weighting and a multiple logistic regression model.

RESULTS: The present study included 910 patients; 426 received amiodarone 300 mg and 484 received amiodarone 450 mg. The amiodarone 300 mg group had a higher estimated probability of ROSC at ED arrival as compared with the amiodarone 450 mg group (30.8% [95% CI, 26.6-35.1] vs 24.2% [95% CI, 20.5-27.9], respectively; adjusted probability difference, 6.6% (0.9-12.3), p = 0.0234). The group differences in survival at hospital discharge (21.3% [95% CI, 17.2-25.4] vs 18.0% [95% CI, 14.6-21.5]; adjusted probability difference, 3.3% [-2.3-8.8]) and favorable neurologic outcome at discharge (16.5% [95% CI, 12.9-20.2] vs 12.7% [95% CI, 9.5-16.0]; adjusted probability difference, 3.8% [95% CI, -1.2-8.7]) did not reach statistical significance.

CONCLUSION: In patients with shockable OHCA who received 5 or more defibrillation attempts, a dose of amiodarone 300 mg was associated with a similar survival compared with a total dose of amiodarone 450 mg. Further study is needed to evaluate the need for a second administration of amiodarone in patients with shockable OHCA.}, } @article {pmid39947099, year = {2025}, author = {Tan, HHG and Nitert, AD and van Veenhuijzen, K and Dukic, S and van Zandvoort, MJE and Hendrikse, J and van Es, MA and Veldink, JH and Westeneng, HJ and van den Berg, LH}, title = {Neuroimaging correlates of domain-specific cognitive deficits in amyotrophic lateral sclerosis.}, journal = {NeuroImage. Clinical}, volume = {45}, number = {}, pages = {103749}, pmid = {39947099}, issn = {2213-1582}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/complications ; Male ; Female ; Middle Aged ; *Magnetic Resonance Imaging/methods ; Aged ; *Cognitive Dysfunction/diagnostic imaging/etiology/physiopathology/pathology ; Gray Matter/diagnostic imaging/pathology ; Adult ; Neuroimaging/methods ; White Matter/diagnostic imaging/pathology ; Brain/diagnostic imaging/pathology ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with frequent extra-motor involvement. In the present study, we investigated whether specific cognitive and behavioral deficits in ALS correlate with distinct extra-motor neurodegeneration patterns on brain MRI.

METHODS: We performed multimodal brain MRI and Edinburgh cognitive and behavioral ALS screen (ECAS) in 293 patients and 237 controls. Follow-up data were acquired from 171 patients with a median duration of 7.9 months. Domain-level cognitive scores from the ECAS were compared with grey and white matter MRI parameters. Interaction analyses between patients and controls were performed to explore whether correlates were specific to ALS, rather than related to normal aging. Follow-up data were used to assess changes of domain-associated brain structures over time.

RESULTS: Language impairment was significantly associated with (left predominant) frontal, temporal, parietal and subcortical grey matter neurodegeneration. Letter fluency with widespread cortical and subcortical grey matter involvement. Memory dysfunction with hippocampal and medial-temporal atrophy. Executive impairment was exclusively correlated with widespread white matter impairment. Visuospatial scores did not correlate with MRI parameters. Interaction analyses between patients and controls showed that most ECAS-MRI correlations were stronger in ALS than in controls (75.7% significant in grey matter, 52.7% in white matter). Longitudinal analyses showed that all grey matter structures associated with cognitive domains worsened over time while, for this study population, ECAS domain scores did not decline significantly.

CONCLUSIONS: MRI can capture the heterogeneity of cognitive and behavioral involvement in ALS and provides a useful longitudinal biomarker for progression of extra-motor neurodegeneration.}, } @article {pmid39946662, year = {2025}, author = {Cordts, I and Fuetterer, C and Wachinger, A and von Heynitz, R and Kessler, T and Freigang, M and Quinten, AL and Bjelica, B and Brakemeier, S and Hobbiebrunken, E and Hagenacker, T and Petri, S and Koch, JC and Hahn, A and Lingor, P and Deschauer, M and Günther, R and Weiler, M and Haller, B and Feneberg, E}, title = {Long-Term Dynamics of CSF and Serum Neurofilament Light Chain in Adult Patients With 5q Spinal Muscular Atrophy Treated With Nusinersen.}, journal = {Neurology}, volume = {104}, number = {5}, pages = {e213371}, pmid = {39946662}, issn = {1526-632X}, mesh = {Humans ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Male ; Female ; Adult ; *Oligonucleotides/therapeutic use ; Retrospective Studies ; Middle Aged ; *Muscular Atrophy, Spinal/drug therapy/blood/cerebrospinal fluid ; *Biomarkers/blood/cerebrospinal fluid ; Young Adult ; }, abstract = {BACKGROUND AND OBJECTIVES: The availability of disease-modifying therapies for 5q-associated spinal muscular atrophy (SMA) has heightened the need to identify suitable biomarkers. This study investigates neurofilament light chain (NfL) concentrations during long-term nusinersen treatment in adult SMA.

METHODS: In a retrospective study of prospectively collected data, NfL concentrations in the CSF (cNfL) and serum (sNfL) were measured in patients with SMA from 8 German centers and in neurologic controls using a single-molecule array (Simoa) assay. NfL concentrations and clinical characteristics, including the clinical scores Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), were analyzed for defined treatment intervals (T1-T4 [loading phase until 4 months], T5-T8 [until 23 months], T9-T12 [until 37 months], and T13-T19 [until 60 months]). Linear mixed models with a random intercept were used to assess the changes in NfL levels during treatment, considering time and covariates as fixed effects.

RESULTS: One hundred thirteen adult patients with SMA (median age 35, 46% female), with a treatment duration of maximum 60 months, and 52 controls were included. At baseline, NfL concentrations were significantly higher in SMA {cNfL median, 585 (interquartile range [IQR] 428-787) pg/mL; sNfL, 11 (IQR 8-14) pg/mL} than in controls (cNfL, 420 [IQR 323-662] pg/mL; sNfL, 8 [IQR 6-12] pg/mL) (cNfL, p = 0.021; sNfL, p = 0.030). Median differences for all clinical scores were the highest for T5-T8 compared with the loading phase (Δ HFMSE, 0.6 [IQR 0.1-1.4], p = 0.017; Δ RULM, 0.9 [IQR 0.4-1.3], p < 0.001; Δ ALSFRS-R, 0.7 [IQR 0.4-1.0], p < 0.001), but not for subsequent intervals. Longitudinal analysis revealed a significant decrease of NfL concentrations during each treatment interval compared with the loading phase (p < 0.05, respectively) except for sNfL in T13-T19. Even among patients with no measurable clinical improvement (Δ HFMSE ≤ 0), more than 50% showed declining cNfL and sNfL levels up to T13-T19.

DISCUSSION: NfL decreased during nusinersen treatment, suggesting its potential as a pharmacodynamic response marker in adult SMA. However, in patients without detectable clinical improvement, our study cannot determine whether they represent a more sensitive outcome measure or are not clinically meaningful.}, } @article {pmid39946043, year = {2025}, author = {Patnana, DP and Kanikaram, SP and Kumar, P and Cheerala, VSK and Sivaramakrishnan, V and Tripathi, P and Chandra, BP}, title = {Simultaneous determination of polycyclic aromatic hydrocarbons, their derivatives, and phthalic acid esters bound to ambient PM2.5 during pre-summer season in Bengaluru, India, and potential effect on protein aggregation diseases.}, journal = {Environmental science and pollution research international}, volume = {}, number = {}, pages = {}, pmid = {39946043}, issn = {1614-7499}, abstract = {Air pollution pertaining to particulate matter (PM) is a major issue in most of the metropolitan cities across the world. Inhalation exposure to organic species like polycyclic aromatic hydrocarbons (PAHs), derivatives of PAHs (oxygenated and nitrated PAHs), and phthalic acid esters (PAEs) bound to PM is of major concern owing to its carcinogenic, mutagenic, and endocrine disrupting nature. In this study for the first time, we report a total of 22 aromatic organic species which include PAHs, derivatives of PAHs, and PAEs using an optimized high-performance liquid chromatography coupled to the tandem mass spectrometer (HPLC-MS/MS) method. Further, this optimized method was used to carry out the measurements of the 22 targeted organic constituents bound to the ambient fine particulate matter (PM2.5) collected in Bengaluru, a metropolitan city in India as a part of a pilot study during the pre-summer season. Among the reported compounds, benzo[b]fluoranthene (3.82 ng m[-3]), 9-nitroanthracene (10.47 ng m[-3]), and diethyl phthalate (5.38 ng m[-3]) are the most abundant PAHs, the derivatives of PAHs, and PAEs, respectively. Determined diagnostic ratios of PAHs have shown that the sampling site is majorly influenced by traffic emissions. Benzo[a]pyrene, a Group 1 carcinogen has occasionally exceeded the limits set by National Ambient Air Quality Standards (NAAQs), India during the sampling period. Further, a preliminary study was performed using a yeast model of amyotrophic lateral sclerosis (ALS) expressing transactive response DNA binding protein 43 (TDP43) and we demonstrated that commonly reported organics such as PAHs and PAEs bound to PM2.5 have induced significantly elevated aggregation in wild type TDP43. Preliminary results of this study indicate that there is a need for further detailed health risk assessment due to inhalation exposure of organic constituents bound to the ambient PM in Bengaluru.}, } @article {pmid39945358, year = {2025}, author = {Badger, SE and Coldicott, I and Kyrgiou-Balli, E and Higginbottom, A and Moutin, C and Mohd Imran, K and Day, JC and Cooper-Knock, J and Mead, RJ and Alix, JJP}, title = {A bacterial artificial chromosome mouse model of amyotrophic lateral sclerosis manifests 'space cadet syndrome' on two FVB backgrounds.}, journal = {Disease models & mechanisms}, volume = {18}, number = {2}, pages = {}, pmid = {39945358}, issn = {1754-8411}, support = {Alix/Apr19/871-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; //University of Sheffield/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Disease Models, Animal ; *C9orf72 Protein/genetics ; *Mice, Transgenic ; *Chromosomes, Artificial, Bacterial/genetics ; *Phenotype ; Frontotemporal Dementia/genetics/pathology ; Mice ; Humans ; Syndrome ; }, abstract = {C9orf72-related amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) has proven difficult to model in mice. Liu et al. (2016) reported a bacterial artificial chromosome (BAC) transgenic mouse displaying behavioural, motor and pathological abnormalities. This was followed by multiple laboratories independently refuting and confirming phenotypes. A proposed explanation centred on the use of different FVB background lines (from The Jackson Laboratory and Janvier Labs). We studied C9orf72 BAC mice on both backgrounds and found significantly elevated levels of dipeptide repeat proteins, but no evidence of a transgene-associated phenotype. We observed seizures and a gradual decline in functional performance in transgenic and non-transgenic mice, irrespective of genetic background. The phenotype was in keeping with the so-called 'space cadet syndrome'. Our findings indicate that the differences previously reported are not due to C9orf72 status and highlight the importance of using genetic backgrounds that do not confound interpretation of neurodegenerative phenotypes.}, } @article {pmid39944773, year = {2025}, author = {Cheng, R and Dimitriou, D and Yao, G and Li, X and Lv, X and Yang, Y and Ying, H and Wang, Z and Tsai, TY}, title = {Outperformance of Combined Artificial Anterolateral Ligament and ACL Reconstruction Compared With Isolated Artificial ACL Reconstruction in Knees With Anterolateral Structure and ACL Deficiency: A Biomechanical Analysis.}, journal = {Orthopaedic journal of sports medicine}, volume = {13}, number = {2}, pages = {23259671241309270}, pmid = {39944773}, issn = {2325-9671}, abstract = {BACKGROUND: Despite the promising clinical outcomes of artificial polyethylene terephthalate (PET) ligaments in isolated anterior cruciate ligament reconstruction (ACLR), their biomechanical performance after combined anterolateral ligament reconstruction (ALLR)/ACLR in anterolateral structure (ALS)/anterior cruciate ligament (ACL)-deficient knees has not been investigated.

PURPOSE/HYPOTHESIS: The purpose of this study was to compare biomechanical performance in cadaveric knees between combined artificial ALLR/ACLR and isolated artificial ACLR using PET ligaments. It was hypothesized that combined artificial ALLR/ACLR would restore native knee stability and outperform isolated artificial ACLR in ALS/ACL-deficient knees.

STUDY DESIGN: Controlled laboratory study.

METHODS: Eight fresh-frozen cadaveric knees were tested using a robotic manipulator. Each knee was tested in 4 states: (1) ALS/ACL intact, (2) ALS/ACL deficient, (3) ACLR, and (4) ALLR/ACLR. The anterior tibial translation (ATT) and tibial internal rotation (IR) in each knee condition were measured under 3 loads: (1) 89 N of anterior tibial loading, (2) 5 N·m of IR torque, and (3) simulated pivot shift (combined 5 N·m of IR torque and 7 N·m of valgus load).

RESULTS: During 89 N of anterior tibial loading, there were no significant differences in ATT between the isolated ACLR and ALLR/ACLR knees. During 5 N·m of IR torque, the mean tibial IR at 45° of flexion was significantly higher in the ACLR knees (32.49°± 7.96°) than in the ALLR/ACLR knees (21.78°± 3.03°) (P < .05). During the simulated pivot shift, the mean ATT and tibial IR at 30° and 45° of flexion were significantly higher in the ACLR knees (ATT: 5.09 ± 2.74 mm at 30°, 5.43 ± 2.79 mm at 45°; IR: 30.08°± 7.31° at 30°, 32.55°± 6.48° at 45°) than in the ALLR/ACLR knees (ATT: 1.93 ± 2.71 mm at 30°, 1.17 ± 2.26 mm at 45°; IR: 22.12°± 4.05° at 30°, 22.18°± 3.37° at 45°) (P < .05).

CONCLUSION: Combined artificial ALLR/ACLR restored native knee stability across multiple flexion angles and outperformed isolated artificial ACLR in ALS/ACL-deficient knees, particularly with respect to ATT and tibial IR during the pivot-shift test.

CLINICAL RELEVANCE: The indications of the artificial PET ligament may be expanded to include combined ALLR/ACLR to restore knee stability better than isolated artificial ACLR in ALS/ACL-deficient knees.}, } @article {pmid39944166, year = {2025}, author = {Islam, S and Noorani, A and Sun, Y and Michikawa, M and Zou, K}, title = {Multi-functional role of apolipoprotein E in neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1535280}, pmid = {39944166}, issn = {1663-4365}, abstract = {Genetic diversity in the apolipoprotein E (ApoE) gene has been identified as the major susceptibility genetic risk factor for sporadic Alzheimer's disease (SAD). Specifically, the ApoEε4 allele is a significant risk factor for SAD, while ApoEε2 allele provides protection compared to the more common ApoEε3 allele. This review discusses the role of the ApoE in AD and other neurodegenerative disorders. ApoE, a cholesterol transport protein, influences several pathways involved in neurodegeneration, particularly in AD. Beyond its established role in amyloid β-protein (Aβ) metabolism and deposition, ApoE also impacts tau pathology, neurodegeneration, and the microglial response to AD. The review aims to provide an updated overview of ApoE's diverse roles, emphasizing its involvement in Aβ clearance through ApoE receptors. It also covers ApoE's influence in other neurodegenerative diseases like Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Huntington's disease (HD), vascular dementia (VD), and multiple sclerosis (MS). New research highlights the interaction between ApoE and presenilin (PS), suggesting connections between familial AD (FAD) and SAD. The review also explores protective effects of ApoE mutations against AD and ApoE4-induced tauopathy, neurodegeneration, and neuroinflammation. The insights from this comprehensive update could indeed lead to new therapeutic strategies for neurodegenerative diseases.}, } @article {pmid39944085, year = {2025}, author = {Sakurai, H and Suzuki, M and Asakura, A}, title = {Editorial: Induced pluripotent stem cells (iPSCs) for skeletal muscle diseases.}, journal = {Frontiers in cell and developmental biology}, volume = {13}, number = {}, pages = {1556403}, pmid = {39944085}, issn = {2296-634X}, } @article {pmid39942798, year = {2025}, author = {Długosz, A and Błaszak, B and Czarnecki, D and Szulc, J}, title = {Mechanism of Action and Therapeutic Potential of Xanthohumol in Prevention of Selected Neurodegenerative Diseases.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {3}, pages = {}, pmid = {39942798}, issn = {1420-3049}, mesh = {*Propiophenones/pharmacology/therapeutic use ; *Flavonoids/pharmacology/chemistry/therapeutic use ; Humans ; *Neurodegenerative Diseases/prevention & control/drug therapy/metabolism ; Animals ; Antioxidants/pharmacology/therapeutic use ; Alzheimer Disease/prevention & control/drug therapy/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Signal Transduction/drug effects ; Parkinson Disease/drug therapy/metabolism/prevention & control ; Humulus/chemistry ; }, abstract = {Xanthohumol (XN), a bioactive plant flavonoid, is an antioxidant, and as such, it exhibits numerous beneficial properties, including anti-inflammatory, antimicrobial, and antioxidative effects. The main dietary source of XN is beer, where it is introduced through hops. Although the concentration of XN in beer is low, the large quantities of hop-related post-production waste present an opportunity to extract XN residues for technological or pharmaceutical purposes. The presented study focuses on the role of XN in the prevention of neurodegenerative diseases, analyzing its effect at a molecular level and including its signal transduction and metabolism. The paper brings up XN's mechanism of action, potential effects, and experimental and clinical studies on Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Additionally, challenges and future research directions on XN, including its bioavailability, safety, and tolerance, have been discussed.}, } @article {pmid39942481, year = {2025}, author = {Kavanaugh, MS and Zawadzki, MJ and Johnson, KT and Boville, MR}, title = {Moments of Care: Perceptions of Young Carers and Day-to-Day Well-Being.}, journal = {Healthcare (Basel, Switzerland)}, volume = {13}, number = {3}, pages = {}, pmid = {39942481}, issn = {2227-9032}, abstract = {Background/Objectives: Over 5 million youth under the age of 19 provide daily, hands-on care to an ill or injured family member across the United States. Yet how these young carers perceive the care they deliver in the moment, and how these perceptions relate to well-being, is unexplored, particularly in complex neurological conditions. This paper presents initial data on young carers for a family member with amyotrophic lateral sclerosis (ALS). Methods: Ecological momentary assessment (EMA) was used to measure perceptions of care in the moments of care and the cognitive and emotional states of the young carers during those moments. Young carers (n = 15) aged 10-19 were followed for seven days, completing assessments three times per day, which provided 260 total measurements. Young carers reported frequently engaging in caregiving (~39% of assessments). Results: The results indicated that it was not simply performing a caregiving task that related to outcomes, but rather how caregiving moments were perceived that mattered. Caregiving moments perceived as more fulfilling resulted in young carers feeling less discontent and more focused, whereas caregiving moments perceived as lacking resources predicted more discontent and distress. Exploratory analyses highlighted the potential for burden for young carers. They reported high levels of worry when they were not around the care recipient, with this worry predicting feeling more discontent and distressed. Conclusions: Young carers are deeply involved in care and perceive care differently across moments, both positive and negative. These initial data can be used to develop targeting support programs in the moment of care, potentially lessening the negative impacts of care.}, } @article {pmid39941101, year = {2025}, author = {Orywal, K and Socha, K and Iwaniuk, P and Kaczyński, P and Farhan, JA and Zoń, W and Łozowicka, B and Perkowski, M and Mroczko, B}, title = {Vitamins in the Prevention and Support Therapy of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39941101}, issn = {1422-0067}, support = {NdS/551580/2022/2022//Polish Ministry of Education and Science/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/prevention & control/metabolism ; *Vitamins/therapeutic use ; Dietary Supplements ; Animals ; Alzheimer Disease/prevention & control/metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), which are a consequence of the progressive loss of neuronal function and structure, cause significant cognitive impairment. The incidence of these diseases in the world's population is constantly increasing as a result of an aging population. Although genetic and environmental factors are most often mentioned as the pathogenetic factors of these diseases, increasing evidence points to the important role of proper nutrition in the prevention and support of the treatment of these disorders. A healthy, balanced diet can mitigate the risks associated with the risk factors mentioned above and slow the progression of the disease by reducing oxidative stress and inflammation. Vitamins B, D, E, C, K, and A have been shown to support cognitive functions and protect the nervous system. This review demonstrates the importance of vitamins in preventing and supporting the therapy of neurodegenerative diseases. Information regarding the health-promoting properties of these vitamins must be effectively communicated to consumers seeking to protect their health, particularly in the context of neurodegenerative diseases. Consequently, this review also examines the authorized health claims under EU food law related to these vitamins, assessing their role in promoting awareness of the vitamins' potential benefits for neuroprotection and the management of neurodegenerative diseases.}, } @article {pmid39941012, year = {2025}, author = {Sonkodi, B}, title = {PIEZO2 Proton Affinity and Availability May Also Regulate Mechanical Pain Sensitivity, Drive Central Sensitization and Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39941012}, issn = {1422-0067}, mesh = {Humans ; *Ion Channels/metabolism ; Animals ; Protons ; Central Nervous System Sensitization ; Pain/metabolism/physiopathology ; Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Pain Threshold ; }, abstract = {The current opinion manuscript posits that not only Piezo2 voltage block, but also proton affinity and availability in relation to Piezo2, a mechanically gated ion channel, may count in the mediation of pain and its sensitivity. Moreover, this paper argues that autonomously acquired Piezo2 channelopathy on somatosensory terminals is likely the initiating peripheral impaired input source that drives the central sensitization of spinal nociceptive neurons on the chronic path as being the autonomous pain generator. In parallel, impaired proprioception and the resultant progressive deficit in neuromuscular junctions of motoneurons might be initiated on the chronic path by the impairment of the proton-based ultrafast proprioceptive feedback to motoneurons due to disconnection through vesicular glutamate transporter 1. The irreversible form of this autonomously acquired Piezo2 ion channel microdamage, in association with genetic predisposition and/or environmental risk factors, is suggested to lead to progressive motoneuron death in addition to loss of pain sensation in amyotrophic lateral sclerosis. Furthermore, the impairment of the proton-based ultrafast long-range oscillatory synchronization to the hippocampus through vesicular glutamate transporter 2 may gain further importance in pain modulation and formation on the chronic path. Overall, this novel, unaccounted Piezo2-initiated protonic extrafast signaling, including both the protonic ultrafast proprioceptive and the rapid nociceptive ones, within the nervous system seems to be essential in order to maintain life. Hence, its microdamage promotes neurodegeneration and accelerates aging, while the complete loss of it is incompatible with life sustainment, as is proposed in amyotrophic lateral sclerosis.}, } @article {pmid39940966, year = {2025}, author = {Jamerlan, AM and Shim, KH and Sharma, N and An, SSA}, title = {Multimer Detection System: A Universal Assay System for Differentiating Protein Oligomers from Monomers.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39940966}, issn = {1422-0067}, support = {RS-2023-00251396//National Research Foundation of Korea/ ; 2021R1A6A1A03038996//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Protein Multimerization ; alpha-Synuclein/metabolism/chemistry ; Amyloid beta-Peptides/metabolism/chemistry ; Neurodegenerative Diseases/metabolism/diagnosis ; Protein Aggregates ; DNA-Binding Proteins/metabolism/chemistry ; tau Proteins/metabolism/chemistry ; Protein Aggregation, Pathological/metabolism ; }, abstract = {Depositions of protein aggregates are typical pathological hallmarks of various neurodegenerative diseases (NDs). For example, amyloid-beta (Aβ) and tau aggregates are present in the brain and plasma of patients with Alzheimer's disease (AD); α-synuclein in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA); mutant huntingtin protein (Htt) in Huntington's disease (HD); and DNA-binding protein 43 kD (TDP-43) in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The same misfolded proteins can be present in multiple diseases in the form of mixed proteinopathies. Since there is no cure for all these diseases, understanding the mechanisms of protein aggregation becomes imperative in modern medicine, especially for developing diagnostics and therapeutics. A Multimer Detection System (MDS) was designed to distinguish and quantify the multimeric/oligomeric forms from the monomeric form of aggregated proteins. As the unique epitope of the monomer is already occupied by capturing or detecting antibodies, the aggregated proteins with multiple epitopes would be accessible to both capturing and detecting antibodies simultaneously, and signals will be generated from the oligomers rather than the monomers. Hence, MDS could present a simple solution for measuring various conformations of aggregated proteins with high sensitivity and specificity, which may help to explore diagnostic and treatment strategies for developing anti-aggregation therapeutics.}, } @article {pmid39940644, year = {2025}, author = {Lee, AJB and Bi, S and Ridgeway, E and Al-Hussaini, I and Deshpande, S and Krueger, A and Khatri, A and Tsui, D and Deng, J and Mitchell, CS}, title = {Restoring Homeostasis: Treating Amyotrophic Lateral Sclerosis by Resolving Dynamic Regulatory Instability.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39940644}, issn = {1422-0067}, support = {U19 AG065169/AG/NIA NIH HHS/United States ; 1944247//National Science Foundation/ ; 253558//Chan Zuckerberg Initiative/ ; R35 GM152245/GM/NIGMS NIH HHS/United States ; R35GM152245/NH/NIH HHS/United States ; K01 NS069616/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy/pathology ; Animals ; *Homeostasis ; Mice ; *Mice, Transgenic ; *Disease Models, Animal ; Humans ; Disease Progression ; Superoxide Dismutase-1/genetics/metabolism ; Computer Simulation ; Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has an interactive, multifactorial etiology that makes treatment success elusive. This study evaluates how regulatory dynamics impact disease progression and treatment. Computational models of wild-type (WT) and transgenic SOD1-G93A mouse physiology dynamics were built using the first-principles-based first-order feedback framework of dynamic meta-analysis with parameter optimization. Two in silico models were developed: a WT mouse model to simulate normal homeostasis and a SOD1-G93A ALS model to simulate ALS pathology dynamics and their response to in silico treatments. The model simulates functional molecular mechanisms for apoptosis, metal chelation, energetics, excitotoxicity, inflammation, oxidative stress, and proteomics using curated data from published SOD1-G93A mouse experiments. Temporal disease progression measures (rotarod, grip strength, body weight) were used for validation. Results illustrate that untreated SOD1-G93A ALS dynamics cannot maintain homeostasis due to a mathematical oscillating instability as determined by eigenvalue analysis. The onset and magnitude of homeostatic instability corresponded to disease onset and progression. Oscillations were associated with high feedback gain due to hypervigilant regulation. Multiple combination treatments stabilized the SOD1-G93A ALS mouse dynamics to near-normal WT homeostasis. However, treatment timing and effect size were critical to stabilization corresponding to therapeutic success. The dynamics-based approach redefines therapeutic strategies by emphasizing the restoration of homeostasis through precisely timed and stabilizing combination therapies, presenting a promising framework for application to other multifactorial neurodegenerative diseases.}, } @article {pmid39939579, year = {2025}, author = {Zhou, T and Solis, NV and Marshall, M and Yao, Q and Pearlman, E and Filler, SG and Liu, H}, title = {Fungal Als proteins hijack host death effector domains to promote inflammasome signaling.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1562}, pmid = {39939579}, issn = {2041-1723}, support = {R01 EY036478/EY/NEI NIH HHS/United States ; R01 GM117111/GM/NIGMS NIH HHS/United States ; R01EY036478//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; R01GM117111//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, mesh = {*Inflammasomes/metabolism ; Humans ; *Caspase 8/metabolism ; *Fas-Associated Death Domain Protein/metabolism/genetics ; Animals ; *Fungal Proteins/metabolism/genetics ; *Signal Transduction ; *Candida albicans/metabolism ; Mice ; *Interleukin-1beta/metabolism ; Jurkat Cells ; Protein Domains ; Apoptosis ; Macrophages/metabolism/microbiology ; CARD Signaling Adaptor Proteins/metabolism/genetics ; }, abstract = {High-damaging Candida albicans strains tend to form hyphae and exacerbate intestinal inflammation in ulcerative colitis patients through IL-1β-dependent mechanisms. Fungal agglutinin-like sequence (Als) proteins worsen DSS-induced colitis in mouse models. FADD and caspase-8 are important regulators of gut homeostasis and inflammation. However, whether they link directly to fungal proteins is not fully understood. Here, we report that Als proteins induce IL-1β release in immune cells. We show that hyphal Als3 is internalized in macrophages and interacts with caspase-8 and the inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC). Caspase-8 is essential for Als3-mediated ASC oligomerization and IL-1β processing. In non-immune cells, Als3 is associated with cell death core components FADD and caspase-8. N-terminal Als3 (N-Als3) expressed in Jurkat cells partially inhibits apoptosis. Mechanistically, N-Als3 promotes oligomerization of FADD and caspase-8 through their death effector domains (DEDs). N-Als3 variants with a mutation in the peptide-binding cavity or amyloid-forming region are impaired in DED oligomerization. Together, these results demonstrate that DEDs are intracellular sensors of Als3. This study identifies additional potential targets to control hypha-induced inflammation.}, } @article {pmid39938954, year = {2025}, author = {Flügel, V and Hering, T and Dadaczynski, K}, title = {Development and validation of a questionnaire on parental health literacy in the context of promoting healthy lifestyles during childhood: a study protocol.}, journal = {BMJ open}, volume = {15}, number = {2}, pages = {e088037}, pmid = {39938954}, issn = {2044-6055}, mesh = {Humans ; *Health Literacy ; Surveys and Questionnaires ; *Parents ; Child ; *Health Promotion/methods ; *Healthy Lifestyle ; Child, Preschool ; Reproducibility of Results ; Research Design ; Female ; Male ; Factor Analysis, Statistical ; }, abstract = {INTRODUCTION: Becoming a parent presents profound changes and numerous challenges, notably the necessity for reliable information regarding their child's health. Given the overabundance of information available today, it is important for parents to acquire the skills necessary to find, understand, evaluate and apply health information. Research demonstrates that this ability, known as parental health literacy (PHL), is crucial for developing and maintaining a healthy lifestyle during childhood. However, there is currently no reliable instrument for measuring PHL in the field of prevention and health promotion. This paper presents the development and validation of a new questionnaire designed to assess parents' ability to process health-related information to support the healthy development of their children aged 3-6 years.

METHODS AND ANALYSIS: The development of the item pool is based on Sørensen et al's conceptualisation of general health literacy (finding, understanding, evaluating and applying health information). Empirical findings suggest that communication with healthcare providers and the social network represents another important skill area for parents and is therefore included as an additional subscale. The questionnaire will be developed in four stages, including a literature search and analysis, expert consultations via Delphi study, cognitive interviews with parents and a validation study. The validation study uses exploratory (EFA) and confirmatory factor analysis (CFA) for construct validity, first identifying test dimensions through EFA, then confirming these dimensions with CFA to ensure the factor structure aligns with theoretical expectations. This methodology, alongside reliability and correlational analyses, seeks to assess the questionnaire's validity and reliability, expecting strong correlations with existing related constructs.

ETHICS AND DISSEMINATION: Ethical approval was obtained from the Ethics Committee of Fulda University of Applied Sciences. All participants receive a consent form together with the study information, in which they give their written consent to the storage, processing and linking of all data collected. The results of the study will be presented at national and international conferences and published in specialist journals.

TRIAL REGISTRATION NUMBER: DRKS00033482.}, } @article {pmid39938752, year = {2025}, author = {Zhu, Y and Tian, M and Lu, S and Qin, Y and Zhao, T and Shi, H and Li, Z and Qin, D}, title = {The antioxidant role of aromatic plant extracts in managing neurodegenerative diseases: A comprehensive review.}, journal = {Brain research bulletin}, volume = {222}, number = {}, pages = {111253}, doi = {10.1016/j.brainresbull.2025.111253}, pmid = {39938752}, issn = {1873-2747}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Antioxidants/therapeutic use/pharmacology ; *Plant Extracts/therapeutic use/pharmacology ; *Oxidative Stress/drug effects ; Animals ; Flavonoids/therapeutic use/pharmacology ; Polyphenols/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative diseases (NDDs) are a class of cognitive and motor disorders including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), and others. They are caused by lesions in cells and tissues of the central nervous system, resulting in corresponding dysfunctions and consequent decline in cognitive and motor functions. Neural tissues are extremely vulnerable to oxidative stress, which plays critical biological roles in NDDs. Aromatic compounds are found extensively in natural plants and have substantial effects of anti-oxidative stress damage, which not only have a wide range of research applications in cosmetics, foods, etc., but are also frequently utilized in the treatment of various central nervous system diseases. This review summarizes the relevant oxidative stress mechanisms in NDDs (AD, PD, HD, and ALS) and reviews aromatic compounds such as polyphenols, terpenoids, and flavonoids that can be used in the management of neurodegenerative diseases, as well as their specific mechanisms of antioxidant action. This review will serve as a reference for future experimental studies on neurodegenerative illnesses while also offering fresh insights into clinical therapy.}, } @article {pmid39937422, year = {2025}, author = {Grassano, M and Chiò, A}, title = {microRNA in ALS: finally ready for prime time?.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {4}, pages = {1463-1464}, pmid = {39937422}, issn = {1590-3478}, } @article {pmid39936986, year = {2025}, author = {Ramírez, OA and Hellwig, A and Zhang, Z and Bading, H}, title = {Pharmacological Targeting of the NMDAR/TRPM4 Death Signaling Complex with a TwinF Interface Inhibitor Prevents Excitotoxicity-Associated Dendritic Blebbing and Organelle Damage.}, journal = {Cells}, volume = {14}, number = {3}, pages = {}, pmid = {39936986}, issn = {2073-4409}, mesh = {*Receptors, N-Methyl-D-Aspartate/metabolism ; *Dendrites/drug effects/metabolism ; Animals ; *TRPM Cation Channels/metabolism ; *Mitochondria/metabolism/drug effects ; *Signal Transduction/drug effects ; Endoplasmic Reticulum/metabolism/drug effects ; Humans ; Calcium/metabolism ; Organelles/metabolism/drug effects ; Neurons/drug effects/metabolism/pathology ; Rats ; N-Methylaspartate/pharmacology/toxicity ; Calcium Signaling/drug effects ; }, abstract = {Focal swellings of dendrites ("dendritic blebbing") together with structural damage of mitochondria and the endoplasmic reticulum (ER) are morphological hallmarks of glutamate neurotoxicity, also known as excitotoxicity. These pathological alterations are generally thought to be caused by the so-called "overactivation" of N-methyl-D-aspartate receptors (NMDARs). Here, we demonstrate that the activation of extrasynaptic NMDARs, specifically when forming a protein-protein complex with TRPM4, drives these pathological traits. In contrast, strong activation of synaptic NMDARs fails to induce cell damage despite evoking plateau-type calcium signals that are comparable to those generated by activation of the NMDAR/TRPM4 complex, indicating that high intracellular calcium levels per se are not toxic to neurons. Using confocal laser scanning microscopy and transmission electron microscopy, we show that disrupting the NMDAR/TRPM4 complex using the recently discovered small-molecule TwinF interface inhibitor FP802 inhibits the NMDA-induced neurotoxicity-associated dendritic blebbing and structural damage to mitochondria and the ER. It also prevents, at least in part, the disruption of ER-mitochondria contact sites. These findings establish the NMDAR/TRPM4 complex as the trigger for the structural damage of dendrites and intracellular organelles associated with excitotoxicity. They also suggest that activation of the NMDAR/TRPM4 complex, in addition to inducing high-amplitude, plateau-type calcium signals, generates a second signal required for glutamate neurotoxicity ("two-hit hypothesis"). As structural damage to organelles, particularly mitochondria, is a common feature of many human neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis (ALS), TwinF interface inhibitors have the potential to provide neuroprotection across a broad spectrum of these diseases.}, } @article {pmid39936815, year = {2025}, author = {Mendes, RA and Lima, ILB and Dourado Júnior, MET and Gonçalves, MJ}, title = {Is there a decline in speech and swallowing in Amyotrophic Lateral Sclerosis over ten years?.}, journal = {CoDAS}, volume = {37}, number = {2}, pages = {e20240159}, pmid = {39936815}, issn = {2317-1782}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Female ; Retrospective Studies ; *Deglutition Disorders/physiopathology/etiology ; Middle Aged ; Longitudinal Studies ; *Disease Progression ; Aged ; Speech Disorders/etiology/physiopathology ; Adult ; Dysarthria/etiology/physiopathology ; Deglutition/physiology ; Time Factors ; Cohort Studies ; }, abstract = {PURPOSE: To analyze the evolution of speech and swallowing decline in patients with amyotrophic lateral sclerosis (ALS) over a ten-year period.

METHODS: A retrospective and longitudinal cohort study. Data were collected using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) from 101 medical records of ALS patients treated at the multidisciplinary neuromuscular diseases clinic of a University Hospital over a ten-year period. The data were statistically analyzed, adopting a significance level of p<0.05.

RESULTS: The analysis of the studied functions indicated that speech, swallowing, and salivation are altered over ten years in ALS. There are differences in patterns between the variables sex and disease type concerning symptoms related to dysarthria and dysphagia in these individuals, which may indicate the rate of progression over a given time interval.

CONCLUSION: There is a decline in speech and swallowing over ten years in ALS. The bulbar type leads to a faster decline in the studied functions than the spinal type.}, } @article {pmid39936380, year = {2025}, author = {Lero, CM and Yang, A and Everett, E and Pitzer, KA and McCoy Gross, K and Washington, KT}, title = {Associations Between End-Stage ALS Care and Specialty Palliative Care: A Hypothesis-Generating Study.}, journal = {Muscle & nerve}, volume = {71}, number = {4}, pages = {632-638}, pmid = {39936380}, issn = {1097-4598}, support = {T32 MH019960/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/mortality ; Male ; Female ; *Palliative Care ; Middle Aged ; Aged ; Terminal Care ; Hospice Care ; Aged, 80 and over ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) care is typically delivered via a multidisciplinary approach that may include specialty palliative care (SPC). Opportunities for SPC to enhance ALS care have been identified; however, investigation of these proposed benefits is scant. In this exploratory study, investigators examined associations between receipt of SPC and variables particularly relevant to end-stage ALS.

METHODS: Researchers reviewed electronic health records for all patients with ALS who received standard ALS care from one Midwestern US academic medical center and died between January 1, 2020, and June 30, 2022 (N = 156). Receipt of SPC, duration of illness, hospice enrollment and length of service, report of a healthcare proxy, documentation of a healthcare proxy, participation in goals of care conversations, and location of death were examined.

RESULTS: Patients who received SPC (59%), had lower mean forced vital capacity (FVC) (p < 0.05), and more often used respiratory support (p < 0.001), participated in goals of care conversations (p < 0.001), reported a healthcare proxy (p < 0.01), and enrolled in hospice (p < 0.001) than patients who received standard care alone. No differences between groups were found in duration of illness (mean = 51.7 months), use of assistive feeding, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores (mean = 32.1), documentation of a healthcare proxy, length of hospice stay (mean = 47.3 days), or location of death.

DISCUSSION: Clinical characteristics and end-of-life outcome differences between groups support further investigation of the proposed benefits of SPC regarding hospice enrollment, report of healthcare proxies, and documented goals of care conversations.}, } @article {pmid39936266, year = {2025}, author = {Denton, TT and Carter, GT and Goddard, M and Weiss, J and Weeks, DL and Weydt, P and Russo, EB and Weiss, MD}, title = {Amyotrophic Lateral Sclerosis, the Endocannabinoid System, and Exogenous Cannabinoids: Current State and Clinical Implications.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28359}, pmid = {39936266}, issn = {1097-4598}, abstract = {A unifying mechanistic cause for amyotrophic lateral sclerosis (ALS) remains uncertain. Multiple pathophysiological processes appear to occur simultaneously. Cannabinoids, including delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), and others found in cannabis, and cannabis extracts (CEs), appear to have activity in these pathogenic pathways, which have led to increasing interest in cannabinoids as therapeutic agents for ALS. The use of cannabinoids as a treatment strategy is substantiated by preclinical evidence suggesting a role for the endocannabinoid system (ECS) in ALS and other neurodegenerative disorders. Preclinical data indicate that cannabis and CEs have powerful antioxidative, anti-inflammatory, and neuroprotective effects in the SOD1[G93A] mouse model of ALS. The use of CEs in SOD1[G93A] murine models has been shown to prolong neuronal cell survival, which leads to delayed onset of the disease state, and slows progression of the disease. Although research in humans remains limited, a few studies suggest that cannabis and CBD, in humans, provide benefits for both motor symptoms, including rigidity, cramps, and fasciculations, and non-motor symptoms including sleep quality, pain, emotional state, quality of life, and depression. There remains a need for further, well-designed clinical trials to validate further the use of an individual cannabinoid, or a combination of cannabinoids, as a disease-modifying therapy for ALS.}, } @article {pmid39936211, year = {2025}, author = {Naveed, A and Usmani, WA and Vandara, MP and Karmani, VK}, title = {Tofersen for Amyotrophic Lateral Sclerosis: A Step Forward or Another False Hope?.}, journal = {Journal of the College of Physicians and Surgeons--Pakistan : JCPSP}, volume = {35}, number = {2}, pages = {259-260}, doi = {10.29271/jcpsp.2025.02.259}, pmid = {39936211}, issn = {1681-7168}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Treatment Outcome ; }, abstract = {Null.}, } @article {pmid39936179, year = {2025}, author = {Morrison, AH and Jimenez, JV and Hsu, JY and Elman, L and Choi, PJ and Ackrivo, J}, title = {Identifying Daytime Hypercapnia Using Transcutaneous Carbon Dioxide Monitoring in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {71}, number = {4}, pages = {611-619}, pmid = {39936179}, issn = {1097-4598}, support = {K23 HL151879/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/physiopathology ; *Hypercapnia/blood/diagnosis ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; *Blood Gas Monitoring, Transcutaneous/methods ; *Carbon Dioxide/blood ; Respiratory Function Tests ; Vital Capacity/physiology ; Adult ; }, abstract = {INTRODUCTION/AIMS: Respiratory failure from hypoventilation is the most common cause of death in amyotrophic lateral sclerosis (ALS). However, ALS care rarely assesses hypercapnia, a physiologic measure of hypoventilation. We investigated the prevalence and clinical significance of daytime hypercapnia measured by transcutaneous carbon dioxide (tcCO2) monitoring in patients with ALS.

METHODS: This retrospective study included patients seen at two ALS clinics in the United States between 2012 and 2024 who had tcCO2 measured concurrently with pulmonary function tests (PFTs), which included forced vital capacity (FVC) and, at one site, maximum inspiratory pressure (MIP). We assessed the prevalence of hypercapnia (tcCO2 > 45 mmHg), the sensitivity and specificity of patient symptoms and PFTs for hypercapnia, and the relationship between hypercapnia and survival.

RESULTS: Daytime hypercapnia was present in 33/328 (10%) patients at baseline. Hypercapnia was associated with an increased rate of death (aHR 2.1, 95% CI 1.4-3.3). Orthopnea or dyspnea was 70% sensitive for hypercapnia (95% CI 51%-84%). Absolute value of MIP (|MIP|) < 60 cmH2O was 95% sensitive (95% CI 74%-100%) and 22% specific (95% CI 16%-30%), FVC < 50% predicted was 33% sensitive (95% CI 18%-52%) and 82% specific (95% CI 78%-87%), and FVC < 80% predicted was 85% sensitive (95% CI 68%-95%) and 31% specific (95% CI 26%-36%) for hypercapnia.

DISCUSSION: TcCO2 monitoring identified strengths and weaknesses of PFTs in identifying hypercapnia in ALS. We found high sensitivity of |MIP| < 60 cmH2O and FVC < 80% predicted and high specificity of FVC < 50% predicted. Prospective studies should investigate the optimal clinical role for tcCO2.}, } @article {pmid39935503, year = {2025}, author = {Tsuruta, M and Shil, S and Taniguchi, S and Kawauchi, K and Miyoshi, D}, title = {The role of cytosine methylation in regulating the topology and liquid-liquid phase separation of DNA G-quadruplexes.}, journal = {Chemical science}, volume = {16}, number = {10}, pages = {4213-4225}, pmid = {39935503}, issn = {2041-6520}, abstract = {Aberrant expansion of GGGGCC DNA repeats that form G-quadruplexes (G4) is the main cause of amyotrophic lateral sclerosis (ALS). Expanded GGGGCC repeats induce liquid-liquid phase separation (LLPS) through their interaction with cellular proteins. Furthermore, GGGGCC expansion induces cytosine methylation (mC). Previous studies have shown that even slight chemical modifications of RNAs and proteins can drastically affect their LLPS ability, yet the relationship between LLPS and epigenetic DNA modifications like mC remains unexplored. As a model system, we investigated the effects of mC on LLPS induced by GGGGCC repeat DNAs and show for the first time that mC suppresses LLPS by altering the topology of G4 from being parallel to antiparallel.}, } @article {pmid39933444, year = {2025}, author = {Rob, M and Yousef, M and Lakshmanan, AP and Mahboob, A and Terranegra, A and Chaari, A}, title = {Microbial signatures and therapeutic strategies in neurodegenerative diseases.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {184}, number = {}, pages = {117905}, doi = {10.1016/j.biopha.2025.117905}, pmid = {39933444}, issn = {1950-6007}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/microbiology ; *Gastrointestinal Microbiome ; Dysbiosis/microbiology ; Probiotics/therapeutic use ; Animals ; Metabolome ; Fecal Microbiota Transplantation ; Machine Learning ; Biomarkers/metabolism ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), arise from complex interactions between genetic factors, environmental exposures, and aging. Additionally, gut dysbiosis has been linked to systemic inflammation and neurodegeneration. Advances in microbiome and metabolome profiling techniques have provided deeper insights into how alterations in gut microbiota and dietary patterns affect metabolic pathways and contribute to the progression of NDs. This review explores the profiles of gut microbiome and metabolome derived biomarkers and their roles in NDs. Across phyla, families, and genera, we identified 55 microbial alterations in PD, 24 in AD, 4 in ALS, and 17 in MS. Some notable results include an increase in Akkermansia in PD, AD, and MS and a decrease in short-chain fatty acids (SCFAs) in PD and AD. We examined the effects of probiotics, prebiotics, fecal microbiota transplants (FMT), sleep, exercise, and diet on the microbiota, all of which contributed to delayed onset and alleviation of symptoms. Further, artificial intelligence (AI) and machine learning (ML) algorithms applied to omics data have been crucial in identifying novel therapeutic targets, diagnosing and predicting prognosis, and enabling personalized medicine using microbiota-modulating therapies in NDs patients.}, } @article {pmid39933412, year = {2025}, author = {Noli, B and Borghero, G and Mascia, MM and Hkir, M and Puligheddu, M and Cocco, C}, title = {NERP-1 modifications in amyotrophic lateral sclerosis.}, journal = {Tissue & cell}, volume = {93}, number = {}, pages = {102780}, doi = {10.1016/j.tice.2025.102780}, pmid = {39933412}, issn = {1532-3072}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/blood/pathology ; Humans ; Male ; Female ; Middle Aged ; Aged ; Motor Neurons/metabolism/pathology ; Nerve Growth Factors/metabolism/blood ; Oxidative Stress ; Cell Line ; Adult ; Protein Precursors/metabolism ; Nerve Growth Factor ; }, abstract = {VGF peptides, such as NERPs (neuroendocrine regulatory peptides 1 and 2), are derived from amino acids 282-306 and 313-350, respectively, of the human proVGF, which is produced in spinal cord motor neurons. Although certain VGF-derived peptides are changed in ALS, less is known about NERPs. Possible modulations of NERPs and additional VGF peptides (NAPP and TPGH) were investigated using specific antibodies through competitive ELISA in the plasma of ALS patients (at both the initial and advanced phases; n = 46 each vs. 46 controls). As additional controls, naïve PD patients were also enrolled (n = 19 vs. 18 controls) while the potential VGF peptide role in oxidative stress was investigated using a motoneuron-like cell line (NSC34) stressed with sodium arsenate (SA). Western blot (WB) and sephadex chromatography (SC) were used to identify the molecular weight (MW) forms recognized by the VGF antibodies. Exclusively NERP-1 immunoreactivity was changed (elevated) in all plasma samples of ALS patients (compared to controls). Therefore, the NERP-1 antibody was the sole antibody used in ELISA with PD samples and NSC-34 cells. No alterations were seen in PD samples (vs. controls) while NERP-1 immunoreactivity decreased within SA-treated cells but increased in their culture medium. The viability test performed by adding NERP-1 to the stressed cells showed no protective effect. Using WB and SC, we revealed NERP-1 antibody reactivity against various MW forms, including those compatible with the NERP-1 peptide and/or proVGF. NERP-1 is suggested as a possible ALS blood biomarker.}, } @article {pmid39933343, year = {2025}, author = {Hatamli, K and Eritja, R and Giménez, E and Benavente, F and Gargallo, R}, title = {Resolution of complex mixtures of duplex and antiparallel triplex DNA structures by capillary electrophoresis and multivariate analysis.}, journal = {Talanta}, volume = {288}, number = {}, pages = {127616}, doi = {10.1016/j.talanta.2025.127616}, pmid = {39933343}, issn = {1873-3573}, mesh = {*Electrophoresis, Capillary/methods ; *DNA/chemistry/analysis ; Multivariate Analysis ; Nucleic Acid Conformation ; Spectrophotometry, Ultraviolet ; }, abstract = {Triplex DNA structures, which are formed by the addition of an extra strand to a target B-DNA duplex, have attracted increasing interest due to their analytical and therapeutic applications. These structures are classified into parallel and antiparallel, depending on the orientation of the Triplex-Forming Oligonucleotide (TFO) relative to the B-DNA duplex. Whereas the formation of parallel triplexes is easily detected by monitoring spectral changes in the UV region, the formation of antiparallel triplexes produces small or even no spectral variations, which makes their detection difficult and uncertain. In this study, we propose the use of capillary electrophoresis with ultraviolet absorption spectrophotometric (CE-UV) detection combined with the multivariate curve resolution-alternating least squares (MCR-ALS) chemometric method to analyse mixtures of DNA sequences capable of forming mixtures of B-DNA duplex and triplex antiparallel structures. Rapid and reproducible CE-UV analysis in hydroxypropylcellulose (HPC)-coated capillaries are done in a pH 7.4 buffer containing Mg(II) for the stabilization of the intermolecular species. Spectra measured from 220 to 300 nm along the CE-UV analysis of individual DNA strands and of their mixtures at different ratios are merged into an augmented data matrix. This is later analyzed with MCR-ALS to deconvolute characteristic pure spectra and electropherograms for each one of the CE-UV analysis considered. This procedure has allowed the resolution and detection of DNA species present in mixtures of DNA strands capable of forming duplexes, as well as antiparallel triplex structures.}, } @article {pmid39933303, year = {2025}, author = {Zeng, JY and Huang, HW and Zhuang, SP and Wu, Y and Chen, S and Zou, ZY and Chen, HJ}, title = {Soma and neurite density imaging detects brain microstructural impairments in amyotrophic lateral sclerosis.}, journal = {European journal of radiology}, volume = {184}, number = {}, pages = {111981}, doi = {10.1016/j.ejrad.2025.111981}, pmid = {39933303}, issn = {1872-7727}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Female ; Male ; Middle Aged ; *Neurites/pathology ; Adult ; Aged ; Brain/diagnostic imaging/pathology ; Diffusion Tensor Imaging/methods ; Diffusion Magnetic Resonance Imaging/methods ; }, abstract = {OBJECTIVE: To investigate whole-brain microstructural changes in amyotrophic lateral sclerosis (ALS) using soma and neurite density imaging (SANDI), a novel multicompartment model of diffusion-weighted imaging that estimates apparent soma and neurite density.

METHODS: This study consists of 41 healthy controls and 43 patients with ALS, whose diffusion-weighted data were acquired. The SANDI-derived (including signal fractions of soma (fsoma), neurite (fneurite), and extra-cellular space (fextra)) and diffusion tensor imaging (DTI)-derived metrics were obtained. Voxel-based analyses were performed to evaluate intergroup differences and the correlation of SANDI and DTI metrics with clinical parameters.

RESULTS: In ALS patients, fneurite reduction involved both gray matter (primarily the bilateral precentral gyri, supplementary motor area, medial frontal gyrus, anterior cingulate cortex, inferior frontal gyrus, orbital gyrus, paracentral lobule, postcentral gyrus, middle cingulate cortex, hippocampus and parahippocampal gyrus, and insula, and left anterior parts of the temporal lobe) and white matter (primarily the bilateral corticospinal tract, body of corpus callosum, and brainstem) (P <0.05 after false discovery rate correction). The fextra increment showed a similar spatial distribution in ALS patients. Interestingly, the decreased fsoma in ALS primarily located in gray matter; while, the increased fsoma primarily involved white matter. The spatial distribution of fneurite/fextra/fsoma changes was larger than that detected by conventional DTI metrics, and the fneurite/fextra/fsoma were correlated with disease severity.

CONCLUSIONS: SANDI may serve as a clinically relevant model, superior to conventional DTI, for characterizing microstructural impairments such as neurite degeneration and soma alteration in ALS.}, } @article {pmid39933302, year = {2025}, author = {Li, H and Qiao, Z and Xiao, X and Cao, X and Li, Z and Liu, M and Jiao, Q and Chen, X and Du, X and Jiang, H}, title = {G protein-coupled receptors: A golden key to the treasure-trove of neurodegenerative diseases.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {46}, number = {}, pages = {155-168}, doi = {10.1016/j.clnu.2025.01.032}, pmid = {39933302}, issn = {1532-1983}, mesh = {Humans ; *Receptors, G-Protein-Coupled/metabolism ; *Neurodegenerative Diseases/drug therapy ; *Signal Transduction/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Animals ; Parkinson Disease/drug therapy/metabolism ; }, abstract = {G protein-coupled receptors (GPCRs) are a class of transmembrane proteins that distribute in various organs extensively. They can regulate physiological functions such as perception, neurotransmission and endocrinology through the synergies of signaling pathways. At present, Food and Drug Administration (FDA) have approved more than 500 drugs targeting GPCRs to treat a variety of conditions, including neurological diseases, gastrointestinal diseases and tumors. Conformational diversity and dynamic changes make GPCRs a star target for the treatment of neurodegenerative diseases. Moreover, GPCRs can also open biased signaling pathways for G protein and β-arrestin, which has unique functional selectivity and the possibility of overcoming side effects. Some studies believe that biased drugs will be the mainstream direction of drug innovation in the future. To disclose the essential role and research process of GPCRs in neurodegenerative diseases, we firstly reviewed several pivotal GPCRs and their mediated signaling pathways in Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Then we focused on the biased signaling pathway of GPCRs in these diseases. Finally, we updated the GPCR drugs under research for the treatment of neurodegenerative diseases in the clinical trials or approval. This review could provide valuable targets for precision therapy to cope with the dysfunction of neurodegenerative diseases in the future.}, } @article {pmid39932579, year = {2025}, author = {Ando, M and Higuchi, Y and Yuan, JH and Yoshimura, A and Yano, C and Hobara, T and Kojima, F and Hiramatsu, Y and Nozuma, S and Nakamura, T and Sakiyama, Y and Hashiguchi, A and Okamoto, Y and Matsushige, T and Mitsui, J and Tsuji, S and Takashima, H}, title = {SOD1-related inherited peripheral neuropathies in a Japanese cohort: genetic variants and clinical insights.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {191}, pmid = {39932579}, issn = {1432-1459}, support = {2016100002B//Ministry of Health, Labour and Welfare/ ; 201442014A//Agency for Medical Research and Development/ ; 201442071A//Agency for Medical Research and Development/ ; 18H02742//JSPS KAKENHI/ ; 20K16604//JSPS KAKENHI/ ; 21K15702//JSPS KAKENHI/ ; 21H02842//JSPS KAKENHI/ ; 22K15713//JSPS KAKENHI/ ; 22K07495//JSPS KAKENHI/ ; 22K07519//JSPS KAKENHI/ ; 23K06931//JSPS KAKENHI/ ; }, mesh = {Humans ; Male ; Female ; *Superoxide Dismutase-1/genetics ; Middle Aged ; Japan ; Adult ; Cohort Studies ; Aged ; *Peripheral Nervous System Diseases/genetics/diagnosis/physiopathology ; East Asian People ; }, abstract = {BACKGROUND: Inherited peripheral neuropathies (IPNs) encompass a wide range of disorders affecting the peripheral nervous system, often with complex genetic causes and frequent underdiagnosis. The variants in the superoxide dismutase 1 (SOD1) gene, primarily linked to amyotrophic lateral sclerosis (ALS), have also been associated with peripheral neuropathy. The recent approval of Tofersen, targeting SOD1-related ALS, highlights the importance of precise genetic diagnosis. This study explores the clinical and genetic profiles of SOD1-related IPNs (SOD1-IPN) in a nationwide Japanese IPN cohort.

METHODS: Clinical and genetic data were assessed from 1483 Japanese patients with IPN, with a focus on those harboring SOD1 pathogenic variants. The clinical evaluations included age of onset, gender, muscle weakness patterns, sensory disturbances, reflex responses, and electrophysiological findings.

RESULTS: Seventeen patients with SOD1 pathogenic variants were identified, reinforcing SOD1's role in IPN. The average onset age was 47, with a slight male predominance. Distal muscle weakness was noted in 9 of 13 patients, and asymmetric muscle weakness and atrophy in 10 of 14 cases. Mild sensory disturbances were observed in eight patients, with some showing hyperreflexia and abnormal reflexes. Electrophysiology predominantly indicated a length-dependent, motor-dominant axonal neuropathy.

CONCLUSION: This study reveals the clinical variability and likely underdiagnosis of SOD1-IPN, supporting the integration of SOD1 screening in IPN genetic testing, especially for patients with asymmetric, length-dependent axonal neuropathy evident in clinical and electrophysiological assessments.}, } @article {pmid39932195, year = {2025}, author = {Ruggieri, V and Scaricamazza, S and Bracaglia, A and D'Ercole, C and Parisi, C and D'Angelo, P and Proietti, D and Cappelletti, C and Macone, A and Lozanoska-Ochser, B and Bouchè, M and Latella, L and Valle, C and Ferri, A and Giordani, L and Madaro, L}, title = {Polyamine metabolism dysregulation contributes to muscle fiber vulnerability in ALS.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115123}, doi = {10.1016/j.celrep.2024.115123}, pmid = {39932195}, issn = {2211-1247}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Animals ; *Muscle Fibers, Skeletal/metabolism/pathology ; Mice ; *Polyamines/metabolism ; *Mice, Transgenic ; Disease Models, Animal ; Humans ; Homeostasis ; Superoxide Dismutase-1/metabolism/genetics ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease causing progressive paralysis due to motor neuron degeneration with no curative therapy despite extensive biomedical research. One of the primary targets of ALS is skeletal muscle, which undergoes profound functional changes as the disease progresses. To better understand how altered innervation interferes with muscle homeostasis during disease progression, we generated a spatial transcriptomics dataset of skeletal muscle in the SOD1[G93A] mouse model of ALS. Using this strategy, we identified polyamine metabolism as one of the main altered pathways in affected muscle fibers. By establishing a correlation between the vulnerability of muscle fibers and the dysregulation of this metabolic pathway, we show that disrupting polyamine homeostasis causes impairments similar to those seen in ALS muscle. Finally, we show that restoration of polyamine homeostasis rescues the muscle phenotype in SOD1[G93A] mice, opening new perspectives for the treatment of ALS.}, } @article {pmid39931973, year = {2025}, author = {Xu, C and Diemant, T and Zhang, S and Liu, X and Passerini, S}, title = {Enhanced Cathode-Electrolyte Interphase for Prolonged Cycling Stability of Aluminum-Selenium Batteries Using Locally Concentrated Ionic Liquid Electrolytes.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {}, number = {}, pages = {e202500041}, doi = {10.1002/anie.202500041}, pmid = {39931973}, issn = {1521-3773}, support = {//China Sponsorship Council/ ; //China Scholarship Council/ ; //Helmholtz Association/ ; Start-up Research Fund of Southeast University4003002418//Start-up Research Fund of Southeast University/ ; }, abstract = {Al-Se batteries (ASeBs) with high theoretical specific capacity and discharge voltage are promising energy storage devices. However, the detrimental shuttle effect occurring in conventional ionic liquid electrolytes (ILEs) challenges their development. Herein, a thicker cathode/electrolyte interphase (CEI) is constructed via employing locally concentrated IL electrolytes (LCILEs) to overcome these issues. It is demonstrated that LCILEs facilitate the incorporation of Emim[+] into the electrode/electrolyte interphases, and, meanwhile, more Al-Cl species deposits are observed in the CEI. The formed CEI effectively prevents the dissolution of poly-selenides, inhibiting their related parasitic reactions. These result in ASeBs, employing the LCILE, to deliver a specific discharge capacity of 218 mAh g[-1] at 0.5 A g[-1] after 100 cycles at 20 °C, while the cell using the neat ILE only maintains 38 mAh g[-1] under the same conditions. Moreover, an Al-S cell operated in LCILEs reaches 578 mAh g[-1] at 0.1 A g[-1] after 150 cycles, which is also significantly better than 317 mAh g[-1] in the neat ILE. This study provides an LCILE-based strategy to reinforce the CEI in order to suppress the shuttle effect, realizing Al-chalcogen batteries with better performance.}, } @article {pmid39930680, year = {2025}, author = {Guzanova, EV and Sorokina, TA and Zorkova, AV}, title = {[Nutritional care for patients with neurodegenerative diseases in the outpatient practice of a neurologist].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {125}, number = {1}, pages = {76-83}, doi = {10.17116/jnevro202512501176}, pmid = {39930680}, issn = {1997-7298}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/complications ; *Malnutrition/therapy ; *Ambulatory Care ; Neurologists ; Nutritional Support/methods ; Dehydration/therapy/etiology ; Amyotrophic Lateral Sclerosis/therapy/complications ; Aged ; Outpatients ; }, abstract = {Nutrition is a basic factor of health and well-being of people, affecting the quality and duration of life. Meanwhile, patients with neurodegenerative diseases of the central nervous system are particularly at risk of malnutrition and dehydration with serious health consequences. The article presents an analysis of the main causes of malnutrition in patients with neurodegenerative diseases, and considers a clinical case of including additional nutritional support in the comprehensive management of a patient with amyotrophic lateral sclerosis. The importance of screening elderly patients for the risks of malnutrition and dehydration during an outpatient medical appointment and including appropriate additional diagnostic and therapeutic (additional enteral nutrition and fluid regimen) measures in the work of an outpatient neurologist is emphasized.}, } @article {pmid39929612, year = {2025}, author = {Chen, BL and Lu, JZ and Zhou, XM and Wen, XD and Jiang, YJ and Luo, N}, title = {[Mechanism of Daotan Xixin Decoction in treating APP/PS1 mice based on high-throughput sequencing technology and bioinformatics analysis].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {2}, pages = {301-313}, doi = {10.19540/j.cnki.cjcmm.20241011.401}, pmid = {39929612}, issn = {1001-5302}, mesh = {Animals ; Mice ; *Drugs, Chinese Herbal/pharmacology/administration & dosage ; Male ; *Computational Biology ; *Mice, Inbred C57BL ; *Alzheimer Disease/drug therapy/genetics/metabolism ; *Hippocampus/drug effects/metabolism ; Mice, Transgenic ; High-Throughput Nucleotide Sequencing ; Amyloid beta-Peptides/metabolism/genetics ; Memory/drug effects ; Amyloid beta-Protein Precursor/genetics/metabolism ; Signal Transduction/drug effects ; }, abstract = {This study aims to investigate the therapeutic effect and mechanism of Daotan Xixin Decoction on APP/PS1 mice. Twelve APP/PS1 male mice were randomized into four groups: APP/PS1 and low-, medium-, and high-dose Daotan Xixin Decoction. Three C57BL/6 wild-type mice were used as the control group. The learning and memory abilities of mice in each group were examined by the Morris water maze test. The pathological changes of hippocampal nerve cells were observed by hematoxylin-eosin staining and Nissl staining. Immunohistochemistry was employed to detect the expression of β-amyloid(Aβ)_(1-42) in the hippocampal tissue. The high-dose Daotan Xixin Decoction group with significant therapeutic effects and the model group were selected for high-throughput sequencing. The differentially expressed gene(DEG) analysis, Gene Ontology(GO) analysis, Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis, and Gene Set Variation Analysis(GSVA) were performed on the sequencing results. RT-qPCR and Western blot were conducted to determine the mRNA and protein levels, respectively, of some DEGs. Compared with the APP/PS1 group, Daotan Xixin Decoction at different doses significantly improved the learning and memory abilities of APP/PS1 mice, ameliorated the neuropathological damage in the CA1 region of the hippocampus, increased the number of neurons, and decreased the deposition of Aβ_(1-42) in the brain. A total of 1 240 DEGs were screened out, including 634 genes with up-regulated expression and 606 genes with down-regulated expression. The GO analysis predicted the biological processes including RNA splicing and protein folding, the cellular components including spliceosome complexes and nuclear spots, and the molecular functions including unfolded protein binding and heat shock protein binding. The KEGG pathway enrichment analysis revealed the involvement of neurodegenerative disease pathways, amyotrophic lateral sclerosis, and splicing complexes. Further GSVA pathway enrichment analysis showed that the down-regulated pathways involved nuclear factor-κB(NF-κB)-mediated tumor necrosis factor-α(TNF-α) signaling pathway, UV response, and unfolded protein response, while the up-regulated pathways involved the Wnt/β-catenin signaling pathway. The results of RT-qPCR and Western blot showed that compared with the APP/PS1 group, Daotan Xixin Decoction at different doses down-regulated the mRNA and protein levels of signal transducer and activator of transcription 3(STAT3), NF-κB, and interleukin-6(IL-6) in the hippocampus. In conclusion, Daotan Xixin Decoction can improve the learning and memory abilities of APP/PS1 mice by regulating the STAT3/NF-κB/IL-6 signaling pathway.}, } @article {pmid39929585, year = {2025}, author = {Huang, M and Stremlau, M and Zavras, J and Zivko, C and Thomas, AG and Pietri, P and Machairaki, V and Slusher, BS}, title = {Neutral sphingomyelinase 2: A promising drug target for CNS disease.}, journal = {Advances in pharmacology (San Diego, Calif.)}, volume = {102}, number = {}, pages = {65-101}, doi = {10.1016/bs.apha.2024.10.015}, pmid = {39929585}, issn = {1557-8925}, mesh = {Humans ; *Sphingomyelin Phosphodiesterase/metabolism/antagonists & inhibitors ; Animals ; *Central Nervous System Diseases/drug therapy/metabolism/enzymology ; Enzyme Inhibitors/pharmacology/therapeutic use ; Molecular Targeted Therapy ; }, abstract = {Neutral sphingomyelinase 2 (nSMase2), encoded by the SMPD3 gene, is a pivotal enzyme in sphingolipid metabolism, hydrolyzing sphingomyelin to produce ceramide, a bioactive lipid involved in apoptosis, inflammation, membrane structure, and extracellular vesicle (EV) biogenesis. nSMase2 is abundantly expressed in the central nervous system (CNS), particularly in neurons, and its dysregulation is implicated in pathologies such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), prion diseases, and neuroviral diseases. In this review, we discuss the critical role of nSMase2 in the CNS and its involvement in neurological as well as non-neurological diseases. We explore the enzyme's functions in sphingolipid metabolism, its regulatory mechanisms, and the implications of its dysregulation in disease pathogenesis. The chapter highlights the therapeutic potential of pharmacologically targeting nSMase2 with small molecule inhibitors and emphasizes the need for further research to optimize inhibitor specificity and efficacy for clinical applications. By understanding the multifaceted roles of nSMase2, we aim to provide insights into novel therapeutic strategies for treating complex diseases associated with its dysregulation.}, } @article {pmid39929580, year = {2025}, author = {Matheoudakis, K and O'Connor, JJ}, title = {Modulatory and protective effects of prolyl hydroxylase domain inhibitors in the central nervous system.}, journal = {Advances in pharmacology (San Diego, Calif.)}, volume = {102}, number = {}, pages = {211-235}, doi = {10.1016/bs.apha.2024.10.006}, pmid = {39929580}, issn = {1557-8925}, mesh = {Humans ; Animals ; *Prolyl-Hydroxylase Inhibitors/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Central Nervous System/metabolism/drug effects ; }, abstract = {Oxygen is essential for all mammalian species, with complex organs such as the brain requiring a large and steady supply to function. During times of low or inadequate oxygen supply (hypoxia), adaptation is required in order to continue to function. Hypoxia inducible factors (HIF) are transcription factors which are activated during hypoxia and upregulate protective genes. Normally, when oxygen levels are sufficient (normoxia) HIFs are degraded by oxygen sensing prolyl hydroxylase domain proteins (PHD), but during hypoxia PHDs no longer exert influence on HIFs allowing their activation. Given that PHDs regulate the activity of HIFs, their pharmacological inhibition through PHD inhibitors (PHDIs) is believed to be the basis of their neuroprotective benefits. This review discusses some of the potential therapeutic benefits of PHDIs in a number of neurological disorders which see hypoxia as a major pathophysiological mechanism. These include stroke, Parkinson's disease, and amyotrophic lateral sclerosis. We also explore the potential neuroprotective benefits and limitations of PHDIs in a variety of disorders in the central nervous system (CNS). Additionally, the activation of HIFs by PHDIs can have modulatory effects on CNS functions such as neurotransmission and synaptic plasticity, mechanisms critical to cognitive processes such as learning and memory.}, } @article {pmid39929112, year = {2025}, author = {Zhao, H and Liu, L and Zeng, Y and Nie, X and Wang, J and Bai, L and Pan, L}, title = {Identification of metabolic enzyme genes linked to mesosulfuron-methyl resistance in Bromus japonicus.}, journal = {Plant physiology and biochemistry : PPB}, volume = {221}, number = {}, pages = {109609}, doi = {10.1016/j.plaphy.2025.109609}, pmid = {39929112}, issn = {1873-2690}, mesh = {*Sulfonylurea Compounds/pharmacology ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Acetolactate Synthase/genetics/metabolism ; Plant Proteins/genetics/metabolism ; Cytochrome P-450 Enzyme System/genetics/metabolism ; Gene Expression Regulation, Plant/drug effects ; Genes, Plant ; }, abstract = {Bromus japonicus is a very troublesome weed in major winter wheat fields in China and substantially reduces wheat yield. Resistance to acetolactate synthase (ALS)-inhibiting herbicides in B. japonicus has become increasingly prevalent in recent years. While the mechanism of target site resistance (TSR) to ALS-inhibiting herbicides in B. japonicus has been well elucidated, the understanding of non-target site resistance (NTSR) remains limited. In this study, we identified a B. japonicus population (BJ-NTSR-1) which has developed resistance to mesosulfuron-methyl. Compared to the mesosulfuron-methyl-susceptible population (BJ-S), the resistance level of BJ-NTSR-1 was found to be 22.56 times higher. Based on the results of ALS gene sequencing and relative expression analyses, TSR was not detected in the BJ-NTSR-1 population. Additionally, pretreatment with cytochrome P450 (CYP450) and glutathione S-transferase (GST) inhibitors did not reverse the resistance to mesosulfuron-methyl in BJ-NTSR-1 population. RNA-seq and RT-qPCR analyses revealed that, three uridine 5'-diphospho-glucosyl transferase (UGT) genes (UGT76F1, UGT88F5, and UGT85A1), four ATP-binding cassette (ABC) transporter genes (ABCB19s, ABCG1, and ABCB21), and three CYP450 genes (CYP71C1, CYP71C2, and CYP72A15) are significantly upregulated in the BJ-NTSR-1 population. Among these genes, the overexpression of ABCG1 enhanced yeast resistance to mesosulfuron-methyl. These genes are likely involved in mediating NTSR to mesosulfuron-methyl in the BJ-NTSR-1 population. This study presents the first global report that CYP450, UGT, and ABC transporter genes may collectively mediate NTSR to ALS-inhibiting herbicides in Brome species.}, } @article {pmid39928509, year = {2025}, author = {Scafide, KN and Arundel, L and Assas, G and King, EL}, title = {Pressure injury detection using alternate light: a proof-of-concept study.}, journal = {Journal of wound care}, volume = {34}, number = {Sup2}, pages = {S17-S23}, doi = {10.12968/jowc.2023.0304}, pmid = {39928509}, issn = {0969-0700}, mesh = {Humans ; *Pressure Ulcer/diagnostic imaging ; Female ; Male ; Middle Aged ; *Proof of Concept Study ; Adult ; Aged ; Skin Pigmentation ; Light ; Ultrasonography ; Aged, 80 and over ; Contusions ; }, abstract = {OBJECTIVE: Identification of early-stage pressure injuries (PIs) during visual skin assessment may be subjective and unreliable. An alternate light source (ALS) has been shown to increase the probability of detecting evidence of bruises on individuals with darker skin tones. Bruises and early-stage PIs are often difficult to identify, especially in those with darker skin tones, where melanin concentration is high. Given the effect skin pigmentation has on detecting both types of cutaneous injuries, this proof-of-concept study aimed to describe the characteristics of Stage 1 PIs and deep tissue PIs as viewed under an ALS.

METHOD: Eligible participants were first examined by a certified wound ostomy continence nurse using environmentally available white light. A blinded second examiner then evaluated the size of the potential tissue impairment using violet (406nm) and blue (448nm) ALS viewed through yellow and orange goggles, respectively. Portable ultrasound was used to confirm tissue involvement. Data were summarised using descriptive statistics.

RESULTS: The study included 10 participants (40% of whom were from minority racial/ethnic groups) with a mean Braden Scale score of 11.1. The majority of PIs (80%) involved deep tissue and were located on lower extremities (60%). The median PI size was larger by 17.5cm[2] and 13.7cm[2], respectively, using ALS compared with white light when viewed under violet and blue wavelengths. Ultrasound data were limited to non-extremity regions (n=3 participants) with hypoechoic areas noted as being 10-13mm in thickness and up to 16.7mm deep.

CONCLUSION: Evidence of tissue damage that extended beyond that visualised under white light was noted with ALS. Usefulness of ultrasound was limited over bony prominences where there was too little subcutaneous tissue. Further research is warranted to investigate the potential application of ALS for the early detection of PIs.}, } @article {pmid39928236, year = {2025}, author = {Kaspute, G and Ramanavicius, A and Prentice, U}, title = {Natural drug delivery systems for the treatment of neurodegenerative diseases.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {217}, pmid = {39928236}, issn = {1573-4978}, support = {S-MIP-24-111//Research Council of Lithuania (LMTLT)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Drug Delivery Systems/methods ; *Biological Products/administration & dosage ; Blood-Brain Barrier/metabolism/drug effects ; Animals ; Liposomes ; Anti-Inflammatory Agents/administration & dosage ; Nanoparticles/chemistry ; }, abstract = {Today, herbal drugs are prominent in the pharmaceutical industry due to their well-known therapeutic and side effects. Plant-based compounds often face limitations such as poor solubility, low bioavailability, and instability in physiological environments, restricting their therapeutic efficacy and delivery. Nanotechnology-based solutions, including nanoparticle formulations and advanced delivery systems like liposomes and transfersomes, address these issues by enhancing solubility, stability, bioavailability, and targeted delivery, thereby optimizing the therapeutic potential of phytoactive compounds. Neuroinflammation can be a cause of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, or amyotrophic lateral sclerosis. Consequently, there is a need for the optimal delivery of a pharmacological anti-inflammatory agents to the CNS. Thus, the non-invasive administration of a stable compound at a therapeutic concentration is needed to assure molecule crossing through the blood-brain barrier. Natural resources have more structural diversity and novelty than synthetic compounds, e.g. plant-derived drug products have higher molecular weights, incorporate more oxygen atoms, and are more complex. As a result, plant-derived products have unique features which can be used to effectively modulate neuroinflammation. Therefore, this review aims to identify herbal molecules capable of targeting neuroinflammation and present novel strategies for their efficient delivery.}, } @article {pmid39927436, year = {2025}, author = {}, title = {Novel Biomarkers of FTD-ALS.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {31}, number = {1}, pages = {6}, doi = {10.1177/10738584241308752}, pmid = {39927436}, issn = {1089-4098}, } @article {pmid39926223, year = {2025}, author = {Moore, S and Donlon, NE}, title = {Improving gastrointestinal scoring systems for predicting short-term mortality in critically ill patients.}, journal = {World journal of gastroenterology}, volume = {31}, number = {5}, pages = {102622}, pmid = {39926223}, issn = {2219-2840}, mesh = {Humans ; *Critical Illness/mortality ; *Intensive Care Units/statistics & numerical data ; *Gastrointestinal Diseases/mortality/diagnosis ; Retrospective Studies ; *Severity of Illness Index ; Prognosis ; Hospital Mortality ; Predictive Value of Tests ; }, abstract = {Shen et al's retrospective study aims to compare the utility of two separate scoring systems for predicting mortality attributable to gastrointestinal (GI) injury in critically ill patients [the GI Dysfunction Score (GIDS) and the Acute Gastrointestinal Injury (AGI) grade]. The authors note that this study is the first proposal that suggests an equivalence between the ability of both scores to predict mortality at 28 days from intensive care unit (ICU) admission. Shen et al retrospectively analysed an ICU cohort of patients utilising two physicians administering both the AGI grade and GIDS score, using electronic healthcare records and ICU flowsheets. Where these physicians disagreed about the scores, the final decision as to the scores was made by an associate chief physician, or chief physician. We note that the primary reason for the development of GIDS was to create a clear score for GI dysfunction, with minimal subjectivity or inter-operator variability. The subjectivity inherent to the older AGI grading system is what ultimately led to the development of GIDS in 2021. By ensuring consensus between physicians administering the AGI, Shen et al have controlled for one of this grading systems biggest issues. We have concerns, however, that this does not represent the real-world challenges associated with applying the AGI compared to the newer GIDS, and wonder if this arbitration process had not been instituted, would the two scoring systems remain equivalent in terms of predicted mortality?}, } @article {pmid39924298, year = {2025}, author = {Malouin-Lachance, A and Capolupo, J and Laplante, C and Hudon, A}, title = {Does the Digital Therapeutic Alliance Exist? Integrative Review.}, journal = {JMIR mental health}, volume = {12}, number = {}, pages = {e69294}, pmid = {39924298}, issn = {2368-7959}, mesh = {Humans ; *Therapeutic Alliance ; *Artificial Intelligence ; *Mental Disorders/therapy ; Telemedicine ; Psychotherapy/methods ; }, abstract = {BACKGROUND: Mental health disorders significantly impact global populations, prompting the rise of digital mental health interventions, such as artificial intelligence (AI)-powered chatbots, to address gaps in access to care. This review explores the potential for a "digital therapeutic alliance (DTA)," emphasizing empathy, engagement, and alignment with traditional therapeutic principles to enhance user outcomes.

OBJECTIVE: The primary objective of this review was to identify key concepts underlying the DTA in AI-driven psychotherapeutic interventions for mental health. The secondary objective was to propose an initial definition of the DTA based on these identified concepts.

METHODS: The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) for scoping reviews and Tavares de Souza's integrative review methodology were followed, encompassing systematic literature searches in Medline, Web of Science, PsycNet, and Google Scholar. Data from eligible studies were extracted and analyzed using Horvath et al's conceptual framework on a therapeutic alliance, focusing on goal alignment, task agreement, and the therapeutic bond, with quality assessed using the Newcastle-Ottawa Scale and Cochrane Risk of Bias Tool.

RESULTS: A total of 28 studies were identified from an initial pool of 1294 articles after excluding duplicates and ineligible studies. These studies informed the development of a conceptual framework for a DTA, encompassing key elements such as goal alignment, task agreement, therapeutic bond, user engagement, and the facilitators and barriers affecting therapeutic outcomes. The interventions primarily focused on AI-powered chatbots, digital psychotherapy, and other digital tools.

CONCLUSIONS: The findings of this integrative review provide a foundational framework for the concept of a DTA and report its potential to replicate key therapeutic mechanisms such as empathy, trust, and collaboration in AI-driven psychotherapeutic tools. While the DTA shows promise in enhancing accessibility and engagement in mental health care, further research and innovation are needed to address challenges such as personalization, ethical concerns, and long-term impact.}, } @article {pmid39923073, year = {2025}, author = {Wang, Z and Yin, Z and Sun, G and Zhang, D and Zhang, J}, title = {Genetic evidence for the liver-brain axis: lipid metabolism and neurodegenerative disease risk.}, journal = {Lipids in health and disease}, volume = {24}, number = {1}, pages = {41}, pmid = {39923073}, issn = {1476-511X}, mesh = {Humans ; *Lipid Metabolism/genetics ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; *Liver/metabolism/pathology ; *Cholesterol, LDL/blood ; *Neurodegenerative Diseases/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Brain/metabolism/pathology ; *Alzheimer Disease/genetics/metabolism ; Parkinson Disease/genetics/metabolism ; Multiple Sclerosis/genetics/metabolism ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease ; Female ; Risk Factors ; Male ; Apolipoprotein B-100/genetics ; }, abstract = {BACKGROUND: The liver‒brain axis is critical in neurodegenerative diseases (NDs), with lipid metabolism influencing neuroinflammation and microglial function. A systematic investigation of the genetic relationship between lipid metabolism abnormalities and ND, namely, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), is lacking. To assess potential causal links between ND and six lipid parameters, two-sample Mendelian randomization (MR) was used.

METHODS: Large-scale European ancestry GWAS data for lipid parameters and ND (AD, ALS, PD, and MS) were used. Genetic variants demonstrating significant correlations (P < 5 × 10[-8]) with lipid metabolism parameters were identified and employed as instrumental variables (IVs) after proper validation. The research incorporated UK Biobank genomic data to examine associations between genetic variants and lipid metabolism parameters. The analysis included primary MR, sensitivity analyses, and multivariable MR, which considered potential mediators.

RESULTS: MR via the inverse-variance weighted method revealed causal effects of cholesterol (CHOL, OR = 1.10, 95% CI: 1.03-1.18, P = 4.23 × 10⁻[3]) and low-density lipoprotein cholesterol (LDLC, OR = 1.10, 95% CI: 1.03-1.17, P = 3.28 × 10⁻[3]) on the risk of ALS, which were validated across multiple methods. Potential correlations were observed between ApoB and ALS and inversely correlated with AD, whereas no significant associations were found for PD or MS. CHOL and LDLC associations with ALS demonstrated no significant heterogeneity or pleiotropy, supporting their reliability.

CONCLUSIONS: Higher CHOL and LDLC levels were associated with increased ALS risk, suggesting a potential causal link, and supporting the liver‒brain axis hypothesis in ND. Current genetic evidence does not support a significant role for lipid metabolism in PD and MS etiology, suggesting the relationship between lipid metabolism and other NDs may be more complex and warrants further investigation.}, } @article {pmid39922547, year = {2025}, author = {Rossi, S and Milani, M and Della Valle, I and Apolloni, S}, title = {Transcriptomic profiling of symptomatic and end-stage SOD1-G93A transgenic mice reveals extracellular matrix components as key players in ALS pathogenesis.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1871}, number = {4}, pages = {167707}, doi = {10.1016/j.bbadis.2025.167707}, pmid = {39922547}, issn = {1879-260X}, } @article {pmid39922366, year = {2025}, author = {Kopalli, SR and Behl, T and Kyada, A and Rekha, MM and Kundlas, M and Rani, P and Nathiya, D and Satyam Naidu, K and Gulati, M and Bhise, M and Gupta, P and Wal, P and Fareed, M and Ramniwas, S and Koppula, S and Gasmi, A}, title = {Synaptic plasticity and neuroprotection: The molecular impact of flavonoids on neurodegenerative disease progression.}, journal = {Neuroscience}, volume = {569}, number = {}, pages = {161-183}, doi = {10.1016/j.neuroscience.2025.02.007}, pmid = {39922366}, issn = {1873-7544}, mesh = {*Neuronal Plasticity/drug effects/physiology ; Humans ; *Flavonoids/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Neuroprotective Agents/pharmacology ; Neuroprotection/drug effects/physiology ; Disease Progression ; Signal Transduction/drug effects ; }, abstract = {Flavonoids are a broad family of polyphenolic chemicals that are present in a wide variety of fruits, vegetables, and medicinal plants. Because of their neuroprotective qualities, flavonoids have attracted a lot of interest. The potential of flavonoids to control synaptic plasticity-a crucial process underlying memory, learning, and cognitive function-is becoming more and more clear. Dysregulation of synaptic plasticity is a feature of neurodegenerative diseases such as amyotrophic lateral sclerosis (0.4 %), Parkinson's (1-2 %), Alzheimer's (5-7 %), and Huntington's ((0.2 %)). This review discusses the molecular mechanisms via which flavonoids influence synaptic plasticity as well as their therapeutic potential in neurodegenerative diseases. Flavonoids modulate key signaling pathways such as MAPK/ERK and PI3K/Akt/mTOR to support neuroprotection, synaptic plasticity, and neuronal health, while also influencing neurotrophic factors (BDNF, NGF) and their receptors (TrkB, TrkA). They regulate neurotransmitter receptors like GABA, AMPA, and NMDA to balance excitatory and inhibitory transmission, and exert antioxidant effects via the Nrf2-ARE pathway and anti-inflammatory actions by inhibiting NF-κB signaling, highlighting their potential for treating neurodegenerative diseases. These varied reactions support the preservation of synapse function and neuronal integrity in the face of neurodegenerative insults. Flavonoids can reduce the symptoms of neurodegeneration, prevent synaptic loss, and enhance cognitive function, according to experimental studies. However, there are still obstacles to using these findings in clinical settings, such as limited bioavailability and the need for consistent dose. The focus of future research should be on improving flavonoid delivery systems and combining them with conventional medications.}, } @article {pmid39921200, year = {2025}, author = {Shiozumi, T and Matsuyama, T and Nishioka, N and Kiguchi, T and Kitamura, T and Ohta, B and Iwami, T}, title = {Evaluation of interventions in prehospital and in-hospital settings and outcomes for out-of-hospital cardiac arrest patients meeting the termination of resuscitation rule in Japan: A nationwide database study (The JAAM-OHCA Registry).}, journal = {Resuscitation}, volume = {208}, number = {}, pages = {110530}, doi = {10.1016/j.resuscitation.2025.110530}, pmid = {39921200}, issn = {1873-1570}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Japan/epidemiology ; Male ; Female ; *Registries ; *Emergency Medical Services/methods ; Retrospective Studies ; Aged ; *Cardiopulmonary Resuscitation/methods ; Middle Aged ; Resuscitation Orders ; Aged, 80 and over ; Advanced Cardiac Life Support/methods ; Databases, Factual ; }, abstract = {BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a global health burden with low survival rates. The termination of resuscitation (TOR) rule, widely adopted internationally, aims to preserve dignity, optimize resources, and protect healthcare providers. However, prehospital TOR is not implemented in Japan, presenting legal and practical challenges. This study analyzes temporal trends in prehospital and in-hospital interventions for OHCA patients with poor predicted outcomes.

METHODS: This retrospective study analyzed data from the Japanese Association for Acute Medicine Out-of-Hospital Cardiac Arrest (JAAM-OHCA) registry (June 2014-December 2021). Adult OHCA patients with medical causes were included if they fulfilled all the advanced life support (ALS) TOR rule criteria: unwitnessed arrest, no return of spontaneous circulation, no bystander-initiated cardiopulmonary resuscitation, and no automated external defibrillator use or defibrillation. Prehospital and in-hospital interventions were evaluated.

RESULTS: Among 11,334 patients meeting the inclusion criteria, 2,447 received all three ALS interventions (advanced airway management, intravenous access, and epinephrine administration). Over time, in-hospital interventions, including endotracheal intubation (56%) and epinephrine administration (82%), decreased, while advanced therapies, including coronary angiography, extracorporeal membrane oxygenation, and targeted temperature management, remained rare (<1%). The median time to TOR after hospital arrival shortened to 18 min. In contrast, prehospital epinephrine administration increased, while advanced airway management and intravenous access decreased.

CONCLUSIONS: OHCA patients who met TOR rule showed a decrease in in-hospital interventions. Further efforts are warranted to avoid futile medical treatments and promote patient-centered care.}, } @article {pmid39920775, year = {2025}, author = {Yousefian-Jazi, A and Kim, S and Chu, J and Choi, SH and Nguyen, PTT and Park, U and Kim, MG and Hwang, H and Lee, K and Kim, Y and Hyeon, SJ and Rhim, H and Ryu, HL and Lim, G and Stein, TD and Lim, K and Ryu, H and Lee, J}, title = {Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {16}, pmid = {39920775}, issn = {1750-1326}, support = {R01NS109537//NIH R01/ ; 2E30954//KIST Grant/ ; HU23C0217//Korea Dementia Research Project Grant/ ; 2022R1A2C3013138//National Research Foundation/ ; R01 NS109537/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *MEF2 Transcription Factors/metabolism/genetics ; Mice ; *Mitochondria/metabolism ; Humans ; *Motor Neurons/metabolism/pathology ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Disease Models, Animal ; Mutation/genetics ; Enhancer Elements, Genetic/genetics ; HEK293 Cells ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, leading to progressive paralysis. Both genetic alterations and epigenetic modifications contribute to neuronal dysfunction in the pathogenesis of ALS. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear.

METHODS: Convolutional neural network was used to identify an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element. To examine the alteration of MEF2C transcription by the SNP, we generated HEK293T cells carrying the major or minor allele by CRISPR-Cas9. To verify the role of MEF2C-knockdown (MEF2C-KD) in mice, we developed AAV expressing shRNA for MEF2C based on AAV-U6 promoter vector. Neuropathological alterations of MEF2C-KD mice with mitochondrial dysfunction and motor neuronal damage were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through longitudinal study by tail suspension, inverted grid test and automated gait analysis.

RESULTS: Here, we show that enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits.

CONCLUSIONS: Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.}, } @article {pmid39920055, year = {2025}, author = {Ramsden, V and McInnes, E and Wilson, P and Babl, FE and Kuhn, L and Cowie, J and Campbell, P and Middleton, S and Wilson, C and Straiton, N and Tavender, E}, title = {Sustainability of healthcare system improvements, programmes and interventions in acute care settings: protocol for a mixed methods systematic review.}, journal = {BMJ open}, volume = {15}, number = {2}, pages = {e094174}, pmid = {39920055}, issn = {2044-6055}, mesh = {Humans ; *Systematic Reviews as Topic ; *Delivery of Health Care/organization & administration ; Research Design ; Quality Improvement/organization & administration ; }, abstract = {INTRODUCTION: Sustaining evidence-based care is challenging in all clinical settings. Acute care settings have a unique set of contextual factors that may impact sustainability (eg, fast-paced, regular staff turnover). Much of the previous research explores sustainability across undifferentiated healthcare settings making it difficult to determine factors that influence sustainability in acute care settings. The aim of this review is to identify facilitators and barriers that influence the delivery of sustained healthcare interventions (eg, integration of clinical guidelines) within adult and paediatric hospital-based acute care settings.

METHODS AND ANALYSIS: A mixed methods systematic review updating Cowie et al's (which included studies from 2008 to 2017) previously published systematic review will be conducted. The following databases will be searched: Medline, Embase, Cochrane Database of Systematic Reviews, CINAHL and Allied and Complementary Medicine (AMED), from November 2017 to the present for studies published in English. Relevant reference lists of included studies will be manually searched. Empirical quantitative and qualitative studies that report the sustainability of an intervention or programme in acute care settings using a theoretical framework(s), model(s) or theory(ies) to explore facilitators and barriers, will be included. Studies will be exported into Covidence (Melbourne) and pairs of reviewers will independently screen abstracts and full-text studies. The discussion will be used to resolve any disagreements and a third coauthor enlisted should a consensus not be reached. Two independent coauthors will extract key study characteristics and assess each study's quality. Data will be extracted using Covidence (Melbourne). Evidence tables will be used to present descriptive data. Facilitators and barriers will be mapped to the Consolidated Framework for Sustainability Constructs in Healthcare and a narrative approach will be used to present key findings.

ETHICS AND DISSEMINATION: No primary data will be collected so formal ethical approval is not required. Findings will be disseminated through peer-reviewed publications, presented at international conferences and on social media.

PROSPERO REGISTRATION NUMBER: PROSPERO CRD42024547535.}, } @article {pmid39918735, year = {2025}, author = {Wentzel, A and Smith, W and Jansen van Vuren, E and Kruger, R and Breet, Y and Wonkam-Tingang, E and Hanchard, NA and Chung, ST}, title = {Allostatic load and cardiometabolic health in a young adult South African population: the African-PREDICT study.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {328}, number = {3}, pages = {H581-H593}, doi = {10.1152/ajpheart.00845.2024}, pmid = {39918735}, issn = {1522-1539}, support = {//HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; //South African Medical Research Council (SAMRC)/ ; //South African National Research Foundation (SA-NRF)/ ; //Newton Fund (NF)/ ; //Pfizer (South Africa)/ ; //Boeringer-Ingelheim (South Africa)/ ; //Norvatis (South Africa)/ ; //MediClinic Hospital Group (South Africa)/ ; //Roche Holding | Roche Diagnostics (Roche Diagnostics Corporation)/ ; }, mesh = {Humans ; Adult ; Male ; Female ; *Allostasis ; South Africa/epidemiology ; Young Adult ; Prospective Studies ; Blood Pressure ; Cardiometabolic Risk Factors ; Cardiovascular Diseases/physiopathology/epidemiology ; Biomarkers/blood ; Prediabetic State/physiopathology/epidemiology/blood ; Black People ; Masked Hypertension/physiopathology/epidemiology/diagnosis ; Dehydroepiandrosterone/blood ; Risk Assessment ; Hydrocortisone/blood/metabolism ; C-Reactive Protein/metabolism ; Age Factors ; Risk Factors ; }, abstract = {Sustained stress, assessed as a high allostatic load score (ALS), is an independent cardiovascular disease (CVD) risk factor in older adults but its associations in young people are undefined. Since neurological maturation impacts stress adaptation and CVD risk, we assessed the relationship of ALS with CVD profile by using a tiered approach stratified by age [emerging adults (EA) aged 20-24 yr vs. young adults (YA) aged 25-30 yr] and ALS (high vs. low). In 1,054 healthy participants of the African Prospective Study on Early Detection and Identification of Cardiovascular Disease and Hypertension (African-PREDICT), we determined: 1) ALS in EA versus YA; 2) the relationship between ALS and cardiovascular (CV) health, and 3) the odds of high ALS > 4 to identify masked hypertension (HT) and prediabetes as cardiometabolic outcomes. A nine-component, four-domain ALS was compiled: neuroendocrine [dehydroepiandrosterone (DHEA), cortisol], inflammatory [interleukin-6 (IL-6), C-reactive protein (CRP)], cardiovascular [systolic blood pressure (SBP) and diastolic blood pressure (DBP)], and metabolic [total cholesterol, high density lipoprotein cholesterol (HDL-cholesterol), body mass index (BMI)]. Retinal vessel caliber, pulse wave velocity (PWV), and cardiac structure and function were assessed. Median ALS was 3 (range: 1-9). A high-ALS > 4 was more common in YA versus EA (47 vs. 35%, P = 0.032). Higher ALS associated with narrower retinal arteries (P < 0.01), greater PWV (P ≤ 0.01), lower diastolic function (P < 0.01), and left ventricular (LV) function (P < 0.01). High-ALS increased the odds of having masked hypertension, prediabetes, narrower retinal arteries, higher LV mass, poorer diastolic and ventricular functions (all P ≤ 0.01), in EA and YA independent of traditional CVD risk factors. The composite ALS identified early-stress dysregulation in cardiometabolic health and higher odds for masked hypertension and prediabetes in young adults. Cumulative stress may be a modifiable, independent cardiometabolic risk factor in younger populations that needs further investigation.NEW & NOTEWORTHY This is the first study to assess the effect of stress, as a composite allostatic load score, on micro-, macrovascular, and central cardiac features in healthy emerging and young adults, independent of traditional cardiovascular risk markers. It exemplifies independent stress-induced changes throughout the cardiovascular tree, which may increase the risk of cardiometabolic complications, masked hypertension, and prediabetes. Sustained stress may be a key etiological factor in cardiometabolic disease development in a young population.}, } @article {pmid39917359, year = {2025}, author = {Ahmadi Marzaleh, M and Bastani, P and Raeyat Mohtashami, A and Farhadi, P and Ghanbari, S and Ravangard, R}, title = {Predicting Factors Affecting the Behavior of Healthcare Employees in the Use of Personal Protective Equipment During Epidemics Based on Godin et al's Model: A Study in Iran.}, journal = {Health services insights}, volume = {18}, number = {}, pages = {11786329251316668}, pmid = {39917359}, issn = {1178-6329}, abstract = {BACKGROUND: Protecting healthcare employees and preventing infection transmission are paramount concerns during epidemics. Predicting healthcare employees' behavior regarding the use of personal protective equipment (PPE) and identifying the related effective factors can guide educational and administrative strategies and enable timely interventions during outbreaks. This study aimed to predict factors affecting the healthcare employees' behavior in the use of PPE at Shiraz University of Medical Sciences in Iran, based on Godin et al's model.

METHODS: This was a cross-sectional and descriptive-analytical study. After reviewing the related articles and interviewing the experts and based on the model of Godin et al. (2008), a questionnaire was developed, validated, and tested for reliability using face and content validity as well as Cronbach's alpha. Collected data were analyzed using SPSS v.21 and modeled by Structural Equation Modeling (SEM) via SPSS v.21 and Smart PLS v.3 software.

RESULTS: The questionnaire was valid (CVI = 86.42, CVR = 81.71) and reliable (α = .85). The model exhibited appropriate measurement, structural, and overall fit. Beliefs about consequences, social influences, habits/past behavior, role and identity, characteristics of employees, moral norms, and beliefs about capabilities indirectly and significantly influenced behavior (P < .001). Additionally, beliefs about capabilities (P < .001), habits/past behavior (P = .001), and intention (P = .001) directly and significantly influenced PPE use behavior during epidemics.

CONCLUSION: The results emphasized the necessity of targeted interventions based on the studied model constructs within healthcare organizations. By promoting positive beliefs about PPE effectiveness and encouraging appropriate intentions and behaviors, healthcare organizations can significantly improve employee's adherence to PPE use during pandemics.}, } @article {pmid39916983, year = {2024}, author = {González Bolívar, S and Ayoubi, R and Alende, C and Fothouhi, M and Shlaifer, I and McPherson, PS and Laflamme, C and , and , }, title = {A guide to selecting high-performing antibodies for VAPB (UniProt ID: O95292) for use in western blot, immunoprecipitation, and immunofluorescence.}, journal = {F1000Research}, volume = {13}, number = {}, pages = {1559}, pmid = {39916983}, issn = {2046-1402}, mesh = {Humans ; *Fluorescent Antibody Technique/methods ; *Immunoprecipitation/methods ; *Blotting, Western ; *Antibodies/immunology ; HEK293 Cells ; Vesicular Transport Proteins ; }, abstract = {VAPB is an adaptor protein known for its role as an anchor for other proteins at the endoplasmic reticulum. A mutant form of VAPB has been linked to amyotrophic lateral sclerosis and the underlying mechanisms resulting from this defect are studied by researchers in this area to uncover its implication in the disease. Here we have characterized six VAPB commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.}, } @article {pmid39916853, year = {2025}, author = {Rosina, M and Scaricamazza, S and Riggio, F and Fenili, G and Giannessi, F and Matteocci, A and Nesci, V and Salvatori, I and Angelini, DF and Aquilano, K and Chiurchiù, V and Lettieri Barbato, D and Mercuri, NB and Valle, C and Ferri, A}, title = {Brown Adipose Tissue undergoes pathological perturbations and shapes C2C12 myoblast homeostasis in the SOD1-G93A mouse model of Amyotrophic Lateral Sclerosis.}, journal = {Heliyon}, volume = {11}, number = {3}, pages = {e41801}, pmid = {39916853}, issn = {2405-8440}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of motor neurons. The contribution of peripheral organs remains incompletely understood. We focused our attention on brown adipose tissue (BAT) and its secreted extracellular vesicles (EVs) given their role in regulating systemic energy balance. In this study, we employed a multi-omics approach, including RNA sequencing (GEO identifier GSE273052) and proteomics (ProteomeXchange identifier PXD054147), to investigate the alterations in BAT and its EVs in the SOD1-G93A mouse model of ALS. Our results revealed consistent changes in the proteomic and transcriptomic profiles of BAT from SOD1-G93A mice, highlighting alterations such as mitochondrial dysfunction and impaired differentiation capacity. Specifically, primary brown adipocytes (PBAs) from SOD1-G93A mice exhibited differentiation impairment, respiratory defects, and alterations in mitochondrial dynamics. Furthermore, the BAT-derived EVs from SOD1-G93A mice displayed distinct changes in size distribution and cargo content. In parallel, such EVs negatively impacted the differentiation and homeostasis of C2C12 murine myoblasts, as well as induced atrophy in C2C12-derived myotubes. These findings suggest that BAT undergoes pathological perturbations in ALS mouse model and could impact on skeletal muscle homeostasis through the secretion of dysfunctional EVs.}, } @article {pmid39916336, year = {2025}, author = {Calvi, F and Fortuna, A and Bello, L and Anglani, M and Cecchin, D and Sabbatini, D and Andrigo, C and Ferullo, M and Ruggero, S and Falda, M and Pegoraro, E and Sorarù, G}, title = {MEPs and MRI Motor Band Sign as Potential Complementary Markers of Upper Motor Neuron Involvement in Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {32}, number = {2}, pages = {e70055}, pmid = {39916336}, issn = {1468-1331}, support = {//EuroBiobank/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/pathology ; Male ; Female ; Middle Aged ; *Magnetic Resonance Imaging ; Aged ; *Motor Neurons/pathology ; Retrospective Studies ; *Evoked Potentials, Motor/physiology ; Adult ; Positron-Emission Tomography ; Biomarkers ; Neural Conduction/physiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of both upper and lower motor neurons (UMNs and LMNs). Recognizing the involvement of UMNs is challenging because of the absence of reliable biomarkers beyond clinical evaluation.

AIM: To identify a reliable marker of UMN damage in a cohort of patients with ALS referring to the Motor Neuron Disease Clinic of the University Hospital of Padova.

METHODS: We retrospectively evaluated the clinical records of 79 patients with ALS and compared the results of various investigations, including the motor-evoked potentials (MEPs), positron emission tomography-magnetic resonance imaging (MRI) and light neurofilaments (NfLs), with the degree of UMN clinical involvement, as assessed by the Penn Upper Motor Neuron Score (PUMNS).

RESULTS: MEPs, considering the central motor conduction time (CMCT) values in both the upper and lower limbs, showed a significant correlation with the relative PUMNS subscores (p = 0.01, ρ = 0.4; and p = 0.005, ρ = 0.45, respectively). Additionally, there was a positive correlation between NfLs and PUMNS values (p = 0.04, ρ = 0.33). The presence of the motor band sign on MRI was associated with higher PUMNS values. Receiver operating characteristic analysis revealed that PUMNS accurately predicted abnormalities in CMCT values (specificity 86%, sensitivity 62%) and the presence of the motor band sign (specificity 58%, sensitivity 80%).

INTERPRETATION: In our cohort of patients with ALS, CMCT values proved to be the most reliable test for assessing UMN involvement, albeit the presence of the motor band sign on MRI showed higher sensitivity.}, } @article {pmid39915090, year = {2025}, author = {Noh, MY and Kwon, MS and Oh, KW and Nahm, M and Park, J and Jin, HK and Bae, JS and Son, B and Kim, SH}, title = {miRNA-214 to predict progression and survival in ALS.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-335177}, pmid = {39915090}, issn = {1468-330X}, abstract = {BACKGROUND: Reliable biomarkers are essential for predicting the progression speed and prognosis of patients with amyotrophic lateral sclerosis (ALS). We previously identified NCK-associated protein 1 (NCKAP1) as a critical factor in the defective phagocytosis observed in induced microglia-like cells (iMGs) from patients with rapidly progressive sporadic ALS. This study explored the roles of microRNA (miRNA)-214, which targets the NCKAP1 gene, in the progression of ALS.

METHODS: The discovery cohort (n=29) was used to identify miR-214 targeting NCKAP1 genes. The validation cohort (n=132) was used to determine the clinical usability of miR-214 for predicting disease progression speed and survival time.

RESULTS: In the discovery cohort, miR-214 levels were increased in plasma and iMGs from rapidly progressive ALS participants. This finding was validated in another cohort of 132 ALS participants and 30 age-matched healthy volunteers. Plasma miR-214 levels correlated with disease progression, severity and survival, distinguishing between rapidly progressive and slowly progressive ALS. In addition, miR-214 levels also correlated with plasma neurofilament light chain (NfL) and cerebrospinal fluid inflammatory cytokines, showing specific associations with increased NfL and monocyte chemoattractant protein 1 (MCP-1). Survival prediction accuracy improved when miR-214 levels were considered with NfL or MCP-1 levels.

CONCLUSIONS: Plasma miRNA-214 could serve as a novel biomarker for predicting the progression and prognosis of ALS.}, } @article {pmid39914774, year = {2025}, author = {Zamani, A and Walker, AK and Wright, DK}, title = {Glymphatic dysfunction and neurodegeneration in ALS: Longitudinal insights from rNLS8 TDP-43 mice.}, journal = {Neurobiology of disease}, volume = {206}, number = {}, pages = {106832}, doi = {10.1016/j.nbd.2025.106832}, pmid = {39914774}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Glymphatic System/metabolism/pathology ; Mice ; *DNA-Binding Proteins/metabolism/genetics ; *Disease Models, Animal ; Mice, Transgenic ; Aquaporin 4/metabolism/genetics ; Magnetic Resonance Imaging ; Brain/metabolism/pathology/diagnostic imaging ; Male ; Humans ; Longitudinal Studies ; }, abstract = {Dysfunctional Tar DNA binding protein-43 (TDP-43) is found in approximately 95 % of all people with amyotrophic lateral sclerosis (ALS). Recent evidence suggests that the glymphatic system, which clears the brain of waste proteins, is impaired in ALS and may contribute to the accumulation of TDP-43. This study extends this work to investigate how glymphatic function changes over time in the rNLS8 doxycycline (Dox)-dependent TDP-43 mouse model of ALS. Motor function, advanced MRI biomarkers of neurodegeneration, and cortical glymphatic pathway gene expression were assessed together with dynamic contrast-enhanced MRI (DCE-MRI) assessment of glymphatic function at 0-, 3-, 7-, and 21-days after removing mice from Dox feed to initiate cytoplasmic human TDP-43 expression. A trend toward increased glymphatic influx was observed at 3-days post-Dox, together with MRI evidence of brain changes that occurred in the absence of hind-limb clasping and motor impairment. Glymphatic flow is facilitated by aquaporin-4 (AQP4) water channels polarized to astrocytic end feet. We found that while glymphatic function normalized to control levels at 7-days post-Dox, AQP4 expression in the cortex was significantly decreased. After 3-weeks of human TDP-43 expression, glymphatic dysfunction, weight loss, neurodegeneration, motor impairments and astrogliosis were observed. Our findings highlight early glymphatic dysfunction in ALS, suggesting its potential as a therapeutic target.}, } @article {pmid39914266, year = {2025}, author = {Wei, D and Freydenzon, A and Guinebretiere, O and Zaidi, K and Yang, F and Ye, W and Hammar, N and Modig, K and Wray, NR and Feychting, M and Hamieh, N and Ventelou, B and Lekens, B and Gantzer, L and Durrleman, S and McRae, A and Couvy-Duchesne, B and Fang, F and Nedelec, T and , }, title = {Ten years preceding a diagnosis of neurodegenerative disease in Europe and Australia: medication use, health conditions, and biomarkers associated with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {113}, number = {}, pages = {105585}, pmid = {39914266}, issn = {2352-3964}, mesh = {Humans ; *Biomarkers/blood ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis/blood ; *Alzheimer Disease/diagnosis/epidemiology/blood/etiology ; Australia/epidemiology ; Europe/epidemiology ; Male ; *Parkinson Disease/diagnosis/epidemiology/blood/drug therapy ; Female ; Aged ; Aged, 80 and over ; Case-Control Studies ; Neurodegenerative Diseases/epidemiology/diagnosis/etiology/blood ; Risk Factors ; Middle Aged ; }, abstract = {BACKGROUND: Many studies have investigated early predictors for Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, evidence is sparse regarding specific and common predictors for these diseases. We aimed to identify medication use, health conditions, and blood biomarkers that might be associated with the risk of AD, PD, and ALS ten years later.

METHODS: We conducted population-based nested case-control studies of AD, PD, and ALS using electronic medical records in Europe (France, the UK, and Sweden) and Australia. We retrieved data on medication use, diagnosed health conditions, and measured blood biomarkers from electronic medical records or biomedical cohorts. Conditional logistic regression models and meta-analysis were applied to assess the associations between these factors and the risk of receiving a diagnosis of AD, PD, or ALS.

FINDINGS: We included a total of 149,642 AD cases (mean age: 79.1-81.2 years), 252,696 PD cases (73.2-75.9 years), and 27,533 ALS cases (64.4-69.6 years). The prescription of psychoanaleptics and nasal preparations was consistently associated with an increased risk of AD, PD, and ALS 5-10 years later. Constipation and use of related medications were associated with an increased risk of AD and PD, while diabetes and use of antidiabetics were associated with a reduced risk of ALS. A higher level of triglycerides was associated with a lower risk of AD, whereas a higher level of Apolipoprotein B was associated with a lower risk of PD, 5-10 years later.

INTERPRETATION: Psychoanaleptics and nasal preparations may serve as common predictors for diagnosis of AD, PD, and ALS 5-10 years later. Conversely, the increased prevalence of constipation is specific to AD and PD, while the decreased prevalence of diabetes and use of antidiabetics is specific to ALS.

FUNDING: EU Joint Programme-Neurodegenerative Disease Research.}, } @article {pmid39914221, year = {2025}, author = {Gusain, S and Mishra, CB and Yadav, K and Sharma, M and Saluja, D and Tiwari, M}, title = {Development of carbazole-based molecules for inhibition of mutant hSOD1 protein aggregation in Amyotrophic Lateral Sclerosis.}, journal = {Bioorganic & medicinal chemistry}, volume = {120}, number = {}, pages = {118091}, doi = {10.1016/j.bmc.2025.118091}, pmid = {39914221}, issn = {1464-3391}, mesh = {*Carbazoles/chemistry/pharmacology/chemical synthesis ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Humans ; *Superoxide Dismutase-1/metabolism/genetics/chemistry/antagonists & inhibitors ; *Protein Aggregates/drug effects ; Mutation ; Animals ; Apoptosis/drug effects ; Mice ; Molecular Structure ; Structure-Activity Relationship ; Dose-Response Relationship, Drug ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the loss of upper and lower motor neurons. Cu/Zn superoxide dismutase (SOD1) is one of the genes associated with the familial form of the disease (fALS). The mechanism of neuron degeneration by SOD1 is not clear, it is hypothesised that there is a toxic gain of function in the protein which leads to the downstream effects. In the present study, carbazole-based molecules have been rationally designed and synthesised as potential inhibitors of mutant hSOD1 protein aggregation. SG-9 and SG-10 prevented the aggregation of all three purified mutant hSOD1 proteins. Transmission electron microscopy and dynamic light scattering experiments also revealed that co-incubation of SG-9 and SG-10 with mutant hSOD1 protein resulted in smaller and slender fibril forming. Molecules SG-9 and SG-10 did not display toxicity and prevented Neuro-2a cells expressing hSOD1 G85R protein from its associated cytotoxicity. SG-9 and SG-10 were also able to prevent the transfected cells from apoptosis and were also able to reduce ROS levels associated with hSOD1 G85R protein aggregation significantly. Therefore, novel carbazole derivatives SG-9 and SG-10 proved to be effective inhibitors of mutant hSOD1 protein aggregation and can be further utilised as lead molecules for the amelioration of mutant hSOD1 aggregation-associated ALS.}, } @article {pmid39913612, year = {2025}, author = {Thomas, EV and Han, C and Kim, WJ and Asress, S and Li, Y and Taylor, JA and Gearing, M and Fournier, CN and McEachin, ZT and Seyfried, NT and Glass, JD}, title = {ALS plasma biomarkers reveal neurofilament and pTau correlate with disease onset and progression.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70001}, pmid = {39913612}, issn = {2328-9503}, support = {5P01NS084974/CL/CLC NIH HHS/United States ; //American Academy of Neurology/ ; }, abstract = {OBJECTIVE: We performed a pilot screen to assess the utility of the NULISA™ (Nucleic-acid-Linked Immuno-Sandwich Assay) platform in the identification of amyotrophic lateral sclerosis (ALS) biomarkers.

METHODS: Plasma from 86 individuals (48 ALS, 18 asymptomatic C9orf72 repeat expansion carriers (AsymC9), and 20 healthy controls) was analyzed via a multiplexed NULISA™ assay that includes 120 neurodegeneration-associated proteins. Statistical analysis of NULISA™ results was performed to identify proteins differentially expressed in plasma and their correlation with disease-associated parameters.

RESULTS: ALS plasma showed elevation of the established biomarkers, neurofilament light chain (NEFL) and neurofilament heavy chain (NEFH). Compared to controls and AsymC9, microtubule-associated protein tau (MAPT), phosphorylated tau 181 (pTau181), phosphorylated tau 217 (pTau217), phosphorylated tau 231 (pTau231), and phosphorylated TDP-43 (pTDP-43) were elevated in ALS. NEFL levels positively correlated with pTau181, pTau217, pTau231, and pTDP-43. MAPT and pTDP-43 were also correlated with pTau181, pTau217 and pTau231. Elevated pTau was negatively correlated with survival and ALSFRS-R. Spinal onset ALS was associated with higher pTau181, pTau217, and pTau231.

INTERPRETATION: We confirm previous reports showing elevated pTau181 in ALS plasma and show elevation of other phosphorylated tau forms, pTau217 and pTau231, typically observed in Alzheimer's disease. We provide preliminary data showing the detection and elevation of pTDP-43-409/410 in a subset of ALS samples compared to healthy controls. Neurofilament and tau levels are highly correlated suggesting their elevation may reflect a common pathology and disease state. Total and phosphorylated tau are correlated with multiple disease measures, such as ALS duration, ALSFRS-R, and site of onset.}, } @article {pmid39910731, year = {2025}, author = {Singh, S and Khan, S and Khan, S and Ansari, O and Malhotra, N and Shukla, SK and Narang, J}, title = {Muscle Matters: Transforming Amyotrophic Lateral Sclerosis Diagnostics with Next-Gen Biosensors and Smart Detection.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {4}, pages = {563-587}, doi = {10.1021/acschemneuro.4c00664}, pmid = {39910731}, issn = {1948-7193}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; *Biosensing Techniques/methods ; Electromyography/methods ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily targets the motor system, causing patients' speech and swallowing ability to rapidly deteriorate. Although ALS is usually classified into familial and sporadic forms, diagnosing it can be extremely difficult due to the absence of definitive biomarkers, often resulting in delays in diagnosis. Current diagnostic practices rely heavily on clinical assessments that indicate damage to both upper motor neurons (UMNs) and lower motor neurons (LMNs). This includes comprehensive physical examinations, electromyography (EMG) to assess neuromuscular function, and the exclusion of other similar conditions such as cervical spondylotic myelopathy, multifocal motor neuropathy, and Kennedy's disease through appropriate diagnostic procedures. The urgent need for specific biomarkers is critical for timely diagnosis and therapeutic advancements in ALS management. While many recent developments in research have not yet translated into direct patient benefits, the recognition of ALS as a complex disease is beginning to influence clinical practice significantly. Optimal management strategies emphasize on symptom control and improving the quality of life for patients within a holistic healthcare framework. This review provides a comprehensive overview of ALS, delving into its pathophysiology, clinical symptoms, and the latest advancements in detection methods that utilize traditional approaches, innovative biosensors, and smart diagnostic technologies. It discusses various treatment options available for ALS while exploring future developments that may enhance patient screening and improve clinical outcomes. By integrating assessments into the underlying mechanisms of the disease with cutting-edge diagnostic approaches, this review aims to contribute meaningfully to ongoing efforts to optimize ALS management and therapeutic strategies, ultimately improving patient care and outcomes.}, } @article {pmid39910638, year = {2025}, author = {Möhwald, LM and Maier, A and Grehl, T and Weyen, U and Weydt, P and Günther, R and Lingor, P and Göricke, B and Petri, S and Grosskreutz, J and Boentert, M and Cordts, I and Weishaupt, JH and Dorst, J and Münch, C and Meyer, T and Baum, P}, title = {Shared prognostic information in amyotrophic lateral sclerosis - systematic assessment of the patients' perception of neurofilament light chain and the ALS functional rating scale.}, journal = {Neurological research and practice}, volume = {7}, number = {1}, pages = {6}, pmid = {39910638}, issn = {2524-3489}, support = {Open Access Publishing Fund of Leipzig University ("Read & Publish" contract with Springer Nature)//Open Access Publishing Fund of Leipzig University ("Read & Publish" contract with Springer Nature)/ ; }, abstract = {BACKGROUND: In amyotrophic lateral sclerosis (ALS), neurofilament light chain (NfL) was introduced as a prognostic biomarker. More recently, NfL values can be shared on the patient's ALS app. Also, the ALS functional rating scale (ALSFRS-R) is an established patient-reported assessment of disease progression. The scale can be obtained during clinic visits or remotely. However, few systematic data are available on the patients' perception of prognostic information about NfL and ALSFRS-R and the remote sharing of these data.

METHODS: In a multicenter study, 149 ALS patients were assessed for their perception of shared information about NfL and ALSFRS-R using an investigator-designed survey and established questionnaires. The recommendation of NfL and ALSFRS-R to fellow patients was assessed using the Net Promoter Score (NPS). Burden by shared information was investigated in two distinct settings: (1) clinic information when receiving results on NfL and/or ALSFRS-R during clinic visits and (2) remote information about NfL values and self-rating of the ALSFRS-R via the ALS app. General anxiety was measured by the Fear of Progression Questionnaire - Short Form (FoP-Q-SF).

RESULTS: Information about NfL and ALSFRS-R, respectively (n = 149), were regarded as relevant for patients themselves (75.2% and 77.2%) and for research (98% and 96%). The NPS showed a high recommendation rate for NfL (+ 21) and ALSFRS-R (+ 26). Only a minority of patients perceived shared information about NfL as burdensome, with a lower burden in the clinic setting (n = 1, 4.2%) than in the remote setting (n = 8, 12%; p = 0.015). Remote digital assessment of the ALSFRS-R was well received, with a reported burden in 9.8% (n = 9) of the participants. The FoP-Q-SF revealed fear of progression in 40% of the respondents (n = 60).

CONCLUSIONS: This study underscored the relevance of information about NfL and ALSFRS-R from the patient's perspective. Furthermore, patients proved to appreciate the relevance of this data for ALS research. Sharing information about NfL or ALSFRS-R was rarely perceived as burdensome even in a remote setting using the ALS app. These findings pave the way for further development of the patient-centered approach to sharing prognostic information in ALS.}, } @article {pmid39910617, year = {2025}, author = {Mai, YD and Zhang, Q and Fung, CL and Leung, SO and Chong, CH}, title = {CD22 modulation alleviates amyloid β-induced neuroinflammation.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {32}, pmid = {39910617}, issn = {1742-2094}, mesh = {Animals ; Mice ; Humans ; *Sialic Acid Binding Ig-like Lectin 2/metabolism ; *Amyloid beta-Peptides/metabolism/toxicity ; *Mice, Transgenic ; *Neuroinflammatory Diseases/metabolism ; Microglia/metabolism/drug effects ; Mice, Inbred C57BL ; Antibodies, Monoclonal, Humanized/pharmacology/therapeutic use ; Male ; }, abstract = {Neuroinflammation is a crucial driver of multiple neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Yet, therapeutic targets for neurodegenerative diseases based on neuroinflammation still warrant investigation. CD22 has been implicated in neuroinflammatory diseases, namely AD. Specifically, plasma soluble CD22 (sCD22) level is upregulated in patients with AD. Direct experimental evidence for the role of CD22 in neuroinflammation is needed, as is a better understanding of its impact on microglia activation and therapeutic potential. Here we reported that sCD22 promotes neuroinflammation both in vivo and in vitro. sCD22 activated microglia via both p38 and ERK1/2 signaling pathway for the secretion of TNFα, IL-6 and CCL3. Moreover, sCD22 activated microglia via sialic acid binding domain and 2,6 linked sialic acid glycan on sCD22. The pivotal therapeutic potential of targeting CD22 was demonstrated in Amyloid β (Aβ) induced-neuroinflammation in hCD22 transgenic mice. Suciraslimab improved working memory and resolved neuroinflammation in vivo. Further, membrane CD22 inhibited Amyloid β (Aβ) induced-NFκB signaling pathway and mechanistic study delineated that suciraslimab suppressed Aβ-induced IL-1β secretion in human microglia and PBMC. Suciraslimab also suppressed IL-12 and IL-23 secretion in human PBMC. Moreover, suciraslimab reduced the surface expression of α4 integrin on B cells. Intriguingly, we discovered that CD22 interact with Aβ and suciraslimab enhanced internalization of CD22-Aβ complex in microglia. Our data highlights the importance of sCD22 in driving neuroinflammation and the dual mechanism of targeting CD22 to resolve Aβ-induced inflammation and promote Aβ phagocytosis.}, } @article {pmid39910275, year = {2025}, author = {Peters, TL and Qiu, W and Yang, H and Huang, W and Hu, Y and Zou, Z and Ye, W}, title = {Associations of cachexia and frailty with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {4437}, pmid = {39910275}, issn = {2045-2322}, support = {2024XH028//Postdoctoral Fund project of Fujian Medical University Union Hospital/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; *Cachexia/etiology ; Female ; Male ; *Frailty/complications ; Middle Aged ; Aged ; Prospective Studies ; Risk Factors ; Hand Strength ; United Kingdom/epidemiology ; Body Mass Index ; }, abstract = {In the present study, we investigated the associations of cachexia (loss of muscle, weight and fat) and frailty (loss of weight and muscle) status with the risk of developing amyotrophic lateral sclerosis, because these specific terms are rarely used in this research area. In this prospective study, we extracted cachexia and frailty status from the UK Biobank cohort to study the associations of these conditions (as determined via international classification of disease-10 codes) with amyotrophic lateral sclerosis. There was a greater risk of developing amyotrophic lateral sclerosis among individuals with cachexia and frailty status after adjusting for age, sex, income (pounds), body mass index, UK Biobank centers and smoking status. Among individuals with frailty status: a grip strength of < 21 kg, a slow walking speed, and exhaustion (more than half the days or nearly every day) increase the risk of developing amyotrophic lateral sclerosis. We believe that studying cachexia and frailty status can be used to help define and treat amyotrophic lateral sclerosis.}, } @article {pmid39908935, year = {2025}, author = {Lu, T and Li, J and Xiao, E and Zhong, H and Deng, J and Ma, L and Ning, Z and Xiao, T}, title = {Assemblage of root-associated microbiome contributes to disparate performance of two rice genotypes under aluminum stress.}, journal = {Plant physiology and biochemistry : PPB}, volume = {220}, number = {}, pages = {109539}, doi = {10.1016/j.plaphy.2025.109539}, pmid = {39908935}, issn = {1873-2690}, mesh = {*Oryza/microbiology/genetics/drug effects ; *Aluminum/toxicity ; *Microbiota/drug effects/genetics ; *Genotype ; *Plant Roots/microbiology/drug effects/genetics ; *Stress, Physiological/genetics ; Rhizosphere ; Soil Microbiology ; }, abstract = {Aluminum (Al) toxicity severely inhibits rice growth under acidic soils, posing a significant threat to food security. The assemblies of root-associated microbiomes throughout the lifecycle of rice are hypothesized to furnish a resilient reservoir of ecological functions for rice growth performance under Al stresses. However, the mechanisms that drive the assembly of root-associated microbiomes of rice are largely unknown. In this study, we chose two rice genotypes (including aluminum-tolerant (Al-T) and aluminum-sensitive (Al-S)) as model plants to investigate the microbial assemblage of root-associated microbiome and their potential roles on the plant growth performance under Al stress. The microbial community diversity (Shannon) and evenness (Chao1) in the endosphere of the Al-T genotype gradually decreased, converging towards levels observed in the Al-S genotype. In addition, the rhizosphere and endosphere microbiomes of Al-T genotype are primarily influenced by deterministic processes, while those of Al-S genotype are more influenced by stochastic processes. Compared to Al-S genotype, Al-T genotype exhibited higher complexity and stability in its rhizosphere and endosphere microbiomes, while the rhizoplane microbiome showed the opposite trend. In the rhizosphere microbiome of the Al-T genotype, we identified Gallionellales, Rhodobacterales, and Rhizobiales as keystone taxa. Their abundance was closely associated with microbial functions, including indole-3-acetic acid (IAA) synthesis, phosphorus solubilization, glutathione (GSH) metabolism, and 1-aminocyclopropane-1-carboxylate (ACC) metabolism. In the Al-S genotype, the keystone taxa included Actinomycetales and Burkholderiales. This study offers new insights into plant adaptation to abiotic stress and underscores the significance of the assemblage of root-associated microbiome in this process.}, } @article {pmid39908735, year = {2025}, author = {Ghannam, IAY and Hassan, RM and Abdel-Maksoud, MS}, title = {Peroxisome proliferator-activated receptors (PPARs) agonists as promising neurotherapeutics.}, journal = {Bioorganic chemistry}, volume = {156}, number = {}, pages = {108226}, doi = {10.1016/j.bioorg.2025.108226}, pmid = {39908735}, issn = {1090-2120}, mesh = {Humans ; *Peroxisome Proliferator-Activated Receptors/agonists/metabolism ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis/therapeutic use ; Molecular Structure ; }, abstract = {Neurodegenerative disorders are characterized by a continuous neurons loss resulting in a wide range of pathogenesis affecting the motor impairment. Several strategies are outlined for therapeutics of synthetic and natural PPARs agonists in some neurological disorders; Parkinson's disease (PD), Alzheimer's disease (AD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The aim of this review is to provide a recent update of the previously reported studies, and reviews dealing with the medicinal chemistry of PPARs and their agonists, and to highlight the outstanding advances in the development of both synthetic compounds including; PPARα agonists (fibrates), PPARγ agonists (thiazolidindiones), and PPARβ/δ agonists either as sole or dual acting PPAR full or pan agonists, in addition to the natural phytochemicals; acids, cannabinoids, and flavonoids for their different neuroprotection effects in the previously mentioned neurodegenerative disorders (PD, AD, MS, ALS, and HD). Moreover, this review reports the diverse pre-clinical and clinical studies of PPARs agonists in the neurodegenerative diseases via cellular, and animal models and human.}, } @article {pmid39908264, year = {2025}, author = {Hobert, MA and Helle, N and Siebert, C and Eisenhauer, A and Gledhill, M and Maetzler, W}, title = {Exploiting the Fractionation of Stable Isotopes in Biochemical Processes for Medical Diagnosis: A Narrative Review.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.1577}, pmid = {39908264}, issn = {2152-5250}, abstract = {Analysis of isotope distributions plays a crucial role in medical diagnostics. While radioactive and radiogenic isotopes - those that undergo or result from radioactive decay - are widely used, stable isotopes are less commonly applied despite their significant diagnostic potential. For example, calcium isotope ratio analysis is already commercially utilized for calcium loss and the early diagnosis of osteoporosis. Additionally, analyses of iron, copper, and zinc isotope ratios have been explored in various conditions, including hemochromatosis, Wilson's disease, cancer, Alzheimer's disease, and amyotrophic lateral sclerosis. Altered isotope ratios in these diseases are thought to reflect pathophysiologically relevant processes, making them promising biomarkers. This review provides a comprehensive overview of the current and potential applications of stable isotope analysis in medicine.}, } @article {pmid39907297, year = {2024}, author = {Čižek Sajko, M and Suklan, J and Osmanović, D and Peterlin, B}, title = {Translational Research on Polygenic Risk Scores in Common Neurodegenerative Diseases - A Scoping Review Protocol.}, journal = {Acta medica academica}, volume = {53}, number = {3}, pages = {303-308}, pmid = {39907297}, issn = {1840-2879}, mesh = {Humans ; Alzheimer Disease/genetics/diagnosis ; Amyotrophic Lateral Sclerosis/genetics ; Genetic Predisposition to Disease ; Genetic Risk Score ; *Multifactorial Inheritance ; Multiple Sclerosis/genetics ; *Neurodegenerative Diseases/genetics ; Parkinson Disease/genetics/diagnosis ; Research Design ; Risk Assessment ; Risk Factors ; *Translational Research, Biomedical ; Scoping Review as Topic ; }, abstract = {OBJECTIVE: The purpose of this protocol is to clearly describe the process for the scoping review we plan to conduct on the topic of polygenic risk scores (PRS) in common neurodegenerative diseases. We will present the review's objective, the strategy for evidence search, the data extraction and analysis procedure, and how the results will be presented.

METHODS: The inclusion criteria for the planned scoping review will focus on evidence sources that involve PRS applied to neurogenerative diseases such as Multiple sclerosis, Parkinson's disease, Alzheimer's disease, and Amyotrophic lateral sclerosis in any phase of translational research, from early development to clinical implementation. This includes its use in risk prediction, early diagnosis, prognosis, and treatment decision-making. The research questions were created based on the population, context, and concept framework. We will consider both peer-reviewed papers and grey literature published in English or German for inclusion. Two independent reviewers will search for information.

CONCLUISON: The findings from the scoping review will be presented descriptively and summarized according to the research questions to illustrate the current status of translational research on PRS in common neurodegenerative diseases.}, } @article {pmid39907139, year = {2025}, author = {Matera, AG}, title = {Chaperone dysfunction in motor neuron disease: new insights from studies of the SMN complex.}, journal = {Genetics}, volume = {229}, number = {3}, pages = {}, pmid = {39907139}, issn = {1943-2631}, support = {R35 GM136435/GM/NIGMS NIH HHS/United States ; //USA National Institutes of Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Muscular Atrophy, Spinal/genetics/metabolism ; Motor Neuron Disease/genetics/metabolism/pathology/etiology ; Animals ; SMN Complex Proteins/metabolism/genetics ; Molecular Chaperones/metabolism/genetics ; Motor Neurons/metabolism/pathology ; }, abstract = {Spinal muscular atrophy and amyotrophic lateral sclerosis are devastating neurodegenerative diseases characterized by motor neuron loss. Although these 2 disorders have distinct genetic origins, recent studies suggest that they share common etiological mechanisms rooted in proteostatic dysfunction. At the heart of this emerging understanding is the survival motor neuron (SMN) complex.}, } @article {pmid39906330, year = {2024}, author = {Hruška, J and Bachmann, P and Odei, SA}, title = {Enhancing ALS disease management: exploring integrated user value through online communities evidence.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1393261}, pmid = {39906330}, issn = {1664-2295}, abstract = {INTRODUCTION: Assistive technologies (ATs) offer significant potential to improve the quality of life for individuals with Amyotrophic Lateral Sclerosis (ALS). This study explores the concept of integrated user value (IUV), focusing on five key aspects: quality, user experience, cost-effectiveness, safety, and accessibility. Understanding IUV is crucial for enhancing the development and deployment of ATs in ALS disease management.

METHODS: A systematic search approach was utilized to collect data from Facebook ALS support groups, comprising posts from individuals with ALS and their caregivers. Using a predefined set of keywords, 416 posts were analyzed. The posts were categorized based on the five aspects of IUV, and an in-depth content analysis was conducted to explore patterns, challenges, and experiences associated with AT usage.

RESULTS: The analysis revealed significant challenges across all aspects of IUV. Quality and user experience were interlinked, with users frequently citing inadequate designs and unmet customization needs. Cost-effectiveness was a key concern, with high costs and limited insurance coverage contributing to financial strain. Accessibility issues, including delays in acquiring devices and insufficient public facilities, further highlighted systemic challenges. Safety concerns emphasized the need for personalized and intuitive AT designs.

DISCUSSION: The findings underscore the importance of a holistic approach to AT development, integrating all five aspects of IUV. Recommendations include enhancing product quality, ensuring affordability, prioritizing user-centered design, and addressing accessibility gaps. Collaboration between AT designers, healthcare providers, and policymakers is essential to optimize AT value and improve the quality of life for individuals with ALS and their caregivers.}, } @article {pmid39905402, year = {2025}, author = {Li, J and Guo, S and Sun, Q and An, N and Lin, J and Fei, Q}, title = {Bioinformatics screening and clinical validation of CircRNA and related miRNA in male osteoporosis.}, journal = {BMC musculoskeletal disorders}, volume = {26}, number = {1}, pages = {117}, pmid = {39905402}, issn = {1471-2474}, mesh = {Humans ; Male ; *RNA, Circular/genetics ; *Osteoporosis/genetics/diagnosis ; *Computational Biology ; *MicroRNAs/genetics ; Middle Aged ; Gene Regulatory Networks ; Gene Expression Profiling ; Aged ; RNA, Messenger/genetics/metabolism ; Protein Interaction Maps ; Biomarkers/blood ; Case-Control Studies ; }, abstract = {BACKGROUND: The pathogenesis of male osteoporosis (MOP) remains unclear, with the role of genetic factors attracting the attention of researchers. In the present study, we aimed to investigate critical circRNA biomarkers associated with male osteoporosis.

METHODS: RNA-sequencing was performed to investigate the circRNA expression profiles between 3 men with osteoporosis and 3 with normal mass density. Then, shared mRNAs between host genes acquired in this present study and mRNAs acquired in previous study were identified to screen vital circRNAs associated with male osteoporosis. PPI networks of shared mRNAs were constructed and the hub genes in the PPI networks were identified with CytoHubba, a plugin in Cytoscape software (3.10.1). Finally, a ceRNA network of four circRNAs derived from three hub genes was constructed. Validation experiments were performed on selected circRNAs and related miRNAs in this ceRNA network using peripheral blood clinical samples.

RESULTS: In total, 657 circRNAs were detected in male osteoporosis. The shared mRNAs were significantly enriched in the metabolic pathways, RNA transport, Ubiquitin mediated proteolysis and Amyotrophic lateral sclerosis. Then, three genes, including SETD2, ATM and XPO1, were identified as hub genes with four algorithms. Ultimately, the ceRNA network, involving 4 circRNAs, 40 miRNAs, and 592 mRNAs, was obtained. Using 35 clinical samples, three potential circRNAs and three miRNAs associated with male osteoporosis were selected for validation. It was ultimately found that three miRNAs were upregulated in MOP, while hsa-circ-9130, novel_circ_0014940 and hsa-circ-0054894 were upregulated, hsa-circ-2484 and novel_circ_0033084 were downregulated in patients with MOP.

CONCLUSION: We emphasized the roles of several significantly up- and down-regulated circRNAs and four circRNAs derived from three hub genes in male osteoporosis. Differences in expression were confirmed for three miRNAs and five circRNAs in the ceRNA network among patients with male osteoporosis.}, } @article {pmid39904421, year = {2025}, author = {Dragoni, F and Garofalo, M and Di Gerlando, R and Rizzo, B and Bordoni, M and Scarian, E and Viola, C and Bettoni, V and Fiamingo, G and Tornabene, D and Scanu, L and Pansarasa, O and Diamanti, L and Gagliardi, S}, title = {Whole transcriptome analysis of unmutated sporadic ALS patients' peripheral blood reveals phenotype-specific gene expression signature.}, journal = {Neurobiology of disease}, volume = {206}, number = {}, pages = {106823}, doi = {10.1016/j.nbd.2025.106823}, pmid = {39904421}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/diagnosis ; Female ; Male ; Middle Aged ; *Phenotype ; Aged ; *Transcriptome ; *Gene Expression Profiling/methods ; Adult ; Biomarkers/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult neurodegenerative disorder. According to clinical criteria, ALS patients can be classified into eight subgroups: classic, bulbar, pyramidal, pure lower motor neuron, flail arm, pure upper motor neuron, flail leg, and respiratory. There are no well-established molecular biomarkers for early diagnosis, prognosis, and progression monitoring of this fatal disease. Classification based on clinical phenotypes could be associated with peculiar gene expression patterns shaped during lifespan, allowing the identification of specific sporadic ALS (sALS) subtypes with less heterogeneous clinical and biological features. Our objective was to define a phenotype-specific transcriptomic signature of distinct ALS phenotypes, and lay the foundation for biomarkers development. We characterized 48 sALS patients by clinical and paraclinical parameters, and subdivided them in "Classic" (n = 12), "Bulbar" (n = 10), "Flail Arm" (n = 7), "Flail Leg" (n = 10) and "Pyramidal" (n = 9) phenotypes. RNAs extracted from patients' PBMCs and 19 controls were sequenced. Our analysis allowed the visualization of gene expression differential clusters between patients and controls. Interestingly, only one gene (Y3_RNA, a misc_RNA component of the Ro60 ribonucleoprotein involved in cellular response to interferon-alpha) was upregulated at different levels across all phenotypes, whereas other genes appeared phenotype-specific. The work proposed stress the innovative view of ALS as a multi-systemic disorder rather than a pure motor neuron-associated and 'neurocentric' pathology. The possibility to cluster ALS patients based on their molecular signature pave the way for future personalized clinical trials and early diagnosis.}, } @article {pmid39902643, year = {2025}, author = {Abad-Yang, N and Raguseo, F and Di Michele, L and Patani, R and Di Antonio, M}, title = {The potential of multimolecular G-quadruplex structures for targeted treatment of Amyotrophic Lateral Sclerosis.}, journal = {Expert opinion on therapeutic targets}, volume = {29}, number = {1-2}, pages = {1-4}, doi = {10.1080/14728222.2025.2463361}, pmid = {39902643}, issn = {1744-7631}, } @article {pmid39902522, year = {2025}, author = {Yu, WQ and Zhao, LX and Bian, Y and Zhang, PX and Jia, L and Zhao, DM and Fu, Y and Ye, F}, title = {Pharmacophore Recombination Design, Synthesis, and Bioactivity of Ester-Substituted Pyrazole Purine Derivatives as Herbicide Safeners.}, journal = {Journal of agricultural and food chemistry}, volume = {73}, number = {6}, pages = {3341-3352}, doi = {10.1021/acs.jafc.4c07027}, pmid = {39902522}, issn = {1520-5118}, mesh = {*Herbicides/chemistry/pharmacology/chemical synthesis ; *Pyrazoles/chemistry/pharmacology/chemical synthesis ; *Purines/chemistry/pharmacology ; *Molecular Docking Simulation ; *Acetolactate Synthase/metabolism/antagonists & inhibitors/chemistry/genetics ; *Drug Design ; Triticum/chemistry/drug effects ; Structure-Activity Relationship ; Sulfonylurea Compounds/chemistry/pharmacology ; Molecular Structure ; Plant Proteins/chemistry/metabolism ; Esters/chemistry/pharmacology ; Enzyme Inhibitors/chemistry/pharmacology/chemical synthesis ; Pharmacophore ; }, abstract = {Mesosulfuron-methyl, an acetolactate synthase (ALS) inhibitor primarily applied to wheat and rye, can injure or even kill wheat crops. Herbicide safeners can improve the herbicide resistance of crops without reducing the herbicidal effect on targeted weed species. Herein, we present a series of pyrazole purine derivatives with the primary structure of the natural product cytokinin and commercialized safener mefenpyridyl, designed using the pharmacophore recombination method. The title compounds were synthesized and characterized using infrared spectroscopy, [1]H and [13]C nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. A bioactivity assay proved that most of the target compounds can reduce the wheat phytotoxicity of mesosulfuron-methyl. Measurements of chlorophyll and glutathione contents, along with other enzyme activity assays, confirmed that compounds I-15 and I-13 exhibit higher safety activities compared with the mefenpyr-diethyl safener. Molecular structure comparisons demonstrated that I-15 is more readily absorbed and disseminated through the crop than the commercialized safener mefenpyr-diethyl. Molecular docking models and molecular dynamics simulations elucidated the protective mechanism of safeners; specifically, compound I-15 competitively binds to the ALS active site with mesosulfuron-methyl. The current study reveals the potential of pyrazole purine derivatives in the future discovery of novel herbicide safeners.}, } @article {pmid39902127, year = {2024}, author = {Ma, J and Wang, H and Gui, Z and Yang, Y}, title = {Unveiling the role of SYNGR4 in breast cancer development: a novel target for immunotherapy.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1490073}, pmid = {39902127}, issn = {2234-943X}, abstract = {INTRODUCTION: SYNGR4 is considered to be one of the causative genes for amyotrophic lateral sclerosis, but its role in breast cancer development has not been revealed.

METHODS: The expression of SYNGR4 in a variety of malignancies including breast cancer was analyzed using Genotype Tissue Expression (GTEx) and the Cancer Genome Atlas (TCGA) databases and verified by specimens collected from our center. The effect of SYNGR4 on breast cancer prognosis was analyzed using bioinformatics and possible pathways by which this molecule affects breast cancer prognosis were explored. The effect of SYNGR4 on immune infiltration of breast cancer was analyzed using GSVA, and the effects of SYNGR4 on breast cancer proliferation, migration, and tumor-associated macrophage polarization in cancer foci were verified by cellular and animal experiments, respectively.

RESULTS: SYNGR4 is highly expressed in a variety of malignant tumors, including breast cancer, and affects the prognosis of breast cancer patients. This may be a volatile effect through Organelle fission, chromosome segregation, nuclear division, etc. SYNGR4 overexpression affects breast cancer proliferation, migration, and tumor immune infiltration, and promotes breast cancer tumor-associated macrophage polarization toward M2.

DISCUSSION: SYNGR4 overexpression can affect the prognosis of breast cancer patients by promoting M2 polarization of tumor-associated macrophages in breast cancer, and this molecule may be a novel target for breast cancer immunotherapy.}, } @article {pmid39901730, year = {2025}, author = {Wu, W and Wang, X and Xu, Y and Ma, C and Qian, X and Qiu, W}, title = {Neuropathological comorbidity, genetics and cognition in a Chinese community-based autopsy cohort.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf039}, pmid = {39901730}, issn = {1460-2156}, abstract = {Neurodegenerative comorbidities are common and critical, yet data specific to the Chinese population remains limited. The study aims to investigate the prevalence and associations of neuropathologic changes and comorbidities, and their correlation with genetics and cognition in a community-dwelling autopsy cohort in China. Datasets of 610 participants were obtained from the National Human Brain Bank for Development and Function at the Chinese Academy of Medical Sciences/Peking Union Medical College. Neuropathological changes analysed included Alzheimer's disease neuropathological change (ADNC) (n = 331); α-synucleinopathies (n = 124) with 120 Lewy body disease (LBD) and 4 multiple system atrophy; limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) (n = 341); primary age-related tauopathy (PART) (n = 231); argyrophilic grain disease (AGD) (n = 107); age-related tau astrogliopathy (ARTAG) (n = 144); cerebral amyloid angiopathy (CAA) (n = 183); hippocampus sclerosis (HS) (n = 46). Frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and amygdala-predominant LBD are rare. Descriptive statistics and logistic regression models were used to assess the neuropathological associations. Increased age at death was correlated with increased severity in ADNC, LBD, and LATE-NC, as well as with a higher number of comorbidities. APOE ε4 allele frequency in the present autopsy cohort was 13.63%. The presence of the APOE ε4 allele was linked to an advanced ADNC stage and increased comorbidities. The co-pathology prevalence varied by pathologies, with notable increases in specific subgroups: within the ADNC subgroups, LBD, LATE-NC, CAA, and HS were more frequent in advanced stages; in the LATE-NC subgroups, ADNC, CAA, and ARTAG increased, while PART decreased in higher LATE-NC stages. PART cases presented the highest proportion of pure pathology (37.2%) compared to other groups. Advanced ADNC stages were significantly associated with higher LATE-NC stages, and vice versa. Neocortical LBD was correlated with elevated ADNC levels, and higher LATE-NC stages were associated with worsening LBD pathology. High level ADNC, neocortical LBD, and stage 3 of LATE-NC were identified as independent predictors of severe cognition status. Our study suggests that older age at death and APOE ε4 presence are the risk factors for neuropathologic comorbidities in Chinese people. The findings underscore the importance of considering comorbid neurologic diagnoses and therapies in clinical practice.}, } @article {pmid39901566, year = {2025}, author = {Park, NY and Heo, Y and Yang, JW and Yoo, JM and Jang, HJ and Jo, JH and Park, SJ and Lin, Y and Choi, J and Jeon, H and Cha, SJ and Bae, G and Kim, D and Kim, J and Zeno, W and Park, JB and Isozumi, N and Saio, T and Kim, SH and Lee, H and Hong, BH and Nahm, M and Lee, YH and Hong, YB}, title = {Graphene Quantum Dots Attenuate TDP-43 Proteinopathy in Amyotrophic Lateral Sclerosis.}, journal = {ACS nano}, volume = {19}, number = {9}, pages = {8692-8710}, pmid = {39901566}, issn = {1936-086X}, mesh = {*Quantum Dots/chemistry ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/drug therapy ; Animals ; *Graphite/chemistry/pharmacology ; *DNA-Binding Proteins/metabolism/chemistry ; Mice ; Humans ; Mice, Transgenic ; TDP-43 Proteinopathies/pathology/metabolism/drug therapy ; Motor Neurons/metabolism/pathology/drug effects ; Amyloid/chemistry/metabolism/antagonists & inhibitors ; Disease Models, Animal ; }, abstract = {Aberrant phase separation- and stress granule (SG)-mediated cytosolic aggregation of TDP-43 in motor neurons is the hallmark of amyotrophic lateral sclerosis (ALS). In this study, we found that graphene quantum dots (GQDs) potentially modulate TDP-43 aggregation during SG dynamics and phase separation. The intrinsically disordered region in the C-terminus of TDP-43 exhibited amyloid fibril formation; however, GQDs inhibited the formation of amyloid fibrils through direct intermolecular interactions with TDP-43. These effects were accompanied by attenuation of the ALS phenotype in animal models. Additionally, GQDs delayed the onset and survival of TDP-43 transgenic mouse models by enhancing motor neuron survival, reducing glial activation, and reducing the cytosolic aggregation of TDP-43 in motor neurons. In this research, we demonstrated the efficacy of GQDs on the SG-mediated aggregation of TDP-43 and the binding property of GQDs with TDP-43. Additionally, we demonstrated the clinical feasibility of GQDs using several animal models and other types of ALS caused by FUS and C9orf72. Therefore, GQDs could offer a new therapeutic approach for proteinopathy-associated ALS.}, } @article {pmid39901378, year = {2025}, author = {San Gil, R and Walker, AK}, title = {Unlocking Disease-Modifying Treatments for TDP-43-Mediated Neurodegeneration.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {47}, number = {4}, pages = {e202400257}, pmid = {39901378}, issn = {1521-1878}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Animals ; Neurodegenerative Diseases/metabolism/genetics/pathology ; }, abstract = {Neurons degenerate in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), causing progressive and inevitably fatal neurological decline. The best therapeutic strategies target underlying disease mediators, but after decades of intensive research, the causes of these neurodegenerative diseases remain elusive. Recently, coordinated activities of large consortia, increasing open access to large datasets, new methods such as cryo-transmission electron microscopy, and advancements in high-resolution omics technologies have offered new insights into the biology of disease that bring us closer to understanding mechanisms of neurodegeneration. In particular, improved understanding of the roles of the key pathological protein TAR DNA binding protein 43 (TDP-43) in disease has revealed intriguing new opportunities that provide hope for better diagnostic tools and effective treatments for ALS and FTD.}, } @article {pmid39900510, year = {2025}, author = {van Altena, EJE and Jansen, BHE and Vis, AN}, title = {Reply to Ignacio Puche-Sanz, Ugo Giovanni Falagario, Giorgio Gandaglia, et al's Letter to the Editor re: Evelien J.E. van Altena, Bernard H.E. Jansen, Marieke L. Korbee, et al. Prostate-specific Membrane Antigen Positron Emission Tomography Before Reaching the Phoenix Criteria for Biochemical Recurrence of Prostate Cancer After Radiotherapy: Earlier Detection of Recurrences. Eur Urol Oncol. In press. https://doi.org/10.1016/j.euo.2024.09.015.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2025.01.011}, pmid = {39900510}, issn = {2588-9311}, } @article {pmid39899435, year = {2025}, author = {Blake, J and Peryer, G and Dance, R and Parke, S and Aryankhesal, A and Farquhar, M}, title = {How can healthcare professionals work with families to address misaligned expectations of recovery in brain injury rehabilitation? A scoping review.}, journal = {Brain injury}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/02699052.2025.2450603}, pmid = {39899435}, issn = {1362-301X}, abstract = {INTRODUCTION: Most survivors of severe acquired brain injuries will have significant long-term disability. During inpatient rehabilitation, families often have expectations of recovery that do not match healthcare professional opinion. This impacts on patient care, service processes, professional-family relations, and wellbeing. This review aimed to understand how family expectations are managed in this setting, and to explore potential areas of improvement.

METHOD: A scoping review was conducted by searching CINAHL, Medline, EMBASE and Web of Science. Krieger et al's 'Conceptual Building Blocks' provided a framework to analyze the data using a 'best fit' framework synthesis approach.

RESULTS: Twenty-one papers were included in the review. Six sub-themes within three overarching themes were generated, which explored recommendations for effective expectation management. The sub-themes within the 'staff behaviors' theme were 'appropriate information provision,' 'open communication' and 'prioritize family.' Sub-themes within 'system behaviors' were 'cultural change' and 'increased resource.' 'Rehabilitation as a shared process' was the third theme.

DISCUSSION: Misaligned expectations of recovery appear to reflect a range of unmet family needs related to their position within the healthcare hierarchy, professional-family communication, and their involvement in rehabilitation processes. Early identification of family and healthcare professional expectations alongside regular review may prevent misunderstanding and conflict.}, } @article {pmid39898446, year = {2025}, author = {Boddy, SL and Simpson, RM and Walters, SJ and Bamford, H and Walsh, T and McDermott, CJ and , }, title = {Estimating the minimum important difference in the ALSFRS-R-instrument in people living with MND.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2447916}, pmid = {39898446}, issn = {2167-9223}, support = {MCRGS-07-16-13/MCCC_/Marie Curie/United Kingdom ; }, abstract = {Objective: The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is a commonly used outcome measure in clinical trials for motor neuron disease (MND) therapies. As such, understanding how differences in scores relate to patient perception of their disease status is important when interpreting ALSFRS-R data. Our study sought to estimate the minimal important difference (MID) for the ALSFRS-R, the smallest difference in scores at which patients perceive a change in their quality of life. Methods: Data were collected as part of a longitudinal, observational saliva management study, ProSec3. These included both the ALSFRS-R and a global rating of change question (GRoC), which asked participants to rate how their disease had progressed since the previous visit. Anchor-based and distribution-based methods have been used to estimate the MID of the ALSFRS-R. The MID was estimated using two methods of calculating the total ALSFRS-R score, the original summation scale method and the recently proposed interval scale method. Results: A total of 145 people with MND had longitudinal ALSFRS-R and GRoC data. Different methods estimated the ALSFRS-R MID to be in the range of 2.02-5.43 for the summation scale and 1.23-3.31 for the interval scale method over a 3-month period, the time between study visits. Using anchor-based methods our MID estimates for the ALSFRS-R are 3.8 points and 2 points, respectively. Conclusions: The results of this study can guide clinicians and researchers in the interpretation of ALSFRS-R data. However, further studies are required to more precisely estimate the ALSFRS-R MID.}, } @article {pmid39897942, year = {2025}, author = {Quarracino, C and Capani, F and Otero-Losada, M and Rodríguez, GE and Pérez-Lloret, S}, title = {Frequency of orthostatic hypotension in the Pooled Resource Open-Access ALS Clinical Trials database.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1512357}, pmid = {39897942}, issn = {1664-2295}, abstract = {PURPOSE: To explore the frequency of orthostatic hypotension (OH) in a large sample of amyotrophic lateral sclerosis patients (ALS).

METHODS: From the PRO-ACT database, data of 1,240 ALS patients were analyzed, focusing on blood pressure and heart rate before and after standing. OH was defined as a drop in systolic/diastolic blood pressure > 20/10 mm Hg within 3 min of standing. Neurogenic OH was diagnosed when the heart rate increase was below 15 bpm in patients not taking medications that could affect this response.

RESULTS: At baseline, 138 (11.1%) patients showed OH, 76.1% of whom had neurogenic OH. At follow-up, 163 patients (13.1%) had OH, 71.2% with neurogenic OH. Only 22.5% of the patients with OH at baseline had OH at follow-up.

CONCLUSION: In a large sample of ALS patients, OH occurred in 11-13%, pointing to a subgroup that might require special care to avoid related complications.}, } @article {pmid39897290, year = {2025}, author = {McBenedict, B and Hauwanga, WN and Nezam, U and Ko Oo, A and Eapi, S and Pradhan, S and Dang, NB and Cher, PW and Orsini, MA and Lima Pessôa, B}, title = {Amyotrophic Lateral Sclerosis (ALS) Type 8: A Narrative Review.}, journal = {Cureus}, volume = {17}, number = {1}, pages = {e76717}, pmid = {39897290}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis type 8 (ALS8) is a rare familial subtype of ALS caused by mutations in the vesicle-associated membrane protein-associated protein B (VAPB) gene, particularly the p.P56S mutation. It is distinguished by slower disease progression and an earlier onset compared to sporadic ALS forms, along with unique clinical features such as severe cramping, fasciculations, postural tremors, and cognitive and behavioral impairments. Although current pharmacological options, such as riluzole, edaravone, and sodium phenylbutyrate/taurursodiol, provide modest benefits, they fail to address the underlying genetic mechanisms of ALS8. Emerging gene therapies, RNA-based interventions, and stem cell approaches hold promise for precision-targeted treatments but face challenges in clinical application. Symptom management strategies, including respiratory, nutritional, and psychological support, are crucial for improving patient outcomes and quality of life. Despite significant progress in understanding the genetic and molecular pathogenesis of ALS8, its rarity, phenotypic variability, and limited clinical data pose challenges to therapeutic advancements. This narrative review highlights current therapeutic strategies, the unique clinical trajectory of ALS8, and potential pathways for innovative, subtype-specific interventions, emphasizing the need for multidisciplinary and targeted approaches to optimize care for this distinct ALS subtype.}, } @article {pmid39896335, year = {2025}, author = {Eckardt, A and Marble, C and Fern, B and Moritz, H and Kotula, C and Ke, J and Rebancos, C and Robertson, S and Nishimune, H and Suzuki, M}, title = {Muscle-specific Bet1L knockdown induces neuromuscular denervation, motor neuron degeneration, and motor dysfunction in a rat model of familial ALS.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1527181}, pmid = {39896335}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by specific loss of motor neurons in the spinal cord and brain stem. Although ALS has historically been characterized as a motor neuron disease, there is evidence that motor neurons degenerate in a retrograde manner, beginning in the periphery at the neuromuscular junctions (NMJs) and skeletal muscle. We recently reported a vesicle trafficking protein Bet1L (Bet1 Golgi Vesicular Membrane Trafficking Protein Like) as a new molecule possibly linked to NMJ degeneration in ALS. In this study, we tested the hypothesis that Bet1L gene silencing in skeletal muscle could influence NMJ integrity, motor neuron function, and survival in a rat model of familial ALS (SOD1[G93A] transgenic). Small interfering RNA (siRNA) targeting the Bet1L gene was injected on a weekly basis into the hindlimb muscle of pre-symptomatic ALS and wild-type (WT) rats. After 3 weeks, intramuscular Bet1L siRNA injection significantly increased the number of denervated NMJs in the injected muscle. Bet1L knockdown decreased motor neuron size in the lumbar spinal cord, which innervated the siRNA-injected hindlimb. Impaired motor function was identified in the hindlimbs of Bet1L siRNA-injected rats. Notably, the effects of Bet1L knockdown on NMJ and motor neuron degeneration were more significant in ALS rats when compared to WT rats. Together, Bet1L knockdown induces denervation of NMJs, but also this knockdown accelerates the disease progression in ALS. Our results provide new evidence to support the potential roles of Bet1L as a key molecule in NMJ maintenance and ALS pathogenesis.}, } @article {pmid39894843, year = {2025}, author = {Chen, L and Shen, Q and Liu, Y and Zhang, Y and Sun, L and Ma, X and Song, N and Xie, J}, title = {Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases.}, journal = {Signal transduction and targeted therapy}, volume = {10}, number = {1}, pages = {31}, pmid = {39894843}, issn = {2059-3635}, support = {32471049//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32170984//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32200802//National Natural Science Foundation of China (National Science Foundation of China)/ ; ZR2020YQ23//Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)/ ; ZR2024MC153//Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)/ ; }, mesh = {Humans ; *Iron/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; *Homeostasis ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Copper/metabolism ; Metals/metabolism ; Ferroptosis/genetics ; Oxidative Stress ; Zinc/metabolism ; Alzheimer Disease/metabolism/genetics/pathology/drug therapy ; Animals ; }, abstract = {As essential micronutrients, metal ions such as iron, manganese, copper, and zinc, are required for a wide range of physiological processes in the brain. However, an imbalance in metal ions, whether excessive or insufficient, is detrimental and can contribute to neuronal death through oxidative stress, ferroptosis, cuproptosis, cell senescence, or neuroinflammation. These processes have been found to be involved in the pathological mechanisms of neurodegenerative diseases. In this review, the research history and milestone events of studying metal ions, including iron, manganese, copper, and zinc in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), will be introduced. Then, the upstream regulators, downstream effector, and crosstalk of mental ions under both physiologic and pathologic conditions will be summarized. Finally, the therapeutic effects of metal ion chelators, such as clioquinol, quercetin, curcumin, coumarin, and their derivatives for the treatment of neurodegenerative diseases will be discussed. Additionally, the promising results and limitations observed in clinical trials of these metal ion chelators will also be addressed. This review will not only provide a comprehensive understanding of the role of metal ions in disease development but also offer perspectives on their modulation for the prevention or treatment of neurodegenerative diseases.}, } @article {pmid39894561, year = {2025}, author = {Ito, T and Ohuchi, K and Kurita, H and Murakami, T and Takizawa, S and Fujimaki, A and Murata, J and Oida, Y and Hozumi, I and Kitaichi, K and Inden, M}, title = {Activated Fibroblast Growth Factor Receptor 1 Mitigated Poly-PR-Induced Oxidative Stress and Protein Translational Impairment.}, journal = {Biological & pharmaceutical bulletin}, volume = {48}, number = {2}, pages = {93-100}, doi = {10.1248/bpb.b24-00794}, pmid = {39894561}, issn = {1347-5215}, mesh = {*Oxidative Stress/drug effects ; *Receptor, Fibroblast Growth Factor, Type 1/metabolism/genetics ; Animals ; Mice ; *NF-E2-Related Factor 2/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Protein Biosynthesis ; Cell Line ; Motor Neurons/metabolism ; Dipeptides/pharmacology ; Neuroprotective Agents/pharmacology ; C9orf72 Protein/genetics/metabolism ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron cell death. A GGGGCC hexanucleotide repeat expansion (HRE) within the chromosome 9 open reading frame 72 (C9orf72) gene is a major causative factor in ALS. This abnormal HRE triggers five types of dipeptide repeat protein (DPR), each composed of two alternating amino acid expressions. Among the DPRs, arginine-rich Poly-PR localizes predominantly to the nucleus, exerting particularly strong toxicity on motor and cortical neurons. Several mechanisms have been proposed for poly-PR-induced neurotoxicity. In this study, poly-PR-expressing NSC34 motor neuron-like cells showed an increase in oxidative stress. Fibroblast growth factor receptor 1 (FGFR1) is known to promote neurogenesis and inhibit apoptosis in neurons. However, its neuroprotective effects against DPR-induced toxicity have not been previously reported. Here, we demonstrated that FGFR1 activation reduced oxidative stress by upregulating nuclear factor erythroid 2-related factor 2 (NRF2) expression. Furthermore, we propose that the increase in NRF2 through FGFR1 activation may result from the alleviation of protein translation impairment. Overall, these findings suggest that FGFR1 activation provides neuroprotection against poly-PR toxicity and may represent a potential therapeutic strategy for ALS.}, } @article {pmid39894369, year = {2025}, author = {Jairath, N and Manduca, S and Que, SKT}, title = {Response to Wang et al's limitations and risks of custom GPTs in dermatology. Comment on "ReconGPT: A novel artificial intelligence tool and its potential use in post-Mohs reconstructive decision-making".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.01.072}, pmid = {39894369}, issn = {1097-6787}, } @article {pmid39893487, year = {2025}, author = {Pilotto, F and Smeele, PH and Scheidegger, O and Diab, R and Schobesberger, M and Sierra-Delgado, JA and Saxena, S}, title = {Kaempferol enhances ER-mitochondria coupling and protects motor neurons from mitochondrial dysfunction and ER stress in C9ORF72-ALS.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {21}, pmid = {39893487}, issn = {2051-5960}, support = {725825//European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program/ ; 725825//European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program/ ; 725825//European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program/ ; }, mesh = {*Kaempferols/pharmacology ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics/drug therapy ; *Endoplasmic Reticulum Stress/drug effects ; Humans ; *Mitochondria/drug effects/metabolism/pathology ; *Motor Neurons/drug effects/metabolism/pathology ; Mice ; *Neuroprotective Agents/pharmacology ; *C9orf72 Protein/genetics/metabolism ; *Endoplasmic Reticulum/drug effects/metabolism ; Mice, Transgenic ; Male ; Female ; Mice, Inbred C57BL ; }, abstract = {Repeat expansions in the C9ORF72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Considerable progress has been made in identifying C9ORF72-mediated disease and resolving its underlying etiopathogenesis. The contributions of intrinsic mitochondrial deficits as well as chronic endoplasmic reticulum stress to the development of the C9ORF72-linked pathology are well established. Nevertheless, to date, no cure or effective therapy is available, and thus attempts to find a potential drug target, have received increasing attention. Here, we investigated the mode of action and therapeutic effect of a naturally occurring dietary flavanol, kaempferol in preclinical rodent and human models of C9ORF72-ALS. Notably, kaempferol treatment of C9ORF72-ALS human patient-derived motor neurons/neurons, resolved mitochondrial deficits, promoted resiliency against severe ER stress, and conferred neuroprotection. Treatment of symptomatic C9ORF72 mice with kaempferol, normalized mitochondrial calcium uptake, restored mitochondria function, and diminished ER stress. Importantly, in vivo, chronic kaempferol administration ameliorated pathological motor dysfunction and inhibited motor neuron degeneration, highlighting the translational potential of kaempferol. Lastly, in silico modelling identified a novel kaempferol target and mechanistically the neuroprotective mechanism of kaempferol is through the iP3R-VDAC1 pathway via the modulation of GRP75 expression. Thus, kaempferol holds great promise for treating neurodegenerative diseases where both mitochondrial and ER dysfunction are causally linked to the pathophysiology.}, } @article {pmid39893047, year = {2025}, author = {Zhu, A and Hu, JC}, title = {Reply to Alireza Ghoreifi, Jaffar Hussain, Wei Phin Tan, et al's Letter to the Editor re: Alec Zhu, Mary O. Strasser, Timothy D. McClure, et al. Comparative Effectiveness of Partial Gland Cryoablation Versus Robotic Radical Prostatectomy for Cancer Control. Eur Urol Focus 2024;10:843-50.}, journal = {European urology focus}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euf.2025.01.013}, pmid = {39893047}, issn = {2405-4569}, } @article {pmid39891470, year = {2025}, author = {Iazzolino, B and Palumbo, F and Moglia, C and Manera, U and Grassano, M and Matteoni, E and Cabras, S and Brunetti, M and Vasta, R and Pagani, M and Mora, G and Canosa, A and Calvo, A and Chiò, A}, title = {Frequency and Early Predictors of Cognitive Deterioration in Amyotrophic Lateral Sclerosis: A Longitudinal Population-Based Study.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27194}, pmid = {39891470}, issn = {1531-8249}, support = {ALS-Care//EU Joint Programme - Neurodegenerative Disease Research/ ; Brain-Mend//EU Joint Programme - Neurodegenerative Disease Research/ ; 101017598//HORIZON EUROPE Health/ ; RF-2016-02362405//Ministero della Salute/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca (Department of Excellence)/ ; 20228N7573//Ministero dell'Università e della Ricerca (Department of Excellence)/ ; 259867//FP7 Health/ ; }, abstract = {OBJECTIVE: The objective is to evaluate cognitive and behavioral progression and identify early predictors of these changes in a cohort of amyotrophic lateral sclerosis (ALS) patients.

METHODS: A total of 161 ALS patients were tested at diagnosis (T0), and 107 were re-tested after 1 year (T1) using cognitive/behavioral tests. All patients underwent whole-genome sequencing, and 46 patients (ALS-normal cognition [CN]) underwent [18F]Fluorodeoxyglucose positron emission tomography.

RESULTS: Of the 161 patients, 107 were re-rested at T1; non-retested patients included 10 with frontotemporal dementia and 44 who were either non-testable or deceased. At T0, 67 patients (62.6%) were classified as ALS-CN, whereas 40 (38.4%) showed some degree of cognitive/behavioral impairment. Eighteen ALS-CN patients (26.9%) experienced cognitive decline at T1. Phenoconverters had lower baseline scores in letter fluency (Letter Fluency Test [FAS]) (p < 0.001), Edinburgh Cognitive and Behavioral ALS Screen (ECAS) verbal fluency score (p = 0.017). Both tests were independently predictive of phenoconversion in binary logistic regression models, with optimal cut-off scores of 28.75 and 14.2, with good sensitivity and specificity. Other predictors included older age, lower education, and ALS-related genetic variants. Phenoconverters were hypometabolic in the left temporal lobe. Thirteen (32.5%) of the 40 patients with cognitive impairment at T0 worsened by T1, with FAS (p = 0.02) and the ECAS verbal fluency score (p = 0.023) predicting further decline.

INTERPRETATION: Approximately 30% of ALS patients experienced cognitive/behavioral decline within the first year after diagnosis. FAS and ECAS verbal fluency were predictive of cognitive phenoconversion. Our findings highlight the importance of early detection of at-risk individuals and the need for longitudinal cognitive assessments to monitor disease progression. ANN NEUROL 2025.}, } @article {pmid39891383, year = {2025}, author = {Chen, M and Cui, H and Zhang, X and Ma, S and Guo, J and Liu, Z and Gu, D and Fan, Y}, title = {Super-Enhancer Protects Cells From Toxicity of C9orf72 Poly(proline-arginine) by Inducing the Expression of KPNA2/KPNB1.}, journal = {Cell biochemistry and function}, volume = {43}, number = {2}, pages = {e70053}, doi = {10.1002/cbf.70053}, pmid = {39891383}, issn = {1099-0844}, support = {//This work was supported by the National Natural Science Foundation of China (31970616, 82070505) and Jiangsu Provincial Natural Science Foundation (BK20211330)./ ; }, mesh = {*C9orf72 Protein/metabolism/genetics ; Humans ; beta Karyopherins/metabolism ; alpha Karyopherins/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; }, abstract = {Hexanucleotide repeat expansions in C9orf72 are the most common genetic mutation associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Dipeptide repeat (DPR) proteins, such as poly(proline-arginine) (polyPR) generated from G4C2 repeat expansions, have been shown to be highly toxic. In this study, PR20 was labeled with fluorescein isothiocyanate (FITC) to track its cellular localization. Several cell lines demonstrated survival under PR20 treatment by sequestering PR20 in the cytoplasm. Treatment with JQ-1 or Ivermectin (Iver) translocated PR20 into the nucleus, leading to cell death. Mechanistically, KPNA2/KPNB1 interacted with PR20 in the cytoplasm and hindered PR20 from entering the cell nucleus. Genetic silencing of KPNA2/KPNB1 converted PR20-resistant cells into PR20-sensitive cells. Treatment with JQ1 significantly reduced the protein levels of KPNA2/KPNB1, allowing PR20 to enter the nucleus. Overexpression of KPNA2 or KPNB1 effectively blocked cell death induced by co-treatment with JQ-1 and PR20. Our results indicate that super-enhancers shield cells from PR20 toxicity by upregulating the expression of KPNA2/KPNB1.}, } @article {pmid39891231, year = {2025}, author = {Rakab, MS and Zaid, AB and Hamadein, MA and Hamadein, SA and Ashour, MAE and El-Shamia, AS and Mostafa, DA and Rateb, RM and Elashry, MA and El-Badawy, MM and Shaheen, RSB}, title = {Assessment of ABCDE approach knowledge among residents and interns in multiple Egyptian hospitals, a cross-sectional study.}, journal = {BMC medical education}, volume = {25}, number = {1}, pages = {164}, pmid = {39891231}, issn = {1472-6920}, mesh = {Humans ; Egypt ; *Internship and Residency ; Cross-Sectional Studies ; Male ; Female ; Adult ; *Clinical Competence ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: The Airway, Breathing, Circulation, Disability, and Exposure (ABCDE) approach is crucial in emergency care, but there may be variability in adherence among healthcare professionals. Inconsistent application of this approach may lead to variations in patient care quality and outcomes. Identifying the factors influencing adherence can help improve training to ensure more effective application across emergency settings. This study explores the theoretical knowledge of the ABCDE approach among Egyptian resident doctors and medical interns.

METHODS: An online survey was conducted in Egypt targeting resident doctors and medical interns. Statistical analyses were performed using SPSS 26 and Excel, descriptive statistics and association tests were used to measure the relationship between knowledge and demographic factors.

RESULTS: The study included 422 medical residents and interns, with most in university hospitals. The average knowledge score of 59.1% exposed specific gaps in understanding, emphasizing deficiencies in 12 questions answered by less than 50%. Notably, 49.5% acquired ABCDE knowledge from medical school, while 28.2% had ALS/BLS courses. Encouragingly, 91.2% expressed willingness for life support training. Statistical analyses unveiled significant associations between knowledge scores and both medical practice settings and sources of ABCDE knowledge. Surgeons exhibited the lowest knowledge scores among participants, emphasizing the need for tailored interventions across specialties.

CONCLUSION: This study addresses a critical gap in ABCDE approach knowledge among Egyptian resident doctors and medical interns. The study points to the need for focused education, especially for surgeons, to improve emergency care skills and patient outcomes through continued training.}, } @article {pmid39889925, year = {2025}, author = {Bian, Y and Fukui, Y and Ota-Elliott, RS and Hu, X and Sun, H and Bian, Z and Zhai, Y and Yu, H and Hu, X and An, H and Liu, H and Morihara, R and Ishiura, H and Yamashita, T}, title = {The potential mechanism maintaining transactive response DNA binding protein 43 kDa in the mouse stroke model.}, journal = {Neuroscience research}, volume = {213}, number = {}, pages = {128-137}, doi = {10.1016/j.neures.2025.01.006}, pmid = {39889925}, issn = {1872-8111}, mesh = {Animals ; Male ; *DNA-Binding Proteins/metabolism ; *Mice, Inbred C57BL ; *Disease Models, Animal ; *Stroke/metabolism/pathology ; Mice ; Infarction, Middle Cerebral Artery/metabolism ; Histone Deacetylase 6/metabolism ; Brain/metabolism ; }, abstract = {The disruption of transactive response DNA binding protein 43 kDa (TDP-43) shuttling leads to the depletion of nuclear localization and the cytoplasmic accumulation of TDP-43. We aimed to evaluate the mechanism underlying the behavior of TDP-43 in ischemic stroke. Adult male C57BL/6 J mice were subjected to 30 or 60 min of transient middle cerebral artery occlusion (tMCAO), and examined at 1, 6, and 24 h post reperfusion. Immunostaining was used to evaluate the expression of TDP-43, G3BP1, HDAC6, and RAD23B. The total and cytoplasmic number of TDP-43-positive cells increased compared with sham operation group and peaked at 6 h post reperfusion after tMCAO. The elevated expression of G3BP1 protein peaked at 6 h after reperfusion and decreased at 24 h after reperfusion in ischemic mice brains. We also observed an increase of expression level of HDAC6 and the number of RAD23B-positive cells increased after tMCAO. RAD23B was colocalized with TDP-43 24 h after tMCAO. We proposed that the formation of stress granules might be involved in the mislocalization of TDP-43, based on an evaluation of G3BP1 and HDAC6. Subsequently, RAD23B, may also contribute to the downstream degradation of mislocalized TDP-43 in mice tMCAO model.}, } @article {pmid39889542, year = {2025}, author = {Albrecht, F and Kvist, A and Franzén, E}, title = {Resting-state functional near-infrared spectroscopy in neurodegenerative diseases - A systematic review.}, journal = {NeuroImage. Clinical}, volume = {45}, number = {}, pages = {103733}, pmid = {39889542}, issn = {2213-1582}, mesh = {Humans ; *Spectroscopy, Near-Infrared/methods/standards ; *Neurodegenerative Diseases/diagnostic imaging/physiopathology ; Brain/diagnostic imaging/physiopathology ; Rest/physiology ; }, abstract = {OBJECTIVE: To systematically review and summarize alterations found in resting-state activity as measured via functional near-infrared spectroscopy (fNIRS) in neurodegenerative diseases.

BACKGROUND: fNIRS is a novel and emerging neuroimaging method suitable for a variety of study designs. Resting-state is the measure of brain activity in the absence of a task, which has been investigated for yielding information about neurodegenerative diseases, mainly using magnetic resonance imaging. We aimed to systematically review the usage of resting-state fNIRS (rsfNIRS) in neurodegenerative diseases.

INCLUSION CRITERIA: Studies investigating people diagnosed with a neurodegenerative disease and resting-state activity obtained with fNIRS using at least two channels.

METHODS: We searched three databases for publications. After the screening, 16 studies were included in the systematic review. The quality of the studies was assessed, and data were extracted. Data were qualitatively synthesized and in the case of at least 10 similar studies, a meta-analysis was planned.

RESULTS: Most studies investigated Mild cognitive impairment (50%), followed by Alzheimer's disease (25%). Other neurodegenerative diseases encompassed Parkinson's disease, Multiple sclerosis, and Amyotrophic lateral sclerosis. All studies reported oxygenated hemoglobin. Still, studies were heterogeneous in terms of study design, measurement duration, fNIRS device, montage, pre-processing, and analyses. A meta-analysis was not considered possible due to this heterogeneity.

CONCLUSION: rsfNIRS shows promise in neurodegenerative disease, as most studies have observed resting-state alterations when compared to healthy controls. However, inconsistencies across studies limit data comparison and meta-analysis. Hence, we strongly advocate the application of fNIRS reporting guidelines and the establishment of rsfNIRS-specific guidelines. This will ensure reliable and comparable results in future research.}, } @article {pmid39889424, year = {2025}, author = {Pascual, A and May, PB and Cárdenas-Martínez, A and Guerra-Hernández, J and Hunka, N and Bruening, JM and Healey, SP and Armston, JD and Dubayah, RO}, title = {Calibration of GEDI footprint aboveground biomass models in Mediterranean forests with NFI plots: A comparison of approaches.}, journal = {Journal of environmental management}, volume = {375}, number = {}, pages = {124313}, doi = {10.1016/j.jenvman.2025.124313}, pmid = {39889424}, issn = {1095-8630}, mesh = {*Biomass ; *Forests ; Ecosystem ; Spain ; Models, Theoretical ; Calibration ; }, abstract = {Observations from the NASA Global Ecosystem Dynamics Investigation (GEDI) provide global information on forest structure and biomass. Footprint-level predictions of aboveground biomass density (AGBD) in the GEDI mission are based on training data sourced from sparsely distributed field plots coincident with airborne laser scanning surveys. National Forest Inventories (NFI) are rarely used to calibrate GEDI footprint biomass models because their sampling and positional accuracy prevent accurate colocation with GEDI or ALS. This omission can limit the harmonization of jurisdictional biomass estimates from NFI's and GEDI; however, there are methods available to improve the colocation of NFI plots with GEDI footprints. Focusing on Mediterranean forests in Spain, we compared different approaches to the collocation of NFI and GEDI data: (i) simulated waveforms from ALS; (ii) nearest-neighbor on-orbit GEDI waveforms; and (iii) imputed GEDI waveforms imputed to NFI plot locations using a novel geostatistical method. These methods are potential solutions to improve the local performance of biomass models and address potential local systematic deviations between GEDI and NFI estimates. We assess the advantages and limitations of these methods to locally calibrate GEDI biomass models and quantify the impact of geolocation errors in reference NFI plot data. The new biomass models from each method were used to predict footprint level AGBD, which were then gridded for a province in the North-West of Spain. It was found that the imputation approach is not sensitive to common errors in NFI plot geolocation, but it can outperform ALS-based simulation in some cases, highlighting the benefit of information from multiple GEDI footprints proximate to NFI plots for improving biomass predictions. This research provides users with benchmark of available techniques to locally-calibrate GEDI footprint biomass models.}, } @article {pmid39887552, year = {2025}, author = {Dopler, MB and Abeer, MI and Arezoumandan, S and Cox, K and Petersen, TL and Daniel, EH and Cannon, CL and Bautista, A and Blancher, KD and Bland, AM and Bond, KJ and Davis, DA and Francois, JM and McCray, EJ and Morgan, JM and Pulliam, JL and Robinson, ZA and Taylor, MJ and Dowell, JA and Cairns, NJ and Gitcho, MA}, title = {A cellular model of TDP-43 induces phosphorylated TDP-43 aggregation with distinct changes in solubility and autophagy dysregulation.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.17413}, pmid = {39887552}, issn = {1742-4658}, support = {52008702//HHMI/ ; 2023004//National Science Foundation/ ; P20GM103446/GM/NIGMS NIH HHS/United States ; 0823//The Paul H. Boerger Fund of the Delaware Community Foundation/ ; R25 GM122722/GM/NIGMS NIH HHS/United States ; P20GM103653/GM/NIGMS NIH HHS/United States ; T32GM144895-03/GM/NIGMS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that affects neurons in the brain and spinal cord, causing loss of muscle control, and eventually leads to death. Phosphorylated transactive response DNA binding protein-43 (TDP-43) is the major pathological protein in both sporadic and familial ALS, forming cytoplasmic aggregates in over 95% of cases. Of the 10-15% of ALS cases that are familial, mutations in TDP-43 represent about 5% of those with a family history. We have developed an in vitro overexpression model by introducing three familial ALS mutations (A315T, M337V, and S379P) in the TDP-43 (TARDBP) gene which we define as 3X-TDP-43. This overexpression model TDP-43 shows deficits in autophagy flux and colocalization of TDP-43 with stress granules. We also observe a progressive shift of TDP-43 to the cytoplasm in this model. This overexpression model shows a reduction in solubility of phosphorylated TDP-43 from RIPA to urea soluble. Four glycolytic enzymes, phosphoglycerate kinase one (PGK1), aldolase A (ALDOA), enolase 1 (ENO1), and pyruvate dehydrogenase kinase 1 (PDK1) show significant time-dependent decreases in 3X-TDP-43 expressing cells. Shotgun proteomic analysis shows global changes in the importin subunit alpha-1 (KPNA2), heat shock 70 kDa protein 1A (HSPA1A), and protein disulfide-isomerase A3 (PDIA3) expression levels and coimmunoprecipitation reveals that these proteins complex with TDP-43. Overall, these results suggest that the 3X-TDP-43 model may provide new insights into pathophysiology and an avenue for drug screening in vitro for those suffering from ALS and related TDP-43 proteinopathies.}, } @article {pmid39886777, year = {2025}, author = {Alkhazaali-Ali, Z and Sahab-Negah, S and Boroumand, AR and Farkhad, NK and Khodadoust, MA and Ganjali, R and Tavakol-Afshari, J}, title = {Evaluation of Safety and Efficacy of Repeated Mesenchymal Stem Cell Transplantation in Patients with Amyotrophic Lateral Sclerosis (ALS) by Investigating Patient's Specific microRNAs as Novel Biomarkers: A Clinical Trial Study.}, journal = {Current stem cell research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.2174/011574888X330199250106081717}, pmid = {39886777}, issn = {2212-3946}, abstract = {BACKGROUND: Since there is currently no cure for amyotrophic lateral sclerosis (ALS), it is essential to search for diagnostic biomarkers and novel treatments to reduce the severity of this disease. One of these treatment approaches is stem cell transplantation.

OBJECTIVE: This study aims to evaluate the safety and efficacy of repeated transplantation of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with ALS by analyzing clinical and molecular data.

METHODS: This one-arm, single-center, open-label without a control group, prospective clinical trial, twenty-one confirmed ALS patients entered the study based on defined inclusion and exclusion criteria and underwent repeated stem cell transplantation (3 times BM-MSCs transplantation (1×10^6, MSC/Kg BW per injection) concurrently intrathecally (IT) and intravenously (IV), with one-month interval). Clinical assessment using ALS functional rating scale-revised (ALSFRS) and forced vital capacity (FVC) values and also molecular investigation by evaluating specific microRNAs expression (mir206, 133a-3p, 338-3p) in patient's serum and Cerebra spinal fluid (CSF) samples were done three times during the 3-month follow-up period.

RESULT: No serious adverse effects were reported during the study. Besides, significant improvement in FVC when compared the baseline with the end of the research and the p-value was (0.036), and stability in ALSFRS was observed, and the p-value was (p=0.16) following stem cell transplantation in patients; also, the mentioned microRNA expression was non-significant (p > 0.05) as reported as well.

CONCLUSION: Our results demonstrated that repeated transplantation of BM-MSCs was a safe procedure in ALS patients, leading to delay in disease progression and improvement in clinical symptoms. Future studies are needed to confirm these results.}, } @article {pmid39885830, year = {2025}, author = {Marthinsen, A and Gaweł, BA and Warden, GK and Górska-Ratusznik, A and Gaweł, K and Di Sabatino, M and Hallam, B}, title = {Al doped silica glass: investigation of structural response and defect interactions based on crystalline models.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {27}, number = {7}, pages = {3803-3809}, doi = {10.1039/d4cp04581e}, pmid = {39885830}, issn = {1463-9084}, abstract = {High purity quartz glass is an important material in high-tech industries like semiconductors and photovoltaics due to, among other properties, its good mechanical performance at high temperatures. Small amounts of Al in silica glass (in the range between 20 ppm and 100 ppm) have previously been shown to increase the viscosity of the SiO2 glass. The underlying mechanism for this increase is, however, not well understood. In this paper we report on the local structural and electronic effects of the presence of Al in the SiO2 structure by density functional theory (DFT). Comparing the quartz and cristobalite polymorphs, we found that the driving force for Al substitution is larger in the denser quartz structure compared to cristobalite, and that oxygen vacancy (Vo) formation is most stabilized in the nearest neighbour position relative to Al in both polymorphs. Al was not found to inherently strengthen the SiO2 network in the two crystalline polymorphs considered. However, our results suggest that Al preferentially substitutes Si in denser ring configurations, which combined with local Vo formation could lead to locally favourable SiO2 network reconstructions in SiO2 glasses (likely towards 6-membered rings), which could propagate causing an increase in the viscosity. Furthermore, we show that the presence of Al can lower the stability of OH groups due to increased electrostatic interactions between the substitutional Al and H2O which may also be a contributing factor in the increased viscosity of Al doped SiO2 glass. The modelling results are in line with the experimental fluorescence and FT-IR spectroscopy data confirming that the presence of Al in the glass causes formation of oxygen vacancies and correlates with a lower fictive temperature which typically corresponds to a larger average Si-O-Si angle in the glass structure. Our results suggest that Al's contribution to high glass viscosity is not solely due to the substitution of Si atoms by Al atoms in the glass structure but rather due to structural changes of the silica network the substitution causes.}, } @article {pmid39885728, year = {2025}, author = {Gondim, F and Fernandes, JMA}, title = {Another family with ALS and homozygosity for p.Val120Leu (c.358G > C) mutation of SOD1.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-2}, doi = {10.1080/21678421.2025.2457973}, pmid = {39885728}, issn = {2167-9223}, } @article {pmid39884586, year = {2025}, author = {Ye, L and Dittlau, KS and Sicart, A and Janky, R and Van Damme, P and Van Den Bosch, L}, title = {Sporadic ALS hiPSC-derived motor neurons show axonal defects linked to altered axon guidance pathways.}, journal = {Neurobiology of disease}, volume = {206}, number = {}, pages = {106815}, doi = {10.1016/j.nbd.2025.106815}, pmid = {39884586}, issn = {1095-953X}, mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Axon Guidance/physiology ; *Axons/pathology/metabolism ; Female ; Neuromuscular Junction/metabolism/pathology ; Male ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective and progressive loss of motor neurons, leading to gradual paralysis and death within 2 to 5 years after diagnosis. The exact underlying pathogenic mechanism(s) remain elusive. This is particularly the case for sporadic ALS (sALS), representing 90 % of cases, as modelling a sporadic disease is extremely difficult. We used human induced pluripotent stem cell (hiPSC)-derived motor neurons from sALS patients to investigate early disease mechanisms. The earliest phenotype that we observed were profound axonal defects including impaired axonal transport, defective axonal outgrowth and a reduced formation of neuromuscular junctions. Transcriptomic profiling revealed significant dysregulation in axon guidance pathways, with upregulation of specific axonal regeneration-inhibiting genes, such as EphA4 and DCC in sALS motor neurons. Our findings suggest that dysregulation of axon guidance pathways contributes to axonal defects and that this could play a crucial role in the pathogenesis of sALS.}, } @article {pmid39884579, year = {2025}, author = {Liu, WW and Wei, JC}, title = {Response to Vera et al's "Interleukin-23 inhibition associates with lower incidence of cardiovascular risk factor type diseases compared to biologic naïve patients with psoriasis: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.12.044}, pmid = {39884579}, issn = {1097-6787}, } @article {pmid39883905, year = {2025}, author = {Hollin, IL and Giler, G and Heiman-Patterson, TD and , }, title = {Health Care Delivery and Financial Considerations in Amyotrophic Lateral Sclerosis Clinics: A Survey of Clinic Directors.}, journal = {Neurology}, volume = {104}, number = {4}, pages = {e210015}, pmid = {39883905}, issn = {1526-632X}, mesh = {*Amyotrophic Lateral Sclerosis/economics/therapy ; Humans ; *Delivery of Health Care/economics ; Ambulatory Care Facilities/economics ; Surveys and Questionnaires ; Patient Care Team/economics ; United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Clinical care for people living with amyotrophic lateral sclerosis (PLWALS) is directed at slowing disease progression and symptom management. The American Academy of Neurology recommends a multidisciplinary approach to providing ALS health care because observational studies show that multidisciplinary clinics (MDCs) extend survival and improve quality of life. However, providing multidisciplinary care is a challenging financial proposition. To understand how MDCs are financed, we surveyed ALS MDCs across the Northeast ALS Consortium network in the United States.

METHODS: We surveyed clinic directors in the Northeast ALS Consortium, a group of institutions equipped to provide ALS care and perform research and clinical trials in ALS. Respondents (n = 61; response rate = 49.6%) provided information regarding their care model, services, funding sources, and financial solvency between December 2020 and August 2021.

RESULTS: In 74% (n = 45) of clinics, PLWALS were seen by the entire multidisciplinary team, and in 26% (n = 16) of clinics, PLWALS were seen by the physician and triaged according to needs. In 79% (n = 48) of clinics, visit duration was ≥3 hours, and on average, 8.4 services were available, compared with 6.8 in clinics lasting <3 hours. Most of the MDCs offer occupational (97%; n = 59), speech (97%; n = 59), and physical (95%; n = 58) therapies on site. The most common source of financial support was third-party nonprofits/philanthropy (92%; n = 56). Fifty-nine percent (n = 36) of clinics received financial support from their parent organizations (e.g., universities). Only 17% (n = 10) of clinics reported no deficit, and all clinics used multiple income sources.

DISCUSSION: These findings reconfirm the range of services available to PLWALS and highlight the financial challenges facing ALS MDCs. The main limitation is that recruitment was through the NEALS network which primarily includes MDCs, so we were not able to compare with non-MDCs. Since not all centers responded, there may be other differences in the characteristics of the centers that did respond and those that did not leading to some bias. Future work should support the goal of reducing reliance on funding from nonprofits and increase reimbursement from payers, so health care providers can provide high-quality ALS care and cover costs.}, } @article {pmid39883903, year = {2025}, author = {Fournier, CN and Quinn, CC}, title = {The Amyotrophic Lateral Sclerosis Multidisciplinary Clinic: Broke but Not Broken.}, journal = {Neurology}, volume = {104}, number = {4}, pages = {e210189}, doi = {10.1212/WNL.0000000000210189}, pmid = {39883903}, issn = {1526-632X}, } @article {pmid39882923, year = {2025}, author = {Koltsova, E and Smotraiev, R and Nehrii, A and Zhekeev, M and Ratnaweera, H}, title = {Mechanisms for removing phosphorus species through sequential coagulation using inorganic coagulants and organic polymers.}, journal = {Water science and technology : a journal of the International Association on Water Pollution Research}, volume = {91}, number = {2}, pages = {202-218}, pmid = {39882923}, issn = {0273-1223}, mesh = {*Phosphorus/chemistry ; *Polymers/chemistry ; Water Pollutants, Chemical/chemistry ; Water Purification/methods ; Alum Compounds/chemistry ; Waste Disposal, Fluid/methods ; }, abstract = {The need for stringent phosphorus removal from domestic wastewater is increasing to mitigate eutrophication, while efficient phosphate reuse is critical due to the global phosphate crisis. Combining aluminum sulfate (ALS) with high molecular weight organic polymers achieved 95-99% removal of particles, turbidity, and phosphates, reducing ALS usage by 40%. We propose mechanisms to explain the enhanced treatment efficiency. Particle and turbidity removal is more influenced by polymer charge density than molecular weight, while orthophosphate (OP) removal is linked to a change in zeta potential from negative to positive, allowing additional OP binding through complex formation with hydrolysis products and polymers. Enhanced phospholipid (PL) removal likely results from adsorption and neutralization of micelle PL charges by intermediate positively charged aluminum hydroxyphosphate ions. Higher PL removal with low ALS doses is attributed to a two-stage dosing process that optimizes coagulant and polymer dosages. The combined removal of OP and PL improves phosphorus bioavailability, increasing the sludge's fertilizer value.}, } @article {pmid39882298, year = {2024}, author = {Johnsen, JT and Rafaela Lima do Vale, M and Bhangaonkar, R and Nyaga, W and Ayyad, S and Ray, S}, title = {COVID-19's impact on food environment in the Indian states of Telangana, Maharashtra, West Bengal, Tamil Nadu and Punjab: a descriptive qualitative study to build further research in India's food environment resilience building.}, journal = {BMJ nutrition, prevention & health}, volume = {7}, number = {2}, pages = {e000844}, pmid = {39882298}, issn = {2516-5542}, abstract = {BACKGROUND AND AIM: Globally, COVID-19 has had a profound impact on food and nutrition security. This paper aims to gather the perspective from Transforming India's Green Revolution by Research and Empowerment for Sustainable food Supplies (TIGR2ESS) Flagship Project 6 (FP-6) team on the impact of COVID-19 on the food systems in India. The responses collected will be used for further research projects after TIGR2ESS ends in March 2022.

METHOD: Members of the TIGR2ESS FP-6 team in India were invited to complete an online open-ended questionnaire with 21 questions exploring the impact of the COVID-19 pandemic on food systems and environments in India. The questionnaire and data analysis were guided by the food environment framework developed by Turner et al and the adaptations proposed by the United Nations System Standing Committee on Nutrition. Discussions and organisation of codes under the respective themes and subthemes were held online using the virtual platform Miro. 35 individual codes and 65 subcodes were agreed on. Responses were collated and analysed using the template with support from NVivo software and synthesised the relevant themes under Turner et al's framework.

RESULTS: The organisation representatives from TIGR2ESS FP-6 (n=16) captured the perceived impact of the COVID-19 on food systems and the environment from the Indian states of Maharashtra, Punjab, Tamil Nadu, Telangana and West Bengal. Negative disruptions were caused by the COVID-19 restrictions across all the themes affecting food actors and consumers. Myths and misconception on dietary intake were reported across the state affecting especially the consumption of poultry. Positive aspects such as home cooking and awareness around healthy food emerged.

CONCLUSION: Potential research areas were identified and involve the effects of supply chain resilience buidling, farmers selling their produce directly to consumer and the revival of local and traditional food's impact on diets, understanding the harm for consumers by implementing restrictions, how indigenous and local food may impact peoples' diets, how to build on the encouragement of healthy home cooking during the pandemic, investigate the negative and positive effects of digital environments during the pandemic and dispelling myths and misconception while advocating for healthy diets.}, } @article {pmid39881481, year = {2025}, author = {Steenland, K and Tan, Y and Mullins, SM and Kidd, TE and Gong, Q and Lah, JJ}, title = {Survival of Patients at a Neurology Clinic: No Improvement Over 12 Years.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000658}, pmid = {39881481}, issn = {1546-4156}, abstract = {INTRODUCTION: We previously followed Emory patients with neurodegenerative disease from 1993 to 2006. Here, we follow survivor and new patients for 2007 to 2018.

METHODS: We studied mortality from 10 different diagnostic groups among 4322 research volunteers, and compared mortality rates to controls with normal cognition, using Cox regression. We assessed mortality through the National Death Index, controlling for sex, education, race, comorbidities, and age. Supplemental analyses considered APOE and cognitive test scores.

RESULTS: Fifty-nine percent of patients died during follow-up. Mortality rate ratios, compared with controls (n=641) in descending order were 12.54, 6.61, 4.77, 4.92, 3.36, 2.25, 2.21 1.71, 1.39, and 1.17 for diagnostic groups ALS, (n=571), FTD (n=197), LBD (n=134), PD (n=584), AD (n=1118), MCI/dementia (n=82), dementia not specified (n=165), PD symptoms (n=256), vascular dementia (n=234), and MCI (n=340), respectively. Women, non-whites, those with higher education, with no comorbidities, and lower ages had lower mortality rates for most diagnostic groups. Mortality rates were higher in the presence of APOE4 variants for several diagnostic groups. Lower MMSEs predicted worse survival for most diseases. Overall, 41% of patients survived during 12 years of follow-up, compared with an expected 75% in the US population.

CONCLUSION: Survival times for different diagnostic groups have changed little over several decades.}, } @article {pmid39880678, year = {2025}, author = {Kozlowski, MM and Strickland, A and Benitez, AM and Schmidt, RE and Bloom, AJ and Milbrandt, J and DiAntonio, A}, title = {Pmp2+ Schwann Cells Maintain the Survival of Large-Caliber Motor Axons.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {45}, number = {13}, pages = {}, pmid = {39880678}, issn = {1529-2401}, support = {R01 NS105645/NS/NINDS NIH HHS/United States ; R37 NS065053/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Schwann Cells/metabolism/drug effects ; Mice ; Female ; *Motor Neurons/drug effects/metabolism ; Male ; *Axons/drug effects ; Cell Survival/drug effects/physiology ; Mice, Transgenic ; Myelin Proteins/metabolism/genetics ; Mice, Inbred C57BL ; Tamoxifen/pharmacology ; }, abstract = {Neurodegenerative diseases of both the central and peripheral nervous system are characterized by selective neuronal vulnerability, i.e., pathology that affects particular types of neurons. While much of this cell type selectivity may be driven by intrinsic differences among the neuron subpopulations, neuron-extrinsic mechanisms such as the selective malfunction of glial support cells may also play a role. Recently, we identified a population of Schwann cells (SCs) expressing Adamtsl1, Cldn14, and Pmp2 (a.k.a. PMP2+ SCs) that preferentially myelinate large-caliber motor axons. PMP2+ SCs are decreased in both amyotrophic lateral sclerosis (ALS) model mice and ALS patient nerves. Thus, PMP2+ SC dysfunction could contribute to motor-selective neuropathies. We engineered a tamoxifen-inducible Pmp2-CreERT2 mouse and expressed diphtheria toxin in PMP2+ SCs to assess the consequences of ablating this SC subtype in male and female mice. Loss of PMP2+ SCs led to significant loss of large-caliber motor axons with concomitant behavioral, electrophysiological, and ultrastructural defects. Subsequent withdrawal of tamoxifen restored both PMP2+ SCs and large-caliber motor axons and improved behavioral and electrophysiological readouts. Together, our findings highlight that the survival of large-caliber motor axons relies on PMP2+ SCs, demonstrating that malfunction of a specific SC subtype can lead to selective neuronal vulnerability.}, } @article {pmid39880333, year = {2025}, author = {Izrael, M and Chebath, J and Molakandov, K and Revel, M}, title = {Clinical perspective on pluripotent stem cells derived cell therapies for the treatment of neurodegenerative diseases.}, journal = {Advanced drug delivery reviews}, volume = {218}, number = {}, pages = {115525}, doi = {10.1016/j.addr.2025.115525}, pmid = {39880333}, issn = {1872-8294}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Pluripotent Stem Cells ; Animals ; Cell- and Tissue-Based Therapy/methods ; Stem Cell Transplantation/methods ; Clinical Trials as Topic ; }, abstract = {Self-renewal capacity and potential to differentiate into almost any cell type of the human body makes pluripotent stem cells a valuable starting material for manufacturing of clinical grade cell therapies. Neurodegenerative diseases are characterized by gradual loss of structure or function of neurons, often leading to neuronal death. This results in gradual decline of cognitive, motor, and physiological functions due to the degeneration of the central nervous systems. Over the past two decades, comprehensive preclinical efficacy (proof-of-concept) and safety studies have led to the initiation of First-in-Human phase I-II clinical trials for a range of neurodegenerative diseases. In this review, we explore the fundamentals and challenges of neural-cell therapies derived from pluripotent stem cells for treating neurodegenerative diseases. Additionally, we highlight key preclinical investigations that paved the way for regulatory approvals of these trials. Furthermore, we provide an overview on progress and status of clinical trials done so far in treating neurodegenerative diseases such as spinal cord injury (SCI), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), as well as advances in retina diseases such as Stargardt disease (a.k.a fundus flavimaculatus), retinitis pigmentosa (RP) and age-related macular degeneration (AMD). These trials will pave the way for the development of new cell-based therapies targeting additional neurological conditions, including Alzheimer's disease and epilepsy.}, } @article {pmid39880289, year = {2025}, author = {Chen, SJ and Li, QY and Zhou, J and Wu, Q and Zhang, Y and Zhang, QQ and Hu, H and Xu, XQ and Wu, FY and Niu, Q}, title = {Differed brain spontaneous neural activity between limb-onset and bulbar-onset amyotrophic lateral sclerosis patients.}, journal = {Brain research bulletin}, volume = {221}, number = {}, pages = {111229}, doi = {10.1016/j.brainresbull.2025.111229}, pmid = {39880289}, issn = {1873-2747}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Male ; Female ; Middle Aged ; *Magnetic Resonance Imaging/methods ; *Brain/physiopathology/diagnostic imaging ; Aged ; Adult ; Support Vector Machine ; Brain Mapping/methods ; }, abstract = {PURPOSE: To investigate the differences in brain spontaneous neural activity between limb-onset and bulbar-onset amyotrophic lateral sclerosis (ALS-L and ALS-B, respectively) patients using resting-state functional MRI (rs-fMRI) with amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo).

MATERIALS AND METHODS: The rs-fMRI data were collected from 41 ALS patients (11 ALS-B and 30 ALS-L) and 25 healthy controls (HC). ALFF and ReHo values were calculated, and group differences were assessed using one-way ANCOVA and two-sample t-tests. Correlation analyses with clinical measures were conducted. Support vector machine (SVM) analysis was performed to distinguish ALS subtypes.

RESULTS: Compared with ALS-L, ALS-B showed increased ALFF values in the right gyrus rectus/ orbital part of right middle frontal gyrus, orbital part of left middle frontal gyrus and left dorsolateral superior frontal gyrus/ left medial superior frontal gyrus and decreased ALFF values in the left superior occipital gyrus (FDR-corrected, P < 0.05). Both ALS subtypes demonstrated distinct ALFF alterations compared to HC. Differences in ReHo values were only found between ALS-B and HC. Correlation analyses revealed associations between ALFF in specific brain regions and ALS clinical scores. SVM analysis achieved an accuracy of 90.2 %, with an AUC of 0.909 in differentiating ALS-B and ALS-L.

CONCLUSION: ALS-B and ALS-L patients had distinct alterations in brain spontaneous neural activity, which could serve as potential biomarkers for accurately distinguishing these two subtypes. Our findings offer a new insight into the neural mechanism of ALS, underscoring the importance of personalized diagnostic approaches for this complex neurological disorder.}, } @article {pmid39880202, year = {2025}, author = {Xu, F and Liu, H and Yin, Z and Xing, X and Chen, X}, title = {Associations of dietary factors with amyotrophic lateral sclerosis: A Mendelian randomization study.}, journal = {Clinical nutrition ESPEN}, volume = {66}, number = {}, pages = {226-235}, doi = {10.1016/j.clnesp.2025.01.042}, pmid = {39880202}, issn = {2405-4577}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; *Diet ; Vegetables ; Feeding Behavior ; Risk Factors ; Polymorphism, Single Nucleotide ; Fruit ; }, abstract = {BACKGROUND: An inconsistent yet notable relationship between dietary habits and the risk of amyotrophic lateral sclerosis (ALS) has been previously established, with the causative nature of this relationship remaining uncertain. This study aims to explore the causal connections at a genetic level.

METHODS: A two-sample Mendelian Randomization (MR) based analysis was conducted utilizing a comprehensive, publicly assessable Genome-wide association study (GWAS) database. Fourteen dietary variables were examined as potential exposure factors, and the ALS outcome data was statistically analyzed. The inverse-variance weighted (IVW) approach was used as the primary analytical method, supplemented by sensitivity analyses to assess the reliability of our findings.

RESULTS: Our analysis identified significant protective effects against ALS from increased intake of water (fixed-effects IVW: OR = 0.700, 95 % CI: 0.524-0.935, P = 0.016), fresh fruit (random-effects IVW: OR = 0.561, 95 % CI: 0.361-0.871, P = 0.010), and cooked vegetable (fixed-effects IVW: OR = 0.200, 95 % CI: 0.090-0.445, P = 0.000). No significant associations were found for the other 11 dietary factors examined.

CONCLUSION: The study highlights the protective association of cooked vegetables and fresh fruit intake with ALS risk reduction. Additionally, an intriguing association between water intake and ALS was observed, warranting further investigation to elucidate the underlying mechanisms.}, } @article {pmid39879721, year = {2025}, author = {Derevyanko, A and Tao, T and Allen, NJ}, title = {Common alterations to astrocytes across neurodegenerative disorders.}, journal = {Current opinion in neurobiology}, volume = {90}, number = {}, pages = {102970}, doi = {10.1016/j.conb.2025.102970}, pmid = {39879721}, issn = {1873-6882}, mesh = {Humans ; *Astrocytes/metabolism/pathology ; *Neurodegenerative Diseases/pathology/metabolism ; Animals ; Brain/pathology/metabolism ; }, abstract = {Astrocytes perform multiple functions in the nervous system, many of which are altered in neurodegenerative disorders. In this review, we explore shared astrocytic alterations across neurodegenerative disorders, including Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobe degeneration. Assessing recent datasets of single-nucleus RNA-sequencing of human brains, a theme emerges of common alterations in astrocyte state across disorders including in neuroinflammation, synaptic organization, metabolic support, and the cellular stress response. Immune pathways are upregulated by astrocytes across disorders and may exacerbate neurodegeneration. Dysregulated expression of synaptogenic factors could contribute to synaptic loss, while compromised metabolic support affects neuronal homeostasis. On the other hand, upregulated responses to cellular stress may represent a protective response of astrocytes and thus mitigate pathology. Understanding these shared responses offers insights into disease progression and provides potential therapeutic targets for various neurodegenerative disorders.}, } @article {pmid39879575, year = {2025}, author = {Jang, DG and Kind, AJ and Patterson, A and Pedde, M and Powell, WR and Feldman, EL and Goutman, SA}, title = {Impact of the Adverse Social Exposome on Survival in Individuals With Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {104}, number = {4}, pages = {e213362}, pmid = {39879575}, issn = {1526-632X}, support = {R01 TS000327/TS/ATSDR CDC HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 AG070883/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality ; Female ; Male ; Aged ; Retrospective Studies ; Middle Aged ; *Exposome ; Aged, 80 and over ; Survival Analysis ; }, abstract = {BACKGROUND AND OBJECTIVES: An adverse social exposome negatively affects many diseases, but its association with amyotrophic lateral sclerosis (ALS) survival is unknown. This study examined the association between the social exposome measure Area Deprivation Index (ADI) and ALS survival.

METHODS: This is a retrospective analysis of patients with ALS at the University of Michigan Pranger ALS Clinic diagnosed after January 1, 2012. Extracted data included age, sex, race, residential address, disease characteristics, and survival. National ADI ranking was assigned to each patient's geocoded address. Accelerated failure time survival analysis determined association between the ADI group and survival with adjustment for clinicodemographic covariates.

RESULTS: 1,085 patients (median age at diagnosis, 72 years; 45% female) met inclusion criteria. The highest ADI decile (most disadvantaged neighborhood group) was associated with 37.0% shorter survival time (95% CI -50.4% to -20.1%). Results were similar when grouping patients by ADI ranking (as opposed to decile) or including only those with a classical ALS phenotype.

DISCUSSION: Exposure to adverse social exposome, as measured by ADI, associates with poorer ALS survival. Because this is a single-center study, replication in other cohorts is encouraged. Further research is needed to understand the underlying mechanisms, which could influence ALS clinical care.}, } @article {pmid39879320, year = {2025}, author = {Guillot, SJ and Lang, C and Simonot, M and Beckett, D and Lulé, D and Balz, LT and Knehr, A and Stuart-Lopez, G and Vercruysse, P and Dieterlé, S and Weydt, P and Dorst, J and Kandler, K and Kassubek, J and Wassermann, L and Rouaux, C and Arthaud, S and Da Cruz, S and Luppi, PH and Roselli, F and Ludolph, AC and Dupuis, L and Bolborea, M}, title = {Early-onset sleep alterations found in patients with amyotrophic lateral sclerosis are ameliorated by orexin antagonist in mouse models.}, journal = {Science translational medicine}, volume = {17}, number = {783}, pages = {eadm7580}, doi = {10.1126/scitranslmed.adm7580}, pmid = {39879320}, issn = {1946-6242}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; *Orexins/metabolism ; *Disease Models, Animal ; Humans ; Sleep/drug effects ; Male ; Melanins/metabolism ; Mice ; Wakefulness/drug effects ; Female ; Motor Neurons/drug effects/pathology/metabolism ; Hypothalamic Hormones/metabolism ; Pituitary Hormones/metabolism ; Orexin Receptors/metabolism ; Superoxide Dismutase-1/metabolism/genetics ; Mice, Transgenic ; }, abstract = {Sleep alterations have been described in several neurodegenerative diseases yet are currently poorly characterized in amyotrophic lateral sclerosis (ALS). This study investigates sleep macroarchitecture and related hypothalamic signaling disruptions in ALS. Using polysomnography, we found that both patients with ALS as well as asymptomatic C9ORF72 and SOD1 mutation carriers exhibited increased wakefulness and reduced non-rapid eye movement sleep. Increased wakefulness correlated with diminished cognitive performance in both clinical cohorts. Similar changes in sleep macroarchitecture were observed in three ALS mouse models (Sod1[G86R], Fus[ΔNLS/+], and TDP43[Q331K]). A single oral administration of a dual-orexin receptor antagonist or intracerebroventricular delivery of melanin-concentrating hormone (MCH) through an osmotic pump over 15 days partially normalized sleep patterns in mouse models. MCH treatment did not extend the survival of Sod1[G86R] mice but did decrease the loss of lumbar motor neurons. These findings suggest MCH and orexin signaling as potential targets to treat sleep alterations that arise in early stages of the disease.}, } @article {pmid39877726, year = {2025}, author = {Fournier, CN and Levine, M and Simmons, K and García-Santibáñez, RC and Rowland, A and Quinn, CC and Ho, DT and Bedlack, RS and Glass, JD}, title = {ALS Motor Observational Telemedicine Objective Rasch-Built Assessment: A Quantitative Scale for the Era of Teleneurology.}, journal = {Neurology. Clinical practice}, volume = {15}, number = {2}, pages = {e200432}, pmid = {39877726}, issn = {2163-0402}, abstract = {BACKGROUND AND OBJECTIVES: Telemedicine has become a mainstay of ALS clinical care, but there is currently no standardized approach for assessing and tracking changes to the neurologic examination in this format. The goal of this study was to create a standardized telemedicine-based motor examination scale to objectively and reliably track ALS progression and use Rasch methodology to validate the scale and improve its psychometric properties.

METHODS: A draft telemedicine examination scale with 25 items assessing movement in the bulbar muscles, neck, trunk, and extremities was created by an ALS expert panel, incorporating input from patient advisors. This prospective, observational study was approved by the Emory IRB, and participants provided informed consent. Adults with a diagnosis of ALS who were able to undergo a video telemedicine evaluation by an Emory clinician were eligible for participation. Rasch analyses were performed to determine the final item responses and optimize the scoring structure. Test-retest reliability was assessed in a subset of participants through 2 separate examinations by 2 different examiners within a 7-day period. Construct validity was assessed by calculating correlations with simultaneously administered Rasch-built Overall ALS Disability Scale (ROADS) and revised ALS Functional Rating Scale (ALSFRS-R).

RESULTS: The ALS Motor Observational Telemedicine Objective Rasch-built assessment was administered to a total of 258 PALS representing the full spectrum of a typical ALS clinic population. After performing Rasch analyses, 3 items were removed and item response categories were consolidated for 8 items. The final 22-item ALS MOTOR scale conformed to Rasch model criteria. The inter-rater reliability was 95%. The ALS MOTOR had a 0.78 (95% CI 0.72-0.83) correlation with ALSFRS-R and 0.81 (95% CI 0.76-0.85) correlation with ROADS.

DISCUSSION: The ALS MOTOR is a novel, accessible tool for remotely and objectively tracking ALS progression for both clinical care and research studies. Use of Rasch methodology for scale validation allowed for optimization of scale psychometric properties, which is particularly important when using the sum score as an overall outcome measure. Longitudinal and external validation studies are ongoing.}, } @article {pmid39877010, year = {2024}, author = {Stavrovskaya, AV and Voronkov, DN and Pavlova, AK and Olshanskiy, AS and Belugin, BV and Ivanova, MV and Zakharova, MN and Illarioshkin, SN}, title = {Intraventricular Administration of Exosomes from Patients with Amyotrophic Lateral Sclerosis Provokes Motor Neuron Disease in Mice.}, journal = {Acta naturae}, volume = {16}, number = {4}, pages = {73-80}, pmid = {39877010}, issn = {2075-8251}, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe disease of the central nervous system (CNS) characterized by motor neuron damage leading to death from respiratory failure. The neurodegenerative process in ALS is characterized by an accumulation of aberrant proteins (TDP-43, SOD1, etc.) in CNS cells. The trans-synaptic transmission of these proteins via exosomes may be one of the mechanisms through which the pathology progresses. The aim of this work was to study the effect of an intraventricular injection of exosomes obtained from the cerebrospinal fluid (CSF) of ALS patients on the motor activity and CNS pathomorphology of mice. The exosomes were obtained from two ALS patients and a healthy donor. Exosome suspensions at high and low concentrations were injected into the lateral brain ventricles of male BALB/c mice (n = 45). Motor activity and physiological parameters were evaluated twice a month; morphological examination of the spinal cord was performed 14 months after the start of the experiment. Nine months after administration of exosomes from the ALS patients, the animals started exhibiting a pathological motor phenotype; i.e., altered locomotion with paresis of hind limbs, coordination impairment, and increasing episodes of immobility. The motor symptoms accelerated after administration of a higher concentration of exosomes. The experimental group showed a significant decrease in motor neuron density in the ventral horns of the spinal cord, a significant increase in the number of microglial cells, and microglia activation. The TDP43 protein in the control animals was localized in the nuclei of motor neurons. TDP43 mislocation with its accumulation in the cytoplasm was observed in the experimental group. Thus, the triggering effect of the exosomal proteins derived from the CSF of ALS patients in the development of a motor neuron pathology in the experimental animals was established. This confirms the pathogenetic role of exosomes in neurodegenerative progression and makes it possible to identify a new target for ALS therapy.}, } @article {pmid39876814, year = {2025}, author = {Papadopoulou, M and Stefanou, MI and Fanouraki, S and Moschovos, C and Bakola, E and Salakou, S and Zouvelou, V and Papadimas, GK and Tsivgoulis, G}, title = {Motor neuron diseases are not exclusively motor; the SSR paradigm.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2458694}, pmid = {39876814}, issn = {2167-9223}, abstract = {Motor Neuron Diseases (MNDs), familial and sporadic, are progressive neurodegenerative disorders that, for an extended period in the past, were considered purely motor disorders. During the course of the disease, however, some patients exhibit concomitant non-motor signs; thus, MNDs are currently perceived as multisystem disorders. Assessment of non-motor symptoms is usually performed clinically, although laboratory tests can also be routinely used to objectively evaluate these symptoms. Sympathetic Skin Response (SSR) is an example of a neurophysiological test that has been used in cases of Amyotrophic Lateral Sclerosis, Spinal Muscular Atrophy, and Monomelic Atrophy, mostly to assess Autonomic Nervous System (ANS) disorders. Dysautonomia affects quality of life and life expectancy, as it is involved in cardiovascular events and incidents of sudden death. SSR abnormalities are present even in subclinical involvement of the ANS in MNDs. In this review, we present published research examining SSR findings in various MNDs, and discuss the correlation of SSR findings with clinical symptoms and disease severity, as well as the potential sources of abnormal findings. The aim of this study is to raise clinician awareness of autonomic dysfunction in MNDs and present the benefits of SSR examination in patient care.}, } @article {pmid39875596, year = {2025}, author = {Tomar, VR and Sharma, S and Siddhanta, S and Deep, S}, title = {Biophysical and spectroscopical insights into structural modulation of species in the aggregation pathway of superoxide dismutase 1.}, journal = {Communications chemistry}, volume = {8}, number = {1}, pages = {22}, pmid = {39875596}, issn = {2399-3669}, support = {CRG/2020/002091//DST | Science and Engineering Research Board (SERB)/ ; }, abstract = {Superoxide dismutase 1 (SOD1) aggregation is implicated in the development of Amyotrophic Lateral Sclerosis (ALS). Despite knowledge of the role of SOD1 aggregation, the mechanistic understanding remains elusive. Our investigation aimed to unravel the complex steps involved in SOD1 aggregation associated with ALS. Therefore, we probed the aggregation using ThT fluorescence, size-exclusion chromatography, and surface-enhanced Raman spectroscopy (SERS). The removal of metal ions and disulfide bonds resulted in the dimers rapidly first converting to an extended monomers then coming together slowly to form non-native dimers. The rapid onset of oligomerization happens above critical non-native dimer concentration. Structural features of oligomer was obtained through SERS. The kinetic data supported a fragmentation-dominant mechanism for the fibril formation. Quercetin acts as inhibitor by delaying the formation of non-native dimer and soluble oligomers by decreasing the elongation rate. Thus, results provide significant insights into the critical steps in oligomer formation and their structure.}, } @article {pmid39875548, year = {2025}, author = {Rabhi, C and Babault, N and Martin, C and Desforges, B and Maucuer, A and Joshi, V and Pankivskyi, S and Feng, Y and Bollot, G and Rattenbach, R and Pastré, D and Bouhss, A}, title = {TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {136}, pmid = {39875548}, issn = {2399-3642}, support = {ANR-24-CE44-3867-01-SUFATOP//Agence Nationale de la Recherche (French National Research Agency)/ ; CIFRE Grant//Association Nationale de la Recherche et de la Technologie (National Association for Research and Technology)/ ; }, mesh = {Phosphorylation ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Cytoplasm/metabolism ; *Cell Nucleus/metabolism ; RNA, Messenger/metabolism/genetics ; }, abstract = {Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), in which TDP-43, a nuclear RNA-binding protein, forms cytoplasmic inclusions. Here, we have developed a robust and automated method to assess protein self-assembly in the cytoplasm using microtubules as nanoplatforms. Importantly, we have analyzed specifically the self-assembly of full-length TDP-43 and its mRNA binding that are regulated by the phosphorylation of its self-adhesive C-terminus, which is the recipient of many pathological mutations. We show that C-terminus phosphorylation prevents the recruitment of TDP-43 in mRNA-rich stress granules only under acute stress conditions because of a low affinity for mRNA but not under mild stress conditions. In addition, the self-assembly of the C-terminus is negatively regulated by phosphorylation in the cytoplasm which in turn promotes TDP-43 nuclear import. We anticipate that reducing TDP-43 C-terminus self-assembly in the cytoplasm may be an interesting strategy to reverse TDP-43 nuclear depletion in neurodegenerative diseases.}, } @article {pmid39874287, year = {2025}, author = {Baek, Y and Kim, H and Lee, D and Kim, D and Jo, E and Roh, SH and Ha, NC}, title = {Structural insights into the role of reduced cysteine residues in SOD1 amyloid filament formation.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {5}, pages = {e2408582122}, pmid = {39874287}, issn = {1091-6490}, support = {RS-2021-IP321036//Ministry of Agriculture, Food and Rural Affairs (MAFRA)/ ; RS-2024-00344154//Ministry of Science and ICT, South Korea (MSIT)/ ; RS-2023-00245941//National Research Foundation of Korea (NRF)/ ; 2021M3A9I4021220//Ministry of Science and ICT, South Korea (MSIT)/ ; }, mesh = {*Superoxide Dismutase-1/metabolism/genetics/chemistry ; *Cysteine/metabolism/chemistry ; Humans ; *Amyloid/metabolism/chemistry ; *Cryoelectron Microscopy ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Mutation ; Models, Molecular ; }, abstract = {The formation of superoxide dismutase 1 (SOD1) filaments has been implicated in amyotrophic lateral sclerosis (ALS). Although the disulfide bond formed between Cys57 and Cys146 in the active state has been well studied, the role of the reduced cysteine residues, Cys6 and Cys111, in SOD1 filament formation remains unclear. In this study, we investigated the role of reduced cysteine residues by determining and comparing cryoelectron microscopy (cryo-EM) structures of wild-type (WT) and C6A/C111A SOD1 filaments under thiol-based reducing and metal-depriving conditions, starting with protein samples possessing enzymatic activity. The C6A/C111A mutant SOD1 formed filaments more rapidly than the WT protein. The mutant structure had a unique paired-protofilament arrangement, with a smaller filament core than that of the single-protofilament structure observed in WT SOD1. Although the single-protofilament form developed more slowly, cross-seeding experiments demonstrated the predominance of single-protofilament morphology over paired protofilaments, regardless of the presence of the Cys6 and Cys111 mutations. These findings highlight the importance of the number of amino acid residues within the filament core in determining the energy requirements for assembly. Our study provides insights into ALS pathogenesis by elucidating the initiation and propagation of filament formation, which potentially leads to deleterious amyloid filaments.}, } @article {pmid39872677, year = {2025}, author = {Pulst, SM}, title = {Spinocerebellar Ataxia Type 2: A Review and Personal Perspective.}, journal = {Neurology. Genetics}, volume = {11}, number = {1}, pages = {e200225}, pmid = {39872677}, issn = {2376-7839}, support = {R35 NS127253/NS/NINDS NIH HHS/United States ; }, abstract = {Spinocerebellar ataxias (SCAs) are dominantly inherited diseases that lead to neurodegeneration in the cerebellum and other parts of the nervous system. This review examines the progress that has been made in SCA2 from its initial clinical description to discovery of DNA CAG-repeat expansions in the ATXN2 gene. ATXN2 repeat alleles cover the range from recessive and dominant mendelian alleles to risk alleles for amyotrophic lateral sclerosis. We review studies aimed at defining the normal function of ATXN2 and mutant ATXN2 using cellular and mouse models. Progress in testing small compounds and antisense oligonucleotides in preclinical studies is described as well including our recent focus on staufen-1 (STAU1) and mRNA metabolism and control of autophagy.}, } @article {pmid39871987, year = {2024}, author = {Ribichini, E and Pallotta, N and Badiali, D and Carlucci, M and Ceccanti, M and Cambieri, C and Libonati, L and Corazziari, ES and Ruoppolo, G and Inghilleri, M}, title = {Assessment of upper GI motor activity and GI symptoms in patients with amyotrophic lateral sclerosis: an observational study.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1509917}, pmid = {39871987}, issn = {1664-2295}, abstract = {BACKGROUND/AIMS: Oro-pharyngeal dysfunction has been reported in Amyotrophic Lateral Sclerosis (ALS). We aimed to assess ALS patients upper gastrointestinal (GI) motor activity and GI symptoms according to bulbar and spinal onset and severity of ALS.

METHODS: ALS bulbar (B) and spinal (S) patients with ALS Functional Rating Scale (ALSFRS-r) ≥35, bulbar sub-score ≥10, and Forced Vital Capacity (FVC) >50%, underwent to: Fiberoptic Endoscopic Evaluation of Swallowing (FEES); esophageal manometry; gastric emptying; Rome symptom questionnaire. Medical Research Council Scale for Muscle Strength (MRC) was performed for the upper and lower limbs. Mann-Whitney's U, Fisher's ranks test, Pearson's test was used.

RESULTS: Thirteen ALS patients were included (6 F; mean age 61.2 ± 13.7 years, range: 37-87), 5 with B and 8 with S onset (ALSFRS-R score 39.5 ± 4.9, MRC score 128.6 ± 23.3, disease duration 22.8 ± 17.9 months). FEES detected a high dysphagia score in 5 patients with no difference between S and B phenotype. Lower esophageal sphincter pressure was normal in all patients. Esophageal dysmotility was observed in three S and two B onset patients. Upper esophageal sphincter (UES) pressure was higher in all ALS patients. UES spasms and delayed gastric emptying were detected in two B and one S and in two B and four S patients, respectively. There was no correlation between esophagogastric motor abnormalities and clinical characteristics of ALS, nor GI symptoms.

CONCLUSIONS: The presence of UES spasm and the delayed gastric emptying in a subgroup of ALS patients may suggest the role of ANS dysfunction in ALS.}, } @article {pmid39871563, year = {2025}, author = {Guo, J and Liu, XY and Yang, SS and Li, Q and Duan, Y and Zhu, SS and Zhou, K and Yan, YZ and Zeng, P}, title = {Roles of C/EBPβ/AEP in Neurodegenerative Diseases.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266357822250119172351}, pmid = {39871563}, issn = {1873-4294}, abstract = {In recent years, an increasing number of studies have shown that increased activation of aspartic endopeptidases (AEPs) is a common symptom in neurodegenerative diseases (NDDs). AEP cleaves amyloid precursor protein (APP), tau (microtubule-associated protein tau), α- synuclein (α-syn), SET (a 39-KDa phosphoprotein widely expressed in various tissues and localizes predominantly in the nucleus), and TAR DNA-binding protein 43 (TDP-43), and promotes their aggregation, contributing to Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) pathogenesis. Abundant evidence supports the notion that CCAAT/enhancer-binding protein β (C/EBPβ)/AEP may play an important role in NDDs. Developing its small molecule inhibitors is a promising treatment of NDDs. However, current research suggests that the pathophysiological mechanism of the C/EBPβ/AEP pathway is very complex in NDDs. This review summarizes the structure of C/EBPβ and AEP, their major physiological functions, potential pathogenesis, their small molecule inhibitors, and how C/EBPβ/AEP offers a novel pathway for the treatment of NDDs.}, } @article {pmid39871559, year = {2025}, author = {Rani, S and Tuteja, M}, title = {Chaperones as Potential Pharmacological Targets for Treating Protein Aggregation Illness.}, journal = {Current protein & peptide science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892037338028241230092414}, pmid = {39871559}, issn = {1875-5550}, abstract = {The three-dimensional structure of proteins, achieved through the folding of the nascent polypeptide chain in vivo, is largely facilitated by molecular chaperones, which are crucial for determining protein functionality. In addition to aiding in the folding process, chaperones target misfolded proteins for degradation, acting as a quality control system within the cell. Defective protein folding has been implicated in a wide range of clinical conditions, including neurodegenerative and metabolic disorders. It is now well understood that the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and Creutzfeldt-Jakob disease shares a common mechanism: the accumulation of misfolded proteins, which aggregate and become toxic to cells. Among the family of molecular chaperones, Heat Shock Proteins (HSPs) are highly expressed in response to cellular stress and play a pivotal role in preventing protein aggregation. Specific chaperones, particularly HSPs, are now recognized as critical in halting the accumulation and aggregation of misfolded proteins in these conditions. Consequently, these chaperones are increasingly considered promising pharmacological targets for the treatment of protein aggregation-related diseases. This review highlights research exploring the potential roles of specific molecular chaperones in disorders characterized by the accumulation of misfolded proteins.}, } @article {pmid39870504, year = {2025}, author = {Wilson, C and Giaquinto, L and Santoro, M and Di Tullio, G and Morra, V and Kukulski, W and Venditti, R and Navone, F and Borgese, N and De Matteis, MA}, title = {A role for mitochondria-ER crosstalk in amyotrophic lateral sclerosis 8 pathogenesis.}, journal = {Life science alliance}, volume = {8}, number = {4}, pages = {}, pmid = {39870504}, issn = {2575-1077}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Mitochondria/metabolism/genetics ; Humans ; *Endoplasmic Reticulum/metabolism ; *Motor Neurons/metabolism/pathology ; *Mutation ; *Vesicular Transport Proteins/metabolism/genetics ; Animals ; Saccharomyces cerevisiae/metabolism/genetics ; Protein Aggregation, Pathological/genetics/metabolism ; Protein Aggregates ; }, abstract = {Protein aggregates in motoneurons, a pathological hallmark of amyotrophic lateral sclerosis, have been suggested to play a key pathogenetic role. ALS8, characterized by ER-associated inclusions, is caused by a heterozygous mutation in VAPB, which acts at multiple membrane contact sites between the ER and almost all other organelles. The link between protein aggregation and cellular dysfunction is unclear. A yeast model, expressing human mutant and WT-VAPB under the control of the orthologous yeast promoter in haploid and diploid cells, was developed to mimic the disease situation. Inclusion formation was found to be a developmentally regulated process linked to mitochondrial damage that could be attenuated by reducing ER-mitochondrial contacts. The co-expression of the WT protein retarded P56S-VAPB inclusion formation. Importantly, we validated these results in mammalian motoneuron cells. Our findings indicate that (age-related) damage to mitochondria influences the propensity of the mutant VAPB to form aggregates via ER-mitochondrial contacts, initiating a series of events leading to disease progression.}, } @article {pmid39870443, year = {2025}, author = {Zhang, Q and Walkley, CR}, title = {Mouse models for understanding physiological functions of ADARs.}, journal = {Methods in enzymology}, volume = {710}, number = {}, pages = {153-185}, doi = {10.1016/bs.mie.2024.11.024}, pmid = {39870443}, issn = {1557-7988}, mesh = {Animals ; *Adenosine Deaminase/metabolism/genetics ; Mice ; Humans ; *RNA Editing ; *Disease Models, Animal ; *RNA-Binding Proteins/metabolism/genetics ; Adenosine/metabolism/genetics ; Mutation ; Inosine/metabolism/genetics ; Autoimmune Diseases of the Nervous System/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Nervous System Malformations/genetics/metabolism ; Mice, Knockout ; }, abstract = {Adenosine-to-inosine (A-to-I) editing, is a highly prevalent posttranscriptional modification of RNA, mediated by the adenosine deaminases acting on RNA (ADAR) proteins. Mammalian transcriptomes contain tens of thousands to millions of A-to-I editing events. Mutations in ADAR can result in rare autoinflammatory disorders such as Aicardi-Goutières syndrome (AGS) through to irreversible conditions such as motor neuron disease, amyotrophic lateral sclerosis (ALS). Mouse models have played an important role in our current understanding of the physiology of ADAR proteins. With the advancement of genetic engineering technologies, a number of new mouse models have been recently generated, each providing additional insight into ADAR function. This review highlights both past and current mouse models, exploring the methodologies used in their generation, their respective discoveries, and the significance of these findings in relation to human ADAR physiology.}, } @article {pmid39868844, year = {2025}, author = {Elyaman, W and Stern, LJ and Jiang, N and Dressman, D and Bradley, P and Klatzmann, D and Bradshaw, EM and Farber, DL and Kent, SC and Chizari, S and Funk, K and Devanand, D and Thakur, KT and Raj, T and Dalahmah, OA and Sarkis, RA and Weiner, HL and Shneider, NA and Przedborski, S}, title = {Exploring the role of T cells in Alzheimer's and other neurodegenerative diseases: Emerging therapeutic insights from the T Cells in the Brain symposium.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14548}, pmid = {39868844}, issn = {1552-5279}, support = {T32 AI148099/AI/NIAID NIH HHS/United States ; P01 AI106697/AI/NIAID NIH HHS/United States ; R01AI137198/NH/NIH HHS/United States ; R13 AG090018/AG/NIA NIH HHS/United States ; R01 AG067581/AG/NIA NIH HHS/United States ; R01 AG076018/AG/NIA NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; T32AI148099-4/NH/NIH HHS/United States ; AI106697/NH/NIH HHS/United States ; R01 AG055422/AG/NIA NIH HHS/United States ; R01AG067581/NH/NIH HHS/United States ; R13AG090018-01/NH/NIH HHS/United States ; R01AG076018/NH/NIH HHS/United States ; AG R01AG055422/NH/NIH HHS/United States ; R35GM141457/NH/NIH HHS/United States ; R01 AI137198/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/immunology/therapy ; *Neurodegenerative Diseases/immunology/therapy ; *T-Lymphocytes/immunology ; Immunotherapy/methods ; Brain/pathology/immunology ; }, abstract = {This proceedings article summarizes the inaugural "T Cells in the Brain" symposium held at Columbia University. Experts gathered to explore the role of T cells in neurodegenerative diseases. Key topics included characterization of antigen-specific immune responses, T cell receptor (TCR) repertoire, microbial etiology in Alzheimer's disease (AD), and microglia-T cell crosstalk, with a focus on how T cells affect neuroinflammation and AD biomarkers like amyloid beta and tau. The symposium also examined immunotherapies for AD, including the Valacyclovir Treatment of Alzheimer's Disease (VALAD) trial, and two clinical trials leveraging regulatory T cell approaches for multiple sclerosis and amyotrophic lateral sclerosis therapy. Additionally, single-cell RNA/TCR sequencing of T cells and other immune cells provided insights into immune dynamics in neurodegenerative diseases. This article highlights key findings from the symposium and outlines future research directions to further understand the role of T cells in neurodegeneration, offering innovative therapeutic approaches for AD and other neurodegenerative diseases. HIGHLIGHTS: Researchers gathered to discuss approaches to study T cells in brain disorders. New technologies allow high-throughput screening of antigen-specific T cells. Microbial infections can precede several serious and chronic neurological diseases. Central and peripheral T cell responses shape neurological disease pathology. Immunotherapy can induce regulatory T cell responses in neuroinflammatory disorders.}, } @article {pmid39867453, year = {2024}, author = {Rong, P and Heidrick, L and Pattee, G}, title = {A novel muscle network approach for objective assessment and profiling of bulbar involvement in ALS.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1491997}, pmid = {39867453}, issn = {1662-4548}, abstract = {INTRODUCTION: As a hallmark feature of amyotrophic lateral sclerosis (ALS), bulbar involvement significantly impacts psychosocial, emotional, and physical health. A validated objective marker is however lacking to characterize and phenotype bulbar involvement, positing a major barrier to early detection, progress monitoring, and tailored care. This study aimed to bridge this gap by constructing a multiplex functional mandibular muscle network to provide a novel objective measurement tool of bulbar involvement.

METHODS: A noninvasive electrophysiological technique-surface electromyography-was combined with graph network analysis to extract 48 features measuring the regulatory mechanisms, connectivity, integration, segregation, assortativity, and lateralization of the functional muscle network during a speech task. These features were clustered into 10 interpretable latent factors. To evaluate the utility of the muscle network as a bulbar measurement tool, a heterogenous ALS cohort, consisting of eight individuals with overt clinical bulbar symptoms and seven without, along with 10 neurologically healthy controls, was employed to train and validate statistical and machine learning algorithms to assess the disease effects on the network features and the relation of the network performance to the current clinical diagnostic standard and behavioral patterns of bulbar involvement.

RESULTS: Significant disease effects were found on most network features. The most robust effects were manifested by reduced and more variable myoelectric activities, and reduced functional connectivity and integration of the muscle network. The 10 latent factors (1) demonstrated acceptably high efficacy for detecting bulbar neuromuscular changes across all clinically confirmed symptomatic cases and clinically silent prodromal cases (area under the curve = 0.89-0.91; F1 score = 0.85-0.87; precision = 0.84-0.86; recall = 0.87-0.88); and (2) selectively correlated with clinically meaningful behavioral patterns (conditional R [2] = 0.45-0.81).

CONCLUSION: The functional muscle network shows promise for an objective quantifiable measurement tool to improve early detection and profiling of bulbar involvement across the prodromal and symptomatic stages. This tool has various strengths, including the use of a clinically readily available noninvasive instrument, fully automated data processing and analytics, and generation of interpretable objective outcome measures (i.e., latent factors), together rendering it highly scalable in routine clinical practice for assessing and monitoring of bulbar involvement.}, } @article {pmid39866212, year = {2025}, author = {Wang, W and Cooper, C}, title = {Metabolic dysfunction-associated steatotic liver disease and type 2 diabetes: A dual threat to cardiac dysfunction progression.}, journal = {World journal of cardiology}, volume = {17}, number = {1}, pages = {102467}, pmid = {39866212}, issn = {1949-8462}, abstract = {Metabolic dysfunction-associated steatotic liver disease (MASLD), particularly in patients with type 2 diabetes mellitus (T2DM), is increasingly recognized as a multi-system disease that affects both hepatic and cardiovascular health. This study explores the association between MASLD-related liver fibrosis and cardiac dysfunction, focusing on how liver fibrosis contributes to cardiac remodeling and dysfunction. Cernea et al's research highlights the strong correlation between liver fibrosis and changes in left ventricular mass, left atrial dimensions, and systolic and diastolic function in diabetic patients. Notably, the study suggests a protective role of sex-hormone binding protein against cardiac remodeling. These findings underline the importance of early detection of liver fibrosis using non-invasive markers like fibrosis-4 index and nonalcoholic fatty liver disease fibrosis scores, which may offer dual protection for both liver and heart health in T2DM patients. Moreover, this study calls for further research into the shared pathogenic mechanisms, including inflammation and fibrosis pathways, between the liver and heart. It advocates for the integration of liver fibrosis screening into cardiovascular risk management, urging clinicians to adopt a more holistic approach in treating patients with MASLD and T2DM. The research has broad implications for preventing cardiovascular complications and improving outcomes in this high-risk population.}, } @article {pmid39865792, year = {2025}, author = {Murakami, E and Shibata, T and Tomemori, M and Kawai, G and Nakatani, K}, title = {The role of spatial arrangement of aromatic rings on the binding of N,N'-diheteroaryl guanidine ligands to the G2C4/G2C4 motif DNA.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {27}, number = {6}, pages = {3341-3350}, doi = {10.1039/d4cp03213f}, pmid = {39865792}, issn = {1463-9084}, mesh = {*DNA/chemistry/metabolism ; Ligands ; *Guanidine/chemistry/analogs & derivatives ; Guanidines/chemistry ; Circular Dichroism ; Humans ; Surface Plasmon Resonance ; Hydrogen Bonding ; Nucleic Acid Conformation ; }, abstract = {Non-canonical DNA structures formed by aberrantly expanded repeat DNA are implicated in promoting repeat instability and the onset of repeat expansion diseases. Small molecules that target these disease-causing repeat DNAs hold promise as therapeutic agents for such diseases. Specifically, 1,3-di(quinolin-2-yl)guanidine (DQG) has been identified to bind to the disease-causing GGCCCC (G2C4) repeat DNA associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In this study, we investigate the structure-binding relationships between DQG analogs and double-stranded DNA (dsDNA) containing a G2C4/G2C4 unit. Our findings, derived from UV melting temperature, circular dichroism spectra, and surface plasmon resonance (SPR) analyses of DQG analogs, highlight the crucial role of the spatial arrangements of aromatic rings in binding to the G2C4/G2C4 unit. Among the tested DQG analogs, N,N'-di(quinazolin-2-yl)guanidine (DQzG) stands out for its ability to form seven planar conformers. These conformers enable ADD-DAA hydrogen bonding with cytosine and multiple spatial arrangements of aromatic rings, including those resembling DQG. Our binding analyses revealed that DQzG exhibits the highest affinity binding for the G2C4/G2C4 unit. NMR analysis of the DQzG-bound G2C4/G2C4-dsDNA further suggested that DQzG binds to the G2C4/G2C4 unit via hydrogen bonding. Moreover, SPR analysis demonstrated that DQzG binds more strongly to G2C4 repeat DNA compared to DQG. These results position DQzG as a promising lead compound for targeting the G2C4 repeat, offering potential therapeutic avenues for the treatment of ALS/FTD and other repeat expansion diseases.}, } @article {pmid39865616, year = {2025}, author = {Dong, S and Liu, X and Zhou, Y and Li, J and Qi, Z and Wang, Z and Yang, W and Chen, X}, title = {Prognostic Value of Cerebrospinal Fluid and Serum Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: A Correlation Study.}, journal = {Brain and behavior}, volume = {15}, number = {1}, pages = {e70256}, pmid = {39865616}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/diagnosis ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Female ; Male ; Middle Aged ; Prognosis ; Aged ; Biomarkers/blood/cerebrospinal fluid ; Disease Progression ; Adult ; }, abstract = {BACKGROUND: The diagnostic and prognostic values of serum neurofilament light chain (sNfL), in comparison to cerebrospinal fluid (CSF) neurofilament light chain (cNfL), and other clinical parameters in amyotrophic lateral sclerosis (ALS) at the time of diagnosis remain elusive.

METHODS: We examine paired serum and CSF samples from 80 ALS patients and 21 control subjects, all obtained at the time of diagnosis. Additional serum samples were collected from 51 other ALS patients. NfL concentrations were quantified using the single molecule array (Simoa) technique.

RESULTS: Our findings demonstrate a robust correlation between NfL levels in matched CSF and serum samples. Notably, both sNfL (p < 0.0001) and cNfL (p < 0.0001) exhibited significantly elevated levels in ALS patients compared to controls. Furthermore, baseline sNfL concentrations, as well as cNfL levels, emerged as predictive indicators of subsequent disease progression rate (sNfL: p < 0.0001, cNfL: p = 0.0005) and overall survival (sNfL: p = 0.0073, cNfL: p = 0.0044). Employing a Cox regression model, we identified baseline sNfL level (HR = 1.01, p = 0.013), and diagnostic delay (HR = 0.94, p = 0.003) as independent prognostic factors for mortality. Furthermore, we constructed a nomogram model that incorporates both sNfL and pertinent clinical variables, which substantially enhances the accuracy of predicting disease outcomes (Concordance Index, 0.808).

CONCLUSION: Our study underscores the robust correlation between sNfL and cNfL in ALS patients and establishes baseline sNfL as a potent and independent prognostic marker for mortality.}, } @article {pmid39863573, year = {2025}, author = {Ting, HC and Guo, YT and Su, HL and Chen, YS and Lin, SZ and Harn, HJ and Chang, CY}, title = {Rapid iPSC-derived neuromuscular junction model uncovers motor neuron dominance in amyotrophic lateral sclerosis cytopathy.}, journal = {Cell death discovery}, volume = {11}, number = {1}, pages = {23}, pmid = {39863573}, issn = {2058-7716}, abstract = {The neuromuscular junction (NMJ) is essential for transmitting signals from motor neurons (MNs) to skeletal muscles (SKMs), and its dysfunction can lead to severe motor disorders. However, our understanding of the NMJ is limited by the absence of accurate human models. Although human induced pluripotent stem cell (iPSC)-derived models have advanced NMJ research, their application is constrained by challenges such as limited differentiation efficiency, lengthy generation times, and cryopreservation difficulties. To overcome these limitations, we developed a rapid human NMJ model using cryopreserved MNs and SKMs derived from iPSCs. Within 12 days of coculture, we successfully recreated NMJ-specific connectivity that closely mirrors in vivo synapse formation. Using this model, we investigated amyotrophic lateral sclerosis (ALS) and replicated ALS-specific NMJ cytopathies with SOD1 mutant and corrected isogenic iPSC lines. Quantitative analysis of 3D confocal microscopy images revealed a critical role of MNs in initiating ALS-related NMJ cytopathies, characterized by alterations in the volume, number, intensity, and distribution of acetylcholine receptors, ultimately leading to impaired muscle contractions. Our rapid and precise in vitro NMJ model offers significant potential for advancing research on NMJ physiology and pathology, as well as for developing treatments for NMJ-related diseases.}, } @article {pmid39863163, year = {2025}, author = {Kearney, CA and Needle, CD and Brinks, AL and Gutierrez, D and Lo Sicco, KI}, title = {Response to Sood et al's "Systemic Janus kinase inhibitor treatment for vitiligo: An evidence-based review".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.01.059}, pmid = {39863163}, issn = {1097-6787}, } @article {pmid39863029, year = {2025}, author = {Liu, X and Li, T and Tu, X and Xu, M and Wang, J}, title = {Mitochondrial fission and fusion in neurodegenerative diseases:Ca[2+] signalling.}, journal = {Molecular and cellular neurosciences}, volume = {132}, number = {}, pages = {103992}, doi = {10.1016/j.mcn.2025.103992}, pmid = {39863029}, issn = {1095-9327}, mesh = {*Mitochondrial Dynamics ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Calcium Signaling/physiology ; Mitochondria/metabolism ; Endoplasmic Reticulum/metabolism ; Mitochondrial Proteins/metabolism/genetics ; }, abstract = {Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive loss of neuronal structure and function. The pathogenesis is intricate and involves a network of interactions among multiple causes and systems. Mitochondria and Ca[2+] signaling have long been considered to play important roles in the development of various NDs. Mitochondrial fission and fusion dynamics are important processes of mitochondrial quality control, ensuring the stability of mitochondrial structure and function. Mitochondrial fission and fusion imbalance and Ca[2+] signaling disorders can aggravate the disease progression of NDs. In this review, we explore the relationship between mitochondrial dynamics and Ca[2+] signaling in AD, PD, ALS, and HD, focusing on the roles of key regulatory proteins (Drp1, Fis1, Mfn1/2, and Opa1) and the association structures between mitochondria and the endoplasmic reticulum (MERCs/MAMs). We provide a detailed analysis of their involvement in the pathogenesis of these four NDs. By integrating these mechanisms, we aim to clarify their contributions to disease progression and offer insights into the development of therapeutic strategies that target mitochondrial dynamics and Ca[2+] signaling. We also examine the progress in drug research targeting these pathways, highlighting their potential as therapeutic targets in the treatment of NDs.}, } @article {pmid39862884, year = {2025}, author = {Moens, TG and Da Cruz, S and Neumann, M and Shelkovnikova, TA and Shneider, NA and Van Den Bosch, L}, title = {Amyotrophic lateral sclerosis caused by FUS mutations: advances with broad implications.}, journal = {The Lancet. Neurology}, volume = {24}, number = {2}, pages = {166-178}, doi = {10.1016/S1474-4422(24)00517-9}, pmid = {39862884}, issn = {1474-4465}, support = {SHELKOVNIKOVA/OCT17/968-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *RNA-Binding Protein FUS/genetics ; *Mutation/genetics ; Animals ; }, abstract = {Autosomal dominant mutations in the gene encoding the DNA and RNA binding protein FUS are a cause of amyotrophic lateral sclerosis (ALS), and about 0·3-0·9% of patients with ALS are FUS mutation carriers. FUS-mutation-associated ALS (FUS-ALS) is characterised by early onset and rapid progression, compared with other forms of ALS. However, different pathogenic mutations in FUS can result in markedly different age at symptom onset and rate of disease progression. Most FUS mutations disrupt its nuclear localisation, leading to its cytoplasmic accumulation in the CNS. FUS also forms inclusions in around 5% of patients with the related neurodegenerative condition frontotemporal dementia. However, there are key differences between the two diseases at the genetic and neuropathological level, which suggest distinct pathogenic processes. Experimental models have uncovered potential pathogenic mechanisms in FUS-ALS and informed therapeutic strategies that are currently in development, including the silencing of FUS expression using an intrathecally administered antisense oligonucleotide.}, } @article {pmid39862877, year = {2025}, author = {Feldman, EL and Sattler, R and Kiernan, MC and Goutman, SA and Chiò, A and Al-Chalabi, A}, title = {Transforming amyotrophic lateral sclerosis into a liveable disease.}, journal = {The Lancet. Neurology}, volume = {24}, number = {2}, pages = {100-101}, doi = {10.1016/S1474-4422(24)00523-4}, pmid = {39862877}, issn = {1474-4465}, } @article {pmid39861520, year = {2025}, author = {Tripolskaja, L and Kazlauskaite-Jadzevice, A and Razukas, A and Baksiene, E}, title = {Perennial Grasses on Stony Sandy Loam Arenosol: Summary of Results of Long-Term Experiment in Northern Europe Region (1995-2024).}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {2}, pages = {}, pmid = {39861520}, issn = {2223-7747}, support = {"Improvement of the preparation of highly skilled professionals for development of science-intensive economic entities-NKPDOKT" (project code No: VP1-3.1-ŠMM-01-V-03-001)//Lietuvos mokslų taryba/ ; }, abstract = {Grasses can sustain soil functions despite nutrient depletion, which can have serious consequences for soil processes and ecosystem services. This paper summarizes the results of the long-term experiment (1995-2024) carried out in Arenosol within a temperate climate zone, focusing on the productivity of natural and managed grasslands; their succession changes over time, and so do the effects on soil chemical properties, and soil organic carbon (SOC) sequestration. The results indicated that two land uses-abandoned land (AL) and grassland fertilized with mineral fertilizers (MGf)-can be effectively applied to prevent Arenosol soil degradation. SOC accumulation occurs more rapidly in AL soils, and their chemical properties show less change over time. The ability of grasses to sequester SOC is better reflected by SOC stocks across the Ah horizon, where thickness varies over long-term grassland use. Significant changes in soil properties were observed more than 20 years after converting arable to herbaceous land use. While MGf has the highest biomass productivity, the use of fertilizers leads to soil acidification. The biomass productivity of AL and MGf increased with longer grassland use; however, in MG, productivity decreased without fertilizers, reaching AL's productivity levels after 20 years. As the age of AL increased, plant biodiversity decreased, and drought-resistant plants began to spread.}, } @article {pmid39860557, year = {2025}, author = {Chmiel, J and Stępień-Słodkowska, M}, title = {Resting-State EEG Oscillations in Amyotrophic Lateral Sclerosis (ALS): Toward Mechanistic Insights and Clinical Markers.}, journal = {Journal of clinical medicine}, volume = {14}, number = {2}, pages = {}, pmid = {39860557}, issn = {2077-0383}, abstract = {Introduction: Amyotrophic lateral sclerosis (ALS) is a complex, progressive neurodegenerative disorder characterized by the degeneration of motor neurons in the brain, brainstem, and spinal cord. Several neuroimaging techniques can help reveal the pathophysiology of ALS. One of these is the electroencephalogram (EEG), a noninvasive and relatively inexpensive tool for examining electrical activity of the brain with excellent temporal precision. Methods: This mechanistic review examines the pattern of resting-state EEG activity. With a focus on publications published between January 1995 and October 2024, we carried out a comprehensive search in October 2024 across a number of databases, including PubMed/Medline, Research Gate, Google Scholar, and Cochrane. Results: The literature search yielded 17 studies included in this review. The studies varied significantly in their methodology and patient characteristics. Despite this, a common biomarker typical of ALS was found-reduced alpha power. Regarding other oscillations, the findings are less consistent and sometimes contradictory. As this is a mechanistic review, three possible explanations for this biomarker are provided. The main and most important one is increased cortical excitability. In addition, due to the limitations of the studies, recommendations for future research on this topic are outlined to enable a further and better understanding of EEG patterns in ALS. Conclusions: Most studies included in this review showed alpha power deficits in ALS patients, reflecting pathological hyperexcitability of the cerebral cortex. Future studies should address the methodological limitations identified in this review, including small sample sizes, inconsistent frequency-band definitions, and insufficient functional outcome measures, to solidify and extend current findings.}, } @article {pmid39859339, year = {2025}, author = {Yashooa, RK and Duranti, E and Conconi, D and Lavitrano, M and Mustafa, SA and Villa, C}, title = {Mitochondrial microRNAs: Key Drivers in Unraveling Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {2}, pages = {}, pmid = {39859339}, issn = {1422-0067}, mesh = {*MicroRNAs/genetics/metabolism ; Humans ; *Neurodegenerative Diseases/genetics/metabolism ; *Mitochondria/metabolism/genetics ; Animals ; Gene Expression Regulation ; DNA, Mitochondrial/genetics/metabolism ; }, abstract = {MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) crucial for regulating gene expression at the post-transcriptional level. Recent evidence has shown that miRNAs are also found in mitochondria, organelles that produce energy in the cell. These mitochondrial miRNAs, also known as mitomiRs, are essential for regulating mitochondrial function and metabolism. MitomiRs can originate from the nucleus, following traditional miRNA biogenesis pathways, or potentially from mitochondrial DNA, allowing them to directly affect gene expression and cellular energy dynamics within the mitochondrion. While miRNAs have been extensively investigated, the function and involvement of mitomiRs in the development of neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis remain to be elucidated. This review aims to discuss findings on the role of mitomiRs in such diseases and their potential as therapeutic targets, as well as to highlight future research directions.}, } @article {pmid39859258, year = {2025}, author = {Szablewski, L}, title = {Associations Between Diabetes Mellitus and Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {2}, pages = {}, pmid = {39859258}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/etiology ; *Diabetes Mellitus, Type 2/complications/metabolism ; Parkinson Disease/metabolism/pathology ; Oxidative Stress ; Alzheimer Disease/metabolism/etiology/pathology ; Amyotrophic Lateral Sclerosis/metabolism/etiology/pathology ; Diabetes Mellitus, Type 1/complications/metabolism ; Huntington Disease/metabolism/pathology ; Diabetes Mellitus/metabolism ; Animals ; }, abstract = {Diabetes mellitus (DM) and neurodegenerative diseases/disturbances are worldwide health problems. The most common chronic conditions diagnosed in persons 60 years and older are type 2 diabetes mellitus (T2DM) and cognitive impairment. It was found that diabetes mellitus is a major risk for cognitive decline, dementia, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Different mechanisms of associations between these diseases and diabetes mellitus have been suggested. For example, it is postulated that an impaired intracellular insulin signaling pathway, together with hyperglycemia and hyperinsulinemia, may cause pathological changes, such as dysfunction of the mitochondria, oxidative stress inflammatory responses, etc. The association between diabetes mellitus and neurodegenerative diseases, as well as the mechanisms of these associations, needs further investigation. The aim of this review is to describe the associations between diabetes mellitus, especially type 1 (T1DM) and type 2 diabetes mellitus, and selected neurodegenerative diseases, i.e., Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Suggested mechanisms of these associations are also described.}, } @article {pmid39858428, year = {2024}, author = {Argueti-Ostrovsky, S and Barel, S and Kahn, J and Israelson, A}, title = {VDAC1: A Key Player in the Mitochondrial Landscape of Neurodegeneration.}, journal = {Biomolecules}, volume = {15}, number = {1}, pages = {}, pmid = {39858428}, issn = {2218-273X}, support = {#284/19 and #485/24//Israel Science Foundation/ ; }, mesh = {Humans ; *Voltage-Dependent Anion Channel 1/metabolism/genetics ; *Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Animals ; alpha-Synuclein/metabolism/genetics ; Alzheimer Disease/metabolism/pathology/genetics ; Superoxide Dismutase-1/metabolism/genetics ; Oxidative Stress ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Mitochondrial Membranes/metabolism ; }, abstract = {Voltage-Dependent Anion Channel 1 (VDAC1) is a mitochondrial outer membrane protein that plays a crucial role in regulating cellular energy metabolism and apoptosis by mediating the exchange of ions and metabolites between mitochondria and the cytosol. Mitochondrial dysfunction and oxidative stress are central features of neurodegenerative diseases. The pivotal functions of VDAC1 in controlling mitochondrial membrane permeability, regulating calcium balance, and facilitating programmed cell death pathways, position it as a key determinant in the delicate balance between neuronal viability and degeneration. Accordingly, increasing evidence suggests that VDAC1 is implicated in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and others. This review summarizes the current findings on the contribution of VDAC1 to neurodegeneration, focusing on its interactions with disease-specific proteins, such as amyloid-β, α-synuclein, and mutant SOD1. By unraveling the complex involvement of VDAC1 in neurodegenerative processes, this review highlights potential avenues for future research and drug development aimed at alleviating mitochondrial-related neurodegeneration.}, } @article {pmid39857761, year = {2025}, author = {Sun, C and Chen, Y and Xu, L and Wang, W and Zhang, N and Fournier, CN and Li, N and Fan, D}, title = {Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale as a Novel Tool to Measure Disease Progression.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, pmid = {39857761}, issn = {2227-9059}, support = {82001347//National Natural Science Foundation of China/ ; 82071426//National Natural Science Foundation of China/ ; 81701067//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; }, abstract = {Background: A valuable outcome measure to monitor amyotrophic lateral sclerosis (ALS) disease progression is crucial in clinical trials. Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) is a novel questionnaire assessing ALS disability. Currently, there are no studies on the relationship between ROADS and ALS survival. This study explored the value of Chinese ROADS as a novel tool for measuring disease progression and the correlation between ROADS and ALS survival. Methods: A total of 170 ALS participants were included in this study. Clinical characteristics and baseline ROADS, ΔROADS, ALSFRS-R, and ΔFRS of patients were collected. Participants were followed for 18 months to assess time to tracheostomy and survival. Scales were collected every 3 to 6 months. We evaluated the association of baseline ROADS and ΔROADS with survival using Cox regression analyses. Linear mixed effects models were used to assess changes over time in ROADS and ALSFRS-R. Results: Multivariate Cox models confirmed that baseline ROADS positively correlated with ALS survival (HR = 0.95, p < 0.001), while baseline ΔROADS negatively correlated with survival (HR = 1.26, p < 0.001). Additionally, linear mixed effects models suggested that ROADS, similar to ALSFRS-R, declined significantly over time, but there was no significant difference between these two. Conclusions: Our study indicates that Chinese ROADS is strongly related to ALS survival. Changes in ROADS with disease progression are similar to those in ALSFRS-R. These findings support Chinese ROADS as a reliable outcome measure for clinical trials, potentially enhancing the dimension of evaluating treatment effectiveness in ALS trials.}, } @article {pmid39857633, year = {2024}, author = {Zhang, G and Cao, W and Wang, Z and Xia, K and Deng, B and Fan, D}, title = {Associations of Abnormal Sleep Duration and Chronotype with Higher Risk of Incident Amyotrophic Lateral Sclerosis: A UK Biobank Prospective Cohort Study.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, pmid = {39857633}, issn = {2227-9059}, support = {82301601 81873784 82071426//National Natural Science Foundation of China/ ; }, abstract = {Background: The occurrence of sleep disturbances in amyotrophic lateral sclerosis (ALS) patients is widely reported. However, there is still a lack of reliable evidence of a relationship between sleep disturbances and the risk of developing ALS. The aim of this study was to prospectively investigate the longitudinal associations between sleep traits and the risk of incident ALS. Methods: We included information from 409,045 individuals from the prospective cohort of the UK Biobank. Sleep traits at baseline were measured using a standardized questionnaire. All sleep traits were analyzed in relation to the subsequent incidence of ALS using Cox proportional hazards models. Results: Multivariate analysis showed that 6-7 h of sleep was related to the lowest risk for ALS. A long sleep duration (≥8 h) was associated with an increased risk of ALS incidence (HR: 1.31, 95% CI: 1.07-1.61; p = 0.009). A short sleep duration (<6 h) was associated with an increased risk of ALS incidence (HR: 1.91, 95% CI: 1.10-3.30, p = 0.021) in females. In participants aged ≥65 years, eveningness was associated with increased ALS risk (HR: 1.32, 95% CI: 1.08-1.61; p = 0.006). Conclusion: Our results hint at a sleep duration that is too short or too long, and certain chronotypes might be related to the risk of developing ALS. Despite the limitations imposed by the study design and the subjectivity of sleep information, our findings suggest that sleep disturbances may influence the risk of developing ALS.}, } @article {pmid39857620, year = {2024}, author = {Frawley, L and Taylor, NT and Sivills, O and McPhillamy, E and To, TD and Wu, Y and Chin, BY and Wong, CY}, title = {Stem Cell Therapy for the Treatment of Amyotrophic Lateral Sclerosis: Comparison of the Efficacy of Mesenchymal Stem Cells, Neural Stem Cells, and Induced Pluripotent Stem Cells.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, pmid = {39857620}, issn = {2227-9059}, support = {Australian Government New Colombo Plan (NCP) scheme//Australian Government New Colombo Plan (NCP) scheme/ ; }, abstract = {BACKGROUND/OBJECTIVES: Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a debilitating, incurable neurodegenerative disorder characterised by motor neuron death in the spinal cord, brainstem, and motor cortex. With an incidence rate of about 4.42 cases per 100,000 people annually, ALS severely impacts motor function and quality of life, causing progressive muscle atrophy, spasticity, paralysis, and eventually death. The cause of ALS is largely unknown, with 90% of cases being sporadic and 10% familial. Current research targets molecular mechanisms of inflammation, excitotoxicity, aggregation-prone proteins, and proteinopathy.

METHODS: This review evaluates the efficacy of three stem cell types in ALS treatment: mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs).

RESULTS: MSCs, derived from various tissues, show neuroprotective and regenerative qualities, with clinical trials suggesting potential benefits but limited by small sample sizes and non-randomised designs. NSCs, isolated from the fetal spinal cord or brain, demonstrate promise in animal models but face functional integration and ethical challenges. iPSCs, created by reprogramming patient-specific somatic cells, offer a novel approach by potentially replacing or supporting neurons. iPSC therapy addresses ethical issues related to embryonic stem cells but encounters challenges regarding genotoxicity and epigenetic irregularities, somatic cell sources, privacy concerns, the need for extensive clinical trials, and high reprogramming costs.

CONCLUSIONS: This research is significant for advancing ALS treatment beyond symptomatic relief and modest survival extensions to actively modifying disease progression and improving patient outcomes. Successful stem cell therapies could lead to new ALS treatments, slowing motor function loss and reducing symptom severity.}, } @article {pmid39857328, year = {2025}, author = {Stoccoro, A}, title = {Epigenetic Mechanisms Underlying Sex Differences in Neurodegenerative Diseases.}, journal = {Biology}, volume = {14}, number = {1}, pages = {}, pmid = {39857328}, issn = {2079-7737}, support = {GR-2021-12374436//Italian Ministry of Health, Ricerca Finalizzata/ ; }, abstract = {Neurodegenerative diseases are characterized by profound differences between females and males in terms of incidence, clinical presentation, and disease progression. Furthermore, there is evidence suggesting that differences in sensitivity to medical treatments may exist between the two sexes. Although the role of sex hormones and sex chromosomes in driving differential susceptibility to these diseases is well-established, the molecular alterations underlying these differences remain poorly understood. Epigenetic mechanisms, including DNA methylation, histone tail modifications, and the activity of non-coding RNAs, are strongly implicated in the pathogenesis of neurodegenerative diseases. While it is known that epigenetic mechanisms play a crucial role in sexual differentiation and that distinct epigenetic patterns characterize females and males, sex-specific epigenetic patterns have been largely overlooked in studies aiming to identify epigenetic alterations associated with neurodegenerative diseases. This review aims to provide an overview of sex differences in epigenetic mechanisms, the role of sex-specific epigenetic processes in the central nervous system, and the main evidence of sex-specific epigenetic alterations in three neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Understanding the sex-related differences of these diseases is essential for developing personalized treatments and interventions that account for the unique epigenetic landscapes of each sex.}, } @article {pmid39855275, year = {2025}, author = {Zhang, W and Zhang, L and Fu, S and Yan, R and Zhang, X and Song, J and Lu, Y}, title = {Roles of NLRC4 inflammasome in neurological disorders: Mechanisms, implications, and therapeutic potential.}, journal = {Pharmacology & therapeutics}, volume = {267}, number = {}, pages = {108803}, doi = {10.1016/j.pharmthera.2025.108803}, pmid = {39855275}, issn = {1879-016X}, mesh = {Humans ; *Inflammasomes/metabolism ; Animals ; *Calcium-Binding Proteins/metabolism ; Nervous System Diseases/drug therapy/metabolism/immunology ; Neurodegenerative Diseases/drug therapy/metabolism ; Pyroptosis ; CARD Signaling Adaptor Proteins ; }, abstract = {The nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 4 (NLRC4) inflammasome, a vital component of the innate immune system, is known for defending against bacterial infections. However, recent insights have revealed its significant impact on neurological disorders. This comprehensive review discussed the mechanisms underlying the activation and regulation of the NLRC4 inflammasome, highlighting the complexity of its response to cellular stress and damage signals. The biological functions of NLRC4 were explored, particularly its influence on cytokine production and the induction of pyroptosis, a form of inflammatory cell death. This review further emphasized the role of the NLRC4 inflammasome in brain injuries and neurodegenerative disorders. In the realm of brain injuries such as stroke and traumatic brain injury, as well as in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, the NLRC4 inflammasome played a pivotal role in modulating neuroinflammatory responses, which was crucial for understanding the progression and potential therapeutic targeting of these conditions. The emerging role of NLRC4 in psychiatric disorders and its potential impact on glioma progression were also examined. Additionally, this review presented a thorough summary of the latest research on inhibitors that impeded the assembly and activation of the NLRC4 inflammasome, pointing to new therapeutic possibilities in neurological disorders. In conclusion, by integrating current knowledge on the activation and regulation of NLRC4 with its biological functions and clinical implications, this article underscored the importance of NLRC4 inflammasome in neurological pathologies, which opened new possibilities for the treatment of challenging neurological conditions.}, } @article {pmid39854930, year = {2025}, author = {Drouet, C and Priou, P and Gagnadoux, F and Trzepizur, W}, title = {Constraints to the initiation of home non-invasive ventilation and short-term efficacy in different diagnostic groups (as a prelude to an ambulatory shift).}, journal = {Respiratory medicine and research}, volume = {87}, number = {}, pages = {101154}, doi = {10.1016/j.resmer.2025.101154}, pmid = {39854930}, issn = {2590-0412}, abstract = {INTRODUCTION: Non-invasive ventilation (NIV) is the reference treatment for chronic respiratory failure (CRF) due to impairment of the ventilatory system. Home initiation is increasingly practiced. To better support this ambulatory shift, we aimed to assess the implementation constraints and short-term efficacy according to different aetiologies of CRF.

METHODS: This retrospective study with cross-sectional and longitudinal analysis included patients initiated with NIV at Angers University Hospital. Patients were separated according to the following aetiologies: obesity hypoventilation syndrome (OHS), chronic obstruction pulmonary disease (COPD), amyotrophic lateral sclerosis (ALS), myopathy and chest wall disease. Implementation constraints were assessed by analysing the variability of NIV settings, the number of masks tried and the duration of hospitalisation. NIV effectiveness was assessed by measuring residual PaCO2 (arterial pressure in CO2), apnoea hypopnea index (AHIflow) and tidal volume (VT) (as displayed by the NIV software).

RESULTS: Between October 2020 and May 2022, 102 patients were started with NIV, including a majority of ALS patients. We found a moderate variability in NIV settings (pressure, slope, triggers, etc.) within the different etiological groups, particularly in ALS. On the other hand, ALS patients required more interface trials than other groups and often had unmet efficacy criteria at hospital discharge. Interestingly, longitudinal follow-up showed a progressive improvement in efficacy criteria, particularly in patients who were initially inadequately ventilated.

CONCLUSION: Each aetiological group has specific constraints in the initiation of NIV that should be considered when initiating NIV in the outpatient setting.}, } @article {pmid39854095, year = {2025}, author = {Hansen, G and Shaw, A and Bolt, K and Verity, R and Nataraj, RT and Schellenberg, KL}, title = {Thoracic Electric Impedance Tomography Detects Lung Volume Changes in Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {71}, number = {4}, pages = {552-557}, pmid = {39854095}, issn = {1097-4598}, support = {//ALS Society of Saskatchewan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; *Electric Impedance ; Female ; Male ; Middle Aged ; Aged ; Vital Capacity/physiology ; *Tomography/methods ; Lung/physiopathology/diagnostic imaging ; Lung Volume Measurements/methods ; Spirometry ; Supine Position ; Adult ; Respiratory Function Tests ; }, abstract = {INTRODUCTION/AIMS: Spirometry is the conventional means to measure lung function in amyotrophic lateral sclerosis (ALS), but is dependent on patient effort and bulbar strength. We aimed to use electric impedance tomography (EIT), an emerging non-invasive imaging modality, to measure dynamic lung volume changes.

METHODS: Twenty-one patients with ALS underwent sitting and supine spirometry for forced vital capacity (FVC), and sitting and supine EIT. There were 13 patients in the high FVC group (FVC ≥ 80% predicted) and 8 in the low FVC group (FVC < 80% predicted). Additional demographic and clinical data were collected from clinical records.

RESULTS: Only the low FVC group had significant loss of lung volumes in the supine position (R [2] = 0.89 and p < 0.001). The supine volume loss measurement at 10 min correlated with sitting (r [2] = 0.47) and supine FVC (r [2] = 0.36), maximum inspiratory (r [2] = -0.44) and expiratory pressures (r [2] = 0.36) (MIP and MEP), and the ALS Functional Rating Scale-Revised (ALSFRS-R) dyspnea subscore (r [2] = 0.36).

DISCUSSION: EIT is an emerging alternative to existing measures of lung function in ALS, but without need for patient effort or bulbar strength. Significant losses in lung volume are seen on supine compared to upright position in patients with respiratory dysfunction. Further study is needed to determine relationships to existing clinical measures.}, } @article {pmid39853150, year = {2025}, author = {Shune, S and Gray, LT and Perry, S and Kosty, D and Namasivayam-MacDonald, A}, title = {Validation of the Caregiver Analysis of Reported Experiences with Swallowing Disorders (CARES) Screening Tool for Neurodegenerative Disease.}, journal = {American journal of speech-language pathology}, volume = {34}, number = {2}, pages = {633-645}, doi = {10.1044/2024_AJSLP-24-00253}, pmid = {39853150}, issn = {1558-9110}, mesh = {Humans ; *Deglutition Disorders/diagnosis ; *Caregivers ; Male ; Female ; Middle Aged ; Reproducibility of Results ; Aged ; *Neurodegenerative Diseases/diagnosis ; Adult ; Aged, 80 and over ; Deglutition ; Surveys and Questionnaires ; Cost of Illness ; Caregiver Burden/psychology ; Amyotrophic Lateral Sclerosis/diagnosis ; Parkinson Disease/diagnosis ; Predictive Value of Tests ; ROC Curve ; Dementia/diagnosis ; }, abstract = {PURPOSE: Swallowing difficulties have a substantial impact on the burden experienced by care partners of individuals with neurodegenerative disease. Given this, there is a clear need to easily identify and quantify the unique aspects of swallowing-related burden. The purpose of this study was to establish the validity and reliability of the Caregiver Analysis of Reported Experiences with Swallowing Disorders (CARES) screening tool in care partners of individuals with neurodegenerative disease.

METHOD: Survey data were collected from an international sample of 212 individuals caring for family members with amyotrophic lateral sclerosis (n = 49), dementia (n = 110), or Parkinson's disease (n = 53). Respondents completed the CARES, Eating Assessment Tool-10, International Dysphagia Diet Standardisation Initiative-Functional Diet Scale, and Zarit Burden Interview. Reliability and validity of the CARES were evaluated via internal consistency alpha coefficients, Spearman's rho correlations, and logistic regression analyses with receiver operating characteristic (ROC) curves.

RESULTS: CARES scores demonstrated excellent internal consistency (α = .90-.95) and high test-retest reliability (r = .86-.91). The CARES was found to be valid, as increased swallowing-related burden was associated with increased severity of swallowing difficulties (r = .79 to .84), diet restrictiveness (r = -.50 to -.54), and general caregiver burden (r = .36 to .40). The CARES had excellent discrimination between care partners with and without self-reported swallowing-related burden, with a score of ≥ 4 suggesting a heightened risk of experiencing this burden.

CONCLUSIONS: Results establish the CARES as a valid and reliable screening tool that can detect burden related to swallowing difficulties among care partners of individuals living with neurodegenerative disease (score ≥ 4). Clinical implementation of the CARES requires the concerted efforts of the larger multidisciplinary team who can collaboratively identify the presence of burden and target the multifaceted sources of burden that a care partner may be experiencing.}, } @article {pmid39852553, year = {2025}, author = {Tang, X and Chen, Y and Ren, Y and Yang, W and Yu, W and Zhou, Y and Guo, J and Hu, J and Chen, X and Gu, Y and Wang, C and Dong, Y and Yang, H and Sato, C and He, J and Fan, D and You, L and Zinman, L and Rogaeva, E and Chen, Y and Zhang, M}, title = {Deep learning analyses of splicing variants identify the link of PCP4 with amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf025}, pmid = {39852553}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease, with most sporadic cases lacking clear genetic causes. Abnormal pre-mRNA splicing is a fundamental mechanism in neurodegenerative diseases. For example, TAR DNA-binding protein 43 (TDP-43) loss-of-function (LOF) causes widespread RNA mis-splicing events in ALS. Additionally, splicing mutations are major contributors to neurological disorders. However, the role of intronic variants driving RNA mis-splicing in ALS remains poorly understood. To address this, we developed Spliformer to predict RNA splicing. Spliformer is a transformer-based deep learning model trained and tested on splicing events from the GENCODE database, as well as RNA-seq data from blood and central nervous system tissues. We benchmarked Spliformer against SpliceAI and Pangolin using testing datasets and paired whole-genome sequencing (WGS) with RNA-seq data. We further developed the Spliformer-motif model to identify splicing regulatory motifs. We analyzed Clinvar dataset to identify the link of splicing variants with disease pathogenicity. Additionally, we analyzed WGS data of ALS patients and controls to identify common intronic splicing variants linked to ALS risk or disease phenotypes. We also profiled rare intronic splicing variants in ALS patients to identify known or novel ALS-associated genes. Minigene assays were employed to validate candidate splicing variants. Finally, we measured spine density in neurons with a specific gene knockdown or those expressing a TDP-43 disease-causing mutant. Spliformer accurately predicts the possibilities of a nucleotide within a pre-mRNA sequence being a splice donor, acceptor, or neither. Spliformer outperformed SpliceAI and Pangolin in both speed and accuracy in tested splicing events and/or paired WGS/RNA-seq data. Spliformer-motif successfully identified canonical and novel splicing regulatory motifs. In Clinvar dataset, splicing variants are highly related to disease pathogenicity. Genome-wide analyses of common intronic splicing variants nominated one variant linked to ALS progression. Deep learning analyses of WGS data from 1,370 ALS patients revealed rare splicing variants in reported ALS genes (such as PTPRN2 and CFAP410, validated through minigene assays and RNA-seq), and TDP-43 LOF related RNA mis-splicing genes (such as PTPRD). Further genetic analysis and minigene assays nominated PCP4 and TMEM63A as ALS-associated genes. Functional assays demonstrated that PCP4 is critical for maintaining spine density and can rescue spine loss in neurons expressing a disease-causing TDP-43 mutant. In summary, we developed Spliformer and Spliformer-motif that accurately predict and interpret pre-mRNA splicing. Our findings highlight an intronic genetic mechanism driving RNA mis-splicing in ALS and nominate PCP4 as an ALS-associated gene.}, } @article {pmid39852477, year = {2025}, author = {Bennett, SA and Cobos, SN and Fisher, RMA and Son, E and Frederic, R and Segal, R and Yousuf, H and Chan, K and Dansu, DK and Torrente, MP}, title = {Direct and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification Dysregulation and Growth Suppression in an ALS/FTD Yeast Model.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {11}, number = {1}, pages = {}, pmid = {39852477}, issn = {2309-608X}, support = {S10 OD010582/OD/NIH HHS/United States ; R35 NS111604/NS/NINDS NIH HHS/United States ; K22NS09131401//NIH NINDS/ ; R35NS111604//NIH NINDS/ ; R15NS125394//NIH NINDS/ ; N/A//Brooklyn College, CUNY/ ; N/A//The Graduate Center, CUNY/ ; K12 GM102778/GM/NIGMS NIH HHS/United States ; R15 NS125394/NS/NINDS NIH HHS/United States ; R15NS125394-01S1//NIH NINDS/ ; K12GM102778//NIH NIGMS/ ; 1S01OD010582-01A1/GF/NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative disorders sharing pathological and genetic features, including mutations in the FUS gene. FUS is an RNA-binding protein that mislocalizes to the cytoplasm and aggregates in ALS/FTD. In a yeast model, FUS proteinopathy is connected to changes in the epigenome, including reductions in the levels of H3S10ph, H3K14ac, and H3K56ac. Exploiting the same model, we reveal novel connections between FUS aggregation and epigenetic dysregulation. We show that the histone-modifying enzymes Ipl1 and Rtt109-responsible for installing H3S10ph and H3K56ac-are excluded from the nucleus in the context of FUS proteinopathy. Furthermore, we found that Ipl1 colocalizes with FUS, but does not bind it directly. We identified Nop1 and Rrp5, a histone methyltransferase and rRNA biogenesis protein, respectively, as FUS binding partners involved in the growth suppression phenotype connected to FUS proteinopathy. We propose that the nuclear exclusion of Ipl1 through indirect interaction with FUS drives the dysregulation of H3S10ph as well as H3K14ac via crosstalk. We found that the knockdown of Nop1 interferes with these processes. In a parallel mechanism, Rtt109 mislocalization results in reduced levels of H3K56ac. Our results highlight the contribution of epigenetic mechanisms to ALS/FTD and identify novel targets for possible therapeutic intervention.}, } @article {pmid39851451, year = {2025}, author = {Milligan, C and Cowley, DO and Stewart, W and Curry, AM and Forbes, E and Rector, B and Hastie, A and Liu, L and Hawkins, GA}, title = {Enhanced Interleukin 6 Trans-Signaling Modulates Disease Process in Amyotrophic Lateral Sclerosis Mouse Models.}, journal = {Brain sciences}, volume = {15}, number = {1}, pages = {}, pmid = {39851451}, issn = {2076-3425}, support = {R03 AI137866/AI/NIAID NIH HHS/United States ; Hope for Tomorrow ALS Fund//Wake Forest University School of Medicine/ ; TAB Williams Endowment//Wake Forest University School of Medicine/ ; 1R03AI137866-21A1/NH/NIH HHS/United States ; UM1 TR004929/TR/NCATS NIH HHS/United States ; DoD W81XWH1810377//US Department of the Army/ ; Neuroscience Clinical Trial and Innovation Center//Wake Forest University School of Medicine/ ; }, abstract = {Background/Objectives: Charcot first described ALS in 1869, but the specific mechanisms that mediate the disease pathology are still not clear. Intense research efforts have provided insight into unique neuroanatomical regions, specific neuronal populations and genetic associations for ALS and other neurodegenerative diseases; however, the experimental results also suggest a convergence of these events to common toxic pathways. We propose that common toxic pathways can be therapeutically targeted, and this intervention will be effective in slowing progression and improving patient quality of life. Here, we focus on understanding the role of IL6 trans-signaling in ALS disease processes. Methods: We leveraged unique mouse models of IL6 trans-signaling that we developed that recapitulate the production of active sIL6R in a genotypic and quantitative fashion observed in humans. Given that the SOD1 transgenic mouse is one of the most highly studied and characterized models of ALS, we bred SOD1[G93A] mice with IL6R trans-signaling mice to determine how enhanced trans-signaling influenced symptom onset and pathological processes, including neuromuscular junction (NMJ) denervation, glial activation and motoneuron (MN) survival. Results: The results indicate that in animals with enhanced trans-signaling, symptom onset and pathological processes were accelerated, suggesting a role in disease modification. Administration of an IL6R functional blocking antibody failed to alter accelerated symptom onset and disease progression. Conclusions: Future work to investigate the site-specific influence of enhanced IL6 trans-signaling and the tissue-specific bioavailability of potential therapeutics will be necessary to identify targets for precise therapeutic interventions that may limit disease progression in the 60% of ALS patients who inherit the common Il6R Asp[358]Ala variant.}, } @article {pmid39850989, year = {2025}, author = {Matsuda, C and Nakayama, Y and Haraguchi, M and Morishima, R and Itagaki, Y and Bokuda, K and Kimura, H and Takahashi, K and Shimizu, T}, title = {Patients' choices regarding ventilatory support affect opioid use in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2025.2453463}, pmid = {39850989}, issn = {2167-9223}, abstract = {OBJECTIVE: To investigate the impact of different ventilatory support options on opioid use among patients with amyotrophic lateral sclerosis (ALS).

METHODS: We retrospectively reviewed 889 consecutive patients with ALS and enrolled 399 eligible patients. All patients were followed until death or tracheostomy. Clinical characteristics of patients and the timing of initial opioid administration were evaluated. Patients were categorized into four subgroups: (1) 160 patients who never used a ventilator, (2) 120 patients who used only noninvasive ventilation (NIV), (3) 61 patients who transitioned from NIV to tracheostomy and invasive ventilation (TIV), and (4) 58 patients who underwent TIV without prior NIV. We compared the prevalence of opioid use across these groups and assessed its relationship with ventilatory support options using multivariate logistic analysis.

RESULTS: A total of 130 patients (32.6%) used opioids. The number of patients who used opioids in each group was as follows: 55 (34.4%) in Group 1, 69 (57.5%) in Group 2, 5 (8.2%) in Group 3, and 1 (1.7%) in Group 4 (p < 0.0001). Multivariate logistic analysis revealed that, compared to Group 1, the use of NIV only was positively associated with opioid use (p = 0.002). In contrast, transitioning from NIV to TIV (Group 3) and using TIV only (Group 4) were negatively associated with opioid use (p = 0.0001 and 0.001, respectively).

CONCLUSIONS: The choice of ventilatory support significantly influences opioid use in patients with ALS. Patients who opted against TIV required opioids to relieve distress more commonly than those who chose TIV.}, } @article {pmid39849490, year = {2025}, author = {Álvarez-Sánchez, E and Carbayo, Á and Valle-Tamayo, N and Muñoz, L and Aumatell, J and Torres, S and Rubio-Guerra, S and García-Castro, J and Selma-González, J and Alcolea, D and Turon-Sans, J and Lleó, A and Illán-Gala, I and Fortea, J and Rojas-García, R and Dols-Icardo, O}, title = {Single-cell RNA sequencing highlights the role of distinct natural killer subsets in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {15}, pmid = {39849490}, issn = {1742-2094}, support = {PI21/00791//Instituto de Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España)/ ; AARF-22-924456/ALZ/Alzheimer's Association/United States ; R01 AG056850/NH/NIH HHS/United States ; Por un mundo sin ELA//Fundación Española para el Fomento de la Investigación de la Esclerosis Lateral Amiotrófica/ ; INT21/00073//Instituto de Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España)/ ; PI19/01543//Instituto de Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España)/ ; PDC-2023-51; #202307//Fondation Jérôme Lejeune/ ; RF1 AG056850/AG/NIA NIH HHS/United States ; AACSF-21-850193/ALZ/Alzheimer's Association/United States ; FI22/00077//Instituto de Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España)/ ; GBHI ALZ UK-21-720973//Global Brain Health Institute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/immunology/blood ; Male ; *Killer Cells, Natural/immunology/metabolism ; Female ; Middle Aged ; Aged ; *Single-Cell Analysis ; *Sequence Analysis, RNA/methods ; Leukocytes, Mononuclear/metabolism/immunology ; Adult ; Neurofilament Proteins ; }, abstract = {BACKGROUND: Neuroinflammation plays a major role in amyotrophic lateral sclerosis (ALS), and cumulative evidence suggests that systemic inflammation and the infiltration of immune cells into the brain contribute to this process. However, no study has investigated the role of peripheral blood immune cells in ALS pathophysiology using single-cell RNA sequencing (scRNAseq).

METHODS: We aimed to characterize immune cells from blood and identify ALS-related immune alterations at single-cell resolution. For this purpose, peripheral blood mononuclear cells (PBMC) were isolated from 14 ALS patients and 14 cognitively unimpaired healthy individuals (HC), matched by age and gender, and cryopreserved until library preparation and scRNAseq. We analyzed differences in the proportions of PBMC, gene expression, and cell-cell communication patterns between ALS patients and HC, as well as their association with plasma neurofilament light (NfL) concentrations, a surrogate biomarker for neurodegeneration. Flow cytometry was used to validate alterations in cell type proportions.

RESULTS: We identified the expansion of CD56[dim] natural killer (NK) cells in ALS (fold change = 2; adj. p-value = 0.0051), mainly driven by a specific subpopulation, NK_2 cells (fold change = 3.12; adj. p-value = 0.0001), which represent a mature and cytotoxic CD56[dim] NK subset. Our results revealed extensive gene expression alterations in NK_2 cells, pointing towards the activation of immune response (adj. p-value = 9.2 × 10[- 11]) and the regulation of lymphocyte proliferation (adj. p-value = 6.46 × 10[- 6]). We also identified gene expression changes in other immune cells, such as classical monocytes, and distinct CD8 + effector memory T cells which suggested enhanced antigen presentation via major histocompatibility class-II (adj. p-value = 1.23 × 10[- 8]) in ALS. The inference of cell-cell communication patterns demonstrated that the interaction between HLA-E and CD94:NKG2C from different lymphocytes to NK_2 cells is unique to ALS blood compared to HC. Finally, regression analysis revealed that the proportion of CD56[bright] NK cells along with the ALSFRS-r, disease duration, and gender, explained up to 76.4% of the variance in plasma NfL levels.

CONCLUSION: Our results reveal a signature of relevant changes occurring in peripheral blood immune cells in ALS and underscore alterations in the proportion, gene expression, and signaling patterns of a cytotoxic and terminally differentiated CD56[dim] NK subpopulation (NK_2), as well as a possible role of CD56[bright] NK cells in neurodegeneration.}, } @article {pmid39849126, year = {2025}, author = {Gupta, S and Kishore, A and Rishi, V and Aggarwal, A}, title = {Mitochondria and its epigenetic dynamics: Insight into synaptic regulation and synaptopathies.}, journal = {Functional & integrative genomics}, volume = {25}, number = {1}, pages = {26}, pmid = {39849126}, issn = {1438-7948}, mesh = {Humans ; *Epigenesis, Genetic ; *Mitochondria/metabolism/genetics ; *Synapses/metabolism/genetics ; *Mitochondrial Dynamics ; Animals ; Calcium/metabolism ; Synaptic Transmission ; }, abstract = {Mitochondria, the cellular powerhouses, are pivotal to neuronal function and health, particularly through their role in regulating synaptic structure and function. Spine reprogramming, which underlies synapse development, depends heavily on mitochondrial dynamics-such as biogenesis, fission, fusion, and mitophagy as well as functions including ATP production, calcium (Ca[2+]) regulation, and retrograde signaling. Mitochondria supply the energy necessary for assisting synapse development and plasticity, while also regulating intracellular Ca[2+] homeostasis to prevent excitotoxicity and support synaptic neurotransmission. Additionally, the dynamic processes of mitochondria ensure mitochondrial quality and adaptability, which are essential for maintaining effective synaptic activity. Emerging evidence highlights the significant role of epigenetic modifications in regulating mitochondrial dynamics and function. Epigenetic changes influence gene expression, which in turn affects mitochondrial activity, ensuring coordinated responses necessary for synapse development. Furthermore, metabolic changes within mitochondria can impact the epigenetic machinery, thereby modulating gene expression patterns that support synaptic integrity. Altered epigenetic regulation affecting mitochondrial dynamics and functions is linked to several neurological disorders, including Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases, emphasizing its crucial function. The review delves into the molecular machinery involved in mitochondrial dynamics, ATP and Ca[2+] regulation, highlighting the role of key proteins that facilitate the processes. Additionally, it also shed light on the emerging epigenetic factors influencing these regulations. It provides a thorough summary on the current understanding of the role of mitochondria in synapse development and emphasizes the importance of both molecular and epigenetic mechanisms in maintaining synaptic integrity.}, } @article {pmid39845951, year = {2024}, author = {Zucchi, E and Banchelli, F and Simonini, C and De Biasi, S and Martinelli, I and Gianferrari, G and Lo Tartaro, D and Cossarizza, A and D'Amico, R and Mandrioli, J}, title = {Tregs levels and phenotype modifications during Amyotrophic Lateral Sclerosis course.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1508974}, pmid = {39845951}, issn = {1664-3224}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology ; *T-Lymphocytes, Regulatory/immunology/metabolism ; Male ; Female ; Middle Aged ; *Disease Progression ; *Phenotype ; Aged ; Biomarkers ; Adult ; Immunophenotyping ; }, abstract = {INTRODUCTION: T regulatory cells (Tregs) inversely correlate with disease progression in Amyotrophic Lateral Sclerosis (ALS) and fast-progressing ALS patients have been reported to exhibit dysfunctional, as well as reduced, levels of Tregs. This study aimed to evaluate the longitudinal changes in Tregs among ALS patients, considering potential clinical and biological modifiers of their percentages and concentrations. Additionally, we explored whether measures of ALS progression, such as the decline over time in the revised ALS Functional Rating Scale (ALSFRS-r) or forced vital capacity (FVC) correlated Treg levels and whether Treg phenotype varied during the course of ALS.

METHODS: Total Tregs (detected by CD3, CD4, FoxP3, CD25, and CD127) were quantified at five time points over 54 weeks in 21 patients in the placebo arm of the RAP-ALS trial; next they were characterized for the expression of surface markers including CD38, CD39, CXCR3, and PD1. Repeated measures mixed models were used to analyze the longitudinal course of Tregs, considering potential associations with other clinical and laboratory characteristics. Correlations between ALSFRS-r or FVC and Tregs over time were similarly investigated.

RESULTS: Our study showed that Treg levels did not change significantly on average during the observation period in our ALS cohort. However, PD1+Tregs decreased and CD39+Tregs increased over time. Male sex and cholesterol levels were associated with increasing Tregs (%) over time, while monocytes positively affected Treg concentrations. Treg concentrations showed a modesty association with FVC decline but were not associated with ALSFRS-r decline.

DISCUSSION: Treg levels remained stable during the ALS observation period and were not significantly associated with ALSFRS-r variations, suggesting that Treg numbers alone may have limited utility as a pharmaco-dynamic biomarker for ALS trials. However the observed changes in Treg phenotypes, such as the decrease in PD1+Tregs, indicate that phenotypic variations may warrant further investigation for their potential role in ALS progression and therapeutic targeting.}, } @article {pmid39845577, year = {2025}, author = {Ludolph, A and Wiesenfarth, M}, title = {Tofersen and other antisense oligonucleotides in ALS.}, journal = {Therapeutic advances in neurological disorders}, volume = {18}, number = {}, pages = {17562864251313915}, pmid = {39845577}, issn = {1756-2856}, abstract = {The advent of antisense oligonucleotide (ASO) therapies in neurodegenerative disorders is associated with enormous hope. Nusinersen treatment was a breakthrough intervention in the recessive disease spinal muscular atrophy, and superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS) seems to be the paradigm disease in dominant degenerative diseases. The results of treatment with the ASO tofersen in SOD1-ALS show that the drug has a convincing beneficial effect on ALS caused by SOD1 mutations, that preclinical studies in rodents predicted the therapeutic effect in the human disease, and that clinical efficacy is associated with a specific sequence of effects of the drug on mechanistic and degenerative biomarkers and, subsequently, functional outcomes such as weight stabilization and ALSFRS-R. Therefore, the enthusiasm seems to be justified; but this should be followed by an attempt to obtain further insights with the goal to improve this therapy. In particular, the following issues are only partially resolved: Which mechanisms are responsible for the clinical effect following the downregulation of SOD1 protein by ASOs? Is long-term downregulation of SOD1 function associated with side effects? Is there an autoimmune response caused by this and other ASO? Is prevention of SOD1-associated ALS possible?}, } @article {pmid39844967, year = {2025}, author = {de Melo, R and Alcantara, L and Sarmet, M and Sheers, NL and Berlowitz, DJ and Maldaner, V}, title = {Use of Lung Volume Recruitment Technique in Patients With Chronic Respiratory Disease Among Brazilian Health Professionals.}, journal = {Pulmonary medicine}, volume = {2025}, number = {}, pages = {4073171}, pmid = {39844967}, issn = {2090-1844}, mesh = {Humans ; Brazil ; Cross-Sectional Studies ; Chronic Disease ; Adult ; Surveys and Questionnaires ; *Allied Health Personnel ; Male ; Respiratory Therapy/methods ; }, abstract = {Background: Lung volume recruitment (LVR) is a stacked-breath assisted inflation technique in which consecutive insufflations are delivered, without exhaling in between, until the maximum tolerable inflation capacity is reached. Although LVR is recommended in some neuromuscular disease guidelines, there is little information detailing when and how allied health professionals (AHPs) prescribe LVR. Objective: This study is aimed at describing the use of LVR in practice across Brazil. Methods: A cross-sectional e-survey (Sep-Nov 2023) explored LVR practices among qualified clinical or home care AHPs in Brazil. It gathered participant data on geographical region, profession, and experience. It delved into LVR specifics: clinical population and indications for use, prescription (frequency, dosage, and interfaces), related side effects, outcomes assessed, and combined therapies. Results were presented descriptively. Results: One hundred two surveys (74 physical therapists (PTs) and 28 speech and language pathologists (SLPs)) from diverse locations were collected. LVR was predominantly prescribed for adults (57%), with the most common diagnosis being amyotrophic lateral sclerosis (84%). Changes in peak cough flow and vital capacity were the most common reasons for LVR prescription. Maximal insufflation capacity was reportedly measured by 58% of PTs and 22% of SLPs. Chest wall soreness and discomfort were the most common side effects, and many respondents did not provide warnings about potential side effects (42% PTs and 50% SLPs). The study highlighted common use of other respiratory therapy devices alongside LVR. Conclusion: LVR is available in routine clinical and home care settings in Brazil. There is a lack of standardization regarding indications, prescription, and outcome measures among PTs and SLPs in Brazil. Clear recommendations and guidelines are needed to standardize these parameters, enabling more objective data and facilitating comparisons between centers.}, } @article {pmid39844875, year = {2024}, author = {Kõks, S and Rallmann, K and Muldmaa, M and Price, J and Pfaff, AL and Taba, P}, title = {Whole blood transcriptome profile identifies motor neurone disease RNA biomarker signatures.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {249}, number = {}, pages = {10401}, pmid = {39844875}, issn = {1535-3699}, mesh = {Humans ; *Motor Neuron Disease/genetics/blood/diagnosis ; Female ; Male ; *Biomarkers/blood ; *Transcriptome/genetics ; Middle Aged ; *Gene Expression Profiling/methods ; Aged ; RNA/blood/genetics ; Case-Control Studies ; Adult ; }, abstract = {Blood-based biomarkers for motor neuron disease are needed for better diagnosis, progression prediction, and clinical trial monitoring. We used whole blood-derived total RNA and performed whole transcriptome analysis to compare the gene expression profiles in (motor neurone disease) MND patients to the control subjects. We compared 42 MND patients to 42 aged and sex-matched healthy controls and described the whole transcriptome profile characteristic for MND. In addition to the formal differential analysis, we performed functional annotation of the genomics data and identified the molecular pathways that are differentially regulated in MND patients. We identified 12,972 genes differentially expressed in the blood of MND patients compared to age and sex-matched controls. Functional genomic annotation identified activation of the pathways related to neurodegeneration, RNA transcription, RNA splicing and extracellular matrix reorganisation. Blood-based whole transcriptomic analysis can reliably differentiate MND patients from controls and can provide useful information for the clinical management of the disease and clinical trials.}, } @article {pmid39844762, year = {2025}, author = {Theuriet, J and Bernard, E and Guy, N and Taithe, F and Even, C and Maisonobe, T and Sangaré, A and Lardeux, P and Tilikete, CF and Couratier, P and Lenglet, T and Pegat, A}, title = {Electrophysiological Abnormalities in Finger Extension Weakness and DOwnbeat Nystagmus Motor Neuron Disease: Three New Patients and Review of the Literature.}, journal = {Muscle & nerve}, volume = {71}, number = {4}, pages = {644-650}, pmid = {39844762}, issn = {1097-4598}, mesh = {Humans ; Male ; Middle Aged ; *Nystagmus, Pathologic/physiopathology/etiology ; *Muscle Weakness/physiopathology/etiology ; *Electromyography ; *Motor Neuron Disease/physiopathology/complications/diagnosis ; Fingers/physiopathology ; Neural Conduction/physiology ; Female ; Aged ; Adult ; Muscle, Skeletal/physiopathology ; }, abstract = {INTRODUCTION/AIMS: Finger Extension Weakness and DOwnbeat Nystagmus Motor Neuron Disease (FEWDON-MND) is characterized by motor weakness predominantly affecting finger extension, accompanied by downbeat nystagmus. To date, only 11 patients have been reported. The present study adds a further three and aims to provide a more detailed description of the electrodiagnostic features of these patients.

METHODS: We present the clinical and electrophysiological features of three French patients from specialized motor neuron centers and review the electrophysiological findings of previously reported patients.

RESULTS: These three patients presented with pure motor weakness affecting finger extension and downbeat nystagmus. They exhibited a slowly progressive disease course without respiratory involvement. Nerve conduction studies showed decreased compound muscle action potential amplitudes in the extensor indicis muscles. Abnormal spontaneous activity on needle electromyography (EMG) was rare in two patients, absent in one, and otherwise limited to weak muscles. Additionally, chronic motor axon loss features suggestive of motor neuronopathy were seen in our patients. Importantly, they were also detected in distant asymptomatic muscles.

DISCUSSION: The three patients reported here confirm the typical phenotype of FEWDON-MND, characterized by slowly progressive distal motor weakness initially affecting finger extension, associated with downbeat nystagmus. Although chronic motor axon loss features have been found in all reported patients, our three patients show that active denervation can be absent or rare. Thus, finger drop and diffuse chronic neurogenic changes on EMG should lead clinicians to look for downbeat nystagmus and to consider FEWDON-MND.}, } @article {pmid39843865, year = {2025}, author = {Calancie, B and Alexeeva, N}, title = {Revisiting motor unit recruitment to TMS in amyotrophic lateral sclerosis: cortical inhibition is retained during voluntary contractions.}, journal = {Experimental brain research}, volume = {243}, number = {2}, pages = {51}, pmid = {39843865}, issn = {1432-1106}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Transcranial Magnetic Stimulation ; Male ; Middle Aged ; Female ; Aged ; *Recruitment, Neurophysiological/physiology ; *Neural Inhibition/physiology ; *Electromyography ; Adult ; *Muscle, Skeletal/physiopathology/physiology ; *Motor Cortex/physiopathology ; Evoked Potentials, Motor/physiology ; Muscle Contraction/physiology ; Motor Neurons/physiology ; }, abstract = {Transcranial magnetic stimulation (TMS) has been used for many years to study the pathophysiology of amyotrophic lateral sclerosis (ALS). Based on single- or dual-pulse TMS and EMG and/or single motor unit (MU) recordings, many groups have described a loss of central inhibition as an early marker of ALS dysfunction, reflecting a state of cortical 'hyperexcitability'. This conclusion is not without its detractors, however, leading us to reexamine this issue using 4-pulse TMS, shown previously to be more effective for testing central motor pathway functional integrity. A total of 221 motor units were tested in 13 subjects (6 controls; 7 with ALS) across a total of 798 unique TMS conditions. MUs were studied from hand muscles (usually first dorsal interosseus) and from tibialis anterior (TA). Subjects were required to recruit a MU to fire rhythmically, during which time 4-pulse trains of TMS were delivered. A given motor unit's recruitment was examined for different stimulus intensities and interpulse intervals (IPI). All motor units from control subjects showed short latency excitation to TMS, and short latency inhibition for TMS pulses of slightly weaker intensity (i.e. the threshold for inhibition was lower than that for excitation). The same was largely true for MUs studied in subjects with ALS, with the primary difference between control and ALS subjects being the need for stronger stimulus intensities to effect recruitment in subjects with ALS. We saw no evidence for a loss or reduction of inhibition of central motor output in persons with ALS, at least when tested during voluntary contractions.}, } @article {pmid39842380, year = {2025}, author = {Faltracco, V and Pain, D and Dalla Bella, E and Riva, N and Telesca, A and Soldini, E and Gandini, G and Radici, A and Poletti, B and Lauria, G and Consonni, M}, title = {Mood disorders in patients with motor neuron disease and frontotemporal symptoms: Validation of the Hospital Anxiety and Depression Scale for use in motor neuron disease.}, journal = {Journal of the neurological sciences}, volume = {469}, number = {}, pages = {123378}, doi = {10.1016/j.jns.2024.123378}, pmid = {39842380}, issn = {1878-5883}, mesh = {Humans ; Female ; Male ; *Motor Neuron Disease/psychology/diagnosis/complications ; Middle Aged ; Aged ; *Mood Disorders/diagnosis/etiology/psychology ; *Anxiety/diagnosis/etiology/psychology ; *Depression/diagnosis/etiology/psychology ; Reproducibility of Results ; Psychiatric Status Rating Scales ; Adult ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a heterogeneous neurodegenerative disorder, with nearly 50 % of patients exhibiting cognitive and behavioral symptoms in addition to motor decline. Anxiety and depression, though frequently observed in this population, have been understudied in relation to motor and extra-motor profiles.

OBJECTIVES: Our study addresses this gap by validating the Hospital Anxiety and Depression Scale for Motor Neuron Disease (HADS-MND) and investigating the interplay between mood, clincial, and frontotemporal symptoms in a large sample of MND patients.

METHODS: A total of 249 MND patients underwent clinical, genetic, and neuropsychological assessments. The validity, reliability, sensitivity, and specificity of the HADS-MND global score and subscores were explored. Correlation analyses and group comparisons tested the link between mood, motor and extra-motor profiles.

RESULTS: The bidirectional structure of the HADS-MND was confirmed, but receiver operating characteristics analysis suggests caution for clinical use of the anxiety and depression subscales. The global HADS-MND score is recommended as a measure of psychological distress, with a cut-off point of 10 detecting 38 % of patients with altered scores. Moderate symptoms of anxiety and depression were present in 14 % and 11 % of cases, respectively. Depressive mood was higher in women, patients with frontotemporal symptoms, and severe motor-functional disabilities. Depressive and/or anxiety symptoms were linked to loneliness, behavioral changes, emotional dysregulation, and poor quality of life. Cognitive efficiency was not associated with mood.

CONCLUSION: Mood disorders appeared independent of cognitive profiles but related to behavioral changes. This is particularly relevant for clinicians discussing end-of-life decisions with patients.}, } @article {pmid39841674, year = {2025}, author = {Grapperon, AM and El Mendili, MM and Maarouf, A and Ranjeva, JP and Guye, M and Verschueren, A and Attarian, S and Zaaraoui, W}, title = {In vivo mapping of sodium homeostasis disturbances in individual ALS patients: A brain 23Na MRI study.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0316916}, pmid = {39841674}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; *Magnetic Resonance Imaging/methods ; Male ; Female ; Middle Aged ; *Homeostasis ; *Sodium/metabolism ; *Brain/diagnostic imaging/metabolism/pathology ; Aged ; Sodium Isotopes ; Adult ; Brain Mapping/methods ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by significant heterogeneity among patients. 23Na MRI maps abnormal sodium homeostasis that reflects metabolic alterations and energetic failure contributing to the neurodegenerative process. In this study, we investigated disease severity at the individual level in ALS patients using brain 23Na MRI.

METHODS: 1H and 23Na brain MRI were collected prospectively from 28 ALS patients. Individual map of abnormal total sodium concentration (TSC) was computed using voxel-based statistical mapping for each patient compared to a local database of 62 healthy controls. Clinical data included the revised ALS functional rating scale (ALSFRS-R), ALSFRS-R slope, ALSFRS-R at 6-month and survival time.

RESULTS: Individual maps quantifying voxels with TSC increase evidenced a high heterogeneity between patients consistent with clinical presentation. The main areas involved were the corticospinal tracts. Half of patients showed abnormal TSC increase within more than 1% of whole brain voxels. Patients with TSC increase had worse clinical severity: higher ALSFRS-R slope (p = 0.02), lower ALSFRS-R at 6-month (p = 0.04), and shorter survival (p = 0.04). ALS patients with limited TSC increase had slower progression of disability or predominant lower motor neuron phenotype or shorter disease duration.

DISCUSSION: This study mapping sodium homeostasis disturbances at the individual level in ALS patients through 23Na MRI evidenced heterogeneity of TSC increase among patients associated with clinical presentation and disease severity. These findings suggest that TSC increase detected at the individual level by 23Na MRI may be a useful marker of the clinical heterogeneity of ALS patients, a factor that is likely to greatly influence the results of therapeutic trials.}, } @article {pmid39841625, year = {2025}, author = {Hoengenaert, L and Anders, C and Van Doorsselaere, J and Vanholme, R and Boerjan, W}, title = {Transgene-free genome editing in poplar.}, journal = {The New phytologist}, volume = {}, number = {}, pages = {}, doi = {10.1111/nph.20415}, pmid = {39841625}, issn = {1469-8137}, support = {//Universiteit Gent/ ; G011620N//Fonds Wetenschappelijk Onderzoek/ ; //Energy Transition Fund/ ; //Advanced ERC grant POPMET/ ; }, abstract = {Precise gene-editing methods are valuable tools to enhance genetic traits. Gene editing is commonly achieved via stable integration of a gene-editing cassette in the plant's genome. However, this technique is unfavorable for field applications, especially in vegetatively propagated plants, such as many commercial tree species, where the gene-editing cassette cannot be segregated away without breaking the genetic constitution of the elite variety. Here, we describe an efficient method for generating gene-edited Populus tremula × P. alba (poplar) trees without incorporating foreign DNA into its genome. Using Agrobacterium tumefaciens, we expressed a base-editing construct targeting CCoAOMT1 along with the ALS genes for positive selection on a chlorsulfuron-containing medium. About 50% of the regenerated shoots were derived from transient transformation and were free of T-DNA. Overall, 7% of the chlorsulfuron-resistant shoots were T-DNA free, edited in the CCoAOMT1 gene and nonchimeric. Long-read whole-genome sequencing confirmed the absence of any foreign DNA in the tested gene-edited lines. Additionally, we evaluated the CodA gene as a negative selection marker to eliminate lines that stably incorporated the T-DNA into their genome. Although the latter negative selection is not essential for selecting transgene-free, gene-edited Populus tremula × P. alba shoots, it may prove valuable for other genotypes or varieties.}, } @article {pmid39840922, year = {2025}, author = {Saucier, D and Bélanger, M and Liu, Z and Lavigne, E and O'Connell, C}, title = {Associations between water exposure and the development of amyotrophic lateral sclerosis: a matched case-control study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2025.2453450}, pmid = {39840922}, issn = {2167-9223}, abstract = {OBJECTIVE: Previous studies have hinted at an association between water exposure and the development of ALS. However, proximity measures to these water sources have been limited to questionnaires or large buffers due to a lack of fine geospatial measures. They also do not distinguish the various classes of hydrographic features. Thus, we created a robust database to investigate the association between proximity to water bodies at place of residence and the development of ALS.

METHODS: A matched (sex and year of birth) case-control study was conducted in New Brunswick, Canada from January 2003 to February 2021. Study population included 304 ALS patients and 1207 controls with their historical postal codes linked to spatial proximity datasets and air pollution index indicators (proxy measures for contamination by run-off).

RESULTS: Odds of ALS were not significantly associated with proximity to water bodies, even within a 250 m buffer from place of residence (Oceans: 1.10, 0.60-2.00 [95% CI], Reservoirs/Ponds/Lakes: 1.24, 0.47-3.30 [95% CI]). As for interaction models investigating proximity to potentially contaminated water bodies, none of the final fitted models observed an association between proximity to water bodies with indicators of potential run-off sources and the development of ALS.

CONCLUSIONS: No significant association between proximity to water bodies at place of residence and the development of ALS were observed in the current study. Future studies should consider taking direct measurements of water quality or utilize geomaps of spraying activities and cyanobacteria blooms alongside proximity measures. Household water quality is another avenue to explore, particularly well water use.}, } @article {pmid39840885, year = {2025}, author = {McKinnon, S and Qiang, Z and Keerie, A and Wells, T and Shaw, PJ and Alix, JJP and Mead, RJ}, title = {Maximizing the translational potential of neurophysiology in amyotrophic lateral sclerosis: a study on compound muscle action potentials.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2024.2448540}, pmid = {39840885}, issn = {2167-9223}, abstract = {Mouse models of amyotrophic lateral sclerosis (ALS) enable testing of novel therapeutic interventions. However, treatments that have extended survival in mice have often failed to translate into human benefit in clinical trials. Compound muscle action potentials (CMAPs) are a simple neurophysiological test that measures the summation of muscle fiber depolarization in response to maximal stimulation of the innervating nerve. CMAPs can be measured in both mice and humans and decline with motor axon loss in ALS, making them a potential translational read-out of disease progression. We assessed the translational potential of CMAPs and ascertained time points when human and mouse data aligned most closely. We extracted data from 18 human studies and compared with results generated from SOD1[G93A] and control mice at different ages across different muscles. The relative CMAP amplitude difference between SOD1[G93A] and control mice in tibialis anterior (TA) and gastrocnemius muscles at 70 days of age was most similar to the relative difference between baseline ALS patient CMAP measurements and healthy controls in the abductor pollicis brevis (APB) muscle. We also found that the relative decline in SOD1[G93A] TA CMAP amplitude between 70 and 140 days was similar to that observed in 12 month human longitudinal studies in APB. Our findings suggest CMAP amplitudes can provide a "translational window", from which to make comparisons between the SOD1[G93A] model and human ALS patients. CMAPs are easy to perform and can help determine the most clinically relevant starting/end points for preclinical studies and provide a basis for predicting potential clinical effect sizes.}, } @article {pmid39840019, year = {2024}, author = {De Cleene, N and Schwarzová, K and Labrecque, S and Cerejo, C and Djamshidian, A and Seppi, K and Heim, B}, title = {Olfactory dysfunction as potential biomarker in neurodegenerative diseases: a narrative review.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1505029}, pmid = {39840019}, issn = {1662-4548}, abstract = {Neurodegenerative diseases represent a group of disorders characterized by progressive degeneration of neurons in the central nervous system, leading to a range of cognitive, motor, and sensory impairments. In recent years, there has been growing interest in the association between neurodegenerative diseases and olfactory dysfunction (OD). Characterized by a decline in the ability to detect or identify odors, OD has been observed in various conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). This phenomenon often precedes the onset of other clinical symptoms, suggesting its potential utility as an early marker or prodromal symptom of neurodegenerative diseases. This review provides a vast literature overview on the current knowledge of OD in PD, AD, ALS, and HD in order to evaluate its potential as a biomarker, particularly in the early and prodromal stages of these diseases. We summarize the most common methods used to measure olfactory function and delve into neuropathological correlations and the alterations in neurotransmitter systems associated with OD in those neurodegenerative diseases, including differences in genetic variants if applicable, and cater to current pitfalls and shortcomings in the research.}, } @article {pmid39840015, year = {2024}, author = {Yang, J and Li, W and Tian, M and Zhang, L and Du, F and Li, X and Liu, Q and Li, R and Li, Z and Dong, H and Liu, Y}, title = {Cortical thickness correlated with peripheral inflammatory cytokines in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1514554}, pmid = {39840015}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare, devastating neurodegenerative disease that affects upper and lower motor neurons, resulting in muscle atrophy, spasticity, hyperreflexia, and paralysis. Inflammation plays an important role in the development of ALS, and associated with rapid disease progression. Current observational studies indicate the thinning of cortical thickness in patients with ALS is associated with rapid disease progression and cognitive changes. However, the effects of inflammatory cytokines on cortical thickness in patients with ALS are unclear. Here, we investigated the relationship between inflammatory cytokines and cortical thickness in patients with ALS.

METHODS: We evaluated 51 patients with ALS for inflammatory cytokines including interleukin (IL)-4, interferon (IFN)-α, IL-1β, IL-2, IL-5, IL-12, tumor necrosis factor (TNF)-α, IL-6, IL-10, IL-8, IL-17, and IFN-γ and analyzed the correlation between these indicators and the ALS functional rating scale-revised (ALSFRS-R) score or disease progression rate (ΔFS score). Twenty-six patients with ALS and 26 controls were studied using whole-cortex analysis, and post-hoc analyses were performed to examine the correlation between brain cortical thickness and ALSFRS-R or ΔFS scores.

RESULTS: IL-4, IFN-α, IL-1β, and IL-2 levels were significantly correlated with ALSFRS-R scores, and the IL-2 level was significantly correlated with ΔFS scores. After controlling for age and sex, the ALS group had thinner cortexes in multiple clusters across the brain than the control group. Further analyses revealed that cortical thickness in the right superior temporal and lingual gyrus regions was inversely correlated with ΔFS scores. There was a significant positive correlation between the clusters in the right lingual cortex and IL-2 level.

CONCLUSION: These results suggest cortical thickness was reduced in patients with ALS in motor and non-motor cortical areas. Inflammatory factors (especially IL-2) were correlated with cortical thickness, and both were related to the disease progression rate, suggesting IL-2 plays an important role in ALS.}, } @article {pmid39839899, year = {2025}, author = {Goyal, MK and Goyal, O}, title = {Can Emax and platelet count truly differentiate between benign and malignant liver lesions?.}, journal = {World journal of gastroenterology}, volume = {31}, number = {3}, pages = {98758}, pmid = {39839899}, issn = {2219-2840}, mesh = {Humans ; *Liver Neoplasms/blood/pathology/diagnosis ; Platelet Count ; *Carcinoma, Hepatocellular/blood/diagnosis/pathology ; Diagnosis, Differential ; Liver/pathology ; Liver Cirrhosis/blood/diagnosis/pathology ; Nomograms ; Blood Platelets ; }, abstract = {This letter critically evaluates Jiang et al's article on the differentiation of benign and malignant liver lesions using Emax and platelet count. Despite notable findings, significant methodological and interpretative limitations are identified. The study lacks detailed assay conditions for Emax measurement, employs inadequate statistical methods without robust multivariate analysis, and does not provide clinically relevant threshold values. The nomogram's reliance on Emax as a major diagnostic contributor is questionable due to attenuation in hepatocellular carcinoma patients with cirrhosis. Moreover, the study's limitations, such as selection bias and confounding factors, are not adequately addressed. Future research should adopt more rigorous methodologies, including prospective studies with larger cohorts and standardized protocols for biomarker measurement, to enhance validity and clinical applicability.}, } @article {pmid39839897, year = {2025}, author = {Jiang, QR and Zeng, DW}, title = {Gut microbiota shifts in hepatitis B-related portal hypertension after transjugular intrahepatic portosystemic shunt: Mechanistic and clinical implications.}, journal = {World journal of gastroenterology}, volume = {31}, number = {3}, pages = {100752}, pmid = {39839897}, issn = {2219-2840}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Hypertension, Portal/diagnosis/etiology/microbiology ; *Portasystemic Shunt, Transjugular Intrahepatic/adverse effects ; *Hepatic Encephalopathy/etiology/microbiology/diagnosis ; *Liver Cirrhosis/microbiology/virology/diagnosis ; Hepatitis B virus/isolation & purification ; Hepatitis B/diagnosis/complications/microbiology ; Dysbiosis ; Animals ; }, abstract = {In this article, we provide commentary on the recent article by Zhao et al. We focus on the shifts in the gut microbiota of patients with hepatitis B virus (HBV)-associated cirrhosis/portal hypertension (PH) following transjugular intrahepatic portosystemic shunt (TIPS) and the implications for understanding the mechanisms, diagnosis, and treatment. By comparing the gut microbiota composition and dynamic changes before and after TIPS in patients with and without hepatic encephalopathy, the authors found an increase in non-probiotic bacteria in those who developed hepatic encephalopathy post-TIPS, with Morganella species present only in the hepatic encephalopathy group. The gut microbiota changes post-TIPS among patients without the occurrence of hepatic encephalopathy suggest potential therapeutic benefits through prophylactic microbiome therapies. Furthermore, the specific gut microbiota alterations may hold promise to predict the risk of hepatic encephalopathy in individuals undergoing TIPS for HBV-related PH. Despite these promising findings, future studies are needed to address limitations, including a small sample size, a relatively short evaluation period for gut microbiota alterations, the absence of data on dynamic alterations in gut microbiota post-TIPS and their correlation with blood ammonia levels, and the lack of validation in animal models. In conclusion, Zhao et al's study has shed new light on the link of gut microbiota with post-TIPS hepatic encephalopathy, potentially through the intricate gut-liver axis, and has important clinical implications for improving the management of patients with HBV-related PH.}, } @article {pmid39839311, year = {2024}, author = {Zhang, J and Li, Y and Shi, Q}, title = {Decremental response in patients with amyotrophic lateral sclerosis during repetitive nerve stimulation and its relationships with impaired homeostasis.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1502025}, pmid = {39839311}, issn = {1663-4365}, abstract = {BACKGROUND: Previous studies have suggested that neuromuscular junction (NMJ) denervation plays a critical role in amyotrophic lateral sclerosis (ALS). Repetitive nerve stimulation (RNS) has been used as a technique to test neuromuscular transmission, but the sensitivity and stability of its parameters have not been investigated in patients with ALS. In addition, the impact of impaired homeostasis on NMJ stability in patients with ALS remains unclear.

METHODS: A total of 421 patients with ALS were enrolled. Data on their clinical, biochemical and electrophysiological indicators were divided into a training set (collected from June 2019 to June 2022) and a test set (collected from July 2022 to June 2023). The coefficient of variation (CV) was used to assess the extent of variability. Stepwise regression was used in independent variable selection and model building.

RESULTS: In patients with ALS, area decrement had a higher rate of abnormal result and a lower CV than amplitude decrement. No significant difference in the rate of abnormal decrement was found when the first compound muscle action potential (CMAP) was compared with either the fourth or fifth one. Moreover, multivariate regression analysis suggests high-density lipoprotein cholesterol (HDL-C) had the greatest impact on decremental response, followed by serum uric acid (UA) and forced vital capacity (FVC). Females had a larger range of area decrement than males.

CONCLUSION: During RNS test, assessing area decrement significantly enhances our ability to detect the impairment of neuromuscular transmission in patients with ALS. Independent factors contributing to decremental response need to be considered in drug development and clinical trials targeting NMJ in patients with ALS.}, } @article {pmid39838960, year = {2025}, author = {Min, SM and Bashore, FM and Smith, JL and Havener, TM and Howell, S and Li, H and Couñago, RM and Popov, KI and Axtman, AD}, title = {Development of a Second-Generation, In Vivo Chemical Probe for PIKfyve.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {3}, pages = {3282-3308}, pmid = {39838960}, issn = {1520-4804}, support = {S10 OD032476/OD/NIH HHS/United States ; }, mesh = {Humans ; *Phosphoinositide-3 Kinase Inhibitors/pharmacology/chemistry/chemical synthesis/pharmacokinetics ; Animals ; Phosphatidylinositol 3-Kinases/metabolism ; Mice ; Morpholines/chemistry/pharmacokinetics/pharmacology/chemical synthesis ; Structure-Activity Relationship ; Crohn Disease/drug therapy ; COVID-19 Drug Treatment ; Molecular Probes/chemistry/pharmacokinetics ; Hydrazones ; Pyrimidines ; }, abstract = {We optimized our highly potent and cell-active chemical probe for phosphatidylinositol-3-phosphate 5-kinase (PIKfyve), SGC-PIKFYVE-1, resulting in compounds with improved potency and demonstrated in vivo stability. Use of an in-cell, kinome-wide selectivity panel allowed for confirmation of excellent in-cell selectivity of our lead compound, 40, and another promising analogue, 46. Evaluation of the pharmacokinetic (PK) profiles of these two compounds revealed that both are well tolerated systemically and orally bioavailable. Coupled with its subnanomolar cellular potency and impressive selectivity in cells, the long half-life of 40 makes it an ideal candidate for the evaluation of the consequences of PIKfyve inhibition in vivo. PIKfyve inhibition has been investigated clinically for indications including rheumatoid arthritis, Crohn's disease, COVID-19, and ALS using a single compound (apilimod), supporting the development of orthogonal PIKfyve inhibitors with in vivo stability.}, } @article {pmid39838927, year = {2025}, author = {Wang, Z and Sun, Y and Bai, Z and Li, M and Kong, D and Wu, G}, title = {Mitochondria-Related Genome-Wide Mendelian Randomization Identifies Putatively Causal Genes for Neurodegenerative Diseases.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {}, number = {}, pages = {}, doi = {10.1002/mds.30123}, pmid = {39838927}, issn = {1531-8257}, support = {SDQLQN2021-01//Qilu Young Scholars Program of Shandong University/ ; 202306352//Taishan Scholar Foundation of Shandong Province/ ; }, abstract = {BACKGROUND: Mitochondrial dysfunction is increasingly recognized as a key factor in neurodegenerative diseases (NDDs), underscoring the therapeutic potential of targeting mitochondria-related genes. This study aimed to identify novel biomarkers and drug targets for these diseases through a comprehensive analysis that integrated genome-wide Mendelian randomization (MR) with genes associated with mitochondrial function.

METHODS: Using existing publicly available genome-wide association studies (GWAS) summary statistics and comprehensive data on 1136 mitochondria-related genes, we initially identified a subset of genes related to mitochondrial function that exhibited significant associations with NDDs. We then conducted colocalization and summary-data-based Mendelian randomization (SMR) analyses using expression quantitative trait loci (eQTL) to validate the causal role of these candidate genes. Additionally, we assessed the druggability of the encoded proteins to prioritize potential therapeutic targets for further exploration.

RESULTS: Genetically predicted levels of 10 genes were found to be significantly associated with the risk of NDDs. Elevated DMPK and LACTB2 levels were associated with increased Alzheimer's disease risk. Higher expression of NDUFAF2, BCKDK, and MALSU1, along with lower TTC19, raised Parkinson's disease risk. Higher ACLY levels were associated with both amyotrophic lateral sclerosis and multiple sclerosis (MS) risks, while decreased MCL1, TOP3A, and VWA8 levels raised MS risk. These genes primarily impact mitochondrial function and energy metabolism. Notably, several druggable protein targets identified are being explored for potential NDDs treatment.

CONCLUSIONS: This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in NDDs. Additionally, this study identified candidate genes that could serve as potential pharmacological targets for the prevention and treatment of NDDs. © 2025 International Parkinson and Movement Disorder Society.}, } @article {pmid39838446, year = {2025}, author = {Ou, K and Jia, Q and Li, D and Li, S and Li, XJ and Yin, P}, title = {Application of antisense oligonucleotide drugs in amyotrophic lateral sclerosis and Huntington's disease.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {4}, pmid = {39838446}, issn = {2047-9158}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; Humans ; *Huntington Disease/genetics/drug therapy/therapy ; *Oligonucleotides, Antisense/therapeutic use ; Animals ; Genetic Therapy/methods/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) are diverse in clinical presentation and are caused by complex and multiple factors, including genetic mutations and environmental factors. Numerous therapeutic approaches have been developed based on the genetic causes and potential mechanisms of ALS and HD. Currently, available treatments for various neurodegenerative diseases can alleviate symptoms but do not provide a definitive cure. Gene therapy, which aims to modify or express specific proteins for neuroprotection or correction, is considered a powerful tool in managing neurodegenerative conditions. To date, antisense oligonucleotide (ASO) drugs targeting the pathological genes associated with ALS and HD have shown promising results in numerous animal studies and several clinical trials. This review provides a comprehensive overview of the development, mechanisms of action, limitations, and clinical applications of ASO drugs in neurodegenerative diseases, with a specific focus on ALS and HD therapeutic strategies.}, } @article {pmid39838017, year = {2025}, author = {McCaig, CD}, title = {Neurological Diseases can be Regulated by Phase Separation.}, journal = {Reviews of physiology, biochemistry and pharmacology}, volume = {187}, number = {}, pages = {273-338}, pmid = {39838017}, issn = {0303-4240}, mesh = {Humans ; *Nervous System Diseases ; Animals ; Superoxide Dismutase/metabolism ; Motor Neuron Disease ; Neurons/metabolism ; Phase Separation ; }, abstract = {Several neurological diseases arise from abnormal protein aggregation within neurones and this is closely regulated by phase separation. One such is motor neurone disease and aberrant aggregation of superoxide dismutase. Again these events are regulated by electrical forces that are examined.}, } @article {pmid39837582, year = {2025}, author = {Brubacher, LJ and Yellappa, V and Lestari, BW and Heitkamp, P and Aguilera Vasquez, N and Sassi, A and Olusola-Faleye, B and Thapa, P and Shyam Klinton, J and Sheokand, S and Pai, M and Oga-Omenka, C}, title = {Health and tuberculosis systems resilience, the role of the private sector and pandemic preparedness: insights from a cross-country qualitative study with policy-makers in India, Indonesia and Nigeria.}, journal = {BMJ global health}, volume = {10}, number = {1}, pages = {}, pmid = {39837582}, issn = {2059-7908}, mesh = {Humans ; *COVID-19/epidemiology ; India ; Nigeria ; Indonesia ; *Tuberculosis/prevention & control ; *Qualitative Research ; *Private Sector ; Delivery of Health Care/organization & administration ; Administrative Personnel ; SARS-CoV-2 ; Pandemics ; Health Policy ; Pandemic Preparedness ; }, abstract = {INTRODUCTION: The COVID-19 pandemic was an unprecedented challenge to health systems worldwide and had a severe impact on tuberculosis (TB) case notifications and service delivery. India, Indonesia and Nigeria are high TB-burden countries where the majority of initial care-seeking happens in the private health sector. The objectives of this study were to (1) explore policy-makers' perspectives on the impact of the COVID-19 pandemic on private sector TB service delivery in India, Indonesia and Nigeria and (2) identify cross-cutting insights for pandemic preparedness with respect to TB service delivery.

METHODS: From May to November 2021, 33 interviews were conducted with key policy-makers involved in health service administration, TB service delivery and/or the COVID-19 response in India, Indonesia and Nigeria (n=11 in each country). Interviews focused on the impact of COVID-19 on TB services and lessons learnt for pandemic preparedness with respect to TB in each study context. Data were analysed thematically using a hybrid inductive-deductive approach, informed by Haldane et al's Determinants of Health Systems Resilience Framework.

RESULTS: Policy-makers highlighted the crucial role of intersectoral collaboration, effective governance, innovative financing strategies, health workforce reallocation and technological advancements such as virtual consultations and mHealth in strengthening TB service delivery amid the COVID-19 pandemic. India relied on patient-provider support agencies to implement a joint strategy for TB care across sectors and states. Indonesia engaged networks of private provider professional associations to facilitate coordination of the COVID-19 response. Nigeria implemented a pandemic policy for public-private referral for the continuity of TB care.

CONCLUSIONS: Countries implemented varied measures to support TB service delivery during the COVID-19 pandemic. This study presents insights from three countries (India, Indonesia and Nigeria) that together offer a 'menu' of possibilities for supporting pandemic preparedness with respect to TB care vis-à-vis strengthening health systems resilience.}, } @article {pmid39837305, year = {2025}, author = {Tan, Y and Yang, T and Cheng, Y and Zhang, S and Xiao, Y and Liu, J and Shang, H}, title = {Association between Psychiatric Disorders and Amyotrophic Lateral Sclerosis: A Prospective Cohort Study from the UK Biobank.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-13}, doi = {10.1159/000543473}, pmid = {39837305}, issn = {1423-0208}, abstract = {INTRODUCTION: Psychiatric disorders have been reported to be associated with amyotrophic lateral sclerosis (ALS). However, evidence for the association remains inconsistent, and it is unclear whether specific categories of psychiatric disorders constitute risk factors for ALS. The study aimed to investigate the association between different categories of psychiatric disorders and the risk of ALS.

METHODS: We utilized data from the UK Biobank to conduct a population-based prospective cohort study. Cox proportional hazards models were employed to evaluate the association between a history of various psychiatric disorders including schizophrenia, bipolar disorder, depression, anxiety, stress-related disorders, and the risk of ALS. Analyses were adjusted for covariates including sociodemographic factors, lifestyle factors, and medical history.

RESULTS: Among the 484,065 participants initially included, 558 participants were diagnosed with ALS during a median follow-up of 13.63 years. With complete adjustment, previous schizophrenia (hazard ratio [HR] 6.32; 95% confidence interval [CI]: 2.60-15.36; p < 0.001) and depression (HR 1.37; 95% CI: 1.03-1.81; p = 0.03) were found to be significantly associated with ALS.

CONCLUSION: This large prospective cohort study indicated the association between schizophrenia, depression, and a higher risk of subsequent ALS. These findings suggest potential implications for early process of global neurodegeneration in ALS, underlining the need for further research to explore the underlying mechanisms.}, } @article {pmid39836386, year = {2025}, author = {Babu, S and Sharfstein, JM and Feldman, EL}, title = {Reimagining Care and Research for Amyotrophic Lateral Sclerosis.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2024.4757}, pmid = {39836386}, issn = {2168-6157}, } @article {pmid39836043, year = {2025}, author = {Berry, JD and Hagan, M and Zhang, J and Liu, Y and Ciepielewska, M}, title = {Longer disease progression milestone-free time in people with amyotrophic lateral sclerosis treated versus not treated with intravenous edaravone: results from an administrative claims analysis.}, journal = {Journal of comparative effectiveness research}, volume = {14}, number = {2}, pages = {e240007}, pmid = {39836043}, issn = {2042-6313}, mesh = {Humans ; *Edaravone/therapeutic use/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Disease Progression ; Male ; Female ; Retrospective Studies ; Middle Aged ; Aged ; Administration, Intravenous ; Insurance Claim Review ; Free Radical Scavengers/therapeutic use/administration & dosage ; }, abstract = {Aim: To estimate time-to-progression milestones in people with amyotrophic lateral sclerosis (PALS) treated versus not treated with intravenous (IV) edaravone (Radicava[®] IV, Mitsubishi Tanabe Pharma America [MTPA], hereafter "IV edaravone") in a real-world setting. Background: IV edaravone is US FDA approved for the treatment of ALS and was shown in clinical trials to slow the rate of physical functional decline. Patients & methods: This retrospective observational analysis included PALS continuously enrolled in Optum's Clinformatics[®] Data Mart between 8 August 2017 and 31 December 2021. Cases treated with IV edaravone and controls not treated with IV edaravone were propensity score matched for: age, sex, race, US region of residence, pre-index disease duration, insurance, riluzole prescription; and pre-index claims for cardiovascular disease, artificial nutrition/gastrostomy tube, noninvasive ventilation and all-cause hospitalization. The index date was the first IV edaravone claim for cases; for controls, the index date was randomly assigned after IV edaravone market availability. Restricted mean time lost was calculated for the following disease progression milestones: new use of canes/walkers/wheelchairs, artificial nutrition, noninvasive ventilation, invasive ventilation, speech-generating devices and hospice. Results: Cases (n = 395) were matched to controls (n = 395). Cases had less restricted mean time lost, indicating longer disease progression milestone-free time, for all disease progression milestones. From 0 to 24 months post index, more cases (n = 129) than controls (n = 103) reported no milestones and more controls (n = 232) than cases (n = 131) reported deaths. Conclusion: In a US-based real-world setting, IV edaravone-treated PALS had a longer time to disease progression milestone events and fewer deaths in 2 years compared with PALS not treated with IV edaravone.}, } @article {pmid39835561, year = {2025}, author = {Rai, A and Shukla, S and Gupta, RK and Mishra, A}, title = {ALS: A Silent Slayer of Motor Neurons. Traditional Chinese Herbal Medicine as an Effective Therapy.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128329141241205063352}, pmid = {39835561}, issn = {1873-4286}, abstract = {Amyotrophic Lateral Sclerosis (ALS), is a progressive neurodegenerative disease characterized by motor symptoms, and cognitive impairment. The complexity in treating ALS arises from genetic and environmental factors, contributing to the gradual decline of lower and upper motor neurons. The anticipated pharmaceutical market valuation for ALS is projected to reach $1,038.94 million by 2032. This projection underscores the escalating impact of ALS on global healthcare systems. ALS prevalence is expected to surge to 376,674 cases by 2040. In 2022, India ranked among the top 3 Asian-Pacific nations, while North America dominated the global ALS market. Ongoing investigations explore the potential of neuroprotective drugs like riluzole and edaravone in ALS treatment. Recently approved drugs, Relyvrio (sodium phenylbutyrate and taurursodiol) and Tofersen (Qalsody) have completed the trials, and others are currently undergoing extensive clinical trials. Continuous research and exploration of therapeutic avenues, including gene therapy and neuroprotective treatments, are imperative to address the challenges posed by ALS and other neurodegenerative diseases. Traditional Chinese Medicine (TCM) approaches and clinical trials are being explored for treating ALS symptoms, targeting neuroinflammation, oxidative damage, and muscle weakness, showcasing the potential benefits of integrating traditional and modern approaches in ALS management.}, } @article {pmid39835009, year = {2024}, author = {Frolov, A and D'sa, E and Henderson, C and Guzman, MA and Hayat, G and Martin, JR}, title = {Complex Genetic Framework in Familial Amyotrophic Lateral Sclerosis With a C9ORF72 Mutation: A Case Report.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e76027}, pmid = {39835009}, issn = {2168-8184}, abstract = {A significantly diverse clinical presentation of amyotrophic lateral sclerosis (ALS), even in its best-studied familial form, continues to hinder current efforts to develop effective disease-modifying drugs for the cure of this rapidly progressive, fatal neuromuscular disease. We have previously shown that clinical heterogeneity of sporadic ALS (sALS) could be explained, at least in part, by its polygenic nature as well as by the presence of mutated genes linked to non-ALS neurological diseases and genes known to mediate ALS-related pathologies. We hypothesized that a similar genetic framework could also be present in patients with familial ALS (fALS). To test this hypothesis, we conducted post-mortem genetic screening of an individual with fALS and a mutation in the C9ORF72 gene. C9ORF72 mutations are highly penetrant and are present in the majority of fALS patients. Genetic screening by whole exome sequencing (WES) on the next generation sequencing (NGS) Illumina platform (San Diego, CA, USA) followed by examination of the respective rare (minor allele frequency (MAF) ≤ 0.01) pathological/deleterious genetic variants yielded results consistent with our hypothesis of the presence of a complex genetic framework in fALS. Additional members of this genetic framework were identified when the low-frequency (0.01 < MAF < 0.05) pathological/deleterious genetic variants were analyzed with the low-frequency biallelic AHNAK2, GLI3, PTIRM1, and ZNF254 variants, warranting a closer look at their potentially important role in fALS as C9ORF72 genetic modifiers as well as their link to both neuromuscular disorders/ALS and cancer. Therefore, in addition to the current genetic screening using a standard panel of ALS-related genes, a supplementary screening by WES could be very beneficial for the development of personalized treatment of ALS patients as well as in search of the respective efficient disease-modifying drugs.}, } @article {pmid39834841, year = {2024}, author = {Coutinho, KMD and Fernandes, F and Medeiros, KC and Coutinho, KD and Dias, AP and Valentim, RAM and Leite-Lais, L and Lima, KC}, title = {Data Report: Educational pathway addressing food and nutrition in amyotrophic lateral sclerosis on the AVASUS platform.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1476293}, pmid = {39834841}, issn = {2673-253X}, } @article {pmid39834554, year = {2025}, author = {Sarallah, R and Jahani, S and Soltani Khaboushan, A and Moaveni, AK and Amiri, M and Majidi Zolbin, M}, title = {The role of CXCL12/CXCR4/CXCR7 axis in cognitive impairment associated with neurodegenerative diseases.}, journal = {Brain, behavior, & immunity - health}, volume = {43}, number = {}, pages = {100932}, pmid = {39834554}, issn = {2666-3546}, abstract = {Neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal loss and cognitive impairment (CI). The: Cysteine-X-cysteine chemokine ligand 12(CXCL12)/CXC chemokine receptor type 4 (CXCR4)/CXC chemokine receptor type 7 (CXCR7) axis has emerged as a critical molecular pathway in the development of CI in these disorders. This review explores the role of this axis in the pathogenesis of CI across these neurodegenerative diseases, synthesizing current evidence and its implications for targeted therapies. In AD, dysregulation of this axis contributes to amyloid-β accumulation and tau hyperphosphorylation, leading to synaptic dysfunction and cognitive decline. PD studies reveal that CXCL12/CXCR4 signaling influences dopaminergic neuron survival and microglial activation, affecting cognitive function. In MS, the axis modulates neuroinflammation and demyelination processes, impacting cognitive performance. ALS research indicates that the CXCL12/CXCR4/CXCR7 pathway is involved in motor neuron degeneration and associated cognitive deficits. Across these diseases, the axis influences neuroinflammation, synaptic plasticity, and neuronal survival through various signaling cascades, including PI3K/AKT, MAPK, and JAK/STAT pathways. Emerging evidence suggests that modulating this axis could provide neuroprotective effects and potentially alleviate cognitive symptoms. This review highlights the potential of the CXCL12/CXCR4/CXCR7 axis as a therapeutic target for addressing CI in neurodegenerative diseases. It also underscores the need for further research to fully elucidate its role and develop effective interventions, potentially leading to improved clinical management strategies for these devastating disorders.}, } @article {pmid39834320, year = {2025}, author = {Lero, CM and Park, S and Mroz, EL}, title = {Mapping the evidence of self-compassion in caregiver wellbeing for caregivers of persons with neurodegenerative disease: A scoping review.}, journal = {Palliative & supportive care}, volume = {23}, number = {}, pages = {e38}, doi = {10.1017/S1478951524001639}, pmid = {39834320}, issn = {1478-9523}, mesh = {Humans ; *Caregivers/psychology ; *Neurodegenerative Diseases/psychology/complications ; *Empathy ; }, abstract = {OBJECTIVES: Caregivers of those with neurodegenerative disease (ND) manage complex symptoms which impact their wellbeing. Self-compassion can promote maintenance of wellbeing during challenging experiences, including caregiving. Little guidance exists for observationally studying self-compassion or targeted interventions for this population. Our objective was to complete a scoping review of research describing self-compassion in the context of caregiver wellbeing of caregivers of those living with ND.

METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-analysis extension for Scoping Reviews (PRISMA-ScR) guidelines, 3 online databases identified 350 peer-reviewed articles, 18 of which were included in this study. Eligibility included being written in English, targeting caregivers of those living with ND, and examination of self-compassion. Articles were organized by the incorporation or characterization of self-compassion in the study design.

RESULTS: Alzheimer's disease predominated study samples of care recipients. Across study types self-compassion appeared as a theoretical concept, emerging theme, variable associated with other outcomes, and main outcome variable. Self-compassion is frequently measured using the Self-Compassion Scale, full or short form .

SIGNIFICANCE OF RESULTS: The study of self-compassion with caregivers of individuals living with ND is growing. Current literature is somewhat unfocussed, leading to gaps in understanding conceptualization to achieve maximum intervention benefits. Clarifying the role of self-compassion in caregiver wellbeing will provide a lens through which non-pharmacologic, psychotherapeutic, and behavioral intervention development may be framed to reduce negative psychological outcomes. The most frequently represented ND is Alzheimer's disease or other dementia, obscuring other NDs like amyotrophic lateral sclerosis, Parkinson's disease, and others.}, } @article {pmid39834142, year = {2025}, author = {Stikvoort García, DJL and van den Berg, LH and Sleutjes, BTHM and Goedee, HS}, title = {Diagnostic Accuracy of Median Nerve Cross-Sectional Area in Suspected Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {71}, number = {4}, pages = {680-684}, pmid = {39834142}, issn = {1097-4598}, support = {//Stichting ALS Nederland/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/diagnosis/pathology ; Female ; Male ; *Median Nerve/diagnostic imaging/physiopathology ; Middle Aged ; Aged ; *Ultrasonography ; Prospective Studies ; Retrospective Studies ; Adult ; ROC Curve ; Wrist/diagnostic imaging/innervation ; }, abstract = {INTRODUCTION/AIMS: Reduced nerve sizes obtained by nerve ultrasound (NUS) have been proposed as a potential diagnostic marker for amyotrophic lateral sclerosis (ALS). However, prospective studies evaluating patients with suspected ALS are currently lacking. We, therefore, evaluated the diagnostic accuracy of a standardized NUS protocol in a large sample of suspected ALS patients.

METHODS: We prospectively recruited 193 patients with suspected ALS, all of whom underwent the relevant ancillary tests. They also underwent a standardized NUS protocol, evaluating median nerve cross-sectional area (CSA) at upper arm, forearm and wrist. Additionally, we selected, retrospectively, a random sample of incident patients with multifocal motor neuropathy (MMN, n = 42). We determined diagnostic accuracy using receiver operating characteristic (ROC) analysis.

RESULTS: Ultimately, 143/193 patients received a final diagnosis of ALS, at a median disease duration of 10 months. Fifty patients were classified as non-ALS. Diagnostic yield of NUS to distinguish between patients with and without ALS was low (highest area under the curve (AUC) at the wrist: 0.57). In contrast, abnormal nerve sizes accurately discriminated MMN from patients with ALS, with AUCs ranging from 0.65 at the wrist to 0.86 at the upper arm.

DISCUSSION: Our study shows that reductions in nerve size are unlikely to have diagnostic utility during routine evaluation of suspected patients with ALS. However, when the differential diagnosis includes both ALS and MMN, median nerve size demonstrates high diagnostic accuracy.}, } @article {pmid39833708, year = {2025}, author = {Bidarolli, M and Das, B and Rawat, VS and Manocha, S and Sony, HT and Agnihotri, A and Gupta, M and Agera, F}, title = {Polypharmacy and anticholinergic burden scales in older adults: a cross-sectional study among psychiatric outpatients in a tertiary care hospital.}, journal = {BMC geriatrics}, volume = {25}, number = {1}, pages = {43}, pmid = {39833708}, issn = {1471-2318}, mesh = {Humans ; Male ; *Polypharmacy ; Female ; Aged ; Cross-Sectional Studies ; *Cholinergic Antagonists/adverse effects ; Middle Aged ; *Tertiary Care Centers/trends ; *Mental Disorders/drug therapy/epidemiology ; India/epidemiology ; Outpatients ; Aged, 80 and over ; Psychotropic Drugs/adverse effects ; }, abstract = {INTRODUCTION: Mental disorders are prevalent among older adults, often leading to the use of multiple medications, many with anticholinergic properties. Polypharmacy, common in this population, is a major contributor to anticholinergic burden, which is linked to cognitive and physical decline. This study investigates the relationship between polypharmacy and anticholinergic burden across seven anticholinergic burden scales in elderly patients attending the psychiatric outpatient.

METHODS: Study was conducted at a psychiatry outpatient clinic at All India Institute of Medical Sciences, Rishikesh, India, from December 2021 to March 2023. Elderly patients (aged ≥ 60 years) who were on at least one psychotropic medication and had a primary working diagnosis of psychiatric illness were included. All psychotropic medications, including antidepressants, antipsychotics, mood stabilizers, and hypnotics, were evaluated. Anticholinergic burden scales were calculated by the respective tools. Univariate analysis was adopted to determine the factors that may affect polypharmacy.

RESULTS: Study included 1165 elderly patients aged ≥ 60 years. The prevalence of polypharmacy was 20.43% (n = 238). Clonazepam (n = 364, 17.28%), escitalopram (n = 197, 9.35%), metformin (n = 165, 7.83%), sertraline (n = 141, 6.69%), mirtazapine (n = 129, 6.12%), and lorazepam (n = 110, 5.22%) were among the most frequently prescribed anticholinergic drugs. Univariate analysis demonstrated that all anticholinergic risk assessment scales were closely correlated with polypharmacy, with the strongest association observed for the Anticholinergic Load Scale (ALS) (Odds Ratio = 4.3; p < 0.001). Polypharmacy was also positively associated with adverse drug reactions (Odds Ratio = 1.81; 95% Confidence Interval = 1.27-2.56).

CONCLUSION: The anticholinergic burden in this cohort of elderly psychiatry patients was high, with 95.1% (n = 1108) experiencing a significant burden. Adverse drug events and anticholinergic burden scales were positively associated with polypharmacy, with a stronger correlation between polypharmacy and ALS scores than with other anticholinergic burden scales in older adults.}, } @article {pmid39832811, year = {2025}, author = {Ghaderi, S and Mohammadi, S and Ahmadzadeh, AM and Darmiani, K and Arab Bafrani, M and Jashirenezhad, N and Helfi, M and Alibabaei, S and Azadi, S and Heidary, S and Fatehi, F}, title = {Thalamic Magnetic Susceptibility (χ) Alterations in Neurodegenerative Diseases: A Systematic Review and Meta-Analysis of Quantitative Susceptibility Mapping Studies.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {}, number = {}, pages = {}, doi = {10.1002/jmri.29698}, pmid = {39832811}, issn = {1522-2586}, abstract = {BACKGROUND: Quantitative Susceptibility Mapping (QSM) provides a non-invasive post-processing method to investigate alterations in magnetic susceptibility (χ), reflecting iron content within brain regions implicated in neurodegenerative diseases (NDDs).

PURPOSE: To investigate alterations in thalamic χ in patients with NDDs using QSM.

STUDY TYPE: Systematic review and meta-analysis.

POPULATION: A total of 696 patients with NDDs and 760 healthy controls (HCs) were included in 27 studies.

FIELD STRENGTH/SEQUENCE: Three-dimensional multi-echo gradient echo sequence for QSM at mostly 3 Tesla.

ASSESSMENT: Studies reporting QSM values in the thalamus of patients with NDDs were included. Following PRISMA 2020, we searched the four major databases including PubMed, Scopus, Web of Science, and Embase for peer-reviewed studies published until October 2024.

STATISTICAL TESTS: Meta-analysis was conducted using a random-effects model to calculate the standardized mean difference (SMD) between patients and HCs.

RESULTS: The pooled SMD indicated a significant increase in thalamic χ in NDDs compared to HCs (SMD = 0.42, 95% CI: 0.05-0.79; k = 27). Notably, amyotrophic lateral sclerosis patients showed a significant increase in thalamic χ (1.09, 95% CI: 0.65-1.53, k = 2) compared to HCs. Subgroup analyses revealed significant χ alterations in younger patients (mean age ≤ 62 years; 0.56, 95% CI: 0.10-1.02, k = 11) and studies using greater coil channels (coil channels > 16; 0.64, 95% CI: 0.28-1.00, k = 9). Publication bias was not detected and quality assessment indicated that studies with a lower risk of bias presented more reliable findings (0.75, 95% CI: 0.32-1.18, k = 9). Disease type was the primary driver of heterogeneity, while other factors, such as coil type and geographic location, also contributed to variability.

DATA CONCLUSION: Our findings support the potential of QSM for investigating thalamic involvement in NDDs. Future research should focus on disease-specific patterns, thalamic-specific nucleus analysis, and temporal evolution.

PLAIN LANGUAGE SUMMARY: Our research investigated changes in iron levels within the thalamus, a brain region crucial for motor and cognitive functions, in patients with various neurodegenerative diseases (NDDs). The study utilized a specific magnetic resonance imaging technique called Quantitative Susceptibility Mapping (QSM) to measure iron content. It identified a significant increase in thalamic iron levels in NDD patients compared to healthy individuals. This increase was particularly prominent in patients with Amyotrophic Lateral Sclerosis, younger individuals, and studies employing advanced imaging equipment.

LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.}, } @article {pmid39831450, year = {2025}, author = {Hoehne, SN and Cary, JA and Bailey, LN and Davidow, EB and Martin, LG and DeJong, TL}, title = {An exploratory study on the effect of rescuer team size on basic and advanced life support technical skills in a high-fidelity simulation of canine cardiopulmonary arrest.}, journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)}, volume = {35}, number = {1}, pages = {9-18}, pmid = {39831450}, issn = {1476-4431}, support = {//Converse Fund, Washington State University College of Veterinary Medicine 2021-2022 CVM Intramural Research Grants/ ; }, mesh = {Animals ; Dogs ; *Heart Arrest/veterinary/therapy ; *Cardiopulmonary Resuscitation/veterinary/methods/education ; Prospective Studies ; *Advanced Cardiac Life Support/veterinary/education ; Humans ; Clinical Competence ; Dog Diseases/therapy ; Simulation Training/methods ; Female ; }, abstract = {OBJECTIVE: To evaluate the effect of rescuer team size on objective skill measures of basic life support (BLS) and advanced life support (ALS) using high-fidelity canine CPR simulation.

DESIGN: Prospective, experimental study.

SETTING: Veterinary clinical simulation center.

SUBJECTS: Forty-eight Reassessment Campaign on Veterinary Resuscitation CPR-certified veterinary students.

MEASUREMENTS AND MAIN RESULTS: Five groups of participants each conducted 3 CPR simulations in configurations of 4, 6, and 8 rescuers. Simulations represented a shock patient declining into asystole, followed by ventricular fibrillation and return of spontaneous circulation. Resuscitation efforts were video-recorded to evaluate BLS and ALS tasks. Mean (±SD) was derived and data were compared among team sizes using ANOVA and Tukey's post hoc analysis. Significance was set at P < 0.05. Among teams of 4, 6, and 8 rescuers, time to first chest compression (13 s [±6], 9 s [±2], 8 s [±4]; P = 0.24) and positive-pressure breath (101 s [±37], 56 s [±15], 67 s [±24]; P = 0.05) were not significantly different. Chest compression (100/min [±5], 108/min [±6], 107/min [±6]; P = 0.12) and ventilatory rates (9/min [±1], respectively, P = 0.52) were not significantly different. Time without chest compressions/total length of CPR was not significantly different (72 s [±16], 61 s [±16], 54 s [±8]; P = 0.15). Capnography and ECG monitoring were used by all teams. Time to first vasopressor administration was significantly different among team sizes (268 s [±70], 164 s [±65], 174 s [±34]; P = 0.04), with vasopressors being most quickly administered by teams of 6 rescuers. Time to electrical defibrillation was not significantly different (486 s [±45], 424 s [±22], 488 s [±181]; P = 0.57). Incorrect ALS interventions occurred in 60%, 0%, and 40% of CPR events in 4, 6, and 8 rescuer teams, respectively.

CONCLUSIONS: Although the achievement of BLS tasks was comparable in teams of 4 rescuers, teams of 6 rescuers may be preferable based on differences in the rate of guideline-incompliant treatments and ALS task efficiency. Teams of 8 rescuers were neither more efficient nor more accurate at conducting BLS and ALS tasks.}, } @article {pmid39831399, year = {2025}, author = {Wang, F and Jing, Z and Wang, Q and Li, M and Lu, B and Huo, A and Zhao, C and Zhou, H and Liang, W and Hu, W and Fu, X}, title = {Bidirectional Mendelian Randomization Analysis of the Association Between Mitochondrial Proteins and Neurodegenerative Diseases.}, journal = {Brain and behavior}, volume = {15}, number = {1}, pages = {e70283}, pmid = {39831399}, issn = {2162-3279}, support = {82303029//National Natural Science Foundation of China/ ; 2024YLZDJH027//the Zhengzhou Science and Technology Innovation Project for Healthcare/ ; YXKC2022020//Health Commission of Henan Province/ ; 232102311134//Science and Technology Department of Henan Province/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics ; *Mitochondrial Proteins/genetics ; *Genome-Wide Association Study ; Alzheimer Disease/genetics ; }, abstract = {BACKGROUND: Neurodegenerative diseases involve progressive neuronal dysfunction and cognitive decline, posing substantial global challenges. Although the precise causes remain unclear, several studies highlight the role of protein metabolism abnormalities in disease development. This study investigates the causal links between variations in mitochondrial protein genes and neurodegenerative diseases, aiming to elucidate their potential contributions to disease progression and identify novel therapeutic strategies.

METHODS: Herein, we utilized data from genome-wide association studies (GWAS) on mitochondrial proteins and neurodegenerative diseases. Bidirectional Mendelian randomization (MR), employing instrumental variables (IVs), was used to assess causal relationships. The primary method for estimating causal effects was the inverse variance-weighted (IVW) method, supplemented by additional MR approaches.

RESULTS: Bidirectional MR revealed significant associations between mitochondrial protein gene variants and neurodegenerative diseases. Specifically, associations were found with Alzheimer's disease (AD) (three proteins), Parkinson's disease (PD) (four proteins), amyotrophic lateral sclerosis (ALS) (six proteins), multiple sclerosis (two proteins), and dementia with Lewy bodies (four proteins). Conversely, analyses indicated significant associations of neurodegenerative diseases with mitochondrial protein gene variants, notably with AD, dementia with Lewy bodies, and multiple sclerosis, affecting multiple mitochondrial protein levels. Bidirectional causality was observed between dementia with Lewy bodies and C21orf33.

CONCLUSIONS: Using MR, we identified significant links between mitochondrial protein gene mutations and the risk of neurodegenerative diseases. These results highlight reciprocal relationships where certain neurodegenerative diseases influence mitochondrial protein expression levels. These findings underscore the pivotal role of mitochondrial proteins in neurodegenerative diseases, offering critical insights into disease mechanisms and potential therapeutic avenues.}, } @article {pmid39831374, year = {2025}, author = {Risi, B and Imarisio, A and Cuconato, G and Padovani, A and Valente, EM and Filosto, M}, title = {Mitochondrial DNA (mtDNA) as fluid biomarker in neurodegenerative disorders: A systematic review.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e70014}, pmid = {39831374}, issn = {1468-1331}, mesh = {Humans ; *DNA, Mitochondrial/cerebrospinal fluid/genetics ; *Biomarkers/cerebrospinal fluid/blood ; *Neurodegenerative Diseases/cerebrospinal fluid/genetics/diagnosis/blood ; Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid/blood/diagnosis ; }, abstract = {BACKGROUND: Several studies evaluated peripheral and cerebrospinal fluid (CSF) mtDNA as a putative biomarker in neurodegenerative diseases, often yielding inconsistent findings. We systematically reviewed the current evidence assessing blood and CSF mtDNA levels and variant burden in Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Multiple sclerosis (MS) was also included as a paradigm of chronic neuroinflammation-driven neurodegeneration.

METHODS: Medline, Embase, Scopus and Web of Science were searched for articles published from inception until October 2023. Studies focused on mtDNA haplogroups or hereditary pathogenic variants were excluded. Critical appraisal was performed using the Quality Assessment for Diagnostic Accuracy Studies criteria.

RESULTS: Fifty-nine original studies met our a priori-defined inclusion criteria. The majority of CSF-focused studies showed (i) decreased mtDNA levels in PD and AD; (ii) increased levels in MS compared to controls. No studies evaluated CSF mtDNA in ALS. Results focused on blood cell-free and intracellular mtDNA were contradictory, even within studies evaluating the same disease. This poor reproducibility is likely due to the lack of consideration of the many factors known to affect mtDNA levels. mtDNA damage and methylation levels were increased and reduced in patients compared to controls, respectively. A few studies investigated the correlation between mtDNA and disease severity, with conflicting results.

CONCLUSIONS: Additional well-designed studies are needed to evaluate CSF and blood mtDNA profiles as putative biomarkers in neurodegenerative diseases. The identification of "mitochondrial subtypes" of disease may enable novel precision medicine strategies to counteract neurodegeneration.}, } @article {pmid39831022, year = {2025}, author = {Okpete, UE and Byeon, H}, title = {Brain-derived neurotrophic factor alterations and cognitive decline in schizophrenia: Implications for early intervention.}, journal = {World journal of psychiatry}, volume = {15}, number = {1}, pages = {102131}, pmid = {39831022}, issn = {2220-3206}, abstract = {This manuscript explores the recent study by Cui et al which assessed the interplay between inflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels in first-episode schizophrenia patients. The study revealed that higher levels of interleukin-6 and tumor necrosis factor-α correlated with reduced BDNF levels and poorer cognitive performance. Schizophrenia is a severe psychiatric disorder impacting approximately 1% of the global population, characterized by positive symptoms (hallucinations and delusions), negative symptoms (diminished motivation and cognitive impairments) and disorganized thoughts and behaviors. Emerging research highlights the role of BDNF as a potential biomarker for early diagnosis and therapeutic targeting. The findings from Cui et al's study suggest that targeting neuroinflammation and enhancing BDNF levels may improve cognitive outcomes. Effective treatment approaches involve a combination of pharmacological and non-pharmacological interventions tailored to individual patient needs. Hence, monitoring cognitive and neuroinflammatory markers is essential for improving patient outcomes and quality of life. Consequently, this manuscript highlights the need for an integrated approach to schizophrenia management, considering both clinical symptoms and underlying neurobiological changes.}, } @article {pmid39829394, year = {2025}, author = {Buddenhagen, CE and Ngow, Z and Wynne-Jones, B and Rolston, MP}, title = {Resistance to the herbicides haloxyfop and iodosulfuron is common in commercial ryegrass (Lolium) seed lines.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.8665}, pmid = {39829394}, issn = {1526-4998}, support = {//AgResearch Ltd via its contribution to the Better Border Biosecurity (B3) research collaboration, www.b3nz.org/ ; }, abstract = {BACKGROUND: Ryegrass (Lolium spp.) is a key forage providing a $14 billion contribution to New Zealand's gross domestic product (GDP). However, ryegrass can also act as a weed and evolve resistance to herbicides used for its control. Farmers suspected that imported seed might contribute to resistance issues. Herbicide resistance frequencies were investigated in commercial ryegrass seed lines intended for multiplication in New Zealand. Samples from 56 basic seed lots and 52 unique cultivars sourced from regions including New Zealand, United States, Europe and Japan were planted in field trials. Seedlings were then sprayed with three common herbicides: glyphosate, iodosulfuron, and haloxyfop. Surviving plants were retested to confirm resistance.

RESULTS: Resistance to haloxyfop and or iodosulfuron was detected in 79% of seed lines. However, frequencies were not significantly higher in imported lines (from United States and Europe) compared with New Zealand lines. Resistance was detected at frequencies between 0.00112% and 10% for haloxyfop and between 0.00212% and 14.28% for iodosulfuron Resistance to glyphosate was not found. There was no significant difference between the resistance detected in seed samples sourced from different seed companies.

CONCLUSIONS: It was found that 63% of resistant lines had resistance frequencies rarer than 0.1%, but this is potentially problematic considering typical sowing rates. Imported versus domestic seed sources were not significantly different; they pose similar levels of resistance risk to farmers. Lolium multiflorum had a higher resistance frequency compared to Lolium perenne (although only six L. multiflorum lots were evaluated). Breeders should screen progeny of early crosses for herbicide resistance. © 2025 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid39829368, year = {2025}, author = {Bedlack, R}, title = {Stitching strength: things I've learned about hope and how I am trying to weave them into my in ALS practice.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2025.2454903}, pmid = {39829368}, issn = {2167-9223}, } @article {pmid39829311, year = {2025}, author = {Falanga, AP and Piccialli, I and Greco, F and D'Errico, S and Nolli, MG and Borbone, N and Oliviero, G and Roviello, GN}, title = {Nanostructural Modulation of G-Quadruplex DNA in Neurodegeneration: Orotate Interaction Revealed Through Experimental and Computational Approaches.}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16296}, pmid = {39829311}, issn = {1471-4159}, support = {IR0000010 "ELIXIRxNextGenIT"//European Commission/ ; PNRRMUR-M4C2-I//European Commission/ ; FOE 2020-ISBE-IT Joint Research Unit//Ministero dell'Università e della Ricerca/ ; }, mesh = {*G-Quadruplexes/drug effects ; Humans ; *Orotic Acid/pharmacology ; DNA/genetics ; Molecular Docking Simulation ; Neurodegenerative Diseases/genetics/metabolism ; Nanostructures/chemistry ; }, abstract = {The natural compound orotic acid and its anionic form, orotate, play a pivotal role in various biological processes, serving as essential intermediates in pyrimidine de novo synthesis, with demonstrated connections to dietary, supplement, and neurodrug applications. A novel perspective on biomolecular aggregation at the nanoscale, particularly pertinent to neurodegeneration, challenges the established paradigm positing that peptide (amyloid beta) and protein (tau) aggregation mainly govern the molecular events underlying prevalent neuropathologies. Emerging biological evidence indicates a notable role for G-quadruplex (G4) DNA aggregation in neurodegenerative processes affecting neuronal cells, particularly in the presence of extended (G4C2)n repeats in nuclear DNA sequences. Our study concerns d[(GGGGCC)3GGGG], a G4-forming DNA model featuring G4C2 repeats that is in correlation with neurodegeneration. Through different investigations utilizing spectroscopic techniques (CD, UV, and thermal denaturations), PAGE electrophoresis, and molecular docking, the study explores the influence of orotate on the aggregation of this neurodegeneration-associated DNA. A computational approach was employed to construct an in silico model of the DNA aggregate, which involved the docking of multiple G4 units and subsequent integration of the ligand into both the DNA monomer and its in silico aggregated model. The convergence of computational analyses and empirical data collectively supports the hypothesis that orotate possesses the capability to modulate the aggregation of neurodegeneration-related DNA. Notably, the findings suggest the potential utility of orotate as a neurodrug, especially for the therapy of amyotrophic lateral sclerosis (ALS) and Frontotemporal Dementia (FTD), with its current status as a dietary supplement indicating minimal safety concerns. Additionally, orotate demonstrated a slight increase in mitochondrial dehydrogenase activity as assessed by the MTT assay, which is beneficial for a neurodrug as it suggests a potential role in enhancing mitochondrial function and supporting neuronal health.}, } @article {pmid39828328, year = {2025}, author = {Yorimoto, K and Ariake, Y and Kawaguchi, T and Hara, T}, title = {Long-term lung volume recruitment therapy maintains ventilator weaning in a patient with ALS following tracheostomy.}, journal = {BMJ case reports}, volume = {18}, number = {1}, pages = {}, doi = {10.1136/bcr-2024-262945}, pmid = {39828328}, issn = {1757-790X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Tracheostomy ; Middle Aged ; *Ventilator Weaning/methods ; Male ; Respiratory Therapy/methods ; Vital Capacity ; }, abstract = {We report a case of amyotrophic lateral sclerosis (ALS) in a patient in their 50s, presenting with spastic paraparesis and bulbar palsy, treated with lung volume recruitment therapy (LVRT). From early stage in the disease, vital capacity (VC), lung insufflation capacity (LIC) and ALS Functional Rating Scale-Revised scores were regularly measured, and LVRT was continuously performed at home. After 10 years, the patient had complete limb function loss and required nutritional management via gastrostomy and full assistance with daily activities. Despite this, the gap between VC and LIC remained approximately 2000 mL, and the patient was not ventilator-dependent during the day after tracheostomy. Chest CT showed improvement in lower lobe atelectasis due to LVRT. Typically, respiratory physiotherapy is challenging in patients with bulbar palsy or post-tracheostomy, but in this case, LVRT successfully maintained lung mobility. Early LVRT implementation may improve ALS patients' survival prognosis and warrants further exploration.}, } @article {pmid39828029, year = {2025}, author = {Fantini, J and Azzaz, F and Di Scala, C and Aulas, A and Chahinian, H and Yahi, N}, title = {Conformationally adaptive therapeutic peptides for diseases caused by intrinsically disordered proteins (IDPs). New paradigm for drug discovery: Target the target, not the arrow.}, journal = {Pharmacology & therapeutics}, volume = {267}, number = {}, pages = {108797}, doi = {10.1016/j.pharmthera.2025.108797}, pmid = {39828029}, issn = {1879-016X}, mesh = {*Intrinsically Disordered Proteins/chemistry/metabolism ; Humans ; *Drug Discovery/methods ; *Peptides/chemistry/pharmacology/therapeutic use ; *Protein Conformation ; Animals ; Drug Design ; }, abstract = {The traditional model of protein structure determined by the amino acid sequence is today seriously challenged by the fact that approximately half of the human proteome is made up of proteins that do not have a stable 3D structure, either partially or in totality. These proteins, called intrinsically disordered proteins (IDPs), are involved in numerous physiological functions and are associated with severe pathologies, e.g. Alzheimer, Parkinson, Creutzfeldt-Jakob, amyotrophic lateral sclerosis (ALS), and type 2 diabetes. Targeting these proteins is challenging for two reasons: i) we need to preserve their physiological functions, and ii) drug design by molecular docking is not possible due to the lack of reliable starting conditions. Faced with this challenge, the solutions proposed by artificial intelligence (AI) such as AlphaFold are clearly unsuitable. Instead, we suggest an innovative approach consisting of mimicking, in short synthetic peptides, the conformational flexibility of IDPs. These peptides, which we call adaptive peptides, are derived from the domains of IDPs that become structured after interacting with a ligand. Adaptive peptides are designed with the aim of selectively antagonizing the harmful effects of IDPs, without targeting them directly but through selected ligands, without affecting their physiological properties. This "target the target, not the arrow" strategy is promised to open a new route to drug discovery for currently undruggable proteins.}, } @article {pmid39828018, year = {2025}, author = {Sharma, D and Singh, V and Kumar, A and Singh, TG}, title = {Genistein: A promising ally in combating neurodegenerative disorders.}, journal = {European journal of pharmacology}, volume = {991}, number = {}, pages = {177273}, doi = {10.1016/j.ejphar.2025.177273}, pmid = {39828018}, issn = {1879-0712}, mesh = {*Genistein/pharmacology/therapeutic use ; Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; Antioxidants/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative disorders arise when nerve cells in the brain or peripheral nervous system gradually lose functions and eventually die. Although certain therapies may alleviate some of the physical and mental symptoms associated with neurodegenerative disorders, hence slowing their progression, but no sure-shot treatment is currently available. It was shown that the rise in life expectancy and the number of elderly people in the community led to an increasing trend in the incidence and prevalence of neurodegenerative disease. Phytomolecules are demonstrating their effectiveness in combating, regression, and delaying various diseases. Genistein is one of soy isoflavone with antioxidant, anti-inflammatory, and estrogenic effects. Researchers demonstrated that Genistein treatment significantly reduced hyperglycemia, improved cognitive performance by modulating acetylcholinesterase activity and oxidative stress, and alleviated neuroinflammatory conditions in mice. This paper evaluates (in vivo and in vitro) various molecular targets of isoflavones and their ability to effectively counter several neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases and amyotrophic lateral sclerosis. In this review, we aim to provide an overview of the role that genistein plays in delaying the development of neurodegenerative disorders.}, } @article {pmid39827940, year = {2025}, author = {Jinno, J and Abdelhamid, RF and Morita, J and Saga, R and Yamasaki, Y and Kadowaki, A and Ogawa, K and Kimura, Y and Ikenaka, K and Beck, G and Baba, K and Nagai, Y and Kasahara, E and Sekiyama, A and Hirayama, T and Hozumi, I and Hasegawa, T and Araki, T and Mochizuki, H and Nagano, S}, title = {TDP-43 transports ferritin heavy chain mRNA to regulate oxidative stress in neuronal axons.}, journal = {Neurochemistry international}, volume = {184}, number = {}, pages = {105934}, doi = {10.1016/j.neuint.2025.105934}, pmid = {39827940}, issn = {1872-9754}, mesh = {*Oxidative Stress/physiology ; *Apoferritins/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *RNA, Messenger/metabolism/genetics ; *Axons/metabolism/pathology ; Animals ; Humans ; Neurons/metabolism ; Iron/metabolism ; Ferritins ; Oxidoreductases ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the mislocalization and abnormal deposition of TAR DNA-binding protein 43 (TDP-43). This protein plays important roles in RNA metabolism and transport in motor neurons and glial cells. In addition, abnormal iron accumulation and oxidative stress are observed in the brain and spinal cord of patients with ALS exhibiting TDP-43 pathology and in animal models of ALS. We have previously demonstrated that TDP-43 downregulation significantly affects the expression of ferritin heavy chain (Fth1) mRNA in the axonal regions of neurons. Nevertheless, the mechanisms by which TDP-43 contributes to oxidative stress and iron accumulation in the central nervous system remain elusive. In this study, we aimed to investigate whether Fth1 mRNA is a target transported to the axon by TDP-43 using biophysical and biochemical analyses. Our results revealed Fth1 mRNA as a target mRNA transported to axons by TDP-43. Moreover, we demonstrated that TDP-43 regulates iron homeostasis and oxidative stress in neurons via Fth1 mRNA transport to the axons, possibly followed by a local translation of the ferritin heavy chain in the axons. This study suggests that TDP-43 plays an important role in preventing iron-mediated oxidative stress in neurons, with its loss contributing to ALS pathogenesis.}, } @article {pmid39827337, year = {2025}, author = {Mwale, PF and Hsieh, CT and Yen, TL and Jan, JS and Taliyan, R and Yang, CH and Yang, WB}, title = {Chitinase-3-like-1: a multifaceted player in neuroinflammation and degenerative pathologies with therapeutic implications.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {7}, pmid = {39827337}, issn = {1750-1326}, support = {NSTC 112-2320-B-038 -018 -MY3//National Science and Technology Council/ ; CGH-MR-A11315//Cathay General Hospital/ ; CGH-MR-A11314//Cathay General Hospital/ ; }, mesh = {Humans ; *Chitinase-3-Like Protein 1/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Neuroinflammatory Diseases/metabolism ; Animals ; }, abstract = {Chitinase-3-like-1 (CHI3L1) is an evolutionarily conserved protein involved in key biological processes, including tissue remodeling, angiogenesis, and neuroinflammation. It has emerged as a significant player in various neurodegenerative diseases and brain disorders. Elevated CHI3L1 levels have been observed in neurological conditions such as traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD), multiple sclerosis (MS), Neuromyelitis optica (NMO), HIV-associated dementia (HAD), Cerebral ischemic stroke (CIS), and brain tumors. This review explores the role of CHI3L1 in the pathogenesis of these disorders, with a focus on its contributions to neuroinflammation, immune cell infiltration, and neuronal degeneration. As a key regulator of neuroinflammation, CHI3L1 modulates microglia and astrocyte activity, driving the release of proinflammatory cytokines that exacerbate disease progression. In addition to its role in disease pathology, CHI3L1 has emerged as a promising biomarker for the diagnosis and monitoring of brain disorders. Elevated cerebrospinal fluid (CSF) levels of CHI3L1 have been linked to disease severity and cognitive decline, particularly in AD and MS, highlighting its potential for clinical diagnostics. Furthermore, therapeutic strategies targeting CHI3L1, such as small-molecule inhibitors and neutralizing antibodies, have shown promise in preclinical studies, demonstrating reduced neuroinflammation, amyloid plaque accumulation, and improved neuronal survival. Despite its therapeutic potential, challenges remain in developing selective and safe CHI3L1-targeted therapies, particularly in ensuring effective delivery across the blood-brain barrier and mitigating off-target effects. This review addresses the complexities of targeting CHI3L1, highlights its potential in precision medicine, and outlines future research directions aimed at unlocking its full therapeutic potential in treating neurodegenerative diseases and brain pathologies.}, } @article {pmid39825381, year = {2025}, author = {Gupta, R and Bhandari, M and Grover, A and Al-Shehari, T and Kadrie, M and Alfakih, T and Alsalman, H}, title = {Correction: Predictive modeling of ALS progression: an XGBoost approach using clinical features.}, journal = {BioData mining}, volume = {18}, number = {1}, pages = {5}, pmid = {39825381}, issn = {1756-0381}, } @article {pmid39824815, year = {2025}, author = {Leau, C and Wang, Y and Gervillié-Mouravieff, C and Boles, ST and Zhang, XH and Coudray, S and Boussard-Plédel, C and Tarascon, JM}, title = {Tracking solid electrolyte interphase dynamics using operando fibre-optic infra-red spectroscopy and multivariate curve regression.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {757}, pmid = {39824815}, issn = {2041-1723}, abstract = {As batteries drive the transition to electrified transportation and energy systems, ensuring their quality, reliability, lifetime, and safety is crucial. While the solid electrolyte interphase (SEI) is known to govern these performance characteristics, its dynamic nature makes understanding its nucleation, growth, and composition an ambitious, yet elusive aspiration. This work employs chalcogenide fibres embedded in negative electrode materials for operando Infra-red Fibre-optic Evanescent Wave Spectroscopy (IR-FEWS), combined with Multivariate Curve Resolution by Alternating Least Squares (MCR-ALS) algorithms for spectra analysis. By establishing molecular fingerprints that can be used to identify reaction products, IR-FEWS combined with MCR-ALS enables improved understanding of SEI evolution during cell formation with notable differences stemming from electrolyte or anode material. For example, despite operating at an elevated potential, lithium titanate's SEI has intrinsic instability, evidenced by continued carbonate formation. This approach leads the hunt for the SEI down a new path, giving empirical formulations theoretical roots.}, } @article {pmid39824736, year = {2025}, author = {Chow, G and Scher, M and Krisciunas, GP and Tracy, LF}, title = {Comprehensive Review of Multilingual Patient-Reported Outcome Measures for Dysphonia.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2025.01.005}, pmid = {39824736}, issn = {1873-4588}, abstract = {INTRODUCTION: Patient-reported outcome measures (PROMs) represent an important part of a comprehensive voice assessment for clinical care and research. Access to multilingual PROMs enables inclusion of information from diverse patient populations. This review compares available translated and validated PROMs for adult dysphonia.

METHODS: A comprehensive review of Cochrane Library, PubMed, and OnBase was performed for PROMs evaluating adult dysphonia in all languages. References were additionally queried. PROM development process, available languages, and study group demographics were compared between PROMs available in at least one language other than English. Cultural validation for each PROM was assessed against Beaton et al's six-stage cross-cultural adaptation guidelines.

RESULTS: Of 21 PROMs assessing adult dysphonia, 13 (62%) were available in one or more language other than English, and nine (43%) were available in seven or more. Voice Handicap Index (VHI) and VHI-10 were the most widely available translated questionnaires (n = 29, n = 15) followed by Vocal Fatigue Index (VFI), Singing-VHI (S-VHI), and Voice-Related Quality of Life (V-RQOL) (n = 11). Identified questionnaires were available in English (n = 21), Persian (n = 9), Kannada (n = 8), and Turkish (n = 7) as the most common languages. Females averaged 60% (range 13%-81%) of dysphonic subject groups and 59% of non-dysphonic subject groups (range 20%-88%). Of the 113 articles that reported cultural validation techniques, 16 (14%) adequately fulfilled the cross-cultural adaptation guidelines used.

CONCLUSION: Multilingual PROMs for dysphonia are widely available, but linguistic representation varied. VHI, VFI, S-VHI, and V-RQOL are the most widely translated. The most represented languages were Persian, Kannada, and Turkish. Few studies adequately followed cross-cultural adaptation standards. Efforts to translate and validate questionnaires into different languages may allow more diverse assessment and comparison of larger populations with dysphonia. This review identifies translated PROMs for dysphonia and analyzes their level of cultural validation for future use.}, } @article {pmid39824655, year = {2025}, author = {Jia, M and Li, P and Yan, Y and Liu, X and Gao, L and Zhu, G and Chen, Z}, title = {Antimicrobial susceptibility and genomic characterization of Vibrio cholerae non-O1/non-O139 isolated from clinical and environmental samples in Jiaxing City, China.}, journal = {FEMS microbiology letters}, volume = {372}, number = {}, pages = {}, doi = {10.1093/femsle/fnaf009}, pmid = {39824655}, issn = {1574-6968}, support = {2024KY1697//Medical Science and Technology Project of Zhejiang Province/ ; 2023AY31028//Science and Technology Bureau of Jiaxing City/ ; }, mesh = {China ; Humans ; *Anti-Bacterial Agents/pharmacology ; *Multilocus Sequence Typing ; *Microbial Sensitivity Tests ; Vibrio cholerae non-O1/genetics/drug effects/isolation & purification ; Genome, Bacterial ; Environmental Microbiology ; Virulence/genetics ; Cholera/microbiology ; Drug Resistance, Bacterial/genetics ; Genetic Variation ; Virulence Factors/genetics ; }, abstract = {Non-O1/non-O139 (NOVC) strains inhabit aquatic environments and sporadically induce human illnesses. This study involved the virulence and antimicrobial genetic characterization of 176 NOVC strains, comprising 25 from clinical samples and 151 from environmental sources, collected between 2021 and 2023. The antimicrobial susceptibility of the examined NOVC population was predominantly high, exhibiting only poor susceptibility to colistin, with 89.2% resistance. The examination of virulence genes revealed that the majority of strains were positive for glucose metabolism (als gene) (169/176, 96.0%). Through multilocus sequence typing, the 176 NOVC strains were categorised into 121 sequence types, 79 of which were novel. NOVC strains demonstrate significant genetic variability and frequently engage in recombination. This work offers genetic characterization of the pathogenicity and antimicrobial resistance of a NOVC community. Our findings offer insights that may aid in the development of preventative and treatment methods for this pathogen.}, } @article {pmid39823474, year = {2025}, author = {Zhang, Y and He, L and Gundelach, J and Ge, A and Edlund, H and Norlin, S and Bram, RJ}, title = {Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.}, journal = {PLoS genetics}, volume = {21}, number = {1}, pages = {e1011547}, pmid = {39823474}, issn = {1553-7404}, mesh = {Animals ; Mice ; *Motor Neurons/metabolism ; Mice, Transgenic ; Humans ; Endoplasmic Reticulum/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Neuromuscular Junction/metabolism ; Qa-SNARE Proteins/metabolism/genetics ; Spinal Cord/metabolism ; Disease Models, Animal ; Protein Transport ; Dystonin ; Intracellular Signaling Peptides and Proteins ; }, abstract = {Motor neuron diseases, such as amyotrophic lateral sclerosis (ALS) and progressive bulbar palsy, involve loss of muscle control resulting from death of motor neurons. Although the exact pathogenesis of these syndromes remains elusive, many are caused by genetically inherited mutations. Thus, it is valuable to identify additional genes that can impact motor neuron survival and function. In this report, we describe mice that express globally reduced levels of calcium-modulating cyclophilin ligand (CAML) protein. CAML is an essential component in the transmembrane domain recognition complex (TRC) pathway, responsible for inserting C-terminal tail anchored (TA) proteins into the endoplasmic reticulum membrane. The primary phenotype observed in these mice was rapid development of hind limb weakness and paralysis. Spinal cord sections revealed a loss of motor neuron cell bodies. Targeting CAML loss specifically to neurons using SLICK-H-Cre or synapsin-Cre transgenic mice yielded similar phenotypes, indicating that CAML plays a cell autonomous role in this process. We found that intracellular trafficking was perturbed in cells depleted of CAML, with aberrant release of procathepsin D and defective retention of CD222 within the trans-Golgi network, as well as reduced levels and mislocalization of syntaxin 5 (Stx5). Dysfunctional lysosomes and abnormal protein glycosylation were also revealed in CAML deficient cells, further indicating a defect in Golgi trafficking. In addition, we observed an identical phenotype in mice lacking ASNA1 in neurons, suggesting that CAML's role in sustaining muscle function is related to its involvement in the TRC pathway. Together, these findings implicate motor neuron survival as a key role for the TA protein insertion machinery in mice, which may shed light on the pathogenesis of neuromuscular disease in humans.}, } @article {pmid39823433, year = {2025}, author = {Tindale, A and Cretu, I and Gomez, N and Haynes, R and Meng, H and Mason, MJ and Francis, DP}, title = {Central venous pressure as a method of optimising atrio-ventricular delay after cardiac surgery.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0310905}, pmid = {39823433}, issn = {1932-6203}, mesh = {Humans ; *Central Venous Pressure/physiology ; *Cardiac Surgical Procedures/methods ; Female ; Male ; Aged ; Middle Aged ; Hemodynamics ; Pacemaker, Artificial ; Aged, 80 and over ; }, abstract = {INTRODUCTION: Haemodynamic atrioventricular delay (AVD) optimisation has primarily focussed on signals that are not easy to acquire from a pacing system itself, such as invasive left ventricular catheterisation or arterial blood pressure (ABP). In this study, standard clinical central venous pressure (CVP) signals are tested as a potential alternative.

METHODS: Sixteen patients with a temporary pacemaker after cardiac surgery were studied. AV delay optimisation was performed by alternating between a reference AVD of 120ms and tested settings ranging from 40 to 280ms, with 8 replicates for each setting. Alongside (a) the raw data, three methods of correcting for respiration were tested: (b) limiting analysis to a respiratory cycle, (c) asymmetric least squares (ALS) and (d) discrete wavelet transform (DWT). The utility of a quality control step was tested.

RESULTS: CVP signals were a mirror image of the systolic ABP signals: The four R values were -0.674, -0.692, -0.631, -0.671 respectively (all p<0.001). With quality control, the mirror image was best for DWT (R = -0.76, p<0.001), with the CVP and ABP optima agreeing well (R = 0.78, p<0.001). The automated quality control signal correctly predicted the gap between the AVD optima calculated from ABP and CVP (R = 0.8, p<0.001).

CONCLUSIONS: Central venous pressure signals could be used to optimise AVD, because they have a reliable inverse relationship with ABP when pacemaker settings undergo protocolised testing. However, protocols need careful design to circumvent spontaneous biological variability.}, } @article {pmid39822067, year = {2025}, author = {Zhu, Y and Verkhratsky, A and Chen, H and Yi, C}, title = {Understanding glucose metabolism and insulin action at the blood-brain barrier: Implications for brain health and neurodegenerative diseases.}, journal = {Acta physiologica (Oxford, England)}, volume = {241}, number = {2}, pages = {e14283}, pmid = {39822067}, issn = {1748-1716}, support = {RCJC20231211090018040//Shenzhen Fundamental Research Program/ ; ZDSYS20220606100801003//Shenzhen Fundamental Research Program/ ; 2022B1515020012//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 32170980//National Natural Science Foundation of China/ ; }, mesh = {*Blood-Brain Barrier/metabolism ; Humans ; *Neurodegenerative Diseases/metabolism ; Animals ; *Insulin/metabolism ; *Glucose/metabolism ; Brain/metabolism ; }, abstract = {The blood-brain barrier (BBB) is a highly selective, semipermeable barrier critical for maintaining brain homeostasis. The BBB regulates the transport of essential nutrients, hormones, and signaling molecules between the bloodstream and the central nervous system (CNS), while simultaneously protecting the brain from potentially harmful substances and pathogens. This selective permeability ensures that the brain is nourished and shielded from toxins. An exception to this are brain regions, such as the hypothalamus and circumventricular organs, which are irrigated by fenestrated capillaries, allowing rapid and direct response to various blood components. We overview the metabolic functions of the BBB, with an emphasis on the impact of altered glucose metabolism and insulin signaling on BBB in the pathogenesis of neurodegenerative diseases. Notably, endothelial cells constituting the BBB exhibit distinct metabolic characteristics, primarily generating ATP through aerobic glycolysis. This occurs despite their direct exposure to the abundant oxygen in the bloodstream, which typically supports oxidative phosphorylation. The effects of insulin on astrocytes, which form the glial limitans component of the BBB, show a marked sexual dimorphism. BBB nutrient sensing in the hypothalamus, along with insulin signaling, regulates systemic metabolism. Insulin modifies BBB permeability by regulating the expression of tight junction proteins, angiogenesis, and vascular remodeling, as well as modulating blood flow in the brain. The disruptions in glucose and insulin signaling are particularly evident in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, where BBB breakdown accelerates cognitive decline. This review highlights the critical role of normal glucose metabolism and insulin signaling in maintaining BBB functionality and investigates how disruptions in these pathways contribute to the onset and progression of neurodegenerative diseases.}, } @article {pmid39821843, year = {2025}, author = {Zhang, J and Guo, R and Zhou, Z and Fu, Z and Akogo, HY and Li, Y and Zhang, X and Wang, N and Liu, Y and Li, H and Feng, B and Cui, H and Ma, J}, title = {Neural Stem/Progenitor Cell Therapy in Patients and Animals with Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-analysis.}, journal = {Molecular neurobiology}, volume = {62}, number = {5}, pages = {6521-6536}, pmid = {39821843}, issn = {1559-1182}, support = {81801278//National Natural Science Foundation of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/pathology ; *Neural Stem Cells/transplantation ; Animals ; Humans ; *Stem Cell Transplantation/methods ; Treatment Outcome ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative malady that causes progressive degeneration and loss of motor neuron function in the brain and spinal cord, eventually resulting in muscular atrophy, paralysis, and death. Neural stem/progenitor cell (NSPC) transplantation can improve bodily function in animals and delay disease progression in patients with ALS. This paper summarizes and analyzes the efficacy and safety of neural stem/progenitor cell (NSPC) transplantation as a treatment for ALS, aiming to improve function and delay disease progression in patients. We present a summary of the pathogenic mechanism and causative genes associated with ALS and describe the mechanism and efficacy of NSPC treatment for ALS. We comprehensively searched for relevant English-language articles published between January 1, 2000 and October 1, 2023, across the following five medical databases: PubMed, EMBASE, OVID, Web of Science, and the Cochrane Library. We examined experimental indices of physical function in animals and patients who underwent stem cell transplantation. All statistical analyses were performed via Review Manager 5.4. The study comprised a total of 16 investigations, including 5 clinical studies and 11 animal studies and involving 66 patients and 203 animals. The meta-analysis revealed that the administration of NSPCs appeared to yield positive outcomes in clinical patients, as assessed by the ALS functional rating scale and forced vital capacity. Furthermore, improvements following cell injection were observed in the rotarod test results, the Basso-Beattie-Bresnahan Locomotor Rating Scale score, weight, and survival time. Our meta-analysis, which was grounded in randomized controlled trials, revealed that the transplantation of neural stem/progenitor cells (NSPCs), has potential effects on ALS patients, enhancing the physical function of animals and mitigating degenerative effects in individuals. These underscored the promise of NSPC therapy as a viable treatment option. We report that the transplantation of neural stem/progenitor cells (NSPCs) is promising for enhancing bodily function and slowing the progression of ALS in affected patients. In this review, we summarize the treatment of ALS with NSPCs, evaluating both its efficacy and safety. Through database searches, we identified 16 studies involving 66 patients and 203 animals and analyzed the experimental indices of physical function following stem cell transplantation. The meta-analysis results indicated a positive impact of NSPCs on the clinical conditions of patients and the behavior of animals. A meta-analysis of randomized controlled trials further supported the conclusion that NSPC transplantation has a beneficial effect on improving physical function and mitigating degeneration in ALS patients.}, } @article {pmid39820998, year = {2025}, author = {Hamad, AA and Alkhawaldeh, IM and Nashwan, AJ and Meshref, M and Imam, Y}, title = {Tofersen for SOD1 amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {39820998}, issn = {1590-3478}, abstract = {OBJECTIVE: Tofersen, an antisense oligonucleotide, has recently received FDA and EMA approval for treating amyotrophic lateral sclerosis (ALS) in adults with SOD1 gene mutations. This systematic review and meta-analysis synthesized evidence on tofersen's safety and efficacy in patients with SOD1-related ALS.

METHODS: A comprehensive search of three databases was conducted from inception through October 2024. Eligible studies included clinical trials, observational studies, and case studies. Meta-analyses were conducted using a random-effects model in RevMan.

RESULTS: Twelve studies involving 195 patients treated with tofersen met the inclusion criteria, comprising two randomized controlled trials (RCTs), five cohort studies, one case series, and four case reports. Tofersen demonstrated promising effects, notably reducing SOD1 levels in cerebrospinal fluid and neurofilament light chain (NfL) in plasma, a biomarker strongly correlated with ALS progression and survival. Meta-analysis of RCTs showed a significantly lower rate of decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores from baseline in the tofersen group compared to placebo (SMD = 0.44, 95% CI [0.05 to 0.83], P = 0.03) and a significant reduction in the decline of predicted Slow Vital Capacity (P = 0.005). In a pre-post meta-analysis of five studies, a significant decrease in ALS progression rate (ALSFRS-R decline rate) was observed (MD = -0.28, 95% CI [-0.40 to -0.15], P < 0.0001). Reported adverse events were consistent with ALS progression or procedural effects.

CONCLUSION: Current evidence suggests that tofersen effectively reduces SOD1 and NfL levels and slow disease progression in SOD1 ALS, showing promise as a targeted therapeutic option.}, } @article {pmid39820861, year = {2025}, author = {van Zundert, B and Montecino, M}, title = {Epigenetics in Neurodegenerative Diseases.}, journal = {Sub-cellular biochemistry}, volume = {108}, number = {}, pages = {73-109}, pmid = {39820861}, issn = {0306-0225}, mesh = {Humans ; *Epigenesis, Genetic ; Animals ; *Neurodegenerative Diseases/genetics/metabolism ; Alzheimer Disease/genetics/metabolism ; DNA Methylation ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Frontotemporal Dementia/genetics/pathology ; }, abstract = {Healthy brain functioning requires a continuous fine-tuning of gene expression, involving changes in the epigenetic landscape and 3D chromatin organization. Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) are three multifactorial neurodegenerative diseases (NDDs) that are partially explained by genetics (gene mutations and genetic risk factors) and influenced by non-genetic factors (i.e., aging, lifestyle, and environmental conditions). Examining comprehensive studies of global and locus-specific (epi)genomic and transcriptomic alterations in human and mouse brain samples at the cell-type resolution has uncovered important phenomena associated with AD. First, DNA methylation and histone marks at promoters contribute to transcriptional dysregulation of genes that are directly implicated in AD pathogenesis (i.e., APP), neuroplasticity and cognition (i.e., PSD95), and microglial activation (i.e., TREM2). Second, the presence of AD genetic risk variants in cell-type-specific distal enhancers (i.e., BIN1 in microglia) alters transcription, presumably by disrupting associated enhancer-promoter interactions and chromatin looping. Third, epigenomic erosion is associated with widespread transcriptional disruption and cell identity loss. And fourth, aging, high cholesterol, air pollution, and pesticides have emerged as potential drivers of AD by inducing locus-specific and global epigenetic modifications that impact key AD-related pathways. Epigenetic studies in ALS/FTD also provide evidence that genetic and non-genetic factors alter gene expression profiles in neurons and astrocytes through aberrant epigenetic mechanisms. We additionally overview the recent development of potential new therapeutic strategies involving (epi)genetic editing and the use of small chromatin-modifying molecules (epidrugs).}, } @article {pmid39820267, year = {2025}, author = {Martinez-Thompson, JM and Mazurek, KA and Parra Cantu, C and Naddaf, E and Gogineni, V and Botha, H and Jones, DT and Laughlin, RS and Barnard, L and Staff, NP}, title = {Artificial intelligence models using F-wave responses predict amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf014}, pmid = {39820267}, issn = {1460-2156}, abstract = {Nerve conduction F-wave studies contain critical information about subclinical motor dysfunction which may be used to diagnose patients with amyotrophic lateral sclerosis (ALS). However, F-wave responses are highly variable in morphology, making waveform interpretation challenging. Artificial Intelligence techniques can extract time-frequency features to provide new insights into ALS diagnosis and prognosis. A retrospective analysis was performed on F-wave responses from 46,802 patients. Discrete wavelet transforms were applied to time-series waveform responses after stimulating ulnar, median, fibular, and tibial nerves. Wavelet coefficient statistics, onset age, sex, and BMI were features for training a Gradient Boosting Machine model on 40,095 (5,329 diagnosed with motor neuron disease). Model performance was tested on responses from 689 ALS patients meeting Gold Coast criteria and 689 age- and sex-matched controls. An exploratory analysis examined model performance on cohorts of patients with inclusion body myositis (IBM), cervical radiculopathy, lumbar radiculopathy, or peripheral neuropathy which can mimic ALS symptoms. Factors affecting survival were estimated through cox proportional hazards regression. The model trained using wavelet-features on the full waveform had 90% recall, 87% precision, and 88% accuracy. Similar model performance was measured using features only from the M-Wave or F-Wave. Classification probabilities for ALS patients were statistically different from the diagnoses mimicking ALS symptoms (p<0.001, ANOVA, Tukey's post-hoc), Higher model classification probabilities of ALS, older age at onset, and family history of ALS alone or with frontotemporal dementia were factors decreasing survival. Longer diagnostic delay and upper limb onset site were factors increasing survival. Model scores two standard deviations below the mean had 4 months increased survival (two standard deviations below had 3 months decreased survival). Artificial intelligence techniques extracted important information from F-wave responses to estimate a patient's likelihood of ALS and their survival risks. Although the model can make predictions at specific decision threshold as presented here, the true strength of such a model lies in its ability to provide probabilities about whether a patient is likely to have ALS compared to other mimicking diagnoses such as IBM, cervical or lumbar radiculopathy, or peripheral neuropathy. These probabilities provide clinicians with additional information they can use to make the final diagnosis with greater confidence and precision. Integrating such a model into the clinical workflow could help clinicians diagnose ALS sooner and manage treatment based on estimated survival, which may improve outcomes and patients' quality of life.}, } @article {pmid39819944, year = {2025}, author = {Kristensen, RK and Andersen, PT and Bilenberg, N and Milling, ED and Dalgaard Guldager, J}, title = {Mapping the landscape and evidence of cross-sectoral collaboration models targeting individuals referred for assessment of attention-deficit hyperactivity disorder or autism spectrum disorder: protocol for a scoping review.}, journal = {BMJ open}, volume = {15}, number = {1}, pages = {e088850}, pmid = {39819944}, issn = {2044-6055}, mesh = {Humans ; *Attention Deficit Disorder with Hyperactivity ; *Autism Spectrum Disorder ; Research Design ; Review Literature as Topic ; Cooperative Behavior ; Referral and Consultation ; }, abstract = {INTRODUCTION: Neurodevelopmental disorders, notably attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), present substantial challenges in mental health. Individuals referred for assessment in a psychiatric unit experience complex needs. This implies that their needs necessitate coordination across multiple sectors. Cross-sectoral collaboration models have emerged as essential strategies for addressing the complexities of these disorders. However, evidence of their existence, implementation and success remains limited. This protocol aims to outline a scoping review where we will explore existing collaboration models, evaluate their implementation and gain an understanding of how cross-sectoral collaboration models can be developed to ultimately benefit individuals referred for assessment of ADHD or ASD.

METHODS AND ANALYSIS: This proposed scoping review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. A comprehensive search will be conducted across PubMed, CINAHL, Embase, PsycINFO and Google Scholar, as well as grey literature sources, between 1 December 2024 and 1 January 2025. Inclusion criteria will encompass studies focusing on cross-sectoral collaboration for individuals referred for assessment of ADHD or ASD, published in English, Danish, Norwegian or Swedish. The search will use a three-block search string, with iterative refinement guided by familiarity with the evidence base. Data extraction will involve study characteristics and implementation details, using the Consolidated Framework for Implementation Research in combination with Proctor et al's implementation outcomes framework. Results will be synthesised into descriptive tables, providing a comprehensive mapping of existing models and emphasising implementation feasibility.

ETHICS AND DISSEMINATION: Ethical approval is not required for this protocol since it involves the review of existing literature without the involvement of human participants or personal data. Findings will be disseminated at national and international conferences and will be integrated into future efforts to develop cross-sectoral collaboration models in Denmark.}, } @article {pmid39819841, year = {2025}, author = {Cintora-Sanz, AM and Horrillo-García, C and Quesada-Cubo, V and Pérez-Alonso, AM and Gutiérrez-Misis, A}, title = {Prevalence and Economic Impact of Acute Respiratory Failure in the Prehospital Emergency Medical Service of the Madrid Community: Retrospective Cohort Study.}, journal = {JMIR public health and surveillance}, volume = {11}, number = {}, pages = {e66179}, pmid = {39819841}, issn = {2369-2960}, mesh = {Humans ; Spain/epidemiology ; Retrospective Studies ; *Emergency Medical Services/economics/statistics & numerical data ; *Respiratory Insufficiency/epidemiology/therapy ; Male ; Aged ; Female ; *COVID-19/epidemiology ; Prevalence ; Middle Aged ; Aged, 80 and over ; Adult ; Health Care Costs/statistics & numerical data ; Cohort Studies ; Acute Disease ; }, abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), and acute pulmonary edema (APE) are serious illnesses that often require acute care from prehospital emergency medical services (EMSs). These respiratory diseases that cause acute respiratory failure (ARF) are one of the main reasons for hospitalization and death, generating high health care costs. The prevalence of the main respiratory diseases treated in a prehospital environment in the prepandemic period and during the COVID-19 pandemic in Spain is unknown. The Madrid Community EMS is a public service that serves all types of populations and represents an epidemiological reference for supporting a population of 6.4 million inhabitants. The high volume of patients treated by Madrid's medical advanced life supports (ALSs) allows us to analyze this little-studied problem.

OBJECTIVES: Our goal was to lay the groundwork for comprehensive data collection and surveillance of respiratory failure, with an emphasis on the most prevalent diseases that cause it, an aspect that has been largely overlooked in previous initiatives. By achieving these objectives, we hope to inform efforts to address respiratory failure and establish a standardized methodology and framework that can facilitate expansion to a continuous community-wide registry in Madrid, driving advances in emergency care and care practices in these pathologies. The aim of this retrospective observational study was to determine the pathologies that have mainly caused respiratory failure in patients and required medicalized ALS and to evaluate the cost of care for these pathologies collected through this pilot registry.

METHODS: A multicenter descriptive study was carried out in the Madrid Community EMS. The anonymized medical records of patients treated with medical ALS, who received any of the following medical diagnoses, were extracted: ARF not related to chronic respiratory disease, ARF in chronic respiratory failure, exacerbations of COPD, APE, CHF, and bronchospasm (not from asthma or COPD). The prevalence of each pathology, its evolution from 2014 to 2020, and the economic impact of the Medical ALSs were calculated.

RESULTS: The study included 96,221 patients. The most common pathology was exacerbation of COPD, with a prevalence of 0.07% in 2014; it decreased to 0.03% in 2020. CHF followed at 0.06% in 2014 and 0.03% in 2020. APE had a prevalence of 0.01% in 2014, decreasing to 0.005% in 2020 with the pandemic. The greatest economic impact was on exacerbation of COPD in 2015, with an annual cost of €2,726,893 (which equals to US $2,864,628).

CONCLUSIONS: COPD exacerbations had the higher prevalence in the Madrid region among the respiratory diseases studied. With the COVID-19 pandemic, the prevalence and costs of almost all these diseases decreased, except for ARF not related to chronic disease. The cost of these pathologies over 5 years was €58,791,031 (US $61,832,879).}, } @article {pmid39819742, year = {2025}, author = {Xu, B and Lei, X and Yang, Y and Yu, J and Chen, J and Xu, Z and Ye, K and Zhang, J}, title = {Peripheral proteinopathy in neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {2}, pmid = {39819742}, issn = {2047-9158}, support = {82020108012//National Natural Science Foundation of China/ ; 82371250//National Natural Science Foundation of China/ ; LY24H090006//Natural Science Foundation of Zhejiang Province/ ; LZ23H090002//Natural Science Foundation of Zhejiang Province/ ; 2024C03098//Key Research and Development Program of Zhejiang Province/ ; 2024SSYS0018//Key Research and Development Program of Zhejiang Province/ ; ZR2022QH177//Natural Science Foundation of Shandong Province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; alpha-Synuclein/metabolism ; }, abstract = {Proteinopathies in neurology typically refer to pathological changes in proteins associated with neurological diseases, such as the aggregation of amyloid β and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease and multiple system atrophy, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis and frontotemporal dementia. Interestingly, these proteins are also commonly found in peripheral tissues, raising important questions about their roles in neurological disorders. Multiple studies have shown that peripherally derived pathological proteins not only travel to the brain through various routes, aggravating brain pathology, but also contribute significantly to peripheral dysfunction, highlighting their crucial impact on neurological diseases. Investigating how these peripherally derived proteins influence the progression of neurological disorders could open new horizons for achieving early diagnosis and treatment. This review summarizes the distribution, transportation pathways, and pathogenic mechanisms of several neurodegenerative disease-related pathological proteins in the periphery, proposing that targeting these peripheral pathological proteins could be a promising strategy for preventing and managing neurological diseases.}, } @article {pmid39819257, year = {2025}, author = {Barton, M and Roman, A and Spencer, K and Cheng, L and Baylor, C}, title = {Examining the perspectives of augmentative and alternative communication (AAC) specialists on conducting AAC evaluations with people with amyotrophic lateral sclerosis via telehealth.}, journal = {Augmentative and alternative communication (Baltimore, Md. : 1985)}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/07434618.2024.2443669}, pmid = {39819257}, issn = {1477-3848}, abstract = {The purpose of this study was to explore what speech-language pathologists (SLPs) who are AAC specialists see as advantages and disadvantages of providing AAC services via telehealth, how well tele-AAC assessments align with guidelines for in-person assessments, and how SLPs' perspectives of tele-AAC services changed post-COVID. Fifteen SLPs who are AAC specialists and experienced working with people with amyotrophic lateral sclerosis watched videos of speech generating device (SGD) assessments conducted via telehealth for eight people with amyotrophic lateral sclerosis. Using a checklist based on the AAC Clinical Assessment Project (AAC-CAP), the SLPs rated how comparable remote assessment was to in-person assessment, and described advantages and challenges. Across checklist elements, most participants rated AAC assessment via telemedicine as "same/comparable" to in-person assessment. The most common advantages of tele-AAC assessment were that tele-AAC was more functional, increased care partner availability, and increased clients' comfort at home. The most common challenges were technical difficulties and a limited comprehensive assessment due to the remote modality. Tele-AAC should be considered a viable assessment option as it may increase equitable access to care for more people with amyotrophic lateral sclerosis. Tools such as the AAC-CAP may help generalist SLPs increase their comfort and proficiency providing AAC services.}, } @article {pmid39818026, year = {2025}, author = {Choi, Y and Jung, HJ and Jung, HK and Jeong, E and Kim, S and Kim, JY and Lee, EJ and Lim, YM and Kim, H}, title = {In vivo imaging markers of glymphatic dysfunction in amyotrophic lateral sclerosis: Analysis of ALPS index and choroid plexus volume.}, journal = {Journal of the neurological sciences}, volume = {469}, number = {}, pages = {123393}, doi = {10.1016/j.jns.2025.123393}, pmid = {39818026}, issn = {1878-5883}, mesh = {*Glymphatic System/diagnostic imaging/pathology ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *Choroid Plexus/diagnostic imaging ; Organ Size ; *Biomarkers/analysis ; Humans ; Male ; Female ; Middle Aged ; Aged ; Sensitivity and Specificity ; Diffusion Tensor Imaging ; Magnetic Resonance Imaging ; }, abstract = {BACKGROUND: The glymphatic system, essential for brain waste clearance, has been implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Emerging imaging markers, such as the analysis along the perivascular space (ALPS) index and choroid plexus volume (CPV), may provide insights into glymphatic function, but their relevance to ALS remains unclear.

OBJECTIVE: To assess glymphatic dysfunction in ALS patients using the ALPS index and CPV.

METHODS: In this prospective single-center study, we analyzed 51 ALS patients and 51 age- and sex-matched healthy controls (HC). The ALPS index was calculated using diffusion tensor imaging, and 3D T1-weighted MRI was used for automated estimation of CPV and its fraction (CPV/total intracranial volume). Diagnostic performance was assessed using area under the receiver operating curve (AUC). Correlations between imaging markers and clinical parameters were also examined.

RESULTS: ALS patients had a significantly lower ALPS index (ALS: 1.45 ± 0.15; HC: 1.55 ± 0.16; p = 0.002) and higher CPV fraction (ALS: 0.12 ± 0.04 %; HC: 0.10 ± 0.02 %; p < 0.001). The ALPS index and CPV fraction had AUCs of 0.70 and 0.72, respectively. A significant inverse correlation was observed between the ALPS index and CPV fraction (r = -0.31, p = 0.002). Both markers correlated with aging but not with clinical disability or progression rate.

CONCLUSION: This study identifies glymphatic dysfunction in ALS, as evidenced by changes in the ALPS index and CPV. Larger studies are warranted to validate these findings and assess their potential as biomarkers for ALS.}, } @article {pmid39817908, year = {2025}, author = {Aikio, M and Odeh, HM and Wobst, HJ and Lee, BL and Chan, Ú and Mauna, JC and Mack, KL and Class, B and Ollerhead, TA and Ford, AF and Barbieri, EM and Cupo, RR and Drake, LE and Smalley, JL and Lin, YT and Lam, S and Thomas, R and Castello, N and Baral, A and Beyer, JN and Najar, MA and Dunlop, J and Gitler, AD and Javaherian, A and Kaye, JA and Burslem, GM and Brown, DG and Donnelly, CJ and Finkbeiner, S and Moss, SJ and Brandon, NJ and Shorter, J}, title = {Opposing roles of p38α-mediated phosphorylation and PRMT1-mediated arginine methylation in driving TDP-43 proteinopathy.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115205}, pmid = {39817908}, issn = {2211-1247}, support = {K99 AG075242/AG/NIA NIH HHS/United States ; T32 AG000255/AG/NIA NIH HHS/United States ; R01 NS127187/NS/NINDS NIH HHS/United States ; R21 AG065854/AG/NIA NIH HHS/United States ; R35 GM142505/GM/NIGMS NIH HHS/United States ; F32 NS108598/NS/NINDS NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; R01 LM013617/LM/NLM NIH HHS/United States ; F31 AG060672/AG/NIA NIH HHS/United States ; T32 GM008275/GM/NIGMS NIH HHS/United States ; F31 NS087676/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Phosphorylation ; *Protein-Arginine N-Methyltransferases/metabolism ; Methylation ; *DNA-Binding Proteins/metabolism ; *TDP-43 Proteinopathies/metabolism/pathology ; *Mitogen-Activated Protein Kinase 14/metabolism ; *Arginine/metabolism ; Repressor Proteins/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Motor Neurons/metabolism/pathology ; Mice ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation of p38 mitogen-activated protein kinase (MAPK) is implicated in ALS. However, it is unclear how p38 MAPK affects TDP-43 proteinopathy. Here, we show that p38α MAPK inhibition reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity. Remarkably, p38α MAPK inhibition mitigates aberrant TDP-43 phenotypes in diverse ALS patient-derived motor neurons. p38α MAPK phosphorylates TDP-43 at pathological S409/S410 and S292, which reduces TDP-43 liquid-liquid phase separation (LLPS) but allows pathological TDP-43 aggregation. Moreover, we establish that PRMT1 methylates TDP-43 at R293. Importantly, S292 phosphorylation reduces R293 methylation, and R293 methylation reduces S409/S410 phosphorylation. Notably, R293 methylation permits TDP-43 LLPS and reduces pathological TDP-43 aggregation. Thus, strategies to reduce p38α-mediated TDP-43 phosphorylation and promote PRMT1-mediated R293 methylation could have therapeutic utility for ALS and related TDP-43 proteinopathies.}, } @article {pmid39817235, year = {2024}, author = {Cicardi, ME and Trotti, D}, title = {C9orf72 role in myeloid cells: new perspectives in the investigation of the neuro-immune crosstalk in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Annals of translational medicine}, volume = {12}, number = {6}, pages = {120}, pmid = {39817235}, issn = {2305-5839}, } @article {pmid39817215, year = {2025}, author = {Liu, SQ and Wang, D and Tang, CC}, title = {Association between age at diagnosis of diabetes and ocular disease: Insights from a recent article.}, journal = {World journal of diabetes}, volume = {16}, number = {1}, pages = {94846}, pmid = {39817215}, issn = {1948-9358}, abstract = {In this article, we discuss Ye et al's recent article on the association between age at diabetes diagnosis and subsequent risk of age-related ocular diseases. The study, which utilized United Kingdom Biobank data, highlighted a strong link between early diabetes onset and major eye conditions, such as cataracts, glaucoma, age-related macular degeneration, and vision loss, independent of glycemic control and disease duration. This finding challenges the previous belief that diabetic eye disease primarily correlates with hyperglycemia. As lifestyles evolve and the age of diabetes diagnosis decreases, understanding this relationship may reveal the complex pathogenesis underlying diabetes-related complications. This editorial summarizes potential mechanisms connecting the age of diabetes onset with four types of ocular diseases, emphasizing the significance of early diagnosis.}, } @article {pmid39817143, year = {2025}, author = {Chew, FY and Tsai, CH and Chang, KH and Chang, YK and Chou, RH and Liu, YJ}, title = {Exosomes as promising frontier approaches in future cancer therapy.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {1}, pages = {100713}, pmid = {39817143}, issn = {1948-5204}, abstract = {In this editorial, we will discuss the article by Tang et al published in the recent issue of the World Journal of Gastrointestinal Oncology. They explored an innovative approach to enhancing gemcitabine (GEM) delivery and efficacy using human bone marrow mesenchymal stem cells (HU-BMSCs)-derived exosomes. The manufacture of GEM-loaded HU-BMSCs-derived exosomes (Exo-GEM) has been optimized. The Tang et al's study demonstrated that Exo-GEM exhibits enhanced cytotoxicity and apoptosis-inducing effects compared to free GEM, highlighting the potential of exosome-based drug delivery systems as a more effective and targeted approach to chemotherapy in pancreatic cancer. Additional in vivo studies are required to confirm the safety and effectiveness of Exo-GEM before it can be considered for clinical use.}, } @article {pmid39817131, year = {2025}, author = {Lampridis, S}, title = {Unraveling the landscape of pediatric pancreatic tumors: Insights from Japan.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {1}, pages = {101477}, pmid = {39817131}, issn = {1948-5204}, abstract = {Pediatric pancreatic tumors, though rare, pose significant diagnostic and management challenges. The recent, 22-year nationwide survey on pediatric pancreatic tumors in Japan by Makita et al offers valuable insights into this uncommon entity, revealing striking geographical variations and questioning current treatment paradigms. This editorial commentary analyzes the study's key findings, including the predominance of solid pseudopapillary neoplasms and their younger age of onset, which contrast sharply with Western data. It explores the implications for clinical practice and research, emphasizing the need for population-specific approaches to diagnosis and treatment. The revealed limited institutional experience and surgical management patterns prompt a reevaluation of optimal care delivery for these complex cases, suggesting benefits of centralizing healthcare services. Furthermore, the commentary advocates for international collaborative studies to elucidate the genetic, environmental, and lifestyle factors influencing the development and progression of pediatric pancreatic tumors across diverse populations. It also outlines future directions, calling for advancements in precision medicine and innovative care delivery models to improve global patient outcomes. Unraveling Makita et al's findings within the broader landscape of pediatric oncology can stimulate further research and clinical advancements in managing pancreatic and other rare tumors in children.}, } @article {pmid39816800, year = {2025}, author = {Shokr, MM and Badawi, GA and Elshazly, SM and Zaki, HF and Mohamed, AF}, title = {Sigma 1 Receptor and Its Pivotal Role in Neurological Disorders.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {1}, pages = {47-65}, pmid = {39816800}, issn = {2575-9108}, abstract = {Sigma 1 receptor (S1R) is a multifunctional, ligand-activated protein located in the membranes of the endoplasmic reticulum (ER). It mediates a variety of neurological disorders, including epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease. The wide neuroprotective effects of S1R agonists are achieved by a variety of pro-survival and antiapoptotic S1R-mediated signaling functions. Nonetheless, relatively little is known about the specific molecular mechanisms underlying S1R activity. Many studies on S1R protein have highlighted the importance of maintaining normal cellular homeostasis through its control of calcium and lipid exchange between the ER and mitochondria, ER-stress response, and many other mechanisms. In this review, we will discuss S1R different cellular localization and explain S1R-associated biological activity, such as its localization in the ER-plasma membrane and Mitochondrion-Associated ER Membrane interfaces. While outlining the cellular mechanisms and important binding partners involved in these processes, we also explained how the dysregulation of these pathways contributes to neurodegenerative disorders.}, } @article {pmid39816195, year = {2025}, author = {Yildiz, O and Hunt, GP and Schroth, J and Dhillon, G and Spargo, TP and Al-Chalabi, A and Koks, S and Turner, MR and Shaw, PJ and Henson, SM and Iacoangeli, A and Malaspina, A}, title = {Lipid-mediated resolution of inflammation and survival in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {1}, pages = {fcae402}, pmid = {39816195}, issn = {2632-1297}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Neuroinflammation impacts on the progression of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Specialized pro-resolving mediators trigger the resolution of inflammation. We investigate the specialized pro-resolving mediator blood profile and their receptors' expression in peripheral blood mononuclear cells in relation to survival in ALS. People living with ALS (pwALS) were stratified based on bulbar versus limb onset and on key progression metrics using a latent class model, to separate faster progressing from slower progressing ALS. Specialized pro-resolving mediator blood concentrations were measured at baseline and in one additional visit in 20 pwALS and 10 non-neurological controls (Cohort 1). Flow cytometry was used to study the GPR32 and GPR18 resolvin receptors' expression in peripheral blood mononuclear cells from 40 pwALS and 20 non-neurological controls (Cohort 2) at baseline and in two additional visits in 17 pwALS. Survival analysis was performed using Cox proportional hazards models, including known clinical predictors and GPR32 and GPR18 mononuclear cell expression. Differential expression and linear discriminant analyses showed that plasma resolvins were able to distinguish phenotypic variants of ALS from non-neurological controls. RvE3 was elevated in blood from pwALS, whilst RvD1, RvE3, RvT4 and RvD1n-3 DPA were upregulated in A-S and RvD2 in A-F. Compared to non-neurological controls, GPR32 was upregulated in monocytes expressing the active inflammation-suppressing CD11b[+] integrin from fast-progressing pwALS, including those with bulbar onset disease (P < 0.0024), whilst GPR32 and GPR18 were downregulated in most B and T cell subtypes. Only GPR18 was upregulated in naïve double positive Tregs, memory cytotoxic Tregs, senescent late memory B cells and late senescent CD8[+] T cells from pwALS compared to non-neurological controls (P < 0.0431). Higher GPR32 and GPR18 median expression in blood mononuclear cells was associated with longer survival, with GPR32 expression in classical monocytes (hazard ratio: 0.11, P = 0.003) and unswitched memory B cells (hazard ratio: 0.44, P = 0.008) showing the most significant association, along with known clinical predictors. Low levels of resolvins and downregulation of their membrane receptors in blood mononuclear cells are linked to a faster progression of ALS. Higher mononuclear cell expression of resolvin receptors is a predictor of longer survival. These findings suggest a lipid-mediated neuroprotective response that could be harnessed to develop novel therapeutic strategies and biomarkers for ALS.}, } @article {pmid39814005, year = {2025}, author = {Teive, HAG and Coutinho, L and Cardoso, FEC and Tsuji, S}, title = {Neurology pioneers in Japan.}, journal = {Arquivos de neuro-psiquiatria}, volume = {83}, number = {1}, pages = {1-3}, pmid = {39814005}, issn = {1678-4227}, mesh = {*Neurology/history ; Japan ; History, 20th Century ; History, 19th Century ; Humans ; }, abstract = {The pioneers of neurology in Japan were professors Hiroshi Kawahara and Kinnosuke Miura. Kawahara published the first description of progressive bulbar palsy and wrote the first neurology textbook in Japan. Miura, on the other hand, published studies about amyotrophic lateral sclerosis, in addition to participating in the founding of the Japanese Society of Neurology. The influence of European neurology, particularly French and German, in the figures of Professor Jean-Martin Charcot and Professor Erwin Bälz, was fundamental in the consolidation of neurology in Japan.}, } @article {pmid39813104, year = {2025}, author = {Corti, S and Hedlund, E}, title = {Intrinsic neuronal resilience as a tool for therapeutic discovery.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {4}, pages = {1058-1061}, pmid = {39813104}, issn = {1460-2156}, support = {RF-2018-12366357//MoH/ ; //Ricerca Corrente 2024/ ; 2020-01049//The Swedish Research Council/ ; //Radala Foundation for ALS Research/ ; FO2023-0346//The Swedish Brain Foundation/ ; //Olov Thon's Foundation/ ; 233021//Åhlen Foundation/ ; //Ollie & Elof Ericssons Foundation to E.H./ ; }, abstract = {Corti and Hedlund argue that understanding the molecular underpinnings of neuronal resilience and vulnerability to neurodegenerative diseases such as ALS is key to identifying new therapeutic targets.}, } @article {pmid39813072, year = {2025}, author = {Raines, C and Mefferd, A}, title = {Disease-Specific Speech Movement Characteristics of the Tongue and Jaw.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {}, number = {}, pages = {1-14}, doi = {10.1044/2024_JSLHR-24-00351}, pmid = {39813072}, issn = {1558-9102}, support = {R01 DC019648/DC/NIDCD NIH HHS/United States ; R03 DC015075/DC/NIDCD NIH HHS/United States ; }, abstract = {PURPOSE: To advance our understanding of disease-specific articulatory impairment patterns in speakers with dysarthria, this study investigated the articulatory performance of the tongue and jaw in speakers with differing neurological diseases (Parkinson's disease [PD], amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease).

METHOD: Fifty-seven speakers with dysarthria and 30 controls produced the sentence "Buy Kaia a kite" five times. A three-dimensional electromagnetic articulography was used to record the articulatory movements of the posterior tongue and jaw. Sentence-length kinematic measures (e.g., duration, tongue range of motion [ROM], jaw ROM, tongue speed, jaw speed) were extracted.

RESULTS: Results revealed significant group effects for the duration, jaw ROM, and tongue speed but not for tongue ROM. Post hoc pairwise comparisons revealed more significant between-groups differences for duration and jaw ROM than for tongue speed. Statistically significant findings between clinical groups were predominantly driven by the difference between speakers with PD and speakers of other clinical groups.

CONCLUSIONS: Reduced jaw ROM and trends toward reduced tongue ROM confirm hypokinesia as a distinguishing motor feature of speakers with PD. However, deviancies in speed or movement duration did not emerge as a distinguishing motor feature for any of the four studied clinical groups. Nevertheless, movement duration, but not movement speed, may be useful to index dysarthria severity.}, } @article {pmid39812841, year = {2025}, author = {Didcote, L and Vitoratou, S and Al-Chalabi, A and Goldstein, LH}, title = {Predicting ALS informant distress from cognitive and behavioural change in people with ALS.}, journal = {Journal of neurology}, volume = {272}, number = {2}, pages = {144}, pmid = {39812841}, issn = {1432-1459}, support = {Goldstein/Oct17/892-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology/diagnosis ; Male ; Female ; Middle Aged ; Aged ; *Cognitive Dysfunction/etiology/diagnosis ; *Caregivers/psychology ; *COVID-19/complications ; Depression/etiology/diagnosis ; Psychological Distress ; Anxiety/etiology/diagnosis ; Adult ; }, abstract = {BACKGROUND: The cognitive and behavioural changes that occur in around 50% of people with amyotrophic lateral sclerosis (ALS) may significantly affect people around them, contributing to heightened burden, anxiety, and depression. Despite existing evidence linking behavioural impairment to caregiver distress, the role of cognitive impairment remains less clear, with mixed findings on its impact.

METHODS: This study assessed the influence of cognitive and behavioural impairments in people with ALS on the distress of their nominated informants. The data were collected face-to-face and remotely due to the COVID-19 pandemic. The cognitive and behavioural impairments were measured using established screening tools. Informants' distress was evaluated through composite measures of burden, anxiety, and depression. Regression analyses were employed to determine the predictive value of cognitive and behavioural impairment on informant distress.

RESULTS: A total of 98 ALS patients and 84 informants participated. Behavioural impairment predicted informant distress across various tools. In contrast, cognitive impairment was a less consistent predictor of informant distress across screening measures and did not significantly interact with behavioural impairment in predicting distress. Administration mode did not affect predictive relationships.

CONCLUSIONS: Behavioural impairment in ALS significantly predicts informant distress, with varying predictive power across different screening tools. Cognitive impairment also affects informant distress, but its impact is less substantial compared to behavioural factors. The interaction between cognitive and behavioural impairments did not significantly predict informant distress.}, } @article {pmid39812044, year = {2025}, author = {Liu, B and Chen, L and Chen, H and Pan, J and Yu, C}, title = {Bioinformatics Analysis Reveals Microrchidia Family Genes as the Prognostic and Therapeutic Markers for Colorectal Cancer.}, journal = {Endocrine, metabolic & immune disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715303367767241231113110}, pmid = {39812044}, issn = {2212-3873}, abstract = {AIM: The aim of this study is to examine the role of the microrchidia (MORC) family, a group of chromatin remodeling proteins, as the therapeutic and prognostic markers for colorectal cancer (CRC).

BACKGROUND: MORC protein family genes are a highly conserved nucleoprotein superfamily whose members share a common domain but have distinct biological functions. Previous studies have analyzed the roles of MORCs as epigenetic regulators and chromatin remodulators; however, the involvement of MORCs in the development and pathogenesis of CRC was less examined.

OBJECTIVE: The current work examined the role of the MORCs as the therapeutic and prognostic markers for CRC.

METHODS: The expressions and prognostic significance of MORC family genes in CRC were explored. The role of these genes in tumor immunity was comprehensively analyzed in terms of their functions in immune cell infiltration, tumor microenvironment (TME), and their interaction with immune regulatory genes such as immunosuppressive genes, immune checkpoints and immunostimulatory genes. The relations between MORC family genes, tumor mutation burden (TMB), DNA, mismatch repair (MMR), RNA methylation, microsatellite instability (MSI), and drug sensitivity were investigated using the R statistical software. The expressions of MORC4 in 150 CRC tissues and 60 paracancer tissues were detected by immunohistochemical method. CRC cell proliferation, migration, and invasion were measured by cell counting kit-8 (CCK-8), scratch assay, and transwell cell invasion assay.

RESULTS: The expressions of MORC2 and MORC4 were significantly upregulated, whereas those of MORC1 and MORC3 were noticeably downregulated in CRC in comparison to their expressions in normal colorectal mucosal tissues. Patients with high-expressed MORC2 showed a more unfavorable prognosis than those with a low MORC2 level. Functional annotation analysis identified 100 MORC family genes with the most significant negative or positive correlations to diabetic cardiomyopathy, amyotrophic lateral sclerosis, oxidative phosphorylation, Huntington's disease, thermogenesis, Parkinson's disease, olfactory transduction, Alzheimer's disease, prion disease. MORC3 expression was positively correlated with Stromal score, Immune score and ESTIMATE score, while MORC2 expression was negatively related to the three scores in CRC, these correlations were not statistically significant. Additionally, the MORC family genes were significantly positively correlated with tumor-infiltrating immune cells such as T helper cells and exhibited close relations to some immunosuppressive genes such as CXCR4 and PVR, immunostimulatory genes such as TGFBR1, KDR, and CD160 as well as some immune checkpoint genes. It was found that the expressions of some members of MORC family genes were positively correlated with DNA methylation, MSI, TMB, MMRs, and drug sensitivity in CRC and that the mRNA and protein levels of MORC4 were remarkably upregulated in CRC tissues than in adjacent normal tissues (P<0.05). In the MORC4 knockdown group, DLD-1 cell proliferation was more inhibited than in the negative control (NC) and siRNA groups (P<0.05). Furthermore, the migratory capacity of DLD-1 cells and the number of cells crossing the basement membrane in the MORC4 knockdown group were reduced compared to the NC and siRNA groups (all P<0.05).

CONCLUSION: The expressions of MORC family genes were significantly different in CRC samples, which was related to the immune cell infiltration and prognosis of CRC. Thus, the MORC family genes were considered as markers for indicating the clinical immunotherapy and prognostic outcome of CRC.}, } @article {pmid39811452, year = {2024}, author = {Li, R and Bao, T and Li, B and Xia, P and Zhang, T and Zhang, H and Huang, F}, title = {Effectiveness and safety of traditional Chinese therapies intreating patients with amyotrophic lateral sclerosis: a protocol for systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1519513}, pmid = {39811452}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a chronic, progressive disease that affects both upper and lower motor neurons. Some physicians have used traditional Chinese therapies (TCT) to treat ALS. However, there has been no systematic review or meta-analysis to evaluate the effectiveness and safety of TCT interventions. This review aims to analyze the effects of TCT interventions for patients with amyotrophic lateral sclerosis.

METHODS AND ANALYSIS: This study will include randomized, non-randomized, and quasi-experimental clinical trials, with participants being any age Amyotrophic Lateral Sclerosis (ALS) patients who have undergone TCT treatment. Two researchers will independently search databases including CENTRAL, PubMed, PEDro, EMBASE, CNKI, CBM, and SPORTDiscus, without restrictions on language or publication date. These researchers will independently screen titles and abstracts and extract data from the included studies. If deemed suitable for meta-analysis, data synthesis will be conducted using Review Manager V.5.3 software; any discrepancies will be resolved by a third researcher. The meta-analysis will compare the effects of TCT with placebo or other interventions. The main endpoint evaluated was the decrease in the overall score of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; scoring from 0 to 48, where higher scores denote greater functionality) over a period of 24 weeks. Additional endpoints included the reduction rates in isometric muscle power, levels of phosphorylated axonal neurofilament H subunits in plasma, and slow vital capacity measurements. Furthermore, the study monitored the duration until occurrence of death, tracheostomy, or the need for long-term ventilation, as well as the time until death, tracheostomy, long-term ventilation, or hospital admission.

ETHICS AND DISSEMINATION: Throughout the entire process of this systematic review, no personal information was used, hence ethical review is not required. The results of this meta-analysis will be disseminated through publication in peer-reviewed journals and/or conference presentations.}, } @article {pmid39810199, year = {2025}, author = {Eck, RJ and Valdmanis, PN and Liachko, NF and Kraemer, BC}, title = {Alternative 3' UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLD.}, journal = {Molecular brain}, volume = {18}, number = {1}, pages = {1}, pmid = {39810199}, issn = {1756-6606}, support = {RF1 AG078374/AG/NIA NIH HHS/United States ; F99AG088436/NH/NIH HHS/United States ; R01 AG066729/AG/NIA NIH HHS/United States ; IK6 BX006467/BX/BLRD VA/United States ; I01 BX005762/BX/BLRD VA/United States ; IK6BX006467//U.S. Department of Veterans Affairs/ ; R21AG082032/NH/NIH HHS/United States ; R01AG066729/NH/NIH HHS/United States ; RF1AG078374/NH/NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Polyadenylation ; *3' Untranslated Regions/genetics ; *Disease Models, Animal ; Humans ; DNA-Binding Proteins/metabolism/genetics ; Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; Mice ; }, abstract = {Recent research has highlighted widespread dysregulation of alternative polyadenylation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Here, we identify significant disruptions to 3` UTR polyadenylation in the ALS/FTLD-TDP mouse model rNLS8 that correlate with changes in gene expression and protein levels through the re-analysis of published RNA sequencing and proteomic data. A subset of these changes are shared with TDP-43 knock-down mice suggesting depletion of endogenous mouse TDP-43 is a contributor to polyadenylation dysfunction in rNLS8 mice. Some conservation exists between alternative polyadenylation in rNLS8 mice and human disease models including in disease relevant genes and biological pathways. Together, these findings support both TDP-43 loss and toxic gain-of-function phenotypes as contributors to the neurodegeneration in rNLS8 mice, nominating its continued utility as a preclinical model for investigating mechanisms of neurodegeneration in ALS/FTLD-TDP.}, } @article {pmid39810183, year = {2025}, author = {Harvey, C and Nowak, A and Zhang, S and Moll, T and Weimer, AK and Barcons, AM and Souza, CDS and Ferraiuolo, L and Kenna, K and Zaitlen, N and Caggiano, C and Shaw, PJ and Snyder, MP and Mill, J and Hannon, E and Cooper-Knock, J}, title = {Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons.}, journal = {BMC medical genomics}, volume = {18}, number = {1}, pages = {10}, pmid = {39810183}, issn = {1755-8794}, support = {CEGS 5P50HG00773504//NIH (USA)/ ; 899-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; NF-SI-0617-10077//National Institute for Health and Care Research/ ; /WT_/Wellcome Trust/United Kingdom ; IS-BRC-1215-20017//NIHR Sheffield Biomedical Research Centre/ ; 216596/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood ; Humans ; *Motor Neurons/metabolism/pathology ; *Biomarkers/blood ; *DNA Methylation ; Cell-Free Nucleic Acids/blood/genetics ; Induced Pluripotent Stem Cells/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) lacks a specific biomarker, but is defined by relatively selective toxicity to motor neurons (MN). As others have highlighted, this offers an opportunity to develop a sensitive and specific biomarker based on detection of DNA released from dying MN within accessible biofluids. Here we have performed whole genome bisulfite sequencing (WGBS) of iPSC-derived MN from neurologically normal individuals. By comparing MN methylation with an atlas of tissue methylation we have derived a MN-specific signature of hypomethylated genomic regions, which accords with genes important for MN function. Through simulation we have optimised the selection of regions for biomarker detection in plasma and CSF cell-free DNA (cfDNA). However, we show that MN-derived DNA is not detectable via WGBS in plasma cfDNA. In support of our experimental finding, we show theoretically that the relative sparsity of lower MN sets a limit on the proportion of plasma cfDNA derived from MN which is below the threshold for detection via WGBS. Our findings are important for the ongoing development of ALS biomarkers. The MN-specific hypomethylated genomic regions we have derived could be usefully combined with more sensitive detection methods and perhaps with study of CSF instead of plasma. Indeed we demonstrate that neuronal-derived DNA is detectable in CSF. Our work is relevant for all diseases featuring death of rare cell-types.}, } @article {pmid39809929, year = {2025}, author = {Antico, O and Thompson, PW and Hertz, NT and Muqit, MMK and Parton, LE}, title = {Targeting mitophagy in neurodegenerative diseases.}, journal = {Nature reviews. Drug discovery}, volume = {24}, number = {4}, pages = {276-299}, pmid = {39809929}, issn = {1474-1784}, mesh = {Humans ; *Mitophagy/drug effects/physiology ; *Neurodegenerative Diseases/drug therapy/metabolism/genetics ; Animals ; Mitochondria/drug effects/metabolism ; Protein Kinases ; }, abstract = {Mitochondrial dysfunction is a hallmark of idiopathic neurodegenerative diseases, including Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease and Huntington disease. Familial forms of Parkinson disease and amyotrophic lateral sclerosis are often characterized by mutations in genes associated with mitophagy deficits. Therefore, enhancing the mitophagy pathway may represent a novel therapeutic approach to targeting an underlying pathogenic cause of neurodegenerative diseases, with the potential to deliver neuroprotection and disease modification, which is an important unmet need. Accumulating genetic, molecular and preclinical model-based evidence now supports targeting mitophagy in neurodegenerative diseases. Despite clinical development challenges, small-molecule-based approaches for selective mitophagy enhancement - namely, USP30 inhibitors and PINK1 activators - are entering phase I clinical trials for the first time.}, } @article {pmid39809899, year = {2025}, author = {Cui, Y and Arnold, FJ and Li, JS and Wu, J and Wang, D and Philippe, J and Colwin, MR and Michels, S and Chen, C and Sallam, T and Thompson, LM and La Spada, AR and Li, W}, title = {Multi-omic quantitative trait loci link tandem repeat size variation to gene regulation in human brain.}, journal = {Nature genetics}, volume = {57}, number = {2}, pages = {369-378}, pmid = {39809899}, issn = {1546-1718}, mesh = {Humans ; *Quantitative Trait Loci ; *Brain/metabolism ; *Gene Expression Regulation ; Tandem Repeat Sequences/genetics ; Phenotype ; Alzheimer Disease/genetics ; Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Multiomics ; }, abstract = {Tandem repeat (TR) size variation is implicated in ~50 neurological disorders, yet its impact on gene regulation in the human brain remains largely unknown. In the present study, we quantified the impact of TR size variation on brain gene regulation across distinct molecular phenotypes, based on 4,412 multi-omics samples from 1,597 donors, including 1,586 newly sequenced ones. We identified ~2.2 million TR molecular quantitative trait loci (TR-xQTLs), linking ~139,000 unique TRs to nearby molecular phenotypes, including many known disease-risk TRs, such as the G2C4 expansion in C9orf72 associated with amyotrophic lateral sclerosis. Fine-mapping revealed ~18,700 TRs as potential causal variants. Our in vitro experiments further confirmed the causal and independent regulatory effects of three TRs. Additional colocalization analysis indicated the potential causal role of TR variation in brain-related phenotypes, highlighted by a 3'-UTR TR in NUDT14 linked to cortical surface area and a TG repeat in PLEKHA1, associated with Alzheimer's disease.}, } @article {pmid39806943, year = {2024}, author = {Lee, K and Kim, SI and Shim, YM and Kim, EE and Yoo, S and Won, JK and Park, SH}, title = {Current Status and Future Perspective of Seoul National University Hospital-Dementia Brain Bank with Concordance of Clinical and Neuropathological Diagnosis.}, journal = {Experimental neurobiology}, volume = {33}, number = {6}, pages = {295-311}, pmid = {39806943}, issn = {1226-2560}, abstract = {This paper introduces the current status of Seoul National University Hospital Dementia Brain Bank (SNUH-DBB), focusing on the concordance rate between clinical diagnoses and postmortem neuropathological diagnoses. We detail SNUH-DBB operations, including protocols for specimen handling, induced pluripotent stem cells (iPSC) and cerebral organoids establishment from postmortem dural fibroblasts, and adult neural progenitor cell cultures. We assessed clinical-neuropathological diagnostic concordance rate. Between 2015 and September 2024, 162 brain specimens were collected via brain donation and autopsy. The median donor age was 73 years (1-94) with a male-to -female ratio of 2:1. The median postmortem interval was 9.5 hours (range: 2.5-65). Common neuropathological diagnoses included pure Lewy body disease (10.6%), Lewy body disease (LBD) with other brain diseases (10.6%), pure Alzheimer's disease-neuropathological change (ADNC) (6.0%), ADNC with other brain diseases (10.7%), vascular brain injury (15.2%), and primary age-related tauopathy (7.3%). APOE genotype distribution was following: ε3/ε3: 62.3%, ε2/ε3: 9.6%, ε2/ε4: 3.4%, ε3/ε4: 24.0%, and ε4/ε4: 0.7%. Concordance rates between pathological and clinical diagnoses were: ADNC/AD at 42.4%; LBD at 59.0%; PSP at 100%; ALS at 85.7%; Huntington's disease 100%. The varying concordance rates across different diseases emphasize the need for improved diagnostic criteria and biomarkers, particularly for AD and LBD. Tissues have been distributed to over 40 national studies. SNUH-DBB provides high-quality brain tissues and cell models for neuroscience research, operating under standardized procedures and international guidelines. It supports translational research in dementia and neurodegenerative diseases, potentially advancing diagnostic and therapeutic strategies.}, } @article {pmid39806490, year = {2025}, author = {Shen, Y and Zhang, X and Liu, S and Xin, L and Xuan, W and Zhuang, C and Chen, Y and Chen, B and Zheng, X and Wu, R and Lin, Y}, title = {CEST imaging combined with [1]H-MRS reveal the neuroprotective effects of riluzole by improving neurotransmitter imbalances in Alzheimer's disease mice.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {20}, pmid = {39806490}, issn = {1758-9193}, support = {240428226498013//Shantou Science and Technology Project/ ; 213769/SNSF_/Swiss National Science Foundation/Switzerland ; 82020108016//National Natural Science Foundation of China/ ; 82071973//National Natural Science Foundation of China/ ; 2023A1515010326//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2022ZDZX2020//Key Research Platform and Project of Guangdong University/ ; }, mesh = {Animals ; *Riluzole/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Neuroprotective Agents/pharmacology ; Mice ; *Mice, Transgenic ; *Glutamic Acid/metabolism ; *gamma-Aminobutyric Acid/metabolism ; Proton Magnetic Resonance Spectroscopy/methods ; Brain/drug effects/metabolism/diagnostic imaging ; Disease Models, Animal ; Male ; Magnetic Resonance Imaging/methods ; Neurotransmitter Agents/metabolism ; }, abstract = {BACKGROUND: The imbalance of glutamate (Glu) and gamma-aminobutyric acid (GABA) neurotransmitter system plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Riluzole is a Glu modulator originally approved for amyotrophic lateral sclerosis that has shown potential neuroprotective effects in various neurodegenerative disorders. However, whether riluzole can improve Glu and GABA homeostasis in AD brain and its related mechanism of action remain unknown. This study utilized chemical exchange saturation transfer (CEST) imaging combined with proton magnetic resonance spectroscopy ([1]H-MRS) to monitor the dynamic changes of Glu and GABA in riluzole-treated AD mice, aiming to evaluate the efficacy and mechanism of riluzole in AD treatment.

METHODS: GluCEST, GABACEST and [1]H-MRS were used to longitudinally monitor Glu and GABA levels in 3xTg AD mice treated with riluzole (12.5 mg/kg/day) or vehicle for 20 weeks. Magnetic resonance measurements were performed at baseline, 6, 12, and 20 weeks post-treatment. Cognitive performance was assessed using the Morris Water Maze (MWM) at baseline, 10, and 20 weeks. At the study endpoint, immunohistochemistry, Nissl staining, and Western blot were used to evaluate the brain pathology, neuronal survival, and protein expression.

RESULTS: GluCEST, GABACEST and [1]H-MRS consistently revealed higher levels of Glu and GABA in the brain of riluzole-treated AD mice compared to untreated controls, which were associated with improvements in spatial learning and memory. The cognitive improvements significantly correlated with the increased GluCEST signals and Glu levels. Immunohistochemistry and Nissl staining demonstrated that riluzole treatment reduced amyloid-beta (Aβ) deposition, tau hyperphosphorylation, GFAP-positive astrocyte activation, and prevented neuronal loss. Moreover, riluzole upregulated the expression of excitatory amino acid transporter 2 (EAAT2), glutamic acid decarboxylase 65/67 (GAD65/67), and glutamine synthetase (GS), suggesting enhanced neurotransmitter metabolism.

CONCLUSIONS: CEST imaging combined with [1]H-MRS demonstrated the effectiveness of riluzole in modulating Glu- and GABA-related changes and improving cognitive function in 3xTg AD mice, potentially through regulating key proteins involved in neurotransmitter metabolism. These findings suggest riluzole as a therapeutic agent for Alzheimer's disease and highlight the utility of multimodal MR imaging in monitoring treatment response and exploring disease mechanisms.}, } @article {pmid39805247, year = {2025}, author = {Uzunçakmak-Uyanık, H and Yıldız, FG and Tan, E and Temuçin, ÇM}, title = {Thoracic paraspinal muscle concentric needle electrode jitter analysis in electrophysiological diagnosis of ALS.}, journal = {Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology}, volume = {81}, number = {}, pages = {102975}, doi = {10.1016/j.jelekin.2025.102975}, pmid = {39805247}, issn = {1873-5711}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Electromyography/methods ; Male ; Female ; Middle Aged ; *Paraspinal Muscles/physiopathology ; *Electrodes ; Aged ; Needles ; Adult ; }, abstract = {OBJECTIVES: Jitter analysis with concentric needle electrode of the thoracic 9 (T9) paraspinal muscle (PM), where the needle EMG examination at rest is difficult, was performed in both amyotrophic lateral sclerosis (ALS) patients and the controls.

METHODS: For the T9 PM, both upper limit for mean and individual mean consecutive difference (MCD) values and spike numbers were calculated according to jitter values of pairs from controls. In addition to the descriptive statistics, differences between two groups and T9 PM needle EMG and jitter analysis findings of patients were compared (p = 0.05).

RESULTS: Mean MCD median values of T9 PM were 62.8 and 26.2 µs in patient and controls respectively. Upper limit of mean and individual MCDs for the T9 PM were determined as 36.95 μs, 57.95 μs respectively. The differences between controls and patients in terms of all jitter analysis parametres (p < 0.001) and the comparison of patients' T9 PM needle EMG and jitter analysis findings grading were statistically significant (p = 0.029).

CONCLUSION: The T9 PM jitter analysis performed during routine EMG can be used to support the electrophysiological diagnosis of ALS in challenging cases and may contribute to minimizing the number of muscles examined. Furthermore, our study contributed to the T9 PM reference values for jitter analysis.}, } @article {pmid39804774, year = {2025}, author = {Agnihotri, D and Lee, CC and Lu, PC and He, RY and Huang, YA and Kuo, HC and Huang, JJ}, title = {C9ORF72 poly-PR induces TDP-43 nuclear condensation via NEAT1 and is modulated by HSP70 activity.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115173}, doi = {10.1016/j.celrep.2024.115173}, pmid = {39804774}, issn = {2211-1247}, mesh = {*HSP70 Heat-Shock Proteins/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; *C9orf72 Protein/metabolism/genetics ; *RNA, Long Noncoding/metabolism/genetics ; Cell Nucleus/metabolism ; }, abstract = {The toxicity of C9ORF72-encoded polyproline-arginine (poly-PR) dipeptide is associated with its ability to disrupt the liquid-liquid phase separation of intrinsically disordered proteins participating in the formation of membraneless organelles, such as the nucleolus and paraspeckles. Amyotrophic lateral sclerosis (ALS)-related TAR DNA-binding protein 43 (TDP-43) also undergoes phase separation to form nuclear condensates (NCs) in response to stress. However, whether poly-PR alters the nuclear condensation of TDP-43 in ALS remains unclear. In this study, we find that the poly-PR dipeptide enhances the formation of TDP-43 NCs with decreased fluidity. While the non-coding RNA, nuclear-enriched abundant transcript 1 (NEAT1), is essential for the formation of TDP-43 NCs, heat shock protein 70 (HSP70) chaperone maintains their fluidity. Under prolonged poly-PR stress, HSP70 delocalizes from TDP-43 NCs, leading to the oligomerization of TDP-43 within these condensates. This phenomenon is accompanied with TDP-43 mislocalization and increasing cytotoxicity. Our study demonstrates the role of NEAT1 and HSP70 in the aberrant phase transition of TDP-43 NCs under poly-PR stress.}, } @article {pmid39804470, year = {2025}, author = {Edgar, S and Zulhairy-Liong, NA and Ellis, M and Trivedi, S and Zhu, D and Odongo, JO and Goh, KJ and Capelle, DP and Shahrizaila, N and Kennerson, ML and Ahmad-Annuar, A}, title = {ATXN2 polyglutamine intermediate repeats length expansions in Malaysian patients with amyotrophic lateral sclerosis (ALS).}, journal = {Neurogenetics}, volume = {26}, number = {1}, pages = {19}, pmid = {39804470}, issn = {1364-6753}, support = {FRGS/1/2018/SKK08/UM/01/1//Malaysian Ministry of Education Fundamental Research Grant Scheme/ ; IF091-2022//ALS Association Seed Grant/ ; IF095-2023//ALS Association Seed Grant/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Malaysia ; *Ataxin-2/genetics ; Male ; Female ; Middle Aged ; *Trinucleotide Repeat Expansion/genetics ; Adult ; Aged ; Peptides/genetics ; Asian People/genetics ; Genetic Predisposition to Disease ; }, abstract = {Intermediate CAG repeats from 29 to 33 in the ATXN2 gene contributes to the risk of amyotrophic lateral sclerosis (ALS) in European and Asian populations. In this study, 148 ALS patients of multiethnic descent: Chinese (56.1%), Malay (24.3%), Indian (12.8%), others (6.8%) and 100 neurologically normal controls were screened for the ATXN2 CAG repeat expansion. The most common repeat length in both the controls and patients was 22. No familial ALS patients were positive for the intermediate repeat sizes (29-33), while four sporadic patients (2.8%) were positive, with one harbouring a rare ATXN2 homozygous 32 repeat expansion, and a likely pathogenic variant in SPAST. All four patients had limb-onset ALS. Despite representing the smallest ethnic group in our patient cohort, three of the four patients with intermediate repeat sizes were of Indian ancestry. This study, which is the first in Malaysia and Southeast Asia, shows that ATXN2 intermediate risk expansions are relevant to ALS in these populations and will help to inform future genetic testing strategies in the clinic.}, } @article {pmid39803328, year = {2025}, author = {Niu, T and Wang, P and Zhou, X and Liu, T and Liu, Q and Li, R and Yang, H and Dong, H and Liu, Y}, title = {An overlap-weighted analysis on the association of constipation symptoms with disease progression and survival in amyotrophic lateral sclerosis: a nested case-control study.}, journal = {Therapeutic advances in neurological disorders}, volume = {18}, number = {}, pages = {17562864241309811}, pmid = {39803328}, issn = {1756-2856}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing and rare neurodegenerative disease. Therefore, evaluating the risk factors affecting the survival of patients with ALS is crucial. Constipation, a common but overlooked symptom of ALS, can be effectively managed. It is currently unknown whether constipation contributes to the progression and survival of ALS.

OBJECTIVES: This study aimed to investigate the association between constipation and ALS development and survival using a novel overlap-weighted (OW) method to enhance the robustness and reliability of results.

DESIGN: This prospective matching nested case-control (NCC) study was conducted within an ongoing ALS cohort at the Second Hospital of Hebei Medical University. Baseline data were collected from patients meeting the inclusion and exclusion criteria, with constipation as the exposure factor. A 9-month follow-up was conducted, with death as the endpoint event.

METHODS: We primarily used the OW method in NCC studies to examine the association between constipation and ALS development and survival. Weighted Cox proportional hazards model was used to assess risk factors associated with overall survival. Survival differences between the two groups were analyzed using Kaplan-Meier's plots and log-rank tests. Finally, the bioinformatic analysis explored common pathways between ALS and constipation.

RESULTS: Among the 190 patients included, the prevalence of constipation was 50%. Patients with ALS constipation exhibited faster disease progression (p < 0.001), with a positive correlation between constipation severity and progression rate (r = 0.356, p < 0.001). The constipation group had poorer survival before and after OW (log-rank test, p < 0.0001). In the Cox proportional hazards model of 114 patients, constipation was a risk factor for ALS both before (hazard ratio (HR) = 5.840, 95% confidence interval (CI) = 1.504-22.675, p = 0.011) and after (HR = 5.271, 95% CI = 1.241-22.379, p = 0.024) OW.

CONCLUSION: Constipation in individuals with ALS is associated with faster disease progression and reduced survival rates, potentially through the peroxisome proliferator-activated receptor pathway.}, } @article {pmid39802934, year = {2025}, author = {Ogonah, MGT and Botchway, S and Yu, R and Schofield, PW and Fazel, S}, title = {An umbrella review of health outcomes following traumatic brain injury.}, journal = {Nature. Mental health}, volume = {3}, number = {1}, pages = {83-91}, pmid = {39802934}, issn = {2731-6076}, abstract = {While numerous reviews have assessed the association between traumatic brain injury (TBI) and various mental and physical health outcomes, a comprehensive evaluation of the scope, validity, and quality of evidence is lacking. Here we present an umbrella review of a wide range of health outcomes following TBI and outline outcome risks across subpopulations. On 17 May 2023, we searched Embase, Medline, Global Health, PsycINFO, and Cochrane Database of Systematic Reviews for systematic reviews and meta-analyses. We compared risk ratios across different outcomes for risks compared with people without TBI and examined study quality, including heterogeneity, publication bias, and prediction intervals. The study was registered with PROSPERO (CRD42023432255). We identified 24 systematic reviews and meta-analyses covering 24 health outcomes in 31,397,958 participants. The current evidence base indicates an increased risk of multiple mental and physical health outcomes, including psychotic disorders, attention-deficit/hyperactivity disorder, suicide, and depression. Three outcomes-dementia, violence perpetration, and amyotrophic lateral sclerosis-had meta-analytical evidence of at least moderate quality, which suggest targets for more personalized assessment. Health-care services should review how to prevent adverse long-term outcomes in TBI.}, } @article {pmid39801873, year = {2025}, author = {Kumar, AJ and Sathiyaseelan, N and Vinodh, JB and Vignesh, A and Rathi, NK}, title = {Recent Advances in Managing Ankylosing Spondylitis with Andersson Lesion: A Clinical Overview and Case Report.}, journal = {Journal of orthopaedic case reports}, volume = {15}, number = {1}, pages = {21-25}, pmid = {39801873}, issn = {2250-0685}, abstract = {INTRODUCTION: Ankylosing spondylitis (AS) is a chronic inflammatory disorder that primarily affects the spine and sacroiliac joints, leading to pain, stiffness, and progressive thoracolumbar kyphotic deformity. A key complication in advanced AS is the development of Andersson lesions (AL), degenerative vertebral lesions resulting from the disease's progression. These lesions can cause significant mechanical pain, often mistaken for the chronic discomfort associated with AS. The exact cause of AL remains unclear, with hypotheses ranging from spinal stress fractures to delays in the ankylosing process. Understanding AL's pathophysiology is essential for timely diagnosis and effective management.

CASE REPORT: A 52-year-old male presented with a 20-year history of diffuse abdominal pain, later developing insidious lower back pain over the past 2 months. The pain was aggravated by walking and prolonged standing. Physical examination revealed tenderness in the D11 region of the spine, with limited chest expansion and positive findings on the modified Schober's test. Radiographic studies showed irregularities and erosions at the D11-D12 vertebral levels, and magnetic resonance imaging confirmed the presence of an AL associated with asymmetrical bilateral sacroiliitis. The patient tested positive for human leukocyte antigen-B27, supporting a diagnosis of AS with an AL. Medical management, including methotrexate, sulfasalazine, non-steroidal anti-inflammatory drugs, and corticosteroids, led to significant pain reduction and improved mobility. The patient's condition remained stable with continued treatment over a 2-year follow-up period.

CONCLUSION: AL s are chronic, often overlooked complications of AS that can lead to spinal instability and neurological deficits if untreated. Early recognition and management are critical to preventing progressive kyphotic deformities and associated complications. While conservative treatment remains the cornerstone for managing AL, surgical intervention may be required in cases of severe pain, deformity, or neurological involvement. Understanding AL's presentation and treatment options is vital for improving patient outcomes in AS.}, } @article {pmid39801792, year = {2024}, author = {Ansari, U and Wen, J and Syed, B and Nadora, D and Sedighi, R and Nadora, D and Chen, V and Lui, F}, title = {Analyzing the potential of neuronal pentraxin 2 as a biomarker in neurological disorders: A literature review.}, journal = {AIMS neuroscience}, volume = {11}, number = {4}, pages = {505-519}, pmid = {39801792}, issn = {2373-7972}, abstract = {Neuronal pentraxin 2 (NP2) plays a significant role in synaptic plasticity, neuronal survival, and excitatory synapse regulation. Emerging research suggests that NP2 is implicated in the pathogenesis of various neurological disorders, including neurodegenerative diseases, neuropsychiatric disorders, and neuropathies. This literature review extensively analyzes NP2's role in these conditions, thereby highlighting its contributions to synaptic dysfunction, neuroinflammation, and neurotoxic protein aggregation. In Alzheimer's and Parkinson's diseases, NP2 is linked to amyloid-beta aggregation and dopaminergic neuron degeneration, respectively. Additionally, altered NP2 expression is observed in schizophrenia and bipolar disorder, thus suggesting its involvement in synaptic dysfunction and neurotransmitter imbalance. In neuropathic pain and epilepsy, NP2 modulates the synaptic plasticity and inflammatory responses, with altered levels correlating with disease severity. Furthermore, NP2's involvement in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) emphasizes its broad impact on neuronal health. Understanding NP2's multifaceted roles may reveal novel therapeutic targets and improve the clinical outcomes for these neurological disorders. Though the precise role of NP2 remains uncertain, its clinical potential and initial findings justify further investigations into neuronal pentraxins and other related neuroproteins.}, } @article {pmid39801778, year = {2025}, author = {Ngo, HM and Khatib, T and Thai, MT and Kahveci, T}, title = {QOMIC: quantum optimization for motif identification.}, journal = {Bioinformatics advances}, volume = {5}, number = {1}, pages = {vbae208}, pmid = {39801778}, issn = {2635-0041}, abstract = {MOTIVATION: Network motif identification (MI) problem aims to find topological patterns in biological networks. Identifying disjoint motifs is a computationally challenging problem using classical computers. Quantum computers enable solving high complexity problems which do not scale using classical computers. In this article, we develop the first quantum solution, called QOMIC (Quantum Optimization for Motif IdentifiCation), to the MI problem. QOMIC transforms the MI problem using a integer model, which serves as the foundation to develop our quantum solution. We develop and implement the quantum circuit to find motif locations in the given network using this model.

RESULTS: Our experiments demonstrate that QOMIC outperforms the existing solutions developed for the classical computer, in term of motif counts. We also observe that QOMIC can efficiently find motifs in human regulatory networks associated with five neurodegenerative diseases: Alzheimer's, Parkinson's, Huntington's, Amyotrophic Lateral Sclerosis, and Motor Neurone Disease.

Our implementation can be found in https://github.com/ngominhhoang/Quantum-Motif-Identification.git.}, } @article {pmid39801516, year = {2024}, author = {Kamiyama, D and Nishida, Y and Kamiyama, R and Sego, A and Vining, G and Bui, K and Fitch, M and Do, H and Avraham, O and Chihara, T}, title = {The VAPB Axis Precisely Coordinates the Timing of Motoneuron Dendritogenesis in Neural Map Development.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39801516}, issn = {2693-5015}, support = {P40 OD018537/OD/NIH HHS/United States ; R01 NS107558/NS/NINDS NIH HHS/United States ; }, abstract = {In Drosophila motoneurons, spatiotemporal dendritic patterns are established in the ventral nerve cord. While many guidance cues have been identified, the mechanisms of temporal regulation remain unknown. Previously, we identified the actin modulator Cdc42 GTPase as a key factor in this process. In this report, we further identify the upstream factors that activate Cdc42. Using single-cell genetics, FRET-based imaging, and biochemical techniques, we demonstrate that the guanine nucleotide exchange factor Vav is anchored to the plasma membrane via the Eph receptor tyrosine kinase, enabling Cdc42 activation. VAMP-associated protein 33 (Vap33), an Eph ligand supplied non-cell-autonomously, may induce Eph autophosphorylation, initiating downstream signaling. Traditionally known as an ER-resident protein, Vap33 is secreted extracellularly at the onset of Cdc42 activation, acting as a temporal cue. In humans, VAPB-the ortholog of Vap33-is similarly secreted in the spinal cord, and its dysregulation leads to amyotrophic lateral sclerosis type 8 (ALS8) and spinal muscular atrophy (SMA). Our findings provide a framework linking VAPB signaling to motor circuitry formation in both health and disease.}, } @article {pmid39801319, year = {2025}, author = {Oliveira Santos, M and Domingues, S and Simão, S and Gromicho, M and Alves, I and de Carvalho, M}, title = {The Role of Gastrostomy and Noninvasive Ventilation in Primary Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {71}, number = {3}, pages = {450-456}, doi = {10.1002/mus.28346}, pmid = {39801319}, issn = {1097-4598}, mesh = {Humans ; *Gastrostomy ; Female ; Male ; *Noninvasive Ventilation/methods ; Middle Aged ; Retrospective Studies ; *Deglutition Disorders/etiology/therapy ; Aged ; *Respiratory Insufficiency/etiology/therapy ; Adult ; }, abstract = {INTRODUCTION/AIMS: Literature on the role of gastrostomy and noninvasive ventilation (NIV) in primary lateral sclerosis (PLS) is limited. We aim to investigate whether PLS patients develop dysphagia requiring feeding tubes or respiratory failure necessitating NIV.

METHODS: We conducted a retrospective study of PLS patients with a definite diagnosis followed at our center (1994-2024). Patients with marked dysphagia (score < 3 on Question 3 of the ALSFRS-R) received a recommendation for gastrostomy and were divided into two groups: G1/G2 (accepted/declined gastrostomy). We investigated NIV indications due to respiratory failure and compared these patients (G3) to those without respiratory impairment (G4). Demographic, clinical, and neurophysiological data were collected and compared.

RESULTS: Forty-eight patients had a definite diagnosis of PLS. Gastrostomy was recommended to 18 (37.5%), yet only 7 patients (38.9%-G1) consented. The median time to gastrostomy was 77 months. Total survival and survival post-gastrostomy recommendation were not different between G1 and G2. Six PLS patients (12.5%-G3) developed respiratory failure and initiated NIV (median of 63 months). At 63 months, G3 had significantly lower median forced vital capacity (65% vs. 99%; p < 0.001) and phrenic nerve amplitude (0.43 vs. 0.75 mV; p = 0.039), but a greater ALSFRS-R slope (0.34 vs. 0.14; p = 0.046) and shorter survival (35 vs. 94.9 months; p = 0.009) compared to G4.

DISCUSSION: Dysphagia requiring gastrostomy was common in our PLS cohort, but survival after gastrostomy recommendation did not differ between groups. Patients who developed respiratory impairment may represent a distinct group with faster disease progression and shorter survival. Our findings may contribute to a deeper understanding and improved management of PLS.}, } @article {pmid39799559, year = {2025}, author = {Üremiş, N and Üremiş, MM}, title = {Oxidative/Nitrosative Stress, Apoptosis, and Redox Signaling: Key Players in Neurodegenerative Diseases.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {1}, pages = {e70133}, pmid = {39799559}, issn = {1099-0461}, support = {//This research was supported by the Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (grant number: TUB1)./ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Apoptosis ; *Oxidative Stress ; *Nitrosative Stress ; *Oxidation-Reduction ; Animals ; *Signal Transduction ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases are significant health concerns that have a profound impact on the quality and duration of life for millions of individuals. These diseases are characterized by pathological changes in various brain regions, specific genetic mutations associated with the disease, deposits of abnormal proteins, and the degeneration of neurological cells. As neurodegenerative disorders vary in their epidemiological characteristics and vulnerability of neurons, treatment of these diseases is usually aimed at slowing disease progression. The heterogeneity of genetic and environmental factors involved in the process of neurodegeneration makes current treatment methods inadequate. However, the existence of common molecular mechanisms in the pathogenesis of these diseases may allow the development of new targeted therapeutic strategies. Oxidative and nitrosative stress damages membrane components by accumulating ROS and RNS and disrupting redox balance. This process results in the induction of apoptosis, which is important in the pathogenesis of neurodegenerative diseases through oxidative stress. Studies conducted using postmortem human samples, animal models, and cell cultures have demonstrated that oxidative stress, nitrosative stress, and apoptosis are crucial factors in the development of diseases such as Alzheimer's, Parkinson's, Multiple Sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. The excessive production of reactive oxygen and nitrogen species, elevated levels of free radicals, heightened mitochondrial stress, disturbances in energy metabolism, and the oxidation and nitrosylation of cellular macromolecules are recognized as triggers for neuronal cell death. Challenges in managing and treating neurodegenerative diseases require a better understanding of this field at the molecular level. Therefore, this review elaborates on the molecular mechanisms by which oxidative and nitrosative stress are involved in neuronal apoptosis.}, } @article {pmid39799393, year = {2025}, author = {Valenzuela, V and Becerra, D and Astorga, JI and Fuentealba, M and Diaz, G and Bargsted, L and Chacón, C and Martinez, A and Gozalvo, R and Jackson, K and Morales, V and Heras, ML and Tamburini, G and Petrucelli, L and Sardi, SP and Plate, L and Hetz, C}, title = {Artificial enforcement of the unfolded protein response reduces disease features in multiple preclinical models of ALS/FTD.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {3}, pages = {1226-1245}, pmid = {39799393}, issn = {1525-0024}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy ; *Unfolded Protein Response ; Mice ; *Disease Models, Animal ; *Frontotemporal Dementia/genetics/metabolism ; *X-Box Binding Protein 1/metabolism/genetics ; *Endoplasmic Reticulum Stress ; *Dependovirus/genetics ; Humans ; Mice, Transgenic ; Genetic Vectors/administration & dosage/genetics ; C9orf72 Protein/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a spectrum of diseases that share several causative genes, resulting in a combinatory of motor and cognitive symptoms and abnormal protein aggregation. Multiple unbiased studies have revealed that proteostasis impairment at the level of the endoplasmic reticulum (ER) is a transversal pathogenic feature of ALS/FTD. The transcription factor XBP1s is a master regulator of the unfolded protein response (UPR), the main adaptive pathway to cope with ER stress. Here, we provide evidence of suboptimal activation of the UPR in ALS/FTD models under experimental ER stress. To artificially engage the UPR, we intracerebroventricularly administrated adeno-associated viruses (AAVs) to express the active form of XBP1 (XBP1s) in the nervous system of ALS/FTD models. XBP1s expression improved motor performance and extended lifespan of mutant SOD1 mice, associated with reduced protein aggregation. AAV-XBP1s administration also attenuated disease progression in models of TDP-43 and C9orf72 pathogenesis. Proteomic profiling of spinal cord tissue revealed that XBP1s overexpression improved proteostasis and modulated the expression of a cluster of synaptic and cell morphology proteins. Our results suggest that strategies to improve ER proteostasis may serve as a pan-therapeutic strategy to treat ALS/FTD.}, } @article {pmid39799324, year = {2025}, author = {Freiha, J and Grand, E and Marshall, B and Arunchalam, R and Pinto, A and Osman, C}, title = {Amyotrophic lateral sclerosis in a patient with chronic lymphocytic leukaemia and drug related sarcoid-like reaction.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {16}, pmid = {39799324}, issn = {1471-2377}, mesh = {Humans ; Male ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/complications ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Sarcoidosis/diagnosis/complications ; Rituximab/therapeutic use/adverse effects ; Central Nervous System Diseases ; }, abstract = {Sarcoid-like reaction is an immunological reaction that can affect lymph nodes and organs but does not meet the diagnostic criteria for systemic sarcoidosis. Anti-CD20 auto-antibodies have been reported to be responsible for such reactions. There are several reported associations between Chronic lymphocytic leukaemia (CLL), Amyotrophic lateral sclerosis (ALS) and Sarcoid-like reactions (SLR). We report a case of ALS developing in a patient with treated CLL and drug related SLR one day after exposure to Venetoclax and Rituximab. A 60-year-old male presented with lower limb rash, left leg weakness followed by bulbar symptoms which progressed over 12-months. Workup demonstrated a Cerebrospinal fluid (CSF) pleocytosis and inguinal lymphadenopathy. Skin and inguinal lymph node biopsies showed non-necrotising granulomata. Electromyography met diagnostic criteria for ALS. He was treated for presumed neurosarcoidosis mimicking ALS. Despite prednisolone and infliximab treatment, the motor symptoms rapidly progressed; Hence, we made a clinical diagnosis of ALS. We discuss the diagnostic and treatment challenges of this case.}, } @article {pmid39799044, year = {2025}, author = {Bracca, V and Premi, E and Cotelli, MS and Micheli, A and Altomare, D and Cantoni, V and Gasparotti, R and Borroni, B}, title = {Loss of Insight in Syndromes Associated with Frontotemporal Lobar Degeneration: Clinical and Imaging Features.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {33}, number = {4}, pages = {450-462}, doi = {10.1016/j.jagp.2024.12.005}, pmid = {39799044}, issn = {1545-7214}, mesh = {Humans ; Male ; Female ; Aged ; *Frontotemporal Lobar Degeneration/diagnostic imaging/pathology/epidemiology ; *Magnetic Resonance Imaging ; Middle Aged ; Retrospective Studies ; Longitudinal Studies ; Atrophy/pathology ; Aphasia, Primary Progressive/diagnostic imaging/pathology ; Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/epidemiology ; Frontotemporal Dementia/diagnostic imaging/pathology ; Prevalence ; Brain/diagnostic imaging/pathology ; }, abstract = {OBJECTIVES: The present study aims to assess the prevalence, associated clinical symptoms, longitudinal changes, and imaging correlates of Loss of Insight (LOI), which is still unexplored in syndromes associated with Frontotemporal Lobar Degeneration (FTLD).

DESIGN: Retrospective longitudinal cohort study, from Oct 2009 to Feb 2023.

SETTING: Tertiary Frontotemporal Dementia research clinic.

PARTICIPANTS: A sample of 712 FTLD patients, 331 of whom had follow-up evaluation.

MEASUREMENTS: LOI was assessed by interview with the primary caregiver. Univariate and multiple logistic regression and linear mixed models were used to estimate predictors and longitudinal changes over time associated with LOI. Voxel-based morphometry and structural covariance analyses of brain structural MRI images were implemented in Statistical Parametric Mapping.

RESULTS: LOI was reported in 45% of patients (321/712, 95%CI = 41-49), with progressively increased prevalence from prodromal to severe dementia stages. LOI was more prevalent in the behavioural variant FTD, in the semantic variant of Primary Progressive Aphasia (svPPA) and FTD with Amyotrophic Lateral Sclerosis than in other phenotypes (all p-values<0.001). LOI severity increased over time only in patients with svPPA (β = +0.59, p <0.001) and clustered with other behavioral symptoms (all p-values <0.05). Finally, LOI was significantly associated with greater atrophy in the right medial orbital gyrus (p <0.001 uncorrected). Structural covariance analysis demonstrated loss of negative correlation between right medial orbital gyrus and regions belonging to the Default Mode Network (DMN), such as the left precuneus and the left angular gyrus (p ≤0.05 family-wise error-corrected) in FTLD patients with LOI.

CONCLUSIONS: A better comprehension of LOI mechanisms could lead to more effective interventions and healthcare policies.}, } @article {pmid39798947, year = {2025}, author = {Sorice, V and Ekumah, ND}, title = {Exploring the psychosocial dimensions and impacts of infertility in Africa: a commentary on Roomaney et al's scoping review of current evidence.}, journal = {Evidence-based nursing}, volume = {}, number = {}, pages = {}, doi = {10.1136/ebnurs-2024-104222}, pmid = {39798947}, issn = {1468-9618}, } @article {pmid39798853, year = {2025}, author = {Guan, D and Liang, C and Zheng, D and Liu, S and Luo, J and Cai, Z and Zhang, H and Chen, J}, title = {The role of mitochondrial remodeling in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {183}, number = {}, pages = {105927}, doi = {10.1016/j.neuint.2024.105927}, pmid = {39798853}, issn = {1872-9754}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; Mitochondrial Dynamics/physiology ; Energy Metabolism/physiology ; }, abstract = {Neurodegenerative diseases are a group of diseases that pose a serious threat to human health, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, it has been found that mitochondrial remodeling plays an important role in the onset and progression of neurodegenerative diseases. Mitochondrial remodeling refers to the dynamic regulatory process of mitochondrial morphology, number and function, which can affect neuronal cell function and survival by regulating mechanisms such as mitochondrial fusion, division, clearance and biosynthesis. Mitochondrial dysfunction is an important intrinsic cause of the pathogenesis of neurodegenerative diseases. Mitochondrial remodeling abnormalities are involved in energy metabolism in neurodegenerative diseases. Pathological changes in mitochondrial function and morphology, as well as interactions with other organelles, can affect the energy metabolism of dopaminergic neurons and participate in the development of neurodegenerative diseases. Since the number of patients with PD and AD has been increasing year by year in recent years, it is extremely important to take effective interventions to significantly reduce the number of morbidities and to improve people's quality of life. More and more researchers have suggested that mitochondrial remodeling and related dynamics may positively affect neurodegenerative diseases in terms of neuronal and self-adaptation to the surrounding environment. Mitochondrial remodeling mainly involves its own fission and fusion, energy metabolism, changes in channels, mitophagy, and interactions with other cellular organelles. This review will provide a systematic summary of the role of mitochondrial remodeling in neurodegenerative diseases, with the aim of providing new ideas and strategies for further research on the treatment of neurodegenerative diseases.}, } @article {pmid39798254, year = {2025}, author = {Cao, S and Fu, X and Li, W and Wang, P and Li, C and Shang, H}, title = {Protective role of apolipoprotein A and B in Parkinson's disease: A prospective study from UK Biobank.}, journal = {Parkinsonism & related disorders}, volume = {132}, number = {}, pages = {107266}, doi = {10.1016/j.parkreldis.2025.107266}, pmid = {39798254}, issn = {1873-5126}, mesh = {Humans ; Male ; *Parkinson Disease/blood ; Female ; Aged ; United Kingdom/epidemiology ; Middle Aged ; *Biological Specimen Banks ; Prospective Studies ; Apolipoproteins A/blood ; Apolipoproteins B/blood ; Protective Factors ; UK Biobank ; Apolipoprotein B-100 ; }, abstract = {INTRODUCTION: Evidence have indicated relation between apolipoproteins and neurodegenerative disorders (NDDs). However, previous studies have produced inconsistent results, and a comprehensive analysis of apolipoproteins in NDDs is currently lacking.

METHODS: Using Cox proportional hazards regression analysis based on data from UK Biobank, we examined the association between baseline serum levels of apolipoprotein A (ApoA) and apolipoprotein B (ApoB) and risk of Parkinson's disease (PD), Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and multiple sclerosis.

RESULTS: Elevated baseline levels of serum ApoA (HR = 0.84, 95 % CI: 0.71-0.99, P = 0.047) and ApoB (HR = 0.67, 95 % CI: 0.57-0.78, P = 3.18E-07) were associated with a reduced risk of incident PD. Subgroup analyses suggested the protective effect of serum ApoA was more significant for older participants and those with lower alcohol consumption, while higher serum ApoB was a more significant protective factor in males and those without stroke. No significant associations were found between apolipoproteins and other NDDs.

CONCLUSION: Increased baseline levels of serum ApoA and ApoB are linked to a lower risk of PD. These findings enhance understanding of the role of apolipoproteins in PD, and have implications for the development of therapeutic strategies in clinical trials.}, } @article {pmid39797438, year = {2025}, author = {Zeng, Y and Liu, M and Qian, H and Zhao, H and Fang, Y and Yu, Q and Bai, L and Pan, L}, title = {Investigating non-target site resistance to pyroxsulam in a glyphosate-resistant Lolium rigidum population.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.8636}, pmid = {39797438}, issn = {1526-4998}, support = {//the National Key RandD Program of China (no. 2023YFD1401100)/ ; //National Natural Science Foundation of China (32372568 and 32130091)/ ; //Young Elite Scientists Sponsorship Program by CAST (2021QNRC001)/ ; //Earmarked Fund for China Agriculture Research System (CARS-16-E19)/ ; //Postgraduate Scientific Research Innovation Project of Hunan Province (QL20230088)/ ; //Scientific Research Fund of Hunan Provincial Education Department (23B0225)/ ; //National Natural Science Foundation of China (U23A20174)/ ; //Australian Grains and Research Development and Corporation (GRDC)/ ; }, abstract = {BACKGROUND: Resistance to multiple herbicides is common in Lolium rigidum. Here, resistance to acetolactate synthase (ALS)- and susceptibility to acetyl-CoA carboxylase (ACCase)-inhibiting herbicides was confirmed in a glyphosate-resistant L. rigidum population (NLR70) from Australia and the mechanisms of pyroxsulam resistance were examined.

RESULTS: No ALS target-site mutations nor gene overexpression were detected. Cytochrome P450 monooxygenase (P450) and glutathione S-transferase (GST) inhibitors (indicators of some certain P450s or GSTs) did not significantly affect the resistance to pyroxsulam. Nevertheless, HPLC analysis showed that plants of the NLR70 population metabolized pyroxsulam faster than plants of the herbicide-susceptible population (SVLR1). RNA sequencing analysis and RT-qPCR validation confirmed that four P450s (CYP709B2, CYP72A14, CYP89A2, CYP94B3), one GT (UGT79), and one ABC transporter (ABCG41) genes were constitutively upregulated in NLR70 plants.

CONCLUSION: This study demonstrates that the glyphosate-resistant L. rigidum population (NLR70) also exhibits resistance to pyroxsulam and identifies six candidate genes associated with non-target site resistance to pyroxsulam. © 2025 Society of Chemical Industry.}, } @article {pmid39796536, year = {2024}, author = {Cuffaro, F and Lamminpää, I and Niccolai, E and Amedei, A}, title = {Nutritional and Microbiota-Based Approaches in Amyotrophic Lateral Sclerosis: From Prevention to Treatment.}, journal = {Nutrients}, volume = {17}, number = {1}, pages = {}, pmid = {39796536}, issn = {2072-6643}, support = {PNRR-MAD-2022-12375798//Ministero della Salute/ ; PE0000006//Ministry of University and Research (MUR)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Gastrointestinal Microbiome ; *Dysbiosis/therapy ; Probiotics/therapeutic use ; Brain-Gut Axis/physiology ; Fecal Microbiota Transplantation ; Fatty Acids, Omega-3 ; Prebiotics/administration & dosage ; Oxidative Stress ; Nutritional Status ; Diet, Mediterranean ; Antioxidants ; }, abstract = {Metabolic alterations, including hypermetabolism, lipid imbalances, and glucose dysregulation, are pivotal contributors to the onset and progression of Amyotrophic Lateral Sclerosis (ALS). These changes exacerbate systemic energy deficits, heighten oxidative stress, and fuel neuroinflammation. Simultaneously, gastrointestinal dysfunction and gut microbiota (GM) dysbiosis intensify disease pathology by driving immune dysregulation, compromising the intestinal barrier, and altering gut-brain axis (GBA) signaling, and lastly advancing neurodegeneration. Therapeutic and preventive strategies focused on nutrition offer promising opportunities to address these interconnected pathophysiological mechanisms. Diets enriched with antioxidants, omega-3 fatty acids, and anti-inflammatory compounds-such as the Mediterranean diet-have shown potential in reducing oxidative stress and systemic inflammation. Additionally, microbiota-targeted approaches, including probiotics, prebiotics, postbiotics, and fecal microbiota transplantation, are emerging as innovative tools to restore microbial balance, strengthen gut integrity, and optimize GBA function. This review highlights the critical need for personalized strategies integrating immunonutrition and microbiota modulation to slow ALS progression, improve quality of life, and develop preventive measures for neurodegenerative and neuroinflammatory diseases. Future research should prioritize comprehensive dietary and microbiota-based interventions to uncover their therapeutic potential and establish evidence-based guidelines for managing ALS and related disorders.}, } @article {pmid39795334, year = {2024}, author = {Bhattacharya, S and Sen, MK and Hamouzová, K and Košnarová, P and Bharati, R and Menendez, J and Soukup, J}, title = {Pyroxsulam Resistance in Apera spica-venti: An Emerging Challenge in Crop Protection.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {1}, pages = {}, pmid = {39795334}, issn = {2223-7747}, support = {QL24010167//National Agency for Agricultural Research (NAZV)/ ; }, abstract = {Apera spica-venti, a prevalent weed in Czech winter wheat fields, has developed resistance to ALS-inhibiting herbicides due to their frequent use. This study reports a biotype of A. spica-venti resistant to pyroxsulam, with cross and multiple resistance to iodosulfuron, propoxycarbazone, pinoxaden, and chlortoluron. Dose-response experiments revealed high resistance of both R1 and R2 biotypes to pyroxsulam, with resistance factors (RF) of 6.69 and 141.65, respectively. Pre-treatment with malathion reduced RF by 2.40× and 1.25× in R1 and R2, indicating the potential involvement of cytochrome P450 (CytP450). NBD-Cl pre-treatment decreased RF only in R2, suggesting possible GST involvement. Gene analysis revealed no mutations (at previously reported sites) or overexpression in the acetolactate synthase (ALS) gene. However, a significant difference in ALS enzyme activity between resistant and susceptible biotypes points to target-site resistance mechanisms. Studies with [14]C-labeled pyroxsulam showed that reduced absorption and translocation were not likely resistance mechanisms. In summary, herbicide resistance in A. spica-venti appears to result from multiple mechanisms. Possible causes include target-site resistance from an unidentified ALS mutation (within coding or regulatory regions). Enhanced herbicide metabolism via CytP450s and GSTs is also a contributing factor. Further experimental validation is needed to confirm these mechanisms and fully understand the resistance. This evolution underscores the adaptive capacity of weed populations under herbicide pressure, emphasizing the need for alternative control strategies.}, } @article {pmid39794859, year = {2025}, author = {Niccolai, E and Di Gloria, L and Trolese, MC and Fabbrizio, P and Baldi, S and Nannini, G and Margotta, C and Nastasi, C and Ramazzotti, M and Bartolucci, G and Bendotti, C and Nardo, G and Amedei, A}, title = {Correction: Host genetics and gut microbiota influence lipid metabolism and inflammation: potential implications for ALS pathophysiology in SOD1G93A mice.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {5}, pmid = {39794859}, issn = {2051-5960}, } @article {pmid39794401, year = {2025}, author = {Cheng, J and Wu, BT and Liu, HP and Lin, WY}, title = {Machine learning identified novel players in lipid metabolism, endosomal trafficking, and iron metabolism of the ALS spinal cord.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1564}, pmid = {39794401}, issn = {2045-2322}, support = {CMU110-MF-92//China Medical University, Taiwan/ ; CMU112-MF-62//China Medical University, Taiwan/ ; MOST 111-2314-B-039-017-MY3//National Science and Technology Council of Taiwan/ ; DMR-112-125//China Medical University Hospital, Taiwan/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Iron/metabolism ; Humans ; *Machine Learning ; *Lipid Metabolism ; *Endosomes/metabolism ; *Spinal Cord/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Although genes causing familial cases have been identified, those of sporadic ALS, which occupies the majority of patients, are still elusive. In this study, we adopted machine learning to build binary classifiers based on the New York Genome Center (NYGC) ALS Consortium's RNA-seq data of the postmortem spinal cord of ALS and non-neurological disease control. The accuracy of the classifiers was greater than 83% and 77% for the training set and the unseen test set, respectively. The classifiers contained 114 genes. Among them, 41 genes have been reported in previous ALS studies, and others are novel in this field. These genes are involved in mitochondrial respiration, lipid metabolism, endosomal trafficking, and iron metabolism, which may promote the progression of ALS pathology.}, } @article {pmid39793633, year = {2025}, author = {Baker, RS and Wang, JT and Rouatbi, N and Lu, Y and Al-Adhami, T and Asker, D and Rahman, KM and Al-Chalabi, A and Forbes, B and Bansal, S and Al-Jamal, KT}, title = {Brain distribution study of [[14]C]-Riluzole following intranasal administration in mice.}, journal = {International journal of pharmaceutics}, volume = {670}, number = {}, pages = {125195}, doi = {10.1016/j.ijpharm.2025.125195}, pmid = {39793633}, issn = {1873-3476}, mesh = {Animals ; *Administration, Intranasal ; *Brain/metabolism ; Male ; Mice ; *Carbon Radioisotopes ; Tissue Distribution ; Biological Availability ; Tetrahydroisoquinolines/administration & dosage/pharmacokinetics ; Blood-Brain Barrier/metabolism ; Administration, Oral ; Neuroprotective Agents/pharmacokinetics/administration & dosage ; Acridines ; }, abstract = {Amyotrophic lateral sclerosis (ALS) presents a substantial challenge due to its complex nature, limited effective treatment options, and modest benefits from current therapies in slowing disease progression. This study explores the potential of intranasal (IN) delivery to enhance the CNS delivery of riluzole (RLZ), a standard ALS treatment which is subject to blood-brain barrier efflux mechanisms. Additionally, the impact of elacridar (ELC), an efflux pump inhibitor, on IN RLZ CNS bioavailability was examined. To quantify RLZ in vivo in mice, [[14]C]-RLZ was synthesised using an optimised one-pot method. [[14]C]-RLZ yield was 21.3 ± 3.4 %, measured by High Performance Liquid Chromatography (HPLC), with a specific activity of 40.4 ± 3.9 µCi/mg measured by HPLC and liquid scintillation counting. RLZ synthesis was verified using proton nuclear magnetic resonance ([1]H NMR), and liquid chromatography-mass spectrometry. IN RLZ (5 mg/kg) produced double the maximum brain levels (1.11 ± 0.34 % Injected Dose (ID)/brain) at 30 min as oral RLZ (5 mg/kg). The uptake of RLZ in the liver was reduced by half for intranasal administration compared to oral administration. Intravenous ELC (5 mg/kg) substantially increased brain levels of IN RLZ to 3.52 ± 0.62 % ID/g brain at 60 min post-administration, compared to 1.87 ± 0.33 % ID/g brain in the absence of the efflux pump inhibitor. However, increased concentrations were also observed in the liver and blood. These results indicate that intranasal delivery of RLZ enhances brain targeting and reduces liver accumulation compared to the oral route. Brain uptake of IN RLZ was enhanced further by ELC, although not selectively as accumulation in the liver or blood was also observed. Further metabolic research using Chromatography-Mass spectrometry (LC-MS) or NMR along with excretion studies are warranted for a more comprehensive understanding of the pharmacokinetics of IN RLZ and IN RLZ/ELC. Additionally, employing suitable ALS animal models is crucial for understanding RLZ's effects on disease progression, mechanism of action, efficacy, and potential side effects to aid further development.}, } @article {pmid39792652, year = {2025}, author = {Mercadante, S and Petronaci, P and Lo Cascio, A}, title = {Living Will and Advance Care Planning in Patients With Amyotrophic Lateral Sclerosis Admitted to Specialistic Home Palliative Care.}, journal = {The American journal of hospice & palliative care}, volume = {}, number = {}, pages = {10499091241312906}, doi = {10.1177/10499091241312906}, pmid = {39792652}, issn = {1938-2715}, abstract = {Objectives: In Italy a recent law was approved for providing patients' wishes regarding end of life issues, commonly referred internationally to as "living wills", (Dichiarazione anticipata di trattamento, DAT). Regardless of this official document, advance care planning (ACP) is often used in a palliative care setting to share the treatments to start, to continue, to withdraw, thus preventing the stress on an acute decision. The aim of this study was to assess DAT and ACP in patients with amyotropic lateral sclerosis admitted to home palliative care. Methods: Patients consecutively admitted to speciliazed home palliative care were prospectively assessed. The presence of DAT or ACP was recorded. Results: Sixty-eight patients were enrolled in the period taken into consideration. No patient had drown up DAT, and only one patient provided his ACP prior to home palliative care admission. Along the course of home palliative care care assistance, 30.9% of patients provided their ACP. Discussion: In Italy DAT resulted scarcely widespread, despite an existing law, as no patient officially provided their indication on end of life issues. In addition, ACP was given only after starting specialized home palliative care in less than 1/3 of patients. Home palliative care seems to be a fundamental resource for improving communication and soliciting expression of patients' wishes regarding end of life issues.}, } @article {pmid39792557, year = {2025}, author = {Dykstra, MM and Weskamp, K and Gómez, NB and Waksmacki, J and Tank, E and Glineburg, MR and Snyder, A and Pinarbasi, E and Bekier, M and Li, X and Miller, MR and Bai, J and Shahzad, S and Nedumaran, N and Wieland, C and Stewart, C and Willey, S and Grotewold, N and McBride, J and Moran, JJ and Suryakumar, AV and Lucas, M and Tessier, PM and Ward, M and Todd, PK and Barmada, SJ}, title = {TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115113}, pmid = {39792557}, issn = {2211-1247}, support = {F31 NS115257/NS/NINDS NIH HHS/United States ; K08 NS072233/NS/NINDS NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; F31 NS134123/NS/NINDS NIH HHS/United States ; R35 GM136300/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Protein Isoforms/metabolism/genetics ; Homeostasis ; Nonsense Mediated mRNA Decay ; Transcription, Genetic ; Protein Processing, Post-Translational ; HEK293 Cells ; Animals ; HeLa Cells ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; }, abstract = {The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal TDP43 isoforms that are predominantly cytosolic in localization, prone to aggregation, and enriched in susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 isoforms are difficult to detect in comparison to full-length (fl)TDP43, raising questions regarding their origin and selective regulation. Here, we show that sTDP43 is created as a by-product of TDP43 autoregulation and cleared by nonsense-mediated RNA decay (NMD). sTDP43-encoding transcripts that escape NMD are rapidly degraded post-translationally via the proteasome and macroautophagy. Circumventing these regulatory mechanisms by overexpressing sTDP43 results in neurodegeneration via N-terminal oligomerization and impairment of flTDP43 splicing activity, in addition to RNA-binding-dependent gain-of-function toxicity. Collectively, these studies highlight endogenous mechanisms that tightly regulate sTDP43 expression and underscore the consequences of aberrant sTDP43 accumulation in disease.}, } @article {pmid39792201, year = {2025}, author = {Fu, Z and Feng, B and Akogo, HY and Ma, J and Liu, Y and Quan, H and Zhang, X and Hou, Y and Zhang, X and Ma, J and Cui, H}, title = {Amyotrophic Lateral Sclerosis and Parkinson's Disease: Brain Tissue Transcriptome Analysis Reveals Interactions.}, journal = {Molecular neurobiology}, volume = {62}, number = {5}, pages = {6383-6396}, pmid = {39792201}, issn = {1559-1182}, support = {81801278//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Parkinson Disease/genetics/metabolism ; *Brain/metabolism/pathology ; *Gene Expression Profiling ; Gene Regulatory Networks ; Protein Interaction Maps/genetics ; Transcriptome/genetics ; MicroRNAs/genetics/metabolism ; Gene Ontology ; }, abstract = {This study utilises amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) human brain samples from the GEO database and employs differential expression gene (DEG) analysis to identify genes that are pivotal in both neurodegenerative diseases. Through in depth GO and KEGG enrichment analyses, we elucidated the biological functions and potential pathways associated with these DEGs. Furthermore, by constructing protein‒protein interaction networks, we highlight the significance of shared DEGs in both cellular physiology and disease contexts. Analysis of drug‒gene associations revealed potential therapeutic compounds linked to ALS and PD treatment. Additionally, we explored the interactions between transcription factors, miRNAs, and common DEGs, revealing aspects of gene regulatory networks. This study provides insights into the molecular mechanisms of ALS and PD, offering valuable contributions to ongoing research and potential therapeutic avenues.}, } @article {pmid39791815, year = {2025}, author = {Rossi, A and Cuccioloni, M and Pellegrino, F and Giovannetti, R and Alladio, E}, title = {Discriminating Analysis of Metal Ions via Multivariate Curve Resolution-Alternating Least Squares Applied to Silver Nanoparticle Sensor.}, journal = {Nanomaterials (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, pmid = {39791815}, issn = {2079-4991}, abstract = {Heavy metals are life-threatening pollutions because of their great toxicity, long-term persistence in nature and their bioaccumulation in living organisms. In this work, we performed multivariate curve resolution-alternating least squares analysis of UV-Vis raw spectra received by a colorimetric sensor constructed on mercaptoundecanoic acid functionalized silver nanoparticles (AgNPs@11MUA) to detect Cd[2+], Cu[2+], Mn[2+], Ni[2+], and Zn[2+] in water. This combined approach allowed the rapid identification and quantification of multiple heavy metals and showed adequate sensitivity and selectivity, thus representing a promising analytical and computational method for both laboratory and field applications such as environmental safety and public health monitoring.}, } @article {pmid39791748, year = {2025}, author = {Moss, KR and Saxena, S}, title = {Schwann Cells in Neuromuscular Disorders: A Spotlight on Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {14}, number = {1}, pages = {}, pmid = {39791748}, issn = {2073-4409}, support = {K22 NS125057/NS/NINDS NIH HHS/United States ; }, mesh = {*Schwann Cells/pathology/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Humans ; Animals ; Neuromuscular Diseases/pathology ; Motor Neurons/pathology/metabolism ; Charcot-Marie-Tooth Disease/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disease primarily affecting motor neurons, leading to progressive muscle atrophy and paralysis. This review explores the role of Schwann cells in ALS pathogenesis, highlighting their influence on disease progression through mechanisms involving demyelination, neuroinflammation, and impaired synaptic function. While Schwann cells have been traditionally viewed as peripheral supportive cells, especially in motor neuron disease, recent evidence indicates that they play a significant role in ALS by impacting motor neuron survival and plasticity, influencing inflammatory responses, and altering myelination processes. Furthermore, advancements in understanding Schwann cell pathology in ALS combined with lessons learned from studying Charcot-Marie-Tooth disease Type 1 (CMT1) suggest potential therapeutic strategies targeting these cells may support nerve repair and slow disease progression. Overall, this review aims to provide comprehensive insights into Schwann cell classification, physiology, and function, underscoring the critical pathological contributions of Schwann cells in ALS and suggests new avenues for targeted therapeutic interventions aimed at modulating Schwann cell function in ALS.}, } @article {pmid39791705, year = {2024}, author = {Sun, D and Amiri, M and Meng, Q and Unnithan, RR and French, C}, title = {Calcium Signalling in Neurological Disorders, with Insights from Miniature Fluorescence Microscopy.}, journal = {Cells}, volume = {14}, number = {1}, pages = {}, pmid = {39791705}, issn = {2073-4409}, support = {DP170100363//Australian Research Council under Discovery Project/ ; }, mesh = {*Calcium Signaling ; Humans ; *Nervous System Diseases/metabolism/pathology ; Animals ; *Microscopy, Fluorescence/methods ; Calcium/metabolism ; Neurons/metabolism ; }, abstract = {Neurological disorders (NDs), such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and schizophrenia, represent a complex and multifaceted health challenge that affects millions of people around the world. Growing evidence suggests that disrupted neuronal calcium signalling contributes to the pathophysiology of NDs. Additionally, calcium functions as a ubiquitous second messenger involved in diverse cellular processes, from synaptic activity to intercellular communication, making it a potential therapeutic target. Recently, the development of the miniature fluorescence microscope (miniscope) enabled simultaneous recording of the spatiotemporal calcium activity from large neuronal ensembles in unrestrained animals, providing a novel method for studying NDs. In this review, we discuss the abnormalities observed in calcium signalling and its potential as a therapeutic target for NDs. Additionally, we highlight recent studies that utilise miniscope technology to investigate the alterations in calcium dynamics associated with NDs.}, } @article {pmid39791335, year = {2025}, author = {Dogan, EO and Simonini, SR and Bouley, J and Weiss, A and Brown, RH and Henninger, N}, title = {Genetic Ablation of Sarm1 Mitigates Disease Acceleration after Traumatic Brain Injury in the SOD1[G93A] Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27174}, pmid = {39791335}, issn = {1531-8249}, support = {NS131756/NS/NINDS NIH HHS/United States ; //Moloney Fellowship/ ; //Angel Fund for ALS Research/ ; }, abstract = {OBJECTIVE: Approximately 20% of familial cases of amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Epidemiological data have identified traumatic brain injury (TBI) as an exogenous risk factor for ALS; however, the mechanisms by which TBI may worsen SOD1 ALS remain largely undefined.

METHODS: We sought to determine whether repetitive TBI (rTBI) accelerates disease onset and progression in the transgenic SOD1[G93A] mouse ALS model, and whether loss of the primary regulator of axonal degeneration sterile alpha and TIR motif containing 1 (Sarm1) mitigates the histological and behavioral pathophysiology. We subjected wild-type (n = 23), Sarm1 knockout (KO; n = 17), SOD1[G93A] (n = 19), and SOD1[G93A]xSarm1[KO] (n = 26) mice of both sexes to rTBI or sham surgery at age 64 days (62-68 days). Body weight and ALS-deficit score were serially assessed up to 17 weeks after surgery and histopathology assessed in layer V of the primary motor cortex at the study end point.

RESULTS: In sham injured SOD1[G93A] mice, genetic ablation of Sarm1 did not attenuate axonal loss, improve neurological deficits, or survival. The rTBI accelerated onset of G93A-SOD1 ALS, as indicated by accentuated body weight loss, earlier onset of hindlimb tremor, and shortened survival. The rTBI also triggered TDP-43 mislocalization, enhanced axonal and neuronal loss, microgliosis, and astrocytosis. Loss of Sarm1 significantly diminished the impact of rTBI on disease progression and rescued rTBI-associated neuropathology.

INTERPRETATION: SARM1-mediated axonal death pathway promotes pathogenesis after TBI in SOD1[G93A] mice suggesting that anti-SARM1 therapeutics are a viable approach to preserve neurological function in injury-accelerated G93A-SOD1 ALS. ANN NEUROL 2025.}, } @article {pmid39789167, year = {2025}, author = {Kassubek, J and Roselli, F and Witzel, S and Dorst, J and Ludolph, AC and Rasche, V and Vernikouskaya, I and Müller, HP}, title = {Hypothalamic atrophy in primary lateral sclerosis, assessed by convolutional neural network-based automatic segmentation.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1551}, pmid = {39789167}, issn = {2045-2322}, mesh = {Humans ; Female ; Male ; *Hypothalamus/pathology/diagnostic imaging ; Middle Aged ; *Neural Networks, Computer ; *Magnetic Resonance Imaging/methods ; *Atrophy/pathology ; Aged ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging ; Adult ; Motor Neuron Disease/pathology/diagnostic imaging ; Image Processing, Computer-Assisted/methods ; Case-Control Studies ; }, abstract = {Primary lateral sclerosis (PLS) is a motor neuron disease (MND) which mainly affects upper motor neurons. Within the MND spectrum, PLS is much more slowly progressive than amyotrophic laterals sclerosis (ALS). `Classical` ALS is characterized by catabolism and abnormal energy metabolism preceding onset of motor symptoms, and previous studies indicated that the disease progression of ALS involves hypothalamic atrophy. Very limited weight loss is observed in patients with PLS, which raises the question of whether there are also less hypothalamic alterations. The purpose of this study was to quantitatively investigate the hypothalamic volume in a group of PLS patients and to compare it with ALS and controls. Recently, we have introduced automatic hypothalamic quantification method based on the use of convolutional neural network (CNN) to reduce human variability and enhance analysis robustness. This CNN of U-Net architecture was applied for automatic segmentation of the hypothalamus and intracranial volume (ICV) to allow adjustments of the hypothalamic volume between subjects with different head sizes respectively. Automatic segmentation and volumetric analysis were performed in high resolution T1 weighted MRI volumes (acquired on a 1.5 T MRI scanner) of 46 PLS patients in comparison to 107 healthy controls and 411 `classical` ALS patients, respectively. Significant hypothalamic volume reduction was observed in PLS (818 ± 73 mm[3]) when compared to controls (852 ± 77 mm[3]); significant hypothalamic volume reduction was also confirmed in ALS (823 ± 84 mm[3]), in support of previous studies. No significant differences were found in normalized hypothalamic volumes between ALS patients and PLS patients at the group level. This unbiased CNN-based hypothalamus volume quantification study demonstrated similarly reduced hypothalamus volume in PLS and ALS patients, despite the clinical phenotypic differences.}, } @article {pmid39788313, year = {2025}, author = {Cassina, P and Miquel, E and Martínez-Palma, L and Cassina, A}, title = {Mitochondria and astrocyte reactivity: Key mechanism behind neuronal injury.}, journal = {Neuroscience}, volume = {567}, number = {}, pages = {227-234}, doi = {10.1016/j.neuroscience.2024.12.058}, pmid = {39788313}, issn = {1873-7544}, mesh = {Animals ; Humans ; *Astrocytes/metabolism/pathology ; *Mitochondria/metabolism ; *Neurons/metabolism/pathology ; }, abstract = {In this special issue to celebrate the 30th anniversary of the Uruguayan Society for Neuroscience (SNU), we find it pertinent to highlight that research on glial cells in Uruguay began almost alongside the history of SNU and contributed to the understanding of neuron-glia interactions within the international scientific community. Glial cells, particularly astrocytes, traditionally regarded as supportive components in the central nervous system (CNS), undergo notable morphological and functional alterations in response to neuronal damage, a phenomenon referred to as glial reactivity. Among the myriad functions of astrocytes, metabolic support holds significant relevance for neuronal function, given the high energy demand of the nervous system. Although astrocytes are typically considered to exhibit low mitochondrial respiratory chain activity, they possess a noteworthy mitochondrial network. Interestingly, both the morphology and activity of these organelles change following glial reactivity. Despite receiving less attention compared to studies on neuronal mitochondria, recent studies indicate that mitochondria play a crucial role in driving the transition of astrocytes from a quiescent to a reactive state in various neurological disorders. Notably, stimulating mitochondria in astrocytes has been shown to reduce damage associated with the neurodegenerative disease amyotrophic lateral sclerosis. Here, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage. In this review, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage.}, } @article {pmid39786806, year = {2025}, author = {Yang, S and Song, J and Deng, M and Cheng, S}, title = {Identification of Drug-Targetable Genes for Eczema and Dermatitis Using Integrated Genomic and Proteomic Approaches.}, journal = {Dermatitis : contact, atopic, occupational, drug}, volume = {}, number = {}, pages = {}, doi = {10.1089/derm.2024.0429}, pmid = {39786806}, issn = {2162-5220}, abstract = {Background: Eczema and dermatitis are common inflammatory skin conditions with significant morbidity. Identifying drug-targetable genes can facilitate the development of effective treatments. Methods: This study analyzed data obtained by meta-analysis of 2 genome-wide association studies on eczema/dermatitis (57,311 cases and 896,779 controls, European ancestry). We identified drug-targetable genes from the Drug-Gene Interaction Database and Finan et al's findings. Cis-expression quantitative trait loci (eQTL) data from human blood and skin tissues were used for Mendelian randomization (MR) analysis. Bayesian colocalization, proteomic MR, and meta-analysis validated the causal relationships. Finally, protein-protein interactions (PPIs) and correlation analysis of potential drug targets and cytokines were performed. Results: We identified 2532 drug-targetable genes; 3378 Single Nucleotide Polymorphism (SNPs) were associated with 1531 genes in blood cis-eQTLs, 664 SNPs with 667 genes in sun-exposed skin eQTLs, and 572 SNPs with 574 genes in nonsun-exposed skin eQTLs. Five genes (SLC22A5, NOTCH4, AGER, HLA-DRB5, and EHMT2) showed causal relationships with eczema/dermatitis across multiple datasets. Single-variable and multi-variable Mendelian randomization (SMR) and multi-SNP SMR analysis identified 8 genes (PIK3R4, DHODH, CXCR2, Interleukin (IL)18, LGALS9, RPS6KB2, SLC22A5, and AGER) across all tissues. Functional Summary Information for Variants in the Online Network (FUSION) analysis confirmed associations for SLC22A5 and AGER. Bayesian colocalization indicated AGER (PPH4: 0.95) as a shared causal variant. Proteomic MR and meta-analysis showed that increased AGER protein levels were associated with a lower risk of eczema or dermatitis (odds ratio: 0.995, 95% confidence interval: 0.997-0.993, P = 0.0002). A PPI network revealed interactions of AGER with NOTCH4 and multiple cytokines, whereas SLC22A5 showed no cytokine interactions. Conclusions: This study identified potential drug-targetable genes, with AGER showing strong potential as a target for reducing eczema/dermatitis risk. These findings provide a basis for developing targeted therapies.}, } @article {pmid39786727, year = {2025}, author = {Midgley, SD and Bariami, S and Habgood, M and Mackey, M}, title = {Adaptive Lambda Scheduling: A Method for Computational Efficiency in Free Energy Perturbation Simulations.}, journal = {Journal of chemical information and modeling}, volume = {65}, number = {2}, pages = {512-516}, pmid = {39786727}, issn = {1549-960X}, mesh = {*Thermodynamics ; Ligands ; Proteins/chemistry/metabolism ; Protein Binding ; Computer Simulation ; }, abstract = {Recent increases in the availability of computational power have improved the accessibility of ligand-protein relative binding free energy (RBFE) calculations; however, these calculations remain resource-intensive, which can limit their practical application. RBFE calculations typically use a set of thermodynamic intermediates mediated by the transformation coordinate λ. Optimizing λ offers a way to tune the computational efforts required for a given RBFE calculation. Here, we present Adaptive Lambda Scheduling (ALS), a streamlined approach for on-the-fly bespoke λ scheduling. We show it can achieve substantial reductions in computational cost while retaining predictive performance.}, } @article {pmid39786321, year = {2025}, author = {Kim, K and Kim, S and Katana, M and Terentyev, D and Radwański, PB and Munger, MA}, title = {Riluzole is associated with reduced risk of heart failure.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e70033}, pmid = {39786321}, issn = {1468-1331}, support = {R01HL14488/HL/NHLBI NIH HHS/United States ; R01 NS121234/NS/NINDS NIH HHS/United States ; R01 HL166604/HL/NHLBI NIH HHS/United States ; R01HL166604/HL/NHLBI NIH HHS/United States ; R01HL155378/HL/NHLBI NIH HHS/United States ; }, mesh = {*Riluzole/therapeutic use ; Humans ; *Heart Failure/epidemiology/drug therapy ; Male ; Female ; Aged ; Middle Aged ; Incidence ; Amyotrophic Lateral Sclerosis/epidemiology/drug therapy ; Aged, 80 and over ; Cohort Studies ; United States/epidemiology ; }, abstract = {BACKGROUND: Reduction of intracellular Na[+] accumulation through late Na[+] current inhibition has been recognized as a target for cardiac Ca[2+] handling which underlies myocardial contractility and relaxation in heart failure (HF). Riluzole, an Na[+] channel blocker with enhancement of Ca[2+]-activated K[+] channel function, used for management of amyotrophic lateral sclerosis (ALS), is effective in suppressing Ca[2+] leak and therefore may improve cardiac function.

OBJECTIVES: The study aim was to investigate whether riluzole lowers HF incidence.

METHODS: Rates of HF incident were compared using a commercial insurance and Medicare supplement claims databases. Patients with a filled riluzole prescription (treatment) between 06/2009 and 12/2019 were compared to those with no-riluzole (control). We excluded HF patients during the 180-day baseline period. Study endpoint was the first HF diagnosis from the index riluzole prescription or ALS diagnosis. HF onset was compared between the propensity score matched treatment and control cohorts.

RESULTS: The matched cohort consisted of 4060 pairs of riluzole/control patients. The 24-month cumulative incidence of HF onset for riluzole versus control patients was 4.96% versus 7.27%, calculating hazard ratio (HR) [95% CI, p-value] of 0.55 [0.40-0.76, p < 0.01]. The HR estimates favoring riluzole over the ALS control were consistent across the 3 months to 2-year follow-up. The clinically and statistically significant effect on HF onset was driven by the lower rate of HFrEF with the 2-year HR [95% CI] of 0.46 [0.21-0.99].

CONCLUSIONS: Riluzole is associated with a lower rate of HF onset, suggesting a potential prevention strategy for early management.}, } @article {pmid39786151, year = {2025}, author = {Harrison, J and Bhardwaj, A and Houck, O and Sather, K and Sekiya, A and Knack, S and Saarunya Clarke, G and Puskarich, MA and Tignanelli, C and Rogers, L and Marmor, S and Beilman, G}, title = {Emergency medical services level of training is associated with mortality in trauma patients: A combined prehospital and in hospital database analysis.}, journal = {The journal of trauma and acute care surgery}, volume = {98}, number = {3}, pages = {402-409}, pmid = {39786151}, issn = {2163-0763}, mesh = {Humans ; Male ; Middle Aged ; Female ; *Wounds and Injuries/mortality/therapy ; Adult ; *Emergency Medical Services/statistics & numerical data ; Aged ; Trauma Centers/statistics & numerical data ; Propensity Score ; Databases, Factual ; Young Adult ; Retrospective Studies ; Adolescent ; Aged, 80 and over ; Emergency Medical Technicians/education/statistics & numerical data ; }, abstract = {BACKGROUND: There is conflicting evidence regarding emergency medical service (EMS) provider level of training and outcomes in trauma. We hypothesized that advanced life support (ALS) provider transport is associated with lower mortality compared with basic life support transport.

METHODS: We performed secondary analysis of a combined prehospital and in-hospital database of trauma patients utilizing ESO electronic medical records from 2018 to 2022. We included encounters with patients aged 15 years to 100 years transported by ground to a Level I or II trauma center with trauma-specific ICD-10-CM codes. Patients dead upon EMS arrival and transfers were excluded. We matched patients using 1:1 nearest neighbor propensity scores based on demographic, injury, and EMS characteristics, prehospital vitals, and trauma center designation. The exposure variable was EMS level of training and outcome was mortality. We conducted subgroup analyses on predefined cohorts (age > 50 years, mechanism of injury, prehospital EMS time > 30 minutes).

RESULTS: We identified 30,735 ALS and 1,758 basic life support encounters, representing 1,154 pairs following propensity matching. Mortality was lower among patients transported by ALS providers (odds ratio [OR], 0.40; 95% confidence interval [CI], 0.18-0.88; p = 0.023). Mortality was also lower in the subgroups of patients aged > 50 years (OR, 0.35; 95% CI, 0.13-0.98; p = 0.046), and in patients with mechanisms of injury excluding falls (OR, 0.35; 95% CI, 0.13-0.98; p = 0.047). In those with prolonged prehospital time, the association approached significance (OR, 0.30; 95% CI, 0.08-1.08; p = 0.067). In those with mechanisms of injury of fall, the association was not significant.

CONCLUSION: In this retrospective, propensity matched cohort study using a national sample of trauma patients, attendance by ALS providers was associated with reduced mortality. This was observed in the entire cohort, in those aged > 50 years, and those with a higher-risk mechanism of injury. It approached significance in those with prolonged prehospital time.

LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.}, } @article {pmid39783196, year = {2025}, author = {Lee, I and Mitsumoto, H and Lee, S and Kasarskis, E and Rosenbaum, M and Factor-Litvak, P and Nieves, JW}, title = {Interaction between riluzole treatment and dietary glycemic index in the disease progression of amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {3}, pages = {491-498}, pmid = {39783196}, issn = {2328-9503}, support = {K23 NS131586/NS/NINDS NIH HHS/United States ; K23NS131586/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Riluzole/pharmacology/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Male ; Female ; Middle Aged ; *Disease Progression ; *Glycemic Index/drug effects/physiology ; Aged ; *Neuroprotective Agents/pharmacology/administration & dosage ; Cohort Studies ; Adult ; }, abstract = {OBJECTIVE: We examined whether riluzole treatment modifies the associations between the dietary glycemic index (GI) and load (GL) and disease progression in amyotrophic lateral sclerosis (ALS).

METHODS: Sporadic ALS patients in the Multicenter Cohort Study of Oxidative Stress who completed a baseline food frequency questionnaire were included (n = 304). Interactions between baseline riluzole treatment and GI/GL on functional decline and tracheostomy-free survival were examined using linear regression and Cox proportional hazard models adjusted for covariates. Age, sex, disease duration, diagnostic certainty, body mass index, bulbar onset, revised ALS functional rating scale (ALSFRS-r) total score, and forced vital capacity, from baseline were included as covariates.

RESULTS: Baseline higher GI and GL were associated with less decline of ALSFRS-r total score at 3-month follow-up in the riluzole treatment group (RTG) but not in the no-riluzole group (NRG). When quartile groups were used, GI second [β = -1.9, 95% CI (-4.1, -0.2), p = 0.07], third [β = -3.0, 95% CI (-5.1, -0.8), p < 0.01] and fourth [β = -2.2, 95% CI (-4.3, -0.01), p < 0.05] quartile groups were associated with less ALSFRS-r decline at 3-months compared to the first quartile group (GI < 47.2) among the RTG. Similarly, GL fourth quartile group (GL > 109.5) was associated with less ALSFRS-r decline at 3 months compared to the first quartile group [β = -2.6, 95% CI (-4.7, -0.5), p < 0.05] among the RTG. In NRG, no statistically significant differences in ALSFRS-r decline were found among GI/GL quartile groups.

INTERPRETATION: High dietary GI and GL are associated with a slower functional decline only among ALS patients taking riluzole.}, } @article {pmid39783194, year = {2025}, author = {Smith, SE and McCoy-Gross, K and Malcolm, A and Oranski, J and Markway, JW and Miller, TM and Bucelli, RC}, title = {Tofersen treatment leads to sustained stabilization of disease in SOD1 ALS in a "real-world" setting.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {2}, pages = {311-319}, pmid = {39783194}, issn = {2328-9503}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/physiopathology ; Male ; Female ; *Superoxide Dismutase-1/genetics ; Middle Aged ; Aged ; *Neurofilament Proteins/blood ; Disease Progression ; Muscle Strength/drug effects/physiology ; Adult ; }, abstract = {OBJECTIVE: Patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1 ALS) treated with tofersen have shown slowing of disease progression, and disease stabilization with recovery of function in some patients. We report our clinical experience with treating patients with SOD1 ALS and the effects of tofersen on outcome measures.

METHODS: This was a single-center observational study of patients with SOD1 ALS receiving treatment with tofersen. The effects of tofersen treatment on neurofilament levels, muscle strength, and clinical outcome measures were assessed. Several patients had outpatient neuromuscular rehabilitation in addition to tofersen treatment and we report changes in functional outcomes.

RESULTS: Seven SOD1 ALS patients received treatment at our institution. All patients showed robust and sustained declines in serum NfL and CSF pNFH (mean change serum NfL: -57.9%; mean change CSF pNFH: -67.6%). There was apparent disease stabilization as assessed by the ALSFRS-R total score, mean change 1.1 (SD = 0.7). There was notable improvement in functional independence measured by the FIM motor score, mean change 5.13 points (SD = 3.85).

INTERPRETATION: This study provides evidence that tofersen treatment in SOD1 ALS can lead to meaningful preservation of function and suggestions of sustained improvement in neurologic function in some patients, and strongly supports the role of neurofilaments as therapeutic biomarkers.}, } @article {pmid39779800, year = {2025}, author = {Regondi, S and Donvito, G and Frontoni, E and Kostovic, M and Minazzi, F and Bratières, S and Filosto, M and Pugliese, R}, title = {Artificial intelligence empowered voice generation for amyotrophic lateral sclerosis patients.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1361}, pmid = {39779800}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/therapy/complications/psychology ; Humans ; *Artificial Intelligence ; *Voice ; Female ; Male ; Middle Aged ; *Quality of Life ; Aged ; Communication Aids for Disabled ; Speech/physiology ; Adult ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that can result in a progressive loss of speech due to bulbar dysfunction, which can have significant negative impact on the patient's mental well-being. Alternative Augmentative Communication (AAC) strategies based on synthetic voices have been shown to assist patients in maintaining communication and improving their Quality of Life (QoL). However, such synthetic voices are often perceived as impersonal and fail to capture the unique voice and identity of the patient. To tackle this issue, combining voice banking (VB) and artificial intelligence (AI) has emerged as a more natural communication strategy, enabling individuals to preserve their voice for use with AAC devices as needed. This involves recording speech samples to generate a synthetic voice closely resembling the individual's own. Despite the increasing interest in VB, there's a lack of clear strategies for its effective implementation in rapidly progressing diseases like ALS. Additionally, the perceptual quality of VB on patients with preserved speech, especially when offered early in the disease, remains poorly understood. In light of these challenges, this study aims to assess the effectiveness and the perceptual impact of AI-generated voices on ALS patients with preserved speech, utilizing a personalized voice synthesis system based on machine learning. The AI-generated patient-specific voice is achieved through voice recording, followed by fine-tuning using a Generative Adversarial Network for Efficient and High Fidelity Speech Synthesis (HiFi-GAN), resulting in a model capable of producing speech highly similar to the patient's own voice, with exceptional expressive and audio quality. By addressing these aspects, this study intends to offer valuable insights into the potential benefits and challenges of combining VB with AI voices to enhance communication support for ALS patients.}, } @article {pmid39779704, year = {2025}, author = {Kempthorne, L and Vaizoglu, D and Cammack, AJ and Carcolé, M and Roberts, MJ and Mikheenko, A and Fisher, A and Suklai, P and Muralidharan, B and Kroll, F and Moens, TG and Yshii, L and Verschoren, S and Hölbling, BV and Moreira, FC and Katona, E and Coneys, R and de Oliveira, P and Zhang, YJ and Jansen, K and Daughrity, LM and McGown, A and Ramesh, TM and Van Den Bosch, L and Lignani, G and Rahim, AA and Coyne, AN and Petrucelli, L and Rihel, J and Isaacs, AM}, title = {Dual-targeting CRISPR-CasRx reduces C9orf72 ALS/FTD sense and antisense repeat RNAs in vitro and in vivo.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {459}, pmid = {39779704}, issn = {2041-1723}, support = {/WT_/Wellcome Trust/United Kingdom ; 217150/Z/19/Z//Wellcome Trust (Wellcome)/ ; 648716 - C9ND//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Humans ; *Frontotemporal Dementia/genetics/metabolism ; Animals ; *CRISPR-Cas Systems ; *RNA, Antisense/genetics ; Mice ; HEK293 Cells ; *Induced Pluripotent Stem Cells/metabolism ; DNA Repeat Expansion/genetics ; Disease Models, Animal ; Neurons/metabolism ; Genetic Therapy/methods ; }, abstract = {The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is an intronic G4C2 repeat expansion in C9orf72. The repeats undergo bidirectional transcription to produce sense and antisense repeat RNA species, which are translated into dipeptide repeat proteins (DPRs). As toxicity has been associated with both sense and antisense repeat-derived RNA and DPRs, targeting both strands may provide the most effective therapeutic strategy. CRISPR-Cas13 systems mature their own guide arrays, allowing targeting of multiple RNA species from a single construct. We show CRISPR-Cas13d variant CasRx effectively reduces overexpressed C9orf72 sense and antisense repeat transcripts and DPRs in HEK cells. In C9orf72 patient-derived iPSC-neuron lines, CRISPR-CasRx reduces endogenous sense and antisense repeat RNAs and DPRs and protects against glutamate-induced excitotoxicity. AAV delivery of CRISPR-CasRx to two distinct C9orf72 repeat mouse models significantly reduced both sense and antisense repeat-containing transcripts. This highlights the potential of RNA-targeting CRISPR systems as therapeutics for C9orf72 ALS/FTD.}, } @article {pmid39779681, year = {2025}, author = {McCallister, TX and Lim, CKW and Singh, M and Zhang, S and Ahsan, NS and Terpstra, WM and Xiong, AY and Zeballos C, MA and Powell, JE and Drnevich, J and Kang, Y and Gaj, T}, title = {A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {460}, pmid = {39779681}, issn = {2041-1723}, support = {1R01NS123556-01A1//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 1U01NS122102-01A1//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 5R01GM141296//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; MDA602798//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; R01 GM141296/GM/NIGMS NIH HHS/United States ; 20-IIP-516//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; T32 EB019944/EB/NIBIB NIH HHS/United States ; U01 NS122102/NS/NINDS NIH HHS/United States ; R01 NS123556/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *CRISPR-Cas Systems ; Humans ; Animals ; DNA Repeat Expansion/genetics ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Mice ; }, abstract = {An abnormal expansion of a GGGGCC (G4C2) hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving transcribed forms of the repeat expansion. By utilizing a Cas13 variant with reduced collateral effects, we develop here a high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to the brain of a transgenic rodent model, this Cas13-based platform curbed the expression of the G4C2 repeat-containing RNA without affecting normal C9ORF72 levels, which in turn decreased the formation of RNA foci, reduced the production of a dipeptide repeat protein, and reversed transcriptional deficits. This high-fidelity system possessed improved transcriptome-wide specificity compared to its native form and mediated targeting in motor neuron-like cells derived from a patient with ALS. These results lay the foundation for the implementation of RNA-targeting CRISPR technologies for C9ORF72-linked ALS/FTD.}, } @article {pmid39779313, year = {2025}, author = {Xiao, Y and Tan, Y and Li, C and Wei, Q and Jiang, Q and Wang, S and Yang, T and Lin, J and Zhang, L and Shang, H}, title = {Genetic and clinical analysis of OPTN in amyotrophic lateral sclerosis.}, journal = {Journal of medical genetics}, volume = {62}, number = {4}, pages = {242-248}, doi = {10.1136/jmg-2024-109978}, pmid = {39779313}, issn = {1468-6244}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; *Cell Cycle Proteins/genetics ; *Membrane Transport Proteins/genetics ; *Transcription Factor TFIIIA/genetics ; Male ; Female ; Middle Aged ; Mutation ; Phenotype ; Aged ; Genetic Association Studies/methods ; Adult ; Genetic Predisposition to Disease ; Asian People/genetics ; Genotype ; }, abstract = {BACKGROUND: Considerable heterogeneity in genotypes and phenotypes has been observed among patients with amyotrophic lateral sclerosis (ALS) harbouring optineurin gene (OPTN) mutations, as reported in prior studies. The study aimed to elucidate the correlation between OPTN genotypes and phenotypes.

METHODS: OPTN gene variants were screened within a substantial Chinese cohort of patients with ALS, encompassing LoF and rare missense variants. Additionally, a systematic literature review was conducted to compile the spectrum of OPTN mutations and explore the relationship between the genotype and phenotype of patients with ALS with OPTN.

RESULTS: A total of 33 unrelated patients with ALS with 24 rare OPTN variants, including 17 novel variants, were identified in 2279 patients with ALS. Among 24 variants in our cohort and 106 variants in previous studies, only 33.3% and 35.8% were pathogenic/likely pathogenic variants. Moreover, the frequency of OPTN variants in the Asian ALS population was higher (1.08%) than that of the Caucasian population (0.55%). For the phenotype of patients with ALS carrying OPTN variants, we found that patients with pathogenic/likely pathogenic variants had the highest baseline progression rate and the shortest survival time among groups in our cohort.

CONCLUSION: Our study contributed to a broader understanding of the genotype and phenotype spectrum of patients with ALS carrying OPTN variants. Further investigations are warranted to definitively establish the genotype-phenotype associations.}, } @article {pmid39778888, year = {2025}, author = {Etxebeste-Mitxeltorena, M and Flores-Romero, H and Ramos-Inza, S and Masiá, E and Nenchova, M and Montesinos, J and Martinez-Gonzalez, L and Porras, G and Orzáez, M and Vicent, MJ and Gil, C and Area-Gomez, E and Garcia-Saez, AJ and Martinez, A}, title = {Modulation of Mitochondria-Endoplasmic Reticulum Contacts (MERCs) by Small Molecules as a New Strategy for Restoring Lipid Metabolism in an Amyotrophic Lateral Sclerosis Model.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {2}, pages = {1179-1194}, pmid = {39778888}, issn = {1520-4804}, support = {/ERC_/European Research Council/International ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Humans ; *Endoplasmic Reticulum/metabolism/drug effects ; *Mitochondria/metabolism/drug effects ; *Lipid Metabolism/drug effects ; *Small Molecule Libraries/pharmacology/chemistry ; Cholesterol/metabolism ; HCT116 Cells ; Mitochondria Associated Membranes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without effective treatment. The progressive motoneuron death in ALS is associated with alterations in lipid metabolism. As its regulation occurs in mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), modulation of mitochondria-ER contacts (MERCs) is emerging as a crucial factor in MAM formation and lipid metabolism control. Using the MERLIN biosensor in a high-throughput screening within the EU-OPENSCREEN ERIC, we discovered small molecules that increase MERCs in HCT116 cells, enhancing their ability to uptake cholesterol. We demonstrated that cholesterol trafficking is decreased in an ALS patient-derived cell model, and this trafficking is restored after treatment with the discovered MERC modulator 24. Electron microscopy revealed that treatment with compound 24 increases MERCs, promotes lipid droplet formation, and restores mitochondrial cristae. Overall, the brain-permeable MERC modulator, compound 24, may serve as a valuable pharmacological tool for studying MAM function and holds potential for in vivo studies in ALS and other MAM dysfunction diseases.}, } @article {pmid39778605, year = {2025}, author = {Urano, Y and Iwagaki, A and Takeishi, A and Uchiyama, N and Noguchi, N}, title = {Downregulation of the SREBP pathways and disruption of redox status by 25-hydroxycholesterol predispose cells to ferroptosis.}, journal = {Free radical biology & medicine}, volume = {228}, number = {}, pages = {319-328}, doi = {10.1016/j.freeradbiomed.2025.01.010}, pmid = {39778605}, issn = {1873-4596}, mesh = {*Hydroxycholesterols/metabolism ; *Ferroptosis/drug effects/genetics ; Animals ; Mice ; *Oxidation-Reduction ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics ; Signal Transduction ; Schwann Cells/metabolism/drug effects/pathology ; Down-Regulation ; Sterol Regulatory Element Binding Protein 1/metabolism/genetics ; Sterol Regulatory Element Binding Protein 2/metabolism/genetics ; Cell Line ; Cell Survival/drug effects ; Humans ; Steroid Hydroxylases ; }, abstract = {Enzymatically formed side-chain oxysterols function as signaling molecules regulating cholesterol homeostasis and act as intermediates in the biosynthesis of bile acids. In addition to these physiological functions, an imbalance in oxysterol homeostasis has been implicated in pathophysiology. Cholesterol 25-hydroxylase (CH25H) and its product 25-hydroxycholesterol (25-OHC), also formed by autoxidation, are associated with amyotrophic lateral sclerosis. However, the effects of 25-OHC on cell viability in glial cells remain unclear. This study demonstrates that 25-OHC induces ferroptosis, an iron-dependent programmed cell death, in mouse Schwann IMS32 cells. Mechanistically, 25-OHC suppressed the expression of selenoprotein glutathione peroxidase 4 (GPX4) at both the transcriptional and translational levels by inhibiting the processing of sterol regulatory element-binding proteins (SREBPs). In addition, 25-OHC upregulated the expression of NADH-cytochrome b5 reductase 1 (CYB5R1) and NADPH-cytochrome P450 reductase (POR), enzymes that promote lipid peroxidation. We further found that 25-OHC increases the expression of glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) and decreases glutathione levels. Importantly, non-cytotoxic concentrations of 25-OHC enhanced cellular sensitivity to ferroptosis inducers by downregulating GPX4 expression. These findings reveal a multifaceted approach whereby 25-OHC induces ferroptosis through SREBP pathway suppression and redox imbalance in mouse Schwann IMS32 cells.}, } @article {pmid39778593, year = {2025}, author = {Chen, Q and Chen, G and Wang, Q}, title = {Application of Network Pharmacology in the Treatment of Neurodegenerative Diseases with Traditional Chinese Medicine.}, journal = {Planta medica}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2512-8928}, pmid = {39778593}, issn = {1439-0221}, support = {2023AFB677//the Natural Science Foundation of Hubei Province/ ; 2024AFB578//the Natural Science Foundation of Hubei Province/ ; 2023LYYYGZRP0003//the Intramural Research Program of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology/ ; 2023LYYYSZRP0001//the Intramural Research Program of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology/ ; }, abstract = {In recent years, the incidence of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, has exhibited a steadily rising trend, which has posed a major challenge to the global public health. Traditional Chinese medicine, with its multicomponent and multitarget characteristics, offers a promising approach to treating neurodegenerative diseases. However, comprehensively elucidating the complex mechanisms underlying traditional Chinese medicine formulations remains challenging. As an emerging systems biology method, network pharmacology has provided a vital tool for revealing the multitarget mechanisms of traditional Chinese medicine through high-throughput technologies, molecular docking, and network analysis. This paper reviews the advancements in the application of network pharmacology in treating neurodegenerative diseases using traditional Chinese medicine, analyzes the current status of relevant databases and technological methods, discusses the limitations, and proposes future directions to promote the modernization of traditional Chinese medicine and the development of precision medicine.}, } @article {pmid39778572, year = {2025}, author = {Je, Y and Park, YE and Shin, YB}, title = {Differentiating Inclusion Body Myositis From Amyotrophic Lateral Sclerosis Based on the Features of Dysphagia: Insights From a Patient With Rapidly Progressive Dysphagia.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {21}, number = {1}, pages = {83-85}, pmid = {39778572}, issn = {1738-6586}, support = {/PNUH/Pusan National University Hospital/Korea ; }, } @article {pmid39777244, year = {2025}, author = {Moura, FA and Siqueira, AIAN}, title = {Gut-liver axis in sepsis-associated liver injury: Epidemiology, challenges and clinical practice.}, journal = {World journal of gastroenterology}, volume = {31}, number = {1}, pages = {99987}, pmid = {39777244}, issn = {2219-2840}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Sepsis/complications/epidemiology ; *Dysbiosis ; *Liver/metabolism/pathology ; Animals ; *Oxidative Stress ; Bacterial Translocation ; Liver Diseases/epidemiology/microbiology ; Critical Illness ; Intensive Care Units/statistics & numerical data ; Anti-Bacterial Agents/therapeutic use ; }, abstract = {Although the liver has a remarkable regenerative capacity, sepsis-associated liver injury (SLI) is a complication often seen in intensive care units. Due to its role in immune and inflammatory regulation, the liver is particularly vulnerable during severe infections. Understanding the global prevalence, causes, and management of SLI is essential to improve outcomes and reduce healthcare costs. This paper aims to explore these factors, with an emphasis on identifying effective strategies for clinical management. Zhang et al's bibliometric analysis of 787 publications (745 original articles and 42 reviews, mostly in animal models) from 2000 to 2023 highlights the growing interest in SLI, focusing on oxidative stress, gut microbiota, and inflammatory processes. Key components such as nuclear factor-kappa B and the NOD-like receptor thermal protein domain associated protein 3 inflammasome pathway, along with their links to gut microbiota imbalance and oxidative stress, are crucial for understanding SLI pathogenesis. The gut-liver axis, particularly the role of intestinal permeability and bacterial translocation in liver inflammation, is emphasized. In this context, bacterial translocation is especially relevant for critically ill patients, as it can exacerbate liver inflammation. The findings underscore the need for integrated care in intensive care units, prioritizing gut health and careful antibiotic use to prevent dysbiosis. Despite extensive research, there remains a lack of clinical trials to validate therapeutic approaches. The abundance of experimental studies highlights potential therapeutic targets, stressing the need for high-quality randomized clinical trials to translate these findings into clinical practice.}, } @article {pmid39776752, year = {2024}, author = {Schwamburger, J and Brock, K and Cooper, R}, title = {The effect of GV-58, a calcium channel modifier, on synaptic transmission at the larval Drosophila and crayfish neuromuscular junctions.}, journal = {microPublication biology}, volume = {2024}, number = {}, pages = {}, pmid = {39776752}, issn = {2578-9430}, abstract = {GV-58 is known to increase the opening time of the mammalian P-type calcium channel in presynaptic motor nerve terminals. GV-58 is suggested as a therapeutic agent for dampening the symptoms of amyotrophic lateral sclerosis. To further understand the mechanisms of GV-58 actions, the Drosophila and crayfish neuromuscular junctions were used as models. Their presynaptic calcium channels are a P-type based on pharmacology profiles. However, exposure of GV-58 (1mM) did not produce any consistent alteration in synaptic transmission in these two preparations. It is possible that the molecular structure of the P-type channels is different in the Drosophila and crayfish.}, } @article {pmid39776251, year = {2025}, author = {Öijerstedt, L and Foucher, J and Lovik, A and Yazdani, S and Juto, A and Kläppe, U and Fang, F and Ingre, C}, title = {Correction: Repeated cognitive assessments show stable function over time in patients with ALS.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {104}, doi = {10.1007/s00415-024-12833-z}, pmid = {39776251}, issn = {1432-1459}, } @article {pmid39775908, year = {2025}, author = {de Vries, E and Hagbohm, C and Ouellette, R and Granberg, T}, title = {Clinical 7 Tesla magnetic resonance imaging: Impact and patient value in neurological disorders.}, journal = {Journal of internal medicine}, volume = {297}, number = {3}, pages = {244-261}, pmid = {39775908}, issn = {1365-2796}, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Nervous System Diseases/diagnostic imaging ; Neuroimaging/methods ; }, abstract = {Magnetic resonance imaging (MRI) is a cornerstone of non-invasive diagnostics and treatment monitoring, particularly for diseases of the central nervous system. Although 1.5- and 3 Tesla (T) field strengths remain the clinical standard, the advent of 7 T MRI represents a transformative step forward, offering superior spatial resolution, contrast, and sensitivity for visualizing neuroanatomy, metabolism, and function. Recent innovations, including parallel transmission and deep learning-based reconstruction, have resolved many prior technical challenges of 7 T MRI, enabling its routine clinical use. This review examines the diagnostic impact, patient value, and practical considerations of 7 T MRI, emphasizing its role in facilitating earlier diagnoses and improving care in conditions, such as amyotrophic lateral sclerosis (ALS), epilepsy, multiple sclerosis (MS), dementia, parkinsonism, tumors, and vascular diseases. Based on insights from over 1200 clinical scans with a second-generation 7 T system, the review highlights disease-specific biomarkers such as the motor band sign in ALS and the new diagnostic markers in MS, the central vein sign, and paramagnetic rim lesions. The unparalleled ability of 7 T MRI to study neurological diseases ex vivo at ultra-high resolution is also explored, offering new opportunities to understand pathophysiology and identify novel treatment targets. Additionally, the review provides a clinical perspective on patient handling and safety considerations, addressing challenges and practicalities associated with clinical 7 T MRI. By bridging research and clinical practice, 7 T MRI has the potential to redefine neuroimaging and advance the understanding and management of complex neurological disorders.}, } @article {pmid39775401, year = {2025}, author = {Grassi, M and Tarantino, B}, title = {SEMdag: Fast learning of Directed Acyclic Graphs via node or layer ordering.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0317283}, pmid = {39775401}, issn = {1932-6203}, mesh = {Humans ; *Algorithms ; *COVID-19 ; SARS-CoV-2 ; Breast Neoplasms ; Software ; }, abstract = {A Directed Acyclic Graph (DAG) offers an easy approach to define causal structures among gathered nodes: causal linkages are represented by arrows between the variables, leading from cause to effect. Recently, industry and academics have paid close attention to DAG structure learning from observable data, and many techniques have been put out to address the problem. We provide a two-step approach, named SEMdag(), that can be used to quickly learn high-dimensional linear SEMs. It is included in the R package SEMgraph and employs a two-stage order-based search using previous knowledge (Knowledge-based, KB) or data-driven method (Bottom-up, BU), under the premise that a linear SEM with equal variance error terms is assumed. We evaluated our framework's for finding plausible DAGs against six well-known causal discovery techniques (ARGES, GES, PC, LiNGAM, CAM, NOTEARS). We conducted a series of experiments using observed expression (or RNA-seq) data, taking into account a pair of training and testing datasets for four distinct diseases: Amyotrophic Lateral Sclerosis (ALS), Breast cancer (BRCA), Coronavirus disease (COVID-19) and ST-elevation myocardial infarction (STEMI). The results show that the SEMdag() procedure can recover a graph structure with good disease prediction performance evaluated by a conventional supervised learning algorithm (RF): in the scenario where the initial graph is sparse, the BU approach may be a better choice than the KB one; in the case where the graph is denser, both BU an KB report high performance, with highest score for KB approach based on topological layers. Besides its superior disease predictive performance compared to previous research, SEMdag() offers the user the flexibility to define distinct structure learning algorithms and can handle high dimensional issues with less computing load. SEMdag() function is implemented in the R package SEMgraph, easily available at https://CRAN.R-project.org/package=SEMgraph.}, } @article {pmid39774976, year = {2025}, author = {Naito, H and Nakamori, M and Toko, M and Hayashi, Y and Tazuma, T and Watanabe, T and Ishihara, K and Tachiyama, K and Yamazaki, Y and Maruyama, H}, title = {A single-center, single-arm, prospective, open-label, and comparative trial to evaluate the safety and tolerability profile of a 90-day oral L-arginine hydrochloride intervention for patients with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1120}, pmid = {39774976}, issn = {2045-2322}, support = {23K16642//Japan Society for the Promotion of Science/ ; NA//ALS Foundation, Japan ALS Association/ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Administration, Oral ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Arginine/administration & dosage/adverse effects/therapeutic use ; Nutritional Status ; Prospective Studies ; Treatment Outcome ; }, abstract = {Weight loss, a key indicator of malnutrition in amyotrophic lateral sclerosis (ALS) patients, negatively impacts patient prognosis. However, effective nutritional interventions have not been adequately established. Research in ALS model mice has shown that L-arginine can prolong survival; however, no human intervention studies have been conducted. We conducted a single-center, single-arm, prospective, open-label, and comparative trial to assess the safety and tolerability of L-arginine hydrochloride in ALS patients. ALS patients were administered 15 g/day L-arginine hydrochloride for 90 days. The primary outcome of safety was evaluated on days 45 and 90. The secondary outcome of efficacy was evaluated by measuring nutritional status, ALS Functional Rating Scale (ALSFRS) scores, and the occurrence of events such as the initiation of tracheostomy positive pressure ventilation (TPPV) and death. The study included 20 patients (40% female; mean age, 62.0 ± 6.9 years; median disease duration, 1.9 years). Six participants (30%) experienced treatment-emergent adverse events (TEAEs), including elevated creatine kinase levels, liver function test abnormalities, glucose tolerance issues, hyperammonemia, anorexia, dysgeusia, and vasculitis. No serious TEAEs were associated with L-arginine hydrochloride. Over the course of three months, the average changes in body weight, body mass index, and the ALSFRS score were - 0.37 kg, -1.1 kg/m[2], and - 1.7 points, respectively. There were no events requiring TPPV initiation or deaths. This study demonstrated that the oral administration of L-arginine hydrochloride over three months was well tolerated by ALS patients, with no serious TEAEs or deaths attributed to the study drug.Trial Registration number: Japan Registry of Clinical Trials (jRCTs061230001), first registered 11/04/2023.}, } @article {pmid39772789, year = {2025}, author = {Stolwyk, K and Lee, I}, title = {Rapid progression of amyotrophic lateral sclerosis after initiation of GLP-1 agonist: a case report.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2024.2446847}, pmid = {39772789}, issn = {2167-9223}, } @article {pmid39771101, year = {2024}, author = {Chetverikova, D and Bakaeva, M and Starikov, S and Kendjieva, A and Chetverikov, S}, title = {The Influence of Plant Growth-Stimulating Bacteria on the Glutathione-S-Transferase Activity and the Toxic Effect of the Herbicide Metsulfuron-Methyl in Wheat and Canola Plants.}, journal = {Toxics}, volume = {12}, number = {12}, pages = {}, pmid = {39771101}, issn = {2305-6304}, support = {23-26-00097//Russian Science Foundation/ ; }, abstract = {The ability of some rhizosphere bacteria to mitigate herbicidal stress in cultivated plants may be useful in agriculture and bioremediation. There is poor understanding of how bacteria directly or through herbicide degradation affect the biochemical processes in plants exposed to sulfonylurea herbicides. In this study, treatment with a combination of herbicide metsulfuron-methyl (MSM) and bacteria (Pseudomonas protegens DA1.2 or P. chlororaphis 4CH) of wheat (Triticum aestivum L.) and canola (Brassica napus L.) plants was carried out. Activity of glutathione-S-transferase (GST), an important enzyme for the herbicide detoxification, and acetolactate synthase (ALS), a target for MSM in plants, was measured by spectrophotometric assays. MSM residues were analyzed using the HPLC-MS. Then, 24 h after bacterial treatment, GST activity increased by 75-91% in wheat and by 38-94% in canola. On the 30th day, a decrease in MSM in the soil associated with bacterial treatment was 54.6-79.7%. An increase in GST activity and acceleration of MSM degradation were accompanied by a decrease in inhibition of the ALS enzyme in plants, which indicated a mitigation of the toxic effect. The results obtained are evidence that rhizospheric bacteria can have beneficial effects on plants exposed to MSM due to the combination of abilities to directly affect detoxification enzymes in plants and degrade MSM in the soil.}, } @article {pmid39770989, year = {2024}, author = {Pekdemir, B and Raposo, A and Saraiva, A and Lima, MJ and Alsharari, ZD and BinMowyna, MN and Karav, S}, title = {Mechanisms and Potential Benefits of Neuroprotective Agents in Neurological Health.}, journal = {Nutrients}, volume = {16}, number = {24}, pages = {}, pmid = {39770989}, issn = {2072-6643}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy ; Brain/drug effects/metabolism ; Animals ; Flavonoids/pharmacology/therapeutic use ; Apoptosis/drug effects ; Antioxidants/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {The brain contains many interconnected and complex cellular and molecular mechanisms. Injury to the brain causes permanent dysfunctions in these mechanisms. So, it continues to be an area where surgical intervention cannot be performed except for the removal of tumors and the repair of some aneurysms. Some agents that can cross the blood-brain barrier and reach neurons show neuroprotective effects in the brain due to their anti-apoptotic, anti-inflammatory and antioxidant properties. In particular, some agents act by reducing or modulating the accumulation of protein aggregates in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and prion disease) caused by protein accumulation. Substrate accumulation causes increased oxidative stress and stimulates the brain's immune cells, microglia, and astrocytes, to secrete proinflammatory cytokines. Long-term or chronic neuroinflammatory response triggers apoptosis. Brain damage is observed with neuronal apoptosis and brain functions are impaired. This situation negatively affects processes such as motor movements, memory, perception, and learning. Neuroprotective agents prevent apoptosis by modulating molecules that play a role in apoptosis. In addition, they can improve impaired brain functions by supporting neuroplasticity and neurogenesis. Due to the important roles that these agents play in central nervous system damage or neurodegenerative diseases, it is important to elucidate many mechanisms. This review provides an overview of the mechanisms of flavonoids, which constitute a large part of the agents with neuroprotective effects, as well as vitamins, neurotransmitters, hormones, amino acids, and their derivatives. It is thought that understanding these mechanisms will enable the development of new therapeutic agents and different treatment strategies.}, } @article {pmid39770252, year = {2024}, author = {Guo, H and Yao, J and Chen, S and Qian, C and Pan, X and Yin, K and Zhu, H and Gao, X and Wang, S and Sun, L}, title = {Enhancing Resistive Switching in AlN-Based Memristors Through Oxidative Al2O3 Layer Formation: A Study on Preparation Techniques and Performance Impact.}, journal = {Micromachines}, volume = {15}, number = {12}, pages = {}, pmid = {39770252}, issn = {2072-666X}, support = {11874105//National Natural Science Foundation of China/ ; }, abstract = {Aluminum nitride (AlN) with a wide band gap (approximately 6.2 eV) has attractive characteristics, including high thermal conductivity, a high dielectric constant, and good insulating properties, which are suitable for the field of resistive random access memory. AlN thin films were deposited on ITO substrate using the radio-frequency magnetron sputtering technique. Al's and Au's top electrodes were deposited on AlN thin films to make a Au/Al/AlN/ITO sandwich structure memristor. The effects of the Al2O3 film on the on/off window and voltage characteristics of the device were investigated. The deposition time and nitrogen content in the sputtering atmosphere were changed to adjust the thickness and composition of AlN films, respectively. The possible mechanism of resistive switching was examined via analyses of the electrical resistive switching characteristics, forming voltage, and switching ratio.}, } @article {pmid39769215, year = {2024}, author = {Wei, Z and Iyer, MR and Zhao, B and Deng, J and Mitchell, CS}, title = {Artificial Intelligence-Assisted Comparative Analysis of the Overlapping Molecular Pathophysiology of Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769215}, issn = {1422-0067}, support = {1944247//National Science Foundation/ ; R35GM152245/NH/NIH HHS/United States ; U19-AG056169/NH/NIH HHS/United States ; 253558//Chan Zuckerberg Initiative/ ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/physiopathology ; *Alzheimer Disease/metabolism/genetics/physiopathology/pathology ; *Artificial Intelligence ; Algorithms ; }, abstract = {The overlapping molecular pathophysiology of Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Frontotemporal Dementia (FTD) was analyzed using relationships from a knowledge graph of 33+ million biomedical journal articles. The unsupervised learning rank aggregation algorithm from SemNet 2.0 compared the most important amino acid, peptide, and protein (AAPP) nodes connected to AD, ALS, or FTD. FTD shared 99.9% of its nodes with ALS and AD; AD shared 64.2% of its nodes with FTD and ALS; and ALS shared 68.3% of its nodes with AD and FTD. The results were validated and mapped to functional biological processes using supervised human supervision and an external large language model. The overall percentages of mapped intersecting biological processes were as follows: inflammation and immune response, 19%; synapse and neurotransmission, 19%; cell cycle, 15%; protein aggregation, 12%; membrane regulation, 11%; stress response and regulation, 9%; and gene regulation, 4%. Once normalized for node count, biological mappings for cell cycle regulation and stress response were more prominent in the intersection of AD and FTD. Protein aggregation, gene regulation, and energetics were more prominent in the intersection of ALS and FTD. Synapse and neurotransmission, membrane regulation, and inflammation and immune response were greater at the intersection of AD and ALS. Given the extensive molecular pathophysiology overlap, small differences in regulation, genetic, or environmental factors likely shape the underlying expressed disease phenotype. The results help prioritize testable hypotheses for future clinical or experimental research.}, } @article {pmid39769213, year = {2024}, author = {Gu, A and Zhang, Y and He, J and Zhao, M and Ding, L and Liu, W and Xiao, J and Huang, J and Liu, M and Liu, X}, title = {Chronic Oxidative Stress and Stress Granule Formation in UBQLN2 ALS Neurons: Insights into Neuronal Degeneration and Potential Therapeutic Targets.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769213}, issn = {1422-0067}, support = {2016YFC0905100//National Key Research and Development Program of China/ ; 2021JJ30801//Natural Science Foundation of Hunan Province, China/ ; kq2202077//Natural Science Foundation of Changsha, China/ ; 1053320222758//Fundamental Research Funds for the Central Universities of Central South University/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Autophagy-Related Proteins/metabolism/genetics ; *Oxidative Stress ; *Motor Neurons/metabolism/pathology ; Adaptor Proteins, Signal Transducing/metabolism/genetics ; Stress Granules/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Autophagy ; Cell Cycle Proteins/metabolism/genetics ; Nerve Degeneration/pathology/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Sodium Compounds/pharmacology ; }, abstract = {The pathogenesis of neurodegenerative diseases results from the interplay between genetic and environmental factors. Aging and chronic oxidative stress are critical contributors to neurodegeneration. UBQLN2, a ubiquitin-related protein, aids in protein degradation and protects against oxidative stress. In ALS neurons harboring UBQLN2 mutations, oxidative stress accelerates pathological changes, yet the precise mechanisms remain unclear. Using induced motor neurons (iMNs) derived from UBQLN2 P497H iPSCs, we observed ALS-like phenotypes, including TDP-43 mislocalization, increased cell death, and reduced viability. Sodium arsenite (SA)-induced oxidative stress triggered stress granule formation, while autophagy dysfunction exacerbated neuronal degeneration. CHX and bosutinib treatments reduced ubiquitinated protein accumulation and alleviated degeneration, highlighting potential therapeutic pathways. These findings emphasize the role of chronic oxidative stress and stress granule formation in UBQLN2 ALS, offering insights into novel therapeutic targets.}, } @article {pmid39769209, year = {2024}, author = {Xing, C and Chen, H and Bi, W and Lei, T and Hang, Z and Du, H}, title = {Targeting 5-HT Is a Potential Therapeutic Strategy for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769209}, issn = {1422-0067}, support = {32300682//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Serotonin/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; Alzheimer Disease/metabolism/drug therapy ; Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Parkinson Disease/metabolism/drug therapy ; Receptors, Serotonin/metabolism ; }, abstract = {There is increasing interest in the potential therapeutic role of 5-HT (serotonin) in the treatment of neurodegenerative diseases, which are characterized by the progressive degeneration and death of nerve cells. 5-HT is a vital neurotransmitter that plays a central role in regulating mood, cognition, and various physiological processes in the body. Disruptions in the 5-HT system have been linked to several neurological and psychiatric disorders, making it an attractive target for therapeutic intervention. Although the exact causes of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are not fully understood, researchers believe that regulating the 5-HT system could help alleviate symptoms and potentially slow the progression of these diseases. Here, we delve into the potential of harnessing 5-HT as a therapeutic target for the treatment of neurodegenerative diseases. It is important to note that the current clinical drugs targeting 5-HT are still limited in the treatment of these complex diseases. Therefore, further research and clinical trials are needed to evaluate the feasibility and effectiveness of its clinical application.}, } @article {pmid39769187, year = {2024}, author = {O'Day, DH}, title = {The Search for a Universal Treatment for Defined and Mixed Pathology Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769187}, issn = {1422-0067}, mesh = {Animals ; Humans ; alpha-Synuclein/metabolism ; Alzheimer Disease/metabolism/pathology/drug therapy/therapy ; Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; Calmodulin/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; Parkinson Disease/metabolism/pathology/therapy ; Protein Glutamine gamma Glutamyltransferase 2 ; RNA-Binding Protein FUS/metabolism/genetics ; tau Proteins/metabolism ; Transglutaminases/metabolism ; }, abstract = {The predominant neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are rarely pure diseases but, instead, show a diversity of mixed pathologies. At some level, all of them share a combination of one or more different toxic biomarker proteins: amyloid beta (Aβ), phosphorylated Tau (pTau), alpha-synuclein (αSyn), mutant huntingtin (mHtt), fused in sarcoma, superoxide dismutase 1, and TAR DNA-binding protein 43. These toxic proteins share some common attributes, making them potentially universal and simultaneous targets for therapeutic intervention. First, they all form toxic aggregates prior to taking on their final forms as contributors to plaques, neurofibrillary tangles, Lewy bodies, and other protein deposits. Second, the primary enzyme that directs their aggregation is transglutaminase 2 (TGM2), a brain-localized enzyme involved in neurodegeneration. Third, TGM2 binds to calmodulin, a regulatory event that can increase the activity of this enzyme threefold. Fourth, the most common mixed pathology toxic biomarkers (Aβ, pTau, αSyn, nHtt) also bind calmodulin, which can affect their ability to aggregate. This review examines the potential therapeutic routes opened up by this knowledge. The end goal reveals multiple opportunities that are immediately available for universal therapeutic treatment of the most devastating neurodegenerative diseases facing humankind.}, } @article {pmid39768371, year = {2024}, author = {Orlova, A and Malygin, Y and Gofman, A and Sotulenko, S and Gandalian, V and Kartashov, I and Brylev, L and Bolevich, S and Nikolic Turnic, T and Jakovljevic, V}, title = {Survival Prognostic Factors of Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {12}, pages = {}, pmid = {39768371}, issn = {2075-1729}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis is a neurodegenerative disease with high rates of disability and mortality. Non-invasive ventilation (NIV) is an effective method of treating patients, increasing life expectancy, but currently, predictors available to determine the best outcome of therapy in this category of patients are unknown. This systematic review aimed to determine the impact of prognostic factors on benefits from NIV application compared with non-NIV tools of treatment (invasive ventilation and standard care) in case of survival of ALS patients.

METHOD: We systematically sought relevant longitudinal cohort and case-control studies published in PubMed, CINAHL/EMBASE, Cochrane library, and Scopus.

RESULTS: We included seven prospective studies, published in 2010-2020, in the analysis. According to the evidence base available to date, NIV favors survival compared to non-NIV in patients with bulbar onset ALS. We obtained conflicting data on the significance of spinal onset and bulbar function. Survival depending on patient age, and also for spinal, cervical, and flail limb phenotypes during NIV therapy has not been sufficiently studied and needs further investigation.

CONCLUSIONS: The studies analyzed in this review allow us to state with confidence that NIV is effective in bulbar onset ALS, taking into account recommendations for duration of ventilation and the use of the full range of symptomatic therapy, including mechanically assisted coughing. The effectiveness of NIV on severe bulbar symptoms requires further research.}, } @article {pmid39768167, year = {2024}, author = {Chen, X and Lv, S and Liu, J and Guan, Y and Xu, C and Ma, X and Li, M and Bai, X and Liu, K and Zhang, H and Yan, Q and Zhou, F and Chen, Y}, title = {Exploring the Role of Axons in ALS from Multiple Perspectives.}, journal = {Cells}, volume = {13}, number = {24}, pages = {}, pmid = {39768167}, issn = {2073-4409}, support = {82271483//The National Natural Science Foundation of China/ ; ZR2024MH112; ZR2024QH628//Shandong Province Natural Science Foundation of China/ ; 2023YX036; 2022YX043//Weifang Science and Technology Development Plan Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Axons/pathology/metabolism ; Animals ; Axonal Transport ; Motor Neurons/pathology ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS), commonly known as motor neuron disease, is a neurodegenerative disorder characterized by the progressive degeneration of both upper and lower motor neurons. This pathological process results in muscle weakness and can culminate in paralysis. To date, the precise etiology of ALS remains unclear. However, a burgeoning body of research indicates that axonal dysfunction is a pivotal element in the pathogenesis of ALS and significantly influences the progression of disease. Dysfunction of axons in ALS can result in impediments to nerve impulse transmission, leading to motor impairment, muscle atrophy, and other associated complications that severely compromise patients' quality of life and survival prognosis. In this review, we concentrate on several key areas: the ultrastructure of axons, the mechanisms of axonal degeneration in ALS, the impact of impaired axonal transport on disease progression in ALS, and the potential for axonal regeneration within the central nervous system (CNS). Our objective is to achieve a more holistic and profound understanding of the multifaceted role that axons play in ALS, thereby offering a more intricate and refined perspective on targeted axonal therapeutic interventions.}, } @article {pmid39767639, year = {2024}, author = {Wan, M and Zhang, L and Huo, J and Fu, Y and Huang, T and Fan, D}, title = {Genetic Variation in Targets of Antidiabetic Drugs and Amyotrophic Lateral Sclerosis Risk.}, journal = {Biomedicines}, volume = {12}, number = {12}, pages = {}, pmid = {39767639}, issn = {2227-9059}, support = {82101490, and 82071426//National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Previous studies have suggested that antidiabetic drug use may be associated with amyotrophic lateral sclerosis. However, these studies are limited by many confounding and reverse causality biases. We aimed to determine whether antidiabetic drug use has causal effects on ALS.

METHODS: Drug-target Mendelian randomization analysis was conducted to evaluate the association between genetic variation in the targets of antidiabetic drugs and ALS risk. The antidiabetic drugs included sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin/insulin analogues, metformin, and SGLT2 inhibitors. Summary statistics for ALS were retrieved from previous genome-wide association studies comprising 27,205 ALS patients and 55,058 controls. The instrumental variables for these drugs are from previous published articles.

RESULTS: Genetic variation in SGLT2 inhibition targets was associated with lower risk of ALS (odds ratio [OR] = 0.32, 95% CI = 0.14-0.74; p = 0.008). We did not find that genetic variation in metformin targets was associated with ALS (OR = 1.61, 95% CI = 0.94-2.73; p = 0.081). Nevertheless, mitochondrial complex I, a target of metformin, was associated with a higher risk of ALS (OR = 1.83, 95% CI = 1.01-3.32; p = 0.047). The analysis showed that genetic variation in sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin or insulin analogues targets was not associated with ALS (all p > 0.05).

CONCLUSIONS: The complex interaction between hypoglycemic, antioxidation, and anti-inflammatory effects may account for the different results across antidiabetic drug types. These findings provide key evidence to guide the use of antidiabetic drugs and will help to identify novel therapeutic targets in ALS.}, } @article {pmid39766833, year = {2024}, author = {Bisogni, G and Conte, A and Costantino, U and Lattante, S and Bernardo, D and Lucioli, G and Patanella, AK and Cimbolli, P and Del Giudice, E and Vettor, F and Marangi, G and Doronzio, PN and Zollino, M and Sabatelli, M}, title = {Exploring the Role of CCNF Variants in Italian ALS Patients.}, journal = {Genes}, volume = {15}, number = {12}, pages = {}, pmid = {39766833}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Italy ; Middle Aged ; Aged ; Mutation, Missense ; Cyclins/genetics ; Frontotemporal Dementia/genetics/pathology ; Genetic Association Studies ; High-Throughput Nucleotide Sequencing ; Phenotype ; Adult ; Genetic Predisposition to Disease ; }, abstract = {Objectives: Variants in Cyclin F (CCNF) have been associated to amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) in a group of cases. The objectives of this study were to determine the contribution of CCNF in a large cohort of Italian ALS patients, to look for genotype-phenotype correlation of the mutations and to evaluate the CCNF-associated clinical features. Methods: We applied next-generation sequencing technologies on 971 unrelated Italian ALS patients and we filtered results to look for variants in CCNF gene. Results: We identified 13 rare missense variants in 16 index cases (2 familial and 14 sporadic), with a cumulative mutational frequency of 1.6%. The most prevalent variant was p.Phe197Leu, found in three patients. The clinical presentation was heterogeneous, with a classic phenotype in eight patients, upper motor neuron dominant (UMN-D) phenotype in four patients, and flail arm in four patients. Clinical evaluation for cognitive impairment was performed in 13 patients using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) test, demonstrating that almost half of the patients (n = 6) had variable degrees of frontal dysfunction. Discussion: In our cohort, we observed CCNF variants in 1.6% of patients (16/971), a percentage similar to that found in other series. Clinical presentation is heterogeneous, but CCNF variants are significantly associated to cognitive impairment. Conclusions: Our study expands the CCNF genetic variant spectrum in a large cohort of Italian ALS patients. Further studies are needed to assess genotype-phenotype associations of CCNF variants and to specify the role of each variant, which are quite common, especially in sALS patients.}, } @article {pmid39766450, year = {2024}, author = {Donaghy, R and Pioro, EP}, title = {Neurophysiologic Innovations in ALS: Enhancing Diagnosis, Monitoring, and Treatment Evaluation.}, journal = {Brain sciences}, volume = {14}, number = {12}, pages = {}, pmid = {39766450}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease of both upper motor neurons (UMNs) and lower motor neurons (LMNs) leading invariably to decline in motor function. The clinical exam is foundational to the diagnosis of the disease, and ordinal severity scales are used to track its progression. However, the lack of objective biomarkers of disease classification and progression delay clinical trial enrollment, muddle inclusion criteria, and limit accurate assessment of drug efficacy. Ultimately, biomarker evidence of therapeutic target engagement will support, and perhaps supplant, more traditional clinical trial outcome measures. Electrophysiology tools including nerve conduction study and electromyography (EMG) have already been established as diagnostic biomarkers of LMN degeneration in ALS. Additional understanding of the motor manifestations of disease is provided by motor unit number estimation, electrical impedance myography, and single-fiber EMG techniques. Dysfunction of UMN and non-motor brain areas is being increasingly assessed with transcranial magnetic stimulation, high-density electroencephalography, and magnetoencephalography; less common autonomic and sensory nervous system dysfunction in ALS can also be characterized. Although most of these techniques are used to explore the underlying disease mechanisms of ALS in research settings, they have the potential on a broader scale to noninvasively identify disease subtypes, predict progression rates, and assess physiologic engagement of experimental therapies.}, } @article {pmid39766276, year = {2024}, author = {Wysoczański, B and Świątek, M and Wójcik-Gładysz, A}, title = {Organ-on-a-Chip Models-New Possibilities in Experimental Science and Disease Modeling.}, journal = {Biomolecules}, volume = {14}, number = {12}, pages = {}, pmid = {39766276}, issn = {2218-273X}, mesh = {*Lab-On-A-Chip Devices ; Humans ; Animals ; Models, Biological ; Liver/metabolism/cytology ; Cell Culture Techniques/methods ; Microphysiological Systems ; }, abstract = {'Organ-on-a-chip' technology is a promising and rapidly evolving model in biological research. This innovative microfluidic cell culture device was created using a microchip with continuously perfused chambers, populated by living cells arranged to replicate physiological processes at the tissue and organ levels. By consolidating multicellular structures, tissue-tissue interfaces, and physicochemical microenvironments, these microchips can replicate key organ functions. They also enable the high-resolution, real-time imaging and analysis of the biochemical, genetic, and metabolic activities of living cells in the functional tissue and organ contexts. This technology can accelerate research into tissue development, organ physiology and disease etiology, therapeutic approaches, and drug testing. It enables the replication of entire organ functions (e.g., liver-on-a-chip, hypothalamus-pituitary-on-a-chip) or the creation of disease models (e.g., amyotrophic lateral sclerosis-on-a-chip, Parkinson's disease-on-a-chip) using specialized microchips and combining them into an integrated functional system. This technology allows for a significant reduction in the number of animals used in experiments, high reproducibility of results, and the possibility of simultaneous use of multiple cell types in a single model. However, its application requires specialized equipment, advanced expertise, and currently incurs high costs. Additionally, achieving the level of standardization needed for commercialization remains a challenge at this stage of development.}, } @article {pmid39765493, year = {2024}, author = {Zhang, T and Xu, Q and Zhou, B and Xiao, J and Zheng, S and Li, J and Lv, Q and Zhang, Y and Wang, R and Su, R and Wang, Z}, title = {Development and Validation of a 5K Liquid Chip for Identifying Cashmere Goat Populations in Inner Mongolia Autonomous Region.}, journal = {Animals : an open access journal from MDPI}, volume = {14}, number = {24}, pages = {}, pmid = {39765493}, issn = {2076-2615}, support = {2022YFE0113300，2022YFD1300201,2022YFD1300204//National Key Research and Development Program/ ; BR220112//Project for Enhancing Young Teacher's Research Ability/ ; NJYT22038//Program for Young Talents of Science and Technology in Universities of Inner Mongolia Autonomous Region/ ; 2023ZD0405102//Project for 2030 Science and Technology Innovation Major/ ; NMGIRT2322//Program for Inner Mongolia Autonomous Region Higher Education Innovation Team Development/ ; }, abstract = {(1) Background: Cashmere goats, as one of the characteristic species, are rich in genetic resources. Protecting and rationally utilizing these genetic resources is of great significance for the genetic improvement of cashmere goats. (2) Methods: In this study, tissue samples were collected from Inner Mongolia white cashmere goats, which included the Arbas type (ARBS); Erlangshan type (ELS); Alashan type (ALS), Hanshan white cashmere goats (HS), and Ujimqin white cashmere goats (WZMQ). Genomic DNA was extracted and subjected to high-depth genome resequencing. GenoBait technology was used for probe design and site optimization, followed by the synthesis of a low-density liquid phase chip. Finally, a total of 281 individuals from five cashmere goat populations in the Inner Mongolia Autonomous Region were randomly selected to verify the chip. (3) Results: The results showed that a total of 5002 SNP sites were finally screened and retained for the synthesis of the low-density liquid chip for identifying cashmere goats in Inner Mongolia Autonomous Region. Principal component analysis and phylogenetic tree construction indicated that the ARBS, ELS, and ALS populations were clustered into one category. (4) Conclusions: This chip can accurately identify the three breeds: Inner Mongolia white cashmere goats, Hanshan white cashmere goats, and Ujimqin white cashmere goats.}, } @article {pmid39764140, year = {2024}, author = {Akif, A and My Nguyen, TT and Liu, L and Xu, X and Kulkarni, A and Jiang, J and Zhang, Y and Hao, J}, title = {Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39764140}, issn = {2693-5015}, support = {R01 NS105787/NS/NINDS NIH HHS/United States ; R21 NS133895/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflammatory responses in the brain, contributing to the development of neurodegenerative diseases such as ischemic stroke, vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Therefore, the NLRP3 signaling pathway is a promising therapeutic target for the treatment of neurodegenerative diseases, including VaD.

METHODS: In this study, we investigated the therapeutic effects of a synthetic sulfonylurea NLRP3 inhibitor, AMS-17, in a VaD mouse model using bilateral common carotid artery stenosis (BCAS) and elucidated the underlying mechanisms. All mice were randomly divided into three groups: Sham, VaD + Vehicle, and VaD + AMS-17. Cognitive function was assessed using the Y-maze and Morris water maze (MWM) on the 50[th] day after BCAS. Brain sections and blood serum samples were collected for biomarker analysis and immunohistochemistry. Neurodegeneration, expressions of the molecules involved in the NLRP3 signaling pathways, tight junction proteins, and myelination were assessed using western blotting and immunofluorescence (IF). The levels of Interleukin-1 beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-4 (IL-4) in the blood were measured using ELISA.

RESULTS: AMS-17 treatment improved cognitive function, enhanced blood-brain barrier (BBB) integrity, and promoted remyelination in VaD mice. Additionally, AMS-17 reduced neurodegeneration and decreased the expression of NLRP3 and its associated proteins, Apoptosis-associated speck-like protein (ASC), and cleaved caspase-1 in the brain. It also lowered pro-inflammatory TNF-α and IL-1β levels, while increasing the anti-inflammatory IL-4 level in the blood.

CONCLUSIONS: The findings of this study provide the first promising evidence for the use of AMS-17 in VaD treatment in mice. This study introduces AMS-17 as a novel chemical scaffold with NLRP3 inhibitory activity, which can be further developed for the treatment of VaD in humans.}, } @article {pmid39763885, year = {2024}, author = {Shelest, O and Tindel, I and Lauzon, M and Dawson, A and Ho, R}, title = {Delineating sex-dependent and anatomic decline of motor functions in the SOD1G93A mouse model of amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39763885}, issn = {2692-8205}, support = {R00 AG056678/AG/NIA NIH HHS/United States ; }, abstract = {The transgenic SOD1G93A mouse model is the most widely used animal model of amyotrophic lateral sclerosis (ALS), a fatal disease of motor neuron degeneration. While genetic background influences onset and progression variability of motor dysfunction, the C57BL/6 background most reliably exhibits robust ALS phenotypes; thus, it is the most widely used strain in mechanistic studies. In this model, paresis begins in the hindlimbs and spreads rostrally to the forelimbs. Males experience earlier onset, greater disease severity, and shorter survival than females. However, the influence of sex on patterns of declining motor function between forelimbs and hindlimbs as well as among distinct, spinal-innervated muscle groups within each limb are not fully understood. To provide a higher resolution framework of degenerating motor function across the body, we conducted more comprehensive, limb-dependent and independent measures of motor decline over the course of disease. Subsequently, we compared the timing and intensity of these features across sex, and we consider to what extent these patterns are conserved in clinical observations from human ALS patients. We found male mice experienced earlier and less localized onset than females. We also report distinct motor features decline at different rates between sexes. Finally, mice showed differences in correlation between the decline of left- and right-side measures of the hindlimb. Consequently, our findings reinforce and refine the utility of the SOD1 mouse in modeling more highly resolved, sex-specific differences in ALS patient motor behavior. This may better guide preclinical studies in stratifying patients by sex and anatomical site of onset.}, } @article {pmid39762986, year = {2025}, author = {Berlowitz, DJ and Rowe, D and Howard, ME and Piper, A and Graco, M and Braat, S and Singh, B and Souza, TV and Lannin, N and McLean, A and Sawyer, A and Carey, KA and Ahamed, Y and , }, title = {Polysomnographic titration of non-invasive ventilation in motor neurone disease (3TLA): study protocol for a randomised controlled trial.}, journal = {Trials}, volume = {26}, number = {1}, pages = {10}, pmid = {39762986}, issn = {1745-6215}, mesh = {Humans ; *Noninvasive Ventilation/methods/adverse effects/instrumentation ; *Motor Neuron Disease/therapy/physiopathology ; *Polysomnography ; *Randomized Controlled Trials as Topic ; Treatment Outcome ; Australia ; Multicenter Studies as Topic ; Time Factors ; Sleep ; Respiratory Insufficiency/therapy/physiopathology ; Quality of Life ; }, abstract = {BACKGROUND: Non-invasive ventilation (NIV) uses positive pressure to assist people with respiratory muscle weakness or severe respiratory compromise to breathe. Most people use this treatment during sleep when breathing is most susceptible to instability. The benefits of using NIV in motor neurone disease (MND) are well-established. However, uptake and usage are low (~ 19%) and there is no consensus on how to best implement NIV in MND in Australia. Consequently, clinical practice models are highly variable. Our team has recently provided evidence that specific and individualised NIV titration using a sleep study (polysomnography; PSG) leads to better outcomes in people with MND. However, for this clinical practice model to result in sustained benefits, evidence of effectiveness across multiple sites, as well as culture and practice change, must occur.

METHODS: A two-arm, assessor-blinded, individual participant randomised controlled trial in MND care centres across Australia will be undertaken. Two-hundred and forty-four participants will be randomised (1:1) to either the intervention group (PSG-assisted commencement of NIV settings; PSG) or a control group (sham PSG). Participants will be asked to use their NIV device for 7 weeks and will then return for follow-up assessments. Respiratory, sleep and patient-reported outcome measures will be collected at baseline and follow-up. The primary aim is to determine if the proportion of participants using NIV for > 4 h/day during the intervention period is higher in the PSG than the control group. A process evaluation, health economic evaluation and 12-month cohort follow-up will be undertaken and reported separately.

DISCUSSION: The results of this trial will demonstrate the effects of PSG-assisted titration of NIV on usage of NIV in people with MND. We hypothesise that the PSG intervention will improve synchrony between the user and the machine, which will lead to greater NIV usage compared to the control group.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05136222. Registered on November 25, 2021.}, } @article {pmid39762711, year = {2025}, author = {Apostolo, D and Ferreira, LL and D'Onghia, D and Vincenzi, F and Vercellino, N and Perazzi, M and Pirisi, M and Cantello, R and Minisini, R and Mazzini, L and Bellan, M and De Marchi, F}, title = {Lower Circulating Gas6 Levels Are Associated with Bulbar Phenotype and Faster Disease Progression in Amyotrophic Lateral Sclerosis Patients.}, journal = {Molecular neurobiology}, volume = {62}, number = {5}, pages = {6273-6282}, pmid = {39762711}, issn = {1559-1182}, support = {2021-1541//Fondazione Cariplo/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/pathology ; Female ; Male ; *Disease Progression ; Middle Aged ; *Intercellular Signaling Peptides and Proteins/blood ; *Phenotype ; Aged ; Biomarkers/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily affects the motor neurons in the brain and spinal cord. While the exact cause of ALS is not fully understood, a combination of genetic and environmental factors is believed to contribute to its development. Growth arrest-specific 6 (Gas6), a vitamin K-dependent protein, has been recognized to enhance oligodendrocytes and neurons' survival and is associated with different kinds of (neuro)inflammatory conditions. Therefore, we aimed to determine a possible implication of Gas6 in ALS phenotype and progression by evaluating the value of circulating Gas6 and its soluble receptors (sAxl, sMer, sTyro-3) in ALS patients. We conducted a prospective observational study including 65 ALS patients and measured the circulating serum levels of Gas6, sAxl, sMer, soluble Tyro-3 (sTyro-3), and neurofilaments (NfLs). In our ALS cohort, lower serum levels of Gas6 and concomitantly higher levels of NfLs were associated with a more aggressive disease, expressed with bulbar phenotype (p-value for Gas6 = 0.03) and faster progression (p-value for Gas6 = 0.03). Also, serum Gas6 was able to distinguish (area under the curve, cut-off 13.70 ng/mL, sensitivity 69.57%, specificity 72.72%) between fast and slow progressors. Due to its neuroprotective properties, our data suggest that Gas6 could be an intriguing biomarker in ALS patients.}, } @article {pmid39761853, year = {2025}, author = {Weeks, AT and Bird, AJ}, title = {Regulation of sod1 mRNA and protein abundance by zinc in fission yeast is dependent on the CCR4-NOT complex.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {2}, pages = {108156}, pmid = {39761853}, issn = {1083-351X}, support = {R01 GM105695/GM/NIGMS NIH HHS/United States ; }, mesh = {*Schizosaccharomyces/metabolism/genetics ; *Zinc/metabolism ; *Schizosaccharomyces pombe Proteins/metabolism/genetics ; *RNA, Messenger/metabolism/genetics ; *Gene Expression Regulation, Fungal/drug effects ; *Superoxide Dismutase/metabolism/genetics ; Superoxide Dismutase-1/metabolism/genetics ; }, abstract = {Zinc is an essential micronutrient that serves as a cofactor in a wide variety of enzymes, including Cu-Zn Superoxide Dismutase 1 (Sod1). We have discovered in Schizosaccharomyces pombe that Sod1 mRNA and protein levels are regulated in response to cellular zinc availability. We demonstrate that lower levels of sod1 mRNA and protein accumulate under low zinc conditions and that this regulation does not require the sod1 promoter or known factors that regulate the transcription of sod1 in response to zinc and other environmental stresses. Further analyses using yeast deletion strains and an inactive allele of Caf1 revealed that the reduced accumulation of sod1 mRNA and protein under low zinc conditions depends on the Caf1 and Ccr4 deadenylases of the CCR4-NOT complex. We also found that Caf1 and Ccr4 are both required for growth under zinc-limiting conditions. To gain additional mechanistic insight we used immunoblot analysis to map the regions required for the regulation of the Sod1 protein by zinc. We found that the sod1 ORF and 3'UTR are both necessary and sufficient for the zinc-dependent changes in Sod1 protein abundance. Our studies reveal a novel mechanism of altering mRNA and protein abundance in response to zinc status, which depends on the CCR4-NOT complex.}, } @article {pmid39759580, year = {2025}, author = {Chourpiliadis, C and Lovik, A and Seitz, C and Hu, Y and Wu, J and Ljungman, P and Press, R and Samuelsson, K and Ingre, C and Fang, F}, title = {Association between cardiometabolic diseases and the risk and progression of motor neuron diseases in Sweden: a population-based case-control study.}, journal = {The Lancet regional health. Europe}, volume = {49}, number = {}, pages = {101173}, pmid = {39759580}, issn = {2666-7762}, abstract = {BACKGROUND: The evidence on the link between cardiometabolic diseases (CMDs) and motor neuron diseases (MNDs) remains inconsistent. We aimed to determine whether there is an association of CMDs, namely, any cardiovascular disease, cardiac arrhythmia, heart failure, thromboembolic disease, hypertension, cerebrovascular disease, ischemic heart disease, diabetes mellitus type 2, and hypercholesterolemia with the risk and progression of MNDs.

METHODS: We included 1463 MND patients (amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive spinal muscular atrophy (PSMA), and unspecified MND) diagnosed from January 1, 2015, to July 1, 2023, in Sweden according to the Swedish Motor Neuron Disease Quality Registry (i.e., cases), up to 5 MND-free population controls per case (N = 7311) who were individually matched to the cases on age and sex, and the full siblings (N = 2002) and spouses (N = 1220) of MND patients (i.e., relative controls). Conditional logistic regression models were used to estimate the risk of MND diagnosis in relation to previous CMDs, through comparing MND patients to population controls or relative controls. MND patients were followed from diagnosis to assess the role of pre-diagnostic CMDs on disease progression. A joint longitudinal-survival model was used to estimate risk of mortality (or use of invasive ventilation) in relation to CMDs after taking into account the longitudinal changes of ALS functional rating scale-revised (ALSFRS-R) in the time-to-event analysis. Hierarchical clustering with the Ward's linkage and a dissimilarity matrix created by Gower's method was used to identify clusters of MND patients with distinct phenotypes.

FINDINGS: Among the CMDs studied, a history of diabetes mellitus type 2 (OR 0.75; 95% CI 0.62, 0.93) or hypercholesterolemia (OR 0.82; 95% CI 0.71, 0.94) more than one year before diagnosis was associated with a lower risk for MNDs. The associations persisted for more than five years before MND diagnosis. MND patients with a history of any cardiovascular disease (HR 1.43; 95% CI 1.13, 1.81), arrhythmia (HR 1.42; 95% CI 1.04, 1.93), heart failure (HR 1.79; 95% CI 1.02, 3.14), hypertension (HR 1.41; 95% CI 1.12, 1.77), or hypercholesterolemia (HR 1.28; 95% CI 1.01, 1.62) had an increased mortality risk, compared to others, after taking into consideration the longitudinal changes in ALSFRS-R. Cluster analysis identified two clusters of MND patients, where one cluster demonstrated higher age, worse functional status, and higher prevalence of CMDs at the time of diagnosis as well as a higher mortality and faster functional decline during follow-up, compared to the ones included in the other cluster.

INTERPRETATION: Diabetes mellitus type 2 and hypercholesterolemia were associated with a lower future risk of MND. On the other hand, most of the CMDs were indicative of a poor disease progression after an MND diagnosis.

FUNDING: European Research Council, US Center for Disease Control and Prevention, Swedish Research Council.}, } @article {pmid39759457, year = {2024}, author = {Ahmad, SR and Zeyaullah, M and Khan, MS and AlShahrani, AM and Altijani, AAG and Ali, H and Dawria, A and Mohieldin, A and Alam, MS and Mohamed, AOA}, title = {Pharmacogenomics for neurodegenerative disorders - a focused review.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1478964}, pmid = {39759457}, issn = {1663-9812}, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by the progressive degeneration of neuronal structure and function, leading to severe cognitive and motor impairments. These conditions present significant challenges to healthcare systems, and traditional treatments often fail to account for genetic variability among patients, resulting in inconsistent therapeutic outcomes. Pharmacogenomics aims to tailor medical treatments based on an individual's genetic profile, thereby improving therapeutic efficacy and reducing adverse effects. This focused review explores the genetic factors influencing drug responses in neurodegenerative diseases and the potential of pharmacogenomics to revolutionize their treatment. Key genetic markers, such as the APOE ε4 allele in AD and the CYP2D6 polymorphisms in PD, are highlighted for their roles in modulating drug efficacy. Additionally, advancements in pharmacogenomic tools, including genome-wide association studies (GWAS), next-generation sequencing (NGS), and CRISPR-Cas9, are discussed for their contributions to personalized medicine. The application of pharmacogenomics in clinical practice and its prospects, including ethical and data integration challenges, are also examined.}, } @article {pmid39757610, year = {2024}, author = {Mojgani, N and Dadar, M and Shahali, Y and Simal-Gandara, J and Kumar, P and Ashique, S and Bhowmick, M and Kumar, H}, title = {Antioxidant Nutraceuticals: Their Adjunct Role in the Management of COVID-19 Infections and Post-COVID Syndrome.}, journal = {Infectious disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715265320091241017161919}, pmid = {39757610}, issn = {2212-3989}, abstract = {The COVID-19 epidemic in recent years has been produced by various coronavirus strains that nearly destroyed world health policies and economics. Emerging viral strains exac-erbated the pandemic. Huge investments have been made in preventative vaccines to combat the disease, but the genetic instability of these viruses has hampered their usefulness. However, in addition to traditional therapeutic approaches, nutraceuticals have been considered effica-cious in preventing and or treating COVID-19 and post-COVID syndrome. In this context, nutraceuticals such as vitamins or dietary supplements including multiple vitamins and miner-als and propolis have been widely studied for their significant impact on viral respiratory dis-eases like SARS-CoV-2 and COVID-19. Some of these nutraceuticals having antioxidant, anti-inflammatory, and immune-modulatory properties have been highly recommended for use as an adjunct option to moderate the adverse effects associated with the COVID-19 pandemic. In this review, we intend to present the recent understanding and converse scientific implications for the use of nutraceutical antioxidants such as vitamins, minerals, probiotics, and polyphenols like bee propolis, in the management of viral respiratory diseases and post-COVID-19 syn-drome. Future challenges and limitations regarding the use and bioavailability of these ingre-dients, and dose-response studies are further emphasized.}, } @article {pmid39756374, year = {2025}, author = {Loap, P and Kirova, Y}, title = {Initial Characterization and Outcome Assessment of Anal Lymphomas in a Large-Size Contemporary Cohort: A Population-Based SEER Database Study (2000-2022).}, journal = {Acta haematologica}, volume = {}, number = {}, pages = {1-7}, doi = {10.1159/000541595}, pmid = {39756374}, issn = {1421-9662}, abstract = {INTRODUCTION: Anal lymphoma (AL) is a rare presentation of extranodal lymphomas, characterized by occurrence in the anal area and largely understudied due to its infrequency. This study aimed to address gaps in knowledge about AL's demographic and clinical profiles, treatments, and survival outcomes, leveraging data from the SEER program.

METHODS: We conducted a retrospective analysis of 79 AL cases identified in the SEER database from 2000 to 2022; 36 stage I AL cases were identified and defined as localized primary anal lymphoma (L-PAL). Data on demographics, tumor specifics, treatment modalities, and survival were analyzed using the Kaplan-Meier method and Cox proportional hazards models.

RESULTS: The majority of AL cases were diffuse large B-cell lymphoma (70.9%). Other notable subtypes included anaplastic T-cell lymphoma, marginal zone lymphoma, B-cell non-Hodgkin lymphoma, Burkitt lymphoma/leukemia (each accounting for 6.3%), followed by follicular lymphoma and mantle-cell lymphoma (each at 1.3%). AL primarily affected younger males (median age 50), with a significant majority being Caucasian. Initial stages (I and II) were more commonly observed, and treatments varied, with chemotherapy being most prevalent (67.1%), followed by radiation (30.4%) and surgery (30.4%). The 5- and 10-year overall survival (OS) rates were 59.4% and 44.1%, respectively, while the corresponding cancer-specific survival (CSS) rates were 67.9% and 58.0%, respectively. Age was a significant prognostic factor for OS but not for CSS. Radiotherapy tended to improve CSS in the AL population.

CONCLUSION: This research corresponds to the first in-depth analysis of AL, highlighting its distinct demographic patterns, clinical features, and responses to various treatments, distinguishing it from other types of anal cancers. Our results underscore the importance of developing specialized diagnostic and treatment strategies. To enhance our understanding and management of this uncommon form of lymphoma, future studies should aim for broader and more collaborative international research efforts.}, } @article {pmid39756021, year = {2025}, author = {Akaree, N and Secco, V and Levy-Adam, F and Younis, A and Carra, S and Shalgi, R}, title = {Regulation of physiological and pathological condensates by molecular chaperones.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.17390}, pmid = {39756021}, issn = {1742-4658}, support = {//AriSLA/ ; //Giovanni Armenise Harvard Foundation/ ; HT94252310319//Congressionally Directed Medical Research Programs/ ; AHA-MCA 2022//AriAlzh/ ; //Rappaport Family Institute for Research in Medical Sciences/ ; //Prince Center for Neurodegenerative Disorders of the Brain/ ; }, abstract = {Biomolecular condensates are dynamic membraneless compartments that regulate a myriad of cellular functions. A particular type of physiological condensate called stress granules (SGs) has gained increasing interest due to its role in the cellular stress response and various diseases. SGs, composed of several hundred RNA-binding proteins, form transiently in response to stress to protect mRNAs from translation and disassemble when the stress subsides. Interestingly, SGs contain several aggregation-prone proteins, such as TDP-43, FUS, hnRNPA1, and others, which are typically found in pathological inclusions seen in autopsy tissues from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. Moreover, mutations in these genes lead to the familial form of ALS and FTD. This has led researchers to propose that pathological aggregation is seeded by aberrant SGs: SGs that fail to properly disassemble, lose their dynamic properties, and become pathological condensates which finally 'mature' into aggregates. Here, we discuss the evidence supporting this model for various ALS/FTD-associated proteins. We further continue to focus on molecular chaperone-mediated regulation of ALS/FTD-associated physiological condensates on one hand, and pathological condensates on the other. In addition to SGs, we review ALS/FTD-relevant nuclear condensates, namely paraspeckles, anisosomes, and nucleolar amyloid bodies, and discuss their emerging regulation by chaperones. As the majority of chaperoning mechanisms regulate physiological condensate disassembly, we highlight parallel themes of physiological and pathological condensation regulation across different chaperone families, underscoring the potential for early disease intervention.}, } @article {pmid39755715, year = {2025}, author = {Liu, Q and Sun, Y and He, B and Chen, H and Wang, L and Wang, G and Zhang, K and Zhao, X and Zhang, X and Shen, D and Zhang, X and Cui, L}, title = {Gain-of-function ANXA11 mutation cause late-onset ALS with aberrant protein aggregation, neuroinflammation and autophagy impairment.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {2}, pmid = {39755715}, issn = {2051-5960}, support = {2021-I2M-1-034//the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences/ ; 2021-I2M-1-034//the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences/ ; 2022YFC2703904//National Key Research and Development Program/ ; 2022YFC2703900//National Key Research and Development Program/ ; 2022-PUMCH-B-017//National High Level Hospital Clinical Research Funding/ ; 81971293//National Natural Science Foundation of China/ ; 82201562//National Natural Science Foundation of China/ ; XDB39040000//Strategic Priority Research Program (Pilot study) "Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; }, mesh = {Animals ; *Autophagy/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Mice ; Humans ; Male ; *Gain of Function Mutation ; Neuroinflammatory Diseases/pathology/genetics/metabolism ; Female ; Annexins/genetics/metabolism ; Mice, Transgenic ; Protein Aggregation, Pathological/genetics/pathology/metabolism ; Motor Neurons/pathology/metabolism ; Middle Aged ; Age of Onset ; Protein Aggregates ; RNA-Binding Proteins/genetics/metabolism ; Mice, Inbred C57BL ; }, abstract = {Mutations in the ANXA11 gene, encoding an RNA-binding protein, have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but the underlying in vivo mechanisms remain unclear. This study examines the clinical features of ALS patients harboring the ANXA11 hotspot mutation p.P36R, characterized by late-onset motor neuron disease and occasional multi-system involvement. To elucidate the pathogenesis, we developed a knock-in mouse model carrying the p.P36R mutation. In both heterozygous and homozygous mutant mice, ANXA11 protein levels were comparable to those in wild-type. Both groups exhibited late-onset motor dysfunction at approximately 10 months of age, with similar survival rates to wild-type (> 24 months) and no signs of dementia. Pathological analysis revealed early abnormal aggregates in spinal cord motor neurons, cortical neurons, and muscle cells of homozygous mice. From 2 months of age, we observed mislocalized ANXA11 aggregates, SQSTM1/p62-positive inclusions, and cytoplasmic TDP-43 mislocalization, which intensified with disease progression. Importantly, mutant ANXA11 co-aggregated with TDP-43 and SQSTM1/p62-positive inclusions. Electron microscopy of the gastrocnemius muscle uncovered myofibrillar abnormalities, including sarcomeric disorganization, Z-disc dissolution, and subsarcolemmal electron-dense structures within autophagic vacuoles. Autophagic flux, initially intact at 2 months, was impaired by 9 months, as evidenced by decreased Beclin-1 and LC3BII/I levels and increased SQSTM1/p62 expression, coinciding with mTORC1 hyperactivation. Significant motor neuron loss and neuroinflammation were detected by 9 months, with marked muscle dystrophy apparent by 12 months compared to wild-type controls. These findings implicate the gain-of-function ANXA11 mutation drives late-onset motor neuron disease by early presymptomatic proteinopathy, progressive neuronal degeneration, neuroinflammation, and autophagic dysfunction.}, } @article {pmid39753993, year = {2025}, author = {Cheng, L and Liu, Z and Shen, C and Xiong, Y and Shin, SY and Hwang, Y and Yang, SB and Chen, Z and Zhang, X}, title = {A Wonderful Journey: The Diverse Roles of Adenosine Deaminase Action on RNA 1 (ADAR1) in Central Nervous System Diseases.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {1}, pages = {e70208}, pmid = {39753993}, issn = {1755-5949}, support = {20224BAB216045//Youth Foundation of Natural Science Foundation of Jiangxi Province/ ; GJJ211812//Science and Technology Project Funded by the Education Department of Jiangxi Province/ ; GJJ211813//Science and Technology Project Funded by the Education Department of Jiangxi Province/ ; 202131084//Jiangxi Provincial Health Commission Science and Technology Plan Project/ ; 202211982//Jiangxi Provincial Health Commission Science and Technology Plan Project/ ; RZYB202201//Research project of Cognitive Science and Transdisciplinary Studies Center of Jiangxi Province/ ; 20224BAB206040//Provincial Natural Science Foundation of Jiangxi Province/ ; 202411843024//Foundation of Students' Platform for Innovation and Entrepreneurship Training Program/ ; S202411843050//Foundation of Students' Platform for Innovation and Entrepreneurship Training Program/ ; 2022B1010//Administration of Traditional Chinese Medicine of Jiangxi Province/ ; }, mesh = {*Adenosine Deaminase/genetics/metabolism ; Humans ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; *Central Nervous System Diseases/genetics/metabolism/therapy ; RNA Editing ; }, abstract = {BACKGROUND: Adenosine deaminase action on RNA 1 (ADAR1) can convert the adenosine in double-stranded RNA (dsRNA) molecules into inosine in a process known as A-to-I RNA editing. ADAR1 regulates gene expression output by interacting with RNA and other proteins; plays important roles in development, including growth; and is linked to innate immunity, tumors, and central nervous system (CNS) diseases.

RESULTS: In recent years, the role of ADAR1 in tumors has been widely discussed, but its role in CNS diseases has not been reviewed. It is worth noting that recent studies have shown ADAR1 has great potential in the treatment of neurodegenerative diseases, but the mechanisms are still unclear. Therefore, it is necessary to elaborate on the role of ADAR1 in CNS diseases.

CONCLUSIONS: Here, we focus on the effects and mechanisms of ADAR1 on CNS diseases such as Aicardi-AicardiGoutières syndrome, Alzheimer's disease, Parkinson's disease, glioblastoma, epilepsy, amyotrophic lateral sclerosis, and autism. We also evaluate the impact of ADAR1-based treatment strategies on these diseases, with a particular focus on the development and treatment strategies of new technologies such as microRNAs, nanotechnology, gene editing, and stem cell therapy. We hope to provide new directions and insights for the future development of ADAR1 gene editing technology in brain science and the treatment of CNS diseases.}, } @article {pmid39753665, year = {2025}, author = {Quintanilla, CA and Fitzgerald, Z and Kashow, O and Radojicic, MS and Ulupinar, E and Bitlis, D and Genc, B and Andjus, P and van Drongelen, W and Ozdinler, PH}, title = {High-density multielectrode arrays bring cellular resolution to neuronal activity and network analyses of corticospinal motor neurons.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {732}, pmid = {39753665}, issn = {2045-2322}, support = {778405 "AUTOIGG"//EU H2020 MSCA RISE/ ; R01 AG061708/AG/NIA NIH HHS/United States ; 4242 "NIMOCHIP"//Science Fund of the Republic of Serbia/ ; R01AG061708-03/NH/NIH HHS/United States ; 5T32NS041234-18/NH/NIH HHS/United States ; }, mesh = {Animals ; *Motor Neurons/physiology ; Mice ; *Microelectrodes ; Motor Cortex/physiology ; Pyramidal Tracts/physiology ; Nerve Net/physiology ; Mice, Transgenic ; }, abstract = {Corticospinal motor neurons (CSMN), located in the motor cortex of the brain, are one of the key components of the motor neuron circuitry. They are in part responsible for the initiation and modulation of voluntary movement, and their degeneration is the hallmark for numerous diseases, such as amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia, and primary lateral sclerosis. Cortical hyperexcitation followed by in-excitability suggests the early involvement of cortical dysfunction in ALS pathology. However, a high-spatiotemporal resolution on our understanding of their functional health and connectivity is lacking. Here, we combine optical imaging with high-density microelectrode array (HD-MEA) system enabling single cell resolution and utilize UCHL1-eGFP mice to bring cell-type specificity to our understanding of the electrophysiological features of healthy CSMN, as they mature and form network connections with other cortical neurons, in vitro. This novel approach lays the foundation for future cell-type specific analyses of CSMN that are diseased due to different underlying causes with cellular precision, and it will allow the assessment of their functional response to compound treatment, especially for drug discovery efforts in upper motor neuron diseases.}, } @article {pmid39753643, year = {2025}, author = {Mravinacová, S and Bergström, S and Olofsson, J and de San José, NG and Anderl-Straub, S and Diehl-Schmid, J and Fassbender, K and Fliessbach, K and Jahn, H and Kornhuber, J and Landwehrmeyer, GB and Lauer, M and Levin, J and Ludolph, AC and Prudlo, J and Schneider, A and Schroeter, ML and Wiltfang, J and Steinacker, P and , and Otto, M and Nilsson, P and Månberg, A}, title = {Addressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseases.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {668}, pmid = {39753643}, issn = {2045-2322}, mesh = {Humans ; *Neurodegenerative Diseases/cerebrospinal fluid/diagnosis ; *Biomarkers/cerebrospinal fluid ; Male ; Female ; Aged ; Middle Aged ; Brain/metabolism/pathology ; Alzheimer Disease/cerebrospinal fluid/diagnosis ; Cerebrospinal Fluid Proteins/analysis ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; }, abstract = {Accurate diagnosis and monitoring of neurodegenerative diseases require reliable biomarkers. Cerebrospinal fluid (CSF) proteins are promising candidates for reflecting brain pathology; however, their diagnostic utility may be compromised by natural variability between individuals, weakening their association with disease. Here, we measured the levels of 69 pre-selected proteins in cerebrospinal fluid using antibody-based suspension bead array technology in a multi-disease cohort of 499 individuals with neurodegenerative disorders including Alzheimer's disease (AD), behavioral variant frontotemporal dementia, primary progressive aphasias, amyotrophic lateral sclerosis (ALS), corticobasal syndrome, primary supranuclear palsy, along with healthy controls. We identify significant inter-individual variability in overall CSF levels of brain-derived proteins, which could not be attributed to specific disease associations. Using linear modelling, we show that adjusting for median CSF levels of brain-derived proteins increases the diagnostic accuracy of proteins previously identified as altered in CSF in the context of neurodegenerative disorders. We further demonstrate a simplified approach for the adjustment using pairs of correlated proteins with opposite alteration in the diseases. With this approach, the proteins adjust for each other and further increase the biomarker performance through additive effect. When comparing the diseases, two proteins-neurofilament medium and myelin basic protein-showed increased levels in ALS compared to other diseases, and neurogranin showed a specific increase in AD. Several other proteins showed similar trends across the studied diseases, indicating that these proteins likely reflect shared processes related to neurodegeneration. Overall, our findings suggest that accounting for inter-individual variability is crucial in future studies to improve the identification and performance of relevant biomarkers. Importantly, we highlight the need for multi-disease studies to identify disease-specific biomarkers.}, } @article {pmid39753538, year = {2025}, author = {Larrea, D and Tamucci, KA and Kabra, K and Velasco, KR and Yun, TD and Pera, M and Montesinos, J and Agrawal, RR and Paradas, C and Smerdon, JW and Lowry, ER and Stepanova, A and Yoval-Sanchez, B and Galkin, A and Wichterle, H and Area-Gomez, E}, title = {Altered mitochondria-associated ER membrane (MAM) function shifts mitochondrial metabolism in amyotrophic lateral sclerosis (ALS).}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {379}, pmid = {39753538}, issn = {2041-1723}, support = {R21 NS125466/NS/NINDS NIH HHS/United States ; R01 NS131322/NS/NINDS NIH HHS/United States ; R01 AG056387/AG/NIA NIH HHS/United States ; F31 NS095571/NS/NINDS NIH HHS/United States ; T32 DK007647/DK/NIDDK NIH HHS/United States ; R01 NS112381/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Endoplasmic Reticulum/metabolism ; *Mitochondria/metabolism ; Humans ; Animals ; Spinal Cord/metabolism ; Mice ; Glucose/metabolism ; Fatty Acids/metabolism ; Male ; Energy Metabolism ; Pyruvic Acid/metabolism ; Intracellular Membranes/metabolism ; Electron Transport Complex I/metabolism/genetics ; Brain/metabolism ; Mitochondria Associated Membranes ; }, abstract = {Mitochondrial function is modulated by its interaction with the endoplasmic reticulum (ER). Recent research indicates that these contacts are disrupted in familial models of amyotrophic lateral sclerosis (ALS). We report here that this impairment in the crosstalk between mitochondria and the ER impedes the use of glucose-derived pyruvate as mitochondrial fuel, causing a shift to fatty acids to sustain energy production. Over time, this deficiency alters mitochondrial electron flow and the active/dormant status of complex I in spinal cord tissues, but not in the brain. These findings suggest mitochondria-associated ER membranes (MAM domains) play a crucial role in regulating cellular glucose metabolism and that MAM dysfunction may underlie the bioenergetic deficits observed in ALS.}, } @article {pmid39753182, year = {2025}, author = {Swarup, G and Medchalmi, S and Ramachandran, G and Sayyad, Z}, title = {Molecular aspects of cytoprotection by Optineurin during stress and disease.}, journal = {Biochimica et biophysica acta. Molecular cell research}, volume = {1872}, number = {3}, pages = {119895}, doi = {10.1016/j.bbamcr.2024.119895}, pmid = {39753182}, issn = {1879-2596}, mesh = {Humans ; *Cell Cycle Proteins/genetics/metabolism ; *Membrane Transport Proteins/genetics/metabolism ; *Transcription Factor TFIIIA/genetics/metabolism ; Signal Transduction ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Oxidative Stress ; Cytoprotection/genetics ; Animals ; Glaucoma/genetics/metabolism/pathology ; Neurodegenerative Diseases/genetics/metabolism ; Endoplasmic Reticulum Stress/genetics ; Mutation ; Autophagy/genetics ; }, abstract = {Optineurin/OPTN is an adapter protein that plays a crucial role in mediating many cellular functions, including autophagy, vesicle trafficking, and various signalling pathways. Mutations of OPTN are linked with neurodegenerative disorders, glaucoma, and amyotrophic lateral sclerosis (ALS). Recent work has shown that OPTN provides cytoprotection from many types of stress, including oxidative stress, endoplasmic reticulum stress, protein homeostasis stress, tumour necrosis factor α, and microbial infection. Here, we discuss the mechanisms involved in cytoprotective functions of OPTN, which possibly depend on its ability to modulate various stress-induced signalling pathways. ALS- and glaucoma-causing mutants of OPTN are altered in this regulation, which may affect cell survival, particularly under various stress conditions. We suggest that OPTN deficiency created by mutations may cooperate with stress-induced signalling to enhance or cause neurodegeneration. Other functions of OPTN, such as neurotrophin secretion and vesicle trafficking, may also contribute to cytoprotection.}, } @article {pmid39752797, year = {2025}, author = {Ju, W and Min, YG and Kim, JS and Ryu, S and Ahn, SW and Hong, YH and Choi, SJ and Sung, JJ}, title = {Clinical features of FOSMN syndrome in Korea: A comparative analysis with bulbar-onset amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {469}, number = {}, pages = {123372}, doi = {10.1016/j.jns.2024.123372}, pmid = {39752797}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Male ; Female ; Middle Aged ; Republic of Korea/epidemiology ; Aged ; Adult ; Age of Onset ; Motor Neuron Disease/epidemiology/diagnosis ; Cohort Studies ; Disease Progression ; }, abstract = {Facial onset sensory and motor neuronopathy (FOSMN) syndrome is a rare neurodegenerative disorder initially characterized by facial sensory deficits, which later progress to motor deficits in a rostral-caudal distribution. This study investigated the prevalence, clinical features, and prognosis of FOSMN syndrome and compared these aspects with those of bulbar-onset amyotrophic lateral sclerosis (ALS) within a single institutional cohort of motor neuron diseases. We identified four patients with FOSMN syndrome who had been misclassified as having bulbar-onset ALS, representing approximately 2 % of such ALS cases. The median age of onset for FOSMN syndrome was similar to that of bulbar-onset ALS. However, patients with FOSMN syndrome were often diagnosed at more advanced stages and had lower ALS Functional Rating Scale-revised (ALSFRS-R) scores. Despite the slower progression of FOSMN syndrome, therapeutic interventions such as gastrostomy or non-invasive ventilation were frequently required. In conclusion, this study provides detailed clinical profiles of patients with FOSMN syndrome and deepens our understanding of a heterogeneous group of neurodegenerative disorders.}, } @article {pmid39751824, year = {2025}, author = {Sghaier, I and Kacem, I and Ratti, A and Takout, K and Abida, Y and Peverelli, S and Ticozzi, N and Gargouri-Berrachid, A and Silani, V and Gouider, R}, title = {Impact of APOE and MAPT genetic profile on the cognitive functions among Amyotrophic Lateral Sclerosis Tunisian patients.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {132}, number = {4}, pages = {609-618}, pmid = {39751824}, issn = {1435-1463}, mesh = {Humans ; *tau Proteins/genetics ; Male ; Female ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Tunisia/epidemiology ; Middle Aged ; Aged ; *Apolipoproteins E/genetics ; Cognitive Dysfunction/genetics/epidemiology ; Adult ; Genotype ; }, abstract = {Amyotrophic Lateral Sclerosis(ALS) has traditionally been managed as a neuromuscular disorder. However, recent evidence suggests involvement of non-motor domains. This study aims to evaluate the impact of APOE and MAPT genotypes on the cognitive features of ALS. We included confirmed ALS cases from the Neurology department at Razi University Hospital, Tunisia. APOE and MAPT screening were conducted with Sanger sequencing validation, and preliminary screening for four main ALS genes was performed. Clinical phenotypes and genotypes were analyzed using appropriate tests, with healthy controls (HC) representing the Tunisian population. Two-hundred-seventy ALS patients were included, stratified as 213 spinal cases,49 with bulbar onset and 8 patients with generalized form with 140 HC. Regarding APOE, we reported high frequency of ALS cases carrier of APOE-ε4 isoform compared to controls(p < 0.0001).We found a significant association between APOE-ɛ4 and ALS onset site (p = 0.05,r = 0.33),with higher frequencies in bulbar onset patients. Cognitive signs were more frequent in ɛ4 carriers (r = 0.43,p < 0.01),and a significant link was observed between dysexecutive functions and the APOE risk allele (p = 0.0495).Concerning the MAPT haplotypes, we reported high frequency of ALS cases carrier of MAPT H1-haplotype HC (94.45% and 72.14% respectively, p < 0.001).Among ALS cases,MAPT-H1 showed a stronger positive correlation with the presence of oculomotor signs(p = 0.05,r = 0.28).As well as significant positive association between cognitive impairments(p = 0.039,r = 0.59). Our findings emphasize the correlation between APOE and MAPT genotypes and the cognitive features in our ALS patients. We also observed other interesting, though weak, significant correlations (with coefficients not exceeding 0.20),which require further validation in a larger cohort to confirm our results.}, } @article {pmid39749679, year = {2025}, author = {Young, CA and Chaouch, A and Mcdermott, CJ and Al-Chalabi, A and Chhetri, SK and Bidder, C and Edmonds, E and Ellis, C and Annadale, J and Wilde, L and Sharrack, B and Malaspina, A and Leach, O and Mills, R and Tennant, A}, title = {Determinants and progression of stigma in amyotrophic lateral sclerosis/motor neuron disease.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2024.2435969}, pmid = {39749679}, issn = {2167-9223}, abstract = {Objective: Stigma in amyotrophic lateral sclerosis/motor neurone disease (ALS/MND) may be felt or enacted; felt stigma covers feeling devalued by the illness, whereas enacted stigma refers to being treated differently because of it. Stigma in ALS/MND has been shown to increase social withdrawal, worsen quality of life, and reduce use of assistive devices, so we explored prevalence and factors influencing stigma. Methods: Participants in the Trajectories of Outcome in Neurological Conditions-ALS study completed scales measuring stigma, fatigue, spasticity, functioning, mood, worry, self-esteem, and perceived health, as well as demographic information and symptoms like head drop or emotional lability. Following transformation to interval-scale estimates, data were analyzed by regression, structural equation modeling, and trajectory models. Results: Stigma was experienced by 83.5% of 1059 respondents. Worry, disease severity (King's stage ≥ 3), emotional lability, fatigue, spasticity, and bulbar onset increase stigma. In contrast, increasing age, living with spouse/partner, and greater self-esteem were associated with reduced stigma. Trajectory analysis over 30 months (N = 1049) showed three groups, the largest (70.2%) had high levels of stigma which significantly increased during follow-up. In a recently diagnosed subset of 347 participants, stigma was experienced early in the disease course (<7 months after diagnosis), and for 77.2% stigma significantly increased over time. Conclusions: Both felt and enacted stigma are frequently perceived by people living with ALS/MND. Younger people and those with bulbar onset, emotional lability, worry, fatigue, and spasticity, or at more advanced clinical stages, are at greater risk.}, } @article {pmid39749674, year = {2025}, author = {Tankéré, P and Cascarano, E and Saint Raymond, C and Mallaret, M and Toribio Ruiz, C and Herquelot, E and Denis, H and Cals Maurette, M and Tamisier, R and Pépin, JL}, title = {Care trajectories and adherence to respiratory management recommendations in persons living with amyotrophic lateral sclerosis: a ten-year cohort study in a French tertiary university centre.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2024.2447911}, pmid = {39749674}, issn = {2167-9223}, abstract = {Objective: This study determined real-life care trajectories before and after initiation of noninvasive ventilation (NIV) in patients with amyotrophic lateral sclerosis (ALS). Caregiver adherence to respiratory management recommendations and the associated survival rate of people with ALS were also assessed. Methods: Data were obtained from a tertiary center prospective ALS database that included 10 years of follow-up data for people with ALS. Results are presented numerically and with graphical time sequence analysis through K clustering (TAK) representation. Kaplan Meier and Cox models were used to determine survival and associated prognostic factors. Results: 109 patients with ALS patients were included; median [interquartile range] follow-up was 25.0 months [15.3-43.3]. During study timeframe patients had a median of 4.0 [2.0-6.0] clinical visits; death occurred in 54.1%. Median time between clinical visits was 3.9 [2.8-6.5] months, between arterial blood gases was 4.3 months [3.0-6.6], between spirometry testing was 5.8 months [4.1-8.2], and between nocturnal oximetry was 4.4 months [3.0-7.8]. Visualization of care trajectories TAK show marked heterogeneity in survival, time to NIV initiation, and time from NIV initiation to death. Mortality was correlated with NIV initiation and arterial carbon dioxide pressure increase. Conclusions: The current framework in ALS guidelines should be adapted to the ALS disease stage and individual patient characteristics. Understanding how subgroups of patients with ALS use healthcare services over time could help to highlight fragility areas and priorities in the allocation of care resources and implementation of best practices.}, } @article {pmid39749668, year = {2025}, author = {Mehta, P and Raymond, J and Nair, T and Han, M and Berry, J and Punjani, R and Larson, T and Mohidul, S and Horton, DK}, title = {Amyotrophic lateral sclerosis estimated prevalence cases from 2022 to 2030, data from the national ALS Registry.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/21678421.2024.2447919}, pmid = {39749668}, issn = {2167-9223}, abstract = {Objective: To estimate the projected number of ALS cases in the United States from 2022 to 2030. Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease with no known cure. Because ALS is not a notifiable disease in the United States, the accurate ascertainment of prevalent ALS cases continues to be a challenge. To overcome this, the National ALS Registry (Registry) uses novel methods to estimate newly diagnosed and existing cases in the United States. Methods: We estimated ALS prevalence retrospectively from 2022 to 2024 and prospectively from 2025 to 2030 using prevalence obtained through previous CRC analyses on 2018 Registry data (the most current data available) to generate projected observed, missing, and total cases. Projected prevalent cases were then stratified by age, race, and sex. Results: The number of estimated ALS cases in 2022 was 32,893. By 2030, projected cases increase more than 10%, to 36,308. The largest increase occurs for the population ages 66 years and older, with a 25% increase (from 16,349 cases in 2022 to 20,438 cases in 2030). The projected number of cases classified as "other race" will increase by 15% (from 2,473 cases in 2022 to 2,854 cases in 2030). Conclusions: These estimates of projected ALS cases reflect anticipated changes in the underlying demographics of the United States. Our projections are likely an underestimation because emerging therapeutics and improved healthcare will improve survivability in this vulnerable population. These results should inform policy to more efficiently allocate resources for ALS patients and programs.}, } @article {pmid39749172, year = {2024}, author = {Chauhan, A and Begum, J and Lavanya, KM and Gupta, A and Ghosh, S and Kulkarni, S}, title = {Experiential Learning of Active Learning Strategies in Mentor Learner Web-based Discussions: A Perceptions Study.}, journal = {International journal of applied & basic medical research}, volume = {14}, number = {4}, pages = {258-265}, pmid = {39749172}, issn = {2229-516X}, abstract = {BACKGROUND: Active learning strategies (ALSs) in medical education are valued for their effectiveness but face adoption challenges among educators, underscoring the need for a deeper understanding of their implementation and impact.

AIM: The aim of the study was to investigate the perceptions of medical educators regarding the effectiveness and challenges of ALS through mentor-learner (ML) web-based discussions.

SETTINGS AND DESIGN: The retrospective cross-sectional study analyzed data from 32 medical educators enrolled in the Foundation for Advancement of International Medical Education Research course at Christian Medical College, Ludhiana. It utilized a mixed-method approach, gathering both quantitative and qualitative data through ML web discussions.

MATERIALS AND METHODS: The study used a "dual-method" approach, combining traditional online discussions with a "role-reversal" method on an ML web platform, promoting experiential learning. Participant responses on ALS implementation tasks were collected and analyzed within these discussions.

RESULTS: Participants shared various ALS for collaborative learning (20), classroom engagement (26), assessing prior knowledge (12), and note-taking during lectures (10). Further, among the 11 ALS examined, the ease of implementation varied significantly among participants (P < 0.0001). Challenges in ALS implementation included inadequate faculty training (91%), motivation (84%), resource constraints (81%), student (75%), and administrative resistance (69%). Four themes emerged as recommendations for effective ALS implementation: empowering educators, engaging students, streamlining support systems, and monitoring impact.

CONCLUSION: The study highlights a mixed perspective of medical educators on ALS. Although ALS was perceived as effective in fostering critical thinking and developing collaborative learning among students, various challenges, such as a lack of skilled faculty and resources, necessitated robust faculty development initiatives.}, } @article {pmid39748876, year = {2025}, author = {Salter, S and Salter, E and Kim, AJ and Liu, AK}, title = {Rising Voltage-Gated Potassium Channel Antibody Level as a Possible Disease Progression Marker for Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Cureus}, volume = {17}, number = {1}, pages = {e76760}, pmid = {39748876}, issn = {2168-8184}, abstract = {A subset of amyotrophic lateral sclerosis (ALS) patients tests positive for antibodies commonly associated with autoimmune neurological diseases, including voltage-gated potassium channel (VGKC)-complex antibodies. Although an autoimmune basis for ALS remains speculative, and immunomodulatory therapies have shown minimal benefit as of yet, isolated cases suggest that VGKC-complex antibodies may be relevant to disease type and progression. In this report, we present a case of ALS in which increasing VGKC-complex antibody levels correlated with clinical decline, raising the question of whether such antibodies could serve as biomarkers of progression in VGKC-complex antibody-positive ALS patients. To date, no published studies have systematically evaluated changes in VGKC-complex antibody levels in ALS patients over time. Our findings suggest that tracking VGKC-complex antibodies in ALS may offer insights into disease progression and prompt further investigation into their potential role as prognostic biomarkers, especially in certain subtypes of the disease.}, } @article {pmid39748816, year = {2024}, author = {Li, Z and Liu, X and Zhang, H and Li, P and Yao, F}, title = {Improving resistance to lepidopteran pests and herbicide using Sanming dominant genic male sterile rice (Oryza sativa L.).}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1525620}, pmid = {39748816}, issn = {1664-462X}, abstract = {In order to improve both resistance to lepidopteran pests and resistance to the herbicide imazethapyr in mainstay japonica varieties of the Huang-Huai rice region, Sanming dominant genic male sterile (S-DGMS) rice was used as a platform to facilitate the pyramiding of functional genes and the replacement of the genomic background. Twelve novel lines were developed, each carrying a crystal toxin gene conferring resistance to lepidopteran pests and the ALS[627N] allele conferring resistance to herbicide imazethapyr in the background of a mainstay japonica variety. The genomic background of the 12 novel lines was examined using 48 specified molecular markers, and each line carried less than two polymorphic markers relative to the corresponding mainstay variety. All 12 lines displayed high resistance to lepidopteran pests and the herbicide imazethapyr. The major agronomic traits of the 12 lines showed no difference relative to the responding mainstay variety when sprayed with pesticide. The popularization of the 12 japonica lines could reduce the use of pesticides and provide highly efficient control of weeds and weedy rice in the future, thus promoting the development of japonica rice production. Therefore, S-DGMS rice could be a powerful tool for the genetic improvement of target traits in rice.}, } @article {pmid39748214, year = {2025}, author = {Brown, G and Jesus, S and Leboffe, E and Esch, A and Newport, K}, title = {Advance Care Planning Billing Codes Associated With Decreased Healthcare Utilization in Neurological Disease.}, journal = {Journal of healthcare management / American College of Healthcare Executives}, volume = {70}, number = {1}, pages = {58-73}, pmid = {39748214}, issn = {1096-9012}, mesh = {Humans ; Aged ; Male ; Female ; *Advance Care Planning/statistics & numerical data ; United States ; *Nervous System Diseases/therapy ; Aged, 80 and over ; *Patient Acceptance of Health Care/statistics & numerical data ; Cohort Studies ; }, abstract = {GOALS: Advance care planning (ACP) procedure codes have been established to reimburse meaningful care goal discussions; however, the utilization frequency of these codes in neurological disease is unknown. The objective of this study is to identify the association between ACP codes and healthcare utilization in chronic neurodegenerative diseases.

METHODS: This is a multicenter cohort study using real-world electronic health data. Using the TriNetX database, we collected electronic health data from 92 institutions in the United States. We included patients aged 65 and older who had been diagnosed with one of four neurological diseases: Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis (ALS). Patients with congestive heart failure were included as a reference. From the 64,683,009 total patients in the database, 877,138 had Alzheimer's disease, 544,610 had Parkinson's disease, 208,341 had multiple sclerosis, 9,944 had amyotrophic lateral sclerosis, and 1,500,186 had congestive heart failure. For each disease, we compared hospitalizations and emergency department (ED) visits over a two-year period between patients with and without ACP codes documented. Then, in patients with ACP, we investigated the rates of hospitalizations and ED visits over the two years before ACP and two years after ACP to understand the impact of ACP on the healthcare utilization trend. All patients had records for at least two years after index.

PRINCIPAL FINDINGS: The rate of ACP code documentation ranged from 1.8% of multiple sclerosis patients to 3.6% of Alzheimer's disease patients. After matching for demographic and health variables, usage of ACP codes was associated with significantly fewer hospitalizations for Alzheimer's disease patients. Across all diseases, there was a 20% to 30% decrease in ED visits, which was significant. Furthermore, there was a significant change in the trend of hospitalizations and ED visits for patients after ACP documentation. Patients went from increasing utilization before ACP documentation to decreasing utilization after documentation.

PRACTICAL APPLICATIONS: ACP billing codes are used infrequently in neurological disease, which may indicate that reimbursement alone is not sufficient to drive code usage. Usage of ACP billing codes was associated with decreased healthcare utilization, particularly in terms of ED visits. Beyond the primary objective of providing goal-concordant care, ACP may impact the economic burden of chronic neurodegenerative disease, which has high costs of care in our aging society. There may be particular benefits with Alzheimer's disease, which had an impact on both hospitalizations and ED visits and is the most prevalent neurodegenerative disease. Future work is needed to better understand the best implementation strategy for ACP in a multifaceted approach that emphasizes patient care preferences for their illness.}, } @article {pmid39747792, year = {2025}, author = {Lee, J and Kouznetsova, VL and Kesari, S and Tsigelny, I}, title = {Selective diagnostics of Amyotrophic Lateral Sclerosis, Alzheimer's and Parkinson's Diseases with machine learning and miRNA.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {79}, pmid = {39747792}, issn = {1573-7365}, mesh = {*MicroRNAs/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/metabolism ; *Machine Learning ; *Alzheimer Disease/diagnosis/genetics/metabolism ; *Parkinson Disease/diagnosis/genetics/metabolism ; *Biomarkers ; }, abstract = {The diagnosis of neurological diseases can be expensive, invasive, and inaccurate, as it is often difficult to distinguish between different types of diseases with similar motor symptoms. However, the dysregulation of miRNAs can be used to create a robust machine-learning model for a reliable diagnosis of neurological diseases. We used miRNA sequence descriptors and gene target data to create machine-learning models that can be used as diagnostic tools. The top-performing machine-learning models, trained on filtered miRNA datasets for Amyotrophic Lateral Sclerosis, Alzheimer's and Parkinson's Diseases of this research yielded 94, 97, and 96, percent accuracies, respectively. Analysis of dysregulated miRNA in neurological diseases elucidated novel biomarkers that could be used to diagnose and distinguish between the diseases. Machine-learning models developed using sequence and gene target descriptors of miRNA biomarkers can achieve favorable accuracies for disease classification and attain a robust discerning capability of neurological diseases.}, } @article {pmid39747573, year = {2025}, author = {Kim, KM and Girdhar, A and Cicardi, ME and Kankate, V and Hayashi, M and Yang, R and Carey, JL and Fare, CM and Shorter, J and Cingolani, G and Trotti, D and Guo, L}, title = {NLS-binding deficient Kapβ2 reduces neurotoxicity via selective interaction with C9orf72-ALS/FTD dipeptide repeats.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {2}, pmid = {39747573}, issn = {2399-3642}, support = {R35GM138109//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; F31 NS111870/NS/NINDS NIH HHS/United States ; R21 NS128396/NS/NINDS NIH HHS/United States ; 628389//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; R01 NS121143/NS/NINDS NIH HHS/United States ; F31NS111870//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35 GM140733/GM/NIGMS NIH HHS/United States ; R35GM140733//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; RF1NS121143//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21-NS090912//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21NS128396//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01GM099836//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R21 NS090912/NS/NINDS NIH HHS/United States ; RF1 NS121143/NS/NINDS NIH HHS/United States ; T32GM008275//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 GM099836/GM/NIGMS NIH HHS/United States ; RF1 AG057882/AG/NIA NIH HHS/United States ; T32 GM008275/GM/NIGMS NIH HHS/United States ; R35 GM138109/GM/NIGMS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Frontotemporal Dementia/metabolism/genetics ; *Dipeptides/metabolism ; beta Karyopherins/metabolism/genetics ; RNA-Binding Protein FUS/metabolism/genetics ; Protein Binding ; HEK293 Cells ; }, abstract = {Arginine-rich dipeptide repeat proteins (R-DPRs) are highly toxic proteins found in patients with C9orf72-linked amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). R-DPRs can cause toxicity by disrupting the natural phase behavior of RNA-binding proteins (RBPs). Mitigating this abnormal phase behavior is, therefore, crucial to reduce R-DPR-induced toxicity. Here, we use FUS as a model RBP to investigate the mechanism of R-DPR-induced aberrant RBP phase transition. We find that this phase transition can be mitigated by Kapβ2. However, as a nuclear import receptor and phase modifier for PY-NLS-containing RBPs, the function of WT Kapβ2 could lead to undesired interaction with its native substrates when used as therapeutics for C9-ALS/FTD. To address this issue, it is crucial to devise effective strategies that allow Kapβ2 to selectively target its binding to the R-DPRs, instead of the RBPs. We show that NLS-binding deficient Kapβ2W460A:W730A can indeed selectively interact with R-DPRs in FUS assembly without affecting normal FUS phase separation. Importantly, Kapβ2W460A:W730A prevents enrichment of poly(GR) in stress granules and mitigates R-DPR neurotoxicity. Thus, NLS-binding deficient Kapβ2 may be implemented as a potential therapeutic for C9-ALS/FTD.}, } @article {pmid39747563, year = {2025}, author = {Adim, H and Fahmideh, L and Fakheri, BA and Zarrini, HN and Sasanfar, H}, title = {iTRAQ-based quantitative proteomic analysis of herbicide stress in Avena ludoviciana Durieu.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {577}, pmid = {39747563}, issn = {2045-2322}, mesh = {*Herbicides/pharmacology/toxicity ; *Avena/drug effects/genetics/metabolism ; *Proteomics/methods ; *Herbicide Resistance/genetics ; *Plant Proteins/metabolism/genetics ; Gene Expression Regulation, Plant/drug effects ; Stress, Physiological/drug effects ; Acetyl-CoA Carboxylase/metabolism/genetics ; }, abstract = {Winter wild oat (Avena sterilis subsp. ludoviciana (Durieu) Gillet & Magne) has been considered the most common and troublesome weed in wheat fields of Iran. The widespread and continuous use of herbicides has led to the emergence and development of resistant biotypes in A. ludoviciana, making it one of the most important herbicide-resistant weeds within field crops. Considering the importance of understanding the mechanisms underlying resistance to herbicides and identifying key proteins involved in the response to Acetyl-coenzyme A carboxylase (ACCase) and Acetolactate synthase (ALS) inhibitor herbicides in A. ludoviciana. This study aimed to identify the proteins involved in herbicide resistance in A. ludoviciana using the Isobaric Tags for Relative and Absolute Quantification (iTRAQ) technique. In this study, a total of 18,313 peptides were identified with ≤ 0.01 FDR, which could be classified into 484 protein groups. Additionally, 138 differentially expressed proteins (DEPs) were identified in the resistant biotype (R), while 93 DEPs were identified in the susceptible biotype (S). Gene Ontology (GO) analysis revealed that these DEPs mainly consisted of proteins related to photosynthesis, respiration, amino acid synthesis and translation, secondary metabolite biosynthesis, defense proteins, and detoxification. Furthermore, enrichment pathway analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that the most important pathways included metabolic pathways, carbohydrate metabolism, secondary metabolites, amino acid synthesis, and photosynthesis. The function of DEPs indicated that some proteins, such as cytochrome P450, play a direct role in herbicide detoxification. Overall, the results of this study demonstrated the complex response of the resistant biotype to herbicides and its ability to increase antioxidant capacity through up-regulated detoxification proteins, particularly cytochrome P450 (Q6YSB4), and defense proteins, particularly superoxide dismutase (Q0DRV6) and polyamine oxidase (Q7XR46). In the resistant A. ludoviciana populations, in addition to the activation of enzymatic and non-enzymatic defense systems, other strategies such as reduced photosynthesis and respiration, increased transcription and translation activity, enhanced lipid metabolism, regulation of cellular processes and homeostasis, and up-regulation of proteins associated with signaling and ion channels play a role in resistance to herbicide. Overall these findings provide new insights into the role of different proteins in resistance to herbicides and contribute to a comprehensive understanding of herbicide resistance in A. ludoviciana.}, } @article {pmid39745174, year = {2025}, author = {Antonelli, S and Castañeda, FN and Olivieri, AC and Carabajal, MD and Pellegrino Vidal, RB}, title = {Novel Data Fusion Strategy for Second-Order Data: Multivariate Curve Resolution for the Determination of Pharmaceuticals by Means of Fluorimetric Measurements.}, journal = {Analytical chemistry}, volume = {97}, number = {1}, pages = {962-968}, doi = {10.1021/acs.analchem.4c05725}, pmid = {39745174}, issn = {1520-6882}, mesh = {Multivariate Analysis ; Least-Squares Analysis ; *Water Pollutants, Chemical/analysis ; Pharmaceutical Preparations/analysis/chemistry ; Fluorometry/methods ; }, abstract = {A new strategy is proposed for second-order data fusion based on the simultaneous modeling of two data sets using the multivariate curve resolution-alternating least-squares (MCR-ALS) model, applying a new constraint during the ALS stage, called "Proportionality of Scores". This approach allows for the fusion of data from different sources, without requiring common dimensionality, and enables the application of specific constraints to each data set. This strategy was applied to the determination of five pharmaceutical contaminants (naproxen, danofloxacin, ofloxacin, sarafloxacin, and enoxacin) in environmental water samples, by fusing two sets of excitation-emission fluorescence matrices, measured before and after photochemical derivatization. The predictive performance of the fused model was compared to individual PARAFAC models built for each fluorescence data set, showing that data fusion significantly increases precision and accuracy, as indicated by the elliptical joint confidence region test. Data fusion allowed improvement of relative errors of prediction, from 13-32% to 8-15% in validation samples and from 25-121% to 13-20% in real samples. The advantages of data fusion were evident in both cases, particularly in instances of substantial signal overlap between analytes or the presence of uncalibrated interferents with similar profiles, as demonstrated by the superior predictive capacity achieved through the proposed strategy.}, } @article {pmid39744204, year = {2024}, author = {Morales-Galicia, AE and Ramírez-Mejía, MM and Ponciano-Rodriguez, G and Méndez-Sánchez, N}, title = {Revolutionizing the understanding of liver disease: Metabolism, function and future.}, journal = {World journal of hepatology}, volume = {16}, number = {12}, pages = {1365-1370}, pmid = {39744204}, issn = {1948-5182}, abstract = {The intersection between metabolic-associated steatotic liver disease (MASLD) and chronic hepatitis B virus (HBV) infection is an emerging area of research with significant implications for public health and clinical practice. Wang et al's study highlights the complexities of managing patients with concurrent MASLD and HBV. The findings revealed that patients with concurrent MASLD-HBV exhibited more severe liver inflammation and fibrosis, whereas those with HBV alone presented a better lipid profile. The growing recognition of metabolic dysfunction in liver disease, reflected in the shift from nonalcoholic liver disease to MASLD, demands updates to clinical guidelines, particularly for patients with dual etiologies. Understanding the biological interactions between MASLD and HBV could lead to novel therapeutic approaches, emphasizing the need for personalized treatment strategies. The coexistence of MASLD and HBV presents therapeutic challenges, particularly in managing advanced fibrosis and cirrhosis, which are more likely in these patients. The aim of this editorial is to analyze the interaction between MASLD and HBV, highlight the pathophysiological mechanisms that exacerbate liver disease when both conditions coexist, and discuss the clinical implications of the findings of Wang et al.}, } @article {pmid39743746, year = {2025}, author = {Wang, Z and Wang, X and Li, P and Xia, H and Yang, X}, title = {Genetic associations between immune-related plasma proteins and neurodegenerative diseases.}, journal = {Neurological research}, volume = {47}, number = {2}, pages = {129-138}, doi = {10.1080/01616412.2024.2448745}, pmid = {39743746}, issn = {1743-1328}, mesh = {Humans ; *Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics/immunology/blood ; *Blood Proteins/genetics/metabolism ; *Genetic Predisposition to Disease/genetics ; Alzheimer Disease/genetics/immunology/blood ; Amyotrophic Lateral Sclerosis/genetics/immunology/blood ; Parkinson Disease/genetics/immunology/blood ; Multiple Sclerosis/genetics/blood/immunology ; }, abstract = {BACKGROUND: Immune dysregulation is commonly associated with neurodegenerative diseases (NDs), yet the underlying causes and mechanisms still require further investigation.

OBJECTIVE: This study investigates the correlation between immune-related plasma proteins and the risk of NDs by integrating genome-wide association study (GWAS) data for Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) with plasma proteome analysis.

METHODS: By analyzing GWAS data for 4907 immune-related plasma proteins, this research evaluates the direct impact of plasma proteins on the risk of four NDs: AD, PD, ALS, and MS. Additionally, the study conducts an analysis of protein expression levels using single-cell RNA sequencing data.

RESULTS: We have identified plasma proteins that are closely associated with the risk of NDs. Using stringent criteria, we identified 88 proteins associated with AD, 115 with PD, 100 with ALS, and 87 with MS. Additionally, single-cell sequencing analyzed the protein expression and its distribution within different cell types in the brain.

CONCLUSIONS: Our research has demonstrated that plasma proteins may contribute to the risk of NDs, and it has also provided concrete evidence linking genetic susceptibility for these diseases to immune mechanisms. Furthermore, we found that specific proteins influence genetic variations linked to NDs risk via plasma-mediated regulation, emphasizing the importance of interactions between the brain and circulatory system.}, } @article {pmid39743546, year = {2025}, author = {Faller, KME and Chaytow, H and Gillingwater, TH}, title = {Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {2}, pages = {86-102}, pmid = {39743546}, issn = {1759-4766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism ; Animals ; }, abstract = {The motor neuron disease amyotrophic lateral sclerosis (ALS) is a devastating condition with limited treatment options. The past few years have witnessed a ramping up of translational ALS research, offering the prospect of disease-modifying therapies. Although breakthroughs using gene-targeted approaches have shown potential to treat patients with specific disease-causing mutations, the applicability of such therapies remains restricted to a minority of individuals. Therapies targeting more general mechanisms that underlie motor neuron pathology in ALS are therefore of considerable interest. ALS pathology is associated with disruption to a complex array of key cellular pathways, including RNA processing, proteostasis, metabolism and inflammation. This Review details attempts to restore cellular homeostasis by targeting these pathways in order to develop effective, broadly-applicable ALS therapeutics.}, } @article {pmid39743298, year = {2024}, author = {Wang, L and Liu, H and Li, L}, title = {Autophagy receptor-inspired chimeras: a novel approach to facilitate the removal of protein aggregates and organelle by autophagy degradation.}, journal = {Journal of Zhejiang University. Science. B}, volume = {25}, number = {12}, pages = {1115-1119}, pmid = {39743298}, issn = {1862-1783}, support = {81970431//the National Natural Science Foundation of China/ ; 2023JJ50136//the Hunan Provincial Natural Science Foundation of China/ ; }, mesh = {*Autophagy ; Humans ; *Neurodegenerative Diseases/metabolism ; *Protein Aggregates ; Animals ; Organelles/metabolism ; Alzheimer Disease/metabolism ; Neurons/metabolism ; Huntington Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Neurodegenerative diseases (NDDs), mainly including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD), are sporadic and rare genetic disorders of the central nervous system. A key feature of these conditions is the slow accumulation of misfolded protein deposits in brain neurons, the excessive aggregation of which leads to neurotoxicity and further disorders of the nervous system.}, } @article {pmid39743215, year = {2024}, author = {Chiu, Y and Xia, S and Qiao, H and Zhao, Z}, title = {Genetically Engineered Mouse Models for Alzheimer Disease and Frontotemporal Dementia: New Insights from Single-Cell and Spatial Transcriptomics.}, journal = {The American journal of pathology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajpath.2024.11.006}, pmid = {39743215}, issn = {1525-2191}, abstract = {Neurodegenerative diseases, including Alzheimer disease, frontotemporal dementia, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis, are often casually linked to protein aggregation and inclusion. As the origins of those proteinopathies have been biochemically traced and genetically mapped, genetically engineered animal models carrying the specific mutations or variants are widely used for investigating the etiology of these diseases, as well as for testing potential therapeutics. This article focuses on the mouse models of Alzheimer disease and closely related frontotemporal dementia, particularly the ones that have provided most valuable knowledge, or are in a trajectory of doing so. More importantly, some of the major findings from these models are summarized, based on the recent single-cell transcriptomics, multiomics, and spatial transcriptomics studies. While no model is perfect, it is hoped that the new insights from these models and the practical use of these models will continue to help to establish a path forward.}, } @article {pmid39743032, year = {2025}, author = {Li, Y and Zhang, W and Zhang, Q and Li, Y and Xin, C and Tu, R and Yan, H}, title = {Oxidative stress of mitophagy in neurodegenerative diseases: Mechanism and potential therapeutic targets.}, journal = {Archives of biochemistry and biophysics}, volume = {764}, number = {}, pages = {110283}, doi = {10.1016/j.abb.2024.110283}, pmid = {39743032}, issn = {1096-0384}, mesh = {*Mitophagy ; Humans ; *Oxidative Stress/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; Animals ; *Antioxidants/metabolism/therapeutic use ; Mitochondria/metabolism ; }, abstract = {Neurodegenerative diseases are now significant chronic progressive neurological conditions that affect individuals' physical health. Oxidative stress is crucial in the development of these diseases. Among the various neurodegenerative diseases, mitochondrial damage has become a major factor in oxidative stress and disease advancement. During this process, oxidative stress and mitophagy plays an important role. In this paper, we introduced the role of mitophagy and oxidative stress in detail, and expounded the relationship between them. In addition, we summarized the pathogenesis of some neurodegenerative diseases and the mechanism of three antioxidants. The former includes AD, PD, HD and ALS, while the latter includes carnosine, adiponectin and resveratrol. Provide goals and directions for further research and treatment of neurodegenerative diseases. This review summarizes the impact of oxidative stress on neurodegenerative diseases by regulating mitophagy, provides a deeper understanding of their pathological mechanisms, and suggests potential new therapeutic targets.}, } @article {pmid39742161, year = {2024}, author = {Mashimo, S and Matsuoka, A and Tanese, K and Kano, O and Ishiko, A}, title = {Idiopathic Multiple Localized Lipoatrophy Mimicking Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e74887}, pmid = {39742161}, issn = {2168-8184}, abstract = {Localized lipoatrophy is a rare condition characterized by the localized loss of subcutaneous adipose tissue. It may occur idiopathically without specific triggers. The pathogenesis of idiopathic localized lipoatrophy remains largely unknown. We present the case of a 53-year-old Japanese woman with multiple localized lipoatrophy who exhibited upper motor neuron signs clinically and panniculitis histologically. She was initially suspected to have amyotrophic lateral sclerosis due to progressive left limb volume loss. Histologically, the lesions showed adipocyte destruction accompanied by predominant plasma infiltration.}, } @article {pmid39741274, year = {2024}, author = {Mandeville, R and Sedghamiz, H and Mansfield, P and Sheean, G and Studer, C and Cordice, D and Ghanbari, G and Malhotra, A and Nemati, S and Koola, J}, title = {Deep learning enhanced transmembranous electromyography in the diagnosis of sleep apnea.}, journal = {BMC neuroscience}, volume = {25}, number = {1}, pages = {80}, pmid = {39741274}, issn = {1471-2202}, support = {R01 HL157985/HL/NHLBI NIH HHS/United States ; T15 LM011271/LM/NLM NIH HHS/United States ; R01 HL166485/HL/NHLBI NIH HHS/United States ; R01 AG063925/AG/NIA NIH HHS/United States ; R01 HL154926/HL/NHLBI NIH HHS/United States ; R01 HL148436/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Deep Learning ; *Electromyography/methods ; Male ; Middle Aged ; Female ; Adult ; Sleep Apnea, Obstructive/diagnosis/physiopathology ; Polysomnography/methods ; Aged ; Sleep Apnea Syndromes/diagnosis/physiopathology ; }, abstract = {Obstructive sleep apnea (OSA) is widespread, under-recognized, and under-treated, impacting the health and quality of life for millions. The current gold standard for sleep apnea testing is based on the in-lab sleep study, which is costly, cumbersome, not readily available and represents a well-known roadblock to managing this huge societal burden. Assessment of neuromuscular function involved in the upper airway using electromyography (EMG) has shown potential to characterize and diagnose sleep apnea, while the development of transmembranous electromyography (tmEMG), a painless surface probe, has made this opportunity practical and highly feasible. However, experience and ability to interpret electrical signals from the upper airway are scarce, and much of the pertinent information within the signal is likely difficult to detect visually. To overcome this issue, we explored the use of transformers, a deep learning (DL) model architecture with attention mechanisms, to model tmEMG data and distinguish between electromyographic signals from a cohort of control, neurogenic, and sleep apnea patients. Our approach involved three strategies to train a generalizable model on a relatively small dataset including, (1) transfer learning using an audio spectral transformer (AST), (2) the use of 6,000 simulated EMG recordings, converted to spectrograms and using standard backpropagation for fine-tuning, and (3) application of regularization to prevent overfitting and enhance generalizability. This DL approach was tested using 177 transoral EMG recordings from a prior study's database that included six healthy controls, five moderate to severe OSA patients, and five amyotrophic lateral sclerosis (ALS) patients with evidence of bulbar involvement (neurogenic injury). Sensitivity and specificity for classifying neurogenic cases from controls were 98% and 73%, respectively, while classifying OSA from controls were 88% and 64%, respectively. Notably, by averaging the predicted probabilities of each segment for individual patients, the model correctly classified up to 82% of control and OSA patients. These results not only suggest a potential to diagnose OSA patients accurately, but also to identify OSA endotypes that involve neuromuscular pathology, which has major implications for clinical management, patient outcomes, and research.}, } @article {pmid39741002, year = {2024}, author = {Lembo, A and Schiavetti, I and Serafino, M and Caputo, R and Nucci, P}, title = {Comparison of the performance of myopia control in European children and adolescents with defocus incorporated multiple segments (DIMS) and highly aspherical lenslets (HAL) spectacles.}, journal = {BMJ paediatrics open}, volume = {8}, number = {1}, pages = {}, pmid = {39741002}, issn = {2399-9772}, mesh = {Humans ; *Eyeglasses ; Adolescent ; Child ; Male ; Female ; Retrospective Studies ; *Myopia/therapy/epidemiology/physiopathology/prevention & control ; *Refraction, Ocular/physiology ; Disease Progression ; Europe/epidemiology ; Equipment Design ; Visual Acuity/physiology ; }, abstract = {PURPOSE: A performance comparison of two myopia control spectacle lens designs, defocus incorporated multiple segments (DIMS) and highly aspherical lenslets (HAL), at slowing myopia progression in a European child/adolescent population. Previous research directly comparing these designs has been limited to Chinese participants and 1-year follow-up. The prevalence of myopia in European child/adolescent has been estimated at 22.60%.

METHODS: Retrospective cohort study of individuals (6-17 years) with myopia progression. Participants wore DIMS (Hoya MiyoSmart) or HAL (Essilor Stellest) spectacles for a minimum of 2 years. Axial length (AL) and cycloplegic autorefraction (spherical equivalent refraction (SER)) were measured at baseline and 1 and 2 years.

RESULTS: Mean 1-year SER changes for DIMS were -0.34D (±0.46 SD) and HAL -0.30D (±0.30); 2-year changes for DIMS were -0.50D (±0.64 SD) and HAL -0.63D (±0.56). Mean 1-year AL increases for DIMS were 0.19 mm (±0.56) and HAL 0.15 mm (±0.47); 2-year increases for DIMS were 0.29 mm (±0.63) and HAL 0.32 mm (±0.72). For equivalence margins of 0.25D and 0.50D for SER at 1 and 2 years, respectively, and similarly 0.20 mm and 0.30 mm margins for AL, DIMS and HAL lenses were equivalent apart from AL at 1 year where the 0.21 mm 95% CI upper limit just exceeded 0.20 mm. At both 1 and 2 years, none of the differences in mean SERs or ALs between DIMS and HAL were clinically or statistically significant (p≥0.05 Mann-Whitney U test). Using linear mixed model analysis, the interaction between lens type and time did not significantly affect SER or AL at 1- or 2-year follow-up (p≥0.05). 38.4% of children/adolescents with DIMS had no SER progression at 2 years, compared with 21.9% with HAL (p=0.047).

CONCLUSION: In a European population, DIMS and HAL lenses are essentially equivalent in their ability to reduce myopia progression and AL elongation over a 2-year follow-up period.}, } @article {pmid39740768, year = {2025}, author = {Jiang, Y and Fan, W and Li, Y and Xue, H}, title = {Genetic Insights Into the Role of Cathepsins in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis: Evidence From Mendelian Randomization Study.}, journal = {Brain and behavior}, volume = {15}, number = {1}, pages = {e70207}, pmid = {39740768}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Mendelian Randomization Analysis ; *Alzheimer Disease/genetics ; *Parkinson Disease/genetics ; *Cathepsins/genetics ; *Genome-Wide Association Study ; Cathepsin B/genetics/metabolism ; Cathepsin H/genetics ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: Previous studies have confirmed the significant role of cathepsins in the development of neurodegenerative diseases. We aimed to determine whether genetically predicted 10 cathepsins may have a causal effect on Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

METHODS: We conducted a two-sample bidirectional Mendelian randomization (MR) study using publicly available data from genome-wide association study (GWAS) to assess the causal associations between 10 cathepsins and three neurodegenerative diseases, including AD, PD, and ALS. We employed the following methods, including inverse variance weighting (IVW), MR-Egger, and weighted median (WM). The results were further validated using sensitivity analysis.

RESULTS: The forward MR analysis results indicate that elevated cathepsin H levels increase the risk of AD (p = 0.005, odds ratio [OR] = 1.040, 95% confidence interval [CI] = 1.011-1.069), elevated cathepsin B levels decrease the risk of PD (p < 0.001, OR = 0.890, 95% CI = 0.831-0.954), and no significant association was found between cathepsin levels and ALS. Reverse MR analysis suggests that there is no causal association between 10 cathepsins and three neurodegenerative diseases.

CONCLUSION: Our study provides new genetic insights into the role of cathepsin H in AD and cathepsin B in PD. However, our findings need to be further validated in a wider population, and future research should explore the potential mechanisms of cathepsins in these diseases in order to provide a basis for the development of new therapeutic strategies.}, } @article {pmid39740575, year = {2025}, author = {Fortuna, A and Sorarù, G}, title = {Cervical lower motor neuron syndromes: A diagnostic challenge.}, journal = {Journal of the neurological sciences}, volume = {468}, number = {}, pages = {123357}, doi = {10.1016/j.jns.2024.123357}, pmid = {39740575}, issn = {1878-5883}, mesh = {Humans ; *Motor Neuron Disease/diagnosis/physiopathology/diagnostic imaging ; Magnetic Resonance Imaging/methods ; }, abstract = {Cervical lower motor neuron (LMN) syndromes, also known as brachial paresis, are characterized by muscle atrophy, weakness, and decreased reflexes in the upper limbs, devoid of sensory symptoms. These syndromes can stem from various factors, including degenerative conditions, immune-mediated diseases, infections, toxic exposures, metabolic disorders, and vascular anomalies.[1] Clinical presentations vary, with motor neuron involvement potentially limited to the cervical area or extending to other regions, affecting prognosis. Misdiagnosis is a significant issue, particularly in lower motor neuron presentations, with an error rate nearing 20 %.[2] This review proposes a classification system based on magnetic resonance imaging (MRI) findings, the onset timing of symptoms (acute, subacute, or chronic), the symmetry and distribution of atrophy, and the etiology (sporadic or hereditary). Acute conditions may include spinal ischemia,[3] whereas subacute or chronic forms can manifest as symmetric (e.g., cervical spondylogenic myelopathy)[4] or asymmetric (e.g., Hirayama disease)[5] presentations. Neurophysiological assessments and cervical MRI are crucial for accurate diagnosis, as they reveal patterns that provide lesion localization and additional clues to the underlying cause. A systematic diagnostic approach is essential for navigating the complexities of these syndromes.}, } @article {pmid39739690, year = {2024}, author = {Tian, Y and Heinsinger, N and Hu, Y and Lim, UM and Wang, Y and Fernandis, AZ and Parmentier-Batteur, S and Klein, B and Uslaner, JM and Smith, SM}, title = {Deciphering the interactome of Ataxin-2 and TDP-43 in iPSC-derived neurons for potential ALS targets.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0308428}, pmid = {39739690}, issn = {1932-6203}, mesh = {*Induced Pluripotent Stem Cells/metabolism ; *Ataxin-2/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Neurons/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Protein Binding ; }, abstract = {Ataxin-2 is a protein containing a polyQ extension and intermediate length of polyQ extensions increases the risk of Amyotrophic Lateral Sclerosis (ALS). Down-regulation of Ataxin-2 has been shown to mitigate TDP-43 proteinopathy in ALS models. To identify alternative therapeutic targets that can mitigate TDP-43 toxicity, we examined the interaction between Ataxin-2 and TDP-43. Co-immunoprecipitation demonstrated that Ataxin-2 and TDP-43 interact, that their interaction is mediated through the RNA recognition motif (RRM) of TDP-43, and knocking down Ataxin-2 or mutating the RRM domains rescued TDP-43 toxicity in an iPSC-derived neuronal model with TDP-43 overexpression. To decipher the Ataxin-2 and TDP-43 interactome, we used co-immunoprecipitation followed by mass spectrometry to identify proteins that interacted with Ataxin-2 and TDP-43 under conditions of endogenous or overexpressed TDP-43 in iPSC-derived neurons. Multiple interactome proteins were differentially regulated by TDP-43 overexpression and toxicity, including those involved in RNA regulation, cell survival, cytoskeleton reorganization, protein modification, and diseases. Interestingly, the RNA-binding protein (RBP), TAF15 which has been implicated in ALS was identified as a strong binder of Ataxin-2 in the condition of TDP-43 overexpression. Together, this study provides a comprehensive annotation of the Ataxin-2 and TDP-43 interactome and identifies potential therapeutic pathways and targets that could be modulated to alleviate Ataxin-2 and TDP-43 interaction-induced toxicity in ALS.}, } @article {pmid39739500, year = {2025}, author = {Saiduzzaman, M and Roy, S and Bhattacharjee, M}, title = {Young Patient with Amyotrophic Lateral Sclerosis Following Suicidal Organophosphorus Compounds Poisoning: A Case Report.}, journal = {Mymensingh medical journal : MMJ}, volume = {34}, number = {1}, pages = {272-275}, pmid = {39739500}, issn = {2408-8757}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/therapy/complications ; *Organophosphate Poisoning/complications/therapy/etiology ; Suicide, Attempted ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving both upper and lower motor neurons. Its underlying etiology is not well established. But certain risk factors including genetic predilection and exposure to certain environmental toxins like Organophosphorus Compounds (OPC) have been postulated. Here we describe a young male patient presented with progressive weakness of all four limbs immediately following survival from OPC ingestion as a suicidal attempt. He also had slurred, indistinct speech without swallowing difficulty and sensory findings. Neurological examination findings are having mixed upper and lower motor neuron signs. EMG (Electromyography) shows features of denervation and reinnervation suggestive of ALS. ALS following single exposure to OPC is a relatively rare finding. Supportive treatments including physiotherapy and psychotherapy were given. This case may strengthen the etiological link between OPC and ALS.}, } @article {pmid39739450, year = {2025}, author = {Aiello, EN and Poletti, B and Consonni, M and Iazzolino, B and Torre, S and Faltracco, V and Telesca, A and Palumbo, F and Curti, B and De Luca, G and Bella, ED and Bersano, E and Riva, N and Verde, F and Messina, S and Doretti, A and Maranzano, A and Morelli, C and Calvo, A and Silani, V and Lauria, G and Chiò, A and Ticozzi, N}, title = {Education moderates the association between motor involvement and executive status in ALS.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e70027}, pmid = {39739450}, issn = {1468-1331}, support = {//BIBLIOSAN/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/physiopathology ; Male ; Female ; *Executive Function/physiology ; Middle Aged ; *Educational Status ; Aged ; *Cognitive Reserve/physiology ; Neuropsychological Tests ; Cohort Studies ; }, abstract = {BACKGROUND: This study aimed to determine whether educational attainment-a common proxy of cognitive reserve (CR)-influences the association between motor and cognitive/behavioural outcomes in a large cohort of ALS patients without dementia.

METHODS: N = 726 ALS patients without FTD were assessed for motor (ALSFRS-R), cognitive (Edinburgh Cognitive and Behavioural ALS Screen, ECAS) and behavioural outcomes (ECAS-Carer Interview, ECAS-CI). CR was operationalized via educational attainment (in years). Moderation models were run on each subscale of the cognitive section of the ECAS and on the ECAS-CI by addressing ALSFRS-R as the predictor and education as the moderator.

RESULTS: Education was associated with both the ALSFRS-R and all the cognitive subscales of the ECAS, while not with the ECAS-CI. As to moderation models, a significant Education*ALSFRS-R interaction was detected solely with regard to the ECAS-Executive-with its simple slope-based decomposition revealing that higher ALSFRS-R scores were associated with higher scores on the ECAS-Executive for patients with low (p < 0.001) and average (p = 0.007), while not high, levels of education.

DISCUSSION: Education seems to moderate the association between motor involvement and executive status in ALS patients without dementia, thus possibly exerting a protective role towards both motor function and cognition in this population.}, } @article {pmid39738171, year = {2024}, author = {Jeon, P and Ham, HJ and Choi, H and Park, S and Jang, JW and Park, SW and Cho, DH and Lee, HJ and Song, HK and Komatsu, M and Han, D and Jang, DJ and Lee, JA}, title = {NS1 binding protein regulates stress granule dynamics and clearance by inhibiting p62 ubiquitination.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10925}, pmid = {39738171}, issn = {2041-1723}, support = {2020M3E5D9079911//National Research Foundation of Korea (NRF)/ ; 2023R1A2C2008092//National Research Foundation of Korea (NRF)/ ; 2023R1A2C2008092//National Research Foundation of Korea (NRF)/ ; RS-2023-00218515//National Research Foundation of Korea (NRF)/ ; JP19H05706//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP21H004771//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23K20044//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 24H00060//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP22gm1410004h0003//Japan Agency for Medical Research and Development (AMED)/ ; }, mesh = {Humans ; *Ubiquitination ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Stress Granules/metabolism ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; *Sequestosome-1 Protein/metabolism/genetics ; Microtubule-Associated Proteins/metabolism/genetics ; Neurons/metabolism ; HEK293 Cells ; Oxidative Stress ; HeLa Cells ; Autophagy ; Viral Nonstructural Proteins/metabolism/genetics ; Protein Binding ; Cytoplasmic Granules/metabolism ; Apoptosis Regulatory Proteins ; }, abstract = {The NS1 binding protein, known for interacting with the influenza A virus protein, is involved in RNA processing, cancer, and nerve cell growth regulation. However, its role in stress response independent of viral infections remains unclear. This study investigates NS1 binding protein's function in regulating stress granules during oxidative stress through interactions with GABARAP subfamily proteins. We find that NS1 binding protein localizes to stress granules, interacting with core components, GABARAP proteins, and p62, a protein involved in autophagy. In cells lacking NS1 binding protein, stress granule dynamics are altered, and p62 ubiquitination is increased, suggesting impaired stress granule degradation. Overexpression of NS1 binding protein reduces p62 ubiquitination. In amyotrophic lateral sclerosis patient-derived neurons, reduced NS1 binding protein and p62 disrupt stress granule morphology. These findings identify NS1 binding protein as a negative regulator of p62 ubiquitination and a facilitator of GABARAP recruitment to stress granules, implicating it in stress granule regulation and amyotrophic lateral sclerosis pathogenesis.}, } @article {pmid39737952, year = {2024}, author = {Alecki, C and Rizwan, J and Le, P and Jacob-Tomas, S and Comaduran, MF and Verbrugghe, M and Xu, JMS and Minotti, S and Lynch, J and Biswas, J and Wu, T and Durham, HD and Yeo, GW and Vera, M}, title = {Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10796}, pmid = {39737952}, issn = {2041-1723}, support = {RF1 MH126719/MH/NIMH NIH HHS/United States ; 300232//Fonds de Recherche du Québec - Santé (Fonds de la recherche en sante du Quebec)/ ; MH126719//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; HG009889//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U24 HG009889/HG/NHGRI NIH HHS/United States ; R01 HG004659/HG/NHGRI NIH HHS/United States ; HG011864//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; PJT-186141//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; HG004659//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; Hudson Translational Team Grant//ALS Society of Canada (ALS Canada)/ ; R01 HG011864/HG/NHGRI NIH HHS/United States ; R01 NS103172/NS/NINDS NIH HHS/United States ; 2022-ALS Discovery Grant//ALS Society of Canada (ALS Canada)/ ; P30 CA008748/CA/NCI NIH HHS/United States ; U41 HG009889/HG/NHGRI NIH HHS/United States ; }, mesh = {*Dendrites/metabolism ; *Proteostasis ; Animals ; Humans ; Mice ; *RNA-Binding Protein FUS/metabolism/genetics ; *RNA, Messenger/metabolism/genetics ; *Motor Neurons/metabolism ; *HSC70 Heat-Shock Proteins/metabolism/genetics ; *Hippocampus/metabolism/cytology ; Spinal Cord/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Protein Biosynthesis ; Molecular Chaperones/metabolism/genetics ; HSP70 Heat-Shock Proteins/metabolism/genetics ; Microtubules/metabolism ; }, abstract = {Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal projections because of their polarized morphology and constant synaptic proteome remodeling. Using high-resolution fluorescence microscopy, we discover that hippocampal and spinal cord motor neurons of mouse and human origin localize a subset of chaperone mRNAs to their dendrites and use microtubule-based transport to increase this asymmetric localization following proteotoxic stress. The most abundant dendritic chaperone mRNA encodes a constitutive heat shock protein 70 family member (HSPA8). Proteotoxic stress also enhances HSPA8 mRNA translation efficiency in dendrites. Stress-mediated HSPA8 mRNA localization to the dendrites is impaired by depleting fused in sarcoma-an amyotrophic lateral sclerosis-related protein-in cultured spinal cord mouse motor neurons or by expressing a pathogenic variant of heterogenous nuclear ribonucleoprotein A2/B1 in neurons derived from human induced pluripotent stem cells. These results reveal a neuronal stress response in which RNA-binding proteins increase the dendritic localization of HSPA8 mRNA to maintain proteostasis and prevent neurodegeneration.}, } @article {pmid39737769, year = {2025}, author = {Akyuz, E and Aslan, FS and Hekimoglu, A and Yilmaz, BN}, title = {Insights Into Retinal Pathologies in Neurological Disorders: A Focus on Parkinson's Disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Alzheimer's Disease.}, journal = {Journal of neuroscience research}, volume = {103}, number = {1}, pages = {e70006}, doi = {10.1002/jnr.70006}, pmid = {39737769}, issn = {1097-4547}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/pathology ; *Parkinson Disease/diagnosis/diagnostic imaging/pathology ; *Multiple Sclerosis/pathology/diagnosis/diagnostic imaging ; *Alzheimer Disease/pathology/diagnosis ; *Retina/pathology/diagnostic imaging ; Tomography, Optical Coherence/methods ; Retinal Diseases/diagnosis/pathology/etiology ; Animals ; }, abstract = {Neurological diseases are central nervous system (CNS) disorders affecting the whole body. Early diagnosis of the diseases is difficult due to the lack of disease-specific tests. Adding new biomarkers external to the CNS facilitates the diagnosis of neurological diseases. In this respect, the retina has a common embryologic origin with the CNS. Retinal imaging technologies including optical coherence tomography (OCT) can be used in the understanding and processual monitoring of neurological diseases. Retinal imaging has been recently recognized as a potential source of biomarkers for neurological diseases, increasing the number of studies in this direction. In this review, the association of retinal abnormalities with Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD) is explained. Structural and functional abnormalities in retina as a predictive marker may facilitate early diagnosis of diseases. Although not all retinal abnormalities are predictive of neurologic diseases, changes in the retinal layers including retinal pigment epithelium and plexiform layers should suggest the risk of PD, MS, ALS, and AD.}, } @article {pmid39737526, year = {2024}, author = {Nakaya, T}, title = {Release of FUS into the extracellular space is regulated by its amino-terminal prion-like domain.}, journal = {FEBS letters}, volume = {}, number = {}, pages = {}, doi = {10.1002/1873-3468.15086}, pmid = {39737526}, issn = {1873-3468}, support = {22K07374//Japan Society for the Promotion of Science/ ; }, abstract = {Fused in sarcoma (FUS) is a causative factor of amyotrophic lateral sclerosis (ALS) and is believed to propagate pathologically by transmission from cell to cell. However, the mechanism underlying FUS release from cells, which is a critical step for the propagation system, remains poorly understood. This study conducted an analysis of the release of human and mouse FUS from neurons, revealing that human FUS is significantly released into the media compared to its mouse counterpart. Further study using chimeric FUS proteins identified the amino-terminal region of human FUS as essential for its release. These findings indicate that human FUS is released directly from neurons and underscore the novel functional role of its amino-terminal region in this process.}, } @article {pmid39736981, year = {2024}, author = {Zhang, Y and Li, N and Ge, Z and Li, F}, title = {Blood component therapy for dry eye disease: a systematic review and network meta-analysis.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1500160}, pmid = {39736981}, issn = {2296-858X}, abstract = {OBJECTIVE: Blood component therapy has shown promising potential as an emerging treatment for dry eye disease; however, it remains unclear which specific blood component is the most effective. This study aims to compare the efficacy of different blood components in the treatment of dry eye disease through a network meta-analysis, with the goal of providing the latest and most reliable evidence for clinical practice.

METHODS: We conducted a systematic search of the PubMed, Web of Science, Cochrane, Embase, and Scopus databases, with the search concluding on June 1, 2024. Two independent researchers performed literature screening, data extraction, and quality assessment.

RESULTS: A total of 16 randomized controlled trials (RCTs) involving 898 patients with dry eye disease were included. Six different blood components were utilized in treating dry eye disease, with platelet-rich plasma (PRP) being the most widely used. The results of the network meta-analysis indicated that platelet-rich plasma eye drops (PRPD) significantly outperformed artificial tears (AT) in improving the corneal fluorescein staining score (CFSS), while autologous serum (ALS) and umbilical cord serum (UCS) also demonstrated significantly better effects than AT in enhancing tear break-up time (TBUT). Additionally, ALS, PRP injection (PRPI), and PRPD showed significantly superior outcomes compared to AT in improving the ocular surface disease index (OSDI). However, no statistically significant differences were found among the various treatment modalities regarding their effects on Schirmer's I value, CFSS, TBUT, and OSDI. SUCRA analysis predicted that UCS was the most effective in improving Schirmer's I value and TBUT, while PRP excelled in enhancing CFSS and OSDI. Limitations such as publication bias and issues related to randomization, allocation concealment, and blinding may affect the reliability of the current findings.

CONCLUSION: Blood component therapy can significantly improve the pathological damage and ocular surface health in patients with dry eye disease. For those with aqueous-deficient dry eye, UCS may represent the optimal treatment option. In contrast, for patients with more severe corneal epithelial damage, PRP may offer a more effective therapeutic approach.

https://www.crd.york.ac.uk/PROSPERO/, CRD42024534091.}, } @article {pmid39736783, year = {2024}, author = {Zeng, J and Luo, C and Jiang, Y and Hu, T and Lin, B and Xie, Y and Lan, J and Miao, J}, title = {Decoding TDP-43: the molecular chameleon of neurodegenerative diseases.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {205}, pmid = {39736783}, issn = {2051-5960}, support = {YNXM2024062//High-quality development project of public hospitals in Baoan District, Shenzhen/ ; YNXM2024015//High-quality development project of public hospitals in Baoan District, Shenzhen/ ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics/pathology ; Animals ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) has emerged as a critical player in neurodegenerative disorders, with its dysfunction implicated in a wide spectrum of diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer's disease (AD). This comprehensive review explores the multifaceted roles of TDP-43 in both physiological and pathological contexts. We delve into TDP-43's crucial functions in RNA metabolism, including splicing regulation, mRNA stability, and miRNA biogenesis. Particular emphasis is placed on recent discoveries regarding TDP-43's involvement in DNA interactions and chromatin dynamics, highlighting its broader impact on gene expression and genome stability. The review also examines the complex pathogenesis of TDP-43-related disorders, discussing the protein's propensity for aggregation, its effects on mitochondrial function, and its non-cell autonomous impacts on glial cells. We provide an in-depth analysis of TDP-43 pathology across various neurodegenerative conditions, from well-established associations in ALS and FTLD to emerging roles in diseases such as Huntington's disease and Niemann-Pick C disease. The potential of TDP-43 as a therapeutic target is explored, with a focus on recent developments in targeting cryptic exon inclusion and other TDP-43-mediated processes. This review synthesizes current knowledge on TDP-43 biology and pathology, offering insights into the protein's central role in neurodegeneration and highlighting promising avenues for future research and therapeutic interventions.}, } @article {pmid39735276, year = {2024}, author = {Moyana, TN}, title = {Small cell lung carcinoma metastatic to the stomach: Commonly overlooked, limited treatment options.}, journal = {World journal of gastroenterology}, volume = {30}, number = {48}, pages = {5198-5204}, pmid = {39735276}, issn = {2219-2840}, mesh = {Humans ; *Small Cell Lung Carcinoma/therapy/secondary/pathology/diagnostic imaging ; *Stomach Neoplasms/pathology/therapy/diagnostic imaging ; *Lung Neoplasms/secondary/therapy/pathology/diagnostic imaging ; Prognosis ; Biomarkers, Tumor/analysis/metabolism ; Positron Emission Tomography Computed Tomography/methods ; Immune Checkpoint Inhibitors/therapeutic use ; Immunohistochemistry ; }, abstract = {Small cell lung carcinoma metastatic to the stomach, whether synchronous or metachronous, is a rare phenomenon accounting for < 0.5% of lung cancers. Hence it can be overlooked by clinicians resulting in delayed diagnosis. This manuscript comments on Yang et al's article which reported 3 such cases. The main diagnostic features are based on routine morphology comprised of small cells with hyperchromatic nuclei, scant cytoplasm, brisk mitoses and necrosis. This can be supplemented by immunohistochemistry demonstrating positivity for cytokeratin, thyroid transcription factor-1 and neuroendocrine markers as well as a high Ki-67 labelling index. Imaging modalities such as positron emission tomography/contrast computed tomography help to confirm lung origin and rule out the possibility of extra-pulmonary small cell carcinoma. The predominant mechanism of spread is most likely hematogeneous. Prognosis is generally poor since this represents stage 4 disease but survival can be improved by chemo/radiotherapy and palliative surgery in select cases. Though outcomes have not changed much in the last several decades, the recent Food and Drug Administration approval of immune checkpoint inhibitors was a significant milestone as was the delineation of small cell lung carcinoma molecular subtypes. Liquid biopsies are increasingly being used for biomarker studies in clinical trials to assess treatment response and prognosis.}, } @article {pmid39735081, year = {2024}, author = {Dost, W and Rasully, MQ and Zaman, MN and Dost, W and Ali, W and Ayobi, SA and Dost, R and Niazi, J and Bakht, K and Iqbal, A and Bokhari, SFH}, title = {Predictive Biomarkers for the Early Detection of Anastomotic Leaks in Colorectal Surgeries: A Systematic Review.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e74616}, pmid = {39735081}, issn = {2168-8184}, abstract = {Anastomotic leaks (ALs) remain a serious postoperative complication in colorectal surgery, often resulting in significant morbidity, prolonged hospitalization, and increased mortality risk. This systematic review aims to evaluate the role of predictive biomarkers in the early detection of ALs, focusing on their diagnostic accuracy and clinical utility. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive literature search was conducted across MEDLINE, Scopus, CENTRAL, and Web of Science, identifying studies that examined biomarkers such as C-reactive protein (CRP), procalcitonin (PCT), and white blood cell (WBC) count in the context of AL. A total of 20 studies met the inclusion criteria, with sample sizes ranging from 59 to 2,655 patients undergoing colorectal surgeries with primary anastomosis. CRP emerged as the most widely studied and reliable biomarker, with studies suggesting that elevated CRP levels, particularly on postoperative days 3-4, can effectively indicate AL risk, showing high negative predictive value. PCT has also shown promise as a complementary biomarker, offering enhanced specificity for infectious complications. Although WBC count alone was a limited predictor, it may add diagnostic value when used with other markers. In addition, innovative biomarkers, such as inflammatory indices in peritoneal fluid, demonstrated potential for further improving AL detection accuracy.}, } @article {pmid39731449, year = {2024}, author = {Fabbrizio, P and Baindoor, S and Margotta, C and Su, J and Morrissey, EP and Woods, I and Hogg, MC and Vianello, S and Venø, MT and Kjems, J and Sorarù, G and Bendotti, C and Prehn, JHM and Nardo, G}, title = {Protective role of Angiogenin in muscle regeneration in amyotrophic lateral sclerosis: Diagnostic and therapeutic implications.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {}, number = {}, pages = {e13328}, doi = {10.1111/bpa.13328}, pmid = {39731449}, issn = {1750-3639}, support = {CUP E48I20000000007//Regione Lombardia/ ; 17/JPND/3455/SFI_/Science Foundation Ireland/Ireland ; 20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; 21/RC/10294_P2/SFI_/Science Foundation Ireland/Ireland ; //EU Joint Programme-Neurodegenerative Disease Research/ ; SG-2018-12366226//Ministero della Salute, Italy/ ; MUSALS-AChR//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; 18/CRT/6214//Science Foundation Ireland CRT in Genomics Data Science/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease with no effective treatments, in part caused by variations in progression and the absence of biomarkers. Mice carrying the SOD1G93A transgene with different genetic backgrounds show variable disease rates, reflecting the diversity of patients. While extensive research has been done on the involvement of the central nervous system, the role of skeletal muscle remains underexplored. We examined the impact of angiogenin, including its RNase activity, in skeletal muscles of ALS mouse models and in biopsies from ALS patients. Elevated levels of angiogenin were found in slowly progressing mice but not in rapidly progressing mice, correlating with increased muscle regeneration and vascularisation. In patients, higher levels of angiogenin in skeletal muscles correlated with milder disease. Mechanistically, angiogenin promotes muscle regeneration and vascularisation through satellite cell-endothelial interactions during myogenesis and angiogenesis. Furthermore, specific angiogenin-derived tiRNAs were upregulated in slowly progressing mice, suggesting their role in mediating the effects of angiogenin. These findings highlight angiogenin and its tiRNAs as potential prognostic markers and therapeutic targets for ALS, offering avenues for patient stratification and interventions to mitigate disease progression by promoting muscle regeneration.}, } @article {pmid39731185, year = {2024}, author = {Itou, T and Fujita, K and Okuzono, Y and Warude, D and Miyakawa, S and Mihara, Y and Matsui, N and Morino, H and Kikukawa, Y and Izumi, Y}, title = {Th17 and effector CD8 T cells relate to disease progression in amyotrophic lateral sclerosis: a case control study.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {331}, pmid = {39731185}, issn = {1742-2094}, support = {NA//Takeda Pharmaceutical Company/ ; JPMH23FC1008//Ministry of Health, Labour and Welfare/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/immunology/pathology ; Humans ; *Disease Progression ; Female ; *CD8-Positive T-Lymphocytes/immunology ; Middle Aged ; Male ; *Th17 Cells/immunology/metabolism ; Case-Control Studies ; Aged ; Adult ; }, abstract = {The immune system has garnered attention due to its association with disease progression in amyotrophic lateral sclerosis (ALS). However, the role of peripheral immune cells in this context remains controversial. Here, we conducted single-cell RNA-sequencing of peripheral blood mononuclear cells to comprehensively profile immune cells concerning the rate of disease progression in patients with ALS. Our analysis revealed increased frequencies of T helper 17 cells (Th17) relative to regulatory T cells, effector CD8 T cells relative to naïve CD8 T cells, and CD16[high]CD56[low] mature natural killer cells relative to CD16[low]CD56[high] naïve natural killer cells in patients with rapidly progressive ALS. Additionally, we employed serum proteomics through a proximity extension assay combined with next-generation sequencing to identify inflammation-related proteins associated with rapid disease progression. Among these proteins, interleukin-17 A correlated with the frequency of Th17, while killer cell lectin-like receptor D1 (CD94) correlated with the frequency of effector CD8 T cells. These findings further support the active roles played by these specific immune cell types in the progression of ALS.}, } @article {pmid39730482, year = {2024}, author = {Mitsi, E and Votsi, C and Koutsou, P and Georghiou, A and Christodoulou, CC and Kleopa, K and Zamba-Papanicolaou, E and Christodoulou, K and Nicolaou, P}, title = {Genetic epidemiology of amyotrophic lateral sclerosis in Cyprus: a population-based study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {30781}, pmid = {39730482}, issn = {2045-2322}, support = {73234//Telethon Cyprus/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Male ; Cyprus/epidemiology ; Female ; Middle Aged ; Aged ; *C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; Genetic Predisposition to Disease ; Molecular Epidemiology ; DNA-Binding Proteins/genetics ; Adult ; RNA-Binding Protein FUS/genetics ; High-Throughput Nucleotide Sequencing ; Mutation ; Cohort Studies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal degenerative disease of motor neurons, presenting with relentlessly progressive muscle atrophy and weakness. More than fifty genes carrying causative or disease-modifying variants have been identified since the 1990s, when the first ALS-associated variant in the gene SOD1 was discovered. The most commonly mutated ALS genes in the European populations include the C9orf72, SOD1, TARDBP and FUS. Understanding the genetic causes of ALS within a population is becoming more significant, especially in light of the possible development of personalized medicine. Here, we provide clinical and genetic data on familial and sporadic ALS patients in a Greek-Cypriot population-based cohort. Eighty-nine ALS patients, including 21 familial ALS (fALS) (23.6%) and 68 sporadic ALS (sALS) (76.4%), provided the cohort for variant screening of the most common ALS-associated genes. Moreover, next-generation sequencing (NGS) was also performed to identify rare ALS variants, and in silico prediction tools were applied to predict the downstream effect of the variants detected in our study. The pathogenic hexanucleotide G4C2 repeat expansion in C9orf72 was the predominant genetic cause (22.47%) of ALS in our population, while variants in six additional ALS-associated genes were identified, including ALS2, TARDBP, FIG4, TBK1, GLT8D1, and BICD2.}, } @article {pmid39729643, year = {2024}, author = {Meiling, JB and Caress, JB and Cartwright, MS}, title = {Ultra High-Frequency Ultrasound of Median Nerve Fascicles at the Wrist in Amyotrophic Lateral Sclerosis: An Exploratory Study.}, journal = {Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society}, volume = {}, number = {}, pages = {}, doi = {10.1097/WNP.0000000000001136}, pmid = {39729643}, issn = {1537-1603}, abstract = {PURPOSE: High-frequency ultrasound (HFUS) of muscle and nerve has the potential to be a reliable, responsive, and informative biomarker of disease progression for individuals with amyotrophic lateral sclerosis (ALS). High-frequency ultrasound is not able to visualize median nerve fascicles to the same extent as ultra-high-frequency ultrasound (UHFUS). Evaluating the number and size of fascicles within a nerve may facilitate a better understanding of nerve diseases. This exploratory study aims to image median nerve fascicles at the wrist in individuals with ALS using UHFUS and compare these findings with those from previously observed controls.

METHODS: Fifteen individuals with ALS underwent sonographic examination of the median nerves on each upper limb using UHFUS with a 48-MHz linear array transducer. Fascicle count and density in each examined nerve were determined by a single rater. Demographic and sonographic data from 20 previously studied controls were compared.

RESULTS: In individuals with ALS, the average fascicle number was 22.4 (SD 5.2) and average fascicle density 1.7 (SD 0.5). There was no significant difference in fascicle counts between individuals with ALS and controls.

CONCLUSIONS: Fascicular quantification using UHFUS is possible in individuals with ALS. Given the lack of appreciable difference between fascicle counts in individuals with ALS and controls, UHFUS of the median nerve at the wrist may not be a responsive biomarker for ALS disease progression.}, } @article {pmid39728809, year = {2024}, author = {Al Haffar, M and Fajloun, Z and Azar, S and Sabatier, JM and Abi Khattar, Z}, title = {Lesser-Known Cyanotoxins: A Comprehensive Review of Their Health and Environmental Impacts.}, journal = {Toxins}, volume = {16}, number = {12}, pages = {}, pmid = {39728809}, issn = {2072-6651}, mesh = {Humans ; *Cyanobacteria/metabolism ; *Bacterial Toxins/toxicity ; Animals ; Harmful Algal Bloom ; Cyanobacteria Toxins ; Microcystins/toxicity ; }, abstract = {Cyanobacteria, also known as blue-green algae, are a diverse phylum of photosynthetic, Gram-negative bacteria and one of the largest microbial taxa. These organisms produce cyanotoxins, which are secondary metabolites that can have significant impacts on both human health and the environment. While toxins like Microcystins and Cylindrospermopsins are well-documented and have been extensively studied, other cyanotoxins, including those produced by Lyngbya and Nostoc, remain underexplored. These lesser-known toxins can cause various health issues in humans, including neurotoxicity, hepatotoxicity, and dermatotoxicity, each through distinct mechanisms. Moreover, recent studies have shown that cyanobacteria can be aerosolized and transmitted through the air over long distances, providing an additional route for human exposure to their harmful effects. However, it remains an area that requires much more investigation to accurately assess the health risks and develop appropriate public health guidelines. In addition to direct exposure to toxins, cyanobacteria can lead to harmful algal blooms, which pose further risks to human and wildlife health, and are a global concern. There is limited knowledge about these lesser-known cyanotoxins, highlighting the need for further research to understand their clinical manifestations and improve society's preparedness for the associated health risks. This work aims to review the existing literature on these underexplored cyanotoxins, which are associated with human intoxication, elucidate their clinical relevance, address significant challenges in cyanobacterial research, and provide guidance on mitigating their adverse effects.}, } @article {pmid39728753, year = {2024}, author = {Boziki, M and Theotokis, P and Kesidou, E and Nella, M and Bakirtzis, C and Karafoulidou, E and Tzitiridou-Chatzopoulou, M and Doulberis, M and Kazakos, E and Deretzi, G and Grigoriadis, N and Kountouras, J}, title = {Impact of Mast Cell Activation on Neurodegeneration: A Potential Role for Gut-Brain Axis and Helicobacter pylori Infection.}, journal = {Neurology international}, volume = {16}, number = {6}, pages = {1750-1778}, pmid = {39728753}, issn = {2035-8385}, abstract = {BACKGROUND: The innate immune response aims to prevent pathogens from entering the organism and/or to facilitate pathogen clearance. Innate immune cells, such as macrophages, mast cells (MCs), natural killer cells and neutrophils, bear pattern recognition receptors and are thus able to recognize common molecular patterns, such as pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs), the later occurring in the context of neuroinflammation. An inflammatory component in the pathology of otherwise "primary cerebrovascular and neurodegenerative" disease has recently been recognized and targeted as a means of therapeutic intervention. Activated MCs are multifunctional effector cells generated from hematopoietic stem cells that, together with dendritic cells, represent first-line immune defense mechanisms against pathogens and/or tissue destruction.

METHODS: This review aims to summarize evidence of MC implication in the pathogenesis of neurodegenerative diseases, namely, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis.

RESULTS: In view of recent evidence that the gut-brain axis may be implicated in the pathogenesis of neurodegenerative diseases and the characterization of the neuroinflammatory component in the pathology of these diseases, this review also focuses on MCs as potential mediators in the gut-brain axis bi-directional communication and the possible role of Helicobacter pylori, a gastric pathogen known to alter the gut-brain axis homeostasis towards local and systemic pro-inflammatory responses.

CONCLUSION: As MCs and Helicobacter pylori infection may offer targets of intervention with potential therapeutic implications for neurodegenerative disease, more clinical and translational evidence is needed to elucidate this field.}, } @article {pmid39728018, year = {2024}, author = {Jeyarajan, S and Ranjith, S and Veerapandian, R and Natarajaseenivasan, K and Chidambaram, P and Kumarasamy, A}, title = {Antibiofilm Activity of Epinecidin-1 and Its Variants Against Drug-Resistant Candida krusei and Candida tropicalis Isolates from Vaginal Candidiasis Patients.}, journal = {Infectious disease reports}, volume = {16}, number = {6}, pages = {1214-1229}, pmid = {39728018}, issn = {2036-7430}, support = {BT/PR2071/BBE/117/241/2016//Department of Biotechnology, India/ ; 311/RUSA(2.0)/2018//RUSA 2.0 Biological Sciences/ ; 01706/P6/2021//Tamil Nadu State Council for Higher Education (TANSCHE)/ ; ICMR-NET- 61754/2010//Indian Council of Medical Research/ ; }, abstract = {Background/Objective: Indwelling intrauterine contraceptive devices (IUDs) have surfaces that facilitate the attachment of Candida spp., creating a suitable environment for biofilm formation. Due to this, vulvovaginal candidiasis (VVC) is frequently linked to IUD usage, necessitating the prompt removal of these devices for effective treatment. In this study, we evaluated the susceptibility of antimicrobial peptides in vitro against biofilm forming, Amphotericin B (MIC50 > 2 mg L[-1]) resistant Candida krusei and Candida tropicalis isolated from IUD users who had signs of vaginal candidiasis (hemorrhage, pelvic pain, inflammation, itching, and vaginal discharge). Three antimicrobial peptides, namely, epinecidin-1 (epi-1) and its two variants, namely, variant-1 (Var-1) and variant-2 (Var-2), which were reported to have enhanced antibacterial activity were tested against IUD isolates (C. krusei and C. tropicalis) with pathogenic form of Candida albicans as control. Variants of epi-1, namely, Var-1 and Var-2 were created by substituting lysine in the place of histidine and alanine. Methods: The antimicrobial activity was measured using the microbroth dilution method to determine the minimum inhibitory concentration (MIC) of peptides against C. albicans, C. krusei and C. tropicalis. The MIC of each peptide was used for biofilm assay by Crystal violet staining, Scanning Electron Microscopy, and Reactive Oxygen Species (ROS) assay. To find the possible mechanism of anti-biofilm activity by the peptides, their ability to interact with Candida spp. cell membrane proteins such as Exo-β-(1,3)-Glucanase, Secreted Aspartic Proteinase (Sap) 1, and N-terminal Domain Adhesin: Als 9-2 were determined through PatchDock. Results: The MIC values of peptides: epi-1, var-1 and var-2 against C. albicans are 128 μg mL[-1], 64 μg mL[-1] and 32 μg mL[-1], C. tropicalis are 256 μg mL[-1], 64 μg mL[-1,] and 32 μg mL[-1] and C. krusei are 128 µg mL[-1], 128 µg mL[-1] and 64 µg mL[-1], respectively. Both the variants outperformed epi-1. Specifically for tested Candida spp., var-1 showed two- to four-fold enhancements and var-2 showed two- to eight-fold enhancements compared to epi-1. Electron microscopy confirmed that the mechanism of action involves pore formation thus inducing reactive oxygen species in Candida spp. cell membrane. Computational analysis showed that the peptides have a high tendency to interact with Candida spp. cell membrane proteins such as Exo-β-(1,3)-Glucanase, Secreted Aspartic Proteinase (Sap) 1, and N-terminal Domain Adhesin: Als 9-2, thereby preventing biofilm formation. Conclusions: The in vitro evidence supports the potential use of epi-1 and its variants to be used as an anti-biofilm agent to coat IUDs in the future for therapeutic purposes.}, } @article {pmid39727843, year = {2024}, author = {An, J and Gopalakrishnan, L and Ortega, V and Saul, J and Kadali, R and Bowser, R}, title = {Development of a Sensitive and Reliable Meso Scale Discovery-Based Electrochemiluminescence Immunoassay to Quantify TDP-43 in Human Biofluids.}, journal = {Biosensors}, volume = {14}, number = {12}, pages = {}, pmid = {39727843}, issn = {2079-6374}, support = {Development of TDP-43 Immunoassays//Target ALS/ ; }, mesh = {Humans ; Immunoassay ; *DNA-Binding Proteins/metabolism ; Amyotrophic Lateral Sclerosis/diagnosis ; Luminescent Measurements ; Biomarkers/blood ; Reproducibility of Results ; Electrochemical Techniques ; Biosensing Techniques ; Limit of Detection ; }, abstract = {Transactive response DNA-binding protein of 43 kDa (TDP-43) is a major component of pathological inclusions in various neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The detection of TDP-43 in biofluids is crucial for the development of diagnostic and prognostic indicators of disease and therapeutic development for TDP-43-related proteinopathies. Despite its potential as a biomarker for numerous neurological disorders, the lack of a sensitive and reproducible TDP-43 assay hinders progress in TDP-43-based therapy development, underscoring the need for an effective and standardized method for accurate quantification. Addressing the limitations of sensitivity and reproducibility in existing assays, in this study, we developed and validated a highly sensitive electrochemiluminescence immunoassay on the Meso Scale Discovery platform. The assay demonstrated the detection of full-length TDP-43 in human biofluids with a limit of detection of 4pg/mL, a working range of 4-20,000 pg/mL, and a total assay time of 16 h. In this study, we developed and validated a sensitive immunoassay for the detection of full-length TDP-43 in human biofluids using the Meso Scale Discovery platform. We used this immunoassay to quantify TDP-43 levels in the plasma and serum of healthy controls and ALS patients. Our results indicate a reduction in full-length TDP-43 in the blood of ALS patients compared to healthy controls.}, } @article {pmid39726289, year = {2025}, author = {Kollstrøm, AM and Christiansen, N and Sandvig, A and Sandvig, I}, title = {Dysregulation of synaptic transcripts underlies network abnormalities in ALS patient-derived motor neurons.}, journal = {American journal of physiology. Cell physiology}, volume = {328}, number = {3}, pages = {C1029-C1044}, doi = {10.1152/ajpcell.00725.2024}, pmid = {39726289}, issn = {1522-1563}, support = {//Alf Harborgs fund/ ; //Olav Thon Stiftelsen (Olav Thon Foundation)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/physiopathology ; Humans ; *Motor Neurons/metabolism/pathology ; *Synapses/metabolism/pathology/genetics ; *C9orf72 Protein/genetics/metabolism ; Nerve Net/metabolism/pathology/physiopathology ; Mutation ; Neuronal Outgrowth/genetics ; Action Potentials ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by dysfunction and loss of upper and lower motor neurons. Several studies have identified structural and functional alterations in the motor neurons before the manifestation of symptoms, yet the underlying cause of such alterations and how they contribute to the progressive degeneration of affected motor neuron networks remain unclear. Importantly, the short- and long-term spatiotemporal dynamics of neuronal network activity make it challenging to discern how ALS-related network reconfigurations emerge and evolve. To address this, we systematically monitored the structural and functional dynamics of motor neuron networks with a confirmed endogenous C9orf72 mutation. We show that ALS patient-derived motor neurons display time-dependent neural network dysfunction, specifically reduced firing rate and spike amplitude, impaired bursting, but higher overall synchrony in network activity. These changes coincided with altered neurite outgrowth and branching within the networks. Moreover, transcriptional analyses revealed dysregulation of molecular pathways involved in synaptic development and maintenance, neurite outgrowth, and cell adhesion, suggesting impaired synaptic stabilization. This study identifies early synaptic dysfunction as a contributing mechanism resulting in network-wide structural and functional compensation, which may over time render the networks vulnerable to neurodegeneration.NEW & NOTEWORTHY RNA-sequencing of ALS patient-derived motor neurons revealed altered expression of genes involved in cell adhesion, neurite outgrowth, synaptic development and maintenance, and synaptic plasticity. These alterations were accompanied by time-dependent structural impairments and disrupted neuronal activity, suggesting that early synaptic changes and network-wide structural and functional compensations contribute to motor neuron vulnerability in ALS.}, } @article {pmid39725771, year = {2024}, author = {Pagliari, E and Taiana, M and Manzini, P and Sali, L and Quetti, L and Bertolasi, L and Oldoni, S and Melzi, V and Comi, G and Corti, S and Nizzardo, M and Rizzo, F}, title = {Targeting STMN2 for neuroprotection and neuromuscular recovery in Spinal Muscular Atrophy: evidence from in vitro and in vivo SMA models.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {82}, number = {1}, pages = {29}, pmid = {39725771}, issn = {1420-9071}, support = {Craiplo Grant 2020-3623//Fondazione Cariplo/ ; 22739//SMA Europe Grant/ ; }, mesh = {Animals ; *Stathmin/metabolism/genetics ; *Muscular Atrophy, Spinal/therapy/genetics/pathology/metabolism ; Humans ; Mice ; *Disease Models, Animal ; *Motor Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism/cytology ; Neuromuscular Junction/metabolism/pathology ; Neuroprotection ; Dependovirus/genetics ; Genetic Therapy/methods ; }, abstract = {The development of ground-breaking Survival Motor Neuron (SMN) replacement strategies has revolutionized the field of Spinal Muscular Atrophy (SMA) research. However, the limitations of these therapies have now become evident, highlighting the need for the development of complementary targets beyond SMN replacement. To address these challenges, here we explored, in in vitro and in vivo disease models, Stathmin-2 (STMN2), a neuronal microtubule regulator implicated in neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), as a novel SMN-independent target for SMA therapy. Our findings revealed that STMN2 overexpression effectively restored axonal growth and outgrowth defects in induced pluripotent stem cell-(iPSC)-derived motor neurons (MNs) from SMA patients. Intracerebroventricular administration of adeno-associated virus serotype 9 (AAV9) carrying Stmn2 cDNA significantly ameliorated survival rates, motor functions, muscular and neuromuscular junction pathological features in SMA mice, mirrored by in vitro outcomes. Overall, this pioneering study not only provides insight into the therapeutic potential of STMN2 in SMA, but also suggests its broader applications for MN diseases, marking a substantial step forward in addressing the multifaceted challenges of neurological diseases treatment.}, } @article {pmid39724103, year = {2024}, author = {Garcia-Toscano, L and Currey, HN and Hincks, JC and Stair, JG and Lehrbach, NJ and Liachko, NF}, title = {Decreased Hsp90 activity protects against TDP-43 neurotoxicity in a C. elegans model of amyotrophic lateral sclerosis.}, journal = {PLoS genetics}, volume = {20}, number = {12}, pages = {e1011518}, pmid = {39724103}, issn = {1553-7404}, support = {P40 OD010440/OD/NIH HHS/United States ; R01 AG066729/AG/NIA NIH HHS/United States ; I01 BX005762/BX/BLRD VA/United States ; I01 BX004044/BX/BLRD VA/United States ; R35 GM142728/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Caenorhabditis elegans/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *HSP90 Heat-Shock Proteins/metabolism/genetics ; *Disease Models, Animal ; *DNA-Binding Proteins/metabolism/genetics ; *Caenorhabditis elegans Proteins/metabolism/genetics ; Humans ; Phosphorylation ; Mutation ; Heat-Shock Response/genetics ; TDP-43 Proteinopathies/genetics/metabolism ; }, abstract = {Neuronal inclusions of hyperphosphorylated TDP-43 are hallmarks of disease for most patients with amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene coding for TDP-43, can cause some cases of familial inherited ALS (fALS), indicating dysfunction of TDP-43 drives disease. Aggregated, phosphorylated TDP-43 may contribute to disease phenotypes; alternatively, TDP-43 aggregation may be a protective cellular response sequestering toxic protein away from the rest of the cell. The heat shock responsive chaperone Hsp90 has been shown to interact with TDP-43 and stabilize its normal conformation; however, it is not known whether this interaction contributes to neurotoxicity in vivo. Using a C. elegans model of fALS mutant TDP-43 proteinopathy, we find that loss of function of HSP-90 protects against TDP-43 neurotoxicity and subsequent neurodegeneration in adult animals. This protection is accompanied by a decrease in both total and phosphorylated TDP-43 protein. We also find that hsp-90 mutation or inhibition upregulates key stress responsive heat shock pathway gene expression, including hsp-70 and hsp-16.1, and we demonstrate that normal levels of hsp-16.1 are required for hsp-90 mutation effects on TDP-43. We also observe that the neuroprotective effect due to HSP-90 dysfunction does not involve direct regulation of proteasome activity in C. elegans. Our data demonstrate for the first time that Hsp90 chaperone activity contributes to adverse outcomes in TDP-43 proteinopathies in vivo using a whole animal model of ALS.}, } @article {pmid39722698, year = {2024}, author = {Jiao, L and Yang, J and Wang, W and Liu, X and Fu, Y and Fan, D}, title = {sTREM2 cerebrospinal fluid levels are a potential biomarker in amyotrophic lateral sclerosis and associate with UMN burden.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1515252}, pmid = {39722698}, issn = {1664-2295}, abstract = {OBJECTIVES: The aims of this study were to investigate whether CSF sTREM2 may be a potential marker of disease monitoring for amyotrophic lateral sclerosis (ALS).

METHODS: We investigated whether CSF sTREM2 levels are altered in ALS patients and are correlated with upper motor neuron (UMN) burden and disease progression.

RESULTS: CSF sTREM2 was greater in the ALS patients than in the controls (p = 0.002). Elevated CSF sTREM2 was associated with the UMN score (r = 0.38, p = 0.009), ΔFS (r = 0.30, p = 0.04) and serum NFL (lg) (r = 0.35, p = 0.015). As the motor band sign (MBS) score increased, the CSF sTREM2 level increased (p-trend = 0.014). Furthermore, the correlations became stronger (UMN score (r = 0.50, p = 0.01) ΔFRS (r = 0.52, p = 0.008) and serum NFL (lg) (r = 0.55, p = 0.004) when estimated only among patients with a disease duration >12 months.

CONCLUSION: We found that CSF sTREM2 is elevated in ALS patients and may be a novel marker, probably reflecting upper motor unit severity and prognosis.}, } @article {pmid39722495, year = {2024}, author = {García-Ramírez, Y and Cayuela-Fuentes, JM and Mira-Escolano, MP and Maceda-Roldán, LA and Mikulasova, E and Oliva-López, C and Sánchez-Escámez, A and Ciller-Montoya, P and Palomar-Rodríguez, JA}, title = {Characterization, epidemiology, and factors associated with evolution and survival in patients with amyotrophic lateral sclerosis in southeastern Spain, 2008-2021: a population-based study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/21678421.2024.2439454}, pmid = {39722495}, issn = {2167-9223}, abstract = {OBJECTIVE: To describe the epidemiology, characteristics, and factors associated with the evolution and survival in patients with amyotrophic lateral sclerosis (ALS) in a region of southeastern Spain.

METHODS: An observational study was carried out in people with a diagnosis of ALS in the period 2008-2021 who were registered in the Information System of Rare Diseases of the Region of Murcia (SIER). We calculated crude and standardized incidence rate (SIR) using European Standard Population of 2013 and point prevalence. The Kaplan-Meier method and the log-rank test were used to estimate and compare survival curves.

RESULTS: We identified 374 cases. The mean age at diagnosis was 66.5 ± 11.7 and 50.3% persons were spinal onset. Mean time from the onset of symptoms to diagnosis was 0.9 ± 1.0 years. The global SIR was 1.95/100,000 person-years (95%CI: 1.77-2.12), which was higher in men (ratio 1.34), and the point prevalence in 2021 was 4.57 per 100,000 (95% CI: 4.46-4.68). There were 297 deaths with a mean age of 69.8 ± 10.8. The median survival from clinical onset was 2 years (95%CI: 1.0-3.0). Factors associated with lower survival were bulbar onset (p < 0.001), older age at the onset of symptoms (p < 0.001), and the absence of riluzole treatment (p = 0.003).

CONCLUSIONS: This study is one of few to evaluate the epidemiological, characteristics, and prognostic factors of ALS in Spain, with findings similar to previous population studies. The use of population-based registries offers reliable information on the magnitude, or evolution in these patients.}, } @article {pmid39722149, year = {2024}, author = {Simão, S and Naumann, LL and de Carvalho, M and Santos, MO and Martins, IP}, title = {Adaptation and Validation of Version B of the Edinburgh Cognitive and Behavioural ALS Screen for the Portuguese Population.}, journal = {Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists}, volume = {}, number = {}, pages = {}, doi = {10.1093/arclin/acae118}, pmid = {39722149}, issn = {1873-5843}, support = {GA101017598//European Union's Horizon 2020/ ; }, abstract = {OBJECTIVE: This study aims to adapt and provide psychometric support for the validation of version B of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) for the Portuguese population, addressing the need for consistent cognitive evaluations in amyotrophic lateral sclerosis (ALS). A second culturally adapted ECAS screen facilitates the accurate characterization of ALS progression, mitigates learning effects, and supports tailored care management.

METHODS: The adaptation process included forward-backward translation, cultural adaptation, and cognitive debriefing on a prospective sample of 193 ALS patients and 106 controls. A multiple regression analysis identified predictors relevant for establishing ECAS cut-off scores. Psychometric evaluations, including reliability assessments and tests of convergent, construct, and criterion validity, were conducted. Additionally, version A's psychometric properties were reevaluated with complementary analyses and a larger sample.

RESULTS: Version B demonstrated good internal consistency with Cronbach's alpha of 0.802, comparable to the previously established version A. Moderate inter-item correlations further supported reliability, reflecting internal coherence. Equivalence testing between the Portuguese versions supported convergent validity, confirming version B's alignment with version A's theoretical framework. Exploratory factor analysis provided preliminary support for construct validity, and receiver operating characteristic analyses established cut-off values for both versions, revealing moderate sensitivity with a tendency toward false negatives, and higher specificity.

CONCLUSIONS: This study provided evidence for the cultural suitability, reliability, and validity of the Portuguese ECAS B. As evidence supports the equivalence of the Portuguese ECAS versions, they can be used for flexible screenings and applied with the calculated cut-off values to enhance diagnostic accuracy.}, } @article {pmid39722074, year = {2024}, author = {Thompson, EG and Spead, O and Akerman, SC and Curcio, C and Zaepfel, BL and Kent, ER and Philips, T and Vijayakumar, BG and Zacco, A and Zhou, W and Nagappan, G and Rothstein, JD}, title = {A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (G4C2)66 mouse model.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {203}, pmid = {39722074}, issn = {2051-5960}, support = {R35 NS132179/NS/NINDS NIH HHS/United States ; R01 5R35NS132179/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *C9orf72 Protein/genetics ; *Disease Models, Animal ; *DNA-Binding Proteins/genetics/metabolism ; *DNA Repeat Expansion/genetics ; Mice ; *Mice, Transgenic ; *Frontotemporal Dementia/genetics/pathology/metabolism ; Dependovirus/genetics ; Humans ; Male ; Behavior, Animal/physiology ; Mice, Inbred C57BL ; }, abstract = {The G4C2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. The model displays key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis. However, the AAV-(G4C2)66 mouse model in this study has marginal neurodegeneration with negligible neuronal loss, or clinical deficits. Human C9orf72 is typically associated with altered TAR DNA-binding protein (TDP-43) function, yet studies of this rodent model revealed no significant evidence of TDP-43 dysfunction. While our findings indicate and support that this is a highly valuable robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease- associated TDP-43 dysfunction or clinical impairment. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.}, } @article {pmid39721808, year = {2024}, author = {Almukhlifi, Y and Crowfoot, G and Hutton, A}, title = {Barriers and Facilitators Toward Disaster Knowledge, Skills, and Preparedness among Emergency Medical Services in Saudi Arabia.}, journal = {Prehospital and disaster medicine}, volume = {39}, number = {6}, pages = {395-401}, doi = {10.1017/S1049023X24000670}, pmid = {39721808}, issn = {1945-1938}, mesh = {Humans ; Saudi Arabia ; Male ; Female ; Adult ; *Disaster Planning ; Emergency Medical Services/organization & administration ; Interviews as Topic ; Qualitative Research ; Health Knowledge, Attitudes, Practice ; Emergency Medical Technicians ; Middle Aged ; }, abstract = {INTRODUCTION: Disasters pose significant challenges globally, affecting millions of people annually. In Saudi Arabia, floods constitute a prevalent natural disaster, underscoring the necessity for effective disaster preparedness among Emergency Medical Services (EMS) workers. Despite their critical role in disaster response, research on disaster preparedness among EMS workers in Saudi Arabia is limited.

STUDY OBJECTIVE/METHODS: The study aimed to explore the disaster preparedness among EMS workers in Saudi Arabia. This study applied an explanatory sequential mixed-methods design to explore disaster preparedness among EMS workers in Saudi Arabia, focusing on the qualitative phase. Semi-structured interviews were conducted with 15 EMS workers from National Guard Health Affairs (NGHA) and Ministry of Health (MOH) facilities in Riyadh, Dammam, and Jeddah. Thematic analysis was conducted following Braun and Clarke's six-step process, ensuring data rigor through Schwandt, et al's criteria for trustworthiness.

FINDINGS: The demographic characteristics of participants revealed a predominantly young, male workforce with varying levels of experience and educational backgrounds. Thematic analysis identified three key themes: (1) Newly/developed profession, highlighting the challenges faced by young EMS workers in acquiring disaster preparedness; (2) Access to opportunities and workplace resources (government versus military), indicating discrepancies in disaster preparedness support between government and military hospitals; and (3) Workplace policies and procedures, highlighting the need for clearer disaster policies, training opportunities, and role clarity among EMS workers.

CONCLUSION: The study underscores the importance of addressing the unique challenges faced by EMS workers in Saudi Arabia to enhance disaster preparedness. Recommendations include targeted support for young EMS professionals, standardization of disaster training across health care facilities, and improved communication of disaster policies and procedures. These findings have implications for policy and practice in disaster management and EMS training in Saudi Arabia.}, } @article {pmid39720511, year = {2024}, author = {Terao, SI and Nosaki, Y and Murao, A and Torii, R and Ogawa, N and Miura, N and Sasaki, Y and Sobue, G}, title = {Onset of age, site and respiratory symptoms are strongly associated with respiratory decline in sporadic amyotrophic lateral sclerosis: a long-term longitudinal study.}, journal = {BMJ neurology open}, volume = {6}, number = {2}, pages = {e000829}, pmid = {39720511}, issn = {2632-6140}, abstract = {OBJECTIVE: The objective of this study is to identify factors influencing progression of respiratory decline from the onset of neurological symptoms to respiratory failure in patients with amyotrophic lateral sclerosis (ALS).

METHODS: In 100 patients with sporadic ALS, %vital capacity (%VC) was continuously measured from the first visit to the respiratory endpoint (REP). Cox proportional hazards model identified factors influencing the duration from onset of ALS to REP (Onset-REP). We performed Kaplan-Meier survival curve analysis for onset-REP according to identified factors.

RESULTS: Onset sites were the upper limb (U-ALS), lower limb (L-ALS), bulbar paralysis (B-ALS) and respiratory paralysis (R-ALS) in 37, 19, 32 and 12 patients, respectively. Duration from the onset of ALS to the onset of respiratory symptoms (Onset-Rp) and REP (Onset-REP) was 16.1 (SD 12.1) and 24.9 months (SD 14.6), respectively. Multivariate analysis revealed that age at onset, site of onset, Onset-Rp and %VC decline rate significantly influenced Onset-REP duration. Elderly patients had a significantly shorter Onset-REP duration. Onset-REP duration did not significantly differ between patients with U-ALS and L-ALS, but was longer in these patients than in those with B-ALS and R-ALS. Onset-REP duration was positively associated with Onset-Rp duration. The average monthly %VC decline rate was -5.6% (SD 3.3). Age at onset, onset site and Onset-Rp duration significantly influenced the %VC decline rate.

CONCLUSIONS: Our findings revealed strong and independent patient-specific factors that influence the Onset-REP duration and the %VC decline rate in patients with ALS. These could inform future clinical trials and interventions considering the respiratory function and natural history of patients with ALS.}, } @article {pmid39720419, year = {2024}, author = {Haikal, C and Weissert, R}, title = {Editorial: Aging, peripheral inflammation, and neurodegeneration.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1529026}, pmid = {39720419}, issn = {1663-4365}, } @article {pmid39719859, year = {2025}, author = {Koumasopoulos, E and Stanitsa, E and Angelopoulou, E and Koros, C and Barbarousi, V and Velonakis, G and Michaletou, C and Alevetsovitis, SK and Constantinides, VC and Kyrozis, A and Stefanis, L and Kroupis, C and Papageorgiou, SG}, title = {Heterozygous p62/SQSTM1 mutation and right temporal variant of frontotemporal dementia: Α case report.}, journal = {Neurocase}, volume = {31}, number = {2}, pages = {70-73}, doi = {10.1080/13554794.2024.2446315}, pmid = {39719859}, issn = {1465-3656}, mesh = {Humans ; *Frontotemporal Dementia/genetics/pathology/physiopathology ; *Sequestosome-1 Protein/genetics ; *Mutation ; Male ; Heterozygote ; Middle Aged ; Female ; }, abstract = {Mutations in sequestosome 1 (SQSTM1) gene have been associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia - ALS (FTD-ALS), and very recently, progressive supranuclear palsy (PSP), paget disease of bone (PDB), distal myopathy with rimmed vacuoles (DMRV), and neurodegenerative disorders in childhood. We present a case of right temporal variant of FTD (rtvFTD) with heterozygous mutation (c.823_824del(p.Ser275Phefs *17)) in SQSTM1 gene.}, } @article {pmid39719601, year = {2024}, author = {Kelani, KM and Hegazy, MA and Hassan, AM and Nadim, AH}, title = {Ecological multivariate assisted spectrophotometric methods for determination of antipyrine and benzocaine HCl in presence of antipyrine official impurity and benzocaine HCl degradant: toward greenness and whiteness.}, journal = {BMC chemistry}, volume = {18}, number = {1}, pages = {250}, pmid = {39719601}, issn = {2661-801X}, abstract = {A simple and green chemometrics-assisted spectrophotometric technique has beendeveloped and validated for the determination of antipyrine (ANT) and benzocaine HCl (BEN) along with the official impurity of ANT, antipyrine impurity A (ANT imp-A), and the degradation product of BEN, p-amino benzoic acid (PABA), in their quaternary mixture. Three models were developed and compared: partial least squares (PLS), artificial neural networks (ANN), and multivariate curve resolution-alternating least squares (MCR-ALS) where the four studied drugs were successfully quantified. The quantitative determination of the studied drugs was assessed using percentage recoveries, standard errors of prediction, and root mean square errors of prediction. The ANN model demonstrated the lowest error and the best correlation making it the most accurate method for analysis. The models were constructed in the ranges of 5.0-9.0 µg mL[-1] for ANT, 1.0-5.0 µg mL[-1] for BEN, 0.5-2.5 µg mL[-1] for ANT imp-A, and 0.25-1.25 µg mL[-1] for PABA. The established models successfully determined ANT, BEN, ANT imp-A, and PABA with detection limits of 0.312, 0.178, 0.093, and 0.042 µg mL[-1] for PLS, 0.185, 0.085, 0.001, and 0.034 µg mL[-1] for ANN; and 0.473, 0.240, 0.073, and 0.069 µg mL[-1] for MCR-ALS, respectively. The greenness and the whiteness of the proposed method were assessed using two green evaluating approaches: analytical Eco-scale, and AGREE, along with one white analytical chemistry evaluating tool, RGB. The three proposed models were successfully applied for determination of ANT and BEN in their pharmaceutically co-formulated dosage forms. They are also recommended for stability assays and purity testing of these drugs in quality control laboratories.}, } @article {pmid39719207, year = {2025}, author = {Jirström, E and Matveeva, A and Baindoor, S and Donovan, P and Ma, Q and Morrissey, EP and Arijs, I and Boeckx, B and Lambrechts, D and Garcia-Munoz, A and Dillon, ET and Wynne, K and Ying, Z and Matallanas, D and Hogg, MC and Prehn, JHM}, title = {Effects of ALS-associated 5'tiRNA[Gly-GCC] on the transcriptomic and proteomic profile of primary neurons in vitro.}, journal = {Experimental neurology}, volume = {385}, number = {}, pages = {115128}, doi = {10.1016/j.expneurol.2024.115128}, pmid = {39719207}, issn = {1090-2430}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Mice ; *Neurons/metabolism ; *Transcriptome ; Cells, Cultured ; Mice, Transgenic ; Proteome/metabolism ; Proteomics ; Ribonuclease, Pancreatic/metabolism/genetics ; Humans ; Mice, Inbred C57BL ; RNA, Transfer/genetics/metabolism ; RNA, Small Untranslated/genetics ; }, abstract = {tRNA-derived stress-induced RNAs (tiRNAs) are a new class of small non-coding RNA that have emerged as important regulators of cellular stress responses. tiRNAs are derived from specific tRNA cleavage by the stress-induced ribonuclease angiogenin (ANG). Loss-of-function mutations in the ANG gene are linked to amyotrophic lateral sclerosis (ALS), and elevated levels of specific tiRNAs were recently identified in ALS patient serum samples. However, the biological role of tiRNA production in neuronal stress responses and neurodegeneration remains largely unknown. Here, we investigated the genome-wide regulation of neuronal stress responses by a specific tiRNA, 5'tiRNA[Gly-GCC], which we found to be upregulated in primary neurons exposed to ALS-relevant stresses and in the spinal cord of three ALS mouse models. Whole-transcript RNA sequencing and label-free mass spectrometry on primary neurons transfected with a synthetic mimic of 5'tiRNA[Gly-GCC] revealed predominantly downregulated RNA and protein levels, with more pronounced changes in the proteome. Over half of the downregulated mRNAs contained predicted 5'tiRNA[Gly-GCC] binding sites, indicating that this tiRNA may silence target genes via complementary binding. On the proteome level, we observed reduction in proteins involved in translation initiation and ribosome assembly, pointing to inhibitory effects on translation. Together, these findings suggest that 5'tiRNA[Gly-GCC] is an ALS-associated tiRNA that functions to fine-tune gene expression and supress protein synthesis as part of an ANG-induced neuronal stress response.}, } @article {pmid39718981, year = {2024}, author = {Chen, JQA and McNamara, NB and Engelenburg, HJ and Jongejan, A and Wever, DD and Hopman, K and van Rixel, E and Nijhuis, PJH and de Winter, F and Moerland, PD and Smolders, J and Verhaagen, J and Hamann, J and Huitinga, I}, title = {Distinct transcriptional changes distinguish efficient and poor remyelination in multiple sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awae414}, pmid = {39718981}, issn = {1460-2156}, abstract = {Multiple sclerosis (MS) is a highly heterogeneous disease with varying remyelination potential across individuals and between lesions. However, the molecular mechanisms underlying the potential to remyelinate remain poorly understood. In this study, we aimed to take advantage of the intrinsic heterogeneity in remyelinating capacity between MS donors and lesions to uncover known and novel pro-remyelinating molecules for MS therapies. To elucidate distinct molecular signatures underlying the potential to remyelinate, we stratified MS donors from the Netherlands Brain Bank cohort (n=239) based on proportions of remyelinated lesions (RLs) into efficiently remyelinating donors (ERDs; n=21) and poorly remyelinating donors (PRDs; n=19). We performed bulk RNA sequencing of RLs, active lesions with ramified and amoeboid microglia/macrophage morphology (ALs non-foamy), active lesions with foamy microglia/macrophage morphology (ALs foamy), and normal-appearing white matter (NAWM) from ERDs and PRDs. We found that ALs non-foamy were positively correlated with remyelination, whereas ALs foamy were not, indicating a role for microglia/macrophage state in influencing remyelination potential. Bioinformatics analyses were performed to identify key pathways and molecules implicated in the remyelination process. We found distinct differences between the donors with differing remyelination potential in comparable MS lesion types. RLs and ALs non-foamy of ERDs versus PRDs showed upregulation of epithelial-mesenchymal transition pathway, while in ALs foamy of PRDs, inflammation and damage-associated pathways (i.e. MTORC1 signaling, TNF signaling and oxidative phosphorylation) were upregulated compared to ALs foamy of ERDs, suggesting that these latter pathways may counteract remyelination. We found genes significantly upregulated in RLs and/or ALs non-foamy of ERDs that have previously been associated with remyelination, including CXCL12, EGF, HGF, IGF2, IL10, PDGFB, PPARG, and TREM2, illustrating the strength of our donor and lesion stratification. TGFB1, TGFB2, EGF, and IGF1 were determined as key upstream regulators of genes upregulated in RLs and ALs non-foamy of ERDs. We further identified potential novel pro-remyelinating molecules, such as BTC, GDF10, GDF15, CCN1, CCN4, FGF5, FGF10, and INHBB. Our study identified both known and novel genes associated with efficient remyelination that may facilitate the development of therapeutic strategies to promote tissue repair and clinical recovery in MS.}, } @article {pmid39718871, year = {2025}, author = {Jiang, W and Hua, L and Chakraborty, S}, title = {Degenerate phase-matching for multi-wavelength nonlinear mixing in aperiodic lattice lasers.}, journal = {Optics letters}, volume = {50}, number = {1}, pages = {133-136}, doi = {10.1364/OL.544664}, pmid = {39718871}, issn = {1539-4794}, abstract = {Holographically designed aperiodic lattices (ALs) have proven to be an exciting engineering technique for achieving electrically switchable single- or multi-frequency emissions in terahertz (THz) semiconductor lasers. Here, we employ the nonlinear transfer matrix modeling method to investigate multi-wavelength nonlinear (sum- or difference-) frequency generation within an integrated THz (idler) laser cavity that also supports optical (pump and signal) waves. The laser cavity includes an aperiodic lattice, which engineers the idler photon lifetimes and effective refractive indices. The key findings are the following: (i) the nonlinear conversion efficiency reveals resonant enhancement at those idler frequencies where the photon lifetime is high; (ii) the resonant phase-matching (PM) process between the pump and idler waves has a one-to-one link with the engineered effective index dispersion; and (iii) in the absence of any other dispersion, the lowest threshold, multi-wavelength defect modes of the aperiodic lattice laser have degenerate phase-matched pump frequencies. This set of results will potentially have a significant impact on the wavelength multiplexing in electronically switchable THz-over-fiber communication systems [U.S. patent application 20,150,248,047A1 (3 September 2015)].}, } @article {pmid39718201, year = {2025}, author = {}, title = {Correction to "Access for ALL in ALS: A Large-Scale, Inclusive, Collaborative Consortium to Unlock the Molecular and Genetic Mechanisms of Amyotrophic Lateral Sclerosis" J. D. Berry , S. Paganoni , M. B. Harms , et al., "Access for ALL in ALS: A Large-Scale, Inclusive, Collaborative Consortium to Unlock the Molecular and Genetic Mechanisms of Amyotrophic Lateral Sclerosis," Muscle & Nerve 70, no. 6 (2024): 1140-1150, https://doi.org/10.1002/mus.28244.}, journal = {Muscle & nerve}, volume = {71}, number = {2}, pages = {280}, doi = {10.1002/mus.28317}, pmid = {39718201}, issn = {1097-4598}, } @article {pmid39717968, year = {2024}, author = {Vergini, DE and Hadjipavlou-Litina, D}, title = {"A patent review on arachidonic acid lipoxygenase (LOX) inhibitors for the treatment of neurodegenerative diseases (2018-present)".}, journal = {Expert opinion on therapeutic patents}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/13543776.2024.2447067}, pmid = {39717968}, issn = {1744-7674}, abstract = {INTRODUCTION: Neuroinflammation is correlated to neurodegenerative diseases like Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Huntington Disease (HD), and Parkinson's disease (PD). A lot of recent research and patents are focused on the design and synthesis of arachidonic acid lipoxygenase (ALOX) inhibitors for the treatment of neurodegenerative diseases.

AREAS COVERED: The survey covers natural products, synthesis, hybrids, and assessments of biological effects in biological studies as ALOX inhibitors. A survey of patent publications from 2018 to present, taken from Google Scholar, Espanet, Web of Science, Drugbank, Scopus, or PubMed is analyzed.

EXPERT OPINION: The authors suggest that (i) numerous areas of biology-pharmacology need to be considered: selectivity, in vivo studies, toxicity, bioavailability, and drug-likeness, the mechanism of action in different animals and humans, evaluation of more efficient and selective biological tests; (ii) synthetic method outbalance in the discovery and production of ALOX inhibitors with greater selectivity. Several ALOX inhibitors show promising results for the treatment of neurological disorders. Their clinical evaluation will be critical to assess therapeutic utility. The compounds for which the mechanism of action and their bioavailability are well defined can be used as lead compounds for the treatment of neurodegenerative diseases.}, } @article {pmid39717315, year = {2024}, author = {Alhayali, M}, title = {Concomitant Amyotrophic Lateral Sclerosis and Rheumatoid Arthritis: A Case Report.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e74301}, pmid = {39717315}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative motor neuron disease that leads to a gradual loss of motor neurons manifesting as progressive weakness, dysarthria, and respiratory decline, with a relatively short life expectancy. Rheumatoid arthritis (RA) is an autoimmune disorder characterized by polyarthritis and affects multiple systems. Motor neuron involvement is rare in rheumatoid arthritis. Here, we report a unique case of a patient with an established diagnosis of ALS who later developed seropositive RA. A 58-year-old male from Baghdad presented to our center with polyarticular joint pain, stiffness, and swelling for about four months, the patient had a history of progressive neurological deficits. The final diagnosis was seropositive rheumatoid arthritis with concomitant amyotrophic lateral sclerosis. While the patient's joint symptoms responded well to methotrexate and prednisolone, he continued to experience a neurological decline. This is one of the few reported cases of concurrent ALS and RA, highlighting the complexity of managing overlapping neurodegenerative and autoimmune conditions.}, } @article {pmid39715603, year = {2024}, author = {Dibling, M and Ortholand, J and Salachas, F and Hesters, A and Tezenas du Montcel, S}, title = {Care Pathway Heterogeneity in Amyotrophic Lateral Sclerosis: Effects of Gender, Age, and Onset.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-14}, doi = {10.1159/000542300}, pmid = {39715603}, issn = {1423-0208}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron degeneration resulting in loss of muscle function. Care management is restricted to symptomatic and palliative strategies, while clinical manifestations are heterogeneous. However, assessing the timing and benefits of ALS major clinical interventions remains challenging, with varying and nonspecific time-to-events estimates reported in the literature. Consequently, we proposed a retrospective cohort study leveraging healthcare system data to investigate ALS patients care pathway stratified by gender, age class, and onset site to describe strategies diversity and temporality.

METHODS: We developed an algorithm to identify incident ALS patients in the French hospitalization registry and assessed its quality through comparison with literature. We described 7 states, encompassing patient status regarding clinical intervention history, considered 15 transitions, and stratified the analysis depending on 12 different patient profiles, defined according to gender, the presence of symptoms indicative of disease onset site, and age class, to model profile-specific care pathway trajectories. Alongside analysis of median time before transition, we compared acceleration factors resulting from accelerated failure time and time-inhomogeneous models.

RESULTS: We identified 21,153 incident patients with ALS between 2013 and 2022 with a mean age of 67.7±13.1 years at time of in-registry detection, male/female and spinal/bulbar ratios of 1.2 and 1.9, respectively. Noninvasive ventilation (NIV), gastrostomy, tracheostomy, or death at hospital were recorded for 55.24% of the study population. We identified significant variations in utilization based on gender, age class, and onset site. Notably, older age and bulbar onset site accelerated gastrostomy use and spinal onset site was associated with delayed NIV initiation while tracheostomy, mainly considered for younger patients (<64 years), is rarely indicated in ALS care management. Alongside investigation of time-to-event speed, we report extensively the patient profile-specific estimated median delay before clinical event start.

CONCLUSION: Leveraging real-world data from hospital registries provides a large sample size to investigate low prevalence diseases. In conjunction with multistate models, such data enable a comprehensive analysis of care pathways, which revealed variations in ALS management strategies based on patient profiles. By identifying these disparities, our study contributes to enhancing the foreseeability of support strategies for ALS patients.}, } @article {pmid39715100, year = {2025}, author = {Wu, Y and Tian, X and Ma, J and Lin, Y and Ye, J and Wang, Y and Lu, J and Yin, W}, title = {Label-free discrimination analysis of breast cancer tumor and adjacent tissues of patients after neoadjuvant treatment using Raman spectroscopy: a diagnostic study.}, journal = {International journal of surgery (London, England)}, volume = {111}, number = {2}, pages = {1788-1800}, doi = {10.1097/JS9.0000000000002201}, pmid = {39715100}, issn = {1743-9159}, mesh = {Humans ; *Spectrum Analysis, Raman ; Female ; *Breast Neoplasms/therapy/pathology ; *Neoadjuvant Therapy ; Middle Aged ; Adult ; Aged ; Support Vector Machine ; Mastectomy, Segmental ; }, abstract = {BACKGROUND AND OBJECTIVE: Breast-conserving surgery (BCS) plays a crucial role in breast cancer treatment, with a primary focus on ensuring cancer-free surgical margins, particularly for patients undergoing neoadjuvant treatment. After neoadjuvant treatment, tumor regression can complicate the differentiation between breast cancer tumor and adjacent tissues. Raman spectroscopy, as a rapid and non-invasive optical technique, offers the advantage of providing detailed biochemical information and molecular signatures of internal molecular components in tissue samples. Despite its potential, there is currently no research on using label-free Raman spectroscopy to distinguish between breast cancer tumors and adjacent tissues after neoadjuvant treatment. This study intends to distinguish between tumor and adjacent tissues after neoadjuvant treatment in breast cancer through label-free Raman spectroscopy.

METHODS: In this study, the intraoperative frozen samples of breast cancer tumor and adjacent tissue were collected from patients who underwent neoadjuvant treatment during surgery. The samples were examined using Raman confocal microscopy, and Raman spectra were collected by LabSpec6 software. Spectra were preprocessed by Savitz-Golay filter, adaptive iterative reweighted penalized least squares and MinMax normalization method. The differences in Raman spectra between breast cancer tumor and adjacent tissues after neoadjuvant treatment were analyzed by Wilcoxon rank-sum test, with a Bonferroni correction for multiple comparisons. Based on the support vector machine (SVM) method in machine learning, a predictive model for classification was established in the total group and subgroups of different hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) status and Ki-67 expression level. The independent test set was used to evaluate the performance of the model, and the area under curve (AUC) of the receiver operating characteristic (ROC) curve, sensitivity, specificity and accuracy of different models were obtained.

RESULT: This study comprised 4260 Raman spectra of breast cancer tumor and adjacent frozen tissue samples from 142 breast cancer patients treated with neoadjuvant treatment. The Raman peaks associated with nucleotides and their metabolites in the Raman spectra of breast cancer tumor tissues were higher in intensities than those of adjacent tissues after neoadjuvant therapy (676 cm -1 : Bonferroni adjusted P < 0.0001; 724 cm -1 : P < 0.0001; 754 cm -1 : P < 0.0001), and the Raman peaks from amide III bands were more intense (1271 cm -1 : P < 0.01). Multivariate curve resolution-alternating least squares (MCR-ALS) decomposition of Raman spectra revealed reduced lipid content and increased collagen and nucleic acid content in breast cancer tumor tissues compared to adjacent tissues following neoadjuvant therapy. The predictive model based on the Raman spectral signature of breast cancer tumor and adjacent tissues after neoadjuvant treatment achieved an AUC of 0.98, with accuracy, sensitivity, and specificity values of 0.89, 0.97, and 0.83, respectively. The AUC of subgroup analysis according to different status of molecular pathological biomarkers was stably around 99%.

CONCLUSION: This study demonstrated that label-free Raman spectroscopy can differentiate tumor and adjacent tissues of breast cancer patients treated with neoadjuvant therapy thorough getting the panoramic perspective of the biochemical compounds for the first time. Our study provided a novel technique for determining the margin status in BCS in breast cancer following neoadjuvant treatment rapidly and precisely.}, } @article {pmid39715090, year = {2025}, author = {Huggon, L and Clayton, EL}, title = {Beginning from the end: the presynaptic terminal as a pathomechanism hub in frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3217-3218}, pmid = {39715090}, issn = {1673-5374}, } @article {pmid39714593, year = {2024}, author = {Eldeeb, MA and Hohman, G and Shahid, M}, title = {Novel Approaches in Targeting Cell Surface and Secreted Proteins for Lysosomal Degradation.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {}, number = {}, pages = {e202400887}, doi = {10.1002/cbic.202400887}, pmid = {39714593}, issn = {1439-7633}, abstract = {Protein degradation is pivotal for all biochemical aspects of cellular function. In mammalian cells, protein degradation is mediated mainly by the ubiquitin proteasome system (UPS) and the autophagic-lysosomal system (ALS). Over the last two decades, different types of targeted protein degradation approaches have been developed including proteolysis targeting chimeras (PROTACs) and lysosome targeting chimeras (LYTACs), which employ the UPS to degrade intracellular proteins and the ALS to degrade extracellular and membrane proteins respectively. Nevertheless, Current targeted membrane protein degradation approaches face some inherent challenges including limited target protein degradation efficacy and cell type specific applicability. Herein, we highlight some recent developments of novel targeted membrane protein degradation modalities that exhibit wide-applicability and high protein degradation efficiency. These novel membrane protein degraders hold tremendous promise as new pharmacological and biochemical tools in targeting membrane and secretory proteins for lysosomal degradation.}, } @article {pmid39713159, year = {2024}, author = {Wang, YB and Jin, CZ}, title = {Roles of traditional Chinese medicine extracts in hyperuricemia and gout treatment: Mechanisms and clinical applications.}, journal = {World journal of gastroenterology}, volume = {30}, number = {47}, pages = {5076-5080}, pmid = {39713159}, issn = {2219-2840}, mesh = {*Hyperuricemia/drug therapy/blood ; Humans ; *Gout/drug therapy ; *Gastrointestinal Microbiome/drug effects ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Medicine, Chinese Traditional/methods ; *Uric Acid/blood/metabolism ; Gout Suppressants/therapeutic use ; Animals ; }, abstract = {In this manuscript, we comment on the article by Liu et al published in the recent issue of the journal. Hyperuricemia (HUA) has become the second most common metabolic disease after type 2 diabetes mellitus and is the most important risk factor for gout. This discussion focuses on the targets and clinical application value of traditional Chinese medicine (TCM) extracts in the treatment of HUA and gout, emphasizing the role of gut microbiota. Liu et al's study demonstrated that Poecilobdella manillensis protein extract alleviated HUA through multiple mechanisms, including inhibition of uric acid (UA) reabsorption, promotion of UA excretion, repair of intestinal barrier function, and regulation of gut microbiota and metabolome. Unlike the commonly used urate-lowering drugs such as allopurinol and febuxostat, which have clear and single targets, many TCMs have multi-target effects. However, the active components and mechanisms of TCMs are not fully understood, limiting their clinical application in the treatment of HUA and gout. Additionally, the role of gut microbiota in UA metabolic homeostasis needs to be further explored.}, } @article {pmid39712644, year = {2024}, author = {Yusuf, IO and Camille, W and Thompson, PR and Xu, Z}, title = {Protein Citrullination in Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases.}, journal = {Journal of experimental neurology}, volume = {5}, number = {4}, pages = {183-191}, pmid = {39712644}, issn = {2692-2819}, support = {R01 NS118145/NS/NINDS NIH HHS/United States ; R35 GM118112/GM/NIGMS NIH HHS/United States ; }, abstract = {Protein citrullination (PC) is a posttranslational modification (PTM) that converts a peptidyl arginine into a peptidyl citrulline. Aberrant PC is a hallmark of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, prion disease, and multiple sclerosis. Common among these diseases is a dramatic increase of PC in reactive astrocytes. Some citrullinated proteins have been identified. The most prominent are astrocytic cytoskeletal proteins such as GFAP and vimentin, and myelin protein MBP. Recent investigation in ALS has revealed new changes, including a decreased PC in neurons and an association of PC with myelin protein aggregates. These findings suggest that PC contributes to protein aggregation, neuronal dysfunction, neuroinflammation, and axonal degeneration. However, how PC impact neurodegeneration remains to be understood. Further studies are needed to understand a range of questions, from how PC modulates individual protein functions to its impact on diseases. Because of the PC's robust changes in neurodegenerative diseases, there are also prospects that this PTM may be harnessed as biomarkers, and modulation of this PTM may be an avenue for therapy. In this review, we summarize the current understanding of PC in ALS and other neurodegenerative diseases, the investigative methods for PC, and PC's potential as a biomarker and a therapeutic target.}, } @article {pmid39711523, year = {2024}, author = {Thompson, EG and Spead, O and Akerman, SC and Curcio, C and Zaepfel, BL and Kent, ER and Philips, T and Vijayakumar, BG and Zacco, A and Zhou, W and Nagappan, G and Rothstein, JD}, title = {A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV- C9ORF72 (G 4 C 2) 66 mouse model.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39711523}, issn = {2693-5015}, support = {F32 NS120940/NS/NINDS NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {The G4C2 hexanucleotide repeat expansion in C9ORF72is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. The model displays key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis. However, the AAV-(G4C2)66 mouse model in this study has marginal neurodegeneration with negligible neuronal loss, or clinical deficits. Human C9orf72 is typically associated with altered TAR DNA-binding protein (TDP-43) function, yet studies of this rodent model revealed no significant evidence of TDP-43 dysfunction. While our findings indicate and support that this is a highly valuable robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease- associated TDP-43 dysfunction or clinical impairment. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.}, } @article {pmid39709547, year = {2024}, author = {Bakshi, B and Yerraguntla, S and Armon, C and Barkhaus, P and Bertorini, T and Bowser, R and Breevoort, S and Bromberg, M and Brown, A and Carter, GT and Chang, V and Crayle, J and Fullam, T and Greene, M and Heiman-Patterson, T and Jackson, C and Jhooty, S and Mallon, E and Cadavid, JM and Mcdermott, CJ and Pattee, G and Pierce, K and Ratner, D and Sun, Y and Wang, O and Wicks, P and Wiedau, M and Bedlack, R}, title = {ALSUntangled #77: Psilocybin.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2024.2441274}, pmid = {39709547}, issn = {2167-9223}, abstract = {ALSUntangled reviews alternate and off-label treatments prompted by patient interest. Here, we review psilocybin, a chemical derived from mushrooms and belonging in the category of drugs known as psychedelics. Psilocybin has plausible mechanisms for slowing ALS progression because of its ability to cross the blood brain barrier and effect neurogenesis and inflammation. Currently, there are no pre-clinical ALS models, case reports, or trials for psilocybin and ALS in the context of disease modifying therapy. Depending on dosing, there can be a high risk of psychological side effects including hallucinations and physical harm. Based on the above information, we do not currently support the use of psilocybin as a means to slow ALS progression.}, } @article {pmid39709476, year = {2024}, author = {Udine, E and Finch, NA and DeJesus-Hernandez, M and Jackson, JL and Baker, MC and Saravanaperumal, SA and Wieben, E and Ebbert, MTW and Shah, J and Petrucelli, L and Rademakers, R and Oskarsson, B and van Blitterswijk, M}, title = {Targeted long-read sequencing to quantify methylation of the C9orf72 repeat expansion.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {99}, pmid = {39709476}, issn = {1750-1326}, support = {ALS Association//ALS Association/ ; R21 NS099631/NS/NINDS NIH HHS/United States ; Muscular Dystrophy Association//Muscular Dystrophy Association/ ; P01 NS084974/NS/NINDS NIH HHS/United States ; Robert Packard Center for ALS Research, Johns Hopkins University//Robert Packard Center for ALS Research, Johns Hopkins University/ ; RF1 NS123052/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *DNA Repeat Expansion/genetics ; *DNA Methylation/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Middle Aged ; Aged ; Frontotemporal Dementia/genetics ; Sequence Analysis, DNA/methods ; }, abstract = {BACKGROUND: The gene C9orf72 harbors a non-coding hexanucleotide repeat expansion known to cause amyotrophic lateral sclerosis and frontotemporal dementia. While previous studies have estimated the length of this repeat expansion in multiple tissues, technological limitations have impeded researchers from exploring additional features, such as methylation levels.

METHODS: We aimed to characterize C9orf72 repeat expansions using a targeted, amplification-free long-read sequencing method. Our primary goal was to determine the presence and subsequent quantification of observed methylation in the C9orf72 repeat expansion. In addition, we measured the repeat length and purity of the expansion. To do this, we sequenced DNA extracted from blood for 27 individuals with an expanded C9orf72 repeat.

RESULTS: For these individuals, we obtained a total of 7,765 on-target reads, including 1,612 fully covering the expanded allele. Our in-depth analysis revealed that the expansion itself is methylated, with great variability in total methylation levels observed, as represented by the proportion of methylated CpGs (13 to 66%). Interestingly, we demonstrated that the expanded allele is more highly methylated than the wild-type allele (P-Value = 2.76E-05) and that increased methylation levels are observed in longer repeat expansions (P-Value = 1.18E-04). Furthermore, methylation levels correlate with age at collection (P-Value = 3.25E-04) as well as age at disease onset (P-Value = 0.020). Additionally, we detected repeat lengths up to 4,088 repeats (~ 25 kb) and found that the expansion contains few interruptions in the blood.

CONCLUSIONS: Taken together, our study demonstrates robust ability to quantify methylation of the expanded C9orf72 repeat, capturing differences between individuals harboring this expansion and revealing clinical associations.}, } @article {pmid39709457, year = {2024}, author = {Keeley, O and Mendoza, E and Menon, D and Coyne, AN}, title = {CHMP2B promotes CHMP7 mediated nuclear pore complex injury in sporadic ALS.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {199}, pmid = {39709457}, issn = {2051-5960}, support = {R00 NS123242/NS/NINDS NIH HHS/United States ; R01 NS132836/NS/NINDS NIH HHS/United States ; R00NS123242//National Institute of Aging/ ; R01NS132836/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Nuclear Pore/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Endosomal Sorting Complexes Required for Transport/metabolism/genetics ; Neurons/metabolism/pathology ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {Alterations to the composition and function of neuronal nuclear pore complexes (NPCs) have been documented in multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). Moreover, recent work has suggested that injury to the NPC can at least in part contribute to TDP-43 loss of function and mislocalization, a pathological hallmark of ALS and related neurodegenerative diseases. Collectively, these studies highlight a role for disruptions in NPC homeostasis and surveillance as a significant pathophysiologic event in neurodegeneration. The ESCRT-III nuclear surveillance pathway plays a critical role in the surveillance and maintenance of NPCs and the surrounding nuclear environment. Importantly, pathologic alterations to this pathway and its protein constituents have been implicated in neurodegenerative diseases such as ALS. However, the mechanism by which this pathway contributes to disease associated alterations in the NPC remains unknown. Here we use an induced pluripotent stem cell (iPSC) derived neuron (iPSN) model of sALS to demonstrate that CHMP7/ESCRT-III nuclear maintenance/surveillance is overactivated in sALS neurons. This overactivation is dependent upon the ESCRT-III protein CHMP2B and sustained CHMP2B dependent "activation" is sufficient to contribute to pathologic CHMP7 nuclear accumulation and POM121 reduction. Importantly, partial knockdown of CHMP2B was sufficient to alleviate NPC injury and downstream TDP-43 dysfunction in sALS neurons thereby highlighting CHMP2B as a potential therapeutic target in disease.}, } @article {pmid39708835, year = {2024}, author = {Davalos, L and Kushlaf, H}, title = {Advances in Disease-Modifying Therapeutics for Chronic Neuromuscular Disorders.}, journal = {Seminars in respiratory and critical care medicine}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2463-3385}, pmid = {39708835}, issn = {1098-9048}, abstract = {Neuromuscular disorders can cause respiratory impairment by affecting the muscle fibers, neuromuscular junction, or innervation of respiratory muscles, leading to significant morbidity and mortality. Over the past few years, new disease-modifying therapies have been developed and made available for treating different neuromuscular disorders. Some of these therapies have remarkable effectiveness, resulting in the prevention and reduction of respiratory complications. For myasthenia gravis (MG), efgartigimod, ravulizumab, rozanolixizumab, and zilucoplan have been Food and Drug Administration (FDA)-approved for the treatment of acetylcholine receptor (AChR) antibody-positive generalized MG in the past 2 years. Rozanolixiumab is also approved for treating MG caused by muscle-specific tyrosine kinase (MuSK) antibodies. The new MG therapeutics target the complement system or block the neonatal fragment crystallizable (Fc) receptors (FcRn), leading to significant clinical improvement. For spinal muscular atrophy (SMA), nusinersen (intrathecal route) and risdiplam (oral route) modify the splicing of the SMN2 gene, increasing the production of normal survival motor neuron (SMN) protein. Onasemnogene abeparvovec is a gene replacement therapy that encodes a functional SMN protein. All SMA medications, particularly onasemnogene abeparvovec, have led to clinically meaningful improvement. For late-onset Pompe disease (LOPD), avalglucosidase alfa has shown a greater improvement in respiratory function, ambulation, and functional outcomes in comparison to alglucosidase alfa, and cipaglucosidase alfa combined with miglustat has shown improvement in respiratory and motor function in a cohort of enzyme replacement therapy-experienced LOPD patients. Amyotrophic lateral sclerosis (ALS) remains a challenge. The two most recent FDA-approved medications, namely sodium phenylbutyrate and tofersen, may slow down the disease by a few months in a selected population but do not stop the progression of the disease.}, } @article {pmid39707523, year = {2024}, author = {Straczkiewicz, M and Burke, KM and Calcagno, N and Premasiri, A and Vieira, FG and Onnela, JP and Berry, JD}, title = {Free-living monitoring of ALS progression in upper limbs using wearable accelerometers.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {21}, number = {1}, pages = {223}, pmid = {39707523}, issn = {1743-0003}, mesh = {*Upper Extremity/physiopathology ; Disease Progression ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Monitoring, Ambulatory/instrumentation/methods ; Accelerometry/instrumentation/methods ; *Wearable Electronic Devices ; *Motor Activity/physiology ; Sensitivity and Specificity ; Humans ; Male ; Female ; Young Adult ; Adult ; Middle Aged ; Aged ; Self Report ; }, abstract = {BACKGROUND: Wearable technology offers objective and remote quantification of disease progression in neurological diseases such as amyotrophic lateral sclerosis (ALS). Large population studies are needed to determine generalization and reproducibility of findings from pilot studies.

METHODS: A large cohort of patients with ALS (N = 202) wore wearable accelerometers on their dominant and non-dominant wrists for a week every two to four weeks and self-entered the ALS Functional Rating Scale-Revised (ALSFRS-RSE) in similar time intervals. Wearable device data were processed to quantify digital biomarkers on four upper limb movements: flexion, extension, supination, and pronation using previously developed and validated open-source methodology. In this study, we determined the association between digital biomarkers and disease progression, studied the impact of study design in terms of required sensor wear-time and sensor position, and determined the impact of self-reported disease onset location on upper limb movements.

RESULTS: The main investigation considered data from a sensor placed on the non-dominant wrist. Participants with higher ALSFRS-RSE scores performed more frequent and faster upper limb movements compared to participants with more advanced disease status. Digital biomarkers exhibited statistically significant change over time while their rate of change was more profound compared to survey responses. Using data from the dominant wrist and changing data inclusion criteria did not alter our findings. ALS disease onset location significantly impacted use of upper limbs. Results presented here were comparable to an earlier study on twenty patients with ALS.

DISCUSSION: Digital health technologies provide sensitive and objective means to quantify ALS disease progression. Interpretable approaches, such as the one used in this paper, can improve patient evaluation and hasten therapeutic development.}, } @article {pmid39706636, year = {2025}, author = {Benatar, M and Robertson, J and Andersen, PM}, title = {Amyotrophic lateral sclerosis caused by SOD1 variants: from genetic discovery to disease prevention.}, journal = {The Lancet. Neurology}, volume = {24}, number = {1}, pages = {77-86}, doi = {10.1016/S1474-4422(24)00479-4}, pmid = {39706636}, issn = {1474-4465}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/prevention & control ; Disease Models, Animal ; Genetic Therapy/methods ; *Superoxide Dismutase-1/genetics ; }, abstract = {Pathogenic variants in the superoxide dismutase 1 (SOD1) gene were the first identified genetic cause of amyotrophic lateral sclerosis (ALS), in 1993. This discovery enabled the development of transgenic rodent models for studying the biology of SOD1 ALS. The understanding that SOD1 ALS is driven by a toxic gain-of-function mutation has led to therapeutic strategies that aim to lower concentrations of SOD1 protein, an endeavour that has been complicated by the phenotypic heterogeneity of SOD1 ALS. The successful development of genetically targeted therapies to reduce SOD1 expression, together with a better understanding of pre-symptomatic disease and the discovery of neurofilament light protein as a susceptibility/risk biomarker that predicts phenoconversion, has ushered in a new era of trials that aim to prevent clinically manifest SOD1 ALS. The 30-year journey from gene discovery to gene therapy has not only uncovered the pathophysiology of SOD1 ALS, but has also facilitated the development of biomarkers that should aid therapy development for all forms of ALS.}, } @article {pmid39706627, year = {2025}, author = {Andersen, PM and Benatar, M}, title = {Patrikios syndrome and SOD1 ALS.}, journal = {The Lancet. Neurology}, volume = {24}, number = {1}, pages = {27}, doi = {10.1016/S1474-4422(24)00491-5}, pmid = {39706627}, issn = {1474-4465}, } @article {pmid39706377, year = {2025}, author = {Rush, CL and Lyons, C and Gittle, J and Seward, M and Scalia, J and Ho, D and Babu, S and Garret, MA and Brizzi, K and Berry, JD and Fava, M and Lindenberger, E and Vranceanu, AM and , }, title = {Clinician Perspectives Highlight the Need for Early Dyadic Coping Skills for People Living With Amyotrophic Lateral Sclerosis.}, journal = {Journal of pain and symptom management}, volume = {69}, number = {3}, pages = {236-242.e4}, doi = {10.1016/j.jpainsymman.2024.12.010}, pmid = {39706377}, issn = {1873-6513}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Adaptation, Psychological ; Male ; Female ; *Caregivers/psychology ; *Focus Groups ; Psychological Distress ; Middle Aged ; Interviews as Topic ; Attitude of Health Personnel ; Adult ; Qualitative Research ; Coping Skills ; }, abstract = {CONTEXT: A diagnosis of ALS can be challenging, and many people find ways to adapt. At the same time, emotional distress can arise early after an ALS diagnosis even when high quality multidisciplinary care is provided. When emotional distress occurs, it can become chronic over time, and can affect both the person living with ALS and their care-partner (together called a dyad).

OBJECTIVES: We set out to understand ALS multidisciplinary clinicians' perception of the challenges experienced by people with ALS and care-partners who experience emotional distress after diagnosis and potential benefits of a coping skills program to help these patients and their care-partners, Resilient Together-ALS (RT-ALS).

METHODS: We conducted semi-structured focus groups and individual interviews with 17 clinicians at the Sean M. Healey & AMG Center for ALS at MGH (N = 2 focus groups and five interviews) to elicit feedback on four domains: 1) Psychosocial Needs of ALS Dyads seen in the clinic; 2) Clinic Flow and Referral System to RT-ALS; 3) Clinic Partnership Approach in Support of RT-ALS; 4) RT-ALS Program Content and Manual Format. We conducted rapid data analyses for a time-efficient hybrid inductive-deductive thematic approach.

RESULTS: Clinicians noted that dyadic distress (distress experienced by both patient and their care-partner individually and as a unit), though not universal, is often present early after diagnosis. The response to the proposed program content (dyadic and individual coping skills) and structure (6 weekly virtual sessions delivered within about 2 months after diagnosis) was positive. Multidisciplinary clinicians emphasized the importance of a skills-based program for dyads experiencing elevated early emotional distress for which referral can be easily integrated within clinic flow so as not to not increase provider and dyad burden.

CONCLUSION: RT-ALS program content and structure is acceptable to clinicians. It is imperative to next seek further input from dyads about whether this type of program would be of interest and if yes, to pilot and refine the program for feasibility testing and then efficacy.}, } @article {pmid39706179, year = {2025}, author = {Setsu, S and Morimoto, S and Nakamura, S and Ozawa, F and Utami, KH and Nishiyama, A and Suzuki, N and Aoki, M and Takeshita, Y and Tomari, Y and Okano, H}, title = {Swift induction of human spinal lower motor neurons and robust ALS cell screening via single-cell imaging.}, journal = {Stem cell reports}, volume = {20}, number = {1}, pages = {102377}, pmid = {39706179}, issn = {2213-6711}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Motor Neurons/metabolism/cytology ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Single-Cell Analysis/methods ; *Cell Differentiation ; Machine Learning ; Cells, Cultured ; }, abstract = {This study introduces a novel method for rapidly and efficiently inducing human spinal lower motor neurons (LMNs) from induced pluripotent stem cells (iPSCs) to eventually elucidate the pathomechanisms of amyotrophic lateral sclerosis (ALS) and facilitate drug screening. Previous methods were limited by low induction efficiency, poor LMN purity, or labor-intensive induction and evaluation processes. Our protocol overcomes these challenges, achieving around 80% induction efficiency within just two weeks by combining a small molecule-based approach with transcription factor transduction. Moreover, to exclude non-LMN cells from the analysis, we utilized time-lapse microscopy and machine learning to analyze the morphology and viability of iPSC-derived LMNs on a single-cell basis, establishing an effective pathophysiological evaluation system. This rapid, efficient, and streamlined protocol, along with our single-cell-based evaluation method, enables large-scale analysis and drug screening using iPSC-derived motor neurons.}, } @article {pmid39705668, year = {2024}, author = {Khandia, R and Gurjar, P and Priyanka, and Romashchenko, V and Al-Hussain, SA and Zaki, MEA}, title = {Recent advances in stem cell therapy: efficacy, ethics, safety concerns, and future directions focusing on neurodegenerative disorders - a review.}, journal = {International journal of surgery (London, England)}, volume = {110}, number = {10}, pages = {6367-6381}, pmid = {39705668}, issn = {1743-9159}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Stem Cell Transplantation/methods ; }, abstract = {Neurodegeneration refers to the gradual loss of neurons and extensive changes in glial cells like tau inclusions in astrocytes and oligodendrocytes, α-synuclein inclusions in oligodendrocytes and SOD1 aggregates in astrocytes along with deterioration in the motor, cognition, learning, and behavior. Common neurodegenerative disorders are Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxia (SCA), and supranuclear palsy. There is a lack of effective treatment for neurodegenerative diseases, and scientists are putting their efforts into developing therapies against them. Stem cell therapy has emerged as a hope for neurodegenerative disorders since it is not only the damaged neurons that might be replaced, but other neuromodulators and neuroprotectors are secreted. Stem cell terminal differentiation before implantation ensures the implantation of correct cells and molecular markers like carbonic anhydrase II, CNPase (2',3'-cyclic nucleotide 3'-phosphohydrolase), myelin basic protein (MBP), and myelin oligodendrocyte glycoprotein (MOG) elucidate the differentiation. Secretion of various growth factors like epidermal growth factor (EGF), keratinocyte growth factor (KGF), vascular endothelial growth factor-α (VEGF-α), transforming growth factor (TGF), and macrophage inflammatory protein (MIP) supports cell survival, cell proliferation, blood vessel formation, axon regeneration, and neuroglial functional connection formation at the site of degeneration. Adverse effects of stem cell therapy, like teratogenicity and differentiation in different cells other than the desired one under the influence of microenvironment, are a few key concerns. Post-transplantation improved synaptic plasticity, apoptosis inhibition, and reduction in tau-phosphorylation and amyloid beta (Aβ) production has been observed in Alzheimer's patients. A large number of experimental, preclinical, and clinical studies have been conducted, and encouraging results have been obtained. The present review exhaustively discusses various kinds of stem cells, their usage in treating neurodegenerative disorders, limitations and challenges, and ethical issues related to stem cell therapy.}, } @article {pmid39705453, year = {2024}, author = {Jeong, J and Song, KJ and Lee, JC and Shin, SD and Kim, YJ}, title = {Optimal wearable camera mount locations for medical supervision during simulated out-of-hospital cardiopulmonary resuscitation.}, journal = {Medicine}, volume = {103}, number = {51}, pages = {e40973}, pmid = {39705453}, issn = {1536-5964}, support = {2020R1F1A1076561//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Cardiopulmonary Resuscitation/instrumentation/methods ; Prospective Studies ; *Video Recording ; *Out-of-Hospital Cardiac Arrest/therapy ; *Wearable Electronic Devices ; Male ; Female ; Emergency Medical Technicians/education ; Emergency Medical Services/methods ; Adult ; Simulation Training/methods ; }, abstract = {The quality of the visual information transmitted from a scene is crucial for effective medical supervision in prehospital settings. This study investigated the influence of wearable camera mount locations on visibility during simulated out-of-hospital cardiopulmonary resuscitation. A prospective, observational, non-randomized simulation study was conducted to replicate a cardiac arrest scenario adhering to an advanced life support (ALS) protocol. Seven advanced emergency medical technicians (AEMTs) participated, and 5 camera mount locations were tested: the sternum, forehead, lateral side of the eyelid, mid-nasal, and glabella. Video recordings were captured from the Airway, Intravenous (IV), and Leading providers. Five experienced medical directors independently evaluated visibility scores (1-5) for each procedure with optimal visibility defined as a score of 4 to 5. Glabella mount demonstrated the highest median visibility score and interquartile range (5 [4-5]) and proportion of optimal visibility (77.5%) for most procedures across provider positions. Mixed models revealed significant estimates for the lateral side of the eyelid, mid-nasal, and glabella mounts compared to the sternum, with glabella having the largest effect size (estimate = 1.62). Generalized linear mixed models showed that the glabella mount had the highest odds ratio (OR = 8.07, 95% confidence interval [CI]: 3.01-21.6) to achieve optimal visibility. Wearable camera mount location significantly affected visibility during simulated resuscitation. Mounting cameras closer to eye level provided the most accurate visual data. Further research using objective measures, such as artificial intelligence, and evaluating the visibility of wearable cameras in real-world situations is warranted to optimize simulation-based training for prehospital care.}, } @article {pmid39705326, year = {2025}, author = {}, title = {Correction to Supporting Information for Le et al., Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {2}, pages = {e2424914121}, doi = {10.1073/pnas.2424914121}, pmid = {39705326}, issn = {1091-6490}, } @article {pmid39705260, year = {2024}, author = {Lima, TBWE and Fonseca, JDMD and Silva, AAMD and Vieira, RGDS and Montemezzo, D and Otto-Yáñez, M and Torres-Castro, R and Júnior, METD and Resqueti, VR and Fregonezi, GAF}, title = {Methods to normalize surface electromyography in respiratory muscles: Is it similar between amyotrophic lateral sclerosis and healthy people?.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0315846}, pmid = {39705260}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Electromyography/methods ; Male ; Female ; *Respiratory Muscles/physiopathology ; Middle Aged ; Adult ; Cross-Sectional Studies ; Aged ; Case-Control Studies ; Isometric Contraction/physiology ; }, abstract = {The normalization process is important to determine the best approach for normalizing electromyographic signals from respiratory muscles in healthy subjects and those with ALS. The aim of this study is to compare different methods of normalizing the sEMG signal of respiratory muscles in both healthy subjects and those with Amyotrophic Lateral Sclerosis (ALS). This cross-sectional study was conducted in 67 subjects (50 healthy and 17 with ALS). The electrical activity of the sternocleidomastoid (SCM), scalene (ESC), diaphragm (DIA), parasternal (PS), external intercostal (EI), external oblique (EO), and rectus abdominal (RA) muscles were analyzed during maximal inspiratory pressure maneuvers (MIP), maximal nasal inspiratory pressure (SNIP), maximal expiratory pressure (MEP), and maximal voluntary isometric contraction of SCM and ESC (MVICSCM/ESC) and RA (MVICRA) using surface electromyography (sEMG). In the healthy group, inspiratory and expiratory muscles displayed higher electrical activity during MVICSCM/ESC and MIVCRA maneuvers, respectively (p<0.05). In the ALS group, inspiratory muscle activity was higher during the SNIP maneuver, while expiratory muscles showed higher activity during MVICRA (p<0.05). Based on the findings, it can be concluded that the MVIC resulted in greater inspiratory muscle activity, being the ideal method of normalization for inspiratory and expiratory muscles in healthy subjects. In ALS patients, the SNIP maneuver resulted in greater inspiratory muscle activity, while MVIC resulted in greater muscle activity in expiratory muscles.}, } @article {pmid39703667, year = {2024}, author = {Lewis, RD and Keilholz, AN and Smith, CL and Burd, EA and Nichols, NL}, title = {Spinal TNF-α receptor 1 is differentially required for phrenic long-term facilitation (pLTF) over the course of motor neuron death in adult rats.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1488951}, pmid = {39703667}, issn = {1664-042X}, support = {T32 OD011126/OD/NIH HHS/United States ; }, abstract = {INTRODUCTION: Intrapleural injections of cholera toxin B conjugated to saporin (CTB-SAP) result in selective respiratory (e.g., phrenic) motor neuron death and mimics aspects of motor neuron disease [(e.g., amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA)], such as breathing deficits. This rodent model allows us to study the impact motor neuron death has on the output of surviving phrenic motor neurons as well as the compensatory mechanisms that are recruited. Microglial density in the phrenic motor nucleus as well as cervical gene expression of markers associated with inflammation (e.g., tumor necrosis factor α; TNF-α) are increased following CTB-SAP-induced phrenic motor neuron death, and ketoprofen (nonsteroidal anti-inflammatory drug) delivery attenuated phrenic long-term facilitation (pLTF) in 7 day (d) CTB-SAP rats but enhanced pLTF in 28d CTB-SAP rats.

METHODS: Here, we worked to determine the impact of TNF-α in the phrenic motor nucleus by: 1) quantifying TNFR1 (a high affinity transmembrane receptor for TNF-α) expression; 2) investigating astrocytes (glial cells known to release TNF-α) by performing a morphological analysis in the phrenic motor nucleus; and 3) determining whether acute TNFR1 inhibition differentially affects phrenic plasticity over the course of CTB-SAP-induced motor neuron loss by delivering an inhibitor for TNF-α receptor 1 (sTNFR1i) in 7d and 28d male CTB-SAP and control rats.

RESULTS: Results revealed that TNFR1 expression was increased on phrenic motor neurons of 28d CTB-SAP rats (p < 0.05), and that astrocytes were increased and exhibited reactive morphology (consistent with an activated phenotype; p < 0.05) in the phrenic motor nucleus of CTB-SAP rats. Additionally, we found that pLTF was attenuated in 7d CTB-SAP rats but enhanced in 28d CTB-SAP rats (p < 0.05) following intrathecal sTNFR1i delivery.

CONCLUSION: This work suggests that we could harness TNFR1 as a potential therapeutic agent in CTB-SAP rats and patients with respiratory motor neuron disease by increasing compensatory plasticity in surviving neurons to improve phrenic motor neuron function and breathing as well as quality of life. Future studies will focus on microglial and astrocytic cytokine release, the role they play in the differential mechanisms of pLTF utilized by 7d and 28d CTB-SAP rats, and potential therapies that target them.}, } @article {pmid39703459, year = {2024}, author = {Oliveira, D and Nishimura, AL}, title = {Editorial: Mechanisms of neurodegeneration in amyotrophic lateral sclerosis and related disorders.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1531449}, doi = {10.3389/fncel.2024.1531449}, pmid = {39703459}, issn = {1662-5102}, } @article {pmid39703273, year = {2024}, author = {Solano, J and Eni, G and Viswanath, A and Enany, B}, title = {Successful Rescue of Ventricular Fibrillation Electrical Storm Secondary to Acute Myocardial Infarction in a Patient Presenting to a District General Hospital: A Case Report.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e73959}, pmid = {39703273}, issn = {2168-8184}, abstract = {Ventricular arrhythmia is a critical and challenging cardiovascular complication of myocardial infarction (MI). An electrical storm (ES), characterised by three or more episodes of sustained ventricular arrhythmia within 24 hours, poses a significant life-threatening risk. Standard management includes advanced life support (ALS) protocols and specialised pharmacological interventions. We present the case of a 43-year-old female who presented to the emergency department (ED) following an out-of-hospital ventricular fibrillation (OOHVF) arrest, with the return of spontaneous circulation (ROSC) achieved after multiple defibrillation shocks. Electrocardiography (ECG) revealed anterior ST-segment elevation MI (STEMI) involving the left anterior descending (LAD) artery. During her ED stay, she experienced recurrent ventricular fibrillation (VF) arrests requiring repeated defibrillation, adrenaline, amiodarone, and thrombolysis with alteplase. She was subsequently intubated and transferred to a primary percutaneous coronary intervention (PPCI) centre with intensive care support. Angiography confirmed a 100% occlusion of the LAD, which was successfully treated with stenting. The patient was admitted to the intensive care unit (ICU) and later discharged with full neurological recovery, on secondary prevention and heart failure therapy, with follow-up planned. This case underscores the complexity of managing electrical storms in MI, particularly in non-PPCI centres. It emphasises the importance of thrombolysis as an early reperfusion strategy in STEMI, especially when PPCI is not immediately available.}, } @article {pmid39703094, year = {2025}, author = {De Decker, M and Zelina, P and Moens, TG and Beckers, J and Contardo, M and Dittlau, KS and Van Schoor, E and Ronisz, A and Eggermont, K and Moisse, M and Chandran, S and Veldink, JH and Thal, DR and Van Den Bosch, L and Pasterkamp, RJ and Van Damme, P}, title = {C21ORF2 mutations point towards primary cilia dysfunction in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {3}, pages = {803-816}, pmid = {39703094}, issn = {1460-2156}, support = {C1-C14-17-107//KU Leuven/ ; //Opening the Future Fund (KU Leuven)/ ; 150031//Agency for Innovation by Science and Technology/ ; //ALS Liga België/ ; //National Lottery of Belgium/ ; //European E-Rare-3 project INTEGRALS/ ; //European E-Rare-3 project MAXOMOD/ ; //Stichting ALS Nederland/ ; //Vlaanderen/ ; 772376/ERC_/European Research Council/International ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *Cilia/pathology/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Mutation ; Animals ; Cells, Cultured ; Male ; Neuromuscular Junction/metabolism/pathology/genetics ; Female ; }, abstract = {Progressive loss of motor neurons is the hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain incompletely understood. In this study, we investigate the effects of C21ORF2 mutations, a gene recently linked to ALS, and find that primary cilia are dysfunctional. Human patient-derived mutant C21ORF2 motor neurons have a reduced ciliary frequency and length. We report that C21ORF2 is located at the basal body of the primary cilium, and mutations associated with ALS alter this localization. Furthermore, we show that a reduction of C21ORF2 levels in cell lines and motor neurons is sufficient to cause fewer primary cilia and reduced cilial length. This ciliary dysfunction leads to defective downstream sonic hedgehog signalling and reduces the expression of cellular retinoic acid binding protein 1 (CRABP1), a protein involved in motor neuron maintenance and survival. In a compartmentalized co-culture system of motor neurons and muscle cells, these ciliary defects were associated with a reduced ability of neuromuscular junction formation. Interestingly, these cilia defects are seemingly not restricted to C21ORF2 ALS, as we also observed perturbed primary cilia in cultured motor neurons and post-mortem motor cortex from patients with the most common genetic subtype of ALS caused by repeat expansions in the C9ORF72 gene. Finally, overexpression of C21ORF2 in mutant C21ORF2 motor neurons rescued the ciliary frequency and length, CRAPBP1 expression and neuromuscular junction formation, confirming the importance of primary cilia for motor neuron function. These results point towards primary cilia dysfunction contributing to motor neuron degeneration in ALS and open new avenues for further research and interventions for this as yet untreatable disease.}, } @article {pmid39702138, year = {2024}, author = {Chen, C and Meng, J and Cheng, K and Kang, C and Zhou, L and Guo, H and Zhu, X}, title = {Spatial and morphologic features of lenses with different axial lengths in cataract patients: a swept-source optical coherence tomography-based study.}, journal = {BMC ophthalmology}, volume = {24}, number = {1}, pages = {542}, pmid = {39702138}, issn = {1471-2415}, support = {82122017, 82271069, 81870642, 82371040, 81970780, 81470613 and 81670835//National Natural Science Foundation of China/ ; 23Y11909800 and 21S31904900//Science and Technology Innovation Action Plan of Shanghai Science and Technology Commission/ ; SHDC12020111//Clinical Research Plan of Shanghai Shenkang Hospital Development Center/ ; shslczdzk01901//Shanghai Municipal Key Clinical Specialty Program/ ; }, mesh = {Humans ; *Tomography, Optical Coherence/methods ; Female ; Male ; *Cataract/pathology ; *Axial Length, Eye/pathology/diagnostic imaging ; Aged ; Middle Aged ; *Lens, Crystalline/diagnostic imaging/pathology ; Visual Acuity/physiology ; Myopia/physiopathology ; Retrospective Studies ; Aged, 80 and over ; Cataract Extraction ; }, abstract = {BACKGROUND: To investigate the spatial and morphologic features of lenses with different axial length (ALs) in cataract patients using swept-source optical coherence tomography (SS-OCT).

METHODS: Totally 105 eyes of 105 patients scheduled to have cataract surgery were included. Eyes were divided into the control (AL < 24.5 mm), moderate myopia (MM, 24.5 ≤ AL < 26 mm) and high myopia (HM, AL ≥ 26 mm) groups. Spatial features including lens vault (LV) and iris-to-lens distance (ILD), and morphologic features including radii of curvature of anterior and posterior surface (Ra, Rp), lens diameter (LD) and lens thickness (LT) were measured in eight directions by SS-OCT.

RESULTS: Spatially, the HM group had larger LV and ILD than the control group (both P < .05). LV and ILD were negatively correlated with AL, respectively (LV: r = -.484, P < .0001; ILD: r = -.656, P < .0001). Morphologically, both MM and HM groups had greater Ra and Rp than the control group. Ra was positively correlated with AL (r = .622, P < .0001), while the relationship between Rp and AL was non-linear. Moreover, the MM and HM groups had larger LD than the control group (both P < .001). Anterior LT was thinner in the HM than in the MM group (P = .026), while posterior LT between these two groups was similar. When compared in eight directions, similar trends were seen in Ra, Rp and LD, and the HM group showed a greater difference in Ra between horizontal and vertical directions.

CONCLUSIONS: This SS-OCT-based study showed that longer axial length is associated with a flatter lens, which was mainly attributed to the increase of Ra and LD. Longitudinal studies would be necessary to establish a causal relationship and temporal progression.}, } @article {pmid39701414, year = {2025}, author = {Tantoco, AM and Peterson, R and Corbin, B and Coyne, F and Herbst, B and Hunt, S and Levoy, E and Luttrell, H and Shanske, S and Sanyal, S and Dwyer-Matzky, K and Jenkins, AM}, title = {Pediatric to Adult Care Transition in the Hospital Context (PATCH) Tool: A Novel Tool to Assess Pediatric Institutional Guidelines for Inpatient Care of Adults.}, journal = {Academic pediatrics}, volume = {25}, number = {3}, pages = {102625}, doi = {10.1016/j.acap.2024.102625}, pmid = {39701414}, issn = {1876-2867}, mesh = {Humans ; *Transition to Adult Care/standards ; Adult ; *Hospitals, Pediatric ; *Practice Guidelines as Topic ; Reproducibility of Results ; Adolescent ; Chronic Disease/therapy ; Child ; }, abstract = {OBJECTIVE: The growing number of adults with childhood onset chronic conditions (COCC) is reflected in the increase of adult-aged admissions to pediatric institutions. Despite national bodies advising pediatric institutions to have a pediatric to adult health care transition (HCT) policy, little guidance is available on if or how to include inpatient care. We sought to create a framework-based Pediatric to Adult Transitional Care in the Hospital Context (PATCH) tool to assess how inpatient care of adults is addressed in pediatric institutional guidelines or policies (hereafter guidelines) as a first step towards informing future PATCH guideline development.

METHODS: We used convenience and snowball sampling to obtain 11 pediatric institutional guidelines. Combining the GotTransition core elements with Coller et al's inpatient transition conceptual model through iterative consensus building, we developed the PATCH tool. Interrater reliability was assessed by using mean percent agreement among raters. A three-phase content validity process utilizing existing guidelines refined the finalized tool.

RESULTS: The PATCH tool included 42 items within nine domains. There was a high degree of agreeability among reviewers, and qualitative analysis revealed no missing items. Twenty-five (59%) of our 42 PATCH tool items were present in at least one of the reviewed guidelines, with age being present in all.

CONCLUSIONS: We developed the PATCH tool as a guide for pediatric institutions regarding the care of adolescent and adult patients. The PATCH tool, embedded in multidisciplinary stakeholder discussion and patient- and system-specific knowledge, may help institutions incorporate HCT into processes for adolescent and adult patients with COCCs.}, } @article {pmid39701395, year = {2025}, author = {Force, E and Alvarez, C and Fuentes, A and Maria, A and Bozzolan, F and Debernard, S}, title = {Diet influence on male sexual maturation through interplay between insulin signaling and juvenile hormone in insects.}, journal = {Insect biochemistry and molecular biology}, volume = {177}, number = {}, pages = {104252}, doi = {10.1016/j.ibmb.2024.104252}, pmid = {39701395}, issn = {1879-0240}, mesh = {Animals ; Male ; *Juvenile Hormones/metabolism ; *Moths/metabolism/growth & development ; *Insulin/metabolism ; *Signal Transduction ; *Sexual Maturation ; *Diet ; Receptor, Insulin/metabolism/genetics ; Corpora Allata/metabolism ; }, abstract = {In animals, sexual maturation coincides with the development of sexual behaviors and reproductive system. These developmental events are influenced by diet and governed by endocrine signals. Here, for the first time in insects, we explored functional links between nutrition and juvenile hormone (JH) in the male reproductive physiology through the insulin signaling pathway (ISP) acting as a transducer of nutritional signals. We turned to the male moth Agrotis ipsilon for which sexual maturation, including accessory sex glands (ASGs) development concomitantly with antennal lobes (ALs) maturation for female sex pheromone processing and display of sexual behavior, is known to be JH- and diet-dependent. Indeed, a diet rich in sugars with sodium was previously shown to accelerate sexual maturation, which was achieved from the third day of adult life. In this study, we demonstrated that such a diet raised i) the expression of JH signaling actors (Methoprene-tolerant, Taiman, and Krüppel homolog 1) in ALs and ASGs, ii) the biosynthesis and circulating levels of JH, and iii) the expression of both insulin receptor (InR) and insulin-like peptides (ILPs) in corpora allata (CAs) and brain respectively. Insulin injection raised JH biosynthesis following increased HMG-CoA reductase expression in CAs; opposite effects were induced in InR-deficient males. Thus, we highlighted that promoting effects of a diet composed of sugars with sodium on male sexual maturation results from an early induction of ISP causing an increase in JH biosynthesis followed by a potentiation of JH actions on the development of ASGs and ALs in A. ipsilon.}, } @article {pmid39700696, year = {2025}, author = {Ghaderi, S and Mohammadi, S and Fatehi, F}, title = {Current evidence of arterial spin labeling in amyotrophic lateral sclerosis: A systematic review.}, journal = {Clinical neurology and neurosurgery}, volume = {249}, number = {}, pages = {108691}, doi = {10.1016/j.clineuro.2024.108691}, pmid = {39700696}, issn = {1872-6968}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/diagnosis ; Humans ; *Spin Labels ; *Cerebrovascular Circulation/physiology ; Brain/diagnostic imaging/blood supply/physiopathology ; Magnetic Resonance Imaging/methods ; }, abstract = {OBJECTIVE: This study aimed to evaluate the utility of arterial spin labeling (ASL) in assessing cerebral blood flow (CBF) changes in amyotrophic lateral sclerosis (ALS), and its potential as a biomarker for early diagnosis.

METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies that employed ASL to compare CBF between ALS patients and healthy controls were included.

RESULTS: Seven studies were included. A consistent finding across these studies was hypoperfusion in both the motor and non-motor regions, particularly in the frontotemporal cortex. Hypoperfusion in motor regions was correlated with functional impairment and was observed prior to structural changes, suggesting its potential as an early biomarker. There is limited evidence to suggest that monitoring changes in CBF patterns in the brain. Besides, limited findings showed initial hyperperfusion in regions not yet involved in the pathological process, and progressing hypoperfusion in regions with increasing pathological burden.

CONCLUSIONS: This review highlights the potential of ASL as a valuable tool for understanding the neurovascular dysfunction in ALS. Further research is required to validate its clinical utility for diagnosing ALS and monitoring disease progression.}, } @article {pmid39698283, year = {2024}, author = {Kos, JA and Langiu, M and Hellyer, SD and Gregory, KJ}, title = {Pharmacology, Signaling and Therapeutic Potential of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {12}, pages = {3671-3690}, pmid = {39698283}, issn = {2575-9108}, abstract = {Metabotropic glutamate receptors are a family of eight class C G protein-coupled receptors regulating higher order brain functions including cognition and motion. Metabotropic glutamate receptors have thus been heavily investigated as potential drug targets for treating neurological disorders. Drug discovery efforts directed toward metabotropic glutamate receptor subtype 5 (mGlu5) have been particularly fruitful, with a wealth of drug candidates and pharmacological tools identified. mGlu5 negative allosteric modulators (NAMs) are promising novel therapeutics for developmental, neuropsychiatric and neurodegenerative disorders (e.g., Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, autism spectrum disorders, substance use disorders, stroke, anxiety and depression) and show promise in ameliorating adverse effects induced by other medications (e.g., L-dopa induced dyskinesia in Parkinson's Disease). However, despite preclinical success, mGlu5 NAMs are yet to reach the market due to poor safety and efficacy profiles in clinical trials. Herein, we review the physiology and signal transduction of mGlu5. We provide a comprehensive critique of therapeutic options with respect to mGlu5 inhibitors, spanning from orthosteric antagonists to NAMs. Finally, we address the challenges associated with drug development and highlight future directions to guide rational drug discovery of safe and effective novel therapeutics.}, } @article {pmid39697625, year = {2024}, author = {Zhao, X and Huang, S}, title = {Plasma extracellular vesicle: a novel biomarker for neurodegenerative disease diagnosis.}, journal = {Extracellular vesicles and circulating nucleic acids}, volume = {5}, number = {3}, pages = {569-573}, pmid = {39697625}, issn = {2767-6641}, abstract = {Extracellular vesicles (EVs) are membrane-bound structures that carry proteins, lipids, RNA, and DNA, playing key roles in cell communication and material transport. Recent research highlights their potential as disease biomarkers due to their stability in bodily fluids. This study explores using tau and TDP-43 proteins in plasma EVs as diagnostic biomarkers for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Analyzing plasma EVs from clinical cohorts, the study found that the 3R/4R tau ratio and TDP-43 levels effectively differentiate between diagnostic groups with high accuracy. Notably, plasma EV biomarkers demonstrate higher diagnostic accuracy and stability compared to direct plasma testing, providing new insights and approaches for future research and clinical practice. Further research is needed to validate these biomarkers in diverse populations and to establish standardized protocols. Future studies should continue to explore the potential of EV biomarkers in a broader range of neurodegenerative diseases and delve deeper into the mechanisms of EV secretion and sorting to enhance their diagnostic utility.}, } @article {pmid39697444, year = {2024}, author = {He, SY and Cai, WC and Su, WM and Duan, QQ and Jiang, Z and Yin, KF and Gu, XJ and Chen, YP and Cao, B}, title = {Quantifying the split-elbow sign: a comprehensive study in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1499668}, pmid = {39697444}, issn = {1664-2295}, abstract = {PURPOSE: The split-elbow sign (SES), characterized by preferential dysfunction of the biceps brachii compared to the triceps, is a clinical feature observed in amyotrophic lateral sclerosis (ALS). However, the quantified SES index has not been extensively investigated, and its role in diagnosing ALS remains unknown. Therefore, this study aimed to investigate the split-elbow index (SEI) derived from compound muscle action potential (CMAP), motor unit number index (MUNIX), and echo intensity (EI) in ALS.

METHODS: A cohort comprising 70 individuals diagnosed with ALS, along with 41 disease controls and 40 healthy controls, was recruited for the study. The SEI was calculated by dividing the recorded values of CMAP, MUNIX, and EI obtained over the biceps brachii by the corresponding value measured in the triceps, resulting in SEICMAP, SEIMUNIX, and SEIEI, respectively. Receiver operating characteristic (ROC) curves of the three methods were used for comparison. Statistical analyses were performed using SPSS V.26.0 and R software.

RESULTS: Both SEICMAP and SEIMUNIX exhibited significant reductions in ALS patients compared to that in controls (PSEICMAp  < 0.0001, PSEIMUNIX < 0.0001), while SEIEI showed an elevation (P < 0.0001). Furthermore, there was a notable decrease in SEIMUNIX values as the disease progressed (p < 0.001). Moreover, ROC for SEIMUNIX exhibited superior diagnostic performance (AUC = 0.846), and a comprehensive diagnostic approach combining SEICMAP, SEIMUNIX, and SEIEI resulted in AUC (0.90) on the ROC curve.

CONCLUSION: Our study suggested that SES has emerged as a significant clinical characteristic in ALS and indicated the potential of SES indicators as biomarkers for both diagnosis and assessment of disease progression in ALS.}, } @article {pmid39696694, year = {2024}, author = {El-Khatib, SM and Vagadia, AR and Le, ACD and Baulch, JE and Ng, DQ and Du, M and Johnston, KG and Tan, Z and Xu, X and Chan, A and Acharya, MM}, title = {BDNF augmentation reverses cranial radiation therapy-induced cognitive decline and neurodegenerative consequences.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {190}, pmid = {39696694}, issn = {2051-5960}, support = {R01 CA276212/CA/NCI NIH HHS/United States ; P30CA062203//National Institutes of Health (UC Irvine Comprehensive Cancer Center)/ ; P30 CA062203/CA/NCI NIH HHS/United States ; UL1TR001414//National Institutes of Health (UC Irvine and National Center for Advancing Translational Sciences, NCATS)/ ; UL1 TR001414/TR/NCATS NIH HHS/United States ; R01CA276212/NH/NIH HHS/United States ; }, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; *Cognitive Dysfunction/etiology/metabolism ; *Cranial Irradiation/adverse effects ; Mice ; Male ; Mice, Inbred C57BL ; Neuroprotective Agents/pharmacology ; Neurodegenerative Diseases/radiotherapy ; Hippocampus/metabolism/radiation effects/drug effects ; Female ; }, abstract = {Cranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNF in vivo in the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNF in vivo. In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT + Vehicle with the RT + RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6-7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and mature neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.}, } @article {pmid39696212, year = {2024}, author = {Giusti, A and Pukrittayakamee, P and Wannarit, K and Thongchot, L and Janwanishstaporn, S and Nkhoma, K and Venkatapuram, S and Harding, R}, title = {How to deliver person-centred care for people living with heart failure: a multi stakeholder interview study with patients, caregivers and healthcare professionals in Thailand.}, journal = {BMC health services research}, volume = {24}, number = {1}, pages = {1570}, pmid = {39696212}, issn = {1472-6963}, support = {GHRU 16/136/54//National Institute of Health Research (NIHR) Global Health Research Unit on Health System Strengthening in Sub-Saharan Africa, King's College London/ ; GA-00937//Funds for Graduate Women (FfGW)/ ; }, mesh = {Humans ; *Heart Failure/therapy/psychology ; Thailand ; *Caregivers/psychology ; Male ; *Patient-Centered Care ; Cross-Sectional Studies ; Female ; Middle Aged ; *Qualitative Research ; *Health Personnel/psychology ; Aged ; Adult ; Interviews as Topic ; }, abstract = {CONTEXT: Heart failure has high, growing global prevalence, morbidity and mortality, and is a leading cause of death with serious health-related suffering in low- and middle-income countries. Person-centred care (PCC) is a critical component of high-quality healthcare and is particularly vital in the context of a serious illness such as heart failure. However, there are limited data exploring PCC in this population in low- and middle-income settings.

AIM: The aim of this study was to explore how clinical services could respond to the PCC needs of individuals living with heart failure in Thailand, with potential for adaptation in other settings. The specific objectives were (i) to understand the experiences and needs of persons living with heart failure, their caregivers and HCPs; (ii) to explore specific practical actions that can help deliver PCC for heart failure patients in this setting.

METHODS: Cross-sectional qualitative study. In depth, semi-structured interviews were conducted in Thailand with heart failure patients (n = 14), their caregivers (n = 10) and healthcare professionals (n = 12). Framework analysis was conducted with deductive coding to populate an a priori coding frame based on Santana et al's PCC model (2018) and Giusti et al's systematic review (2020), with further inductive coding of novel findings to expand the frame. The study is reported in accordance with the consolidated criteria for reporting qualitative research guidelines (COREQ).

RESULTS: The findings reveal specific practice actions that deliver PCC for persons living with heart failure in Thailand, such as (i) compassionate communication by healthcare professionals; (ii) effective teamwork amongst multidisciplinary healthcare professionals; (iii) proactive responses to physical, psychosocial, relational and information needs of patients and caregivers; (iv) engaging patients and families in symptom management; (v) providing opportunities for patients to be cared for in the community; and (vi) responding to the social determinants of health, illness and healthcare access.

CONCLUSION: Person-centred healthcare systems must aim to address the social determinants of illness and place focus on community- and home-based care. Heart failure patients and caregivers must be supported to self-manage, including how to recognise symptoms and take appropriate action. Delivering PCC in such a way has the potential to improve outcomes for patients, enhance patients' sense of agency and experiences of care, improve health equity, and reduce hospital admissions, relieving pressure on the hospital system and reducing overall costs of care.}, } @article {pmid39694549, year = {2024}, author = {Ma, YL and Qiu, T and Xu, XL and Wang, LX and Zhuang, PY}, title = {[Analysis of clinical characteristics of amyotrophic lateral sclerosis patients initially diagnosed with abnormal laryngeal function].}, journal = {Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery}, volume = {59}, number = {12}, pages = {1293-1298}, doi = {10.3760/cma.j.cn115330-20240630-00388}, pmid = {39694549}, issn = {1673-0860}, support = {82271155//National Natural Science Foundation of China/ ; 2020J011212//Fujian Provincial Natural Science Foundation/ ; }, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Adult ; Larynx/physiopathology ; }, abstract = {Objective: To study the laryngeal functional characteristics of patients with amyotrophic lateral sclerosis (ALS)disease diagnosed at the voice clinic. Methods: A retrospective analysis(case series study) was conducted on the laryngeal functional characteristics of 7 patients [2 males, 5 females, age ranged from 43 to 76(60.85±13.18)]with motor neuron disease who visited the voice clinic and were ultimately diagnosed by neurologists. The data included laryngostroboscopy, fiberoptic endoscopic examination of swallowing(FEES), acoustic analysis and laryngeal electromyography(LEMG). Descriptive methods were used for analysis. Results: ①There were 2 males and 5 females, with an average age of (60.85±13.18) years. They had previously visited the otolaryngology department more than twice, visit frequency with an average of 3.57 and an average diagnosis time of 12.28 months. The main complaints of the patient at the time of treatment were voice change, dysphagia or vocal fatigue. ②LEMG: Among 7 cases, 4 cases demonstrated neurogenic damage, all of which were bilateral, and 3 cases showed normal findings on examination. Spontaneous potentials (SP) were present in three cases for more than 6 months, with the longest duration being 24 months. Three cases exhibited the coexistence of spontaneous potential and reinnervated motor unit potentials (MUPs), and two cases showed bundle tremor potential.③Laryngostroboscopy revealed bilateral vocal fold asymmetry and glottic insufficiency in 7 cases, and decreased vocal cord movement in 4 cases, and vocal cord atrophy in 5 cases. FEES showed that 7 patients presented with mild to severe swallowing dysfunction, 3 cases had soft palate insufficiency and mild to severe food residues in the epiglottic valley and pyriform fossa. 1 case showed leakage and 1 case showed aspiration. Conclusions: Patients presenting with initial symptoms of abnormal laryngeal function should be vigilant for the possibility of motor neuron disease, especially when laryngostroboscopy reveals abnormal vocal fold movement and swallowing dysfunction. LEMG examination reveals bilateral neurogenic damage, prolonged spontaneous potential, coexistence of spontaneous potential and reinnervated MUPs, and the appearance of bundle tremor potential, which is beneficial for early detection of motor neuron disease.}, } @article {pmid39694468, year = {2025}, author = {Cornell, PY and Gadkari, G and Hua, CL and Smith, L and Johnson, A and Schwartz, L and Rahman, M and Thomas, KS}, title = {Risk of Hospitalization Among Assisted Living Residents Dually Enrolled in Medicare and Medicaid.}, journal = {Journal of the American Medical Directors Association}, volume = {26}, number = {2}, pages = {105421}, doi = {10.1016/j.jamda.2024.105421}, pmid = {39694468}, issn = {1538-9375}, mesh = {Humans ; United States ; *Hospitalization/statistics & numerical data ; *Assisted Living Facilities ; Male ; Female ; Retrospective Studies ; Aged ; *Medicare ; *Medicaid/statistics & numerical data ; Aged, 80 and over ; }, abstract = {OBJECTIVES: To examine how risk of hospitalization among assisted living (AL) residents differs by dual enrollment in Medicare and Medicaid and by the percent of dually enrolled individuals in an AL community.

DESIGN: Retrospective cohort study.

SETTING AND PARTICIPANTS: We used Medicare data from 2008 to 2018 and a national directory of licensed AL communities to identify Medicare beneficiaries with a change in their ZIP+4 code suggesting a new residence in an AL.

METHODS: We estimated linear regression models of hospitalization onto interactions of residents' dual enrollment status and categories of the AL community's percentage of dually enrolled residents. In the models, we adjusted for person-level clinical and demographic characteristics, year-fixed effects, and fixed effects for the AL residents' prior ZIP code.

RESULTS: Among 620,542 Medicare beneficiaries who moved to an AL community, the 1-year risk of hospitalization was higher for dually enrolled residents compared with Medicare-only residents. In adjusted models, dually enrolled residents in high-dual AL communities (>50% dually enrolled) had an 7.4% higher risk of hospital admission compared with dually enrolled residents in low-dual AL communities. Medicare-only beneficiaries in high-dual AL communities had a 9.4% higher risk of hospitalization than Medicare-only beneficiaries in low-dual ALs.

CONCLUSIONS AND IMPLICATIONS: The proportion of residents in an AL community who were dually enrolled was associated with residents' risk of hospitalization, regardless of their dual enrollment status. Additional research is needed to understand whether differences observed in residents' risk of hospitalization are due to differences in the types of services provided, unmeasured resident acuity, or the quality of care delivered in these settings.}, } @article {pmid39693933, year = {2025}, author = {Taisei Ito, and Ohuchi, K and Kurita, H and Murakami, T and Takizawa, S and Fujimaki, A and Murata, J and Oida, Y and Hozumi, I and Kitaichi, K and Inden, M}, title = {Neuroprotective effects of activated fibroblast growth factor receptor 1 via the suppression of p53 accumulation against poly-PR-mediated toxicity.}, journal = {Biochemical and biophysical research communications}, volume = {743}, number = {}, pages = {151181}, doi = {10.1016/j.bbrc.2024.151181}, pmid = {39693933}, issn = {1090-2104}, mesh = {*Tumor Suppressor Protein p53/metabolism/genetics ; *Receptor, Fibroblast Growth Factor, Type 1/metabolism/genetics/antagonists & inhibitors ; Animals ; Mice ; *Neuroprotective Agents/pharmacology ; Cell Line ; Proto-Oncogene Proteins c-mdm2/metabolism/genetics ; Cell Survival/drug effects ; Motor Neurons/metabolism/drug effects ; Humans ; }, abstract = {A GGGGCC hexanucleotide repeat expansion (HRE) within the C9orf72 gene is a major causative factor in amyotrophic lateral sclerosis (ALS). This aberrant HRE results in the generation of five distinct dipeptide repeat proteins (DPRs). Among the DPRs, poly-PR accumulates in the nucleus and exhibits particularly strong toxicity to motor and cortical neurons. Fibroblast growth factor receptor 1 (FGFR1) is known to promote neurogenesis and inhibit apoptosis in neurons. Nevertheless, there has been no previous report of its neuroprotective effects against poly-PR toxicity. The objective of this study was to investigate the neuroprotective effects of FGFR1 activation in poly-PR-expressing NSC34 motor neuron-like cells. RT-qPCR analysis in NSC34 cells showed that Fgfr1 was the most highly expressed member of the Fgfr family in NSC34 cells. The activation of FGFR1 by FGF2, a common ligand for all FGFRs, exerted neuroprotective effects against the toxicity of poly-PR. Additionally, FGFR1 activation was observed to enhance cell viability through the PI3K-AKT pathway, while the contribution of the MEK-ERK pathway was found to be limited. Furthermore, FGFR1 activation suppressed the accumulation of p53 protein and promoted its degradation through increased murine double minute 2 (MDM2), an E3 ubiquitin ligase that targets p53. The neuroprotective effects were attenuated by PD173074, a selective FGFR1 inhibitor or Nutlin-3a, an inhibitor of the p53-MDM2 interaction. Overall, these findings suggest that FGFR1 activation provides neuroprotection against poly-PR toxicity. Consequently, this study suggests the potential utility of FGFR1 activation as a therapeutic strategy for ALS.}, } @article {pmid39693632, year = {2024}, author = {Hausmann, F and Caldi Gomes, L and Hänzelmann, S and Khatri, R and Oller, S and Gebelin, M and Parvaz, M and Tzeplaeff, L and Pasetto, L and Zhou, Q and Zelina, P and Edbauer, D and Pasterkamp, RJ and Rehrauer, H and Schlapbach, R and Carapito, C and Bonetto, V and Bonn, S and Lingor, P}, title = {A dataset profiling the multiomic landscape of the prefrontal cortex in amyotrophic lateral sclerosis.}, journal = {GigaScience}, volume = {13}, number = {}, pages = {}, pmid = {39693632}, issn = {2047-217X}, support = {01GM1917A//Bundesministerium für Bildung und Forschung/ ; CRC1192//DFG/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Prefrontal Cortex/metabolism/pathology ; Humans ; Female ; Mice ; Male ; Animals ; Mice, Transgenic ; Transcriptome ; Proteome ; Disease Models, Animal ; Aged ; Gene Expression Profiling/methods ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, which still lacks effective disease-modifying therapies. Similar to other neurodegenerative disorders, such as Alzheimer and Parkinson disease, ALS pathology is presumed to propagate over time, originating from the motor cortex and spreading to other cortical regions. Exploring early disease stages is crucial to understand the causative molecular changes underlying the pathology. For this, we sampled human postmortem prefrontal cortex (PFC) tissue from Brodmann area 6, an area that exhibits only moderate pathology at the time of death, and performed a multiomic analysis of 51 patients with sporadic ALS and 50 control subjects. To compare sporadic disease to genetic ALS, we additionally analyzed PFC tissue from 4 transgenic ALS mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS) using the same methods. This multiomic data resource includes transcriptome, small RNAome, and proteome data from female and male samples, aimed at elucidating early and sex-specific ALS mechanisms, biomarkers, and drug targets.}, } @article {pmid39691755, year = {2025}, author = {Sood, A and Mishra, GV and Kar, P and Khandelwal, S and Gaur, S and Manuja, N}, title = {Amyotrophic lateral sclerosis in a tricenarian female.}, journal = {Radiology case reports}, volume = {20}, number = {2}, pages = {1121-1123}, pmid = {39691755}, issn = {1930-0433}, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by the progressive degeneration of the upper and lower motor neurons. This disease is mostly observed in patients of the 6th decade or above, and it is extremely rare to observe this pathology in patients less than 50 years of age. This manuscript depicts the magnetic resonance imaging findings of ALS showing a wine glass sign in a 31-year-old female from a rural area with complaints of progressive limb weakness and muscle wasting.}, } @article {pmid39691422, year = {2024}, author = {Fang, K}, title = {Modulation of the central nervous system immune response and neuroinflammation via Wnt signaling in health and neurodegenerative diseases.}, journal = {Ibrain}, volume = {10}, number = {4}, pages = {462-476}, pmid = {39691422}, issn = {2769-2795}, abstract = {The immune response in the central nervous system (CNS) is a highly specialized and tightly regulated process essential for maintaining neural health and protecting against pathogens and injuries. The primary immune cells within the CNS include microglia, astrocytes, T cells, and B cells. They work together, continuously monitor the CNS environment for signs of infection, injury, or disease, and respond by phagocytosing debris, releasing cytokines, and recruiting other immune cells. In addition to providing neuroprotection, these immune responses must be carefully balanced to prevent excessive inflammation that can lead to neuronal damage and contribute to neurodegenerative diseases. Dysregulated immune responses in the CNS are implicated in various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Wnt signaling is a crucial pathway in the CNS that regulates various cellular processes critical for brain development, function, and maintenance. Despite enhancing immune responses in the health CNS, dysregulated Wnt signaling exacerbates neuroinflammation in the neurodegenerative brains. This review summarized the role of Wnt signaling in regulating immune response under different conditions. We then examined the role of immune response in healthy brains and during the development of neurodegenerative diseases. We also discussed therapeutic intervention in various neurodegenerative diseases through the modulation of the Wnt signaling pathway and neuroinflammation and highlighted challenges and limitations in current clinical trials.}, } @article {pmid39690447, year = {2025}, author = {Koch, R and Nagoshi, E}, title = {Examining the potential involvement of NONO in TDP-43 proteinopathy in Drosophila.}, journal = {The European journal of neuroscience}, volume = {61}, number = {1}, pages = {e16632}, pmid = {39690447}, issn = {1460-9568}, support = {310030_189169//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung/ ; 310030_189169//The Swiss National Science Foundation/ ; }, mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; *TDP-43 Proteinopathies/metabolism/pathology/genetics ; *Drosophila Proteins/metabolism/genetics ; RNA-Binding Proteins/metabolism/genetics ; Drosophila ; Neurons/metabolism ; Longevity ; Cell Nucleus/metabolism ; }, abstract = {The misfolding and aggregation of TAR DNA binding protein-43 (TDP-43), leading to the formation of cytoplasmic inclusions, emerge as a key pathological feature in a spectrum of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). TDP-43 shuttles between the nucleus and cytoplasm but forms nuclear bodies (NBs) in response to stress. These NBs partially colocalise with nuclear speckles and paraspeckles that sequester RNAs and proteins, thereby regulating many cellular functions. The laboratory of Steven Brown has recently found that the non-POU domain-containing octamer-binding protein (NONO), a component of paraspeckles, forms novel nuclear speckle-like structures in mouse cortical neurons in response to stress and sleep deprivation. These findings suggest the possibility of a functional link between NONO and TDP-43, potentially contributing to TDP-43 proteinopathy. Here, we demonstrate that pathological phenotypes caused by TDP-43 gain of function-locomotor defects and life span shortening-are exacerbated by silencing the Drosophila homolog of NONO, no on or off transient A (NonA). Additionally, NonA silencing results in an increase in nuclear TDP-43 NBs. These results provide supporting evidence for the functional link between NONO and TDP-43 and lay the foundation for dissecting underlying mechanisms.}, } @article {pmid39690343, year = {2025}, author = {Lamichhane, S and Seo, JE and Jeong, JH and Lee, S and Lee, S}, title = {Ideal animal models according to multifaceted mechanisms and peculiarities in neurological disorders: present and challenges.}, journal = {Archives of pharmacal research}, volume = {48}, number = {1}, pages = {62-88}, pmid = {39690343}, issn = {1976-3786}, support = {Research grant 2024//Chung-Ang University/ ; NRF-2016R1A6A1A03011325//Ministry of Education/ ; }, mesh = {Animals ; *Disease Models, Animal ; Humans ; *Nervous System Diseases/metabolism ; Translational Research, Biomedical/methods ; }, abstract = {Neurological disorders, encompassing conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), pose a significant global health challenge, affecting millions worldwide. With an aging population and increased life expectancy, the prevalence of these disorders is escalating rapidly, leading to substantial economic burdens exceeding trillions of dollars annually. Animal models play a crucial role in understanding the underlying mechanisms of these disorders and developing effective treatments. Various species, including rodents, non-human primates, and fruit flies, are utilized to replicate specific aspects of human neurological conditions. However, selecting the ideal animal model requires careful consideration of its proximity to human disease conditions and its ability to mimic disease pathobiology and pharmacological responses. An Animal Model Quality Assessment (AMQA) tool has been developed to facilitate this selection process, focusing on assessing models based on their similarity to human conditions and disease pathobiology. Therefore, integrating intrinsic and extrinsic factors linked to the disease into the study's objectives aids in constructing a biological information matrix for comparing disease progression between the animal model and human disease. Ultimately, selecting an ideal animal disease model depends on its predictive, face, and construct validity, ensuring relevance and reliability in translational research efforts.}, } @article {pmid39689069, year = {2024}, author = {Junedahl, E and Lundgren, P and Andersson, E and Gupta, V and Råmunddal, T and Rawshani, A and Rawshani, A and Riva, G and Arnetorp, I and Hessulf, F and Herlitz, J and Djärv, T}, title = {The evidence supporting AHA guidelines on adult cardiopulmonary resuscitation (CPR).}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0309241}, pmid = {39689069}, issn = {1932-6203}, mesh = {Humans ; *Cardiopulmonary Resuscitation/standards/methods ; *American Heart Association ; Adult ; *Practice Guidelines as Topic ; United States ; *Heart Arrest/therapy ; Evidence-Based Medicine/standards ; }, abstract = {BACKGROUND: Guidelines for the management of cardiac arrest play a crucial role in guiding clinical decisions and care. We examined the strength and quality of evidence underlying these recommendations in order to elucidate strengths and gaps in knowledge.

METHODS: Using the 2020 American Heart Association (AHA) Guidelines for Adult CPR, we subdivided all recommendations into advanced life support (ALS), basic life support (BLS), and recovery after cardiac arrest, as well as a more granular categorization by topic (i.e. the intervention or evaluation recommended). The Class of Recommendation (COR) and Level of Evidence (LOE) for each were reviewed. Additionally, we reviewed the 2023 guidelines to ensure the inclusion of the most recent updates.

RESULTS: We noted 254 recommendations, of which 181 were ALS, 69 were BLS, and 4 were recovery after resuscitation. In total, only 2 (1%) had the most robust evidence (LOE A), while 23% were at LOE B-NR (Non-Randomized), 15% at LOE B-R (Randomized), 50% at LOE C-LD (Limited Data), and 12% relied on expert opinion LOE C-EO (Expert Opinion). Despite the strength of ALS recommendations (Class 1, 2a, or 2b), none had LOE A. In BLS, no recommendations were supported by LOE A. For BLS, 7% of recommendations had LOE C (C-LD or C-EO). The evidence for specific BLS topics, such as airway management, was notably low. Among ALS topics, neurological prognostication had relatively stronger evidence.

CONCLUSIONS: Only 26 out of the 81 COR 1 recommendations (32%) were supported by LOE A or B, indicating a strong discrepancy between the strength of recommendation and the underlying evidence in cardiac arrest guidelines. The findings underscore a pressing need for more rigorous research, particularly randomized trials.}, } @article {pmid39688956, year = {2024}, author = {Spargo, TP and Gilchrist, L and Hunt, GP and Dobson, RJB and Proitsi, P and Al-Chalabi, A and Pain, O and Iacoangeli, A}, title = {Statistical examination of shared loci in neuropsychiatric diseases using genome-wide association study summary statistics.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {39688956}, issn = {2050-084X}, support = {DRIVE-Health Centre for Doctoral Training//King's College London/ ; 772376-EScORIAL//Horizon 2020/ ; ES/L008238/1//Economic and Social Research Council/ ; 633413//Horizon 2020/ ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; 259867//European Community's Health Seventh Framework Programme/ ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; 10.35802/222811/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Genome-Wide Association Study ; Genetic Predisposition to Disease ; Mental Disorders/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Schizophrenia/genetics ; Genetic Loci ; Parkinson Disease/genetics ; Alzheimer Disease/genetics ; }, abstract = {Continued methodological advances have enabled numerous statistical approaches for the analysis of summary statistics from genome-wide association studies. Genetic correlation analysis within specific regions enables a new strategy for identifying pleiotropy. Genomic regions with significant 'local' genetic correlations can be investigated further using state-of-the-art methodologies for statistical fine-mapping and variant colocalisation. We explored the utility of a genome-wide local genetic correlation analysis approach for identifying genetic overlaps between the candidate neuropsychiatric disorders, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Parkinson's disease, and schizophrenia. The correlation analysis identified several associations between traits, the majority of which were loci in the human leukocyte antigen region. Colocalisation analysis suggested that disease-implicated variants in these loci often differ between traits and, in one locus, indicated a shared causal variant between ALS and AD. Our study identified candidate loci that might play a role in multiple neuropsychiatric diseases and suggested the role of distinct mechanisms across diseases despite shared loci. The fine-mapping and colocalisation analysis protocol designed for this study has been implemented in a flexible analysis pipeline that produces HTML reports and is available at: https://github.com/ThomasPSpargo/COLOC-reporter.}, } @article {pmid39688717, year = {2024}, author = {Ghaderi, S and Fatehi, F and Kalra, S and Mohammadi, S and Batouli, SAH}, title = {Involvement of the left uncinate fasciculus in the amyotrophic lateral sclerosis: an exploratory longitudinal multi-modal neuroimaging and neuropsychological study.}, journal = {Brain structure & function}, volume = {230}, number = {1}, pages = {8}, pmid = {39688717}, issn = {1863-2661}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/physiopathology ; Female ; Male ; Middle Aged ; *Diffusion Tensor Imaging/methods ; Longitudinal Studies ; *Magnetic Resonance Imaging ; Aged ; Neuropsychological Tests ; Adult ; Neural Pathways/diagnostic imaging/physiopathology/pathology ; White Matter/diagnostic imaging/pathology ; Neuroimaging/methods ; Multimodal Imaging ; }, abstract = {To investigate the microstructural integrity, tract volume analysis, and functional connectivity (FC) alterations of the left uncinate fasciculus (UF) in patients with amyotrophic lateral sclerosis (ALS) compared to healthy controls (HCs). Fourteen limb-onset ALS patients were recruited at baseline and ten at follow-up, along with 14 HCs. All participants underwent 3D T1-weighted, diffusion tensor imaging and kurtosis imaging (DTI/DKI), and resting-state functional MRI (rs-fMRI) using a 3 Tesla scanner with 64-channel coils. Eight metrics of diffusion, rs-FC of the left UF, and graph theory analyses were extracted. Statistical group comparisons and correlation analysis for significant diffusion metrics were also conducted. Significantly lower radial kurtosis (RK), mean kurtosis (MK), and higher DTI diffusivity metrics were observed in the left UF of ALS patients than in HCs. RK and MK were correlated with various cognitive scores, particularly executive function and visuospatial ability. The volume of the left UF was positively correlated only with RK and MK at follow-up. While rs-FC analysis did not reveal group differences, a negative functional link between the left UF and cerebellum was observed in HCs but not in patients. Graph theory analysis suggested decreased connectivity in baseline patients and potential compensatory effects during the follow-up. Our study reveals microstructural abnormalities and potential network changes in left UF. DKI metrics, especially RK and MK, may be more sensitive biomarkers than DTI metrics, particularly longitudinally. Diffusion changes appear to precede volume and functional connectivity alterations, suggesting diffusion as a potential early biomarker.}, } @article {pmid39688317, year = {2025}, author = {Tseriotis, VS and Eleftheriadou, K and Mavridis, T and Konstantis, G and Falkenburger, B and Arnaoutoglou, M}, title = {Is the Swallow Tail Sign a Useful Imaging Biomarker in Clinical Neurology? A Systematic Review.}, journal = {Movement disorders clinical practice}, volume = {12}, number = {2}, pages = {134-147}, pmid = {39688317}, issn = {2330-1619}, support = {//Hellenic Academic Libraries Link/ ; }, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Substantia Nigra/diagnostic imaging/pathology ; Parkinson Disease/diagnostic imaging/diagnosis/pathology ; Parkinsonian Disorders/diagnostic imaging ; Biomarkers/analysis ; }, abstract = {BACKGROUND: Loss of dorsolateral nigral hyperintensity (DNH) in iron-sensitive sequences of Magnetic Resonance Imaging (MRI), also described as "swallow tail sign" (STS) loss, has shown promising diagnostic value in Parkinson's Disease (PD) and Atypical Parkinsonian Syndromes (APS).

OBJECTIVE: To conduct a bibliometric analysis on substantia nigra MRI and a systematic review on the clinical utility of STS visual assessment on Susceptibility-Weighted Imaging in various clinical entities.

METHODS: VOSviewer's keyword co-occurrence network was employed using Web of Science (WOS). Complying with the PRISMA statement, we searched MEDLINE, WOS, SCOPUS, ProQuest and Google Scholar for peer-reviewed studies conducted in vivo, excluding quantitative imaging techniques.

RESULTS: DNH is a relatively novel parameter in substantia nigra MRI literature. Our SWI-focused review included 42 studies (3281 patients). Diagnostic accuracy of STS loss for PD/APS differentiation from controls and for Lewy Body Dementia differentiation from other dementias was 47.8-98.5% and 76-90%, respectively, with poorer capacity, however, in delineating PD from APS. STS evaluation in idiopathic REM sleep behavior disorder, a sign of prodromal PD, was typically concordant with nuclear scans, identifying subjects with high conversion risk. Iron deposition can affect STS in Multiple Sclerosis and STS loss in Amyotrophic Lateral Sclerosis is linked with multisystem degeneration, with poorer prognosis. In healthy individuals iron-induced microvessel changes are suspected for false positive results.

CONCLUSION: STS assessment exhibits potential in different settings, with a possibly intermediate role in the diagnostic work-up of various conditions. Its clinical utility should be explored further, through standardized MRI protocols on larger cohorts.}, } @article {pmid39687363, year = {2024}, author = {Stal, C and Covătaru, C and De Wolf, Q and Ignat, T and Pecheniuk, D and Lazăr, C}, title = {Towards a spatial data repository for archaeological research in the Romanian Mostiștea Basin and Danube Valley.}, journal = {Data in brief}, volume = {57}, number = {}, pages = {111119}, doi = {10.1016/j.dib.2024.111119}, pmid = {39687363}, issn = {2352-3409}, abstract = {Spatial data are crucial in archaeological research, where orthophotos, digital elevation models, and 3D models are widely used for mapping, documenting, and monitoring archaeological sites. The introduction of affordable and compact unmanned aerial vehicles (UAVs) has significantly advanced the use of UAV-based photogrammetry in the past 20 years. Recently, compact airborne systems have also enabled the capture of thermal, multispectral, and aerial laser scanning data. This paper presents the data acquired with different platforms and sensors at Chalcolithic archaeological sites in Romania's Mostiștea Basin and Danube Valley. Since laser scanning and photogrammetry generate large data volumes, data storage and dissemination must also be carefully considered. Based on a thorough study of system performance, data acquisition and processing methods, and data outputs, a workflow for the systematic mapping and documentation of sites has been proposed. Given the experience obtained in the last 5 summer campaigns (2018-2023), 19 sites have been accurately mapped, of which 5 sites are mapped using airborne laser scanning. 18 sites are documented using multispectral photogrammetry, and for 17 sites, interactive image-based 3D models are acquired using true-color photogrammetry. All data are stored on a publicly accessible website for visualization, as well as on an open-data platform for data exchange. For the multispectral data, a raster tile service has been implemented, allowing the use of the data in a GIS environment.}, } @article {pmid39687198, year = {2024}, author = {Pappalardo, XG and Jansen, G and Amaradio, M and Costanza, J and Umeton, R and Guarino, F and De Pinto, V and Oliver, SG and Messina, A and Nicosia, G}, title = {Inferring gene regulatory networks of ALS from blood transcriptome profiles.}, journal = {Heliyon}, volume = {10}, number = {23}, pages = {e40696}, pmid = {39687198}, issn = {2405-8440}, abstract = {One of the most robust approaches to the prediction of causal driver genes of complex diseases is to apply reverse engineering methods to infer a gene regulatory network (GRN) from gene expression profiles (GEPs). In this work, we analysed 794 GEPs of 1117 human whole-blood samples from Amyotrophic Lateral Sclerosis (ALS) patients and healthy subjects reported in the GSE112681 dataset. GRNs for ALS and healthy individuals were reconstructed by ARACNe-AP (Algorithm for the Reconstruction of Accurate Cellular Networks - Adaptive Partitioning). In order to examine phenotypic differences in the ALS population surveyed, several datasets were built by arranging GEPs according to sex, spinal or bulbar onset, and survival time. The designed reverse engineering methodology identified a significant number of potential ALS-promoting mechanisms and putative transcriptional biomarkers that were previously unknown. In particular, the characterization of ALS phenotypic networks by pathway enrichment analysis has identified a gender-specific disease signature, namely network activation related to the radiation damage response, reported in the networks of bulbar and female ALS patients. Also, focusing on a smaller interaction network, we selected some hub genes to investigate their inferred pathological and healthy subnetworks. The inferred GRNs revealed the interconnection of the four selected hub genes (TP53, SOD1, ALS2, VDAC3) with p53-mediated pathways, suggesting the potential neurovascular response to ALS neuroinflammation. In addition to being well consistent with literature data, our results provide a novel integrated view of ALS transcriptional regulators, expanding information on the possible mechanisms underlying ALS and also offering important insights for diagnostic purposes and for developing possible therapies for a disease yet incurable.}, } @article {pmid39686920, year = {2025}, author = {Sodagari, S and Sodagari, N}, title = {Examining vaccination-related adverse events in frequent neurodegenerative diseases.}, journal = {Brain, behavior, & immunity - health}, volume = {43}, number = {}, pages = {100902}, pmid = {39686920}, issn = {2666-3546}, abstract = {This study investigates adverse events following vaccination in patients with four neurodegenerative diseases: Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, Multiple Sclerosis (MS), and Parkinson's disease. We applied advanced data processing techniques to analyze symptom patterns and severity scores across these disease groups. Patients were identified through filtering, and symptom clusters were extracted to group similar symptoms into distinct clusters, and severity scores were computed based on hospitalization and death reports. A chi-squared test was performed to assess the statistical significance of adverse event distributions among the diseases for different vaccines. The results reveal that ALS patients exhibit severe respiratory symptoms post-vaccination, while Alzheimer's patients report significant respiratory and gastrointestinal issues. MS patients commonly experience general symptoms such as fatigue, while Parkinson's patients face exacerbated motor symptoms. Notably, our analysis showed no significant difference in adverse event reporting rates between COVID-19 and pneumococcal vaccines across these disease groups. This research provides new insights into disease-specific responses to vaccines, emphasizing the importance of personalized monitoring and treatment strategies to mitigate risks and improve clinical outcomes in these vulnerable populations.}, } @article {pmid39684507, year = {2024}, author = {Tournezy, J and Léger, C and Klonjkowski, B and Gonzalez-Dunia, D and Szelechowski, M and Garenne, A and Mathis, S and Chevallier, S and Le Masson, G}, title = {The Neuroprotective Effect of the X Protein of Orthobornavirus Bornaense Type 1 in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684507}, issn = {1422-0067}, support = {Evaluation of the therapeutic potential of the Borna virus X protein and X-derived peptides in ALS//Association pour la recherche sur la Sclérose Latérale Amyotrophique/ ; Award Fabrice Le Mouaher 2020//Fondation pour la Recherche Médicale/ ; trampoline grant 20219//Association Francaise contre les Myopathies/ ; X protein and ALS//Rotary Club of Bergerac/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Motor Neurons/metabolism/pathology ; Mice ; *Neuroprotective Agents/pharmacology ; *Disease Models, Animal ; Adenosine Triphosphate/metabolism ; Viral Proteins/metabolism/genetics ; Mice, Transgenic ; Humans ; }, abstract = {In amyotrophic lateral sclerosis (ALS), early mitochondrial dysfunction may contribute to progressive motor neuron loss. Remarkably, the ectopic expression of the Orthobornavirus bornaense type 1 (BoDV-1) X protein in mitochondria blocks apoptosis and protects neurons from degeneration. Therefore, this study examines the neuroprotective effects of X protein in an ALS mouse model. We first tested in vitro the effect of the X-derived peptide (PX3) on motoneurons primary cultures of SOD1[G93A] mice. The total intracellular adenosine triphosphate (ATP) content was measured after incubation of the peptide. We next tested in vivo the intramuscular injection of X protein using a canine viral vector (CAV2-X) and PX3 intranasal administrations in SOD1[G93A] mice. Disease onset and progression were assessed through rotarod performance, functional motor unit analysis via electrophysiology, and motor neuron survival by immunohistochemistry. The results showed that in vitro PX3 restored the ATP level in SOD1[G93A] motor neurons. In vivo, treated mice demonstrated better motor performance, preserved motor units, and higher motor neuron survival. Although life expectancy was not extended in this severe mouse model of motor neuron degeneration, the present findings clearly demonstrate the neuroprotective potential of X protein in a model of ALS. We are convinced that further studies may improve the therapeutic impact of X protein with optimized administration methods.}, } @article {pmid39684324, year = {2024}, author = {Toader, C and Tataru, CP and Munteanu, O and Serban, M and Covache-Busuioc, RA and Ciurea, AV and Enyedi, M}, title = {Decoding Neurodegeneration: A Review of Molecular Mechanisms and Therapeutic Advances in Alzheimer's, Parkinson's, and ALS.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684324}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/therapy/metabolism/genetics ; *Parkinson Disease/therapy/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism ; Animals ; Neurodegenerative Diseases/therapy/metabolism/genetics ; Drug Delivery Systems ; Gene Editing ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, ALS, and Huntington's, remain formidable challenges in medicine, with their relentless progression and limited therapeutic options. These diseases arise from a web of molecular disturbances-misfolded proteins, chronic neuroinflammation, mitochondrial dysfunction, and genetic mutations-that slowly dismantle neuronal integrity. Yet, recent scientific breakthroughs are opening new paths to intervene in these once-intractable conditions. This review synthesizes the latest insights into the underlying molecular dynamics of neurodegeneration, revealing how intertwined pathways drive the course of these diseases. With an eye on the most promising advances, we explore innovative therapies emerging from cutting-edge research: nanotechnology-based drug delivery systems capable of navigating the blood-brain barrier, gene-editing tools like CRISPR designed to correct harmful genetic variants, and stem cell strategies that not only replace lost neurons but foster neuroprotective environments. Pharmacogenomics is reshaping treatment personalization, enabling tailored therapies that align with individual genetic profiles, while molecular diagnostics and biomarkers are ushering in an era of early, precise disease detection. Furthermore, novel perspectives on the gut-brain axis are sparking interest as mounting evidence suggests that microbiome modulation may play a role in reducing neuroinflammatory responses linked to neurodegenerative progression. Taken together, these advances signal a shift toward a comprehensive, personalized approach that could transform neurodegenerative care. By integrating molecular insights and innovative therapeutic techniques, this review offers a forward-looking perspective on a future where treatments aim not just to manage symptoms but to fundamentally alter disease progression, presenting renewed hope for improved patient outcomes.}, } @article {pmid39684308, year = {2024}, author = {Ścibior, A and Llopis, J and Dobrakowski, PP and Męcik-Kronenberg, T}, title = {Magnesium (Mg) and Neurodegeneration: A Comprehensive Overview of Studies on Mg Levels in Biological Specimens in Humans Affected Some Neurodegenerative Disorders with an Update on Therapy and Clinical Trials Supplemented with Selected Animal Studies.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684308}, issn = {1422-0067}, mesh = {Humans ; *Magnesium/therapeutic use ; Animals ; *Neurodegenerative Diseases/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Clinical Trials as Topic ; Disease Models, Animal ; Neuroprotective Agents/therapeutic use/pharmacology ; Parkinson Disease/drug therapy/metabolism ; Alzheimer Disease/drug therapy/metabolism ; }, abstract = {Neurodegenerative diseases, characterized by neuron loss, are a group of neurological disorders that adversely affect the lives of millions of people worldwide. Although several medicines have been approved for managing neurodegenerative diseases, new therapies allowing for a significant slowdown in the progression of neurodegenerative syndromes are constantly being sought. Magnesium (Mg), a crucial mineral necessary for the functioning of organisms, is important to normal central nervous system (CNS) activity. Although the effects of this bioelement on the CNS are relatively well recognized, its role in the pathophysiology of neurological disorders in humans is not yet well characterized. Therefore, the main goal of this review is to collect data about a possible association between Mg and neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's Disease (PD), and Amyotrophic lateral sclerosis (ALS) in humans. Hence, the levels of Mg in blood, cerebrospinal fluid (CSF), urine, and hair from subjects with AD, PD, and ALS are compiled to detect possible variations in the levels of this mineral in the biological specimens of people with neurodegenerative illnesses. Additionally, the findings from an animal model are summarized to offer the reader a deeper insight into studies on Mg in the context of neuroprotection and neurodegeneration. Data provided in the present review indicate that Mg, due to its neuroprotective, antioxidant, anti-inflammatory, and mitochondrial-supportive properties, could be a potential therapeutic agent for AD, PD, and ALS. However, more epidemiological studies with standardized methods of dietary assessment and Mg measurement are necessary to recognize its exact role in neurodegenerative disorders. Moreover, extensive well-designed clinical trials are also needed to establish definitive therapeutic protocols and optimal dosages, and to ensure long-term safety of this mineral supplementation in AD, PD, and ALS patients.}, } @article {pmid39684197, year = {2024}, author = {García-González, N and Gonçalves-Sánchez, J and Gómez-Nieto, R and Gonçalves-Estella, JM and López, DE}, title = {Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684197}, issn = {1422-0067}, mesh = {Humans ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/therapy/genetics ; Animals ; Amyotrophic Lateral Sclerosis/therapy/genetics ; }, abstract = {This review explores recent advancements in gene therapy as a potential treatment for neurodegenerative diseases, focusing on intervention mechanisms, administration routes, and associated limitations. Following the PRISMA procedure guidelines, we systematically analyzed studies published since 2020 using the PICO framework to derive reliable conclusions. The efficacy of various gene therapies was evaluated for Parkinson's disease (n = 12), spinal muscular atrophy (n = 8), Huntington's disease (n = 3), Alzheimer's disease (n = 3), and amyotrophic lateral sclerosis (n = 6). For each condition, we assessed the therapeutic approach, curative or disease-modifying potential, delivery methods, advantages, drawbacks, and side effects. Results indicate that gene therapies targeting specific genes are particularly effective in monogenic disorders, with promising clinical outcomes expected in the near future. In contrast, in polygenic diseases, therapies primarily aim to promote cell survival. A major challenge remains: the translation of animal model success to human clinical application. Additionally, while intracerebral delivery methods enhance therapeutic efficacy, they are highly invasive. Despite these hurdles, gene therapy represents a promising frontier in the treatment of neurodegenerative diseases, underscoring the need for continued research to refine and personalize treatments for each condition.}, } @article {pmid39682764, year = {2024}, author = {Huang, R and Xia, H and Lin, W and Wang, Z and Li, L and Deng, J and Ye, T and Li, Z and Yang, Y and Huang, Y}, title = {Riluzole Reverses Blood-Testis Barrier Loss to Rescue Chemotherapy-Induced Male Infertility by Binding to TRPC.}, journal = {Cells}, volume = {13}, number = {23}, pages = {}, pmid = {39682764}, issn = {2073-4409}, support = {No. U22A20277, 32170865, and 82071634//National Natural Science Foundation of China/ ; No. 2022A1515012178//Natural Science Foundation of Guangdong Province/ ; No. 202103030003//Guangzhou Key R&D Program/ ; No.2022B1111080007//Kea-Area Research and Development Program of Guangdong Province/ ; }, mesh = {Male ; *Riluzole/pharmacology/therapeutic use ; Animals ; *Blood-Testis Barrier/drug effects/metabolism ; *Infertility, Male/chemically induced/drug therapy/pathology ; Mice ; TRPC Cation Channels/metabolism ; Busulfan/pharmacology/adverse effects ; Antineoplastic Agents/pharmacology/adverse effects ; Mice, Inbred C57BL ; Molecular Docking Simulation ; Protein Binding/drug effects ; }, abstract = {Cancer treatments, including cytotoxic therapy, often result in male infertility, necessitating the development of safe and effective strategies to preserve male reproductive potential during chemotherapy. Notably, our study uncovers the potential of repurposing riluzole, an FDA-approved drug for amyotrophic lateral sclerosis (ALS), in enhancing spermatogenesis. Hence, this research aims to explore the feasibility of utilizing riluzole to alleviate male infertility induced by busulfan (BSF), a commonly used chemotherapy drug. We established a BSF-induced oligospermia model in 4-week-old male mice and found that riluzole could effectively counter the detrimental effects of BSF on sperm production in mice with oligospermia. By restoring blood-testis barrier (BTB) functionality, riluzole improves sperm quality and reduces testicular atrophy. Through transcriptomic and molecular docking analyses, we identify transient receptor potential canonical subfamily member 5 (TRPC5) as a potential target for riluzole-mediated regulation of blood-testis barrier function. These findings propose riluzole as a promising therapeutic option for chemotherapy-induced male infertility, thereby addressing the fertility challenges associated with cancer treatments. Moreover, repurposing riluzole could streamline the drug development process, providing a cost-effective approach with reduced risk compared to developing entirely new drugs.}, } @article {pmid39681722, year = {2025}, author = {Weiner, HL}, title = {Immune mechanisms and shared immune targets in neurodegenerative diseases.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {2}, pages = {67-85}, pmid = {39681722}, issn = {1759-4766}, mesh = {Humans ; *Neurodegenerative Diseases/immunology/therapy ; Microglia/immunology ; Animals ; Immunotherapy/methods/trends ; Alzheimer Disease/immunology/therapy ; }, abstract = {The immune system plays a major part in neurodegenerative diseases. In some, such as multiple sclerosis, it is the primary driver of the disease. In others, such as Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, it has an amplifying role. Immunotherapeutic approaches that target the adaptive and innate immune systems are being explored for the treatment of almost all neurological diseases, and the targets and approaches are often common across diseases. Microglia are the primary immune cells in the brain that contribute to disease pathogenesis, and are consequently a common immune target for therapy. Other therapeutic approaches target components of the peripheral immune system, such as regulatory T cells and monocytes, which in turn act within the CNS. This Review considers in detail how microglia, monocytes and T cells contribute to the pathogenesis of multiple sclerosis, Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, and their potential as shared therapeutic targets across these diseases. The microbiome is also highlighted as an emerging therapeutic target that indirectly modulates the immune system. Therapeutic approaches being developed to target immune function in neurodegenerative diseases are discussed, highlighting how immune-based approaches developed to treat one disease could be applicable to multiple other neurological diseases.}, } @article {pmid39681698, year = {2025}, author = {Aschemacher, NA and Siano, ÁS and Teglia, CM and Goicoechea, HC}, title = {Development, optimization and comparison of solid-liquid and liquid-liquid microextraction for the determination of four flavonols in Schinus molle L. using high-performance liquid chromatography coupled with second-order data modeling.}, journal = {Analytical and bioanalytical chemistry}, volume = {417}, number = {7}, pages = {1381-1392}, pmid = {39681698}, issn = {1618-2650}, support = {PICT 2020-0304//Fondo para la Investigación Científica y Tecnológica/ ; }, mesh = {Chromatography, High Pressure Liquid/methods ; *Liquid Phase Microextraction/methods ; Flavonols/analysis ; Solid Phase Microextraction/methods ; Limit of Detection ; Plant Extracts/chemistry ; Flavonoids/analysis/isolation & purification ; Schinus ; }, abstract = {Flavonoids are particularly interesting because they have a broad spectrum of biological effects, including antioxidant and free radical scavenging activities. In this work, solid-liquid microextraction and dispersive liquid-liquid microextraction enhanced by ultrasound were developed and compared with the conventional method (Soxhlet extraction) to optimize the extraction of four flavonoids: rutin, quercitrin, quercetin, and myricetin in samples of Schinus molle (Aguaribay). During the development of the analytical method, different chemometric tools were used to optimize the microextraction procedure. In addition, an analytical method based on high-performance liquid chromatography with diode array detector (HPLC-DAD) and second order calibration using multivariate curve resolution-alternating least square (MCR-ALS) is presented to quantify the flavonoids with limits of quantification between 0.011 and 0.082 µg mL[-1]. Finally, solid-liquid microextraction using 4.00 mL water/ethanol (54.3:45.7%), 14 s vortex, and 45 min was selected as the most suitable method due to its high recovery rate and environmental friendliness (with a greenness score of 0.78). After the optimization step, the concentrations found in the plant samples were 1825.3, 632.6, 110.2, and 18.9 µg g[-1] for rutin, quercitrin, quercetin, and myricetin, respectively. The present work is the first achievement of simultaneously determining these four analytes with exceptional sensitivity, demonstrating lower LOQs compared to previous reports.}, } @article {pmid39680524, year = {2024}, author = {Rocha, PS and Bento, N and Folgado, D and Carreiro, AV and Santos, MO and de Carvalho, M and Miranda, B}, title = {Evaluation of smartphone-based cough data in amyotrophic lateral sclerosis as a potential predictor of functional disability.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0301734}, pmid = {39680524}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; *Cough/physiopathology ; Male ; Female ; *Smartphone ; Middle Aged ; Case-Control Studies ; Aged ; Cross-Sectional Studies ; Support Vector Machine ; Adult ; }, abstract = {OBJECTIVES: Cough dysfunction is a feature of patients with amyotrophic lateral sclerosis (ALS). The cough sounds carry information about the respiratory system and bulbar involvement. Our goal was to explore the association between cough sound characteristics and the respiratory and bulbar functions in ALS.

METHODS: This was a single-center, cross-sectional, and case-control study. On-demand coughs from ALS patients and healthy controls were collected with a smartphone. A total of 31 sound features were extracted for each cough recording using time-frequency signal processing analysis. Logistic regression was applied to test the differences between patients and controls, and in patients with bulbar and respiratory impairment. Support vector machines (SVM) were employed to estimate the accuracy of classifying between patients and controls and between patients with bulbar and respiratory impairment. Multiple linear regressions were applied to examine correlations between cough sound features and clinical variables.

RESULTS: Sixty ALS patients (28 with bulbar dysfunction, and 25 with respiratory dysfunction) and forty age- and gender-matched controls were recruited. Our results revealed clear differences between patients and controls, particularly within the frequency-related group of features (AUC 0.85, CI 0.79-0.91). Similar results were observed when comparing patients with and without bulbar dysfunction. Sound features related to intensity displayed the strongest correlation with disease severity, and were the most significant in distinguishing patients with and without respiratory dysfunction.

DISCUSSION: We found a good relationship between specific cough sound features and clinical variables related to ALS functional disability. The findings relate well with some expected impact from ALS on both respiratory and bulbar contributions to the physiology of cough. Finally, our approach could be relevant for clinical practice, and it also facilitates home-based data collection.}, } @article {pmid39680215, year = {2024}, author = {Wu, H and Erenay, FS and Özaltın, OY and Dalgıç, ÖO and Sır, MY and He, QM and Crum, BA and Pasupathy, KS and , }, title = {Prognostic factors affecting ALS progression through disease tollgates.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {69}, pmid = {39680215}, issn = {1432-1459}, support = {2018-06596//NSERC (Natural Sciences and Engineering Research Council of Canada)/ ; 2017-04001//NSERC (Natural Sciences and Engineering Research Council of Canada)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Disease Progression ; Male ; Female ; Prognosis ; Middle Aged ; Aged ; }, abstract = {BACKGROUND AND OBJECTIVES: Understanding factors affecting the timing of critical clinical events in ALS progression.

METHODS: We captured ALS progression based on the timing of critical events (tollgates), by augmenting 6366 patients' data from the PRO-ACT database with tollgate-passed information using classification. Time trajectories of passing ALS tollgates after the first visit were derived using Kaplan-Meier analyses. The significant prognostic factors were found using log-rank tests. Decision-tree-based classifications identified significant ALS phenotypes characterized by the list of body segments involved at the first visit.

RESULTS: Standard (e.g., gender and onset type) and tollgate-related (phenotype and initial tollgate level) prognostic factors affect the timing of ALS tollgates. For instance, by the third year after the first visit, 80-100% of bulbar-onset patients vs. 43-48% of limb-onset patients, and 65-73% of females vs. 42-49% of males lost the ability to talk and started using a feeding tube. Compared to the standard factors, tollgate-related factors had a stronger effect on ALS progression. The initial impairment level significantly impacted subsequent ALS progression in a segment while affected segment combinations further characterized progression speed. For instance, patients with normal speech (Tollgate Level 0) at the first visit had less than a 10% likelihood of losing speech within a year, while for patients with Tollgate Level 1 (affected speech), this likelihood varied between 23 and 53% based on additional segment (leg) involvement.

CONCLUSIONS: Tollgate- and phenotype-related factors have a strong effect on the timing of ALS tollgates. All factors should be jointly considered to better characterize patient groups with different progression aggressiveness.}, } @article {pmid39679928, year = {2024}, author = {Bhattacharjee, T and Vengalil, S and Belur, Y and Atchayaram, N and Ghosh, PK}, title = {Inter-speaker acoustic differences of sustained vowels at varied dysarthria severities for amyotrophic lateral sclerosis.}, journal = {JASA express letters}, volume = {4}, number = {12}, pages = {}, doi = {10.1121/10.0034613}, pmid = {39679928}, issn = {2691-1191}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Dysarthria/etiology/physiopathology ; *Speech Acoustics ; Male ; Female ; Middle Aged ; Aged ; Severity of Illness Index ; Phonetics ; }, abstract = {We study inter-speaker acoustic differences during sustained vowel utterances at varied severities of Amyotrophic Lateral Sclerosis-induced dysarthria. Among source attributes, jitter and standard deviation of fundamental frequency exhibit enhanced inter-speaker differences among patients than healthy controls (HCs) at all severity levels. Though inter-speaker differences in vocal tract filter attributes at most severity levels are higher than those among HCs for close vowels /i/ and /u/, these are comparable with or lower than those among HCs for the relatively more open vowels /a/ and /o/. The differences typically increase with severity except for a few parameters for /a/ and /i/.}, } @article {pmid39679063, year = {2024}, author = {Kodavati, M and Hegde, ML}, title = {A Commentary on Mitochondrial Dysfunction and Compromised DNA Repair in Neurodegeneration: The Emerging Role of FUS in ALS.}, journal = {Neuroscience insights}, volume = {19}, number = {}, pages = {26331055241305151}, pmid = {39679063}, issn = {2633-1055}, support = {R01 NS088645/NS/NINDS NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {Mitochondrial dysfunction plays a pivotal role in the progression of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's, and Parkinson's disease. Recent discoveries have highlighted the involvement of DNA damage and repair processes, particularly mitochondrial DNA (mtDNA) damage, in these conditions. This commentary reflects on our recent findings, demonstrating the RNA/DNA binding protein fused in sarcoma (FUS)'s crucial role in maintaining mtDNA integrity through interactions with mitochondrial DNA ligase IIIα (mtLig3). Our studies provide direct evidence of increased mtDNA damage in ALS-linked FUS mutant cells, emphasizing the potential of targeting DNA repair pathways to mitigate neurodegeneration. Furthermore, the restoration of mitochondrial function through targeted expression of human DNA ligase 1 (Lig1) in FUS mutant models showcases the therapeutic promise of DNA repair mechanisms in neurodegenerative diseases. These insights offer new molecular understanding and open up future avenues for therapeutic interventions, particularly in FUS-associated ALS and related disorders.}, } @article {pmid39678608, year = {2024}, author = {Dong, F}, title = {Bioinformatic materials science reconsidered.}, journal = {American journal of translational research}, volume = {16}, number = {11}, pages = {7200-7204}, pmid = {39678608}, issn = {1943-8141}, abstract = {Bioinformatic materials science integrates medical science, materials science, informatics, and other disciplines, aiming to maintain the balance of tissues and organs in the human body. This paper explores the relationship between structural information and the structures synthesized through regulated gene expression. Specifically, it describes the transformation of information into substances via biological structural systems, using mathematical formulas to develop bioinformatic materials. These materials have applications in medical treatments, functional foods for preventive healthcare, and cosmetic products for health maintenance. Notably, bioinformatic materials have been applied in treating acromegaly, a rare and life-threatening disease of unknown etiology, and have improved the neurofilament light chain (NFL) index and typical symptoms of Amyotrophic Lateral Sclerosis (ALS). In summary, bioinformatic materials science holds potential for enhancing human health and contributing to advances in medicine.}, } @article {pmid39678458, year = {2024}, author = {Sulek, A}, title = {Secretome - the role of extracellular vesicles in the pathogenesis and therapy of neurodegenerative diseases.}, journal = {Postepy psychiatrii neurologii}, volume = {33}, number = {3}, pages = {147-162}, pmid = {39678458}, issn = {2720-5371}, abstract = {PURPOSE: Extracellular vesicles are the subject of many studies in various medical specialties. Their role in neurodegenerative diseases is increasing and they worth introducing in more detail.

METHODS: This review was performed following an electronic search of the database PubMed/Medline and Web of Science for English-language articles between 2010 and 2024 in the fields of medicine, molecular biology, and biochemistry. Keywords searches included combinations of the following terms: "extracellular vesicles" OR "exosomes" AND "neurodeg*" AND "microRNA" OR "miRNA" AND "AD" OR "PD" OR "ALS" OR "HD". Articles had to be original work or reviews.

RESULTS: The classification of extracellular vesicles is based on their size or origin. Their content is of key importance in communication between cells and can be treated as a physiological determinant of the normal or pathological condition of a body. The cargo transported in the extracellular space and over longer distances in various body fluids is diversified and may be nucleic acids (DNA, RNA, miRNA) as well as proteins and lipids, and, in the case of apoptotic bodies also a cell's organelles. Exosomes are the most thoroughly studied extracellular vesicles and the most often considered for therapeutic applications. Vesicles carrying biological substances in the body perform three basic functions: participation in a pathological mechanism, a biomarker role that also has diagnostic and prognostic functions, and a role in therapeutic activities. In the case of neurodegenerative diseases, it appears that extracellular vesicles can transport misfolded proteins, initiating pathological processes in previously normal cells.

CONCLUSIONS: The transport of various substances enclosed in vesicles seems to be very promising in therapeutic prospects in various diseases, and the possibility of their crossing the blood-brain barrier particularly indicates diseases of the central nervous system. Despite many years of research on extracellular vesicles in the context of neurodegenerative diseases, their practical use is currently limited to studies on animal and cellular models, and their practical application in clinical trials in neurodegenerative diseases is to date extremely rare.}, } @article {pmid39678223, year = {2025}, author = {Banos, M and Preuilh, A and Pradat, PF and Lackmy-Vallée, A and Marchand-Pauvert, V}, title = {Exercises and Brain Stimulation to Preserve Function in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {Neurology. Clinical practice}, volume = {15}, number = {1}, pages = {e200408}, pmid = {39678223}, issn = {2163-0402}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to the loss of motor function and muscle strength. Nonpharmacologic neuromodulative therapeutic approaches such as active exercise may contribute to preserve motor functions in ALS, but this hypothesis remains debated. The present meta-analysis first aimed to evaluate the effect of active exercise on function and muscle strength preservation. Moreover, since the responsiveness to induced neuroplasticity of patients with ALS is being discussed, the second objective was to review the analogous effects of noninvasive brain stimulation (NIBS).

METHODS: Following PRISMA guidelines, we systematically reviewed PubMed, CENTRAL, NIH PMC, PEDro, ScienceDirect, and Web of Science databases from the period between January 10 and July 1, 2023. Criteria limited inclusion to randomized controlled trials comparing active exercise (aerobic or resistance) with usual care or NIBS with sham. The primary outcome was assessed based on functional assessment scores reported on validated clinical scales, and the secondary outcome analysis included muscle strength and neurophysiologic changes. Methodologic quality of the selected studies was assessed using the Physiotherapy Evidence-Based (PEDro) scale. Relative risk (RR) and heterogeneity (I[2]) were calculated with Revman software, and evidence quality was estimated by the GRADE quality scale.

RESULTS: Thirteen studies were included. Analysis involved 393 patients among whom 164 underwent active exercise and 155 received usual care, 41 received NIBS and 33 underwent sham stimulations. The nature of active exercise was consistent across studies but varied in frequency. NIBS parameters were consistent for stimulation sites and session frequency. Function was significantly preserved in 5 of 9 studies on active exercise and 2 of 4 NIBS trials. Meta-analysis on functional scales indicated a moderate quality of evidence for the effectiveness of active exercises (RR = 0.61 [0.18, 1.04] with I[2] = 69%) compared with usual care and very low quality of evidence for NIBS (RR = -1.41 [-0.44, 3.26] with I[2] = 89%). Only 1 NIBS study revealed neuroplastic changes in the brain.

DISCUSSION: Active exercise likely slows functional loss in ALS, but the effects of NIBS need further investigation to support their neuroprotective effectiveness. Moreover, both interventions require further neurophysiologic investigation to elucidate ALS neuroplasticity.

This review has been registered in PROSPERO (CRD42023408121).}, } @article {pmid39678056, year = {2024}, author = {Baslo, SA and Şirin, NG and Orhan, EK and Baslo, MB and Öge, AE}, title = {Selective Muscle Involvement in Amyotrophic Lateral Sclerosis: Evidence Inferred from the Point of Motor Unit Firing Rates.}, journal = {Noro psikiyatri arsivi}, volume = {61}, number = {4}, pages = {296-305}, pmid = {39678056}, issn = {1300-0667}, abstract = {INTRODUCTION: The aim of the study is to determine the role of upper motor neuron (UMN) or lower motor neuron (LMN) dysfunction as the primary initiator of distal-proximal and lateral-medial gradients of muscle involvement in amyotrophic lateral sclerosis (ALS).

METHODS: Concentric needle electromyography recordings were performed in deltoid, abductor digiti minimi, and first dorsal interosseous (FDI) muscles in patients with ALS and controls during slight voluntary contraction needed to activate two motor units (MU). Five motor unit potential (MUP) pairs were recorded from each muscle. Motor unit potential analyses were performed offline using Multi-MUP analysis program. Quantitative MUP parameters, MU firing rate (FR), FR variability (FRV), and mean consecutive difference (MCD) were calculated. Motor-evoked potentials and the triple stimulation technique (TST) were performed to evaluate UMN involvement.

RESULTS: Twenty patients with ALS along with 20 age and sex-matched healthy volunteers were enrolled. Quantitative MUP parameters compatible with denervation and reinnervation were found in patients with ALS, who also showed higher FR, FRV, and MCD values, most prominently in FDI. First dorsal interosseous FRV was lower in patients with abnormal central motor conduction time (CMCT). Firing rate and FRV were negatively correlated with CMCT, but not with TST.

CONCLUSION: Distal limb muscles, particularly FDI, revealed more prominent FR abnormalities in patients with ALS in parallel with the distal-proximal and lateral-medial gradients of the selective muscle involvement pattern which seems predominantly to be correlated with LMN dysfunction. Reduced FRV may be associated with the presence of UMN dysfunction in ALS.}, } @article {pmid39678053, year = {2024}, author = {Finsterer, J and Mehri, S}, title = {The Causality Spectrum of Dropped Head Syndrome is Broad and Includes Myopathy, Neurodegenerative Disorders, and Varia.}, journal = {Noro psikiyatri arsivi}, volume = {61}, number = {4}, pages = {382-383}, pmid = {39678053}, issn = {1300-0667}, abstract = {Dropped head syndrome is a common complication of various neurological disorders. Most commonly, dropped head syndrome is due to primary or secondary myopathy. However, neurodegenerative diseases and various other conditions can also be complicated by dropped head syndrome. Among the primary myopathies, dropped head occurs most commonly in association with mitochondrial disorders, congenital myasthenic syndrome, and axial myopathies. Among the secondary myopathies, dropped occurs most commonly in association with inflammatory myopathies. Myasthenia is the most common transmission disorder associated with dropped head syndrome. The neurodegenerative disorder most commonly associated with dropped head syndrome is Parkinson syndrome. The diagnosis and treatment of dropped head syndrome from any cause requires a multidisciplinary approach. Outcome varies considerably but early diagnosis and early treatment are associated with a more favourable outcome.}, } @article {pmid39677679, year = {2024}, author = {Chen, L and Smith, M and Roe, DR and Miranda-Quintana, RA}, title = {Extended Quality (eQual): Radial threshold clustering based on n-ary similarity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39677679}, issn = {2692-8205}, support = {R35 GM150620/GM/NIGMS NIH HHS/United States ; }, abstract = {We are transforming Radial Threshold Clustering (RTC), an O (N 2) algorithm, into Extended Quality Clustering, an O (N) algorithm with several novel features. Daura et al's RTC algorithm is a partitioning clustering algorithm that groups similar frames together based on their similarity to the seed configuration. Two current issues with RTC is that it scales as O (N 2) making it inefficient at high frame counts, and the clustering results are dependent on the order of the input frames. To address the first issue, we have increased the speed of the seed selection by using k -means++ to select the seeds of the available frames. To address the second issue and make the results invariant with respect to frame ordering, whenever there is a tie in the most populated cluster, the densest and most compact cluster is chosen using the extended similarity indices. The new algorithm is able to cluster in linear time and produce more compact and separate clusters.}, } @article {pmid39677629, year = {2024}, author = {Park, S and Park, SK and Liebman, SW}, title = {A model of inborn metabolism errors associated with adenine amyloid-like fiber formation reduces TDP-43 aggregation and toxicity in yeast.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.12.03.626668}, pmid = {39677629}, issn = {2692-8205}, abstract = {TDP-43 is linked to human diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Expression of TDP-43 in yeast is known to be toxic, cause cells to elongate, form liquid-like aggregates, and inhibit autophagy and TOROID formation. Here, we used the apt1Δ aah1Δ yeast model of disorders of inborn errors of metabolism, previously shown to lead to intracellular adenine accumulation and adenine amyloid-like fiber formation, to explore interactions with TDP-43. Results show that the double deletion shifts the TDP-43 aggregates from a liquid-like, toward a more amyloid-like, state. At the same time the deletions reduce TDP-43's effects on toxicity, cell morphology, autophagy, and TOROID formation without affecting the level of TDP-43. This suggests that the liquid-like and not amyloid-like TDP-43 aggregates are responsible for the deleterious effects in yeast. How the apt1Δ aah1Δ deletions alter TDP-43 aggregate formation is not clear. Possibly, it results from adenine/TDP-43 fiber interactions as seen for other heterologous fibers. The work offers new insights into the potential interactions between metabolite-based amyloids and pathological protein aggregates, with broad implications for understanding protein misfolding diseases.}, } @article {pmid39677625, year = {2024}, author = {Li, A and Dong, L and Li, X and Yi, J and Ma, J and Zhou, J}, title = {ALDH3A1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to denervation and Amyotrophic Lateral Sclerosis progression.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39677625}, issn = {2692-8205}, support = {R01 NS105621/NS/NINDS NIH HHS/United States ; R01 NS129219/NS/NINDS NIH HHS/United States ; }, abstract = {Different muscles exhibit varied susceptibility to degeneration in Amyotrophic Lateral Sclerosis (ALS), a fatal neuromuscular disorder. Extraocular muscles (EOMs) are particularly resistant to ALS progression and exploring the underlying molecular nature may deliver great therapeutic value. Reactive aldehyde 4-hydroxynonenal (HNE) is implicated in ALS pathogenesis and ALDH3A1 is an inactivation-resistant intracellular detoxifier of 4-HNE protecting eyes against UV-induced oxidative stress. Here we detected prominently higher levels of ALDH3A1 in mouse EOMs than other muscles under normal physiological conditions. In an ALS mouse model (hSOD1[G93A]) reaching end-stage, ALDH3A1 expression was sustained at high level in EOMs, whereas substantial upregulation of ALDH3A1 occurred in soleus and diaphragm. The upregulation was less pronounced in extensor digitorum longus (EDL) muscle, which endured the most severe pathological remodeling as demonstrated by unparalleled upregulation of a denervation marker ANKRD1 expression. Interestingly, sciatic nerve transection in wildtype mice induced ALDH3A1 and ANKRD1 expression in an inverse manner over muscle type and time. Adeno-associated virus enforced overexpression of ALDH3A1 protected myotubes from 4-HNE-induced DNA fragmentation, plasma membrane leakage and restored MG53-mediated membrane repair. Our data indicate that ALDH3A1 may contribute to distinct muscle resistance to ALS through detoxifying reactive aldehydes.}, } @article {pmid39676614, year = {2024}, author = {Roscoe, S and Allen, SP and McDermott, C and Stavroulakis, T}, title = {Exploring the role of anthropometric measurements to assess nutritional status in amyotrophic lateral sclerosis: a longitudinal prospective cohort study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/21678421.2024.2434176}, pmid = {39676614}, issn = {2167-9223}, abstract = {OBJECTIVE: To observe longitudinal correlations between limb anthropometry against weight, BMI and functional decline in patients with amyotrophic lateral sclerosis.

METHODS: A longitudinal, prospective, cohort study was undertaken. Four consecutive measurements of weight, height, triceps skinfold thickness (TSF), mid-upper arm (MUAC) and calf circumferences were collected at three-monthly intervals. Fat- and lean body mass were estimated using measurements of TSF and derivations of arm muscle area, respectively. Correlation analyses indicated associations between anthropometric assessments and functional decline (ALSFRS-R). Longitudinal changes were assessed using repeated measures analyses.

RESULTS: Data from 18 participants was analyzed. At enrollment, weight positively correlated with MUAC (n = 17, p = 0.0001), arm muscle area (n = 17, p = 0.04) and calf circumference (n = 17, p < 0.0001). The ALSFRS-R score negatively correlated with weight (n = 17, p = 0.03), MUAC (n = 18, p = 0.01), TSF (n = 18, p = 0.04), and calf circumference (n = 18, p = 0.003). Function significantly declined by a difference of 6.3 points per month (p = 0.009). A positive correlation was observed between the changes in weight and calf circumference over nine months (r = 0.70, p = 0.02, n = 10).

CONCLUSION: Limb anthropometric measurements may be surrogate indicators of weight and BMI; TSF may be a practical, reliable indicator of fat mass, whilst changes in calf circumference may be alternatively used to monitor changes in nutritional status in the clinic.}, } @article {pmid39674407, year = {2025}, author = {Xue, S and Bao, W and Lyu, J and Wang, C and Zhang, Y and Li, H and Chen, D and Lu, Y}, title = {In vitro nephrotoxicity and structure-toxicity relationships of eight natural aristolactams.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {254}, number = {}, pages = {108214}, doi = {10.1016/j.toxicon.2024.108214}, pmid = {39674407}, issn = {1879-3150}, mesh = {Humans ; Structure-Activity Relationship ; Cell Line ; *Reactive Oxygen Species/metabolism ; *Cell Survival/drug effects ; *Transforming Growth Factor beta1/metabolism ; Aristolochic Acids/toxicity ; Hepatitis A Virus Cellular Receptor 1 ; Epithelial Cells/drug effects ; Fibronectins/metabolism ; Kidney Tubules/drug effects/pathology/cytology ; }, abstract = {The structural similarity between aristolactams (ALs) and aristolochic acids (AAs) raises constant concerns about the safety of ALs-containing plants. Natural ALs are distributed more extensively than AAs, leading to a higher risk of ALs exposure in daily consumption. This study aimed to evaluate and compare the in vitro nephrotoxicity on human renal tubular epithelial cells (HK-2 cells) of eight natural ALs with different substituents on the phenanthrene ring and amide ring, including aristolactam Ⅰ (AL Ⅰ), AL BⅡ, velutinam, AL AⅡ, sauristolactam, AL AⅠa, AL FⅠ and N-methyl piperolactam A. Their IC50 values of cell viability were tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of kidney injury molecule-1 (KIM-1), transforming growth factor-β1 (TGF-β1) and fibronectin (FN). The reactive oxygen species (ROS) assay was used to detect the intracellular oxidative stress level. The results showed that the eight ALs all had specific nephrotoxicity on HK-2 cells. Particularly, AL Ⅰ, AL BⅡ and velutinam exhibited more potent cytotoxicity on HK-2 cells (IC50 = 2.49-2.78 μM) than the other five ALs (IC50 = 12.33-43.84 μM). The structure-toxicity relationships indicated that both methylenedioxy (-OCH2O-) and methoxy (-OCH3) were positively contributing functional groups of ALs on nephrotoxicity, while the hydroxy group (-OH) and methyl substitution on nitrogen (N-CH3) accounted for a detrimental effect conversely. Consistent with this structure-toxicity relationship, the eight ALs increased KIM-1 levels in the same trend as their cytotoxicity at the same concentration of 2.5 μg/mL, associating with different levels of ROS generation. And the four most toxic ALs, AL Ⅰ, AL BⅡ, velutinam and AL AⅡ, could also induce fibrosis by increasing TGF-β1 and FN levels.}, } @article {pmid39674307, year = {2025}, author = {Pistolesi, A and Ranieri, G and Calvani, M and Guasti, D and Chiarugi, A and Buonvicino, D}, title = {Microglial suppression by myeloperoxidase inhibitor does not delay neurodegeneration in a mouse model of progressive multiple sclerosis.}, journal = {Experimental neurology}, volume = {385}, number = {}, pages = {115095}, doi = {10.1016/j.expneurol.2024.115095}, pmid = {39674307}, issn = {1090-2430}, mesh = {Animals ; *Microglia/drug effects/metabolism ; Mice ; *Peroxidase/metabolism ; *Multiple Sclerosis, Chronic Progressive/drug therapy ; *Disease Models, Animal ; Mice, Inbred NOD ; Female ; Enzyme Inhibitors/pharmacology/therapeutic use ; Piperidines/pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; Nerve Degeneration/drug therapy/pathology ; Spinal Cord/drug effects/pathology/metabolism ; }, abstract = {Drugs able to efficiently counteract the progression of multiple sclerosis (MS) are still an unmet need. Numerous preclinical evidence indicates that reactive oxygen-generating enzyme myeloperoxidase (MPO), expressed by neutrophils and microglia, might play a key role in neurodegenerative disorders. Then, the MPO inhibition has been evaluated in clinical trials in Parkinson's and multiple system atrophy patients, and a clinical trial for the treatment of amyotrophic lateral sclerosis is underway. The effects of MPO inhibition on MS patients have not yet been explored. In the present study, by adopting the NOD mouse model of progressive MS (PMS), we evaluated the pharmacological effects of the MPO inhibitor verdiperstat (also known as AZD3241) on functional, immune, and mitochondrial parameters during disease evolution. We found that daily treatment with verdiperstat did not affect the pattern of progression as well as survival, despite its ability to reduce mitochondrial reactive oxygen species and microglia activation in the spinal cord of immunized mice. Remarkably, verdiperstat did not affect adaptive immunity, neutrophils invasion as well as mitochondrial derangement in the spinal cords of immunized mice. Data suggest that microglia suppression is not sufficient to prevent disease evolution, corroborating the hypothesis that immune-independent components drive neurodegeneration in progressive MS.}, } @article {pmid39657109, year = {2025}, author = {Benatar, M and McDermott, C and Turner, MR and van Eijk, RPA}, title = {Rethinking phase 2 trials in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {4}, pages = {1106-1111}, pmid = {39657109}, issn = {1460-2156}, support = {/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; *Clinical Trials, Phase II as Topic/methods ; }, abstract = {There is a long history in amyotrophic lateral sclerosis (ALS) of promoting therapies based on phase 2 data, which then fail in phase 3 trials. Experience suggests that studies of 6 months in duration are too short, especially with function-based outcome measures. Multiplicity poses a serious threat to data interpretation, and strategies to impute missing data may not be appropriate for ALS where progression is always expected. Emerging surrogate markers of clinical benefit such as reduction of neurofilament light chain levels may be better suited to phase 2 go/no-go decisions. Over-interpretation of phase 2 data, and overly optimistic communication of exploratory analyses must be avoided to ensure optimal prioritization for the investment needed for definitive phase 3 trials and to minimize the harm of false hope for people living with ALS. Delivering on advances in understanding of the neurobiology of ALS requires urgent attention to phase 2 design and implementation.}, } @article {pmid39656857, year = {2024}, author = {Alvarado, M and Gómez-Navajas, JA and Blázquez-Muñoz, MT and Gómez-Molero, E and Fernández-Sánchez, S and Eraso, E and Munro, CA and Valentín, E and Mateo, E and de Groot, PWJ}, title = {The good, the bad, and the hazardous: comparative genomic analysis unveils cell wall features in the pathogen Candidozyma auris typical for both baker's yeast and Candida.}, journal = {FEMS yeast research}, volume = {24}, number = {}, pages = {}, pmid = {39656857}, issn = {1567-1364}, support = {PID2020-117983RB-I00//Agencia Estatal de Investigación/ ; SBPLY/23/180225/000029//UCLM/ ; //European Regional Development Fund/ ; JDC2023-051226-I//European Social Fund Plus/ ; }, mesh = {*Cell Wall/metabolism ; *Saccharomyces cerevisiae/genetics/metabolism ; Computational Biology ; Genomics ; Candida auris/genetics/metabolism/drug effects ; beta-Glucans/metabolism ; Genome, Fungal ; Fungal Proteins/genetics/metabolism ; Glycosylphosphatidylinositols/metabolism/genetics ; Candida albicans/genetics/pathogenicity ; Candida/genetics/metabolism/pathogenicity ; }, abstract = {The drug-resistant pathogenic yeast Candidozyma auris (formerly named Candida auris) is considered a critical health problem of global importance. As the cell wall plays a crucial role in pathobiology, here we performed a detailed bioinformatic analysis of its biosynthesis in C. auris and related Candidozyma haemuli complex species using Candida albicans and Saccharomyces cerevisiae as references. Our data indicate that the cell wall architecture described for these reference yeasts is largely conserved in Candidozyma spp.; however, expansions or reductions in gene families point to subtle alterations, particularly with respect to β--1,3--glucan synthesis and remodeling, phosphomannosylation, β-mannosylation, and glycosylphosphatidylinositol (GPI) proteins. In several aspects, C. auris holds a position in between C. albicans and S. cerevisiae, consistent with being classified in a separate genus. Strikingly, among the identified putative GPI proteins in C. auris are adhesins typical for both Candida (Als and Hyr/Iff) and Saccharomyces (Flo11 and Flo5-like flocculins). Further, 26 putative C. auris GPI proteins lack homologs in Candida genus species. Phenotypic analysis of one such gene, QG37_05701, showed mild phenotypes implicating a role associated with cell wall β-1,3-glucan. Altogether, our study uncovered a wealth of information relevant for the pathogenicity of C. auris as well as targets for follow-up studies.}, } @article {pmid39656589, year = {2024}, author = {Nascimento, F and Özyurt, MG and Halablab, K and Bhumbra, GS and Caron, G and Bączyk, M and Zytnicki, D and Manuel, M and Roselli, F and Brownstone, R and Beato, M}, title = {Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration.}, journal = {Cell reports}, volume = {43}, number = {12}, pages = {115046}, pmid = {39656589}, issn = {2211-1247}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 NS110953/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Motor Neurons/metabolism/pathology ; Mice ; *Homeostasis ; *Disease Models, Animal ; *Spinal Cord/pathology/metabolism ; Synaptic Transmission/physiology ; Receptors, Glycine/metabolism ; Nerve Degeneration/pathology ; Mice, Inbred C57BL ; Renshaw Cells/metabolism ; }, abstract = {In many neurological conditions, early-stage neural circuit adaptation preserves relatively normal behavior. In some diseases, spinal motoneurons progressively degenerate yet movement remains initially preserved. This study investigates whether these neurons and associated microcircuits adapt in a mouse model of progressive motoneuron degeneration. Using a combination of in vitro and in vivo electrophysiology and super-resolution microscopy, we find that, early in the disease, neurotransmission in a key pre-motor circuit, the recurrent inhibition mediated by Renshaw cells, is reduced by half due to impaired quantal size associated with decreased glycine receptor density. This impairment is specific and not a widespread feature of spinal inhibitory circuits. Furthermore, it recovers at later stages of disease. Additionally, an increased probability of release from proprioceptive afferents leads to increased monosynaptic excitation of motoneurons. We reveal that, in this motoneuron degenerative condition, spinal microcircuits undergo specific multiphasic homeostatic compensations that may contribute to preservation of force output.}, } @article {pmid39673573, year = {2024}, author = {Riaz, S and Steinsland, H and Andersen, AZ and Boysen, A and Hanevik, K}, title = {Proportions of IgA antibodies targeting glycosylated epitopes of secreted Escherichia coli mucinase YghJ in initial plasmablast response differ from salivary and intestinally secreted IgA.}, journal = {Medical microbiology and immunology}, volume = {214}, number = {1}, pages = {2}, pmid = {39673573}, issn = {1432-1831}, support = {234364//Research Council of Norway/ ; 234364//Research Council of Norway/ ; 234364//Research Council of Norway/ ; 7041-00220//Innovation Fund Denmark/ ; 7041-00220//Innovation Fund Denmark/ ; }, mesh = {Humans ; Glycosylation ; *Saliva/immunology ; *Epitopes/immunology ; Enterotoxigenic Escherichia coli/immunology ; Escherichia coli Proteins/immunology ; Antibodies, Bacterial/immunology/blood ; Plasma Cells/immunology ; Immunoglobulin A, Secretory/immunology ; Immunoglobulin A/immunology/blood ; Adult ; Male ; Female ; Escherichia coli Infections/immunology ; Young Adult ; }, abstract = {Mucosal infections normally cause an immune response including activation of antigen-specific B cells in regional mucosa-associated lymphoid tissue. After recirculation of plasmablasts, and maturation at mucosal surfaces or bone marrow, plasma cells produce secretory or systemic IgA. It remains uncertain to what extent secretory and systemic IgA share the same target specificities. For vaccine candidate optimization, it is important to know whether IgA targeting of glycosylated epitopes of a protein antigen vary between mucosal and systemic sites. We evaluated glycosylated epitope specificity of systemic and mucosally secreted IgA against YghJ, a potential vaccine candidate antigen secreted by most pathogenic Escherichia coli. IgA from intestinal lavage, saliva, serum, and blood-derived antibody in lymphocyte supernatants (ALS) were collected from 21 volunteers following experimental infection with enterotoxigenic E. coli. Methods for preparing IgA from saliva and ALS were developed, and multiplex bead flow cytometric immunoassays were used to determine levels of IgA targeting natively glycosylated YghJ and estimating what proportion of these antibodies specifically targeted glycosylated epitopes. Following infection, anti-YghJ IgA levels increased substantially for most volunteers across all four specimen types. Target specificity of ALS IgA correlated well with serum IgA, but not with mucosally secreted IgA. Furthermore, glycosylation-specific proportion of salivary IgA was higher than, and did not correlate with, intestinally secreted IgA. These results indicate a new degree of complexity to our understanding of epitope-targeting and tissue specificity of mucosal antibody responses. Our findings also suggest that all features of an intestinal IgA response may not be well reflected in serum, saliva, or ALS, which are commonly used proxy specimens for evaluating intestinal immune responses.}, } @article {pmid39673548, year = {2024}, author = {Alzahrani, AK and Imran, M and Alshrari, AS}, title = {Investigating the impact of SOD1 mutations on amyotrophic lateral sclerosis progression and potential drug repurposing through in silico analysis.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/07391102.2024.2439577}, pmid = {39673548}, issn = {1538-0254}, abstract = {Superoxide dismutase 1 (SOD1) is a vital enzyme responsible for attenuating oxidative stress through its ability to facilitate the dismutation of the superoxide radical into oxygen and hydrogen peroxide. The progressive loss of motor neurons characterize amyotrophic lateral sclerosis (ALS), a crippling neurodegenerative disease that is caused by mutations in the SOD1 gene. In this study, in silico mutational analysis was performed to study the various mutations, the pathogenicity and stability ΔΔG (binding free energy) of the variant of SOD1. x in the protein variant analysis showed a considerable destabilizing effect with a ΔΔG value of -4.2 kcal/mol, signifying a notable impact on protein stability. Molecular dynamics simulations were conducted on both wild-type and C146R mutant SOD1. RMSD profiles indicated that both maintained consistent structural conformation over time. Additionally, virtual screening of 3067 FDA-approved drugs against the mutant SOD1 identified two potential binders, Tucatinib (51039094) and Regorafenib (11167602), which interacted with Leu106, similar to the control drug, Ebselen. Further simulations assessed the dynamic properties of SOD1 in monomeric and dimeric forms while bound to these compounds. 11167602 maintained stable interaction with the monomeric SOD1 mutant, whereas 51039094 and Ebselen dissociated from the monomeric protein's binding site. However, all three compounds were stably bound to the dimeric SOD1. MM/GBSA analysis revealed similar negative binding free energies for 11167602 and 51039094, identifying them as strong binders due to their interaction with Cys111. Experimental validation, including in vitro, cell-based, and in vivo assays are essential to confirm these candidates before advancing to clinical trials.}, } @article {pmid39672239, year = {2025}, author = {Cocozza, G and Busdraghi, LM and Chece, G and Menini, A and Ceccanti, M and Libonati, L and Cambieri, C and Fiorentino, F and Rotili, D and Scavizzi, F and Raspa, M and Aronica, E and Inghilleri, M and Garofalo, S and Limatola, C}, title = {GDF15-GFRAL signaling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis.}, journal = {Brain, behavior, and immunity}, volume = {124}, number = {}, pages = {280-293}, doi = {10.1016/j.bbi.2024.12.010}, pmid = {39672239}, issn = {1090-2139}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Growth Differentiation Factor 15/metabolism/genetics ; Mice ; *Lipid Metabolism/physiology ; *Weight Loss ; *Disease Models, Animal ; *Signal Transduction ; *Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism/genetics ; Humans ; Male ; Mice, Transgenic ; Female ; Brain Stem/metabolism ; Adipose Tissue/metabolism ; Muscular Atrophy/metabolism ; Microglia/metabolism ; Mice, Inbred C57BL ; }, abstract = {Weight loss is a common early sign in amyotrophic lateral sclerosis (ALS) patients and negatively correlates with survival. In different cancers and metabolic disorders, high levels of serum growth differentiation factor 15 (GDF15) contribute to a decrease of food intake and body weight, acting through GDNF family receptor alpha-like (GFRAL). Here we report that GDF15 is highly expressed in the peripheral blood of ALS patients and in the hSOD1[G93A] mouse model and that GFRAL is upregulated in the brainstem of hSOD1[G93A] mice. We demonstrate that the localized GFRAL silencing by shRNA in the area postrema/nucleus tractus solitarius of hSOD1[G93A] mice induces weight gain, reduces adipose tissue wasting, ameliorates the motor function and muscle atrophy and prolongs the survival time. We report that microglial cells could be involved in mediating these effects because their depletion with PLX5622 reduces brainstem GDF15 expression, weight loss and the expression of lipolytic genes in adipose tissue. Altogether these results reveal a key role of GDF15-GFRAL signaling in regulating weight loss and the alteration of and lipid metabolism in the early phases of ALS.}, } @article {pmid39672208, year = {2025}, author = {Liu, Y and Wu, L and Peng, W and Mao, X}, title = {Glial polarization in neurological diseases: Molecular mechanisms and therapeutic opportunities.}, journal = {Ageing research reviews}, volume = {104}, number = {}, pages = {102638}, doi = {10.1016/j.arr.2024.102638}, pmid = {39672208}, issn = {1872-9649}, mesh = {Humans ; Animals ; *Nervous System Diseases/therapy ; *Neuroglia/metabolism/physiology ; Cell Polarity/physiology ; Astrocytes/metabolism/physiology ; }, abstract = {Glial cell polarization plays a pivotal role in various neurological disorders. In response to distinct stimuli, glial cells undergo polarization to either mitigate neurotoxicity or facilitate neural repair following injury, underscoring the importance of glial phenotypic polarization in modulating central nervous system function. This review presents an overview of glial cell polarization, focusing on astrocytes and microglia. It explores the involvement of glial polarization in neurological diseases such as Alzheimer's disease, Parkinson's disease, stroke, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis and meningoencephalitis. Specifically, it emphasizes the role of glial cell polarization in disease pathogenesis through mechanisms including neuroinflammation, neurodegeneration, calcium signaling dysregulation, synaptic dysfunction and immune response. Additionally, it summarizes various therapeutic strategies including pharmacological treatments, dietary supplements and cell-based therapies, aimed at modulating glial cell polarization to ameliorate brain dysfunction. Future research focused on the spatio-temporal manipulation of glial polarization holds promise for advancing precision diagnosis and treatment of neurological diseases.}, } @article {pmid39671529, year = {2024}, author = {Katzman, D and Kalman, G and Almog, O and Fogel, I}, title = {Deployment of Physician Resources and Innovative Medical Strategies in the 2023-2024 Israel-Hamas War: Israel's Strategy to Deliver Advanced Life Support and Whole Blood Transfusion to the Battlefield via Forward Medical Teams and the Impact on the Case Fatality Rate.}, journal = {Military medicine}, volume = {}, number = {}, pages = {}, doi = {10.1093/milmed/usae553}, pmid = {39671529}, issn = {1930-613X}, abstract = {The 2023-2024 Israel-Hamas War, which began following a Hamas attack on Israel on October 7, 2023, has seen a case fatality rate (CFR) among the lowest in the history of warfare. In resultant ground maneuvers, the Israel Defense Forces Medical Corps (IDF-MC) doctrine for the delivery of combat casualty care has been battle tested. We suggest the decreased CFR in part reflects a paradigm shift in combat deployment of medical resources, so as to introduce life-saving strategies not previously seen on the battlefield in large scale to date. These changes, which began in the 2006 Lebanon war and have been in evolution since, include strategic physician deployment to positions more forward than in previous wars and in teams smaller than the previous standard. These forward medical teams have replaced the battalion aid station in the Gaza theater of operations and serve to increase the availability of Advanced Life Support (ALS) level care at the point of injury, wherever a casualty might be on a multidimensional battlefield. These forward medical teams deploy with advanced medical capabilities, including in some cases the ability to transfuse low titer O whole blood. This article reviews aspects of the IDF-MC combat casualty care doctrine as implemented during the current war, the role and advantages of transfusion-capable ALS forward medical teams, and the apparent impact on the CFR thereof.}, } @article {pmid39671291, year = {2024}, author = {Lin, J and Carman, PJ and Gambogi, CW and Kendsersky, NM and Chuang, E and Gates, SN and Yokom, AL and Rizo, AN and Southworth, DR and Shorter, J}, title = {Design principles to tailor Hsp104 therapeutics.}, journal = {Cell reports}, volume = {43}, number = {12}, pages = {115005}, pmid = {39671291}, issn = {2211-1247}, support = {R01 GM099836/GM/NIGMS NIH HHS/United States ; R01 GM110001/GM/NIGMS NIH HHS/United States ; T32 GM008076/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Heat-Shock Proteins/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Adenosine Triphosphate/metabolism ; Saccharomyces cerevisiae Proteins/metabolism/genetics ; HSP40 Heat-Shock Proteins/metabolism/genetics ; HEK293 Cells ; Adenosine Diphosphate/metabolism ; Protein Binding ; }, abstract = {The hexameric AAA+ disaggregase, Hsp104, collaborates with Hsp70 and Hsp40 via its autoregulatory middle domain (MD) to solubilize aggregated proteins. However, how ATP- or ADP-specific MD configurations regulate Hsp104 hexamers remains poorly understood. Here, we define an ATP-specific network of interprotomer contacts between nucleotide-binding domain 1 (NBD1) and MD helix L1, which tunes Hsp70 collaboration. Manipulating this network can (1) reduce Hsp70 collaboration without enhancing activity, (2) generate Hsp104 hypomorphs that collaborate selectively with class B Hsp40s, (3) produce Hsp70-independent potentiated variants, or (4) create species barriers between Hsp104 and Hsp70. Conversely, ADP-specific intraprotomer contacts between MD helix L2 and NBD1 restrict activity, and their perturbation frequently potentiates Hsp104. Importantly, adjusting an NBD1:MD helix L1 rheostat via rational design enables finely tuned collaboration with Hsp70 to safely potentiate Hsp104, minimize off-target toxicity, and counteract FUS and TDP-43 proteinopathies in human cells. Thus, we establish design principles to tailor Hsp104 therapeutics.}, } @article {pmid39671140, year = {2025}, author = {Ikehata, A}, title = {Extension of the molar absorption coefficient for non-ideal mixtures: an application to aqueous monovalent alcohol solutions.}, journal = {Analytical sciences : the international journal of the Japan Society for Analytical Chemistry}, volume = {41}, number = {4}, pages = {353-363}, pmid = {39671140}, issn = {1348-2246}, abstract = {The hydration state of the alcohols was investigated using the extended molar absorption coefficient, which redefines the molar absorption coefficient as a differential coefficient of concentration. The extended molar absorption coefficient is a function of the concentration calculated from the difference in absorbance, and is consistent with the conventional molar absorption coefficient, allowing a complete quantitative comparison. The quantitative performance was verified using IR and NIR absorption spectra of aqueous solutions of monovalent alcohols (methanol, ethanol, 1-propanol, 2-propanol, and tert-butanol) that were soluble in water at any mixing ratio. Extended molar absorption coefficient spectra were calculated for the combination bands of water, which were further separated by multivariate curve resolution-alternating least squares (MCR-ALS) into molecular species with different peak wavenumbers: strongly hydrogen-bonded (SHB), weakly hydrogen-bonded (WHB), and free OH species. The number of water species that change when one alcohol molecule increases, i.e., the perturbed hydration number (PHN), was calculated by comparison with the conventional molar absorption coefficient of pure water. The calculated PHN indicates that the numbers of SHB and WHB species are reversed at approximately 20 wt%, and that the free OH species increase at higher alcohol concentrations and are more pronounced for alcohols with bulky alkyl groups. These results provide a quantitative answer to the long-debated question of anomalies in water-alcohol mixing.}, } @article {pmid39670820, year = {2025}, author = {Lagiakos, HR and Zou, Y and Igawa, H and Therrien, E and Lawrenz, M and Kato, M and Svensson, M and Gray, F and Jensen, K and Dahlgren, MK and Pelletier, RD and Dingley, K and Bell, JA and Liu, Z and Jiang, Y and Zhou, H and Skene, RJ and Nie, Z}, title = {In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {3}, pages = {2720-2741}, doi = {10.1021/acs.jmedchem.4c02074}, pmid = {39670820}, issn = {1520-4804}, mesh = {Animals ; *Neurodegenerative Diseases/drug therapy ; Humans ; Mice ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use/chemical synthesis ; *Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis ; MAP Kinase Kinase Kinases/antagonists & inhibitors/metabolism ; Neurons/drug effects/pathology/metabolism ; Drug Discovery ; Computer Simulation ; Structure-Activity Relationship ; Rats ; }, abstract = {Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge in silico tools. KAI-11101 displayed an excellent in vitro safety profile and showed neuroprotective properties in an ex vivo axon fragmentation assay as well as dose-dependent activity in a mouse PD model.}, } @article {pmid39670434, year = {2024}, author = {Piga, G and Fadda, L and Borghero, G and Maccabeo, A and Pala, F and Murru, MR and Giglio, S and Puligheddu, M and Floris, G}, title = {Semantic behavioral variant frontotemporal dementia and semantic dementia associated with TARDBP mutations.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2439448}, pmid = {39670434}, issn = {2167-9223}, abstract = {Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, characterized by varying clinical and pathological features. TARDBP gene has been described worldwide within the FTD/ALS spectrum but its association with right and left temporal variant of FTD (tvFTD) is still unclear. This study aimed to reclassify a Sardinian FTD cohort according to proposed criteria for the semantic behavioral variant FTD (sbvFTD), explore TARDBP mutations' association with tvFTD, and review related literature. From our FTD cohort of 94 patients, ten fulfilled the criteria for sbvFTD. Therefore, in light of the diagnostic reclassification carried out, we describe the largest series of unrelated patients with TARDBP p.A382T missense mutation, including four new cases of tvFTD: two sbvFTD and two svPPA, exhibiting semantic and behavioral disorders and showing predominant right and left anterior temporal lobe involvement, respectively. We present for the first time two sbvFTD cases carrying the pA382T TARDBP mutation. Comparison with C9orf72 and non-mutated patients revealed lower age at onset (p = 0.006), and a higher prevalence of tvFTD, particularly sbvFTD (p < 0.001), and motor neuron disease in TARDBP carriers (p < 0.001). Our findings along with a review of the literature highlighted TARDBP mutations' association with sbvFTD and semantic dementia, suggesting a genetic role in temporal variants of FTD and emphasizing the need for TARDBP mutation screening in these cases. Reclassifying FTD cohorts, including the sbvFTD phenotype, could aid in better defining the clinical spectrum of tvFTD and guide differential diagnosis across different FTD populations with TARDBP or other FTD-related mutations.}, } @article {pmid39670345, year = {2024}, author = {D'Anna, L and Wragg, D and Mauro, D and Rubino, S and Terenzi, A and Barone, G and Thomas, SR and Casini, A and Bonsignore, R and Spinello, A}, title = {Unraveling the Molecular Basis for G-Quadruplex-Binders to ALS/FTD-Associated G4C2 Repeats of the C9orf72 Gene.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {}, number = {}, pages = {e202400974}, doi = {10.1002/cbic.202400974}, pmid = {39670345}, issn = {1439-7633}, support = {PNRR-M4C2-I1.3//European Union-NextGenerationEU/ ; PE_00000019//European Union-NextGenerationEU/ ; B73C22001250006//European Union-NextGenerationEU/ ; }, abstract = {The most recurrent familial cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the presence of an abnormal number of intronic GGGGCC (G4C2) repetitions in the C9orf72 gene, which has been proposed to drive ALS/FTD pathogenesis. Recently, it has been shown that such G4C2 repetitions can fold into G-quadruplex (G4) secondary structures. These G4s have been selectively stabilized by small-molecule binders, furnishing proof-of-principle that targeting these non-canonical nucleic acid sequences represents a novel and effective therapeutic strategy to tackle neurodegenerative disorders. However, precise information on the mechanism of action of these compounds is still lacking. Here, by performing in silico investigations, we unraveled the molecular basis for the selectivity of a series of known structurally related C9orf72 G4-binders. Moreover, we investigated the binding properties of a strong and selective metal-based G4 stabilizer, the Au[I] bis-N-heterocyclic carbene (NHC) complex - Au(TMX)2 - showing that it moderately stabilizes G4C2 G4 RNA by Förster resonance energy transfer (FRET) DNA melting assays. Using metadynamics (metaD) simulations, the Au(TMX)2 binding mode and the associated free-energy landscape were also evaluated. This information paves the way for developing improved compounds to tackle ALS/FTD neurodegenerative disorders.}, } @article {pmid39670112, year = {2024}, author = {Pinkerton, M and Adler, GL and Ledger, M and Ni, CY and Yang, Y and Tan, RH}, title = {Heterogeneous nuclear ribonucleoprotein D - an understudied subfamily affected in sporadic TDP-43 proteinopathies.}, journal = {Brain communications}, volume = {6}, number = {6}, pages = {fcae352}, pmid = {39670112}, issn = {2632-1297}, abstract = {Despite the recognition that heterogeneous nuclear ribonucleoproteins (hnRNPs) modulate TDP-43 and can limit aberrant splicing events to compensate for TDP-43 loss, their role in TDP-43 proteinopathies remains poorly understood and studies in patient tissue are lacking. This study assesses seven heterogeneous nuclear ribonucleoproteins from the A/B, C, D and H subfamilies in two cortical regions implicated in early TDP-43 dysfunction versus late TDP-43 dysfunction in sporadic amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration. Our results reveal significant nuclear loss of hnRNPD, hnRNPC and hnRNPA1 in the frontal cortex of frontotemporal lobar degeneration compared to amyotrophic lateral sclerosis but not in the motor cortical neurons or Betz cells of amyotrophic lateral sclerosis cases. Cytoplasmic co-occurrence was observed between hnRNPA1 and hnRNPC but not with phosphorylated TDP-43 (pTDP-43). Interestingly, nuclear hnRNPD loss associated with increasing cytoplasmic pTDP-43, highlighting an understudied subfamily in sporadic TDP-43 proteinopathies. In summary, this study identifies the nuclear loss of hnRNPD, C and A1 in a predilection brain region of TDP-43 in frontotemporal lobar degeneration compared to amyotrophic lateral sclerosis cases without significant pTDP-43 in this region. This highlights the need for further investigation into the involvement of these heterogeneous nuclear ribonucleoproteins in disease pathogenesis and potential to serve as modulatory targets and/or proximal markers of TDP-43 dysfunction in sporadic TDP-43 proteinopathies.}, } @article {pmid39669591, year = {2024}, author = {Beauregard-Lacroix, É and Scott, A and Nguyen, TTM and Wierenga, KJ and Purcarin, G and Karstensen, AB and Carvalho, DR and Alessandri, JL and Payet, F and Girisha, KM and Ferron, M and Campeau, PM}, title = {Exploring the phenotypic spectrum and osteopenia mechanisms in Yunis-Varón syndrome.}, journal = {Genetics in medicine open}, volume = {2}, number = {}, pages = {101837}, pmid = {39669591}, issn = {2949-7744}, abstract = {PURPOSE: Biallelic variants in FIG4 or VAC14 are associated with Yunis-Varón syndrome (YVS), which is characterized by multisystem involvement including skeletal findings, craniofacial dysmorphisms and central nervous system anomalies. Pathogenic variants in those same genes have also been associated with a predominantly neurological phenotype and with nonsyndromic conditions, such as Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. By describing 5 new cases of FIG4-associated YVS and reviewing the literature, we better delineate the clinical phenotype associated with loss of function of those genes. We also explore osteopenia mechanisms by assessing bone physiologic parameters in a mouse model.

METHODS: Exome sequencing or Sanger sequencing was performed in 5 unrelated individuals. Bone histomorphometry was performed in Fig4 [plt/plt] mice and compared with wild type. Relevant literature from the last 10 years was reviewed.

RESULTS: All individuals presented a phenotype overlapping the typical YVS and the brain anomalies and neurologic syndrome. Clinical features included developmental delay, structural brain malformations, and skeletal anomalies, such as osteopenia. Biallelic FIG4 variants were identified in each individual. In mice, bone histomorphometry parameters suggested that osteopenia might be secondary to reduced bone formation rather than increased bone degradation.

CONCLUSION: This study contributes to a better understanding of the phenotypic variability caused by pathogenic variants in FIG4 or VAC14 and suggests an important overlap between previously described phenotypes. The brain anomalies and neurologic syndrome is likely in the same spectrum as classical YVS. Further studies are still needed to clarify the effects of partial loss-of-function (hypomorphic) variants and to identify genotype-phenotype correlations.}, } @article {pmid39669124, year = {2024}, author = {Mirceta, M and Schmidt, MHM and Shum, N and Prasolava, TK and Meikle, B and Lanni, S and Mohiuddin, M and McKeever, PM and Zhang, M and Liang, M and van der Werf, I and Scheers, S and Dion, PA and Wang, P and Wilson, MD and Abell, T and Philips, EA and Sznajder, ŁJ and Swanson, MS and Mehkary, M and Khan, M and Yokoi, K and Jung, C and de Jong, PJ and Freudenreich, CH and McGoldrick, P and Yuen, RKC and Abrahão, A and Keith, J and Zinman, L and Robertson, J and Rogaeva, E and Rouleau, GA and Kooy, RF and Pearson, CE}, title = {C9orf72 repeat expansion creates the unstable folate-sensitive fragile site FRA9A.}, journal = {NAR molecular medicine}, volume = {1}, number = {4}, pages = {ugae019}, pmid = {39669124}, issn = {2976-856X}, support = {P50 NS048843/NS/NINDS NIH HHS/United States ; R01 GM122880/GM/NIGMS NIH HHS/United States ; R35 GM144215/GM/NIGMS NIH HHS/United States ; U54 NS048843/NS/NINDS NIH HHS/United States ; }, abstract = {The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. C9orf72Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immunostimulatory or damaged DNA is unknown. Here, we show C9orf72Exp in pre-symptomatic and amyotrophic lateral sclerosis-frontotemporal dementia patient cells and brains cause the folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33 kb of C9orf72 as highly compacted chromatin embedded in an 8.2 Mb fragility zone spanning 9p21, encompassing 46 genes, making FRA9A one of the largest fragile sites. C9orf72Exp cells show chromosomal instability, heightened global- and Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s and Chr9-containing micronuclei, providing endogenous sources of damaged and immunostimulatory DNA. Cells from one C9orf72Exp patient contained a highly rearranged FRA9A-expressing Chr9 with Chr9-wide dysregulated gene expression. Somatic C9orf72Exp repeat instability and chromosomal fragility are sensitive to folate deficiency. Age-dependent repeat instability, chromosomal fragility and chromosomal instability can be transferred to CNS and peripheral tissues of transgenic C9orf72Exp mice, implicating C9orf72Exp as the source. Our results highlight unappreciated effects of C9orf72 expansions that trigger vitamin-sensitive chromosome fragility, adding structural variations to the disease-enriched 9p21 locus, and likely elsewhere.}, } @article {pmid39667814, year = {2025}, author = {Rousseau, JA and Maier, M and Ait-Mohand, S and Dumulon-Perreault, V and Sarrhini, O and Tremblay, S and Rousseau, E and Salzmann, M and Guérin, B}, title = {Antibody-Based PET Imaging of Misfolded Superoxide Dismutase 1 in an Amyotrophic Lateral Sclerosis Mouse Model.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {66}, number = {1}, pages = {130-135}, pmid = {39667814}, issn = {1535-5667}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Mice ; *Superoxide Dismutase-1/metabolism/genetics ; *Positron-Emission Tomography/methods ; *Disease Models, Animal ; *Zirconium/chemistry ; Protein Folding ; Mice, Transgenic ; Deferoxamine/chemistry ; Antibodies/chemistry ; Radioisotopes ; Tissue Distribution ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease characterized by motor neuron loss in the motor cortex, brain stem, and spinal cord. Mutations in the superoxide dismutase 1 (SOD1) gene, resulting in misfolding of its protein product, are a common cause of ALS. Currently, there is no approved ALS diagnostic tool. Here, we present the development of a PET radiotracer, [[89]Zr]Zr-desferoxamine (DFO)-α-miSOD1, targeting selectively misfolded SOD1 (misSOD1). Methods: DFO-α-miSOD1 was prepared by conjugating α-miSOD1 antibody with DFO and labeled with [89]Zr. A longitudinal imaging study was performed to identify the optimal mouse age and time after administration of [[89]Zr]Zr-DFO-α-miSOD1 for the detection of misSOD1 aggregation in transgenic mice overexpressing misSOD1 and in wild-type mice. Subsets of mice were either coinjected with an excess of α-miSOD1 or imaged with deglycosylated [[89]Zr]Zr-DFO-α-miSOD1 to assess target specificity. The internal radiation dose for [[89]Zr]Zr-DFO-α-miSOD1 was estimated by extrapolating data from mouse biodistribution experiments. Results: Imaging with [[89]Zr]Zr-DFO-α-miSOD1 was optimal in 136-d-old transgenic mice on day 10 after administration. Significant accumulation of [[89]Zr]Zr-DFO-α-miSOD1 was detected in the spinal cord and cartilage of ALS transgenic mice compared with the wild-type mice (P = 0.01). The radiotracer accumulation is selective and blockable with an excess of α-miSOD1. Deglycosylated [[89]Zr]Zr-DFO-α-miSOD1 results in high-contrast detection of misSOD1 but is prone to aggregation. The dosimetry for [[89]Zr]Zr-DFO-α-miSOD1 is comparable to that for other [89]Zr-based tracers currently used in humans. Conclusion: This work thus establishes that [[89]Zr]Zr-DFO-α-miSOD1 PET can detect misSOD1 in transgenic mice, paving the way for application in early diagnosis of ALS and therapeutic monitoring.}, } @article {pmid39667295, year = {2025}, author = {Spencer, PS and Berntsson, SG and Buguet, A and Butterfield, P and Calne, DB and Calne, SM and Giménez-Roldán, S and Hugon, J and Kahlon, S and Kisby, GE and Lagrange, E and Landtblom, AE and Ludolph, AC and Nunn, PB and Palmer, VS and Reis, J and Román, GC and Sipilä, JOT and Spencer, SS and Angues, RV and Vernoux, JP and Yabushita, M}, title = {Brain health: Pathway to primary prevention of neurodegenerative disorders of environmental origin.}, journal = {Journal of the neurological sciences}, volume = {468}, number = {}, pages = {123340}, doi = {10.1016/j.jns.2024.123340}, pmid = {39667295}, issn = {1878-5883}, mesh = {Humans ; *Neurodegenerative Diseases/epidemiology/prevention & control/etiology ; *Primary Prevention/methods ; Brain ; Environmental Exposure/adverse effects ; Amyotrophic Lateral Sclerosis/epidemiology/prevention & control ; Environment ; }, abstract = {While rising global rates of neurodegenerative disease encourage early diagnosis and therapeutic intervention to block clinical expression (secondary prevention), a more powerful approach is to identify and remove environmental factors that trigger long-latencybrain disease (primary prevention) by acting on a susceptible genotype or acting alone. The latter is illustrated by the post-World War II decline and disappearance of Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC), a prototypical often-familial neurodegenerative disease formerly present in very high incidence on the island of Guam. Lessons learned from 75 years of investigation on the etiology of ALS/PDC include: the importance of focusing field research on the disease epicenter and patients with early-onset disease; soliciting exposure history from patients, family, and community to guide multidisciplinary biomedical investigation; recognition that disease phenotype may vary with exposure history, and that familial brain disease may have a primarily environmental origin. Furthermore, removal from exposure to the environmental trigger effects primary disease prevention.}, } @article {pmid39666202, year = {2024}, author = {van Eijk, RPA and van Loon, FT and van Unnik, JWJ and Weemering, DN and Seitidis, G and Mavridis, D and van den Berg, LH and Nikolakopoulos, S}, title = {Attrition and discontinuation in amyotrophic lateral sclerosis clinical trials: a meta-analysis.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {40}, pmid = {39666202}, issn = {1432-1459}, support = {EVIDENCE//Stichting ALS Nederland/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Randomized Controlled Trials as Topic ; Patient Dropouts/statistics & numerical data ; }, abstract = {OBJECTIVES: Attrition due to adverse events and disease progression impacts the integrity and generalizability of clinical trials. The aim of this study is to provide evidence-based estimates of attrition for clinical trials in amyotrophic lateral sclerosis (ALS), and identify study-related predictors, through a comprehensive systematic review and meta-analysis.

METHODS: We systematically reviewed the literature to identify all randomized, placebo-controlled clinical trials in ALS and determined the number of patients who discontinued the study per randomized arm. Subsequently, we meta-analyzed attrition rates across studies, evaluated the difference between study arms, and explored the impact of study-level characteristics. Finally, a meta-regression model predicting study discontinuation for future clinical trials was translated into a web application.

RESULTS: In total, 60 randomized placebo-controlled clinical trials were included in the meta-analysis, randomizing 14,493 patients with ALS. Attrition varied significantly between studies, ranging from 3.1% to 75.7% of all randomized patients, with a pooled effect of 32.0% (90% prediction interval 6.1% to 66.3%). Attrition was similar between the intervention and placebo arm (odds ratio 1.08, 95% CI 0.89 to 1.31, p = 0.43). The follow-up duration was identified as the sole study-level predictor (0.032, 95% CI 0.026 to 0.039, p < 0.001), resulting in predicted attrition of 19.3% for 6-month, 36.4% for 12-month, and 55.6% for 18-month clinical trials.

CONCLUSIONS: ALS clinical trials encounter high attrition, which increases with the follow-up duration. These findings underscore the need to refine our strategies to manage attrition, preserving the integrity and generalizability of ALS clinical trials.}, } @article {pmid39666144, year = {2024}, author = {Levison, LS and Blicher, JU and Andersen, H}, title = {Incidence and mortality of ALS: a 42-year population-based nationwide study.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {44}, pmid = {39666144}, issn = {1432-1459}, support = {A3520//Health Research Fund of Central Denmark Region/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/mortality ; Male ; Female ; Incidence ; Middle Aged ; Denmark/epidemiology ; Aged ; Adult ; Aged, 80 and over ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND AND AIM: Recent studies have suggested that the incidence rate (IR) and the rate of death (MR) of amyotrophic lateral sclerosis (ALS) are increasing. Still, it remains unclear whether this is due to improved case ascertainment or represents a true increase. We examined the development in the incidence and mortality of ALS in Denmark for 42 years.

METHODS: We retrieved individual-level data of all patients aged above 18 years with first-time ALS diagnosed at any Danish department of neurology. The IR and MR were calculated based on data from 1980 to 2021, stratified by gender and age.

RESULTS: We identified 5,943 patients with ALS and identified a total of 5,069 deaths in the nationwide population. Overall, the IR was 3.4 per 100,000 persons per year (95% CI 3.4-3.5). ALS incidence rose gradually during the study period, and the IR was 2.8 times higher (95% CI 2.4-3.2) when comparing the latest period (2018-2021) with the first (1980-1983). Parallel to the IR, the MR increased over time and was associated with male gender and rose with age at diagnosis, peaking in the 70-79-year age group.

CONCLUSION: In Denmark, the IR and MR of ALS increased threefold from 1980 to 2021, with steadily increasing risk related to male gender and in particular to higher age. Considering our aging societies, the number of elderly patients with ALS can be expected to increase considerably.}, } @article {pmid39666121, year = {2024}, author = {Okubo, S and Naruse, H and Ishiura, H and Sudo, A and Esaki, K and Mitsui, J and Matsukawa, T and Satake, W and Greimel, P and Shingai, N and Oya, Y and Yoshikawa, T and Tsuji, S and Toda, T}, title = {Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {36}, pmid = {39666121}, issn = {1432-1459}, support = {JPMH23FC1008//Ministry of Health, Labour and Welfare/ ; JP23ek0109673//Japan Agency for Medical Research and Development/ ; JP23ek0109617//Japan Agency for Medical Research and Development/ ; JP23ek0109631//Japan Agency for Medical Research and Development/ ; JP24K18698//Japan Society for the Promotion of Science/ ; JP23K27514//Japan Society for the Promotion of Science/ ; 21K07512//Japan Society for the Promotion of Science/ ; Glyco-lipidologue Initiative Program//RIKEN/ ; }, mesh = {Adolescent ; Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/blood ; Mutation ; Pedigree ; *Serine C-Palmitoyltransferase/genetics ; Sphingolipids/blood ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the motor system. Pathogenic variants in SPTLC1, encoding a subunit of serine palmitoyltransferase, cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), and have recently been associated with juvenile ALS. SPTLC1 variants associated with ALS cause elevated levels of sphinganines and ceramides. Reports on ALS associated with SPTLC1 remain limited. This study aimed to investigate the frequency of SPTLC1 variants in ALS and relevant clinical characteristics.

METHODS: We analyzed whole-exome and whole-genome sequence data from 40 probands with familial ALS and 413 patients with sporadic ALS without previously identified causative variants. Reverse transcription polymerase chain reaction (RT-PCR) analysis and droplet digital PCR (ddPCR) were used to assess splicing and mosaicism, respectively. Plasma sphingolipid levels were quantified to analyze biochemical consequences.

RESULTS: The heterozygous c.58G>A, p.Ala20Thr variant was identified in a 21-year-old Japanese female patient presenting with symmetric weakness which slowly progressed over 15 years. RT-PCR analysis showed no splice defects. Plasma sphingolipid levels in the patient were significantly increased compared to her asymptomatic parents. ddPCR revealed that the asymptomatic father harbored a mosaic variant with 17% relative mutant allele abundance in peripheral blood leukocytes.

CONCLUSIONS: We identified a pathogenic c.58G>A, p.Ala20Thr SPTLC1 variant in a patient with juvenile ALS, likely inherited from an asymptomatic parent with mosaicism. Lipid analysis results are consistent with previous findings on SPTLC1-associated ALS. Further studies are necessary to determine the clinical effect of mosaic variants of SPTLC1.}, } @article {pmid39666115, year = {2024}, author = {Psychogios, I and Hu, Y and Seitz, C and Joyce, EE and Lovik, A and Ingre, C and Fang, F}, title = {Exploring clinical chemistry markers in amyotrophic lateral sclerosis: insights into survival and disease trajectories.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {7}, pmid = {39666115}, issn = {1432-1459}, support = {2019-01088//Swedish Research Council/ ; 2023-02428//Swedish Research Council/ ; MegaALS 802091//European Research Council Starting Grant/ ; R01 TS000324/TS/ATSDR CDC HHS/United States ; R01TS000324-01-00/CC/CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; *Biomarkers/blood ; Aged ; *Disease Progression ; Cohort Studies ; Sweden ; Adult ; Prognosis ; }, abstract = {OBJECTIVE: Commonly measured clinical chemistry markers might be indicative of survival and disease progression in amyotrophic lateral sclerosis (ALS).

METHODS: In a cohort study of 270 ALS patients diagnosed from April 2014 to May 2021 in Stockholm, Sweden, we examined the link between 29 clinical chemistry markers at diagnosis and mortality risk at 6 months, 1 year, and 3 years after diagnosis. Summary variables from exploratory factor analysis (EFA) assessed the markers' collective impact on survival. We integrated ALS functional rating scale-revised (ALSFRS-R) scores with survival data using a joint latent class model to identify patterns of functional decline. Multinomial logistic regression determined how the EFA-derived factors predicted the decline trajectories post-diagnosis.

RESULTS: Higher levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, and albumin at diagnosis were linked to lower mortality in ALS patients, while increased neurofilament light chain (NfL), leukocyte count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and carbon dioxide (CO2) levels indicated higher mortality. The 'Red blood cell profile' factor, derived from EFA, emerged as a significant predictor of survival, independent of other prognostic indicators. The joint latent class model identified three distinct patient groups based on functional decline, with 'Red blood cell profile' suggesting a lower likelihood of being in the groups with slower progression.

CONCLUSION: Clinical chemistry markers, including NfL, lipids, albumin, leukocyte count, MCV, MCH, CO2, and the 'Red blood cell profile,' were associated with ALS survival. As these markers represent broader bodily functions, integrating them in ALS patient care could improve disease management.}, } @article {pmid39666103, year = {2024}, author = {Zimmermann, M and Mengel, D and Raupach, K and Haack, T and Neumann, M and Synofzik, M}, title = {Frequency and neuropathology of HTT repeat expansions in FTD/ALS: co-existence rather than causation.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {58}, pmid = {39666103}, issn = {1432-1459}, mesh = {Humans ; *Frontotemporal Dementia/genetics/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Male ; Female ; *Huntingtin Protein/genetics ; Middle Aged ; Aged ; *Trinucleotide Repeat Expansion/genetics ; Brain/pathology/diagnostic imaging ; }, abstract = {INTRODUCTION: While ≥ 40 CAG repeat expansions in HTT present a well-established cause of Huntington's disease (HD), an enrichment of HTT repeat expansions was recently reported also in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including FTD/ALS patients with additional HD neuropathology. This raises the question whether the phenotypic spectrum of HTT expansions can be extended to ALS and FTD, and whether HTT should be considered as a new causative gene of FTD/ALS. If HTT repeat expansions were indeed systematically related to FTD/ALS, one would expect an increased frequency of HTT carriers in FTD/ALS, who can clinically/neuropathologically not be explained better than by the presence of the HTT repeat expansions.

METHODS: Screening of HTT repeat expansions in 249 consecutive patients with ALS or FTD by short-read genome sequencing took place. The post-mortem neuropathological examination was performed in the identified HTT repeat expansion carrier.

RESULTS: One HTT repeat expansion [40/22 repeats (± 1)] was identified in an ALS patient, giving a frequency of 0.4% (1/249) (frequency in the general population: 0.03-0.18%). This patient showed a classic ALS phenotype, but no clinical or imaging signs of HD. Post-mortem brain examination revealed-in addition to ALS-typical degeneration of upper and lower motor neurons with TDP-43 inclusions-HD-typical polyQ-aggregates in gyrus cinguli, striatum and frontal lobe, yet without evidence of striatal degeneration.

CONCLUSIONS: Our study does not support the notion of an increased frequency of HTT repeat expansions in FTD/ALS. Moreover, the phenotype of the HTT carrier identified can be better explained by two co-existent, but independent diseases: (i) ALS and (ii) presymptomatic HD, which-given the low repeat number-is likely to become manifest only later in life. These findings corroborate the concept that HTT repeat expansions are likely co-existent/coincidental, but not causative in FTD/ALS.}, } @article {pmid39666071, year = {2024}, author = {de Boer, EMJ and de Vries, BS and Van Hecke, W and Mühlebner, A and Vincken, KL and Mol, CP and van Rheenen, W and Westeneng, HJ and Veldink, JH and Höglinger, GU and Morris, HR and Litvan, I and Raaphorst, J and Ticozzi, N and Corcia, P and Vandenberghe, W and Pijnenburg, YAL and Seelaar, H and Ingre, C and Van Damme, P and van den Berg, LH and van de Warrenburg, BPC and van Es, MA}, title = {Diagnosing primary lateral sclerosis: a clinico-pathological study.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {46}, pmid = {39666071}, issn = {1432-1459}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/diagnosis/pathology/genetics ; Autopsy ; Brain/pathology/diagnostic imaging ; Diagnosis, Differential ; *Motor Neuron Disease/diagnosis/pathology ; }, abstract = {BACKGROUND: Primary lateral sclerosis (PLS) is a rare motor neuron disease characterized by upper motor neuron degeneration, diagnosed clinically due to the absence of a (neuropathological) gold standard. Post-mortem studies, particularly TDP-43 pathology analysis, are limited.

METHODS: This study reports on 5 cases in which the diagnostic criteria for PLS were met, but in which neuropathology findings showed (partially) conflicting results. These discrepancies prompted us to perform a clinico-pathology study focussing on diagnostic challenges and accuracy in PLS. To this end, all cases were reviewed by an international panel of 11 experts using an e-module and structured questionnaires.

RESULTS: Autopsy exhibited neuropathological findings consistent with amyotrophic lateral sclerosis (ALS) in one case, while two cases exhibited similar, but more limited lower motor neuron involvement, hinting at PLS or ALS overlap. Another case displayed tau-pathology indicative of progressive supranuclear palsy. The final case displayed extensive myelin loss without a proteinopathy or a clear diagnosis. The expert panel identified 24 different ancillary investigations lacking across cases (e.g. genetic testing, DAT scans, neuropsychological evaluation), listed 28 differential diagnoses, and identified 13 different conditions as the most likely diagnosis. Autopsy results led panel members to change their final diagnosis in 42% of the cases.

CONCLUSIONS: This study underscores the diagnostic challenges posed by diverse underlying pathologies resulting in upper motor neuron phenotypes. Despite adhering to the same diagnostic criteria, consensus amongst experts was limited. Ensuring the diagnostic consistency is crucial for advancing understanding and treatment of PLS. Explicit guidelines for excluding potential mimics along with a neuropathological gold standard are imperative.}, } @article {pmid39665821, year = {2025}, author = {Serneels, PJ and De Schutter, JD and De Groef, L and Moons, L and Bergmans, S}, title = {Oligodendroglial heterogeneity in health, disease, and recovery: deeper insights into myelin dynamics.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3179-3192}, pmid = {39665821}, issn = {1673-5374}, abstract = {Decades of research asserted that the oligodendroglial lineage comprises two cell types: oligodendrocyte precursor cells and oligodendrocytes. However, recent studies employing single-cell RNA sequencing techniques have uncovered novel cell states, prompting a revision of the existing terminology. Going forward, the oligodendroglial lineage should be delineated into five distinct cell states: oligodendrocyte precursor cells, committed oligodendrocyte precursor cells, newly formed oligodendrocytes, myelin-forming oligodendrocytes, and mature oligodendrocytes. This new classification system enables a deeper understanding of the oligodendroglia in both physiological and pathological contexts. Adopting this uniform terminology will facilitate comparison and integration of data across studies. This, including the consolidation of findings from various demyelinating models, is essential to better understand the pathogenesis of demyelinating diseases. Additionally, comparing injury models across species with varying regenerative capacities can provide insights that may lead to new therapeutic strategies to overcome remyelination failure. Thus, by standardizing terminology and synthesizing data from diverse studies across different animal models, we can enhance our understanding of myelin pathology in central nervous system disorders such as multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis, all of which involve oligodendroglial and myelin dysfunction.}, } @article {pmid39664805, year = {2025}, author = {Xing, H and McGregor, SKM and Batista, BD and Whitefield, C and Stone, ISJ and Murray, CE and Hurst, RM and Liu, Y and Chow, S and Fahrenhorst-Jones, T and Zhao, Q and Houston, SD and Hu, SH and Lonhienne, T and Nouwens, A and Burns, JM and Savage, GP and Walter, GH and Guddat, LW and Rafter, MA and Williams, CM}, title = {In search of herbistasis: COT-metsulfuron methyl displays rare herbistatic properties.}, journal = {Chemical science}, volume = {16}, number = {2}, pages = {649-658}, pmid = {39664805}, issn = {2041-6520}, abstract = {Weed management is an essential intervention for maintaining food security and protecting biodiversity but is heavily reliant on chemical control measures (i.e., herbicides). Concerningly, only one herbicide has been developed with a new mode of action (MOA) since the 1980s. Therefore, alternative strategies for preventing weed growth need to be explored. The lesser-known concept of halting weed growth through herbistasis could be one strategy to alleviate the lack of success in obtaining new MOA leads, but this type of activity has rarely been investigated. Herein reported is a bioisosteric cyclooctatetraene (COT) for phenyl ring replacement tactic, using the commercial acetolactate synthase (ALS) inhibitor metsulfuron methyl, that has unearthed a rare agent displaying herbistatic properties against the weed, Cryptostegia grandiflora (rubber vine).}, } @article {pmid39664295, year = {2024}, author = {Chen, LX and Zhang, MD and Xu, HF and Ye, HQ and Chen, DF and Wang, PS and Bao, ZW and Zou, SM and Lv, YT and Wu, ZY and Li, HF}, title = {Single-Nucleus RNA Sequencing Reveals the Spatiotemporal Dynamics of Disease-Associated Microglia in Amyotrophic Lateral Sclerosis.}, journal = {Research (Washington, D.C.)}, volume = {7}, number = {}, pages = {0548}, pmid = {39664295}, issn = {2639-5274}, abstract = {Disease-associated microglia (DAM) are observed in neurodegenerative diseases, demyelinating disorders, and aging. However, the spatiotemporal dynamics and evolutionary trajectory of DAM during the progression of amyotrophic lateral sclerosis (ALS) remain unclear. Using a mouse model of ALS that expresses a human SOD1 gene mutation, we found that the microglia subtype DAM begins to appear following motor neuron degeneration, primarily in the brain stem and spinal cord. Using reverse transcription quantitative polymerase chain reaction, RNAscope in situ hybridization, and flow cytometry, we found that DAM increased in number as the disease progressed, reaching their peak in the late disease stage. DAM responded to disease progression in both SOD1[G93A] mice and sporadic ALS and C9orf72-mutated patients. Motor neuron loss in SOD1[G93A] mice exhibited 2 accelerated phases: P90 to P110 (early stage) and P130 to P150 (late stage). Some markers were synchronized with the accelerated phase of motor neuron loss, suggesting that these proteins may be particularly responsive to disease progression. Through pseudotime trajectory analysis, we tracked the dynamic transition of homeostatic microglia into DAM and cluster 6 microglia. Interestingly, we used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia in SOD1[G93A] mice and observed that DAM survival is independent of CSF1R. An in vitro phagocytosis assay directly confirmed that DAM could phagocytose more beads than other microglia subtypes. These findings reveal that the induction of the DAM phenotype is a shared cross-species and cross-subtype characteristic in ALS. Inducing the DAM phenotype and enhancing its function during the early phase of disease progression, or the time window between P130 and P150 where motor neuron loss slows, could serve as a neuroprotective strategy for ALS.}, } @article {pmid39663989, year = {2025}, author = {Das, U and Gayan, A and Biswas, R}, title = {A highly sensitive facile plasmonic scheme for assessment of melamine in raw milk.}, journal = {Analytical methods : advancing methods and applications}, volume = {17}, number = {3}, pages = {552-561}, doi = {10.1039/d4ay01764a}, pmid = {39663989}, issn = {1759-9679}, mesh = {*Triazines/chemistry/analysis ; *Milk/chemistry ; Animals ; *Metal Nanoparticles/chemistry ; *Gold/chemistry ; *Silver/chemistry ; Food Contamination/analysis ; Limit of Detection ; Colorimetry/methods ; }, abstract = {This work presents two novel devices with a microcontroller and two different light sensors, namely, Light Dependent Resistor (LDR) and Ambient Light Sensor (ALS), which can provide a quantitative output from the colorimetric variations of citrate capped borohydride reduced silver nanoparticles (AgNPs) and citrate capped gold nanoparticles (AuNPs) upon addition of melamine adulterated milk. The limit of detection (LOD) of the LDR setup with AgNPs and AuNPs was found to be 1.24 ppm and 1.68 ppm, respectively, and the corresponding recovery rates were 92.86% and 88.57%, respectively. The device fabricated with the ALS with AgNPs displayed a recovery rate of 97.14% with a LOD value of 0.64 ppm.}, } @article {pmid39662855, year = {2025}, author = {Yang, ZF and Jiang, XC and Gao, JQ}, title = {Present insights into the progress in gene therapy delivery systems for central nervous system diseases.}, journal = {International journal of pharmaceutics}, volume = {669}, number = {}, pages = {125069}, doi = {10.1016/j.ijpharm.2024.125069}, pmid = {39662855}, issn = {1873-3476}, mesh = {Humans ; *Genetic Therapy/methods ; *Central Nervous System Diseases/therapy ; Animals ; *Gene Transfer Techniques ; *Genetic Vectors/administration & dosage ; Dependovirus/genetics ; }, abstract = {Central nervous system (CNS) diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), spinal cord injury (SCI), and ischemic strokes and certain rare diseases, such as amyotrophic lateral sclerosis (ALS) and ataxia, present significant obstacles to treatment using conventional molecular pharmaceuticals. Gene therapy, with its ability to target previously "undruggable" proteins with high specificity and safety, is increasingly utilized in both preclinical and clinical research for CNS ailments. As our comprehension of the pathophysiology of these conditions deepens, gene therapy stands out as a versatile and promising strategy with the potential to both prevent and treat these diseases. Despite the remarkable progress in refining and enhancing the structural design of gene therapy agents, substantial obstacles persist in their effective and safe delivery within living systems. To surmount these obstacles, a diverse array of gene delivery systems has been devised and continuously improved. Notably, Adeno-Associated Virus (AAVs)-based viral gene vectors and lipid-based nanocarriers have each advanced the in vivo delivery of gene therapies to various extents. This review aims to concisely summarize the pathophysiological foundations of CNS diseases and to shed light on the latest advancements in gene delivery vector technologies. It discusses the primary categories of these vectors, their respective advantages and limitations, and their specialized uses in the context of gene therapy delivery.}, } @article {pmid39662651, year = {2025}, author = {Keethedeth, N and Anantha Shenoi, R}, title = {Mitochondria-targeted nanotherapeutics: A new frontier in neurodegenerative disease treatment.}, journal = {Mitochondrion}, volume = {81}, number = {}, pages = {102000}, doi = {10.1016/j.mito.2024.102000}, pmid = {39662651}, issn = {1872-8278}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Mitochondria/drug effects/metabolism ; Drug Delivery Systems ; Nanoparticles/chemistry ; Animals ; }, abstract = {Mitochondria are the seat of cellular energy and play key roles in regulating several cellular processes such as oxidative phosphorylation, respiration, calcium homeostasis and apoptotic pathways. Mitochondrial dysfunction results in error in oxidative phosphorylation, redox imbalance, mitochondrial DNA mutations, and disturbances in mitochondrial dynamics, all of which can lead to several metabolic and degenerative diseases. A plethora of studies have provided evidence for the involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Hence mitochondria have been used as possible therapeutic targets in the regulation of neurodegenerative diseases. However, the double membranous structure of mitochondria poses an additional barrier to most drugs even if they are able to cross the plasma membrane. Most of the drugs acting on mitochondria also required very high doses to exhibit the desired mitochondrial accumulation and therapeutic effect which in-turn result in toxic effects. Mitochondrial targeting has been improved by direct conjugation of drugs to mitochondriotropic molecules like dequalinium (DQA) and triphenyl phosphonium (TPP) cations. But being cationic in nature, these molecules also exhibit toxicity at higher doses. In order to further improve the mitochondrial localization with minimal toxicity, TPP was conjugated with various nanomaterials like liposomes. inorganic nanoparticles, polymeric nanoparticles, micelles and dendrimers. This review provides an overview of the role of mitochondrial dysfunction in neurodegenerative diseases and various nanotherapeutic strategies for efficient targeting of mitochondria-acting drugs in these diseases.}, } @article {pmid39662532, year = {2025}, author = {Bayansan, O and Bhan, P and Chang, CY and Barmaver, SN and Shen, CP and Wagner, OI}, title = {UNC-10/SYD-2 links kinesin-3 to RAB-3-containing vesicles in the absence of the motor's PH domain.}, journal = {Neurobiology of disease}, volume = {204}, number = {}, pages = {106766}, doi = {10.1016/j.nbd.2024.106766}, pmid = {39662532}, issn = {1095-953X}, mesh = {Animals ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Caenorhabditis elegans/metabolism ; *rab3 GTP-Binding Proteins/metabolism/genetics ; *Synaptic Vesicles/metabolism ; Kinesins/metabolism/genetics ; Intracellular Signaling Peptides and Proteins/metabolism/genetics ; Animals, Genetically Modified ; Pleckstrin Homology Domains ; Nerve Tissue Proteins ; Intercellular Signaling Peptides and Proteins ; }, abstract = {Kinesin-3 KIF1A (UNC-104 in C. elegans) is the major axonal transporter of synaptic vesicles and mutations in this molecular motor are linked to KIF1A-associated neurological disorders (KAND), encompassing Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis and hereditary spastic paraplegia. UNC-104 binds to lipid bilayers of synaptic vesicles via its C-terminal PH (pleckstrin homology) domain. Since this interaction is relatively weak and non-specific, we hypothesize that other, more specific, interaction schemes exist. From the literature, it is evident that UNC-104 regulator SYD-2 interacts with UNC-10 and that UNC-10 itself interacts with RAB-3 bound to synaptic vesicles. RT-PCR and Western blot experiments expose genetic relationships between unc-10 and syd-2, but not between unc-10 and rab-3. Also, neither unc-10 nor rab-3 affects UNC-104 expression. However, co-immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays reveal functional interactions between UNC-104, SYD-2, UNC-10 and RAB-3. Though both SNB-1 and RAB-3 are actively transported by UNC-104, motility of RAB-3 is facilitated in the presence of SYD-2 and UNC-10. Deletion of UNC-104's PH domain did not affect UNC-104/RAB-3 colocalization, but significantly affected UNC-104/SNB-1 colocalization. Similarly, motility of RAB-3-labeled vesicles is only slightly altered in nematodes carrying a point mutation in the PH domain, whereas movement of SNB-1 is significantly reduced in this mutant. Western blots from purified fractions of synaptic vesicles reveal strong reduction of UNC-104 in rab-3/unc-10 double mutants. Our findings suggest that the UNC-10/SYD-2 complex acts as a functional linker to connect UNC-104 to RAB-3-containing vesicles. Thus, this linker complex contributes to the specificity of motor/cargo interactions.}, } @article {pmid39662462, year = {2025}, author = {Huang, C and Qiu, L and Zhou, W and Shao, C and Wang, X and Zhang, Q and Chen, W and Xiong, M and Huang, M and Tang, M and Zou, L and Xu, X}, title = {A human-induced pluripotent stem cell (iPSC) line (SMUSHi006-A) from an ALS patient carrying a mutation c.1126C > T in the FUS gene.}, journal = {Stem cell research}, volume = {82}, number = {}, pages = {103604}, doi = {10.1016/j.scr.2024.103604}, pmid = {39662462}, issn = {1876-7753}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; *Induced Pluripotent Stem Cells/metabolism ; *RNA-Binding Protein FUS/genetics ; *Mutation ; Cell Line ; Cell Differentiation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Four major genes associated with ALS-SOD1, TARDBP, FUS, and C9orf72-have been identified, with the fused in sarcoma (FUS) gene demonstrating considerable genetic heterogeneity. Our research group has previously established an induced pluripotent stem (iPS) cell line harboring the c.1562G > A mutation in the FUS gene. The objective of this study is to create another iPS cell line featuring the pathogenic c.1126C > T mutation in the FUS gene. This research aims not only to establish a disease model for ALS linked to FUS mutations but also to pave the way for potential therapeutic interventions.}, } @article {pmid39660938, year = {2025}, author = {Kashiwagi-Hakozaki, M and Ikemura, M and Naruse, H and Takahashi, Y and Toda, T and Ushiku, T}, title = {An autopsy case report of amyotrophic lateral sclerosis with unusual basophilic inclusions exhibiting immunopositivity for optineurin.}, journal = {Pathology international}, volume = {75}, number = {2}, pages = {121-123}, doi = {10.1111/pin.13501}, pmid = {39660938}, issn = {1440-1827}, } @article {pmid39659975, year = {2024}, author = {Kim, HJ and Ban, JJ and Kang, J and Im, HR and Ko, SH and Sung, JJ and Park, SH and Park, JE and Choi, SJ}, title = {Single-cell analysis reveals expanded CD8[+] GZMK [high] T cells in CSF and shared peripheral clones in sporadic amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {6}, pages = {fcae428}, pmid = {39659975}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons in the brain and spinal cord. Despite the crucial role of aberrant immune responses in ALS pathogenesis, studies investigating immunological profiles in the cerebrospinal fluid (CSF) of patients with ALS have reported inconsistent findings. Herein, we explored the intrathecal adaptive immune response and features of circulating T cells between CSF and blood of patients with ALS using single-cell RNA and T-cell receptor (TCR) sequencing. This study comprised a total of 11 patients with apparently sporadic ALS and three controls with non-inflammatory diseases. We collected CSF from all participants, and for three patients with ALS, we additionally obtained paired samples of peripheral blood mononuclear cells (PBMCs). Utilizing droplet-based single-cell RNA and TCR sequencing, we analysed immunological profiles, gene expression characteristics and clonality. Furthermore, we examined T-cell characteristics in both PBMC and CSF samples, evaluating the shared T-cell clones across these compartments. In the CSF, patients with ALS exhibited a lower proportion of CD4[+] T cells (45.2 versus 61.2%, P = 0.005) and a higher proportion of CD8[+] GZMK [hi] effector memory T cells (TEMs) than controls (21.7 versus 16.8%, P = 0.060). Higher clonality was observed in CD8[+] TEMs in patients with ALS compared with controls. In addition, CSF macrophages of patients with ALS exhibited a significant increase in chemokines recruiting CD8[+] TEMs. Immunohistochemical analysis showed slightly higher proportions of T cells in the perivascular and parenchymal spaces in patients with ALS than in controls, and CD8[+] TEMs co-localized with neurons or astrocytes in the motor cortices of patients with ALS. Clonally expanded CD8[+] GZMK [hi] TEMs primarily comprised shared T-cell clones between CSF and PBMCs. Moreover, the shared CD8[+] TEMs of PBMCs exhibited gene expression profiles similar to CSF T cells. Patients with ALS showed an increase in proportion and clonality of CD8[+] GZMK [hi] TEMs and activated features of macrophages in CSF. The shared T-cell clone between CSF and blood was mainly composed of expanded CD8[+] GZMK [hi] TEMs. In conclusion, single-cell immune profiling provided novel insights into the pathogenesis of ALS, characterized by activated macrophages and clonally expanded CD8[+] T cells potentially communicating with the central nervous system and peripheral circulation.}, } @article {pmid39659885, year = {2024}, author = {Wan, H and Qian, W and Wei, B and Tian, K and Chen, Z and Zhang, J and Chen, F}, title = {A bibliometric analysis of gene editing and amyotrophic lateral sclerosis (from 2004 to 2024).}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1499025}, pmid = {39659885}, issn = {1662-4548}, abstract = {OBJECTIVE: To learn more about gene editing and ALS, and to provide a comprehensive view of gene editing for further treatment of amyotrophic lateral sclerosis.

METHODS: We searched 1981 records from Web of Science core collection and Pubmed, Scopus, of which 1,292 records were obtained after exclusion. We then scientifically and metrologically analyzed these records for spatial and temporal distribution, author distribution, subject categories, subject distribution, references, and keywords using R, software CiteSpace and VOSviewer.

RESULTS: Our analysis provides basic information about research in the field, suggests that the field has stabilized over the past decade, and identifies potential partners for interested researchers. Current research in this area is focused on inflammatory mechanisms, immune mechanisms, related diseases, and associated cytokines in ALS.

CONCLUSION: RNA Editing, Antisense Bligonucleotide, and Glycine Receptor are cutting-edge research topics in this field, which is undergoing rapid development. We hope that this work will provide new ideas for advancing the scientific research and clinical application of ALS.}, } @article {pmid39659205, year = {2024}, author = {Alzahrani, AK and A S, A and Imran, M}, title = {Unraveling the molecular mechanisms of ALS: a network biology and structural modeling approach of investigating the impact of C9orf72 mutations.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/07391102.2024.2437682}, pmid = {39659205}, issn = {1538-0254}, abstract = {C9orf72 is a major genetic factor in Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disorder affecting brain and spinal cord neurons, and comprehending its mutational impact is crucial for developing ALS therapies. Therefore, the current study's protein-protein interaction (PPI) network for C9orf72 was meticulously mapped to identify key interactors that might influence the disease mechanism. Among the identified proteins, SMCR8 emerged as a prominent candidate due to its high connectivity (total network contribution = 7.896) within the C9orf72-associated network, suggesting a potential role in modulating the effects of C9orf72 mutations. Analysis of C9orf72 mutations highlighted the I525T mutation, which significantly destabilizes the protein, as indicated by a ΔΔG value of -2.02 kcal/mol. Further investigation involved comparing the structural dynamics of the wild-type C9orf72 and its mutant variants through molecular docking and dynamics simulations. The wild-type demonstrated more stable structural conformation over time, as shown by its RMSD profile than its mutant counterpart. However, after 80 nanoseconds, the mutant variant achieved a similar RMSD stability level. Intriguingly, the mutant formed a more stable complex with SMCR8, evident from its lower binding free energy (-64.18 kcal/mol compared to the wild type's -34.82 kcal/mol). Moreover, per-residue decomposition analysis further revealed critical interactions at specific residues. The wild-type protein showed a significant stabilizing interaction at Arg785, whereas the mutant favored Arg262, indicating a potential shift in binding affinity and site due to the mutation. This shift suggests an altered binding landscape in the mutant C9orf72, which might contribute to the dysregulated protein interactions and cellular processes associated with ALS pathology. The study thus underscores the pathological hyper-stability of the mutant C9orf72, highlighting its potential role in the progression of ALS.}, } @article {pmid39656022, year = {2024}, author = {Prentiss, AM and Baggio, C and Pagett, J and Kulinich, AO and Ethell, IM and Muzzarelli, K and Assar, Z and Pellecchia, M}, title = {Constrained β-Hairpins Targeting the EphA4 Ligand Binding Domain.}, journal = {Journal of medicinal chemistry}, volume = {67}, number = {24}, pages = {22245-22253}, pmid = {39656022}, issn = {1520-4804}, support = {R01 CA168517/CA/NCI NIH HHS/United States ; P41 GM103311/GM/NIGMS NIH HHS/United States ; R01 NS129555/NS/NINDS NIH HHS/United States ; P20 CA242620/CA/NCI NIH HHS/United States ; R01 NS107479/NS/NINDS NIH HHS/United States ; }, mesh = {*Receptor, EphA4/metabolism/antagonists & inhibitors/chemistry ; Ligands ; Humans ; Binding Sites ; Protein Binding ; Peptides, Cyclic/chemistry/pharmacology/metabolism/chemical synthesis ; Drug Design ; Protein Domains/drug effects ; Models, Molecular ; }, abstract = {The activity of the receptor tyrosine kinase EphA4 has been implicated in several pathologies including oncology (gastric and pancreatic cancers) and neurodegenerative diseases (amyotrophic lateral sclerosis and Alzheimer's disease). However, advances in validating EphA4 as a possible drug target have been limited by the lack of suitable pharmacological inhibitors. Recently, we reported on the design of potent EphA4 agonistic agents targeting its ligand binding domain (LBD). Based on previous studies with a phage display cyclic peptide inhibitor, we designed a β-hairpin mimetic with high affinity for EphA4-LBD. These agents hold great promise for further validation and development of EphA4-based therapeutics. Moreover, our studies introduce a possible strategy for the design of constrained β-hairpin peptides.}, } @article {pmid39655696, year = {2025}, author = {Di Iacovo, A and D'Agostino, C and Bhatt, M and Romanazzi, T and Giovannardi, S and Cinquetti, R and Roseti, C and Bossi, E}, title = {The kinase LRRK2 is required for the physiological function and expression of the glial glutamate transporter EAAT2 (SLC1A2).}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16265}, pmid = {39655696}, issn = {1471-4159}, support = {860954//H2020 Marie Skłodowska-Curie Actions/ ; }, mesh = {Animals ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics/metabolism/biosynthesis ; *Excitatory Amino Acid Transporter 2/metabolism/genetics/biosynthesis ; *Xenopus laevis ; Humans ; Oocytes/metabolism ; Female ; Neuroglia/metabolism ; }, abstract = {Neurotransmitter transporters (NTTs) control synaptic responses by modulating the concentration of neurotransmitters at the synaptic cleft. Glutamate is the most abundant excitatory neurotransmitter in the brain and needs to be finely tuned in time and space to maintain a healthy brain and precise neurotransmission. The glutamate transporter EAAT2 (SLC1A2) is primarily responsible for glutamate clearance. EAAT2 impairment has been associated with Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both monogenic and sporadic forms of PD, of which the common substitution Gly2019Ser is associated with a significant deficit in EAAT2 expression. The role of pathological mutants of the LRRK2 is intensively studied and reviewed. Here we have focused the attention on the physiological role of LRRK2 on EAAT2, comparing the activity of NTTs with or without the LRRK2 kinase. By heterologous expression in Xenopus laevis oocytes and two-electrode voltage clamp, the current amplitudes of the selected NTTs and kinetic parameters have been collected in the presence and absence of LRRK2. The results show that EAAT2 expression and function are impaired in the absence of the kinase and also under its pharmacological inhibition via MLi-2 treatment. LRRK2 stabilizes EAAT2 expression increasing the amount of transporter at the plasma membrane. Interestingly, the LRRK2 action is EAAT2-specific, as we observed no significant changes in the transport current amplitude and kinetic parameters obtained for the other excitatory and inhibitory NTTs studied. This study, for the first time, demonstrates the physiological importance of LRRK2 in EAAT2 function, highlighting the specificity of LRRK2-mediated modulation of EAAT2 and suggesting a potential role for the kinase as a checkpoint for preserving neurons from excitotoxicity. In brain conditions associated with impaired glutamate clearance, targeting LRRK2 for EAAT2 regulation may offer novel therapeutic opportunities.}, } @article {pmid39655539, year = {2025}, author = {Canosa, A and Martino, A and Manera, U and Giuliani, A and Vasta, R and Palumbo, F and Grassano, M and Morbelli, SD and Pardini, M and Chiaravalloti, A and Schillaci, O and Leenders, KL and Kogan, RV and Polverari, G and Zocco, G and Pede, FD and Mattei, F and Cabras, S and Matteoni, E and Moglia, C and Calvo, A and Chiò, A and Pagani, M}, title = {Sex-related differences in amyotrophic lateral sclerosis: A 2-[[18]F]FDG-PET study.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16588}, pmid = {39655539}, issn = {1468-1331}, support = {//Dipartimenti di Eccellenza/ ; RF-2016- 02362405//Ministero della Salute/ ; 259867//Seventh Framework Programme/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; //Fondation Thierry Latran/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Male ; Female ; Middle Aged ; *Positron-Emission Tomography ; *Fluorodeoxyglucose F18 ; Aged ; *Sex Characteristics ; *Brain/diagnostic imaging/metabolism ; Adult ; }, abstract = {PURPOSE: We investigated sex-related brain metabolic differences in Amyotrophic Lateral Sclerosis (ALS) and healthy controls (HC).

METHODS: We collected two equal-sized groups of male (m-ALS) and female ALS (f-ALS) patients (n = 130 each), who underwent 2-[[18]F]FDG-PET at diagnosis, matched for site of onset, cognitive status and King's stage. We included 168 age-matched healthy controls, half female (f-HC) and half male (m-HC). We compared brain metabolism of males and females separately for ALS and HC, including age as covariate. A differential network analysis was performed to evaluate brain connectivity.

RESULTS: M-ALS showed relative hypometabolism of bilateral medial frontal, parietal and occipital cortices, and left temporal cortex, compared to f-ALS. In node-wise comparison, f-ALS showed significantly higher connectivity in right middle cingulate cortex and left superior and medial frontal gyrus. In HC we did not find any sex-related differences.

CONCLUSION: Sex resulted a major determinant of brain metabolism and connectivity in ALS patients.}, } @article {pmid39655175, year = {2024}, author = {Palm, A and Ekström, M and Emilsson, Ö and Ersson, K and Ljunggren, M and Sundh, J and Grote, L}, title = {Control of hypercapnia and mortality in home mechanical ventilation: the population-based DISCOVERY study.}, journal = {ERJ open research}, volume = {10}, number = {6}, pages = {}, pmid = {39655175}, issn = {2312-0541}, abstract = {BACKGROUND: Studies on the survival of patients with home mechanical ventilation (HMV) are sparse. We aimed to analyse the impact of controlled hypercapnia on survival over 27 years among patients with HMV in Sweden.

STUDY DESIGN AND METHODS: Population-based cohort study of adult patients starting HMV in the Swedish Registry for Respiratory Failure (Swedevox) during 1996-2022 cross-linked with the National Cause of Death registry. Mortality risk factors were analysed using crude and multivariable Cox regression models, including adjustments for anthropometrics, comorbidities, the underlying diagnosis causing chronic hypercapnic respiratory failure (CRF) and the control of hypercapnia (P aCO2 ≤6.0 kPa) at follow-up.

RESULTS: We included 10 190 patients (50.1% women, age 62.9±14.5 years). Control of hypercapnia at follow-up after 1.3±0.9 years was associated with lower mortality, hazard ratio (HR) 0.74 (95% CI 0.68-0.80) and the association was strongest in those with pulmonary disease, restrictive thoracal disease (RTD), obesity hypoventilation syndrome (OHS) and amyotrophic lateral sclerosis (ALS). Predictors for increased mortality included age, Charlson Comorbidity Index, supplemental oxygen therapy and acute start of HMV therapy. Median survival varied between 0.8 years (95% CI 0.8-0.9 (n=1401)) for ALS and 7.6 years (95% CI 6.9-8.6 (n=1061)) for neuromuscular disease. Three-year survival decreased from 76% (95% CI 71-80) between 1996 and 1998 to 52% (95% CI 50-55) between 2017 and 2019. When adjusting for underlying diagnosis and age, the association between start year and decreased survival disappeared, HR 1.00 (95% CI 0.99-1.01).

CONCLUSION: Controlling P aCO2 is a key treatment goal for survival in HMV therapy. Survival differed markedly between diagnosis and age groups, and survival rates have declined as the patient group has aged.}, } @article {pmid39655131, year = {2024}, author = {Mori, Y and Kenzaka, T}, title = {Systemic Amyloid Light Chain Amyloidosis With Repeated Syncope Due to Severe Orthostatic Hypotension Caused by Autonomic Neuropathy: A Case Report.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e73320}, pmid = {39655131}, issn = {2168-8184}, abstract = {Amyloid light chain (AL) amyloidosis is a disease in which ALs, which are proteins with fibrous structures, are deposited in systemic organs, causing functional impairment. Diagnosis is often difficult because of non-specific and varied symptoms. We report a case of systemic AL amyloidosis that was diagnosed as a result of repeated syncope. A 76-year-old woman was brought to the emergency room with multiple episodes of loss of consciousness over the past five years. She visited the major hospital, where pulmonary thromboembolism and symptomatic epilepsy were considered possible causes. Orthostatic hypotension was observed after being transferred to our hospital for rehabilitation. We performed diagnostic tests, including blood tests, imaging, and a head-up tilt test, which confirmed severe orthostatic hypotension. A gastrointestinal biopsy with Congo red staining confirmed the presence of amyloid deposits. AL amyloidosis (λ) was diagnosed using immunohistochemical staining. Given her age and prolonged bed rest, she was determined that she could not tolerate chemotherapy and was discharged upon her request. To the best of our knowledge, this is the first report of systemic AL amyloidosis presenting with orthostatic hypotension severe enough to cause syncope due to autonomic neuropathy. Autonomic neuropathy should be considered, and amyloidosis should be included in the differential diagnosis when a patient presents with recurrent syncope.}, } @article {pmid39654963, year = {2024}, author = {Sun, P and Niu, L and He, P and Yu, H and Chen, J and Cui, H and Li, X}, title = {Trp-574-Leu and the novel Pro-197-His/Leu mutations contribute to penoxsulam resistance in Echinochloa crus-galli (L.) P. Beauv.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1488976}, pmid = {39654963}, issn = {1664-462X}, abstract = {Recently, due to the widespread use of the acetolactate synthase (ALS)-inhibiting herbicide penoxsulam in paddy fields in China, Echinochloa crus-galli (L.) P. Beauv. has become a problematic grass weed that is frequently not controlled, posing a threat to weed management and rice yield. There are many reports on target-site mutations of ALS inhibiting herbicides; however, the detailed penoxsulam resistance mechanism in E. crus-galli remains to be determined. Greenhouse and laboratory studies were conducted to characterize target-site resistance mechanisms in JL-R, AH-R, and HLJ-R suspected resistant populations of E. crus-galli survived the field-recommended dose of penoxsulam. The whole-plant dose-response testing of E. crus-galli to penoxsulam confirmed the evolution of moderate-level resistance in two populations, JL-R (9.88-fold) and HLJ-R (8.66-fold), and a high-level resistance in AH-R (59.71-fold) population. ALS gene sequencing identified specific mutations in resistant populations, including Pro-197-His in ALS1 for JL-R, Trp-574-Leu in ALS1 for AH-R, and Pro-197-Leu in ALS2 for HLJ-R. In vitro ALS activity assays demonstrated a significantly higher activity in AH-R compared to the susceptible population (YN-S). Molecular docking studies revealed that Trp-574-Leu mutation primarily reduced the enzyme's ability to bind to the triazole-pyrimidine ring of penoxsulam due to decreased π-π stacking interactions, while Pro-197-His/Leu mutations impaired binding to the benzene ring by altering hydrogen bonds and hydrophobic interactions. Additionally, the Pro-197-His/Leu amino acid residue changes resulted in alterations in the shape of the active channel, impeding the efficient entry of penoxsulam into the binding site in the ALS protein. The three mutant ALS proteins expressed via the Bac-to-Bac baculovirus system exhibited notably lower activity inhibition rates than the non-mutant ALS proteins to penoxsulam, indicating all three ALS mutations reduce sensitivity to penoxsulam. This study elucidated the distinct impacts of the Pro-197-His/Leu and Trp-574-Leu mutations in E. crus-galli to penoxsulam resistance. Notably, the Trp-574-Leu mutation conferred stronger resistance to penoxsulam compared to the Pro-197-His/Leu mutations in E. crus-galli. The Pro-197-His/Leu mutations were first detected in E. crus-galli conferring penoxsulam resistance. These findings provide deeper insights into the molecular mechanisms underlying target-site resistance to penoxsulam in E. crus-galli.}, } @article {pmid39654532, year = {2024}, author = {Dave, KD and Oskarsson, B and Yersak, J and Krauss, R and Heiman-Patterson, T and Lomen-Hoerth, C and Selig, WKD and Halpern Paul, I and Schaeffer, M and Garcia-Trujillo, B and Waldo, D and Thakur, N and Babu, S}, title = {Contributions of neurologists to diagnostic timelines of ALS and thinkALS as an early referral instrument for clinicians.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2432034}, pmid = {39654532}, issn = {2167-9223}, abstract = {Objectives: To evaluate neurologists and other clinicians' contributions to U.S. ALS diagnostic timelines. Background: Over the past two decades, the average time to ALS diagnosis in the U.S. has remained unchanged at 12 months. ALS patients see 3-4 clinicians prior to referral to an ALS specialist for diagnosis confirmation and/or treatment initiation. There is an urgent need to identify where delays occur, so that targeted clinician awareness may be raised about early suspicion and referrals. Methods: Review of Medicare claims database for health care utilization patterns by ALS beneficiaries during diagnostic journey. Survey of typical clinic wait times for new consultations reported by 75-78 ALS Certified Treatment Centers of Excellence (2019-2021). Results: During 2011-2021, 78,520 Medicare beneficiaries were diagnosed with ALS (T0). The mean (median) timelines between first neurologist ambulatory visit and T0, is 16.5 (11.0) months; mean ± SD for ALS/neuromuscular providers being 9.6 ± 12.6 months versus 16.7 ± 17.5 months for non-neuromuscular neurologists. During the 12-months preceding T0, an ALS patient undergoes median(max) 1.5(4.0) brain-MRIs, 1.6(6.0) spine-MRIs, and 1.3(4.0) electromyography studies. Greater than 75% of ALS centers consistently report ≤ 4 week wait times for new ALS consults. This study introduces "thinkALS," an easy-to-use clinical diagnostic and referral guide for non-ALS neurologists to tackle this challenge. Conclusions: This study is the first to provide metrics on how non-neuromuscular/ALS specialists contribute to ALS diagnostic timelines in the U.S.}, } @article {pmid39651269, year = {2024}, author = {O'Neill, K and Shaw, R and Bolger, I and , and Tam, O and Phatnani, H and Hammell, MG}, title = {ALS molecular subtypes are a combination of cellular, genetic, and pathological features learned by deep multiomics classifiers.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.07.19.603731}, pmid = {39651269}, issn = {2692-8205}, support = {R01 NS116350/NS/NINDS NIH HHS/United States ; R01 NS118183/NS/NINDS NIH HHS/United States ; R01 NS118570/NS/NINDS NIH HHS/United States ; RF1 NS118570/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex syndrome with multiple genetic causes and wide variation in disease presentation. Despite this general heterogeneity, several common factors have been identified. For example, nearly all patients show pathological accumulations of phosphorylated TDP-43 protein in affected regions of the motor cortex and spinal cord. Moreover, large patient cohort studies have revealed that most patient samples can be grouped into a small number of ALS subtypes, as defined by their transcriptomic profiles. These ALS molecular subtypes can be grouped by whether postmortem motor cortex samples display signatures of: mitochondrial dysfunction and oxidative stress (ALS-Ox), microglial activation and neuroinflammation (ALS-Glia), or dense TDP-43 pathology and associated transposable element de-silencing (ALS-TE). In this study, we have built a deep layer ALS neural network classifier (DANcer) that has learned to accurately assign patient samples to these ALS subtypes, and which can be run on either bulk or single-cell datasets. Upon applying this classifier to an expanded ALS patient cohort from the NYGC ALS Consortium, we show that ALS Molecular Subtypes are robust across clinical centers, with no new subtypes appearing in a cohort that has quadrupled in size. Signatures from two of these molecular subtypes strongly correlate with disease duration: ALS-TE signatures in cortex and ALS-Glia signatures in spinal cord, revealing molecular correlates of clinical features. Finally, we use single nucleus RNA sequencing to reveal the cell type-specific contributions to ALS subtype, as determined by our single-cell classifier (scDANCer). Single-cell transcriptomes reveal that ALS molecular subtypes are recapitulated in neurons and glia, with both ALS-wide shared alterations in each cell type as well as ALS subtype-specific alterations. In summary, ALS molecular subtypes: (1) are robust across large cohorts of sporadic and familial ALS patient samples, (2) represent a combination of cellular, genetic, and pathological features, and (3) correlate with clinical features of ALS.}, } @article {pmid39651224, year = {2024}, author = {Kodavati, M and Maloji Rao, VH and Mitra, J and Hegde, ML}, title = {Selective Inhibition of Cytosolic PARylation via PARG99: A Targeted Approach for Mitigating FUS-associated Neurodegeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.25.625276}, pmid = {39651224}, issn = {2692-8205}, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) are characterized by complex etiologies, often involving disruptions in functions of RNA/DNA binding proteins (RDBPs) such as FUS and TDP-43. The cytosolic mislocalization and aggregation of these proteins are linked to accumulation of unresolved stress granules (SGs), which exacerbate the disease progression. Poly-ADP-ribose polymerase (PARP)-mediated PARylation plays a critical role in this pathological cascade, making it a potential target for intervention. However, conventional PARP inhibitors are limited by their detrimental effects on DNA repair pathways, which are already compromised in ALS. To address this limitation, we investigated a strategy focused on targeting the cytosolic compartment by expressing the cytosol-specific, natural PAR- glycohydrolase (PARG) isoform, PARG99. Using ALS patient derived FUS mutant induced pluripotent cells (iPSCs) and differentiated neurons, we observed elevated levels of FUS in insoluble fractions in mutant cells compared to mutation-corrected isogenic lines. The insoluble FUS as well as TDP-43 levels increased further in sodium arsenite-treated or oxidatively stressed cells, correlating with accumulation of unresolved SGs. Notably, both PARG99 and PARP inhibitors reduced SG formation and insoluble FUS levels, however, PARG99 treated cells exhibited significantly lower DNA damage markers and improved viability under oxidative and arsenite stress. This study highlights the potential of PARG99 as a cytosol-specific intervention to mitigate FUS-associated toxicity while preserving critical nuclear DNA repair mechanisms, offering a promising strategy for addressing the underlying pathology of ALS and potentially other SG-associated neurodegenerative diseases.}, } @article {pmid39651197, year = {2024}, author = {Grant, OA and Iacoangeli, A and Zwamborn, RAJ and van Rheenen, W and Byrne, R and Van Eijk, KR and Kenna, K and van Vugt, JJFA and Cooper-Knock, J and Kenna, B and Vural, A and Topp, S and Campos, Y and Weber, M and Smith, B and Dobson, R and van Es, MA and Vourc'h, P and Corcia, P and de Carvalho, M and Gotkine, M and Panades, MP and Mora, JS and Mill, J and Garton, F and McRae, A and Wray, NR and Shaw, PJ and Landers, JE and Glass, JD and Shaw, CE and Basak, N and Hardiman, O and Van Damme, P and McLaughlin, RL and van den Berg, LH and Veldink, JH and Al-Chalabi, A and Al Khleifat, A}, title = {Sex-specific DNA methylation differences in Amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.22.624866}, pmid = {39651197}, issn = {2692-8205}, abstract = {Sex is an important covariate in all genetic and epigenetic research due to its role in the incidence, progression and outcome of many phenotypic characteristics and human diseases. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a sex bias towards higher incidence in males. Here, we report for the first time a blood-based epigenome-wide association study meta-analysis in 9274 individuals after stringent quality control (5529 males and 3975 females). We identified a total of 226 ALS saDMPs (sex-associated DMPs) annotated to a total of 159 unique genes. These ALS saDMPs were depleted at transposable elements yet significantly enriched at enhancers and slightly enriched at 3'UTRs. These ALS saDMPs were enriched for transcription factor motifs such as ESR1 and REST. Moreover, we identified an additional 10 genes associated with ALS saDMPs through chromatin loop interactions, suggesting a potential regulatory role for these saDMPs on distant genes. Furthermore, we investigated the relationship between DNA methylation at specific CpG sites and overall survival in ALS using Cox proportional hazards models. We identified two ALS saDMPs, cg14380013 and cg06729676, that showed significant associations with survival. Overall, our study reports a reliable catalogue of sex-associated ALS saDMPs in ALS and elucidates several characteristics of these sites using a large-scale dataset. This resource will benefit future studies aiming to investigate the role of sex in the incidence, progression and risk for ALS.}, } @article {pmid39651147, year = {2024}, author = {Fleming, AC and Rao, NR and Wright, M and Savas, JN and Kiskinis, E}, title = {The ALS-associated co-chaperone DNAJC7 mediates neuroprotection against proteotoxic stress by modulating HSF1 activity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.12.01.626216}, pmid = {39651147}, issn = {2692-8205}, abstract = {The degeneration of neurons in patients with amyotrophic lateral sclerosis (ALS) is commonly associated with accumulation of misfolded, insoluble proteins. Heat shock proteins (HSPs) are central regulators of protein homeostasis as they fold newly synthesized proteins and refold damaged proteins. Heterozygous loss-of- function mutations in the DNAJC7 gene that encodes an HSP co-chaperone were recently identified as a cause for rare forms of ALS, yet the mechanisms underlying pathogenesis remain unclear. Using mass spectrometry, we found that the DNAJC7 interactome in human motor neurons (MNs) is enriched for RNA binding proteins (RBPs) and stress response chaperones. MNs generated from iPSCs with the ALS-associated mutation R156X in DNAJC7 exhibit increased insolubility of its client RBP HNRNPU and associated RNA metabolism alterations. Additionally, DNAJC7 haploinsufficiency renders MNs increasingly susceptible to proteotoxic stress and cell death as a result of an ablated HSF1 stress response pathway. Critically, expression of HSF1 in mutant DNAJC7 MNs is sufficient to rescue their sensitivity to proteotoxic stress, while postmortem ALS patient cortical neurons exhibit a reduction in the expression of HSF1 pathway genes. Taken together, our work identifies DNAJC7 as a crucial mediator of HNRNPU function and stress response pathways in human MNs and highlights HSF1 as a therapeutic target in ALS.}, } @article {pmid39650285, year = {2024}, author = {Hu, Y and Deeba, E and Kläppe, U and Öijerstedt, L and Andersson, J and Ruffin, N and Piehl, F and Ingre, C and Fang, F and Seitz, C}, title = {Immune cells and the trajectories of depression, anxiety, and cognitive function among people with amyotrophic lateral sclerosis.}, journal = {Brain, behavior, & immunity - health}, volume = {42}, number = {}, pages = {100907}, pmid = {39650285}, issn = {2666-3546}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) represents a complex syndrome characterized by motor, psychiatric, and cognitive symptoms, where associations between cellular immune features and non-motor manifestations remain unknown.

METHODS: In this cohort study, we enrolled 250 incident people with ALS (pwALS) assessed with the Hospital Anxiety and Depression Scale, and 226 pwALS with the Montreal Cognitive Assessment, including 218 overlapping pwALS. All individuals were diagnosed between January 2015 and January 2023 in Stockholm, Sweden. We applied joint latent class models to delineate distinct trajectories of anxiety, depression, and cognition, incorporating survival outcomes. A majority of the pwALS had data on leukocyte counts and flow cytometric analyses using a comprehensive T cell panel. We then used immune cell subtypes measured at diagnosis to predict trajectories of these outcomes following ALS diagnosis.

RESULTS: We identified two distinct trajectories for anxiety, depression, and cognitive function following ALS diagnosis. PwALS with longer survival displayed more stable trajectories, while those with shorter survival showed decreasing anxiety symptom, increasing depressive symptom, and declining cognitive function. Higher count of leukocytes at the time of ALS diagnosis tended to associate with anxiety and depression trajectories related to shorter survival. Among T cell subpopulations, several CD8[+] T cell subsets were associated with a stable trajectory of depressive symptom, and, in turn, better survival.

CONCLUSION: ALS-associated psychiatric and cognitive trajectories vary significantly between pwALS with different prognosis. Certain T cell subsets measured at diagnosis might be indicative of depression trajectories post-diagnosis.}, } @article {pmid39649550, year = {2024}, author = {Han, S and Li, RH and Gao, P}, title = {Gut microbiota participates and remodels host metabolism: From treating patients to treating their gut flora.}, journal = {World journal of gastroenterology}, volume = {30}, number = {45}, pages = {4839-4843}, pmid = {39649550}, issn = {2219-2840}, mesh = {Humans ; *Gastrointestinal Microbiome ; Animals ; Uric Acid/blood/metabolism ; Hyperuricemia/microbiology/drug therapy/blood/metabolism ; Metabolomics/methods ; Feces/microbiology ; }, abstract = {In this editorial, we comment on Liu et al's article published in the recent issue of the World Journal of Gastroenterology. Biochemically and pathologically, Liu et al proved that the urate-lowering activity of leech total protein (LTP) was mainly attributed to the rectification of gut microbiota. Specifically, we noticed the change in Bacteroides and Akkermansia after LTP administration. Both bacteria have been reported to alleviate metabolic dysfunction-associated steatohepatitis and other chronic metabolic diseases. LTP was administrated through intragastric manners. Most possibly, LTP would be digested by the gut microbiota further. The anti-hyperuricemia effects should, to the most possible extent, be exerted by the peptides or their secondary metabolic products. Human gut microbiota communicates with other organs through metabolites generated by the microbes or co-metabolized with the host. Whether the anti-hyperuricemia effect could be partially ascribed to the microbiota metabolites also deserves to be discussed. Although metabolomics analysis was performed for serum samples, fecal metabolomics was highly advocated which could facilitate exact mechanism explanation. This study implied that gut microbiota contains many unexplored targets with different therapeutic potentials. It is foreseeable that utilizing these targets can avoid the impairment or side effects of directly using human targets to some extent.}, } @article {pmid39649175, year = {2024}, author = {Harvey, C and Nowak, A and Zhang, S and Moll, T and Weimer, AK and Barcons, AM and Dos Santos Souza, C and Ferraiuolo, L and Kenna, K and Zaitlen, N and Caggiano, C and Shaw, PJ and Snyder, MP and Mill, J and Hannon, E and Cooper-Knock, J}, title = {Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39649175}, issn = {2693-5015}, support = {R01 HL101388/HL/NHLBI NIH HHS/United States ; P50 HL083800/HL/NHLBI NIH HHS/United States ; P30 DK116074/DK/NIDDK NIH HHS/United States ; R01 HL122939/HL/NHLBI NIH HHS/United States ; UM1 HG009442/HG/NHGRI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis (ALS) lacks a specific biomarker, but is defined by relatively selective toxicity to motor neurons (MN). As others have highlighted, this offers an opportunity to develop a sensitive and specific biomarker based on detection of DNA released from dying MN within accessible biofluids. Here we have performed whole genome bisulfite sequencing (WGBS) of iPSC-derived MN from neurologically normal individuals. By comparing MN methylation with an atlas of tissue methylation we have derived a MN-specific signature of hypomethylated genomic regions, which accords with genes important for MN function. Through simulation we have optimised the selection of regions for biomarker detection in plasma and CSF cell-free DNA (cfDNA). However, we show that MN-derived DNA is not detectable via WGBS in plasma cfDNA. In support of our experimental finding, we show theoretically that the relative sparsity of lower MN sets a limit on the proportion of plasma cfDNA derived from MN which is below the threshold for detection of WGBS. Our findings are important for the ongoing development of ALS biomarkers. The MN-specific hypomethylated genomic regions we have derived could be usefully combined with more sensitive detection methods and perhaps with study of CSF instead of plasma. Indeed we demonstrate that neuronal-derived DNA is detectable in CSF. Our work is relevant for all diseases featuring death of rare cell-types.}, } @article {pmid39647703, year = {2025}, author = {Watters, JJ and Bell, MC and Que, SKT}, title = {Regarding response to Watters et al's "Educational intervention targeting primary care residents improves skin cancer recognition in patients with skin of color".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {4}, pages = {e105-e106}, doi = {10.1016/j.jaad.2024.11.051}, pmid = {39647703}, issn = {1097-6787}, } @article {pmid39645528, year = {2024}, author = {Ríos-López, AL and Garza-Velásquez, MF and González, GM and Becerril-García, MA and Flores-Maldonado, O}, title = {Prevalence, virulence factors and antifungal susceptibility of oral isolates of Candida albicans from patients with cystic fibrosis in Mexico.}, journal = {Revista iberoamericana de micologia}, volume = {41}, number = {2-3}, pages = {31-36}, doi = {10.1016/j.riam.2024.09.001}, pmid = {39645528}, issn = {2173-9188}, mesh = {Humans ; *Cystic Fibrosis/microbiology/complications ; *Virulence Factors/genetics ; *Candida albicans/drug effects/isolation & purification/genetics ; Mexico/epidemiology ; *Antifungal Agents/pharmacology ; *Microbial Sensitivity Tests ; Female ; Male ; Adult ; Young Adult ; Adolescent ; *Candidiasis, Oral/microbiology/epidemiology ; Prevalence ; Child ; Drug Resistance, Fungal ; Biofilms/growth & development ; Mouth/microbiology ; Child, Preschool ; }, abstract = {BACKGROUND: Candida species are frequently isolated from the oral cavity of patients with cystic fibrosis. However, the information on the role of Candida in cystic fibrosis is scarce.

AIMS: This study aimed to evaluate the prevalence, virulence profile and antifungal susceptibility of oral isolates of Candida albicans recovered from patients with cystic fibrosis.

METHODS: Oropharyngeal swab samples were collected from sixty-five cystic fibrosis patients and sixty-five healthy individuals. Candida isolates were identified by MALDI-TOF VITEK-MS. Proteinase, phospholipase and esterase activity, biofilm production and level expression of ALS, SAP and PLB genes in C. albicans were evaluated. Minimal inhibitory concentration values were determined by means of an antifungal susceptibility test.

RESULTS: Oral Candida colonization in cystic fibrosis patients was 66.15%, while in healthy individuals was 36.92%. C. albicans was the most frequently isolated species. C. albicans strains from cystic fibrosis patients were high producers of protease and biofilm, and had higher expression levels of adhesin and protease-associated genes in comparison with healthy subjects. Among the C. albicans strains isolated from cystic fibrosis patients, 18.91% were resistant to itraconazole, while 16.21% exhibited resistance to ketoconazole and fluconazole, and only one strain was resistant to voriconazole.

CONCLUSIONS: This work represents a surveillance study on virulence patterns and antifungal susceptibility of Candida from the oropharyngeal tract in cystic fibrosis.}, } @article {pmid39645221, year = {2025}, author = {Bajpai, A and Bharathi, V and Patel, BK}, title = {Therapeutic targeting of the oxidative stress generated by pathological molecular pathways in the neurodegenerative diseases, ALS and Huntington's.}, journal = {European journal of pharmacology}, volume = {987}, number = {}, pages = {177187}, doi = {10.1016/j.ejphar.2024.177187}, pmid = {39645221}, issn = {1879-0712}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics ; *Antioxidants/pharmacology/therapeutic use ; *Huntington Disease/metabolism/drug therapy/pathology/genetics ; Molecular Targeted Therapy/methods ; Neurodegenerative Diseases/metabolism/drug therapy/pathology ; *Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative disorders are characterized by a progressive decline of specific neuronal populations in the brain and spinal cord, typically containing aggregates of one or more proteins. They can result in behavioral alterations, memory loss and a decline in cognitive and motor abilities. Various pathways and mechanisms have been outlined for the potential treatment of these diseases, where redox regulation is considered as one of the most common druggable targets. For example, in amyotrophic lateral sclerosis (ALS) with superoxide dismutase-1 (SOD1) pathology, there is a downregulation of the antioxidant response nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. TDP-43 proteinopathy in ALS is associated with elevated levels of reactive oxygen species and mitochondrial dyshomeostasis. In ALS with mutant FUS, poly ADP ribose polymerase-dependent X ray repair cross complementing 1/DNA-ligase recruitment to the sites of oxidative DNA damage is affected, thereby causing defects in DNA damage repair. Oxidative stress in Huntington's disease (HD) with mutant huntingtin accumulation manifests as protein oxidation, metabolic energetics dysfunction, metal ion dyshomeostasis, DNA damage and mitochondrial dysfunction. The impact of oxidative stress in the progression of these diseases further warrants studies into the role of antioxidants in their treatment. While an antioxidant, edaravone, has been approved for therapeutics of ALS, numerous antioxidant molecules failed to pass the clinical trials despite promising initial studies. In this review, we summarize the oxidative stress pathways and redox modulators that are investigated in ALS and HD using various models.}, } @article {pmid39645085, year = {2025}, author = {Ediriweera, GR and Sivaram, AJ and Cowin, G and Brown, ML and McAlary, L and Lum, JS and Fletcher, NL and Robinson, L and Simpson, JD and Chen, L and Wasielewska, JM and Byrne, E and Finnie, JW and Manavis, J and White, AR and Yerbury, JJ and Thurecht, KJ and Vine, KL}, title = {Lipid nanoparticles and transcranial focused ultrasound enhance the delivery of SOD1 antisense oligonucleotides to the murine brain for ALS therapy.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {378}, number = {}, pages = {221-235}, doi = {10.1016/j.jconrel.2024.11.074}, pmid = {39645085}, issn = {1873-4995}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy ; *Oligonucleotides, Antisense/administration & dosage ; *Superoxide Dismutase-1/genetics ; *Brain/metabolism ; *Mice, Inbred C57BL ; *Nanoparticles/administration & dosage/chemistry ; *Mice, Transgenic ; Blood-Brain Barrier/metabolism ; Lipids/chemistry/administration & dosage ; Male ; Motor Neurons/metabolism ; Mice ; Microbubbles ; Liposomes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with extremely limited therapeutic options. One key pathological feature of ALS is the abnormal accumulation of misfolded proteins within motor neurons. Hence, reducing the burden of misfolded protein has emerged as a promising therapeutic approach. Antisense oligonucleotides (ASOs) have the potential to effectively silence proteins with gain-of-function mutations, such as superoxide dismutase 1 (SOD1). However, ASO delivery to the central nervous system (CNS) is hindered by poor blood-brain barrier (BBB) penetration and the invasiveness of intrathecal administration. In the current study, we demonstrate effective systemic delivery of a next-generation SOD1 ASO (Tofersen) into the brain of wildtype and G93A-SOD1 transgenic C57BL/6 mice using calcium phosphate lipid nanoparticles (CaP lipid NPs). We show that transcranial focused ultrasound (FUS) with intravenously administered microbubbles can significantly enhance ASO-loaded nanoparticle delivery into the mouse brain. Magnetic resonance imaging (MRI) and immunohistological analysis showed reduced SOD1 expression in the FUS-exposed brain regions and increased motor neuron count in the spinal cord of treated mice suggesting decreased motor neuron degeneration. Importantly, the BBB opening was transient without evidence of structural changes, neuroinflammation or damage to the brain tissue, indicating that the treatment is well tolerated. Overall, our results highlight FUS-assisted nanoparticle delivery of ASOs as a promising non-invasive therapeutic strategy for the treatment of ALS and CNS diseases more broadly.}, } @article {pmid39645043, year = {2025}, author = {Needle, C and Brinks, A and Shapiro, J and Lo Sicco, K}, title = {Response to Chen et al's "Emergence of Janus kinase inhibitors led to increase in proportion of severe alopecia areata patients receiving treatment: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {4}, pages = {e119-e120}, doi = {10.1016/j.jaad.2024.10.118}, pmid = {39645043}, issn = {1097-6787}, } @article {pmid39644980, year = {2025}, author = {Guerra San Juan, I and Brunner, JW and Eggan, K and Toonen, RF and Verhage, M}, title = {KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons.}, journal = {Neurobiology of disease}, volume = {204}, number = {}, pages = {106759}, doi = {10.1016/j.nbd.2024.106759}, pmid = {39644980}, issn = {1095-953X}, mesh = {*Kinesins/metabolism/genetics ; *Axonal Transport/physiology ; Humans ; *Mitochondria/metabolism ; *Motor Neurons/metabolism ; *Axons/metabolism ; PTB-Associated Splicing Factor/metabolism ; Nerve Regeneration/physiology ; Cells, Cultured ; Neuronal Outgrowth/physiology ; }, abstract = {Mutations in the microtubule-binding motor protein kinesin 5 A (KIF5A) are implicated in several adult-onset motor neuron diseases, including Amyotrophic Lateral Sclerosis, Spastic Paraplegia Type 10 and Charcot-Marie-Tooth Disease Type 2. While KIF5 family members transport a variety of cargos along axons, the specific cargos affected by KIF5A mutations remain poorly understood. Here, we generated KIF5Anull mutant human motor neurons and analyzed the impact on axonal transport and motor neuron outgrowth and regeneration in vitro. KIF5A deficiency caused reduced neurite complexity in young neurons (DIV14) and defects in axonal regeneration. KIF5A deficiency did not affect neurofilament transport but impaired mitochondrial motility and anterograde speed at DIV42. Notably, KIF5A deficiency strongly reduced anterograde transport of splicing factor proline/glutamine-rich (SFPQ)-associated RNA granules in DIV42 axons. Hence, KIF5A plays a critical role in promoting axonal regrowth after injury and in driving the anterograde transport of mitochondria and especially SFPQ-associated RNA granules in mature neurons.}, } @article {pmid39644798, year = {2025}, author = {Toko, M and Ohshita, T and Nakamori, M and Ueno, H and Akiyama, Y and Maruyama, H}, title = {Myelin measurement in amyotrophic lateral sclerosis with synthetic MRI: A potential diagnostic and predictive method.}, journal = {Journal of the neurological sciences}, volume = {468}, number = {}, pages = {123337}, doi = {10.1016/j.jns.2024.123337}, pmid = {39644798}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; *Myelin Sheath/pathology ; Middle Aged ; *Magnetic Resonance Imaging/methods ; Aged ; Adult ; }, abstract = {BACKGROUND: Myelin damage has recently been highlighted as a major causative factor of amyotrophic lateral sclerosis (ALS). Although myelin damage has been pathologically identified in ALS, it has not been clinically evaluated. This study aimed to quantify myelin volume using synthetic MRI to evaluate myelin damage in patients with ALS, and determine its association with clinical parameters.

METHODS: We evaluated patients with ALS (n = 35) and individuals (n = 16) without intracranial disease using synthetic magnetic resonance imaging (MRI) and measured total myelin volume (TMV), myelin fraction (MYF), and myelin partial volume (VMY) in the cerebral peduncle and the posterior limb of the internal capsule (PLIC). We also investigated factors associated with acquired quantitative values.

RESULTS: The TMV was significantly lower in the patients with ALS than in the control group (P = 0.045). The TMV (r = 0.42, P = 0.013) and MYF (r = 0.34, P = 0.047) significantly correlated with Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores in the patients, and MYF was independent of the traditional white matter lesion grading score. The VMY of the PLIC was significantly lower in the ALS than the control group (P = 0.018), and the ALS group significantly correlated with ALSFRS-R scores (r = 0.36, P = 0.033).

CONCLUSIONS: Myelin damage can be quantified by synthetic MRI as reduced myelin volume, with the possibility of predicting prognoses in patients with ALS. Furthermore, myelin measurements in the PLIC might be a novel diagnostic marker for ALS.}, } @article {pmid39643934, year = {2025}, author = {Farrokhzad, R and Seyedalipour, B and Baziyar, P and Hosseinkhani, S}, title = {Insight Into Factors Influencing the Aggregation Process in Wild-Type and P66R Mutant SOD1: Computational and Spectroscopic Approaches.}, journal = {Proteins}, volume = {93}, number = {4}, pages = {885-907}, doi = {10.1002/prot.26765}, pmid = {39643934}, issn = {1097-0134}, mesh = {*Superoxide Dismutase-1/chemistry/genetics/metabolism ; Humans ; *Molecular Dynamics Simulation ; *Hydrophobic and Hydrophilic Interactions ; Protein Aggregates ; Mutation ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Spectroscopy, Fourier Transform Infrared ; Protein Aggregation, Pathological/genetics/metabolism ; Protein Folding ; Thermodynamics ; Protein Conformation, beta-Strand ; Gene Expression ; }, abstract = {Disturbances in metal ion homeostasis associated with amyotrophic lateral sclerosis (ALS) have been described for several years, but the exact mechanism of involvement is not well understood. To elucidate the role of metalation in superoxide dismutase (SOD1) misfolding and aggregation, we comprehensively characterized the structural features (apo/holo forms) of WT-SOD1 and P66R mutant in loop IV. Using computational and experimental methodologies, we assessed the physicochemical properties of these variants and their correlation with protein aggregation at the molecular level. Modifications in apo-SOD1 compared to holo-SOD1 were more pronounced in flexibility, stability, hydrophobicity, and intramolecular interactions, as indicated by molecular dynamics simulations. The enzymatic activities of holo/apo-WT SOD1 were 1.30 and 1.88-fold of the holo/apo P66R mutant, respectively. Under amyloid-inducing conditions, decreased ANS fluorescence intensity in the apo-form relative to the holo-form suggested pre-fibrillar species and amyloid aggregate growth due to occluded hydrophobic pockets. FTIR spectroscopy revealed that apo-WT-SOD1 and apo-P66R exhibited a mixture of parallel and intermolecular β-sheet structures, indicative of aggregation propensity. Aggregate species were identified using TEM, Congo red staining, and ThT/ANS fluorescence spectroscopy. Thermodynamic analyses with GdnHCl demonstrated that metal deficit, mutation, and intramolecular disulfide bond reduction are essential for initiating SOD1 misfolding and aggregation. These disruptions destabilize the dimer-monomer equilibrium, promoting dimer dissociation into monomers and decreasing the thermodynamic stability of SOD1 variants, thus facilitating amyloid/amorphous aggregate formation. Our findings offer novel insights into protein aggregation mechanisms in disease pathology and highlight potential therapeutic strategies against toxic protein aggregation, including SOD1.}, } @article {pmid39643926, year = {2025}, author = {Wang, J and Du, Y and Zhang, L and Deng, Y and Wang, T and Wang, S and Ji, M}, title = {Pro-197-Ser mutation combinations in acetolactate synthase (ALS) homoeologous genes affect ALS inhibitor herbicide resistance levels in Monochoria korsakowii.}, journal = {Pest management science}, volume = {81}, number = {4}, pages = {1894-1902}, doi = {10.1002/ps.8586}, pmid = {39643926}, issn = {1526-4998}, support = {32372594//National Natural Science Foundation of China/ ; }, mesh = {*Acetolactate Synthase/genetics ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Mutation ; *Plant Proteins/genetics ; Sulfonylurea Compounds/pharmacology ; Nicotinic Acids ; }, abstract = {BACKGROUND: Monochoria korsakowii is a common broadleaf weed found in rice (Oryza sativa) fields. Acetolactate synthase (ALS) inhibitor herbicides are commonly used to control broadleaf weeds in rice fields. However, prolonged herbicide use has exacerbated resistance issues. In this study, we evaluated the resistance to ALS inhibitors in populations where the same mutation occurred separately and simultaneously in the two ALS homoeologous genes (ALS1 and ALS2) and investigated the resistance mechanisms in M. korsakowii.

RESULTS: Monochoria korsakowii exhibited high resistance to bensulfuron-methyl, low resistance to penoxsulam, and sensitivity to imazethapyr. Three resistant populations were identified: M-1 and M-2, which independently evolved the Pro-197-Ser mutation in ALS1 and ALS2, respectively, and M-3, which harbored this mutation in both ALS1 and ALS2. The sensitivity of ALS isolated from these populations to herbicide inhibition corresponded to the whole-plant resistance levels. Subsequently, we cloned and transformed Pro-197-Ser-mutated ALS1 and ALS2 into Arabidopsis thaliana. The resistance of homozygous A. thaliana to bensulfuron-methyl and penoxsulam aligned with bioassay trends. Furthermore, we measured the ploidy, relative expression, and copy number of ALS1 and ALS2, and found no significant differences, suggesting that the evolution of resistance was primarily attributed to the Pro-197-Ser mutation. Finally, we developed a derived cleaved amplified polymorphic sequence marker for detecting Pro-197-Ser mutation in ALS.

CONCLUSION: The same mutation occurring separately in homoeologous genes resulted in similar resistance levels, whereas simultaneous mutations in homoeologous genes led to increased resistance levels. © 2024 Society of Chemical Industry.}, } @article {pmid39642451, year = {2025}, author = {He, X}, title = {Hyperspectral Raman imaging with multivariate curve resolution-alternating least square (MCR-ALS) analysis for xylazine-containing drug mixtures.}, journal = {Forensic science international}, volume = {367}, number = {}, pages = {112314}, doi = {10.1016/j.forsciint.2024.112314}, pmid = {39642451}, issn = {1872-6283}, mesh = {*Xylazine ; *Spectrum Analysis, Raman ; Least-Squares Analysis ; Humans ; Multivariate Analysis ; Acetaminophen/analysis ; Dipyrone/analysis ; Mannitol ; Excipients/chemistry ; }, abstract = {Xylazine, increasingly implicated in illicit opioid overdose deaths, poses a significant public health threat due to its synergistic effects with fentanyl and resistance to naloxone reversal. Despite its rising prevalence, xylazine is not classified as a controlled substance, leading to its exclusion from routine forensic screening. This study introduces a novel analytical method combining Raman hyperspectral imaging with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to detect xylazine in drug mixtures containing common excipients such as acetaminophen, dipyrone, and mannitol. Utilizing only non-negativity constraints, MCR-ALS successfully resolved the Raman spectrum of xylazine at levels as low as 5 % without reference spectra. The method demonstrated robust performance, with percent variance explained (R[2]) values of 99.60 %, 99.80 %, and 99.91 % for the drug mixtures containing 25 %, 10 %, and 5 % xylazine, respectively.}, } @article {pmid39641862, year = {2024}, author = {Zhang, J and Zhang, X and Xiao, B and Ouyang, J and Wang, P and Peng, X}, title = {Mendelian randomization study of causal link from Cerebrospinal fluid metabolomics to neurodegenerative diseases.}, journal = {Neurogenetics}, volume = {26}, number = {1}, pages = {15}, pmid = {39641862}, issn = {1364-6753}, support = {No. YZ2020MS04//President Foundation of The Fifth Affiliated Hospital, Southern Medical University/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics/cerebrospinal fluid ; *Metabolomics/methods ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid ; Multiple Sclerosis/genetics/cerebrospinal fluid ; Alzheimer Disease/genetics/cerebrospinal fluid ; Parkinson Disease/genetics/cerebrospinal fluid ; Polymorphism, Single Nucleotide ; }, abstract = {To investigate the causal relationships between cerebrospinal fluid (CSF) metabolites and various neurodegenerative diseases (NDDs), we conducted a two-sample Mendelian randomization (MR) analysis. This study utilized summary statistics from genome-wide association studies (GWAS) of CSF metabolites and four common neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). MR methods were employed to determine causal associations, with the inverse variance weighted method as the primary approach. Additionally, different GWAS summary data for NDDs were used to validate the initial results and perform sensitivity analyses to enhance the robustness of the findings. Finally, reverse MR analyses were conducted to assess the possibility of reverse causation. Combining results from the initial and replication phases of MR analysis, we identified potential causal relationships between various CSF metabolites and different NDDs. Specifically, we found potential causal relationships between five CSF metabolites and AD, six CSF metabolites and MS, and thirteen CSF metabolites and ALS. Further sensitivity analyses confirmed the robustness of these associations. Reverse MR analysis indicated causal effects of AD on glucuronate and ALS on acetylcarnitine (C2). Our study, through genetic means, demonstrates close causal associations between the specific types of CSF metabolites and the risk of NDDS (AD, PD, MS, and ALS), providing useful guidance for future clinical researches.}, } @article {pmid39641521, year = {2025}, author = {Manera, U and Callegaro, S and Canosa, A and Palumbo, F and Grassano, M and Bombaci, A and Dagliati, A and Bosoni, P and Daviddi, M and Casale, F and Cabras, S and Matteoni, E and De Marchi, F and Mazzini, L and Moglia, C and Vasta, R and Calvo, A and Chiò, A}, title = {Croplands proximity is associated with amyotrophic lateral sclerosis incidence and age at onset.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16464}, pmid = {39641521}, issn = {1468-1331}, support = {//Dipartimenti di Eccellenza/ ; //EU Joint Programme - Neurodegenerative Disease Research/ ; 259867//Seventh Framework Programme/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; RF-2016-02362405//Ministero della Salute/ ; GA101017598//Horizon 2020 Framework Programme/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology ; Humans ; Incidence ; *Age of Onset ; Female ; Male ; Middle Aged ; Aged ; *Crops, Agricultural ; Adult ; Registries ; Italy/epidemiology ; Risk Factors ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting from an intricate interplay between genetics and environmental factors. Many studies have explored living in rural areas as a possible risk factor for ALS, without focusing simultaneously on incidence, age at onset and phenotypic features.

OBJECTIVE: To evaluate the effect of croplands residential proximity on ALS incidence and phenotype, focusing on age of onset, site of onset and progression rate.

METHODS: The address history of ALS patients belonging to the population-based Piemonte and Valle d'Aosta registry (PARALS), diagnosed between 2007 and 2014, was obtained for the 20 years prior to the onset date. The smoothed ALS incidence per year (im) was compared with the percentage of area covered by each crop for each municipality. A proximity score was calculated for each cropland by geolocation, measuring the percentage of area surrounding patients' residence for variable radii, and was used to compare croplands exposure and phenotype.

RESULTS: We observed an increased ALS incidence in the municipalities with a higher percentage of area covered by arable crops (R = 0.191, p < 0.001). Age at onset was significantly lower in those patients who lived near arable crops, with a median anticipation ranging from 1.8 to 3.4 years; using historical data, a significant anticipation was found also for patients living near vineyards.

DISCUSSION: Our study proved a direct association between arable crops and ALS risk and an inverse association between arable crops and vineyards proximity and age at onset, suggesting the possible causative role of specific environmental contaminants.}, } @article {pmid39640847, year = {2024}, author = {Raineri, D and De Marchi, F and Vilardo, B and Barbero Mazzucca, C and Scotti, L and Kustrimovic, N and Mazzini, L and Cappellano, G and Chiocchetti, A}, title = {Circulating GLAST[+] EVs are increased in amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular biosciences}, volume = {11}, number = {}, pages = {1507498}, pmid = {39640847}, issn = {2296-889X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, hallmarked by the gradual deterioration of motor neurons, culminating in muscle weakness and fatal paralysis. The exact etiology of ALS remains elusive, and there is a critical need for reliable biomarkers to aid in diagnosis and monitoring of disease progression. Extracellular vesicles (EVs) have emerged as promising candidates for biomarker discovery in neurodegenerative diseases such as ALS, giving access to pathologically relevant tissues otherwise typically challenging or invasive to sample. Indeed, EVs can derive by many cell types within the central nervous system, cross the blood-brain barrier and reach the blood, where they can be easily measured. One of the central mechanisms implicated in ALS pathology is glutamate excitotoxicity, which involves excessive glutamate accumulation due to impaired uptake by astrocytes and other glial cells, leading to neuronal damage. GLAST is a key glutamate transporter responsible for maintaining extracellular gluta-mate levels, and its dysregulation is thought to contribute significantly to ALS development and associated neuropathogenesis. Here, we applied a quick and validated method, to evaluate GLAST[+] EVs in ALS patients' plasma and age-matched healthy controls. We found an increase in GLAST[+] EVs that holds promise for uncovering novel diagnostic and therapeutic avenues in ALS research.}, } @article {pmid39640633, year = {2024}, author = {Nikafshan Rad, H and Su, Z and Trinh, A and Hakim Newton, MA and Shamsani, J and Nygc Als Consortium, and Karim, A and Sattar, A}, title = {Amyotrophic lateral sclerosis diagnosis using machine learning and multi-omic data integration.}, journal = {Heliyon}, volume = {10}, number = {20}, pages = {e38583}, pmid = {39640633}, issn = {2405-8440}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex and rare neurodegenerative disorder characterized by significant genetic, molecular, and clinical heterogeneity. Despite numerous endeavors to discover the genetic factors underlying ALS, a significant number of these factors remain unknown. This knowledge gap highlights the necessity for personalized medicine approaches that can provide more comprehensive information for the purposes of diagnosis, prognosis, and treatment of ALS. This work utilizes an innovative approach by employing a machine learning-facilitated, multi-omic model to develop a more comprehensive knowledge of ALS. Through unsupervised clustering on gene expression profiles, 9,847 genes associated with ALS pathways are isolated and integrated with 7,699 genes containing rare, presumed pathogenic genomic variants, leading to a comprehensive amalgamation of 17,546 genes. Subsequently, a Variational Autoencoder is applied to distil complex biomedical information from these genes, culminating in the creation of the proposed Multi-Omics for ALS (MOALS) model, which has been designed to expose intricate genotype-phenotype interconnections within the dataset. Our meticulous investigation elucidates several pivotal ALS signaling pathways and demonstrates that MOALS is a superior model, outclassing other machine learning models based on single omic approaches such as SNV and RNA expression, enhancing accuracy by 1.7 percent and 6.2 percent, respectively. The findings of this study suggest that analyzing the relationships within biological systems can provide heuristic insights into the biological mechanisms that help to make highly accurate ALS diagnosis tools and achieve more interpretable results.}, } @article {pmid39639468, year = {2024}, author = {Arango-Cortes, ML and Giraldo-Cadavid, LF and Latorre Quintana, M and Forero-Cubides, JD and Gonzalez-Bermejo, J}, title = {Diaphragm pacing compared with mechanical ventilation in patients with chronic respiratory failure caused by diaphragmatic dysfunction: a systematic review and meta-analysis.}, journal = {Expert review of respiratory medicine}, volume = {18}, number = {12}, pages = {1101-1111}, doi = {10.1080/17476348.2024.2421846}, pmid = {39639468}, issn = {1747-6356}, mesh = {Humans ; Chronic Disease/therapy ; *Diaphragm/physiopathology ; *Electric Stimulation Therapy/methods/statistics & numerical data ; Length of Stay/statistics & numerical data ; Quality of Life ; *Respiration, Artificial/adverse effects/methods/statistics & numerical data ; *Respiratory Paralysis/etiology/mortality/physiopathology/therapy ; Spinal Cord Injuries/complications/mortality/physiopathology/therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: The effectiveness of diaphragmatic electrical stimulation (DES) compared to mechanical ventilation (MV) in improving clinical outcomes such as quality-of-life (QOL) and hospital stay remains inconsistent.

METHODS: We conducted a systematic review and meta-analysis by searching PubMed, Scopus, Google Scholar, LILACS, and IEEE Xplore. We included comparative studies (randomized controlled trials and observational studies) of DES administered via the phrenic nerve or intramuscular electrodes, compared with MV in adults with diaphragmatic paralysis or paresis. Two authors independently extracted data and assessed bias, with discrepancies resolved by a senior author. Results were pooled using the inverse variance method.

RESULTS: Out of 1,290 articles, nine were included in the systematic review, totaling 852 subjects. In spinal cord injury (SCI), one study reported lower mortality with DES, while three found no difference compared to MV. In these patients, DES was associated with shorter hospital stay, similar QOL, and heterogeneous results on respiratory infections. In amyotrophic lateral sclerosis (ALS), DES was associated with higher mortality and similar QOL compared to MV. Most SCI studies had a serious risk of bias.

CONCLUSION: DES shows potential in reducing hospital stay and respiratory infections in SCI but is associated with higher mortality in ALS.}, } @article {pmid39638345, year = {2025}, author = {Webster, CP and Hall, B and Crossley, OM and Dauletalina, D and King, M and Lin, YH and Castelli, LM and Yang, ZL and Coldicott, I and Kyrgiou-Balli, E and Higginbottom, A and Ferraiuolo, L and De Vos, KJ and Hautbergue, GM and Shaw, PJ and West, RJ and Azzouz, M}, title = {RuvBL1/2 reduce toxic dipeptide repeat protein burden in multiple models of C9orf72-ALS/FTD.}, journal = {Life science alliance}, volume = {8}, number = {2}, pages = {}, pmid = {39638345}, issn = {2575-1077}, support = {MR/V000470/1/MRC_/Medical Research Council/United Kingdom ; MR/V030140/1/MRC_/Medical Research Council/United Kingdom ; MR/W00416X/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Humans ; Mice ; *Disease Models, Animal ; *Dipeptides/metabolism ; *ATPases Associated with Diverse Cellular Activities/metabolism/genetics ; *DNA Helicases/genetics/metabolism ; *Mice, Transgenic ; DNA Repeat Expansion/genetics ; Carrier Proteins/metabolism/genetics ; Motor Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Male ; }, abstract = {A G4C2 hexanucleotide repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Bidirectional transcription and subsequent repeat-associated non-AUG (RAN) translation of sense and antisense transcripts leads to the formation of five dipeptide repeat (DPR) proteins. These DPRs are toxic in a wide range of cell and animal models. Therefore, decreasing RAN-DPRs may be of therapeutic benefit in the context of C9ALS/FTD. In this study, we found that C9ALS/FTD patients have reduced expression of the AAA+ family members RuvBL1 and RuvBL2, which have both been implicated in aggregate clearance. We report that overexpression of RuvBL1, but to a greater extent RuvBL2, reduced C9orf72-associated DPRs in a range of in vitro systems including cell lines, primary neurons from the C9-500 transgenic mouse model, and patient-derived iPSC motor neurons. In vivo, we further demonstrated that RuvBL2 overexpression and consequent DPR reduction in our Drosophila model was sufficient to rescue a number of DPR-related motor phenotypes. Thus, modulating RuvBL levels to reduce DPRs may be of therapeutic potential in C9ALS/FTD.}, } @article {pmid39638270, year = {2025}, author = {Ruzzante, B and Fruzzetti, F and Cattaneo, M and Lauria Pinter, G and Marcuzzo, S and Candiani, G and Bono, N}, title = {Harnessing osmotic shock for enhanced intracellular delivery of (nano)cargos.}, journal = {International journal of pharmaceutics}, volume = {669}, number = {}, pages = {125008}, doi = {10.1016/j.ijpharm.2024.125008}, pmid = {39638270}, issn = {1873-3476}, mesh = {*Osmotic Pressure ; Humans ; *Cell Survival/drug effects ; Nanoparticles/administration & dosage/chemistry ; Drug Delivery Systems/methods ; Fibroblasts/drug effects/metabolism ; Animals ; Cell Size ; Cell Line ; Cells, Cultured ; }, abstract = {Efficient intracellular delivery of exogenous (nano)materials is critical for both research and therapeutic applications. The physicochemical properties of the cargo play a crucial role in determining internalization efficacy. Consequently, significant research efforts are focused on developing innovative and effective methodologies to optimize (nano)material delivery. In this study, we utilized osmotic shock to enhance (nano)cargos internalization. We examined the effects of hypotonic/hypertonic shock on both primary and cell lines, assessing parameters such as cell viability, cell volume, membrane tension changes, and particle uptake. Our results indicate that short-lived osmotic shock does not harm cells. Hypotonic shock induced temporary shape changes lasting up to 5 min, followed by a 15-minute recovery period. Importantly, hypotonic shock increased the uptake of 100-nm and 500-nm particles by ∼ 3- and ∼ 5-fold, respectively, compared to isotonic conditions. In contrast, the hypertonic shock did not impact cell behavior or particle uptake. Notably, the internalization mechanisms triggered by osmotic shock operate independently of active endocytic pathways, making hypotonic stimulation particularly beneficial for hard-to-treat cells. When primary fibroblasts derived from amyotrophic lateral sclerosis (ALS)-patients were exposed to hypotonic shock in the presence of the therapeutic cargo icerguastat, there was an increased expression of miR-106b-5p compared to isotonic conditions. In conclusion, osmotic shock presents a promising strategy for improving drug delivery within cells and, potentially, in tissues such as muscles or skin, where localized drug administration is preferred.}, } @article {pmid39637982, year = {2024}, author = {Vallée, S and Deneux, V and Funaro, D and Marcoux, D and Powell, J and Hatami, A and Coulombe, J and Piram, M and McCuaig, CC}, title = {Long-term evolution of prepubertal-onset anogenital lichen sclerosus: A 35-year retrospective and cross-sectional study from a single tertiary care maternal and pediatric center.}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.09.086}, pmid = {39637982}, issn = {1097-6787}, abstract = {BACKGROUND: Anogenital lichen sclerosus (ALS) in children may persist after puberty with potential clinical repercussions.

OBJECTIVE: The purpose of this study was to evaluate postpubertal evolution of girls with ALS diagnosed in the prepubertal period based on physical examination, the persistence of functional symptoms, and the effect on quality of life.

METHODS: We retrospectively reviewed 65 cases of girls with prepubertal-onset ALS. Onset, signs/symptoms, photos, evolution, and treatment were collected from the medical records. Subsequently, 30 of these 65 patients were assessed for persistence of signs/symptoms by physical examination and/or standardized questionnaire.

RESULTS: Signs of active disease after puberty based on physical examination were present in 92% (N = 23) of examined patients. A high proportion of cases with persistent ALS after puberty were asymptomatic (47%, N = 14).

LIMITATIONS: This is a single-center retrospective study with a limited number of patients. Half of our original cohort could not be reached or declined a follow-up visit.

CONCLUSION: Prepubertal lichen sclerosus is a chronic condition that can be asymptomatic after puberty despite continued disease activity. We recommend long-term follow-up of patients with prepubertal ALS to prevent associated morbidity.}, } @article {pmid39636751, year = {2025}, author = {Desai, AB and Agarwal, A and Mohamed, AS and Mohamed, KH and Middlebrooks, EH and Bhatt, AA and Gupta, V and Kumar, N and Sechi, E and Flanagan, EP and López Chiriboga, S}, title = {Motor Neuron Diseases and Central Nervous System Tractopathies: Clinical-Radiologic Correlation and Diagnostic Approach.}, journal = {Radiographics : a review publication of the Radiological Society of North America, Inc}, volume = {45}, number = {1}, pages = {e240067}, doi = {10.1148/rg.240067}, pmid = {39636751}, issn = {1527-1323}, mesh = {Humans ; *Motor Neuron Disease/diagnostic imaging ; Diagnosis, Differential ; Magnetic Resonance Imaging/methods ; Pyramidal Tracts/diagnostic imaging ; }, abstract = {White matter tracts within the central nervous system are organized into ascending and descending pathways that transmit sensory input and motor output, respectively. Tractopathy, or damage to these tracts, can impair sensory or motor functions. Motor neuron diseases are pathologic processes affecting the upper or lower motor neurons. Amyotrophic lateral sclerosis (ALS) is the most common form of acquired motor neuron disease. Traditionally, ALS has affected upper and lower motor neurons of the extremities, torso, and head and neck. There are several ALS variants, some of which affect only the upper motor neurons (eg, primary lateral sclerosis), lower motor neurons (eg, progressive muscular atrophy), or motor neurons of the head and neck (eg, progressive bulbar palsy). Characteristic imaging features of ALS include abnormal T2 hyperintensity within the brain along the corticospinal tract, as well as cortical susceptibility signal intensity along the precentral gyrus, termed the "motor band" sign. Spinal muscular atrophy is a less common primary motor neuron disease and appears on images as atrophy of the anterior horn of the spinal cord, as well as proximal muscle atrophy. In addition to pure motor neuron diseases, there are numerous toxic and metabolic conditions, genetic disorders, infectious diseases, and immune-mediated disorders that can secondarily affect the corticospinal tracts (corticospinal tractopathies), producing symptoms of upper motor neuron injury. These tractopathies are visible at MRI as T2-hyperintense lesions along varying segments of the corticospinal tract. A comprehensive diagnostic approach that integrates clinical symptoms with radiologic and laboratory findings is crucial to distinguish among these varied conditions. [©]RSNA, 2024 Supplemental material is available for this article.}, } @article {pmid39636698, year = {2024}, author = {Nona, RJ and Henderson, RD and Mccombe, PA}, title = {Routine blood biochemical biomarkers in amyotrophic lateral sclerosis: Systematic review and cohort analysis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/21678421.2024.2435976}, pmid = {39636698}, issn = {2167-9223}, abstract = {Introduction: Blood biochemical biomarkers, including urate, creatinine, albumin, and creatine kinase, have been shown to be useful in ALS. To provide further information about the roles of these four biomarkers roles we performed a systematic review. In addition, we also performed a new study of the role of these biomarkers in predicting survival, using data from our local ALS cohort. Methods: (1) Using established databases and other sources, we searched for papers about the use of urate, creatinine, albumin, and creatine kinase as biomarkers in ALS. Included articles were reviewed for information about biomarker levels in ALS and controls, association with markers of functional decline, and survival. (2) For our local ALS cohort, we performed survival analysis, Cox-proportionate-hazard ratio and ROC curves to investigate the use of these biomarkers in predicting survival. Results: (1) For systematic review, 104 papers were included. There was some variability in the findings. For urate, there was evidence of decreased levels in ALS, with higher levels associated ith longer survival. For creatinine, there was evidence of decreased levels in ALS, and higher levels correlated with longer survival. For albumin, some reports of reduced levels in ALS, but no consistent association with survival. For creatine kinase, some reports of increased levels in ALS, with inconsistent association with survival. (2) For the local ALS cohort there was evidence that urate and creatinine were associated with survival, but no significant association with survival. There was less evidence for albumin and CK. Discussion: This study provides support for further studies of these readily available biochemical measurement as bioamerkers in ALS.}, } @article {pmid39635310, year = {2024}, author = {Yuan, J and Zhang, YJ and Wen, W and Liu, XC and Chen, FL and Yang, Y}, title = {Afferent loop syndrome of a patient with recurrent fever: A case report.}, journal = {World journal of radiology}, volume = {16}, number = {11}, pages = {678-682}, pmid = {39635310}, issn = {1949-8470}, abstract = {BACKGROUND: Afferent loop syndrome (ALS) is a rare complication, Aoki et al reported that the incidence of distal gastrectomy in Billroth-II is 0.3%-1.0%. The clinical manifestations of ALS are atypical, which can manifest as severe abdominal pain, vomiting, obstructive jaundice, malnutrition, etc.

CASE SUMMARY: The patient was a 58-year-old man who complained of recurrent high fever for more than 1 week. Laboratory tests showed an increase in neutrophil ratio, procalcitonin, C-reactive protein, and abnormal liver function. Enhanced computed tomography scan of the abdomen showed small intestinal obstruction between the anastomosis of the gastrojejunum, bile duct, and pancreaticoduodenum. Gastroscopy revealed significant narrowing of the lumen 15 cm from the anastomosis into the afferent loop. After performing balloon dilation and placement of the nutrition tube, the patient did not experience further fever.

CONCLUSION: ALS is relatively rare after pancreaticoduodenectomy, and the treatment depends on the nature of the obstructive lesion. The traditional treatment method is surgery, and in recent years, endoscopy has provided a new treatment method for ALS.}, } @article {pmid39634573, year = {2024}, author = {Braimah, RO and Taiwo, AO and Olasoji, HO and Legbo, JN and Amundson, M and Ibikunle, AA and Suleiman, IK and Bala, M and Ile-Ogedengbe, BO}, title = {Braimah-Taiwo et al New Classification System and Treatment Algorithm of Mandibulo-Maxillary Synostosis Related to Noma. Field Experience From Noma Children Hospital Sokoto, Nigeria.}, journal = {Craniomaxillofacial trauma & reconstruction}, volume = {17}, number = {4}, pages = {279-290}, pmid = {39634573}, issn = {1943-3875}, abstract = {STUDY DESIGN: This was a retrospective study at Noma Children Hospital, Sokoto, Nigeria, from January 2018 to December 2021.

OBJECTIVE: The main objective of this appraisal was to present Braimah-Taiwo et al's new classification system for mandibulo-maxillary synostosis secondary to noma and also to provide a guide to their treatment.

METHODS: Noma with mandibulo-maxillary synostosis was the main inclusion criteria. Excluded were cases of acute noma and noma without mandibulo-maxillary synostosis. Data retrieved include demographics of patients and extent of bony ankylosis and mandibulo-maxillary synostosis.

RESULTS: A total of 64 patients (30 (46.9%) males and 34 (53.1%) females) were managed. Ages ranged from 6 to 40 years with mean ± SD (18.2 ± 7.6) years. Regarding the new classification system of mandibulo-maxillary synostosis, 6 (9.4%) patients presented with Type 1 (Mild joint obliteration)±Soft tissue scarring, 24 (37.5%) presented with Type II (Total joint obliteration)±Soft tissue scarring, 21 (32.8%) presented with Type III (Coronoid, zygoma and maxilla) ±Soft tissue scarring, 4 (6.3%) presented with Type IV (Condyle, glenoid fossa, coronoid, sigmoid notch and zygoma) ±Soft tissue scarring, 7 (10.9%) presented with Type V (Condyle, glenoid fossa, coronoid, sigmoid notch, zygoma and pterygo-maxilla) ±Soft tissue scarring, while 2 (3.1%) patients presented with Type VI (condyle, glenoid fossa, coronoid, sigmoid notch, zygoma, pterygo-maxilla and the orbit) ±Soft tissue scarring.

CONCLUSIONS: Pattern of tissue destruction in noma patients is complex involving both soft and hard tissues. This new classification will guide surgeons in the effective management of these patients.}, } @article {pmid39633896, year = {2024}, author = {Bhaskaran, S and Piekarz, KM and Brown, J and Yang, B and Ocañas, SR and Wren, JD and Georgescu, C and Bottoms, C and Murphy, A and Thomason, J and Saunders, D and Smith, N and Towner, R and Van Remmen, H}, title = {The nitrone compound OKN-007 delays motor neuron loss and disease progression in the G93A mouse model of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1505369}, pmid = {39633896}, issn = {1662-4548}, abstract = {Our study investigated the therapeutic potential of OKN-007 in the SOD1 G93A mouse model of amyotrophic lateral sclerosis (ALS). The impact of OKN-007, known for its antioxidant, anti-inflammatory, and neuroprotective properties, was tested at two doses (150 mg/kg and 300 mg/kg) at onset and late-stage disease. Results demonstrated a significant delay in disease progression at both doses, with treated mice showing a slower advance to early disease stages compared to untreated controls. Motor neuron counts in the lumbar spinal cord were notably higher in OKN-007 treated mice at the time of disease onset, suggesting neuroprotection. Additionally, OKN-007 reduced microglial activation and preserved reduced neuromuscular junction fragmentation, although it did not significantly alter the increase in astrocyte number or the decline in hindlimb muscle mass. MR spectroscopy (MRS) revealed improved spinal cord perfusion and normalized myo-inositol levels in treated mice, supporting reduced neuroinflammation. While the expression of several proteins associated with inflammation is increased in spinal cord extracts from G93A mice, OKN-007 dampened the expression of IL-1β, IL-1ra and IL-1α. Despite its promising effects on early-stage disease progression, in general, the beneficial effects of OKN-007 diminished over longer treatment durations. Further, we found no improvement in muscle atrophy or weakness phenotypes in OKN-007 treated G93A mice, and no effect on mitochondrial function or lifespan. Overall, our findings suggest that OKN-007 holds potential as a disease-modifying treatment for ALS, although further research is needed to optimize dosing regimens and understand its long-term effects.}, } @article {pmid39633494, year = {2024}, author = {Ko, VI and Ong, K and Kwon, DY and Li, X and Pietrasiewicz, A and Harvey, JS and Lulla, M and Bhat, G and Cleveland, DW and Ravits, JM}, title = {CK1δ/ε-mediated TDP-43 phosphorylation contributes to early motor neuron disease toxicity in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {187}, pmid = {39633494}, issn = {2051-5960}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Phosphorylation ; *DNA-Binding Proteins/metabolism/genetics ; *Casein Kinase Idelta/metabolism/genetics ; *Casein Kinase 1 epsilon/metabolism/genetics ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Humans ; Motor Neurons/metabolism/pathology/drug effects ; Mice, Inbred C57BL ; Male ; Mice, Knockout ; }, abstract = {Hyperphosphorylated TDP-43 aggregates in the cytoplasm of motor neurons is a neuropathological signature of amyotrophic lateral sclerosis (ALS). These aggregates have been proposed to possess a toxic disease driving role in ALS pathogenesis and progression, however, the contribution of phosphorylation to TDP-43 aggregation and ALS disease mechanisms remains poorly understood. We've previously shown that CK1δ and CK1ε phosphorylate TDP-43 at disease relevant sites, and that genetic reduction and chemical inhibition could reduce phosphorylated TDP-43 (pTDP-43) levels in cellular models. In this study, we advanced our findings into the hTDP-43-ΔNLS in vivo mouse model of ALS and TDP-43 proteinopathy. This mouse model possesses robust disease-relevant features of ALS, including TDP-43 nuclear depletion, cytoplasmic pTDP-43 accumulation, motor behavior deficits, and shortened survival. We tested the effect of homozygous genetic deletion of Csnk1e in the hTDP-43-ΔNLS mouse model and observed a delay in the formation of pTDP-43 without significant ultimate rescue of TDP-43 proteinopathy or disease progression. Homozygous genetic deletion of Csnk1d is lethal in mice, and we were unable to test the role of CK1δ alone. We then targeted both CK1δ and CK1ε kinases by way of CK1δ/ε-selective PF-05236216 inhibitor in the hTDP-43-ΔNLS mouse model, reasoning that inhibiting CK1ε alone would be insufficient as shown by our Csnk1e knockout mouse model study. Treated mice demonstrated reduced TDP-43 phosphorylation, lowered Nf-L levels, and improved survival in the intermediate stages. The soluble TDP-43 may have been more amenable to the inhibitor treatment than insoluble TDP-43. However, the treatments did not result in improved functional measurements or in overall survival. Our results demonstrate that phosphorylation contributes to neuronal toxicity and suggest CK1δ/ε inhibition in combination with other therapies targeting TDP-43 pathology could potentially provide therapeutic benefit in ALS.}, } @article {pmid39631325, year = {2024}, author = {Zhang, Y and Liu, Q and Xie, H and Zhang, W and Lin, X and Zhang, H and Yu, H and Ma, Y and Zhang, C and Geng, H and Shi, N and Cui, L and Li, B and Li, YF}, title = {Fecal microbiota transplantation as an effective way in treating methylmercury-poisoned rats.}, journal = {The Science of the total environment}, volume = {957}, number = {}, pages = {177850}, doi = {10.1016/j.scitotenv.2024.177850}, pmid = {39631325}, issn = {1879-1026}, mesh = {Animals ; *Methylmercury Compounds/metabolism ; *Fecal Microbiota Transplantation ; Rats ; *Gastrointestinal Microbiome ; Male ; Feces/microbiology ; }, abstract = {Methylmercury (MeHg) can cause devastating neurotoxicity in animals and human beings. Gut microbiota dysbiosis has been found in MeHg-poisoned animals. Fecal microbiota transplantation (FMT) has been shown to improve clinical outcomes in a variety of diseases such as epilepsy, amyotrophic lateral sclerosis (ALS) and autism. The aim of this study was to investigate the effects of FMT on MeHg-poisoned rats. FMT treatment was applied to MeHg-poisoned rats for 14 days. The neurobehavior, weight changes, dopamine (DA), the total Hg and MeHg level were evaluated. Besides, the gut microbiota and metabolites change in feces were also checked. It was found that FMT helped weight gain, alleviated the neurological disorders, enhanced fecal mercury excretion and MeHg demethylation, reconstructed gut microbiome and promoted the production of gut-brain axis related-metabolites in MeHg-poisoned rats. This study elaborates on the therapeutic efficacy of FMT in treating of MeHg-poisoned rats, which sheds lights on the treatment of neurological diseases like Minamata Disease and even Parkinson's Disease.}, } @article {pmid39630626, year = {2024}, author = {Szeky, B and Jurakova, V and Fouskova, E and Feher, A and Zana, M and Karl, VR and Farkas, J and Bodi-Jakus, M and Zapletalova, M and Pandey, S and Kucera, R and Lochman, J and Dinnyes, A}, title = {Efficient derivation of functional astrocytes from human induced pluripotent stem cells (hiPSCs).}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0313514}, pmid = {39630626}, issn = {1932-6203}, mesh = {*Astrocytes/cytology/metabolism ; Humans ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Cell Differentiation ; *S100 Calcium Binding Protein beta Subunit/metabolism ; Cytokines/metabolism ; Aquaporin 4/metabolism ; Glial Fibrillary Acidic Protein/metabolism ; Cells, Cultured ; }, abstract = {Astrocytes are specialized glial cell types of the central nervous system (CNS) with remarkably high abundance, morphological and functional diversity. Astrocytes maintain neural metabolic support, synapse regulation, blood-brain barrier integrity and immunological homeostasis through intricate interactions with other cells, including neurons, microglia, pericytes and lymphocytes. Due to their extensive intercellular crosstalks, astrocytes are also implicated in the pathogenesis of CNS disorders, such as ALS (amyotrophic lateral sclerosis), Parkinson's disease and Alzheimer's disease. Despite the critical importance of astrocytes in neurodegeneration and neuroinflammation are recognized, the lack of suitable in vitro systems limits their availability for modeling human brain pathologies. Here, we report the time-efficient, reproducible generation of astrocytes from human induced pluripotent stem cells (hiPSCs). Our hiPSC-derived astrocytes expressed characteristic astrocyte markers, such as GFAP, S100b, ALDH1L1 and AQP4. Furthermore, hiPSC-derived astrocytes displayed spontaneous calcium transients and responded to inflammatory stimuli by the secretion of type A1 and type A2 astrocyte-related cytokines.}, } @article {pmid39630042, year = {2024}, author = {Zinman, L and Duni, E and Abrahao, A}, title = {Rethinking Drug Reimbursement Criteria in Amyotrophic Lateral Sclerosis.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {51}, number = {5}, pages = {606-607}, doi = {10.1017/cjn.2023.320}, pmid = {39630042}, issn = {0317-1671}, } @article {pmid39629626, year = {2025}, author = {Boutin, RCT and Shobeirian, F and Adam, S and Lehman, A and Salvarinova, R and Friedman, JM}, title = {Immune Dysregulation in a Child With SOD1-Related Neurological Disease.}, journal = {American journal of medical genetics. Part A}, volume = {197}, number = {4}, pages = {e63949}, doi = {10.1002/ajmg.a.63949}, pmid = {39629626}, issn = {1552-4833}, support = {//Mining for Miracles (BCCH Foundation)/ ; //Genome British Columbia/ ; }, mesh = {Humans ; Male ; *Superoxide Dismutase-1/genetics ; *Homozygote ; Young Adult ; Child ; Nervous System Diseases/genetics/pathology ; Phenotype ; Mutation/genetics ; Quadriplegia/genetics/pathology ; }, abstract = {Spastic tetraplegia and axial hypotonia (STAHP) associated with biallelic SOD1 deficiency is a recently described neurological disorder affecting children. Five studies have described a total of nine cases thus far, all characterized by the onset of progressive spastic tetraplegia beginning before 2 years of age. All but two of these cases are associated with homozygosity for the same genetic variant (NM_000454.4:c.335dupG; NP_000445.1:p.Cys112Trpfs*11) that leads to a non-functional enzyme product. More recently, a homozygous 3-base pair in-frame deletion (NM_000454.5: c.357_357+2delGGT) and a truncating frameshift variant (NM_000454.5: c.52_56del5ins154) in SOD1 have been described in similarly affected patients lacking SOD1 activity. Here we expand on the neurological and extra-neuronal phenotypes of STAHP in a patient with a novel homozygous SOD1 variant predicted to result in disrupted calcium- and zinc-binding activity of the encoded enzyme. We describe a 19-year-old male born to consanguineous parents who is homozygous for an NM_000454.4:c.369_371del SOD1 variant. The patient had progressive neuromuscular degeneration with onset before 1 year of age, consistent with a diagnosis of STAHP. Brain MRI at 7 years of age showed cerebellar atrophy, as has previously been described in this condition, as well as small optic nerves and a hypoplastic optic chiasm, which have not been reported previously. Our patient also exhibited clinical features of immune dysregulation with treatment-refractory inflammatory bowel disease, asthma, recurrent infections, and dermatitis. Overall, the early-onset progressive neurological disorder in our patient, found in association with homozygosity for an SOD1 variant that is predicted to result in impaired function of the transcribed protein, is consistent with a diagnosis of STAHP. Our patient also demonstrates optic atrophy and disrupted immune homeostasis, which have not been previously described as part of this condition. Taken together with previous case studies in children carrying loss-of-function variants of SOD1, this case highlights a possible role for antioxidant therapy in slowing disease progression in patients lacking SOD1 activity. These cases also draw attention to the need for careful consideration of possible harmful neuronal and extra-neuronal complications of proposed SOD1 knockdown therapies against ALS.}, } @article {pmid39628898, year = {2024}, author = {Stansberry, WM and Fiur, NC and Robins, MM and Pierchala, BA}, title = {Analysis of translatomic changes in the Ubqln2[P497S] model of ALS reveals that motor neurons express muscle-associated genes in non-disease states.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1491415}, pmid = {39628898}, issn = {1664-2295}, support = {T32 AG071444/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressively worsening motor symptoms that lead to eventual fatal paralysis. The number of gene mutations associated with ALS have increased dramatically in recent years, suggesting heterogeneity in the etiology of ALS and the need to develop new models of the disease that encompass these pathologies. In 2011, mutations in the UBQLN2 gene were identified in families with both ALS and frontotemporal dementia (FTD) and have since been linked to ubiquitinated TDP43 inclusion pathology. The involvement of UBQLN2 in ubiquitination and proteasome function suggests an important role in proteostasis, which is reported to be impaired in ALS.

METHODS: A UBQLN2 mouse model was generated for the P497S mutation and recapitulates some of the motor symptoms of ALS. We utilized ribosomal profiling followed by mRNA sequencing of associated transcripts to characterize gene expression changes of motor neurons in the Ubqln2[P497S] model and evaluated ALS phenotypes in these animals.

RESULTS: At 12 months of age, we observed reduced motor neuron survival and neuromuscular junction denervation in these mice that translated into motor deficits observed in locomotor behavioral trials. The sequencing of motor neuron transcripts revealed that Wnt pathways and muscle-related transcripts were downregulated in Ubqln2[P497S] mice, while metabolic pathways were upregulated.

DISCUSSION: Surprisingly, genes often reported to be muscle-specific, such as Desmin and Acta1, were expressed in motor neurons and were dramatically downregulated in symptomatic Ubqln2[P497S] mice. The expression of muscle transcripts by motor neurons suggests their potentially supportive role in skeletal muscle maintenance.}, } @article {pmid39628659, year = {2024}, author = {Ye, Q and Li, X and Gao, W and Gao, J and Zheng, L and Zhang, M and Yang, F and Li, H}, title = {Role of Rho-associated kinases and their inhibitor fasudil in neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1481983}, pmid = {39628659}, issn = {1662-4548}, abstract = {Neurodegenerative diseases (NDDs) are prevalent in the elderly. The pathogenesis of NDDs is complex, and currently, there is no cure available. With the increase in aging population, over 20 million people are affected by common NDDs alone (Alzheimer's disease and Parkinson's disease). Therefore, NDDs have profound negative impacts on patients, their families, and society, making them a major global health concern. Rho-associated kinases (ROCKs) belong to the serine/threonine protein kinases family, which modulate diverse cellular processes (e.g., apoptosis). ROCKs may elevate the risk of various NDDs (including Huntington's disease, Parkinson's disease, and Alzheimer's disease) by disrupting synaptic plasticity and promoting inflammatory responses. Therefore, ROCK inhibitors have been regarded as ideal therapies for NDDs in recent years. Fasudil, one of the classic ROCK inhibitor, is a potential drug for treating NDDs, as it repairs nerve damage and promotes axonal regeneration. Thus, the current review summarizes the relationship between ROCKs and NDDs and the mechanism by which fasudil inhibits ROCKs to provide new ideas for the treatment of NDDs.}, } @article {pmid39627937, year = {2024}, author = {Gielas, AM}, title = {Wounds and Vulnerabilities. The Participation of Special Operations Forces in Experimental Brain-Computer Interface Research.}, journal = {Cambridge quarterly of healthcare ethics : CQ : the international journal of healthcare ethics committees}, volume = {}, number = {}, pages = {1-22}, doi = {10.1017/S096318012400063X}, pmid = {39627937}, issn = {1469-2147}, abstract = {Brain-computer interfaces (BCIs) exemplify a dual-use neurotechnology with significant potential in both civilian and military contexts. While BCIs hold promise for treating neurological conditions such as spinal cord injuries and amyotrophic lateral sclerosis in the future, military decisionmakers in countries such as the United States and China also see their potential to enhance combat capabilities. Some predict that U.S. Special Operations Forces (SOF) will be early adopters of BCI enhancements. This article argues for a shift in focus: the U.S. Special Operations Command (SOCOM) should pursue translational research of medical BCIs for treating severely injured or ill SOF personnel. After two decades of continuous military engagement and on-going high-risk operations, SOF personnel face unique injury patterns, both physical and psychological, which BCI technology could help address. The article identifies six key medical applications of BCIs that could benefit wounded SOF members and discusses the ethical implications of involving SOF personnel in translational research related to these applications. Ultimately, the article challenges the traditional civilian-military divide in neurotechnology, arguing that by collaborating more closely with military stakeholders, scientists can not only help individuals with medical needs, including servicemembers, but also play a role in shaping the future military applications of BCI technology.}, } @article {pmid39627617, year = {2024}, author = {Wiersema, AF and Rennenberg, A and Smith, G and Varderidou-Minasian, S and Pasterkamp, RJ}, title = {Shared and distinct changes in the molecular cargo of extracellular vesicles in different neurodegenerative diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {479}, pmid = {39627617}, issn = {1420-9071}, support = {XS grant//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; GoALS//Stichting ALS Nederland/ ; TOTALS//Stichting ALS Nederland/ ; MUSALS//Stichting ALS Nederland/ ; ATAXALS//Stichting ALS Nederland/ ; MAXOMOD//E-rare3/ ; INTEGRALS//Rare-3/ ; TRIAGE//JPND/ ; }, mesh = {Animals ; Humans ; Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Biomarkers/analysis/metabolism ; *Cell Communication ; *Extracellular Vesicles/metabolism ; MicroRNAs/metabolism/genetics ; *Neurodegenerative Diseases/diagnosis/metabolism/pathology ; Parkinson Disease/metabolism/pathology ; tau Proteins/metabolism ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) affect millions of people worldwide. Curative treatment for these neurodegenerative disorders is still lacking and therefore a further understanding of their cause and progression is urgently needed. Extracellular vesicles (EVs) are nanosized vesicles loaded with cargo, such as proteins and miRNAs, that are released by cells and play an important role in intercellular communication. Intercellular communication through EVs can contribute to the spread of pathological proteins, such as amyloid-beta and tau, or cause pathogenesis through other mechanisms. In addition, EVs may serve as potential biomarkers for diagnosis and for monitoring disease progression. In this review, we summarize and discuss recent advances in our understanding of the role of EVs in AD, ALS an PD with an emphasis on dysregulated cargo in each disease. We highlight shared dysregulated cargo between these diseases, discuss underlying pathways, and outline future implications for therapeutic strategies.}, } @article {pmid39624969, year = {2024}, author = {Yuan, D and Jiang, S and Xu, R}, title = {Clinical features and progress in diagnosis and treatment of amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2399962}, pmid = {39624969}, issn = {1365-2060}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy/epidemiology/genetics ; Humans ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the central nervous system. Despite a large number of studies, the current prognosis of ALS is still not ideal. This article briefly describes the clinical features including epidemiology, genetic structure and clinical manifestations, as well as the progress of new diagnostic criteria and treatment of ALS. Meanwhile, we also discussed further both developments and improvements to enhance understanding and accelerating the introduction of the effective treatments of ALS.}, } @article {pmid39624674, year = {2024}, author = {Nakamura, K and Fujita, K and Suzuki, M and Kunugi, A and Hirozane, Y and Kunikata, T and Takahashi, B and Narazaki, G and Kondo, H and Haji, S and Hirai, K and Izumi, Y}, title = {Neuroinflammation and glycosylation-related cerebrospinal fluid proteins for predicting functional decline in amyotrophic lateral sclerosis: a proteomic study.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1418320}, pmid = {39624674}, issn = {1664-2295}, abstract = {BACKGROUND: The rate of disease progression varies widely among patients with amyotrophic lateral sclerosis (ALS). Prognostic assessment using biomarkers is highly anticipated to improve clinical trial design. We aimed to explore the cerebrospinal fluid (CSF) for prognostic biomarkers to predict future functional decline in patients with ALS.

METHODS: We collected CSF samples from 64 patients with ALS and 25 disease controls. The prospective progression rate was calculated using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) at CSF collection and in 6 months. The ALS patients were classified into slow, intermediate, and fast progression groups. We performed comprehensive proteomic analyses of the CSF samples. Factors with significant changes between slow and fast progression groups were investigated via receiver operating characteristic curve analyses. Moreover, the correlation of the CSF factors with progression rate was evaluated by multiple regression analyses.

RESULTS: In total, 26 proteins changed significantly (p < 0.05 and q < 0.10), with levels varying within a large dynamic range (fold change of >1.5 or < 0.5). A receiver operating characteristic curve analyses showed that the following proteins showed high discrimination power between slow and fast progression groups: glycoprotein non-metastatic melanoma protein B (GPNMB; area under the curve [AUC], 0.88), glial fibrillary acidic protein (AUC, 0.81), glypican-1 (GPC1; AUC, 0.79), alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase (AUC, 0.74), and chitinase-3-like protein 2 (CHI3L2; AUC, 0.73). Of these, GPNMB, GPC1, and CHI3L2 were significantly correlated to prognostic progression rate.

CONCLUSION: This study demonstrated that CSF levels of neuroinflammation and glycosylation-related proteins were significantly correlated with prospective progression rates in patients with ALS. These proteins could be useful prognostic biomarkers for ALS.}, } @article {pmid39623504, year = {2024}, author = {Gupta, R and Bhandari, M and Grover, A and Al-Shehari, T and Kadrie, M and Alfakih, T and Alsalman, H}, title = {Predictive modeling of ALS progression: an XGBoost approach using clinical features.}, journal = {BioData mining}, volume = {17}, number = {1}, pages = {54}, pmid = {39623504}, issn = {1756-0381}, support = {RSP2024R244//King Saud University/ ; }, abstract = {This research presents a predictive model aimed at estimating the progression of Amyotrophic Lateral Sclerosis (ALS) based on clinical features collected from a dataset of 50 patients. Important features included evaluations of speech, mobility, and respiratory function. We utilized an XGBoost regression model to forecast scores on the ALS Functional Rating Scale (ALSFRS-R), achieving a training mean squared error (MSE) of 0.1651 and a testing MSE of 0.0073, with R[2] values of 0.9800 for training and 0.9993 for testing. The model demonstrates high accuracy, providing a useful tool for clinicians to track disease progression and enhance patient management and treatment strategies.}, } @article {pmid39623474, year = {2024}, author = {Hoyle, AC and Stevenson, R and Leonhardt, M and Gillett, T and Martinez-Hernandez, U and Gompertz, N and Clarke, C and Cazzola, D and Metcalfe, BW}, title = {Exploring the 'EarSwitch' concept: a novel ear based control method for assistive technology.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {21}, number = {1}, pages = {210}, pmid = {39623474}, issn = {1743-0003}, mesh = {Humans ; Female ; Male ; Adult ; Middle Aged ; *Self-Help Devices ; Aged ; Tensor Tympani/physiology ; Young Adult ; Nervous System Diseases/rehabilitation ; Adolescent ; Motor Neuron Disease/rehabilitation ; Communication Devices for People with Disabilities ; Muscle Contraction/physiology ; Multiple Sclerosis/rehabilitation ; }, abstract = {BACKGROUND: Loss of communication with loved ones and carers is one of the most isolating and debilitating effects of many neurological disorders. Assistive technology (AT) supports individuals with communication, but the acceptability of AT solutions is highly variable. In this paper a novel ear based control method of AT, the concept of 'EarSwitch', is presented. This new approach is based on detecting ear rumbling, which is the voluntary contraction of the tensor tympani muscle (TTM), resulting in observable movement of the eardrum and a dull rumbling sound. 'EarSwitch' has the potential to be a discreet method that can complement existing AT control methods. However, only a subset of the population can ear rumble and little is known about the ability of rumbling in populations with neurological disorders.

METHODS: To explore the viability of the 'EarSwitch' concept as an AT control method we conducted in-depth online surveys with (N=1853) respondents from the general population and (N=170) respondents with self-declared neurological disorders including Motor Neurone Disease (MND) and Multiple Sclerosis (MS).This is the largest ever study to explore ear rumbling and the first to explore whether rumbling is preserved among individuals with neurological disorders. In addition, we validated rumbling, and investigated usability of the 'EarSwitch' concept as a control input, using in-person otoscopic examination with a subset of participants.

RESULTS: A significant proportion of the population with neurological disorders could benefit from 'EarSwitch' controllable AT. The upper bound prevalence of the ability to rumble without accompanying movements was 55% in the general population, 38% in the neurological population, and 20% of participants with MND (N=95) reported this ability. During the validation procedure, participants achieved high accuracy in self-reporting the ability to rumble (80%) and proved concept of using the 'EarSwitch' method to control a basic interface.

DISCUSSION: 'EarSwitch' is a potential new AT control method control, either by itself or as a supplement to other existing methods. Results demonstrate self-reported ear rumbling is present among patients with different neurological disorders, including MND. Further research should explore how well the ability to rumble is preserved in different types and stages of neurological disorders.}, } @article {pmid39622292, year = {2025}, author = {Ojo, O and Boateng, J and Pacella, R and Hanrahan, A and Essex, R and Dibley, L}, title = {Factors Influencing the Care and Management of Diabetic Foot Ulcers: A Scoping Review.}, journal = {Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists}, volume = {31}, number = {3}, pages = {380-389}, doi = {10.1016/j.eprac.2024.11.010}, pmid = {39622292}, issn = {1530-891X}, mesh = {Humans ; *Diabetic Foot/therapy ; Patient Education as Topic ; Health Knowledge, Attitudes, Practice ; Health Personnel ; Communication ; Disease Management ; }, abstract = {OBJECTIVE: The objective of this scoping review is to explore the experiences of patients' and healthcare practitioners on the factors that influence the care and management of diabetes-related foot ulcers (DFUs).

METHODS: Levac et al's 6-stage framework and the Preferred Reporting Items for Systematic Review and Meta-analysis extension for scoping reviews, guided the review. The SPIDER tool was used to define key elements of the review question. Searches for relevant articles were conducted in electronic databases (PUBMED, CINAHL, AMED, Embase, Cochrane Database of Systematic Reviews, and PsycINFO), Google Scholar, and hand searches of reference lists.

RESULTS: Eight articles met the inclusion criteria and were included in the review. Three themes were identified: Communication and Education about DFUs; Challenges of managing DFUs; and Barriers to treatment and management. The themes are presented as a narrative synthesis.

CONCLUSION: Inadequate knowledge of diabetic foot care by patients and inconsistent communication by healthcare professionals were primary factors affecting the effective management of diabetes-related foot ulcers. Consistent, patient-focused education that is supported by knowledgeable health care professionals should form the foundation of effective diabetic foot ulcer care.}, } @article {pmid39621905, year = {2024}, author = {Van Nerom, M and Ahmed, J and Lazar, T and Meszaros, A and Galand, Q and De Malsche, W and Van Lindt, J and Pancsa, R and Maes, D and Tompa, P}, title = {C9orf72-linked arginine-rich dipeptide repeats aggravate pathological phase separation of G3BP1.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {50}, pages = {e2402847121}, pmid = {39621905}, issn = {1091-6490}, support = {952334//EC | Horizon 2020 Framework Programme (H2020)/ ; 778247//EC | Horizon 2020 Framework Programme (H2020)/ ; K124670//National Research, Development and Innovation Office/ ; K131702//National Research, Development and Innovation Office/ ; SRP51//Vrije Universiteit Brussel (VUB)/ ; A0-2004-070//European Space Agency (ESA)/ ; FWOSB77//Fonds Wetenschappelijk Onderzoek (FWO)/ ; 11D2522N//Fonds Wetenschappelijk Onderzoek (FWO)/ ; HBC.2022.0194//Agentschap Innoveren en Ondernemen (VLAIO)/ ; FK-142285//National Research, Development and Innovation Office/ ; BO/00174/22//Magyar Tudományos Akadémia (MTA)/ ; 184018//Tempus Közalapítvány (TPF)/ ; }, mesh = {*RNA Recognition Motif Proteins/metabolism/genetics/chemistry ; *Poly-ADP-Ribose Binding Proteins/metabolism/genetics/chemistry ; Humans ; *C9orf72 Protein/genetics/metabolism ; *RNA Helicases/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Dipeptides/metabolism/chemistry ; *DNA Helicases/metabolism/genetics ; *Arginine/metabolism/chemistry ; *Nucleophosmin/genetics ; Frontotemporal Dementia/metabolism/genetics/pathology ; Stress Granules/metabolism ; DNA-Binding Proteins/metabolism/genetics/chemistry ; Heterogeneous Nuclear Ribonucleoprotein A1/metabolism/genetics ; Protein Binding ; Phase Separation ; }, abstract = {The toxic effects of C9orf72-derived arginine-rich dipeptide repeats (R-DPRs) on cellular stress granules in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia remain unclear at the molecular level. Stress granules are formed through the switch of Ras GTPase-activating protein-binding protein 1 (G3BP1) by RNA from a closed inactive state to an open activated state, driving the formation of the organelle by liquid-liquid phase separation (LLPS). We show that R-DPRs bind G3BP1 a thousand times stronger than RNA and initiate LLPS much more effectively. Their pathogenic effect is underscored by the slow transition of R-DPR-G3BP1 droplets to aggregated, ThS-positive states that can recruit ALS-linked proteins hnRNPA1, hnRNPA2, and TDP-43. Deletion constructs and molecular simulations show that R-DPR binding and LLPS are mediated via the negatively charged intrinsically disordered region 1 (IDR1) of the protein, allosterically regulated by its positively charged IDR3. Bioinformatic analyses point to the strong mechanistic parallels of these effects with the interaction of R-DPRs with nucleolar nucleophosmin 1 (NPM1) and underscore that R-DPRs interact with many other similar nucleolar and stress-granule proteins, extending the underlying mechanism of R-DPR toxicity in cells. Our results also highlight characteristic differences between the two R-DPRs, poly-GR and poly-PR, and suggest that the primary pathological target of poly-GR is not NPM1 in nucleoli, but G3BP1 in stress granules in affected cells.}, } @article {pmid39621705, year = {2024}, author = {Foldvari, KM and Stolee, P and Neiterman, E and Boscart, V and Tong, C}, title = {"…but I know something's not right here": Exploring the diagnosis and disclosure experiences of persons living with ALS.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0301249}, pmid = {39621705}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis ; Female ; Male ; Middle Aged ; Aged ; *Caregivers/psychology ; Disclosure ; Focus Groups ; Truth Disclosure ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS), an incurable motor neuron disease, primarily affects those between the ages of 60-79, and has an approximate post-diagnosis life-expectancy of only two to five years. The condition has an unpredictable but ultimately terminal trajectory that poses challenges for patients, caregivers and healthcare providers. While the diagnosis and disclosure are critical periods for intervention and support, knowledge regarding the relational, communicational and psychodynamic forces that occur within the process of diagnostic disclosure is relatively limited.

OBJECTIVES: The purpose of this study was to explore the experiences of persons living with ALS in the diagnosis and disclosure of the condition, with the support of their caregivers.

METHODS: We conducted a focus group and in-depth individual interviews with people living with ALS (n = 9), and caregivers (n = 9). The interviews were transcribed, cleaned, and anonymized, and then entered into NVivo 11 for thematic analysis.

RESULTS: Participants discussed the diagnostic process, including inklings and subtle changes prior to diagnosis, attempts at self-diagnosis, and the lengthy assessment process. Time was also a consideration in the diagnostic disclosure process, in which participants shared how the disclosure was the product of longstanding conversations with their care providers. It was described as rarely a shock to finally have confirmation. Participants shared their information seeking strategies and needs for a diagnosis that, for them, typically came with insufficient information on the disease, prognosis, and next steps.

SIGNIFICANCE: This project serves as a step in bridging the relevant gaps in our knowledge and understanding towards improved person-centered care practices in the diagnosis and disclosure of ALS.}, } @article {pmid39621188, year = {2025}, author = {Gerometta, M and Henderson, RD and Friend, R and Cooper, LT and Zhao, J and Boyd, AW and Bartlett, PF}, title = {Evaluation of NUN-004, a Novel Engineered Ephrin Antagonist, in Healthy Volunteers and Patients with Amyotrophic Lateral Sclerosis: A Phase I/Ib, Open-Label, Escalating Dose and Extended Access Study.}, journal = {Clinical drug investigation}, volume = {45}, number = {1}, pages = {17-28}, pmid = {39621188}, issn = {1179-1918}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Adult ; Aged ; Healthy Volunteers ; Dose-Response Relationship, Drug ; Young Adult ; }, abstract = {BACKGROUND: Erythropoietin-producing hepatocellular carcinoma A4 (EphA4) is implicated in the pathophysiology of amyotrophic lateral sclerosis. EphA4 fusion protein (EphA4-Fc) inhibits EphA4 function in vivo but is too short-lived for prolonged therapy. NUN-004 (mEphA4-Fc) is a modified EphA4-Fc engineered for an extended half-life.

OBJECTIVE: This first-in-human phase I/Ib study evaluated the safety, tolerability, pharmacokinetics, immunogenicity and efficacy of NUN-004 in healthy volunteers and patients with amyotrophic lateral sclerosis.

METHODS: In this open-label study, Part 1 enrolled 20 healthy volunteers in five single ascending dose cohorts (1, 3, 10, 20 and 30 mg/kg), followed by Part 2, which enrolled eight patients with amyotrophic lateral sclerosis in two multiple ascending dose cohorts (cycle 1: 15 and 30 mg/kg) who could continue into an extended access phase (cycles 2-6: 15 mg/kg) for a total of 6 months' treatment. All participants received intravenous NUN-004; multiple dosing was administered weekly in 28-day cycles. Primary endpoints included safety assessments, single-dose and multiple-dose pharmacokinetics, and anti-drug antibodies. Efficacy assessments were Amyotrophic Lateral Sclerosis Function Rating Score Revised (ALSFRS-R) and forced vital capacity.

RESULTS: NUN-004 was well tolerated, with no serious adverse events or discontinuations. NUN-004 exposure generally increased with dose. Single-dose half-life was 111.7 (± 22.8) h in healthy volunteers (n = 20) and 74.4 (± 19.4) h in patients (n = 6). Steady state was observed in patients by day 8. Steady-state half-life (cycle 1 doses 2-4) was 83.7 (± 26.6) to 101.1 (± 46.0) h. No antibody response was observed. ALSFRS-R showed a slight improvement (+0.09 points/month) to cycle 4 and a slight decline (-0.35 points/month) over the whole study. Forced vital capacity trends were consistent with ALSFRS-R.

CONCLUSIONS: This study supports the safety, tolerability and extended half-life of NUN-004, and provides preliminary evidence for its ability to ameliorate disease progression in an amyotrophic lateral sclerosis cohort.

CLINICAL TRIAL REGISTRATION: Registered on ANZCTR under identifier ACTRN12621000514808 (3 May, 2021).}, } @article {pmid39621126, year = {2024}, author = {Mikhailova, MM and Klein, OI and Patsaev, TD and Panteleyev, AA}, title = {Co-culture of postnatal mouse spinal cord and skeletal muscle explants as an experimental model of neuromuscular interactions.}, journal = {Histochemistry and cell biology}, volume = {163}, number = {1}, pages = {15}, pmid = {39621126}, issn = {1432-119X}, support = {1п.2.3//National Research Center "Kurchatov Institute"/ ; 1п.2.3//National Research Center "Kurchatov Institute"/ ; 1п.2.3//National Research Center "Kurchatov Institute"/ ; 1п.2.3//National Research Center "Kurchatov Institute"/ ; }, mesh = {Animals ; Mice ; *Muscle, Skeletal/metabolism ; *Coculture Techniques ; *Spinal Cord/metabolism ; Mice, Inbred C57BL ; Animals, Newborn ; }, abstract = {The intercommunication between nerves and muscles plays an important role in the functioning of our body, and its failure leads to severe neuromuscular disorders such as spinal muscular atrophy and amyotrophic lateral sclerosis. Understanding the cellular and molecular mechanisms underlying nerve-muscle interactions and mediating their mutual influence is an integral part of strategies aimed at curing neuromuscular diseases. Here, we propose a novel ex vivo experimental model for the spinal cord (SC) and skeletal muscle interactions which for the first time utilizes only fully formed (but not yet quite functional) postnatal tissues. The model represents an organotypic co-culture comprising a longitudinal slice of the mouse postnatal SC and an extensor digitorum longus (EDL) muscle explant placed in the "damage zone" of transversally dissected longitudinal slice of the SC. Using this model, we have shown that SC tissue stimulates muscle contractions and reduces the area occupied by acetylcholine receptors on muscle surface. In turn, EDL muscles stimulate the growth of SC-derived neurites. Thus, our organotypic model allows one to assess the mutual influence of neurons and muscles in a nearly natural setting which maintains the architecture and cellular composition of intact tissues. Therefore, this model may provide an effective platform for studying molecular and cellular mechanisms linked to defective neuromuscular interactions in associated pathologies.}, } @article {pmid39620262, year = {2025}, author = {Chen, Y and Sun, S and Yun, Y and Sun, X and Xin, J and Shao, K and Lin, P and Yu, D and Yan, C and Liu, S}, title = {Connectivity-based striatal subregion microstructural changes in sporadic amyotrophic lateral sclerosis patients: Relation to motor disability, cognitive deficits, and serum biomarkers.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16577}, pmid = {39620262}, issn = {1468-1331}, support = {2020M672067//China Postdoctoral Science Foundation/ ; NSFC82001354//National Natural Science Foundation of China/ ; NSFC82471395//National Natural Science Foundation of China/ ; ZR2023LSW020//Shandong Provincial Natural Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; Aged ; *Biomarkers/blood ; *Cognitive Dysfunction/blood/etiology/diagnostic imaging/pathology/physiopathology ; Retrospective Studies ; *Corpus Striatum/diagnostic imaging/pathology ; Adult ; Neurofilament Proteins/blood ; Diffusion Tensor Imaging ; Diffusion Magnetic Resonance Imaging ; }, abstract = {BACKGROUND AND PURPOSE: To date, no previous studies have used multishell diffusion MRI to identify striatal microstructural damage in vivo in amyotrophic lateral sclerosis (ALS) patients. Thus, in the present study, we aimed to comprehensively explore connectivity-based selective striatal subregion microstructural damage in sporadic ALS patients and its associations with motor disability, cognitive deficits, and serum biomarkers.

METHODS: In this retrospective study, 79 ALS patients and 53 healthy controls (HCs) who underwent clinical assessment, serum neurofilament light (NfL) measurement, genetic testing, and multishell diffusion MRI scanning were included. Using a probabilistic tractography approach, the striatum was segmented into six subregions based on their corticostriatal connectivity. Three neurite orientation dispersion and density imaging (NODDI) parameters, the neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISO), of the connectivity-based striatal subregions were measured.

RESULTS: Compared with HCs, ALS patients had a significantly lower NDI in the bilateral motor and right frontal subregions, a significantly lower ODI in the right motor and frontal subregions, and a significantly higher ISO in the bilateral motor and frontal subregions of the striatum after familywise error (p < 0.05). Moreover, striatal subregion microstructural damage was significantly correlated with motor disabilities, cognitive deficits, and serum NfL levels in ALS patients (p = 0.020-0.002).

CONCLUSIONS: Our study provides clear evidence demonstrating that connectivity-based selective striatal subregion microstructural damage is a definite feature of sporadic ALS patients and suggesting that striatal damage may play an important role in motor disability and cognitive deficits in ALS patients.}, } @article {pmid39617896, year = {2024}, author = {Feng, R and Zhu, Q and Wang, A and Wang, H and Wang, J and Chen, P and Zhang, R and Liang, D and Teng, J and Ma, M and Ding, X and Wang, X}, title = {Effect of fecal microbiota transplantation on patients with sporadic amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled trial.}, journal = {BMC medicine}, volume = {22}, number = {1}, pages = {566}, pmid = {39617896}, issn = {1741-7015}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Fecal Microbiota Transplantation/methods ; Double-Blind Method ; Female ; Male ; Middle Aged ; Aged ; Gastrointestinal Microbiome/physiology ; Treatment Outcome ; Quality of Life ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the progressive loss of motor neurons. Recent insights into ALS pathogenesis underscore the pivotal role of the gut microbiome, prompting an investigation into the potential therapeutic impact of fecal microbiota transplantation (FMT) on sporadic ALS patients.

METHODS: Conducted as a double-blind, placebo-controlled, parallel-group, randomized clinical trial, the study enrolled 27 participants from October 2022 to April 2023. The participants were followed up for 6 months from February 2023 to October 2023, during in-person visits at baseline, week 15, week 23, and week 35. The participants, evenly randomized, received either healthy donor FMT (FMT, n = 14) or a mixture of 0.9% saline and food coloring (E150c) as sham transplantation (placebo, n = 13). The primary outcome measured the change in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score from baseline to week 35. Secondary outcomes included changes in gastrointestinal and respiratory functions, muscle strength, autonomic function, cognition, quality of life, intestinal microbiome composition, and plasm neurofilament light chain protein (NFL). Efficacy and safety outcomes were assessed in the intention-to-treat population.

RESULTS: A total of 27 randomized patients (47% women; mean age, 67.2 years), 24 participants completed the entire study. Notably, ALSFRS-R score changes exhibited no significant differences between FMT (6.1 [SD, 3.11]) and placebo (6.41[SD, 2.73]) groups from baseline to week 35. Secondary efficacy outcomes, encompassing respiratory function, muscle strength, autonomic function, cognition, quality of life, and plasm NFL, showed no significant differences. Nevertheless, the FMT group exhibited improvements in constipation, depression, and anxiety symptoms. FMT induced a shift in gut microbiome community composition, marked by increased abundance of Bifidobacterium, which persisted until week 15 (95% CI, 0.04 to 0.28; p = 0.01). Gastrointestinal adverse events were the primary manifestations of FMT-related side effects.

CONCLUSIONS: In this clinical trial involving 27 sporadic ALS patients, FMT did not significantly slow the decline in ALSFRS-R score. Larger multicenter trials are needed to confirm the efficacy of FMT in sporadic ALS patients and to explore the underlying biological mechanisms.

TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR 2200064504.}, } @article {pmid39617118, year = {2025}, author = {Liang, YF and Niu, ZX and Wu, ZW and Zhang, QY and Zhao, XY and Chao, LL and Li, H and Gao, WY}, title = {Catalytic insights of acetolactate synthases from different bacteria.}, journal = {Archives of biochemistry and biophysics}, volume = {764}, number = {}, pages = {110248}, doi = {10.1016/j.abb.2024.110248}, pmid = {39617118}, issn = {1096-0384}, mesh = {*Acetolactate Synthase/metabolism/genetics/chemistry ; *Bacillus subtilis/enzymology/genetics ; *Molecular Docking Simulation ; *Bacterial Proteins/metabolism/genetics/chemistry ; Substrate Specificity ; Klebsiella pneumoniae/enzymology/genetics ; Amino Acid Sequence ; Pyruvic Acid/metabolism ; Catalytic Domain ; }, abstract = {Acetolactate synthase (ALS) is an essential enzyme involved in the biosynthesis of platform chemicals acetoin and 2,3-butanediol in several microorganisms. In this study, we investigated the catalytic differences among three bacterial ALSs involved in the ligation of two molecules of pyruvate or 2-ketobutyrate. Based on the findings, we predicted three amino acid residues in each enzyme that caused a discrepancy in accordance with the multi-sequence alignment and molecular docking experiments: I398, A402, and T480 in Bacillus subtilis ALS; V400, Y404, and S482 in Listeria seleigeri serovar 1/2b ALS; and M394, H398, and G476 in Klebsiella pneumoniae ALS. Subsequently, we mutually mutated the residues in the three ALSs. The data obtained confirmed our inference that these three residues in each enzyme are truly correlated with substrate recognition, particularly in recognizing compounds that are larger than pyruvate, such as 2-ketobutyrate, benzaldehyde, and nitrosobenzene. This study further clarifies the biochemical traits of ALSs derived from various bacteria and expands the scope of ALS research.}, } @article {pmid39616922, year = {2024}, author = {Santurtún, A and Medín, P and Riancho, JA and Santiago-Setién, M and Ortiz, F and López de Munain, A and Almendra, R and Riancho, J}, title = {Temporo-spatial analysis of amyotrophic lateral sclerosis in Spain: Altitude and land use as new determinants of the disease.}, journal = {The Science of the total environment}, volume = {957}, number = {}, pages = {177796}, doi = {10.1016/j.scitotenv.2024.177796}, pmid = {39616922}, issn = {1879-1026}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/mortality ; Spain/epidemiology ; Humans ; Male ; Female ; *Altitude ; Spatio-Temporal Analysis ; Middle Aged ; Aged ; Incidence ; Adult ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. Currently, ALS is conceived as the result of the interaction between genetics, environmental factors, and aging. This study analyzed the spatial and temporal patterns of ALS in Spain, delving into the potential relationships between altitude, land cover, and this disease.

METHODOLOGY: ALS death data were collected over a 19-year period, including information on sex, age and municipality of residence. The standardized mortality rate was calculated for each municipality of residencia, and Anselin's local Moran's I statistic was used to identify clusters of high and low incidence. Altitude data were sourced from the Copernicus Land Monitoring Services, while land cover data came from CORINE satellite images and national agricultural statistics.

RESULTS: The average annual incidence of ALS deaths among adults was 2.5 per 100,000 people. Higher mortality rates were noted in males (2.8) than in females (2.3), with both sexes exhibiting a rising mortality trend in a temporal analysis. Cluster analysis revealed that high mortality areas were mostly located in the North and Northeast of the country. Municipalities in these clusters had significantly lower median altitudes and larger areas of Permanently Irrigated Arable Land and Broad-Leaved Forest.

CONCLUSION: This study provides new evidence about the increase in ALS cases in European countries during the last decades, reporting for the first time altitude and certain agricultural land uses as potential geographic determinants of the disease.}, } @article {pmid39616446, year = {2024}, author = {Rutkove, SB and McIlduff, CE and Stommel, E and Levy, S and Smith, C and Gutierrez, H and Verga, S and Samaan, S and Yator, C and Nanda, A and Sonbas-Cobb, B and Capella, T and Pastel, L and Doussan, A and Phipps, K and Murphy, E and Halter, R}, title = {Thoracic electrical impedance tomography for assessing progression of pulmonary dysfunction in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2024.2434174}, pmid = {39616446}, issn = {2167-9223}, support = {R21 NS118434/NS/NINDS NIH HHS/United States ; }, abstract = {Objective: We compared thoracic electrical impedance tomography (EIT) with slow vital capacity (SVC) to determine if EIT could monitor pulmonary function in ALS patients longitudinally. Methods: Of 32 ALS patients and 32 age- and sex-matched healthy controls (HCs) initially enrolled in the Pulmonary Function via Impedance Tomography (PuFIT) study, 22 ALS and 20 HCs returned for a follow-up visit ∼3.9 months later. All participants had thoracic EIT measurements performed simultaneously with standard SVC in upright and supine positions at both visits. EIT data from each measurement were summarized as a single parameter, the impedance-SVC (zSVC), representing an averaged impedance change across both lungs. We assessed alterations over time for both cohorts of participants. Results: Sufficient quality EIT and SVC data were available for 18 of the patients with ALS and 19 HCs. Over time, mean upright SVC significantly declined by 5% in the ALS group and did not change in the healthy group. Supine SVC showed no change in either group. Although mean trajectories of zSVC mirrored mean SVC trajectories in both participant cohorts, changes in zSVC in ALS patients did not reach significance, due to greater variability in the repeated measures. Conclusion: Despite strong cross-sectional correlations to SVC, EIT did not detect a decline in pulmonary function over approximately four months. Increased variability in EIT data explains the lack of sensitivity to change. Technological improvements and special care with electrode placement will be needed for EIT to reach its full potential in longitudinal assessment of pulmonary function in ALS.}, } @article {pmid39615150, year = {2025}, author = {Garbey, M and Lesport, Q and Öztosun, G and Ghodasara, V and Kaminski, HJ and Bayat, E}, title = {Improving care for amyotrophic lateral sclerosis with artificial intelligence and affective computing.}, journal = {Journal of the neurological sciences}, volume = {468}, number = {}, pages = {123328}, doi = {10.1016/j.jns.2024.123328}, pmid = {39615150}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Male ; Female ; Middle Aged ; Aged ; *Artificial Intelligence ; *Natural Language Processing ; *Emotions/physiology ; Speech/physiology ; Oximetry ; Adult ; }, abstract = {BACKGROUND: Patients with ALS often face difficulties expressing emotions due to impairments in facial expression, speech, body language, and cognitive function. This study aimed to develop non-invasive AI tools to detect and quantify emotional responsiveness in ALS patients, providing objective insights. Improved understanding of emotional responses could enhance patient-provider communication, telemedicine effectiveness, and clinical trial outcome measures.

METHODS: In this preliminary exploratory study, fourteen patients with ALS had audio recordings performed during routine clinic visits while wearing a wireless pulse oximeter. Emotion-triggering questions related to symptom progression, breathing, mobility, feeding tube, and financial burden were randomly asked. The same questions were posed in separate psychiatric evaluations. Natural language processing (NLP) was used to analyze transcriptions, topic classifications, sentiment, and emotional states, combining pulse and speech data. AI-generated reports summarized the findings.

RESULTS: Pulse alterations consistent with emotional arousal were identified, with longer consultations and positive communication reducing pulse fluctuations. Financial concerns triggered the strongest emotional response, while discussions about breathing, mobility, and feeding tube increased anxiety. AI-generated reports prioritized patient concerns and streamlined documentation for providers.

CONCLUSIONS: This study introduces a novel approach to linking pulse and speech analysis to evaluate emotional responses in ALS patients. AI and affective computing provide valuable insights into emotional responses and disease progression, with potential applications for other neurological disorders. This approach could augment clinical trial outcomes by offering a more comprehensive view of patient well-being.}, } @article {pmid39614020, year = {2025}, author = {Shi, DL and Grifone, R and Zhang, X and Li, H}, title = {Rbm24-mediated post-transcriptional regulation of skeletal and cardiac muscle development, function and regeneration.}, journal = {Journal of muscle research and cell motility}, volume = {46}, number = {1}, pages = {53-65}, pmid = {39614020}, issn = {1573-2657}, support = {23545//the French Muscular Dystrophy Association/ ; }, mesh = {Humans ; *RNA-Binding Proteins/metabolism/genetics ; *Muscle, Skeletal/metabolism ; Animals ; *Muscle Development/physiology ; *Regeneration/physiology ; *Myocardium/metabolism ; }, abstract = {RNA-binding proteins are critically involved in the post-transcriptional control of gene expression during embryonic development and in adult life, contributing to regulating cell differentiation and maintaining tissue homeostasis. Compared to the relatively well documented functions of transcription factors, the regulatory roles of RNA-binding proteins in muscle development and function remain largely elusive. However, deficiency of many RNA-binding proteins has been associated with muscular defects, neuromuscular disorders and heart diseases, such as myotonic dystrophy, amyotrophic lateral sclerosis, and cardiomyopathy. Rbm24 is highly conserved among vertebrates and is one of the best characterized RNA-binding proteins with crucial implication in the myogenic and cardiomyogenic programs. It presents the distinctive particularity of displaying highly restricted expression in both skeletal and cardiac muscles, with changes in subcellular localization during the process of differentiation. Functional analyses using different vertebrate models have clearly demonstrated its requirement for skeletal muscle differentiation and regeneration as well as for myocardium organization and cardiac function, by regulating the expression of both common and distinct target genes in these tissues. The challenge remains to decipher the dynamic feature of post-transcriptional circuits regulated by Rbm24 during skeletal myogenesis, cardiomyogenesis, and muscle repair. This review discusses current understanding of its function in striated muscles and its possible implication in human disease, with the aim of identifying research gaps for future investigation.}, } @article {pmid39612826, year = {2025}, author = {Xu, H and Cheng, J and Leng, Q and Cao, R and Su, W and Sun, L and Xue, F and Han, Y and Wu, R}, title = {Characterization of acetolactate synthase genes and resistance mechanisms of multiple herbicide resistant Lolium multiflorum.}, journal = {Plant physiology and biochemistry : PPB}, volume = {219}, number = {}, pages = {109324}, doi = {10.1016/j.plaphy.2024.109324}, pmid = {39612826}, issn = {1873-2690}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Plant Proteins/genetics/metabolism ; *Lolium/genetics/enzymology/drug effects ; Imidazoles/pharmacology ; Genes, Plant ; }, abstract = {Combining imidazolinone-tolerant wheat with imazamox presents an effective solution to combat weed resistance. However, Lolium multiflorum, a troublesome resistant weed infesting wheat fields, may have developed resistance to imazamox, and the potential resistance mechanisms are intriguing. In this study, we explored the susceptibility of L. multiflorum to imazamox and investigated the resistance mechanisms, including the contribution of the target enzyme acetolactate synthase (ALS) to resistance and the presence of non-target-site resistance (NTSR). Eight L. multiflorum populations suspected of being resistant to imazamox were collected, and six populations exhibited resistance, ranging from 2.45-fold to 16.32-fold. The LmALS1 gene from susceptible population D3 plants and multiple copies of the LmALS gene (LmALS1, LmALS2, LmALS2α, LmALS3, LmALS3α, LmALS3β) from resistant populations D5 and D8 plants were separately amplified. Two mutations (Pro/Gln197 to Thr, Trp574 to Leu) were found in LmALS1 in the resistant populations. Compared to D3, LmALS1 was overexpressed in D5 but not in D8. The presence of LmALS1 mutants (LmALS1-Thr197 and LmALS1- Leu574), along with LmALS2, LmALS3, and their subunits, contribute to the resistance phenotype by increasing bonding energies, weakening hydrogen bonds, or decreasing protein binding pocket volumes and surface area. Additionally, D5 and D8 populations exhibited multiple resistance (>40-fold) to three other ALS inhibitors: pyroxsulam, flucarbazone-sodium, and mesosulfuron-methyl. Pre-treatment with malathion and 4-chloro-7-nitrobenzoxadiazole (cytochrome P450 monooxygenase and glutathione S-transferase inhibitors respectively) reversed the resistance of the D8 population and partially reversed the resistance of the D5 population to imazamox. This study characterizes ALS genes and extends our knowledge into the ALS resistance mechanisms involved in L. multiflorum. It also deepens our understanding of the complex diversification resistance mechanisms, thereby facilitating advances in weed resistance management strategies in wheat fields.}, } @article {pmid39612643, year = {2024}, author = {Egorov, VV and Grudinina, NA and Polyakov, DS and Zabrodskaya, YA and Gavrilova, NV and Shavlovsky, MM}, title = {Spontaneous formation of different forms of alpha-synuclein fibrils from a recombinant protein.}, journal = {Biochemical and biophysical research communications}, volume = {741}, number = {}, pages = {151068}, doi = {10.1016/j.bbrc.2024.151068}, pmid = {39612643}, issn = {1090-2104}, mesh = {*alpha-Synuclein/metabolism/chemistry ; *Recombinant Proteins/chemistry/metabolism/genetics ; Humans ; *Amyloid/chemistry/metabolism ; Protein Processing, Post-Translational ; Protein Conformation ; }, abstract = {Alpha-synuclein is a protein, the conformational changes of which lead to the development of such socially significant diseases as Parkinson's disease and amyotrophic lateral sclerosis. The methods for differential diagnostics of these diseases based on the use of alpha-synuclein in a non-native conformation obtained from patients as a seed for inducing fibrillogenesis and studying the morphology of the resulting amyloid-like fibrils were described in a number of studies. The authors associate such properties of the seed with the presence of post-translational modifications in the protein obtained from patients. At the same time, the production of fibrils differing in morphology from recombinant alpha-synuclein under various conditions of fibrillogenesis is also described. In this work, we show that the formation of morphologically distinct fibril types from recombinant alpha-synuclein lacking post-translational modifications is possible under the same conditions, and that spontaneously arising different fibril types, when used as a seed for fibrillogenesis, lead to the formation of recombinant protein fibrils morphological similar to the parental seed. The results of the work can be used both in studying the fundamental mechanisms of conformation transfer and in developing test systems for synucleinopathies.}, } @article {pmid39611550, year = {2024}, author = {Veyrat-Durebex, C and Osman, S and Al Ojaimi, Y and Gosset, P and Dupuy, C and Lefevre, A and Emond, P and Vourc'h, P and Corcia, P and Mereghetti, L and Kempf, F and Raoul, C and Blasco, H}, title = {Gut metabolomic and microbiota analyses in ALS mice reveal specific metabolites despite the absence of significant gut dysbiosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2024.2433578}, pmid = {39611550}, issn = {2167-9223}, abstract = {OBJECTIVE: Over the past years, interest in the role of gut microbiota in neurodegenerative diseases has emerged. Despite numerous publications over the past decade, both in human and pre-clinical studies, there is no clear consensus on the microbiota's role or involvement in ALS. Few studies on mouse models of ALS highlighted a correlation between specific bacteria species and the prognostic or severity of the disease. Still these results lack reproducibility and remain controverted. In this article we present a study of fecal microbiota in the SOD1[G93A] mouse model associated with a metabolomic analysis of cecum content, compared to controls.

METHODS: Intestinal metabolomic profile and fecal microbiota were assessed in two cohorts of SOD[G93A] mice compared to wildtype controls at the terminal stage of the ALS disease.

RESULTS: Results showed a significant difference in metabolomic profile in SOD1[G93A] mice compared to controls but without a marked change in composition and diversity of fecal microbiota. Nevertheless, we observed an increase of Lachnospiraceae family, which are butyrate-producer bacteria, in SOD1[G93A] mice. Moreover, some metabolites with significantly different intestinal concentrations are partially produced and linked with intestinal bacteria, such as riboflavin, hippurate, and N-acetylputrescine, leaving us convinced of the interest in looking further into the role of the microbiota in ALS.

CONCLUSIONS: Despite an alteration of the intestinal metabolome in SOD1[G93A] mice, microbiota data did not show significant changes, underlying the need for further research.}, } @article {pmid39611310, year = {2025}, author = {Diaz, F and Thornton, JS and Wastling, SS and Asaab, A and Morrow, JM and Zafeiropoulos, N and Bresee, C and Allred, P and Avalos, P and Lewis, RA and Baloh, RH and Svendsen, CN}, title = {Longitudinal Quantitative MRI Provides Responsive Outcome Measures for Early and Late Muscle Changes in ALS.}, journal = {Muscle & nerve}, volume = {71}, number = {2}, pages = {171-182}, doi = {10.1002/mus.28306}, pmid = {39611310}, issn = {1097-4598}, support = {CLIN2-09284//This study was supported with funding from The California Institute of Regenerative Medicine./ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology ; *Disease Progression ; Longitudinal Studies ; *Magnetic Resonance Imaging ; Muscle Strength/physiology ; *Muscle, Skeletal/diagnostic imaging/physiopathology ; Outcome Assessment, Health Care ; Clinical Trials, Phase I as Topic ; }, abstract = {INTRODUCTION/AIMS: Studies have demonstrated the potential of muscle MRIs to measure disease progression in ALS. However, the responsiveness and utility of quantitative muscle MRIs in an ALS clinical trial remain unknown. This study aimed to determine the responsiveness of quantitative muscle MRIs to measure disease progression in ALS.

METHODS: Longitudinal quantitative muscle MRIs were obtained in an ALS study that delivered human neural progenitor cells to the spinal cord (NCT02943850). Participants underwent MRIs at baseline, 1, 3, 6, 9, and 12 months. MRI measures included fat fraction (ff), water T2 (T 2m), cross-sectional area (CSA), and remaining muscle area (RMA). Non-MRI measures included strength via Accurate Test of Limb Isometric Strength (ATLIS) and the ALSFRS-R. Standardized response means (SRM) were calculated at 1, 3, 6, and 12 months.

RESULTS: Significant increases in muscle FF and decreases in CSA and RMA were seen as early as 1 month from baseline. At 6 months, the most responsive measures were muscle FF (SRMthigh = 1.85, SRMcalf = 1.39), T 2m (SRMthigh = 1.2, SRMcalf = 1.71), CSA (SRMthigh = -1.58, SRMcalf = -1.14), RMA (SRMthigh = -1.77, SRMcalf = -1.28), and strength tested via ATLIS (SRMknee extension = -1.79, SRMknee flexion = -1.3). The ALSFRS-R was the least responsive at 6 months (SRM = -0.85). Muscle FF and T 2m correlated with ALSFRS-R leg subscores and MRI measures demonstrated varying degrees of correlation with strength.

DISCUSSION: High responsiveness and low variability make quantitative muscle MRI a novel and complementary outcome measure for ALS clinical trials.}, } @article {pmid39611137, year = {2024}, author = {Valančius, D and Burnytė, B and Masaitienė, R and Morkūnienė, A and Klimašauskienė, A}, title = {Rapidly Progressing and Early-Onset Forms of Amyotrophic Lateral Sclerosis Caused by a Novel SOD1 Variant in a Lithuanian Family.}, journal = {Neurology. Genetics}, volume = {10}, number = {6}, pages = {e200217}, pmid = {39611137}, issn = {2376-7839}, abstract = {OBJECTIVES: To describe a novel familial variant of superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS) in a Lithuanian family, highlighting its variable progression and implications for treatment inclusion criteria.

METHODS: This study presents the clinical and genetic findings of a family with the novel SOD1 variant, including one member diagnosed with early-onset ALS (onset <40 years) and one with a particularly rapidly progressing course of ALS.

RESULTS: The SOD1 variant NM_000454.5:c.446T>C, NP_000445.1:p.(Val149Ala) was identified in affected family members and 4 asymptomatic members aged 32-56 years. We present detailed disease course of the affected family members obtained during follow-up. Clinically, this variant is associated with variable disease progression, with the time from symptom onset to death ranging from 5 to 77 months.

DISCUSSION: The novel SOD1 variant p.Val149Ala in this Lithuanian family causes ALS of variable onset and course, including a case of early-onset ALS and one case of rapidly progressing ALS, necessitating recognition by the scientific community and development of tailored therapeutic approaches.}, } @article {pmid39610104, year = {2025}, author = {Bar Avi, O and Perlson, E}, title = {Navigating the pathways: TAR-DNA-binding-protein-43 aggregation, axonal transport, and local synthesis in amyotrophic lateral sclerosis pathology.}, journal = {Neural regeneration research}, volume = {20}, number = {10}, pages = {2921-2922}, pmid = {39610104}, issn = {1673-5374}, } @article {pmid39608855, year = {2024}, author = {Budworth, L and Wilson, B and Sutton-Klein, J and Basu, S and O'Keeffe, C and Mason, SM and Ang, A and Anne-Wilson, S and Reynard, K and Croft, S and Shah, AD and Bank, S and Conner, M and Lawton, R}, title = {Is emergency doctors' tolerance of clinical uncertainty on a novel measure associated with doctor well-being, healthcare resource use and patient outcomes?.}, journal = {Emergency medicine journal : EMJ}, volume = {42}, number = {1}, pages = {}, pmid = {39608855}, issn = {1472-0213}, abstract = {INTRODUCTION: Emergency doctors routinely face uncertainty-they work with limited patient information, under tight time constraints and receive minimal post-discharge feedback. While higher uncertainty tolerance (UT) among staff is linked with reduced resource use and improved well-being in various specialties, its impact in emergency settings is underexplored. We aimed to develop a UT measure and assess associations with doctor-related factors (eg, experience), patient outcomes (eg, reattendance) and resource use (eg, episode costs).

METHODS: From May 2021 to February 2022, emergency doctors (specialty trainee 3 and above) from five Yorkshire (UK) departments completed an online questionnaire. This included a novel UT measure-an adapted Physicians' Reaction to Uncertainty scale collaboratively modified within our team according to Hillen et al's (2017) UT model. The questionnaire also included well-being-related measures (eg, Brief Resilience Scale) and assessed factors like doctors' seniority. Patient encounters involving prespecified 'uncertainty-inducing' problems (eg, headache) were analysed. Multilevel regression explored associations between doctor-level factors, resource use and patient outcomes.

RESULTS: 39 doctors were matched with 384 patients. The UT measure demonstrated high reliability (Cronbach's α=0.92) and higher UT was significantly associated with better psychological well-being including greater resilience (Pearson's r=0.56; 95% CI=0.30 to 0.74) and lower burnout (eg, Cohen's d=-2.98; -4.62 to -1.33; mean UT difference for 'no' vs 'moderate/high' burnout). UT was not significantly associated with resource use (eg, episode costs: β=-0.07; -0.32 to 0.18) or patient outcomes including 30-day readmission (eg, OR=0.82; 0.28 to 2.35).

CONCLUSIONS: We developed a reliable UT measure for emergency medicine. While higher UT was linked to doctor well-being, its impact on resource use and patient outcomes remains unclear. Further measure validation and additional research including intervention trials are necessary to confirm these findings and explore the implications of UT in emergency practice.}, } @article {pmid39608699, year = {2025}, author = {Kale, MB and Wankhede, NL and Bishoyi, AK and Ballal, S and Kalia, R and Arya, R and Kumar, S and Khalid, M and Gulati, M and Umare, M and Taksande, BG and Upaganlawar, AB and Umekar, MJ and Kopalli, SR and Fareed, M and Koppula, S}, title = {Emerging biophysical techniques for probing synaptic transmission in neurodegenerative disorders.}, journal = {Neuroscience}, volume = {565}, number = {}, pages = {63-79}, doi = {10.1016/j.neuroscience.2024.11.055}, pmid = {39608699}, issn = {1873-7544}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/physiopathology ; *Synaptic Transmission/physiology ; Animals ; Synapses/metabolism/pathology/physiology ; }, abstract = {Plethora of research has shed light on the critical role of synaptic dysfunction in various neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Synapses, the fundamental units for neural communication in the brain, are highly vulnerable to pathological conditions and are central to the progression of neurological diseases. The presynaptic terminal, a key component of synapses responsible for neurotransmitter release and synaptic communication, undergoes structural and functional alterations in these disorders. Understanding synaptic transmission abnormalities is crucial for unravelling the pathophysiological mechanisms underlying neurodegeneration. In the quest to probe synaptic transmission in NDDs, emerging biophysical techniques play a pivotal role. These advanced methods offer insights into the structural and functional changes occurring at nerve terminals in conditions like AD, PD, HD & ALS. By investigating synaptic plasticity and alterations in neurotransmitter release dynamics, researchers can uncover valuable information about disease progression and potential therapeutic targets. The review articles highlighted provide a comprehensive overview of how synaptic vulnerability and pathology are shared mechanisms across a spectrum of neurological disorders. In major neurodegenerative diseases, synaptic dysfunction is a common thread linking these conditions. The intricate molecular machinery involved in neurotransmitter release, synaptic vesicle dynamics, and presynaptic protein regulation are key areas of focus for understanding synaptic alterations in neurodegenerative diseases.}, } @article {pmid39608571, year = {2025}, author = {Diggins, L and Ross, D and Bhanot, S and Corallo, R and Daley, R and Patel, K and Lewis, O and Donahue, S and Thaddeus, J and Hiers, L and Syed, C and Eagerton, D and Mohanty, BK}, title = {CD spectra reveal the state of G-quadruplexes and i-motifs in repeated and other DNA sequences.}, journal = {Biophysical reports}, volume = {5}, number = {1}, pages = {100187}, pmid = {39608571}, issn = {2667-0747}, mesh = {*G-Quadruplexes ; *Circular Dichroism ; Hydrogen-Ion Concentration ; DNA/chemistry/genetics ; Nucleotide Motifs/genetics ; Base Sequence ; Temperature ; Humans ; DNA-Binding Proteins/chemistry/metabolism/genetics ; }, abstract = {The B-DNA of the genome contains numerous sequences that can form various noncanonical structures including G-quadruplex (G4), formed by two or more stacks of four guanine residues in a plane, and intercalating motif (i-motif [iM]) formed by alternately arranged C-C[+] pairs. One of the easy yet sensitive methods to study G4s and iMs is circular dichroism (CD) spectroscopy, which generates characteristic G4 and iM peaks. We have analyzed and compared the effects of various environmental factors including pH, buffer composition, temperature, flanking sequences, complimentary DNA strands, and single-stranded DNA binding protein (SSB) on the CD patterns of G4s and iMs generated by two groups of DNA molecules, one containing tandem repeats of GGGGCC and CCCCGG from the C9ORF72 gene associated with amyotrophic lateral sclerosis and frontotemporal dementia, and the second containing polyG/polyC clusters from oncogene promoter-proximal regions without such tandem repeats. Changes in pH caused drastic changes in CCCCGG-iM and GGGGCC-G4 and the changes were dependent on repeat numbers and G-C basepairing. In contrast, with the DNA sequences from the promoter-proximal regions of oncogenes, iMs disassembled upon pH changes with the peak slowly shifting to lower wavelength but the G4s did not show significant change. Complementary DNA strands and flanking DNA sequences also regulate G4 and iM formation. The SSB disassembled both G4s and iMs formed by almost all sequences suggesting an in vivo role for SSBs in the disassembly of G4s and iMs during DNA replication and other DNA transactions.}, } @article {pmid39606446, year = {2024}, author = {Du, M and Akerman, SC and Fare, CM and Ruan, L and Vidensky, S and Mamedova, L and Lee, J and Rothstein, JD}, title = {Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39606446}, issn = {2693-5015}, support = {P50 AG005146/AG/NIA NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models of C9ORF72-related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimer's disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals considerations that must be taken into account when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.}, } @article {pmid39606178, year = {2024}, author = {Tröger, J and Dörr, F and Schwed, L and Linz, N and König, A and Thies, T and Barbe, MT and Orozco-Arroyave, JR and Rusz, J}, title = {Corrigendum: An automatic measure for speech intelligibility in dysarthrias-validation across multiple languages and neurological disorders.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1488178}, doi = {10.3389/fdgth.2024.1488178}, pmid = {39606178}, issn = {2673-253X}, abstract = {[This corrects the article DOI: 10.3389/fdgth.2024.1440986.].}, } @article {pmid39605661, year = {2024}, author = {Zimyanin, V and Dash, BP and Großmann, D and Simolka, T and Glaß, H and Verma, R and Khatri, V and Deppmann, C and Zunder, E and Redemann, S and Hermann, A}, title = {Axonal transcriptome reveals upregulation of PLK1 as a protective mechanism in response to increased DNA damage in FUS [P525L] spinal motor neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.20.624439}, pmid = {39605661}, issn = {2692-8205}, support = {R01 NS091617/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in the gene FUSED IN SARCOMA (FUS) are among the most frequently occurring genetic forms of amyotrophic lateral sclerosis (ALS). Early pathogenesis of FUS -ALS involves impaired DNA damage response and axonal degeneration. However, it is still poorly understood how these gene mutations lead to selective spinal motor neuron (MN) degeneration and how nuclear and axonal phenotypes are linked. To specifically address this, we applied a compartment specific RNA-sequencing approach using microfluidic chambers to generate axonal as well as somatodendritic compartment-specific profiles from isogenic induced pluripotent stem cells (iPSCs)-derived MNs. We demonstrate high purity of axonal and soma fractions and show that the axonal transcriptome is unique and distinct from that of somas including significantly fewer number of transcripts. Functional enrichment analysis revealed that differentially expressed genes (DEGs) in axons were mainly enriched in key pathways like RNA metabolism and DNA damage, complementing our knowledge of early phenotypes in ALS pathogenesis and known functions of FUS. In addition, we demonstrate a strong enrichment for cell cycle associated genes including significant upregulation of polo-like kinase 1 (PLK1) in FUS [P525L] mutant MNs. PLK1 was increased upon DNA damage induction and PLK1 inhibition further increased the number of DNA damage foci in etoposide-treated cells, an effect that was diminished in case of FUS mutant MNs. In contrast, inhibition of PLK1 increased late apoptotic or necrosis-induced neuronal cell death in mutant neurons. Taken together, our findings provide insights into compartment-specific transcriptomics in human FUS -ALS MNs and we propose that specific upregulation of PLK1 might represent an early event in the pathogenesis of ALS, possibly modulating DNA damage response and other associated pathways.}, } @article {pmid40098659, year = {2023}, author = {Serrano-Giraldo, J and Becerra-Muñoz, MP and Tijaro-Santos, JA and Zarante, I}, title = {[Current situation of rare diseases in Bogotá: Notification to Sivigila from 2019 to 2022].}, journal = {Revista de salud publica (Bogota, Colombia)}, volume = {25}, number = {4}, pages = {107594}, pmid = {40098659}, issn = {2539-3596}, abstract = {OBJECTIVE: To analyze the reports of orphan diseases in Bogotá, in order to describe the epidemiological profile, based on the cases reported to the Public Health System (Sivigila), from January 2019 to March 2022.

METHODS: A descriptive and cross-sectional study was carried out in which the cases reported to Sivigila in Bogotá were analyzed in the period between January 2019 and March 2022. Absolute and relative frequencies, frequency distribution and prevalences and averages of different variables were calculated. notified in the notification sheets.

RESULTS: From January 2019 to March 2022, 10,399 patients with orphan diseases have been notified to Sivigila in Bogotá, of which 56.25% (5,849) are female and 43.75% (4,550) are female. male sex. 87.10% (9,060) of the cases belong to the contributory regime. The town with the highest number of reports was Suba with 15.85% (1,294). The most reported orphan diseases were: multiple sclerosis with 13.1% (1,363), amyotrophic lateral sclerosis with 4.04% (421) and Guillain-Barre syndrome with 3.6% (374). A patient with an orphan disease in Bogotá takes 61.3 months on average from the beginning of their symptoms to obtaining a diagnosis (SD 101.9).

CONCLUSIONS: From the notification to Sivigila in Bogotá, compared to the global prevalence, there is an under-registration of patients with orphan diseases and the delay in the diagnosis of these diseases is evident.}, } @article {pmid39872952, year = {2023}, author = {Wang, J and Zhou, XF and Wang, YJ}, title = {Continuous antioxidant drug exposure: a bridge from ideal world to real world of therapy for amyotrophic lateral sclerosis.}, journal = {Life medicine}, volume = {2}, number = {1}, pages = {lnac042}, pmid = {39872952}, issn = {2755-1733}, } @article {pmid39605556, year = {2024}, author = {Singer-Clark, T and Hou, X and Card, NS and Wairagkar, M and Iacobacci, C and Peracha, H and Hochberg, LR and Stavisky, SD and Brandman, DM}, title = {Speech motor cortex enables BCI cursor control and click.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39605556}, issn = {2692-8205}, support = {DP2 DC021055/DC/NIDCD NIH HHS/United States ; }, abstract = {Decoding neural activity from ventral (speech) motor cortex is known to enable high-performance speech brain-computer interface (BCI) control. It was previously unknown whether this brain area could also enable computer control via neural cursor and click, as is typically associated with dorsal (arm and hand) motor cortex. We recruited a clinical trial participant with ALS and implanted intracortical microelectrode arrays in ventral precentral gyrus (vPCG), which the participant used to operate a speech BCI in a prior study. We developed a cursor BCI driven by the participant's vPCG neural activity, and evaluated performance on a series of target selection tasks. The reported vPCG cursor BCI enabled rapidly-calibrating (40 seconds), accurate (2.90 bits per second) cursor control and click. The participant also used the BCI to control his own personal computer independently. These results suggest that placing electrodes in vPCG to optimize for speech decoding may also be a viable strategy for building a multi-modal BCI which enables both speech-based communication and computer control via cursor and click.}, } @article {pmid39605399, year = {2024}, author = {Tuddenham, JF and Fujita, M and Khairallah, A and Harbison, C and Flowers, XE and Coronas-Samano, G and Maniatis, S and Daly, A and Schneider, JA and Teich, AF and Vonsattel, JPG and Sims, PA and Elyaman, W and Bradshaw, EM and Phatnani, H and Shneider, N and Bennett, DA and De Jager, PL and Przedborski, S and Menon, V and Olah, M}, title = {Single-cell transcriptomic landscape of the neuroimmune compartment in amyotrophic lateral sclerosis brain and spinal cord.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.12.623183}, pmid = {39605399}, issn = {2692-8205}, support = {R25 MH129256/MH/NIMH NIH HHS/United States ; }, abstract = {Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS. Additionally, we observe an enrichment of non-microglial immune cell, mainly NK/T cells, in ALS central nervous system, primarily in the spinal cord. These findings pave the way for the development of microglia subset-specific therapeutic interventions to slow or even stop ALS progression.}, } @article {pmid39605053, year = {2024}, author = {Horiuchi, M and Watanabe, S and Komine, O and Takahashi, E and Kaneko, K and Itohara, S and Shimada, M and Ogi, T and Yamanaka, K}, title = {ALS-linked mutant TDP-43 in oligodendrocytes induces oligodendrocyte damage and exacerbates motor dysfunction in mice.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {184}, pmid = {39605053}, issn = {2051-5960}, support = {JP23K06826//Japan Society for the Promotion of Science/ ; JP19KK0214//Japan Society for the Promotion of Science/ ; JP22H00467//Japan Society for the Promotion of Science/ ; JP22ek0109426//Japan Agency for Medical Research and Development/ ; JP24wm0425014//Japan Agency for Medical Research and Development/ ; JP24wm0625301//Japan Agency for Medical Research and Development/ ; }, mesh = {Animals ; *Oligodendroglia/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Mice, Transgenic ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Mutation ; Spinal Cord/metabolism/pathology ; Mice, Inbred C57BL ; }, abstract = {Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and its pathogenic mechanism is mediated by both loss-of-function and gain-of-toxicity of TDP-43. However, the role of TDP-43 gain-of-toxicity in oligodendrocytes remains unclear. To investigate the impact of excess TDP-43 on oligodendrocytes, we established transgenic mice overexpressing the ALS-linked mutant TDP-43[M337V] in oligodendrocytes through crossbreeding with Mbp-Cre mice. Two-step crossbreeding of floxed TDP-43[M337V] and Mbp-Cre mice resulted in the heterozygous low-level systemic expression of TDP-43[M337V] with (Cre-positive) or without (Cre-negative) oligodendrocyte-specific overexpression of TDP-43[M337V]. Although Cre-negative mice also exhibit subtle motor dysfunction, TDP-43[M337V] overexpression in oligodendrocytes aggravated clasping signs and gait disturbance accompanied by myelin pallor in the corpus callosum and white matter of the lumbar spinal cord in Cre-positive mice. RNA sequencing analysis of oligodendrocyte lineage cells isolated from whole brains of 12-month-old transgenic mice revealed downregulation of myelinating oligodendrocyte marker genes and cholesterol-related genes crucial for myelination, along with marked upregulation of apoptotic pathway genes. Immunofluorescence staining showed cleaved caspase 3-positive apoptotic oligodendrocytes surrounded by activated microglia and astrocytes in aged transgenic mice. Collectively, our findings demonstrate that an excess amount of ALS-linked mutant TDP-43 expression in oligodendrocytes exacerbates motor dysfunction in mice, likely through oligodendrocyte dysfunction and neuroinflammation. Therefore, targeting oligodendrocyte protection, particularly through ameliorating TDP-43 pathology, could represent a potential therapeutic approach for ALS.}, } @article {pmid39604641, year = {2025}, author = {Mi, Y and Zhang, P and Hou, X and Ding, Y and Wang, Y and Du, H and Deng, M}, title = {A rare genetic variant in APEX1 is associated with familial amyotrophic lateral sclerosis with slow progression.}, journal = {Acta neurologica Belgica}, volume = {125}, number = {1}, pages = {191-203}, pmid = {39604641}, issn = {2240-2993}, support = {No. 82273915//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Middle Aged ; *DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics ; *Disease Progression ; *Pedigree ; Adult ; Aged ; Mutation, Missense/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of motor neurons and progressive muscle weakness. We aimed to identify the pathogenic genetic variants in familial ALS (fALS) pedigrees and to elucidate their impact on the disease phenotype. Through the analysis of whole-genome sequencing data of 34 fALS probands that screened negative for mutations in the most common ALS-causing genes, we identified a rare missense variant in APEX1 (NM_001641.4: c.22G > A, p.Gly8Arg) associated with ALS in one pedigree. Fluorescence microscopy images using green fluorescent protein (GFP)-fusion proteins suggested that this amino acid substitution could cause an impairment in nuclear localization of the protein. We described the clinical characteristics of this cohort analyzed and found that patients carrying this variant exhibit lower motor neuron onset and prolonged survival. The relation between APEX1 and ALS occurrence has been elusive despite evidence of a neuroprotective role for the gene. This study provides evidence linking an APEX1 variant with fALS and information on the distinct clinical manifestation. This study contributes to the understanding of the genetic basis of ALS, as well as a potential mechanism leading to loss of neurons, highlighting possible opportunities of targeted treatment harnessing the DNA repair process or ameliorating the oxidative stress.}, } @article {pmid39603574, year = {2024}, author = {Wen, J and Li, Y and Qin, Y and Yan, L and Zhang, K and Li, A and Wang, Z and Yu, F and Lai, J and Yang, W and Liu, YU and Qin, D and Su, H}, title = {Lycorine protects motor neurons against TDP-43 proteinopathy-induced degeneration in cross-species models with amyotrophic lateral sclerosis.}, journal = {Pharmacological research}, volume = {210}, number = {}, pages = {107518}, doi = {10.1016/j.phrs.2024.107518}, pmid = {39603574}, issn = {1096-1186}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Phenanthridines/pharmacology/therapeutic use ; *Amaryllidaceae Alkaloids/pharmacology/therapeutic use ; *Caenorhabditis elegans/drug effects/metabolism ; *Motor Neurons/drug effects/pathology/metabolism ; Humans ; *Disease Models, Animal ; TDP-43 Proteinopathies/drug therapy/metabolism/pathology ; DNA-Binding Proteins/metabolism/genetics ; Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; Mice, Transgenic ; }, abstract = {Aggregation of TAR-DNA binding protein-43 (TDP-43) is a pathological feature present in nearly 97 % cases of amyotrophic lateral sclerosis (ALS), making it an attractive target for pathogenic studies and drug screening. Here, we have performed a high-throughput screening of 1500 compounds from a natural product library and identified that lycorine, a naturally occurring alkaloid, significantly decreases the level of TDP-43[A315T] in a cellular model. We further demonstrate that lycorine reduces the level of TDP-43[A315T] both through inhibiting its synthesis and by promoting its degradation by the ubiquitin-proteasome system (UPS). Importantly, treatment with lycorine significantly attenuates TDP-43 proteinopathy and improves functional recovery in TDP-43[A315T]-expressing Caenorhabditis elegans and mouse models. These findings suggest that lycorine is a promising lead compound that has therapeutic potential for ALS.}, } @article {pmid39603486, year = {2025}, author = {Krus, KL and Benitez, AM and Strickland, A and Milbrandt, J and Bloom, AJ and DiAntonio, A}, title = {Two cardinal features of ALS, reduced STMN2 and pathogenic TDP-43, synergize to accelerate motor decline in mice.}, journal = {Experimental neurology}, volume = {384}, number = {}, pages = {115068}, doi = {10.1016/j.expneurol.2024.115068}, pmid = {39603486}, issn = {1090-2430}, support = {R01 NS119812/NS/NINDS NIH HHS/United States ; RF1 AG013730/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Stathmin/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Mice, Transgenic ; Mice, Inbred C57BL ; Male ; }, abstract = {Pathological TDP-43 loss from the nucleus and cytoplasmic aggregation occurs in almost all cases of ALS and half of frontotemporal dementia patients. Stathmin2 (Stmn2) is a key target of TDP-43 regulation and aberrantly spliced Stmn2 mRNA is found in patients with ALS, frontotemporal dementia, and Alzheimer's Disease. STMN2 participates in the axon injury response and its depletion in vivo partially replicates ALS-like symptoms including progressive motor deficits and distal NMJ denervation. The interaction between STMN2 loss and TDP-43 dysfunction has not been studied in mice because TDP-43 regulates human but not murine Stmn2 splicing. Therefore, we generated trans-heterozygous mice that lack one functional copy of Stmn2 and express one mutant TDP-43[Q331K] knock-in allele to investigate whether reduced STMN2 function exacerbates TDP-43-dependent pathology. Indeed, we observe synergy between these two alleles, resulting in an early onset, progressive motor deficit. Surprisingly, this behavioral defect is not accompanied by detectable neuropathology in the brain, spinal cord, peripheral nerves or at neuromuscular junctions (NMJs). However, the trans-heterozygous mice exhibit abnormal mitochondrial morphology in their distal axons and NMJs. As both STMN2 and TDP-43 affect mitochondrial dynamics, and neuronal mitochondrial dysfunction is a cardinal feature of many neurodegenerative diseases, this abnormality likely contributes to the observed motor deficit. These findings demonstrate that partial loss of STMN2 significantly exacerbates TDP-43-associated phenotypes, suggesting that STMN2 restoration could ameliorate TDP-43 related disease before the onset of degeneration.}, } @article {pmid39602529, year = {2024}, author = {Jin, S and Tian, Y and Hacker, J and Chen, X and Bertolio, M and Reynolds, C and Jarvis, R and Hu, J and Promes, V and Halim, D and Gao, FB and Yang, Y}, title = {Inflammatory cytokines disrupt astrocyte exosomal HepaCAM-mediated protection against neuronal excitotoxicity in the SOD1G93A ALS model.}, journal = {Science advances}, volume = {10}, number = {48}, pages = {eadq3350}, pmid = {39602529}, issn = {2375-2548}, support = {R37 NS057553/NS/NINDS NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; R01 AG078728/AG/NIA NIH HHS/United States ; R01 NS118747/NS/NINDS NIH HHS/United States ; R01 NS125490/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *Astrocytes/metabolism ; *Exosomes/metabolism ; Mice ; Humans ; *Cytokines/metabolism ; *Disease Models, Animal ; *Superoxide Dismutase-1/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Mice, Transgenic ; Induced Pluripotent Stem Cells/metabolism ; Neurons/metabolism ; }, abstract = {Astrocyte secreted signals substantially affect disease pathology in neurodegenerative diseases. It remains little understood about how proinflammatory cytokines, such as interleukin-1α/tumor necrosis factor-α/C1q (ITC), often elevated in neurodegenerative diseases, alter astrocyte-secreted signals and their effects in disease pathogenesis. By selectively isolating astrocyte exosomes (A-Exo.) and employing cell type-specific exosome reporter mice, our current study showed that ITC cytokines significantly reduced A-Exo. secretion and decreased spreading of focally labeled A-Exo. in diseased SOD1G93A mice. Our results also found that A-Exo. were minimally associated with misfolded SOD1 and elicited no toxicity to mouse spinal and human iPSC-derived motor neurons. In contrast, A-Exo. were neuroprotective against excitotoxicity, which was completely diminished by ITC cytokines and partially abolished by SOD1G93A expression. Subsequent proteomic characterization of A-Exo. and genetic analysis identified that surface expression of glial-specific HepaCAM preferentially mediates A-Exo's axon protection effect. Together, our study defines a cytokine-induced loss-of-function mechanism of A-Exo. in protecting neurons from excitotoxicity in amyotrophic lateral sclerosis.}, } @article {pmid39602508, year = {2024}, author = {Lynch, EM and Pittman, S and Daw, J and Ikenaga, C and Chen, S and Dhavale, DD and Jackrel, ME and Ayala, YM and Kotzbauer, P and Ly, CV and Pestronk, A and Lloyd, TE and Weihl, CC}, title = {Seeding-competent TDP-43 persists in human patient and mouse muscle.}, journal = {Science translational medicine}, volume = {16}, number = {775}, pages = {eadp5730}, pmid = {39602508}, issn = {1946-6242}, support = {F32 NS124841/NS/NINDS NIH HHS/United States ; K24 AR073317/AR/NIAMS NIH HHS/United States ; R01 AG031867/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; *DNA-Binding Proteins/metabolism ; Mice ; *Muscle, Skeletal/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Myositis, Inclusion Body/metabolism/pathology ; Disease Models, Animal ; }, abstract = {TAR DNA binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous systems of some patients with neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy. TDP-43 aggregates from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis, and changes in TDP-43-related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding-competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with sporadic inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), and ALS, we found that TDP-43 seeding capacity was specific to IBM. TDP-43 seeding capacity anticorrelated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.}, } @article {pmid39601192, year = {2025}, author = {Sørensen, DM and Tankisi, H}, title = {Reliability of MScanFit Motor Unit Number Estimation in the Trapezius Muscle.}, journal = {Muscle & nerve}, volume = {71}, number = {2}, pages = {166-170}, doi = {10.1002/mus.28303}, pmid = {39601192}, issn = {1097-4598}, support = {//Aage & Johanne Louis-Hansens Foundation/ ; //Grosserer L. F. Foghts Foundation/ ; //Dagmar Marshalls Fond/ ; //The Jascha Foundation,/ ; //Lundbeck Foundation/ ; }, mesh = {Humans ; Male ; *Superficial Back Muscles/physiology ; Female ; Reproducibility of Results ; Adult ; *Electromyography/methods ; *Action Potentials/physiology ; Motor Neurons/physiology ; Young Adult ; Middle Aged ; Recruitment, Neurophysiological/physiology ; Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; }, abstract = {INTRODUCTION/AIMS: MScanFit motor unit number estimation (MUNE) is the most recent MUNE method which has shown promising results in extremity muscles, but it has not been applied to bulbar muscles. Bulbar muscles are particularly important in the diagnosis of amyotrophic lateral sclerosis (ALS). This study aimed to investigate the feasibility and reliability of MScanFit MUNE in the accessory nerve and trapezius muscles.

METHODS: A total of twenty healthy participants were examined twice within 1-2 weeks. We extracted the MScanFit MUNE and size parameter, and compound muscle action potential (CMAP) amplitude values. The reliability of these parameters was assessed using the intra-rater coefficient of variation (CoV), intraclass correlation coefficient (ICC), and Bland-Altman plots. We also correlated MUNE values with CMAP amplitudes using correlation coefficients.

RESULTS: Mean MUNE values (Day 1 = 132.1 and Day 2 = 137.4), CMAP amplitudes (Day 1 = 9.71 mV and Day 2 = 10.10 mV) and size parameters did not differ between the two sessions (p > 0.05). CoV showed excellent reliability for MUNE values, size parameters, and CMAP amplitudes (CoV < 7%) whereas ICCs showed moderate reliability for MUNE values (ICC = 0.619), poor to moderate reliability for size parameters (between 0.393 and 0.689), and good reliability for CMAP amplitude (ICC = 0.864) There was no correlation between MUNE values and CMAP amplitudes.

DISCUSSION: MScanFit MUNE is applicable and mostly reliable in the trapezius muscle. Further studies in patients are needed to investigate the sensitivity of MScanFit in this muscle in detecting motor unit loss, particularly in ALS.}, } @article {pmid39598374, year = {2024}, author = {Li, Y and Fu, J and Wang, H}, title = {Advancements in Targeting Ion Channels for the Treatment of Neurodegenerative Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {11}, pages = {}, pmid = {39598374}, issn = {1424-8247}, support = {2023YFF1205500//National Key Research and Development Program of China/ ; 82471465//NSFC/ ; C2024202005//Distinguished Young Scholars Science Fund of the Natural Science Foundation of Hebei Province/ ; JZX2023002//Technology Project of Hebei Education Department/ ; 22JCQNJC01110//Tianjin Applied Basic Research Project/ ; 236Z2602G, 246Z2605G, 236Z2401G//the central government guides local funds for science and technology development for Hebei Province/ ; NV20230015//The Key Laboratory of Neural and Vascular Biology, Ministry of Education/ ; }, abstract = {Ion channels are integral membrane proteins embedded in biological membranes, and they comprise specific proteins that control the flow of ion transporters in and out of cells, playing crucial roles in the biological functions of different cells. They maintain the homeostasis of water and ion metabolism by facilitating ion transport and participate in the physiological processes of neurons and glial cells by regulating signaling pathways. Neurodegenerative diseases are a group of disorders characterized by the progressive loss of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Despite significant progress in understanding the pathophysiological processes of various neurological diseases in recent years, effective treatments for mitigating the damage caused by these diseases remain inadequate. Increasing evidence suggests that ion channels are closely associated with neuroinflammation; oxidative stress; and the characteristic proteins in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Therefore, studying the pathogenic mechanisms closely related to ion channels in neurodegenerative diseases can help identify more effective therapeutic targets for treating neurodegenerative diseases. Here, we discuss the progress of research on ion channels in different neurodegenerative diseases and emphasize the feasibility and potential of treating such diseases from the perspective of ion channels.}, } @article {pmid39598025, year = {2024}, author = {Vacchiano, V and Morabito, F and Bonan, L and Teodorani, L and Faini, C and Rizzo, G and Liguori, R}, title = {Reverse Split Hand as a Neurophysiological Hallmark of Spinal Muscular Atrophy.}, journal = {Journal of clinical medicine}, volume = {13}, number = {22}, pages = {}, pmid = {39598025}, issn = {2077-0383}, abstract = {Objective: Motor unit number estimation (MUNE) methods are crucial for estimating lower motor neuron loss in motor neuron diseases. The MScanFit MUNE (MScanFit) is a novel method that estimates MUNE values from compound motor action potential (CMAP) scans, demonstrating high sensitivity and reproducibility in detecting motor unit loss in amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we aimed to characterize the pattern of motor unit loss in the hand intrinsic muscles of SMA patients compared to ALS patients and healthy controls (HC) using MScanFit MUNE. Methods: Patients diagnosed with ALS, adult SMA patients, and HC were prospectively enrolled. MScanFit examinations were performed on the abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. To focus on the different patterns of motor neuron degeneration in the intrinsic hand muscles, the ratio of CMAP amplitude of APB to ADM (CMAP ratio) and the ratio of MUNE values of APB to those of the ADM muscle (MUNE ratio) were calculated. Results: The study included 46 ALS patients, 16 SMA patients, and 23 HC. MScanFit MUNE revealed distinct patterns of motor unit degeneration in SMA patients, notably more severe in the ADM than in the APB muscle, indicating a "reverse" split-hand phenomenon. Both CMAP and MUNE ratios demonstrated high diagnostic accuracy in distinguishing ALS from SMA, with the MUNE ratio performing better. Conclusions: MScanFit MUNE is a valuable tool for exploring distinct patterns of motor neuron degeneration in patients with different types of motor neuron diseases.}, } @article {pmid39596864, year = {2024}, author = {McKenna, MC and Kleinerova, J and Power, A and Garcia-Gallardo, A and Tan, EL and Bede, P}, title = {Quantitative and Computational Spinal Imaging in Neurodegenerative Conditions and Acquired Spinal Disorders: Academic Advances and Clinical Prospects.}, journal = {Biology}, volume = {13}, number = {11}, pages = {}, pmid = {39596864}, issn = {2079-7737}, support = {2023//Spastic Paraplegia Foundation/ ; }, abstract = {Introduction: Quantitative spinal cord imaging has facilitated the objective appraisal of spinal cord pathology in a range of neurological conditions both in the academic and clinical setting. Diverse methodological approaches have been implemented, encompassing a range of morphometric, diffusivity, susceptibility, magnetization transfer, and spectroscopy techniques. Advances have been fueled both by new MRI platforms and acquisition protocols as well as novel analysis pipelines. The quantitative evaluation of specific spinal tracts and grey matter indices has the potential to be used in diagnostic and monitoring applications. The comprehensive characterization of spinal disease burden in pre-symptomatic cohorts, in carriers of specific genetic mutations, and in conditions primarily associated with cerebral disease, has contributed important academic insights. Methods: A narrative review was conducted to examine the clinical and academic role of quantitative spinal cord imaging in a range of neurodegenerative and acquired spinal cord disorders, including hereditary spastic paraparesis, hereditary ataxias, motor neuron diseases, Huntington's disease, and post-infectious or vascular disorders. Results: The clinical utility of specific methods, sample size considerations, academic role of spinal imaging, key radiological findings, and relevant clinical correlates are presented in each disease group. Conclusions: Quantitative spinal cord imaging studies have demonstrated the feasibility to reliably appraise structural, microstructural, diffusivity, and metabolic spinal cord alterations. Despite the notable academic advances, novel acquisition protocols and analysis pipelines are yet to be implemented in the clinical setting.}, } @article {pmid39596631, year = {2024}, author = {Sneha, NP and Dharshini, SAP and Taguchi, YH and Gromiha, MM}, title = {Tracing ALS Degeneration: Insights from Spinal Cord and Cortex Transcriptomes.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596631}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Transcriptome ; *Spinal Cord/metabolism/pathology ; Frontal Lobe/metabolism/pathology ; Gene Regulatory Networks ; Motor Neurons/metabolism/pathology ; }, abstract = {BACKGROUND/OBJECTIVES: Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons. Key factors contributing to neuronal death include mitochondrial energy damage, oxidative stress, and excitotoxicity. The frontal cortex is crucial for action initiation, planning, and voluntary movements whereas the spinal cord facilitates communication with the brain, walking, and reflexes. By investigating transcriptome data from the frontal cortex and spinal cord, we aim to elucidate common pathological mechanisms and pathways involved in ALS for understanding the disease progression and identifying potential therapeutic targets.

METHODS: In this study, we quantified gene and transcript expression patterns, predicted variants, and assessed their functional effects using computational tools. It also includes predicting variant-associated regulatory effects, constructing functional interaction networks, and performing a gene enrichment analysis.

RESULTS: We found novel genes for the upregulation of immune response, and the downregulation of metabolic-related and defective degradation processes in both the spinal cord and frontal cortex. Additionally, we observed the dysregulation of histone regulation and blood pressure-related genes specifically in the frontal cortex.

CONCLUSIONS: These results highlight the distinct and shared molecular disruptions in ALS, emphasizing the critical roles of immune response and metabolic dysfunction in neuronal degeneration. Targeting these pathways may provide new therapeutic avenues to combat neurodegeneration and preserve neuronal health.}, } @article {pmid39596615, year = {2024}, author = {Papapanagiotou, AP and Anthimidou, EA and Eleftherohorinos, IG and Giantsis, IA}, title = {Comparison of Molecularly Identified Resistant and Susceptible Johnsongrass (Sorghum halepense L.) Populations at ALS Gene, in the Absence and Presence of Field Crops.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596615}, issn = {2073-4425}, mesh = {*Herbicide Resistance/genetics ; *Acetolactate Synthase/genetics ; *Sorghum/genetics/growth & development ; *Herbicides/pharmacology ; Plant Weeds/genetics/growth & development/drug effects ; Plant Proteins/genetics ; Zea mays/genetics/growth & development ; Crops, Agricultural/genetics/growth & development ; Genotype ; Biomass ; Helianthus/genetics/growth & development ; }, abstract = {BACKGROUND/OBJECTIVES: Johnsongrass (Sorghum halepense) is an erect tetraploid, perennial, C4 grass weed species categorized among the world's most noxious weeds due to its high competitive ability against crops and the increased number of field-evolved herbicide-resistant populations. The aim of the present study was to assess the growth rate and performance of resistant (R) johnsongrass genotypes hosting Trp574Leu target-site cross-resistance at ALS gene, inhibiting various herbicides, compared to susceptible (S) conspecific weeds, in the absence and presence of corn or sunflower antagonism.

METHODS: The aboveground biomass, tiller, and rhizome production ability of one S and one R johnsongrass population with a Trp574-Leu substitution conferring cross-resistance to ALS-inhibiting herbicides were compared under non-competitive conditions. Furthermore, the competitive ability of these two johnsongrass populations against corn or sunflower was determined in a target-neighborhood design.

RESULTS: The S and R johnsongrass populations displayed similar growth rates concerning aboveground biomass and tiller number, whereas the R population displayed a slightly greater growth rate for rhizome production compared to the S population. Both populations grown with corn produced more aboveground biomass than the ones grown with sunflowers. The aboveground biomass of corn was reduced to a greater extent than sunflower by the presence of both johnsongrass populations, while both crops were affected more by the S than by the R population.

CONCLUSIONS: Although the inheritance and the genetic background of plant materls were not addressed, the findings of this study indicate clearly that the growth rate and competitive ability of the ALS-resistant johnsongrass population are not associated with the resistance mechanism involved.}, } @article {pmid39596609, year = {2024}, author = {Luglio, A and Maggi, E and Riviello, FN and Conforti, A and Sorrentino, U and Zuccarello, D}, title = {Hereditary Neuromuscular Disorders in Reproductive Medicine.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596609}, issn = {2073-4425}, support = {PNRR-MR1-2022-12376108//European Union/ ; }, mesh = {Humans ; *Neuromuscular Diseases/genetics/diagnosis ; Female ; Pregnancy ; Reproductive Medicine/methods ; Genetic Testing/methods ; Prenatal Diagnosis ; Preimplantation Diagnosis ; Muscular Atrophy, Spinal/genetics ; Charcot-Marie-Tooth Disease/genetics/diagnosis ; }, abstract = {Neuromuscular disorders (NMDs) encompass a broad range of hereditary and acquired conditions that affect motor units, significantly impacting patients' quality of life and reproductive health. This narrative review aims to explore in detail the reproductive challenges associated with major hereditary NMDs, including Charcot-Marie-Tooth disease (CMT), dystrophinopathies, Myotonic Dystrophy (DM), Facioscapulohumeral Muscular Dystrophy (FSHD), Spinal Muscular Atrophy (SMA), Limb-Girdle Muscular Dystrophy (LGMD), and Amyotrophic Lateral Sclerosis (ALS). Specifically, it discusses the stages of diagnosis and genetic testing, recurrence risk estimation, options for preimplantation genetic testing (PGT) and prenatal diagnosis (PND), the reciprocal influence between pregnancy and disease, potential obstetric complications, and risks to the newborn.}, } @article {pmid39596581, year = {2024}, author = {Paubel, A and Marouillat, S and Dangoumau, A and Maurel, C and Haouari, S and Blasco, H and Corcia, P and Laumonnier, F and Andres, CR and Vourc'h, P}, title = {Dynamic Expression of Genes Encoding Ubiquitin Conjugating Enzymes (E2s) During Neuronal Differentiation and Maturation: Implications for Neurodevelopmental Disorders and Neurodegenerative Diseases.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596581}, issn = {2073-4425}, mesh = {Animals ; *Ubiquitin-Conjugating Enzymes/genetics/metabolism ; Mice ; *Neurons/metabolism ; *Neurodevelopmental Disorders/genetics/pathology ; *Neurodegenerative Diseases/genetics ; *Hippocampus/metabolism ; *Cell Differentiation/genetics ; Neurogenesis/genetics ; Cells, Cultured ; N-Methylaspartate/pharmacology/metabolism ; }, abstract = {Background: The ubiquitination process plays a crucial role in neuronal differentiation and function. Numerous studies have focused on the expression and functions of E3 ligases during these different stages, far fewer on E2 conjugating enzymes. In mice, as in humans, these E2s belong to 17 conjugating enzyme families. Objectives: We analyzed by real-time PCR the expression dynamics of all known E2 genes during an in vitro differentiation of mouse hippocampal neuronal cultures, and after, we analyzed their stimulation with N-methyl-D-aspartate (NMDA). Results: We found that 36 of the 38 E2 genes were expressed in hippocampal neurons. Many were up-regulated during neuritogenesis and/or synaptogenesis stages, such as Ube2h, Ube2b, and Aktip. Rapid and delayed responses to NMDA stimulation were associated with the increased expression of several E2 genes, such as Ube2i, the SUMO-conjugating E2 enzyme. We also observed similar expression profiles within the same E2 gene family, consistent with the presence of similar transcription factor binding sites in their respective promoter sequences. Conclusions: Our study indicates that specific expression profiles of E2 genes are correlated with changes in neuronal differentiation and activity. A better understanding of the regulation and function of E2s is needed to better understand the role played by the ubiquitination process in physiological mechanisms and pathophysiological alterations involved in neurodevelopmental or neurodegenerative diseases.}, } @article {pmid39596445, year = {2024}, author = {Jiang, LL and Zhang, XL and Hu, HY}, title = {Co-Aggregation of TDP-43 with Other Pathogenic Proteins and Their Co-Pathologies in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {22}, pages = {}, pmid = {39596445}, issn = {1422-0067}, support = {31670782, 31700669//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *DNA-Binding Proteins/metabolism ; *Protein Aggregation, Pathological/metabolism ; Animals ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Protein Aggregates ; }, abstract = {Pathological aggregation of a specific protein into insoluble aggregates is a common hallmark of various neurodegenerative diseases (NDDs). In the earlier literature, each NDD is characterized by the aggregation of one or two pathogenic proteins, which can serve as disease-specific biomarkers. The aggregation of these specific proteins is thought to be a major cause of or deleterious result in most NDDs. However, accumulating evidence shows that a pathogenic protein can interact and co-aggregate with other pathogenic proteins in different NDDs, thereby contributing to disease onset and progression synergistically. During the past years, more than one type of NDD has been found to co-exist in some individuals, which may increase the complexity and pathogenicity of these diseases. This article reviews and discusses the biochemical characteristics and molecular mechanisms underlying the co-aggregation and co-pathologies associated with TDP-43 pathology. The TDP-43 aggregates, as a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), can often be detected in other NDDs, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and spinocerebellar ataxia type 2 (SCA2). In many cases, TDP-43 is shown to interact and co-aggregate with multiple pathogenic proteins in vitro and in vivo. Furthermore, the co-occurrence and co-aggregation of TDP-43 with other pathogenic proteins have important consequences that may aggravate the diseases. Thus, the current viewpoint that the co-aggregation of TDP-43 with other pathogenic proteins in NDDs and their relevance to disease progression may gain insights into the patho-mechanisms and therapeutic potential of various NDDs.}, } @article {pmid39595895, year = {2024}, author = {Pongrácová, E and Buratti, E and Romano, M}, title = {Prion-like Spreading of Disease in TDP-43 Proteinopathies.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595895}, issn = {2076-3425}, abstract = {TDP-43 is a ubiquitous nuclear protein that plays a central role in neurodegenerative disorders collectively known as TDP-43 proteinopathies. Under physiological conditions, TDP-43 is primarily localized to the nucleus, but in its pathological form it aggregates in the cytoplasm, contributing to neuronal death. Given its association with numerous diseases, particularly ALS and FTLD, the mechanisms underlying TDP-43 aggregation and its impact on neuronal function have been extensively investigated. However, little is still known about the spreading of this pathology from cell to cell. Recent research has unveiled the possibility that TDP-43 may possess prion-like properties. Specifically, misfolded TDP-43 aggregates can act as templates inducing conformational changes in native TDP-43 molecules and propagating the misfolded state across neural networks. This review summarizes the mounting and most recent evidence from in vitro and in vivo studies supporting the prion-like hypothesis and its underlying mechanisms. The prion-like behavior of TDP-43 has significant implications for diagnostics and therapeutics. Importantly, emerging strategies such as small molecule inhibitors, immunotherapies, and gene therapies targeting TDP-43 propagation offer promising avenues for developing effective treatments. By elucidating the mechanisms of TDP-43 spreading, we therefore aim to pave the way for novel therapies for TDP-43-related neurodegenerative diseases.}, } @article {pmid39595845, year = {2024}, author = {Rocha, PS and Bento, N and Svärd, H and Lopes, DM and Hespanhol, S and Folgado, D and Carreiro, AV and de Carvalho, M and Miranda, B}, title = {Voice Assessment in Patients with Amyotrophic Lateral Sclerosis: An Exploratory Study on Associations with Bulbar and Respiratory Function.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595845}, issn = {2076-3425}, support = {PTDC/MEC-NEU/6855/202//Fundação para a Ciência e Tecnologia/ ; }, abstract = {BACKGROUND: Speech production is a possible way to monitor bulbar and respiratory functions in patients with amyotrophic lateral sclerosis (ALS). Moreover, the emergence of smartphone-based data collection offers a promising approach to reduce frequent hospital visits and enhance patient outcomes. Here, we studied the relationship between bulbar and respiratory functions with voice characteristics of ALS patients, alongside a speech therapist's evaluation, at the convenience of using a simple smartphone.

METHODS: For voice assessment, we considered a speech therapist's standardized tool-consensus auditory-perceptual evaluation of voice (CAPE-V); and an acoustic analysis toolbox. The bulbar sub-score of the revised ALS functional rating scale (ALSFRS-R) was used, and pulmonary function measurements included forced vital capacity (FVC%), maximum expiratory pressure (MEP%), and maximum inspiratory pressure (MIP%). Correlation coefficients and both linear and logistic regression models were applied.

RESULTS: A total of 27 ALS patients (12 males; 61 years mean age; 28 months median disease duration) were included. Patients with significant bulbar dysfunction revealed greater CAPE-V scores in overall severity, roughness, strain, pitch, and loudness. They also presented slower speaking rates, longer pauses, and higher jitter values in acoustic analysis (all p < 0.05). The CAPE-V's overall severity and sub-scores for pitch and loudness demonstrated significant correlations with MIP% and MEP% (all p < 0.05). In contrast, acoustic metrics (speaking rate, absolute energy, shimmer, and harmonic-to-noise ratio) significantly correlated with FVC% (all p < 0.05).

CONCLUSIONS: The results provide supporting evidence for the use of smartphone-based recordings in ALS patients for CAPE-V and acoustic analysis as reliable correlates of bulbar and respiratory function.}, } @article {pmid39595818, year = {2024}, author = {Ferullo, L and Risi, B and Caria, F and Olivieri, E and Poli, L and Gazzina, S and Leggio, U and Bertella, E and Giovanelli, G and Labella, B and Padovani, A and Filosto, M}, title = {Gold Coast Criteria in ALS Diagnosis: A Real-World Experience.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595818}, issn = {2076-3425}, abstract = {Background: Revised El Escorial (rEEC) and Awaji criteria are currently used for diagnosing and categorizing amyotrophic lateral sclerosis (ALS). However, they are complex; their sensitivity is still not optimal for research purposes, and they present high inter-rater variability in clinical practice. To address these points, in 2019, a new set of diagnostic criteria was proposed, namely the Gold Coast criteria (GCC), characterized by a dichotomous diagnostic categorization, i.e., ALS or not ALS. Methods: In order to investigate the sensitivity, specificity, and clinical usefulness of GCC in a practical clinical setting, we retrospectively evaluated 131 patients diagnosed with ALS and 104 control subjects. ALSFRS-R score, electrophysiological tests, neuroradiological investigations, and CSF analysis were obtained. rEEC, Awaji, and GCC were applied at the first and last evaluations. Results: The sensitivity of GCC (93.1%; 96.1%) was greater than rEEC (71.8%; 87%) and Awaji criteria (77.8%; 89.3%) both at the first visit and last follow-up. The GCC's specificity (28.8%) is lower than that of the other two criteria (rEEC 45.2%; Awaji 43.3%). Conclusions: Our study suggests that in a real-world setting, the GCC are more sensitive and have substantially lower risk of false negative diagnoses than rEEC and Awaji criteria. Although rEEC had the highest specificity, they may delay the diagnosis. Systematically using the GCC could help to achieve an earlier diagnosis and quickly refer patients to the correct management. The low specificity of GCC is likely to not significantly impact patient recruitment in clinical trials; therefore, its use might allow a faster and earlier enrollment.}, } @article {pmid39595816, year = {2024}, author = {Shandiz, E and Fernandes, GL and Henkin, JS and McCombe, PA and Trajano, GS and Henderson, RD}, title = {Assessing the Effect of Riluzole on Motor Unit Discharge Properties.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595816}, issn = {2076-3425}, abstract = {Background. This study aims to determine if Riluzole usage can change the function and excitability of motor neurons. Methods. The clinical data and indices of motor neuron excitability were assessed using high-density surface EMG parameters from 80 ALS participants. The persistent inward current was assessed using the discharge rate from paired motor units obtained from the tibialis anterior muscle. This enabled the discharge rate at recruitment, peak discharge rates and the hysteresis of the recruitment-derecruitment frequencies (also known as delta F) to be calculated. Limbs were classified according to their strength. Results. No differences in these motor neuron discharge properties were found according to whether Riluzole was used. Conclusions. The possible interpretations of this finding are discussed.}, } @article {pmid39595812, year = {2024}, author = {Zhang, S and Yang, Y and Lv, X and Zhou, X and Zhao, W and Meng, L and Zhu, S and Zhang, Z and Wang, Y}, title = {Exosome Cargo in Neurodegenerative Diseases: Leveraging Their Intercellular Communication Capabilities for Biomarker Discovery and Therapeutic Delivery.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595812}, issn = {2076-3425}, support = {82171871//National Natural Science Foundation of China/ ; BK20230488//Youth Fund Project of the Jiangsu Province Basic Research Program (Natural Science Foundation)/ ; None//Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)/ ; }, abstract = {The inexorable progression of neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, is closely related to irreversible brain decline. Accurately characterizing pathophysiological features and identifying reliable biomarkers for early diagnosis and optimized treatment are critical. Hindered by the blood-brain barrier (BBB), obtaining sensitive monitoring indicators for disease progression and achieving efficient drug delivery remain significant challenges. Exosomes, endogenous nanoscale vesicles that carry key bioactive substances, reflect the intracellular environment and play an important role in cell signaling. They have shown promise in traversing the BBB, serving dual roles as potential biomarkers for NDs and vehicles for targeted drug delivery. However, the specific mechanisms by which exosome influence NDs are not fully understood, necessitating further investigation into their attributes and functionalities in the context of NDs. This review explores how exosomes mediate multifaceted interactions, particularly in exacerbating pathogenic processes such as oxidative stress, neuronal dysfunction, and apoptosis integral to NDs. It provides a comprehensive analysis of the profound impact of exosomes under stress and disease states, assessing their prospective utility as biomarkers and drug delivery vectors, offering new perspectives for tackling these challenging diseases.}, } @article {pmid39595543, year = {2024}, author = {Stoccoro, A and Coppedè, F}, title = {Exposure to Metals, Pesticides, and Air Pollutants: Focus on Resulting DNA Methylation Changes in Neurodegenerative Diseases.}, journal = {Biomolecules}, volume = {14}, number = {11}, pages = {}, pmid = {39595543}, issn = {2218-273X}, mesh = {*DNA Methylation/drug effects ; Humans ; *Pesticides/toxicity/adverse effects ; *Neurodegenerative Diseases/genetics/metabolism/chemically induced ; *Epigenesis, Genetic/drug effects ; *Air Pollutants/toxicity/adverse effects ; Environmental Exposure/adverse effects ; Animals ; Metals, Heavy/toxicity/adverse effects ; Metals/toxicity/metabolism/adverse effects ; }, abstract = {Individuals affected by neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are dramatically increasing worldwide. Thus, several efforts are being made to develop strategies for stopping or slowing the spread of these illnesses. Although causative genetic variants linked to the onset of these diseases are known, they can explain only a small portion of cases. The etiopathology underlying the neurodegenerative process in most of the patients is likely due to the interplay between predisposing genetic variants and environmental factors. Epigenetic mechanisms, including DNA methylation, are central candidates in translating the effects of environmental factors in genome modulation, and they play a critical role in the etiology of AD, PD, and ALS. Among the main environmental exposures that have been linked to an increased risk for these diseases, accumulating evidence points to the role of heavy metals, pesticides, and air pollutants. These compounds could trigger neurodegeneration through different mechanisms, mainly neuroinflammation and the induction of oxidative stress. However, increasing evidence suggests that they are also capable of inducing epigenetic alterations in neurons. In this article, we review the available literature linking exposure to metals, pesticides, and air pollutants to DNA methylation changes relevant to neurodegeneration.}, } @article {pmid39595127, year = {2024}, author = {Cardona, F}, title = {Special Issue "Mechanisms and Novel Therapeutic Approaches for Neurodegenerative Diseases".}, journal = {Biomedicines}, volume = {12}, number = {11}, pages = {}, pmid = {39595127}, issn = {2227-9059}, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are among the major health problems of the elderly, and represent a major global health challenge due to their increasing prevalence and complex pathophysiological mechanisms [...].}, } @article {pmid39594452, year = {2024}, author = {Dibwe, DF and Oba, S and Monde, S and Hui, SP}, title = {Inhibition of Accumulation of Neutral Lipids and Their Hydroperoxide Species in Hepatocytes by Bioactive Allium sativum Extract.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {39594452}, issn = {2076-3921}, abstract = {Our ongoing research suggests that extracts from plant-based foods inhibit the accumulation of lipid droplets (LDs) and oxidized lipid droplets (oxLDs) in liver cells. These findings suggest their potential use in the alleviation of metabolic dysfunction-associated fatty liver disease (MAFLD) and its most severe manifestation, metabolic dysfunction-associated steatohepatitis (MASH). Allium extracts (ALs: AL1-AL9) were used to assess their ability to reduce lipid droplet accumulation (LDA) and oxidized lipid droplet accumulation (oxLDA) by inhibiting neutral lipid accumulation and oxidation in LD. Among the tested Allium extracts, AL1, AL3, and AL6 demonstrated substantial inhibitory effects on the LDA. Furthermore, AL1 extract showed real-time inhibition of LDA in HepG2 cells in DMEM supplemented with oleic acid (OA) within 12 h of treatment. Our lipidomic approach was used to quantify the accumulation and inhibition of intracellular triacylglycerol (TAG) and oxidized TAG hydroperoxide [TG (OOH) n = 3] species in hepatocytes under OA and linoleic acid loading conditions. These results suggest that Allium-based foods inhibit LD accumulation by decreasing intracellular lipids and lipid hydroperoxides in the hepatocytes. The metabolomic analysis of AL1-the bioactive LDAI extract-using both LC-MS/MS and 1D-NMR [[1]H, [13]C, and Dept (135 and 90)] approaches revealed that AL1 contains mainly carbohydrates and glucoside metabolites, including iridoid glucosides, as well as minor amino acids, organosulfur compounds, and organic acids such as the antioxidant ascorbic acid (KA2 = S13), and their derivatives, suggesting that AL1 could be a potential resource for the development of functional foods and in drug discovery targeting MAFLD/MASH and other related diseases.}, } @article {pmid39593881, year = {2024}, author = {Favier, G and Rocha, DS}, title = {Overview of Tensor-Based Cooperative MIMO Communication Systems-Part 2: Semi-Blind Receivers.}, journal = {Entropy (Basel, Switzerland)}, volume = {26}, number = {11}, pages = {}, pmid = {39593881}, issn = {1099-4300}, abstract = {Cooperative MIMO communication systems play an important role in the development of future sixth-generation (6G) wireless systems incorporating new technologies such as massive MIMO relay systems, dual-polarized antenna arrays, millimeter-wave communications, and, more recently, communications assisted using intelligent reflecting surfaces (IRSs), and unmanned aerial vehicles (UAVs). In a companion paper, we provided an overview of cooperative communication systems from a tensor modeling perspective. The objective of the present paper is to provide a comprehensive tutorial on semi-blind receivers for MIMO one-way two-hop relay systems, allowing the joint estimation of transmitted symbols and individual communication channels with only a few pilot symbols. After a reminder of some tensor prerequisites, we present an overview of tensor models, with a detailed, unified, and original description of two classes of tensor decomposition frequently used in the design of relay systems, namely nested CPD/PARAFAC and nested Tucker decomposition (TD). Some new variants of nested models are introduced. Uniqueness and identifiability conditions, depending on the algorithm used to estimate the parameters of these models, are established. Two families of algorithms are presented: iterative algorithms based on alternating least squares (ALS) and closed-form solutions using Khatri-Rao and Kronecker factorization methods, which consist of SVD-based rank-one matrix or tensor approximations. In a second part of the paper, the overview of cooperative communication systems is completed before presenting several two-hop relay systems using different codings and configurations in terms of relaying protocol (AF/DF) and channel modeling. The aim of this presentation is firstly to show how these choices lead to different nested tensor models for the signals received at destination. Then, by capitalizing on these models and their correspondence with the generic models studied in the first part, we derive semi-blind receivers to jointly estimate the transmitted symbols and the individual communication channels for each relay system considered. In a third part, extensive Monte Carlo simulation results are presented to compare the performance of relay systems and associated semi-blind receivers in terms of the symbol error rate (SER) and channel estimate normalized mean-square error (NMSE). Their computation time is also compared. Finally, some perspectives are drawn for future research work.}, } @article {pmid39593143, year = {2024}, author = {Clarke, BE and Ziff, OJ and Tyzack, G and Petrić Howe, M and Wang, Y and Klein, P and Smith, CA and Hall, CA and Helmy, A and Howell, M and Kelly, G and Patani, R}, title = {Human VCP mutant ALS/FTD microglia display immune and lysosomal phenotypes independently of GPNMB.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {90}, pmid = {39593143}, issn = {1750-1326}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Microglia/metabolism ; *Membrane Glycoproteins/metabolism/genetics ; *Valosin Containing Protein/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Animals ; *Lysosomes/metabolism ; Mice ; Mutation/genetics ; Phenotype ; Motor Neurons/metabolism/pathology ; Astrocytes/metabolism ; }, abstract = {BACKGROUND: Microglia play crucial roles in maintaining neuronal homeostasis but have been implicated in contributing to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the role of microglia in ALS/FTD remains incompletely understood.

METHODS: Here, we generated highly enriched cultures of VCP mutant microglia derived from human induced pluripotent stem cells (hiPSCs) to investigate their cell autonomous and non-cell autonomous roles in ALS pathogenesis. We used RNA-sequencing, proteomics and functional assays to study hiPSC derived VCP mutant microglia and their effects on hiPSC derived motor neurons and astrocytes.

RESULTS: Transcriptomic, proteomic and functional analyses revealed immune and lysosomal dysfunction in VCP mutant microglia. Stimulating healthy microglia with the inflammatory inducer lipopolysaccharide (LPS) showed partial overlap with VCP mutant microglia in their reactive transformation. LPS-stimulated VCP mutant microglia displayed differential activation of inflammatory pathways compared with LPS-stimulated healthy microglia. Conserved gene expression changes were identified between VCP mutant microglia, SOD1 mutant mice microglia, and postmortem ALS spinal cord microglial signatures, including increased expression of the transmembrane glycoprotein GPNMB. While knockdown of GPNMB affected inflammatory and phagocytosis processes in microglia, this was not sufficient to ameliorate cell autonomous phenotypes in VCP mutant microglia. Secreted factors from VCP mutant microglia were sufficient to activate the JAK-STAT pathway in hiPSC derived motor neurons and astrocytes.

CONCLUSIONS: VCP mutant microglia undergo cell autonomous reactive transformation involving immune and lysosomal dysfunction that partially recapitulate key phenotypes of microglia from other ALS models and post mortem tissue. These phenotypes occur independently of GPNMB. Additionally, VCP mutant microglia elicit non cell autonomous responses in motor neurons and astrocytes involving the JAK-STAT pathway.}, } @article {pmid39592088, year = {2025}, author = {Mahakalakar, N and Mohariya, G and Taksande, B and Kotagale, N and Umekar, M and Vinchurney, M}, title = {"Nattokinase as a potential therapeutic agent for preventing blood-brain barrier dysfunction in neurodegenerative disorders".}, journal = {Brain research}, volume = {1849}, number = {}, pages = {149352}, doi = {10.1016/j.brainres.2024.149352}, pmid = {39592088}, issn = {1872-6240}, mesh = {*Blood-Brain Barrier/drug effects/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; Humans ; *Subtilisins/metabolism ; *Neuroprotective Agents/pharmacology ; Brain/metabolism/drug effects ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are characterized by progressive destruction of neurons and cognitive impairment, and thorough studies have provided evidence that these pathologies have a close relationship to the failure of the blood-brain barrier (BBB). Nattokinase (NK), a protease found in fermented soybeans, has been extensively studied because it displays powerful neuroprotective abilities, which is why current research was reviewed in the present article. It was concluded that there is enough evidence in preclinical studies using experimental animals that NK supplementation can alleviate the condition related to BBB dysfunction, reduce brain inflammation, and improve cognitive ability. Furthermore, the study of NK on the cardiovascular system leads to certain assumptions, which include the impact on vasculature function and the ability to manage blood flow, which is the key feature of BBB integrity. Such assumed mechanisms are fibrinolytic action, anti-inflammatory and antioxidant action, and endothelium function modulation. There are many positive research findings, and it seems that NK may serve as an effective opponent for BBB breakdown; however, a new research level should be taken to disclose the application and therapeutic use of NK in brain neurodegenerative disease.}, } @article {pmid39592063, year = {2024}, author = {Lorenc, F and Dupuis, L and Cassel, R}, title = {Impairments of inhibitory neurons in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Neurobiology of disease}, volume = {203}, number = {}, pages = {106748}, doi = {10.1016/j.nbd.2024.106748}, pmid = {39592063}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology ; *Frontotemporal Dementia/pathology/physiopathology ; Humans ; Animals ; *Neurons/pathology ; *Neural Inhibition/physiology ; }, abstract = {Amyotrophic lateral sclerosis and frontotemporal dementia are two fatal neurodegenerative disorders. They are part of a pathophysiological continuum, displaying clinical, neuropathological, and genetic overlaps. There is compelling evidence that neuronal circuit dysfunction is an early feature of both diseases. Impaired neuronal excitability, imbalanced excitatory and inhibitory influences, and altered functional connectivity have been reported. These phenomena are likely due to combined alterations in the various cellular components involved in the functioning of neuronal networks. This review focuses on one of these cellular components: inhibitory neurons. We assess the evidence for inhibitory neuron impairments in amyotrophic lateral sclerosis and frontotemporal dementia, as well as the mechanisms leading to the loss of inhibition. We also discuss the contributions of these alterations to symptoms, and the potential therapeutic strategies for targeting inhibitory neuron deficits.}, } @article {pmid39591907, year = {2024}, author = {Bajpai, A and Bharathi, V and Kumawat, R and Tomar, RS and Patel, BK}, title = {Activation of the yeast MAP kinase, Slt2, protects against TDP-43 and TDP-25 toxicity in the Saccharomyces cerevisiae proteinopathy model.}, journal = {Biochemical and biophysical research communications}, volume = {741}, number = {}, pages = {151062}, doi = {10.1016/j.bbrc.2024.151062}, pmid = {39591907}, issn = {1090-2104}, mesh = {*Saccharomyces cerevisiae/metabolism/genetics ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Unfolded Protein Response/drug effects ; *Mitogen-Activated Protein Kinases/metabolism/genetics ; TDP-43 Proteinopathies/metabolism/genetics/pathology ; Humans ; Enzyme Activation ; Oxidative Stress/drug effects ; }, abstract = {TDP-43 proteinopathy is observed in human neurodegenerative diseases like ALS. Heterologous TDP-43 expression in the yeast model also mimics several proteinopathy features such as cytotoxicity, cytoplasmic mis-localization and oxidative stress. Among the pathways implicated in modulating the TDP-43 toxicity in yeast, the unfolded protein response (UPR) activation was also identified. Here, we examine the role of stress-regulated yeast MAP kinase, Slt2, which also links cellular stress with UPR activation, in modulating the toxicities of the full-length TDP-43 and its 25 kDa C-terminal fragment, TDP-25. We find enhancement in the cytotoxicity of TDP-43, as well as TDP-25, in the yeast cells deleted for the MAP kinase, Slt2, but not in those lacking other yeast MAP kinases, Kss1 and Fus3. Unlike in the wild-type yeast, upon treatment with an antioxidant N-acetyl cysteine, the TDP-43 toxicity could not be mitigated in the slt2Δ yeast but the TDP-25 toxicity was significantly rescued suggesting oxidative stress as an important contributor to the TDP-25 toxicity. Notably, TDP-43 as well as TDP-25 expressions could cause significant phosphorylation of Slt2 suggesting activation of this MAP Kinase due to their toxicities. Interestingly, in the slt2Δ cells, lacking the MAP Kinase activity, a treatment with low concentrations of an UPR activator molecule, DTT, caused significant reduction in the toxicities of both TDP-43 as well as TDP-25. Taken together, these findings suggest that TDP-43 and TDP-25 toxicity-induced stress-mediated activation of the MAP kinase Slt2 helps in mitigating their toxicities in the yeast model possibly through UPR activation.}, } @article {pmid39589985, year = {2024}, author = {Tkachenko, K and González-Saíz, JM and Calvo, AC and Lunetta, C and Osta, R and Pizarro, C}, title = {Comparative Blood Profiling Based on ATR-FTIR Spectroscopy and Chemometrics for Differential Diagnosis of Patients with Amyotrophic Lateral Sclerosis-Pilot Study.}, journal = {Biosensors}, volume = {14}, number = {11}, pages = {}, pmid = {39589985}, issn = {2079-6374}, support = {N· 801586//European Union's H2020/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/blood ; Humans ; Pilot Projects ; Diagnosis, Differential ; Spectroscopy, Fourier Transform Infrared ; Middle Aged ; Female ; Male ; Aged ; Adult ; Biomarkers/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neurodegenerative disease characterized by poor prognosis. Currently, screening and diagnostic methods for ALS remain challenging, often leading to diagnosis at an advanced stage of the disease. This delay hinders the timely initiation of therapy, negatively impacting patient well-being. Additionally, misdiagnosis with other neurodegenerative disorders that present similar profiles often occurs. Therefore, there is an urgent need for a cost-effective, rapid, and user-friendly tool capable of predicting ALS onset. In this pilot study, we demonstrate that infrared spectroscopy, coupled with chemometric analysis, can effectively identify and predict disease profiles from blood samples drawn from ALS patients. The selected predictive spectral markers, which are used in various discriminant models, achieved an AUROC sensitivity of almost 80% for distinguishing ALS patients from controls. Furthermore, the differentiation of ALS at both the initial and advanced stages from other neurodegenerative disorders showed even higher AUROC values, with sensitivities of 87% (AUROC: 0.70-0.97). These findings highlight the elevated potential of ATR-FTIR spectroscopy for routine clinical screening and early diagnosis of ALS.}, } @article {pmid39589981, year = {2024}, author = {Mohaček-Grošev, V and Škrabić, M and Gebavi, H and Blažek Bregović, V and Marić, I and Amendola, V and Grdadolnik, J}, title = {Binding of Glutamic Acid to Silver and Gold Nanoparticles Investigated by Surface-Enhanced Raman Spectroscopy.}, journal = {Biosensors}, volume = {14}, number = {11}, pages = {}, pmid = {39589981}, issn = {2079-6374}, support = {croatian-slovenian bilateral project//Ministry of Scirence and Education of the Republic of Croatia/ ; }, mesh = {*Spectrum Analysis, Raman ; *Glutamic Acid/chemistry ; *Silver/chemistry ; *Gold/chemistry ; *Metal Nanoparticles/chemistry ; Hydrogen-Ion Concentration ; }, abstract = {Glutamate is the most important excitatory neurotransmitter, which is relevant for the study of several diseases such as amyotrophic lateral sclerosis and Alzheimer. It is the form L-glutamic acid (Glu) takes at physiologically relevant pHs. The surface-enhanced Raman spectra of Glu obtained at pH values ranging from 3.3 to 12 are collected in the presence of silver and gold colloids and on solid substrates. The observed bands are compared with the positions of calculated normal modes for free neutral glutamic acid, glutamic acid monohydrate, glutamic acid bound to gold and silver atoms, and sodium glutamate. Although gold atoms prefer to bind to the NH2 group as compared to carbonyl groups, silver atoms prefer binding to hydroxyl groups more than binding to the amino group. SERS spectra of glutamic acid solutions with a pH value of 12, in which both carboxylic groups are deprotonated, indicate a complexation of the glutamic acid dianion with the sodium cation, which was introduced into the solution to adjust the pH value. Further research towards an optimal substrate is needed.}, } @article {pmid39589881, year = {2024}, author = {Jean Gregoire, M and Sirtori, R and Donatelli, L and Morgan Potts, E and Collins, A and Zamor, D and Katenka, N and Fallini, C}, title = {Early disruption of the CREB pathway drives dendritic morphological alterations in FTD/ALS cortical neurons.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {49}, pages = {e2406998121}, pmid = {39589881}, issn = {1091-6490}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; Early Career Development Award//RI-INBRE/ ; R01NS116143//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; P20GM103430//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 NS116143/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Dendrites/metabolism ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *Frontotemporal Dementia/metabolism/genetics/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Neurons/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Signal Transduction ; C9orf72 Protein/genetics/metabolism ; Phosphorylation ; Cerebral Cortex/metabolism/pathology ; }, abstract = {Synaptic loss and dendritic degeneration are common pathologies in several neurodegenerative diseases characterized by progressive cognitive and/or motor decline, such as Alzheimer's disease (AD) and frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). An essential regulator of neuronal health, the cAMP-dependent transcription factor CREB positively regulates synaptic growth, learning, and memory. Phosphorylation of CREB by protein kinase A (PKA) and other cellular kinases promotes neuronal survival and maturation via transcriptional activation of a wide range of downstream target genes. CREB pathway dysfunction has been strongly implicated in AD pathogenesis, and recent data suggest that impaired CREB activation may contribute to disease phenotypes in FTD/ALS as well. However, the mechanisms behind reduced CREB activity in FTD/ALS pathology are not clear. In this study, we found that cortical-like neurons derived from iPSC lines carrying the hexanucleotide repeat expansion in the C9ORF72 gene, a common genetic cause of FTD/ALS, displayed a diminished activation of CREB, resulting in decreased dendritic and synaptic health. Importantly, we determined such impairments to be mechanistically linked to an imbalance in the ratio of regulatory and catalytic subunits of the CREB activator PKA and to be conserved in C9-ALS patient's postmortem tissue. Modulation of cAMP upstream of this impairment allowed for a rescue of CREB activity and an amelioration of dendritic morphology and synaptic protein levels. Our data elucidate the mechanism behind early CREB pathway dysfunction and discern a feasible therapeutic target for the treatment of FTD/ALS and possibly other neurodegenerative diseases.}, } @article {pmid39589500, year = {2025}, author = {Apolloni, S and D'Ambrosi, N}, title = {Biochemical dissection of STAT3 signaling in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3229-3230}, pmid = {39589500}, issn = {1673-5374}, } @article {pmid39589178, year = {2025}, author = {Peng, Y and Zhou, L and Jin, Y and Wu, D and Chen, N and Zhang, C and Liu, H and Li, C and Ning, R and Yang, X and Mao, Q and Liu, J and Zhang, P}, title = {Calcium bridges built by mitochondria-associated endoplasmic reticulum membranes: potential targets for neural repair in neurological diseases.}, journal = {Neural regeneration research}, volume = {20}, number = {12}, pages = {3349-3369}, pmid = {39589178}, issn = {1673-5374}, abstract = {The exchange of information and materials between organelles plays a crucial role in regulating cellular physiological functions and metabolic levels. Mitochondria-associated endoplasmic reticulum membranes serve as physical contact channels between the endoplasmic reticulum membrane and the mitochondrial outer membrane, formed by various proteins and protein complexes. This microstructural domain mediates several specialized functions, including calcium (Ca 2+) signaling, autophagy, mitochondrial morphology, oxidative stress response, and apoptosis. Notably, the dysregulation of Ca 2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes is a critical factor in the pathogenesis of neurological diseases. Certain proteins or protein complexes within these membranes directly or indirectly regulate the distance between the endoplasmic reticulum and mitochondria, as well as the transduction of Ca 2+ signaling. Conversely, Ca 2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes influences other mitochondria-associated endoplasmic reticulum membrane-associated functions. These functions can vary significantly across different neurological diseases-such as ischemic stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease-and their respective stages of progression. Targeted modulation of these disease-related pathways and functional proteins can enhance neurological function and promote the regeneration and repair of damaged neurons. Therefore, mitochondria-associated endoplasmic reticulum membranes-mediated Ca 2+ signaling plays a pivotal role in the pathological progression of neurological diseases and represents a significant potential therapeutic target. This review focuses on the effects of protein complexes in mitochondria-associated endoplasmic reticulum membranes and the distinct roles of mitochondria-associated endoplasmic reticulum membranes-mediated Ca 2+ signaling in neurological diseases, specifically highlighting the early protective effects and neuronal damage that can result from prolonged mitochondrial Ca 2+ overload or deficiency. This article provides a comprehensive analysis of the various mechanisms of Ca 2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes in neurological diseases, contributing to the exploration of potential therapeutic targets for promoting neuroprotection and nerve repair.}, } @article {pmid39589160, year = {2025}, author = {Wang, Y and Li, D and Xu, K and Wang, G and Zhang, F}, title = {Copper homeostasis and neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3124-3143}, pmid = {39589160}, issn = {1673-5374}, abstract = {Copper, one of the most prolific transition metals in the body, is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations. Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins, including copper transporters (CTR1 and CTR2), the two copper ion transporters the Cu -transporting ATPase 1 (ATP7A) and Cu-transporting beta (ATP7B), and the three copper chaperones ATOX1, CCS, and COX17. Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue. Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins, including ceruloplasmin and metallothionein, is involved in the pathogenesis of neurodegenerative disorders. However, the exact mechanisms underlying these processes are not known. Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress. Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction. Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation, with elevated levels activating several critical inflammatory pathways. Additionally, copper can bind aberrantly to several neuronal proteins, including alpha-synuclein, tau, superoxide dismutase 1, and huntingtin, thereby inducing neurotoxicity and ultimately cell death. This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases, with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis. By synthesizing the current findings on the functions of copper in oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein misfolding, we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders, such as Wilson's disease, Menkes' disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Potential clinically significant therapeutic targets, including superoxide dismutase 1, D-penicillamine, and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline, along with their associated therapeutic agents, are further discussed. Ultimately, we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.}, } @article {pmid39588282, year = {2024}, author = {Dash, BP and Freischmidt, A and Helferich, AM and Ludolph, AC and Andersen, PM and Weishaupt, JH and Hermann, A}, title = {Upregulated miR-10b-5p as a potential miRNA signature in amyotrophic lateral sclerosis patients.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1457704}, pmid = {39588282}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset disease marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Death in most patients usually occurs within 2-4 years after symptoms onset. Despite promising progress in delineating underlying mechanisms, such as disturbed proteostasis, DNA/RNA metabolism, splicing or proper nucleocytoplasmic shuttling, there are no effective therapies for the vast majority of cases. A reason for this might be the disease heterogeneity and lack of substantial clinical and molecular biomarkers. The identification and validation of such pathophysiology driven biomarkers could be useful for early diagnosis and treatment stratification. Recent advances in next generation RNA-sequencing approaches have provided important insights to identify key changes of non-coding RNAs (ncRNAs) implicated with ALS disease. Especially, microRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression to target several genes/pathways by degrading messenger RNAs (mRNAs) or repressing levels of gene expression. In this study, we expand our previous work to identify top-regulated differentially expressed (DE)-miRNAs by combining different normalizations to search for important and generalisable pathomechanistic dysregulations in ALS as putative novel biomarkers of the disease. For this we performed a consensus pipeline of existing datasets to investigate the transcriptomic profile (mRNAs and miRNAs) of MN cell lines from iPSC-derived SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls to identify potential signatures and their related pathways associated with neurodegeneration. Transcriptional profiling of miRNA-mRNA interactions from MN cell lines in ALS patients revealed differential expression of genes showed greater vulnerability to KEAP1-NRF2 stress response pathway, sharing a common molecular denominator linked to both disease conditions. We also reported that mutations in above genes led to significant upregulation of the top candidate miR-10b-5p, which we could validate in immortalized lymphoblast cell lines (LCLs) derived from sporadic and familial ALS patients and postmortem tissues of familial ALS patients. Collectively, our findings suggest that miRNA analysis simultaneously performed in various human biological samples may reveal shared miRNA profiles potentially useful as a biomarker of the disease.}, } @article {pmid39587229, year = {2024}, author = {Wang, C and Wang, S and Xue, Y and Zhong, Y and Li, H and Hou, X and Kang, DD and Liu, Z and Tian, M and Wang, L and Cao, D and Yu, Y and Liu, J and Cheng, X and Markovic, T and Hashemi, A and Kopell, BH and Charney, AW and Nestler, EJ and Dong, Y}, title = {Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system.}, journal = {Nature biotechnology}, volume = {}, number = {}, pages = {}, pmid = {39587229}, issn = {1546-1696}, abstract = {Delivery of biomacromolecules to the central nervous system (CNS) remains challenging because of the restrictive nature of the blood-brain barrier (BBB). We developed a BBB-crossing conjugate (BCC) system that facilitates delivery into the CNS through γ-secretase-mediated transcytosis. Intravenous administration of a BCC10-oligonucleotide conjugate demonstrated effective transportation of the oligonucleotide across the BBB and gene silencing in wild-type mice, human brain tissues and an amyotrophic lateral sclerosis mouse model.}, } @article {pmid39585162, year = {2024}, author = {Savvidis, C and Kouroglou, E and Kallistrou, E and Ragia, D and Dionysopoulou, S and Gavriiloglou, G and Tsiama, V and Proikaki, S and Belis, K and Ilias, I}, title = {IGFBP-2 in Critical Illness: A Prognostic Marker in the Growth Hormone/Insulin-like Growth Factor Axis.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {31}, number = {4}, pages = {621-630}, pmid = {39585162}, issn = {1873-149X}, abstract = {Critical illness (CI) triggers complex disruptions in the growth hormone (GH)/insulin-like growth factor (IGF) axis, significantly affecting the dynamics of insulin-like growth-factor-binding proteins (IGFBPs). Among these, IGFBP-2 shows a sustained elevation during CI, which inversely correlates with serum levels of IGF-1, IGFBP-3, and the acid-labile subunit (ALS). Although IGFBP-2 does not directly interact with ALS, it may influence the availability of IGFs by competing with other IGFBPs for binding to IGF-1 and IGF-2. Research suggests that this persistent elevation of IGFBP-2 is largely driven by cytokine activity during CI, reflecting an adaptive response rather than a direct result of GH/IGF axis dysregulation. The clinical importance of IGFBP-2 is emphasized by its correlation with disease severity in conditions like sepsis and coronavirus disease 2019 (COVID-19), where its levels are markedly elevated compared to healthy controls and are similar to those observed in sepsis from various causes. Beyond its role in endocrine regulation, IGFBP-2 appears to play a part in metabolic and inflammatory pathways. Elevated IGFBP-2 levels have been linked to increased mortality and longer hospital stays, indicating its potential utility as a prognostic marker. Furthermore, measuring plasma IGFBP-2 may have other diagnostic applications, aiding in the assessment of CI when traditional biomarkers are inconclusive.}, } @article {pmid39585060, year = {2024}, author = {Magni, E and Hochsprung, A and Cáceres-Matos, R and Pabón-Carrasco, M and Heredia-Camacho, B and Solís-Marcos, I and Luque-Moreno, C}, title = {Effects of Respiratory Training on Pulmonary Function, Cough, and Functional Independence in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Neurology international}, volume = {16}, number = {6}, pages = {1332-1342}, pmid = {39585060}, issn = {2035-8385}, abstract = {BACKGROUND: Respiratory complications in patients with amyotrophic lateral sclerosis (ALS), due to the involvement of respiratory muscles, are the leading cause of death, and respiratory physiotherapy (RP) focuses on addressing these complications.

OBJECTIVES: The objective was to evaluate the effectiveness of an RP intervention that combines the four specific techniques (inspiratory muscle training, lung volume recruitment, manually assisted coughing, and diaphragmatic breathing training) in patients with ALS.

METHODS: A quasi-experimental study was carried out, and a specific RP programme was implemented in 15 patients with ALS (12 sessions, 30 min/session, one session/week, duration of three months), based on directed ventilation techniques, lung volume recruitment, manually assisted coughing, and the use of incentive spirometry and a cough assist device, along with a daily home exercise programme. Respiratory functions were assessed (pre- and post-intervention, with follow-up at three months) using Forced Vital Capacity (FVC) and Peak Expiratory Cough Flow (PECF); functionality was assessed using the Revised ALS Functional Rating Scale (ALSFRS-R) and the Modified Barthel Index by Granger.

RESULTS: FVC experienced an increase after three months of the intervention initiation (p = 0.30), which was not sustained at the three-month follow-up after the intervention ended. All other variables remained practically constant after treatment, with their values decreasing at follow-up.

CONCLUSION: A specific RP intervention could have beneficial effects on respiratory functions, potentially preventing pulmonary infections and hospitalisations in patients with ALS. It may improve FVC and help stabilize the patient's functional decline. Considering the progressive and degenerative nature of the disease, this finding could support the usefulness of these techniques in maintaining respiratory function.}, } @article {pmid39584466, year = {2024}, author = {Daneshpour, A and Rezvanimehr, A and Niktalab, P and Sharif, H and Yazdanpanah, N and Saleki, K and Rezaei, N}, title = {Exploring the role of vault complex in the nervous system: a literature review.}, journal = {Reviews in the neurosciences}, volume = {}, number = {}, pages = {}, pmid = {39584466}, issn = {2191-0200}, abstract = {Vault RNAs (vtRNAs) are a novel group of non-coding RNAs that are involved in various signaling mechanisms. vtRNAs are joined by three proteins major vault protein (MVP), vault poly (ADP-ribose) polymerase (VPARP), and telomerase-associated protein 1 (TEP1) to form the vault complex. In humans, only four vtRNA including vtRNA 1-1, vtRNA 1-2, vtRNA 1-3, vtRNA 2-1) have been discovered. In nerve cells, vtRNA is involved in synapse formation through MAPK signaling. vtRNA travels to the distal area of neurites as a key unit in the vault complex. Moreover, tRNA is detached from the vault complex in the neurite via a mitotic kinase Aurora-A-reliant MVP phosphorylation. Several molecules contribute to the formation of vtRNAs. For instance, SRSF2 and NSUN2 and their attachment to vtRNA1-1 determines the production of small-vtRNAs. Through the same factors, vtRNAs could play a role in neurodevelopmental deficits. Addition the role of vtRNA expression and vault proteins has been recently studied in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) as well as brain cancers. While the mechanisms of vtRNA involvement in neurological disorders is not well-demonstrated, we believe this could be related to the impact of vtRNA regulation in autophagy, immunoregulation, RNA stability, cellular stress, apoptosis, and regulation of other epigenetic pathways. The present review captures the state-of-the-art regarding the role of vtRNAs in neurodevelopment, normal nervous system function, and neurological disorders.}, } @article {pmid39583905, year = {2024}, author = {Townley, MA}, title = {Spinneret spinning field ontogeny and life history observations in the spider Palpimanus uncatus (Araneae: Palpimanidae).}, journal = {The Journal of arachnology}, volume = {52}, number = {1}, pages = {41-70}, pmid = {39583905}, issn = {0161-8202}, support = {P20 GM113131/GM/NIGMS NIH HHS/United States ; }, abstract = {As in other Palpimanidae, two pairs of posterior spinnerets present in typical Araneomorphae are vestigial in Palpimanus uncatus Kulczyński, 1909, with only the anterior lateral spinneret (ALS) pair prominent. Nevertheless, in late juvenile and adult females, spigots appear in the ancestral posterior spinneret region (PS). Consistent with these spigots serving cylindrical silk glands, females construct substantial egg sacs. While juveniles and adults exhibit a compressed PS, in postembryos it is fully extended. Piriform silk gland (PI) spigots form a linear array on ALSs from the 1[st] stadium, increasing in number during ontogeny by addition of PIs of the tartipore-accommodated (T-A) subtype (i.e., functional during proecdyses). The number of T-A PIs added from one stadium to the next and locations occupied by their spigots often exhibit a stereotypic pattern, especially consistent in early instars. The number of non-T-A PIs remains constant through ontogeny from the 1[st] stadium: one per ALS rather than the two per ALS inferred in a few araneoids. The secondary major ampullate silk gland (2° MaA) spigot, primitively uni-shafted among araneomorphs, has become modified into a multi-shafted spigot with extended base, the number of shafts increasing during ontogeny. However, the multiple ducts that connect to the shafts continue to be accommodated during proecdysis by a single enormous tartipore. Sexual dimorphism is present, with late stadium females having greater numbers of T-A PI spigots and 2° MaA spigot shafts. Observations are presented pertaining to feeding behavior, sexual cannibalism (absent), habitat, winter diapause, numbers of molts, and longevity.}, } @article {pmid39582565, year = {2024}, author = {Byeon, H}, title = {Glymphatic system function in diverse glucose metabolism states.}, journal = {World journal of diabetes}, volume = {15}, number = {11}, pages = {2245-2250}, pmid = {39582565}, issn = {1948-9358}, abstract = {The rising prevalence of diabetes and prediabetes globally necessitates a deeper understanding of associated complications, including glymphatic system dysfunction. The glymphatic system, crucial for brain waste clearance, is implicated in cognitive decline and neurodegenerative diseases like Alzheimer's disease. This letter explores recent research on glymphatic function across different glucose metabolism states. Tian et al's study reveals significant glymphatic dysfunction in type 2 diabetes mellitus patients, evidenced by lower diffusion tensor imaging analysis along perivascular space indices compared to those with normal glucose metabolism and prediabetes. The research also reveals a link between glymphatic dysfunction and cognitive impairment. Additional research underscores the role of glymphatic impairment in neurodegenerative diseases. These findings highlight the importance of integrating glymphatic health into diabetes management and suggest potential biomarkers for early diagnosis and targeted therapeutic interventions.}, } @article {pmid39581840, year = {2025}, author = {Hannaford, A and Pavey, N and Menon, P and van den Bos, MAJ and Kiernan, MC and Simon, N and Vucic, S}, title = {Muscle ultrasound aids diagnosis in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {170}, number = {}, pages = {234-243}, doi = {10.1016/j.clinph.2024.11.008}, pmid = {39581840}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/diagnosis ; Male ; Female ; Middle Aged ; *Ultrasonography/methods/standards ; Aged ; *Muscle, Skeletal/diagnostic imaging/physiopathology ; Adult ; Cohort Studies ; Prospective Studies ; Fasciculation/diagnostic imaging/physiopathology ; }, abstract = {OBJECTIVE: There is a need for improved diagnostic tools in Amyotrophic Lateral Sclerosis (ALS). Our objective was to assess muscle ultrasound as a diagnostic tool in patients with ALS and determine a simplified screening protocol to aid implementation in clinical practice.

METHODS: Ultrasound of bulbar and limb muscles was prospectively performed on all patients referred to a single centre with suspected ALS. Clinical measures of disease severity and upper motor neuron impairment were also recorded. Receiver operating characteristic (ROC) curves were calculated to assess the diagnostic utility of muscle ultrasound.

RESULTS: 94 patients initially suspected of ALS were recruited to this observational cohort study. Forty-four were subsequently diagnosed as ALS and 50 as disease mimics. ALS patients demonstrated a higher frequency and more generalised distribution of fasciculations compared to mimics. A simplified 5 muscle screening protocol exhibited an AUC of 0.94 (95 %CI 0.89-0.99) in discriminating ALS from mimics. The presence of ≥ 3 fasciculating muscles detected using this screening protocol was 89 % sensitive and 88 % specific for the diagnosis of ALS.

CONCLUSIONS: Muscle ultrasound, screening as few as 5 muscles, has diagnostic utility in ALS.

SIGNIFICANCE: Muscle ultrasound enhances clinical diagnosis in ALS.}, } @article {pmid39581338, year = {2025}, author = {Kokona, B and Cunningham, NR and Quinn, JM and Jacobsen, DR and Garcia, FJ and Galindo, SM and Petrucelli, L and Stafford, WF and Laue, TM and Fairman, R}, title = {Studying C9orf72 dipeptide repeat polypeptide aggregation using an analytical ultracentrifuge equipped with fluorescence detection.}, journal = {Analytical biochemistry}, volume = {697}, number = {}, pages = {115720}, pmid = {39581338}, issn = {1096-0309}, support = {P40 OD018537/OD/NIH HHS/United States ; R15 NS081681/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *C9orf72 Protein/genetics ; *Caenorhabditis elegans/genetics ; *Dipeptides/chemistry ; Ultracentrifugation ; Drosophila melanogaster/genetics ; Humans ; Protein Aggregates ; Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia/genetics ; Peptides/chemistry/genetics/analysis ; Fluorescence ; }, abstract = {Sedimentation velocity, using an analytical ultracentrifuge equipped with fluorescence detection, and electrophoresis methods are used to study aggregation of proteins in transgenic animal model systems. Our previous work validated the power of this approach in an analysis of mutant huntingtin aggregation. We demonstrate that this method can be applied to another neurodegenerative disease studying the aggregation of three dipeptide repeats (DPRs) produced by aberrant translation of mutant c9orf72 containing large G4C2 hexanucleotide repeats. These repeat expansions are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We analyzed the aggregation patterns of (Gly-Pro)47, (Gly-Ala)50, and (Gly-Arg)50 fused to fluorescent proteins in samples prepared from D. melanogaster, and (Gly-Ala)50 in C. elegans, using AU-FDS and SDD-AGE. Results suggest that (GP)47 is largely monomeric. In contrast, (GA)50 forms both intermediate and large-scale aggregates. (GR)50 is partially monomeric with some aggregation noted in SDD-AGE analysis. The aggregation of this DPR is likely to represent co-aggregated states with DNA and/or RNA. The power of these methods is the ability to gather data on aggregation patterns and characteristics in animal model systems, which may then be used to interpret the mitigation of aggregation through genetic or molecular therapeutic interventions.}, } @article {pmid39580968, year = {2024}, author = {Lewandowski, SA and Kular, L and Jagodic, M}, title = {Epigenetic age acceleration as a biomarker of amyotrophic lateral sclerosis severity?.}, journal = {EBioMedicine}, volume = {110}, number = {}, pages = {105470}, pmid = {39580968}, issn = {2352-3964}, } @article {pmid39580792, year = {2025}, author = {Kaplan, E and Weissbach, A and Kadmon, G and Nahum, E and Stein, J}, title = {Plasma exchange using peripheral arterial and venous access in the pediatric intensive care unit.}, journal = {Transfusion}, volume = {65}, number = {1}, pages = {152-158}, pmid = {39580792}, issn = {1537-2995}, mesh = {Humans ; *Plasma Exchange/methods/adverse effects ; Retrospective Studies ; *Intensive Care Units, Pediatric ; Child ; Male ; Female ; Child, Preschool ; Infant ; Adolescent ; Catheterization, Peripheral/methods/adverse effects ; Radial Artery ; }, abstract = {OBJECTIVE: Therapeutic plasma exchange (TPE) is a vital therapeutic modality in pediatric intensive care units (PICU) for various indications. Traditionally, pediatric TPE is performed via a large bore, double lumen catheter, whose insertion necessitates deep sedation, and poses risk of hemorrhagic and thrombotic complications. Building on our previous success utilizing percutaneous radial artery catheters (ALs) for apheresis procedures, we present our experience with ALs for TPE procedures in the PICU.

METHODS: A retrospective cohort study, conducted in the PICU of a tertiary, university affiliated pediatric hospital, including all children aged 19 years and younger, who underwent TPE using an AL for vascular access, between 2018 and 2023. TPE procedures were evaluated for utility (the procedure was performed as planned) and safety.

RESULTS: A total of 72 procedures were performed on 20 children, using ALs for inlet access and peripheral intra-venous catheters for blood return. Procedure success rate was 94%, with AL malfunction causing transient delays in 6%. All were successfully completed following AL replacement. ALs were mostly 20 and 22 gauge, predominantly located in the radial artery. AL gauge did not significantly affect flow rate or procedure duration.

CONCLUSIONS: Our findings support AL use for vascular access, as a viable alternative to the traditional large bore, double lumen catheters most often used for TPE in children. Benefits of AL use may include a decrease in sedation requirements and a lower risk of vascular complications. Further investigation is warranted, for consideration as routine practice in PICUs.}, } @article {pmid39579998, year = {2025}, author = {Baroukhian, J and Seiffert-Sinha, K and Sinha, AA}, title = {Response to Kasperkiewicz et al's "Pemphigus following herpes simplex infection: A global comprehensive cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {4}, pages = {e99-e100}, doi = {10.1016/j.jaad.2024.07.1536}, pmid = {39579998}, issn = {1097-6787}, } @article {pmid39579996, year = {2025}, author = {Watanabe, Y and Yamaguchi, Y}, title = {Regarding response to Yamaguchi et al's "Anti-SS-A antibody is a potential predictor of severe Stevens-Johnson syndrome and toxic epidermal necrolysis: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e73-e74}, doi = {10.1016/j.jaad.2024.11.030}, pmid = {39579996}, issn = {1097-6787}, } @article {pmid39579963, year = {2024}, author = {Carracedo, S and Launay, A and Dechelle-Marquet, PA and Faivre, E and Blum, D and Delarasse, C and Boué-Grabot, E}, title = {Purinergic-associated immune responses in neurodegenerative diseases.}, journal = {Progress in neurobiology}, volume = {243}, number = {}, pages = {102693}, doi = {10.1016/j.pneurobio.2024.102693}, pmid = {39579963}, issn = {1873-5118}, mesh = {Humans ; *Neurodegenerative Diseases/immunology/metabolism ; Animals ; *Receptors, Purinergic/metabolism ; }, abstract = {The chronic activation of immune cells can participate in the development of pathological conditions such as neurodegenerative diseases including Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, compelling evidence indicates that purinergic signaling plays a key role in neuro-immune cell functions. The extracellular release of adenosine 5'-triphosphate (ATP), and its breakdown products (ADP and adenosine) provide the versatile basis for complex purinergic signaling through the activation of several families of receptors. G-protein coupled adenosine A2A receptors, ionotropic P2X and G-protein coupled P2Y receptors for ATP and other nucleotides are abundant and widely distributed in neurons, microglia, and astrocytes of the central nervous system as well as in peripheral immune cells. These receptors are strongly linked to inflammation, with a functional interplay that may influence the intricate purinergic signaling involved in inflammatory responses. In the present review, we examine the roles of the purinergic receptors in neuro-immune cell functions with particular emphasis on A2AR, P2X4 and P2X7 and their possible relevance to specific neurodegenerative disorders. Understanding the molecular mechanisms governing purinergic receptor interaction will be crucial for advancing the development of effective immunotherapies targeting neurodegenerative diseases.}, } @article {pmid39579350, year = {2024}, author = {Alfahel, L and Rajkovic, A and Israelson, A}, title = {Protocol for handling and using SOD1 mice for amyotrophic lateral sclerosis pre-clinical studies.}, journal = {STAR protocols}, volume = {5}, number = {4}, pages = {103459}, pmid = {39579350}, issn = {2666-1667}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Superoxide Dismutase-1/genetics/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; Female ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that has no proper cure. Pre-clinical studies on ALS mice are an essential milestone toward clinical trials. Here, we present a protocol for handling and using SOD1[G37R] mice for ALS pre-clinical studies. We describe steps for breeding, genotyping, monitoring, and behavioral testing of mice. We then detail procedures for perfusion, organ harvesting, and immunostaining for postmortem analysis. This protocol can be easily modified for other mouse lines. For complete details on the use and execution of this protocol, please refer to Alfahel et al.[1].}, } @article {pmid39578404, year = {2025}, author = {Phrathep, DD and Abdo, Z and Tadros, M and Lewandowski, E and Evans, J}, title = {The role of osteopathic manipulative treatment for dystonia: a literature review.}, journal = {Journal of osteopathic medicine}, volume = {125}, number = {4}, pages = {203-211}, pmid = {39578404}, issn = {2702-3648}, mesh = {Humans ; *Manipulation, Osteopathic/methods ; *Dystonia/therapy ; }, abstract = {CONTEXT: Dystonia is a movement disorder that causes involuntary muscle contractions leading to abnormal movements and postures, such as twisting. Dystonia is the third most common movement disorder in the United States, with as many as 250,000 people affected. Because of its complexity, dystonia presents a significant challenge in terms of management and treatment. Despite limited research, osteopathic manipulative treatment (OMT) has been considered as an adjunctive treatment due to its inexpensive and noninvasive nature, as opposed to other modalities such as botulinum toxin injections, deep brain stimulation (DBS), and transcranial magnetic stimulation, which are often expensive and inaccessible. OMT treatments performed in case studies and series such as balanced ligamentous tension/articular ligamentous strain (BLT/ALS), muscle energy (ME), high-velocity low-amplitude (HVLA), and myofascial release (MFR) have shown reduction of pain and muscle hypertonicity, including in patients with dystonia.

OBJECTIVES: The studies reviewed in this paper provide a snapshot of the literature regarding the current evidence of OMT's role for dystonia.

METHODS: A medical reference librarian conducted a thorough literature search across multiple databases including PubMed and Google Scholar to find articles relevant to the use of OMT for dystonia. The search employed a combination of Medical Subject Headings (MeSH) terms and keywords related to osteopathic medicine and dystonia to ensure precise retrieval of relevant articles within the last 20 years. Despite limited research on the topic, all four relevant reports found in the literature were selected for review.

RESULTS: Of the four relevant reports, case series and studies highlighted the potential benefits of OMT in managing dystonia, particularly cervical dystonia and foot dystonia. OMT has shown promising results addressing pain, stiffness, and impaired motor function. In cases of foot dystonia in Parkinson's disease, OMT has helped improve gait and reduce pain by targeting somatic dysfunctions (SDs) associated with dystonia, such as abnormalities in foot progression angle (FPA) and musculoskeletal imbalances. Also, OMT has been found to alleviate symptoms of cervical dystonia, including tremors, muscle spasms, and neck stiffness. These interventions performed in case studies and series led to improvements in gait biomechanics in foot dystonia and overall symptom severity in patients with cervical dystonia.

CONCLUSIONS: Currently, botulinum toxin, oral medications, physical therapy, and rehabilitation are commonly utilized in managing dystonia. The studies reviewed in this paper suggest that these treatments may lead to improvements in pain and muscle hypertonicity in patients with dystonia. It is important to investigate whether factors such as the type of dystonia (eg, focal vs. segmental) and its underlying cause (eg, idiopathic, trauma, infection, autoimmune, medication side effects) influence treatment outcomes. Further research is recommended to explore the role of OMT in managing dystonia.}, } @article {pmid39578133, year = {2025}, author = {Travaglia, A and Lal, S and Pullagura, SR}, title = {Advancing ALS research: public-private partnerships to accelerate drug and biomarker development.}, journal = {Trends in neurosciences}, volume = {48}, number = {1}, pages = {1-2}, doi = {10.1016/j.tins.2024.10.008}, pmid = {39578133}, issn = {1878-108X}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Public-Private Sector Partnerships ; *Biomarkers ; Drug Development/methods ; Drug Discovery/methods ; Biomedical Research/methods ; Animals ; }, abstract = {Developing effective treatments for amyotrophic lateral sclerosis (ALS) has been hindered by both the complexity of the disease and decentralized research efforts. By fostering collaboration, standardization, and inclusivity, the Accelerating Medicines Partnership® (AMP®) ALS initiative aims to lay the foundation for future discoveries in ALS biomarkers and treatments.}, } @article {pmid39577830, year = {2024}, author = {Morikawa, K and Izumiya, Y and Takashio, S and Kawano, Y and Oguni, T and Kuyama, N and Oike, F and Yamamoto, M and Tabata, N and Ishii, M and Hanatani, S and Hoshiyama, T and Kanazawa, H and Matsuzawa, Y and Usuku, H and Yamamoto, E and Ueda, M and Tsujita, K}, title = {Early experience with daratumumab-containing regimens in patients with light-chain cardiac amyloidosis.}, journal = {Journal of cardiology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jjcc.2024.11.003}, pmid = {39577830}, issn = {1876-4738}, abstract = {BACKGROUND: Immunoglobulin light-chain (AL) amyloidosis is a lethal condition resulting from misfolded immunoglobulin ALs produced by clonal CD38-positive plasma cells. Treatment with daratumumab, an anti-human CD38 monoclonal antibody, led to higher frequencies of complete hematologic response and better clinical outcomes compared with conventional treatment. This study sought to evaluate the survival benefit of daratumumab-containing regimens in patients with AL cardiac amyloidosis.

METHODS AND RESULTS: We examined 65 consecutive patients with AL cardiac amyloidosis (mean age: 67.2 ± 10.4 years, male: 69 %) who underwent chemotherapy. We divided patients into a daratumumab group, which used daratumumab-containing regimens before second-line treatment (n = 32), and a conventional treatment group (n = 33). Compared with the conventional treatment group, the daratumumab group tended to be older, but there were no significant differences between groups in biomarkers and echocardiographic parameters. A total of 26 patients (40 %) died (median follow-up duration: 395 days). Kaplan-Meier survival analysis showed that the daratumumab group had significantly lower mortality compared with the conventional treatment group (p = 0.04; log-rank test). Cox hazard analysis revealed that use of daratumumab-containing regimens was associated with lower mortality after adjustment for the revised Mayo staging of AL amyloidosis (hazard ratio: 0.32; 95 % confidence interval: 0.12 to 0.85; p = 0.02).

CONCLUSION: Daratumumab-containing regimens may be associated with improved survival in patients with AL cardiac amyloidosis.}, } @article {pmid39577774, year = {2025}, author = {Olesen, MA and Villavicencio-Tejo, F and Cuevas-Espinoza, V and Quintanilla, RA}, title = {Unknown roles of tau pathology in neurological disorders. Challenges and new perspectives.}, journal = {Ageing research reviews}, volume = {103}, number = {}, pages = {102594}, doi = {10.1016/j.arr.2024.102594}, pmid = {39577774}, issn = {1872-9649}, mesh = {Humans ; *tau Proteins/metabolism ; Animals ; *Nervous System Diseases/metabolism/pathology ; Tauopathies/metabolism/pathology ; Aging/metabolism/pathology ; }, abstract = {Aging presents progressive changes that increase the susceptibility of the central nervous system (CNS) to suffer neurological disorders (NDs). Several studies have reported that an aged brain suffering from NDs shows the presence of pathological forms of tau protein, a microtubule accessory protein (MAP) critical for neuronal function. In this context, accumulative evidence has shown a pivotal contribution of pathological forms of tau to Alzheimer's disease (AD) and tauopathies. However, current investigations have implicated tau toxicity in other NDs that affect the central nervous system (CNS), including Parkinson's disease (PD), Huntington's disease (HD), Traumatic brain injury (TBI), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). These diseases are long-term acquired, affecting essential functions such as motor movement, cognition, hearing, and vision. Previous evidence indicated that toxic forms of tau do not have a critical contribution to the genesis or progression of these diseases. However, recent studies have shown that these tau forms contribute to neuronal dysfunction, inflammation, oxidative damage, and mitochondrial impairment events that contribute to the pathogenesis of these NDs. Recent studies have suggested that these neuropathologies could be associated with a prion-like behavior of tau, which induces a pathological dissemination of these toxic protein forms to different brain areas. Moreover, it has been suggested that this toxic propagation of tau from neurons into neighboring cells impairs the function of glial cells, oligodendrocytes, and endothelial cells by affecting metabolic function and mitochondrial health and inducing oxidative damage by tau pathology. Therefore, in this review, we will discuss current evidence demonstrating the critical role of toxic tau forms on NDs not related to AD and how its propagation and induced-bioenergetics failure may contribute to the pathogenic mechanism present in these NDs.}, } @article {pmid39577687, year = {2025}, author = {Li, Z and Zhang, Y and Li, D and Du, X and Chen, L and Guo, Y}, title = {Microglial upregulation of CD109 expression in spinal cord of amyotrophic lateral sclerosis mouse model and its role in modulating inflammation and TGFβ/SMAD pathway.}, journal = {Neuroscience}, volume = {564}, number = {}, pages = {202-213}, doi = {10.1016/j.neuroscience.2024.11.053}, pmid = {39577687}, issn = {1873-7544}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Microglia/metabolism ; *Spinal Cord/metabolism/pathology ; *Up-Regulation ; Mice ; *Smad Proteins/metabolism ; *Signal Transduction/physiology ; *Disease Models, Animal ; *Antigens, CD/metabolism ; *Transforming Growth Factor beta/metabolism ; Mice, Transgenic ; Inflammation/metabolism ; Lipopolysaccharides/pharmacology ; Transforming Growth Factor beta1/metabolism ; }, abstract = {CD109 is a multifunctional coreceptor, whose function has been widely studied in tumor progression and metastasis. One of the reported primary roles of CD109 involves down-regulating TGFβ signaling. However, the role of CD109 in central nervous system, especially neurodegenerative disease, is barely known. Here, we examined the expression changes and cellular location of CD109 and TGFβ/SMAD pathway molecules in lumbar spinal cord of SOD1-G93A mice, and explored the role and mechanism of CD109 on LPS-treated BV2 microglia and primary microglia derived from SOD1-G93A mice. Our results showed an increased expression of CD109 and TGFβ/SMAD pathway molecules in lumbar spinal cord of SOD1-G93A mice. Further cellular localization analysis demonstrated that proliferating microglia contributed mainly to the upregulation of CD109 and TGFβ1. Moreover, CD109 intervention in vitro partially reduced inflammatory response and TGFβ/SMAD pathway activation in both LPS-treated BV2 microglia and primary SOD1-G93A microglia. Thus, CD109 was involved in pathogenesis of ALS mice, and interventions targeting on CD109 modulation could be a potential therapeutic strategy for ALS.}, } @article {pmid39577621, year = {2024}, author = {Reiche, L and Plaack, B and Lehmkuhl, M and Weyers, V and Gruchot, J and Picard, D and Perron, H and Remke, M and Knobbe-Thomsen, C and Reifenberger, G and Küry, P and Kremer, D}, title = {HERV-W envelope protein is present in microglial cells of the human glioma tumor microenvironment and differentially modulates neoplastic cell behavior.}, journal = {Microbes and infection}, volume = {}, number = {}, pages = {105460}, doi = {10.1016/j.micinf.2024.105460}, pmid = {39577621}, issn = {1769-714X}, abstract = {Gliomas are the most common parenchymal tumors of the central nervous system (CNS). With regard to their still unclear etiology, several recent studies have provided evidence of a new category of pathogenic elements called human endogenous retroviruses (HERVs) which seem to contribute to the evolution and progression of many neurological diseases such as amyotrophic lateral sclerosis (ALS), schizophrenia, chronic inflammatory polyneuropathy (CIDP) and, particularly, multiple sclerosis (MS). In these diseases, HERVs exert effects on cellular processes such as inflammation, proliferation, and migration. In previous studies, we demonstrated that in MS, the human endogenous retrovirus type-W envelope protein (HERV-W ENV) interferes with lesion repair through the activation of microglia (MG), the innate myeloid immune cells of the CNS. Here, we now show that HERV-W ENV is also present in the microglial cells (MG) of the tumor microenvironment (TME) in gliomas. It modulates the behavior of glioblastoma (GBM) cell lines in GBM/MG cocultures by altering their gene expression, secreted cytokines, morphology, proliferation, and migration properties and could thereby contribute to key tumor properties.}, } @article {pmid39577228, year = {2025}, author = {Sojdeh, S and Safarkhani, M and Daneshgar, H and Aldhaher, A and Heidari, G and Nazarzadeh Zare, E and Iravani, S and Zarrabi, A and Rabiee, N}, title = {Promising breakthroughs in amyotrophic lateral sclerosis treatment through nanotechnology's unexplored frontier.}, journal = {European journal of medicinal chemistry}, volume = {282}, number = {}, pages = {117080}, doi = {10.1016/j.ejmech.2024.117080}, pmid = {39577228}, issn = {1768-3254}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Nanotechnology ; Genetic Therapy ; Animals ; Drug Delivery Systems ; Neuroprotective Agents/chemistry/therapeutic use/pharmacology ; }, abstract = {This review explores the transformative potential of nanotechnology in the treatment and diagnosis of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder characterized by motor neuron degeneration, muscle weakness, and eventual paralysis. Nanotechnology offers innovative solutions across various domains, including targeted drug delivery, neuroprotection, gene therapy and editing, biomarker detection, advanced imaging techniques, and tissue engineering. By enhancing the precision and efficacy of therapeutic interventions, nanotechnology facilitates key advancements such as crossing the blood-brain barrier, targeting specific cell types, achieving sustained therapeutic release, and enabling combination therapies tailored to the complex pathophysiology of ALS. Despite its immense promise, the clinical translation of these approaches faces challenges, including potential cytotoxicity, biocompatibility, and regulatory compliance, which must be addressed through rigorous research and testing. This review emphasizes the application of nanotechnology in targeted drug delivery and gene therapy/editing for ALS, drawing on the author's prior work with various nanotechnological platforms to illustrate strategies for overcoming similar obstacles in drug and gene delivery. By bridging the gap between cutting-edge technology and clinical application, this article aims to highlight the vital role of nanotechnology in shaping the future of ALS treatment.}, } @article {pmid39577115, year = {2024}, author = {Abdian, S and Fakhri, S and Moradi, SZ and Khirehgesh, MR and Echeverría, J}, title = {Saffron and its major constituents against neurodegenerative diseases: A mechanistic review.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {135}, number = {}, pages = {156097}, doi = {10.1016/j.phymed.2024.156097}, pmid = {39577115}, issn = {1618-095X}, mesh = {Animals ; Humans ; *Carotenoids/pharmacology/therapeutic use ; *Crocus/chemistry ; Cyclohexenes/pharmacology ; Glucosides/pharmacology ; *Neurodegenerative Diseases/drug therapy ; Neuroprotective Agents/chemistry/pharmacology ; Phytochemicals/pharmacology ; *Plant Extracts/chemistry/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Terpenes/pharmacology ; Vitamin A/analogs & derivatives ; }, abstract = {BACKGROUND: Neurodegeneration has been recognized as the main pathophysiological alteration in the majority of brain-related diseases. Despite contemporary attempts to provide acceptable medicinal therapies, the conclusion has not been much beneficial. Besides, the complex pathophysiological mechanisms behind neurodegenerative diseases (NDDs) urge the needs for finding novel multi-target agents. Accordingly, saffron with major active constituents and as multi-targeting agents have shown beneficial effects in modulating NDDs with higher efficacy and lower side effects.

PURPOSE: The present study provides a systematic and comprehensive review of the existing in vitro, in vivo, and clinical data on the effectiveness, and signaling pathways of saffron and its key phytochemical components in the management of NDDs. The need to develop novel saffron delivery systems is also considered.

METHODS: Studies were identified through a systematic and comprehensive search in Science Direct, PubMed, and Scopus databases through April 30, 2024. The whole saffron major constituents (e.g., saffron, crocin, crocetin, picrocrocin, and safranal) and NDDs (e.g., neuro*, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Huntington*, Parkinson*, Alzheimer*, and brain) were selected as keywords to find related studies. In the systematic analysis, 64 articles were directly included in the current study. Additional reports were added within the comprehensive studies in the review.

RESULTS: Saffron and its active metabolites crocin, crocetin, safranal, and picrocrocin have shown acceptable efficacy in managing NDDs like Alzheimer's disease, Parkinson's disease, Attention deficit hyperactivity disorder, depression, and other NDDs via modulating apoptotic (e.g., caspases, Bax/Bcl-2, cytochrome c, and death receptors), inflammatory (e.g., NF-κB, IL-1β, IL-6, TNF-α, and COX-2), and oxidative strass (e.g., Nrf2, GSH, GPx, CAT, SOD, MDA, ROS, and nitrite) signaling pathways. The presented in vitro, in vivo, and clinical evidences showed us a better future of controlling NDDs with higher efficacy, while decreasing associated side effects with no significant toxicity. Additionally, employing novel delivery systems could increase the efficacy of saffron phytoconstituents to resolve the issues pharmacokinetic limitations.

CONCLUSION: Saffron and its major constituents employ anti-inflammatory, anti-apoptotic and antioxidant mechanisms in modulating several dysregulated-signaling pathways in NDDs. However, further research is necessary to elucidate the precise underlying mechanisms in exploring the feasibility of using saffron active compounds against NDDs. More studies should focus on dose-response relationships, long-term effects, highlighting key mechanisms, and designing more well-controlled clinical trials. Additionally, developing stable and cost-benefit novel delivery systems in future works helps to remove the pharmacokinetic limitations of saffron major constituents.}, } @article {pmid39575748, year = {2024}, author = {Xu, Z and He, S and Begum, MM and Han, X}, title = {Myelin Lipid Alterations in Neurodegenerative Diseases: Landscape and Pathogenic Implications.}, journal = {Antioxidants & redox signaling}, volume = {41}, number = {16-18}, pages = {1073-1099}, pmid = {39575748}, issn = {1557-7716}, support = {P30 AG013319/AG/NIA NIH HHS/United States ; P30 AG044271/AG/NIA NIH HHS/United States ; R01 AG061729/AG/NIA NIH HHS/United States ; R01 AG085545/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Myelin Sheath/metabolism ; *Lipid Metabolism ; Animals ; Lipids ; }, abstract = {Significance: Lipids, which constitute the highest portion (over 50%) of brain dry mass, are crucial for brain integrity, energy homeostasis, and signaling regulation. Emerging evidence revealed that lipid profile alterations and abnormal lipid metabolism occur during normal aging and in different forms of neurodegenerative diseases. Moreover, increasing genome-wide association studies have validated new targets on lipid-associated pathways involved in disease development. Myelin, the protective sheath surrounding axons, is crucial for efficient neural signaling transduction. As the primary site enriched with lipids, impairments of myelin are increasingly recognized as playing significant and complex roles in various neurodegenerative diseases, beyond simply being secondary effects of neuronal loss. Recent Advances: With advances in the lipidomics field, myelin lipid alterations and their roles in contributing to or reflecting the progression of diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and others, have recently caught great attention. Critical Issues: This review summarizes recent findings of myelin lipid alterations in the five most common neurodegenerative diseases and discusses their implications in disease pathogenesis. Future Directions: By highlighting myelin lipid abnormalities in neurodegenerative diseases, this review aims to encourage further research focused on lipids and the development of new lipid-oriented therapeutic approaches in this area. Antioxid. Redox Signal. 00, 000-000.}, } @article {pmid39575564, year = {2025}, author = {Olofsson, J and Bergström, S and Mravinacová, S and Kläppe, U and Öijerstedt, L and Zetterberg, H and Blennow, K and Ingre, C and Nilsson, P and Månberg, A}, title = {Cerebrospinal fluid levels of NfM in relation to NfL and pNfH as prognostic markers in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {113-123}, doi = {10.1080/21678421.2024.2428930}, pmid = {39575564}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; *Neurofilament Proteins/cerebrospinal fluid ; Male ; Female ; Middle Aged ; Aged ; *Biomarkers/cerebrospinal fluid ; Prognosis ; *Disease Progression ; Adult ; Cohort Studies ; Phosphorylation ; }, abstract = {OBJECTIVE: To evaluate the prognostic potential of neurofilament medium chain (NfM) in CSF from patients with ALS and explore its relationship with the extensively studied neurofilament light chain (NfL) and phosphorylated heavy chain (pNfH).

METHOD: CSF levels of NfL, NfM, and pNfH were analyzed in 235 samples from patients with ALS, ALS mimics, and healthy controls in a well-characterized cohort from Karolinska ALS Clinical Research Center in Stockholm, Sweden. NfM levels were analyzed using an antibody-based suspension bead-array and NfL and pNfH levels were measured using ELISA. Clinical data, including ALS Revised Functional Rating Scale (ALSFRS-R), and survival outcomes were utilized for disease progression estimations.

RESULT: Increased NfM levels were observed in patients with ALS compared with mimics and healthy controls. Similarly, higher NfM levels were found in fast compared with slow progressing patients for baseline and longitudinal progression when evaluating both total and subscores of ALSFRS-R. These findings were consistent with the results observed for NfL and pNfH. All three proteins, used individually as well as in combination, showed comparable performance when classifying fast vs slow progressing patients (AUCs 0.78-0.85). For all neurofilaments, higher survival probability was observed for patients with low CSF levels.

CONCLUSION: Based on this cross-sectional study, the prognostic value provided by NfM aligns with the more established markers, NfL and pNfH. Additional investigations with independent cohorts and longitudinal studies are needed to further assess the potential added value of NfM.}, } @article {pmid39574866, year = {2024}, author = {Manohar, R and Yang, FX and Stephen, CD and Schmahmann, JD and Eklund, NM and Gupta, AS}, title = {At-home wearables and machine learning capture motor impairment and progression in adult ataxias.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39574866}, support = {R01 NS117826/NS/NINDS NIH HHS/United States ; R01 NS134597/NS/NINDS NIH HHS/United States ; }, abstract = {A significant barrier to developing disease-modifying therapies for spinocerebellar ataxias (SCAs) and multiple system atrophy of the cerebellar type (MSA-C) is the scarcity of tools to sensitively measure disease progression in clinical trials. Wearable sensors worn continuously during natural behavior at home have the potential to produce ecologically valid and precise measures of motor function by leveraging frequent and numerous high-resolution samples of behavior. Here we test whether movement-building block characteristics (i.e., submovements), obtained from the wrist and ankle during natural behavior at home, can sensitively capture disease progression in SCAs and MSA-C, as recently shown in amyotrophic lateral sclerosis (ALS) and ataxia telangiectasia (A-T). Remotely collected cross-sectional (n = 76) and longitudinal data (n = 27) were analyzed from individuals with ataxia (SCAs 1, 2, 3, and 6, MSA-C) and controls. Machine learning models were trained to produce composite outcome measures based on submovement properties. Two models were trained on data from individuals with ataxia to estimate ataxia rating scale scores. Two additional models, previously trained entirely on longitudinal ALS data to optimize sensitivity to change, were also evaluated. All composite outcomes from both wrist and ankle sensor data had moderate to strong correlations with ataxia rating scales and self-reported function, strongly separated ataxia and control populations, and had high within-week reliability. The composite outcomes trained on longitudinal ALS data most strongly captured disease progression over time. These data demonstrate that outcome measures based on accelerometers worn at home can accurately capture the ataxia phenotype and sensitively measure disease progression. This assessment approach is scalable and can be used in clinical or research settings with relatively low individual burden.}, } @article {pmid39574800, year = {2024}, author = {Bouajila, N and Domenighetti, C and Aubin, HJ and Naassila, M}, title = {Alcohol consumption and its association with cancer, cardiovascular, liver and brain diseases: a systematic review of Mendelian randomization studies.}, journal = {Frontiers in epidemiology}, volume = {4}, number = {}, pages = {1385064}, pmid = {39574800}, issn = {2674-1199}, abstract = {BACKGROUND: The health effects of alcohol consumption, particularly regarding potential protective benefits of light to moderate intake compared to abstinence, remain a subject of ongoing debate. However, epidemiological studies face limitations due to imprecise exposure measurements and the potential for bias through residual confounding and reverse causation. To address these limitations, we conducted a systematic review of Mendelian Randomization (MR) studies examining the causal relationship between alcohol consumption and cancers, cardiovascular, liver, and neurological diseases.

METHODOLOGY: We searched PubMed, ScienceDirect and Embase and Europe PMC up to 05/2024 for MR studies investigating the association of genetically predicted alcohol consumption with cancers, cardiovascular, liver and neurological diseases. We assessed methodological quality based on key elements of the MR design a genetic association studies tool.

RESULTS: We included 70 MR studies that matched our inclusion criteria. Our review showed a significant association of alcohol consumption with multiple cancers such as oral and oropharyngeal, esophageal, colorectal cancers, hepatocellular carcinoma and cutaneous melanoma. While the available studies did not consistently confirm the adverse or protective effects of alcohol on other cancers, such as lung cancer, as suggested by observational studies. Additionally, MR studies confirmed a likely causal effect of alcohol on the risk of hypertension, atrial fibrillation, myocardial infraction and vessels disease. However, there was no evidence to support the protective effects of light to moderate alcohol consumption on cognitive function, Alzheimer's disease, and amyotrophic lateral sclerosis, as reported in observational studies while our review revealed an increased risk of epilepsy and multiple sclerosis. The available studies provided limited results on the link between alcohol consumption and liver disease.

CONCLUSIONS: Despite the valuable insights into the causal relationship between alcohol consumption and various health outcomes that MR studies provided, it is worth noting that the inconsistent ability of genetic instrumental variables to distinguish between abstainers, light and moderate drinkers makes it difficult to differentiate between U or J-shaped vs. linear relationships between exposure and outcome. Additional research is necessary to establish formal quality assessment tools for MR studies and to conduct more studies in diverse populations, including non-European ancestries.

www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021246154, Identifier: PROSPERO (CRD42021246154).}, } @article {pmid39574607, year = {2024}, author = {Fürtjes, AE and Foote, IF and Xia, C and Davies, G and Moodie, J and Taylor, A and Liewald, DC and Redmond, P and Corley, J and McIntosh, AM and Whalley, HC and Maniega, SM and Hernández, MV and Backhouse, E and Ferguson, K and Bastin, ME and Wardlaw, J and de la Fuente, J and Grotzinger, AD and Luciano, M and Hill, WD and Deary, IJ and Tucker-Drob, EM and Cox, SR}, title = {Lifetime brain atrophy estimated from a single MRI: measurement characteristics and genome-wide correlates.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39574607}, issn = {2692-8205}, support = {R01 AG073593/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 MH120219/MH/NIMH NIH HHS/United States ; MR/M013111/1/MRC_/Medical Research Council/United Kingdom ; P2C HD042849/HD/NICHD NIH HHS/United States ; P30 AG066614/AG/NIA NIH HHS/United States ; U54 MH091657/MH/NIMH NIH HHS/United States ; }, abstract = {A measure of lifetime brain atrophy (LBA) obtained from a single magnetic resonance imaging (MRI) scan could be an attractive candidate to boost statistical power in uncovering novel genetic signals and mechanisms of neurodegeneration. We analysed data from five young and old adult cohorts (MRi-Share, Human Connectome Project, UK Biobank, Generation Scotland Subsample, and Lothian Birth Cohort 1936 [LBC1936]) to test the validity and utility of LBA inferred from cross-sectional MRI data, i.e., a single MRI scan per participant. LBA was simply calculated based on the relationship between total brain volume (TBV) and intracranial volume (ICV), using three computationally distinct approaches: the difference (ICV-TBV), ratio (TBV/ICV), and regression-residual method (TBV~ICV). LBA derived with all three methods were substantially correlated with well-validated neuroradiological atrophy rating scales (r = 0.37-0.44). Compared with the difference or ratio method, LBA computed with the residual method most strongly captured phenotypic variance associated with cognitive decline (r = 0.36), frailty (r = 0.24), age-moderated brain shrinkage (r = 0.45), and longitudinally-measured atrophic changes (r = 0.36). LBA computed using a difference score was strongly correlated with baseline (i.e., ICV; r = 0.81) and yielded GWAS signal similar to ICV (rg = 0.75). We performed the largest genetic study of LBA to date (N = 43,110), which was highly heritable (h [2] SNP GCTA = 41% [95% CI = 38-43%]) and had strong polygenic signal (LDSC h [2] = 26%; mean χ2 = 1.23). The strongest association in our genome-wide association study (GWAS) implicated WNT16, a gene previously linked with neurodegenerative diseases such as Alzheimer, and Parkinson disease, and amyotrophic lateral sclerosis. This study is the first side-by-side evaluation of different computational approaches to estimate lifetime brain changes and their measurement characteristics. Careful assessment of methods for LBA computation had important implications for the interpretation of existing phenotypic and genetic results, and showed that relying on the residual method to estimate LBA from a single MRI scan captured brain shrinkage rather than current brain size. This makes this computationally-simple definition of LBA a strong candidate for more powerful analyses, promising accelerated genetic discoveries by maximising the use of available cross-sectional data.}, } @article {pmid39574440, year = {2024}, author = {Kaur, N and Verma, AK and Girdhar, M and Kumar, A and Siddiqui, MA and Al-Khedhairy, AA and Malik, T and Mohan, A}, title = {Genome-wide analysis of the Cannabis sativa cytochrome P450 monooxygenase superfamily and uncovering candidate genes for improved herbicide tolerance.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1490036}, pmid = {39574440}, issn = {1664-462X}, abstract = {Cannabis sativa is an economically important crop, yet weed management remains a significant challenge due to limited herbicide options. Cytochrome P450 enzymes play crucial roles in plant metabolism, including herbicide detoxification. This study aimed to identify and characterize the CYP gene family in Cannabis and investigate their potential role in herbicide metabolism. We identified 225 CYP proteins encoded by 221 genes in the Cannabis genome, classified into 9 clans and 47 families. The majority of CsCYPs were predicted to be located in endomembrane system and chromosomal mapping revealed that they were present in all the chromosomes. Motif and gene structure analysis supported the results from phylogenetic analysis. The gene duplication analysis results showed that tandem duplication plays a pivotal role in evolutionary expansion of CsCYP superfamily. Promoter analysis revealed various cis-acting elements involved in stress, light, hormone and development responses. Molecular docking simulations identified several CsCYPs with strong binding affinities to ALS-inhibiting herbicides, particularly bispyribac-sodium, propoxycarbazone-sodium, and pyriftalid. CsCYP_215, CsCYP_213, CsCYP_217 and CsCYP_14 emerged as promising candidates for herbicide metabolism. Analysis of binding site residues revealed the importance of hydrophobic and aromatic interactions in herbicide binding. This study provides the first comprehensive characterization of the CYP gene family in C. sativa and offers new insights into their potential roles in herbicide metabolism. The identification of promising herbicide-metabolizing CYP candidates opens new avenues for developing herbicide-tolerant Cannabis varieties, potentially addressing key challenges in weed management and crop productivity.}, } @article {pmid39572918, year = {2024}, author = {Changkakoti, L and Rajabalaya, R and David, SR and Balaraman, AK and Sivasubramanian, H and Mukherjee, AK and Bala, A}, title = {Exploration of the Role of Vitamins in Preventing Neurodegenerative Diseases: Comprehensive Review on Preclinical and Clinical Findings.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X327677240902105443}, pmid = {39572918}, issn = {1875-6190}, abstract = {Neurodegenerative diseases (NDDs) are a multifaceted and heterogeneous group of complex diseases. Unfortunately, a cure for these conditions has yet to be found, but there are ways to reduce the risk of developing them. Studies have shown that specific vitamins regulate the brain molecules and signaling pathways, which may help prevent degeneration. This review focuses on examining the role of vitamins in preventing five significant types of neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS). This review also highlights promising and controversial findings about the potential impact of vitamins on this group of diseases. Several developed countries standardize daily dietary vitamin intake to meet nutrient requirements, improve health, and prevent chronic diseases like NDDs. However, more research is necessary to gain a more comprehensive understanding of their therapeutic benefits, including studies exploring different drug-dose paradigms, diverse humanized animal models, and clinical trials conducted in various locations.}, } @article {pmid39572390, year = {2024}, author = {Morales, JMN and Alcaraz, MR and Loto, A and Parellada, EA and Tulli, F and Morán Vieyra, FE and Borsarelli, CD}, title = {Chemometric modeling of spectroscopic data for characterizing the visible-light-driven photocatalytic N-dealkylation of rhodamine B on a TiO2 film.}, journal = {Photochemistry and photobiology}, volume = {}, number = {}, pages = {}, doi = {10.1111/php.14043}, pmid = {39572390}, issn = {1751-1097}, support = {PIP-2020-101043CO//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; PUE-2018-035//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; PICT-2019-02052//Fondo para la Investigación Científica y Tecnológica/ ; 23A/254//Universidad Nacional de Santiago del Estero/ ; }, abstract = {The green-light driven photocatalytic N-deethylation reaction of Rhodamine B (RhB) on a TiO2 film was investigated by UV-vis absorption and fluorescence emission spectroscopies, in addition to HPLC and HR-MS, to ascertain the nature of the reaction products. The evolution of the photocatalytic reaction was chemometrically analyzed using Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) of the spectroscopic data to obtain the kinetic and spectral decomposition of the RhB derivatives involved in the reaction. This was then compared with the results obtained by standard HPLC analysis. The MCR-ALS analysis yielded satisfactory spectral and kinetic profiles for RhB and the fully deethylated product, Rhodamine 110. However, the spectral profiles for the N-triethyl (3EtRh) and the mixture of the two isomeric N-diethyl (2EtRh) derivatives exhibited some spectral distortions due to significant spectral overlap between these compounds. In contrast to the HPLC analysis, the MCR-ALS could not resolve the N-ethylrhodamine (EtRh) derivative. The deethylation reactions occurred via independent zero-order steps at the surface of TiO2, indicating that the RhB degradation reaction is governed by the adsorption-desorption equilibrium of the dye and derivatives on the photocatalyst surface, thereby enhancing the diffusion of compounds on the surface.}, } @article {pmid39572211, year = {2025}, author = {Benatar, M and Heiman-Patterson, TD and Cooper-Knock, J and Brickman, D and Casaletto, KB and Goutman, SA and Vinceti, M and Dratch, L and Arias, JJ and Swidler, J and Turner, MR and Shefner, J and Westeneng, HJ and van den Berg, LH and Al-Chalabi, A and , }, title = {Guidance for clinical management of pathogenic variant carriers at elevated genetic risk for ALS/FTD.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-334339}, pmid = {39572211}, issn = {1468-330X}, abstract = {There is a growing understanding of the presymptomatic stages of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and nascent efforts aiming to prevent these devastating neurodegenerative diseases have emerged. This progress is attributable, in no small part, to the altruism of people living with pathogenic variants at elevated genetic risk for ALS/FTD via their willingness to participate in natural history studies and disease prevention trials. Increasingly, this community has also highlighted the urgent need to develop paradigms for providing appropriate clinical care for those at elevated risk for ALS and FTD. This manuscript summarises recommendations emanating from a multi-stakeholder Workshop (Malvern, Pennsylvania, 2023) that aimed to develop guidance for at-risk carriers and their treating physicians. Clinical care recommendations span genetic testing (including counselling and sociolegal implications); monitoring for the emergence of early motor, cognitive and behavioural signs of disease; and the use of Food and Drug Administration-approved small molecule drugs and gene-targeting therapies. Lifestyle recommendations focus on exercise, smoking, statin use, supplement use, caffeine intake and head trauma, as well as occupational and environmental exposures. While the evidence base to inform clinical and lifestyle recommendations is limited, this guidance document aims to appraise carriers and clinicians of the issues and best available evidence, and also to define the research agenda that could yield more evidence-informed guidelines.}, } @article {pmid39572209, year = {2024}, author = {Grassano, M}, title = {Navigating the presymptomatic frontier in genetic ALS and FTD.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-334924}, pmid = {39572209}, issn = {1468-330X}, } @article {pmid39571437, year = {2025}, author = {Parastar, H and Yazdanpanah, H and Weller, P}, title = {Non-targeted volatilomics for the authentication of saffron by gas chromatography-ion mobility spectrometry and multivariate curve resolution.}, journal = {Food chemistry}, volume = {465}, number = {Pt 2}, pages = {142074}, doi = {10.1016/j.foodchem.2024.142074}, pmid = {39571437}, issn = {1873-7072}, mesh = {*Crocus/chemistry ; *Ion Mobility Spectrometry/methods ; Food Contamination/analysis ; Gas Chromatography-Mass Spectrometry ; Volatile Organic Compounds/chemistry/analysis ; Discriminant Analysis ; Multivariate Analysis ; Principal Component Analysis ; Least-Squares Analysis ; Iran ; }, abstract = {In the present contribution, a novel non-targeted volatilomic study based on headspace GC-IMS (HS-GC-IMS) was developed for the authentication and geographical origin discrimination of saffron. In this regard, multivariate curve resolution-alternating least squares (MCR-ALS) was employed to recover the pure GC elution and IMS profiles of saffron metabolites. Iranian saffron samples from seven important areas were analyzed by HS-GC-IMS. The resulting second-order GC-IMS datasets were organized in a augmented matrix and processed using MCR-ALS with various constraints. The MCR-ALS resolved GC profiles were analyzed by different pattern recognition techniques; principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA) and data driven-soft independent modeling of class analogy (DD-SIMCA). The saffron samples were assigned to their seven geographical origins with an accuracy of 89.0 %. Additionally, four adulterants (style, safflower, madder and calendula) were reliably detected with over 94.0 % accuracy. In this context, GC-IMS substantially outperformed the commonly used FT-NIR spectroscopy approach.}, } @article {pmid39571211, year = {2025}, author = {Wang, Z and Wu, P and Zhao, Y and Li, X and Kong, D}, title = {Application of excitation-emission matrix fluorescence spectroscopy and chemometrics for quantitative analysis of emulsified oil concentration.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {328}, number = {}, pages = {125423}, doi = {10.1016/j.saa.2024.125423}, pmid = {39571211}, issn = {1873-3557}, abstract = {Emulsified oil concentration is an important index for quantitative analysis of sea surface oil spill pollution, and the development of a fast and effective quantitative analysis method for emulsified oil concentration plays a crucial role in the estimation of oil spill volume and post-spill assessment. A quantitative analysis method for emulsified oil concentration based on excitation-emission matrix (EEM) fluorescence spectroscopy and chemometrics was proposed. Firstly, the EEM fluorescence spectra of two emulsified oils were measured using a FLS1000 fluorescence spectrometer. Then, the measured EEM fluorescence spectra were decomposed by parallel factor analysis (PARAFAC), and several key excitation wavelengths were filtered from the loading matrix obtained from the decomposition. Subsequently, the three-band fluorescence index (TBFI) at these excitation wavelengths was calculated and combined with the optimal band selection algorithm, from which the optimal emission band combinations were selected. Finally, the selected optimal emission bands were combined with partial least squares regression (PLSR) to establish a prediction model for emulsified oil concentration. By comparing the prediction results with those based on PARAFAC-PLSR and multivariate curve resolved-alternating least squares (MCR-ALS)-PLSR models, the TBFI-PLSR model showed the best results in the quantitative analysis of emulsified oil concentration. The coefficient of determination, mean square relative error, and ratio of performance to interquartile distance for the gasoline and diesel fuel emulsion validation sets were 0.93, 3.67%, 4.72, and 0.93, 3.72%, 4.60, respectively.}, } @article {pmid39570667, year = {2024}, author = {Burks, CA and Brenner, MJ}, title = {Commentary on Von Sneidern et al's "Evaluation and Treatment of Acute Facial Palsy: Opportunities for Optimization at a Single Institution."-Bridging the Gap Between Guidelines and Practice.}, journal = {Facial plastic surgery & aesthetic medicine}, volume = {}, number = {}, pages = {}, doi = {10.1089/fpsam.2024.0263}, pmid = {39570667}, issn = {2689-3622}, } @article {pmid39570437, year = {2025}, author = {Maity, D and Kaundal, RK}, title = {Exploring dysregulated miRNAs in ALS: implications for disease pathogenesis and early diagnosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {4}, pages = {1661-1686}, pmid = {39570437}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Humans ; *MicroRNAs/genetics/metabolism ; *Early Diagnosis ; Biomarkers/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor neuron degeneration, leading to muscle weakness and paralysis, with no effective treatments available. Early diagnosis could slow disease progression and optimize treatment. MicroRNAs (miRNAs) are being investigated as potential biomarkers due to their regulatory roles in cellular processes and stability in biofluids. However, variability across studies complicates their diagnostic utility in ALS. This study aims to identify significantly dysregulated miRNAs in ALS through meta-analysis to elucidate disease mechanisms and improve diagnostic strategies.

METHODS: We systematically searched PubMed, Google Scholar, and the Cochrane Library, following predefined inclusion and exclusion criteria. The primary effect measure was the standardized mean difference (SMD) with a 95% confidence interval, analyzed using a random-effects model. Additionally, we used network pharmacology to examine the targets of dysregulated miRNAs and their roles in ALS pathology.

RESULTS: Analysing 34 studies, we found significant upregulation of hsa-miR-206, hsa-miR-133b, hsa-miR-23a, and hsa-miR-338-3p, and significant downregulation of hsa-miR-218, hsa-miR-21-5p, and hsa-let-7b-5p in ALS patients. These miRNAs are involved in ALS pathophysiology, including stress granule formation, nuclear pore complex, SMCR8 and Sig1R dysfunction, histone methyltransferase complex alterations, and MAPK signaling perturbation, highlighting their critical role in ALS progression.

CONCLUSION: This study identifies several dysregulated miRNAs in ALS patients, offering insights into their role in the disease and potential as diagnostic biomarkers. These findings enhance our understanding of ALS mechanisms and may inform future diagnostic strategies. Validating these results and exploring miRNA-based interventions are crucial for improving ALS diagnosis and treatment outcomes.}, } @article {pmid39569894, year = {2024}, author = {Brannigan, JFM and Liyanage, K and Horsfall, HL and Bashford, L and Muirhead, W and Fry, A}, title = {Brain-computer interfaces patient preferences: a systematic review.}, journal = {Journal of neural engineering}, volume = {21}, number = {6}, pages = {}, doi = {10.1088/1741-2552/ad94a6}, pmid = {39569894}, issn = {1741-2552}, mesh = {*Brain-Computer Interfaces ; Humans ; *Patient Preference ; Adult ; Middle Aged ; Spinal Cord Injuries/rehabilitation/psychology/physiopathology ; Amyotrophic Lateral Sclerosis/psychology/rehabilitation/physiopathology ; }, abstract = {Objective. Brain-computer interfaces (BCIs) have the potential to restore motor capabilities and functional independence in individuals with motor impairments. Despite accelerating advances in the performance of implanted devices, few studies have identified patient preferences underlying device design, and each study typically captures a single aetiology of motor impairment. We aimed to characterise BCI patient preferences in a large cohort across multiple aetiologies.Approach. We performed a systematic review of all published studies reporting patient preferences for BCI devices, including both qualitative and quantitative data. We searched MEDLINE, Embase, and CINAHL from inception to 18 April 2023. Two reviewers independently screened articles and extracted data on demographic information, device use, invasiveness preference, device design, and functional preferences.Main results. From 1316 articles identified, 28 studies met inclusion criteria, capturing preferences from 1701 patients (mean age 42.1-64.3 years). The most represented conditions were amyotrophic lateral sclerosis (n= 15 studies, 53.6%) and spinal cord injury (n= 13 studies 46.4%). Individuals with motor impairments prioritised device accuracy over other design characteristics. In four studies where patients ranked performance characteristics, accuracy was ranked first each time. We found that the speed and accuracy of BCI systems in recent publications exceeds reported patient preferences, however this performance has been achieved with a level of training and setup burden that would not be tolerated by most patients. Preferences varied by disease aetiology and severity; amyotrophic lateral sclerosis patients typically prioritised communication functions, whereas spinal cord injury patients emphasised limb control and sphincteric functions.Significance.Our findings highlight that despite advances in BCI performance exceeding patient expectations, there remains a need to reduce training and setup burdens to enhance usability. Moreover, patient preferences differ across conditions and impairment severities, underscoring the importance of personalised BCI configurations and tailored training regimens to meet individual needs.}, } @article {pmid39569650, year = {2025}, author = {Luo, S and Wang, X and Ma, B and Liu, D and Li, L and Wang, L and Ding, N and Zou, L and Wang, J and Pan, J and Sang, D and Zhou, H and Qu, H and Lu, Y and Yang, L}, title = {Therapeutic potential of simvastatin in ALS: Enhanced axonal integrity and motor neuron survival through Apoa4 and Alb modulation.}, journal = {Biomolecules & biomedicine}, volume = {25}, number = {3}, pages = {632-647}, doi = {10.17305/bb.2024.11218}, pmid = {39569650}, issn = {2831-090X}, mesh = {*Simvastatin/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism/genetics ; Animals ; *Motor Neurons/drug effects/pathology/metabolism ; *Mice, Transgenic ; Mice ; *Axons/drug effects/pathology ; *Mice, Inbred C57BL ; Disease Models, Animal ; Superoxide Dismutase/metabolism/genetics ; Cell Survival/drug effects ; Spinal Cord/drug effects/pathology/metabolism ; Male ; Apolipoproteins A ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type mice, C57BL/6J SOD1G93A mice treated with PBS (SOD1G93A + PBS), and C57BL/6J SOD1G93A mice treated with simvastatin (SOD1G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using hematoxylin and eosin staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1G93A + simvastatin and SOD1G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1G93A + PBS and SOD1G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1G93A + simvastatin group compared to the SOD1G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression.}, } @article {pmid39569145, year = {2024}, author = {Mirceta, M and Schmidt, MHM and Shum, N and Prasolava, TK and Meikle, B and Lanni, S and Mohiuddin, M and Mckeever, PM and Zhang, M and Liang, M and van der Werf, I and Scheers, S and Dion, PA and Wang, P and Wilson, MD and Abell, T and Philips, EA and Sznajder, ŁJ and Swanson, MS and Mehkary, M and Khan, M and Yokoi, K and Jung, C and de Jong, PJ and Freudenreich, CH and McGoldrick, P and Yuen, RKC and Abrahão, A and Keith, J and Zinman, L and Robertson, J and Rogaeva, E and Rouleau, GA and Kooy, RF and Pearson, CE}, title = {C9orf72 expansion creates the unstable folate-sensitive fragile site FRA9A.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.10.26.620312}, pmid = {39569145}, issn = {2692-8205}, abstract = {The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72 Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. C9orf72 Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immuno-stimulatory or damaged DNA is unknown. Here, we show C9orf72 Exp in pre-symptomatic and ALS-FTD patient cells and brains cause the folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33kb of C9orf72 as highly-compacted chromatin embedded in an 8.2Mb fragility zone spanning 9p21, encompassing 46 genes, making FRA9A one of the largest fragile sites. C9orf72 Exp cells show chromosomal instability, heightened global- and Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s and Chr9-containing micronuclei, providing endogenous sources of damaged and immunostimulatory DNA. Cells from one C9orf72 Exp patient contained highly-rearranged FRA9A-expressing Chr9 with Chr9-wide dysregulated gene expression. Somatic C9orf72 Exp repeat instability and chromosomal fragility are sensitive to folate-deficiency. Age-dependent repeat instability, chromosomal fragility, and chromosomal instability can be transferred to CNS and peripheral tissues of transgenic C9orf72 Exp mice, implicating C9orf72 Exp as the source. Our results highlight unappreciated effects of C9orf72 expansions that trigger vitamin-sensitive chromosome fragility, adding structural variations to the disease-enriched 9p21 locus, and likely elsewhere.}, } @article {pmid39568840, year = {2024}, author = {Souayah, N and Chong, ZZ and Patel, T and Nasar, A and Pahwa, A and W Sander, H}, title = {Regression equation analysis enhances detection of conduction slowing beyond axonal loss in diabetic neuropathy.}, journal = {Heliyon}, volume = {10}, number = {21}, pages = {e39712}, pmid = {39568840}, issn = {2405-8440}, abstract = {OBJECTIVES: To evaluate the utility of regression analysis in the assessment of conduction slowing in diabetic distal symmetrical polyneuropathy (DSP) and in identifying superimposed demyelination beyond fiber loss.

BACKGROUND: Causes of conduction slowing beyond pure axonal loss has been attributed to an additional demyelinating component. We therefore evaluated the utility of regression analysis in the assessment of conduction slowing in diabetic DSP and in identifying superimposed demyelination beyond fiber loss.

METHODS: We previously established regression analysis to develop confidence intervals that assess the range of conduction slowing from primary demyelination in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). In this study, by using the regression equations, we analyzed conduction slowing in patients with diabetic DSP.

RESULTS: Mean conduction velocity (CV) was significantly slower in diabetic DSP than in the non-diabetic DSP for all tested nerves. More patients were found to fulfill the regression equation criteria in the diabetic group compared to the non-diabetic group (47.0 % vs. 23.3 %). The estimated likelihood of having more than two motor nerves with CV slowing in the demyelination range by American Academy of Neurology or regression equations criteria was significantly higher in the diabetic DSP (0.73) compared to non-diabetic DSP (0.52).

CONCLUSIONS: Conduction slowing in diabetic DSP beyond what is expected exclusively from axonal loss could be identified by regression analysis.}, } @article {pmid39568376, year = {2024}, author = {Held-Bradford, EC and Sells, M and Longhurst, JK and Doherty, M}, title = {Variation in amyotrophic lateral sclerosis presentation and outcomes based on phenotype and physical therapy movement system diagnosis: a case series.}, journal = {Physiotherapy theory and practice}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/09593985.2024.2430745}, pmid = {39568376}, issn = {1532-5040}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neuron disease and presentation varies. There is limited description of this variability and how physical therapy (PT) specific movement system diagnoses (MSD) may impact care.

PURPOSE: The purpose of this case series is to describe the variability of ALS presentation longitudinally across early, middle, and late stages of ALS based on phenotype and MSD.

METHODS: Four individuals were selected from an ALS clinic chart review representing a unique combination of phenotypes and MSDs (Case 1: bulbar onset force production deficit (FPD), Case 2: bulbar onset fractionated movement deficit (FMD), Case 3: limb onset FPD, Case 4: limb onset FMD). Descriptions of care over 9 years included outcomes of disability (ALS Functional Rating scale-revised), activity (10 Meter Walk Test, Five Times Sit to Stand Test, Trunk Impairment Scale-version 2), and impairment (strength and spasticity).

RESULTS: Persons with ALS were seen every 3 to 6 months (10 to 19 visits total). Determination of MSD was hardest to complete in early stage bulbar onset ALS. Patterns of decline through stages varied by MSD and phenotype, most notably in length of time in middle stage. Limb onset FMD had the slowest progression. Falls and fall related injuries were most frequent in limb onset ALS but falls occurred in all cases.

CONCLUSION: The combination of MSD and phenotype enhanced variability description offers new insights into clinical decision-making in ALS care.}, } @article {pmid39568060, year = {2024}, author = {Abbas, AEF and Abdelshafi, NA and Gamal, M and Halim, MK and Said, BAM and Naguib, IA and Mansour, MMA and Morshedy, S and Salem, YA}, title = {Simultaneously quantifying a novel five-component anti- migraine formulation containing ergotamine, propyphenazone, caffeine, camylofin, and mecloxamine using UV spectrophotometry and chemometric models.}, journal = {BMC chemistry}, volume = {18}, number = {1}, pages = {233}, pmid = {39568060}, issn = {2661-801X}, support = {TU-DSPP-2024-49//Taif University/ ; }, abstract = {This study presents a new method for simultaneously quantifying a complex anti-migraine formulation containing five components (ergotamine, propyphenazone, caffeine, camylofin, and mecloxamine) using UV spectrophotometry and chemometric models. The formulation presents analytical challenges due to the wide variation in component concentrations (ERG: PRO: CAF: CAM: MEC ratio of 0.075:20:8:5:4) and highly overlapping UV spectra. To create a comprehensive validation dataset, the Kennard-Stone Clustering Algorithm was used to address the limitations of arbitrary data partitioning in chemometric methods. Three different chemometric models were evaluated: Classical Least Squares (CLS), Partial Least Squares (PLS), and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS). Among these, MCR-ALS demonstrated excellent performance, achieving recovery values of 98-102% for all components, accompanied by minimal root mean square errors of calibration (0.072-0.378) and prediction (0.077-0.404). Moreover, the model exhibited high accuracy, with relative errors ranging from 1.936 to 3.121%, bias-corrected mean square errors between 0.074 and 0.389, and a good sensitivity (0.2097-1.2898 μg mL[-1]) for all components. The Elliptical Joint Confidence Region analysis further confirmed the predictive performance of the models, with MCR-ALS consistently showing the smallest ellipses closest to the ideal point (slope = 1, intercept = 0) for most analytes, indicating superior accuracy and precision. The approach's sustainability was rigorously assessed using six advanced metrics, validating its environmental friendliness, economic viability, and practical application. This approach effectively resolves complex pharmaceutical formulations, contributing to sustainable development objectives in quality control processes.}, } @article {pmid39567497, year = {2024}, author = {Zhu, Z and Song, M and Ren, J and Liang, L and Mao, G and Chen, M}, title = {Copper homeostasis and cuproptosis in central nervous system diseases.}, journal = {Cell death & disease}, volume = {15}, number = {11}, pages = {850}, pmid = {39567497}, issn = {2041-4889}, mesh = {Humans ; *Copper/metabolism ; *Homeostasis ; *Central Nervous System Diseases/metabolism/pathology ; Animals ; }, abstract = {Copper (Cu), an indispensable micronutrient for the sustenance of living organisms, contributes significantly to a vast array of fundamental metabolic processes. The human body maintains a relatively low concentration of copper, which is mostly found in the bones, liver, and brain. Despite its low concentration, Cu plays a crucial role as an indispensable element in the progression and pathogenesis of central nervous system (CNS) diseases. Extensive studies have been conducted in recent years on copper homeostasis and copper-induced cell death in CNS disorders, including glioma, Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease, and stroke. Cuproptosis, a novel copper-induced cell death pathway distinct from apoptosis, necrosis, pyroptosis, and ferroptosis, has been identified as potentially intricately linked to the pathogenic mechanisms underlying various CNS diseases. Therefore, a systematic review of copper homeostasis and cuproptosis and their relationship with CNS disorders could deepen our understanding of the pathogenesis of these diseases. In addition, it may provide new insights and strategies for the treatment of CNS disorders.}, } @article {pmid39567371, year = {2024}, author = {Nuzum, ND and Deady, C and Kittel-Schneider, S and Cryan, JF and O'Mahony, SM and Clarke, G}, title = {More than just a number: the gut microbiota and brain function across the extremes of life.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2418988}, pmid = {39567371}, issn = {1949-0984}, mesh = {*Gastrointestinal Microbiome/physiology ; Humans ; *Brain/microbiology ; Animals ; Brain-Gut Axis/physiology ; Alzheimer Disease/microbiology/physiopathology ; Neurodegenerative Diseases/microbiology ; }, abstract = {Understanding the interrelationship between the gut microbiota and host physiology, although still in its relative infancy, has taken important steps forward over the past decade. In the context of brain disorders including those characterized by neurodevelopmental and neurodegenerative changes there have been important advances. However, initially research involved correlational analyses, had limited translational scope, and lacked functional assessments. Thus, largescale longitudinal clinical investigations that assess causation and underlying mechanisms via in depth analysis methods are needed. In neurodegeneration research, strong causal evidence now links the gut microbiome to Alzheimer's (AD), and Parkinson's Disease (PD), as supported by human-to-animal transplantation studies. Longitudinal interventions are being conducted in AD, PD, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Neurodevelopmental research has also seen a boon in microbiome-related clinical research including in autism, Attention-deficit/hyperactivity disorder, and schizophrenia, which is confirming prior animal model work regarding the key time-windows in the gut microbiome important for infant cognition. While recent research advances represent important progress, fundamental knowledge gaps and obstacles remain. Knowing how and why the gut microbiome changes at the extremes of life will develop our mechanistic understanding and help build the evidence base as we strive toward counteracting microbial missteps with precision therapeutic interventions.}, } @article {pmid39565466, year = {2025}, author = {Crowley, PD and Mira, P and Saleh, OMA}, title = {Minocycline susceptibility in Stenotrophomonas maltophilia: a closer look at institutional data amid CLSI breakpoint revisions.}, journal = {European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology}, volume = {44}, number = {2}, pages = {459-460}, doi = {10.1007/s10096-024-04995-5}, pmid = {39565466}, issn = {1435-4373}, mesh = {*Stenotrophomonas maltophilia/drug effects/genetics ; *Microbial Sensitivity Tests ; *Anti-Bacterial Agents/pharmacology ; Humans ; *Minocycline/pharmacology ; *Gram-Negative Bacterial Infections/microbiology/drug therapy ; }, abstract = {In this letter we respond Bakthavatchalam et al's brief report on susceptibility of Stenotrophomonas maltophilia to Minocycline in the setting of new susceptibility breakpoints. We outline our institution's experience with this organism and new data of susceptibility with the breakpoint of < 1 mg/L from the past 5 months showing 93.8% of 144 isolates remained susceptible.}, } @article {pmid39564190, year = {2024}, author = {Cavaliere, F and Hermann, DM and Magliaro, C}, title = {Editorial: Human brain organoids to model neurodegenerative diseases at the BOSS23 Brain Organoid Summer School.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1501036}, doi = {10.3389/fncel.2024.1501036}, pmid = {39564190}, issn = {1662-5102}, } @article {pmid39564171, year = {2024}, author = {Byeon, H}, title = {Holistic approaches to mitigating psychological distress in gynecological cancer patients.}, journal = {World journal of psychiatry}, volume = {14}, number = {11}, pages = {1766-1771}, pmid = {39564171}, issn = {2220-3206}, abstract = {This article delves into the psychological impact of gynecological malignancies and suggests pathways to improve the quality of life (QoL) for affected patients. Building on Shang et al's comprehensive analysis, this piece integrates insights from various studies to highlight the profound influence of psychological and physical symptoms on patients undergoing treatment for gynecological cancers. The study underscores that anxiety and depression significantly exacerbate the disease's toll. Factors such as physical exercise and digital and interactive health interventions show promise in mitigating these adverse effects. The article emphasizes the necessity for a holistic care approach that addresses both physical and emotional needs. Recommendations include enhanced training for healthcare providers, public awareness campaigns, streamlined diagnostic pathways, and improved access to specialist care. These integrated strategies aim to ensure that women facing gynecological cancers can maintain an optimal QoL through comprehensive and multidisciplinary care models.}, } @article {pmid39563746, year = {2024}, author = {Moyana, TN}, title = {Metabolic dysfunction-associated steatotic liver disease: The question of long-term high-normal alanine aminotransferase as a screening test.}, journal = {World journal of gastroenterology}, volume = {30}, number = {42}, pages = {4576-4582}, pmid = {39563746}, issn = {2219-2840}, mesh = {Humans ; *Alanine Transaminase/blood ; *Biomarkers/blood ; Mass Screening/methods/standards ; Fatty Liver/diagnosis/blood/epidemiology ; Obesity/complications/diagnosis/epidemiology ; Early Diagnosis ; Reference Values ; Male ; Liver/pathology ; Non-alcoholic Fatty Liver Disease/diagnosis/blood/epidemiology ; }, abstract = {The growing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is being driven by the obesity epidemic. The quest for solutions continues particularly with regard to early detection. This editorial comments on the utility of long-term high-normal alanine aminotransferase (ALT) in screening for MASLD. Chen et al found that new onset MASLD can be detected by repetitively high normal ALT. Implicit in this concept is the question of what should be the accepted upper limit of normal (ULN) for ALT. It was previously set at 40 IU/L based on studies that included people with subclinical liver disease but the new consensus is 30/19 U/L in healthy males/females. Thus, when Chen et al defines the ULN as 40 U/L, others may view it as excessively high. It is important to recognize the variables affecting ULN e.g. instrumentation, diurnal variations, exercise and ageing. These variables matter when the distinctions are subtle e.g. normal vs high-normal. In this regard, the utility of long-term high normal ALT as a disease marker could be enhanced by combining it with other biomarkers, imaging and MASLD genetics to create machine learning classifiers. All in all, Chen et al's work on long-term high normal ALT as a marker of new-onset MASLD deserves merit.}, } @article {pmid39563026, year = {2025}, author = {Hawley, ZCE and Pardo, ID and Cao, S and Zavodszky, MI and Casey, F and Ferber, K and Luo, Y and Hana, S and Chen, SK and Doherty, J and Costa, R and Cullen, P and Liu, Y and Carlile, TM and Chowdhury, T and Doyle, B and Clarner, P and Mangaudis, K and Guilmette, E and Bourque, S and Koske, D and Nadella, MVP and Trapa, P and Hawes, ML and Raitcheva, D and Lo, SC}, title = {Dorsal root ganglion toxicity after AAV intra-CSF delivery of a RNAi expression construct into non-human primates and mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {1}, pages = {215-234}, pmid = {39563026}, issn = {1525-0024}, mesh = {Animals ; *Dependovirus/genetics ; Mice ; *MicroRNAs/genetics ; *Ganglia, Spinal/metabolism ; *Genetic Vectors/administration & dosage/genetics ; *RNA Interference ; Superoxide Dismutase-1/genetics ; Humans ; Neurons/metabolism ; Male ; }, abstract = {Dorsal root ganglion (DRG) toxicity has been consistently reported as a potential safety concern after delivery of adeno-associated viruses (AAVs) containing gene-replacement vectors but has yet to be reported for RNAi-based vectors. Here, we report DRG toxicity after AAV intra-CSF delivery of an RNAi expression construct-artificial microRNA targeting superoxide dismutase 1 (SOD1)-in non-human primates (NHPs) and provide evidence that this can be recapitulated within mice. Histopathology evaluation showed that NHPs and mice develop DRG toxicity after AAV delivery, including DRG neuron degeneration and necrosis and nerve-fiber degeneration that were associated with increases in cerebrospinal fluid (CSF) and serum phosphorylated neurofilament heavy chain (pNF-H). RNA-sequencing analysis of DRGs showed that dysregulated pathways were preserved between NHPs and mice, including increases in innate/adaptive immune responses and decreases in mitochondrial- and neuronal-related genes, following AAV treatment. Finally, endogenous miR-21-5p was upregulated in DRGs of AAV-treated NHPs and mice. Increases in miR-21-5p were also identified within the CSF of NHPs, which significantly correlated with pNF-H, implicating miR-21-5p as a potential biomarker of DRG toxicity in conjunction with other molecular analytes. This work highlights the importance of assessing safety concerns related to DRG toxicity when developing RNAi-based AAV vectors for therapeutic purposes.}, } @article {pmid39562997, year = {2024}, author = {Zheng, W and Xia, T and Zhang, X and Han, J and Li, Y and Tian, N and Zheng, G and Wang, J and Peng, Y and Yao, D and Long, F}, title = {Tailoring Multifunctional Amine Salts Based on Anisole Liquid Soaking for Fabricating Efficient and Stable Perovskite Solar Cells.}, journal = {ACS applied materials & interfaces}, volume = {16}, number = {48}, pages = {66643-66654}, doi = {10.1021/acsami.4c12455}, pmid = {39562997}, issn = {1944-8252}, abstract = {The post-treatment based on spin-coating (SC) organic amine salts is commonly used for surface modification of perovskite films to eliminate defects. However, there is still a lack of systematic study and a unified understanding of the functions and mechanisms of different organic amine salts. The SC method is also not conducive to the industrialization of solar cells. In this work, we study three different organic amine salts, and a passivation strategy for perovskite films based on green anisole liquid soaking (ALS) has been developed. Phenylethylammonium iodide (PEAI), diethylamine hydroiodide (DEAI), and guanidine hydroiodide (GAI) organic amine salt passivators are selected to modify perovskite films, and their effect and working mechanism are also systematically estimated. It is found that PEAI passivates shallow-level defects on the surface of perovskite films, while DEAI incorporates into the perovskite lattice to suppress point defects, and GAI eliminates excess PbI2 residuals in perovskite films. These three organic-amine-salt-modified devices achieve enhanced power conversion efficiencies (PCE) of 21.82% (PEAI-ALS), 21.74% (DEAI-ALS), and 22.21% (GAI-ALS), which is much higher than that of the pristine device without treatment (19.95%). The PCE of the PEAI-ALS device retains nearly 94% of the initial efficiency after 1200 h in unpackaged conditions and about 40% ambient humidity, achieving the best stability performance. Particularly, the PEAI-ALS device has the best comprehensive performance in efficiency and stability. And PEAI is estimated by the SC method and ALS method, and it is found that the PEAI-ALS device achieves a higher PCE compared to the PEAI-SC device (21.51%). We believe that the post-treatment based on a combination of appropriate amine salts and ALS enables a universal approach for fabrication of perovskite solar cells with enhanced photovoltaic performance.}, } @article {pmid39562594, year = {2024}, author = {Tahmasebi, BK and Zand, E and Yousefi, A and Babaei, S and Sadeghpour, A}, title = {Surveillance and mapping of tribenuron-methyl-resistant weeds in wheat fields.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28626}, pmid = {39562594}, issn = {2045-2322}, mesh = {*Plant Weeds/drug effects ; *Triticum/drug effects/genetics/growth & development ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Arylsulfonates/pharmacology ; Iran ; Weed Control/methods ; }, abstract = {Tribenuron-methyl (TBM) is among the herbicides that are widely used for controlling broadleaf weeds in wheat fields in Iran due to its low mammalian toxicity and environmental risk, use at low doses, the broad spectrum of weed control, and low price compared to other herbicides. However, wheat farmers' repeated application and dissatisfaction with the optimal and effective control of the TBM herbicide have led to investigating broadleaf weed resistance in Iranian wheat fields. For this purpose, through a national call in 2018, a total of 240 broadleaf weed populations belonging to 13 species and 7 plant families were collected from 153 wheat fields in 72 counties across 14 provinces suspected to be resistant to the TBM herbicide. Then, a screening test was conducted in a completely randomized design with 5 replications of each biotype using the recommended dose of 25 g a.i. ha[- 1] of TBM in the greenhouse. Overall, the results indicated that 124 (51.7%) of the screened populations were resisted to TBM. Specifically, 44 populations (81%) of Sinapis arvensis L., 18 populations (45%) of Malva neglecta Wallr., 25 populations (45%) of Silybum marianum (L.) Gaertn, 2 populations (66.6%) of Ammi majus L., 1 population (50%) of Rapistrum rugosum L., 3 populations (21%) of Descurainia Sophia (L.) Webb ex Prantl, 9 populations (36%) of Vaccaria hispanica Mill., 8 populations (48%) of Galium aparine L., 9 populations (75%) of Melilotus indicus L. According to the Adkins and Maas evaluation, 4 populations (100%) of Raphanus raphanistrum L. were classified as resistant to TBM. This study is the first comprehensive investigation of broadleaf weed resistance to TBM across Iranian wheat fields, providing crucial insights for future herbicide management strategies. Given the high incidence of resistance, continued use of TBM in Iranian wheat fields may lead to increased yield loss and environmental pollution. Additionally, it is necessary to investigate cross-resistance in resistant populations to other ALS-inhibiting herbicides.}, } @article {pmid39561111, year = {2024}, author = {Rohrer, C and Palumbo, A and Paul, M and Reese, E and Basu, S}, title = {Neurotransmitters and neural hormone-based probes for quadruplex DNA sequences associated with neurodegenerative diseases.}, journal = {Nucleosides, nucleotides & nucleic acids}, volume = {}, number = {}, pages = {1-24}, doi = {10.1080/15257770.2024.2431145}, pmid = {39561111}, issn = {1532-2335}, abstract = {The potential of neurotransmitters and neural hormones as possible G-quadruplex DNA binders was analyzed using fluorescence spectroscopy, surface-enhanced Raman spectroscopy (SERS), DNA melting analysis, and molecular docking. G-quadruplex sequences, (GGC)3 and G4C2, with roles in Fragile X syndrome and amyotrophic lateral sclerosis (ALS), respectively, were selected, and their interactions with melatonin, serotonin, and gamma-aminobutyric acid (GABA), were studied. Both melatonin and serotonin demonstrated strong interactions with the DNA sequences with hydrogen bonding being the primary mode of interaction, with some non-intercalative interactions involving the π systems. GABA demonstrated much weaker interactions and may not be a suitable candidate as a probe for low concentrations of G-quadruplex DNA.}, } @article {pmid39560839, year = {2024}, author = {Wu, R and Ramakrishnan, S and Lin, H and Dong, Z and Liu, M and Qiang, L}, title = {Development and validation a novel FEZF2 based fluorescent reporter for corticospinal motor neurons.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {17}, pmid = {39560839}, issn = {1573-7365}, support = {R01 NS115977/NS/NINDS NIH HHS/United States ; 4100083087//the CURE program via Drexel University College of Medicine/ ; 32070725//the National Natural Science Foundation/ ; }, mesh = {Animals ; *Motor Neurons/metabolism ; Mice ; Nerve Tissue Proteins/genetics/metabolism ; Pyramidal Tracts/metabolism ; Green Fluorescent Proteins/genetics/metabolism ; Genes, Reporter ; Cells, Cultured ; DNA-Binding Proteins ; }, abstract = {Corticospinal motor neurons (CSMNs), also named upper motor neurons, are the giant pyramidal neurons called Betz cells. In mammals, the majority of CSMNs reside within layer V of the primary motor cortex, where they extend long axon bundles named the pyramidal tract into the brainstem and the spinal cord to control voluntary movement. CSMN lesions are implicated in a variety of neurodegenerative disorders, such Amyotrophic Lateral Sclerosis, Primary Lateral Sclerosis and Hereditary Spastic paraplegia. Although FEZF2-CTIP2 genetic axis have been indicated as the cardinal molecular pathway underlying the development of CSMNs, these proteins are transcription factors that are mostly used to label the nuclei of CSMNs in the fixed cells and tissues. Therefore, a fluorescent reporter to mark CSMNs will be invaluable in identifying living CSMNs, including their extended processes, for time-lapse imaging and high-throughput molecular analyses with much more improved specificity. Based on the in-silico analysis, we identified a putative region within the promoter sequence of FEZF2 and assembled it with an indispensable enhancer motif at its downstream of the gene to form a complex promoter that drives the expression of reporter GFP. The plasmid and virus of FEZF2:eGFP reporter constructs were further validated for its use in specifically labeling CSMNs in primary neuronal cultures from the embryonic rat motor cortex, postnatal mouse cortex. This innovative molecular labeling tool has the potential to offer indispensable support in diverse experimental setups, enabling a comprehensive understanding of the susceptibility and specificity of CSMNs in a wide array of neurological disorders.}, } @article {pmid39559551, year = {2024}, author = {Wang, J and Chi, L and Liu, S and Yin, J and Zhang, Y and Shen, J and Wang, X}, title = {Overlooked role of long capping time and environmental factors in the plateau lake for impairing lanthanum-modified-bentonite's immobilization to phosphate.}, journal = {Water research X}, volume = {25}, number = {}, pages = {100272}, pmid = {39559551}, issn = {2589-9147}, abstract = {Lanthanum-modified-bentonite(LMB) has been applied for eutrophication management as a phosphate(P)-binding agent in many lakes. However, re-eutrophication took place several years or decades later after the first practice of capping due to dynamic environmental factors in the plateau lake. Here, we investigated the effect of long-term capping and integrated environmental factors in the plateau lake including alkalinity, organic matter, disturbance and photodegradation to the LMB immobilization. Long-term LMB immobilization exhibited C accumulation(82.3%), La depletion(53.5%) and lager size effect in the sediment particle, indicating the breakage of La-O-P bonds and the formation of La-O-C bonds over immobilization time. Additionally, pH(8-10) in the plateau lake could enhance the P desorption and decrease P adsorption through electrostatic repulsion enhancement with the zeta potential reduction(7.2 mV). Further disturbance experiment indicated a significant releasing trend of active P and DGT-labile P from the solid phase, pore water to the overlying water after disturbances due to resuspended releasing, particle size and amorphous Fe, Mn and Al's redistribution. Moreover, [31]P NMR and EPR results indicated photodegradation after disturbance converted diester phosphate into orthophosphate with long-term LMB immobilization via the oxidation of ·OH in the sediment of the plateau lake. Therefore, management issues for Xingyun Lake may apply to other plateau lakes with low external P input, intermediate depth and intense disturbance.}, } @article {pmid39558635, year = {2024}, author = {Pillai, M and Patil, AD and Das, A and Jha, SK}, title = {Pathological Mutations D169G and P112H Electrostatically Aggravate the Amyloidogenicity of the Functional Domain of TDP-43.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {23}, pages = {4267-4283}, doi = {10.1021/acschemneuro.4c00372}, pmid = {39558635}, issn = {1948-7193}, mesh = {Humans ; *DNA-Binding Proteins/genetics/metabolism/chemistry ; *Static Electricity ; *Amyloid/metabolism/genetics ; Mutation ; Protein Domains/genetics ; Hydrogen-Ion Concentration ; Protein Aggregation, Pathological/genetics/metabolism ; }, abstract = {Aggregation of TDP-43 is linked to the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Notably, electrostatic point mutations such as D169G and P112H, located within the highly conserved functional tandem RNA recognition motif (RRM) domains of the TDP-43 protein (TDP-43[tRRM]), have been identified in diseased patients as well. In this study, we address how the electrostatic mutations alter both the native state stability and aggregation propensity of TDP-43[tRRM]. The mutants D169G and P112H show increased chemical stability compared to the TDP-43[tRRM] at physiological pH. However, at low pH, both the mutants undergo a conformational change to form amyloid-like fibrils, though with variable rates─the P112H mutant being substantially faster than the other two sequences (TDP-43[tRRM] and D169G mutant) showing comparable rates. Moreover, among the three sequences, only the P112H mutant undergoes a strong ionic strength-dependent aggregability trend. These observations signify the substantial contribution of the excess charge of the P112H mutant to its unique aggregation process. Complementary simulated observables with atomistic resolution assign the experimentally observed sequence-, pH-, and ionic strength-dependent aggregability pattern to the degree of thermal lability of the mutation site-containing RRM1 domain and its extent of dynamical anticorrelation with the RRM2 domain whose combination eventually dictate the extent of generation of aggregation-prone partially unfolded conformational ensembles. Our choice of a specific charge-modulated pathogenic mutation-based experiment-simulation-combination approach unravels the otherwise hidden residue-wise contribution to the individual steps of this extremely complicated multistep aggregation process.}, } @article {pmid39557859, year = {2024}, author = {Pamphlett, R and Parkin Kullmann, J}, title = {Early life events may be the first steps on the multistep path to amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28497}, pmid = {39557859}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/etiology/genetics ; Humans ; Female ; Male ; Middle Aged ; Risk Factors ; Adult ; Aged ; Case-Control Studies ; Surveys and Questionnaires ; }, abstract = {A combination of multiple genetic and environmental factors appear to be required to trigger the onset of amyotrophic lateral sclerosis (ALS). Early life environmental exposures have been reported to be risk factors for a variety of adult-onset diseases, so we used data from an online international ALS case-control questionnaire to estimate whether any of these could be risk factors for the clinical onset of ALS. Responses were obtained from 1,049 people aged 40 years or more, 568 with ALS and 481 controls. People with ALS were more likely to have been born and lived longer in a country area than in a city area, to have younger parents, and to have lower educational attainment and fewer years of education. No ALS-control differences were found in sibling numbers, birth order, adult height, birth weight, parent smoking, Cesarean delivery, or age of starting smoking. In conclusion, early life events and conditions may be part of a group of polyenvironmental risk factors that act together with polygenetic variants to trigger the onset of ALS. Reducing exposure to adverse environmental factors in early life could help to lower the risk of later developing ALS.}, } @article {pmid39557152, year = {2025}, author = {Yu, H and Ren, K and Jin, Y and Zhang, L and Liu, H and Huang, Z and Zhang, Z and Chen, X and Yang, Y and Wei, Z}, title = {Mitochondrial DAMPs: Key mediators in neuroinflammation and neurodegenerative disease pathogenesis.}, journal = {Neuropharmacology}, volume = {264}, number = {}, pages = {110217}, doi = {10.1016/j.neuropharm.2024.110217}, pmid = {39557152}, issn = {1873-7064}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/immunology ; *Neuroinflammatory Diseases/metabolism/immunology/pathology ; Animals ; *Mitochondria/metabolism ; *Alarmins/metabolism ; Inflammasomes/metabolism ; DNA, Mitochondrial/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are increasingly linked to mitochondrial dysfunction and neuroinflammation. Central to this link are mitochondrial damage-associated molecular patterns (mtDAMPs), including mitochondrial DNA, ATP, and reactive oxygen species, released during mitochondrial stress or damage. These mtDAMPs activate inflammatory pathways, such as the NLRP3 inflammasome and cGAS-STING, contributing to the progression of neurodegenerative diseases. This review delves into the mechanisms by which mtDAMPs drive neuroinflammation and discusses potential therapeutic strategies targeting these pathways to mitigate neurodegeneration. Additionally, it explores the cross-talk between mitochondria and the immune system, highlighting the complex interplay that exacerbates neuronal damage. Understanding the role of mtDAMPs could pave the way for novel treatments aimed at modulating neuroinflammation and slowing disease progression, ultimately improving patient outcome.}, } @article {pmid39556975, year = {2024}, author = {Yu, Z and Qi, J and Liu, S and Zhao, X and Huang, H}, title = {Evaluating forest aboveground biomass estimation model using simulated ALS point cloud from an individual-based forest model and 3D radiative transfer model across continents.}, journal = {Journal of environmental management}, volume = {372}, number = {}, pages = {123287}, doi = {10.1016/j.jenvman.2024.123287}, pmid = {39556975}, issn = {1095-8630}, mesh = {*Biomass ; *Forests ; Models, Theoretical ; Computer Simulation ; Trees/growth & development ; Algorithms ; }, abstract = {Area-based approach (ABA) has been widely employed for estimating forest aboveground biomass (AGB) using airborne laser scanning (ALS) data. However, its scalability is limited due to challenges in model generalization across different forest types and regions. The selection of sensitive variables from ALS data is crucial for constructing robust forest AGB estimation models, yet this selection varies significantly among forest types and regions. Traditionally, assessing the influence of variable selection is hindered by the lack of accurate reference forest AGB values. Computer simulation-based method provides a perspective for exploring these challenges. This study employs an individual-based forest growth process model, FORMIND, coupled with a 3D radiative transfer model (RTM), LESS, to evaluate the transferability of ABA-based forest AGB estimation models and the generalization of ALS-derived variables. We used six virtual 3D forest scenes and two real-world forest sites, representing a range of global forest types, along with their simulated ALS data, to develop a forest AGB estimation model using the random forest algorithm, which allowed us to analyze the importance of various variables. We assessed model transferability through cross-comparison. Additionally, we validated the model using field plots and ALS data collected from two distinct regions. The results showed that the canopy surface area and volume extracted using the α-shape algorithm and parameters fitted from the Weibull distribution are vital variables when using ALS for forest AGB estimation across forest types and regions. Incorporating these variables into the model significantly improves the accuracy of forest AGB estimation. The optimized model achieved a R[2] of 0.945, a RMSE of 34.22 t/ha, and a MAE of 20.53 t/ha. Our study not only deepens the understanding of the relationship between forest vertical structural metrics and AGB but also highlights the potential of computer simulation as a tool for refining the estimation of forest structural parameters.}, } @article {pmid39556393, year = {2024}, author = {Ishii, J and Nishikimi, M and Kikutani, K and Ohki, S and Ota, K and Anzai, T and Takahashi, K and Okubo, M and Ohshimo, S and Iwami, T and Shime, N}, title = {Resuscitation Attempt and Outcomes in Patients With Asystole Out-of-Hospital Cardiac Arrest.}, journal = {JAMA network open}, volume = {7}, number = {11}, pages = {e2445543}, pmid = {39556393}, issn = {2574-3805}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality/epidemiology ; Male ; Female ; Aged ; Middle Aged ; Japan/epidemiology ; *Cardiopulmonary Resuscitation/methods ; *Registries ; *Emergency Medical Services/statistics & numerical data ; Aged, 80 and over ; Advanced Cardiac Life Support/methods ; Prospective Studies ; Epinephrine/therapeutic use/administration & dosage ; Treatment Outcome ; Cohort Studies ; }, abstract = {IMPORTANCE: Little is known about the epidemiology of out-of-hospital cardiac arrest (OHCA) in patients with asystole in countries where prehospital resuscitation is not withheld or terminated.

OBJECTIVE: To investigate the secular trends in the patient outcomes and advanced life support (ALS) procedures and evaluate the association of ALS procedures with favorable outcomes among patients with OHCA and asystole.

This cohort study analyzed data from a nationwide prospective OHCA registry in Japan. OHCA occurred from June 1, 2014, to December 31, 2020. Adults with an initial rhythm of asystole and OHCA were included in the analysis, which was conducted between July 29, 2022, and August 24, 2024.

EXPOSURES: Year of OHCA and prehospital ALS procedures (advanced airway management [AAM] and intravenous epinephrine administration).

MAIN OUTCOMES AND MEASURES: Trends in prehospital and in-hospital ALS procedures and patient outcomes were described using the Jonckheere-Terpstra trend test for continuous variables and the Cochran-Armitage trend test for categorical variables. The primary outcome was a favorable neurological outcome at 30 days. The secondary outcomes included a favorable neurological outcome at 90 days and survival at 30 and 90 days. Associations between prehospital procedures and outcomes were analyzed using time-dependent propensity score and risk-set matching.

RESULTS: Of 60 349 patients with OHCA, 35 843 (59.4%) presented with asystole (median age, 77 [IQR, 64-85] years; 20 573 [57.4%] men). Among these, 33 674 patients (93.9%) underwent ALS procedures, with 67 (0.2%) achieving a favorable neurological outcome at 30 days. No significant trends in the outcomes were noted, except for a decline in return of spontaneous circulation (424 of 1848 [22.9%] to 1178 of 5892 [20.0%]; P = .003). Neither AAM (odds ratio [OR], 1.27 [95% CI, 0.76-2.12]; P = .36) nor intravenous epinephrine administration (OR, 0.53 [95% CI, 0.24-1.13]; P = .10) was associated with a favorable neurological outcome at 30 days, although both were associated with survival at 30 days (ORs, 1.45 [95% CI, 1.21-1.74] and 1.81 [95% CI, 1.44-2.27], respectively; P < .001 for both).

CONCLUSIONS AND RELEVANCE: In this cohort study of patients with OHCA presenting with asystole, the proportion with a favorable neurological outcome at 30 days was substantially low, and no prehospital ALS procedure was associated with a favorable neurological outcome. These findings suggest that discussions regarding implementation of a termination of resuscitation rule for such patients are warranted.}, } @article {pmid39556113, year = {2025}, author = {Yeganeh Markid, T and Pourahmadiyan, A and Hamzeh, S and Sharifi-Bonab, M and Asadi, MR and Jalaiei, A and Rezazadeh, M and Ghafouri-Fard, S}, title = {A special focus on polyadenylation and alternative polyadenylation in neurodegenerative diseases: A systematic review.}, journal = {Journal of neurochemistry}, volume = {169}, number = {2}, pages = {e16255}, doi = {10.1111/jnc.16255}, pmid = {39556113}, issn = {1471-4159}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics ; *Polyadenylation ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) are one of the prevailing conditions characterized by progressive neuronal loss. Polyadenylation (PA) and alternative polyadenylation (APA) are the two main post-transcriptional events that regulate neuronal gene expression and protein production. This systematic review analyzed the available literature on the role of PA and APA in NDDs, with an emphasis on their contributions to disease development. A comprehensive literature search was performed using the PubMed, Scopus, Cochrane, Google Scholar, Embase, Web of Science, and ProQuest databases. The search strategy was developed based on the framework introduced by Arksey and O'Malley and supplemented by the inclusion and exclusion criteria. The study selection was performed by two independent reviewers. Extraction and data organization were performed in accordance with the predefined variables. Subsequently, quantitative and qualitative analyses were performed. Forty-seven studies were included, related to a variety of NDDs, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Disease induction was performed using different models, including human tissues, animal models, and cultured cells. Most investigations were related to PA, although some were related to APA or both. Amyloid precursor protein (APP), Tau, SNCA, and STMN2 were the major genes identified; most of the altered PA patterns were related to mRNA stability and translation efficiency. This review particularly underscores the key roles of PA and APA in the pathogenesis of NDDs through their mechanisms that contribute to gene expression dysregulation, protein aggregation, and neuronal dysfunction. Insights into these mechanisms may lead to new therapeutic strategies focused on the modulation of PA and APA activities. Further research is required to investigate the translational potential of targeting these pathways for NDD treatment.}, } @article {pmid39553255, year = {2024}, author = {Zeinali, M and Almasi Dooghaee, M and Ziaee, M and Haghi Ashtiani, B}, title = {Evaluation of Relationship Between Laboratory, Electrodiagnostic, and Functional Parameters in Patients With Amyotrophic Lateral Sclerosis; A Cross Sectional Study.}, journal = {Basic and clinical neuroscience}, volume = {15}, number = {4}, pages = {553-560}, pmid = {39553255}, issn = {2008-126X}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a poor prognosis that leads to limb and or bulbar muscle degeneration. Several demographic and biological factors have prognostic importance, but little data exist on the relationship between clinical, electrodiagnostic, and laboratory markers as predictors of disease progression. We aimed to assess the relationships between different aspects of ALS patients' clinical, electrodiagnostic, and laboratory features and their level of functioning.

METHODS: We included 27 ALS patients diagnosed within the last two years. A neurology resident conducted clinical assessment and electrodiagnostic studies. The motor unit number index (MUNIX) and compound motor action potential (CMAP) were used to measure motor unit loss. Serum creatinine, urea, albumin, and creatine kinase were measured as laboratory markers. We used the Persian version of the ALS functional rating scale (ALS-FRS) as the main outcome measure. The Pearson correlation coefficient was calculated to assess the correlations using the SPSS software, version 16.

RESULTS: None of the demographic or laboratory parameters were correlated with ALSFRS. Patients with the onset of disease in the limbs had a higher MUNIX score than those with bulbar onset. Also, increased body mass index (BMI) was associated with lower CMAP and MUNIX scores (P=0.02). Higher serum creatinine levels were significantly associated with higher lower limb MUNIX (P=0.04). Higher lower limb MUNIX was associated with a higher lower limb functional score.

CONCLUSION: Decreased serum creatinine may indicate lower limb motor unit loss in patients with ALS. Also, MUNIX scores may be used as substitutes for ALS-FRS in ALS trials. Further research is needed to elucidate the clinical application of these findings.}, } @article {pmid39552508, year = {2025}, author = {Zhong, R and Dionela, DLA and Kim, NH and Harris, EN and Geisler, JG and Wei-LaPierre, L}, title = {Micro-Doses of DNP Preserve Motor and Muscle Function with a Period of Functional Recovery in Amyotrophic Lateral Sclerosis Mice.}, journal = {Annals of neurology}, volume = {97}, number = {3}, pages = {542-557}, pmid = {39552508}, issn = {1531-8249}, support = {R56 NS117429/NS/NINDS NIH HHS/United States ; NS99545/NS/NINDS NIH HHS/United States ; R01 NS127858/NS/NINDS NIH HHS/United States ; R21 NS099545/NS/NINDS NIH HHS/United States ; NS117429/NS/NINDS NIH HHS/United States ; NS127858/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; *2,4-Dinitrophenol/pharmacology ; Mice ; *Muscle, Skeletal/drug effects/physiopathology ; *Mice, Transgenic ; *Disease Models, Animal ; *Recovery of Function/drug effects/physiology ; Muscle Contraction/drug effects/physiology ; Male ; Uncoupling Agents/pharmacology ; Motor Neurons/drug effects ; Neuromuscular Junction/drug effects ; }, abstract = {OBJECTIVE: Mitochondrial dysfunction is one of the earliest pathological events observed in amyotrophic lateral sclerosis (ALS). The aim of this study is to evaluate the therapeutic efficacy of 2,4-dinitrophenol (DNP), a mild mitochondrial uncoupler, in an ALS mouse model to provide preclinical proof-of-concept evidence of using DNP as a potential therapeutic drug for ALS.

METHODS: hSOD1[G93A] mice were treated with 0.5-1.0 mg/kg DNP through daily oral gavage from presymptomatic stage or disease onset until 18 weeks old. Longitudinal behavioral studies were performed weekly or biweekly from 6 to 18 weeks old. In situ muscle contraction measurements in extensor digitorum longus muscles were conducted to evaluate the preservation of contractile force and motor unit numbers in hSOD1[G93A] mice following DNP treatment. Muscle innervation and inflammatory markers were assessed using immunostaining. Extent of protein oxidation and activation of Akt pathway were also examined.

RESULTS: DNP delayed disease onset; improved motor coordination and muscle performance in vivo; preserved muscle contractile function, neuromuscular junction morphology, and muscle innervation; and reduced inflammation and protein oxidation at 18 weeks old in hSOD1[G93A] mice. Strikingly, symptomatic hSOD1[G93A] mice exhibited a period of recovery in running ability at 20 cm/s several weeks after 2,4-dinitrophenol treatment started at disease onset, offering the first observation in disease phenotype reversal using a small molecule.

INTERPRETATION: Our results strongly support that micro-dose DNP may be used as a potential novel treatment for ALS patients, with a possibility for recovery, when used at optimal doses and time of intervention. ANN NEUROL 2025;97:542-557.}, } @article {pmid39552337, year = {2024}, author = {Baindoor, S and Gibriel, HAY and Venø, MT and Su, J and Morrissey, EP and Jirström, E and Woods, I and Kenny, A and Alves, M and Halang, L and Fabbrizio, P and Bilen, M and Engel, T and Hogg, MC and Bendotti, C and Nardo, G and Slack, RS and Kjems, J and Prehn, JHM}, title = {Distinct fingerprints of tRNA-derived small non-coding RNA in animal models of neurodegeneration.}, journal = {Disease models & mechanisms}, volume = {17}, number = {11}, pages = {}, pmid = {39552337}, issn = {1754-8411}, support = {17/JPND/3455//Research Ireland/ ; //European Regional Development Fund/ ; //FutureNeuro/ ; //Precision ALS/ ; 18/CRT/6214//Research Ireland Centre for Research Training in Genomics Data Science/ ; //EU Joint Programme - Neurodegenerative Disease Research/ ; CUP E48I20000000007//Regione Lombardia/ ; SG-2018-12366226//Ministero della Salute/ ; //Royal College of Surgeons in Ireland/ ; }, mesh = {Animals ; *Disease Models, Animal ; *RNA, Transfer/genetics/metabolism ; *RNA, Small Untranslated/genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Neurodegenerative Diseases/genetics/pathology ; Mice ; Humans ; Mice, Transgenic ; Parkinson Disease/genetics/pathology ; Frontotemporal Dementia/genetics/pathology ; }, abstract = {Transfer RNA-derived small RNAs (tsRNAs) - categorized as tRNA-derived fragments (tRFs), tRNA-derived stress-induced RNAs (tiRNAs) and internal tRF (itRF) - are small non-coding RNAs that participate in various cellular processes such as translation inhibition and responses to cellular stress. We here identified tsRNA profiles within susceptible tissues in animal models of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Parkinson's disease (PD) to pinpoint disease-specific tsRNAs and those shared across neurodegenerative diseases. We performed small RNA sequencing in the SOD1G93A and TDP43A315T mouse models of ALS (spinal cord), the TauP301S model of FTD (hippocampus), and the parkin/POLG model of PD (substantia nigra). Bioinformatic analysis showed higher expression of 5' tiRNAs selectively in the two ALS models, lower expression of 3' tRFs in both the ALS and FTD mouse models, and lower expression of itRF Arg in the PD model. Experimental validation confirmed the expression of tsRNAs. Gene Ontology analysis of targets associated with validated 3' tRFs indicated functions in the regulation of synaptic and neuronal pathways. Our profiling of tsRNAs indicates disease-specific fingerprints in animal models of neurodegeneration, which require validation in human disease.}, } @article {pmid39551788, year = {2024}, author = {Sadeghdoust, M and Das, A and Kaushik, DK}, title = {Fueling neurodegeneration: metabolic insights into microglia functions.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {300}, pmid = {39551788}, issn = {1742-2094}, support = {MS220110//U.S. Department of Defense/ ; 916184//Multiple Sclerosis Society of Canada/ ; }, mesh = {*Microglia/metabolism/pathology ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; }, abstract = {Microglia, the resident immune cells of the central nervous system, emerge in the brain during early embryonic development and persist throughout life. They play essential roles in brain homeostasis, and their dysfunction contributes to neuroinflammation and the progression of neurodegenerative diseases. Recent studies have uncovered an intricate relationship between microglia functions and metabolic processes, offering fresh perspectives on disease mechanisms and possible treatments. Despite these advancements, there are still significant gaps in our understanding of how metabolic dysregulation affects microglial phenotypes in these disorders. This review aims to address these gaps, laying the groundwork for future research on the topic. We specifically examine how metabolic shifts in microglia, such as the transition from oxidative phosphorylation and mitochondrial metabolism to heightened glycolysis during proinflammatory states, impact the disease progression in Alzheimer's disease, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Additionally, we explore the role of iron, fatty and amino acid metabolism in microglial homeostasis and repair. Identifying both distinct and shared metabolic adaptations in microglia across neurodegenerative diseases could reveal common therapeutic targets and provide a deeper understanding of disease-specific mechanisms underlying multiple CNS disorders.}, } @article {pmid39551782, year = {2024}, author = {Labrador, L and Rodriguez, L and Beltran, S and Hernandez, F and Gomez, L and Ojeda, P and Bergmann, C and Calegaro-Nassif, M and Kerr, B and Medinas, DB and Manque, P and Woehlbier, U}, title = {Overexpression of autophagy enhancer PACER/RUBCNL in neurons accelerates disease in the SOD1[G93A] ALS mouse model.}, journal = {Biological research}, volume = {57}, number = {1}, pages = {86}, pmid = {39551782}, issn = {0717-6287}, support = {1200459//Agencia Nacional de Investigación y Desarrollo/ ; 1150743//Agencia Nacional de Investigación y Desarrollo/ ; 11160288//Agencia Nacional de Investigación y Desarrollo/ ; 1191538//Agencia Nacional de Investigación y Desarrollo/ ; 1230905//Agencia Nacional de Investigación y Desarrollo/ ; ACT210039//Agencia Nacional de Investigación y Desarrollo/ ; 11240328//Agencia Nacional de Investigación y Desarrollo/ ; 1240176//Agencia Nacional de Investigación y Desarrollo/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Mice, Transgenic ; *Disease Models, Animal ; *Autophagy/genetics/physiology ; Mice ; Humans ; Superoxide Dismutase-1/genetics ; Motor Neurons/pathology ; Superoxide Dismutase/genetics ; Neurons/pathology ; Male ; Female ; Autophagy-Related Proteins/genetics/metabolism ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal paralytic disorder associated with motor neuron death. Mutant superoxide dismutase 1 (SOD1) misfolding and aggregation have been linked to familial ALS, with the accumulation of abnormal wild-type SOD1 species being also observed in postmortem tissue of sporadic ALS cases. Both wild-type and mutated SOD1 are reported to contribute to motoneuron cell death. The autophagic pathway has been shown to be dysregulated in ALS. Recent evidence suggests a dual time-dependent role of autophagy in the progression of the disease. PACER, also called RUBCNL (Rubicon-like), is an enhancer of autophagy and has been found diminished in its levels during ALS pathology in mice and humans. Pacer loss of function disturbs the autophagy process and leads to the accumulation of SOD1 aggregates, as well as sensitizes neurons to death. Therefore, here we investigated if constitutive overexpression of PACER in neurons since early development is beneficial in an in vivo model of ALS. We generated a transgenic mouse model overexpressing human PACER in neurons, which then was crossbred with the mutant SOD1[G93A] ALS mouse model. Unexpectedly, PACER/SOD1[G93A] double transgenic mice exhibited an earlier disease onset and shorter lifespan than did littermate SOD1[G93A] mice. The overexpression of PACER in neurons in vivo and in vitro increased the accumulation of SOD1 aggregates, possibly due to impaired autophagy. These results suggest that similar to Pacer loss-of function, Pacer gain-of function is detrimental to autophagy, increases SOD1 aggregation and worsens ALS pathogenesis. In a wider context, our results indicate the requirement to maintain a fine balance of PACER protein levels to sustain proteostasis.}, } @article {pmid39551156, year = {2025}, author = {Chen, LC and Martin, A and Senna, MM}, title = {Response to Truel J. et al's "Response to 'Topical tofacitinib for patients with lichen planopilaris and/or frontal fibrosing alopecia'".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e69}, doi = {10.1016/j.jaad.2024.11.011}, pmid = {39551156}, issn = {1097-6787}, } @article {pmid39551139, year = {2024}, author = {Liu, C and Chen, IS and Barri, M and Murrell-Lagnado, R and Kubo, Y}, title = {Structural determinants of M2R involved in inhibition by Sigma-1R.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {12}, pages = {108006}, pmid = {39551139}, issn = {1083-351X}, mesh = {*Receptors, sigma/metabolism/genetics ; Humans ; *Sigma-1 Receptor ; HEK293 Cells ; *Receptor, Muscarinic M2/metabolism/genetics ; Animals ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism/genetics ; }, abstract = {Sigma-1 receptor (S1R) is a multimodal chaperone protein that is implicated in various pathophysiological conditions including drug addiction, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). S1R interacts with various ion channels and receptors on the endoplasmic reticulum or plasma membrane (PM). It has been reported that S1R colocalizes with the M2-muscarinic acetylcholine receptor (M2R) on the soma of motoneurons, although a functional interaction between these two proteins has not been established. Here, we investigated the regulation of M2R signaling by S1R using electrophysiological recordings of GIRK currents in HEK293T cells. We observed that S1R strongly inhibited M2R-mediated activation of GIRK1/2, but the disease mutant linked to ALS, S1R E102Q, did not. The inhibitory effect of S1R was selective for M2R and wasn't seen when S1R was co-expressed with other Gi/o coupled receptors including M4R. Chimeric and mutant receptors of M2R and M4R were generated and analyzed, and this highlighted Ala401 in the transmembrane 6 domain (TM6) of M2R and Glu172 as well as Glu175 in the extracellular loop 2 regions of M2R, as essential for the inhibition by S1R. Co-immunoprecipitation confirmed the physical interaction between M2R and S1R. Immunocytochemical labeling of M2R and S1R expressed in HeLa cells, HEK293T cells, and cultured hippocampal neurons, showed clear PM expression of M2R throughout the cell which was decreased by coexpression with S1R but was still apparent. Taken together, our results show that S1R interacts with M2R to reduce both its PM expression and function, and this involves TM6 and the extracellular loop 2.}, } @article {pmid39551138, year = {2024}, author = {Yang, C and Leifer, C and Lammerding, J and Hu, F}, title = {Regulation of TAR DNA binding protein 43 (TDP-43) homeostasis by cytosolic DNA accumulation.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {12}, pages = {107999}, pmid = {39551138}, issn = {1083-351X}, support = {R21 AG078741/AG/NIA NIH HHS/United States ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics ; *Cytosol/metabolism ; Humans ; Animals ; *Homeostasis ; DNA/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Cytoplasm/metabolism ; beta Karyopherins/metabolism/genetics ; Neurons/metabolism/pathology ; Mice ; Cell Nucleus/metabolism ; Oligodeoxyribonucleotides/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA binding protein predominantly localized in the nucleus under physiological conditions. TDP-43 proteinopathy, characterized by cytoplasmic aggregation and nuclear loss, is associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Thus it is crucial to understand the molecular mechanism regulating TDP-43 homeostasis. Here, we show that the uptake of oligodeoxynucleotides (ODNs) from the extracellular space induces reversible TDP-43 cytoplasmic puncta formation in both neurons and glia. ODNs facilitate the liquid-liquid phase separation of TDP-43 in vitro. Importantly, persistent accumulation of DNA in the cytoplasm leads to nuclear depletion of TDP-43 and enhanced production of a short isoform of TDP-43 (sTDP-43). In addition, in response to ODN uptake, the nuclear import receptor karyopherin subunit β1 (KPNB1) is sequestered in the cytosolic TDP-43 puncta. ALS-linked Q331K mutation decreases the dynamics of cytoplasmic TDP-43 puncta and increases the levels of sTDP-43. Moreover, the TDP-43 cytoplasmic puncta are induced by DNA damage and by impaired nuclear envelope integrity due to Lamin A/C deficiency. In summary, our data support that abnormal DNA accumulation in the cytoplasm may be one of the key mechanisms leading to TDP-43 proteinopathy and provides novel insights into molecular mechanisms of ALS caused by TDP-43 mutations.}, } @article {pmid39550606, year = {2024}, author = {Rabadi, MH and Russell, KA and Xu, C}, title = {Analysis of Mortality Causes and Locations in Veterans with ALS: A Decade Review.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {30}, number = {}, pages = {e945816}, pmid = {39550606}, issn = {1643-3750}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology ; *Veterans ; Male ; Female ; Middle Aged ; Aged ; *Cause of Death ; Retrospective Studies ; United States/epidemiology ; Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that leads to rapid degeneration of nerves in the brain and spinal cord, with eventual loss of voluntary movements, including breathing. This retrospective study of medical record data from 105 US veterans diagnosed with ALS at the Oklahoma City VA Medical Center between 2010 and 2021 aimed to identify patient demographics, and the causes and places of death for these veterans. MATERIAL AND METHODS Data from 105 US veterans diagnosed with ALS by the El Escorial criteria and supported by neurophysiology testing was reviewed. The information about the place and cause of death was obtained from each patient's care provider and death certificate. Crude mortality rates (per 100 person-years) and standardized mortality ratios (SMRs) were calculated for the causes of death, by sex, age group, and location of death. RESULTS During the 11-year follow-up period, 80 (76.2%) veterans with ALS died. The mean (SD) follow-up time was 4.53 (4.55) years. Most of the deaths were due to respiratory failure and pneumonia (n=43, mortality rate=9.21 per 100 person-years). Most patients died at home (n=71, 88.7%). The annual crude mortality rate was 16.7 and the all-cause death SMR was 25.63 (95% CI, 20.32-31.55). CONCLUSIONS This study's findings are that in veterans with ALS, the main cause of death is respiratory disease (failure). The main location of death was the home, with their family members. The all-cause mortality rate among veterans with ALS was 26 times greater than for the general Oklahoma population.}, } @article {pmid39550435, year = {2024}, author = {Wang, Z and Cao, W and Deng, B and Fan, D}, title = {Lower creatinine-to-cystatin c ratio associated with increased risk of incident amyotrophic lateral sclerosis in the prospective UK biobank cohort.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28289}, pmid = {39550435}, issn = {2045-2322}, support = {81873784//National Natural Science Foundation of China/ ; BYSYDL2019002//Peking University Third Hospital/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/blood/epidemiology ; Humans ; Male ; Female ; *Creatinine/blood ; Middle Aged ; United Kingdom/epidemiology ; Aged ; Incidence ; Prospective Studies ; *Cystatin C/blood ; Risk Factors ; *Biological Specimen Banks ; *Biomarkers/blood ; Proportional Hazards Models ; Adult ; UK Biobank ; }, abstract = {Reduced muscle mass has been associated with the progression and prognosis of amyotrophic lateral sclerosis (ALS). However, it remains unclear whether decreased muscle mass is a risk factor for ALS or a consequence of motor neuron degeneration. Recently, serum creatinine-to-cystatin C ratio (CCR) have emerged as promising biomarkers for assessing muscle mass. We aimed to explore the association between CCR and the incidence of ALS using data from the UK Biobank. Between 2006 and 2010, 446,945 participants were included in the baseline. CCR was calculated as the ratio of serum creatinine to cystatin C. Cox regression models were used to analyze the relationship between CCR and ALS incidence. Furthermore, subgroup analyses were conducted to investigate potential covariates in these relationships. After adjusting for all covariates, the multivariate Cox regression analysis revealed a significant association between decreased CCR and an increased risk of ALS (hazard ratio (HR) = 0.990, 95% confidence interval (CI): 0.982-0.999, P = 0.026). Participants were stratified into groups based on CCR tertiles. Compared with participants in the highest tertiles of CCR, those in the lowest (HR = 1.388, 95% CI: 1.032-1.866, P = 0.030) and medium tertiles (HR = 1.348, 95% CI: 1.045-1.739, P = 0.021) had an increased risk of ALS incidence. Subgroup analysis showed that the relationship between CCR and ALS incidence was particularly significant among participants aged < 65 years (CCR tertile 1: HR = 1.916, 95% CI: 1.366-2.688, P < 0.001; CCR tertile 2: HR = 1.699, 95% CI: 1.267-2.278, P < 0.001). The present results demonstrate that lower CCR is significantly associated with a higher risk of ALS.}, } @article {pmid39548852, year = {2025}, author = {Dellar, ER and Vendrell, I and Amein, B and Lester, DG and Edmond, EC and Yoganathan, K and Dharmadasa, T and Sogorb-Esteve, A and Fischer, R and Talbot, K and Rohrer, JD and Turner, MR and Thompson, AG}, title = {Elevated Cerebrospinal Fluid Ubiquitin Carboxyl-Terminal Hydrolase Isozyme L1 in Asymptomatic C9orf72 Hexanucleotide Repeat Expansion Carriers.}, journal = {Annals of neurology}, volume = {97}, number = {3}, pages = {449-459}, pmid = {39548852}, issn = {1531-8249}, support = {2018-I2M-2-002//Chinese Academy of Medical Sciences Innovation Fund for Medical Science/ ; Lester/2450/795/MNDA_/Motor Neurone Disease Association/United Kingdom ; Thompson/Jan20/952-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; MR/Y001095/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; Female ; Male ; *Frontotemporal Dementia/cerebrospinal fluid/genetics ; Middle Aged ; Cross-Sectional Studies ; Aged ; *DNA Repeat Expansion/genetics ; *Heterozygote ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/genetics ; Biomarkers/cerebrospinal fluid ; Adult ; Isoenzymes/cerebrospinal fluid/genetics ; }, abstract = {OBJECTIVE: To identify biochemical changes in individuals at higher risk of developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) via C9orf72 hexanucleotide repeat expansion (HRE) heterozygosity.

METHODS: Cross-sectional observational study of 48 asymptomatic C9orf72 HRE carriers, 39 asymptomatic non-carrier controls, 19 people with sporadic ALS, 10 with C9orf72 ALS, 14 with sporadic FTD, and 10 with C9orf72 FTD. Relative abundance of 30 pre-defined cerebrospinal fluid biomarkers of ALS and FTD were compared in asymptomatic C9orf72 HRE carriers and age-matched non-carrier controls. Differential abundance of these proteins was quantified using data independent acquisition mass spectrometry or electro chemiluminescent assay for neurofilament light chain. Unbiased analysis of the entire cerebrospinal fluid proteome was then carried out.

RESULTS: Ubiquitin carboxyl-hydrolase isozyme L1 levels were higher in asymptomatic C9orf72 HRE carriers compared with age-matched non-carriers (log2fold change 0.20, FDR-adjusted p-value = 0.034), whereas neurofilament light chain levels did not significantly differ. Ubiquitin carboxyl-hydrolase isozyme L1 levels remained elevated after matching of groups by neurofilament levels (p = 0.011), and after adjusting for age, sex, and neurofilament levels. A significant difference was also observed when restricting analysis to younger participants (<37) matched by neurofilament level (p = 0.007).

INTERPRETATION: Elevated cerebrospinal fluid ubiquitin carboxyl-hydrolase isozyme L1 levels in C9orf72 HRE carriers can occur in the absence of increased neurofilament levels, potentially reflecting either compensatory or pathogenic mechanisms preceding rapid neuronal loss. This brings forward the window on changes associated with the C9orf72 HRE carrier state, with potential to inform understanding of penetrance and approaches to prevention. ANN NEUROL 2025;97:449-459.}, } @article {pmid39548731, year = {2024}, author = {Shino, Y and Muraki, N and Kobatake, Y and Kamishina, H and Kato, R and Furukawa, Y}, title = {Disulfide-mediated oligomerization of mutant Cu/Zn-superoxide dismutase associated with canine degenerative myelopathy.}, journal = {Protein science : a publication of the Protein Society}, volume = {33}, number = {12}, pages = {e5210}, pmid = {39548731}, issn = {1469-896X}, support = {JP21am0101083//Japan Agency for Medical Research and Development/ ; 19H05765//The Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; 22H02768//The Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; 22K19389//The Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; 23EXC334//Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences/ ; }, mesh = {Animals ; Dogs ; *Disulfides/chemistry/metabolism ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; Protein Multimerization ; Dog Diseases/genetics ; Spinal Cord Diseases/genetics/metabolism ; Amino Acid Substitution ; Zinc/metabolism/chemistry ; Mutation ; Mutation, Missense ; Copper/metabolism/chemistry ; }, abstract = {A homozygous E40K mutation in the gene coding canine Cu/Zn-superoxide dismutase (cSOD1) causes degenerative myelopathy (DM) in dogs. A pathological hallmark of DM with the cSOD1 mutation is the aggregation of mutant cSOD1 proteins in neurons. The amino acid substitution E40K disrupts a salt bridge between Glu40 and Lys91 and is considered to destabilize the native state of cSOD1; however, the mechanism by which mutant cSOD1 aggregates remains unclear. Here, we show that mutant cSOD1 losing a copper and zinc ion forms oligomers crosslinked via disulfide bonds. The E40K substitution was found to result in the increased solvent exposure of the Cys7 side chain, which then attacked the disulfide bond (Cys57-Cys146) in cSOD1 to form disulfide-linked oligomers. We also successfully prevented the Cys7 exposure and thus the oligomerization of mutant cSOD1 by a fragment antibody that specifically recognizes the region around the mutation site. The fragment antibody covered the β-plug region, reinforcing the interactions compromised by the E40K substitution and thus contributing to the maintenance of the structural integrity of the β-barrel core of cSOD1. Taken together, we propose that the Cys7 exposure in cSOD1 upon the salt bridge disruption plays a central role in the aggregation mechanism of DM-associated mutant cSOD1.}, } @article {pmid39548508, year = {2024}, author = {Panei, FP and Di Rienzo, L and Zacco, E and Armaos, A and Tartaglia, GG and Ruocco, G and Milanetti, E}, title = {Synchronized motion of interface residues for evaluating protein-RNA complex binding affinity: Application to aptamer-mediated inhibition of TDP-43 aggregates.}, journal = {Protein science : a publication of the Protein Society}, volume = {33}, number = {12}, pages = {e5201}, pmid = {39548508}, issn = {1469-896X}, support = {855923//ERC-2019-Synergy Grant (ASTRA, 855923)/ ; ivBM4PAP,101098989//EIC-2022-PathfinderOpen/ ; CN00000041//National Center for Gene Therapy and Drugs Based on RNA Technology/ ; CUPj33C22001130001//Potenziamento Strutture di Ricerca e Creazione di Campioni Nazionali Di R&S/ ; }, mesh = {*Aptamers, Nucleotide/chemistry/metabolism ; *Molecular Dynamics Simulation ; Humans ; *DNA-Binding Proteins/chemistry/metabolism ; *Protein Binding ; RNA/chemistry/metabolism ; Molecular Docking Simulation ; }, abstract = {Investigating the binding between proteins and aptamers, such as peptides or RNA molecules, is of crucial importance both for understanding the molecular mechanisms that regulate cellular activities and for therapeutic applications in several pathologies. Here, a new computational procedure, employing mainly docking, clustering analysis, and molecular dynamics simulations, was designed to estimate the binding affinities between a protein and some RNA aptamers, through the investigation of the dynamical behavior of the predicted molecular complex. Using the state-of-the-art software catRAPID, we computationally designed a set of RNA aptamers interacting with the TAR DNA-binding protein 43 (TDP-43), a protein associated with several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We thus devised a computational protocol to predict the RNA-protein molecular complex, so that the structural and dynamical behavior of such a complex can be investigated through extensive molecular dynamics simulation. We hypothesized that the coordinated and synchronized motion of the protein-binding residues, when in contact with RNA molecule, is a critical requisite in order to have a stable binding. Indeed, we calculated the motion covariance exhibited by the interface residues during molecular dynamics simulation: we tested the results against experimental measurements of binding affinity (in this case, the dissociation constant) for six RNA molecules, resulting in a linear correlation of about 0.9. Our findings suggest that the synchronized movement of interface residues plays a pivotal role in ensuring the stability within RNA-protein complexes, moreover providing insights into the contribution of each interface residue. This promising pipeline could thus contribute to the design of RNA aptamers interacting with proteins.}, } @article {pmid39548409, year = {2024}, author = {Ruan, K and Cheng, D and Zhu, X and Sun, S and Bao, F and Zhu, J and Li, F and Shen, M and Ye, Y}, title = {Corneal higher-order aberrations and their relationship with choroid in myopic patients.}, journal = {BMC ophthalmology}, volume = {24}, number = {1}, pages = {500}, pmid = {39548409}, issn = {1471-2415}, support = {81900910//Innovative Research Group Project of the National Natural Science Foundation of China/ ; LQ19H120003//Natural Science Foundation of Zhejiang Province/ ; Y2023809, Y20190638//Basic Scientific Research Project of Wenzhou/ ; }, mesh = {Humans ; Female ; Male ; *Choroid/pathology/diagnostic imaging/blood supply ; Adult ; *Myopia/physiopathology/complications ; *Corneal Wavefront Aberration/physiopathology ; *Tomography, Optical Coherence/methods ; Young Adult ; *Cornea/pathology/diagnostic imaging ; Axial Length, Eye/pathology/diagnostic imaging ; Refraction, Ocular/physiology ; Visual Acuity/physiology ; Corneal Topography ; Middle Aged ; Cross-Sectional Studies ; }, abstract = {BACKGROUND: To investigate corneal higher-order aberrations (HOAs) and choroidal characteristics in myopic individuals and explore the association between HOAs and choroidal parameters.

METHODS: Myopic participants were categorized into three groups based on axial lengths (ALs). We compared corneal HOAs, including spherical (Z4[0]), comatic (Z3 [- 1] and Z3[1]), and trefoil (Z3 [- 3] and Z3[3]) aberrations, as well as choroidal vascularity index (CVI) and choroidal thickness (CT). Linear regression analysis was used to assess the relationships among corneal HOAs, CVI, CT, spherical equivalent, and AL.

RESULTS: Groups 1, 2, and 3 included 105, 98, and 118 eyes, respectively. Group 3 exhibited lower spherical HOA root mean square and Z4[0] values than group 1(p < 0.05). Group 1 showed lower Z3[1] levels than other groups (p < 0.001). Groups 1 and 2 had higher mean, central, and I2 vertical CVIs than group 3 (p < 0.05). Group 1 had a larger vertical S1 CVI than group 3 (p < 0.05). Group 3 had smaller horizontal CVI values in all regions except N2 (p < 0.05). Both the mean and CT in all regions decreased as AL increased (p < 0.001). The comatic (Z3[1]) and trefoil (Z3[3]) components were predictors of mean horizontal CVI, and the comatic (Z3[1]) component was correlated with both mean vertical and horizontal CT.

CONCLUSION: Longer AL myopic patients exhibited lower absolute values of spherical aberration and horizontal coma. Alterations in choroid in myopic patients correlated with corneal HOAs. Our results suggest a potential connection between the optical quality and ocular perfusion in myopia.}, } @article {pmid39548226, year = {2024}, author = {Qin, J and Wang, X and Fan, G and Zhang, W and Wu, X and Wang, B and Liu, Y}, title = {Identifying amyotrophic lateral sclerosis using diffusion tensor imaging, and correlation with neurofilament markers.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28110}, pmid = {39548226}, issn = {2045-2322}, support = {202103021224405//the Basic Research Project of Shanxi Province/ ; 201903D321049//the Key Research and Development Project Plan of Shanxi Province concerning social advancement/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/cerebrospinal fluid/blood/pathology ; *Diffusion Tensor Imaging/methods ; Middle Aged ; Male ; Female ; *Neurofilament Proteins/cerebrospinal fluid/blood ; *Biomarkers/blood/cerebrospinal fluid ; Aged ; Adult ; ROC Curve ; Case-Control Studies ; Anisotropy ; Pyramidal Tracts/diagnostic imaging/pathology ; }, abstract = {To determine diagnostic value of diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS) patients and investigate the association between DTI and neurofilaments (NFs), including serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH). Forty-three clinically diagnosed ALS patients and 32 control subjects without neurological disorders underwent routine MRI (magnetic resonance imaging) and DTI scans. DTI parameters (mean diffusivity [MD] and fractional anisotropy [FA]) at axial levels of internal capsules and cerebral peduncles along the corticospinal tract (CST) were measured. The study compared the differences of DTI parameters between ALS patients and controls using the Mann-Whitney U test. Diagnostic efficacy of each DTI metric was evaluated using the receiver operating characteristic (ROC) curve. NFs (NFL and pNFH levels in serum and CSF) were measured by enzyme-linked immunosorbent assay. Correlation analyses were conducted between DTI parameters and NFs. Capsule-MD and Peduncle-MD in ALS patients were higher than those in controls; whereas Capsule-FA and Peduncle-FA in ALS patients were lower than those in controls (all, p < 0.05). The area under curve (AUC) was 0.730 for Capsule-FA, 0.828 for Capsule-MD, 0.890 for Peduncle-FA, and 0.896 for Peduncle-MD. Capsule-FA was negatively correlated with CSF-NFL (r = - 0.813, p < 0.001), Serum-NFL (r = - 0.493, p = 0.001), CSF-pNFH (r = - 0.637, p < 0.001), and Serum-pNFH (r = - 0.672, p < 0.001); Peduncle-FA negatively with CSF-NFL (r = - 0.562, p < 0.001), CSF-pNFH (r = - 0.506, p = 0.001), and Serum-pNFH (r = - 0.488, p = 0.001); Peduncle-MD positively with CSF-NFL (r = 0.516, p < 0.001), CSF-pNFH (r = 0.494, p = 0.001). DTI had superior performance in identifying ALS patients and could serve as a reliable predictor. DTI parameters related to neurofilament markers, and Capsule-FA may become a robust surrogate biomarker indicating disease severity and progression rate for ALS patients.}, } @article {pmid39547910, year = {2025}, author = {Khamaysa, M and El Mendili, M and Marchand, V and Querin, G and Pradat, PF}, title = {Quantitative spinal cord imaging: Early ALS diagnosis and monitoring of disease progression.}, journal = {Revue neurologique}, volume = {181}, number = {3}, pages = {172-183}, doi = {10.1016/j.neurol.2024.10.005}, pmid = {39547910}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/diagnostic imaging/pathology ; Humans ; *Disease Progression ; *Spinal Cord/diagnostic imaging/pathology ; *Early Diagnosis ; Neuroimaging/methods ; Biomarkers/analysis ; Magnetic Resonance Imaging/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons in the cortex, brainstem, and spinal cord. This degeneration leads to muscular weakness, progressively impairing motor functions and ultimately resulting in respiratory failure. The clinical, genetic, and pathological heterogeneity of ALS, combined with the absence of reliable biomarkers, significantly challenge the efficacy of therapeutic trials. Despite these hurdles, neuroimaging, and particularly spinal cord imaging, has emerged as a promising tool. It provides insights into the involvement of both upper and lower motor neurons. Quantitative spinal imaging has the potential to facilitate early diagnosis, enable accurate monitoring of disease progression, and refine the design of clinical trials. In this review, we explore the utility of spinal cord imaging within the broader context of developing spinal imaging biomarkers in ALS. We focus on a both diagnostic and prognostic biomarker in ALS, highlighting its pivotal role in elucidating the disease's underlying pathology. We also discuss the existing limitations and future avenues for research, aiming to bridge the translational gap between academic research and its application in clinical practice and therapeutic trials.}, } @article {pmid39547816, year = {2024}, author = {Salmerón-Mendoza, AN and Aguilar-Vázquez, CA and Aguilar-Castillo, SJ}, title = {[Electromyography in atypical variants of motor neuron disease: a case series].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {62}, number = {4}, pages = {1-6}, doi = {10.5281/zenodo.11397347}, pmid = {39547816}, issn = {2448-5667}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Electromyography ; Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Adult ; Aged, 80 and over ; Motor Neuron Disease/diagnosis/physiopathology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both the upper and lower motor neurons, it has a heterogeneous clinical presentation, there are atypical variants that differ from the classic form of the disease. The criteria for diagnosis have evolved over time, with the support of electromyography (EMG), we present a patient series with these variants in which EMG was crucial to make the diagnosis.

CLINICAL CASES: Six cases are described with atypical presentation of motor neuron disease, for the isolated bulbar ALS phenotype, three cases are reported: two male patients (68 and 62 years old) and one woman (33 years old), with initial symptoms in the bulbar segment and late progression. to a second segment, corroborating characteristic findings by EMG. For the variant of Vulpian-Bernhardt syndrome (VBS), two male patients aged 82 and 72 years are reported, with initial symptoms in the thoracic segment with electromyographic support for the diagnosis; Finally, a case of amyotrophic diplegia of the legs (APD) is described in a 50-year-old female patient with symptoms isolated to the pelvic limbs, with a slow clinical evolution, corroborated by EMG with involvement of other spinal segments.

CONCLUSIONS: ALS a spectrum of motor neuron disease, a neurodegenerative disease of the CNS, without curative treatment and one with a fatal outcome, the diagnosis of ELA is complex and becomes more complex for atypical phenotypes, as observed in the presented cases EMG is an essential part of the approach and part of the diagnostic criteria.}, } @article {pmid39546178, year = {2025}, author = {Li, N and Zhang, Z and Shen, L and Song, G and Tian, J and Liu, Q and Ni, J}, title = {Selenium metabolism and selenoproteins function in brain and encephalopathy.}, journal = {Science China. Life sciences}, volume = {68}, number = {3}, pages = {628-656}, pmid = {39546178}, issn = {1869-1889}, mesh = {*Selenoproteins/metabolism ; Humans ; *Selenium/metabolism ; *Brain/metabolism ; Animals ; Brain Diseases/metabolism ; Neurodegenerative Diseases/metabolism ; }, abstract = {Selenium (Se) is an essential trace element of the utmost importance to human health. Its deficiency induces various disorders. Se species can be absorbed by organisms and metabolized to hydrogen selenide for the biosynthesis of selenoproteins, selenonucleic acids, or selenosugars. Se in mammals mainly acts as selenoproteins to exert their biological functions. The brain ranks highest in the specific hierarchy of organs to maintain the level of Se and the expression of selenoproteins under the circumstances of Se deficiency. Dyshomeostasis of Se and dysregulation of selenoproteins result in encephalopathy such as Alzheimer's disease, Parkinson's disease, depression, amyotrophic lateral sclerosis, and multiple sclerosis. This review provides a summary and discussion of Se metabolism, selenoprotein function, and their roles in modulating brain diseases based on the most currently published literature. It focuses on how Se is utilized and transported to the brain, how selenoproteins are biosynthesized and function physiologically in the brain, and how selenoproteins are involved in neurodegenerative diseases. At the end of this review, the perspectives and problems are outlined regarding Se and selenoproteins in the regulation of encephalopathy.}, } @article {pmid39545975, year = {2024}, author = {Eickhoff, C and Schöne-Seifert, B and Kettemann, D and Bormann, E and Grehl, T and Boentert, M and Koch, JC and Schmitt, C and Schrank, B and Schröter, C and Meyer, T}, title = {[End of life perspectives: a systematic survey of patients with amyotrophic lateral sclerosis].}, journal = {Der Nervenarzt}, volume = {95}, number = {12}, pages = {1131-1138}, pmid = {39545975}, issn = {1433-0407}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/psychology ; Humans ; Male ; Female ; Middle Aged ; *Terminal Care/psychology ; Aged ; *Advance Directives/psychology ; Surveys and Questionnaires ; Germany ; Adult ; Aged, 80 and over ; Noninvasive Ventilation ; Palliative Care ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease that still has to be primarily treated symptomatically or palliatively. It is therefore all the more important, in addition to initiating treatment, such as percutaneous endoscopic gastrostomy (PEG), noninvasive ventilation therapy (NIVT) and invasive ventilation therapy via tracheotomy (IVT), to discuss the possible termination of these measures early on.

QUESTION: What is the importance of advance directives for those affected and where are possible deficits in therapy planning for the end of life?

MATERIAL AND METHOD: Between March 2017 and January 2019 patients with a clinically confirmed diagnosis of ALS at six treatment centers were asked to fill out a questionnaire. A total of 328 people returned the completed forms.

RESULTS: Of the participants 72% had already made an advance directive (AD), 25% planned to fill one out and only 3% refused to do so. In composing the AD most patients (90%) had support, although 56% lacked medical counselling and only 18% had drawn up the will together with the doctor and relatives, with the majority of the rest also wanting support from a doctor. A total of 37% of all patients wanted a contact person to talk about their illness but only 40% of them had such a contact person. Of the patients 22% stated that they had considered suicide and of these only 55% stated that they had no contact person for the psychological stress caused by the illness but 31% wished to have such a person.

DISCUSSION AND CONCLUSION: A coordinated care of ALS patients, which also takes the psychosocial aspects into account is urgently needed.}, } @article {pmid39545606, year = {2024}, author = {A Virata, MC and Catahay, JA and Lippi, G and Henry, BM}, title = {Neurofilament light chain: a biomarker at the crossroads of clarity and confusion for gene-directed therapies.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {6}, pages = {227-239}, pmid = {39545606}, issn = {1758-2032}, mesh = {Humans ; *Biomarkers/blood ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/diagnosis/drug therapy/genetics ; *Neurofilament Proteins/blood ; }, abstract = {Neurofilament light chain (NfL) is a promising biomarker for neurodegenerative diseases, measurable in both CSF and blood upon neuroaxonal damage. While CSF analysis was traditionally used, blood-based assays now offer a less invasive alternative. NfL levels correlate with disease severity and progression in conditions like Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and Huntington's disease. Clinical trials demonstrate its utility as a pharmacodynamic biomarker in MS and ALS. The FDA's approval of Tofersen for SOD1-ALS based on NfL reduction underscores its growing acceptance as surrogate marker. However, challenges remain in standardizing assays, interpreting clinical correlations, low specificity and understanding the dynamics between CSF and blood NfL levels. Addressing these issues is crucial for maximizing NfL's potential in neurodegenerative disease management.}, } @article {pmid39545045, year = {2024}, author = {Xu, X and Huang, Y and Zhu, Y and Jin, Q}, title = {Association between dietary patterns and the prognosis of amyotrophic lateral sclerosis in China: a cross-sectional study.}, journal = {Frontiers in nutrition}, volume = {11}, number = {}, pages = {1437521}, pmid = {39545045}, issn = {2296-861X}, abstract = {BACKGROUND: Recently, a growing number of studies have specifically examined the impact of dietary variables on the development and progression of amyotrophic lateral sclerosis (ALS). The purpose of this study was to investigate the correlation between different dietary patterns and Chinese ALS patients' prognosis.

METHODS: A retrospective study was conducted by recruiting 590 patients with ALS who attended and were regularly followed at hospitals in Nanjing from 2016 to 2023. Nutrient intake was calculated using dietary information collected through the food frequency questionnaire (FFQ), and patients were divided into a control group and special diet groups, including a high-calorie group (HC), a high-protein group (HP), and a ketogenic diet group (KD), based on their specific intake. And used the Kaplan-Meier product limiting distribution to compare the time required to transition between phases of different dietary patterns and to estimate cumulative survival probabilities.

RESULTS: Patients in the HP had a better nutritional status. And the disease progression rate (ΔFS) was significantly associated with dietary patterns, with the KD group having the lowest ΔFS. Meanwhile, special diets extended the survival time of stage 4 patients but had no effect on the overall survival of the disease.

CONCLUSION: A special diet can be one of effective options for patients with advanced ALS. Patients with poor nutritional status may choose the HP diet, whereas those with underlying conditions should consider the ketogenic diet with caution.}, } @article {pmid39544780, year = {2024}, author = {Silva, JF and de Souza, WM and Mello, JDC and Ceccato, HD and Oliveira, PSP and Ayrizono, MLS and Leal, RF}, title = {Evidence linking gut-brain axis and Crohn's disease, focusing on neurotrophic dysfunctions and radiological imaging analysis - a systematic review.}, journal = {American journal of translational research}, volume = {16}, number = {10}, pages = {6029-6040}, pmid = {39544780}, issn = {1943-8141}, abstract = {OBJECTIVE: To conduct a systematic review (SR) to find evidence for a connection between Crohn's disease (CD) and the gut-brain axis (GBA).

METHODS: This study conducted a systematic review (SR) employing a search strategy and strict inclusion criteria. It was conducted by searching for studies published between 2017 and 2024 in the following databases: PUBMED, PUBMED PMC, BVS-BIREME, SCOPUS, WEB OF SCIENCE, EMBASE, and COCHRANE.

RESULTS: Fifty original research articles were included. Among these, 20 studies addressed neuroimaging methods to evaluate CD patients' functional or structural brain changes. Neurodegenerative diseases were the second most addressed topic in the studies, with 18 articles related to different diseases such as Parkinson's disease, Alzheimer's disease, dementia, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Multiple System Atrophy. Eight articles addressed sleep disorders related to CD; two explored Electroencephalography changes; one investigated Brain-Derived Neurotrophic Factor serum levels and one correlated vagotomy with CD.

CONCLUSION: Interest in the link between CD and GBA is increasing, but studies remain varied and inconclusive, spanning from epidemiology to brain imaging and neglecting to investigate a mechanistic relationship. This SR underscores the need for further research to better understand the potential role of GBA in the prognosis and etiology of CD, highlighting its complexity.}, } @article {pmid39544700, year = {2024}, author = {Parnianpour, P and Steinbach, R and Buchholz, IJ and Grosskreutz, J and Kalra, S}, title = {T1-weighted MRI texture analysis in amyotrophic lateral sclerosis patients stratified by the D50 progression model.}, journal = {Brain communications}, volume = {6}, number = {6}, pages = {fcae389}, pmid = {39544700}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis, a progressive neurodegenerative disease, presents challenges in predicting individual disease trajectories due to its heterogeneous nature. This study explores the application of texture analysis on T1-weighted MRI in patients with amyotrophic lateral sclerosis, stratified by the D50 disease progression model. The D50 model, which offers a more nuanced representation of disease progression than traditional linear metrics, calculates the sigmoidal curve of functional decline and provides independent quantifications of disease aggressiveness and accumulation. In this research, a representative cohort of 116 patients with amyotrophic lateral sclerosis was studied using the D50 model and texture analysis on MRI images. Texture analysis, a technique used for quantifying voxel intensity patterns in MRI images, was employed to discern alterations in brain tissue associated with amyotrophic lateral sclerosis. This study examined alterations of the texture feature autocorrelation across sub-groups of patients based on disease accumulation, aggressiveness and the first site of onset, as well as in direct regressions with accumulation/aggressiveness. The findings revealed distinct patterns of the texture-derived autocorrelation in grey and white matter, increase in bilateral corticospinal tract, right hippocampus and left temporal pole as well as widespread decrease within motor and extra-motor brain regions, of patients stratified based on their disease accumulation. Autocorrelation alterations in grey and white matter, in clusters within the left cingulate gyrus white matter, brainstem, left cerebellar tonsil grey matter and right inferior fronto-occipital fasciculus, were also negatively associated with disease accumulation in regression analysis. Otherwise, disease aggressiveness correlated with only two small clusters, within the right superior temporal gyrus and right posterior division of the cingulate gyrus white matter. The findings suggest that texture analysis could serve as a potential biomarker for disease stage in amyotrophic lateral sclerosis, with potential for quick assessment based on using T1-weighted images.}, } @article {pmid39542176, year = {2024}, author = {Tian, Z and Zhang, Q and Wang, L and Li, M and Li, T and Wang, Y and Cao, Z and Jiang, X and Luo, P}, title = {Progress in the mechanisms of pain associated with neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {102}, number = {}, pages = {102579}, doi = {10.1016/j.arr.2024.102579}, pmid = {39542176}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Pain/physiopathology/metabolism/etiology ; Animals ; Neuroinflammatory Diseases ; }, abstract = {Neurodegenerative diseases (NDDs) represent a class of neurological disorders characterized by the progressive degeneration or loss of neurons, impacting millions of individuals globally. In addition to the typical manifestations, pain is a prevalent symptom associated with NDDs, seriously impacting the quality of life for patients. The pathogenesis of pain associated with NDDs is intricate and multifaceted. Currently, the clinical management of NDDs-related pain symptoms predominantly relies on conventional pharmacological agents or physical therapy. However, these approaches often fail to produce satisfactory outcomes. This article summarizes the underlying mechanisms of major NDDs-associated pain: Neuroinflammation, Brain and spinal cord dysfunctions, Mitochondrial dysfunction, Risk gene and pathological protein, as well as Receptor, channel, and neurotransmitter. While numerous studies have investigated the downstream pathological processes associated with these mechanisms, there remains a significant gap in identifying the key initiating factors. Specifically, there is insufficient evidence for the upstream elements that activate microglia and astrocytes in neuroinflammation leading to pain in NDDs. Likewise, there is an absence of upstream factors elucidating how dysfunctions in the brain and spinal cord, as well as mitochondrial impairments, contribute to the development of pain. Furthermore, the specific mechanisms through which hallmark pathological proteins related to NDDs contribute to these pathological processes remain inadequately understood. The objective of this article is to synthesize the existing mechanisms underlying pain associated with NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, Schizophrenia, Amyotrophic lateral sclerosis, and Multiple sclerosis, while also identifying gaps and deficiencies in these mechanisms. This paper offers insights for future research trajectories. Given the intricate pathogenesis of NDDs-related pain, it emphasizes that a promising short-term strategy is combination therapy-intervening concurrently in multiple pathological processes-akin to the cocktail approach utilized in treating acquired immunodeficiency syndrome (AIDS). For long-term advancements, achieving breakthroughs in the treatment of the NDDs themselves will remain essential for alleviating accompanying pain symptoms.}, } @article {pmid39542047, year = {2024}, author = {Ghaderi, S and Fatehi, F and Kalra, S and Okhovat, AA and Nafissi, S and Mohammadi, S and Batouli, SAH}, title = {Metabolite alterations in the left dorsolateral prefrontal cortex and its association with cognitive assessments in amyotrophic lateral sclerosis: A longitudinal magnetic resonance spectroscopy study.}, journal = {Brain research bulletin}, volume = {219}, number = {}, pages = {111125}, doi = {10.1016/j.brainresbull.2024.111125}, pmid = {39542047}, issn = {1873-2747}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging ; Male ; Female ; Middle Aged ; *Magnetic Resonance Spectroscopy/methods ; Longitudinal Studies ; Aged ; *Cognition/physiology ; *Dorsolateral Prefrontal Cortex/metabolism ; Choline/metabolism ; Creatine/metabolism ; Neuropsychological Tests ; Adult ; Cognitive Dysfunction/metabolism/diagnostic imaging ; Aspartic Acid/analogs & derivatives/metabolism ; Prefrontal Cortex/metabolism/diagnostic imaging ; }, abstract = {OBJECTIVE: To characterize the longitudinal metabolite profile of the left dorsolateral prefrontal cortex (DLPFC) in amyotrophic lateral sclerosis (ALS) using magnetic resonance spectroscopy (MRS) and to examine its correlation with cognitive assessments.

METHODS: Thirteen patients at baseline and ten at follow-up, along with 14 age-, sex-, and handedness-matched healthy controls (HCs), were recruited. Three Tesla with a 64-channel coil, Point-RESolved Spectroscopy (PRESS) sequence (TR=1500 ms and TE=140 ms) was used. Metabolites in the left DLPFC were quantified using LCModel. Cognitive performance and functional impairment were assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) and Revised ALS Functional Rating Scale (ALSFRS-R), respectively. Group comparisons were adjusted for multiple comparisons (p < 0.05, Bonferroni correction). The links between the brain metabolites and cognitive function were investigated using relevant correlation tests (Pearson's or Spearman's).

RESULTS: Our analysis revealed a significant difference in the choline-to-creatine ratio (tCho/tCr) among the three groups. Baseline ALS patients showed a higher tCho/tCr ratio than HCs (p = 0.033, Bonferroni-corrected). Interestingly, the total N-acetyl aspartate (tNAA)/tCr ratio, a marker of neuronal health, was strongly positively correlated with visuospatial cognitive scores at baseline and follow-up. Furthermore, at follow-up, tNAA/tCr was positively correlated with the total scores and specific sub-scores on the ECAS, encompassing both ALS-specific and non-specific cognitive domains. At follow-up, positive correlations emerged between tNAA/tCr and the total language and executive function scores.

CONCLUSIONS: Metabolite alterations and correlations with cognition were observed in the left DLPFC of ALS patients, supporting extra-motor involvement and its association with cognitive decline.}, } @article {pmid39541975, year = {2025}, author = {Márquez-Moñino, MÁ and Santiveri, CM and de León, P and Camero, S and Campos-Olivas, R and Jiménez, MÁ and Sáiz, M and González, B and Pérez-Cañadillas, JM}, title = {The ALS drug riluzole binds to the C-terminal domain of SARS-CoV-2 nucleocapsid protein and has antiviral activity.}, journal = {Structure (London, England : 1993)}, volume = {33}, number = {1}, pages = {39-50.e6}, doi = {10.1016/j.str.2024.10.025}, pmid = {39541975}, issn = {1878-4186}, mesh = {*SARS-CoV-2/drug effects/metabolism ; *Antiviral Agents/pharmacology/chemistry ; Binding Sites ; Humans ; *Riluzole/pharmacology/chemistry/metabolism ; *Protein Binding ; Crystallography, X-Ray ; Coronavirus Nucleocapsid Proteins/chemistry/metabolism ; Phosphoproteins/metabolism/chemistry ; Protein Domains ; COVID-19 Drug Treatment ; Models, Molecular ; }, abstract = {Nucleoproteins (N) play an essential role in virus assembly and are less prone to mutation than other viral structural proteins, making them attractive targets for drug discovery. Using an NMR fragment-based drug discovery approach, we identified the 1,3-benzothiazol-2-amine (BZT) group as a scaffold to develop potential antivirals for SARS-CoV-2 nucleocapsid (N) protein. A thorough characterization of BZT derivatives using NMR, X-ray crystallography, antiviral activity assays, and intrinsic fluorescence measurements revealed their binding in the C-terminal domain (CTD) domain of the N protein, to residues Arg 259, Trp 330, and Lys 338, coinciding with the nucleotide binding site. Our most effective compound exhibits a slightly better affinity than GTP and the ALS drug riluzole, also identified during the screening, and displays notable viral inhibition activity. A virtual screening of 218 BZT-based compounds revealed a potential extended binding site that could be exploited for the future development of new SARS-CoV-2 antivirals.}, } @article {pmid39541203, year = {2024}, author = {Russo, A and Maiorano, G and Cortese, B and D'Amone, S and Invidia, A and Quattrini, A and Romano, A and Gigli, G and Palamà, IE}, title = {Optimizing TDP-43 silencing with siRNA-loaded polymeric nanovectors in neuronal cells for therapeutic applications: balancing knockdown and function.}, journal = {Nanoscale}, volume = {16}, number = {48}, pages = {22337-22349}, doi = {10.1039/d4nr03159h}, pmid = {39541203}, issn = {2040-3372}, mesh = {*DNA-Binding Proteins/metabolism/genetics/chemistry ; *RNA, Small Interfering/chemistry/metabolism ; Humans ; *Neurons/metabolism/pathology ; Amyotrophic Lateral Sclerosis/therapy/metabolism/pathology/genetics ; Polymers/chemistry ; Nanoparticles/chemistry ; Gene Knockdown Techniques ; Cell Line, Tumor ; Gene Silencing ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a ubiquitously expressed DNA/RNA binding protein critical for regulating gene expression, including transcription, splicing, mRNA stability, and protein translation. Aggregation of pathological TDP-43 proteins in the cytoplasm of neurons and glial cells appears to be a common feature of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases such as frontotemporal dementia (FTD), contributing to motor neuron degeneration and clinical symptoms. Downregulation of TDP-43 expression to prevent or reduce the formation of pathological aggregates is a potential therapeutic approach for treating TDP-43-related diseases. However, therapeutic strategies to reduce TDP-43 aggregation face significant challenges, as the downregulation of TDP-43 must balance the need to maintain its normal functions, which are essential for RNA metabolism and cellular homeostasis. In this study, we developed novel polymeric nanovectors for the delivery of TDP-43 siRNAs in neuronal cells. These nanovectors were designed to provide adequate TDP-43 silencing to achieve the desired functional reduction of TDP-43 levels, thereby optimizing its impact on cellular functions. Our results demonstrate that the polymeric nanovector formulations effectively reduced TDP-43 mRNA and protein levels to an extent comparable to those observed with traditional lipid-based systems. Concurrently, the polymeric nanovectors exhibited an enhanced capacity to reduce stress granules (SG) formation and facilitate TDP-43-containing SG disassembly, while preserving its essential cellular functions. This study provides the first evidence that polymeric nanovectors may be a valuable tool for developing therapeutic strategies to treat TDP-43 protein diseases, such as ALS and FTD, by directly silencing TDP-43 to reduce its aggregation.}, } @article {pmid39539269, year = {2024}, author = {Risen, S and Sharma, S and Gilberto, VS and Brindley, S and Aguilar, M and Brown, JM and Chatterjee, A and Moreno, JA and Nagpal, P}, title = {Large- and Small-Animal Studies of Safety, Pharmacokinetics, and Biodistribution of Inflammasome-Targeting Nanoligomer in the Brain and Other Target Organs.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {11}, pages = {3439-3451}, pmid = {39539269}, issn = {2575-9108}, abstract = {Immune malfunction or misrecognition of healthy cells and tissue, termed autoimmune disease, is implicated in more than 80 disease conditions and multiple other secondary pathologies. While pan-immunosuppressive therapies like steroids can offer limited relief for systemic inflammation for some organs, many patients never achieve remission, and such drugs do not cross the blood-brain barrier, making them ineffective for tackling neuroinflammation. Especially in the brain, unintended activation of microglia and astrocytes is hypothesized to be directly or indirectly responsible for multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Recent studies have also shown that targeting inflammasomes and specific immune targets can be beneficial for these diseases. Furthermore, our previous studies have shown targeting NF-κB and NLRP3 through brain penetrant Nanoligomer cocktail SB_NI_112 (abbreviated as NI112) can be therapeutic for several neurodegenerative diseases. Here, we show safety-toxicity studies, followed by pharmacokinetics and biodistribution in small- (mice) and large-animal (dog) studies of this inflammasome-targeting Nanoligomer cocktail NI112. We conducted studies using four different routes of administration: intravenous, subcutaneous, intraperitoneal, and intranasal, and identified the drug concentration over time using inductively coupled plasma mass spectrometry in the blood serum, the brain (including different brain regions), and other target organs such as liver, kidney, and colon. Our results indicate that the Nanoligomer cocktail has a strong safety profile and shows high biodistribution (F ∼ 0.98) and delivery across multiple routes of administration. Further analysis showed high brain bioavailability with a ratio of NI112 in brain tissue to blood serum of ∼30%. Our model accurately shows dose scaling, translation between different routes of administration, and interspecies scaling. These results provide an excellent platform for human clinical translation and prediction of therapeutic dosage between different routes of administration.}, } @article {pmid39538364, year = {2025}, author = {Terra, R and Éthier, V and Busque, L and Morin-Quintal, A and D'Angelo, G and Hébert, J and Wang, X and Lépine, G and LeBlanc, R and Bergeron, J}, title = {Improved identification of clinically relevant Acute Leukemia subtypes using standardized EuroFlow panels versus non-standardized approach.}, journal = {Cytometry. Part B, Clinical cytometry}, volume = {108}, number = {2}, pages = {116-127}, doi = {10.1002/cyto.b.22213}, pmid = {39538364}, issn = {1552-4957}, support = {//BD Biosciences/ ; }, mesh = {Humans ; *Flow Cytometry/methods ; *Immunophenotyping/methods ; *Leukemia, Myeloid, Acute/diagnosis/pathology ; Adult ; Male ; Female ; Middle Aged ; Aged ; Dendritic Cells/pathology ; Adolescent ; Young Adult ; Aged, 80 and over ; Cell Differentiation ; Child ; Mutation/genetics ; }, abstract = {Rare acute leukemia (AL) components or subtypes such as blastic plasmacytoid dendritic cell neoplasm (BPDCN) or early T-cell precursor acute Lymphoblastic Leukemia (ETP-ALL) can be difficult to detect by routine flow cytometry due to their immunophenotypes overlapping with other poorly differentiated AL. We hypothesized that using standardized EuroFlow™ Consortium approach could better diagnose such entities among cases that previously classified as acute myeloid leukemia (AML)-M0, AML with minimal differentiation, AML with myelodysplasia-related changes without further lineage differentiation, and AL of ambiguous lineage. In order to confirm this hypothesis and assess whether these AL subtypes such as BPDCN and ETP-ALL had previously gone undetected, we reanalyzed 49 banked cryopreserved sample cases using standardized EuroFlow™ Consortium panels. We also performed target sequencing to capture the mutational commonalities between these AL subtypes. Reanalysis led to revised or refined diagnoses for 23 cases (47%). Of these, five diagnoses were modified, uncovering 3 ETP-ALL and 2 typical BPDCN cases. In 12 AML cases, a variable proportion of immature plasmacytoid dendritic cell and/or monocytic component was newly identified. In one AML case, we have identified a megakaryoblastic differentiation. Finally, in five acute lymphoblastic leukemia (ALL) cases, we were able to more precisely determine the maturation stage. The application of standardized EuroFlow flow cytometry immunophenotyping improves the diagnostic accuracy of ALs and could impact treatment decisions.}, } @article {pmid39538124, year = {2024}, author = {Sun, Y and Hu, S and Lan, Y and Wang, R and Wei, S and Huang, H and Cui, H and Li, X and Huang, Z}, title = {Investigation of resistance mechanisms to flucarbazone-sodium in wild oat (Avena fatua L.) from China.}, journal = {BMC plant biology}, volume = {24}, number = {1}, pages = {1073}, pmid = {39538124}, issn = {1471-2229}, mesh = {*Avena/genetics/drug effects ; China ; Herbicide Resistance/genetics ; Herbicides/pharmacology ; Plant Proteins/genetics/metabolism ; Gene Expression Regulation, Plant/drug effects ; Plant Weeds/genetics/drug effects ; }, abstract = {BACKGROUND: Wild oat (Avena fatua L.) is a self-pollinating, allohexaploid species in the family Gramineae (grasses), which is a malignant weed that mainly harms crops such as wheat. In recent years, a decline in the control efficiency of flucarbazone-sodium against wild oat has occurred in some regions of China.

RESULTS: We identified an ALS-resistant A. fatua population (R population). Whole-plant response assays revealed that the R population exhibited a moderate level of resistance (5.9-fold) to flucarbazone-sodium. Pre-treatment with malathion significantly reduced flucarbazone-sodium resistance in the R population. The known mutation sites and ALS gene relative expression that confer resistance to ALS inhibitor herbicides were not found in R population. Following flucarbazone-sodium treatment, the expression of eight genes related to metabolic enzymes was investigated using quantitative real-time PCR (qRT-PCR). CYP92A6 and the Aldo/keto reductase family were highly expressed in the R population after the application of flucarbazone-sodium.

CONCLUSIONS: The mechanism of flucarbazone-sodium resistance in A. fatua is mediated by NTSR, nor TSR. Two genes, CYP92A6 and the Aldo/keto reductase family, were discovered to be possibly related in the metabolism of NTSR in the A. fatua population, justifying more functional studies. The results will serve as a data resource for further studies on the molecular mechanisms of A. fatua to flucarbazone-sodium.}, } @article {pmid39537536, year = {2025}, author = {Zou, J and Meng, X and Hong, Z and Rao, Y and Wang, K and Li, J and Yu, H and Wang, C}, title = {Cas9-PE: a robust multiplex gene editing tool for simultaneous precise editing and site-specific random mutation in rice.}, journal = {Trends in biotechnology}, volume = {43}, number = {2}, pages = {433-446}, doi = {10.1016/j.tibtech.2024.10.012}, pmid = {39537536}, issn = {1879-3096}, mesh = {*CRISPR-Associated Protein 9/genetics/metabolism ; *Gene Editing/instrumentation/methods ; *Oryza/genetics ; Mutation ; *Mutagenesis, Site-Directed ; Acetolactate Synthase/genetics ; Herbicide Resistance/genetics ; }, abstract = {In molecular design breeding, the simultaneous introduction of desired functional genes through specific nucleotide modifications and the elimination of genes regulating undesired phenotypic traits or agronomic components require advanced gene editing tools. Due to limited editing efficiency, even with the use of highly precise editing tools, such as prime editing (PE), simultaneous editing of multiple mutation types poses a challenge. Here, we replaced Cas9 nickase (nCas9) with Cas9 to construct a Cas9-mediated PE (Cas9-PE) system in rice. This system not only enables precise editing, but also allows for site-specific random mutation. Moreover, leveraging the precision of Cas9-PE, we established a transgene-free multiplex gene editing system using a co-editing strategy. This strategy involved the Agrobacterium-mediated transient expression of the precise editing rice endogenous acetolactate synthase gene ALS[S627I] to confer herbicide bispyribac-sodium (BS) resistance as a selection marker. This study provides a versatile and efficient multiplex gene editing tool for molecular design breeding.}, } @article {pmid39536963, year = {2025}, author = {Casiraghi, V and Sorce, MN and Santangelo, S and Invernizzi, S and Bossolasco, P and Lattuada, C and Battaglia, C and Venturin, M and Silani, V and Colombrita, C and Ratti, A}, title = {Modeling of TDP-43 proteinopathy by chronic oxidative stress identifies rapamycin as beneficial in ALS patient-derived 2D and 3D iPSC models.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {115057}, doi = {10.1016/j.expneurol.2024.115057}, pmid = {39536963}, issn = {1090-2430}, mesh = {Humans ; *Induced Pluripotent Stem Cells/drug effects ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/drug therapy ; *Oxidative Stress/drug effects/physiology ; *Sirolimus/pharmacology ; *TDP-43 Proteinopathies/pathology/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Arsenites/toxicity/pharmacology ; Sodium Compounds/toxicity/pharmacology ; Motor Neurons/drug effects/metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized neuropathologically by TDP-43 proteinopathy with loss of TDP-43 nuclear splicing activity and formation of cytoplasmic TDP-43 aggregates. The lack of suitable experimental models of TDP-43 proteinopathy has hampered the discovery of effective therapies. We already showed that chronic and mild oxidative insult by sodium arsenite (ARS) triggered TDP-43 cytoplasmic aggregation and stress granules (SGs) formation in ALS patient-derived fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs). However, whether this insult induces a reduction of TDP-43 splicing activity in the nucleus, thus recapitulating both gain and loss of function pathomechanisms, still remains to be determined. In this study we first showed that chronic ARS in human neuroblastoma cells triggered TDP-43 cytoplasmic mislocalization, SGs formation and defective splicing of TDP-43 target genes UNC13A and POLDIP3 as functional readouts of TDP-43 proteinopathy. Additionally, a dysregulation of autophagy and senescence markers was observed in this condition. In a preliminary drug screening approach with autophagy-promoting drugs, namely rapamycin, lithium carbonate and metformin, only rapamycin prevented ARS-induced loss of TDP-43 splicing activity. We then demonstrated that, in addition to TDP-43 cytoplasmic aggregation, chronic ARS triggered TDP-43 loss of splicing activity also in ALS patient-derived primary fibroblasts and iPSC-MNs and that rapamycin was beneficial to reduce these TDP-43 pathological features. By switching to a neuro-glial 3D in vitro model, we observed that treatment of ALS iPSC-brain organoids with chronic ARS also induced a defective TDP-43 splicing activity which was prevented by rapamycin. Collectively, we established different human cell models of TDP-43 proteinopathy which recapitulate TDP-43 gain and loss of function, prevented by rapamycin administration. Human neuroblastoma cells and patient-derived fibroblasts and 2D- and 3D-iPSC models exposed to chronic oxidative stress represent therefore suitable in vitro platforms for future drug screening approaches in ALS.}, } @article {pmid39536438, year = {2024}, author = {Henderson, NL and Ortiz-Olguin, E and Bourne, G and Pywell, C and Rose, JB and Williams, GR and Nipp, RD and Rocque, GB}, title = {Implementation of ePROs Into Multidisciplinary Tumor Board Discussions for Patients With Pancreatic Cancer: The INSPIRE Intervention.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {9}, pages = {602-609}, doi = {10.6004/jnccn.2024.7052}, pmid = {39536438}, issn = {1540-1413}, mesh = {Humans ; *Pancreatic Neoplasms/therapy ; Female ; Male ; *Patient Reported Outcome Measures ; Aged ; Middle Aged ; Patient Care Team/standards ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: The incorporation of electronic patient-reported outcomes (ePROs), such as the Geriatric Assessment (GA) and treatment preferences, into decision-making for pancreatic cancer has been limited by clinician- and system-level barriers concerning workflow. We hypothesized that ePRO inclusion within multidisciplinary tumor boards (MDTBs) would circumvent barriers and provide a venue for systematic consideration of critical patient-provided information.

PATIENTS AND METHODS: The INtegrating Systematic PatIent-Reported Evaluations (INSPIRE) intervention consists of (1) patient survey completion, including GA and patient preferences, and (2) screensharing patient ePROs during MDTBs. Proctor et al's implementation outcomes were assessed, with penetration (the proportion of consented patients who were presented at MDTBs) acting as the primary outcome (considered successful at 70%). Secondary outcomes included adoption, feasibility, acceptability, appropriateness, cost, and sustainability, assessed by clinician post-MDTB exit surveys, clinician postintervention surveys, clinician postintervention semistructured interviews, and time-coding analysis of recorded and transcribed historical (November 2021-February 2022) and intervention (September 2022-June 2023) MDTBs.

RESULTS: A total of 50 patients completed surveys and all were presented at MDTBs (penetration=100%). All eligible clinicians (n=9) enrolled patients (adoption=100%) and reported that ePROs were useful in 90% and led to a change in treatment plan in 30% of cases. In postintervention surveys and interviews, clinicians primarily responded positively to feasibility, acceptability, and appropriateness questions. Time-coding analysis found a modest time cost of an additional 51.1 seconds in mean discussion time-per-patient between preintervention (mean [SD], 172.7 [111.4] seconds) and intervention patients (mean [SD], 223.8 [107.1] seconds); 86% of clinicians reported the intervention did not take too much time. All surveyed clinicians reported interest in continuing the intervention and suggested adaptations to further promote sustainability.

CONCLUSIONS: The integration of ePROs into pancreatic MDTBs was feasible and acceptable, providing a potential approach to increase the utilization of ePROs by clinical teams in their management of patients with pancreatic cancer.}, } @article {pmid39535960, year = {2024}, author = {Soares, RV and Pedrosa, RBDS and Sandars, J and Cecilio-Fernandes, D}, title = {The importance of combined use of spacing and testing effects for complex skills training: A quasi-experimental study.}, journal = {Medical teacher}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/0142159X.2024.2427735}, pmid = {39535960}, issn = {1466-187X}, abstract = {INTRODUCTION: A major challenge is retention of complex clinical skills. Spacing training and testing have been demonstrated to increase knowledge and skill retention but the combination has not been previously investigated in complex clinical skills. The aim of our study was to compare the effectiveness of combined spacing and testing for Basic Life Support (BLS) and Advance Life Support (ALS) simulation training in one group (intervention group), with combined spacing and testing, and another group (control) that received simulation training in a single-session simulation training without testing.

METHODS: A quasi-experimental study.

RESULTS: Thirteen nursing students were in the intervention group and 18 in the control group. After three months, there was no significant reduction in retention of BLS knowledge (p > 0.05) or BLS skills (p < 0.05) in the intervention group, but there was a significant reduction in both (p < 0.05) in the control group. We found no significant reduction in retention of ALS knowledge in the control group (p > 0.05), but there was a significant reduction in the intervention group (p < 0.05). There was no significant decay of ALS skills in both groups (p < 0.05).

DISCUSSION: This is the first study to demonstrate that combined spacing and testing could be highly effective for complex skills simulation training to increase retention after three months.}, } @article {pmid39535924, year = {2024}, author = {Hannestad, J and Smith, S and Lam, A and Hurt, J and Harada, N and Kim, R and Das, A and Brunello, J and Whitaker, G and Chalmers, D and Senjoti, F and Lin, W and Coghill, J and Bansal, Y and Sidhu, S and Zann, V and Liu, E}, title = {A randomized, placebo-controlled first-in-human study of oral TQS-168 in healthy volunteers: Assessment of safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect.}, journal = {Clinical and translational science}, volume = {17}, number = {11}, pages = {e70064}, pmid = {39535924}, issn = {1752-8062}, mesh = {Humans ; Male ; *Food-Drug Interactions ; Adult ; Administration, Oral ; *Healthy Volunteers ; Young Adult ; Middle Aged ; Area Under Curve ; Double-Blind Method ; Dose-Response Relationship, Drug ; Methylcellulose/administration & dosage/analogs & derivatives/chemistry ; Spray Drying ; Suspensions ; Cross-Over Studies ; Placebos/administration & dosage ; }, abstract = {TQS-168, a first-in-class small-molecule inducer of peroxisome proliferator-activated receptor gamma coactivator 1-alpha gene expression, is in development for the treatment of amyotrophic lateral sclerosis. A single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study of TQS-168 was carried out in healthy male subjects to investigate safety, tolerability, pharmacokinetics (PK), food effect, and preliminary pharmacodynamic effects (PD). Since solubility enhancement could be beneficial, assessment of three formulations was incorporated into the study using an integrated rapid manufacturing and clinical testing approach. Dosing in the SAD part was initiated with a crystalline methylcellulose (MC) suspension, and then spray-dried dispersion (SDD) and hot-melt extrusion (HME) suspensions were evaluated. The HME and SDD formulations showed two and fourfold higher exposure than the MC suspension, respectively, and the SDD formulation was selected for progression to subsequent SAD and MAD cohorts, in which there was further investigation of the food effect on exposure in addition to assessments of safety, tolerability, PK, and PD. Cmax and AUC plasma exposures of TQS-168 were supra-proportional at higher doses, irrespective of formulation. Median Tmax for TQS-168 occurred between 0.5 and 4.0 h post-dose and occurred later with higher doses. Geometric mean half-lives (T1/2) for TQS-168 were independent of formulation and food, ranging from 3.2 to 10.5 h following single doses and 4.1 to 7.3 h following multiple doses. Food blunted TQS-168 Cmax but had minimal impact on AUC. TQS-168 was considered to be safe and generally well tolerated following single and multiple oral doses. The SDD formulation was selected for future patient studies.}, } @article {pmid39534418, year = {2024}, author = {Wang, WL and Tam, PKH and Chen, Y}, title = {Abnormally activated wingless/integrated signaling modulates tumor-associated macrophage polarization and potentially promotes hepatocarcinoma cell growth.}, journal = {World journal of gastroenterology}, volume = {30}, number = {41}, pages = {4490-4495}, pmid = {39534418}, issn = {2219-2840}, mesh = {Humans ; *Carcinoma, Hepatocellular/pathology/metabolism ; *Liver Neoplasms/pathology/metabolism ; *Tumor-Associated Macrophages/metabolism/immunology ; *Cell Proliferation ; *Wnt Signaling Pathway ; *Tumor Microenvironment ; Cell Movement ; Animals ; Disease Progression ; Macrophage Activation ; }, abstract = {In this article, we comment on the article by Huang et al. The urgent development of new therapeutic strategies targeting macrophage polarization is critical in the fight against liver cancer. Tumor-associated macrophages (TAMs), primarily of the M2 subtype, are instrumental in cellular communication within the tumor microenvironment and are influenced by various signaling pathways, including the wingless/integrated (Wnt) pathway. Activation of the Wnt signaling pathway is pivotal in promoting M2 TAMs polarization, which in turn can exacerbate hepatocarcinoma cell proliferation and migration. This manuscript emphasizes the burgeoning significance of the Wnt signaling pathway and M2 TAMs polarization in the pathogenesis and progression of liver cancer, highlighting the potential therapeutic benefits of inhibiting the Wnt pathway. Lastly, we point out areas in Huang et al's study that require further research, providing guidance and new directions for similar studies.}, } @article {pmid39525702, year = {2024}, author = {Ravichandran, VV and Coleman, E and Brown, A and Boh, E}, title = {Response to Rodríguez-Cuadrado et al's "Clinical, histopathologic, immunohistochemical, and electron microscopic findings in cutaneous monkeypox: A multicenter retrospective case series in Spain".}, journal = {JAAD case reports}, volume = {53}, number = {}, pages = {149-150}, pmid = {39525702}, issn = {2352-5126}, } @article {pmid39524179, year = {2024}, author = {Trinh, QD and Mai, HN and Pham, DT}, title = {Application of mesenchymal stem cells for neurodegenerative diseases therapy discovery.}, journal = {Regenerative therapy}, volume = {26}, number = {}, pages = {981-989}, pmid = {39524179}, issn = {2352-3204}, abstract = {Neurodegenerative diseases are central or peripheral nervous system disorders associated with progressive brain cell degeneration. Common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis have been widely studied. However, current therapeutics only reduce the symptoms and do not ameliorate the pathogenesis of these diseases. Recent studies suggested the roles of neuroinflammation, apoptosis, and oxidative stress in neurodegenerative diseases. Mesenchymal stem cells (MSCs) exert anti-apoptotic, anti-inflammatory, and antioxidative effects. Therefore, investigating the effects of MSCs and their applications may lead to the discovery of more effective therapies for neurodegenerative diseases. In this study, we review different approaches used to identify therapies for neurodegenerative diseases using MSCs.}, } @article {pmid39534515, year = {2024}, author = {Watanabe, S and Sekiguchi, K and Suehiro, H and Yoshikawa, M and Noda, Y and Kamiyama, N and Matsumoto, R}, title = {Decreased diaphragm moving distance measured by ultrasound speckle tracking reflects poor prognosis in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology practice}, volume = {9}, number = {}, pages = {252-260}, pmid = {39534515}, issn = {2467-981X}, abstract = {OBJECTIVE: Decreased cephalocaudal diaphragm movement may indicate respiratory dysfunction in amyotrophic lateral sclerosis (ALS). We aimed to evaluate diaphragm function in ALS using ultrasound speckle tracking, an image-analysis technology that follows similar pixel patterns.

METHODS: We developed an offline application that tracks pixel patterns of recorded ultrasound video images using speckle-tracking methods. Ultrasonography of the diaphragm movement during spontaneous quiet respiration was performed on 19 ALS patients and 21 controls to measure the diaphragm moving distance (DMD) in the cephalocaudal direction during a single respiration. We compared respiratory function measures and analyzed the relationship between the clinical profiles and DMD.

RESULTS: DMD was significantly lower in ALS patients than in the control group (0.6 ± 1.4 mm vs 2.2 ± 2.2 mm, p < 0.01) and positively correlated with phrenic nerve compound motor action potential amplitude (R = 0.63, p = 0.01). DMD was negatively correlated with the change in the ALS Functional Rating Scale-Revised scores per month after the exam (R = -0.61, p = 0.02), and those with a larger rate of decline had a significantly lower DMD (p = 0.03).

CONCLUSIONS: Diaphragm ultrasound speckle tracking enabled the detection of diaphragm dysfunction in ALS.

SIGNIFICANCE: Diaphragm ultrasound speckle tracking may be useful for predicting prognosis.}, } @article {pmid39534483, year = {2024}, author = {Sbarigia, C and Rome, S and Dini, L and Tacconi, S}, title = {New perspectives of the role of skeletal muscle derived extracellular vesicles in the pathogenesis of amyotrophic lateral sclerosis: the 'dying back' hypothesis.}, journal = {Journal of extracellular biology}, volume = {3}, number = {11}, pages = {e70019}, pmid = {39534483}, issn = {2768-2811}, abstract = {Amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord, and is characterized by muscle weakness, paralysis and ultimately, respiratory failure. The exact causes of ALS are not understood, though it is believed to combine genetic and environmental factors. Until now, it was admitted that motor neurons (MN) in the brain and spinal cord degenerate, leading to muscle weakness and paralysis. However, as ALS symptoms typically begin with muscle weakness or stiffness, a new hypothesis has recently emerged to explain the development of the pathology, that is, the 'dying back hypothesis', suggesting that this degeneration starts at the connections between MN and muscles, resulting in the loss of muscle function. Over time, this damage extends along the length of the MN, ultimately affecting their cell bodies in the spinal cord and brain. While the dying back hypothesis provides a potential framework for understanding the progression of ALS, the exact mechanisms underlying the disease remain complex and not fully understood. In this review, we are positioning the role of extracellular vesicles as new actors in ALS development.}, } @article {pmid39534022, year = {2024}, author = {Li, Y and Bhinge, A and Inoue, S and Garcia, G}, title = {Editorial: Noncoding RNAs in neurodegenerative disorders: from current insights and future directions to translational modeling and therapeutic approaches.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1497673}, pmid = {39534022}, issn = {1662-4548}, } @article {pmid39531950, year = {2025}, author = {Kacem, I and Sghaier, I and Ben Rhouma, H and Ratti, A and Ticozzi, N and Silani, V and Gouider-Khouja, N and Gouider, R}, title = {Association of Amyotrophic Lateral Sclerosis and Dopa-responsive dystonia in a Tunisian patient.}, journal = {Parkinsonism & related disorders}, volume = {130}, number = {}, pages = {107171}, doi = {10.1016/j.parkreldis.2024.107171}, pmid = {39531950}, issn = {1873-5126}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/complications ; *Dystonic Disorders/genetics/drug therapy ; GTP Cyclohydrolase/genetics ; Tunisia ; }, abstract = {Dopa-responsive dystonia (DRD) is an autosomal dominant disease with parkinsonian and dystonic symptoms caused by GCH1 gene pathogenic variants affecting dopamine synthesis. The present case report is the first to link DRD with childhood-onset with ALS, suggesting that complex inheritance patterns in the North African population may contribute to multiple disorders.}, } @article {pmid39531940, year = {2024}, author = {Pioro, EP and Brooks, BR and Liu, Y and Zhang, J and Apple, S}, title = {Efficacy of Radicava® IV (intravenous edaravone) in subjects with differing trajectories of disease progression in amyotrophic lateral sclerosis: Use of a novel statistical approach for post hoc analysis of a pivotal phase 3 clinical trial.}, journal = {Journal of the neurological sciences}, volume = {467}, number = {}, pages = {123290}, doi = {10.1016/j.jns.2024.123290}, pmid = {39531940}, issn = {1878-5883}, mesh = {Humans ; *Edaravone/therapeutic use/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Disease Progression ; Male ; Female ; Middle Aged ; Aged ; Treatment Outcome ; Double-Blind Method ; Free Radical Scavengers/therapeutic use/administration & dosage ; Administration, Intravenous ; }, abstract = {INTRODUCTION: Subjects with amyotrophic lateral sclerosis (ALS) treated with Radicava® (edaravone) IV (intravenous; Mitsubishi Tanabe Pharma America [MTPA], hereafter "MTPA IV edaravone") in Study MCI186-19 had a significantly slower physical functional decline vs placebo-treated subjects as measured by the revised ALS Functional Rating Scale (ALSFRS-R) and analyzed by the linear mixed model for repeated measures (MMRM). This Study 19 post hoc analysis of MTPA IV edaravone-treated and placebo-treated subjects evaluated linear and nonlinear latent class mixed models defining trajectories based on identifying the model with the lowest Bayesian information criterion. The best model differentiated 4 nonlinear trajectories in ALS subjects. ALSFRS-R total score in MTPA IV edaravone-treated and placebo-treated subjects was evaluated for these 4 nonlinear latent class trajectory groups.

METHODS: Disease trajectories of MCI186-19 MTPA IV edaravone-treated or placebo-treated ALS subjects who completed the double-blind period were investigated using latent class analysis (LCA) statistical models to identify potential unique nonlinear ALSFRS-R disease trajectories.

RESULTS: ALSFRS-R trajectories revealed 4 unique nonlinear trajectory latent classes per treatment group in MTPA IV edaravone-treated and placebo-treated ALS subjects completing the MCI186-19 double-blind period. Latent classes 2-4 had statistically significant slowing of ALSFRS-R total score decline in the predicted nonlinear trajectories of MTPA IV edaravone-treated vs placebo-treated ALS subjects.

CONCLUSIONS: This post hoc analysis suggests MTPA IV edaravone treatment results in slower ALSFRS-R decline vs placebo in most predicted nonlinear trajectories. LCA is a novel approach that may benefit future trial analyses.}, } @article {pmid39529471, year = {2025}, author = {Trojsi, F and Canna, A and Sharbafshaaer, M and di Nardo, F and Canale, F and Passaniti, C and Pirozzi, MA and Silvestro, M and Orologio, I and Russo, A and Cirillo, M and Tessitore, A and Siciliano, M and Esposito, F}, title = {Brain neurovascular coupling in amyotrophic lateral sclerosis: Correlations with disease progression and cognitive impairment.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16540}, pmid = {39529471}, issn = {1468-1331}, support = {NRRP project MNESYS (PE0000006, to NT)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Male ; Female ; *Disease Progression ; Middle Aged ; *Cognitive Dysfunction/physiopathology/etiology/diagnostic imaging ; Aged ; *Magnetic Resonance Imaging ; *Neurovascular Coupling/physiology ; Adult ; *Brain/physiopathology/diagnostic imaging/blood supply ; Nerve Net/diagnostic imaging/physiopathology ; Default Mode Network/physiopathology/diagnostic imaging ; }, abstract = {BACKGROUND AND PURPOSE: 'Neurovascular coupling' (NVC) alterations, assessing the interplay between local cerebral perfusion and neural activity within a given brain region or network, may reflect neurovascular unit impairment in amyotrophic lateral sclerosis (ALS). The aim was to explore NVC as a correlation between the functional connectivity and cerebral blood flow within the large-scale resting-state functional magnetic resonance imaging brain networks in a sample of ALS patients compared to healthy controls (HCs).

METHODS: Forty-eight ALS patients (30 males; mean age 60.64 ± 9.62 years) and 32 HC subjects (14 males; mean age 55.06 ± 16 years) were enrolled and underwent 3 T magnetic resonance imaging. ALS patients were screened by clinical and neuropsychological scales and were retrospectively classified as very fast progressors (VFPs), fast progressors and slow progressors (SPs).

RESULTS: Neurovascular coupling reduction within the default mode network (DMN) (p = 0.005) was revealed in ALS patients compared to HCs, observing, for this network, significant NVC differences between VFP and SP groups. Receiver operating characteristic curve analysis showed that impaired NVC in the DMN at baseline best discriminated VFPs and SPs (area under the curve 75%). Significant correlations were found between NVC and the executive (r = 0.40, p = 0.01), memory (r = 0.32, p = 0.04), visuospatial ability (r = 0.40, p = 0.01) and non-ALS-specific (r = 0.40, p = 0.01) subscores of the Edinburgh Cognitive and Behavioural ALS Screen.

CONCLUSIONS: The reduction of brain NVC in the DMN may reflect largely distributed abnormalities of the neurovascular unit. NVC alterations in the DMN could play a role in anticipating a faster clinical progression in ALS patients, aiding patient selection and monitoring during clinical trials.}, } @article {pmid39528814, year = {2024}, author = {Ovchinnikova, LA and Dzhelad, SS and Simaniv, TO and Zakharova, MN and Lomakin, YA and Gabibov, AG and Illarioshkin, SN}, title = {Development of a Panel of Biomarkers for Differential Diagnosis of Multiple Sclerosis.}, journal = {Doklady. Biochemistry and biophysics}, volume = {519}, number = {1}, pages = {593-596}, pmid = {39528814}, issn = {1608-3091}, mesh = {Humans ; *Multiple Sclerosis/diagnosis/metabolism/blood ; *Biomarkers/metabolism ; Diagnosis, Differential ; Female ; Male ; Adult ; Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Middle Aged ; Neuromyelitis Optica/diagnosis/metabolism ; }, abstract = {Demyelinating diseases are a group of heterogeneous pathologies that affect the nervous system and reduce the quality of life. One of such diseases is multiple sclerosis (MS), an inflammatory autoimmune neurodegenerative disease of the central nervous system (CNS). At the initial stages, MS can mimic some infectious, neoplastic, genetic, metabolic, vascular, and other pathologies. Accurate differential diagnosis of this disease is important to improve the quality of life of patients and reduce possible irreversible damage to the central nervous system. In this work, we confirmed the possibility of using our previously proposed candidate panel of MS biomarkers to distinguish MS from neuromyelitis optica spectrum disorder (NMOSD) and amyotrophic lateral sclerosis (ALS). We have shown that our proposed panel (SPTAN1601-644 + PRX451-494 + PTK6301-344 + LMP1285-330) allows us to distinguish MS from ALS (AUC = 0.796) and NMOSD (AUC = 0.779).}, } @article {pmid39526716, year = {2024}, author = {Šljivo, A and Jevtić, T and Siručić, I and Terzić-Salihbašić, S and Abdulkhaliq, A and Reiter, L and Salihbašić, F and Bečar-Alijević, A and Alijević, A and Dadić, I and Gavrankapetanović, F}, title = {Out-of-hospital cardiac arrest (OHCA) in Bosnia and Herzegovina in the period 2018-2022: current trends, usage of automated external defibrillators (AED) and bystanders' involvement.}, journal = {Medicinski glasnik : official publication of the Medical Association of Zenica-Doboj Canton, Bosnia and Herzegovina}, volume = {21}, number = {2}, pages = {267-273}, doi = {10.17392/1719-21-2}, pmid = {39526716}, issn = {1840-2445}, abstract = {AIM: To investigate out-of-hospital cardiac arrest (OHCA) trend, provided advanced life support (ALS) measures, automated external defibrillator (AEDs) utilization and bystanders' involvement in cardiopulmonary resuscitation (CPR) during OHCA incidents.

METHODS: This cross-sectional study encompassed data pertaining to all OHCA incidents attended to by the Emergency Medical Service of Canton Sarajevo, Bosnia and Herzegovina, covering the period from January 2018 to December 2022.

RESULTS: Among a total of 1131 OHCA events, 236 (20.8 %) patients achieved return of spontaneous circulation (ROSC); there were 175 (74.1%) males and 61 (25.9%) females. The OHCA incidence was 54/100,000 inhabitants per year. After a 30-day period post-ROSC, 146 (61.9%) patients fully recovered, while 90 (38.1%) did not survive during this timeframe. Younger age (p<0.05), initial rhythm of ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) (p<0.05), and faster emergency medical team (EMT) response time (p<0.05) were significantly associated with obtaining ROSC. Only 38 (3.3%) OHCA events were assisted by bystanders, who were mostly medical professionals, 25 (65.7%), followed by close family members, 13 (34.3%). There was no report of AED usage.

CONCLUSION: This follow-up study showed less ROSC achievement, similar bystanders' involvement, similar factors associated with achieving ROSC (age, EMT response time), and a decline in OHCA events (especially in year 2021 and 2022) compared to our previous study (2015-2019). There was an extremely low rate of bystander engagement and no AEDs usage. Governments and health organizations must swiftly improve public awareness, promote better practice (basic life support), and actively encourage bystander participation.}, } @article {pmid39523617, year = {2024}, author = {Iguchi, Y and Katsuno, M}, title = {[Current Status of Drug Development for Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1241-1249}, doi = {10.11477/mf.1416202766}, pmid = {39523617}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Drug Development ; Clinical Trials as Topic ; Animals ; Riluzole/therapeutic use ; Neuroprotective Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease of motor neuron. Although riluzole and edaravone have been approved for the treatment of ALS, it remains a lethal disease that causes rapid motor impairment, and there is an urgent need to develop more effective treatments. Advances in understanding the pathomechanisms of ALS, efficient clinical trial design, and research support programs have led to many clinical trials for ALS both domestically and internationally.}, } @article {pmid39523616, year = {2024}, author = {Ishiguro, T and Nagata, T and Yokota, T}, title = {[Current Landscape of Tofersen in SOD-1-associated Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1233-1239}, doi = {10.11477/mf.1416202765}, pmid = {39523616}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; Humans ; *Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Since the identification, in 1993, of the causative gene for familial amyotrophic lateral sclerosis (ALS), which is associated with SOD1 mutations, research has focused on the pathogenesis and therapeutics of ALS for more than 30 years. Tofersen, a highly anticipated gene-specific therapy that has been aligned with the disease-specific pathology, has been approved for marketing by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) However, as significant data on tofersen's safety and efficacy are required, the evaluation of this treatment is ongoing. This paper introduces the current clinical and commercial status of Tofersen, along with expectations for its approval in Japan.}, } @article {pmid39523615, year = {2024}, author = {Ogino, M}, title = {[Palliative Care for Persons with Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1225-1232}, doi = {10.11477/mf.1416202764}, pmid = {39523615}, issn = {1881-6096}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Analgesics, Opioid/administration & dosage ; Japan ; *Palliative Care ; }, abstract = {Palliative care in Japan is available mainly for patients with cancer, and palliative care specialists do not have sufficient experience with management of palliation in persons with amyotrophic lateral sclerosis (ALS). Treatment of ALS symptoms is an important component of palliative care, and it is important that neurologists and home care physicians familiarize themselves with palliative care for ALS in consultation with palliative care specialists. Notably, the use of opioids at the end of life differs from that of pain relief for cancer. Physicians should be mindful that opioids are not a perfect solution for palliative care of persons with ALS.}, } @article {pmid39523614, year = {2024}, author = {Yamakawa, I and Urushitani, M}, title = {[Gold Coast Criteria: A New Diagnostic Paradigm in the Era of Disease-Modifying Therapy for Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1217-1223}, doi = {10.11477/mf.1416202763}, pmid = {39523614}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Humans ; }, abstract = {Significant progress has been made in the development of disease-modifying drugs for amyotrophic lateral sclerosis (ALS), with the introduction of tofersen, an antisense oligonucleotide drug for familial ALS, marking a turning point in the treatment. These drugs are most effective when administered early in the disease course, highlighting the need for improved diagnostic sensitivity. The 2020 Gold Coast Diagnostic Criteria allow ALS diagnosis in cases without upper motor neuron symptoms, potentially increasing early detection rates. However, careful differential diagnoses are necessary when applying these criteria to maintain diagnostic specificity. This review outlines the key points to consider when using the Gold Coast Criteria, balancing the need for an early diagnosis with caution to avoid overdiagnosis.}, } @article {pmid39523613, year = {2024}, author = {Fukutake, T}, title = {[Diagnosis, Notification, and Managements of ALS: A Personal Perspective from 40 years of Experience as a Clinical Neurologist].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1205-1216}, doi = {10.11477/mf.1416202762}, pmid = {39523613}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Humans ; *Neurologists ; Female ; Middle Aged ; Male ; Aged ; }, abstract = {This narrative summary presents the author's 40-year experience as a clinical neurologist who treated patients with amyotrophic lateral sclerosis (ALS). Five representative cases from the author's first 20 years at Chiba University Hospital and its affiliated hospitals were selected, including a patient of respiratory-onset who was ignorantly extubated by a female relative for patient's distress to the intratracheal tube. Based on the latter 20 years of experience at the author's current hospital, the author first describes a famous patient with ALS who was being treated at this medical center before the author was assigned to this hospital and fought against ALS for 31 years before eventually succumbing to total locked-in syndrome. Thereafter, the author has summarized the ages, sex, phenotypes, comorbidities, responses to the available treatment options, and total number of years that have elapsed for the 24 patients that the author initially examined in the outpatient clinic. In terms of diagnostic delay, the author describes "foot drop" in patients who developed lower limb symptoms, and hoarseness in those who developed bulbar palsy. Furthermore, the author discusses issues regarding family caregiving capacity, patient's and families' understanding of notification, and medical management (i.e., medications, rehabilitation for ADL, nutrition and respiration, complications of frontotemporal dementia, and medical cooperation with other clinics and hospitals).}, } @article {pmid39522728, year = {2025}, author = {Lauck, KC and Narayanan, D and Tolkachjov, SN}, title = {Regarding response to Narayanan et al's "Adverse events in cemiplimab therapy for locally advanced or metastatic cSCC: A global propensity-matched retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e59-e60}, doi = {10.1016/j.jaad.2024.10.059}, pmid = {39522728}, issn = {1097-6787}, } @article {pmid39522725, year = {2025}, author = {Tsai, SY}, title = {Response to Narayanan et al's "Adverse events in cemiplimab therapy for locally advanced or metastatic cSCC: A global propensity-matched retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e57}, doi = {10.1016/j.jaad.2024.08.085}, pmid = {39522725}, issn = {1097-6787}, } @article {pmid39522723, year = {2025}, author = {Nardone, V and Esposito, A and D'Ippolito, E and Argenziano, G and Reginelli, A and Troiani, T}, title = {Response to Sajid et al's "Response to Valerio Nardone et al's 'Previous radiotherapy increases the efficacy of cemiplimab in the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma: A retrospective analysis'".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e55-e56}, doi = {10.1016/j.jaad.2024.10.058}, pmid = {39522723}, issn = {1097-6787}, } @article {pmid39522697, year = {2024}, author = {Gao, L and Yang, XN and Dong, YX and Han, YJ and Zhang, XY and Zhou, XL and Liu, Y and Liu, F and Fang, JS and Ji, JL and Gao, ZR and Qin, XM}, title = {The potential therapeutic strategy in combating neurodegenerative diseases: Focusing on natural products.}, journal = {Pharmacology & therapeutics}, volume = {264}, number = {}, pages = {108751}, doi = {10.1016/j.pharmthera.2024.108751}, pmid = {39522697}, issn = {1879-016X}, mesh = {Humans ; *Biological Products/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and Multiple sclerosis (MS), pose a significant global health challenge due to their intricate pathology and limited therapeutic interventions. Natural products represent invaluable reservoirs for combating these neurodegenerative diseases by targeting key pathological hallmarks such as protein aggregation, synaptic dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, inflammation, and neuronal cell death. This review provides an in-depth analysis of the mechanisms and therapeutic targets of natural products for their neuroprotective effects. Furthermore, it elucidates the current progress of clinical trials investigating the potential of natural products in delaying neurodegeneration. The objective of this review is to enhance the comprehension of natural products in the prevention and treatment of neurodegenerative diseases, offering new insights and potential avenues for future pharmaceutical research.}, } @article {pmid39522672, year = {2025}, author = {Shapiro, O and Woods, C and Gleixner, AM and Sannino, S and Ngo, M and McDaniels, MD and Wipf, P and Hukriede, NA and Donnelly, CJ and Brodsky, JL}, title = {Assays to measure small molecule Hsp70 agonist activity in vitro and in vivo.}, journal = {Analytical biochemistry}, volume = {697}, number = {}, pages = {115712}, pmid = {39522672}, issn = {1096-0309}, support = {U54 DK137329/DK/NIDDK NIH HHS/United States ; P30 DK079307/DK/NIDDK NIH HHS/United States ; R35 GM131732/GM/NIGMS NIH HHS/United States ; R21 NS133676/NS/NINDS NIH HHS/United States ; R01 NS127187/NS/NINDS NIH HHS/United States ; R01 NS105756/NS/NINDS NIH HHS/United States ; }, mesh = {*HSP70 Heat-Shock Proteins/metabolism/agonists ; Animals ; *Zebrafish ; Humans ; Small Molecule Libraries/pharmacology/chemistry ; Optogenetics/methods ; DNA-Binding Proteins/agonists/metabolism ; }, abstract = {Hsp70 prevents protein aggregation and is cytoprotective, but sustained Hsp70 overexpression is problematic. Therefore, we characterized small molecule agonists that augment Hsp70 activity. Because cumbersome assays were required to assay agonists, we developed cell-based and in vivo assays in which disease-associated consequences of Hsp70 activation can be quantified. One assay uses an optogenetic system in which the formation of TDP-43 inclusions can be controlled, and the second assay employs a zebrafish model for acute kidney injury (AKI). These complementary assays will facilitate future work to identify new Hsp70 agonists as well as optimized agonist derivatives.}, } @article {pmid39521994, year = {2024}, author = {Liang, H and Zhou, X and Zhang, J and Xu, W and Liu, Y and Wang, X and Hu, Y and Xu, R and Li, X}, title = {The therapeutic potential of Apigenin in amyotrophic lateral sclerosis through ALDH1A2/Nrf2/ARE signaling.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {30}, number = {1}, pages = {206}, pmid = {39521994}, issn = {1528-3658}, support = {81960244//National Natural Science Foundation of China/ ; 20212BAB216026//Jiangxi Natural Science Foundation/ ; 202110016//Science and Technology Plan of Jiangxi Provincial Health Commission/ ; 2022B975//Science and Technology Plan of Jiangxi Provincial Administration of Traditional Chinese Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; Animals ; *Apigenin/pharmacology/therapeutic use ; Mice ; *Signal Transduction/drug effects ; *Mice, Transgenic ; *Disease Models, Animal ; *NF-E2-Related Factor 2/metabolism/genetics ; Oxidative Stress/drug effects ; Aldehyde Dehydrogenase 1 Family/metabolism/genetics ; Humans ; Apoptosis/drug effects ; Retinal Dehydrogenase/metabolism/genetics ; Cell Line ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss leading to muscle weakness and atrophy. Apigenin (APG), known for its antioxidant properties, holds potential as a therapeutic compound in ALS.

METHODS: We used the Tg(SOD1*G93A)1Gur/J transgenic mouse model of ALS to investigate the therapeutic effects of APG. Key measured included motor function via the ALSTDI score, molecular markers of oxidative stress (OS) and apoptosis in spinal cord tissues. Techniques used included pathological, Western blotting, flow cytometry, and qRT-PCR to assess the effect of ALDH1A2.

RESULTS: APG treatment attenuated weight loss and improved motor function scores in ALS mice compared to untreated ALS models. Molecular analyses revealed a significant upregulation of ALDH1A2 in APG-treated groups, along with a reduction in markers of OS and apoptosis. In vitro studies in NSC34 cells further confirmed the protective effects of APG against SOD1*G93A mutation-induced cytotoxicity. In addition, suppression of ALDH1A2 by shRNA exacerbated disease markers that were ameliorated by APG treatment.

CONCLUSIONS: Our results suggest that APG attenuates the progression of ALS pathology by regulating OS and apoptosis through ALDH1A2. These results support further investigation of APG as a potential therapeutic agent for the treatment of ALS.}, } @article {pmid39521135, year = {2025}, author = {Sajid, SL and Ur Rehman, MA and Sajid, SA and Shahid, N}, title = {Response to Valerio Nardone et al's "Previous radiotherapy increases the efficacy of cemiplimab in the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma: A retrospective analysis".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e53-e54}, doi = {10.1016/j.jaad.2024.08.084}, pmid = {39521135}, issn = {1097-6787}, } @article {pmid39520580, year = {2024}, author = {Hyldgaard Andersen, S and Harsløf, S and Tøttrup, A}, title = {Laparoscopic ileopexy for afferent loop syndrome after restorative proctocolectomy-a retrospective case series.}, journal = {International journal of colorectal disease}, volume = {39}, number = {1}, pages = {180}, pmid = {39520580}, issn = {1432-1262}, mesh = {Humans ; *Proctocolectomy, Restorative/adverse effects ; *Laparoscopy/adverse effects ; Female ; Male ; Retrospective Studies ; Middle Aged ; Adult ; *Afferent Loop Syndrome/surgery/etiology ; *Ileum/surgery ; Aged ; Treatment Outcome ; Postoperative Complications/etiology/surgery ; }, abstract = {BACKGROUND: To study the effect of laparoscopic ileopexy in patients with afferent-loop syndrome (ALS) after restorative proctocolectomy (RP).

METHOD: Ileopexy has been the treatment of choice in patients with ALS for the last 5 years at our department. All patients who had undergone ileopexy for ALS between January 2019 and August 2023 were identified. Data were extracted from the medical records. All patients were contacted and asked standardized questions regarding symptoms of ALS. A symptom score was calculated and compared before surgery and at the last follow-up.

RESULTS: Ten patients, who had undergone ileopexy for ALS, were identified. Eight of these (80%) had been admitted with small bowel obstruction due to ALS. The remaining 2 patients had other symptoms indicative of ALS. In all patients, ileopexy was immediately effective in reducing symptoms. Symptoms recurred after 16.5 weeks (2-80) in 8 patients. Repeat laparoscopy showed that the ileopexy had slipped in 6 of these. Six had a new ileopexy with mesh. Later, one of these developed recurrent symptoms and had a new mesh ileopexy performed. No mesh complications were seen. Symptom score was reduced from 6.5 (1-9) to 2 (0-7) (p = 0.02) at the last follow-up.

CONCLUSIONS: In this study, ileopexy is effective in reducing symptoms of ALS after RP. In a high proportion of patients, it is necessary to use mesh to ensure long-term fixation of the ileum.}, } @article {pmid39520508, year = {2024}, author = {Larose, A and Miller, CCJ and Mórotz, GM}, title = {The lemur tail kinase family in neuronal function and disfunction in neurodegenerative diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {447}, pmid = {39520508}, issn = {1420-9071}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism/enzymology ; Animals ; *Neurons/metabolism/pathology ; Cyclin-Dependent Kinase 5/metabolism/genetics ; Signal Transduction ; Synapses/metabolism/pathology ; Protein-Tyrosine Kinases/metabolism/genetics ; Phosphorylation ; Axonal Transport ; Glycogen Synthase Kinase 3 beta/metabolism ; }, abstract = {The complex neuronal architecture and the long distance of synapses from the cell body require precisely orchestrated axonal and dendritic transport processes to support key neuronal functions including synaptic signalling, learning and memory formation. Protein phosphorylation is a major regulator of both intracellular transport and synaptic functions. Some kinases and phosphatases such as cyclin dependent kinase-5 (cdk5)/p35, glycogen synthase kinase-3β (GSK3β) and protein phosphatase-1 (PP1) are strongly involved in these processes. A primary pathological hallmark of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis/frontotemporal dementia, is synaptic degeneration together with disrupted intracellular transport. One attractive possibility is that alterations to key kinases and phosphatases may underlie both synaptic and axonal transport damages. The brain enriched lemur tail kinases (LMTKs, formerly known as lemur tyrosine kinases) are involved in intracellular transport and synaptic functions, and are also centrally placed in cdk5/p35, GSK3β and PP1 signalling pathways. Loss of LMTKs is documented in major neurodegenerative diseases and thus can contribute to pathological defects in these disorders. However, whilst function of their signalling partners became clearer in modulating both synaptic signalling and axonal transport progress has only recently been made around LMTKs. In this review, we describe this progress with a special focus on intracellular transport, synaptic functions and neurodegenerative diseases.}, } @article {pmid39519213, year = {2024}, author = {Bova, V and Mannino, D and Capra, AP and Lanza, M and Palermo, N and Filippone, A and Esposito, E}, title = {CK and LRRK2 Involvement in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {21}, pages = {}, pmid = {39519213}, issn = {1422-0067}, mesh = {Humans ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics ; Animals ; Mutation ; Phosphorylation ; Autophagy/genetics ; }, abstract = {Neurodegenerative diseases (NDDs) are currently the most widespread neuronal pathologies in the world. Among these, the most widespread are Alzheimer's disease (AD), dementia, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD)-all characterized by a progressive loss of neurons in specific regions of the brain leading to varied clinical symptoms. At the basis of neurodegenerative diseases, an emerging role is played by genetic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene that cause increased LRRK2 activity with consequent alteration of neuronal autophagy pathways. LRRK2 kinase activity requires GTPase activity which functions independently of kinase activity and is required for neurotoxicity and to potentiate neuronal death. Important in the neurodegeneration process is the upregulation of casein kinase (CK), which causes the alteration of the AMPK pathway by enhancing the phosphorylation of α-synuclein and huntingtin proteins, known to be involved in PD and HD, and increasing the accumulation of the amyloid-β protein (Aβ) for AD. Recent research has identified CK of the kinases upstream of LRRK2 as a regulator of the stability of the LRRK2 protein. Based on this evidence, this review aims to understand the direct involvement of individual kinases in NDDs and how their crosstalk may impact the pathogenesis and early onset of neurodegenerative diseases.}, } @article {pmid39519209, year = {2024}, author = {Firdaus, Z and Li, X}, title = {Epigenetic Explorations of Neurological Disorders, the Identification Methods, and Therapeutic Avenues.}, journal = {International journal of molecular sciences}, volume = {25}, number = {21}, pages = {}, pmid = {39519209}, issn = {1422-0067}, support = {DK129241 DK126662/GF/NIH HHS/United States ; }, mesh = {Humans ; *Epigenesis, Genetic ; *DNA Methylation ; Neurodegenerative Diseases/genetics/therapy ; Animals ; Nervous System Diseases/genetics/therapy ; Histones/metabolism/genetics ; Epigenomics/methods ; Histone Code/genetics ; }, abstract = {Neurodegenerative disorders are major health concerns globally, especially in aging societies. The exploration of brain epigenomes, which consist of multiple forms of DNA methylation and covalent histone modifications, offers new and unanticipated perspective into the mechanisms of aging and neurodegenerative diseases. Initially, chromatin defects in the brain were thought to be static abnormalities from early development associated with rare genetic syndromes. However, it is now evident that mutations and the dysregulation of the epigenetic machinery extend across a broader spectrum, encompassing adult-onset neurodegenerative diseases. Hence, it is crucial to develop methodologies that can enhance epigenetic research. Several approaches have been created to investigate alterations in epigenetics on a spectrum of scales-ranging from low to high-with a particular focus on detecting DNA methylation and histone modifications. This article explores the burgeoning realm of neuroepigenetics, emphasizing its role in enhancing our mechanistic comprehension of neurodegenerative disorders and elucidating the predominant techniques employed for detecting modifications in the epigenome. Additionally, we ponder the potential influence of these advancements on shaping future therapeutic approaches.}, } @article {pmid39518442, year = {2024}, author = {Laucius, O and Drūteika, J and Balnytė, R and Palačionytė, J and Ališauskienė, M and Petrikonis, K and Vaitkus, A}, title = {Phrenic Nerve Sonography Alterations in Patients with ALS: Insight with Clinical and Neurophysiological Findings.}, journal = {Journal of clinical medicine}, volume = {13}, number = {21}, pages = {}, pmid = {39518442}, issn = {2077-0383}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, and although the diagnosis is primarily based on clinical criteria, ENMG, as the "gold standard", does not always show detectable changes. Therefore, our study suggests that alterations in echogenicity and heterogeneity of the phrenic nerve (PN) may serve as potential additional diagnostic tools for ALS. Methods: Our study included 32 patients in the ALS group and 64 individuals in the control group. Each participant underwent an interview and completed questionnaires to collect clinical and demographic data, including age, gender, height, body mass index (BMI), hip and waist circumference, duration of illness, ALS-FRS-R score, comorbidities, and medication use. Ultrasound examinations of the PN were performed by two authors using a high-resolution "Philips EPIQ 7" ultrasound machine equipped with a linear 4-18 MHz transducer. The ALS group participants underwent PN sonography and conduction examinations, arterial blood gas (ABG) analysis, respiratory function tests (RFT), and electroneuromyography (ENMG). Results: The study demonstrated that the phrenic nerve is significantly smaller on both sides in patients with ALS compared to the control group (p < 0.01). Changes in the homogeneity and echogenicity of the PN were also observed on both sides. On the right side, 43.8% of the nerves showed heterogeneity, 40.6% were isoechoic, and 21.9% were hyperechoic. On the left side, 59.4% of the nerves exhibited heterogeneity, 34.4% were isoechoic, and 28.1% were hyperechoic. Moreover, sonography on both sides showed significant correlation with ALS-FRS-R, COMPASS-31, and ENMG results. Conclusions: Our study highlights the importance of phrenic nerve ultrasound as a promising supplementary diagnostic tool for ALS. The significant differences in phrenic nerve size, echogenicity, and homogeneity between patients with ALS and the control group demonstrate that ultrasound imaging can detect morphological changes in the phrenic nerve. Incorporating phrenic nerve ultrasound into routine diagnostic protocols could improve early detection, enhance disease monitoring, and offer a more comprehensive understanding of the neurodegenerative processes in ALS.}, } @article {pmid39517754, year = {2024}, author = {Ciou, TS and Lin, CH and Wang, CK}, title = {Airborne LiDAR Point Cloud Classification Using Ensemble Learning for DEM Generation.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {21}, pages = {}, pmid = {39517754}, issn = {1424-8220}, abstract = {Airborne laser scanning (ALS) point clouds have emerged as a predominant data source for the generation of digital elevation models (DEM) in recent years. Traditionally, the generation of DEM using ALS point clouds involves the steps of point cloud classification or ground point filtering to extract ground points and labor-intensive post-processing to correct the misclassified ground points. The current deep learning techniques leverage the ability of geometric recognition for ground point classification. However, the deep learning classifiers are generally trained using 3D point clouds with simple geometric terrains, which decrease the performance of model inferencing. In this study, a point-based deep learning model with boosting ensemble learning and a set of geometric features as the model inputs is proposed. With the ensemble learning strategy, this study integrates specialized ground point classifiers designed for different terrains to boost classification robustness and accuracy. In experiments, ALS point clouds containing various terrains were used to evaluate the feasibility of the proposed method. The results demonstrated that the proposed method can improve the point cloud classification and the quality of generated DEMs. The classification accuracy and F1 score are improved from 80.9% to 92.2%, and 82.2% to 94.2%, respectively, by using the proposed methods. In addition, the DEM generation error, in terms of mean squared error (RMSE), is reduced from 0.318-1.362 m to 0.273-1.032 m by using the proposed ensemble learning.}, } @article {pmid39515011, year = {2024}, author = {Mauri, L and Taccaliti, F and Lingua, E}, title = {Modeling the interaction between wildfires and windthrows: A pilot case study for Italian Alps.}, journal = {Journal of environmental management}, volume = {371}, number = {}, pages = {123150}, doi = {10.1016/j.jenvman.2024.123150}, pmid = {39515011}, issn = {1095-8630}, mesh = {*Wildfires ; Italy ; *Forests ; Pilot Projects ; Models, Theoretical ; Ecosystem ; Wind ; }, abstract = {Wildland fires and windthrows represent relevant disturbances for forest ecosystems worldwide. In this context, especially for Italian catchments, the interaction between windthrows and changes in wildfire behaviour starting from ALS data processing is scarcely investigated. Therefore, this research aims to compute a multi-temporal analysis of the interaction between windthrows and wildfire behaviour in a forested area (Veneto region, northern Italy), recently affected by the renamed Vaia windstorm. The semi-empirical FlamMap model was applied, starting from ALS data processing implemented in R for mapping the spatial distribution of forest attributes and fuels within the catchment. The role of windthrows in altering wildfire behaviour was investigated considering ALS point clouds acquired before and after the occurrence of the storm Vaia. Digital Terrain Models (DTMs), Canopy Height Models (CHMs), topographic data and metrics describing forest structure were extracted from ALS data for both scenarios at 5 m resolution, to compare changes in wildfire behaviour over time. Differences in Rate of Spread (RoS), flame length (FL), midflame windspeed (WS) and arrival time (AT) were assessed, and their correlation with windstorm damages was investigated at the catchment detail. , An increase of RoS, FL, and WS greater than 30 m/min, 3 m and 1.1 m/s were respectively estimated in windthrown areas, as well as a decrease of AT greater than 30 min, attesting the key role of windthrows in altering wildfire behaviour over time. The correlation between windthrows and changes in wildfire attributes was finally modeled by computing regression analysis, with R[2] of 0.86, 0.93, 0.62, and 0.91 resulted for RoS, FL, WS and AT. This research represents a pilot case study for better detecting changes in wildfires behaviour due to windthrows occurrence, therefore proposing and carrying out effective planning and management strategies for disturbed forest stands over time.}, } @article {pmid39514515, year = {2024}, author = {Ohnari, K and Mafune, K and Adachi, H}, title = {Fasciculation potentials are related to the prognosis of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0313307}, pmid = {39514515}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality/diagnosis ; Male ; Female ; Middle Aged ; Prognosis ; *Fasciculation/physiopathology/diagnosis ; *Electromyography ; Aged ; Retrospective Studies ; Disease Progression ; Adult ; Biomarkers/blood ; }, abstract = {Some prognostic biomarkers of amyotrophic lateral sclerosis (ALS) have been described; however, they are inadequate for satisfactorily predicting individual patient outcomes. Fasciculation potentials (FPs) on electromyography (EMG) are useful for the early diagnosis of ALS, and complex FPs are associated with shorter survival in ALS. In this study, we investigated the relationship between the proportion of muscles with FPs, biochemical markers, and the prognosis of ALS. 89 Patients with ALS were retrospectively classified into three groups based on the interval from onset to death or tracheostomy (less than 1 year: fast progression; from 1 year to less than 3 years: average progression; 3 years or more: slow progression). We performed statistical analysis of the electrophysiological findings, including the percentage of examined muscles with FPs, and biochemical markers evaluated on admission. Patients with fast ALS progression had a higher percentage of muscles with FPs (93.1% vs. 37.9%, P<0.001) and lower uric acid (UA) levels (male: 4.19 mg/dl vs 5.55 mg/dl, P<0.001; female: 3.71 mg/dl vs 5.41 mg/dl, P<0.001) than patients with slow progression. Survival curves demonstrated a relationship between these factors and the survival time in patients with ALS. Furthermore, UA levels were correlated with the percentage of muscles with FPs. Our electrophysiological findings suggest that ALS presents with multisystem neurological manifestations, and these manifestations differed among the groups classified by disease progression. The percentage of muscles with FPs on EMG and serum UA levels were especially associated with the prognosis of ALS.}, } @article {pmid39513379, year = {2025}, author = {Simkins, TJ and Kupfer, S and Malik, FI and Meng, L and Rudnicki, SA and Wei, J and Shefner, JM and Bowser, R}, title = {Plasma neurofilament analysis in VITALITY-ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {103-112}, doi = {10.1080/21678421.2024.2423707}, pmid = {39513379}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/drug therapy ; Middle Aged ; Double-Blind Method ; *Neurofilament Proteins/blood ; Aged ; *Disease Progression ; Biomarkers/blood ; Longitudinal Studies ; Adult ; Intermediate Filaments/metabolism ; }, abstract = {OBJECTIVE: To evaluate correlations between neurofilament (Nf) concentrations and clinical characteristics and disease progression using a large longitudinal dataset from VITALITY-ALS (ClinicalTrials.gov identifier: NCT02496767), a 48-week, randomized, double-blind, placebo-controlled clinical trial of tirasemtiv in people with ALS (pALS).

METHODS: Plasma was collected at baseline and every 8 weeks thereafter. Results were compared between treatment groups and evaluated by clinical characteristics and over time. Pearson's correlation coefficients (r) were calculated to evaluate associations between Nf concentrations and slow vital capacity (SVC), Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score, and pre-study/in-study rates of disease progression (psRDP/isRDP).

RESULTS: Nf measurements were available from 101 placebo- and 161 tirasemtiv-treated people with ALS (pALS). There were no significant differences in Nf between placebo and tirasemtiv groups at any time point; further analyses grouped all samples. At baseline, Nf concentration did not differ by multiple clinical characteristics. Baseline Nf light chain (NfL) concentration correlated with the psRDP (r = 0.50, p < 0.001) and isRDP (r = 0.53, p < 0.0001). Phosphorylated Nf heavy chain (pNfH) demonstrated a similar, but less robust, pattern of results. Baseline Nf concentration correlated with change in SVC and ALSFRS-R score over time. Plasma pNfH concentration continuously decreased over time. There was no meaningful change in plasma NfL concentration over the study period.

CONCLUSIONS: In this large longitudinal study, baseline NfL concentration correlated with multiple markers of disease progression. The findings suggest Nfs show promise primarily as prognostic markers for pALS, particularly for those with rapid disease progression.}, } @article {pmid39513316, year = {2024}, author = {Yadav, H and Malviya, R and Kaushik, N and Sridhar, SB}, title = {Therapeutic Potential of Quercetin Analogous: Prospective and Advances.}, journal = {Recent advances in food, nutrition & agriculture}, volume = {}, number = {}, pages = {}, doi = {10.2174/012772574X332803240930065210}, pmid = {39513316}, issn = {2772-5758}, abstract = {The purpose of the article is to investigate the therapeutic potential of quer-cetin and related compounds by elucidating their pharmacological characteristics and molecular mechanisms of action. The potential benefits of quercetin and its analogs for cardiovascular health, disorders of the brain, metabolic disorders, and more are discussed in the discussion part of this page. Concerns about their clinical efficacy due to issues with bioavailability and distribution are also discussed. This region of the paper emphasizes the importance of researchers and clinicians working together to maximize the incorporation of these chemicals into real-world therapeutic approaches. In conclusion, quercetin, along with related substances, shows great potential in a wide range of therapeutic settings. Potentially useful for the management of a wide variety of illnesses, their multiple methods of action include the regulation of pathways for cell signaling and interaction with different enzymes. However, additional clinical tri-als are needed to verify their efficacy and safety.}, } @article {pmid39512134, year = {2025}, author = {Pattee, GL}, title = {Gastrostomy in Amyotrophic Lateral Sclerosis: Timing Enhances Survival.}, journal = {Muscle & nerve}, volume = {71}, number = {1}, pages = {3-5}, doi = {10.1002/mus.28294}, pmid = {39512134}, issn = {1097-4598}, } @article {pmid39512085, year = {2024}, author = {White, CG and Hancewicz, TM and Fasasi, A and Wright, J and Lavine, BK}, title = {Alternating and Modified Alternating Least Squares Applied to Raman Spectra of Finished Gasolines.}, journal = {Applied spectroscopy}, volume = {}, number = {}, pages = {37028241292649}, doi = {10.1177/00037028241292649}, pmid = {39512085}, issn = {1943-3530}, abstract = {Extraction of components from individual refinery streams (e.g., reformates and alkylates) in finished gasoline was undertaken using Raman spectroscopy to characterize the chemical content of the finished product. Modified alternating least squares (MALS) was used for separating Raman spectroscopic data sets of the finished product into its pure individual components. The advantages of MALS over alternating least squares (ALS) for multicomponent resolution are highlighted in this study using three Raman spectroscopic data sets which provide a suitable benchmark for comparing the performance of these two methods. MALS is superior to ALS in terms of accuracy and can better resolve components than ALS, and it is also more robust toward collinear data. Finally, components near the noise level usually cannot be extracted by ALS because of instability when inverting the covariance structure which inflates the noise present in the data. However, these same components can be extracted by MALS due to the stabilization of the least squares regression with respect to the matrix inversion using modified techniques from ridge regression.}, } @article {pmid39511965, year = {2025}, author = {Bhai, S and Levine, T and Moore, D and Bowser, R and Heim, AJ and Walsh, M and Shibani, A and Simmons, Z and Grogan, J and Goyal, NA and Govindarajan, R and Hussain, Y and Papsdorf, T and Schwasinger-Schmidt, T and Olney, N and Goslin, K and Pulley, M and Kasarskis, E and Weiss, M and Katz, SW and Moser, S and Jabari, D and Jawdat, O and Statland, J and Dimachkie, MM and Barohn, R and , }, title = {A 40-week phase 2B randomized, multicenter, double-blind, placebo-controlled study evaluating the safety and efficacy of memantine in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {71}, number = {1}, pages = {63-72}, pmid = {39511965}, issn = {1097-4598}, support = {R01 FD003937/FD/FDA HHS/United States ; R01FD003937//FDA-OPD/ ; //U.S. Food and Drug Administration/ ; }, mesh = {Humans ; *Memantine/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Double-Blind Method ; Middle Aged ; Aged ; Adult ; Aged, 80 and over ; *Disease Progression ; Treatment Outcome ; Young Adult ; Excitatory Amino Acid Antagonists/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with no known cure, limited treatment options with minimal benefits, and significant unmet need for disease modifying therapies.

AIMS: This study investigated memantine's impact on ALS progression, with an additional focus on the effects of memantine on cognitive and behavioral changes associated with the disease.

METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted from December 2018 to September 2020. ALS patients were enrolled in-person and remotely across 13 sites in the United States. Participants were randomized to memantine (20 mg twice daily) or placebo in a 2:1 ratio and completed 36 weeks of treatment. The primary outcome of disease progression was assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and blood was collected for biomarker analysis.

RESULTS: Of the 99 participants enrolled in the study, 89 were randomized to memantine or placebo (ages 24-83 years, male-to-female ratio ~3:2). Fifty-two participants completed the study treatment with no significant differences in disease progression, biomarker changes (including neurofilament light chain [NfL]), or neuropsychiatric testing noted between the groups. Initial NfL values correlated with the rate of ALSFRS-R decline.

DISCUSSION: In this study, memantine did not impact ALS disease progression or neuropsychiatric symptoms. Trials with remote enrollment may help trial participation and success.}, } @article {pmid39511939, year = {2025}, author = {Eisen, A and Vucic, S and Kiernan, MC}, title = {Amyotrophic lateral sclerosis represents corticomotoneuronal system failure.}, journal = {Muscle & nerve}, volume = {71}, number = {4}, pages = {499-511}, pmid = {39511939}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology/genetics ; Humans ; Animals ; Motor Neurons/pathology ; }, abstract = {Several decades have passed since the anterograde corticomotoneuronal hypothesis for amyotrophic lateral sclerosis (ALS) was proposed. The intervening years have witnessed its emergent support based on anatomical, pathological, physiological, neuroimaging, and molecular biological studies. The evolution of an extensive corticomotoneuronal system appears restricted to the human species, with ALS representing a uniquely human disease. While some, very select non-human primates have limited corticomotoneuronal projections, these tend to be absent in all other animals. From a general perspective, the early clinical features of ALS may be considered to reflect failure of the corticomotoneuronal system. The characteristic loss of skilled motor dexterity involving the limbs, and speech impairment through progressive bulbar dysfunction specifically involve those motor units having the strongest corticomotoneuronal projections. A similar explanation likely underlies the unique "split phenotypes" that have now been well characterized in ALS. Large Betz cells and other pyramidal corticomotoneuronal projecting neurons, with their extensive dendritic arborization, are particularly vulnerable to the elements of the ALS exposome such as aging, environmental stress and lifestyle changes. Progressive failure of the proteosome impairs nucleocytoplasmic shuffling and induces toxic but soluble TDP-43 to aggregate in corticomotoneurons. Betz cell failure is further accentuated through dysfunction of its profuse dendritic arborizations. Clarification of system specific genomes and neural networks will likely promote the initiation of precision medicine approaches directed to support the key structure that underlies the neurological manifestations of ALS, the corticomotoneuronal system.}, } @article {pmid39511821, year = {2025}, author = {Grady, A and Lorch, R and Giles, L and Lamont, H and Anderson, A and Pearson, N and Romiti, M and Lum, M and Stuart, A and Leigh, L and Yoong, SL}, title = {The impact of early childhood education and care-based interventions on child physical activity, anthropometrics, fundamental movement skills, cognitive functioning, and social-emotional wellbeing: A systematic review and meta-analysis.}, journal = {Obesity reviews : an official journal of the International Association for the Study of Obesity}, volume = {26}, number = {2}, pages = {e13852}, pmid = {39511821}, issn = {1467-789X}, support = {APP1170042//National Health and Medical Research Council/ ; Heart Foundation Postdoctoral Fellowship 102518//National Heart Foundation of Australia/ ; Heart Foundation Future Leader Fellowship 106654//National Heart Foundation of Australia/ ; }, mesh = {Humans ; *Cognition ; Child, Preschool ; *Exercise/psychology ; Child ; Infant ; Motor Skills/physiology ; Pediatric Obesity/psychology/prevention & control ; Anthropometry ; Early Intervention, Educational ; }, abstract = {This review assessed the effectiveness of ECEC-based interventions to improve child physical activity, and intervention impact on child weight-based anthropometrics, fundamental movement skills (FMS), cognitive functioning, and social-emotional wellbeing. Adverse effects and costs were assessed. Finch et al's 2014 systematic review was updated. Electronic databases were searched 10 September 2014 to 27 October 2022. Included studies were randomized controlled trials of ECEC interventions targeting physical activity among children aged 0-6 years. The methodological quality of studies was assessed using Cochrane's Risk of Bias tool v2. Standardized mean differences (SMD) were calculated for each outcome with meta-analysis undertaken; otherwise, findings were described narratively. Fifty-three studies were included. ECEC-based interventions were found to significantly improve child physical activity (SMD 0.193, 95% confidence interval [CI] 0.09 to 0.3; p < 0.001) and FMS (SMD 0.544, 95% CI 0.1 to 0.98; p = 0.015), compared to control. Small positive, but non-significant, effects were found for weight-based anthropometrics, cognitive functioning, and social-emotional wellbeing. Few studies reported adverse effects (n = 10), and no studies reported formal economic analyses. While ECEC-based interventions can significantly improve child physical activity and FMS, further evidence of their impact on cognitive functioning, social-emotional wellbeing, and the cost-effectiveness of such interventions is required to inform policy and practice.}, } @article {pmid39511709, year = {2024}, author = {Fontaine, M and Horowitz, K and Anoja, N and Genge, A and Salmon, K}, title = {How the prospect of a clinical trial impacts decision-making for predictive genetic testing in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2024.2423718}, pmid = {39511709}, issn = {2167-9223}, abstract = {Objective: Genetic testing practices are rapidly evolving for people living with, or at-risk for, amyotrophic lateral sclerosis (ALS), due to emerging genotype-driven therapies. This study explored how individuals at-risk for familial ALS (fALS) perceive the opportunity to participate in a clinical trial, and to better understand how that may influence the decision-making process for predictive genetic testing. Methods: This study used both quantitative and qualitative data analyses. Data were collected through an online questionnaire, followed by semi-structured interviews conducted with twelve (n = 12) individuals at-risk for either SOD1- or C9orf72-ALS who had predictive testing prior to study participation. Interview data were analyzed using reflexive thematic analysis. Results: Three overarching themes were conceptualized from the data: i) the psychosocial impact of fALS; ii) perspectives of at-risk individuals on research involvement; and iii) predictive genetic counseling and testing considerations. These results contribute perspectives of the lived experience to inform predictive genetic counseling and testing practices for individuals at-risk for fALS. Conclusion: Individuals at-risk for fALS view potential participation in a presymptomatic clinical trial as an actionable measure that may increase their desire for predictive genetic testing. Genetic counseling was identified as a critical component of the predictive testing process given the life-changing implications associated with a positive result. Increased access to predictive genetic counseling, and in a timely manner, is a significant need in the ALS population given potential access to gene-specific therapies in the presymptomatic stage.}, } @article {pmid39511225, year = {2024}, author = {Silvestri, B and Mochi, M and Mawrie, D and de Turris, V and Colantoni, A and Borhy, B and Medici, M and Anderson, EN and Garone, MG and Zammerilla, CP and Simula, M and Ballarino, M and Pandey, UB and Rosa, A}, title = {HuD impairs neuromuscular junctions and induces apoptosis in human iPSC and Drosophila ALS models.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9618}, pmid = {39511225}, issn = {2041-1723}, support = {CN00000041//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; 2022BYB33L//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; CN00000041//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; RP123188EC9F2349//Sapienza Università di Roma (Sapienza University of Rome)/ ; RM12117A5DE7A45B//Sapienza Università di Roma (Sapienza University of Rome)/ ; LT0024/2022-L//Human Frontier Science Program (HFSP)/ ; }, mesh = {Humans ; *Neuromuscular Junction/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *Apoptosis/genetics ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; *RNA-Binding Protein FUS/metabolism/genetics ; *Disease Models, Animal ; *ELAV-Like Protein 4/metabolism/genetics ; Mutation ; Oxidative Stress ; Drosophila Proteins/metabolism/genetics ; Drosophila melanogaster/genetics ; Female ; Male ; Drosophila ; }, abstract = {Defects at the neuromuscular junction (NMJ) are among the earliest hallmarks of amyotrophic lateral sclerosis (ALS). According to the "dying-back" hypothesis, NMJ disruption not only precedes but also triggers the subsequent degeneration of motoneurons in both sporadic (sALS) and familial (fALS) ALS. Using human induced pluripotent stem cells (iPSCs), we show that the RNA-binding protein HuD (ELAVL4) contributes to NMJ defects and apoptosis in FUS-ALS. HuD overexpression mimics the severe FUS[P525L] mutation, while its knockdown rescues the FUS[P525L] phenotypes. In Drosophila, neuronal overexpression of the HuD ortholog, elav, induces motor dysfunction, and its knockdown improves motor function in a FUS-ALS model. Finally, we report increased HuD levels upon oxidative stress in human motoneurons and in sALS patients with an oxidative stress signature. Based on these findings, we propose that HuD plays a role downstream of FUS mutations in fALS and in sALS related to oxidative stress.}, } @article {pmid39510899, year = {2024}, author = {Kaul, M and Mukherjee, D and Weiner, HL and Cox, LM}, title = {Gut microbiota immune cross-talk in amyotrophic lateral sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {6}, pages = {e00469}, pmid = {39510899}, issn = {1878-7479}, support = {P51 OD011133/OD/NIH HHS/United States ; R01 NS115951/NS/NINDS NIH HHS/United States ; R21 NS126866/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/immunology/microbiology ; *Gastrointestinal Microbiome/immunology/physiology ; Humans ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons. While there has been significant progress in defining the genetic contributions to ALS, greater than 90 % of cases are sporadic, which suggests an environmental component. The gut microbiota is altered in ALS and is an ecological factor that contributes to disease by modulating immunologic, metabolic, and neuronal signaling. Depleting the microbiome worsens disease in the SOD1 ALS animal model, while it ameliorates disease in the C9orf72 model of ALS, indicating critical subtype-specific interactions. Furthermore, administering beneficial microbiota or microbial metabolites can slow disease progression in animal models. This review discusses the current state of microbiome research in ALS, including interactions with different ALS subtypes, evidence in animal models and human studies, key immunologic and metabolomic mediators, and a path toward microbiome-based therapies for ALS.}, } @article {pmid39510439, year = {2024}, author = {Tan, X and Su, X and Wang, Y and Liang, W and Wang, D and Huo, D and Wang, H and Qi, Y and Zhang, W and Han, L and Zhang, D and Wang, M and Xu, J and Feng, H}, title = {BRD7 regulates cellular senescence and apoptosis in ALS by modulating p21 expression and p53 mitochondrial translocation respectively.}, journal = {Neuroscience}, volume = {563}, number = {}, pages = {51-62}, doi = {10.1016/j.neuroscience.2024.11.004}, pmid = {39510439}, issn = {1873-7544}, mesh = {*Cellular Senescence/physiology ; *Apoptosis/physiology ; *Tumor Suppressor Protein p53/metabolism/genetics ; Humans ; *Cyclin-Dependent Kinase Inhibitor p21/metabolism/genetics ; *Mitochondria/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Motor Neurons/metabolism/pathology ; Chromosomal Proteins, Non-Histone/metabolism/genetics ; Male ; Female ; Middle Aged ; Aged ; Bromodomain Containing Proteins ; }, abstract = {Cellular senescence is involved in the progression of neurodegenerative diseases. Motor neurons exhibit senescence-like alterations in ALS. BRD7, identified as a regulatory factor associated with cellular senescence, its function in ALS remains unclear. This study aims to investigate the potential role and mechanisms of BRD7 in ALS. We analyzed RNA levels using qRT-PCR, protein levels through immunofluorescence and western blot, and apoptosis via TUNEL staining. Cell transfection was conducted for in vitro experiments. The level of β-galactosidase was measured by β-galactosidase activity detection kit. ALS motor neurons exhibited senescence-like alterations, characterized by increased activity of p53, p21, and β-galactosidase, as well as reduced lamin B1 staining. Additionally, the expression of BRD7 was upregulated and induced cellular senescence and apoptosis. Downregulation of BRD7 alleviates the cellular senescence by inhibiting p21 rather than p53. Knockdown of BRD7 inhibited p53 mitochondrial translocation, leading to reduced apoptosis. Our results suggest that BRD7 plays an important role in the survival of ALS motor neurons. BRD7 knockdown can reduce cellular senescence and apoptosis by inhibiting p21 and p53 mitochondrial translocation.}, } @article {pmid39509425, year = {2024}, author = {Deng, YC and Liu, JW and Ting, HC and Kuo, TC and Chiang, CH and Lin, EY and Harn, HJ and Lin, SZ and Chang, CY and Chiou, TW}, title = {n-Butylidenephthalide recovered calcium homeostasis to ameliorate neurodegeneration of motor neurons derived from amyotrophic lateral sclerosis iPSCs.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0311573}, pmid = {39509425}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; *Induced Pluripotent Stem Cells/metabolism/drug effects ; Humans ; *Motor Neurons/drug effects/metabolism/pathology ; *Calcium/metabolism ; *Homeostasis/drug effects ; *Superoxide Dismutase-1/genetics/metabolism ; *Phthalic Anhydrides/pharmacology ; Cell Differentiation/drug effects ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that causes muscle atrophy and primarily targets motor neurons (MNs). Approximately 20% of familial ALS cases are caused by gain-of-function mutations in superoxide dismutase 1 (SOD1), leading to MN degeneration and ion channel dysfunction. Previous studies have shown that n-Butylidenephthalide (BP) delays disease progression and prolongs survival in animal models of ALS. However, no studies have been conducted on models from human sources. Herein, we examined the protective efficacy of BP on MNs derived from induced pluripotent stem cells (iPSCs) of an ALS patient harboring the SOD1G85R mutation as well as on those derived from genetically corrected iPSCs (SOD1G85G). Our results demonstrated that the motor neurons differentiated from iPSC with SOD1G85R mutation exhibited characteristics of neuron degeneration (as indicated by the reduction of neurofilament expression) and ion channel dysfunction (in response to potassium chloride (KCl) and L-glutamate stimulation), in contrast to those derived from the gene corrected iPSC (SOD1G85G). Meanwhile, BP treatment effectively restored calcium ion channel function by reducing the expression of glutamate receptors including glutamate ionotropic receptor AMPA type subunit 3 (GluR3) and glutamate ionotropic receptor NMDA type subunit 1 (NMDAR1). Additionally, BP treatment activated autophagic pathway to attenuate neuron degeneration. Overall, this study supports the therapeutic effects of BP on ALS patient-derived neuron cells, and suggests that BP may be a promising candidate for future drug development.}, } @article {pmid39508675, year = {2024}, author = {}, title = {DSP-01 conversion from PLS to ALS: a Dutch cohort study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {sup1}, pages = {262-279}, doi = {10.1080/21678421.2024.2403307}, pmid = {39508675}, issn = {2167-9223}, } @article {pmid39508663, year = {2024}, author = {}, title = {Platform Communications: Abstract Book 35th International Symposium on ALS/MND (Complete printable file).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {sup1}, pages = {1-92}, doi = {10.1080/21678421.2024.2403293}, pmid = {39508663}, issn = {2167-9223}, } @article {pmid39508354, year = {2025}, author = {Bhatele, P and Pai, AR}, title = {Wine Glass Sign in Bulbar Onset Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {97}, number = {3}, pages = {558-560}, doi = {10.1002/ana.27131}, pmid = {39508354}, issn = {1531-8249}, } @article {pmid39506867, year = {2024}, author = {Ishihara, T and Koyama, A and Atsuta, N and Tada, M and Toyoda, S and Kashiwagi, K and Hirokawa, S and Hatano, Y and Yokoseki, A and Nakamura, R and Tohnai, G and Izumi, Y and Kaji, R and Morita, M and Tamura, A and Kano, O and Aoki, M and Kuwabara, S and Kakita, A and Sobue, G and Onodera, O}, title = {SMN2 gene copy number affects the incidence and prognosis of motor neuron diseases in Japan.}, journal = {BMC medical genomics}, volume = {17}, number = {1}, pages = {263}, pmid = {39506867}, issn = {1755-8794}, support = {17K09750//Scientific Research from the Japan Society for the Promotion of Science/ ; 21K07272//Scientific Research from the Japan Society for the Promotion of Science/ ; 17ek0109284h0001//Japan Agency for Medical Research and Development/ ; 17ek0109284h0001//Japan Agency for Medical Research and Development/ ; 17ek0109284h0001//Japan Agency for Medical Research and Development/ ; 26117006//Scientific Research on Innovative Areas from MEXT/ ; JPMH23FC1008//MHLW Research on rare and intractable diseases Program/ ; }, mesh = {Humans ; *Survival of Motor Neuron 2 Protein/genetics ; Male ; Japan/epidemiology ; Middle Aged ; Female ; Prognosis ; *Motor Neuron Disease/genetics ; *Gene Dosage ; Incidence ; Amyotrophic Lateral Sclerosis/genetics ; Aged ; Adult ; Case-Control Studies ; DNA Copy Number Variations ; }, abstract = {BACKGROUND: The copy number status (CNS) of the survival motor neuron (SMN) gene may influence the risk and prognosis of amyotrophic lateral sclerosis (ALS) and lower motor neuron diseases (LMND) other than spinal muscular atrophy (SMA). However, previous studies of this association, mainly from Europe, have yielded controversial results, suggesting possible regional differences. Here, we investigated the effect of the SMN gene in Japanese patients with ALS and LMND.

METHODS: We examined the SMN copy numbers and clinical histories of 487 Japanese patients with sporadic ALS (281 men; mean age at onset 61.5 years), 50 with adult LMND (50 men; mean age at onset 58.4 years) and 399 Japanese controls (171 men; mean age 62.2 years). Patients with pathogenic mutations in ALS-causing genes were excluded. SMN1 and SMN2 copy numbers were determined using the droplet digital polymerase chain reaction.

RESULTS: The frequency of a copy number of one for the SMN2 gene was higher in patients with ALS (38.0%) than in healthy controls (30.8%) (odds ratio (OR) = 1.37, 95% confidence interval (CI) = 1.04-1.82, p < 0.05). The SMN2 copy number affected the survival time of patients with ALS (median time: 0 copies, 34 months; 1 copy, 39 months; 2 copies, 44 months; 3 copies, 54 months; log-rank test, p < 0.05). Cox regression analysis revealed that the SMN2 copy number was associated with increased mortality (hazard ratio = 0.84, 95% CI = 0.72-0.98, p < 0.05). Also, null SMN2 cases were significantly more frequent in the LMND group (12.0%) than in the control group (4.8%) (OR = 2.73, 95% CI = 1.06-6.98, p < 0.05).

CONCLUSIONS: Our findings suggest that SMN2 copy number reduction may adversely affect the onset and prognosis of MND, including ALS and LMND, in Japanese.}, } @article {pmid39506789, year = {2024}, author = {Niccolai, E and Di Gloria, L and Trolese, MC and Fabbrizio, P and Baldi, S and Nannini, G and Margotta, C and Nastasi, C and Ramazzotti, M and Bartolucci, G and Bendotti, C and Nardo, G and Amedei, A}, title = {Host genetics and gut microbiota influence lipid metabolism and inflammation: potential implications for ALS pathophysiology in SOD1[G93A] mice.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {174}, pmid = {39506789}, issn = {2051-5960}, support = {SG-2019-12371083//Italian Ministry of Health/ ; PE0000006//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; }, mesh = {Animals ; *Gastrointestinal Microbiome/physiology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/microbiology/pathology ; Mice ; *Mice, Transgenic ; *Lipid Metabolism/genetics ; Inflammation/metabolism/pathology ; Mice, Inbred C57BL ; Superoxide Dismutase-1/genetics/metabolism ; Disease Models, Animal ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons, with genetic and environmental factors contributing to its complex pathogenesis. Dysregulated immune responses and altered energetic metabolism are key features, with emerging evidence implicating the gut microbiota (GM) in disease progression. We investigated the interplay among genetic background, GM composition, metabolism, and immune response in two distinct ALS mouse models: 129Sv_G93A and C57Ola_G93A, representing rapid and slow disease progression, respectively.Using 16 S rRNA sequencing and fecal metabolite analysis, we characterized the GM composition and metabolite profiles in non-transgenic (Ntg) and SOD1[G93A] mutant mice of both strains. Our results revealed strain-specific differences in GM composition and functions, particularly in the abundance of taxa belonging to Erysipelotrichaceae and the levels of short and medium-chain fatty acids in fecal samples. The SOD1 mutation induces significant shifts in GM colonization in both strains, with C57Ola_G93A mice showing changes resembling those in 129 Sv mice, potentially affecting disease pathogenesis. ALS symptom progression does not significantly alter microbiota composition, suggesting stability.Additionally, we assessed systemic immunity and inflammatory responses revealing strain-specific differences in immune cell populations and cytokine levels.Our findings underscore the substantial influence of genetic background on GM composition, metabolism, and immune response in ALS mouse models. These strain-specific variations may contribute to differences in disease susceptibility and progression rates. Further elucidating the mechanisms underlying these interactions could offer novel insights into ALS pathogenesis and potential therapeutic targets.}, } @article {pmid39508106, year = {2024}, author = {Gao, XF and Chen, AQ and Tang, HY and Kong, XQ and Zhang, H and Wang, ZM and Lu, W and Wang, LG and Wang, F and Zhou, WY and Gu, Y and Zuo, GF and Ge, Z and Zhang, JJ and Chen, SL}, title = {m[6]A Modification of Profilin-1 in Vascular Smooth Muscle Cells Drives Phenotype Switching and Neointimal Hyperplasia via Activation of the p-ANXA2/STAT3 Pathway.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {44}, number = {12}, pages = {2543-2559}, pmid = {39508106}, issn = {1524-4636}, mesh = {Animals ; *Neointima ; *Muscle, Smooth, Vascular/metabolism/pathology ; *Hyperplasia ; *Phenotype ; *STAT3 Transcription Factor/metabolism/genetics ; *Myocytes, Smooth Muscle/metabolism/pathology ; *Signal Transduction ; *Disease Models, Animal ; *Proto-Oncogene Mas ; Male ; *Profilins/metabolism/genetics ; *Mice, Knockout ; *Adenosine/metabolism/analogs & derivatives ; Humans ; Mice ; Mice, Inbred C57BL ; Rats ; Cells, Cultured ; Rats, Sprague-Dawley ; Phosphorylation ; Coronary Restenosis/metabolism/pathology/genetics/etiology ; Carotid Stenosis/metabolism/pathology/genetics ; Cell Proliferation ; }, abstract = {BACKGROUND: In-stent restenosis is characterized by a significant reduction in lumen diameter within the stented segment, primarily attributed to excessive proliferation of vascular smooth muscle cells (VSMCs) and neointimal hyperplasia. PFN1 (profilin-1), an actin-sequestering protein extensively studied in amyotrophic lateral sclerosis, remains less explored in neointimal hyperplasia.

METHODS: Utilizing single-cell RNA sequencing alongside data from in-stent restenosis patients and various experimental in-stent restenosis models (swine, rats, and mice), we investigated the role of PFN1 in promoting VSMC phenotype switching and neointimal hyperplasia.

RESULTS: Single-cell RNA sequencing of stenotic rat carotid arteries revealed a critical role for PFN1 in neointimal hyperplasia, a finding corroborated in stented swine coronary arteries, in-stent restenosis patients, PFN1[SMC-IKO] (SMC-specific PFN1 knockout) mice, and PFN1 overexpressed mice. PFN1 deletion was shown to suppress VSMC phenotype switching and neointimal hyperplasia in PFN1[SMC-IKO] mice subjected to a wire-injured model. To elucidate the observed discordance in PFN1 mRNA and protein levels, we identified that METTL3 (N[6]-methyladenosine methyltransferase) and YTHDF3 (YTH N6-methyladenosine RNA binding protein F3; N[6]-methyladenosine-specific reader) enhance PFN1 translation efficiency in an N[6]-methyladenosine-dependent manner, confirmed through experiments involving METTL3 knockout and YTHDF3 knockout mice. Furthermore, PFN1 was mechanistically found to interact with the phosphorylation of ANXA2 (annexin A2) by recruiting Src (SRC proto-oncogene, nonreceptor tyrosine kinase), promoting the phosphorylation of STAT3 (signal transducer and activator of transcription 3), a typical transcription factor known to induce VSMC phenotype switching.

CONCLUSIONS: This study unveils the significance of PFN1 N[6]-methyladenosine modification in VSMCs, demonstrating its role in promoting phenotype switching and neointimal hyperplasia through the activation of the p-ANXA2 (phospho-ANXA2)/STAT3 pathway.}, } @article {pmid39505881, year = {2024}, author = {Li, J and Jaiswal, MK and Chien, JF and Kozlenkov, A and Jung, J and Zhou, P and Gardashli, M and Pregent, LJ and Engelberg-Cook, E and Dickson, DW and Belzil, VV and Mukamel, EA and Dracheva, S}, title = {Author Correction: Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9588}, doi = {10.1038/s41467-024-53972-1}, pmid = {39505881}, issn = {2041-1723}, } @article {pmid39505319, year = {2024}, author = {Lee, J and Kim, A and Choi, SJ and Cho, E and Seo, J and Oh, SI and Jung, J and Kim, JS and Sung, JJ and Abrahams, S and Hong, YH}, title = {Erratum: Development and Validation of the Korean Version of the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS-K).}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {20}, number = {6}, pages = {637}, doi = {10.3988/jcn.2022.0403e}, pmid = {39505319}, issn = {1738-6586}, abstract = {This corrects the article on p. 454 in vol. 19, PMID: 37488957.}, } @article {pmid39505137, year = {2024}, author = {Abbasi, H and Jourabchi-Ghadim, N and Asgarzade, A and Mirshekari, M and Ebrahimi-Mameghani, M}, title = {Unveiling the veil of adipokines: A meta-analysis and systematic review in amyotrophic lateral sclerosis.}, journal = {Neuroscience}, volume = {563}, number = {}, pages = {1-9}, doi = {10.1016/j.neuroscience.2024.11.003}, pmid = {39505137}, issn = {1873-7544}, mesh = {*Amyotrophic Lateral Sclerosis/blood/metabolism ; Humans ; *Adipokines/blood ; Ghrelin/blood ; Leptin/blood ; Adiponectin/blood ; Disease Progression ; }, abstract = {BACKGROUND: Adipokines are proposed to be associated with ALS progression through assorted pathways. Therefore, The present meta-analysis explored the link between various adipokines and ALS progression.

METHOD: International database like PubMed, Scopus, and Web of Science databases were searched to achieve eligible papers published before December 2023. The following PICO structure was utilized: Population (patients with ALS); Intervention (serum concentrations of ghrelin, leptin, and adiponectin), Comparison (with or without controls), and Outcome (ALS progression). the risk of bias of selected papers was assessed through the Newcastle-Ottawa Scale (NOS) tool.

RESULTS: 11 out of 240 papers were selected for this study which were published between 2010 and 2024. Lower serum leptin concentrations were detected in the ALS compared to control groups (WMD: -0.91, 95% CI:-1.77, -0.05). Serum concentrations of adiponectin were higher in ALS compared to control groups (WMD: 0.41, 95% CI:-0.7, 0.89). Ultimately, The serum concentrations of ghrelin in the ALS groups were lower than control groups (WMD: -1.21, 95% CI: -2.95, 0.53).

CONCLUSION: Our findings revealed that serum concentrations of ghrelin and leptin were higher in ALS patients compared to control, unlike adiponectin.}, } @article {pmid39503426, year = {2025}, author = {Shimizu, M and Okuno, T}, title = {Disruption of neuronal actin barrier promotes the entry of disease-implicated proteins to exacerbate amyotrophic lateral sclerosis pathology.}, journal = {Neural regeneration research}, volume = {20}, number = {9}, pages = {2589-2590}, pmid = {39503426}, issn = {1673-5374}, } @article {pmid39503423, year = {2025}, author = {Alfahel, L and Rajkovic, A and Israelson, A}, title = {Translational challenges in amyotrophic lateral sclerosis therapy with macrophage migration inhibitory factor.}, journal = {Neural regeneration research}, volume = {20}, number = {9}, pages = {2583-2584}, pmid = {39503423}, issn = {1673-5374}, } @article {pmid39503319, year = {2024}, author = {Bedlack, R and Li, X and Evangelista, BA and Panzetta, ME and Kwan, J and Gittings, LM and Sattler, R}, title = {The Scientific and Therapeutic Rationale for Off-Label Treatments in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {97}, number = {1}, pages = {15-27}, pmid = {39503319}, issn = {1531-8249}, support = {//ALS Association/ ; }, abstract = {There are no dramatically effective pharmacological treatments for most patients with amyotrophic lateral sclerosis, a complex disease with multiple underlying mechanisms, such as neuroinflammation, oxidative stress, mitochondrial dysfunction, microbiome alteration, and antiretroviral activity. We sifted through 15 years of reviews by a group called ALSUntangled to identify 8 alternative and off-label treatments that target ≥1 of these mechanisms, and have ≥1 human trial suggesting meaningful benefits. Given the overlapping pathological mechanisms of the highlighted products, we suggest that combinations of these treatments targeting diverse mechanisms might be worthwhile for future amyotrophic lateral sclerosis therapy development. ANN NEUROL 2024.}, } @article {pmid39503018, year = {2024}, author = {Rennie, O and Sharma, M and Helwa, N}, title = {Hepatobiliary anastomotic leakage: a narrative review of definitions, grading systems, and consequences of leaks.}, journal = {Translational gastroenterology and hepatology}, volume = {9}, number = {}, pages = {70}, pmid = {39503018}, issn = {2415-1289}, abstract = {BACKGROUND AND OBJECTIVE: Hepatobiliary diseases are a longstanding and significant medical challenge which, despite advances in surgical techniques, still carry risks for postoperative complications such as anastomotic leaks (ALs), which can include both postoperative pancreatic fistula (POPF) and bile leaks (BL). These complications incur significant human and economic costs on all those involved, including the patient, healthcare providers, and hospital systems. The aim of this study was to construct a narrative review of literature surrounding definitions and grading systems for ALs in the context of hepato-pancreato-biliary (HPB) procedures, and consequences of POPF and BL.

METHODS: A literature review was conducted by examining databases including PubMed, Web of Science, OVID Embase, Google Scholar, and Cochrane library databases. Searches were performed with the following search criteria: (((((((anastomosis) OR (anastomotic leak*)) OR (postoperative pancreatic fistula)) OR (bile leak*)) OR (pancreaticoduodenectomy)) OR (whipple)) AND ((hepatobiliary) OR (hepato-pancreato-biliary)) AND ((definition) OR (grading system*) OR (consequences) OR (outcomes) OR (risk factor*) OR (morbidity) OR (mortality))). Publications that were retrieved underwent further assessment to ensure other relevant publications were identified and included.

KEY CONTENT AND FINDINGS: A universally accepted definition and grading system for POPF and BL continues to be lacking, leading to variability in reported incidence in the literature. Various groups have worked to publish guidelines for defining and grading POPF and BL, with the International Study Group in Pancreatic Surgery (ISGPS) and International Study Group for Liver Surgery (ISGLS) definitions the current most recommended definitions for POPF and BL, respectively. The burden of AL on patients, healthcare providers, and hospitals is well documented in evidence from leak consequences, such as increased morbidity and mortality, higher reoperation rates, and increased readmission rates, among others.

CONCLUSIONS: AL remains a significant challenge in HPB surgery, despite medical advancements. Understanding the progress made in defining and grading leaks, as well as the range of negative outcomes that arise from AL, is crucial in improving patient care, reduce surgical mortality, and drive further advancements in earlier detection and treatment of AL.}, } @article {pmid39502740, year = {2024}, author = {Nishiyama, A and Niihori, T and Suzuki, N and Izumi, R and Akiyama, T and Kato, M and Funayama, R and Nakayama, K and Warita, H and Aoki, Y and Aoki, M}, title = {Updated Genetic Analysis of Japanese Familial ALS Patients Carrying SOD1 Variants Revealed Phenotypic Differences for Common Variants.}, journal = {Neurology. Genetics}, volume = {10}, number = {6}, pages = {e200196}, pmid = {39502740}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease. Approximately 10% of ALS cases are familial, and more than 20 causative genes have been identified. As we have previously reported, SOD1 variants are the most common causes of familial ALS in Japan. Because antisense oligonucleotides for SOD1-linked ALS are being used in practical applications, the types of variants and the clinical features of patients need to be updated.

METHODS: We consecutively recruited 160 families with familial ALS in Japan. We performed genetic analyses, focusing on SOD1-linked ALS as the most common in our cohort, updated their genotypes, and characterized clinical phenotypes.

RESULTS: A total of 26 SOD1 variants in 56 patients and 49 families (30.6%) were collected, with the 3 most common (p.His47Arg [the conventional numbering; H46R], p.Leu127Ser [L126S], p.Asn87Ser [N86S]) accounting for 38.8% of all families. We also identified 2 novel variants (p.Ile36Phe [I35F] and p.Asn132Argfs*3 [N131Rfs*3]). The mean age at onset was 48.9 ± 12.2 (mean ± SD) years for all patients with SOD1-linked ALS. Lower limb onset comprised 70% of cases. The mean disease duration was 64.7 ± 82 months, and the median survival was 71.5 months. Some variants led to a relatively homogeneous phenotype, although clinical characteristics differed among types of variants and families. Patients with p.His47Arg (H46R) showed slower progression with lower limb onset and a predominance of lower motor neuron involvement. The p.Leu127Ser (L126S) variant led to varying degrees of progression in heterozygous or homozygous states and presented incomplete penetrance. Intrafamilial phenotypic differences were observed in families carrying p.Asn87Ser (N86S). Four variants (p.Cys7Gly [C6G], p.His44Arg [H43R], p.Leu85Val [L84V], and p.Cys147Arg [C146R]) were found to be associated with rapid disease progression.

DISCUSSION: The genetic basis of familial ALS, at least for SOD1 variants, still differed by geographic and ethnic background. Understanding these clinical profiles will help optimize evaluation in targeted gene therapy worldwide and benefit efficient diagnosis, leading to precise application in clinical practice.}, } @article {pmid39501538, year = {2024}, author = {Bampton, A and McHutchison, C and Talbot, K and Benatar, M and Thompson, AG and Turner, MR}, title = {The Basis of Cognitive and Behavioral Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Brain and behavior}, volume = {14}, number = {11}, pages = {e70115}, pmid = {39501538}, issn = {2162-3279}, support = {MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; Thompson/Jan20/952-795//Motor Neurone Disease Association Lady Edith Wolfson Clinician Scientist Fellowship/ ; //Foulkes Foundation/ ; //National Institutes of Health (NIH)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Cognitive Dysfunction/etiology/physiopathology ; }, abstract = {OBJECTIVE: To summarize and evaluate evidence pertaining to the clinical, genetic, histopathological, and neuroimaging correlates of cognitive and behavioral dysfunction in amyotrophic lateral sclerosis (ALS).

METHODOLOGY: We comprehensively reviewed the literature on cognitive and behavioral manifestations of ALS, narrating findings from both cross-sectional and longitudinal studies. We discussed knowledge gaps in the evidence base and key limitations affecting studies to date, before formulating a framework for future research paradigms aimed at investigating clinicopathological correlates of neuropsychological dysfunction in ALS.

RESULTS: Studies have demonstrated clinical associations with cognitive dysfunction in ALS e.g., bulbar-onset of symptoms, pathological associations (extramotor TDP-43 deposition), and imaging associations (frontotemporal involvement). The most common behavioral deficit, apathy, is highly associated with verbal fluency, but longitudinal studies assessing behavioral dysfunction in ALS are comparatively lacking.

CONCLUSION: Longitudinal studies have been helpful in identifying several potential correlates of cognitive and behavioral dysfunction but have frequently been confounded by selection bias and inappropriate testing platforms. This review provides a framework for more robust assessment of clinicopathological associations of neuropsychological abnormalities in ALS in the future, advocating for greater utilization of pre-symptomatic C9orf72 repeat expansion-carrying cohorts.}, } @article {pmid39501102, year = {2025}, author = {Howard, J and Chaouch, A and Douglas, AGL and MacLeod, R and Roggenbuck, J and McNeill, A}, title = {Genetic testing for monogenic forms of motor neuron disease/amyotrophic lateral sclerosis in unaffected family members.}, journal = {European journal of human genetics : EJHG}, volume = {33}, number = {1}, pages = {7-13}, pmid = {39501102}, issn = {1476-5438}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Family ; Genetic Counseling ; *Genetic Testing/methods/standards ; *Motor Neuron Disease/genetics/diagnosis ; }, abstract = {Motor neuron disease (MND), also referred to as amyotrophic lateral sclerosis (ALS), is a monogenic disease in a minority of cases, with autosomal dominant inheritance. Increasing numbers of people with MND are requesting genetic testing, and indeed receiving a genetic diagnosis. Consequently, requests for genetic counselling and predictive testing (i.e. of unaffected family members) are similarly expected to rise, alongside pre-symptomatic clinical trials. Despite this, there is no evidence-based guideline for predictive genetic testing in MND. This paper provides an overview of the genomic basis of MND, focusing specifically on the most common monogenic causes of MND. It then lays out the complexities of MND predictive testing, including the genetic landscape characterised by incomplete penetrance, clinical and genetic heterogeneity, and an oligogenic mechanism of pathogenesis in some cases. Additionally, there is limited research on the psychosocial impact of predictive genetic testing for MND, with studies suggesting potential difficulty in adjusting to the news, in part due to a lack of support and follow-up. This underscores a case for evidence-based, disease-specific guidance for predictive testing in MND.}, } @article {pmid39500920, year = {2024}, author = {Yu, M and Xu, J and Dutta, R and Trapp, B and Pieper, AA and Cheng, F}, title = {Network medicine informed multiomics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis.}, journal = {NPJ systems biology and applications}, volume = {10}, number = {1}, pages = {128}, pmid = {39500920}, issn = {2056-7189}, support = {R21 AG083003/AG/NIA NIH HHS/United States ; R01 AG082118/AG/NIA NIH HHS/United States ; R56 AG074001/AG/NIA NIH HHS/United States ; RF1 AG082211/AG/NIA NIH HHS/United States ; R01 AG084250/AG/NIA NIH HHS/United States ; RF1 NS133812/NS/NINDS NIH HHS/United States ; RF1NS133812//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; U01 AG073323/AG/NIA NIH HHS/United States ; U01AG073323//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG082118//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG066707//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG066707/AG/NIA NIH HHS/United States ; R01AG076448//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R21AG083003//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG076448/AG/NIA NIH HHS/United States ; RF1AG082211//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG084250//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism ; Humans ; *Quantitative Trait Loci/genetics ; Genome-Wide Association Study/methods ; Drug Repositioning/methods ; Genomics/methods ; Protein Interaction Maps/genetics/drug effects ; Multiomics ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. We developed a network medicine methodology via integrating human brain multi-omics data to prioritize drug targets and repurposable treatments for ALS. We leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on human brain expression quantitative trait loci (QTL) (eQTL), protein QTL (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Using a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in known ALS pathobiological pathways. Applying network proximity analysis of predicted ALS-associated genes and drug-target networks under the human protein-protein interactome (PPI) model, we identified potential repurposable drugs (i.e., Diazoxide and Gefitinib) for ALS. Subsequent validation established preclinical evidence for top-prioritized drugs. In summary, we presented a network-based multi-omics framework to identify drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.}, } @article {pmid39500483, year = {2024}, author = {Piotrkiewicz, M}, title = {Possible changes in motor neuron discharge characteristics in presymptomatic amyotrophic lateral sclerosis.}, journal = {The Journal of physiology}, volume = {602}, number = {24}, pages = {6631-6635}, doi = {10.1113/JP287788}, pmid = {39500483}, issn = {1469-7793}, } @article {pmid39496878, year = {2025}, author = {Yang, T and Wei, Q and Pang, D and Cheng, Y and Huang, J and Lin, J and Xiao, Y and Jiang, Q and Wang, S and Li, C and Shang, H}, title = {Mutation Screening of ATXN1, ATXN2, and ATXN3 in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {62}, number = {4}, pages = {4854-4865}, pmid = {39496878}, issn = {1559-1182}, support = {82371430//National Natural Science Foundation of China/ ; 2022ZDZX0023//Sichuan Science and Technology Program/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Ataxin-3/genetics ; Female ; *Ataxin-2/genetics ; Male ; *Ataxin-1/genetics ; Middle Aged ; *Genetic Predisposition to Disease ; Mutation/genetics ; Aged ; DNA Mutational Analysis ; Cohort Studies ; Repressor Proteins ; }, abstract = {Emerging evidence suggests potential disease modifying roles of ATXN1, ATXN2, and ATXN3 in amyotrophic lateral sclerosis (ALS). We aimed to provide a comprehensive variants profile of the ATXN1, ATXN2, and ATXN3 genes and examine the association of these variants with the risk and clinical characteristics of ALS. We screened and analyzed the rare variants in a cohort of 2220 ALS patients from Southwest China, using controls from the Genome Aggregation Database (gnomAD) and the China Metabolic Analytics Project (ChinaMAP). The over-representation of rare variants and their association with disease risk in ALS patients were assessed using Fisher's exact test with Bonferroni correction at both allele and gene levels. Kaplan-Meier analysis was employed to explore the relationship between the distribution of variants and survival. A total of 62 eligible rare missense variants were identified, comprising 32 from ATXN1, 21 from ATXN2, and 9 from ATXN3. Allelic association testing revealed a significant enrichment of the ATXN1 (c.2122C > G, p.Leu708Val) variant and the ATXN2 (c.3778C > G, p.Pro1260Ala) variant in ALS. Gene burden analysis indicated that variants in the ATXN1 and ATXN3 genes had a higher burden in ALS. Substantial heterogeneity in survival time was observed among patients carrying different variants within the same gene. However, there were no significant differences in survival between ALS patients grouped by N-terminal or C-terminal distribution. Our results provided a genetic variation profile of ATXN1, ATXN2, and ATXN3 in ALS patients, along with the clinical characteristics of individuals carrying these variations. This information might offer valuable insights for the ongoing ALS disease-modifying treatments.}, } @article {pmid39496465, year = {2024}, author = {Baker, MR and Maitland, S}, title = {Response to: 'Cortical Inexcitability in ALS: Correlating a Clinical Phenotype'.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-334587}, pmid = {39496465}, issn = {1468-330X}, } @article {pmid39496035, year = {2024}, author = {Xu, W and Zhao, X and Wang, J and Guo, Y and Ren, Z and Cai, L and Wu, S and Zhou, M}, title = {Different intensities of physical activity for amyotrophic lateral sclerosis and Parkinson disease: A Mendelian randomization study and meta-analysis.}, journal = {Medicine}, volume = {103}, number = {44}, pages = {e40141}, pmid = {39496035}, issn = {1536-5964}, support = {ZYYLJRC201911//the Anhui Province Traditional Chinese Medicine Leading Talents Construction Project/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Amyotrophic Lateral Sclerosis/genetics ; *Parkinson Disease/genetics/epidemiology ; *Exercise ; Genome-Wide Association Study ; }, abstract = {BACKGROUND: The causal relationships between amyotrophic lateral sclerosis (ALS), Parkinson disease and different intensities of physical activity (PA) are still inconclusive. To evaluate the causal impact of PA on ALS and Parkinson disease (PD), this study integrates evidence from Mendelian randomization (MR) using a meta-analysis approach.

METHODS: MR analyses on genetically predicted levels of PA (compose of self-reported moderate-to-vigorous physical activity [MVPA], self-reported vigorous physical activity [VPA], and strenuous sports or other exercises [SSOE]) regarding ALS and PD published up to July 27, 2024, were obtained from PubMed, Scopus, Web of Science, and Embase. De novo MR studies were analyzed utilizing publicly accessible datasets from genome-wide association studies and then meta-analyses were performed to pool the results.

RESULTS: Meta-analyses of results of 12 de novo MR studies analyses and 2 published MR studies indicated that genetic predicted levels of MVPA (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.08-1.38), VPA (OR: 1.32, 95% CI: 1.08-1.60), and SSOE (OR: 1.35, 95% CI: 1.07-1.70) were related to a raised risk of ALS, but not causally with PD.

CONCLUSION: Our findings showed no causal relationships between MVPA, VPA, SSOE, and PD, while MVPA, VPA, and SSOE were associated with increased ALS risk, highlighting the need for targeted PA recommendations for disease management.}, } @article {pmid39495912, year = {2024}, author = {Wheeler, HB and Madrigal, AA and Chaim, IA}, title = {Mapping the future of oxidative RNA damage in neurodegeneration: Rethinking the status quo with new tools.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {46}, pages = {e2317860121}, pmid = {39495912}, issn = {1091-6490}, support = {R00 NS121511/NS/NINDS NIH HHS/United States ; 4R00NS121511-03//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics ; *RNA/metabolism/genetics ; *Oxidation-Reduction ; Oxidative Stress ; RNA-Binding Proteins/metabolism/genetics ; Proteomics/methods ; Animals ; }, abstract = {Over two decades ago, increased levels of RNA oxidation were reported in postmortem patients with ALS, Alzheimer's, Parkinson's, and other neurodegenerative diseases. Interestingly, not all cell types and transcripts were equally oxidized. Furthermore, it was shown that RNA oxidation is an early phenomenon, altogether indicating that oxidative RNA damage could be a driver, and not a consequence, of disease. Despite all these exciting observations, the field appears to have stagnated since then. We argue that this is a consequence of the shortcomings of technologies to model these diseases, limiting our understanding of which transcripts are being oxidized, which RNA-binding proteins are interacting with these RNAs, what their implications are in RNA processing, and as a result, what their potential role is in disease onset and progression. Here, we discuss the limits of previous technologies and propose ways by which advancements in iPSC-derived disease modeling, proteomics, and sequencing technologies can be combined and leveraged to answer new and decades-old questions.}, } @article {pmid39494889, year = {2024}, author = {Ito, SI and Tanaka, Y}, title = {Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {212}, pages = {}, doi = {10.3791/67385}, pmid = {39494889}, issn = {1940-087X}, mesh = {*Extracellular Vesicles/metabolism ; Humans ; *Microtubule-Associated Proteins/metabolism/genetics ; Autophagy/physiology ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {(Macro)autophagy represents a fundamental cellular degradation pathway. In this process, double-membraned vesicles known as autophagosomes engulf cytoplasmic contents, subsequently fusing with lysosomes for degradation. Beyond the canonical role, autophagy-related genes also modulate a secretory pathway involving the release of inflammatory molecules, tissue repair factors, and extracellular vesicles (EVs). Notably, the process of disseminating pathological proteins between cells, particularly in neurodegenerative diseases affecting the brain and spinal cord, underscores the significance of understanding this phenomenon. Recent research suggests that the transactive response DNA-binding protein 43 kDa (TDP-43), a key player in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, is released in an autophagy-dependent manner via EVs enriched with the autophagosome marker microtubule-associated proteins 1A/1B light chain 3B-II (LC3-II), especially when autophagosome-lysosome fusion is inhibited. To elucidate the mechanism underlying the formation and release of LC3-II-positive EVs, it is imperative to establish an accessible and reproducible method for evaluating both intracellular and extracellular LC3-II-positive vesicles. This study presents a detailed protocol for assessing LC3-II levels via immunoblotting in cellular and EV fractions obtained through differential centrifugation. Bafilomycin A1 (Baf), an inhibitor of autophagosome-lysosome fusion, serves as a positive control to enhance the levels of intracellular and extracellular LC3-II-positive vesicles. Tumor susceptibility gene 101 (TSG101) is used as a marker for multivesicular bodies. Applying this protocol, it is demonstrated that siRNA-mediated knockdown of syntaxin-6 (STX6), a genetic risk factor for sporadic Creutzfeldt-Jakob disease, augments LC3-II levels in the EV fraction of cells treated with Baf while showing no significant effect on TSG101 levels. These findings suggest that STX6 may negatively regulate the extracellular release of LC3-II via EVs, particularly under conditions where autophagosome-lysosome fusion is impaired. Combined with established methods for evaluating autophagy, this protocol provides valuable insights into the role of specific molecules in the formation and release of LC3-II-positive EVs.}, } @article {pmid39494653, year = {2025}, author = {Springer, SA}, title = {Commentary on Gregory et al.: Fear of precipitated opioid withdrawal should not prevent buprenorphine initiation.}, journal = {Addiction (Abingdon, England)}, volume = {120}, number = {1}, pages = {21-22}, pmid = {39494653}, issn = {1360-0443}, support = {DP1 DA056106/DA/NIDA NIH HHS/United States ; NIDA DP1DA056106/DA/NIDA NIH HHS/United States ; }, abstract = {Provision of buprenorphine treatment for opioid use disorder is often stymied by clinicians’ concerns for precipitated opioid withdrawal. Gregory et al’s systematic review identified a low level of precipitated withdrawal with buprenorphine induction even among persons who reported fentanyl use. Evidence, not fear should guide treatment.}, } @article {pmid39494632, year = {2025}, author = {Uzunçakmak-Uyanık, H and Tan, E and Temuçin, ÇM and Yıldız, FG}, title = {Lack of habituation in somatosensory cortex but not in visual cortex of ALS patients.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {93-102}, doi = {10.1080/21678421.2024.2421747}, pmid = {39494632}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Visual Cortex/physiopathology ; Aged ; *Habituation, Psychophysiologic/physiology ; *Somatosensory Cortex/physiopathology ; *Evoked Potentials, Somatosensory/physiology ; *Evoked Potentials, Visual/physiology ; Adult ; Electroencephalography/methods ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a multisystem degenerative disease with extra-motor components. In ALS, there is also hyperexcitability of extra-motor areas. Habituation is defined as ''a response decrement" caused by repeated stimulations. Studies on evoked potential habituation can be conducted to detect cortical excitability. This study aimed to explore lack of habituation in non-motor cortical structures in ALS.

METHODS: Twenty-one ALS patients and 14 controls were enrolled. Recordings were obtained in 3 and 10 consecutive blocks (each containing 100 responses) during right median somatosensory evoked potential (SEP) and bilateral visual evoked potential (VEP), respectively. "Habituation" and "lack of habituation" were defined as the amount of increase or decrease in the average N20 or N75-P100 amplitude of the last blocks compared to the first blocks, respectively. Comparative analyses were performed between patient and control groups, as well as the first and last block within groups.

RESULTS: Paired sample t-test showed that in control group N20 peak amplitude of last blocks were significantly lower than first block values (p = 0.025) that indicate the physiological habituation as expected. On the other hand, there was not such a difference in ALS group (p = 0.239) which indicated lack of habituation.

CONCLUSIONS: Our study results suggest somatosensory hyperexcitability in line with cortical reorganization in ALS patients.}, } @article {pmid39494512, year = {2024}, author = {Donohoe, MN and Upadhyay, A and Pratt, DA}, title = {Ligand-Based Radical Reactivity of Metal Thiosemicarbazones Prompts the Identification of Platinum(II)-Based Cytoprotectants.}, journal = {Journal of the American Chemical Society}, volume = {146}, number = {45}, pages = {31307-31320}, doi = {10.1021/jacs.4c12713}, pmid = {39494512}, issn = {1520-5126}, mesh = {*Thiosemicarbazones/chemistry/pharmacology ; Ligands ; *Platinum/chemistry/pharmacology ; *Coordination Complexes/chemistry/pharmacology/chemical synthesis ; Humans ; Antioxidants/chemistry/pharmacology ; Lipid Peroxidation/drug effects ; Molecular Structure ; Copper/chemistry ; Neuroprotective Agents/chemistry/pharmacology/chemical synthesis ; }, abstract = {CuATSM, a copper(II) complex of a bis(thiosemicarbazone) of diacetyl, prevents oxidative cell death and acts as a neuroprotectant in vivo, prompting its evaluation to treat amyotrophic lateral sclerosis and other neurodegenerative conditions in the clinic. We recently demonstrated that CuATSM functions as a potent radical-trapping antioxidant (RTA), inhibiting lipid peroxidation and associated ferroptotic cell death by a noncanonical mechanism based on radical addition to the ligand backbone. Herein we report our investigations of the generality of this reactivity, which include studies of corresponding complexes of various other metals, including Co, Ru, Ni, Pd, Pt, and Au. Inhibited autoxidations of styrene and dioxane reveal that most of these complexes exhibit RTA activity, consistent with ligand-based reactivity, but the identity of the metal atom nevertheless plays a role. In particular, analyses of the electronic structures of the complexes of metals within the same group (i.e., the group 10 metals Ni, Pd and Pt) highlight how the metal atom can modulate the ligand-based reactivity by enabling spin delocalization to the other thiosemicarbazone moiety. The RTA activity determined in organic solution largely translates to phospholipid bilayers and mammalian cells, where most complexes inhibited lipid peroxidation and associated ferroptotic cell death. A preliminary structure-activity study revealed Pt complexes with potencies eclipsing those of archetype ferroptosis inhibitors ferrostatin-1 and liproxstatin-1, suggesting that Pt (and to a lesser extent Ni) bis(thiosemicarbazone)s may be better suited to optimization for therapeutic development than those based on Cu.}, } @article {pmid39494508, year = {2024}, author = {Mariani, D and Setti, A and Castagnetti, F and Vitiello, E and Stufera Mecarelli, L and Di Timoteo, G and Giuliani, A and D'Angelo, A and Santini, T and Perego, E and Zappone, S and Liessi, N and Armirotti, A and Vicidomini, G and Bozzoni, I}, title = {ALS-associated FUS mutation reshapes the RNA and protein composition of stress granules.}, journal = {Nucleic acids research}, volume = {52}, number = {21}, pages = {13269-13289}, pmid = {39494508}, issn = {1362-4962}, support = {ERC-2019-SyG 855923-ASTRA//ERC/ ; IG 2019 Id. 23053//Associazione Italiana per la Ricerca sul Cancro/ ; CN00000041//NextGenerationEU/ ; //Istituto Italiano di Tecnologia/ ; }, mesh = {*RNA-Binding Protein FUS/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Mutation ; *Stress Granules/metabolism/genetics ; Cell Line, Tumor ; Transcriptome ; RNA/metabolism/genetics ; RNA, Messenger/metabolism/genetics ; RNA-Binding Proteins/metabolism/genetics ; Cytoplasmic Granules/metabolism/genetics ; }, abstract = {Stress granules (SG) are part of a cellular protection mechanism where untranslated messenger RNAs and RNA-binding proteins are stored upon conditions of cellular stress. Compositional variations due to qualitative or quantitative protein changes can disrupt their functionality and alter their structure. This is the case of different forms of amyotrophic lateral sclerosis (ALS) where a causative link has been proposed between the cytoplasmic de-localization of mutant proteins, such as FUS (Fused in Sarcoma), and the formation of cytotoxic inclusions. Here, we describe the SG transcriptome in neuroblastoma cells and define several features for RNA recruitment in these condensates. We demonstrate that SG dynamics and RNA content are strongly modified by the incorporation of mutant FUS, switching to a more unstructured, AU-rich SG transcriptome. Moreover, we show that mutant FUS, together with its protein interactors and their target RNAs, are responsible for the reshaping of the mutant SG transcriptome with alterations that can be linked to neurodegeneration. Our data describe the molecular differences between physiological and pathological SG in ALS-FUS conditions, showing how FUS mutations impact the RNA and protein composition of these condensates.}, } @article {pmid39494098, year = {2024}, author = {Xu, AX and Zhao, ZF and Zhu, L and Zhang, YH and Li, Y and Wei, YF and Zhang, BY and Jiang, B and Gao, TZ and Li, MS and Liu, JY}, title = {Promise and challenges of traditional Chinese medicine, specifically Calculus bovis, in liver cancer treatment.}, journal = {World journal of gastroenterology}, volume = {30}, number = {40}, pages = {4380-4385}, pmid = {39494098}, issn = {2219-2840}, mesh = {Humans ; Drugs, Chinese Herbal/therapeutic use ; *Liver Neoplasms/therapy/pathology/mortality ; *Medicine, Chinese Traditional/methods ; Neoplasm Staging ; Quality of Life ; Treatment Outcome ; }, abstract = {Liver cancer, one of the most common malignancies worldwide, ranks sixth in incidence and third in mortality. Liver cancer treatment options are diverse, including surgical resection, liver transplantation, percutaneous ablation, transarterial chemoembolization, radiotherapy, chemotherapy, targeted therapy, immunotherapy, and traditional Chinese medicine (TCM). A multidisciplinary team (MDT) is essential to customize treatment plans based on tumor staging, liver function, and performance status (PS), ensuring individualized patient care. Treatment decisions require a MDT to tailor strategies based on tumor staging, liver function, and PS, ensuring personalized care. The approval of new first-line and second-line drugs and the establishment of standard treatments based on immune checkpoint inhibitors have significantly expanded treatment options for advanced liver cancer, improving overall prognosis. However, many patients do not respond effectively to these treatments and ultimately succumb to the disease. Modern oncology treatments, while extending patient survival, often come with severe side effects, resistance, and damage to the body, negatively impacting quality of life. Huang et al's study published at World Journal of Gastroenterology rigorously validates the anticancer properties of Calculus bovis, enhancing our understanding of TCM and contributing to new liver cancer treatment strategies. For over 5000 years, TCM has been used in East Asian countries like China to treat various diseases, including liver conditions. Analysis of real-world clinical data suggests that for patients with advanced-stage tumors lacking effective treatments, integrated TCM therapies could provide significant breakthroughs.}, } @article {pmid39493687, year = {2024}, author = {Kato, N and Hashida, G and Kobayashi, M and Sahara, W}, title = {Characteristics and factors associated with independence in the activities of daily living of patients with amyotrophic lateral sclerosis at diagnosis.}, journal = {Journal of physical therapy science}, volume = {36}, number = {11}, pages = {692-698}, pmid = {39493687}, issn = {0915-5287}, abstract = {[Purpose] To investigate the characteristics and factors associated with independence in the activities of daily living in patients with amyotrophic lateral sclerosis at diagnosis based on clinical phenotypes. [Participants and Methods] Fifty-seven participants diagnosed with amyotrophic lateral sclerosis were assessed using the Barthel Index. Participants were classified into three clinical phenotypes (bulbar-onset, upper limb-onset, and lower limb-onset), and the total and subitem scores were compared. To statistically examine factors associated with independence in the activities of daily living, the participants were divided into two groups: Barthel Index of 100 and ≤95. [Results] The total, bulbar-onset, upper limb-onset, and lower limb-onset Barthel Index scores were 87.9 ± 17.7, 96.7 ± 5.9, 92.5 ± 11.9, and 70.0 ± 22.2, respectively. The Total Barthel Index and lower limb-related activities of daily living scores were significantly lower in the lower limb-onset group, and knee extension muscle strength was identified as a factor associated with independence, with a cutoff value of 32.0%. [Conclusion] Patients with lower limb onset had more impairments in lower limb-related activities of daily living than those with other clinical phenotypes. To maintain independence in patients with amyotrophic lateral sclerosis at diagnosis, it is necessary to improve knee extension muscle strength through exercise and perform environment adjustments using the cutoff values as indicators.}, } @article {pmid39492846, year = {2024}, author = {Matera, AG and Steiner, RE and Mills, CA and McMichael, BD and Herring, LE and Garcia, EL}, title = {Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network.}, journal = {Frontiers in RNA research}, volume = {2}, number = {}, pages = {}, pmid = {39492846}, issn = {2813-7116}, support = {P30 CA016086/CA/NCI NIH HHS/United States ; R35 GM136435/GM/NIGMS NIH HHS/United States ; }, abstract = {INTRODUCTION: Molecular chaperones and co-chaperones are highly conserved cellular components that perform a variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN. The Survival Motor Neuron (SMN) complex is an assembly chaperone and serves as a paradigm for studying how specific RNAs are identified and paired with their client substrate proteins to form RNPs. SMN is the eponymous component of a large complex, required for the biogenesis of uridine-rich small nuclear ribonucleoproteins (U-snRNPs), that localizes to distinct membraneless organelles in both the nucleus and cytoplasm of animal cells. SMN protein forms the oligomeric core of this complex, and missense mutations in the human SMN1 gene are known to cause Spinal Muscular Atrophy (SMA). The basic framework for understanding how snRNAs are assembled into U-snRNPs is known. However, the pathways and mechanisms used by cells to regulate their biogenesis are poorly understood.

METHODS: Given the importance of these processes to normal development as well as neurodegenerative disease, we set out to identify and characterize novel SMN binding partners. We carried out affinity purification mass spectrometry (AP-MS) of Drosophila SMN complexes using fly lines exclusively expressing either wildtype or SMA-causing missense alleles.

RESULTS: Bioinformatic analyses of the pulldown data, along with comparisons to proximity labeling studies carried out in human cells, revealed conserved connections to at least two other major chaperone systems including heat shock folding chaperones (HSPs) and histone/nucleosome assembly chaperones. Notably, we found that heat shock cognate protein Hsc70-4 and other HspA family members preferentially associated with SMA-causing alleles of SMN.

DISCUSSION: Hsc70-4 is particularly interesting because its mRNA is aberrantly sequestered by a mutant form of TDP-43 in mouse and Drosophila ALS (Amyotrophic Lateral Sclerosis) disease models. Most important, a missense allele of Hsc70-4 (HspA8 in mammals) was recently identified as a bypass suppressor of the SMA phenotype in mice. Collectively, these findings suggest that chaperone-related dysfunction lies at the etiological root of both ALS and SMA.}, } @article {pmid39492487, year = {2023}, author = {Xu, L and Ma, Y and Ji, Y and Ma, Y and Wang, Y and Zhao, X and Ge, S}, title = {Obesity exacerbates postoperative cognitive dysfunction by activating the PARP1/NAD[+]/SIRT1 axis through oxidative stress.}, journal = {Experimental gerontology}, volume = {}, number = {}, pages = {112320}, doi = {10.1016/j.exger.2023.112320}, pmid = {39492487}, issn = {1873-6815}, abstract = {The purposes of this study were to explore the impact of obesity on postoperative cognitive dysfunction (POCD) and to investigate the underlying mechanism by which obesity exacerbates POCD. In this study, fifteen-month-old male C57BL/6 J mice were fed a High-fat diet for three months to establish obesity models. Internal fixation of tibial fractures under isoflurane inhalation was performed to construct a POCD animal model. Three days after surgery, mice were subjected to the Morris water maze (MWM) experiment to evaluate their learning and memory abilities. The findings from the MWM experiment revealed that in comparison to the Ad Libitum Surgical group (ALS), mice in the High-fat Surgical group (HFS) exhibited prolonged escape latencies and reduced platform crossings. These outcomes suggest the potential exacerbating role of obesity in cognitive impairment within the POCD mouse models. Immunofluorescence (IF) findings demonstrate that obesity intensifies anesthesia and surgery-induced oxidative stress levels within the hippocampus. Compared to the Ad Libitum Control group (ALC), an elevation in PARP1 expression and a reduction in the NAD[+]/NADH ratio and SIRT1 expression were observed in the hippocampus of mice from the ALS. Moreover, when contrasting the HFS group with the ALS group, increased PARP1 expression along with decreased NAD[+]/NADH ratio and SIRT1 expression were evident. In vitro studies found that compared with the Control group (CON), oil red staining and BODIPY probe staining showed significant lipid droplet aggregation in the palmitic acid (PA) group. IF results demonstrated that HT22 cells in the PA group experienced oxidative stress and activation of the PARP1/NAD[+]/SIRT1 axis in contrast to the CON group. Moreover, manipulation of PARP1 expression in HT22 cells through PARP1 lentivirus-based silencing or overexpression revealed a converse relationship between PARP1 expression levels and the NAD[+]/NADH ratio as well as SIRT1 expression levels. This study concludes that obesity may exacerbate POCD by triggering activation of the oxidative stress-induced PARP1/NAD[+]/SIRT1 axis.}, } @article {pmid39492438, year = {2023}, author = {Hamzeh, O and Rabiei, F and Shakeri, M and Parsian, H and Saadat, P and Rostami-Mansoor, S}, title = {Mitochondrial dysfunction and inflammasome activation in neurodegenerative diseases: Mechanisms and therapeutic implications.}, journal = {Mitochondrion}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.mito.2023.10.003}, pmid = {39492438}, issn = {1872-8278}, abstract = {Impaired mitochondrial function is crucial to the pathogenesis of several neurodegenerative diseases. It causes the release of mitochondrial DNA (mtDNA), mitochondrial reactive oxygen species (mtROS), ATP, and cardiolipin, which activate the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. NLRP3 inflammasome is an important innate immune system element contributing to neuroinflammation and neurodegeneration. Therefore, targeting the NLRP3 inflammasome has become an interesting therapeutic approach for treating neurodegenerative diseases. This review describes the role of mitochondrial abnormalities and over-activated inflammasomes in the progression of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Friedrich ataxia (FRDA). We also discuss the therapeutic strategies focusing on signaling pathways associated with inflammasome activation, which potentially alleviate neurodegenerative symptoms and impede disease progression.}, } @article {pmid39492095, year = {2023}, author = {Mohammadi, S and Mohammadi, M and Ghaderi, S}, title = {Sleep-related regions in neurodegenerative diseases by central nervous system localization using magnetic resonance imaging.}, journal = {Psychiatry research. Neuroimaging}, volume = {336}, number = {}, pages = {111727}, doi = {10.1016/j.pscychresns.2023.111727}, pmid = {39492095}, issn = {1872-7506}, abstract = {Sleep disruptions associated with neurodegenerative diseases (NDDs) damage the brain's sleep-regulating regions. Advanced magnetic resonance imaging (MRI) techniques can characterize the signature of each neurodegenerative pathology. We performed an evaluation of sleep-related regions in NDDs using MRI to localize the central nervous system (CNS). In the initial search, 61 related papers were discovered using predetermined inclusion and exclusion criteria. Finally, 30 articles were included in this study. The study included patients with Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), rapid eye movement (REM) sleep behavior disorder (RBD), idiopathic RBD (iRBD), amyotrophic lateral sclerosis (ALS), and mild cognitive impairment (MCI). Sleep-related regions recognized by CNS localization in NDDs can be linked to important regions. MRI also revealed cortical thinning, GM atrophy, WM, and tract loss, changes in diffusion tensor imaging (DTI) biomarkers (fractional anisotropy (FA), axial diffusivity (Da), and radial diffusivity (Dr)), a decrease in DMN connectivity, a reduction in functional connectivity (FC), and amplitude of low-frequency fluctuation (ALFF) alterations. Sleep plays an important role in predicting future risks for the development of NDDs. Other neuroimaging, cognitive-behavioral, and clinical research can use the information found in this research about the brain regions, MRI biomarker changes, and their relationships.}, } @article {pmid39491718, year = {2024}, author = {Sharma, R and Khan, Z and Mehan, S and Das Gupta, G and Narula, AS}, title = {Unraveling the multifaceted insights into amyotrophic lateral sclerosis: Genetic underpinnings, pathogenesis, and therapeutic horizons.}, journal = {Mutation research. Reviews in mutation research}, volume = {794}, number = {}, pages = {108518}, doi = {10.1016/j.mrrev.2024.108518}, pmid = {39491718}, issn = {1388-2139}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Mutation/genetics ; RNA-Binding Protein FUS/genetics ; C9orf72 Protein/genetics ; Animals ; Superoxide Dismutase-1/genetics ; DNA-Binding Proteins/genetics ; Genetic Predisposition to Disease ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS), a progressive neurodegenerative disease, primarily impairs upper and lower motor neurons, leading to debilitating motor dysfunction and eventually respiratory failure, widely known as Lou Gehrig's disease. ALS presents with diverse symptomatology, including dysarthria, dysphagia, muscle atrophy, and hyperreflexia. The prevalence of ALS varies globally, with incidence rates ranging from 1.5 to 3.8 per 100,000 individuals, significantly affecting populations aged 45-80. A complex interplay of genetic and environmental factors underpins ALS pathogenesis. Key genetic contributors include mutations in chromosome 9 open reading frame 72 (C9ORF72), superoxide dismutase type 1 (SOD1), Fusedin sarcoma (FUS), and TAR DNA-binding protein (TARDBP) genes, accounting for a considerable fraction of both familial (fALS) and sporadic (sALS) cases. The disease mechanism encompasses aberrant protein folding, mitochondrial dysfunction, oxidative stress, excitotoxicity, and neuroinflammation, contributing to neuronal death. This review consolidates current insights into ALS's multifaceted etiology, highlighting the roles of environmental exposures (e.g., toxins, heavy metals) and their interaction with genetic predispositions. We emphasize the polygenic nature of ALS, where multiple genetic variations cumulatively influence disease susceptibility and progression. This aspect underscores the challenges in ALS diagnosis, which currently lacks specific biomarkers and relies on symptomatology and familial history. Therapeutic strategies for ALS, still in nascent stages, involve symptomatic management and experimental approaches targeting molecular pathways implicated in ALS pathology. Gene therapy, focusing on specific ALS mutations, and stem cell therapy emerge as promising avenues. However, effective treatments remain elusive, necessitating a deeper understanding of ALS's genetic architecture and the development of targeted therapies based on personalized medicine principles. This review aims to provide a comprehensive understanding of ALS, encouraging further research into its complex genetic underpinnings and the development of innovative, effective treatment modalities.}, } @article {pmid39491634, year = {2024}, author = {Tedeschi, V and Nele, V and Valsecchi, V and Anzilotti, S and Vinciguerra, A and Zucaro, L and Sisalli, MJ and Cassiano, C and De Iesu, N and Pignataro, G and Canzoniero, LMT and Pannaccione, A and De Rosa, G and Secondo, A}, title = {Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channel.}, journal = {Pharmacological research}, volume = {210}, number = {}, pages = {107491}, doi = {10.1016/j.phrs.2024.107491}, pmid = {39491634}, issn = {1096-1186}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology ; Animals ; *Transient Receptor Potential Channels/metabolism ; *Lysosomes/drug effects/metabolism ; *Motor Neurons/drug effects/metabolism ; *Disease Models, Animal ; Neuroprotective Agents/pharmacology/therapeutic use ; Mice, Transgenic ; Humans ; Mice ; Phosphatidylinositols/metabolism ; Phosphatidylinositol Phosphates/metabolism ; Male ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease currently incurable, in which motor neuron degeneration leads to voluntary skeletal muscle atrophy. Molecularly, ALS is characterized by protein aggregation, synaptic and organellar dysfunction, and Ca[2+] dyshomeostasis. Of interest, autophagy dysfunction is emerging as one of the main putative targets of ALS therapy. A tune regulation of this cleansing process is affordable by a proper stimulation of TRPML1, one of the main lysosomal channels. However, TRPML1 activation by PI(3,5)P2 has low open probability to remain in an active conformation. To overcome this drawback we developed a lipid-based formulation of PI(3,5)P2 whose putative therapeutic potential has been tested in in vitro and in vivo ALS models. Pharmacodynamic properties of PI(3,5)P2 lipid-based formulations (F1 and F2) on TRPML1 activity have been characterized by means of patch-clamp electrophysiology and Fura-2AM video-imaging in motor neuronal cells. Once selected for the ability to stabilize TRPML1 activity, the most effective preparation F1 was studied in vivo to measure neuromuscular function and survival of SOD1[G93A] ALS mice, thereby establishing its therapeutic profile. F1, but not PI(3,5)P2 alone, stabilized the open state of the lysosomal channel TRPML1 and increased the persistence of intracellular calcium concentration ([Ca[2+]]i). Then, F1 was effective in delaying motor neuron loss, improving innervated endplants and muscle performance in SOD1[G93A] mice, extending overall lifespan by an average of 10 days. Of note F1 prevented gliosis and autophagy dysfunction in ALS mice by restoring PI(3,5)P2 level. Our novel self-assembling lipidic formulation for PI(3,5)P2 delivery exerts a neuroprotective effect in preclinical models of ALS mainly regulating dysfunctional autophagy through TRPML1 activity stabilization.}, } @article {pmid39491419, year = {2023}, author = {Talebi, M and Sadoughi, MM and Ayatollahi, SA and Ainy, E and Kiani, R and Zali, A and Miri, M}, title = {Therapeutic potentials of cannabidiol: Focus on the Nrf2 signaling pathway.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {168}, number = {}, pages = {115805}, doi = {10.1016/j.biopha.2023.115805}, pmid = {39491419}, issn = {1950-6007}, abstract = {Cannabidiol (CBD), a cannabinoid that does not create psychoactive activities, has been identified as having a multitude of therapeutic benefits. This study delves into the chemical properties, pharmacokinetics, safety and toxicity, pharmacological effects, and most importantly, the association between the therapeutic potential of CBD and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The relationship between Nrf2 and CBD is closely linked to certain proteins that are associated with cardiovascular dysfunctions, cancers, and neurodegenerative conditions. Specifically, Nrf2 is connected to the initiation and progression of diverse health issues, including nephrotoxicity, bladder-related diseases, oral mucositis, cancers, obesity, myocardial injury and angiogenesis, skin-related inflammations, psychotic disorders, neuropathic pain, Huntington's disease, Alzheimer's disease, Parkinson's disease, neuroinflammation, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. The association between CBD and Nrf2 is a zone of great interest in the medical field, as it has the potential to significantly impact the treatment and prevention of wide-ranging health conditions. Additional investigation is necessary to entirely apprehend the mechanisms underlying this crucial interplay and to develop effective therapeutic interventions.}, } @article {pmid39491120, year = {2023}, author = {Stachel, SJ and Wang, D and Ginnetti, AT and Niroomand, S and Ma, L and Hu, Y and Fay, JF and Lemaire, W and Krosky, DJ and Ramirez, AD and Zariwala, HA and Coleman, PJ}, title = {Virtual screening for early identification of potent and selective histone deacetylase 6 inhibitor series.}, journal = {Bioorganic & medicinal chemistry letters}, volume = {}, number = {}, pages = {129537}, doi = {10.1016/j.bmcl.2023.129537}, pmid = {39491120}, issn = {1464-3405}, abstract = {Virtual screening was leveraged to identify novel series of histone deacetylase 6 (HDAC6) inhibitors prior to conducting a high-throughput screen. The virtual screen was designed to augment and expand on chemical matter that would otherwise be unavailable for high-throughput screening. Through this effort we succeeded in identifying four novel, potent and highly selective HDAC6 inhibitor series. These series displayed favorable ligand binding efficiencies and good potential for further optimization. The virtual design specifications and results are discussed herein.}, } @article {pmid39490684, year = {2024}, author = {Liu, YJ and Lee, CW and Liao, YC and Huang, JJ and Kuo, HC and Jih, KY and Lee, YC and Chern, Y}, title = {The role of adiponectin-AMPK axis in TDP-43 mislocalization and disease severity in ALS.}, journal = {Neurobiology of disease}, volume = {202}, number = {}, pages = {106715}, doi = {10.1016/j.nbd.2024.106715}, pmid = {39490684}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; *Adiponectin/metabolism ; *DNA-Binding Proteins/metabolism ; Male ; Female ; Middle Aged ; *AMP-Activated Protein Kinases/metabolism ; Aged ; Motor Neurons/metabolism ; Severity of Illness Index ; }, abstract = {Hypermetabolism is a prominent characteristic of ALS patients. Aberrant activation of AMPK, an energy sensor regulated by adiponectin, is known to cause TDP-43 mislocalization, an early event in ALS pathogenesis. This study aims to evaluate the association between key energy mediators and clinical severity in ALS patients. We found that plasma adiponectin levels were significantly higher in ALS patients with ALSFRS-R scores below 38 compared to controls (p = 0.047). Additionally, adiponectin concentration was inversely correlated with ALSFRS-R scores (p = 0.021). Immunofluorescence staining of PBMCs revealed negative associations between AMPK activation, TDP-43 mislocalization, and ALSFRS-R scores. We then examined the hypothesis that adiponectin may activate the AMPK-TDP-43 axis in motor neurons. Our results demonstrated that adiponectin treatment of NSC34 cells and HiPSC-MNs induced AMPK activation and TDP-43 mislocalization in an adiponectin receptor-dependent manner. Collectively, these findings suggest that elevated plasma adiponectin may enhance AMPK activation, leading to TDP-43 mislocalization in both PBMCs and motor neurons of ALS patients. This highlights the potential involvement of the adiponectin-AMPK-TDP-43 axis in the dysregulated energy balance observed in ALS.}, } @article {pmid39490682, year = {2024}, author = {Leykam, L and Forsberg, KME and Nordström, U and Hjertkvist, K and Öberg, A and Jonsson, E and Andersen, PM and Marklund, SL and Zetterström, P}, title = {Specific analysis of SOD1 enzymatic activity in CSF from ALS patients with and without SOD1 mutations.}, journal = {Neurobiology of disease}, volume = {202}, number = {}, pages = {106718}, doi = {10.1016/j.nbd.2024.106718}, pmid = {39490682}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid ; *Superoxide Dismutase-1/genetics ; Male ; *Mutation ; Female ; Middle Aged ; Superoxide Dismutase/genetics/cerebrospinal fluid ; Adult ; Aged ; }, abstract = {Mutations in superoxide dismutase-1 (SOD1) are a cause of hereditary amyotrophic lateral sclerosis (ALS) through a gain-of-function mechanism involving unfolded mutant SOD1. Intrathecal gene therapy using the antisense-oligo-nucleotide drug tofersen to reduce SOD1 expression delays disease progression and has recently been approved in the United States and the European Union. However, the discovery of children homozygous for inactivating SOD1 mutations developing the SOD1 Deficiency Syndrome (ISODDES) with injury to the motor system suggests that a too low SOD1 antioxidant activity may be deleterious in humans. Measuring SOD1 activity in cerebrospinal fluid (CSF) in tofersen-treated patients is recommended but difficult due to low concentration and the presence of the isoenzyme SOD3. We here present a sensitive method to assess SOD1 activity by removing SOD3 from CSF samples using highly specific immobilized antibodies and subsequent measurement of the SOD activity. We validated the method on 171 CSF samples from ALS patients with and without mutations and controls and used paired erythrocyte samples for comparison. We found that in ALS patients with wildtype SOD1, the SOD1 activity in CSF was equal to controls, but patients with mutant SOD1 show lower activity in CSF, even for patients with mutants previously reported to have full activity in erythrocytes. Activity variation in CSF was large among patients carrying the same SOD1 mutation and larger than in erythrocytes and in post-mortem nervous tissue. Additionally, we identified a discrepancy between the SOD1 activity and protein level measured with ELISA in both CSF and erythrocytes. Since antibodies used for SOD1 ELISA-quantification are raised against the natively folded wildtype SOD1, the concentration of mutant SOD1s may be underestimated. Analysis of SOD1 enzymatic activity in CSF is therefore a more reliable way to monitor the effect of SOD1-lowering drugs.}, } @article {pmid39490400, year = {2024}, author = {Zhang, Y and Zou, M and Wu, H and Zhu, J and Jin, T}, title = {The cGAS-STING pathway drives neuroinflammation and neurodegeneration via cellular and molecular mechanisms in neurodegenerative diseases.}, journal = {Neurobiology of disease}, volume = {202}, number = {}, pages = {106710}, doi = {10.1016/j.nbd.2024.106710}, pmid = {39490400}, issn = {1095-953X}, mesh = {Humans ; *Nucleotidyltransferases/metabolism ; *Membrane Proteins/metabolism ; *Neurodegenerative Diseases/metabolism ; *Signal Transduction/physiology ; Animals ; *Neuroinflammatory Diseases/metabolism ; }, abstract = {Neurodegenerative diseases (NDs) are a type of common chronic progressive disorders characterized by progressive damage to specific cell populations in the nervous system, ultimately leading to disability or death. Effective treatments for these diseases are still lacking, due to a limited understanding of their pathogeneses, which involve multiple cellular and molecular pathways. The triggering of an immune response is a common feature in neurodegenerative disorders. A critical challenge is the intricate interplay between neuroinflammation, neurodegeneration, and immune responses, which are not yet fully characterized. In recent years, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway, a crucial immune response for intracellular DNA sensing, has gradually gained attention. However, the specific roles of this pathway within cellular types such as immune cells, glial and neuronal cells, and its contribution to ND pathogenesis, remain not fully elucidated. In this review, we systematically explore how the cGAS-STING signaling links various cell types with related cellular effector pathways under the context of NDs for multifaceted therapeutic directions. We emphasize the discovery of condition-dependent cellular heterogeneity in the cGAS-STING pathway, which is integral for understanding the diverse cellular responses and potential therapeutic targets. Additionally, we review the pathogenic role of cGAS-STING activation in Parkinson's disease, ataxia-telangiectasia, and amyotrophic lateral sclerosis. We focus on the complex bidirectional roles of the cGAS-STING pathway in Alzheimer's disease, Huntington's disease, and multiple sclerosis, revealing their double-edged nature in disease progression. The objective of this review is to elucidate the pivotal role of the cGAS-STING pathway in ND pathogenesis and catalyze new insights for facilitating the development of novel therapeutic strategies.}, } @article {pmid39489870, year = {2024}, author = {Van Weehaeghe, D and Devrome, M and de Vocht, J and Masrori, P and Schramm, G and Deckers, W and Baete, K and De Weerdt, C and Van Damme, P and Koole, M and Van Laere, K}, title = {Combined brain and spinal FDG PET in the differentiation between ALS and ALS mimics - correction and additional validation study.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {52}, number = {1}, pages = {109-112}, pmid = {39489870}, issn = {1619-7089}, } @article {pmid39489397, year = {2024}, author = {Desouky, MA and Michel, HE and Elsherbiny, DA and George, MY}, title = {Recent pharmacological insights on abating toxic protein species burden in neurological disorders: Emphasis on 26S proteasome activation.}, journal = {Life sciences}, volume = {359}, number = {}, pages = {123206}, doi = {10.1016/j.lfs.2024.123206}, pmid = {39489397}, issn = {1879-0631}, mesh = {*Proteasome Endopeptidase Complex/metabolism ; Humans ; Animals ; Neurodegenerative Diseases/metabolism/drug therapy ; Nervous System Diseases/drug therapy/metabolism ; Proteolysis/drug effects ; Signal Transduction/drug effects ; Proteostasis/drug effects ; Ubiquitin/metabolism ; }, abstract = {Protein homeostasis (proteostasis) refers to the plethora of mechanisms that safeguard the proper folding of the newly synthesized proteins. It entails various intricately regulated cues that demolish the toxic protein species to prevent their aggregation. The ubiquitin-proteasome system (UPS) is recognized as a salient protein degradation system, with a substantial role in maintaining proteostasis. However, under certain circumstances the protein degradation capacity of the UPS is overwhelmed, leading to the accumulation of misfolded proteins. Several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington disease, and amyotrophic lateral sclerosis are characterized with the presence of protein aggregates and proteinopathy. Accordingly, enhancing the 26S proteasome degradation activity might delineate a pioneering approach in targeting various proteotoxic disorders. Regrettably, the exact molecular approaches that enhance the proteasomal activity are still not fully understood. Therefore, this review aimed to underscore several signaling cascades that might restore the degradation capacity of this molecular machine. In this review, we discuss the different molecular components of the UPS and how 26S proteasomes are deleteriously affected in many neurodegenerative diseases. Moreover, we summarize different signaling pathways that can be utilized to renovate the 26S proteasome functional capacity, alongside currently known druggable targets in this circuit and various classes of proteasome activators.}, } @article {pmid39487163, year = {2024}, author = {Cai, S and Venugopalan, S and Seaver, K and Xiao, X and Tomanek, K and Jalasutram, S and Morris, MR and Kane, S and Narayanan, A and MacDonald, RL and Kornman, E and Vance, D and Casey, B and Gleason, SM and Nelson, PQ and Brenner, MP}, title = {Using large language models to accelerate communication for eye gaze typing users with ALS.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9449}, pmid = {39487163}, issn = {2041-1723}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Communication Devices for People with Disabilities ; Female ; Male ; Pilot Projects ; *Fixation, Ocular/physiology ; Language ; Adult ; User-Computer Interface ; Middle Aged ; Communication ; }, abstract = {Accelerating text input in augmentative and alternative communication (AAC) is a long-standing area of research with bearings on the quality of life in individuals with profound motor impairments. Recent advances in large language models (LLMs) pose opportunities for re-thinking strategies for enhanced text entry in AAC. In this paper, we present SpeakFaster, consisting of an LLM-powered user interface for text entry in a highly-abbreviated form, saving 57% more motor actions than traditional predictive keyboards in offline simulation. A pilot study on a mobile device with 19 non-AAC participants demonstrated motor savings in line with simulation and relatively small changes in typing speed. Lab and field testing on two eye-gaze AAC users with amyotrophic lateral sclerosis demonstrated text-entry rates 29-60% above baselines, due to significant saving of expensive keystrokes based on LLM predictions. These findings form a foundation for further exploration of LLM-assisted text entry in AAC and other user interfaces.}, } @article {pmid39486809, year = {2024}, author = {Van Loon, FT and Seitidis, G and Mavridis, D and van Unnik, JWJ and Weemering, DN and van den Berg, LH and Bethani, I and Nikolakopoulos, S and van Eijk, RPA}, title = {Living systematic review and comprehensive network meta-analysis of ALS clinical trials: study protocol.}, journal = {BMJ open}, volume = {14}, number = {10}, pages = {e087970}, pmid = {39486809}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Clinical Trials as Topic ; Disease Progression ; Network Meta-Analysis ; Research Design ; Systematic Reviews as Topic ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurogenerative disease with no effective treatment to date. Despite numerous clinical trials, the majority of studies have been futile in their effort to significantly alter the course of the disease. However, these studies may still provide valuable information for identifying patient subgroups and generating new hypotheses for future research. Additionally, synthesising evidence from these studies may help overcome the limitations of individual studies. Network meta-analysis may refine the assessment of efficacy in specific patient subgroups, evaluate intervention characteristics such as mode of administration or biological mechanisms of action, and rank order promising therapeutic areas of interest. Therefore, we aim to synthesise the available evidence from ALS clinical trials.

METHODS AND ANALYSIS: We will conduct a systematic review to identify all clinical trials that assessed disease-modifying pharmaceutical therapies, cell therapies, or supplements in patients with ALS. Outcomes of interest are clinical disease progression outcomes and survival. We will conduct this search in the period Q4 2024 in three databases: PubMed, Embase and ClinicalTrials.gov for studies from 1999 to 2023. Individual patient data and aggregate data will be collected and subsequentially synthesised in meta-analytical models. The final model will be presented as an open-source web application with biannual updates of the underlying data, thereby providing a 'living' overview of the ALS clinical trial landscape.

ETHICS AND DISSEMINATION: No ethics approvals are required. Findings will be presented at relevant conferences and submitted to peer-reviewed journals. Data will be stored anonymously in secure repositories.}, } @article {pmid39484239, year = {2024}, author = {Leinders, S and Aarnoutse, EJ and Branco, MP and Freudenburg, ZV and Geukes, SH and Schippers, A and Verberne, MSW and van den Boom, M and van der Vijgh, B and Crone, NE and Denison, T and Ramsey, NF and Vansteensel, MJ}, title = {DO NOT LOSE SLEEP OVER IT: IMPLANTED BRAIN-COMPUTER INTERFACE FUNCTIONALITY DURING NIGHTTIME IN LATE-STAGE AMYOTROPHIC LATERAL SCLEROSIS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39484239}, support = {U01 DC016686/DC/NIDCD NIH HHS/United States ; UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Brain-computer interfaces (BCIs) hold promise as augmentative and alternative communication technology for people with severe motor and speech impairment (locked-in syndrome) due to neural disease or injury. Although such BCIs should be available 24/7, to enable communication at all times, feasibility of nocturnal BCI use has not been investigated. Here, we addressed this question using data from an individual with amyotrophic lateral sclerosis (ALS) who was implanted with an electrocorticography-based BCI that enabled the generation of click-commands for spelling words and call-caregiver signals.

METHODS: We investigated nocturnal dynamics of neural signal features used for BCI control, namely low (LFB: 10-30Hz) and high frequency band power (HFB: 65-95Hz). Additionally, we assessed the nocturnal performance of a BCI decoder that was trained on daytime data by quantifying the number of unintentional BCI activations at night. Finally, we developed and implemented a nightmode decoder that allowed the participant to call a caregiver at night, and assessed its performance.

RESULTS: Power and variance in HFB and LFB were significantly higher at night than during the day in the majority of the nights, with HFB variance being higher in 88% of nights. Daytime decoders caused 245 unintended selection-clicks and 13 unintended caregiver-calls per hour when applied to night data. The developed nightmode decoder functioned error-free in 79% of nights over a period of ±1.5 years, allowing the user to reliably call the caregiver, with unintended activations occurring only once every 12 nights.

DISCUSSION: Reliable nighttime use of a BCI requires decoders that are adjusted to sleep-related signal changes. This demonstration of a reliable BCI nightmode and its long-term use by an individual with advanced ALS underscores the importance of 24/7 BCI reliability.

TRIAL REGISTRATION: This trial is registered in clinicaltrials.gov under number NCT02224469 (https://clinicaltrials.gov/study/NCT02224469?term=NCT02224469&rank=1). Date of submission to registry: August 21, 2014. Enrollment of first participant: September 7, 2015.}, } @article {pmid39483635, year = {2024}, author = {Murakami, Y and Ando, M and Imamura, A and Oketani, R and Leproux, P and Honjoh, S and Kano, H}, title = {Molecular Fingerprinting of Mouse Brain Using Ultrabroadband Coherent Anti-Stokes Raman Scattering (CARS) Microspectroscopy Empowered by Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS).}, journal = {Chemical & biomedical imaging}, volume = {2}, number = {10}, pages = {689-697}, pmid = {39483635}, issn = {2832-3637}, abstract = {The Raman fingerprint spectral region provides abundant structural information on molecules. However, analyzing vibrational images within this region using coherent Raman imaging remains challenging due to the small Raman cross section and congested spectral features. In this study, we combined ultrabroadband coherent anti-Stokes Raman scattering (CARS) microspectroscopy across the spectral range of 500-4000 cm[-1] with multivariate curve resolution-alternating least-squares (MCR-ALS) to reveal hidden Raman bands in the fingerprint region. Applying this method to mouse brain tissue, we extracted information on cholesterol and collagen, leveraging their distinctive molecular signatures, as well as on key molecules such as lipids, proteins, water, and nucleic acids. Moreover, the simultaneous detection of second harmonic generation facilitated label-free visualization of organelles, including arachnoid membrane and Rootletin filaments.}, } @article {pmid39483234, year = {2024}, author = {Fujimoto, A and Kinjo, M and Kitamura, A}, title = {Short Repeat Ribonucleic Acid Reduces Cytotoxicity by Preventing the Aggregation of TDP-43 and Its 25 KDa Carboxy-Terminal Fragment.}, journal = {JACS Au}, volume = {4}, number = {10}, pages = {3896-3909}, pmid = {39483234}, issn = {2691-3704}, abstract = {TAR DNA/RNA-binding protein 43 kDa (TDP-43) proteinopathy is a hallmark of neurodegenerative disorders, such as amyotrophic lateral sclerosis, in which cytoplasmic aggregates containing TDP-43 and its C-terminal fragments, such as TDP-25, are observed in degenerative neuronal cells. However, few reports have focused on small molecules that can reduce their aggregation and cytotoxicity. Here, we show that short RNA repeats of GGGGCC and AAAAUU are aggregation suppressors of TDP-43 and TDP-25. TDP-25 interacts with these RNAs, as well as TDP-43, despite the lack of major RNA-recognition motifs using fluorescence cross-correlation spectroscopy. Expression of these RNAs significantly decreases the number of cells harboring cytoplasmic aggregates of TDP-43 and TDP-25 and ameliorates cell death by TDP-25 and mislocalized TDP-43 without altering the cellular transcriptome of molecular chaperones. Consequently, short RNA repeats of GGGGCC and AAAAUU can maintain proteostasis by preventing the aggregation of TDP-43 and TDP-25.}, } @article {pmid39488863, year = {2024}, author = {Lopes, M and Swash, M and de Carvalho, M}, title = {F-waves responses derived from low-intensity electrical stimulation: A method to explore split-hand pathogenesis.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {54}, number = {6}, pages = {103018}, doi = {10.1016/j.neucli.2024.103018}, pmid = {39488863}, issn = {1769-7131}, mesh = {Humans ; Male ; Female ; *Hand/physiopathology ; Adult ; *Muscle, Skeletal/physiopathology/physiology ; *Electric Stimulation/methods ; Middle Aged ; Motor Neurons/physiology ; Electromyography ; Amyotrophic Lateral Sclerosis/physiopathology/therapy ; Young Adult ; Evoked Potentials, Motor/physiology ; Aged ; }, abstract = {OBJECTIVES: The "split-hand syndrome" is a common clinical sign in amyotrophic lateral sclerosis (ALS), being characterized by more severe atrophy of the hand muscles on the radial side of the hand compared to the ulnar side. We aimed to investigate possible physiological differences between relevant hand muscles using low-intensity F-wave stimulation to assess spinal motoneuron excitability.

METHODS: We recruited 36 healthy volunteers. F-waves were recorded from the abductor pollicis brevis (APB), first dorsal interosseous (FDI) and abductor digiti minimi (ADM), using 20 supramaximal stimuli followed by 20 stimuli at a low-intensity required to obtain M-waves with 10 % amplitude of maximal CMAP. We evaluated the following F-wave parameters: F-M latency, chronodispersion, persistence, amplitude, F/CMAP amplitude ratio and number of F-wave repeaters (with low-intensity). In 10 subjects, low-intensity stimulation F-waves were compared after 20 and 50 stimuli in each muscle.

RESULTS: Low-intensity stimulation resulted in lower F-wave amplitude and persistence and higher F/CMAP amplitude ratios. There were no significant differences in F-wave latencies and chronodispersion. When comparing the three muscles, we found higher F-wave persistence and F/CMAP amplitude ratios when recording over the ADM and APB compared to the FDI. We also found a higher number of F-wave repeaters in the ADM with low-intensity stimulation. Results from 20 to 50 low-intensity stimuli were similar.

DISCUSSION: A small number of low-intensity stimuli is appropriate to study F-wave latencies and chronodispersion. We found differences in some physiological properties of the ADM spinal motoneuron pool compared to other hand muscles.}, } @article {pmid39480764, year = {2024}, author = {Perrin, S and Ladha, S and Maragakis, N and Rivner, MH and Katz, J and Genge, A and Olney, N and Lange, D and Heitzman, D and Bodkin, C and Jawdat, O and Goyal, NA and Bornstein, JD and Mak, C and Appel, SH and Paganoni, S}, title = {Safety and tolerability of tegoprubart in patients with amyotrophic lateral sclerosis: A Phase 2A clinical trial.}, journal = {PLoS medicine}, volume = {21}, number = {10}, pages = {e1004469}, pmid = {39480764}, issn = {1549-1676}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/immunology ; Male ; Middle Aged ; Female ; Aged ; Adult ; CD40 Ligand/blood ; Biomarkers/blood ; Antibodies, Monoclonal, Humanized/adverse effects/administration & dosage/therapeutic use/pharmacokinetics ; Antibodies, Monoclonal/adverse effects/administration & dosage/therapeutic use ; Neurofilament Proteins/blood ; Dose-Response Relationship, Drug ; Treatment Outcome ; Disease Progression ; Imidazoles ; Pyrazines ; }, abstract = {BACKGROUND: The interaction of CD40L and its receptor CD40 on activated T cells and B cells respectively control pro-inflammatory activation in the pathophysiology of autoimmunity and transplant rejection. Previous studies have implicated signaling pathways involving CD40L (interchangeably referred to as CD154), as well as adaptive and innate immune cell activation, in the induction of neuroinflammation in neurodegenerative diseases. This study aimed to assess the safety, tolerability, and impact on pro-inflammatory biomarker profiles of an anti CD40L antibody, tegoprubart, in individuals with amyotrophic lateral sclerosis (ALS).

METHODS AND FINDINGS: In this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation.

CONCLUSIONS: Tegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS.

TRIAL REGISTRATION: Clintrials.gov ID:NCT04322149.}, } @article {pmid39480562, year = {2025}, author = {Cao, G and Wang, S and Yu, J and Wang, X and Shi, X and Yang, L and Zhang, X and Tong, P and Tan, H}, title = {Outcomes of combined single-bundle anterior cruciate ligament reconstruction and anterolateral structure reconstruction through a modified single femoral tunnel.}, journal = {International orthopaedics}, volume = {49}, number = {1}, pages = {83-91}, pmid = {39480562}, issn = {1432-5195}, support = {82104896//National Natural Science Foundation of China/ ; 242102310025//Henan Provincial Science and Technology Research Project/ ; 2024HLTJ17//Heluo Youth Talent Support Program/ ; }, mesh = {Humans ; Male ; Female ; *Anterior Cruciate Ligament Reconstruction/methods ; Adult ; Middle Aged ; Young Adult ; Adolescent ; *Femur/surgery ; *Anterior Cruciate Ligament Injuries/surgery ; Treatment Outcome ; Arthroscopy/methods ; Hamstring Tendons/transplantation ; Transplantation, Autologous/methods ; }, abstract = {PURPOSE: To explore the clinical outcomes of combining anterior cruciate ligament (ACL) reconstruction and anterolateral structure (ALS) reconstruction through a modified single femoral tunnel in patients with high risk of clinical failure.

METHODS: From December 2018 to August 2022, a total of 62 patients with ACL injury in our institution were enrolled in this study. All patients were associated with high risk of clinical failure, meeting the indications of ALS reconstruction. All patients accepted arthroscopic single-bundle ACL reconstruction and ALS reconstruction using hamstring autograft through a modified single femoral tunnel. Perioperative clinical outcome measurements consisted of functions, stability and safety evaluation at different time points (preoperative, postoperative three month, six month, one year, two year, three year and more). Functional evaluation included Lysholm score, Tegner activity scale, subjective and objective International Knee Documentation Committee (IKDC) score.

RESULTS: All patients, including 47 males and 15 females, aged 16-52 years with an average age of 29.3 ± 9.2 years, were followed up for 12-58 months. At the last follow-up, the Lysholm, subjective IKDC and Tegner activity scale (93.8 ± 7.0, 88.8 ± 10.7 and 5.8 ± 1.4 respectively) were significantly higher than those before surgery (65.0 ± 20.8, 51.2 ± 21.1 and 2.3 ± 1.3 respectively)(P < 0.05). Postoperative pivot shift and Lachman test were markedly improved (P < 0.05). One patient still had grade II pivot shift, defined as clinical failure. During follow-up, no graft rupture occurred according to magnetic resonance imaging and physical examination, no lateral compartment osteoarthritis were found in all patients.

CONCLUSIONS: Combined single bundle ACL reconstruction and ALS reconstruction through a modified single femoral tunnel could significantly improve knee function and stability with low related risk in patients with high risk of failure in ACL injury.}, } @article {pmid39487710, year = {2025}, author = {van Veenhuijzen, K and Tan, HHG and Nitert, AD and van Es, MA and Veldink, JH and van den Berg, LH and Westeneng, HJ}, title = {Longitudinal Magnetic Resonance Imaging in Asymptomatic C9orf72 Mutation Carriers Distinguishes Phenoconverters to Amyotrophic Lateral Sclerosis or Amyotrophic Lateral Sclerosis With Frontotemporal Dementia.}, journal = {Annals of neurology}, volume = {97}, number = {2}, pages = {281-295}, pmid = {39487710}, issn = {1531-8249}, support = {//Stichting ALS Nederland/ ; 772376-EScORIAL//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/pathology ; *C9orf72 Protein/genetics ; *Frontotemporal Dementia/genetics/diagnostic imaging/pathology ; Female ; Male ; Middle Aged ; *Magnetic Resonance Imaging/methods ; Aged ; Longitudinal Studies ; *Mutation ; Adult ; Atrophy/pathology ; Heterozygote ; Prospective Studies ; Brain/diagnostic imaging/pathology ; }, abstract = {OBJECTIVE: We prospectively studied asymptomatic C9orf72 mutation carriers, identifying those developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD).

METHODS: We enrolled 56 asymptomatic family members (AFM) with a C9orf72 mutation (AFM C9+), 132 non-carriers (AFM C9-), and 359 population-based controls. Using 3 T magnetic resonance imaging, we measured cortical thickness, gyrification, and subcortical volumes longitudinally. Linear mixed-effects models on non-converting AFM C9+ scans (n = 107) created a reference for these measurements, establishing individual atrophy patterns. Atrophy patterns from presymptomatic phenoconverters (n = 10 scans) served as a template for group comparisons and similarity assessments. Similarity with phenoconverters was quantified using Dice similarity coefficient (DSC) for cortical and Kullback-Leibler similarity (KLS) for subcortical measures. Using longitudinal similarity assessments, we predicted when participants would reach the average similarity level of phenoconverters at their first post-onset scan.

RESULTS: Five AFM C9+ converted to ALS or ALS-FTD. Up to 6 years before symptoms, these phenoconverters exhibited significant atrophy in frontal, temporal, parietal, and cingulate cortex, along with smaller thalamus, hippocampus, and amygdala compared to other AFM C9+. Some non-converted AFM C9+ had high DSC and KLS, approaching values of phenoconverters, whereas others, along with AFM C9- and controls, had lower values. At age 80, we predicted 27.9% (95% confidence interval, 13.2-40.1%) of AFM C9+ and no AFM C9- would reach the same DSC as phenoconverters.

INTERPRETATION: Distinctive atrophy patterns are visible years before symptom onset on presymptomatic scans of phenoconverters. Combining baseline and follow-up similarity measures may serve as a promising imaging biomarker for identifying those at risk of ALS or ALS-FTD. ANN NEUROL 2025;97:281-295.}, } @article {pmid39487328, year = {2024}, author = {Paganoni, S and Harkey, B and Giacomelli, E and Cudkowicz, M and , }, title = {Lessons from the HEALEY adaptive platform trial in amyotrophic lateral sclerosis.}, journal = {Nature aging}, volume = {4}, number = {11}, pages = {1512-1515}, pmid = {39487328}, issn = {2662-8465}, } @article {pmid39486621, year = {2024}, author = {Stephani, C and Krämer, H and Chakalov, I and Bähr, M and Paulus, W and Antal, A and Koch, JC}, title = {Static transcranial magnetic stimulation does not alter cortical excitability in patients with amyotrophic lateral sclerosis on riluzole.}, journal = {Brain stimulation}, volume = {17}, number = {6}, pages = {1244-1246}, doi = {10.1016/j.brs.2024.10.013}, pmid = {39486621}, issn = {1876-4754}, } @article {pmid39486473, year = {2024}, author = {Wang, HE and Daya, MR and Schmicker, R and Nassal, M and Okubo, M and Aramendi, E and Alonso, E and Idris, A and Panchal, AR and Jaureguibeitia, X and Aufderheide, T and Carlson, J and Nichol, G}, title = {Vasopressor or advanced airway first in cardiac arrest?.}, journal = {Resuscitation}, volume = {205}, number = {}, pages = {110422}, doi = {10.1016/j.resuscitation.2024.110422}, pmid = {39486473}, issn = {1873-1570}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Airway Management/methods ; *Cardiopulmonary Resuscitation/methods ; Epinephrine/administration & dosage ; Intubation, Intratracheal/methods ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Return of Spontaneous Circulation ; *Vasoconstrictor Agents/therapeutic use/administration & dosage ; Vasopressins/therapeutic use/administration & dosage ; }, abstract = {BACKGROUND: While resuscitation guidelines emphasize early vasopressor administration and advanced airway management, their optimal sequence remains unclear. We sought to determine the associations between vasopressor-airway resuscitation sequence and out-of-hospital cardiac arrest (OHCA) outcomes in the Pragmatic Airway Resuscitation Trial (PART).

METHODS: We analyzed data from the PART trial. For each patient we determined times of first vasopressor administration (epinephrine or vasopressin), and successful advanced airway insertion (laryngeal tube or endotracheal tube). We classified each case as vasopressor-first or advanced airway-first. We used Generalized Estimating Equations to determine associations between vasopressor-airway sequence and outcomes (72-hour survival, return of spontaneous circulation (ROSC) on emergency department arrival, survival to hospital discharge, hospital survival with favorable neurologic status) and CPR outside of recommended parameters (chest compression fraction <0.8, chest compression rate <100 or >120 per min, or ventilation rate <8 or >12 breaths/min), adjusting for confounders.

RESULTS: Of 3,004 patients in the parent trial, we analyzed 2,404, including 1,821 vasopressor-first and 583 advanced airway-first. Median intervention times: ALS arrival-to-vasopressor 8 min (IQR 6-11) and ALS arrival-to-airway 11 min (8-15). Compared with airway-first, vasopressor-first sequence was not associated with 72-hour survival (adjusted OR 0.96; 95% CI: 0.71-1.31), ROSC (0.83; 0.66-1.06), hospital survival (1.09; 0.68-1.73), or hospital survival with favorable neurologic status (0.97; 0.53-1.78). Vasopressor-first sequence was not associated with non-compliance with recommended CPR performance parameters.

CONCLUSIONS: Vasopressor-airway resuscitation sequence was not associated with OHCA outcomes or CPR quality.}, } @article {pmid39486415, year = {2024}, author = {Al-Azzam, N and To, JH and Gautam, V and Street, LA and Nguyen, CB and Naritomi, JT and Lam, DC and Madrigal, AA and Lee, B and Jin, W and Avina, A and Mizrahi, O and Mueller, JR and Ford, W and Schiavon, CR and Rebollo, E and Vu, AQ and Blue, SM and Madakamutil, YL and Manor, U and Rothstein, JD and Coyne, AN and Jovanovic, M and Yeo, GW}, title = {Inhibition of RNA splicing triggers CHMP7 nuclear entry, impacting TDP-43 function and leading to the onset of ALS cellular phenotypes.}, journal = {Neuron}, volume = {112}, number = {24}, pages = {4033-4047.e8}, doi = {10.1016/j.neuron.2024.10.007}, pmid = {39486415}, issn = {1097-4199}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; *RNA Splicing ; *Motor Neurons/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Cell Nucleus/metabolism ; Phenotype ; Active Transport, Cell Nucleus ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is linked to the reduction of certain nucleoporins in neurons. Increased nuclear localization of charged multivesicular body protein 7 (CHMP7), a protein involved in nuclear pore surveillance, has been identified as a key factor damaging nuclear pores and disrupting transport. Using CRISPR-based microRaft, followed by gRNA identification (CRaft-ID), we discovered 55 RNA-binding proteins (RBPs) that influence CHMP7 localization, including SmD1, a survival of motor neuron (SMN) complex component. Immunoprecipitation-mass spectrometry (IP-MS) and enhanced crosslinking and immunoprecipitation (CLIP) analyses revealed CHMP7's interactions with SmD1, small nuclear RNAs, and splicing factor mRNAs in motor neurons (MNs). ALS induced pluripotent stem cell (iPSC)-MNs show reduced SmD1 expression, and inhibiting SmD1/SMN complex increased CHMP7 nuclear localization. Crucially, overexpressing SmD1 in ALS iPSC-MNs restored CHMP7's cytoplasmic localization and corrected STMN2 splicing. Our findings suggest that early ALS pathogenesis is driven by SMN complex dysregulation.}, } @article {pmid39478664, year = {2024}, author = {Ropert, B and Bannwarth, S and Genin, EC and Vaillant-Beuchot, L and Lacas-Gervais, S and Hounoum, BM and Bernardin, A and Dinh, N and Mauri-Crouzet, A and D'Elia, MA and Augé, G and Lespinasse, F and Di Giorgio, A and Meira, W and Bonnefoy, N and Monassier, L and Schiff, M and Sago, L and Kilinc, D and Brau, F and Redeker, V and Bohl, D and Tribouillard-Tanvier, D and Procaccio, V and Azoulay, S and Ricci, JE and Delahodde, A and Paquis-Flucklinger, V}, title = {Nifuroxazide rescues the deleterious effects due to CHCHD10-associated MICOS defects in disease models.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awae348}, pmid = {39478664}, issn = {1460-2156}, abstract = {The identification of a point mutation (p.Ser59Leu) in the CHCHD10 gene was the first genetic evidence that mitochondrial dysfunction can trigger motor neuron disease. Since then, we have shown that this mutation leads to the disorganization of the MItochondrial contact site and Cristae Organizing System (MICOS) complex that maintains the mitochondrial cristae structure. Here, we generated yeast mutant strains mimicking MICOS instability and used them to test the ability of more than 1600 compounds from 2 repurposed libraries to rescue the growth defect of those cells. Among the hits identified, we selected nifuroxazide, a broad-spectrum antibacterial molecule. We show that nifuroxazide rescues mitochondrial network fragmentation and cristae abnormalities in CHCHD10S59L/+ patient fibroblasts. This molecule also decreases caspase-dependent death of human CHCHD10S59L/+ iPSC-derived motor neurons. Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons. Our findings strengthen the MICOS-mitochondrial transport connection. Nifuroxazide and analogues emerge as potential therapeutics for MICOS-related disorders like motor neuron disease. Its impact on syntaphilin hints at broader neurological disorder applicability for nifuroxazide.}, } @article {pmid39478194, year = {2024}, author = {Yang, M and You, D and Liu, G and Lu, Y and Yang, G and O'Brien, T and Henshall, DC and Hardiman, O and Cai, L and Liu, M and Shen, S}, title = {Polyethyleneimine facilitates the growth and electrophysiological characterization of iPSC-derived motor neurons.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {26106}, pmid = {39478194}, issn = {2045-2322}, support = {16/RC/3948/SFI_/Science Foundation Ireland/Ireland ; C2024205026//Natural Science Foundation of Hebei Province/ ; L2024B36//Doctoral Research Initiation Fund Project of Hebei Normal University/ ; GJHZ20200731095005016//International Scientific and Technological Cooperation Foundation of Shenzhen/ ; 00000326//Medical-Engineering Interdisciplinary Research Foundation of ShenZhen University/ ; }, mesh = {*Polyethyleneimine/pharmacology ; *Electrophysiology ; *Induced Pluripotent Stem Cells/drug effects ; *Cell Proliferation/drug effects ; Motor Neurons/drug effects ; Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Cells, Cultured ; Cell Differentiation ; }, abstract = {Induced pluripotent stem cell (iPSC) technology, in combination with electrophysiological characterization via multielectrode array (MEA), has facilitated the utilization of iPSC-derived motor neurons (iPSC-MNs) as highly valuable models for underpinning pathogenic mechanisms and developing novel therapeutic interventions for motor neuron diseases (MNDs). However, the challenge of MN adherence to the MEA plate and the heterogeneity presented in iPSC-derived cultures raise concerns about the reproducibility of the findings obtained from these cellular models. We discovered that one novel factor modulating the electrophysiological activity of iPSC-MNs is the extracellular matrix (ECM) used in the coating to support in vitro growth, differentiation and maturation of iPSC-MNs. The current study showed that two coating conditions, namely, Poly-L-ornithine/Matrigel (POM) and Polyethyleneimine (PEI) strongly promoted attachment of iPSC-MNs on MEA culture dishes compared to three other coating conditions, and both facilitated the maturation of iPSC-MNs as characterized by the detection of extensive electrophysiological activities from the MEA plates. POM coating accelerated the maturation of the iPSC-MNs for up to 5 weeks, which suits modeling of neurodevelopmental disorders. However, the application of PEI resulted in more even distribution of the MNs on the culture dish and reduced variability of electrophysiological signals from the iPSC-MNs in 7-week cultures, which permitted the detection of enhanced excitability in iPSC-MNs from patients with amyotrophic lateral sclerosis (ALS). This study provides a comprehensive comparison of five coating conditions and offers POM and PEI as favorable coatings for in vitro modeling of neurodevelopmental and neurodegenerative disorders, respectively.}, } @article {pmid39475611, year = {2024}, author = {Wang, LQ and Ma, Y and Zhang, MY and Yuan, HY and Li, XN and Xia, W and Zhao, K and Huang, X and Chen, J and Li, D and Zou, L and Wang, Z and Le, W and Liu, C and Liang, Y}, title = {Amyloid fibril structures and ferroptosis activation induced by ALS-causing SOD1 mutations.}, journal = {Science advances}, volume = {10}, number = {44}, pages = {eado8499}, pmid = {39475611}, issn = {2375-2548}, mesh = {*Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Amyloid/metabolism ; *Mutation ; *Ferroptosis/genetics ; Cryoelectron Microscopy ; Models, Molecular ; Mitochondria/metabolism ; }, abstract = {Over 200 genetic mutations in copper-zinc superoxide dismutase (SOD1) have been linked to amyotrophic lateral sclerosis (ALS). Among these, two ALS-causing mutants, histidine-46→arginine (H46R) and glycine-85→arginine (G85R), exhibit a decreased capacity to bind metal ions. Here, we report two cryo-electron microscopy structures of amyloid fibrils formed by H46R and G85R. These mutations lead to the formation of amyloid fibrils with unique structures distinct from those of the native fibril. The core of these fibrils features a serpentine arrangement with seven or eight β strands, secured by a hydrophobic cavity and a salt bridge between arginine-85 and aspartic acid-101 in the G85R fibril. We demonstrate that these mutant fibrils are notably more toxic and capable of promoting the aggregation of wild-type SOD1 more effectively, causing mitochondrial impairment and activating ferroptosis in cell cultures, compared to wild-type SOD1 fibrils. Our study provides insights into the structural mechanisms by which SOD1 mutants aggregate and induce cytotoxicity in ALS.}, } @article {pmid39475283, year = {2025}, author = {Ziser, L and van Eijk, RPA and Kiernan, MC and McRae, A and Henderson, RD and Schultz, D and Needham, M and Mathers, S and McCombe, P and Talman, P and Vucic, S}, title = {Amyotrophic lateral sclerosis established as a multistep process across phenotypes.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16532}, pmid = {39475283}, issn = {1468-1331}, support = {//National Health and Medical Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Middle Aged ; *Phenotype ; Male ; Female ; Aged ; *Registries ; *Age of Onset ; Australia/epidemiology ; Disease Progression ; Incidence ; Adult ; }, abstract = {BACKGROUND AND PURPOSE: Given the accepted multistep process of disease causation in amyotrophic lateral sclerosis (ALS), the present study was undertaken to determine the number of steps required for disease onset across each of the ALS phenotypes.

METHODS: Clinical and demographic data were prospectively accumulated using the Australian Motor Neurone Disease Registry (2005-2016), and age-specific incidence rates were calculated. Poisson regression was utilized to assess the relationship between log age-specific incidence and log age of onset, with McFadden's R[2] used to assess the goodness of fit of the model.

RESULTS: In total, 2647 ALS patients were included, with mean disease-onset age being 62.2 ± 12.1 years. A linear relationship between log incidence and log age was established across ALS phenotypes, with variable slope estimates: bulbar 5.1 (95% confidence interval [CI] 4.6-5.6); cervical 2.7 (95% CI 2.3-3.0); lumbar 3.5 (95% CI 3.2-3.9); flail arm 4.7 (95% CI 3.9-5.5); flail leg 3.6 (95% CI 2.6-4.5); primary lateral sclerosis 2.7 (95% CI 1.8-3.7). Slope estimates were significantly higher in the bulbar compared to the cervical, lumbar and primary lateral sclerosis phenotypes. McFadden's R[2] values were >0.4 for all phenotypes indicating excellent model fit.

DISCUSSION: A multistep process has been established across all ALS phenotypes with variable slope estimates, suggesting that the number of steps to develop disease is different across clinical presentations. Identification of mechanisms underlying slope estimate variability could exert pathophysiological significance.}, } @article {pmid39475135, year = {2024}, author = {Jackowski, T and Horodnicka-Józwa, A and Berus, E and Walczak, M and Petriczko, E}, title = {An analysis of acid-labile subunit (ALS) levels in children with short stature born with normal weight.}, journal = {Endokrynologia Polska}, volume = {75}, number = {5}, pages = {548-557}, doi = {10.5603/ep.100285}, pmid = {39475135}, issn = {2299-8306}, mesh = {Humans ; Child ; Female ; Male ; *Glycoproteins ; Growth Disorders/diagnosis ; Carrier Proteins ; Child, Preschool ; Insulin-Like Growth Factor I/metabolism/analysis ; Insulin-Like Growth Factor Binding Protein 3/blood ; Body Height ; }, abstract = {INTRODUCTION: The acid-labile subunit (ALS) is a protein best known for its function in stabilising the insulin like growth factor-1/2-insulin-like growth factor-1 binding protein 3/5 (IGF-1/2-IGFBP3/5) binary complex by creating the ternary complex and in consequence regulating the biological activity of IGF-1. The aim of the study was to assess ALS concentrations in a chosen population of children with short stature taking into account their clinical diagnosis.

MATERIAL AND METHODS: A total of 109 prepubertal children were involved in the study - 85 children in the study group and 24 in controls. In all the children IGF-1, IGFBP3, and ALS were measured. The study group was divided according to diagnosis into groups: growth hormone deficiency (GHD), constitutional delay of growth and puberty (CDGP), idiopathic short stature (ISS), and familial short stature (FSS).

RESULTS: In the control group the ALS concentration ranged from 4.81 to 13.66 μg/mL. In the whole study group the ALS concentration ranged from 2.73 to 15.81 μg/mL. The difference between both groups was statistically significant (p < 0.0001, R = 0.39). A strong, statistically significant correlation between ALS levels and age was observed, but only in the study group (p < 0.0001, r = 0.59). The ALS standard deviation score (SDS) was not significantly different between the control and CDGP children (p = 0.0644). The ALS concentration was significantly lower in children with short stature. There was, however, no difference between the subgroups of the study group.

CONCLUSION: There was no significant difference in ALS SDS between the control group and children with constitutional delay of growth and development. The usefulness of ALS in routine short stature diagnostics is uncertain, but it might play a role in the diagnosis of children with ISS and CDGP in the future.}, } @article {pmid39474398, year = {2024}, author = {Goyal, O and Goyal, MK}, title = {Critical analysis of the effects of proton pump inhibitors on inflammatory bowel disease: An updated review.}, journal = {World journal of gastroenterology}, volume = {30}, number = {37}, pages = {4160-4162}, pmid = {39474398}, issn = {2219-2840}, mesh = {Humans ; *Colitis, Ulcerative/drug therapy/immunology/diagnosis ; *Crohn Disease/diagnosis/drug therapy/immunology ; *Proton Pump Inhibitors/therapeutic use/adverse effects ; Treatment Outcome ; Review Literature as Topic ; }, abstract = {This letter critically evaluates the effects of proton pump inhibitors (PPIs) on inflammatory bowel disease, particularly focusing on Crohn's disease (CD) and ulcerative colitis (UC), as discussed in Liang et al's recent review. While the review provides significant insights, it relies heavily on cross-sectional and observational studies, which limits the ability to draw causal inferences. The heterogeneous study populations and inconsistent definitions of long-term PPI use further complicate the findings. This letter also highlights the need for rigorous control of confounding factors and considers the potential publication bias in the existing literature. The implications of these issues are discussed in the context of both CD and UC, and future research directions are proposed to address these shortcomings.}, } @article {pmid39474168, year = {2024}, author = {Sandler, AB and Wells, ME and Tran, C and Arakawa, R and Klahs, KJ and Scanaliato, JP and Green, CK and Hettrich, CM and Dunn, JC and Adler, A and Parnes, N}, title = {High rates of return to sport after suprascapular nerve decompression: an updated systematic review.}, journal = {JSES reviews, reports, and techniques}, volume = {4}, number = {4}, pages = {654-661}, pmid = {39474168}, issn = {2666-6391}, abstract = {BACKGROUND: Suprascapular nerve decompression (SSND) remains a controversial procedure. In 2018, Momaya et al published the first systematic review of SSND noting satisfactory outcomes with low rates of complications; however, numerous studies published since have noted no benefit in routinely adding SSND to other arthroscopic surgeries, contributing to existing contention regarding the procedure. The purpose of this study is to provide an updated assessment of outcomes after SSND.

METHODS: To conduct this updated systematic review, a search of PubMed (MEDLINE) for relevant studies published prior to January 21, 2023 was conducted. Outcomes including patient-reported clinical outcomes, return to sport, preoperative and postoperative electrodiagnostic testing, and adverse events were collected and pooled for assessment. Studies were eligible for inclusion if they met Momaya et al's inclusion criteria and/or reported outcomes following SSND at either the suprascapular notch or spinoglenoid notch.

RESULTS: In total, 730 patients from 33 studies were eligible for inclusion. All patient-reported outcome measure scores including American Shoulder Elbow Surgeon Standardized Shoulder Assessment; Constant-Murley score; Disabilities of the Arm, Shoulder, and Hand; Subjective Shoulder Value; University of California-Los Angeles shoulder; and visual analog scale pain scores improved significantly postoperatively, with improvements ranging from 53.5% to 102.6% of preoperative values. Ultimately, 98% (n = 90/92) of patients returned to sport or military duty and 96% of these patients returned at their previous level of activity (n = 48/50) without heterogeneity among rates between studies (P = .176, P = .238, respectively). Preoperative electrodiagnostic testing was conducted in 93% of patients, and 90% had associated abnormal findings. Continued symptoms were noted among 12% of patients (n = 39/322) with significantly different rates observed between studies. Complications from operative management not limited to SSND occurred in 11% of patients (n = 64/576) and reoperations occurred in 3.3% of patients (n = 15/455).

CONCLUSION: Suprascapular neuropathy treated with SSND significantly improves patient-reported outcomes and is noninferior to similar procedures without SSND. Appropriate clinical diagnosis of suprascapular neuropathy is required as opposed to a routine adjunct procedure with other arthroscopic shoulder surgery. Ultimately, SSND is associated with high rates of return to sport and relatively low rates of adverse events; however, the risk of continued symptoms and electrodiagnostic test-related complications is an important point on preoperative counseling.}, } @article {pmid39473991, year = {2024}, author = {Hobro, AJ and Sakaguchi, T and Akira, S and Smith, NI}, title = {Correlative Quantitative Raman Chemical Imaging and MCR-ALS in Mouse NASH Model Reveals Direct Relationships between Diet and Resultant Liver Pathology.}, journal = {Chemical & biomedical imaging}, volume = {2}, number = {8}, pages = {577-583}, pmid = {39473991}, issn = {2832-3637}, abstract = {Raman imaging has the capability to provide unlabeled, spatially aware analysis of chemical components, with no a priori assumptions. Several lifestyle diseases such as nonalcoholic steatohepatitis (NASH) can appear in the liver as changes in the nature, abundance, and distribution of lipids, proteins, and other biomolecules and are detectable by Raman imaging. In order to identify which of these liver-associated changes occur as a direct result of the diet and which are secondary effects, we developed correlative imaging and analysis of diet and liver samples. Oleic acid was found to be a direct contributor to NASH liver composition, whereas protein and collagen distributions were found to be affected in a manner consistent with early fibrotic transformation, as a secondary consequence of the high-fat diet.}, } @article {pmid39473807, year = {2024}, author = {Oliveira, GC and Ngo, QC and Passos, LA and Oliveira, LS and Stylianou, S and Papa, JP and Kumar, D}, title = {Video Assessment to Detect Amyotrophic Lateral Sclerosis.}, journal = {Digital biomarkers}, volume = {8}, number = {1}, pages = {171-180}, pmid = {39473807}, issn = {2504-110X}, abstract = {INTRODUCTION: Weakened facial movements are early-stage symptoms of amyotrophic lateral sclerosis (ALS). ALS is generally detected based on changes in facial expressions, but large differences between individuals can lead to subjectivity in the diagnosis. We have proposed a computerized analysis of facial expression videos to detect ALS.

METHODS: This study investigated the action units obtained from facial expression videos to differentiate between ALS patients and healthy individuals, identifying the specific action units and facial expressions that give the best results. We utilized the Toronto NeuroFace Dataset, which includes nine facial expression tasks for healthy individuals and ALS patients.

RESULTS: The best classification accuracy was 0.91 obtained for the pretending to smile with tight lips expression.

CONCLUSION: This pilot study shows the potential of using computerized facial expression analysis based on action units to identify facial weakness symptoms in ALS.}, } @article {pmid39473490, year = {2024}, author = {Fei, Y and Ding, Y}, title = {The role of ferroptosis in neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1475934}, pmid = {39473490}, issn = {1662-5102}, abstract = {Ferroptosis represents an iron[-] and lipid peroxidation (LPO)-mediated form of regulated cell death (RCD). Recent evidence strongly suggests the involvement of ferroptosis in various neurodegenerative diseases (NDs), particularly Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), among others. The treatment of ferroptosis poses both opportunities and challenges in the context of ND. This review provides a comprehensive overview of characteristic features, induction and inhibition of ferroptosis, highlighting the ferroptosis inhibitor and the underlying mechanisms responsible for its occurrence. Moreover, the review explores how these mechanisms contribute to the pathogenesis and progression of major neurodegenerative disorders. Additionally, it presents novel insights into the role of ferroptosis in ND and summarizes recent advancements in the development of therapeutic approaches targeting ferroptosis. These insights and advancements hold potential to guide future strategies aimed at effectively managing these debilitating medical conditions.}, } @article {pmid39473462, year = {2024}, author = {Zhang, Y and Xu, N and Yan, C and Zhou, X and Qiao, Q and Miao, L and Xu, Z}, title = {Live-Cell Imaging to Resolve Salt-Induced Liquid-Liquid Phase Separation of FUS Protein by Dye Self-Labeling.}, journal = {Chemical & biomedical imaging}, volume = {2}, number = {1}, pages = {70-80}, pmid = {39473462}, issn = {2832-3637}, abstract = {The aggregation of fusion in sarcoma (FUS) in the cytoplasm and nucleus is a pathological feature of Amyotrophic lateral sclerosis (ALS) and Frontotemporal Dementia (FTD). Genetic mutations, abnormal protein synthesis, environmental stress, and aging have all been implicated as causative factors in this process. Salt ions are essential to many physiological processes in the body, and the imbalance of them is an important environmental stress factor in cells. However, their effect on liquid-liquid phase separation (LLPS) of FUS proteins in living cells is not well understood. Here, we map the various salt-induced LLPS of FUS in living cells by genetically coding and self-labeling FUS with organic dyes. The brightness and photostability of the dyes enable long-term imaging to track the mechanism of the assembly and disappearance of FUS phase separation. The FUS protein showed a better phase separation tendency under 0.3 M salt stimulation, and there was a large amount of FUS shuttling from the nucleus to the cytoplasm. At this concentration, various salt solutions displayed different effects on the phase separation of FUS protein, following the Hofmeister effects. We further observed that the assembly of FUS droplets underwent a process of rapid formation of small droplets, plateaus, and mutual fusion. Strikingly, The CsCl-stimulated FUS droplets were not completely reversible after washing, and some solid-like granules remained in the nucleus. Taken together, these results help broaden our understanding of the LLPS of FUS proteins in cellular stress responses.}, } @article {pmid39473221, year = {2024}, author = {Ito, D and Okada, K}, title = {Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {12}, pages = {3054-3063}, pmid = {39473221}, issn = {2328-9503}, support = {21H02812//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; *Oligonucleotides, Antisense/administration & dosage/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Antisense oligonucleotides, which are used to silence target genes, are gaining attention as a novel drug discovery modality for proteinopathies. However, while clinical trials for neurodegenerative diseases like amyotrophic lateral sclerosis have been conducted in recent years, the results have not always been favorable. The results from a Phase III trial of the antisense oligonucleotide, that is, tofersen, which targets SOD1 mRNA, showed decreased levels of cerebrospinal fluid SOD1 and plasma neurofilament light chain but no improvements in primary clinical endpoint. Moreover, case reports pertaining to patients with amyotrophic lateral sclerosis carrying FUS and C9orf72 mutations who received antisense oligonucleotide-based treatments have demonstrated a notable reduction in the targeted protein (thus providing the proof of mechanism) but with no discernible clinical benefits. There are several possible reasons why antisense oligonucleotides knockdown fails to achieve proof of concept, which need to be addressed: on-target adverse effects resulting from the loss of function of target gene and irreversible neuronal death cascade due to toxic protein accumulation, among other factors. This review provides an overview of the current status and discusses the prospects of antisense oligonucleotides treatment for amyotrophic lateral sclerosis.}, } @article {pmid39472924, year = {2024}, author = {Stikvoort García, DJL and Sleutjes, BTHM and Mugge, W and Plouvier, JJ and Goedee, HS and Schouten, AC and van der Helm, FCT and van den Berg, LH}, title = {Instrumented assessment of lower and upper motor neuron signs in amyotrophic lateral sclerosis using robotic manipulation: an explorative study.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {21}, number = {1}, pages = {193}, pmid = {39472924}, issn = {1743-0003}, support = {AV20180012//Stichting ALS Nederland/ ; AV20180012//Stichting ALS Nederland/ ; AV20180012//Stichting ALS Nederland/ ; AV20180012//Stichting ALS Nederland/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Middle Aged ; Female ; *Robotics/instrumentation/methods ; *Electromyography/methods/instrumentation ; Aged ; *Motor Neurons/physiology ; *Muscle, Skeletal/physiopathology/physiology ; Torque ; Wrist Joint/physiopathology ; Adult ; Muscle Strength/physiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a lethal progressive neurodegenerative disease characterized by upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Their varying degree of involvement results in a clinical heterogenous picture, making clinical assessments of UMN signs in patients with ALS often challenging. We therefore explored whether instrumented assessment using robotic manipulation could potentially be a valuable tool to study signs of UMN involvement.

METHODS: We examined the dynamics of the wrist joint of 15 patients with ALS and 15 healthy controls using a Wristalyzer single-axis robotic manipulator and electromyography (EMG) recordings in the flexor and extensor muscles in the forearm. Multi-sinusoidal torque perturbations were applied, during which participants were asked to either relax, comply or resist. A neuromuscular model was used to study muscle viscoelasticity, e.g. stiffness (k) and viscosity (b), and reflexive properties, such as velocity, position and force feedback gains (kv, kp and kf, respectively) that dominated the responses. We further obtained clinical signs of LMN (muscle strength) and UMN (e.g. reflexes, spasticity) dysfunction, and evaluated their relation with the estimated neuromuscular model parameters.

RESULTS: Only force feedback gains (kf) were elevated in patients (p = 0.033) compared to controls. Higher kf, as well as the resulting reflexive torque (Tref), were both associated with more severe UMN dysfunction in the examined arm (p = 0.040 and p < 0.001). Patients with UMN symptoms in the examined arm had increased kf and Tref compared to controls (both p = 0.037). Neither of these measures was related to muscle strength, but muscle stiffness (k) was lower in weaker patients (p = 0.012). All these findings were obtained from the relaxed test. No differences were observed during the instructions comply and resist.

CONCLUSIONS: This findings are proof-of-concept that instrumented assessment using robotic manipulation is a feasible technique in ALS, which may provide quantitative, operator-independent measures relating to UMN symptoms. Elevated force feedback gains, driving larger reflexive muscle torques, appear to be particularly indicative of clinically established levels of UMN dysfunction in the examined arm.}, } @article {pmid39472842, year = {2024}, author = {Guazzo, A and Atzeni, M and Idi, E and Trescato, I and Tavazzi, E and Longato, E and Manera, U and Chió, A and Gromicho, M and Alves, I and de Carvalho, M and Vettoretti, M and Di Camillo, B}, title = {Predicting clinical events characterizing the progression of amyotrophic lateral sclerosis via machine learning approaches using routine visits data: a feasibility study.}, journal = {BMC medical informatics and decision making}, volume = {24}, number = {Suppl 4}, pages = {318}, pmid = {39472842}, issn = {1472-6947}, support = {GA01017598//HORIZON EUROPE Health/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Feasibility Studies ; *Disease Progression ; *Machine Learning ; Male ; Middle Aged ; Female ; Aged ; Prognosis ; Noninvasive Ventilation ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in death within a short time span (3-5 years). One of the major challenges in treating ALS is its highly heterogeneous disease progression and the lack of effective prognostic tools to forecast it. The main aim of this study was, then, to test the feasibility of predicting relevant clinical outcomes that characterize the progression of ALS with a two-year prediction horizon via artificial intelligence techniques using routine visits data.

METHODS: Three classification problems were considered: predicting death (binary problem), predicting death or percutaneous endoscopic gastrostomy (PEG) (multiclass problem), and predicting death or non-invasive ventilation (NIV) (multiclass problem). Two supervised learning models, a logistic regression (LR) and a deep learning multilayer perceptron (MLP), were trained ensuring technical robustness and reproducibility. Moreover, to provide insights into model explainability and result interpretability, model coefficients for LR and Shapley values for both LR and MLP were considered to characterize the relationship between each variable and the outcome.

RESULTS: On the one hand, predicting death was successful as both models yielded F1 scores and accuracy well above 0.7. The model explainability analysis performed for this outcome allowed for the understanding of how different methodological approaches consider the input variables when performing the prediction. On the other hand, predicting death alongside PEG or NIV proved to be much more challenging (F1 scores and accuracy in the 0.4-0.6 interval).

CONCLUSIONS: In conclusion, predicting death due to ALS proved to be feasible. However, predicting PEG or NIV in a multiclass fashion proved to be unfeasible with these data, regardless of the complexity of the methodological approach. The observed results suggest a potential ceiling on the amount of information extractable from the database, e.g., due to the intrinsic difficulty of the prediction tasks at hand, or to the absence of crucial predictors that are, however, not currently collected during routine practice.}, } @article {pmid39472796, year = {2024}, author = {Zheng, K and Chen, M and Xu, X and Li, P and Yin, C and Wang, J and Liu, B}, title = {Chemokine CXCL13-CXCR5 signaling in neuroinflammation and pathogenesis of chronic pain and neurological diseases.}, journal = {Cellular & molecular biology letters}, volume = {29}, number = {1}, pages = {134}, pmid = {39472796}, issn = {1689-1392}, support = {82474625//National Natural Science Foundation of China/ ; 82305368//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Chemokine CXCL13/metabolism/genetics ; *Chronic Pain/metabolism/immunology ; *Receptors, CXCR5/metabolism ; *Signal Transduction ; *Nervous System Diseases/metabolism ; Animals ; *Neuroinflammatory Diseases/metabolism ; }, abstract = {Chronic pain dramatically affects life qualities of the sufferers. It has posed a heavy burden to both patients and the health care system. However, the current treatments for chronic pain are usually insufficient and cause many unwanted side effects. Chemokine C-X-C motif ligand 13 (CXCL13), formerly recognized as a B cell chemokine, binds with the cognate receptor CXCR5, a G-protein-coupled receptor (GPCR), to participate in immune cell recruitments and immune modulations. Recent studies further demonstrated that CXCL13-CXCR5 signaling is implicated in chronic pain via promoting neuroimmune interaction and neuroinflammation in the sensory system. In addition, some latest work also pointed out the involvement of CXCL13-CXCR5 in the pathogenesis of certain neurological diseases, including ischemic stroke and amyotrophic lateral sclerosis. Therefore, we aim to outline the recent findings in regard to the involvement of CXCL13-CXCR5 signaling in chronic pain as well as certain neurological diseases, with the focus on how this chemokine signaling contributes to the pathogenesis of these neurological diseases via regulating neuroimmune interaction and neuroinflammation. Strategies that can specifically target CXCL13-CXCR5 signaling in distinct locations may provide new therapeutic options for these neurological diseases.}, } @article {pmid39471924, year = {2024}, author = {Xu, Y and Xu, T and Huang, C and Liu, L and Kwame, AW and Zhu, Y and Ren, J}, title = {Preventive intervention with Agaricus blazei murill polysaccharide exerts anti-tumor immune effect on intraperitoneal metastasis colorectal cancer.}, journal = {International journal of biological macromolecules}, volume = {282}, number = {Pt 3}, pages = {136810}, doi = {10.1016/j.ijbiomac.2024.136810}, pmid = {39471924}, issn = {1879-0003}, mesh = {Animals ; *Agaricus/chemistry ; *Colorectal Neoplasms/pathology/immunology/prevention & control/drug therapy ; Mice ; Cell Line, Tumor ; Tumor Microenvironment/drug effects ; Peritoneal Neoplasms/secondary/drug therapy/prevention & control/immunology ; Fungal Polysaccharides/pharmacology/chemistry ; CD8-Positive T-Lymphocytes/drug effects/immunology ; Polysaccharides/pharmacology/chemistry ; Antineoplastic Agents/pharmacology ; }, abstract = {Agaricus blazei murill (ABM) mainly exerts its antitumor effect via modulation of the immune system. However, the immunomodulatory role of the ABM polysaccharide (ABMP) in mice with subcutaneously and intraperitoneally implanted MC38 tumor remains to be explored. This study aimed to define the progression effect of inhibiting tumor of ABMP in subcutaneous and intraperitoneal models and its effect on tumor microenvironment (TME) metabolism. In vitro experiments showed that ABMP could significantly promote the activity of CD8+ T immune cells in the co-culture system and promoted their colorectal cancer killing function (p < 0.05). In vivo animal exploration further showed that ABMP could inhibit the growth of intraperitoneal but not subcutaneous tumors. MCR-ALS analysis revealed a significant reduction in the signal of lipid-related spectral components in the TME of peritoneal tumors after ABMP intervention. In addition, preventive intervention with ABMP increased ω-3 polyunsaturated fatty acids content in intraperitoneal TME, revealing that ABMP shifted the metabolic landscape of the TME to promote T cell function and achieved immune regulation. These results suggest that the inhibitory effect of ABMP on colon cancer may be tumor stage-dependent, and that remodeling of fatty acid composition may be an important determinant of its action at any given stage.}, } @article {pmid39471842, year = {2024}, author = {Ferro, F and Wolf, CR and Henstridge, C and Inesta-Vaquera, F}, title = {Novel in vivo TDP-43 stress reporter models to accelerate drug development in ALS.}, journal = {Open biology}, volume = {14}, number = {10}, pages = {240073}, pmid = {39471842}, issn = {2046-2441}, support = {//MND Scotland/ ; //ARUK/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy/genetics/pathology ; Animals ; Mice ; *DNA-Binding Proteins/metabolism/genetics ; *Disease Models, Animal ; Humans ; *Mice, Transgenic ; *Genes, Reporter ; Oxidative Stress/drug effects ; NF-E2-Related Factor 2/metabolism/genetics ; Drug Development ; DNA Damage ; Biomarkers ; }, abstract = {The development of therapies to combat neurodegenerative diseases is widely recognized as a research priority. Despite recent advances in understanding their molecular basis, there is a lack of suitable early biomarkers to test selected compounds and accelerate their translation to clinical trials. We have investigated the utility of in vivo reporters of cytoprotective pathways (e.g. NRF2, p53) as surrogate early biomarkers of the ALS degenerative disease progression. We hypothesized that cellular stress observed in a model of ALS may precede overt cellular damage and could activate our cytoprotective pathway reporters. To test this hypothesis, we generated novel ALS-reporter mice by crossing the hTDP-43tg model into our oxidative stress/inflammation (Hmox1; NRF2 pathway) and DNA damage (p21; p53 pathway) stress reporter models. Histological analysis of reporter expression in a homozygous hTDP-43tg background demonstrated a time-dependent and tissue-specific activation of the reporters in tissues directly associated with ALS, before moderate clinical signs are observed. Further work is warranted to determine the specific mechanisms by which TDP-43 accumulation leads to reporter activation and whether therapeutic intervention modulates reporters' expression. We anticipate the reporter strategy could be of great value in developing treatments for a range of degenerative disorders.}, } @article {pmid39471269, year = {2024}, author = {Stenson, K and Chew, S and Dong, S and Heithoff, K and Wang, MJ and Rosenfeld, J}, title = {Health care resource utilization and costs across stages of amyotrophic lateral sclerosis in the United States.}, journal = {Journal of managed care & specialty pharmacy}, volume = {30}, number = {11}, pages = {1239-1247}, pmid = {39471269}, issn = {2376-1032}, mesh = {*Amyotrophic Lateral Sclerosis/economics/therapy ; Humans ; United States ; Male ; Female ; Middle Aged ; Aged ; *Patient Acceptance of Health Care/statistics & numerical data ; *Health Care Costs/statistics & numerical data ; Adult ; Health Resources/economics/statistics & numerical data ; Severity of Illness Index ; Retrospective Studies ; Disease Progression ; Cost of Illness ; Databases, Factual ; }, abstract = {BACKGROUND: People living with ALS (plwALS) experience motor control loss, speech/swallowing difficulties, respiratory insufficiency, and early death. Advancing disease stage is typically associated with a greater burden on the health care system, and delays in diagnosis can result in substantial health care resource utilization (HCRU).

OBJECTIVE: To estimate HCRU and cost burden of plwALS across disease stages from a US payer perspective we assessed HCRU and costs in early-, mid-, and late-stage ALS.

METHODS: Using insurance claims data from the IBM MarketScan Databases between January 2013 and December 2019, we identified plwALS as having at least 2 claims at least 27 days apart with an ALS International Classification of Diseases, Ninth or Tenth Revision diagnosis code (335.20/G12.21) or at least 1 ALS diagnosis code and prescription filled for riluzole/edaravone. Eligible plwALS were aged at least 18 years and had at least 12 months of enrollment data before and at least 6 months after the index date (date diagnosis criteria met). plwALS were grouped into disease stages using an ALS severity-based staging algorithm developed using ALS symptom and staging survey data from 142 neurologists reporting on 880 plwALS. The starting date of each severity stage was defined as the first date of an ALS symptom within the early-, mid-, and late-stage categories, respectively. The ending date for a severity stage was defined as the day before the first date of an ALS symptom from a more severe category. plwALS could transition to more severe stages, with reverse transition of severity excluded. Mixed regression modeling was used to assess differences in HCRU and costs per person-year between severity stages, adjusted for age and sex.

RESULTS: 2,273 plwALS were included in the total ALS study sample, with 1,215 early-stage, 1,511 midstage, and 1,186 late-stage plwALS. 90% of early-stage plwALS had ALS symptoms before diagnosis, and 27% of late-stage plwALS had a late-stage symptom before diagnosis. In the evaluation period, later-stage ALS groups had more overall hospital admissions (early = 0.15, middle = 0.23, and late = 0.74; P < 0.01), outpatient visits/service (early = 26.81, middle = 32.78, and late = 48.54; P < 0.01), emergency department visits (early = 0.46, middle = 0.69, and late = 1.03; P < 0.01), and total prescription count (early = 9.23, middle = 11.37, and late = 12.72; P < 0.01) over 12 months. Annualized costs increased as ALS progressed (early = $31,411, middle = $51,481, and late = $121,903; P < 0.01), which was primarily driven by higher frequency of and cost per hospital admission.

CONCLUSIONS: HCRU and costs increased with ALS progression, with diagnosis frequently occurring even after experiencing late-stage symptoms. These findings highlight the potential value of delaying progression into a more resource-intensive stage by diagnosing and adequately treating plwALS earlier in the disease course.}, } @article {pmid39470866, year = {2024}, author = {Liu, Y and Fu, R and Jia, H and Yang, K and Ren, F and Zhou, MS}, title = {GHRH and its analogues in central nervous system diseases.}, journal = {Reviews in endocrine & metabolic disorders}, volume = {}, number = {}, pages = {}, pmid = {39470866}, issn = {1573-2606}, support = {82270434//National Natural Science Foundation of China/ ; }, abstract = {Growth hormone-releasing hormone (GHRH) is primarily produced by the hypothalamus and stimulates the release of growth hormone (GH) in the anterior pituitary gland, which subsequently regulates the production of hepatic insulin-like growth factor-1 (IGF-1). GH and IGF-1 have potent effects on promoting cell proliferation, inhibiting cell apoptosis, as well as regulating cell metabolism. In central nerve system (CNS), GHRH/GH/IGF-1 promote brain development and growth, stimulate neuronal proliferation, and regulate neurotransmitter release, thereby participating in the regulation of various CNS physiological activities. In addition to hypothalamus-pituitary gland, GHRH and GHRH receptor (GHRH-R) are also expressed in other brain cells or tissues, such as endogenous neural stem cells (NSCs) and tumor cells. Alternations in GHRH/GH/IGF-1 axis are associated with various CNS diseases, for example, Alzheimer's disease, amyotrophic lateral sclerosis and emotional disorders manifest GHRH, GH or IGF-1 deficiency, and GH or IGF-1 supplementation exerts beneficial therapeutic effects on these diseases. CNS tumors, such as glioma, can express GHRH and GHRH-R, and activating this signaling pathway promotes tumor cell growth. The synthesized GHRH antagonists have shown to inhibit glioma cell growth and may hold promising as an adjuvant therapy for treating glioma. In addition, we have shown that GHRH agonist MR-409 can improve neurological sequelae after ischemic stroke by activating extrapituitary GHRH-R signaling and promoting endogenous NSCs-derived neuronal regeneration. This article reviews the involvement of GHRH/GH/IGF-1 in CNS diseases, and potential roles of GHRH agonists and antagonists in treating CNS diseases.}, } @article {pmid39470847, year = {2025}, author = {Jellinger, KA}, title = {Mild cognitive impairment in amyotrophic lateral sclerosis: current view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {132}, number = {3}, pages = {357-368}, pmid = {39470847}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {Humans ; *Cognitive Dysfunction/etiology/physiopathology/metabolism/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/complications/metabolism/physiopathology ; Brain/diagnostic imaging/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal multi-system neurodegenerative disorder with no effective treatment or cure. Although primarily characterized by motor degeneration, cognitive dysfunction is an important non-motor symptom that has a negative impact on patient and caregiver burden. Mild cognitive deficits are present in a subgroup of non-demented patients with ALS, often preceding motor symptoms. Detailed neuropsychological assessments reveal deficits in a variety of cognitive domains, including those of verbal fluency and retrieval, language, executive function, attention and verbal memory. Mild cognitive impairment (MCI), a risk factor for developing dementia, affects between 10% and over 50% of ALS patients. Neuroimaging revealed atrophy of frontal and temporal cortices, disordered white matter Integrity, volume reduction in amygdala and thalamus, hypometabolism in the frontal and superior temporal gyrus and anterior insula. Neuronal loss in non-motor brain areas, associated with TDP-43 deposition, one of the morphological hallmarks of ALS, is linked to functional disruption of frontostriatal and frontotemporo-limbic connectivities as markers for cognitive deficits in ALS, the pathogenesis of which is still poorly understood. Early diagnosis by increased cerebrospinal fluid or serum levels of neurofilament light/heavy chain or glial fibrillary acidic protein awaits confirmation for MCI in ALS. These fluid biomarkers and early detection of brain connectivity signatures before structural changes will be helpful not only in establishing early premature diagnosis but also in clarifying the pathophysiological mechanisms of MCI in ALS, which might serve as novel targets for prohibition/delay and future adequate treatment of this debilitating disorder.}, } @article {pmid39470585, year = {2024}, author = {Lin, W and Wu, X and Ou, G}, title = {Causal association of circulating inflammatory proteins on neurodegenerative diseases: Insights from a mendelian randomization study.}, journal = {Journal of cellular and molecular medicine}, volume = {28}, number = {20}, pages = {e70176}, pmid = {39470585}, issn = {1582-4934}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics/blood ; *Genome-Wide Association Study ; *Cytokines/blood/genetics ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; Alzheimer Disease/genetics/blood ; Amyotrophic Lateral Sclerosis/genetics/blood ; Inflammation/genetics/blood ; Multiple Sclerosis/genetics/blood ; Parkinson Disease/genetics/blood ; }, abstract = {Neuroinflammation is increasingly recognized as a pivotal factor in the development and progression of neurodegenerative disorders. While correlations between inflammatory cytokines and these diseases are documented, the definitive causal dynamics remain to be elucidated. We explored the causal association between 91 circulating inflammatory cytokines and Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Parkinson's disease (PD) through Mendelian randomization analysis. Leveraging genetic variants from the most comprehensive genome-wide association studies (GWAS) available for these cytokines, AD, ALS, MS and PD, we sought to uncover the causality. Our study validated a causal influence of genetically determined cytokine levels on the susceptibility to AD, with notable cytokines including C-X-C motif chemokine 1 (OR = 0.9993, p = 0.0424), Interleukin-18 (OR = 0.9994, p = 0.0186), Leukaemia inhibitory factor receptor (OR = 0.9993, p = 0.0122) and Monocyte chemoattractant protein-1 (OR = 0.9992, p = 0.0026) in risk attenuation. Additionally, a positive causal relationship was identified between two cytokines-C-C motif chemokine 19 (OR = 1.0005, p = 0.0478) and Fms-related tyrosine kinase 3 ligand (OR = 1.0005, p = 0.0210)-and AD incidence. Conversely, transforming growth factor-alpha (OR = 0.8630, p = 0.0298), CD40L receptor (OR = 0.7737, p = 1.1265E-09) and Interleukin-12 subunit beta (OR = 0.8987, p = 0.0333) showed inverse associations with ALS, MS and PD, respectively. The consistency observed in various MR analyses, alongside sensitivity analysis, underscored the absence of horizontal pleiotropy, thus supporting our causal findings. This study reveals, for the first time, a genetically anchored causal nexus between levels of circulating inflammatory cytokines and the risk of neurodegenerative diseases.}, } @article {pmid39470153, year = {2024}, author = {Xu, R}, title = {Overview of nomenclature and diagnosis of amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2422572}, pmid = {39470153}, issn = {1365-2060}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/classification/physiopathology ; Humans ; *Terminology as Topic ; Electromyography/methods ; Motor Neurons/pathology ; }, abstract = {The nomenclature of amyotrophic lateral sclerosis (ALS) currently is blurred, indistinct and no accurate and haven't been properly updated since the first description, which is far from being suitable for the current implementation of clinical practise and scientific research of ALS, and urgently need an solution. Furthermore, the current diagnostic criteria need also further been improved, because the current clinical diagnosis of ALS majorly depends on the clinical manifestations yet. Up to now, no any objective clinical auxiliary examination can be helpful to diagnose ALS besides the electromyogram identifying the lower motor neuron damage, which isn't conducive to early diagnosis and prolongs the time of ALS confirmed diagnosis. In this mini review, we discussed the current doubt about the nomenclature and diagnostic criteria of ALS, and prospected in order to further improve and normalize the nomenclature and diagnosis of ALS.}, } @article {pmid39468607, year = {2024}, author = {Liu, C and Wu, Y and Wang, F and Sun, S and Wei, J and Tao, L}, title = {Cost-utility analysis for sublingual versus intravenous edaravone in the treatment of amyotrophic lateral sclerosis.}, journal = {Orphanet journal of rare diseases}, volume = {19}, number = {1}, pages = {400}, pmid = {39468607}, issn = {1750-1172}, mesh = {*Edaravone/therapeutic use/economics/administration & dosage ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/economics ; *Cost-Benefit Analysis ; Administration, Sublingual ; Antipyrine/analogs & derivatives/therapeutic use/economics/administration & dosage ; Free Radical Scavengers/therapeutic use/economics/administration & dosage ; Administration, Intravenous ; Male ; }, abstract = {BACKGROUND: Edaravone has been widely used in amyotrophic lateral sclerosis (ALS) treatment, and a sublingual (SL) tablet has been developed to offer a more convenient alternative for injection. We present a cost-utility analysis to comprehensively evaluate the costs and health outcomes of oral and intravenous edaravone for the treatment of ALS in Chinese medical context.

METHODS: Cost-utility analysis of SL tablets of edaravone versus intravenous edaravone at home was performed by constructing a 20-year Markov model of ALS stage 1-4 and death. The data were extracted from the literature with model assumptions. Typical sensitivity analysis and scenario analysis for administering SL tablets at home versus intravenous tablets at the hospital were performed.

RESULTS: In the base case analysis, with SL tablets and intravenous injections both at home, the model estimated an additional cost of ¥12,670.04 and an additional 0.034 QALYs over 20 years (life time) of modeling analysis, and the ICER was ¥372,648.24 per QALY. However, in the scenario of intravenous administration at the hospital, SL tablet was demonstrated dominance to intravenous injection.

CONCLUSIONS: Using 3 times the GDP per capita of China in 2023 as the threshold, the SL tablet edaravone was not cost-effective in the context of home treatment for both formulationst, but was dominance to intravenous injection in hospital treatment. The results highlighted the importance of treatment context for health economic analysis.}, } @article {pmid39467933, year = {2025}, author = {Kang, M and Kim, BJ and Nguyen, B and Park, JS}, title = {Computed tomography-based radiological gynecomastia in SBMA as an independent differential diagnostic biomarker: a retrospective study.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {2}, pages = {783-789}, doi = {10.1007/s10072-024-07820-1}, pmid = {39467933}, issn = {1590-3478}, mesh = {Humans ; *Gynecomastia/diagnostic imaging ; Retrospective Studies ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Diagnosis, Differential ; *Tomography, X-Ray Computed/methods ; Aged ; Adult ; }, abstract = {BACKGROUND: Spinal bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS) are motor neuron disorders that demonstrate overlapping clinical features, especially in the early stage. Therefore, the aim of this study was to investigate the utility of chest tomography (CT) imaging in distinguishing between SBMA and ALS.

METHODS: This was a retrospective study reviewing CT images from patients with SBMA and sporadic ALS and those in the control group. The CT images were assessed to measure the diameter and morphology of glandular tissue associated with gynecomastia. We compared CT-measured gynecomastia between the SBMA, ALS, and control groups. Additionally, correlation analyses were performed between the quantitative measurements of gynecomastia obtained from CT scans and various clinical/laboratory parameter in the SBMA group.

RESULTS: 15 chest CT images were collected from SBMA, 41 from ALS, and 29 from control group. No statistical differences were observed in BMI, functional scales, or age at the time of CT scans between the SBMA and ALS groups. Despite similar functional scales and age in both groups, the mean glandular tissue diameter of breast tissue observed in chest CT imaging differed significantly between SBMA, ALS, and controls: 32.22 ± 12.57 mm, 15.91 ± 4.81 mm, and 15.76 ± 7.26 mm, respectively. This disparity allowed for the differentiation of SBMA from ALS and controls with statistical significance. Clinical gynecomastia was 80%, while radiological gynecomastia was 93.3% in SBMA. A significantly higher prevalence of diffuse glandular morphology pattern in SBMA (50%) was observed, contrasting with the predominance of nodular morphology in ALS and controls (9.1% and 20%). Correlative analysis between glandular tissue diameter and other clinical/laboratory parameters within the SBMA group showed no specific finding.

CONCLUSION: CT-based radiological gynecomastia effectively differentiated SBMA from ALS. These findings support the usefulness of radiological gynecomastia as a potential differential diagnostic marker for SBMA, especially in the early stages.}, } @article {pmid39466798, year = {2025}, author = {Correa, T and Owen, SR}, title = {Invited Commentary on: Santamaría-Gadea et al's "Non-Surgical Rhinoplasty After Rhinoplasty: A Systematic Review of the Technique, Results, and Complications".}, journal = {Facial plastic surgery & aesthetic medicine}, volume = {27}, number = {1}, pages = {75-76}, doi = {10.1089/fpsam.2024.0267}, pmid = {39466798}, issn = {2689-3622}, } @article {pmid39465944, year = {2024}, author = {Chen, C and Rafael, KA and Cho, G and Lim, Y}, title = {Split-Luciferase Reassembly Assay to Measure Endoplasmic Reticulum-Mitochondria Contacts in Live Cells.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {212}, pages = {}, doi = {10.3791/66862}, pmid = {39465944}, issn = {1940-087X}, mesh = {*Endoplasmic Reticulum/metabolism ; *Mitochondria/metabolism ; Humans ; Luciferases/metabolism/genetics ; Animals ; Mitochondria Associated Membranes ; }, abstract = {Endoplasmic reticulum (ER)-mitochondria contact sites play a critical role in cell health and homeostasis, such as the regulation of Ca[2+] and lipid homeostasis, mitochondrial dynamics, autophagosome and mitophagosome biogenesis, and apoptosis. Failure to maintain normal ER-mitochondrial coupling is implicated in many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and hereditary spastic paraplegia. It is of considerable significance to explore how the dysregulation of ER-mitochondrial contacts could lead to cell death and whether repairing these contacts to the normal level could ameliorate neurodegenerative conditions. Thus, improved assays that measure the level of these contacts could help to illuminate the pathogenic mechanisms of these diseases. Ultimately, establishing simple and reliable assays will facilitate the development of new therapeutic strategies. Here we describe a split-luciferase assay to quantitatively measure the level of ER-mitochondria contacts in live cells. This assay can be used to study the pathophysiological role of these contacts as well as to identify their modulators in high-throughput screening.}, } @article {pmid39465642, year = {2024}, author = {Erdaş, ÇB and Sümer, E}, title = {CNN-Based Neurodegenerative Disease Classification Using QR-Represented Gait Data.}, journal = {Brain and behavior}, volume = {14}, number = {10}, pages = {e70100}, pmid = {39465642}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/classification/diagnosis/physiopathology ; *Huntington Disease/diagnosis/physiopathology/classification ; *Parkinson Disease/classification/diagnosis/physiopathology ; *Neurodegenerative Diseases/classification/diagnosis/physiopathology ; Male ; Middle Aged ; Female ; Neural Networks, Computer ; Gait/physiology ; Aged ; Deep Learning ; Gait Analysis/methods ; Adult ; }, abstract = {PURPOSE: The primary aim of this study is to develop an effective and reliable diagnostic system for neurodegenerative diseases by utilizing gait data transformed into QR codes and classified using convolutional neural networks (CNNs). The objective of this method is to enhance the precision of diagnosing neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Huntington's disease (HD), through the introduction of a novel approach to analyze gait patterns.

METHODS: The research evaluates the CNN-based classification approach using QR-represented gait data to address the diagnostic challenges associated with neurodegenerative diseases. The gait data of subjects were converted into QR codes, which were then classified using a CNN deep learning model. The dataset includes recordings from patients with Parkinson's disease (n = 15), Huntington's disease (n = 20), and amyotrophic lateral sclerosis (n = 13), and from 16 healthy controls.

RESULTS: The accuracy rates obtained through 10-fold cross-validation were as follows: 94.86% for NDD versus control, 95.81% for PD versus control, 93.56% for HD versus control, 97.65% for ALS versus control, and 84.65% for PD versus HD versus ALS versus control. These results demonstrate the potential of the proposed system in distinguishing between different neurodegenerative diseases and control groups.

CONCLUSION: The results indicate that the designed system may serve as a complementary tool for the diagnosis of neurodegenerative diseases, particularly in individuals who already present with varying degrees of motor impairment. Further validation and research are needed to establish its wider applicability.}, } @article {pmid39464638, year = {2024}, author = {Altuwaijri, F and Alrabiah, A and Alqarni, A and Habash, AK and Alghofili, M and Alotaibi, O and Altuwaijri, M}, title = {Comparison Between the Advanced Cardiac Life Support and Adult Advanced Life Support Protocols: A Simulation-Based Pilot Study.}, journal = {Emergency medicine international}, volume = {2024}, number = {}, pages = {6696879}, pmid = {39464638}, issn = {2090-2840}, abstract = {Introduction: Cardiac arrest is a public health concern associated with unfavorable disease outcomes. Cardiopulmonary resuscitation (CPR) of optimal quality is widely acknowledged as an indispensable technique in restoring spontaneous circulation. In order to perform advanced cardiac life support (ACLS), chest compression must be paused twice: once to assess the rhythm and again to administer the shock. Australian advanced life support (ALS) recommends that the defibrillator needs to be precharged in order to administer the shock during a solitary interval in chest compressions. While performing chest compressions, precharging defibrillators can decrease hands-off time without posing a risk of injury. Aim: To compare chest compression fraction (CCF)-which is the cumulative time spent providing chest compressions divided by the total time taken for the entire resuscitation-by calculating the hands-off time duration in cardiac arrest between the Australian Resuscitation Council (ARC) and American Heart Association (AHA) protocols for CPR. Methods: A simulation-based pilot study was designed using a Laerdal Resusci Anne mannequin and a LIFEPACK 20 defibrillator. The study included six participants recruited from King Khalid University Hospital in Riyadh, Saudi Arabia, where three participants were certified ACLS providers and there were certified ALS providers. Participants were divided into two groups, ALS and ACLS, each following one protocol. For each scenario, a random job was assigned to each participant, regardless of their role as assistant, team leader, or performer of CPR. Each case's shockable and nonshockable rhythms were hidden from the team leader and the chest compressor. Ten trials of CPR were performed, each for four cycles with a total time of 8 min. The simulation was video recorded for hands-off time counting. Comparison between CCF (seconds) per cycle between the two protocols was performed using an independent sample t-test. A p value of 0.05 was used to measure statistical significance. Results: Comparing CCF in shockable rhythms between ARC and AHA protocols, it was observed that the CCF of ALS-ARC was significantly higher than ACLS-AHA in all cycles; the first cycle: t = 3.782, p=0.004; the second cycle: t = 3.380, p=0.007; the third cycle: t = 3.803, p=0.003; and the fourth cycle: t = 4.341, p=0.001. Conclusion: Precharging a defibrillator before a rhythm check during chest compression, in anticipation of a potentially shockable rhythm, reduces the time required for defibrillation and limits interruptions in chest compression during CPR. This practice effectively enhances the CCF. Enhancing the continuity of chest compressions can potentially improve survival rates in ARC.}, } @article {pmid39464461, year = {2024}, author = {Karunakaran, V and Dadgar, S and Paidi, SK and Mordi, AF and Lowe, WA and Mim, UM and Ivers, JD and Rodriguez Troncoso, JI and McPeake, JA and Fernandes, A and Tripathi, SD and Barman, I and Rajaram, N}, title = {Investigating In Vivo Tumor Biomolecular Changes Following Radiation Therapy Using Raman Spectroscopy.}, journal = {ACS omega}, volume = {9}, number = {42}, pages = {43025-43033}, pmid = {39464461}, issn = {2470-1343}, support = {P20 GM139768/GM/NIGMS NIH HHS/United States ; P41 EB015871/EB/NIBIB NIH HHS/United States ; R01 CA238025/CA/NCI NIH HHS/United States ; R15 CA238861/CA/NCI NIH HHS/United States ; }, abstract = {Treatment resistance is a major bottleneck in the success of cancer therapy. Early identification of the treatment response or lack thereof in patients can enable an earlier switch to alternative treatment strategies that can enhance response rates. Here, Raman spectroscopy was applied to monitor early tumor biomolecular changes in sensitive (UM-SCC-22B) and resistant (UM-SCC-47) head and neck tumor xenografts for the first time in in vivo murine tumor models in response to radiation therapy. We used a validated multivariate curve resolution-alternating least-squares (MCR-ALS) model to resolve complex multicomponent Raman spectra into individual pure spectra and their respective contributions. We observed a significant radiation-induced increase in the contributions of lipid-like species (p = 0.0291) in the radiation-sensitive UM-SCC-22B tumors at 48 h following radiation compared to the nonradiated baseline (prior to commencing treatment). We also observed an increase in the contribution of collagen-like species in the radiation-resistant UM-SCC-47 tumors at 24 h following radiation compared to the nonradiated baseline (p = 0.0125). In addition to the in vivo analysis, we performed ex vivo confocal Raman microscopic imaging of frozen sections derived from the same tumors. A comparison of all control and treated tumors revealed similar trends in the contributions of lipid-like and collagen-like species in both in vivo and ex vivo measurements; however, when evaluated as a function of time, longitudinal trends in the scores of collagen-like and lipid-like components were not consistent between the two data sets, likely due to sample numbers and differences in sampling depth at which information is obtained. Nevertheless, this study demonstrates the potential of fiber-based Raman spectroscopy for identifying early tumor microenvironmental changes in response to clinical doses of radiation therapy.}, } @article {pmid39464100, year = {2024}, author = {Du, M and Akerman, SC and Fare, CM and Ruan, L and Vidensky, S and Mamedova, L and Lee, J and Rothstein, JD}, title = {Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39464100}, issn = {2692-8205}, support = {P50 AG005146/AG/NIA NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models of C9ORF72-related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimer's disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals considerations that must be taken into account when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.}, } @article {pmid39463426, year = {2025}, author = {Yang, SF and Patel, PN}, title = {Invited Commentary on: Youssefi et al's 3D Smartphone Photography During Rhinoplasty Surgery.}, journal = {Facial plastic surgery & aesthetic medicine}, volume = {27}, number = {2}, pages = {199-200}, doi = {10.1089/fpsam.2024.0265}, pmid = {39463426}, issn = {2689-3622}, } @article {pmid39462586, year = {2024}, author = {Kurita, H and Hirasawa, N and Yabe, S and Okuda, A and Murakami, T and Ohuchi, K and Ogata, A and Yoshioka, H and Kakita, A and Hozumi, I and Inden, M}, title = {MicroRNA-5572 Is Associated with Endoplasmic Reticulum Stress Responses in Low Zinc Treated and SOD1 G85R-Transfected HEK293 Cells.}, journal = {Biological & pharmaceutical bulletin}, volume = {47}, number = {10}, pages = {1717-1725}, doi = {10.1248/bpb.b24-00418}, pmid = {39462586}, issn = {1347-5215}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Endoplasmic Reticulum Stress/drug effects/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; *Zinc/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; HEK293 Cells ; Transfection ; Tunicamycin/toxicity ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fetal neurodegenerative disease. The mechanism of sporadic ALS onset remains unclarified in detail. Disruption of zinc homeostasis could be related to sporadic ALS. Previously, we first reported miR-5572 as a microRNA (miRNA) among those identified in the spinal cords of patients with sporadic ALS. However, since its function in ALS remained unknown, this study further examined the role of miR-5572 in low-zinc status and ALS model cells which transfected with causative gene, Cu/Zn superoxide dismutase 1 (SOD1) G85R mutant vector. The miR-5572 level was increased by low-zinc condition accompanied by increase of endoplasmic reticulum (ER) stress. In addition, increase of miR-5572 enhanced the cellular toxicity induced by low-zinc treatment. The expression of miR-5572 was also increased, which was accompanied by an increase of ER stress markers associated with SOD1 aggregation formation. Cell death and ER stress makers levels induced by tunicamycin treatment were further increased in miR-5572 mimic-transfected cells. This study showed that miR-5572 exacerbated ER stress toxicity associated with low-zinc status and mutant SOD1 aggregates in ALS.}, } @article {pmid39462509, year = {2024}, author = {Dauer, LT and Mumma, MT and Lima, JC and Cohen, SS and Andresen, D and Bahadori, AA and Bellamy, M and Bierman, DA and Blattnig, S and French, B and Giunta, E and Held, K and Hertel, N and Keohane, L and Leggett, R and Lipworth, L and Miller, KB and Norman, RB and Samuels, C and Thomas, KS and Tolmachev, SY and Walsh, L and Boice, JD}, title = {A Million Person Study Innovation: Evaluating Cognitive Impairment and other Morbidity Outcomes from Chronic Radiation Exposure Through Linkages with the Centers for Medicaid and Medicare Services Assessment and Claims Data.}, journal = {Radiation research}, volume = {202}, number = {6}, pages = {847-861}, doi = {10.1667/RADE-23-00186.1}, pmid = {39462509}, issn = {1938-5404}, mesh = {Humans ; United States/epidemiology ; *Radiation Exposure/adverse effects ; Centers for Medicare and Medicaid Services, U.S. ; Male ; Medicare ; Female ; Cognition Disorders/epidemiology/etiology ; }, abstract = {The study of One Million U.S. Radiation Workers and Veterans, the Million Person Study (MPS), examines the health consequences, both cancer and non-cancer, of exposure to ionizing radiation received gradually over time. Recently the MPS has focused on mortality patterns from neurological and behavioral conditions, e.g., Parkinson's disease, Alzheimer's disease, dementia, and motor neuron disease such as amyotrophic lateral sclerosis. A fuller picture of radiation-related late effects comes from studying both mortality and the occurrence (incidence) of conditions not leading to death. Accordingly, the MPS is identifying neurocognitive diagnoses from fee-for-service insurance claims from the Centers for Medicare and Medicaid Services (CMS), among Medicare beneficiaries beginning in 1999 (the earliest date claims data are available). Linkages to date have identified ∼540,000 workers with available health information. Such linkages provide individual information on important co-factor and confounding variables such as smoking, alcohol consumption, blood pressure, obesity, diabetes and many other health and demographic characteristics. The total person-level set of time-dependent variables, outcomes, organ-specific dose measures, co-factors, and demographics will be massive and much too large to be evaluated with standard software. Thus, development of specialized open-source software designed for large datasets (Colossus) is nearly complete. The wealth of information available from CMS claims data, coupled with individual dose reconstructions, will thus greatly enhance the quality and precision of health evaluations for this new field of low-dose radiation and neurocognitive effects.}, } @article {pmid39461864, year = {2024}, author = {Imamura, K and Izumi, Y and Egawa, N and Ayaki, T and Nagai, M and Nishiyama, K and Watanabe, Y and Murakami, T and Hanajima, R and Kataoka, H and Kiriyama, T and Nanaura, H and Sugie, K and Hirayama, T and Kano, O and Nakamori, M and Maruyama, H and Haji, S and Fujita, K and Atsuta, N and Tatebe, H and Tokuda, T and Takahashi, N and Morinaga, A and Tabuchi, R and Oe, M and Kobayashi, M and Lobello, K and Morita, S and Sobue, G and Takahashi, R and Inoue, H}, title = {Protocol for a phase 2 study of bosutinib for amyotrophic lateral sclerosis using real-world data: induced pluripotent stem cell-based drug repurposing for amyotrophic lateral sclerosis medicine (iDReAM) study.}, journal = {BMJ open}, volume = {14}, number = {10}, pages = {e082142}, pmid = {39461864}, issn = {2044-6055}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Aniline Compounds/therapeutic use ; Clinical Trials, Phase II as Topic ; *Drug Repositioning ; Induced Pluripotent Stem Cells ; Japan ; Multicenter Studies as Topic ; *Nitriles/therapeutic use ; Protein Kinase Inhibitors/therapeutic use ; *Quinolines/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive, severe neurodegenerative disease caused by motor neuron death. Development of a medicine for ALS is urgently needed, and induced pluripotent cell-based drug repurposing identified a Src/c-Abl inhibitor, bosutinib, as a candidate for molecular targeted therapy of ALS. A phase 1 study confirmed the safety and tolerability of bosutinib in a 12-week treatment of ALS patients. The objectives of this study are to evaluate the efficacy and longer-term safety of bosutinib in ALS patients.

METHODS AND ANALYSIS: An open-label, multicentre phase 2 study was designed. The study consisted of a 12-week observation period, a 1-week transitional period, a 24-week study treatment period and a 4-week follow-up period. Following the transitional period, patients whose total Revised ALS Functional Rating Scale (ALSFRS-R) score declined by 1 to 4 points during the 12-week observation period were to receive bosutinib for 24 weeks. In this study, 25 ALS patients will be enrolled; patients will be randomly assigned to the following groups: 12 patients in the 200 mg quaque die (QD) group and 13 patients in the 300 mg QD group of bosutinib. The safety and exploratory efficacy of bosutinib in ALS patients for 24 weeks will be assessed. Efficacy using the ALSFRS-R score will be compared with the external published data from an edaravone study (MCI186-19) and registry data from a multicentre ALS cohort study, the Japanese Consortium for Amyotrophic Lateral Sclerosis Research.

ETHICS AND DISSEMINATION: This study was approved by the ethics committees of Kyoto University, Tokushima University, Kitasato University, Tottori University, Nara Medical University School of Medicine, Toho University and Hiroshima University. The findings will be disseminated in peer-reviewed journals and at scientific conferences.

TRIAL REGISTRATION NUMBER: jRCT2051220002; Pre-results, NCT04744532; Pre-results.}, } @article {pmid39461630, year = {2024}, author = {Kouhi, ZH and Seyedalipour, B and Hosseinkhani, S and Chaichi, MJ}, title = {Bisdemethoxycurcumin, a novel potent polyphenolic compound, effectively inhibits the formation of amyloid aggregates in ALS-associated hSOD1 mutant (L38R).}, journal = {International journal of biological macromolecules}, volume = {282}, number = {Pt 2}, pages = {136701}, doi = {10.1016/j.ijbiomac.2024.136701}, pmid = {39461630}, issn = {1879-0003}, mesh = {*Diarylheptanoids/chemistry/pharmacology ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism ; *Protein Aggregates/drug effects ; *Amyloid/metabolism/chemistry ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Mutation ; *Molecular Dynamics Simulation ; *Molecular Docking Simulation ; Curcumin/pharmacology/analogs & derivatives/chemistry ; Polyphenols/pharmacology/chemistry ; Protein Aggregation, Pathological/genetics/drug therapy ; Hemolysis/drug effects ; Hydrophobic and Hydrophilic Interactions ; }, abstract = {Protein misfolding is a biological process that leads to protein aggregation. Anomalous misfolding and aggregation of human superoxide dismutase (hSOD1) into amyloid aggregates is a characteristic feature of amyotrophic lateral sclerosis (ALS), a neurodegenerative illness. Thus, focusing on the L38R mutant may be a wise decision to comprehend the SOD1 disease process in ALS. We suggest that Bisdemethoxycurcumin (BDMC) may be a strong anti-amyloidogenic polyphenol against L38R mutant aggregation. Protein stability, hydrophobicity, and flexibility were altered when BDMC was bound to the L38R mutant, as shown by molecular dynamic (MD) simulations and molecular docking. FTIR data shows α-Helix dominance in BDMC-containing samples, with reduced β-sheet and disordered peaks, indicating the decrease of aggregate species. ThT aggregation kinetics curves show BDMC reduces L38R mutant aggregation dose-dependently, with higher BDMC concentrations yielding greater reductions. TEM images showed various quantities of amorphous aggregates, but notably, 60 μM BDMC markedly reduced aggregate density, underscoring BDMC's inhibitory effect. Hemolysis tests revealed aggregate species in BDMC-treated samples were less toxic than in L38R mutant samples alone at the same concentrations and exposure times. Overall, BDMC has substantial potential to develop highly effective inhibitors that mitigate the risk of fatal ALS.}, } @article {pmid39461320, year = {2024}, author = {Didcote, L and Vitoratou, S and Al-Chalabi, A and Goldstein, LH}, title = {The reliability and validity of in-person and remote behavioural screening tools for people with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123282}, doi = {10.1016/j.jns.2024.123282}, pmid = {39461320}, issn = {1878-5883}, support = {GOLDSTEIN/OCT17/892-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Male ; Female ; Middle Aged ; Reproducibility of Results ; Aged ; *Psychometrics/methods/standards ; Surveys and Questionnaires/standards ; Neuropsychological Tests/standards ; Adult ; }, abstract = {OBJECTIVE: This study aimed to assess the psychometric properties of and relationships between total scores on different screening tools assessing behavioural change for people with amyotrophic lateral sclerosis (ALS), and whether administering the screens as online questionnaires (rather than on paper, in-person) influences total scores.

METHODS: The behavioural component of the Edinburgh Cognitive and Behavioural ALS Screen (ECASb); the behavioural component of the ALS Cognitive Behavioural Screen (ALS-CBSb), the ALS-Frontotemporal Dementia Questionnaire (ALS-FTD-Q), the Beaumont Behavioural Inventory (BBI), and the Motor Neuron Disease Behavioural Instrument (MiND-B) were administered to 35 informants on paper. Online questionnaire versions of the behavioural screens were administered to 49 informants. Forward stepwise linear regressions were conducted to assess whether scores on behavioural screens were predicted by scores on the other behavioural screens and to assess whether total scores were predicted by the mode of administration (paper or online) of the screens.

RESULTS: Behavioural screening tools, except the ECASb, had good internal consistency but mixed item-total correlations. All regression models assessing whether behavioural screen scores predict other behavioural screen scores were significant. The BBI performed best and the ECASb performed worst in terms of their predictive relationships with other screening tools. The administration mode of the questionnaires did not significantly affect total scores.

CONCLUSIONS: The psychometric properties of the scales varied. The scales predicted each other's scores, supporting convergent validity. Online and paper versions performed similarly, and demographics did not predict scores.}, } @article {pmid39460670, year = {2025}, author = {Gondim, FAA and Fernandes, JMA}, title = {ALS due to c.1189 + 1G > T (splice donor) TBK1 mutation.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {180}, doi = {10.1080/21678421.2024.2421754}, pmid = {39460670}, issn = {2167-9223}, } @article {pmid39459584, year = {2024}, author = {Silva, F and Silva, J and Salgueira, S and Mendes, A and Matos, E and Conde, B}, title = {Sleep Disturbances in Amyotrophic Lateral Sclerosis and Prognostic Impact-A Retrospective Study.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, pmid = {39459584}, issn = {2075-1729}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with sleep disturbance, namely insomnia and sleep-disordered breathing. This study aims to evaluate the overall sleep characteristics of ALS patients, their association with lung function tests, and possible predictive survival factors. We conducted a retrospective observation study among ALS patients monitored during a pulmonology consultation. Type one polysomnography (PSG) and lung function tests were performed once the patients presented with sleep-related symptoms, and the relationship between their parameters was assessed, as well as a survival analysis. We included 35 patients, with an overall diminished sleep efficiency, a partially conserved forced vital capacity (FVC), and low maximal inspiratory pressure (MIP). A positive correlation between FVC and REM sleep percentage was observed. A survival analysis showed that a normal rapid eye movement (REM) sleep percentage and respiratory disturbance index (RDI) ≥ 15/h were independent predictors of survival. We observed a trend for higher sleep quality in patients with conserved lung function. A better sleep quality was associated with a higher survival. Obstructive events (reduced or absence of airflow associated with continued or increased inspiratory effort) did not seem to impact survival.}, } @article {pmid39459534, year = {2024}, author = {Nakhal, MM and Yassin, LK and Alyaqoubi, R and Saeed, S and Alderei, A and Alhammadi, A and Alshehhi, M and Almehairbi, A and Al Houqani, S and BaniYas, S and Qanadilo, H and Ali, BR and Shehab, S and Statsenko, Y and Meribout, S and Sadek, B and Akour, A and Hamad, MIK}, title = {The Microbiota-Gut-Brain Axis and Neurological Disorders: A Comprehensive Review.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, pmid = {39459534}, issn = {2075-1729}, support = {12M159//UAEU/ ; G00004325//UAEU/ ; 12M142//UAEU/ ; }, abstract = {Microbes have inhabited the earth for hundreds of millions of years longer than humans. The microbiota-gut-brain axis (MGBA) represents a bidirectional communication pathway. These communications occur between the central nervous system (CNS), the enteric nervous system (ENS), and the emotional and cognitive centres of the brain. The field of research on the gut-brain axis has grown significantly during the past two decades. Signalling occurs between the gut microbiota and the brain through the neural, endocrine, immune, and humoral pathways. A substantial body of evidence indicates that the MGBA plays a pivotal role in various neurological diseases. These include Alzheimer's disease (AD), autism spectrum disorder (ASD), Rett syndrome, attention deficit hyperactivity disorder (ADHD), non-Alzheimer's neurodegeneration and dementias, fronto-temporal lobe dementia (FTLD), Wilson-Konovalov disease (WD), multisystem atrophy (MSA), Huntington's chorea (HC), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), temporal lobe epilepsy (TLE), depression, and schizophrenia (SCZ). Furthermore, the bidirectional correlation between therapeutics and the gut-brain axis will be discussed. Conversely, the mood of delivery, exercise, psychotropic agents, stress, and neurologic drugs can influence the MGBA. By understanding the MGBA, it may be possible to facilitate research into microbial-based interventions and therapeutic strategies for neurological diseases.}, } @article {pmid39459490, year = {2024}, author = {Banciu, C and Chiriac, S and Pojoga, C and Marian, L and Fabian, A and Gogulescu, A and Simu, M and Parvanescu, R and Mioc, A and Racoviceanu, R and Munteanu, A}, title = {An Uncommon Overlap Syndrome Between Ankylosing Spondylitis and Amyotrophic Lateral Sclerosis-Case Report.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {10}, pages = {}, pmid = {39459490}, issn = {1648-9144}, support = {//"Victor Babes" University of Medicine and Pharmacy Timisoara/ ; }, mesh = {Humans ; *Spondylitis, Ankylosing/complications/drug therapy ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Middle Aged ; Etanercept/therapeutic use ; Tumor Necrosis Factor-alpha/antagonists & inhibitors ; Syndrome ; }, abstract = {This case report describes an uncommon overlap syndrome between ankylosing spondylitis (AS) and amyotrophic lateral sclerosis (ALS). Initially, the patient was diagnosed with AS, for which he received various specific treatments, including TNF-α inhibitors. After five years of treatment with TNF-α inhibitor etanercept, the patient was referred for a full neurological assessment after he reported balance disturbances, postural instability, muscle weakness, and other neurological symptoms that indicated the presence of a neurological disorder. After a thorough investigation, the patient was diagnosed with ALS. This case report aims to contribute to the limited literature by providing a detailed case study regarding the crosstalk between AS and ALS while also exploring the potential underlying mechanisms and the possible link between TNF-α inhibitors therapy and ALS.}, } @article {pmid39459030, year = {2024}, author = {Al-Khayri, JM and Ravindran, M and Banadka, A and Vandana, CD and Priya, K and Nagella, P and Kukkemane, K}, title = {Amyotrophic Lateral Sclerosis: Insights and New Prospects in Disease Pathophysiology, Biomarkers and Therapies.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {10}, pages = {}, pmid = {39459030}, issn = {1424-8247}, support = {GRANT0000//Deanship of Scientific Research, King Faisal University/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disorder marked by the gradual loss of motor neurons, leading to significant disability and eventual death. Despite ongoing research, there are still limited treatment options, underscoring the need for a deeper understanding of the disease's complex mechanisms and the identification of new therapeutic targets. This review provides a thorough examination of ALS, covering its epidemiology, pathology, and clinical features. It investigates the key molecular mechanisms, such as protein aggregation, neuroinflammation, oxidative stress, and excitotoxicity that contribute to motor neuron degeneration. The role of biomarkers is highlighted for their importance in early diagnosis and disease monitoring. Additionally, the review explores emerging therapeutic approaches, including inhibitors of protein aggregation, neuroinflammation modulators, antioxidant therapies, gene therapy, and stem cell-based treatments. The advantages and challenges of these strategies are discussed, with an emphasis on the potential for precision medicine to tailor treatments to individual patient needs. Overall, this review aims to provide a comprehensive overview of the current state of ALS research and suggest future directions for developing effective therapies.}, } @article {pmid39458929, year = {2024}, author = {Giannakou, M and Akrani, I and Tsoka, A and Myrianthopoulos, V and Mikros, E and Vorgias, C and Hatzinikolaou, DG}, title = {Discovery of Novel Inhibitors against ALS-Related SOD1(A4V) Aggregation through the Screening of a Chemical Library Using Differential Scanning Fluorimetry (DSF).}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {10}, pages = {}, pmid = {39458929}, issn = {1424-8247}, support = {MIS-5000432//state scholarship foundation (GR)/ ; }, abstract = {BACKGROUND: Cu/Zn Superoxide Dismutase 1 (SOD1) is a 32 kDa cytosolic dimeric metalloenzyme that neutralizes superoxide anions into oxygen and hydrogen peroxide. Mutations in SOD1 are associated with ALS, a disease causing motor neuron atrophy and subsequent mortality. These mutations exert their harmful effects through a gain of function mechanism, rather than a loss of function. Despite extensive research, the mechanism causing selective motor neuron death still remains unclear. A defining feature of ALS pathogenesis is protein misfolding and aggregation, evidenced by ubiquitinated protein inclusions containing SOD1 in affected motor neurons. This work aims to identify compounds countering SOD1(A4V) misfolding and aggregation, which could potentially aid in ALS treatment.

METHODS: The approach employed was in vitro screening of a library comprising 1280 pharmacologically active compounds (LOPAC[®]) in the context of drug repurposing. Using differential scanning fluorimetry (DSF), these compounds were tested for their impact on SOD1(A4V) thermal stability.

RESULTS AND CONCLUSIONS: Dimer stability was the parameter chosen as the criterion for screening, since the dissociation of the native SOD1 dimer is the step prior to its in vitro aggregation. The screening revealed one compound raising protein-ligand Tm by 6 °C, eleven inducing a higher second Tm, suggesting a stabilization effect, and fourteen reducing Tm from 10 up to 26 °C, suggesting possible interactions or non-specific binding.}, } @article {pmid39458862, year = {2024}, author = {Palacıoğlu, G}, title = {Chitosan, Methyl Jasmonate, and Silicon Induce Resistance to Angular Leaf Spot in Common Bean, Caused by Pseudocercospora griseola, with Expression of Defense-Related Genes and Enzyme Activities.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {20}, pages = {}, pmid = {39458862}, issn = {2223-7747}, abstract = {This study assessed the efficacy of chitosan, methyl jasmonate, and silicon in the reduction of disease severity and the induction of defense responses in common bean plants against angular leaf spot caused by Pseudocercospora griseola. The expression level of several pathogenesis-related (PR) proteins, PR1, PR2 (β-1,3-glucanase), and PR3 (chitinase), and defense-related enzymes, phenylalanine ammonia-lyase, peroxidase, and lipoxygenase, was analyzed at different time points in common bean plants after different treatments. Elicitor treatments significantly reduced disease severity 21 days after inoculation, with silicon at a 2 mM concentration proving most effective with 38.93% disease control, followed by 1 mM MeJA and 2% chitosan, respectively. Treatments with chitosan, methyl jasmonate, and silicon, regardless of pathogen infection, significantly elevated PR1, PR2, and PR3 gene expressions at 48 h after inoculation (hpi). PAL and POD activities were similarly increased following elicitor treatments and pathogen infection, especially at 48 hpi. Chemical elicitors applied post-inoculation induced PR proteins, PAL, and POD enzyme activities at 48 hpi, while LOX activity exhibited a variable fluctuation with treatments. These findings suggested that chemical elicitors, especially silicon, were effective in reducing ALS disease severity in common beans, with improved resistance associated with the expression of pathogen-responsive genes. This study is the first to analyze the expression profiles of defense-related genes in common beans treated with chemical elicitors prior to P. griseola infection.}, } @article {pmid39457680, year = {2024}, author = {McGrath, MS and Zhang, R and Bracci, PM and Azhir, A and Forrest, BD}, title = {Systemic Innate Immune System Restoration as a Therapeutic Approach for Neurodegenerative Disease: Effects of NP001 on Amyotrophic Lateral Sclerosis (ALS) Progression.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457680}, issn = {2227-9059}, support = {Neuvivo-NP001//Neuvivo, Inc./ ; }, abstract = {BACKGROUND/OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a diagnosis that incorporates a heterogeneous set of neurodegenerative processes into a single progressive and uniformly fatal disease making the development of a uniformly applicable therapeutic difficult. Recent multinational ALS natural history incidence studies have identified systemic chronic activation of the innate immune system as a major risk factor for developing ALS. Persistent immune activation in patients with ALS leads to loss of muscle and lowering of serum creatinine. The goal of the current study was to test whether the slowing of nerve and muscle destruction in NP001-treated ALS patients compared with controls in phase 2 studies would lead to extension of survival.

METHODS: Phase 2 clinical studies with NP001, an intravenously administered form of the innate immune system regulator NaClO2, are now reporting long-term survival benefits for drug recipients vs. placebo controls after only six months of intermittent treatment. As a prodrug, NP001 is converted by macrophages to taurine chloramine, a long-lived regulator of inflammation. We performed a pooled analysis of all patients who had completed the studies in two six-month NP001 phase 2 trials. Changes in respiratory vital capacity and the muscle mass product, creatinine, defined treated patients who, compared to placebo, had up to a year of extended survival.

CONCLUSIONS: The observed longer survival in ALS patients with the greatest inflammation-associated muscle loss provides further evidence that ALS is a disease of ongoing innate immune dysfunction and that NP001 is a disease-modifying drug with sustained clinical activity.}, } @article {pmid39457678, year = {2024}, author = {Forrest, BD and Goyal, NA and Fleming, TR and Bracci, PM and Brett, NR and Khan, Z and Robinson, M and Azhir, A and McGrath, M}, title = {The Effectiveness of NP001 on the Long-Term Survival of Patients with Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457678}, issn = {2227-9059}, support = {01//Neuvivo, Inc./ ; }, abstract = {BACKGROUND/OBJECTIVES: The aim of this study was to estimate the effect of a 6 months' treatment course of the innate immune modulator NP001 (a pH-adjusted intravenous formulation of purified sodium chlorite), on disease progression, as measured by overall survival (OS) in patients with amyotrophic lateral sclerosis.

METHODS: Blinded survival data were retrospectively collected for 268 of the 273 patients who had participated in two phase 2 placebo-controlled clinical trials of NP001 (ClinicalTrials.gov: NCT01281631 and NCT02794857) and received at least one dose of either 1 mg/kg or 2 mg/kg of NP001 as chlorite based on actual body weight, or placebo. Kaplan-Meier methods were used on the intent-to-treat population to estimate survival probabilities.

RESULTS: In the overall population, the median OS was 4.8 months (2.7 years [95% CI: 2.3, 3.5] in the 2 mg/kg NP001group and 2.3 years [95% CI: 1.8, 2.9] in the placebo group). Hazard ratio (HR): 0.77 (95% CI: 0.57, 1.03), p = 0.073. Among patients aged ≤ 65 years, the median OS for the 2 mg/kg NP001 group was 10.8 months (3.3 years [95% CI: 2.4, 3.8] in the 2 mg/kg NP001 group and 2.4 years [95% CI: 1.7, 3.3] in the placebo group). HR: 0.69 (95% CI: 0.50, 0.95). No differences were observed in the 1 mg/kg NP001 group or in patients aged > 65 years.

CONCLUSIONS: The findings from this study suggest that a 6 months' treatment course of NP001 resulted in a 4.8-month increase in overall survival in patients with ALS. The findings from this study indicate that targeting inflammation associated with the innate immune system may provide a pathway for new therapeutic options for the treatment of ALS.}, } @article {pmid39457513, year = {2024}, author = {Montiel-Troya, M and Mohamed-Mohamed, H and Pardo-Moreno, T and González-Díaz, A and Ruger-Navarrete, A and de la Mata Fernández, M and Tovar-Gálvez, MI and Ramos-Rodríguez, JJ and García-Morales, V}, title = {Advancements in Pharmacological Interventions and Novel Therapeutic Approaches for Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457513}, issn = {2227-9059}, support = {PID2019-110960GB-I00//Ministry of Science and Innovation, Spain./ ; }, abstract = {(1) Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which the patient suffers from an affection of both upper and lower motor neurons at the spinal and brainstem level, causing a progressive paralysis that leads to the patient's demise. Gender is also considered a predisposing risk factor for developing the disease. A brief review of the pathophysiological mechanisms of the disease is also described in this work. Despite the fact that a cure for ALS is currently unknown, there exists a variety of pharmacological and non-pharmacological therapies that can help reduce the progression of the disease over a certain period of time and alleviate symptoms. (2) We aim to analyze these pharmacological and non-pharmacological therapies through a systematic review. A comprehensive, multidisciplinary approach to treatment is necessary. (3) Drugs such as riluzole, edaravone, and sodium phenylbutyrate, among others, have been investigated. Additionally, it is important to stay updated on research on new drugs, such as masitinib, from which very good results have been obtained. (4) Therapies aimed at psychological support, speech and language, and physical therapy for the patient are also available, which increase the quality of life of the patients.}, } @article {pmid39457505, year = {2024}, author = {Seta, Y and Kimura, K and Masahiro, G and Tatsumori, K and Murakami, Y}, title = {SHED-CM: The Safety and Efficacy of Conditioned Media from Human Exfoliated Deciduous Teeth Stem Cells in Amyotrophic Lateral Sclerosis Treatment: A Retrospective Cohort Analysis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457505}, issn = {2227-9059}, abstract = {BACKGROUND/OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive and irreversible neurodegenerative disease with limited treatment options. Advances in regenerative medicine have opened up new treatment options. The primary and exploratory objectives of this retrospective cohort study were to evaluate the safety and efficacy of stem cells from human exfoliated deciduous teeth-conditioned media (SHED-CM).

METHODS: Safety assessments included adverse events, vital signs, and laboratory test changes before and after administration, and efficacy was measured using the ALS Functional Rating Scale-Revised (ALSFRS-R), grip strength, and forced vital capacity in 24 patients with ALS treated at a single facility between 1 January 2022, and 30 November 2023.

RESULTS: While ALSFRS-R scores typically decline over time, the progression rate in this cohort was slower, suggesting a potential delay in disease progression. Alternatively, improvements in muscle strength and mobility were observed in some patients. Although adverse events were reported in only 3% of cases (no serious allergic reactions), the treatment-induced changes in vital signs and laboratory results were not clinically significant.

CONCLUSIONS: The SHED-CM treatment is a safe and potentially effective therapeutic option for patients with ALS. Further research is needed to optimize the SHED-CM treatment; however, this study lays the groundwork for future exploration of regenerative therapies for ALS.}, } @article {pmid39457470, year = {2024}, author = {Trabacca, A and Ferrante, C and Oliva, MC and Fanizza, I and Gallo, I and De Rinaldis, M}, title = {Update on Inherited Pediatric Motor Neuron Diseases: Clinical Features and Outcome.}, journal = {Genes}, volume = {15}, number = {10}, pages = {}, pmid = {39457470}, issn = {2073-4425}, support = {2024//The Italian Health Ministry - Ricerca Corrente/ ; }, mesh = {Humans ; *Motor Neuron Disease/genetics/pathology ; Child ; Mutation ; Muscular Atrophy, Spinal/genetics/pathology/diagnosis ; Exome Sequencing ; }, abstract = {BACKGROUND: Inherited pediatric motor neuron diseases (MNDs) are a group of neurodegenerative disorders characterized by the degeneration of motor neurons in the brain and the spinal cord. These diseases can manifest as early as infancy and originate from inherited pathogenic mutations in known genes. Key clinical features of MNDs include muscle weakness, hypotonia, and atrophy due to the degeneration of lower motor neurons or spasticity, hypertonia, and hyperreflexia caused by upper motor neuron dysfunction. The course of the disease varies among individuals and is influenced by the specific subtype.

METHODS: We performed a non-systematic, narrative clinical review, employing a systematic methodology for the literature search and article selection to delineate the features of hereditary pediatric motor neuron diseases.

RESULTS: The growing availability of advanced molecular testing, such as whole-exome sequencing (WES) and whole-genome sequencing (WGS), has expanded the range of identified genetic factors. These advancements provide insights into the genetic complexity and underlying mechanisms of these disorders. As more MND-related genes are discovered, the accumulating genetic data will help prioritize promising candidate genes for future research. In some cases, targeted treatments based on specific genetic mechanisms have already emerged, underscoring the critical role of early and timely diagnosis in improving patient outcomes. Common MNDs include amyotrophic lateral sclerosis, spinal muscular atrophy, and bulbar spinal muscular atrophy.

CONCLUSION: This narrative clinical review covers the clinical presentation, genetics, molecular features, and pathophysiology of inherited pediatric MNDs.}, } @article {pmid39457468, year = {2024}, author = {Boura, I and Giannopoulou, IA and Pavlaki, V and Xiromerisiou, G and Mitsias, P and Spanaki, C}, title = {FIG4-Related Parkinsonism and the Particularities of the I41T Mutation: A Review of the Literature.}, journal = {Genes}, volume = {15}, number = {10}, pages = {}, pmid = {39457468}, issn = {2073-4425}, mesh = {Humans ; *Parkinsonian Disorders/genetics/pathology/diagnostic imaging ; *Charcot-Marie-Tooth Disease/genetics/pathology ; *Flavoproteins/genetics ; Female ; Male ; Mutation, Missense ; Middle Aged ; Mutation ; Adult ; Phosphoric Monoester Hydrolases ; }, abstract = {Background/Objectives: The genetic underpinnings of Parkinson's disease (PD) and parkinsonism have drawn increasing attention in recent years. Mutations in the Factor-Induced Gene 4 (FIG4) have been implicated in various neurological disorders, including Charcot-Marie-Tooth disease type 4J (CMT4J), amyotrophic lateral sclerosis (ALS), and Yunis-Varón syndrome. This review aims to explore the association between FIG4 mutations and parkinsonism, with a specific focus on the rare missense mutation p.Ile41Thr (I41T). Methods: We identified 12 cases from 10 different families in which parkinsonism was reported in conjunction with CMT4J polyneuropathy. All cases involved the I41T mutation in a compound heterozygous state, combined with a FIG4 loss-of-function mutation. Data from clinical observations, neuroimaging studies, and genetic analyses were evaluated to understand the characteristics of parkinsonism in these patients. Results: In all 12 cases, parkinsonism developed either concurrently or following the onset of CMT4J neuropathy, but was never observed in isolation. Cases of both early- and late-onset parkinsonism were identified, reflecting similarities to genetic forms of parkinsonism with autosomal recessive inheritance. Imaging studies, including Dopamine transporter Single Photon Emission Computed Tomography (DaTscan) and brain magnetic resonance imaging (MRI), revealed abnormalities indicative of neurodegeneration, consistent with findings in other neurodegenerative disorders. Conclusions: The co-occurrence of parkinsonism with CMT4J in patients carrying the I41T mutation suggests an expanded spectrum of FIG4-related disorders, potentially implicating the same molecular mechanisms seen in other neurodegenerative disorders. Further research into FIG4-mediated pathways may offer valuable insights into potential therapeutic targets for disorders of both the central and peripheral nervous systems.}, } @article {pmid39457466, year = {2024}, author = {Moriyama, H and Yokota, T}, title = {Recent Progress of Antisense Oligonucleotide Therapy for Superoxide-Dismutase-1-Mutated Amyotrophic Lateral Sclerosis: Focus on Tofersen.}, journal = {Genes}, volume = {15}, number = {10}, pages = {}, pmid = {39457466}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; Humans ; *Superoxide Dismutase-1/genetics ; *Oligonucleotides, Antisense/therapeutic use/genetics ; *Mutation ; Animals ; Oligonucleotides/therapeutic use/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a refractory neurodegenerative disease characterized by the degeneration and loss of motor neurons, typically resulting in death within five years of onset. There have been few effective treatments, making the development of robust therapies an urgent challenge. Genetic mutations have been identified as contributors to ALS, with mutations in superoxide dismutase 1 (SOD1), which neutralizes the harmful reactive oxygen species superoxide, accounting for approximately 2% of all ALS cases. To counteract the toxic gain of function caused by SOD1 mutations, therapeutic strategies aimed at suppressing SOD1 gene expression have shown promise. Antisense oligonucleotide (ASO) is an artificially synthesized, short, single-stranded DNA/RNA molecule that binds to target RNA to alter gene expression, representing a next-generation therapeutic approach. In 2023, tofersen became the first ASO drug approved by the FDA for ALS. Administered intrathecally, tofersen specifically binds to SOD1 mRNA, inhibiting the production of toxic SOD1 protein, thereby improving biomarkers of ALS. The long-term efficacy and safety of tofersen require further validation, and the development of more optimized treatment protocols is essential. A series of studies and therapeutic developments related to SOD1 mutations have advanced the understanding of ALS pathophysiology and significantly contributed to treatment strategies for central nervous system disorders. This review focuses on an overview of SOD1 mutations and the development process of tofersen, aiming to deepen the understanding of advancements in ALS research and discuss future challenges and directions for ASO therapy.}, } @article {pmid39456682, year = {2024}, author = {Alshehri, RS and Abuzinadah, AR and Alrawaili, MS and Alotaibi, MK and Alsufyani, HA and Alshanketi, RM and AlShareef, AA}, title = {A Review of Biomarkers of Amyotrophic Lateral Sclerosis: A Pathophysiologic Approach.}, journal = {International journal of molecular sciences}, volume = {25}, number = {20}, pages = {}, pmid = {39456682}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/physiopathology/diagnosis ; Humans ; *Biomarkers/metabolism ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. The heterogeneous nature of ALS at the clinical, genetic, and pathological levels makes it challenging to develop diagnostic and prognostic tools that fit all disease phenotypes. Limitations associated with the functional scales and the qualitative nature of mainstay electrophysiological testing prompt the investigation of more objective quantitative assessment. Biofluid biomarkers have the potential to fill that gap by providing evidence of a disease process potentially early in the disease, its progression, and its response to therapy. In contrast to other neurodegenerative diseases, no biomarker has yet been validated in clinical use for ALS. Several fluid biomarkers have been investigated in clinical studies in ALS. Biofluid biomarkers reflect the different pathophysiological processes, from protein aggregation to muscle denervation. This review takes a pathophysiologic approach to summarizing the findings of clinical studies utilizing quantitative biofluid biomarkers in ALS, discusses the utility and shortcomings of each biomarker, and highlights the superiority of neurofilaments as biomarkers of neurodegeneration over other candidate biomarkers.}, } @article {pmid39456494, year = {2024}, author = {De Stefano, S and Tiberi, M and Salvatori, I and De Bardi, M and Gimenez, J and Pirshayan, M and Greco, V and Borsellino, G and Ferri, A and Valle, C and Mercuri, NB and Chiurchiù, V and Spalloni, A and Longone, P}, title = {Hydrogen Sulfide Modulates Astrocytic Toxicity in Mouse Spinal Cord Cultures: Implications for Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {10}, pages = {}, pmid = {39456494}, issn = {2076-3921}, abstract = {Hydrogen sulfide (H2S), a known inhibitor of the electron transport chain, is endogenously produced in the periphery as well as in the central nervous system, where is mainly generated by glial cells. It affects, as a cellular signaling molecule, many different biochemical processes. In the central nervous system, depending on its concentration, it can be protective or damaging to neurons. In the study, we have demonstrated, in a primary mouse spinal cord cultures, that it is particularly harmful to motor neurons, is produced by glial cells, and is stimulated by inflammation. However, its role on glial cells, especially astrocytes, is still under-investigated. The present study was designed to evaluate the impact of H2S on astrocytes and their phenotypic heterogeneity, together with the functionality and homeostasis of mitochondria in primary spinal cord cultures. We found that H2S modulates astrocytes' morphological changes and their phenotypic transformation, exerts toxic properties by decreasing ATP production and the mitochondrial respiration rate, disturbs mitochondrial depolarization, and alters the energetic metabolism. These results further support the hypothesis that H2S is a toxic mediator, mainly released by astrocytes, possibly acting as an autocrine factor toward astrocytes, and probably involved in the non-cell autonomous mechanisms leading to motor neuron death.}, } @article {pmid39456257, year = {2024}, author = {Perni, M and Mannini, B}, title = {Targeting Protein Aggregation in ALS.}, journal = {Biomolecules}, volume = {14}, number = {10}, pages = {}, pmid = {39456257}, issn = {2218-273X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/drug therapy ; *Protein Aggregation, Pathological/metabolism ; Protein Aggregates ; Animals ; }, abstract = {Proteinopathies involve the abnormal accumulation of specific proteins. Maintaining the balance of the proteome is a finely regulated process managed by a complex network of cellular machinery responsible for protein synthesis, folding, and degradation. However, stress and ageing can disrupt this balance, leading to widespread protein aggregation. Currently, several therapies targeting protein aggregation are in clinical trials for ALS. These approaches mainly focus on two strategies: addressing proteins that are prone to aggregation due to mutations and targeting the cellular mechanisms that maintain protein homeostasis to prevent aggregation. This review will cover these emerging drugs. Advances in ALS research not only offer hope for better outcomes for ALS patients but also provide valuable insights and methodologies that can benefit the broader field of neurodegenerative disease drug discovery.}, } @article {pmid39456026, year = {2024}, author = {Albagli, EA and Calliari, A and Gendron, TF and Zhang, YJ}, title = {HDGFL2 cryptic protein: a portal to detection and diagnosis in neurodegenerative disease.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {79}, pmid = {39456026}, issn = {1750-1326}, support = {P01NS084974/NS/NINDS NIH HHS/United States ; U19AG063911/AG/NIA NIH HHS/United States ; R21NS127331/NS/NINDS NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R21 NS127331/NS/NINDS NIH HHS/United States ; R01NS121125/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R01NS117461/NS/NINDS NIH HHS/United States ; Target ALS//Target ALS/ ; R01 NS117461/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; P30AG062677/AG/NIA NIH HHS/United States ; R01 AG085307/AG/NIA NIH HHS/United States ; R01AG085307/AG/NIA NIH HHS/United States ; }, } @article {pmid39455963, year = {2024}, author = {Alexander, E and Leong, KW}, title = {Discovery of nanobodies: a comprehensive review of their applications and potential over the past five years.}, journal = {Journal of nanobiotechnology}, volume = {22}, number = {1}, pages = {661}, pmid = {39455963}, issn = {1477-3155}, mesh = {*Single-Domain Antibodies/chemistry ; Humans ; Animals ; *SARS-CoV-2/immunology ; COVID-19/virology/immunology ; Neurodegenerative Diseases/drug therapy ; }, abstract = {Nanobodies (Nbs) are antibody fragments derived from heavy-chain-only IgG antibodies found in the Camelidae family as well as cartilaginous fish. Their unique structural and functional properties, such as their small size, the ability to be engineered for high antigen-binding affinity, stability under extreme conditions, and ease of production, have made them promising tools for diagnostics and therapeutics. This potential was realized in 2018 with the approval of caplacizumab, the world's first Nb-based drug. Currently, Nbs are being investigated in clinical trials for a broad range of treatments, including targeted therapies against PDL1 and Epidermal Growth Factor Receptor (EGFR), cardiovascular diseases, inflammatory conditions, and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. They are also being studied for their potential for detecting and imaging autoimmune conditions and infectious diseases such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A variety of methods are now available to generate target-specific Nbs quickly and efficiently at low costs, increasing their accessibility. This article examines these diverse applications of Nbs and their promising roles. Only the most recent articles published in the last five years have been used to summarize the most advanced developments in the field.}, } @article {pmid39455931, year = {2024}, author = {Martínez, P and Silva, M and Abarzúa, S and Tevy, MF and Jaimovich, E and Constantine-Paton, M and Bustos, FJ and van Zundert, B}, title = {Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {30}, number = {1}, pages = {185}, pmid = {39455931}, issn = {1528-3658}, support = {1181645//Agencia Nacional de Investigación y Desarrollo/ ; DI-06-24/REG//UNAB/ ; 1221745//Agencia Nacional de Investigación y Desarrollo/ ; 21151265//Agencia Nacional de Investigación y Desarrollo/ ; R01-638 EY014420//National Institute of Mental Health and Neurosciences/ ; R01-EY014074//National Institute of Mental Health and Neurosciences/ ; R03 EY014420/EY/NEI NIH HHS/United States ; 1151293//Agencia Nacional de Investigación y Desarrollo/ ; 13220203 explorador//Agencia Nacional de Investigación y Desarrollo/ ; NCN2023_32//Agencia Nacional de Investigación y Desarrollo/ ; }, mesh = {Animals ; *Muscle Fibers, Skeletal/metabolism/pathology ; *Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Mitochondria/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Humans ; *Mice, Transgenic ; *Axonal Transport ; Cell Death ; Disease Models, Animal ; Mutation ; Cells, Cultured ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1[G93A] (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2 + transients and reactive oxygen species (i.e., H2O2). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.}, } @article {pmid39454934, year = {2025}, author = {Takeda, T and Her, YR and Kim, JK and Jha, NN and Monani, UR}, title = {A variant of the Hspa8 synaptic chaperone modifies disease in a SOD1[G86R] mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {115024}, pmid = {39454934}, issn = {1090-2430}, support = {R01 NS104218/NS/NINDS NIH HHS/United States ; R01 NS123292/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Disease Models, Animal ; *Mice, Transgenic ; *HSC70 Heat-Shock Proteins/metabolism/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Motor Neurons/pathology/metabolism ; Humans ; Mutation ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relatively common and invariably fatal, paralyzing motor neuron disease for which there are few treatment options. ALS is frequently associated with ubiquitin-positive motor neuronal aggregates, a pathology suggestive of perturbed proteostasis. Indeed, cellular chaperones, which are involved in protein trafficking and degradation often underlie familial ALS. Spinal muscular atrophy (SMA) is a second, common paralytic condition resulting from motor neuron loss and muscle atrophy. While SMA is now effectively treated, mechanisms underlying motor neuron degeneration in the disease remain far from clear. To address mechanistic questions about SMA, we recently identified a genetic modifier of the disease. The factor, a G470R variant in the constitutively expressed cellular chaperone, Hspa8, arrested motor neuron loss, prevented the abnormal accumulation of neurofilament aggregates at nerve terminals and suppressed disease. Hspa8 is best known for its role in autophagy. Amongst its many clients is the ALS-associated superoxide dismutase 1 (SOD1) protein. Given its suppression of the SMA phenotype, we tested potential disease-mitigating effects of Hspa8[G470R] in a mutant SOD1 mouse model of ALS. Unexpectedly, disease in mutant SOD1 mice expressing the G470R variant was aggravated. Motor performance of the mice deteriorated, muscle atrophy worsened, and lifespan shrunk even further. Paradoxically, SOD1 protein in spinal cord tissue of the mice was dramatically reduced. Our results suggest that Hspa8 modulates the ALS phenotype. However, rather than mitigating disease, the G470R variant exacerbates it.}, } @article {pmid39451992, year = {2024}, author = {Ozdinler, PH}, title = {Sleep Apnea and Amyotrophic Lateral Sclerosis: Cause, Correlation, Any Relation?.}, journal = {Brain sciences}, volume = {14}, number = {10}, pages = {}, pmid = {39451992}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with progressive neurodegeneration, affecting both the cortical and the spinal component of the motor neuron circuitry in patients. The cellular and molecular basis of selective neuronal vulnerability is beginning to emerge. Yet, there are no effective cures for ALS, which affects more than 200,000 people worldwide each year. Recent studies highlight the importance of the glymphatic system and its proper function for the clearance of the cerebral spinal fluid, which is achieved mostly during the sleep period. Therefore, a potential link between problems with sleep and neurodegenerative diseases has been postulated. This paper discusses the present understanding of this potential correlation.}, } @article {pmid39451800, year = {2024}, author = {Drăgoi, MV and Nisipeanu, I and Frimu, A and Tălîngă, AM and Hadăr, A and Dobrescu, TG and Suciu, CP and Manea, AR}, title = {Real-Time Home Automation System Using BCI Technology.}, journal = {Biomimetics (Basel, Switzerland)}, volume = {9}, number = {10}, pages = {}, pmid = {39451800}, issn = {2313-7673}, abstract = {A Brain-Computer Interface (BCI) processes and converts brain signals to provide commands to output devices to carry out certain tasks. The main purpose of BCIs is to replace or restore the missing or damaged functions of disabled people, including in neuromuscular disorders like Amyotrophic Lateral Sclerosis (ALS), cerebral palsy, stroke, or spinal cord injury. Hence, a BCI does not use neuromuscular output pathways; it bypasses traditional neuromuscular pathways by directly interpreting brain signals to command devices. Scientists have used several techniques like electroencephalography (EEG) and intracortical and electrocorticographic (ECoG) techniques to collect brain signals that are used to control robotic arms, prosthetics, wheelchairs, and several other devices. A non-invasive method of EEG is used for collecting and monitoring the signals of the brain. Implementing EEG-based BCI technology in home automation systems may facilitate a wide range of tasks for people with disabilities. It is important to assist and empower individuals with paralysis to engage with existing home automation systems and gadgets in this particular situation. This paper proposes a home security system to control a door and a light using an EEG-based BCI. The system prototype consists of the EMOTIV Insight™ headset, Raspberry Pi 4, a servo motor to open/close the door, and an LED. The system can be very helpful for disabled people, including arm amputees who cannot close or open doors or use a remote control to turn on or turn off lights. The system includes an application made in Flutter to receive notifications on a smartphone related to the status of the door and the LEDs. The disabled person can control the door as well as the LED using his/her brain signals detected by the EMOTIV Insight™ headset.}, } @article {pmid39451396, year = {2024}, author = {Yang, CH and Huang, JL and Tsai, LK and Taniar, D and Pai, TW}, title = {An Effective DNA Methylation Biomarker Screening Mechanism for Amyotrophic Lateral Sclerosis (ALS) Based on Comorbidities and Gene Function Analysis.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {39451396}, issn = {2306-5354}, support = {MOST 111-2221-E-027-113-414 MY2//National Science and Technology Council (Taiwan)/ ; NSTC113-2221-E-027-109//National Science and Technology Council (Taiwan)/ ; MOST104-2321-B-019-009//National Science and Technology Council (Taiwan)/ ; }, abstract = {This study used epigenomic methylation differential expression analysis to identify primary biomarkers in patients with amyotrophic lateral sclerosis (ALS). We combined electronic medical record datasets from MIMIC-IV (United States) and NHIRD (Taiwan) to explore ALS comorbidities in depth and discover any comorbidity-related biomarkers. We also applied word2vec to these two clinical diagnostic medical databases to measure similarities between ALS and other similar diseases and evaluated the statistical assessment of the odds ratio to discover significant comorbidities for ALS subjects. Important and representative DNA methylation biomarker candidates could be effectively selected by cross-comparing similar diseases to ALS, comorbidity-related genes, and differentially expressed methylation loci for ALS subjects. The screened epigenomic and comorbidity-related biomarkers were clustered based on their genetic functions. The candidate DNA methylation biomarkers associated with ALS were comprehensively discovered. Gene ontology annotations were then applied to analyze and cluster the candidate biomarkers into three different groups based on gene function annotations. The results showed that a potential testing kit for ALS detection can be composed of SOD3, CACNA1H, and ERBB4 for effective early screening of ALS using blood samples. By developing an effective DNA methylation biomarker screening mechanism, early detection and prophylactic treatment of high-risk ALS patients can be achieved.}, } @article {pmid39451238, year = {2024}, author = {Crescioli, C and Paronetto, MP}, title = {The Emerging Role of Phosphodiesterase 5 Inhibition in Neurological Disorders: The State of the Art.}, journal = {Cells}, volume = {13}, number = {20}, pages = {}, pmid = {39451238}, issn = {2073-4409}, mesh = {Humans ; *Phosphodiesterase 5 Inhibitors/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy ; Animals ; Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism ; Neuroinflammatory Diseases/drug therapy/metabolism ; }, abstract = {Growing evidence suggests that neuroinflammation is not just a consequence of neurodegeneration in pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease or Amyotrophic lateral sclerosis, but it is rather a determinant factor, which plays a pivotal role in the onset and progression of these disorders. Neuroinflammation can affect cells and processes in the central nervous system (CNS) as well as immune cells, and might precede protein aggregation, which is a hallmark of the neurodegenerative process. Standard treatment methods are far from being able to counteract inflammation and delay neurodegeneration. Remarkably, phosphodiesterase 5 inhibitors (PDE5is), which represent potent vasoactive drugs used as a first-line treatment for erectile dysfunction (ED), display important anti-inflammatory effects through cyclic guanosine monophosphate (cGMP) level stabilization. Since PDE5 hydrolyzes cGMP, several studies positioned PDE5 as a therapeutic target, and more specifically, PDE5is as potential alternative strategies for the treatment of a variety of neurological disorders. Indeed, PDE5is can limit neuroinflammation and enhance synaptic plasticity, with beneficial effects on cognitive function and memory. The aim of this review is to provide an overview of some of the main processes underlying neuroinflammation and neurodegeneration which may be potential targets for PDE5is, focusing on sildenafil, the most extensively studied. Current strategies using PDEis for the treatment of neurodegenerative diseases will be summarized.}, } @article {pmid39449756, year = {2024}, author = {Filipi, T and Tureckova, J and Vanatko, O and Chmelova, M and Kubiskova, M and Sirotova, N and Matejkova, S and Vargova, L and Anderova, M}, title = {ALS-like pathology diminishes swelling of spinal astrocytes in the SOD1 animal model.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1472374}, pmid = {39449756}, issn = {1662-5102}, abstract = {Astrocytes are crucial for the functioning of the nervous system as they maintain the ion homeostasis via volume regulation. Pathological states, such as amyotrophic lateral sclerosis (ALS), affect astrocytes and might even cause a loss of such functions. In this study, we examined astrocytic swelling/volume recovery in both the brain and spinal cord of the SOD1 animal model to determine the level of their impairment caused by the ALS-like pathology. Astrocyte volume changes were measured in acute brain or spinal cord slices during and after exposure to hyperkalemia. We then compared the results with alterations of extracellular space (ECS) diffusion parameters, morphological changes, expression of the Kir4.1 channel and the potassium concentration measured in the cerebrospinal fluid, to further disclose the link between potassium and astrocytes in the ALS-like pathology. Morphological analysis revealed astrogliosis in both the motor cortex and the ventral horns of the SOD1 spinal cord. The activated morphology of SOD1 spinal astrocytes was associated with the results from volume measurements, which showed decreased swelling of these cells during hyperkalemia. Furthermore, we observed lower shrinkage of ECS in the SOD1 spinal ventral horns. Immunohistochemical analysis then confirmed decreased expression of the Kir4.1 channel in the SOD1 spinal cord, which corresponded with the diminished volume regulation. Despite astrogliosis, cortical astrocytes in SOD1 mice did not show alterations in swelling nor changes in Kir4.1 expression, and we did not identify significant changes in ECS parameters. Moreover, the potassium level in the cerebrospinal fluid did not deviate from the physiological concentration. The results we obtained thus suggest that ALS-like pathology causes impaired potassium uptake associated with Kir4.1 downregulation in the spinal astrocytes, but based on our data from the cortex, the functional impairment seems to be independent of the morphological state.}, } @article {pmid39449457, year = {2024}, author = {Rosa, D and Ingrande, L and Marcomini, I and Poliani, A and Villa, G and Sodano, M and Manara, DF}, title = {Perceived Pain in People Living with Amyotrophic Lateral Sclerosis-A Scoping Review.}, journal = {Nursing reports (Pavia, Italy)}, volume = {14}, number = {4}, pages = {3023-3039}, pmid = {39449457}, issn = {2039-4403}, abstract = {(1) Background: Pain is a common symptom in patients with Amyotrophic Lateral Sclerosis (ALS). There are no evidence-based pharmacological treatments for pain in ALS; recommendations are based on guidelines for chronic non-oncological pain and clinical experience. The aim is to map the literature on how people with ALS experience pain, and how this affects their daily activities and social relationships. (2) Methods: This scoping review included studies concerning patients with spinal/bulbar ALS aged ≥ 18 years who experience pain, focusing on perception, characteristics, treatment, and impact on quality of life. Temporal and linguistic criteria were applied when searching the MEDLINE, CINAHL, and SCOPUS databases. (3) Results: The management of pain in these patients is complex and involves the use of anti-inflammatory drugs, analgesics, and opioids. Pain is associated with other conditions such as depression and anxiety, which contribute to a deterioration in the quality of life. Moreover, pain may also negatively influence patient compliance with prescribed treatment regimens and the quality of care they perceive themselves to be receiving. (4) Conclusions: It is of the most importance to identify effective ways to assess and treat this issue, with health care professionals taking an active role in this process.}, } @article {pmid39449162, year = {2024}, author = {Zhu, Y and Zhang, Y and Li, M and Bai, J and Wang, H and Pang, X and Du, R and Wang, J and Huang, X}, title = {Prognostic Value of Systemic Inflammation, Nutritional Status and Sarcopenia in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {15}, number = {6}, pages = {2743-2755}, pmid = {39449162}, issn = {2190-6009}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/mortality/blood ; Female ; Male ; *Nutritional Status ; *Sarcopenia/etiology/blood ; Middle Aged ; Prognosis ; *Inflammation/blood ; Aged ; Biomarkers/blood ; Proportional Hazards Models ; ROC Curve ; Kaplan-Meier Estimate ; Adult ; }, abstract = {BACKGROUND: Nutritional status, systemic inflammatory responses and muscle mass are associated with the prognosis of patients with amyotrophic lateral sclerosis (ALS). However, the optimal biomarker for predicting prognosis remains unclear. This study aimed to identify the optimal indicators of survival among the nutrition-based, inflammation-based and muscle mass-related markers for ALS patients.

METHODS: We enrolled ALS patients from January 2014 to December 2019. Experienced neurologists followed up with the participants until January 2022. This study included a total of 17 nutritional, systemic inflammatory or muscle mass-related indicators. Maximally selected rank statistics determined the cut-off points for these indicators. Kaplan-Meier estimation was used to assess survival. Uni- and multivariate Cox proportional hazards models were used to determine the effects of indicators on survival. Finally, time-dependent receiver operating characteristic (time-ROC) curves and the C-index were calculated to evaluate the predictive efficacy of different indicators.

RESULTS: A total of 506 patients with ALS were enrolled in this study, including 288 males (56.9%) and 218 females (43.1%), with a mean age of 54.2 ± 10.5 years. Among these ALS patients, 334 cases (68.0%) either died or underwent tracheotomy. In univariate Cox proportional hazards regression, 11 indicators were significantly associated with ALS survival (p < 0.05). And systemic immune inflammation (SII), platelet-to-lymphocyte ratio (PLR), modified geriatric nutritional risk index (mGNRI), creatinine and sarcopenia index (SI, (creatinine/cystatin C) × 100) were determined as independent predictors (p < 0.05) in multivariate Cox proportional hazards regression. A higher SI predicted longer survival (hazard ratio, 0.59; 95% confidence interval [CI], 0.46-0.76; p < 0.001). The results of time-ROC and C-index analyses indicated that SI had the best predictive efficacy for ALS survival, with a C-index of 0.65 (95% CI, 0.54-0.75) for 1-year, 0.61 (95% CI, 0.57-0.65) for 3-year and 0.59 (95% CI, 0.55-0.62) for 5-year survival. Across different subgroups, SI had the highest C-index in men and women, limb onset and aged < 60 year ALS patients, compared with other indicators. However, cystatin C was the best indicator for predicting the survival of ALS patients with bulbar onset, whereas the prognostic nutritional index (PNI) was the best for those aged ≥60 years.

CONCLUSIONS: The serum SI demonstrates superior prognostic ability compared to other inflammation-based, nutrition-based and muscle mass-related indicators for patients with ALS. Given its simplicity and availability, it is well suited for clinical use in evaluating the prognosis of ALS patients.}, } @article {pmid39448670, year = {2024}, author = {Stankiewicz-Kosyl, M and Wińska-Krysiak, M and Wrochna, M and Haliniarz, M and Marcinkowska, K}, title = {Regional diversity of the ALS gene and hormesis due to tribenuron-methyl in Centaurea cyanus L.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {25197}, pmid = {39448670}, issn = {2045-2322}, support = {BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; }, mesh = {*Acetolactate Synthase/genetics ; *Hormesis ; *Herbicides/pharmacology ; *Centaurea/genetics ; Arylsulfonates/pharmacology ; Herbicide Resistance/genetics ; Mutation ; Poland ; Plant Proteins/genetics ; Genetic Variation ; }, abstract = {Centaurea cyanus L. is a common field weed in Eastern Europe but only in Poland biotypes of this species with resistance to acetolactate synthase (ALS) inhibitors have been confirmed. This phenomenon is constantly developing and spreading to consecutive regions of Poland. This study aimed to assess the response of selected Polish C. cyanus populations to tribenuron-methyl and to analyse the genetic variability of the ALS gene of C. cyanus populations resistant to ALS inhibitors. Between 2017 and 2021, 13 seed samples were collected from eastern Poland and a dose-response study with tribenuron-methyl was performed. Eleven populations resistant to tribenuron-methyl were identified. All populations from this study as well as 6 additional resistant populations characterised in the previous dose-response studies were subjected to molecular analysis of the ALS gene. Target-site resistance due to mutations P197S, P197Q, P197T and P197A were identified in 8 populations from Warmia-Masuria and Podlaskie provinces. This is the first case of target-site resistance (TSR) in C. cyanus confirmed by sequencing of the ALS gene. Moreover in some resistant plants, ten changes in the amino acid ALS sequence were identified in comparison to those in the susceptible ones. In none of the populations were all mutations detected in the same individual. The highest frequency of mutations was detected in Warmia-Masuria province. Some C. cyanus populations resistant to ALS inhibitors showed hormesis effect concerning shoot fresh weight after tribenuron-methyl treatment. Stimulation due to half the recommended dose of tribenuron-methyl was the highest and the difference between untreated and treated plants was statistically significant in two populations from Warmia-Masuria and in one from Podlaskie province.}, } @article {pmid39447539, year = {2024}, author = {Zhu, H}, title = {Interference of nuclear speckles: A nexus of RNA foci, dipeptide repeats, and mis-splicing in C9ORF72 ALS/FTD.}, journal = {Neuron}, volume = {112}, number = {20}, pages = {3375-3377}, doi = {10.1016/j.neuron.2024.10.001}, pmid = {39447539}, issn = {1097-4199}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *C9orf72 Protein/genetics ; *Frontotemporal Dementia/genetics/metabolism ; *RNA Splicing/genetics ; Dipeptides/metabolism ; DNA Repeat Expansion/genetics ; Proteins/genetics/metabolism ; RNA/genetics ; }, abstract = {In this issue of Neuron, Wu et al.[1] show that nuclear speckle proteins are sequestered by both nuclear RNA foci and cytoplasmic dipeptide repeat aggregates in C9ORF72-ALS/FTD. Consequently, dysregulation of splicing induces widespread splicing alterations and contributes to neurodegeneration.}, } @article {pmid39444183, year = {2025}, author = {Alici, H and Uversky, VN and Kang, DE and Woo, JA and Coskuner-Weber, O}, title = {Effects of the Amyotrophic Lateral Sclerosis-related Q108P Mutation on the Structural Ensemble Characteristics of CHCHD10.}, journal = {Current protein & peptide science}, volume = {26}, number = {3}, pages = {201-212}, pmid = {39444183}, issn = {1875-5550}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Mutation ; }, abstract = {INTRODUCTION: The Q108P pathological variant of the mitochondrial Coiled-Coil-Helix-- Coiled-Coil-Helix Domain-Containing Protein 10 (CHCHD10) has been implicated in amyotrophic lateral sclerosis (ALS). Both the wild-type and CHCHD10[Q108P] proteins exhibit intrinsically disordered regions, posing challenges for structural studies with conventional experimental tools.

METHODS: This study presents the foundational characterization of the structural features of CHCHD10[Q108P] and compares them with those of the wild-type counterpart. We conducted multiple run molecular dynamics simulations and bioinformatics analyses.

RESULTS: Our findings reveal distinct differences in structural properties, free energy surfaces, and the outputs of principal component analysis between these two proteins. These results contribute significantly to the comprehension of CHCHD10 and its Q108P variant in terms of pathology, biochemistry, and structural biology.

CONCLUSION: The reported structural properties hold promise for informing the development of more effective treatments for ALS.}, } @article {pmid39444004, year = {2024}, author = {Hoshino, T and Mukai, A and Yamashita, H and Misawa, H and Urushitani, M and Tashiro, Y and Matsuzawa, SI and Takahashi, R}, title = {NDRG1 upregulation by ubiquitin proteasome system dysfunction aggravates neurodegeneration.}, journal = {Molecular brain}, volume = {17}, number = {1}, pages = {77}, pmid = {39444004}, issn = {1756-6606}, support = {16H01695//Japan Society for the Promotion of Science/ ; }, mesh = {Animals ; *Up-Regulation/genetics ; *Cell Cycle Proteins/metabolism/genetics ; *Proteasome Endopeptidase Complex/metabolism ; Mice ; *Ubiquitin/metabolism ; *Intracellular Signaling Peptides and Proteins/metabolism/genetics ; Cell Line, Tumor ; Motor Neurons/metabolism/pathology ; Nerve Degeneration/pathology ; Cell Death ; Humans ; }, abstract = {Protein turnover is crucial for cell survival, and the impairment of proteostasis leads to cell death. Aging is associated with a decline in proteostasis, as the progressive accumulation of damaged proteins is a hallmark of age-related disorders such as neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We previously discovered that the declining function of the ubiquitin-proteasome system (UPS) in motor neurons contributes to sporadic ALS pathologies, such as progressive motor neuron loss, protein accumulation, and glial activation. However, the mechanisms of UPS dysfunction-induced cell damage, such as cell death and aggregation, are not fully understood. This study used transcriptome analysis of motor neurons with UPS dysfunction and found that the expression of N-myc downstream regulated 1 (NDRG1) gets upregulated by UPS dysfunction. Additionally, the upregulation of NDRG1 induces cell death in the Neuro2a mouse neuroblastoma cell line. These results suggest that NDRG1 is a potential marker for UPS dysfunction and may play a role in neurodegeneration, such as that seen in ALS.}, } @article {pmid39443862, year = {2024}, author = {Paulin, J and Lahti, M and Riihimäki, H and Hänninen, J and Vesanen, T and Koivisto, M and Peltonen, LM}, title = {The rate and predictors of violence against EMS personnel.}, journal = {BMC emergency medicine}, volume = {24}, number = {1}, pages = {200}, pmid = {39443862}, issn = {1471-227X}, mesh = {Humans ; Male ; Retrospective Studies ; Female ; Finland ; Adult ; Middle Aged ; *Emergency Medical Technicians/statistics & numerical data ; Emergency Medical Services/statistics & numerical data ; Workplace Violence/statistics & numerical data ; Violence/statistics & numerical data ; Logistic Models ; Electronic Health Records ; }, abstract = {BACKGROUND: Violence against Emergency Medical Services (EMS) personnel vary between studies. Current studies are mainly based on self-reporting, thus other designs are needed to provide more perspective. The purpose of this study was to explore the rate and predictors of violent behavior targeted at EMS personnel by exploring the Electronic patient care records (ePCR) documentation by EMS personnel.

METHODS: This was a retrospective cohort study of EMS patients in Finland. The data were collected from three regions between 1st June and 30th November 2018. Text mining and manual evaluation were used to identify and explore predictors of violence targeted at EMS personnel from the ePCR narratives. Multivariable logistic regressions were used to determine factors that were independently associated with violent behavior. The results are presented with odds ratios (ORs) with 95% confidence intervals (CIs).

RESULTS: The EMS personnel reported experiences of violence in a total of 297 identified missions (0.7%) of all EMS missions (n = 40,263). The violence was mostly verbal (62.3%) and the most common violence perpetrator was the patient (98.0%). The police were alarmed to many missions where violence was reported (40.7%). Sometimes violence occurred suddenly although the police were present. The multivariable logistic regression model indicates that violence occurred typically in urban areas (OR 1.699; 95% CI 1.283 to 2.248), at weekend nights (OR 1.357; 95% CI 1.043 to 1.765), by male (OR 1.501; 95% CI 1.160 to 1.942), and patients influenced by alcohol (OR 3.464; 95% CI 2.644 to 4.538). A NEWS2 score of 3 in any parameter (vs. score 0-4, OR 2.386; 95% CI: 1.788 to 3.185) and ALS unit type (vs. BLS, OR 1.373; 95% CI: 1.009 to 1.866) increased the likelihood as well.

CONCLUSIONS: The documentation in ePCRs show low rates of violence targeted at EMS personnel. However, violence is a multidimensional phenomenon connected to unfamiliar patients, rushed situations, and an uncontrolled environment. This means that the EMS personnels' safety cannot be ensured in all situations. Therefore, a balance between safety margins and treating patients needs to be considered.}, } @article {pmid39443410, year = {2024}, author = {Zhang, T and Rui, W and Sun, Y and Tian, Y and Li, Q and Zhang, Q and Zhao, Y and Liu, Z and Wang, T}, title = {Identification of nitric oxide-mediated necroptosis as the predominant death route in Parkinson's disease.}, journal = {Molecular biomedicine}, volume = {5}, number = {1}, pages = {44}, pmid = {39443410}, issn = {2662-8651}, mesh = {*Necroptosis ; *Parkinson Disease/pathology/metabolism/genetics ; *Nitric Oxide/metabolism ; Humans ; Animals ; Mice ; Neurons/metabolism/pathology ; Signal Transduction ; Male ; Brain/pathology/metabolism ; Alzheimer Disease/pathology/metabolism/genetics ; Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; Membrane Potential, Mitochondrial ; }, abstract = {Parkinson's disease (PD) involves multiple forms of neuronal cell death, but the dominant pathway involved in disease progression remains unclear. This study employed RNA sequencing (RNA-seq) of brain tissue to explore gene expression patterns across different stages of PD. Using the Scaden deep learning algorithm, we predicted neurocyte subtypes and modelled dynamic interactions for five classic cell death pathways to identify the predominant routes of neuronal death during PD progression. Our cell type-specific analysis revealed an increasing shift towards necroptosis, which was strongly correlated with nitric oxide synthase (NOS) expression across most neuronal subtypes. In vitro experiments confirmed that nitric oxide (NO) is a key mediator of necroptosis, leading to nuclear shrinkage and decreased mitochondrial membrane potential via phosphorylation of the PIP1/PIP3/MLKL signalling cascade. Importantly, specific necroptosis inhibitors significantly mitigated neuronal damage in both in vitro and in vivo PD models. Further analysis revealed that NO-mediated necroptosis is prevalent in early-onset Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) and across multiple brain regions but not in brain tumours. Our findings suggest that NO-mediated necroptosis is a critical pathway in PD and other neurodegenerative disorders, providing potential targets for therapeutic intervention.}, } @article {pmid39441150, year = {2024}, author = {Hamad, AA and Alkhawaldeh, IM and Abbas, A and Elaraby, A and Meshref, M}, title = {Incidence and risk factors of venous thromboembolism in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {La Tunisie medicale}, volume = {102}, number = {10}, pages = {610-515}, pmid = {39441150}, issn = {2724-7031}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/complications ; Humans ; *Venous Thromboembolism/epidemiology/etiology ; Incidence ; Risk Factors ; Male ; Female ; }, abstract = {AIMS: This systematic review and meta-analysis aimed to determine the annual incidence rate of venous thromboembolism (VTE) and identify risk factors of VTE in amyotrophic lateral sclerosis (ALS) patients.

METHODS: A comprehensive search of three databases was conducted up to April 8, 2024, to identify longitudinal studies reporting VTE incidence in ALS patients. The included studies were either prospective or retrospective, following up with ALS patients. Quality assessment was performed using the NIH tool for observational cohort studies. Meta-analysis was conducted using Open Meta Analyst, employing a random-effect model. Subgroup, Meta-regression, and sensitivity analyses were also carried out.

RESULTS: Our analysis included eight studies comprising a total of 26,758 ALS patients that met the inclusion criteria. The pooled annual incidence of VTE across all studies was found to be 22 cases per 1,000 person-year (95% CI = 18 to 27). Subgroup analysis revealed that the annual incidence of VTE in males was 19 cases per 1,000 person-year (95% CI = 15 to 22), while in females, it was 20 cases per 1,000 person-year (95% CI = 16 to 25). Leave-one-out analysis demonstrated that the incidence ranged from 21 to 28 cases per 1,000 person-year when excluding each study individually. Meta-regression analysis did not find a significant association between age and the risk of VTE (P = 0.079). Based on the included studies, risk factors of VTE in ALS patients included a history of VTE, non-invasive ventilation, immobility, and decreased functional status.

CONCLUSION: Patients with ALS face a higher risk of developing VTE compared to individuals of the same age. These findings underscore the importance of implementing preventive measures and closely monitoring VTE in ALS patients.}, } @article {pmid39441015, year = {2024}, author = {Liu, Y and Li, Y and Zhang, P}, title = {Stress granules and organelles: Coordinating cellular responses in health and disease.}, journal = {Protein & cell}, volume = {}, number = {}, pages = {}, doi = {10.1093/procel/pwae057}, pmid = {39441015}, issn = {1674-8018}, abstract = {Membrane-bound organelles and membraneless organelles (MLOs) coordinate various biological processes within eukaryotic cells. Among these, stress granules (SGs) are significant cytoplasmic MLOs that form in response to cellular stress, exhibiting liquid-like properties alongside stable substructures. SGs interact with diverse organelles, thereby influencing cellular pathways that are critical in both health and disease contexts. This review discusses the interplay between SGs and organelles and explores the methodologies employed to analyze interactions between SGs and other MLOs. Furthermore, it highlights the pivotal roles SGs play in regulating cellular responses and the pathogenesis of ALS. Gaining insights into these interactions is essential for deciphering the mechanisms underlying both physiological processes and pathological conditions.}, } @article {pmid39440770, year = {2024}, author = {Allowitz, K and Taylor, J and Harames, K and Yoo, J and Baloch, O and Ramana, KV}, title = {Oxidative Stress-mediated Lipid Peroxidation-derived Lipid Aldehydes in the Pathophysiology of Neurodegenerative Diseases.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X342720241014164650}, pmid = {39440770}, issn = {1875-6190}, abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis cause damage and gradual loss of neurons affecting the central nervous system. Neurodegenerative diseases are most commonly seen in the ageing process. Ageing causes increased reactive oxygen species and decreased mitochondrial ATP generation, resulting in redox imbalance and oxidative stress. Oxidative stress-generated free radicals cause damage to membrane lipids containing polyunsaturated fatty acids, leading to the formation of toxic lipid aldehyde products such as 4- hydroxynonenal and malondialdehyde. Several studies have shown that lipid peroxidation-derived aldehyde products form adducts with cellular proteins, altering their structure and function. Thus, these lipid aldehydes could act as secondary signaling intermediates, modifying important metabolic pathways, and contributing to the pathophysiology of several human diseases, including neurodegenerative disorders. Additionally, they could serve as biomarkers for disease progression. This narrative review article discusses the biological and clinical significance of oxidative stress-mediated lipid peroxidation-derived lipid aldehydes in the pathophysiology of various neurodegenerative diseases.}, } @article {pmid39440303, year = {2024}, author = {Dafinca, R and Tosat-Bitrian, C and Carroll, E and Vahsen, BF and Gilbert-Jaramillo, J and Scaber, J and Feneberg, E and Johnson, E and Talbot, K}, title = {Dynactin-1 mediates rescue of impaired axonal transport due to reduced mitochondrial bioenergetics in amyotrophic lateral sclerosis motor neurons.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae350}, pmid = {39440303}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. A key pathological signature of ALS is the cytoplasmic mislocalization and aggregation of TDP-43 in affected motor neurons, which is found in 97% of cases. Recent reports have shown that mitochondrial dysfunction plays a significant role in motor neuron degeneration in ALS, and TDP-43 modulates several mitochondrial transcripts. In this study, we used induced pluripotent stem cell-derived motor neurons from ALS patients with TDP-43 mutations and a transgenic TDP-43[M337V] mouse model to determine how TDP-43 mutations alter mitochondrial function and axonal transport. We detected significantly reduced mitochondrial respiration and ATP production in patient induced pluripotent stem cell-derived motor neurons, linked to an interaction between TDP-43[M337V] with ATPB and COX5A. A downstream reduction in speed of retrograde axonal transport in patient induced pluripotent stem cell-derived motor neurons was detected, which correlated with downregulation of the motor protein complex, DCTN1/dynein. Overexpression of DCTN1 in patient induced pluripotent stem cell-derived motor neurons significantly increased the percentage of retrograde travelling mitochondria and reduced the percentage of stationary mitochondria. This study shows that ALS induced pluripotent stem cell-derived motor neurons with mutations in TDP-43 have deficiencies in essential mitochondrial functions with downstream effects on retrograde axonal transport, which can be partially rescued by DCTN1 overexpression.}, } @article {pmid39439710, year = {2024}, author = {Kelser, BM and Teichner, EM and Subtirelu, RC and Hoss, KN}, title = {A review of proposed mechanisms for neurodegenerative disease.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1370580}, pmid = {39439710}, issn = {1663-4365}, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) affect millions and present significant challenges in healthcare and treatment costs. The debate in the field pivots around two hypotheses: synaptic spread and selective vulnerability. Pioneers like Virginia Lee and John Trojanowski have been instrumental in identifying key proteins (tau, alpha-synuclein, TDP-43) central to these diseases. The synaptic spread hypothesis suggests a cell-to-cell propagation of pathogenic proteins across neuronal synapses, influencing disease progression, with studies highlighting the role of proteins like alpha-synuclein and amyloid-beta in this process. In contrast, the selective vulnerability hypothesis proposes inherent susceptibility of certain neurons to degeneration due to factors like metabolic stress, leading to protein aggregation. Recent advancements in neuroimaging, especially PET/MRI hybrid imaging, offer new insights into these mechanisms. While both hypotheses offer substantial evidence, their relative contributions to neurodegenerative processes remain to be fully elucidated. This uncertainty underscores the necessity for continued research, with a focus on these hypotheses, to develop effective treatments for these devastating diseases.}, } @article {pmid39437787, year = {2024}, author = {Saez-Atienzar, S and Souza, CDS and Chia, R and Beal, SN and Lorenzini, I and Huang, R and Levy, J and Burciu, C and Ding, J and Gibbs, JR and Jones, A and Dewan, R and Pensato, V and Peverelli, S and Corrado, L and van Vugt, JJFA and van Rheenen, W and Tunca, C and Bayraktar, E and Xia, M and , and , and , and , and Iacoangeli, A and Shatunov, A and Tiloca, C and Ticozzi, N and Verde, F and Mazzini, L and Kenna, K and Al Khleifat, A and Opie-Martin, S and Raggi, F and Filosto, M and Piccinelli, SC and Padovani, A and Gagliardi, S and Inghilleri, M and Ferlini, A and Vasta, R and Calvo, A and Moglia, C and Canosa, A and Manera, U and Grassano, M and Mandrioli, J and Mora, G and Lunetta, C and Tanel, R and Trojsi, F and Cardinali, P and Gallone, S and Brunetti, M and Galimberti, D and Serpente, M and Fenoglio, C and Scarpini, E and Comi, GP and Corti, S and Del Bo, R and Ceroni, M and Pinter, GL and Taroni, F and Bella, ED and Bersano, E and Curtis, CJ and Lee, SH and Chung, R and Patel, H and Morrison, KE and Cooper-Knock, J and Shaw, PJ and Breen, G and Dobson, RJB and Dalgard, CL and , and Scholz, SW and Al-Chalabi, A and van den Berg, LH and McLaughlin, R and Hardiman, O and Cereda, C and Sorarù, G and D'Alfonso, S and Chandran, S and Pal, S and Ratti, A and Gellera, C and Johnson, K and Doucet-O'Hare, T and Pasternack, N and Wang, T and Nath, A and Siciliano, G and Silani, V and Başak, AN and Veldink, JH and Camu, W and Glass, JD and Landers, JE and Chiò, A and Sattler, R and Shaw, CE and Ferraiuolo, L and Fogh, I and Traynor, BJ}, title = {Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data.}, journal = {Cell genomics}, volume = {4}, number = {11}, pages = {100679}, pmid = {39437787}, issn = {2666-979X}, support = {R35 NS127253/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Drug Repositioning ; *Frontotemporal Dementia/genetics/drug therapy ; Genomics/methods ; Riluzole/therapeutic use ; Male ; Female ; Neuroprotective Agents/therapeutic use/pharmacology ; DNA Repeat Expansion/genetics ; }, abstract = {Repeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related disease. We used an agnostic approach based on genomic data (n = 41,273 ALS and healthy samples, and n = 1,516 C9orf72 carriers) to overcome these bottlenecks. Our drug-repurposing screen, based on gene- and expression-pattern matching and information about the genetic variants influencing onset age among C9orf72 carriers, identified acamprosate, a γ-aminobutyric acid analog, as a potentially repurposable treatment for patients carrying C9orf72 repeat expansions. We validated its neuroprotective effect in cell models and showed comparable efficacy to riluzole, the current standard of care. Our work highlights the potential value of genomics in repurposing drugs in situations where the underlying pathomechanisms are inherently complex. VIDEO ABSTRACT.}, } @article {pmid39436867, year = {2025}, author = {Firozjae, AA and Shiran, MR and Rashidi, M}, title = {The neuropharmacological and clinical effects of lutein: a systematic review.}, journal = {Hormone molecular biology and clinical investigation}, volume = {46}, number = {1}, pages = {27-38}, pmid = {39436867}, issn = {1868-1891}, mesh = {*Lutein/pharmacology/therapeutic use ; Humans ; *Neurodegenerative Diseases/drug therapy ; Alzheimer Disease/drug therapy ; }, abstract = {OBJECTIVES: Neurodegenerative diseases are defined by specific protein accumulation and anatomic vulnerability leading to neuronal loss. Some studies have shown that lutein may have an effect on neurodegenerative diseases. As most of the neurodegenerative diseases don't have certain cure and therapies focus on symptom control, Lutein may be a complementary treatment. Due to controversies in studies investigating lutein effect on neurodegenerative diseases, we decided to perform a systematic review on these studies.

METHODS: A systematic search was carried out in the available databases. We used all MeSH terms and relevant keywords. Studies that reported relationship between lutein and any neurodegenerative disease were included.

RESULTS: We found 278 studies. After removing duplicates, screening by titles and abstracts and excluding irrelevant papers, 17 articles were included in this study. Fourteen studies investigated Alzheimer's disease, 2 studies Parkinson's disease and 1 study Amyotrophic lateral sclerosis. 1/17 study found that high serum levels of lutein at baseline were associated with a lower risk of AD mortality and lutein effect on lipid profile have been investigated in 2/17 studies. Also, 1/17 study has been shown that high intake of lutein may reduce the risk of ALS progression.

CONCLUSIONS: 4/17 studies confirm that lutein can improve cognitive function. 8/17 studies demonstrate a reduction in the progression of AD, and 2/17 studies indicate an improvement in lipid profiles. However, some studies did not find any significant associations. Additionally, there is a limited number of studies investigating the effects of lutein on other neurodegenerative diseases.}, } @article {pmid39436522, year = {2025}, author = {Ma, J and Wen, Q and Pang, X and Huang, S and Zhang, J and Wang, J and Chang, X and Guo, J and Zhang, W}, title = {Correction to: Fasciculation score: a sensitive biomarker in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {1}, pages = {525-526}, doi = {10.1007/s10072-024-07807-y}, pmid = {39436522}, issn = {1590-3478}, } @article {pmid39435791, year = {2024}, author = {Brylev, LV and Bryukhov, VV and Druzhinina, ES and Kovalchuk, MO}, title = {[Lower motor neuron disease with MRI «snake eyes» pattern].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {9}, pages = {141-144}, doi = {10.17116/jnevro2024124091141}, pmid = {39435791}, issn = {1997-7298}, mesh = {Humans ; *Magnetic Resonance Imaging ; *Motor Neuron Disease/diagnostic imaging/diagnosis ; Motor Neurons/pathology ; *Pyramidal Tracts/diagnostic imaging ; }, abstract = {Motor neuron disease with isolated or predominant lesion of the lower motor neuron at one level of the pyramidal tract is a rare diagnostic finding. In the article, we analyze the case of a patient with asymmetric lesion of the inferior motor neuron at the cervical level: clinical manifestations, results of additional studies and dynamic observation of the patient. Special attention is paid to the MRI picture of changes in the pyramidal tracts in the cervical region, which have been called the «snake eyes» in the literature, and the impact of this finding on the diagnosis and prognosis of the disease.}, } @article {pmid39435635, year = {2025}, author = {Yang, X and Gao, X and Jiang, X and Yue, K and Luo, P}, title = {Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3076-3094}, pmid = {39435635}, issn = {1673-5374}, abstract = {Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases. Owing to their therapeutic properties and ability to cross the blood-brain barrier, extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions, including ischemic stroke, traumatic brain injury, neurodegenerative diseases, glioma, and psychosis. However, the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body. To address these limitations, multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles, thereby enabling the delivery of therapeutic contents to specific tissues or cells. Therefore, this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles, exploring their applications in treating traumatic brain injury, ischemic stroke, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, glioma, and psychosis. Additionally, we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases. This review offers new insights for developing highly targeted therapies in this field.}, } @article {pmid39434139, year = {2024}, author = {Agah, E and Mojtabavi, H and Behkar, A and Heidari, A and Ajdari, A and Shaka, Z and Mousavi, SV and Firoozeh, N and Tafakhori, A and Rezaei, N}, title = {CSF and blood levels of Neurofilaments, T-Tau, P-Tau, and Abeta-42 in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of translational medicine}, volume = {22}, number = {1}, pages = {953}, pmid = {39434139}, issn = {1479-5876}, mesh = {Humans ; *Amyloid beta-Peptides/cerebrospinal fluid/blood ; *Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/diagnosis ; Biomarkers/blood/cerebrospinal fluid ; Neurofilament Proteins/blood/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid/blood ; Phosphorylation ; Publication Bias ; *tau Proteins/cerebrospinal fluid/blood ; }, abstract = {Recent literature suggests that markers of neuroaxonal damage, such as neurofilaments and tau protein, might serve as potential biomarkers for ALS. We conducted this systematic review and meta-analysis study to compare cerebrospinal fluid (CSF) and blood levels of total tau (t-tau), phosphorylated tau (p-tau), amyloid beta peptide 42 (Abeta-42), and neurofilaments in ALS patients and controls. A systematic search of Cochrane Library, PubMed, Embase, and ISI Web of Science was conducted on March 18, 2022, and updated on January 26, 2023. Observational studies that compared the concentrations of neurofilament light chain (NfL), neurofilament heavy chain (NFH), t-tau, p-tau, or Abeta-42 in CSF or peripheral blood of ALS patients and controls were included. Data from relevant studies were independently extracted and screened for quality using a standard tool, by at least two authors. Meta-analysis was conducted when a minimum of 3 studies reported the same biomarker within the same biofluid. A total of 100 studies were eligible for at least one meta-analysis. CSF and blood levels of NfL (standardized mean difference (SMD) [95% CI]; CSF: 1.46 [1.25-1.68]; blood: 1.35 [1.09-1.60]) and NFH (CSF: 1.32 [1.13-1.50], blood: 0.90 [0.58-1.22]) were significantly higher in ALS patients compared with controls. The pooled differences between ALS patients and controls were not significant for CSF t-tau, blood t-tau, and CSF Abeta-42, but CSF p-tau was lower in ALS patients (-0.27 [-0.47- -0.07]). Significantly decreased p-tau/t-tau ratios were found in ALS patients compared with controls (-0.84 [-1.16- -0.53]). Heterogeneity was considerable in most of our meta-analyses. CSF and blood neurofilament levels, as well as the CSF p-tau/t-tau ratio, might be potential candidates for improving ALS diagnosis. Further research is warranted to better understand the underlying mechanisms and the clinical implications of these biomarker alterations.}, } @article {pmid39434103, year = {2024}, author = {Sun, S and Chen, Y and Yun, Y and Zhao, B and Ren, Q and Sun, X and Meng, X and Yan, C and Lin, P and Liu, S}, title = {Elevated peripheral inflammation is associated with choroid plexus enlargement in independent sporadic amyotrophic lateral sclerosis cohorts.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {83}, pmid = {39434103}, issn = {2045-8118}, support = {qnts202306347//Taishan Young Scholar Program/ ; ZR2024MH178//Shandong Provincial Natural Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnostic imaging/pathology ; Male ; *Choroid Plexus/diagnostic imaging/pathology ; Female ; Middle Aged ; *Inflammation/blood/diagnostic imaging ; *Magnetic Resonance Imaging ; Cohort Studies ; Aged ; Adult ; }, abstract = {BACKGROUND: Using neuroimaging techniques, growing evidence has suggested that the choroid plexus (CP) volume is enlarged in multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Notably, the CP has been suggested to play an important role in inflammation-induced CNS damage under disease conditions. However, to our knowledge, no study has investigated the relationships between peripheral inflammation and CP volume in sporadic ALS patients. Thus, in this study, we aimed to verify CP enlargement and explore its association with peripheral inflammation in vivo in independent ALS cohorts.

METHODS: Based on structural MRI data, CP volume was measured using Gaussian mixture models and further manually corrected in two independent cohorts of sporadic ALS patients and healthy controls (HCs). Serum inflammatory protein levels were measured using a novel high-sensitivity Olink proximity extension assay (PEA) technique. Xtreme gradient boosting (XGBoost) was used to explore the contribution of peripheral inflammatory factors to CP enlargement. Then, partial correlation analyses were performed.

RESULTS: CP volumes were significantly higher in ALS patients than in HCs in the independent cohorts. Compared with HCs, serum levels of CRP, IL-6, CXCL10, and 35 other inflammatory factors were significantly increased in ALS patients. Using the XGBoost approach, we established a model-based importance of features, and the top three predictors of CP volume in ALS patients were CRP, IL-6, and CXCL10 (with gains of 0.24, 0.18, and 0.15, respectively). Correlation analyses revealed that CRP, IL-6, and CXCL10 were significantly associated with CP volume in ALS patients (r = 0.462 ∼ 0.636, p < 0.001).

CONCLUSION: Our study is the first to reveal a consistent and replicable contribution of peripheral inflammation to CP enlargement in vivo in sporadic ALS patients. Given that CP enlargement has been recently detected in other brain diseases, these findings should consider extending to other disease conditions with a peripheral inflammatory component.}, } @article {pmid39433597, year = {2024}, author = {Candrea, DN and Shah, S and Luo, S and Angrick, M and Rabbani, Q and Coogan, C and Milsap, GW and Nathan, KC and Wester, BA and Anderson, WS and Rosenblatt, KR and Uchil, A and Clawson, L and Maragakis, NJ and Vansteensel, MJ and Tenore, FV and Ramsey, NF and Fifer, MS and Crone, NE}, title = {A click-based electrocorticographic brain-computer interface enables long-term high-performance switch scan spelling.}, journal = {Communications medicine}, volume = {4}, number = {1}, pages = {207}, pmid = {39433597}, issn = {2730-664X}, support = {UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Brain-computer interfaces (BCIs) can restore communication for movement- and/or speech-impaired individuals by enabling neural control of computer typing applications. Single command click detectors provide a basic yet highly functional capability.

METHODS: We sought to test the performance and long-term stability of click decoding using a chronically implanted high density electrocorticographic (ECoG) BCI with coverage of the sensorimotor cortex in a human clinical trial participant (ClinicalTrials.gov, NCT03567213) with amyotrophic lateral sclerosis. We trained the participant's click detector using a small amount of training data (<44 min across 4 days) collected up to 21 days prior to BCI use, and then tested it over a period of 90 days without any retraining or updating.

RESULTS: Using a click detector to navigate a switch scanning speller interface, the study participant can maintain a median spelling rate of 10.2 characters per min. Though a transient reduction in signal power modulation can interrupt usage of a fixed model, a new click detector can achieve comparable performance despite being trained with even less data (<15 min, within 1 day).

CONCLUSIONS: These results demonstrate that a click detector can be trained with a small ECoG dataset while retaining robust performance for extended periods, providing functional text-based communication to BCI users.}, } @article {pmid39432543, year = {2024}, author = {Liu, X and Dong, L and Li, S and Li, Z and Wang, Y and Mao, Z and Deng, L}, title = {Improving AGB estimations by integrating tree height and crown radius from multisource remote sensing.}, journal = {PloS one}, volume = {19}, number = {10}, pages = {e0311642}, pmid = {39432543}, issn = {1932-6203}, mesh = {*Biomass ; *Trees/growth & development ; *Remote Sensing Technology/methods ; *Forests ; }, abstract = {Precise estimation of forest above ground biomass (AGB) is essential for assessing its ecological functions and determining forest carbon stocks. It is difficult to directly obtain diameter at breast height (DBH) based on remote sensing imagery. Therefore, it is crucial to accurately estimate the AGB with features extracted directly from RS. This paper demonstrates the feasibility of estimating AGB from crown radius (R) and tree height (H) features extracted from multi-source RS data. Accurate information on tree height (H), crown radius (R), and diameter at breast height (DBH) can be obtained through point clouds generated by airborne laser scanning (ALS) and terrestrial laser scanning (TLS), respectively. Nine allometric growth equations were used to fit coniferous forests (Larix principis-rupprechtii) and broadleaf forests (Fraxinus chinensis and Sophora japonica). The fitting performance of models constructed using only "H" or "R" was compared with that of models constructed using both combined. The results showed that the quadratic polynomial model constructed with "H+R" fitted the AGB estimation better in each vegetation type, especially in the scenario of mixed tall and short coniferous forests, in which the R2 and RMSE were 0.9282 and 25.30 kg (rRMSE 17.31%), respectively. Therefore, using high-resolution data to extract crown radius and tree height can achieve high-precision, global-scale estimation of forest above ground biomass.}, } @article {pmid39432435, year = {2024}, author = {Anjaneyulu, J and Godbole, A}, title = {Small organism models for mode of action research on anti-ageing and nootropic herbs, foods, and formulations.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/1028415X.2024.2409128}, pmid = {39432435}, issn = {1476-8305}, abstract = {With global increase in ageing population along with increasing age-related neurodegenerative diseases (NDs), development of sustainable, safe and effective solutions for promoting healthy ageing and preventing diseases has become a priority. Traditional healthcare systems/medicines prescribe several herbs, foods and formulations to promote healthy ageing and prevent and/or treat age-related diseases. However, the scientific data elucidating their mechanism of action is very limited and deeper research using different models is warranted for timely and wider use. The clinical studies and research with higher model organisms, although useful, have several practical, technical, and financial limitations. Conversely, small organism models like Yeast, Roundworm, Fruit fly, and Zebrafish, which have genetic similarities to humans, can replicate the disease features and provide behavioural, cellular and molecular insights. The common features of ageing and NDs, like amyloid protein aggregations, oxidative stress, energy dysregulation, inflammation and neurodegeneration can be mimicked in the small organism models for Alzheimer's, Parkinson's, Huntington's diseases, and Amyotrophic Lateral Sclerosis. This review focuses on small organism model- based research unveiling interesting modes of action and synergistic effects of herbal extracts, foods, and formulations, which are indicated especially for healthy ageing and management of NDs. This will provide leads for the quick and sustainable development of scientifically evaluated solutions for clinically relevant, age-related conditions.}, } @article {pmid39431591, year = {2024}, author = {Sheers, NL and Hannan, LM and Rautela, L and Graco, M and Jones, J and Retica, S and Saravanan, K and Burgess, N and McGaw, R and Donovan, A and Clohessy, T and Chao, C and Charles, C and Howard, ME and Berlowitz, DJ}, title = {NIV@Home: a pilot randomized controlled trial of in-home noninvasive ventilation initiation compared to a single-day admission model.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2416668}, pmid = {39431591}, issn = {2167-9223}, abstract = {Objective: Noninvasive ventilation (NIV) is the primary treatment for respiratory insufficiency in neuromuscular disease. NIV implementation is usually conducted within hospitals; however, in-home implementation with intensive follow-up is an effective alternative. This pilot study aimed to assess model feasibility, acceptability, and NIV usage at 12-weeks after a single visit in-home implementation of NIV with remote monitoring follow-up (NIV@Home) compared to an in-hospital day admission NIV initiation plus planned polysomnography (Usual care). Methods: A single-blinded randomized controlled trial (www.anzctr.org.au ACTRN12620000682943) of adults with neuromuscular disease referred for NIV implementation. Participants were stratified by disease (MND or Other diagnoses) and bulbar symptoms before randomization to NIV@Home or Usual care, with follow-up at 12-weeks. The primary outcome was NIV usage. Secondary outcomes included feasibility, health-related quality of life, symptoms, carer burden, and NIV experience (semi-structured qualitative interviews). Results: Twenty-three participants (MND bulbar = 9, MND non-bulbar = 11, Other = 3) were randomized (NIV@Home = 9). No statistical differences were observed in the percentage of MND participants using NIV for >4 hours/day (NIV@Home = 33% vs. Usual care = 60%, p = 0.370), average use (NIV@Home = 2.4 [1.5-9.3] vs. 5.3 [1.8-7.0] hours/day, p = 0.568), or secondary outcomes. In-home NIV implementation was feasible and safe but took more therapist time (NIV@Home = 278 [270-305] vs. 172 [130-200] minutes, p < 0.001). Participants in the NIV@Home group reported substantial advantages to receiving care in home. Conclusion: In-home NIV implementation is feasible and acceptable to people with MND but requires more therapist time. Larger studies are required to determine whether there are clinically important differences between this model of NIV initiation and a traditional hospital-based model.}, } @article {pmid39431590, year = {2024}, author = {Correa-Arrieta, C and Castellar-Leones, S and Forero Diaz, JJ and Peña-Preciado, M and Ortiz-Corredor, F}, title = {Slowly progressing Amyotrophic lateral sclerosis associated with the F21L variant in the SOD1 gene: Demographic and clinical characteristics.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2024.2416669}, pmid = {39431590}, issn = {2167-9223}, abstract = {INTRODUCTION/OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which genetic variants can significantly influence clinical presentation and prognosis. This study aims to describe the demographic and clinical characteristics of ALS patients carrying the SOD1: c.63C > G (p.Phe21Leu) [NM_000454.4] variant, as treated at a national reference center in Colombia.

METHODS: A descriptive study was conducted on patients identified with the SOD1: c.63C > G (p.Phe21Leu) [NM_000454.4] variant, selected from the database of a neuromuscular disease center in Colombia. Demographic and clinical data were collected through medical records and patient interviews. Molecular analysis was performed using PCR and automated sequencing to confirm the presence of the variant.

RESULTS: Eleven patients with SOD1: c.63C > G (p.Phe21Leu) [NM_000454.4] variant were identified. The mean age at onset was 48.4 years, with a mean disease duration of 76.7 months. The majority (90.9%) exhibited a slowly progressive course, predominantly with spinal onset and no cognitive impairment. Bulbar symptoms developed in 72.2% of the patients, and 81.8% required noninvasive ventilation. A family history of ALS or other neurodegenerative disorders was present in 54.5% of the patients.

CONCLUSIONS: The SOD1: c.63C > G (p.Phe21Leu) [NM_000454.4] variant is associated with a slowly progressive ALS phenotype, characterized by predominant lower motor neuron involvement and delayed onset of bulbar and respiratory symptoms. This variant appears to be predominantly distributed in central Colombia. Early detection of this variant may enable timely interventions and personalized care plans. Further research is required to establish a definitive causal relationship between this variant and the observed clinical course.}, } @article {pmid39428513, year = {2024}, author = {Shibasaki, N and Konishi, K and Nishiyama, Y and Miyagawa, T and Numayama, T}, title = {[A case of amyotrophic lateral sclerosis managed by tracheostomy and invasive ventilation in which air leaks occurred at the cuff].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {64}, number = {11}, pages = {789-793}, doi = {10.5692/clinicalneurol.cn-001990}, pmid = {39428513}, issn = {1882-0654}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/therapy ; Middle Aged ; *Tracheostomy ; *Respiration, Artificial ; Tomography, X-Ray Computed ; Trachea/diagnostic imaging ; Air ; Pressure ; Treatment Outcome ; }, abstract = {The patient was a 64-year-old woman who had been diagnosed with amyotrophic lateral sclerosis 8 years ago, and had been under artificial ventilation with tracheotomy for 6 years. Computed tomography indicated a dilated tracheal diameter of 29.6 ‍mm at the cuff, and a high cuff pressure of 80 ‍cmH2O. An adjustable flange tracheostomy tube with an optional length setting was used to extend the effective length by 28 ‍mm. A previously evident air leak disappeared with the change in cuff level, and cuff pressure decreased to 25 ‍cmH2O. X-ray images indicated a reduction in the size of the previous cuff area. Tracheal dilatation due to improper management of cuff pressure is a contributing factor to air leakage at the cuff area, and using an adjustable flange tracheostomy tube in an effort to resolve such air leaks is a valid option.}, } @article {pmid39428436, year = {2024}, author = {Assialioui, A and Marco-Pascual, C and Torrente-Segarra, V and Domínguez, R and Santos, N and Peñafiel, J and Juanola, X and Povedano, M and Ferrer, I}, title = {Microvascular abnormalities in skin capillaries of individuals with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {24648}, pmid = {39428436}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Middle Aged ; Male ; *Capillaries/pathology ; Female ; *Skin/blood supply/pathology ; Aged ; Microscopic Angioscopy ; Case-Control Studies ; Adult ; }, abstract = {This is the first study aimed to detect morphological abnormalities in vivo in the skin capillaries of amyotrophic lateral sclerosis patients (ALS). Videocapillaroscopy assessed subungueal capillaries in 28 ALS patients (cases) and 35 controls (p = 0.42). The mean age was 61.46 and 61.23 years, respectively (p > 0.99). No statistically significant differences were observed between the groups regarding dominant hand, arterial hypertension, dyslipidemia, diabetes mellitus, active smoker, and former smoker variables. 78.57% of cases had spinal onset and 21.43% bulbar. The median disease duration (time between the onset of symptoms and the date of videocapillarscopy) was 29.71 months. Dilated capillaries were detected in 17.8% of cases and 11.43% of controls (p = 0.49). The median of capillary diameter in cases was 10.15 µm and 8.72 µm in controls (p = 0.011). 35.71% of cases and 2.86% of controls had severe capillary tortuosities (p < 0.001). Ramified capillaries were observed in 46.43% of cases and 11.43% of controls (p < 0.002). Micro-hemorrhages were only observed in 10.71% of cases. No significant correlations were observed between disease duration and dilated capillaries, tortuosity, ramified capillaries, and micro-hemorrhages. The present in vivo study shows abnormalities in the skin capillaries of ALS patients that do not depend on disease duration.}, } @article {pmid39428248, year = {2024}, author = {Luo, N and Wang, J and Zhang, ZY and Zhao, XY and Huang, RR and Wu, QY}, title = {[Research progress on Pb-induced neurotoxicity through glial cells].}, journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]}, volume = {58}, number = {10}, pages = {1610-1615}, doi = {10.3760/cma.j.cn112150-20240513-00382}, pmid = {39428248}, issn = {0253-9624}, support = {8217348282, 82173554, 82101593//National Natural Science Foundation of China/ ; }, mesh = {*Neuroglia/drug effects ; Humans ; *Lead/toxicity ; }, abstract = {Lead is one of the most important occupational hazards in China, and occupational exposure is the leading cause of lead poisoning. Lead can be absorbed by the body through air, food, drinking water and skin, and accumulate in multiple organs in the body, posing health risks to humans, especially to lead workers. Many previous studies have shown that lead can affect the function of glial cells such as microglia, astrocytes and oligodendrocytes, resulting in irreversible neurological damage. This article provides an overview of the neurotoxic mechanism induced by lead through glial cells, elucidates that lead can induce neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, and reviews the relationship between lead and glial cells, in order to provide reference for further research on the neurotoxic mechanism of lead on glial cells.}, } @article {pmid39428001, year = {2025}, author = {Simoes, FA and Christoforidou, E and Cassel, R and Dupuis, L and Hafezparast, M}, title = {Severe dynein dysfunction in cholinergic neurons exacerbates ALS-like phenotypes in a new mouse model.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1871}, number = {1}, pages = {167540}, doi = {10.1016/j.bbadis.2024.167540}, pmid = {39428001}, issn = {1879-260X}, mesh = {Animals ; *Disease Models, Animal ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Phenotype ; *Cholinergic Neurons/metabolism/pathology ; Cytoplasmic Dyneins/metabolism/genetics ; Neuromuscular Junction/metabolism/pathology ; DNA-Binding Proteins/genetics/metabolism ; Mice, Knockout ; Male ; Dyneins/metabolism/genetics ; Point Mutation ; }, abstract = {Cytoplasmic dynein 1, a motor protein essential for retrograde axonal transport, is increasingly implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). In this study, we developed a novel mouse model that combines the Legs at odd angles (Loa, F580Y) point mutation in the dynein heavy chain with a cholinergic neuron-specific knockout of the dynein heavy chain. This model, for the first time, allows us to investigate the impact of Loa allele exclusivity in these neurons into adulthood. Our findings reveal that this selective increase in dynein dysfunction exacerbated the phenotypes observed in heterozygous Loa mice including pre-wean survival, reduced body weight and grip strength. Additionally, it induced ALS-like pathology in neuromuscular junctions (NMJs) not seen in heterozygous Loa mice. Notably, we also found a previously unobserved significant increase in neurons displaying TDP-43 puncta in both Loa mutants, suggesting early TDP-43 mislocalisation - a hallmark of ALS. The novel model also exhibited a concurrent rise in p62 puncta that did not co-localise with TDP-43, indicating broader impairments in autophagic clearance mechanisms. Overall, this new model underscores the fact that dynein impairment alone can induce ALS-like pathology and provides a valuable platform to further explore the role of dynein in ALS.}, } @article {pmid39427550, year = {2024}, author = {Pan, Y and Sun, X and Tian, Y and Yu, M and Luo, Y and Sun, X}, title = {L-NRB alleviates amyotrophic lateral sclerosis by regulating P11-Htr4 signaling pathway.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {180}, number = {}, pages = {117588}, doi = {10.1016/j.biopha.2024.117588}, pmid = {39427550}, issn = {1950-6007}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; *Signal Transduction/drug effects ; Mice ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice, Transgenic ; Male ; Benzofurans/pharmacology/therapeutic use ; Disease Models, Animal ; Motor Neurons/drug effects/pathology/metabolism ; Apoptosis/drug effects ; Mice, Inbred C57BL ; }, abstract = {INTRODUCTION: L-NRB is a compound formed as a ring cleavage product of butylphthalide and borneol in a molar ratio 1:2. This study aimed to explore the therapeutic effect of L-NRB on amyotrophic lateral sclerosis (ALS) and its possible mechanism.

METHODS: SOD1-G93A mice were used as an ALS model. Behavioral tests, histopathological staining, Nissl staining, immunohistochemistry, enzyme-linked immunosorbent assays, and Western blotting were used to analyze the therapeutic effect. The underlying mechanism of L-NRB in treating ALS was investigated using transcriptomic analyses.

RESULTS: It was found that L-NRB alleviated motor dysfunction, pathological changes in the gastrocnemius muscle, and motor neuron injuries. The results indicated that L-NRB had a neuroprotective function associated with the inhibition of neuroinflammation. The anti-apoptotic effect of L-NRB was found to be related to the regulation of the P11-Htr4 signaling pathway.

CONCLUSION: In summary, the results demonstrated the therapeutic effect of L-NRB on ALS and suggest a promising new therapeutic candidate for ALS.}, } @article {pmid39426615, year = {2024}, author = {Mackness, BC and Morgan, BR and Deveau, LM and Kathuria, SV and Zitzewitz, JA and Massi, F}, title = {A Hydrophobic Core Stabilizes the Residual Structure in the RRM2 Intermediate State of the ALS-linked Protein TDP-43.}, journal = {Journal of molecular biology}, volume = {436}, number = {22}, pages = {168823}, doi = {10.1016/j.jmb.2024.168823}, pmid = {39426615}, issn = {1089-8638}, support = {P41 GM103622/GM/NIGMS NIH HHS/United States ; R01 GM137529/GM/NIGMS NIH HHS/United States ; }, mesh = {*Protein Folding ; *DNA-Binding Proteins/chemistry/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Hydrophobic and Hydrophilic Interactions ; *Molecular Dynamics Simulation ; Protein Structure, Secondary ; Protein Stability ; RNA Recognition Motif/genetics ; Protein Conformation ; Models, Molecular ; }, abstract = {Folding intermediates mediate both protein folding and the misfolding and aggregation observed in human diseases, including amyotrophic lateral sclerosis (ALS), and are prime targets for therapeutic interventions. In this study, we identified the core nucleus of structure for a folding intermediate in the second RNA recognition motif (RRM2) of the ALS-linked RNA-binding protein, TDP-43 (TAR DNA-binding protein-43), using a combination of experimental and computational approaches. Urea equilibrium unfolding studies revealed that the RRM2 intermediate state consists of collapsed residual secondary structure localized to the N-terminal half of RRM2, while the C-terminus is largely disordered. Steered molecular dynamics simulations and mutagenesis studies yielded key stabilizing hydrophobic contacts that, when mutated to alanine, severely disrupt the overall fold of RRM2. In combination, these findings suggest a role for this RRM intermediate in normal TDP-43 function as well as serving as a template for misfolding and aggregation through the low stability and non-native secondary structure.}, } @article {pmid39425598, year = {2024}, author = {Zhang, L and Zhou, X and Cha, S}, title = {Comprehensive Analysis of Sex Differences in Amyotrophic Lateral Sclerosis Prognosis and Disease Progression.}, journal = {Annals of neurology}, volume = {96}, number = {5}, pages = {1028}, doi = {10.1002/ana.27092}, pmid = {39425598}, issn = {1531-8249}, } @article {pmid39425590, year = {2025}, author = {Zhu, L and Li, Y and Yu, X and Chen, Y and Zhang, J and Pang, C and Xie, J and Gao, L and Du, L and Cao, W and Fan, D and Cui, C and Yu, H and Deng, B}, title = {Fighting Amyotrophic Lateral Sclerosis by Protecting the Liver? A Prospective Cohort Study.}, journal = {Annals of neurology}, volume = {97}, number = {2}, pages = {270-280}, doi = {10.1002/ana.27115}, pmid = {39425590}, issn = {1531-8249}, support = {12101460//National Natural Science Foundation of China/ ; 81901273//National Natural Science Foundation of China/ ; ZCLY24H0903//Natural Science Foundation of Zhejiang Province/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnostic imaging ; Female ; Male ; Middle Aged ; Aged ; Prospective Studies ; Magnetic Resonance Imaging ; Liver Diseases/epidemiology ; Adult ; Risk Factors ; Cohort Studies ; Liver/diagnostic imaging/pathology ; }, abstract = {BACKGROUND: Previous studies have observed liver abnormalities in amyotrophic lateral sclerosis (ALS) patients. This study aimed to investigate whether early signs of liver disease, measured by magnetic resonance imaging-derived iron-corrected T1-mapping (cT1), are risk factors for developing ALS.

METHODS: cT1 and proton density fat fraction were measured and automatically analyzed using LiverMultiScan® software. The Fibrosis-4 index was calculated using an established formula based on age and blood markers. Cox proportional hazard models were used to examine the relationship between liver disease, liver biomarkers, and incident ALS.

RESULTS: In a cohort of 533,707 individuals from UK Biobank, 24 ALS cases were identified among 28,328 participants with liver disease during the follow-up period. Among a total of 33,959 individuals with complete liver imaging data, 15 incident ALS cases were observed during a median follow-up period of 5.6 years. Individuals with liver disease had a higher risk of developing ALS, with an adjusted hazard ratio of 7.35 (95% CI 4.47-12.09; p < 0.001). An increase in cT1 was also associated with a higher risk of ALS. After adjusting for age, sex, Townsend deprivation index, smoking status, alcohol intake frequency, body mass index, proton density fat fraction, Fibrosis-4, and metabolic syndrome, an increase in cT1 remained significantly associated with a higher risk of ALS, with an adjusted hazard ratio of 3.15 (95% CI 1.79-5.55) per 1-SD increase. Sensitivity analyses confirmed these robust results.

INTERPRETATION: Liver disease activity, indicated by cT1, increases the risk of developing ALS, independent of metabolic syndrome, liver fat, or fibrosis. ANN NEUROL 2025;97:270-280.}, } @article {pmid39424779, year = {2024}, author = {Wu, H and Wang, LC and Sow, BM and Leow, D and Zhu, J and Gallo, KM and Wilsbach, K and Gupta, R and Ostrow, LW and Yeo, CJJ and Sobota, RM and Li, R}, title = {TDP43 aggregation at ER-exit sites impairs ER-to-Golgi transport.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9026}, pmid = {39424779}, issn = {2041-1723}, support = {A-0007081-00-00//Ministry of Education - Singapore (MOE)/ ; NRF-MSG-2023-0001//National Research Foundation Singapore (National Research Foundation-Prime Minister's office, Republic of Singapore)/ ; NRF-SIS "SingMass"//A*STAR | Singapore Institute of Manufacturing Technology (Singapore Institute of Manufacturing Technology - A STAR)/ ; }, mesh = {Humans ; *Golgi Apparatus/metabolism ; *Endoplasmic Reticulum/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Protein Transport ; Protein Aggregates ; Motor Neurons/metabolism ; HeLa Cells ; HEK293 Cells ; }, abstract = {Protein aggregation plays key roles in age-related degenerative diseases, but how different proteins coalesce to form inclusions that vary in composition, morphology, molecular dynamics and confer physiological consequences is poorly understood. Here we employ a general reporter based on mutant Hsp104 to identify proteins forming aggregates in human cells under common proteotoxic stress. We identify over 300 proteins that form different inclusions containing subsets of aggregating proteins. In particular, TDP43, implicated in Amyotrophic Lateral Sclerosis (ALS), partitions dynamically between two distinct types of aggregates: stress granule and a previously unknown non-dynamic (solid-like) inclusion at the ER exit sites (ERES). TDP43-ERES co-aggregation is induced by diverse proteotoxic stresses and observed in the motor neurons of ALS patients. Such aggregation causes retention of secretory cargos at ERES and therefore delays ER-to-Golgi transport, providing a link between TDP43 aggregation and compromised cellular function in ALS patients.}, } @article {pmid39424648, year = {2024}, author = {Chartier, C and Godard, J and Durand, S and Humeau-Heurtier, A and Menetrier, E and Allain, P and Besnard, J}, title = {Combinations of physical and cognitive training for subcortical neurodegenerative diseases with physical, cognitive and behavioral symptoms: a systematic review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {12}, pages = {5571-5589}, pmid = {39424648}, issn = {1590-3478}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Behavioral Symptoms/therapy/etiology ; Cognitive Behavioral Therapy/methods ; Exercise Therapy/methods ; Cognitive Dysfunction/therapy/rehabilitation/etiology ; Cognitive Training ; }, abstract = {BACKGROUND: The onset of the symptoms of subcortical NDs is due to a unique part of the brain which strengthens the idea of reciprocal influence of physical activity and cognitive training in improving clinical symptoms. Consequently, protocols combining the two stimulations are becoming increasingly popular in NDs. Our threefold aim was to (A) describe the different combinations of physical and cognitive training used to alleviate the motor and cognitive symptoms of patients with subcortical neurodegenerative disorders, (B) compare the effects of these different combinations (sequential, dual tasking, synergical) on symptoms, and (C) recommend approaches for further studies.

METHODS: We conducted literature searches of PubMed, BASE and ACM, to carry out a systematic review of randomized controlled trials and controlled trials of combined physical and cognitive training among patients with Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, Lewy body dementia, spinocerebellar ataxia, Friedreich's ataxia, and progressive supranuclear palsy. Physical, neuropsychological, behavioral outcomes were considered. The Cochrane risk-of-bias tool was used to verify the critical appraisal.

RESULTS: Twenty-one studies focused on Parkinson's disease with 940 participants were included. Despites promising benefits on cognitive and physical function, our results revealed discrepant findings for research on combined training.

DISCUSSION: Inconsistencies were linked to the choice of tests, the functions that were targeted, disease progression, and trainings. There was a dearth of follow-up data.

CONCLUSIONS: Differences between combined training are unclear, particularly regarding the role of cognitive load. Future studies should focus on comparing the feasibility, tolerability, and effectiveness of different combinations of motor-cognitive training.}, } @article {pmid39424561, year = {2024}, author = {Crow, YJ}, title = {CNS disease associated with enhanced type I interferon signalling.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1158-1168}, pmid = {39424561}, issn = {1474-4465}, support = {786142/ERC_/European Research Council/International ; MC_UU_00035/11/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Interferon Type I/metabolism/immunology ; *Signal Transduction ; Animals ; Central Nervous System Diseases/immunology/metabolism ; }, abstract = {The ability to mount an interferon-mediated innate immune response is essential in protection against neurotropic viruses, but antiviral type I interferons also have neurotoxic potential. The production of type I interferons can be triggered by self-derived nucleic acids, and the brain can be susceptible to inappropriate upregulation of type I interferon signalling. Homoeostatic dysregulation of type I interferons has been implicated in rare inborn errors of immunity (referred to as type I interferonopathies) and more common neurodegenerative disorders (eg, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis). Recent developments include new insights into the pathogenesis of these disorders that involve dysregulated type I interferon signalling, as well as advances in their diagnosis and management. The role of type I interferons in brain cellular health suggests the future therapeutic potential of approaches that target these interferons and their signalling.}, } @article {pmid39424560, year = {2024}, author = {Koch, JC and Leha, A and Bidner, H and Cordts, I and Dorst, J and Günther, R and Zeller, D and Braun, N and Metelmann, M and Corcia, P and De La Cruz, E and Weydt, P and Meyer, T and Großkreutz, J and Soriani, MH and Attarian, S and Weishaupt, JH and Weyen, U and Kuttler, J and Zurek, G and Rogers, ML and Feneberg, E and Deschauer, M and Neuwirth, C and Wuu, J and Ludolph, AC and Schmidt, J and Remane, Y and Camu, W and Friede, T and Benatar, M and Weber, M and Lingor, P and , }, title = {Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1133-1146}, doi = {10.1016/S1474-4422(24)00373-9}, pmid = {39424560}, issn = {1474-4465}, mesh = {Humans ; *1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives/therapeutic use/pharmacology/adverse effects ; Middle Aged ; Male ; Double-Blind Method ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy ; Aged ; Adult ; *rho-Associated Kinases/antagonists & inhibitors ; *Protein Kinase Inhibitors/adverse effects/therapeutic use/administration & dosage ; Treatment Outcome ; Aged, 80 and over ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis.

METHODS: ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18-80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6-24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed.

FINDINGS: Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1·00 (95% CI 0·91 to 1·00) with placebo, 1·00 (0·89 to 1·00) with fasudil 30 mg, and 1·00 (0·90 to 1·00) with fasudil 60 mg; the difference in proportions was 0·00 (95% CI -0·11 to 0·10; p>0·99) for fasudil 30 mg versus placebo and 0·00 (-0·10 to 0·10; p>0·99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0·93 (95% CI 0·81 to 0·99) with placebo, 1·00 (0·90 to 1·00) with fasudil 30 mg, and 0·90 (0·76 to 0·97) with fasudil 60 mg; the difference in proportions was 0·07 (95% CI -0·05 to 0·20; p=0·25) for fasudil 30 mg versus placebo, and -0·03 (-0·18 to 0·10; p=0·70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group.

INTERPRETATION: Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug.

FUNDING: Framework of the E-Rare Joint Transnational Call 2016 "Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases".}, } @article {pmid39424548, year = {2024}, author = {Andrews, JA}, title = {A new era of drug discovery for amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1070-1072}, doi = {10.1016/S1474-4422(24)00407-1}, pmid = {39424548}, issn = {1474-4465}, } @article {pmid39424348, year = {2025}, author = {Yoganathan, S and Kumar, M and Aaron, R and Rangan, SR and Umakant, BS and Thomas, M and Oommen, SP and Danda, S}, title = {Phenotype and Genotype of Children with ALS2 gene-Related Disorder.}, journal = {Neuropediatrics}, volume = {56}, number = {1}, pages = {20-28}, doi = {10.1055/s-0044-1791256}, pmid = {39424348}, issn = {1439-1899}, mesh = {Humans ; *Phenotype ; *Guanine Nucleotide Exchange Factors/genetics ; Male ; Female ; *Genotype ; Child ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Child, Preschool ; Adolescent ; Pedigree ; Mutation ; Spastic Paraplegia, Hereditary ; }, abstract = {INTRODUCTION: The Alsin Rho Guanine Nucleotide Exchange Factor (ALS2) gene encodes a protein alsin that functions as a guanine nucleotide exchange factor. The variations in ALS2 gene leads to degeneration of upper motor neurons of the corticospinal tract. The phenotypes resulting from variants in ALS2 gene are infantile-onset ascending hereditary spastic paralysis (IAHSP, OMIM # 607225), juvenile primary lateral sclerosis (JPLS, OMIM # 606353), and juvenile amyotrophic lateral sclerosis (JALS, OMIM # 205100). Our study objectives were to describe the clinical phenotype and genotype of children with an established diagnosis of ALS2 gene-related disorder.

METHODS: The clinical details, laboratory data, and genotype findings of children with an established diagnosis of ALS2 gene-related disorder were collected from the hospital electronic database after obtaining institutional review board approval.

RESULTS: One family with three affected siblings, a second family with a proband and an affected fetus, and a third family with two affected siblings with ALS2 gene variants were identified. IAHSP was diagnosed in all of our patients with variants in ALS2 gene. The clinical findings observed in our patients were insidious onset progressive spastic paraparesis, contractures, and dysarthria. Nonsense variants were observed in four patients while frameshift variant was observed in one family. Novel variants in ALS2 gene were identified in two unrelated families.

CONCLUSION: ALS2 mutation results in rare neurodegenerative disorders with the clinical spectrum encompassing IAHSP, JPLS, and JALS disorders. In view of allelic heterogeneity described in the literature, more research studies are needed for establishing genotype-phenotype correlation in patients with ALS2 gene-related disorder.}, } @article {pmid39423873, year = {2024}, author = {Thapa, R and Moglad, E and Afzal, M and Gupta, G and Bhat, AA and Hassan Almalki, W and Kazmi, I and Alzarea, SI and Pant, K and Singh, TG and Singh, SK and Ali, H}, title = {The role of sirtuin 1 in ageing and neurodegenerative disease: A molecular perspective.}, journal = {Ageing research reviews}, volume = {102}, number = {}, pages = {102545}, doi = {10.1016/j.arr.2024.102545}, pmid = {39423873}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Sirtuin 1/metabolism ; *Aging/metabolism/genetics ; Animals ; Oxidative Stress/physiology ; }, abstract = {Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, has emerged as a key regulator of cellular processes linked to ageing and neurodegeneration. SIRT1 modulates various signalling pathways, including those involved in autophagy, oxidative stress, and mitochondrial function, which are critical in the pathogenesis of neurodegenerative diseases. This review explores the therapeutic potential of SIRT1 in several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Preclinical studies have demonstrated that SIRT1 activators, such as resveratrol, SRT1720, and SRT2104, can alleviate disease symptoms by reducing oxidative stress, enhancing autophagic flux, and promoting neuronal survival. Ongoing clinical trials are evaluating the efficacy of these SIRT1 activators, providing hope for future therapeutic strategies targeting SIRT1 in neurodegenerative diseases. This review explores the role of SIRT1 in ageing and neurodegenerative diseases, with a particular focus on its molecular mechanisms, therapeutic potential, and clinical applications.}, } @article {pmid39422938, year = {2024}, author = {Pappolla, MA and Wu, P and Fang, X and Poeggeler, B and Sambamurti, K and Wisniewski, T and Perry, G}, title = {Stem Cell Interventions in Neurology: From Bench to Bedside.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {101}, number = {s1}, pages = {S395-S416}, doi = {10.3233/JAD-230897}, pmid = {39422938}, issn = {1875-8908}, mesh = {Humans ; Animals ; *Stem Cell Transplantation/methods/trends ; Nervous System Diseases/therapy ; Neurology/trends/methods ; Translational Research, Biomedical/trends ; Neural Stem Cells/transplantation ; }, abstract = {Stem cell therapies are progressively redefining the treatment landscape for a spectrum of neurological and age-related disorders. This review discusses the molecular and functional attributes of stem cells, emphasizing the roles of neural stem cells and mesenchymal stem cells in the context of neurological diseases such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, Parkinson's disease, and Alzheimer's disease. The review also explores the potential of stem cells in addressing the aging process. The paper analyzes stem cells' intrinsic properties of self-renewal, differentiation, and paracrine effects, alongside the importance of laboratory-modified stem cells like induced pluripotent stem cells and transgenic stem cells. Insights into disease-specific stem cell treatments are offered, reviewing both successes and challenges in the field. This includes the translational difficulties from rodent studies to human trials. The review concludes by acknowledging the uncharted territories that warrant further investigation, emphasizing the potential roles of stem cell-derived exosomes and indole-related molecules, and aiming at providing a basic understanding of stem cell therapies.}, } @article {pmid39420987, year = {2024}, author = {Sun, H and Tang, Q and Yan, X and Xie, W and Xu, Y and Zhang, W}, title = {Cathepsins and neurological diseases: a Mendelian randomization study.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1454369}, pmid = {39420987}, issn = {1662-4548}, abstract = {BACKGROUND: The causal relationship between cathepsins and neurological diseases remains uncertain. To address this, we utilized a two-sample Mendelian randomization (MR) approach to assess the potential causal effect of cathepsins on the development of neurological diseases.

METHODS: This study conducted a two-sample two-way MR study using pooled data from published genome-wide association studies to evaluate the relationship between 10 cathepsins (B, D, E, F, G, H, L2, O, S, and Z) and 7 neurological diseases, which included ischemic stroke, cerebral hemorrhage, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and epilepsy. The analysis employed various methods such as inverse variance weighting (IVW), weighted median, MR Egger regression, MR pleiotropy residual sum and outlier, Cochran Q statistic, and leave-one-out analysis.

RESULTS: We found a causal relationship between cathepsins and neurological diseases, including Cathepsin B and Parkinson's disease (IVW odds ratio (OR): 0.89, 95% confidence interval (CI): 0.83, 0.95, p = 0.001); Cathepsin D and Parkinson's disease (OR: 0.80, 95%CI: 0.68, 0.95, p = 0.012); Cathepsin E and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.09, p = 0.015); Cathepsin O and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.10, p = 0.021). Reverse MR analyses revealed that multiple sclerosis and Cathepsin E (OR: 1.05, 95%CI: 1.01, 1.10, p = 0.030). There is currently no significant relationship has been found between other cathepsins and neurological diseases.

CONCLUSION: Our study reveals a causal relationship between Cathepsins B, D, E, and O and neurological diseases, offering valuable insights for research aimed at improving the diagnosis and treatment of such conditions.}, } @article {pmid39419765, year = {2024}, author = {Johns, AE and Taga, A and Charalampopoulou, A and Gross, SK and Rust, K and McCray, BA and Sullivan, JM and Maragakis, NJ}, title = {Exploring P2X7 receptor antagonism as a therapeutic target for neuroprotection in an hiPSC motor neuron model.}, journal = {Stem cells translational medicine}, volume = {13}, number = {12}, pages = {1198-1212}, pmid = {39419765}, issn = {2157-6580}, mesh = {Humans ; *Motor Neurons/metabolism/drug effects ; *Receptors, Purinergic P2X7/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Purinergic P2X Receptor Antagonists/pharmacology ; Animals ; Adenosine Triphosphate/metabolism ; Neuroprotection/drug effects ; Mice ; Rats ; }, abstract = {ATP is present in negligible concentrations in the interstitium of healthy tissues but accumulates to significantly higher concentrations in an inflammatory microenvironment. ATP binds to 2 categories of purine receptors on the surface of cells, the ionotropic P2X receptors and metabotropic P2Y receptors. Included in the family of ionotropic purine receptors is P2X7 (P2X7R), a non-specific cation channel with unique functional and structural properties that suggest it has distinct roles in pathological conditions marked by increased extracellular ATP. The role of P2X7R has previously been explored in microglia and astrocytes within the context of neuroinflammation, however the presence of P2X7R on human motor neurons and its potential role in neurodegenerative diseases has not been the focus of the current literature. We leveraged the use of human iPSC-derived spinal motor neurons (hiPSC-MN) as well as human and rodent tissue to demonstrate the expression of P2X7R on motor neurons. We extend this observation to demonstrate that these receptors are functionally active on hiPSC-MN and that ATP can directly induce death via P2X7R activation in a dose dependent manner. Finally, using a highly specific P2X7R blocker, we demonstrate how modulation of P2X7R activation on motor neurons is neuroprotective and could provide a unique pharmacologic target for ATP-induced MN death that is distinct from the role of ATP as a modulator of neuroinflammation.}, } @article {pmid39419433, year = {2025}, author = {Majumder, P and Hsu, TI and Hu, CJ and Huang, JK and Lee, YC and Hsieh, YC and Ahsan, A and Huang, CC}, title = {Potential role of solid lipid curcumin particle (SLCP) as estrogen replacement therapy in mitigating TDP-43-related neuropathy in the mouse model of ALS disease.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {114999}, doi = {10.1016/j.expneurol.2024.114999}, pmid = {39419433}, issn = {1090-2430}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Mice ; Female ; *Disease Models, Animal ; Male ; *DNA-Binding Proteins/metabolism/genetics ; *Estrogen Replacement Therapy/methods ; *Curcumin/pharmacology/administration & dosage/therapeutic use ; Mice, Transgenic ; Aromatase/metabolism ; Estradiol/pharmacology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) was first identified in 1869, but it wasn't until the 2014 Ice Bucket Challenge that widespread attention was drawn to the disease. Since then, substantial research has been dedicated to developing treatments for ALS. Despite this, only three drugs - riluzole, edaravone and AMX0035, have been approved for clinical use, and they can only temporarily alleviate mild symptoms without significant disease modification or cure. Therefore, there remains a critical unmet need to identify disease modifying or curative therapies for ALS. The higher incidence and more severe progression of ALS and FTLD (frontotemporal lobar degeneration) observed in men and postmenopausal woman compared to young women suggests that sex hormones may significantly influence disease onset and progression. In both animal models and human clinical studies, 17β estradiol (E2) has been shown to delay and improve the outcomes of many neurodegenerative diseases. Here, we examined the role of TDP-43 in the regulation of estrogen-related enzymes, CYP19A1 and CYP3A4. In addition, we examined the impact of curcumin on the regulation of estrogen E2 levels and TDP-43-associated neuropathy as a potential therapeutic strategy for the treatment of FTLD and ALS.

METHODS: Prp-TDP-43[A315T] mice was used as a model of ALS/FTLD to examine the expression patterns of E2 and its biosynthesis and degradation enzymes, CYP19A1 and CYP3A4. Moreover, the molecular mechanisms and the potency of solid lipid curcumin particles (SLCP) as an E2 replacement therapy for TDP-43 associated neuropathy was analyzed. We further examined the survival rates and the pathological TDP43 patterns in female and male Prp-TDP-43[A315T] mice administrated with or without SLCP. In addition, the changed expression levels of enzymes corresponding to E2 biosynthesis and degradation in the spinal cord of female and male Prp-TDP-43[A315T] mice with or without SLCP were determined.

RESULTS: We found that in addition to E2, the expression patterns of CYP19A1 and CYP3A4 proteins differed between Prp-TDP-43[A315T] mice compared to wild-type control, suggesting that toxic phosphorylated TDP43 oligomers may disrupt the balance between CYP19A1 and CYP3A4 expression, leading to reduced estrogen biosynthesis and accelerated degradation. In addition, we found that oral administration of SLCP prolonged the survival rates in female Prp-TDP-43[A315T] mice and significantly reduced the pathological insoluble phosphorylated TDP-43 species. Furthermore, SLCP attenuated disease progression associated with TDP-43-related neuropathies through modulating estrogen biosynthesis and the activity of CYP450 enzymes.

CONCLUSIONS: Our results showed that Prp-TDP-43[A315T] mice exhibit altered estradiol levels. Moreover, we demonstrated the efficacy of SLCP as an estrogen replacement therapy in mitigating TDP-43-associated disease progression and pathogenesis. These findings suggest that SLCP could be a promising strategy to induce E2 expression for the treatment of ALS and FTLD.}, } @article {pmid39419034, year = {2025}, author = {Wijegunawardana, D and Nayak, A and Vishal, SS and Venkatesh, N and Gopal, PP}, title = {Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43 ribonucleoprotein condensates disrupting mRNA transport and local translation in neurons.}, journal = {Developmental cell}, volume = {60}, number = {2}, pages = {253-269.e5}, doi = {10.1016/j.devcel.2024.09.023}, pmid = {39419034}, issn = {1878-1551}, mesh = {Animals ; *Ataxin-2/metabolism/genetics ; *Peptides/metabolism/genetics ; *RNA, Messenger/genetics/metabolism ; Mice ; *DNA-Binding Proteins/metabolism/genetics ; *Motor Neurons/metabolism ; Protein Biosynthesis ; Neurons/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Rats ; Ribonucleoproteins/metabolism/genetics ; Axons/metabolism ; RNA Transport ; Humans ; }, abstract = {Altered RNA metabolism and misregulation of transactive response DNA-binding protein of 43 kDa (TDP-43), an essential RNA-binding protein (RBP), define amyotrophic lateral sclerosis (ALS). Intermediate-length polyglutamine (polyQ) expansions of Ataxin-2, a like-Sm (LSm) RBP, are associated with increased risk for ALS, but the underlying biological mechanisms remain unknown. Here, we studied the spatiotemporal dynamics and mRNA regulatory functions of TDP-43 and Ataxin-2 ribonucleoprotein (RNP) condensates in rodent (rat) primary cortical neurons and mouse motor neuron axons in vivo. We report that Ataxin-2 polyQ expansions aberrantly sequester TDP-43 within RNP condensates and disrupt both its motility along the axon and liquid-like properties. We provide evidence that Ataxin-2 governs motility and translation of neuronal RNP condensates and that Ataxin-2 polyQ expansions fundamentally perturb spatial localization of mRNA and suppress local translation. Overall, our results support a model in which Ataxin-2 polyQ expansions disrupt stability, localization, and/or translation of critical axonal and cytoskeletal mRNAs, particularly important for motor neuron integrity.}, } @article {pmid39418491, year = {2025}, author = {Kumar, R and Ghai, S and Finelli, A and Klotz, L and Kinnaird, A and Mannas, M and Bhindi, B and Sanchez-Salas, R and Anidjar, M and Ahmad, A and Chin, J and Inman, B and Perlis, N}, title = {The use of focal therapy for the treatment of prostate cancer in Canada Where are we, how did we get here, and where are we going?.}, journal = {Canadian Urological Association journal = Journal de l'Association des urologues du Canada}, volume = {19}, number = {2}, pages = {63-72}, pmid = {39418491}, issn = {1911-6470}, abstract = {INTRODUCTION: Focal therapy is an emerging treatment for localized prostate cancer (PCa). The objectives of this review were to: 1) review how focal therapies are regulated and approved; 2) summarize the scope and quality of the literature regarding safety, efficacy, and side-effects; and 3) outline ongoing clinical trials of focal therapy in Canada.

METHODS: Using the PRISMA framework for scoping reviews, we searched PubMed, Embase, and Cochrane from 2021-2024, complementing Hopstaken et al's search up to 2020. We focused on studies reporting functional and oncologic outcomes. Additionally, we examined the FDA database for regulatory details and ongoing trials in Canada via ClinicalTrials.gov.

RESULTS: FDA approval for prostate tissue ablation was granted to high-intensity focused ultrasound (HIFU) in 2015 via the de novo pathway; other therapies followed the 510(k) route, citing equivalence to predicate devices. Most studies are in early stages, primarily single-arm, prospective cohort designs. Oncologic outcomes like cancer detection and survival rates, alongside functional data, such as adverse events and erectile function, were assessed. Recurrence-free survival at 48 months ranged from 58-92%, pad-free rates were greater than 95%, and rates of new-onset erectile dysfunction were variable, ranging from no change to 50%. Rates of serious adverse events were low, ranging from 0-14%. Three Canadian clinical trials are actively enrolling participants, and five private clinics were found offering private HIFU, irreversible electroporation, or transurethral ultrasound ablation.

CONCLUSIONS: Focal therapy technologies have gained regulatory approval for prostate tissue ablation, and aside from provincial support for cryoablation in Alberta, are available to Canadians through private payment or clinical trials. Many studies demonstrate promising cancer control and impressive functional outcomes but are limited by their short followup and lack of comparator group. Clinical trial or registry participation should be prioritized to ensure an evidence-based integration into current prostate cancer treatment approaches.}, } @article {pmid39416141, year = {2024}, author = {Winkelsas, A and Apfel, A and Johnson, B and Harmison, G and Li, D and Cheung, V and Grunseich, C}, title = {Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39416141}, issn = {2692-8205}, support = {R21 ES034919/ES/NIEHS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis 4 (ALS4) is an autosomal dominant motor neuron disease that is molecularly characterized by reduced R-loop levels and caused by pathogenic variants in senataxin (SETX). SETX encodes an RNA/DNA helicase that resolves three-stranded nucleic acid structures called R-loops. Currently, there are no disease-modifying therapies available for ALS4. Given that SETX is haplosufficient, removing the product of the mutated allele presents a potential therapeutic strategy. We designed a series of siRNAs to selectively target the RNA transcript from the ALS4 allele containing the c.1166T>C mutation (p.Leu389Ser). Transfection of HEK293 cells with siRNA and plasmids encoding either wild-type or mutant (Leu389Ser) epitope tagged SETX revealed that three siRNAs specifically reduced mutant SETX protein levels without affecting the wild-type SETX protein. In ALS4 primary fibroblasts, siRNA treatment silenced the endogenous mutant SETX allele, while sparing the wild-type allele, and restored R-loop levels in patient cells. Our findings demonstrate that mutant SETX, differing from wild-type by a single nucleotide, can be effectively and specifically silenced by RNA interference, highlighting the potential of allele-specific siRNA as a therapeutic approach for ALS4.}, } @article {pmid39416104, year = {2024}, author = {Gunner, G and Basu, H and Lu, Y and Bergstresser, M and Neel, D and Choi, SY and Chiu, IM}, title = {Gasdermin D is activated but does not drive neurodegeneration in SOD1 [G93A] model of ALS: Implications for targeting pyroptosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.10.10.617609}, pmid = {39416104}, issn = {2692-8205}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, microgliosis, and neuroinflammation. While pyroptosis, an inflammatory form of programmed cell death, has been implicated in ALS, the specific role of Gasdermin D (GSDMD) - the primary executioner of pyroptosis - remains unexplored. In this study, we examined the function of GSDMD in the well-established SOD1 [G93A] mouse model of ALS. Our results showed robust GSDMD activation in the spinal cords of SOD1 [G93A] animals across two strain backgrounds, with elevated expression in Iba1+ microglia. To explore its role in disease progression, we bred B6.SOD1 [G93A] mice onto a GSDMD - deficient background. In comparing SOD1 [G93A] ; Gsdmd +/+ and SOD1 [G93A] ; Gsdmd -/- mice, we found that Gsdmd loss did not affect disease onset, weight loss, or grip strength decline in either male or female animals. Notably, GSDMD deficiency resulted in a modest but statistically significant increase in mortality in SOD1 [G93A] mice. Moreover, GSDMD absence had minimal impact on astrogliosis, microgliosis and motor neuron loss. These findings show that while GSDMD is activated in the ALS mouse model, its loss does not mitigate key ALS behavioral phenotypes, gliosis or motor neuron loss. This study provides insights into the potential therapeutic relevance of targeting pyroptosis and inflammatory pathways in ALS.}, } @article {pmid39415649, year = {2024}, author = {Kim, Y and O, JH and Cho, H and Ye, S}, title = {Recognized cases of amyotrophic lateral sclerosis in automobile workers by the Korean Epidemiologic Investigation Evaluation Committee.}, journal = {Annals of occupational and environmental medicine}, volume = {36}, number = {}, pages = {e28}, pmid = {39415649}, issn = {2052-4374}, abstract = {BACKGROUND: Three automobile company workers (one from Factory D and two from Factory E) were diagnosed with amyotrophic lateral sclerosis. The Korean Epidemiologic Investigation and Evaluation Committee determined that there is considerable scientific evidence supporting the association between amyotrophic lateral sclerosis and combined exposure to heavy metals, organic solvents, and diesel exhaust at the manufacturing plant.

CASE PRESENTATION: Patient A, who primarily engaged in engine processing and completed vehicle inspection at Factory D, was exposed to considerable amounts of heavy metals and organic solvents during medium- and large-engine processing, welding, and painting for over 23 years. Additionally, the patient was likely exposed to diesel exhaust for 33 years from forklifts delivering engines in the workshop. Patients B and C, who were responsible for engine assembly, ignition testing, and engine shipment at Factory E since around 1990, were exposed to lead and benzene from gasoline during engine ignition tests in the engine department for 15 and 16 years, respectively. They also encountered welding fumes, heavy metals, and organic solvents during welding and painting tasks. In addition, Patients B and C were continuously exposed to diesel exhaust from logistics vehicles on standby during work hours for 25 and 30 years, respectively.

CONCLUSIONS: Although the specific level of lead exposure causing amyotrophic lateral sclerosis remains undetermined, numerous studies have consistently reported a relationship between lead exposure and disease development. Limited evidence suggests that exposure to organic solvents and diesel exhaust may increase the risk of amyotrophic lateral sclerosis. Therefore, the Epidemiological Investigation and Evaluation Committee concluded that the three patients' work-related exposure to heavy metals, organic solvents, and diesel exhaust is significantly supported by scientific evidence as a cause of their amyotrophic lateral sclerosis.}, } @article {pmid39415277, year = {2024}, author = {Abdelnaby, R and Shabib, AS and El Din Moawad, MH and Salem, T and Wagih Youssef Awad, M and Awad, PD and Maallem, I and Atwan, H and Rabie, SA and Mohamed, KA and Abdelmageed, H and Karkour, AM and Elsayed, M and Cartwright, MS}, title = {Nerve ultrasound in amyotrophic lateral sclerosis: systematic review and meta-analysis.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {47}, pmid = {39415277}, issn = {2524-3489}, abstract = {BACKGROUND/ AIM: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons, causing progressive atrophy of muscles, hypertonia, and paralysis. This study aimed to evaluate the current evidence and effectiveness of ultrasound in investigating nerve cross-sectional area (CSA) of peripheral nerves, vagus and cervical roots in those with ALS compared with healthy controls and to pool the CSA measurements.

METHODS: A systematic search was conducted on Cochrane, Clarivate Web of Science, PubMed, Scopus, and Embase for the mesh terms nerve, ultrasonography, and amyotrophic lateral sclerosis. A quality assessment was performed using the New-Ottawa scale. In addition, a double-arm meta-analysis using Review Manager 5 software version 5.4 was performed.

RESULTS: From the seventeen studies included in this review, the overall mean difference showed that individuals with ALS had a significantly smaller CSA in comparison to healthy controls for median, ulnar, C6 root, and phrenic nerves. However, no significant difference in the CSA was found in radial, vagal, sural, and tibial nerves.

DISCUSSION: This study confirmed results of some of the included studies regards the anatomic sites, where nerve atrophy in ALS could be detected to potentially support the diagnosis of ALS. However, we recommend further large, prospective studies to assess the diagnostic value of these anatomical sites for the diagnosis of ALS.

CONCLUSIONS: Our findings confirmed specific anatomic sites to differentiate ALS patients from healthy controls through ultrasound. However, these findings cannot be used to confirm the ALS diagnosis, but rather assist in differentiating it from other diagnoses.

TRIAL REGISTRATION: Retrospectively registered on July 30th 2024 in PROSPERO (PROSPERO (york.ac.uk)) with ID574702.}, } @article {pmid39414899, year = {2024}, author = {Kawata, S and Seki, S and Nishiura, A and Kitaoka, Y and Iwamori, K and Fukada, SI and Kogo, M and Tanaka, S}, title = {Preservation of masseter muscle until the end stage in the SOD1G93A mouse model for ALS.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {24279}, pmid = {39414899}, issn = {2045-2322}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics ; *Masseter Muscle/pathology ; *Disease Models, Animal ; Mice ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Satellite Cells, Skeletal Muscle/pathology/metabolism ; Motor Neurons/pathology/metabolism ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) progressively impairs motor neurons, leading to muscle weakness and loss of voluntary muscle control. This study compared the effects of SOD1 mutation on masticatory and limb muscles from disease onset to death in ALS model mice. Notably, limb muscles begin to atrophy soon after ALS-like phenotype appear, whereas masticatory muscles maintain their volume and function in later stages. Our analysis showed that, unlike limb muscles, masticatory muscles retain their normal structure and cell makeup throughout most of the disease course. We found an increase in the number of muscle satellite cells (SCs), which are essential for muscle repair, in masticatory muscles. In addition, we observed no reduction in the number of muscle nuclei and no muscle fibre-type switching in masticatory muscles. This indicates that masticatory muscles have a higher resistance to ALS-related damage than limb muscles, likely because of differences in cell composition and repair mechanisms. Understanding why masticatory muscles are less affected by ALS could lead to the development of new treatments. This study highlights the importance of studying different muscle groups in ALS to clarify disease aetiology and mechanisms.}, } @article {pmid39413009, year = {2024}, author = {Ralbovsky, NM and Zhang, Y and Williams, DM and McKelvey, CA and Smith, JP}, title = {Machine Learning and Hyperspectral Imaging for Analysis of Human Papillomaviruses (HPV) Vaccine Self-Healing Particles.}, journal = {Analytical chemistry}, volume = {96}, number = {43}, pages = {17118-17127}, doi = {10.1021/acs.analchem.4c02327}, pmid = {39413009}, issn = {1520-6882}, mesh = {*Papillomavirus Vaccines/immunology ; *Machine Learning ; Humans ; Vaccines, Virus-Like Particle ; Human Papillomavirus Viruses ; }, abstract = {Human papillomaviruses (HPV) are known to cause a variety of diseases, including cervical cancer and genital warts. HPV is a highly prevalent virus and is considered the most common sexually transmitted disease. Because of the risks associated with HPV, Gardasil, a quadrivalent recombinant vaccine, was developed by Merck & Co., Inc., Rahway, NJ, USA, and approved by the Food and Drug Administration (FDA) in 2006. The second generation of the vaccine, Gardasil9, was subsequently approved by the FDA in 2014, providing significant protection against HPV. The HPV vaccine may be given as 2 or 3 doses; however, vaccine administration as a single dose with a sustained release mechanism may potentially offer benefits to meet emerging health needs. To explore this, HPV vaccines were formulated within microporous self-healing particles (SHPs) to enable potential controlled release of HPV virus-like particle (VLP) antigen. Machine learning, in the form of multivariate curve resolution-alternating least-squares (MCR-ALS), with Raman hyperspectral imaging was used to determine the molecular identity and spatial distribution of all relevant species within this HPV vaccine formulation. The results indicate that machine learning with Raman hyperspectral imaging was able to spatially resolve HPV VLP antigens within SHP vaccines for the first time, providing crucial information necessary for vaccine development.}, } @article {pmid39412921, year = {2024}, author = {Bahador, M and Soltaninejad, S and Mobasheri, M}, title = {Correlation of new two-dimensional geometrical parameters to lung and heart dose-volume parameters in breast cancer radiation therapy.}, journal = {Journal of cancer research and therapeutics}, volume = {20}, number = {5}, pages = {1570-1577}, doi = {10.4103/jcrt.jcrt_2351_23}, pmid = {39412921}, issn = {1998-4138}, mesh = {Humans ; Female ; *Heart/radiation effects/diagnostic imaging ; *Radiotherapy Dosage ; *Radiotherapy Planning, Computer-Assisted/methods ; *Lung/radiation effects/diagnostic imaging/pathology ; *Breast Neoplasms/radiotherapy/pathology ; *Organs at Risk/radiation effects ; Tomography, X-Ray Computed/methods ; ROC Curve ; Middle Aged ; }, abstract = {OBJECTIVE: To develop new two-dimensional geometric parameters for pulmonary and cardiac dose estimation in left-sided breast cancer radiation therapy without dose-volume histogram (DVH).

METHODS: On the CT image of 90 patients with left breast cancer, treatment planning was performed using two opposed tangent fields with/without supraclavicular. The field-in-field technique and 6MV photons were used. From DVH dosimetric parameters of mean dose, Vx (x (Gy) =5, 10, 15, 20, 30, 40, 50) were calculated, and from heart and lung outlines on the beam's eye view, new geometric parameters of percent of lung area in tangent and supraclavicular fields (%area of the lung in the tangent (ALT), %ALS) and percent of heart in tangent field (%area of the heart in the tangent (AHT)) were measured. Correlation, regression, and diagnostic performance by receiver operating characteristic curve (ROC) were investigated for statistical analysis.

RESULTS: The Pearson coefficient between %ALT and Vx (x = 10, 15, 20, 30, 40) show strong correlation in patient treatment with only opposed tangents (>0.85) and weaker in treatment by opposed tangents with supraclavicular (0.56-0.88), the %ALS indicate weak correlation (<0.5) and %AHT show strong correlation (0.93-0.98). The regression analysis shows a positive relation between %ALT and mean dose (R2 = 0.8), V20Gy (R2 = 0.9) in the lung (tangent treatment), and between %AHT and mean dose (R2 = 0.9), V20Gy (R2 = 1.0) in the heart. The ROC analysis shows by %ALT <20.3 for treatment by just opposed fields, %ALT <22.1% for treatment tangents with supra, and %AHT <11.6%, practical lung and heart dose constraints are addressed.

CONCLUSION: The proposed geometric parameters could replace previous one-dimensional maximum and central distances for predicting doses to lung and heart.

ADVANCES IN KNOWLEDGE: This study presents simple geometric parameters that could estimate pulmonary and cardiac dose in left breast cancer treatment from a 2D radiograph.}, } @article {pmid39412565, year = {2024}, author = {Sangari, S and Lackmy-Vallee, A and Preuilh, A and Peyre, I and Pradat, PF and Marchand-Pauvert, V}, title = {Synaptic dynamics linked to widespread elevation of H-reflex before peripheral denervation in amyotrophic lateral sclerosis.}, journal = {Journal of neurophysiology}, volume = {132}, number = {5}, pages = {1541-1560}, doi = {10.1152/jn.00144.2024}, pmid = {39412565}, issn = {1522-1598}, support = {VMarchand/2013//ARSLA/ ; DdT1 2015- 2; CTL/SS/2016-0029/no 16597//AFM-Telethon/ ; FTL AAP7/2015//Fondation Thierry Latran (Thierry Latran Foundation)/ ; }, mesh = {Humans ; *H-Reflex/physiology ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Evoked Potentials, Motor/physiology ; *Muscle, Skeletal/physiopathology/physiology ; Aged ; Adult ; Excitatory Postsynaptic Potentials/physiology ; Riluzole/pharmacology ; Motor Neurons/physiology ; }, abstract = {Changes in Hoffmann reflex (H-reflex) exhibit heterogeneity among patients with amyotrophic lateral sclerosis (ALS), likely due to phenotype diversity. Current knowledge primarily focuses on soleus H-reflex, which may demonstrate an initial increase before subsequent decline throughout the disease course. The main objective was to investigate other muscles, to determine whether H-reflex changes could be associated with patient phenotype (onset site, functional disabilities). Additional experiments were performed to elucidate the neurophysiological mechanisms underlying H-reflex modifications. In age- and sex-matched groups of control subjects and patients, we compared H-reflex recruitment curves in soleus, quadriceps, and forearm flexors. Additionally, we examined H-reflex and motor evoked potential (MEP) recruitment curves in quadriceps. Last, to assess potential changes in monosynaptic excitatory postsynaptic potentials (EPSPs) of both peripheral and cortical origins, we analyzed peristimulus time histograms (PSTHs) and peristimulus frequencygrams (PSFs) of single motor units, along with H-reflex occurrence after paired-pulse stimuli. The ratio between maximal amplitudes of H-reflex and direct motor response increased in all muscles, irrespective of disease onset, and was found positively correlated with exaggerated osteotendinous reflexes and spasticity but depressed in patients on riluzole. This finding was accompanied by a reduction in MEP size and no changes in PSTH, PSF, and paired-pulse H-reflex probability. It is speculated that spinal interneurons may compensate for potential depression of monosynaptic EPSPs in ALS. From a clinical perspective, although the added value of H-reflex to osteotendinous reflex evaluation may be limited, it can serve as a valuable quantitative biomarker of pyramidal dysfunction in clinical trials.NEW & NOTEWORTHY Without significant evidence of peripheral denervation, H-reflex enhancement appears to be a widespread phenomenon, regardless of disease onset site. This increase is likely associated with a decrease in inhibitory control over presynaptic transmission of the synapse between muscle group Ia afferents and motoneurons. Although the link to exaggerated osteotendinous reflexes and spasticity implies a restricted role in identifying a pyramidal syndrome, its quantitative aspect positions the H-reflex as a valuable biomarker in clinical trials.}, } @article {pmid39412227, year = {2024}, author = {Mascías Cadavid, J and Radakovic, R and Radakovic, C and Moran Benito, Y and Marín Esteban, S and Rodríguez-Santos, F and Salas Campos, T}, title = {Spanish adaptation of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2024.2416665}, pmid = {39412227}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized functional decline, traditionally measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). The Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) is an alternative comprehensive, detailed functional disability measure for people with ALS (pwALS), not yet translated to Spanish. The aim of this study was to translate and validate the Spanish ROADS. 53 Spanish speaking pwALS were recruited. They completed the ALSFRS-R and Spanish ROADS. Reliability (internal consistency, intra-class correlation) and validity (ALSFRS-R total and item-total correlations) were determined. The Spanish ROADS internal consistency reliability was excellent (Cronbach's standardized alpha = 0.94), the test-retest reliability intra-class correlation value was 0.93. There was a strong significant correlation between the Spanish ROADS and ALSFRS-R totals (rs(52) = .89, p < .001). Additionally, the ALSFRS-R subscales and ROADS items correlations showed domain-to-item specific expected significant correlations. The Spanish ROADS is a psychometrically robust, valid and reliable measure for quantifying functional disability for pwALS.}, } @article {pmid39411168, year = {2024}, author = {An, D and Han, J and Fang, P and Bu, Y and Ji, G and Liu, M and Deng, J and Song, X}, title = {Evidence for the potential role of m6A modification in regulating autophagy in models of amyotrophic lateral sclerosis.}, journal = {CytoJournal}, volume = {21}, number = {}, pages = {33}, pmid = {39411168}, issn = {0974-5963}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. Research indicates that N6-methyladenosine (m6A) modification plays a crucial role in cellular autophagy during ALS development. This study investigates the role of autophagy in ALS, with a focus on the effect of messenger ribonucleic acid m6A methylation modification on disease progression.

MATERIAL AND METHODS: We compared m6A levels and regulatory molecule expressions in transgenic superoxide dismutase (SOD1)-G93A and non-transgenic mice, categorized into end-stage and control groups, using quantitative polymerase chain reaction and Western blotting. The NSC-34 cell line, which was modified to model ALS, enabled the investigation of apoptosis, autophagy, and autophagy disruption through terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assays, Western blotting, and fluorescent staining.

RESULTS: Our findings indicate significantly elevated m6A methylation levels in ALS mice (0.262 ± 0.005) compared with the controls (0.231 ± 0.003) and in the ALS model cells (0.242±0.005) relative to those belonging to the wild-type control group (0.183 ± 0.007). Furthermore, the proteins involved in m6A RNA modification differed between groups, which suggest impaired autophagy flux in the ALS models.

CONCLUSION: These results suggest that m6A methylation may accelerate ALS progression through the disruption of autophagic processes. Our study underscores the role of m6A methylation in the pathology of ALS and proposes the targeting of m6A methylation as a potential therapeutic strategy for disease treatment. Although this study primarily used transgenic SOD1-G93A mice and NSC-34 cell models to investigate ALS pathology, potential differences in disease mechanisms between animal models and humans must be considered. Although a correlation was detected between m6A methylation levels and autophagy disruption in ALS, the study primarily established an association rather than provided detailed mechanistic insights.}, } @article {pmid39410995, year = {2024}, author = {Zaninotto, AL and Makary, MM and Rowe, HP and Eshghi, M and Tseng, CJ and Chan, J and Zürcher, NR and Hooker, J and Lewis, A and Keegan, M and Gifford, RF and Green, JR and Babu, S}, title = {Speech motor impairment in ALS is associated with multiregional cortical thinning beyond primary motor cortex.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1451177}, pmid = {39410995}, issn = {1664-2295}, abstract = {INTRODUCTION: Cortical thinning is well-documented in individuals with amyotrophic lateral sclerosis (ALS), yet its association with speech deterioration remains understudied. This study characterizes anatomical changes in the brain within the context of speech impairment patterns in individuals with ALS, providing insight into the disease's multiregional spread and biology.

METHODS: To evaluate patterns of cortical thickness in speakers with ALS with and without functional speech changes compared to healthy controls (HCs) using whole-brain and region of interest (ROI) analyses. Forty individuals with ALS and 22 HCs underwent a T1-weighted 3-Tesla magnetic resonance imaging (MRI). Individuals with ALS were divided into two groups based on the preserved speech [ps-ALS] (n = 18) or deteriorated speech [ds-ALS] (n = 22) as measured by the ALSFRSF-R speech subscore (=4 or <4 points, respectively). Sixteen a priori-defined and automatically segmented cortical and subcortical brain ROIs were selected based on their previously documented roles in speech production. Two cortical thickness analyses were performed: (1) group-level whole-brain surface-based analyses and (2) group-level ROI analyses. A case study of 6 ALS individuals examined the cortical thickness, and their speech was characterized using quantitative and qualitative measures.

RESULTS: Based on the group-level whole-brain surface-based analyses, the ds-ALS group demonstrated significant cortical thinning compared to HCs in the left primary motor and somatosensory cortices and the right inferior parietal lobe with its adjacent lateral occipital cortical regions. The ps-ALS group demonstrated no significant cortical thinning compared to HCs. Based on the group-level ROI analyses, the ds-ALS group demonstrated significant cortical thinning compared to HCs in bilateral middle motor cortices, right posterior dorsal premotor cortex, and left anterior cingulate cortex. The case study analysis revealed that ALS speakers with speech features characteristic of spastic dysarthria exhibited cortical thinning, while those with speech features characteristic of flaccid dysarthria did not.

DISCUSSION: Individuals with ALS have anatomical changes involving multiregional neocortical areas beyond the primary motor cortex that may manifest as subjective (i.e., clinical judgment) and objective (i.e., speaking rate) changes in speech production. Further longitudinal work in ALS is needed to better understand the link between MRI cortical thickness changes and bulbar dysfunction.}, } @article {pmid39408720, year = {2024}, author = {Du, X and Dong, Q and Zhu, J and Li, L and Yu, X and Liu, R}, title = {Rutin Ameliorates ALS Pathology by Reducing SOD1 Aggregation and Neuroinflammation in an SOD1-G93A Mouse Model.}, journal = {International journal of molecular sciences}, volume = {25}, number = {19}, pages = {}, pmid = {39408720}, issn = {1422-0067}, support = {XDB39050600//Strategic Priority Research Program of Chinese Academy of Sciences/ ; 82150107//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Rutin/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; Mice ; *Superoxide Dismutase-1/metabolism/genetics ; *Disease Models, Animal ; *Mice, Transgenic ; *Spinal Cord/drug effects/metabolism/pathology ; Motor Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/pharmacology/therapeutic use ; Neuroinflammatory Diseases/drug therapy/metabolism ; Humans ; Protein Aggregation, Pathological/drug therapy/metabolism ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of motor neurons, with limited effective treatments. Recently, the exploration of natural products has unveiled their potential in exerting neuroprotective effects, offering a promising avenue for ALS therapy. In this study, the therapeutic effects of rutin, a natural flavonoid glycoside with neuroprotective properties, were evaluated in a superoxide dismutase 1 (SOD1)-G93A mouse model of ALS. We showed that rutin reduced the level of SOD1 aggregation and diminished glial cell activation in spinal cords and brainstems, resulting in significantly improved motor function and motor neuron restoration in SOD1-G93A mice. Our findings indicated that rutin's multi-targeted approach to SOD1-related pathology makes it a promising candidate for the treatment of ALS.}, } @article {pmid39408173, year = {2024}, author = {Rolling, J and Fath, M and Zanfonato, T and Durpoix, A and Mengin, AC and Schröder, CM}, title = {EMDR-Teens-cPTSD: Efficacy of Eye Movement Desensitization and Reprocessing in Adolescents with Complex PTSD Secondary to Childhood Abuse: A Case Series.}, journal = {Healthcare (Basel, Switzerland)}, volume = {12}, number = {19}, pages = {}, pmid = {39408173}, issn = {2227-9032}, abstract = {Background: Mental healthcare for children and adolescents with a history of childhood abuse constitutes a major public health issue. Indeed, abuse exposes children to severe and complex post-traumatic stress disorder (cPTSD) but also to neurodevelopmental and psychological repercussions impacting the developmental trajectory. Trauma-focused care is essential to avoid the chronicization of symptoms and disorders. Objective: The aim of this prospective case series study was to investigate the efficacy of eye movement desensitization and reprocessing (EMDR) on complex post-traumatic symptoms and associated psychiatric disorders in adolescents with a history of abuse. Method: Twenty-two adolescents, aged 12 to 17, who had been abused during childhood were included. All adolescents met ICD-11 criteria for complex PTSD. Subjective measures of PTSD and associated psychiatric disorders were taken before (T0) and after 3 months of EMDR therapy (T1). Results: The average PTSD symptom score on the CPTS-RI significantly decreased from 40.2 to 34.4 after EMDR, indicating improvement in post-traumatic symptoms. A significant decrease in the average depression score (CDI from 18.2 at T0 to 10.6 at T1), anxiety score (R-CMAS from 21.3 at T0 to 13.3 at T1), emotional regulation score (ALS from 29 at T0 to 10.8 at T1), insomnia score (ISI from 18.5 at T0 to T1 of 9.2 at T1), and harmful use of alcohol and drugs score (ADOSPA from 2.3 at T0 to 0.3 at T1) was observed after EMDR therapy, as well as an increase in quality of life (CBCL 4-16 score from 57.9 at T0 to 77.4 at T1). Conclusions: The results of this study are encouraging and suggest that EMDR may be effective in the symptom management reducing post-traumatic symptoms and certain comorbid disorders frequently seen in adolescents who have experienced childhood abuse. Further research is needed on adolescent populations suffering from cPTSD (e.g., randomized controlled trials with control groups and other therapies or evaluating the action of the different phases of the study).}, } @article {pmid39407861, year = {2024}, author = {Proaño, B and Cuerda-Ballester, M and Daroqui-Pajares, N and Del Moral-López, N and Seguí-Sala, F and Martí-Serer, L and Calisaya Zambrana, CK and Benlloch, M and de la Rubia Ortí, JE}, title = {Clinical and Sociodemographic Factors Related to Amyotrophic Lateral Sclerosis in Spain: A Pilot Study.}, journal = {Journal of clinical medicine}, volume = {13}, number = {19}, pages = {}, pmid = {39407861}, issn = {2077-0383}, support = {2021-203-003//Catholic University of Valencia San Vicente Mártir/ ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknow etiology. Male sex is a well stablished risk factor, but other factors such as early and adult life expositions show contradictory evidence. Aim: to explore the link of clinical, sociodemographic, and occupational factors with ALS patients in Spain and the impact of these factors in functionality. Methods: A cross-sectional study was conducted with ALS patients and healthy controls. Registered variables were smoking, arterial hypertension, diabetes mellitus type 2, previous cancer to reproductive organs or breast, occupational exposure, and early life exposures. Functionality in ALS patients was compared according to each exposure. Results: The ALS group consisted of 59 participants and the control group of 90 participants. ALS patients showed a significant association with previous cancer (p = 0.011), occupational exposure (p < 0.001), and older siblings (p = 0.029). ALS patients presented significant differences in BMI according to hypertension and older-sibling factors. Moreover, respiratory function was affected in patients with previous cancer (p = 0.031). Conclusions: Occupational exposure and previous cancer to reproductive organs or breast could be linked to ALS patients. In addition, hypertension and previous cancer could affect their BMI and respiratory function. Other factors such as longer smoking periods and exposition to older siblings could also characterize ALS patients.}, } @article {pmid39407580, year = {2024}, author = {Forleo, T and Giannossa, LC and De Juan Capdevila, A and Lagioia, G and Mangone, A}, title = {Hats Off to Modeling! Profiling Early Synthetic Dyes on Historic Woolen Samples with ATR-FTIR Spectroscopy and Multivariate Curve Resolution-Alternating Least Square Algorithm.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {19}, pages = {}, pmid = {39407580}, issn = {1420-3049}, abstract = {This research focuses on analyzing wool samples dyed with synthetic dyes from the early 20th century. A methodology to identify and distinguish wool fibers dyed with azo, triphenylmethane, and xanthene dyes, which are no longer in use, using the ATR-FTIR spectra, is presented. Firstly, the dataset was subjected to PCA, which revealed the similarities and differences among the samples, illustrating a distribution pattern based on dye classes. MCR-ALS was employed to extract the spectral profiles of the dyed fibers, thereby enhancing the efficacy of the analytical techniques and extracting the comprehensive information from a single instrument. The combination of ATR-FTIR spectroscopy with chemometric methods, such as PCA and MCR-ALS, has proven to be an effective strategy for identifying and differentiating wool fibers dyed with early azo, triphenylmethane, and xanthene dyes. This approach has demonstrated particular effectiveness in enabling rapid analysis without requiring sampling or pretreatment. Moreover, the analysis is supported by thorough bibliographic research on these no longer used colorants. In order to maximize the potential of non-destructive spectroscopic techniques, such as ATR-FTIR, the approach used has proven to be crucial. This study underscores how chemometric techniques expand the capabilities of spectroscopy, extracting extensive information from a single instrument and aligning with the goals of cultural heritage analysis.}, } @article {pmid39406675, year = {2025}, author = {Schilfarth, P and Réginault, T and Mathis, S and Le Masson, G and Pillet, O and Grassion, L}, title = {Changes in Non-invasive Ventilation Compliance in Patients With Amyotrophic Lateral Sclerosis: A Post-hoc Analysis.}, journal = {Archivos de bronconeumologia}, volume = {61}, number = {1}, pages = {47-49}, doi = {10.1016/j.arbres.2024.09.003}, pmid = {39406675}, issn = {1579-2129}, } @article {pmid39406341, year = {2024}, author = {López-Royo, T and Moreno-Martínez, L and Zaragoza, P and García-Redondo, A and Manzano, R and Osta, R}, title = {Differentially expressed lncRNAs in SOD1[G93A] mice skeletal muscle: H19, Myhas and Neat1 as potential biomarkers in amyotrophic lateral sclerosis.}, journal = {Open biology}, volume = {14}, number = {10}, pages = {240015}, pmid = {39406341}, issn = {2046-2441}, support = {//Gobierno de Aragón/ ; //Instituto de Salud Carlos III/ ; //European Union/ ; //Gobierno de España/ ; //Center for Biomedical Research/ ; }, mesh = {*RNA, Long Noncoding/genetics/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Muscle, Skeletal/metabolism/pathology ; *Mice, Transgenic ; *Disease Models, Animal ; *Biomarkers/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Humans ; Gene Expression Regulation ; Gene Expression Profiling ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterized by progressive motor function and muscle mass loss. Despite extensive research in the field, the underlying causes of ALS remain incompletely understood, contributing to the absence of specific diagnostic and prognostic biomarkers and effective therapies. This study investigates the expression of long-non-coding RNAs (lncRNAs) in skeletal muscle as a potential source of biomarkers and therapeutic targets for the disease. The expression profiles of 12 lncRNAs, selected from the literature, were evaluated across different disease stages in tissue and muscle biopsies from the SOD1[G93A] transgenic mouse model of ALS. Nine out of the 12 lncRNAs were differentially expressed, with Pvt1, H19 and Neat1 showing notable increases in the symptomatic stages of the disease, and suggesting their potential as candidate biomarkers to support diagnosis and key players in muscle pathophysiology in ALS. Furthermore, the progression of Myhas and H19 RNA levels across disease stages correlated with longevity in the SOD1[G93A] animal model, effectively discriminating between long- and short-term survival individuals, thereby highlighting their potential as prognostic indicators. These findings underscore the involvement of lncRNAs, especially H19 and Myhas, in ALS pathophysiology, offering novel insights for diagnostic, prognostic and therapeutic targets.}, } @article {pmid39406000, year = {2024}, author = {Zhang, L and Du, Y and Deng, Y and Bai, T and Wang, J and Wang, W and Ji, M}, title = {Mutations in target gene confers resistance to acetolactate synthase inhibitors in Echinochloa phyllopogon.}, journal = {Plant physiology and biochemistry : PPB}, volume = {216}, number = {}, pages = {109194}, doi = {10.1016/j.plaphy.2024.109194}, pmid = {39406000}, issn = {1873-2690}, mesh = {*Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Echinochloa/genetics/drug effects/enzymology ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Mutation ; *Plant Proteins/genetics/metabolism ; Plants, Genetically Modified ; Enzyme Inhibitors/pharmacology ; Arabidopsis/genetics/enzymology/drug effects ; Molecular Docking Simulation ; Sulfonamides ; Uridine/analogs & derivatives ; }, abstract = {Echinochloa phyllopogon is a noxious weed that can harm rice over prolonged periods. Recently, a penoxsulam-resistant variant of E. phyllopogon with a mutation in the acetolactate synthase (ALS) gene was collected in Northeastern China. In the present study, the molecular mechanism underlying herbicide resistance in mutant populations was evaluated. The GR50 and IC50 values of the herbicide-resistant mutant 1-11 were 27.0- and 21.4-fold higher than those of the susceptible population 2-31, respectively. In addition, pre-application of malathion reduced the GR50 value of the resistant population. Additionally, mutant populations developed cross-resistance to other ALS inhibitors. E. phyllopogon ALS sequencing showed a Trp-574-Leu mutation in ALS2 variant 1-11. Molecular docking showed that the Trp-574-Leu substitution reduced the number of hydrogen bonds and altered the interaction between penoxsulam and ALS2. Transgenic Arabidopsis plants harboring the ALS2 mutant gene also showed resistance to penoxsulam and other ALS inhibitors. Overall, our study demonstrated that the Trp-574-Leu mutation and P450-mediated metabolic resistance lead to the cross-resistance of E. phyllopogon to ALS inhibitors.}, } @article {pmid39405005, year = {2024}, author = {Cheng, JL and Cook, AL and Talbot, J and Perry, S}, title = {How is Excitotoxicity Being Modelled in iPSC-Derived Neurons?.}, journal = {Neurotoxicity research}, volume = {42}, number = {5}, pages = {43}, pmid = {39405005}, issn = {1476-3524}, mesh = {*Induced Pluripotent Stem Cells/drug effects/physiology ; Humans ; *Neurons/drug effects/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Cell Differentiation/drug effects/physiology ; }, abstract = {Excitotoxicity linked either to environmental causes (pesticide and cyanotoxin exposure), excitatory neurotransmitter imbalance, or to intrinsic neuronal hyperexcitability, is a pathological mechanism central to neurodegeneration in amyotrophic lateral sclerosis (ALS). Investigation of excitotoxic mechanisms using in vitro and in vivo animal models has been central to understanding ALS mechanisms of disease. In particular, advances in induced pluripotent stem cell (iPSC) technologies now provide human cell-based models that are readily amenable to environmental and network-based excitotoxic manipulations. The cell-type specific differentiation of iPSC, combined with approaches to modelling excitotoxicity that include editing of disease-associated gene variants, chemogenetics, and environmental risk-associated exposures make iPSC primed to examine gene-environment interactions and disease-associated excitotoxic mechanisms. Critical to this is knowledge of which neurotransmitter receptor subunits are expressed by iPSC-derived neuronal cultures being studied, how their activity responds to antagonists and agonists of these receptors, and how to interpret data derived from multi-parameter electrophysiological recordings. This review explores how iPSC-based studies have contributed to our understanding of ALS-linked excitotoxicity and highlights novel approaches to inducing excitotoxicity in iPSC-derived neurons to further our understanding of its pathological pathways.}, } @article {pmid39404920, year = {2025}, author = {Aiello, EN and Curti, B and Torre, S and De Luca, G and Maranzano, A and Colombo, E and Gendarini, C and Cocuzza, A and Messina, S and Doretti, A and Verde, F and Morelli, C and Silani, V and Ticozzi, N and Poletti, B}, title = {Clinical usefulness of the Verbal Fluency Index (VFI) in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {2}, pages = {775-782}, pmid = {39404920}, issn = {1590-3478}, support = {NA//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/complications/psychology ; Male ; Female ; Middle Aged ; Aged ; *Neuropsychological Tests/standards ; Verbal Behavior/physiology ; Executive Function/physiology ; Italy ; Speech Disorders/etiology/diagnosis/physiopathology ; }, abstract = {BACKGROUND: This study aimed at assessing the clinical utility of the Verbal Fluency Index (VFI) over a classical phonemic verbal fluency test in Italian-speaking amyotrophic lateral sclerosis (ALS) patients.

METHODS: N = 343 non-demented ALS patients and N = 226 healthy controls (HCs) were administered the Verbal fluency - S task from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The associations between the number of words produced (NoW), the time to read words aloud (TRW) and the VFI (computed as [(60"-TRW)/NoW]) on one hand and both bulbar/respiratory scores from the ALS Functional Rating Scale - Revised (ALSFRS-R) and the ECAS-Executive on the other were tested. Italian norms for the NoW and the VFI were derived in HCs via the Equivalent Score method. Patients were classified based on their impaired/unimpaired performances on the NoW and the VFI (NoW-VFI-; NoW-VFI+; NoW + VFI-; NoW + VFI+), with these groups being compared on ECAS-Executive scores.

RESULTS: The VFI, but neither the NoW nor the TRW, were related to ALSFRS-Bulbar/-Respiratory scores; VFI and NoW measures, but not the TRW, were related to the ECAS-Executive (p < .001). The NoW slightly overestimated the number of executively impaired patients when compared to the VFI (31.1% vs. 26.8%, respectively). Patients with a defective VFI score - regardless of whether they presented or not with a below-cutoff NoW - reported worse ECAS-Executive scores than NoW + VFI + ones.

CONCLUSIONS: The present reports support the use of the Italian VFI as a mean to validly assess ALS patients' executive status by limiting the effect of motor disabilities that might undermine their speech rate.}, } @article {pmid39404532, year = {2024}, author = {Tanioka, S and Wu, B and Ballmer, SW}, title = {Experimental demonstration of frequency- downconverted arm-length stabilization for a future upgraded gravitational wave detector.}, journal = {Optics letters}, volume = {49}, number = {20}, pages = {5763-5766}, doi = {10.1364/OL.534141}, pmid = {39404532}, issn = {1539-4794}, abstract = {Ground-based laser interferometric gravitational wave detectors (GWDs) consist of multiple optical cavity systems whose lengths need to be interferometrically controlled. An arm-length stabilization (ALS) system has played an important role in bringing these interferometers into an operational state and enhancing their duty cycle. The sensitivity of these detectors can be improved if the thermal noise of their test mass mirror coatings is reduced. Crystalline AlGaAs coatings are a promising candidate for this. However, the current ALS system with a frequency-doubled 532 nm light is no longer an option with AlGaAs coatings because the 532 nm light is absorbed by AlGaAs coatings due to the narrow bandgap of GaAs. Therefore, alternative locking schemes must be developed. In this Letter, we describe an experimental demonstration of a novel ALS scheme, to the best of our knowledge, which is compatible with AlGaAs coatings. This ALS scheme will enable the use of AlGaAs coatings in current and future terrestrial gravitational wave detectors.}, } @article {pmid39403566, year = {2024}, author = {Biswas, DD and Sethi, R and Woldeyohannes, Y and Scarrow, ER and El Haddad, L and Lee, J and ElMallah, MK}, title = {Respiratory pathology in the TDP-43 transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1430875}, pmid = {39403566}, issn = {1664-042X}, support = {R21 NS098131/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in death within 2-5 years of diagnosis. Respiratory failure is the most common cause of death in ALS. Mutations in the transactive response DNA binding protein 43 (TDP-43) encoded by the TARDBP gene are associated with abnormal cellular aggregates in neurons of patients with both familial and sporadic ALS. The role of these abnormal aggregates on breathing is unclear. Since respiratory failure is a major cause of death in ALS, we sought to determine the role of TDP-43 mutations on the respiratory motor unit in the Prp-hTDP-43[A315T] mouse model - a model that expresses human TDP-43 containing the A315T mutation. We assessed breathing using whole-body plethysmography, and investigated neuropathology in hypoglossal and phrenic respiratory motor units. Postmortem studies included quantification of hypoglossal and putative phrenic motor neurons, activated microglia and astrocytes in respiratory control centers, and assessment of hypoglossal and phrenic nerves of TDP43[A315T] mice. The male TDP43[A315T] mice display an early onset of rapid progression of disease, and premature death (less than 15 weeks) compared to control mice and compared to female TDP43[A315T] mice who die between 20 and 35 weeks of age. The TDP43[A315T] mice have progressive and profound breathing deficits at baseline and during a respiratory challenge. Histologically, hypoglossal and putative phrenic motor neurons of TDP43[A315T] mice are decreased and have increased microglial and astrocyte activation, indicating pronounced neurodegeneration and neuroinflammation. Further, there is axonopathy and demyelination in the hypoglossal and phrenic nerve of TDP43[A315T] mice. Thus, the TDP-43[A315T] mice have significant respiratory pathology and neuropathology, which makes them a useful translatable model for the study of novel therapies on breathing in ALS.}, } @article {pmid39403300, year = {2024}, author = {Aminianfar, A and Fatemi, MH and Azimi, F}, title = {Comprehensive characterization of volatile compounds in Iranian black teas using chemometric analysis of GC-MS fingerprints.}, journal = {Food chemistry: X}, volume = {24}, number = {}, pages = {101859}, pmid = {39403300}, issn = {2590-1575}, abstract = {Black tea, a widely popular non-alcoholic beverage, is renowned for its unique aroma and has attracted significant attention due to its complex composition. However, the chemical profile of Iranian tea remains largely unexplored. In this research, black tea samples from key tea cultivation regions in four geographical areas in northern Iran were firstly analyzed using headspace solid-phase microextraction followed by gas chromatography-mass spectrometry (HS-SPME-GC-MS) to separate, identify, and quantify their volatile organic compounds. Subsequently, employing a robust investigative strategy, we utilized for the first time the well-known multivariate curve resolution-alternating least square (MCR-ALS) method as a deconvolution technique to analyze the complex GC-MS peak clusters of tea samples. This approach effectively addressed challenges such as severe baseline drifts, overlapping peaks, and background noise, enabling the identification of minor components responsible for the distinct flavors and tastes across various samples. The MCR-ALS technique significantly improved the resolution of spectral and elution profiles, enabling both qualitative and semi-quantitative analysis of tea constituents. Qualitative analysis involved comparing resolved peak profiles to theoretical spectra, along with retention indices, while semi-quantification was conducted using the overall volume integration (OVI) approach for volatile compounds, providing a more accurate correlation between peak areas and concentrations. The application of chemometric tools in GC-MS analysis increased the number of recognized components in four tea samples, expanding from 54 to 256 components, all with concentrations exceeding 0.1 %. Among them, 32 volatile compounds were present in every tea sample. Hydrocarbons (including alkenes, alkanes, cycloalkanes, monoterpenes and sesquiterpenes), esters and alcohols were the three major chemical classes, comprising 78 % of the total relative content of volatile compounds. Analyzing black teas from four distinct regions revealed variations not only in their volatile components but also in their relative proportions. This integrated approach provides a comprehensive understanding of the volatile chemical profiles in Iranian black teas, enhances knowledge about their unique characteristics across diverse geographical origin, and lays the groundwork for quality improvement.}, } @article {pmid39402245, year = {2024}, author = {Wood, H}, title = {Altered muscle cholesterol transport in ALS.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {11}, pages = {643}, doi = {10.1038/s41582-024-01029-8}, pmid = {39402245}, issn = {1759-4766}, } @article {pmid39402174, year = {2025}, author = {Jellinger, KA}, title = {The spectrum of behavioral disorders in amyotrophic lateral sclerosis: current view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {132}, number = {2}, pages = {217-236}, pmid = {39402174}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/complications ; Humans ; *Mental Disorders/physiopathology/etiology ; Brain/physiopathology ; }, abstract = {Behavioral disorders, with an average prevalence of 30-60% are important non-motor symptoms in amyotrophic lateral sclerosis (ALS) that have a negative impact on prognosis, management and quality of life, yet the underlying neurobiology is poorly understood. Among people with ALS, apathy, fatigue, anxiety, irritability and other behavioral symptoms are the most prominent, although less frequent than cognitive impairment. The present review explores the current understanding of behavioral changes in ALS with particular emphasis on our current knowledge about their structural and functional brain correlates, substantiating a multisystem degeneration with particular dysfunction of frontal-subcortical circuits and dysfunction of fronto-striatal, frontotemporal and other essential brain systems. The natural history of behavioral dysfunctions in ALS and their relationship to frontotemporal lobe degeneration (FTLD) are not fully understood, although they form a clinical continuum, suggesting a differential vulnerability of non-motor brain networks, ALS being considered a brain network disorder. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of behavioral impairment in ALS. Treatment of both ALS and co-morbid behavioral disorders is a multidisciplinary task, but whereas no causal or disease-modifying therapies for ALS are available, symptomatic treatment of a variety of behavioral symptoms plays a pivotal role in patient care, although the management of behavioral symptoms in clinical care still remains limited.}, } @article {pmid39401554, year = {2025}, author = {Duarte, RRR and Nixon, DF and Powell, TR}, title = {Ancient viral DNA in the human genome linked to neurodegenerative diseases.}, journal = {Brain, behavior, and immunity}, volume = {123}, number = {}, pages = {765-770}, pmid = {39401554}, issn = {1090-2139}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/virology ; *Endogenous Retroviruses/genetics ; *Genome, Human ; Genome-Wide Association Study ; DNA, Viral/genetics ; Amyotrophic Lateral Sclerosis/genetics/virology ; Multiple Sclerosis/genetics/virology ; Genetic Predisposition to Disease/genetics ; Brain/metabolism/virology ; Parkinson Disease/genetics/virology ; Male ; Female ; }, abstract = {BACKGROUND: Human endogenous retroviruses (HERVs) are sequences in the human genome that originated from infections with ancient retroviruses during our evolution. Previous studies have linked HERVs to neurodegenerative diseases, but defining their role in aetiology has been challenging. Here, we used a retrotranscriptome-wide association study (rTWAS) approach to assess the relationships between genetic risk for neurodegenerative diseases and HERV expression in the brain, calculated with genomic precision.

METHODS: We analysed genetic association statistics pertaining to Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson's disease, using HERV expression models calculated from 792 cortical samples. Robust risk factors were considered those that survived multiple testing correction in the primary analysis, which were also significant in conditional and joint analyses, and that had a posterior inclusion probability above 0.5 in fine-mapping analyses.

RESULTS: The primary analysis identified 12 HERV expression signatures associated with neurodegenerative disease susceptibility. We found one HERV expression signature robustly associated with amyotrophic lateral sclerosis on chromosome 12q14 (MER61_12q14.2) and one robustly associated with multiple sclerosis on chromosome 1p36 (ERVLE_1p36.32a). A co-expression analysis suggested that these HERVs are involved in homophilic cell adhesion via plasma membrane adhesion molecules.

CONCLUSIONS: We found HERV expression profiles robustly associated with amyotrophic lateral sclerosis and multiple sclerosis susceptibility, highlighting novel risk mechanisms underlying neurodegenerative disease, and offering potential new targets for therapeutic intervention.}, } @article {pmid39401249, year = {2024}, author = {Pérez de la Lastra Aranda, C and Tosat-Bitrián, C and Porras, G and Dafinca, R and Muñoz-Torrero, D and Talbot, K and Martín-Requero, Á and Martínez, A and Palomo, V}, title = {Proteome Aggregation in Cells Derived from Amyotrophic Lateral Sclerosis Patients for Personalized Drug Evaluation.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {21}, pages = {3945-3953}, doi = {10.1021/acschemneuro.4c00328}, pmid = {39401249}, issn = {1948-7193}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/drug therapy/pathology ; *Proteome/metabolism ; Precision Medicine/methods ; Motor Neurons/metabolism/drug effects ; Lymphocytes/metabolism/drug effects ; Protein Aggregates/drug effects/physiology ; Induced Pluripotent Stem Cells/metabolism/drug effects ; Protein Aggregation, Pathological/metabolism ; DNA-Binding Proteins/metabolism ; Drug Evaluation, Preclinical/methods ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that currently lacks effective therapy. Given the heterogeneity of clinical and molecular profiles of ALS patients, personalized diagnostics and pathological characterization represent a powerful strategy to optimize patient stratification, thereby enabling personalized treatment. Immortalized lymphocytes from sporadic and genetic ALS patients recapitulate some pathological hallmarks of the disease, facilitating the fundamental task of drug screening. However, the molecular aggregation of ALS has not been characterized in this patient-derived cellular model. Indeed, protein aggregation is one of the most prominent features of neurodegenerative diseases, and therefore, models to test drugs against personalized pathological aggregation could help discover improved therapies. With this work, we aimed to characterize the aggregation profile of ALS immortalized lymphocytes and test several drug candidates with different mechanisms of action. In addition, we have evaluated the molecular aggregation in motor neurons derived from two hiPSC cell lines corresponding to ALS patients with different mutations in TARDBP. The results provide valuable insight into the different characterization of sporadic and genetic ALS patients' immortalized lymphocytes, their differential response to drug treatment, and the usefulness of proteome homeostasis characterization in patients' cells.}, } @article {pmid39400557, year = {2024}, author = {Gelpi, E and Reinecke, R and Gaig, C and Iranzo, A and Sabater, L and Molina-Porcel, L and Aldecoa, I and Endmayr, V and Högl, B and Schmutzhard, E and Poewe, W and Pfausler, B and Popovic, M and Pretnar-Oblak, J and Leypoldt, F and Matschke, J and Glatzel, M and Erro, EM and Jerico, I and Caballero, MC and Zelaya, MV and Mariotto, S and Heidbreder, A and Kalev, O and Weis, S and Macher, S and Berger-Sieczkowski, E and Ferrari, J and Reisinger, C and Klupp, N and Tienari, P and Rautila, O and Niemelä, M and Yilmazer-Hanke, D and Guasp, M and Bloem, B and Van Gaalen, J and Kusters, B and Titulaer, M and Fransen, NL and Santamaria, J and Dawson, T and Holton, JL and Ling, H and Revesz, T and Myllykangas, L and Budka, H and Kovacs, GG and Lewerenz, J and Dalmau, J and Graus, F and Koneczny, I and Höftberger, R}, title = {Neuropathological spectrum of anti-IgLON5 disease and stages of brainstem tau pathology: updated neuropathological research criteria of the disease-related tauopathy.}, journal = {Acta neuropathologica}, volume = {148}, number = {1}, pages = {53}, pmid = {39400557}, issn = {1432-0533}, support = {SYNABS//Austrian Science Fund/ ; I6565-B//Austrian Science Fund/ ; T996-B30//Austrian Science Fund/ ; 01GM2208B//Bundesministerium für Bildung und Forschung/ ; 01GM2208A//Bundesministerium für Bildung und Forschung/ ; PI21/00165//Instituto de Salud Carlos III/ ; PI21/00165//Instituto de Salud Carlos III/ ; N° 825575//Horizon 2020 Framework Programme/ ; 341007//Tekniikan Akatemia/ ; TYH2022316//Helsingin Yliopisto/ ; }, mesh = {Humans ; *Tauopathies/pathology/immunology ; Middle Aged ; *Brain Stem/pathology/metabolism/immunology ; Male ; Female ; Aged ; Aged, 80 and over ; *tau Proteins/metabolism/immunology ; *Cell Adhesion Molecules, Neuronal/metabolism/immunology ; Adult ; Autoantibodies/immunology ; DNA-Binding Proteins/metabolism ; }, abstract = {Anti-IgLON5 disease is a unique condition that bridges autoimmunity and neurodegeneration. Since its initial description 10 years ago, an increasing number of autopsies has led to the observation of a broader spectrum of neuropathologies underlying a particular constellation of clinical symptoms. In this study, we describe the neuropathological findings in 22 patients with anti-IgLON5 disease from 9 different European centers. In 15 patients (68%), we observed a hypothalamic and brainstem-predominant tauopathy of varying severity in which the original research neuropathological criteria were readily applicable. This pathology was observed in younger patients (median age at onset 61 years) with a long disease duration (median 9 years). In contrast, in 7 (32%) patients, the originally described brainstem tauopathy was nearly absent or only minimal in the form of delicate threads, despite mild-to-moderate neurodegenerative features, consistent clinical symptoms and the presence of anti-IgLON5 antibodies in CSF and serum. These patients were older at onset (median 79 years) and had shorter disease duration (median < 1 year). Overall, about one-third of the patients showed concomitant TDP-43 pathology within the regions affected by tau pathology and/or neurodegeneration. Based on these observations and in view of the spectrum of the tau burden in the core regions involved in the disease, we propose a simple staging system: stage 1 mild neurodegeneration without overt or only minimal tau pathology, stage 2 moderate neurodegeneration and mild/ moderate tauopathy and stage 3 prominent neurodegeneration and tau pathology. This staging intends to reflect a potential (age- and time-dependent) progression of tau pathology, supporting the current notion that tau accumulation is a secondary phenomenon related to the presence of anti-IgLON5 antibodies in the CNS. Finally, we adapt the original research criteria of the anti-IgLON5 disease-related tauopathy to include the spectrum of pathologies observed in this larger postmortem series.}, } @article {pmid39400020, year = {2024}, author = {Ali, A and A Emad, N and Sultana, N and Waheed, A and Aqil, M and Sultana, Y and Mujeeb, M}, title = {Navigating into the Paradigm of Nose-to-brain Delivery of Nanotherapeutics and their Repurposing as Nanotheranostics for Neurodegenerative Diseases.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273319597240927044906}, pmid = {39400020}, issn = {1996-3181}, abstract = {Repurposing drugs for neurodegenerative diseases using the nose-to-brain route of administration is an intriguing concept with potential benefits. The nose-to-brain route involves delivering drugs directly to the brain via the olfactory or trigeminal pathways, bypassing the blood-brain barrier, which can improve drug efficacy and reduce systemic side effects. Treatment of numerous neurodegenerative diseases such as Multiple sclerosis, Amyotrophic lateral sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases has been attempted using this route of administration. These drugs may include neuroprotective agents, anti-inflammatory drugs, antioxidants, or diseasemodifying therapies. Nanotheranostics, which integrates therapeutic and diagnostic functions in a nanosystem, improves treatment precision and efficacy. Repurposing nanotherapeutics as nanotheranostics for neurodegenerative diseases through the nose-to-brain route of administration holds great potential for both diagnosis and treatment. This review highlights the various mechanisms engaged in transporting nanocarriers from nose-to-brain and the proposed fate of these nanocarriers using different live imaging techniques. Additionally, the discussion covers the recent combinatorial therapeutic approaches and theranostic applications of various nanocarriers used for neurodegenerative diseases through the nose-to-brain. Toxicity to the CNS and nasal mucosa and regulatory considerations about these delivery systems are also deliberated. Overall, repurposed nanoparticles designed as nanotheranostic agents offer a versatile platform for precise diagnosis, targeted therapy, and personalized management of neurodegenerative diseases, holding great promise for improving patient care and advancing our understanding of these complex disorders.}, } @article {pmid39399380, year = {2024}, author = {Cossu, L and Cappon, G and Facchinetti, A}, title = {Automated pipeline for denoising, missing data processing, and feature extraction for signals acquired via wearable devices in multiple sclerosis and amyotrophic lateral sclerosis applications.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1402943}, pmid = {39399380}, issn = {2673-253X}, abstract = {INTRODUCTION: The incorporation of health-related sensors in wearable devices has increased their use as essential monitoring tools for a wide range of clinical applications. However, the signals obtained from these devices often present challenges such as artifacts, spikes, high-frequency noise, and data gaps, which impede their direct exploitation. Additionally, clinically relevant features are not always readily available. This problem is particularly critical within the H2020 BRAINTEASER project, funded by the European Community, which aims at developing models for the progression of Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS) using data from wearable devices.

METHODS: The objective of this study is to present the automated pipeline developed to process signals and extract features from the Garmin Vivoactive 4 smartwatch, which has been chosen as the primary wearable device in the BRAINTEASER project. The proposed pipeline includes a signal processing step, which applies retiming, gap-filling, and denoising algorithms to enhance the quality of the data. The feature extraction step, on the other hand, utilizes clinical partners' knowledge and feedback to select the most relevant variables for analysis.

RESULTS: The performance and effectiveness of the proposed automated pipeline have been evaluated through pivotal beta testing sessions, which demonstrated the ability of the pipeline to improve the data quality and extract features from the data. Further clinical validation of the extracted features will be performed in the upcoming steps of the BRAINTEASER project.

DISCUSSION: Developed in Python, this pipeline can be used by researchers for automated signal processing and feature extraction from wearable devices. It can also be easily adapted or modified to suit the specific requirements of different scenarios.}, } @article {pmid39397192, year = {2024}, author = {Hamdi, N and Mueller, K and Hamza, A and Soliman, R and Onbool, E and Omran, K and Ocab, O and Freischmidt, A and Siebert, R and Ludolph, A and Fahmy, N}, title = {First insights into genotype and phenotype of familial amyotrophic lateral sclerosis in Egypt: early onset and high consanguinity.}, journal = {Frontiers of medicine}, volume = {18}, number = {6}, pages = {1115-1118}, pmid = {39397192}, issn = {2095-0225}, } @article {pmid39396990, year = {2024}, author = {Hazell, G and McCallion, E and Ahlskog, N and Sutton, ER and Okoh, M and Shaqoura, EIH and Hoolachan, JM and Scaife, T and Iqbal, S and Bhomra, A and Kordala, AJ and Scamps, F and Raoul, C and Wood, MJA and Bowerman, M}, title = {Exercise, disease state and sex influence the beneficial effects of Fn14-depletion on survival and muscle pathology in the SOD1[G93A] amyotrophic lateral sclerosis (ALS) mouse model.}, journal = {Skeletal muscle}, volume = {14}, number = {1}, pages = {23}, pmid = {39396990}, issn = {2044-5040}, support = {SBF006/1162/AMS_/Academy of Medical Sciences/United Kingdom ; SBF006/1162/AMS_/Academy of Medical Sciences/United Kingdom ; MR/Y003640/1/MRC_/Medical Research Council/United Kingdom ; MR/Y003640/1/MRC_/Medical Research Council/United Kingdom ; 18GRO-PS48-0114//Muscular Dystrophy UK/ ; 18GRO-PS48-0114//Muscular Dystrophy UK/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *TWEAK Receptor/metabolism/genetics ; *Muscle, Skeletal/metabolism/pathology ; Male ; Female ; *Disease Models, Animal ; *Mice, Transgenic ; Mice ; Physical Conditioning, Animal ; Mice, Knockout ; Cytokine TWEAK/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease. Accumulating evidence strongly suggests that intrinsic muscle defects exist and contribute to disease progression, including imbalances in whole-body metabolic homeostasis. We have previously reported that tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor inducible 14 (Fn14) are significantly upregulated in skeletal muscle of the SOD1[G93A] ALS mouse model. While antagonising TWEAK did not impact survival, we did observe positive effects in skeletal muscle. Given that Fn14 has been proposed as the main effector of the TWEAK/Fn14 activity and that Fn14 can act independently from TWEAK in muscle, we suggest that manipulating Fn14 instead of TWEAK in the SOD1[G93A] ALS mice could lead to differential and potentially improved benefits.

METHODS: We thus investigated the contribution of Fn14 to disease phenotypes in the SOD1[G93A] ALS mice. To do so, Fn14 knockout mice (Fn14[-/-]) were crossed onto the SOD1[G93A] background to generate SOD1[G93A];Fn14[-/-] mice. Investigations were performed on both unexercised and exercised (rotarod and/or grid test) animals (wild type (WT), Fn14[-/-], SOD1[G93A] and SOD1[G93A];Fn14[-/-]).

RESULTS: Here, we firstly confirm that the TWEAK/Fn14 pathway is dysregulated in skeletal muscle of SOD1[G93A] mice. We then show that Fn14-depleted SOD1[G93A] mice display increased lifespan, myofiber size, neuromuscular junction endplate area as well as altered expression of known molecular effectors of the TWEAK/Fn14 pathway, without an impact on motor function. Importantly, we also observe a complex interaction between exercise (rotarod and grid test), genotype, disease state and sex that influences the overall effects of Fn14 deletion on survival, expression of known molecular effectors of the TWEAK/Fn14 pathway, expression of myosin heavy chain isoforms and myofiber size.

CONCLUSIONS: Our study provides further insights on the different roles of the TWEAK/Fn14 pathway in pathological skeletal muscle and how they can be influenced by age, disease, sex and exercise. This is particularly relevant in the ALS field, where combinatorial therapies that include exercise regimens are currently being explored. As such, a better understanding and consideration of the interactions between treatments, muscle metabolism, sex and exercise will be of importance in future studies.}, } @article {pmid39396709, year = {2024}, author = {Wu, J and Wu, J and Chen, T and Cai, J and Ren, R}, title = {Protein aggregation and its affecting mechanisms in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {180}, number = {}, pages = {105880}, doi = {10.1016/j.neuint.2024.105880}, pmid = {39396709}, issn = {1872-9754}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Protein Aggregation, Pathological/metabolism ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; Protein Aggregates/physiology ; tau Proteins/metabolism ; }, abstract = {Protein aggregation serves as a critical pathological marker in a spectrum of neurodegenerative diseases (NDs), including the formation of amyloid β (Aβ) and Tau neurofibrillary tangles in Alzheimer's disease, as well as α-Synuclein (α-Syn) aggregates in Parkinson's disease, Parkinson's disease-related dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). A significant proportion of patients with amyotrophic lateral sclerosis (ALS) exhibit TDP-43 aggregates. Moreover, a confluence of brain protein pathologies, such as Aβ, Tau, α-Syn, and TDP-43, has been identified in individual NDs cases, highlighting the intricate interplay among these proteins that is garnering heightened scrutiny. Importantly, protein aggregation is modulated by an array of factors, with burgeoning evidence suggesting that it frequently results from perturbations in protein homeostasis, influenced by the cellular membrane milieu, metal ion concentrations, post-translational modifications, and genetic mutations. This review delves into the pathological underpinnings of protein aggregation across various NDs and elucidates the intercommunication among disparate proteins within the same disease context. Additionally, we examine the pathogenic mechanisms by which diverse factors impinge upon protein aggregation, offering fresh perspectives for the future therapeutic intervention of NDs.}, } @article {pmid39396264, year = {2024}, author = {Bermudo Fuenmayor, S and Serrano Castro, PJ and Quiroga Subirana, P and López Palmero, S and Requena Mullor, MM and Parrón Carreño, T}, title = {Design and validation of a questionnaire for monitoring neurological dysphagia and respiratory deterioration in patients with amyotrophic lateral sclerosis (DEREDELA).}, journal = {Neurologia}, volume = {39}, number = {8}, pages = {666-674}, doi = {10.1016/j.nrleng.2024.09.003}, pmid = {39396264}, issn = {2173-5808}, mesh = {*Amyotrophic Lateral Sclerosis/complications ; Humans ; *Deglutition Disorders/diagnosis/etiology ; Surveys and Questionnaires ; Male ; Female ; Reproducibility of Results ; Middle Aged ; Aged ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a degenerative disease of unknown origin that affects the motor neurons. It has a rapid, fatal course.

METHOD: For this study, an initial questionnaire of eleven items was developed by experts in the field, who evaluated the suitability and relevance of the items.

RESULTS: The questionnaire was then applied to a pilot group of 22 patients diagnosed with ALS. Confirmatory factor analysis, based on estimating maximum likelihood, confirmed the three domains detected in the exploratory factor analysis. The reliability of the scale was tested using Cronbach's α (0.801) and the Kaiser-Meyer-Olkin test (0.770) confirmed the construct validity.

CONCLUSIONS: The DEREDELA questionnaire is valid, in terms of its content, for monitoring the neurological dysphagia and respiratory deterioration suffered by patients diagnosed with ALS.}, } @article {pmid39395841, year = {2024}, author = {Tran, M and Rhee, J and Hu, W and Magin, P and Shulruf, B}, title = {General practice trainee, supervisor and educator perspectives on the transitions in postgraduate training: a scoping review.}, journal = {Family medicine and community health}, volume = {12}, number = {4}, pages = {}, pmid = {39395841}, issn = {2009-8774}, mesh = {Humans ; *General Practice/education ; Education, Medical, Graduate ; General Practitioners/education ; Students, Medical/psychology ; }, abstract = {UNLABELLED: Transitions are a period and a process, through which there is a longitudinal adaptation in response to changing circumstances in clinical practice and responsibilities. While the experience of the transition in medical student learning and in hospital-based specialty training programmes are well described and researched, the experience of the transition in community-based postgraduate general practitioner (GP) training has not been described comprehensively.

OBJECTIVE: We aimed to identify, and categorise, the formative experiences of transitions in GP training and their impacts on personal and professional development.

DESIGN: We adopted Levac et al's scoping review methodology. Of 1543 retrieved records, 76 were selected for data extraction. Based on a combined model of the socioecological and multiple and multi-dimensional theories of transitions, data relating to the experiences of transitions were organised into contextual themes: being physical, psychosocial, organisational culture and chronological.

ELIGIBILITY CRITERIA: Empirical studies focused on general practice trainees or training, that discussed the transitions experienced in general practice training and that were published in English were included.

INFORMATION SOURCES: PubMed, MEDLINE and Web of Science databases were searched in January 2024 with no date limits for empirical studies on the transition experiences of GP into, and through, training.

RESULTS: Our findings describe context-dependent formative experiences which advance, or impede, learning and development. Time is a significant modulator of the factors contributing to more negative experiences, with some initially adverse experiences becoming more positive. Identification of the inflection point that represents a shift from initially adverse to more positive experiences of transitions may help moderate expectations for learning and performance at different stages of training.

CONCLUSION: Challenges in training can either advance development and contribute positively to professional identity formation and clinical competency, or detract from learning and potentially contribute to burnout and attrition from training programmes. These findings will assist future research in identifying predictive factors of positive and adverse experiences of transitions and may strengthen existing and nascent GP training programmes. The findings are transferable to other community-based specialty training programmes.}, } @article {pmid39395630, year = {2024}, author = {Yeewa, R and Sangphukieo, A and Jantaree, P and Wongkummool, W and Yamsri, T and Poompouang, S and Chaiyawat, P and Lo Piccolo, L and Jantrapirom, S}, title = {ERO1A inhibition mitigates neuronal ER stress and ameliorates UBQLN2[ALS] phenotypes in Drosophila melanogaster.}, journal = {Progress in neurobiology}, volume = {242}, number = {}, pages = {102674}, doi = {10.1016/j.pneurobio.2024.102674}, pmid = {39395630}, issn = {1873-5118}, mesh = {Animals ; *Drosophila melanogaster ; *Endoplasmic Reticulum Stress/drug effects/physiology ; *Drosophila Proteins/metabolism/genetics ; *Neurons/metabolism/drug effects ; Phenotype ; Autophagy-Related Proteins/metabolism/genetics ; Disease Models, Animal ; Animals, Genetically Modified ; Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {Modulating the ER stress pathway holds therapeutic promise for neurodegenerative diseases; however, identifying optimal targets remains challenging. In this study, we conducted an unbiased screening to systematically search for commonly up-regulated proteins in ER stress-related neurodegenerative conditions, with endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) emerging as a significant hit. Further experiments conducted in the model organism Drosophila melanogaster demonstrated that elevated levels of Drosophila ERO1A (ERO1L) were indeed detrimental to neurons. Conversely, genetic suppression or pharmacological inhibition of ERO1L activity provided neuroprotection under ER stress and extended the lifespan of flies. To translate these findings, we performed a genetic modifier screening and underscored significant neuroprotective effects against UBQLN2[ALS] pathology. Additionally, administration of the chemical probe inhibitor of ERO1A, known as EN460, enhanced locomotive functions and neuromuscular junction (NMJ) morphology in Drosophila UBQLN2[ALS] model. Mechanistically, targeting ERO1L during environmental or pathological ER stress mitigated proteotoxic stress by lowering either the PERK or IRE1 branches of the unfolded protein response (UPR). These findings suggest ERO1A as a promising therapeutic target in UBQLN2[ALS] and other ER stress-related conditions.}, } @article {pmid39395475, year = {2024}, author = {Kim, SY and Kim, M and Park, K and Hong, S}, title = {A systematic review on analytical methods of the neurotoxin β-N-methylamino-L-alanine (BMAA), and its causative microalgae and distribution in the environment.}, journal = {Chemosphere}, volume = {366}, number = {}, pages = {143487}, doi = {10.1016/j.chemosphere.2024.143487}, pmid = {39395475}, issn = {1879-1298}, mesh = {*Amino Acids, Diamino/analysis ; *Microalgae/metabolism ; *Cyanobacteria Toxins ; *Neurotoxins/analysis ; *Cyanobacteria/metabolism ; *Tandem Mass Spectrometry ; *Environmental Monitoring/methods ; Ecosystem ; Chromatography, Liquid ; Diatoms/metabolism ; Water Pollutants, Chemical/analysis/metabolism ; }, abstract = {β-N-Methylamino-L-alanine (BMAA), a neurotoxin produced by various microalgal groups, is associated with neurodegenerative diseases and is considered a major environmental factor potentially linked to sporadic amyotrophic lateral sclerosis. This study systematically reviews the analytical methods used to study BMAA in publications from 2019 to the present. It also investigates the causative microalgae of BMAA and its geographical distributions in aquatic ecosystems based on studies conducted since 2003. A comprehensive search using the Web of Science database revealed that hydrolysis for extraction (67%), followed by quantification using LC-MS/MS (LC: 84%; MS/MS: 88%), is the most commonly employed method in BMAA analysis. Among analytical methods, RPLC-MS/MS had the highest percentage (88%) of BMAA-positive results and included a high number of quality control (QC) assessments. Various genera of cyanobacteria and diatoms have been reported to produce BMAA. The widespread geographical distribution of BMAA across diverse ecosystems highlights significant environmental and public health concerns. Notably, BMAA accumulation and biomagnification are likely more potent in marine or brackish water ecosystems than in freshwater ecosystems, potentially amplifying its ecological impacts. Future research should prioritize advanced, sensitive methods, particularly LC-MS/MS with as many QC assessments as possible, and should expand investigations to identify novel microalgal producers and previously uncharted geographical areas, with a special focus on marine or brackish water ecosystems. This effort will enhance our understanding of the environmental distribution and impacts of BMAA.}, } @article {pmid39394860, year = {2024}, author = {Zhao, J and Kong, D and Zhang, G and Zhang, S and Wu, Y and Dai, C and Chen, Y and Yang, Y and Liu, Y and Wei, D}, title = {An Efficient CRISPR/Cas Cooperative Shearing Platform for Clinical Diagnostics Applications.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {63}, number = {52}, pages = {e202411705}, doi = {10.1002/anie.202411705}, pmid = {39394860}, issn = {1521-3773}, support = {22304031, 61890940//National Natural Science Foundation of China/ ; 2021YFC2301100//the National Key R&D Program of China/ ; XDB30000000//the Strategic Priority Research Program of the Chinese Academy of Sciences/ ; 23XD1420200//the Program of Shanghai Academic Research Leaders/ ; DP2020036//the Chong-qing Bayu Scholar Program/ ; 2023M730635//the China Postdoctoral Science Foundation/ ; T2425006//National Science Fund for Distinguished Young Scholars/ ; }, mesh = {*CRISPR-Cas Systems/genetics ; Humans ; Electrochemical Techniques ; Amyotrophic Lateral Sclerosis/diagnosis/genetics ; }, abstract = {The CRISPR/Cas system is a powerful genome editing tool and possesses widespread applications in molecular diagnostics, therapeutics and genetic engineering. But easy folding of the target sequences causes remarkable deterioration of the recognition and shear efficiency in the case of single Cas-CRISPR RNA (crRNA) duplex. Here, we develop a CRISPR/Cas cooperative shearing (CRISPR-CS) system. Compared with traditional CRISPR/Cas system, two CRISPR/Cas-crRNA duplexes simultaneously recognize different sites in the target sequence, increasing recognition possibility and shearing efficiency. Cooperative shearing cuts more methylene blue-ssDNA reporters on the electrode, enabling unamplified nucleic acid electrochemical assay in less than 5 minutes with a detection limit of 9.5×10[-20] M, 2 to 9 orders of magnitude lower than those of other electrochemical assays. The CRISPR-CS platform detects monkeypox, human papilloma virus and amyotrophic lateral sclerosis with an accuracy up to 98.1 %, demonstrating the potential application of the efficient cooperative shearing.}, } @article {pmid39393594, year = {2024}, author = {Coppieters, R and Bouzigues, A and Jiskoot, L and Montembeault, M and Tee, BL and , and Rohrer, JD and Bruffaerts, R}, title = {A systematic review of the quantitative markers of speech and language of the frontotemporal degeneration spectrum and their potential for cross-linguistic implementation.}, journal = {Neuroscience and biobehavioral reviews}, volume = {167}, number = {}, pages = {105909}, doi = {10.1016/j.neubiorev.2024.105909}, pmid = {39393594}, issn = {1873-7528}, mesh = {Humans ; *Frontotemporal Dementia/physiopathology/diagnosis ; *Speech/physiology ; Linguistics ; Language ; Biomarkers ; }, abstract = {Frontotemporal dementia (FTD) is a neurodegenerative disease spectrum with an urgent need for reliable biomarkers for early diagnosis and monitoring. Speech and language changes occur in the early stages of FTD and offer a potential non-invasive, early, and accessible diagnostic tool. The use of speech and language markers in this disease spectrum is limited by the fact that most studies investigate English-speaking patients. This systematic review examines the literature on psychoacoustic and linguistic features of speech that occur across the FTD spectrum across as many different languages as possible. 76 papers were identified that investigate psychoacoustic and linguistic markers in discursive speech. 75 % of these papers studied English-speaking patients. The most generalizable features found across different languages, are speech rate, articulation rate, pause frequency, total pause duration, noun-verb ratio, and total number of nouns. While there are clear interlinguistic differences across patient groups, the results show promise for implementation of cross-linguistic markers of speech and language across the FTD spectrum particularly for psychoacoustic features.}, } @article {pmid39393030, year = {2024}, author = {Aamodt, WW and Sun, C and Dahodwala, N and Elser, H and Schneider, ALC and Farrar, JT and Coe, NB and Willis, AW}, title = {End-of-Life Health Care Service Use and Cost Among Medicare Decedents With Neurodegenerative Diseases.}, journal = {Neurology}, volume = {103}, number = {9}, pages = {e209925}, pmid = {39393030}, issn = {1526-632X}, mesh = {Humans ; United States ; Male ; Female ; *Medicare/economics/statistics & numerical data ; Aged ; Retrospective Studies ; *Terminal Care/economics/statistics & numerical data ; Aged, 80 and over ; *Neurodegenerative Diseases/economics/therapy/epidemiology ; Patient Acceptance of Health Care/statistics & numerical data ; Health Care Costs/statistics & numerical data ; Emergency Service, Hospital/statistics & numerical data/economics ; Parkinson Disease/economics/therapy/epidemiology ; Hospice Care/economics/statistics & numerical data ; Alzheimer Disease/economics/therapy/epidemiology ; Amyotrophic Lateral Sclerosis/economics/therapy/epidemiology ; }, abstract = {BACKGROUND AND OBJECTIVES: Although neurodegenerative diseases are a leading cause of death, little is known about health care utilization and cost during the end-of-life (EoL) period or how it compares with that of other life-limiting conditions. We aimed to describe and compare resource utilization among US Medicare decedents with neurodegenerative diseases with decedents with cancer.

METHODS: We conducted a retrospective study of Medicare Part A and B beneficiaries with Alzheimer disease (AD), Parkinson disease (PD), or amyotrophic lateral sclerosis (ALS) who died in 2018. Decedents diagnosed with malignant brain tumors or pancreatic cancer served as non-neurodegenerative comparators. Descriptive analyses examined demographic and clinical characteristics in the last year of life. The probabilities and associated costs of emergency department (ED), inpatient, skilled nursing facility (SNF), and hospice utilization during the last 12 and 6 months of life were also compared between persons with neurodegenerative diseases and cancer, adjusting for sociodemographic factors and comorbidity burden.

RESULTS: A total of 1,126,799 Medicare beneficiaries died in 2018, of which 357,926 had a qualifying diagnosis. Persons with neurodegenerative diseases were older and more frequently received Medicaid assistance than persons with brain or pancreatic cancer. In all groups, health care service utilization increased over the last year of life, and total costs were predominantly attributable to inpatient care. In the last 6 months of life, neurologist care was infrequent among patients with neurodegenerative disease (AD: 1.5%; PD: 8.6%; ALS: 32.0%). Persons with neurodegenerative diseases as compared to persons with malignant brain tumors also had greater odds of ED use (AD: adjusted odds ratio [aOR] 1.17, 95% CI 1.11-1.23; PD: aOR 1.18, 95% CI 1.11-1.25; ALS: aOR 1.11, 95% CI 1.01-1.23), lower odds of hospitalization (AD: aOR 0.64, 95% CI 0.60-0.68; PD: aOR 0.65, 95% CI 0.61-0.69; ALS: aOR 0.33, 95% CI 0.30-0.37), and lower odds of hospice enrollment (AD: aOR 0.33, 95% CI 0.31-0.36; PD: aOR 0.33, 95% CI 0.31-0.36; ALS: aOR 0.41, 95% CI 0.36-0.46). The findings were similar in pancreatic cancer.

DISCUSSION: Persons with neurodegenerative diseases in the United States are more likely to visit the ED and less likely to use inpatient and hospice services at EoL than persons with brain or pancreatic cancer. These group differences may stem from prognostic uncertainty and reflect inadequate EoL care practices, requiring further investigation to ensure more timely palliative care and hospice referrals.}, } @article {pmid39392186, year = {2025}, author = {Corcia, P and Piras, R and Lunetta, C}, title = {Why is the treatment and management of amyotrophic lateral sclerosis so difficult?.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {1}, pages = {1-3}, doi = {10.1080/14737175.2024.2415002}, pmid = {39392186}, issn = {1744-8360}, } @article {pmid39392096, year = {2024}, author = {}, title = {Correction to "Differential activation of neuronal and glial STAT3 in the spinal cord of the SOD1G93A mouse model of amyotrophic lateral sclerosis".}, journal = {The European journal of neuroscience}, volume = {60}, number = {8}, pages = {6125-6126}, doi = {10.1111/ejn.16562}, pmid = {39392096}, issn = {1460-9568}, } @article {pmid39391721, year = {2024}, author = {Hodgson, RE and Rayment, JA and Huang, WP and Sanchez Avila, A and Ellis, BCS and Lin, YH and Soni, N and Hautbergue, GM and Shelkovnikova, TA}, title = {C9orf72 poly-PR forms anisotropic condensates causative of nuclear TDP-43 pathology.}, journal = {iScience}, volume = {27}, number = {10}, pages = {110937}, pmid = {39391721}, issn = {2589-0042}, support = {MR/W028522/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Proteinaceous inclusions formed by C9orf72-derived dipeptide-repeat (DPR) proteins are a histopathological hallmark in ∼50% of familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) cases. However, DPR aggregation/inclusion formation could not be efficiently recapitulated in cell models for four out of five DPRs. In this study, using optogenetics, we achieved chemical-free poly-PR condensation/aggregation in cultured cells including human motor neurons, with spatial and temporal control. Strikingly, nuclear poly-PR condensates had anisotropic, hollow-center appearance, resembling TDP-43 anisosomes, and their growth was limited by RNA. These condensates induced abnormal TDP-43 granulation in the nucleus without stress response activation. Cytoplasmic poly-PR aggregates forming under prolonged opto-stimulation were more persistent than its nuclear condensates, selectively sequestered TDP-43 in a demixed state and surrounded spontaneous stress granules. Thus, poly-PR condensation accompanied by nuclear TDP-43 dysfunction may constitute an early pathological event in C9-ALS/FTD. Anisosome-type condensates of disease-linked proteins may represent a common molecular species in neurodegenerative disease.}, } @article {pmid39391382, year = {2024}, author = {Osaro, E and Fajardo-Rojas, F and Cooper, GM and Gómez-Gualdrón, D and Colón, YJ}, title = {Active learning of alchemical adsorption simulations; towards a universal adsorption model.}, journal = {Chemical science}, volume = {15}, number = {42}, pages = {17671-17684}, pmid = {39391382}, issn = {2041-6520}, abstract = {Adsorption is a fundamental process studied in materials science and engineering because it plays a critical role in various applications, including gas storage and separation. Understanding and predicting gas adsorption within porous materials demands comprehensive computational simulations that are often resource intensive, limiting the identification of promising materials. Active learning (AL) methods offer an effective strategy to reduce the computational burden by selectively acquiring critical data for model training. Metal-organic frameworks (MOFs) exhibit immense potential across various adsorption applications due to their porous structure and their modular nature, leading to diverse pore sizes and chemistry that serve as an ideal platform to develop adsorption models. Here, we demonstrate the efficacy of AL in predicting gas adsorption within MOFs using "alchemical" molecules and their interactions as surrogates for real molecules. We first applied AL separately to each MOF, reducing the training dataset size by 57.5% while retaining predictive accuracy. Subsequently, we amalgamated the refined datasets across 1800 MOFs to train a multilayer perceptron (MLP) model, successfully predicting adsorption of real molecules. Furthermore, by integrating MOF features into the AL framework using principal component analysis (PCA), we navigated MOF space effectively, achieving high predictive accuracy with only a subset of MOFs. Our results highlight AL's efficiency in reducing dataset size, enhancing model performance, and offering insights into adsorption phenomenon in large datasets of MOFs. This study underscores AL's crucial role in advancing computational material science and developing more accurate and less data intensive models for gas adsorption in porous materials.}, } @article {pmid39390888, year = {2024}, author = {Boran, HE and Kılınç, H and Kurtkaya Koçak, Ö and Yanık, E and Kuruoğlu, HR and Cengiz, B}, title = {Somatosensory temporal discrimination analysis reveals impaired processing in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {6}, pages = {1257-1262}, doi = {10.1002/mus.28278}, pmid = {39390888}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; *Evoked Potentials, Somatosensory/physiology ; Aged ; *Somatosensory Cortex/physiopathology ; Adult ; Hand/physiopathology ; Sensory Thresholds/physiology ; }, abstract = {INTRODUCTION/AIMS: While amyotrophic lateral sclerosis (ALS) is primarily characterized as a motor system disorder, there is a growing body of evidence indicating sensory involvement. This study aimed to examine the hypothesis that somatosensory processing is impaired in ALS.

METHODS: Study participants were ALS patients followed at the Neuromuscular Outpatient Unit, as well as healthy volunteers, from March 2021 to July 2023. The Medical Research Council (MRC) sum score was calculated for nine muscle groups bilaterally. The clinical status of patients was evaluated with the ALS Functional Rating Scale-Revised (ALSFRS-R) and the Penn Upper Motor Neuron core. Somatosensory temporal discrimination thresholds (STDTs) were recorded on the medial and lateral parts of both hands. Somatosensory cortex excitability was investigated with the paired somatosensory evoked potentials (SEP) paradigm in a subgroup.

RESULTS: Increased STD values were detected in ALS patients compared to controls in both medial (107.66 ± 35 ms vs. 82.7 ± 32.5 ms, p = .001) and lateral (106.5 ± 34.5 ms vs. 82.9 ± 31.3 ms, p = .002) hands. There were no significant differences in STDTs among ALS patients across four regions (medial and lateral parts of the right and left hands). Amplitude ratios obtained from the paired-pulse SEP paradigm were approximately 1 for all interstimulus intervals (ISIs). STDTs did not show any correlations with motor findings or scales.

DISCUSSION: Somatosensory processing appears to be compromised among ALS patients. The lack of correlation between impaired STDT and motor findings implies that it is a purely sensory deficit in ALS.}, } @article {pmid39390661, year = {2024}, author = {Howard, IM and Babu, S and Carter, C and Sakowski, SA and Kurent, JE and Cudkowicz, ME and Feldman, EL}, title = {Priorities and Recommendations to Make ALS a Livable Disease Emanating from the 2024 National Academies of Sciences, Engineering, and Medicine Report Living with ALS.}, journal = {Annals of neurology}, volume = {96}, number = {6}, pages = {1035-1039}, pmid = {39390661}, issn = {1531-8249}, support = {R01 TS000327/TS/ATSDR CDC HHS/United States ; OT2 NS136938/NS/NINDS NIH HHS/United States ; U01 NS077179/NS/NINDS NIH HHS/United States ; U01 NS136020/NS/NINDS NIH HHS/United States ; //Charles H. Abdalian, Jr. ALS Research Fund/ ; OT2 NS136939/NS/NINDS NIH HHS/United States ; //NeuroNetwork for Emerging Therapies/ ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R01TS000344//Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry/ ; //American Academy of Neurology/ ; //ALS One/ ; //ALS Association/ ; UF1 NS131791/NS/NINDS NIH HHS/United States ; R01TS000327//Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry/ ; 1U01NS136021-01/NH/NIH HHS/United States ; 1U01NS136020-01/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; //Scott L. Pranger/ ; //The Sean M. Healey & AMG Center for ALS/ ; 1U01NS077179-01/NH/NIH HHS/United States ; //Muscular Dystrophy Association/ ; U01 NS136021/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; //The Neurological Clinical Research Institute/ ; UF1NS131791-01/NH/NIH HHS/United States ; 1OT2NS136938-1/NH/NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; //ALS Finding a Cure/ ; OT2NS136939/NH/NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/diagnosis ; Humans ; United States ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentless, fatal neurodegenerative disease. The progressive loss of voluntary muscle function, diagnostic delays, lack of effective treatments, and challenges accessing multidisciplinary care and resources have tremendous impact on quality of life. The congressionally directed ALS committee of the National Academies of Science, Engineering, and Medicine, in their 2024 report "Living with ALS," recommends critical actions for specific United States stakeholders to make ALS a livable disease over the next decade. This review summarizes the context and recommendations of the report. Advocacy efforts are critical to make these recommendations a reality for the ALS community. ANN NEUROL 2024;96:1035-1039.}, } @article {pmid39390590, year = {2024}, author = {Vanderhaeghe, S and Prerad, J and Tharkeshwar, AK and Goethals, E and Vints, K and Beckers, J and Scheveneels, W and Debroux, E and Princen, K and Van Damme, P and Fivaz, M and Griffioen, G and Van Den Bosch, L}, title = {A pathogenic mutation in the ALS/FTD gene VCP induces mitochondrial hypermetabolism by modulating the permeability transition pore.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {161}, pmid = {39390590}, issn = {2051-5960}, support = {HBC.2019.2575//VLAIO Baekeland mandate/ ; 030383//Flanders Innovation & Entrepreneurship (VLAIO)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Valosin Containing Protein/genetics/metabolism ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Mitochondria/metabolism/pathology ; *Mitochondrial Permeability Transition Pore/metabolism ; *Mutation ; Cell Line, Tumor ; Membrane Potential, Mitochondrial/genetics ; Mitochondrial Membrane Transport Proteins/genetics/metabolism ; Calcium/metabolism ; }, abstract = {Valosin-containing protein (VCP) is a ubiquitously expressed type II AAA[+] ATPase protein, implicated in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This study aimed to explore the impact of the disease-causing VCP[R191Q/wt] mutation on mitochondrial function using a CRISPR/Cas9-engineered neuroblastoma cell line. Mitochondria in these cells are enlarged, with a depolarized mitochondrial membrane potential associated with increased respiration and electron transport chain activity. Our results indicate that mitochondrial hypermetabolism could be caused, at least partially, by increased calcium-induced opening of the permeability transition pore (mPTP), leading to mild mitochondrial uncoupling. In conclusion, our findings reveal a central role of the ALS/FTD gene VCP in maintaining mitochondrial homeostasis and suggest a model of pathogenesis based on progressive alterations in mPTP physiology and mitochondrial energetics.}, } @article {pmid39390534, year = {2024}, author = {Xu, M and Li, B and Li, C and Chai, P and Qiu, Q and Zheng, Z and Chen, Q and Luo, D and Xu, X and Zhou, C}, title = {Is longer axial length protective of vision-threatening diabetic retinopathy across different ages? A multicenter cohort of 736 patients.}, journal = {International journal of retina and vitreous}, volume = {10}, number = {1}, pages = {74}, pmid = {39390534}, issn = {2056-9920}, support = {22QA1407500//Shanghai Science and Technology Development Foundation/ ; SHWSRS [2022-65]//Shanghai Rising Stars of Medical Talent Youth Development Program/ ; CTCCR-2021C01//Clinical Research Innovation Plan of Shanghai General Hospital/ ; 82471104//National Natural Science Foundation of China/ ; }, abstract = {PURPOSE: Vision-threatening diabetic retinopathy (VTDR) included severe non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR) and clinically significant diabetic macular edema (DME). To compare the axial length (AL) and assess its influence on VTDR across different ages.

METHODS: A retrospective cohort study. Medical chart review was performed in 736 consecutive patients with VTDR. The patients were divided into young (≤ 45 years) and elderly group (> 45 years) based on their age at the diagnosis of VTDR. After at least one year of standardized treatments, all eligible patients were followed up. The main outcome measures included the presence of tractional retinal detachment (TRD) involving foveal, final best-corrected visual acuity (BCVA), the development of neovascular glaucoma (NVG), and recurrent vitreous hemorrhage (VH) post-vitrectomy. ALs were compared between two age groups. The impact of AL on clinical outcomes was determined by logistic analyses after controlling for systemic parameters.

RESULTS: The study included 144 patients ≤ 45 years and 592 patients > 45 years. Young patients had significantly longer AL than elderly participants (23.9 mm vs 23.0 mm, p < 0.001). Over a median follow-up of 25.9 months, a larger proportion of young patients developed TRD (34.7% vs 16.2%, p < 0.001) and recurrent VH (18.6% vs 10.3%, p = 0.040) than elderly patients. In elderly group, longer AL is an independent protective factor in preventing TRD (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.4-0.7; P < 0.001). However, this beneficial effect was not observed in young patients.

CONCLUSIONS: Young patients with VTDR exhibited significantly longer AL but more aggressive clinical signs with compromised prognosis. In elderly group, a longer AL independently reduced the risk of TRD, while this protective effect did not exist for young patients.}, } @article {pmid39389966, year = {2024}, author = {Kamemura, K and Kozono, R and Tando, M and Okumura, M and Koga, D and Kusumi, S and Tamai, K and Okumura, A and Sekine, S and Kamiyama, D and Chihara, T}, title = {Secretion of endoplasmic reticulum protein VAPB/ALS8 requires topological inversion.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8777}, pmid = {39389966}, issn = {2041-1723}, support = {P40 OD010949/OD/NIH HHS/United States ; R01 NS107558/NS/NINDS NIH HHS/United States ; 21K18236//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 21H02479//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; }, mesh = {*Endoplasmic Reticulum/metabolism ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Vesicular Transport Proteins/metabolism/genetics ; Cell Membrane/metabolism ; Mutation ; Protein Domains ; Membrane Proteins/metabolism/genetics ; HEK293 Cells ; Matrix Metalloproteinase 1/metabolism/genetics ; Protein Transport ; }, abstract = {VAMP-associated protein (VAP) is a type IV integral transmembrane protein at the endoplasmic reticulum (ER). Mutations in human VAPB/ALS8 are associated with amyotrophic lateral sclerosis (ALS). The N-terminal major sperm protein (MSP) domain of VAPB (Drosophila Vap33) is cleaved, secreted, and acts as a signaling ligand for several cell-surface receptors. Although extracellular functions of VAPB are beginning to be understood, it is unknown how the VAPB/Vap33 MSP domain facing the cytosol is secreted to the extracellular space. Here we show that Vap33 is transported to the plasma membrane, where the MSP domain is exposed extracellularly by topological inversion. The externalized MSP domain is cleaved by Matrix metalloproteinase 1/2 (Mmp1/2). Overexpression of Mmp1 restores decreased levels of extracellular MSP domain derived from ALS8-associated Vap33 mutants. We propose an unprecedented secretion mechanism for an ER-resident membrane protein, which may contribute to ALS8 pathogenesis.}, } @article {pmid39389563, year = {2025}, author = {Feindt, B and Roth, A and Heyde, CE and Behrens, J and Feist, B and Kasprick, L and Sultzer, R and Baerwald, C}, title = {GeriNOT in the Surgical Inpatient Setting.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {163}, number = {2}, pages = {137-145}, doi = {10.1055/a-2343-4014}, pmid = {39389563}, issn = {1864-6743}, mesh = {Humans ; Aged ; Female ; Male ; Aged, 80 and over ; Germany ; Retrospective Studies ; *Geriatric Assessment ; Risk Assessment ; Hospitalization/statistics & numerical data ; Femoral Fractures/surgery ; Hip Fractures/surgery ; }, abstract = {Die Richtlinie des Gemeinsamen Bundesausschusses (G-BA) über Maßnahmen zur Qualitätssicherung zur Versorgung von Patient*innen mit hüftgelenknaher Femurfraktur verpflichtet Krankenhäuser zum Einsatz eines validierten geriatrischen Screeninginstruments. Die systematische Anwendung des GeriNOT mit prozessproduzierter Datenerhebung im Akutaufnahmeprozess durch Integration in das Krankenhausinformationssystem (KIS) ermöglicht die Identifikation von Risikopotenzialen auch in anderen geriatrischen Diagnosegruppen.Mit Einbindung des GeriNOT in den Akutaufnahmeprozess wurde geprüft, ob auch andere vulnerable geriatrische Diagnosegruppen von einer frühzeitig eingeleiteten Risikoidentifikation profitieren können.Datengrundlage dieser Untersuchung bildete eine retrospektive bizentrische Erhebung elektronischer Fallakten (Mai 2014 bis April 2015, n = 3443). Aus diesem Primärdatensatz wurde die Subgruppe stationärer Akutaufnahmen (n = 821) der Orthopädie/Unfallchirurgie eines Zentrums in Bezug auf die Endpunkte "Inanspruchnahme bedarfsgerechter poststationärer Pflegeleistungen" und "Neueinzug in stationäre Dauer-/Kurzzeitpflege" analysiert. Es wurden Prädiktionskraft und Klassifikationsgenauigkeit von GeriNOT dieser ab 70-jährigen Personen in Diagnosegruppen für die definierten Endpunkte beurteilt: Akutaufnahmen insgesamt, Frakturen insgesamt, hüftgelenknahe Femurfraktur und Wirbelsäulenerkrankungen inklusive Wirbelsäulenfrakturen.Im Untersuchungszeitraum wurden 821 Personen akutstationär aufgenommen. Das mittlere Alter betrug 81,4 ± 6,8 Jahre (n = 821; 68,1% Frauen, 31,9% Männer). Folgende Diagnosegruppen wurden gebildet und analysiert: Frakturen insgesamt (n = 490), Wirbelsäulenerkrankungen (n = 265), davon Wirbelsäulenfrakturen (n = 174), hüftgelenknahe Femurfraktur (n = 108). In der Gesamtgruppe (n = 821; MW = 4,279; SD = 2,180) und in den Diagnosegruppen lag der Mittelwert des GeriNOT-Scores über dem Schwellenwert ≥ 4. In der Gruppe der hüftgelenknahen Femurfraktur wurde der höchste Wert ermittelt (MW = 4,852; SD = 2,022), der niedrigste in der Gruppe der Wirbelsäulenfrakturen (MW = 4,177; SD = 2,171). In der Aufnahmesituation bez. behandlungsbedürftiger Diagnosen, Polypharmazie und bereits in Anspruch genommener Pflegeleistungen unterschieden sich die Diagnosegruppen nur geringfügig. Einweisungen aus stationärer Kurz- und Dauerpflege erfolgten in der Gesamtgruppe (n = 821) in 16,44% der Fälle, am häufigsten mit 31,48% in der Gruppe der hüftgelenknahen Femurfraktur, hingegen am seltensten in der Diagnosegruppe der Wirbelsäulenerkrankungen mit 6,79%. GeriNOT detektierte für diese Gruppe ein erhöhtes Risiko in Bezug auf die definierten Endpunkte. Nur 4,26% aller Patient*innen mit identifiziertem geriatrischen Risikopotenzial wurden akutgeriatrisch weiterversorgt.Die Ergebnisse zeigten ein erhöhtes geriatrisches Risiko in allen analysierten Diagnosegruppen, am stärksten innerhalb der Gruppe der Wirbelsäulenerkrankungen. Der KIS-gestützte Einsatz des GeriNOT initiiert die systematische Risikoidentifikation im akutstationären Aufnahmemanagement. Die fallbegleitende Ergebnisvisualisierung in den KIS-Arbeitsplätzen könnte als Ausgangspunkt für die nachfolgende Anwendung von Assessmentinstrumenten und risikoadjustierter Behandlungspfade genutzt werden. Mit diesen Erkenntnissen könnte das Patientenoutcome potenziell positiv beeinflusst werden.}, } @article {pmid39386562, year = {2024}, author = {Dargan, R and Mikheenko, A and Johnson, NL and Packer, B and Li, Z and Craig, EJ and Sarbanes, SL and Bereda, C and Mehta, PR and Keuss, M and Nalls, MA and Qi, YA and Weller, CA and Fratta, P and Ryan, VH}, title = {Altered mRNA transport and local translation in iNeurons with RNA binding protein knockdown.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39386562}, issn = {2692-8205}, support = {ZIA AG000547/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Neurons rely on mRNA transport and local translation to facilitate rapid protein synthesis in processes far from the cell body. These processes allow precise spatial and temporal control of translation and are mediated by RNA binding proteins (RBPs), including those known to be associated with neurodegenerative diseases. Here, we use proteomics, transcriptomics, and microscopy to investigate the impact of RBP knockdown on mRNA transport and local translation in iPSC-derived neurons. We find thousands of transcripts enriched in neurites and that many of these transcripts are locally translated, possibly due to the shorter length of transcripts in neurites. Loss of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS)-associated RBPs TDP-43 and hnRNPA1 lead to distinct alterations in the neuritic proteome and transcriptome. TDP-43 knockdown (KD) leads to increased neuritic mRNA and translation. In contrast, hnRNPA1 leads to increased neuritic mRNA, but not translation, and more moderate effects on local mRNA profiles, possibly due to compensation by hnRNPA3. These results highlight the crucial role of FTD/ALS-associated RBPs in mRNA transport and local translation in neurons and the importance of these processes in neuron health and disease.}, } @article {pmid39386496, year = {2024}, author = {El-Khatib, SM and Vagadia, AR and Le, ACD and Ng, DQ and Baulch, JE and Du, M and Tan, Z and Xu, X and Chan, A and Acharya, MM}, title = {BDNF augmentation reverses cranial radiation therapy-induced cognitive decline and neurodegenerative consequences.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.09.23.614590}, pmid = {39386496}, issn = {2692-8205}, abstract = {Cranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNF in vivo in the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNF in vivo . In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT+Veh with the RT+RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6-7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.}, } @article {pmid39386447, year = {2024}, author = {Rodemer, W and Ra, I and Jia, E and Gujral, J and Zhang, B and Hoxha, K and Xing, B and Mehta, S and Farag, M and Porta, S and Jensen, FE and Talos, DM and Lee, VM}, title = {Hyperexcitability precedes CA3 hippocampal neurodegeneration in a dox-regulatable TDP-43 mouse model of ALS-FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.09.24.612703}, pmid = {39386447}, issn = {2692-8205}, abstract = {UNLABELLED: Neuronal hyperexcitability is a hallmark of amyotrophic lateral sclerosis (ALS) but its relationship with the TDP-43 aggregates that comprise the predominant pathology in over 90% of ALS cases remains unclear. Emerging evidence in tissue and slice culture models indicate that TDP-43 pathology induces neuronal hyperexcitability suggesting it may be responsible for the excitotoxicity long believed to be a major driver of ALS neuron death. Here, we characterized hyperexcitability and neurodegeneration in the hippocampus of doxycycline-regulatable rNLS8 mice (NEFH-tTA x tetO-hTDP-43ΔNLS), followed by treatment with AAV encoded DREADDs and anti-seizure medications to measure the effect on behavioral function and neurodegeneration. We found that approximately half of the CA3 neurons in the dorsal hippocampus are lost between 4 and 6 weeks after TDP-43ΔNLS induction. Neurodegeneration was preceded by selective hyperexcitability in the mossy fiber - CA3 circuit, leading us to hypothesize that glutamate excitotoxicity may be a significant contributor to neurodegeneration in this model. Interestingly, hippocampal injection of AAV encoded inhibitory DREADDs (hM4Di) and daily activation with CNO ligand rescued anxiety deficits on elevated zero maze (EZM) but did not reduce neurodegeneration. Therapeutic doses of the anti-seizure medications, valproic acid and levetiracetam, did not improve behavior or prevent neurodegeneration. These results highlight the complexity of TDP-43 - induced alterations to neuronal excitability and suggest that whereas targeting hyperexcitability can meliorate some behavioral deficits, it may not be sufficient to halt or slow neurodegeneration in TDP-43-related proteinopathies.

SIGNIFICANCE STATEMENT: Cytoplasmic aggregates of TAR DNA Binding Protein 43 (TDP-43) are the predominant pathology in over 90% of Amyotrophic lateral sclerosis (ALS) and the majority of frontotemporal lobar degeneration (FTLD-TDP) cases. Understanding how TDP-43 pathology promotes neurodegeneration may lead to therapeutic strategies to slow disease progression in humans. Recent reports in mouse and cell culture models suggest loss-of-normal TDP-43 function may drive neuronal hyperexcitability, a key physiological hallmark of ALS and possible contributor to neurodegeneration. In this study, we identified region-specific hyperexcitability that precedes neurodegeneration in the inducible rNLS8 TDP-43 mouse model. Suppressing hyperexcitability with chemogenetics improved behavioral function but did not reduce hippocampal neuron loss. Anti-seizure medications had no beneficial effects suggesting directly targeting hyperexcitability may not be therapeutically effective.}, } @article {pmid39386324, year = {2024}, author = {Ross, CW and Loudermilk, EL and O'Brien, JJ and Snitker, G}, title = {Lidar-derived structural-complexity data across four experimental forests.}, journal = {Data in brief}, volume = {57}, number = {}, pages = {110955}, pmid = {39386324}, issn = {2352-3409}, abstract = {Structural complexity refers to the three-dimensional arrangement and variability of both biotic and abiotic components of an ecosystem. Metrics that characterize structural complexity are often used to manage various aspects of ecosystem function, such as light transmittance, wildlife habitat, and biological diversity. Additionally, these metrics aid in evaluating resilience to disturbance events, including hurricanes, bark-beetle outbreaks, and wildfire. Recent advances in wildland fire modelling have facilitated the integration of forest structural complexity metrics into the QUIC-Fire model, enabling real-time prediction of fire spread and behaviour by simulating interactions between fire, weather, topography, and forest structure. While QUIC-Fire is designed to be highly adaptable, model performance depends on the availability and accuracy of local data inputs. Expanding the model's usability across different regions can be facilitated by the availability of more comprehensive and high-quality data. Thus, the primary goal behind the data products we developed was to establish a basis for collaborative research across various disciplines, particularly within the focal areas of the Southern Research Station, such as forestry, wildland fire, hydrology, soil science, and cultural resources at Bent Creek, Coweeta, Escambia, and Hitchiti Experimental Forests (EFs). Airborne laser scanning (ALS) was used to collect point-cloud data for each EF during the leaf-off season to minimize interference from foliage. Subsequent processing of the raw lidar data involved outlier detection and filtering, ground and non-ground classification, and the computation of a variety of metrics representing various aspects of topography and forest structure at both the pixel-level and the tree-level. Pixel-level topographic data products include: digital elevation model (DEM), slope, aspect, topographic position index (TPI), topographic roughness index (TRI), roughness, and flow direction. Forest structural-complexity metrics include canopy height, foliar height diversity (FHD), vertical distribution ratio (VDR), canopy rugosity, crown relief ratio (CRR), understory complexity index (UCI), vertical complexity index (VCI), canopy cover, mean vegetation height, and the standard deviation of vegetation height. Tree-level data products were computed from the point cloud using multiple algorithms to perform individual tree detection (ITD) and individual tree segmentation (ITS). The datasets have been harmonized and are openly accessible through the USDA Forest Service Research Data Archive.}, } @article {pmid39385824, year = {2024}, author = {Chen, L and Chen, J and Weng, W and Wu, M and Zhou, X and Yan, P}, title = {Bibliometric analysis of microRNAs and Parkinson's disease from 2014 to 2023.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1466186}, pmid = {39385824}, issn = {1664-2295}, abstract = {BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons. Recent research has emphasized a significant correlation between microRNAs (miRNAs) and PD. To identify key research areas, provide a comprehensive overview of current research in various fields, and propose potential directions for future studies, a bibliometric analysis was conducted on the involvement of miRNAs in Parkinson's disease from 2014 to 2023.

METHODS: Relevant literature records were collected from the Web of Science Core Collection on February 29, 2024. Subsequently, the data underwent analysis using the Bibliometrix R package and VOSviewer (version 1.6.19).

RESULTS: The annual scientific publications on miRNAs and Parkinson's disease demonstrated an increasing trend, with an annual growth rate of 12.67%. China, the United States, and India emerged as the top three most productive countries/regions. The University of Barcelona had the highest annual publications, followed by Central South University and the Helmholtz Association. The INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES held the top position in terms of H-index and total citations, reflecting its extensive influence and prolific publication output. Kim, J., Junn, E., Hébert, S.S., and Doxakis, E. were the most frequently co-cited authors in the field. Based on the analysis of keywords, the most frequently occurring terms included "alpha-synuclein," "neurodegenerative disease," "exosome," "neuroinflammation," "oxidative stress," "autophagy," and "amyotrophic lateral sclerosis," which have emerged as prominent research topics. Concurrently, there has been notable interest in topics such as "ceRNA," "lncRNAs," "mitochondrial dysfunction," and "circular RNA."

CONCLUSION: This study focused on identifying emerging trends and critical research topics in the bibliometric analysis of microRNAs related to Parkinson's disease. These findings highlight the diverse research landscape and evolving trend of miRNA-related research in PD. The field of miRNA research in Parkinson's disease is actively exploring the underlying mechanisms of miRNA function, identifying potential diagnostic markers, and developing innovative therapeutic strategies. The results of our study offer significant contributions to researchers' ability to track contemporary developments and guide the trajectory of future research in this domain.}, } @article {pmid39385724, year = {2025}, author = {van den Bos, MAJ and Menon, P and Pavey, N and Higashihara, M and Kiernan, MC and Vucic, S}, title = {Direct interrogation of cortical interneuron circuits in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {4}, pages = {1169-1179}, doi = {10.1093/brain/awae317}, pmid = {39385724}, issn = {1460-2156}, support = {//MND Research Australia/ ; #2021/GNT2010812//NHMRC/ ; //Millhouse Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Male ; *Interneurons/physiology ; Transcranial Magnetic Stimulation/methods ; Middle Aged ; Female ; Aged ; Electroencephalography/methods ; *Motor Cortex/physiopathology ; Evoked Potentials, Motor/physiology ; Adult ; }, abstract = {Cortical hyperexcitability is a key pathogenic feature of amyotrophic lateral sclerosis (ALS), believed to be mediated through complex interplay of cortical interneurons. To date, there has been no technological approach to facilitate the direct capture of cortical interneuron function. Through combination of transcranial magnetic stimulation (TMS) with advanced EEG, the present study examined GABAergic dysfunction in ALS by recording focused cortical output whilst applying TMS over the primary motor cortex contralateral to the site of symptom onset. Using both a single-pulse and a novel inhibitory paired-pulse paradigm, TMS-EEG studies were undertaken on 21 ALS patients and results compared with healthy controls. TMS responses captured by EEG form a discrete waveform known as the transcranial evoked potential (TEP), with positive (P) or upward deflections occurring at 30 (P30), 60 (P60) and 190 ms (P190) after TMS stimulus. Negative (N) or downward deflections occur at 44 (N44), 100 (N100) and 280 ms (N280) after TMS stimulus. The single-pulse TEPs recorded in ALS patients demonstrated novel differences suggestive of cortical GABAergic dysfunction. When compared with controls, the N100 component was significantly reduced (P < 0.05), whereas the P190 component increased (P < 0.05) in ALS patients. Additionally, the N44 component was correlated with muscle weakness (r = -0.501, P < 0.05). These findings were supported by reduced paired-pulse inhibition of TEP components in ALS patients (P60, P < 0.01; N100, P < 0.005), consistent with dysfunction of cortical interneuronal GABAA-ergic circuits. Furthermore, the reduction in short-interval intracortical inhibition, as reflected by changes in paired-pulse inhibition of the N100 component, was associated with longer disease duration in ALS patients (r = -0.698, P < 0.001). In conclusion, intensive and focused interrogation of the motor cortex using novel TMS-EEG combined technologies has established localized dysfunction of GABAergic circuits, supporting the notion that cortical hyperexcitability is mediated by cortical disinhibition in ALS. Dysfunction of GABAergic circuits was correlated with greater clinical disability and disease duration, implying pathophysiological significance.}, } @article {pmid39385461, year = {2025}, author = {Li, X and Wicks, P and Brown, A and Shivaprasad, A and Greene, M and Crayle, J and Barnes, B and Jhooty, S and Ratner, D and Olby, N and Glass, JD and Jackson, C and Cole, N and Armon, C and Mascias Cadavid, J and Pattee, G and Mcdermott, CJ and Chang, V and Maragakis, N and Bertorini, T and Bowser, R and Bedlack, R}, title = {ALSUntangled #76: Wahls protocol.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {181-185}, doi = {10.1080/21678421.2024.2407407}, pmid = {39385461}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/diet therapy ; Humans ; Disease Progression ; Animals ; Diet ; Fatty Acids, Omega-3/therapeutic use ; }, abstract = {The Wahls diet is a modified Paleolithic diet that emphasizes dark green leafy vegetables, colorful fruits, high-quality animal proteins, and omega-3 polyunsaturated fatty acids, while limiting grains, legumes, dairy products, sugar, and processed foods containing proinflammatory omega-6 fatty acids. The Wahls diet may reduce inflammation, oxidative stress, and mitochondrial dysfunction and has plausible mechanisms for slowing amyotrophic lateral sclerosis (ALS) progression. However, research on its dietary components in the ALS animal models has yielded conflicting results. Though multiple cohort studies suggest high carotenoids, omega-3 fatty acids and fruit intake are associated with reduced ALS risks, neither the diet nor its components has been demonstrated to slow down ALS progression in case studies or clinical trials. On the contrary, the Wahls diet, a restrictive, low-carbohydrate and low glycemic index diet, caused an average weight loss of 7.2% BMI in multiple sclerosis clinical trials, which is a significant concern for people living with amyotrophic lateral sclerosis (PALS) as weight loss is associated with faster ALS progression and shorter survival. Considering the above, we cannot endorse the Wahls diet for slowing ALS progression.}, } @article {pmid39385408, year = {2024}, author = {Shekhar, AC and Alexander, A and Simms, M and Jahan, M and Haugen, A and Lu, M and Ball, R and Clement, J}, title = {Ambulance Transports from NCAA Division 1 Football Games.}, journal = {Prehospital and disaster medicine}, volume = {39}, number = {3}, pages = {266-269}, pmid = {39385408}, issn = {1945-1938}, mesh = {Humans ; *Ambulances ; Male ; Cross-Sectional Studies ; *Football ; Female ; Young Adult ; Minnesota ; Adult ; Emergency Medical Services ; Universities ; Adolescent ; Crowding ; }, abstract = {INTRODUCTION: There is significant public health interest towards providing medical care at mass-gathering events. Furthermore, mass gatherings have the potential to have a detrimental impact on the availability of already-limited municipal Emergency Medical Services (EMS) resources. This study presents a cross-sectional descriptive analysis to report broad trends regarding patients who were transported from National Collegiate Athletic Association (NCAA) Division 1 collegiate football games at a major public university in order to better inform emergency preparedness and resource planning for mass gatherings.

METHODS: Patient care reports (PCRs) from ambulance transports originating from varsity collegiate football games at the University of Minnesota across six years were examined. Pertinent information was abstracted from each PCR.

RESULTS: Across the six years of data, there were a total of 73 patient transports originating from NCAA collegiate football games: 45.2% (n = 33) were male, and the median age was 22 years. Alcohol-related chief complaints were involved in 50.7% (n = 37) of transports. In total, 31.5% of patients had an initial Glasgow Coma Scale (GCS) of less than 15. The majority (65.8%; n = 48; 0.11 per 10,000 attendees) were transported by Basic Life Support (BLS) ambulances. The remaining patients (34.2%; n = 25; 0.06 per 10,000 attendees) were transported by Advanced Life Support (ALS) ambulances and were more likely to be older, have abnormal vital signs, and have a lower GCS.

CONCLUSIONS: This analysis of ambulance transports from NCAA Division 1 collegiate football games emphasizes the prevalence of alcohol-related chief complaints, but also underscores the likelihood of more life-threatening conditions at mass gatherings. These results and additional research will help inform emergency preparedness at mass-gathering events.}, } @article {pmid39382075, year = {2025}, author = {Liang, B and Khan, M and Storts, H and Zhang, EH and Zheng, X and Xing, X and Claybon, H and Wilson, J and Li, C and Jin, N and Fishel, R and Miles, WO and Wang, JJ}, title = {Riluzole Enhancing Anti-PD-1 Efficacy by Activating cGAS/STING Signaling in Colorectal Cancer.}, journal = {Molecular cancer therapeutics}, volume = {24}, number = {1}, pages = {131-140}, pmid = {39382075}, issn = {1538-8514}, support = {R01 CA251753/CA/NCI NIH HHS/United States ; R01 CA208063/CA/NCI NIH HHS/United States ; R01CA215389//National Cancer Institute (NCI)/ ; P30 CA016058/CA/NCI NIH HHS/United States ; R01 CA215389/CA/NCI NIH HHS/United States ; R01 CA067007/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Nucleotidyltransferases/metabolism ; *Colorectal Neoplasms/drug therapy/metabolism/pathology ; Mice ; *Membrane Proteins/metabolism ; Humans ; *Signal Transduction/drug effects ; *Programmed Cell Death 1 Receptor/antagonists & inhibitors/metabolism ; *Riluzole/pharmacology/therapeutic use ; CD8-Positive T-Lymphocytes/drug effects/immunology/metabolism ; Cell Line, Tumor ; Immune Checkpoint Inhibitors/pharmacology/therapeutic use ; }, abstract = {Colorectal cancer is the second leading cause of cancer mortality in the United States. Although immune checkpoint blockade therapies including anti-PD-1/PD-L1 have been successful in treating a subset of patients with colorectal cancer, the response rates remain low. We have found that riluzole, a well-tolerated FDA-approved oral medicine for treating amyotrophic lateral sclerosis, increased intratumoral CD8+ T cells and suppressed tumor growth of colon cancer cells in syngeneic immune-competent mice. Riluzole-mediated tumor suppression was dependent on the presence of CD8+ T cells. Riluzole activates the cytosolic DNA sensing cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway in colon cancer cells, resulting in increased expression of IFNβ and IFNβ-regulated genes including CXCL10. Inhibition of ataxia telangiectasia mutated (ATM), but not ATM-related, resulted in a synergistic increase in IFNβ expression, suggesting that riluzole induces ATM-mediated damage response that contributes to cGAS/STING activation. Depletion of cGAS or STING significantly attenuated riluzole-induced expression of IFNβ and CXCL10 as well as increase of intratumoral CD8+ T cells and suppression of tumor growth. These results indicate that riluzole-mediated tumor infiltration of CD8+ T cells and attenuation of tumor growth is dependent on tumor cell-intrinsic STING activation. To determine whether riluzole treatment primes the tumor microenvironment for immune checkpoint modulation, riluzole was combined with anti-PD-1 treatment. This combination showed greater efficacy than either single agent and strongly suppressed tumor growth in vivo. Taken together, our studies indicate that riluzole activates cGAS/STING-mediated innate immune responses, which might be exploited to sensitize colorectal tumors to anti-PD-1/PD-L1 therapies.}, } @article {pmid39381976, year = {2024}, author = {Grassano, M and Moglia, C and Palumbo, F and Koumantakis, E and Cugnasco, P and Callegaro, S and Canosa, A and Manera, U and Vasta, R and De Mattei, F and Matteoni, E and Fuda, G and Salamone, P and Marchese, G and Casale, F and De Marchi, F and Mazzini, L and Mora, G and Calvo, A and Chiò, A}, title = {Reply to "Comprehensive Analysis of Sex Differences in Amyotrophic Lateral Sclerosis Prognosis and Disease Progression".}, journal = {Annals of neurology}, volume = {96}, number = {5}, pages = {1029}, doi = {10.1002/ana.27095}, pmid = {39381976}, issn = {1531-8249}, support = {//ALS Association/ ; //American Brain Foundation/ ; //American Academy of Neurology/ ; }, } @article {pmid39381934, year = {2024}, author = {Calati, R and Tambuzzi, S and Gravagnuolo, R and Muscatiello, L and Magrin, ME and Crippa, F and Madeddu, F and Zoja, R and Gentile, G}, title = {Suicide in prison in the North of Italy (1993-2022): a case-control study examining differences between suicides inside and outside prison.}, journal = {International clinical psychopharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1097/YIC.0000000000000569}, pmid = {39381934}, issn = {1473-5857}, abstract = {Prisoners constitute a group at suicide risk, showing higher relative rates of suicides than the general population. However, there is limited knowledge about the characteristics of those who die by suicide in Italian prisons. Based on the total sample of suicides of the Institute of Forensic Medicine of Milan (1993-2022), suicides in prison (N = 120) were matched by age and gender with cases that occurred outside prison (N = 300) and compared with them. The considered variables were sociodemographic, clinical, and suicide-related. Univariate analyses and logistic regression model were performed. In univariate analyses, suicides in prison showed higher rates of ethnicity different from white Caucasian, lower rates of depression, higher rates of alcoholism, addiction, respiratory system diseases, hepatitis, and amyotrophic lateral sclerosis, lower use of any medication, and in particular psychotropic medications, and a higher percentage of violent suicide method versus nonviolent compared to suicides outside prison. In the logistic regression model, ethnicity, depression, and addiction were the only features differentiating suicides in prison from ones outside prison. Particular attention should be paid to inmates with non-white ethnicity and those with addiction. Ensuring adequate access to psychiatric care and implementing comprehensive suicide prevention strategies within Italian prisons is crucial.}, } @article {pmid39380150, year = {2024}, author = {Meshram, VD and Balaji, R and Saravanan, P and Subbamanda, Y and Deeksha, W and Bajpai, A and Joshi, H and Bhargava, A and Patel, BK}, title = {Computational Insights Into the Mechanism of EGCG's Binding and Inhibition of the TDP-43 Aggregation.}, journal = {Chemical biology & drug design}, volume = {104}, number = {4}, pages = {e14640}, doi = {10.1111/cbdd.14640}, pmid = {39380150}, issn = {1747-0285}, support = {//Science and Engineering Research Board ; Department of Science and Technology/ ; SRG/2022/002109;SERB/CRG/2021/006856//Science Engineering Research Board, Govt. of India/ ; IFA20-PH-256//Deprartment of Science and Technology, Ministry of Science and Technology, Govt. of India, Inspire faculty fellowship/ ; }, mesh = {*Catechin/analogs & derivatives/chemistry/pharmacology/metabolism ; *DNA-Binding Proteins/metabolism/chemistry/antagonists & inhibitors ; Humans ; *Molecular Dynamics Simulation ; *Molecular Docking Simulation ; *Protein Binding ; Binding Sites ; Thermodynamics ; Protein Aggregates/drug effects ; Protein Domains ; }, abstract = {Misfolding and aggregation of TAR DNA-binding protein, TDP-43, is linked to devastating proteinopathies such as ALS. Therefore, targeting TDP-43's aggregation is significant for therapeutics. Recently, green tea polyphenol, EGCG, was observed to promote non-toxic TDP-43 oligomer formation disallowing TDP-43 aggregation. Here, we investigated if the anti-aggregation effect of EGCG is mediated via EGCG's binding to TDP-43. In silico molecular docking and molecular dynamics (MD) simulation suggest a strong binding of EGCG with TDP-43's aggregation-prone C-terminal domain (CTD). Three replicas, each having 800 ns MD simulation of the EGCG-TDP-43-CTD complex, yielded a high negative binding free energy (ΔG) inferring a stable complex formation. Simulation snapshots show that EGCG forms close and long-lasting contacts with TDP-43's Phe-313 and Ala-341 residues, which were previously identified for monomer recruitment in CTD's aggregation. Notably, stable physical interactions between TDP-43 and EGCG were also detected in vitro using TTC staining and isothermal titration calorimetry which revealed a high-affinity binding site of EGCG on TDP-43 (Kd, 7.8 μM; ΔG, -6.9 kcal/mol). Additionally, TDP-43 co-incubated with EGCG was non-cytotoxic when added to HEK293 cells. In summary, EGCG's binding to TDP-43 and blocking of residues important for aggregation can be a possible mechanism of its anti-aggregation effects on TDP-43.}, } @article {pmid39379597, year = {2024}, author = {Fontdevila, L and Povedano, M and Domínguez, R and Boada, J and Serrano, JC and Pamplona, R and Ayala, V and Portero-Otín, M}, title = {Examining the complex Interplay between gut microbiota abundance and short-chain fatty acid production in amyotrophic lateral sclerosis patients shortly after onset of disease.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {23497}, pmid = {39379597}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/microbiology/metabolism ; *Gastrointestinal Microbiome ; Male ; *Fatty Acids, Volatile/metabolism ; Female ; Middle Aged ; Aged ; Adult ; Case-Control Studies ; }, abstract = {This study aimed to assess differences in the enteral microbiome of relatively recent-onset amyotrophic lateral sclerosis (ALS) patients (< 6-15 months since symptom onset) compared to healthy individuals, focusing on short-chain fatty acids (SCFAs) as potential mediators of host metabolism. We included 28 volunteers (16 ALS, 12 controls) with informed consent. No significant effect of ALS on alpha diversity (measuring the variety and abundance of species within a single sample, and indicating the health and complexity of the microbiome) was observed, but ALS patients had higher abundances of Fusobacteria and Acidobacteria. ALS subtypes influenced specific species, with increased Fusobacteria and Tenericutes in spinal ALS compared to bulbar ALS. ALS patients showed increased Enterobacter, Clostridium, Veillonella, Dialister, Turicibacter, and Acidaminococcus species and decreased Prevotella, Lactobacillus, and Butyricimonas. Correlations between species varied between ALS patients and healthy individuals and among ALS subtypes. No significant differences in SCFA concentrations were found, but spinal ALS samples showed a trend towards decreased propionate content. Relationships between SCFAs and phyla colonization differed by disease status. This study suggests distinct enteral microbiome characteristics in ALS patients, though the implications are unclear. Further research is needed to determine if these differences are causative or consequential and to explore their potential as diagnostic or therapeutic targets. The study also underscores the heterogeneity of microbiome constraints in ALS and the need for more research into ALS and SCFA metabolism.}, } @article {pmid39378795, year = {2024}, author = {Lehto, A and Schumacher, J and Kasper, E and Teipel, S and Hermann, A and Prudlo, J}, title = {Loss of the ipsilateral silent period in amyotrophic lateral sclerosis is associated with reduced white matter integrity in the motor section of the corpus callosum.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123267}, doi = {10.1016/j.jns.2024.123267}, pmid = {39378795}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/psychology ; *Corpus Callosum/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *White Matter/diagnostic imaging/pathology ; *Transcranial Magnetic Stimulation/methods ; Aged ; *Motor Cortex/diagnostic imaging/pathology/physiopathology ; Diffusion Tensor Imaging ; Functional Laterality/physiology ; Diffusion Magnetic Resonance Imaging/methods ; Adult ; Neural Inhibition/physiology ; Evoked Potentials, Motor/physiology ; }, abstract = {OBJECTIVE: Interhemispheric neurons in the motor section of the corpus callosum have an inhibitory effect on neurons of the contralateral motor cortex. Three quarters of patients with amyotrophic laterals sclerosis (ALS) show impaired transcallosal inhibition. We aimed to investigate whether structural changes co-occur with this functional impairment and to explore its phenotypic correlates.

METHODS: The demographic, clinical, and neuropsychological data of 127 ALS patients were analysed. Transcallosal inhibition was assessed with an ipsilateral silent period (iSP) protocol using transcranial magnetic stimulation. Patients were categorised based on an iSP response or its loss, and the groups were characterised by demographic, clinical, and neuropsychological variables. Diffusion-weighted images from a subset of 63 patients were analysed using tractography, and white matter (WM) structural integrity metrics were compared across groups.

RESULTS: 54 % of patients displayed iSP loss. The average free-water-corrected fractional anisotropy values within the callosal tract between the primary motor cortices were lower for patients with iSP loss compared to patients with an iSP response. There were no group differences based on other diffusivity metrics. The groups did not differ regarding any of the demographic, clinical, or neuropsychological variables.

INTERPRETATION: We found reduced WM integrity in the motor section of the corpus callosum that differentiated ALS patients with iSP loss from patients with an iSP response, but with a small effect size. Nevertheless, the underlying pathological substrate and potential genetic drivers for these structural and functional changes in a subset of ALS patients remain to be satisfactorily investigated.}, } @article {pmid39378530, year = {2025}, author = {Meng, T and Wu, W and Wang, B and Li, C and Li, J and Liu, J and Wang, J and Qie, R}, title = {Treating chronic pulmonary heart disease with traditional Chinese medicine: Systematic evaluation and mechanistic insights into the resolving phlegm and activating blood approach.}, journal = {Heart & lung : the journal of critical care}, volume = {69}, number = {}, pages = {111-126}, doi = {10.1016/j.hrtlng.2024.09.017}, pmid = {39378530}, issn = {1527-3288}, mesh = {Humans ; Chronic Disease ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Medicine, Chinese Traditional/methods ; *Pulmonary Heart Disease/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Chronic Pulmonary Heart Disease (CPHD) significantly impacts global health, especially among middle-aged and older adults. In China, the Traditional Chinese Medicine (TCM) technique of Resolving Phlegm and Activating Blood (RPAB) is widely used to treat CPHD, although high-quality evidence supporting its efficacy remains limited.

OBJECTIVES: The purpose of this study was to rigorously assess the clinical efficacy of RPAB for CPHD and elucidate the mechanisms underlying its primary herbal components.

METHODS: Through a detailed search of literature in both Chinese and English and strict inclusion and exclusion criteria, 18 randomized controlled trials (RCTs) were selected for meta-analysis. We identified RPAB's core herbal combinations using association rule analysis. This method statistically analyzes the frequency and correlation of herbal medicine usage. We then analyzed the chemical components of these combinations and investigated their potential intervention mechanisms on CPHD through network pharmacology.

RESULTS: The combination of RPAB with Western medicine was superior to Western medicine alone in improving blood gas analysis and pulmonary function and reducing plasma viscosity in CPHD patients. The core herbal combination identified was Astragalus membranaceus (Fisch.) Bunge, Ligusticum chuanxiong Hort. ex S. H. Qiu & al., and Stellaria alsine Grimm (ALS). This combination targeted 588 therapeutic and 27 core targets. It influenced ten core compounds across 34 pathways, primarily through the chemokine signaling pathway and the JAK-STAT signaling pathway.

CONCLUSION: RPAB with Western medicine significantly improves CPHD treatment outcomes. The study highlights the therapeutic potential of the ALS combination, which operates through multiple pathways to remodel pulmonary arteries, decrease inflammation, and lessen oxidative stress. These insights support the clinical application of RPAB in CPHD treatment and open new avenues for research and therapeutic development.}, } @article {pmid39378421, year = {2024}, author = {Knox, L and Coates, E and Griffiths, A and Ali, Y and Hobson, E and McDermott, C}, title = {Development and Evaluation of the Telehealth in Motor Neuron Disease System: The TIME Study Protocol.}, journal = {JMIR research protocols}, volume = {13}, number = {}, pages = {e57685}, pmid = {39378421}, issn = {1929-0748}, mesh = {*Motor Neuron Disease/therapy ; Humans ; *Telemedicine ; Surveys and Questionnaires ; Caregivers/psychology ; }, abstract = {BACKGROUND: For more responsive care provision for motor neuron disease and caregivers, a digital system called Telehealth in MND-Care (TiM-C) was created. TiM-C sends regular symptom questionnaires to users; their responses are sent to health care professionals (HCPs). To enable people with motor neuron disease to participate in research studies more easily, a parallel platform was developed from TiM-C, called Telehealth in MND-Research (TiM-R). TiM-R can advertise studies, collect data, and make them available to MND researchers.

OBJECTIVE: This study has 4 work packages (WPs) to facilitate service approval, codevelop the TiM systems, and evaluate the service. Each WP aims to understand (1) what helps and hinders the approval of the TiM-C system as a National Health Service; (2) what aspects of MND care and research are currently unmet and can be addressed through the TiM-C and TiM-R systems; (3) how TiM-C influences MND care, from the perspective of people with motor neuron disease, their caregivers, and HCPs; and (4) the costs and benefits associated with TiM-C.

METHODS: WP1 will use semistructured interviews with 10-15 people involved in the approval of TiM-C to understand the barriers and facilitators to governance processes. WP2 will use individual and group interviews with 25-35 users (people with motor neuron disease, caregivers, HCPs, MND researchers, and industry) of TiM-C and TiM-R to understand the current unmet needs of these user groups and how TiM services can be developed to meet these needs. WP3 will use a process evaluation involving 5 elements; local context, engagement, user experiences, service impact, and mechanisms of action. A range of methods, including audits, analysis of routine data, questionnaires, interviews, and observations will be used with people with motor neuron disease, caregivers, and HCPs, both those using the system and those who declined the service when invited. WP4 will use data collected through the process evaluation and known costs to conduct a cost-consequence and budget impact analysis to explore the cost-benefit of the TiM-C service. Most data collected will be qualitative, with thematic and framework analysis used to develop themes from transcripts and observations. Descriptive statistics or t tests and chi-square tests will be used to describe and analyze quantitative data.

RESULTS: This study has received ethical approval and has begun recruitment in 1 site. Further, 13 specialist MND centers will adopt TiM-C and the TIME study, beginning in July 2024. The study will conclude in November 2026 and a final report will be produced 3 months after the completion date.

CONCLUSIONS: This study will facilitate the implementation and development of TiM-C and TiM-R and fully evaluate the TiM-C service, enabling informed decision-making among health care providers regarding continued involvement and contribute to the wider literature relating to how technology-enabled care services can affect clinical care.

DERR1-10.2196/57685.}, } @article {pmid39377567, year = {2024}, author = {Rani, P and Rajak, BK and Mahato, GK and Rathore, RS and Chandra, G and Singh, DV}, title = {Strategic lead compound design and development utilizing computer-aided drug discovery (CADD) to address herbicide-resistant Phalaris minor in wheat fields.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.8455}, pmid = {39377567}, issn = {1526-4998}, support = {//Science and Engineering Research Board, India/ ; //Department of Biotechnology, Ministry of Science and Technology, India/ ; //Department of Science and Technology, Ministry of Science and Technology, India/ ; }, abstract = {Wheat (Triticum aestivum) is a vital cereal crop and a staple food source worldwide. However, wheat grain productivity has significantly declined as a consequence of infestations by Phalaris minor. Traditional weed control methods have proven inadequate owing to the physiological similarities between P. minor and wheat during early growth stages. Consequently, farmers have turned to herbicides, targeting acetyl-CoA carboxylase (ACCase), acetolactate synthase (ALS) and photosystem II (PSII). Isoproturon targeting PSII was introduced in mid-1970s, to manage P. minor infestations. Despite their effectiveness, the repetitive use of these herbicides has led to the development of herbicide-resistant P. minor biotypes, posing a significant challenge to wheat productivity. To address this issue, there is a pressing need for innovative weed management strategies and the discovery of novel herbicide molecules. The integration of computer-aided drug discovery (CADD) techniques has emerged as a promising approach in herbicide research, that facilitates the identification of herbicide targets and enables the screening of large chemical libraries for potential herbicide-like molecules. By employing techniques such as homology modelling, molecular docking, molecular dynamics simulation and pharmacophore modelling, CADD has become a rapid and cost-effective medium to accelerate the herbicide discovery process significantly. This approach not only reduces the dependency on traditional experimental methods, but also enhances the precision and efficacy of herbicide development. This article underscores the critical role of bioinformatics and CADD in developing next-generation herbicides, offering new hope for sustainable weed management and improved wheat cultivation practices. © 2024 Society of Chemical Industry.}, } @article {pmid39376539, year = {2024}, author = {Kouchmeshky, A and Whiting, A and McCaffery, P}, title = {Neuroprotective effects of ellorarxine in neuronal models of degeneration.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1422294}, pmid = {39376539}, issn = {1662-4548}, abstract = {INTRODUCTION: Retinoic acid (RA) was first recognised to be important for the central nervous system (CNS) in its developmental regulatory role and, given this action, it has been proposed in the adult CNS to regulate plasticity and promote regeneration. These types of roles have included support of neurogenesis, induction of neurite outgrowth, and protection from neuronal death. These functions are predominantly mediated by the retinoic acid receptor (RAR) transcription factor, and hence agonists for the RARs have been tested in a variety of models of neurodegeneration. This present study employs several in vitro models less explored for the action of RAR agonists to reverse neurodegeneration.

METHODS: A series of assays are used in which neuronal cells are placed under the types of stress that have been linked to neurodegeneration, in particular amyotrophic lateral sclerosis (ALS), and the neuroprotective influence of a new potent agonist for RAR, ellorarxine, is tested out. In these assays, neuronal cells were subjected to excitotoxic stress induced by glutamate, proteostasis disruption caused by epoxomicin, and oxidative stress leading to stress granule formation triggered by sodium arsenite.

RESULTS: Ellorarxine effectively reversed neuronal death in excitotoxic and proteostasis disruption assays and mitigated stress granule formation induced by sodium arsenite. This study also highlights for the first time the novel observation of RAR modulation of stress granules, although it is unknown whether this change in stress granules will be neuroprotective or potentially regenerative. Furthermore, the distribution of RAR agonists following intraperitoneal injection was assessed in mice, revealing preferential accumulation in the central nervous system, particularly in the spinal cord, compared to the liver. Gene expression studies in the spinal cord demonstrated that ellorarxine induces transcriptional changes at a low dose (0.01 mg/kg).

DISCUSSION: These findings underscore the therapeutic potential of RAR agonists, such as ellorarxine, for ALS and potentially other neurodegenerative diseases.}, } @article {pmid39376212, year = {2024}, author = {Tomiyama, ALMR and Cartarozzi, LP and de Oliveira Coser, L and Chiarotto, GB and Oliveira, ALR}, title = {Corrigendum: Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1[G93A] mice.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1493884}, doi = {10.3389/fncel.2024.1493884}, pmid = {39376212}, issn = {1662-5102}, abstract = {[This corrects the article DOI: 10.3389/fncel.2023.1211486.].}, } @article {pmid39375835, year = {2024}, author = {Altomare, D and Bracca, V and Premi, E and Micheli, A and Cotelli, MS and Gasparotti, R and Alberici, A and Borroni, B}, title = {Clinical and imaging correlates of hyperorality in syndromes associated with frontotemporal lobar degeneration.}, journal = {Psychiatry and clinical neurosciences}, volume = {78}, number = {12}, pages = {818-825}, pmid = {39375835}, issn = {1440-1819}, mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; *Frontotemporal Lobar Degeneration/diagnostic imaging/pathology/physiopathology ; Retrospective Studies ; *Frontotemporal Dementia/diagnostic imaging/physiopathology/pathology ; Longitudinal Studies ; Magnetic Resonance Imaging ; Amyotrophic Lateral Sclerosis/diagnostic imaging/complications ; }, abstract = {AIM: Empirical research investigating hyperorality in syndromes associated with frontotemporal lobar degeneration (FTLD) is limited. The present study aims to assess and describe hyperorality and its clinical and imaging correlates in patients with FTLD-associated syndromes.

METHODS: This retrospective longitudinal study included consecutive patients with FTLD who underwent a clinical, cognitive, and behavioral assessment. The presence and severity of hyperorality was assessed using the Frontal Behavior Inventory.

RESULTS: A total of 712 patients with FTLD were included in the study. Hyperorality was reported by 29% (204 of 712 [95% CI: 25-32%]) of patients; was more frequent in those with severe dementia than in those with prodromal or mild to moderate dementia (P < 0.05); was associated with younger age (odds ratio [OR] = 0.96 [95% CI: 0.94-0.99]), (P = 0.003) and positive family history for dementia (OR = 2.03 [95% CI: 1.18-3.49], P = 0.010); was overall more probable in the behavioral variant of frontotemporal dementia (bvFTD) and frontotemporal dementia with amyotrophic lateral sclerosis phenotypes, and less probable in other language or motor phenotypes; and was associated with higher severity of neuropsychiatric symptoms (OR = 1.08 [95% CI: 1.06-1.10], P < 0.001) and with the presence of several behavioral symptoms (P < 0.05). Moreover, hyperorality severity increased over time only in patients with bvFTD (β = +0.15, P = 0.011) or semantic variant of primary progressive aphasia (β = +0.34, P = 0.010). Finally, the presence of hyperorality was significantly associated with greater atrophy in the right anterior insula and right orbitofrontal region (false discovery rate-corrected P < 0.05).

CONCLUSION: Hyperorality is common in certain FTLD-associated syndromes. Understanding its correlates can help clinicians define pharmacological and educational interventions and clarify related anatomical circuits.}, } @article {pmid39375041, year = {2024}, author = {Shah, NM and Rossel, A and Abdulaziz, B and Sheridan, S and Madden-Scott, S and Radcliffe, G and D'Cruz, R and Suh, ES and Steier, J and Hart, N and Murphy, PB and Ramsay, M and Kaltsakas, G}, title = {Effect of nostril occlusion and mouth sealing in the measurement of sniff nasal inspiratory pressure.}, journal = {Thorax}, volume = {80}, number = {1}, pages = {42-44}, doi = {10.1136/thorax-2024-221910}, pmid = {39375041}, issn = {1468-3296}, mesh = {Humans ; Male ; Female ; Middle Aged ; Aged ; *Respiratory Muscles/physiology/physiopathology ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Inhalation/physiology ; *Mouth ; Adult ; Nose ; Muscle Strength/physiology ; Respiratory Function Tests/methods ; }, abstract = {Sniff nasal inspiratory pressure (SNIP) is used to assess respiratory muscle strength in neuromuscular diseases like amyotrophic lateral sclerosis (ALS). The effect of contralateral nostril occlusion and mouth sealing on SNIP measurement are unclear. 81 participants were included (16 healthy, 39 patients with limb-onset ALS and 26 patients with bulbar-onset ALS). SNIP was obtained with combinations of mouth open/sealed and contralateral nostril open/occluded. Occluding the contralateral nostril (with mouth closed) increased SNIP by 12 cmH2O (95% CI 4, 20; p=0.003) in the healthy participants, by 9 cmH2O (95% CI 5, 12; p<0.001) in the limb-onset cohort and by 10 cmH2O (95% CI 5, 14; p<0.001) in the bulbar-onset cohort. Opening the mouth decreased SNIP by 19 cmH2O (95% CI 5, 34; p<0.009) in healthy participants, by 8 cmH2O (95% CI 4, 13; p<0.001) in the limb-onset cohort and by 13 cmH2O (95% CI 7, 19; p<0.001) in the bulbar-onset cohort. With contralateral nostril occlusion, 11% fewer individuals would have qualified for non-invasive ventilation. In conclusion, contralateral nostril occlusion increased SNIP compared with standard technique, likely reflecting true strength. Opening the mouth reduced SNIP, emphasising the need for good mouth sealing. Documenting SNIP technique is important for longitudinal assessments and clinical decision-making.}, } @article {pmid39374890, year = {2024}, author = {Zhang, J and Liu, L and Li, M and Liu, H and Gong, X and Tang, Y and Zhang, Y and Zhou, X and Lin, Z and Guo, H and Pan, L}, title = {Molecular Basis of the Recognition of the Active Rab8a by Optineurin.}, journal = {Journal of molecular biology}, volume = {436}, number = {22}, pages = {168811}, doi = {10.1016/j.jmb.2024.168811}, pmid = {39374890}, issn = {1089-8638}, mesh = {*rab GTP-Binding Proteins/metabolism/chemistry/genetics ; *Cell Cycle Proteins/metabolism/chemistry/genetics ; *Membrane Transport Proteins/metabolism/chemistry/genetics ; Humans ; *Protein Binding ; *Transcription Factor TFIIIA/metabolism/genetics/chemistry ; Models, Molecular ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Crystallography, X-Ray ; GTPase-Activating Proteins/metabolism/chemistry/genetics ; Mutation ; Protein Conformation ; }, abstract = {Optineurin (OPTN), a multifunctional adaptor protein in mammals, plays critical roles in many cellular processes, such as vesicular trafficking and autophagy. Notably, mutations in optineurin are directly associated with many human diseases, such as amyotrophic lateral sclerosis (ALS). OPTN can specifically recognize Rab8a and the GTPase-activating protein TBC1D17, and facilitate the inactivation of Rab8a mediated by TBC1D17, but with poorly understood mechanism. Here, using biochemical and structural approaches, we systematically characterize the interaction between OPTN and Rab8a, revealing that OPTN selectively recognizes the GTP-bound active Rab8a through its leucine-zipper domain (LZD). The determined crystal structure of OPTN LZD in complex with the active Rab8a not only elucidates the detailed binding mechanism of OPTN with Rab8a but also uncovers a unique binding mode of Rab8a with its effectors. Furthermore, we demonstrate that the central coiled-coil domain of OPTN and the active Rab8a can simultaneously interact with the TBC domain of TBC1D17 to form a ternary complex. Finally, based on the OPTN LZD/Rab8a complex structure and relevant biochemical analyses, we also evaluate several known ALS-associated mutations found in the LZD of OPTN. Collectively, our findings provide mechanistic insights into the interaction of OPTN with Rab8a, expanding our understanding of the binding modes of Rab8a with its effectors and the potential etiology of diseases caused by OPTN mutations.}, } @article {pmid39374680, year = {2024}, author = {Tirassa, P and Rosso, P and Fico, E and Marenco, M and Mallone, F and Gharbiya, M and Lambiase, A and Severini, C}, title = {Perspective role of Substance P in Amyotrophic Lateral Sclerosis: From neuronal vulnerability to neuroprotection.}, journal = {Neuroscience and biobehavioral reviews}, volume = {167}, number = {}, pages = {105914}, doi = {10.1016/j.neubiorev.2024.105914}, pmid = {39374680}, issn = {1873-7528}, mesh = {*Substance P/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; Humans ; Animals ; Receptors, Neurokinin-1/metabolism ; Neuroprotection/physiology ; Motor Neurons/metabolism/physiology ; }, abstract = {The neuropeptide Substance P (SP) and its preferred Neurokinin1 Receptor (NK1R) are known to participate in the physiopathology of neurodegenerative diseases and mainly exert a neuroprotective role. In the present work, we have described the involvement of SP and NK1R in Amyotrophic Lateral Sclerosis (ALS). This was demonstrated by the detection of altered levels of SP in the brain, spinal cord and cerebrospinal fluid (CSF) of patients and preclinical models of ALS, and by its ability to inhibit excitotoxicity-induced neurodegeneration in ALS animal models. These data are supported by results indicating an excitatory effect of SP at the motor neuron (MN) level, which promotes locomotor activity. ALS patients are characterized by a differential susceptibility to MNs degeneration, since sphincters and extraocular muscles are classically spared. It is hypothesized that SP may play a role in the maintenance of the ocular system and the innervation of the pelvic floor by contributing directly or indirectly to the selective resistance of this subset of MNs.}, } @article {pmid39373990, year = {2024}, author = {Appel, SH and Thonhoff, JR}, title = {Barriers to Tofersen Therapy for Variant SOD1-Mediated ALS.}, journal = {JAMA neurology}, volume = {81}, number = {12}, pages = {1239-1240}, doi = {10.1001/jamaneurol.2024.3331}, pmid = {39373990}, issn = {2168-6157}, } @article {pmid39373307, year = {2025}, author = {Rajagopalan, V and Pioro, EP}, title = {Graph theory network analysis reveals widespread white matter damage in brains of patients with classic ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {85-92}, doi = {10.1080/21678421.2024.2410281}, pmid = {39373307}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging ; Male ; Female ; *White Matter/diagnostic imaging/pathology ; Middle Aged ; Aged ; *Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/pathology ; Gray Matter/diagnostic imaging/pathology ; Adult ; Image Processing, Computer-Assisted ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) exhibits several different presentations and clinical phenotypes. Of these, classic ALS (ALS-Cl), which is the most common phenotype, presents with relatively equal amounts of upper motor neuron and lower motor neuron signs. Magnetic resonance imaging (MRI) provides a noninvasive way to assess central nervous system damage in these patients. To our knowledge no study is available where exploratory whole brain grey matter (GM) and white matter (WM) network analysis is performed considering only the ALS-Cl subgroup of ALS patients.

METHODS: GM voxel-based morphometry analysis and WM network analysis using graph theory was performed in the MRI dataset of 14 neurologic controls and 25 ALS-Cl patients.

RESULTS AND CONCLUSIONS: No significant GM differences were observed between ALS-Cl and neurologic controls. WM network revealed significant (p < 0.05) reduction and increase in degree measure in several extramotor brain regions of ALS-Cl patients. Both global and local graph metrics revealed significant abnormal values in ALS-Cl patients when compared to neurologic controls. Significant WM changes in ALS-Cl patients with no significant GM changes suggest that neurodegeneration may onset as an "axonopathy" in this ALS subtype.}, } @article {pmid39372031, year = {2024}, author = {Pillai, M and Jha, SK}, title = {Conformational Enigma of TDP-43 Misfolding in Neurodegenerative Disorders.}, journal = {ACS omega}, volume = {9}, number = {39}, pages = {40286-40297}, pmid = {39372031}, issn = {2470-1343}, abstract = {Misfolding and aggregation of the protein remain some of the most common phenomena observed in neurodegeneration. While there exist multiple neurodegenerative disorders characterized by accumulation of distinct proteins, what remains particularly interesting is the ability of these proteins to undergo a conformational change to form aggregates. TDP-43 is one such nucleic acid binding protein whose misfolding is associated with many neurogenerative diseases including amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD). TDP-43 protein assumes several different conformations and oligomeric states under the diseased condition. In this review, we explore the intrinsic relationship between the conformational variability of TDP-43 protein, with a particular focus on the RRM domains, and its propensity to undergo aggregation. We further emphasize the probable mechanism behind the formation of these conformations and suggest a potential diagnostic and therapeutic strategy in the context of these conformational states of the protein.}, } @article {pmid39371851, year = {2024}, author = {Po, K and Olaivar, M}, title = {Juvenile Amyotrophic Lateral Sclerosis: A Case Report of a Rare and Aggressive Presentation in a 22-Year-Old Filipino Male.}, journal = {Cureus}, volume = {16}, number = {9}, pages = {e68579}, pmid = {39371851}, issn = {2168-8184}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disorder primarily affecting adults, but juvenile-onset ALS is exceptionally rare. We report a rare case of a 22-year-old Filipino male patient who exhibited early-onset weakness, muscle atrophy, and tongue fasciculations, followed by rapidly progressive dysphagia and respiratory distress. Electromyography - Nerve Conduction Velocity (EMG-NCV) findings showed evidence for a chronic, active predominantly motor neuronal-axonal loss type of neuropathy involving the tongue and limb muscles bilaterally consistent with a motor neuron disease. The patient was treated with riluzole with no significant improvement in symptoms. Despite multidisciplinary interventions, the disease rapidly progressed, highlighting the challenges in managing juvenile ALS cases. This case report emphasizes the importance of considering ALS in the differential diagnosis of progressive motor dysfunction in younger patients and the complexities involved in their care.}, } @article {pmid39371161, year = {2024}, author = {Angrick, M and Luo, S and Rabbani, Q and Joshi, S and Candrea, DN and Milsap, GW and Gordon, CR and Rosenblatt, K and Clawson, L and Maragakis, N and Tenore, FV and Fifer, MS and Ramsey, NF and Crone, NE}, title = {Real-time detection of spoken speech from unlabeled ECoG signals: A pilot study with an ALS participant.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39371161}, support = {UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVE: Brain-Computer Interfaces (BCIs) hold significant promise for restoring communication in individuals with partial or complete loss of the ability to speak due to paralysis from amyotrophic lateral sclerosis (ALS), brainstem stroke, and other neurological disorders. Many of the approaches to speech decoding reported in the BCI literature have required time-aligned target representations to allow successful training - a major challenge when translating such approaches to people who have already lost their voice.

APPROACH: In this pilot study, we made a first step toward scenarios in which no ground truth is available. We utilized a graph-based clustering approach to identify temporal segments of speech production from electrocorticographic (ECoG) signals alone. We then used the estimated speech segments to train a voice activity detection (VAD) model using only ECoG signals. We evaluated our approach using held-out open-loop recordings of a single dysarthric clinical trial participant living with ALS, and we compared the resulting performance to previous solutions trained with ground truth acoustic voice recordings.

MAIN RESULTS: Our approach achieves a median error rate of around 0.5 seconds with respect to the actual spoken speech. Embedded into a real-time BCI, our approach is capable of providing VAD results with a latency of only 10 ms.

SIGNIFICANCE: To the best of our knowledge, our results show for the first time that speech activity can be predicted purely from unlabeled ECoG signals, a crucial step toward individuals who cannot provide this information anymore due to their neurological condition, such as patients with locked-in syndrome.

CLINICAL TRIAL INFORMATION: ClinicalTrials.gov, registration number NCT03567213.}, } @article {pmid39370211, year = {2024}, author = {Kajitani, GS and Xavier, G and Villena-Rueda, BE and Karia, BTR and Santoro, ML}, title = {Extracellular vesicles in neurodegenerative, mental, and other neurological disorders: Perspectives into mechanisms, biomarker potential, and therapeutic implications.}, journal = {Current topics in membranes}, volume = {94}, number = {}, pages = {299-336}, doi = {10.1016/bs.ctm.2024.06.002}, pmid = {39370211}, issn = {1063-5823}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; *Biomarkers/metabolism ; Mental Disorders/metabolism/drug therapy/therapy ; Animals ; Nervous System Diseases/metabolism/pathology ; }, abstract = {Extracellular vesicles (EVs) are produced, secreted, and targeted by most human cells, including cells that compose nervous system tissues. EVs carry several types of biomolecules, such as lipids, proteins and microRNA, and can function as signaling agents in physiological and pathological processes. In this chapter, we will focus on EVs and their cargo secreted by brain cells, especially neurons and glia, and how these aspects are affected in pathological conditions. The chapter covers neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, as well as several psychiatric disorders, namely schizophrenia, autism spectrum disorder and major depressive disorder. This chapter also addresses other types of neurological dysfunctions, epilepsy and traumatic brain injury. EVs can cross the blood brain barrier, and thus brain EVs may be detected in more accessible peripheral tissue, such as circulating blood. Alterations in EV composition and contents can therefore impart valuable clues into the molecular etiology of these disorders, and serve biomarkers regarding disease prevalence, progression and treatment. EVs can also be used to carry drugs and biomolecules into brain tissue, considered as a promising drug delivery agent for neurological diseases. Therefore, although this area of research is still in its early development, it offers great potential in further elucidating and in treating neurological disorders.}, } @article {pmid39369804, year = {2024}, author = {Daniels, N and Bindoff, AD and Vickers, JC and King, AE and Collins, JM}, title = {Vulnerability of neurofilament-expressing neurons in frontotemporal dementia.}, journal = {Molecular and cellular neurosciences}, volume = {131}, number = {}, pages = {103974}, doi = {10.1016/j.mcn.2024.103974}, pmid = {39369804}, issn = {1095-9327}, mesh = {Humans ; *Frontotemporal Dementia/metabolism/genetics/pathology ; Aged ; *Neurons/metabolism/pathology ; *Neurofilament Proteins/metabolism ; Female ; Male ; Middle Aged ; *tau Proteins/metabolism/genetics ; Aged, 80 and over ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {Frontotemporal dementia (FTD) is an umbrella term for several early onset dementias, that are caused by frontotemporal lobar degeneration (FTLD), which involves the atrophy of the frontal and temporal lobes of the brain. Neuron loss in the frontal and temporal lobes is a characteristic feature of FTLD, however the selective vulnerability of different neuronal populations in this group of diseases is not fully understood. Neurofilament-expressing neurons have been shown to be selectively vulnerable in other neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis, therefore we sought to investigate whether this neuronal population is vulnerable in FTLD. We also examined whether neuronal sub-type vulnerability differed between FTLD with TDP-43 inclusions (FTLD-TDP) and FTLD with tau inclusions (FTLD-Tau). Post-mortem human tissue from the superior frontal gyrus (SFG) of FTLD-TDP (n = 15), FTLD-Tau (n = 8) and aged Control cases (n = 6) was immunolabelled using antibodies against non-phosphorylated neurofilaments (SMI32 antibody), calretinin and NeuN, to explore neuronal cell loss. The presence of non-phosphorylated neurofilament immunolabelling in axons of the SFG white matter was also quantified as a measure of axon pathology, as axonal neurofilaments are normally phosphorylated. We demonstrate the selective loss of neurofilament-expressing neurons in both FTLD-TDP and FTLD-Tau cases compared to aged Controls. We also show that non-phosphorylated neurofilament axonal pathology in the SFG white matter was associated with increasing age, but not FTLD. This data suggests neurofilament-expressing neurons are vulnerable in both FTLD-TDP and FTLD-Tau.}, } @article {pmid39369616, year = {2024}, author = {Zhao, Y and Li, X and Wang, K and Iyer, G and Sakowski, SA and Zhao, L and Teener, S and Bakulski, KM and Dou, JF and Traynor, BJ and Karnovsky, A and Batterman, SA and Feldman, EL and Sartor, MA and Goutman, SA}, title = {Epigenetic age acceleration is associated with occupational exposures, sex, and survival in amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {109}, number = {}, pages = {105383}, pmid = {39369616}, issn = {2352-3964}, support = {R01 TS000289/TS/ATSDR CDC HHS/United States ; R01 TS000327/TS/ATSDR CDC HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; UL1 TR002240/TR/NCATS NIH HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/etiology/mortality ; Male ; Female ; *Epigenesis, Genetic ; *Occupational Exposure/adverse effects ; Middle Aged ; *DNA Methylation ; Aged ; Sex Factors ; Aging/genetics ; Case-Control Studies ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is linked to ageing and genetic and environmental risk factors, yet underlying mechanisms are incompletely understood. We aimed to evaluate epigenetic age acceleration (EAA), i.e., DNA methylation (DNAm) age acceleration, and its association with ALS case status and survival.

METHODS: In this study, we included 428 ALS and 288 control samples collected between 2011 and 2021. We calculated EAA using the GrimAge residual method from ALS and control blood samples and grouped participants with ALS into three ageing groups (fast, normal, slow). We associated EAA with ALS case status and survival, stratified by sex, and correlated it with environmental and biological factors through occupational exposure assessments, immune cell proportions, and transcriptome changes.

FINDINGS: Participants with ALS had higher average EAA by 1.80 ± 0.30 years (p < 0.0001) versus controls. Participants with ALS in the fast ageing group had a hazard ratio of 1.52 (95% confidence interval 1.16-2.00, p = 0.0028) referenced to the normal ageing group. In males, this hazard ratio was 1.55 (95% confidence interval 1.11-2.17, p = 0.010), and EAA was positively correlated with high-risk occupational exposures including particulate matter (adj.p < 0.0001) and metals (adj.p = 0.0087). Also, in male participants with ALS, EAA was positively correlated with neutrophil proportions and was negatively correlated with CD4+ T cell proportions. Pathways dysregulated in participants with ALS with fast ageing included spliceosome, nucleocytoplasmic transport, axon guidance, and interferons.

INTERPRETATION: EAA was associated with ALS case status and, at least in males, with shorter survival after diagnosis. The effect of EAA on ALS was partially explained by occupational exposures and immune cell proportions in a sex-dependent manner. These findings highlight the complex interactions of ageing and exposures in ALS.

FUNDING: NIH, CDC/National ALS Registry, ALS Association, Dr. Randall Whitcomb Fund for ALS Genetics, Peter Clark Fund for ALS Research, Sinai Medical Staff Foundation, Scott L. Pranger ALS Clinic Fund, NeuroNetwork Therapeutic Discovery Fund, NeuroNetwork for Emerging Therapies.}, } @article {pmid39368746, year = {2024}, author = {Sharma, R and Mehan, S and Khan, Z and Das Gupta, G and Narula, AS}, title = {Therapeutic potential of oleanolic acid in modulation of PI3K/Akt/mTOR/STAT-3/GSK-3β signaling pathways and neuroprotection against methylmercury-induced neurodegeneration.}, journal = {Neurochemistry international}, volume = {180}, number = {}, pages = {105876}, doi = {10.1016/j.neuint.2024.105876}, pmid = {39368746}, issn = {1872-9754}, mesh = {Animals ; *Oleanolic Acid/pharmacology/therapeutic use ; Rats ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; Male ; *Methylmercury Compounds/toxicity ; *Glycogen Synthase Kinase 3 beta/metabolism ; *TOR Serine-Threonine Kinases/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Phosphatidylinositol 3-Kinases/metabolism ; Rats, Wistar ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Neuroprotection/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that gradually deteriorates motor neurons, leading to demyelination, muscle weakness, and eventually respiratory failure. The disease involves several pathological processes, such as increased glutamate levels, mitochondrial dysfunction, and persistent neuroinflammation, often exacerbated by environmental toxins like mercury. This study explores the therapeutic potential of Olea europaea active phytoconstituents oleanolic acid (OLA) against ALS by targeting the overactivated PI3K/Akt/mTOR/STAT-3/GSK-3β signalling pathways. Methods involved in-silico studies, in vitro and in vivo experiments in which varying doses of methylmercury 5 mg/kg, p.o. and OLA (100 and 200 mg/kg, i.p.) were administered to rats for 42 days. Behavioural assessments, gross morphological, histopathological, and neurochemical parameters were measured in cerebrospinal fluid (CSF), blood plasma, and brain homogenates (cerebral cortex, hippocampus, striatum, midbrain, cerebellum) along with complete blood count (CBC) analysis. Results revealed OLA's significant neuroprotective properties. OLA effectively modulated targeted pathways, reducing pro-inflammatory cytokines, restoring normal levels of myelin basic protein (MBP) and neurofilament light chain (NEFL), and reducing histopathological changes. Gross pathological studies indicated less tissue damage, while CBC analysis showed improved hematology parameters. Additionally, the combination of OLA and edaravone (10 mg/kg, i.p.) demonstrated enhanced efficacy, improving motor functions and extending survival in ALS model rats. In conclusion, OLA exhibits significant therapeutic potential for ALS, acting as a potent modulator of key pathological signaling pathways. The findings suggest the feasibility of integrating OLA into existing treatment regimens, potentially improving clinical outcomes for ALS patients. However, further research must validate these findings in human clinical trials.}, } @article {pmid39368179, year = {2025}, author = {Brito, ALB and Cardoso, IF and Viegas, LP and Fausto, R}, title = {Semi-quantitative chemometric models for characterization of mixtures of sugars using infrared spectral data.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {326}, number = {}, pages = {125225}, doi = {10.1016/j.saa.2024.125225}, pmid = {39368179}, issn = {1873-3557}, mesh = {*Chemometrics/methods ; *Models, Chemical ; *Sugars/analysis ; Spectrophotometry, Infrared ; Principal Component Analysis ; Multivariate Analysis ; Least-Squares Analysis ; }, abstract = {Sugars (saccharides) are sweet-tasting carbohydrates that are abundant in foods and play very important roles in living organisms, particularly as sources and stores of energy, and as structural elements in cellular membranes. They are desirable therapeutic targets, as they participate in multiple metabolic processes as fundamental elements. However, the physicochemical characterization of sugars is a challenging task, mostly due to the structural similarity shared by the large diversity of compounds of this family. The need for fast, accurate enough, and cost-effective analytical methods for these substances is of extreme relevance, in particular because of the recently increasing importance of carbohydrates in Medicine and food industry. With this in view, this work focused on the development of chemometric models for semi-quantitative analysis of samples of different types of sugars (glucose, galactose, mannitol, sorbose and fructose) using infrared spectra as data, as an example of application of a novel approach, where the Principal Component Analysis (PCA) score plots are used to estimate the composition (weight-%) of the mixtures of the sugars. In these plots, polygonal geometric shapes emerge in the vectorial space of the most significant principal components, that allow grouping different types of samples on the vertices, edges, faces and interior of the polygons according to the composition of the samples. This approach was applied successfully to mixtures of up to 5 sugars and shown to appropriately extract the compositional information from the hyper-redundant complex spectral data. Thought the method has been applied here to a specific problem, it shall be considered as a general procedure for the semi-quantitative analysis of other types of mixtures and applicable to other types of data reflecting their composition. In fact, the methodology appears as an efficient tool to solve three main general problems: (i) use hyper-redundant (in variables) data, as spectral information, directly and with minimum pre-treatment, to evaluate semi-quantitatively the composition of mixtures; (ii) do this for systems which produce data that can be considered rather similar; and (iii) do it for a number of substances present in the mixtures that might be greater than that usually considered in chemistry, which in general is limited to 3 components. In addition, this work also demonstrates that, similarly to the developed analysis based on the PCA score plots, the Multivariate Curve Resolution with Alternating Least Squares (MCR-ALS) chemometric method can also be used successfully for the qualitative (when used without any previous knowledge of the components present in the samples) or semi-quantitative (when the pure components spectral profiles are provided as references) analyses of mixtures of (at least) up to 5 distinct sugars.}, } @article {pmid39367779, year = {2025}, author = {Duran, S and Aydogdu, A}, title = {The effect of structured psychoeducation for caregivers of ALS patients on perceived stress, psychological resilience and self-compassion.}, journal = {Health education research}, volume = {40}, number = {1}, pages = {}, doi = {10.1093/her/cyae031}, pmid = {39367779}, issn = {1465-3648}, mesh = {Humans ; *Caregivers/psychology/education ; *Resilience, Psychological ; Female ; Male ; Middle Aged ; *Stress, Psychological ; *Adaptation, Psychological ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Empathy ; Adult ; Surveys and Questionnaires ; Aged ; }, abstract = {Patients diagnosed with amyotrophic lateral sclerosis (ALS) become dependent on caregivers to meet their daily needs and perform personal care activities. For this reason, ALS is a disease that can challenge both the patient and the caregiver physically, mentally and socially. Supporting the caregiver indirectly affects the patient's quality of care and mental well-being. Therefore, this study aimed to determine the effect of a structured psychoeducation program on coping with stress, psychological resilience and self-compassion in caregivers of ALS patients. This quasi-experimental study with a pre-test-post-test control group was conducted with caregivers of 62 ALS patients in Türkiye. The study was conducted between July 2023 and February 2024. A psychoeducation program was applied to five different groups via zoom application for 6 weeks each. The survey form, Perceived Stress Scale, Brief Resilience Scale and Short Form of Self-Compassion Questionnaire were used as measurement tools. The chi-squared test and paired samples t-test were used to analyze the data. While there was no significant difference between the intervention group and the control group in the pre-test in terms of their mean scores on the coping with stress inventory, short psychological resilience scale and self-compassion scale, at the post-test, psychological resilience and self-compassion scores were significantly higher in the intervention group. This study revealed that psychoeducational programs that support caregivers are effective in increasing psychological resilience and self-compassion.}, } @article {pmid39367309, year = {2024}, author = {Makled, AF and Ali, SAM and Labeeb, AZ and Salman, SS and Shebl, DZM and Hegazy, SG and Sabal, MS}, title = {Characterization of Candida species isolated from clinical specimens: insights into virulence traits, antifungal resistance and molecular profiles.}, journal = {BMC microbiology}, volume = {24}, number = {1}, pages = {388}, pmid = {39367309}, issn = {1471-2180}, mesh = {Humans ; *Candida/genetics/pathogenicity/drug effects/isolation & purification/classification ; *Drug Resistance, Fungal/genetics ; *Antifungal Agents/pharmacology ; *Virulence Factors/genetics ; *Candidiasis/microbiology ; *Biofilms/growth & development ; *Microbial Sensitivity Tests ; Virulence/genetics ; Multiplex Polymerase Chain Reaction ; Male ; Female ; Adult ; Middle Aged ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Candida species have emerged as a significant cause of opportunistic infections. Alongside the expression of various virulence factors, the rise of antifungal resistance among Candida species presents a considerable clinical challenge.

AIM: This study aimed to identify different Candida species isolated from clinical specimens, evaluate their antifungal sensitivity patterns, identify key genes regulating virulence mechanisms using multiplex PCR and to assess any correlation between their virulence profiles and antifungal resistance patterns.

METHOD: A total of 100 Candida spp. was isolated from 630 different clinical specimens and identified to the species level. Their antifungal susceptibility was phenotypically evaluated in accordance with CLSI guidelines using the Vitek-2 Compact System. Virulence markers, including biofilm formation capacity, protease production, melanin production, coagulase production and hemolysin production, were also phenotypically detected. The genetic determinants for biofilm formation and extracellular hydrolytic enzymes were assessed using a multiplex PCR assay.

RESULTS: The prevalence of Candida spp. was 15.9%, with C. albicans (48%) and C. glabrata (16%) being the most common. C. albicans showed the highest virulence, with strong biofilm formation, and high proteinase and melanin production. Multiplex PCR revealed Hlp in 22.0%, Hwp in 80.0%, Als in 56.0%, and Sap genes in 56.0% of isolates. Virulence genes were more common in C. albicans than in non-albicans Candida (NAC). Resistance patterns significantly correlated with virulence profiles, with notable associations between flucytosine resistance and the presence of Hlp and Hwp genes.

CONCLUSION: The significant correlation between virulent markers such as germination, coagulase, hemolysin production and resistance patterns among different Candida isolates is crucial for predicting the severity and outcomes of Candida infections. This understanding aids in guiding tailored treatment strategies.}, } @article {pmid39367212, year = {2024}, author = {Cogan, G and Zaki, MS and Issa, M and Keren, B and Guillaud-Bataille, M and Renaldo, F and Isapof, A and Lallemant, P and Stevanin, G and Guillot-Noel, L and Courtin, T and Buratti, J and Freihuber, C and Gleeson, JG and Howarth, R and Durr, A and de Sainte Agathe, JM and Mignot, C}, title = {Biallelic variants in ERLIN1: a series of 13 individuals with spastic paraparesis.}, journal = {Human genetics}, volume = {143}, number = {11}, pages = {1353-1362}, pmid = {39367212}, issn = {1432-1203}, mesh = {Humans ; Female ; Male ; *Paraparesis, Spastic/genetics ; *Pedigree ; Child ; Adolescent ; Adult ; Membrane Proteins/genetics ; Alleles ; Phenotype ; Mutation ; Child, Preschool ; Young Adult ; Intellectual Disability/genetics ; }, abstract = {Biallelic variants in the ERLIN1 gene were recently reported as the cause of two motor neuron degeneration diseases, SPG62 and a recessive form of amyotrophic lateral sclerosis. However, only 12 individuals from five pedigrees have been identified so far. Thus, the description of the disease remains limited. Following the discovery of a homozygous pathogenic variant in a girl with SPG62, presenting with intellectual disability, and epilepsy, we gathered the largest series of SPG62 cases reported so far (13 individuals) to better understand the phenotype associated with ERLIN1. We collected molecular and clinical data for 13 individuals from six families with ERLIN1 biallelic variants. We performed RNA-seq analyses to characterize intronic variants and used Alphafold and a transcripts database to characterize the molecular consequences of the variants. We identified three new variants suspected to alter the bell-shaped ring formed by the ERLIN1/ERLIN2 complex. Affected individuals had childhood-onset paraparesis with slow progression. Six individuals presented with gait ataxia and three had superficial sensory loss. Aside from our proband, none had intellectual disability or epilepsy. Biallelic pathogenic ERLIN1 variants induce a rare, predominantly pure, spastic paraparesis, with possible cerebellar and peripheral nerve involvement.}, } @article {pmid39367160, year = {2024}, author = {Metzger, M and Dukic, S and McMackin, R and Giglia, E and Mitchell, M and Bista, S and Costello, E and Peelo, C and Tadjine, Y and Sirenko, V and McManus, L and Buxo, T and Fasano, A and Chipika, R and Pinto-Grau, M and Schuster, C and Heverin, M and Coffey, A and Broderick, M and Iyer, PM and Mohr, K and Gavin, B and Pender, N and Bede, P and Muthuraman, M and Hardiman, O and Nasseroleslami, B}, title = {Distinct Longitudinal Changes in EEG Measures Reflecting Functional Network Disruption in ALS Cognitive Phenotypes.}, journal = {Brain topography}, volume = {38}, number = {1}, pages = {3}, pmid = {39367160}, issn = {1573-6792}, support = {HRA-POR-2013-246; MRCG-2018-02 and HRB ILP-POR-2022-046//Health Research Board of Ireland/ ; IceBucket Award; MRCG2018-02 to B.N., McManus/Apr22/888-791 to L.M. and McMackin/Oct20/972-799 to R.M//Irish/UK Motor Neurone Disease Research Foundation/ ; Project-ID 424778381-TRR 295//Deutsche Forschungsgemeinschaft/ ; Emerging Investigator Award HRB-EIA-2017-019//Health Research Board of Ireland/ ; GOIPD/2015/213 to B.N. and GOIPG/2017/1014 to R.M.//Irish Research Council/ ; /WT_/Wellcome Trust/United Kingdom ; 16/ ERCD/3854 and Royal Society/SFI URF\R1\221917 to L.M./SFI_/Science Foundation Ireland/Ireland ; multi-year grant 20-IIA-546//ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; *Electroencephalography/methods ; Middle Aged ; Longitudinal Studies ; Aged ; Phenotype ; Brain/physiopathology ; Cognition/physiology ; Disease Progression ; Cognitive Dysfunction/physiopathology ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterised primarily by motor system degeneration, with clinical evidence of cognitive and behavioural change in up to 50% of cases. We have shown previously that resting-state EEG captures dysfunction in motor and cognitive networks in ALS. However, the longitudinal development of these dysfunctional patterns, especially in networks linked with cognitive-behavioural functions, remains unclear. Longitudinal studies on non-motor changes in ALS are essential to further develop our understanding of disease progression, improve care and enhance the evaluation of new treatments. To address this gap, we examined 124 ALS individuals with 128-channel resting-state EEG recordings, categorised by cognitive impairment (ALSci, n = 25), behavioural impairment (ALSbi, n = 58), or non-impaired (ALSncbi, n = 53), with 12 participants meeting the criteria for both ALSci and ALSbi. Using linear mixed-effects models, we characterised the general and phenotype-specific longitudinal changes in brain network, and their association with cognitive performance, behaviour changes, fine motor symptoms, and survival. Our findings revealed a significant decline in [Formula: see text]-band spectral power over time in the temporal region along with increased [Formula: see text]-band power in the fronto-temporal region in the ALS group. ALSncbi participants showed widespread β-band synchrony decrease, while ALSci participants exhibited increased co-modulation correlated with verbal fluency decline. Longitudinal network-level changes were specific of ALS subgroups and correlated with motor, cognitive, and behavioural decline, as well as with survival. Spectral EEG measures can longitudinally track abnormal network patterns, serving as a candidate stratification tool for clinical trials and personalised treatments in ALS.}, } @article {pmid39366938, year = {2024}, author = {Hutchings, AJ and Hambrecht, B and Veh, A and Giridhar, NJ and Zare, A and Angerer, C and Ohnesorge, T and Schenke, M and Selvaraj, BT and Chandran, S and Sterneckert, J and Petri, S and Seeger, B and Briese, M and Stigloher, C and Bischler, T and Hermann, A and Damme, M and Sendtner, M and Lüningschrör, P}, title = {Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8622}, pmid = {39366938}, issn = {2041-1723}, support = {LU 2347/3-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; VORAN-2 16LW066//Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)/ ; }, mesh = {Animals ; Humans ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Autophagy ; Disease Models, Animal ; Exocytosis ; *Guanine Nucleotide Exchange Factors/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism ; Lysosomes/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; *Motor Neurons/metabolism ; Presynaptic Terminals/metabolism ; rab GTP-Binding Proteins/metabolism/genetics ; *Superoxide Dismutase-1/metabolism/genetics ; }, abstract = {Increasing evidence suggests an essential function for autophagy in unconventional protein secretion (UPS). However, despite its relevance for the secretion of aggregate-prone proteins, the mechanisms of secretory autophagy in neurons have remained elusive. Here we show that the lower motoneuron disease-associated guanine exchange factor Plekhg5 drives the UPS of Sod1. Mechanistically, Sod1 is sequestered into autophagosomal carriers, which subsequently fuse with secretory lysosomal-related organelles (LROs). Exocytosis of LROs to release Sod1 into the extracellular milieu requires the activation of the small GTPase Rab26 by Plekhg5. Deletion of Plekhg5 in mice leads to the accumulation of Sod1 in LROs at swollen presynaptic sites. A reduced secretion of toxic ALS-linked SOD1[G93A] following deletion of Plekhg5 in SOD1[G93A] mice accelerated disease onset while prolonging survival due to an attenuated microglia activation. Using human iPSC-derived motoneurons we show that reduced levels of PLEKHG5 cause an impaired secretion of ALS-linked SOD1. Our findings highlight an unexpected pathophysiological mechanism that converges two motoneuron disease-associated proteins into a common pathway.}, } @article {pmid39365785, year = {2024}, author = {Putri, KD and Guntoro, D and Ardie, SW and Hariyadi, }, title = {A new amino acid substitution in the MvALS1 gene of metsulfuron-methyl resistant biotypes Monochoria vaginalis (Burm. f.) C. Presl from West Java, Indonesia.}, journal = {PloS one}, volume = {19}, number = {10}, pages = {e0308465}, pmid = {39365785}, issn = {1932-6203}, mesh = {Indonesia ; *Arylsulfonates/pharmacology ; *Amino Acid Substitution ; *Herbicide Resistance/genetics ; Herbicides/pharmacology ; Plant Proteins/genetics ; Mutation ; }, abstract = {The most bothersome weed in rice fields in the Indonesian province of West Java is Monochoria vaginalis (Burm. F.) C. Presl, an aquatic herbaceous plant. Metsulfuron-methyl has long been used in wetland rice in West Java with a high enough intensity. However, the case of Monochoria vaginalis resistance to metsulfuron-methyl herbicides in Indonesia has not been widely reported and investigated. The study aims to (1) classify the resistance level of M. vaginalis toward metsulfuron-methyl, (2) identify Target Site Resistance (TSR) mechanism mutations in the MvALS1 gene of the resistant biotype of M. vaginalis. The Whole Plant Pot Test method was utilized to assess the resistance level of Monochoria vaginalis. Following that, all samples were subjected to DNA sequencing using the PCR method to identify mutations in the MvALS1 gene from the resistant biotype. After then, this study used DUET, a server with an integrated computational methodology, to anticipate the effect of mutations on protein stability. The result showed that Monochoria vaginalis from Rawamerta, Karawang showed a moderate level of resistance to metsulfuron-methyl with a resistance ratio of 6.00, Patokbeusi, Subang showed a low level of resistance to metsulfuron-methyl with a resistance ratio of 3.89, compared to susceptible Monochoria vaginalis. Nucleotide base alignment in the MvALS1 gene revealed that base substitutions occurred in the Monochoria vaginalis biotype from Rawamerta and Patokbeusi, resulting in 5 amino acid substitutions: Ser-64-Ala, Asp-66-Glu, Asn-240-Asp, Glu-426-Asn, and Ser-469-Asn and Sukra: Ser-64-Ala, Asp-66-Glu, and Asn-240-Asp. The analysis showed that S64A, D66E, and N240D stabilize the protein, whereas E426N and S469N destabilize it. This study confirms for the first time that Ser-64-Ala, Asn-240-Asp, and Glu-426-Asn amino acid mutations were found in cases of M. vaginalis resistance to metsulfuron-methyl (ALS inhibitor).}, } @article {pmid39364420, year = {2024}, author = {Aiello, EN and Contarino, VE and Conte, G and Solca, F and Curti, B and Maranzano, A and Torre, S and Casale, S and Doretti, A and Colombo, E and Verde, F and Silani, V and Liu, C and Cinnante, C and Triulzi, FM and Morelli, C and Poletti, B and Ticozzi, N}, title = {QSM-detected iron accumulation in the cerebellar gray matter is selectively associated with executive dysfunction in non-demented ALS patients.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1426841}, pmid = {39364420}, issn = {1664-2295}, abstract = {BACKGROUND: This study aimed to assess whether quantitative susceptibility imaging (QSM)-based measures of iron accumulation in the cerebellum predict cognitive and behavioral features in non-demented amyotrophic lateral sclerosis (ALS) patients.

METHODS: A total of ALS patients underwent 3-T MRI and a clinical assessment using the ALS Functional Rating Scale-Revised (ALSFRS-R) and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Regression models were applied to each subscale of the cognitive section of the ECAS and the ECAS-Carer Interview to examine the effect of QSM-based measures in white and gray matter (WM; GM) of the cerebellum, separately for right, left, and bilateral cerebellar regions of interest (ROIs). These effects were compared to those of cerebellar volumetrics in WM/GM, right and left hemispheres while controlling for demographics, disease status, and total intracranial volume.

RESULTS: Higher QSM measures of the cerebellar GM on the left, right, and bilateral sides significantly predicted (ps ≤ 0.003) a greater number of errors on the executive functioning (EF) subscale of the ECAS (ECAS-EF). Moreover, higher GM-related, QSM measures of the cerebellum were associated with an increased probability of a below-cut-off performance on the ECAS-EF (ps ≤ 0.024). No significant effects were observed for QSM measures of the cerebellar WM or for volumetric measures on the ECAS-EF. Other ECAS measures showed no significant effects. Bilateral QSM measures of the cerebellar GM also selectively predicted performance on backward digit span and social cognition tasks.

DISCUSSION: Iron accumulation within the cerebellar GM, particularly in the cerebellar cortices, may be associated with executive functioning deficits in non-demented ALS patients. Therefore, QSM-based measures could be useful for identifying the neural correlates of extra-motor cognitive deficits in ALS patients.}, } @article {pmid39364217, year = {2024}, author = {Samuel Olajide, T and Oyerinde, TO and Omotosho, OI and Okeowo, OM and Olajide, OJ and Ijomone, OM}, title = {Microglial senescence in neurodegeneration: Insights, implications, and therapeutic opportunities.}, journal = {Neuroprotection}, volume = {2}, number = {3}, pages = {182-195}, pmid = {39364217}, issn = {2770-730X}, support = {K43 TW011920/TW/FIC NIH HHS/United States ; }, abstract = {The existing literature on neurodegenerative diseases (NDDs) reveals a common pathological feature: the accumulation of misfolded proteins. However, the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs. Dementia, a hallmark symptom across various NDDs, serves as a multifaceted denominator, contributing to the clinical manifestations of these disorders. There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression. Recent research has linked disease-associated microglia to their transition into a senescent state-characterized by irreversible cell cycle arrest-in aging populations and NDDs. Although senescent microglia are consistently observed in NDDs, few studies have utilized animal models to explore their role in disease pathology. Emerging evidence from experimental rat models suggests that disease-associated microglia exhibit characteristics of senescence, indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets. This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Additionally, it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age-related NDDs.}, } @article {pmid39363643, year = {2025}, author = {Capelle, DP and Sabirin, W and Zulhairy-Liong, NA and Edgar, S and Goh, KJ and Ahmad-Annuar, A and Shahrizaila, N}, title = {Multistep modeling applied to a Malaysian ALS registry.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {157-161}, doi = {10.1080/21678421.2024.2410280}, pmid = {39363643}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Malaysia/epidemiology ; Male ; *Registries ; Female ; Middle Aged ; Aged ; Adult ; *Disease Progression ; Incidence ; Age of Onset ; }, abstract = {OBJECTIVE: To apply the multistep model of pathogenesis in amyotrophic lateral sclerosis (ALS) to data from a multiethnic Malaysian registry.

METHODS: Clinical data, including age at symptom onset, was collected from 289 patients who presented to our multidisciplinary clinic from 2016 until 2024. A least squares linear regression model was constructed from the logarithm of approximated incidence and the logarithm of age. Population incidence was approximated by adjusting the absolute numbers of patients in 5 year groups by the size of the general population in the respective age group.

RESULTS: A linear relationship between log of incidence versus log of age was observed, with a slope of 4.57 (95% CI, 3.3-5.8) and an r[2] value of 0.93, suggesting a 6-step process.

CONCLUSION: Progression toward symptom onset in Malaysian ALS patients appears consistent with a multistep model of disease as observed in other cohorts.}, } @article {pmid39363348, year = {2024}, author = {Chevalier, E and Audrain, M and Ratnam, M and Ollier, R and Fuchs, A and Piorkowska, K and Pfeifer, A and Kosco-Vilbois, M and Seredenina, T and Afroz, T}, title = {Targeting the TDP-43 low complexity domain blocks spreading of pathology in a mouse model of ALS/FTD.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {156}, pmid = {39363348}, issn = {2051-5960}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; Mice ; *Disease Models, Animal ; *Frontotemporal Dementia/pathology/metabolism ; *Antibodies, Monoclonal/pharmacology ; Humans ; Mice, Transgenic ; }, abstract = {Abnormal cytoplasmic localization and accumulation of pathological transactive response DNA binding protein of 43 kDa (TDP-43) underlies several devastating diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). A key element is the correlation between disease progression and spatio-temporal propagation of TDP-43-mediated pathology in the central nervous system. Several lines of evidence support the concept of templated aggregation and cell to cell spreading of pathological TDP-43. To further investigate this mechanism in vivo, we explored the efficacy of capturing and masking the seeding-competent region of extracellular TDP-43 species. For this, we generated a novel monoclonal antibody (mAb), ACI-6677, that targets the pathogenic protease-resistant amyloid core of TDP-43. ACI-6677 has a picomolar binding affinity for TDP-43 and is capable of binding to all C-terminal TDP-43 fragments. In vitro, ACI-6677 inhibited TDP-43 aggregation and boosted removal of pathological TDP-43 aggregates by phagocytosis. When injecting FTLD-TDP brain extracts unilaterally in the CamKIIa-hTDP-43NLSm mouse model, ACI-6677 significantly limited the induction of phosphorylated TDP-43 (pTDP-43) inclusions. Strikingly, on the contralateral side, the mAb significantly prevented pTDP-43 inclusion appearance exemplifying blocking of the spreading process. Taken together, these data demonstrate for the first time that an immunotherapy targeting the protease-resistant amyloid core of TDP-43 has the potential to restrict spreading, substantially slowing or stopping progression of disease.}, } @article {pmid39362869, year = {2024}, author = {Ma, YY and Li, X and Yu, ZY and Luo, T and Tan, CR and Bai, YD and Xu, G and Sun, BD and Bu, XL and Liu, YH and Jin, WS and Gao, YQ and Zhou, XF and Liu, J and Wang, YJ}, title = {Oral antioxidant edaravone protects against cognitive deficits induced by chronic hypobaric hypoxia at high altitudes.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {415}, pmid = {39362869}, issn = {2158-3188}, support = {92249305//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Animals ; *Edaravone/pharmacology/administration & dosage ; *Cognitive Dysfunction/etiology/drug therapy/prevention & control ; Mice ; *Oxidative Stress/drug effects ; Male ; *Hypoxia/complications/drug therapy/metabolism ; *Altitude ; Antioxidants/pharmacology/administration & dosage ; Mice, Inbred C57BL ; Administration, Oral ; Hippocampus/drug effects/metabolism ; Disease Models, Animal ; Free Radical Scavengers/administration & dosage/pharmacology ; Brain/drug effects/metabolism ; }, abstract = {Chronic hypobaric hypoxia at high altitudes can impair cognitive functions, especially causing deficits in learning and memory, which require therapeutic intervention. Here, we showed that mice subjected to hypobaric hypoxia (simulating an altitude of 5000 m) for one month experienced significant cognitive impairment, accompanied by increased biomarker levels of oxidative stress in the brain and blood. Oral administration of a novel formulation of edaravone, a free radical scavenger approved for the treatment of ischaemic stroke and amyotrophic lateral sclerosis, significantly alleviated oxidative stress and cognitive impairments caused by chronic hypobaric hypoxia. Furthermore, oral edaravone treatment also mitigated neuroinflammation and restored hippocampal neural stem cell exhaustion. Additionally, periostin (Postn) is vital in the cognitive deficits caused by chronic hypobaric hypoxia and may be a molecular target of edaravone. In conclusion, our results suggest that oxidative stress plays a crucial role in the cognitive deficits caused by chronic hypobaric hypoxia and that oral edaravone is a potential medicine for protecting against cognitive deficits caused by chronic hypobaric hypoxia in high-altitude areas.}, } @article {pmid39362568, year = {2024}, author = {Velasquez, E and Savchenko, E and Marmolejo-Martínez-Artesero, S and Challuau, D and Aebi, A and Pomeshchik, Y and Lamas, NJ and Vihinen, M and Rezeli, M and Schneider, B and Raoul, C and Roybon, L}, title = {TNFα prevents FGF4-mediated rescue of astrocyte dysfunction and reactivity in human ALS models.}, journal = {Neurobiology of disease}, volume = {201}, number = {}, pages = {106687}, doi = {10.1016/j.nbd.2024.106687}, pmid = {39362568}, issn = {1095-953X}, mesh = {*Astrocytes/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; Animals ; Mice ; *Tumor Necrosis Factor-alpha/metabolism ; *Fibroblast Growth Factor 4/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Spinal Cord/metabolism/pathology ; }, abstract = {Astrocytes play a crucial role in the onset and progression of amyotrophic lateral sclerosis (ALS), a fatal disorder marked by the degeneration of motor neurons (MNs) in the central nervous system. Although astrocytes in ALS are known to be toxic to MNs, the pathological changes leading to their neurotoxic phenotype remain poorly understood. In this study, we generated human astrocytes from induced pluripotent stem cells (iPSCs) carrying the ALS-associated A4V mutation in superoxide dismutase 1 (SOD1) to examine early cellular pathways and network changes. Proteomic analysis revealed that ALS astrocytes are both dysfunctional and reactive compared to control astrocytes. We identified significant alterations in the levels of proteins linked to ALS pathology and the innate immune cGAS-STING pathway. Furthermore, we found that ALS astrocyte reactivity differs from that of control astrocytes treated with tumor necrosis factor alpha (TNFα), a key cytokine in inflammatory reactions. We then evaluated the potential of fibroblast growth factor (FGF) 2, 4, 16, and 18 to reverse ALS astrocyte phenotype. Among these, FGF4 successfully reversed ALS astrocyte dysfunction and reactivity in vitro. When delivered to the spinal cord of the SOD1[G93A] mouse model of ALS, FGF4 lowered astrocyte reactivity. However, this was not sufficient to protect MNs from cell death. Further analysis indicated that TNFα abrogated the reactivity reduction achieved by FGF4, suggesting that complete rescue of the ALS phenotype by FGF4 is hindered by ongoing complex neuroinflammatory processes in vivo. In summary, our data demonstrate that astrocytes generated from ALS iPSCs are inherently dysfunctional and exhibit an immune reactive phenotype. Effectively targeting astrocyte dysfunction and reactivity in vivo may help mitigate ALS and prevent MN death.}, } @article {pmid39361871, year = {2025}, author = {Fernandes, JPM and Garcia, LP and Gouhie, FA and Pereira, RC and Santos, DFD}, title = {Association between motor neuron disease and HIV infection: A systematic review of case reports.}, journal = {International journal of STD & AIDS}, volume = {36}, number = {1}, pages = {24-35}, doi = {10.1177/09564624241288283}, pmid = {39361871}, issn = {1758-1052}, mesh = {Humans ; *HIV Infections/drug therapy/complications ; *Motor Neuron Disease/complications ; Adult ; Male ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; Female ; Middle Aged ; Riluzole/therapeutic use ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a well-known group of neurodegenerative diseases, with amyotrophic lateral sclerosis (ALS) being the most common form. Since 1985, a possible association between MND/ALS and HIV infection has been described.

METHODS: We performed a systematic review of case reports and case series involving people living with HIV with MND/ALS through PubMed, Bireme, Embase, and Lilacs databases. The risk of bias was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Tool for Case Reports.

RESULTS: We analyzed 36 articles presenting 88 cases. The mean age was 41.6 years. Antiretroviral therapy (ART) was used by 89.8% and riluzole by 16.9%. First signs and symptoms were similarly present on cervical/upper (25%) and lumbosacral/lower limbs (23.9%), mostly with fasciculations (69.8%) and hyperreflexia (58.8%). MND had a progressive course in 32.9% patients and a clinical improve in 54.6% following ART. The mean survival of the 32 patients who died was 12.3 months and the mean survival of the living patients was 62 months. Respiratory failure was the main cause of death (35.7%).

CONCLUSIONS: MND/ALS may present differently in the people living with HIV as a rapidly progressive disease in younger people but with the potential to improve weakness and survival through antiretroviral therapy.}, } @article {pmid39361759, year = {2024}, author = {Wilkins, OG and Chien, MZYJ and Wlaschin, JJ and Barattucci, S and Harley, P and Mattedi, F and Mehta, PR and Pisliakova, M and Ryadnov, E and Keuss, MJ and Thompson, D and Digby, H and Knez, L and Simkin, RL and Diaz, JA and Zanovello, M and Brown, AL and Darbey, A and Karda, R and Fisher, EMC and Cunningham, TJ and Le Pichon, CE and Ule, J and Fratta, P}, title = {Creation of de novo cryptic splicing for ALS and FTD precision medicine.}, journal = {Science (New York, N.Y.)}, volume = {386}, number = {6717}, pages = {61-69}, pmid = {39361759}, issn = {1095-9203}, support = {MR/M008606/1/MRC_/Medical Research Council/United Kingdom ; CC0102/ARC_/Arthritis Research UK/United Kingdom ; 215593/WT_/Wellcome Trust/United Kingdom ; CC0102/CRUK_/Cancer Research UK/United Kingdom ; CC0102/MRC_/Medical Research Council/United Kingdom ; ZIA HD008966/ImNIH/Intramural NIH HHS/United States ; CC0102/WT_/Wellcome Trust/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Deep Learning ; *DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics/therapy ; Gene Editing ; HEK293 Cells ; *Precision Medicine ; RNA Splice Sites ; *RNA Splicing ; RNA-Binding Proteins/metabolism/genetics ; }, abstract = {Loss of function of the RNA-binding protein TDP-43 (TDP-LOF) is a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Here we describe TDP-REG, which exploits the specificity of cryptic splicing induced by TDP-LOF to drive protein expression when and where the disease process occurs. The SpliceNouveau algorithm combines deep learning with rational design to generate customizable cryptic splicing events within protein-coding sequences. We demonstrate that expression of TDP-REG reporters is tightly coupled to TDP-LOF in vitro and in vivo. TDP-REG enables genomic prime editing to ablate the UNC13A cryptic donor splice site specifically upon TDP-LOF. Finally, we design TDP-REG vectors encoding a TDP-43/Raver1 fusion protein that rescues key pathological cryptic splicing events, paving the way for the development of precision therapies for TDP43-related disorders.}, } @article {pmid39360635, year = {2024}, author = {Abbassi, Y and Cappelli, S and Spagnolo, E and Gennari, A and Visani, G and Barattucci, S and Paron, F and Stuani, C and Droppelmann, CA and Strong, MJ and Buratti, E}, title = {Axon guidance genes are regulated by TDP-43 and RGNEF through long-intron removal.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {38}, number = {19}, pages = {e70081}, doi = {10.1096/fj.202400743RR}, pmid = {39360635}, issn = {1530-6860}, support = {//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (AriSLA)/ ; //Temetry Family Foundation/ ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics ; Humans ; Introns ; Guanine Nucleotide Exchange Factors/metabolism/genetics ; Animals ; Axon Guidance/genetics ; Motor Neurons/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Gene Expression Regulation ; }, abstract = {Rho guanine nucleotide exchange factor (RGNEF) is a guanine nucleotide exchange factor (GEF) mainly involved in regulating the activity of Rho-family GTPases. It is a bi-functional protein, acting both as a guanine exchange factor and as an RNA-binding protein. RGNEF is known to act as a destabilizing factor of neurofilament light chain RNA (NEFL) and it could potentially contribute to their sequestration in nuclear cytoplasmic inclusions. Most importantly, RGNEF inclusions in the spinal motor neurons of ALS patients have been shown to co-localize with inclusions of TDP-43, the major well-known RNA-binding protein aggregating in the brain and spinal cord of human patients. Therefore, it can be hypothesized that loss-of-function of both proteins following aggregation may contribute to motor neuron death/survival in ALS patients. To further characterize their relationship, we have compared the transcriptomic profiles of neuronal cells depleted of TDP-43 and RGNEF and show that these two factors predominantly act in an antagonistic manner when regulating the expression of axon guidance genes. From a mechanistic point of view, our experiments show that the effect of these genes on the processivity of long introns can explain their mode of action. Taken together, our results show that loss-of-function of factors co-aggregating with TDP-43 can potentially affect the expression of commonly regulated neuronal genes in a very significant manner, potentially acting as disease modifiers. This finding further highlights that neurodegenerative processes at the RNA level are the result of combinatorial interactions between different RNA-binding factors that can be co-aggregated in neuronal cells. A deeper understanding of these complex scenarios may lead to a better understanding of pathogenic mechanisms occurring in patients, where more than one specific protein may be aggregating in their neurons.}, } @article {pmid39360554, year = {2025}, author = {Quigley, S and McNamara, B and Cronin, S}, title = {Alteration in ornithine metabolism due to mutation in ALDH18A1 masquerading as ALS in pregnancy.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {172-174}, doi = {10.1080/21678421.2024.2410982}, pmid = {39360554}, issn = {2167-9223}, mesh = {Humans ; Female ; Pregnancy ; Adult ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Ornithine/blood ; *Mutation/genetics ; Aldehyde Dehydrogenase/genetics ; Pregnancy Complications/genetics/diagnosis ; Spastic Paraplegia, Hereditary/genetics/diagnosis ; Diagnosis, Differential ; }, abstract = {Clinical onset and exacerbation of autosomal dominant SPG9A hereditary spastic paraplegia, including reversible wasting, has been described during pregnancy. SPG9A is due to ALDH18A1 mutations resulting in proline and ornithine deficiency. We present the case of a 29 year old primagravida at 32 weeks who presented with six months of upper limb amyotrophic wasting on a background unrecognized progressive spasticity due to SPG9A. The wasting reversed significantly following delivery. Our report highlights the unusual clinical features including cataract and joint laxity which may suggest SPG9A, echoes the existing descriptions of pregnancy-related provocation of amyotrophy in this condition and documents the outcome of two subsequent pregnancies following dietary intervention.}, } @article {pmid39360074, year = {2024}, author = {Puri, SN and Raghuveer, R and Jachak, S and Tikhile, P}, title = {Exploring the Impact of Personalized Physical Therapy on a Patient With Motor Neuron Disorder: A Case Study.}, journal = {Cureus}, volume = {16}, number = {9}, pages = {e68373}, pmid = {39360074}, issn = {2168-8184}, abstract = {This case study examines the effect of a tailor-made physiotherapy regimen on an 85-year-old male patient who was suffering from bulbar motor neuron disease (MND) and had a history of stroke and COVID-19. The physiotherapy plan was designed to strategically address the patient's respiratory issues, generalized weakness affecting limb muscles, and speech and swallowing difficulties. Frequent evaluations made it possible to adjust the treatment plan, emphasizing a holistic strategy to improve the patient's overall quality of life. Improvements in scores on multiple functional scales and manual muscle testing were shown by outcome measures and follow-up evaluations. This case emphasizes how important customized physiotherapy is for maximizing functional outcomes and enhancing the quality of life for patients dealing with the complicated conditions of bulbar MND.}, } @article {pmid39359088, year = {2025}, author = {Kim, K}, title = {Carboplatin restores neuronal toxicity in FUS-linked amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {8}, pages = {2319-2320}, pmid = {39359088}, issn = {1673-5374}, } @article {pmid39353548, year = {2025}, author = {Bosco, DB and Kremen, V and Haruwaka, K and Zhao, S and Wang, L and Ebner, BA and Zheng, J and Xie, M and Dheer, A and Perry, JF and Barath, A and Nguyen, AT and Worrell, GA and Wu, LJ}, title = {Microglial TREM2 promotes phagocytic clearance of damaged neurons after status epilepticus.}, journal = {Brain, behavior, and immunity}, volume = {123}, number = {}, pages = {540-555}, pmid = {39353548}, issn = {1090-2139}, support = {R01 NS088627/NS/NINDS NIH HHS/United States ; R01 NS112144/NS/NINDS NIH HHS/United States ; R35 NS132326/NS/NINDS NIH HHS/United States ; }, mesh = {*Receptors, Immunologic/metabolism/genetics ; Animals ; *Status Epilepticus/metabolism/genetics ; *Microglia/metabolism ; *Membrane Glycoproteins/metabolism/genetics ; *Mice, Knockout ; Male ; *Phagocytosis/physiology/genetics ; Mice ; *Neurons/metabolism ; Humans ; Disease Models, Animal ; Kainic Acid ; Mice, Inbred C57BL ; Epilepsy, Temporal Lobe/metabolism/genetics ; Seizures/metabolism/genetics ; Antigens, CD/metabolism ; Antigens, Differentiation, Myelomonocytic/metabolism ; }, abstract = {In the central nervous system, triggering receptor expressed on myeloid cells 2 (TREM2) is exclusively expressed by microglia and is critical for microglial proliferation, migration, and phagocytosis. Microglial TREM2 plays an important role in neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis. However, little is known about how TREM2 affects microglial function within epileptogenesis. To investigate this, we utilized male TREM2 knockout (KO) mice within the intra-amygdala kainic acid seizure model. Electroencephalographic analysis, immunocytochemistry, and RNA sequencing revealed that TREM2 deficiency significantly promoted seizure-induced pathology. We found that TREM2 KO increased both the severity of acute status epilepticus and the number of spontaneous recurrent seizures characteristic of chronic focal epilepsy. Phagocytic clearance of damaged neurons by microglia was also impaired by TREM2 KO and reduced phagocytic activity correlated with increased spontaneous seizures. Analysis of human tissue from patients who underwent surgical resection for drug resistant temporal lobe epilepsy also showed a negative correlation between expression of the microglial phagocytic marker CD68 and focal to bilateral tonic-clonic generalized seizure history. These results indicate that microglial TREM2 and phagocytic activity are important to epileptogenic pathology.}, } @article {pmid39355693, year = {2024}, author = {Leger, D and Bater, S and Paulin, MV and Linn, K and Taylor, S and Shelton, GD}, title = {Presumptive motor neuron degeneration in an adult cat.}, journal = {The Canadian veterinary journal = La revue veterinaire canadienne}, volume = {65}, number = {10}, pages = {1034-1040}, pmid = {39355693}, issn = {0008-5286}, mesh = {Cats ; Male ; Animals ; *Cat Diseases/pathology/diagnosis/drug therapy ; *Motor Neuron Disease/veterinary/pathology/diagnosis ; Prednisolone/therapeutic use ; Immunosuppressive Agents/therapeutic use ; Motor Neurons/pathology ; Muscular Atrophy/veterinary/pathology ; Muscle, Skeletal/pathology ; }, abstract = {An 8-year-old neutered male Bengal cat was referred because of a 1-year history of progressive and relapsing generalized muscle weakness and muscle atrophy. Before referral, the cat was treated with immunosuppressive doses of oral prednisolone, intermittently for 6 mo, and had responded well when the immunosuppressive dose was maintained. Generalized paresis, diffuse muscle atrophy, and diminished spinal reflexes were present in all limbs, consistent with a generalized lower motor neuron disease. Histopathologic evaluation of muscle biopsies confirmed a pattern of muscle fiber atrophy consistent with chronic and severe denervation. No specific abnormalities were identified in the nerve biopsy or within intramuscular nerve branches. A presumptive antemortem diagnosis of an adult-onset motor neuron degeneration resembling amyotrophic lateral sclerosis (ALS) or spinal muscle atrophy was suspected. However, given the response to immunosuppressive doses of corticosteroids, an autoimmune process or other degenerative process could not be definitively excluded. Key clinical message: In this case, an adult cat had a chronic, progressive history of lower motor neuron weakness and absent spinal reflexes; biopsies revealed a neurogenic pattern of muscle fiber atrophy and histologically normal peripheral nerve and intramuscular nerve branches. Although reports of motor neuron disease are rare in the veterinary literature, this case report highlights the importance of muscle and nerve biopsies that lead to a presumptive diagnosis of motor neuron degeneration.}, } @article {pmid39355247, year = {2024}, author = {Yang, JL and Wu, JY and Liu, JJ and Zheng, GQ}, title = {Herbal medicines for SOD1[G93A] mice of amyotrophic lateral sclerosis: preclinical evidence and possible immunologic mechanism.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1433929}, pmid = {39355247}, issn = {1664-3224}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/immunology/genetics ; Animals ; Mice ; *Disease Models, Animal ; Mice, Transgenic ; Humans ; Superoxide Dismutase-1/genetics ; Herbal Medicine ; }, abstract = {Currently, there is no cure or effective treatment for Amyotrophic Lateral Sclerosis (ALS). The mechanisms underlying ALS remain unclear, with immunological factors potentially playing a significant role. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), a systematic review of preclinical studies was conducted, searching seven databases including PubMed, covering literature from the inception of the databases to April 10, 2024. Methodological quality of the included literature was assessed using CAMARADES, while the risk of bias in the included studies was evaluated using SYRCLE's ROB tool. Review Manager 5.4.1 statistical software was used for meta-analysis of the outcomes. The scoping review followed the Joanna Briggs Institute Methodological Guidelines and reporting of this review followed the PRISMA-extension for Scoping Reviews (PRISMA -ScR) checklist to explore the immunological mechanisms of Herbal Medicine (HM) in treating ALS. This systematic review and meta-analysis involved 18 studies with a total of 443 animals. The studies scored between 4 to 8 for methodological quality and 3 to 7 for risk of bias, both summing up to 10.A remarkable effects of HM in ALS mice, including onset time(Standardized Mean Difference(SMD): 1.75, 95% Confidence Interval(CI) (1.14 ~ 2.36), Z = 5.60, P < 0.01), survival time(SMD = 1.42, 95% CI (0.79 ~ 2.04), Z = 4.44, P < 0.01), stride length(SMD=1.90, 95% CI (1.21 to 2.59), Z = 5.39, P < 0.01) and duration time (Mean Difference(MD)=6.79, 95% CI [-0.28, 13.87], Z=1.88, P =0.06), showing HM's certain efficiency in treating ALS mice. The scoping review ultimately included 35 articles for review. HMs may treat ALS through mechanisms such as combating oxidative stress, excitatory amino acid toxicity, and calcium cytotoxicity, understanding and exploring the mechanisms will bring hope to patients. Individual herbs and their formulations within HM address ALS through a variety of immune pathways, including safeguarding the blood-brain barrier, countering neuroinflammation, impeding complement system activation, mitigating natural killer cell toxicity, and regulating T cell-mediated immune pathways. The preclinical evidence supports the utilization of HM as a conventional treatment for ALS mice. Growing evidence indicates that HM may potentially delay neurological degeneration in ALS by activating diverse signaling pathways, especially immune pathways.}, } @article {pmid39352715, year = {2024}, author = {Sung, SF and Hu, YH and Chen, CY}, title = {Disambiguating Clinical Abbreviations by One-to-All Classification: Algorithm Development and Validation Study.}, journal = {JMIR medical informatics}, volume = {12}, number = {}, pages = {e56955}, pmid = {39352715}, issn = {2291-9694}, mesh = {*Natural Language Processing ; *Electronic Health Records ; Humans ; *Algorithms ; *Abbreviations as Topic ; }, abstract = {BACKGROUND: Electronic medical records store extensive patient data and serve as a comprehensive repository, including textual medical records like surgical and imaging reports. Their utility in clinical decision support systems is substantial, but the widespread use of ambiguous and unstandardized abbreviations in clinical documents poses challenges for natural language processing in clinical decision support systems. Efficient abbreviation disambiguation methods are needed for effective information extraction.

OBJECTIVE: This study aims to enhance the one-to-all (OTA) framework for clinical abbreviation expansion, which uses a single model to predict multiple abbreviation meanings. The objective is to improve OTA by developing context-candidate pairs and optimizing word embeddings in Bidirectional Encoder Representations From Transformers (BERT), evaluating the model's efficacy in expanding clinical abbreviations using real data.

METHODS: Three datasets were used: Medical Subject Headings Word Sense Disambiguation, University of Minnesota, and Chia-Yi Christian Hospital from Ditmanson Medical Foundation Chia-Yi Christian Hospital. Texts containing polysemous abbreviations were preprocessed and formatted for BERT. The study involved fine-tuning pretrained models, ClinicalBERT and BlueBERT, generating dataset pairs for training and testing based on Huang et al's method.

RESULTS: BlueBERT achieved macro- and microaccuracies of 95.41% and 95.16%, respectively, on the Medical Subject Headings Word Sense Disambiguation dataset. It improved macroaccuracy by 0.54%-1.53% compared to two baselines, long short-term memory and deepBioWSD with random embedding. On the University of Minnesota dataset, BlueBERT recorded macro- and microaccuracies of 98.40% and 98.22%, respectively. Against the baselines of Word2Vec + support vector machine and BioWordVec + support vector machine, BlueBERT demonstrated a macroaccuracy improvement of 2.61%-4.13%.

CONCLUSIONS: This research preliminarily validated the effectiveness of the OTA method for abbreviation disambiguation in medical texts, demonstrating the potential to enhance both clinical staff efficiency and research effectiveness.}, } @article {pmid39352708, year = {2024}, author = {Crose, JJ and Crose, A and Ransom, JT and Lightner, AL}, title = {Bone marrow mesenchymal stem cell-derived extracellular vesicle infusion for amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {3-4}, pages = {111-117}, pmid = {39352708}, issn = {1758-2032}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Extracellular Vesicles ; Male ; Middle Aged ; Female ; Pilot Projects ; Aged ; Mesenchymal Stem Cells ; Mesenchymal Stem Cell Transplantation/methods ; Infusions, Intravenous ; Adult ; Treatment Outcome ; }, abstract = {Background: In this pilot safety study, we hypothesized that a human bone marrow stem cell-derived extracellular vesicle (hBM-MSC EV) investigational product (IP) would be safe and exhibit potential efficacy in amyotrophic lateral sclerosis (ALS) patients.Methods: Ten ALS patients received two 10-ml intravenous infusions of the IP given 1 month apart and evaluated over 3 months.Results: There were no serious adverse events or adverse events related to the IP and 30% of subjects' ALS functional rating scale-revised (ALSFRS-R) scores did not decline.Conclusion: HBM-MSC EVs appear safe in ALS patients. This early investigation suggests a controlled study of EVs for the treatment of ALS is warranted.}, } @article {pmid39351695, year = {2024}, author = {Wang, PS and Yang, XX and Wei, Q and Lv, YT and Wu, ZY and Li, HF}, title = {Clinical characterization and founder effect analysis in Chinese amyotrophic lateral sclerosis patients with SOD1 common variants.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2407522}, pmid = {39351695}, issn = {1365-2060}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Age of Onset ; *Amyotrophic Lateral Sclerosis/genetics ; China/epidemiology ; East Asian People ; Exome Sequencing ; *Founder Effect ; Genetic Association Studies ; Haplotypes ; Mutation ; Phenotype ; *Superoxide Dismutase-1/genetics ; }, abstract = {OBJECTIVE: In the Asian population, SOD1 variants are the most common cause of amyotrophic lateral sclerosis (ALS). To date, more than 200 variants have been reported in SOD1. This study aimed to summarize the genotype-phenotype correlation and determine whether the patients carrying common variants derive from a common ancestor.

METHODS: A total of 103 sporadic ALS (SALS) and 11 familial ALS (FALS) probands were included and variants were screened by whole exome sequencing. Functional analyses were performed on fibroblasts derived from patients with SOD1 p.V48A and control. Haplotype analysis was performed in the probands with p.H47R or p.V48A and their familial members.

RESULTS: A total of 25 SOD1 variants were identified in 44 probands, in which p.H47R, p.V48A and p.C112Y variants were the most common variants. 94.3% and 60% of patients with p.H47R or p.V48A had lower limb onset with predominant lower motor neurons (LMNs) involvement. Patients with p.H47R had a slow progression and prolonged survival time, while patients with p.V48A exhibited a duration of 2-5 years. Patients with p.C112Y variant showed remarkable phenotypic variation in age at onset and disease course. SOD1[V48A] fibroblasts showed mutant SOD1 aggregate formation, enhanced intracellular reactive oxygen species level, and decreased mitochondrial membrane potential compared to the control fibroblast. Haplotype analysis showed that seven families had two different haplotypes. p.H47R and p.V48A variants did not originate from a common founder.

CONCLUSIONS: Our study expanded the understanding of the genotype-phenotype correlation of ALS with SOD1 variants and revealed that the common p.H47R or p.V48A variant did not have a founder effect.}, } @article {pmid39351260, year = {2024}, author = {Gao, FQ and Zhu, JQ and Feng, XD}, title = {Innovative mesenchymal stem cell treatments for fatty liver disease.}, journal = {World journal of stem cells}, volume = {16}, number = {9}, pages = {846-853}, pmid = {39351260}, issn = {1948-0210}, abstract = {The incidence of non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) is increasing year by year due to changes in the contemporary environment and dietary structure, and is an important public health problem worldwide. There is an urgent need to continuously improve the understanding of their disease mechanisms and develop novel therapeutic strategies. Mesenchymal stem cells (MSCs) have shown promise as a potential therapeutic strategy in therapeutic studies of NAFLD and ALD. NAFLD and ALD have different triggers and their specific mechanisms of disease progression are different, but both involve disease processes such as hepatocellular steatosis and potential fibrosis, cirrhosis, and even hepatocellular carcinoma. MSCs have metabolic regulatory, anti-apoptotic, antioxidant, and immunomodulatory effects that together promote liver injury repair and functional recovery, and have demonstrated positive results in preclinical studies. This editorial is a continuum of Jiang et al's review focusing on the advantages and limitations of MSCs and their derivatives as therapeutics for NAFLD and ALD. They detail how MSCs attenuate the progression of NAFLD by modulating molecular pathways involved in glucolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. Based on recent advances, we discuss MSCs and their derivatives as therapeutic strategies for NAFLD and ALD, providing useful information for their clinical application.}, } @article {pmid39350404, year = {2025}, author = {Mohan, M and Mannan, A and Kakkar, C and Singh, TG}, title = {Nrf2 and Ferroptosis: Exploring Translational Avenues for Therapeutic Approaches to Neurological Diseases.}, journal = {Current drug targets}, volume = {26}, number = {1}, pages = {33-58}, pmid = {39350404}, issn = {1873-5592}, mesh = {Humans ; *Ferroptosis/drug effects ; *NF-E2-Related Factor 2/metabolism ; *Oxidative Stress/drug effects ; *Nervous System Diseases/drug therapy/metabolism ; Animals ; Reactive Oxygen Species/metabolism ; Translational Research, Biomedical ; Iron/metabolism ; }, abstract = {Nrf2, a crucial protein involved in defense mechanisms, particularly oxidative stress, plays a significant role in neurological diseases (NDs) by reducing oxidative stress and inflammation. NDs, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, stroke, epilepsy, schizophrenia, depression, and autism, exhibit ferroptosis, iron-dependent regulated cell death resulting from lipid and iron-dependent reactive oxygen species (ROS) accumulation. Nrf2 has been shown to play a critical role in regulating ferroptosis in NDs. Age-related decline in Nrf2 expression and its target genes (HO-1, Nqo-1, and Trx) coincides with increased iron-mediated cell death, leading to ND onset. The modulation of iron-dependent cell death and ferroptosis by Nrf2 through various cellular and molecular mechanisms offers a potential therapeutic pathway for understanding the pathological processes underlying these NDs. This review emphasizes the mechanistic role of Nrf2 and ferroptosis in multiple NDs, providing valuable insights for future research and therapeutic approaches.}, } @article {pmid39349916, year = {2025}, author = {Soliman, R and Onbool, E and Omran, K and Fahmy, N}, title = {Clinical and epidemiological characteristics of amyotrophic lateral sclerosis in an Egyptian cohort.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {3}, pages = {1225-1236}, pmid = {39349916}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics/diagnosis ; Male ; Female ; Egypt/epidemiology ; Adult ; Middle Aged ; Age of Onset ; Prospective Studies ; Disease Progression ; Cohort Studies ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive loss of motor neurons. It is a growing and underestimated disease, prompting this epidemiological study to describe the characteristics of ALS in Egyptian patients.

METHODS: This is a prospective hospital based study. ALS patients were recruited consecutively from Neuromuscular Unit in Ain Shams university Hospital from December 2018 to June 2023. Demographic data and disease related parameters were recorded.

RESULTS: 203 ALS patients had a mean age of onset equal 39 years and an inter quartile range IQR of (28.00-51.00). 76% of the cases were spinal onset ALS. Median disease duration was 2 years with IQR of (1-4 years); male to female ratio was 2.5:1; 18% of patients were familial ALS (FALS), while 19% were Juvenile ALS (JALS). Median diagnostic delay was 12 ± (6-36) months. Median Amyotrophic Lateral Sclerosis Functional Rating Scale Revised scores (ALSFRS-R) at presentation was 34.5 IQR of (26.00-40.00). Also, the mean rate of disease progression ALSFRS-R decline [points/month] was 0.76 ± 0.51.

CONCLUSION: Our cohort was characterized by a younger age of onset, male predominance, more familial cases, within average Initial ALSFRS-R scores as well as diagnostic delay. Juvenile ALS patients were much more common in our population. These findings suggest an influential presence of genetic and epigenetic factors affecting the clinical phenotype of Egyptian ALS patients.}, } @article {pmid39349171, year = {2024}, author = {Khanna, RK and Catanese, S and Mortemousque, G and Dupuy, C and Lefevre, A and Emond, P and Beltran, S and Gissot, V and Pisella, PJ and Blasco, H and Corcia, P}, title = {Metabolomics of basal tears in amyotrophic lateral sclerosis: A cross-sectional study.}, journal = {The ocular surface}, volume = {34}, number = {}, pages = {363-369}, doi = {10.1016/j.jtos.2024.09.005}, pmid = {39349171}, issn = {1937-5913}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnosis ; Male ; Female ; Prospective Studies ; Middle Aged ; *Metabolomics/methods ; Cross-Sectional Studies ; Aged ; *Tears/metabolism ; Case-Control Studies ; Biomarkers/metabolism ; Chromatography, High Pressure Liquid ; Adult ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) clinical variability, along with the lack of conclusive diagnostic instruments, result in average diagnosis delays of 9 months. This study aimed to assess whether metabolomic profiling of basal tears in ALS patients could act as a biological marker for diagnosing ALS, predicting prognosis, and discriminating between endophenotypes.

METHODS: A single-center prospective case-control study was conducted in France from September 2021 to March 2023 including patients with ALS according to the revised EI Escorial criteria. Two microliters of basal tears were collected using microcapillary glass tubes and analyzed with ultra-high performance liquid chromatography coupled with mass spectrometry. Both univariate and multivariate analyses were performed.

RESULTS: Twenty-five patients with ALS and 30 controls were included. No significant differences in metabolite levels were found between ALS and control groups (p > 0.05). The basal tear metabolome significantly discriminated bulbar and spinal forms of ALS based on 6 metabolites, among which 5 were decreased (aniline, trigonelline, caffeine, theophylline and methyl beta-D-galactoside) in the bulbar form and 1 was decreased in the spinal form (dodecanedioic acid).

CONCLUSION: This study represents the first prospective analysis of basal tear metabolomics in individuals with ALS. Despite the inability to distinguish between ALS patients and controls based on metabolic signatures, these findings could contribute to understanding the phenotypic diversity of ALS. Notably, distinct metabolic profiles were identified that differentiate between the bulbar and spinal forms of the disease.}, } @article {pmid39349054, year = {2025}, author = {Simpson, JT and Nordham, KD and Tatum, D and Haut, ER and Ali, A and Maher, Z and Goldberg, AJ and Tatebe, LC and Chang, G and Taghavi, S and Raza, S and Toraih, E and Mendiola Plá, M and Ninokawa, S and Anderson, C and Maluso, P and Keating, J and Burruss, S and Reeves, M and Craugh, LE and Shatz, DV and Bhupathi, A and Spalding, MC and LaRiccia, A and Bird, E and Noorbakhsh, MR and Babowice, J and Nelson, MC and Jacobson, LE and Williams, J and Vella, M and Dellonte, K and Hayward, TZ and Holler, E and Lieser, MJ and Berne, JD and Mederos, DR and Askari, R and Okafor, B and Etchill, E and Fang, R and Roche, SL and Whittenburg, L and Bernard, AC and Haan, JM and Lightwine, KL and Norwood, SH and Murry, J and Gamber, MA and Carrick, MM and Bugaev, N and Tatar, A}, title = {Stop the Bleed-Wait for the Ambulance or Get in the Car and Drive? A Post Hoc Analysis of an EAST Multicenter Trial.}, journal = {The American surgeon}, volume = {91}, number = {2}, pages = {233-241}, doi = {10.1177/00031348241265135}, pmid = {39349054}, issn = {1555-9823}, mesh = {Humans ; Male ; Female ; Adult ; *Ambulances ; Emergency Medical Services ; Wounds, Penetrating/mortality/therapy ; Middle Aged ; Hemorrhage/therapy/mortality ; Trauma Centers ; Propensity Score ; Transportation of Patients ; }, abstract = {Background: The Stop the Bleed campaign gives bystanders an active role in prehospital hemorrhage control. Whether extending bystanders' role to private vehicle transport (PVT) for urban penetrating trauma improves survival is unknown, but past research has found benefit to police and PVT. We hypothesized that for penetrating trauma in an urban environment, where prehospital procedures have been proven harmful, PVT improves outcomes compared to any EMS or advanced life support (ALS) transport.Methods: Post-hoc analysis of an EAST multicenter trial was performed on adult patients with penetrating torso/proximal extremity trauma at 25 urban trauma centers from 5/2019-5/2020. Patients were allocated to PVT and any EMS or ALS transport using nearest neighbor propensity score matching. Univariate analyses included Wilcoxon signed rank or McNemar's Test and logistic regression.Results: Of 1999 penetrating trauma patients in urban settings, 397 (19.9%) had PVT, 1433 (71.7%) ALS transport, and 169 (8.5%) basic life support (BLS) transport. Propensity matching yielded 778 patients, distributed equally into balanced groups. PVT patients were primarily male (90.5%), Black (71.2%), and sustained gunshot wounds (68.9%). ALS transport had significantly higher ED mortality (3.9% vs 1.9%, P = 0.03). There was no difference in in-hospital mortality rate, hospital LOS, or complications for all EMS or ALS only transport patients.Conclusion: Compared to PVT, ALS, which provides more prehospital procedures than BLS, provided no survival benefit for penetrating trauma patients in urban settings. Bystander education incorporating PVT for early arrival of penetrating trauma patients in urban settings to definitive care merits further investigation.}, } @article {pmid39347895, year = {2025}, author = {Yin, KF and Chen, T and Gu, XJ and Jiang, Z and Su, WM and Duan, QQ and Wen, XJ and Cao, B and Li, JR and Chi, LY and Chen, YP}, title = {Identification of Potential Causal Genes for Neurodegenerative Diseases by Mitochondria-Related Genome-Wide Mendelian Randomization.}, journal = {Molecular neurobiology}, volume = {62}, number = {3}, pages = {3892-3902}, pmid = {39347895}, issn = {1559-1182}, support = {2022NSFSC0749//National Natural Science Fund of Sichuan/ ; 2023HXFH032//1·3·5 project for disciplines of excellence-Clinical Research Fund, West China Hospital, Sichuan University/ ; 2022YFC2703101//National Key Research and Development Program of China/ ; 2023YFS0269//Science and Technology Bureau Fund of Sichuan Province/ ; 81971188//National Natural Science Fund of China/ ; C2023124417//National Innovation and Entrepreneurship Training Program for College Students/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; *Mitochondria/genetics/metabolism ; *Neurodegenerative Diseases/genetics ; *Quantitative Trait Loci/genetics ; *Bayes Theorem ; Genetic Predisposition to Disease ; DNA, Mitochondrial/genetics ; }, abstract = {Current research lacks comprehensive investigations into the potential causal link between mitochondrial-related genes and the risk of neurodegenerative diseases (NDDs). We aimed to identify potential causative genes for five NDDs through an examination of mitochondrial-related gene expression levels. Through the integration of summary statistics from expression quantitative trait loci (eQTL) datasets (human blood and brain tissue), mitochondrial DNA copy number (mtDNA-CN), and genome-wide association studies (GWAS) datasets of five NDDs from European ancestry, we conducted a Mendelian randomization (MR) analysis to explore the potential causal relationship between mitochondrial-related genes and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Sensitivity analysis and Bayesian colocalization were employed to validate this causal relationship. Through MR analysis, we have identified potential causal relationships between 12 mitochondria-related genes and AD, PD, ALS, and FTD overlapping with motor neuron disease (FTD_MND) in human blood or brain tissue. Bayesian colocalization analysis further confirms 9 causal genes, including NDUFS2, EARS2, and MRPL41 for AD; NDUFAF2, MALSU1, and METTL8 for PD; MYO19 and MRM1 for ALS; and FASTKD1 for FTD_MND. Importantly, in both human blood and brain tissue, NDUFS2 exhibits a significant pathogenic effect on AD, while NDUFAF2 demonstrates a robust protective effect on PD. Additionally, the mtDNA-CN plays a protected role in LBD (OR = 0.62, p = 0.031). This study presents evidence establishing a causal relationship between mitochondrial dysfunction and NDDs. Furthermore, the identified candidate genes may serve as potential targets for drug development aimed at preventing NDDs.}, } @article {pmid39347334, year = {2024}, author = {Aljehani, NS and Al-Gunaid, ST and Hobani, AH and Alhinti, MF and Khubrani, YA and Abu-Hamoud, LM and Alrayes, AA and Alharbi, LB and Sultan, AA and Turkistani, DA and Naiser, SS and Albraik, L and Alakel, AM and Alotaibi, M and Asiri, AY}, title = {Ultrasound Blood-Brain Barrier Opening and Aducanumab in Alzheimer's Disease: A Systematic Review and Meta-Analysis.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e68008}, pmid = {39347334}, issn = {2168-8184}, abstract = {The blood-brain barrier (BBB) presents a significant challenge in treating Alzheimer's disease, as it restricts the delivery of therapeutic medications to brain tissue. Reversible breaking of the BBB using low-intensity focused ultrasound guided by magnetic resonance imaging (MRI) may benefit patients with Alzheimer's disease and other neurological illnesses, such as brain tumors, amyotrophic lateral sclerosis, and Parkinson's disease. This systematic study and meta-analysis aimed to assess aducanumab and the ultrasonography of BBB opening in Alzheimer's patients. According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), the study was conducted by searching six digital repositories for relevant scholarly literature, focusing on English papers published between 2015 and 2024; the data was extracted using an Excel sheet, and data was analyzed using Revman 5.4.1 software. The study's findings indicate that the groups receiving ultrasound and aducanumab treatment benefited from it; however, overall, the effect was not statistically significant (P=0.29) at 95% CI 0.86 (0.75, 1.00). With regard to side effects, the results indicate that the treatment had fewer side effects compared to the control group; however, the difference was not statistically significant (p=0.94) at 95% CI 0.93 (0.70, 1.22). The study found a positive effect of ultrasound and aducanumab on the treatment groups, but it was not statistically significant. The control group had less side effects than the treatment group. Therefore, future studies should focus on the quantity or combination of the drug that yields more effective results.}, } @article {pmid39346793, year = {2024}, author = {Ghaderi, S and Mohammadi, S and Fatehi, F}, title = {Calcium accumulation or iron deposition: Delving into the temporal sequence of amyotrophic lateral sclerosis pathophysiology in the primary motor cortex.}, journal = {Ibrain}, volume = {10}, number = {3}, pages = {375-377}, pmid = {39346793}, issn = {2769-2795}, abstract = {Amyotrophic lateral sclerosis (ALS) causes progressive motor neuron degeneration, but an in vivo understanding of its early pathology remains limited. A recent study used topographic layer imaging to investigate iron and calcium accumulation in the primary motor cortex (M1) of patients with ALS compared with controls. Despite the preserved cortical thickness, ALS patients showed increased iron in layer 6 and calcium accumulation in layer 5a and the superficial layer. Calcium accumulation was particularly prominent in the low-myelin borders, potentially preceding the demyelination. This study reveals a novel in vivo pathology in ALS, suggesting that calcium dysregulation may precede iron accumulation and contribute to early M1 cell degeneration. Further investigation using quantitative susceptibility mapping and complementary techniques, such as diffusion kurtosis imaging, along with ultrahigh-field magnetic resonance imaging, into the role of calcium and early intervention strategies is warranted.}, } @article {pmid39346681, year = {2024}, author = {Fisher, RMA and Torrente, MP}, title = {Histone post-translational modification and heterochromatin alterations in neurodegeneration: revealing novel disease pathways and potential therapeutics.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1456052}, pmid = {39346681}, issn = {1662-5099}, support = {R15 NS125394/NS/NINDS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), Frontotemporal Dementia (FTD), and Amyotrophic lateral sclerosis (ALS) are complex and fatal neurodegenerative diseases. While current treatments for these diseases do alleviate some symptoms, there is an imperative need for novel treatments able to stop their progression. For all of these ailments, most cases occur sporadically and have no known genetic cause. Only a small percentage of patients bear known mutations which occur in a multitude of genes. Hence, it is clear that genetic factors alone do not explain disease occurrence. Chromatin, a DNA-histone complex whose basic unit is the nucleosome, is divided into euchromatin, an open form accessible to the transcriptional machinery, and heterochromatin, which is closed and transcriptionally inactive. Protruding out of the nucleosome, histone tails undergo post-translational modifications (PTMs) including methylation, acetylation, and phosphorylation which occur at specific residues and are connected to different chromatin structural states and regulate access to transcriptional machinery. Epigenetic mechanisms, including histone PTMs and changes in chromatin structure, could help explain neurodegenerative disease processes and illuminate novel treatment targets. Recent research has revealed that changes in histone PTMs and heterochromatin loss or gain are connected to neurodegeneration. Here, we review evidence for epigenetic changes occurring in AD, PD, and FTD/ALS. We focus specifically on alterations in the histone PTMs landscape, changes in the expression of histone modifying enzymes and chromatin remodelers as well as the consequences of these changes in heterochromatin structure. We also highlight the potential for epigenetic therapies in neurodegenerative disease treatment. Given their reversibility and pharmacological accessibility, epigenetic mechanisms provide a promising avenue for novel treatments. Altogether, these findings underscore the need for thorough characterization of epigenetic mechanisms and chromatin structure in neurodegeneration.}, } @article {pmid39345637, year = {2024}, author = {Morgan, KJ and Carley, E and Coyne, AN and Rothstein, JD and Lusk, CP and King, MC}, title = {Visualizing nuclear pore complex plasticity with Pan-Expansion Microscopy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39345637}, issn = {2692-8205}, support = {F31 HL158119/HL/NHLBI NIH HHS/United States ; R01 GM129308/GM/NIGMS NIH HHS/United States ; R01 NS122236/NS/NINDS NIH HHS/United States ; R21 AR081661/AR/NIAMS NIH HHS/United States ; }, abstract = {Cell-type specific and environmentally-responsive plasticity in nuclear pore complex (NPC) composition and structure is an emerging area of investigation, but its molecular underpinnings remain ill defined. To understand the cause and consequence of NPC plasticity requires technologies to visualize differences within individual NPCs across the thousands in a given nucleus. We evaluate the utility of Pan Expansion Microscopy (Pan-ExM), which enables 16-20 fold isotropic cell enlargement while preserving the proteome, to reveal NPC plasticity. NPCs are robustly identified by deep learning-facilitated segmentation as tripartite structures corresponding to the nucleoplasmic ring, inner ring with central transport channel, and cytoplasmic ring, as confirmed by immunostaining. We demonstrate a range of NPC diameters with a bias for dilated NPCs at the basal nuclear surface, often in local clusters. These diameter biases are eliminated by disrupting linker of nucleoskeleton and cytoskeleton (LINC) complex-dependent connections between the nuclear envelope (NE) and the cytoskeleton, supporting that they reflect local variations in NE tension. Pan-ExM further reveals that the transmembrane nucleoporin/nup POM121 resides specifically at the nuclear ring in multiple model cell lines, surprising given the expectation that it would be a component of the inner ring like other transmembrane nups. Remarkably, however, POM121 shifts from the nuclear ring to the inner ring specifically in aged induced pluripotent stem cell derived neurons (iPSNs) from a patient with C9orf72 amyotrophic lateral sclerosis (ALS). Thus, Pan-ExM allows the visualization of changes in NPC architecture that may underlie early steps in an ALS pathomechanism. Taken together, Pan-ExM is a powerful and accessible tool to visualize NPC plasticity in physiological and pathological contexts at single NPC resolution.}, } @article {pmid39345438, year = {2024}, author = {Elsayyid, M and Tanis, JE and Yu, Y}, title = {In-cell processing enables rapid and in-depth proteome analysis of low-input Caenorhabditis elegans.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39345438}, issn = {2692-8205}, support = {P20 GM104316/GM/NIGMS NIH HHS/United States ; R01 GM135433/GM/NIGMS NIH HHS/United States ; T32 GM133395/GM/NIGMS NIH HHS/United States ; }, abstract = {Caenorhabditis elegans is a widely used genetic model organism, however, the worm cuticle complicates extraction of intracellular proteins, a prerequisite for typical bottom-up proteomics. Conventional physical disruption procedures are not only time-consuming, but can also cause significant sample loss, making it difficult to perform proteomics with low-input samples. Here, for the first time, we present an on-filter in-cell (OFIC) processing approach, which can digest C. elegans proteins directly in the cells of the organism after methanol fixation. With OFIC processing and single-shot LCMS analysis, we identified over 9,400 proteins from a sample of only 200 worms, the largest C. elegans proteome reported to date that did not require fractionation or enrichment. We systematically evaluated the performance of the OFIC approach by comparing it with conventional lysis-based methods. Our data suggest equivalent and unbiased performance of OFIC processing for C. elegans proteome identification and quantitation. We further evaluated the OFIC approach with even lower input samples, then used this method to determine how the proteome is impacted by loss of superoxide dismutase sod-1, the ortholog of human SOD-1, a gene associated with amyotrophic lateral sclerosis (ALS). Analysis of 8,800 proteins from only 50 worms as the initial input showed that loss of sod-1 affects the abundance of proteins required for stress response, ribosome biogenesis, and metabolism. In conclusion, our streamlined OFIC approach, which can be broadly applied to other systems, minimizes sample loss while offering the simplest workflow reported to date for C. elegans proteomics analysis.}, } @article {pmid39344431, year = {2025}, author = {Quail, NPA and Leighton, DJ and Newton, J and Davidson, S and Kelly, L and McKeown, A and Chandran, S and Pal, S and Gorrie, GH}, title = {Influences of Specialist Palliative Care Team Input, Advance Care Planning, Non-Invasive Ventilation and Gastrostomy Status on Unscheduled Hospital Admissions and Place of Death for People with Motor Neuron Disease: A Retrospective Cohort Analysis.}, journal = {Journal of palliative care}, volume = {40}, number = {1}, pages = {89-97}, doi = {10.1177/08258597241283179}, pmid = {39344431}, issn = {2369-5293}, mesh = {Humans ; Male ; *Motor Neuron Disease/therapy/mortality ; Female ; *Advance Care Planning/statistics & numerical data ; Retrospective Studies ; Aged ; *Gastrostomy/statistics & numerical data ; Middle Aged ; *Palliative Care/statistics & numerical data ; *Noninvasive Ventilation/statistics & numerical data ; Aged, 80 and over ; Scotland ; Cohort Studies ; Hospitalization/statistics & numerical data ; Terminal Care/statistics & numerical data ; Adult ; }, abstract = {Objective: Motor neuron disease is a rapidly progressing neurological condition. People with life-limiting conditions generally prefer to die at home and avoid hospital admissions, with Specialist Palliative Care Team involvement often pivotal. Our aim was to investigate the role of advance care planning, Specialist Palliative Care Team input and other relevant variables on place of death and unscheduled hospital admissions in a Scottish population of people with motor neuron disease. Methods: National CARE-MND audit data, primary and secondary care data, and local Palliative Care records were interrogated. Chi-square, point-biserial correlation and binary logistic regression analysed associations (p < 0.05 statistically significant). Participants (188) were deceased, having a verified motor neuron disease diagnosis between 2015-2017, diagnosis occurring ≥28 days before death. Results: Advance care planning and Specialist Palliative Care Team input of ≥28 days were associated with increased odds of dying outside hospital (BLR:OR 3.937, CI 1.558-9.948, p = 0.004 and OR 2.657, CI 1.135-6.222, p = 0.024 respectively). Non-invasive ventilation decreased the odds of dying outside hospital (BLR:OR 0.311, CI 0.124-0.781, p = 0.013). Having a gastrostomy increased odds of ≥1 admissions in the last year of life (BLR:OR 5.142, CI 1.715-15.417, p = 0.003). Statistical significance was retained with removal of gastrostomy-related complications. Conclusion: Early Specialist Palliative Care input and advance care planning may increase the likelihood of death outside of hospital for persons with motor neuron disease. Further research is warranted into barriers of facilitating death outside of hospital with home non-invasive ventilation use and the association between gastrostomy status and unscheduled admissions.}, } @article {pmid39344228, year = {2024}, author = {Li, P and Tao, Z and Zhao, X}, title = {The Role of Osteopontin (OPN) in Regulating Microglia Phagocytosis in Nervous System Diseases.}, journal = {Journal of integrative neuroscience}, volume = {23}, number = {9}, pages = {169}, doi = {10.31083/j.jin2309169}, pmid = {39344228}, issn = {0219-6352}, mesh = {*Osteopontin/metabolism/physiology ; *Microglia/metabolism/physiology ; *Phagocytosis/physiology ; Animals ; Humans ; Nervous System Diseases/metabolism ; }, abstract = {Phagocytosis is the process by which certain cells or organelles internalise foreign substances by engulfing them and then digesting or disposing of them. Microglia are the main resident phagocytic cells in the brain. It is generally believed that microglia/macrophages play a role in guiding the brain's repair and functional recovery processes. However, the resident and invading immune cells of the central nervous system can also exacerbate tissue damage by stimulating inflammation and engulfing viable neurons. The functional consequences of microglial phagocytosis remain largely unexplored. Overall, phagocytosis is considered a beneficial phenomenon in acute brain injury because it eliminates dead cells and induces an anti-inflammatory response. Osteopontin (OPN) is a phosphorylated glycoprotein induced by injury in various tissues, including brain tissue. In acute brain injuries such as hemorrhagic stroke and ischemic stroke, OPN is generally believed to have anti-inflammatory effects. OPN can promote the reconstruction of the blood-brain barrier and up-regulate the scavenger receptor CD36. But in chronic diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), OPN can cause microglia to engulf neurons and worsen disease progression. We explored the role of OPN in promoting microglial phagocytosis in nervous system disorders.}, } @article {pmid39344189, year = {2025}, author = {Khorshidi, Z and Adibi, I and Ghasemi, M}, title = {Association between cerebrospinal fluid chitotriosidase level and amyotrophic lateral sclerosis: a systematic review.}, journal = {Hormone molecular biology and clinical investigation}, volume = {46}, number = {1}, pages = {13-19}, pmid = {39344189}, issn = {1868-1891}, mesh = {*Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Humans ; *Hexosaminidases/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; }, abstract = {INTRODUCTION: One of the fatal and debilitating neurodegenerative diseases is amyotrophic lateral sclerosis (ALS). Increasing age is one of the risk factors of ALS. Considering that the elderly population in the world is increasing, it is very important to identify useful and effective diagnostic and treatment methods. The purpose of this systematic review is to determine the relationship between chitotriosidase (CHIT1) level and ALS disorder.

CONTENT: Keywords "Amyotrophic Lateral Sclerosis", "Gehrig* Disease", "Charcot Disease", "Guam Disease", ALS, CHIT1 and chitotriosidase were searched in PubMed, Scopus, Web of Science and Science Direct databases without time limit on September 2023. Hundred twenty studies were obtained by searching, and finally, 14 studies were included in this study using the inclusion and exclusion criteria. In all 14 selected studies, the level of biomarker CHIT1 in the CSF of ALS patients was significantly higher than that of healthy control and disease control groups. But, in 8 studies that included 3 groups, no significant difference was observed between the CHIT1 levels in the two control groups. Six studies have reported the amount of CHIT1 level quantitatively. Among these 6 studies, in 5 studies CHIT1 level in disease control was higher than healthy control (not significant) and in only one study CHIT1 level was higher in healthy control compared to disease control (not significant).

SUMMARY AND OUTLOOK: In all 14 studies, a multifold increase in CHIT1 levels has been observed in patients compared to healthy and disease control groups. Therefore, based on the findings of the studies, this study confirms the relationship between CHIT1 increase and ALS disorder.}, } @article {pmid39343990, year = {2024}, author = {Xia, L and Qiu, Y and Li, J and Xu, M and Dong, Z}, title = {The Potential Role of Artemisinins Against Neurodegenerative Diseases.}, journal = {The American journal of Chinese medicine}, volume = {52}, number = {6}, pages = {1641-1660}, doi = {10.1142/S0192415X24500642}, pmid = {39343990}, issn = {1793-6853}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Artemisinins/pharmacology ; *Neuroprotective Agents/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Parkinson Disease/drug therapy/metabolism ; Ferroptosis/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy ; Huntington Disease/drug therapy/metabolism ; Autophagy/drug effects ; }, abstract = {Artemisinin (ART) and its derivatives, collectively referred to as artemisinins (ARTs), have been approved for the treatment of malaria for decades. ARTs are converted into dihydroartemisinin (DHA), the only active form, which is reductive in vivo. In this review, we provide a brief overview of the neuroprotective potential of ARTs and the underlying mechanisms on several of the most common neurodegenerative diseases, particularly considering their potential application in those associated with cognitive and motor impairments including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). ARTs act as autophagy balancers to alleviate AD and PD. They inhibit neuroinflammatory responses by regulating phosphorylation of signal transduction proteins, such as AKT, PI3K, ERK, NF-κB, p38 MAPK, IκBα. In addition, ARTs regulate GABAergic signaling in a dose-dependent manner. Although they competitively inhibit the binding of gephyrin to GABAergic receptors, low doses of ARTs enhance GABAergic signaling. ARTs can also inhibit ferroptosis, activate the Akt/Bcl-2, AMPK, or ERK/CREB pathways to reduce oxidative stress, and maintain mitochondrial homeostasis, protecting neurons from oxidative stress injury. More importantly, ARTs structurally combine with and suppress β-Amyloid (A[Formula: see text]-induced neurotoxicity, reduce P-tau, and maintain O-GlcNAcylation/Phosphorylation balance, leading to relieved pathological changes in neurodegenerative diseases. Collectively, these natural properties endow ARTs with unique potential for application in neurodegenerative diseases.}, } @article {pmid39343443, year = {2024}, author = {O'Brien, D and Shaw, PJ}, title = {New developments in the diagnosis and management of motor neuron disease.}, journal = {British medical bulletin}, volume = {152}, number = {1}, pages = {4-15}, doi = {10.1093/bmb/ldae010}, pmid = {39343443}, issn = {1471-8391}, support = {NIHR 203321//NIHR Sheffield Biomedical Research Centre/ ; 972-797//AMBRoSIA Biosampling Programme/ ; 764-780//MNDA (Sheffield Care and Research Centre for Motor Neuron Disorders/ ; }, mesh = {Humans ; *Motor Neuron Disease/therapy/diagnosis ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {INTRODUCTION: Motor neuron disease (MND) is a devastating neurodegenerative disease characterized by progressive muscle weakness.

SOURCES OF DATA: PubMed, MEDLINE, and Cochrane databases were searched for articles to March 2024. Searches involved the terms 'motor neuron disease' or 'amyotrophic lateral sclerosis' and 'epidemiology', 'diagnosis', 'clinical', 'genetic', 'management', 'treatment', or 'trial'.

AREAS OF AGREEMENT: Evidence-based management involves riluzole, multidisciplinary care, provision of noninvasive ventilation and gastrostomy, and symptomatic treatments. Tofersen should be offered to treat SOD1-MND.

AREAS OF CONTROVERSY: Edaravone and Relyvrio are approved treatments in the USA, but insufficient evidence was found to support approval in the UK and Europe.

GROWING POINTS: The discovery of neurofilaments as MND biomarkers, growth of platform trials and development of novel therapies provide optimism for more powerful neuroprotective therapies.

Further work should focus on the elucidation of environmental causes of MND, gene-environment interactions, and advanced cellular models of disease.}, } @article {pmid39342484, year = {2025}, author = {Deneubourg, C and Salimi Dafsari, H and Lowe, S and Martinez-Cotrina, A and Mazaud, D and Park, SH and Vergani, V and Almacellas Barbanoj, A and Maroofian, R and Averdunk, L and Ghayoor-Karimiani, E and Jayawant, S and Mignot, C and Keren, B and Peters, R and Kamath, A and Mattas, L and Verma, S and Silwal, A and Distelmaier, F and Houlden, H and Lignani, G and Antebi, A and Jepson, J and Jungbluth, H and Fanto, M}, title = {Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis in Drosophila and Vici syndrome patients.}, journal = {Autophagy}, volume = {21}, number = {2}, pages = {447-459}, pmid = {39342484}, issn = {1554-8635}, mesh = {Animals ; *Autophagy/physiology/genetics ; Humans ; *Drosophila melanogaster/metabolism ; *Drosophila Proteins/metabolism/genetics ; *Epilepsy/genetics/metabolism/physiopathology/pathology ; Cataract/metabolism/pathology/genetics/physiopathology ; Male ; Mutation/genetics ; Vesicular Transport Proteins/metabolism/genetics ; Female ; Autophagy-Related Proteins/metabolism/genetics ; Disease Models, Animal ; Proteotoxic Stress ; Agenesis of Corpus Callosum ; }, abstract = {Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy is an essential neuronal housekeeping mechanism, which causes severe proteotoxic stress when impaired. Autophagy impairment has been associated to epileptogenesis through a variety of molecular mechanisms. Vici Syndrome (VS) is the paradigmatic congenital autophagy disorder in humans due to recessive variants in the ectopic P-granules autophagy tethering factor 5 (EPG5) gene that is crucial for autophagosome-lysosome fusion and autophagic clearance. Here, we used Drosophila melanogaster to study the importance of Epg5 in development, aging, and seizures. Our data indicate that proteotoxic stress due to impaired autophagic clearance and seizure-like behaviors correlate and are commonly regulated, suggesting that seizures occur as a direct consequence of proteotoxic stress and age-dependent neurodegenerative progression. We provide complementary evidence from EPG5-mutated patients demonstrating an epilepsy phenotype consistent with Drosophila predictions.Abbreviations: AD: Alzheimer's disease; ALS-FTD: Amyotrophic Lateral Sclerosis-FrontoTemoporal Dementia; DART: Drosophila Arousal Tracking; ECoG: electrocorticogram; EEG: electroencephalogram; EPG5: ectopic P-granules 5 autophagy tethering factor; KA: kainic acid; MBs: mushroom bodies; MRI magnetic resonance imaging; MTOR: mechanistic target of rapamycin kinase; PD: Parkinson's disease; TSC: TSC complex; VS: Vici syndrome.}, } @article {pmid39341837, year = {2024}, author = {Hollingworth, D and Thomas, F and Page, DA and Fouda, MA and De Castro, RL and Sula, A and Mykhaylyk, VB and Kelly, G and Ulmschneider, MB and Ruben, PC and Wallace, BA}, title = {Structural basis for the rescue of hyperexcitable cells by the amyotrophic lateral sclerosis drug Riluzole.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8426}, pmid = {39341837}, issn = {2041-1723}, support = {BB/105581//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; CC1078/ARC_/Arthritis Research UK/United Kingdom ; mutiple grants//Diamond Light Source/ ; /WT_/Wellcome Trust/United Kingdom ; BB/V0183511//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; CF2-100001//Rosetrees Trust/ ; BB/S017844//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; studentship//Wellcome Trust (Wellcome)/ ; }, mesh = {*Riluzole/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; Humans ; *Neuroprotective Agents/pharmacology ; Voltage-Gated Sodium Channels/metabolism/chemistry ; HEK293 Cells ; Animals ; Sodium/metabolism ; Motor Neurons/drug effects/metabolism ; }, abstract = {Neuronal hyperexcitability is a key element of many neurodegenerative disorders including the motor neuron disease Amyotrophic Lateral Sclerosis (ALS), where it occurs associated with elevated late sodium current (INaL). INaL results from incomplete inactivation of voltage-gated sodium channels (VGSCs) after their opening and shapes physiological membrane excitability. However, dysfunctional increases can cause hyperexcitability-associated diseases. Here we reveal the atypical binding mechanism which explains how the neuroprotective ALS-treatment drug riluzole stabilises VGSCs in their inactivated state to cause the suppression of INaL that leads to reversed cellular overexcitability. Riluzole accumulates in the membrane and enters VGSCs through openings to their membrane-accessible fenestrations. Riluzole binds within these fenestrations to stabilise the inactivated channel state, allowing for the selective allosteric inhibition of INaL without the physical block of Na[+] conduction associated with traditional channel pore binding VGSC drugs. We further demonstrate that riluzole can reproduce these effects on a disease variant of the non-neuronal VGSC isoform Nav1.4, where pathologically increased INaL is caused directly by mutation. Overall, we identify a model for VGSC inhibition that produces effects consistent with the inhibitory action of riluzole observed in models of ALS. Our findings will aid future drug design and supports research directed towards riluzole repurposing.}, } @article {pmid39341656, year = {2024}, author = {Paris, A and Lakatos, A}, title = {Cell and gene therapy for amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {205}, number = {}, pages = {217-241}, doi = {10.1016/B978-0-323-90120-8.00017-4}, pmid = {39341656}, issn = {0072-9752}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; *Genetic Therapy/methods ; Animals ; Cell- and Tissue-Based Therapy/methods/trends ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disorder with rapidly progressive skeletal muscle weakness, which can also cause a variable cognitive deficit. Genetic causes are only identified in approximately 10% of all cases, with complex genotype-phenotype associations, making it challenging to identify treatment targets. What further hampers therapeutic development is a broad heterogeneity in mechanisms, possible targets, and disturbances across various cell types, aside from the cortical and spinal motor neurons that lie at the heart of the pathology of ALS. Over the last decade, significant progress in biotechnologic techniques, cell and ribonucleic acid (RNA) engineering, animal models, and patient-specific human stem cell and organoid models have accelerated both mechanistic and therapeutic discoveries. The growing number of clinical trials mirrors this. This chapter reviews the current state of human preclinical models supporting trial strategies as well as recent clinical cell and gene therapy approaches.}, } @article {pmid39341507, year = {2024}, author = {Sivalingam, AM}, title = {Advances in understanding biomarkers and treating neurological diseases - Role of the cerebellar dysfunction and emerging therapies.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102519}, doi = {10.1016/j.arr.2024.102519}, pmid = {39341507}, issn = {1872-9649}, mesh = {Humans ; *Biomarkers/metabolism ; Animals ; *Cerebellar Diseases/therapy/diagnosis/metabolism/genetics ; Genetic Therapy/methods/trends ; Nervous System Diseases/therapy/diagnosis/metabolism ; Cerebellum/metabolism/pathology ; }, abstract = {Cerebellar dysfunction is increasingly recognized as a critical factor in various neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Research has revealed distinct cerebellar atrophy patterns in conditions such as AD and multiple system atrophy, and studies in mice have highlighted its impact on motor control and cognitive functions. Emerging research into autism spectrum disorder (ASD) has identified key targets, such as elevated levels of chemokine receptors and ZIC family genes. Biomarkers, including cerebrospinal fluid (CSF), genetic markers, and advances in AI and bioinformatics, are enhancing early diagnosis and personalized treatment across neurodegenerative disorders. Notable advancements include improved diagnostic tools, gene therapy, and novel clinical trials. Despite progress, challenges such as the bloodbrain barrier and neuroinflammation persist. Current therapies for AD, PD, HD, and ALS, including antisense oligonucleotides and stem cell treatments, show promise but require further investigation. A comprehensive approach that integrates diagnostic methods and innovative therapies is essential for effective management and improved patient outcomes.}, } @article {pmid39340928, year = {2024}, author = {Dahl, R and Bezprozvanny, I}, title = {SERCA pump as a novel therapeutic target for treating neurodegenerative disorders.}, journal = {Biochemical and biophysical research communications}, volume = {734}, number = {}, pages = {150748}, doi = {10.1016/j.bbrc.2024.150748}, pmid = {39340928}, issn = {1090-2104}, support = {R01 AG071310/AG/NIA NIH HHS/United States ; R56 AG078337/AG/NIA NIH HHS/United States ; R42 AG062001/AG/NIA NIH HHS/United States ; }, mesh = {*Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; Humans ; Animals ; Disease Models, Animal ; Allosteric Regulation/drug effects ; Molecular Targeted Therapy/methods ; *Neuroprotective Agents/pharmacology/therapeutic use ; Calcium Signaling/drug effects ; Calcium/metabolism ; }, abstract = {The neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and Spinocerebellar ataxias (SCAs), present an enormous medical, social, financial and scientific problem. Despite intense research into the causes of these disorders, only marginal progress has been made in the clinic and no cures exist for any of them. Most of the scientific effort has been focused on identification of the major causes of these diseases and on developing ways to target them, such as targeting amyloid accumulation for AD or targeting expression of mutant Huntingtin for HD. Calcium (Ca[2+]) signaling has long been proposed to play an important role in the pathogenesis of neurodegenerative disorders, but blockers of Ca[2+] channels and Ca[2+] signaling proteins have not been translated to clinic primarily due to side effects related to the important roles of target molecules for these compounds at the peripheral tissues. In this review article, we would like to discuss an idea that recently identified positive allosteric modulators (PAMs) of the sarco-endoplasmic reticulum calcium (SERCA) pump may provide a promising approach to develop therapeutic compounds for treatment of these disorders. This hypothesis is supported by the preclinical data obtained with animal models of AD and PD. The first critical test of this idea will be an imminent phase I study that will offer an opportunity to evaluate potential side effects of this class of compounds in humans.}, } @article {pmid39340874, year = {2024}, author = {Xiong, Z and Zeng, Q and Hu, Y and Lai, C and Wu, H}, title = {Optineurin inhibits IBDV replication via interacting with VP1.}, journal = {Veterinary microbiology}, volume = {298}, number = {}, pages = {110261}, doi = {10.1016/j.vetmic.2024.110261}, pmid = {39340874}, issn = {1873-2542}, mesh = {*Virus Replication ; Animals ; *Infectious bursal disease virus/physiology ; *Chickens ; Membrane Transport Proteins/metabolism/genetics ; Cell Cycle Proteins/metabolism/genetics ; Poultry Diseases/virology ; Humans ; Ubiquitination ; Birnaviridae Infections/veterinary/virology ; Cell Line ; Capsid Proteins/metabolism/genetics ; Transcription Factor TFIIIA/metabolism/genetics ; HEK293 Cells ; }, abstract = {Avibirnavirus, specifically Infectious Bursal Disease Virus (IBDV), is a highly contagious pathogen that causes significant economic losses in the poultry industry. The polymerase protein VP1 of IBDV is critical to the viral life cycle, facilitating the synthesis of viral mRNA and the genome. Previous studies have suggested that various host factors influence the regulation of IBDV polymerase activity. In this study, we identified that IBDV infection induces the expression of optineurin (OPTN), a mitophagy receptor and a protein associated with amyotrophic lateral sclerosis (ALS), as well as a negative regulator of interferon I production. The induced expression of OPTN acts as a suppressor of IBDV replication, a function dependent on its ubiquitin-binding domain (UBAN). Furthermore, we demonstrated that OPTN exerts its antiviral effects through direct interactions with VP1 and VP3, which inhibit the polymerase activity of VP1 by preventing K63-linked ubiquitination of VP1. To our knowledge, this study is the first to report that OPTN, upregulated during IBDV infection, functions as a novel antiviral host factor that limits the virus's replicative capacity, offering a potential target for anti-IBDV therapeutic strategies.}, } @article {pmid39340590, year = {2024}, author = {Ghiasvand, K and Amirfazli, M and Moghimi, P and Safari, F and Takhshid, MA}, title = {The role of neuron-like cell lines and primary neuron cell models in unraveling the complexity of neurodegenerative diseases: a comprehensive review.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {1024}, doi = {10.1007/s11033-024-09964-x}, pmid = {39340590}, issn = {1573-4978}, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Neurons/metabolism ; Animals ; Coculture Techniques/methods ; Cell Line ; Models, Biological ; Alzheimer Disease/pathology/genetics ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by the progressive loss of neurons. As to developing effective therapeutic interventions, it is crucial to understand the underlying mechanisms of NDs. Cellular models have become invaluable tools for studying the complex pathogenesis of NDs, offering insights into disease mechanisms, determining potential therapeutic targets, and aiding in drug discovery. This review provides a comprehensive overview of various cellular models used in ND research, focusing on Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Cell lines, such as SH-SY5Y and PC12 cells, have emerged as valuable tools due to their ease of use, reproducibility, and scalability. Additionally, co-culture models, involving the growth of distinct cell types like neurons and astrocytes together, are highlighted for simulating brain interactions and microenvironment. While cell lines cannot fully replicate the complexity of the human brain, they provide a scalable method for examining important aspects of neurodegenerative diseases. Advancements in cell line technologies, including the incorporation of patient-specific genetic variants and improved co-culture models, hold promise for enhancing our understanding and expediting the development of effective treatments. Integrating multiple cellular models and advanced technologies offers the potential for significant progress in unraveling the intricacies of these debilitating diseases and improving patient outcomes.}, } @article {pmid39340541, year = {2024}, author = {Gagliardi, D and Rizzuti, M and Masrori, P and Saccomanno, D and Del Bo, R and Sali, L and Meneri, M and Scarcella, S and Milone, I and Hersmus, N and Ratti, A and Ticozzi, N and Silani, V and Poesen, K and Van Damme, P and Comi, GP and Corti, S and Verde, F}, title = {Exploiting the role of CSF NfL, CHIT1, and miR-181b as potential diagnostic and prognostic biomarkers for ALS.}, journal = {Journal of neurology}, volume = {271}, number = {12}, pages = {7557-7571}, pmid = {39340541}, issn = {1432-1459}, support = {RF-2018-12366357//Ministero della Salute/ ; RF-2021-12374238//Ministero della Salute/ ; GR-2016-02364373//Ministero della Salute/ ; Ricerca corrente//Ministero della Salute/ ; C1//VIB, KU Leuven/ ; 'Opening the Future' Fund//VIB, KU Leuven/ ; FWO-Vlaanderen//Fund for Scientific Research Flanders/ ; T003519N//TBM grant from FWO-Vlaanderen/ ; G077121N//FWO-Vlaanderen/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis/genetics ; Female ; Male ; *Neurofilament Proteins/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; Middle Aged ; *Hexosaminidases/cerebrospinal fluid ; Aged ; *MicroRNAs/cerebrospinal fluid ; Prognosis ; Adult ; Cohort Studies ; Disease Progression ; Aged, 80 and over ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder characterized by relentless and progressive loss of motor neurons. A molecular diagnosis, supported by the identification of specific biomarkers, might promote the definition of multiple biological subtypes of ALS, improving patient stratification and providing prognostic information. Here, we investigated the levels of neurofilament light chain (NfL), chitotriosidase (CHIT1) and microRNA-181b (miR-181b) in the cerebrospinal fluid (CSF) of ALS subjects (N = 210) as well as neurologically healthy and neurological disease controls (N = 218, including N = 74 with other neurodegenerative diseases) from a large European multicentric cohort, evaluating their specific or combined utility as diagnostic and prognostic biomarkers. NfL, CHIT1 and miR-181b all showed significantly higher levels in ALS subjects compared to controls, with NfL showing the most effective diagnostic performance. Importantly, all three biomarkers were increased compared to neurodegenerative disease controls and, specifically, to patients with Alzheimer's disease (AD; N = 44), with NfL and CHIT1 being also higher in ALS than in alpha-synucleinopathies (N = 22). Notably, ALS patients displayed increased CHIT1 levels despite having, compared to controls, a higher prevalence of a polymorphism lowering CHIT1 expression. While no relationship was found between CSF miR-181b and clinical measures in ALS (disease duration, functional disability, and disease progression rate), CSF NfL was the best independent predictor of disease progression and survival. This study deepens our knowledge of ALS biomarkers, highlighting the relative specificity of CHIT1 for ALS among neurodegenerative diseases and appraising the potential diagnostic utility of CSF miR-181b.}, } @article {pmid39340452, year = {2024}, author = {Tchounwou, C and Jobanputra, AJ and Lasher, D and Fletcher, BJ and Jacinto, J and Bhaduri, A and Best, RL and Fisher, WS and Ewert, KK and Li, Y and Feinstein, SC and Safinya, CR}, title = {Mixtures of Intrinsically Disordered Neuronal Protein Tau and Anionic Liposomes Reveal Distinct Anionic Liposome-Tau Complexes Coexisting with Tau Liquid-Liquid Phase-Separated Coacervates.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {40}, number = {40}, pages = {21041-21051}, doi = {10.1021/acs.langmuir.4c02471}, pmid = {39340452}, issn = {1520-5827}, mesh = {*tau Proteins/chemistry/metabolism ; *Liposomes/chemistry ; *Anions/chemistry ; Humans ; Phosphatidylcholines/chemistry ; Phosphatidylserines/chemistry ; Phosphatidylglycerols/chemistry ; Intrinsically Disordered Proteins/chemistry ; }, abstract = {Tau, an intrinsically disordered neuronal protein and polyampholyte with an overall positive charge, is a microtubule (MT) associated protein that binds to anionic domains of MTs and suppresses their dynamic instability. Aberrant tau-MT interactions are implicated in Alzheimer's and other neurodegenerative diseases. Here, we studied the interactions between full-length human protein tau and other negatively charged binding substrates, as revealed by differential interference contrast (DIC) and fluorescence microscopy. As a binding substrate, we chose anionic liposomes (ALs) containing either 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS, -1e) or 1,2-dioleoyl-sn-glycero-3-phosphatidylglycerol (DOPG, -1e) mixed with zwitterionic 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) to mimic anionic plasma membranes of axons where tau resides. At low salt concentrations (0 to 10 mM KCl or NaCl) with minimal charge screening, reaction mixtures of tau and ALs resulted in the formation of distinct states of AL-tau complexes coexisting with liquid-liquid phase-separated tau self-coacervates arising from the polyampholytic nature of tau containing cationic and anionic domains. AL-tau complexes (i.e. tau-lipoplexes) exhibited distinct types of morphologies. This included large ∼20-30 μm tau-decorated giant vesicles with additional smaller liposomes with bound tau attached to the giant vesicles and tau-mediated finite-size assemblies of small liposomes. As the salt concentration was increased to near and above 150 mM for 1:1 electrolytes, AL-tau complexes remained stable, while tau self-coacervate droplets were found to dissolve, indicative of the breaking of (anionic/cationic) electrostatic bonds between tau chains due to increased charge screening. The findings are consistent with the hypothesis that distinct cationic domains of tau may interact with anionic lipid domains of the lumen-facing monolayer of the axon's plasma membrane, suggesting the possibility of transient yet robust interactions near relevant ionic strengths found in neurons.}, } @article {pmid39340290, year = {2025}, author = {Alves, I and Gromicho, M and Oliveira Santos, M and Pinto, S and de Carvalho, M}, title = {Assessing disease progression in ALS: prognostic subgroups and outliers.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {58-63}, doi = {10.1080/21678421.2024.2407412}, pmid = {39340290}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/mortality/physiopathology ; *Disease Progression ; Male ; Female ; Middle Aged ; Prognosis ; Aged ; Adult ; Cohort Studies ; }, abstract = {BACKGROUND: The rate of disease progression, measured by the decline of ALS Functional Rating Scale-Revised (ALSFRS-R) from symptom onset to diagnosis (ΔFS) is a well-established prognostic biomarker for predicting survival. Objectives: This study aims to categorize a large patient cohort based on the initial ΔFS and subsequently investigate survival deviations from the expected prognosis defined by ΔFS.

METHODS: 1056 ALS patients were stratified into three progression categories based on their ΔFS: slow progressors (below 25th percentile), intermediate progressors (between 25th and 75th percentiles), and fast progressors (above 75th percentile). Survival outcomes were classified as short survivors (<2 years), average survivors (2-5 years), and long survivors (>5 years). Clinical and demographic characteristics within each subgroup were then analyzed.

RESULTS: ΔFS stratification yielded cutoff values of <0.29, 0.29-1.03, and >1.03 points/month. Long survivors comprised 26% and 21% were short survivors. Six percent of the fast progressors had a life expectancy of more than 5 years, and none of the clinical and demographic characteristics analyzed could fully explain this discrepancy. Conversely, 13% of intermediate progressors lived less than 2 years, according to a short-diagnostic delay in these patients.

DISCUSSION: Our study reaffirms ΔFS as a prognostic biomarker for ALS. We disclosed outliers defying anticipated patterns. The observed shift in progression categories underscores the non-linear nature of disease progression. Genetic and unknown biological reasons may explain these deviations. Further research is needed to fully understand modulation of ALS survival.}, } @article {pmid39338620, year = {2024}, author = {Razzaq, Z and Brahimi, N and Rehman, HZU and Khan, ZH}, title = {Intelligent Control System for Brain-Controlled Mobile Robot Using Self-Learning Neuro-Fuzzy Approach.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {18}, pages = {}, pmid = {39338620}, issn = {1424-8220}, mesh = {*Fuzzy Logic ; *Robotics/methods ; Humans ; *Brain-Computer Interfaces ; *Electroencephalography/methods ; Algorithms ; Brain/physiology ; Neural Networks, Computer ; Machine Learning ; }, abstract = {Brain-computer interface (BCI) provides direct communication and control between the human brain and physical devices. It is achieved by converting EEG signals into control commands. Such interfaces have significantly improved the lives of disabled individuals suffering from neurological disorders-such as stroke, amyotrophic lateral sclerosis (ALS), and spinal cord injury-by extending their movement range and thereby promoting self-independence. Brain-controlled mobile robots, however, often face challenges in safety and control performance due to the inherent limitations of BCIs. This paper proposes a shared control scheme for brain-controlled mobile robots by utilizing fuzzy logic to enhance safety, control performance, and robustness. The proposed scheme is developed by combining a self-learning neuro-fuzzy (SLNF) controller with an obstacle avoidance controller (OAC). The SLNF controller robustly tracks the user's intentions, and the OAC ensures the safety of the mobile robot following the BCI commands. Furthermore, SLNF is a model-free controller that can learn as well as update its parameters online, diminishing the effect of disturbances. The experimental results prove the efficacy and robustness of the proposed SLNF controller including a higher task completion rate of 94.29% (compared to 79.29%, and 92.86% for Direct BCI and Fuzzy-PID, respectively), a shorter average task completion time of 85.31 s (compared to 92.01 s and 86.16 s for Direct BCI and Fuzzy-PID, respectively), and reduced settling time and overshoot.}, } @article {pmid39338563, year = {2024}, author = {Dow, CT and Pierce, ES and Sechi, LA}, title = {Mycobacterium paratuberculosis: A HERV Turn-On for Autoimmunity, Neurodegeneration, and Cancer?.}, journal = {Microorganisms}, volume = {12}, number = {9}, pages = {}, pmid = {39338563}, issn = {2076-2607}, abstract = {Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that, over millions of years, became integrated into the human genome. While normally inactive, environmental stimuli such as infections have contributed to the transcriptional reactivation of HERV-promoting pathological conditions, including the development of autoimmunity, neurodegenerative disease and cancer. What infections trigger HERV activation? Mycobacterium avium subspecies paratuberculosis (MAP) is a pluripotent driver of human disease. Aside from granulomatous diseases, Crohn's disease, sarcoidosis and Blau syndrome, MAP is associated with autoimmune disease: type one diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis (RA) and autoimmune thyroiditis. MAP is also associated with Alzheimer's disease (AD) and Parkinson's disease (PD). Autoimmune diabetes, MS and RA are the diseases with the strongest MAP/HERV association. There are several other diseases associated with HERV activation, including diseases whose epidemiology and/or pathology would prompt speculation for a causal role of MAP. These include non-solar uveal melanoma, colon cancer, glioblastoma and amyotrophic lateral sclerosis (ALS). This article further points to MAP infection as a contributor to autoimmunity, neurodegenerative disease and cancer via the un-silencing of HERV. We examine the link between the ever-increasing number of MAP-associated diseases and the MAP/HERV intersection with these diverse medical conditions, and propose treatment opportunities based upon this association.}, } @article {pmid39337908, year = {2024}, author = {Wang, R and Chen, L and Zhang, Y and Sun, B and Liang, M}, title = {Expression Changes of miRNAs in Humans and Animal Models of Amyotrophic Lateral Sclerosis and Their Potential Application for Clinical Diagnosis.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {9}, pages = {}, pmid = {39337908}, issn = {2075-1729}, support = {YJXJ-JZ-2021-0014//Scientific Research Project of Beijing Yicheng Cooperative Development Foundation in 2021-Public welfare projects of rare disease related topics/ ; KM202310858001//R&D Program of Beijing Municipal Education Commission/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease. Current detection methods can only confirm the diagnosis at the onset of the disease, missing the critical window for early treatment. Recent studies using animal models have found that detecting changes in miRNA sites can predict the onset and severity of the disease in its early stages, facilitating early diagnosis and treatment. miRNAs show expression changes in motor neurons that connect the brain, spinal cord, and brain stem, as well as in the skeletal muscle in mouse models of ALS. Clinically, expression changes in some miRNAs in patients align with those in mouse models, such as the upregulation of miR-29b in the brain and the upregulation of miR-206 in the skeletal muscle. This study provides an overview of some miRNA study findings in humans as well as in animal models, including SOD1, FUS, TDP-43, and C9orf72 transgenic mice and wobbler mice, highlighting the potential of miRNAs as diagnostic markers for ALS. miR-21 and miR-206 are aberrantly expressed in both mouse model and patient samples, positioning them as key potential diagnostic markers in ALS. Additionally, miR-29a, miR-29b, miR-181a, and miR-142-3p have shown aberrant expression in both types of samples and show promise as clinical targets for ALS. Finally, miR-1197 and miR-486b-5p have been recently identified as aberrantly expressed miRNAs in mouse models for ALS, although further studies are needed to determine their viability as diagnostic targets.}, } @article {pmid39337696, year = {2024}, author = {Niazi, SK}, title = {Bioavailability as Proof to Authorize the Clinical Testing of Neurodegenerative Drugs-Protocols and Advice for the FDA to Meet the ALS Act Vision.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337696}, issn = {1422-0067}, mesh = {Humans ; *United States Food and Drug Administration ; United States ; *Drug Approval ; *Biological Availability ; *Amyotrophic Lateral Sclerosis/drug therapy ; Neurodegenerative Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; Clinical Trials as Topic ; }, abstract = {Although decades of intensive drug discovery efforts to treat neurodegenerative disorders (NDs) have failed, around half a million patients in more than 2000 studies continue being tested, costing over USD 100 billion, despite the conclusion that even those drugs which have been approved have no better effect than a placebo. The US Food and Drug Administration (FDA) has established multiple programs to innovate the treatment of rare diseases, particularly NDs, providing millions of USD in funding primarily by encouraging novel clinical trials to account for issues related to study sizes and adopting multi-arm studies to account for patient dropouts. Instead, the FDA should focus on the primary reason for failure: the poor bioavailability of drugs reaching the brain (generally 0.1% at most) due to the blood-brain barrier (BBB). There are several solutions to enhance entry into the brain, and the FDA must require proof of significant entry into the brain as the prerequisite to approving Investigational New Drug (IND) applications. The FDA should also rely on factors other than biomarkers to confirm efficacy, as these are rarely relevant to clinical use. This study summarizes how the drugs used to treat NDs can be made effective and how the FDA should change its guidelines for IND approval of these drugs.}, } @article {pmid39337560, year = {2024}, author = {Malaguarnera, M and Cabrera-Pastor, A}, title = {Emerging Role of Extracellular Vesicles as Biomarkers in Neurodegenerative Diseases and Their Clinical and Therapeutic Potential in Central Nervous System Pathologies.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337560}, issn = {1422-0067}, support = {PI23/00204//Instituto de Salud Carlos III (ISCIII) through the project "PI23/00204" and co-funded by the European Union; and Conselleria de Educación/Innovación, Universidades, Ciencia y Sociedad Digital, subvenciones para la realización de proyectos de I+D+i desarro/ ; CIGE/083//This research was funded by Instituto de Salud Carlos III (ISCIII) through the project "PI23/00204" and co-funded by the European Union; and Conselleria de Educación/Innovación, Universidades, Ciencia y Sociedad Digital, subvenciones para la realización d/ ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/therapy/metabolism/diagnosis ; Animals ; Central Nervous System Diseases/metabolism/therapy/diagnosis ; Blood-Brain Barrier/metabolism ; }, abstract = {The emerging role of extracellular vesicles (EVs) in central nervous system (CNS) diseases is gaining significant interest, particularly their applications as diagnostic biomarkers and therapeutic agents. EVs are involved in intercellular communication and are secreted by all cell types. They contain specific markers and a diverse cargo such as proteins, lipids, and nucleic acids, reflecting the physiological and pathological state of their originating cells. Their reduced immunogenicity and ability to cross the blood-brain barrier make them promising candidates for both biomarkers and therapeutic agents. In the context of CNS diseases, EVs have shown promise as biomarkers isolable from different body fluids, providing a non-invasive method for diagnosing CNS diseases and monitoring disease progression. This makes them useful for the early detection and monitoring of diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, where specific alterations in EVs content can be detected. Additionally, EVs derived from stem cells show potential in promoting tissue regeneration and repairing damaged tissues. An evaluation has been conducted on the current clinical trials studying EVs for CNS diseases, focusing on their application, treatment protocols, and obtained results. This review aims to explore the potential of EVs as diagnostic markers and therapeutic carriers for CNS diseases, highlighting their significant advantages and ongoing clinical trials evaluating their efficacy.}, } @article {pmid39337454, year = {2024}, author = {Rizea, RE and Corlatescu, AD and Costin, HP and Dumitru, A and Ciurea, AV}, title = {Understanding Amyotrophic Lateral Sclerosis: Pathophysiology, Diagnosis, and Therapeutic Advances.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337454}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/diagnosis/physiopathology/metabolism/genetics ; Humans ; Biomarkers ; Genetic Therapy/methods ; Oxidative Stress ; Animals ; Mitochondria/metabolism ; }, abstract = {This review offers an in-depth examination of amyotrophic lateral sclerosis (ALS), addressing its epidemiology, pathophysiology, clinical presentation, diagnostic techniques, and current as well as emerging treatments. The purpose is to condense key findings and illustrate the complexity of ALS, which is shaped by both genetic and environmental influences. We reviewed the literature to discuss recent advancements in understanding molecular mechanisms such as protein misfolding, mitochondrial dysfunction, oxidative stress, and axonal transport defects, which are critical for identifying potential therapeutic targets. Significant progress has been made in refining diagnostic criteria and identifying biomarkers, leading to earlier and more precise diagnoses. Although current drug treatments provide some benefits, there is a clear need for more effective therapies. Emerging treatments, such as gene therapy and stem cell therapy, show potential in modifying disease progression and improving the quality of life for ALS patients. The review emphasizes the importance of continued research to address challenges such as disease variability and the limited effectiveness of existing treatments. Future research should concentrate on further exploring the molecular foundations of ALS and developing new therapeutic approaches. The implications for clinical practice include ensuring the accessibility of new treatments and that healthcare systems are equipped to support ongoing research and patient care.}, } @article {pmid39337436, year = {2024}, author = {Guo, D and Liu, Z and Zhou, J and Ke, C and Li, D}, title = {Significance of Programmed Cell Death Pathways in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337436}, issn = {1422-0067}, support = {2023Y9415//Joint Funds for the innovation of science and Technology, Fujian province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Signal Transduction ; Animals ; *Apoptosis ; Ferroptosis ; Neurons/metabolism/pathology ; }, abstract = {Programmed cell death (PCD) is a form of cell death distinct from accidental cell death (ACD) and is also referred to as regulated cell death (RCD). Typically, PCD signaling events are precisely regulated by various biomolecules in both spatial and temporal contexts to promote neuronal development, establish neural architecture, and shape the central nervous system (CNS), although the role of PCD extends beyond the CNS. Abnormalities in PCD signaling cascades contribute to the irreversible loss of neuronal cells and function, leading to the onset and progression of neurodegenerative diseases. In this review, we summarize the molecular processes and features of different modalities of PCD, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, and other novel forms of PCD, and their effects on the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), multiple sclerosis (MS), traumatic brain injury (TBI), and stroke. Additionally, we examine the key factors involved in these PCD signaling pathways and discuss the potential for their development as therapeutic targets and strategies. Therefore, therapeutic strategies targeting the inhibition or facilitation of PCD signaling pathways offer a promising approach for clinical applications in treating neurodegenerative diseases.}, } @article {pmid39337251, year = {2024}, author = {Escudier, O and Zhang, Y and Whiting, A and Chazot, P}, title = {Evaluation of a Synthetic Retinoid, Ellorarxine, in the NSC-34 Cell Model of Motor Neuron Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337251}, issn = {1422-0067}, mesh = {Animals ; Mice ; *Neuroprotective Agents/pharmacology ; Retinoids/pharmacology ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Cell Line ; Humans ; Receptors, AMPA/metabolism ; Motor Neurons/drug effects/metabolism/pathology ; Benzoates/pharmacology ; Motor Neuron Disease/drug therapy/metabolism/pathology ; Calcium/metabolism ; Neurites/drug effects/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease worldwide and is characterized by progressive muscle atrophy. There are currently two approved treatments, but they only relieve symptoms briefly and do not cure the disease. The main hindrance to research is the complex cause of ALS, with its pathogenesis not yet fully elucidated. Retinoids (vitamin A derivatives) appear to be essential in neuronal cells and have been implicated in ALS pathogenesis. This study explores 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxalin-2-yl)ethylnyl]benzoic acid (Ellorarxine, or DC645 or NVG0645), a leading synthetic retinoic acid, discussing its pharmacological mechanisms, neuroprotective properties, and relevance to ALS. The potential therapeutic effect of Ellorarxine was analyzed in vitro using the WT and SOD1G93A NSC-34 cell model of ALS at an administered concentration of 0.3-30 nM. Histological, functional, and biochemical analyses were performed. Elorarxine significantly increased MAP2 expression and neurite length, increased AMPA receptor GluA2 expression and raised intracellular Ca[2+] baseline, increased level of excitability, and reduced Ca[2+] spike during depolarization in neurites. Ellorarxine also displayed both antioxidant and anti-inflammatory effects. Overall, these results suggest Ellorarxine shows relevance and promise as a novel therapeutic strategy for treatment of ALS.}, } @article {pmid39336788, year = {2024}, author = {Tourtourikov, I and Todorov, T and Angelov, T and Chamova, T and Tournev, I and Mitev, V and Todorova, A}, title = {Genetic Modifiers of ALS: The Impact of Chromogranin B P413L in a Bulgarian ALS Cohort.}, journal = {Genes}, volume = {15}, number = {9}, pages = {}, pmid = {39336788}, issn = {2073-4425}, support = {Grant No. D-148/ 03.08.2023//Medical University of Sofia/ ; National Recovery and Resilience Plan of the Republic of Bulgaria, project № BG-RRP-2.004-0004-C01//European Union-NextGenerationEU/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Bulgaria ; Middle Aged ; Aged ; Adult ; *Genetic Predisposition to Disease ; *Chromogranin B/genetics ; Age of Onset ; Alleles ; Genotype ; Polymorphism, Single Nucleotide ; Cohort Studies ; Gene Frequency ; Kaplan-Meier Estimate ; }, abstract = {This study investigated the role of the CHGB P413L variant (rs742710) in sporadic amyotrophic lateral sclerosis (sALS) within the Bulgarian population. We analyzed 150 patients with sALS (85 male and 65 female) for the presence of this variant, its potential impact on disease susceptibility, and age of onset. Genotyping was performed using PCR amplification and direct Sanger sequencing. Statistical analyses included comparisons with control data from GnomAD v2.1.1, one-way ANOVA, and Kaplan-Meier survival analysis. Results revealed a higher frequency of the minor T allele in patients with sALS compared to all control groups and a statistically significant increase in carrier genotypes compared to non-Finnish Europeans (χ[2] = 15.4572, p = 0.000440). However, the impact on age of onset was less clear, with no statistically significant differences observed across genotypes or between carriers and non-carriers of the T allele. Kaplan-Meier analysis suggested a potential 2.5-year-earlier onset in T allele carriers, but the small sample size of carriers limits the reliability of this finding. Our study provides evidence for an association between the CHGB P413L variant and sALS susceptibility in the Bulgarian population, while its effect on age of onset remains uncertain, highlighting the need for further research in larger, diverse cohorts.}, } @article {pmid39336748, year = {2024}, author = {Chami, AA and Bedja-Iacona, L and Richard, E and Lanznaster, D and Marouillat, S and Veyrat-Durebex, C and Andres, CR and Corcia, P and Blasco, H and Vourc'h, P}, title = {N-Terminal Fragments of TDP-43-In Vitro Analysis and Implication in the Pathophysiology of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration.}, journal = {Genes}, volume = {15}, number = {9}, pages = {}, pmid = {39336748}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; HEK293 Cells ; Protein Domains ; Cell Survival/genetics ; }, abstract = {Abnormal cytoplasmic aggregates containing the TDP-43 protein and its fragments are present in the central nervous system of the majority of patients with amyotrophic lateral sclerosis (ALS) and in patients with frontotemporal lobar degeneration (FTLD). Many studies have focused on the C-terminal cleavage products of TDP-43 (CTFs), but few have focused on the N-terminal products (NTFs), yet several works and their protein domain composition support the involvement of NTFs in pathophysiology. In the present study, we expressed six NTFs of TDP-43, normally generated in vivo by proteases or following the presence of pathogenic genetic truncating variants, in HEK-293T cells. The N-terminal domain (NTD) alone was not sufficient to produce aggregates. Fragments containing the NTD and all or part of the RRM1 domain produced nuclear aggregates without affecting cell viability. Only large fragments also containing the RRM2 domain, with or without the glycine-rich domain, produced cytoplasmic aggregates. Of these, only NTFs containing even a very short portion of the glycine-rich domain caused a reduction in cell viability. Our results provide insights into the involvement of different TDP-43 domains in the formation of nuclear or cytoplasmic aggregates and support the idea that work on the development of therapeutic molecules targeting TDP-43 must also take into account NTFs and, in particular, those containing even a small part of the glycine-rich domain.}, } @article {pmid39336146, year = {2024}, author = {Duranti, E and Villa, C}, title = {From Brain to Muscle: The Role of Muscle Tissue in Neurodegenerative Disorders.}, journal = {Biology}, volume = {13}, number = {9}, pages = {}, pmid = {39336146}, issn = {2079-7737}, abstract = {Neurodegenerative diseases (NDs), like amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), primarily affect the central nervous system, leading to progressive neuronal loss and motor and cognitive dysfunction. However, recent studies have revealed that muscle tissue also plays a significant role in these diseases. ALS is characterized by severe muscle wasting as a result of motor neuron degeneration, as well as alterations in gene expression, protein aggregation, and oxidative stress. Muscle atrophy and mitochondrial dysfunction are also observed in AD, which may exacerbate cognitive decline due to systemic metabolic dysregulation. PD patients exhibit muscle fiber atrophy, altered muscle composition, and α-synuclein aggregation within muscle cells, contributing to motor symptoms and disease progression. Systemic inflammation and impaired protein degradation pathways are common among these disorders, highlighting muscle tissue as a key player in disease progression. Understanding these muscle-related changes offers potential therapeutic avenues, such as targeting mitochondrial function, reducing inflammation, and promoting muscle regeneration with exercise and pharmacological interventions. This review emphasizes the importance of considering an integrative approach to neurodegenerative disease research, considering both central and peripheral pathological mechanisms, in order to develop more effective treatments and improve patient outcomes.}, } @article {pmid39335997, year = {2024}, author = {Dork, J and Mangan, E and Burns, L and Dimenstein, E}, title = {Affective Instability: Impact of Fluctuating Emotions on Regulation and Psychological Well-Being.}, journal = {Behavioral sciences (Basel, Switzerland)}, volume = {14}, number = {9}, pages = {}, pmid = {39335997}, issn = {2076-328X}, abstract = {Previous research has focused on understanding the occurrence of intense and fluctuating emotions and the ability to manage these emotions and affective states. These phenomena have been, respectively, labeled as affective instability and emotion regulation and have been studied among individuals diagnosed with borderline personality disorder (BPD), attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), and post-traumatic stress disorder (PTSD). Previous findings suggest that affective instability may be associated with poorer psychological well-being. The present study aims to investigate the general tendency of affective instability and capacity for emotional regulation among college students, regardless of a previous psychological diagnosis, and to understand the relationship between these processes and psychological well-being. Three questionnaires were administered to measure levels of affective instability, the ability to manage fluctuating affective states, and overall psychological well-being. The findings suggest that (1) individuals with diagnoses experience affective lability and difficulty regulating emotions at a greater rate than those without, (2) higher affective lability scores are consistent with more significant emotion dysregulation and lower overall psychological well-being, and (3) scores on the Affective lability Scale (ALS) and the Difficulties in Emotional Regulation Scale (DERS) are reliable predictors of one's estimated Global Assessment of Functioning (GAF) scores. Although causation has not been established, the evidence suggests that individuals with diagnoses experience greater difficulty in regulating their emotions, have greater affective lability, and experience diminished psychological well-being and day-to-day functionality. Certain anecdotal evidence suggests that emotional lability can be endogenous and affect multiple aspects of an individual's social, occupational, and personal life. By revising the existing literature and the present findings, the authors provide insights into the significance of endogenous factors in the context of affective lability and offer suggestions for future research.}, } @article {pmid39335582, year = {2024}, author = {Carata, E and Muci, M and Mariano, S and Panzarini, E}, title = {BV2 Microglial Cell Activation/Polarization Is Influenced by Extracellular Vesicles Released from Mutated SOD1 NSC-34 Motoneuron-like Cells.}, journal = {Biomedicines}, volume = {12}, number = {9}, pages = {}, pmid = {39335582}, issn = {2227-9059}, abstract = {Microglia-mediated neuroinflammation is a key player in the pathogenesis of amyotrophic lateral sclerosis (ALS) as it can contribute to the progressive degeneration of motor neurons (MNs). Here, we investigated the role of mSOD1 NSC-34 MN-like cell-derived extracellular vesicles (EVs) in inducing the activation of BV2 microglial cells. NSC-34-released EVs were isolated by culture medium differential ultracentrifugation to obtain two fractions, one containing small EVs (diameter < 200 nm) and the other containing large EVs (diameter > 200 nm). BV2 cells were incubated with the two EV fractions for 12, 24, and 48 h to evaluate 1) the state of microglial inflammation through RT-PCR of IL-1β, IL-6, IL-4, and IL-10 and 2) the expression of proteins involved in inflammasome activation (IL-β and caspase 1), cell death (caspase 3), and glial cell recruitment (CXCR1), and presence of the TGFβ cytokine receptor (TGFβ-R2). The obtained results suggest a mSOD1 type-dependent polarization of BV2 cells towards an early neurotoxic phenotype and a late neuroprotective status, with an appearance of mixed M1 and M2 microglia subpopulations. A significant role in driving microglial cell activation is played by the TGFβ/CX3CR1 axis. Therefore, targeting the dysregulated microglial response and modulating neuroinflammation could hold promise as a therapeutic strategy for ALS.}, } @article {pmid39335395, year = {2024}, author = {Ore, A and Angelastro, JM and Giulivi, C}, title = {Integrating Mitochondrial Biology into Innovative Cell Therapies for Neurodegenerative Diseases.}, journal = {Brain sciences}, volume = {14}, number = {9}, pages = {}, pmid = {39335395}, issn = {2076-3425}, support = {R21 NS128751/NS/NINDS NIH HHS/United States ; }, abstract = {The role of mitochondria in neurodegenerative diseases is crucial, and recent developments have highlighted its significance in cell therapy. Mitochondrial dysfunction has been implicated in various neurodegenerative disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases. Understanding the impact of mitochondrial biology on these conditions can provide valuable insights for developing targeted cell therapies. This mini-review refocuses on mitochondria and emphasizes the potential of therapies leveraging mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, stem cell-derived secretions, and extracellular vesicles. Mesenchymal stem cell-mediated mitochondria transfer is highlighted for restoring mitochondrial health in cells with dysfunctional mitochondria. Additionally, attention is paid to gene-editing techniques such as mito-CRISPR, mitoTALENs, mito-ZNFs, and DdCBEs to ensure the safety and efficacy of stem cell treatments. Challenges and future directions are also discussed, including the possible tumorigenic effects of stem cells, off-target effects, disease targeting, immune rejection, and ethical issues.}, } @article {pmid39334855, year = {2024}, author = {Hasan, A and Staveley, BE}, title = {Bcl-2 Orthologues, Buffy and Debcl, Can Suppress Drp1-Dependent Age-Related Phenotypes in Drosophila.}, journal = {Biomolecules}, volume = {14}, number = {9}, pages = {}, pmid = {39334855}, issn = {2218-273X}, support = {RGPIN-2016-04828//Natural Sciences and Engineering Research Council/ ; }, mesh = {Animals ; *Aging/genetics/metabolism ; Cytoskeletal Proteins ; *Drosophila melanogaster/genetics/metabolism ; *Drosophila Proteins/metabolism/genetics ; Dynamins/genetics/metabolism ; GTP-Binding Proteins ; Longevity/genetics ; Mitochondrial Proteins/genetics/metabolism ; Phenotype ; *Proto-Oncogene Proteins c-bcl-2/metabolism/genetics ; *Membrane Proteins/metabolism ; }, abstract = {The relationship of Amyotrophic Lateral Sclerosis, Parkinson's disease, and other age-related neurodegenerative diseases with mitochondrial dysfunction has led to our study of the mitochondrial fission gene Drp1 in Drosophila melanogaster and aspects of aging. Previously, the Drp1 protein has been demonstrated to interact with the Drosophila Bcl-2 mitochondrial proteins, and Drp1 mutations can lead to mitochondrial dysfunction and neuronal loss. In this study, the Dopa decarboxylase-Gal4 (Ddc-Gal4) transgene was exploited to direct the expression of Drp1 and Drp1-RNAi transgenes in select neurons. Here, the knockdown of Drp1 seems to compromise locomotor function throughout life but does not alter longevity. The co-expression of Buffy suppresses the poor climbing induced by the knockdown of the Drp1 function. The consequences of Drp1 overexpression, which specifically reduced median lifespan and diminished climbing abilities over time, can be suppressed through the directed co-overexpression of pro-survival Bcl-2 gene Buffy or by the co-knockdown of the pro-cell death Bcl-2 homologue Debcl. Alteration of the expression of Drp1 acts to phenocopy neurodegenerative disease phenotypes in Drosophila, while overexpression of Buffy can counteract or rescue these phenotypes to improve overall health. The diminished healthy aging due to either the overexpression of Drp1 or the RNA interference of Drp1 has produced novel Drosophila models for investigating mechanisms underlying neurodegenerative disease.}, } @article {pmid39334843, year = {2024}, author = {Lucchi, C and Simonini, C and Rustichelli, C and Avallone, R and Zucchi, E and Martinelli, I and Biagini, G and Mandrioli, J}, title = {Reduced Levels of Neurosteroids in Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients.}, journal = {Biomolecules}, volume = {14}, number = {9}, pages = {}, pmid = {39334843}, issn = {2218-273X}, support = {Ricerca Finalizzata bando 2021 (RF-2021-12373036)//Ministero della Salute/ ; bando FAR 2021, Progetti di ricerca Interdisciplinari Mission Oriented, NEURALS project//University of Modena and Reggio Emilia/ ; Neurobiobanca di Modena//Fondazione Cassa di Risparmio di Modena/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/cerebrospinal fluid ; Humans ; Middle Aged ; Male ; Female ; *Neurosteroids/cerebrospinal fluid ; Case-Control Studies ; Aged ; Biomarkers/cerebrospinal fluid ; Pregnanolone/cerebrospinal fluid ; Adult ; Pregnenolone/cerebrospinal fluid ; Progesterone/cerebrospinal fluid ; Testosterone/cerebrospinal fluid ; Chromatography, Liquid ; Tandem Mass Spectrometry ; }, abstract = {Produced by the mitochondria and endoplasmic reticulum, neurosteroids such as allopregnanolone are neuroprotective molecules that influence various neuronal functions and regulate neuroinflammation. They are reduced in neurodegenerative diseases, while in the Wobbler mouse model, allopregnanolone and its precursor progesterone showed protective effects on motor neuron degeneration. This single-center case-control study included 37 patients with amyotrophic lateral sclerosis (ALS) and 28 healthy controls. Cerebrospinal fluid (CSF) neurosteroid levels were quantified using liquid chromatography-electrospray tandem mass spectrometry and compared between the two cohorts. Neurosteroid concentrations have been correlated with neuroinflammation and neurodegeneration biomarkers detected through an automated immunoassay, along with disease features and progression. Pregnenolone, progesterone, allopregnanolone, pregnanolone, and testosterone levels were significantly lower in ALS patients' CSF compared to healthy controls. A significant inverse correlation was found between neurofilament and neurosteroid levels. Neurosteroid concentrations did not correlate with disease progression, phenotype, genotype, or survival prediction. Our study suggests the independence of the disease features and its progression, from the dysregulation of neurosteroids in ALS patients' CSF. This neurosteroid reduction may relate to disease pathogenesis or be a consequence of disease-related processes, warranting further research. The inverse correlation between neurosteroids and neurofilament levels may indicate a failure of compensatory neuroprotective mechanisms against neurodegeneration.}, } @article {pmid39334720, year = {2024}, author = {Munteanu, C and Galaction, AI and Turnea, M and Blendea, CD and Rotariu, M and Poștaru, M}, title = {Redox Homeostasis, Gut Microbiota, and Epigenetics in Neurodegenerative Diseases: A Systematic Review.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {9}, pages = {}, pmid = {39334720}, issn = {2076-3921}, abstract = {Neurodegenerative diseases encompass a spectrum of disorders marked by the progressive degeneration of the structure and function of the nervous system. These conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and Multiple sclerosis (MS), often lead to severe cognitive and motor deficits. A critical component of neurodegenerative disease pathologies is the imbalance between pro-oxidant and antioxidant mechanisms, culminating in oxidative stress. The brain's high oxygen consumption and lipid-rich environment make it particularly vulnerable to oxidative damage. Pro-oxidants such as reactive nitrogen species (RNS) and reactive oxygen species (ROS) are continuously generated during normal metabolism, counteracted by enzymatic and non-enzymatic antioxidant defenses. In neurodegenerative diseases, this balance is disrupted, leading to neuronal damage. This systematic review explores the roles of oxidative stress, gut microbiota, and epigenetic modifications in neurodegenerative diseases, aiming to elucidate the interplay between these factors and identify potential therapeutic strategies. We conducted a comprehensive search of articles published in 2024 across major databases, focusing on studies examining the relationships between redox homeostasis, gut microbiota, and epigenetic changes in neurodegeneration. A total of 161 studies were included, comprising clinical trials, observational studies, and experimental research. Our findings reveal that oxidative stress plays a central role in the pathogenesis of neurodegenerative diseases, with gut microbiota composition and epigenetic modifications significantly influencing redox balance. Specific bacterial taxa and epigenetic markers were identified as potential modulators of oxidative stress, suggesting novel avenues for therapeutic intervention. Moreover, recent evidence from human and animal studies supports the emerging concept of targeting redox homeostasis through microbiota and epigenetic therapies. Future research should focus on validating these targets in clinical settings and exploring the potential for personalized medicine strategies based on individual microbiota and epigenetic profiles.}, } @article {pmid39333504, year = {2024}, author = {Cozzi, M and Magri, S and Tedesco, B and Patelli, G and Ferrari, V and Casarotto, E and Chierichetti, M and Pramaggiore, P and Cornaggia, L and Piccolella, M and Galbiati, M and Rusmini, P and Crippa, V and Mandrioli, J and Pareyson, D and Pisciotta, C and D'Arrigo, S and Ratti, A and Nanetti, L and Mariotti, C and Sarto, E and Pensato, V and Gellera, C and Di Bella, D and Cristofani, RM and Taroni, F and Poletti, A}, title = {Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders.}, journal = {Cell death & disease}, volume = {15}, number = {9}, pages = {692}, pmid = {39333504}, issn = {2041-4889}, support = {GGP19128//Fondazione Telethon (Telethon Foundation)/ ; 23236//AFM-Téléthon (French Muscular Dystrophy Association)/ ; PRIN n. 2022EFLFL8//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PRIN n. P2022B5J32//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; Scientific Exchange Grant n. 9643//European Molecular Biology Organization (EMBO)/ ; 2021-1544//Fondazione Cariplo (Cariplo Foundation)/ ; 2021-1544//Fondazione Cariplo (Cariplo Foundation)/ ; RF-2018-12367768//Ministero della Salute (Ministry of Health, Italy)/ ; RRC 2023//Ministero della Salute (Ministry of Health, Italy)/ ; }, mesh = {Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Charcot-Marie-Tooth Disease/genetics/metabolism/pathology ; *Kinesins/metabolism/genetics ; Mitochondria/metabolism/genetics ; *Mutation/genetics ; Neurodegenerative Diseases/genetics/metabolism/pathology ; *Neurodevelopmental Disorders/genetics/metabolism/pathology ; }, abstract = {Mutations targeting distinct domains of the neuron-specific kinesin KIF5A associate with different neurodegenerative/neurodevelopmental disorders, but the molecular bases of this clinical heterogeneity are unknown. We characterised five key mutants covering the whole spectrum of KIF5A-related phenotypes: spastic paraplegia (SPG, R17Q and R280C), Charcot-Marie-Tooth disease (CMT, R864*), amyotrophic lateral sclerosis (ALS, N999Vfs*40), and neonatal intractable myoclonus (NEIMY, C975Vfs*73) KIF5A mutants. CMT-R864*-KIF5A and ALS-N999Vfs*40-KIF5A showed impaired autoinhibition and peripheral localisation accompanied by altered mitochondrial distribution, suggesting transport competence disruption. ALS-N999Vfs*40-KIF5A formed SQSTM1/p62-positive inclusions sequestering WT-KIF5A, indicating a gain of toxic function. SPG-R17Q-KIF5A and ALS-N999Vfs*40-KIF5A evidenced a shorter half-life compared to WT-KIF5A, and proteasomal blockage determined their accumulation into detergent-insoluble inclusions. Interestingly, SPG-R280C-KIF5A and ALS-N999Vfs*40-KIF5A both competed for degradation with proteasomal substrates. Finally, NEIMY-C975Vfs*73-KIF5A displayed a similar, but more severe aberrant behaviour compared to ALS-N999Vfs*40-KIF5A; these two mutants share an abnormal tail but cause disorders on the opposite end of KIF5A-linked phenotypic spectrum. Thus, our observations support the pathogenicity of novel KIF5A mutants, highlight abnormalities of recurrent variants, and demonstrate that both unique and shared mechanisms underpin KIF5A-related diseases.}, } @article {pmid39332091, year = {2024}, author = {Sharma, O and Kaur Grewal, A and Khan, H and Gurjeet Singh, T}, title = {Exploring the nexus of cGAS STING pathway in neurodegenerative terrain: A therapeutic odyssey.}, journal = {International immunopharmacology}, volume = {142}, number = {Pt B}, pages = {113205}, doi = {10.1016/j.intimp.2024.113205}, pmid = {39332091}, issn = {1878-1705}, mesh = {Humans ; *Membrane Proteins/metabolism/genetics ; Animals ; *Neurodegenerative Diseases/drug therapy/immunology/metabolism ; *Nucleotidyltransferases/metabolism/genetics ; *Signal Transduction ; Immunity, Innate ; }, abstract = {By detecting and responding to cytosolic DNA, the cGAS STING pathway regulates the innate immune responses bymediatinginflammatory reactions and antiviral defense. Thederegulation and modification of this system have been linked to variousneurodegenerative diseases like AD, PD and ALS. Accumulation of tau protein and Aβ aggregates to activate the pathway and releases neuroinflammatory cytokines which accelerates neuronal dysfunction and cognitive impairment as the symptom of AD. Similarly, in PD Alpha-synuclein aggregates activate the cGAS STING pathway and regulate the neuroinflammation and oxidative stress. In ALS, mutation of the genes causes the activation of the pathway which leads to motor neuron degeneration. Alteration of the cGAS STING pathway also leads to mitochondrial dysfunction and impaired autophagy. Preclinical investigations of AD, PD, and ALS animal models showed that STING pathway inhibitors reduced inflammation and improved neurological outcomes and modulators of the cGAS STING pathway may treat these neurodegenerative disorders. In this review we focus on the fact thatneuroinflammation, neuronal dysfunction, and various disease progressions can be treated byaltering the cGAS STING pathway. Understanding the processes and creating specific interventions for this route may offer new treatments for these terrible illnesses.}, } @article {pmid39330700, year = {2024}, author = {Everett, WH and Bucelli, RC}, title = {Tofersen for SOD1 ALS.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {5}, pages = {149-160}, pmid = {39330700}, issn = {1758-2032}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Oligonucleotides/therapeutic use ; *Superoxide Dismutase-1/antagonists & inhibitors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition affecting the motor system. The heterogenous nature of ALS complicates trial design. Genetic forms of ALS present an opportunity to intervene in a less heterogeneous population. ALS associated with gain of function mutations in SOD1 make 'knock-down' strategies an attractive therapeutic approach. Tofersen, an antisense oligonucleotide that reduces expression of SOD1 via RNAase mediated degradation of SOD1 mRNA, has shown robust effects on ALS biomarkers. While a Phase III trial of tofersen failed to meet its primary end point, open label extension data suggests that tofersen slows progression of SOD1 ALS.}, } @article {pmid39329756, year = {2024}, author = {Trainito, A and Muscarà, C and Gugliandolo, A and Chiricosta, L and Salamone, S and Pollastro, F and Mazzon, E and D'Angiolini, S}, title = {Cannabinol (CBN) Influences the Ion Channels and Synaptic-Related Genes in NSC-34 Cell Line: A Transcriptomic Study.}, journal = {Cells}, volume = {13}, number = {18}, pages = {}, pmid = {39329756}, issn = {2073-4409}, support = {Current Research Funds 2024//Ministero della Salute/ ; }, mesh = {*Ion Channels/metabolism/genetics ; Animals ; *Synapses/metabolism/drug effects ; *Transcriptome/drug effects/genetics ; Mice ; Cell Line ; Gene Expression Profiling ; Cannabinoids/pharmacology ; Humans ; Gene Expression Regulation/drug effects ; }, abstract = {Neurological disorders such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and schizophrenia are associated with altered neuronal excitability, resulting from dysfunctions in the molecular architecture and physiological regulation of ion channels and synaptic transmission. Ion channels and synapses are regarded as suitable therapeutic targets in modern pharmacology. Cannabinoids have received great attention as an original therapeutic approach for their effects on human health due to their ability to modulate the neurotransmitter release through interaction with the endocannabinoid system. In our study, we explored the effect of cannabinol (CBN) through next-generation sequencing analysis of NSC-34 cell physiology. Our findings revealed that CBN strongly influences the ontologies related to ion channels and synapse activity at all doses tested. Specifically, the genes coding for calcium and potassium voltage-gated channel subunits, and the glutamatergic and GABAergic receptors (Cacna1b, Cacna1h, Cacng8, Kcnc3, Kcnd1, Kcnd2, Kcnj4, Grik5, Grik1, Slc17a7, Gabra5), were up-regulated. Conversely, the genes involved into serotoninergic and cholinergic pathways (Htr3a, Htr3b, Htr1b, Chrna3, Chrnb2, Chrnb4), were down-regulated. These findings highlight the influence of CBN in the expression of genes involved into ion influx and synaptic transmission.}, } @article {pmid39329381, year = {2025}, author = {Lee, I and Vestrucci, M and Lee, S and Rosenbaum, M and Mitsumoto, H}, title = {Blood glycated hemoglobin level is not associated with disease progression in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {175-179}, pmid = {39329381}, issn = {2167-9223}, support = {K23 NS131586/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; Male ; *Disease Progression ; Female ; *Glycated Hemoglobin/metabolism/analysis ; Middle Aged ; Aged ; Cohort Studies ; Blood Glucose/metabolism ; }, abstract = {OBJECTIVE: A high glycemic index and high glycemic load diet has been associated with slower progression of amyotrophic lateral sclerosis (ALS), suggesting a benefit from high blood glucose levels. We examined the association between average blood glucose level and ALS progression in two independent cohorts.

METHODS: Sporadic ALS patients enrolled in the ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS) who completed a 3-month follow-up visit and had available blood samples were included. Hemoglobin A1c (HbA1c) was measured from whole blood collected at the 3-month follow-up. From the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we included ALS patients with one or more HbA1c measurements at enrollment and available death information. Associations between HbA1c with revised ALS functional rating scale (ALSFRS-R)/ALSFRS total score change, and tracheostomy-free survival/survival were examined in these cohorts using linear regression, linear mixed-effects models, and Cox proportional hazard models, adjusted for covariates.

RESULTS: In the ALS COSMOS cohort (n = 193), HbA1c level was not significantly associated with the change in the ALSFRS-R total score from baseline to the 3-month follow-up (p = 0.8) nor baseline to the 6-month follow-up (p = 0.4). No significant association was found between HbA1c level and tracheostomy-free survival (p = 0.8). In the PRO-ACT cohort (n = 928), no significant association was found between HbA1c level and the rate of ALSFRS decline in the first 200 days (p = 0.81 for interaction) nor between HbA1c level and survival (p = 0.45).

INTERPRETATION: We did not find convincing evidence that mean blood glucose level is associated with disease progression among ALS patients.}, } @article {pmid39328853, year = {2024}, author = {Ali, M and Ramadan, A and Surani, S}, title = {Obstructive sleep apnea-hypopnea syndrome immunological relationship.}, journal = {World journal of clinical cases}, volume = {12}, number = {27}, pages = {6011-6014}, pmid = {39328853}, issn = {2307-8960}, abstract = {Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a complex disorder characterized by symptoms resulting from intermittent hypoxia and hypopnea, with research indicating a crucial role of immune system dysregulation and genetic variations in its pathogenesis. A recent Zhao et al study utilizes Mendelian randomization analysis to explore the causal relationship between immune cell characteristics and OSAHS. The study identifies specific lymphocyte subsets associated with OSAHS, providing valuable insights into the disease's pathophysiology and potential targets for therapeutic intervention. The findings underscore the significance of genetic and immunological factors in sleep disorders, offering a fresh perspective on OSAHS's complexities. Compared to existing literature, Zhao et al's study stands out for its focus on genetic markers and specific immune responses associated with OSAHS, expanding upon previous research primarily centered on systemic inflammation. In conclusion, the study represents a significant advancement in the field, shedding light on the causal role of immune cells in OSAHS and paving the way for future research and targeted treatments.}, } @article {pmid39328135, year = {2024}, author = {Sharma, S and Mehan, S and Khan, Z and Tiwari, A and Kumar, A and Gupta, GD and Narula, AS and Kalfin, R}, title = {Exploring the Neuroprotective Potential of Icariin through Modulation of Neural Pathways in the Treatment of Neurological Diseases.}, journal = {Current molecular medicine}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115665240317650240924041923}, pmid = {39328135}, issn = {1875-5666}, abstract = {Neuropathological diseases involve the death of neurons and the aggregation of proteins with altered properties in the brain. Proteins are used at the molecular level to categorize neurodegenerative disorders, emphasizing the importance of protein-processing mechanisms in their development. Natural herbal phytoconstituents, such as icariin, have addressed these neurological complications. Icariin, the principal compound in Epimedium, has been studied for its antineuroinflammatory, anti-oxidative, and antiapoptotic properties. Recent scientific investigations have shown that icariin exhibits promising therapeutic and preventive properties for mental and neurodegenerative disorders. In preclinical, icariin has been shown to inhibit amyloid development and reduce the expression of APP and BACE-1. Previous preclinical studies have demonstrated that icariin can regulate proinflammatory responses in neurological conditions like Parkinson's disease, depression, cerebral ischemia, ALS, and multiple sclerosis. Studies have shown that icariin possesses neuroprotective properties by modulating signaling pathways and crossing the blood-brain barrier, suggesting its potential to address various neurocomplications. This review aims to establish a foundation for future clinical investigations by examining the existing literature on icariin and exploring its potential therapeutic implications in treating neurodegenerative disorders and neuropsychiatric conditions. Future research may address numerous concerns and yield captivating findings with far-reaching implications for various aspects of icariin.}, } @article {pmid39328012, year = {2024}, author = {Cui, Y and Chen, J and Li, H and Zheng, D and Shi, X}, title = {The causal association between epilepsy and amyotrophic lateral sclerosis: A two-sample Mendelian randomization study.}, journal = {Brain and behavior}, volume = {14}, number = {10}, pages = {e70018}, pmid = {39328012}, issn = {2162-3279}, support = {2023A03J0438//Science and Technology Program of Guangzhou/ ; 2020A1515010063//Natural Science Foundation of Guangdong Province/ ; 2023A1515011047//Natural Science Foundation of Guangdong Province/ ; //Guangzhou Research-oriented Hospital/ ; //Guangzhou High-level Clinical Key Specialty/ ; 2022A1515220119//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2021-2023//Guangzhou Municipal Key Discipline in Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Humans ; *Mendelian Randomization Analysis ; *Epilepsy/genetics/epidemiology/etiology ; *Genome-Wide Association Study ; Causality ; }, abstract = {OBJECTIVES: Epilepsy and amyotrophic lateral sclerosis (ALS) are common neurological disorders. The association between the two disorders has been raised in observational studies. However, it is uncertain to what extent they have mutual causal effects. In this study, we aimed to investigate their causal association using a two-sample Mendelian randomization (MR) method.

METHODS: We performed a two-sample bidirectional MR analysis to evaluate the causal association of epilepsy with the risk of ALS. Publicly published genome-wide association study statistics for epilepsy and ALS were used in the study. The primary analysis included genetic variants with a p value of less than 1 × 10[-5] as instrumental variables. We applied several alternative methods, including inverse variance weighting, weighted median, simple mode, weighted mode, MR-Egger regression and MR pleiotropy residual sum and outlier, and statistical graphs to assess the associations of epilepsy and its subtype with the risk of ALS. Reverse MR analyses were also performed to examine the association of ALS with the risk of epilepsy.

RESULTS: The primary MR analysis found no causal effect of epilepsy on risk of ALS (odds ration [OR]: 1.133, 95% confidence interval [CI]: 0.964-1.332, p = .130). Among subtypes of epilepsy, it also failed to observe any causal association between general epilepsy and ALS (OR: 1.036, 95% CI: 0.969-1.108, P = .300). However, focal epilepsy contributed to an increase in the risk of ALS (OR: 1.177, 95% CI: 1.027-1.348, p = .019). Moreover, the investigation of reverse causalities did not reveal significant results.

CONCLUSIONS: The current study supports a causal influence of focal epilepsy on ALS risk. Future studies are needed to explore its potential role in ALS.}, } @article {pmid39327888, year = {2024}, author = {Fitri, HU and Saputra, R and Suhardita, K and Suarta, IM and Oktasari, M and Aminah, S and Laras, PB}, title = {Digging deeper: A critique of the mediation study of spirituality in ALS patients.}, journal = {Palliative & supportive care}, volume = {22}, number = {5}, pages = {1550-1551}, doi = {10.1017/S1478951524001275}, pmid = {39327888}, issn = {1478-9523}, } @article {pmid39327159, year = {2024}, author = {Vassallu, F and Igaz, LM}, title = {TDP-43 nuclear condensation and neurodegenerative proteinopathies.}, journal = {Trends in neurosciences}, volume = {47}, number = {11}, pages = {849-850}, doi = {10.1016/j.tins.2024.09.003}, pmid = {39327159}, issn = {1878-108X}, mesh = {Animals ; Humans ; Cell Nucleus/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Neurodegenerative Diseases/metabolism ; *TDP-43 Proteinopathies/metabolism/genetics/pathology ; }, abstract = {RNA-binding proteins (RBPs) can undergo phase separation and form condensates, processes that, in turn, can be critical for their functionality. In a recent study, Huang, Ellis, and colleagues show that cellular stress can trigger transient alterations in nuclear TAR DNA-binding protein 43 (TDP-43), leading to changes crucial for proper neuronal function. These findings have implications for understanding neurological TDP-43 proteinopathies.}, } @article {pmid39326369, year = {2024}, author = {Suzuki, Y and Adachi, T and Yoshida, K and Sakuwa, M and Hanajima, R}, title = {Psychiatric symptoms and TDP-43 pathology in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123249}, doi = {10.1016/j.jns.2024.123249}, pmid = {39326369}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/psychology ; Male ; Female ; Aged ; *DNA-Binding Proteins/metabolism ; Middle Aged ; Mental Disorders/etiology/pathology/metabolism ; Brain/pathology/metabolism ; Aged, 80 and over ; Neurons/pathology/metabolism ; }, abstract = {BACKGROUND: ALS is not a pure motor neuron disease but co-occurs with cognitive impairment and psychiatric symptoms. The neuropathological origin of the psychiatric symptoms is unclear. This study examined the association between the psychiatric symptoms and neuropathology of ALS.

METHODS: We investigated the clinicopathological characteristics of 15 autopsy cases of ALS, including neuronal loss, gliosis, and the burden of TDP-43 pathology. We divided TDP-43-positive structures by morphology into four categories (neuronal cytoplasmic inclusion, dystrophic neurite, dot, and glial cytoplasmic inclusion) and gave each a semiquantitative score in nine brain regions. Braak neurofibrillary tangle stage, Thal amyloid phase, Lewy-related pathology, and argyrophilic grains were also assessed.

RESULTS: Of the 15 ALS patients, seven had presented with psychiatric symptoms and eight had not. Significantly higher TDP-43 pathology scores were found in the group with psychiatric symptoms in the temporal tip, transentorhinal cortex, entorhinal cortex, subiculum, and the hippocampal CA1 region and dentate gyrus. Cognitive impairment was not significantly associated with the degree of TDP-43 pathology. There were no significant differences in the degree of neuronal loss/gliosis or in other concurrent pathologies between patients with and without psychiatric symptoms. Morphological evaluation showed that neuronal cytoplasmic inclusions, dystrophic neurites, and dots tended to be more common in the group with psychiatric symptoms.

CONCLUSION: Psychiatric symptoms in ALS may be related to TDP-43 pathology in the perforant pathway. (224 words).}, } @article {pmid39324867, year = {2024}, author = {Li, J and Gao, C and Wang, Q and Liu, J and Xie, Z and Zhao, Y and Yu, M and Zheng, Y and Lv, H and Zhang, W and Yuan, Y and Meng, L and Deng, J and Wang, Z}, title = {Elevated serum circulating cell-free mitochondrial DNA in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16493}, pmid = {39324867}, issn = {1468-1331}, support = {82071409//National Natural Science Foundation of China/ ; 82101469//National Natural Science Foundation of China/ ; 82171846//National Natural Science Foundation of China/ ; U20A20356//National Natural Science Foundation of China/ ; 2022-4-40716//Capitals Funds for Health Improvement and Research/ ; 20220484017//Beijing Nova Program/ ; 20230484403//Beijing Nova Program/ ; 2023CX05//Scientific and Technological Achievements Transformation Incubation Guidance Fund Project of Peking University First Hospital/ ; 2023HQ03//National High Level Hospital Clinical Research Funding (High Quality Clinical Research Project of Peking University First Hospital/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics ; Male ; Female ; *DNA, Mitochondrial/blood/genetics ; Middle Aged ; Aged ; *Interleukin-6/blood ; *Cell-Free Nucleic Acids/blood ; *Superoxide Dismutase-1/blood/genetics ; Mutation ; Adult ; Biomarkers/blood ; }, abstract = {BACKGROUND AND PURPOSE: The substantial role of inflammation in amyotrophic lateral sclerosis (ALS) is gaining support from recent research. Studies indicate that circulating cell-free mitochondrial DNA (ccf-mtDNA) can activate the immune system and is associated with neurodegenerative diseases. This research was designed to quantify ccf-mtDNA levels in the serum of ALS patients.

METHODS: The medical records of ALS patients were reviewed. Serum ccf-mtDNA levels of patients with ALS (n = 62) and age-matched healthy controls (n = 46) were measured and compared. Additionally, serum interleukin-6 (IL-6) levels were measured using an enzyme-linked immunosorbent assay in 26 ALS patients. Correlations between variables were analyzed.

RESULTS: Serum ccf-mtDNA was notably higher in the patients with ALS. When stratified by genotype, the superoxide dismutase 1 (SOD1) mutation group showed the greatest increase in ccf-mtDNA levels relative to other ALS patients. Among all 108 individuals, a cut-off set at 1.1 × 10[5] mtDNA copies on a receiver-operating characteristic curve identified patients with ALS with 80.7% sensitivity and 50.0% specificity; the area under the curve was 0.69 (p < 0.001). Furthermore, serum ccf-mtDNA levels correlated negatively with the progression rate of ALS (ΔFS; rs = -0.26, p = 0.044), but not the ALSFRS-R score (rs = 0.06, p = 0.625). Importantly, the correlation between ccf-mtDNA and ΔFS was more pronounced in the SOD1 mutation group (rs = -0.62, p = 0.018). Lastly, a significant positive association was observed between serum ccf-mtDNA levels and IL-6 levels in ALS (r s= 0.41, p = 0.038).

CONCLUSION: Our study found increased serum ccf-mtDNA in ALS patients, suggesting a link to inflammatory processes and disease mechanism. Moreover, ccf-mtDNA could be an indicator for ALS progression, especially in those with the SOD1 mutation.}, } @article {pmid39323877, year = {2024}, author = {Engelberg-Cook, E and Shah, JS and Teixeira da Silva Hucke, A and Vera-Garcia, DV and Dagher, JE and Donahue, MH and Belzil, VV and Oskarsson, B}, title = {Prognostic Factors and Epidemiology of Amyotrophic Lateral Sclerosis in Southeastern United States.}, journal = {Mayo Clinic proceedings. Innovations, quality & outcomes}, volume = {8}, number = {5}, pages = {482-492}, pmid = {39323877}, issn = {2542-4548}, abstract = {OBJECTIVE: To assess the performance of known survival predictors and evaluate their stratification capability in patients with amyotrophic lateral sclerosis (ALS).

PATIENTS AND METHODS: We analyzed demographic and clinical variables collected at the Mayo Clinic, Florida ALS center during the first clinical visit of 1442 (100%) patients with ALS.

RESULTS: Our cohort had a median (interquartile range [IQR]) age at diagnosis of 64.8 (57-72) years; 1350 (92%) were non-Hispanic White; and 771 (53.5%) were male. The median (IQR) diagnostic delay was 10.1 (6-18) months, body mass index was 25.4 (23-49), and forced vital capacity was 72% (52%-87%). Approximately 12% of patients tested carried a pathologic C9orf72 hexanucleotide repeat expansion. Median (IQR) ALS functional rating scale-revised score was 35 (29-40) and ALS cognitive behavioral screen score was 15 (12-17). The median (IQR) survival after diagnosis was 17.2 (9-31) months, and survival from symptom onset was 30 (20-48) months. We found that older age decreased forced vital capacity, and fast-progressing ALS functional rating scale-revised scores significantly (P<.0001) influence survival curves and associated hazard risk.

CONCLUSION: Although results obtained from our cohort are consistent with other reports (eg, men with spinal onset experience a longer survival than women with bulbar onset), they remind us of the complexity of the disease's natural history and the limited prognostic power of the most common clinical predictors.}, } @article {pmid39323817, year = {2024}, author = {Zeng, A and Huang, Y and Xin, J and Li, J and Qiu, W and Zhang, M}, title = {Progress and recommendations of developing occupational exposure limits for noise-A systematic review.}, journal = {Heliyon}, volume = {10}, number = {18}, pages = {e37878}, pmid = {39323817}, issn = {2405-8440}, abstract = {OBJECTIVE: Noise exposure limit is one of the critical measures to prevent noise-induced hearing loss (NIHL). This review aimed to review the progress and recommendations for developing occupational exposure limits (OELs) for workplace noise.

METHODS: A systematic review was used. Thirty-eight national or international organizations' noise exposure standards (including OEL) and laws, regulations, and guidelines for noise exposure control were analyzed. Articles on recommendations for revising noise OEL standards between 2000 and 2023 were selected.

RESULTS: The definition of different noise types (especially for non-steady and impulsive noise) varied worldwide, and the used 8-h OEL varied from 80 to 90 dB(A). Maximum sound pressure level (Lmax) and noise dose for industrial noise and peak sound pressure level (Lpeak) for impulsive noise have been incorporated into the OELs. Countries developed noise risk management measures based on OELs, action levels (ALs), and exposure risk ratio or classification. The risk of co-exposure to noise and ototoxic organic substances and the effects of noise on susceptible populations were concerns in EU country standards. Scholars suggested revising the existing noise exposure standards based on noise's temporal structure (expressed by kurtosis), effective noise level, impulsive noise OEL, action level, and key factors of risk assessment.

CONCLUSIONS: Indicators such as Lmax, noise dose, Lpeak, and action level can be incorporated into noise OELs. Developing noise OEL standards should consider the co-exposure of noise and ototoxic substances, HPD's noise attenuation, susceptible groups, and noise's temporal structure.}, } @article {pmid39323783, year = {2024}, author = {You, J and Maksimovic, K and Metri, MN and Schoeppe, A and Chen, K and Lee, J and Santos, JR and Youssef, MMM and Salter, MW and Park, J}, title = {Knockout of Dectin-1 does not modify disease onset or progression in a MATR3 S85C knock-in mouse model of ALS.}, journal = {Heliyon}, volume = {10}, number = {18}, pages = {e37926}, pmid = {39323783}, issn = {2405-8440}, abstract = {Microglia have been increasingly implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Dectin-1, encoded by the Clec7a gene, is highly upregulated in a specific microglial response state called disease-associated microglia (DAM) in various neurodegenerative conditions. However, the role of Dectin-1 in ALS is undetermined. Here, we show that Clec7a mRNA upregulation occurs in central nervous system (CNS) regions that exhibit neurodegeneration in a MATR3 S85C knock-in mouse model (Matr3 [S85C/S85C]) of ALS. Furthermore, a significant increase in the number of Dectin-1[+] microglia coincides with the onset of motor deficits, and this number increases with disease progression. We demonstrate that the knockout of Dectin-1 does not affect survival, motor function, neurodegeneration, or microglial responses in Matr3 [S85C/S85C] mice. These findings suggest that Dectin-1 does not play a role in modifying ALS onset or progression.}, } @article {pmid39322357, year = {2024}, author = {Mehta, RI and Ranjan, M and Haut, MW and Carpenter, JS and Rezai, AR}, title = {Focused Ultrasound for Neurodegenerative Diseases.}, journal = {Magnetic resonance imaging clinics of North America}, volume = {32}, number = {4}, pages = {681-698}, doi = {10.1016/j.mric.2024.03.001}, pmid = {39322357}, issn = {1557-9786}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging ; Ultrasonic Therapy/methods ; Brain/diagnostic imaging ; Animals ; }, abstract = {Neurodegenerative diseases are a leading cause of death and disability and pose a looming global public health crisis. Despite progress in understanding biological and molecular factors associated with these disorders and their progression, effective disease modifying treatments are presently limited. Focused ultrasound (FUS) is an emerging therapeutic strategy for Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In these contexts, applications of FUS include neuroablation, neuromodulation, and/or blood-brain barrier opening with and without facilitated intracerebral drug delivery. Here, the authors review preclinical evidence and current and emerging applications of FUS for neurodegenerative diseases and summarize future directions in the field.}, } @article {pmid39321879, year = {2024}, author = {Lei, T and Zhang, X and Fu, G and Luo, S and Zhao, Z and Deng, S and Li, C and Cui, Z and Cao, J and Chen, P and Yang, H}, title = {Advances in human cellular mechanistic understanding and drug discovery of brain organoids for neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {102}, number = {}, pages = {102517}, doi = {10.1016/j.arr.2024.102517}, pmid = {39321879}, issn = {1872-9649}, mesh = {Humans ; *Organoids/drug effects/pathology ; *Neurodegenerative Diseases/pathology/drug therapy ; *Drug Discovery/methods ; *Brain/pathology/drug effects ; Animals ; }, abstract = {The prevalence of neurodegenerative diseases (NDs) is increasing rapidly as the aging population accelerates, and there are still no treatments to halt or reverse the progression of these diseases. While traditional 2D cultures and animal models fail to translate into effective therapies benefit patients, 3D cultured human brain organoids (hBOs) facilitate the use of non-invasive methods to capture patient data. The purpose of this study was to review the research and application of hBO in disease models and drug screening in NDs. The pluripotent stem cells are induced in multiple stages to form cerebral organoids, brain region-specific organoids and their derived brain cells, which exhibit complex brain-like structures and perform electrophysiological activities. The brain region-specific organoids and their derived neurons or glial cells contribute to the understanding of the pathogenesis of NDs and the efficient development of drugs, including Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Glial-rich brain organoids facilitate the study of glial function and neuroinflammation, including astrocytes, microglia, and oligodendrocytes. Further research on the maturation enhancement, vascularization and multi-organoid assembly of hBO will help to enhance the research and application of NDs cellular models.}, } @article {pmid39319809, year = {2024}, author = {Karra, R and Rice, AD and Hardcastle, A and V Lara, J and Hollen, A and Glenn, M and Munn, R and Hannan, P and Arcaris, B and Derksen, D and Spaite, DW and Gaither, JB}, title = {Telemedical Direction to Optimize Resource Utilization in a Rural Emergency Medical Services System.}, journal = {The western journal of emergency medicine}, volume = {25}, number = {5}, pages = {777-783}, pmid = {39319809}, issn = {1936-9018}, mesh = {Humans ; Retrospective Studies ; *Telemedicine ; *Emergency Medical Services ; *Rural Health Services ; Female ; *Emergency Medical Technicians ; Male ; Chest Pain/therapy ; Middle Aged ; Pilot Projects ; Adult ; }, abstract = {BACKGROUND: Telemedicine remains an underused tool in rural emergency medical servces (EMS) systems. Rural emergency medical technicians (EMT) and paramedics cite concerns that telemedicine could increase Advanced Life Support (ALS) transports, extend on-scene times, and face challenges related to connectivity as barriers to implementation. Our aim in this project was to implement a telemedicine system in a rural EMS setting and assess the impact of telemedicine on EMS management of patients with chest pain while evaluating some of the perceived barriers.

METHODS: This study was a mixed-methods, retrospective review of quality assurance data collected prior to and after implementation of a telemedicine program targeting patients with chest pain. We compared quantitative data from the 12-month pre-implementation phase to data from 15 months post-implementation. Patients were included if they had a chief complaint of chest pain or a 12-lead electrocardiogram had been obtained. The primary outcome was the rate of ALS transport before and after program implementation. Secondary outcomes included EMS call response times and EMS agency performance on quality improvement benchmarks. Qualitative data were also collected after each telemedicine encounter to evaluate paramedic/EMT and EMS physician perception of call quality.

RESULTS: The telemedicine pilot project was implemented in September 2020. Overall, there were 58 successful encounters. For this analysis, we included 38 patients in both the pre-implementation period (September 9, 2019-September 10, 2020) and the post-implementation period (September 11, 2020-December 5, 2021). Among this population, the ALS transport rate was 42% before and 45% after implementation (odds ratio 1.11; 95% confidence interval 0.45-2.76). The EMS median out-of-service times were 47 minutes before, and 33 minutes after (P = 0.07). Overall, 64% of paramedics/EMTs and 89% of EMS physicians rated the telemedicine call quality as "good."

CONCLUSION: In this rural EMS system, a telehealth platform was successfully used to connect paramedics/EMTs to board-certified EMS physicians over a 15-month period. Telemedicine use did not alter rates of ALS transports and did not increase on-scene time. The majority of paramedics/EMTs and EMS physicians rated the quality of the telemedicine connection as "good."}, } @article {pmid39318842, year = {2024}, author = {Emary, PC and Turner, AJ}, title = {Cervical spondylotic myelopathy in a 68-year-old man diagnosed with amyotrophic lateral sclerosis.}, journal = {The Journal of the Canadian Chiropractic Association}, volume = {68}, number = {2}, pages = {172-176}, pmid = {39318842}, issn = {0008-3194}, abstract = {Owing to similar clinical presentations, cervical spondylotic myelopathy can mimic other neurological disorders. In this imaging case review (ICR), we describe a case of cervical spondylotic myelopathy in a patient diagnosed with amyotrophic lateral sclerosis. The key clinical features, imaging findings and differential diagnoses of cervical spondylotic myelopathy compared with amyotrophic lateral sclerosis are also presented.}, } @article {pmid39318236, year = {2025}, author = {Majewski, S and Klein, P and Boillée, S and Clarke, BE and Patani, R}, title = {Towards an integrated approach for understanding glia in Amyotrophic Lateral Sclerosis.}, journal = {Glia}, volume = {73}, number = {3}, pages = {591-607}, pmid = {39318236}, issn = {1098-1136}, support = {MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Humans ; *Neuroglia/pathology/physiology ; Animals ; }, abstract = {Substantial advances in technology are permitting a high resolution understanding of the salience of glia, and have helped us to transcend decades of predominantly neuron-centric research. In particular, recent advances in 'omic' technologies have enabled unique insights into glial biology, shedding light on the cellular and molecular aspects of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we review studies using omic techniques to attempt to understand the role of glia in ALS across different model systems and post mortem tissue. We also address caveats that should be considered when interpreting such studies, and how some of these may be mitigated through either using a multi-omic approach and/or careful low throughput, high fidelity orthogonal validation with particular emphasis on functional validation. Finally, we consider emerging technologies and their potential relevance in deepening our understanding of glia in ALS.}, } @article {pmid39317854, year = {2024}, author = {Khoshdooz, S and Abbasi, H and Abbasi, MM}, title = {Iron-Status Indicators and HFE Gene Polymorphisms in Individuals with Amyotrophic Lateral Sclerosis: An Umbrella Review of Meta-analyses and Systematic Reviews.}, journal = {Biological trace element research}, volume = {}, number = {}, pages = {}, pmid = {39317854}, issn = {1559-0720}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons. Recent meta-analyses and systematic reviews suggest that HFE gene polymorphisms and iron-associated biomarkers may play a key role in the risk and occurrence of ALS. This umbrella study aimed to explore the roles of HFE gene polymorphisms and iron-associated biomarkers in individuals with ALS. A thorough search of three online scientific databases, namely Scopus, Web of Science, and PubMed, was conducted from their inception until September 13, 2024. The screening and selection processes were executed based on the PICO framework and eligibility criteria, followed by two independent reviewers. The Assessment of Multiple Systematic Reviews (AMSTAR)-2 and GRADE tools were utilized to assess the methodological quality and the certainty of evidence. Through an advanced search, 101 records were retrieved, of which eight meta-analyses and systematic reviews were selected for this umbrella review. A significant increase in iron concentrations was found in individuals with ALS compared to healthy controls (SMD, 0.26; 95% CI - 0.05, 0.57). Conversely, selected meta-analyses reported that serum transferrin concentrations in ALS patients were lower compared to healthy controls (SMD, - 0.15; 95% CI - 0.36, 0.05). Furthermore, mutations in H63D polymorphisms resulted in a 13% significant increase in the risk of ALS (OR, 1.13; 95% CI 1.05, 1.22). Our umbrella study of meta-analyses and systematic reviews reveals that individuals with ALS have lower serum concentrations of transferrin compared to healthy controls. Additionally, the H63D polymorphism in the HFE gene is associated with a slight increase in the risk of ALS. Future research should investigate broader aspects of iron-related biomarkers and HFE genes to elucidate their roles in ALS pathogenesis. Registration: Our umbrella study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the identification number CRD42024559032 (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024559032).}, } @article {pmid39317352, year = {2025}, author = {Kleinerova, J and Garcia-Gallardo, A and Tacheva, A and Bede, P}, title = {Subcortical grey matter involvement in ALS and PLS - vulnerable hubs of cortico-cortical and cortico-basal circuits: extrapyramidal, cognitive, bulbar and respiratory correlates.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {1-4}, doi = {10.1080/21678421.2024.2405130}, pmid = {39317352}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology/diagnostic imaging/genetics ; *Gray Matter/diagnostic imaging/pathology/physiopathology ; Neural Pathways/physiopathology/diagnostic imaging/pathology ; Cerebral Cortex/diagnostic imaging/physiopathology/pathology ; }, abstract = {Evidence from neuroimaging studies suggests that the cardinal clinical manifestations of ALS stem from the dysfunction of specific neural networks. The majority of cortico-cortical and cortico-basal networks are physiologically relayed by deep cerebral and cerebellar grey matter nuclei which have been increasingly implicated in the pathophysiology of ALS. A series of recent human imaging papers revealed volume reductions, shape deformations, metabolic alterations and more recently, susceptibility changes in hippocampal subfields, thalamic, striatal, amygdalar and cerebellar nuclei. Thalamic changes have been identified in presymptomatic mutation carriers long before symptom onset and longitudinal studies have consistently confirmed progressive subcortical degeneration during the symptomatic phase of the disease. The dysfunction of circuits relayed by specific subcortical nuclei has been associated with apathy, amnestic deficits, limbic symptoms, extrapyramidal manifestations, sensory disturbances, pseudobulbar affect and cerebellar deficits. In light of emerging imaging data, the clinical heterogeneity of ALS is probably best approached from a network integrity perspective. Accordingly, the comprehensive assessment of subcortical grey matter nuclei seems imperative to untangle complex clinical phenomena in ALS.}, } @article {pmid39316747, year = {2024}, author = {de Calbiac, H and Renault, S and Haouy, G and Jung, V and Roger, K and Zhou, Q and Campanari, ML and Chentout, L and Demy, DL and Marian, A and Goudin, N and Edbauer, D and Guerrera, C and Ciura, S and Kabashi, E}, title = {Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.}, journal = {Autophagy}, volume = {20}, number = {10}, pages = {2164-2185}, pmid = {39316747}, issn = {1554-8635}, mesh = {*Motor Neurons/metabolism/pathology ; Animals ; *C9orf72 Protein/genetics/metabolism ; *Zebrafish ; *Mitophagy/genetics ; *Apoptosis/genetics ; Humans ; *Autophagy/genetics/physiology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Dipeptides/pharmacology/metabolism ; Loss of Function Mutation/genetics ; Mitochondria/metabolism ; Disease Models, Animal ; }, abstract = {The GGGGCC hexanucleotide repeat expansion (HRE) of the C9orf72 gene is the most frequent cause of amyotrophic lateral sclerosis (ALS), a devastative neurodegenerative disease characterized by motor neuron degeneration. C9orf72 HRE is associated with lowered levels of C9orf72 expression and its translation results in the production of dipeptide-repeats (DPRs). To recapitulate C9orf72-related ALS disease in vivo, we developed a zebrafish model where we expressed glycine-proline (GP) DPR in a c9orf72 knockdown context. We report that C9orf72 gain- and loss-of-function properties act synergistically to induce motor neuron degeneration and paralysis with poly(GP) accumulating preferentially within motor neurons along with Sqstm1/p62 aggregation indicating macroautophagy/autophagy deficits. Poly(GP) levels were shown to accumulate upon c9orf72 downregulation and were comparable to levels assessed in autopsy samples of patients carrying C9orf72 HRE. Chemical boosting of autophagy using rapamycin or apilimod, is able to rescue motor deficits. Proteomics analysis of zebrafish-purified motor neurons unravels mitochondria dysfunction confirmed through a comparative analysis of previously published C9orf72 iPSC-derived motor neurons. Consistently, 3D-reconstructions of motor neuron demonstrate that poly(GP) aggregates colocalize to mitochondria, thus inducing their elongation and swelling and the failure of their processing by mitophagy, with mitophagy activation through urolithin A preventing locomotor deficits. Finally, we report apoptotic-related increased amounts of cleaved Casp3 (caspase 3, apoptosis-related cysteine peptidase) and rescue of motor neuron degeneration by constitutive inhibition of Casp9 or treatment with decylubiquinone. Here we provide evidence of key pathogenic steps in C9ALS-FTD that can be targeted through pharmacological avenues, thus raising new therapeutic perspectives for ALS patients.}, } @article {pmid39316061, year = {2025}, author = {Yang, W and Liu, X and Fan, D}, title = {Low CD3 level is a risk factor for amyotrophic lateral sclerosis: a Mendelian randomization study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {64-72}, doi = {10.1080/21678421.2024.2407408}, pmid = {39316061}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Humans ; *Mendelian Randomization Analysis/methods ; *CD3 Complex/metabolism/genetics ; Risk Factors ; Genetic Predisposition to Disease/genetics ; Valosin Containing Protein/genetics ; Polymorphism, Single Nucleotide/genetics ; Male ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterized by neuronal degeneration of the spinal cord and brain and believed to be related to the immune system. In this study, our aim is to use Mendelian randomization (MR) to search for immune markers related to ALS. A total of 731 immune cell traits were included in this study. MR analysis was used to identify the causality between 731 immune cell traits (with 3,757 Europeans) and ALS (with 138,086 Europeans). Colocalization analysis was used to verify the found causality, protein-protein interaction prediction was used to look for the interacting proteins that are known to be involved in ALS. We found low expression levels of CD3 on central memory CD8+ T cell is risk factor for ALS (OR = 0.90, 95% CI: 0.86-0.95, P = 0.0000303). CD3 can interact with three ALS-related proteins: VCP, HLA-DRA and HLA-DRB5, which are associated with adaptive immune response. Our study reported for the first time that low-level CD3 is a risk factor for ALS and the possible mechanism, which could provide a potential strategy for ALS diagnosis and therapy.}, } @article {pmid39316038, year = {2025}, author = {Olsen, CG and Malmberg, VN and Fahlström, M and Alstadhaug, KB and Bjørnå, IK and Braathen, GJ and Bråthen, G and Demic, N and Hallerstig, E and Hogenesch, I and Horn, MA and Kampman, MT and Kleveland, G and Ljøstad, U and Maniaol, A and Morsund, ÅH and Nakken, O and Schlüter, K and Schuler, S and Seim, E and Flemmen, HØ and Tysnes, OB and Holmøy, T and Høyer, H}, title = {Amyotrophic lateral sclerosis caused by the C9orf72 expansion in Norway - prevalence, ancestry, clinical characteristics and sociodemographic status.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {132-140}, doi = {10.1080/21678421.2024.2405118}, pmid = {39316038}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Norway/epidemiology ; *C9orf72 Protein/genetics ; Female ; Male ; Middle Aged ; Aged ; Prevalence ; Adult ; Proteins/genetics ; Genetic Predisposition to Disease/genetics ; DNA Repeat Expansion/genetics ; Aged, 80 and over ; Socioeconomic Factors ; }, abstract = {OBJECTIVE: The most common genetic cause of amyotrophic lateral sclerosis (ALS) is the C9orf72 expansion. A high incidence of this expansion has been detected in Sweden and Finland. This Norwegian population-based study aimed to identify the prevalence, geographic distribution, ancestry, and relatedness of ALS patients with a C9orf72 expansion (C9pos). Further, we compared C9pos and C9neg patients' clinical presentation, family history of ALS and other neurodegenerative disorders, and sociodemographic status.

METHODS: We recruited ALS patients from all 17 Departments of neurology in Norway. Blood samples and questionnaires regarding clinical characteristics, sociodemographic status and family history of ALS, and other neurodegenerative disorders were collected. The C9orf72 expansion was examined for all patients.

RESULTS: The study enrolled 500 ALS patients, 8.8% of whom were C9pos, with half being sporadic ALS cases. The proportion of C9pos cases differed between regions, ranging from 17.9% in the Northern region to 1.9% in the Western region. The majority of C9pos patients had non-Finnish European descent and were not closely related. C9pos patients exhibited a significantly shorter mean survival time, had a higher frequency of relatives with ALS or dementia, and were more often unmarried/single and childless than C9neg patients.

CONCLUSION: C9pos patients constitute a large portion of the Norwegian ALS population. Ancestry and relatedness do not adequately explain regional differences. Relying on clinical information to identify C9pos patients has proven to be challenging. Half of C9pos patients were reported as having sporadic ALS, underlining the importance of carefully assessing family history and the need for genetic testing.}, } @article {pmid39315390, year = {2024}, author = {Douglas, AGL and Thompson, AG and Turner, MR and Talbot, K}, title = {Personalised penetrance estimation for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {BMJ neurology open}, volume = {6}, number = {2}, pages = {e000792}, pmid = {39315390}, issn = {2632-6140}, abstract = {BACKGROUND: C9orf72 hexanucleotide repeat expansions are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in European populations. Variable disease penetrance between families presents a challenge for genetic counselling of at-risk relatives and reduces the predictive utility of testing asymptomatic relatives. We have developed a novel model for estimating penetrance in individual families affected by C9orf72 using available family history information, allowing the calculation of personalised risk estimates.

METHODS: Published aggregated age-of-onset data for C9orf72-related ALS/FTD were used to generate age-related cumulative relative risks for at-risk relatives within pedigrees. Age-related relative risks are combined with a priori chance of individuals carrying an expansion based on known pedigree information. Penetrance is calculated as a number of affected individuals divided by the sum of cumulative age-related risks of relatives being affected by 80 years.

RESULTS: This method allows family-specific penetrance to be estimated from family history and at-risk relatives' personalised age-related ALS/FTD risks to be calculated and illustrated graphically. Penetrance reduces as the number and age of at-risk unaffected relatives increases.

CONCLUSIONS: Family history remains the best indicator of penetrance in C9orf72 expansion carriers. Calculating family-specific penetrance can aid genetic counselling by allowing at-risk relatives a more accurate understanding of their individual risk.}, } @article {pmid39315308, year = {2024}, author = {Abati, E and Gagliardi, D and Manini, A and Del Bo, R and Ronchi, D and Meneri, M and Beretta, F and Sarno, A and Rizzo, F and Monfrini, E and Di Fonzo, A and Pellecchia, MT and Brusati, A and Silani, V and Comi, GP and Ratti, A and Verde, F and Ticozzi, N and Corti, S}, title = {Investigating the prevalence of MFN2 mutations in amyotrophic lateral sclerosis: insights from an Italian cohort.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae312}, pmid = {39315308}, issn = {2632-1297}, abstract = {The MFN2 gene encodes mitofusin 2, a key protein for mitochondrial fusion, transport, maintenance and cell communication. MFN2 mutations are primarily linked to Charcot-Marie-Tooth disease type 2A. However, a few cases of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis/frontotemporal dementia phenotypes with concomitant MFN2 mutations have been previously reported. This study examines the clinical and genetic characteristics of an Italian cohort of amyotrophic lateral sclerosis patients with rare, non-synonymous MFN2 mutations. A group of patients (n = 385) diagnosed with amyotrophic lateral sclerosis at our Neurology Units between 2008 and 2023 underwent comprehensive molecular testing, including MFN2. After excluding pathogenic mutations in the main amyotrophic lateral sclerosis-related genes (i.e. C9orf72, SOD1, FUS and TARDBP), MFN2 variants were classified based on the American College of Medical Genetics and Genomics guidelines, and demographic and clinical data of MFN2-mutated patients were retrieved. We identified 12 rare, heterozygous, non-synonymous MFN2 variants in 19 individuals (4.9%). Eight of these variants, carried by nine patients (2.3%), were either pathogenic, likely pathogenic or variants of unknown significance according to the American College of Medical Genetics and Genomics guidelines. Among these patients, four exhibited a familial pattern of inheritance. The observed phenotypes included classic and bulbar amyotrophic lateral sclerosis, amyotrophic lateral sclerosis/frontotemporal dementia, flail arm, flail leg and progressive muscular atrophy. Median survival after disease onset was extremely variable, ranging from less than 1 to 13 years. This study investigates the prevalence of rare, non-synonymous MFN2 variants within an Italian cohort of amyotrophic lateral sclerosis patients, who have been extensively investigated, enhancing our knowledge of the underlying phenotypic spectrum. Further research is needed to understand whether MFN2 mutations contribute to motor neuron disease and to what extent. Improving our knowledge regarding the genetic basis of amyotrophic lateral sclerosis is crucial both in a diagnostic and therapeutic perspective.}, } @article {pmid39315251, year = {2024}, author = {Maitra, S and Baek, M and Choe, YJ and Kim, NC}, title = {FDA-approved PDE4 inhibitors alleviate the dominant toxicity of ALS-FTD-associated CHCHD10S59L by reducing the PINK1/Parkin pathway.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39315251}, issn = {2693-5015}, support = {R56 NS112296/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing CHCHD10[S59L], and human cell models expressing CHCHD10[S59L], we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10[S59L]. Evidences using in vitro, in vivo genetic, and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10[S59L]-induced diseases.

METHODS: An in vivo human cell culture and in vivo Drosophila models expressing CHCHD10[S59L] mutant were utilized in this study to evaluate the effect of PDE4 inhibitors in PINK-parkin mediated cytotoxicity through immunohistochemical and seahorse assays. Data were analysed using one-way ANOVA and post-hoc Dunnett's test for statistical significance.

RESULTS: We investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10[S59L]-induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10[S59L]-induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H[S81L]. Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10[S59L].

CONCLUSION: These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10[S59L]-induced ALS-FTD and possibly other related diseases, and that disease treatment with PDE4 inhibitors should include careful consideration of the PINK1/Parkin pathway, as it is generally recognized as a protective pathway.}, } @article {pmid39314515, year = {2025}, author = {He, D and Wang, X and Hao, M and Shen, D and Yang, X and Liu, M and Li, Y and Wang, J and Cui, L}, title = {Mutational and transcriptional profiling of cuproptosis-associated genes in amyotrophic lateral sclerosis.}, journal = {Genes & diseases}, volume = {12}, number = {1}, pages = {101208}, pmid = {39314515}, issn = {2352-3042}, } @article {pmid39314491, year = {2024}, author = {Guerra San Juan, I and Brunner, J and Eggan, K and Toonen, RF and Verhage, M}, title = {KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39314491}, issn = {2692-8205}, support = {R01 NS089742/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in the microtubule binding motor protein, kinesin family member 5A (KIF5A), cause the fatal motor neuron disease, Amyotrophic Lateral Sclerosis. While KIF5 family members transport a variety of cargos along axons, it is still unclear which cargos are affected by KIF5A mutations. We generated KIF5A null mutant human motor neurons to investigate the impact of KIF5A loss on the transport of various cargoes and its effect on motor neuron function at two different timepoints in vitro. The absence of KIF5A resulted in reduced neurite complexity in young motor neurons (DIV14) and significant defects in axonal regeneration capacity at all developmental stages. KIF5A loss did not affect neurofilament transport but resulted in decreased mitochondria motility and anterograde speed at DIV42. More prominently, KIF5A depletion strongly reduced anterograde transport of SFPQ-associated RNA granules in DIV42 motor neuron axons. We conclude that KIF5A most prominently functions in human motor neurons to promote axonal regrowth after injury as well as to anterogradely transport mitochondria and, to a larger extent, SFPQ-associated RNA granules in a time-dependent manner.}, } @article {pmid39314333, year = {2024}, author = {Guha, A and Si, Y and Smith, R and Kazamel, M and Jiang, N and Smith, KA and Thalacker-Mercer, A and Singh, BK and Ho, R and Andrabi, SA and Pereira, JDTDS and Salgado, JS and Agrawal, M and Velic, EH and King, PH}, title = {The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39314333}, issn = {2692-8205}, support = {I01 BX002466/BX/BLRD VA/United States ; I01 BX006231/BX/BLRD VA/United States ; R01 NS092651/NS/NINDS NIH HHS/United States ; R21 NS111275/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1[G93A] mouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, β-Klotho. Plasma FGF21 levels were increased and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In NSC-34 motor neurons and C2C12 muscle cells expressing SOD1[G93A] or exposed to oxidative stress, ectopic FGF21 mitigated loss of cell viability. In summary, FGF21 is a novel biomarker in ALS that correlates with slower disease progression and exerts trophic effects under conditions of cellular stress.}, } @article {pmid39314138, year = {2025}, author = {Lv, Y and Li, H}, title = {Blood diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {9}, pages = {2556-2570}, pmid = {39314138}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited. The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain, brainstem, and spinal cord, as well as abnormal protein deposition in the cytoplasm of neurons and glial cells. The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid, blood, and even urine. Among these biomarkers, neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system, while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles. Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity. However, there are challenges in using neurofilament light chain to differentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury. Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment, oxygen saturation, and the glomerular filtration rate. TAR DNA-binding protein 43, a pathological protein associated with amyotrophic lateral sclerosis, is emerging as a promising biomarker, particularly with advancements in exosome-related research. Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers; however, they show potential in predicting disease prognosis. Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years, the quest for definitive diagnostic and prognostic biomarkers remains a formidable challenge. This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.}, } @article {pmid39313512, year = {2024}, author = {Khan, AF and Iturria-Medina, Y}, title = {Beyond the usual suspects: multi-factorial computational models in the search for neurodegenerative disease mechanisms.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {386}, pmid = {39313512}, issn = {2158-3188}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging/physiopathology ; *Neuroimaging/methods ; *Brain/diagnostic imaging/physiopathology ; Disease Progression ; Biomarkers ; Alzheimer Disease/diagnostic imaging/physiopathology ; Computer Simulation ; }, abstract = {From Alzheimer's disease to amyotrophic lateral sclerosis, the molecular cascades underlying neurodegenerative disorders remain poorly understood. The clinical view of neurodegeneration is confounded by symptomatic heterogeneity and mixed pathology in almost every patient. While the underlying physiological alterations originate, proliferate, and propagate potentially decades before symptomatic onset, the complexity and inaccessibility of the living brain limit direct observation over a patient's lifespan. Consequently, there is a critical need for robust computational methods to support the search for causal mechanisms of neurodegeneration by distinguishing pathogenic processes from consequential alterations, and inter-individual variability from intra-individual progression. Recently, promising advances have been made by data-driven spatiotemporal modeling of the brain, based on in vivo neuroimaging and biospecimen markers. These methods include disease progression models comparing the temporal evolution of various biomarkers, causal models linking interacting biological processes, network propagation models reproducing the spatial spreading of pathology, and biophysical models spanning cellular- to network-scale phenomena. In this review, we discuss various computational approaches for integrating cross-sectional, longitudinal, and multi-modal data, primarily from large observational neuroimaging studies, to understand (i) the temporal ordering of physiological alterations, i(i) their spatial relationships to the brain's molecular and cellular architecture, (iii) mechanistic interactions between biological processes, and (iv) the macroscopic effects of microscopic factors. We consider the extents to which computational models can evaluate mechanistic hypotheses, explore applications such as improving treatment selection, and discuss how model-informed insights can lay the groundwork for a pathobiological redefinition of neurodegenerative disorders.}, } @article {pmid39313484, year = {2025}, author = {Funai, A and Hayashi, K and Kawata, A and Nakayama, Y and Matsuda, C and Haraguchi, M and Takahashi, K and Komori, T}, title = {An autopsy report of a long-survival case of familial amyotrophic lateral sclerosis with SOD1 G93S gene mutation: Lack of SOD1-positive inclusion in the remaining neurons.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {45}, number = {1}, pages = {60-65}, doi = {10.1111/neup.13004}, pmid = {39313484}, issn = {1440-1789}, support = {22H03398//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Male ; Aged ; *Superoxide Dismutase-1/genetics ; *Autopsy ; *Mutation ; Motor Neurons/pathology/metabolism ; Superoxide Dismutase/genetics ; }, abstract = {We describe the case of a 70-year-old Japanese man with familial amyotrophic lateral sclerosis (fALS) associated with a p.Gly93Ser mutation in the copper/zinc superoxide dismutase (SOD1) gene. This mutation is one of the relatively rare SOD1 mutations, with only one previous autopsy report, and is known for its longer disease duration. As previously reported, the patient had weakness in the lower limbs at age 33, followed by dysphagia, dysesthesia in the lower limbs, and autonomic dysfunction. He required mechanical ventilation at age 44 and died of acute pancreatitis at age 70. Neuropathologically, multisystem degeneration was observed beyond lesions typical of familial ALS with posterior column involvement. In addition, there was no SOD1-positive inclusion in the remaining motor neurons. The absence of SOD1-positive inclusion is a rare feature observed predominantly in long survival cases with SOD1 gene mutations. We hypothesize that the considerably lower amount of abnormal SOD1 protein in the motor neuron cells might explain our patient's extraordinarily long clinical course.}, } @article {pmid39313211, year = {2025}, author = {Rahimi, M and Al Masry, Z and Templeton, JM and Schneider, S and Poellabauer, C}, title = {A Comprehensive Multifunctional Approach for Measuring Parkinson's Disease Severity.}, journal = {Applied clinical informatics}, volume = {16}, number = {1}, pages = {11-23}, pmid = {39313211}, issn = {1869-0327}, mesh = {Humans ; *Parkinson Disease/diagnosis/physiopathology ; Male ; Female ; *Severity of Illness Index ; Aged ; Middle Aged ; Neuropsychological Tests ; Machine Learning ; }, abstract = {OBJECTIVES: This research study aims to advance the staging of Parkinson's disease (PD) by incorporating machine learning to assess and include a broader multifunctional spectrum of neurocognitive symptoms in the staging schemes beyond motor-centric assessments. Specifically, we provide a novel framework to modernize and personalize PD staging more objectively by proposing a hybrid feature scoring approach.

METHODS:  We recruited 37 individuals diagnosed with PD, each of whom completed a series of tablet-based neurocognitive tests assessing motor, memory, speech, executive functions, and tasks ranging in complexity from single to multifunctional. Then, the collected data were used to develop a hybrid feature scoring system to calculate a weighted vector for each function. We evaluated the current PD staging schemes and developed a new approach based on the features selected and extracted using random forest and principal component analysis.

RESULTS:  Our findings indicate a substantial bias in current PD staging systems toward fine motor skills, that is, other neurological functions (memory, speech, executive function, etc.) do not map into current PD stages as well as fine motor skills do. The results demonstrate that a more accurate and personalized assessment of PD severity could be achieved by including a more exhaustive range of neurocognitive functions in the staging systems either by involving multiple functions in a unified staging score or by designing a function-specific staging system.

CONCLUSION:  The proposed hybrid feature score approach provides a comprehensive understanding of PD by highlighting the need for a staging system that covers various neurocognitive functions. This approach could potentially lead to more effective, objective, and personalized treatment strategies. Further, this proposed methodology could be adapted to other neurodegenerative conditions such as Alzheimer's disease or amyotrophic lateral sclerosis.}, } @article {pmid39312574, year = {2024}, author = {Plessis-Belair, J and Ravano, K and Han, E and Janniello, A and Molina, C and Sher, RB}, title = {NEMF mutations in mice illustrate how Importin-β specific nuclear transport defects recapitulate neurodegenerative disease hallmarks.}, journal = {PLoS genetics}, volume = {20}, number = {9}, pages = {e1011411}, pmid = {39312574}, issn = {1553-7404}, support = {R01 AG079898/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *beta Karyopherins/metabolism/genetics ; *Active Transport, Cell Nucleus/genetics ; Mice ; Humans ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; *Disease Models, Animal ; Mutation ; ran GTP-Binding Protein/metabolism/genetics ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Cell Nucleus/metabolism/genetics ; Frontotemporal Dementia/genetics/metabolism/pathology ; Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; Alzheimer Disease/genetics/metabolism/pathology ; }, abstract = {Pathological disruption of Nucleocytoplasmic Transport (NCT), such as the mis-localization of nuclear pore complex proteins (Nups), nuclear transport receptors, Ran-GTPase, and RanGAP1, are seen in both animal models and in familial and sporadic forms of amyotrophic lateral sclerosis (ALS), frontal temporal dementia and frontal temporal lobar degeneration (FTD\FTLD), and Alzheimer's and Alzheimer's Related Dementias (AD/ADRD). However, the question of whether these alterations represent a primary cause, or a downstream consequence of disease is unclear, and what upstream factors may account for these defects are unknown. Here, we report four key findings that shed light on the upstream causal role of Importin-β-specific nuclear transport defects in disease onset. First, taking advantage of two novel mouse models of NEMF neurodegeneration (NemfR86S and NemfR487G) that recapitulate many cellular and biochemical aspects of neurodegenerative diseases, we find an Importin-β-specific nuclear import block. Second, we observe cytoplasmic mis-localization and aggregation of multiple proteins implicated in the pathogenesis of ALS/FTD and AD/ADRD, including TDP43, Importin-β, RanGap1, and Ran. These findings are further supported by a pathological interaction between Importin-β and the mutant NEMFR86S protein in cytoplasmic accumulations. Third, we identify similar transcriptional dysregulation in key genes associated with neurodegenerative disease. Lastly, we show that even transient pharmaceutical inhibition of Importin-β in both mouse and human neuronal and non-neuronal cells induces key proteinopathies and transcriptional alterations seen in our mouse models and in neurodegeneration. Our convergent results between mouse and human neuronal and non-neuronal cellular biology provide mechanistic evidence that many of the mis-localized proteins and dysregulated transcriptional events seen in multiple neurodegenerative diseases may in fact arise primarily from a primary upstream defect in Importin- β nuclear import. These findings have critical implications for investigating how sporadic forms of neurodegeneration may arise from presently unidentified genetic and environmental perturbations in Importin-β function.}, } @article {pmid39312484, year = {2024}, author = {Okada, K and Ito, D and Morimoto, S and Kato, C and Oguma, Y and Warita, H and Suzuki, N and Aoki, M and Kuramoto, J and Kobayashi, R and Shinozaki, M and Ikawa, M and Nakahara, J and Takahashi, S and Nishimoto, Y and Shibata, S and Okano, H}, title = {Multiple lines of evidence for disruption of nuclear lamina and nucleoporins in FUS amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {11}, pages = {3933-3948}, pmid = {39312484}, issn = {1460-2156}, support = {21H02812//Japan Society for the Promotion of Science/ ; JP20ek0109395//Japan Agency for Medical Research and Development/ ; //Takeda Science Foundation/ ; //The Yukihiko Miyata Memorial Trust for ALS Research/ ; //Yoshio Koide/ ; //Japan ALS Association/ ; //Daiichi Sankyo Foundation of Life Science/ ; //Keio Medical Association and Keio University Grant-in-Aid for Encouragement of Young Medical Scientists/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *RNA-Binding Protein FUS/genetics/metabolism ; Mice ; Humans ; *Nuclear Pore Complex Proteins/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *Nuclear Lamina/metabolism ; Disease Models, Animal ; Male ; Mice, Transgenic ; Spinal Cord/metabolism/pathology ; Female ; Mutation ; }, abstract = {Advanced pathological and genetic approaches have revealed that mutations in fused in sarcoma/translated in liposarcoma (FUS/TLS), which is pivotal for DNA repair, alternative splicing, translation and RNA transport, cause familial amyotrophic lateral sclerosis (ALS). The generation of suitable animal models for ALS is essential for understanding its pathogenesis and developing therapies. Therefore, we used CRISPR-Cas9 to generate FUS-ALS mutation in the non-classical nuclear localization signal (NLS), H517D (mouse position: H509D) and genome-edited mice. Fus WT/H509D mice showed progressive motor impairment (accelerating rotarod and DigiGait system) with age, which was associated with the loss of motor neurons and disruption of the nuclear lamina and nucleoporins and DNA damage in spinal cord motor neurons. We confirmed the validity of our model by showing that nuclear lamina and nucleoporin disruption were observed in lower motor neurons differentiated from patient-derived human induced pluripotent stem cells (hiPSC-LMNs) with FUS-H517D and in the post-mortem spinal cord of patients with ALS. RNA sequence analysis revealed that most nuclear lamina and nucleoporin-linking genes were significantly decreased in FUS-H517D hiPSC-LMNs. This evidence suggests that disruption of the nuclear lamina and nucleoporins is crucial for ALS pathomechanisms. Combined with patient-derived hiPSC-LMNs and autopsy samples, this mouse model might provide a more reliable understanding of ALS pathogenesis and might aid in the development of therapeutic strategies.}, } @article {pmid39311426, year = {2024}, author = {Azzolino, D and Piras, R and Zulueta, A and Lucchi, T and Lunetta, C}, title = {Amyotrophic lateral sclerosis as a disease model of sarcopenia.}, journal = {Age and ageing}, volume = {53}, number = {9}, pages = {}, doi = {10.1093/ageing/afae209}, pmid = {39311426}, issn = {1468-2834}, mesh = {Humans ; *Sarcopenia/physiopathology/diagnosis ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; *Muscle, Skeletal/pathology/physiopathology ; Aging/pathology ; Animals ; Age Factors ; Aged ; Risk Factors ; }, abstract = {Sarcopenia, the progressive decline of muscle mass and function, has traditionally been viewed as an age-related process leading to a broad range of adverse outcomes. However, it has been widely reported that sarcopenia can occur earlier in life in association with various conditions (i.e. disease-related sarcopenia), including neuromuscular disorders. As early as 2010, the European Working Group on Sarcopenia in Older People included neurodegenerative diseases characterised by motor neuron loss among the mechanisms underlying sarcopenia. Despite some differences in pathogenetic mechanisms, both amyotrophic lateral sclerosis (ALS) and age-related sarcopenia share common characteristics, such as the loss of motor units and muscle fibre atrophy, oxidative stress, mitochondrial dysfunction and inflammation. The histology of older muscle shows fibre size heterogeneity, fibre grouping and a loss of satellite cells, similar to what is observed in ALS patients. Regrettably, the sarcopenic process in ALS patients has been largely overlooked, and literature on the condition in this patient group is very scarce. Some instruments used for the assessment of sarcopenia in older people could also be applied to ALS patients. At this time, there is no approved specific pharmacological treatment to reverse damage to motor neurons or cure ALS, just as there is none for sarcopenia. However, some agents targeting the muscle, like myostatin and mammalian target of rapamycin inhibitors, are under investigation both in the sarcopenia and ALS context. The development of new therapeutic agents targeting the skeletal muscle may indeed be beneficial to both ALS patients and older people with sarcopenia.}, } @article {pmid39311315, year = {2025}, author = {Ortiz-Corredor, F and Correa-Arrieta, C and Forero Diaz, JJ and Castellar-Leones, S and Gil-Salcedo, A}, title = {Profiles of disease progression and predictors of mortality in Colombian patients with amyotrophic lateral sclerosis: a comprehensive longitudinal study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {141-148}, doi = {10.1080/21678421.2024.2405587}, pmid = {39311315}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis ; *Disease Progression ; Colombia/epidemiology ; Male ; Female ; Middle Aged ; Longitudinal Studies ; Aged ; Retrospective Studies ; Adult ; Prognosis ; }, abstract = {OBJECTIVE: This study aimed to assess the prognostic value of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) in predicting mortality and characterizing disease progression patterns in ALS patients in Colombia.

METHODS: We conducted a retrospective longitudinal analysis of 537 ALS patients from the Roosevelt Institute Rehabilitation Service between October 2008 and October 2022. The study excluded nine patients due to incomplete data, resulting in 528 individuals in the analysis. ALS diagnoses were confirmed using the revised El Escorial and Gold Coast criteria. Disease progression was assessed using the ALSFRS-R, and mortality data were sourced from follow-up calls and a national database. Statistical analysis included Cox proportional hazards models to identify mortality predictors and Growth Mixture Modeling (GMM) to explore ALS progression trajectories.

RESULTS: The majority of the cohort (63.8%) deceased within the 84-month follow-up period. Survival analysis revealed that each point increase in the ALSFRS-R rate was associated with a 2.22-fold (95% CI =1.99-2.48, p < 0.001) increased risk of mortality. In the population with data from two clinical visits, the ALSFRS-R rate based on initial assessments predicted mortality more effectively over 36 months than the rate based on two evaluations. GMM identified three distinct progression trajectories: slow, intermediate, and rapid decliners.

CONCLUSIONS: The ALSFRS-R rate, derived from self-reported symptom onset, significantly predicts mortality, underscoring its value in clinical assessments. This study highlights the heterogeneity in disease progression among Colombian ALS patients, indicating the necessity for personalized treatment approaches based on individual progression trajectories. Further studies are needed to refine these predictive models and improve patient management and outcomes.}, } @article {pmid39311028, year = {2024}, author = {Driver, MD and Postema, J and Onck, PR}, title = {The Effect of Dipeptide Repeat Proteins on FUS/TDP43-RNA Condensation in C9orf72 ALS/FTD.}, journal = {The journal of physical chemistry. B}, volume = {128}, number = {39}, pages = {9405-9417}, pmid = {39311028}, issn = {1520-5207}, mesh = {*RNA-Binding Protein FUS/chemistry/metabolism/genetics ; *C9orf72 Protein/chemistry/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Dipeptides/chemistry/metabolism ; *RNA/chemistry/metabolism ; Humans ; *Molecular Dynamics Simulation ; *DNA-Binding Proteins/chemistry/metabolism/genetics ; *Frontotemporal Dementia/genetics/metabolism ; }, abstract = {Condensation of RNA binding proteins (RBPs) with RNA is essential for cellular function. The most common familial cause of the diseases ALS and FTD is C9orf72 repeat expansion disorders that produce dipeptide repeat proteins (DPRs). We explore the hypothesis that DPRs disrupt the native condensation behavior of RBPs and RNA through molecular interactions resulting in toxicity. FUS and TDP43 are two RBPs known to be affected in ALS/FTD. We use our previously developed 1-bead-per-amino acid and a newly developed 3-bead-per-nucleotide molecular dynamics model to explore ternary phase diagrams of FUS/TDP43-RNA-DPR systems. We show that the most toxic arginine containing DPRs (R-DPRs) can disrupt the RBP condensates through cation-π interactions and can strongly sequester RNA through electrostatic interactions. The native droplet morphologies are already modified at small additions of R-DPRs leading to non-native FUS/TDP43-encapsulated condensates with a marbled RNA/DPR core.}, } @article {pmid39310990, year = {2024}, author = {Vallejo Herrera, MJ and Vallejo Herrera, V and Del Toro Ortega, A and Tapia Guerrero, MJ}, title = {[Radiological versus endoscopic gastrostomy in patients with amyotrophic lateral sclerosis].}, journal = {Nutricion hospitalaria}, volume = {41}, number = {6}, pages = {1160-1164}, doi = {10.20960/nh.05190}, pmid = {39310990}, issn = {1699-5198}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Gastrostomy/methods/adverse effects ; Middle Aged ; Retrospective Studies ; Male ; Female ; *Enteral Nutrition/methods ; Aged ; Deglutition Disorders/etiology ; Adult ; Treatment Outcome ; Radiography ; }, abstract = {IIntroduction: patients with amyotrophic lateral sclerosis (ALS) require nutritional support, in most cases with enteral nutrition through gastrostomy, either endoscopic (PEG) or radiological (PRG). Objectives: to analyze the characteristics of patients with ALS at the time of PEG/PRG placement, and to compare the efficacy and safety of PRG versus PEG. Methods: a retrospective descriptive study. All patients with ALS who required gastrostomy in the last 3 years (2021-2023) in our hospital were recruited (4 PEG and 6 PRG). Demographic and nutritional parameters were analyzed. Results: ten patients were included, with an average age of 57 years. All patients presented with dysphagia and received oral or tube supplements prior to gastrostomy placement. The average duration of enteral nutrition was approximately 50 months, with a mortality rate of 30 % at 12 months after gastrostomy. The success rate of PEG and PRG was similar, with no complications. All patients developed deterioration of respiratory function, even after nutritional support. Conclusion: gastrostomy should be indicated as soon as a patient is at risk of aspiration pneumonia or when weight loss begins. Although the nutritional benefit of gastrostomy is well established, there is currently a delay between diagnosis and placement of approximately 4 years. PRG appears to be safer than PEG in patients with ALS and respiratory failure.}, } @article {pmid39310519, year = {2024}, author = {Albadawi, EA}, title = {Microstructural Changes in the Corpus Callosum in Neurodegenerative Diseases.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e67378}, pmid = {39310519}, issn = {2168-8184}, abstract = {The corpus callosum, the largest white matter structure in the brain, plays a crucial role in interhemispheric communication and cognitive function. This review examines the microstructural changes observed in the corpus callosum across various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). New neuroimaging studies, mainly those that use diffusion tensor imaging (DTI) and advanced tractography methods, were put together to show how changes have happened in the organization of white matter and the connections between them. Some of the most common ways the corpus callosum breaks down are discussed, including less fractional anisotropy, higher mean diffusivity, and atrophy in certain regions. The relationship between these microstructural changes and cognitive decline, motor dysfunction, and disease progression is explored. Additionally, we consider the potential of corpus callosum imaging as a biomarker for early disease detection and monitoring. Studies show that people with these disorders have lower fractional anisotropy and higher mean diffusivity in the corpus callosum, often in ways that are specific to the disease. These changes often happen before gray matter atrophy and are linked to symptoms, which suggests that the corpus callosum could be used as an early sign of neurodegeneration. The review also highlights the implications of these findings for understanding disease mechanisms and developing therapeutic strategies. Future directions, including the application of advanced imaging techniques and longitudinal studies, are discussed to elucidate the role of corpus callosum degeneration in neurodegenerative processes. This review underscores the importance of the corpus callosum in understanding the pathophysiology of neurodegenerative diseases and its potential as a target for therapeutic interventions.}, } @article {pmid39307464, year = {2024}, author = {Kalykaki, M and Rubio-Tomás, T and Tavernarakis, N}, title = {The role of mitochondria in cytokine and chemokine signalling during ageing.}, journal = {Mechanisms of ageing and development}, volume = {222}, number = {}, pages = {111993}, doi = {10.1016/j.mad.2024.111993}, pmid = {39307464}, issn = {1872-6216}, mesh = {Humans ; *Mitochondria/metabolism ; *Aging/metabolism ; *Signal Transduction ; *Inflammation/metabolism ; *Cytokines/metabolism ; Animals ; Chemokines/metabolism ; Cellular Senescence/physiology ; }, abstract = {Ageing is accompanied by a persistent, low-level inflammation, termed "inflammageing", which contributes to the pathogenesis of age-related diseases. Mitochondria fulfil multiple roles in host immune responses, while mitochondrial dysfunction, a hallmark of ageing, has been shown to promote chronic inflammatory states by regulating the production of cytokines and chemokines. In this review, we aim to disentangle the molecular mechanisms underlying this process. We describe the role of mitochondrial signalling components such as mitochondrial DNA, mitochondrial RNA, N-formylated peptides, ROS, cardiolipin, cytochrome c, mitochondrial metabolites, potassium efflux and mitochondrial calcium in the age-related immune system activation. Furthermore, we discuss the effect of age-related decline in mitochondrial quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy and UPR[mt], in inflammatory states upon ageing. In addition, we focus on the dynamic relationship between mitochondrial dysfunction and cellular senescence and its role in regulating the secretion of pro-inflammatory molecules by senescent cells. Finally, we review the existing literature regarding mitochondrial dysfunction and inflammation in specific age-related pathological conditions, including neurodegenerative diseases (Alzheimer's and Parkinson's disease, and amyotrophic lateral sclerosis), osteoarthritis and sarcopenia.}, } @article {pmid39307154, year = {2024}, author = {Pal, S and Chataway, J and Swingler, R and Macleod, MR and Carragher, NO and Hardingham, G and Selvaraj, BT and Smith, C and Wong, C and Newton, J and Lyle, D and Stenson, A and Dakin, RS and Ihenacho, A and Colville, S and Mehta, AR and Stallard, N and Carpenter, JR and Parker, RA and Keerie, C and Weir, CJ and Virgo, B and Morris, S and Waters, N and Gray, B and MacDonald, D and MacDonald, E and Parmar, MKB and Chandran, S and , }, title = {Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1097-1107}, doi = {10.1016/S1474-4422(24)00326-0}, pmid = {39307154}, issn = {1474-4465}, mesh = {Humans ; *Trazodone/therapeutic use/pharmacology ; Male ; Middle Aged ; Female ; Aged ; *Memantine/therapeutic use ; Double-Blind Method ; *Motor Neuron Disease/drug therapy ; Treatment Outcome ; Adult ; }, abstract = {BACKGROUND: Motor neuron disease represents a group of progressive and incurable diseases that are characterised by selective loss of motor neurons, resulting in an urgent need for rapid identification of effective disease-modifying therapies. The MND SMART trial aims to test the safety and efficacy of promising interventions efficiently and definitively against a single contemporaneous placebo control group. We now report results of the stage two interim analysis for memantine and trazodone.

METHODS: MND SMART is an investigator-led, phase 3, double-blind, placebo-controlled, multiarm, multistage, randomised, adaptive platform trial recruiting at 20 hospital centres in the UK. Individuals older than 18 years with a confirmed diagnosis of either amyotrophic lateral sclerosis classified by the revised El Escorial criteria, primary lateral sclerosis, progressive muscular atrophy, or progressive bulbar palsy, regardless of disease duration, were eligible for screening. Participants were randomised (1:1:1) to receive oral trazodone 200 mg once a day, oral memantine 20 mg once a day, or matched placebo using a computer-generated minimisation algorithm delivered via a secure web-based system. Co-primary outcome measures were clinical functioning, measured by rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R), and survival. Comparisons were conducted in four stages, with predefined criteria for stopping at the end of stages one and two. We report interim analysis from the stage two results, which was done when 100 participants per group (excluding long survivors, defined as >8 years since diagnosis at baseline) completed a minimum of 12 months of follow-up for the candidate investigational medicinal products. The trial is registered on the European Clinical Trials Registry, 2019-000099-41, and ClinicalTrials.gov, NCT04302870, and is ongoing.

FINDINGS: Between Feb 27, 2020, and July 24, 2023 (database lock for interim analysis two), 554 people with a motor neuron disease were randomly allocated to memantine (183 [33%]), trazodone (185 [33%]), or placebo (186 [34%]). The primary interim analysis population comprised 530 participants, of whom 175 (33%) had been allocated memantine, 175 (33%) had been allocated trazodone, and 180 (34%) had been allocated placebo. Over 12 months of follow-up, the mean rate of change per month in ALSFRS-R was -0·650 for memantine, -0·625 for trazodone, and -0·655 for placebo (memantine versus placebo estimated mean difference 0·033, one-sided 90% CI lower level -0·085; one-sided p=0·36; trazodone vs placebo: 0·065, -0·051; one-sided p=0·24). The one-sided p values were both above the significance threshold of 10%, indicating that neither memantine nor trazodone groups met the criteria for continuation. There were 483 participants with at least one adverse event (145 [77%] on placebo, 170 [91%] on memantine, and 168 [90%] on trazodone). There were 88 participants with at least one serious adverse event (37 [20%] on memantine, 27 [14%] on trazodone, and 24 [13%] on placebo). A total of 11 serious adverse event led to treatment discontinuation. There was no survival difference between comparisons, with 49 deaths in the memantine group, 52 deaths in the trazodone group, and 48 deaths in the placebo group.

INTERPRETATION: Neither memantine nor trazodone improved efficacy outcomes compared with placebo. This result is sufficiently powered to warrant no further testing of trazodone or memantine in motor neuron disease at the doses evaluated in this study. The multiarm multistage design shows important benefits in reducing the time, cost, and participant numbers to reach a definitive result.

FUNDING: The Euan MacDonald Centre, MND Scotland, My Name'5 Doddie Foundation, and Baillie Gifford.}, } @article {pmid39307005, year = {2024}, author = {Austin, JM and Bailey, R and Velazquez, SG and Sainath, H and Jackson, C}, title = {Clinical effectiveness of medical marijuana in patients with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123243}, doi = {10.1016/j.jns.2024.123243}, pmid = {39307005}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; *Medical Marijuana/therapeutic use ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Treatment Outcome ; Disease Progression ; Cohort Studies ; Adult ; Anxiety/drug therapy/etiology ; }, abstract = {Following legalization, Medical Marijuana (MM), has been used to treat the symptoms of Amyotrophic Lateral Sclerosis (ALS), yet data regarding Medical Marijuana's efficacy is lacking. Thus, we conducted a retrospective cohort study to assess Medical Marijuana's impact on ALS symptoms and progression. We reviewed the charts of all ALS patients treated in our clinic over a two-year period to collect data related to the primary outcome measures of symptoms of pain, poor appetite, anxiety, spasticity, insomnia, ALSFRS-R score, BMI, and MM use. Two groups were defined: a control group with target symptoms but no MM prescription, and a test group that filled a MM prescription, including a subgroup on MM for ≥3 visits. Outcomes were correlations between MM usage and symptom prevalence, and between MM usage and BMI and ALSFRS-R decline slope, analyzed using descriptive statistics and qualitative analysis via local regression. Data included 344 ALS patients. We found MM use correlated with alleviation of pain, poor appetite, and anxiety in the short term, but not with spasticity or insomnia. There was no correlation between MM use BMI maintenance. Notably, MM usage correlated with faster ALS progression, although patients using MM exhibited higher symptom burden and progressed faster than controls even pre-MM prescription. In conclusion, MM shows correlation with managing pain, poor appetite, and short-term anxiety in ALS, but is also correlated with faster disease progression based on ALSFRS-R scores. We suggest a multi-center, randomized controlled trial to evaluate both the clinical efficacy and safety of MM in the treatment of ALS.}, } @article {pmid39305776, year = {2024}, author = {Lichtfouse, J and Courtier, A and Vergunst, AC and Giannoni, P}, title = {Effects of environmental concentrations of toxins BMAA and its isomers DAB and AEG on zebrafish larvae.}, journal = {Ecotoxicology and environmental safety}, volume = {285}, number = {}, pages = {117045}, doi = {10.1016/j.ecoenv.2024.117045}, pmid = {39305776}, issn = {1090-2414}, mesh = {Animals ; *Zebrafish ; *Amino Acids, Diamino/toxicity ; *Cyanobacteria Toxins ; *Water Pollutants, Chemical/toxicity ; *Larva/drug effects ; Aminobutyrates/toxicity ; Glycine/toxicity/analogs & derivatives ; Embryo, Nonmammalian/drug effects ; Toxicity Tests, Acute ; Embryonic Development/drug effects ; Isomerism ; }, abstract = {The increasing concern over the environmental presence of β-N-Methylamino-L-alanine (BMAA), a toxin primarily produced by cyanobacteria and diatoms, has stimulated numerous studies to evaluate the risk for exposed populations, mainly aquatic organisms and humans. This study focuses on the toxicity of environmental concentrations of BMAA and its isomers, l-2,4 diaminobutyric acid dihydrochloride (DAB) and N-(2-aminoethyl) glycine (AEG) on zebrafish embryo development (ng.L[-1]). Presence of BMAA in various environments, including aquatic sources, air, and desert crusts, has raised concerns due to its potential link to neurodegenerative diseases such as the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC). Despite its known toxicity at high concentrations, there is limited information on the effects of environmental concentrations of BMAA and its isomers. These isomers are often found in association with BMAA and have been detected in seafood intended for human consumption, indicating potential risks from bioaccumulation and biomagnification. Zebrafish embryos have been chosen as a model due to their relevance for embryonic development and toxicity studies. The study employed fish embryo acute toxicity tests and behavioural analyses to specifically assess the sublethal effects of BMAA, DAB, and AEG. The results demonstrated larval mortality rates between 0 % and 3.75 %, while morphological defects were detected across all tested concentrations for each molecule. Behavioural analyses showed alterations in swimming behaviour. Unexpectedly, the changes in morphology and locomotion of the zebrafish larvae were detected more frequently at the lowest concentrations tested, suggesting potential non-monotonic dose responses. Overall, this research underscores the environmental risks associated with BMAA and its isomers, highlighting the importance of continuous monitoring and understanding of their sublethal effects on aquatic organisms and potential implications for human health. Further studies are warranted to elucidate the mechanisms of toxicity, evaluate long-term effects, and assess the risks associated with chronic exposure to these toxins.}, } @article {pmid39297678, year = {2024}, author = {Paoletti, O and Hyeraci, G and Finochietti, M and Celani, MG and Bacigalupo, I and Lombardi, N and Crescioli, G and Tuccori, M and Cascini, S and Gini, R and Addis, A and Kirchmayer, U and , }, title = {Pharmacological and non-pharmacological treatments in amyotrophic lateral sclerosis: an Italian real-world data study.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16470}, pmid = {39297678}, issn = {1468-1331}, support = {//Agenzia Italiana del Farmaco, Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/epidemiology/drug therapy ; Italy/epidemiology ; *Riluzole/therapeutic use ; Female ; Male ; Aged ; Middle Aged ; Neuroprotective Agents/therapeutic use ; }, abstract = {BACKGROUND AND PURPOSE: The purpose was to describe the use patterns of pharmacological and non-pharmacological therapies and investigate potential determinants of riluzole use in patients newly diagnosed with amyotrophic lateral sclerosis (ALS) in three Italian regions.

METHODS: Amyotrophic lateral sclerosis patients were selected from administrative healthcare databases of Latium, Tuscany and Umbria from 1 January 2014 to 31 December 2019 based on hospital- and disease-specific co-payment exemption data. The first trace of ALS was considered the index date. Incident ALS cases were those without a trace of ALS during the 3-year look back. Patients were described in terms of demographics, clinical characteristics and drug use at baseline, and were classified into four categories based on riluzole use in the 2 years before and 1 year after the index date: prevalent, incident, former users and non-users. Use of symptomatic pharmacological and non-pharmacological therapies was described across these categories during 12 months after the index date. Determinants of riluzole use were also investigated.

RESULTS AND CONCLUSIONS: A total of 1636 ALS incident subjects were detected in the three regions, mainly aged 65-74 years. Patients were generally fragile with a high prevalence of comorbidities at baseline. Riluzole was used by 27.4% of the overall study cohort at baseline and steeply increased in the first year after the index date differently between regions (Latium 61.2%, Tuscany 85.0%, Umbria 76.5%), with about half of the subjects being incident users. In the 12 months after the index date, also symptomatic therapies increased, in riluzole users and non-users. Determinants analysis showed that higher patient severity and complexity were associated with a lower likelihood of being treated with riluzole.}, } @article {pmid39297377, year = {2024}, author = {Akyuz, E and Aslan, FS and Gokce, E and Ilmaz, O and Topcu, F and Kakac, S}, title = {Extracellular vesicle and CRISPR gene therapy: Current applications in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.}, journal = {The European journal of neuroscience}, volume = {60}, number = {8}, pages = {6057-6090}, doi = {10.1111/ejn.16541}, pmid = {39297377}, issn = {1460-9568}, mesh = {Humans ; *Genetic Therapy/methods ; *Extracellular Vesicles/metabolism/genetics ; *CRISPR-Cas Systems ; *Huntington Disease/therapy/genetics ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Parkinson Disease/therapy/genetics ; *Alzheimer Disease/therapy/genetics ; Animals ; Gene Editing/methods ; Neurodegenerative Diseases/therapy/genetics ; }, abstract = {Neurodegenerative diseases are characterized by progressive deterioration of the nervous system. Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are prominently life-threatening examples of neurodegenerative diseases. The complexity of the pathophysiology in neurodegenerative diseases causes difficulties in diagnosing. Although the drugs temporarily help to correct specific symptoms including memory loss and degeneration, a complete treatment has not been found yet. New therapeutic approaches have been developed to understand and treat the underlying pathogenesis of neurodegenerative diseases. With this purpose, clustered-regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas) technology has recently suggested a new treatment option. Editing of the genome is carried out by insertion and deletion processes on DNA. Safe delivery of the CRISPR/Cas system to the targeted cells without affecting surrounding cells is frequently investigated. Extracellular vesicles (EVs), that is exosomes, have recently been used in CRISPR/Cas studies. In this review, CRISPR/Cas and EV approaches used for diagnosis and/or treatment in AD, PD, ALS, and HD are reviewed. CRISPR/Cas and EV technologies, which stand out as new therapeutic approaches, may offer a definitive treatment option in neurodegenerative diseases.}, } @article {pmid39305312, year = {2024}, author = {Torres, P and Rico-Rios, S and Ceron-Codorniu, M and Santacreu-Vilaseca, M and Seoane-Miraz, D and Jad, Y and Ayala, V and Mariño, G and Beltran, M and Miralles, MP and Andrés-Benito, P and Fernandez-Irigoyen, J and Santamaria, E and López-Otín, C and Soler, RM and Povedano, M and Ferrer, I and Pamplona, R and Wood, MJA and Varela, MA and Portero-Otin, M}, title = {TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition.}, journal = {Acta neuropathologica}, volume = {148}, number = {1}, pages = {45}, pmid = {39305312}, issn = {1432-0533}, support = {PI 20-00155//Instituto de Salud Carlos III/ ; 23-00176//Instituto de Salud Carlos III/ ; Programa Margarita Salas//Ministerio de Universidades/ ; SGR//Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya/ ; Ayuda Unzue//Fundación Luzon/ ; }, mesh = {Animals ; *Autophagy-Related Proteins/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; *Microtubule-Associated Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Cysteine Endopeptidases/metabolism/genetics ; Male ; Spinal Cord/metabolism/pathology ; Autophagy/physiology ; Mice, Knockout ; RNA Splicing/genetics ; Female ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Oligonucleotides, Antisense/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including ATG4B, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), Atg4b depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and atg4b[-/-] mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore ATG4B mRNA in TARDBP knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases.}, } @article {pmid39305271, year = {2024}, author = {Panzetta, ME and Valdivia, RH}, title = {Akkermansia in the gastrointestinal tract as a modifier of human health.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2406379}, pmid = {39305271}, issn = {1949-0984}, support = {R01 AI142376/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Gastrointestinal Microbiome ; *Akkermansia/physiology ; Animals ; *Gastrointestinal Tract/microbiology ; Gastrointestinal Diseases/microbiology ; }, abstract = {Akkermansia sp are common members of the human gut microbiota. Multiple reports have emerged linking the abundance of A. muciniphila to health benefits and disease risk in humans and animals. This review highlights findings linking Akkermansia species in the gastrointestinal (GI) tract to health outcomes across a spectrum of disorders, encompassing those that affect the digestive, respiratory, urinary, and central nervous systems. The mechanism through which Akkermansia exerts a beneficial versus a detrimental effect on health is likely dependent on the genetic makeup of the host metabolic capacity and immunomodulatory properties of the strain, the competition or cooperation with other members of the host microbiota, as well as synergy with co-administered therapies.}, } @article {pmid39304897, year = {2024}, author = {Ortiz, DA and Peregrín, N and Valencia, M and Vinueza-Gavilanes, R and Marín-Ordovas, E and Ferrero, R and Nicolás, MJ and González-Aseguinolaza, G and Arrasate, M and Aragón, T}, title = {GCN2 inhibition reduces mutant SOD1 clustering and toxicity and delays disease progression in an amyotrophic lateral sclerosis mouse model.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {49}, pmid = {39304897}, issn = {2047-9158}, support = {BFU2017-90043-P//Ministerio de Ciencia e Innovación, Gobierno de España/ ; PID2020-120497RB-I00//Ministerio de Ciencia y Universidades, Gobierno de España/ ; Proyecto Intramural IdisNa 2022//Navarra Institute for Health Research (IdiSNA)/ ; Proyectos I+D, 2017//Fundación para la Investigación Médica Aplicada/ ; AC Predoctoral Fellowship//Fundación para la Investigación Médica Aplicada/ ; 270-2018-922//República de Panamá, Programa de Becas IFARHU-SENACYT/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy ; Animals ; *Disease Progression ; *Disease Models, Animal ; Mice ; *Superoxide Dismutase-1/genetics ; *Mice, Transgenic ; Protein Serine-Threonine Kinases/genetics/antagonists & inhibitors ; Humans ; Mutation/genetics ; }, } @article {pmid39302099, year = {2024}, author = {Haider, R and Shipley, B and Surewicz, K and Hinczewski, M and Surewicz, WK}, title = {Pathological C-terminal phosphomimetic substitutions alter the mechanism of liquid-liquid phase separation of TDP-43 low complexity domain.}, journal = {Protein science : a publication of the Protein Society}, volume = {33}, number = {10}, pages = {e5179}, pmid = {39302099}, issn = {1469-896X}, support = {F30 AG071339/AG/NIA NIH HHS/United States ; F30 AG071339-03/NH/NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; T32 NS077888/NH/NIH HHS/United States ; T32 GM007250/NH/NIH HHS/United States ; RF1 AG061797/NH/NIH HHS/United States ; }, mesh = {*DNA-Binding Proteins/chemistry/metabolism/genetics ; Humans ; Phosphorylation ; *Protein Domains ; Molecular Dynamics Simulation ; Amino Acid Substitution ; Liquid-Liquid Extraction ; Phase Separation ; }, abstract = {C-terminally phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) marks the proteinaceous inclusions that characterize a number of age-related neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration and Alzheimer's disease. TDP-43 phosphorylation at S403/S404 and (especially) at S409/S410 is, in fact, accepted as a biomarker of proteinopathy. These residues are located within the low complexity domain (LCD), which also drives the protein's liquid-liquid phase separation (LLPS). The impact of phosphorylation at these LCD sites on phase separation of the protein is a topic of great interest, as these post-translational modifications and LLPS are both implicated in proteinopathies. Here, we employed a combination of experimental and simulation-based approaches to explore this question on a phosphomimetic model of the TDP-43 LCD. Our turbidity and fluorescence microscopy data show that phosphomimetic Ser-to-Asp substitutions at residues S403, S404, S409 and S410 alter the LLPS behavior of TDP-43 LCD. In particular, unlike the LLPS of unmodified protein, LLPS of the phosphomimetic variants displays a biphasic dependence on salt concentration. Through coarse-grained modeling, we find that this biphasic salt dependence is derived from an altered mechanism of phase separation, in which LLPS-driving short-range intermolecular hydrophobic interactions are modulated by long-range attractive electrostatic interactions. Overall, this in vitro and in silico study provides a physiochemical foundation for understanding the impact of pathologically relevant C-terminal phosphorylation on the LLPS of TDP-43 in a more complex cellular environment.}, } @article {pmid39302063, year = {2024}, author = {Khanna, RK and Catanese, S and Mortemousque, G and Mureau, N and Emond, P and Pisella, PJ and Blasco, H and Corcia, P}, title = {Exploring amyotrophic lateral sclerosis through the visual system: A systematic review.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16475}, pmid = {39302063}, issn = {1468-1331}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Humans ; Vision Disorders/etiology/physiopathology ; Visual Pathways/physiopathology ; }, abstract = {BACKGROUND AND PURPOSE: The human visual system relies on neural networks throughout the brain that are easily accessible for tests exploring eye structures and movements. Over the past two decades, investigations have been carried out on both afferent and efferent components of the visual system in people with amyotrophic lateral sclerosis (ALS). This approach might represent an innovative biomarker research strategy to better characterise the phenotypic variability of ALS. The purpose of this review was to determine whether exploring the visual system of patients with ALS (pwALS) is an effective strategy.

METHODS: The Medline and Web of science databases were searched for studies with terms relating to ALS and vision. Of 1146 references identified, 43 articles were included.

RESULTS: In this review article, both afferent and efferent components of the visual system were found to be impaired in pwALS in the absence of visual complaint, thereby contributing to the hypothesis that ALS is a multisystem disease with sensory involvement. Of note, some areas of the eye remain unexplored (i.e., tears, and retinal function using electroretinography).

CONCLUSIONS: According to the findings available in the literature, investigating the oculomotor system and exploring the ocular surface could represent two key promising strategies to identify new diagnostic biomarkers in pwALS. Further longitudinal studies are needed to identify relevant indicators of disease progression and response to therapeutic intervention.}, } @article {pmid39301564, year = {2024}, author = {Barnard, J and Hunt, R and Yucel, M and Mazaud, D and Smith, BN and Fanto, M}, title = {Human TDP43 is required for ALS‑related annexin A11 toxicity in Drosophila.}, journal = {Biomedical reports}, volume = {21}, number = {5}, pages = {165}, pmid = {39301564}, issn = {2049-9442}, abstract = {Genomics allows identification of genes and mutations associated with amyotrophic lateral sclerosis (ALS). Mutations in annexin A11 (ANXA11) are responsible for ~1% of all familial ALS and fronto-temporal dementia cases. The present study used the fruit fly, Drosophila melanogaster, to assess the mechanism of toxicity of ANXA11 mutants in residues that are conserved in the fly ANXB11 protein, the closest homolog to human ANXA11. In immune fluorescence, lifespan and negative geotaxis assays ANXA11 mutants, while displaying some degree of alteration in localization and function, did not exert any relevant organism toxicity in Drosophila. However, they showed a specific interaction with human TAR DNA-binding protein (TDP43). The present study illustrated that the ANXA11 mutants interact with human TDP43, but not the fly TAR DNA-binding protein-43 homolog (TBPH) or other ALS-associated genes such as super oxide dismutase 1, to shorten lifespan and increase negative geotaxis defects. This sheds light both on the mechanisms underlying ALS, further elucidating the intricate molecular network implicated in ALS and placing ANXA11 as a key player in its pathology, and on the complexity of using Drosophila as a model organism for researching genes in ALS.}, } @article {pmid39300745, year = {2024}, author = {Guo, Y and Ma, G and Wang, Y and Lin, T and Hu, Y and Zang, T}, title = {Causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity.}, journal = {Aging cell}, volume = {23}, number = {11}, pages = {e14271}, pmid = {39300745}, issn = {1474-9726}, support = {62371161//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Longevity/genetics ; *Neurodegenerative Diseases/genetics ; *Epigenesis, Genetic ; *Aging/genetics ; *Genome-Wide Association Study ; Mendelian Randomization Analysis ; }, abstract = {The causative mechanisms underlying the genetic relationships of neurodegenerative diseases with epigenetic aging and human longevity remain obscure. We aimed to detect causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity. We obtained large-scale genome-wide association study summary statistics data for four measures of epigenetic age (GrimAge, PhenoAge, IEAA, and HannumAge) (N = 34,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (N = 1,349,462), and for multiple neurodegenerative diseases (N = 6618-482,730), including Lewy body dementia, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Main analyses were conducted using multiplicative random effects inverse-variance weighted Mendelian randomization (MR), and conditional/conjunctional false discovery rate (cond/conjFDR) approach. Shared genomic loci were functionally characterized to gain biological understanding. Evidence showed that AD patients had 0.309 year less in exceptional longevity (IVW beta = -0.309, 95% CI: -0.38 to -0.24, p = 1.51E-19). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta = -0.10, 95% CI: -0.188 to -0.013, p = 0.02). Following the discovery of polygenic overlap, we identified rs78143120 as shared genomic locus between AD and GrimAge age acceleration, and rs12691088 between AD and exceptional longevity. Among these loci, rs78143120 was novel for AD. In conclusion, we observed that only AD had causal effects on epigenetic aging and human longevity, while other neurodegenerative diseases did not. The genetic overlap between them, with mixed effect directions, suggested complex shared genetic etiology and molecular mechanisms.}, } @article {pmid39302926, year = {2024}, author = {Chung, YM and Hu, CS and Sun, E and Tseng, HC}, title = {Morphological multiparameter filtration and persistent homology in mitochondrial image analysis.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0310157}, pmid = {39302926}, issn = {1932-6203}, mesh = {Humans ; *Mitochondria/metabolism/genetics ; *Membrane Transport Proteins/genetics/metabolism ; *Image Processing, Computer-Assisted/methods ; Cell Cycle Proteins/genetics/metabolism ; Transcription Factor TFIIIA/genetics/metabolism ; Mutation ; Software ; }, abstract = {The complexity of branching and curvilinear morphology of a complete mitochondrial network within each cell is challenging to analyze and quantify. To address this challenge, we developed an image analysis technique using persistent homology with a multiparameter filtration framework, combining image processing techniques in mathematical morphology. We show that such filtrations contain both topological and geometric information about complex cellular organelle structures, which allows a software program to extract meaningful features. Using this information, we also develop a connectivity index that describes the morphology of the branching patterns. As proof of concept, we utilize this approach to study how mitochondrial networks are altered by genetic changes in the Optineurin gene. Mutations in the autophagy gene Optineurin (OPTN) are associated with primary open-angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS), and Paget's disease of the bone, but the pathophysiological mechanism is unclear. We utilized the proposed mathematical morphology-based multiparameter filtration and persistent homology approach to analyze and quantitatively compare how changes in the OPTN gene alter mitochondrial structures from their normal interconnected, tubular morphology into scattered, fragmented pieces.}, } @article {pmid39300574, year = {2024}, author = {Ashkaran, F and Seyedalipour, B and Baziyar, P and Hosseinkhani, S}, title = {Mutation/metal deficiency in the "electrostatic loop" enhanced aggregation process in apo/holo SOD1 variants: implications for ALS diseases.}, journal = {BMC chemistry}, volume = {18}, number = {1}, pages = {177}, pmid = {39300574}, issn = {2661-801X}, abstract = {Despite the many mechanisms it has created to prevent unfolding and aggregation of proteins, many diseases are caused by abnormal folding of proteins, which are called misfolding diseases. During this process, proteins undergo structural changes and become stable, insoluble beta-sheet aggregates called amyloid fibrils. Mutations/disruptions in metal ion homeostasis in the ALS-associated metalloenzyme superoxide dismutase (SOD1) reduce conformational stability, consistent with the protein aggregation hypothesis for neurodegenerative diseases. However, the exact mechanism of involvement is not well understood. Hence, to understand the role of mutation/ metal deficiency in SOD1 misfolding and aggregation, we investigated the effects of apo/holo SOD1 variants on structural properties using biophysical/experimental techniques. The MD results support the idea that the mutation/metal deficiency can lead to a change in conformation. The increased content of β-sheet structures in apo/holo SOD1 variants can be attributed to the aggregation tendency, which was confirmed by FTIR spectroscopy and dictionary of secondary structure in proteins (DSSP) results. Thermodynamic studies of GdnHCl showed that metal deficiency/mutation/intramolecular S-S reduction together are required to initiate misfolding/aggregation of SOD1. The results showed that apo/holo SOD1 variants under destabilizing conditions induced amyloid aggregates at physiological pH, which were detected by ThT/ANS fluorescence, as well as further confirmation of amyloid/amorphous species by TEM. This study confirms that mutations in the electrostatic loop of SOD1 lead to structural abnormalities, including changes in hydrophobicity, reduced disulfide bonds, and an increased propensity for protein denaturation. This process facilitates the formation of amyloid/amorphous aggregates ALS-associated.}, } @article {pmid39300421, year = {2024}, author = {Koçkaya, PD and Alvur, TM and Odabaşı, O}, title = {Empowering medical students: bridging gaps with high-fidelity simulations; a mixed-methods study on self-efficacy.}, journal = {BMC medical education}, volume = {24}, number = {1}, pages = {1026}, pmid = {39300421}, issn = {1472-6920}, mesh = {Humans ; *Self Efficacy ; *Students, Medical/psychology ; Prospective Studies ; *Clinical Competence ; Male ; Female ; Cardiopulmonary Resuscitation/education ; Simulation Training ; Adult ; Emergency Medicine/education ; High Fidelity Simulation Training ; Young Adult ; Focus Groups ; Education, Medical, Undergraduate/methods ; Empowerment ; }, abstract = {BACKGROUND: High-fidelity simulations play a crucial role in preparing for high-mortality events like cardiopulmonary arrest, emphasizing the need for rapid and accurate intervention. Proficiency in cardiopulmonary resuscitation(CPR) requires a strong self-efficacy(SE); training for both is crucial. This study assesses the impact of Advanced Life Support(ALS) simulation on SE changes in final-year medical students.

METHODS: This mixed-methods prospective simulation study involved medical students in emergency medicine internships, examining self-efficacy perceptions regarding ALS technical skills(ALS-SEP). A comparison was made between students who underwent scenario-based ALS simulation training and those who did not. Competencies in chest compression skills were assessed, and the concordance between ALS-SEP scores and observed CPR performances were evaluated. Focus group interviews were conducted and analyzed using content analysis techniques.

RESULTS: The study involved 80 students, with 53 in the experimental group(EG) and 27 in the control group(CG). The EG, underwent simulation training, showed a significantly higher ALS-SEP change than the CG(p < 0.05). However, there was low concordance between pre-simulation SEP and actual performance. Compression skills success rates were inadequate. Qualitative analysis revealed main themes as"learning"(32.6%), "self-efficacy"(29%), "simulation method"(21.3%), and "development"(16.5%).

DISCUSSION: Post-simulation, students reported improved SEP and increased readiness for future interventions. The findings and qualitative statements support the effectiveness of simulation practices in bridging the gap between SEP and performance. Utilizing simulation-based ALS training enhances learners' belief in their capabilities, raises awareness of their competencies, and encourages reflective thinking. Given the importance of high SEP for ALS, simulation trainings correlating self-efficacy perception and performance may significantly reduce potential medical errors stemming from a disparity between perceived capability and actual performance.}, } @article {pmid39300071, year = {2024}, author = {Castelli, S and Desideri, E and Laureti, L and Felice, F and De Cristofaro, A and Scaricamazza, S and Lazzarino, G and Ciriolo, MR and Ciccarone, F}, title = {N-acetylaspartate promotes glycolytic-to-oxidative fiber-type switch and resistance to atrophic stimuli in myotubes.}, journal = {Cell death & disease}, volume = {15}, number = {9}, pages = {686}, pmid = {39300071}, issn = {2041-4889}, support = {GR-2019-1236998//Ministero della Salute (Ministry of Health, Italy)/ ; MNESYS PNRR - MUR PE00000006//Ministero della Salute (Ministry of Health, Italy)/ ; }, mesh = {Animals ; *Glycolysis/drug effects ; *Muscle Fibers, Skeletal/metabolism/drug effects ; Mice ; *Aspartic Acid/metabolism/analogs & derivatives ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; Oxidation-Reduction ; Cell Line ; Mice, Transgenic ; }, abstract = {N-acetylaspartate (NAA) is a neuronal metabolite that can be extruded in extracellular fluids and whose blood concentration increases in several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Aspartoacylase (ASPA) is the enzyme responsible for NAA breakdown. It is abundantly expressed in skeletal muscle and most other human tissues, but the role of NAA catabolism in the periphery is largely neglected. Here we demonstrate that NAA treatment of differentiated C2C12 muscle cells increases lipid turnover, mitochondrial biogenesis and oxidative metabolism at the expense of glycolysis. These effects were ascribed to NAA catabolism, as CRISPR/Cas9 ASPA KO cells are insensitive to NAA administration. Moreover, the metabolic switch induced by NAA was associated with an augmented resistance to atrophic stimuli. Consistently with in vitro results, SOD1-G93A ALS mice show an increase in ASPA levels in those muscles undergoing the glycolytic to oxidative switch during the disease course. The impact of NAA on the metabolism and resistance capability of myotubes supports a role for this metabolite in the phenotypical adaptations of skeletal muscle in neuromuscular disorders.}, } @article {pmid39299905, year = {2024}, author = {Hetz, C and Thielen, P and Matus, S and Nassif, M and Court, F and Kiffin, R and Martinez, G and Cuervo, AM and Brown, RH and Glimcher, LH}, title = {Corrigendum: XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy.}, journal = {Genes & development}, volume = {38}, number = {15-16}, pages = {785}, doi = {10.1101/gad.352249.124}, pmid = {39299905}, issn = {1549-5477}, } @article {pmid39299508, year = {2024}, author = {Shetty, P and Ren, Y and Dillon, D and Mcleod, A and Nishijima, D and Taylor, SL and , }, title = {Derivation of a clinical decision rule for termination of resuscitation in non-traumatic pediatric out-of-hospital cardiac arrest.}, journal = {Resuscitation}, volume = {204}, number = {}, pages = {110400}, pmid = {39299508}, issn = {1873-1570}, support = {K38 HL165363/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; Retrospective Studies ; Child ; *Clinical Decision Rules ; *Cardiopulmonary Resuscitation/methods ; Child, Preschool ; Emergency Medical Services/methods ; Medical Futility ; Adolescent ; Infant ; Resuscitation Orders ; Withholding Treatment/standards ; }, abstract = {AIM: Prehospital termination of resuscitation (ToR) rules are used to predict medical futility in adult out-of-hospital cardiac arrest (OHCA), however, the available evidence for pediatric patients is limited. The primary aim of this study is to derive a Pediatric Termination of Resuscitation (PToR) prediction rule for use in pediatric non-traumatic OHCA patients.

METHODS: We analyzed a retrospective cohort of pediatric OHCA patients within the CARES database over a 10-year period (2013-2022). We split the dataset into training and test datasets and fit logistic regressions with Least Absolute Shrinkage and Selection Operator (LASSO) to select predictor variables and estimate predictive test characteristics for the primary outcome of death and a secondary composite outcome of death or survival to hospital discharge with unfavorable neurologic status.

RESULTS: We analyzed a sample of 21,240 children where 2,326 (11.0%) survived to hospital discharge, and 1,894 (8.9%) survived to hospital discharge with favorable neurologic status. We derived a PToR rule for death demonstrating a specificity of 99.1% and a positive predictive value (PPV) of 99.8% and a PToR rule for death or survival with poor neurologic status with a specificity of 99.7% and PPV of 99.9% within the test dataset.

CONCLUSION: We derived a clinical prediction rule with high specificity and positive predictive value in prehospital settings utilizing Advanced Life Support (ALS) providers which may inform termination of resuscitation considerations in pediatric patients. Further prospective and validation studies will be necessary to define the appropriateness and applicability of these PToR criteria for routine use.}, } @article {pmid39299489, year = {2024}, author = {Le, NT and Chu, N and Joshi, G and Higgins, NR and Nebie, O and Adelakun, N and Butts, M and Monteiro, MJ}, title = {Prion protein pathology in Ubiquilin 2 models of ALS.}, journal = {Neurobiology of disease}, volume = {201}, number = {}, pages = {106674}, pmid = {39299489}, issn = {1095-953X}, support = {K22 CA241105/CA/NCI NIH HHS/United States ; R01 NS098243/NS/NINDS NIH HHS/United States ; R35 GM151124/GM/NIGMS NIH HHS/United States ; RF1 NS098243/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; Humans ; *Autophagy-Related Proteins/metabolism/genetics ; Mice ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; Mutation ; Disease Models, Animal ; Induced Pluripotent Stem Cells/metabolism/pathology ; Prion Proteins/metabolism/genetics ; Inclusion Bodies/metabolism/pathology ; Neurons/metabolism/pathology ; Mice, Transgenic ; }, abstract = {Mutations in UBQLN2 cause ALS and frontotemporal dementia (FTD). The pathological signature in UBQLN2 cases is deposition of highly unusual types of inclusions in the brain and spinal cord that stain positive for UBQLN2. However, what role these inclusions play in pathogenesis remains unclear. Here we show cellular prion protein (PrP[C]) is found in UBQLN2 inclusions in both mouse and human neuronal induced pluripotent (IPSC) models of UBQLN2 mutations, evidenced by the presence of aggregated forms of PrP[C] with UBQLN2 inclusions. Turnover studies indicated that the P497H UBQLN2 mutation slows PrP[C] protein degradation and leads to mislocalization of PrP[C] in the cytoplasm. Immunoprecipitation studies indicated UBQLN2 and PrP[C] bind together in a complex. The abnormalities in PrP[C] caused by UBQLN2 mutations may be relevant in disease pathogenesis.}, } @article {pmid39299156, year = {2024}, author = {Caswell, G and Wilson, E}, title = {The impact of home mechanical ventilation on the time and manner of death for those with Motor neurone disease (MND): A qualitative study of bereaved family members.}, journal = {Social science & medicine (1982)}, volume = {360}, number = {}, pages = {117345}, doi = {10.1016/j.socscimed.2024.117345}, pmid = {39299156}, issn = {1873-5347}, mesh = {Humans ; *Motor Neuron Disease/psychology/complications ; *Qualitative Research ; Male ; Female ; *Respiration, Artificial/psychology ; Middle Aged ; *Family/psychology ; United Kingdom ; Aged ; *Bereavement ; Attitude to Death ; Adult ; Terminal Care/psychology/methods ; Home Care Services ; Time Factors ; Aged, 80 and over ; }, abstract = {Motor neurone disease (MND) is a progressive neurodegenerative disorder which is ultimately terminal. It causes muscle weakness which can lead to the need for assistance in breathing, for some with the disease. This paper draws on qualitative research using semi-structured interviews with 32 people bereaved by the death of a family member with MND who was dependent on home mechanical ventilation, from across the United Kingdom. Interviews explored how the end-of-life of a person who had used non-invasive ventilation to assist their breathing was experienced by participants, who had cared about, and for them. Four themes are used to examine the impact of dependent ventilation technology on the experience of dying on the part of bereaved family members. Themes are: accompanied dying, planned withdrawal of ventilation, blurred time of death, time post-death. The perception and experience of time was a key component across all four themes. Ventilator technology played a critical role in sustaining life, but it could also contribute to a complex dynamic where the realities of death were mediated or obscured. This raises ethical, emotional, and existential considerations, both for the individuals receiving ventilator support and their families, as well as for healthcare professionals involved in end-of-life care.}, } @article {pmid39299050, year = {2024}, author = {Eshak, D and Arumugam, M}, title = {Unveiling therapeutic biomarkers and druggable targets in ALS: An integrative microarray analysis, molecular docking, and structural dynamic studies.}, journal = {Computational biology and chemistry}, volume = {113}, number = {}, pages = {108211}, doi = {10.1016/j.compbiolchem.2024.108211}, pmid = {39299050}, issn = {1476-928X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Molecular Docking Simulation ; *Biomarkers/metabolism/analysis/blood ; Microarray Analysis ; Molecular Dynamics Simulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a debilitating neurodegenerative disorder characterized by the progressive degeneration of nerve cells in the brain and spinal cord. Despite extensive research, its precise etiology remains elusive, and early diagnosis is challenging due to the absence of specific tests. This study aimed to identify potential blood-based biomarkers for early ALS detection and monitoring using datasets from whole blood samples (GSE112680) and oligodendrocytes, astrocytes, and fibroblasts (GSE87385) obtained from the NCBI-GEO repository. Through bioinformatics analysis, including protein-protein interactions and molecular pathway analyses, we identified differentially expressed genes (DEGs) associated with ALS. Notably, ALS2, ADH7, ALDH8A1, ALDH3B1, ABHD2, ABHD17B, ABHD12, ABHD13, PGAM2, AURKB, ANAPC11, VAPA, UNC45B, and TNNT2 emerged as top-ranked DEGs, implicated in drug metabolism, protein depalmytilation, and the AKT/mTOR signaling pathways. Among these, AurKB established as a potential therapeutic biomarker with relevance to various neurological conditions. Consequently, AurKB was selected for identifying potential therapeutic molecules and utilized for in silico structural characterization studies. Exploration of the IMPATT database led to the discovery of a lead compound similar to Fostamatinib, currently used for AurKB. Initial molecular docking and MMGBSA-based binding energy analysis were followed by molecular dynamics simulation (MDS) and free energy landscape (FEL) analysis to validate the ligand's binding efficacy and understand dynamic processes within the biological system. The identified potential biomarkers and lead molecule provide novel insights into the correlation between blood cell transcripts and ALS pathology, paving the way for blood-based diagnostic tools for early ALS detection and ongoing disease monitoring.}, } @article {pmid39297270, year = {2024}, author = {Doğan, V and Şenormanci, Ö}, title = {Validity and Reliability of the Affective Lability Scale-18 (ALS-18) Turkish Form in the Non-Clinical Group.}, journal = {Turk psikiyatri dergisi = Turkish journal of psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.5080/u27329}, pmid = {39297270}, issn = {2651-3463}, abstract = {OBJECTIVE: Affective lability, which is an important aspect of mood dysregulation, is seen in many psychiatric conditions. The aim of this study is to examine the psychometric properties of the Affective Lability Scale-18 in the Turkish sample of the non-clinical group.

METHOD: A total of 615 individuals (312 females and 303 males) who did not have a past or current psychiatric disorder were included in the study. The participants were administered sociodemographic data form, Affective Lability Scale-18, Difficulties in Emotion Regulation Scale, and Beck Depression Inventory. The participants were divided into 4 groups; a pilot group, EFA (exploratory factor analysis) group, CFA (confirmatory factor analysis) group and test-retest group.

RESULTS: The factor analysis conducted for the construct validity of the scale, revealed similar results to that of the original scale. The Cronbach's alpha internal consistency coefficient was 0.92 for the EFA group and 0.92 for the CFA group. The test-retest reliability coefficient was 0.82. Difficulties in Emotion Regulation Scale (DERS) and Beck's Depression Inventory (BDI) were used tp measure validity. The correlation between the total scores of participants on the ALS-18 and their scores on the DERS and BDI was determined to be positive and moderate (r=0.38, r=41).

CONCLUSION: The Affective Lability Scale-18 in the Turkish sample, three sub-dimensions, anxiety/depression, depression/elevation, anger and the general factor all have sufficient internal consistency and it has been demonstrated that the scale can be applied in our country to evaluate the situations in which affect variability is evaluated.}, } @article {pmid39296960, year = {2024}, author = {Keilholz, AN and Pathak, I and Smith, CL and Osman, KL and Smith, L and Oti, G and Golzy, M and Ma, L and Lever, TE and Nichols, NL}, title = {Tongue exercise ameliorates structural and functional upper airway deficits in a rodent model of hypoglossal motor neuron loss.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1441529}, pmid = {39296960}, issn = {1664-2295}, abstract = {INTRODUCTION: Tongue weakness and atrophy can lead to deficits in the vital functions of breathing and swallowing in patients with motor neuron diseases (MNDs; e.g., amyotrophic lateral sclerosis (ALS) and pseudobulbar palsy), often resulting in aspiration pneumonia, respiratory failure, and death. Available treatments for patients with MNDs are largely palliative; thus, there is a critical need for therapies targeting preservation of upper airway function and suggesting a role for tongue exercise in patients with MNDs. Here, we leveraged our inducible rodent model of hypoglossal (XII) motor neuron degeneration to investigate the effects of a strength endurance tongue exercise program on upper airway structure and function. Our model was created through intralingual injection of cholera toxin B conjugated to saporin (CTB-SAP) into the genioglossus muscle of the tongue to induce targeted death of XII motor neurons.

METHODS: Rats in this study were allocated to 4 experimental groups that received intralingual injection of either CTB-SAP or unconjugated CTB + SAP (i.e., control) +/- tongue exercise. Following tongue exercise exposure, we evaluated the effect on respiratory function (via plethysmography), macrostructure [via magnetic resonance imaging (MRI) of the upper airway and tongue], and ultrafine structure [via ex vivo magnetic resonance spectroscopy (MRS) of the tongue] with a focus on lipid profiles.

RESULTS: Results showed that sham exercise-treated CTB-SAP rats have evidence of upper airway restriction (i.e., reduced airflow) and structural changes present in the upper airway (i.e., airway compression) when compared to CTB-SAP + exercise rats and control rats +/- tongue exercise, which was ameliorated with tongue exercise. Additionally, CTB-SAP + sham exercise rats have evidence of increased lipid expression in the tongue consistent with previously observed tongue hypertrophy when compared to CTB-SAP + exercise rats or control rats +/- tongue exercise.

CONCLUSION: These findings provide further evidence that a strength endurance tongue exercise program may be a viable therapeutic treatment option in patients with XII motor neuron degeneration in MNDs such as ALS. Future directions will focus on investigating the underlying mechanism responsible for tongue exercise-induced plasticity in the hypoglossal-tongue axis, particularly inflammatory associated factors such as BDNF.}, } @article {pmid39296911, year = {2024}, author = {Odat, RM and Alomari, O and Elgenidy, A}, title = {Evaluation of the gold cost criteria as a diagnostic criteria of amyotrophic lateral sclerosis.}, journal = {eNeurologicalSci}, volume = {37}, number = {}, pages = {100524}, pmid = {39296911}, issn = {2405-6502}, } @article {pmid39295200, year = {2025}, author = {Zhang, Z and He, X and Wang, J and Cui, J and Shi, B}, title = {The correlation between social support, coping style, advance care planning readiness, and quality of life in patients with amyotrophic lateral sclerosis: a cross-sectional study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {40-47}, doi = {10.1080/21678421.2024.2400520}, pmid = {39295200}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Quality of Life/psychology ; Male ; Female ; Middle Aged ; *Adaptation, Psychological ; Cross-Sectional Studies ; *Social Support ; *Advance Care Planning ; Aged ; Adult ; Surveys and Questionnaires ; }, abstract = {OBJECTIVE: The primary goal for clinical healthcare professionals is to enhance the quality of life (QOL) of patients with amyotrophic lateral sclerosis (ALS). This study aimed to explore the correlation between social support, coping style, advance care planning (ACP) readiness, and QOL in patients with ALS. We also sought to analyze the mediating effect of coping style and ACP readiness between social support and QOL, and to provide insights for developing targeted interventions to improve patients' QOL.

METHODS: A cross-sectional design was used, with participants recruited through convenience sampling in Tianjin, China. Statistical analysis included the t-test, analysis of variance, correlation analysis, and mediating effect analysis.

RESULTS: The study included 215 participants. The QOL of patients with ALS was at a medium level, with significant correlations between social support, coping style, ACP readiness, and QOL (all p < 0.01). The direct effect of social support on QOL was 0.403 (p = 0.018), accounting for 41.85% of the total effect. The total indirect effect of social support on QOL through coping style and ACP readiness was 0.560 (p < 0.001), accounting for 58.15% of the total effect. The chain mediating effect involving facing, avoiding, and ACP readiness accounted for 16.72%.

CONCLUSION: Social support directly influenced QOL and had an indirect impact through coping style and ACP readiness. Healthcare professionals can improve the QOL of patients with ALS by enhancing social support, disease-coping ability, and ACP readiness in clinical practice.}, } @article {pmid39295118, year = {2024}, author = {Berry, JD and Paganoni, S and Harms, MB and Shneider, N and Andrews, J and Miller, TM and Babu, S and Sherman, AV and Harris, BT and Provenzano, FA and Phatnani, HP and Shefner, J and Garret, MA and Ladha, SS and Tsou, AY and Mohan, P and Igne, C and , and Bowser, R}, title = {Access for ALL in ALS: A large-scale, inclusive, collaborative consortium to unlock the molecular and genetic mechanisms of amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {6}, pages = {1140-1150}, doi = {10.1002/mus.28244}, pmid = {39295118}, issn = {1097-4598}, support = {OT2 NS136938/NS/NINDS NIH HHS/United States ; OT2 NS136939/NS/NINDS NIH HHS/United States ; 1OT2NS136939-01//National Institute of Neurological Disorders and Stroke, NIH/ ; 1OT2NS136938-01//National Institute of Neurological Disorders and Stroke, NIH/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; United States ; Biomedical Research ; National Institutes of Health (U.S.) ; }, abstract = {Recent progress in therapeutics for amyotrophic lateral sclerosis (ALS) has spurred development and imbued the field of ALS with hope for more breakthroughs, yet substantial scientific gaps persist. This unmet need remains a stark reminder that innovative paradigms are needed to invigorate ALS research. To move toward more informative, targeted, and personalized drug development, the National Institutes of Health (NIH) established a national ALS clinical research consortium called Access for ALL in ALS (ALL ALS). This new consortium is a multi-institutional effort that aims to organize the ALS clinical research landscape in the United States. ALL ALS is operating in partnership with several stakeholders to operationalize the recommendations of the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS) Public Private Partnership. ALL ALS will provide a large-scale, centralized, and readily accessible infrastructure for the collection and storage of a wide range of data from people living with ALS (symptomatic cohort) or who may be at risk of developing ALS (asymptomatic ALS gene carriers). Importantly, ALL ALS is designed to encourage community engagement, equity, and inclusion. The consortium is prioritizing the enrollment of geographically, ethnoculturally, and socioeconomically diverse participants. Collected data include longitudinal clinical data and biofluids, genomic, and digital biomarkers that will be harmonized and linked to the central Accelerating Medicines Partnership for ALS (AMP ALS) portal for sharing with the research community. The aim of ALL ALS is to deliver a comprehensive, inclusive, open-science dataset to help researchers answer important scientific questions of clinical relevance in ALS.}, } @article {pmid39294194, year = {2024}, author = {Luthi-Carter, R and Cappelli, S and Le Roux-Bourdieu, M and Tentillier, N and Quinn, JP and Petrozziello, T and Gopalakrishnan, L and Sethi, P and Choudhary, H and Bartolini, G and Gebara, E and Stuani, C and Font, L and An, J and Ortega, V and Sage, J and Kosa, E and Trombetta, BA and Simeone, R and Seredenina, T and Afroz, T and Berry, JD and Arnold, SE and Carlyle, BC and Adolfsson, O and Sadri-Vakili, G and Buratti, E and Bowser, R and Agbas, A}, title = {Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {21837}, pmid = {39294194}, issn = {2045-2322}, support = {P30 AG062421/AG/NIA NIH HHS/United States ; Industry-Led Consortium Project Grant//Target ALS Foundation/ ; BB-2022-C5//Target ALS Foundation/ ; }, mesh = {Humans ; *Blood Platelets/metabolism ; *DNA-Binding Proteins/metabolism ; *Neurodegenerative Diseases/blood/metabolism ; *Biological Specimen Banks ; Amyotrophic Lateral Sclerosis/blood/metabolism/pathology ; Biomarkers/blood ; Cytosol/metabolism ; }, abstract = {The TAR DNA Binding Protein 43 (TDP-43) has been implicated in the pathogenesis of human neurodegenerative diseases and exhibits hallmark neuropathology in amyotrophic lateral sclerosis (ALS). Here, we explore its tractability as a plasma biomarker of disease and describe its localization and possible functions in the cytosol of platelets. Novel TDP-43 immunoassays were developed on three different technical platforms and qualified for specificity, signal-to-noise ratio, detection range, variation, spike recovery and dilution linearity in human plasma samples. Surprisingly, implementation of these assays demonstrated that biobank-archived plasma samples yielded considerable heterogeneity in TDP-43 levels. Importantly, subsequent investigation attributed these differences to variable platelet recovery. Fractionations of fresh blood revealed that ≥ 95% of the TDP-43 in platelet-containing plasma was compartmentalized within the platelet cytosol. We reasoned that this highly concentrated source of TDP-43 comprised an interesting substrate for biochemical analyses. Additional characterization of platelets revealed the presence of the disease-associated phosphoserine 409/410 TDP-43 proteoform and many neuron- and astrocyte-expressed TDP-43 mRNA targets. Considering these striking similarities, we propose that TDP-43 may serve analogous functional roles in platelets and synapses, and that the study of platelet TDP-43 might provide a window into disease-related TDP-43 dyshomeostasis in the central nervous system.}, } @article {pmid39293800, year = {2024}, author = {Gao, J and Chai, N and Wang, T and Han, Z and Chen, J and Lin, G and Wu, Y and Bi, L}, title = {A new technique of percutaneous minimally invasive surgery assisted by magnetic resonance neurography.}, journal = {Bone & joint open}, volume = {5}, number = {9}, pages = {776-784}, pmid = {39293800}, issn = {2633-1462}, abstract = {AIMS: In order to release the contracture band completely without damaging normal tissues (such as the sciatic nerve) in the surgical treatment of gluteal muscle contracture (GMC), we tried to display the relationship between normal tissue and contracture bands by magnetic resonance neurography (MRN) images, and to predesign a minimally invasive surgery based on the MRN images in advance.

METHODS: A total of 30 patients (60 hips) were included in this study. MRN scans of the pelvis were performed before surgery. The contracture band shape and external rotation angle (ERA) of the proximal femur were also analyzed. Then, the minimally invasive GMC releasing surgery was performed based on the images and measurements, and during the operation, incision lengths, surgery duration, intraoperative bleeding, and complications were recorded; the time of the first postoperative off-bed activity was also recorded. Furthermore, the patients' clinical functions were evaluated by means of Hip Outcome Score (HOS) and Ye et al's objective assessments, respectively.

RESULTS: The contracture bands exhibited three typical types of shape - feather-like, striped, and mixed shapes - in MR images. Guided by MRN images, we designed minimally invasive approaches directed to each hip. These approaches resulted in a shortened incision length in each hip (0.3 cm (SD 0.1)), shorter surgery duration (25.3 minutes (SD 5.8)), less intraoperative bleeding (8.0 ml (SD 3.6)), and shorter time between the end of the operation and the patient's first off-bed activity (17.2 hours (SD 2.0)) in each patient. Meanwhile, no serious postoperative complications occurred in all patients. The mean HOS-Sports subscale of patients increased from 71.0 (SD 5.3) to 94.83 (SD 4.24) at six months postoperatively (p < 0.001). The follow-up outcomes from all patients were "good" and "excellent", based on objective assessments.

CONCLUSION: Preoperative MRN analysis can be used to facilitate the determination of the relationship between contracture band and normal tissues. The minimally invasive surgical design via MRN can avoid nerve damage and improve the release effect.}, } @article {pmid39293008, year = {2024}, author = {Ramirez, V and Kittrell, P and Jackson, C and Clegg, A and Allegretti, A}, title = {Sexual Intimacy in Persons with Amyotrophic Lateral Sclerosis and their Partners: A Pilot Study.}, journal = {Journal of allied health}, volume = {53}, number = {3}, pages = {212-217}, pmid = {39293008}, issn = {1945-404X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Pilot Projects ; Male ; Female ; Middle Aged ; *Sexual Partners/psychology ; Aged ; Sexual Behavior ; Adult ; Quality of Life ; }, abstract = {OBJECTIVE: The objective of this study was to describe concerns experienced among persons with amyotrophic lateral sclerosis (PALS) and their partners regarding sexual intimacy, as well as preferences regarding discussion of the topic with healthcare providers.

METHODS: A total of 27 survey responses including 13 PALS and 14 partners were received. Surveys included both quantitative and qualitative data addressing the importance of sexual intimacy to quality of life, assistance required to participate in sexual intimacy, concerns for safety, and preferred timing and method of discussing/receiving information from healthcare professionals.

RESULTS: 100% of respondents stated they had never been asked about sexual intimacy by any healthcare provider. 92% of participants agreed ALS had affected their ability to express sexual intimacy. Participants discussed loss of intimacy as due to muscle weakness, respiratory concerns, and role change among other contributors to the overall experienced change in expression of sexual intimacy. With regards to their preferred method of receiving/discussing information on the effect of ALS on sexual intimacy, 48% of participants preferred use of an online video series, 44% chose a pamphlet, 24% chose a one-on-one discussion with a healthcare provider, and 12% chose a private conversation with their partner and healthcare provider.

CONCLUSIONS: The findings greatly illustrate the difficulties and concerns experienced with sexual intimacy among PALS and their partners as well as the preferred methods for receiving information on the topic.}, } @article {pmid39292705, year = {2024}, author = {Minnella, A and McCusker, KP and Amagata, A and Trias, B and Weetall, M and Latham, JC and O'Neill, S and Wyse, RK and Klein, MB and Trimmer, JK}, title = {Targeting ferroptosis with the lipoxygenase inhibitor PTC-041 as a therapeutic strategy for the treatment of Parkinson's disease.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0309893}, pmid = {39292705}, issn = {1932-6203}, mesh = {Animals ; *Ferroptosis/drug effects ; *Lipoxygenase Inhibitors/pharmacology/therapeutic use ; Humans ; *Parkinson Disease/drug therapy/metabolism/pathology ; Rats ; Mice ; alpha-Synuclein/metabolism ; Lipid Peroxidation/drug effects ; Neurons/drug effects/metabolism/pathology ; Fibroblasts/drug effects/metabolism ; Arachidonate 15-Lipoxygenase/metabolism ; Cells, Cultured ; Male ; }, abstract = {Parkinson's disease is the second most common neurodegenerative disorder, affecting nearly 10 million people worldwide. Ferroptosis, a recently identified form of regulated cell death characterized by 15-lipoxygenase-mediated hydroperoxidation of membrane lipids, has been implicated in neurodegenerative disorders including amyotrophic lateral sclerosis and Parkinson's disease. Pharmacological inhibition of 15 -lipoxygenase to prevent iron- and lipid peroxidation-associated ferroptotic cell death is a rational strategy for the treatment of Parkinson's disease. We report here the characterization of PTC-041 as an anti-ferroptotic reductive lipoxygenase inhibitor developed for the treatment of Parkinson's disease. In these studies, PTC-041 potently protects primary human Parkinson's disease patient-derived fibroblasts from lipid peroxidation and subsequent ferroptotic cell death and prevents ferroptosis-related neuronal loss and astrogliosis in primary rat neuronal cultures. Additionally, PTC-041 prevents ferroptotic-mediated α-synuclein protein aggregation and nitrosylation in vitro, suggesting a potential role for anti-ferroptotic lipoxygenase inhibitors in mitigating pathogenic aspects of synucleinopathies such as Parkinson's disease. We further found that PTC-041 protects against synucleinopathy in vivo, demonstrating that PTC-041 treatment of Line 61 transgenic mice protects against α-synuclein aggregation and phosphorylation as well as prevents associated neuronal and non-neuronal cell death. Finally, we show that. PTC-041 protects against 6-hydroxydopamine-induced motor deficits in a hemiparkinsonian rat model, further validating the potential therapeutic benefits of lipoxygenase inhibitors in the treatment of Parkinson's disease.}, } @article {pmid39292682, year = {2024}, author = {Tang, X and Li, Q and Huang, G and Pei, X and Chen, Z and Huang, Y and Zhao, S and Guo, T and Liu, Z}, title = {Immediate efficacy of auricular acupuncture combined with active exercise in the treatment of acute lumbar sprains in 10 minutes: Protocol of a randomized controlled trial.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0308801}, pmid = {39292682}, issn = {1932-6203}, mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Acupuncture, Ear/methods ; Combined Modality Therapy ; *Exercise Therapy/methods ; Low Back Pain/therapy ; Lumbar Vertebrae/physiopathology ; Lumbosacral Region ; Pain Measurement ; Prospective Studies ; Range of Motion, Articular ; Sprains and Strains/therapy ; Treatment Outcome ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Acute lumbar sprain (ALS) is common musculoskeletal disorder characterized by severe low back pain and activity limitation, which significantly impacts the patient's work and life. Immediate relief of pain and restoration of mobility in a short period of time are the main needs of patients when they visit the clinic. This study aims to evaluate the immediate efficacy of this combined treatment for ALS within 10 minutes.

METHODS: This is a single-center, prospective, randomized clinical trial. 128 eligible patients with ALS will be randomly allocated in a 1:1 ratio to either the auricular acupuncture (AA) group or the sham auricular acupuncture (SAA) group. All patients will receive a single 10-minute treatment. The primary outcome will be the change in pain intensity after 10 minutes of treatment. The secondary outcomes include changes in pain intensity at other time points (2, 5 minutes), changes in lumbar range of motion (ROM) at different time points, blinded assessment, treatment effect expectancy scale evaluation, and treatment satisfaction scale evaluation. All participants will be included in the analysis according to the intention-to-treat principle.

DISCUSSION: This is the first randomized controlled trial to assess the immediate efficacy of AA combined with active exercise for ALS. The findings of this study are expected to provide a simple and rapid treatment for ALS in clinical.

TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2400083740. Registered 30 April 2024.}, } @article {pmid39292611, year = {2024}, author = {Xu, Z and Tang, J and Gong, Y and Zhang, J and Zou, Y}, title = {Atomistic Insights into the Stabilization of TDP-43 Protofibrils by ATP.}, journal = {Journal of chemical information and modeling}, volume = {64}, number = {19}, pages = {7639-7649}, doi = {10.1021/acs.jcim.4c01140}, pmid = {39292611}, issn = {1549-960X}, mesh = {*Adenosine Triphosphate/metabolism ; *Molecular Dynamics Simulation ; *DNA-Binding Proteins/chemistry/metabolism ; Humans ; Protein Stability ; Hydrogen Bonding ; }, abstract = {The aberrant accumulation of the transactive response deoxyribonucleic acid (DNA)-binding protein of 43 kDa (TDP-43) aggregates in the cytoplasm of motor neurons is the main pathological hallmark of amyotrophic lateral sclerosis (ALS). Previous experiments reported that adenosine triphosphate (ATP), the universal energy currency for all living cells, could induce aggregation and enhance the folding of TDP-43 fibrillar aggregates. However, the significance of ATP on TDP-43 fibrillation and the mechanism behind it remain elusive. In this work, we conducted multiple atomistic molecular dynamics (MD) simulations totaling 20 μs to search the critical nucleus size of TDP-43282-360 and investigate the impact of ATP molecules on preformed protofibrils. The results reveal that the trimer is the critical nucleus for TDP-43282-360 fibril formation and the tetramer is the minimal stable nucleus. When ATP molecules bind to the TDP-43282-360 trimer and tetramer, they can consolidate the TDP-43282-360 protofibrils by increasing the content of the β-sheet structure and promoting the formation of hydrogen bonds (H-bonds). Binding site analyses show that the N-terminus of TDP-43282-360 protofibrils is the main binding site of ATP, and R293 dominates the direct binding of ATP. Further analyses reveal that the π-π, cation-π, salt bridge, and H-bonding interactions together contribute to the binding of ATP to TDP-43282-360 protofibrils. This study decoded the detailed stabilization mechanism of protofibrillar TDP-43282-360 oligomers by ATP, and may provide new avenues for the development of drug design against ALS.}, } @article {pmid39292414, year = {2024}, author = {Ataman, R and Alhasani, R and Auneau-Enjalbert, L and Quigley, A and Michael, HU and Ahmed, S}, title = {The psychometric properties of the Quality of Life in Neurological Disorders (Neuro-QoL) measurement system in neurorehabilitation populations: a systematic review.}, journal = {Journal of patient-reported outcomes}, volume = {8}, number = {1}, pages = {106}, pmid = {39292414}, issn = {2509-8020}, support = {36053//Canadian Foundation of Innovation and the Ministry of Health of Quebec/ ; }, mesh = {Humans ; *Nervous System Diseases/rehabilitation/psychology/diagnosis ; *Neurological Rehabilitation/methods ; *Psychometrics/methods ; *Quality of Life/psychology ; Reproducibility of Results ; }, abstract = {OBJECTIVE: To systematically review the literature of existing evidence on the measurement properties of the Quality of Life in Neurological Disorders (Neuro-QoL) measurement system among neurorehabilitation populations.

DATA SOURCES: The Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) guided this systematic review in which we searched nine electronic databases and registries, and hand-searched reference lists of included articles.

STUDY SELECTION: Two independent reviewers screened selected articles and extracted data from 28 included studies.

DATA EXTRACTION: COSMIN's approach guided extraction and synthesizing measurement properties evidence (insufficient, sufficient), and the modified GRADE approach guided synthesizing evidence quality (very-low, low, moderate, high) by diagnosis.

DATA SYNTHESIS: Neuro-QoL has sufficient measurement properties when used by individuals with Huntington's disease, Multiple Sclerosis, Parkinson's disease, stroke, lupus, cognitive decline, and amyotrophic lateral sclerosis. The strongest evidence is for the first four conditions, where test-retest reliability, construct validity, and responsiveness are nearly always sufficient (GRADE: moderate-high). Structural validity is assessed only in multiple sclerosis and stroke but is often insufficient (GRADE: moderate-high). Criterion validity is sufficient in some stroke and Huntington's disease domains (GRADE: high). Item response theory analyses were reported for some stroke domains only. There is limited, mixed evidence for responsiveness and measurement error (GRADE: moderate-high), and no cross-cultural validity evidence CONCLUSIONS: Neuro-QoL domains can describe and evaluate patients with Huntington's disease, multiple sclerosis, Parkinson's disease, and stroke, but predictive validity evidence would be beneficial. In the other conditions captured in this review, a limited number of Neuro-QoL domains have evidence for descriptive use only. For these conditions, further evidence of structural validity, measurement error, cross-cultural validity and predictive validity would enhance the use and interpretation of Neuro-QoL.}, } @article {pmid39292338, year = {2024}, author = {Zhang, H and Gao, C and Yang, D and Nie, L and He, K and Chen, C and Li, S and Huang, G and Zhou, L and Huang, X and Wu, D and Liu, J and Huang, Z and Wang, J and Li, W and Zhang, Z and Yang, X and Zou, L}, title = {Urolithin a Improves Motor Dysfunction Induced by Copper Exposure in SOD1[G93A] Transgenic Mice Via Activation of Mitophagy.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39292338}, issn = {1559-1182}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease pathologically characterized by selective degeneration of motor neurons resulting in a catastrophic loss of motor function. The present study aimed to investigate the effect of copper (Cu) exposure on progression of ALS and explore the therapeutic effect and mechanism of Urolithin A (UA) on ALS. 0.13 PPM copper chloride drinking water was administrated in SOD1[G93A] transgenic mice at 6 weeks, UA at a dosage of 50 mg/kg/day was given for 6 weeks after a 7-week Cu exposure. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl and Immunohistochemistry Staining. Proteomics analysis, Western blotting and ELISA were conducted to detect protein expression. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit. Cu-exposure worsened motor function, promoted muscle fibrosis, loss of motor neurons, and astrocyte and microglial activation. It also induced abnormal changes in mitochondria-related biological processes, leading to a significant reduction in ATP levels and an increase in MDA levels. Upregulation of P62 and downregulation of Parkin, PINK1, and LAMP1 were revealed in SOD1[G93A] mice with Cu exposure. Administration of UA activated mitophagy, modulated mitochondria dysfunction, reduced neuroinflammation, and improved gastrocnemius muscle atrophy and motor dysfunction in SOD1[G93A] mice with Cu exposure. Mitophagy plays critical role in ALS exacerbated by Cu exposure. UA administration may be a promising treatment strategy for ALS.}, } @article {pmid39291248, year = {2024}, author = {Senerchia, G and Dubbioso, R}, title = {Non-invasive brain stimulation therapy in amyotrophic lateral sclerosis: are we ready for clinical use?.}, journal = {The Lancet regional health. Europe}, volume = {45}, number = {}, pages = {101055}, pmid = {39291248}, issn = {2666-7762}, } @article {pmid39291166, year = {2024}, author = {Gianferrari, G and Cuoghi Costantini, R and Crippa, V and Carra, S and Bonetto, V and Pansarasa, O and Cereda, C and Zucchi, E and Martinelli, I and Simonini, C and Vicini, R and Fini, N and Trojsi, F and Passaniti, C and Ticozzi, N and Doretti, A and Diamanti, L and Fiamingo, G and Conte, A and Dalla Bella, E and D'Errico, E and Scarian, E and Pasetto, L and Antoniani, F and Galli, V and Casarotto, E and , and D'Amico, R and Poletti, A and Mandrioli, J}, title = {Colchicine treatment in amyotrophic lateral sclerosis: safety, biological and clinical effects in a randomized clinical trial.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae304}, pmid = {39291166}, issn = {2632-1297}, abstract = {In preclinical studies, the anti-inflammatory drug colchicine, which has never been tested in amyotrophic lateral sclerosis, enhanced the expression of autophagy factors and inhibited accumulation of transactive response DNA-binding protein 43 kDa, a known histopathological marker of amyotrophic lateral sclerosis. This multicentre, randomized, double-blind trial enrolled patients with probable or definite amyotrophic lateral sclerosis who experienced symptom onset within the past 18 months. Patients were randomly assigned in a 1:1:1 ratio to receive colchicine at a dose of 0.005 mg/kg/day, 0.01 mg/kg/day or placebo for a treatment period of 30 weeks. The number of positive responders, defined as patients with a decrease lesser than 4 points in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised total score during the 30-week treatment period, was the primary outcome. Disease progression, survival, safety and quality of life at the end of treatment were the secondary clinical outcomes. Secondary biological outcomes included changes from baseline to treatment end of stress granule and autophagy responses, transactive response DNA-binding protein 43 kDa, neurofilament accumulation and extracellular vesicle secretion, between the colchicine and placebo groups. Fifty-four patients were randomized to receive colchicine (n = 18 for each colchicine arm) or placebo (n = 18). The number of positive responders did not differ between the placebo and colchicine groups: 2 out of 18 patients (11.1%) in the placebo group, 5 out of 18 patients (27.8%) in the colchicine 0.005 mg/kg/day group (odds ratio = 3.1, 97.5% confidence interval 0.4-37.2, P = 0.22) and 1 out of 18 patients (5.6%) in the colchicine 0.01 mg/kg/day group (odds ratio = 0.5, 97.5% confidence interval 0.01-10.2, P = 0.55). During treatment, a slower Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised decline was detected in patients receiving colchicine 0.005 mg/kg/day (mean difference = 0.53, 97.5% confidence interval 0.07-0.99, P = 0.011). Eight patients experienced adverse events in placebo arm (44.4%), three in colchicine 0.005 mg/kg/day (16.7%) and seven in colchicine 0.01 mg/kg/day arm (35.9%). The differences in adverse events were not statistically significant. In conclusion, colchicine treatment was safe for amyotrophic lateral sclerosis patients. Further studies are required to better understand mechanisms of action and clinical effects of colchicine in this condition.}, } @article {pmid39290830, year = {2024}, author = {Noches, V and Campos-Melo, D and Droppelmann, CA and Strong, MJ}, title = {Epigenetics in the formation of pathological aggregates in amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1417961}, pmid = {39290830}, issn = {1662-5099}, abstract = {The progressive degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is accompanied by the formation of a broad array of cytoplasmic and nuclear neuronal inclusions (protein aggregates) largely containing RNA-binding proteins such as TAR DNA-binding protein 43 (TDP-43) or fused in sarcoma/translocated in liposarcoma (FUS/TLS). This process is driven by a liquid-to-solid phase separation generally from proteins in membrane-less organelles giving rise to pathological biomolecular condensates. The formation of these protein aggregates suggests a fundamental alteration in the mRNA expression or the levels of the proteins involved. Considering the role of the epigenome in gene expression, alterations in DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA modifications become highly relevant to understanding how this pathological process takes effect. In this review, we explore the evidence that links epigenetic mechanisms with the formation of protein aggregates in ALS. We propose that a greater understanding of the role of the epigenome and how this inter-relates with the formation of pathological LLPS in ALS will provide an attractive therapeutic target.}, } @article {pmid39290715, year = {2024}, author = {Huang, L and Liu, M and Tang, J and Gong, Z and Li, Z and Yang, Y and Zhang, M}, title = {The role of ALDH2 rs671 polymorphism and C-reactive protein in the phenotypes of male ALS patients.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1397991}, pmid = {39290715}, issn = {1662-4548}, abstract = {BACKGROUND: The aldehyde dehydrogenase 2 (ALDH2) rs671 (A) allele has been implicated in neurodegeneration, potentially through oxidative and inflammatory pathways. The study aims to investigate the effects of the ALDH2 rs671 (A) allele and high sensitivity C-reactive protein (hs-CRP) on the clinical phenotypes of amyotrophic lateral sclerosis (ALS) in male and female patients.

METHODS: Clinical data and ALDH2 rs671 genotype of 143 ALS patients, including 85 males and 58 females, were collected from January 2018 to December 2022. All patients underwent assessment using the Chinese version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Complete blood count and metabolic profiles were measured. Clinical and laboratory parameters were compared between carriers and non-carriers of the rs671 (A) allele in males and females, respectively. The significant parameters and rs671 (A) Allele were included in multivariate linear regression models to identify potential contributors to motor and cognitive impairment. Mediation analysis was employed to evaluate any mediation effects.

RESULTS: Male patients carrying rs671 (A) allele exhibited higher levels of hs-CRP than non-carriers (1.70 mg/L vs. 0.50 mg/L, p = 0.006). The rs671 (A) allele was identified as an independent risk factor for faster disease progression only in male patients (β = 0.274, 95% CI = 0.048-0.499, p = 0.018). The effect of the rs671 (A) allele on the executive function in male patients was fully mediated by hs-CRP (Indirect effect = -1.790, 95% CI = -4.555--0.225). No effects of the rs671 (A) allele or hs-CRP were observed in female ALS patients. The effects of the ALDH2 rs671 (A) allele and the mediating role of hs-CRP in male patients remained significant in the sensitivity analyses.

CONCLUSION: The ALDH2 rs671 (A) allele contributed to faster disease progression and hs-CRP mediated cognitive impairment in male ALS patients.}, } @article {pmid39289761, year = {2024}, author = {van der Geest, AT and Jakobs, CE and Ljubikj, T and Huffels, CFM and Cañizares Luna, M and Vieira de Sá, R and Adolfs, Y and de Wit, M and Rutten, DH and Kaal, M and Zwartkruis, MM and Carcolé, M and Groen, EJN and Hol, EM and Basak, O and Isaacs, AM and Westeneng, HJ and van den Berg, LH and Veldink, JH and Schlegel, DK and Pasterkamp, RJ}, title = {Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {152}, pmid = {39289761}, issn = {2051-5960}, support = {TOTALS//Stichting ALS Nederland/ ; ALS-on-a-chip//Stichting ALS Nederland/ ; MUS-ALS//Stichting ALS Nederland/ ; ATAXALS//Stichting ALS Nederland/ ; GoALS//Stichting ALS Nederland/ ; INTEGRALS//E-Rare/ ; TRIAGE//JPND/ ; EScORIAL/ERC_/European Research Council/International ; }, mesh = {Humans ; *Organoids/pathology ; *Frontotemporal Dementia/genetics/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *C9orf72 Protein/genetics ; *Induced Pluripotent Stem Cells/pathology ; *Synapses/pathology/genetics ; Male ; Female ; Cerebral Cortex/pathology ; DNA Repeat Expansion/genetics ; }, abstract = {A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human brain imaging and experimental studies indicate early changes in brain structure and connectivity in C9-ALS/FTD, even before symptom onset. Because these early disease phenotypes remain incompletely understood, we generated iPSC-derived cerebral organoid models from C9-ALS/FTD patients, presymptomatic C9ORF72-HRE (C9-HRE) carriers, and controls. Our work revealed the presence of all three C9-HRE-related molecular pathologies and developmental stage-dependent size phenotypes in cerebral organoids from C9-ALS/FTD patients. In addition, single-cell RNA sequencing identified changes in cell type abundance and distribution in C9-ALS/FTD organoids, including a reduction in the number of deep layer cortical neurons and the distribution of neural progenitors. Further, molecular and cellular analyses and patch-clamp electrophysiology detected various changes in synapse structure and function. Intriguingly, organoids from all presymptomatic C9-HRE carriers displayed C9-HRE molecular pathology, whereas the extent to which more downstream cellular defects, as found in C9-ALS/FTD models, were detected varied for the different presymptomatic C9-HRE cases. Together, these results unveil early changes in 3D human brain tissue organization and synaptic connectivity in C9-ALS/FTD that likely constitute initial pathologies crucial for understanding disease onset and the design of therapeutic strategies.}, } @article {pmid39289471, year = {2024}, author = {Jawdat, O and Rucker, J and Nakano, T and Takeno, K and Statland, J and Pasnoor, M and Dimachkie, MM and Sabus, C and Badawi, Y and Hunt, SL and Tomioka, NH and Gunewardena, S and Bloomer, C and Wilkins, HM and Herbelin, L and Barohn, RJ and Nishimune, H}, title = {Resistance exercise in early-stage ALS patients, ALSFRS-R, Sickness Impact Profile ALS-19, and muscle transcriptome: a pilot study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {21729}, pmid = {39289471}, issn = {2045-2322}, support = {P30 GM122731/GM/NIGMS NIH HHS/United States ; R01NS078214/NS/NINDS NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; R01 NS078214/NS/NINDS NIH HHS/United States ; U54 HD090216/HD/NICHD NIH HHS/United States ; S10 OD021743/OD/NIH HHS/United States ; 19K24690//Japan Society for the Promotion of Science/ ; UL1 TR002366/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Pilot Projects ; Male ; *Resistance Training ; Female ; Middle Aged ; *Transcriptome ; *Muscle Strength ; Aged ; Adult ; Quadriceps Muscle/metabolism/physiopathology ; Muscle, Skeletal/metabolism/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) patients lack effective treatments to maintain motor and neuromuscular function. This study aimed to evaluate the effect of a home-based exercise program on muscle strength, ALS scores, and transcriptome in ALS patients, Clinical Trials.gov #NCT03201991 (28/06/2017). An open-label, non-randomized pilot clinical trial was conducted in seven individuals with early-stage ALS. Participants were given 3 months of home-based resistance exercise focusing on the quadriceps muscles. The strength of exercised muscle was evaluated using bilateral quadriceps strength with manual muscle testing, handheld dynamometers, five times sit-to-stand, and Timed-Up-and-Go before and after the exercise program. In addition, changes in the Sickness Impact Profile ALS-19 (SIP/ALS-19) as the functional outcome measure and the transcriptome of exercised muscles were compared before and after the exercise. The primary outcome of muscle strength did not change significantly by the exercise program. The exercise program maintained the SIP/ALS-19 and the ALS Functional Rating Scale-Revised (ALSFRS-R). Transcriptome analysis revealed that exercise reverted the expression level of genes decreased in ALS, including parvalbumin. Three months of moderately intense strength and conditioning exercise maintained muscle strength of the exercised muscle and ALSFRS-R scores and had a positive effect on patients' muscle transcriptome.}, } @article {pmid39289025, year = {2024}, author = {Dunlop, CL and Kilpatrick, C and Jones, L and Bonet, M and Allegranzi, B and Brizuela, V and Graham, W and Thompson, A and Cheshire, J and Lissauer, D}, title = {Adapting the WHO hand hygiene 'reminders in the workplace' to improve acceptability for healthcare workers in maternity settings worldwide: a mixed methods study.}, journal = {BMJ open}, volume = {14}, number = {9}, pages = {e083132}, pmid = {39289025}, issn = {2044-6055}, support = {001/WHO_/World Health Organization/International ; }, mesh = {Humans ; *Hand Hygiene ; *Focus Groups ; Female ; *World Health Organization ; *Health Personnel/psychology ; Workplace ; Attitude of Health Personnel ; Reminder Systems ; Adult ; Male ; Cross Infection/prevention & control ; Surveys and Questionnaires ; Hospitals, Maternity ; Developing Countries ; Guideline Adherence ; Interviews as Topic ; }, abstract = {INTRODUCTION: Hand hygiene is key in preventing healthcare-associated infections, but it is challenging in maternity settings due to high patient turnover, frequent emergencies and volume of aseptic procedures. We sought to investigate if adaptions to the WHO hand hygiene reminders could improve their acceptability in maternity settings globally, and use these findings to develop new reminders specific to maternity settings.

METHODS: Informed by Sekhon et al's acceptability framework, we conducted an online survey, semi-structured interviews and a focus group examining the three WHO central hand hygiene reminders ('your five moments of hand hygiene', 'how to hand wash' and 'how to hand rub') and their acceptability in maternity settings. A convergent mixed-methods study design was followed. Findings were examined overall and by country income status. A WHO expert working group tested the integrated findings, further refined results and developed recommendations to improve acceptability for use in the global maternity community. Findings were used to inform the development of two novel and acceptable hand hygiene reminders for use in high-income country (HIC) and low- and middle-income country (LMIC) maternity settings.

RESULTS: Participation in the survey (n=342), semi-structured interviews (n=12) and focus group (n=7) spanned 51 countries (14 HICs and 37 LMICs). The highest scoring acceptability constructs were clarity of the intervention (intervention coherence), confidence in performance (self-efficacy), and alignment with personal values (ethicality). The lowest performing were perceived difficulty (burden) and how the intervention made the participant feel (affective attitude). Overfamiliarity reduced acceptability in HICs (perceived effectiveness). In LMICs, resource availability was a barrier to implementation (opportunity cost). Two new reminders were developed based on the findings, using inclusive female images, and clinical examples from maternity settings.

CONCLUSION: Following methodologically robust adaptation, two novel and inclusive maternity-specific hand hygiene reminders have been developed for use in both HIC and LMICs.}, } @article {pmid39288267, year = {2024}, author = {Liu, H and Zhao, XF and Lu, YN and Hayes, LR and Wang, J}, title = {CRISPR/Cas13d targeting suppresses repeat-associated non-AUG translation of C9orf72 hexanucleotide repeat RNA.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {21}, pages = {}, pmid = {39288267}, issn = {1558-8238}, support = {R01 NS123538/NS/NINDS NIH HHS/United States ; R01 NS128494/NS/NINDS NIH HHS/United States ; R01 NS074324/NS/NINDS NIH HHS/United States ; R01 NS110098/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/therapy/metabolism ; *CRISPR-Cas Systems ; Mice ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *DNA Repeat Expansion/genetics ; *Mice, Transgenic ; Protein Biosynthesis ; Induced Pluripotent Stem Cells/metabolism ; RNA/genetics/metabolism ; Motor Neurons/metabolism/pathology ; }, abstract = {A hexanucleotide GGGGCC repeat expansion in the non-coding region of the C9orf72 gene is the most common genetic mutation identified in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The resulting repeat RNA and dipeptide repeat proteins from non-conventional repeat translation have been recognized as important markers associated with the diseases. CRISPR/Cas13d, a powerful RNA-targeting tool, has faced challenges in effectively targeting RNA with stable secondary structures. Here we report that CRISPR/Cas13d can be optimized to specifically target GGGGCC repeat RNA. Our results demonstrate that the CRISPR/Cas13d system can be harnessed to significantly diminish the translation of poly-dipeptides originating from the GGGGCC repeat RNA. This efficacy has been validated in various cell types, including induced pluripotent stem cells and differentiated motor neurons originating from C9orf72-ALS patients, as well as in C9orf72 repeat transgenic mice. These findings demonstrate the application of CRISPR/Cas13d in targeting RNA with intricate higher-order structures and suggest a potential therapeutic approach for ALS and FTD.}, } @article {pmid39287680, year = {2024}, author = {Castelnovo, V and Canu, E and Aiello, EN and Curti, B and Sibilla, E and Torre, S and Freri, F and Tripodi, C and Lumaca, L and Spinelli, EG and Schito, P and Russo, T and Falzone, Y and Verde, F and Silani, V and Ticozzi, N and Sturm, VE and Rankin, KP and Gorno-Tempini, ML and Poletti, B and Filippi, M and Agosta, F}, title = {How to detect affect recognition alterations in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {11}, pages = {7208-7221}, pmid = {39287680}, issn = {1432-1459}, support = {StG-2016_714388_NeuroTRACK//FP7 Ideas: European Research Council/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; Male ; Female ; Middle Aged ; Aged ; *Neuropsychological Tests ; Recognition, Psychology/physiology ; Cognitive Dysfunction/diagnosis/etiology/physiopathology ; Reproducibility of Results ; }, abstract = {OBJECTIVE: To define the clinical usability of an affect recognition (AR) battery-the Comprehensive Affect Testing System (CATS)-in an Italian sample of patients with amyotrophic lateral sclerosis (ALS).

METHODS: 96 ALS patients and 116 healthy controls underwent a neuropsychological assessment including the AR subtests of the abbreviated version of the CATS (CATS-A). CATS-A AR subtests and their global score (CATS-A AR Quotient, ARQ) were assessed for their factorial, convergent, and divergent validity. The diagnostic accuracy of each CATS-A AR measure in discriminating ALS patients with cognitive impairment from cognitively normal controls and patients was tested via receiver-operating characteristics analyses. Optimal cut-offs were identified for CATS-A AR measures yielding an acceptable AUC value (≥ .70). The ability of CATS-A ARQ to discriminate between different ALS cognitive phenotypes was also tested. Gray-matter (GM) volumes of controls, ALS with normal (ALS-nARQ), and impaired ARQ score (ALS-iARQ) were compared using ANCOVA models.

RESULTS: CATS-A AR subtests and ARQ proved to have moderate-to-strong convergent and divergent validity. Almost all considered CATS-A measures reached acceptable accuracy and diagnostic power (AUC range = .79-.83). ARQ showed to be the best diagnostic measure (sensitivity = .80; specificity = .75) and discriminated between different ALS cognitive phenotypes. Compared to ALS-nARQ, ALS-iARQ patients showed reduced GM volumes in the right anterior cingulate, right middle frontal, left inferior temporal, and superior occipital regions.

CONCLUSIONS: The AR subtests of the CATS-A, and in particular the CATS-A ARQ, are sound measures of AR in ALS. AR deficits may be a valid marker of frontotemporal involvement in these patients.}, } @article {pmid39287519, year = {2024}, author = {Wendebourg, MJ and Kesenheimer, E and Sander, L and Weigel, M and Weidensteiner, C and Haas, T and Madoerin, P and Diebold, M and Deigendesch, N and Neuhaus, D and Naumann, N and Neuwirth, C and Braun, N and Weber, M and Granziera, C and Scheurer, E and Lenz, C and Schweikert, K and Sinnreich, M and Lieb, J and Bieri, O and Schlaeger, R}, title = {The Lateral Corticospinal Tract Sign: An MRI Marker for Amyotrophic Lateral Sclerosis.}, journal = {Radiology}, volume = {312}, number = {3}, pages = {e231630}, doi = {10.1148/radiol.231630}, pmid = {39287519}, issn = {1527-1315}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Prospective Studies ; *Pyramidal Tracts/diagnostic imaging/pathology ; Sensitivity and Specificity ; }, abstract = {Background Radially sampled averaged magnetization inversion-recovery acquisition (rAMIRA) imaging shows hyperintensity in the lateral corticospinal tract (CST) in patients with motor neuron diseases. Purpose To systematically determine the accuracy of the lateral corticospinal tract sign for detecting patients with amyotrophic lateral sclerosis (ALS) at rAMIRA MRI. Materials and Methods This study included prospectively acquired data from participants in ALS and other motor neuron disease imaging studies at the University Hospital Basel, Switzerland. All participants underwent 3-T axial two-dimensional rAMIRA imaging at four cervical intervertebral disk levels. The lateral CST sign was defined as spinal cord white matter hyperintensity dorsolateral to the anterior horns, with higher signal intensity than in the dorsal columns on axial rAMIRA images. Marker accuracy was assessed in a study data set and in an independent validation data set. Postmortem rAMIRA imaging and histopathologic analysis were performed in one participant who died during the study. Results Participants with ALS (study data set: 38 participants [mean age, 61 years; IQR, 15 years], 22 male participants; validation data set: 10 participants [mean age, 61 years; IQR, 21 years], seven male participants), post-polio syndrome (study data set: 25 participants [mean age, 68 years; IQR, 8 years], 12 male participants), spinal muscular atrophy (study data set: 10 participants [mean age, 43 years; IQR, 14 years], eight male participants; validation data set: five participants [mean age, 38 years; IQR, 19 years], two male participants), and healthy control participants (study data set: 60 participants [mean age, 57 years; IQR, 20 years], 36 male participants; validation data set: 10 participants [mean age, 44 years; IQR, 17 years], seven male participants) were included. The sensitivity and specificity of rAMIRA for ALS were 60% (23 of 38) and 97% (91 of 94) in the study data set and 100% (10 of 10) and 93% (14 of 15) in the validation data set, respectively. Histopathologic analysis showed distinct loss of myelinated axons in the localization of the hyperintensities observed at rAMIRA imaging performed in situ and after organ extraction. Conclusion The recently defined marker at rAMIRA MRI may be a promising tool for assessing upper motor neuron degeneration in the lateral CST in patients with ALS. Clinical trials registration no. NCT03561623, NCT05764434, NCT06137612 © RSNA, 2024 Supplemental material is available for this article.}, } @article {pmid39287472, year = {2024}, author = {Kasperkiewicz, M}, title = {Letter to the Editor: Comment on Bocanegra-Oyola et al's "Clinical Characteristics of Ocular Mucous Membrane Pemphigoid: A Systematic Review and Meta-Analysis".}, journal = {Ocular immunology and inflammation}, volume = {32}, number = {10}, pages = {2622-2623}, doi = {10.1080/09273948.2024.2404105}, pmid = {39287472}, issn = {1744-5078}, mesh = {Humans ; Diagnosis, Differential ; *Pemphigoid, Benign Mucous Membrane/diagnosis ; Meta-Analysis as Topic ; }, abstract = {The work by Bocanegra-Oyola et al. provides a qualitative analysis and meta-analysis of ocular pemphigoid characteristics. This correspondence discusses the need for diagnostic process optimization to better differentiate between ocular pemphigoid and its mimicker pseudopemphigoid.}, } @article {pmid39286440, year = {2024}, author = {Kew, SYN and Mok, SY and Goh, CH}, title = {Machine learning and brain-computer interface approaches in prognosis and individualized care strategies for individuals with amyotrophic lateral sclerosis: A systematic review.}, journal = {MethodsX}, volume = {13}, number = {}, pages = {102765}, pmid = {39286440}, issn = {2215-0161}, abstract = {Amyotrophic lateral sclerosis (ALS) characterized by progressive degeneration of motor neurons is a debilitating disease, posing substantial challenges in both prognosis and daily life assistance. However, with the advancement of machine learning (ML) which is renowned for tackling many real-world settings, it can offer unprecedented opportunities in prognostic studies and facilitate individuals with ALS in motor-imagery tasks. ML models, such as random forests (RF), have emerged as the most common and effective algorithms for predicting disease progression and survival time in ALS. The findings revealed that RF models had an excellent predictive performance for ALS, with a testing R2 of 0.524 and minimal treatment effects of 0.0717 for patient survival time. Despite significant limitations in sample size, with a maximum of 18 participants, which may not adequately reflect the population diversity being studied, ML approaches have been effectively applied to ALS datasets, and numerous prognostic models have been tested using neuroimaging data, longitudinal datasets, and core clinical variables. In many literatures, the constraints of ML models are seldom explicitly enunciated. Therefore, the main objective of this research is to provide a review of the most significant studies on the usage of ML models for analyzing ALS. This review covers a variation of ML algorithms involved in applications in ALS prognosis besides, leveraging ML to improve the efficacy of brain-computer interfaces (BCIs) for ALS individuals in later stages with restricted voluntary muscular control. The key future advances in individualized care and ALS prognosis may include the advancement of more personalized care aids that enable real-time input and ongoing validation of ML in diverse healthcare contexts.}, } @article {pmid39286389, year = {2024}, author = {Willman, M and Patel, G and Lucke-Wold, B}, title = {T lymphocyte proportion in Alzheimer's disease prognosis.}, journal = {World journal of clinical cases}, volume = {12}, number = {26}, pages = {6001-6003}, pmid = {39286389}, issn = {2307-8960}, abstract = {Bai et al investigate the predictive value of T lymphocyte proportion in Alzheimer's disease (AD) prognosis. Through a retrospective study involving 62 AD patients, they found that a decrease in T lymphocyte proportion correlated with a poorer prognosis, as indicated by higher modified Rankin scale scores. While the study highlights the potential of T lymphocyte proportion as a prognostic marker, it suggests the need for larger, multicenter studies to enhance generalizability and validity. Additionally, future research could use cognitive exams when evaluating prognosis and delve into immune mechanisms underlying AD progression. Despite limitations inherent in retrospective designs, Bai et al's work contributes to understanding the immune system's role in AD prognosis, paving the way for further exploration in this under-researched area.}, } @article {pmid39283513, year = {2024}, author = {Koopmann, A and Hoffmann, S and Riegler, A and Cordes, J and Kiefer, F}, title = {[Factors influencing hospital readmission rates in alcohol use disorder].}, journal = {Der Nervenarzt}, volume = {}, number = {}, pages = {}, pmid = {39283513}, issn = {1433-0407}, abstract = {BACKGROUND: According to data from the Federal Statistical Office, the diagnosis of alcohol use disorder (AUD) (F 10) is the second most common main diagnosis for hospital treatment. Those affected by this disorder are often repeatedly hospitalized at short intervals due to relapses; however, little is known about the factors that influence readmission rates after initial treatment.

AIM OF THE STUDY: The aim of this retrospective analysis is to analyze the effects of treatment type (qualified withdrawal treatment (QE) versus physical detoxification) and discharge mode on the probability of readmission in alcohol-dependent patients after inpatient treatment.

MATERIAL AND METHODS: Data from 981 male and female alcohol-dependent patients who completed either qualified withdrawal treatment (QE) (68% men; mean age 47.6 years) or inpatient detoxification (74% men; mean age 48.0 years) were analyzed. Predictors of regular discharge were determined separately for both types of treatment using stepwise logistic regression.

RESULTS: Patients who had completed a qualified withdrawal treatment were significantly more likely to be regularly discharged. Regular completion of the qualified withdrawal treatment (QE) led to a relative reduction in the readmission rate of 25.64% within 1 year compared to a physical detoxification.

CONCLUSION: In order to prevent readmission and chronic courses of alcohol use disorder (AUD), qualified withdrawal treatment should always be recommended to affected patients instead of physical detoxification. Aktuelle Daten des Statistischen Bundesamtes für das Jahr 2022 zeigen, dass die Diagnose "Psychische und Verhaltensstörungen durch Alkohol (F 10.X)" die zweithäufigste Hauptdiagnose bei Krankenhausbehandlungen darstellt [13]. Im Gesundheitssystem entstehen durch dieses Erkrankungsbild und seine somatischen und psychischen Folgeerkrankungen jährlich ca. 10 Mrd. € direkte Kosten [13]. Dieser Sachverhalt wird dadurch kontrastiert, dass die Krankenkassen die qualifizierte Entzugsbehandlung (QE) als leitliniengerechte Goldstandardtherapie [4] wiederholt infrage stellen [10].}, } @article {pmid39283487, year = {2024}, author = {Zufiría, M and Pikatza-Menoio, O and Garciandia-Arcelus, M and Bengoetxea, X and Jiménez, A and Elicegui, A and Levchuk, M and Arnold-García, O and Ondaro, J and Iruzubieta, P and Rodríguez-Gómez, L and Fernández-Pelayo, U and Muñoz-Oreja, M and Aiastui, A and García-Verdugo, JM and Herranz-Pérez, V and Zulaica, M and Poza, JJ and Ruiz-Onandi, R and Fernández-Torrón, R and Espinal, JB and Bonilla, M and Lersundi, A and Fernández-Eulate, G and Riancho, J and Vallejo-Illarramendi, A and Holt, IJ and Sáenz, A and Malfatti, E and Duguez, S and Blázquez, L and López de Munain, A and Gerenu, G and Gil-Bea, F and Alonso-Martín, S}, title = {Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {148}, number = {1}, pages = {43}, pmid = {39283487}, issn = {1432-0533}, support = {CB06/05/1126//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; PI2020/08-1//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; P18/01066//Instituto de Salud Carlos III/ ; PI19/00175//Instituto de Salud Carlos III/ ; PI21/00153//Instituto de Salud Carlos III/ ; PI22/00433//Instituto de Salud Carlos III/ ; IJC2019-039965-I//Instituto de Salud Carlos III/ ; 2020-CIEN-000057-01//Diputación Foral de Gipuzkoa/ ; 2021-CIEN-000020-01//Diputación Foral de Gipuzkoa/ ; 2019-FELL-000010-01//Diputación Foral de Gipuzkoa/ ; 2020-FELL-000016-02-01//Diputación Foral de Gipuzkoa/ ; 2021-FELL-000013-02-01//Diputación Foral de Gipuzkoa/ ; BIO17/ND/023/BD//EiTB Maratoia/ ; 2015111122//Osasun Saila, Eusko Jaurlaritzako/ ; 2017222027//Osasun Saila, Eusko Jaurlaritzako/ ; 2018111042//Osasun Saila, Eusko Jaurlaritzako/ ; 2019222020//Osasun Saila, Eusko Jaurlaritzako/ ; 2020111032//Osasun Saila, Eusko Jaurlaritzako/ ; 2020333043//Osasun Saila, Eusko Jaurlaritzako/ ; 2021333050//Osasun Saila, Eusko Jaurlaritzako/ ; PRE_2015_1_0023//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2019_1_0339//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2020_1_0122//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2020_1_0191//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2020_1_0119//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2018_1_0095//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2021_1_0125//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2018_1_0253//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; NEURODEGENPROT//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PIF18/317//Euskal Herriko Unibertsitatea/ ; RYC2018-024397-I//Spanish National Plan for Scientific and Technical Research and Innovation/ ; RF/2019/001//Ikerbasque, Basque Foundation for Science/ ; RF/2023/010//Ikerbasque, Basque Foundation for Science/ ; PP/2022/003//Ikerbasque, Basque Foundation for Science/ ; BIO19/ROCHE/017/BD//Roche España/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; Animals ; *Muscle, Skeletal/metabolism/pathology ; *Forkhead Box Protein O1/metabolism/genetics ; DNA-Binding Proteins/genetics/metabolism ; Male ; RNA-Binding Protein FUS/genetics/metabolism ; Female ; Drosophila ; Muscle Development/physiology ; Middle Aged ; Aged ; Motor Neurons/metabolism/pathology ; Myoblasts/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as TARDBP (TDP-43) and FUS. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (TBPH or caz) in Drosophila muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by foxo inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.}, } @article {pmid39282230, year = {2024}, author = {Tsai, YC and Brown, KA and Bernardi, MT and Harting, J and Clelland, CD}, title = {Single-Molecule Sequencing of the C9orf72 Repeat Expansion in Patient iPSCs.}, journal = {Bio-protocol}, volume = {14}, number = {17}, pages = {e5060}, pmid = {39282230}, issn = {2331-8325}, abstract = {A hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). C9orf72 repeat expansions are currently identified with long-range PCR or Southern blot for clinical and research purposes, but these methods lack accuracy and sensitivity. The GC-rich and repetitive content of the region cannot be amplified by PCR, which leads traditional sequencing approaches to fail. We turned instead to PacBio single-molecule sequencing to detect and size the C9orf72 repeat expansion without amplification. We isolated high molecular weight genomic DNA from patient-derived iPSCs of varying repeat lengths and then excised the region containing the C9orf72 repeat expansion from naked DNA with a CRISPR/Cas9 system. We added adapters to the cut ends, capturing the target region for sequencing on PacBio's Sequel, Sequel II, or Sequel IIe. This approach enriches the C9orf72 repeat region without amplification and allows the repeat expansion to be consistently and accurately sized, even for repeats in the thousands. Key features • This protocol is adapted from PacBio's previous "no-amp targeted sequencing utilizing the CRISPR-Cas9 system." • Optimized for sizing C9orf72 repeat expansions in patient-derived iPSCs and applicable to DNA from any cell type, blood, or tissue. • Requires high molecular weight naked DNA. • Compatible with Sequel I and II but not Revio.}, } @article {pmid39281855, year = {2024}, author = {Jones, VM and Thompson, LDR and Pettus, JR and Green, DC and Lefferts, JA and Shah, PS and Tsongalis, GJ and Sajed, DP and Guilmette, JM and Lewis, JS and Fisch, AS and Tafe, LJ and Kerr, DA}, title = {Angiomyolipomatous Lesions of the Nasal Cavity (Sinonasal Angioleiomyoma with Adipocytic Differentiation): A Multi-Institutional Immunohistochemical and Molecular Study.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39281855}, issn = {2693-5015}, support = {P30 CA023108/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Mesenchymal neoplasms composed of vascular, smooth muscle, and adipocytic components are uncommon in the nasal cavity. While angioleiomyoma (AL) is a smooth muscle tumor in the Head & Neck WHO classification, it is considered of pericytic origin in the Skin as well as Soft Tissue and Bone classifications. For nasal AL with an adipocytic component, the terms AL with adipocytic differentiation and angiomyolipoma (AML) have been applied, among others. AML is a type of perivascular epithelioid cell tumor (PEComa), most often arising in the kidney, sometimes associated with the tuberous sclerosis complex (TSC). It is uncertain whether nasal cavity AML and AL are best considered hamartomas or neoplasms, as their genetics are largely unexplored.

METHODS: We performed a multi-institutional retrospective study of nasal cavity mesenchymal lesions. Patient demographics, clinical histories, and histologic and immunohistochemical findings were collected. DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissue and analyzed by SNP-based chromosomal microarray, targeted RNA fusion sequencing, and whole-exome sequencing.

RESULTS: Fifteen lesions (3 to 42 mm) were identified predominantly in male (87%) patients with a median age of 60. Patients typically presented with obstructive symptoms, and none had a history of TSC. One AL was a recurrence from six years prior; 11 cases showed no recurrence (median 4.7 years, range: 0.88-12.4). Morphologically, 11 AMLs contained 30-80% smooth muscle, 10-25% vasculature, and 2-60% adipose tissue, while four ALs contained 70-80% smooth muscle and 20-30% vasculature. Other histologic observations included surface ulceration, vascular thrombosis, chronic inflammation, and myxoid change; no well-developed epithelioid cell morphology was identified. Immunohistochemically, all cases were positive for smooth muscle markers (actin and/or desmin) and negative for melanocytic markers. Molecular analysis revealed loss of 3p and 11q in a single AML. No other known pathogenic copy number or molecular alterations were seen, including in TSC1/2, TFE3, or NOTCH2.

CONCLUSION: Nasal cavity AML lacks morphologic, immunophenotypic, and genetic features of PEComa family AMLs. The significant histologic overlap between nasal AML and AL without distinguishing molecular features in either entity suggests "sinonasal angioleiomyoma with adipocytic differentiation" may be the most appropriate terminology for hybrid vascular and smooth muscle lesions containing adipocytic components.}, } @article {pmid39280885, year = {2024}, author = {Robinson, SE and Findlay, AR and Li, S and Wang, F and Schiava, M and Daw, J and Diaz-Manera, J and Chou, TF and Weihl, CC}, title = {Elevated VCP ATPase Activity Correlates With Disease Onset in Multisystem Proteinopathy-1.}, journal = {Neurology. Genetics}, volume = {10}, number = {5}, pages = {e200191}, pmid = {39280885}, issn = {2376-7839}, support = {K24 AR073317/AR/NIAMS NIH HHS/United States ; R01 AG031867/AG/NIA NIH HHS/United States ; }, abstract = {OBJECTIVES: Multisystem proteinopathy-1 (MSP1) is a late onset disease with >50 pathogenic variants in p97/VCP. MSP1 patients have multiple phenotypes that include inclusion body myopathy, Paget disease of the bone, amyotrophic lateral sclerosis, and frontotemporal dementia. There have been no clear genotype-phenotype correlations. We sought to identify genotype-phenotype correlations and associate these with VCP intrinsic ATPase activity.

METHODS: Patients with MSP1 were identified from the literature and the Cure VCP patient registry. Age at onset and at loss of ambulation were collated. VCP intrinsic ATPase activity was evaluated from recombinant purified protein.

RESULTS: Among the 5 most common pathogenic VCP variants in MSP1 patients, R155C patients had the earliest average age at onset (38.15 ± 9.78). This correlated with higher ATPase activity. Evaluation of 5 variants confirmed an inverse correlation between age at onset and ATPase activity (r = -0.94, p = 0.01).

DISCUSSION: Previous studies have reported that VCP pathogenic variants are "hyperactive." Whether this elevation in VCP ATPase activity is relevant to disease is unclear. Our study supports that in vitro VCP activity correlates with disease onset and may guide the prognosis of patients with rare or unreported variants. Moreover, it suggests that inhibition of VCP ATPase activity in MSP1 may be therapeutic.}, } @article {pmid39280794, year = {2024}, author = {Ren, K and Wang, Q and Jiang, D and Liu, E and Alsmaan, J and Jiang, R and Rutkove, SB and Tian, F}, title = {A comprehensive review of electrophysiological techniques in amyotrophic lateral sclerosis research.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1435619}, pmid = {39280794}, issn = {1662-5102}, support = {R01 NS055099/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, is characterized by progressive motor neuron degeneration, leading to widespread weakness and respiratory failure. While a variety of mechanisms have been proposed as causes of this disease, a full understanding remains elusive. Electrophysiological alterations, including increased motor axon excitability, likely play an important role in disease progression. There remains a critical need for non-animal disease models that can integrate electrophysiological tools to better understand underlying mechanisms, track disease progression, and evaluate potential therapeutic interventions. This review explores the integration of electrophysiological technologies with ALS disease models. It covers cellular and clinical electrophysiological tools and their applications in ALS research. Additionally, we examine conventional animal models and highlight advancements in humanized models and 3D organoid technologies. By bridging the gap between these models, we aim to enhance our understanding of ALS pathogenesis and facilitate the development of new therapeutic strategies.}, } @article {pmid39280372, year = {2024}, author = {Nishiwaki, T and Oya, A and Fujie, A and Kanaji, A}, title = {Higher Incidence of Venous Thromboembolism in Anterolateral Approach in Lateral Position Compared to Anterolateral Supine and Direct Anterior Approaches in Minimally Invasive Total Hip Arthroplasty.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e66831}, pmid = {39280372}, issn = {2168-8184}, abstract = {INTRODUCTION: Venous thromboembolism (VTE) remains a major complication after total hip arthroplasty (THA), irrespective of the surgical approach. This study investigated the incidence of VTE in patients undergoing THA through intermuscular minimally invasive surgical techniques, which included a direct anterior approach (DAA), an anterolateral approach (AL), and an anterolateral supine approach (ALS), at a single institution.

METHODS: A hundred consecutive patients treated with each surgical approach were evaluated. Plasma D-dimer levels one month preoperatively and one day postoperatively, operative time, and intraoperative blood loss were recorded, and the presence of VTE was evaluated based on multidetector-row computed tomography performed the day after surgery. Student's t-test and Pearson's chi-square test or one-way analysis of variance were used in statistical analysis.

RESULTS: No differences among the groups in terms of age, height, weight, operative time, intraoperative bleeding, and preoperative and postoperative D-dimer levels were observed. The overall incidence of VTE was 21%. The incidences of VTE were 30% in AL, 17% in ALS, and 16% in DAA, representing a significantly higher rate in AL than in ALS and DAA (P=0.025). The incidences of VTE on the operated side were 19% in AL, 13% in ALS, and 12% in DAA, with no statistically significant differences. The incidences of VTE on the non-operated side were 22% in AL, 9% in ALS, and 8% in DAA; these differences were statistically significant (P=0.0045).

DISCUSSION: Results showed that the incidence of VTE was significantly higher in AL than in ALS and DAA, especially for the non-operated side.}, } @article {pmid39280119, year = {2024}, author = {Banack, SA and Dunlop, RA and Mehta, P and Mitsumoto, H and Wood, SP and Han, M and Cox, PA}, title = {A microRNA diagnostic biomarker for amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae268}, pmid = {39280119}, issn = {2632-1297}, abstract = {Blood-based diagnostic biomarkers for amyotrophic lateral sclerosis will improve patient outcomes and positively impact novel drug development. Critical to the development of such biomarkers is robust method validation, optimization and replication with adequate sample sizes and neurological disease comparative blood samples. We sought to test an amyotrophic lateral sclerosis biomarker derived from diverse samples to determine if it is disease specific. Extracellular vesicles were extracted from blood plasma obtained from individuals diagnosed with amyotrophic lateral sclerosis, primary lateral sclerosis, Parkinson's disease and healthy controls. Immunoaffinity purification was used to create a neural-enriched extracellular vesicle fraction. MicroRNAs were measured across sample cohorts using real-time polymerase chain reaction. A Kruskal-Wallis test was used to assess differences in plasma microRNAs followed by post hoc Mann-Whitney tests to compare disease groups. Diagnostic accuracy was determined using a machine learning algorithm and a logistic regression model. We identified an eight-microRNA diagnostic signature for blood samples from amyotrophic lateral sclerosis patients with high sensitivity and specificity and an area under the curve calculation of 98% with clear statistical separation from neurological controls. The eight identified microRNAs represent disease-related biological processes consistent with amyotrophic lateral sclerosis. The direction and magnitude of gene fold regulation are consistent across four separate patient cohorts with real-time polymerase chain reaction analyses conducted in two laboratories from diverse samples and sample collection procedures. We propose that this diagnostic signature could be an aid to neurologists to supplement current clinical metrics used to diagnose amyotrophic lateral sclerosis.}, } @article {pmid39279312, year = {2024}, author = {Banaszak-Ziemska, M and Rojek, A and Niedziela, M}, title = {Genetic analysis of the PAPP-A2 gene and evaluation of free IGF-1, IGFBP-5, and ALS concentrations in a group of 22 patients with idiopathic short stature.}, journal = {Endokrynologia Polska}, volume = {75}, number = {4}, pages = {428-437}, doi = {10.5603/ep.100030}, pmid = {39279312}, issn = {2299-8306}, mesh = {Humans ; *Pregnancy-Associated Plasma Protein-A/genetics/metabolism/analysis ; Female ; *Insulin-Like Growth Factor I/genetics/analysis/metabolism ; Male ; Child ; Adolescent ; *Insulin-Like Growth Factor Binding Protein 5/genetics ; Carrier Proteins/genetics ; Glycoproteins/genetics/blood ; Growth Disorders/genetics/blood ; Mutation ; Child, Preschool ; }, abstract = {INTRODUCTION: Short stature is one of the main reasons for consultation in outpatient clinics and paediatric endocrinology departments and is defined as height below the 3rd centile or less than -2 standard deviations (SDs).

MATERIAL AND METHODS: The study's overarching aim was to analyse the PAPP-A2 gene at mutation sites described to date and at exons 3, 4, and 5, which encode the fragment of the catalytic domain with the active site of the pregnancy-associated plasma protein A2 (PAPP-A2) protein. The secondary aims of the study were clinical and auxological analysis of a group of patients with idiopathic short stature and biochemical analysis of growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis parameters not assessed as part of the routine diagnosis of short stature, such as free IGF-1, insulin-like growth factor binding protein 5 (IGFBP-5), and acid-labile subunit (ALS) levels. Molecular analysis of the PAPP-A2 gene was performed using polymerase chain reaction (PCR) and direct sequencing. Biochemical analysis of free IGF-1, IGFBP-5, and ALS was performed by enzyme-linked immunosorbent assay (ELISA).

RESULTS: The mean height standard deviation score (HSDS) in the study group was -2.95. None of the patients exhibited previously described mutations in the PAPP-A2 gene or mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein. In 4 patients, the known, non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 was found.

CONCLUSIONS: Free IGF-1 levels correlate better with height and HSDS than total IGF-1 levels. The previously described mutations in the PAPP-A2 gene and mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein were not detected; only the known and non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 of the PAPP-A2 gene was observed.}, } @article {pmid39279053, year = {2024}, author = {Lin, PH and Yao, HY and Huang, L and Fu, CC and Yao, XL and Lian, C and Zhang, SF and Lai, WD and Lin, GY and Liao, S and Yang, J and Mao, ZF and Liu, D and Long, BY and Yue, JJ and Gao, C and Long, YM}, title = {Autoimmune astrocytopathy double negative for AQP4-IgG and GFAP-IgG: Retrospective research of clinical practice, biomarkers, and pathology.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {9}, pages = {e70042}, pmid = {39279053}, issn = {1755-5949}, support = {2022A1515110143//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023A1515010225//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2022-LCYJ-YYDZX-04//Multi-center Project of The Second Affiliated Hospital of Guangzhou Medical University/ ; }, mesh = {Humans ; *Glial Fibrillary Acidic Protein/cerebrospinal fluid/immunology ; Female ; Male ; *Aquaporin 4/immunology ; Middle Aged ; *Astrocytes/immunology/metabolism/pathology ; Retrospective Studies ; Adult ; *Biomarkers/cerebrospinal fluid/blood ; Aged ; *Immunoglobulin G/cerebrospinal fluid/blood ; Neurofilament Proteins/cerebrospinal fluid/blood ; Autoantibodies/cerebrospinal fluid/blood ; Young Adult ; Adolescent ; }, abstract = {OBJECTIVE: The objective of this study is to investigate the presence of astrocyte antibodies in patients, excluding aquaporin-4 or glial fibrillary acidic protein (GFAP) antibodies, while evaluating associated biomarkers and pathologies.

METHODS: Patient serum and cerebrospinal fluid (CSF) were tested for antibodies using tissue- and cell-based assays. Neurofilament light chain (NFL) and GFAP in the CSF were detected using single-molecule array (SIMOA).

RESULTS: 116 patients accepted SIMOA. Fifteen functional neurological disorders patients without antibodies were designated as controls. Thirty-five patients were positive for astrocyte antibodies (Anti-GFAP: 7; Anti-AQP4: 7; unknown antibodies: 21, designed as the double-negative group, DNAP). The most frequent phenotype of DNAP was encephalitis (42.9%), followed by myelitis (23.8%), movement disorders (19.0%), and amyotrophic lateral sclerosis-like (ALS-like) disease (14.2%). The levels of CSF GFAP and NFL in DNAP were higher than in the control (GFAP: 1967.29 [776.60-13214.47] vs 475.38 [16.80-943.60] pg/mL, p < 0.001; NFL: 549.11 [162.08-2462.61] vs 214.18 [81.60-349.60] pg/mL, p = 0.002). GFAP levels decreased in DNAP (n = 5) after immunotherapy (2446.75 [1583.45-6277.33] vs 1380.46 [272.16-2005.80] pg/mL, p = 0.043), while there was no difference in NFL levels (2273.78 [162.08-2462.61] vs 890.42 [645.06-3168.06] pg/mL, p = 0.893). Two brain biopsy patterns were observed: one exhibited prominent tissue proliferation and hypertrophic astrocytes, with local loss of astrocytes, while the other showed severe astrocyte depletion with loss of neurofilaments around the vessels. Eighteen patients received immunotherapy, and improved except one with ALS-like symptoms. We identified anti-vimentin in this patient.

DISCUSSION: There are unidentified astrocyte antibodies. The manifestations of double-negativity are heterogeneous; nevertheless, the pathology and biomarkers remain consistent with astrocytopathy. Immunotherapy is effective.}, } @article {pmid39278909, year = {2024}, author = {Reis, ALG and Maximino, JR and Lage, LAPC and Gomes, HR and Pereira, J and Brofman, PRS and Senegaglia, AC and Rebelatto, CLK and Daga, DR and Paiva, WS and Chadi, G}, title = {Proteomic analysis of cerebrospinal fluid of amyotrophic lateral sclerosis patients in the presence of autologous bone marrow derived mesenchymal stem cells.}, journal = {Stem cell research & therapy}, volume = {15}, number = {1}, pages = {301}, pmid = {39278909}, issn = {1757-6512}, support = {401922/2014-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 836458/2016//Ministério da Saúde/ ; 1701/22//Financiadora de Estudos e Projetos/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/therapy/metabolism ; Apolipoprotein A-I/cerebrospinal fluid/metabolism ; Apolipoproteins E/metabolism/genetics/cerebrospinal fluid ; Bone Marrow Cells/metabolism ; *Mesenchymal Stem Cell Transplantation/methods ; *Mesenchymal Stem Cells/metabolism ; Protein Interaction Maps ; *Proteomics/methods ; *Transplantation, Autologous ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressive motoneuron degenerative disorder. There are still no drugs capable of slowing disease evolution or improving life quality of ALS patients. Thus, autologous stem cell therapy has emerged as an alternative treatment regime to be investigated in clinical ALS.

METHOD: Using Proteomics and Protein-Protein Interaction Network analyses combined with bioinformatics, the possible cellular mechanisms and molecular targets related to mesenchymal stem cells (MSCs, 1 × 10[6] cells/kg, intrathecally in the lumbar region of the spine) were investigated in cerebrospinal fluid (CSF) of ALS patients who received intrathecal infusions of autologous bone marrow-derived MSCs thirty days after cell therapy. Data are available via ProteomeXchange with identifier PXD053129.

RESULTS: Proteomics revealed 220 deregulated proteins in CSF of ALS subjects treated with MSCs compared to CSF collected from the same patients prior to MSCs infusion. Bioinformatics enriched analyses highlighted events of Extracellular matrix and Cell adhesion molecules as well as related key targets APOA1, APOE, APP, C4A, C5, FGA, FGB, FGG and PLG in the CSF of cell treated ALS subjects.

CONCLUSIONS: Extracellular matrix and cell adhesion molecules as well as their related highlighted components have emerged as key targets of autologous MSCs in CSF of ALS patients.

TRIAL REGISTRATION: Clinicaltrial.gov identifier NCT0291768. Registered 28 September 2016.}, } @article {pmid39277385, year = {2024}, author = {Porri, A and Panozzo, S and Tekeste Sisay, M and Scarabel, L and Lerchl, J and Milani, A}, title = {3D structure of acetolactate synthase explains why the Asp-376-Glu point mutation does not give the same resistance level to different imidazolinone herbicides.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106070}, doi = {10.1016/j.pestbp.2024.106070}, pmid = {39277385}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism/chemistry ; *Herbicides/pharmacology/chemistry ; *Herbicide Resistance/genetics ; *Imidazoles/pharmacology/chemistry ; *Amaranthus/drug effects/genetics ; *Point Mutation ; Sorghum/genetics/drug effects ; Molecular Docking Simulation ; Plant Proteins/genetics/metabolism/chemistry ; Nicotinic Acids/pharmacology ; Niacin/analogs & derivatives ; }, abstract = {Resistance to ALS-inhibiting herbicides has dramatically increased worldwide due to the persisting evolution of target site mutations that reduce the affinity between the herbicide and the target. We evaluated the effect of the well-known ALS Asp-376-Glu target site mutation on different imidazolinone herbicides, including imazamox and imazethapyr. Greenhouse dose response experiments indicate that the Amaranthus retroflexus biotype carrying Asp-376-Glu was fully controlled by applying the field recommended dose of imazamox, whereas it displayed high level of resistance to imazethapyr. Likewise, Sorghum halepense, carrying Asp-376-Glu showed resistance to field recommended doses of imazethapyr but not of imazamox. Biochemical inhibition and kinetic characterization of the Asp-376-Glu mutant enzyme heterologously expressed using different plant sequence backbones, indicate that the Asp-376-Glu shows high level of insensitivity to imazethapyr but not to imazamox, corroborating the greenhouse results. Docking simulations revealed that imazamox can still inhibit the Asp-376-Glu mutant enzyme through a chalcogen interaction between the oxygen of the ligand and the sulfur atom of the ALS Met200, while imazethapyr does not create such interaction. These results explain the different sensitivity of the Asp-376-Glu mutation towards imidazolinone herbicides, thus providing novel information that can be exploited for defining stewardship guidelines to manage fields infested by weeds harboring the Asp-376-Glu mutation.}, } @article {pmid39277366, year = {2024}, author = {Weng, WF and Yao, X and Zhao, M and Fang, Z and Yang, S and Ruan, JJ}, title = {Novel mutations in acetolactate synthase confer high levels of resistance to tribenuron-methyl in Fagopyrum tataricum.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106039}, doi = {10.1016/j.pestbp.2024.106039}, pmid = {39277366}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Fagopyrum/genetics/drug effects ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Arylsulfonates/pharmacology ; *Mutation ; Plant Proteins/genetics/metabolism ; }, abstract = {Tartary buckwheat (Fagopyrum tataricum) field weeds are rich in species, with many weeds causing reduced quality, yield, and crop failure. The selection of herbicide-resistant Tartary buckwheat varieties, while applying low-toxicity and efficient herbicides as a complementary weed control system, is one way to improve Tartary buckwheat yield and quality. Therefore, the development of herbicide-resistant varieties is important for the breeding of Tartary buckwheat. In this experiment, 50 mM ethyl methyl sulfonate solution was used to treat Tartary buckwheat seeds (M1) and then planted in the field. Harvested seeds (M2) were planted in the experiment field of Guizhou University, and when seedlings had 5-7 leaves, the seedlings were sprayed with 166 mg/L tribenuron-methyl (TBM). A total of 15 resistant plants were obtained, of which three were highly resistant. Using the homologous cloning method, an acetolactate synthase (ALS) gene encoding 547 amino acids was identified in Tartary buckwheat. A GTG (valine) to GGA (glycine) mutation (V409G) occurred at position 409 of the ALS gene in the high tribenuron-methyl resistant mutant sm113. The dm36 mutant harbored a double mutation, a deletion mutation at position 405, and a GTG (valine) to GGA (glycine) mutation (V411G) at position 411. The dm110 mutant underwent a double mutation: an ATG (methionine) to AGG (arginine) mutation (M333R) at position 333 and an insertion mutation at position 372. The synthesis of Chl a, Chl b, total Chl, and Car was significantly inhibited by TBM treatment. TBM was more efficient at suppressing the growth of wild-type plants than that of mutant plants. Antioxidant enzyme activities such as ascorbate peroxidase, peroxidase, and superoxide dismutase were significantly higher in resistant plants than in wild-type after spraying with TBM; malondialdehyde content was significantly lower than in wild-type plants after spraying with TBM. Plants with a single-site mutation in the ALS gene could survive, but their growth was affected by herbicide application. In contrast, plants with dual-site mutations in the ALS gene were not affected, indicating that plants with dual-site mutations in the ALS gene showed higher levels of resistance than plants with a single-site mutation in the ALS gene.}, } @article {pmid39277365, year = {2024}, author = {Guan, Y and Liu, L and Zou, Y and Yang, C and Ji, M}, title = {Involvement of P450s in the metabolic resistance of Digitaria sanguinalis (L.) Scop. To ALS-inhibiting herbicides.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106038}, doi = {10.1016/j.pestbp.2024.106038}, pmid = {39277365}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology/toxicity ; *Acetolactate Synthase/metabolism/genetics/antagonists & inhibitors ; *Herbicide Resistance/genetics ; *Cytochrome P-450 Enzyme System/metabolism/genetics ; *Digitaria/drug effects ; Sulfonylurea Compounds/pharmacology ; Plant Weeds/drug effects/metabolism ; Plant Proteins/genetics/metabolism ; Pyridines ; }, abstract = {Weed resistance to a range of herbicides has rapidly evolved, often with different mechanisms of action. The resulting uninhibited growth of weeds poses demonstrable threats to crop production and sustainable agriculture. Digitaria sanguinalis (L.) Scop., a troublesome weed in corn and other agricultural fields, has developed resistance to herbicides that inhibiting ALS (Acetolactate Synthase), such as nicosulfuron. Understanding the weed's resistance patterns and mechanisms is crucial. However, little is known of the non-target site resistance (NTSR) mechanisms of D. sanguinalis owing to a lack of relevant genome sequences and other materials. Therefore, in this study, a population of D.sanguinalis presenting multiple resistance was tested and found that its high level of resistance to ALS-inhibiting herbicides was not associated with target-related alterations.Administration of P450 inhibitors reversed the resistance to ALS-inhibiting herbicides. Following the application of ALS-inhibiting herbicides, the activities of NADPH-P450 reductase and p-nitroanisole O-demethylase (PNOD) were notably greater in the resistant population of D. sanguinalis than those in the susceptible population. The results suggested P450 enzyme familyplays a major role in the metabolic resistance mechanism, that increased P450 enzyme activity promote cross-resistance in D. sanguinalis to ALS-inhibiting herbicides. RNA-seq analysis showed that five genes from the P450 family (CYP709B2, CYP714C2, CYP71A1, CYP76C2, and CYP81E8) were upregulated in resistant D. sanguinalis. In conclusion, the upregulation of several P450 genes is responsible for establishing resistance to ALS-inhibiting herbicides in D. sanguinalis.}, } @article {pmid39277361, year = {2024}, author = {Liu, L and Zou, Y and Guan, Y and Yang, C and Ji, M}, title = {Diverse mechanisms confer bensulfuron-methyl resistance in Schoenoplectiella juncoides (Roxb.) lye.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106034}, doi = {10.1016/j.pestbp.2024.106034}, pmid = {39277361}, issn = {1095-9939}, mesh = {*Sulfonylurea Compounds/pharmacology ; Herbicide Resistance/genetics ; Herbicides/pharmacology ; Mutation ; Glutathione Transferase/metabolism/genetics ; }, abstract = {The effectiveness of bensulfuron-methyl in controlling Schoenoplectiella juncoides (Roxb.) Lye has significantly decreased in rice fields in China. Hence, a bensulfuron-methyl-resistant S. juncoides population (W15) was collected from Dandong City, Liaoning Province, China, to investigate the underlying resistance mechanisms. Whole-plant dose-response experiments and ALS activity assay confirmed that W15 has evolved high-level resistance to bensulfuron-methyl compared with the susceptible S. juncoides population (W4). Molecular analysis revealed a Pro-197-Ser mutation in ALS1, while there was no significant difference in the relative ALS gene expression between W15 and W4. LC-MS/MS analysis showed W15 metabolized bensulfuron-methyl more rapidly than W4. Furthermore, bensulfuron-methyl resistance in W15 was significantly alleviated by malathion and 4-chloro-7-nitrobenzoxadiazole (NBD-Cl). Glutathione S-transferase activity was higher in W15 than in W4. Meanwhile, W15 displayed cross-resistance to halosulfuron-methyl and multi-resistance to MCPA-Na. In summary, these findings demonstrated for the first time that both target- and non-target-site resistance are relevant in the resistance of S. juncoides to bensulfuron-methyl.}, } @article {pmid39268612, year = {2025}, author = {Meyer, T and Schumann, P and Grehl, T and Weyen, U and Petri, S and Rödiger, A and Steinbach, R and Grosskreutz, J and Bernsen, S and Weydt, P and Wolf, J and Günther, R and Vidovic, M and Baum, P and Metelmann, M and Weishaupt, JH and Streubel, B and Kasper, DC and Koc, Y and Kettemann, D and Norden, J and Schmitt, P and Walter, B and Münch, C and Spittel, S and Maier, A and Körtvélyessy, P}, title = {SOD1 gene screening in ALS - frequency of mutations, patients' attitudes to genetic information and transition to tofersen treatment in a multi-center program.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {162-171}, doi = {10.1080/21678421.2024.2401131}, pmid = {39268612}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/diagnosis ; *Superoxide Dismutase-1/genetics ; Male ; Female ; *Genetic Testing/methods ; Middle Aged ; *Mutation/genetics ; Aged ; Adult ; C9orf72 Protein/genetics ; Germany ; RNA-Binding Protein FUS/genetics ; DNA-Binding Proteins ; }, abstract = {OBJECTIVE: To report the frequency of pathogenic SOD1 gene variants in a screening program in amyotrophic lateral sclerosis (ALS), and the clinical practice of transition to an expanded access program (EAP) of tofersen treatment.

METHODS: From October 2021 to February 2024, at 11 ALS centers in Germany genetic testing for SOD1, FUS, TARDBP, and C9orf72 was performed. Patients were offered to opt for notification either about all genetic variants or SOD1 variants relevant for tofersen therapy. The transition to the EAP with tofersen was assessed.

RESULTS: 1935 patients were screened (94.7% sporadic ALS). 48.8% (n = 928) opted for notification of treatment-relevant information. Genetic variants were found as follows: SOD1 (likely) pathogenic variants (class 4/5) 1.8% (n = 34), variants of unknown significance (class 3) 0.8% (n = 16), FUS (class 4/5) 0.9% (n = 17), TARDBP (class 4/5) 1.3% (n = 25), C9orf72 hexanucleotide repeat expansion 7.0% (n = 135). In SOD1-ALS (encompassing class 3-5 variants, n = 50), 68.0% (n = 34) reported a negative family history. 74.0% (n = 37) of SOD1-ALS patients - which represent 1.9% of all participants of the screening program - were transitioned to tofersen. Median duration from start of genetic testing to treatment was 94 days (57 to 295 days). Eight patients declined treatment whereas five individuals died before initiation of therapy.

CONCLUSION: The finding of SOD1 variants in patients with a negative family history underscores the need for a broad genetic screening in ALS. In SOD1-ALS, the treatment option with tofersen was mostly utilized. The wide range in the transition time to tofersen calls for a SOD1-ALS management program.}, } @article {pmid39276073, year = {2025}, author = {Raymond, J and Berry, JD and Larson, T and Horton, DK and Mehta, P}, title = {Effects of COVID-19 on motor neuron disease mortality in the United States: a population-based cross-sectional study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {149-156}, doi = {10.1080/21678421.2024.2401621}, pmid = {39276073}, issn = {2167-9223}, mesh = {Humans ; *COVID-19/mortality/epidemiology ; United States/epidemiology ; Male ; *Motor Neuron Disease/mortality/epidemiology ; Female ; Aged ; Middle Aged ; Cross-Sectional Studies ; Adult ; Aged, 80 and over ; Young Adult ; SARS-CoV-2 ; }, abstract = {BACKGROUND: In March 2020, the World Health Organization declared the coronavirus disease 2019 (COVID-19) to be a pandemic, stating that those with underlying health conditions are most susceptible, including motor neuron disease (MND).

OBJECTIVE: To examine the effect the COVID-19 pandemic had on deaths from MND in the United States.

METHODS: Death certificate data for all MND deaths aged 20 years and older were analyzed from 2017 to 2019 (pre-COVID), then expanded to include 2020 and 2021 (COVID) deaths to evaluate if COVID-19 impacted MND deaths.

RESULTS: The average number of MND deaths documented during the COVID-19 years was 8009, up from 7485 MND deaths pre-COVID. The age-adjusted mortality rate among the non-Hispanic population increased during COVID to 2.78 per 100,000 persons (95% CI = 2.73-2.82) from 1.81 (95% CI = 1.78-1.84). The Hispanic population also saw an increase in mortality rate during COVID (1.61, 95% CI = 1.51-1.71) compared with pre-COVID (1.10, 95% CI = 1.03-1.17). Decedent's home as a place of death also saw a mortality rate increase during COVID (1.51, 95% CI = 1.48-1.54) compared with pre-COVID (1.30, 95% CI = 1.27-1.32). For the Hispanic population, the rate peaked at 80-84 years pre-COVID, but for the COVID years, the rate peaked earlier, at 75-79 years.

CONCLUSION: The total number of MND deaths was greater during COVID than in the preceding years. The analysis suggests there might have been a consequence of circumstances surrounding the global pandemic and the associated restrictions.}, } @article {pmid39275316, year = {2024}, author = {Hamm, JD and Laferrère, B and Albu, JB and Kini, S and Pi-Sunyer, X and Kissileff, HR}, title = {Responsiveness and Reliability of a Sipping Device to Measure Motivation in Normal-Weight Individuals and Bariatric Surgery Patients.}, journal = {Nutrients}, volume = {16}, number = {17}, pages = {}, pmid = {39275316}, issn = {2072-6643}, support = {R01 DK108643/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Motivation ; *Bariatric Surgery ; Female ; Male ; Adult ; Reproducibility of Results ; Middle Aged ; Obesity/surgery/psychology ; Taste ; Beverages ; Sweetening Agents ; Feeding Behavior/psychology ; }, abstract = {There is an urgent need to measure the motivation to taste a sweet fluid in order to determine the influence of sweet tastes on the potential choices and consumption of beverages in patients with obesity. Current methods utilize either survey instruments or arbitrary operant tasks. The sipometer enables the participant to utilize an actual ingestive behavioral response to measure motivation during access to beverages on either ad libitum (AL) or progressive time ratio (PR) schedules. We determined the sipometer's responsiveness and reliability as a test of change in motivation for sweet tastes after bariatric surgery. Participants (58 patients and 28 controls, BMI: 18.5-24.9 kg/m[2]) sham-consumed an aspartame-sweetened (S) and non-sweetened (N) beverage under AL and PR schedules at a pre-surgery/baseline and a 3-month and 24-month visit (patients only). Cumulative pressure (CumPres), a measure of effort, was the sum of the pressures exerted during sipping under each condition. Baseline CumPres for PRS was higher than ALS and ALN in patients (p < 0.03) and higher than PRN in controls (p = 0.009). At 3 months, CumPres did not differ amongst conditions in patients, but CumPres for PRS was higher than all other conditions in controls (p < 0.0005). There were no baseline group differences; however, patients' CumPres for PRS was lower than controls' at 3 months (p = 0.002). Patients' CumPres for PRS decreased non-significantly between the baseline and 3 months but increased at 24 months compared to 3 months (p = 0.025) and was no different from baseline. Controls' CumPres for PRS increased at 3 months (p = 0.0359), but CumPres for all conditions was correlated between visits (p's < 0.038). The sipometer is a reliable and sensitive measure of motivation to consume sweet beverages and may reflect changes in post-operative energy intake.}, } @article {pmid39273978, year = {2024}, author = {Wu, Z and Liu, S and Zhang, X and Qian, X and Chen, Z and Zhao, H and Wan, H and Yin, N and Li, J and Qu, C and Du, H}, title = {Genome-Wide Characterization of Alfin-like Genes in Brassica napus and Functional Analyses of BnaAL02 and BnaAL28 in Response to Nitrogen and Phosphorus Deficiency.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {17}, pages = {}, pmid = {39273978}, issn = {2223-7747}, support = {32072094//National Key Research and Development Program of China/ ; 2023NSCQ-MSX3166//Natural Science Foundation of Chongqing/ ; }, abstract = {Alfin-like proteins (ALs) form a plant-specific transcription factor (TF) gene family involved in the regulation of plant growth and development, and abiotic stress response. In this study, 30 ALs were identified in Brassica napus ecotype 'Zhongshuang 11' genome (BnaALs), and unevenly distributed on 15 chromosomes. Structural characteristic analysis showed that all of the BnaALs contained two highly conserved domains: the N terminal DUF3594 domain and the C-terminal PHD-finger domain. The BnaALs were classified into four groups (Group I-IV), supported by conserved intron-exon and protein motif structures in each group. The allopolyploid event between B. oleracea and B. rapa ancestors and the small-scale duplication events in B. napus both contributed to the large BnaALs expansion. The promoter regions of BnaALs contained multiple abiotic stress cis-elements. The BnaALs in I-IV groups were mainly expressed in cotyledon, petal, root, silique, and seed tissues, and the duplicated gene pairs shared highly similar expression patterns. RNA-seq and RT-qPCR analysis showed that BnaALs were obviously induced by low nitrogen (LN) and low phosphorus (LP) treatments in roots. Overexpressing BnaAL02 and BnaAL28 in Arabidopsis demonstrated their functions in response to LN and LP stresses. BnaAL28 enhanced primary roots' (PRs) length and lateral roots' (LRs) number under LP and LN conditions, where BnaAL02 can inhibit LR numbers under the two conditions. They can promote root hair (RH) elongation under LP conditions; however, they suppressed RH elongation under LN conditions. Our result provides new insight into the functional dissection of this family in response to nutrient stresses in plants.}, } @article {pmid39273694, year = {2024}, author = {Evangelisti, C and Ramadan, S and Orlacchio, A and Panza, E}, title = {Experimental Cell Models for Investigating Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {17}, pages = {}, pmid = {39273694}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/pathology/metabolism ; Animals ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Organoids/pathology ; Models, Biological ; }, abstract = {Experimental models play a pivotal role in biomedical research, facilitating the understanding of disease mechanisms and the development of novel therapeutics. This is particularly true for neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and motor neuron disease, which present complex challenges for research and therapy development. In this work, we review the recent literature about experimental models and motor neuron disease. We identified three main categories of models that are highly studied by scientists. In fact, experimental models for investigating these diseases encompass a variety of approaches, including modeling the patient's cell culture, patient-derived induced pluripotent stem cells, and organoids. Each model offers unique advantages and limitations, providing researchers with a range of tools to address complex biological questions. Here, we discuss the characteristics, applications, and recent advancements in terms of each model system, highlighting their contributions to advancing biomedical knowledge and translational research.}, } @article {pmid39273435, year = {2024}, author = {Di Chiano, M and Sallustio, F and Fiocco, D and Rocchetti, MT and Spano, G and Pontrelli, P and Moschetta, A and Gesualdo, L and Gadaleta, RM and Gallone, A}, title = {Psychobiotic Properties of Lactiplantibacillus plantarum in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {17}, pages = {}, pmid = {39273435}, issn = {1422-0067}, support = {1062//PON "RICERCA E INNOVAZIONE" 2014-2020-Innovazione/ ; Call for tender No. 341 of 15 March 2022 of Italian Ministry of University and Research funded by the European Union - Next Generation EU//National Recovery and Resilience Plan (NRRP)/ ; Concession Decree No. 1550 of 11 October 2022 adopted by the Italian Ministry of University and Research, CUP D93C22000890001//Italian Ministry of University and Research, CUP D93C22000890001/ ; Codice progetto n. 2022H9MPZ5//MIUR- PRIN Progetti di Ricerca di Rilevante Interesse Nazionale 2022/ ; Id. 23239//AIRC IG 2019/ ; Call for tender No. 3138 of 16/12/2021 of Italian Ministry of University and Research funded by the European Union//National Recovery and Resilience Plan (NRRP)/ ; Project code: CN00000041, CUP H93C22000430007//NextGenerationEU/ ; PNRR-MR1-2022-12376395//European Union - Next Generation EU - PNRR M6C2/ ; "POFACS" - ARS01_00640 -", D.D. 1211/2020 and 1104/2021//Italian Ministry of University and Research (MIUR)/ ; PRA-HE 2021//University of Foggia/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/microbiology/metabolism ; *Gastrointestinal Microbiome ; *Probiotics/therapeutic use ; Dysbiosis/microbiology ; Brain-Gut Axis ; Animals ; }, abstract = {Neurodegenerative disorders are the main cause of cognitive and physical disabilities, affect millions of people worldwide, and their incidence is on the rise. Emerging evidence pinpoints a disturbance of the communication of the gut-brain axis, and in particular to gut microbial dysbiosis, as one of the contributors to the pathogenesis of these diseases. In fact, dysbiosis has been associated with neuro-inflammatory processes, hyperactivation of the neuronal immune system, impaired cognitive functions, aging, depression, sleeping disorders, and anxiety. With the rapid advance in metagenomics, metabolomics, and big data analysis, together with a multidisciplinary approach, a new horizon has just emerged in the fields of translational neurodegenerative disease. In fact, recent studies focusing on taxonomic profiling and leaky gut in the pathogenesis of neurodegenerative disorders are not only shedding light on an overlooked field but are also creating opportunities for biomarker discovery and development of new therapeutic and adjuvant strategies to treat these disorders. Lactiplantibacillus plantarum (LBP) strains are emerging as promising psychobiotics for the treatment of these diseases. In fact, LBP strains are able to promote eubiosis, increase the enrichment of bacteria producing beneficial metabolites such as short-chain fatty acids, boost the production of neurotransmitters, and support the homeostasis of the gut-brain axis. In this review, we summarize the current knowledge on the role of the gut microbiota in the pathogenesis of neurodegenerative disorders with a particular focus on the benefits of LBP strains in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, autism, anxiety, and depression.}, } @article {pmid39273079, year = {2024}, author = {Lundt, S and Ding, S}, title = {Potential Therapeutic Interventions Targeting NAD[+] Metabolism for ALS.}, journal = {Cells}, volume = {13}, number = {17}, pages = {}, pmid = {39273079}, issn = {2073-4409}, support = {R01NS069726/NS/NINDS NIH HHS/United States ; R01 NS123023/NS/NINDS NIH HHS/United States ; R21 AG080715/AG/NIA NIH HHS/United States ; R01 NS069726/NS/NINDS NIH HHS/United States ; R21AG080715/AG/NIA NIH HHS/United States ; R01NS123023/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; *NAD/metabolism ; Humans ; Animals ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons. While there have been many potential factors implicated for ALS development, such as oxidative stress and mitochondrial dysfunction, no exact mechanism has been determined at this time. Nicotinamide adenine dinucleotide (NAD[+]) is one of the most abundant metabolites in mammalian cells and is crucial for a broad range of cellular functions from DNA repair to energy homeostasis. NAD[+] can be synthesized from three different intracellular pathways, but it is the NAD[+] salvage pathway that generates the largest proportion of NAD[+]. Impaired NAD[+] homeostasis has been connected to aging and neurodegenerative disease-related dysfunctions. In ALS mice, NAD[+] homeostasis is potentially disrupted prior to the appearance of physical symptoms and is significantly reduced in the nervous system at the end stage. Treatments targeting NAD[+] metabolism, either by administering NAD[+] precursor metabolites or small molecules that alter NAD[+]-dependent enzyme activity, have shown strong beneficial effects in ALS disease models. Here, we review the therapeutic interventions targeting NAD[+] metabolism for ALS and their effects on the most prominent pathological aspects of ALS in animal and cell models.}, } @article {pmid39271939, year = {2024}, author = {Yu, Y and Pang, D and Huang, J and Li, C and Cui, Y and Shang, H}, title = {Downregulation of Lnc-ABCA12-3 modulates UBQLN1 expression and protein homeostasis pathways in amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {21383}, pmid = {39271939}, issn = {2045-2322}, support = {2022NSFSC0750//The Sichuan Science and Technology Program/ ; 81871000//National Natural Science Foundation of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *RNA, Long Noncoding/genetics/metabolism ; *Autophagy-Related Proteins/genetics/metabolism ; *Down-Regulation ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; *Apoptosis/genetics ; Female ; Proteostasis ; Male ; Middle Aged ; Autophagy/genetics ; Oxidative Stress ; Gene Expression Regulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration. Dysregulation of long non-coding RNAs (lncRNAs) has been implicated in ALS pathogenesis but their roles remain unclear. Previous studies found lnc-ABCA12-3 was downregulated in ALS patients. We aim to characterize the expression and function of lnc-ABCA12-3 in ALS and explore its mechanisms of action. Lnc-ABCA12-3 expression was analyzed in PBMCs from ALS patients and correlated with clinical outcomes. Effect of modulating lnc-ABCA12-3 expression was assessed in cell models using assays of apoptosis, protein homeostasis and pathway analysis. RNA pull-down and interaction studies were performed to identify lnc-ABCA12-3 binding partners. Lnc-ABCA12-3 was downregulated in ALS patients, correlating with faster progression and shorter survival. Overexpression of lnc-ABAC12-3 conferred protection against oxidative stress-induced apoptosis, while knockdown lnc-ABCA12-3 enhanced cell death. Lnc-ABCA12-3 maintained protein quality control pathways, including ubiquitination, autophagy and stress granule formation, by regulating the ubiquitin shuttle protein UBQLN1. This study identified lnc-ABCA12-3 as a novel regulatory lncRNA implicated in ALS pathogenesis by modulating cellular survival and stress responses through interactions with UBQLN1, influencing disease progression. Lnc-ABCA12-3 may influence ALS through regulating protein homeostasis pathways.}, } @article {pmid39271680, year = {2024}, author = {Shan, Y and Zhang, M and Tao, E and Wang, J and Wei, N and Lu, Y and Liu, Q and Hao, K and Zhou, F and Wang, G}, title = {Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges.}, journal = {Signal transduction and targeted therapy}, volume = {9}, number = {1}, pages = {242}, pmid = {39271680}, issn = {2059-3635}, support = {82104184//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82373949//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82073928//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; *Mesenchymal Stem Cells/metabolism/cytology ; *Mesenchymal Stem Cell Transplantation ; Graft vs Host Disease/therapy ; Translational Research, Biomedical ; Amyotrophic Lateral Sclerosis/therapy ; }, abstract = {Over the past two decades, mesenchymal stem/stromal cell (MSC) therapy has made substantial strides, transitioning from experimental clinical applications to commercial products. MSC therapies hold considerable promise for treating refractory and critical conditions such as acute graft-versus-host disease, amyotrophic lateral sclerosis, and acute respiratory distress syndrome. Despite recent successes in clinical and commercial applications, MSC therapy still faces challenges when used as a commercial product. Current detection methods have limitations, leaving the dynamic biodistribution, persistence in injured tissues, and ultimate fate of MSCs in patients unclear. Clarifying the relationship between the pharmacokinetic characteristics of MSCs and their therapeutic effects is crucial for patient stratification and the formulation of precise therapeutic regimens. Moreover, the development of advanced imaging and tracking technologies is essential to address these clinical challenges. This review provides a comprehensive analysis of the kinetic properties, key regulatory molecules, different fates, and detection methods relevant to MSCs and discusses concerns in evaluating MSC druggability from the perspective of integrating pharmacokinetics and efficacy. A better understanding of these challenges could improve MSC clinical efficacy and speed up the introduction of MSC therapy products to the market.}, } @article {pmid39271636, year = {2025}, author = {Wang, Y and Ju, R and Jiang, J and Mao, L and Li, X and Deng, M}, title = {Concomitant presence of a novel ARPP21 variant and CNVs in Chinese familial amyotrophic lateral sclerosis-frontotemporal dementia patients.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {1}, pages = {195-205}, pmid = {39271636}, issn = {1590-3478}, support = {No. 82273915//National Natural Science Foundation of China/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; China ; *DNA Copy Number Variations/genetics ; East Asian People/genetics ; *Frontotemporal Dementia/genetics ; Pedigree ; Profilins/genetics ; Whole Genome Sequencing ; *Phosphoproteins/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the degeneration of motor neurons and progressive muscle weakness. Heredity plays an important part in the pathogenesis of ALS. Recently, with the emergence of the oligogenic pathogenic mechanism in ALS and the ongoing discovery of new mutated genes and genomic variants, there is an emerging need for larger-scale and more comprehensive genetic screenings in higher resolution. In this study, we performed whole-genome sequencing (WGS) on 34 familial ALS probands lacking the most common disease-causing mutations to explore the genetic landscape of Chinese ALS patients further. Among them, we identified a novel ARPP21 c.1231G > A (p.Glu411Lys) variant and two copy number variations (CNVs) affecting the PFN1 and RBCK1 genes in a patient with ALS-frontotemporal dementia (FTD). This marks the first report of an ARPP21 variant in Chinese ALS-FTD patients, providing fresh evidence for the association between ARPP21 and ALS. Our findings also underscore the potential role of CNVs in ALS-FTD, suggesting that the cumulative effect of multiple rare variants may contribute to disease onset. Furthermore, compared to the averages in our cohort and the reported Chinese ALS population, this patient displayed a shorter survival time and more rapid disease progression, suggesting the possibility of an oligogenic mechanism in disease pathogenesis. Further research will contribute to a deeper understanding of the rare mutations and their interactions, thus advancing our understanding of the genetic mechanisms underlying ALS and ALS-FTD.}, } @article {pmid39270726, year = {2024}, author = {Roos, AK and Stenvall, E and Kockum, ES and Grönlund, KÅ and Alstermark, H and Wuolikainen, A and Andersen, PM and Nordin, A and Forsberg, KME}, title = {Small striatal huntingtin inclusions in patients with motor neuron disease with reduced penetrance and intermediate HTT gene expansions.}, journal = {Human molecular genetics}, volume = {33}, number = {22}, pages = {1966-1974}, pmid = {39270726}, issn = {1460-2083}, support = {//Umea University/ ; Nos.FO 2022-0309//Swedish Brain Foundation/ ; 2012-3167//Swedish Research Council/ ; //Research and Development Unit/ ; JLL-980693//Region Jämtland Härjedalen/ ; 2012.0091//Knut and Alice Wallenberg Foundation/ ; //Neuroförbundet patient organization/ ; 2023.16//Ulla-Carin Lindquist Foundation/ ; RV-993493//Västerbotten County Council/ ; //King Gustaf V:s and Queen Victoria's Freemason's Foundation/ ; //Börje Salming ALS Foundation/ ; }, mesh = {Humans ; *Huntingtin Protein/genetics/metabolism ; *Penetrance ; Male ; Female ; *Motor Neuron Disease/genetics/pathology/metabolism ; Middle Aged ; Aged ; *C9orf72 Protein/genetics/metabolism ; *DNA Repeat Expansion/genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Inclusion Bodies/metabolism/genetics/pathology ; Alleles ; Adult ; Huntington Disease/genetics/pathology/metabolism ; Cohort Studies ; Corpus Striatum/metabolism/pathology ; }, abstract = {Short tandem repeat expansions in the human genome are overrepresented in a variety of neurological disorders. It was recently shown that huntingtin (HTT) repeat expansions with full penetrance, i.e. 40 or more CAG repeats, which normally cause Huntington's disease (HD), are overrepresented in patients with amyotrophic lateral sclerosis (ALS). Whether patients carrying HTT repeat expansions with reduced penetrance, (36-39 CAG repeats), or alleles with intermediate penetrance, (27-35 CAG repeats), have an increased risk of ALS has not yet been investigated. Here, we examined the role of HTT repeat expansions in a motor neuron disease (MND) cohort, searched for expanded HTT alleles, and investigated correlations with phenotype and neuropathology. MND patients harboring C9ORF72 hexanucleotide repeat expansions (HREs) were included, to investigate whether HTT repeat expansions were more common in this group. We found a high prevalence of intermediate (range 5.63%-6.61%) and reduced penetrance (range 0.57%-0.66%) HTT gene expansions in this cohort compared to other populations of European ancestry, but no differences between the MND cohort and the control cohort were observed, regardless of C9ORF72HRE status. Upon autopsy of three patients with intermediate or reduced penetrance HTT alleles, huntingtin inclusions were observed in the caudate nucleus and frontal lobe, but no significant somatic mosaicism was detected in different parts of the nervous system. Thus, we demonstrate, for the first time, huntingtin inclusions in individuals with MND and intermediate and reduced penetrance HTT repeat expansions but more clinicopathological investigations are needed to further understand the impact of HTT gene expansion-related pleiotropy.}, } @article {pmid39270623, year = {2024}, author = {Benatar, M and Macklin, EA and Malaspina, A and Rogers, ML and Hornstein, E and Lombardi, V and Renfrey, D and Shepheard, S and Magen, I and Cohen, Y and Granit, V and Statland, JM and Heckmann, JM and Rademakers, R and McHutchison, CA and Petrucelli, L and McMillan, CT and Wuu, J and , }, title = {Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: validation and implications for clinical trial design and analysis.}, journal = {EBioMedicine}, volume = {108}, number = {}, pages = {105323}, pmid = {39270623}, issn = {2352-3964}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/mortality ; *Biomarkers/blood ; *Clinical Trials as Topic ; *Disease Progression ; Neurofilament Proteins/blood ; Prognosis ; Research Design ; Multicenter Studies as Topic ; }, abstract = {BACKGROUND: With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used.

METHODS: A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75[ECD], plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated.

FINDINGS: Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40 pg/mL and >100 pg/mL correspond to future ALSFRS-R slopes of ∼0.5 and ∼1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ∼25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75[ECD], and plasma miR-181ab is more limited.

INTERPRETATION: Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency.

FUNDING: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).}, } @article {pmid39270519, year = {2024}, author = {Nishiyama, M and Koreki, A and Isose, S and Takeda, T and Ishikawa, A and Kokubun, S and Saito, Y and Ito, K and Arai, K and Takahashi, N and Motoda, Y and Kuwabara, S and Honda, K}, title = {Factors associated with psychological distress in patients with amyotrophic lateral sclerosis: A retrospective medical records study.}, journal = {Journal of psychosomatic research}, volume = {187}, number = {}, pages = {111915}, doi = {10.1016/j.jpsychores.2024.111915}, pmid = {39270519}, issn = {1879-1360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; Female ; Middle Aged ; *Psychological Distress ; Aged ; Retrospective Studies ; Adult ; Depression/psychology ; Stress, Psychological/psychology ; Surveys and Questionnaires ; Risk Factors ; Sex Factors ; }, abstract = {OBJECTIVE: Although psychological distress is a prevalent issue among patients with amyotrophic lateral sclerosis (ALS) and can impact survival, the risk factors contributing to this distress remain insufficiently understood.

METHODS: Patients with ALS who completed the Profile of Mood States (POMS) between June 2017 and March 2022 were included. Participants with moderate to severe cognitive decline were excluded, resulting in the recruitment of 121 patients. The associations between POMS profiles and clinical characteristics were analyzed. Physical motor symptoms were evaluated using the Revised ALS Functional Rating Scale (ALSFRS-R) for objective measurement and the 40-item ALS Assessment Questionnaire (ALSAQ-40) for subjective assessment.

RESULTS: Our model, employing the ALSFRS-R, revealed significant factors associated with overall psychological distress, as assessed by the POMS, including upper limb symptoms, the presence of sleep apnea syndrome, older age at onset, and male sex, with an inverse association with tracheostomy. The POMS subscale scores revealed that anger and depression were significantly associated with upper limb symptoms. The second model, which employed subjective scales, yielded similar results, reinforcing the robustness of our findings. Moreover, subjective bulbar symptoms on the ALSAQ-40 were significantly associated with psychological distress, particularly in female patients.

CONCLUSION: This study identified the main clinical characteristics significantly associated with psychological distress in patients with ALS. Our findings may be useful in developing individualized psychological management strategies for these patients.}, } @article {pmid39269505, year = {2024}, author = {Denis, PA and Laranjeira, JAS and Martins, NF and Sambrano, JR}, title = {Codoped germanene with 3p and 4p elements elements.}, journal = {Journal of molecular modeling}, volume = {30}, number = {10}, pages = {331}, pmid = {39269505}, issn = {0948-5023}, abstract = {CONTEXT: The relentless need for new materials to be used in electronic devices has opened new research directions in materials science. One of them involves using two-dimensional materials, among which there is current interest in using germanene. The heteroatom doping of germanene has been proposed as a possible approach to fine-tuning its electronic properties. However, this procedure is complicated because locating the dopants with a specific arrangement is challenging, thus achieving reproducibility. To avoid this problem, we propose the codoping of germanene to understand if dopants prefer to be agglomerated as observed for graphene or if they prefer to adopt a random disposition. Herein, we employed first-principles calculations to study 21 codoped germanene systems with one 3p (Al, Si, P, and S) and one 4p (Ga, As, and Se) element. Our results indicate that in the cases of AlP, AlS, GaP, GaS, GaAs, and GaSe codoped germanene, the dopants show a tendency to be located in specific lattice positions. The ortho disposition of dopants is preferred for AlP, AlS, GaP and GaS codoped germanene and their 4p counterparts GaAs and GaSe codoped germanene, and the materials showed interesting electronic properties making them suitable to develop germanene-based electronic materials.

METHODS: We utilized the M06-L, HSE06 methods accompanied by the 6-31G* basis sets to perform periodic boundary conditions calculations as implemented in Gaussian 09. The unit cells were sampled employing 100 k-points for geometry optimizations and 2000 k-points for electronic properties The ultrafine grid was employed. Results were visualized employing Gaussview 5.0.1. In addition to this, we performed B3LYP-D3 periodic calculations as implemented in CRYSTAL17.}, } @article {pmid39268841, year = {2024}, author = {Xing, C and Luo, M and Sheng, Q and Zhu, Z and Yu, D and Huang, J and He, D and Zhang, M and Fan, W and Chen, D}, title = {Silk Fabric Functionalized by Nanosilver Enabling the Wearable Sensing for Biomechanics and Biomolecules.}, journal = {ACS applied materials & interfaces}, volume = {16}, number = {38}, pages = {51669-51678}, doi = {10.1021/acsami.4c10253}, pmid = {39268841}, issn = {1944-8252}, mesh = {*Wearable Electronic Devices ; *Silver/chemistry ; *Silk/chemistry ; Humans ; *Metal Nanoparticles/chemistry ; Biomechanical Phenomena ; Textiles ; Biosensing Techniques/instrumentation/methods ; Spectrum Analysis, Raman ; }, abstract = {Integrating biomechanical and biomolecular sensing mechanisms into wearable devices is a formidable challenge and key to acquiring personalized health management. To address this, we have developed an innovative multifunctional sensor enabled by plasma functionalized silk fabric, which possesses multimodal sensing capabilities for biomechanics and biomolecules. A seed-mediated in situ growth method was employed to coat silver nanoparticles (AgNPs) onto silk fibers, resulting in silk fibers functionalized with AgNPs (SFs@Ag) that exhibit both piezoresistive response and localized surface plasmon resonance effects. The SFs@Ag membrane enables accurate detection of mechanical pressure and specific biomolecules during wearable sensing, offering a versatile solution for comprehensive personalized health monitoring. Additionally, a machine learning algorithm has been established to specifically recognize muscle strain signals, potentially extending to the diagnosis and monitoring of neuromuscular disorders such as amyotrophic lateral sclerosis (ALS). Unlike electromyography, which detects large muscles in clinical medicine, sensing data for tiny muscles enhance our understanding of muscle coordination using the SFs@Ag sensor. This detection model provides feasibility for the early detection and prevention of neuromuscular diseases. Beyond muscle stress and strain sensing, biomolecular detection is a critical addition to achieving effective health management. In this study, we developed highly sensitive surface-enhanced Raman scattering (SERS) detection for wearable health monitoring. Finite-difference time-domain numerical simulations ware utilized to analyze the efficacy of the SFs@Ag sensor for wearable SERS sensing of biomolecules. Based on the specific SERS spectra, automatic extraction of signals of sweat molecules was also achieved. In summary, the SFs@Ag sensor bridges the gap between biomechanical and biomolecular sensing in wearable applications, providing significant value for personalized health management.}, } @article {pmid39268298, year = {2024}, author = {Contractor, RN and Shah, M and Manwell, W and Dempsey, KJ and Simhadri, P}, title = {Jean-Martin Charcot: Pioneer of Neurology.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e66762}, pmid = {39268298}, issn = {2168-8184}, abstract = {Jean-Martin Charcot, born on November 29, 1825, in Paris, France, is known as the father of neurology. During a time when neurology was not yet a recognized medical specialty, Charcot's pioneering contributions significantly advanced the field. Charcot's use of the anatomo-clinical method, which correlates clinical symptoms with anatomical findings, led to the discovery and characterization of numerous neurological conditions, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Charcot's joint, and Charcot-Marie-Tooth (CMT) disease. His methodical approach to documenting clinical signs and conducting post-mortem examinations revolutionized neurological research and diagnosis, laying the groundwork for modern neurology. The anatomo-clinical methods continue to be a vital tool in neurological research and practice today. Charcot's work extended beyond clinical practice, influencing the study of neurology through his role as an educator and mentor to many, including Sigmund Freud. Despite some controversies and a reputation for being difficult to work with, Charcot's legacy endures, with his initial discoveries fostering greater awareness and the development of therapies for various neurological disorders.}, } @article {pmid39267142, year = {2024}, author = {Wang, YM and Yan, J and Williams, SK and Fairless, R and Bading, H}, title = {TwinF interface inhibitor FP802 prevents retinal ganglion cell loss in a mouse model of amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {149}, pmid = {39267142}, issn = {2051-5960}, support = {BA 1007/7-1//Deutsche Forschungsgemeinschaft/ ; FOR 2289//Deutsche Forschungsgemeinschaft/ ; Advanced Grant 233024//HORIZON EUROPE European Research Council/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/drug therapy ; *Retinal Ganglion Cells/drug effects/pathology/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; Mice ; Electroretinography ; Mice, Inbred C57BL ; Neuroprotective Agents/pharmacology ; Brain-Derived Neurotrophic Factor/metabolism ; Humans ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; }, abstract = {Motor neuron loss is well recognized in amyotrophic lateral sclerosis (ALS), but research on retinal ganglion cells (RGCs) is limited. Ocular symptoms are generally not considered classic ALS symptoms, although RGCs and spinal motor neurons share certain cell pathologies, including hallmark signs of glutamate neurotoxicity, which may be triggered by activation of extrasynaptic NMDA receptors (NMDARs). To explore potential novel strategies to prevent ALS-associated death of RGCs, we utilized inhibition of the TwinF interface, a new pharmacological principle that detoxifies extrasynaptic NMDARs by disrupting the NMDAR/TRPM4 death signaling complex. Using the ALS mouse model SOD1[G93A], we found that the small molecule TwinF interface inhibitor FP802 prevents the loss of RGCs, improves pattern electroretinogram (pERG) performance, increases the retinal expression of Bdnf, and restores the retinal expression of the immediate early genes, Inhibin beta A and Npas4. Thus, FP802 not only prevents, as recently described, death of spinal motor neurons in SOD1[G93A] mice, but it also mitigates ALS-associated retinal damage. TwinF interface inhibitors have great potential for alleviating neuro-ophthalmologic symptoms in ALS patients and offer a promising new avenue for therapeutic intervention.}, } @article {pmid39266192, year = {2024}, author = {Chiappini, FA and Pinto, L and Alcaraz, MR and Omidikia, N and Goicoechea, HC and Olivieri, AC}, title = {Multivariate curve resolution-alternating least-squares and second-order advantage in first-order calibration. A systematic characterisation for three-component analytical systems.}, journal = {Analytica chimica acta}, volume = {1328}, number = {}, pages = {343159}, doi = {10.1016/j.aca.2024.343159}, pmid = {39266192}, issn = {1873-4324}, abstract = {BACKGROUND: Recent interest has been focused on the application of multivariate curve resolution-alternating least-squares (MCR-ALS) to systems involving the measurement of first-order and non-bilinear second-order data. The latter pose important challenges to bilinear decomposition models, due to the phenomenon of rotational ambiguity in the solutions, even under the application of the full set of chemical constraints that is usually employed in MCR-ALS calibration.

RESULTS: After the analysis of several simulated and experimental datasets, important conclusions regarding the role of the selectivity patterns in the constituent spectra have been drawn concerning the achievement of the second-order advantage. Theoretical considerations based on the calculation of the areas of feasible solutions helped to support the observations regarding the predictive ability of MCR- ALS in the various datasets.

SIGNIFICANCE: The understanding of the impact of rotational ambiguity in obtaining the second-order advantage with both first-order and non-bilinear second-order data is of paramount importance in the future development of analytical protocols of complex samples.}, } @article {pmid39264833, year = {2024}, author = {Su, B and He, Z and Liu, J and Li, M and Huang, X}, title = {Mangiferin activates the nuclear factor erythroid 2-related factor pathway to protect SOD1-G93A induced NSC-34 motor neurons from oxidative stress and apoptosis.}, journal = {Journal of biochemical and molecular toxicology}, volume = {38}, number = {10}, pages = {e23849}, doi = {10.1002/jbt.23849}, pmid = {39264833}, issn = {1099-0461}, mesh = {*Xanthones/pharmacology ; *NF-E2-Related Factor 2/metabolism/genetics ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; Mice ; Animals ; *Motor Neurons/metabolism/drug effects/pathology ; *Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; Cell Line ; Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Humans ; NAD(P)H Dehydrogenase (Quinone)/metabolism/genetics ; }, abstract = {One of the main factors in the pathophysiology of amyotrophic lateral sclerosis is oxidative stress. Mangiferin (MF), a natural plant polyphenol, has anti-inflammatory and antioxidant effects. The aim of our study was to investigate the protective effects and mechanisms of MF in the hSOD1-G93A ALS cell model. Our result revealed that MF treatment reduced the generation of reactive oxygen species (ROS) and malondialdehyde (MDA), decreased oxidative damage, and reduced apoptosis. Additionally, it was observed that MF significantly increased the synthesis of the antioxidant genes hemeoxygenase-1 and NAD(P)H: quinone oxidoreductase 1, which are downstream of the Nrf2 signaling pathway, and increased the expression and activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 knockdown greatly promoted apoptosis, which was reversed by MF treatment. To summarize, MF promoted the Nrf2 pathway and scavenged MDA and ROS to protect the ALS cell model.}, } @article {pmid39264557, year = {2024}, author = {Grigoryev, PN and Gaptrakhmanova, GA and Plotnikova, AA and Zefirov, AL and Mukhamedyarov, MA}, title = {Endocytosis of Synaptic Vesicle in Motor Nerve Endings of FUS Transgenic Mice with a Model of Amyotrophic Lateral Sclerosis.}, journal = {Bulletin of experimental biology and medicine}, volume = {177}, number = {4}, pages = {449-453}, pmid = {39264557}, issn = {1573-8221}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/physiopathology ; Diaphragm/innervation/metabolism/physiopathology ; *Disease Models, Animal ; *Endocytosis/physiology ; Fluorescent Dyes/metabolism ; Imidazoles/pharmacology ; Mice, Transgenic ; *Motor Neurons/metabolism/pathology ; Nerve Endings/metabolism ; Pyridinium Compounds/metabolism ; Quaternary Ammonium Compounds/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; Synaptic Transmission/physiology/genetics ; *Synaptic Vesicles/metabolism ; }, abstract = {In experiments on the motor nerve endings of the diaphragm of transgenic FUS mice with a model of amyotrophic lateral sclerosis at the pre-symptomatic stage of the disease, the processes of transmitter release and endocytosis of synaptic vesicles were studied. In FUS mice, the intensity of transmitter release during high-frequency stimulation of the motor nerve (50 imp/sec) was lowered. At the same duration of stimulation, the loading of fluorescent dye FM1-43 was lower in FUS mice. However, at the time of stimulation, during which an equal number of quanta are released in wild-type and FUS mice, no differences in the intensity of dye loading were found. Thus, endocytosis is not the key factor in the mechanism of synaptic dysfunction in FUS mice at the pre-symptomatic stage.}, } @article {pmid39263607, year = {2024}, author = {He, D and He, X and Shen, D and Liu, L and Yang, X and Hao, M and Wang, Y and Li, Y and Liu, Q and Liu, M and Wang, J and Zhang, X and Cui, L}, title = {Loss-of-function variants in RNA binding motif protein X-linked induce neuronal defects contributing to amyotrophic lateral sclerosis pathogenesis.}, journal = {MedComm}, volume = {5}, number = {9}, pages = {e712}, pmid = {39263607}, issn = {2688-2663}, abstract = {Despite being one of the most prevalent RNA modifications, the role of N6-methyladenosine (m6A) in amyotrophic lateral sclerosis (ALS) remains ambiguous. In this investigation, we explore the contribution of genetic defects of m6A-related genes to ALS pathogenesis. We scrutinized the mutation landscape of m6A genes through a comprehensive analysis of whole-exome sequencing cohorts, encompassing 508 ALS patients and 1660 population-matched controls. Our findings reveal a noteworthy enrichment of RNA binding motif protein X-linked (RBMX) variants among ALS patients, with a significant correlation between pathogenic m6A variants and adverse clinical outcomes. Furthermore, Rbmx knockdown in NSC-34 cells overexpressing mutant TDP43[Q331K] results in cell death mediated by an augmented p53 response. Similarly, RBMX knockdown in ALS motor neurons derived from induced pluripotent stem cells (iPSCs) manifests morphological defects and activation of the p53 pathway. Transcriptional analysis using publicly available single-cell sequencing data from the primary motor cortex indicates that RBMX-regulated genes selectively influence excitatory neurons and exhibit enrichment in ALS-implicated pathways. Through integrated analyses, our study underscores the emerging roles played by RBMX in ALS, suggesting a potential nexus between the disease and dysregulated m6A-mediated mRNA metabolism.}, } @article {pmid39262980, year = {2024}, author = {Joshi, R and Goswami, D and Saha, P and Hole, A and Mandhare, P and Wadke, R and Murthy, PR and Borgohain, S and C, MK and Kapoor, S}, title = {Serum Raman spectroscopy: Unearthing the snapshot of distinct metabolic profile in patients with congenital heart defects (CHDs).}, journal = {Heliyon}, volume = {10}, number = {16}, pages = {e34575}, pmid = {39262980}, issn = {2405-8440}, abstract = {In the present study, efficacy of minimally-invasive serum Raman spectroscopy (SRS) in stratification of congenital heart diseases was explored. Blood was collected from 62 subjects [42 congenital heart defect (CHD) patients (19 with atrial septal defect, 13 with ventricular septal defect and 10 with tetralogy of fallot) and 20 controls], and serum separated. Raman spectra of sera were recorded, pre-processed and subjected to spectral and multivariate analyses. Multivariate curve resolution-alternating least squares (MCR-ALS) analyses indicated alterations in lipid and protein levels between the study groups. Principal Component Analysis (PCA) and Principal Component based Linear Discriminant Analysis (PC-LDA), cross-validated with Leave-one-out cross validation (LOOCV), were employed to study stratification between the different groups. CHD could be classified from controls with 76 % efficiency. The different CHD subtypes could be distinguished with efficiencies as high as ∼90 %. To the best of our knowledge, differentiation between controls and CHDs as well as the stratification between controls and CHDs subtypes was for the first time successfully accomplished by serum-based Raman spectroscopy.}, } @article {pmid39261725, year = {2024}, author = {Abe, P and Lavalley, A and Morassut, I and Santinha, AJ and Roig-Puiggros, S and Javed, A and Klingler, E and Baumann, N and Prados, J and Platt, RJ and Jabaudon, D}, title = {Molecular programs guiding arealization of descending cortical pathways.}, journal = {Nature}, volume = {634}, number = {8034}, pages = {644-651}, pmid = {39261725}, issn = {1476-4687}, mesh = {Animals ; Female ; Male ; Mice ; Axons/metabolism ; Gene Expression Regulation, Developmental ; Motor Cortex/cytology/metabolism ; *Neocortex/anatomy & histology/cytology/metabolism ; *Neural Pathways ; *Neurons/metabolism/cytology ; Single-Cell Gene Expression Analysis ; Transcription Factors/metabolism ; }, abstract = {Layer 5 extratelencephalic (ET) neurons are present across neocortical areas and send axons to multiple subcortical targets[1-6]. Two cardinal subtypes exist[7,8]: (1) Slco2a1-expressing neurons (ETdist), which predominate in the motor cortex and project distally to the pons, medulla and spinal cord; and (2) Nprs1- or Hpgd-expressing neurons (ETprox), which predominate in the visual cortex and project more proximally to the pons and thalamus. An understanding of how area-specific ETdist and ETprox emerge during development is important because they are critical for fine motor skills and are susceptible to spinal cord injury and amyotrophic lateral sclerosis[9-12]. Here, using cross-areal mapping of axonal projections in the mouse neocortex, we identify the subtype-specific developmental dynamics of ET neurons. Whereas subsets of ETprox emerge by pruning of ETdist axons, others emerge de novo. We outline corresponding subtype-specific developmental transcriptional programs using single-nucleus sequencing. Leveraging these findings, we use postnatal in vivo knockdown of subtype-specific transcription factors to reprogram ET neuron connectivity towards more proximal targets. Together, these results show the functional transcriptional programs driving ET neuron diversity and uncover cell subtype-specific gene regulatory networks that can be manipulated to direct target specificity in motor corticofugal pathways.}, } @article {pmid39260590, year = {2024}, author = {Petel Légaré, V and Harji, ZA and Rampal, CJ and Antonicka, H and Gurberg, TJN and Persia, O and Rodríguez, EC and Shoubridge, EA and Armstrong, GAB}, title = {CHCHD10[P80L] knock-in zebrafish display a mild ALS-like phenotype.}, journal = {Experimental neurology}, volume = {382}, number = {}, pages = {114945}, doi = {10.1016/j.expneurol.2024.114945}, pmid = {39260590}, issn = {1090-2430}, mesh = {Animals ; *Zebrafish ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Phenotype ; *Mitochondrial Proteins/genetics ; Zebrafish Proteins/genetics ; Motor Neurons/metabolism/pathology ; Gene Knock-In Techniques ; Animals, Genetically Modified ; Disease Models, Animal ; Neuromuscular Junction/pathology/genetics/metabolism ; }, abstract = {Mutations in the nuclear-encoded mitochondrial gene CHCHD10 have been observed in patients with a spectrum of diseases that include amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathogenic nature of disease-associated variants of CHCHD10 we generated a zebrafish knock-in (KI) model expressing the orthologous ALS-associated CHCHD10[P80L] variant (zebrafish: Chchd10[P83L]). Larval chchd10[P83L/P83L] fish displayed reduced Chchd10 protein expression levels, motor impairment, reduced survival and abnormal neuromuscular junctions (NMJ). These deficits were not accompanied by changes in transcripts involved in the integrated stress response (ISR), phenocopying previous findings in our knockout (chchd10[-/-]). Adult, 11-month old chchd10[P83L/P83L] zebrafish, displayed smaller slow- and fast-twitch muscle cell cross-sectional areas compared to wild type zebrafish muscle cells. Motoneurons in the spinal cord of chchd10[P83L/P83L] zebrafish displayed similar cross-sectional areas to that of wild type motor neurons and significantly fewer motor neurons were observed when compared to chchd2[-/-] adult spinal cords. Bulk RNA sequencing using whole spinal cords of 7-month old fish revealed transcriptional changes associated with neuroinflammation, apoptosis, amino acid metabolism and mt-DNA inflammatory response in our chchd10[P83L/P83L] model. The findings presented here, suggest that the CHCHD10[P80L] variant confers an ALS-like phenotype when expressed in zebrafish.}, } @article {pmid39260416, year = {2024}, author = {Arseni, D and Nonaka, T and Jacobsen, MH and Murzin, AG and Cracco, L and Peak-Chew, SY and Garringer, HJ and Kawakami, I and Suzuki, H and Onaya, M and Saito, Y and Murayama, S and Geula, C and Vidal, R and Newell, KL and Mesulam, M and Ghetti, B and Hasegawa, M and Ryskeldi-Falcon, B}, title = {Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C.}, journal = {Nature}, volume = {634}, number = {8034}, pages = {662-668}, pmid = {39260416}, issn = {1476-4687}, support = {R01 AG077444/AG/NIA NIH HHS/United States ; RF1 AG071177/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; U01 NS110437/NS/NINDS NIH HHS/United States ; R01 NS085770/NS/NINDS NIH HHS/United States ; P30 AG013854/AG/NIA NIH HHS/United States ; R01 AG056258/AG/NIA NIH HHS/United States ; R01 DC008552/DC/NIDCD NIH HHS/United States ; RF1 NS110437/NS/NINDS NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; R01 AG080001/AG/NIA NIH HHS/United States ; R01 AG071177/AG/NIA NIH HHS/United States ; R01 NS137469/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyloid/chemistry/metabolism/ultrastructure ; *Annexins/chemistry/metabolism/ultrastructure ; Aphasia/complications/metabolism ; *Brain/metabolism/pathology/ultrastructure ; Cryoelectron Microscopy ; *DNA-Binding Proteins/chemistry/metabolism/ultrastructure ; *Frontotemporal Dementia/classification/complications/metabolism ; Models, Molecular ; Protein Multimerization ; }, abstract = {Neurodegenerative diseases are characterized by the abnormal filamentous assembly of specific proteins in the central nervous system[1]. Human genetic studies have established a causal role for protein assembly in neurodegeneration[2]. However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in cryo-electron microscopy have enabled the structures of the protein filaments to be determined from the brains of patients[1]. All neurodegenerative diseases studied to date have been characterized by the self-assembly of proteins in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) types A and B[3,4]. Here we used cryo-electron microscopy to determine filament structures from the brains of individuals with FTLD-TDP type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/G284-N345 and ANXA11 residues L39-Y74 from their respective low-complexity domains. Regions of TDP-43 and ANXA11 that were previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as an approximately 22 kDa N-terminal fragment lacking the annexin core domain. Immunohistochemistry of brain sections showed the colocalization of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP type C. This work establishes a central role for ANXA11 in FTLD-TDP type C. The unprecedented formation of heteromeric amyloid filaments in the human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.}, } @article {pmid39260140, year = {2024}, author = {Emori, S and Kume, K and Nakayama, Y and Ito, H and Kawakami, H}, title = {C9orf72 repeat expansions in Wakayama: One potential cause of amyotrophic lateral sclerosis in the Kii Peninsula, Japan.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123209}, doi = {10.1016/j.jns.2024.123209}, pmid = {39260140}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *C9orf72 Protein/genetics ; Japan/epidemiology ; Male ; Female ; *DNA Repeat Expansion/genetics ; Middle Aged ; Aged ; Proteins/genetics ; Adult ; Aged, 80 and over ; Genetic Predisposition to Disease/genetics ; Haplotypes ; }, abstract = {A cluster of cases of amyotrophic lateral sclerosis (ALS) exists in the southern part of the Kii Peninsula in Japan. Although both genetic and environmental factors are thought to be causative, the critical cause of this cluster has not been identified. C9orf72 is the most common genetic factor in both familial and sporadic C9orf72-related ALS in people of European ancestry, but it is rare among Japanese populations. However, a previous report revealed that the frequency of C9orf72-related ALS was significantly higher in the cluster area. We evaluated the proportion of C9orf72 hexanucleotide repeat expansions in 99 cases of ALS diagnosed in Wakayama Prefecture, including the cluster area, by using repeat-primed polymerase chain reaction and fluorescence fragment length analysis. We found that 2 of the 99 patients (0 % of those with familial ALS and 2.4 % of those with sporadic ALS) had hexanucleotide repeat expansions in C9orf72, and long-read sequencing revealed that these expansions were causative. No expansions were observed among 90 patients with Parkinson's disease or among 90 healthy controls. Haplotype analysis with long-read sequencing data revealed that the two patients with repeat expansions shared the common haplotype with that previously reported in Finnish patients with C9orf72-related ALS, which suggests a founder effect. C9orf72 was thought to be a rare causative gene in Japan, but this study revealed that it may be relatively common in Wakayama Prefecture.}, } @article {pmid39259763, year = {2024}, author = {Caredio, D and Koderman, M and Frontzek, KJ and Sorce, S and Nuvolone, M and Bremer, J and Mariutti, G and Schwarz, P and Madrigal, L and Mitrovic, M and Sellitto, S and Streichenberger, N and Scheckel, C and Aguzzi, A}, title = {Prion diseases disrupt glutamate/glutamine metabolism in skeletal muscle.}, journal = {PLoS pathogens}, volume = {20}, number = {9}, pages = {e1012552}, pmid = {39259763}, issn = {1553-7374}, mesh = {Animals ; *Muscle, Skeletal/metabolism/pathology ; *Glutamine/metabolism ; *Glutamic Acid/metabolism ; Mice ; *Prion Diseases/metabolism/genetics ; Humans ; Glutamate-Ammonia Ligase/metabolism ; Creutzfeldt-Jakob Syndrome/metabolism/pathology/genetics ; Female ; Mice, Inbred C57BL ; }, abstract = {In prion diseases (PrDs), aggregates of misfolded prion protein (PrPSc) accumulate not only in the brain but also in extraneural organs. This raises the question whether prion-specific pathologies arise also extraneurally. Here we sequenced mRNA transcripts in skeletal muscle, spleen and blood of prion-inoculated mice at eight timepoints during disease progression. We detected gene-expression changes in all three organs, with skeletal muscle showing the most consistent alterations. The glutamate-ammonia ligase (GLUL) gene exhibited uniform upregulation in skeletal muscles of mice infected with three distinct scrapie prion strains (RML, ME7, and 22L) and in victims of human sporadic Creutzfeldt-Jakob disease. GLUL dysregulation was accompanied by changes in glutamate/glutamine metabolism, leading to reduced glutamate levels in skeletal muscle. None of these changes were observed in skeletal muscle of humans with amyotrophic lateral sclerosis, Alzheimer's disease, or dementia with Lewy bodies, suggesting that they are specific to prion diseases. These findings reveal an unexpected metabolic dimension of prion infections and point to a potential role for GLUL dysregulation in the glutamate/glutamine metabolism in prion-affected skeletal muscle.}, } @article {pmid39258797, year = {2024}, author = {Coppedè, F}, title = {DNA methylation in amyotrophic lateral sclerosis: where do we stand and what is next?.}, journal = {Epigenomics}, volume = {16}, number = {17}, pages = {1185-1196}, pmid = {39258797}, issn = {1750-192X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *DNA Methylation ; Epigenesis, Genetic ; }, abstract = {Genes involved in immune response, inflammation and metabolism are among those most likely affected by changes in DNA methylation (DNAm) and expression levels in amyotrophic lateral sclerosis (ALS) tissues. Unfortunately, it is still largely unclear whether any of these changes precede the onset of disease symptoms or whether most of them are the result of the muscular and metabolic changes that follow symptoms onset. In this article the author discusses the strengths and limitations of the available studies of DNAm in ALS and provides some suggestions on what, in his opinion, could be done in the near future for a better understanding of the DNAm changes occurring in ALS, their link with environmental exposures and their potential clinical utility.}, } @article {pmid39258740, year = {2025}, author = {O'Connell, C and Kavanaugh, MS and Cummings, C and Genge, A}, title = {How to break the news in amyotrophic lateral sclerosis/motor neuron disease: practical guidelines from experts.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {5-14}, doi = {10.1080/21678421.2024.2397517}, pmid = {39258740}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Motor Neuron Disease/psychology/therapy ; Communication ; Quality of Life/psychology ; Practice Guidelines as Topic/standards ; }, abstract = {In amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), it is necessary to communicate difficult news during the initial diagnosis and throughout the disease trajectory as the condition progresses. However, delivering difficult news to people with ALS/MND is an emotionally demanding task for healthcare and allied health professionals-one for which many feel ill-prepared because of limited training in this area. Ineffective communication of difficult news damages the patient-provider relationship and negatively impacts patient quality of life (QoL). To address this issue, we developed the A-L S-PIKES protocol based on available literature and our extensive clinical experience. It provides easy-to-follow, stepwise guidelines to effectively deliver difficult news to people with ALS/MND (PALS) that includes: Advance Preparation (preparing for the discussion logistically and emotionally); Location & Setting (creating a comfortable setting that fosters rapport); Patient's Perceptions (assessing PALS' understanding and perception of their condition); Invitation (seeking PALS' permission to share information); Knowledge (sharing information in a clear, understandable manner); Emotion/Empathy (addressing emotions with empathy and providing emotional support); and Strategy & Summary (summarizing the discussion and collaboratively developing a plan of action). A-L S-PIKES provides practical guidelines on how to prepare for and conduct these challenging conversations. It emphasizes effective communication tailored to the individual needs of PALS and their families, empathy, sensitivity, and support for PALS' emotional well-being and autonomy. The aim of A-L S-PIKES is to both enhance skills and confidence in delivering difficult news and to improve the QoL of PALS and their families. Future studies should systematically evaluate the feasibility and effectiveness of A-L S-PIKES to establish its utility in clinical practice.}, } @article {pmid39258714, year = {2024}, author = {Winroth, I and Börjesson, A and Andersen, PM and Karlsson, T}, title = {Cognitive deficits in ALS patients with SOD1 mutations.}, journal = {Journal of clinical and experimental neuropsychology}, volume = {46}, number = {7}, pages = {669-682}, doi = {10.1080/13803395.2024.2393366}, pmid = {39258714}, issn = {1744-411X}, mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/genetics/complications/physiopathology ; *Superoxide Dismutase-1/genetics ; Middle Aged ; *Mutation ; Aged ; *Neuropsychological Tests ; Cognitive Dysfunction/physiopathology/genetics/etiology ; Adult ; Memory, Short-Term/physiology ; C9orf72 Protein/genetics ; Bayes Theorem ; }, abstract = {OBJECTIVE: Cognitive decline is common in patients with amyotrophic lateral sclerosis (ALS), especially in carriers of the mutation C9ORF72HRE. However, cognitive impairment is poorly understood in carriers of mutations in other genes causing ALS. We performed a comprehensive neuropsychological testing in patients with mutations in the SOD1 (mSOD1) gene.

METHODS: We examined 5 cognitive domains in 48 symptomatic patients with either hereditary or sporadic ALS. These were compared with 37 matched controls.

RESULTS: Carriers of SOD1-mutations and sporadic ALS had circumscribed deficits, but in a pattern different from C9ORF72HRE. All groups had deficits in working memory, although mSOD1-carriers significantly outperform sporadic ALS and C9ORF72HRE in an attention-driven visuospatial task involving copying a complex figure. Carriers of the D90A-SOD1 mutation overall performed as well as or better than carriers of other SOD1-mutations, except complex working memory. Bayesian analyses suggest (with evidence of moderate strength) that tasks involving the language domain did not differ between controls, mSOD1 and sporadic ALS.

CONCLUSION: Distinct cognitive impairments are prevalent in different ALS-syndromes and vary in patients with different pathogenic SOD1 mutations. The type and degree of impairment differed depending on genotype and was significantly least pronounced in patients homozygous for the D90A SOD1 mutation. The presence of cognitive deficits may influence optimal clinical management and intervention. We propose that cognitive assessment should be included in the routine examination of new patients suspected of ALS. Neuropsychological assessment is an under-recognized outcome parameter in clinical drug trials.}, } @article {pmid39258588, year = {2025}, author = {Walsh, S and Simmons, Z and Miyamoto, S and Geronimo, A}, title = {A nurse coaching intervention to improve support to individuals living with ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {22-28}, doi = {10.1080/21678421.2024.2399154}, pmid = {39258588}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/nursing/psychology ; Male ; Female ; Middle Aged ; *Quality of Life/psychology ; *Mentoring/methods ; Aged ; *Self Efficacy ; Motivational Interviewing/methods ; Adult ; }, abstract = {OBJECTIVE: Health coaching may supplement the multidisciplinary ALS clinic model to facilitate patient-centered health behavior change. The aim of this study was to determine the effects of nurse health coaching (NHC) on the quality of life and self-efficacy of individuals living with ALS.

METHODS: Twenty-nine participants were randomized at 1:1 to the standard of care and coaching arms. All participants attended multidisciplinary ALS clinic visits quarterly, at which times they completed assessments of quality of life and self-efficacy. Those in the coaching arm participated in monthly coaching with a nurse coach over 12 months. The coaching sessions utilized motivational interviewing to identify personal goals along with barriers and solutions to achieve them. Linear mixed-effect models were used to quantify the effect of coaching on quality of life and self-efficacy outcomes. Thematic analysis was performed to summarize the participants' experiences with coaching.

RESULTS: Adherence to the coaching intervention was good. No effects of coaching were observed on the primary outcomes of quality of life and self-efficacy, although debriefed participants reported that they would recommend it to others. Patients and caregivers reflected on the impacts of coaching that extended beyond the pre-defined study outcomes and measures put in place to gauge effectiveness.

CONCLUSIONS: The elicited qualitative themes illustrating patient experience of coaching demonstrate the utility of nurse coaching as an important adjunct support to complement the multidisciplinary ALS clinic model.}, } @article {pmid39258586, year = {2025}, author = {Sommers-Spijkerman, M and Zwarts-Engelbert, A and Kruitwagen-Van Reenen, E and Van Eijk, RPA and Visser-Meily, JMA and Heijmans, E and Austin, J and Drossaert, C and Bohlmeijer, E and Beelen, A}, title = {Acceptability and potential benefit of a self-compassion intervention for people living with amyotrophic lateral sclerosis: a mixed methods pilot study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {29-39}, doi = {10.1080/21678421.2024.2400516}, pmid = {39258586}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/rehabilitation ; Male ; Female ; Pilot Projects ; Middle Aged ; Aged ; *Empathy ; *Caregivers/psychology ; Adaptation, Psychological/physiology ; Adult ; Surveys and Questionnaires ; Self Concept ; Patient Acceptance of Health Care/psychology/statistics & numerical data ; Psychological Distress ; }, abstract = {OBJECTIVE: This proof-of-concept study aimed to explore the acceptability and potential benefit of a self-guided online self-compassion intervention to aid resilient coping and reduce emotional distress among patients and caregivers living with ALS.

METHODS: A single-arm pilot study was conducted in 20 adults living with ALS either as a patient or as a caregiver. Acceptability was examined using questionnaires (n = 20) and semi-structured interviews (n = 9). Potential benefit was assessed as changes in self-compassion, self-criticism and emotional distress, determined using psychological questionnaires at 3 and 6 weeks. Questionnaires were analyzed using linear mixed-effects models and interview data using inductive thematic analysis.

RESULTS: Out of 20 participants who started the intervention, 16 completed the study (80%). The majority of study completers (12/16) were satisfied with the intervention, but the data suggest room for improvement in terms of personalization. Qualitative data revealed multiple psychological benefits of using the intervention, including self-kindness, emotional self-awareness and savoring. Although not statistically significant, quantitative data showed positive trends with increased self-compassion (mean difference: 2.07; 95% CI: -.5.76 - 1.63) and reduced self-criticism (mean difference: -2.62; 95% CI: -.1.97 - 7.23) and emotional distress (mean difference: -2.49; 95% CI: -.51 - 5.50) at week 6 compared to baseline.

CONCLUSIONS: The findings suggest that a self-compassion intervention is acceptable to people living with ALS, but its beneficial effects and the mechanisms involved have yet to be established in larger and more diverse samples, using controlled designs.}, } @article {pmid39257530, year = {2024}, author = {Baird, MC and Likhite, SB and Vetter, TA and Caporale, JR and Girard, HB and Roussel, FS and Howard, AE and Schwartz, MK and Reed, AR and Kaleem, A and Zhang, X and Meyer, KC}, title = {Combination AAV therapy with galectin-1 and SOD1 downregulation demonstrates superior therapeutic effect in a severe ALS mouse model.}, journal = {Molecular therapy. Methods & clinical development}, volume = {32}, number = {3}, pages = {101312}, pmid = {39257530}, issn = {2329-0501}, abstract = {Neuroinflammation is a miscreant in accelerating progression of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, treatments targeting neuroinflammation alone have led to disappointing results in clinical trials. Both neuronal and non-neuronal cell types have been implicated in the pathogenesis of ALS, and multiple studies have shown correction of each cell type has beneficial effects on disease outcome. Previously, we shown that AAV9-mediated superoxide dismutase 1 (SOD1) suppression in motor neurons and astrocytes significantly improves motor function and extends survival in ALS mouse models. Despite neuron and astrocyte correction, ALS mice still succumb to death with microgliosis observed in endpoint tissue. Therefore, we hypothesized that the optimal therapeutic approach will target and simultaneously correct motor neurons, astrocytes, and microglia. Here, we developed a novel approach to indirectly target microglia with galectin-1 (Gal1) and combined this with our previously established AAV9.SOD1.short hairpin RNA treatment. We show Gal1 conditioning of SOD1 [G93A] microglia decreases inflammatory markers and rescues motor neuron death in vitro. When paired with SOD1 downregulation, we found a synergistic effect of combination treatment in vivo and show a significant extension of survival of SOD1 [G93A] mice over SOD1 suppression alone. These results highlight the importance of targeting inflammatory microglia as a critical component in future therapeutic development.}, } @article {pmid39255192, year = {2024}, author = {Hwang, RD and Lu, Y and Tang, Q and Periz, G and Park, G and Li, X and Xiang, Q and Liu, Y and Zhang, T and Wang, J}, title = {DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {39255192}, issn = {2050-084X}, support = {R01 NS128494/NS/NINDS NIH HHS/United States ; I01 BX002466/BX/BLRD VA/United States ; R01 NS074324/NS/NINDS NIH HHS/United States ; R01 NS110098/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; NS074324/NH/NIH HHS/United States ; NS089616/NH/NIH HHS/United States ; NS128494/NH/NIH HHS/United States ; NS110098/NH/NIH HHS/United States ; }, mesh = {Animals ; *Proteasome Endopeptidase Complex/metabolism ; *Proteostasis ; Humans ; Drosophila/metabolism ; Autophagy ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Neurons/metabolism ; Drosophila melanogaster/metabolism/genetics ; }, abstract = {Proteotoxic stress impairs cellular homeostasis and underlies the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The proteasomal and autophagic degradation of proteins are two major pathways for protein quality control in the cell. Here, we report a genome-wide CRISPR screen uncovering a major regulator of cytotoxicity resulting from the inhibition of the proteasome. Dihydrolipoamide branched chain transacylase E2 (DBT) was found to be a robust suppressor, the loss of which protects against proteasome inhibition-associated cell death through promoting clearance of ubiquitinated proteins. Loss of DBT altered the metabolic and energetic status of the cell and resulted in activation of autophagy in an AMP-activated protein kinase (AMPK)-dependent mechanism in the presence of proteasomal inhibition. Loss of DBT protected against proteotoxicity induced by ALS-linked mutant TDP-43 in Drosophila and mammalian neurons. DBT is upregulated in the tissues of ALS patients. These results demonstrate that DBT is a master switch in the metabolic control of protein quality control with implications in neurodegenerative diseases.}, } @article {pmid39255062, year = {2024}, author = {Germeys, C and Vandoorne, T and Davie, K and Poovathingal, S and Heeren, K and Vermeire, W and Nami, F and Moisse, M and Quaegebeur, A and Sierksma, A and Rué, L and Sicart, A and Eykens, C and De Cock, L and De Strooper, B and Carmeliet, P and Van Damme, P and De Bock, K and Van Den Bosch, L}, title = {Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response.}, journal = {Cell reports}, volume = {43}, number = {9}, pages = {114719}, doi = {10.1016/j.celrep.2024.114719}, pmid = {39255062}, issn = {2211-1247}, support = {/ERC_/European Research Council/International ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; *Astrocytes/metabolism ; Disease Models, Animal ; Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors/genetics/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Interferons/metabolism ; *Motor Neurons/metabolism ; *Zebrafish/metabolism ; }, abstract = {Neuroinflammation and dysregulated energy metabolism are linked to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The egl-9 family hypoxia-inducible factor (EGLN) enzymes, also known as prolyl hydroxylase domain (PHD) enzymes, are metabolic sensors regulating cellular inflammation and metabolism. Using an oligonucleotide-based and a genetic approach, we showed that the downregulation of Egln2 protected motor neurons and mitigated the ALS phenotype in two zebrafish models and a mouse model of ALS. Single-nucleus RNA sequencing of the murine spinal cord revealed that the loss of EGLN2 induced an astrocyte-specific downregulation of interferon-stimulated genes, mediated via the stimulator of interferon genes (STING) protein. In addition, we found that the genetic deletion of EGLN2 restored this interferon response in patient induced pluripotent stem cell (iPSC)-derived astrocytes, confirming the link between EGLN2 and astrocytic interferon signaling. In conclusion, we identified EGLN2 as a motor neuron protective target normalizing the astrocytic interferon-dependent inflammatory axis in vivo, as well as in patient-derived cells.}, } @article {pmid39254699, year = {2024}, author = {Maccabeo, A and Pateri, MI and Pili, F and Pilotto, S and Pierri, V and Muroni, A and Ercoli, T and Montisci, R and Marchetti, MF and Martis, A and Fazzini, L and Defazio, G and Puligheddu, M and Borghero, G}, title = {Takotsubo syndrome in a Sardinian amyotrophic lateral sclerosis cohort.}, journal = {Journal of neurology}, volume = {271}, number = {12}, pages = {7489-7493}, pmid = {39254699}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/complications/physiopathology ; *Takotsubo Cardiomyopathy/physiopathology/epidemiology/etiology ; Female ; Italy/epidemiology ; Aged ; Middle Aged ; Retrospective Studies ; Cohort Studies ; Male ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is known to be associated with varying degrees of autonomic and cardiovascular dysfunction. Recent case reports showed that ALS may be linked to Takotsubo syndrome (TTS). We assessed the frequency of TTS in an incident ALS cohort from Sardinia, Italy, and investigated the relationship of TTS with ALS course.

METHODS: We retrospectively examined a 10-year (2010-2019) incident cohort of ALS patients of Sardinian ancestry, reported TTS frequency and patients' clinical characteristics. Following, we checked for TTS among patients with ALS onset after 2019 and focused on the same features as for the incident cohort.

RESULTS: Our incident cohort included 344 ALS patients and 5 of them (1.45%) developed TTS. All were female and their median onset age was 71.5 years (IQR 62.75-77). Two patients had spinal and three bulbar onset, though all patients had bulbar involvement and were at an advanced stage of disease (ALSFRS ≤ 25, King's ≥ 3) at TTS diagnosis. We identified a potential TTS trigger in three patients (hospitalization for PEG placement, pneumonia). Among patients who had ALS onset after 2019, we identified a further TTS case and described it.

CONCLUSION: TTS is not a rare condition in ALS. Female sex, bulbar involvement, and later age of disease onset may be important risk factors for developing this cardiac condition and a physical or psychological trigger is often observed. Despite autonomic dysfunction in ALS has been already demonstrated, the precise physiopathological mechanism underlying TTS needs to be further clarified.}, } @article {pmid39254548, year = {2025}, author = {Zhang, M and Xiang, C and Niu, R and He, X and Luo, W and Liu, W and Gu, R}, title = {Liposomes as versatile agents for the management of traumatic and nontraumatic central nervous system disorders: drug stability, targeting efficiency, and safety.}, journal = {Neural regeneration research}, volume = {20}, number = {7}, pages = {1883-1899}, pmid = {39254548}, issn = {1673-5374}, abstract = {Various nanoparticle-based drug delivery systems for the treatment of neurological disorders have been widely studied. However, their inability to cross the blood-brain barrier hampers the clinical translation of these therapeutic strategies. Liposomes are nanoparticles composed of lipid bilayers, which can effectively encapsulate drugs and improve drug delivery across the blood-brain barrier and into brain tissue through their targeting and permeability. Therefore, they can potentially treat traumatic and nontraumatic central nervous system diseases. In this review, we outlined the common properties and preparation methods of liposomes, including thin-film hydration, reverse-phase evaporation, solvent injection techniques, detergent removal methods, and microfluidics techniques. Afterwards, we comprehensively discussed the current applications of liposomes in central nervous system diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, and brain tumors. Most studies related to liposomes are still in the laboratory stage and have not yet entered clinical trials. Additionally, their application as drug delivery systems in clinical practice faces challenges such as drug stability, targeting efficiency, and safety. Therefore, we proposed development strategies related to liposomes to further promote their development in neurological disease research.}, } @article {pmid39254482, year = {2025}, author = {García-Parra, B and Guiu, JM and Povedano, M and Modamio, P}, title = {A scoping review of the role of managed entry agreements in upcoming drugs for amyotrophic lateral sclerosis: learning from the case of spinal muscular atrophy.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {48-57}, doi = {10.1080/21678421.2024.2400522}, pmid = {39254482}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Muscular Atrophy, Spinal/drug therapy ; }, abstract = {INTRODUCTION: The therapeutic options for spinal muscular atrophy (SMA) are encouraging. However, there is currently no cure for amyotrophic lateral sclerosis (ALS). The clinical and economic uncertainty surrounding innovative treatments for rare neurodegenerative diseases makes it necessary to understand managed entry agreements (MEAs). The aim of this study was to review whether models of MEAs in SMA could be extrapolated to ALS.

METHODS: We performed a scoping review with information on MEAs on SMA in Web of Science (WOS), PubMed, Lyfegen Library, the National Institute for Health and Care Excellence (NICE), and the Canadian Agency for Drugs and Technologies in Health (CADTH).

RESULTS: We found 45 results in WOS and PubMed. After an initial survey, 10 were reviewed to assess eligibility, and three were selected. We obtained 44 results from Lyfegen Library, and three results each from NICE and CADTH.

CONCLUSION: The main objective of MEAs is to reduce uncertainty in the financing of drugs with a high budgetary impact and clinical concerns, as is the case with drugs for SMA and ALS. While the information available on MEAs in SMA is scarce, some conceptual models are publicly available. MEAs for long-term treatments for SMA could be used for the design of MEAs in ALS because of their similarities in economic and clinical uncertainty.}, } @article {pmid39253877, year = {2024}, author = {Thornburg-Suresh, EJC and Summers, DW}, title = {Microtubules, Membranes, and Movement: New Roles for Stathmin-2 in Axon Integrity.}, journal = {Journal of neuroscience research}, volume = {102}, number = {9}, pages = {e25382}, pmid = {39253877}, issn = {1097-4547}, support = {R01 NS126191/NS/NINDS NIH HHS/United States ; R01NS126191/NH/NIH HHS/United States ; }, mesh = {*Stathmin/metabolism ; *Microtubules/metabolism ; Humans ; *Axons/metabolism/physiology ; Animals ; Cell Membrane/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; }, abstract = {Neurons establish functional connections responsible for how we perceive and react to the world around us. Communication from a neuron to its target cell occurs through a long projection called an axon. Axon distances can exceed 1 m in length in humans and require a dynamic microtubule cytoskeleton for growth during development and maintenance in adulthood. Stathmins are microtubule-associated proteins that function as relays between kinase signaling and microtubule polymerization. In this review, we describe the prolific role of Stathmins in microtubule homeostasis with an emphasis on emerging roles for Stathmin-2 (Stmn2) in axon integrity and neurodegeneration. Stmn2 levels are altered in Amyotrophic Lateral Sclerosis and loss of Stmn2 provokes motor and sensory neuropathies. There is growing potential for employing Stmn2 as a disease biomarker or even a therapeutic target. Meeting this potential requires a mechanistic understanding of emerging complexity in Stmn2 function. In particular, Stmn2 palmitoylation has a surprising contribution to axon maintenance through undefined mechanisms linking membrane association, tubulin interaction, and axon transport. Exploring these connections will reveal new insight on neuronal cell biology and novel opportunities for disease intervention.}, } @article {pmid39253499, year = {2024}, author = {Thompson, EG and Spead, O and Akerman, SC and Curcio, C and Zaepfel, BL and Kent, ER and Philips, T and Vijayakumar, BG and Zacco, A and Zhou, W and Nagappan, G and Rothstein, JD}, title = {A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV-C9ORF72 (G4C2)66 mouse model.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39253499}, issn = {2692-8205}, support = {F32 NS120940/NS/NINDS NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {The G4C2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. Despite displaying key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis, the AAV-(G4C2)66 mouse model in this study exhibits negligible neuronal loss, no motor deficits, and functionally unimpaired TAR DNA-binding protein-43 (TDP-43). While our findings indicate and support that this is a robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease associated neurodegeneration, TDP-43 dysfunction, gliosis, and motor performance. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.}, } @article {pmid39252332, year = {2024}, author = {Li, LS and Tong, Y and Yuan, C and Zhang, W}, title = {Evaluation of diagnostic value and Mendelian randomization study of appendicitis hub genes obtained by WGCNA analysis.}, journal = {Medicine}, volume = {103}, number = {36}, pages = {e39307}, doi = {10.1097/MD.0000000000039307}, pmid = {39252332}, issn = {1536-5964}, mesh = {Humans ; *Appendicitis/genetics/diagnosis ; *Mendelian Randomization Analysis ; Gene Expression Profiling/methods ; ROC Curve ; Gene Regulatory Networks ; Nomograms ; Gastrointestinal Microbiome/genetics ; }, abstract = {The timely and precise diagnosis of appendicitis was deemed essential. This study sought to examine the diagnostic significance of hub genes linked to appendicitis and to delve deeper into the pathophysiology of the condition. Differential gene expression analysis revealed distinct genes in the appendicitis group compared to other abdominal pain group, while weighted gene co-expression network analysis identified appendicitis-associated modules. Further analysis of common genes was conducted using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis. The diagnostic efficiency of hub genes was explored through the use of nomograms and receiver operator characteristic curves. Additionally, immunoinfiltration analysis was performed to investigate the immune cell infiltration in both groups. The causal relationship between hub genes and appendicitis, as well as gut microbiota and appendicitis, was ultimately examined through Mendelian randomization. By conducting differential expression analysis and weighted gene co-expression network analysis, a total of 757 common genes were identified. Subsequent Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses revealed that these common genes were primarily associated with positive regulation of cell adhesion, focal adhesion, protein serine kinase activity, and amyotrophic lateral sclerosis. Utilizing Cytoscape software, the top 10 genes with the highest degree of interaction were identified as RPS3A, RPSA, RPL5, RPL37A, RPS27L, FLT3LG, ARL6IP1, RPL32, MRPL3, and GSPT1. Evaluation using nomograms and receiver operator characteristic curves demonstrated the diagnostic value of these hub genes. Ultimately, a causal relationship between hub genes and appendicitis was not identified in our study. Nevertheless, our findings indicate that appendicitis is correlated with 9 gut microbiota. This study identified 5 hub genes, specifically HSP90AA1, RPL5, MYC, CD44, and RPS3A, which exhibit diagnostic significance of appendicitis. Furthermore, the elucidation of these hub genes aids in enhancing our comprehension of the molecular pathways implicated in the development of appendicitis.}, } @article {pmid39251386, year = {2024}, author = {Liddell, JR and Hilton, JBW and Wang, YJ and Billings, JL and Nikseresht, S and Kysenius, K and Fuller-Jackson, JP and Hare, DJ and Crouch, PJ}, title = {Decreased spinal cord motor neuron numbers in mice depleted of central nervous system copper.}, journal = {Metallomics : integrated biometal science}, volume = {16}, number = {9}, pages = {}, pmid = {39251386}, issn = {1756-591X}, support = {//National Health and Medical Research Council/ ; }, mesh = {Animals ; *Copper/metabolism ; *Motor Neurons/metabolism/pathology ; *Spinal Cord/metabolism/pathology ; Mice ; *Copper Transporter 1/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Central Nervous System/metabolism ; Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism ; Disease Models, Animal ; }, abstract = {Disrupted copper availability in the central nervous system (CNS) is implicated as a significant feature of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Solute carrier family 31 member 1 (Slc31a1; Ctr1) governs copper uptake in mammalian cells and mutations affecting Slc31a1 are associated with severe neurological abnormalities. Here, we examined the impact of decreased CNS copper caused by ubiquitous heterozygosity for functional Slc31a1 on spinal cord motor neurons in Slc31a1+/- mice. Congruent with the CNS being relatively susceptible to disrupted copper availability, brain and spinal cord tissue from Slc31a1+/- mice contained significantly less copper than wild-type littermates, even though copper levels in other tissues were unaffected. Slc31a1+/- mice had less spinal cord α-motor neurons compared to wild-type littermates, but they did not develop any overt physical signs of motor impairment. By contrast, ALS model SOD1G37R mice had fewer α-motor neurons than control mice and exhibited clear signs of motor function impairment. With the expression of Slc31a1 notwithstanding, spinal cord expression of genes related to copper handling revealed only minor differences between Slc31a1+/- and wild-type mice. This contrasted with SOD1G37R mice where changes in the expression of copper handling genes were pronounced. Similarly, the expression of genes related to toxic glial activation was unchanged in spinal cords from Slc31a1+/- mice but highly upregulated in SOD1G37R mice. Together, results from the Slc31a1+/- mice and SOD1G37R mice indicate that although depleted CNS copper has a significant impact on spinal cord motor neuron numbers, the manifestation of overt ALS-like motor impairment requires additional factors.}, } @article {pmid39251203, year = {2025}, author = {Rolf, O and Blana, A and Hagedorn, P}, title = {Implantation of Reverse Shoulder Endoprothesis Using Navigation.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {163}, number = {2}, pages = {176-180}, doi = {10.1055/a-2346-9916}, pmid = {39251203}, issn = {1864-6743}, mesh = {Humans ; *Surgery, Computer-Assisted/methods ; Imaging, Three-Dimensional ; Arthroplasty, Replacement, Shoulder/methods ; Shoulder Prosthesis ; Augmented Reality ; Prosthesis Design ; Tomography, X-Ray Computed ; Shoulder Joint/surgery/diagnostic imaging ; }, abstract = {Die Implantation einer inversen Schulterendoprothese (TEP) stellt eine bewährte Methode zur Schmerzlinderung und Schulterfunktionsverbesserung dar. Die Ergebnisse variieren je nach Patientenalter, Krankheitsgrad und Erfahrung des Operateurs. Indikationen für eine inverse TEP sind vielfältig, von der Defektarthropathie bis hin zu Frakturen. Aktuelle Studien zeigen verbesserte Überlebensraten und reduzierte Komplikationen nach primärer Implantation. Die präoperative Planung mittels 3-D-CT oder MRT gilt als Goldstandard. Patientenspezifische Instrumente (PSI) wurden eingeführt, sind jedoch mit Kosten und Wartezeit verbunden. Die Navigation mit "Augmented Reality" (AR) bietet eine effizientere Alternative. Die intraoperative Übertragung der Planung auf den Patienten erfolgt über AR-Brillen und ermöglicht Echtzeitinformationen, wodurch der Chirurg den Blick vom Situs nicht abwenden muss. Dies optimiert den Workflow und bietet potenziell präzisere Implantationsresultate. Zusammenfassend bietet die Kombination von 3-D-Planung, Navigation und AR eine vielversprechende Methode für präzise und effiziente Implantationen von inversen Schulterendoprothesen. Allerdings steht der Nachweis verbesserter Standzeiten und Funktionsscores noch aus.}, } @article {pmid39251159, year = {2024}, author = {Liu, Y and Chen, H and Zhang, Z and Wang, J}, title = {Development of an integrated framework for dissecting source-oriented ecological and health risks of heavy metals in soils.}, journal = {Chemosphere}, volume = {364}, number = {}, pages = {143299}, doi = {10.1016/j.chemosphere.2024.143299}, pmid = {39251159}, issn = {1879-1298}, mesh = {*Metals, Heavy/analysis ; *Soil Pollutants/analysis ; Environmental Exposure/statistics & numerical data ; Risk Assessment ; Soil/chemistry ; }, abstract = {Heavy metals (HMs) in soils pose significant risks on ecosystem and human health. To design targeted regulatory measures for mitigating and controlling the risk, it is necessary to accurately identify the pollution sources and environmental risks of soil HMs, as well as to reveal the linkages between them. To date, yet systematic investigation aimed at deciphering the links between source apportionment of soil HMs and their associated environmental risks is still lacking. To fill the gap, an integrated framework has been developed in this study and applied for dissecting the source-sink relationship and source-oriented ecological and health risks of soil HMs in Shanxi, a province with rich coal resource, in which long-term coal mining activities in history has resulted in soil HMs pollution and unavoidably posed environmental risks. Two advanced receptor models, multivariate curve resolution alternating least squares based on maximum likelihood principal component analysis (MCR-ALS/MLPCA) and multilinear engine 2 (ME2), have been employed for apportioning the potential sources, and their apportionment results are jointly incorporated into a modified ecological risk index and a probabilistic health risk assessment model for identifying the source-oriented ecological and health risks posed by soil metals. The results show that the soils in study area have been polluted by HMs (i.e., Cd, Cr, Hg and As) to varying degrees. Industrial activities (35%-35.8%), agricultural activities (11.1%-20.5%), atmospheric deposition (10.5%-13%) and mix source (31.5%-42.6%) are apportioned as the main contributors of soil HMs in the area. The source-oriented ecological risk assessment suggests Hg has presented significant ecological risk and largely contributed by the sources from atmospheric deposition and industrial activities. The source-oriented health risk assessment shows the non-carcinogenic hazard level and carcinogenic risk posed by soil HMs in the study area are acceptable. Relatively, industrial activities and mix source have contributed more on the health risks.}, } @article {pmid39251025, year = {2025}, author = {Del Rosso, JQ and Zaenglein, A and Callender, V and Schlosser, B and Graber, E and Keri, J and Weiss, J}, title = {Response to Reynolds et al's "Guidelines of care for the management of acne vulgaris".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {1}, pages = {e15}, doi = {10.1016/j.jaad.2024.07.1528}, pmid = {39251025}, issn = {1097-6787}, } @article {pmid39250425, year = {2025}, author = {Neuhaus, D and Rost, T and Haas, T and Wendebourg, MJ and Schulze, K and Schlaeger, R and Scheurer, E and Lenz, C}, title = {Comparative analysis of in situ and ex situ postmortem brain MRI: Evaluating volumetry, DTI, and relaxometry.}, journal = {Magnetic resonance in medicine}, volume = {93}, number = {1}, pages = {213-227}, doi = {10.1002/mrm.30264}, pmid = {39250425}, issn = {1522-2594}, support = {//Stiftung zur Foerderung der gastroenterologischen und der allgemeinen klinischen Forschung sowie der medizinischen Bildauswertung/ ; //Neuromuscular Research Association Basel/ ; }, mesh = {*Postmortem Imaging/methods ; *Brain/diagnostic imaging/drug effects/pathology ; *Diffusion Tensor Imaging/instrumentation/methods ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Organ Size ; Tissue Fixation/methods ; *Formaldehyde/chemistry ; Anisotropy ; Humans ; Male ; Middle Aged ; Aged ; *Magnetic Resonance Imaging/instrumentation/methods ; }, abstract = {PURPOSE: To compare postmortem in situ with ex situ MRI parameters, including volumetry, diffusion tensor imaging (DTI), and relaxometry for assessing methodology-induced alterations, which is a crucial prerequisite when performing MRI biomarker validation.

METHODS: MRI whole-brain scans of five deceased patients with amyotrophic lateral sclerosis were performed at 3 T. In situ scans were conducted within 32 h after death (SD 18 h), and ex situ scans after brain extraction and 3 months of formalin fixation. The imaging protocol included MP2RAGE, DTI, and multi-contrast spin-echo and multi-echo gradient-echo sequences. Volumetry, fractional anisotropy, mean diffusivity, T1, T2, and T 2 * $$ {T} _2^{\ast } $$ have been assessed for specific brain regions.

RESULTS: When comparing ex situ to in situ values, the following results were obtained. Deep gray matter as well as the thalamus and the hippocampus showed a reduced volume. Fractional anisotropy was reduced in the cortex and the whole brain. Mean diffusivity was decreased in white matter and deep gray matter. T1 and T2 were reduced in all investigated structures, whereas T 2 * $$ {T} _2^{\ast } $$ was increased in the cortex.

CONCLUSION: The results of this study show that the volumes and MRI parameters of several brain regions are potentially affected by tissue extraction and subsequent formalin fixation, suggesting that methodological alterations are present in ex situ MRI. To avoid overlap of indistinguishable methodological and disease-related changes, we recommend performing in situ postmortem MRI as an additional intermediate step for in vivo MRI biomarker validation.}, } @article {pmid39249108, year = {2024}, author = {Jin, W and Boss, J and Bakulski, KM and Goutman, SA and Feldman, EL and Fritsche, LG and Mukherjee, B}, title = {Improving prediction models of amyotrophic lateral sclerosis (ALS) using polygenic, pre-existing conditions, and survey-based risk scores in the UK Biobank.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6923-6934}, pmid = {39249108}, issn = {1432-1459}, support = {R01TS000344/CC/CDC HHS/United States ; 20-IIA-532//ALS Association/ ; K23 ES027221/ES/NIEHS NIH HHS/United States ; K23ES027221/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology/diagnosis ; Humans ; United Kingdom/epidemiology ; *Multifactorial Inheritance ; Male ; Female ; Middle Aged ; *Biological Specimen Banks ; Aged ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Adult ; Phenotype ; UK Biobank ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) causes profound impairments in neurological function, and a cure for this devastating disease remains elusive. This study aimed to identify pre-disposing genetic, phenotypic, and exposure-related factors for amyotrophic lateral sclerosis using multi-modal data and assess their joint predictive potential.

METHODS: Utilizing data from the UK (United Kingdom) Biobank, we analyzed an unrelated set of 292 ALS cases and 408,831 controls of European descent. Two polygenic risk scores (PRS) are constructed: "GWAS Hits PRS" and "PRS-CS," reflecting oligogenic and polygenic ALS risk profiles, respectively. Time-restricted phenome-wide association studies (PheWAS) were performed to identify pre-existing conditions increasing ALS risk, integrated into phenotypic risk scores (PheRS). A poly-exposure score ("PXS") captures the influence of environmental exposures measured through survey questionnaires. We evaluate the performance of these scores for predicting ALS incidence and stratifying risk, adjusting for baseline demographic covariates.

RESULTS: Both PRSs modestly predicted ALS diagnosis but with increased predictive power when combined (covariate-adjusted receiver operating characteristic [AAUC] = 0.584 [0.525, 0.639]). PheRS incorporated diagnoses 1 year before ALS onset (PheRS1) modestly discriminated cases from controls (AAUC = 0.515 [0.472, 0.564]). The "PXS" did not significantly predict ALS. However, a model incorporating PRSs and PheRS1 improved the prediction of ALS (AAUC = 0.604 [0.547, 0.667]), outperforming a model combining all risk scores. This combined risk score identified the top 10% of risk score distribution with a fourfold higher ALS risk (95% CI [2.04, 7.73]) versus those in the 40%-60% range.

DISCUSSION: By leveraging UK Biobank data, our study uncovers pre-disposing ALS factors, highlighting the improved effectiveness of multi-factorial prediction models to identify individuals at highest risk for ALS.}, } @article {pmid39249104, year = {2024}, author = {Hafsteinsdóttir, B and Farman, H and Lagerström, N and Zetterberg, H and Andersen, O and Novakova, L and Nellgård, B and Rosén, H and Malmeström, C and Rosenstein, I and Lycke, J and Axelsson, M}, title = {Neurofilament light chain as a diagnostic and prognostic biomarker in Guillain-Barré syndrome.}, journal = {Journal of neurology}, volume = {271}, number = {11}, pages = {7282-7293}, pmid = {39249104}, issn = {1432-1459}, support = {ALFGBG-722081//Swedish State Support for Clinical Research/ ; }, mesh = {Humans ; *Guillain-Barre Syndrome/blood/diagnosis/cerebrospinal fluid ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Female ; Male ; Middle Aged ; *Biomarkers/blood/cerebrospinal fluid ; Adult ; Prognosis ; Aged ; Amyotrophic Lateral Sclerosis/blood/diagnosis/cerebrospinal fluid ; }, abstract = {BACKGROUND: Elevated neurofilament light chain (NfL) levels are associated with worse prognosis in Guillain-Barré syndrome (GBS). Our objectives were to determine the utility of serum NfL (sNfL), cerebrospinal fluid (CSF)/serum NfL ratio and NfL index as prognostic and diagnostic biomarkers for GBS.

METHODS: We measured NfL in serum and/or CSF obtained from 96 GBS patients between 1989 and 2014 in western Sweden. The sNfL Z-scores, NfL ratios and NfL indices were calculated. Outcome was determined with the GBS disability scale (GBSDS) at 3 and 12 months. NfL parameters in GBS were compared with healthy controls (HC), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).

RESULTS: The sNfL Z-score was higher for GBSDS > 2 at 3 months (median [IQR], 3.5 ng/L [3.2-4.0], vs 2.6 [1.7-3.4], p = 0.008) and at 12 months (3.6 ng/L [3.5-3.8] vs 2.6 [1.8-3.5], p = 0.049). NfL ratio and index were not associated with outcome. The area under the curve (AUC) for sNfL Z-score was 0.76 (95% CI 0.58-0.93, p < 0.0001) for GBSDS > 2 at 3 months. NfL ratio and index were lower in GBS than HC, MS, and ALS. The AUC for the NfL ratio was 0.66 (95% CI 0.55-0.78, p = 0.0018) and for the NfL index 0.86 (95% CI 0.78-0.93, p < 0.0001).

DISCUSSION: Our results confirm sNfL as prognostic biomarker for GBS and the precision was improved using the age-adjusted sNfL Z score. NfL index and Qalb are potential diagnostic biomarkers for GBS.}, } @article {pmid39246739, year = {2024}, author = {Li, S and Gui, J and Passarelli, MN and Andrew, AS and Sullivan, KM and Cornell, KA and Traynor, BJ and Stark, A and Chia, R and Kuenzler, RM and Pioro, EP and Bradley, WG and Stommel, EW}, title = {Genome-Wide and Transcriptome-Wide Association Studies on Northern New England and Ohio Amyotrophic Lateral Sclerosis Cohorts.}, journal = {Neurology. Genetics}, volume = {10}, number = {5}, pages = {e200188}, pmid = {39246739}, issn = {2376-7839}, support = {P30 CA023108/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is an age-associated, fatal neurodegenerative disorder causing progressive paralysis and respiratory failure. The genetic architecture of ALS is still largely unknown.

METHODS: We performed a genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) to understand genetic risk factors for ALS using a population-based case-control study of 435 ALS cases and 279 controls from Northern New England and Ohio. Single nucleotide polymorphism (SNP) genotyping was conducted using the Illumina NeuroChip array. Odds ratios were estimated using covariate-adjusted logistic regression. We also performed a genome-wide SNP-smoking interaction screening. TWAS analyses used PrediXcan to estimate associations between predicted gene expression levels across 15 tissues (13 brain tissues, skeletal muscle, and whole blood) and ALS risk.

RESULTS: GWAS analyses identified the p.A382T missense variant (rs367543041, p = 3.95E-6) in the TARDBP gene, which has previously been reported in association with increased ALS risk and was found to share a close affinity with the Sardinian haplotype. Both GWAS and TWAS analyses suggested that ZNF235 is associated with decreased ALS risk.

DISCUSSION: Our results support the need for future evaluation to clarify the role of these potential genetic risk factors for ALS and to understand genetic susceptibility to environmental risk factors.}, } @article {pmid39246712, year = {2024}, author = {Calderón-Garcidueñas, L and Cejudo-Ruiz, FR and Stommel, EW and González-Maciel, A and Reynoso-Robles, R and Torres-Jardón, R and Tehuacanero-Cuapa, S and Rodríguez-Gómez, A and Bautista, F and Goguitchaichvili, A and Pérez-Guille, BE and Soriano-Rosales, RE and Koseoglu, E and Mukherjee, PS}, title = {Single-domain magnetic particles with motion behavior under electromagnetic AC and DC fields are a fatal cargo in Metropolitan Mexico City pediatric and young adult early Alzheimer, Parkinson, frontotemporal lobar degeneration and amyotrophic lateral sclerosis and in ALS patients.}, journal = {Frontiers in human neuroscience}, volume = {18}, number = {}, pages = {1411849}, pmid = {39246712}, issn = {1662-5161}, abstract = {Metropolitan Mexico City (MMC) children and young adults exhibit overlapping Alzheimer and Parkinsons' diseases (AD, PD) and TAR DNA-binding protein 43 pathology with magnetic ultrafine particulate matter (UFPM) and industrial nanoparticles (NPs). We studied magnetophoresis, electron microscopy and energy-dispersive X-ray spectrometry in 203 brain samples from 14 children, 27 adults, and 27 ALS cases/controls. Saturation isothermal remanent magnetization (SIRM), capturing magnetically unstable FeNPs ~ 20nm, was higher in caudate, thalamus, hippocampus, putamen, and motor regions with subcortical vs. cortical higher SIRM in MMC ≤ 40y. Motion behavior was associated with magnetic exposures 25-100 mT and children exhibited IRM saturated curves at 50-300 mT associated to change in NPs position and/or orientation in situ. Targeted magnetic profiles moving under AC/AD magnetic fields could distinguish ALS vs. controls. Motor neuron magnetic NPs accumulation potentially interferes with action potentials, ion channels, nuclear pores and enhances the membrane insertion process when coated with lipopolysaccharides. TEM and EDX showed 7-20 nm NP Fe, Ti, Co, Ni, V, Hg, W, Al, Zn, Ag, Si, S, Br, Ce, La, and Pr in abnormal neural and vascular organelles. Brain accumulation of magnetic unstable particles start in childhood and cytotoxic, hyperthermia, free radical formation, and NPs motion associated to 30-50 μT (DC magnetic fields) are critical given ubiquitous electric and magnetic fields exposures could induce motion behavior and neural damage. Magnetic UFPM/NPs are a fatal brain cargo in children's brains, and a preventable AD, PD, FTLD, ALS environmental threat. Billions of people are at risk. We are clearly poisoning ourselves.}, } @article {pmid39246264, year = {2024}, author = {Iseli, LM and Poppe, C and Wangmo, T}, title = {Receiving and adjusting to a diagnosis of ALS: A qualitative study with informal caregivers.}, journal = {Palliative & supportive care}, volume = {}, number = {}, pages = {1-7}, doi = {10.1017/S1478951524001044}, pmid = {39246264}, issn = {1478-9523}, abstract = {OBJECTIVES: Diagnosis of amyotrophic lateral sclerosis (ALS) takes more than 1year from detection of first symptoms. The paper seeks to understand the ALS diagnostic process and adjustment from the perspective of informal caregivers.

METHODS: The data stems from an interview study with 9 current and 13 bereaved informal caregivers of people with ALS in Switzerland. The interviews were analyzed using thematic analysis.

RESULTS: We identified 3 key themes pertaining to ALS diagnosis. In the first theme, we present the close involvement of informal caregivers in the "diagnosis journey." Highlighted within this theme is the important role they play, which ultimately leads to diagnosis of ALS avoiding further delays. Second, we relay their perceptions on "diagnosis communication pitfalls" where they underlined empathy and planning from the part of medical professional, while communicating the terminal diagnosis of ALS. Participants' reactions and adjustments post-ALS diagnosis are described in "the aftermath of diagnosis." In this third theme, we highlight participants' shock and their need to rethink overall life plans and roles in their family.

SIGNIFICANCE OF THE RESULTS: Diagnosis communication that is clear, empathetic, and adjusted to the needs of the patients as well as their caregivers is critical. More work is needed to improve diagnosis communication for ALS patients. Receiving the diagnosis of ALS leads to complete changes in life of caregivers. It is therefore necessary that medical professionals provide adequate support that allows them to plan for their future.}, } @article {pmid39244645, year = {2025}, author = {Tang, IW and Hansen, J and Dickerson, AS and Weisskopf, MG}, title = {Occupational lead exposure and amyotrophic lateral sclerosis survival in the Danish National Patient Registry.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {124-131}, pmid = {39244645}, issn = {2167-9223}, support = {P30 ES000002/ES/NIEHS NIH HHS/United States ; R01 ES019188/ES/NIEHS NIH HHS/United States ; T32 ES007069/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/epidemiology ; Male ; *Occupational Exposure/adverse effects/statistics & numerical data ; Female ; Middle Aged ; Denmark/epidemiology ; *Registries ; *Lead/adverse effects ; Aged ; Adult ; Proportional Hazards Models ; }, abstract = {OBJECTIVES: We investigated the relationship between occupational lead exposure and amyotrophic lateral sclerosis (ALS) survival in Denmark.

METHODS: We identified 2,161 ALS cases diagnosed from 1982 to 2013 with at least 5 years of employment history before ALS diagnosis, via the Danish National Patient Registry. Cases were followed until March 2017. We defined lead exposure as never employed in a lead job, ever employed in a lead job, and ever employed in a lead job by exposure probability (<50% vs. ≥50%), excluding jobs held in the 5 years before diagnosis in main analyses. Survival was evaluated using Cox proportional hazards models and stratified by sex and age of diagnosis.

RESULTS: Median age of diagnosis was 63.5 years, and individuals in lead-exposed jobs were diagnosed at a younger age. Adjusted hazard ratios (aHR) were slightly decreased for men ever lead-exposed (aHR:0.92, 95%CI: 0.80, 1.05) and more so among those diagnosed at age 60-69 (lead ≥ 50% aHR: 0.66, 95%CI: 0.45, 0.98), but reversed for men diagnosed at age 70 and later (aHR: 2.03, 95%CI: 1.13, 3.64). No apparent pattern was observed among women.

CONCLUSIONS: Occupational lead exposure contributed to shorter survival among men diagnosed at older ages. The inverse associations observed for men diagnosed earlier could relate to possible healthy worker hire effect or health advantages of working in lead-exposed jobs. Our results are consistent with an adverse impact of lead exposure on ALS survival at older ages, with the age at which lead's effects on survival worsen later on among those in lead-exposed jobs.}, } @article {pmid39243983, year = {2025}, author = {Mohan, M and Mannan, A and Nauriyal, A and Singh, TG}, title = {Emerging targets in amyotrophic lateral sclerosis (ALS): The promise of ATP-binding cassette (ABC) transporter modulation.}, journal = {Behavioural brain research}, volume = {476}, number = {}, pages = {115242}, doi = {10.1016/j.bbr.2024.115242}, pmid = {39243983}, issn = {1872-7549}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; Animals ; *ATP-Binding Cassette Transporters/metabolism ; Signal Transduction/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative primarily affecting motor neurons, leading to disability and neuronal death, and ATP-Binding Cassette (ABC) transporter due to their role in drug efflux and modulation of various cellular pathways contributes to the pathogenesis of ALS. In this article, we extensively investigated various molecular and mechanistic pathways linking ALS transporter to the pathogenesis of ALS; this involves inflammatory pathways such as Mitogen-Activated Protein Kinase (MAPK), Phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/Akt), Toll-Like Receptor (TLR), Glycogen Synthase Kinase 3β (GSK-3β), Nuclear Factor Kappa-B (NF-κB), and Cyclooxygenase (COX). Oxidative pathways such as Astrocytes, Glutamate, Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Sirtuin 1 (SIRT-1), Forkhead box protein O (FOXO), Extracellular signal-regulated kinase (ERK). Additionally, we delve into the role of autophagic pathways like TAR DNA-binding protein 43 (TDP-43), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and lastly, the apoptotic pathways. Furthermore, by understanding these intricate interactions, we aim to develop novel therapeutic strategies targeting ABC transporters, improving drug delivery, and ultimately offering a promising avenue for treating ALS.}, } @article {pmid39243146, year = {2024}, author = {Jimenez, JV and Tang, MJ and Wilson, MW and Morrison, AH and Ackrivo, J and Choi, PJ}, title = {Initiation of noninvasive ventilation in patients with amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {5}, pages = {1099-1103}, doi = {10.1002/mus.28250}, pmid = {39243146}, issn = {1097-4598}, support = {NIH NHLBI K23 HL-151879//Muscular Dystrophy Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/complications ; *Noninvasive Ventilation/methods ; Female ; Male ; Middle Aged ; Aged ; Retrospective Studies ; *Respiratory Insufficiency/therapy/etiology/physiopathology ; Vital Capacity/physiology ; Hypercapnia/therapy/etiology/physiopathology ; Cohort Studies ; }, abstract = {INTRODUCTION/AIMS: Noninvasive ventilation (NIV) has been shown to improve survival and symptom burden in patients with amyotrophic lateral sclerosis (ALS). However, limited data exist regarding the clinical and physiological parameters at the time of NIV initiation. This study aimed to describe the clinical characteristics and respiratory physiological markers in a cohort of ALS patients with chronic respiratory failure.

METHODS: This is a single-center retrospective cohort study of patients with ALS assessed for NIV initiation between February 2012 and January 2021. NIV was initiated based on insurance eligibility criteria: daytime hypercapnia, defined by partial pressure of carbon dioxide (PaCO2) >45 mm Hg using diurnal transcutaneous CO2 (TcCO2) as a surrogate, a maximal inspiratory pressure (MIP) <60 cmH2O or forced vital capacity (FVC) <50% predicted normal.

RESULTS: We identified 335 patients with ALS and chronic respiratory failure referred to an outpatient home ventilation clinic for NIV initiation. The mean age was 64 years ±11; 151 (45%) were female, 326 (97%) were white, and 100 (29%) had bulbar-onset ALS. At the time of NIV initiation, the mean FVC was 64% ± 19%, the mean MIP; 41 cmH2O ± 17, and diurnal TcCO2; 40 ± 6 mmHg. The most common reasons for NIV initiation were MIP <60 cmH2O (58%) and multiple concomitant indications (28%). Within 1 year of NIV initiation, 126 (37%) patients were deceased.

DISCUSSION: We found that impairment in inspiratory force was the most common reason for NIV initiation and often preceded significant declines in FVC.}, } @article {pmid39242803, year = {2024}, author = {Monselise, EB and Vyazmensky, M and Scherf, T and Batushansky, A and Fishov, I}, title = {Author Correction: D-Glutamate production by stressed Escherichia coli gives a clue for the hypothetical induction mechanism of the ALS disease.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {20873}, doi = {10.1038/s41598-024-71813-5}, pmid = {39242803}, issn = {2045-2322}, } @article {pmid39242576, year = {2024}, author = {Phillips, MCL and Picard, M}, title = {Neurodegenerative disorders, metabolic icebergs, and mitohormesis.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {46}, pmid = {39242576}, issn = {2047-9158}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics ; *Mitochondria/metabolism ; Hormesis/physiology ; Animals ; }, abstract = {Neurodegenerative disorders are typically "split" based on their hallmark clinical, anatomical, and pathological features, but they can also be "lumped" by a shared feature of impaired mitochondrial biology. This leads us to present a scientific framework that conceptualizes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) as "metabolic icebergs" comprised of a tip, a bulk, and a base. The visible tip conveys the hallmark neurological symptoms, neurodegenerative regions, and neuronal protein aggregates for each disorder. The hidden bulk depicts impaired mitochondrial biology throughout the body, which is multifaceted and may be subdivided into impaired cellular metabolism, cell-specific mitotypes, and mitochondrial behaviours, functions, activities, and features. The underlying base encompasses environmental factors, especially modern industrial toxins, dietary lifestyles, and cognitive, physical, and psychosocial behaviours, but also accommodates genetic factors specific to familial forms of AD, PD, and ALS, as well as HD. Over years or decades, chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk, which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip. We propose that impaired mitochondrial biology can be repaired and recalibrated by activating "mitohormesis", which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases. Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of, or suffering with, neurodegenerative disorders.}, } @article {pmid39242281, year = {2025}, author = {Amalia, R and Prasetya Wibawa, A and Surya Aditya, R and Andana Pohan, R and Tetteng, B and Zuhroh, L and Ainy Sadijah, N}, title = {Enhancing caregiver well being by integrating mindfulness and technology in amyotrophic lateral sclerosis care.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {131}, number = {}, pages = {110819}, doi = {10.1016/j.jocn.2024.110819}, pmid = {39242281}, issn = {1532-2653}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/psychology ; Humans ; *Mindfulness/methods ; *Caregivers/psychology ; *Quality of Life ; Mobile Applications ; Stress, Psychological/therapy/psychology ; }, abstract = {This letter discusses the pressing issue of caregiver burden in Amyotrophic Lateral Sclerosis (ALS) care, emphasizing the potential of mindfulness practices to alleviate stress and improve quality of life for caregivers. The integration of digital platforms, such as mindfulness apps, offers an accessible and effective solution, particularly in resource-limited settings. By adopting these strategies, we can enhance caregiver well-being and overall patient care, making it a crucial consideration for global health interventions.}, } @article {pmid39242252, year = {2024}, author = {Benmoussa, A and Assernannas, I and Maatoui-Belabbes, H and Dahmaoui, N and Qachouh, M and Cherkaoui, S and Lamchaheb, M and Rachid, M and Madani, A and Khoubila, N}, title = {[Acquired bone marrow aplasia in children and young adults under the age of 30: Experience of the Pediatric Hematology and Oncology Department of the 20 August Hospital, Casablanca].}, journal = {Bulletin du cancer}, volume = {111}, number = {10}, pages = {944-954}, doi = {10.1016/j.bulcan.2024.06.010}, pmid = {39242252}, issn = {1769-6917}, mesh = {Humans ; Male ; Female ; Infant ; Child, Preschool ; Child ; Adolescent ; Adult ; *Anemia, Aplastic/mortality/therapy ; Morocco/epidemiology ; Retrospective Studies ; Prognosis ; Time-to-Treatment ; *Cyclosporine/therapeutic use ; *Antilymphocyte Serum/therapeutic use ; *Hematopoietic Stem Cell Transplantation ; Treatment Outcome ; Delayed Diagnosis ; }, abstract = {Bone marrow aplasia is a rare and serious hematologic disorder. Although benign, it is a hematologic disorder whose prognosis can be poor and whose spontaneous development can be fatal. Treatment is long, difficult and costly. In developing countries, the mortality rate is high due to the difficulties of therapeutic management, both supportive and specific. We conducted a retrospective study of 92 cases of AM identified in the Pediatric Hematology and Oncology Department of the 20 Août University Hospital in Casablanca over a 10-year period (January 2010-January 2020). In this work, we present an overview of the situation and highlight the difficulties encountered in the management of AM in the Pediatric Hematology and Oncology Department of the University Hospital of Casablanca. In our study, the mean age was 19 years, ranging from 3 months to 29 years, with a peak in the 15-20 age group. The sex ratio (M/F) was 2.06, with a male predominance of 67%. In our series, only 35% of patients had complete bone marrow failure. An anemic syndrome was present in 92% of patients, and hemorrhagic and infectious syndromes were present in 70% and 41% of patients, respectively. The median time from diagnosis to treatment was 82 days. According to the Camitta score, 31% of our patients had mild AM, 41% had severe AM, and 28% had very severe AM. After etiologic evaluation, we concluded that 90% of the patients had idiopathic bone marrow aplasia, 2% had constitutional bone marrow aplasia, and 8% of the patients were suspected to have secondary bone marrow aplasia: post-hepatitis (3 cases), toxic (2 cases), drug-induced (1 case), and aplastic PNH (1 case). Mortality in the first three months after diagnosis was 21%. Sixty-nine percent of our patients received specific treatment: 28 were treated with cyclosporin (CIS) alone as first-line therapy, 20 received a combination of antilymphocyte serum (ALS) and cyclosporin, 2 received hematopoietic stem cell transplantation (HSCT), while 3 were treated with androgens alone. The overall response rate was 30% with CIS, 42% with ALS+CIS and 100% with HSCT. In our study, the overall death rate was 44%, while the one-year survival rate was 40%. It is important to note that septic shock was the leading cause of death (53% of deaths), followed by hemorrhagic shock (24%). This highlights the lack of hemodynamic resuscitation and symptomatic treatment. Our multivariate study defined the following risk factors as predictive of worse survival: age greater than 16 years (RR: 3.28; CI: 1.29-8.33; P=0.012), PNN less than 200 or very severe bone marrow aplasia (RR: 3.01; 1.1-8.08; P=0.028), and failure to receive any specific treatment (RR: 4.07; 1.77-9.35; P=0.0003). The high overall mortality in our series was due to several factors: inaccessibility to effective therapies, delayed diagnosis, failure to initiate specific treatment, inadequate symptomatic treatment, and geographical and financial inaccessibility.}, } @article {pmid39242198, year = {2024}, author = {Grassano, M and Canosa, A and D'Alfonso, S and Corrado, L and Brodini, G and Koumantakis, E and Cugnasco, P and Manera, U and Vasta, R and Palumbo, F and Mazzini, L and Gallone, S and Moglia, C and Dewan, R and Chia, R and Ding, J and Dalgard, C and Gibbs, RJ and Scholz, S and Calvo, A and Traynor, B and Chio, A}, title = {Intermediate HTT CAG repeats worsen disease severity in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {1}, pages = {100-102}, pmid = {39242198}, issn = {1468-330X}, } @article {pmid39241508, year = {2024}, author = {Zheng, X and Liu, J and Wang, S and Xiao, Y and Jiang, Q and Li, C and Shang, H}, title = {Total physical activity, plant-based diet and neurodegenerative diseases: A prospective cohort study of the UK biobank.}, journal = {Parkinsonism & related disorders}, volume = {128}, number = {}, pages = {107125}, doi = {10.1016/j.parkreldis.2024.107125}, pmid = {39241508}, issn = {1873-5126}, mesh = {Humans ; Male ; Female ; *Exercise/physiology ; Middle Aged ; United Kingdom/epidemiology ; Aged ; *Diet, Vegetarian ; *Neurodegenerative Diseases/epidemiology ; *Biological Specimen Banks ; Prospective Studies ; Alzheimer Disease/epidemiology ; Parkinson Disease/epidemiology ; Amyotrophic Lateral Sclerosis/epidemiology ; Adult ; Cohort Studies ; Diet, Plant-Based ; UK Biobank ; }, abstract = {INTRODUCTION: Neurodegenerative diseases (NDDs) result from a complex interplay of genetic, environmental and aging factors. A balanced diet and adequate physical activity (PA) are recognized as pivotal components among modifiable environmental factors. The independent impact on NDD incidence has been previously debated. This investigation seeks to delineate the association between PA and NDDs across various levels of adherence to a plant-based diet.

METHODS: In this study, a cohort of 368,934 participants from the UK Biobank was analyzed. Total physical activity (TPA) levels and healthful plant-based diet index (hPDI) were calculated and categorized. A multiple adjusted Cox model was utilized to evaluate the influence of TPA and hPDI on common NDDs, respectively.

RESULTS: Finally, 4602 identified cases diagnosed as Alzheimer's disease (AD), Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS). We found that higher TPA was significantly associated with a reduced risk of developing AD (Q3: HR 0.87; Q4: HR 0.78) and PD (Q3: HR 0.86; Q4: HR 0.81). The protective effect was further accentuated with adherence to a plant-based diet. However, these connections were not observed in the analysis of ALS regardless of dietary patterns.

CONCLUSION: Our findings underscore a significant association between higher TPA and reduced risks of AD and PD, with an enhanced effect observed in conjunction with a plant-based diet. This study contributes to addressing the knowledge gap regarding the combined impact of TPA and a plant-based diet on NDDs occurrence, providing insights into potential underlying mechanisms.}, } @article {pmid39241471, year = {2024}, author = {Casiraghi, V and Milone, I and Brusati, A and Peverelli, S and Doretti, A and Poletti, B and Maderna, L and Morelli, C and Ticozzi, N and Silani, V and Verde, F and Ratti, A}, title = {Quantification of serum TDP-43 and neurofilament light chain in patients with amyotrophic lateral sclerosis stratified by UNC13A genotype.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123210}, doi = {10.1016/j.jns.2024.123210}, pmid = {39241471}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/diagnosis ; Female ; Male ; *Neurofilament Proteins/blood/genetics ; Middle Aged ; Aged ; *Polymorphism, Single Nucleotide ; *DNA-Binding Proteins/genetics/blood ; *Genotype ; Biomarkers/blood ; Cohort Studies ; Adult ; Nerve Tissue Proteins ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative condition affecting upper and/or lower motor neurons and characterized neuropathologically by TDP-43 proteinopathy. Given its role in ALS pathobiology, it is currently under debate whether TDP-43 might represent a suitable ALS biomarker to be measured in patients' biofluids. The rs12608932 A > C single nucleotide polymorphism in the UNC13A gene is a risk factor for ALS and patients homozygous for the high-risk C allele display a higher burden of TDP-43 neuropathology than homozygotes for the low-risk A allele, although the association with TDP-43 levels in biofluids has never been evaluated. In this study, we measured serum levels of TDP-43 and neurofilament light chain (NFL) by Simoa technology in a cohort of 69 ALS patients stratified according to the UNC13A rs12608932 genotype compared to 43 neurologically healthy controls. By multiple linear regression analysis, serum TDP-43 was significantly elevated in ALS patients compared to controls, with UNC13A AA and AC, but not CC, ALS patients showing higher serum TDP-43 levels than controls. We also confirmed that serum NFL concentration was increased in ALS patients, without any correlation with the UNC13A genotype. Our results indicate that serum TDP-43 is higher in ALS patients compared to controls and that, in contrast to NFL, this increase is specifically associated with the UNC13A rs12608932 AA and AC genotypes, but not with the high-risk CC genotype. Studies in larger cohorts will be needed to confirm these findings and to elucidate the biological link between serum TDP-43 levels and UNC13A genotype.}, } @article {pmid39241118, year = {2024}, author = {Sharkey, RJ and Cortese, F and Goodyear, BG and Korngut, LW and Jacob, SM and Sharkey, KA and Kalra, S and Nguyen, MD and Frayne, R and Pfeffer, G}, title = {Longitudinal analysis of glymphatic function in amyotrophic lateral sclerosis and primary lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {12}, pages = {4026-4032}, pmid = {39241118}, issn = {1460-2156}, support = {//ALS Society of Canada/ ; //Barry Barrett Foundation/ ; //Rose Family Foundation/ ; //Hotchkiss Brain Institute/ ; /CAPMC/CIHR/Canada ; //Brain Canada Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; Aged ; Longitudinal Studies ; *Glymphatic System/diagnostic imaging ; *Diffusion Tensor Imaging ; Disease Progression ; White Matter/diagnostic imaging/pathology ; Adult ; Motor Neuron Disease/physiopathology/diagnostic imaging/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons in the brain and spinal cord. Accumulation of misfolded proteins is central to the pathogenesis of ALS and the glymphatic system is emerging as a potential therapeutic target to reduce proteinopathy. Using diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) to assess glymphatic function, we performed a longitudinal analysis of glymphatic function in ALS and compared it to a disorder in the motor neuron disease spectrum, primary lateral sclerosis (PLS). From a cohort of 45 participants from the Calgary site in the CALSNIC study (Canadian ALS Neuroimaging Consortium), including 18 ALS, 5 PLS and 22 control participants, DTI-ALPS was analysed and correlated to clinical features (age, sex, disease presentation, disease severity and progression rate) and white matter hyperintensity burden. This included longitudinal measurements at three time points, 4 months apart. The DTI-ALPS index was reduced in ALS participants compared with PLS and control participants across all three time points. There was no association with clinical factors; however, the index tended to decline with advancing age. Our study suggests heterogeneity in glymphatic dysfunction in motor neuron diseases that may be related to the underlying pathogenesis.}, } @article {pmid39240038, year = {2024}, author = {García-Casanova, PH and Pérez-Martínez, P and Sevilla, T and Doménech, R and León, M and Vázquez-Costa, JF}, title = {Impact of SARS-CoV-2 infection and COVID-19 pandemic on the morbidity and mortality of amyotrophic lateral sclerosis patients in Valencia, Spain.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16465}, pmid = {39240038}, issn = {1468-1331}, support = {JR19/00030//Instituto de Salud Carlos III/ ; PI 21/00737//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *COVID-19/mortality/epidemiology ; *Amyotrophic Lateral Sclerosis/epidemiology/mortality ; Spain/epidemiology ; Female ; Male ; Middle Aged ; Aged ; *Hospitalization/statistics & numerical data ; Risk Factors ; Noninvasive Ventilation/statistics & numerical data ; Pandemics ; SARS-CoV-2 ; }, abstract = {BACKGROUND AND PURPOSE: The purpose was to describe the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospitalization for coronavirus disease 2019 (COVID-19) and related death and to assess the impact of the pandemic in the survival of amyotrophic lateral sclerosis (ALS) patients.

METHODS: The risk of SARS-CoV-2 infection, hospitalization for COVID-19 and related death was assessed in ALS patients alive between March 2020 and July 2022. To evaluate its impact in the overall survival of ALS patients, the survival of patients who died before and during the pandemic was compared.

RESULTS: Amongst 263 ALS patients alive during the pandemic, 62 got infected during the study period (infection rate 14.34 per 100 person-years). Most infections (68%) occurred during the sixth wave (November 2021 to January 2022) and most patients (67%) were vaccinated at the time of infection. The hospitalization rate due to COVID-19 was 4.16 per 100 person-years. The multivariable model confirmed non-invasive ventilation (NIV) use prior to infection as a risk factor for hospitalization (odds ratio [OR] = 7.96, p = 0.003) and COVID-19 vaccination as a protective factor (OR = 0.093, p = 0.025) independent of age, sex and gastrostomy. Within 30 days after infection, 7% of non-ventilated patients started NIV and five patients (8.06%) died, of whom four were previously ventilated. The median survival of ALS patients was similar before and during the pandemic and no effect was found in the Cox regression model (hazard ratio 1.02, p = 0.89).

CONCLUSIONS: This study shows a high risk of severe COVID-19 amongst ALS patients requiring NIV. Nevertheless, the pandemic showed no impact in the overall survival of ALS patients, probably due to a high vaccination rate and an adequate access to healthcare resources.}, } @article {pmid39239358, year = {2024}, author = {Segerstrom, SC and Kasarskis, EJ}, title = {The Seattle Amyotrophic Lateral Sclerosis (ALS) Patient Project Database: observational, longitudinal, dyadic characterization of people with ALS and their partners.}, journal = {Health psychology and behavioral medicine}, volume = {12}, number = {1}, pages = {2396137}, pmid = {39239358}, issn = {2164-2850}, support = {R03 NS128748/NS/NINDS NIH HHS/United States ; R16 NS129748/NS/NINDS NIH HHS/United States ; }, abstract = {INTRODUCTION: The median survival time in ALS is approximately 3 years, but survival times range from less than a year to more than 10 years and much variance in disease course remains to be explained. As is true for physical outcomes, there is considerable variance in QOL, which is influenced by psychological health, coping, and social support, among other psychosocial factors. The Seattle ALS Patient Project Database (SALSPPD) provides a unique opportunity for researchers to address established and novel hypotheses about disease progression and QOL in ALS.

METHODS: The SALSPPD is a longitudinal dataset of people with ALS (n = 143) and their partners (spouses, significant others, or caregivers; n = 123) from clinics and community-based ALS support groups. Participants were interviewed in their homes every 3 months for up to 18 months between March 1987 and August 1989. Follow-up phone calls were completed in 1990, 1994, and 2008, primarily to ascertain disease outcomes.

RESULTS: The provided data dictionary includes details of the over 500 variables measured in the study, which have been subsetted into domain datasets. Domains address physical, psychological, social, and behavioral status on the person with ALS and their partners. Missing data were coded according to their mechanism. Data are available in two formats: The person-level (wide) databases and the time-level (long) databases.

DISCUSSION: The SALSPPD will provide a rich resource to scientists interested in the natural history of ALS, psychosocial effects on ALS outcomes and vice versa, and psychosocial and disease outcomes of treatments.}, } @article {pmid39239150, year = {2024}, author = {Vidovic, M and Lapp, HS and Weber, C and Plitzko, L and Seifert, M and Steinacker, P and Otto, M and Hermann, A and Günther, R}, title = {Comparative analysis of neurofilaments and biomarkers of muscular damage in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae288}, pmid = {39239150}, issn = {2632-1297}, abstract = {Diagnosis of the fatal neurodegenerative disease amyotrophic lateral sclerosis is challenging. Neurofilaments, indicative of neuronal damage, along with creatine kinase, creatinine, myoglobin, and troponin T, representing muscular damage, have been identified as promising fluid biomarkers. This study aims to comprehensively assess and compare their diagnostic and prognostic potential in a 'real-world' cohort of patients with amyotrophic lateral sclerosis. About 77 patients with amyotrophic lateral sclerosis and its clinical variants, and 26 age- and sex-matched controls with various neuromuscular and neurodegenerative diseases, were retrospectively included in this monocentric, cross-sectional study. Neurofilaments in cerebrospinal fluid and biomarkers of muscular damage in serum were measured and correlated with demographic features, motor function, survival time, clinical phenotypes, and the extent of upper and lower motor neuron involvement. Neurofilament, myoglobin, and troponin T concentrations were higher in patients with amyotrophic lateral sclerosis compared to disease controls. Higher neurofilament levels correlated with lower motor function and faster disease progression rate, while higher creatine kinase and creatinine concentrations were linked to preserved motor function. In contrast, troponin T elevation indicated poorer fine and gross motor functions. Increased neurofilament levels were associated with shorter survival, whereas biomarkers of muscular damage lacked survival correlation. Neurofilament concentrations were higher in classical amyotrophic lateral sclerosis than in progressive muscular atrophy, while myoglobin and troponin T levels were elevated in progressive muscular atrophy compared to primary lateral sclerosis. Neurofilaments were predominantly linked to upper motor neuron involvement. Our findings confirmed the robust diagnostic and prognostic value of neurofilaments in amyotrophic lateral sclerosis. Elevated neurofilament concentrations were associated with higher disease severity, faster disease progression, shorter survival, and predominant upper motor neuron degeneration. Biomarkers of muscular damage were inferior in distinguishing amyotrophic lateral sclerosis from other neuromuscular and neurodegenerative diseases. However, they may serve as complementary biomarkers and support in discriminating clinical variants of amyotrophic lateral sclerosis.}, } @article {pmid39239063, year = {2024}, author = {Pezeshgi, S and Ghaderi, S and Mohammadi, S and Karimi, N and Ziaadini, B and Mohammadi, M and Fatehi, F}, title = {Diffusion tensor imaging biomarkers and clinical assessments in amyotrophic lateral sclerosis (ALS) patients: an exploratory study.}, journal = {Annals of medicine and surgery (2012)}, volume = {86}, number = {9}, pages = {5080-5090}, pmid = {39239063}, issn = {2049-0801}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Biomarkers are needed to improve diagnosis, gauge progression, and evaluate treatment. Diffusion tensor imaging (DTI) is a promising biomarker for detecting microstructural alterations in the white matter tracts. This study aimed to assess DTI metrics as biomarkers and to examine their relationship with clinical assessments in patients with ALS. Eleven patients with ALS and 21 healthy controls (HCs) underwent 3T MRI with DTI. DTI metrics, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), were compared between key motor and extra-motor tract groups. Group comparisons and correlations between DTI metrics also correlated with clinical scores of disability (ALSFRS-R), muscle strength (dynamometry), and motor unit loss (MUNIX). Widespread differences were found between patients with ALS and HCs in DTI metrics, including decreased FA and increased diffusivity metrics. However, MD and RD are more sensitive metrics for detecting white matter changes in patients with ALS. Significant interhemispheric correlations between the tract DTI metrics were also observed. DTI metrics showed symmetry between the hemispheres and correlated with the clinical assessments. MD, RD, and AD increases significantly correlated with lower ALSFRS-R and MUNIX scores and weaker dynamometry results. DTI reveals microstructural damage along the motor and extra-motor regions in ALS patients. DTI metrics can serve as quantitative neuroimaging biomarkers for diagnosis, prognosis, monitoring of progression, and treatment. Combined analysis of imaging, electrodiagnostic, and functional biomarkers shows potential for characterizing disease pathophysiology and progression.}, } @article {pmid39236857, year = {2024}, author = {Reiter, RJ and Sharma, RN and Manucha, W and Rosales-Corral, S and Almieda Chuffa, LG and Loh, D and Luchetti, F and Balduini, W and Govitrapong, P}, title = {Dysfunctional mitochondria in age-related neurodegeneration: Utility of melatonin as an antioxidant treatment.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102480}, doi = {10.1016/j.arr.2024.102480}, pmid = {39236857}, issn = {1872-9649}, mesh = {*Melatonin/metabolism/pharmacology/therapeutic use ; Humans ; *Antioxidants/pharmacology/therapeutic use ; *Mitochondria/metabolism/drug effects ; *Aging/metabolism/drug effects ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; Oxidative Stress/drug effects ; }, abstract = {Mitochondria functionally degrade as neurons age. Degenerative changes cause inefficient oxidative phosphorylation (OXPHOS) and elevated electron leakage from the electron transport chain (ETC) promoting increased intramitochondrial generation of damaging reactive oxygen and reactive nitrogen species (ROS and RNS). The associated progressive accumulation of molecular damage causes an increasingly rapid decline in mitochondrial physiology contributing to aging. Melatonin, a multifunctional free radical scavenger and indirect antioxidant, is synthesized in the mitochondrial matrix of neurons. Melatonin reduces electron leakage from the ETC and elevates ATP production; it also detoxifies ROS/RNS and via the SIRT3/FOXO pathway it upregulates activities of superoxide dismutase 2 and glutathione peroxidase. Melatonin also influences glucose processing by neurons. In neurogenerative diseases, neurons often adopt Warburg-type metabolism which excludes pyruvate from the mitochondria causing reduced intramitochondrial acetyl coenzyme A production. Acetyl coenzyme A supports the citric acid cycle and OXPHOS. Additionally, acetyl coenzyme A is a required co-substrate for arylalkylamine-N-acetyl transferase, which rate limits melatonin synthesis; therefore, melatonin production is diminished in cells that experience Warburg-type metabolism making mitochondria more vulnerable to oxidative stress. Moreover, endogenously produced melatonin diminishes during aging, further increasing oxidative damage to mitochondrial components. More normal mitochondrial physiology is preserved in aging neurons with melatonin supplementation.}, } @article {pmid39236792, year = {2024}, author = {Hattori, H and Osumi, K and Tanaka, M and Arai, T and Nishimura, K and Yamamoto, N and Sakamoto, K and Goto, Y and Sugawara, Y}, title = {Discovery of 5-phenyl-3-ureidothiophene-2-carboxamides as protective agents for ALS patient iPSC-derived motor neurons.}, journal = {Bioorganic & medicinal chemistry letters}, volume = {113}, number = {}, pages = {129935}, doi = {10.1016/j.bmcl.2024.129935}, pmid = {39236792}, issn = {1464-3405}, mesh = {Humans ; *Induced Pluripotent Stem Cells/drug effects/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Motor Neurons/drug effects/metabolism ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; *Drug Discovery ; Structure-Activity Relationship ; Molecular Structure ; Thiophenes/chemistry/pharmacology/chemical synthesis ; Protein Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; Protein Kinase Inhibitors/pharmacology/chemistry/chemical synthesis ; Dose-Response Relationship, Drug ; Superoxide Dismutase-1/metabolism/genetics ; Intracellular Signaling Peptides and Proteins ; }, abstract = {We discovered novel neuroprotective compounds by phenotypic screening using SOD1-mutant amyotrophic lateral sclerosis (ALS) patient induced pluripotent stem cell (iPSC)-derived motor neurons. Mechanistic analysis showed that the protective effect of initial hit compound 1 was likely due to the inhibition of MAP4Ks, including MAP4K4, a member of the MAP4K kinase family. Structural transformation led to compound 15f, which showed improved MAP4K4 inhibitory activity and superior neuroprotective effects compared to 1 in motor neurons. The results suggest that structural optimization based on MAP4K4 inhibitory activity might improve the neuroprotective effect of this series of compounds.}, } @article {pmid39236307, year = {2024}, author = {Doneddu, PE and Gallo, C and Gentile, L and Cocito, D and Falzone, Y and Di Stefano, V and Inghilleri, M and Cosentino, G and Matà, S and Mazzeo, A and Filosto, M and Peci, E and Sorrenti, B and Brighina, F and Moret, F and Vegezzi, E and Sperti, M and Risi, B and Nobile-Orazio, E and , }, title = {Comparison of the diagnostic accuracy of the 2010 European Federation of Neurological Societies/Peripheral Nerve Society and American Association of Electrodiagnostic Medicine diagnostic criteria for multifocal motor neuropathy.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16444}, pmid = {39236307}, issn = {1468-1331}, support = {IIR-ITA-BXLT-001955/ IISR-2017-104226//Takeda Italia SPA/ ; //Fondazione Humanitas per la Ricerca/ ; }, mesh = {Humans ; Male ; Middle Aged ; Female ; *Electrodiagnosis/standards/methods ; *Sensitivity and Specificity ; Retrospective Studies ; Aged ; *Neural Conduction/physiology ; *Societies, Medical/standards ; *Polyneuropathies/diagnosis/physiopathology ; Adult ; Europe ; Motor Neuron Disease/diagnosis/physiopathology ; United States ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; }, abstract = {BACKGROUND AND PURPOSE: This study was undertaken to compare the sensitivity and specificity of the 2010 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria for multifocal motor neuropathy (MMN) with those of the American Association of Electrodiagnostic Medicine (AAEM).

METHODS: Sensitivity and specificity of the two sets of criteria were retrospectively evaluated in 53 patients with MMN and 280 controls with axonal peripheral neuropathy, inflammatory demyelinating polyneuropathy, or amyotrophic lateral sclerosis. Comparison of the utility of nerve conduction studies with different numbers of nerves examined was also assessed.

RESULTS: The 2010 EFNS/PNS criteria had a sensitivity of 47% for definite MMN and 57% for probable/definite MMN, whereas the AAEM criteria had a sensitivity of 28% for definite MMN and 53% for probable/definite MMN. The sensitivity of the AAEM criteria was higher when utilizing area compared to amplitude reduction to define conduction block. Using supportive criteria, the sensitivity of the 2010 EFNS/PNS criteria for probable/definite MMN increased to 64%, and an additional 36% patients fulfilled the criteria (possible MMN). Specificity values for definite and probable/definite MMN were slightly higher with the AAEM criteria (100%) compared to the EFNS/PNS criteria (98.5% and 97%). Extended nerve conduction studies yielded slightly increased diagnostic sensitivity for both sets of criteria without significantly affecting specificity.

CONCLUSIONS: In our patient populations, the 2010 EFNS/PNS criteria demonstrated higher sensitivity but slightly lower specificity compared to the AAEM criteria. Extended nerve conduction studies are advised to achieve slightly higher sensitivity while maintaining very high specificity.}, } @article {pmid39235524, year = {2024}, author = {Poletti, B and Aiello, EN and Consonni, M and Iazzolino, B and Torre, S and Solca, F and Faltracco, V and Telesca, A and Palumbo, F and Dalla Bella, E and Bersano, E and Riva, N and Verde, F and Messina, S and Doretti, A and Maranzano, A and Morelli, C and Calvo, A and Silani, V and Lauria, G and Chiò, A and Ticozzi, N}, title = {Prevalence and motor-functional correlates of frontotemporal-spectrum disorders in a large cohort of non-demented ALS patients.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6944-6955}, pmid = {39235524}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/physiopathology/complications ; Male ; Female ; Middle Aged ; Aged ; Prevalence ; Frontotemporal Dementia/physiopathology/epidemiology ; Cohort Studies ; Neuropsychological Tests ; Disease Progression ; Adult ; }, abstract = {BACKGROUND: This study aimed at (1) delivering generalizable estimates of the prevalence of frontotemporal-spectrum disorders (FTSDs) in non-demented ALS patients and (2) exploring their motor-functional correlates.

METHODS: N = 808 ALS patients without FTD were assessed for motor-functional outcomes-i.e., disease duration, severity (ALSFRS-R), progression rate (ΔFS), and stage (King's and Milano-Torino-MiToS-systems)-cognition-via the cognitive section of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS)-and behaviour-via the ECAS-Carer Interview. Neuropsychological phenotypes were retrieved via Strong's revised criteria-i.e., ALS cognitively and behaviourally normal (ALScbn) or cognitively and/or behaviourally impaired (ALSci/bi/cbi).

RESULTS: Defective ECAS-Total performances were detected in ~ 29% of patients, with the ECAS-Executive being failed by the highest number of patients (~ 30%), followed by the ECAS-Language, -Fluency, and -Memory (~ 15-17%) and -Visuospatial (~ %8). Apathy was the most frequent behavioural change (~ 28%), followed by loss of sympathy/empathy (~ 13%); remaining symptoms were reported in < 4% of patients. The distribution of Strong's classifications was as follows: ALScbn: 46.7%; ALSci/bi/cbi: 22.9%/20.0%/10.4%. Multinomial regressions on Strong's classifications revealed that lower ALSFRS-R scores were associated with a higher probability of ALSbi and ALScbi classifications (p ≤ .008). Higher King's and MiToS stages were associated with a higher probability of ALSbi classification (p ≤ .031).

CONCLUSIONS: FTSDs affect ~ 50% of non-demented ALS patients, with cognitive deficits being as frequent as behavioural changes. A higher degree of motor-functional involvement is associated with worse behavioural outcomes-with this link being weaker for cognitive deficits.}, } @article {pmid39234934, year = {2024}, author = {Mao, M and Zeng, W and Zheng, Y and Fan, W and Yao, Y}, title = {Fasudil attenuates syncytin-1-mediated activation of microglia and impairments of motor neurons and motor function in mice.}, journal = {Drug development research}, volume = {85}, number = {6}, pages = {e22254}, doi = {10.1002/ddr.22254}, pmid = {39234934}, issn = {1098-2299}, support = {81860245//National Natural Science Foundation of China/ ; [2019]5664//Department of Science and Technology of Guizhou Province/ ; GZSYBS[2017]01//Doctor Fund of Guizhou Provincial People's Hospital/ ; GZSYQN[2018]09//Youth Fund of Guizhou Provincial People's Hospital/ ; }, mesh = {Animals ; *Microglia/drug effects/metabolism ; *Motor Neurons/drug effects/metabolism ; Mice ; *Mice, Inbred C57BL ; *1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives/pharmacology ; Gene Products, env ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Pregnancy Proteins/metabolism ; Male ; Cytokines/metabolism ; Disease Models, Animal ; Motor Activity/drug effects ; Spinal Cord/metabolism/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. Syncytin-1 (Syn), an envelope glycoprotein encoded by the env gene of the human endogenous retrovirus-W family, has been resorted to be highly expressed in biopsies from the muscles from ALS patients; however, the specific regulatory role of Syn during ALS progression remains uncovered. In this study, C57BL/6 mice were injected with adeno-associated virus-overexpressing Syn, with or without Fasudil administration. The Syn expression was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry analysis. The histological change of anterior tibial muscles was determined by hematoxylin-eosin staining. Qualitative ultrastructural analysis of electron micrographs obtained from lumbar spinal cords was carried out. Serum inflammatory cytokines were assessed by enzyme linked immunosorbent assay (ELISA) assay and motor function was recorded using Basso, Beattie, and Bresnahan (BBB) scoring, climbing test and treadmill running test. Immunofluorescence and western blot assays were conducted to examine microglial- and motor neurons-related proteins. Syn overexpression significantly caused systemic inflammatory response, muscle tissue lesions, and motor dysfunction in mice. Meanwhile, Syn overexpression promoted the impairment of motor neuron, evidenced by the damaged structure of the neurons and reduced expression of microtubule-associated protein 2, HB9, neuronal nuclei and neuron-specific enolase in Syn-induced mice. In addition, Syn overexpression greatly promoted the expression of CD16/CD32 and inducible nitric oxide synthase (M1 phenotype markers), and reduced the expression of CD206 and arginase 1 (M2 phenotype markers). Importantly, the above changes caused by Syn overexpression were partly abolished by Fasudil administration. This study provides evidence that Syn-activated microglia plays a pivotal role during the progression of ALS.}, } @article {pmid39233852, year = {2024}, author = {Gilbert, JW and Kennedy, Z and Godinho, BMDC and Summers, A and Weiss, A and Echeverria, D and Bramato, B and McHugh, N and Cooper, D and Yamada, K and Hassler, M and Tran, H and Gao, FB and Brown, RH and Khvorova, A}, title = {Identification of selective and non-selective C9ORF72 targeting in vivo active siRNAs.}, journal = {Molecular therapy. Nucleic acids}, volume = {35}, number = {3}, pages = {102291}, pmid = {39233852}, issn = {2162-2531}, support = {R01 NS104022/NS/NINDS NIH HHS/United States ; }, abstract = {A hexanucleotide (G4C2) repeat expansion (HRE) within intron one of C9ORF72 is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). C9ORF72 haploinsufficiency, formation of RNA foci, and production of dipeptide repeat (DPR) proteins have been proposed as mechanisms of disease. Here, we report the first example of disease-modifying siRNAs for C9ORF72 driven ALS/FTD. Using a combination of reporter assay and primary cortical neurons derived from a C9-ALS/FTD mouse model, we screened a panel of more than 150 fully chemically stabilized siRNAs targeting different C9ORF72 transcriptional variants. We demonstrate the lack of correlation between siRNA efficacy in reporter assay versus native environment; repeat-containing C9ORF72 mRNA variants are found to preferentially localize to the nucleus, and thus C9ORF72 mRNA accessibility and intracellular localization have a dominant impact on functional RNAi. Using a C9-ALS/FTD mouse model, we demonstrate that divalent siRNAs targeting C9ORF72 mRNA variants specifically or non-selectively reduce the expression of C9ORF72 mRNA and significantly reduce DPR proteins. Interestingly, siRNA silencing all C9ORF72 mRNA transcripts was more effective in removing intranuclear mRNA aggregates than targeting only HRE-containing C9ORF72 mRNA transcripts. Combined, these data support RNAi-based degradation of C9ORF72 as a potential therapeutic paradigm.}, } @article {pmid39233624, year = {2024}, author = {Garnier, M and Camdessanché, JP and Cassereau, J and Codron, P}, title = {From suspicion to diagnosis: exploration strategy for suspected amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2398199}, pmid = {39233624}, issn = {1365-2060}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; Diagnosis, Differential ; Electromyography/methods ; }, abstract = {The diagnosis of amyotrophic lateral sclerosis (ALS) is based on evidence of upper and lower motor neuron degeneration in the bulbar, cervical, thoracic, and lumbar regions in a patient with progressive motor weakness, in the absence of differential diagnosis. Despite these well-defined criteria, ALS can be difficult to diagnose, given the wide variety of clinical phenotypes. Indeed, the central or peripheral location of the disease varies with a spectrum ranging from predominantly central to exclusively peripheral, symptoms can be extensive or limited to the limbs, bulbar area or respiratory muscles, and the duration of the disease may range from a few months to several decades. In the absence of a specific test, the diagnostic strategy relies on clinical, electrophysiological, biological and radiological investigations to confirm the disease and exclude ALS mimics. The main challenge is to establish a diagnosis based on robust clinical and paraclinical evidence without delaying treatment initiation by increasing the number of additional tests. This approach requires a thorough knowledge of the phenotypes of ALS and its main differential diagnoses.}, } @article {pmid39233146, year = {2024}, author = {Wang, H and Liu, S and Sun, Y and Chen, C and Hu, Z and Li, Q and Long, J and Yan, Q and Liang, J and Lin, Y and Yang, S and Lin, M and Liu, X and Wang, H and Yu, J and Yi, F and Tan, Y and Yang, Y and Chen, N and Ai, Q}, title = {Target modulation of glycolytic pathways as a new strategy for the treatment of neuroinflammatory diseases.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102472}, doi = {10.1016/j.arr.2024.102472}, pmid = {39233146}, issn = {1872-9649}, mesh = {Humans ; *Glycolysis/physiology ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Animals ; Aging/metabolism ; }, abstract = {Neuroinflammation is an innate and adaptive immune response initiated by the release of inflammatory mediators from various immune cells in response to harmful stimuli. While initially beneficial and protective, prolonged or excessive neuroinflammation has been identified in clinical and experimental studies as a key pathological driver of numerous neurological diseases and an accelerant of the aging process. Glycolysis, the metabolic process that converts glucose to pyruvate or lactate to produce adenosine 5'-triphosphate (ATP), is often dysregulated in many neuroinflammatory disorders and in the affected nerve cells. Enhancing glucose availability and uptake, as well as increasing glycolytic flux through pharmacological or genetic manipulation of glycolytic enzymes, has shown potential protective effects in several animal models of neuroinflammatory diseases. Modulating the glycolytic pathway to improve glucose metabolism and ATP production may help alleviate energy deficiencies associated with these conditions. In this review, we examine six neuroinflammatory diseases-stroke, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and depression-and provide evidence supporting the role of glycolysis in their treatment. We also explore the potential link between inflammation-induced aging and glycolysis. Additionally, we briefly discuss the critical role of glycolysis in three types of neuronal cells-neurons, microglia, and astrocytes-within physiological processes. This review highlights the significance of glycolysis in the pathology of neuroinflammatory diseases and its relevance to the aging process.}, } @article {pmid39232594, year = {2024}, author = {Martínez-Payá, JJ and Ríos-Díaz, J and Del Baño-Aledo, ME and Hervás, D and Tembl-Ferrairó, JI and Sevilla-Mantecón, T and Vázquez-Costa, JF}, title = {The cross-sectional area of the median nerve: An independent prognostic biomarker in amyotrophic lateral sclerosis.}, journal = {Neurologia}, volume = {39}, number = {7}, pages = {564-572}, doi = {10.1016/j.nrleng.2024.07.003}, pmid = {39232594}, issn = {2173-5808}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Male ; Middle Aged ; Female ; *Median Nerve/diagnostic imaging ; Prognosis ; *Biomarkers ; Aged ; *Ultrasonography ; Disease Progression ; Cohort Studies ; }, abstract = {INTRODUCTION: Ultrasound changes in the cross-sectional area of the median nerve (CSAmn) could be of interest as biomarkers in patients with amyotrophic lateral sclerosis (ALS).

METHODS: Eighty-four ALS patients (51 men [60.7%]; mean 62.0 [SD 11.46] years old) and forty-six controls (27 men [58.7%]; mean 59.9 [SD 8.08] years old) of two different cohorts were recruited between September 2013 and February 2018. The CSAmn was measured bilaterally in each cohort, by two different examiners with two different ultrasound machines (one in each cohort). Its association with clinical variables (disease duration, muscle strength, disability, progression rate and tracheostomy-free survival) was assessed.

RESULTS: The CSAmn was smaller in patients than in controls, and the study cohort did not influence its values. A mild correlation between the strength of the wrist flexor and the CSAmn was found. In the multivariable analysis, the probability of this association being true was 90%. In the cox regression, both a faster progression rate and a larger CSAmn independently predicted poor survival (HR=4.29, [Cr.I95%: 2.71-6.80], p<0.001; and HR=1.14, [Cr.I95%: 1.03-1.25], p=0.01), after adjusting by age, body mass index, bulbar onset, and diagnostic delay.

CONCLUSIONS: The CSAmn is an easy to assess biomarker that seems reliable and reproducible. Our data also suggest that it could act as a progression and prognostic biomarker in ALS patients. Longitudinal studies with repeated measures are warranted to confirm its usefulness in the clinical practice.}, } @article {pmid39232248, year = {2024}, author = {Borchert, GA and Shanks, ME and Whitfield, J and Clouston, P and Raji, S and Sperring, S and Thompson, JA and Xue, K and De Silva, SR and Downes, SM and MacLaren, RE and Cehajic-Kapetanovic, J}, title = {Expanding the genotypic and phenotypic spectra with a novel variant in the ciliopathy gene, CFAP410, associated with selective cone degeneration.}, journal = {Ophthalmic genetics}, volume = {45}, number = {6}, pages = {633-639}, pmid = {39232248}, issn = {1744-5094}, mesh = {Humans ; Female ; Adult ; *Ciliopathies/genetics ; *Pedigree ; *Phenotype ; Retrospective Studies ; Genotype ; Cone Dystrophy/genetics/diagnosis ; Consanguinity ; Visual Acuity/physiology ; Tomography, Optical Coherence ; Mutation ; Homozygote ; }, abstract = {BACKGROUND: CFAP410 (Cilia and Flagella Associated Protein 410) encodes a protein that has an important role in the development and function of cilia. In ophthalmology, pathogenic variants in CFAP410 have been described in association with cone rod dystrophy, retinitis pigmentosa, with or without macular staphyloma, or with systemic abnormalities such as skeletal dysplasia and amyotrophic lateral sclerosis. Herein, we report a consanguineous family with a novel homozygous CFAP410 c.335_346del variant with cone only degeneration and no systemic features.

METHODS: A retrospective analysis of ophthalmic history, examination, retinal imaging, electrophysiology and microperimetry was performed as well as genetic testing with in silico pathogenicity predictions and a literature review.

RESULTS: A systemically well 28-year-old female of Pakistani ethnicity with parental consanguinity and no relevant family history, presented with childhood-onset poor central vision and photophobia. Best-corrected visual acuity and colour vision were reduced (0.5 LogMAR, 6/17 Ishihara plates (right) and 0.6 LogMAR, 3/17 Ishihara plates (left). Fundus examination showed no pigmentary retinopathy, no macular staphyloma and autofluorescence was unremarkable. Optical coherence tomography showed subtle signs of intermittent disruption of the ellipsoid zone. Microperimetry demonstrated a reduction in central retinal sensitivity. Electrodiagnostic testing confirmed a reduction in cone-driven responses. Whole-genome sequencing identified an in-frame homozygous deletion of 12 base pairs at c.335_346del in CFAP410.

CONCLUSIONS: The non-syndromic cone dystrophy phenotype reported herein expands the genotypic and phenotypic spectra of CFAP410-associated ciliopathies and highlights the need for light of potential future genetic therapies.}, } @article {pmid39231585, year = {2025}, author = {Kato, C and Morimoto, S and Takahashi, S and Namba, S and Wang, QS and Okada, Y and Okano, H}, title = {Spinal cord motor neuron phenotypes and polygenic risk scores in sporadic amyotrophic lateral sclerosis: deciphering the disease pathology and therapeutic potential of ropinirole hydrochloride.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {2}, pages = {199-201}, pmid = {39231585}, issn = {1468-330X}, } @article {pmid39231554, year = {2024}, author = {Gong, Z and Deng, W and Li, Z and Tang, J and Zhang, M}, title = {Association between apathy and caregiver burden in patients with amyotrophic lateral sclerosis: a cross-sectional study.}, journal = {BMJ open}, volume = {14}, number = {9}, pages = {e080803}, pmid = {39231554}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Male ; Female ; Cross-Sectional Studies ; *Apathy ; Middle Aged ; *Anxiety/psychology/etiology ; *Depression/psychology/etiology ; China/epidemiology ; *Caregiver Burden/psychology ; Aged ; Caregivers/psychology ; Adult ; Cognitive Dysfunction/etiology/psychology ; Psychiatric Status Rating Scales ; Logistic Models ; Cost of Illness ; }, abstract = {OBJECTIVES: To investigate the relationship among patients' apathy, cognitive impairment, depression, anxiety, and caregiver burden in amyotrophic lateral sclerosis (ALS).

DESIGN: A cross-sectional study design was used.

SETTING: The study was conducted at a tertiary hospital in Wuhan, Hubei, China.

PARTICIPANTS: A total of 109 patients with ALS and their caregivers were included.

OUTCOME MEASURES: Patients with ALS were screened using the Edinburgh Cognitive and Behavioural Screen, Beck Depression Inventory-II, Generalised Anxiety Disorder-7 and Apathy Scale to assess their cognition, depression, anxiety and apathy, respectively. The primary caregivers completed the Zarit Burden Interview. The association between apathy, cognitive impairment, depression, anxiety and caregiver burden was analysed using logistic regression. Mediation models were employed to investigate the mediating effect of patients' apathy on the relationship between depression/anxiety and caregiver burden.

RESULTS: Patients in the high caregiver burden group exhibited significantly higher levels of depression, anxiety and apathy compared with those in the low caregiver burden group (p<0.05). There was a positive association observed between caregiver burden and disease course (rs=0.198, p<0.05), depression (rs=0.189, p<0.05), anxiety (rs=0.257, p<0.05) and apathy (rs=0.388, p<0.05). There was a negative association between caregiver burden and the Revised ALS Functional Rating Scale (rs=-0.275, p<0.05). Apathy was an independent risk factor for higher caregiver burden (OR 1.121, 95% CI 1.041 to 1.206, p<0.05). Apathy fully mediated the relationship between depression and caregiver burden (β=0.35, 95% CI 0.16 to 0.54, p<0.05) while partially mediating the relationship between anxiety and caregiver burden (β=0.34, 95% CI 0.16 to 0.52, p<0.05).

CONCLUSIONS: Apathy, depression and anxiety exerted a detrimental impact on caregiver burden in individuals with ALS. Apathy played a mediating role in the relationship between depression and caregiver burden and between anxiety and caregiver burden. These findings underscore the importance of identifying apathy and developing interventions for its management within the context of ALS.}, } @article {pmid39231437, year = {2024}, author = {Chu, HS and Oh, J}, title = {Family Caregivers' Experiences of People With Amyotrophic Lateral Sclerosis Undergoing Gastrostomy Tube Feeding.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {56}, number = {6}, pages = {224-228}, pmid = {39231437}, issn = {1945-2810}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/nursing/psychology ; *Caregivers/psychology ; *Enteral Nutrition ; *Gastrostomy ; Female ; Male ; Middle Aged ; Republic of Korea ; *Qualitative Research ; Adult ; Aged ; Stress, Psychological ; Interviews as Topic ; }, abstract = {INTRODUCTION: In amyotrophic lateral sclerosis (ALS) patients with impaired swallowing function, gastrostomy tube (G-tube) placement is recommended, but significantly increases the caregiving burden on families. This study aimed to describe the experiences of family caregivers of patients with ALS receiving home enteral nutrition through a G-tube. METHOD: Using purposive sampling, 8 family caregivers participated in the study. Data collection was conducted between February 2021 and October 2022 at a university hospital in Seoul, Korea. Semistructured face-to-face interviews were used to collect data until saturation. Data were analyzed using Krippendorff's content analysis approach. RESULTS: Qualitative analysis of the data revealed 3 main themes regarding caregiving. The emerging themes included psychological distress, unmet practical needs, and the struggle to provide care. CONCLUSION: After a G-tube placement, family caregivers experience various emotional stresses and have numerous unmet practical needs. Healthcare professionals caring for people with ALS receiving enteral nutrition should provide a tailored support program that addresses the specific needs of these family caregivers.}, } @article {pmid39231048, year = {2024}, author = {Trescato, I and Tavazzi, E and Vettoretti, M and Gatta, R and Vasta, R and Chio, A and Camillo, BD}, title = {DYNAMITE: Integrating Archetypal Analysis and Process Mining for Interpretable Disease Progression Modelling.}, journal = {IEEE journal of biomedical and health informatics}, volume = {28}, number = {12}, pages = {7553-7564}, doi = {10.1109/JBHI.2024.3453602}, pmid = {39231048}, issn = {2168-2208}, mesh = {Humans ; *Disease Progression ; *Data Mining/methods ; *Amyotrophic Lateral Sclerosis/physiopathology ; Electronic Health Records ; Algorithms ; }, abstract = {DYNAMITE, an acronym for DYNamic Archetypal analysis for MIning disease TrajEctories, is a new methodology developed specifically to model disease progression by exploiting information available in longitudinal clinical datasets. First, archetypal analysis is applied to data organised in matrix form, with the aim of finding extreme and representative disease states (archetypes) linked to the original data through convex coefficients. Then, each original observation is associated with a single archetype based on their similarity; finally, an event log is created encoding the progression of disease states for each patient in terms of archetype states. In the last stage of the procedure, archetypal analysis is coupled with process mining, which allows the event log archetypes to be visualised graphically as sequences of disease states, allowing the clinical trajectories of patients to be extracted and examined. As a proof of concept, we applied the proposed method to data from a cohort of amyotrophic lateral sclerosis patients whose progression was monitored using the 12-item ALSFRS-R questionnaire. Without any a priori knowledge, DYNAMITE identified six archetypes clearly describing different types and severity of impairment and provided reliable clinical trajectories consistent with the prognosis of amyotrophic lateral sclerosis patients. DYNAMITE offers high interpretability at every stage of the analysis, which makes it particularly suitable for use in healthcare where explainability is paramount, and enables analysis of clinical trajectories at both individual and population levels.}, } @article {pmid39230722, year = {2024}, author = {Chalitsios, CV and Ley, H and Gao, J and Turner, MR and Thompson, AG}, title = {Apolipoproteins, lipids, lipid-lowering drugs and risk of amyotrophic lateral sclerosis and frontotemporal dementia: a meta-analysis and Mendelian randomisation study.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6956-6969}, pmid = {39230722}, issn = {1432-1459}, support = {MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; Thompson/Apr23/896-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/epidemiology ; *Apolipoproteins/antagonists & inhibitors/blood/genetics ; *Frontotemporal Dementia/blood/genetics/epidemiology ; Hypolipidemic Agents/pharmacology/therapeutic use ; Lipids/blood ; Mendelian Randomization Analysis ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have clinical, pathological and genetic overlapping. Lipid pathways are implicated in ALS. This study examined the effect of blood lipid levels on ALS, FTD risk, and survival in ALS.

METHODS: A systematic review and meta-analysis of high and low-density lipoprotein cholesterol (HDL-c and LDL-c), total cholesterol, triglycerides, apolipoproteins B and A1 levels with ALS was performed. Two-sample Mendelian randomisation (MR) analysis sought the causal effects of these exposures on ALS, FTD, and survival in ALS. The effect of lipid-lowering drugs was also examined using genetic proxies for targets of lipid-lowering medications.

RESULTS: Three cohort studies met the inclusion criteria for meta-analysis. Meta-analysis indicated an association between higher LDL-c (HRper mmol/L = 1.07, 95%CI:1.02-1.12; I 2 =18%) and lower HDL-c (HRper mmol/L = 0.83, 95%CI:0.74-0.94; I 2 =0%) with an increased risk of ALS. MR suggested causal effects of higher LDL-c (ORIVW = 1.085, 95%:CI 1.008-1.168, pFDR = 0.0406), total cholesterol (ORIVW = 1.081, 95%:CI 1.013-1.154, pFDR = 0.0458) and apolipoprotein B (ORIVW = 1.104, 95%:CI 1.041-1.171, pFDR = 0.0061) increasing ALS risk, and higher apolipoprotein B level increasing FTD risk (ORIVW = 1.424, 95%CI 1.072-1.829, pFDR = 0.0382). Reducing LDL-c through APOB inhibition was associated with lower ALS (ORIVW = 0.84, 95%CI 0.759-0.929, pFDR = 0.00275) and FTD risk (ORIVW = 0.581, 95%CI 0.387-0.874, pFDR = 0.0362).

CONCLUSION: These data support the influence of LDL-c and total cholesterol on ALS risk and apolipoprotein B on the risk of ALS and FTD. Potential APOB inhibition might decrease the risk of sporadic ALS and FTD. Further work in monogenic forms of ALS and FTD is necessary to determine whether blood lipids influence penetrance and phenotype.}, } @article {pmid39229489, year = {2024}, author = {Feng, F and Feng, G and Liu, J and Hao, W and Huang, W and Bi, X and Li, M and Wang, H and Yang, F and He, Z and Bai, J and Wang, H and Ma, G and Xu, B and Shu, N and Huang, X}, title = {Different patterns of structural network impairments in two amyotrophic lateral sclerosis subtypes driven by [18]F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid imaging.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae222}, pmid = {39229489}, issn = {2632-1297}, abstract = {The structural network damages in amyotrophic lateral sclerosis patients are evident but contradictory due to the high heterogeneity of the disease. We hypothesized that patterns of structural network impairments would be different in amyotrophic lateral sclerosis subtypes by a data-driven method using [18]F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid imaging. The data of positron emission tomography, structural MRI and diffusion tensor imaging in fifty patients with amyotrophic lateral sclerosis and 23 healthy controls were collected by a [18]F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid. Two amyotrophic lateral sclerosis subtypes were identified as the optimal cluster based on grey matter volume and standardized uptake value ratio. Network metrics at the global, local and connection levels were compared to explore the impaired patterns of structural networks in the identified subtypes. Compared with healthy controls, the two amyotrophic lateral sclerosis subtypes displayed a pattern of a locally impaired structural network centralized in the sensorimotor network and a pattern of an extensively impaired structural network in the whole brain. When comparing the two amyotrophic lateral sclerosis subgroups by a support vector machine classifier based on the decreases in nodal efficiency of structural network, the individualized network scores were obtained in every amyotrophic lateral sclerosis patient and demonstrated a positive correlation with disease severity. We clustered two amyotrophic lateral sclerosis subtypes by a data-driven method, which encompassed different patterns of structural network impairments. Our results imply that amyotrophic lateral sclerosis may possess the intrinsic damaged pattern of white matter network and thus provide a latent direction for stratification in clinical research.}, } @article {pmid39229486, year = {2024}, author = {Rivers-Auty, J and Hoyle, C and Pointer, A and Lawrence, C and Pickering-Brown, S and Brough, D and Ryan, S}, title = {C9orf72 dipeptides activate the NLRP3 inflammasome.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae282}, pmid = {39229486}, issn = {2632-1297}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Frontotemporal dementia and amyotrophic lateral sclerosis are neurodegenerative diseases with considerable clinical, genetic and pathological overlap. The most common cause of both diseases is a hexanucleotide repeat expansion in C9orf72. The expansion is translated to produce five toxic dipeptides, which aggregate in patient brain. Neuroinflammation is a feature of frontotemporal dementia and amyotrophic lateral sclerosis; however, its causes are unknown. The nod-like receptor family, pyrin domain-containing 3 inflammasome is implicated in several other neurodegenerative diseases as a driver of damaging inflammation. The inflammasome is a multi-protein complex which forms in immune cells in response to tissue damage, pathogens or aggregating proteins. Inflammasome activation is observed in models of other neurodegenerative diseases such as Alzheimer's disease, and inflammasome inhibition rescues cognitive decline in rodent models of Alzheimer's disease. Here, we show that a dipeptide arising from the C9orf72 expansion, poly-glycine-arginine, activated the inflammasome in microglia and macrophages, leading to secretion of the pro-inflammatory cytokine, interleukin-1β. Poly-glycine-arginine also activated the inflammasome in organotypic hippocampal slice cultures, and immunofluorescence imaging demonstrated formation of inflammasome specks in response to poly-glycine-arginine. Several clinically available anti-inflammatory drugs rescued poly-glycine-arginine-induced inflammasome activation. These data suggest that C9orf72 dipeptides contribute to the neuroinflammation observed in patients, and highlight the inflammasome as a potential therapeutic target for frontotemporal dementia and amyotrophic lateral sclerosis.}, } @article {pmid39229047, year = {2024}, author = {Wairagkar, M and Card, NS and Singer-Clark, T and Hou, X and Iacobacci, C and Hochberg, LR and Brandman, DM and Stavisky, SD}, title = {An instantaneous voice synthesis neuroprosthesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39229047}, issn = {2692-8205}, support = {DP2 DC021055/DC/NIDCD NIH HHS/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; }, abstract = {Brain computer interfaces (BCIs) have the potential to restore communication to people who have lost the ability to speak due to neurological disease or injury. BCIs have been used to translate the neural correlates of attempted speech into text[1-3]. However, text communication fails to capture the nuances of human speech such as prosody, intonation and immediately hearing one's own voice. Here, we demonstrate a "brain-to-voice" neuroprosthesis that instantaneously synthesizes voice with closed-loop audio feedback by decoding neural activity from 256 microelectrodes implanted into the ventral precentral gyrus of a man with amyotrophic lateral sclerosis and severe dysarthria. We overcame the challenge of lacking ground-truth speech for training the neural decoder and were able to accurately synthesize his voice. Along with phonemic content, we were also able to decode paralinguistic features from intracortical activity, enabling the participant to modulate his BCI-synthesized voice in real-time to change intonation, emphasize words, and sing short melodies. These results demonstrate the feasibility of enabling people with paralysis to speak intelligibly and expressively through a BCI.}, } @article {pmid39229019, year = {2024}, author = {Erwin, AL and Chang, ML and Fernandez, MG and Attili, D and Russ, JE and Sutanto, R and Pinarbasi, ES and Bekier, M and Brant, TS and Hahn, T and Dykstra, M and Thomas, D and Li, X and Baldridge, RD and Tank, EMH and Barmada, SJ and Mosalaganti, S}, title = {Molecular Visualization of Neuronal TDP43 Pathology In Situ.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39229019}, issn = {2692-8205}, support = {DP2 GM150019/GM/NIGMS NIH HHS/United States ; S10 OD030275/OD/NIH HHS/United States ; T32 GM007544/GM/NIGMS NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; T32 GM141840/GM/NIGMS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; F31 NS134123/NS/NINDS NIH HHS/United States ; R35 GM128592/GM/NIGMS NIH HHS/United States ; }, abstract = {Nuclear exclusion and cytoplasmic accumulation of the RNA-binding protein TDP43 are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite this, the origin and ultrastructure of cytosolic TDP43 deposits remain unknown. Accumulating evidence suggests that abnormal RNA homeostasis can drive pathological TDP43 mislocalization, enhancing RNA misprocessing due to loss of nuclear TDP43 and engendering a cycle that ends in cell death. Here, we show that adding small monovalent oligonucleotides successfully recapitulates pathological TDP43 mislocalization and aggregation in iPSC-derived neurons (iNeurons). By employing a multimodal in situ cryo-correlative light and electron microscopy pipeline, we examine how RNA influences the localization and aggregation of TDP43 in near-native conditions. We find that mislocalized TDP43 forms ordered fibrils within lysosomes and autophagosomes in iNeurons as well as in patient tissue, and provide the first high-resolution snapshots of TDP43 aggregates in situ. In so doing, we provide a cellular model for studying initial pathogenic events underlying ALS, FTLD, and related TDP43-proteinopathies.}, } @article {pmid39227882, year = {2024}, author = {Zelina, P and de Ruiter, AA and Kolsteeg, C and van Ginneken, I and Vos, HR and Supiot, LF and Burgering, BMT and Meye, FJ and Veldink, JH and van den Berg, LH and Pasterkamp, RJ}, title = {ALS-associated C21ORF2 variant disrupts DNA damage repair, mitochondrial metabolism, neuronal excitability and NEK1 levels in human motor neurons.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {144}, pmid = {39227882}, issn = {2051-5960}, support = {TOTALS//Stichting ALS Nederland/ ; GoALS//Stichting ALS Nederland/ ; MAXOMOD//E-Rare/ ; TRIAGE//JPND/ ; X-omics initiative//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; EScORIAL//H2020 European Research Council/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; DNA Damage ; DNA Repair/genetics ; *Induced Pluripotent Stem Cells/metabolism ; *Mitochondria/metabolism/pathology ; *Motor Neurons/metabolism/pathology ; Mutation ; *NIMA-Related Kinase 1/genetics/metabolism ; *Zebrafish ; Cytoskeletal Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease leading to motor neuron loss. Currently mutations in > 40 genes have been linked to ALS, but the contribution of many genes and genetic mutations to the ALS pathogenic process remains poorly understood. Therefore, we first performed comparative interactome analyses of five recently discovered ALS-associated proteins (C21ORF2, KIF5A, NEK1, TBK1, and TUBA4A) which highlighted many novel binding partners, and both unique and shared interactors. The analysis further identified C21ORF2 as a strongly connected protein. The role of C21ORF2 in neurons and in the nervous system, and of ALS-associated C21ORF2 variants is largely unknown. Therefore, we combined human iPSC-derived motor neurons with other models and different molecular cell biological approaches to characterize the potential pathogenic effects of C21ORF2 mutations in ALS. First, our data show C21ORF2 expression in ALS-relevant mouse and human neurons, such as spinal and cortical motor neurons. Further, the prominent ALS-associated variant C21ORF2-V58L caused increased apoptosis in mouse neurons and movement defects in zebrafish embryos. iPSC-derived motor neurons from C21ORF2-V58L-ALS patients, but not isogenic controls, show increased apoptosis, and changes in DNA damage response, mitochondria and neuronal excitability. In addition, C21ORF2-V58L induced post-transcriptional downregulation of NEK1, an ALS-associated protein implicated in apoptosis and DDR. In all, our study defines the pathogenic molecular and cellular effects of ALS-associated C21ORF2 mutations and implicates impaired post-transcriptional regulation of NEK1 downstream of mutant C21ORF72 in ALS.}, } @article {pmid39227337, year = {2024}, author = {Choi, SJ and Yoo, SH and Lee, SY and Sung, JJ}, title = {Withdrawal of Life-Sustaining Mechanical Ventilation for a Patient With Amyotrophic Lateral Sclerosis in Locked-In Syndrome.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {20}, number = {5}, pages = {537-538}, pmid = {39227337}, issn = {1738-6586}, support = {NRF-2018R1A5A2025964/NRF/National Research Foundation of Korea/Korea ; }, } @article {pmid39226927, year = {2024}, author = {Cossu, L and Cappon, G and Facchinetti, A}, title = {Adaptive and self-learning Bayesian filtering algorithm to statistically characterize and improve signal-to-noise ratio of heart-rate data in wearable devices.}, journal = {Journal of the Royal Society, Interface}, volume = {21}, number = {218}, pages = {20240222}, pmid = {39226927}, issn = {1742-5662}, support = {//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; *Bayes Theorem ; *Wearable Electronic Devices ; *Heart Rate/physiology ; *Algorithms ; *Signal-To-Noise Ratio ; Male ; Female ; Signal Processing, Computer-Assisted ; }, abstract = {The use of wearable sensors to monitor vital signs is increasingly important in assessing individual health. However, their accuracy often falls short of that of dedicated medical devices, limiting their usefulness in a clinical setting. This study introduces a new Bayesian filtering (BF) algorithm that is designed to learn the statistical characteristics of signal and noise, allowing for optimal smoothing. The algorithm is able to adapt to changes in the signal-to-noise ratio (SNR) over time, improving performance through windowed analysis and Bayesian criterion-based smoothing. By evaluating the algorithm on heart-rate (HR) data collected from Garmin Vivoactive 4 smartwatches worn by individuals with amyotrophic lateral sclerosis and multiple sclerosis, it is demonstrated that BF provides superior SNR tracking and smoothing compared with non-adaptive methods. The results show that BF accurately captures SNR variability, reducing the root mean square error from 2.84 bpm to 1.21 bpm and the mean absolute relative error from 3.46% to 1.36%. These findings highlight the potential of BF as a preprocessing tool to enhance signal quality from wearable sensors, particularly in HR data, thereby expanding their applications in clinical and research settings.}, } @article {pmid39226712, year = {2024}, author = {Santos Silva, C and Gormicho, M and Simão, S and Pronto-Laborinho, AC and Alves, I and Pinto, S and Oliveira Santos, M and de Carvalho, M}, title = {C9orf72 gene repeat expansion phenotype profile of motor neurone disease in Portugal.}, journal = {Journal of the neurological sciences}, volume = {465}, number = {}, pages = {123208}, doi = {10.1016/j.jns.2024.123208}, pmid = {39226712}, issn = {1878-5883}, mesh = {Humans ; Male ; Portugal/epidemiology ; Female ; Middle Aged ; *C9orf72 Protein/genetics ; *Motor Neuron Disease/genetics/epidemiology ; Aged ; *Phenotype ; *DNA Repeat Expansion/genetics ; Cohort Studies ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; }, abstract = {BACKGROUND: C9orf72 gene repeat expansion (C9RE) is the most frequent gene variant associated with amyotrophic lateral sclerosis (ALS). We aimed to study the phenotype of motor neurone disease (MND) patients with C9RE in a Portuguese cohort.

METHODS: Demographical and clinical data of MND patients with (C9RE+) and without C9RE were compared. ALS al Rating Scale-Revised (ALSFRS-R) and Edinburgh Cognitive and Behavioural ALS Screen (ECAS) were used to evaluate functional and cognitive performance, respectively. Survival analysis was performed using Kaplan Meier log-rank test and Cox proportional hazards model.

RESULTS: We included 761 patients of whom 61 (8.0 %) were C9RE+. C9RE+ patients had a higher frequency of ALS (95.1 vs 78.4 %, p = 0.002), and lower frequency of progressive muscular atrophy (3.3 vs 16.7 %, p = 0.006). C9RE+ was associated with earlier age of onset (58.1 vs 62.6 years, p = 0.003) and more frequent MND family history (65.5 vs 11.4 %, p < 0.001). Gender, ethnicity, onset site, diagnostic delay, disease progression rate until diagnosis (ΔF), ALSFRS-R and time until non-invasive ventilation did not differ between groups. Cognitive/behavioural symptoms and ECAS did not differ between groups, except a worse visuospatial score in C9RE+ group (p = 0.035). Death rate was 1.8 and 1.6 times higher in C9RE+ patients with MND and ALS, respectively. Significant survival prognostic factors in C9RE+ group were diagnosis delay (HR = 0.96, 95 %CI 0.92-0.99, p = 0.008) and ΔF (HR = 1.93, 95 %CI 1.26-2.96, p = 0.002).

CONCLUSION: Our study corroborates most previous cohorts' findings, but harbours some singularities regarding onset site, phenotype, and cognitive profile, that contribute to a better understanding of C9RE epidemiology.}, } @article {pmid39226692, year = {2024}, author = {Kwon, S and Kim, B and Han, KD and Jung, W and Cho, EB and Shin, DW and Min, JH}, title = {Risk of depression in amyotrophic lateral sclerosis: A nationwide cohort study in South Korea.}, journal = {Journal of psychiatric research}, volume = {178}, number = {}, pages = {414-420}, doi = {10.1016/j.jpsychires.2024.08.030}, pmid = {39226692}, issn = {1879-1379}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Republic of Korea/epidemiology ; Male ; Female ; Middle Aged ; Aged ; *Depression/epidemiology ; Adult ; Cohort Studies ; Proportional Hazards Models ; }, abstract = {Depression is frequently reported in amyotrophic lateral sclerosis (ALS) due to the disastrous prognosis of progressive motor impairment, but the risk of depression in ALS is still unclear. Therefore, we investigated the risk of depression in ALS and analyzed the effect of ALS-related physical disability on the risk of developing depression using the Korean National Health Insurance Service (KNHIS) database. A total of 2241 ALS patients, as defined by the International Classification Diseases (ICD, G12.21) and Rare Intractable Disease codes (V123), and 1:10 sex- and age-matched controls were selected from the KNHIS. After applying exclusion criteria (non-participation in national health screening, history of depression, or having missing data), 595 ALS patients and 9896 non-ALS individuals were finally selected. Primary outcome is newly diagnosed depression during follow-up duration defined by ICD code (F32 or F33). A Cox regression model was used to examine the hazard ratios (HRs) after adjustment for potential confounders. During the follow-up period, 283 cases of depression in the ALS group and 1547 in the controls were recorded. The adjusted HR for depression in ALS was 9.1 (95% confidence interval [CI] 7.87-10.60). The risk of depression was slightly higher in the disabled ALS group (aHR 10.1, 95% CI 7.98-12.67) than in the non-disabled ALS group (aHR 8.78, 95% CI 7.42-10.39). The relative risk of depression was higher in younger patients than in older patients, and in obese patients than in non-obese patients. Our study showed that ALS patients have an increased risk of depression compared to non-ALS individuals.}, } @article {pmid39225243, year = {2024}, author = {Liang, J and Zhu, Y and Liu, S and Kuang, B and Tian, Z and Zhang, L and Yang, S and Lin, M and Chen, N and Liu, X and Ai, Q and Yang, Y}, title = {Progress of Exosomal MicroRNAs and Traditional Chinese Medicine Monomers in Neurodegenerative Diseases.}, journal = {Phytotherapy research : PTR}, volume = {38}, number = {11}, pages = {5323-5349}, doi = {10.1002/ptr.8322}, pmid = {39225243}, issn = {1099-1573}, support = {//The Key Discipline of Biological Engineering of Hunan University of Chinese Medicine [2018] No. 3/ ; 22JBZ052//Hunan University of Chinese Medicine Discipline Construction Project/ ; 202329-2//Key Project of Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University/ ; 2021JJ30512//Hunan Natural Science Foundation/ ; 2022JJ40313//Hunan Natural Science Foundation/ ; 2022JJ40456//Hunan Natural Science Foundation/ ; 2023JJ60126//Hunan Natural Science Foundation/ ; 2023JJ60471//Hunan Natural Science Foundation/ ; 21B0354//Outstanding Youth Project of Hunan Education Department/ ; B2023061//Scientific Research Project of Hunan Provincial Administration of Traditional Chinese Medicine/ ; //Hunan University of Chinese Medicine First-class Disciple Construction Project of Chinese Material Medica/ ; kq2014091//Changsha Natural Science Foundation/ ; kq2202269//Changsha Natural Science Foundation/ ; //The First-class Discipline Construction Project of Chemical Engineering and Technology of Hunan University of Traditional Chinese Medicine/ ; 212010//Special Scientific and Technological Project for Comprehensive Utilization of Ampelopsis grossedentata Resources of Hunan Qiankun Biotechnology Co., Ltd/ ; 2019xjjj001//Key Project of Hunan University of Chinese Medicine School level Scientific Research Fund/ ; 2021XJJJ028//Key Project of Hunan University of Chinese Medicine School level Scientific Research Fund/ ; U2202214//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Exosomes/metabolism ; *MicroRNAs/genetics ; *Neurodegenerative Diseases/drug therapy ; *Medicine, Chinese Traditional/methods ; Drugs, Chinese Herbal/pharmacology ; Animals ; }, abstract = {Exosomes, extracellular vesicles secreted by various cells, actively participate in intercellular communication by facilitating the exchange of crucial molecular information such as DNA, RNA, and lipids. Within this intricate network, microRNAs, endogenous non-coding small RNAs, emerge as pivotal regulators of post-transcriptional gene expression, significantly influencing the development of neurodegenerative diseases. The historical prominence of traditional Chinese medicine (TCM) in clinical practice in China underscores its enduring significance. Notably, TCM monomers, serving as active constituents within herbal medicine, assume a critical role in the treatment of neurodegenerative diseases, particularly in mitigating oxidative stress, inhibiting apoptosis, and reducing inflammation. This comprehensive review aims to delineate the specific involvement of exosomal microRNAs in various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, and amyotrophic lateral sclerosis. Furthermore, the exploration extends to the application of TCM monomers, elucidating their efficacy as therapeutic agents in these conditions. Additionally, the review examines the utilization of exosomes as drug delivery carriers in the context of neurodegenerative diseases, providing a nuanced understanding of the potential synergies between TCM and modern therapeutic approaches. This synthesis of knowledge aims to contribute to the advancement of our comprehension of the intricate molecular mechanisms underlying neurodegeneration and the potential therapeutic avenues offered by TCcom interventions.}, } @article {pmid39225106, year = {2024}, author = {Białobrodzka, E and Flis, DJ and Akdogan, B and Borkowska, A and Wieckowski, MR and Antosiewicz, J and Zischka, H and Dzik, KP and Kaczor, JJ and Ziolkowski, W}, title = {Amyotrophic Lateral Sclerosis and swim training affect copper metabolism in skeletal muscle in a mouse model of disease.}, journal = {Muscle & nerve}, volume = {70}, number = {5}, pages = {1111-1118}, doi = {10.1002/mus.28237}, pmid = {39225106}, issn = {1097-4598}, support = {//Narodowe Centrum Nauki/ ; DEC-2013/09/NZ7/02538//National Science Centre/ ; 2020/39/B/NZ7/03366//National Science Centre/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Muscle, Skeletal/metabolism ; Mice ; *Copper/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; *Swimming ; Superoxide Dismutase/metabolism ; Copper-Transporting ATPases/metabolism/genetics ; Physical Conditioning, Animal/physiology ; Superoxide Dismutase-1/metabolism/genetics ; Adenosine Triphosphatases/metabolism ; Cation Transport Proteins/metabolism ; Male ; Copper Transporter 1/metabolism ; }, abstract = {INTRODUCTION/AIMS: Swim training and regulation of copper metabolism result in clinical benefits in amyotrophic lateral sclerosis (ALS) mice. Therefore, the study aimed to determine whether swim training improves copper metabolism by modifying copper metabolism in the skeletal muscles of ALS mice.

METHODS: SOD1G93A mice (n = 6 per group) were used as the ALS model, and wild-type B6SJL (WT) mice as controls (n = 6). Mice with ALS were analyzed before the onset of ALS (ALS BEFORE), at baseline ALS (first disease symptoms, trained and untrained, ALS ONSET), and at the end of ALS (last stage disease, trained and untrained, ALS TERMINAL). Copper concentrations and the level of copper metabolism proteins in the skeletal muscles of the lower leg were determined.

RESULTS: ALS disease caused a reduction in the copper concentration in ALS TERMINAL untrained mice compared with the ALS BEFORE (10.43 ± 1.81 and 38.67 ± 11.50 μg/mg, respectively, p = .0213). The copper chaperon for SOD1 protein, which supplies copper to SOD1, and ATPase7a protein (copper exporter), increased at the terminal stage of disease by 57% (p = .0021) and 34% (p = .0372), while the CTR1 protein (copper importer) decreased by 45% (p = .002). Swim training moderately affected the copper concentration and the concentrations of proteins responsible for copper metabolism in skeletal muscles.

DISCUSSION: The results show disturbances in skeletal muscle copper metabolism associated with ALS progression, which is moderately affected by swim training. From a clinical point of view, exercise in water for ALS patients should be an essential element of rehabilitation for maintaining quality of life.}, } @article {pmid39224919, year = {2024}, author = {Kiernan, MC and Kaji, R}, title = {Emerging concepts and therapies for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {558-559}, doi = {10.1097/WCO.0000000000001308}, pmid = {39224919}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; }, } @article {pmid39224887, year = {2024}, author = {Yang, J and Tian, M and Zhang, L and Xin, C and Huo, J and Liu, Q and Dong, H and Li, R and Liu, Y}, title = {Assessment of Rab geranylgeranyltransferase subunit beta in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1447461}, pmid = {39224887}, issn = {1664-2295}, abstract = {INTRODUCTION: Geranylgeranyltransferase Subunit Beta (RABGGTB) was expressed at higher levels in patients with Amyotrophic lateral sclerosis (ALS) compared with healthy controls. This study aims to observe the expression of RABGGTB in different cells from patients with ALS and different diseases.

METHODS: In this case-control study, we collected peripheral blood from patients with ALS and healthy controls, and compared the expression of RABGGTB in natural killer cells (NK), T cells and B cells between patients with ALS and healthy controls by flow cytometry. And compared the expression of RABGGTB in monocytes and monocyte-derived macrophages from patients with ALS, Parkinson's disease (PD), acute cerebrovascular disease (ACVD), and healthy controls by flow cytometry and immunofluorescence. Then flow cytometry was used to detect the expression of RABGGTB in monocytes from SOD1G93A mice and WT mice.

RESULTS: The expression of RABGGTB was not significantly changed in NK cells, cytotoxic T cells (CTL), helper T cells (Th), regulatory T cells (Treg), and B cells from patients with ALS compared to healthy controls. And the expression of RABGGTB in monocytes and monocyte-derived macrophages was higher in the ALS group than in the PD, ACVD and control group. The expression of RABGGTB was significantly higher in monocytes of SOD1G93A mice compared to WT mice.

CONCLUSION: These findings suggest that RABGGTB expression was increased in monocytes and monocyte-derived macrophages from patients with ALS, not in NK, CTL, Th, Treg, and B cells. Future studies are needed to find the clinical implication of RABGGTB in ALS.}, } @article {pmid39223525, year = {2024}, author = {Iakovleva, V and Verde, F and Cinnante, C and Sillani, A and Conte, G and Corsini, E and Ciusani, E and Erbetta, A and Silani, V and Ticozzi, N}, title = {Duropathy as a rare motor neuron disease mimic: from bibrachial amyotrophy to infratentorial superficial siderosis.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {309}, pmid = {39223525}, issn = {1471-2377}, support = {PNC-E3-2022-23683266//Italian Ministry of Education and Research (MUR)/ ; }, mesh = {Humans ; Male ; Middle Aged ; *Motor Neuron Disease/diagnosis/complications/diagnostic imaging ; *Siderosis/complications/diagnosis/diagnostic imaging ; Magnetic Resonance Imaging/methods ; Diagnosis, Differential ; Dura Mater/diagnostic imaging/pathology ; }, abstract = {BACKGROUND: Bibrachial amyotrophy associated with an extradural CSF collection and infratentorial superficial siderosis (SS) are rare conditions that may occasionally mimic ALS. Both disorders are assumed to be due to dural tears.

CASE PRESENTATION: A 53-year-old man presented with a 7-year history of slowly progressive asymmetric bibrachial amyotrophy. Initially, a diagnosis of atypical motor neuron disease (MND) was made. At re-evaluation 11 years later, upper limb wasting and weakness had further progressed and were accompanied by sensorineural hearing loss. MRI of the brain and spine demonstrated extensive supra- and infratentorial SS (including the surface of the whole spinal cord) as well as a ventral longitudinal intraspinal fluid collection (VLISFC) extending along almost the entire thoracic spine. Osteodegenerative changes were observed at C5-C7 level, with osteophytes protruding posteriorly. The bony spurs at C6-C7 level were hypothesized to have lesioned the dura, causing a CSF leak and thus a VLISFC. Review of the MRI acquired at first evaluation showed that the VLISFC was already present at that time (actually beginning at C7 level), whereas the SS was not. 19 years after the onset of upper limb weakness, the patient additionally developed parkinsonism. Response to levodopa, brain scintigraphy with [123]I-ioflupane and brain MRI with nigrosome 1 evaluation were consistent with idiopathic Parkinson's disease (PD). On the latest follow-up 21 years after symptom onset, the VLISFC was unchanged, as were upper arm weakness and wasting.

CONCLUSIONS: Based on the long-term follow-up, we could establish that, while the evidence of the VLISFC was concomitant with the clinical presentation of upper limb amyotrophy and weakness, the radiological signs of SS appeared later. This suggests that SS was not per se the cause of the ALS-like clinical picture, but rather a long-term sequela of a dural leak. The latter was instead the causative lesion, giving rise to a VLISFC which compressed the cervical motor roots. Dural tears can actually cause several symptoms, and further studies are needed to elucidate the pathophysiological correlates of "duropathies". Finally, as iron metabolism has been implicated in PD, the co-occurrence of PD with SS deserves further investigation.}, } @article {pmid39222049, year = {2024}, author = {Santangelo, S and Invernizzi, S and Sorce, MN and Casiraghi, V and Peverelli, S and Brusati, A and Colombrita, C and Ticozzi, N and Silani, V and Bossolasco, P and Ratti, A}, title = {NEK1 haploinsufficiency worsens DNA damage, but not defective ciliogenesis, in C9ORF72 patient-derived iPSC-motoneurons.}, journal = {Human molecular genetics}, volume = {33}, number = {21}, pages = {1900-1907}, pmid = {39222049}, issn = {1460-2083}, support = {GR-2016-02364373//BIBLIOSAN/ ; PSR 2021//Italian Ministery of Health/ ; }, mesh = {*Induced Pluripotent Stem Cells/metabolism ; Humans ; *NIMA-Related Kinase 1/genetics ; *DNA Damage/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *C9orf72 Protein/genetics/metabolism ; *Haploinsufficiency/genetics ; *Motor Neurons/metabolism/pathology ; *Frontotemporal Dementia/genetics/pathology ; *Cilia/genetics/pathology/metabolism ; Cell Differentiation/genetics ; DNA Repeat Expansion/genetics ; Mutation ; }, abstract = {The hexanucleotide G4C2 repeat expansion (HRE) in C9ORF72 gene is the major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leading to both loss- and gain-of-function pathomechanisms. The wide clinical heterogeneity among C9ORF72 patients suggests potential modifying genetic and epigenetic factors. Notably, C9ORF72 HRE often co-occurs with other rare variants in ALS/FTD-associated genes, such as NEK1, which encodes for a kinase involved in multiple cell pathways, including DNA damage response and ciliogenesis. In this study, we generated induced pluripotent stem cells (iPSCs) and differentiated motoneurons (iPSC-MNs) from an ALS patient carrying both C9ORF72 HRE and a NEK1 loss-of-function mutation to investigate the biological effect of NEK1 haploinsufficiency on C9ORF72 pathology in a condition of oligogenicity. Double mutant C9ORF72/NEK1 cells showed increased pathological C9ORF72 RNA foci in iPSCs and higher DNA damage levels in iPSC-MNs compared to single mutant C9ORF72 cells, but no effect on DNA damage response. When we analysed the primary cilium, we observed a defective ciliogenesis in C9ORF72 iPSC-MNs which was not worsened by NEK1 haploinsufficiency in the double mutant iPSC-MNs. Altogether, our study shows that NEK1 haploinsufficiency influences differently DNA damage and cilia length, potentially acting as a modifier at biological level in an in vitro ALS patient-derived disease model of C9ORF72 pathology.}, } @article {pmid39218769, year = {2024}, author = {Sun, J and Zhang, Y}, title = {Microbiome and micronutrient in ALS: From novel mechanisms to new treatments.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {6}, pages = {e00441}, pmid = {39218769}, issn = {1878-7479}, support = {I01 BX004824/BX/BLRD VA/United States ; R01 DK114126/DK/NIDDK NIH HHS/United States ; R01 DK134343/DK/NIDDK NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/microbiology/metabolism/therapy ; Humans ; *Micronutrients/metabolism ; *Gastrointestinal Microbiome/physiology ; Animals ; Dysbiosis ; Microbiota/physiology ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disorder. Despite extensive studies, it remains challenging to treat ALS. Recent ALS studies have shown dysbiosis (e.g., loss of microbial diversity and beneficial function in the gut microbiota) is correlated with intestinal inflammation and change of intestinal integrity in ALS. The novel concepts and the roles of microbiome and microbial metabolites through the gut-microbiome-neuron axis in ALS pathogenesis have been slowly recognized by the neurology research field. Here, we will discuss the recent progress of microbiome, including bacteria, fungi, and viruses, in the ALS research. We will discuss our understanding of microbial metabolites in ALS. Micronutrition refers to the intake of essential vitamins, minerals, and other micronutrients. We will summarize the literation related to micronutrition and ALS. Furthermore, we will consider the mutual interactions of microbiome and micronutrition in the ALS progression and treatment. We further propose that the mechanistic and translational studies that shift from suspension of disbelief to cogent ingenuity, and from bench study to bed-side application, should allow new strategies of diagnosis and treatment for ALS.}, } @article {pmid39218293, year = {2024}, author = {Dibaj, P and Safavi-Abbasi, S and Asadollahi, E}, title = {In vivo spectrally unmixed multi-photon imaging of longitudinal axon-glia changes in injured spinal white matter.}, journal = {Neuroscience letters}, volume = {841}, number = {}, pages = {137959}, doi = {10.1016/j.neulet.2024.137959}, pmid = {39218293}, issn = {1872-7972}, mesh = {Animals ; *White Matter/pathology/metabolism/diagnostic imaging ; *Spinal Cord Injuries/pathology/metabolism/diagnostic imaging ; *Axons/pathology/metabolism ; *Mice, Transgenic ; Neuroglia/metabolism/pathology ; Mice ; Microscopy, Fluorescence, Multiphoton/methods ; Spinal Cord/pathology/metabolism ; Microglia/metabolism/pathology ; Astrocytes/metabolism/pathology ; }, abstract = {Understanding the sequence of cellular responses and their contributions to pathomorphogical changes in spinal white matter injuries is a prerequisite for developing efficient therapeutic strategies for spinal cord injury (SCI) as well as neurodegenerative and inflammatory diseases of the spinal cord such as amyotrophic lateral sclerosis and multiple sclerosis. We have developed several types of surgical procedures suitable for acute one-time and chronic recurrent in vivo multiphoton microscopy of spinal white matter [1]. Sophisticated surgical procedures were combined with transgenic mouse technology to image spinal tissue labeled with up to four fluorescent proteins (FPs) in axons, astrocytes, microglia, and blood vessels. To clearly separate the simultaneously excited FPs, spectral unmixing including iterative procedures was performed after imaging the diversely labeled spinal white matter with a custom-made 4-channel two-photon laser-scanning microscope. In our longitudinal multicellular studies of injured spinal white matter, we imaged axonal dynamics and invasion of microglia and astrocytes for a time course of over 200 days after SCI. Our methods offer ideal platforms for investigating acute and chronic cellular dynamics, cell-cell interactions, and metabolite fluctuations in health and disease as well as pharmacological manipulations in vivo.}, } @article {pmid39218010, year = {2024}, author = {Shojaie, A and Al Khleifat, A and Garrahy, S and Habash-Bailey, H and Thomson, R and Opie-Martin, S and Javidnia, S and Leigh, PN and Al-Chalabi, A}, title = {Investigating the impact of socioeconomic status on amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {702-707}, pmid = {39218010}, issn = {2167-9223}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/economics ; Male ; Female ; Middle Aged ; *Social Class ; Aged ; Adult ; Age of Onset ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the gradual death of motor neurons in the brain and spinal cord, leading to fatal paralysis. Socioeconomic status (SES) is a measure of an individual's shared economic and social status, which has been shown to have an association with health outcomes. Understanding the impact of SES on health conditions is crucial, as it can influence and be influenced by health-related variables. The role of socioeconomic status in influencing the risk and progression of ALS has not been established, and understanding the various factors that impact ALS is important in developing strategies for treatment and prevention. To investigate this relationship, we recruited 413 participants with definite, probable, or possible ALS according to the El Escorial criteria, from three tertiary centers in London, Sheffield, and Birmingham. Logistic regression was used to examine the association between case-control status, socioeconomic criteria, and ALS risk. Linear regression was used to examine the association between age of onset and socioeconomic variables. Two sensitivity analyses were performed, one using an alternative occupational classifier, and the other using Mendelian Randomization analysis to examine association. There was no significant relationship between any variables and ALS risk. We found an inverse relationship between mean lifetime salary and age of ALS onset (Beta = -0.157, p = 0.011), but no effect of education or occupation on the age of onset. The finding was confirmed in both sensitivity analyses and in Mendelian Randomization. We find that a higher salary is associated with a younger age of ALS onset taking into account sex, occupation, years of education, and clinical presentation.}, } @article {pmid39217855, year = {2024}, author = {Zhang, J and Chen, K and Chen, Y and Hua, L and Chen, S and Chen, X and Zou, L and Li, S and Yang, X and Shen, Y}, title = {Pathology reduction and motor behavior improvement associated with ultrasound-mediated delivery of arctiin to the motor cortex in a mutant SOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {Ultrasonics}, volume = {144}, number = {}, pages = {107449}, doi = {10.1016/j.ultras.2024.107449}, pmid = {39217855}, issn = {1874-9968}, mesh = {Animals ; Male ; Mice ; *Amyotrophic Lateral Sclerosis ; *Disease Models, Animal ; Drug Delivery Systems ; Furans/pharmacology/administration & dosage ; Glucosides/pharmacology/administration & dosage ; *Mice, Transgenic ; Microbubbles ; *Motor Cortex/drug effects/physiopathology ; Mutation ; Superoxide Dismutase-1/genetics ; Ultrasonic Therapy/methods ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is marked by the deterioration of both cortical and spinal cord motor neurons. Despite the underlying causes of the disease remain elusive, there has been a growing attention on the well-being of cortical motor neurons in recent times. Focused ultrasound combined with microbubbles (FUS/MB) for opening the blood-brain barrier (BBB) provides a means for drug delivery to specific brain regions, holding significant promise for the treatment of neurological disorders.

OBJECTIVES: We aim to explore the outcomes of FUS/MB-mediated delivery of arctiin (Arc), a natural compound with anti-inflammatory activities, to the cerebral motor cortex area by using a transgenic ALS mouse model.

METHODS: The ALS mouse model with the SOD1[G93A] mutation was used and subjected to daily Arc administration with FUS/MB treatment twice a week. After six-week treatments, the motor performance was assessed by grip strength, wire hanging, and climbing-pole tests. Mouse brains, spinal cords and gastrocnemius muscle were harvested for histological staining.

RESULTS: Compared with the mice given Arc administration only, the combined treatments of FUS/MB with Arc induced further mitigation of the motor function decline, accompanied by improved health of the gastrocnemius muscle. Furthermore, notable neuroprotective effect was evidenced by the amelioration of motor neuron failure in the cortex and lumbar spinal cord.

CONCLUSION: These preliminary results indicated that the combined treatment of FUS/MB and arctiin exerted a potentially beneficial effect on neuromuscular function in the ALS disease.}, } @article {pmid39217293, year = {2024}, author = {Aljthalin, R and Albalawi, R and Alyahya, A and Alhathlool, R and Alhashemi, M}, title = {Multiple sclerosis and amyotrophic lateral sclerosis: is there an association or a red flag? A case report and literature review.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {307}, pmid = {39217293}, issn = {1471-2377}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/pathology ; Middle Aged ; *Multiple Sclerosis/complications/diagnosis/pathology ; Magnetic Resonance Imaging ; }, abstract = {BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that causes damage to the myelin and axons and is caused by genetic or environmental factors. Amyotrophic lateral sclerosis (ALS) is characterized by rapidly progressive degeneration of the motor neurons resulting in the presence of upper and lower motor-neuron signs and symptoms.

CASE PRESENTATION: A 46-year-old female patient presented with symmetrical weakness of the lower limbs and numbness that developed over weeks. Magnetic resonance imaging (MRI) of the brain exhibited typical demyelination features, high signal abnormality involving the periventricular and subcortical white matter, and an oval-shaped lesion. The patient was diagnosed with MS based on the clinical presentation and radiological examination. However, there was rapid progression of the symptoms, involvement of bulbar dysfunction, and muscle atrophy. Furthermore, the patient did not respond to acute therapy and immunotherapy, which made the diagnosis of MS less likely or suggested that it could be associated with another diagnosis. Her neurophysiological test met the criteria of ALS, and she was started on riluzole.

LITERATURE REVIEW: We reviewed all articles from 1986 to 2023, and there were 32 reported cases describing the co-occurrence of ALS and MS in different populations. Our case is the 33rd, and to our knowledge, it is the only case reported in the Middle East and specifically in Saudi Arabia. The main proposed mechanism according to postmortem examinations is a combination of degenerative and inflammatory processes with a cascade of production of reactive oxygen species and nitric oxide, which lead to cell death and apoptosis during concomitant ALS with MS.

CONCLUSION: The co-occurrence of ALS and MS is extremely rare, but it can be explained by pathogenesis related to neurodegeneration, inflammation, or genetic susceptibility. Rapid progressive motor and bulbar symptoms could be red-flag symptoms, extensive evaluation might be needed for these patients.}, } @article {pmid39216161, year = {2024}, author = {Wang, J and Qi, J and Ouyang, Y and Zhou, S and Qin, L and Zhang, B and Bai, L and Pan, L}, title = {The mutation Asp-376-Glu in the ALS gene confers resistance to mesosulfuron-methyl in Beckmannia syzigachne.}, journal = {Plant physiology and biochemistry : PPB}, volume = {215}, number = {}, pages = {109083}, doi = {10.1016/j.plaphy.2024.109083}, pmid = {39216161}, issn = {1873-2690}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Sulfonylurea Compounds/pharmacology ; *Mutation ; Plant Proteins/genetics/metabolism ; Poaceae/genetics/drug effects ; Molecular Docking Simulation ; Plant Weeds/genetics/drug effects ; }, abstract = {Understanding the mechanisms by which weeds develop herbicide resistance is crucial for managing resistance effectively and optimizing herbicide use. Beckmannia syzigachne, a harmful grass weed prevalent in wheat and rice-wheat rotation areas, poses a significant threat to crop productivity. A field herbicide resistance survey identified a resistant population with a new ALS mutation (Asp-376-Glu). The Glu-376-Asp population displayed varying resistance levels to seven ALS herbicides, verified using the dCAPS method. qRT-PCR analysis showed that no significant difference existed in the ALS gene expression between the Asp-376-Glu and S populations. P450 and GST inhibitors failed to reverse resistance to mesosulfuron-methyl, suggesting no involvement of P450- and GST-based metabolic resistance. Molecular docking indicated that the Asp-376-Glu mutation reduces the binding affinity between ALS-inhibitors and BsALS. The findings provide valuable insights into herbicide resistance mechanisms for weed resistance control.}, } @article {pmid39216080, year = {2024}, author = {Mazurie, Z and Branchereau, P and Cattaert, D and Henkous, N and Savona-Baron, C and Vouimba, RM}, title = {Acute stress differently modulates interneurons excitability and synaptic plasticity in the primary motor cortex of wild-type and SOD1[G93A] mouse model of ALS.}, journal = {The Journal of physiology}, volume = {602}, number = {19}, pages = {4987-5015}, doi = {10.1113/JP285210}, pmid = {39216080}, issn = {1469-7793}, support = {GPR BRAIN-2030//Université de Bordeaux (University of Bordeaux)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/physiopathology/genetics ; *Interneurons/physiology ; *Neuronal Plasticity ; *Motor Cortex/physiopathology ; Mice ; Male ; *Mice, Transgenic ; Disease Models, Animal ; Stress, Psychological/physiopathology ; Superoxide Dismutase-1/genetics ; Mice, Inbred C57BL ; }, abstract = {Primary motor cortex (M1) network stability depends on activity of inhibitory interneurons, for which susceptibility to stress was previously demonstrated in limbic regions. Hyperexcitability in M1 following changes in the excitatory/inhibitory balance is a key pathological hallmark of amyotrophic lateral sclerosis (ALS). Using electrophysiological approaches, we assessed the impact of acute restraint stress on inhibitory interneurons excitability and global synaptic plasticity in M1 of the SOD1[G93A] ALS mouse model at a late pre-symptomatic stage (10-12.5 weeks). Based on their firing type (continuous, discontinuous, with accommodation or not) and electrophysiological characteristics (resting potential, rheobase, firing frequency), interneurons from M1 slices were separated into four clusters, labelled from 1 to 4. Among them, only interneurons from the first cluster, presenting continuous firing with few accommodations, tended to show increased excitability in wild-type (WT) and decreased excitability in SOD1[G93A] animals following stress. In vivo analyses of evoked field potentials showed that stress suppressed the theta burst-induced plasticity of an excitatory component (N1) recorded in the superficial layers of M1 in WT, with no impact on an inhibitory complex (N2-P1) from the deeper layers. In SOD1[G93A] mice, stress did not affect N1 but suppressed the N2-P1 plasticity. These data suggest that stress can alter M1 network functioning in a different manner in WT and SOD1[G93A] mice, possibly through changes of inhibitory interneurons excitability and synaptic plasticity. This suggests that stress-induced activity changes in M1 may therefore influence ALS outcomes. KEY POINTS: Disruption of the excitatory/inhibitory balance in the primary motor cortex (M1) has been linked to cortical hyperexcitability development, a key pathological hallmark of amyotrophic lateral sclerosis (ALS). Psychological stress was reported to influence excitatory/inhibitory balance in limbic regions, but very little is known about its influence on the M1 functioning under physiological or pathological conditions. Our study revealed that acute stress influences the excitatory/inhibitory balance within the M1, through changes in interneurons excitability along with network plasticity. Such changes were different in pathological (SOD1[G93A] ALS mouse model) vs. physiological (wild-type) conditions. The results of our study help us to better understand how stress modulates the M1 and highlight the need to further characterize stress-induced motor cortex changes because it may be of importance when evaluating ALS outcomes.}, } @article {pmid39215697, year = {2024}, author = {Burrows, DJ and McGown, A and Abduljabbar, O and Castelli, LM and Shaw, PJ and Hautbergue, GM and Ramesh, TM}, title = {RAN Translation of C9orf72-Related Dipeptide Repeat Proteins in Zebrafish Recapitulates Hallmarks of Amyotrophic Lateral Sclerosis and Identifies Hypothermia as a Therapeutic Strategy.}, journal = {Annals of neurology}, volume = {96}, number = {6}, pages = {1058-1069}, doi = {10.1002/ana.27068}, pmid = {39215697}, issn = {1531-8249}, support = {Apr17/854-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R024162/1/MRC_/Medical Research Council/United Kingdom ; BB/S005277/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; *Zebrafish ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; *Animals, Genetically Modified ; *Disease Models, Animal ; *Dipeptides ; Hypothermia, Induced/methods ; Frontotemporal Dementia/genetics/metabolism ; Humans ; Protein Biosynthesis/genetics/physiology ; }, abstract = {OBJECTIVE: Hexanucleotide repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A large body of evidence implicates dipeptide repeats (DPRs) proteins as one of the main drivers of neuronal injury in cell and animal models.

METHODS: A pure repeat-associated non-AUG (RAN) translation zebrafish model of C9orf72-ALS/FTD was generated. Embryonic and adult transgenic zebrafish lysates were investigated for the presence of RAN-translated DPR species and adult-onset motor deficits. Using C9orf72 cell models as well as embryonic C9orf72-ALS/FTD zebrafish, hypothermic-therapeutic temperature management (TTM) was explored as a potential therapeutic option for C9orf72-ALS/FTD.

RESULTS: Here, we describe a pure RAN translation zebrafish model of C9orf72-ALS/FTD that exhibits significant RAN-translated DPR pathology and progressive motor decline. We further demonstrate that hypothermic-TTM results in a profound reduction in DPR species in C9orf72-ALS/FTD cell models as well as embryonic C9orf72-ALS/FTD zebrafish.

INTERPRETATION: The transgenic model detailed in this paper provides a medium throughput in vivo research tool to further investigate the role of RAN-translation in C9orf72-ALS/FTD and further understand the mechanisms that underpin neuroprotective strategies. Hypothermic-TTM presents a viable therapeutic avenue to explore in the context of C9orf72-ALS/FTD. ANN NEUROL 2024;96:1058-1069.}, } @article {pmid39215690, year = {2024}, author = {Suwa, S and Ando, M and Nakashima, T and Horii, S and Anai, T and Takeyama, H}, title = {In Situ Raman Hyperspectral Analysis of Microbial Colonies for Secondary Metabolites Screening.}, journal = {Analytical chemistry}, volume = {96}, number = {37}, pages = {14909-14917}, pmid = {39215690}, issn = {1520-6882}, mesh = {*Spectrum Analysis, Raman/methods ; *Escherichia coli/metabolism/isolation & purification ; Anti-Bacterial Agents/analysis/metabolism ; Streptomyces/metabolism ; Least-Squares Analysis ; }, abstract = {Since the discovery of penicillin, a vast array of microbial antibiotics has been identified and applied in the medical field. Globally, the search for drug candidates via microbial screening is ongoing. Traditional screening methods, however, are time-consuming and require labor-intensive sample processing, significantly reducing throughput. This research introduces a Raman spectroscopy-based screening system tailored to the in situ analysis of microbial colonies on solid culture media. Employing multivariate curve resolution-alternating least-squares (MCR-ALS) for spectral decomposition, our approach reveals the production of secondary metabolites at the single colony level. We enhanced the microbial culture method, enabling direct, high signal-to-noise (S/N) ratio Raman spectroscopic measurements of colonies of Escherichia coli and actinomycetes species. Through semisupervised MCR analysis using the known spectra of actinorhodin and undecylprodigiosin as references, we accurately assessed the production of these compounds by Streptomyces coelicolor A3(2). Furthermore, we herein successfully detected the production of amphotericin B by Streptomyces nodosus, even in the absence of prior spectral information. This demonstrates the potential of our technique in the discovery of secondary metabolites. In addition to enabling the detection of the above-mentioned compounds, this analysis revealed the heterogeneity of the spatial distribution of their production in each colony. Our technique makes a significant contribution to the advancement of microbial screening, offering a rapid, efficient alternative to conventional methods and opening avenues for secondary metabolites discovery.}, } @article {pmid39215326, year = {2024}, author = {Carlton, J and Powell, P and Rowen, D and Williams, C and Griffiths, AW and Hobson, E and McDermott, C}, title = {Development of a novel patient reported outcome measure for health-related quality of life in amyotrophic lateral sclerosis (PROQuALS): study protocol.}, journal = {Health and quality of life outcomes}, volume = {22}, number = {1}, pages = {69}, pmid = {39215326}, issn = {1477-7525}, mesh = {*Amyotrophic Lateral Sclerosis/psychology/therapy ; Humans ; *Quality of Life/psychology ; *Patient Reported Outcome Measures ; Surveys and Questionnaires ; Research Design ; Psychometrics ; Cost-Benefit Analysis ; }, abstract = {BACKGROUND: Patient reported outcome measures (PROMs) can be used to assess the impact of health conditions upon an individual's health-related quality of life (HRQoL). Whilst PROMs have been used to quantify the HRQoL impact of amyotrophic lateral sclerosis (ALS), existing instruments may not fully capture what matters to people living with ALS (plwALS) or be appropriate to be used directly to inform the cost-effectiveness of new treatments. This highlights a need for a new condition-specific PROM that can both capture what's important to plwALS and be used in economic evaluation. This study has two key aims: 1) to produce a novel PROM for measuring HRQoL in plwALS (PROQuALS). 2) to value a set of items from the novel PROM to generate an associated preference-weighted measure (PWM) that will enable utility values to be generated.

METHODS: A mixed-methods study design will be conducted across three stages. Stage 1 involves concept elicitation and the generation of draft PROM content from a robust and comprehensive systematic review of HRQoL in ALS, with input from plwALS. Stage 2 consists of cognitive debriefing of the draft PROM content to ascertain its content validity (Stage 2a), followed by a psychometric survey (Stage 2b) to assess statistical performance. Evidence from Stage 2 will be used to make decisions on the final content and format of the novel PROM. Stage 3 will involve valuation and econometric modeling using health economics methods to generate preference weights, so a PWM derived from the novel PROM can be used in the cost-effectiveness analyses of treatments. Patient and clinical advisory groups will have critical, collaborative input throughout the project.

DISCUSSION: The novel PROM will be designed to comprehensively assess important aspects of HRQoL to plwALS and to quantify HRQoL in terms of subjective impact. The PROQuALS measure will be available for use in research and healthcare settings. The associated PWM component will extend and enable the use of PROQuALS in cost-effective analyses of new treatments for ALS.

TRIAL REGISTRATION: Not applicable.}, } @article {pmid39211392, year = {2024}, author = {Matsuo, K and Nagamatsu, J and Nagata, K and Umeda, R and Shiota, T and Morimoto, S and Suzuki, N and Aoki, M and Okano, H and Nakamori, M and Nishihara, H}, title = {Establishment of a novel amyotrophic lateral sclerosis patient (TARDBP [N345K/+])-derived brain microvascular endothelial cell model reveals defective Wnt/β-catenin signaling: investigating diffusion barrier dysfunction and immune cell interaction.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1357204}, pmid = {39211392}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a major neurodegenerative disease for which there is currently no curative treatment. The blood-brain barrier (BBB), multiple physiological functions formed by mainly specialized brain microvascular endothelial cells (BMECs), serves as a gatekeeper to protect the central nervous system (CNS) from harmful molecules in the blood and aberrant immune cell infiltration. The accumulation of evidence indicating that alterations in the peripheral milieu can contribute to neurodegeneration within the CNS suggests that the BBB may be a previously overlooked factor in the pathogenesis of ALS. Animal models suggest BBB breakdown may precede neurodegeneration and link BBB alteration to the disease progression or even onset. However, the lack of a useful patient-derived model hampers understanding the pathomechanisms of BBB dysfunction and the development of BBB-targeted therapies. In this study, we differentiated BMEC-like cells from human induced pluripotent stem cells (hiPSCs) derived from ALS patients to investigate BMEC functions in ALS patients. TARDBP [N345K/+] carrying patient-derived BMEC-like cells exhibited increased permeability to small molecules due to loss of tight junction in the absence of neurodegeneration or neuroinflammation, highlighting that BMEC abnormalities in ALS are not merely secondary consequences of disease progression. Furthermore, they exhibited increased expression of cell surface adhesion molecules like ICAM-1 and VCAM-1, leading to enhanced immune cell adhesion. BMEC-like cells derived from hiPSCs with other types of TARDBP gene mutations (TARDBP [K263E/K263E] and TARDBP [G295S/G295S]) introduced by genome editing technology did not show such BMEC dysfunction compared to the isogenic control. Interestingly, transactive response DNA-binding protein 43 (TDP-43) was mislocalized to cytoplasm in TARDBP [N345K/+] carrying model. Wnt/β-catenin signaling was downregulated in the ALS patient (TARDBP [N345K/+])-derived BMEC-like cells and its activation rescued the leaky barrier phenotype and settled down VCAM-1 expressions. These results indicate that TARDBP [N345K/+] carrying model recapitulated BMEC abnormalities reported in brain samples of ALS patients. This novel patient-derived BMEC-like cell is useful for the further analysis of the involvement of vascular barrier dysfunctions in the pathogenesis of ALS and for promoting therapeutic drug discovery targeting BMEC.}, } @article {pmid39209824, year = {2024}, author = {Vieira de Sá, R and Sudria-Lopez, E and Cañizares Luna, M and Harschnitz, O and van den Heuvel, DMA and Kling, S and Vonk, D and Westeneng, HJ and Karst, H and Bloemenkamp, L and Varderidou-Minasian, S and Schlegel, DK and Mars, M and Broekhoven, MH and van Kronenburg, NCH and Adolfs, Y and Vangoor, VR and de Jongh, R and Ljubikj, T and Peeters, L and Seeler, S and Mocholi, E and Basak, O and Gordon, D and Giuliani, F and Verhoeff, T and Korsten, G and Calafat Pla, T and Venø, MT and Kjems, J and Talbot, K and van Es, MA and Veldink, JH and van den Berg, LH and Zelina, P and Pasterkamp, RJ}, title = {ATAXIN-2 intermediate-length polyglutamine expansions elicit ALS-associated metabolic and immune phenotypes.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {7484}, pmid = {39209824}, issn = {2041-1723}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Ataxin-2/genetics/metabolism ; Humans ; Animals ; *Peptides/metabolism/genetics ; Mice ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; *Disease Models, Animal ; *Mice, Transgenic ; DNA-Binding Proteins/genetics/metabolism ; Phenotype ; Male ; Female ; Mitochondria/metabolism ; Neurites/metabolism ; }, abstract = {Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are the strongest genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Here, we combine patient-derived and mouse models to dissect the effects of ATXN2 intermediate expansions in an ALS background. iPSC-derived motor neurons from ATXN2-ALS patients show altered stress granules, neurite damage and abnormal electrophysiological properties compared to healthy control and other familial ALS mutations. In TDP-43[Tg]-ALS mice, ATXN2-Q33 causes reduced motor function, NMJ alterations, neuron degeneration and altered in vitro stress granule dynamics. Furthermore, gene expression changes related to mitochondrial function and inflammatory response are detected and confirmed at the cellular level in mice and human neuron and organoid models. Together, these results define pathogenic defects underlying ATXN2-ALS and provide a framework for future research into ATXN2-dependent pathogenesis and therapy.}, } @article {pmid39210549, year = {2024}, author = {Yeo, CJJ and Simmons, Z}, title = {Caring for people living with ALS in Korea: challenges and possible paths forward.}, journal = {Muscle & nerve}, volume = {70}, number = {5}, pages = {881-883}, doi = {10.1002/mus.28241}, pmid = {39210549}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Republic of Korea/epidemiology ; Caregivers/psychology ; }, } @article {pmid39210467, year = {2024}, author = {Faggioli, G and Menotti, L and Marchesin, S and Chió, A and Dagliati, A and de Carvalho, M and Gromicho, M and Manera, U and Tavazzi, E and Di Nunzio, GM and Silvello, G and Ferro, N}, title = {An extensible and unifying approach to retrospective clinical data modeling: the BrainTeaser Ontology.}, journal = {Journal of biomedical semantics}, volume = {15}, number = {1}, pages = {16}, pmid = {39210467}, issn = {2041-1480}, support = {101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; }, mesh = {*Biological Ontologies ; Humans ; Retrospective Studies ; Amyotrophic Lateral Sclerosis ; Multiple Sclerosis ; Semantics ; }, abstract = {Automatic disease progression prediction models require large amounts of training data, which are seldom available, especially when it comes to rare diseases. A possible solution is to integrate data from different medical centres. Nevertheless, various centres often follow diverse data collection procedures and assign different semantics to collected data. Ontologies, used as schemas for interoperable knowledge bases, represent a state-of-the-art solution to homologate the semantics and foster data integration from various sources. This work presents the BrainTeaser Ontology (BTO), an ontology that models the clinical data associated with two brain-related rare diseases (ALS and MS) in a comprehensive and modular manner. BTO assists in organizing and standardizing the data collected during patient follow-up. It was created by harmonizing schemas currently used by multiple medical centers into a common ontology, following a bottom-up approach. As a result, BTO effectively addresses the practical data collection needs of various real-world situations and promotes data portability and interoperability. BTO captures various clinical occurrences, such as disease onset, symptoms, diagnostic and therapeutic procedures, and relapses, using an event-based approach. Developed in collaboration with medical partners and domain experts, BTO offers a holistic view of ALS and MS for supporting the representation of retrospective and prospective data. Furthermore, BTO adheres to Open Science and FAIR (Findable, Accessible, Interoperable, and Reusable) principles, making it a reliable framework for developing predictive tools to aid in medical decision-making and patient care. Although BTO is designed for ALS and MS, its modular structure makes it easily extendable to other brain-related diseases, showcasing its potential for broader applicability.Database URL https://zenodo.org/records/7886998 .}, } @article {pmid39209890, year = {2024}, author = {Prabhakaran, A and Thirumoorthi, P and Sri Dhivya Krishnan, K}, title = {Design and development of an intelligent zone based master electronic control unit for power optimization in electric vehicles.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {20142}, pmid = {39209890}, issn = {2045-2322}, abstract = {The development of electric vehicles (EVs) has been incremental because EVs satisfy a significant demand for energy sources. Electronic control unit (ECU) is an important component that processes the electric signals received from various sensors for generating the control signals for the actuators. Automotive control systems were initially operated manually throughout the automotive revolution based on the responses of input signals received from ECUs and drivers. Most of the functions in EV are controlled by the ECU and every ECU consumes power at all times even if it is not in use. The larger power consumption of passive ECUs like adaptive lighting systems (ALS), automatic wiper systems (AWS) brake light systems (BLS), etc., affect the life of ECUs and the range of EVs. This article is primarily concerned with limiting power consumption by switching the power supply to the passive ECUs based on their requirements. Hence, to achieve the objective, the intelligent zone (i-zone) based master ECU is triggered to activate the slave ECUs. Designing suites including Proteus and KiCAD were used for designing the circuits including master as well as slave ECU. This prototype is built using three secondary ECUs such as ALS & AWS and BLS which are controlled using i-zone-based master ECU. The performance of this implemented design is evaluated, and it is discovered that almost 40% of the battery consumption is reduced. This i-zone-based master ECU and all its slave ECUs manage power while ensuring the safety and reliability of EVs.}, } @article {pmid39208794, year = {2024}, author = {Choi, ES and Hnath, B and Sha, CM and Dokholyan, NV}, title = {Unveiling the double-edged sword: SOD1 trimers possess tissue-selective toxicity and bind septin-7 in motor neuron-like cells.}, journal = {Structure (London, England : 1993)}, volume = {32}, number = {10}, pages = {1776-1792.e5}, pmid = {39208794}, issn = {1878-4186}, support = {R35 GM134864/GM/NIGMS NIH HHS/United States ; UL1 TR002014/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; Male ; Mice ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Brain/metabolism ; Cell Cycle Proteins ; Models, Molecular ; *Motor Neurons/metabolism ; Muscle, Skeletal/metabolism ; *Protein Binding ; *Protein Multimerization ; *Septins/metabolism/genetics/chemistry ; Spinal Cord/metabolism ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; }, abstract = {Misfolded species of superoxide dismutase 1 (SOD1) are associated with increased death in amyotrophic lateral sclerosis (ALS) models compared to insoluble protein aggregates. The mechanism by which structurally independent SOD1 trimers cause cellular toxicity is unknown but may drive disease pathology. Here, we uncovered the SOD1 trimer interactome-a map of potential tissue-selective protein-binding partners in the brain, spinal cord, and skeletal muscle. We identified binding partners and key pathways associated with SOD1 trimers and found that trimers may affect normal cellular functions such as dendritic spine morphogenesis and synaptic function in the central nervous system and cellular metabolism in skeletal muscle. We discovered SOD1 trimer-selective enrichment of genes. We performed detailed computational and biochemical characterization of SOD1 trimer protein binding for septin-7. Our investigation highlights key proteins and pathways within distinct tissues, revealing a plausible intersection of genetic and pathophysiological mechanisms in ALS through interactions involving SOD1 trimers.}, } @article {pmid39207717, year = {2024}, author = {Ling, Y and Crotti, A}, title = {Emerging Microglial Therapies and Targets in Clinical Trial.}, journal = {Advances in neurobiology}, volume = {37}, number = {}, pages = {623-637}, pmid = {39207717}, issn = {2190-5215}, mesh = {*Microglia/metabolism ; Humans ; Clinical Trials as Topic ; Neurodegenerative Diseases/drug therapy/therapy/metabolism ; Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Modulation of microglia function for treatment of neurodegenerative and neuropsychiatric disorders is an emerging field of neuroscience drug development. This is largely attributed to human genetic association studies combined with biological evidence indicating that the innate immune system acts as a causal contributor superimposed on the reactive component of neuronal loss in neurological dysfunction. The identification of disease risk gene variants that encode immune-modulatory proteins in microglia provides tools to evaluate how microglia cellular function or dysfunction affect neuronal health. The development of clinical stage therapeutic compounds that modify myeloid cell function enables us to investigate how modulating microglia function could become a transformational approach to mitigate neurological disorders. Improving our ability to boost microglia-promoting homeostatic and reparative functions hopefully will translate into achieving a better outcome for patients affected by neurological diseases. In this chapter, we aim to provide an overview of the microglial emerging therapies and targets being studied in current clinical trials.}, } @article {pmid39207711, year = {2024}, author = {Holtman, IR and Glass, CK and Nott, A}, title = {Interpretation of Neurodegenerative GWAS Risk Alleles in Microglia and their Interplay with Other Cell Types.}, journal = {Advances in neurobiology}, volume = {37}, number = {}, pages = {531-544}, pmid = {39207711}, issn = {2190-5215}, mesh = {Humans ; *Microglia/metabolism ; *Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics ; *Genetic Predisposition to Disease ; Alleles ; Alzheimer Disease/genetics ; }, abstract = {Microglia have been implicated in numerous neurodegenerative and neuroinflammatory disorders; however, the causal contribution of this immune cell type is frequently debated. Genetic studies offer a unique vantage point in that they infer causality over a secondary consequence. Genome-wide association studies (GWASs) have identified hundreds of loci in the genome that are associated with susceptibility to neurodegenerative disorders. GWAS studies implicate microglia in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and to a lesser degree suggest a role for microglia in vascular dementia (VaD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), and other neurodegenerative and neuropsychiatric disorders. The contribution and function of GWAS risk loci on disease progression is an ongoing field of study, in which large genomic datasets, and an extensive framework of computational tools, have proven to be crucial. Several GWAS risk loci are shared between disorders, pointing towards common pleiotropic mechanisms. In this chapter, we introduce key concepts in GWAS and post-GWAS interpretation of neurodegenerative disorders, with a focus on GWAS risk genes implicated in microglia, their interplay with other cell types and shared convergence of GWAS risk loci on microglia.}, } @article {pmid39207709, year = {2024}, author = {Awogbindin, I and Wanklin, M and Verkhratsky, A and Tremblay, MÈ}, title = {Microglia in Neurodegenerative Diseases.}, journal = {Advances in neurobiology}, volume = {37}, number = {}, pages = {497-512}, pmid = {39207709}, issn = {2190-5215}, mesh = {*Microglia/metabolism/pathology ; Humans ; *Neurodegenerative Diseases/metabolism ; Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/physiopathology ; Animals ; Parkinson Disease/metabolism ; }, abstract = {Neurodegenerative diseases are manifested by a progressive death of neural cells, resulting in the deterioration of central nervous system (CNS) functions, ultimately leading to specific behavioural and cognitive symptoms associated with affected brain regions. Several neurodegenerative disorders are caused by genetic variants or mutations, although the majority of cases are sporadic and linked to various environmental risk factors, with yet an unknown aetiology. Neuroglial changes are fundamental and often lead to the pathophysiology of neurodegenerative diseases. In particular, microglial cells, which are essential for maintaining CNS health, become compromised in their physiological functions with the exposure to environmental risk factors, genetic variants or mutations, as well as disease pathology. In this chapter, we cover the contribution of neuroglia, especially microglia, to several neurodegenerative diseases, including Nasu-Hakola disease, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, infectious disease-associated neurodegeneration, and metal-precipitated neurodegeneration. Future research perspectives for the field pertaining to the therapeutic targeting of microglia across these disease conditions are also discussed.}, } @article {pmid39207520, year = {2024}, author = {Bjelica, B and Petri, S}, title = {Narrative review of diagnosis, management and treatment of dysphagia and sialorrhea in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6508-6513}, pmid = {39207520}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/diagnosis ; *Sialorrhea/etiology/therapy/diagnosis ; *Deglutition Disorders/etiology/therapy/diagnosis/physiopathology ; Disease Management ; }, abstract = {The degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) frequently leads bulbar symptoms like dysarthria, dysphagia, and sialorrhea, in approximately one-third of cases being the initial symptom. Throughout the disease, more than two-thirds of ALS patients experience dysphagia, regardless of the region of onset. In this review, we aimed to offer an updated overview of dysphagia and sialorrhea in ALS, covering its diagnosis, monitoring, and treatment in clinical practice. Regular assessment of dysphagia and sialorrhea during each patient visit is essential and should be a standard aspect of ALS care. Early discussion of potential treatments such as high-calorie diets or percutaneous endoscopic gastrostomy (PEG) is crucial. Furthermore, this review highlights and discusses potential areas for improvement in both clinical practice and research.}, } @article {pmid39207268, year = {2024}, author = {Han, H and Guo, G and Zhang, S and Peng, R and Xia, C}, title = {Reduced Surface Area for the Oxygen Reduction Reaction in Porous Electrode via Electrical Conductivity Relaxation.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {30}, number = {68}, pages = {e202402785}, doi = {10.1002/chem.202402785}, pmid = {39207268}, issn = {1521-3765}, support = {(2021YFB4001401//the National Key R&D Program of China/ ; 52272247//the National Natural Science Foundation of China/ ; }, abstract = {Oxygen reduction reaction (ORR) performance of porous electrodes is critical for solid oxide fuel cells (SOFCs). However, the effects of gas diffusion on the ORR in porous media need further investigation, although some issues, such as nonthermal surface oxygen exchange, have been attributed to gas diffusion. Herein, La0.6Sr0.4Co0.2Fe0.8O3-δ (LSCF) with various porosity, pore radii, and gas permeability were investigated via the electrical conductivity relaxation method and analysed via the distributed of characteristic time (DCT) model. The ORR is revealed with three characteristic times, which are gas diffusion, oxygen exchange via the surface corresponding to small pores, and oxygen exchange to large pores. Gas diffusion delays the oxygen surface exchange reaction, resulting in a very low chemical oxygen surface exchange coefficient compared with that obtained with dense samples under the assumption that all the surfaces are active for the ORR. Reduced surface area is thus defined to quantitatively represent the gas diffusion effects. The reduced surface area increases with increasing gas permeability, demonstrating the importance of electrode engineering for fast gas transport. Moreover, reduced surface area is suggested for replacing the specific surface area to calculate the electrode polarization impedance via the ALS model.}, } @article {pmid39206899, year = {2024}, author = {Ma, J and Liu, J and Chen, S and Zhang, W and Wang, T and Cao, M and Yang, Y and Du, Y and Cui, G and Du, Z}, title = {Understanding the Mechanism of Ferroptosis in Neurodegenerative Diseases.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {29}, number = {8}, pages = {291}, doi = {10.31083/j.fbl2908291}, pmid = {39206899}, issn = {2768-6698}, support = {81602893//National Natural Science Foundation of China (NSFC)/ ; ZR2015YL049//Natural Science Foundation of Shandong Province/ ; ZR2021MH218//Natural Science Foundation of Shandong Province/ ; ZR2022MH184//Natural Science Foundation of Shandong Province/ ; 202104020224//Shandong Province Medical and Health Technology Development Plan/ ; 202312010854//Shandong Province Medical and Health Technology Development Plan/ ; Z-2023114//Shandong Province Traditional Chinese Medicine Science and Technology Plan/ ; 202328074//Jinan Science and Technology Plan/ ; }, mesh = {*Ferroptosis/physiology ; Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Iron/metabolism ; Animals ; Neurons/metabolism/pathology ; }, abstract = {Neurodegenerative disorders are typified by the progressive degeneration and subsequent apoptosis of neuronal cells. They encompass a spectrum of conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), epilepsy, brian ischemia, brian injury, and neurodegeneration with brain iron accumulation (NBIA). Despite the considerable heterogeneity in their clinical presentation, pathophysiological underpinning and disease trajectory, a universal feature of these disorders is the functional deterioration of the nervous system concomitant with neuronal apoptosis. Ferroptosis is an iron (Fe)-dependent form of programmed cell death that has been implicated in the pathogenesis of these conditions. It is intricately associated with intracellular Fe metabolism and lipid homeostasis. The accumulation of Fe is observed in a variety of neurodegenerative diseases and has been linked to their etiology and progression, although its precise role in these pathologies has yet to be elucidated. This review aims to elucidate the characteristics and regulatory mechanisms of ferroptosis, its association with neurodegenerative diseases, and recent advances in ferroptosis-targeted therapeutic strategies. Ferroptosis may therefore be a critical area for future research into neurodegenerative diseases.}, } @article {pmid39206288, year = {2024}, author = {Cui, Y and Li, C and Ke, B and Xiao, Y and Wang, S and Jiang, Q and Zheng, X and Lin, J and Huang, J and Shang, H}, title = {Protective role of serum albumin in dementia: a prospective study from United Kingdom biobank.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1458184}, pmid = {39206288}, issn = {1664-2295}, abstract = {BACKGROUND: A number of studies have explored the link between neurodegenerative disorders (NDDs) and albumin, the main protein in human plasma. However, the results have been inconsistent, highlighting the necessity for a detailed systemic analysis.

METHODS: Utilizing data from the United Kingdom Biobank, we investigated the relationship between baseline levels of serum and urine albumin and the occurrence of common NDDs, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and dementia, employing Cox proportional hazards regression analysis.

RESULTS: Our results reveal that elevated baseline serum albumin levels are linked to a decreased risk of developing dementia (beta = -0.024, SE = 0.004, p < 0.001). Subgroup and interaction analyses highlighted the impact of factors like body mass index (BMI), age, and alcohol consumption on this relationship. Specifically, participants with higher BMI, younger age, or lower alcohol intake exhibited a stronger protective effect. On the other hand, a higher baseline level of urine microalbumin was connected to a slight increase in dementia risk (beta = 0.003, SE = 3.30E-04, p < 0.001). No significant associations were found between albumin levels and the risk of PD or ALS.

CONCLUSION: Our study underscores the potential role of serum albumin as a biomarker associated with reduced dementia risk. These findings contribute valuable insights into the understanding of albumin's impact on NDDs, suggesting its utility as a biomarker for dementia in clinical settings and informing future therapeutic strategies in clinical trials.}, } @article {pmid39206217, year = {2024}, author = {Uzelac, Z and Schwäble, B and Dorst, J and Rosenbohm, A and Wollinsky, K and Wurster, CD and Steinbreier, JS and Ludolph, AC}, title = {Pattern of pareses in 5q-spinal muscular atrophy.}, journal = {Therapeutic advances in neurological disorders}, volume = {17}, number = {}, pages = {17562864241263420}, pmid = {39206217}, issn = {1756-2856}, abstract = {BACKGROUND: This prospective study investigates the pattern of pareses in 5q-associated spinal muscular atrophy (SMA) to identify disease-specific characteristics and potential differences from amyotrophic lateral sclerosis (ALS) and spinobulbar muscular atrophy (SBMA). Detailed knowledge about pareses patterns in SMA facilitates differential diagnosis and supports therapeutic monitoring.

METHODS: Between January 2021, and June 2021, 66 SMA patients (59.1% male, aged 33.6 ± 15.2 years) were included in the study. Most patients had SMA type II (n = 28) or SMA type III (n = 28), seven patients had SMA type I, and three patients had SMA type IV. We analyzed the pattern of pareses using the UK Medical Research Council (MRC) scoring system.

RESULTS: In both, upper and lower limbs muscle weakness was less pronounced in distal (upper limbs: MRC median 3.0 (interquartile range 1.5-3.5); lower limbs: 1.5 (0.5-3.0)) compared to proximal muscle groups (upper limbs: 2.0 (1.5-2.6); p < 0.001; lower limbs: 0.5 (0.5-1.5); p < 0.001). Thenar muscles were stronger than other small hand muscles (3.0 (2.0-3.5) vs 3.0 (1.5-3.5); p = 0.004). Muscles had more strength in upper (2.3 (1.5-3.1)) compared to lower limbs (1.1 (0.5-2.3); p < 0.001) and in flexors compared to extensors.

CONCLUSION: We identified a specific pattern of muscle paresis in SMA which is different from the pattern of paresis in ALS and SBMA. As a rule of thumb, the pattern of pareses is similar, but not identical to ALS in distal, but different in proximal muscle groups.}, } @article {pmid39205388, year = {2024}, author = {Jafarinia, H and Van der Giessen, E and Onck, PR}, title = {C9orf72 polyPR interaction with the nuclear pore complex.}, journal = {Biophysical journal}, volume = {123}, number = {20}, pages = {3533-3539}, pmid = {39205388}, issn = {1542-0086}, mesh = {*Nuclear Pore/metabolism/chemistry ; *C9orf72 Protein/genetics/metabolism/chemistry ; *Molecular Dynamics Simulation ; Nuclear Pore Complex Proteins/metabolism/chemistry/genetics ; Protein Binding ; Saccharomyces cerevisiae/metabolism/genetics ; Active Transport, Cell Nucleus ; Humans ; }, abstract = {The C9orf72 gene associated with amyotrophic lateral sclerosis/frontotemporal dementia is translated to five dipeptide repeat proteins, among which poly-proline-arginine (PR) is the most toxic in cell and animal models, contributing to a variety of cellular defects. It has been proposed that polyPR disrupts nucleocytoplasmic transport (NCT) through several mechanisms including accumulation in the nuclear pore complex (NPC), accumulation in the nucleolus, and direct interactions with transport receptors. The NPC, which is the key regulator of transport between the cytoplasm and nucleus, plays a central role in these suggested mechanisms. Exploring polyPR interaction with the NPC provides valuable insight into the molecular details of polyPR-mediated NCT defects. To address this, we use coarse-grained molecular dynamics models of polyPR and the yeast NPC lined with intrinsically disordered FG-nucleoporins (FG-Nups). Our findings indicate no aggregation of polyPR within the NPC or permanent binding to FG-Nups. Instead, polyPR translocates through the NPC, following a trajectory through the central low-density region of the pore. In the case of longer polyPRs, we observe a higher energy barrier for translocation and a narrower translocation channel. Our study shows that polyPR and FG-Nups are mainly engaged in steric interactions inside the NPC with only a small contribution of specific cation-pi, hydrophobic, and electrostatic interactions, allowing polyPR to overcome the entropic barrier of the NPC in a size-dependent manner.}, } @article {pmid39204741, year = {2024}, author = {Xu, X and Zhao, B and Shen, B and Qi, Z and Wang, J and Cui, H and Li, B and Chen, S and Wang, G and Liu, X}, title = {Using RNA-Seq Analysis to Select Key Genes Related to Seed Dormancy in ALS-Inhibiting Resistant Descurainia sophia with Pro-197-Thr Mutation.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {16}, pages = {}, pmid = {39204741}, issn = {2223-7747}, support = {2024060203//Basic Research Funds of Hebei Academy of Agriculture and Forestry Sciences/ ; 2023LYS03//HAAFS Youth Innovation Fund Project/ ; 2022KJCXZX-LYS-13//HAAFS Science and Technology Innovation Special Project/ ; }, abstract = {Flixweed (Descurainia sophia) is a weed that seriously affects wheat fields in China. Over the past 20 years, it has evolved resistance to the herbicide tribenuron-methyl. In the present study, a resistant D. sophia population with a Pro-197-Thr mutation of acetolactate synthetase (ALS) was found to have a resistance index of 457.37 for tribenuron-methyl. Under the same growth conditions, the seeds of resistant (R) and susceptible (S) populations exhibited similar vitality but the germination rates of R seeds were higher than those of S seeds. This result demonstrated that seed dormancy periods were shorter in the R seeds. RNA-Seq transcriptome analysis was then used to choose candidate genes that could regulate seed dormancy pathways in the R population. A total of 504,976,046 clean reads were selected from nine RNA-Seq libraries and assembled into 79,729 unigenes. Among these, 33,476 unigenes were assigned to 51 GO subgroups, and 26,117 unigenes were assigned to 20 KEGG secondary metabolic pathways. Next, 2473 differentially expressed genes (DEGs) were divided into three groups, as follows: G-24 h (germinating seeds) vs. D (dormant seeds); G-48 h (germinated seeds) vs. D; and G-48 h vs. G-24 h. From these 2473 DEGs, 8 were selected as candidate dormancy unigenes for the R population if their expression levels continuously decreased during the seed germination progress and their functional annotations were related to plant seed dormancy. One candidate unigene was annotated as CYP707A2; two unigenes were annotated as the transcription factors TGA4 and TGA2; one unigene was annotated as the cystathionine beta-synthase gene; and four unigenes could not be annotated as any gene listed in the six public databases. However, qRT-PCR-validated results showed that, during the germination of R seeds, the expression of the three candidate unigenes first decreased and then increased, indicating that they may have other growth-regulating functions in R populations. In brief, the dormancy function of the eight candidate dormancy unigenes needs to be further studied.}, } @article {pmid39204338, year = {2024}, author = {O'Neill, R and Yoo, O and Burcham, P and Lim, LY}, title = {Edaravone for the Treatment of Motor Neurone Disease: A Critical Review of Approved and Alternative Formulations against a Proposed Quality Target Product Profile.}, journal = {Pharmaceutics}, volume = {16}, number = {8}, pages = {}, pmid = {39204338}, issn = {1999-4923}, support = {000990//Australian Government Research Training Program, Stan Perron Charitable Foundation/ ; }, abstract = {Edaravone is one of two main drugs for treating motor neurone disease (MND). This review proposes a specific quality target product profile (QTPP) for edaravone following an appraisal of the issues accounting for the poor clinical uptake of the approved IV and oral liquid edaravone formulations. This is followed by a review of the alternative oral formulations of edaravone described in the published patent and journal literature against the QTPP. A total of 14 texts published by six research groups on 18 novel oral formulations of edaravone for the treatment of MND have been reviewed. The alternative oral formulations included liquid and solid formulations developed with cyclodextrins, lipids, surfactants, co-surfactants, alkalising agents, tablet excipients, and co-solvents. Most were intended to deliver edaravone for drug absorption in the lower gastrointestinal tract (GIT); however, there were also four formulations targeting the oral mucosal absorption of edaravone to avoid first-pass metabolism. All the novel formulations improved the aqueous solubility, stability, and oral bioavailability (BA) of edaravone compared to an aqueous suspension of edaravone. A common limitation of the published formulations is the lack of MND-patient-centred data. Except for TW001, no other formulations have been trialled in MND patients. To meet the QTPP of an oral edaravone formulation for MND patients, it is recommended that a tablet of appropriate size and with acceptable taste and stability be designed for the effective sublingual or buccal absorption of edaravone. This tablet should be designed with input from the MND community.}, } @article {pmid39203762, year = {2024}, author = {Zarco-Martín, MT and Freire, C and Andreo-López, MC and Leyva-Martínez, S and Fernández-Soto, ML}, title = {Malnutrition in Amyotrophic Lateral Sclerosis: Insights from Morphofunctional Assessment and Global Leadership Initiative on Malnutrition Criteria.}, journal = {Nutrients}, volume = {16}, number = {16}, pages = {}, pmid = {39203762}, issn = {2072-6643}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Female ; Male ; *Malnutrition/epidemiology/diagnosis ; Middle Aged ; Aged ; Cross-Sectional Studies ; *Nutrition Assessment ; Hand Strength ; Prevalence ; Nutritional Status ; Electric Impedance ; Severity of Illness Index ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease frequently accompanied by malnutrition due to weight loss, increased energy expenditure, and muscle mass loss. This study aimed to evaluate morphofunctional assessment tools as predictors of malnutrition and to investigate their relationship with muscle status and disease severity in ALS patients. A cross-sectional study was conducted with 45 ALS patients at the San Cecilio University Hospital in Granada. Malnutrition was assessed using the Global Leadership Initiative on Malnutrition (GLIM) criteria. Morphofunctional assessment was performed using Bioimpedance Vectorial Analysis (BIVA), handgrip strength (HGS), and Short Physical Performance Battery (SPPB). Malnutrition prevalence was 38% according to GLIM criteria. Significant differences were observed between malnourished and non-malnourished groups in age (70 ± 9 vs. 62 ± 10 years, p = 0.01), sex (female prevalence: 58.8% vs. 25.0%, p = 0.02), dysphagia prevalence (83% vs. 29%, p < 0.001), PEG/PRG use (35.3% vs. 3.6%, p = 0.01), and ALSFRS-R scores (30 ± 12 vs. 34 ± 12, p = 0.02). Malnourished patients had lower values in anthropometric measurements, muscle mass obtained by BIVA, and phase angle (PA) (4.05 ± 0.8° vs. 5.09 ± 0.8°, p < 0.001). No significant differences were found in muscle strength or functional status. PA showed significant correlations with muscle strength (r = 0.52, p < 0.001) and muscle mass measures (r = 0.48, p < 0.001). Moreover, PA was associated with poorer disease progression and physical performance. In our sample, BIVA metrics such as PA (<4.3°), SPA (<-0.8), body cell mass (<9.2 kg/m), and extracellular water (>49.75%) were identified as malnutrition risk factors. The study underscores the critical importance of comprehensive morphofunctional assessment and the use of advanced diagnostic criteria, for early identification and intervention in malnutrition among people with ALS. Further research is warranted to validate these findings and develop targeted nutritional strategies into routine clinical practice.}, } @article {pmid39202683, year = {2024}, author = {Gianferrari, G and Zucchi, E and Martinelli, I and Simonini, C and Fini, N and Ferro, S and Mercati, A and Ferri, L and Filippini, T and Vinceti, M and Mandrioli, J}, title = {Trends in Hospital Admissions for Patients with Amyotrophic Lateral Sclerosis: Insights from a Retrospective Cohort Study in a Province in Northern Italy.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {8}, pages = {}, pmid = {39202683}, issn = {2075-1729}, support = {//Servizio sanitario dell'Emilia-Romagna/ ; not available//Emilia Romagna Regional Health Authority/ ; }, abstract = {ALS is characterized by a highly heterogeneous course, ranging from slow and uncomplicated to rapid progression with severe extra-motor manifestations. This study investigated ALS-related hospitalizations and their connection to clinical aspects, comorbidities, and prognosis. We performed a retrospective cohort study including patients residing in Modena, Italy, newly diagnosed between 2007 and 2017 and followed up until 31 December 2022. Data were obtained from the Emilia Romagna ALS registry, regional hospitals, and medical records. Among the 249 patients, there were 492 hospital admissions, excluding those for diagnostic purposes; 63% of the patients had at least one hospitalization post-diagnosis, with an average stay of 19.90 ± 23.68 days. Younger patients were more likely to be hospitalized multiple times and experienced longer stays (44.23 ± 51.71 days if <65 years; 26.46 ± 36.02 days if older, p < 0.001). Patients who were hospitalized at least once more frequently underwent gastrostomy (64.97%) or non-invasive (66.24%) and invasive (46.50%) ventilation compared to those never hospitalized (21.74%, 31.52%, 13.04%, respectively, p < 0.001 for all). Emergency procedures led to longer hospitalizations (62.84 ± 48.91 days for non-invasive ventilation in emergencies vs. 39.88 ± 46.46 days electively, p = 0.012). Tracheostomy-free survival was not affected by hospitalizations. In conclusion, younger ALS patients undergo frequent and prolonged hospitalizations, especially after emergency interventions, although these do not correlate with reduced survival.}, } @article {pmid39201793, year = {2024}, author = {Martin, LJ and Koh, SJ and Price, A and Park, D and Kim, BW}, title = {Nuclear Localization of Human SOD1 in Motor Neurons in Mouse Model and Patient Amyotrophic Lateral Sclerosis: Possible Links to Cholinergic Phenotype, NADPH Oxidase, Oxidative Stress, and DNA Damage.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201793}, issn = {1422-0067}, support = {NS34100/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Cell Nucleus/metabolism ; Disease Models, Animal ; *DNA Damage ; *Induced Pluripotent Stem Cells/metabolism ; Mice, Transgenic ; *Motor Neurons/metabolism/pathology ; NADPH Oxidases/metabolism/genetics ; *Oxidative Stress ; Phenotype ; Spinal Cord/metabolism/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease that causes degeneration of motor neurons (MNs) and paralysis. ALS can be caused by mutations in the gene that encodes copper/zinc superoxide dismutase (SOD1). SOD1 is known mostly as a cytosolic antioxidant protein, but SOD1 is also in the nucleus of non-transgenic (tg) and human SOD1 (hSOD1) tg mouse MNs. SOD1's nuclear presence in different cell types and subnuclear compartmentations are unknown, as are the nuclear functions of SOD1. We examined hSOD1 nuclear localization and DNA damage in tg mice expressing mutated and wildtype variants of hSOD1 (hSOD1-G93A and hSOD1-wildtype). We also studied ALS patient-derived induced pluripotent stem (iPS) cells to determine the nuclear presence of SOD1 in undifferentiated and differentiated MNs. In hSOD1-G93A and hSOD1-wildtype tg mice, choline acetyltransferase (ChAT)-positive MNs had nuclear hSOD1, but while hSOD1-wildtype mouse MNs also had nuclear ChAT, hSOD1-G93A mouse MNs showed symptom-related loss of nuclear ChAT. The interneurons had preserved parvalbumin nuclear positivity in hSOD1-G93A mice. hSOD1-G93A was seen less commonly in spinal cord astrocytes and, notably, oligodendrocytes, but as the disease emerged, the oligodendrocytes had increased mutant hSOD1 nuclear presence. Brain and spinal cord subcellular fractionation identified mutant hSOD1 in soluble nuclear extracts of the brain and spinal cord, but mutant hSOD1 was concentrated in the chromatin nuclear extract only in the spinal cord. Nuclear extracts from mutant hSOD1 tg mouse spinal cords had altered protein nitration, footprinting peroxynitrite presence, and the intact nuclear extracts had strongly increased superoxide production as well as the active NADPH oxidase marker, p47phox. The comet assay showed that MNs from hSOD1-G93A mice progressively (6-14 weeks of age) accumulated DNA single-strand breaks. Ablation of the NCF1 gene, encoding p47phox, and pharmacological inhibition of NADPH oxidase with systemic treatment of apocynin (10 mg/kg, ip) extended the mean lifespan of hSOD1-G93A mice by about 25% and mitigated genomic DNA damage progression. In human postmortem CNS, SOD1 was found in the nucleus of neurons and glia; nuclear SOD1 was increased in degenerating neurons in ALS cases and formed inclusions. Human iPS cells had nuclear SOD1 during directed differentiation to MNs, but mutant SOD1-expressing cells failed to establish wildtype MN nuclear SOD1 levels. We conclude that SOD1 has a prominent nuclear presence in the central nervous system, perhaps adopting aberrant contexts to participate in ALS pathobiology.}, } @article {pmid39201731, year = {2024}, author = {Fang, C and Wu, J and Liang, W}, title = {Systematic Investigation of Aluminum Stress-Related Genes and Their Critical Roles in Plants.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201731}, issn = {1422-0067}, support = {242102111164; 222301420106//Key R&D and Promotion Projects in Henan Province; Henan Science & Technology Research and Development Plan Joint Fund/ ; }, mesh = {*Aluminum/toxicity ; *Stress, Physiological/genetics ; *Gene Expression Regulation, Plant/drug effects ; Plant Proteins/genetics/metabolism ; Zea mays/genetics/growth & development/metabolism/drug effects ; Plants/genetics/metabolism/drug effects ; Genes, Plant ; }, abstract = {Aluminum (Al) stress is a dominant obstacle for plant growth in acidic soil, which accounts for approximately 40-50% of the world's potential arable land. The identification and characterization of Al stress response (Al-SR) genes in Arabidopsis, rice, and other plants have deepened our understanding of Al's molecular mechanisms. However, as a crop sensitive to acidic soil, only eight Al-SR genes have been identified and functionally characterized in maize. In this review, we summarize the Al-SR genes in plants, including their classifications, subcellular localizations, expression organs, functions, and primarily molecular regulatory networks. Moreover, we predict 166 putative Al-SR genes in maize based on orthologue analyses, facilitating a comprehensive understanding of the impact of Al stress on maize growth and development. Finally, we highlight the potential applications of alleviating Al toxicity in crop production. This review deepens our understanding of the Al response in plants and provides a blueprint for alleviating Al toxicity in crop production.}, } @article {pmid39201466, year = {2024}, author = {Strong, MJ and McLellan, C and Kaplanis, B and Droppelmann, CA and Junop, M}, title = {Phase Separation of SARS-CoV-2 Nucleocapsid Protein with TDP-43 Is Dependent on C-Terminus Domains.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201466}, issn = {1422-0067}, support = {201806SOP-411481/CAPMC/CIHR/Canada ; not applicable//Temerty Family Foundation/ ; }, mesh = {*DNA-Binding Proteins/metabolism/chemistry ; Humans ; *SARS-CoV-2/metabolism/chemistry ; *Coronavirus Nucleocapsid Proteins/metabolism/chemistry/genetics ; *Protein Domains ; COVID-19/virology/metabolism ; Protein Binding ; Biomolecular Condensates/metabolism/chemistry ; RNA, Viral/metabolism/genetics ; Phosphoproteins/metabolism/chemistry ; Phase Separation ; }, abstract = {The SARS-CoV-2 nucleocapsid protein (N protein) is critical in viral replication by undergoing liquid-liquid phase separation to seed the formation of a ribonucleoprotein (RNP) complex to drive viral genomic RNA (gRNA) translation and in suppressing both stress granules and processing bodies, which is postulated to increase uncoated gRNA availability. The N protein can also form biomolecular condensates with a broad range of host endogenous proteins including RNA binding proteins (RBPs). Amongst these RBPs are proteins that are associated with pathological, neuronal, and glial cytoplasmic inclusions across several adult-onset neurodegenerative disorders, including TAR DNA binding protein 43 kDa (TDP-43) which forms pathological inclusions in over 95% of amyotrophic lateral sclerosis cases. In this study, we demonstrate that the N protein can form biomolecular condensates with TDP-43 and that this is dependent on the N protein C-terminus domain (N-CTD) and the intrinsically disordered C-terminus domain of TDP-43. This process is markedly accelerated in the presence of RNA. In silico modeling suggests that the biomolecular condensate that forms in the presence of RNA is composed of an N protein quadriplex in which the intrinsically disordered TDP-43 C terminus domain is incorporated.}, } @article {pmid39201350, year = {2024}, author = {Bedja-Iacona, L and Richard, E and Marouillat, S and Brulard, C and Alouane, T and Beltran, S and Andres, CR and Blasco, H and Corcia, P and Veyrat-Durebex, C and Vourc'h, P}, title = {Post-Translational Variants of Major Proteins in Amyotrophic Lateral Sclerosis Provide New Insights into the Pathophysiology of the Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201350}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Protein Processing, Post-Translational ; *Superoxide Dismutase-1/genetics/metabolism ; *RNA-Binding Protein FUS/metabolism/genetics ; DNA-Binding Proteins/metabolism/genetics ; Protein Serine-Threonine Kinases/metabolism/genetics ; Mutation ; Animals ; Phosphorylation ; Acetylation ; }, abstract = {Post-translational modifications (PTMs) affecting proteins during or after their synthesis play a crucial role in their localization and function. The modification of these PTMs under pathophysiological conditions, i.e., their appearance, disappearance, or variation in quantity caused by a pathological environment or a mutation, corresponds to post-translational variants (PTVs). These PTVs can be directly or indirectly involved in the pathophysiology of diseases. Here, we present the PTMs and PTVs of four major amyotrophic lateral sclerosis (ALS) proteins, SOD1, TDP-43, FUS, and TBK1. These modifications involve acetylation, phosphorylation, methylation, ubiquitination, SUMOylation, and enzymatic cleavage. We list the PTM positions known to be mutated in ALS patients and discuss the roles of PTVs in the pathophysiological processes of ALS. In-depth knowledge of the PTMs and PTVs of ALS proteins is needed to better understand their role in the disease. We believe it is also crucial for developing new therapies that may be more effective in ALS.}, } @article {pmid39200952, year = {2024}, author = {Schwarzenbacher, L and Wassermann, L and Rezar-Dreindl, S and Reiter, GS and Schmidt-Erfurth, U and Stifter, E}, title = {An Analysis of Ocular Biometrics: A Comprehensive Retrospective Study in a Large Cohort of Pediatric Cataract Patients.}, journal = {Journal of clinical medicine}, volume = {13}, number = {16}, pages = {}, pmid = {39200952}, issn = {2077-0383}, abstract = {Objectives: This study aims to provide a comprehensive analysis of ocular biometric parameters in pediatric patients with cataracts to optimize surgical outcomes. By evaluating various biometric data, we seek to enhance the decision-making process for intraocular lens (IOL) placement, particularly with advanced technologies like femtosecond lasers. Methods: This retrospective comparative study included pediatric patients with cataracts who underwent ocular biometric measurements and cataract extraction with anterior vitrectomy at the Medical University of Vienna between January 2019 and December 2021. Parameters measured included corneal diameter (CD), axial length (AL), corneal thickness (CT) and flat and steep keratometry (Kf and Ks). The study explored the correlations between these parameters and IOL placement. Results: A total of 136 eyes from 68 pediatric patients were included in the study. Significant positive correlations were found between corneal diameter, age and AL. The mean CD was 11.4 mm, mean AL was 19.5 mm, CT was 581.2 ± 51.8 µm, Kf was 7.76 ± 0.55 mm and Ks 7.41 ± 0.59 mm, respectively. Older pediatric patients with larger corneal diameters and longer ALs were more likely to receive in-the-bag IOL implantation. Conversely, younger patients often required alternative IOL placements or remained aphakic. Our data indicated that over 95% of the study population and all patients aged one year and older had a corneal diameter of 10 mm or larger. Conclusions: Detailed ocular biometric analysis is crucial for optimizing both surgical outcomes and postoperative care in pediatric cataract patients. The positive correlations between CD, age and AL underline the importance of individualized surgical planning tailored to each patient's unique anatomical features. Additionally, our findings suggest that the use of a femtosecond laser is both feasible and safe for pediatric patients aged one year and older, potentially offering enhanced surgical precision and improved outcomes.}, } @article {pmid39200200, year = {2024}, author = {Yoo, JK and Kwon, SH and Yoon, SH and Lee, JE and Jeon, JE and Chung, JH and Lee, SY}, title = {Preservation of Vocal Function in Amyotrophic Lateral Sclerosis (ALS) Patients Following Percutaneous Dilatational Tracheostomy (PDT) and Adjuvant Therapies.}, journal = {Biomedicines}, volume = {12}, number = {8}, pages = {}, pmid = {39200200}, issn = {2227-9059}, abstract = {UNLABELLED: The study aimed to evaluate the efficacy of percutaneous dilatational tracheostomy (PDT) combined with adjuvant therapies in preserving vocal function in amyotrophic lateral sclerosis (ALS) patients.

METHODS: We performed a retrospective analysis of 47 ALS patients who underwent PDT at the Rodem Hospital from 2021 to 2023. Post-operatively, these patients were provided with a comprehensive treatment plan that included regenerative injection therapy, low-frequency electrical stimulation, respiratory rehabilitation, and swallowing rehabilitation therapy. Additionally, a balloon reduction program was implemented for effective tracheostomy tube (T-tube) management. The preservation of vocal functions was evaluated 4 weeks following the procedure.

RESULTS: While some patients maintained or slightly improved their ALSFRS-R speech scores, the overall trend indicated a decrease in speech scores post-PDT. This suggests that PDT in combination with adjuvant therapies may not universally improve vocal function, but can help maintain it in certain cases.

CONCLUSIONS: Our findings indicate that PDT combined with mesotherapy, low-frequency electrical stimulation, and swallowing rehabilitation therapy may play a role in maintaining vocal function in limb type ALS patients, though further research is needed to optimize patient management and to validate these results.}, } @article {pmid39200158, year = {2024}, author = {Zhao, M and Wang, J and Liu, M and Xu, Y and Huang, J and Zhang, Y and He, J and Gu, A and Liu, M and Liu, X}, title = {KIF1A, R1457Q, and P1688L Mutations Induce Protein Abnormal Aggregation and Autophagy Impairment in iPSC-Derived Motor Neurons.}, journal = {Biomedicines}, volume = {12}, number = {8}, pages = {}, pmid = {39200158}, issn = {2227-9059}, support = {2016YFC0905100//the National Key Research and Development Program of China/ ; 2021JJ30801//the Natural Science Foundation of Hunan Province, China/ ; kq2202077//the Natural Science Foundation of Changsha, China/ ; CX20230291//the Postgraduate Freedom Explo-ration Project of Central South University/ ; }, abstract = {Mutations in the C-terminal of KIF1A (Kinesin family member 1A) may lead to amyotrophic lateral sclerosis (ALS) through unknown mechanisms that are not yet understood. Using iPSC reprogramming technology and motor neuron differentiation techniques, we generated iPSCs from a healthy donor and two ALS patients with KIF1A mutations (R1457Q and P1688L) and differentiated them into spinal motor neurons (iPSC-MN) to investigate KIF1A-related ALS pathology. Our in vitro iPSC-iMN model faithfully recapitulated specific aspects of the disease, such as neurite fragmentation. Through this model, we observed that these mutations led to KIF1A aggregation at the proximal axon of motor neurons and abnormal accumulation of its transport cargo, LAMP1, resulting in autophagy dysfunction and cell death. RNAseq analysis also indicated that the functions of the extracellular matrix, structure, and cell adhesion were significantly disturbed. Notably, using rapamycin during motor neuron differentiation can effectively prevent motor neuron death.}, } @article {pmid39199527, year = {2024}, author = {Ail, BE and Ramele, R and Gambini, J and Santos, JM}, title = {An Intrinsically Explainable Method to Decode P300 Waveforms from EEG Signal Plots Based on Convolutional Neural Networks.}, journal = {Brain sciences}, volume = {14}, number = {8}, pages = {}, pmid = {39199527}, issn = {2076-3425}, support = {ITBACyT-2020//Instituto Tecnológico de Buenos Aires (ITBA)/ ; }, abstract = {This work proposes an intrinsically explainable, straightforward method to decode P300 waveforms from electroencephalography (EEG) signals, overcoming the black box nature of deep learning techniques. The proposed method allows convolutional neural networks to decode information from images, an area where they have achieved astonishing performance. By plotting the EEG signal as an image, it can be both visually interpreted by physicians and technicians and detected by the network, offering a straightforward way of explaining the decision. The identification of this pattern is used to implement a P300-based speller device, which can serve as an alternative communication channel for persons affected by amyotrophic lateral sclerosis (ALS). This method is validated by identifying this signal by performing a brain-computer interface simulation on a public dataset from ALS patients. Letter identification rates from the speller on the dataset show that this method can identify the P300 signature on the set of 8 patients. The proposed approach achieves similar performance to other state-of-the-art proposals while providing clinically relevant explainability (XAI).}, } @article {pmid39199512, year = {2024}, author = {Turner, N and Faull, C and Palmer, J and Armstrong, A and Bedford, J and Turner, MR and Wilson, E}, title = {Understanding Quality of Life for People with Motor Neurone Disease Who Use Tracheostomy Ventilation and Family Members: A Scoping Review.}, journal = {Brain sciences}, volume = {14}, number = {8}, pages = {}, pmid = {39199512}, issn = {2076-3425}, support = {Wilson/Oct21/968-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {Tracheostomy ventilation (TV) can increase survival time for people living with motor neurone disease (MND); however, the use of TV varies between countries. Concerns regarding anticipated quality of life (QoL) are among the reasons given by healthcare professionals for not recommending this intervention, yet little is known about QoL in this context. This scoping review was conducted to examine the evidence on QoL for those with MND who use TV and family members involved in their care. Using the methodological guidance of the Joanna Briggs Institute, 23 papers were identified for inclusion, and findings were inductively analysed to identify key themes. We found that people living with MND tend to rate QoL post TV more positively than anticipated by healthcare professionals or family members. QoL was found to be related to positive relationships and activities the person could maintain. Feeling able to make a choice and an adequate level of financial resources were also important factors. Family members tended to experience lower QoL, associated with the uncertainty surrounding an emergency procedure and the complexity of subsequently required care. More evidence on QoL from the perspectives of people with MND who use TV is needed to support decision making and inform guidance.}, } @article {pmid39199498, year = {2024}, author = {Kleinerova, J and McKenna, MC and Finnegan, M and Tacheva, A and Garcia-Gallardo, A and Mohammed, R and Tan, EL and Christidi, F and Hardiman, O and Hutchinson, S and Bede, P}, title = {Clinical, Cortical, Subcortical, and White Matter Features of Right Temporal Variant FTD.}, journal = {Brain sciences}, volume = {14}, number = {8}, pages = {}, pmid = {39199498}, issn = {2076-3425}, support = {JPND-Cofund-2-2019-1 & HRB EIA-2017-019//HRB/ ; }, abstract = {UNLABELLED: The distinct clinical and radiological characteristics of right temporal variant FTD have only been recently recognized.

METHODS: Eight patients with right temporal variant FTD were prospectively recruited and underwent a standardised neuropsychological assessment, clinical MRI, and quantitative neuroimaging.

RESULTS: Our voxelwise grey analyses captured bilateral anterior and mesial temporal grey matter atrophy with a clear right-sided predominance. Bilateral hippocampal involvement was also observed, as well as disease burden in the right insular and opercula regions. White matter integrity alterations were also bilateral in anterior temporal and sub-insular regions with a clear right-hemispheric predominance. Extra-temporal white matter alterations have also been observed in orbitofrontal and parietal regions. Significant bilateral but right-predominant thalamus, putamen, hippocampus, and amygdala atrophy was identified based on subcortical segmentation. The clinical profile of our patients was dominated by progressive indifference, decline in motivation, loss of interest in previously cherished activities, incremental social withdrawal, difficulty recognising people, progressive language deficits, increasingly rigid routines, and repetitive behaviours.

CONCLUSIONS: Right temporal variant FTD has an insidious onset and may be mistaken for depression at symptom onset. It manifests in a combination of apathy, language, and behavioural features. Quantitative MR imaging captures a characteristic bilateral but right-predominant temporal imaging signature with extra-temporal frontal and parietal involvement.}, } @article {pmid39199454, year = {2024}, author = {Calma, AD and van den Bos, M and Pavey, N and Santos Silva, C and Menon, P and Vucic, S}, title = {Physiological Biomarkers of Upper Motor Neuron Dysfunction in ALS.}, journal = {Brain sciences}, volume = {14}, number = {8}, pages = {}, pmid = {39199454}, issn = {2076-3425}, abstract = {Upper motor neuron (UMN) dysfunction is an important feature of amyotrophic lateral sclerosis (ALS) for the diagnosis and understanding of pathogenesis. The identification of UMN signs forms the basis of ALS diagnosis, although may be difficult to discern, especially in the setting of severe muscle weakness. Transcranial magnetic stimulation (TMS) techniques have yielded objective physiological biomarkers of UMN dysfunction in ALS, enabling the interrogation of cortical and subcortical neuronal networks with diagnostic, pathophysiological, and prognostic implications. Transcranial magnetic stimulation techniques have provided pertinent pathogenic insights and yielded novel diagnostic and prognostic biomarkers. Cortical hyperexcitability, as heralded by a reduction in short interval intracortical inhibition (SICI) and an increase in short interval intracortical facilitation (SICF), has been associated with lower motor neuron degeneration, patterns of disease evolution, as well as the development of specific ALS clinical features including the split hand phenomenon. Reduction in SICI has also emerged as a potential diagnostic aid in ALS. More recently, physiological distinct inhibitory and facilitatory cortical interneuronal circuits have been identified, which have been shown to contribute to ALS pathogenesis. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction. Resting-state EEG is a novel neurophysiological technique developed for directly interrogating cortical neuronal networks in ALS, that have yielded potentially useful physiological biomarkers of UMN dysfunction. The present review discusses physiological biomarkers of UMN dysfunction in ALS, encompassing conventional and novel TMS techniques developed to interrogate the functional integrity of the corticomotoneuronal system, focusing on pathogenic, diagnostic, and prognostic utility.}, } @article {pmid39199265, year = {2024}, author = {Proaño, B and Benlloch, M and Sancho-Castillo, S and Privado, J and Bargues-Navarro, G and Sanchis-Sanchis, CE and Martínez Bolós, P and Carriquí-Suárez, AB and Cubero-Plazas, L and Platero Armero, JL and Escriva, D and Ceron, JJ and Tvarijonaviciute, A and de la Rubia Ortí, JE}, title = {Paraoxonase I Activity and Its Relationship with Nutrition in Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {8}, pages = {}, pmid = {39199265}, issn = {2076-3921}, support = {2021-203-003//Catholic University of Valencia San Vicente Mártir/ ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration, with oxidative stress playing a key role. Paraoxonase 1 (PON1) is an antioxidant enzyme that may influence ALS progression. This study aimed to establish a predictive model for the influence of PON1 activity on functionality in ALS patients and explore its relationship with nutrition. Methods: In this observational cross-sectional study, 70 ALS patients underwent assessments of PON1 activity, lipid profile, functional capacity, respiratory function, and heart rate variability. A structural equation model was developed to determine the relationships between variables. Nutritional intake was analyzed in 65 patients. Results: The predictive model showed that PON1 activity and LDL levels positively influenced functionality, both directly and indirectly through respiratory capacity. Heart rate variability moderately predicted functionality independently. HDL levels were not significantly associated with functionality. Weak to moderate correlations were found between PON1 activity and intake of certain nutrients, with positive associations for monounsaturated fats and vitamin D, and negative associations for carbohydrates, proteins, and some micronutrients. Conclusions: PON1 activity appears to play an important role in ALS patient functionality, both directly and through effects on respiratory capacity. However, its relationship with nutritional intake was not strongly evident in this sample population.}, } @article {pmid39199129, year = {2024}, author = {Percio, A and Cicchinelli, M and Masci, D and Summo, M and Urbani, A and Greco, V}, title = {Oxidative Cysteine Post Translational Modifications Drive the Redox Code Underlying Neurodegeneration and Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {8}, pages = {}, pmid = {39199129}, issn = {2076-3921}, abstract = {Redox dysregulation, an imbalance between oxidants and antioxidants, is crucial in the pathogenesis of various neurodegenerative diseases. Within this context, the "redoxome" encompasses the network of redox molecules collaborating to maintain cellular redox balance and signaling. Among these, cysteine-sensitive proteins are fundamental for this homeostasis. Due to their reactive thiol groups, cysteine (Cys) residues are particularly susceptible to oxidative post-translational modifications (PTMs) induced by free radicals (reactive oxygen, nitrogen, and sulfur species) which profoundly affect protein functions. Cys-PTMs, forming what is referred to as "cysteinet" in the redox proteome, are essential for redox signaling in both physiological and pathological conditions, including neurodegeneration. Such modifications significantly influence protein misfolding and aggregation, key hallmarks of neurodegenerative diseases such as Alzheimer's, Parkinson's, and notably, amyotrophic lateral sclerosis (ALS). This review aims to explore the complex landscape of cysteine PTMs in the cellular redox environment, elucidating their impact on neurodegeneration at protein level. By investigating specific cysteine-sensitive proteins and the regulatory networks involved, particular emphasis is placed on the link between redox dysregulation and ALS, highlighting this pathology as a prime example of a neurodegenerative disease wherein such redox dysregulation is a distinct hallmark.}, } @article {pmid39198773, year = {2024}, author = {Lei, Y and Zhang, X and Liu, H and Xu, Z and Xu, P}, title = {Amyotrophic lateral sclerosis associated with Sjögren's syndrome: a case report.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {300}, pmid = {39198773}, issn = {1471-2377}, mesh = {Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/drug therapy/pathology ; *Sjogren's Syndrome/complications/diagnosis/drug therapy/pathology ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a chronic and progressive neurodegenerative disorder with an unknown cause. The development of amyotrophic lateral sclerosis (ALS) is believed to be linked to an immune response. Monocytes/macrophages and T cells are key players in the disease's advancement. Monitoring levels of cytokines in the blood can help forecast patient outcomes, while immunotherapy shows promise in alleviating symptoms for certain individuals.

CASE PRESENTATION: A 56-year-old male patient was admitted to the hospital due to progressive limb weakness persisting for eight months. The neurological examination revealed impairments in both upper and lower motor neurons, as well as sensory anomalies, without corresponding signs. Electrophysiological examination results indicated extensive neuronal damage and multiple peripheral nerve impairments, thereby the diagnosis was ALS. One month ago, the patient began experiencing symptoms of dry mouth and a bitter taste. Following tests for rheumatic immune-related antibodies and a lip gland biopsy, a diagnosis of Sjögren's syndrome (SS) was proposed. Despite treatment with medications such as hormones (methylprednisolone), immunosuppressants (hydroxychloroquine sulfate), and riluzole, the symptoms did not significantly improve, but also did not worsen.

CONCLUSION: It is recommended to include screening for SS in the standard assessment of ALS. Furthermore, research should focus on understanding the immune mechanisms involved in ALS, providing new insights for the diagnosis and treatment of ALS in conjunction with SS.}, } @article {pmid39197801, year = {2025}, author = {Zhan, Y and Huang, J and Tang, X and Du, B and Yang, B}, title = {Semen Strychni Pulveratum and vomicine alleviate neuroinflammation in amyotrophic lateral sclerosis through cGAS-STING-TBK1 pathway.}, journal = {Journal of ethnopharmacology}, volume = {336}, number = {}, pages = {118741}, doi = {10.1016/j.jep.2024.118741}, pmid = {39197801}, issn = {1872-7573}, mesh = {Animals ; *Protein Serine-Threonine Kinases/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Mice ; *Membrane Proteins/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Nucleotidyltransferases/metabolism ; Male ; Signal Transduction/drug effects ; Mice, Transgenic ; Neuroinflammatory Diseases/drug therapy ; Spinal Cord/drug effects/metabolism/pathology ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fetal neuromuscular disorder characterized by the gradual deterioration of motor neurons. Semen Strychni pulveratum (SSP), a processed version of Semen Strychni (SS) powder, is widely used to treat ALS in China. Vomicine is one of the most primary components of SS. However, their pharmacological effects and mechanisms for ALS remain elusive.

AIM OF THE STUDY: This study aimed to evaluate the neuroprotective and anti-neuroinflammatory effects of SSP and vomicine, as well as to explore their protective roles in ALS and the underlying mechanisms.

MATERIALS AND METHODS: In vivo, 8-week-old hSOD1-WT mice and hSOD1-G93A mice were orally administered different concentrations of SSP (SSP-L = 5.46 mg/ml, SSP-M = 10.92 mg/ml or SSP-H = 16.38 mg/ml) once every other day for 8 weeks. A series of experiments, including body weight measurement, footprint tests, Hematoxylin & Eosin staining, and Nissl staining, were performed to evaluate the preventive effect of SSP. Immunofluorescence staining, western blotting, and RT-qPCR were subsequently performed to evaluate activation of the cGAS-STING-TBK1 pathway in the spinal cord. In vitro, hSOD1[G93A] NSC-34 cells were treated with vomicine to further explore the pharmacological mechanism of vomicine in the treatment of ALS via the cGAS-STING-TBK1 pathway.

RESULTS: SSP improved motor function, body weight loss, gastrocnemius muscle atrophy, and motor neuron loss in the spine and cortex of hSOD1-G93A mice. Furthermore, the cGAS-STING-TBK1 pathway was activated in the spinal cord of hSOD1-G93A mice, with activation predominantly observed in neurons and microglia. However, the levels of cGAS, STING, and pTBK1 proteins and cGAS, IRF3, IL-6, and IL-1β mRNA were reversed following intervention with SSP. Vomicine not only downregulated the levels of cGAS, TBK1, IL-6 and IFN-β mRNA, but also the levels of cGAS and STING protein in hSOD1[G93A] NSC-34 cells.

CONCLUSION: This study demonstrated that SSP and vomicine exert neuroprotective and anti-neuroinflammatory effects in the treatment of ALS. SSP and vomicine may reduce neuroinflammation by regulating the cGAS-STING-TBK1 pathway, and could thereby play a role in ALS treatment.}, } @article {pmid39197036, year = {2025}, author = {Sapaly, D and Cheguillaume, F and Weill, L and Clerc, Z and Biondi, O and Bendris, S and Buon, C and Slika, R and Piller, E and Sundaram, VK and da Silva Ramos, A and Amador, MDM and Lenglet, T and Debs, R and Le Forestier, N and Pradat, PF and Salachas, F and Lacomblez, L and Hesters, A and Borderie, D and Devos, D and Desnuelle, C and Rolland, AS and Periou, B and Vasseur, S and Chapart, M and Le Ber, I and Fauret-Amsellem, AL and Millecamps, S and Maisonobe, T and Leonard-Louis, S and Behin, A and Authier, FJ and Evangelista, T and Charbonnier, F and Bruneteau, G}, title = {Dysregulation of muscle cholesterol transport in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {3}, pages = {788-802}, pmid = {39197036}, issn = {1460-2156}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics ; Humans ; *Cholesterol/metabolism ; *Muscle, Skeletal/metabolism ; Middle Aged ; Male ; Female ; Aged ; Adult ; Niemann-Pick C1 Protein ; Muscle Fibers, Skeletal/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism/genetics ; Carrier Proteins/metabolism/genetics ; Cells, Cultured ; Biological Transport ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons, with a typical lifespan of 3-5 years. Altered metabolism is a key feature of ALS that strongly influences prognosis, with an increase in whole body energy expenditure and changes in skeletal muscle metabolism, including greater reliance on fat oxidation. Dyslipidaemia has been described in ALS as part of the metabolic dysregulation, but its role in the pathophysiology of the disease remains controversial. Among the lipids, cholesterol is of particular interest as a vital component of cell membranes, playing a key role in signal transduction and mitochondrial function in muscle. The aim of this study was to investigate whether motor dysfunction in ALS might be associated with dysregulation of muscle cholesterol metabolism. We determined cholesterol content and analysed the expression of key determinants of the cholesterol metabolism pathway in muscle biopsies from 13 ALS patients and 10 asymptomatic ALS-mutation gene carriers compared to 16 control subjects. Using human control primary myotubes, we investigated the potential contribution of cholesterol dyshomeostasis to reliance on mitochondrial fatty acid. We found that cholesterol accumulates in the skeletal muscle of ALS patients and that cholesterol overload significantly correlates with disease severity evaluated by the Revised ALS Functional Rating Scale. These defects are associated with overexpression of the genes of the lysosomal cholesterol transporters Niemann-Pick type C1 (NPC1) and 2 (NPC2), which are required for cholesterol transfer from late endosomes/lysosomes to cellular membranes. Most notably, a significant increase in NPC2 mRNA levels could be detected in muscle samples from asymptomatic ALS-mutation carriers, long before disease onset. We found that filipin-stained unesterified cholesterol accumulated in the lysosomal compartment in ALS muscle samples, suggesting dysfunction of the NPC1/2 system. Accordingly, we report here that experimental NPC1 inhibition or lysosomal pH alteration in human primary myotubes was sufficient to induce the overexpression of NPC1 and NPC2 mRNA. Finally, acute NPC1 inhibition in human control myotubes induced a shift towards a preferential use of fatty acids, thus reproducing the metabolic defect characteristic of ALS muscle. We conclude that cholesterol homeostasis is dysregulated in ALS muscle from the presymptomatic stage. Targeting NPC1/2 dysfunction may be a new therapeutic strategy for ALS to restore muscle energy metabolism and slow motor symptom progression.}, } @article {pmid39196396, year = {2024}, author = {Radakovic, R and Carroll, A and Altiero, A and Reichwein, C and Walsh, S and Niven, E and Abrahams, S and Simmons, Z}, title = {Self-perceived quality of life, cognitive and behavioural impairment in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6822-6838}, pmid = {39196396}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/physiopathology ; Male ; *Quality of Life/psychology ; Female ; Middle Aged ; Cross-Sectional Studies ; Aged ; Cognitive Dysfunction/etiology/physiopathology/psychology ; Cohort Studies ; Self Concept ; Mental Disorders/psychology/etiology ; Adult ; }, abstract = {BACKGROUND: Self-perceived quality of life (QoL) is important in amyotrophic lateral sclerosis (ALS). Although caregiver burden and strain have been related to cognitive and behavioural impairment, there has been no comprehensive research looking at these impairments and how they may influence self-perceived QoL subdomains.

AIMS: To explore how cognitive and behavioural impairment are related to different areas of self-perceived QoL using disease-specific measures.

METHODS: This was a quantitative, cross-sectional, observational cohort study, utilising existing specialist ALS clinic data. Clinical and demographic variables were available as well as multidimensional measures, ALS-specific QoL Short Form (ALSsQoL-SF) results and the data from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Group comparison and regression analyses were performed.

RESULTS: Data from 121 participants with ALS were analysed. 61.2% (N = 74) had either cognitive and/or behavioural impairment, with 28.9% (N = 35) with cognitive impairment (ALSci), 14.1% (N = 17) with behavioural impairment (ALSbi) and 18.2% (N = 22) with both (ALScbi). 38.8% (N = 47) were classified as having no impairments (ALSni). Those with ALSbi had significantly lower QoL in the domains of negative emotions and the interaction with people and the environment compared to those with ALSci and ALSni (ps < 0.05). Further, those with ALScbi had significantly lower QoL in the intimacy domains than those with ALSci and ALSni (ps < 0.05). Regression analysis showed specific cognitive and behavioural (inclusive of psychosis) predictors associated with specific QoL subdomains.

CONCLUSIONS: Behavioural impairments effect QoL in specific subdomains, namely relating to internalising (negative emotions) and externalising (interaction with people and the environment subdomains, intimacy).}, } @article {pmid39194682, year = {2024}, author = {Sacharczuk, M and Mickael, ME and Kubick, N and Kamińska, A and Horbańczuk, JO and Atanasov, AG and Religa, P and Ławiński, M}, title = {The Current Landscape of Hypotheses Describing the Contribution of CD4+ Heterogeneous Populations to ALS.}, journal = {Current issues in molecular biology}, volume = {46}, number = {8}, pages = {7846-7861}, pmid = {39194682}, issn = {1467-3045}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a poorly understood and fatal disease. It has a low prevalence and a 2-4 year survival period. Various theories and hypotheses relating to its development process have been proposed, albeit with no breakthrough in its treatment. Recently, the role of the adaptive immune system in ALS, particularly CD4+ T cells, has begun to be investigated. CD4+ T cells are a heterogeneous group of immune cells. They include highly pro-inflammatory types such as Th1 and Th17, as well as highly anti-inflammatory cells such as Tregs. However, the landscape of the role of CD4+ T cells in ALS is still not clearly understood. This review covers current hypotheses that elucidate how various CD4+ T cells can contribute to ALS development. These hypotheses include the SWITCH model, which suggests that, in the early stages of the disease, Tregs are highly capable of regulating the immune response. However, in the later stages of the disease, it seems that pro-inflammatory cells such as Th1 and Th17 are capable of overwhelming Treg function. The reason why this occurs is not known. Several research groups have proposed that CD4+ T cells as a whole might experience aging. Others have proposed that gamma delta T cells might directly target Tregs. Additionally, other research groups have argued that less well-known CD4+ T cells, such as Emoes+ CD4+ T cells, may be directly responsible for neuron death by producing granzyme B. We propose that the ALS landscape is highly complicated and that there is more than one feasible hypothesis. However, it is critical to take into consideration the differences in the ability of different populations of CD4+ T cells to infiltrate the blood-brain barrier, taking into account the brain region and the time of infiltration. Shedding more light on these still obscure factors can help to create a personalized therapy capable of regaining the balance of power in the battle between the anti-inflammatory and pro-inflammatory cells in the central nervous system of ALS patients.}, } @article {pmid39193833, year = {2025}, author = {Jalaiei, A and Asadi, MR and Daneshmandpour, Y and Rezazadeh, M and Ghafouri-Fard, S}, title = {Clinical, molecular, physiologic, and therapeutic feature of patients with CHRNA4 and CHRNB2 deficiency: A systematic review.}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16200}, doi = {10.1111/jnc.16200}, pmid = {39193833}, issn = {1471-4159}, mesh = {Humans ; *Receptors, Nicotinic/genetics ; Mutation/genetics ; Neurodegenerative Diseases/genetics/metabolism ; }, abstract = {The α4β2 nAChRs are crucial ion channels that control neurotransmitter release and play a role in various physiologic and pathologic processes. CHRNA4 encodes the α4-nAChRs, while CHRNB2 encodes the β2-nAChRs. Recent studies have found different variants of α4β2-nAChRs in individuals with conditions such as AD, ADHD, ALS, PD, and brain abnormalities. We conducted a scoping review following a six-stage methodology structure and adhering to PRISMA guidelines. We systematically reviewed articles using relevant keywords up to October 2, 2023. In this summary, we cover the clinical symptoms reported, the genes and protein structure of CHRNA4 and CHRNB2, mutations in these genes, inheritance patterns, the functional impact of mutations and polymorphisms in CHRNA4 and CHRNB2, and the epidemiology of these diseases. Recent research indicates that nAChRs may play a significant role in neurodegenerative disorders, possibly impacting neuronal function through yet undiscovered regulatory pathways. Studying how nAChRs interact with disease-related aggregates in neurodegenerative conditions may lead to new treatment options for these disorders.}, } @article {pmid39193573, year = {2024}, author = {Soresi, M and Giannitrapani, L}, title = {Glucagon-like peptide 1 agonists are potentially useful drugs for treating metabolic dysfunction-associated steatotic liver disease.}, journal = {World journal of gastroenterology}, volume = {30}, number = {30}, pages = {3541-3547}, pmid = {39193573}, issn = {2219-2840}, mesh = {Humans ; *Non-alcoholic Fatty Liver Disease/drug therapy/pathology/metabolism ; *Glucagon-Like Peptides/therapeutic use ; Liver/drug effects/pathology/metabolism ; Insulin Resistance ; Drug Therapy, Combination/methods ; Glucagon-Like Peptide 1/agonists/metabolism ; Treatment Outcome ; Hypoglycemic Agents/therapeutic use/pharmacology ; Disease Progression ; Incretins/therapeutic use ; *Glucagon-Like Peptide-1 Receptor Agonists ; }, abstract = {In this editorial, we comment on Yin et al's recently published Letter to the editor. In particular, we focus on the potential use of glucagon-like peptide 1 receptor agonists (GLP-1RAs) alone, but even more so in combination therapy, as one of the most promising therapies in metabolic dysfunction-associated steatotic liver disease (MASLD), the new definition of an old condition, non-alcoholic fatty liver disease, which aims to better define the spectrum of steatotic pathology. It is well known that GLP-1RAs, having shown outstanding performance in fat loss, weight loss, and improvement of insulin resistance, could play a role in protecting the liver from progressive damage. Several clinical trials have shown that, among GLP-1RAs, semaglutide is a safe, well-studied therapeutic choice for MASLD patients; however, most studies demonstrate that, while semaglutide can reduce steatosis, including steatohepatitis histological signs (in terms of inflammatory cell infiltration and hepatocyte ballooning), it does not improve fibrosis. Combinations of therapies with different but complementary mechanisms of action are considered the best way to improve efficiency and slow disease progression due to the complex pathophysiology of the disease. In particular, GLP-1RAs associated with antifibrotic drug therapy, dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA or GLP-1 and glucagon RAs have promoted greater improvement in hepatic steatosis, liver biochemistry, and non-invasive fibrosis tests than monotherapy. Therefore, although to date there are no definitive indications from international drug agencies, there is the hope that soon the therapeutic lines in the most advanced phase of study will be able to provide a therapy for MASLD, one that will certainly include the use of GLP-1RAs as combination therapy.}, } @article {pmid39193017, year = {2024}, author = {Chen, X and Cai, L and Fan, W and Yang, Q and Mao, X and Yao, L}, title = {Causal relationships between rheumatoid arthritis and neurodegenerative diseases: a two-sample univariable and multivariable Mendelian randomization study.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1439344}, pmid = {39193017}, issn = {2296-858X}, abstract = {BACKGROUND: Observational research has highlighted a potential relationship between rheumatoid arthritis (RA) and neurodegenerative diseases (NDs). However, the confirmation of a causal connection is impeded by the inherent limitations of such studies, including vulnerability to confounding factors and the possibility of reverse causality. This study employs a two-sample Mendelian randomization (MR) approach to assess the causal impact of RA on three NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

METHODS: We aggregated data from genome-wide association studies (GWASs) targeting RA or NDs within populations of European descent. Single nucleotide polymorphisms (SNPs) with robust associations to RA were identified as instrumental variables (IVs). To estimate the association between RA and AD, PD, and ALS, we utilized the inverse variance weighted (IVW) method in our univariable MR (UVMR) analysis. Validation of the IVW results ensued through supplementary analyses using MR-Egger and weighted median methods. The multivariable MR (MVMR) analysis was conducted, adjusting for body mass index (BMI), alcohol drinking, and type 2 diabetes mellitus (T2DM).

RESULTS: The UVMR analysis, based on the IVW method, revealed a significantly positive causal association between RA and late-onset (LO) AD (OR [95% CI] = 1.084 [1.020-1.153]; p = 9.980 × 10[-3]), while suggesting a possible inverse relationship with PD (OR [95% CI] = 0.727 [0.563-0.938]; p = 0.014). Our study did not detect any causal connections between RA and early-onset (EO) AD, atypical or mixed (AM) AD, and ALS (all p > 0.05). The MVMR analysis results indicated that after adjusting for alcohol drinking, RA remains a risk factor for LOAD (OR [95% CI] = 1.094 [1.024-1.169]; p = 0.008). However, MVMR analysis revealed no causal connections between RA and PD after adjustments for BMI, alcohol drinking, or T2DM (all p > 0.05). Sensitivity analyses showed no evidence of heterogeneity and horizontal pleiotropy.

CONCLUSIONS: This research provides genetic evidence indicating that RA potentially causes an increased risk of developing LOAD and PD. Such a revelation underscores the importance for individuals suffering from RA to be vigilant about the potential emergence of LOAD and PD. Ongoing monitoring and prompt detection are essential for successfully managing and intervening in this possible risk.}, } @article {pmid39192891, year = {2024}, author = {Murtazina, A and Subbotin, D and Kuchina, A and Gilvanova, O and Degterev, D and Shchagina, O and Cherevatova, T and Bulakh, M and Sherstyukova, D and Ryzhkova, O and Kurushina, O and Skoblov, M and Borovikov, A and Kutsev, S}, title = {Asymmetric scapuloperoneal phenotype of MATR3-related distal myopathy: case series.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1414928}, pmid = {39192891}, issn = {1664-8021}, abstract = {Recent research has sparked a discussion on the spectrum of diseases linked to the MATR3 gene associated with amyotrophic lateral sclerosis and distal myopathy with vocal cord and pharyngeal weakness (VCPDM). To date, fewer than 50 cases of VCPDM have been reported in the literature. We aim to build upon the work of previous researchers by gathering additional information about VCPDM. In this study, we present six patients from four unrelated families affected by VCPDM. Our observations include patients exhibiting both the typical phenotype associated with MATR3-related distal myopathy and rare symptomatic manifestations of the disease. Notably, two cases presented with an asymmetric scapuloperoneal phenotype, leading in one case to an initial misdiagnosis of facioscapulohumeral muscular dystrophy.}, } @article {pmid39192797, year = {2024}, author = {Luo, RC and Wu, XY and Yu, WW and Zheng, YJ and Wang, D}, title = {[Research progress on the relationship between TRAF6 and neurodegenerative diseases].}, journal = {Sheng li xue bao : [Acta physiologica Sinica]}, volume = {76}, number = {4}, pages = {653-662}, pmid = {39192797}, issn = {0371-0874}, mesh = {Animals ; Humans ; Alzheimer Disease/metabolism/etiology ; Amyotrophic Lateral Sclerosis/metabolism/physiopathology/genetics/etiology ; Multiple Sclerosis/metabolism/physiopathology/etiology ; *Neurodegenerative Diseases/metabolism/etiology ; Parkinson Disease/metabolism/physiopathology ; *TNF Receptor-Associated Factor 6/metabolism/genetics/physiology ; Ubiquitination ; }, abstract = {Given the increasing trend of aging population in the world, neurodegenerative diseases (NDDs), a common type of diseases that mostly occur in the elderly, have attracted much more attention. It has been shown that tumor necrosis factor receptor-associated factor 6 (TRAF6) is involved in the regulation of neuroinflammation, an important pathological feature of NDDs, and affects the occurrence and development of NDDs. Most importantly, the regulatory effect of TRAF6 is related to its ubiquitination. Therefore, in the present paper, the molecular structure, biological function, and ubiquitination mechanism of TRAF6, and its relationship with some common NDDs, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, were analyzed and summarized. The possible molecular mechanisms by which TRAF6 regulates the occurrence of NDDs were also elucidated, providing a theoretical basis for exploring the etiology and treatment of NDDs.}, } @article {pmid39192497, year = {2024}, author = {Lee, I and Garret, MA and Wuu, J and Harrington, EA and Berry, JD and Miller, TM and Harms, M and Benatar, M and Shneider, N}, title = {Body mass index is lower in asymptomatic C9orf72 expansion carriers but not in SOD1 pathogenic variant carriers compared to gene negatives.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {672-679}, pmid = {39192497}, issn = {2167-9223}, support = {K23 NS131586/NS/NINDS NIH HHS/United States ; R01 NS105479/NS/NINDS NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *C9orf72 Protein/genetics ; *Body Mass Index ; *Superoxide Dismutase-1/genetics ; Middle Aged ; *Heterozygote ; Adult ; Cohort Studies ; Genotype ; DNA Repeat Expansion/genetics ; Aged ; }, abstract = {Objective: To examine the relationship between body mass index (BMI) and genotype among pre-symptomatic carriers of different pathogenic variants associated with amyotrophic lateral sclerosis. Methods: C9orf72+ carriers, SOD1+ carriers, and pathogenic variant negative controls (Gene-Negatives) were included from 3 largely independent cohorts: ALS Families Project (ALS-Families); Dominantly inherited ALS (DIALS); and Pre-symptomatic Familial ALS (Pre-fALS). First reported (ALS-Families) or measured (DIALS and Pre-fALS) weight and height were used to calculate BMI. Age at weight measurement, self-reported sex (male vs. female), and highest education (high school or below vs. college education vs. graduate school or above) were extracted. The associations between BMI and genotype in each cohort were examined with multivariable linear regression models, adjusted for age, sex, and education. Results: A total of 223 C9orf72+ carriers, 135 SOD1+ carriers, and 191 Gene-Negatives were included, deriving from ALS-Families (n = 114, median age 46, 37% male), DIALS (n = 221, median age 46, 30% male), and Pre-fALS (n = 214, median age 44, 39% male). Adjusting for age, sex, and education, the mean BMI of C9orf72+ carriers was lower than Gene-Negatives by 2.4 units (95% confidence interval [CI] = 0.3-4.6, p = 0.02) in ALS-Families; 2.7 units (95% CI = 0.9-4.4, p = 0.003) in DIALS; and 1.9 units (95% CI = 0.5-4.2, p = 0.12) in Pre-fALS. There were no significant differences in BMI between SOD1+ carriers and Gene-Negatives in any of the 3 cohorts. Conclusions: Compared to Gene-Negatives, average BMI is lower in asymptomatic C9orf72+ carriers across 3 cohorts while no significant difference was found between Gene-Negatives and SOD1+ carriers.}, } @article {pmid39192451, year = {2024}, author = {Yan, Y and Huang, SY and Feng, YJ and Zhao, CY and Sheng, GX and Chen, J and Jiang, JJ and Gao, F and Mao, SS}, title = {[Pediatric amyotrophic lateral sclerosis caused by FUS gene variation in 2 cases].}, journal = {Zhonghua er ke za zhi = Chinese journal of pediatrics}, volume = {62}, number = {9}, pages = {893-895}, doi = {10.3760/cma.j.cn112140-20240315-00184}, pmid = {39192451}, issn = {0578-1310}, mesh = {Female ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; DNA Mutational Analysis ; Exons ; Fatal Outcome ; Heterozygote ; *Mutation ; *RNA-Binding Protein FUS/genetics ; Child ; Adolescent ; }, } @article {pmid39191336, year = {2024}, author = {Sirtori, CR and Castiglione, S and Pavanello, C}, title = {Metformin: From diabetes to cancer to prolongation of life.}, journal = {Pharmacological research}, volume = {208}, number = {}, pages = {107367}, doi = {10.1016/j.phrs.2024.107367}, pmid = {39191336}, issn = {1096-1186}, mesh = {Humans ; *Metformin/therapeutic use/pharmacology ; Animals ; *Neoplasms/drug therapy/metabolism ; *Hypoglycemic Agents/therapeutic use/pharmacology ; *Diabetes Mellitus/drug therapy/metabolism ; Longevity/drug effects ; Antineoplastic Agents/therapeutic use/pharmacology ; }, abstract = {The metformin molecule dates back to over a century, but its clinical use started in the '50s. Since then, its use in diabetics has grown constantly, with over 150 million users today. The therapeutic profile also expanded, with improved understanding of novel mechanisms. Metformin has a major activity on insulin resistance, by acting on the insulin receptors and mitochondria, most likely by activation of the adenosine monophosphate-activated kinase. These and associated mechanisms lead to significant lipid lowering and body weight loss. An anti-cancer action has come up in recent years, with mechanisms partly dependent on the mitochondrial activity and also on phosphatidylinositol 3-kinase resistance occurring in some malignant tumors. The potential of metformin to raise life-length is the object of large ongoing studies and of several basic and clinical investigations. The present review article will attempt to investigate the basic mechanisms behind these diverse activities and the potential clinical benefits. Metformin may act on transcriptional activity by histone modification, DNA methylation and miRNAs. An activity on age-associated inflammation (inflammaging) may occur via activation of the nuclear factor erythroid 2 related factor and changes in gut microbiota. A senolytic activity, leading to reduction of cells with the senescent associated secretory phenotype, may be crucial in lifespan prolongation as well as in ancillary properties in age-associated diseases, such as Parkinson's disease. Telomere prolongation may be related to the activity on mitochondrial respiratory factor 1 and on peroxisome gamma proliferator coactivator 1-alpha. Very recent observations on the potential to act on the most severe neurological disorders, such as amyotrophic lateral sclerosis and frontotemporal dementia, have raised considerable hope.}, } @article {pmid39191178, year = {2024}, author = {Ruotolo, G and D'Anzi, A and Giovenale, AMG and Giacometti, C and Ferrari, D and Vulcano, E and D'Asdia, C and Lattante, S and Sabatelli, M and Codazzi, F and Consalez, G and Marano, M and Di Lazzaro, V and Pennuto, M and Vescovi, A and Rosati, J}, title = {Induced pluripotent stem cell production (CSSi019-A)(14432) from an asymptomatic subject carrying a expansion of C9orf72 gene.}, journal = {Stem cell research}, volume = {81}, number = {}, pages = {103540}, doi = {10.1016/j.scr.2024.103540}, pmid = {39191178}, issn = {1876-7753}, mesh = {*Induced Pluripotent Stem Cells/metabolism ; Humans ; *C9orf72 Protein/genetics/metabolism ; Aged ; Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; DNA Repeat Expansion ; Male ; Female ; }, abstract = {One of the genetic mutations most associated with the onset of amyotrophic lateral sclerosis, both in sporadic and familial cases, is the expansion of the C9orf72 gene. The presence of more than 30 repeats (GGGGCC) correlates with uncertain ALS symptomatology. Here we collected a dermal biopsy from a subject carrying 36 hexanucleotide repeats and reprogrammed it into an induced pluripotent stem cell line. Despite the number of repeat elements, the subject had no symptoms at the age of the biopsy (76 years), thus resulting in a healthy carrier of the mutation.}, } @article {pmid39191031, year = {2024}, author = {He, Q and Wang, Y and Zhao, F and Wei, S and Li, X and Zeng, G}, title = {APE1: A critical focus in neurodegenerative conditions.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {179}, number = {}, pages = {117332}, doi = {10.1016/j.biopha.2024.117332}, pmid = {39191031}, issn = {1950-6007}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism ; Animals ; }, abstract = {The global growth of the aging population has resulted in an increased prevalence of neurodegenerative diseases, characterized by the progressive loss of central nervous system (CNS) structure and function. Given the high incidence and debilitating nature of neurodegenerative diseases, there is an urgent need to identify potential biomarkers and novel therapeutic targets thereof. Apurinic/apyrimidinic endonuclease 1 (APE1), has been implicated in several neurodegenerative diseases, as having a significant role. Abnormal APE1 expression has been observed in conditions including Alzheimer's disease, stroke, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and epilepsy. However, whether this dysregulation is protective or harmful remains unclear. This review aims to comprehensively review the current understanding of the involvement of APE1 in neurodegenerative diseases.}, } @article {pmid39190906, year = {2024}, author = {Yu, J and Chen, S and Zhang, H and Zhang, S and Dong, D}, title = {Patterns of the Health and Economic Burden of 33 Rare Diseases in China: Nationwide Web-Based Study.}, journal = {JMIR public health and surveillance}, volume = {10}, number = {}, pages = {e57353}, pmid = {39190906}, issn = {2369-2960}, mesh = {Humans ; China/epidemiology ; *Rare Diseases/epidemiology/economics ; Male ; Adult ; Female ; Cross-Sectional Studies ; Middle Aged ; *Cost of Illness ; Adolescent ; Child ; *Internet ; Child, Preschool ; Young Adult ; Surveys and Questionnaires ; Aged ; Infant ; }, abstract = {BACKGROUND: Rare diseases (RDs) affect millions of individuals collectively worldwide, contributing to significant burdens on patients and families in various aspects. However, there is a lack of evidence on the underlying patterns of burdens among diverse RDs for informing targeted social and health policies to address the unmet needs of this vulnerable population.

OBJECTIVE: This study aimed to examine the underlying patterns of the health and economic burden of 33 different RDs in China and identify the potential determinants.

METHODS: A nationwide internet-based cross-sectional survey was conducted in China between 2019 and 2020. Physical and mental health burden was measured by health-related quality of life. Economic burden was evaluated based on the proportions of direct medical, direct nonmedical, and indirect costs relative to household income. We used cluster analysis to identify patterns of health and economic burdens and conducted multinomial logistic regression to explore potential predictors of cluster membership.

RESULTS: The study included 8454 adults and 8491 children affected by 33 RDs. The following 3 clusters were identified: "extremely high burden" (representing 92/8454, 1.1% and 19/8491, 0.2% of adult and pediatric patients, respectively), "overall high burden" (5933/8454, 70.2% and 4864/8491, 57.3%, respectively), and "overall low burden" (2429/8454, 28.7% and 3608/8491, 42.5%, respectively). Wilson disease, Marfan syndrome, and Langerhans cell histiocytosis more likely resulted in an "extremely high burden" than others. Poverty was significantly associated with being in this extremely high burden group. Diseases causing neuromuscular symptoms and requiring long-term treatment (eg, amyotrophic lateral sclerosis, spinocerebellar ataxia, and Dravet syndrome) were prevalent in the "overall high burden" group. Key predictors of this group included older age, lower socioeconomic status, diagnostic delay, and comorbidity.

CONCLUSIONS: This study provides novel and valuable evidence on the burden of RDs in developing regions like China. The findings reveal significant disparities in the impact of RDs, emphasizing the need for targeted health care interventions and policies.}, } @article {pmid39190080, year = {2024}, author = {Jensen, BK}, title = {Astrocyte-Neuron Interactions Contributing to Amyotrophic Lateral Sclerosis Progression.}, journal = {Advances in neurobiology}, volume = {39}, number = {}, pages = {285-318}, pmid = {39190080}, issn = {2190-5215}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Astrocytes/metabolism ; *Disease Progression ; *Motor Neurons/metabolism/pathology ; *Cell Communication/physiology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex disease impacting motor neurons of the brain, brainstem, and spinal cord. Disease etiology is quite heterogeneous with over 40 genes causing the disease and a vast ~90% of patients having no prior family history. Astrocytes are major contributors to ALS, particularly through involvement in accelerating disease progression. Through study of genetic forms of disease including SOD1, TDP43, FUS, C9orf72, VCP, TBK1, and more recently patient-derived cells from sporadic individuals, many biological mechanisms have been identified to cause intrinsic or glial-mediated neurotoxicity to motor neurons. Overall, many of the normally supportive and beneficial roles that astrocytes contribute to neuronal health and survival instead switch to become deleterious and neurotoxic. While the exact pathways may differ based on disease-origin, altered astrocyte-neuron communication is a common feature of ALS. Within this chapter, distinct genetic forms are examined in detail, along with what is known from sporadic patient-derived cells. Overall, this chapter highlights the interplay between astrocytes and neurons in this complex disease and describes the key features underlying: astrocyte-mediated motor neuron toxicity, excitotoxicity, oxidative/nitrosative stress, protein dyshomeostasis, metabolic imbalance, inflammation, trophic factor withdrawal, blood-brain/blood-spinal cord barrier involvement, disease spreading, and the extracellular matrix/cell adhesion/TGF-β signaling pathways.}, } @article {pmid39189114, year = {2024}, author = {Rivera Flores, IV and Monopoli, K and Jackson, S and Echeverria, D and O'Reilly, D and Brown, RH and Khvorova, A}, title = {Near Sequence Homology Does Not Guarantee siRNA Cross-Species Efficacy.}, journal = {Nucleic acid therapeutics}, volume = {34}, number = {5}, pages = {234-244}, pmid = {39189114}, issn = {2159-3345}, support = {R01 NS104022/NS/NINDS NIH HHS/United States ; S10 OD020012/OD/NIH HHS/United States ; T32 GM135751/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *RNA, Small Interfering/genetics/chemistry ; Humans ; Dogs ; Mice ; Rats ; *Superoxide Dismutase-1/genetics ; *Species Specificity ; Sheep ; Base Pair Mismatch/genetics ; Cell Line ; }, abstract = {Small interfering RNAs (siRNAs) represent a novel class of drugs capable of potent and sustained modulation of genes across various tissues. Preclinical development of siRNAs necessitates assessing efficacy and toxicity in animal models. While identifying therapeutic leads with cross-species activity can expedite development, it may compromise efficacy and be infeasible for certain gene targets. Here, we investigate whether deriving species-active siRNAs from potent human-targeting leads-an approach termed mismatch conversion-can yield potent compounds. We systematically altered potent siRNAs targeting human genes associated with diseases-SOD1 (ALS), JAK1 (inflammation), and HTT (HD)-to generate species-matching variants with full complementarity to their target in NHPs, mice, rats, sheep, and dogs. Variants potency and efficacy were measured in corresponding cell lines. We demonstrate that sequence, position, and number of mismatches significantly influence the ability to generate potent species-active compounds via mismatch conversion. Across tested sequences, mismatch conversion strategy ability to identify a species-active lead varied from 0% to 70%. For SOD1, lead compounds identified from species-focus screening in mouse and dog cells were more potent than leads obtained from mismatch conversion. Thus, a focused screening of therapeutic lead and model compounds may represent a more reliable strategy for the clinical advancement of siRNAs.}, } @article {pmid39188590, year = {2024}, author = {Roca-Pereira, S and Domínguez, R and Moreno León, I and Colomina, MJ and Martínez Yélamos, A and Martínez Yélamos, S and Povedano, M and Andrés-Benito, P}, title = {Increased CXCL12, a potential CSF biomarker for differential diagnosis of amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {4}, pages = {fcae271}, pmid = {39188590}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a debilitating and lethal neurodegenerative disorder marked by the gradual deterioration of motor neurons. Diagnosing amyotrophic lateral sclerosis is challenging due to the lack of reliable diagnostic tools, with clinical assessment being the primary criterion. Recently, increased levels of neurofilament light chain in CSF have been considered a useful biomarker in disease, correlating with disease progression but not specific for diagnosis. This study utilized enzyme-linked immunosorbent assay to measure CSF C-X-C motif chemokine ligand 12 levels in healthy controls, amyotrophic lateral sclerosis patients and patients with amyotrophic lateral sclerosis-mimic disorders, assessing its potential as a diagnostic biomarker and comparing it with neurofilament light chain levels. Our results confirmed previous findings, showing increased C-X-C motif chemokine ligand 12 levels in amyotrophic lateral sclerosis patients compared to healthy control (797.07 ± 31.84 pg/mL versus 316.15 ± 16.6 pg/mL; P = 0.000) and increased CSF neurofilament light chain levels in amyotrophic lateral sclerosis (4565.63 ± 263.77 pg/mL) compared to healthy control (847.86 ± 214.37 pg/mL; P = 0.000). Increased C-X-C motif chemokine ligand levels were specific to amyotrophic lateral sclerosis, not seen in amyotrophic lateral sclerosis-mimic conditions like myelopathies (252.20 ± 23.16 pg/mL; P = 0.000), inflammatory polyneuropathies (270.24 ± 32.23 pg/mL; P = 0.000) and other mimic diseases (228.91 ± 29.20 pg/mL; P = 0.000). In contrast, CSF neurofilament light chain levels in amyotrophic lateral sclerosis overlapped with those in myelopathies (2900.11 ± 872.20 pg/mL; P = 0.821) and other mimic diseases (3169.75 ± 1096.65 pg/mL; P = 0.63), but not with inflammatory polyneuropathies (1156.4 ± 356.6 pg/mL; P = 0.000). Receiver operating characteristic curve analysis indicated significant differences between the area under the curve values of C-X-C motif chemokine ligand and neurofilament light chain in their diagnostic capacities. C-X-C motif chemokine ligand could differentiate between amyotrophic lateral sclerosis and myelopathies (area under the curve 0.99 ± 0.005), inflammatory polyneuropathies (area under the curve 0.962 ± 0.027) and other mimic diseases (area under the curve 1.00 ± 0.00), whereas neurofilament light chain was only effective in inflammatory polyneuropathies cases (area under the curve 0.92 ± 0.048), not in myelopathies (area under the curve 0.71 ± 0.09) or other mimic diseases (area under the curve 0.69 ± 0.14). We also evaluated C-X-C motif chemokine ligand levels in plasma [amyotrophic lateral sclerosis (2022 ± 81.8 pg/mL) versus healthy control (1739.43 ± 77.3 pg/mL; P = 0.015)] but found CSF determination (area under the curve 0.97 ± 0.012) to be more accurate than plasma determination (area under the curve 0.65 ± 0.063). In plasma, single molecule array (SIMOA) neurofilament light chain determination [amyotrophic lateral sclerosis (86.00 ± 12.23 pg/mL) versus healthy control (12.69 ± 1.15 pg/mL); P = 0.000] was more accurate than plasma C-X-C motif chemokine ligand 12 (area under the curve 0.98 ± 0.01405). These findings suggest that CSF C-X-C motif chemokine ligand 12 levels can enhance diagnostic specificity in distinguishing amyotrophic lateral sclerosis from amyotrophic lateral sclerosis-mimic disorders, compared to neurofilament light chain. Larger studies are needed to validate these results, but C-X-C motif chemokine ligand 12 determination shows promising diagnostic potential.}, } @article {pmid39187524, year = {2024}, author = {Femiano, C and Bruno, A and Gilio, L and Buttari, F and Dolcetti, E and Galifi, G and Azzolini, F and Borrelli, A and Furlan, R and Finardi, A and Musella, A and Mandolesi, G and Storto, M and Centonze, D and Stampanoni Bassi, M}, title = {Inflammatory signature in amyotrophic lateral sclerosis predicting disease progression.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {19796}, pmid = {39187524}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Female ; Male ; *Disease Progression ; Middle Aged ; *Cytokines/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; Cross-Sectional Studies ; Aged ; Inflammation/cerebrospinal fluid ; Principal Component Analysis ; Adult ; Prognosis ; Case-Control Studies ; }, abstract = {Experimental studies identified a role of neuroinflammation in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the role of inflammatory molecules as diagnostic and prognostic biomarkers in patients with ALS is unclear. In this cross-sectional study, the cerebrospinal fluid (CSF) levels of a set of inflammatory cytokines and chemokines were analyzed in 56 newly diagnosed ALS patients and in 47 age- and sex-matched control patients without inflammatory or degenerative neurological disorders. The molecules analyzed included: interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-17, granulocyte colony stimulating factor (GCSF), macrophage inflammatory protein (MIP)-1a, MIP-1b, tumor necrosis factors (TNF), eotaxin. Principal component analysis (PCA) was used to explore possible associations between CSF molecules and ALS diagnosis. In addition, we analyzed the association between CSF cytokine profiles and clinical characteristics, including the disease progression rate score, and peripheral inflammation assessed using the Neutrophil-to-lymphocyte ratio (NLR). PCA identified six principal components (PCs) explaining 70.67% of the total variance in the CSF cytokine set. The principal component (PC1) explained 26.8% of variance and showed a positive load with CSF levels of IL-9, IL-4, GCSF, IL-7, IL-17, IL-13, IL-6, IL-1β, TNF, and IL-2. Logistic regression showed a significant association between PC1 and ALS diagnosis. In addition, in ALS patients, the same component was significantly associated with higher disease progression rate score and positively correlated with NLR. CSF inflammatory activation in present in ALS at the time of diagnosis and may characterize patients at higher risk for disease progression.}, } @article {pmid39187240, year = {2025}, author = {Lenz, M and Egenolf, P and Menzhausen, J and Heck, V and Perera, A and Eysel, P and Scheyerer, M and Oikonomidis, S}, title = {Clinical Outcome after Endoscopic Facet Denervation in Patients with Chronic Low Back Pain.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {163}, number = {2}, pages = {167-175}, doi = {10.1055/a-2348-1186}, pmid = {39187240}, issn = {1864-6743}, mesh = {Humans ; *Low Back Pain/surgery ; *Zygapophyseal Joint/innervation/surgery ; Female ; Male ; Middle Aged ; *Denervation/methods ; Retrospective Studies ; Adult ; Aged ; Chronic Pain/surgery ; Treatment Outcome ; Pain Measurement ; Endoscopy/methods ; Risk Factors ; }, abstract = {In mehreren Studien wurde berichtet, dass Kreuzschmerzen in der Bevölkerung mit bis zu 85% eine hohe Prävalenz aufweisen. Die perkutane Radiofrequenz-Facettengelenkdenervation (PRFD) ist heute der Goldstandard bei der Rhizotomie von chronischen Kreuzschmerzen (CLBP). Bisher veröffentlichte Studien zeigen jedoch kontroverse Ergebnisse über die Wirksamkeit der PRFD. Ziel dieser Studie war es daher, den Einsatz der endoskopischen Facettengelenkdenervation (EJE) zur Behandlung chronischer Kreuzschmerzen zu analysieren und potenzielle Risikofaktoren zu ermitteln, die die Indikationen für den Eingriff einschränken könnten.Wir haben retrospektiv 31 Patienten in die Studie eingeschlossen, die seit mindestens 24 Monaten an chronische Kreuzschmerzen leiden. Alle Patienten wurden einer endoskopischen Facettengelenkdenervation unterzogen und mussten postoperativ ODI-, COMI-, EQ-5D- und VRS-Scores ausfüllen, wobei die Nachbeobachtungszeit mindestens 12 Monate betrug. Zur Analyse der Korrelationen wurden grundlegende Patientendaten erfasst.Bei allen gemessenen klinischen Werten, wie ODI, COMI, EQ-5D und VRS, wurde eine signifikante Verbesserung festgestellt. Während das beste Ergebnis bei der 3-monatigen Nachuntersuchung erzielt wurde, wurde bei der 12-monatigen Nachuntersuchung eine leichte Verschlechterung festgestellt. Im Vergleich zu den präoperativen Scores wurde jedoch ein signifikanter Nutzen festgestellt. 28/31 Patienten (93,3%) berichteten bei der Nachuntersuchung nach 12 Monaten über geringere Schmerzen und waren mit dem Verfahren zufrieden. Älteres Alter und psychiatrische Vorerkrankungen wurden als potenzielle Risikofaktoren identifiziert, die mit einem schlechteren Ergebnis einhergehen. Postoperative Komplikationen wie Hämatome, eine Sensibilitätsstörung und eine vorübergehende Muskelschwäche der unteren Extremitäten wurden selten beobachtet.Die endoskopische Facettengelenkdenervation zeigte eine signifikante Verbesserung der klinischen Ergebnisse und der VRS im Vergleich zu den präoperativen Werten von Patienten mit einer mindestens 12 Monate bestehenden chronischen Kreuzschmerzen vor der Operation. Ältere Patienten und Patienten mit psychiatrischen Vorerkrankungen profitieren weniger von dem Eingriff.}, } @article {pmid39187176, year = {2025}, author = {Althobaiti, NA}, title = {Heavy metals exposure and Alzheimer's disease: Underlying mechanisms and advancing therapeutic approaches.}, journal = {Behavioural brain research}, volume = {476}, number = {}, pages = {115212}, doi = {10.1016/j.bbr.2024.115212}, pmid = {39187176}, issn = {1872-7549}, mesh = {Humans ; *Alzheimer Disease/chemically induced ; *Metals, Heavy/adverse effects ; Animals ; Oxidative Stress/drug effects/physiology ; Environmental Exposure/adverse effects ; Brain/drug effects/metabolism ; }, abstract = {Heavy metals such as lead, cadmium, mercury, and arsenic are prevalent in the environment due to both natural and anthropogenic sources, leading to significant public health concerns. These heavy metals are known to cause damage to the nervous system, potentially leading to a range of neurological conditions including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and attention-deficit hyperactivity disorder (ADHD). The present study examines the complex relationship between heavy metal exposure and AD, focusing on the underlying mechanisms of toxicity and potential therapeutic approaches. This review article highlights how these metals can impair brain function through mechanisms such as oxidative stress, inflammation, and neurotransmitter disruption, ultimately contributing to neurodegenerative diseases like AD. It also addresses the challenges in diagnosing heavy metal-induced cognitive impairments and emphasizes the need for further research to explore effective treatment strategies and preventive measures against heavy metal exposure.}, } @article {pmid39187026, year = {2024}, author = {Rezaei, K and Mastali, G and Abbasgholinejad, E and Bafrani, MA and Shahmohammadi, A and Sadri, Z and Zahed, MA}, title = {Cadmium neurotoxicity: Insights into behavioral effect and neurodegenerative diseases.}, journal = {Chemosphere}, volume = {364}, number = {}, pages = {143180}, doi = {10.1016/j.chemosphere.2024.143180}, pmid = {39187026}, issn = {1879-1298}, mesh = {*Cadmium/toxicity ; Humans ; *Neurodegenerative Diseases/chemically induced ; Animals ; Environmental Pollutants/toxicity ; Brain/drug effects/metabolism ; Neurotoxicity Syndromes/etiology ; Neurons/drug effects ; }, abstract = {Cadmium (Cd) induced neurotoxicity has become a growing concern due to its potential adverse effects on the Central Nervous System. Cd is a Heavy Metal (HM) that is released into the environment, through several industrial processes. It poses a risk to the health of the community by polluting air, water, and soil. Cd builds up in the brain and other neural tissues, raising concerns about its effect on the nervous system due to its prolonged biological half-life. Cd can enter into the neurons, hence increasing the production of Reactive Oxygen Species (ROS) in them and impairing their antioxidant defenses. Cd disrupts the Calcium (Ca[2+]) balance in neurons, affects the function of the mitochondria, and triggers cell death pathways. As a result of these pathways, the path to the development of many neurological diseases affected by environmental factors, especially Cd, such as Alzheimer's Disease (AD) and Amyotrophic Lateral Sclerosis (ALS) is facilitated. There are cognitive deficits associated with long exposure to Cd. Memory disorders are present in both animals and humans. Cd alters the brain's function and performance in critical periods. There are lifelong consequences of Cd exposure during critical brain development stages. The susceptibility to neurotoxic effects is increased by interactions with a variety of risk factors. Cd poses risks to neuronal function and behavior, potentially contributing to neurodegenerative diseases like Parkinson's disease (PD) and AD as well as cognitive issues. This article offers a comprehensive overview of Cd-induced neurotoxicity, encompassing risk assessment, adverse effect levels, and illuminating intricate pathways.}, } @article {pmid39185513, year = {2024}, author = {Benatar, M and Macklin, EA and Malaspina, A and Rogers, ML and Hornstein, E and Lombardi, V and Renfrey, D and Shepheard, S and Magen, I and Cohen, Y and Granit, V and Statland, JM and Heckmann, JM and Rademakers, R and McHutchison, CA and Petrucelli, L and McMillan, CT and Wuu, J}, title = {Prognostic Clinical and Biological Markers for Amyotrophic Lateral Sclerosis Disease Progression: Validation and Implications for Clinical Trial Design and Analysis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39185513}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; R01 AG066152/AG/NIA NIH HHS/United States ; U01 NS107027/NS/NINDS NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R01 NS109260/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R35 NS097273/NS/NINDS NIH HHS/United States ; T32 AG076411/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used.

METHODS: A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75[ECD], plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated.

FINDINGS: Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40pg/ml and >100pg/ml correspond to future ALSFRS-R slopes of ~0.5 and 1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ~25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75[ECD], and plasma miR-181ab is more limited.

INTERPRETATION: Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency.

FUNDING: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).}, } @article {pmid39185360, year = {2024}, author = {Di Lazzaro, V and Ranieri, F and Doretti, A and Boscarino, M and Maderna, L and Colombo, E and Soranna, D and Zambon, A and Ticozzi, N and Musumeci, G and Capone, F and Silani, V}, title = {Transcranial static magnetic stimulation for amyotrophic lateral sclerosis: a bicentric, randomised, double-blind placebo-controlled phase 2 trial.}, journal = {The Lancet regional health. Europe}, volume = {45}, number = {}, pages = {101019}, pmid = {39185360}, issn = {2666-7762}, abstract = {BACKGROUND: Enhanced glutamatergic transmission leading to motor neuron death is considered the major pathophysiological mechanism of amyotrophic lateral sclerosis (ALS). Motor cortex excitability can be suppressed by transcranial static magnetic stimulation (tSMS), thus tSMS can be evaluated as a potential treatment for ALS. The aim of present study was to investigate the efficacy and safety of tSMS in ALS.

METHODS: In this phase 2 trial, we randomly assigned ALS patients to receive daily tSMS or placebo stimulation over a period of 6 months. For each participant we calculated mean disease monthly progression rate (MPR) as the variation of the total ALS Functional Rating Scale-Revised (ALSRFS-R) score, before the beginning of the treatment (over a period of at least three months) and over the six-month treatment period. The primary efficacy outcome was the difference in MPR before and after the beginning of treatment. Secondary outcomes included safety and tolerability, compliance, and changes in corticospinal output. A long-term follow-up of 18 months was performed in all patients who completed the six-month treatment considering a composite endpoint event (tracheostomy or death). Trial registered at ClinicalTrials.gov, ID: NCT04393467, status: closed.

FINDINGS: Forty participants were randomly assigned to real (n = 21) or placebo stimulation (n = 19). Thirty-two participants (18 real and 14 placebo) completed the 6-month treatment. The MPR did not show statistically significant differences between the two arms during the pre-treatment (mean ± Standard deviation; Real: 1.02 ± 0.62, Sham: 1.02 ± 0.57, p-value = 1.00) and treatment period (Real: 0.90 ± 0.55, Sham: 0.94 ± 0.55, p-value = 0.83). Results for secondary clinical endpoints showed that the treatment is feasible and safe, being compliance with tSMS high. The change in corticospinal output did not differ significantly between the two groups. At the end of the long-term follow-up of 18 months, patients of real group had a statistically significant higher tracheostomy-free survival compared with patients of placebo group (Hazard Ratio = 0.27 95% Confidence interval 0.09-0.80, p-value = 0.019).

INTERPRETATION: tSMS did not modify disease progression during the 6 months of treatment. However, long-term follow-up revealed a substantial increase in tracheostomy free survival in patients treated with real stimulation supporting the evaluation of tSMS in larger and more prolonged studies.

FUNDING: The "Fondazione 'Nicola Irti' per le opere di carità e di cultura", Rome, Italy, supported present study.}, } @article {pmid39184484, year = {2024}, author = {Ozceylan, O and Sezgin-Bayindir, Z}, title = {Current Overview on the Use of Nanosized Drug Delivery Systems in the Treatment of Neurodegenerative Diseases.}, journal = {ACS omega}, volume = {9}, number = {33}, pages = {35223-35242}, pmid = {39184484}, issn = {2470-1343}, abstract = {Neurodegenerative diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, prion disease, and Huntington's disease, present a growing health concern as human life expectancy increases. Despite this, effective treatments to halt disease progression remain elusive due to various factors, including challenges in drug delivery across physiological barriers like the blood-brain barrier and patient compliance issues leading to treatment discontinuation. In response, innovative treatment approaches leveraging noninvasive techniques with higher patient compliance are emerging as promising alternatives. This Review aims to synthesize current treatment options and the challenges encountered in managing neurodegenerative diseases, while also exploring innovative treatment modalities. Specifically, noninvasive strategies such as intranasal administration and nanosized drug delivery systems are gaining prominence for their potential to enhance treatment efficacy and patient adherence. Nanosized drug delivery systems, including liposomes, polymeric micelles, and nanoparticles, are evaluated within the context of outstanding studies. The advantages and disadvantages of these approaches are discussed, providing insights into their therapeutic potential and limitations. Through this comprehensive examination, this Review contributes to the ongoing discourse surrounding the development of effective treatments for neurodegenerative diseases.}, } @article {pmid39184100, year = {2024}, author = {Sikirzhytskaya, A and Tyagin, I and Sutton, SS and Wyatt, MD and Safro, I and Shtutman, M}, title = {AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-4750719/v1}, pmid = {39184100}, issn = {2693-5015}, abstract = {Neurodegenerative pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, HIV-associated neurocognitive disorder, and others significantly affect individuals, their families, caregivers, and healthcare systems. While there are no cures yet, researchers worldwide are actively working on the development of novel treatments that have the potential to slow disease progression, alleviate symptoms, and ultimately improve the overall health of patients. Huge volumes of new scientific information necessitate new analytical approaches for meaningful hypothesis generation. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases, such as PubMed. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. Here we focus on drugs that can be repurposed for dementia treatment as an outcome of neurodegenerative diseases. Therefore, we determined dementia-associated genes statistically highly ranked in other disease classes. Additionally, we report a mechanism for detecting genes common to multiple health conditions. These sets of genes were classified based on their presence in biological pathways, aiding in selecting candidates and biological processes that are exploitable with drug repurposing.}, } @article {pmid39183919, year = {2024}, author = {Ma, S and Cao, Y and Shi, YF and Shang, C and He, L and Liu, ZP}, title = {Data-driven discovery of active phosphine ligand space for cross-coupling reactions.}, journal = {Chemical science}, volume = {15}, number = {33}, pages = {13359-13368}, pmid = {39183919}, issn = {2041-6520}, abstract = {The design of highly active catalysts is a main theme in organic chemistry, but it still relies heavily on expert experience. Herein, powered by machine-learning global structure exploration, we forge a Metal-Phosphine Catalyst Database (MPCD) with a meticulously designed ligand replacement energy metric, a key descriptor to describe the metal-ligand interactions. It pushes the rational design of organometallic catalysts to a quantitative era, where a ±10 kJ mol[-1] window of relative ligand binding strength, a so-called active ligand space (ALS), is identified for highly effective catalyst screening. We highlight the chemistry interpretability and effectiveness of ALS for various C-N, C-C and C-S cross-coupling reactions via a Sabatier-principle-based volcano plot and demonstrate its predictive power in discovering low-cost ligands in catalyzing Suzuki cross-coupling involving aryl chloride. The advent of the MPCD provides a data-driven new route for speeding up organometallic catalysis and other applications.}, } @article {pmid39183185, year = {2024}, author = {Adiningrat, DP and Schlund, M and Skidmore, AK and Abdullah, H and Wang, T and Heurich, M}, title = {Mapping temperate old-growth forests in Central Europe using ALS and Sentinel-2A multispectral data.}, journal = {Environmental monitoring and assessment}, volume = {196}, number = {9}, pages = {841}, pmid = {39183185}, issn = {1573-2959}, support = {397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; 397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; 397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; 397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; 397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; }, mesh = {*Forests ; *Environmental Monitoring/methods ; Europe ; *Remote Sensing Technology ; Conservation of Natural Resources/methods ; Biodiversity ; Satellite Imagery ; Climate Change ; Lasers ; }, abstract = {Old-growth forests are essential to preserve biodiversity and play an important role in sequestering carbon and mitigating climate change. However, their existence across Europe is vulnerable due to the scarcity of their distribution, logging, and environmental threats. Therefore, providing the current status of old-growth forests across Europe is essential to aiding informed conservation efforts and sustainable forest management. Remote sensing techniques have proven effective for mapping and monitoring forests over large areas. However, relying solely on remote sensing spectral or structural information cannot capture comprehensive horizontal and vertical structure complexity profiles associated with old-growth forest characteristics. To overcome this issue, we combined spectral information from Sentinel-2A multispectral imagery with 3D structural information from high-density point clouds of airborne laser scanning (ALS) imagery to map old-growth forests over an extended area. Four features from the ALS data and fifteen from Sentinel-2A comprising raw band (spectral reflectance), vegetation indices (VIs), and texture were selected to create three datasets used in the classification process using the random forest algorithm. The results demonstrated that combining ALS and Sentinel-2A features improved the classification performance and yielded the highest accuracy for old-growth class, with an F1-score of 92% and producer's and user's accuracies of 93% and 90%, respectively. The findings suggest that features from ALS and Sentinel-2A data sensitive to forest structure are essential for identifying old-growth forests. Integrating open-access satellite imageries, such as Sentinel-2A and ALS data, can benefit forest managers, stakeholders, and conservationists in monitoring old-growth forest preservation across a broader spatial extent.}, } @article {pmid39182937, year = {2024}, author = {Silva, ST and Costa, IM and Souza, AA and Pondofe, K and Melo, LP and Resqueti, VR and Valentim, R and Gonçalves, F and Ribeiro, TS}, title = {Physical therapy for the management of global function, fatigue and quality of life in amyotrophic lateral sclerosis: systematic review and meta-analyses.}, journal = {BMJ open}, volume = {14}, number = {8}, pages = {e076541}, pmid = {39182937}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Quality of Life ; *Physical Therapy Modalities ; *Fatigue/therapy/etiology ; Randomized Controlled Trials as Topic ; }, abstract = {OBJECTIVES: To critically evaluate the effectiveness of physical therapy interventions in improving global function, quality of life and fatigue in individuals with amyotrophic lateral sclerosis (ALS).

DESIGN: Systematic review and meta-analyses.

DATA SOURCES: MEDLINE, EMBASE, Cochrane Library (CENTRAL) and Physiotherapy Evidence Database (PEDro) were searched through 31 January 2023.

ELIGIBILITY CRITERIA: We included randomised clinical trials (RCTs) that compared physical therapy interventions that act on global function, fatigue and quality of life in individuals with ALS with any other non-physiotherapeutic methods and techniques, placebo or non-intervention. The primary outcome measure was the evaluation of global function. Secondary outcomes were quality of life, fatigue and adverse events.

DATA EXTRACTION AND SYNTHESIS: Two independent authors used a researcher-developed extraction form and the Rayyan software to search, screen and code included studies. The risk of bias was assessed using the PEDro scale. Meta-analyses were conducted employing random effects. Outcomes were succinctly presented in Grading of Recommendations, Assessment, Development and Evaluation evidence profiles.

RESULTS: Our searches identified 39 415 references. After study selection, three studies were included in the review. Such studies involved 62 participants with a mean age of 54.6 years. In the evaluated trials, 40 were male, while 22 participants were female. Regarding the type of onset of the disease, 58 participants had spinal onset of ALS, and four had bulbar.

CONCLUSIONS: Physical therapy intervention may improve the global function of individuals with ALS in the short term; however, clinically, it was inconclusive. In terms of quality of life and fatigue, physical therapy intervention is not more effective than control in the short term. Adverse events are not increased by physical therapy intervention in the short term. Due to significant methodological flaws, small sample sizes, wide CIs and clinical interpretation, our confidence in the effect estimate is limited.

PROSPERO REGISTRATION NUMBER: CRD42021251350.}, } @article {pmid39182589, year = {2024}, author = {Pupillo, E and Bianchi, E and Bonetto, V and Pasetto, L and Bendotti, C and Paganoni, S and Mandrioli, J and Mazzini, L and , }, title = {Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis.}, journal = {Brain, behavior, and immunity}, volume = {122}, number = {}, pages = {456-462}, doi = {10.1016/j.bbi.2024.08.044}, pmid = {39182589}, issn = {1090-2139}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology ; Male ; Female ; Middle Aged ; Double-Blind Method ; Vital Capacity ; Aged ; *Disease Progression ; Biomarkers/blood ; Treatment Outcome ; Adult ; Neurofilament Proteins ; }, abstract = {BACKGROUND: Positive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS).

OBJECTIVE: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation.

STUDY DESIGN AND SETTINGS: A randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial's last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated.

RESULTS: Mean duration of follow-up was 2.8 years. Long-term median survival was six months longer in the RNS60 group (p = 0.0519). Baseline FVC, and rates of FVC decline during the first 4 weeks of trial participation, were balanced between the active and placebo treatment arms. After 6 months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7 years in slow FVC progressors; 1.6 years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: >4 years in low NfL - RNS60 group; 3.3 years in low NfL - placebo group; 1.9 years in high NfL - RNS60 group; 1.8 years in high NfL - placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7 years in low MCP-1 - RNS60 group; 2.3 years in low MCP-1 - placebo group; 2.8 years in high MCP-1 - RNS60 group; 2.6 years in high MCP-1 - placebo group) levels at baseline.

CONCLUSIONS AND RELEVANCE: In this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug's effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival.

TRIAL REGISTRATION: Study preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.}, } @article {pmid39182251, year = {2024}, author = {Peng, Y and Liu, G and Li, S and Li, Z and Song, J}, title = {A machine learning system for artificial ligaments with desired mechanical properties in ACL reconstruction applications.}, journal = {Journal of the mechanical behavior of biomedical materials}, volume = {159}, number = {}, pages = {106691}, doi = {10.1016/j.jmbbm.2024.106691}, pmid = {39182251}, issn = {1878-0180}, mesh = {*Machine Learning ; *Mechanical Phenomena ; *Anterior Cruciate Ligament Reconstruction/methods ; Materials Testing ; Humans ; Anterior Cruciate Ligament/surgery ; Neural Networks, Computer ; Biomechanical Phenomena ; Ligaments/surgery ; Artificial Organs ; Mechanical Tests ; }, abstract = {The anterior cruciate ligament is one of the important tissues to maintain the stability of the human knee joint, but it is difficult for this ligament to self-heal after injury. Consequently, transplantation of artificial ligaments (ALs) has gained widespread attention as an important alternative treatment method in recent years. However, accurately predicting the intricate mechanical properties of ALs remains a formidable challenge, particularly when employing theoretical frameworks such as braiding theory. This obstacle presents a significant impediment to achieving optimal AL design. Therefore, in this study, a high-precision machine learning model based on an artificial neural network was developed to rapidly and accurately predict the mechanical properties of ALs. The results showed that the proposed model achieved a reduction of 45.22% and 50.17% in the normalized root mean square error on the testing set when compared to traditional machine learning models (Random Forest and Support Vector Machine), demonstrating its higher accuracy. In addition, the design of ALs with desired mechanical properties was achieved by optimizing the braiding parameters, and its effectiveness was verified through experiments. The mechanical properties of the prepared ALs were able to fully meet the desired targets and were at least 2% higher. Finally, the influence weights of different braiding parameters on the mechanical properties of ALs were analyzed by feature importance.}, } @article {pmid39182178, year = {2024}, author = {Serizawa, S}, title = {Exploration of the Factors Impacting Sustained Clinical Care by Multidisciplinary Professionals for Amyotrophic Lateral Sclerosis.}, journal = {The Tokai journal of experimental and clinical medicine}, volume = {49}, number = {3}, pages = {110-116}, pmid = {39182178}, issn = {2185-2243}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Surveys and Questionnaires ; *Patient Care Team ; Japan ; Female ; Male ; Self-Assessment ; Motivation ; Health Personnel ; Middle Aged ; Adult ; Time Factors ; }, abstract = {OBJECTIVE: This study examined the experiences of multidisciplinary medical professionals in providing daily clinical care for patients with amyotrophic lateral sclerosis (ALS), with a focus placed on their persistence in sustaining clinical care for this patient group.

METHODS: A questionnaire survey was administered to multidisciplinary medical professionals involved in ALS care at three hospitals in western Kanagawa Prefecture, Japan. The questionnaire results were used to examine the relationships between years of medical experience, years of ALS care experience, self-evaluation, and motivation to continue providing clinical care to patients with ALS.

RESULTS: Of the 269 questionnaires distributed and 164 collected by the multidisciplinary medical professionals, 143 (53%) were deemed valid. Analysis revealed an association between "years of medical experience" with both "self-assessment of clinical care for ALS patients practice experience" and "commitment to continue clinical care for ALS patients," as well as between "years of ALS medical experience" and "self-assessment of clinical care for ALS patients."

CONCLUSION: Medical professionals with more than ten years of medical experience expressed their commitment to continue providing medical care in a comprehensive self-assessment of both the positive and negative aspects of their practice. Negative evaluations can be used to identify and improve ALS medical practices.}, } @article {pmid39182146, year = {2024}, author = {Kill, C and Manegold, RK and Fistera, D and Risse, J}, title = {Airway management and ventilation techniques in resuscitation during advanced life support: an update.}, journal = {Journal of anesthesia, analgesia and critical care}, volume = {4}, number = {1}, pages = {58}, pmid = {39182146}, issn = {2731-3786}, abstract = {For many years, ventilation has been an essential part of advanced life support (ALS) in cardiopulmonary resuscitation (CPR). Nevertheless, there is little evidence about the best method of ventilation during resuscitation for both out-of-hospital cardiac arrest (OHCA) and inhospital cardiac arrest (IHCA) patients. Effective ventilation is one of the two main keys to successful resuscitation. In this context, the question always arises as to which airway management, along with which ventilation mode, constitutes the best strategy. Conventional ventilation modes are not designed for cardiac arrest and show important limitations that must be considered when used in CPR. Manual ventilation without the use of an automated transport ventilator (ATV) could be shown to be uncontrolled in applied volumes and pressures and should be avoided. Mechanical ventilation with an ATV is therefore superior to manual ventilation, but both volume- and pressure-controlled ventilation modes are significantly influenced by chest compressions. With the newly designed chest compression synchronized ventilation (CCSV), a special ventilation mode for resuscitation is available. Further research should be conducted to obtain more evidence of the effect of ventilation during CPR on outcomes following OHCA and not only about how to secure the airway for ventilation during CPR.}, } @article {pmid39181624, year = {2024}, author = {Mousele, C and Holden, D and Gnanapavan, S}, title = {Neurofilaments in neurologic disease.}, journal = {Advances in clinical chemistry}, volume = {123}, number = {}, pages = {65-128}, doi = {10.1016/bs.acc.2024.06.010}, pmid = {39181624}, issn = {2162-9471}, mesh = {Humans ; *Nervous System Diseases/pathology/metabolism/diagnosis ; *Biomarkers ; Neurofilament Proteins/cerebrospinal fluid/metabolism ; Intermediate Filaments/metabolism ; Animals ; }, abstract = {Neurofilaments (NFs), major cytoskeletal constituents of neurons, have emerged as universal biomarkers of neuronal injury. Neuroaxonal damage underlies permanent disability in various neurological conditions. It is crucial to accurately quantify and longitudinally monitor this damage to evaluate disease progression, evaluate treatment effectiveness, contribute to novel treatment development, and offer prognostic insights. Neurofilaments show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. New assays with high sensitivity allow reliable measurement of neurofilaments in body fluids and open avenues to investigate their role in neurological disorders. This book chapter will delve into the evolving landscape of neurofilaments, starting with their structure and cellular functions within neurons. It will then provide a comprehensive overview of their broad clinical value as biomarkers in diseases affecting the central or peripheral nervous system.}, } @article {pmid39181183, year = {2024}, author = {Ko, YH and Lokareddy, RK and Doll, SG and Yeggoni, DP and Girdhar, A and Mawn, I and Klim, JR and Rizvi, NF and Meyers, R and Gillilan, RE and Guo, L and Cingolani, G}, title = {Single Acetylation-mimetic Mutation in TDP-43 Nuclear Localization Signal Disrupts Importin α1/β Signaling.}, journal = {Journal of molecular biology}, volume = {436}, number = {20}, pages = {168751}, pmid = {39181183}, issn = {1089-8638}, support = {P30 GM124166/GM/NIGMS NIH HHS/United States ; RF1 NS121143/NS/NINDS NIH HHS/United States ; R21 NS128396/NS/NINDS NIH HHS/United States ; S10 OD017987/OD/NIH HHS/United States ; R01 NS121143/NS/NINDS NIH HHS/United States ; R35 GM140733/GM/NIGMS NIH HHS/United States ; S10 OD023479/OD/NIH HHS/United States ; R35 GM138109/GM/NIGMS NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; }, mesh = {*Nuclear Localization Signals/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; *alpha Karyopherins/metabolism/genetics ; *beta Karyopherins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Acetylation ; *Signal Transduction ; Mutation ; Protein Processing, Post-Translational ; Active Transport, Cell Nucleus ; Protein Binding ; Cell Nucleus/metabolism ; }, abstract = {Cytoplasmic aggregation of the TAR-DNA binding protein of 43 kDa (TDP-43) is the hallmark of sporadic amyotrophic lateral sclerosis (ALS). Most ALS patients with TDP-43 aggregates in neurons and glia do not have mutations in the TDP-43 gene but contain aberrantly post-translationally modified TDP-43. Here, we found that a single acetylation-mimetic mutation (K82Q) near the TDP-43 minor Nuclear Localization Signal (NLS) box, which mimics a post-translational modification identified in an ALS patient, can lead to TDP-43 mislocalization to the cytoplasm and irreversible aggregation. We demonstrate that the acetylation mimetic disrupts binding to importins, halting nuclear import and preventing importin α1/β anti-aggregation activity. We propose that perturbations near the NLS are an additional mechanism by which a cellular insult other than a genetically inherited mutation leads to TDP-43 aggregation and loss of function. Our findings are relevant to deciphering the molecular etiology of sporadic ALS.}, } @article {pmid39181135, year = {2024}, author = {Wu, R and Ye, Y and Dong, D and Zhang, Z and Wang, S and Li, Y and Wright, N and Redding-Ochoa, J and Chang, K and Xu, S and Tu, X and Zhu, C and Ostrow, LW and Roca, X and Troncoso, JC and Wu, B and Sun, S}, title = {Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS.}, journal = {Neuron}, volume = {112}, number = {20}, pages = {3434-3451.e11}, pmid = {39181135}, issn = {1097-4199}, support = {P30 AG066507/AG/NIA NIH HHS/United States ; R01 NS107347/NS/NINDS NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; R01 AG078948/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Mice ; Animals ; *RNA Splicing/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; DNA Repeat Expansion/genetics ; Neurons/metabolism ; Male ; Female ; }, abstract = {Expansion of an intronic (GGGGCC)n repeat within the C9ORF72 gene is the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (C9-FTD/ALS), characterized with aberrant repeat RNA foci and noncanonical translation-produced dipeptide repeat (DPR) protein inclusions. Here, we elucidate that the (GGGGCC)n repeat RNA co-localizes with nuclear speckles and alters their phase separation properties and granule dynamics. Moreover, the essential nuclear speckle scaffold protein SRRM2 is sequestered into the poly-GR cytoplasmic inclusions in the C9-FTD/ALS mouse model and patient postmortem tissues, exacerbating the nuclear speckle dysfunction. Impaired nuclear speckle integrity induces global exon skipping and intron retention in human iPSC-derived neurons and causes neuronal toxicity. Similar alternative splicing changes can be found in C9-FTD/ALS patient postmortem tissues. This work identified novel molecular mechanisms of global RNA splicing defects caused by impaired nuclear speckle function in C9-FTD/ALS and revealed novel potential biomarkers or therapeutic targets.}, } @article {pmid39180957, year = {2024}, author = {Harkins, AL and Ambegaokar, PP and Keeler, AM}, title = {Immune responses to central nervous system directed adeno-associated virus gene therapy: Does direct CNS delivery make a difference?.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {4}, pages = {e00435}, pmid = {39180957}, issn = {1878-7479}, mesh = {Humans ; *Dependovirus/genetics/immunology ; *Genetic Therapy/methods ; *Genetic Vectors/immunology/administration & dosage ; Animals ; Central Nervous System/immunology ; Gene Transfer Techniques ; Central Nervous System Diseases/therapy/immunology ; }, abstract = {Adeno-associated virus (AAV) mediated gene therapy is a leading gene delivery platform with potential to transform the landscape of treatment for neurological disorders. While AAV is deemed non-immunogenic compared to other viral vectors, adverse immune reactions have been observed in the clinic, raising concerns. As the central nervous system (CNS) has a tightly regulated immune system, characterized by a degree of tolerance, it has been considered a unique target for AAV gene therapy. AAV vectors have shown promising results for the treatment of several CNS disorders including Spinal Muscular Atrophy, Giant Axonal Neuropathy, Amyotrophic Lateral Sclerosis, Tay Sachs Disease, Parkinson's Disease, and others, demonstrating safety and success. The Food and Drug Administration (FDA) approval of Zolgensma and European Medicines Agency (EMA) approval of Upstaza, for Spinal Muscular Atrophy (SMA) and Aromatic l-amino acid decarboxylase deficiency (AADC) respectively, represent this success, all while highlighting significant differences in immune responses to AAV, particularly with regards to therapeutic administration route. AAV therapies like Upstaza that are injected directly into the immune-specialized brain have been characterized by mild immune response profiles and minor adverse events, whereas therapies like Zolgensma that are injected systemically demonstrate more robust immune stimulation and off-target toxicities. Despite these contrasting parallels, these therapeutics and others in the clinic have demonstrated clinical benefit for patients, warranting further exploration of immune responses to CNS-directed AAV clinical trials. Thus, in this review, we discuss effects of different routes of AAV administration on eliciting local and peripheral immune responses specifically observed in CNS-targeted trials.}, } @article {pmid39180748, year = {2024}, author = {Liu, Z and Zhang, H and Lu, K and Chen, L and Zhang, Y and Xu, Z and Zhou, H and Sun, J and Xu, M and Ouyang, Q and Thompson, GJ and Yang, Y and Su, N and Cai, X and Cao, L and Zhao, Y and Jiang, L and Zheng, Y and Zhang, X}, title = {Low-intensity pulsed ultrasound modulates disease progression in the SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {Cell reports}, volume = {43}, number = {9}, pages = {114660}, doi = {10.1016/j.celrep.2024.114660}, pmid = {39180748}, issn = {2211-1247}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/therapy/metabolism ; *Disease Models, Animal ; Mice ; *Disease Progression ; *Ultrasonic Waves ; *Mice, Transgenic ; *Motor Cortex/pathology/metabolism ; TRPV Cation Channels/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Cerebrovascular Circulation ; Ultrasonic Therapy/methods ; Mice, Inbred C57BL ; Male ; Endothelial Cells/metabolism ; Motor Neurons/pathology/metabolism ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord, and there are no effective drug treatments. Low-intensity pulsed ultrasound (LIPUS) has garnered attention as a promising noninvasive neuromodulation method. In this study, we investigate its effects on the motor cortex and underlying mechanisms using the SOD1[G93A] mouse model of ALS. Our results show that LIPUS treatment delays disease onset and prolongs lifespan in ALS mice. LIPUS significantly increases cerebral blood flow in the motor cortex by preserving vascular endothelial cell integrity and increasing microvascular density, which may be mediated via the ion channel TRPV4. RNA sequencing analysis reveals that LIPUS substantially reduces the expression of genes associated with neuroinflammation. These findings suggest that LIPUS applied to the motor cortex may represent a potentially effective therapeutic tool for the treatment of ALS.}, } @article {pmid39180568, year = {2024}, author = {Yang, J and Tang, C}, title = {Causal relationship between imaging-derived phenotypes and neurodegenerative diseases: a Mendelian randomization study.}, journal = {Mammalian genome : official journal of the International Mammalian Genome Society}, volume = {35}, number = {4}, pages = {711-723}, pmid = {39180568}, issn = {1432-1777}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics/diagnostic imaging ; *Phenotype ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging ; Alzheimer Disease/genetics/diagnostic imaging ; Frontotemporal Dementia/genetics/diagnostic imaging/pathology ; Parkinson Disease/genetics/diagnostic imaging ; Brain/diagnostic imaging/pathology/metabolism ; Multiple Sclerosis/genetics/diagnostic imaging ; Neuroimaging/methods ; }, abstract = {Neurodegenerative diseases are incurable conditions that lead to gradual and progressive deterioration of brain function in patients. With the aging population, the prevalence of these diseases is expected to increase, posing a significant economic burden on society. Imaging techniques play a crucial role in the diagnosis and monitoring of neurodegenerative diseases. This study utilized a two-sample Mendelian randomization (MR) analysis to assess the causal relationship between different imaging-derived phenotypes (IDP) in the brain and neurodegenerative diseases. Multiple MR methods were employed to minimize bias and obtain reliable estimates of the potential causal relationship between the variable exposures of interest and the outcomes. The study found potential causal relationships between different IDPs and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and frontotemporal dementia (FTD). Specifically, the study identified potential causal relationships between 2 different types of IDPs and AD, 8 different types of IDPs and PD, 11 different types of imaging-derived phenotypes and ALS, 1 type of IDP and MS, and 1 type of IDP and FTD. This study provides new insights for the prevention, diagnosis, and treatment of neurodegenerative diseases, offering important clues for understanding the pathogenesis of these diseases and developing relevant intervention strategies.}, } @article {pmid39180054, year = {2024}, author = {Spittel, S and Meyer, T and Weyen, U and Grehl, T and Weydt, P and Steinbach, R and Petri, S and Baum, P and Metelmann, M and Sperfeld, AD and Kettemann, D and Norden, J and Rödiger, A and Ilse, B and Grosskreutz, J and Hildebrandt, B and Walter, B and Münch, C and Maier, A}, title = {User expectations and experiences of an assistive robotic arm in amyotrophic lateral sclerosis: a multicenter observational study.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {42}, pmid = {39180054}, issn = {2524-3489}, abstract = {OBJECTIVE: Robotic arms are innovative assistive devices for ALS patients with progressive motor deficits of arms and hands. The objective was to explore the patients´ expectations towards a robotic arm system and to assess the actual experiences after the provision of the device.

METHODS: A prospective observational study was conducted at 9 ALS centers in Germany. ALS-related functional deficits were assessed using the ALS-Functional Rating Scale-revised (ALSFRS-R). Motor deficit of the upper limbs was determined using a subscore of three arm-related items of the ALSFRS-R (items 4-6; range 0-12 points). User expectations before provision (expectation group, n = 85) and user experiences after provision (experience group, n = 14) with the device (JACO Assistive Robotic Device, Kinova, Boisbriand, QC, Canada) were assessed.

RESULTS: In the total cohort, mean ALSFRS-R subscore for arm function was 1.7 (SD: 2.0, 0-9) demonstrating a severe functional deficit of the upper limbs. In the expectation group (n = 85), the following use cases of the robotic arm have been prioritized: handling objects (89%), close-body movements (88%), pressing buttons (87%), serving drinks (86%), and opening cabinets and doors (85%). In the experience group (n = 14), handling objects (79%), serving drinks (79%), near-body movements (71%), pushing buttons (71%), serving food (64%), and opening doors (64%) were the most frequent used cases. Most patients used the device daily (71.4%, n = 10), and 28.6% (n = 4) several times a week. All patients of the experience group found the device helpful, felt safe while using the device, and were satisfied with its reliability. NPS of the assistive robotic arm revealed 64% "promoters" (strong recommendation), 29% "indifferents" (uncertain recommendation) and 7% "detractors" (no recommendation). Total NPS was + 57 demonstrating strong patient satisfaction.

CONCLUSIONS: Initiation of procurement with a robotic assistive arm was confined to patients with severe functional deficit of the upper limbs. User experience underlined the wide spectrum of use cases of assistive robotic arms in ALS. The positive user experience together with high satisfaction underscore that robotic arm systems serve as a valuable treatment option in ALS patients with severe motor deficits of the arms.}, } @article {pmid39179240, year = {2025}, author = {Sisti, HM and Beebe, A and Gabrielsson, E and Bishop, M}, title = {Postmovement Beta Rebound in Real and Imagined Movement.}, journal = {Motor control}, volume = {29}, number = {1}, pages = {53-68}, doi = {10.1123/mc.2023-0033}, pmid = {39179240}, issn = {1087-1640}, mesh = {Humans ; *Imagination/physiology ; Male ; Female ; Adult ; *Beta Rhythm/physiology ; *Electroencephalography ; *Movement/physiology ; *Psychomotor Performance/physiology ; Young Adult ; Sensorimotor Cortex/physiology ; }, abstract = {Movement disorders, such as stroke and amyotrophic lateral sclerosis, result in loss of upper limb function and, hence, severe impairments of bimanual coordination. Although motor imagery is increasingly used to enhance neurorehabilitation, cognitive and neurophysiological parameters that inform effective strategies remain elusive. The aim of the present study is to elucidate the neural dynamics that underlie learning during real and imagined movement using both unimanual and bimanual coordination patterns. The post movement beta rebound (PMBR) has been implicated as a biomarker of motor control and therefore was the focus of this study. Healthy adults (n = 21) learned a visuomotor tracking task in a single session using either one or both hands while brainwaves were captured using electroencephalography. Postmovement beta rebound was evident in the sensorimotor cortex for both unimanual and bimanual conditions. Task-related power of the beta band demonstrated that actual unimanual movement requires greater contralateral activity compared with both actual bimanual movement and imagined movement of either condition. Notably, the PMBR was evident even in imagined movement, although to a lesser extent than real movement. Neurophysiological results support a functional role for beta band in movement. Results of these data may inform neurorehabilitation strategies for patients recovering from movement disorders of the upper limbs.}, } @article {pmid39178140, year = {2024}, author = {Briois, V and Itié, JP and Polian, A and King, A and Traore, AS and Marceau, E and Ersen, O and La Fontaine, C and Barthe, L and Beauvois, A and Roudenko, O and Belin, S}, title = {Hyperspectral full-field quick-EXAFS imaging at the ROCK beamline for monitoring micrometre-sized heterogeneity of functional materials under process conditions.}, journal = {Journal of synchrotron radiation}, volume = {31}, number = {Pt 5}, pages = {1084-1104}, pmid = {39178140}, issn = {1600-5775}, support = {ANR-10-EQPX-0045//Agence Nationale de la Recherche/ ; ANR-20-CE42-007//Agence Nationale de la Recherche/ ; ANR-07-Stock-E-0 PULSSE//Agence Nationale de la Recherche/ ; }, abstract = {Full-field transmission X-ray microscopy has been recently implemented at the hard X-ray ROCK-SOLEIL quick-EXAFS beamline, adding micrometre spatial resolution to the second time resolution characterizing the beamline. Benefiting from a beam size versatility due to the beamline focusing optics, full-field hyperspectral XANES imaging has been successfully used at the Fe K-edge for monitoring the pressure-induced spin transition of a 150 µm × 150 µm Fe(o-phen)2(NCS)2 single crystal and the charge of millimetre-sized LiFePO4 battery electrodes. Hyperspectral imaging over 2000 eV has been reported for the simultaneous monitoring of Fe and Cu speciation changes during activation of a FeCu bimetallic catalyst along a millimetre-sized catalyst bed. Strategies of data acquisition and post-data analysis using Jupyter notebooks and multivariate data analysis are presented, and the gain obtained using full-field hyperspectral quick-EXAFS imaging for studies of functional materials under process conditions in comparison with macroscopic information obtained by non-spatially resolved quick-EXAFS techniques is discussed.}, } @article {pmid39177232, year = {2024}, author = {Witzel, S and Huss, A and Nagel, G and Rosenbohm, A and Rothenbacher, D and Peter, RS and Bäzner, H and Börtlein, A and Dempewolf, S and Schabet, M and Hecht, M and Kohler, A and Opherk, C and Naegele, A and Sommer, N and Lindner, A and Alexudis, C and Bachhuber, F and Halbgebauer, S and Brenner, D and Ruf, W and Weiland, U and Mayer, B and Schuster, J and Dorst, J and Tumani, H and Ludolph, AC and , }, title = {Population-Based Evidence for the Use of Serum Neurofilaments as Individual Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {96}, number = {6}, pages = {1040-1057}, doi = {10.1002/ana.27054}, pmid = {39177232}, issn = {1531-8249}, support = {577631//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; *Biomarkers/blood ; *Neurofilament Proteins/blood ; Middle Aged ; Female ; Male ; Aged ; Prognosis ; Intermediate Filaments/metabolism ; Adult ; }, abstract = {OBJECTIVE: Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital-based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real-world ALS populations.

METHODS: We measured serum NfL and pNfH levels in all ALS patients (n = 790) and general population controls (n = 570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform-specific (ELLA™) reference data and Z-scores for controls, as well as reference data, disease-specific Z-scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS-related factors and non-ALS confounders.

RESULTS: Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population-based ALS Z-score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels.

INTERPRETATION: Population-based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real-world populations. ANN NEUROL 2024;96:1040-1057.}, } @article {pmid39177131, year = {2024}, author = {Sheremeta, CL and Yarlagadda, S and Smythe, ML and Noakes, PG}, title = {Prostaglandins in the Inflamed Central Nervous System: Potential Therapeutic Targets.}, journal = {Current drug targets}, volume = {25}, number = {13}, pages = {885-908}, pmid = {39177131}, issn = {1873-5592}, support = {Project grant,//Muscular Dystrophy Association/ ; }, mesh = {Humans ; *Prostaglandins/metabolism ; Animals ; *Central Nervous System/metabolism/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Signal Transduction/drug effects ; Multiple Sclerosis/drug therapy/metabolism ; Inflammation/drug therapy/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Central Nervous System Diseases/drug therapy/metabolism ; }, abstract = {The global burden of neurological disorders is evident, yet there remains limited efficacious therapeutics for their treatment. There is a growing recognition of the role of inflammation in diseases of the central nervous system (CNS); among the numerous inflammatory mediators involved, prostaglandins play a crucial role. Prostaglandins are small lipid mediators derived from arachidonic acid via multi-enzymatic pathways. The actions of prostaglandins are varied, with each prostaglandin having a specific role in maintaining homeostasis. In the CNS, prostaglandins can have neuroprotective or neurotoxic properties depending on their specific G-protein receptor. These G-protein receptors have varying subfamilies, tissue distribution, and signal transduction cascades. Further studies into the impact of prostaglandins in CNS-based diseases may contribute to the clarification of their actions, hopefully leading to the development of efficacious therapeutic strategies. This review focuses on the roles played by prostaglandins in neural degeneration, with a focus on Alzheimer's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis in both preclinical and clinical settings. We further discuss current prostaglandin-related agonists and antagonists concerning suggestions for their use as future therapeutics.}, } @article {pmid39176909, year = {2024}, author = {Tiffet, T and Pikaar, A and Trombert-Paviot, B and Jaulent, MC and Bousquet, C}, title = {Comparing a Large Language Model with Previous Deep Learning Models on Named Entity Recognition of Adverse Drug Events.}, journal = {Studies in health technology and informatics}, volume = {316}, number = {}, pages = {781-785}, doi = {10.3233/SHTI240528}, pmid = {39176909}, issn = {1879-8365}, mesh = {*Deep Learning ; *Drug-Related Side Effects and Adverse Reactions ; Humans ; Natural Language Processing ; Adverse Drug Reaction Reporting Systems ; }, abstract = {The ability to fine-tune pre-trained deep learning models to learn how to process a downstream task using a large training set allow to significantly improve performances of named entity recognition. Large language models are recent models based on the Transformers architecture that may be conditioned on a new task with in-context learning, by providing a series of instructions or prompt. These models only require few examples and such approach is defined as few shot learning. Our objective was to compare performances of named entity recognition of adverse drug events between state of the art deep learning models fine-tuned on Pubmed abstracts and a large language model using few-shot learning. Hussain et al's state of the art model (PMID: 34422092) significantly outperformed the ChatGPT-3.5 model (F1-Score: 97.6% vs 86.0%). Few-shot learning is a convenient way to perform named entity recognition when training examples are rare, but performances are still inferior to those of a deep learning model fine-tuned with several training examples. Perspectives are to evaluate few-shot prompting with GPT-4 and perform fine-tuning on GPT-3.5.}, } @article {pmid39176644, year = {2024}, author = {Turner, J and Impey, S and Gibbons, F and Bolger, A and Stephens, G and Hederman, L and Hamed, R and O'Meara, C and de la Varga, F and Kommala, J and Nicholson, M and Farrell, D and Galvin, M and Heverin, M and Mac Domhnaill, É and McFarlane, R and Meldrum, D and Murray, D and Hardiman, O}, title = {Data and Process Harmonisation of Multi-National, Multi-Site Research Data.}, journal = {Studies in health technology and informatics}, volume = {316}, number = {}, pages = {1411-1412}, doi = {10.3233/SHTI240675}, pmid = {39176644}, issn = {1879-8365}, mesh = {Humans ; *Data Collection ; Amyotrophic Lateral Sclerosis/therapy ; Biomedical Research ; }, abstract = {To achieve a single fully harmonised research data set suitable for analysis from data collected at multiple sites requires not only semantic integration of collection concepts and convergence onto single collection units, but harmonisation of data collection processes. We describe our experience of identifying harmonisation challenges in the Precision ALS project, with particular focus on process alignment challenges in a multi-site multi-national research data collection project.}, } @article {pmid39176177, year = {2024}, author = {Al Dera, H and AlQahtani, B}, title = {Molecular mechanisms and antisense oligonucleotide therapies of familial amyotrophic lateral sclerosis.}, journal = {Molecular therapy. Nucleic acids}, volume = {35}, number = {3}, pages = {102271}, pmid = {39176177}, issn = {2162-2531}, abstract = {Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, presents considerable challenges in both diagnosis and treatment. It is categorized into sporadic and familial amyotrophic lateral sclerosis (fALS); the latter accounts for approximately 10% of cases and is primarily inherited in an autosomal dominant manner. This review summarizes the molecular genetics of fALS, highlighting key mutations that contribute to its pathogenesis, such as mutations in SOD1, FUS, and C9orf72. Central to this discourse is exploring antisense oligonucleotides (ASOs) that target these genetic aberrations, providing a promising therapeutic strategy. This review provides a detailed overview of the molecular mechanisms underlying fALS and the potential therapeutic value of ASOs, offering new insights into treating neurodegenerative diseases.}, } @article {pmid39175128, year = {2024}, author = {Wu, A and Lee, D and Xiong, WC}, title = {VPS35 or retromer as a potential target for neurodegenerative disorders: barriers to progress.}, journal = {Expert opinion on therapeutic targets}, volume = {28}, number = {8}, pages = {701-712}, pmid = {39175128}, issn = {1744-7631}, support = {R01 AG045781/AG/NIA NIH HHS/United States ; RF1 AG045781/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology/drug therapy ; *Vesicular Transport Proteins/metabolism ; Animals ; *Molecular Targeted Therapy ; Protein Transport ; Parkinson Disease/physiopathology/drug therapy ; Mutation, Missense ; Drug Development ; }, abstract = {INTRODUCTION: Vacuolar Protein Sorting 35 (VPS35) is pivotal in the retromer complex, governing transmembrane protein trafficking within cells, and its dysfunction is implicated in neurodegenerative diseases. A missense mutation, Asp620Asn (D620N), specifically ties to familial late-onset Parkinson's, while reduced VPS35 levels are observed in Alzheimer's, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and tauopathies. VPS35's absence in certain neurons during development can initiate neurodegeneration, highlighting its necessity for neural health. Present therapeutic research mainly targets the clearance of harmful protein aggregates and symptom management. Innovative treatments focusing on VPS35 are under investigation, although fully understanding the mechanisms and optimal targeting strategies remain a challenge.

AREAS COVERED: This review offers a detailed account of VPS35's discovery, its role in neurodegenerative mechanisms - especially in Parkinson's and Alzheimer's - and its link to other disorders. It shines alight on recent insights into VPS35's function in development, disease, and as a therapeutic target.

EXPERT OPINION: VPS35 is integral to cellular function and disease association, making it a significant candidate for developing therapies. Progress in modulating VPS35's activity may lead to breakthrough treatments that not only slow disease progression but may also act as biomarkers for neurodegeneration risk, marking a step forward in managing these complex conditions.}, } @article {pmid39174972, year = {2024}, author = {Zhou, J and Li, F and Jia, B and Wu, Z and Huang, Z and He, M and Weng, H and So, KF and Qu, W and Fu, QL and Zhou, L}, title = {Intranasal delivery of small extracellular vesicles reduces the progress of amyotrophic lateral sclerosis and the overactivation of complement-coagulation cascade and NF-ĸB signaling in SOD1[G93A] mice.}, journal = {Journal of nanobiotechnology}, volume = {22}, number = {1}, pages = {503}, pmid = {39174972}, issn = {1477-3155}, support = {202310183302//2023 University Innovation and Entrepreneurship Training Plan/ ; 2022YFA1104900//National Key Research and Development Program of China/ ; 2021B1515120062//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023B03J1233, 20220600003//Guangzhou Key R&D Program/ ; }, mesh = {Animals ; Male ; Mice ; Administration, Intranasal ; *Amyotrophic Lateral Sclerosis/metabolism ; Blood Coagulation ; Disease Models, Animal ; *Extracellular Vesicles/metabolism ; Mesenchymal Stem Cells/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/metabolism ; *NF-kappa B/metabolism ; *Signal Transduction ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by progressive motoneuron degeneration, and effective clinical treatments are lacking. In this study, we evaluated whether intranasal delivery of mesenchymal stem cell-derived small extracellular vesicles (sEVs) is a strategy for ALS therapy using SOD1[G93A] mice. In vivo tracing showed that intranasally-delivered sEVs entered the central nervous system and were extensively taken up by spinal neurons and some microglia. SOD1[G93A] mice that intranasally received sEV administration showed significant improvements in motor performances and survival time. After sEV administration, pathological changes, including spinal motoneuron death and synaptic denervation, axon demyelination, neuromuscular junction degeneration and electrophysiological defects, and mitochondrial vacuolization were remarkably alleviated. sEV administration attenuated the elevation of proinflammatory cytokines and glial responses. Proteomics and transcriptomics analysis revealed upregulation of the complement and coagulation cascade and NF-ĸB signaling pathway in SOD1[G93A] mouse spinal cords, which was significantly inhibited by sEV administration. The changes were further confirmed by detecting C1q and NF-ĸB expression using Western blots. In conclusion, intranasal administration of sEVs effectively delays the progression of ALS by inhibiting neuroinflammation and overactivation of the complement and coagulation cascades and NF-ĸB signaling pathway and is a potential option for ALS therapy.}, } @article {pmid39174694, year = {2024}, author = {Layalle, S and Aimond, F and Brugioti, V and Guissart, C and Raoul, C and Soustelle, L}, title = {The ALS-associated KIF5A P986L variant is not pathogenic for Drosophila motoneurons.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {19540}, pmid = {39174694}, issn = {2045-2322}, mesh = {Animals ; *Kinesins/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Mutation ; Humans ; Drosophila Proteins/genetics/metabolism ; Drosophila ; Neuromuscular Junction/metabolism/pathology ; Drosophila melanogaster/genetics ; Synaptic Transmission/genetics ; Disease Models, Animal ; Axons/metabolism/pathology ; Larva/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by the death of motoneurons. Several mutations in the KIF5A gene have been identified in patients with ALS. Some mutations affect the splicing sites of exon 27 leading to its deletion (Δ27 mutation). KIF5A Δ27 is aggregation-prone and pathogenic for motoneurons due to a toxic gain of function. Another mutation found to be enriched in ALS patients is a proline/leucine substitution at position 986 (P986L mutation). Bioinformatic analyses strongly suggest that this variant is benign. Our study aims to conduct functional studies in Drosophila to classify the KIF5A P986L variant. When expressed in motoneurons, KIF5A P986L does not modify the morphology of larval NMJ or the synaptic transmission. In addition, KIF5A P986L is uniformly distributed in axons and does not disturb mitochondria distribution. Locomotion at larval and adult stages is not affected by KIF5A P986L. Finally, both KIF5A WT and P986L expression in adult motoneurons extend median lifespan compared to control flies. Altogether, our data show that the KIF5A P986L variant is not pathogenic for motoneurons and may represent a hypomorphic allele, although it is not causative for ALS.}, } @article {pmid39174305, year = {2025}, author = {Mohamed Yusoff, AA and Mohd Khair, SZN}, title = {Unraveling mitochondrial dysfunction: comprehensive perspectives on its impact on neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {36}, number = {1}, pages = {53-90}, pmid = {39174305}, issn = {2191-0200}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Mitochondria/metabolism ; Animals ; Mitochondrial Dynamics/physiology ; Mitochondrial Diseases/metabolism ; Mitophagy/physiology ; }, abstract = {Neurodegenerative diseases represent a significant challenge to modern medicine, with their complex etiology and progressive nature posing hurdles to effective treatment strategies. Among the various contributing factors, mitochondrial dysfunction has emerged as a pivotal player in the pathogenesis of several neurodegenerative disorders. This review paper provides a comprehensive overview of how mitochondrial impairment contributes to the development of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, driven by bioenergetic defects, biogenesis impairment, alterations in mitochondrial dynamics (such as fusion or fission), disruptions in calcium buffering, lipid metabolism dysregulation and mitophagy dysfunction. It also covers current therapeutic interventions targeting mitochondrial dysfunction in these diseases.}, } @article {pmid39174072, year = {2024}, author = {Yoon, R and Wong, JP and Chung-Lee, L and Akbarian, A and Abdulai, AF and Hou, R and Ho, M and Zinaic, R and Anoushka, A}, title = {Scoping review protocol: what is the state of evidence for the use of communication apps with immigrant seniors in long-term care and community settings?.}, journal = {BMJ open}, volume = {14}, number = {8}, pages = {e089939}, pmid = {39174072}, issn = {2044-6055}, mesh = {Humans ; *Emigrants and Immigrants ; *Long-Term Care ; *Mobile Applications ; Aged ; Research Design ; Communication Barriers ; Scoping Reviews As Topic ; }, abstract = {INTRODUCTION: First language care is critical for older immigrant adults with limited English proficiency, especially in long-term care settings where most residents require staff assistance and experience complex chronic conditions, resulting in multiple communication interactions where language poses a barrier. Although there are a myriad of cultural-language translation apps and devices available, there is a gap in both research and practice on the acceptability and feasibility of these digital resources within the context of long-term care and community settings for older immigrant adults, from a cultural relevance and digital health equity perspective. Our paper outlines a scoping review protocol to examine the state of the literature on the extent to which cultural-language translation apps are used in long-term care settings and community-based elder care. We will also examine the extent to which such apps bridge or further gaps in equitable, accessible and acceptable care for older immigrant adults with limited English language proficiency.

METHODS AND ANALYSIS: This scoping review protocol will employ an adapted five-stage framework outlined by Arksey and O'Malley guided by enhancements recommended by Levac et al and Colquhoun et al. Using the Joanna Briggs Institute's population, concept and context framework, we defined the scope of the scoping review by identifying the target population, concepts for investigation and the context within which the research is situated. We will conduct a search of the literature from 2005 to 2024 using five bibliographic databases from health sciences (Healthstar OVID, MEDLINE OVID and Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO), engineering (Engineering Village Elsevier) and a cross-disciplinary database (Web of Science Clarivate). The research team will adopt a critical, equity-focused approach for the scoping review by integrating Richardson et al's framework for Digital Health Equity into our analysis of the findings. This will ensure that health and social equity perspectives are integrated within our methodology and analytical lens. Our analysis will specifically examine selected studies for their engagement with health equity and their ability to address issues such as ageism, ableism and the digital divide within geriatric care.

ETHICS AND DISSEMINATION: Ethics approval is not required for this scoping review as it involves secondary analysis of published works and no primary data collection involving human subjects. Findings of the review will be shared with community partners and disseminated through publications, conferences and peer-reviewed publications.}, } @article {pmid39174002, year = {2024}, author = {Javaudin, F and Papin, M and Le Bastard, Q and Thibault, M and Boishardy, T and Brau, F and Laribi, S and Petrovic, T and Peluchon, T and Markarian, T and Volteau, C and Arnaudet, I and Pes, P and Le Conte, P}, title = {Early point-of-care echocardiography as a predictive factor for absence of return of spontaneous circulatory in out-of-hospital cardiac arrests: A multicentre observational study.}, journal = {Resuscitation}, volume = {203}, number = {}, pages = {110373}, doi = {10.1016/j.resuscitation.2024.110373}, pmid = {39174002}, issn = {1873-1570}, mesh = {Humans ; Male ; Female ; *Out-of-Hospital Cardiac Arrest/therapy ; Aged ; Prospective Studies ; Middle Aged ; *Echocardiography/methods ; *Cardiopulmonary Resuscitation/methods ; *Return of Spontaneous Circulation ; *Predictive Value of Tests ; Point-of-Care Systems ; Prognosis ; }, abstract = {INTRODUCTION: Early assessment of the prognosis of a patient in cardiac arrest during cardiopulmonary resuscitation is highly challenging. This study aims to evaluate the predictive outcome value of early point-of-care ultrasound (POCUS) in out-of-hospital settings.

METHODS: This observational, prospective, multicentre study's primary endpoint was the positive predictive value (PPV) of POCUS cardiac standstill within the first 12 min of advanced life support (ALS) initiation in determining the absence of return of spontaneous circulation (ROSC). A multivariate logistic regression model was constructed with adjustments for known predictive variables typically used in termination of resuscitation (TOR) rules.

RESULTS: A total of 293 patients were analysed, with a mean age of 66.6 ± 14.6 years, and a majority were men (75.8%). POCUS was performed on average 7.9 ± 2.6 min after ALS initiation. Among patients with cardiac standstill (72.4%), 16.0% achieved ROSC compared with 48.2% in those with visible cardiac motions. The PPV of early POCUS cardiac standstill for the absence of ROSC was 84.0%, 95% CI [78.3-88.6]. In multivariable analysis, only POCUS cardiac standstill (adjusted odds ratio [aOR] 3.89, 95% CI [1.86-8.17]) and end-tidal CO2 (ETCO2) value ≤37 mmHg (aOR 4.27, 95% CI [2.21-8.25]) were associated with the absence of ROSC.

CONCLUSION: Early POCUS cardiac standstill during CPR for out-of-hospital cardiac arrest was a reliable predictor of the absence of ROSC. However, its presence alone was not sufficient to determine the termination of resuscitation efforts.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03494153. Registered March 29, 2018.}, } @article {pmid39173710, year = {2025}, author = {Weber, MP and Strobel, RJ and Norman, AV and Kareddy, A and Young, A and Young, S and El Moheb, M and Noona, SWW and Wisniewski, AM and Quader, M and Mazzeffi, M and Yarboro, LT and Teman, NR}, title = {Cardiac Surgical Unit-Advanced Life Support-certified centers are associated with improved failure to rescue after cardiac arrest: A propensity score-matched analysis.}, journal = {The Journal of thoracic and cardiovascular surgery}, volume = {169}, number = {4}, pages = {1271-1281}, doi = {10.1016/j.jtcvs.2024.08.014}, pmid = {39173710}, issn = {1097-685X}, mesh = {Humans ; *Heart Arrest/mortality/therapy ; Female ; Male ; *Propensity Score ; Middle Aged ; Aged ; *Certification ; Retrospective Studies ; Advanced Cardiac Life Support/standards ; Failure to Rescue, Health Care/statistics & numerical data ; Patient Readmission/statistics & numerical data ; Cardiac Surgical Procedures/adverse effects/mortality ; Risk Factors ; Time Factors ; Risk Assessment ; }, abstract = {OBJECTIVE: The impact of Cardiac Surgical Unit-Advanced Life Support (CSU-ALS) training on failure to rescue after cardiac arrest (FTR-CA) is unknown. We hypothesized that institutional CSU-ALS certification would be associated with lower FTR-CA.

METHODS: Patients undergoing Society of Thoracic Surgeons index operations from 2020 to 2023 from a regional collaborative were analyzed. Each institution was surveyed regarding its status as a CSU-ALS-certified center. Patients stratified by CSU-ALS certification were 1:1 propensity score matched with subsequent multivariable model reviewing associations with FTR-CA.

RESULTS: A total of 12,209 patients were included in the study period across 15 institutions. Eight centers reported CSU-ALS certification. After propensity score matching, 2 patient cohorts were formed (n = 3557). Patients at CSU-ALS centers had greater rates of intensive care unit readmission (3.9% vs 2.3%, P < .01) and total operating room time (340 minutes vs 323 minutes, P < .01). Hospital readmission was less likely in the CSU-ALS centers (9.0% vs 10.1%, P < .01). There was no difference in the rate of postoperative cardiac arrest (1.8% vs 2.2%, P = .24) or operative mortality (2.5% vs 2.9%, P = .30). After risk adjustment, CSU-ALS centers (odds ratio, 0.30; 95% confidence interval, 0.12-0.72, P < .01) and greater-volume centers (odds ratio, 0.15; confidence interval, 0.03-0.74, P = .02) had reduced odds of FTR-CA.

CONCLUSIONS: Centers with CSU-ALS certification are associated with a lower risk-adjusted likelihood of FTR-CA. This highlights the importance of well-trained staff and treatment algorithms in the care of patients postcardiac surgery.}, } @article {pmid39172789, year = {2024}, author = {Ahmed, R and Liang, M and Hudson, RP and Rangadurai, AK and Huang, SK and Forman-Kay, JD and Kay, LE}, title = {Atomic resolution map of the solvent interactions driving SOD1 unfolding in CAPRIN1 condensates.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {35}, pages = {e2408554121}, pmid = {39172789}, issn = {1091-6490}, support = {FND-503573//Canadian Government | Canadian Institutes of Health Research (CIHR)/ ; 2015-04347//Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; FDN-148375//Canadian Government | Canadian Institutes of Health Research (CIHR)/ ; PJT-190060//Canadian Government | Canadian Institutes of Health Research (CIHR)/ ; }, mesh = {*Superoxide Dismutase-1/chemistry/metabolism/genetics ; Humans ; *Solvents/chemistry ; Protein Unfolding ; Protein Binding ; Protein Folding ; Models, Molecular ; Stress Granules/metabolism/chemistry ; RNA-Binding Proteins/metabolism/chemistry ; Protein Conformation ; Magnetic Resonance Spectroscopy ; }, abstract = {Biomolecules can be sequestered into membrane-less compartments, referred to as biomolecular condensates. Experimental and computational methods have helped define the physical-chemical properties of condensates. Less is known about how the high macromolecule concentrations in condensed phases contribute "solvent" interactions that can remodel the free-energy landscape of other condensate-resident proteins, altering thermally accessible conformations and, in turn, modulating function. Here, we use solution NMR spectroscopy to obtain atomic resolution insights into the interactions between the immature form of superoxide dismutase 1 (SOD1), which can mislocalize and aggregate in stress granules, and the RNA-binding protein CAPRIN1, a component of stress granules. NMR studies of CAPRIN1:SOD1 interactions, focused on both unfolded and folded SOD1 states in mixed phase and demixed CAPRIN1-based condensates, establish that CAPRIN1 shifts the SOD1 folding equilibrium toward the unfolded state through preferential interactions with the unfolded ensemble, with little change to the structure of the folded conformation. Key contacts between CAPRIN1 and the H80-H120 region of unfolded SOD1 are identified, as well as SOD1 interaction sites near both the arginine-rich and aromatic-rich regions of CAPRIN1. Unfolding of immature SOD1 in the CAPRIN1 condensed phase is shown to be coupled to aggregation, while a more stable zinc-bound, dimeric form of SOD1 is less susceptible to unfolding when solvated by CAPRIN1. Our work underscores the impact of the condensate solvent environment on the conformational states of resident proteins and supports the hypothesis that ALS mutations that decrease metal binding or dimerization function as drivers of aggregation in condensates.}, } @article {pmid39171600, year = {2025}, author = {Nogueira-Machado, JA and das Chagas Lima E Silva, F and Rocha-Silva, F and Gomes, N}, title = {Amyotrophic Lateral Sclerosis (ALS): An Overview of Genetic and Metabolic Signaling Mechanisms.}, journal = {CNS & neurological disorders drug targets}, volume = {24}, number = {2}, pages = {83-90}, pmid = {39171600}, issn = {1996-3181}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Signal Transduction ; *Mutation ; Animals ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rare, progressive, and incurable disease. Sporadic (sALS) accounts for ninety percent of ALS cases, while familial ALS (fALS) accounts for around ten percent. Reports have identified over 30 different forms of familial ALS. Multiple types of fALS exhibit comparable symptoms with mutations in different genes and possibly with different predominant metabolic signals. Clinical diagnosis takes into account patient history but not genetic mutations, misfolded proteins, or metabolic signaling. As research on genetics and metabolic pathways advances, it is expected that the intricate complexity of ALS will compound further. Clinicians discuss whether a gene's presence is a cause of the disease or just an association or consequence. They believe that a mutant gene alone is insufficient to diagnose ALS. ALS, often perceived as a single disease, appears to be a complex collection of diseases with similar symptoms. This review highlights gene mutations, metabolic pathways, and muscle-neuron interactions.}, } @article {pmid39170988, year = {2024}, author = {Baroni, LM and Funari, MP and So Taa Kum, A and Bestetti, AM and de Oliveira, LB and de Carvalho, MF and Franzini, TAP and de Moura, DTH and Bernardo, WM and de Moura, EGH}, title = {Endoscopic Versus Surgical Treatment for Ampullary Lesions: A Systematic Review With Meta-Analysis.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e65076}, pmid = {39170988}, issn = {2168-8184}, abstract = {Ampullary lesions (ALs) can be treated through either an endoscopic approach (EA) or a surgical approach (SA). However, it is important to note that EAs carry a significant risk of incomplete resection, while opting for surgical interventions can result in substantial morbidity. We performed a systematic review and meta-analysis for R0 resection, recurrence, adverse events in general, major adverse events, mortality, and length of hospital stay between SAs and EAs. Electronic databases were searched from inception to 2023. We identified nine independent studies. The risk difference was -0.32 (95% CI: -0.50, -0.15; p <0.001) for R0, 0.12 (95% CI: 0.06, 0.19; p < 0.001) for recurrence, -0.22 (95% CI: -0.43, 0.00; p 0.05) for overall adverse events, -0.11 (95% CI: -0.32, 0.10; p = 0.31) for major complications, -0.01 (95% CI: -0.02, 0.01; p = 0.43) for mortality, and -14.69 (95% CI: -19.91, -9.47; p < 0.001) for length of hospital stay. As expected, our data suggest a higher complete resection rate and lower recurrence from surgical interventions, but this is associated with an elevated risk of adverse events and a longer hospital stay.}, } @article {pmid39170265, year = {2024}, author = {Pain, O and Jones, A and Al Khleifat, A and Agarwal, D and Hramyka, D and Karoui, H and Kubica, J and Llewellyn, DJ and Ranson, JM and Yao, Z and Iacoangeli, A and Al-Chalabi, A}, title = {Harnessing transcriptomic signals for amyotrophic lateral sclerosis to identify novel drugs and enhance risk prediction.}, journal = {Heliyon}, volume = {10}, number = {15}, pages = {e35342}, pmid = {39170265}, issn = {2405-8440}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. This study integrates common genetic association results from the latest ALS genome-wide association study (GWAS) summary statistics with functional genomic annotations with the aim of providing mechanistic insights into ALS risk loci, inferring drug repurposing opportunities, and enhancing prediction of ALS risk and clinical characteristics.

METHODS: Genes associated with ALS were identified using GWAS summary statistic methodology including SuSiE SNP-based fine-mapping, and transcriptome- and proteome-wide association study (TWAS/PWAS) analyses. Using several approaches, gene associations were integrated with the DrugTargetor drug-gene interaction database to identify drugs that could be repurposed for the treatment of ALS. Furthermore, ALS gene associations from TWAS were combined with observed blood expression in two external ALS case-control datasets to calculate polytranscriptomic scores and evaluate their utility for prediction of ALS risk and clinical characteristics, including site of onset, age at onset, and survival.

RESULTS: SNP-based fine-mapping, TWAS and PWAS identified 118 genes associated with ALS, with TWAS and PWAS providing novel mechanistic insights. Drug repurposing analyses identified six drugs significantly enriched for interactions with ALS associated genes, though directionality could not be determined. Additionally, drug class enrichment analysis showed gene signatures linked to calcium channel blockers may reduce ALS risk, whereas antiepileptic drugs may increase ALS risk. Across the two observed expression target samples, ALS polytranscriptomic scores significantly predicted ALS risk (R [2] = 5.1 %; p-value = 3.2 × 10[-27]) and clinical characteristics.

CONCLUSIONS: Functionally-informed analyses of ALS GWAS summary statistics identified novel mechanistic insights into ALS aetiology, highlighted several therapeutic research avenues, and enabled statistically significant prediction of ALS risk.}, } @article {pmid39170125, year = {2024}, author = {Wenzhi, Y and Xiangyi, L and Dongsheng, F}, title = {The prion-like effect and prion-like protein targeting strategy in amyotrophic lateral sclerosis.}, journal = {Heliyon}, volume = {10}, number = {15}, pages = {e34963}, pmid = {39170125}, issn = {2405-8440}, abstract = {Pathological proteins in amyotrophic lateral sclerosis (ALS), such as superoxide dismutase 1, TAR DNA-binding protein 43, and fused in sarcoma, exhibit a prion-like pattern. All these proteins have a low-complexity domain and seeding activity in cells. In this review, we summarize the studies on the prion-like effect of these proteins and list six prion-like protein targeting strategies that we believe have potential for ALS therapy, including antisense oligonucleotides, antibody-based technology, peptide, protein chaperone, autophagy enhancement, and heteromultivalent compounds. Considering the pathological complexity and heterogeneity of ALS, we believe that the final solution to ALS therapy is most likely to be an individualized cocktail therapy, including clearance of toxicity, blockage of pathological progress, and protection of neurons.}, } @article {pmid39170062, year = {2024}, author = {Wang, H and Yao, G and He, K and Wang, Z and Cheng, CK}, title = {ACL reconstruction combined with anterolateral structures reconstruction for treating ACL rupture and knee injuries: a finite element analysis.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {12}, number = {}, pages = {1437684}, pmid = {39170062}, issn = {2296-4185}, abstract = {Introduction: The biomechanical indication for combining anterolateral structures reconstruction (ASLR) with ACL reconstruction (ACLR) to reduce pivot shift in the knee remains unclear. This study aims to investigate knee functionality after ACL rupture with different combinations of injuries, and to compare the effectiveness of ALSR with ACLR for treating these injuries. Methods: A validated finite element model of a human cadaveric knee was used to simulate pivot shift tests on the joint in different states, including 1) an intact knee; 2) after isolated ACL rupture; 3) after ACL rupture combined with different knee injuries or defect, including a posterior tibial slope (PTS) of 20°, an injury to the anterolateral structures (ALS) and an injury to the posterior meniscotibial ligament of the lateral meniscus (LP); 4) after treating the different injuries using isolated ACLR; v. after treating the different injuries using ACLR with ALSR. The knee kinematics, maximum von Mises stress (Max.S) on the tibial articular cartilage (TC) and force in the ACL graft were compared among the different simulation groups. Results and discussion: Comparing with isolated ACL rupture, combined injury to the ALS caused the largest knee laxity, when a combined PTS of 20° induced the largest Max.S on the TC. The joint stability and Max.S on the TC in the knee with an isolated ACL rupture or a combined rupture of ACL and LP were restored to the intact level after being treated with isolated ACLR. The knee biomechanics after a combined rupture of ACL and ALS were restored to the intact level only when being treated with a combination of ACLR and ALSR using a large graft diameter (6 mm) for ALSR. However, for the knee after ACL rupture combined with a PTS of 20°, the ATT and Max.S on the TC were still greater than the intact knee even after being treated with a combination of ACLR and ALSR. The finite element analysis showed that ACLR should include ALSR when treating ACL ruptures accompanied by ALS rupture. However, pivot shift in knees with a PTS of 20° was not eliminated even after a combined ACLR and ALSR.}, } @article {pmid39168583, year = {2024}, author = {Memudu, AE and Olukade, BA and Adebayo, OS and Raza, ML}, title = {Coffee and amyotrophic lateral sclerosis (ALS).}, journal = {Progress in brain research}, volume = {289}, number = {}, pages = {81-105}, doi = {10.1016/bs.pbr.2024.06.003}, pmid = {39168583}, issn = {1875-7855}, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; Humans ; *Coffee ; Animals ; Neuroprotective Agents/pharmacology ; Oxidative Stress/physiology/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive loss of motor neurons. The effective treatments for ALS remain elusive, necessitating exploration into novel preventive strategies. ALS pathogenesis is triggered by oxidative stress which results in neuroinflammation, exicitotoxicity and neuronal cell death. Nutritional mechanism for halting progression of neurodegeneration is through dietary compounds with antioxidants, anti-inflammatory or neuromodulating activity. Coffee is a widely consumed beverage made up of polyphenols, caffeine and other compounds with possible antioxidants and neuro-protective roles. It is important to say that various epidemiological studies have documented association between coffee intake and ALS. This chapter is aimed to present a comprehensive review of existing literature on coffee consumption and ALS, involving epidemiological studies, preclinical research, and its mechanism of actions in animal model of ALS. It highlights key findings regarding the potential neuroprotective properties of coffee constituents such as caffeine, polyphenols, and other bioactive compounds. Furthermore, it discusses possible pathways through which coffee may modulate ALS pathogenesis, including suppressing oxidative stress and neuroinflammation while boosting adenosine function via the adenosine receptor two on the motor neuron cells membrane in the spinal cord to enhance motor function via the corticospinal tract. Overall, this chapter underscores the significance of further research to unravel the specific mechanisms by which coffee exerts its neuroprotective effects in ALS, with the ultimate goal of identifying dietary strategies for ALS prevention and management.}, } @article {pmid39168577, year = {2024}, author = {Rai, SP and Ansari, AH and Singh, D and Singh, S}, title = {Coffee, antioxidants, and brain inflammation.}, journal = {Progress in brain research}, volume = {289}, number = {}, pages = {123-150}, doi = {10.1016/bs.pbr.2024.06.005}, pmid = {39168577}, issn = {1875-7855}, mesh = {*Coffee/chemistry ; Humans ; *Antioxidants/pharmacology ; Animals ; Neurodegenerative Diseases ; Encephalitis ; Caffeine/pharmacology/administration & dosage ; Neuroinflammatory Diseases ; }, abstract = {Coffee is the most popular beverage in the world and, aside from tea and water, the most often consumed caffeine-containing beverage. Because of its high caffeine concentration, it is typically classified as a stimulant. There are other bioactive ingredients in coffee besides caffeine. The coffee beverage is a blend of several bioactive substances, including diterpenes (cafestol and kahweol), alkaloids (caffeine and trigonelline), and polyphenols (particularly chlorogenic acids in green beans and caffeic acid in roasted coffee beans). Caffeine has also been linked to additional beneficial benefits such as antioxidant and anti-inflammatory properties, which change cellular redox and inflammatory status in a dose-dependent manner. Pyrocatechol, a constituent of roasted coffee that is created when chlorogenic acid is thermally broken down, has anti-inflammatory properties as well. It is postulated that coffee consumption reduces neuroinflammation, which is intimately linked to the onset of neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). This review provides an overview of the most recent studies regarding coffee's possible benefits in preventing brain inflammation and neurodegenerative disorders.}, } @article {pmid39168358, year = {2024}, author = {Ueno, Y and Morishima, Y and Hata, T and Shindo, A and Murata, H and Saito, T and Nakamura, Y and Shindo, K}, title = {Current progress in microRNA profiling of circulating extracellular vesicles in amyotrophic lateral sclerosis: A systematic review.}, journal = {Neurobiology of disease}, volume = {200}, number = {}, pages = {106639}, doi = {10.1016/j.nbd.2024.106639}, pmid = {39168358}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/diagnosis ; Biomarkers/blood ; *Extracellular Vesicles/metabolism/genetics ; *MicroRNAs/blood/genetics ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons, leading to death resulting mainly from respiratory failure, for which there is currently no curative treatment. Underlying pathological mechanisms for the development of ALS are diverse and have yet to be elucidated. Non-invasive testing to isolate circulating molecules including microRNA to diagnose ALS has been reported, but circulating extracellular vesicle (EV)-derived microRNA has not been fully studied in the ALS population.

METHODS: A systematic literature review to explore studies investigating the profile of microRNAs in EVs from blood samples of ALS patients was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline.

RESULTS: Eleven studies including a total of 263 patients with ALS were included in the present systematic review. The majority of patients had sporadic ALS, though a small number of patients with ALS having genetic mutations were included. Seven studies used plasma-derived EVs, and the remaining four studies used serum-derived EVs. RNA sequencing or microarrays were used in eight studies, and quantitative PCR was used in eight studies, of which five studies used RNA sequencing or microarrays for screening and quantitative PCR for validation. There was overlap of miR-199a-3p and miR-199a-5p in three studies.

CONCLUSIONS: Overall, the systematic review addressed the current advances in the profiling of microRNAs in circulating EVs of ALS patients. Blood samples, isolation of EVs, and microRNA analysis were diverse. Although there was an overlap of miR-199a-3p and miR-199a-5p, collection of further evidence is warranted.}, } @article {pmid39167487, year = {2024}, author = {Alirzayeva, H and Loureiro, R and Koyuncu, S and Hommen, F and Nabawi, Y and Zhang, WH and Dao, TTP and Wehrmann, M and Lee, HJ and Vilchez, D}, title = {ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes.}, journal = {Cell reports}, volume = {43}, number = {8}, pages = {114626}, doi = {10.1016/j.celrep.2024.114626}, pmid = {39167487}, issn = {2211-1247}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Histones/metabolism ; *RNA-Binding Protein FUS/metabolism/genetics ; *Caenorhabditis elegans/metabolism/genetics ; Animals ; *Mutation/genetics ; *Poly (ADP-Ribose) Polymerase-1/metabolism/genetics ; Motor Neurons/metabolism/pathology ; Poly ADP Ribosylation ; Induced Pluripotent Stem Cells/metabolism ; Protein Binding ; }, abstract = {The majority of severe early-onset and juvenile cases of amyotrophic lateral sclerosis (ALS) are caused by mutations in the FUS gene, resulting in rapid disease progression. Mutant FUS accumulates within stress granules (SGs), thereby affecting the dynamics of these ribonucleoprotein complexes. Here, we define the interactome of the severe mutant FUS[P525L] variant in human induced pluripotent stem cell (iPSC)-derived motor neurons. We find increased interaction of FUS[P525L] with the PARP1 enzyme, promoting poly-ADP-ribosylation (PARylation) and binding of FUS to histone H1.2. Inhibiting PARylation or reducing H1.2 levels alleviates mutant FUS aggregation, SG alterations, and apoptosis in human motor neurons. Conversely, elevated H1.2 levels exacerbate FUS-ALS phenotypes, driven by the internally disordered terminal domains of H1.2. In C. elegans models, knockdown of H1.2 and PARP1 orthologs also decreases FUS[P525L] aggregation and neurodegeneration, whereas H1.2 overexpression worsens ALS-related changes. Our findings indicate a link between PARylation, H1.2, and FUS with potential therapeutic implications.}, } @article {pmid39167140, year = {2024}, author = {Yu, L and Wu, N and Choi, O and Nguyen, KD}, title = {Inhibition of glycolytic reprogramming suppresses innate immune-mediated inflammation in experimental amyotrophic lateral sclerosis.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {73}, number = {11}, pages = {1847-1857}, pmid = {39167140}, issn = {1420-908X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/immunology/drug therapy ; *Immunity, Innate/drug effects ; *Glycolysis/drug effects ; *Spinal Cord/immunology/pathology/drug effects/metabolism ; *Mice, Transgenic ; Mice ; Inflammation ; Male ; Disease Models, Animal ; Monocytes/drug effects/immunology ; Mice, Inbred C57BL ; Microglia/drug effects/immunology/metabolism ; Female ; }, abstract = {BACKGROUND: Innate immune activation has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, metabolic pathways that govern this bioenergetically demanding process in ALS remains elusive. Here we investigated whether and how immunometabolic transformation of innate immune cells contributes to disease progression in an experimental model of this neurodegenerative disease.

METHODS: We utilized multidimensional flow cytometry and integrative metabolomics to characterize the immunometabolic phenotype of circulating and spinal cord innate immune cells in the B6SJL-Tg(SOD1*G93A)1Gur/J model of ALS (SOD1-G93A) at various disease stages (before vs. after the onset of motor dysfunction). Behavioral and survival analyses were also conducted to determine the impact of an energy-regulating compound on innate immune cell metabolism, inflammation, and disease development.

RESULTS: Temporally coordinated accumulation of circulating inflammatory Ly6C + monocytes and spinal cord F4/80 + CD45[hi] infiltrates precedes the onset of motor dysfunction in SOD1-G93A mice. Subsequent metabolomic analysis reveals that this phenomenon is accompanied by glycolytic reprogramming of spinal cord inflammatory CD11b + cells, comprising both resident F4/80 + CD45[low] microglia and F4/80 + CD45[hi] infiltrates. Furthermore, pharmacologic inhibition of glycolysis by ZLN005, a small molecule activator of Ppargc1a, restrains inflammatory glycolytic activation of spinal cord CD11b + cells, enhances motor function, and prolongs survival in SOD1-G93A mice.

CONCLUSIONS: These observations suggest that modulation of inflammatory glycolytic reprogramming of innate immune cells may represent a promising therapeutic approach in ALS.}, } @article {pmid39163160, year = {2024}, author = {Purcell, N and Manousakis, G}, title = {Diverse Phenotypic Presentation of the Welander Distal Myopathy Founder Mutation, With Myopathy and Amyotrophic Lateral Sclerosis in the Same Family.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {1}, pages = {42-46}, doi = {10.1097/CND.0000000000000501}, pmid = {39163160}, issn = {1537-1611}, mesh = {Female ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; *Distal Myopathies/genetics/diagnosis ; Founder Effect ; *Mutation ; *Pedigree ; *Phenotype ; T-Cell Intracellular Antigen-1/genetics ; Aged ; Aged, 80 and over ; }, abstract = {Welander distal myopathy is a rare myopathy with prominent and early involvement of distal upper extremity muscles, prevalent in individuals of Scandinavian origin, and caused by a founder mutation in the cytotoxic granule-associated RNA-binding protein (T-cell intracellular antigen-1; TIA1), E384K. Different pathogenic variants in the TIA1 gene, distinct from the founder 1, have recently been associated with frontotemporal dementia and amyotrophic lateral sclerosis (ALS), suggesting that TIA1-related disorders belong to the group of multisystem proteinopathies. We describe the first case of a two-generation family with the founder E384K TIA1 mutation demonstrating phenotypic variability; the mother manifested as Welander myopathy, whereas 2 daughters manifested as ALS. No other genetic cause of ALS was found in 1 of the affected daughters. We also discuss the possible mechanisms explaining this pleotropic presentation of the founder mutation.}, } @article {pmid39163156, year = {2024}, author = {Takahashi, K and Hamada, Y and Kobayashi, M and Kobayashi, S and Kanbayashi, T and Hatanaka, Y and Nakayama, T and Imafuku, I and Matsuno, H and Iguchi, Y and Katada, F and Fukutake, T and Ando, T and Mikata, T and Usui, T and Uchino, K and Nishiyama, K and Sonoo, M}, title = {Utility of the Repetitive Nerve Stimulation Test and Needle EMG in the Trapezius Muscle for the Early Diagnosis of ALS.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {1}, pages = {1-11}, doi = {10.1097/CND.0000000000000479}, pmid = {39163156}, issn = {1537-1611}, support = {19K07966 and 22K07524//Ministry of Education, Science, Sports and Culture of Japan/ ; 19ek0109252h0003//AMED/ ; }, mesh = {Humans ; *Electromyography/methods ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Aged ; Retrospective Studies ; *Electric Stimulation ; *Superficial Back Muscles/physiopathology ; *Sensitivity and Specificity ; Adult ; Early Diagnosis ; }, abstract = {OBJECTIVES: To document the utility of decremental responses in the repetitive nerve stimulation test (RNS) and spontaneous activities in needle electromyography (EMG) in the trapezius muscle for the diagnosis of amyotrophic lateral sclerosis.

METHODS: Subjects were retrospectively identified from our EMG database. Cervical spondylosis was represented as a disease control group. We investigated the sensitivity and specificity of RNS and EMG in the trapezius muscle and those of diagnostic criteria including the Gold Coast criteria (GCC).

RESULTS: We reviewed 120 patients with amyotrophic lateral sclerosis and 17 patients with cervical spondylosis. "RNS or EMG" achieved the highest sensitivity (85%). The specificity was the highest for RNS (94%). Addition of RNS of the deltoid muscle achieved 98% sensitivity in the upper-limb onset amyotrophic lateral sclerosis. The sensitivity of the GCC was very high (88%).

CONCLUSIONS: Neurophysiological parameters investigated in this study having close to 100% specificities or sensitivities are useful as complements to the GCC.}, } @article {pmid39163111, year = {2024}, author = {Fenoy, A}, title = {Scientific plurality and amyotrophic lateral sclerosis (ALS): A philosophical and historical perspective on Charcot's texts.}, journal = {Journal of the history of the neurosciences}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/0964704X.2024.2380635}, pmid = {39163111}, issn = {1744-5213}, abstract = {The history of amyotrophic lateral sclerosis (ALS)-also known as Charcot's disease, Lou Gehrig's disease, and motor neuron disease (MND)-freezes the texts of the scientist and physician Jean-Martin Charcot in a hagiographic narrative describing a brilliant discovery, based on the anatomo-clinical method. This narrative is often used by biologists and physicians as a reference point. This article shows that the use of the hagiographic register faces limitations. In particular, it obscures points of interest from Charcot's texts on ALS, such as the epistemological and ontological implications of scientific plurality in medicine. Although Charcot recognized the importance of scientific plurality in medicine, he prioritized the approaches and conferred the most important epistemic authority on clinical and pathological observations. In his view, animal modeling remains secondary to the understanding of disease. The concept of ALS and its diagnostic operability are the result of symptoms and lesions. By studying the past, we can highlight the specific features of the present. Today, although the ALS concept retains its diagnostic and clinical relevance, it is increasingly called into question in etiological and mechanistic research. Despite these differences, Charcot's reflections are a reminder of the importance of theoretical thinking on scientific plurality, all the more so today in the context of ALS research, in which combining different approaches is increasingly valued to understand the phenotypic and genetic heterogeneity of ALS.}, } @article {pmid39162129, year = {2024}, author = {Mazzini, L and De Marchi, F and Buzanska, L and Follenzi, A and Glover, JC and Gelati, M and Lombardi, I and Maioli, M and Mesa-Herrera, F and Mitrečić, D and Olgasi, C and Pivoriūnas, A and Sanchez-Pernaute, R and Sgromo, C and Zychowicz, M and Vescovi, A and Ferrari, D}, title = {Current status and new avenues of stem cell-based preclinical and therapeutic approaches in amyotrophic lateral sclerosis.}, journal = {Expert opinion on biological therapy}, volume = {24}, number = {9}, pages = {933-954}, doi = {10.1080/14712598.2024.2392307}, pmid = {39162129}, issn = {1744-7682}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; Animals ; *Stem Cell Transplantation ; Disease Models, Animal ; Clinical Trials as Topic ; }, abstract = {INTRODUCTION: Cell therapy development represents a critical challenge in amyotrophic lateral sclerosis (ALS) research. Despite more than 20 years of basic and clinical research, no definitive safety and efficacy results of cell-based therapies for ALS have been published.

AREAS COVERED: This review summarizes advances using stem cells (SCs) in pre-clinical studies to promote clinical translation and in clinical trials to treat ALS. New technologies have been developed and new experimental in vitro and animal models are now available to facilitate pre-clinical research in this field and to determine the most promising approaches to pursue in patients. New clinical trial designs aimed at developing personalized SC-based treatment with biological endpoints are being defined.

EXPERT OPINION: Knowledge of the basic biology of ALS and on the use of SCs to study and potentially treat ALS continues to grow. However, a consensus has yet to emerge on how best to translate these results into therapeutic applications. The selection and follow-up of patients should be based on clinical, biological, and molecular criteria. Planning of SC-based clinical trials should be coordinated with patient profiling genetically and molecularly to achieve personalized treatment. Much work within basic and clinical research is still needed to successfully transition SC therapy in ALS.}, } @article {pmid39161942, year = {2024}, author = {Marcu, IR and Rogoveanu, OC and Pădureanu, R and Pădureanu, V and Dop, D}, title = {Diagnostic elements in amyotrophic lateral sclerosis: A case report.}, journal = {Biomedical reports}, volume = {21}, number = {4}, pages = {141}, pmid = {39161942}, issn = {2049-9442}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurological disease that involves the degeneration of both upper and lower motor neurons responsible for controlling voluntary muscle activity. Most people with ALS die within 3-5 years due to respiratory failure. The current study presents the case of a 68-year-old woman diagnosed with ALS based on the subjective and objective findings from the patient's initial physiotherapy assessment and on neurophysiological tests. Physiotherapy interventions are aiming to maintain the patient's strength, balance and functional independence for as long as possible. The present case report aimed to highlight that a multidisciplinary team approach is necessary for the management of a progressive degenerative disease such as ALS.}, } @article {pmid39158304, year = {2024}, author = {Tong, Z and Zhang, X and Guo, X and Wu, G and Cao, S and Zhang, Y and Meng, X and Wang, T and Wang, Y and Song, Y and Yang, R and Du, Z}, title = {Delivery of Yersinia pestis antigens via Escherichia coli outer membrane vesicles offered improved protection against plague.}, journal = {mSphere}, volume = {9}, number = {9}, pages = {e0033024}, pmid = {39158304}, issn = {2379-5042}, support = {2022YFC2303503//National Key Research and Development of China/ ; 32070136//MOST | National Natural Science Foundation of China (NSFC)/ ; }, mesh = {Animals ; *Plague/prevention & control/immunology ; *Antigens, Bacterial/immunology/genetics ; *Bacterial Outer Membrane Proteins/immunology/genetics ; *Escherichia coli/genetics/immunology ; *Yersinia pestis/immunology/genetics ; Mice ; *Pore Forming Cytotoxic Proteins/immunology/genetics ; *Plague Vaccine/immunology/administration & dosage/genetics ; Female ; *Antibodies, Bacterial/blood/immunology ; Mice, Inbred BALB C ; Recombinant Fusion Proteins/immunology/genetics ; Bacterial Outer Membrane/immunology ; Bacterial Proteins ; }, abstract = {Outer membrane vesicles (OMVs) from Gram-negative bacteria can be used as a vaccine platform to deliver heterologous antigens. Here, the major protective antigens of Yersinia pestis, F1 and LcrV, were fused either with the leader sequence or the transmembrane domain of the outer membrane protein A (OmpA), resulting in chimeric proteins OmpA-ls-F1V and OmpA46-159-F1V, respectively. We show that OmpA-ls-F1V and OmpA46-159-F1V can be successfully delivered into the lumen and membrane of the OMVs of Escherichia coli, respectively. Mutation of ompA but not tolR in E. coli enhanced the delivery efficiency of OmpA-ls-F1V into OMVs. The OmpA-ls-F1V protein comprises up to 20% of the total protein in OMVs derived from the ompA mutant (OMVdA-ALS-F1V), a proportion significantly higher than the 1% observed for OmpA46-159-F1V in OMVs produced by an ompA mutant that expresses OmpA46-159-F1V, referred to as OMVdA-LATM5-F1V. Intramuscular (i.m.) immunization of mice with OMVdA-ALS-F1V induced significantly higher levels of serum anti-LcrV and anti-F1 IgG, and provided higher efficacy in protection against subcutaneous (s.c.) Y. pestis infection compared to OMVdA-LATM5-F1V and the purified recombinant F1V (rF1V) protein adsorbed to aluminum hydroxide. The three-dose i.m. immunization with OMVdA-ALS-F1V, administered at 14-day intervals, provides complete protection to mice against s.c. infection with 130 LD50 of Y. pestis 201 and conferred 80% against intranasal (i.n.) challenge with 11.4 LD50 of Y. pestis 201. Taken together, our findings indicate that the engineered OMVs containing F1V fused with the leader sequence of OmpA provide significantly higher protection than rF1V against both s.c. and i.n. infection of Y. pestis and more balanced Th1/Th2 responses.IMPORTANCEThe two major protective antigens of Y. pestis, LcrV and F1, have demonstrated the ability to elicit systemic and local mucosal immune responses as subunit vaccines. However, these vaccines have failed to provide adequate protection against pneumonic plague in African green monkeys. Here, Y. pestis F1 and LcrV antigens were successfully incorporated into the lumen and the surface of the outer membrane vesicles (OMVs) of E. coli by fusion either with the leader sequence or the transmembrane domain of OmpA. We compared the humoral immune response elicited by these OMV formulations and their protective efficacy in mice against Y. pestis. Our results demonstrate that the plague OMV vaccine candidates can induce robust protective immunity against both s.c. and i.n. Y. pestis infections, surpassing the effectiveness of rF1V. In addition, immunization with OMVs generated a relatively balanced Th1/Th2 immune response compared to rF1V immunization. These findings underscore the potential of OMVs-based plague vaccines for further development.}, } @article {pmid39157517, year = {2024}, author = {Zhang, Y and Zhang, Q and Liu, Q and Zhao, Y and Xu, W and Hong, C and Xu, C and Qi, X and Qi, X and Liu, B}, title = {Fine mapping and functional validation of the maize nicosulfuron-resistance gene CYP81A9.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1443413}, pmid = {39157517}, issn = {1664-462X}, abstract = {Nicosulfuron, a widely utilized herbicide, is detrimental to some maize varieties due to their sensitivity. Developing tolerant varieties with resistance genes is an economical and effective way to alleviate phytotoxicity. In this study, map-based cloning revealed that the maize resistance gene to nicosulfuron is Zm00001eb214410 (CYP81A9), which encodes a cytochrome P450 monooxygenase. qRT- PCR results showed that CYP81A9 expression in the susceptible line JS188 was significantly reduced compared to the resistant line B73 during 0-192 hours following 80 mg/L nicosulfuron spraying. Meanwhile, a CYP81A9 overexpression line exhibited normal growth under a 20-fold nicosulfuron concentration (1600 mg/L), while the transgenic acceptor background material Zong31 did not survive. Correspondingly, silencing CYP81A9 through CRISPR/Cas9 mutagenesis and premature transcription termination mutant EMS4-06e182 resulted in the loss of nicosulfuron resistance in maize. Acetolactate Synthase (ALS), the target enzyme of nicosulfuron, exhibited significantly reduced activity in the roots, stems, and leaves of susceptible maize post-nicosulfuron spraying. The CYP81A9 expression in the susceptible material was positively correlated with ALS activity in vivo. Therefore, this study identified CYP81A9 as the key gene regulating nicosulfuron resistance in maize and discovered three distinct haplotypes of CYP81A9, thereby laying a solid foundation for further exploration of the underlying resistance mechanisms.}, } @article {pmid39156974, year = {2024}, author = {Fenili, G and Scaricamazza, S and Ferri, A and Valle, C and Paronetto, MP}, title = {Physical exercise in amyotrophic lateral sclerosis: a potential co-adjuvant therapeutic option to counteract disease progression.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1421566}, pmid = {39156974}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by the selective degeneration of upper and lower motor neurons, leading to progressive muscle weakness and atrophy. The mean survival time is two to five years. Although the hunt for drugs has greatly advanced over the past decade, no cure is available for ALS yet. The role of intense physical activity in the etiology of ALS has been debated for several decades without reaching a clear conclusion. The benefits of organized physical activity on fitness and mental health have been widely described. Indeed, by acting on specific mechanisms, physical activity can influence the physiology of several chronic conditions. It was shown to improve skeletal muscle metabolism and regeneration, neurogenesis, mitochondrial biogenesis, and antioxidant defense. Interestingly, all these pathways are involved in ALS pathology. This review will provide a broad overview of the effect of different exercise protocols on the onset and progression of ALS, both in humans and in animal models. Furthermore, we will discuss challenges and opportunities to exploit physiological responses of imposed exercise training for therapeutic purposes.}, } @article {pmid39156432, year = {2024}, author = {Kaye, AD and Sala, KR and Dethloff, D and Norton, M and Moss, C and Plessala, MJ and Derouen, AG and Lopez Torres, Y and Kim, J and Tirumala, S and Shekoohi, S and Varrassi, G}, title = {The Evolving Use of Gold Nanoparticles as a Possible Reversal Agent for the Symptoms of Neurodegenerative Diseases: A Narrative Review.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64846}, pmid = {39156432}, issn = {2168-8184}, abstract = {Neurodegenerative diseases are broadly hallmarked by impaired energy metabolism and toxic intracellular accumulations such as damaged organelles or reactive oxygen species (ROS). Gold nanoparticles readily cross the blood-brain barrier and increase nicotinamide adenine dinucleotide + hydrogen (NADH) oxidation to nicotinamide adenine dinucleotide (NAD+), which is vital for intracellular energy generation, cellular repair, and protection from ROS. Thus, the use of gold nanoparticles to treat and potentially reverse cellular injury seen in neurodegenerative disease has been an area of ongoing research. This systematic review explores current literature regarding the use of gold nanoparticle therapy in the treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). In vitro studies of CNM-Au8 (Clene Nanomedicine, Salt Lake City, UT) have been shown to reduce TDP-43 aggregates associated with ALS. These studies also exhibited the neuroprotective effects of CNM-Au8 in rat primary neurons exposed to amyloid-beta peptides, which are associated with Alzheimer's disease. In animal models of MS, oral delivery of CNM-Au8 was demonstrated to produce robust and significant remyelination activity, oligodendrocyte maturation, and expression of myelin markers. In these same MS animal models, CNM-Au8 improved the motor function of cuprizone-treated mice in both open-field and kinematic gait studies. Recent phase II trials of CNM-Au8 in 13 patients with Parkinson's disease and 11 patients with stable relapsing MS demonstrated a statistically significant increase in the NAD+/NADH ratio across two cohorts. As the current data repeatedly suggest, these gold nanoparticles are efficacious for the treatment and reversal of symptoms across these varying neurodegenerative pathologies. Further opportunities exist for increasing human trials and eventually incorporating this new technology into existing treatment regimens.}, } @article {pmid39154890, year = {2024}, author = {Brebner, C and Asamoah-Boaheng, M and Zaidel, B and Yap, J and Scheuermeyer, F and Mok, V and Hutton, J and Meckler, G and Schlamp, R and Christenson, J and Grunau, B}, title = {The association of intravenous vs. humeral-intraosseous vascular access with patient outcomes in adult out-of-hospital cardiac arrests.}, journal = {Resuscitation}, volume = {202}, number = {}, pages = {110360}, doi = {10.1016/j.resuscitation.2024.110360}, pmid = {39154890}, issn = {1873-1570}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; *Infusions, Intraosseous/methods ; Middle Aged ; *Cardiopulmonary Resuscitation/methods ; *Registries ; Aged ; Humerus ; Emergency Medical Services/methods ; Treatment Outcome ; Adult ; Propensity Score ; }, abstract = {AIM: While intravenous (IV) vascular access for out-of-hospital cardiac arrest (OHCA) resuscitation is standard, humeral-intraosseous (IO) access is commonly used, despite few supporting data. We investigated the association between IV vs. humeral-IO and outcomes.

METHODS: We utilized BC Cardiac Arrest Registry data, including adult OHCA where the first-attempted intra-arrest vascular access route performed by advanced life support (ALS)-trained paramedics was IV or humeral-IO. We fit a propensity-score adjusted model with inverse probability treatment weighting to estimate the association between IV vs. humeral-IO routes and favorable neurological outcomes (CPC 1-2) and survival at hospital discharge. We repeated models within subgroups defined by initial cardiac rhythm.

RESULTS: We included 2,112 cases; the first-attempted route was IV (n = 1,575) or humeral-IO (n = 537). Time intervals from ALS-paramedic on-scene arrival to vascular access (6.6 vs. 6.9 min) and epinephrine administration (9.0 vs. 9.3 min) were similar between IV and IO groups, respectively. Among IV and humeral-IO groups, 98 (6.2%) and 20 (3.7%) had favorable neurological outcomes. Compared to humeral-IO, an IV-first approach was associated with improved hospital-discharge favorable neurological outcomes (AOR 1.7; 95% CI 1.1-2.7) and survival (AOR 1.5; 95% CI 1.0-2.3). Among shockable rhythm cases, an IV-first approach was associated with improved favorable neurological outcomes (AOR 4.2; 95% CI 2.1-8.2), but not among non-shockable rhythm cases (AOR 0.73; 95% CI 0.39-1.4).

CONCLUSION: An IV-first approach, compared to humeral-IO, for intra-arrest resuscitation was associated with an improved odds of favorable neurological outcomes and survival to hospital discharge. This association was seen among an initial shockable rhythm, but not non-shockable rhythm, subgroups.}, } @article {pmid39154745, year = {2024}, author = {Vu, D and Park, M and Alhusayen, R}, title = {Response to Chawla et al, "Response to Vu et al's "Efficacy of moxifloxacin as a mono-antibiotic therapy for hidradenitis suppurativa: A retrospective cohort study"".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {6}, pages = {e177-e178}, doi = {10.1016/j.jaad.2024.08.013}, pmid = {39154745}, issn = {1097-6787}, } @article {pmid39154744, year = {2024}, author = {Li, JN and Sechi, A and Tosti, A}, title = {Response to Costa Fechine et al's "Correlation of clinical and trichoscopy features with the degree of histologic inflammation in lichen planopilaris and frontal fibrosing alopecia in a cross-sectional study".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {6}, pages = {e187-e188}, doi = {10.1016/j.jaad.2024.07.1495}, pmid = {39154744}, issn = {1097-6787}, } @article {pmid39153378, year = {2024}, author = {Maramai, S and Saletti, M and Paolino, M and Giuliani, G and Cazzola, J and Spaiardi, P and Talpo, F and Frosini, M and Pifferi, A and Ballarotto, M and Carotti, A and Poggialini, F and Vagaggini, C and Dreassi, E and Giorgi, G and Dondio, G and Cappelli, A and Rosario Biella, G and Anzini, M}, title = {Novel multitarget directed ligands inspired by riluzole: A serendipitous synthesis of substituted benzo[b][1,4]thiazepines potentially useful as neuroprotective agents.}, journal = {Bioorganic & medicinal chemistry}, volume = {112}, number = {}, pages = {117872}, doi = {10.1016/j.bmc.2024.117872}, pmid = {39153378}, issn = {1464-3391}, mesh = {Animals ; Humans ; Dose-Response Relationship, Drug ; Ligands ; Molecular Structure ; *Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; *Riluzole/pharmacology/chemical synthesis/chemistry ; Structure-Activity Relationship ; Thiazepines/chemical synthesis/chemistry/pharmacology ; }, abstract = {Riluzole, the first clinically approved treatment for amyotrophic lateral sclerosis (ALS), represents a successful example of a drug endowed with a multimodal mechanism of action. In recent years, different series of riluzole-based compounds have been reported, including several agents acting as Multi-Target-Directed Ligands (MTLDs) endowed with neuroprotective effects. Aiming at identical twin structures inspired by riluzole (2a-c), a synthetic procedure was planned, but the reactivity of the system took a different path, leading to the serendipitous isolation of benzo[b][1,4]thiazepines 3a-c and expanded intermediates N-cyano-benzo[b][1,4]thiazepines 4a-c, which were fully characterized. The newly obtained structures 3a-c, bearing riluzole key elements, were initially tested in an in vitro ischemia/reperfusion injury protocol, simulating the cerebral stroke. Results identified compound 3b as the most effective in reverting the injury caused by an ischemia-like condition, and its activity was comparable, or even higher than that of riluzole, exhibiting a concentration-dependent neuroprotective effect. Moreover, derivative 3b completely reverted the release of Lactate Dehydrogenase (LDH), lowering the values to those of the control slices. Based on its very promising pharmacological properties, compound 3b was then selected to assess its effects on voltage-dependent Na[+] and K[+] currents. The results indicated that derivative 3b induced a multifaceted inhibitory effect on voltage-gated currents in SH-SY5Y differentiated neurons, suggesting its possible applications in epilepsy and stroke management, other than ALS. Accordingly, brain penetration was also measured for 3b, as it represents an elegant example of a MTDL and opens the way to further ex-vivo and/or in-vivo characterization.}, } @article {pmid39153346, year = {2025}, author = {Khazaei, K and Roshandel, P and Parastar, H}, title = {Visible-short wavelength near infrared hyperspectral imaging coupled with multivariate curve resolution-alternating least squares for diagnosis of breast cancer.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {324}, number = {}, pages = {124966}, doi = {10.1016/j.saa.2024.124966}, pmid = {39153346}, issn = {1873-3557}, mesh = {Humans ; Female ; *Breast Neoplasms/diagnosis ; Least-Squares Analysis ; *Principal Component Analysis ; *Spectroscopy, Near-Infrared/methods ; *Hyperspectral Imaging/methods ; Multivariate Analysis ; Discriminant Analysis ; }, abstract = {This study investigates the application of visible-short wavelength near-infrared hyperspectral imaging (Vis-SWNIR HSI) in the wavelength range of 400-950 nm and advanced chemometric techniques for diagnosing breast cancer (BC). The research involved 56 ex-vivo samples encompassing both cancerous and non-cancerous breast tissue from females. First, HSI images were analyzed using multivariate curve resolution-alternating least squares (MCR-ALS) to exploit pure spatial and spectral profiles of active components. Then, the MCR-ALS resolved spatial profiles were arranged in a new data matrix for exploration and discrimination between benign and cancerous tissue samples using principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA). The PLS-DA classification accuracy of 82.1 % showed the potential of HSI and chemometrics for non-invasive detection of BC. Additionally, the resolved spectral profiles by MCR-ALS can be used to track the changes in the breast tissue during cancer and treatment. It is concluded that the proposed strategy in this work can effectively differentiate between cancerous and non-cancerous breast tissue and pave the way for further studies and potential clinical implementation of this innovative approach, offering a promising avenue for improving early detection and treatment outcomes in BC patients.}, } @article {pmid39153108, year = {2024}, author = {Hosseini, L and Babaie, S and Shahabi, P and Fekri, K and Shafiee-Kandjani, AR and Mafikandi, V and Maghsoumi-Norouzabad, L and Abolhasanpour, N}, title = {Klotho: molecular mechanisms and emerging therapeutics in central nervous system diseases.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {913}, pmid = {39153108}, issn = {1573-4978}, mesh = {*Klotho Proteins ; Humans ; *Central Nervous System Diseases/metabolism/drug therapy ; *Signal Transduction ; Animals ; Oxidative Stress ; Glucuronidase/metabolism/genetics ; Autophagy ; Aging/metabolism/genetics ; }, abstract = {Klotho is recognized as an aging-suppressor protein that is implicated in a variety of processes and signaling pathways. The anti-inflammatory, anti-apoptotic, anti-oxidant, and anti-tumor bioactivities of klotho have extended its application in neurosciences and made the protein popular for its lifespan-extending capacity. Furthermore, it has been demonstrated that klotho levels would reduce with aging and numerous pathologies, particularly those related to the central nervous system (CNS). Evidence supports the idea that klotho can be a key therapeutic target in CNS diseases such as amyotrophic lateral sclerosis, Parkinson's disease, stroke, and Alzheimer's disease. Reviewing the literature suggests that the upregulation of klotho expression regulates various signaling pathways related to autophagy, oxidative stress, inflammation, cognition, and ferroptosis in neurological disorders. Therefore, it has been of great interest to develop drugs or agents that boost or restore klotho levels. In this regard, the present review was designed and aimed to gather the delegated documents regarding the therapeutic potential of Klotho in CNS diseases focusing on the molecular and cellular mechanisms.}, } @article {pmid39152573, year = {2024}, author = {Dubbioso, R and Iannotti, FA and Senerchia, G and Verde, R and Iuzzolino, VV and Spisto, M and Fasolino, I and Manganelli, F and Di Marzo, V and Piscitelli, F}, title = {Circulating endocannabinoidome signatures of disease activity in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {10}, pages = {e16400}, pmid = {39152573}, issn = {1468-1331}, support = {E53D23019760001//National Recovery and Resilience Plan (NRRP)/ ; E53D23011330006//Ministry of University and Research (MUR)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood ; *Endocannabinoids/blood ; Male ; Female ; Middle Aged ; Aged ; Adult ; Disease Progression ; Longitudinal Studies ; Biomarkers/blood ; }, abstract = {BACKGROUND AND PURPOSE: Preclinical studies of amyotrophic lateral sclerosis (ALS) have shown altered endocannabinoid (eCB) signalling that may contribute to the disease. Results from human studies are sparse and inconclusive. The aim of this study was to determine the association between serum levels of eCBs or their congeners, the so-called endocannabinoidome, and disease status and activity in ALS patients.

METHODS: Serum concentrations of 2-arachidonoylglycerol and N-arachidonoylethanolamine (AEA), and AEA congeners palmitoylethanolamide (PEA), oleoylethanolamide (OEA), eicosapentaenoylethanolamide (EPEA), 2-docosahexaenoylglycerol (2-DHG) and docosahexaenoylethanolamide (DHEA) were measured in samples from 65 ALS patients, 32 healthy controls (HCs) and 16 neurological disease controls (NALS). A subset of 46 ALS patients underwent a longitudinal study. Disease activity and progression were correlated with eCB and congener levels.

RESULTS: Most circulating mediators were higher in ALS than HCs (all p < 0.001), but not NALS. Across clinical stages, ALS patients showed increased levels of PEA, OEA and EPEA (all p < 0.02), which were confirmed by the longitudinal study (all p < 0.03). Serum PEA and OEA levels were independent predictors of survival and OEA levels were higher in patients complaining of appetite loss. Cluster analysis revealed two distinct profiles of circulating mediators associated with corresponding patterns of disease activity (severe vs. mild). Patients belonging to the 'severe' cluster showed significantly higher levels of OEA and PEA and lower levels of 2-DHG compared to NALS and HCs.

CONCLUSION: Circulating endocannabinoidome profiles are indicative of disease activity, thus possibly paving the way to a personalized, rather than a 'one-fits-all', therapeutic approach targeting the endocannabinoidome.}, } @article {pmid39150867, year = {2024}, author = {Pienaar, K and Kelaita, P and Murphy, D}, title = {COVID-19 and the biopolitics of stigma in public housing: dividing practices and community boundaries in pandemic times.}, journal = {Health sociology review : the journal of the Health Section of the Australian Sociological Association}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/14461242.2024.2390019}, pmid = {39150867}, issn = {1446-1242}, abstract = {The COVID-19 'hard lockdowns' in Melbourne, Australia in 2020 targeted public housing estates thus trading on perceptions of risk associated with public housing as some of the most stigmatised sites in post-industrial cities. This article draws on interviews with Melbourne public housing tenants on their experience of COVID-19 lockdowns to analyse the place of stigma in residents' accounts. Pairing Wacquant et al's (2014) concept of 'territorial stigma' with sociological work on the biopolitics of stigma we consider the dynamics of stigma, tracing how it functions to delimit community boundaries and justify pandemic containment measures. Residents navigate multiple layers of stigma, including stereotypes of public housing, normative judgements of neighbouring residents, and a broader public housing system riven with structural issues. Members of these communities are both the targets of stigma and seek to distance themselves from those seen as vectors of stigma. Our participants report mobilising social distancing strategies couched in normative assessments of perceived risk based on physical appearance, presumed drug use and past conduct. We explore the implications of these enactments of territorial stigma and trace the logics of abjection that construct public housing as deprived urban zones, home to abject 'Others' perceived as threatening the health of the community.}, } @article {pmid39149866, year = {2024}, author = {Cabeza-Fernández, S and Hernández-Rojas, R and Casillas-Bajo, A and Patel, N and de la Fuente, AG and Cabedo, H and Gomez-Sanchez, JA}, title = {Schwann cell JUN expression worsens motor performance in an amyotrophic lateral sclerosis mouse model.}, journal = {Glia}, volume = {72}, number = {12}, pages = {2178-2189}, doi = {10.1002/glia.24604}, pmid = {39149866}, issn = {1098-1136}, support = {PID2019-109762RB-I00//Agencia Estatal de Investigación/ ; PID2022-141062OB-I00//Agencia Estatal de Investigación/ ; CIPROM/2021/048//Conselleria d'Educació, Investigació, Cultura i Esport/ ; GRISOLIAP/2021/026//Conselleria d'Educació, Investigació, Cultura i Esport/ ; }, mesh = {Animals ; *Schwann Cells/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism/physiopathology ; *Mice, Transgenic ; *Disease Models, Animal ; *Motor Neurons/pathology/metabolism ; Proto-Oncogene Proteins c-jun/metabolism/genetics ; Mice ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase/genetics/metabolism ; Axons/pathology/metabolism/physiology ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by motor neuron death and distal axonopathy. Despite its clinical severity and profound impact in the patients and their families, many questions about its pathogenesis remain still unclear, including the role of Schwann cells and axon-glial signaling in disease progression. Upon axonal injury, upregulation of JUN transcription factor promotes Schwann cell reprogramming into a repair phenotype that favors axon regrowth and neuronal survival. To study the potential role of repair Schwann cells on motoneuron survival in amyotrophic lateral sclerosis, we generated a mouse line that over-expresses JUN in the Schwann cells of the SOD1[G93A] mutant, a mouse model of this disease. Then, we explored disease progression by evaluating survival, motor performance and histology of peripheral nerves and spinal cord of these mice. We found that Schwann cell JUN overexpression does not prevent axon degeneration neither motor neuron death in the SOD1[G93A] mice. Instead, it induces a partial demyelination of medium and large size axons, worsening motor performance and resulting in more aggressive disease phenotype.}, } @article {pmid39147172, year = {2024}, author = {Acton, S and O'Donnell, MM and Periyasamy, K and Dixit, B and Eishingdrelo, H and Hill, C and Paul Ross, R and Chesnel, L}, title = {LPA3 agonist-producing Bacillus velezensis ADS024 is efficacious in multiple neuroinflammatory disease models.}, journal = {Brain, behavior, and immunity}, volume = {121}, number = {}, pages = {384-402}, doi = {10.1016/j.bbi.2024.08.024}, pmid = {39147172}, issn = {1090-2139}, mesh = {*Bacillus/metabolism ; Animals ; Mice ; Humans ; *Neuroinflammatory Diseases/metabolism ; Disease Models, Animal ; Mice, Inbred C57BL ; Multiple Sclerosis/metabolism ; Male ; Encephalomyelitis, Autoimmune, Experimental/metabolism ; Anti-Inflammatory Agents/pharmacology ; }, abstract = {Neuroinflammation is a common component of neurological disorders. In the gut-brain-immune axis, bacteria and their metabolites are now thought to play a role in the modulation of the nervous and immune systems which may impact neuroinflammation. In this respect, commensal bacteria of humans have recently been shown to produce metabolites that mimic endogenous G-protein coupled receptor (GPCR) ligands. To date, it has not been established whether plant commensal bacteria, which may be ingested by animals including humans, can impact the gut-brain-immune axis via GPCR agonism. We screened an isopropanol (IPA) extract of the plant commensal Bacillus velezensis ADS024, a non-engrafting live biotherapeutic product (LBP) with anti-inflammatory properties isolated from human feces, against a panel of 168 GPCRs and identified strong agonism of the lysophosphatidic acid (LPA) receptor LPA3. The ADS024 IPA extracted material (ADS024-IPA) did not agonize LPA2, and only very weakly agonized LPA1. The agonism of LPA3 was inhibited by the reversible LPA1/3 antagonist Ki16425. ADS024-IPA signaled downstream of LPA3 through G-protein-induced calcium release, recruitment of β-arrestin, and recruitment of the neurodegeneration-associated proteins 14-3-3γ, ε and ζ but did not recruit the β isoform. Since LPA3 agonism was previously indirectly implicated in the reduction of pathology in models of Parkinson's disease (PD) and multiple sclerosis (MS) by use of the nonselective antagonist Ki16425, and since we identified an LPA3-specific agonist within ADS024, we sought to examine whether LPA3 might indeed be part of a broad underlying mechanism to control neuroinflammation. We tested oral treatment of ADS024 in multiple models of neuroinflammatory diseases using three models of PD, two models of MS, and a model each of amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and chemo-induced peripheral neuropathy (CIPN). ADS024 treatment improved model-specific functional effects including improvements in motor movement, breathing and swallowing, and allodynia suggesting that ADS024 treatment impacted a universal underlying neuroinflammatory mechanism regardless of the initiating cause of disease. We used the MOG-EAE mouse model to examine early events after disease initiation and found that ADS024 attenuated the increase in circulating lymphocytes and changes in neutrophil subtypes, and ADS024 attenuated the early loss of cell-surface LPA3 receptor expression on circulating white blood cells. ADS024 efficacy was partially inhibited by Ki16425 in vivo suggesting LPA3 may be part of its mechanism. Altogether, these data suggest that ADS024 and its LPA3 agonism activity should be investigated further as a possible treatment for diseases with a neuroinflammatory component.}, } @article {pmid39146882, year = {2024}, author = {Aizawa, H and Nagumo, S and Hideyama, T and Kato, H and Kwak, S and Terashi, H and Suzuki, Y and Kimura, T}, title = {Morphometric analysis of spinal motor neuron degeneration in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {464}, number = {}, pages = {123177}, doi = {10.1016/j.jns.2024.123177}, pmid = {39146882}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Male ; Female ; Middle Aged ; Aged ; *DNA-Binding Proteins/metabolism ; *Spinal Cord/pathology/metabolism ; *Nerve Degeneration/pathology ; Anterior Horn Cells/pathology ; Motor Neurons/pathology/metabolism ; }, abstract = {OBJECTIVES: This study aimed to clarify the relationship between 43-kDa TAR DNA-binding protein (TDP-43) pathology and spinal cord anterior horn motor neuron (AHMN) atrophy in sporadic amyotrophic lateral sclerosis (SALS).

METHODS: Eight patients with SALS and 12 controls were included in this study. Formalin-fixed specimens of lumbar spinal cord samples were paraffin-embedded and sectioned at the level of the fourth lumbar spinal cord with a 4 μm thickness. Using a microscope, the long diameters of the neurons with nucleoli were measured in spinal AHMNs stained with an anti-SMI-32 antibody. AHMNs were divided into medial and lateral nuclei for statistical analysis. We also used previously reported data to measure the long diameter of AHMNs with initial TDP-43 pathology, in which TDP-43 was present both in the nucleus and cytoplasm.

RESULTS: The long diameter of the lumbar spinal AHMNs in patients with SALS was smaller in the medial nucleus (42.54 ± 9.33 μm, n = 24) and the lateral nucleus (49.41 ± 13.86 μm, n = 129) than in controls (medial nucleus: 55.84 ± 13.49 μm, n = 85, p < 0.001; lateral nucleus: 62.39 ± 13.29 μm, n = 756, p < 0.001, Mann-Whitney U test). All 21 motor neurons with initial TDP-43 pathology were in the lateral nucleus, and their long diameter (67.60 ± 18.3 μm, p = 0.352) was not significantly different from that of controls.

CONCLUSION: Motor neuron atrophy in SALS does not occur during the initial stages of TDP-43 pathology, and TDP-43 pathology is already advanced in the atrophied motor neurons.}, } @article {pmid39146816, year = {2025}, author = {Sun, Q and Chai, L and Yang, X and Zhang, W and Li, Z}, title = {Hollow tubular sea-urchin structure with high catalytic activity of NiCo2Se4@CS2 cathodes for high-performance Al/S batteries.}, journal = {Journal of colloid and interface science}, volume = {677}, number = {Pt B}, pages = {284-292}, doi = {10.1016/j.jcis.2024.08.071}, pmid = {39146816}, issn = {1095-7103}, abstract = {The shuttle effect of aluminum polysulfides (AlPSs) have been a source of concern for studying Al/S batteries. Due to the weak adsorption of CS composites, research on cathode materials for Al/S batteries has been delayed. As it is generally known that Al2S3 decomposition demands a large Gibbs free energy, this work has tried to reduce the Al2S3 decomposition potential energy. Herein, the Ni/Co bimetallic selenide reduces the energy barrier conversion and mitigates the polarization effects, while morphology control enables the storage and anchoring of S, alleviating the shuttle effect. Additionally, the intermediate products serve as single-atom catalysts, increasing the active sites, synergistically enhancing the ion diffusion kinetics. DFT calculations verify that NiCo2Se4 has a moderate Gibbs free energy change during the rate-limiting step of S reduction and the most robust adsorption energy to Al2S3. NiCo2Se4@CS2/Al has a remaining capacity of 135 mAh/g after 450 cycles (at 200 mA g[-1]), pioneering novel ideas for the development of Al/S batteries.}, } @article {pmid39146722, year = {2024}, author = {Ginanneschi, F and Pucci, B and Casali, S and Lissandri, C and Giannini, F and Rossi, A}, title = {Factors associated with Edinburgh Cognitive and Behavioural ALS Screen (ECAS) alteration at time of diagnosis, in amyotrophic lateral sclerosis.}, journal = {Clinical neurology and neurosurgery}, volume = {245}, number = {}, pages = {108499}, doi = {10.1016/j.clineuro.2024.108499}, pmid = {39146722}, issn = {1872-6968}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Male ; Female ; Middle Aged ; Aged ; C9orf72 Protein/genetics ; Neuropsychological Tests ; Adult ; Mutation ; Cohort Studies ; }, abstract = {BACKGROUND: Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is a validated assessment designed to screen cognitive functions and behavioral disorders in amyotrophic lateral sclerosis (ALS). Objective of this study is to determine the factors associated with ECAS impairment in a cohort of ALS patients without a co-morbid diagnosis of dementia, at the time of diagnosis.

METHODS: We enrolled 71 non-demented ALS patient. We collected clinical and demographic data, ALS familiarity, analysis of the most commonly mutated genes in ALS, ALS Milano Torino Staging System and ALS Functional Rate Scale revised scores, progression rate; finally, we recorded whether symptoms onset involved spinal or bulbar area. The alteration of the ECAS was estimated based on age and education-adjusted-validated cut off for each of the items included in ECAS. A multivariable regression analysis was done.

RESULTS: The significant determinants of ECAS alterations were: bulbar onset in both ALS-specific test and total ECAS score; bulbar onset and familiarity in ALS-non-specific test; finally, familiarity and diagnosis delay in ALS-behavioral test. All the subjects carrying C9orf72 mutations had alteration of both total ECAS score and ALS-specific tests.

DISCUSSION: At diagnosis, bulbar-onset ALS, family history, diagnosis delay and C9orf72 hexanucleotide repeat expansion may contribute to impairment of ECAS.}, } @article {pmid39146246, year = {2024}, author = {Hutten, S and Chen, JX and Isaacs, AM and Dormann, D}, title = {Poly-GR Impairs PRMT1-Mediated Arginine Methylation of Disease-Linked RNA-Binding Proteins by Acting as a Substrate Sink.}, journal = {Biochemistry}, volume = {63}, number = {17}, pages = {2141-2152}, doi = {10.1021/acs.biochem.4c00308}, pmid = {39146246}, issn = {1520-4995}, mesh = {*Protein-Arginine N-Methyltransferases/metabolism/genetics ; Humans ; *Arginine/metabolism ; Methylation ; *Repressor Proteins/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Frontotemporal Dementia/metabolism/genetics ; C9orf72 Protein/metabolism/genetics ; HEK293 Cells ; }, abstract = {Dipeptide repeat proteins (DPRs) are aberrant protein species found in C9orf72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative diseases characterized by the cytoplasmic mislocalization and aggregation of RNA-binding proteins (RBPs). In particular, arginine (R)-rich DPRs (poly-GR and poly-PR) have been suggested to promiscuously interact with multiple cellular proteins and thereby exert high cytotoxicity. Components of the protein arginine methylation machinery have been identified as modulators of DPR toxicity and/or potential cellular interactors of R-rich DPRs; however, the molecular details and consequences of such an interaction are currently not well understood. Here, we demonstrate that several members of the family of protein arginine methyltransferases (PRMTs) can directly interact with R-rich DPRs in vitro and in the cytosol. In vitro, R-rich DPRs reduce solubility and promote phase separation of PRMT1, the main enzyme responsible for asymmetric arginine-dimethylation (ADMA) in mammalian cells, in a concentration- and length-dependent manner. Moreover, we demonstrate that poly-GR interferes more efficiently than poly-PR with PRMT1-mediated arginine methylation of RBPs such as hnRNPA3. We additionally show by two alternative approaches that poly-GR itself is a substrate for PRMT1-mediated arginine dimethylation. We propose that poly-GR may act as a direct competitor for arginine methylation of cellular PRMT1 targets, such as disease-linked RBPs.}, } @article {pmid39145860, year = {2024}, author = {Gondo, TF and Huang, F and Marungruang, N and Heyman-Lindén, L and Turner, C}, title = {Investigating the quality of extraction and quantification of bioactive compounds in berries through liquid chromatography and multivariate curve resolution.}, journal = {Analytical and bioanalytical chemistry}, volume = {416}, number = {24}, pages = {5387-5400}, pmid = {39145860}, issn = {1618-2650}, support = {2018-01863//Svenska Forskningsrådet Formas/ ; }, mesh = {*Fruit/chemistry ; Multivariate Analysis ; Chromatography, Liquid/methods ; Polyphenols/analysis ; Least-Squares Analysis ; Plant Extracts/chemistry ; Anthocyanins/analysis/chemistry ; Phenols/analysis/chemistry ; Chromatography, High Pressure Liquid/methods ; Antioxidants/analysis/chemistry ; }, abstract = {Berries are a rich source of natural antioxidant compounds, which are essential to profile, as they add to their nutritional value. However, the complexity of the matrix and the structural diversity of these compounds pose challenges in extraction and chromatographic separation. By relying on multivariate curve resolution alternating least squares (MCR-ALS) ability to extract components from complex spectral mixtures, our study evaluates the contributions of various extraction techniques to interference, extractability, and quantifying different groups of overlapping compounds using liquid chromatography diode array detection (LC-DAD) data. Additionally, the combination of these methods extends its applicability to evaluate polyphenol degradation in stored berry smoothies, where evolving factor analysis (EFA) is also used to elucidate degradation products. Results indicate that among the extraction techniques, ultrasonication-assisted extraction employing 1% formic acid in methanol demonstrated superior extractability and selectivity for the different phenolic compound groups, compared with both pressurized liquid extraction and centrifugation of the fresh berry smoothie. Employing MCR-ALS on the LC-DAD data enabled reliable estimation of total amounts of compound classes with high spectral overlaps. Degradation studies revealed significant temperature-dependent effects on anthocyanins, with at least 50% degradation after 7 months of storage at room temperature, while refrigeration and freezing maintained fair stability for at least 12 months. The EFA model estimated phenolic derivatives as the main possible degradation products. These findings enhance the reliability of quantifying polyphenolic compounds and understanding their stability during the storage of berry products.}, } @article {pmid39145609, year = {2024}, author = {Adil, O and Adeyeye, C and Shamsi, MH}, title = {Electrografted Laser-Induced Graphene: Direct Detection of Neurodegenerative Disease Biomarker in Cerebrospinal Fluid.}, journal = {ACS sensors}, volume = {9}, number = {9}, pages = {4748-4757}, doi = {10.1021/acssensors.4c01150}, pmid = {39145609}, issn = {2379-3694}, mesh = {*Graphite/chemistry ; Humans ; *Biomarkers/cerebrospinal fluid ; *Electrochemical Techniques/methods ; *Lasers ; Immunoassay/methods ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Electrodes ; Neurodegenerative Diseases/cerebrospinal fluid/diagnosis ; Limit of Detection ; Biosensing Techniques/methods ; }, abstract = {There are more than 50 neurodegenerative disorders, and amyotrophic lateral sclerosis (ALS) is one of the most common disorders that poses diagnostic and treatment challenges. The poly glycine-proline (polyGP) dipeptide repeat is a toxic protein that has been recognized as a pharmacodynamic biomarker of C9orf72-associated (c9+) ALS, a subtype of ALS that originates from genetic mutation. Early detection of polyGP will help healthcare providers start timely gene therapy. Herein, we developed a label-free electrochemical immunoassay for the simple detection of polyGP in unprocessed cerebrospinal fluid (CSF) samples collected from ALS patients in the National ALS Biorepository. For the first time, an electrografted laser-induced graphene (E-LIG) electrode system was employed in a sandwich format to detect polyGP using a label-free electrochemical impedance technique. The results show that the E-LIG-modified surface exhibited high sensitivity and selectivity in buffer and CSF media with limit of detection values of 0.19 and 0.27 ng/mL, respectively. The precision of the calibration model was better in CSF than in the buffer. The E-LIG immunosensor can easily select polyGP targets in the presence of other dipeptide proteins translated from the c9 gene. Further study with CSF samples from ALS patients demonstrated that the label-free E-LIG-based immunosensor not only quantified polyGP in the complex CSF matrix but also distinguished between c9+ and non-c9- ALS patients.}, } @article {pmid39144751, year = {2024}, author = {Szebényi, K and Vargová, I and Petrova, V and Turečková, J and Gibbons, GM and Řehořová, M and Abdelgawad, M and Sándor, A and Marekova, D and Kwok, JCF and Jendelová, P and Fawcett, JW and Lakatos, A}, title = {Inhibition of PHLDA3 expression in human superoxide dismutase 1-mutant amyotrophic lateral sclerosis astrocytes protects against neurotoxicity.}, journal = {Brain communications}, volume = {6}, number = {4}, pages = {fcae244}, pmid = {39144751}, issn = {2632-1297}, abstract = {Pleckstrin homology-like domain family A-member 3 (PHLDA3) has recently been identified as a player in adaptive and maladaptive cellular stress pathways. The outcome of pleckstrin homology-like domain family A-member 3 signalling was shown to vary across different cell types and states. It emerges that its expression and protein level are highly increased in amyotrophic lateral sclerosis (ALS) patient-derived astrocytes. Whether it orchestrates a supportive or detrimental function remains unexplored in the context of neurodegenerative pathologies. To directly address the role of pleckstrin homology-like domain family A-member 3 in healthy and ALS astrocytes, we used overexpression and knockdown strategies. We generated cultures of primary mouse astrocytes and also human astrocytes from control and ALS patient-derived induced pluripotent stem cells harbouring the superoxide dismutase 1 mutation. Then, we assessed astrocyte viability and the impact of their secretome on oxidative stress responses in human stem cell-derived cortical and spinal neuronal cultures. Here, we show that PHLDA3 overexpression or knockdown in control astrocytes does not significantly affect astrocyte viability or reactive oxygen species production. However, PHLDA3 knockdown in ALS astrocytes diminishes reactive oxygen species concentrations in their supernatants, indicating that pleckstrin homology-like domain family A-member 3 can facilitate stress responses in cells with altered homeostasis. In support, supernatants of PHLDA3-silenced ALS and even control spinal astrocytes with a lower pleckstrin homology-like domain family A-member 3 protein content could prevent sodium arsenite-induced stress granule formation in spinal neurons. Our findings provide evidence that reducing pleckstrin homology-like domain family A-member 3 levels may transform astrocytes into a more neurosupportive state relevant to targeting non-cell autonomous ALS pathology.}, } @article {pmid39144569, year = {2024}, author = {Choudhury, C and Egleton, JE and Butcher, NJ and Russell, AJ and Minchin, RF}, title = {Small Molecule Inhibitors of Arylamine N-Acetyltransferase 1 Attenuate Cellular Respiration.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {8}, pages = {2326-2332}, pmid = {39144569}, issn = {2575-9108}, abstract = {Arylamine N-acetyltransferase 1 (NAT1) expression has been shown to attenuate mitochondrial function, suggesting it is a promising drug target in diseases of mitochondrial dysfunction. Here, several second-generation naphthoquinones have been investigated as small molecule inhibitors of NAT1. The results show that the compounds inhibit both in vitro and in whole cells. A lead compound (Cmp350) was further investigated for its ability to alter mitochondrial metabolism in MDA-MB-231 cells. At concentrations that inhibited NAT1 by over 85%, no overt toxicity was observed. Moreover, the inhibitor decreased basal respiration and reserve respiratory capacity without affecting ATP production. Cells treated with Cmp350 were almost exclusively dependent on glucose as a fuel source. We postulate that Cmp350 is an excellent lead compound for the development of NAT1-targeted inhibitors as both experimental tools and therapeutics in the treatment of hypermetabolic diseases such as amyotrophic lateral sclerosis, cancer cachexia, and sepsis.}, } @article {pmid39144302, year = {2024}, author = {Chen, XF and Lin, JP and Zhou, H and Kang, BZ and Nayak, R and Gao, L and Jiang, SS and Wang, F}, title = {The relationship between the collagen score at the anastomotic site of esophageal squamous cell carcinoma and anastomotic leakage.}, journal = {Journal of thoracic disease}, volume = {16}, number = {7}, pages = {4515-4524}, pmid = {39144302}, issn = {2072-1439}, abstract = {BACKGROUND: Anastomotic leakage (AL) has always been one of the most serious complications of esophagectomy with gastric conduit reconstruction. There are many strong risk factors for AL in clinical practice. Notably, the tension at the esophagogastric anastomosis and the blood supply to the gastric conduit directly affect the integrity of the anastomosis. However, there has been a lack of quantitative research on the tension and blood supply of the gastric conduit. Changes in extracellular matrix collagen reflect tension and blood supply, which affect the quality of the anastomosis. This study aimed to establish a quantitative collagen score to describe changes in the collagen structure in the extracellular matrix and to identify patients at high risk of postoperative AL.

METHODS: A retrospective study of 213 patients was conducted. Clinical and pathological data were collected at baseline. Optical imaging of the "donut" specimen at the anastomotic gastric end and collagen feature extraction were performed. Least absolute shrinkage and selection operator (LASSO) regression models were used to select the significant collagen features, compute collagen scores, and validate the predictive efficacy of the collagen scores for ALs.

RESULTS: LASSO regression analysis revealed three collagen-related parameters in the gastric donuts: histogram mean, histogram variance, and histogram energy. Based on this analysis, we established a formula to calculate the collagen score. The results of the univariate analysis revealed significant differences in the preoperative low albumin values (P=0.002) and collagen scores between the AL and non-AL groups (P=0.001), while the results of the multivariate analysis revealed significant differences in the collagen scores between the AL and non-AL groups (P=0.002). The areas under the curve (AUCs) of the experimental and validation cohorts were 0.978 [95% confidence interval (CI): 0.931-0.996] and 0.900 (95% CI: 0.824-0.951), respectively.

CONCLUSIONS: The collagen score established herein was shown to be related to AL and can be used to predict AL in patients who underwent esophagectomy.}, } @article {pmid39144033, year = {2024}, author = {Xiao, XY and Zeng, JY and Cao, YB and Tang, Y and Zou, ZY and Li, JQ and Chen, HJ}, title = {Cortical microstructural abnormalities in amyotrophic lateral sclerosis: a gray matter-based spatial statistics study.}, journal = {Quantitative imaging in medicine and surgery}, volume = {14}, number = {8}, pages = {5774-5788}, pmid = {39144033}, issn = {2223-4292}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS)-related white-matter microstructural abnormalities have received considerable attention; however, gray-matter structural abnormalities have not been fully elucidated. This study aimed to evaluate cortical microstructural abnormalities in ALS and determine their association with disease severity.

METHODS: This study included 34 patients with ALS and 30 healthy controls. Diffusion-weighted data were used to estimate neurite orientation dispersion and density imaging (NODDI) parameters, including neurite density index (NDI) and orientation dispersion index (ODI). We performed gray matter-based spatial statistics (GBSS) in a voxel-wise manner to determine the cortical microstructure difference. We used the revised ALS Functional Rating Scale (ALSFRS-R) to assess disease severity and conducted a correlation analysis between NODDI parameters and ALSFRS-R.

RESULTS: In patients with ALS, the NDI reduction involved several cortical regions [primarily the precentral gyrus, postcentral gyrus, temporal cortex, prefrontal cortex, occipital cortex, and posterior parietal cortex; family-wise error (FWE)-corrected P<0.05]. ODI decreased in relatively few cortical regions (including the precentral gyrus, postcentral gyrus, prefrontal cortex, and inferior parietal lobule; FWE-corrected P<0.05). The NDI value in the left precentral and postcentral gyrus was positively correlated with the ALS disease severity (FWE-corrected P<0.05).

CONCLUSIONS: The decreases in NDI and ODI involved both motor-related and extra-motor regions and indicated the presence of gray-matter microstructural impairment in ALS. NODDI parameters are potential imaging biomarkers for evaluating disease severity in vivo. Our results showed that GBSS is a feasible method for identifying abnormalities in the cortical microstructure of patients with ALS.}, } @article {pmid39143255, year = {2024}, author = {Gehlen, M and Schwarz-Eywill, M and Mahn, K and Pfeiffer, A and Bauer, JM and Maier, A}, title = {[Sonography of muscles : Rheumatology-Neurology-Geriatrics-Sports medicine-Orthopedics].}, journal = {Zeitschrift fur Rheumatologie}, volume = {83}, number = {10}, pages = {829-843}, pmid = {39143255}, issn = {1435-1250}, mesh = {Humans ; *Ultrasonography/methods ; Magnetic Resonance Imaging ; Rheumatology/methods ; Muscle, Skeletal/diagnostic imaging ; Athletic Injuries/diagnostic imaging ; Sarcopenia/diagnostic imaging ; Sports Medicine/methods ; Rheumatic Diseases/diagnostic imaging ; Geriatrics ; Aged ; Neurology ; Muscular Diseases/diagnostic imaging ; Evidence-Based Medicine ; }, abstract = {Muscle sonography is used in rheumatology, neurology, geriatrics, sports medicine and orthopedics. Muscular atrophy with fatty and connective tissue degeneration can be visualized and must be interpreted in conjunction with the sonographic findings of the supplying nerves. Sonography is becoming increasingly more important for the early diagnosis of sarcopenia in rheumatology, geriatrics and osteology. Even if its significance has not yet been conclusively clarified, many publications confirm the high reliability of the method. Sonography can ideally be used in addition to magnetic resonance imaging (MRI) in the diagnostics of myositis as it can speed up the diagnosis, muscle groups that were not imaged by MRI can also be assessed sonographically and all muscle groups can be examined during the course of the procedure. Sonography also helps to make a quick and uncomplicated diagnosis of many sports injuries in addition to MRI and is therefore the basis for a targeted therapeutic approach.}, } @article {pmid39142444, year = {2024}, author = {Tan, X and Su, X and Wang, Y and Liang, W and Wang, D and Huo, D and Wang, H and Qi, Y and Zhang, W and Han, L and Zhang, D and Wang, M and Xu, J and Feng, H}, title = {RBM5 induces motor neuron apoptosis in hSOD1[G93A]-related amyotrophic lateral sclerosis by inhibiting Rac1/AKT pathways.}, journal = {Brain research bulletin}, volume = {216}, number = {}, pages = {111049}, doi = {10.1016/j.brainresbull.2024.111049}, pmid = {39142444}, issn = {1873-2747}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *rac1 GTP-Binding Protein/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Apoptosis/physiology ; *RNA-Binding Proteins/metabolism/genetics ; Mice ; Humans ; *Signal Transduction/physiology ; *Proto-Oncogene Proteins c-akt/metabolism ; Mice, Transgenic ; Superoxide Dismutase/metabolism/genetics ; Male ; DNA-Binding Proteins ; Cell Cycle Proteins ; Tumor Suppressor Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder distinguished by gradual depletion of motor neurons. RNA binding motif protein 5 (RBM5), an abundantly expressed RNA-binding protein, plays a critical role in the process of cellular death. However, little is known about the role of RBM5 in the pathogenesis of ALS. Here, we found that RBM5 was upregulated in ALS hSOD1[G93A]-NSC34 cell models and hSOD1[G93A] mice due to a reduction of miR-141-5p. The upregulation of RBM5 increased the apoptosis of motor neurons by inhibiting Rac1-mediated neuroprotection. In contrast, genetic knockdown of RBM5 rescued motor neurons from hSOD1[G93A]-induced degeneration by activating Rac1 signaling. The neuroprotective effect of RBM5-knockdown was significantly inhibited by the Rac1 inhibitor, NSC23766. These findings suggest that RBM5 could potentially serve as a therapeutic target in ALS by activating the Rac1 signalling.}, } @article {pmid39141854, year = {2024}, author = {Vansteensel, MJ and Leinders, S and Branco, MP and Crone, NE and Denison, T and Freudenburg, ZV and Geukes, SH and Gosselaar, PH and Raemaekers, M and Schippers, A and Verberne, M and Aarnoutse, EJ and Ramsey, NF}, title = {Longevity of a Brain-Computer Interface for Amyotrophic Lateral Sclerosis.}, journal = {The New England journal of medicine}, volume = {391}, number = {7}, pages = {619-626}, pmid = {39141854}, issn = {1533-4406}, support = {INTENSE, 17619//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; UH3 NS114439/NS/NINDS NIH HHS/United States ; U01DC016686/DC/NIDCD NIH HHS/United States ; U01 DC016686/DC/NIDCD NIH HHS/United States ; UH3NS114439/NS/NINDS NIH HHS/United States ; UGT7685, Economic Affairs SSM06011 and STW 12803//Netherlands Institute of Government/ ; }, mesh = {Female ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging/rehabilitation ; *Atrophy/diagnostic imaging/etiology/prevention & control ; Brain/diagnostic imaging ; *Brain-Computer Interfaces ; Communication Devices for People with Disabilities ; Time Factors ; Treatment Failure ; Electrodes, Implanted ; }, abstract = {The durability of communication with the use of brain-computer interfaces in persons with progressive neurodegenerative disease has not been extensively examined. We report on 7 years of independent at-home use of an implanted brain-computer interface for communication by a person with advanced amyotrophic lateral sclerosis (ALS), the inception of which was reported in 2016. The frequency of at-home use increased over time to compensate for gradual loss of control of an eye-gaze-tracking device, followed by a progressive decrease in use starting 6 years after implantation. At-home use ended when control of the brain-computer interface became unreliable. No signs of technical malfunction were found. Instead, the amplitude of neural signals declined, and computed tomographic imaging revealed progressive atrophy, which suggested that ALS-related neurodegeneration ultimately rendered the brain-computer interface ineffective after years of successful use, although alternative explanations are plausible. (Funded by the National Institute on Deafness and Other Communication Disorders and others; ClinicalTrials.gov number, NCT02224469.).}, } @article {pmid39141853, year = {2024}, author = {Card, NS and Wairagkar, M and Iacobacci, C and Hou, X and Singer-Clark, T and Willett, FR and Kunz, EM and Fan, C and Vahdati Nia, M and Deo, DR and Srinivasan, A and Choi, EY and Glasser, MF and Hochberg, LR and Henderson, JM and Shahlaie, K and Stavisky, SD and Brandman, DM}, title = {An Accurate and Rapidly Calibrating Speech Neuroprosthesis.}, journal = {The New England journal of medicine}, volume = {391}, number = {7}, pages = {609-618}, pmid = {39141853}, issn = {1533-4406}, support = {U01DC17844/DC/NIDCD NIH HHS/United States ; AL220043//Congressionally Directed Medical Research Programs/ ; U01 DC019430/DC/NIDCD NIH HHS/United States ; R01 MH060974/MH/NIMH NIH HHS/United States ; 872146SPI//Simons Foundation/ ; A2295-R//U.S. Department of Veterans Affairs/ ; DP2DC021055/DC/NIDCD NIH HHS/United States ; U01DC019430/DC/NIDCD NIH HHS/United States ; I01 RX002295/RX/RRD VA/United States ; DP2 DC021055/DC/NIDCD NIH HHS/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/rehabilitation ; *Brain-Computer Interfaces ; Calibration ; Communication Devices for People with Disabilities ; *Dysarthria/rehabilitation/etiology ; Electrodes, Implanted ; Microelectrodes ; Quadriplegia/etiology/rehabilitation ; *Speech ; }, abstract = {BACKGROUND: Brain-computer interfaces can enable communication for people with paralysis by transforming cortical activity associated with attempted speech into text on a computer screen. Communication with brain-computer interfaces has been restricted by extensive training requirements and limited accuracy.

METHODS: A 45-year-old man with amyotrophic lateral sclerosis (ALS) with tetraparesis and severe dysarthria underwent surgical implantation of four microelectrode arrays into his left ventral precentral gyrus 5 years after the onset of the illness; these arrays recorded neural activity from 256 intracortical electrodes. We report the results of decoding his cortical neural activity as he attempted to speak in both prompted and unstructured conversational contexts. Decoded words were displayed on a screen and then vocalized with the use of text-to-speech software designed to sound like his pre-ALS voice.

RESULTS: On the first day of use (25 days after surgery), the neuroprosthesis achieved 99.6% accuracy with a 50-word vocabulary. Calibration of the neuroprosthesis required 30 minutes of cortical recordings while the participant attempted to speak, followed by subsequent processing. On the second day, after 1.4 additional hours of system training, the neuroprosthesis achieved 90.2% accuracy using a 125,000-word vocabulary. With further training data, the neuroprosthesis sustained 97.5% accuracy over a period of 8.4 months after surgical implantation, and the participant used it to communicate in self-paced conversations at a rate of approximately 32 words per minute for more than 248 cumulative hours.

CONCLUSIONS: In a person with ALS and severe dysarthria, an intracortical speech neuroprosthesis reached a level of performance suitable to restore conversational communication after brief training. (Funded by the Office of the Assistant Secretary of Defense for Health Affairs and others; BrainGate2 ClinicalTrials.gov number, NCT00912041.).}, } @article {pmid39141064, year = {2024}, author = {Wiesenfarth, M and Forouhideh-Wiesenfarth, Y and Elmas, Z and Parlak, Ö and Weiland, U and Herrmann, C and Schuster, J and Freischmidt, A and Müller, K and Siebert, R and Günther, K and Fröhlich, E and Knehr, A and Simak, T and Bachhuber, F and Regensburger, M and Petri, S and Klopstock, T and Reilich, P and Schöberl, F and Schumann, P and Körtvélyessy, P and Meyer, T and Ruf, WP and Witzel, S and Tumani, H and Brenner, D and Dorst, J and Ludolph, AC}, title = {Clinical characterization of common pathogenic variants of SOD1-ALS in Germany.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6667-6679}, pmid = {39141064}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Superoxide Dismutase-1/genetics ; Male ; Female ; Germany ; Middle Aged ; Aged ; *Disease Progression ; Mutation ; Adult ; Phenotype ; }, abstract = {Pathogenic variants in the Cu/Zn superoxide dismutase (SOD1) gene can be detected in approximately 2% of sporadic and 11% of familial amyotrophic lateral sclerosis (ALS) patients in Europe. We analyzed the clinical phenotypes of 83 SOD1-ALS patients focusing on patients carrying the most frequent (likely) pathogenic variants (R116G, D91A, L145F) in Germany. Moreover, we describe the effect of tofersen treatment on ten patients carrying these variants. R116G patients showed the most aggressive course of disease with a median survival of 22.0 months compared to 198.0 months in D91A and 87.0 months in L145F patients (HR 7.71, 95% CI 2.89-20.58 vs. D91A; p < 0.001 and HR 4.25, 95% CI 1.55-11.67 vs. L145F; p = 0.02). Moreover, R116G patients had the fastest median ALSFRS-R progression rate with 0.12 (IQR 0.07-0.20) points lost per month. Median diagnostic delay was 10.0 months (IQR 5.5-11.5) and therefore shorter compared to 57.5 months (IQR 14.0-83.0) in D91A (p < 0.001) and 21.5 months (IQR 5.8-38.8) in L145F (p = 0.21) carriers. As opposed to D91A carriers (50.0%), 96.2% of R116G (p < 0.001) and 100.0% of L145F (p = 0.04) patients reported a positive family history. During tofersen treatment, all patients showed a reduction of neurofilament light chain (NfL) serum levels, independent of the SOD1 variant. Patients with SOD1-ALS carrying R116G, D91A, or L145F variants show commonalities, but also differences in their clinical phenotype, including a faster progression rate with shorter survival in R116G, and a comparatively benign disease course in D91A carriers.}, } @article {pmid39140323, year = {2024}, author = {Nakamura, T and He, X and Hattori, N and Hida, E and Hirata, M}, title = {Dilemma in patients with amyotrophic lateral sclerosis and expectations from brain-machine interfaces.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2386516}, pmid = {39140323}, issn = {1365-2060}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Brain-Computer Interfaces ; Male ; Female ; Middle Aged ; Aged ; Surveys and Questionnaires ; *Motivation ; *Caregivers/psychology ; *Anxiety/psychology/etiology ; Adult ; Tracheostomy ; Caregiver Burden/psychology ; Locked-In Syndrome/psychology ; }, abstract = {OBJECTIVE: We hypothesized that patients with amyotrophic lateral sclerosis (ALS) face a dilemma between motivation to live and difficulty in living, and brain-machine interfaces (BMIs) can reduce this dilemma. This study aimed to investigate the present situation of patients with ALS and their expectations from BMIs.

MATERIALS AND METHODS: Our survey design consisted of an anonymous mail-in questionnaire comprising questions regarding the use of tracheostomy positive pressure ventilation (TPPV), motivation to live, anxiety about the totally locked-in state (TLS), anxiety about caregiver burden, and expectations regarding the use of BMI. Primary outcomes were scores for motivation to live and anxiety about caregiver burden and the TLS. Outcomes were evaluated using the visual analogue scale.

RESULTS: Among 460 participants, 286 (62.6%) were already supported by or had decided to use TPPV. The median scores for motivation to live, anxiety about TLS, and anxiety about caregiver burden were 8.0, 9.0, and 7.0, respectively. Overall, 49% of patients intended to use BMI. Among patients who had refused TPPV, 15.9% intended to use BMI and TPPV. Significant factors for the use of BMI were motivation to live (p = .003), anxiety about TLS (p < .001), younger age (p < .001), and advanced disease stage (p < .001).

CONCLUSIONS: These results clearly revealed a serious dilemma among patients with ALS between motivation to live and their anxiety about TLS and caregiver burden. Patients expected BMI to reduce this dilemma. Thus, the development of better BMIs may meet these expectations.}, } @article {pmid39139642, year = {2024}, author = {Liu, X and Li, Y and Huang, L and Kuang, Y and Wu, X and Ma, X and Zhao, B and Lan, J}, title = {Unlocking the therapeutic potential of P2X7 receptor: a comprehensive review of its role in neurodegenerative disorders.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1450704}, pmid = {39139642}, issn = {1663-9812}, abstract = {The P2X7 receptor (P2X7R), an ATP-gated ion channel, has emerged as a crucial player in neuroinflammation and a promising therapeutic target for neurodegenerative disorders. This review explores the current understanding of P2X7R's structure, activation, and physiological roles, focusing on its expression and function in microglial cells. The article examines the receptor's involvement in calcium signaling, microglial activation, and polarization, as well as its role in the pathogenesis of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. The review highlights the complex nature of P2X7R signaling, discussing its potential neuroprotective and neurotoxic effects depending on the disease stage and context. It also addresses the development of P2X7R antagonists and their progress in clinical trials, identifying key research gaps and future perspectives for P2X7R-targeted therapy development. By providing a comprehensive overview of the current state of knowledge and future directions, this review serves as a valuable resource for researchers and clinicians interested in exploring the therapeutic potential of targeting P2X7R for the treatment of neurodegenerative disorders.}, } @article {pmid39139312, year = {2024}, author = {Kaur, B and Samagh, N and Narang, A and Paliwal, S}, title = {Anesthetic Management of a Neurosurgical Patient With Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64492}, pmid = {39139312}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive form of neurological disorder that affects both the upper and lower motor neurons. Anesthesia management in these patients is always challenging as they can develop respiratory complications because of pre-existing muscle involvement. We report a middle-aged male with ALS posted for chronic subdural hematoma evacuation (CSDH) surgery. Surgery was done under scalp block with monitored anesthesia care. The choice of anesthesia in these patients should be one that interferes the least with the disease pattern while still providing optimal conditions for surgery.}, } @article {pmid39138961, year = {2024}, author = {Rosano, A and Bicaj, M and Cillerai, M and Ponzano, M and Cabona, C and Gemelli, C and Caponnetto, C and Pardini, M and Signori, A and Uccelli, A and Schenone, A and Ferraro, PM}, title = {Psychological resilience is protective against cognitive deterioration in motor neuron diseases.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {717-725}, doi = {10.1080/21678421.2024.2385690}, pmid = {39138961}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Resilience, Psychological ; *Motor Neuron Disease/psychology/complications ; Aged ; *Cognitive Dysfunction/psychology/etiology ; Neuropsychological Tests ; Longitudinal Studies ; Adult ; }, abstract = {OBJECTIVES: Recent studies suggest that psychological resilience (PR) is associated with more well-preserved cognition in healthy subjects (HS), but an investigation of such phenomenon in patients with motor neuron diseases (MNDs) is still lacking. The aim of our study was therefore to evaluate PR and its relationship with baseline cognitive/behavioral and mood symptoms, as well as longitudinal cognitive functioning, in MNDs.

METHODS: 94 MND patients and 87 demographically matched HS were enrolled. PR was assessed using the Connor-Davidson Resilience Scale (CD-RISC). Patients were further evaluated both at baseline and every 6 months for cognitive/behavioral disturbances using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), and for mood symptoms using the Hospital Anxiety and Depression Scale (HADS). CD-RISC scores were compared between patients and HS using the Mann-Whitney U test, and regression models were applied to evaluate the role of CD-RISC scores in predicting baseline cognitive/behavioral and mood measures, as well as longitudinal cognitive performances, in MND patients.

RESULTS: MND cases showed significantly greater PR compared to HS (p from <0.001 to 0.02). In MNDs, higher PR levels were significant predictors of both greater cognitive performance (p from 0.01 to 0.05) and milder mood symptoms (p from <0.001 to 0.04) at baseline, as well as less severe memory decline (p from 0.001 to 0.04) longitudinally.

CONCLUSIONS: PR is an important protective factor against the onset and evolution of cognitive/mood disturbances in MNDs, suggesting the usefulness of resilience enhancement psychological interventions to prevent or delay cognitive and mood disorders in these neurodegenerative conditions.}, } @article {pmid39138578, year = {2024}, author = {Wasielewska, JM and Chaves, JCS and Cabral-da-Silva, MC and Pecoraro, M and Viljoen, SJ and Nguyen, TH and Bella, V and Oikari, LE and Ooi, L and White, AR}, title = {A patient-derived amyotrophic lateral sclerosis blood-brain barrier model for focused ultrasound-mediated anti-TDP-43 antibody delivery.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {65}, pmid = {39138578}, issn = {2045-8118}, support = {PhD Scholarship//University of Queensland/ ; PhD Top-Up Scholarship//QIMR Berghofer Medical Research Institute/ ; APP1125796 and 1118452//National Health and Medical Research Council/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; *Microbubbles ; *DNA-Binding Proteins/metabolism ; Drug Delivery Systems/methods ; Endothelial Cells/metabolism ; Antibodies/administration & dosage ; Ultrasonic Waves ; Cells, Cultured ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder with minimally effective treatment options. An important hurdle in ALS drug development is the non-invasive therapeutic access to the motor cortex currently limited by the presence of the blood-brain barrier (BBB). Focused ultrasound and microbubble (FUS[+ MB]) treatment is an emerging technology that was successfully used in ALS patients to temporarily open the cortical BBB. However, FUS[+ MB]-mediated drug delivery across ALS patients' BBB has not yet been reported. Similarly, the effects of FUS[+ MB] on human ALS BBB cells remain unexplored.

METHODS: Here we established the first FUS[+ MB]-compatible, fully-human ALS patient-cell-derived BBB model based on induced brain endothelial-like cells (iBECs) to study anti-TDP-43 antibody delivery and FUS[+ MB] bioeffects in vitro.

RESULTS: Generated ALS iBECs recapitulated disease-specific hallmarks of BBB pathology, including reduced BBB integrity and permeability, and TDP-43 proteinopathy. The results also identified differences between sporadic ALS and familial (C9orf72 expansion carrying) ALS iBECs reflecting patient heterogeneity associated with disease subgroups. Studies in these models revealed successful ALS iBEC monolayer opening in vitro with no adverse cellular effects of FUS[+ MB] as reflected by lactate dehydrogenase (LDH) release viability assay and the lack of visible monolayer damage or morphology change in FUS[+ MB] treated cells. This was accompanied by the molecular bioeffects of FUS[+ MB] in ALS iBECs including changes in expression of tight and adherens junction markers, and drug transporter and inflammatory mediators, with sporadic and C9orf72 ALS iBECs generating transient specific responses. Additionally, we demonstrated an effective increase in the delivery of anti-TDP-43 antibody with FUS[+ MB] in C9orf72 (2.7-fold) and sporadic (1.9-fold) ALS iBECs providing the first proof-of-concept evidence that FUS[+ MB] can be used to enhance the permeability of large molecule therapeutics across the BBB in a human ALS in vitro model.

CONCLUSIONS: Together, this study describes the first characterisation of cellular and molecular responses of ALS iBECs to FUS[+ MB] and provides a fully-human platform for FUS[+ MB]-mediated drug delivery screening on an ALS BBB in vitro model.}, } @article {pmid39138120, year = {2024}, author = {Euler, L and Deinert, K and Wagener, F and Walpurgis, K and Thevis, M}, title = {Identification of human metabolites of fast skeletal troponin activators Tirasemtiv and Reldesemtiv for doping control purposes.}, journal = {Drug testing and analysis}, volume = {}, number = {}, pages = {}, doi = {10.1002/dta.3786}, pmid = {39138120}, issn = {1942-7611}, support = {//Federal Ministry of Interior, Building and Community/ ; //Manfred-Donike-Institute for Doping Analysis/ ; }, abstract = {The fast skeletal troponin activators (FSTAs) Reldesemtiv and Tirasemtiv were developed for patients suffering from neuro-degenerative diseases of the motor nervous system, e.g. amyotrophic lateral sclerosis (ALS). The drug candidates can increase the sensitivity of troponin C to calcium by selectively activating the troponin complex resulting in increased skeletal muscle contraction. Although the development of the drug candidates is currently discontinued because of missed end points in phase III clinical studies with patients with ALS, phase I clinical trials showed an increase in muscle contraction force in healthy humans. This effect could be abused by athletes to enhance performance in sports. As the substances are listed on the 2024 edition of the World Anti-Doping Agency's Prohibited List, the aim of this study was to identify and characterize metabolites of Reldesemtiv and Tirasemtiv to ensure their reliable identification in doping control analyses. The biotransformation of the drug candidates was studied in vitro using pooled human liver microsomes and 3D cultivated human hepatic cells of the cell line HepaRG, yielding a total of 11 metabolites of Reldesemtiv and eight of Tirasemtiv. In addition, a human elimination study was conducted to investigate the metabolism and elimination profile of Tirasemtiv and Reldesemtiv in vivo, suggesting the N-glucuronide of Tirasemtiv and hydroxylated 3-fluoro-2-(3-fluoro-1-methylcyclobutyl)pyridine as well as its glucuronide as suitable target analytes for routine doping controls. Applying a validating HPLC-MS/MS method, optimized to detect Reldesemtiv and Tirasemtiv in human urine, microdosing (50 μg) of each substance was traceable for 24-72 h.}, } @article {pmid39138039, year = {2024}, author = {Candelo, E and Vasudevan, SS and Orellana, D and Williams, AM and Rutt, AL}, title = {Exploring the Impact of Amyotrophic Lateral Sclerosis on Otolaryngological Functions.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2024.07.025}, pmid = {39138039}, issn = {1873-4588}, abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons at the spinal or bulbar level.

OBJECTIVE: We aim to describe the most frequent otolaryngology (ORL) complaints and voice disturbances in patients with bulbar onset ALS.

DESIGN: Retrospective cohort study.

SETTING: Single-center study with combined ORL and ALS clinic evaluation.

PARTICIPANTS: Patients with a confirmed diagnosis of ALS following an ORL visit and who underwent comprehensive voice assessments between January 2021 and January 2023.

EXPOSURE: Objective voice assessments.

MAIN OUTCOMES AND MEASURES: Glottal functional index (GFI), voice handicap index (VHI), reflux system index (RSI), and voice quality characteristics such as shimmer, jitter, maximum phonation time (MPT), and other essential parameters were assessed.

RESULTS: One hundred and thirty-three patients (age 62.17 ± 10.79, 54.48% female) were included. Three patients were referred from the ORL department to the ALS clinic. The most frequent symptoms were; dysphagia, dysarthria, facial weakness, pseudobulbar affect, and sialorrhea. The mean of forced vital capacity was 59.85%, EAT-10 15.91 ± 11.66, RSI 25.84 ± 9.03, GFI 14.12 ± 5.58, VHI-10 42.81 ± 34.94, MPT 15.22 s ± 8.06. Many patients reported voice impairments mainly related to spastic dysarthria and the combination of lower and upper motor neuron dysarthria, hypernasality, reduced verbal expression, and articulatory accuracy. Shimmer was increased to 8.46% ± 7.20, and jitter to 2.26% ± 1.39.

CONCLUSIONS AND RELEVANCE: Based on our cohort, this population with bulbar onset ALS has a higher frequency of voice disturbance characterized by hypernasality, spastic dysarthria, and reduced verbal expression.

LEVEL OF EVIDENCE: Level 3.}, } @article {pmid39137976, year = {2024}, author = {Pavey, N and Hannaford, A and Higashihara, M and van den Bos, M and Geevasinga, N and Vucic, S and Menon, P}, title = {Cortical inexcitability in ALS: correlating a clinical phenotype.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-333928}, pmid = {39137976}, issn = {1468-330X}, abstract = {BACKGROUND: Cortical inexcitability, a less studied feature of upper motor neuron (UMN) dysfunction in amyotrophic lateral sclerosis (ALS), was identified in a large cross-sectional cohort of ALS patients and their demographic and clinical characteristics were contrasted with normal or hyperexcitable ALS cohorts to assess the impact of cortical inexcitability on ALS phenotype and survival.

METHODS: Threshold-tracking transcranial magnetic stimulation (TMS) technique with measurement of mean short interval intracortical inhibition (SICI) differentiated ALS patients into three groups (1) inexcitable (no TMS response at maximal stimulator output in the setting of preserved lower motor neuron (LMN) function), (2) hyperexcitable (SICI≤5.5%) and (3) normal cortical excitability (SICI>5.5%). Clinical phenotyping and neurophysiological assessment of LMN function were undertaken, and survival was recorded in the entire cohort.

RESULTS: 417 ALS patients were recruited, of whom 26.4% exhibited cortical inexcitability. Cortical inexcitability was associated with a younger age of disease onset (p<0.05), advanced Awaji criteria (p<0.01) and Kings stage (p<0.01) scores. Additionally, patients with cortical inexcitability had higher UMN score (p<0.01), lower revised ALS Functional Rating Scale score (p<0.01) and reduced upper limb strength score (MRC UL, p<0.01). Patient survival (p=0.398) was comparable across the groups, despite lower riluzole use in the cortical inexcitability patient group (p<0.05).

CONCLUSION: The present study established that cortical inexcitability was associated with a phenotype characterised by prominent UMN signs, greater motor and functional decline, and a younger age of onset. The present findings inform patient management and could improve patient stratification in clinical trials.}, } @article {pmid39135084, year = {2024}, author = {Ma, H and Zhu, M and Chen, M and Li, X and Feng, X}, title = {The role of macrophage plasticity in neurodegenerative diseases.}, journal = {Biomarker research}, volume = {12}, number = {1}, pages = {81}, pmid = {39135084}, issn = {2050-7771}, support = {PX2023037//Beijing Municipal Administration of Hospitals Incubating Program/ ; }, abstract = {Tissue-resident macrophages and recruited macrophages play pivotal roles in innate immunity and the maintenance of brain homeostasis. Investigating the involvement of these macrophage populations in eliciting pathological changes associated with neurodegenerative diseases has been a focal point of research. Dysregulated states of macrophages can compromise clearance mechanisms for pathological proteins such as amyloid-β (Aβ) in Alzheimer's disease (AD) and TDP-43 in Amyotrophic lateral sclerosis (ALS). Additionally, recent evidence suggests that abnormalities in the peripheral clearance of pathological proteins are implicated in the pathogenesis and progression of neurodegenerative diseases. Furthermore, numerous genome-wide association studies have linked genetic risk factors, which alter the functionality of various immune cells, to the accumulation of pathological proteins. This review aims to unravel the intricacies of macrophage biology in both homeostatic conditions and neurodegenerative disorders. To this end, we initially provide an overview of the modifications in receptor and gene expression observed in diverse macrophage subsets throughout development. Subsequently, we outlined the roles of resident macrophages and recruited macrophages in neurodegenerative diseases and the progress of targeted therapy. Finally, we describe the latest advances in macrophage imaging methods and measurement of inflammation, which may provide information and related treatment strategies that hold promise for informing the design of future investigations and therapeutic interventions.}, } @article {pmid39134696, year = {2024}, author = {Visser, BS and Lipiński, WP and Spruijt, E}, title = {The role of biomolecular condensates in protein aggregation.}, journal = {Nature reviews. Chemistry}, volume = {8}, number = {9}, pages = {686-700}, pmid = {39134696}, issn = {2397-3358}, mesh = {Humans ; *Biomolecular Condensates/metabolism/chemistry ; *Protein Aggregates ; Neurodegenerative Diseases/metabolism ; Amyloid/metabolism/chemistry ; Protein Aggregation, Pathological/metabolism ; Proteins/chemistry/metabolism ; }, abstract = {There is an increasing amount of evidence that biomolecular condensates are linked to neurodegenerative diseases associated with protein aggregation, such as Alzheimer's disease and amyotrophic lateral sclerosis, although the mechanisms underlying this link remain elusive. In this Review, we summarize the possible connections between condensates and protein aggregation. We consider both liquid-to-solid transitions of phase-separated proteins and the partitioning of proteins into host condensates. We distinguish five key factors by which the physical and chemical environment of a condensate can influence protein aggregation, and we discuss their relevance in studies of protein aggregation in the presence of biomolecular condensates: increasing the local concentration of proteins, providing a distinct chemical microenvironment, introducing an interface wherein proteins can localize, changing the energy landscape of aggregation pathways, and the presence of chaperones in condensates. Analysing the role of biomolecular condensates in protein aggregation may be essential for a full understanding of amyloid formation and offers a new perspective that can help in developing new therapeutic strategies for the prevention and treatment of neurodegenerative diseases.}, } @article {pmid39134599, year = {2024}, author = {Mikawy, NN and Magdy, N and Mohamed, MH and El-Kosasy, AM}, title = {Green highly sensitive and selective spectroscopic detection of guaifenesin in multiple dosage forms and spiked human plasma.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {18694}, pmid = {39134599}, issn = {2045-2322}, mesh = {*Guaifenesin/analysis/administration & dosage ; Humans ; *Limit of Detection ; *Spectrometry, Fluorescence/methods ; Tablets ; Green Chemistry Technology/methods ; }, abstract = {Guaifenesin (GUA) is determined in dosage forms and plasma using two methods. The spectrofluorimetric technique relies on the measurement of native fluorescence intensity at 302 nm upon excitation wavelength "223 nm". The method was validated according to ICH and FDA guidelines. A concentration range of 0.1-1.1 μg/mL was used, with limit of detection (LOD) and quantification (LOQ) values 0.03 and 0.08 µg/mL, respectively. This method was used to measure GUA in tablets and plasma, with %recovery of 100.44% ± 0.037 and 101.03% ± 0.751. Furthermore, multivariate chemometric-assisted spectrophotometric methods are used for the determination of GUA, paracetamol (PARA), oxomemazine (OXO), and sodium benzoate (SB) in their lab mixtures. The concentration ranges of 2.0-10.0, 4.0-16.0, 2.0-10.0, and 3.0-10.0 µg/mL for OXO, GUA, PARA, and SB; respectively, were used. LOD and LOQ were 0.33, 0.68, 0.28, and 0.29 µg/mL, and 1.00, 2.06, 0.84, and 0.87 µg/mL for PARA, GUA, OXO, and SB. For the suppository application, the partial least square (PLS) model was used with %recovery 98.49% ± 0.5, 98.51% ± 0.64, 100.21% ± 0.36 & 98.13% ± 0.51, although the multivariate curve resolution alternating least-squares (MCR-ALS) model was used with %recovery 101.39 ± 0.45, 99.19 ± 0.2, 100.24 ± 0.12, and 98.61 ± 0.32 for OXO, GUA, PARA, and SB. Analytical Eco-scale and Analytical Greenness Assessment were used to assess the greenness level of our techniques.}, } @article {pmid39134031, year = {2025}, author = {Aziz, M and Kniep, I and Ondruschka, B and Püschel, K and Hessler, C}, title = {Cement Leakage after Augmentation of Osteoporotic Vertebral Bodies.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {163}, number = {2}, pages = {146-152}, doi = {10.1055/a-2343-4100}, pmid = {39134031}, issn = {1864-6743}, mesh = {Humans ; Male ; Female ; Aged ; *Spinal Fractures/surgery ; *Osteoporotic Fractures/surgery ; *Bone Cements/adverse effects ; Aged, 80 and over ; Middle Aged ; Germany/epidemiology ; Risk Factors ; Extravasation of Diagnostic and Therapeutic Materials ; Vertebroplasty/adverse effects ; Postoperative Complications/surgery ; Incidence ; }, abstract = {Der Zementaustritt ist die häufigste Komplikation bei der Zementaugmentation von Wirbelkörpern. In der vorliegenden Studie wurden die Zementaustrittsraten bei Zementaugmentationen an der Wirbelsäule untersucht und potenzielle Risikofaktoren für einen Zementaustritt identifiziert.Es wurden 140 Fälle von 131 Patienten und Patientinnen und 9 Verstorbenen ausgewertet. Insgesamt wurden 258 zementaugmentierte Wirbelkörper untersucht. Die Daten dafür stammen aus den Krankenhausdokumentationen von 131 Patienten und Patientinnen, die sich in 2 orthopädisch-unfallchirurgischen Kliniken in der BRD solchen Operationen unterzogen, sowie aus den Untersuchungen von 9 Sterbefällen im Institut für Rechtsmedizin der Universitätsklinikums Hamburg-Eppendorf.Zementaustritte wurden in 64 der 140 Fälle (45,7%) ermittelt. Lokale Zementaustritte waren mit 73,4% (n = 47) die häufigste Austrittsart. Venöse Austritte wurden in 15 Fällen (23,4%) und Lungenzementembolisationen in 2 Fällen (3,1%) evaluiert. Innerhalb des Kollektivs der retrospektiv untersuchten Fälle (n = 131) erlitt lediglich 1 Patient (0,8%) einen symptomatischen Zementaustritt. Als Risikofaktoren für Zementaustritte konnten Zementaugmentationen von Frakturen an Lendenwirbelkörpern sowie eine hohe applizierte Zementmenge identifiziert werden.Sowohl die Daten in der assoziierten Literatur als auch die Ergebnisse dieser Arbeit belegen eine hohe Inzidenz von Zementaustritten nach Wirbelkörperaugmentationen. Trotz des geringen prozentualen Anteils symptomatischer Fälle sollten bei der Planung und Durchführung von Zementaugmentationen an Wirbelkörpern die möglichen Einflussfaktoren für einen Zementaustritt berücksichtigt und in die OP-Planung einbezogen werden.}, } @article {pmid39131911, year = {2024}, author = {Ikeda, A and Meng, H and Taniguchi, D and Mio, M and Funayama, M and Nishioka, K and Yoshida, M and Li, Y and Yoshino, H and Inoshita, T and Shiba-Fukushima, K and Okubo, Y and Sakurai, T and Amo, T and Aiba, I and Saito, Y and Saito, Y and Murayama, S and Atsuta, N and Nakamura, R and Tohnai, G and Izumi, Y and Morita, M and Tamura, A and Kano, O and Oda, M and Kuwabara, S and Yamashita, T and Sone, J and Kaji, R and Sobue, G and Imai, Y and Hattori, N}, title = {CHCHD2 P14L, found in amyotrophic lateral sclerosis, exhibits cytoplasmic mislocalization and alters Ca[2+] homeostasis.}, journal = {PNAS nexus}, volume = {3}, number = {8}, pages = {pgae319}, pmid = {39131911}, issn = {2752-6542}, abstract = {CHCHD2 and CHCHD10, linked to Parkinson's disease and amyotrophic lateral sclerosis-frontotemporal dementia (ALS), respectively, are mitochondrial intermembrane proteins that form a heterodimer. This study aimed to investigate the impact of the CHCHD2 P14L variant, implicated in ALS, on mitochondrial function and its subsequent effects on cellular homeostasis. The missense variant of CHCHD2, P14L, found in a cohort of patients with ALS, mislocalized CHCHD2 to the cytoplasm, leaving CHCHD10 in the mitochondria. Drosophila lacking the CHCHD2 ortholog exhibited mitochondrial degeneration. In contrast, human CHCHD2 P14L, but not wild-type human CHCHD2, failed to suppress this degeneration, suggesting that P14L is a pathogenic variant. The mitochondrial Ca[2+] buffering capacity was reduced in Drosophila neurons expressing human CHCHD2 P14L. The altered Ca[2+]-buffering phenotype was also observed in cultured human neuroblastoma SH-SY5Y cells expressing CHCHD2 P14L. In these cells, transient elevation of cytoplasmic Ca[2+] facilitated the activation of calpain and caspase-3, accompanied by the processing and insolubilization of TDP-43. These observations suggest that CHCHD2 P14L causes abnormal Ca[2+] dynamics and TDP-43 aggregation, reflecting the pathophysiology of ALS.}, } @article {pmid39130445, year = {2024}, author = {Phipps, AJ and Dwyer, S and Collins, JM and Kabir, F and Atkinson, RA and Chowdhury, MA and Matthews, L and Dixit, D and Terry, RS and Smith, J and Gueven, N and Bennett, W and Cook, AL and King, AE and Perry, S}, title = {HDAC6 inhibition as a mechanism to prevent neurodegeneration in the mSOD1[G93A] mouse model of ALS.}, journal = {Heliyon}, volume = {10}, number = {14}, pages = {e34587}, pmid = {39130445}, issn = {2405-8440}, abstract = {The loss of upper and lower motor neurons, and their axons is central to the loss of motor function and death in amyotrophic lateral sclerosis (ALS). Due to the diverse range of genetic and environmental factors that contribute to the pathogenesis of ALS, there have been difficulties in developing effective therapies for ALS. One emerging dichotomy is that protection of the neuronal cell soma does not prevent axonal vulnerability and degeneration, suggesting the need for targeted therapeutics to prevent axon degeneration. Post-translational modifications of protein acetylation can alter the function, stability and half-life of individual proteins, and can be enzymatically modified by histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs), which add, or remove acetyl groups, respectively. Maintenance of post-translational microtubule acetylation has been suggested as a mechanism to stabilize axons, prevent axonal loss and neurodegeneration in ALS. This study used an orally dosed potent HDAC6 inhibitor, ACY-738, prevent deacetylation and stabilize microtubules in the mSOD1[G93A] mouse model of ALS. Co-treatment with riluzole was performed to determine any effects or drug interactions and potentially enhance preclinical research translation. This study shows ACY-738 treatment increased acetylation of microtubules in the spinal cord of mSOD1[G93A] mice, reduced lower motor neuron degeneration in female mice, ameliorated reduction in peripheral nerve axon puncta size, but did not prevent overt motor function decline. The current study also shows peripheral nerve axon puncta size to be partially restored after treatment with riluzole and highlights the importance of co-treatment to measure the potential effects of therapeutics in ALS.}, } @article {pmid39128808, year = {2024}, author = {Farhangian, M and Azarafrouz, F and Valian, N and Dargahi, L}, title = {The role of interferon beta in neurological diseases and its potential therapeutic relevance.}, journal = {European journal of pharmacology}, volume = {981}, number = {}, pages = {176882}, doi = {10.1016/j.ejphar.2024.176882}, pmid = {39128808}, issn = {1879-0712}, mesh = {Humans ; Animals ; *Interferon-beta/therapeutic use/metabolism ; Nervous System Diseases/drug therapy/metabolism ; Signal Transduction/drug effects ; }, abstract = {Interferon beta (IFNβ) is a member of the type-1 interferon family and has various immunomodulatory functions in neuropathological conditions. Although the level of IFNβ is low under healthy conditions, it is increased during inflammatory processes to protect the central nervous system (CNS). In particular, microglia and astrocytes are the main sources of IFNβ upon inflammatory insult in the CNS. The protective effects of IFNβ are well characterized in reducing the progression of multiple sclerosis (MS); however, little is understood about its effects in other neurological/neurodegenerative diseases. In this review, different types of IFNs and their signaling pathways will be described. Then we will focus on the potential role and therapeutic effect of IFNβ in several CNS-related diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, spinal cord injury, prion disease and spinocerebellar ataxia 7.}, } @article {pmid39128727, year = {2024}, author = {George, G and Ajayan, A and Varkey, J and Pandey, NK and Chen, J and Langen, R}, title = {TDP43 and huntingtin Exon-1 undergo a conformationally specific interaction that strongly alters the fibril formation of both proteins.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {9}, pages = {107660}, pmid = {39128727}, issn = {1083-351X}, mesh = {*Huntingtin Protein/metabolism/genetics/chemistry ; Humans ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; *Exons ; Amyloid/metabolism/chemistry ; Protein Aggregates ; Protein Aggregation, Pathological/metabolism/genetics ; Protein Binding ; Protein Conformation ; Protein Domains ; }, abstract = {Protein aggregation is a common feature of many neurodegenerative diseases. In Huntington's disease, mutant huntingtin is the primary aggregating protein, but the aggregation of other proteins, such as TDP43, is likely to further contribute to toxicity. Moreover, mutant huntingtin is also a risk factor for TDP pathology in ALS. Despite this co-pathology of huntingtin and TDP43, it remains unknown whether these amyloidogenic proteins directly interact with each other. Using a combination of biophysical methods, we show that the aggregation-prone regions of both proteins, huntingtin exon-1 (Httex1) and the TDP43 low complexity domain (TDP43-LCD), interact in a conformationally specific manner. This interaction significantly slows Httex1 aggregation, while it accelerates TDP43-LCD aggregation. A key intermediate responsible for both effects is a complex formed by liquid TDP43-LCD condensates and Httex1 fibrils. This complex shields seeding competent surfaces of Httex1 fibrils from Httex1 monomers, which are excluded from the condensates. In contrast, TDP43-LCD condensates undergo an accelerated liquid-to-solid transition upon exposure to Httex1 fibrils. Cellular studies show co-aggregation of untagged Httex1 with TDP43. This interaction causes mislocalization of TDP43, which has been linked to TDP43 toxicity. The protection from Httex1 aggregation in lieu of TDP43-LCD aggregation is interesting, as it mirrors what has been found in disease models, namely that TDP43 can protect from huntingtin toxicity, while mutant huntingtin can promote TDP43 pathology. These results suggest that direct protein interaction could, at least in part, be responsible for the linked pathologies of both proteins.}, } @article {pmid39128005, year = {2024}, author = {Knupp, J and Chen, YJ and Wang, E and Arvan, P and Tsai, B}, title = {Sigma-1 receptor recruits LC3 mRNA to ER-associated omegasomes to promote localized LC3 translation enabling functional autophagy.}, journal = {Cell reports}, volume = {43}, number = {8}, pages = {114619}, pmid = {39128005}, issn = {2211-1247}, support = {F31 DK128868/DK/NIDDK NIH HHS/United States ; R01 AI170514/AI/NIAID NIH HHS/United States ; R01 DK111174/DK/NIDDK NIH HHS/United States ; }, mesh = {*Receptors, sigma/metabolism/genetics ; *Sigma-1 Receptor ; *Autophagy ; *Microtubule-Associated Proteins/metabolism/genetics ; *Endoplasmic Reticulum/metabolism ; Humans ; *RNA, Messenger/metabolism/genetics ; *3' Untranslated Regions/genetics ; *Protein Biosynthesis ; Ribosomes/metabolism ; Animals ; Autophagosomes/metabolism ; HeLa Cells ; }, abstract = {Autophagosome formation initiated on the endoplasmic reticulum (ER)-associated omegasome requires LC3. Translational regulation of LC3 biosynthesis is unexplored. Here we demonstrate that LC3 mRNA is recruited to omegasomes by directly binding to the ER transmembrane Sigma-1 receptor (S1R). Cell-based and in vitro reconstitution experiments show that S1R interacts with the 3' UTR of LC3 mRNA and ribosomes to promote LC3 translation. Strikingly, the 3' UTR of LC3 is also required for LC3 protein lipidation, thereby linking the mRNA-3' UTR to LC3 function. An autophagy-defective S1R mutant responsible for amyotrophic lateral sclerosis cannot bind LC3 mRNA or induce LC3 translation. We propose a model wherein S1R de-represses LC3 mRNA via its 3' UTR at the ER, enabling LC3 biosynthesis and lipidation. Because several other LC3-related proteins use the same mechanism, our data reveal a conserved pathway for localized translation essential for autophagosome biogenesis with insights illuminating the molecular basis of a neurodegenerative disease.}, } @article {pmid39127445, year = {2024}, author = {Wang, MY and Zhou, Y and Li, WL and Zhu, LQ and Liu, D}, title = {Friend or foe: Lactate in neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102452}, doi = {10.1016/j.arr.2024.102452}, pmid = {39127445}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Lactic Acid/metabolism ; Animals ; }, abstract = {Lactate, a byproduct of glycolysis, was considered as a metabolic waste until identified by studies on the Warburg effect. Increasing evidence elucidates that lactate functions as energy fuel, signaling molecule, and donor for protein lactylation. Altered lactate utilization is a common metabolic feature of the onset and progression of neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease. This review offers an overview of lactate metabolism from the perspective of production, transportation and clearance, and the role of lactate in neurodegenerative progression, as well as a summary of protein lactylation and the signaling function of lactate in neurodegenerative diseases. Besides, this review delves into the dual roles of changed lactate metabolism during neurodegeneration and explores prospective therapeutic methods targeting lactate. We propose that elucidating the correlation between lactate and neurodegeneration is pivotal for exploring innovative therapeutic interventions for neurodegenerative diseases.}, } @article {pmid39126873, year = {2024}, author = {Vacchiano, V and Di Stasi, V and Teodorani, L and Faini, C and Morabito, F and Liguori, R}, title = {Comparative assessment of MScanFit MUNE and quantitative EMG in amyotrophic lateral sclerosis diagnosis: A prospective study.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {166}, number = {}, pages = {66-73}, doi = {10.1016/j.clinph.2024.07.017}, pmid = {39126873}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Electromyography/methods ; Male ; Female ; Middle Aged ; Aged ; Prospective Studies ; *Motor Neurons/physiology ; *Action Potentials/physiology ; *Muscle, Skeletal/physiopathology ; Adult ; }, abstract = {OBJECTIVE: Motor Unit Number Estimation (MUNE) techniques are crucial in assessing lower motor neuron loss. MScanFit MUNE (MScanFit) is a novel tool which estimates MUNE values from compound muscle action potential (CMAP) scans by considering the probabilistic nature of motor unit firing. We conducted a prospective study to evaluate the diagnostic utility of MScanFit compared to quantitative electromyography (qEMG) in ALS patients.

METHODS: We enrolled 35 patients diagnosed with amyotrophic lateral sclerosis (ALS) and 14 healthy controls, assessing qEMG and MScanFit MUNE in abductor pollicis brevis, abductor digiti minimi and tibialis anterior muscles.

RESULTS: We found higher sensitivity of qEMG in detecting abnormalities compared to MScanFit, with a high concordance rate between the two techniques. Notably, a few muscles exhibited abnormal MUNE but normal qEMG findings, suggesting a potential complementary role for MScanFit in ALS diagnosis. Neurophysiological parameters from MScanFit showed good correlations with qEMG measures. Subclinical neurophysiological involvement was observed in muscles with normal strength, emphasizing the importance of sensitive diagnostic tools.

CONCLUSION: MScanFit demonstrated validity in distinguishing ALS patients from healthy subjects and correlated well with qEMG parameters.

SIGNIFICANCE: Our study confirmed the diagnostic utility of MScanFit MUNE in ALS, highlighting its role as a supplementary diagnostic tool.}, } @article {pmid39126786, year = {2024}, author = {Neumann, M and Kothare, H and Ramanarayanan, V}, title = {Multimodal speech biomarkers for remote monitoring of ALS disease progression.}, journal = {Computers in biology and medicine}, volume = {180}, number = {}, pages = {108949}, pmid = {39126786}, issn = {1879-0534}, support = {R42 DC019877/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; *Disease Progression ; Female ; Middle Aged ; Aged ; Speech/physiology ; Biomarkers ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that severely impacts affected persons' speech and motor functions, yet early detection and tracking of disease progression remain challenging. The current gold standard for monitoring ALS progression, the ALS functional rating scale - revised (ALSFRS-R), is based on subjective ratings of symptom severity, and may not capture subtle but clinically meaningful changes due to a lack of granularity. Multimodal speech measures which can be automatically collected from patients in a remote fashion allow us to bridge this gap because they are continuous-valued and therefore, potentially more granular at capturing disease progression. Here we investigate the responsiveness and sensitivity of multimodal speech measures in persons with ALS (pALS) collected via a remote patient monitoring platform in an effort to quantify how long it takes to detect a clinically-meaningful change associated with disease progression. We recorded audio and video from 278 participants and automatically extracted multimodal speech biomarkers (acoustic, orofacial, linguistic) from the data. We find that the timing alignment of pALS speech relative to a canonical elicitation of the same prompt and the number of words used to describe a picture are the most responsive measures at detecting such change in both pALS with bulbar (n = 36) and non-bulbar onset (n = 107). Interestingly, the responsiveness of these measures is stable even at small sample sizes. We further found that certain speech measures are sensitive enough to track bulbar decline even when there is no patient-reported clinical change, i.e. the ALSFRS-R speech score remains unchanged at 3 out of a total possible score of 4. The findings of this study have the potential to facilitate improved, accelerated and cost-effective clinical trials and care.}, } @article {pmid39126203, year = {2024}, author = {Tabuchi, R and Momozawa, Y and Hayashi, Y and Noma, H and Ichijo, H and Fujisawa, T}, title = {SoDCoD: a comprehensive database of Cu/Zn superoxide dismutase conformational diversity caused by ALS-linked gene mutations and other perturbations.}, journal = {Database : the journal of biological databases and curation}, volume = {2024}, number = {}, pages = {0}, pmid = {39126203}, issn = {1758-0463}, support = {JP21H04760 JP22H04636 JP22H04804 JP22K06610 JP23K14143//Japan Society for the Promotion of Science/ ; JP21gm5010001//Japan Agency for Medical Research and Development/ ; //SERIKA FUND/ ; 2023-ISMCRP-2033//the ISM Cooperative Research Program/ ; //the researcher exchange promotion program of ROIS (Research Organization of Information and Systems)/ ; JPMJMS2022-18//Japan Science and Technology Agency/ ; JP21H04760 JP22H04636 JP22H04804 JP22K06610 JP23K14143//Japan Society for the Promotion of Science/ ; JP21gm5010001//Japan Agency for Medical Research and Development/ ; //SERIKA FUND/ ; 2023-ISMCRP-2033//the ISM Cooperative Research Program/ ; //the researcher exchange promotion program of ROIS (Research Organization of Information and Systems)/ ; JPMJMS2022-18//Japan Science and Technology Agency/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/enzymology ; Humans ; *Mutation ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; Databases, Protein ; Protein Conformation ; Databases, Genetic ; Superoxide Dismutase/genetics/chemistry/metabolism ; }, abstract = {A structural alteration in copper/zinc superoxide dismutase (SOD1) is one of the common features caused by amyotrophic lateral sclerosis (ALS)-linked mutations. Although a large number of SOD1 variants have been reported in ALS patients, the detailed structural properties of each variant are not well summarized. We present SoDCoD, a database of superoxide dismutase conformational diversity, collecting our comprehensive biochemical analyses of the structural changes in SOD1 caused by ALS-linked gene mutations and other perturbations. SoDCoD version 1.0 contains information about the properties of 188 types of SOD1 mutants, including structural changes and their binding to Derlin-1, as well as a set of genes contributing to the proteostasis of mutant-like wild-type SOD1. This database provides valuable insights into the diagnosis and treatment of ALS, particularly by targeting conformational alterations in SOD1. Database URL: https://fujisawagroup.github.io/SoDCoDweb/.}, } @article {pmid39126144, year = {2024}, author = {Briones, MRS and Campos, JH and Ferreira, RC and Schneper, L and Santos, IM and Antoneli, FM and , and Broach, JR}, title = {Mitochondrial genome variants associated with amyotrophic lateral sclerosis and their haplogroup distribution.}, journal = {Muscle & nerve}, volume = {70}, number = {4}, pages = {862-872}, pmid = {39126144}, issn = {1097-4598}, support = {//Tow Foundation/ ; //NIH/ ; 2013/07838-0//FAPESP/ ; 2014/25602-6//FAPESP/ ; //CAPES/ ; 303912/2017-0//CNPq/ ; T32 LM012415/LM/NLM NIH HHS/United States ; 19-SI-459//ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genome, Mitochondrial/genetics ; Male ; Female ; *Genome-Wide Association Study ; Middle Aged ; Haplotypes ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease/genetics ; Aged ; Genetic Variation/genetics ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) may be familial or sporadic, and twin studies have revealed that even sporadic forms have a significant genetic component. Variants in 55 nuclear genes have been associated with ALS and although mitochondrial dysfunction is observed in ALS, variants in mitochondrial genomes (mitogenomes) have not yet been tested for association with ALS. The aim of this study was to determine whether mitogenome variants are associated with ALS.

METHODS: We conducted a genome-wide association study (GWAS) in mitogenomes of 1965 ALS patients and 2547 controls.

RESULTS: We identified 51 mitogenome variants with p values <10[-7], of which 13 had odds ratios (ORs) >1, in genes RNR1, ND1, CO1, CO3, ND5, ND6, and CYB, while 38 variants had OR <1 in genes RNR1, RNA2, ND1, ND2, CO2, ATP8, ATP6, CO3, ND3, ND4, ND5, ND6, and CYB. The frequencies of haplogroups H, U, and L, the most frequent in our ALS data set, were the same in different onset sites (bulbar, limb, spinal, and axial). Also, intra-haplogroup GWAS revealed unique ALS-associated variants in haplogroups L and U.

DISCUSSION: Our study shows that mitogenome single nucleotide variants (SNVs) are associated with ALS and suggests that these SNVs could be included in routine genetic testing for ALS and that mitochondrial replacement therapy has the potential to serve as a basis for ALS treatment.}, } @article {pmid39126066, year = {2024}, author = {Mejzini, R and Caruthers, MH and Schafer, B and Kostov, O and Sudheendran, K and Ciba, M and Danielsen, M and Wilton, S and Akkari, PA and Flynn, LL}, title = {Allele-Selective Thiomorpholino Antisense Oligonucleotides as a Therapeutic Approach for Fused-in-Sarcoma Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {15}, pages = {}, pmid = {39126066}, issn = {1422-0067}, support = {2322//Motor Neurone Disease Research Australia/ ; }, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use/genetics ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; *RNA-Binding Protein FUS/genetics ; *Alleles ; Fibroblasts/metabolism/drug effects ; Gene Knockdown Techniques ; Morpholinos/therapeutic use/genetics ; }, abstract = {Pathogenic variations in the fused in sarcoma (FUS) gene are associated with rare and aggressive forms of amyotrophic lateral sclerosis (ALS). As FUS-ALS is a dominant disease, a targeted, allele-selective approach to FUS knockdown is most suitable. Antisense oligonucleotides (AOs) are a promising therapeutic platform for treating such diseases. In this study, we have explored the potential for allele-selective knockdown of FUS. Gapmer-type AOs targeted to two common neutral polymorphisms in FUS were designed and evaluated in human fibroblasts. AOs had either methoxyethyl (MOE) or thiomorpholino (TMO) modifications. We found that the TMO modification improved allele selectivity and efficacy for the lead sequences when compared to the MOE counterparts. After TMO-modified gapmer knockdown of the target allele, up to 93% of FUS transcripts detected were from the non-target allele. Compared to MOE-modified AOs, the TMO-modified AOs also demonstrated reduced formation of structured nuclear inclusions and SFPQ aggregation that can be triggered by phosphorothioate-containing AOs. How overall length and gap length of the TMO-modified AOs affected allele selectivity, efficiency and off-target gene knockdown was also evaluated. We have shown that allele-selective knockdown of FUS may be a viable therapeutic strategy for treating FUS-ALS and demonstrated the benefits of the TMO modification for allele-selective applications.}, } @article {pmid39125740, year = {2024}, author = {Bernard, E and Cluse, F and Bohic, A and Hermier, M and Raoul, C and Leblanc, P and Guissart, C}, title = {A Novel De Novo Missense Mutation in KIF1A Associated with Young-Onset Upper-Limb Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {15}, pages = {}, pmid = {39125740}, issn = {1422-0067}, mesh = {Humans ; *Kinesins/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Female ; *Mutation, Missense ; Adult ; Upper Extremity/physiopathology/pathology ; Magnetic Resonance Imaging ; }, abstract = {We investigate the etiology of amyotrophic lateral sclerosis (ALS) in a 35-year-old woman presenting with progressive weakness in her left upper limb. Prior to sequencing, a comprehensive neurological work-up was performed, including neurological examination, electrophysiology, biomarker assessment, and brain and spinal cord MRI. Six months before evaluation, the patient experienced weakness and atrophy in her left hand, accompanied by brisk reflexes and Hoffman sign in the same arm. Electroneuromyography revealed lower motor neuron involvement in three body regions. Neurofilament light chains were elevated in her cerebrospinal fluid. Brain imaging showed asymmetrical T2 hyperintensity of the corticospinal tracts and T2 linear hypointensity of the precentral gyri. Trio genome sequencing identified a likely pathogenic de novo variant in the KIF1A gene (NM_001244008.2): c.574A>G, p.(Ile192Val). Pathogenic variants in KIF1A have been associated with a wide range of neurological manifestations called KIF1A-associated neurological diseases (KAND). This report describes a likely pathogenic de novo variant in KIF1A associated with ALS, expanding the phenotypic spectrum of KAND and our understanding of the pathophysiology of ALS.}, } @article {pmid39124808, year = {2024}, author = {Miyaue, N and Yamanishi, Y and Ito, Y and Ando, R and Nagai, M}, title = {CSF Neopterin Levels Are Elevated in Various Neurological Diseases and Aging.}, journal = {Journal of clinical medicine}, volume = {13}, number = {15}, pages = {}, pmid = {39124808}, issn = {2077-0383}, abstract = {Background/Objectives: Cerebrospinal fluid (CSF) neopterin reflects inflammation of the central nervous system (CNS) and is a potentially useful biomarker for neuroinflammatory assessment and differential diagnosis. However, its optimal cut-off level in adult patients with neurological disease has not been established and it has not been adequately studied in controls. We aimed to determine its usefulness as a biomarker of neuroinflammation and the effect of age on its level. Methods: In this retrospective study, CSF neopterin was evaluated in 652 patients in 38 disease groups. Its levels were analyzed with high-performance liquid chromatography with fluorometric detection. Results: A receiver operating characteristic analysis revealed that the optimal cut-off value of 33.57 pmol/mL for CSF neopterin distinguished the control and meningitis/encephalitis groups with a sensitivity of 100.0% and specificity of 94.4%. In the control group, which consisted of 170 participants (99 men and 71 women; mean ± standard deviation age, 52.56 ± 17.99 years), age was significantly positively correlated with CSF protein (r = 0.474, p < 0.001) and CSF neopterin (r = 0.476, p < 0.001) levels but not with CSF cell count (r = 0.144, p = 0.061). Both male and female controls exhibited significant increases in CSF neopterin levels with age. Similarly, the CSF neopterin level was significantly positively correlated with age in patients with amyotrophic lateral sclerosis, independently of disease duration and respiratory function. Conclusions: CSF neopterin levels were elevated in patients with various CNS diseases, reflecting CNS inflammation; they were also elevated with age. Prospective studies are required to establish CSF neopterin as a sensitive biomarker of neuroinflammation.}, } @article {pmid39123212, year = {2024}, author = {Wang, X and Pan, W and Sun, C and Yang, H and Cheng, Z and Yan, F and Ma, G and Shang, Y and Zhang, R and Gao, C and Liu, L and Zhang, H}, title = {Creating large-scale genetic diversity in Arabidopsis via base editing-mediated deep artificial evolution.}, journal = {Genome biology}, volume = {25}, number = {1}, pages = {215}, pmid = {39123212}, issn = {1474-760X}, support = {TSQN202103160//Taishan Scholar Foundation of Shandong Province/ ; ZR202103010168//Excellent Youth Foundation of Shandong Scientific Committee/ ; 2022YFD1201700//National Key R&D Program of China/ ; }, mesh = {*Arabidopsis/genetics ; *Gene Editing/methods ; *Genetic Variation ; CRISPR-Cas Systems ; Directed Molecular Evolution ; Alleles ; Mutation ; Plant Breeding/methods ; Herbicide Resistance/genetics ; }, abstract = {BACKGROUND: Base editing is a powerful tool for artificial evolution to create allelic diversity and improve agronomic traits. However, the great evolutionary potential for every sgRNA target has been overlooked. And there is currently no high-throughput method for generating and characterizing as many changes in a single target as possible based on large mutant pools to permit rapid gene directed evolution in plants.

RESULTS: In this study, we establish an efficient germline-specific evolution system to screen beneficial alleles in Arabidopsis which could be applied for crop improvement. This system is based on a strong egg cell-specific cytosine base editor and the large seed production of Arabidopsis, which enables each T1 plant with unedited wild type alleles to produce thousands of independent T2 mutant lines. It has the ability of creating a wide range of mutant lines, including those containing atypical base substitutions, and as well providing a space- and labor-saving way to store and screen the resulting mutant libraries. Using this system, we efficiently generate herbicide-resistant EPSPS, ALS, and HPPD variants that could be used in crop breeding.

CONCLUSIONS: Here, we demonstrate the significant potential of base editing-mediated artificial evolution for each sgRNA target and devised an efficient system for conducting deep evolution to harness this potential.}, } @article {pmid39122743, year = {2024}, author = {Shin, B and Kwon, Y and Mittaz, M and Kim, H and Xu, X and Kim, E and Lee, YJ and Lee, J and Yeo, WH and Choo, HJ}, title = {All-in-one wearable drug efficacy assessment systems for bulbar muscle function using amyotrophic lateral sclerosis animal models.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {6803}, pmid = {39122743}, issn = {2041-1723}, support = {R21 EB031535/EB/NIBIB NIH HHS/United States ; UL1 TR002378/TR/NCATS NIH HHS/United States ; R21EB031535//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/drug therapy ; Animals ; *Disease Models, Animal ; *Wearable Electronic Devices ; *Electromyography/methods ; Drug Evaluation, Preclinical ; Deglutition Disorders/physiopathology/etiology ; Muscle, Skeletal/drug effects/physiopathology/innervation ; Humans ; Male ; Motor Neurons/drug effects/physiology ; Rats ; }, abstract = {Preclinical studies are crucial for developing amyotrophic lateral sclerosis drugs. Current FDA-approved drugs have been created by monitoring limb muscle function and histological analysis of amyotrophic lateral sclerosis model animals. Drug candidates for this disease have yet to be tested for bulbar-onset type due to the limitations of traditional preclinical tools: excessive animal use and discrete detection of disease progress. Here, our study introduces an all-in-one, wireless, integrated wearable system for facilitating continuous drug efficacy assessment of dysphagia-related muscles in animals during natural eating behaviors. By incorporating a kirigami-based strain-isolation mechanism, this device mounted on the skin of animals mitigates electromyography signal contamination caused by unpredictable animal movements. Our findings indicate this system, measuring the progression of motor neuron denervation, offers high precision in monitoring drug effects on dysphagia-responsible bulbar muscles. This study paves the way for more humane and efficient approaches to developing treatment solutions for degenerative neuromuscular diseases.}, } @article {pmid39122453, year = {2024}, author = {Khan, S and Bano, N and Ahamad, S and John, U and Dar, NJ and Bhat, SA}, title = {Excitotoxicity, Oxytosis/Ferroptosis, and Neurodegeneration: Emerging Insights into Mitochondrial Mechanisms.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.0125-1}, pmid = {39122453}, issn = {2152-5250}, abstract = {Mitochondrial dysfunction plays a pivotal role in the development of age-related diseases, particularly neurodegenerative disorders. The etiology of mitochondrial dysfunction involves a multitude of factors that remain elusive. This review centers on elucidating the role(s) of excitotoxicity, oxytosis/ferroptosis and neurodegeneration within the context of mitochondrial bioenergetics, biogenesis, mitophagy and oxidative stress and explores their intricate interplay in the pathogenesis of neurodegenerative diseases. The effective coordination of mitochondrial turnover processes, notably mitophagy and biogenesis, is assumed to be critically important for cellular resilience and longevity. However, the age-associated decrease in mitophagy impedes the elimination of dysfunctional mitochondria, consequently impairing mitochondrial biogenesis. This deleterious cascade results in the accumulation of damaged mitochondria and deterioration of cellular functions. Both excitotoxicity and oxytosis/ferroptosis have been demonstrated to contribute significantly to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS). Excitotoxicity, characterized by excessive glutamate signaling, initiates a cascade of events involving calcium dysregulation, energy depletion, and oxidative stress and is intricately linked to mitochondrial dysfunction. Furthermore, emerging concepts surrounding oxytosis/ferroptosis underscore the importance of iron-dependent lipid peroxidation and mitochondrial engagement in the pathogenesis of neurodegeneration. This review not only discusses the individual contributions of excitotoxicity and ferroptosis but also emphasizes their convergence with mitochondrial dysfunction, a key driver of neurodegenerative diseases. Understanding the intricate crosstalk between excitotoxicity, oxytosis/ferroptosis, and mitochondrial dysfunction holds potential to pave the way for mitochondrion-targeted therapeutic strategies. Such strategies, with a focus on bioenergetics, biogenesis, mitophagy, and oxidative stress, emerge as promising avenues for therapeutic intervention.}, } @article {pmid39122262, year = {2024}, author = {Wang, S and Jiang, Q and Zheng, X and Wei, Q and Lin, J and Yang, T and Xiao, Y and Li, C and Shang, H}, title = {Genotype-phenotype correlation of SQSTM1 variants in patients with amyotrophic lateral sclerosis.}, journal = {Journal of medical genetics}, volume = {61}, number = {10}, pages = {966-972}, doi = {10.1136/jmg-2023-109569}, pmid = {39122262}, issn = {1468-6244}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/pathology/epidemiology ; Frontotemporal Dementia/genetics/pathology ; Gene Frequency ; *Genetic Association Studies ; Genetic Predisposition to Disease ; Genotype ; Mutation ; Phenotype ; *Sequestosome-1 Protein/genetics ; Young Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND: Several variants of sequestosome 1 (SQSTM1) were screened in patients with amyotrophic lateral sclerosis (ALS), while the pathogenicity and genotype-phenotype correlation remains unclear.

METHODS: We screened variants of SQSTM1 gene in 2011 Chinese patients with ALS and performed a burden analysis focusing on the rare variants. Furthermore, we conducted a comprehensive analysis of patients with variants of SQSTM1 gene in patients with ALS from our cohort and published studies.

RESULTS: In our cohort, we identified 32 patients with 25 different SQSTM1 variants with a mutant frequency of 1.6%. Notably, 26% (5/19) of the patients with ALS with SQSTM1 variant in our cohort had comorbid cognitive impairment and 43% (3/7) of them had behavioural variant frontotemporal dementia (FTD). Our meta-analysis found a total frequency of SQSTM1 variants in 7183 patients with ALS was 2.4%; burden analysis indicated that patients with ALS had enrichment of ultra-rare (minor allele frequency<0.01%) probably pathogenic variants in SQSTM1. Most variants were missense variants and distributed in various domains of p62 protein, some of which might be related to comorbidities of Paget's disease of bone and FTD.

CONCLUSION: Our study established the largest cohort of patients with ALS with SQSTM1 variants, expanded the mutation spectrum and investigated the genotype-phenotype correlations of SQSTM1 variants.}, } @article {pmid39122006, year = {2024}, author = {Chen, X and Wei, Q and Yang, Z and Chen, X and Guo, S and Jiang, M and Wang, M}, title = {Structural basis for RNA recognition by the C-terminal RRM domain of human RBM45.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {9}, pages = {107640}, pmid = {39122006}, issn = {1083-351X}, mesh = {Humans ; *RNA-Binding Proteins/metabolism/chemistry/genetics ; *RNA/metabolism/chemistry ; Crystallography, X-Ray ; Protein Domains ; Protein Binding ; DNA, Single-Stranded/metabolism/chemistry/genetics ; Models, Molecular ; Nerve Tissue Proteins ; }, abstract = {RBM45 is an RNA-binding protein with roles in neural development by regulating RNA splicing. Its dysfunction and aggregation are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). RBM45 harbors three RRM domains that potentially bind RNA. While the recognitions of RNA by its N-terminal tandem RRM domains (RRM1 and RRM2) have been well understood, the RNA-binding property of its C-terminal RRM (RRM3) remains unclear. In this work, we identified that the RRM3 of the RBM45 sequence specifically binds RNA with a GACG sequence, similar but not identical to those recognized by the RRM1 and RRM2. Further, we determined the crystal structure of RBM45[RRM3] in complex with a GACG sequence-containing single-stranded DNA. Our structural results, together with the RNA-binding assays of mutants at key amino acid residues, revealed the molecular mechanism by which RBM45[RRM3] recognizes an RNA sequence. Our finding on the RNA-binding property of the individual RRM module of RBM45 provides the foundation for unraveling the RNA-binding characteristics of full-length RBM45 and for understanding the biological functions of RBM45.}, } @article {pmid39121134, year = {2024}, author = {Roos, A and Häusler, M and Kollipara, L and Topf, A and Preusse, C and Stucka, R and Nolte, K and Strom, T and Berutti, R and Jiang, X and Koll, R and Lochmüller, H and Schacht, SM and Zahedi, RP and Weis, J and Senderek, J}, title = {HNRNPA1 de novo Variant Associated with Early Childhood Onset, Rapidly Progressive Generalized Myopathy.}, journal = {Journal of neuromuscular diseases}, volume = {11}, number = {5}, pages = {1131-1137}, pmid = {39121134}, issn = {2214-3602}, mesh = {Humans ; Female ; *Heterogeneous Nuclear Ribonucleoprotein A1/genetics ; *Muscular Diseases/genetics ; Disease Progression ; Age of Onset ; Muscle, Skeletal/pathology ; Phenotype ; Mutation ; Child ; }, abstract = {HNRNPA1 variants are known to cause degenerative motoneuron and muscle diseases which manifests in middle age or later. We report on a girl with early childhood onset, rapidly progressive generalized myopathy including ultrastructural findings in line with a proteinopathy. Proteomics of patient-derived muscle and combined screening of genomic data for copy number variations identified a HNRNPA1 de novo intragenic deletion as causative for the phenotype. Our report expands the spectrum of HNRNPA1-related diseases towards early-childhood onset and adds HNRNPA1 to the growing list of ALS and myopathy genes for which certain mutations may cause severe pediatric phenotypes.}, } @article {pmid39120329, year = {2024}, author = {Steffke, C and Agarwal, S and Kabashi, E and Catanese, A}, title = {Overexpression of Toxic Poly(Glycine-Alanine) Aggregates in Primary Neuronal Cultures Induces Time-Dependent Autophagic and Synaptic Alterations but Subtle Activity Impairments.}, journal = {Cells}, volume = {13}, number = {15}, pages = {}, pmid = {39120329}, issn = {2073-4409}, mesh = {*Autophagy ; *Neurons/metabolism ; Animals ; *Synapses/metabolism ; *C9orf72 Protein/genetics/metabolism ; Cells, Cultured ; Peptides/metabolism ; Humans ; Protein Aggregates ; }, abstract = {The pathogenic expansion of the intronic GGGGCC hexanucleotide located in the non-coding region of the C9orf72 gene represents the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation leads to the accumulation of toxic RNA foci and dipeptide repeats (DPRs), as well as reduced levels of the C9orf72 protein. Thus, both gain and loss of function are coexisting pathogenic aspects linked to C9orf72-ALS/FTD. Synaptic alterations have been largely described in C9orf72 models, but it is still not clear which aspect of the pathology mostly contributes to these impairments. To address this question, we investigated the dynamic changes occurring over time at the synapse upon accumulation of poly(GA), the most abundant DPR. Overexpression of this toxic form induced a drastic loss of synaptic proteins in primary neuron cultures, anticipating autophagic defects. Surprisingly, the dramatic impairment characterizing the synaptic proteome was not fully matched by changes in network properties. In fact, high-density multi-electrode array analysis highlighted only minor reductions in the spike number and firing rate of poly(GA) neurons. Our data show that the toxic gain of function linked to C9orf72 affects the synaptic proteome but exerts only minor effects on the network activity.}, } @article {pmid39119557, year = {2024}, author = {Fogarty, MJ and Drieberg-Thompson, JR and Bellingham, MC and Noakes, PG}, title = {Timeline of hypoglossal motor neuron death and intrinsic tongue muscle denervation in high-copy number SOD1[G93A] mice.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1422943}, pmid = {39119557}, issn = {1664-2295}, support = {R01 AG086136/AG/NIA NIH HHS/United States ; R56 HL166204/HL/NHLBI NIH HHS/United States ; }, abstract = {In amyotrophic lateral sclerosis (ALS) postmortem tissue and the SOD1 mouse model at mid-disease, death of hypoglossal motor neurons (XII MNs) is evident. These XII MNs innervate the intrinsic and extrinsic tongue muscles, and despite their importance in many oral and lingual motor behaviours that are affected by ALS (e.g., swallowing, speech, and respiratory functions), little is known about the timing and extent of tongue muscle denervation. Here in the well-characterised SOD1[G93A] (high-copy) mouse model, we evaluated XII MN numbers and intrinsic tongue muscle innervation using standard histopathological approaches, which included stereological evaluation of Nissl-stained brainstem, and the presynaptic and postsynaptic evaluation of neuromuscular junctions (NMJs), using synapsin, neurofilament, and α-bungarotoxin immunolabelling, at presymptomatic, onset, mid-disease, and endstage timepoints. We found that reduction in XII MN size at onset preceded reduced XII MN survival, while the denervation of tongue muscle did not appear until the endstage. Our study suggests that denervation-induced weakness may not be the most pertinent feature of orolingual deficits in ALS. Efforts to preserve oral and respiratory functions of XII MNs are incredibly important if we are to influence patient outcomes.}, } @article {pmid39119436, year = {2024}, author = {Galeazzi, L and Holzman, J and Porporatti, A and Rochefort, J}, title = {Lingual Fasciculation as a Point of Call for the Diagnosis of Amyotrophic Lateral Sclerosis: A Literature Review.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64153}, pmid = {39119436}, issn = {2168-8184}, abstract = {BACKGROUND AND AIM: Dental surgeons often play a pivotal role in the initial detection of lingual fasciculations (LFs). These involuntary micro-movements of the tongue can serve as early clinical indicators of neurodegenerative diseases, with amyotrophic lateral sclerosis (ALS) being the most concerning. Therefore, it is imperative to educate dental surgeons on identifying LF and understanding the potential underlying pathologies.

OBJECTIVES: This study aimed to pinpoint the pathologies in which LFs could emerge as an early clinical marker. Our review focused on articles delineating patient populations exhibiting LF within broader pathological contexts, encompassing neurological and other conditions, with the aim of elucidating their etiologies.

METHODS: We conducted a comprehensive literature review across four databases (PubMed, Embase, Web of Science, and Scopus). Two authors independently extracted data, with consultation from a third author when necessary. Eligible articles included those describing patients with LFs, detailing the methods of detection, diagnosis, and associated pathologies.

RESULTS: Our review identified 22 articles encompassing 153 patients with LF, with an average age of 45.8 years and a female prevalence of 43%. Electromyography and ultrasound emerged as the predominant detection methods. ALS constituted the primary diagnosis in the majority of cases (91%). Additionally, other conditions diagnosed included Machado-Joseph disease (0.046%), familial transthyretin amyloid neuropathy (0.013%), Brown-Vialetto-Van-Laere syndrome (0.006%), chronic inflammatory demyelinating polyneuropathy (0.006%), bulbospinal amyotrophy or Kennedy's disease (0.006%), and osmotic demyelination syndrome (0.006%). LF secondary to organophosphate poisoning was also documented. Symptoms associated with LF encompassed taste alterations, dysphagia, difficulty swallowing, and slurred speech.

CONCLUSION: While primarily indicative of ALS, LFs may also signal diverse underlying pathologies. Healthcare practitioners should be vigilant in their detection and expedite patient referrals to facilitate early integration into care protocols.}, } @article {pmid39119372, year = {2024}, author = {Maristany, AJ and Sa, BC and Murray, C and Subramaniam, AB and Oldak, SE}, title = {Psychiatric Manifestations of Neurological Diseases: A Narrative Review.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64152}, pmid = {39119372}, issn = {2168-8184}, abstract = {Neurological diseases often manifest with psychiatric symptoms, profoundly impacting patients' well-being and treatment outcomes. This comprehensive review examines the psychiatric manifestations associated with Alzheimer's disease, frontotemporal dementia (FTD), Parkinson's disease, multiple sclerosis (MS), stroke, epilepsy, Huntington's disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and multiple system atrophy (MSA). Key psychiatric symptoms include agitation, depression, anxiety, apathy, hallucinations, impulsivity, and aggression across these diseases. In addition, ethical considerations in treating these symptoms are paramount, particularly regarding genetic testing implications, end-of-life discussions, informed consent, and equitable access to innovative treatments. Effective management necessitates interdisciplinary collaboration, personalized interventions, and a focus on patient autonomy. Understanding the psychiatric burden of neurological diseases is crucial for enhancing patients' quality of life. Further research is needed to elucidate underlying mechanisms and develop targeted interventions. This review underscores the importance of comprehensive assessment and ethical treatment practices to address psychiatric manifestations effectively.}, } @article {pmid39118204, year = {2024}, author = {Fang, SY and Tsai, PC and Jih, KY and Hsu, FC and Liao, YC and Yang, CC and Lee, YC}, title = {TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive amyotrophic lateral sclerosis through a haploinsufficiency mechanism.}, journal = {Journal of the Chinese Medical Association : JCMA}, volume = {87}, number = {10}, pages = {920-926}, doi = {10.1097/JCMA.0000000000001147}, pmid = {39118204}, issn = {1728-7731}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; *Protein Serine-Threonine Kinases/genetics ; Adult ; *Haploinsufficiency ; *Age of Onset ; Disease Progression ; }, abstract = {BACKGROUND: TBK1 variants have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia spectrum disorder. The current study elucidated the clinical and molecular genetic features of a novel TBK1 variant identified in a patient with young-onset, rapidly progressive ALS.

METHODS: The coding regions of TBK1 , SOD1 , TARDBP , and FUS were genetically analyzed using Sanger sequencing. Repeat-primed polymerase chain reaction (PCR) was used to survey the GGGGCC repeat in C9ORF72 . The study participant underwent a comprehensive clinical evaluation. The functional effects of the TBK1 variant were analyzed through in vitro transfection studies.

RESULTS: We identified a novel frameshift truncating TBK1 variant, c.456_457delGT (p.Y153Qfs*9), in a man with ALS. The disease initially manifested as right hand weakness at the age of 39 years but progressed rapidly, with the revised ALS Functional Rating Scale score declining at an average monthly rate of 1.92 points in the first year after diagnosis. The patient had no cognitive dysfunction. However, Technetium-99m single photon emission tomography indicated hypoperfusion in his bilateral superior and middle frontal cortices. In vitro studies revealed that the p.Y153Qfs*9 variant resulted in a truncated TBK1 protein product, reduced TBK1 protein expression, loss of kinase function, reduced interaction with optineurin, and impaired dimerization.

CONCLUSION: The heterozygous TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive ALS through a haploinsufficiency mechanism.}, } @article {pmid39117623, year = {2024}, author = {Hale, OJ and Wells, TR and Mead, RJ and Cooper, HJ}, title = {Mass spectrometry imaging of SOD1 protein-metal complexes in SOD1G93A transgenic mice implicates demetalation with pathology.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {6518}, pmid = {39117623}, issn = {2041-1723}, support = {EP/S002979/1//RCUK | Engineering and Physical Sciences Research Council (EPSRC)/ ; EP/S002979/1//RCUK | Engineering and Physical Sciences Research Council (EPSRC)/ ; BB/S019456/1//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; }, mesh = {Animals ; *Mice, Transgenic ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Spinal Cord/metabolism/pathology ; *Mass Spectrometry/methods ; *Brain/metabolism/diagnostic imaging/pathology ; Copper/metabolism ; Zinc/metabolism ; Humans ; Superoxide Dismutase/metabolism/genetics/chemistry ; Mutation ; Protein Processing, Post-Translational ; Protein Multimerization ; Disease Models, Animal ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons in the central nervous system (CNS). Mutations in the metalloenzyme SOD1 are associated with inherited forms of ALS and cause a toxic gain of function thought to be mediated by dimer destabilization and misfolding. SOD1 binds two Cu and two Zn ions in its homodimeric form. We have applied native ambient mass spectrometry imaging to visualize the spatial distributions of intact metal-bound SOD1[G93A] complexes in SOD1[G93A] transgenic mouse spinal cord and brain sections and evaluated them against disease pathology. The molecular specificity of our approach reveals that metal-deficient SOD1[G93A] species are abundant in CNS structures correlating with ALS pathology whereas fully metalated SOD1[G93A] species are homogenously distributed. Monomer abundance did not correlate with pathology. We also show that the dimer-destabilizing post-translational modification, glutathionylation, has limited influence on the spatial distribution of SOD1 dimers.}, } @article {pmid39117616, year = {2024}, author = {Ramzan, F and Kumar, A and Abrar, F and Gray, RAV and Campbell, ZE and Liao, LMQ and Dang, A and Akanni, O and Guyn, C and Martin, DDO}, title = {Fatty links between multisystem proteinopathy and small VCP-interacting protein.}, journal = {Cell death discovery}, volume = {10}, number = {1}, pages = {358}, pmid = {39117616}, issn = {2058-7716}, abstract = {Multisystem proteinopathy (MSP) is a rare, dominantly inherited disorder that includes a cluster of diseases, including frontotemporal dementia, inclusion body myopathy, and Paget's disease of bone. MSP is caused by mutations in the gene encoding valosin-containing protein (VCP). Patients with the same mutation, even within the same family, can present with a different combination of any or all of the above diseases, along with amyotrophic lateral sclerosis (ALS). The pleiotropic effects may be linked to the greater than 50 VCP co-factors that direct VCP's many roles in the cell. Small VCP-interacting protein (SVIP) is a small protein that directs VCP to autophagosomes and lysosomes. We found that SVIP directs VCP localization to lysosomes in an acylation-dependent manner. We demonstrate that SVIP is myristoylated at Glycine 2 and palmitoylated at Cysteines 4 and 7. Acylation of SVIP is required to mediate cell death in the presence of the MSP-associated VCP variant (R155H-VCP), whereas blocking SVIP myristoylation prevents cytotoxicity. Therefore, SVIP acylation may present a novel target in MSP.}, } @article {pmid39117455, year = {2024}, author = {Lam, AYW and Tsuboyama, K and Tadakuma, H and Tomari, Y}, title = {DNAJA2 and Hero11 mediate similar conformational extension and aggregation suppression of TDP-43.}, journal = {RNA (New York, N.Y.)}, volume = {30}, number = {11}, pages = {1422-1436}, pmid = {39117455}, issn = {1469-9001}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/chemistry/genetics ; Fluorescence Resonance Energy Transfer ; Molecular Chaperones/metabolism/chemistry/genetics ; Protein Aggregates ; Protein Aggregation, Pathological/genetics/metabolism ; Protein Conformation ; RNA-Binding Proteins/metabolism/genetics/chemistry ; Chromosomal Proteins, Non-Histone/genetics ; }, abstract = {Many RNA-binding proteins (RBPs) contain low-complexity domains (LCDs) with prion-like compositions. These long intrinsically disordered regions regulate their solubility, contributing to their physiological roles in RNA processing and organization. However, this also makes these RBPs prone to pathological misfolding and aggregation that are characteristic of neurodegenerative diseases. For example, TAR DNA-binding protein 43 (TDP-43) forms pathological aggregates associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While molecular chaperones are well-known suppressors of these aberrant events, we recently reported that highly disordered, hydrophilic, and charged heat-resistant obscure (Hero) proteins may have similar effects. Specifically, Hero proteins can maintain the activity of other proteins from denaturing conditions in vitro, while their overexpression can suppress cellular aggregation and toxicity associated with aggregation-prone proteins. However, it is unclear how these protective effects are achieved. Here, we used single-molecule FRET to monitor the conformations of the aggregation-prone prion-like LCD of TDP-43. While we observed high conformational heterogeneity in wild-type LCD, the ALS-associated mutation A315T promoted collapsed conformations. In contrast, an Hsp40 chaperone, DNAJA2, and a Hero protein, Hero11, stabilized extended states of the LCD, consistent with their ability to suppress the aggregation of TDP-43. Our results link single-molecule effects on conformation to macro effects on bulk aggregation, where a Hero protein, like a chaperone, can maintain the conformational integrity of a client protein to prevent its aggregation.}, } @article {pmid39117043, year = {2024}, author = {Curtisi, J and Ellis-Wittenhagen, J and Kokanovich, T and Volk-Craft, B}, title = {Compassionate Ventilator Release in Patients With Neuromuscular Disease: A Two-Case Comparison.}, journal = {Journal of pain and symptom management}, volume = {68}, number = {5}, pages = {e392-e396}, doi = {10.1016/j.jpainsymman.2024.07.028}, pmid = {39117043}, issn = {1873-6513}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/complications/therapy ; Dyspnea/therapy/etiology ; Myasthenia Gravis/therapy/complications ; Neuromuscular Diseases/complications/therapy ; *Respiration, Artificial ; Terminal Care ; Ventilator Weaning ; }, abstract = {Dyspnea, the subjective sensation of breathlessness, is a distressing and potentially traumatic symptom. Dyspnea associated with mechanical ventilation may contribute to intensive care unit (ICU) associated post-traumatic stress disorder and impaired quality of life. Dyspnea is both difficult to alleviate and a cause of significant distress to patients, their loved ones, and care providers People living with neuromuscular disease, such as amyotrophic lateral sclerosis (ALS) or myasthenia gravis (MG), often rely on a ventilator at late stages of illness due to complications of progressive respiratory muscle weakness and paralysis. When unable to wean from the ventilator, conversations turn towards goals of care and release from the ventilator for comfort and end of life (EOL). Patients with and without neuromuscular disease have high risk for dyspnea at EOL upon ventilator liberation. Although limited recommendations have been published specific to patients with ALS, no guidelines currently exist for the terminal liberation from mechanical ventilation in patients experiencing respiratory muscle insufficiency from a neuromuscular disease. Further research on this topic is needed, including creation of a protocol for ventilator release in patients with neuromuscular disease. The following case reports detail the dissimilar EOL experiences of two patients with different forms of neuromuscular disease.}, } @article {pmid39116956, year = {2024}, author = {Yang, N and Shi, L and Xu, P and Ren, F and Li, C and Qi, X}, title = {Identification of potential drug targets for amyotrophic lateral sclerosis by Mendelian randomization analysis based on brain and plasma proteomics.}, journal = {Experimental gerontology}, volume = {195}, number = {}, pages = {112538}, doi = {10.1016/j.exger.2024.112538}, pmid = {39116956}, issn = {1873-6815}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/drug therapy ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; *Proteomics/methods ; *Brain/metabolism ; *Protein Interaction Maps ; Anoctamins/genetics ; Bayes Theorem ; Blood Proteins/analysis/metabolism ; Genetic Predisposition to Disease ; }, abstract = {Amyotrophic lateral sclerosis as a fatal neurodegenerative disease currently lacks effective therapeutic agents. Thus, finding new therapeutic targets to drive disease treatment is necessary. In this study, we utilized brain and plasma proteins as genetic instruments obtained from genome-wide association studies to conduct a Mendelian randomization analysis to identify potential drug targets for amyotrophic lateral sclerosis. Additionally, we validated our results externally using other datasets. We also used Bayesian co-localization analysis and phenotype scanning. Furthermore, we constructed a protein-protein interaction network to elucidate potential correlations between the identified proteins and existing targets. Mendelian randomization analysis indicated that elevated levels of ANO5 (OR = 1.30; 95 % CI, 1.14-1.49; P = 1.52E-04), SCFD1 (OR = 3.82; 95 % CI, 2.39-6.10; P = 2.19E-08), and SIGLEC9 (OR = 1.05; 95% CI, 1.03-1.07; P = 4.71E-05) are associated with an increased risk of amyotrophic lateral sclerosis, with external validation supporting these findings. Co-localization analysis confirmed that ANO5, SCFD1, and SIGLEC9 (coloc.abf-PPH4 = 0.848, 0.984, and 0.945, respectively) shared the same variant with amyotrophic lateral sclerosis, further substantiating potential role of these proteins as a therapeutic target. There are interactive relationships between the potential proteins and existing targets of amyotrophic lateral sclerosis. Our findings suggested that elevated levels of ANO5, SCFD1, and SIGLEC9 are connected with an increased risk of amyotrophic lateral sclerosis and might be promising therapeutic targets. However, further exploration is necessary to fully understand the underlying mechanisms involved.}, } @article {pmid39116527, year = {2024}, author = {Ceron-Codorniu, M and Torres, P and Fernàndez-Bernal, A and Rico-Rios, S and Serrano, JC and Miralles, MP and Beltran, M and Garcera, A and Soler, RM and Pamplona, R and Portero-Otín, M}, title = {TDP-43 dysfunction leads to bioenergetic failure and lipid metabolic rewiring in human cells.}, journal = {Redox biology}, volume = {75}, number = {}, pages = {103301}, pmid = {39116527}, issn = {2213-2317}, mesh = {Humans ; *Energy Metabolism ; *DNA-Binding Proteins/metabolism/genetics ; *Lipid Metabolism ; HeLa Cells ; *Adenosine Triphosphate/metabolism ; Induced Pluripotent Stem Cells/metabolism/cytology ; Coenzyme A Ligases/metabolism/genetics ; Motor Neurons/metabolism/pathology ; Cell Survival ; Oxygen Consumption ; Ferroptosis ; Long-Chain-Fatty-Acid-CoA Ligase ; }, abstract = {The dysfunction of TAR DNA-binding protein 43 (TDP-43) is implicated in various neurodegenerative diseases, though the specific contributions of its toxic gain-of-function versus loss-of-function effects remain unclear. This study investigates the impact of TARDBP loss on cellular metabolism and viability using human-induced pluripotent stem cell-derived motor neurons and HeLa cells. TARDBP silencing led to reduced metabolic activity and cell growth, accompanied by neurite degeneration and decreased oxygen consumption rates in both cell types. Notably, TARDBP depletion induced a metabolic shift, impairing ATP production, increasing metabolic inflexibility, and elevating free radical production, indicating a critical role for TDP-43 in maintaining cellular bioenergetics. Furthermore, TARDBP loss triggered non-apoptotic cell death, increased ACSL4 expression, and reprogrammed lipid metabolism towards lipid droplet accumulation, while paradoxically enhancing resilience to ferroptosis inducers. Overall, our findings highlight those essential cellular traits such as ATP production, metabolic activity, oxygen consumption, and cell survival are highly dependent on TARDBP function.}, } @article {pmid39116263, year = {2024}, author = {Aguilar-Vázquez, CA and Aguilar-Castillo, SJ and Raymundo-Carrillo, AD}, title = {[Electrodiagnostic support in an atypical form of amyotrophic lateral sclerosis (Vulpian-Bernhardt syndrome)].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {62}, number = {1}, pages = {1-8}, doi = {10.5281/zenodo.10278187}, pmid = {39116263}, issn = {2448-5667}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/mortality/therapy ; *Electrodiagnosis/methods ; }, abstract = {BACKGROUND: Vulpian-Bernhardt syndrome is an atypical form of the motor neuron disease described since the 19th century. The importance of a timely diagnosis lies in the increased survival present in this variant. Due to the clinical rarity and complex diagnosis we report a clinical case of this disease, which is why we describe the typical clinical presentation, the diagnostic approach, and we make a bibliographic review of this neurodegenerative disorder as well.

CLINICAL CASE: Latin American man whose clinical case onset was characterized by thoracic asymmetric and increasing limb weakness, showing affection from distal to proximal upper limbs area. Subsequently, symptoms worsened to the point of limiting day-to-day activities and conditioning patient's physical independence. Physical examination was consistent with motor neuron disease. Nerve conduction studies were performed and confirmed findings compatible with motor neuron involvement limited to thoracic limbs.

CONCLUSION: Vulpian-Bernhardt syndrome is an uncommon form of motor neuron disease. Due to the rarity of its presentation, it is frequent to confuse clinical profile even for trained physicians. The importance of electrodiagnosis relies in identifying the neurogenic origin of the disease, as well as the active denervation and reinnervation data. Considering that with this syndrome patients have a longer survival than with the classic form of amyotrophic lateral sclerosis, it is important to have a clear diagnosis approach in order to provide a better quality of life and supportive treatment.}, } @article {pmid39115673, year = {2024}, author = {Mishra, Y and Kumar, A and Kaundal, RK}, title = {Mitochondrial Dysfunction is a Crucial Immune Checkpoint for Neuroinflammation and Neurodegeneration: mtDAMPs in Focus.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39115673}, issn = {1559-1182}, support = {EEQ/2021/000875//Science & Engineering Research Board (SERB), Department of Science and Technology, Govt of India/ ; }, abstract = {Neuroinflammation is a pivotal factor in the progression of both age-related and acute neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Mitochondria, essential for neuronal health due to their roles in energy production, calcium buffering, and oxidative stress regulation, become increasingly susceptible to dysfunction under conditions of metabolic stress, aging, or injury. Impaired mitophagy in aged or injured neurons leads to the accumulation of dysfunctional mitochondria, which release mitochondrial-derived damage-associated molecular patterns (mtDAMPs). These mtDAMPs act as immune checkpoints, activating pattern recognition receptors (PRRs) and triggering innate immune signaling pathways. This activation initiates inflammatory responses in neurons and brain-resident immune cells, releasing cytokines and chemokines that damage adjacent healthy neurons and recruit peripheral immune cells, further amplifying neuroinflammation and neurodegeneration. Long-term mitochondrial dysfunction perpetuates a chronic inflammatory state, exacerbating neuronal injury and contributing additional immunogenic components to the extracellular environment. Emerging evidence highlights the critical role of mtDAMPs in initiating and sustaining neuroinflammation, with circulating levels of these molecules potentially serving as biomarkers for disease progression. This review explores the mechanisms of mtDAMP release due to mitochondrial dysfunction, their interaction with PRRs, and the subsequent activation of inflammatory pathways. We also discuss the role of mtDAMP-triggered innate immune responses in exacerbating both acute and chronic neuroinflammation and neurodegeneration. Targeting dysfunctional mitochondria and mtDAMPs with pharmacological agents presents a promising strategy for mitigating the initiation and progression of neuropathological conditions.}, } @article {pmid39115327, year = {2024}, author = {Lescouzères, L and Patten, SA}, title = {Promising animal models for amyotrophic lateral sclerosis drug discovery: a comprehensive update.}, journal = {Expert opinion on drug discovery}, volume = {19}, number = {10}, pages = {1213-1233}, doi = {10.1080/17460441.2024.2387791}, pmid = {39115327}, issn = {1746-045X}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Animals ; Humans ; *Disease Models, Animal ; *Drug Discovery/methods ; Mice ; Genetic Therapy/methods ; Translational Research, Biomedical/methods ; Induced Pluripotent Stem Cells ; Drug Development/methods ; Caenorhabditis elegans ; Motor Neurons/drug effects ; Zebrafish ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. Several animal models have been generated to understand ALS pathogenesis. They have provided valuable insight into disease mechanisms and the development of therapeutic strategies.

AREAS COVERED: In this review, the authors provide a concise overview of simple genetic model organisms, including C. elegans, Drosophila, zebrafish, and mouse genetic models that have been generated to study ALS. They emphasize the benefits of each model and their application in translational research for discovering new chemicals, gene therapy approaches, and antibody-based strategies for treating ALS.

EXPERT OPINION: Significant progress is being made in identifying new therapeutic targets for ALS. This progress is being enabled by promising animal models of the disease using increasingly effective genetic and pharmacological strategies. There are still challenges to be overcome in order to achieve improved success rates for translating drugs from animal models to clinics for treating ALS. Several promising future directions include the establishment of novel preclinical protocol standards, as well as the combination of animal models with human induced pluripotent stem cells (iPSCs).}, } @article {pmid39114608, year = {2024}, author = {Koike, Y}, title = {Abnormal Splicing Events due to Loss of Nuclear Function of TDP-43: Pathophysiology and Perspectives.}, journal = {JMA journal}, volume = {7}, number = {3}, pages = {313-318}, pmid = {39114608}, issn = {2433-3298}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with a progressive and fatal course. They are often comorbid and share the same molecular spectrum. Their key pathological features are the formation of the aggregation of TDP-43, an RNA-binding protein, in the cytoplasm and its depletion from the nucleus in the central nervous system. In the nucleus, TDP-43 regulates several aspects of RNA metabolism, ranging from RNA transcription and alternative splicing to RNA transport. Suppressing the aberrant splicing events during RNA processing is one of the significant functions of TDP-43. This function is impaired when TDP-43 becomes depleted from the nucleus. Several critical cryptic splicing targets of TDP-43 have recently emerged, such as STMN2, UNC13A, and others. UNC13A is an important ALS/FTD risk gene, and the genetic variations, single nucleotide polymorphisms, cause disease via the increased susceptibility for cryptic exon inclusion under the TDP-43 dysfunction. Moreover, TDP-43 has an autoregulatory mechanism that regulates the splicing of its mRNA (TARDBP mRNA) in the healthy state. This study provides recent findings on the splicing regulatory function of TDP-43 and discusses the prospects of using these aberrant splicing events as efficient biomarkers.}, } @article {pmid39113924, year = {2024}, author = {Ueta, Y and Kanbayashi, T and Miyaji, Y and Hatanaka, Y and Tachiyama, K and Takahashi, K and Terashi, H and Aizawa, H and Sonoo, M}, title = {The speed of completion of the decremental responses on repetitive nerve stimulation.}, journal = {Clinical neurophysiology practice}, volume = {9}, number = {}, pages = {211-216}, pmid = {39113924}, issn = {2467-981X}, abstract = {OBJECTIVE: It is generally believed that the decremental response in repetitive nerve stimulation (RNS) stabilizes at the fourth or fifth response. We have a preliminary impression that the decremental response approaches a plateau earlier in proximal muscles than in distal muscles. We investigated the speed of the completion of the decremental response in different muscles.

METHODS: The "decrement completion ratio (DCR)" in the second or third response (DCR2 or DCR3) was defined as the ratio of the decremental percentage of the second or third response to that of the fourth response. Patients showing more than 10% decremental response both in the abductor pollicis (APB) and deltoid muscles were retrospectively extracted from our EMG database. The DCR2 and DCR3 were compared between two muscles in patients with myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS).

RESULTS: Identified subjects consisted of 11patients with MG and 11 patients with ALS. Multiple regression analysis revealed that only the difference of muscle influenced on DCR2 and DCR3, with no contribution from the different disorder (MG or ALS) or the initial amplitude of the compound muscle action potential (CMAP). Both DCR2 and DCR3 were significantly higher in deltoid than in APB. In ALS, the normalized CMAP amplitude was not different between APB and deltoid whereas the decremental percentage was significantly higher in deltoid, suggesting a lower safety factor of the neuromuscular transmission in proximal muscles.

CONCLUSIONS: The decremental response completed more rapidly in deltoid than in APB which may be related to the lower safety factor also documented by this study.

SIGNIFICANCE: Unexpected early completion of the decrement such as at the second response in RNS is not a technical error but may be an extreme of the rapid completion in deltoid, a proximal muscle.}, } @article {pmid39113457, year = {2024}, author = {Pervushina, EV and Kutlubaev, MA and Saifullina, EV and Gaisina, EV and Smakova, LA and Khidiyatova, IM}, title = {[Amyotrophic lateral sclerosis associated with a new pathogenic variant of the ERBB4 gene].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {7}, pages = {165-168}, doi = {10.17116/jnevro2024124071165}, pmid = {39113457}, issn = {1997-7298}, mesh = {Humans ; *Receptor, ErbB-4/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Mutation ; Male ; Middle Aged ; Disease Progression ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a sporadic disease in most of the cases; in 10-15% of cases genetic forms are recorded. A genetic form of ALS associated with the mutation in the ERBB4 gene (ALS19) has been reported in 2013. A protein encoded by the ERBB4 is probably involved in ubiquitous component of the pathogenesis of ALS. We present a case of ALS associated with a new pathogenic variant of the ERBB4 gene, with early bulbar onset and slow progression of the disease within 10 years.}, } @article {pmid39113334, year = {2024}, author = {Khadilkar, V and Lad, S and Mondkar, S and Yewale, S and Dange, N and Wagle, S and Khadilkar, A}, title = {Pediatric Advanced Life Support Tape for Indian Children.}, journal = {Indian pediatrics}, volume = {61}, number = {10}, pages = {961-965}, pmid = {39113334}, issn = {0974-7559}, mesh = {Humans ; India ; Male ; Female ; Child, Preschool ; Child ; *Body Height ; *Body Weight ; *Anthropometry/instrumentation ; Reproducibility of Results ; }, abstract = {OBJECTIVE: To design a specific advanced life support (ALS) tape based on recent Indian multicenter height/length and weight data to accurately estimate the weight from the recumbent length.

METHODS: We designed the new ALS tape by matching the median weights to median heights/lengths from the recently published Indian multicenter growth data, maintaining the same color codes as the Broselow tape. The accuracy of weight estimation for the newly designed ALS tape was validated and compared with the Broselow estimated weights at a tertiary care hospital.

RESULTS: The color (weight) band matched median heights (cm) from the new ALS tape were higher (53.0 vs 53.9 for grey, 63.1 vs 67.4 for pink, 70.6 vs 76.4 for red, 79 vs 85.5 for purple, 89.6 vs 95.5 for yellow, 101.9 vs 107.5 for white, 126.1 vs 130.5 for orange and 137 vs 140.5 for green) than the Broselow tape. For every color band on the newly designed ALS tape, a sizable proportion of children (27% for grey, 78% for pink, 83% for red, 38% for purple, 63% for yellow, 41% for white, 35% for blue, 54% for orange) recorded a higher Broselow color band, suggesting overestimated weights at each color band. The percentage difference in the estimated weight from the actual weight was very small (-0.5% for under-5 years and 0.2% for older children) using the new ALS tape as compared to Broselow tape.

CONCLUSION: This Indianized ALS tape estimated Indian children's weights more accurately. Use of the newly designed ALS tape may reduce the errors in calculating emergency medications, fluids and equipment sizes. Further studies are required to validate this tape in pediatric emergency departments in India.}, } @article {pmid39112530, year = {2024}, author = {Tu, S and Li, T and Carroll, AS and Mahoney, CJ and Huynh, W and Park, SB and Henderson, R and Vucic, S and Kiernan, MC and Lin, CS}, title = {Central neurodegeneration in Kennedy's disease accompanies peripheral motor dysfunction.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {18331}, pmid = {39112530}, issn = {2045-2322}, mesh = {Humans ; Male ; Middle Aged ; Female ; Aged ; *Bulbo-Spinal Atrophy, X-Linked/physiopathology/pathology ; Adult ; Amyotrophic Lateral Sclerosis/physiopathology/pathology/diagnostic imaging ; Brain/diagnostic imaging/pathology/physiopathology ; Magnetic Resonance Imaging ; White Matter/diagnostic imaging/pathology/physiopathology ; }, abstract = {Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease (KD), is a rare hereditary neuromuscular disorder demonstrating commonalities with amyotrophic lateral sclerosis (ALS). The current study aimed to define functional and central nervous system abnormalities associated with SBMA pathology, their interaction, and to identify novel clinical markers for quantifying disease activity. 27 study participants (12 SBMA; 8 ALS; 7 Control) were recruited. SBMA patients underwent comprehensive motor and sensory functional assessments, and neurophysiological testing. All participants underwent whole-brain structural and diffusion MRI. SBMA patients demonstrated marked peripheral motor and sensory abnormalities across clinical assessments. Increased abnormalities on neurological examination were significantly associated with increased disease duration in SBMA patients (R[2] = 0.85, p < 0.01). Widespread juxtacortical axonal degeneration of corticospinal white matter tracts were detected in SBMA patients (premotor; motor; somatosensory; p < 0.05), relative to controls. Increased axial diffusivity was significantly correlated with total neuropathy score in SBMA patients across left premotor (R[2] = 0.59, p < 0.01), motor (R[2] = 0.63, p < 0.01), and somatosensory (R[2] = 0.61, p < 0.01) tracts. The present series has identified involvement of motor and sensory brain regions in SBMA, associated with disease duration and increasing severity of peripheral neuropathy. Quantification of annualized brain MRI together with Total Neuropathy Score may represent a novel approach for clinical monitoring.}, } @article {pmid39111585, year = {2024}, author = {Bischoff, KE and Liera, D and Tang, J and Madugala, N and Cohen, E and Galea, MD and Lindenberger, E and Pantilat, SZ and Lomen-Hoerth, C}, title = {Development and Piloting of a Bereaved Care Partner Survey to Inform Quality Improvement in ALS Supportive Care.}, journal = {Journal of pain and symptom management}, volume = {68}, number = {5}, pages = {467-476.e2}, doi = {10.1016/j.jpainsymman.2024.07.031}, pmid = {39111585}, issn = {1873-6513}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Quality Improvement ; Pilot Projects ; *Bereavement ; Female ; Male ; *Palliative Care ; Caregivers ; Middle Aged ; Aged ; Surveys and Questionnaires ; Adult ; }, abstract = {OBJECTIVES: Bereaved care partner surveys typically focus on the experience with care in the final days of life. We sought to develop and pilot a novel bereaved care partner survey to understand experiences with ALS supportive care provided throughout the illness and identify opportunities for quality improvement.

METHODS: We developed the survey using a multisite, interdisciplinary consensus process involving ALS and palliative care clinicians as well as patient advocates. We then piloted the survey at a single site via video interviews with care partners of patients who died from ALS between three and 15 months prior. Qualitative findings were analyzed using Rapid Qualitative Analysis.

RESULTS: The survey includes 17 core questions and nine demographic items. Questions inquire about whether the patient and care partner received adequate help with physical symptoms, emotional and practical needs, education about the illness and how to provide hands-on care, preparing for what was to come, and bereavement. They also query whether care was person-centered and consistent with the patient's values and preferences. During the pilot with 18 bereaved care partners, the tool generated detailed feedback about aspects of care to preserve as well as how to improve ALS supportive care.

DISCUSSION: We developed and piloted a bereaved care partner survey to understand and improve the quality of ALS supportive care, which was found to be feasible and acceptable. Next steps include testing it at additional centers in order to generate learnings that can advance ALS supportive care in ways that are meaningful to patients and care partners.}, } @article {pmid39111522, year = {2024}, author = {Li, Q and Zhu, W and Wen, X and Zang, Z and Da, Y and Lu, J}, title = {Different baseline functional patterns of the frontal cortex in amyotrophic lateral sclerosis patients with Corticospinal tract hyperintensity.}, journal = {Brain research}, volume = {1844}, number = {}, pages = {149140}, doi = {10.1016/j.brainres.2024.149140}, pmid = {39111522}, issn = {1872-6240}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Male ; Female ; *Pyramidal Tracts/physiopathology/diagnostic imaging ; Middle Aged ; *Magnetic Resonance Imaging/methods ; *Frontal Lobe/physiopathology/diagnostic imaging ; Aged ; Adult ; Brain Mapping/methods ; }, abstract = {Nearly half of the amyotrophic lateral sclerosis (ALS) patients showed hyperintensity of the corticospinal tract (CST+), yet whether brain functional pattern differs between CST+and CST- patients remains obscure. In the current study, 19 ALS CST+, 41 ALS CST- patients and 37 healthy controls (HC) underwent resting state fMRI scans. We estimated local activity and connectivity patterns via the Amplitude of Low Frequency Fluctuations (ALFF) and the Network-Based Statistic (NBS) approaches respectively. The ALS CST+patients did not differ from the CST- patients in amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R) score and disease duration. ALFF of the superior frontal gyrus (SFG) and the inferior frontal gyrus pars opercularis (OIFG) were highest in the HC and lowest in the ALS CST- patients, resulting in significant group differences (PFWE<0.05). NBS analysis revealed a frontal network consisting of connections between SFG, OIFG, orbital frontal gyrus, middle cingulate cortex and the basal ganglia, which exhibited HC>ALS CST+ > ALS CST- group differences (PFWE=0.037) as well. The ALFF of the OIFG was significantly correlated with ALSFRS-R (R=0.34, P=0.028) and mean connectivity of the frontal network was trend-wise significantly correlated with disease duration (R=-0.31, P=0.052) in the ALS CST- patients. However, these correlations were insignificant in ALS CST+patients (P values > 0.8). In conclusion, The ALS CST+patients exhibited different patterns of baseline functional activity and connectivity in the frontal cortex which may indicate a functional compensatory effect.}, } @article {pmid39111227, year = {2024}, author = {Torghabeh, FA and Moghadam, EA and Hosseini, SA}, title = {Simultaneous time-frequency analysis of gait signals of both legs in classifying neurodegenerative diseases.}, journal = {Gait & posture}, volume = {113}, number = {}, pages = {443-451}, doi = {10.1016/j.gaitpost.2024.07.302}, pmid = {39111227}, issn = {1879-2219}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/physiopathology ; *Gait Analysis/methods ; Gait Disorders, Neurologic/classification/diagnosis/physiopathology/etiology ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/classification ; Wavelet Analysis ; Male ; Female ; Middle Aged ; Parkinson Disease/diagnosis/physiopathology/classification ; Deep Learning ; Signal Processing, Computer-Assisted ; Case-Control Studies ; Huntington Disease/physiopathology/diagnosis/classification ; Aged ; }, abstract = {BACKGROUND: Neurodegenerative diseases (NDDs) pose significant challenges due to their debilitating nature and limited therapeutic options. Accurate and timely diagnosis is crucial for optimizing patient care and treatment strategies. Gait analysis, utilizing wearable sensors, has shown promise in assessing motor abnormalities associated with NDDs.

RESEARCH QUESTION: Research Question 1 To what extent can analyzing the interaction of both limbs in the time-frequency domain serve as a suitable methodology for accurately classifying NDDs? Research Question 2 How effective is the utilization of color-coded images, in conjunction with deep transfer learning models, for the classification of NDDs?

METHODS: GaitNDD database was used, comprising recordings from patients with Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, and healthy controls. The gait signals underwent signal preparation, wavelet coherence analysis, and principal component analysis for feature enhancement. Deep transfer learning models (AlexNet, GoogLeNet, SqueezeNet) were employed for classification. Performance metrics, including accuracy, sensitivity, specificity, precision, and F1 score, were evaluated using 5-fold cross-validation.

RESULTS: The classification performance of the models varied depending on the time window used. For 5-second gait signal segments, AlexNet achieved an accuracy of 95.91 %, while GoogLeNet and SqueezeNet achieved accuracies of 96.49 % and 92.73 %, respectively. For 10-second segments, AlexNet outperformed other models with an accuracy of 99.20 %, while GoogLeNet and SqueezeNet achieved accuracies of 96.75 % and 95.00 %, respectively. Statistical tests confirmed the significance of the extracted features, indicating their discriminative power for classification.

SIGNIFICANCE: The proposed method demonstrated superior performance compared to previous studies, offering a non-invasive and cost-effective approach for the automated diagnosis of NDDs. By analyzing the interaction between both legs during walking using wavelet coherence, and utilizing deep transfer learning models, accurate classification of NDDs was achieved.}, } @article {pmid39110593, year = {2024}, author = {Hoh, KL and Mu, B and See, T and Ng, AYE and Ng, AQE and Zhang, D}, title = {VAP-mediated membrane-tethering mechanisms implicate ER-PM contact function in pH homeostasis.}, journal = {Cell reports}, volume = {43}, number = {8}, pages = {114592}, doi = {10.1016/j.celrep.2024.114592}, pmid = {39110593}, issn = {2211-1247}, mesh = {*Endoplasmic Reticulum/metabolism ; Hydrogen-Ion Concentration ; *Homeostasis ; *Cell Membrane/metabolism ; Humans ; *Schizosaccharomyces/metabolism ; Schizosaccharomyces pombe Proteins/metabolism ; Vesicular Transport Proteins/metabolism/genetics ; Protein Binding ; Membrane Proteins/metabolism ; Phospholipids/metabolism ; Mutation ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Vesicle-associated membrane protein (VAMP)-associated proteins (VAPs) are highly conserved endoplasmic reticulum (ER)-resident proteins that establish ER contacts with multiple membrane compartments in many eukaryotes. However, VAP-mediated membrane-tethering mechanisms remain ambiguous. Here, focusing on fission yeast ER-plasma membrane (PM) contact formation, using systematic interactome analyses and quantitative microscopy, we predict a non-VAP-protein direct binding-based ER-PM coupling. We further reveal that VAP-anionic phospholipid interactions may underlie ER-PM association and define the pH-responsive nature of VAP-tethered membrane contacts. Such conserved interactions with anionic phospholipids are generally defective in amyotrophic lateral sclerosis-associated human VAPB mutant. Moreover, we identify a conserved FFAT-like motif locating at the autoinhibitory hotspot of the essential PM proton pump Pma1. This modulatory VAP-Pma1 interaction appears crucial for pH homeostasis. We thus propose an ingenious strategy for maintaining intracellular pH by coupling Pma1 modulation with pH-sensory ER-PM contacts via VAP-mediated interactions.}, } @article {pmid39108340, year = {2024}, author = {Tröger, J and Dörr, F and Schwed, L and Linz, N and König, A and Thies, T and Barbe, MT and Orozco-Arroyave, JR and Rusz, J}, title = {An automatic measure for speech intelligibility in dysarthrias-validation across multiple languages and neurological disorders.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1440986}, pmid = {39108340}, issn = {2673-253X}, abstract = {INTRODUCTION: Dysarthria, a motor speech disorder caused by muscle weakness or paralysis, severely impacts speech intelligibility and quality of life. The condition is prevalent in motor speech disorders such as Parkinson's disease (PD), atypical parkinsonism such as progressive supranuclear palsy (PSP), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Improving intelligibility is not only an outcome that matters to patients but can also play a critical role as an endpoint in clinical research and drug development. This study validates a digital measure for speech intelligibility, the ki: SB-M intelligibility score, across various motor speech disorders and languages following the Digital Medicine Society (DiMe) V3 framework.

METHODS: The study used four datasets: healthy controls (HCs) and patients with PD, HD, PSP, and ALS from Czech, Colombian, and German populations. Participants' speech intelligibility was assessed using the ki: SB-M intelligibility score, which is derived from automatic speech recognition (ASR) systems. Verification with inter-ASR reliability and temporal consistency, analytical validation with correlations to gold standard clinical dysarthria scores in each disease, and clinical validation with group comparisons between HCs and patients were performed.

RESULTS: Verification showed good to excellent inter-rater reliability between ASR systems and fair to good consistency. Analytical validation revealed significant correlations between the SB-M intelligibility score and established clinical measures for speech impairments across all patient groups and languages. Clinical validation demonstrated significant differences in intelligibility scores between pathological groups and healthy controls, indicating the measure's discriminative capability.

DISCUSSION: The ki: SB-M intelligibility score is a reliable, valid, and clinically relevant tool for assessing speech intelligibility in motor speech disorders. It holds promise for improving clinical trials through automated, objective, and scalable assessments. Future studies should explore its utility in monitoring disease progression and therapeutic efficacy as well as add data from further dysarthrias to the validation.}, } @article {pmid39108272, year = {2024}, author = {De Federicis, D and Bassani, C and Chiarelli, RR and Montini, F and Giordano, A and Esposito, F and Riva, N and Quattrini, A and Martinelli, V and Filippi, M and Farina, C}, title = {Circulating MAIT cells in multiple sclerosis and amyotrophic lateral sclerosis.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1436717}, pmid = {39108272}, issn = {1664-3224}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/blood ; *Mucosal-Associated Invariant T Cells/immunology/metabolism ; Male ; Middle Aged ; Female ; Adult ; Aged ; Multiple Sclerosis/immunology/blood ; CD8-Positive T-Lymphocytes/immunology/metabolism ; Biomarkers ; Flow Cytometry ; }, abstract = {Neurological disorders, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), may be associated with alterations in blood cell composition and phenotype. Here, we focused our attention on circulating mucosal-associated invariant T (MAIT) cells, a CD8[+] T cell memory population expressing the invariant Vα7.2 region in the T cell receptor and high surface levels of the CD161 marker. Transcriptomics data relative to peripheral blood mononuclear cells (PBMC) highlighted downregulation of CD161 and other MAIT-associated markers in progressive MS and not relapsing remitting (RR)-MS when gene expressions relative to each disease course were compared to those from healthy controls. Multiparametric flow cytometry of freshly isolated PBMC samples from untreated RR-MS, primary or secondary progressive MS (PP- or SP-MS), ALS and age- and sex-matched healthy controls revealed specific loss of circulating CD8[+] MAIT cells in PP-MS and no other MS courses or another neurological disorder such as ALS. Overall, these observations point to the existence of immunological changes in blood specific for the primary progressive course of MS that may support clinical definition of disease.}, } @article {pmid39107374, year = {2024}, author = {Monselise, EB and Vyazmensky, M and Scherf, T and Batushansky, A and Fishov, I}, title = {D-Glutamate production by stressed Escherichia coli gives a clue for the hypothetical induction mechanism of the ALS disease.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {18247}, pmid = {39107374}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/microbiology ; *Escherichia coli/metabolism ; *Glutamic Acid/metabolism ; Humans ; Stress, Physiological ; Complement C1q/metabolism ; Nitrogen/metabolism ; Carbon/metabolism ; }, abstract = {In the search for the origin of Amyotrophic Lateral Sclerosis disease (ALS), we hypothesized earlier (Monselise, 2019) that D-amino acids produced by stressed microbiome may serve as inducers of the disease development. Many examples of D-amino acid accumulation under various stress conditions were demonstrated in prokaryotic and eukaryotic cells. In this work, wild-type Escherichia coli, members of the digestive system, were subjected to carbon and nitrogen starvation stress. Using NMR and LC-MS techniques, we found for the first time that D-glutamate accumulated in the stressed bacteria but not in control cells. These results together with the existing knowledge, allow us to suggest a new insight into the pathway of ALS development: D-glutamate, produced by the stressed microbiome, induces neurobiochemical miscommunication setting on C1q of the complement system. Proving this insight may have great importance in preventive medicine of such MND modern-age diseases as ALS, Alzheimer, and Parkinson.}, } @article {pmid39107037, year = {2025}, author = {Jang, DG and Dou, JF and Koubek, EJ and Teener, S and Zhou, L and Bakulski, KM and Mukherjee, B and Batterman, SA and Feldman, EL and Goutman, SA}, title = {Multiple metal exposures associate with higher amyotrophic lateral sclerosis risk and mortality independent of genetic risk and correlate to self-reported exposures: a case-control study.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {4}, pages = {329-339}, doi = {10.1136/jnnp-2024-333978}, pmid = {39107037}, issn = {1468-330X}, support = {K23 ES027221/ES/NIEHS NIH HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Case-Control Studies ; Female ; Middle Aged ; Aged ; *Metals/urine/adverse effects/blood ; Environmental Exposure/adverse effects ; Polymorphism, Single Nucleotide ; Self Report ; Genome-Wide Association Study ; Risk Factors ; Genetic Predisposition to Disease ; Copper/urine/blood/adverse effects ; Occupational Exposure/adverse effects ; Selenium/blood/urine ; }, abstract = {BACKGROUND: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both genetic and environmental factors. This study investigates associations between metal measures in plasma and urine, ALS risk and survival and exposure sources.

METHODS: Participants with and without ALS from Michigan provided plasma and urine samples for metal measurement via inductively coupled plasma mass spectrometry. ORs and HRs for each metal were computed using risk and survival models. Environmental risk scores (ERS) were created to evaluate the association between exposure mixtures and ALS risk and survival and exposure source. ALS (ALS-PGS) and metal (metal-PGS) polygenic risk scores were constructed from an independent genome-wide association study and relevant literature-selected single-nucleotide polymorphisms.

RESULTS: Plasma and urine samples from 454 ALS and 294 control participants were analysed. Elevated levels of individual metals, including copper, selenium and zinc, significantly associated with ALS risk and survival. ERS representing metal mixtures strongly associated with ALS risk (plasma, OR=2.95, CI=2.38-3.62, p<0.001; urine, OR=3.10, CI=2.43-3.97, p<0.001) and poorer ALS survival (plasma, HR=1.37, CI=1.20-1.58, p<0.001; urine, HR=1.44, CI=1.23-1.67, p<0.001). Addition of the ALS-PGS or metal-PGS did not alter the significance of metals with ALS risk and survival. Occupations with high potential of metal exposure associated with elevated ERS. Additionally, occupational and non-occupational metal exposures were associated with measured plasma and urine metals.

CONCLUSION: Metals in plasma and urine associated with increased ALS risk and reduced survival, independent of genetic risk, and correlated with occupational and non-occupational metal exposures. These data underscore the significance of metal exposure in ALS risk and progression.}, } @article {pmid39106320, year = {2024}, author = {Dong, D and Zhang, Z and Li, Y and Latallo, MJ and Wang, S and Nelson, B and Wu, R and Krishnan, G and Gao, FB and Wu, B and Sun, S}, title = {Poly-GR repeats associated with ALS/FTD gene C9ORF72 impair translation elongation and induce a ribotoxic stress response in neurons.}, journal = {Science signaling}, volume = {17}, number = {848}, pages = {eadl1030}, pmid = {39106320}, issn = {1937-9145}, support = {RF1 NS101986/NS/NINDS NIH HHS/United States ; R21 AG072078/AG/NIA NIH HHS/United States ; T32 GM008403/GM/NIGMS NIH HHS/United States ; R01 NS107347/NS/NINDS NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *DNA Repeat Expansion/genetics ; Peptide Chain Elongation, Translational ; p38 Mitogen-Activated Protein Kinases/metabolism/genetics ; Stress, Physiological/genetics ; Ribosomes/metabolism/genetics ; }, abstract = {Hexanucleotide repeat expansion in the C9ORF72 gene is the most frequent inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansion results in multiple dipeptide repeat proteins, among which arginine-rich poly-GR proteins are highly toxic to neurons and decrease the rate of protein synthesis. We investigated whether the effect on protein synthesis contributes to neuronal dysfunction and degeneration. We found that the expression of poly-GR proteins inhibited global translation by perturbing translation elongation. In iPSC-differentiated neurons, the translation of transcripts with relatively slow elongation rates was further slowed, and stalled, by poly-GR. Elongation stalling increased ribosome collisions and induced a ribotoxic stress response (RSR) mediated by ZAKα that increased the phosphorylation of the kinase p38 and promoted cell death. Knockdown of ZAKα or pharmacological inhibition of p38 ameliorated poly-GR-induced toxicity and improved the survival of iPSC-derived neurons from patients with C9ORF72-ALS/FTD. Our findings suggest that targeting the RSR may be neuroprotective in patients with ALS/FTD caused by repeat expansion in C9ORF72.}, } @article {pmid39106168, year = {2024}, author = {Glineburg, MR and Yildirim, E and Gomez, N and Rodriguez, G and Pak, J and Li, X and Altheim, C and Waksmacki, J and McInerney, GM and Barmada, SJ and Todd, PK}, title = {Stress granule formation helps to mitigate neurodegeneration.}, journal = {Nucleic acids research}, volume = {52}, number = {16}, pages = {9745-9759}, pmid = {39106168}, issn = {1362-4962}, support = {2018-03843//Swedish Research Council/ ; //Ann Arbor Active Against ALS/ ; T32 NS076401/NS/NINDS NIH HHS/United States ; BLRD BX004842//Veterans Affairs/ ; I01 BX004842/BX/BLRD VA/United States ; P50HD104463/NH/NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Stress Granules/metabolism ; *Neurodegenerative Diseases/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Humans ; *Neurons/metabolism ; *Frontotemporal Dementia/metabolism/genetics ; RNA Recognition Motif Proteins/metabolism/genetics ; Drosophila Proteins/metabolism/genetics ; Poly-ADP-Ribose Binding Proteins/metabolism/genetics ; Mice ; Drosophila melanogaster/metabolism/genetics ; RNA Helicases/metabolism/genetics ; Ataxia/genetics/metabolism ; DNA Helicases/metabolism/genetics ; Alphavirus/genetics/metabolism ; Rats ; Carrier Proteins/metabolism ; Drosophila/metabolism ; Cytoplasmic Granules/metabolism ; Stress, Physiological ; DNA-Binding Proteins ; }, abstract = {Cellular stress pathways that inhibit translation initiation lead to transient formation of cytoplasmic RNA/protein complexes known as stress granules. Many of the proteins found within stress granules and the dynamics of stress granule formation and dissolution are implicated in neurodegenerative disease. Whether stress granule formation is protective or harmful in neurodegenerative conditions is not known. To address this, we took advantage of the alphavirus protein nsP3, which selectively binds dimers of the central stress granule nucleator protein G3BP and markedly reduces stress granule formation without directly impacting the protein translational inhibitory pathways that trigger stress granule formation. In Drosophila and rodent neurons, reducing stress granule formation with nsP3 had modest impacts on lifespan even in the setting of serial stress pathway induction. In contrast, reducing stress granule formation in models of ataxia, amyotrophic lateral sclerosis and frontotemporal dementia largely exacerbated disease phenotypes. These data support a model whereby stress granules mitigate, rather than promote, neurodegenerative cascades.}, } @article {pmid39106020, year = {2024}, author = {Mirmotahari, SA and Aliomrani, M and Hassanzadeh, F and Sirous, H and Rostami, M}, title = {Hybrid derivatives containing dimethyl fumarate and benzothiazole scaffolds for the potential treatment of multiple sclerosis; in silico & in vivo study.}, journal = {Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences}, volume = {32}, number = {2}, pages = {599-615}, pmid = {39106020}, issn = {2008-2231}, mesh = {*Dimethyl Fumarate/pharmacology/chemistry ; *Multiple Sclerosis/drug therapy ; Animals ; *Molecular Docking Simulation ; *Benzothiazoles/chemistry/pharmacology ; *Riluzole/pharmacology/chemistry ; Mice ; *Mice, Inbred C57BL ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; Male ; Cuprizone ; Disease Models, Animal ; Computer Simulation ; Neuroprotective Agents/pharmacology/chemistry ; Remyelination/drug effects ; }, abstract = {BACKGROUND: Multiple Sclerosis (MS) is a chronic autoimmune, inflammatory neurological disease of the CNS. Riluzole and dimethyl fumarate (DMF) are two FDA-approved drugs to treat amyotrophic lateral sclerosis (ALS) and MS. Riluzole (a benzothiazole derivative) inhibits glutamate release from nerve terminals by antagonizing the N-Methyl-D-Aspartate (NMDA) receptor, and DMF upregulates anti-oxidative pathways.

OBJECTIVES: Herein, using molecular hybridization strategy, we synthesized some new hybrid structures of Riluzole and DMF through some common successive synthetic pathways for evaluating their potential activity for remyelination in MS treatment.

METHODS: Molecular docking experiments assessed the binding affinity of proposed structures to the NMDA active site. The designed structures were synthesized and purified based on well-known chemical synthesis procedures. Afterward, in vivo evaluation for their activity was done in the C57Bl/6 Cuprizone-induced demyelination MS model.

RESULTS AND CONCLUSION: The proposed derivatives were recognized to be potent enough based on docking studies (ΔGbind of all derivatives were -7.2 to -7.52 compare to the Ifenprodil (-6.98) and Riluzole (-4.42)). The correct structures of desired derivatives were confirmed using spectroscopic methods. Based on in vivo studies, D4 and D6 derivatives exhibited the best pharmacological results, although only D6 showed a statistically significant difference compared to the control. Also, for D4 and D6 derivatives, myelin staining confirmed reduced degeneration in the corpus callosum. Consequently, D4 and D6 derivatives are promising candidates for developing new NMDA antagonists with therapeutic value against MS disorders.}, } @article {pmid39105912, year = {2024}, author = {Andrysiak, K and Stępniewski, J and Spaczyńska-Boczar, M and Łapicka-Bodzioch, K and Słowik, A and Dulak, J}, title = {Generation of Human-Induced Pluripotent Stem Cells from Peripheral Blood Mononuclear Cells of C9ORF72-Associated Amyotrophic Lateral Sclerosis Patients.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2835}, number = {}, pages = {135-146}, pmid = {39105912}, issn = {1940-6029}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *C9orf72 Protein/genetics/metabolism ; Cell Culture Techniques/methods ; *Cell Differentiation ; Cellular Reprogramming ; DNA Repeat Expansion ; *Induced Pluripotent Stem Cells/metabolism/cytology ; *Leukocytes, Mononuclear/metabolism ; }, abstract = {Disease modeling of neuromuscular disorders, such as amyotrophic lateral sclerosis (ALS), is hindered by limited accessibility of affected cells. This problem can be overcome by generation of human induced pluripotent stem cells (hiPSC), which can be then differentiated into required cells. Here, we describe the detailed protocol of hiPSC establishment from peripheral blood mononuclear cells (PBMC) of two ALS patients with detected expansion of G4C2 (GGGGCC) repeats in the first intron of C9ORF72 gene, known to be linked with the most common form of familial ALS.Successful PBMC reprogramming with non-integrating Sendai vectors was confirmed by expression of pluripotency markers: OCT4, NANOG, SSEA4, and TRA-1-60 in obtained hiPSC and their ability to differentiate into cells of three germ layers.The generated ALS-patient-specific hiPSC create a possibility for deciphering molecular basis of this devastating neuromuscular disease.}, } @article {pmid39104673, year = {2024}, author = {Rezvani, S and Hosseini-Zahraei, SH and Tootchi, A and Guger, C and Chaibakhsh, Y and Saberi, A and Chaibakhsh, A}, title = {A review on the performance of brain-computer interface systems used for patients with locked-in and completely locked-in syndrome.}, journal = {Cognitive neurodynamics}, volume = {18}, number = {4}, pages = {1419-1443}, pmid = {39104673}, issn = {1871-4080}, abstract = {Patients with locked-in syndrome (LIS) and complete locked-in syndrome (CLIS) own a fully functional brain restricted within a non-functional body. In order to help LIS patients stay connected with their surroundings, brain-computer interfaces (BCIs) and related technologies have emerged. BCIs translate brain activity into actions that can be performed by external devices enabling LIS patients to communicate, leading to an increase in their quality of life. The past decade has seen the rapid development of BCIs that have the potential to be used for patients with locked-in syndrome, from which a great deal is tested only on healthy subjects and not on actual patients. This study aims to (1) provide the readers with a comprehensive study that contributes to this growing area of research by exploring the performance of BCIs tested specifically on LIS and CLIS patients, (2) give an overview of different modalities and paradigms used in different stages of the locked-in syndrome, and (3) discuss the contributions and limitations of BCIs introduced for the LIS and CLIS patients in the state-of-the-art and lay a groundwork for researchers interested in this field.}, } @article {pmid39104562, year = {2024}, author = {Haikal, A and Ali, AR}, title = {Chemical composition and toxicity studies on Lantana camara L. flower essential oil and its in silico binding and pharmacokinetics to superoxide dismutase 1 for amyotrophic lateral sclerosis (ALS) therapy.}, journal = {RSC advances}, volume = {14}, number = {33}, pages = {24250-24264}, pmid = {39104562}, issn = {2046-2069}, abstract = {Using the gas chromatography mass spectrometry method, the chemical components of essential oil from flowers of Lantana camara growing in Egypt are analyzed. Through this investigation, 22 chemicals from floral oil were identified. Most of the oil is made up of sesquiterpene caryophyllene (15.51%) and monoterpene sabinene (14.90%). When the oil's composition was compared to oils extracted from the same plant on several continents, we observed that the essential components were largely the same with some difference in proportions and some compounds due to geographical differences. A molecular docking study of essential oil components was conducted with human superoxide dismutase 1, a target involved in the pathophysiology of amyotrophic lateral sclerosis (ALS). Isospathulenol showed a comparable docking score to the reference ligand bound to the dismutase enzyme. Isospathulenol showed a reasonable drug score with some safety concerns. In addition, isospathulenol is predicted to have high GI absorption, good permeability through the blood-brain barrier and reasonable bioavailability score with ease access to synthetic modifications. In addition, the same compound is devoid from any violation to Lipinski rules or any PAINS alerts. This may establish the promising characteristics of such a compound to be optimized into potential drug candidates for treatment of ALS.}, } @article {pmid39104446, year = {2024}, author = {Higgins, S and Dlamini, S and Hattingh, M and Rambharose, S and Theron, E and Stassen, W}, title = {Views and perceptions of advanced life support practitioners on initiating, withholding and terminating resuscitation in out-of-hospital cardiac arrest in the Emergency Medical Services of South Africa.}, journal = {Resuscitation plus}, volume = {19}, number = {}, pages = {100709}, pmid = {39104446}, issn = {2666-5204}, abstract = {INTRODUCTION: This study aimed to explore the views and perceptions of Advanced Life Support (ALS) practitioners in two South African provinces on initiating, withholding, and terminating resuscitation in OHCA.

METHODOLOGY: Semi-structured one-on-one interviews were conducted with operational ALS practitioners working within the prehospital setting in the Western Cape and Free State provinces. Recorded interviews were transcribed and subjected to inductive-dominant, manifest content analysis. After familiarisation with the data, meaning units were condensed, codes were applied and collated into categories that were then assessed, reviewed, and refined repeatedly.

RESULTS: A total of 18 ALS providers were interviewed. Five main categories were developed from the data analysis: 1) assessment of prognosis, 2) internal factors affecting decision-making, 3) external factors affecting decision-making, 4) system challenges, and 5) ideas for improvement. Factors influencing the assessment of prognosis were history, clinical presentation, and response to resuscitation. Internal factors affecting decision-making were driven by emotion and contemplation. External factors affecting decision-making included family, safety, and disposition. System challenges relating to bystander response and resources were identified. Ideas for improvement in training and support were brought forward.

CONCLUSION: Many factors influence OHCA decision-making in the Western Cape and Free State provinces, and numerous system challenges have been identified. The findings of this study can be used as a frame of reference for prehospital emergency care personnel and contribute to the development of context-specific guidelines.}, } @article {pmid39103661, year = {2024}, author = {Tomasicchio, G and Martines, G and Tartaglia, N and Buonfantino, M and Restini, E and Carlucci, B and Giove, C and Dezi, A and Ranieri, C and Logrieco, G and Vincenti, L and Ambrosi, A and Altomare, DF and De Fazio, M and Picciariello, A}, title = {Suture reinforcement using a modified cyanoacrylate glue to prevent anastomotic leak in colorectal surgery: a prospective multicentre randomized trial : The Rectal Anastomotic seaL (ReAL) trial.}, journal = {Techniques in coloproctology}, volume = {28}, number = {1}, pages = {95}, pmid = {39103661}, issn = {1128-045X}, mesh = {Humans ; *Anastomotic Leak/prevention & control/etiology ; Female ; Male ; Prospective Studies ; Aged ; Middle Aged ; *Cyanoacrylates/administration & dosage ; *Anastomosis, Surgical/adverse effects/methods ; *Rectum/surgery ; Tissue Adhesives/therapeutic use ; Suture Techniques ; Rectal Neoplasms/surgery ; Treatment Outcome ; }, abstract = {BACKGROUND: Anastomotic leakage (AL) is the most frequent life-threating complication following colorectal surgery. Several attempts have been made to prevent AL. This prospective, randomized, multicentre trial aimed to evaluate the safety and efficacy of nebulised modified cyanoacrylate in preventing AL after rectal surgery.

METHODS: Patients submitted to colorectal surgery for carcinoma of the high-medium rectum across five high-volume centres between June 2021 and January 2023 entered the study and were randomized into group A (anastomotic reinforcement with cyanoacrylate) and group B (no reinforcement) and followed up for 30 days. Anastomotic reinforcement was performed via nebulisation of 1 mL of a modified cyanoacrylate glue. Preoperative features and intraoperative and postoperative results were recorded and compared. The study was registered at ClinicalTrials.gov (ID number NCT03941938).

RESULTS: Out of 152 patients, 133 (control group, n = 72; cyanoacrylate group, n = 61) completed the follow-up. ALs were detected in nine patients (12.5%) in the control group (four grade B and five grade C) and in four patients (6.6%), in the cyanoacrylate group (three grade B and one grade C); however, despite this trend, the differences were not statistically significant (p = 0.36). However, Clavien-Dindo complications grade > 2 were significantly higher in the control group (12.5% vs. 3.3%, p = 0.04). No adverse effects related to the glue application were reported.

CONCLUSION: The role of modified cyanoacrylate application in AL prevention remains unclear. However its use to seal colorectal anastomoses is safe and could help to reduce severe postoperative complications.}, } @article {pmid39103493, year = {2024}, author = {Talaia, G and Bentley-DeSousa, A and Ferguson, SM}, title = {Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition.}, journal = {The EMBO journal}, volume = {43}, number = {18}, pages = {3948-3967}, pmid = {39103493}, issn = {1460-2075}, support = {R01 GM105718/GM/NIGMS NIH HHS/United States ; ASAP-000580//Michael J. Fox Foundation for Parkinson's Research (MJFF)/ ; ASAP-000580//Aligning Science Across Parkinson's (ASAP)/ ; GM105718//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, mesh = {Humans ; *Amino Acids/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Frontotemporal Dementia/metabolism/genetics/pathology ; HEK293 Cells ; *Lysosomes/metabolism ; *Mechanistic Target of Rapamycin Complex 1/metabolism/genetics ; Phosphorylation ; *Protein Serine-Threonine Kinases/metabolism/genetics ; rab GTP-Binding Proteins/metabolism/genetics ; *rab7 GTP-Binding Proteins ; Signal Transduction ; }, abstract = {Lysosomes play a pivotal role in coordinating macromolecule degradation and regulating cell growth and metabolism. Despite substantial progress in identifying lysosomal signaling proteins, understanding the pathways that synchronize lysosome functions with changing cellular demands remains incomplete. This study uncovers a role for TANK-binding kinase 1 (TBK1), well known for its role in innate immunity and organelle quality control, in modulating lysosomal responsiveness to nutrients. Specifically, we identify a pool of TBK1 that is recruited to lysosomes in response to elevated amino acid levels. This lysosomal TBK1 phosphorylates Rab7 on serine 72. This is critical for alleviating Rab7-mediated inhibition of amino acid-dependent mTORC1 activation. Furthermore, a TBK1 mutant (E696K) associated with amyotrophic lateral sclerosis and frontotemporal dementia constitutively accumulates at lysosomes, resulting in elevated Rab7 phosphorylation and increased mTORC1 activation. This data establishes the lysosome as a site of amino acid regulated TBK1 signaling that is crucial for efficient mTORC1 activation. This lysosomal pool of TBK1 has broader implications for lysosome homeostasis, and its dysregulation could contribute to the pathogenesis of ALS-FTD.}, } @article {pmid39102937, year = {2024}, author = {Ali, F and Tang, Z and Mo, G and Zhang, B and Ling, X and Qiu, Z}, title = {Taxonomic and functional changes in wheat rhizosphere microbiome caused by imidazoline-based herbicide and genetic modification.}, journal = {Environmental research}, volume = {262}, number = {Pt 2}, pages = {119726}, doi = {10.1016/j.envres.2024.119726}, pmid = {39102937}, issn = {1096-0953}, mesh = {*Triticum/microbiology/genetics ; *Rhizosphere ; *Herbicides/toxicity ; *Microbiota/drug effects ; Soil Microbiology ; Plants, Genetically Modified/microbiology ; Imidazolines ; Imidazoles/toxicity ; Acetolactate Synthase/genetics ; Soil Pollutants/toxicity ; Bacteria/drug effects/genetics/classification ; }, abstract = {Genetically modified (GM) crop cultivation has received a lot of attention in recent years due to the substantial public debate. Consequently, an in-depth investigation of excessively used GM herbicide-tolerant crops is a vital step for the biosafety of genetically modified plants. Several studies have been conducted to study the impact of transgenic GM crops on soil microbial composition; however, research into the effects of non-transgenic GM crops is inadequate. In the current work, high-throughput sequencing was used to evaluate the impact of the acetolactate synthase (ALS)-mutant (WK170B), its control (YN19B), and the imazamox (IM) herbicide on the wheat rhizobiome. Under normal growth conditions, our work revealed a minimal impact of ALS-mutant WK170B on the rhizosphere microbiome compared to the control YN10B, except for some cyanobacterial microorganisms that showed a significant increase in abundance. This suggests that the gene mutation could potentially have a beneficial impact on the bacterial communities present in the rhizosphere. Following IM exposure, taxonomic analysis revealed a significant reduction in the relative abundance of Ralstonia pickettii and an unidentified member of the genus Ancylothrix 8 PC. Analyses of both alpha and beta diversity revealed a statistically significant increase in both microbial richness and species diversity. IM-induced relative abundance modulation was also evident through Linear discriminant analysis Effect Size (LEfSe), MetaStat, and heatmap analyses. The SIMPER analysis revealed that the microbial taxa Massilia, Limnobacter, Hydrogenophaga, Ralstonia, Nitrospira, and Ramlibacter exhibited the highest vulnerability to IM exposure. The functional attributes analysis revealed that the relative abundance of genes associated with the extracellular matrix-receptor interaction, which is responsible for structural support and stress response, increased significantly following IM exposure. Collectively, our study identifies key microbial taxa in the wheat rhizobiome that are sensitive to IM herbicides and provides a foundation for assessing the environmental risks associated with IM herbicide use.}, } @article {pmid39101689, year = {2024}, author = {Simão, S and Oliveira Santos, M and Gromicho, M and Pavão Martins, I and De Carvalho, M}, title = {Cognitive reserve as a modulator of cognitive decline and of behavioral symptoms in patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {726-736}, doi = {10.1080/21678421.2024.2385684}, pmid = {39101689}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/psychology/complications/physiopathology ; Male ; Female ; *Cognitive Reserve/physiology ; Middle Aged ; *Cognitive Dysfunction/etiology/genetics/physiopathology/psychology ; Aged ; Neuropsychological Tests ; Behavioral Symptoms/etiology ; C9orf72 Protein/genetics ; Prospective Studies ; Adult ; Executive Function/physiology ; }, abstract = {Introduction: Amyotrophic lateral sclerosis (ALS) has heterogeneous manifestations ranging from motor neuron degeneration to cognitive and behavioral impairment. This study aims to clarify the interactions between cognition and behavioral symptoms with relevant disease predictors and with cognitive reserve (CR), quantified through education, physical activity, and occupation proxies. Methods: A prospective sample of 162 ALS patients and 61 controls were evaluated with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) (dependent variable), a Cognitive Reserve Index questionnaire (CRIq) and demographic data (age and sex), and, for patients, clinical variables: disease duration, site of onset, the ALS Functional Rating Scale (ALSFRS), forced vital capacity (FVC), and gene mutation chromosome 9 open reading frame 72 (C9orf72) (independent variables). Multiple regression and mediation analyses were performed to predict cognitive and behavioral symptoms. Results: For the ALS group, the statistical model explained 38.8% of variance in ECAS total (p < 0.001), 59.4% of executive functions (p < 0.001), and 55% of behavioral symptoms (p < 0.001). For controls, it accounted for 52.8% of variance in ECAS total (p < 0.001). Interaction effects and mediation analysis showed CR is an ECAS total modulator, with a differential effect within groups (p < 0.001). Verbal fluency was the single best cognitive score to differentiate patients from controls (p = 0.004), and the gene mutation C9orf72 was found to be a behavioral symptom' predictor in patients (p = 0.009). Conclusion: This study supports the proposed concept that CR acts as a cognitive modulator in ALS patients and healthy individuals. Moreover, CR also modulates behavioral manifestations in ALS.}, } @article {pmid39101354, year = {2024}, author = {Faleco, FA and Machado, FM and Bobadilla, LK and Tranel, PJ and Stoltenberg, D and Werle, R}, title = {Resistance to protoporphyrinogen oxidase inhibitors in giant ragweed (Ambrosia trifida).}, journal = {Pest management science}, volume = {80}, number = {12}, pages = {6211-6221}, doi = {10.1002/ps.8349}, pmid = {39101354}, issn = {1526-4998}, mesh = {*Protoporphyrinogen Oxidase/genetics/antagonists & inhibitors ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Ambrosia ; Plant Weeds/drug effects/genetics/enzymology ; Plant Proteins/genetics/metabolism ; Acetolactate Synthase/genetics/antagonists & inhibitors ; Enzyme Inhibitors/pharmacology ; Weed Control ; }, abstract = {BACKGROUND: Giant ragweed (Ambrosia trifida L.) is one of the most troublesome weed species in corn (Zea mays L.) and soybean [Glycine max (L.) Merr.] cropping systems. Following numerous reports in 2018 of suspected herbicide resistance in several Ambrosia trifida populations from Wisconsin, our objective was to characterize the response of these accessions to acetolactate synthase (ALS), enolpyruvyl shikimate phosphate synthase (EPSPS), and protoporphyrinogen oxidase (PPO) inhibitors applied POST.

RESULTS: Four accessions (AT1, AT4, AT6, and AT10) exhibited ≥ 50% plant survival after exposure to the cloransulam 3× rate. Two accessions (AT8 and AT10) and one accession (AT2) exhibited ≥ 50% plant survival after exposure to glyphosate and fomesafen 1× rates, respectively. The AT10 accession exhibited multiple resistance to cloransulam and glyphosate. The AT12 accession was 28.8-fold resistant to fomesafen and 3.7-fold resistant to lactofen. A codon change in PPX2 conferring a R98L substitution was identified as the most likely mechanism conferring PPO-inhibitor resistance.

CONCLUSION: To our knowledge, this is the first confirmed case of PPO-inhibitor resistance in Ambrosia trifida globally and we identified the genetic mutation likely conferring resistance. Proactive and diversified integrated weed management strategies are of paramount importance for sustainable long-term Ambrosia trifida management. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid39100390, year = {2024}, author = {Johnson, G and Tabner, A and Tilbury, N and Wesson, A and Hughes, GD and Elder, R and Bryson, P}, title = {Development of an algorithm to guide management of cardiorespiratory arrest in a diving bell.}, journal = {Resuscitation plus}, volume = {19}, number = {}, pages = {100724}, pmid = {39100390}, issn = {2666-5204}, abstract = {AIM: The management of cardiorespiratory arrest in a diving bell presents multiple clinical, technical, and environmental considerations that standard resuscitation algorithms do not address, and no situation-specific algorithm exists. The development and testing of an algorithm to guide the management of cardiorespiratory arrest in a bell is described.

METHODS: An iterative approach to algorithm development was used. Phase 1 involved a small multidisciplinary group and took place in a simulation centre and a decommissioned diving bell. The algorithm was then refined in a purpose-build simulation complex with repeated simulation by a group of divers, and with input from industry experts. ALS principles were followed unless contextual or technical factors necessitated deviation.

RESULTS: Clinical and technical aspects of the resuscitation are addressed. Key priorities that conflict with standard ALS principles are: prioritisation of rescue breaths; use of mechanical CPR when available; and the provision of CPR with the casualty in a seated position where necessary.

CONCLUSION: This is the first algorithm to guide the delivery of resuscitation in a diving bell. It incorporates adapted ALS principles and available data concerning compression technique effectiveness, and was informed by industry and clinical expertise. It provides guiding principles that can be adapted to setting-specific needs, and we would encourage its industry-wide international adoption.}, } @article {pmid39099373, year = {2024}, author = {Serangeli, I and Diamanti, T and De Jaco, A and Miranda, E}, title = {Role of mitochondria-endoplasmic reticulum contacts in neurodegenerative, neurodevelopmental and neuropsychiatric conditions.}, journal = {The European journal of neuroscience}, volume = {60}, number = {5}, pages = {5040-5068}, doi = {10.1111/ejn.16485}, pmid = {39099373}, issn = {1460-9568}, support = {//Sapienza Università di Roma/ ; //Sapienza University of Rome/ ; }, mesh = {Humans ; *Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Endoplasmic Reticulum/metabolism ; Animals ; *Neurodevelopmental Disorders/metabolism ; *Mental Disorders/metabolism/physiopathology ; Mitochondria Associated Membranes ; }, abstract = {Mitochondria-endoplasmic reticulum contacts (MERCs) mediate a close and continuous communication between both organelles that is essential for the transfer of calcium and lipids to mitochondria, necessary for cellular signalling and metabolic pathways. Their structural and molecular characterisation has shown the involvement of many proteins that bridge the membranes of the two organelles and maintain the structural stability and function of these contacts. The crosstalk between the two organelles is fundamental for proper neuronal function and is now recognised as a component of many neurological disorders. In fact, an increasing proportion of MERC proteins take part in the molecular and cellular basis of pathologies affecting the nervous system. Here we review the alterations in MERCs that have been reported for these pathologies, from neurodevelopmental and neuropsychiatric disorders to neurodegenerative diseases. Although mitochondrial abnormalities in these debilitating conditions have been extensively attributed to the high energy demand of neurons, a distinct role for MERCs is emerging as a new field of research. Understanding the molecular details of such alterations may open the way to new paths of therapeutic intervention.}, } @article {pmid39099169, year = {2024}, author = {Wang, J and Qiu, Y and Yang, L and Wang, J and He, J and Tang, C and Yang, Z and Hong, W and Yang, B and He, Q and Weng, Q}, title = {Preserving mitochondrial homeostasis protects against drug-induced liver injury via inducing OPTN (optineurin)-dependent Mitophagy.}, journal = {Autophagy}, volume = {20}, number = {12}, pages = {2677-2696}, pmid = {39099169}, issn = {1554-8635}, mesh = {*Mitophagy/drug effects/physiology ; *Homeostasis/drug effects ; *Membrane Transport Proteins/metabolism ; Animals ; *Cell Cycle Proteins/metabolism ; Humans ; *Valosin Containing Protein/metabolism ; *Chemical and Drug Induced Liver Injury/metabolism ; *Hepatocytes/metabolism/drug effects ; Mitochondria/metabolism/drug effects ; Mice ; Transcription Factor TFIIIA/metabolism/genetics ; Mice, Inbred C57BL ; Beclin-1/metabolism ; Mitochondria, Liver/metabolism/drug effects ; }, abstract = {Disruption of mitochondrial function is observed in multiple drug-induced liver injuries (DILIs), a significant global health threat. However, how the mitochondrial dysfunction occurs and whether maintain mitochondrial homeostasis is beneficial for DILIs remains unclear. Here, we show that defective mitophagy by OPTN (optineurin) ablation causes disrupted mitochondrial homeostasis and aggravates hepatocytes necrosis in DILIs, while OPTN overexpression protects against DILI depending on its mitophagic function. Notably, mass spectrometry analysis identifies a new mitochondrial substrate, GCDH (glutaryl-CoA dehydrogenase), which can be selectively recruited by OPTN for mitophagic degradation, and a new cofactor, VCP (valosin containing protein) that interacts with OPTN to stabilize BECN1 during phagophore assembly, thus boosting OPTN-mediated mitophagy initiation to clear damaged mitochondria and preserve mitochondrial homeostasis in DILIs. Then, the accumulation of OPTN in different DILIs is further validated with a protective effect, and pyridoxine is screened and established to alleviate DILIs by inducing OPTN-mediated mitophagy. Collectively, our findings uncover a dual role of OPTN in mitophagy initiation and implicate the preservation of mitochondrial homeostasis via inducing OPTN-mediated mitophagy as a potential therapeutic approach for DILIs.Abbreviation: AILI: acetaminophen-induced liver injury; ALS: amyotrophic lateral sclerosis; APAP: acetaminophen; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DILI: drug-induced liver injury; FL: full length; GCDH: glutaryl-CoA dehydrogenase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GO: gene ontology; GSEA: gene set enrichment analysis; GPT/ALT: glutamic - pyruvic transaminase; INH: isoniazid; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MMP: mitochondrial membrane potential; MST: microscale thermophoresis; MT-CO2/COX-II: mitochondrially encoded cytochrome c oxidase II; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; TSN: toosendanin; VCP: valosin containing protein, WIPI2: WD repeat domain, phosphoinositide interacting 2.}, } @article {pmid39098767, year = {2025}, author = {Endo, F}, title = {Deciphering the spectrum of astrocyte diversity: Insights into molecular, morphological, and functional dimensions in health and neurodegenerative diseases.}, journal = {Neuroscience research}, volume = {210}, number = {}, pages = {1-10}, doi = {10.1016/j.neures.2024.07.008}, pmid = {39098767}, issn = {1872-8111}, mesh = {*Astrocytes/pathology/metabolism ; Humans ; *Neurodegenerative Diseases/pathology/metabolism ; Animals ; Alzheimer Disease/pathology/metabolism ; Central Nervous System/pathology ; }, abstract = {Astrocytes are the most abundant and morphologically complex glial cells that play active roles in the central nervous system (CNS). Recent research has identified shared and region-specific astrocytic genes and functions, elucidated the cellular origins of their regional diversity, and uncovered the molecular networks for astrocyte morphology, which are essential for their functional complexity. Reactive astrocytes exhibit a wide range of functional diversity in a context-specific manner in CNS disorders. This review discusses recent advances in understanding the molecular and morphological diversity of astrocytes in healthy individuals and those with neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis.}, } @article {pmid39098618, year = {2024}, author = {Koehn, LM and Jalaldeen, R and Pelle, J and Nicolazzo, JA}, title = {Plasma, brain and spinal cord concentrations of caffeine are reduced in the SOD1[G93A] mouse model of amyotrophic lateral sclerosis following oral administration.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {203}, number = {}, pages = {114434}, doi = {10.1016/j.ejpb.2024.114434}, pmid = {39098618}, issn = {1873-3441}, mesh = {Animals ; *Caffeine/administration & dosage/pharmacokinetics ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Spinal Cord/metabolism/drug effects ; Male ; Female ; Mice ; Administration, Oral ; *Brain/metabolism/drug effects ; *Disease Models, Animal ; *Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism ; Digoxin/pharmacokinetics/administration & dosage ; Sulfasalazine/pharmacokinetics/administration & dosage ; Intestinal Absorption/drug effects/physiology ; }, abstract = {Modifications to the small intestine and liver are known to occur during the symptomatic disease period of amyotrophic lateral sclerosis (ALS), a member of the motor neuron disease (MND) family of neurodegenerative disorders. How these modifications impact on oral absorption and pharmacokinetics of drugs remains unknown. In this study, model drugs representing different mechanisms of intestinal transport (caffeine for passive diffusion, digoxin for P-glycoprotein efflux, and sulfasalazine for breast cancer resistance protein efflux) were administered via oral gavage to postnatal day 114-120 male and female SOD1[G93A] mice (model of familial ALS) and wild-type (WT) littermates. Samples of blood, brain and spinal cord were taken at either 15, 30, 60 or 180 min after administration. In addition, the in vivo gastric emptying of 70 kDa fluorescein isothiocyanate-dextran (FITC-dextran) and the ex vivo intestinal permeability of caffeine were assessed. The area under the plasma concentration-time curves (AUCplasma) of digoxin and sulfasalazine were not significantly different between SOD1[G93A] and WT mice for both sexes. However, the AUCplasma of caffeine was significantly lower (female: 0.79-fold, male: 0.76-fold) in SOD1[G93A] compared to WT mice, which was associated with lower AUCbrain (female: 0.76-fold, male: 0.80-fold) and AUCspinal cord (female: 0.81-fold, male: 0.82-fold). The AUCstomach of caffeine was significantly higher (female: 1.5-fold, male: 1.9-fold) in SOD1[G93A] compared to WT mice, suggesting reduced gastric emptying in SOD1[G93A] mice. In addition, there was a significant reduction in gastric emptying of FITC-dextran (0.66-fold) and ex vivo intestinal permeability of caffeine (0.52-fold) in male SOD1[G93A] compared to WT mice. Reduced systemic and brain/spinal cord exposure of caffeine in SOD1[G93A] mice may therefore result from alterations to gastric emptying and small intestinal permeability. Specific dosing requirements may therefore be required for certain medicines in ALS to ensure that they remain in a safe and effective concentration range.}, } @article {pmid39098187, year = {2024}, author = {R K Roy, A and Noohi, F and Morris, NA and Ljubenkov, P and Heuer, H and Fong, J and Hall, M and Lario Lago, A and Rankin, KP and Miller, BL and Boxer, AL and Rosen, HJ and Seeley, WW and Perry, DC and Yokoyama, JS and Lee, SE and Sturm, VE}, title = {Basal parasympathetic deficits in C9orf72 hexanucleotide repeat expansion carriers relate to smaller frontoinsula and thalamus volume and lower empathy.}, journal = {NeuroImage. Clinical}, volume = {43}, number = {}, pages = {103649}, pmid = {39098187}, issn = {2213-1582}, support = {R01 AG052496/AG/NIA NIH HHS/United States ; R01 AG059794/AG/NIA NIH HHS/United States ; R01 AG062758/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; Middle Aged ; *C9orf72 Protein/genetics ; Aged ; *Empathy/physiology ; *Frontotemporal Dementia/genetics/physiopathology/pathology/diagnostic imaging ; *DNA Repeat Expansion/genetics ; *Magnetic Resonance Imaging/methods ; *Parasympathetic Nervous System/physiopathology ; *Thalamus/diagnostic imaging/physiopathology/pathology ; *Cognitive Dysfunction/physiopathology/genetics/diagnostic imaging/etiology/pathology ; Heterozygote ; Respiratory Sinus Arrhythmia/physiology ; Cerebral Cortex/diagnostic imaging/physiopathology/pathology ; }, abstract = {Diminished basal parasympathetic nervous system activity is a feature of frontotemporal dementia that relates to left frontoinsula dysfunction and empathy impairment. Individuals with a pathogenic expansion of the hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis, provide a unique opportunity to examine whether parasympathetic activity is disrupted in genetic forms of frontotemporal dementia and to investigate when parasympathetic deficits manifest in the pathophysiological cascade. We measured baseline respiratory sinus arrhythmia, a parasympathetic measure of heart rate variability, over two minutes in a sample of 102 participants that included 19 asymptomatic expansion carriers (C9[+] asymp), 14 expansion carriers with mild cognitive impairment (C9[+] MCI), 16 symptomatic expansion carriers with frontotemporal dementia (C9[+] FTD), and 53 expansion-negative healthy controls (C9[-] HC) who also underwent structural magnetic resonance imaging. In follow-up analyses, we compared baseline respiratory sinus arrhythmia in the C9[+] FTD group with an independent age-, sex-, and clinical severity-matched group of 26 people with sporadic behavioral variant frontotemporal dementia. The Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating-Sum of Boxes score was used to quantify behavioral symptom severity, and informant ratings on the Interpersonal Reactivity Index provided measures of participants' current emotional (empathic concern) and cognitive (perspective-taking) empathy. Results indicated that the C9[+] FTD group had lower baseline respiratory sinus arrhythmia than the C9[+] MCI, C9[+] asymp, and C9[-] HC groups, a deficit that was comparable to that of sporadic behavioral variant frontotemporal dementia. Linear regression analyses indicated that lower baseline respiratory sinus arrhythmia was associated with worse behavioral symptom severity and lower empathic concern and perspective-taking across the C9orf72 expansion carrier clinical spectrum. Whole-brain voxel-based morphometry analyses in participants with C9orf72 pathogenic expansions found that lower baseline respiratory sinus arrhythmia correlated with smaller gray matter volume in the left frontoinsula and bilateral thalamus, key structures that support parasympathetic function, and in the bilateral parietal lobes, occipital lobes, and cerebellum, regions that are also vulnerable in individuals with C9orf72 expansions. This study provides novel evidence that basal parasympathetic functioning is diminished in FTD due to C9orf72 expansions and suggests that baseline respiratory sinus arrhythmia may be a potential non-invasive biomarker that is sensitive to behavioral symptoms in the early stages of disease.}, } @article {pmid39097850, year = {2024}, author = {Luan, T and Li, Q and Huang, Z and Feng, Y and Xu, D and Zhou, Y and Hu, Y and Wang, T}, title = {Axonopathy Underlying Amyotrophic Lateral Sclerosis: Unraveling Complex Pathways and Therapeutic Insights.}, journal = {Neuroscience bulletin}, volume = {40}, number = {11}, pages = {1789-1810}, pmid = {39097850}, issn = {1995-8218}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/therapy ; Animals ; *Axons/pathology/metabolism ; Mitochondria/metabolism ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by progressive axonopathy, jointly leading to the dying back of the motor neuron, disrupting both nerve signaling and motor control. In this review, we highlight the roles of axonopathy in ALS progression, driven by the interplay of multiple factors including defective trafficking machinery, protein aggregation, and mitochondrial dysfunction. Dysfunctional intracellular transport, caused by disruptions in microtubules, molecular motors, and adaptors, has been identified as a key contributor to disease progression. Aberrant protein aggregation involving TDP-43, FUS, SOD1, and dipeptide repeat proteins further amplifies neuronal toxicity. Mitochondrial defects lead to ATP depletion, oxidative stress, and Ca[2+] imbalance, which are regarded as key factors underlying the loss of neuromuscular junctions and axonopathy. Mitigating these defects through interventions including neurotrophic treatments offers therapeutic potential. Collaborative research efforts aim to unravel ALS complexities, opening avenues for holistic interventions that target diverse pathological mechanisms.}, } @article {pmid39097602, year = {2024}, author = {Lehmann, J and Aly, A and Steffke, C and Fabbio, L and Mayer, V and Dikwella, N and Halablab, K and Roselli, F and Seiffert, S and Boeckers, TM and Brenner, D and Kabashi, E and Mulaw, M and Ho, R and Catanese, A}, title = {Heterozygous knockout of Synaptotagmin13 phenocopies ALS features and TP53 activation in human motor neurons.}, journal = {Cell death & disease}, volume = {15}, number = {8}, pages = {560}, pmid = {39097602}, issn = {2041-4889}, support = {SFB 1506-Project 01//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 2019_A111//Else Kröner-Fresenius-Stiftung (Else Kroner-Fresenius Foundation)/ ; }, mesh = {Humans ; *Tumor Suppressor Protein p53/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Synaptotagmins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Heterozygote ; Phenotype ; Induced Pluripotent Stem Cells/metabolism/pathology ; Cell Differentiation/genetics ; Gene Knockout Techniques ; }, abstract = {Spinal motor neurons (MNs) represent a highly vulnerable cellular population, which is affected in fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we show that the heterozygous loss of SYT13 is sufficient to trigger a neurodegenerative phenotype resembling those observed in ALS and SMA. SYT13[+/-] hiPSC-derived MNs displayed a progressive manifestation of typical neurodegenerative hallmarks such as loss of synaptic contacts and accumulation of aberrant aggregates. Moreover, analysis of the SYT13[+/-] transcriptome revealed a significant impairment in biological mechanisms involved in motoneuron specification and spinal cord differentiation. This transcriptional portrait also strikingly correlated with ALS signatures, displaying a significant convergence toward the expression of pro-apoptotic and pro-inflammatory genes, which are controlled by the transcription factor TP53. Our data show for the first time that the heterozygous loss of a single member of the synaptotagmin family, SYT13, is sufficient to trigger a series of abnormal alterations leading to MN sufferance, thus revealing novel insights into the selective vulnerability of this cell population.}, } @article {pmid39097310, year = {2024}, author = {Christian, CS and Nkonki, L and Desmond, C and Hoegfeldt, C and Dube, S and Rochat, T and Stein, A}, title = {Protocol of a cost-effectiveness analysis of a combined intervention for depression and parenting compared with enhanced standard of care for perinatally depressed, HIV-positive women and their infants in rural South Africa.}, journal = {BMJ open}, volume = {14}, number = {8}, pages = {e082977}, pmid = {39097310}, issn = {2044-6055}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/P006965/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Female ; Humans ; Infant ; Infant, Newborn ; Pregnancy ; *Cost-Effectiveness Analysis/methods ; Depression/therapy ; Depression, Postpartum/therapy/economics ; *HIV Infections ; Parenting ; Randomized Controlled Trials as Topic ; Rural Population ; South Africa ; Standard of Care ; Research Design ; }, abstract = {INTRODUCTION: Poverty, HIV and perinatal depression represent a triple threat to public health in sub-Saharan Africa because of their combined negative effects on parenting and child development. In the resource-constrained context of low-income and middle-income countries, a lay-counsellor-delivered intervention that combines a psychological and parenting intervention could offer the potential to mitigate the consequences of perinatal depression while also optimising scarce resources for healthcare.Measuring the cost-effectiveness of such a novel intervention will help decision-makers to better understand the relative costs and effects associated with replicating the intervention, thereby supporting evidence-based decision-making. This protocol sets out the methodological framework for analysing the cost-effectiveness of a cluster randomised controlled trial (RCT) that compares a combined intervention to enhanced standard of care when treating depressed, HIV-positive pregnant women and their infants in rural South Africa.

METHODS AND ANALYSIS: This cost-effectiveness analysis (CEA) protocol complies with the Consolidated Health Economic Evaluation Reporting Standards 2022 checklist. A societal perspective will be chosen.The proposed methods will determine the cost and efficiency of implementing the intervention as per the randomised control trial protocol, as well as the cost of replicating the intervention in a non-research setting. The costs will be calculated using an appropriately adjusted version of the Standardised Early Childhood Development Costing Tool.Primary health outcomes will be used in combination with costs to determine the cost per improvement in maternal perinatal depression at 12 months postnatal and the cost per improvement in child cognitive development at 24 months of age. To facilitate priority setting, the incremental cost-effectiveness ratios for improvements in child cognitive development will be ranked against six other child cognitive-development interventions according to Verguet et al's methodology (2022).A combination of activity-based and ingredient-based costing approaches will be used to identify, measure and value activities and inputs for all alternatives. Outcomes data will be sourced from the RCT team.

ETHICS AND DISSEMINATION: The University of Oxford is the sponsor of the CEA. Ethics approval has been obtained from the Human Sciences Research Council (HSRC, #REC 5/23/08/17), South Africa and the Oxford Tropical Research Ethics Committee (OxTREC #31-17), UK.Consent for publication is not applicable since no participant data are used in this protocol.We plan to disseminate the CEA results to key policymakers and researchers in the form of a policy brief, meetings and academic papers.

TRIAL REGISTRATION DETAILS: ISRCTN registry #11 284 870 (14/11/2017) and SANCTR DOH-27-102020-9097 (17/11/2017).}, } @article {pmid39096593, year = {2024}, author = {Ozeloglu, IG and Akman Aydin, E}, title = {Combining features on vertical ground reaction force signal analysis for multiclass diagnosing neurodegenerative diseases.}, journal = {International journal of medical informatics}, volume = {191}, number = {}, pages = {105542}, doi = {10.1016/j.ijmedinf.2024.105542}, pmid = {39096593}, issn = {1872-8243}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis ; Male ; Female ; Middle Aged ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis ; Support Vector Machine ; Parkinson Disease/diagnosis ; Neural Networks, Computer ; Huntington Disease/diagnosis/physiopathology ; Signal Processing, Computer-Assisted ; Gait/physiology ; Algorithms ; }, abstract = {Neurodegenerative diseases (NDDs), which are caused by the degeneration of neurons and their functions, affect a significant part of the world's population. Although gait disorders are one of the critical and common markers to determine the presence of NDDs, diagnosing which NDD the patients have among a group of NDDs using gait data is still a significant challenge to be addressed. In this study, we addressed the multi-class classification of NDDs and aim to diagnose Parkinson's disease (PD), Amyotrophic lateral sclerosis disease (AD), and Huntington's disease (HD) from a group containing NDDs and healthy control subjects. We also examined the impact of disease-specific identified features derived from VGRF signals. Detrended Fluctuation Analysis (DFA), Dynamic Time Warping (DTW) and Autocorrelation (AC) were used for feature extraction on Vertical Ground Reaction Force (VGRF) signals. To compare the performance of the features, we employed Support Vector Machines, K-Nearest Neighbors, and Neural Networks as classifiers. In three-class problem addressing the classification of AD, PD and HD 93.3% accuracy rate was achieved, while in the four classes case, in which NDDs and HC groups were considered together, 93.5% accuracy rate was yielded. Considering the disease-specific impact of features, it is revealed that while DFA based features diagnose patients with AD with the highest accuracy, DTW has been shown to be more successful in diagnosing PD. AC based features provided the highest accuracy in diagnosing HD. Although gait disorder is common for NDDs, each disease may have its own distinctive gait rhythms; therefore, it is important to identify disease-specific patterns and parameters for the diagnosis of each disease. To increase the diagnostic accuracy, it is necessary to use a combination of features, which were effective for each disease diagnosis. Determining a limited number of disease-specific features would provide NDD diagnostic systems suitable to be deployed in edge-computing environments.}, } @article {pmid39096334, year = {2025}, author = {Paterson, M and Doeltgen, S and Francis, R}, title = {Sensory Changes Related to Swallowing in Motor Neurone Disease.}, journal = {Dysphagia}, volume = {40}, number = {2}, pages = {407-418}, pmid = {39096334}, issn = {1432-0460}, mesh = {Humans ; *Deglutition Disorders/physiopathology/etiology ; *Deglutition/physiology ; *Motor Neuron Disease/physiopathology/complications ; Sensation/physiology ; Male ; Female ; Sensation Disorders/physiopathology/etiology ; }, abstract = {Dysphagia is common in motor neurone disease (MND) and associated with negative health and psychosocial outcomes. Although largely considered a motor disease, a growing body of evidence suggests that MND can also affect the sensory system. As intact sensation is vital for safe swallowing, and sensory changes can influence the clinical management of dysphagia in people living with MND, this review evaluated and summarised the current evidence for sensory changes related to swallowing in MND. Of 3,481 articles originally identified, 29 met the inclusion criteria. Of these, 20 studies reported sensory changes, which included laryngeal sensation, taste, gag reflex, cough reflex, tongue sensation, smell, palatal and pharyngeal sensation, silent aspiration, and undefined sensation of the swallowing mechanism. Sensory changes were either described as decreased (n = 16) or heightened (n = 4). In the remaining nine studies, sensory function was reported as unaffected. The presence of changes to sensory function related to swallowing in MND remains inconclusive, although an increasing number of studies report sensory changes in some sensory domains. Future research is needed to evaluate the prevalence of sensory changes in MND and how such changes may influence dysphagia and its management.}, } @article {pmid39096043, year = {2024}, author = {Rabadi, MH and Russell, KA and Xu, C}, title = {Veterans with familial ALS and bulbar and respiratory presentations at onset had shorter survival.}, journal = {Science progress}, volume = {107}, number = {3}, pages = {368504241262902}, pmid = {39096043}, issn = {2047-7163}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology/genetics/diagnosis ; Middle Aged ; Male ; *Veterans/statistics & numerical data ; Female ; Aged ; Age of Onset ; Prognosis ; Kaplan-Meier Estimate ; }, abstract = {OBJECTIVE: We sought to characterize the clinical prognostic factors in veterans with amyotrophic lateral sclerosis (ALS) followed in our ALS clinic.

BACKGROUND: ALS is a rare, progressive neurodegenerative condition associated with decreased survival compared to that in the normal population.

METHOD: The electronic medical records of 105 veterans diagnosed with ALS who are followed in our ALS clinic between 2010 and 2021 were reviewed. Approval from the institutional review board was obtained from the study protocol. Demographic and clinical variables included age at symptom onset, age at initial evaluation, survival (from symptom onset to death), gender, site of onset (appendicular, bulbar, and respiratory), initial amyotrophic lateral sclerosis functional-related score-revised (ALSFRS-R), total functional independence measure (TFIM) scores, initial forced vital capacity (FVC), and interventions (Riluzole, gastrostomy, noninvasive ventilation [NIV], and tracheostomy). Normally distributed data was expressed as mean ± standard deviation. Fischer's exact analysis of the distribution differences of categorical data. The Kaplan-Meier plot analyzed the time-to-event.

RESULTS: The mean (SD) age at symptom onset was 62.0 (11.1) years, age at diagnosis was 65 (11) years, with 72% of the patients being over 60 years at diagnosis. The median survival time from symptom onset was 4.12 (3) years. Limb-onset ALS (appendicular) was the most frequent (52%) followed by bulbar-onset ALS (43%). The mean ALSFRS-R and TFIM scores were 31 (8) and 91 (25), respectively. Family history (familial), bulbar, and respiratory presentation at diagnosis were associated with shorter survival times.

CONCLUSION: This study suggests that of the clinical prognostic factors veterans with familial ALS, bulbar, and respiratory onset at presentations had shorter survival. The presence of Agent Orange, PEG placement, and NIV did not affect survival.}, } @article {pmid39095145, year = {2024}, author = {Sheers, NL and Andersen, T and Chatwin, M}, title = {Airway Clearance in Neuromuscular Disease.}, journal = {Sleep medicine clinics}, volume = {19}, number = {3}, pages = {485-496}, doi = {10.1016/j.jsmc.2024.04.009}, pmid = {39095145}, issn = {1556-4088}, mesh = {Humans ; *Neuromuscular Diseases/therapy/physiopathology ; Respiratory Therapy/methods ; Cough/therapy/physiopathology ; Airway Management/methods ; }, abstract = {High-quality respiratory care and airway clearance is essential for people with neuromuscular disease (pwNMD) as respiratory tract infections are a major cause of morbidity and mortality. This review expands on published guidelines by highlighting the role of cough peak flow along with other options for cough evaluation, and discusses recent key research findings which have influenced the practice of respiratory therapy for pwNMD.}, } @article {pmid39094561, year = {2024}, author = {Gomes, C and Huang, KC and Harkin, J and Baker, A and Hughes, JM and Pan, Y and Tutrow, K and VanderWall, KB and Lavekar, SS and Hernandez, M and Cummins, TR and Canfield, SG and Meyer, JS}, title = {Induction of astrocyte reactivity promotes neurodegeneration in human pluripotent stem cell models.}, journal = {Stem cell reports}, volume = {19}, number = {8}, pages = {1122-1136}, pmid = {39094561}, issn = {2213-6711}, support = {R01 EY033022/EY/NEI NIH HHS/United States ; T32 GM148382/GM/NIGMS NIH HHS/United States ; U24 EY033269/EY/NEI NIH HHS/United States ; }, mesh = {*Astrocytes/metabolism ; Humans ; *Pluripotent Stem Cells/metabolism/cytology ; *Coculture Techniques ; Neurodegenerative Diseases/metabolism/pathology ; Complement C3/metabolism ; Cell Differentiation ; Neurons/metabolism ; Alzheimer Disease/pathology/metabolism ; Phagocytosis ; Blood-Brain Barrier/metabolism ; Glaucoma/pathology/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Calcium/metabolism ; Phenotype ; }, abstract = {Reactive astrocytes are known to exert detrimental effects upon neurons in several neurodegenerative diseases, yet our understanding of how astrocytes promote neurotoxicity remains incomplete, especially in human systems. In this study, we leveraged human pluripotent stem cell (hPSC) models to examine how reactivity alters astrocyte function and mediates neurodegeneration. hPSC-derived astrocytes were induced to a reactive phenotype, at which point they exhibited a hypertrophic profile and increased complement C3 expression. Functionally, reactive astrocytes displayed decreased intracellular calcium, elevated phagocytic capacity, and decreased contribution to the blood-brain barrier. Subsequently, co-culture of reactive astrocytes with a variety of neuronal cell types promoted morphological and functional alterations. Furthermore, when reactivity was induced in astrocytes from patient-specific hPSCs (glaucoma, Alzheimer's disease, and amyotrophic lateral sclerosis), the reactive state exacerbated astrocytic disease-associated phenotypes. These results demonstrate how reactive astrocytes modulate neurodegeneration, significantly contributing to our understanding of a role for reactive astrocytes in neurodegenerative diseases.}, } @article {pmid39092466, year = {2024}, author = {Soubannier, V and Chaineau, M and Gursu, L and Lépine, S and Kalaydjian, D and Sirois, J and Haghi, G and Rouleau, G and Durcan, TM and Stifani, S}, title = {Early nuclear phenotypes and reactive transformation in human iPSC-derived astrocytes from ALS patients with SOD1 mutations.}, journal = {Glia}, volume = {72}, number = {11}, pages = {2079-2094}, doi = {10.1002/glia.24598}, pmid = {39092466}, issn = {1098-1136}, support = {//ALS Canada/Brain Canada Hudson Translational Team Grant/ ; //Canada First Research Excellence Fund/ ; //ALS Canada/Brain Canada Discovery Grant/ ; }, mesh = {Humans ; *Astrocytes/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; *Mutation ; *Phenotype ; Cells, Cultured ; Cell Nucleus/metabolism ; Motor Neurons/pathology/metabolism ; Oxidative Stress/physiology/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive death of motor neurons (MNs). Glial cells play roles in MN degeneration in ALS. More specifically, astrocytes with mutations in the ALS-associated gene Cu/Zn superoxide dismutase 1 (SOD1) promote MN death. The mechanisms by which SOD1-mutated astrocytes reduce MN survival are incompletely understood. To characterize the impact of SOD1 mutations on astrocyte physiology, we generated astrocytes from human induced pluripotent stem cell (iPSC) derived from ALS patients carrying SOD1 mutations, together with control isogenic iPSCs. We report that astrocytes harboring SOD1(A4V) and SOD1(D90A) mutations exhibit molecular and morphological changes indicative of reactive astrogliosis when compared to isogenic astrocytes. We show further that a number of nuclear phenotypes precede, or coincide with, reactive transformation. These include increased nuclear oxidative stress and DNA damage, and accumulation of the SOD1 protein in the nucleus. These findings reveal early cell-autonomous phenotypes in SOD1-mutated astrocytes that may contribute to the acquisition of a reactive phenotype involved in alterations of astrocyte-MN communication in ALS.}, } @article {pmid39091724, year = {2024}, author = {Lv, G and Sayles, NM and Huang, Y and Mancinelli, CD and McAvoy, K and Shneider, NA and Manfredi, G and Kawamata, H and Eliezer, D}, title = {Amyloid fibril structures link CHCHD10 and CHCHD2 to neurodegeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39091724}, issn = {2692-8205}, support = {P30 CA016087/CA/NCI NIH HHS/United States ; RF1 AG066493/AG/NIA NIH HHS/United States ; S10 OD028556/OD/NIH HHS/United States ; U01 NS134684/NS/NINDS NIH HHS/United States ; R35 NS122209/NS/NINDS NIH HHS/United States ; S10 OD016320/OD/NIH HHS/United States ; F31 HL154651/HL/NHLBI NIH HHS/United States ; F31 AG077836/AG/NIA NIH HHS/United States ; }, abstract = {CHCHD10 is mutated in rare cases of FTD and ALS and aggregates in mouse models of disease. Here we show that the disordered N-terminal domain of CHCHD10 forms amyloid fibrils and report their cryoEM structure. Disease-associated mutations cannot be accommodated by the WT fibril structure, while sequence differences between CHCHD10 and CHCHD2 are tolerated, explaining the co-aggregation of the two proteins and linking CHCHD10 and CHCHD2 amyloid fibrils to neurodegeneration.}, } @article {pmid39091345, year = {2024}, author = {Hernández, CA and Peikert, K and Qiao, M and Darras, A and de Wilde, JRA and Bos, J and Leibowitz, M and Galea, I and Wagner, C and Rab, MAE and Walker, RH and Hermann, A and van Beers, EJ and van Wijk, R and Kaestner, L}, title = {Osmotic gradient ektacytometry - a novel diagnostic approach for neuroacanthocytosis syndromes.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1406969}, pmid = {39091345}, issn = {1662-4548}, abstract = {INTRODUCTION: The unique red blood cell (RBC) properties that characterize the rare neuroacanthocytosis syndromes (NAS) have prompted the exploration of osmotic gradient ektacytometry (Osmoscan) as a diagnostic tool for these disorders. In this exploratory study, we assessed if Osmoscans can discriminate NAS from other neurodegenerative diseases.

METHODS: A comprehensive assessment was conducted using Osmoscan on a diverse group of patients, including healthy controls (n = 9), neuroacanthocytosis syndrome patients (n = 6, 2 VPS13A and 4 XK disease), Parkinson's disease patients (n = 6), Huntington's disease patients (n = 5), and amyotrophic lateral sclerosis patients (n = 4). Concurrently, we collected and analyzed RBC indices and patients' characteristics.

RESULTS: Statistically significant changes were observed in NAS patients compared to healthy controls and other conditions, specifically in osmolality at minimal elongation index (Omin), maximal elongation index (EImax), the osmolality at half maximal elongation index in the hyperosmotic part of the curve (Ohyper), and the width of the curve close to the osmolality at maximal elongation index (Omax-width).

DISCUSSION: This study represents an initial exploration of RBC properties from NAS patients using osmotic gradient ektacytometry. While specific parameters exhibited differences, only Ohyper and Omax-width yielded 100% specificity for other neurodegenerative diseases. Moreover, unique correlations between Osmoscan parameters and RBC indices in NAS versus controls were identified, such as osmolality at maximal elongation index (Omax) vs. mean cellular hemoglobin content (MCH) and minimal elongation index (EImin) vs. red blood cell distribution width (RDW). Given the limited sample size, further studies are essential to establish diagnostic guidelines based on these findings.}, } @article {pmid39091344, year = {2024}, author = {Goffin, L and Lemoine, D and Clotman, F}, title = {Potential contribution of spinal interneurons to the etiopathogenesis of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1434404}, pmid = {39091344}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) consists of a group of adult-onset fatal and incurable neurodegenerative disorders characterized by the progressive death of motor neurons (MNs) throughout the central nervous system (CNS). At first, ALS was considered to be an MN disease, caused by cell-autonomous mechanisms acting specifically in MNs. Accordingly, data from ALS patients and ALS animal models revealed alterations in excitability in multiple neuronal populations, including MNs, which were associated with a variety of cellular perturbations such as protein aggregation, ribonucleic acid (RNA) metabolism defects, calcium dyshomeostasis, modified electrophysiological properties, and autophagy malfunctions. However, experimental evidence rapidly demonstrated the involvement of other types of cells, including glial cells, in the etiopathogenesis of ALS through non-cell autonomous mechanisms. Surprisingly, the contribution of pre-motor interneurons (INs), which regulate MN activity and could therefore critically modulate their excitability at the onset or during the progression of the disease, has to date been severely underestimated. In this article, we review in detail how spinal pre-motor INs are affected in ALS and their possible involvement in the etiopathogenesis of the disease.}, } @article {pmid39091255, year = {2024}, author = {Roggenbuck, J and Kaschalk, M and Eustace, R and Vicini, L and Gokun, Y and Harms, MB and Kolb, SJ}, title = {The Answer ALS return of results study: Answering the duty to disclose.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {743-750}, doi = {10.1080/21678421.2024.2385004}, pmid = {39091255}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/psychology ; Male ; Female ; Middle Aged ; *Genetic Testing/methods ; *Disclosure ; Aged ; Adult ; Prospective Studies ; }, abstract = {Objective: The Return of Answer ALS Results (RoAR) Study was designed to provide a mechanism for participants in Answer ALS, a large, prospectively designed natural history and biorepository study to receive select clinical genetic testing results and study participants' experience with the results disclosure. Methods: Participants consented to receive results of five ALS genes (C9orf72, SOD1, FUS, TARDP, TBK1) and/or 59 medically actionable genes as designated by the American College of Medical Genetics. Patient-reported genetic testing outcomes were measured via a post-disclosure survey. Results: Of 645 eligible Answer ALS enrollees, 143 (22%) enrolled and completed participation in RoAR. Pathogenic variants were identified in 22/143 (15.4%) participants, including 13/143 (9.0%) in ALS genes and 9/143 (6.3%) in ACMG genes. Participant-reported measures of result utility indicated the research result disclosure was as or more successful than published patient-reported outcomes of result disclosure the clinical setting. Conclusions: This study serves as a model of a "disclosure study" to share results from genomic research with participants who were not initially offered the option to receive results, and our findings can inform the design of future, large scale genomic projects to empower research participants to access their genetic information.}, } @article {pmid39091098, year = {2024}, author = {Annetta, MG and Barbato, G and Pisciaroli, E and Marche, B and Sabatelli, M and Pittiruti, M}, title = {Central venous catheter-related thrombosis in patients with amyotrophic lateral sclerosis.}, journal = {The journal of vascular access}, volume = {}, number = {}, pages = {11297298241262821}, doi = {10.1177/11297298241262821}, pmid = {39091098}, issn = {1724-6032}, abstract = {BACKGROUND: Central venous catheterization may be required in patients with amyotrophic lateral sclerosis (ALS) for parenteral nutrition, antibiotic treatment, or blood sampling. Different venous access devices can be taken into consideration-centrally inserted central catheters (CICC), peripherally inserted central catheters (PICC), and femorally inserted central catheters (FICCs)-depending on the clinical conditions of the patients. Regardless of the type of access, the presence of paraplegia or tetraplegia is commonly considered a risk factor for catheter-related thrombosis (CRT).

METHOD: This retrospective study analyzes the rate of CRT and other non-infectious complications associated with central venous access in a cohort of 115 patients with paraplegia or tetraplegia, most of them affected by ALS (n = 109).

RESULTS: In a period of 34 months, from January 2021 to October 2023, we inserted 75 FICCs, 29 CICCs, and 11 PICCs. PICCs were inserted only in patients with preserved motility of the upper limbs. All devices were inserted by trained operators adopting appropriate insertion bundles. We had no immediate or early complication. Though antithrombotic prophylaxis was adopted only in 61.7% of patients, we had no symptomatic CRT. Other non-infectious complications were infrequent (4 out of 115 patients).

CONCLUSION: These results suggest (a) that the presence of paraplegia or tetraplegia is not necessarily associated with an increased risk of CRT, (b) that the adoption of well-designed insertion bundles plays a key role in minimizing non-infectious complications, and (c) that the insertion of FICCs by direct cannulation of the superficial femoral vein at mid-thigh in paraplegic/tetraplegic patients may have the same advantages which have been described in the general population.}, } @article {pmid39088455, year = {2024}, author = {Bonthron, C and Burley, S and Broadhead, MJ and Metodieva, V and Grant, SGN and Chandran, S and Miles, GB}, title = {Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS.}, journal = {PloS one}, volume = {19}, number = {8}, pages = {e0306423}, pmid = {39088455}, issn = {1932-6203}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology/metabolism/genetics ; Animals ; *Astrocytes/metabolism/pathology ; Mice ; *Disease Models, Animal ; *Coculture Techniques ; *Synapses/metabolism/physiology ; *Motor Neurons/metabolism/pathology/physiology ; *Spinal Cord/metabolism/pathology ; Humans ; Excitatory Postsynaptic Potentials ; Mice, Transgenic ; Cells, Cultured ; Synaptic Transmission ; }, abstract = {Hyperexcitability of motor neurons and spinal cord motor circuitry has been widely reported in the early stages of Amyotrophic Lateral Sclerosis (ALS). Changes in the relative amount of excitatory to inhibitory inputs onto a neuron (E:I synaptic ratio), possibly through a developmental shift in synapse formation in favour of excitatory transmission, could underlie pathological hyperexcitability. Given that astrocytes play a major role in early synaptogenesis and are implicated in ALS pathogenesis, their potential contribution to disease mechanisms involving synaptic imbalances and subsequent hyperexcitability is also of great interest. In order to assess E:I ratios in ALS, we utilised a novel primary spinal neuron / astrocyte co-culture system, derived from neonatal mice, in which synapses are formed in vitro. Using multiple ALS mouse models we found that no combination of astrocyte or neuron genotype produced alterations in E:I synaptic ratios assessed using pre- and post-synaptic anatomical markers. Similarly, we observed that ephrin-B1, a major contact-dependent astrocytic synaptogenic protein, was not differentially expressed by ALS primary astrocytes. Further to this, analysis of E:I ratios across the entire grey matter of the lumbar spinal cord in young (post-natal day 16-19) ALS mice revealed no differences versus controls. Finally, analysis in co-cultures of human iPSC-derived motor neurons and astrocytes harbouring the pathogenic C9orf72 hexanucleotide repeat expansion showed no evidence of a bias toward excitatory versus inhibitory synapse formation. We therefore conclude, utilising multiple ALS models, that we do not observe significant changes in the relative abundance of excitatory versus inhibitory synapses as would be expected if imbalances in synaptic inputs contribute to early hyperexcitability.}, } @article {pmid39088003, year = {2024}, author = {Lai, HJ and Kuo, YC and Ting, CH and Yang, CC and Kao, CH and Tsai, YC and Chao, CC and Hsueh, HW and Hsieh, PF and Chang, HY and Wang, IF and Tsai, LK}, title = {Increase of HCN current in SOD1-associated amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {12}, pages = {4240-4253}, doi = {10.1093/brain/awae248}, pmid = {39088003}, issn = {1460-2156}, support = {108-2314-B-002-082-MY3//Ministry of Science and Technology, ROC/ ; MQ999//National Taiwan University Hospital/ ; 112-BIH001//National Taiwan University Hospital Hsinchu branch/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Animals ; *Superoxide Dismutase-1/genetics ; Mice ; Male ; Female ; *Mice, Transgenic ; *Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics/metabolism ; Middle Aged ; Aged ; Axons/metabolism ; Disease Models, Animal ; Potassium Channels/metabolism/genetics ; Adult ; }, abstract = {The clinical manifestations of sporadic amyotrophic lateral sclerosis (ALS) vary widely. However, the current classification of ALS is based mainly on clinical presentations, and the roles of electrophysiological and biomedical biomarkers remain limited. Herein, we investigated a group of patients with sporadic ALS and an ALS mouse model with superoxide dismutase 1 (SOD1)/G93A transgenes using nerve excitability tests (NETs) to investigate axonal membrane properties and chemical precipitation, followed by ELISA analysis to measure plasma misfolded protein levels. Six of 19 patients (31.6%) with sporadic ALS had elevated plasma misfolded SOD1 protein levels. In sporadic ALS patients, only those with elevated misfolded SOD1 protein levels showed an increased inward rectification in the current-voltage threshold curve and an increased threshold reduction in the hyperpolarizing threshold electrotonus in the NET study. Two familial ALS patients with SOD1 mutations also exhibited similar electrophysiological patterns of NET. For patients with sporadic ALS showing significantly increased inward rectification in the current-voltage threshold curve, we noted an elevation in plasma misfolded SOD1 level, but not in total SOD1, misfolded C9orf72 or misfolded phosphorylated TDP43 levels. Computer simulations demonstrated that the aforementioned axonal excitability changes are likely to be associated with an increase in hyperpolarization-activated cyclic nucleotide-gated (HCN) current. In SOD1/G93A mice, NET also showed an increased inward rectification in the current-voltage threshold curve, which could be reversed by a single injection of the HCN channel blocker, ZD7288. Daily treatment of SOD1/G93A mice with ZD7288 partly prevented the early motor function decline and spinal motor neuron death. In summary, sporadic ALS patients with elevated plasma misfolded SOD1 exhibited similar patterns of motor axonal excitability changes to familial ALS patients and ALS mice with mutant SOD1, suggesting the existence of SOD1-associated sporadic ALS. The observed NET pattern of increased inward rectification in the current-voltage threshold curve was attributable to an elevation in the HCN current in SOD1-associated ALS.}, } @article {pmid39087137, year = {2024}, author = {Chisthi, MM}, title = {Unveiling the potential of electrocautery-enhanced lumen-apposing metal stents in endoscopic ultrasound-guided biliary drainage.}, journal = {World journal of gastrointestinal surgery}, volume = {16}, number = {7}, pages = {1956-1959}, pmid = {39087137}, issn = {1948-9366}, abstract = {This editorial delves into Peng et al's article, published in the World Journal of Gastrointestinal Surgery. Peng et al's meta-analysis investigates the effectiveness of electrocautery-enhanced lumen-apposing metal stents (ECE-LAMS) in ultrasound-guided biliary drainage for alleviating malignant biliary obstruction. Examining 14 studies encompassing 620 participants, the research underscores a robust technical success rate of 96.7%, highlighting the efficacy of ECE-LAMS, particularly in challenging cases which have failed endoscopic retrograde cholangio pancreatography. A clinical success rate of 91.0% underscores its impact on symptom alleviation, while a reasonably tolerable adverse event rate of 17.5% is observed. However, the 7.3% re-intervention rate stresses the need for post-procedural monitoring. Subgroup analyses validate consistent outcomes, bolstering the applicability of ECE-LAMS. These findings advocate for the adoption of ECE-LAMS as an appropriate approach for biliary palliation, urging further exploration in real-world clinical contexts. They offer valuable insights for optimizing interventions targeting malignant biliary obstruction management.}, } @article {pmid39086926, year = {2024}, author = {Tilliole, P and Fix, S and Godin, JD}, title = {hnRNPs: roles in neurodevelopment and implication for brain disorders.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1411639}, pmid = {39086926}, issn = {1662-5099}, abstract = {Heterogeneous nuclear ribonucleoproteins (hnRNPs) constitute a family of multifunctional RNA-binding proteins able to process nuclear pre-mRNAs into mature mRNAs and regulate gene expression in multiple ways. They comprise at least 20 different members in mammals, named from A (HNRNP A1) to U (HNRNP U). Many of these proteins are components of the spliceosome complex and can modulate alternative splicing in a tissue-specific manner. Notably, while genes encoding hnRNPs exhibit ubiquitous expression, increasing evidence associate these proteins to various neurodevelopmental and neurodegenerative disorders, such as intellectual disability, epilepsy, microcephaly, amyotrophic lateral sclerosis, or dementias, highlighting their crucial role in the central nervous system. This review explores the evolution of the hnRNPs family, highlighting the emergence of numerous new members within this family, and sheds light on their implications for brain development.}, } @article {pmid39086672, year = {2023}, author = {Pasinelli, P and Meyer, K and Ferraiuolo, L and Culibrk, RA and Sattler, R}, title = {Editorial: The role of glial cells in neurodegeneration.}, journal = {Frontiers in molecular medicine}, volume = {3}, number = {}, pages = {1337286}, doi = {10.3389/fmmed.2023.1337286}, pmid = {39086672}, issn = {2674-0095}, support = {T32 AG044402/AG/NIA NIH HHS/United States ; }, } @article {pmid39086635, year = {2024}, author = {Pérez-Holanda, S}, title = {Non-participation of asymptomatic candidates in screening protocols reduces early diagnosis and worsens prognosis of colorectal cancer.}, journal = {World journal of gastroenterology}, volume = {30}, number = {26}, pages = {3198-3200}, pmid = {39086635}, issn = {2219-2840}, mesh = {Humans ; *Colorectal Neoplasms/diagnosis ; *Early Detection of Cancer/methods/statistics & numerical data ; Prognosis ; Asymptomatic Diseases ; Mass Screening/methods/statistics & numerical data ; Japan/epidemiology ; Neoplasm Staging ; Colonoscopy/statistics & numerical data ; }, abstract = {The Agatsuma et al's study shows that despite the evidence of the benefits of an early colorectal cancer (CRC) diagnosis, through screening in asymptomatic subjects, up to 50% of candidates reject this option and many of those affected are diagnosed later, in advanced stages. The efficacy of screening programs has been well-established for several years, which reduces the risk of CRC morbidity and mortality, without taking into account the test used for screening, or other tools. Nevertheless, a significant proportion of patients remain unscreened, so understanding the factors involved, as well as the barriers of the population to adherence is the first step to possibly modify the participation rate. These barriers could include a full range of social and political aspects, especially the type of financial provision of each health service. In Japan, health services are universal, and this advantageous situation makes it easier for citizens to access to these services, contributing to the detection of various diseases, including CRC. Interestingly, the symptomatic CRC group had a lower early-stage diagnosis rate than the patients detected during follow-up for other comorbidities, and symptomatic and cancer screening groups showed similar early-stage diagnosis.}, } @article {pmid39086545, year = {2024}, author = {Carrera-Juliá, S and Obrador, E and López-Blanch, R and Oriol-Caballo, M and Moreno-Murciano, P and Estrela, JM}, title = {Ketogenic effect of coconut oil in ALS patients.}, journal = {Frontiers in nutrition}, volume = {11}, number = {}, pages = {1429498}, pmid = {39086545}, issn = {2296-861X}, abstract = {A recent pilot study in amyotrophic lateral sclerosis (ALS) patients analyzed the effect of a Mediterranean diet (MeDi) supplemented with nicotinamide riboside (NR, a NAD[+] promoter), pterostilbene (PTER, a natural antioxidant) and/or coconut oil on anthropometric variables in ALS patients. The results suggested that the MeDi supplemented with NR, PTER and coconut oil is the nutritional intervention showing the greatest benefits at anthropometric levels. Over the last 30 years, glucose intolerance has been reported in ALS patients. Thus, suggesting that an alternative source of energy may be preferential for motor neurons to survive. Ketone bodies (KBs), provided through a MeDi with a lower carbohydrate content but enriched with medium chain triglycerides, could be a therapeutic alternative to improve the neuromotor alterations associated with the disease. Nevertheless, the use of a coconut oil-supplemented diet, as potentially ketogenic, is a matter of controversy. In the present report we show that a MeDi supplemented with coconut oil increases the levels of circulating KBs in ALS patients.}, } @article {pmid39086006, year = {2024}, author = {An, TJ and Jang, S and Hering, K and Vazquez, R and Scalia, J and Berry, JD and Kalva, SP and Arellano, RS}, title = {Gastrostomy placement in patients with amyotrophic lateral sclerosis: assessment of risk factors for post-procedural respiratory failure.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {680-686}, doi = {10.1080/21678421.2024.2384994}, pmid = {39086006}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/surgery ; *Gastrostomy/methods ; Male ; Female ; Middle Aged ; Aged ; Retrospective Studies ; *Respiratory Insufficiency/etiology ; Risk Factors ; Adult ; Aged, 80 and over ; Deglutition Disorders/etiology/epidemiology ; }, abstract = {OBJECTIVE: Radiologically inserted gastrostomy placement may be performed in patients with dysphagia secondary to amyotrophic lateral sclerosis (ALS). This study assessed technical outcomes and complications related to gastrostomy placement in patients with ALS.

METHODS: A retrospective review of patients with ALS who underwent gastrostomy placement between 2021 and 2023 was performed. Patient demographics, medical history, ALS disease manifestations, survival, and post-procedural complications were obtained from the electronic medical record. Technical outcomes related to gastrostomy placement were obtained from operative notes and review of procedural imaging.

RESULTS: A total of 100 patients were included in the study. The mean duration of ALS diagnosis at time of gastrostomy placement was 1.3 +/-1.2 years. The mean slow vital capacity at time of gastrostomy placement was 54.0 +/-20.2% (range 10-155%). Technical success was 100%, with 91 placed using fluoroscopic guidance and 9 placed with computed tomography guidance. Eighty-three percent of gastrostomies were performed as outpatient procedures, while 17/100 patients were admitted following the procedure for monitoring. Post-procedural adverse events were noted in 21/100 patients (15 mild and 6 moderate or greater). Three patients developed respiratory failure after gastrostomy tube placement and died within 1-week post-procedure. Lower pre-procedural slow vital capacity was associated with higher risk of post-procedural respiratory failure (p = 0.0003*).

CONCLUSIONS: Gastrostomy placement in patients with ALS has a high technical success rate and may be performed safely in the outpatient setting in appropriate patients. Patients with low slow vital capacity related to ALS should be admitted post-procedurally for airway monitoring and support.}, } @article {pmid39085618, year = {2024}, author = {Müller, KJ and Schmidbauer, ML and Schönecker, S and Kamm, K and Pelz, JO and Holzapfel, K and Papadopoulou, M and Bakola, E and Tsivgoulis, G and Naumann, M and Hermann, A and Walter, U and Dimitriadis, K and Reilich, P and Schöberl, F}, title = {Diagnostic accuracy and confounders of vagus nerve ultrasound in amyotrophic lateral sclerosis-a single-center case series and pooled individual patient data meta-analysis.}, journal = {Journal of neurology}, volume = {271}, number = {9}, pages = {6255-6263}, pmid = {39085618}, issn = {1432-1459}, support = {DFG TRR 338//Deutsche Forschungsgemeinschaft/ ; DFG TRR 274//Deutsche Forschungsgemeinschaft/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/diagnosis ; Humans ; Male ; Aged ; Female ; Middle Aged ; *Ultrasonography ; *Vagus Nerve/diagnostic imaging ; }, abstract = {BACKGROUND: Several single-center studies proposed utility of vagus nerve (VN) ultrasound for detecting disease severity, autonomic dysfunction, and bulbar phenotype in amyotrophic lateral sclerosis (ALS). However, the resulting body of literature shows opposing results, leaving considerable uncertainty on the clinical benefits of VN ultrasound in ALS.

METHODS: Relevant studies were identified up to 04/2024 and individual patient data (IPD) obtained from the respective authors were pooled with a so far unpublished cohort (from Munich). An IPD meta-analysis of 109 patients with probable or definite ALS (El Escorial criteria) and available VN cross-sectional area (CSA) was performed, with age, sex, ALS Functional Rating Scale-revised (ALSFRS-R), disease duration, and bulbar phenotype as independent variables.

RESULTS: Mean age was 65 years (± 12) and 47% of patients (± 12) had bulbar ALS. Mean ALSFRS-R was 38 (± 7), and mean duration was 18 months (± 18). VN atrophy was highly prevalent [left: 67% (± 5), mean CSA 1.6mm[2] (± 0.6); right: 78% (± 21), mean CSA 1.8 mm[2] (± 0.7)]. VN CSA correlated with disease duration (mean slope: left - 0.01; right - 0.01), but not with ALSFRS-R (mean slope: left 0.004; mean slope: right - 0.002). Test accuracy for phenotyping bulbar vs. non-bulbar ALS was poor (summary receiver operating characteristic area under the curve: left 0.496; right 0.572).

CONCLUSION: VN atrophy in ALS is highly prevalent and correlates with disease duration, but not with ALSFRS-R. VN CSA is insufficient to differentiate bulbar from non-bulbar ALS phenotypes. Further studies are warranted to analyze the link between VN atrophy, autonomic impairment, and survival in ALS.}, } @article {pmid39084789, year = {2024}, author = {Wang, H and Zhang, Y and Ren, Y and Liu, Y and Feng, Z and Dong, L}, title = {Mechanism of multiple resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon in Avena fatua L. from China.}, journal = {Pesticide biochemistry and physiology}, volume = {203}, number = {}, pages = {105985}, doi = {10.1016/j.pestbp.2024.105985}, pmid = {39084789}, issn = {1095-9939}, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Oxazoles/pharmacology ; China ; *Phenylurea Compounds/pharmacology ; *Acetyl-CoA Carboxylase/genetics/metabolism ; *Propionates/pharmacology ; *Acetolactate Synthase/genetics/metabolism ; Poaceae/drug effects ; Phenylpropionates/pharmacology ; Plant Proteins/genetics/metabolism ; Sulfonylurea Compounds ; }, abstract = {Avena fatua L. is one of the most damaging and malignant weeds in wheat fields in China. Fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon, which belong to Acetyl-CoA carboxylase- (ACCase), acetolactate synthase- (ALS), and photosystem II- (PS II) inhibitors, respectively, are commonly used in wheat fields and have a long history of use on A. fatua. An A. fatua population (R) resistant to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon was collected from a wheat field in 2020. This study explored the mechanisms of target site resistance (TSR) and non-target site resistance (NTSR) in the multi-resistant A. fatua. Whole-plant bioassays showed that the R population had evolved high resistance to fenoxaprop-P-ethyl and moderate resistance to mesosulfuron-methyl and isoproturon. However, no mutations were detected in the ACCase, ALS, or psbA genes in the R population. In addition, the ACCase and ALS gene expression levels in the R group were significantly higher than those in the susceptible population (S) after treatment with fenoxaprop-P-ethyl or mesosulfuron-methyl. In vitro ACCase and ALS activity assays showed that ACCase and ALS from the R population were insensitive to fenoxaprop and mesosulfuron-methyl, respectively, with resistance indices 6.12-fold and 17.46-fold higher than those of the S population. Furthermore, pretreatment with P450 inhibitors significantly (P < 0.05) reversed the multi-resistant A. fatua's resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon. Sethoxydim, flucarbazone‑sodium, chlortoluron, and cypyrafluone were effective in controlling multi-resistance A. fatua. Therefore, the overexpression of ACCase and ALS to synthesize sufficient herbicide-targeting proteins, along with P450-mediated metabolism, conferred resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon in the R population.}, } @article {pmid39084788, year = {2024}, author = {Ohta, K and Kawamata, E and Hori, T and Sada, Y}, title = {Connecting genes to whole plants in dilution effect of target-site ALS inhibitor resistance of Schoenoplectiella juncoides (Roxb.) Lye (Cyperaceae).}, journal = {Pesticide biochemistry and physiology}, volume = {203}, number = {}, pages = {105984}, doi = {10.1016/j.pestbp.2024.105984}, pmid = {39084788}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Cyperaceae/genetics/drug effects ; Plant Proteins/genetics/metabolism ; Gene Expression Regulation, Plant/drug effects ; Mutation ; Genes, Plant ; }, abstract = {This study focuses on dilution effect of target-site resistance (TSR) to acetolactate synthase (ALS) inhibitors in Schoenoplectiella juncoides, which harbors two ALS genes, ALS1 and ALS2. We assessed gene expression, enzyme activity, and whole-plant resistance profiles across four S. juncoides lines: the susceptible line, the parental resistant lines with a homozygous mutation in either ALS1 or ALS2, and the bred progeny line with homozygous mutations in both ALS1 and ALS2. Gene expression and enzyme function showed a proportional relationship that the expression ratios of ALS1 to ALS2, approximately 70:30, were consistent with the functional ratio predicted by the double-sigmoidal plateau positions observed in enzyme assays. However, at the whole-plant level, resistance did not correlate to the putative abundance of susceptible enzyme, but the parental lines showed similar resistance to each other despite different enzyme-level resistances. This suggests a non-proportional mechanism in the reflection of physiological enzymatic profiles to whole-plant resistance profiles. These findings highlight the complexity of herbicide resistance and the need for further research to understand the mechanisms that influence resistance outcomes. Understanding these relationships is essential for developing strategies to manage herbicide resistance effectively.}, } @article {pmid39084570, year = {2024}, author = {Liu, J and Zhao, W and Guo, J and Kang, K and Li, H and Yang, X and Li, J and Wang, Q and Qiao, H}, title = {Electroacupuncture alleviates motor dysfunction by regulating neuromuscular junction disruption and neuronal degeneration in SOD1[G93A] mice.}, journal = {Brain research bulletin}, volume = {216}, number = {}, pages = {111036}, doi = {10.1016/j.brainresbull.2024.111036}, pmid = {39084570}, issn = {1873-2747}, mesh = {Animals ; *Electroacupuncture/methods ; *Neuromuscular Junction/pathology/metabolism ; *Motor Neurons/pathology/physiology ; *Mice, Transgenic ; Mice ; *Amyotrophic Lateral Sclerosis/therapy/pathology/genetics ; Disease Models, Animal ; Male ; Nerve Degeneration/therapy/pathology ; Muscle, Skeletal/pathology ; Superoxide Dismutase-1/genetics/metabolism ; Sciatic Nerve/injuries/pathology ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by the progressive destruction of the neuromuscular junction (NMJ) and the degeneration of motor neurons, eventually leading to atrophy and paralysis of voluntary muscles responsible for motion and breathing. NMJs, synaptic connections between motor neurons and skeletal muscle fibers, are extremely fragile in ALS. To determine the effects of early electroacupuncture (EA) intervention on nerve reinnervation and regeneration following injury, a model of sciatic nerve injury (SNI) was first established using SOD1[G93A] mice, and early electroacupuncture (EA) intervention was conducted at Baihui (DU20), and bilateral Zusanli (ST36). The results revealed that EA increased the Sciatic nerve Functional Index, the structural integrity of the gastrocnemius muscles, and the cross-sectional area of muscle fibers, as well as up-regulated the expression of acetylcholinesterase and facilitated the co-location of α7 nicotinic acetate choline receptors and α-actinin. Overall, these results suggested that EA can promote the repair and regeneration of injured nerves and delay NMJ degeneration in SOD1[G93A]-SNI mice. Moreover, analysis of the cerebral cortex demonstrated that EA alleviated cortical motor neuron damage in SOD1[G93A] mice, potentially attributed to the inhibition of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway and the release of interferon-β suppressing the activation of natural killer cells and the secretion of interferon-γ, thereby further inhibiting microglial activation and the expression of inflammatory factors. In summary, EA delayed the degeneration of NMJ and mitigated the loss of cortical motor neurons, thus delaying disease onset, accompanied by alleviation of muscle atrophy and improvements in motor function in SOD1[G93A] mice.}, } @article {pmid39084211, year = {2024}, author = {Sharma, S and Gilberto, VS and Rask, J and Chatterjee, A and Nagpal, P}, title = {Inflammasome-Inhibiting Nanoligomers Are Neuroprotective against Space-Induced Pathology in Healthy and Diseased Three-Dimensional Human Motor and Prefrontal Cortex Brain Organoids.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {16}, pages = {3009-3021}, doi = {10.1021/acschemneuro.4c00160}, pmid = {39084211}, issn = {1948-7193}, mesh = {Humans ; *Prefrontal Cortex/drug effects/metabolism ; *Organoids/drug effects ; *Inflammasomes/metabolism ; Neuroprotective Agents/pharmacology ; Space Flight ; Weightlessness ; Neurodegenerative Diseases ; Alzheimer Disease/pathology/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Frontotemporal Dementia/metabolism ; }, abstract = {The microgravity and space environment has been linked to deficits in neuromuscular and cognitive capabilities, hypothesized to occur due to accelerated aging and neurodegeneration in space. While the specific mechanisms are still being investigated, spaceflight-associated neuropathology is an important health risk to astronauts and space tourists and is being actively investigated for the development of appropriate countermeasures. However, such space-induced neuropathology offers an opportunity for accelerated screening of therapeutic targets and lead molecules for treating neurodegenerative diseases. Here, we show a proof-of-concept high-throughput target screening (on Earth), target validation, and mitigation of microgravity-induced neuropathology using our Nanoligomer platform, onboard the 43-day SpaceX CRS-29 mission to the International Space Station. First, comparing 3D healthy and diseased prefrontal cortex (PFC, for cognition) and motor neuron (MN, for neuromuscular function) organoids, we assessed space-induced pathology using biomarkers relevant to Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Both healthy and diseased PFC and MN organoids showed significantly enhanced neurodegeneration in space, as measured through relevant disease biomarkers, when compared to their respective Earth controls. Second, we tested the top two lead molecules, NI112 that targeted NF-κB and NI113 that targeted IL-6. We observed that these Nanoligomers significantly mitigate the AD, FTD, and ALS relevant biomarkers like amyloid beta-42 (Aβ42), phosphorylated tau (pTau), Kallikrein (KLK-6), Tar DNA-binding protein 43 (TDP-43), and others. Moreover, the 43-day Nanoligomer treatment of these brain organoids did not appear to cause any observable toxicity or safety issues in the target organoid tissue, suggesting good tolerability for these molecules in the brain at physiologically relevant doses. Together, these results show significant potential for both the development and translation of NI112 and NI113 molecules as potential neuroprotective countermeasures for safer space travel and demonstrate the usefulness of the space environment for rapid, high-throughput screening of targets and lead molecules for clinical translation. We assert that the use of microgravity in drug development and screening may ultimately benefit millions of patients suffering from debilitating neurodegenerative diseases on Earth.}, } @article {pmid39083229, year = {2024}, author = {Kaji, R and Izumi, Y and Oki, R}, title = {Ultra-high dose methylcobalamin and other emerging therapies for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {593-602}, doi = {10.1097/WCO.0000000000001311}, pmid = {39083229}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Vitamin B 12/analogs & derivatives/therapeutic use/administration & dosage ; Clinical Trials as Topic ; }, abstract = {PURPOSE OF REVIEW: Recent development in understanding the pathophysiology of amyotrophic lateral sclerosis (ALS) has led to increasing number of promising test drugs in the pipeline along with the existing ones. We will review these agents focusing on ultra-high dose methylcobalamin, which is pending approval in Japan. Clinical trial design best suited for ALS will also be discussed.

RECENT FINDINGS: The most recent phase 3 trial (JETALS) of ultra-high dose methylcobalamin demonstrated significant slowing of ALSFRSR changes (0.5/month), with marked reduction of serum homocysteine levels in the initial double-blind period. The post hoc analysis of the previous phase 2/3 study (E761 trial; Eisai) showed that it prolonged survival of ALS patients, if started within 1 year of onset, but the previous studies suggested its efficacy even in later stages, depending upon the rate of progression. Phase 3 trial of AMX0035 or Relyvrio on the other hand showed negative results despite the promising phase 2 data. The latter did not adjust the disease progression rate before entry.

SUMMARY: Ultra-high dose methylcobalamin is not a vitamin supplement but a novel disease-modifying therapy for ALS, and it emphasizes homocysteine as a key factor in the disease process. Clinical trial design must include entering patients early and with similar rates of progression using pretrial observation periods for meaningful results, since ALS is a chronologically heterogenous condition with similar phenotypes.}, } @article {pmid39080220, year = {2024}, author = {Han, M and Raymond, J and Larson, TC and Mehta, P and Horton, DK}, title = {Correction to: Comparison of Demographics: National Amyotrophic Lateral Sclerosis Registry and Clinical Trials Data.}, journal = {Journal of racial and ethnic health disparities}, volume = {}, number = {}, pages = {}, doi = {10.1007/s40615-024-02110-0}, pmid = {39080220}, issn = {2196-8837}, } @article {pmid39079696, year = {2024}, author = {Tress, F and Luecke, E and Stegemann-Koniszewski, S and Lux, A and Singla, A and Schreiber, J}, title = {Prediction of nocturnal ventilation by pulmonary function testing in patients with amyotrophic lateral sclerosis.}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {78}, number = {9}, pages = {626-633}, doi = {10.1055/a-2349-0936}, pmid = {39079696}, issn = {1438-8790}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/therapy/diagnosis/complications ; Female ; Male ; Aged ; *Respiratory Function Tests ; Retrospective Studies ; Middle Aged ; Noninvasive Ventilation/methods ; Sensitivity and Specificity ; Reproducibility of Results ; Respiratory Insufficiency/therapy/physiopathology/etiology/diagnosis ; Polysomnography/methods ; Circadian Rhythm/physiology ; }, abstract = {BACKGROUND: In amyotrophic lateral sclerosis (ALS) prognosis is poor due to progressive weakening of the respiratory muscles. Survival and quality of life can be improved by noninvasive ventilation (NIV), which is initially applied while sleeping. The indication for NIV is based on pulmonary function testing (PFT) and polysomnography (PSG) with capnography (tCO2). While it is desirable to predict nocturnal ventilation by waking PFT in ALS, the parameters suited for reliable predictions remain elusive.

METHODS: We retrospectively analyzed parameters derived from PFT (spirometry, body plethysmography, diffusion capacity, respiratory muscle testing) and blood gas analysis, PSG and tCO2 in 42 patients with ALS (27 men, 15 women, age 69 ± 12.1 years) and performed Spearman's correlation analysis of daytime waking parameters and nighttime sleep parameters.

RESULTS: 28 patients (66.7%) showed restrictive impairment of ventilation and 15 patients (48.3%) showed insufficiency of the respiratory musculature. There was no obstructive impairment of ventilation. We did not observe any significant correlations between any single daytime PFT parameter with nocturnal pCO2. However, there were significant correlations between the ratios PIF/PEF, MEF50/MIF50, DLCO/VA as well as FEV1/FVC and nocturnal pCO2. Highly normal FEV1/FVC and Krogh-Factor (DLCOc/VA) indicated nocturnal hypercapnia. Furthermore, waking hypercapnia, concentrations of bicarbonate and base excess were each positively correlated with nocturnal hypercapnia.

CONCLUSIONS: Waking PFT is not a good predictor of nocturnal ventilation. Inspiratory parameters as well as the ratios FEV1/FVC and DLCO/VA performed best and should be included in the interpretation. Our analyses confirm the relevance of inspiratory muscle weakness in ALS. PSG and tCO2 remain the gold standard for the assessment of nocturnal ventilation.}, } @article {pmid39079071, year = {2024}, author = {Crayle, JI and Rampersaud, E and Myers, JR and Wuu, J and Taylor, JP and Wu, G and Benatar, M and Bedlack, RS}, title = {Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype.}, journal = {Neurology}, volume = {103}, number = {4}, pages = {e209696}, pmid = {39079071}, issn = {1526-632X}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; Cohort Studies ; *Genome-Wide Association Study ; *Phenotype ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Whole Genome Sequencing ; }, abstract = {BACKGROUND AND OBJECTIVES: The term "ALS Reversal" describes patients who initially meet diagnostic criteria for amyotrophic lateral sclerosis (ALS) or had clinical features most consistent with progressive muscular atrophy (PMA) but subsequently demonstrated substantial and sustained clinical improvement. The objective of this genome-wide association study (GWAS) was to identify correlates of this unusual clinical phenotype.

METHODS: Participants were recruited from a previously created database of individuals with the ALS Reversal phenotype. Whole-genome sequencing (WGS) data were compared with ethnicity-matched patients with typically progressive ALS enrolled through the CReATe Consortium's Phenotype-Genotype-Biomarker (PGB) study. These results were replicated using an independent ethnically matched WGS data set from Target ALS. Significant results were further explored with available databases of genetic regulatory markers and expression quantitative trait loci (eQTL) analysis.

RESULTS: WGS from 22 participants with documented ALS Reversals was compared with the PGB primary cohort (n = 103) and the Target ALS validation cohort (n = 140). Two genetic loci met predefined criteria for statistical significance (two-sided permutation p ≤ 0.01) and remained plausible after fine-mapping. The lead single nucleotide variant (SNV) from the first locus was rs4242007 (primary cohort GWAS OR = 12.0, 95% CI 4.1 to 34.6), which is in an IGFBP7 intron and is in near-perfect linkage disequilibrium with a SNV in the IGFBP7 promoter region. Both SNVs are associated with decreased frontal cortex IGFBP7 expression in eQTL data sets. Notably, 3 Reversals, but none of the typically progressive individuals (n = 243), were homozygous for rs4242007. The importance of the second locus, located near GRIP1, is uncertain given the absence of an associated effect on nearby gene transcription.

DISCUSSION: We found a significant association between the Reversal phenotype and an IGFBP7 noncoding SNV that is associated with IGFBP7 expression. This is biologically relevant as IGFBP7 is a reported inhibitor of the insulin growth factor-1 (IGF-1) receptor that activates the possibly neuroprotective IGF-1 signaling pathway. This finding is limited by small sample size but suggests that there may be merit in further exploration of IGF-1 pathway signaling as a therapeutic mechanism for ALS.

This study was registered with ClinicalTrials.gov (NCT03464903) on March 14, 2018. The first participant was enrolled on June 22, 2018.}, } @article {pmid39079069, year = {2024}, author = {Fournier, CN}, title = {Learning From the Exception and Not the Rule: Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype.}, journal = {Neurology}, volume = {103}, number = {4}, pages = {e209780}, doi = {10.1212/WNL.0000000000209780}, pmid = {39079069}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Phenotype ; }, } @article {pmid39076845, year = {2024}, author = {Liu, X and Chen, L and Ye, S and Liu, X and Zhang, Y and Fan, D}, title = {Postural instability and lower extremity dysfunction in upper motor neuron-dominant amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1406109}, pmid = {39076845}, issn = {1664-2295}, abstract = {BACKGROUND: Upper motor neuron-dominant ALS (UMND ALS) is recognized to have early onset and good prognosis, but may have a rapid decline in motor function due to gait instability in the early stage. We investigated changes in lower extremity function in UMND ALS, particularly UMND ALS patients accompanied with postural instability or repeated falls (UMND ALS plus).

RESULTS: Among the 2,353 ALS patients reviewed, 211 (9.0%) had UMND ALS. UMND ALS had a longer diagnosis delay and restricted symptoms. Although UMND ALS patients had better lower extremity function and strength than matched classic ALS patients on first evaluation, there was no difference in the time of needing assistance or not being able to walk after disease onset. In contrast, UMND ALS plus has severe UMN symptoms and a more rapid decline in motor function. The lower extremity function was no better than that in the matched classic ALS. The prognosis of UMND ALS and UMND ALS plus were significantly better than those of overall ALS.

CONCLUSION: UMND ALS has restricted symptoms but has a rapid decline in lower extremity function in the early stage of the disease. The motor function decline of UMND ALS plus is as fast as classic ALS. Whether these patients represent a distinct subgroup of ALS deserves further investigation.}, } @article {pmid39076207, year = {2024}, author = {Zheng, W and He, J and Chen, L and Yu, W and Zhang, N and Liu, X and Fan, D}, title = {Genetic link between KIF1A mutations and amyotrophic lateral sclerosis: evidence from whole-exome sequencing.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1421841}, pmid = {39076207}, issn = {1663-4365}, abstract = {OBJECTIVES: Genetics have been shown to have a substantial impact on amyotrophic lateral sclerosis (ALS). The ALS process involves defects in axonal transport and cytoskeletal dynamics. It has been identified that KIF1A, responsible for encoding a kinesin-3 motor protein that carries synaptic vesicles, is considered a genetic predisposing factor for ALS.

METHODS: The analysis of whole-exome sequencing data from 1,068 patients was conducted to examine the genetic link between ALS and KIF1A. For patients with KIF1A gene mutations and a family history, we extended the analysis to their families and reanalyzed them using Sanger sequencing for cosegregation analysis.

RESULTS: In our cohort, the KIF1A mutation frequency was 1.31% (14/1,068). Thirteen nonsynonymous variants were detected in 14 ALS patients. Consistent with the connection between KIF1A and ALS, the missense mutation p.A1083T (c.3247G>A) was shown to cosegregate with disease. The mutations related to ALS in our study were primarily located in the cargo-binding region at the C-terminal, as opposed to the mutations of motor domain at the N-terminal of KIF1A which were linked to hereditary peripheral neuropathy and spastic paraplegia. We observed high clinical heterogeneity in ALS patients with missense mutations in the KIF1A gene. KIF5A is a more frequent determinant of ALS in the European population, while KIF1A accounts for a similar proportion of ALS in both the European and Chinese populations.

CONCLUSION: Our investigation revealed that mutations in the C-terminus of KIF1A could increase the risk of ALS, support the pathogenic role of KIF1A in ALS and expand the phenotypic and genetic spectrum of KIF1A-related ALS.}, } @article {pmid39075916, year = {2025}, author = {Wu, J and Ye, S and Liu, X and Xu, Y and Fan, D}, title = {The burden of upper motor neuron involvement is correlated with the bilateral limb involvement interval in patients with amyotrophic lateral sclerosis: a retrospective observational study.}, journal = {Neural regeneration research}, volume = {20}, number = {5}, pages = {1505-1512}, pmid = {39075916}, issn = {1673-5374}, abstract = {JOURNAL/nrgr/04.03/01300535-202505000-00032/figure1/v/2024-07-28T173839Z/r/image-tiff Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor neurons. Early bilateral limb involvement significantly affects patients' daily lives and may lead them to be confined to bed. However, the effect of upper and lower motor neuron impairment and other risk factors on bilateral limb involvement is unclear. To address this issue, we retrospectively collected data from 586 amyotrophic lateral sclerosis patients with limb onset diagnosed at Peking University Third Hospital between January 2020 and May 2022. A univariate analysis revealed no significant differences in the time intervals of spread in different directions between individuals with upper motor neuron-dominant amyotrophic lateral sclerosis and those with classic amyotrophic lateral sclerosis. We used causal directed acyclic graphs for risk factor determination and Cox proportional hazards models to investigate the association between the duration of bilateral limb involvement and clinical baseline characteristics in amyotrophic lateral sclerosis patients. Multiple factor analyses revealed that higher upper motor neuron scores (hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 1.01-1.09, P = 0.018), onset in the left limb (HR = 0.72, 95% CI = 0.58-0.89, P = 0.002), and a horizontal pattern of progression (HR = 0.46, 95% CI = 0.37-0.58, P < 0.001) were risk factors for a shorter interval until bilateral limb involvement. The results demonstrated that a greater degree of upper motor neuron involvement might cause contralateral limb involvement to progress more quickly in limb-onset amyotrophic lateral sclerosis patients. These findings may improve the management of amyotrophic lateral sclerosis patients with limb onset and the prediction of patient prognosis.}, } @article {pmid39075908, year = {2025}, author = {Araúzo-Bravo, MJ and Gerovska, D and Schwab, M and Kretz, A}, title = {Small extrachromosomal circular DNA in amyotrophic lateral sclerosis matter.}, journal = {Neural regeneration research}, volume = {20}, number = {5}, pages = {1411-1413}, pmid = {39075908}, issn = {1673-5374}, } @article {pmid39075842, year = {2024}, author = {Lomnicka, I and Dubey, S and Waller, P and Vora, D and Dirikolu, L}, title = {Development and validation of general plasma screening method for performance enhancing drugs in racehorses utilizing liquid chromatography-high-resolution mass spectrometry (LC-HRMS).}, journal = {Drug testing and analysis}, volume = {}, number = {}, pages = {}, doi = {10.1002/dta.3774}, pmid = {39075842}, issn = {1942-7611}, support = {//Louisiana State Racing Commission, New Orleans, LA 70119/ ; }, abstract = {The screening of drugs in plasma and urine often requires initial extraction (such as liquid-liquid extraction and solid-phase extraction) before the samples are submitted to instrumental analyses. These extraction procedures are often laborious and time-consuming. In this manuscript, a high-throughput automated assay based on liquid chromatography-high-resolution mass spectrometry (LC-HRMS) suitable for use as an initial testing procedure covering multiple classes of compounds prohibited in horse racing is described. The assay requires a 600-μL plasma aliquot, which is subjected to solid phase extraction (SPE) using OASIS HLB 96-well SPE with Biotage Extrahera system, evaporation, and reconstitution in a 96-well collection plate. LC-HRMS analyses were carried out on a Thermo Q-Exactive Mass spectrometer coupled with Thermo UHPLC system equipped with Thermo Accela ALS 2.4.0 autosampler linked to ACE Excel column. Drug targets were detected by retention time and accurate mass, with a mass tolerance window of 5 ppm in positive and negative ionization mode. The screening method was validated for over 300 drug targets in a 13-min run. Validation data including sensitivity, specificity, extraction recovery, and precision are presented. As the method employs full-scan mass spectrometry, unlimited number of drug targets can theoretically be incorporated into this method.}, } @article {pmid39075493, year = {2024}, author = {Mangal, AL and Mücke, M and Rolke, R and Appelmann, I}, title = {Advance directives in amyotrophic lateral sclerosis - a systematic review and meta-analysis.}, journal = {BMC palliative care}, volume = {23}, number = {1}, pages = {191}, pmid = {39075493}, issn = {1472-684X}, mesh = {*Amyotrophic Lateral Sclerosis/psychology/therapy/complications ; Humans ; *Advance Directives/statistics & numerical data/psychology ; Advance Care Planning/statistics & numerical data/standards ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motoneuron. It is associated with a life expectancy of 2-4 years after diagnosis. Individuals experience paralysis, dysphagia, respiratory failure and loss of communicative function, rendering advance care planning (ACP) critically important. This systematic review primarily aimed to internationally compare the application of advance directives (AD) and ACP in ALS. Its secondary aim was to identify ACP preferences, identify fields for future research and to generate recommendations for improving patient care through ACP.

METHODS: We conducted a systematic literature review and meta-analysis. Five electronic databases (Embase, Medline, Scopus, PsycInfo and CENTRAL) were searched for qualitative and quantitative primary literature from 1999 to 2024. Cross-references were used to identify additional publications. Study selection was performed based on inclusion criteria. Number and content of AD were extracted systematically. After statistical analysis consecutive meta-analysis was performed for international differences and changes over time. Quality assessment of studies was performed using the MMAT (Mixed Methods Appraisal Tool). PROSPERO Registration (June 07, 2021) : CRD42021248040.

RESULTS: A total of 998 records was screened of which 26 were included in the synthesis. An increase in publication numbers of 88.9% was observed from 1999 to 2024. Results regarding use and content of AD were heterogeneous and international differences were detected. AD were signed in 60.4% of records (1,629 / 2,696 patients). The number of AD decreased over time when separating the review period in two decades (1st 1999-2011: 78% vs. 2nd 2012-2024: 42%). Study quality was superior in qualitative and mixed method designs compared to quantitative studies.

CONCLUSION: Further prospective studies should include detailed analyses on preferences regarding ventilation and artificial nutrition in ALS and should encompass countries of the global south. Despite the complexity of ACP with regard to individual patient needs, ACP should be part of each individual support plan for ALS patients and should specifically comprise a discussion on the preferred place of death. The available disease-specific AD documents should be preferred.}, } @article {pmid39073874, year = {2024}, author = {Gatch, AJ and Ding, F}, title = {TDP-43 Promotes Amyloid-Beta Toxicity by Delaying Fibril Maturation via Direct Molecular Interaction.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {15}, pages = {2936-2953}, pmid = {39073874}, issn = {1948-7193}, support = {P20 GM121342/GM/NIGMS NIH HHS/United States ; R35 GM145409/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amyloid beta-Peptides/metabolism ; *DNA-Binding Proteins/metabolism ; Humans ; *Molecular Dynamics Simulation ; *Amyloid/metabolism ; Protein Binding ; Alzheimer Disease/metabolism ; }, abstract = {Amyloid-β (Aβ) is a peptide that undergoes self-assembly into amyloid fibrils, which compose the hallmark plaques observed in Alzheimer's disease (AD). TAR DNA-binding protein 43 (TDP-43) is a protein with mislocalization and aggregation implicated in amyotrophic lateral sclerosis and other neurodegenerative diseases. Recent work suggests that TDP-43 may interact with Aβ, inhibiting the formation of amyloid fibrils and worsening AD pathology, but the molecular details of their interaction remain unknown. Using all-atom discrete molecular dynamics simulations, we systematically investigated the direct molecular interaction between Aβ and TDP-43. We found that Aβ monomers were able to bind near the flexible nuclear localization sequence of the N-terminal domain (NTD) of TDP-43, adopting β-sheet rich conformations that were promoted by the interaction. Furthermore, Aβ associated with the nucleic acid binding interface of the tandem RNA recognition motifs of TDP-43 via electrostatic interactions. Using the computational peptide array method, we found the strongest C-terminal domain interaction with Aβ to be within the amyloidogenic core region of TDP-43. With experimental evidence suggesting that the NTD is necessary for inhibiting Aβ fibril growth, we also simulated the NTD with an Aβ40 fibril seed. We found that the NTD was able to strongly bind the elongation surface of the fibril seed via extensive hydrogen bonding and could also diffuse along the lateral surface via electrostatic interactions. Our results suggest that TDP-43 binding to the elongation surface, thereby sterically blocking Aβ monomer addition, is responsible for the experimentally observed inhibition of fibril growth. We conclude that TDP-43 may promote Aβ toxicity by stabilizing the oligomeric state and kinetically delaying fibril maturation.}, } @article {pmid39073543, year = {2024}, author = {Litvinov, VV and Freynd, GG}, title = {[Clinical and morphologic characterization of Pick's dementia: case report and review of the literature].}, journal = {Arkhiv patologii}, volume = {86}, number = {4}, pages = {51-57}, doi = {10.17116/patol20248604151}, pmid = {39073543}, issn = {0004-1955}, mesh = {Humans ; *Cerebral Cortex/metabolism/pathology ; *Pick Disease of the Brain/pathology/diagnosis ; tau Proteins/metabolism ; }, abstract = {Diseases morphologically characterized by frontotemporal lobar degeneration have relatively recently been considered as a group of frontotemporal dementias. This group is characterized by a tendency to early clinical onset of dementia, common genetic and morphological features, as well as a possible association with diseases such as amyotrophic lateral sclerosis and atypical parkinsonism syndrome. Historically, Pick's dementia (Pick's disease) was described as the first of the frontotemporal dementias, which is morphologically characterized by the presence of argyrophilic Pick's bodies represented by 3R-tau protein in the neurons of the cerebral cortex. Despite the characteristic clinical and morphological picture due to the relative rarity, the diagnosis of Pick's dementia is infrequently made by both clinicians and pathologists. The article presents current data on frontotemporal dementia. A case of Pick's dementia with characteristic clinical manifestations in the form of early onset of behavioral and personality disorders, as well as specific morphological changes in the brain, is described.}, } @article {pmid39073531, year = {2024}, author = {Moglia, C and Palumbo, F and Botto, R and Iazzolino, B and Ticozzi, N and Calvo, A and Leombruni, P and , }, title = {Prognostic communication in amyotrophic lateral sclerosis: findings from a Nationwide Italian survey.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {12}, pages = {5787-5794}, pmid = {39073531}, issn = {1590-3478}, support = {RF-2016-02362405//Ministero della Salute/ ; 23C306//Ministero della Salute/ ; 101017598//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 259867//Seventh Framework Programme/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/diagnosis ; Humans ; Italy ; Prognosis ; *Neurologists ; *Attitude of Health Personnel ; Communication ; Surveys and Questionnaires ; Male ; Female ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron disease with a highly variable prognosis. Among the proposed prognostic models, the European Network for the cure of ALS (ENCALS) survival model has demonstrated good predictive performance. However, few studies have examined prognostic communication and the diffusion of prognostic algorithms in ALS care.

OBJECTIVE: To investigate neurologists' attitudes toward prognostic communication and their knowledge and utilization of the ENCALS survival model in clinical practice.

METHODS: A web-based survey was administered between May 2021 and March 2022 to the 40 Italian ALS Centers members of the Motor Neuron Disease Study Group of the Italian Society of Neurology.

RESULTS: Twenty-two out of 40 (55.0%) Italian ALS Centers responded to the survey, totaling 37 responses. The model was known by 27 (73.0%) respondents. However, it was predominantly utilized for research (81.1%) rather than for clinical prognostic communication (7.4%). Major obstacles to prognostic communication included the unpredictability of disease course, fear of a negative impact on patients or caregivers, dysfunctional reaction to diagnosis, and cognitive impairment. Nonetheless, the model was viewed as potentially useful for improving clinical management, increasing disease awareness, and facilitating care planning, especially end-of-life planning.

CONCLUSIONS: Despite the widespread recognition and positive perceptions of the ENCALS survival model among Italian neurologists with expertise in ALS, its implementation in clinical practice remains limited. Addressing this disparity may require systematic investigations and targeted training to integrate tailored prognostic communication into ALS care protocols, aligning with the growing availability of prognostic tools for ALS.}, } @article {pmid39073225, year = {2024}, author = {Liu, X and Xue, H and Wirdefeldt, K and Song, H and Smedby, K and Fang, F and Liu, Q}, title = {Clonal hematopoiesis of indeterminate potential and risk of neurodegenerative diseases.}, journal = {Journal of internal medicine}, volume = {296}, number = {4}, pages = {327-335}, doi = {10.1111/joim.20001}, pmid = {39073225}, issn = {1365-2796}, support = {//Initial Founding for High Level Talented Scholars in Nanfang Hospital/ ; 2023G001//Southern Medical University/ ; 2021-00696//Swedish Research Council (JPND)/ ; P1030//Initial Founding for Postdoc in Greater Bay Area Institute of Precision Medicine (Guangzhou)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics/epidemiology ; Female ; Male ; *Clonal Hematopoiesis/genetics ; Middle Aged ; Aged ; Risk Factors ; DNA Methyltransferase 3A ; United Kingdom/epidemiology ; Cohort Studies ; DNA (Cytosine-5-)-Methyltransferases/genetics ; Repressor Proteins/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Parkinson Disease/genetics ; DNA-Binding Proteins ; Dioxygenases ; }, abstract = {BACKGROUND: Little is known regarding the association between clonal hematopoiesis of indeterminate potential (CHIP) and risk of neurodegenerative diseases.

OBJECTIVE: To estimate the risk of neurodegenerative diseases among individuals with CHIP.

METHODS: We conducted a community-based cohort study based on UK Biobank and used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of any neurodegenerative disease, subtypes of neurodegenerative diseases (including primary neurodegenerative diseases, vascular neurodegenerative diseases, and other neurodegenerative diseases), and specific diagnoses of neurodegenerative diseases (i.e., amyotrophic lateral sclerosis [ALS], Alzheimer's disease [AD], and Parkinson's disease [PD]) associated with CHIP.

RESULTS: We identified 14,440 individuals with CHIP and 450,907 individuals without CHIP. Individuals with CHIP had an increased risk of any neurodegenerative disease (HR 1.10, 95% CI: 1.01-1.19). We also observed a statistically significantly increased risk for vascular neurodegenerative diseases (HR 1.31, 95% CI 1.05-1.63) and ALS (HR 1.50, 95% CI 1.05-2.15). An increased risk was also noted for other neurodegenerative diseases (HR 1.13, 95% CI 0.97-1.32), although not statistically significant. Null association was noted for primary neurodegenerative diseases (HR 1.06, 95% CI 0.96-1.17), AD (HR 1.04, 95% CI 0.88-1.23), and PD (HR 1.02, 95% CI 0.86-1.21). The risk increase in any neurodegenerative disease was mainly observed for DNMT3A-mutant CHIP, ASXL1-mutant CHIP, or SRSF2-mutant CHIP.

CONCLUSION: Individuals with CHIP were at an increased risk of neurodegenerative diseases, primarily vascular neurodegenerative diseases and ALS, but potentially also other neurodegenerative diseases. These findings suggest potential shared mechanisms between CHIP and neurodegenerative diseases.}, } @article {pmid39073146, year = {2024}, author = {Bublitz, SK and Eham, M and Ellrott, H and Littger, B and Richter, J and Lorenzl, S}, title = {Homecare amyotrophic lateral sclerosis (ALS): A multidisciplinary, home-based model of care for patients with ALS and their caregivers.}, journal = {Muscle & nerve}, volume = {70}, number = {5}, pages = {937-943}, doi = {10.1002/mus.28218}, pmid = {39073146}, issn = {1097-4598}, support = {//Bavarian Ministry of Health/ ; //Krankenhaus Agatharied/ ; //Dr. Mähler-Linke Stiftung/ ; //ALS Hilfe Bayern e.V./ ; //Marion von Tessin-Stiftung/ ; //Archdiocese München and Freising/ ; //Amylyx Pharmaceuticals Germany GmbH/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Male ; Female ; *Caregivers/psychology ; Middle Aged ; Aged ; *Home Care Services ; Pilot Projects ; Longitudinal Studies ; Patient Satisfaction ; Patient Care Team ; Adult ; Palliative Care ; Cohort Studies ; Germany ; Terminal Care ; Aged, 80 and over ; }, abstract = {INTRODUCTION/AIMS: Multidisciplinary care for patients with amyotrophic lateral sclerosis (ALS) is recommended in international guidelines, but reaches its limits when immobility increases. This pilot project addresses this gap by delivering home-based, specialized, multiprofessional support to ALS patients who are not able to attend outpatient care. The study assessed the feasibility of this model of care and the satisfaction of both patients and caregivers.

METHODS: This was a longitudinal cohort study of patients with ALS and their caregivers in the surroundings of Munich, Germany. Patients were regularly visited at home by a multiprofessional team (neurologists/palliative care physicians, nurse, social worker, chaplain).

RESULTS: A total of 94 patients with ALS were included in the homecare project and 88 patients and 74 caregivers were enrolled in the accompanying study. The mean care duration was 221 days, enabling 61% of the 49 deceased patients to die at home. Notably, 20% of patients chose a way to hasten death. Patient satisfaction (ICECAP Supportive Care Measure [SCM]: 23.7/28, CollaboRATE: 10.6/12) and caregiver perception of the end-of-life phase (Caregiver Evaluation of the Quality of End-Of-Life Care [CEQUEL]: 24.9/26) were high.

DISCUSSION: This pilot project successfully implemented specialized, home-based multidisciplinary care for ALS patients and caregivers, demonstrating both feasibility and high satisfaction. The program enabled a large proportion of patients to remain in their homes, reducing the need for hospital care. The multiprofessional approach, including neuropalliative, psychosocial and spiritual support provided comprehensive care that addressed needs of patients and caregivers. Further research is warranted to explore cost-effectiveness.}, } @article {pmid39072769, year = {2024}, author = {Turner, J and Bruels, CC and Daugherty, AL and Estrella, EA and Stafki, S and Syeda, SB and Littel, HR and Pais, L and Ganesh, VS and Lidov, HGW and Paine, SML and Maddison, P and Harrison, RE and Straub, V and Ghosh, PS and Pacak, CA and Kunkel, LM and Draper, I and Topf, A and Kang, PB}, title = {Dominant stop-loss HNRNPA1 variants in juvenile-onset myopathy.}, journal = {Muscle & nerve}, volume = {70}, number = {4}, pages = {843-850}, pmid = {39072769}, issn = {1097-4598}, support = {//Muscular Dystrophy UK/ ; //Ultragenyx/ ; R01 HG009141/HG/NHGRI NIH HHS/United States ; //Coalition to Cure Calpain 3/ ; //LGMD2I Research Fund/ ; R01HG009141/HG/NHGRI NIH HHS/United States ; //Kurt+Peter Foundation/ ; UM1HG008900//National Heart, Lung and Blood Institute/ ; //Sanofi Genzyme/ ; UM1 HG008900/HG/NHGRI NIH HHS/United States ; P50 HD105351/HD/NICHD NIH HHS/United States ; //Bernard F. and Alva B. Gimbel Foundation/ ; //LGMD2D Foundation/ ; //Samantha J. Brazzo Foundation/ ; /EY/NEI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Heterogeneous Nuclear Ribonucleoprotein A1/genetics ; Female ; Adolescent ; Muscular Diseases/genetics ; Muscle, Skeletal/pathology ; Young Adult ; Phenotype ; }, abstract = {INTRODUCTION/AIMS: Heterogeneous nuclear ribonucleoprotein A1 is involved in nucleic acid homeostatic functions. The encoding gene HNRNPA1 has been associated with several neuromuscular disorders including an amyotrophic lateral sclerosis-like phenotype, distal hereditary motor neuropathy, multisystem proteinopathy, and various myopathies. We report two unrelated individuals with monoallelic stop loss variants affecting the same codon of HNRNPA1.

METHODS: Two individuals with unsolved juvenile-onset myopathy were enrolled under approved institutional protocols. Phenotype data were collected and genetic analyses were performed, including whole-exome sequencing (WES).

RESULTS: The two probands (MNOT002-01 and K1440-01) showed a similar onset of slowly progressive extremity and facial weakness in early adolescence. K1440-01 presented with facial weakness, winged scapula, elevated serum creatine kinase (CK) levels, and mild neck weakness. MNOT002-01 also exhibited elevated CK levels along with facial weakness, cardiomyopathy, respiratory dysfunction, pectus excavatum, a mildly rigid spine, and loss of ambulation. On quadriceps muscle biopsy, K1440-01 displayed rounded myofibers, mild variation in fiber diameter, and type 2 fiber hypertrophy, while MNOT002-01 displayed rimmed vacuoles. Monoallelic stop-loss variants in HNRNPA1 were identified for both probands: c.1119A>C p.*373Tyrext*6 (K1440-01) and c.1118A>C p.*373Serext*6 (MNOT002-01) affect the same codon and are both predicted to lead to the addition of six amino acids before termination at an alternative stop codon.

DISCUSSION: Both stop-loss variants in our probands are likely pathogenic. Our findings contribute to the disease characterization of pathogenic variants in HNRNPA1. This gene should be screened in clinical diagnostic testing of unsolved cases of sporadic or dominant juvenile-onset myopathy.}, } @article {pmid39072749, year = {2025}, author = {Stevenor, BA and Burgess, Y and Sampson, G and McBride, NL and Gugiu, MR and Copella, J and Davis, J and Wu, B and Panchal, AR}, title = {Examining the Reliability and Validity of the ALS Certification Examinations with the Inclusion of Clinical Judgment: An Update on the ALS Examination Redesign.}, journal = {Prehospital emergency care}, volume = {29}, number = {3}, pages = {289-295}, doi = {10.1080/10903127.2024.2379879}, pmid = {39072749}, issn = {1545-0066}, mesh = {Humans ; Reproducibility of Results ; *Certification/standards ; *Emergency Medical Technicians/standards/education ; Psychometrics ; *Clinical Competence/standards ; *Educational Measurement/methods/standards ; *Emergency Medical Services/standards ; *Advanced Cardiac Life Support/standards ; Male ; Female ; }, abstract = {OBJECTIVES: Clinical judgment describes the process an emergency medical service clinician uses to evaluate problems and make decisions in the out-of-hospital setting. As part of the redesign of the Advanced Life Support (ALS) certification examinations, the National Registry of Emergency Medical Technicians is developing and evaluating items that measure clinical judgment, with the intention of assessing these as a new domain in the ALS certification examinations. In this study, we provide evidence around the redesign by evaluating the reliability and validity of the advanced emergency medical technician (AEMT) and paramedic certification examinations when clinical judgment is included as a sixth domain along with the five current domains.

METHODS: Pretest (i.e., pilot, unscored) clinical judgment items were included as a new sixth clinical judgment domain. We then used the combination of operational (i.e., scored) and pretest items for all six domains and scored the redesigned AEMT and paramedic certification examinations. We evaluated the psychometric properties of these ALS examinations within the Rasch measurement framework with multiple assessments of reliability and validity including item-level statistics (e.g., mean-square infit and outfit, local dependence) and examination-level statistics (e.g., person reliability, item reliability, item separation, decision consistency, decision accuracy). Wright Maps were produced to evaluate whether the examination item difficulty statistics aligned with the candidate ability continuum.

RESULTS: The total population of all examination forms included were 20,136 (AEMT 4,983; paramedic 15,153). The Rasch-based statistics for the redesigned AEMT and paramedic examinations, for both item and examination-level statistics, were well within the psychometric standard values. Wright maps demonstrated that the developed items fall along the candidate ability continuum for both examinations. Further, the distribution of clinical judgment item difficulties fell within the current item distribution, providing evidence that these new items are of similar difficulty to the items measuring the five current domains.

CONCLUSION: We demonstrate strong reliability and validity evidence to support that the integrity of the examinations is upheld with the addition of clinical judgment items, while also providing a more robust candidate evaluation. Most importantly, the pass/fail decisions that candidates receive accurately reflect their level of ALS knowledge at the entry-level.}, } @article {pmid39072727, year = {2024}, author = {Defilippi, V and Petereit, J and Handlos, VJL and Notterpek, L}, title = {Quantitative proteomics unveils known and previously unrecognized alterations in neuropathic nerves.}, journal = {Journal of neurochemistry}, volume = {168}, number = {9}, pages = {3154-3170}, pmid = {39072727}, issn = {1471-4159}, support = {P20 GM130459/GM/NIGMS NIH HHS/United States ; GM104944/NH/NIH HHS/United States ; P20 GM103440/GM/NIGMS NIH HHS/United States ; P20GM130459/NH/NIH HHS/United States ; GM103440/NH/NIH HHS/United States ; U54 GM104944/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Proteomics/methods ; Mice ; Charcot-Marie-Tooth Disease/genetics/metabolism/pathology ; Myelin Proteins/genetics/metabolism ; Peripheral Nerves/metabolism/pathology ; Mice, Inbred C57BL ; Male ; Peripheral Nervous System Diseases/genetics/metabolism/pathology ; Female ; }, abstract = {Charcot-Marie-Tooth disease type 1E (CMT1E) is an inherited autosomal dominant peripheral neuropathy caused by mutations in the peripheral myelin protein 22 (PMP22) gene. The identical leucine-to-proline (L16P) amino acid substitution in PMP22 is carried by the Trembler J (TrJ) mouse and is found in CMT1E patients presenting with early-onset disease. Peripheral nerves of patients diagnosed with CMT1E display a complex and varied histopathology, including Schwann cell hyperproliferation, abnormally thin myelin, axonal degeneration, and subaxonal morphological changes. Here, we have taken an unbiased data-independent analysis (DIA) mass spectrometry (MS) approach to quantify proteins from nerves of 3-week-old, age and genetic strain-matched wild-type (Wt) and heterozygous TrJ mice. Nerve proteins were dissolved in lysis buffer and digested into peptide fragments, and protein groups were quantified by liquid chromatography-mass spectrometry (LC-MS). A linear model determined statistically significant differences between the study groups, and proteins with an adjusted p-value of less than 0.05 were deemed significant. This untargeted proteomics approach identified 3759 quality-controlled protein groups, of which 884 demonstrated differential expression between the two genotypes. Gene ontology (GO) terms related to myelin and myelin maintenance confirm published data while revealing a previously undetected prominent decrease in peripheral myelin protein 2. The dataset corroborates the described pathophysiology of TrJ nerves, including elevated activity in the proteasome-lysosomal pathways, alterations in protein trafficking, and an increase in three macrophage-associated proteins. Previously unrecognized perturbations in RNA processing pathways and GO terms were also discovered. Proteomic abnormalities that overlap with other human neurological disorders besides CMT include Lafora Disease and Amyotrophic Lateral Sclerosis. Overall, this study confirms and extends current knowledge on the cellular pathophysiology in TrJ neuropathic nerves and provides novel insights for future examinations. Recognition of shared pathomechanisms across discrete neurological disorders offers opportunities for innovative disease-modifying therapeutics that could be effective for distinct neuropathies.}, } @article {pmid39072497, year = {2025}, author = {Alonso, JP and Ini, N and Villarejo, A and Belizán, M and Roberti, J}, title = {Amyotrophic lateral sclerosis in Argentina: unveiling the burden of treatment through patient and caregiver perspectives.}, journal = {Disability and rehabilitation}, volume = {47}, number = {7}, pages = {1828-1835}, doi = {10.1080/09638288.2024.2385732}, pmid = {39072497}, issn = {1464-5165}, mesh = {Humans ; Argentina ; *Caregivers/psychology ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Male ; Female ; Middle Aged ; *Qualitative Research ; *Cost of Illness ; Aged ; *Interviews as Topic ; Adult ; Activities of Daily Living ; COVID-19/epidemiology ; }, abstract = {PURPOSE: To examine the burden of treatment (BoT) experienced by people with Amyotrophic Lateral Sclerosis (ALS) in Argentina.

METHODS: Qualitative methodological design based on semi-structured interviews. Nineteen semi-structured interviews were conducted (PwALS = 7, informal caregivers= 12). The interview guides were designed based on the literature and BoT theory. Data were analysed following a framework analysis approach.

RESULTS: The research highlighted the arduous journey toward obtaining a diagnosis, marked by delays influenced by healthcare system inefficiencies, lack of disease awareness and pandemic-related anxiety. Receiving the diagnosis was a destabilising experience, triggering the need to reframe self-identity, a new reality. As the disease progressed, patients encountered significant challenges in their daily activities and basic tasks, affecting their ability to work, communicate, and manage personal care. The burden extended beyond the patients to their primary caregivers. Access to specialised care, bureaucratic complexities in securing treatment, and the financial impact of managing the disease posed substantial challenges.

CONCLUSION: The findings offer valuable insights into the experiences of PwALS and their caregivers in Argentina. They underscore the need for increased disease awareness, improved access to specialised care, and enhanced support networks to alleviate the burdens PwALS and their families face.}, } @article {pmid39071530, year = {2024}, author = {Gaspar, AD and Banayat, AC}, title = {Undergraduate Student Nurses' Satisfaction, Self-confidence, and Perception of High-fidelity Simulation-based Learning on Critically-ill Patients.}, journal = {Acta medica Philippina}, volume = {58}, number = {12}, pages = {110-117}, pmid = {39071530}, issn = {2094-9278}, abstract = {BACKGROUND AND OBJECTIVE: Replicating critical care practice settings in high-fidelity simulation (HFS) provides more learning opportunities to develop competencies, improve self-confidence, and learner satisfaction in a safe environment. Simulation is increasingly adopted globally as an alternative teaching strategy. Yet, data on the HFS experience of Filipino undergraduate nursing students is limited. This study describes the satisfaction, self-confidence, and perception of undergraduate nursing students on the use of HFS-based learning on critically-ill adult and pediatric patients requiring advanced life support (ALS).

METHODS: A quantitative, descriptive, correlational study was conducted using purposive sampling on all fourth-year BS Nursing students enrolled in Critical Care Nursing course in a state university. Data were collected through an online survey on demographic data, and the students' perceptions towards high-fidelity simulation-based learning (SBL) using three tools, namely: Simulation Design Scale, Educational Practices Questionnaire, and Student Satisfaction and Self-confidence in Learning. T-test and ANOVA were used to compare the means of the variables. Bivariate analysis (Pearson's product-moment correlation) was performed to find the relationship between variables.

RESULTS: A total of 86 students participated in the survey. Overall, the students were highly satisfied with the simulation experience (4.46 out of 5.0, SD=0.47), and had high ratings of self-confidence in SBL (4.44 out of 5.0, SD=0.42). Overall satisfaction level was positively related to student's perception on simulation design (r=0.61, p<0.01) and educational practices (r=0.59, p<0.01). Similarly, the students' overall self-confidence with SBL was also positively correlated with their perceptions of the simulation design (r=0.32, p<0.01), and educational practices (r=0.34, p<0.01).

CONCLUSION: Effective use of technology through HFS-based learning is useful in increasing satisfaction and self-confidence of Filipino undergraduate nursing students in caring for critically-ill patients needing ALS. Educators must highly consider all parameters of simulation design and educational practices in planning and implementing HFS-based learning to achieve meaningful learner experience.}, } @article {pmid39071309, year = {2024}, author = {Yousefian-Jazi, A and Kim, S and Choi, SH and Chu, J and Nguyen, PT and Park, U and Lim, K and Hwang, H and Lee, K and Kim, Y and Hyeon, SJ and Rhim, H and Ryu, HL and Lim, G and Stein, TD and Ryu, H and Lee, J}, title = {Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.07.15.603186}, pmid = {39071309}, issn = {2692-8205}, support = {R01 NS109537/NS/NINDS NIH HHS/United States ; }, abstract = {Genetic changes and epigenetic modifications are associated with neuronal dysfunction in the pathogenesis of neurodegenerative disorders. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear. Here, we identified an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element, using convolutional neural network. The enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits. Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.}, } @article {pmid39071287, year = {2024}, author = {Tchounwou, C and Jobanputra, AJ and Lasher, D and Fletcher, BJ and Jacinto, J and Bhaduri, A and Best, RL and Fisher, WS and Ewert, KK and Li, Y and Feinstein, SC and Safinya, CR}, title = {Mixtures of Intrinsically Disordered Neuronal Protein Tau and Anionic Liposomes Reveal Distinct Anionic Liposome-Tau Complexes Coexisting with Tau Liquid-Liquid Phase Separated Coacervates.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39071287}, issn = {2692-8205}, support = {R01 NS035010/NS/NINDS NIH HHS/United States ; }, abstract = {Tau, an intrinsically disordered neuronal protein and polyampholyte with an overall positive charge, is a microtubule (MT) associated protein, which binds to anionic domains of MTs and suppresses their dynamic instability. Aberrant tau-MT interactions are implicated in Alzheimer's and other neurodegenerative diseases. Here, we studied the interactions between full length human protein tau and other negatively charged binding substrates, as revealed by differential-interference-contrast (DIC) and fluorescence microscopy. As a binding substrate, we chose anionic liposomes (ALs) containing either 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS, -1e) or 1,2-dioleoyl-sn-glycero-3-phosphatidylglycerol (DOPG, -1e) mixed with zwitterionic 1,2dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) to mimic anionic plasma membranes of axons where tau resides. At low salt concentrations (0 to 10 mM KCl or NaCl) with minimal charge screening, reaction mixtures of tau and ALs resulted in the formation of distinct states of AL-tau complexes coexisting with liquid-liquid phase separated tau self-coacervates arising from the polyampholytic nature of tau containing cationic and anionic domains. AL-tau complexes exhibited distinct types of morphologies. This included, large ≈20-30 micron tau-decorated giant vesicles with additional smaller liposomes with bound tau attached to the giant vesicles, and tau-mediated finite-size assemblies of small liposomes. As the ionic strength of the solution was increased to near and above physiological salt concentrations for 1:1 electrolytes (≈150 mM), AL-tau complexes remained stable while tau self-coacervate droplets were found to dissolve indicative of breaking of (anionic/cationic) electrostatic bonds between tau chains due to increased charge screening. The findings are consistent with the hypothesis that distinct cationic domains of tau may interact with anionic lipid domains of the lumen facing monolayer of the axon plasma membrane suggesting the possibility of transient yet robust interactions at physiologically relevant ionic strengths.}, } @article {pmid39070547, year = {2024}, author = {Kannan, A and Gangadharan Leela, S and Branzei, D and Gangwani, L}, title = {Role of senataxin in R-loop-mediated neurodegeneration.}, journal = {Brain communications}, volume = {6}, number = {4}, pages = {fcae239}, pmid = {39070547}, issn = {2632-1297}, support = {R01 NS115834/NS/NINDS NIH HHS/United States ; }, abstract = {Senataxin is an RNA:DNA helicase that plays an important role in the resolution of RNA:DNA hybrids (R-loops) formed during transcription. R-loops are involved in the regulation of biological processes such as immunoglobulin class switching, gene expression and DNA repair. Excessive accumulation of R-loops results in DNA damage and loss of genomic integrity. Senataxin is critical for maintaining optimal levels of R-loops to prevent DNA damage and acts as a genome guardian. Within the nucleus, senataxin interacts with various RNA processing factors and DNA damage response and repair proteins. Senataxin interactors include survival motor neuron and zinc finger protein 1, with whom it co-localizes in sub-nuclear bodies. Despite its ubiquitous expression, mutations in senataxin specifically affect neurons and result in distinct neurodegenerative diseases such as amyotrophic lateral sclerosis type 4 and ataxia with oculomotor apraxia type 2, which are attributed to the gain-of-function and the loss-of-function mutations in senataxin, respectively. In addition, low levels of senataxin (loss-of-function) in spinal muscular atrophy result in the accumulation of R-loops causing DNA damage and motor neuron degeneration. Senataxin may play multiple functions in diverse cellular processes; however, its emerging role in R-loop resolution and maintenance of genomic integrity is gaining attention in the field of neurodegenerative diseases. In this review, we highlight the role of senataxin in R-loop resolution and its potential as a therapeutic target to treat neurodegenerative diseases.}, } @article {pmid39069396, year = {2024}, author = {Codron, P and Millecamps, S and Corcia, P}, title = {EVolution in ALS diagnosis: molecular markers in extracellular vesicles.}, journal = {Trends in molecular medicine}, volume = {30}, number = {12}, pages = {1097-1099}, doi = {10.1016/j.molmed.2024.07.006}, pmid = {39069396}, issn = {1471-499X}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/metabolism/genetics ; Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {The identification of biomarkers for amyotrophic lateral sclerosis (ALS) is a central issue in disease research. In a recent article, Chatterjee et al. show that blood extracellular vesicles (EVs) with high levels of transactive response DNA-binding protein 43 (TDP-43) accurately discriminate patients with ALS from controls and correlate with disease severity, providing a promising biomarker for early diagnosis and monitoring.}, } @article {pmid39069095, year = {2024}, author = {Ho, PC and Hsieh, TC and Tsai, KJ}, title = {TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: From pathomechanisms to therapeutic strategies.}, journal = {Ageing research reviews}, volume = {100}, number = {}, pages = {102441}, doi = {10.1016/j.arr.2024.102441}, pmid = {39069095}, issn = {1872-9649}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics/therapy ; *Frontotemporal Lobar Degeneration/metabolism/pathology/therapy/genetics ; *TDP-43 Proteinopathies/metabolism/pathology/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; Autophagy/physiology ; }, abstract = {Proteostasis failure is a common pathological characteristic in neurodegenerative diseases. Revitalizing clearance systems could effectively mitigate these diseases. The transactivation response (TAR) DNA-binding protein 43 (TDP-43) plays a critical role as an RNA/DNA-binding protein in RNA metabolism and synaptic function. Accumulation of TDP-43 aggregates in the central nervous system is a hallmark of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Autophagy, a major and highly conserved degradation pathway, holds the potential for degrading aggregated TDP-43 and alleviating FTLD/ALS. This review explores the causes of TDP-43 aggregation, FTLD/ALS-related genes, key autophagy factors, and autophagy-based therapeutic strategies targeting TDP-43 proteinopathy. Understanding the underlying pathological mechanisms of TDP-43 proteinopathy can facilitate therapeutic interventions.}, } @article {pmid39068922, year = {2024}, author = {Srivastava, K and Arshad, F and Mujawar, WJ and Cranberg, L and Rajeshwaran, J and Afsar, M and Thanissery, N and Desai, V and Keerthana, BS and Shubhangi, B and Vengalil, S and Nashi, S and Baskar, D and Polavarapu, K and Preethish-Kumar, V and Alladi, S and Nalini, A}, title = {Cognitive and Behavioral Profile of Patients with Amyotrophic Lateral Sclerosis Spectrum in the Indian Context.}, journal = {Dementia and geriatric cognitive disorders}, volume = {53}, number = {6}, pages = {310-320}, doi = {10.1159/000540018}, pmid = {39068922}, issn = {1421-9824}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; Female ; Middle Aged ; India/epidemiology ; *Frontotemporal Dementia/psychology ; *Neuropsychological Tests ; *Cognitive Dysfunction/psychology ; Aged ; Cognition/physiology ; Adult ; Executive Function ; Case-Control Studies ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is characterized by motor, cognitive, and behavioral impairment. There is a paucity of evidence about the cognitive/behavioral features of ALS patients from India. We aimed to investigate the cognitive/behavioral profile of ALS spectrum disorders in the Indian context.

METHODS: Sixty patients with ALS spectrum and 40 age-, gender-, and education-matched healthy controls were recruited. The scales used were Addenbrooke's Cognitive Examination (ACE-III), Clinical Dementia Rating (CDR) scale, and Frontal Systems Behavior (FrSBe) Scale.

RESULTS: The mean age of the overall cohort was 55 years, and male-to-female ratio was 2.5:1. The mean duration of illness of the cohort was 16 months. Patients were classified as ALS with normal cognition (ALS-cn, n = 21), mild cognitive or behavioral deficits (ALS-ci/-bi, n = 28), and frontotemporal dementia (ALS-FTD, n = 11). ALS-cn had poorer scores compared to healthy controls in global cognition, memory, and language (p < 0.05). ALS-ci/-bi performed poorer than healthy controls on all cognitive domains (p < 0.05). ALS-FTD had poorer scores than healthy controls and ALS-cn on all cognitive domains (p < 0.001). Behavioral assessment showed an increase in apathy among all subtypes. ALS-FTD showed significant worsening in disinhibition and executive function compared to ALS-cn and ALS-ci/-bi.

CONCLUSION: Our findings suggest that there are key cognitive and behavior characteristics in Indian patients with ALS spectrum. This further strengthens the evidence of a cognitive continuum in ALS and FTD in a diverse context and highlights the importance of meticulous evaluation and correct diagnosis that would assist in better management.}, } @article {pmid39067491, year = {2024}, author = {Cheung, SW and Willis, EF and Simmons, DG and Bellingham, MC and Noakes, PG}, title = {Phagocytosis of aggrecan-positive perineuronal nets surrounding motor neurons by reactive microglia expressing MMP-9 in TDP-43[Q331K] ALS model mice.}, journal = {Neurobiology of disease}, volume = {200}, number = {}, pages = {106614}, doi = {10.1016/j.nbd.2024.106614}, pmid = {39067491}, issn = {1095-953X}, mesh = {Animals ; Mice ; *Aggrecans/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Disease Models, Animal ; DNA-Binding Proteins/metabolism/genetics ; *Matrix Metalloproteinase 9/metabolism ; Mice, Transgenic ; *Microglia/metabolism ; *Motor Neurons/metabolism/pathology ; *Phagocytosis/physiology ; Spinal Cord/metabolism/pathology ; }, abstract = {Perineuronal nets (PNNs) are extracellular matrix structures that surround excitable neurons and their proximal dendrites. PNNs play an important role in neuroprotection against oxidative stress. Oxidative stress within motor neurons can act as a trigger for neuronal death, and this has been implicated in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). We therefore characterised PNNs around alpha motor neurons and the possible contributing cellular factors in the mutant TDP-43[Q331K] transgenic mouse, a slow onset ALS mouse model. PNNs around alpha motor neurons showed significant loss at mid-stage disease in TDP-43[Q331K] mice compared to wild type strain control mice. PNN loss coincided with an increased expression of matrix metallopeptidase-9 (MMP-9), an endopeptidase known to cleave PNNs, within the ventral horn. During mid-stage disease, increased numbers of microglia and astrocytes expressing MMP-9 were present in the ventral horn of TDP-43[Q331K] mice. In addition, TDP-43[Q331K] mice showed increased levels of aggrecan, a PNN component, in the ventral horn by microglia and astrocytes during this period. Elevated aggrecan levels within glia were accompanied by an increase in fractalkine expression, a chemotaxic protein responsible for the recruitment of microglia, in alpha motor neurons of onset and mid-stage TDP-43[Q331K] mice. Following PNN loss, alpha motor neurons in mid-stage TDP-43[Q331K] mice showed increased 3-nitrotyrosine expression, an indicator of protein oxidation. Together, our observations along with previous PNN research provide suggests a possible model whereby microglia and astrocytes expressing MMP-9 degrade PNNs surrounding alpha motor neurons in the TDP-43[Q331K] mouse. This loss of nets may expose alpha-motor neurons to oxidative damage leading to degeneration of the alpha motor neurons in the TDP-43[Q331K] ALS mouse model.}, } @article {pmid39066921, year = {2024}, author = {Guarnaccia, M and Morello, G and La Cognata, V and La Bella, V and Conforti, FL and Cavallaro, S}, title = {Increased copy-number variant load of associated risk genes in sporadic cases of amyotrophic lateral sclerosis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {316}, pmid = {39066921}, issn = {1420-9071}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *DNA Copy Number Variations/genetics ; Female ; *Genetic Predisposition to Disease ; Middle Aged ; Male ; Aged ; Risk Factors ; Polymorphism, Single Nucleotide ; Adult ; Case-Control Studies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disease characterized by selective loss of motor neurons in the brainstem and spinal cord. Several genetic factors have been associated to ALS, ranging from causal genes and potential risk factors to disease modifiers. The search for pathogenic variants in these genes has mostly focused on single nucleotide variants (SNVs) while relatively understudied and not fully elucidated is the contribution of structural variants, such as copy number variations (CNVs). Here, we applied an exon-centric aCGH method to investigate, in sporadic ALS patients, the load of CNVs in 131 genes previously associated to ALS. Our approach revealed that CNV load, defined as the total number of CNVs or their size, was significantly higher in ALS cases than controls. About 87% of patients harbored multiple CNVs in ALS-related genes, and 75% structural variants compromised genes directly implicated in ALS pathogenesis (C9orf72, CHCHD10, EPHA4, FUS, HNRNPA1, KIF5A, NEK1, OPTN, PFN1, SOD1, TARDBP, TBK1, UBQLN2, UNC13A, VAPB, VCP). CNV load was also associated to higher onset age and disease progression rate. Although the contribution of individual CNVs in ALS is still unknown, their extensive load in disease-related genes may have relevant implications for the diagnostic, prognostic and therapeutical management of this devastating disorder.}, } @article {pmid39066735, year = {2024}, author = {Reis, PVM and Vargas, BS and Rebelo, RA and Massafera, MP and Prado, FM and Oreliana, H and de Oliveira, HV and Freitas, FP and Ronsein, GE and Miyamoto, S and Di Mascio, P and Medeiros, MHG}, title = {Quantitative Analysis of Glutathione and Carnosine Adducts with 4-Hydroxy-2-nonenal in Muscle in a hSOD1[G93A] ALS Rat Model.}, journal = {Chemical research in toxicology}, volume = {37}, number = {8}, pages = {1306-1314}, pmid = {39066735}, issn = {1520-5010}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Aldehydes/metabolism/chemistry ; *Carnosine/metabolism ; *Glutathione/metabolism ; Rats ; *Disease Models, Animal ; Muscle, Skeletal/metabolism ; Humans ; Superoxide Dismutase/metabolism ; Male ; Chromatography, High Pressure Liquid ; Rats, Transgenic ; Superoxide Dismutase-1/metabolism ; Rats, Sprague-Dawley ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the dysfunction and death of motor neurons through multifactorial mechanisms that remain unclear. ALS has been recognized as a multisystemic disease, and the potential role of skeletal muscle in disease progression has been investigated. Reactive aldehydes formed as secondary lipid peroxidation products in the redox processes react with biomolecules, such as DNA, proteins, and amino acids, resulting in cytotoxic effects. 4-Hydroxy-2-nonenal (HNE) levels are elevated in the spinal cord motor neurons of ALS patients, and HNE-modified proteins have been identified in the spinal cord tissue of an ALS transgenic mice model, suggesting that reactive aldehydes can contribute to motor neuron degeneration in ALS. One biological pathway of aldehyde detoxification involves conjugation with glutathione (GSH) or carnosine (Car). Here, the detection and quantification of Car, GSH, GSSG (glutathione disulfide), and the corresponding adducts with HNE, Car-HNE, and GS-HNE, were performed in muscle and liver tissues of a hSOD1[G93A] ALS rat model by reverse-phase high-performance liquid chromatography coupled to electrospray ion trap tandem mass spectrometry in the selected reaction monitoring mode. A significant increase in the levels of GS-HNE and Car-HNE was observed in the muscle tissue of the end-stage ALS animals. Therefore, analyzing variations in the levels of these adducts in ALS animal tissue is crucial from a toxicological perspective and can contribute to the development of new therapeutic strategies.}, } @article {pmid39065892, year = {2024}, author = {Liu, K and Guan, X and Ren, X and Wu, J}, title = {Disciplining a Rubidium Atomic Clock Based on Adaptive Kalman Filter.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {14}, pages = {}, pmid = {39065892}, issn = {1424-8220}, abstract = {Rubidium atomic clocks have been used extensively in various fields, with applications such as a core component of Global Navigation Satellite Systems (GNSS). However, they exhibit inherently poor long-term stability. This paper presents the development of a control system for rubidium atomic clocks. It introduces an adaptive Kalman filtering algorithm for the disciplining of a rubidium atomic clock, utilizing autocovariance least squares (ALS) to estimate the clock's noise parameters. The experimental results demonstrate that the proposed algorithm achieves a high estimation accuracy. The standard deviation of the clock error between the steered rubidium atomic clock 1 Pulse Per Second (1PPS) and Coordinated Universal Time (UTC) provided by the National Time Service Center (NTSC) is better than 2.568 nanoseconds(ns), with peak-to-peak values improving to within 11.358 ns. Notably, its frequency stability is reduced to 3.06 × 10[-13] @100,000 s. The results for the rubidium atomic clock demonstrate that the adaptive Kalman filtering algorithm proposed herein constitutes an accurate and effective control strategy for the rubidium atomic clock discipline.}, } @article {pmid39063341, year = {2024}, author = {Lagrange, E and Vernoux, JP and Chambon, C and Camu, W and Spencer, PS}, title = {Cramp-Fasciculation Syndrome Associated with Natural and Added Chemicals in Popular Food Items.}, journal = {Foods (Basel, Switzerland)}, volume = {13}, number = {14}, pages = {}, pmid = {39063341}, issn = {2304-8158}, abstract = {Cramp-fasciculation syndrome (CFS) is a rare and benign neuromuscular disorder that may initially masquerade as motor neuron disease/amyotrophic lateral sclerosis. While CFS may have a familial disposition, we report on cases associated with high consumption of popular food items. One set of patients reversibly experienced acute onset of headache, flushing, muscle stiffness and fasciculations following the consumption of umami-flavored food containing a large concentration of monosodium glutamate. A second group of patients consuming food derived from lupin seed developed acute cholinergic toxicity, CFS, and, with chronic intake, significant, self-limiting, but incompletely reversible upper and lower motor neuron deficits. While these cases may improve our knowledge about the possible causes of CFS, our series also demonstrates that excessive consumption of some popular foods is not harmless. This warrants further research on their safety at all stages of human development from a neurological point of view.}, } @article {pmid39063053, year = {2024}, author = {Alanazi, N and Fitzgerald, M and Hume, P and Hellewell, S and Horncastle, A and Anyaegbu, C and Papini, MG and Hargreaves, N and Halicki, M and Entwistle, I and Hind, K and Chazot, P}, title = {Concussion-Related Biomarker Variations in Retired Rugby Players and Implications for Neurodegenerative Disease Risk: The UK Rugby Health Study.}, journal = {International journal of molecular sciences}, volume = {25}, number = {14}, pages = {}, pmid = {39063053}, issn = {1422-0067}, mesh = {Humans ; *Biomarkers/blood ; Male ; *Brain Concussion/blood/epidemiology ; Middle Aged ; United Kingdom/epidemiology ; *Retirement ; *Football/injuries ; Adult ; *Athletes ; *Neurodegenerative Diseases/blood/epidemiology/etiology ; Rugby ; tau Proteins/blood ; Risk Factors ; Retinol-Binding Proteins, Plasma/metabolism ; Athletic Injuries/blood/epidemiology ; }, abstract = {The health and well-being of retired rugby union and league players, particularly regarding the long-term effects of concussions, are of major concern. Concussion has been identified as a major risk factor for neurodegenerative diseases, such as Alzheimer's and Amyotrophic Lateral Sclerosis (ALS), in athletes engaged in contact sports. This study aimed to assess differences in specific biomarkers between UK-based retired rugby players with a history of concussion and a non-contact sports group, focusing on biomarkers associated with Alzheimer's, ALS, and CTE. We randomly selected a sample of male retired rugby or non-contact sport athletes (n = 56). The mean age was 41.84 ± 6.44, and the mean years since retirement from the sport was 7.76 ± 6.69 for participants with a history of substantial concussions (>5 concussions in their career) (n = 30). The mean age was 45.75 ± 11.52, and the mean years since retirement was 6.75 ± 4.64 for the healthy controls (n = 26). Serum biomarkers (t-tau, RBP-4, SAA, Nf-L, and retinol), plasma cytokines, and biomarkers associated with serum-derived exosomes (Aβ42, p-tau181, p-tau217, and p-tau231) were analyzed using validated commercial ELISA assays. The results of the selected biomarkers were compared between the two groups. Biomarkers including t-tau and p-tau181 were significantly elevated in the history of the substantial concussion group compared to the non-contact sports group (t-tau: p < 0.01; p-tau181: p < 0.05). Although between-group differences in p-tau217, p-tau231, SAA, Nf-L, retinol, and Aβ42 were not significantly different, there was a trend for higher levels of Aβ42, p-tau217, and p-tau231 in the concussed group. Interestingly, the serum-derived exosome sizes were significantly larger (p < 0.01), and serum RBP-4 levels were significantly reduced (p < 0.05) in the highly concussed group. These findings indicate that retired athletes with a history of multiple concussions during their careers have altered serum measurements of exosome size, t-tau, p-tau181, and RBP-4. These biomarkers should be explored further for the prediction of future neurodegenerative outcomes, including ALS, in those with a history of concussion.}, } @article {pmid39062967, year = {2024}, author = {Kisielewska, M and Filipski, M and Sebastianka, K and Karaś, D and Molik, K and Choromańska, A}, title = {Investigation into the Neuroprotective and Therapeutic Potential of Plant-Derived Chk2 Inhibitors.}, journal = {International journal of molecular sciences}, volume = {25}, number = {14}, pages = {}, pmid = {39062967}, issn = {1422-0067}, mesh = {*Checkpoint Kinase 2/metabolism/antagonists & inhibitors ; Humans ; Animals ; Protein Kinase Inhibitors/pharmacology/therapeutic use/chemistry ; Neuroprotective Agents/pharmacology/therapeutic use ; Neoplasms/drug therapy ; DNA Damage/drug effects ; DNA Repair/drug effects ; }, abstract = {Nature provides us with a rich source of compounds with a wide range of applications, including the creation of innovative drugs. Despite advancements in chemically synthesized therapeutics, natural compounds are increasingly significant, especially in cancer treatment, a leading cause of death globally. One promising approach involves the use of natural inhibitors of checkpoint kinase 2 (Chk2), a critical regulator of DNA repair, cell cycle arrest, and apoptosis. Chk2's activation in response to DNA damage can lead to apoptosis or DNA repair, influencing glycolysis and mitochondrial function. In cancer therapy, inhibiting Chk2 can disrupt DNA repair and cell cycle progression, promoting cancer cell death and enhancing the efficacy of radiotherapy and chemotherapy. Additionally, Chk2 inhibitors can safeguard non-cancerous cells during these treatments by inhibiting p53-dependent apoptosis. Beyond oncology, Chk2 inhibition shows potential in treating hepatitis C virus (HCV) infections, as the virus relies on Chk2 for RNA replication in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), in which DNA damage plays a crucial role. Plant-derived Chk2 inhibitors, such as artemetin, rhamnetin, and curcumin, offer a promising future for treating various diseases with potentially milder side effects and broader metabolic impacts compared to conventional therapies. The review aims to underscore the immense potential of natural Chk2 inhibitors in various therapeutic contexts, particularly in oncology and the treatment of other diseases involving DNA damage and repair mechanisms. These natural Chk2 inhibitors hold significant promise for revolutionizing the landscape of cancer treatment and other diseases. Further research into these compounds could lead to the development of innovative therapies that offer hope for the future with fewer side effects and enhanced efficacy.}, } @article {pmid39062592, year = {2024}, author = {Gao, J and Sterling, E and Hankin, R and Sikal, A and Yao, Y}, title = {Therapeutics Targeting Skeletal Muscle in Amyotrophic Lateral Sclerosis.}, journal = {Biomolecules}, volume = {14}, number = {7}, pages = {}, pmid = {39062592}, issn = {2218-273X}, support = {W81XWH2210261//United States Department of Defense/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/therapy ; Humans ; *Muscle, Skeletal/metabolism/pathology ; Animals ; Neuromuscular Junction/metabolism/pathology ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neuromuscular disease characterized by progressive motor neuron degeneration, neuromuscular junction dismantling, and muscle wasting. The pathological and therapeutic studies of ALS have long been neurocentric. However, recent insights have highlighted the significance of peripheral tissue, particularly skeletal muscle, in disease pathology and treatment. This is evidenced by restricted ALS-like muscle atrophy, which can retrogradely induce neuromuscular junction and motor neuron degeneration. Moreover, therapeutics targeting skeletal muscles can effectively decelerate disease progression by modulating muscle satellite cells for muscle repair, suppressing inflammation, and promoting the recovery or regeneration of the neuromuscular junction. This review summarizes and discusses therapeutic strategies targeting skeletal muscles for ALS treatment. It aims to provide a comprehensive reference for the development of novel therapeutics targeting skeletal muscles, potentially ameliorating the progression of ALS.}, } @article {pmid39061876, year = {2024}, author = {Magalhães, RSS and Monteiro Neto, JR and Ribeiro, GD and Paranhos, LH and Eleutherio, ECA}, title = {Trehalose Protects against Superoxide Dismutase 1 Proteinopathy in an Amyotrophic Lateral Sclerosis Model.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {7}, pages = {}, pmid = {39061876}, issn = {2076-3921}, support = {PROBRAL 88881.371325/2019-01//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)/ ; CNE 201.174/2022 and Posdoc Nota 10 202.267/2019//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; Universal 401780/2023-6//National Council for Scientific and Technological Development/ ; }, abstract = {This work aimed to study the effect of trehalose in protecting cells against Sod1 proteinopathy associated with amyotrophic lateral sclerosis (ALS). Humanized yeast cells in which native Sod1 was replaced by wild-type human Sod1 or an ALS mutant (WT-A4V Sod1 heterodimer) were used as the experimental model. Cells were treated with 10% trehalose (p/v) before or after the appearance of hSod1 proteinopathy induced by oxidative stress. In both conditions, trehalose reduced the number of cells with Sod1 inclusions, increased Sod1 activity, and decreased the levels of intracellular oxidation, demonstrating that trehalose avoids Sod1 misfolding and loss of function in response to oxidative stress. The survival rates of ALS Sod1 cells stressed in the presence of trehalose were 60% higher than in their absence. Treatment with trehalose after the appearance of Sod1 inclusions in cells expressing WT Sod1 doubled longevity; after 5 days, non-treated cells did not survive, but 15% of cells treated with sugar were still alive. Altogether, our results emphasize the potential of trehalose as a novel therapy, which might be applied preventively in ALS patients with a family history of the disease or after diagnosis in ALS patients who discover the disease following the first symptoms.}, } @article {pmid39061402, year = {2024}, author = {Correia, JP and Gromicho, M and Pronto-Laborinho, AC and Oliveira Santos, M and de Carvalho, M}, title = {Creatine Kinase and Respiratory Decline in Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {14}, number = {7}, pages = {}, pmid = {39061402}, issn = {2076-3425}, abstract = {Respiratory dysfunction is an important hallmark of amyotrophic lateral sclerosis (ALS). Elevation of creatine kinase (CK) has been reported in 23-75% of ALS patients, but the underlying mechanisms remain unknown. This work aims to enlighten the role of CK as a prognostic factor of respiratory dysfunction in ALS. A retrospective analysis of demographic and clinical variables, CK, functional decline per month (ΔFS), forced vital capacity (%FVC), and mean amplitude of the phrenic nerve compound motor action potential (pCMAP) in 319 ALS patients was conducted. These measurements were evaluated at study entry, and patients were followed from the moment of first observation until death or last follow-up visit. High CK values were defined as above the 90th percentile (CK ≥ P90) adjusted to sex. We analyzed survival and time to non-invasive ventilation (NIV) as proxies for respiratory impairment. Linear regression analysis revealed that high CK was associated with male sex (p < 0.001), spinal onset (p = 0.018), and FVC ≥ 80% (p = 0.038). CK was 23.4% higher in spinal-onset ALS patients (p < 0.001). High CK levels were not linked with an increased risk of death (p = 0.334) in Cox multivariate regression analysis. CK ≥ P90 (HR = 1.001, p = 0.038), shorter disease duration (HR = 0.937, p < 0.001), lower pCMAP (HR = 0.082, p < 0.001), and higher ΔFS (HR = 1.968, p < 0.001) were risk factors for respiratory failure. The association between high CK levels and poorer respiratory outcomes could derive from cellular metabolic stress or a specific phenotype associated with faster respiratory decline. Our study suggests that CK measurement at diagnosis should be more extensively investigated as a possible marker of poor respiratory outcome in future studies, including a larger population of patients.}, } @article {pmid39060907, year = {2025}, author = {Asai, Y and Yano, K and Higashino, T and Yoshihara, D and Sakiyama, H and Eguchi, H and Fukushima, K and Suzuki, K and Fujiwara, N}, title = {The Ile35 Residue of the ALS-Associated Mutant SOD1 Plays a Crucial Role in the Intracellular Aggregation of the Molecule.}, journal = {Molecular neurobiology}, volume = {62}, number = {2}, pages = {2023-2038}, pmid = {39060907}, issn = {1559-1182}, support = {22K11870//Japan Society for the Promotion of Science/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; Humans ; *Mutation/genetics ; Green Fluorescent Proteins/metabolism ; Protein Aggregates ; Animals ; Intracellular Space/metabolism ; Mutant Proteins/metabolism ; Amino Acid Sequence ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an unknown pathogenesis. It has been reported that mutations in the gene for Cu/Zn superoxide dismutase (SOD1) cause familial ALS. Mutant SOD1 undergoes aggregation and forms amyloid more easily, and SOD1-immunopositive inclusions have been observed in the spinal cords of ALS patients. Because of this, SOD1 aggregation is thought to be related to the pathogenesis of ALS. Some core regions of amyloid have been identified, but the issue of whether these regions form aggregates in living cells remains unclear, and the mechanism responsible for intracellular SOD1 aggregation also remains unclear. The findings reported in this study indicate that the aggregation of the ALS-linked mutant SOD1-EGFP was significantly enhanced when the BioID2 gene was fused to the N-terminus of the mutant SOD1-EGFP plasmid for cellular expression. Expression of a series of BioID2-(C-terminal deletion peptides of SOD1)-EGFP permitted us to identify 1-35 as a minimal N-terminal sequence and Ile35 as an essential amino acid residue that contributes to the intracellular aggregation of SOD1. The findings also showed that an additional substitution of Ile35 with Ser into the ALS mutant SOD1 resulted in the significant suppression of aggregate formation. The fact that no Ile35 mutations have been reported to date in ALS patients indicates that all ALS mutant SOD1s contain Ile35. Taken together, we propose that Ile35 plays a pivotal role in the aggregation of the ALS-linked SOD1 and that this study will contribute to our understanding of the mechanism responsible for SOD1 aggregation.}, } @article {pmid39060854, year = {2024}, author = {Raymond, J and Nair, T and Gwathmey, KG and Larson, T and Horton, DK and Mehta, P}, title = {Racial Disparities in the Diagnosis and Prognosis of ALS Patients in the United States.}, journal = {Journal of racial and ethnic health disparities}, volume = {}, number = {}, pages = {}, pmid = {39060854}, issn = {2196-8837}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease with largely unknown etiology. This study compares racial differences in clinical characteristics of ALS patients enrolled in the National ALS Registry (Registry).

METHODS: Data from ALS patients who completed the Registry's online clinical survey during 2013-2022 were analyzed to determine characteristics such as site of onset, associated symptoms, time of symptom onset to diagnosis, and pharmacological and non-pharmacological interventions for White, Black, and other race patients.

RESULTS: Surveys were completed by 4242 participants. Findings revealed that Black ALS patients were more likely to be diagnosed at a younger age, to have arm or hand initial site of onset, and to experience pneumonia than were White ALS patients. ALS patients of other races were more likely than White ALS patients to be diagnosed at a younger age and to experience twitching. The mean interval between the first sign of weakness and an ALS diagnosis for Black patients was almost 24 months, statistically greater than that of White (p = 0.0374; 16 months) and other race patients (p = 0.0518; 15.8 months). The mean interval between problems with speech until diagnosis was shorter for White patients (6.3 months) than for Black patients (17.7 months) and other race patients (14.8 months).

CONCLUSIONS AND RELEVANCE: Registry data shows racial disparities still exist in the diagnosis and clinical characteristics of ALS patients. Increased recruitment of non-White ALS patients and better characterization of symptom onset between races might aid clinicians in diagnosing ALS sooner, leading to earlier therapeutic interventions.}, } @article {pmid39060317, year = {2024}, author = {Wu, J and Zhang, G and Zhang, L and Ye, S and Huang, T and Fan, D}, title = {The integrity of the corticospinal tract and corpus callosum, and the risk of ALS: univariable and multivariable Mendelian randomization.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {17216}, pmid = {39060317}, issn = {2045-2322}, support = {81873784//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/pathology ; *Mendelian Randomization Analysis ; *Pyramidal Tracts/diagnostic imaging/pathology ; *Corpus Callosum/diagnostic imaging/pathology ; *Genome-Wide Association Study ; Risk Factors ; Male ; Female ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; White Matter/diagnostic imaging/pathology ; Diffusion Magnetic Resonance Imaging ; Anisotropy ; }, abstract = {Studies suggest that amyotrophic lateral sclerosis (ALS) compromises the integrity of white matter fiber tracts, primarily affecting motor fibers. However, it remains uncertain whether the integrity of these fibers influences the risk of ALS. We performed bidirectional two-sample Mendelian randomization (MR) and multivariable MR analyses to evaluate the associative relationships between the integrity of fiber tracts [including the corticospinal tract (CST) and corpus callosum (CC)] and the risk of ALS. Genetic instrumental variables for specific fiber tracts were obtained from published genome-wide association studies (GWASs), including 33,292 European individuals from five diffusion magnetic resonance imaging (dMRI) datasets. Summary-level GWAS data for ALS were derived from 27,205 ALS patients and 110,881 controls. The MR results suggested that an increase in the first principal component (PC1) of fractional anisotropy (FA) in the genu of the CC (GCC) was correlated with an increased risk of ALS (PFDR = 0.001, odds ratio = 1.363, 95% confidence interval 1.178-1.577). Although other neuroimaging phenotypes [mean diffusivity in the CST, radial diffusivity (RD) in the CST, FA in the GCC, PC1 in the body of the CC (BCC), PC1 in the CST, and RD in the GCC] did not pass correction, they were also considered to have suggestive associations with the risk of ALS. No evidence revealed that ALS caused changes in the integrity of fiber tracts. In summary, the results of this study provide genetic support for the potential association between the integrity of specific fiber tracts and the risk of ALS. Greater fiber integrity in the GCC and BCC may be a risk factor for ALS, while greater fiber integrity in the CST may have a protective effect on ALS. This study provides insights into ALS development.}, } @article {pmid39060265, year = {2024}, author = {Doi, H and Kageyama, I and Katoh-Fukui, Y and Hattori, A and Fukami, M and Shimura, N}, title = {Homozygous 6-bp deletion of IGFALS in a prepubertal boy with short stature.}, journal = {Human genome variation}, volume = {11}, number = {1}, pages = {27}, pmid = {39060265}, issn = {2054-345X}, abstract = {Biallelic IGFALS variants lead to acid‒labile subunit (ALS) deficiency characterized by growth hormone resistance with or without delayed puberty. Here, we report a prepubertal boy with a homozygous 2-amino acid deletion within the fourth N-glycosylation motif (c.1103_1108del, p.N368_S370delinsT) associated with parental consanguinity. He showed short stature consistent with ALS deficiency. This case expands the mutation spectrum of IGFALS to include the elimination of only one N-glycosylation motif of ALS.}, } @article {pmid39059442, year = {2024}, author = {Kilim, O and Báskay, J and Biricz, A and Bedőházi, Z and Pollner, P and Csabai, I}, title = {Transfer learning may explain pigeons' ability to detect cancer in histopathology.}, journal = {Bioinspiration & biomimetics}, volume = {19}, number = {5}, pages = {}, doi = {10.1088/1748-3190/ad6825}, pmid = {39059442}, issn = {1748-3190}, mesh = {Animals ; *Columbidae/physiology ; *Neoplasms/pathology/diagnostic imaging ; *Neural Networks, Computer ; Machine Learning ; Flight, Animal/physiology ; }, abstract = {Pigeons' unexpected competence in learning to categorize unseen histopathological images has remained an unexplained discovery for almost a decade (Levensonet al2015PLoS One10e0141357). Could it be that knowledge transferred from their bird's-eye views of the earth's surface gleaned during flight contributes to this ability? Employing a simulation-based verification strategy, we recapitulate this biological phenomenon with a machine-learning analog. We model pigeons' visual experience during flight with the self-supervised pre-training of a deep neural network on BirdsEyeViewNet; our large-scale aerial imagery dataset. As an analog of the differential food reinforcement performed in Levensonet al's study 2015PLoS One10e0141357), we apply transfer learning from this pre-trained model to the same Hematoxylin and Eosin (H&E) histopathology and radiology images and tasks that the pigeons were trained and tested on. The study demonstrates that pre-training neural networks with bird's-eye view data results in close agreement with pigeons' performance. These results support transfer learning as a reasonable computational model of pigeon representation learning. This is further validated with six large-scale downstream classification tasks using H&E stained whole slide image datasets representing diverse cancer types.}, } @article {pmid39059407, year = {2024}, author = {van den Berg, LH and Rothstein, JD and Shaw, PJ and Babu, S and Benatar, M and Bucelli, RC and Genge, A and Glass, JD and Hardiman, O and Libri, V and Mobach, T and Oskarsson, B and Pattee, GL and Ravits, J and Shaw, CE and Weber, M and Zinman, L and Jafar-Nejad, P and Rigo, F and Lin, L and Ferguson, TA and Gotter, AL and Graham, D and Monine, M and Inra, J and Sinks, S and Eraly, S and Garafalo, S and Fradette, S}, title = {Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study.}, journal = {The Lancet. Neurology}, volume = {23}, number = {9}, pages = {901-912}, doi = {10.1016/S1474-4422(24)00216-3}, pmid = {39059407}, issn = {1474-4465}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Double-Blind Method ; *C9orf72 Protein/genetics ; *Oligonucleotides, Antisense/pharmacokinetics/administration & dosage/adverse effects/pharmacology ; Aged ; Adult ; Dose-Response Relationship, Drug ; }, abstract = {BACKGROUND: Hexanucleotide repeat expansion of C9orf72 is a common genetic cause of amyotrophic lateral sclerosis (ALS). No C9orf72-targeted treatments are available. BIIB078 is an investigational antisense oligonucleotide targeting C9orf72 sense RNA. We aimed to assess the safety, tolerability, and pharmacokinetics of BIIB078 in participants with C9orf72-associated ALS.

METHODS: This phase 1, randomised controlled trial was done at 22 sites in six countries (Canada, Ireland, Netherlands, Switzerland, UK, and USA). Adults with ALS and a pathogenic repeat expansion in C9orf72 were randomly assigned within six cohorts, via Interactive Response Technology in a 3:1 ratio per cohort, to receive BIIB078 (5 mg, 10 mg, 20 mg, 35 mg, 60 mg, or 90 mg in cohorts 1-6, respectively) or placebo, via an intrathecal bolus injection. The treatment period consisted of three loading doses of study treatment, administered approximately once every 2 weeks, followed by monthly maintenance doses during a treatment period of about 3 months for cohorts 1-3 and about 6 months for cohorts 4-6. Patients and investigators were masked to treatment assignment. The primary endpoint was the incidence of adverse events and serious adverse events. This trial was registered with ClinicalTrials.gov (NCT03626012) and is completed.

FINDINGS: Between Sept 10, 2018, and Nov 17, 2021, 124 patients were screened for inclusion in the study. 18 patients were excluded and 106 participants were enrolled and randomly assigned to receive 5 mg (n=6), 10 mg (n=9), 20 mg (n=9), 35 mg (n=19), 60 mg (n=18), or 90 mg (n=18) of BIIB078, or placebo (n=27). 58 (55%) of 106 patients were female. All patients received at least one dose of study treatment and were included in all analyses. All participants had at least one adverse event; most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. The most common adverse events in BIIB078-treated participants were falls, procedural pain, headache, and post lumbar puncture syndrome. 14 (18%) of 79 patients who received any dose of BIIB078 reported serious adverse events, compared with nine (33%) of 27 patients who received placebo. Five participants who received BIIB078 and three participants who received placebo had fatal adverse events: respiratory failure in a participant who received 10 mg BIIB078, ALS worsening in two participants who received 35 mg BIIB078, traumatic intracerebral haemorrhage in one participant who received 35 mg BIIB078, pulmonary embolism in one participant who received 60 mg BIIB078, and respiratory failure in three participants who received placebo. All deaths were assessed as not related to the study treatment by the reporting investigator.

INTERPRETATION: On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS.

FUNDING: Biogen.}, } @article {pmid39059406, year = {2024}, author = {Petri, S}, title = {Targeting C9orf72 in people with ALS.}, journal = {The Lancet. Neurology}, volume = {23}, number = {9}, pages = {850-852}, doi = {10.1016/S1474-4422(24)00284-9}, pmid = {39059406}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *C9orf72 Protein/genetics ; }, } @article {pmid39059260, year = {2024}, author = {Luo, L and Jiang, L and Chen, T and Zhao, Z and Kang, C and Chen, D and Long, Y}, title = {Analysis of spatiotemporal changes mechanism of cell wall biopolymers and monosaccharide components in kiwifruit during Botryosphaeria dothidea infection.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {322}, number = {}, pages = {124837}, doi = {10.1016/j.saa.2024.124837}, pmid = {39059260}, issn = {1873-3557}, mesh = {*Cell Wall/chemistry ; *Ascomycota/chemistry ; *Plant Diseases/microbiology ; *Monosaccharides/analysis ; *Actinidia/microbiology/chemistry ; *Spectrum Analysis, Raman/methods ; Fruit/microbiology/chemistry ; Biopolymers/chemistry/analysis ; Pectins/chemistry/metabolism ; Polysaccharides ; }, abstract = {To further reveal the interaction mechanism between plants and pathogens, this study used confocal Raman microscopy spectroscopy (CRM) combined with chemometrics to visualize the biopolymers distribution of kiwifruit cell walls at different infection stages at the cellular micro level. Simultaneously, the changes in the content of various monosaccharides in fruit were studied at the molecular level using high-performance liquid chromatography (HPLC). There were significant differences in the composition of various nutrient components in the cell wall structure of kiwifruit at different infection times after infection by Botryosphaeria dothidea. PCA could cluster samples with infection time of 0-9 d into different infection stages, and SVM was used to predict the PCA classification results, the accuracy >96 %. Multivariate curve resolution-alternating least squares (MCR-ALS) helped to identify single substance spectra and concentration signals from mixed spectral signals. The pure substance chemical imaging maps of low methylated pectin (LMP), high methylated pectin (HMP), cellulose, hemicellulose, and lignin were obtained by analyzing the resolved concentration data. The imaging results showed that the lignin content in the kiwifruit cell wall increased significantly to resist pathogens infection after the infection of B. dothidea. With the development of infection, B. dothidea decomposed various substances in the host cell walls, allowing them to penetrate the interior of fruit cells. This caused significant changes in the form, structure, and distribution of various chemicals on the fruit cell walls in time and space. HPLC showed that glucose was the main carbon source and energy substance obtained by pathogens from kiwifruit during infection. The contents of galactose and arabinose, which maintained the structure and function of the fruit cell walls, decreased significantly and the cell wall structure was destroyed in the late stage of pathogens infection. This study provided a new perspective on the cellular structure changes caused by pathogenic infection of fruit and the defense response process of fruit and provided effective references for further research on the mechanisms of host-pathogen interactions in fruit infected by pathogens.}, } @article {pmid39059072, year = {2024}, author = {Grieco, I and Bassani, D and Trevisan, L and Salmaso, V and Cescon, E and Prencipe, F and Da Ros, T and Martinez-Gonzalez, L and Martinez, A and Spalluto, G and Moro, S and Federico, S}, title = {7-Amino-[1,2,4]triazolo[1,5-a][1,3,5]triazines as CK1δ inhibitors: Exploring substitutions at the 2 and 5-positions.}, journal = {Bioorganic chemistry}, volume = {151}, number = {}, pages = {107659}, doi = {10.1016/j.bioorg.2024.107659}, pmid = {39059072}, issn = {1090-2120}, mesh = {*Protein Kinase Inhibitors/pharmacology/chemistry/chemical synthesis ; Humans ; *Casein Kinase Idelta/antagonists & inhibitors/metabolism ; Structure-Activity Relationship ; Molecular Structure ; Triazines/chemistry/pharmacology/chemical synthesis ; Dose-Response Relationship, Drug ; Triazoles/chemistry/pharmacology/chemical synthesis ; Animals ; Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Molecular Docking Simulation ; }, abstract = {CK1δ is a serine-threonine kinase involved in several pathological conditions including neuroinflammation and neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Specifically, it seems that an inhibition of CK1δ could have a neuroprotective effect in these conditions. Here, a series of [1,2,4]triazolo[1,5-a][1,3,5]triazines were developed as ATP-competitive CK1δ inhibitors. Both positions 2 and 5 have been explored leading to a total of ten compounds exhibiting IC50s comprised between 29.1 µM and 2.08 µM. Three of the four most potent compounds (IC50 < 3 µM) bear a thiophene ring at the 2 position. All compounds have been submitted to computational studies that identified the chain composed of at least 2 atoms (e.g., nitrogen and carbon atoms) at the 5 position as crucial to determine a key bidentate hydrogen bond with Leu85 of CK1δ. Most potent compounds have been tested in vitro, resulting passively permeable to the blood-brain barrier and, safe and slight neuroprotective on a neuronal cell model. These results encourage to further structural optimize the series to obtain more potent CK1δ inhibitors as possible neuroprotective agents to be tested on models of the above-mentioned neurodegenerative diseases.}, } @article {pmid39058450, year = {2024}, author = {Baumgartner, D and Mušová, Z and Zídková, J and Hedvičáková, P and Vlčková, E and Joppeková, L and Kramářová, T and Fajkusová, L and Stránecký, V and Geryk, J and Votýpka, P and Mazanec, R}, title = {Genetic Landscape of Amyotrophic Lateral Sclerosis in Czech Patients.}, journal = {Journal of neuromuscular diseases}, volume = {11}, number = {5}, pages = {1035-1048}, pmid = {39058450}, issn = {2214-3602}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Czech Republic ; Male ; Middle Aged ; Female ; *C9orf72 Protein/genetics ; Aged ; *DNA Repeat Expansion ; Adult ; *Frontotemporal Dementia/genetics ; RNA-Binding Protein FUS/genetics ; Cohort Studies ; DNA-Binding Proteins/genetics ; Protein Serine-Threonine Kinases/genetics ; Age of Onset ; Genetic Predisposition to Disease ; High-Throughput Nucleotide Sequencing ; }, abstract = {BACKGROUND: Genetic factors are involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS) and constitute a link to its association with frontotemporal dementia (FTD). Gene-targeted therapies for some forms of ALS (C9orf72, SOD1) have recently gained momentum. Genetic architecture in Czech ALS patients has not been comprehensively assessed so far.

OBJECTIVE: We aimed to deliver pilot data on the genetic landscape of ALS in our country.

METHODS: A cohort of patients with ALS (n = 88), recruited from two Czech Neuromuscular Centers, was assessed for hexanucleotide repeat expansion (HRE) in C9orf72 and also for genetic variations in other 36 ALS-linked genes via next-generation sequencing (NGS). Nine patients (10.1%) had a familial ALS. Further, we analyzed two subgroups of sporadic patients - with concomitant FTD (n = 7) and with young-onset of the disease (n = 22).

RESULTS: We detected the pathogenic HRE in C9orf72 in 12 patients (13.5%) and three other pathogenic variants in FUS, TARDBP and TBK1, each in one patient. Additional 7 novel and 9 rare known variants with uncertain causal significance have been detected in 15 patients. Three sporadic patients with FTD (42.9%) were harbouring a pathogenic variant (all HRE in C9orf72). Surprisingly, none of the young-onset sporadic patients harboured a pathogenic variant and we detected no pathogenic SOD1 variant in our cohort.

CONCLUSION: Our findings resemble those from other European populations, with the highest prevalence of HRE in the C9orf72 gene. Further, our findings suggest a possibility of a missing genetic variability among young-onset patients.}, } @article {pmid39057679, year = {2024}, author = {Parvanovova, P and Hnilicova, P and Kolisek, M and Tatarkova, Z and Halasova, E and Kurca, E and Holubcikova, S and Koprusakova, MT and Baranovicova, E}, title = {Disturbances in Muscle Energy Metabolism in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Metabolites}, volume = {14}, number = {7}, pages = {}, pmid = {39057679}, issn = {2218-1989}, support = {1/0371/21//VEGA/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease type of motor neuron disorder characterized by degeneration of the upper and lower motor neurons resulting in dysfunction of the somatic muscles of the body. The ALS condition is manifested in progressive skeletal muscle atrophy and spasticity. It leads to death, mostly due to respiratory failure. Within the pathophysiology of the disease, muscle energy metabolism seems to be an important part. In our study, we used blood plasma from 25 patients with ALS diagnosed by definitive El Escorial criteria according to ALSFR-R (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) criteria and 25 age and sex-matched subjects. Aside from standard clinical biochemical parameters, we used the NMR (nuclear magnetic resonance) metabolomics approach to determine relative plasma levels of metabolites. We observed a decrease in total protein level in blood; however, despite accelerated skeletal muscle catabolism characteristic for ALS patients, we did not detect changes in plasma levels of essential amino acids. When focused on alterations in energy metabolism within muscle, compromised creatine uptake was accompanied by decreased plasma creatinine. We did not observe changes in plasma levels of BCAAs (branched chain amino acids; leucine, isoleucine, valine); however, the observed decrease in plasma levels of all three BCKAs (branched chain alpha-keto acids derived from BCAAs) suggests enhanced utilization of BCKAs as energy substrate. Glutamine, found to be increased in blood plasma in ALS patients, besides serving for ammonia detoxification, could also be considered a potential TCA (tricarboxylic acid) cycle contributor in times of decreased pyruvate utilization. When analyzing the data by using a cross-validated Random Forest algorithm, it finished with an AUC of 0.92, oob error of 8%, and an MCC (Matthew's correlation coefficient) of 0.84 when relative plasma levels of metabolites were used as input variables. Although the discriminatory power of the system used was promising, additional features are needed to create a robust discriminatory model.}, } @article {pmid39056697, year = {2024}, author = {Christidi, F and Kleinerova, J and Tan, EL and Delaney, S and Tacheva, A and Hengeveld, JC and Doherty, MA and McLaughlin, RL and Hardiman, O and Siah, WF and Chang, KM and Lope, J and Bede, P}, title = {Limbic Network and Papez Circuit Involvement in ALS: Imaging and Clinical Profiles in GGGGCC Hexanucleotide Carriers in C9orf72 and C9orf72-Negative Patients.}, journal = {Biology}, volume = {13}, number = {7}, pages = {}, pmid = {39056697}, issn = {2079-7737}, support = {JPND-Cofund-2-2019-1 & HRB EIA-2017-019//HRB/ ; }, abstract = {Background: While frontotemporal involvement is increasingly recognized in Amyotrophic lateral sclerosis (ALS), the degeneration of limbic networks remains poorly characterized, despite growing evidence of amnestic deficits, impaired emotional processing and deficits in social cognition. Methods: A prospective neuroimaging study was conducted with 204 individuals with ALS and 111 healthy controls. Patients were stratified for hexanucleotide expansion status in C9orf72. A deep-learning-based segmentation approach was implemented to segment the nucleus accumbens, hypothalamus, fornix, mammillary body, basal forebrain and septal nuclei. The cortical, subcortical and white matter components of the Papez circuit were also systematically evaluated. Results: Hexanucleotide repeat expansion carriers exhibited bilateral amygdala, hypothalamus and nucleus accumbens atrophy, and C9orf72 negative patients showed bilateral basal forebrain volume reductions compared to controls. Both patient groups showed left rostral anterior cingulate atrophy, left entorhinal cortex thinning and cingulum and fornix alterations, irrespective of the genotype. Fornix, cingulum, posterior cingulate, nucleus accumbens, amygdala and hypothalamus degeneration was more marked in C9orf72-positive ALS patients. Conclusions: Our results highlighted that mesial temporal and parasagittal subcortical degeneration is not unique to C9orf72 carriers. Our radiological findings were consistent with neuropsychological observations and highlighted the importance of comprehensive neuropsychological testing in ALS, irrespective of the underlying genotype.}, } @article {pmid39056295, year = {2025}, author = {Lindamood, HL and Liu, TM and Read, TA and Vitriol, EA}, title = {Using ALS to understand profilin 1's diverse roles in cellular physiology.}, journal = {Cytoskeleton (Hoboken, N.J.)}, volume = {82}, number = {3}, pages = {111-129}, pmid = {39056295}, issn = {1949-3592}, support = {R35 GM137959/GM/NIGMS NIH HHS/United States ; }, mesh = {*Profilins/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; }, abstract = {Profilin is an actin monomer-binding protein whose role in actin polymerization has been studied for nearly 50 years. While its principal biochemical features are now well understood, many questions remain about how profilin controls diverse processes within the cell. Dysregulation of profilin has been implicated in a broad range of human diseases, including neurodegeneration, inflammatory disorders, cardiac disease, and cancer. For example, mutations in the profilin 1 gene (PFN1) can cause amyotrophic lateral sclerosis (ALS), although the precise mechanisms that drive neurodegeneration remain unclear. While initial work suggested proteostasis and actin cytoskeleton defects as the main pathological pathways, multiple novel functions for PFN1 have since been discovered that may also contribute to ALS, including the regulation of nucleocytoplasmic transport, stress granules, mitochondria, and microtubules. Here, we will review these newly discovered roles for PFN1, speculate on their contribution to ALS, and discuss how defects in actin can contribute to these processes. By understanding profilin 1's involvement in ALS pathogenesis, we hope to gain insight into this functionally complex protein with significant influence over cellular physiology.}, } @article {pmid39054893, year = {2024}, author = {Rajput, SS and Singh, SB and Subramanyam, D and Patil, S}, title = {Soft glassy rheology of single cells with pathogenic protein aggregates.}, journal = {Soft matter}, volume = {20}, number = {31}, pages = {6266-6274}, doi = {10.1039/d4sm00595c}, pmid = {39054893}, issn = {1744-6848}, mesh = {*Rheology ; Animals ; *Hemocytes/metabolism ; Protein Aggregates ; Viscosity ; Endocytosis ; Actins/metabolism/chemistry ; Single-Cell Analysis ; Microscopy, Atomic Force ; }, abstract = {A correlation between the mechanical properties of cells and various diseases has been emerging in recent years. Atomic force microscopy (AFM) has been widely used to measure a single cell's apparent Young's modulus by treating it as a fully elastic object. More recently, quantitative characterization of the complete viscoelasticity of single cells has become possible. We performed AFM-based nano-indentation experiments on hemocytes isolated from third instar larvae to determine their viscoelasticity and found that live hemocytes, like many other cells, follow a scale-free power-law rheology (PLR) akin to soft glasses. Further, we examined the changes in the rheological response of hemocytes in the presence of pathogenic protein aggregates known to cause neurodegenerative diseases such as Huntington's disorder and amyotrophic lateral sclerosis. Our results show that cells lose their fluidity and appear more solid-like in the presence of certain aggregates, in a manner correlated to actin reorganization. More solid-like cells also display reduced intracellular transport through clathrin-mediated endocytosis (CME). However, the cell's rheology remains largely unaffected and is similar to that of wild-type (WT) hemocytes, if aggregates do not perturb the actin organization and CME. Moreover, the fluid-like nature was significantly recovered when actin organization was rescued by overexpressing specific actin interacting proteins or chaperones. Our study, for the first time, underscores a direct correlation between parameters governing glassy dynamics, actin organization and CME.}, } @article {pmid39054501, year = {2024}, author = {Rahimi Darehbagh, R and Seyedoshohadaei, SA and Ramezani, R and Rezaei, N}, title = {Stem cell therapies for neurological disorders: current progress, challenges, and future perspectives.}, journal = {European journal of medical research}, volume = {29}, number = {1}, pages = {386}, pmid = {39054501}, issn = {2047-783X}, mesh = {Humans ; *Nervous System Diseases/therapy ; *Stem Cell Transplantation/methods/trends ; Animals ; Cell- and Tissue-Based Therapy/methods/trends ; Neural Stem Cells/transplantation/physiology ; }, abstract = {Stem cell-based therapies have emerged as a promising approach for treating various neurological disorders by harnessing the regenerative potential of stem cells to restore damaged neural tissue and circuitry. This comprehensive review provides an in-depth analysis of the current state of stem cell applications in primary neurological conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other related disorders. The review begins with a detailed introduction to stem cell biology, discussing the types, sources, and mechanisms of action of stem cells in neurological therapies. It then critically examines the preclinical evidence from animal models and early human trials investigating the safety, feasibility, and efficacy of different stem cell types, such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs). While ESCs have been studied extensively in preclinical models, clinical trials have primarily focused on adult stem cells such as MSCs and NSCs, as well as iPSCs and their derivatives. We critically assess the current state of research for each cell type, highlighting their potential applications and limitations in different neurological conditions. The review synthesizes key findings from recent, high-quality studies for each neurological condition, discussing cell manufacturing, delivery methods, and therapeutic outcomes. While the potential of stem cells to replace lost neurons and directly reconstruct neural circuits is highlighted, the review emphasizes the critical role of paracrine and immunomodulatory mechanisms in mediating the therapeutic effects of stem cells in most neurological disorders. The article also explores the challenges and limitations associated with translating stem cell therapies into clinical practice, including issues related to cell sourcing, scalability, safety, and regulatory considerations. Furthermore, it discusses future directions and opportunities for advancing stem cell-based treatments, such as gene editing, biomaterials, personalized iPSC-derived therapies, and novel delivery strategies. The review concludes by emphasizing the transformative potential of stem cell therapies in revolutionizing the treatment of neurological disorders while acknowledging the need for rigorous clinical trials, standardized protocols, and multidisciplinary collaboration to realize their full therapeutic promise.}, } @article {pmid39054363, year = {2024}, author = {Weishaupt, JH and Körtvélyessy, P and Schumann, P and Valkadinov, I and Weyen, U and Hesebeck-Brinckmann, J and Weishaupt, K and Endres, M and Andersen, PM and Regensburger, M and Dreger, M and Koch, JC and Conrad, J and Meyer, T}, title = {Tofersen decreases neurofilament levels supporting the pathogenesis of the SOD1 p.D91A variant in amyotrophic lateral sclerosis patients.}, journal = {Communications medicine}, volume = {4}, number = {1}, pages = {150}, pmid = {39054363}, issn = {2730-664X}, abstract = {BACKGROUND: Since the antisense oligonucleotide tofersen has recently become available for the treatment of amyotrophic lateral sclerosis (ALS) caused by mutations in SOD1, determining the causality of the over 230 SOD1 variants has become even more important. The most common SOD1 variant worldwide is p.D91A (c.272A > C), whose causality for ALS is contested when in a heterozygous state. The reason is the high allele frequency of SOD1[D91A] in Europe, exceeding 1% in Finno-Scandinavia.

METHODS: We present the clinical disease course and serum neurofilament light chain (NfL) results of treating 11 patients either homo- or heterozygous for the SOD1[D91A] allele for up to 16 months with tofersen.

RESULTS: Tofersen decreases serum neurofilament levels (sNFL), which are associated with the ALS progression rate, in the 6 ALS patients homozygous for SOD1[D91A]. We observe significantly lower sNfL levels in the 5 patients heterozygous for SOD1[D91A]. The results indicate that both mono- and bi-allelic SOD1[D91A] are causally relevant targets, with a possibly reduced effect size of SOD1[D91Ahet].

CONCLUSIONS: The finding is relevant for decision making regarding tofersen treatment, patient counseling and inclusion of SOD1[D91A] patients in drug trials. As far as we are aware, the approach is conceptually new since it provides evidence for the causality of an ALS variant based on a biomarker response to gene-specific treatment.}, } @article {pmid39054069, year = {2024}, author = {Wong, HC and Lang, AE and Stein, C and Drerup, CM}, title = {ALS-Linked VapB P56S Mutation Alters Neuronal Mitochondrial Turnover at the Synapse.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {44}, number = {35}, pages = {}, pmid = {39054069}, issn = {1529-2401}, support = {R01 NS124692/NS/NINDS NIH HHS/United States ; T32 GM007133/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Zebrafish ; *Mitochondria/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Synapses/metabolism/genetics ; *Animals, Genetically Modified ; Vesicular Transport Proteins/genetics/metabolism ; Neurons/metabolism ; Humans ; Mutation ; Endoplasmic Reticulum/metabolism/genetics ; Mitophagy/genetics/physiology ; Zebrafish Proteins/genetics/metabolism ; }, abstract = {Mitochondrial population maintenance in neurons is essential for neuron function and survival. Contact sites between mitochondria and the endoplasmic reticulum (ER) are poised to regulate mitochondrial homeostasis in neurons. These contact sites can facilitate transfer of calcium and lipids between the organelles and have been shown to regulate aspects of mitochondrial dynamics. Vesicle-associated membrane protein-associated protein B (VapB) is an ER membrane protein present at a subset of ER-mitochondrial contact sites. A proline-to-serine mutation in VapB at amino acid 56 (P56S) correlates with susceptibility to amyotrophic lateral sclerosis (ALS) type 8. Given the relationship between failed mitochondrial health and neurodegenerative disease, we investigated the function of VapB in mitochondrial population maintenance. We demonstrated that transgenic expression of VapB[P56S] in zebrafish larvae (sex undetermined) increased mitochondrial biogenesis, causing increased mitochondrial population size in the axon terminal. Expression of wild-type VapB did not alter biogenesis but, instead, increased mitophagy in the axon terminal. Using genetic manipulations to independently increase mitochondrial biogenesis, we show that biogenesis is normally balanced by mitophagy to maintain a constant mitochondrial population size. VapB[P56S] transgenics fail to increase mitophagy to compensate for the increase in mitochondrial biogenesis, suggesting an impaired mitophagic response. Finally, using a synthetic ER-mitochondrial tether, we show that VapB's function in mitochondrial turnover is likely independent of ER-mitochondrial tethering by contact sites. Our findings demonstrate that VapB can control mitochondrial turnover in the axon terminal, and this function is altered by the P56S ALS-linked mutation.}, } @article {pmid39053342, year = {2024}, author = {Hideyama, T and Teramoto, S and Kato, H and Terashi, H and Kwak, S and Aizawa, H}, title = {Negative features of sporadic amyotrophic lateral sclerosis: Motor neurons of Onuf's nucleus survive in ADAR2-conditional knockout mice.}, journal = {Journal of the neurological sciences}, volume = {463}, number = {}, pages = {123142}, doi = {10.1016/j.jns.2024.123142}, pmid = {39053342}, issn = {1878-5883}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Adenosine Deaminase/genetics/deficiency/metabolism ; *Motor Neurons/pathology/metabolism ; *RNA-Binding Proteins/genetics/metabolism ; Mice ; *Mice, Knockout ; DNA-Binding Proteins/genetics/metabolism ; Disease Models, Animal ; Receptors, AMPA/genetics/metabolism ; Mice, Transgenic ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) do not develop oculomotor disturbances and vesicorectal dysfunction until end-stage disease owing to the survival of certain motor neurons (MNs), including oculomotor neurons and MNs within Onuf's nucleus. In sporadic ALS, adenosine deaminase acting on RNA 2 (ADAR2)-mediated editing of GluA2 mRNA at the Q/R site is compromised in lower MNs. We previously developed genetically modified mice with a conditional knockout of ADAR2 in cholinergic neurons (ADAR2[flox/flox]/VAChT-Cre, Fast; AR2). These mice displayed slow and progressive lower motor neuron death with TAR DNA-binding protein 43 (TDP-43) pathology, attributable to insufficient editing at the GluA2 Q/R site due to ADAR2 deficiency. MN death was more common in fast-fatigable MNs owing to differential vulnerability under conditions of ADAR2 deficiency. Although facial and hypoglossal nerves were impaired in AR2 mice, cell death did not occur within the oculomotor nerve nucleus, as observed in patients with sporadic ALS. Since the basis for avoiding cystorectal damage in ALS is unknown, we compared the features of Onuf's nucleus MNs in 12-month-old AR2 mice with those in age-matched wild-type mice. Although the number of MNs was not significantly lower in AR2 mice, the neurons exhibited a shrunken morphology and TDP-43 pathology. Onuf's nucleus MNs could survive in an ADAR2-deficient state and mainly included fast fatigue-resistant (FR) and slow (S) MNs. In summary, FR and S MNs show increased resilience to ADAR2 deficiency, potentially participating in an important neuronal death avoidance mechanism in ALS.}, } @article {pmid39050823, year = {2024}, author = {Min, JH and Sarlus, H and Harris, RA}, title = {Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1408159}, pmid = {39050823}, issn = {1662-5099}, abstract = {The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease.}, } @article {pmid39050003, year = {2024}, author = {Özaydin Aksun, Z and Erdoğan, S and Kalkanci, A and Şahin, EA and Çuhadar, T and Şener, HÖ}, title = {Is gut microbiota of patients with ALS different from that of healthy individuals?.}, journal = {Turkish journal of medical sciences}, volume = {54}, number = {3}, pages = {579-587}, pmid = {39050003}, issn = {1303-6165}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/microbiology ; *Gastrointestinal Microbiome/genetics/physiology ; Female ; Male ; Middle Aged ; Adult ; Feces/microbiology ; RNA, Ribosomal, 16S/analysis/genetics ; Aged ; Case-Control Studies ; }, abstract = {BACKGROUND/AIM: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Several studies have shown that alterations of microbiota increase the risk of neurodegenerative disorders. We aimed to reveal whether there is a difference in the gut microbiota of patients with ALS.

MATERIALS AND METHODS: The participants are divided into three groups. Group 1 comprised patients with ALS. Healthy family members living in the same house of the patients formed Group 2. Lastly, sex- and age-matched healthy people were included in Group 3. Fecal samples were collected in 15-mL falcon tubes and stored at -80 °C. Genomic DNA isolation was performed on samples. Bacterial primers selected from the 16S rRNA region for the bacterial genome and ITS1 and ITS4 (internal transcribed spacer) were used for the identification of DNA. Next generation sequence analysis (NGS) and taxonomic analyses were performed at the level of bacterial phylum, class, order, family, genus, and species. Alpha and beta diversity indexes were used. The linear discriminant analysis (LDA) effect size method (LEfSe) was applied to identify a microbial taxon specific to ALS disease.

RESULTS: The relative abundances of the Succinivibrionaceae and Lachnospiraceae families were significantly lower in patients. The dominant families among patients were Streptococcaceae and Ruminococcaceae, while the dominant families among healthy controls were Bacteroidaceae and Succinivibrionaceae. The LEfSe analysis revealed that four families (Atopobiaceae, Actinomycetaceae, Erysipelatoclostridiaceae, Peptococcacceae) differed significantly between the patients and healthy controls (LDA values> 2.5, p < 0.05).

CONCLUSION: Comparison with family members living in the same house is the strength of this study. We found that there were changes in the microbiota of the patients, consistent with the literature. Studies that analyze the composition of the gut microbiota in the predisease period may be needed to understand whether dysbiosis is caused by the mechanisms inherent in the disease or whether it is dysbiosis that initiates the disease.}, } @article {pmid39047759, year = {2024}, author = {Schmid, G and Schneeweiss, P and Hirtl, R and Jhala, T and Samaras, T}, title = {Numerical assessment of induced electric fields in a worker's hand with commonly used metallic implants under exposure to low frequency magnetic fields.}, journal = {Journal of radiological protection : official journal of the Society for Radiological Protection}, volume = {44}, number = {3}, pages = {}, doi = {10.1088/1361-6498/ad66dc}, pmid = {39047759}, issn = {1361-6498}, mesh = {Humans ; *Occupational Exposure/analysis ; *Hand ; *Electromagnetic Fields ; Metals ; Magnetic Fields ; Prostheses and Implants ; Bone Screws ; Bone Plates ; }, abstract = {The European Union's Workers' Directive 2013/35/EU on the minimum health and safety requirements regarding the exposure of workers to electromagnetic fields specifies action levels (ALs) for external electric and magnetic fields, which should protect against induced tissue-internal electric field strengthEiabove the exposure limit values, the latter being defined in order to prevent tissue stimulation at low frequencies. However, although 2013/35/EU explicitly calls for the protection of 'workers at particular risk' (including workers with metallic implants), the AL specified in the Directive have been derived under the assumption that there are no metallic parts present inside the body. Therefore, in the present work, we analysed the situation of a worker's hand and forearm bearing metallic implants (Herbert screw and volar radius plate) used for osteosynthesis after the most common bone fractures of the hand/forearm, exposed to low frequency magnetic fields. The uniform exposure of the whole hand and forearm as well as the exposure to a specific and widely used device, a deactivator for single-use labels of acousto-magnetic electronic article surveillance systems, were considered based on numerical computations using a high-resolution anatomical hand and forearm model. The results obtained indicated that the maximum induced electric field strength averaged in a volume of 2 mm × 2 mm × 2 mm cube was higher in the presence of the metallic implants by a factor of up to 4.2 for bone tissue and 2.3 for soft tissue compared with the case without an implant. Hence, it is obvious that the local induced electric field strengths may be substantially increased by the implants. The extent of this increase, however, is highly dependent on the implant's position inside the body, the implant's geometry, and the field distribution and orientation with respect to the anatomical structure and the implant.}, } @article {pmid39046818, year = {2024}, author = {Brink, V and Kirkbride, J}, title = {Reply to Zhou et al's "Refining Psychosis Research: Insights on Cannabis Use and Data Accuracy".}, journal = {Schizophrenia bulletin}, volume = {50}, number = {5}, pages = {965-967}, pmid = {39046818}, issn = {1745-1701}, support = {//European Community's Seventh Framework/ ; 2012/0417-0//São Paulo Research Foundation/ ; MD-PhD 18-41//University Medical Centre Groningen/ ; //National Institute for Health and Care Research/ ; //University College London Hospitals NHS Foundation Trust/ ; //UK Research and Innovation/ ; MR/W030608/1//Clinical Academic Research Partnership/ ; }, mesh = {Humans ; *Psychotic Disorders ; Data Accuracy ; Biomedical Research/standards ; Marijuana Use/epidemiology ; Marijuana Abuse/epidemiology ; }, } @article {pmid39473802, year = {2024}, author = {Lukac, M and Luben, H and Martin, AE and Simmons, Z and Geronimo, A}, title = {Spatial-Temporal Analysis of Gait in Amyotrophic Lateral Sclerosis Using Foot-Worn Inertial Sensors: An Observational Study.}, journal = {Digital biomarkers}, volume = {8}, number = {1}, pages = {22-29}, pmid = {39473802}, issn = {2504-110X}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that alters gait and increases the risk of falls. The current model of care involves in-person multidisciplinary clinic visits to, in part, assess alterations in gait, evaluate safety, and make recommendations for management. Clinic visits, however, are relatively infrequent, and multidisciplinary evaluations can be physically demanding for patients. To better understand how gait changes over time in those with ALS and enable healthcare providers to properly respond to these changes, remote monitoring of functional mobility would be advantageous.

METHODS: The objective of this study was to remotely track long-term changes in walking speed using wearable inertial measurement units (IMUs). Nine ALS patients and 6 healthy controls submitted twice-weekly home walking recordings for 24 and 4 weeks, respectively. An IMU data processing method was developed and validated against laboratory-measured walking speed.

RESULTS: For both ALS patients and healthy controls, home walking speed was less than clinic walking speed by an average of 0.19 m/s (p = 0.0024). Over 24 weeks, home walking speed significantly decreased for 5 of 9 ALS patients at an average of -0.021 m/s/months (p = 0.005). Those who eventually transitioned to using assistive device (AD) while on the study demonstrated a greater decrease in walking speed than those who did not.

CONCLUSIONS: Remote longitudinal gait monitoring of ALS patients is feasible with the use of an IMU. Decreases in walking speed were detected in the majority of patients, most strongly in those who eventually transitioned to an AD. Home walking speed may more accurately represent the walking abilities of ALS patients in their real-life environments, a finding which further supports the case for remote monitoring in ALS.}, } @article {pmid39355053, year = {2023}, author = {Cortés Mancera, EA and Sinisterra Solis, FA and Romero-Castellanos, FR and Diaz-Meneses, IE and Kerik-Rotenberg, NE}, title = {[18]F-FDG PET/CT as a molecular biomarker in the diagnosis of amyotrophic lateral sclerosis associated with prostate cancer and progressive supranuclear palsy: A case report.}, journal = {Frontiers in nuclear medicine}, volume = {3}, number = {}, pages = {1137875}, pmid = {39355053}, issn = {2673-8880}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative, multisystem disorder. Its clinical presentation typically consists of progressive focal muscle atrophy and weakness. In addition to motor disorders, the association between ALS and cancer has been researched, such as frontotemporal dementia and progressive supranuclear palsy. The diagnosis is based primarily on the clinical history, physical examination, electrodiagnostic tests (with an EMG needle), and neuroimaging, such as MRI and [18]F-FDG PET/CT.

PRESENTATION OF THE CASE: A 67-year-old male patient was diagnosed with prostate adenocarcinoma with a clinical picture of muscle weakness in the lower limbs that caused falls and was associated with fasciculations in the thighs and arms, alterations in the tone of voice, poor memory, and difficulty articulating words. In the neurological assessment, he described walking supported by a walker with decreased strength in both lower limbs and sensitivity without alterations. The diagnoses of upper and lower motor neuron disease and probable ALS were integrated. Furthermore, the probable coexistence of frontotemporal dementia/disorder (FDD) with ALS was considered. The main findings in the [18]F-FDG PET/CT study was hypometabolism in the cortex of the bilateral motor and premotor areas, the anterior cingulate, both caudate and putamen, a metabolic pattern compatible with ALS, and progressive supranuclear palsy.

CONCLUSION: Through the PET/CT studies, we demonstrated a case in which ALS, prostate cancer and progressive supranuclear palsy coexisted molecularly; it was clinically difficult to diagnose. Molecular imaging has potential in the diagnostic and prognostic evaluation of ALS. It is crucial to identify the disease early and reliably through metabolic patterns that allow us to confirm the disease or differentiate it from other pathologies.}, } @article {pmid39291146, year = {2023}, author = {Mathew, AM and Bhuvanendran, S and Nair, RS and K Radhakrishnan, A}, title = {Exploring the anti-inflammatory activities, mechanism of action and prospective drug delivery systems of tocotrienol to target neurodegenerative diseases.}, journal = {F1000Research}, volume = {12}, number = {}, pages = {338}, pmid = {39291146}, issn = {2046-1402}, abstract = {A major cause of death in the elderly worldwide is attributed to neurodegenerative diseases, such as AD (Alzheimer's disease), PD (Parkinson's disease), ALS (Amyotrophic lateral sclerosis), FRDA (Friedreich's ataxia), VaD (Vascular dementia) etc. These can be caused due to multiple factors such as genetic, physiological problems like stroke or tumor, or even external causes like viruses, toxins, or chemicals. T3s (tocotrienols) exhibit various bioactive properties where it acts as an antioxidant, anti-inflammatory, anti-tumorigenic, and cholesterol lowering agent. Since T3 interferes with and influences several anti-inflammatory mechanisms, it aids in combating inflammatory responses that lead to disease progression. T3s are found to have a profound neuroprotective ability, however, due to their poor oral bioavailability, their full potential could not be exploited. Hence there is a need to explore other drug delivery techniques, especially focusing on aspects of nanotechnology. In this review paper we explore the anti-inflammatory mechanisms of T3 to apply it in the treatment of neurodegenerative diseases and also discusses the possibilities of nano methods of administering tocotrienols to target neurodegenerative diseases.}, } @article {pmid39165755, year = {2023}, author = {Bustos, LM and Sattler, R}, title = {The Fault in Our Astrocytes - cause or casualties of proteinopathies of ALS/FTD and other neurodegenerative diseases?.}, journal = {Frontiers in molecular medicine}, volume = {3}, number = {}, pages = {1075805}, pmid = {39165755}, issn = {2674-0095}, support = {R21 NS125861/NS/NINDS NIH HHS/United States ; }, abstract = {Many neurodegenerative diseases fall under the class of diseases known as proteinopathies, whereby the structure and localization of specific proteins become abnormal. These aberrant proteins often aggregate within cells which disrupts vital homeostatic and physiological cellular functions, ultimately contributing to cell death. Although neurodegenerative disease research is typically neurocentric, there is evidence supporting the role of non-neuronal cells in the pathogenesis of these diseases. Specifically, the role of astrocytes in neurodegenerative diseases has been an ever-growing area of research. Astrocytes are one of the most abundant cell types in the central nervous system (CNS) and provide an array of essential homeostatic functions that are disrupted in neurodegenerative diseases. Astrocytes can exhibit a reactive phenotype that is characterized by molecular changes, as well as changes in morphology and function. In neurodegenerative diseases, there is potential for reactive astrocytes to assume a loss-of-function phenotype in homeostatic operations such as synapse maintenance, neuronal metabolic support, and facilitating cell-cell communication between glia and neurons. They are also able to concurrently exhibit gain-of-function phenotypes that can be destructive to neural networks and the astrocytes themselves. Additionally, astrocytes have been shown to internalize disease related proteins and reflect similar or exacerbated pathology that has been observed in neurons. Here, we review several major neurodegenerative disease-specific proteinopathies and what is known about their presence in astrocytes and the potential consequences regarding cell and non-cell autonomous neurodegeneration.}, } @article {pmid39086676, year = {2023}, author = {Stoklund Dittlau, K and Van Den Bosch, L}, title = {Why should we care about astrocytes in a motor neuron disease?.}, journal = {Frontiers in molecular medicine}, volume = {3}, number = {}, pages = {1047540}, pmid = {39086676}, issn = {2674-0095}, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults, causing progressive degeneration of motor neurons, which results in muscle atrophy, respiratory failure and ultimately death of the patients. The pathogenesis of ALS is complex, and extensive efforts have focused on unravelling the underlying molecular mechanisms with a large emphasis on the dying motor neurons. However, a recent shift in focus towards the supporting glial population has revealed a large contribution and influence in ALS, which stresses the need to explore this area in more detail. Especially studies into astrocytes, the residential homeostatic supporter cells of neurons, have revealed a remarkable astrocytic dysfunction in ALS, and therefore could present a target for new and promising therapeutic entry points. In this review, we provide an overview of general astrocyte function and summarize the current literature on the role of astrocytes in ALS by categorizing the potentially underlying molecular mechanisms. We discuss the current efforts in astrocyte-targeted therapy, and highlight the potential and shortcomings of available models.}, } @article {pmid39281332, year = {2022}, author = {Kirikae, H and Harada, R and Hosaka, T and Misu, T and Ando, D and Warita, H and Endo, T and Sonobe, S and Niizuma, K and Aoki, M}, title = {Case Report: Vertebro-vertebral arteriovenous fistula showing symptoms mimicking ALS: Diagnostic imaging supports accurate differentiation between ALS and mimicking conditions.}, journal = {F1000Research}, volume = {11}, number = {}, pages = {546}, pmid = {39281332}, issn = {2046-1402}, abstract = {We report a rare case of a vertebro-vertebral arteriovenous fistula (VVAVF) manifesting as amyotrophic lateral sclerosis (ALS). A 76-year-old female patient presented with progressive weakness, muscle atrophy, fasciculation, and preserved deep tendon reflexes in the right upper limb. Electrophysiological testing showed lower motor neuron dysfunction. The patient was suspected to have ALS, but cervical magnetic resonance imaging (MRI) revealed enlarged blood vessels in the spinal canal, which compressed the cervical spinal cord and nerve roots. Angiography showed a shunt from the right vertebral artery to the right intervertebral vein and the vertebral venous plexus; therefore, the patient was diagnosed with VVAVF. Transarterial embolization was performed to obliterate the shunt, and weakness in the patient's right upper limb subsequently improved. It is worth considering VVAVF as a differential diagnosis of ALS-like diseases.}, } @article {pmid39484675, year = {2022}, author = {Chopra, N and Menounos, S and Choi, JP and Hansbro, PM and Diwan, AD and Das, A}, title = {Blood-Spinal Cord Barrier: Its Role in Spinal Disorders and Emerging Therapeutic Strategies.}, journal = {NeuroSci}, volume = {3}, number = {1}, pages = {1-27}, pmid = {39484675}, issn = {2673-4087}, abstract = {The blood-spinal cord barrier (BSCB) has been long thought of as a functional equivalent to the blood-brain barrier (BBB), restricting blood flow into the spinal cord. The spinal cord is supported by various disc tissues that provide agility and has different local immune responses compared to the brain. Though physiologically, structural components of the BSCB and BBB share many similarities, the clinical landscape significantly differs. Thus, it is crucial to understand the composition of BSCB and also to establish the cause-effect relationship with aberrations and spinal cord dysfunctions. Here, we provide a descriptive analysis of the anatomy, current techniques to assess the impairment of BSCB, associated risk factors and impact of spinal disorders such as spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS), peripheral nerve injury (PNI), ischemia reperfusion injury (IRI), degenerative cervical myelopathy (DCM), multiple sclerosis (MS), spinal cavernous malformations (SCM) and cancer on BSCB dysfunction. Along with diagnostic and mechanistic analyses, we also provide an up-to-date account of available therapeutic options for BSCB repair. We emphasize the need to address BSCB as an individual entity and direct future research towards it.}, } @article {pmid39045865, year = {2024}, author = {Sanpei, Y and Yasuda, K and Takahashi, Y and Hanazono, A and Sugawara, M and Iijima, K}, title = {Evaluation of the applicability of weak shoulder and arm sparing signs in amyotrophic lateral sclerosis by multiple neurologists and neurology residents: A single-center study.}, journal = {Muscle & nerve}, volume = {70}, number = {4}, pages = {761-765}, doi = {10.1002/mus.28216}, pmid = {39045865}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; Aged ; *Shoulder/physiopathology ; Retrospective Studies ; *Arm/physiopathology ; *Neurologists ; *Muscle Weakness/diagnosis/physiopathology ; Internship and Residency ; Neurology/education ; Muscle, Skeletal/physiopathology ; Adult ; Sensitivity and Specificity ; Aged, 80 and over ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) exhibits selective muscle weakness. The weak shoulder and arm sparing signs, assessed by a single experienced neurologist, have been reported to be superior to previous signs in sensitivity and specificity. However, it is unknown whether the same results are observed when assessed by multiple neurologists.

METHODS: Subjects were retrospectively identified from our department's inpatient database from 2014 to 2023. Medical Research Council (MRC) scores of the deltoid (Del), biceps brachii (BB), triceps brachii (TB), and first dorsal interosseous (FDI) muscles were evaluated. The weak shoulder sign was defined as positive when Del was weaker than BB and TB. The arm sparing sign was defined as positive when both Del and FDI were weaker than BB and TB. Sensitivity was analyzed in all ALS patients and in subgroups based on the region of symptom onset, presence or absence of upper motor neuron (UMN) signs, and the Japanese ALS Severity Classification.

RESULTS: Seventy-one patients with ALS were identified. Eight neurologists and three neurology residents evaluated each patient's MRC scores. The weak shoulder and arm sparing signs were observed in 72% and 48% of patients, respectively, with no significant difference in sensitivity across patient subgroups.

DISCUSSION: The weak shoulder and arm sparing signs showed high and moderate sensitivity, respectively, consistent with a previous report, even when evaluated by multiple examiners. This expands the clinical utility and increases the reliability of these signs, potentially contributing to accurate ALS diagnosis when combined with other clinical features and objective assessments.}, } @article {pmid39044591, year = {2024}, author = {Wang, J and Feng, L and Zhang, Y and Xu, P}, title = {[Establishment of a stable THP-1 cell line expressing PSMB9-eGFP-His protein and detection of immunoproteasome activity].}, journal = {Sheng wu gong cheng xue bao = Chinese journal of biotechnology}, volume = {40}, number = {7}, pages = {2282-2293}, doi = {10.13345/j.cjb.240124}, pmid = {39044591}, issn = {1872-2075}, mesh = {Humans ; *Proteasome Endopeptidase Complex/genetics/metabolism ; *Green Fluorescent Proteins/genetics/metabolism ; THP-1 Cells ; Lentivirus/genetics ; Recombinant Fusion Proteins/genetics ; Cysteine Endopeptidases/genetics/metabolism ; }, abstract = {The ubiquitin/proteasome system (UPS) plays a crucial role in maintaining cellular protein homeostasis. The catalytic activity of proteasome in the UPS is regulated by β1 (PSMB6), β2 (PSMB7), and β5 (PSMB5) subunits. Interferon (IFN)-γ, tumor necrosis factor (TNF)-α, inflammation, and oxidative stress can induce the replacement of β1, β2, and β5 with their respective immuno-subunits β1i (PSMB9), β2i (PSMB10), and β5i (PSMB8), which can be assembled into the immunoproteasome. Compared with the standard proteasome, the immunoproteasome exerts enhanced regulatory effects on immune responses, such as processing and presenting MHC class Ⅰ antigens, production of pro-inflammatory cytokines, and T cell differentiation and proliferation. Abnormal aggregation of immunoproteasomes can cause neurodegenerative diseases like Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. To explore the function of PSMB9 after bacterial infection, we constructed a lentivirus plasmid overexpressing PSMB9-eGFP-His and transfected the plasmid into HEK293T cells for packaging by using a triple-plasmid system in this study. After screening with puromycin, we obtained a stable human leukemia monocytic THP-1 cell line expressing the fusion protein of PSMB9. Western blotting (WB) and fluorescence microscopy verified the expression of the fusion protein in the stable THP-1 cells. Quantitative PCR (qPCR) was employed to measure the copies of PSMB9-eGFP in THP-1 cells. Immunofluorescence results found that eGFP-His did not affect the subcellular localization of PSMB9. The purification with nickel affinity chromatography confirmed that the fusion protein could be assembled into the 20S immunoproteasome and exhibited cleaving activity for fluorescent peptide substrates. These results indicated that the PSMB9-eGFP fusion gene was integrated into the chromosome, and could be stably expressed in the constructed THP-1 cell line. This cell line can be utilized for the research on subcellular localization, dynamic expression, and activity of PSMB9 in live cells at different infection conditions and disease stages. It also provides a model for the stable cell lines construction of other immunoproteasome subunits PSMB8 and PSMB10.}, } @article {pmid39044379, year = {2024}, author = {Goutman, SA and Goyal, NA and Payne, K and Paisán-Ruiz, C and Kupelian, V and Kang, ML and Mitchell, AA and Fecteau, TE}, title = {ALS Identified: two-year findings from a sponsored ALS genetic testing program.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {8}, pages = {2201-2211}, pmid = {39044379}, issn = {2328-9503}, support = {//Biogen (Cambridge, MA, USA)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Male ; *Genetic Testing ; Female ; Middle Aged ; Aged ; Adult ; United States ; }, abstract = {OBJECTIVE: To report initial results from the Amyotrophic Lateral Sclerosis (ALS) Identified genetic testing (GT) program on characteristics of individuals tested and frequency of reported disease-causing variants.

METHODS: ALS Identified used the Invitae Amyotrophic Lateral Sclerosis panel (Invitae, San Francisco, CA, USA) to assay 22 ALS-associated genes. Sponsored by Biogen (Cambridge, MA, USA), the program was launched in June 2021 and was available at no charge to individuals ≥18 years in the United States and Puerto Rico with an ALS diagnosis or a known family history of ALS. Deidentified data were available to Biogen.

RESULTS: As of 26 October 2023, 998 healthcare professionals ordered the panel at 681 unique care sites. Of 8054 individuals examined, 7483 (92.9%) were reported to have a clinical diagnosis of ALS, while 571 (7.1%) were asymptomatic relatives. Of the individuals with a clinical ALS diagnosis, 57.7% were male (n = 4319) and 42.3% female (n = 3164). Mean (SD) age at diagnosis is 62 (13) years. Out of the 7483 clinically diagnosed individuals, 1810 (24.2%) showed genetic variations in ALS-associated genes. Among these, 865 individuals (47.8%) carried pathogenic variants, and 44 (2.4%) had likely pathogenic variants, totaling 12.1% of the clinically diagnosed population.

INTERPRETATION: Since 2021 there has been robust uptake and sustained use of the ALS Identified program, one of the largest samples of people with ALS to date across the United States, demonstrating the interest and need for genetic ALS testing.}, } @article {pmid39044305, year = {2024}, author = {Chen, HH and Yeo, HT and Huang, YH and Tsai, LK and Lai, HJ and Tsao, YP and Chen, SL}, title = {AAV-NRIP gene therapy ameliorates motor neuron degeneration and muscle atrophy in ALS model mice.}, journal = {Skeletal muscle}, volume = {14}, number = {1}, pages = {17}, pmid = {39044305}, issn = {2044-5040}, support = {NSTC 112-2320-B-002-004//National Science and Technology Council/ ; NSTC 112-2320-B-002-004//National Science and Technology Council/ ; 10R891903//National Taiwan University/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/pathology ; *Genetic Therapy/methods ; *Muscular Atrophy/genetics/therapy/metabolism/pathology ; *Disease Models, Animal ; *Motor Neurons/metabolism/pathology ; *Mice, Transgenic ; *Dependovirus/genetics ; Mice ; Humans ; Muscle, Skeletal/metabolism/pathology ; Neuromuscular Junction/metabolism/pathology ; Genetic Vectors/administration & dosage ; Nerve Degeneration/genetics/therapy ; Male ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration, leading to neuromuscular junction (NMJ) dismantling and severe muscle atrophy. The nuclear receptor interaction protein (NRIP) functions as a multifunctional protein. It directly interacts with calmodulin or α-actinin 2, serving as a calcium sensor for muscle contraction and maintaining sarcomere integrity. Additionally, NRIP binds with the acetylcholine receptor (AChR) for NMJ stabilization. Loss of NRIP in muscles results in progressive motor neuron degeneration with abnormal NMJ architecture, resembling ALS phenotypes. Therefore, we hypothesize that NRIP could be a therapeutic factor for ALS.

METHODS: We used SOD1 G93A mice, expressing human SOD1 with the ALS-linked G93A mutation, as an ALS model. An adeno-associated virus vector encoding the human NRIP gene (AAV-NRIP) was generated and injected into the muscles of SOD1 G93A mice at 60 days of age, before disease onset. Pathological and behavioral changes were measured to evaluate the therapeutic effects of AAV-NRIP on the disease progression of SOD1 G93A mice.

RESULTS: SOD1 G93A mice exhibited lower NRIP expression than wild-type mice in both the spinal cord and skeletal muscle tissues. Forced NRIP expression through AAV-NRIP intramuscular injection was observed in skeletal muscles and retrogradely transduced into the spinal cord. AAV-NRIP gene therapy enhanced movement distance and rearing frequencies in SOD1 G93A mice. Moreover, AAV-NRIP increased myofiber size and slow myosin expression, ameliorated NMJ degeneration and axon terminal denervation at NMJ, and increased the number of α-motor neurons (α-MNs) and compound muscle action potential (CMAP) in SOD1 G93A mice.

CONCLUSIONS: AAV-NRIP gene therapy ameliorates muscle atrophy, motor neuron degeneration, and axon terminal denervation at NMJ, leading to increased NMJ transmission and improved motor functions in SOD1 G93A mice. Collectively, AAV-NRIP could be a potential therapeutic drug for ALS.}, } @article {pmid39042810, year = {2024}, author = {Haridevamuthu, B and Sathishkumar, K}, title = {Comment on Tsioti et al's "Systemic Lipopolysaccharide Exposure Exacerbates Choroidal Neovascularization in Mice".}, journal = {Ocular immunology and inflammation}, volume = {32}, number = {10}, pages = {2614-2615}, doi = {10.1080/09273948.2024.2377732}, pmid = {39042810}, issn = {1744-5078}, mesh = {*Choroidal Neovascularization/drug therapy ; Animals ; *Lipopolysaccharides ; Mice ; *Disease Models, Animal ; Macrophages/drug effects ; Fluorescein Angiography ; }, abstract = {The study "Systemic Lipopolysaccharide Exposure Exacerbates Choroidal Neovascularization in Mice" by Tsioti et al. explores the impact of systemic lipopolysaccharide (LPS) on choroidal neovascularization (CNV) progression. The findings reveal systemic LPS exposure significantly enhances fluorescein leakage, driven by increased pro-inflammatory monocyte-derived macrophages and microglia activation. The study underscores the importance of managing systemic inflammation to mitigate CNV progression, suggesting potential therapeutic strategies targeting CSF1R inhibition and Müller cell modulation. Future research should focus on elucidating the molecular pathways involved in LPS-induced CNV exacerbation and translating these findings into clinical interventions.}, } @article {pmid39042693, year = {2024}, author = {Celona, B and Salomonsson, SE and Wu, H and Dang, B and Kratochvil, HT and Clelland, CD and DeGrado, WF and Black, BL}, title = {Zfp106 binds to G-quadruplex RNAs and inhibits RAN translation and formation of RNA foci caused by G4C2 repeats.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {31}, pages = {e2220020121}, pmid = {39042693}, issn = {1091-6490}, support = {U01NS134062//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; HL146366//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; GM122603//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; K08 NS112330/NS/NINDS NIH HHS/United States ; U19 NS132303/NS/NINDS NIH HHS/United States ; R01 DK119621/DK/NIDDK NIH HHS/United States ; DK119621//HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; NS126499//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35 GM122603/GM/NIGMS NIH HHS/United States ; R01 NS126499/NS/NINDS NIH HHS/United States ; U01 NS134062/NS/NINDS NIH HHS/United States ; P01 HL146366/HL/NHLBI NIH HHS/United States ; AL210129//U.S. Department of Defense (DOD)/ ; U19NS132303//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; K99 GM138753/GM/NIGMS NIH HHS/United States ; K99GM138753//HHS | National Institutes of Health (NIH)/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *C9orf72 Protein/genetics/metabolism ; DNA Repeat Expansion ; Frontotemporal Dementia/genetics/metabolism ; *G-Quadruplexes ; Nerve Tissue Proteins/metabolism/genetics ; Protein Binding ; Protein Biosynthesis ; *RNA/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; }, abstract = {Expansion of intronic GGGGCC repeats in the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Transcription of the expanded repeats results in the formation of RNA-containing nuclear foci and altered RNA metabolism. In addition, repeat-associated non-AUG (RAN) translation of the expanded GGGGCC-repeat sequence results in the production of highly toxic dipeptide-repeat (DPR) proteins. GGGGCC repeat-containing transcripts form G-quadruplexes, which are associated with formation of RNA foci and RAN translation. Zfp106, an RNA-binding protein essential for motor neuron survival in mice, suppresses neurotoxicity in a Drosophila model of C9orf72 ALS. Here, we show that Zfp106 inhibits formation of RNA foci and significantly reduces RAN translation caused by GGGGCC repeats in cultured mammalian cells, and we demonstrate that Zfp106 coexpression reduces the levels of DPRs in C9orf72 patient-derived cells. Further, we show that Zfp106 binds to RNA G-quadruplexes and causes a conformational change in the G-quadruplex structure formed by GGGGCC repeats. Together, these data demonstrate that Zfp106 suppresses the formation of RNA foci and DPRs caused by GGGGCC repeats and suggest that the G-quadruplex RNA-binding function of Zfp106 contributes to its suppression of GGGGCC repeat-mediated cytotoxicity.}, } @article {pmid39039445, year = {2024}, author = {Jonsdottir, G and Haraldsdottir, E and Vilhjalmsson, R and Sigurdardottir, V and Hjaltason, H and Klinke, ME and Tryggvadottir, GB and Jonsdottir, H}, title = {Transition to end-of-life care in patients with neurological diseases in an acute hospital ward.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {253}, pmid = {39039445}, issn = {1471-2377}, support = {71545//The Icelandic Nurses´ Association/ ; }, mesh = {Humans ; Male ; *Terminal Care/methods/statistics & numerical data ; Female ; Aged ; Middle Aged ; Retrospective Studies ; *Nervous System Diseases/therapy/diagnosis/epidemiology ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/therapy/diagnosis/mortality ; }, abstract = {BACKGROUND: Transitioning to end-of-life care and thereby changing the focus of treatment directives from life-sustaining treatment to comfort care is important for neurological patients in advanced stages. Late transition to end-of-life care for neurological patients has been described previously.

OBJECTIVE: To investigate whether previous treatment directives, primary medical diagnoses, and demographic factors predict the transition to end-of-life care and time to eventual death in patients with neurological diseases in an acute hospital setting.

METHOD: All consecutive health records of patients diagnosed with stroke, amyotrophic lateral sclerosis (ALS), and Parkinson's disease or other extrapyramidal diseases (PDoed), who died in an acute neurological ward between January 2011 and August 2020 were retrieved retrospectively. Descriptive statistics and multivariate Cox regression were used to examine the timing of treatment directives and death in relation to medical diagnosis, age, gender, and marital status.

RESULTS: A total of 271 records were involved in the analysis. Patients in all diagnostic categories had a treatment directive for end-of-life care, with patients with haemorrhagic stroke having the highest (92%) and patients with PDoed the lowest (73%) proportion. Cox regression identified that the likelihood of end-of-life care decision-making was related to advancing age (HR = 1.02, 95% CI: 1.007-1.039, P = 0.005), ischaemic stroke (HR = 1.64, 95% CI: 1.034-2.618, P = 0.036) and haemorrhagic stroke (HR = 2.04, 95% CI: 1.219-3.423, P = 0.007) diagnoses. End-of-life care decision occurred from four to twenty-two days after hospital admission. The time from end-of-life care decision to death was a median of two days. Treatment directives, demographic factors, and diagnostic categories did not increase the likelihood of death following an end-of-life care decision.

CONCLUSIONS: Results show not only that neurological patients transit late to end-of-life care but that the timeframe of the decision differs between patients with acute neurological diseases and those with progressive neurological diseases, highlighting the particular significance of the short timeframe of patients with the progressive neurological diseases ALS and PDoed. Different trajectories of patients with neurological diseases at end-of-life should be further explored and clinical guidelines expanded to embrace the high diversity in neurological patients.}, } @article {pmid39039135, year = {2024}, author = {Tahir, M and Yude, B and Mehmood, T and Bashir, S and Zhenping, Y and Awais, M}, title = {Classification of LAMOST spectra of B-type and hot subdwarf stars using kernel support vector machine.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {16815}, pmid = {39039135}, issn = {2045-2322}, abstract = {Machine learning has emerged as a leading field in artificial intelligence, demonstrating expert-level performance in various domains. Astronomy has benefited from machine learning techniques, particularly in classifying and identifying stars based on their features. This study focuses on the spectra-based classification of 11,408 B-type and 2422 hot subdwarf stars. The study employs baseline correction using Asymmetric Least Squares (ALS) to enhance classification accuracy. It applies the Pan-Core concept to identify 500 unique patterns or ranges for both types of stars. These patterns are the foundation for creating Support Vector Machine (SVM) models, including the linear (L-SVM), polynomial (P-SVM), and radial basis (R-SVM) kernels. Parameter tuning for the SVM models is achieved through cross-validation. Evaluation of the SVM models on test data reveals that the linear kernel SVM achieves the highest accuracy (87.0%), surpassing the polynomial kernel SVM (84.1%) and radial kernel SVM (80.1%). The average calibrated accuracy falls within the range of 90-95%. These results demonstrate the potential of using spectrum-based classification to aid astronomers in improving and expanding their understanding of stars, with a specific focus on the identification of hot subdwarf stars. This study presents a valuable investigation for astronomers, as it enables the classification of stars based on their spectra, leveraging machine learning techniques to enhance their knowledge and insights in astronomy.}, } @article {pmid39039102, year = {2024}, author = {Acien, A and Calcagno, N and Burke, KM and Mondesire-Crump, I and Holmes, AA and Mruthik, S and Goldy, B and Syrotenko, JE and Scheier, Z and Iyer, A and Clark, A and Keegan, M and Ushirogawa, Y and Kato, A and Yasuda, T and Lahav, A and Iwasaki, S and Pascarella, M and Johnson, SA and Arroyo-Gallego, T and Berry, JD}, title = {A novel digital tool for detection and monitoring of amyotrophic lateral sclerosis motor impairment and progression via keystroke dynamics.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {16851}, pmid = {39039102}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; *Disease Progression ; Female ; Male ; Middle Aged ; Aged ; *Smartphone ; Machine Learning ; Case-Control Studies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative condition leading to progressive muscle weakness, atrophy, and ultimately death. Traditional ALS clinical evaluations often depend on subjective metrics, making accurate disease detection and monitoring disease trajectory challenging. To address these limitations, we developed the nQiALS toolkit, a machine learning-powered system that leverages smartphone typing dynamics to detect and track motor impairment in people with ALS. The study included 63 ALS patients and 30 age- and sex-matched healthy controls. We introduce the three core components of this toolkit: the nQiALS-Detection, which differentiated ALS from healthy typing patterns with an AUC of 0.89; the nQiALS-Progression, which separated slow and fast progression at specific thresholds with AUCs ranging between 0.65 and 0.8; and the nQiALS-Fine Motor, which identified subtle progression in fine motor dysfunction, suggesting earlier prediction than the state-of-the-art assessment. Together, these tools represent an innovative approach to ALS assessment, offering a complementary, objective metric to traditional clinical methods and which may reshape our understanding and monitoring of ALS progression.}, } @article {pmid39038319, year = {2024}, author = {Zhao, T and Huang, J and Chi, W}, title = {The Diagnostic Advantages of MRI in Cerebral Infarction: Multi-Sequence Imaging and Improved Sensitivity in Early Detection.}, journal = {Alternative therapies in health and medicine}, volume = {}, number = {}, pages = {}, pmid = {39038319}, issn = {1078-6791}, abstract = {OBJECTIVE: The study aimed to investigate the diagnostic value of computed tomography (CT) and magnetic resonance imaging (MRI) in cerebral infarction (CI) in cerebrovascular diseases.

METHOD: 100 patients with acute ischemic cerebral infarction (AICI) were divided into a CT group and an MRI group. The diagnostic efficacy of the two diagnostic methods for CI was compared and analyzed.

RESULTS: Only 6 patients with acute early stage (AES) CI and 30 patients with acute late stage (ALS) CI were detected by CT, which was significantly less than those detected by MRI (P < .05); 5 patients with <5 mm infarction were detected by CT in ALS and 10 patients with 5-15 mm infarction were detected by CT in ALS, which were significantly less than those detected by MRI (P < .05); 3 patients were diagnosed with cerebral sulcus, fissure, and shallow and disappeared brain cistern, 4 patients with local gyrus swelling, and 31 patients with significant swelling by CT examination, which was significantly less than those detected by MRI (P < .05); the infarct area ratio measured by CT/ diffusion weighted imaging (DWI) was significantly lower than that measured by fluid attenuated inversion recovery (FLAIR)/DWI (P < .05); the diagnostic specificity (Sp), sensitivity (Se), Youden index, positive predictive value (PV), and negative PV of MRI were 0.82, 0.79, 0.58, 0.7, and 0.88, respectively, which were significantly better than those of CT (P < .05).

CONCLUSION: CT is not a sensitive technique for the diagnosis of early CI. Compared to CT, MRI has the characteristics of multi-sequence and multi-parameter imaging, is more sensitive to infarction within 2 hours after onset, and can more clearly and accurately diagnose CI.}, } @article {pmid39037980, year = {2024}, author = {Souza, AA and da Silva, ST and Macedo, LRD and Aires, DN and Pondofe, KM and Melo, LP and Valentim, RAM and Ribeiro, TS}, title = {Physical therapy for muscle strengthening in individuals with amyotrophic lateral sclerosis: A protocol for a systematic review and meta-analysis.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0307470}, pmid = {39037980}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Muscle Strength ; *Systematic Reviews as Topic ; *Meta-Analysis as Topic ; Physical Therapy Modalities ; Female ; Male ; }, abstract = {INTRODUCTION: People with Amyotrophic Lateral Sclerosis (ALS) can present initially muscle weakness, which is a debilitating symptom that may be improved by engaging in muscle strengthening activities. Currently, the effects of motor interventions for muscle strengthening in people with ALS are unclear. This review intends to analyze the effects of motor interventions for muscle strengthening in individuals with ALS.

METHODS AND ANALYSIS: Randomized, non-randomized, and quasi-experimental clinical trials assessing individuals with ALS of both sexes, aged 18 years or older, who have received motor interventions for muscle strengthening considering all practices that can lead to increased strength, endurance, power and muscular hypertrophy will be included. No restriction on language, location, or publication date will be applied. MEDLINE, EMBASE, Cochrane Library (CENTRAL), SPORTDiscus, and Physiotherapy Evidence Database (PEDro) databases will be searched. The US National Institutes of Health Ongoing, ClinicalTrials.gov, and the reference lists of included studies will also be searched. Two reviewers will independently screen titles and abstracts and extract data from included studies. The methodological quality of the included studies will be assessed by the PEDro scale and the certainty of the evidence by the GRADE approach. Disagreements will be resolved by a third researcher. Findings will be presented in text and table formats. A meta-analysis will compare the effects of motor interventions for muscle strengthening versus placebo or other interventions.}, } @article {pmid39037015, year = {2024}, author = {Timmins, HC and Thompson, AE and Kiernan, MC}, title = {Diagnostic criteria for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {570-576}, doi = {10.1097/WCO.0000000000001302}, pmid = {39037015}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Humans ; *Biomarkers/analysis ; }, abstract = {PURPOSE OF REVIEW: The present review will discuss the evolution of diagnostic criteria for amyotrophic lateral sclerosis (ALS) and biomarker considerations.

RECENT FINDINGS: To address the limitations of existing ALS diagnostic criteria, a consortium of key stakeholders developed the Gold Coast consensus criteria (GCC). The GCC has similar or greater sensitivity compared with the revised El Escorial (rEEC) and Awaji criteria (AC), particularly for atypical phenotypes, maintained across disease duration, severity, and site of onset. In addition to improving diagnostic sensitivity, using the GCC in clinical trials may promote an increased enrolment of up to 50% of ALS patients who do not currently meet the full diagnostic eligibility requirements of the rEEC. Future inclusion of genetic biomarkers may mitigate some limitations of the GCC, to further improve diagnostic utility. In advance of such a process, validation of these biomarkers will be required before inclusion as additional criteria.

SUMMARY: The GCC are simpler to use than previous consensus criteria, with demonstrated greater sensitivity and, enabling an earlier and more definitive ALS diagnosis, thereby facilitating wider enrolment into clinical trials. Broader implementation of the GCC in clinical trial settings is currently underway, globally.}, } @article {pmid39033904, year = {2024}, author = {Lu, XY and Li, MQ and Li, YT and Yao, JY and Zhang, LX and Zeng, ZH and Yu-Liu, and Chen, ZR and Li, CQ and Zhou, XF and Li, F}, title = {Oral edaravone ameliorates behavioral deficits and pathologies in a valproic acid-induced rat model of autism spectrum disorder.}, journal = {Neuropharmacology}, volume = {258}, number = {}, pages = {110089}, doi = {10.1016/j.neuropharm.2024.110089}, pmid = {39033904}, issn = {1873-7064}, mesh = {Animals ; *Valproic Acid/pharmacology/administration & dosage ; *Edaravone/pharmacology ; *Autism Spectrum Disorder/drug therapy/chemically induced ; *Disease Models, Animal ; Female ; *Oxidative Stress/drug effects ; Male ; Administration, Oral ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Brain/drug effects/metabolism/pathology ; Prenatal Exposure Delayed Effects/chemically induced ; Free Radical Scavengers/pharmacology/administration & dosage/therapeutic use ; Dose-Response Relationship, Drug ; Stereotyped Behavior/drug effects ; Behavior, Animal/drug effects ; Social Interaction/drug effects ; }, abstract = {Autism spectrum disorder (ASD) is neurodevelopmental disorder with a high incidence rate, characterized by social deficits and repetitive behaviors. There is currently no effective management available to treat the core symptoms of ASD; however, oxidative stress has been implicated in its pathogenesis. Edaravone (EDA), a free-radical scavenger, is used to treat amyotrophic lateral sclerosis (ALS) and acute ischemic stroke (AIS). Here, we hypothesized that an oral formula of EDA may have therapeutic efficacy in the treatment of core ASD symptoms. A rat model of autism was established by prenatal exposure to valproic acid (VPA), and the offsprings were orally treated with EDA at low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg) doses once daily for 28 days starting from postnatal day 25 (PND25). Oral EDA administration alleviated the core symptoms in VPA rats in a dose-dependent manner, including repetitive stereotypical behaviors and impaired social interaction. Furthermore, oral administration of EDA significantly reduced oxidative stress in a dose-dependent manner, as evidenced by a reduction in oxidative stress markers and an increase in antioxidants in the blood and brain. In addition, oral EDA significantly attenuated downstream pathologies, including synaptic and mitochondrial damage in the brain. Proteomic analysis further revealed that EDA corrected the imbalance in brain oxidative reduction and mitochondrial proteins induced by prenatal VPA administration. Overall, these findings demonstrate that oral EDA has therapeutic potential for ASD by targeting the oxidative stress pathway of disease pathogenesis and paves the way towards clinical studies.}, } @article {pmid39032803, year = {2024}, author = {He, Q and Zhou, Y and Jin, J and Tian, Q and Li, H and Hou, B and Xie, A}, title = {Association between NEK1 gene polymorphisms and the potential risk of sporadic Parkinson's disease in the Chinese Northern Han population: A case-control study.}, journal = {Neuroscience letters}, volume = {837}, number = {}, pages = {137913}, doi = {10.1016/j.neulet.2024.137913}, pmid = {39032803}, issn = {1872-7972}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Case-Control Studies ; China/epidemiology ; East Asian People/genetics ; Genetic Association Studies ; *Genetic Predisposition to Disease ; Genotype ; *NIMA-Related Kinase 1/genetics ; *Parkinson Disease/genetics ; *Polymorphism, Single Nucleotide ; }, abstract = {OBJECTIVE: Parkinson's disease (PD) has been identified as a genetically influenced disease linked to various genetic loci. Previous studies have suggested that neurodegenerative illnesses, including PD, Alzheimer's disease, and Amyotrophic lateral sclerosis (ALS), may share certain genetic loci. Recently, the NEK1 gene was identified as overlapping between PD and ALS. We therefore wanted to explore the potential association between the NEK1 gene single nucleotide polymorphisms (SNPs) and the clinical features and pathophysiology of sporadic PD in a northern Chinese population.

METHODS: A total of 510 sporadic PD patients and 510 age- and sex-matched healthy controls (HCs) were included in this study. Two SNPs (rs4563461 and rs66509122) of the NEK1 gene were genotyped using polymerase chain reaction (PCR). And we analyzed the association between NEK1 gene polymorphisms and clinical manifestations.

RESULTS: Allele T (C vs. T, P = 0.018) and genotype TT (CC vs. TT: P = 0.021) of rs66509122 among PD group and HCs were significantly different. In addition, we discovered that the rs66509122 genotype TT was associated with depression in early-onset PD (EOPD) (P = 0.031) and diabetes in female PD (P = 0.032). Unfortunately, no distinct correlation of rs4563461 polymorphisms with sporadic PD susceptibility was found in either the overall group (C vs. T, P = 0.086) or other subgroups. However, the T allele of rs4563461 was significantly correlated with sleep disorders in the PD group, especially in the late-onset PD (LOPD) group and male PD group.

CONCLUSION: This study found that the NEK1 rs66509122 polymorphism was associated with a lower risk of sporadic PD, while T allele of rs66509122 may be a protective factor for PD. The NEK1 rs4563461 and rs66509122 polymorphisms both showed correlations with some non-motor symptoms in sporadic PD patients. Further research with a larger sample and varied ethnic groups is needed to investigate the role of NEK1 gene polymorphisms in the pathophysiology of PD.}, } @article {pmid39032788, year = {2024}, author = {Wu, KJ and Wei, KC}, title = {Response to Hasan et al's "Dupilumab therapy for atopic dermatitis is associated with increased risk of cutaneous T cell lymphoma: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {5}, pages = {e145-e146}, doi = {10.1016/j.jaad.2024.06.091}, pmid = {39032788}, issn = {1097-6787}, } @article {pmid39031772, year = {2024}, author = {Meyer, T and Schumann, P and Weydt, P and Petri, S and Weishaupt, JH and Weyen, U and Koch, JC and Günther, R and Regensburger, M and Boentert, M and Wiesenfarth, M and Koc, Y and Kolzarek, F and Kettemann, D and Norden, J and Bernsen, S and Elmas, Z and Conrad, J and Valkadinov, I and Vidovic, M and Dorst, J and Ludolph, AC and Hesebeck-Brinckmann, J and Spittel, S and Münch, C and Maier, A and Körtvélyessy, P}, title = {Clinical and patient-reported outcomes and neurofilament response during tofersen treatment in SOD1-related ALS-A multicenter observational study over 18 months.}, journal = {Muscle & nerve}, volume = {70}, number = {3}, pages = {333-345}, doi = {10.1002/mus.28182}, pmid = {39031772}, issn = {1097-4598}, support = {(H4017703513237604)//Boris Canessa ALS Stiftung (Düsseldorf, Germany) and Martin Herrenknecht Fonds for ALS Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Male ; Female ; *Patient Reported Outcome Measures ; Middle Aged ; Aged ; *Superoxide Dismutase-1/genetics ; *Neurofilament Proteins/blood ; Treatment Outcome ; Disease Progression ; Adult ; Oligonucleotides/therapeutic use ; }, abstract = {INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (SOD1-ALS), tofersen received accelerated approval in the United States and is available via expanded access programs (EAP) outside the United States. This multicenter study investigates clinical and patient-reported outcomes (PRO) and serum neurofilament light chain (sNfL) during tofersen treatment in an EAP in Germany.

METHODS: Sixteen SOD1-ALS patients receiving tofersen for at least 6 months were analyzed. The ALS progression rate (ALS-PR), as measured by the monthly change of the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity (SVC), and sNfL were investigated. PRO included the Measure Yourself Medical Outcome Profile (MYMOP2), Treatment Satisfaction Questionnaire for Medication (TSQM-9), and Net Promoter Score (NPS).

RESULTS: Mean tofersen treatment was 11 months (6-18 months). ALS-PR showed a mean change of -0.2 (range 0 to -1.1) and relative reduction by 25%. Seven patients demonstrated increased ALSFRS-R. SVC was stable (mean 88%, range -15% to +28%). sNfL decreased in all patients except one heterozygous D91A-SOD1 mutation carrier (mean change of sNfL -58%, range -91 to +27%, p < .01). MYMOP2 indicated improved symptom severity (n = 10) or yet perception of partial response (n = 6). TSQM-9 showed high global treatment satisfaction (mean 83, SD 16) although the convenience of drug administration was modest (mean 50, SD 27). NPS revealed a very high recommendation rate for tofersen (NPS +80).

DISCUSSION: Data from this EAP supported the clinical and sNfL response to tofersen in SOD1-ALS. PRO suggested a favorable patient perception of tofersen treatment in clinical practice.}, } @article {pmid39030740, year = {2024}, author = {Jonson, C and Levine, KS and Lake, J and Hertslet, L and Jones, L and Patel, D and Kim, J and Bandres-Ciga, S and Terry, N and Mata, IF and Blauwendraat, C and Singleton, AB and Nalls, MA and Yokoyama, JS and Leonard, HL}, title = {Assessing the lack of diversity in genetics research across neurodegenerative diseases: A systematic review of the GWAS Catalog and literature.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {20}, number = {8}, pages = {5740-5756}, pmid = {39030740}, issn = {1552-5279}, support = {U19AG079774/NS/NINDS NIH HHS/United States ; R01 AG062588/AG/NIA NIH HHS/United States ; ZO1AG000534/HH/HHS/United States ; U19 AG079774/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; 75N95022C00031/NS/NINDS NIH HHS/United States ; //Intramural Research Program/ ; P01AG019724/NS/NINDS NIH HHS/United States ; P30AG062422/NS/NINDS NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; U54NS123985/NS/NINDS NIH HHS/United States ; 75N95022C00031/DA/NIDA NIH HHS/United States ; U54 NS123985/NS/NINDS NIH HHS/United States ; R01AG057234/NS/NINDS NIH HHS/United States ; R01AG062588/NS/NINDS NIH HHS/United States ; //Global Brain Health Institute; and the Mary Oakley Foundation/ ; //Rainwater Charitable Foundation/ ; }, mesh = {Humans ; Genetic Predisposition to Disease/genetics ; *Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics ; White People/genetics ; }, abstract = {The under-representation of non-European cohorts in neurodegenerative disease genome-wide association studies (GWAS) hampers precision medicine efforts. Despite the inherent genetic and phenotypic diversity in these diseases, GWAS research consistently exhibits a disproportionate emphasis on participants of European ancestry. This study reviews GWAS up to 2022, focusing on non-European or multi-ancestry neurodegeneration studies. We conducted a systematic review of GWAS results and publications up to 2022, focusing on non-European or multi-ancestry neurodegeneration studies. Rigorous article inclusion and quality assessment methods were employed. Of 123 neurodegenerative disease (NDD) GWAS reviewed, 82% predominantly featured European ancestry participants. A single European study identified over 90 risk loci, compared to a total of 50 novel loci in identified in all non-European or multi-ancestry studies. Notably, only six of the loci have been replicated. The significant under-representation of non-European ancestries in NDD GWAS hinders comprehensive genetic understanding. Prioritizing genomic diversity in future research is crucial for advancing NDD therapies and understanding. HIGHLIGHTS: Eighty-two percent of neurodegenerative genome-wide association studies (GWAS) focus on Europeans. Only 6 of 50 novel neurodegenerative disease (NDD) genetic loci have been replicated. Lack of diversity significantly hampers understanding of NDDs. Increasing diversity in NDD genetic research is urgently required. New initiatives are aiming to enhance diversity in NDD research.}, } @article {pmid39030617, year = {2024}, author = {Chen, T and Dai, Y and Hu, C and Lin, Z and Wang, S and Yang, J and Zeng, L and Li, S and Li, W}, title = {Cellular and molecular mechanisms of the blood-brain barrier dysfunction in neurodegenerative diseases.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {60}, pmid = {39030617}, issn = {2045-8118}, support = {LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; No.X-202102//Scientific Research Foundation of Zhejiang University City College/ ; }, mesh = {*Blood-Brain Barrier/metabolism/physiopathology ; Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; Animals ; }, abstract = {BACKGROUND: Maintaining the structural and functional integrity of the blood-brain barrier (BBB) is vital for neuronal equilibrium and optimal brain function. Disruptions to BBB performance are implicated in the pathology of neurodegenerative diseases.

MAIN BODY: Early indicators of multiple neurodegenerative disorders in humans and animal models include impaired BBB stability, regional cerebral blood flow shortfalls, and vascular inflammation associated with BBB dysfunction. Understanding the cellular and molecular mechanisms of BBB dysfunction in brain disorders is crucial for elucidating the sustenance of neural computations under pathological conditions and for developing treatments for these diseases. This paper initially explores the cellular and molecular definition of the BBB, along with the signaling pathways regulating BBB stability, cerebral blood flow, and vascular inflammation. Subsequently, we review current insights into BBB dynamics in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The paper concludes by proposing a unified mechanism whereby BBB dysfunction contributes to neurodegenerative disorders, highlights potential BBB-focused therapeutic strategies and targets, and outlines lessons learned and future research directions.

CONCLUSIONS: BBB breakdown significantly impacts the development and progression of neurodegenerative diseases, and unraveling the cellular and molecular mechanisms underlying BBB dysfunction is vital to elucidate how neural computations are sustained under pathological conditions and to devise therapeutic approaches.}, } @article {pmid39030200, year = {2024}, author = {Erb, ML and Sipple, K and Levine, N and Chen, X and Moore, DJ}, title = {Adult-onset deletion of ATP13A2 in mice induces progressive nigrostriatal pathway dopaminergic degeneration and lysosomal abnormalities.}, journal = {NPJ Parkinson's disease}, volume = {10}, number = {1}, pages = {133}, pmid = {39030200}, issn = {2373-8057}, support = {PF-FBS-1894//Parkinson's Foundation (Parkinson's Foundation, Inc.)/ ; PF-FBS-1894//Parkinson's Foundation (Parkinson's Foundation, Inc.)/ ; }, abstract = {Although most cases of Parkinson's disease (PD) are sporadic, mutations in over 20 genes are known to cause heritable forms of the disease. Recessive loss-of-function mutations in ATP13A2, a lysosomal transmembrane P5B-type ATPase and polyamine exporter, can cause early-onset familial PD. Familial ATP13A2 mutations are also linked to related neurodegenerative diseases, including Kufor-Rakeb syndrome, hereditary spastic paraplegias, neuronal ceroid lipofuscinosis, and amyotrophic lateral sclerosis. Despite the severe effects of ATP13A2 mutations in humans, ATP13A2 knockout (KO) mice fail to exhibit neurodegeneration even at advanced ages, making it challenging to study the neuropathological effects of ATP13A2 loss in vivo. Germline deletion of ATP13A2 in rodents may trigger the upregulation of compensatory pathways during embryonic development that mask the full neurotoxic effects of ATP13A2 loss in the brain. To explore this idea, we selectively deleted ATP13A2 in the adult mouse brain by the unilateral delivery of an AAV-Cre vector into the substantia nigra of young adult mice carrying conditional loxP-flanked ATP13A2 KO alleles. We observe a progressive loss of striatal dopaminergic nerve terminals at 3 and 10 months after AAV-Cre delivery. Cre-injected mice also exhibit robust dopaminergic neuronal degeneration in the substantia nigra at 10 months. Adult-onset ATP13A2 KO also recreates many of the phenotypes observed in aged germline ATP13A2 KO mice, including lysosomal abnormalities, p62-positive inclusions, and neuroinflammation. Our study demonstrates that the adult-onset homozygous deletion of ATP13A2 in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration that serves as a useful in vivo model of ATP13A2-related neurodegenerative diseases.}, } @article {pmid39030186, year = {2024}, author = {Dubbioso, R and Spisto, M and Verde, L and Iuzzolino, VV and Senerchia, G and Salvatore, E and De Pietro, G and De Falco, I and Sannino, G}, title = {Voice signals database of ALS patients with different dysarthria severity and healthy controls.}, journal = {Scientific data}, volume = {11}, number = {1}, pages = {800}, pmid = {39030186}, issn = {2052-4463}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; *Dysarthria/physiopathology ; Male ; Female ; Voice ; Databases, Factual ; Middle Aged ; Adult ; Aged ; Case-Control Studies ; }, abstract = {This paper describes a new publicly-available database of VOiCe signals acquired in Amyotrophic Lateral Sclerosis (ALS) patients (VOC-ALS) and healthy controls performing different speech tasks. This dataset consists of 1224 voice signals recorded from 153 participants: 51 healthy controls (32 males and 19 females) and 102 ALS patients (65 males and 37 females) with different severity of dysarthria. Each subject's voice was recorded using a smartphone application (Vox4Health) while performing several vocal tasks, including a sustained phonation of the vowels /a/, /e/, /i/, /o/, /u/ and /pa/, /ta/, /ka/ syllable repetition. Basic derived speech metrics such as harmonics-to-noise ratio, mean and standard deviation of fundamental frequency (F0), jitter and shimmer were calculated. The F0 standard deviation of vowels and syllables showed an excellent ability to identify people with ALS and to discriminate the different severity of dysarthria. These data represent the most comprehensive database of voice signals in ALS and form a solid basis for research on the recognition of voice impairment in ALS patients for use in clinical applications.}, } @article {pmid39030042, year = {2024}, author = {Haberkamp, M and Aislaitner, G and Martínez-Lapiscina, EH and Weise, M}, title = {Tofersen for SOD-1-associated amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {23}, number = {8}, pages = {772-773}, doi = {10.1016/S1474-4422(24)00259-X}, pmid = {39030042}, issn = {1474-4465}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Superoxide Dismutase-1/genetics ; }, } @article {pmid39029959, year = {2024}, author = {}, title = {Erratum: Garbuzova-Davis et al., "Apolipoprotein A1 Enhances Endothelial Cell Survival in an In Vitro Model of ALS".}, journal = {eNeuro}, volume = {11}, number = {7}, pages = {}, doi = {10.1523/ENEURO.0280-24.2024}, pmid = {39029959}, issn = {2373-2822}, } @article {pmid39028002, year = {2025}, author = {Mercadante, S and Petronaci, A and Terranova, A and Casuccio, A}, title = {Characteristics of Patients With Amyotrophic Lateral Sclerosis Followed by a Home Palliative Care Team.}, journal = {The American journal of hospice & palliative care}, volume = {42}, number = {5}, pages = {483-488}, doi = {10.1177/10499091241266985}, pmid = {39028002}, issn = {1938-2715}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Male ; *Palliative Care/organization & administration ; Female ; *Home Care Services/organization & administration ; Middle Aged ; Aged ; Retrospective Studies ; *Patient Care Team/organization & administration ; Noninvasive Ventilation ; Aged, 80 and over ; Respiration, Artificial/statistics & numerical data ; Advance Care Planning/organization & administration ; Advance Directives/statistics & numerical data ; Nutritional Support ; }, abstract = {BackgroundInformation about patients with amyothrophic lateral sclerosis (ALS) followed at home is limited.ObjectivesTo assess patients's characteristics at admission to a home palliative care program based on a multidisciplinary team, and the temporal course along the trajectory of ALS disease.DesignRetrospective. Setting/subjects: Charts of a consecutive number of ALS patients who were referred to a specialistic home palliative care were reviewed.MeasurementGeneral data, referral, start of home palliative care, use of ventilator support and nutritional support, were recorded. The existence of advance directives and shared care planning was also collected.Results82 patients were examined; 31 patients died before the term of the study and 51 patients were still living. No patient anticipately expressed their will regarding their treatments. However, a certain number of patients shared a care planning with ALS team, generally after starting home care. Most patients did not have ventilatory support at the beginning of home care assistance, but progressively received ventilatory support by NIV or MV, particularly those who were still living. NIV at start of home care was negatively correlated to frontotemporal dementia. (P = 0.015), and directly correlated to referral from hospital and GP (P = 0.031) and awareness of disease (P = 0.034). Gastrostomy at start of home care was positively correlated to referral from hospital (P = 0.046). Gastrostomy during home care was correlated to bulbar SLA (P = 0.017). The use of NIV during home care was positively correlated to shared care planning (P = 0.001).ConclusionThe continuous presence of a multi-specialist team may provide timely intervention, guarantee and trust on the part of the patient and family members.}, } @article {pmid39026758, year = {2024}, author = {Onwunma, J and Binsabaan, S and Allen, SP and Sankaran, B and Wohlever, ML}, title = {The structural and biophysical basis of substrate binding to the hydrophobic groove in Ubiquilin Sti1 domains.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39026758}, issn = {2692-8205}, support = {P30 GM124169/GM/NIGMS NIH HHS/United States ; R35 GM137904/GM/NIGMS NIH HHS/United States ; }, abstract = {Ubiquilins are a family of cytosolic proteins that ferry ubiquitinated substrates to the proteasome for degradation. Recent work has demonstrated that Ubiquilins can also act as molecular chaperones, utilizing internal Sti1 domains to directly bind to hydrophobic sequences. Ubiquilins are associated with several neurodegenerative diseases with point mutations in UBQLN2 causing dominant, X-linked Amyotrophic Lateral Sclerosis (ALS). The molecular basis of Ubiquilin chaperone activity and how ALS mutations in the Sti1 domains affect Ubiquilin activity are poorly understood. This study presents the first crystal structure of the Sti1 domain from a fungal Ubiquilin homolog bound to a transmembrane domain (TMD). The structure reveals that two Sti1 domains form a head-to-head dimer, creating a hydrophobic cavity that accommodates two TMDs. Mapping the UBQLN2 sequence onto the structure shows that several ALS mutations are predicted to disrupt the hydrophobic groove. Using a newly developed competitive binding assay, we show that Ubiquilins preferentially bind to hydrophobic substrates with low helical propensity, motifs that are enriched in both substrates and in Ubiquilins. This study provides insights into the molecular and structural basis for Ubiquilin substrate binding, with broad implications for the role of the Sti1 domain in phase separation and ALS.}, } @article {pmid39026010, year = {2024}, author = {Read, TA and Cisterna, BA and Skruber, K and Ahmadieh, S and Liu, TM and Vitriol, JA and Shi, Y and Black, JB and Butler, MT and Lindamood, HL and Lefebvre, AE and Cherezova, A and Ilatovskaya, DV and Bear, JE and Weintraub, NL and Vitriol, EA}, title = {The actin binding protein profilin 1 localizes inside mitochondria and is critical for their function.}, journal = {EMBO reports}, volume = {25}, number = {8}, pages = {3240-3262}, pmid = {39026010}, issn = {1469-3178}, support = {R35 GM130312/GM/NIGMS NIH HHS/United States ; R35 GM137959/GM/NIGMS NIH HHS/United States ; R35GM137959//Foundation for the National Institutes of Health (FNIH)/ ; }, mesh = {*Profilins/metabolism/genetics ; *Mitochondria/metabolism/genetics ; Humans ; *Actins/metabolism ; Mitophagy/genetics ; Lysosomes/metabolism ; Cytosol/metabolism ; Gene Knockout Techniques ; Autophagosomes/metabolism ; HeLa Cells ; }, abstract = {The monomer-binding protein profilin 1 (PFN1) plays a crucial role in actin polymerization. However, mutations in PFN1 are also linked to hereditary amyotrophic lateral sclerosis, resulting in a broad range of cellular pathologies which cannot be explained by its primary function as a cytosolic actin assembly factor. This implies that there are important, undiscovered roles for PFN1 in cellular physiology. Here we screened knockout cells for novel phenotypes associated with PFN1 loss of function and discovered that mitophagy was significantly upregulated. Indeed, despite successful autophagosome formation, fusion with the lysosome, and activation of additional mitochondrial quality control pathways, PFN1 knockout cells accumulate depolarized, dysmorphic mitochondria with altered metabolic properties. Surprisingly, we also discovered that PFN1 is present inside mitochondria and provide evidence that mitochondrial defects associated with PFN1 loss are not caused by reduced actin polymerization in the cytosol. These findings suggest a previously unrecognized role for PFN1 in maintaining mitochondrial integrity and highlight new pathogenic mechanisms that can result from PFN1 dysregulation.}, } @article {pmid39025824, year = {2024}, author = {Lorenc, T and Khouja, C and Harden, M and Fulbright, H and Thomas, J}, title = {Defensive healthcare practice: systematic review of qualitative evidence.}, journal = {BMJ open}, volume = {14}, number = {7}, pages = {e085673}, pmid = {39025824}, issn = {2044-6055}, mesh = {Humans ; *Qualitative Research ; *Defensive Medicine ; Attitude of Health Personnel ; }, abstract = {OBJECTIVE: To synthesise qualitative evidence on clinicians' views and experiences of defensive practice.

DESIGN: Systematic review of qualitative data.

DATA SOURCES: MEDLINE, Embase, PsycINFO, AMED, Maternity and Infant Care, CINAHL, ASSIA, Sociological Abstracts, Proquest Dissertations & Theses and PROSPERO were searched from 2000 to October 2023.

ELIGIBILITY CRITERIA: We included English-language studies of clinicians which reported qualitative data on the impact of litigation or complaints on clinical practice.

DATA EXTRACTION AND SYNTHESIS: We coded findings data line by line using a grounded theory approach. We assessed quality using Hawker et al's tool and synthesised data thematically.

RESULTS: 17 studies were included. Participants identify a range of clinical decisions which may be defensively motivated, relating to diagnosis and documentation as well as to treatment. Defensive practice often relates to a diffuse sense of risk rather than the direct threat of litigation and may overlap with other motivations, such as perceived pressure from patients or the desire to avoid harm. Defensive practice is seen to be harmful in many ways, but again, these perceptions may gain force from broader narratives of mistrust and disempowerment, as much as from the risk of litigation.

CONCLUSIONS: The idea of defensive practice, as enacted, is more complex than some theoretical accounts suggest and may often function to express broader concerns about the work of clinical care. The qualitative evidence calls into question the view of defensive practice as a key mediator linking litigation risk to inappropriate treatment and excess costs.}, } @article {pmid39023312, year = {2024}, author = {Miceli, M and Cannariato, M and Tortarolo, R and Pallante, L and Zizzi, EA and Deriu, MA}, title = {Conformational Dynamics and Molecular Characterization of Alsin MORN Monomer and Dimeric Assemblies.}, journal = {Proteins}, volume = {92}, number = {11}, pages = {1343-1353}, doi = {10.1002/prot.26728}, pmid = {39023312}, issn = {1097-0134}, support = {GSP 20005_PAsIAHSP007//Fondazione Telethon/ ; //Associazione Help Olly Onlus-Italy/ ; }, mesh = {*Protein Multimerization ; Humans ; Molecular Dynamics Simulation ; Protein Conformation, alpha-Helical ; Protein Stability ; Protein Conformation, beta-Strand ; Protein Domains ; Amino Acid Sequence ; Models, Molecular ; Protein Interaction Domains and Motifs ; Protein Conformation ; Guanine Nucleotide Exchange Factors ; }, abstract = {Despite the ubiquity of membrane occupation recognition nexus (MORN) motifs across diverse species in both eukaryotic and prokaryotic organisms, these protein domains remain poorly characterized. Their significance is underscored in the context of the Alsin protein, implicated in the debilitating condition known as infantile-onset ascending hereditary spastic paralysis (IAHSP). Recent investigations have proposed that mutations within the Alsin MORN domain disrupt proper protein assembly, precluding the formation of the requisite tetrameric configuration essential for the protein's inherent biological activity. However, a comprehensive understanding of the relationship between the biological functions of Alsin and its three-dimensional molecular structure is hindered by the lack of available experimental structures. In this study, we employed and compared several protein structure prediction algorithms to identify a three-dimensional structure for the putative MORN of Alsin. Furthermore, inspired by experimental pieces of evidence from previous studies, we employed the developed models to predict and investigate two homo-dimeric assemblies, characterizing their stability. This study's insights into the three-dimensional structure of the Alsin MORN domain and the stability dynamics of its homo-dimeric assemblies suggest an antiparallel linear configuration stabilized by a noncovalent interaction network.}, } @article {pmid39023172, year = {2024}, author = {Zaky, MH and Shoorangiz, R and Poudel, GR and Yang, L and Innes, CRH and Jones, RD}, title = {Conscious but not thinking-Mind-blanks during visuomotor tracking: An fMRI study of endogenous attention lapses.}, journal = {Human brain mapping}, volume = {45}, number = {11}, pages = {e26781}, pmid = {39023172}, issn = {1097-0193}, support = {08-VDV-01 EHB//Marsden Fund, Royal Society of New Zealand/ ; //University of Canterbury/ ; //University of Otago/ ; 236930//Lottery Health Research/ ; }, mesh = {Humans ; Adult ; *Magnetic Resonance Imaging ; Female ; Male ; Young Adult ; *Attention/physiology ; *Psychomotor Performance/physiology ; Middle Aged ; Eye-Tracking Technology ; Thinking/physiology ; Nerve Net/diagnostic imaging/physiopathology/physiology ; Consciousness/physiology ; Visual Perception/physiology ; Motor Activity/physiology ; }, abstract = {Attention lapses (ALs) are complete lapses of responsiveness in which performance is briefly but completely disrupted and during which, as opposed to microsleeps, the eyes remain open. Although the phenomenon of ALs has been investigated by behavioural and physiological means, the underlying cause of an AL has largely remained elusive. This study aimed to investigate the underlying physiological substrates of behaviourally identified endogenous ALs during a continuous visuomotor task, primarily to answer the question: Were the ALs during this task due to extreme mind-wandering or mind-blanks? The data from two studies were combined, resulting in data from 40 healthy non-sleep-deprived subjects (20M/20F; mean age 27.1 years, 20-45). Only 17 of the 40 subjects were used in the analysis due to a need for a minimum of two ALs per subject. Subjects performed a random 2-D continuous visuomotor tracking task for 50 and 20 min in Studies 1 and 2, respectively. Tracking performance, eye-video, and functional magnetic resonance imaging (fMRI) were recorded simultaneously. A human expert visually inspected the tracking performance and eye-video recordings to identify and categorise lapses of responsiveness as microsleeps or ALs. Changes in neural activity during 85 ALs (17 subjects) relative to responsive tracking were estimated by whole-brain voxel-wise fMRI and by haemodynamic response (HR) analysis in regions of interest (ROIs) from seven key networks to reveal the neural signature of ALs. Changes in functional connectivity (FC) within and between the key ROIs were also estimated. Networks explored were the default mode network, dorsal attention network, frontoparietal network, sensorimotor network, salience network, visual network, and working memory network. Voxel-wise analysis revealed a significant increase in blood-oxygen-level-dependent activity in the overlapping dorsal anterior cingulate cortex and supplementary motor area region but no significant decreases in activity; the increased activity is considered to represent a recovery-of-responsiveness process following an AL. This increased activity was also seen in the HR of the corresponding ROI. Importantly, HR analysis revealed no trend of increased activity in the posterior cingulate of the default mode network, which has been repeatedly demonstrated to be a strong biomarker of mind-wandering. FC analysis showed decoupling of external attention, which supports the involuntary nature of ALs, in addition to the neural recovery processes. Other findings were a decrease in HR in the frontoparietal network before the onset of ALs, and a decrease in FC between default mode network and working memory network. These findings converge to our conclusion that the ALs observed during our task were involuntary mind-blanks. This is further supported behaviourally by the short duration of the ALs (mean 1.7 s), which is considered too brief to be instances of extreme mind-wandering. This is the first study to demonstrate that at least the majority of complete losses of responsiveness on a continuous visuomotor task are, if not due to microsleeps, due to involuntary mind-blanks.}, } @article {pmid39022351, year = {2024}, author = {Corvino, A and Caliendo, G and Fiorino, F and Frecentese, F and Valsecchi, V and Lombardi, G and Anzilotti, S and Andreozzi, G and Scognamiglio, A and Sparaco, R and Perissutti, E and Severino, B and Gargiulo, M and Santagada, V and Pignataro, G}, title = {Newly Synthesized Indolylacetic Derivatives Reduce Tumor Necrosis Factor-Mediated Neuroinflammation and Prolong Survival in Amyotrophic Lateral Sclerosis Mice.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {7}, pages = {1996-2005}, pmid = {39022351}, issn = {2575-9108}, abstract = {The debilitating neurodegenerative disease known as amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons (MNs) in the brain, spinal cord, and motor cortex. The ALS neuroinflammatory component is being characterized and includes the overexpression of mediators, such as inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α). Currently, there are no effective treatments for ALS. Indeed, riluzole, an N-methyl-D-aspartate (NMDA) glutamate receptor blocker, and edaravone, a reactive oxygen species (ROS) scavenger, are currently the sole two medications approved for ALS treatment. However, their efficacy in extending life expectancy typically amounts to only a few months. In order to improve the medicaments for the treatment of neurodegenerative diseases, preferably ALS, novel substituted 2-methyl-3-indolylacetic derivatives (compounds II-IV) were developed by combining the essential parts of two small molecules, namely, the opioids containing a 4-piperidinyl ring with indomethacin, previously shown to be efficacious in different experimental models of neuroinflammation. The synthesized compounds were evaluated for their potential capability of slowing down neurodegeneration associated with ALS progression in preclinical models of the disease in vitro and in vivo. Notably, we produced data to demonstrate that the treatment with the newly synthesized compound III: (1) prevented the upregulation of TNF-α observed in BV-2 microglial cells exposed to the toxin lipopolysaccharides (LPS), (2) preserved SHSY-5Y cell survival exposed to β-N-methylamino-l-alanine (L-BMAA) neurotoxin, and (3) mitigated motor symptoms and improved survival rate of SOD1G93A ALS mice. In conclusion, the findings of the present work support the potential of the synthesized indolylacetic derivatives II-IV in ALS treatment. Indeed, in the attempt to realize an association between two active molecules, we assumed that the combination of the indispensable moieties of two small molecules (the opioids containing a 4-piperidinyl ring with the FANS indomethacin) might lead to new medicaments potentially useful for the treatment of amyotrophic lateral sclerosis.}, } @article {pmid39020237, year = {2024}, author = {Yuan, ZL and Ren, J and Huang, ML and Qi, YF and Gao, X and Sun, YY and He, YL and Zhu, L and Xue, HD}, title = {A new magnetic resonance imaging-based PUMCH classification system for congenital cervical malformations: devising a standardised diagnosis pathway.}, journal = {Insights into imaging}, volume = {15}, number = {1}, pages = {177}, pmid = {39020237}, issn = {1869-4101}, support = {2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; 2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; 2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; 2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; }, abstract = {OBJECTIVES: To develop an innovative magnetic resonance imaging (MRI)-based PUMCH (Peking Union Medical College Hospital) classification system aimed at standardising the diagnosis of congenital cervical malformations (CCMs) by identifying their distinctive MRI features.

METHODS: Seventy-nine consecutive patients with CCM underwent pre-treatment pelvic MRI; three experienced gynaecological radiologists retrospectively analysed these images. Qualitative assessments included Rock et al's classification; PUMCH classification; haematometra; cervical signal features; ovarian endometriosis; haematosalpinx; and uterine, vaginal, urinary, and musculoskeletal malformations. Quantitative assessments involved the uterine volume, sagittal cervical length, and maximum ovarian cross-sectional area. The surgical treatment types were also recorded. Statistical methods were used to incorporate differences in clinical features and surgical methods into our classification.

RESULTS: Morphologically, CCMs were categorised into three types: type I (53%) was characterised by the presence of a cervix with visible cervical canals; type II (23%) featured an existing cervix with concealed cervical canals; and type III (24%) indicated cervical aplasia, which involves a blind end in the lower part of the uterine corpus. Haematometra was significantly more prevalent in patients with type I CCM than in those with type II (p < 0.001). There were three cervical signal patterns: no signal (27%), no evident layer differentiation (21%), and multi-layer differentiation with haematocele (52%). Most patients (94%) had complete vaginal atresia. Type I CCM patients had a higher likelihood of regaining normal uterovaginal anatomy compared to types II and III.

CONCLUSIONS: Our proposed PUMCH classification system has a high potential for enhancing the efficiency of clinical diagnosis among patients with CCM.

CRITICAL RELEVANCE STATEMENT: The proposed new PUMCH classification promised to elevate the conventional diagnostic trajectory for congenital cervical malformations, offering a valuable framework to refine the selection and planning of surgical interventions, thereby enhancing overall clinical efficacy.

KEY POINTS: Effective classification of congenital cervical malformations is desirable to optimise the diagnostic process. We presented a PUMCH classification of congenital cervical malformations using pelvic MRI. The new classification significantly aids clinical triage for congenital cervical malformations.}, } @article {pmid39019674, year = {2024}, author = {Georges, M and Perez, T and Rabec, C and Jacquin, L and Finet-Monnier, A and Ramos, C and Patout, M and Attali, V and Amador, M and Gonzalez-Bermejo, J and Salachas, F and Morelot-Panzini, C}, title = {[Proposals from a French expert panel for respiratory care in ALS patients].}, journal = {Revue des maladies respiratoires}, volume = {41}, number = {8}, pages = {620-637}, doi = {10.1016/j.rmr.2024.06.006}, pmid = {39019674}, issn = {1776-2588}, mesh = {*Amyotrophic Lateral Sclerosis/complications/therapy ; Humans ; France/epidemiology ; *Noninvasive Ventilation/methods/standards/instrumentation ; *Respiratory Insufficiency/therapy/etiology ; Respiratory Therapy/methods/standards ; Quality of Life ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive diaphragm weakness and deteriorating lung function. Bulbar involvement and cough weakness contribute to respiratory morbidity and mortality. ALS-related respiratory failure significantly affects quality of life and is the leading cause of death. Non-invasive ventilation (NIV), which is the main recognized treatment for alleviating the symptoms of respiratory failure, prolongs survival and improves quality of life. However, the optimal timing for the initiation of NIV is still a matter of debate. NIV is a complex intervention. Multiple factors influence the efficacy of NIV and patient adherence. The aim of this work was to develop practical evidence-based advices to standardize the respiratory care of ALS patients in French tertiary care centres.

METHODS: For each proposal, a French expert panel systematically searched an indexed bibliography and prepared a written literature review that was then shared and discussed. A combined draft was prepared by the chairman for further discussion. All of the proposals were unanimously approved by the expert panel.

RESULTS: The French expert panel updated the criteria for initiating NIV in ALS patients. The most recent criteria were established in 2005. Practical advice for NIV initiation were included and the value of each tool available for NIV monitoring was reviewed. A strategy to optimize NIV parameters was suggested. Revisions were also suggested for the use of mechanically assisted cough devices in ALS patients.

CONCLUSION: Our French expert panel proposes an evidence-based review to update the respiratory care recommendations for ALS patients in daily practice.}, } @article {pmid39019135, year = {2024}, author = {Cao, M and Yi, L and Xu, Y and Tian, Y and Li, Z and Bi, Y and Guo, M and Li, Y and Liu, Y and Xu, X and Sun, J and Li, C and Duan, W}, title = {Inhibiting NF-κB inducing kinase improved the motor performance of ALS animal model.}, journal = {Brain research}, volume = {1843}, number = {}, pages = {149124}, doi = {10.1016/j.brainres.2024.149124}, pmid = {39019135}, issn = {1872-6240}, mesh = {Animals ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/drug therapy ; *Disease Models, Animal ; Mice, Inbred C57BL ; *Mice, Transgenic ; *NF-kappa B/metabolism ; *NF-kappaB-Inducing Kinase ; *Protein Serine-Threonine Kinases/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a typical neurodegenerative disorder typically characterized by inflammation activation. However, the relationship between non-canonical NF-κB (ncNF-κB) pathway activation and ALS progression is not clear.

METHODS: We tested the ncNF-κB pathway in the ALS animal model including hSOD1-G93A transgenic mice and TBK1 deletion mice.We treated age-matched SOD1-G93A mice with B022 (a NIK inhibitor) to investigate the role of NIK in the ALS animal model. We also established a new mice model by crossing SOD1-G93A mice with NIK[+/-] mice to further evaluate the interrelationship between the NIK and the disease progression in ALS animal model.

RESULTS: In this study, we found the ncNF-κB pathway was activated in SOD1-G93A animal model and TBK1 deletion model. Inhibition of NIK activity by small molecule B022 significantly improved the motor performance of the ALS animal model. However, NIK deletion enhanced the mutant SOD1 toxicity by inflammatory infiltration.

CONCLUSION: TBK1 deletion and mutant SOD1 shared the common pathological feature possibly via effects on NIK activation and inhibitor of NIK could be a novel strategy for treating ALS.}, } @article {pmid39017978, year = {2025}, author = {Vinceti, M and Urbano, T and Filippini, T and Bedin, R and Simonini, C and Sorarù, G and Trojsi, F and Michalke, B and Mandrioli, J}, title = {Changes in Cerebrospinal Fluid Concentrations of Selenium Species Induced by Tofersen Administration in Subjects with Amyotrophic Lateral Sclerosis Carrying SOD1 Gene Mutations.}, journal = {Biological trace element research}, volume = {203}, number = {4}, pages = {2355-2364}, pmid = {39017978}, issn = {1559-0720}, support = {"PRIN 2022" (no. 2022MHMRPR)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; "PRIN 2022 PNRR" (no. P20229KSXB)//Ministero dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/drug therapy/genetics ; *Selenium/cerebrospinal fluid ; *Superoxide Dismutase-1/genetics/cerebrospinal fluid ; Male ; *Mutation ; Female ; Middle Aged ; Aged ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the brain and spinal cord motor neurons. On 25 April 2023, the drug tofersen, an antisense oligonucleotide, received the US Food and Drug Administration approval for treating ALS in adults carrying mutations of the SOD1 gene. We aimed at assessing whether cerebrospinal fluid concentrations of selenium, an element of both toxicological and nutritional interest possibly involved in disease etiology and progression, are modified by tofersen administration. We determined concentrations of selenium species by anion exchange chromatography hyphenated to inductively coupled plasma-dynamic reaction cell-mass spectrometry and overall selenium by using inductively coupled plasma sector-field mass spectrometry, at baseline and 6 months after active tofersen treatment in ten Italian ALS patients carrying the SOD1 gene mutation. Concentrations of total selenium and many selenium species substantially increased after the intervention, particularly of inorganic (tetravalent and hexavalent) selenium and of the organic species selenomethionine and a compound co-eluting with the selenocystine standard. Overall, these findings suggest that tofersen treatment markedly alters selenium status and probably the redox status within the central nervous system, possibly due to a direct effect on neurons and/or the blood-brain barrier. Further studies are required to investigate the biological and clinical relevance of these findings and how they might relate to the pharmacological effects of the drug and to disease progression.}, } @article {pmid39017652, year = {2024}, author = {Ranta-Aho, J and Johari, M and Udd, B}, title = {Current advance on distal myopathy genetics.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {515-522}, pmid = {39017652}, issn = {1473-6551}, mesh = {Humans ; *Distal Myopathies/genetics/pathology ; }, abstract = {PURPOSE OF REVIEW: Distal myopathies are a clinically heterogenous group of rare, genetic muscle diseases, that present with weakness in hands and/or feet at onset. Some of these diseases remain accentuated in the distal muscles whereas others may later progress to the proximal muscles. In this review, the latest findings related to genetic and clinical features of distal myopathies are summarized.

RECENT FINDINGS: Variants in SMPX , DNAJB2, and HSPB6 have been identified as a novel cause of late-onset distal myopathy and neuromyopathy. In oculopharyngodistal myopathies, repeat expansions were identified in two novel disease-causing genes, RILPL1 and ABCD3. In multisystem proteinopathies, variants in HNRNPA1 and TARDBP , genes previously associated with amyotrophic lateral sclerosis, have been shown to cause late-onset distal myopathy without ALS. In ACTN2 -related distal myopathy, the first recessive forms of the disease have been described, adding it to the growing list of genes were both dominant and recessive forms of myopathy are present.

SUMMARY: The identification of novel distal myopathy genes and pathogenic variants contribute to our ability to provide a final molecular diagnosis to a larger number of patients and increase our overall understanding of distal myopathy genetics and pathology.}, } @article {pmid39015513, year = {2024}, author = {Barahim Bastani, P and Saber Tehrani, AS and Badihian, S and Rieiro, H and Rastall, D and Farrell, N and Parker, M and Otero-Millan, J and Hassoon, A and Newman-Toker, D and Clawson, LL and Uchil, A and Riley, K and Zeiler, SR}, title = {Self-Recording of Eye Movements in Amyotrophic Lateral Sclerosis Patients Using a Smartphone Eye-Tracking App.}, journal = {Digital biomarkers}, volume = {8}, number = {1}, pages = {111-119}, pmid = {39015513}, issn = {2504-110X}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) can affect various eye movements, making eye tracking a potential means for disease monitoring. In this study, we evaluated the feasibility of ALS patients self-recording their eye movements using the "EyePhone," a smartphone eye-tracking application.

METHODS: We prospectively enrolled ten participants and provided them with an iPhone equipped with the EyePhone app and a PowerPoint presentation with step-by-step recording instructions. The goal was for the participants to record their eye movements (saccades and smooth pursuit) without the help of the study team. Afterward, a trained physician administered the same tests using video-oculography (VOG) goggles and asked the participants to complete a questionnaire regarding their self-recording experience.

RESULTS: All participants successfully completed the self-recording process without assistance from the study team. Questionnaire data indicated that participants viewed self-recording with EyePhone favorably, considering it easy and comfortable. Moreover, 70% indicated that they prefer self-recording to being recorded by VOG goggles.

CONCLUSION: With proper instruction, ALS patients can effectively use the EyePhone to record their eye movements, potentially even in a home environment. These results demonstrate the potential for smartphone eye-tracking technology as a viable and self-administered tool for monitoring disease progression in ALS, reducing the need for frequent clinic visits.}, } @article {pmid39015316, year = {2024}, author = {Liu, Y and Chen, Y and Gao, M and Luo, J and Wang, Y and Wang, Y and Gao, Y and Yang, L and Wang, J and Wang, N}, title = {Association between glioma and neurodegenerative diseases risk: a two-sample bi-directional Mendelian randomization analysis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1413015}, pmid = {39015316}, issn = {1664-2295}, abstract = {BACKGROUND: Earlier observational studies have demonstrated a correlation between glioma and the risk of neurodegenerative diseases (NDs), but the causality and direction of their associations remain unclear. The objective of this study was to ascertain the causal link between glioma and NDs using Mendelian randomization (MR) methodology.

METHODS: Genome-wide association study (GWAS) data were used in a two-sample bi-directional MR analysis. From the largest meta-analysis GWAS, encompassing 18,169 controls and 12,488 cases, summary statistics data on gliomas was extracted. Summarized statistics for NDs, including Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) were obtained from the GWAS of European ancestry. Inverse variance weighted (IVW) method was elected as the core MR approach with weighted median (WM) method and MR-Egger method as complementary methods. In addition, sensitivity analyses were performed. A Bonferroni correction was used to correct the results.

RESULTS: Genetically predicted glioma had been related to decreased risk of AD. Specifically, for all glioma (IVW: OR = 0.93, 95% CI = 0.90-0.96, p = 4.88 × 10[-6]) and glioblastoma (GBM) (IVW: OR = 0.93, 95% CI = 0.91-0.95, p = 5.11 × 10[-9]). We also found that genetically predicted all glioma has a suggestive causative association with MS (IVW: OR = 0.90, 95% CI = 0.81-1.00, p = 0.045). There was no evidence of causal association between glioma and ALS or PD. According to the results of reverse MR analysis, no discernible causal connection of NDs was found on glioma. Sensitivity analyses validated the robustness of the above associations.

CONCLUSION: We report evidence in support of potential causal associations of different glioma subtypes with AD and MS. More studies are required to uncover the underlying mechanisms of these findings.}, } @article {pmid39010704, year = {2024}, author = {Liu, J and Shi, X and Shao, Y}, title = {Sodium-glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: A Mendelian randomization study.}, journal = {Brain and behavior}, volume = {14}, number = {7}, pages = {e3624}, pmid = {39010704}, issn = {2162-3279}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; *Polymorphism, Single Nucleotide ; *Neurodegenerative Diseases/genetics ; *Glycated Hemoglobin/metabolism ; *Sodium-Glucose Transporter 1/genetics ; Diabetes Mellitus, Type 2/drug therapy/genetics ; Sodium-Glucose Transporter 2/genetics/metabolism ; Parkinson Disease/genetics/drug therapy ; Amyotrophic Lateral Sclerosis/genetics/drug therapy ; Alzheimer Disease/genetics/drug therapy ; Multiple Sclerosis/drug therapy/genetics ; }, abstract = {INTRODUCTION: This study aims to evaluate the effects of sodium-glucose cotransporter 1 inhibitors (SGLT1i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) on neurodegenerative disorders and to investigate the role of hemoglobin A1c (HbA1c) levels.

METHODS: Utilizing drug target Mendelian randomization, we employed single nucleotide polymorphisms (SNPs) proximal to the SLC5A1 and SLC5A2 genes to analyze the influence of SGLT1i and SGLT2i on Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), frontotemporal dementia (FTD), Lewy body dementia (LBD), and amyotrophic lateral sclerosis (ALS), with type 2 diabetes (T2D) as a positive control. An additional analysis examined the impact of HbA1c levels on the same disorders.

RESULTS: SGLT1i exhibited a significant association with decreased risk for ALS and MS. Conversely, SGLT2i were linked to an increased risk of AD, PD, and MS. Elevated HbA1c levels, independent of SGLT1 and SGLT2 effects, were associated with an increased risk of PD. Sensitivity analyses supported the robustness of these findings.

CONCLUSION: Our study suggests that SGLT1i may confer protection against ALS and MS, whereas SGLT2i could elevate the risk of AD, PD, and MS. Additionally, elevated HbA1c levels emerged as a risk factor for PD. These findings underscore the importance of personalized approaches in the utilization of SGLT inhibitors, considering their varying impacts on the risks of neurodegenerative diseases.}, } @article {pmid39009686, year = {2024}, author = {Neupane, K and Narayan, A and Sen Mojumdar, S and Adhikari, G and Garen, CR and Woodside, MT}, title = {Direct observation of prion-like propagation of protein misfolding templated by pathogenic mutants.}, journal = {Nature chemical biology}, volume = {20}, number = {9}, pages = {1220-1226}, pmid = {39009686}, issn = {1552-4469}, support = {N/A//Gouvernement du Canada | National Research Council Canada (Conseil national de recherches Canada)/ ; RGPIN-2018-04673//Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada)/ ; N/A//Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada)/ ; PJT-185931//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; N/A//Alberta Innovates | Alberta Innovates - Health Solutions (AIHS)/ ; }, mesh = {*Protein Folding ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; Humans ; *Mutation ; *Prions/metabolism/genetics/chemistry ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Optical Tweezers ; }, abstract = {Many neurodegenerative diseases feature misfolded proteins that propagate via templated conversion of natively folded molecules. However, crucial questions about how such prion-like conversion occurs and what drives it remain unsolved, partly because technical challenges have prevented direct observation of conversion for any protein. We observed prion-like conversion in single molecules of superoxide dismutase-1 (SOD1), whose misfolding is linked to amyotrophic lateral sclerosis. Tethering pathogenic misfolded SOD1 mutants to wild-type molecules held in optical tweezers, we found that the mutants vastly increased misfolding of the wild-type molecule, inducing multiple misfolded isoforms. Crucially, the pattern of misfolding was the same in the mutant and converted wild-type domains and varied when the misfolded mutant was changed, reflecting the templating effect expected for prion-like conversion. Ensemble measurements showed decreased enzymatic activity in tethered heterodimers as conversion progressed, mirroring the single-molecule results. Antibodies sensitive to disease-specific epitopes bound to the converted protein, implying that conversion produced disease-relevant misfolded conformers.}, } @article {pmid39009447, year = {2024}, author = {Akter, M and Sepehrimanesh, M and Xu, W and Ding, B}, title = {Assembling a Coculture System to Prepare Highly Pure Induced Pluripotent Stem Cell-Derived Neurons at Late Maturation Stages.}, journal = {eNeuro}, volume = {11}, number = {7}, pages = {}, pmid = {39009447}, issn = {2373-2822}, mesh = {*Induced Pluripotent Stem Cells/physiology ; *Coculture Techniques ; Animals ; *Motor Neurons/physiology ; Mice ; *Astrocytes/physiology ; Humans ; Cell Differentiation/physiology ; Cells, Cultured ; Neurogenesis/physiology ; }, abstract = {Generation of human induced pluripotent stem cell (hiPSC)-derived motor neurons (MNs) offers an unprecedented approach to modeling movement disorders such as dystonia and amyotrophic lateral sclerosis. However, achieving survival poses a significant challenge when culturing induced MNs, especially when aiming to reach late maturation stages. Utilizing hiPSC-derived motor neurons and primary mouse astrocytes, we assembled two types of coculture systems: direct coculturing of neurons with astrocytes and indirect coculture using culture inserts that physically separate neurons and astrocytes. Both systems significantly enhance neuron survival. Compared with these two systems, no significant differences in neurodevelopment, maturation, and survival within 3 weeks, allowing to prepare neurons at maturation stages. Using the indirect coculture system, we obtained highly pure MNs at the late mature stage from hiPSCs. Transcriptomic studies of hiPSC-derived MNs showed a typical neurodevelopmental switch in gene expression from the early immature stage to late maturation stages. Mature genes associated with neurodevelopment and synaptogenesis are highly enriched in MNs at late stages, demonstrating that these neurons achieve maturation. This study introduces a novel tool for the preparation of highly pure hiPSC-derived neurons, enabling the determination of neurological disease pathogenesis in neurons at late disease onset stages through biochemical approaches, which typically necessitate highly pure neurons. This advancement is particularly significant in modeling age-related neurodegeneration.}, } @article {pmid39009032, year = {2024}, author = {Scheithauer, S and Hoffmann, J and Lang, C and Fenz, D and Berens, MM and Köster, AM and Panchyrz, I and Harst, L and Adorjan, K and Apfelbacher, C and Ciesek, S and Denkinger, CM and Drosten, C and Geraedts, M and Hecker, R and Hoffmann, W and Karch, A and Koch, T and Krefting, D and Lieb, K and Meerpohl, JJ and Rehfuess, EA and Skoetz, N and Sopka, S and von Lengerke, T and Wiegand, H and Schmitt, J}, title = {Pandemic Preparedness - A Proposal for a Research Infrastructure and its Functionalities for a Resilient Health Research System.}, journal = {Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany))}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2365-9179}, pmid = {39009032}, issn = {1439-4421}, support = {01KX2121//Bundesministerium für Bildung und Forschung/ ; }, abstract = {Während einer Pandemie muss Resilienz nicht nur als Eigenschaft des Gesundheitssystems, sondern auch des umgebenden Forschungsumfelds betrachtet werden. Um verlässliche, evidenzbasierte Empfehlungen aus der Universitätsmedizin an die Gesundheitspolitik und die Entscheidungsträger bereitstellen zu können, müssen wissenschaftliche Erkenntnisse schnell, integrativ und multidisziplinär generiert, synthetisiert und kommuniziert werden. Die Resilienz der öffentlichen Gesundheitssysteme und der Gesundheitsforschungssysteme sind somit eng verknüpft. Die Reaktion auf die SARS-CoV-2-Pandemie in Deutschland wurde jedoch durch das Fehlen einer adäquat vernetzten Gesundheitsforschungsinfrastruktur erschwert. Das Netzwerk Universitätsmedizin (NUM) wurde zu Beginn der Pandemie mit dem Ziel gegründet, Deutschland auf zukünftige Pandemien vorzubereiten. Ziel des Projektes "PREparedness and PAndemic REsponse in Deutschland (PREPARED)" ist es, ein ganzheitliches Konzept für eine kooperative, adaptierbare und nachhaltige Gesundheitsforschungsinfrastruktur innerhalb des NUM zu entwickeln und damit einen Beitrag zu einer umfassenden Pandemiebereitschaft zu leisten. Das vorgeschlagene Konzept dieser Infrastruktur vereint vier Kern- und drei Unterstützungsfunktionalitäten in vier verschiedenen Handlungsfeldern. Die Funktionalitäten gewährleisten im Falle zukünftiger Gesundheitskrisen ein effizientes Funktionieren des Gesundheitsforschungssystems und eine rasche Übertragung entsprechender Implikationen in andere Systeme. Die vier Handlungsfelder sind (a) Monitoring und Surveillance, (b) Synthese und Transfer, (c) Koordination und Organisation sowie (d) Kapazitäten und Ressourcen. Die sieben Funktionalitäten umfassen 1) eine Monitoring- und Surveillance-Einheit, 2) eine Pathogenkompetenz-Plattform, 3) Evidenzsynthese und vertrauenswürdige Empfehlungen, 4) eine Einheit zur regionalen Vernetzung und Implementierung, 5) eine Strategische Kommunikationseinheit, 6) Human Resources Management und 7) ein Rapid Reaction & Response (R[3])-Cockpit. Die Governance wird als Kontroll- und Regulierungssystem eingerichtet, wobei agile Management-Methoden in interpandemischen Phasen trainiert werden, um die Reaktionsfähigkeit zu verbessern sowie die Eignung agiler Methoden für die wissenschaftliche Infrastruktur für die Pandemiebereitschaft zu untersuchen. Der Aufbau der PREPARED-Forschungsinfrastruktur muss vor der nächsten Pandemie erfolgen, da Training und regelmäßige Stresstests grundlegende Voraussetzungen für deren Funktionieren sind.During a pandemic, resilience must be considered not only as an attribute of the health care system, but also of the surrounding research environment. To provide reliable evidence-based advice from university medicine to health policy and decision makers, scientific evidence must be generated, synthesized and communicated in a rapid, integrative and multidisciplinary manner. The resilience of public health systems and the health research systems are thus closely linked. However, the response to the SARS-CoV-2 pandemic in Germany was hampered by the lack of an adequate health research infrastructure. The Network University Medicine (NUM) was founded at the beginning of the pandemic with the aim of preparing Germany for future pandemics. The aim of the project "PREparedness and PAndemic REsponse in Deutschland (PREPARED)" is to develop a holistic concept for a cooperative, adaptable and sustainable health research infrastructure within the NUM and thus contribute to pandemic preparedness and rapid response. The proposed concept for a health research infrastructure includes four core and three supporting functionalities in four different fields of action. The functionalities aim to ensure efficient functioning within the health research system and a rapid translation to other systems in future health crises. The four fields of action are (a) monitoring and surveillance, (b) synthesis and transfer, (c) coordination and organization, and (d) capacities and resources. The seven functionalities include 1) a monitoring and surveillance unit, 2) a pathogen competence platform, 3) evidence synthesis and trustworthy recommendations, 4) a regional networking and implementation unit, 5) a strategic communication unit, 6) human resources management, and 7) a rapid reaction and the response (R[3])-cockpit. A governance will be established as a control and regulatory system for all structures and processes, testing agile management in non-pandemic times to improve responsiveness and flexibility and to investigate the suitability of the methods for scientific pandemic preparedness. The establishment of the PREPARED health research infrastructure must take place before the next pandemic, as training and regular stress tests are its fundamental prerequisites.}, } @article {pmid39008674, year = {2024}, author = {Mason, AH and Motta, A and Kratish, Y and Marks, TJ}, title = {Demystifying group-4 polyolefin hydrogenolysis catalysis. Gaseous propane hydrogenolysis mechanism over the same catalysts.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {30}, pages = {e2406133121}, pmid = {39008674}, issn = {1091-6490}, support = {DE-FG02-03ER15457//DOE | Office of Science (SC)/ ; DOE DE-SC0024448//Dow Chemical Company (Dow)/ ; ECCS-2025633//National Science Foundation (NSF)/ ; NNA04CC36G//NASA | Ames Research Center (ARC)/ ; DOE DE-SC0001329//Dow Chemical Company (Dow)/ ; HP10CPXHA1 2023//CINECA HPC/ ; }, abstract = {A kinetic/mechanistic investigation of gaseous propane hydrogenolysis over the single-site heterogeneous polyolefin depolymerization catalysts AlS/ZrNp2 and AlS/HfNp2 (AlS = sulfated alumina, Np = neopentyl), is use to probe intrinsic catalyst properties without the complexities introduced by time- and viscosity-dependent polymer medium effects. In a polymer-free automated plug-flow catalytic reactor, propane hydrogenolysis turnover frequencies approach 3,000 h[-1] at 150 °C. Both catalysts exhibit approximately linear relationships between rate and [H2] at substoichiometric [H2] with rate law orders of 0.66 ± 0.09 and 0.48 ± 0.07 for Hf and Zr, respectively; at higher [H2], the rates approach zero-order in [H2]. Reaction orders in [C3H8] and [catalyst] are essentially zero-order under all conditions, with the former implying rapid, irreversible alkane binding/activation. This rate law, activation parameter, and DFT energy span analysis support a scenario in which [H2] is pivotal in one of two plausible and competing rate-determining transition states-bimolecular metal-alkyl bond hydrogenolysis vs. unimolecular β-alkyl elimination. The Zr and Hf catalyst activation parameters, ΔH[‡] = 16.8 ± 0.2 kcal mol[-1] and 18.2 ± 0.6 kcal mol[-1], respectively, track the relative turnover frequencies, while ΔS[‡] = -19.1 ± 0.8 and -16.7 ± 1.4 cal mol[-1] K[-1], respectively, imply highly organized transition states. These catalysts maintain activity up to 200 °C, while time-on-stream data indicate multiday activities with an extrapolated turnover number ~92,000 at 150 °C for the Zr catalyst. This methodology is attractive for depolymerization catalyst discovery and process optimization.}, } @article {pmid39008617, year = {2024}, author = {Tsitkanou, S and Lindsay, A and Abbott, G and Foletta, V and Walker, AK and Russell, AP and Della Gatta, PA}, title = {Exercise training induces mild skeletal muscle adaptations without altering disease progression in a TDP-43 mouse model.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {137}, number = {3}, pages = {728-745}, doi = {10.1152/japplphysiol.00192.2023}, pmid = {39008617}, issn = {1522-1601}, support = {//Deakin University | Institute for Physical Activity and Nutrition (IPAN)/ ; //Onassis Foundation Greece/ ; //Deakin University, Alfread Deakin PostDoc Fellowship/ ; //Neurological Foundation of New Zealand/ ; 1124005//Australian National Health and Medical Research Council/ ; //Ross Maclean Fellowship/ ; //Bill Guest FightMND Mid-Career Development Fellowship/ ; //Brazil Family Program for Neurology/ ; }, mesh = {Animals ; *Disease Progression ; *Muscle, Skeletal/metabolism/physiopathology ; Mice ; *Physical Conditioning, Animal/physiology/methods ; *Adaptation, Physiological/physiology ; *Disease Models, Animal ; *DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/physiopathology/metabolism/therapy ; Male ; Mice, Transgenic ; }, abstract = {Exercise training is considered a nonpharmacological therapeutic approach for many diseases. Mild-to-moderate endurance exercise training is suggested to improve the mental and physical state of people with amyotrophic lateral sclerosis (ALS). The aim of the present study was to determine the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TAR DNA-binding protein 43 (TDP-43) pathology and motor dysfunction, to perform mild-to-moderate intensity treadmill exercise training and to evaluate the effects of this training on skeletal muscle health and disease progression. Symptomatic rNLS8 mice were able to complete 4 wk of mild-to-moderate treadmill running (30 min at 6-13 m/min, 3 days a week). Exercise training induced an increase in the percentage of type IIA fibers in the tibialis anterior muscle as well as minor adaptations in molecular markers of myogenic, mitochondrial, and neuromuscular junction health in some forelimb and hindlimb muscles. However, this exercise training protocol did not attenuate the loss in motor function or delay disease progression. Alternative exercise regimens need to be investigated to better understand the role exercise training may play in alleviating symptoms of ALS.NEW & NOTEWORTHY This is the first study to investigate the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TDP-43 pathology and motor dysfunction, to perform exercise training. We demonstrate that despite the ALS-reminiscent aggressive disease progression characterizing the rNLS8 mouse model, rNLS8 mice are capable of performing mild-to-moderate endurance treadmill training for at least 3-4 wk. We demonstrate that exercise training induces several minor skeletal muscle adaptations without delaying disease progression in rNLS8 mice.}, } @article {pmid39007704, year = {2024}, author = {Gandhi, P and Waito, AA and Peladeau-Pigeon, M and Plowman, EK and Steele, CM}, title = {How Do Quantitative Videofluoroscopy Measures Differ Between People With Amyotrophic Lateral Sclerosis and Age-Matched Healthy Adults?.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {67}, number = {8}, pages = {2512-2532}, pmid = {39007704}, issn = {1558-9102}, support = {R01 AG077481/AG/NIA NIH HHS/United States ; R01 DC011020/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/complications ; Male ; Female ; Aged ; Middle Aged ; Fluoroscopy/methods ; *Deglutition Disorders/physiopathology/etiology/diagnostic imaging ; Aged, 80 and over ; Retrospective Studies ; *Deglutition/physiology ; *Video Recording ; Case-Control Studies ; }, abstract = {PURPOSE: Dysphagia is a leading cause of morbidity in people with amyotrophic lateral sclerosis (PwALS). Previous videofluoroscopic swallowing studies (VFSS) in PwALS do not account for the influence of senescence. We aimed to compare swallowing in PwALS and an age- and sex-matched control group using healthy reference data to define typical and atypical values.

METHOD: We conducted retrospective analysis of VFSS data from 19 PwALS (10 male, Mage = 63 years, range: 47-82) compared to control data from a cohort of healthy adults. Participants swallowed 20% w/v liquid barium from thin to extremely thick consistency. Blinded duplicate VFSS analysis using the ASPEKT (Analysis of Swallowing Physiology: Events, Kinematics and Timing) method yielded descriptive statistics for 16 quantitative VFSS parameters by consistency. Mann-Whitney U tests were used to identify significant cohort differences. Additionally, the frequencies of atypical values (in the 25% tails of the reference distribution) were tabulated by cohort and compared using odds ratios.

RESULTS: PwALS showed increased frequencies of multiple swallows per bolus, incomplete laryngeal vestibule closure, and reduced hyoid speed across consistencies. By contrast, similar frequencies of atypical values for pharyngeal constriction and residue in both cohorts suggest that age-related changes may contribute to the presence of these features in PwALS.

CONCLUSIONS: This analysis builds on previous descriptions of swallowing pathophysiology in amyotrophic lateral sclerosis (ALS) by clarifying the extent to which aging may account for some of the atypical findings seen in this patient population. Longitudinal studies are recommended to further differentiate the effects of ALS from age-related changes in swallowing over the course of disease progression.}, } @article {pmid39007446, year = {2024}, author = {Torra, J and Mora, G and Montull, JM and Royo-Esnal, A and Notter, JS and Salas, M}, title = {A 4-year field study monitoring the evolution of Trp574Leu-resistant plants in an Echinochloa crus-galli population under different crop rotation and herbicide programs in maize.}, journal = {Pest management science}, volume = {80}, number = {11}, pages = {5843-5851}, doi = {10.1002/ps.8315}, pmid = {39007446}, issn = {1526-4998}, support = {//Corteva Agriscience/ ; RYC2018-023866-I//Spanish Ministry of Science, Innovation, and Universities/ ; //Spanish State Research Agency/ ; PID2020-113229RB-C42//European Regional Development Fund (ERDF)/ ; }, mesh = {*Echinochloa/drug effects/genetics ; *Zea mays/growth & development ; *Herbicide Resistance ; *Herbicides/pharmacology ; *Weed Control/methods ; *Plant Weeds/drug effects ; *Acetolactate Synthase/antagonists & inhibitors/metabolism ; Agriculture/methods ; }, abstract = {BACKGROUND: A 4-year experiment evaluated the effects of different integrated weed management (IWM) programs on the evolution of a Echinochloa crus-galli population resistant to acetolactate synthase (ALS) inhibitors in a maize cropping system. The programs included the continued use of ALS inhibitors, mixing them with alternative herbicides, or without ALS-inhibitors, in all cases under maize monocrop or a biennial crop rotation.

RESULTS: IWM programs that relied solely on non-ALS-inhibitors usually achieved high control levels across years (> 90%). Additionally, Trp574Leu-resistant plants became prevalent (> 90%) in programs only using ALS inhibitors, while in the rest the frequency of susceptible plants did not substantially decrease below 40%. Regarding the other monitored grass weeds, Digitaria sanguinalis and Panicum dichotomiflorum were effectively controlled in programs using ALS-inhibitors without soybean rotation or in programs without ALS-inhibitors altogether, excepting the program relying on an 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibitor under maize monocrop for the latter species (0%).

CONCLUSION: At the end of the experiment, the only IWM programs that reduced infestation levels were the one without ALS-inhibitors under soybean rotation, and the one with standard pre-emergence treatments. These findings highlight the effectiveness of crop rotation and alternative herbicides both pre- or post-emergence in controlling E. crus-galli. ALS-inhibitors, while challenged by resistance in E. crus-galli, remain valuable tools for managing other grass weed species in maize. It is crucial to adapt IWM strategies for herbicide-resistant E. crus-galli and other grass weed populations to mitigate the further evolution of resistance. © 2024 Corteva Agriscience. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid39007083, year = {2024}, author = {Chidambaram, SB and Anand, N and Varma, SR and Ramamurthy, S and Vichitra, C and Sharma, A and Mahalakshmi, AM and Essa, MM}, title = {Superoxide dismutase and neurological disorders.}, journal = {IBRO neuroscience reports}, volume = {16}, number = {}, pages = {373-394}, pmid = {39007083}, issn = {2667-2421}, abstract = {Superoxide dismutase (SOD) is a common antioxidant enzyme found majorly in living cells. The main physiological role of SOD is detoxification and maintain the redox balance, acts as a first line of defence against Reactive nitrogen species (RNS), Reactive oxygen species (ROS), and other such potentially hazardous molecules. SOD catalyses the conversion of superoxide anion free radicals (O 2 -.) into molecular oxygen (O 2) and hydrogen peroxide (H 2O 2) in the cells. Superoxide dismutases (SODs) are expressed in neurons and glial cells throughout the CNS both intracellularly and extracellularly. Endogenous oxidative stress (OS) linked with enlarged production of reactive oxygen metabolites (ROMs), inflammation, deregulation of redox balance, mitochondrial dysfunction and bioenergetic crisis are found to be prerequisite for neuronal loss in neurological diseases. Clinical and genetic studies indicate a direct correlation between mutations in SOD gene and neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), Parkinson's Disease (PD) and Alzheimer's Disease (AD). Therefore, inhibitors of OS are considered as an optimistic approach to prevent neuronal loss. SOD mimetics like Metalloporphyrin Mn (II)-cyclic polyamines, Nitroxides and Mn (III)- Salen complexes are designed and used as therapeutic extensively in the treatment of neurological disorders. SODs and SOD mimetics are promising future therapeutics in the field of various diseases with OS-mediated pathology.}, } @article {pmid39006832, year = {2023}, author = {Neumann, M and Kothare, H and Ramanarayanan, V}, title = {Combining Multiple Multimodal Speech Features into an Interpretable Index Score for Capturing Disease Progression in Amyotrophic Lateral Sclerosis.}, journal = {Interspeech}, volume = {2023}, number = {}, pages = {2353-2357}, pmid = {39006832}, issn = {2308-457X}, support = {R42 DC019877/DC/NIDCD NIH HHS/United States ; }, abstract = {Multiple speech biomarkers have been shown to carry useful information regarding Amyotrophic Lateral Sclerosis (ALS) pathology. We propose a two-step framework to compute optimal linear combinations (indexes) of these biomarkers that are more discriminative and noise-robust than the individual markers, which is important for clinical care and pharmaceutical trial applications. First, we use a hierarchical clustering based method to select representative speech metrics from a dataset comprising 143 people with ALS and 135 age- and sex-matched healthy controls. Second, we analyze three methods of index computation that optimize linear discriminability, Youden Index, and sparsity of logistic regression model weights, respectively, and evaluate their performance with 5-fold cross validation. We find that the proposed indexes are generally more discriminative of bulbar vs non-bulbar onset in ALS than their individual component metrics as well as an equally-weighted baseline.}, } @article {pmid39006831, year = {2023}, author = {Kothare, H and Neumann, M and Liscombe, J and Green, J and Ramanarayanan, V}, title = {Responsiveness, Sensitivity and Clinical Utility of Timing-Related Speech Biomarkers for Remote Monitoring of ALS Disease Progression.}, journal = {Interspeech}, volume = {2023}, number = {}, pages = {2323-2327}, pmid = {39006831}, issn = {2308-457X}, support = {R42 DC019877/DC/NIDCD NIH HHS/United States ; }, abstract = {In this study, we describe the responsiveness of timing-related measures extracted from read speech in persons with ALS (pALS) collected via a remote patient monitoring platform in an effort to quantify how long it takes to detect a clinically-meaningful change associated with disease progression. We found that the timing alignment of pALS speech relative to a canonical elicitation of the same prompt is the most responsive measure, of the ones considered in this study, at detecting such change in both pALS with bulbar (n = 35) and non-bulbar onset (n = 94). We further evaluated the sensitivity of speech metrics in tracking disease progression in pALS while their ALSFRS-R speech score remained unchanged at 3 out of a total possible score of 4. We observed that timing-related speech metrics showed significant longitudinal changes even after accounting for learning effects. The findings of this study have the potential to inform disease prognosis and functional outcomes of clinical trials.}, } @article {pmid39006764, year = {2024}, author = {Yang, C and Liu, G and Chen, X and Le, W}, title = {Cerebellum in Alzheimer's disease and other neurodegenerative diseases: an emerging research frontier.}, journal = {MedComm}, volume = {5}, number = {7}, pages = {e638}, pmid = {39006764}, issn = {2688-2663}, abstract = {The cerebellum is crucial for both motor and nonmotor functions. Alzheimer's disease (AD), alongside other dementias such as vascular dementia (VaD), Lewy body dementia (DLB), and frontotemporal dementia (FTD), as well as other neurodegenerative diseases (NDs) like Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias (SCA), are characterized by specific and non-specific neurodegenerations in central nervous system. Previously, the cerebellum's significance in these conditions was underestimated. However, advancing research has elevated its profile as a critical node in disease pathology. We comprehensively review the existing evidence to elucidate the relationship between cerebellum and the aforementioned diseases. Our findings reveal a growing body of research unequivocally establishing a link between the cerebellum and AD, other forms of dementia, and other NDs, supported by clinical evidence, pathological and biochemical profiles, structural and functional neuroimaging data, and electrophysiological findings. By contrasting cerebellar observations with those from the cerebral cortex and hippocampus, we highlight the cerebellum's distinct role in the disease processes. Furthermore, we also explore the emerging therapeutic potential of targeting cerebellum for the treatment of these diseases. This review underscores the importance of the cerebellum in these diseases, offering new insights into the disease mechanisms and novel therapeutic strategies.}, } @article {pmid39006715, year = {2024}, author = {Suleiman Khoury, Z and Sohail, F and Wang, J and Mendoza, M and Raake, M and Tahoor Silat, M and Reddy Bathinapatta, M and Sadeghzadegan, A and Meghana, P and Paul, J}, title = {Neuroinflammation: A Critical Factor in Neurodegenerative Disorders.}, journal = {Cureus}, volume = {16}, number = {6}, pages = {e62310}, pmid = {39006715}, issn = {2168-8184}, abstract = {This review offers a comprehensive review of the signals and the paramount role neuroinflammation plays in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The study explores the sophisticated interactions between microglial, astrocytic, and dendritic cells and how neuroinflammation affects long-term neuronal damage and dysfunction. There are specific pathways related to the mentioned inflammatory processes, including Janus kinases/signal transducer and activator of transcriptions, nuclear factor-κB, and mitogen-activated protein kinases pathways. Neuroinflammation is argued to be a double-edged sword, being not only a protective agent that prevents further neuron damage but also the causative factor in more cell injury development. This concept of contrasting inflammation with neuroprotection advocates for the use of therapeutic techniques that seek to modulate neuroinflammatory responses as part of the neurodegeneration treatment. The recent research findings are integrated with the established knowledge to help present a comprehensive image of neuroinflammation's impact on neurodegenerative diseases and its implications for future therapy.}, } @article {pmid39006307, year = {2023}, author = {Ayoubi, R and Alshafie, W and Shlaifer, I and Southern, K and McPherson, PS and Laflamme, C and , }, title = {The identification of high-performing antibodies for Sequestosome-1 for use in Western blot, immunoprecipitation and immunofluorescence.}, journal = {F1000Research}, volume = {12}, number = {}, pages = {324}, pmid = {39006307}, issn = {2046-1402}, mesh = {*Sequestosome-1 Protein/immunology/metabolism ; Humans ; *Fluorescent Antibody Technique/methods ; *Immunoprecipitation/methods ; *Blotting, Western ; Antibodies/immunology ; }, abstract = {Sequestosome-1, encoded by the gene SQSTM1, functions as a bridge between ubiquitinated proteins and the proteasome or autophagosome, thereby regulating protein degradation pathways. Loss of Sequestosome-1 is hypothesized to enhance neurodegeneration progression in several diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal disorders (FTD). Sequestosome-1 reproducible research would be facilitated with the availability of well-characterized anti-Sequestosome-1 antibodies. In this study, we characterized seventeen Sequestosome-1 commercial antibodies for Western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.}, } @article {pmid39005475, year = {2024}, author = {Xie, M and Miller, AS and Pallegar, PN and Umpierre, A and Liang, Y and Wang, N and Zhang, S and Nagaraj, NK and Fogarty, ZC and Ghayal, NB and Oskarsson, B and Zhao, S and Zheng, J and Qi, F and Nguyen, A and Dickson, DW and Wu, LJ}, title = {Rod-shaped microglia interact with neuronal dendrites to regulate cortical excitability in TDP-43 related neurodegeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.30.601396}, pmid = {39005475}, issn = {2692-8205}, abstract = {Motor cortical hyperexcitability is well-documented in the presymptomatic stage of amyotrophic lateral sclerosis (ALS). However, the mechanisms underlying this early dysregulation are not fully understood. Microglia, as the principal immune cells of the central nervous system, have emerged as important players in sensing and regulating neuronal activity. Here we investigated the role of microglia in the motor cortical circuits in a mouse model of TDP-43 neurodegeneration (rNLS8). Utilizing multichannel probe recording and longitudinal in vivo calcium imaging in awake mice, we observed neuronal hyperactivity at the initial stage of disease progression. Spatial and single-cell RNA sequencing revealed that microglia are the primary responders to motor cortical hyperactivity. We further identified a unique subpopulation of microglia, rod-shaped microglia, which are characterized by a distinct morphology and transcriptional profile. Notably, rod-shaped microglia predominantly interact with neuronal dendrites and excitatory synaptic inputs to attenuate motor cortical hyperactivity. The elimination of rod-shaped microglia through TREM2 deficiency increased neuronal hyperactivity, exacerbated motor deficits, and further decreased survival rates of rNLS8 mice. Together, our results suggest that rod-shaped microglia play a neuroprotective role by attenuating cortical hyperexcitability in the mouse model of TDP-43 related neurodegeneration.}, } @article {pmid39005384, year = {2024}, author = {Dykstra, MM and Weskamp, K and Gómez, NB and Waksmacki, J and Tank, E and Glineburg, MR and Snyder, A and Pinarbasi, E and Bekier, M and Li, X and Bai, J and Shahzad, S and Nedumaran, J and Wieland, C and Stewart, C and Willey, S and Grotewold, N and McBride, J and Moran, JJ and Suryakumar, AV and Lucas, M and Tessier, P and Ward, M and Todd, P and Barmada, SJ}, title = {TDP43 autoregulation gives rise to shortened isoforms that are tightly controlled by both transcriptional and post-translational mechanisms.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39005384}, issn = {2692-8205}, support = {F31 NS134123/NS/NINDS NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; F31 NS115257/NS/NINDS NIH HHS/United States ; T32 GM145470/GM/NIGMS NIH HHS/United States ; }, abstract = {The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal TDP43 isoforms that are predominantly cytosolic in localization, highly prone to aggregation, and enriched in susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 isoforms are difficult to detect in comparison to full-length (fl)TDP43, raising questions regarding their origin and selective regulation. Here, we show that sTDP43 is created as a byproduct of TDP43 autoregulation and cleared by nonsense mediated RNA decay (NMD). The sTDP43-encoding transcripts that escape NMD can lead to toxicity but are rapidly degraded post-translationally. Circumventing these regulatory mechanisms by overexpressing sTDP43 results in neurodegeneration in vitro and in vivo via N-terminal oligomerization and impairment of flTDP43 splicing activity, in addition to RNA binding-dependent gain-of-function toxicity. Collectively, these studies highlight endogenous mechanisms that tightly regulate sTDP43 expression and provide insight into the consequences of aberrant sTDP43 accumulation in disease.}, } @article {pmid39005345, year = {2024}, author = {Rizuan, A and Shenoy, J and Mohanty, P and Dos Passos, PMS and Mercado Ortiz, JF and Bai, L and Viswanathan, R and Wang, SH and Johnson, V and Mamede, LD and Ayala, YM and Ghirlando, R and Mittal, J and Fawzi, NL}, title = {Structural details of helix-mediated TDP-43 C-terminal domain multimerization.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39005345}, issn = {2692-8205}, support = {R01 NS116176/NS/NINDS NIH HHS/United States ; }, abstract = {The primarily disordered C-terminal domain (CTD) of TAR DNA binding protein-43 (TDP-43), a key nuclear protein in RNA metabolism, forms neuronal inclusions in several neurodegenerative diseases. A conserved region (CR, spanning residues 319-341) in CTD forms transient helix-helix contacts important for its higher-order oligomerization and function that are disrupted by ALS-associated mutations. However, the structural details of CR assembly and the explanation for several ALS-associated variants' impact on phase separation and function remain unclear due to challenges in analyzing the dynamic association of TDP-43 CTD using traditional structural biology approaches. By employing an integrative approach, combining biophysical experiments, biochemical assays, AlphaFold2-Multimer (AF2-Multimer), and atomistic simulations, we generated structural models of helical oligomerization of TDP-43 CR. Using NMR, we first established that the native state of TDP-43 CR under physiological conditions is α-helical. Next, alanine scanning mutagenesis revealed that while hydrophobic residues in the CR are important for CR assembly, phase separation and TDP-43 nuclear retention function, polar residues down regulate these processes. Finally, pairing AF2-Multimer modeling with AAMD simulations indicated that dynamic, oligomeric assemblies of TDP-43 that are stabilized by a methionine-rich core with specific contributions from a tryptophan/leucine pair. In conclusion, our results advance the structural understanding of the mechanisms driving TDP-43 function and provide a window into the initial stages of its conversion into pathogenic aggregates.}, } @article {pmid39005286, year = {2024}, author = {Krattli, RP and Do, AH and El-Khatib, SM and Alikhani, L and Markarian, M and Vagadia, AR and Usmani, MT and Madan, S and Baulch, JE and Clark, RJ and Woodruff, TM and Tenner, AJ and Acharya, MM}, title = {C5aR1 inhibition alleviates cranial radiation-induced cognitive decline.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.07.02.601806}, pmid = {39005286}, issn = {2692-8205}, abstract = {UNLABELLED: Cranial radiation therapy (RT) for brain cancers leads to an irreversible decline in cognitive function without an available remedy. Radiation-induced cognitive deficits (RICD) are a particularly pressing problem for the survivors of pediatric and low grade glioma (LGG) cancers who often live long post-RT lives. Radiation-induced elevated neuroinflammation and gliosis, triggered by the detrimental CNS complement cascade, lead to excessive synaptic and cognitive loss. Using intact and brain cancer-bearing mouse models, we now show that targeting anaphylatoxin complement C5a receptor (C5aR1) is neuroprotective against RICD. We used a genetic knockout, C5aR1 KO mouse, and a pharmacologic approach, employing the orally active, brain penetrant C5aR1 antagonist PMX205 to reverse RICD. Irradiated C5aR1 KO and WT mice receiving PMX205 showed significant neurocognitive improvements in object recognition memory and memory consolidation tasks. Inhibiting C5a/C5aR1 axis reduced microglial activation, astrogliosis, and synaptic loss in the irradiated brain. Importantly, C5aR1 blockage in two syngeneic, orthotopic glioblastoma-bearing mice protected against RICD without interfering with the therapeutic efficacy of RT to reduce tumor volume in vivo . PMX205 clinical trials with healthy individuals and amyotrophic lateral sclerosis (ALS) patients showed no toxicity, drug-related adverse events, or infections. Thus, C5aR1 inhibition is a translationally feasible approach to address RICD, an unmet medical need.

SIGNIFICANCE: Cranial radiotherapy for brain cancers activates CNS complement cascade, leading to cognitive decline. Ablation of the complement C5a/C5aR1 axis alleviates radiation-induced neuroinflammation, synaptic loss, and cognitive dysfunction, providing a novel tractable approach.}, } @article {pmid39005258, year = {2024}, author = {Feringa, FM and Hertog, SJK and Wang, L and Derks, RJE and Kruijff, I and Erlebach, L and Heijneman, J and Miramontes, R and Pömpner, N and Blomberg, N and Olivier-Jimenez, D and Johansen, LE and Cammack, AJ and Giblin, A and Toomey, CE and Rose, IVL and Yuan, H and Ward, M and Isaacs, AM and Kampmann, M and Kronenberg-Versteeg, D and Lashley, T and Thompson, LM and Ori, A and Mohammed, Y and Giera, M and van der Kant, R}, title = {The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39005258}, issn = {2692-8205}, support = {P01 NS084974/NS/NINDS NIH HHS/United States ; P30 CA062203/CA/NCI NIH HHS/United States ; T32 NS115706/NS/NINDS NIH HHS/United States ; }, abstract = {Lipid changes in the brain have been implicated in many neurodegenerative diseases including Alzheimer's Disease (AD), Parkinson's disease and Amyotrophic Lateral Sclerosis. To facilitate comparative lipidomic research across brain-diseases we established a data commons named the Neurolipid Atlas, that we have pre-populated with novel human, mouse and isogenic induced pluripotent stem cell (iPSC)-derived lipidomics data for different brain diseases. We show that iPSC-derived neurons, microglia and astrocytes display distinct lipid profiles that recapitulate in vivo lipotypes. Leveraging multiple datasets, we show that the AD risk gene ApoE4 drives cholesterol ester (CE) accumulation in human astrocytes recapitulating CE accumulation measured in the human AD brain. Multi-omic interrogation of iPSC-derived astrocytes revealed that cholesterol plays a major role in astrocyte interferon-dependent pathways such as the immunoproteasome and major histocompatibility complex (MHC) class I antigen presentation. We show that through enhanced cholesterol esterification ApoE4 suppresses immune activation of astrocytes. Our novel data commons, available at neurolipidatlas.com, provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases.}, } @article {pmid39004530, year = {2024}, author = {Vacchiano, V and Di Stasi, V and Bruni, S and Rizzo, G and Liguori, R}, title = {Thoracic paraspinal muscles denervation assessment in amyotrophic lateral sclerosis: Clinical-neurophysiological correlations and prognostic value.}, journal = {Journal of the neurological sciences}, volume = {463}, number = {}, pages = {123133}, doi = {10.1016/j.jns.2024.123133}, pmid = {39004530}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Paraspinal Muscles/physiopathology ; Male ; Middle Aged ; Female ; Prognosis ; Aged ; Electromyography/methods ; Muscle Denervation/methods ; Adult ; }, } @article {pmid39004370, year = {2024}, author = {Hajdukiewicz, H and Hajdukiewicz, M and Ruiz-Villanueva, V and Radecki-Pawlik, A and Zawiejska, J}, title = {Exploring historical changes in mountain river hydrodynamics induced by human impact.}, journal = {The Science of the total environment}, volume = {948}, number = {}, pages = {174742}, doi = {10.1016/j.scitotenv.2024.174742}, pmid = {39004370}, issn = {1879-1026}, abstract = {During the 20th-century many mountain rivers in Europe were subjected to intensive human impacts which substantially modified their channel morphology. How these changes affected river hydrodynamics and response to floods remains uncertain. In this work, we perform hydraulic modelling using data from archival aerial photos to explore relations between hydraulic parameters of floods and human-induced channel incision occurring on the Czarny Dunajec River (Polish Carpathians) between 1964 and 2012. Data on vertical position of the channel used for two-dimensional modelling of flood flows were extracted (as Digital Elevation Models DEMs) from archival aerial photos from 1964 and 1983 and ALS (Airborne Laser Skanning)-derived DEM from 2012. Water depth, flow velocity, bed shear stress, and sediment critical diameter were modelled for four flood scenarios (2-year, 5-year, 20-year, and 50-year floods) as well as the extent of flooded area and additionally the grain size of channel sediment was calculated. The values of water depth, flow velocity, bed shear stress and sediment critical diameter increased significantly between 1964 and 1983, especially for 20-year and 50-year floods. Only the flow velocity within the floodplain zone did not increase for the two largest flood scenarios due to the expansion of riparian forest in the second half of the twentieth century. The increase in flow rate was accompanied by a progressive reduction of the extent of flooded area, especially between 1964 and 1983, as well as by increase in mean grain size of channel sediment. Between 1983 and 2012 changes in hydraulic parameters were less pronounced, and coarser and well packed channel sediment dominated on the river bed. Our work demonstrates that reconstruction of past river hydrodynamics, rather than river state at time horizons, can give essential insights into functioning of the river channel and floodplain during the intensification of human impacts after 1950s.}, } @article {pmid39003629, year = {2024}, author = {Yao, S and Yin, H and Li, Y and Yang, Q and Yuan, S and Deng, W}, title = {Cytochrome P450 CYP81A104 in Eleusine indica confers resistance to multiherbicide with different modes of action.}, journal = {Pest management science}, volume = {80}, number = {11}, pages = {5791-5798}, doi = {10.1002/ps.8310}, pmid = {39003629}, issn = {1526-4998}, support = {32372569//National Natural Science Foundation of China/ ; 137050535//Qing Lan Project of Yangzhou University/ ; }, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Cytochrome P-450 Enzyme System/genetics/metabolism ; *Eleusine/genetics/drug effects/enzymology ; Acetolactate Synthase/genetics/metabolism ; Plant Proteins/genetics/metabolism ; Arabidopsis/genetics/drug effects/enzymology ; Plant Weeds/drug effects/genetics ; Imidazoles ; }, abstract = {BACKGROUND: Developing herbicide-resistant (HR) crop cultivars is an efficient way to control weeds and minimize crop yield losses. However, widespread and long-term herbicide application has led to the evolution of resistant weeds. Here, we established a resistant (R) E. indica population, collected from imidazolinone-resistant rice cultivar fields.

RESULTS: The R population evolved 4.5-fold resistance to imazamox. Acetolactate synthase (ALS) gene sequencing and ALS activity assays excluded the effect of target-site resistance in this population. P450 inhibitor malathion pretreatment significantly reversed resistance to imazamox. RNA sequencing showed that a P450 gene CYP81A104 was expressed higher in R versus susceptible (S) plants. Arabidopsis overexpressing CYP81A104 showed resistance to ALS inhibitors (imazamox, tribenuron-methyl, penoxsulam and flucarbazone-sodium), PSII inhibitor (bentazone), hydroxyphenyl pyruvate dioxygenase inhibitor (mesotrione) and auxin mimics (MCPA), which was generally consistent with the results presented in the R population.

CONCLUSION: This study confirmed that the CYP81A104 gene endowed resistance to multiherbicides with different modes-of-action. Our findings provide an insight into the molecular characteristics of resistance and contribute to formulating an appropriate strategy for weed management in HR crops. © 2024 Society of Chemical Industry.}, } @article {pmid39002811, year = {2024}, author = {Huin, V and Blum, D and Delforge, V and Cailliau, E and Djeziri, S and Dujardin, K and Genet, A and Viard, R and Attarian, S and Bruneteau, G and Cassereau, J and Genestet, S and Kaminsky, AL and Soriani, MH and Lefilliatre, M and Couratier, P and Pittion-Vouyovitch, S and Esselin, F and De La Cruz, E and Guy, N and Kolev, I and Corcia, P and Cintas, P and Desnuelle, C and Buée, L and Danel-Brunaud, V and Devos, D and Rolland, AS}, title = {Caffeine consumption outcomes on amyotrophic lateral sclerosis disease progression and cognition.}, journal = {Neurobiology of disease}, volume = {199}, number = {}, pages = {106603}, doi = {10.1016/j.nbd.2024.106603}, pmid = {39002811}, issn = {1095-953X}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; Basic Helix-Loop-Helix Transcription Factors ; *Caffeine ; Central Nervous System Stimulants/therapeutic use ; Cognition/physiology/drug effects ; Cognitive Dysfunction/genetics ; Cytochrome P-450 CYP1A1/genetics ; *Cytochrome P-450 CYP1A2/genetics ; *Disease Progression ; *Polymorphism, Single Nucleotide ; Prospective Studies ; *Receptor, Adenosine A2A/genetics ; Receptors, Aryl Hydrocarbon/genetics ; Riluzole/therapeutic use ; }, abstract = {Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.}, } @article {pmid39002563, year = {2024}, author = {Shih, PC and Wei, JCC}, title = {Response to Hasan et al's "Dupilumab therapy for atopic dermatitis is associated with increased risk of cutaneous T cell lymphoma: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {5}, pages = {e137-e138}, doi = {10.1016/j.jaad.2024.06.076}, pmid = {39002563}, issn = {1097-6787}, } @article {pmid39001793, year = {2024}, author = {Gao, J and Okolo, O and Siedlak, SL and Friedland, RP and Wang, X}, title = {Ferritin is closely associated with microglia in amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {83}, number = {11}, pages = {917-926}, pmid = {39001793}, issn = {1554-6578}, support = {HHSN275200900011C/HD/NICHD NIH HHS/United States ; RF1AG066578/NH/NIH HHS/United States ; AARG-22-923849/ALZ/Alzheimer's Association/United States ; //Brain and Tissue Bank for Developmental Disorders/ ; //Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; RF1 AG065342/AG/NIA NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Microglia/metabolism/pathology ; *Ferritins/metabolism ; Humans ; *Mice, Transgenic ; Animals ; Female ; Male ; Mice ; Middle Aged ; *Spinal Cord/pathology/metabolism ; Aged ; Aged, 80 and over ; DNA-Binding Proteins/metabolism/genetics ; Superoxide Dismutase/metabolism/genetics ; }, abstract = {Iron deposition is a hallmark of amyotrophic lateral sclerosis (ALS) and has been strongly implicated in its pathogenesis. As a byproduct of cellular oxidative stress, iron dysregulation modifies basal levels of the regulatory iron-binding protein ferritin. Examination of thoracic and lumbar spinal cord tissues found increased ferritin immunostaining in white matter axons that corresponded to areas of increased microgliosis in 8 ALS patients versus 8 normal subjects. Gray matter areas containing the motor neurons also demonstrated increased ferritin and microglia in ALS compared to controls but at lower levels than in the white matter. Motor neurons with or without TDP-43 inclusions did not demonstrate either increased ferritin or associated microglial activation. We also observed an association of ferritin with microglia in cerebral cortical tissue samples of ALS cases and in the spinal cord tissues of transgenic mice expressing the SOD1G93A mutation. Elevated ferritin levels were detected in the insoluble fraction from spinal cord tissues of individuals with ALS. These findings suggest that activated microglia and increased ferritin may play significant roles in ALS progression since they are found closely associated in areas of axonal and cortical degeneration.}, } @article {pmid39000814, year = {2024}, author = {Fan, S and Jing, S and Xu, W and Wu, B and Li, M and Jing, H}, title = {Extraction of Moso Bamboo Parameters Based on the Combination of ALS and TLS Point Cloud Data.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {13}, pages = {}, pmid = {39000814}, issn = {1424-8220}, support = {LTGC23C160002//Zhejiang Provincial Natural Science Foundation of China/ ; 2021LFR057//Research Fund of Zhejiang A&F University/ ; 2023LFK141//Research Fund of Zhejiang A&F University/ ; }, mesh = {*Algorithms ; Sasa ; Lasers ; Poaceae ; }, abstract = {Extracting moso bamboo parameters from single-source point cloud data has limitations. In this article, a new approach for extracting moso bamboo parameters using airborne laser scanning (ALS) and terrestrial laser scanning (TLS) point cloud data is proposed. Using the field-surveyed coordinates of plot corner points and the Iterative Closest Point (ICP) algorithm, the ALS and TLS point clouds were aligned. Considering the difference in point distribution of ALS, TLS, and the merged point cloud, individual bamboo plants were segmented from the ALS point cloud using the point cloud segmentation (PCS) algorithm, and individual bamboo plants were segmented from the TLS and the merged point cloud using the comparative shortest-path (CSP) method. The cylinder fitting method was used to estimate the diameter at breast height (DBH) of the segmented bamboo plants. The accuracy was calculated by comparing the bamboo parameter values extracted by the above methods with reference data in three sample plots. The comparison results showed that by using the merged data, the detection rate of moso bamboo plants could reach up to 97.30%; the R[2] of the estimated bamboo height was increased to above 0.96, and the root mean square error (RMSE) decreased from 1.14 m at most to a range of 0.35-0.48 m, while the R[2] of the DBH fit was increased to a range of 0.97-0.99, and the RMSE decreased from 0.004 m at most to a range of 0.001-0.003 m. The accuracy of moso bamboo parameter extraction was significantly improved by using the merged point cloud data.}, } @article {pmid39000336, year = {2024}, author = {Bodai, L and Borosta, R and Ferencz, Á and Kovács, M and Zsindely, N}, title = {The Role of miR-137 in Neurodegenerative Disorders.}, journal = {International journal of molecular sciences}, volume = {25}, number = {13}, pages = {}, pmid = {39000336}, issn = {1422-0067}, support = {OTKA 145898//National Research, Development and Innovation Office [Hungary]/ ; }, mesh = {*MicroRNAs/genetics/metabolism ; Humans ; *Neurodegenerative Diseases/genetics/metabolism ; Animals ; Gene Expression Regulation ; }, abstract = {Neurodegenerative diseases affect an increasing part of the population of modern societies, burdening healthcare systems and causing immense suffering at the personal level. The pathogenesis of several of these disorders involves dysregulation of gene expression, which depends on several molecular processes ranging from transcription to protein stability. microRNAs (miRNAs) are short non-coding RNA molecules that modulate gene expression by suppressing the translation of partially complementary mRNAs. miR-137 is a conserved, neuronally enriched miRNA that is implicated in neurodegeneration. Here, we review the current body of knowledge about the role that miR-137 plays in five prominent neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The presented data indicate that, rather than having a general neuroprotective role, miR-137 modulates the pathology of distinct disorders differently.}, } @article {pmid39000168, year = {2024}, author = {Ciuro, M and Sangiorgio, M and Cacciato, V and Cantone, G and Fichera, C and Salvatorelli, L and Magro, G and Leanza, G and Vecchio, M and Valle, MS and Gulino, R}, title = {Mitigating the Functional Deficit after Neurotoxic Motoneuronal Loss by an Inhibitor of Mitochondrial Fission.}, journal = {International journal of molecular sciences}, volume = {25}, number = {13}, pages = {}, pmid = {39000168}, issn = {1422-0067}, support = {2015MJBEM2_006//the Italian "Ministero dell'Istruzione, dell'Università e della Ricerca"/ ; }, mesh = {Animals ; *Motor Neurons/drug effects/metabolism/pathology ; *Mitochondrial Dynamics/drug effects ; Mice ; *Disease Models, Animal ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; Cholera Toxin/metabolism ; Saporins ; Quinazolinones/pharmacology ; Neuronal Plasticity/drug effects ; Male ; Mitochondria/drug effects/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an extremely complex neurodegenerative disease involving different cell types, but motoneuronal loss represents its main pathological feature. Moreover, compensatory plastic changes taking place in parallel to neurodegeneration are likely to affect the timing of ALS onset and progression and, interestingly, they might represent a promising target for disease-modifying treatments. Therefore, a simplified animal model mimicking motoneuronal loss without the other pathological aspects of ALS has been established by means of intramuscular injection of cholera toxin-B saporin (CTB-Sap), which is a targeted neurotoxin able to kill motoneurons by retrograde suicide transport. Previous studies employing the mouse CTB-Sap model have proven that spontaneous motor recovery is possible after a subtotal removal of a spinal motoneuronal pool. Although these kinds of plastic changes are not enough to counteract the functional effects of the progressive motoneuron degeneration, it would nevertheless represent a promising target for treatments aiming to postpone ALS onset and/or delay disease progression. Herein, the mouse CTB-Sap model has been used to test the efficacy of mitochondrial division inhibitor 1 (Mdivi-1) as a tool to counteract the CTB-Sap toxicity and/or to promote neuroplasticity. The homeostasis of mitochondrial fission/fusion dynamics is indeed important for cell integrity, and it could be affected during neurodegeneration. Lesioned mice were treated with Mdivi-1 and then examined by a series of behavioral test and histological analyses. The results have shown that the drug may be capable of reducing functional deficits after the lesion and promoting synaptic plasticity and neuroprotection, thus representing a putative translational approach for motoneuron disorders.}, } @article {pmid38999600, year = {2024}, author = {Chakraborty, N and Das, A and Pal, S and Roy, S and Sil, SK and Adak, MK and Hassanzamman, M}, title = {Exploring Aluminum Tolerance Mechanisms in Plants with Reference to Rice and Arabidopsis: A Comprehensive Review of Genetic, Metabolic, and Physiological Adaptations in Acidic Soils.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {13}, pages = {}, pmid = {38999600}, issn = {2223-7747}, abstract = {Aluminum (Al) makes up a third of the Earth's crust and is a widespread toxic contaminant, particularly in acidic soils. It impacts crops at multiple levels, from cellular to whole plant systems. This review delves into Al's reactivity, including its cellular transport, involvement in oxidative redox reactions, and development of specific metabolites, as well as the influence of genes on the production of membrane channels and transporters, alongside its role in triggering senescence. It discusses the involvement of channel proteins in calcium influx, vacuolar proton pumping, the suppression of mitochondrial respiration, and the initiation of programmed cell death. At the cellular nucleus level, the effects of Al on gene regulation through alterations in nucleic acid modifications, such as methylation and histone acetylation, are examined. In addition, this review outlines the pathways of Al-induced metabolic disruption, specifically citric acid metabolism, the regulation of proton excretion, the induction of specific transcription factors, the modulation of Al-responsive proteins, changes in citrate and nucleotide glucose transporters, and overall metal detoxification pathways in tolerant genotypes. It also considers the expression of phenolic oxidases in response to oxidative stress, their regulatory feedback on mitochondrial cytochrome proteins, and their consequences on root development. Ultimately, this review focuses on the selective metabolic pathways that facilitate Al exclusion and tolerance, emphasizing compartmentalization, antioxidative defense mechanisms, and the control of programmed cell death to manage metal toxicity.}, } @article {pmid38999592, year = {2024}, author = {Li, Q and Wang, H and Yu, J and Zhang, W and Guo, W and Liu, Y}, title = {Metabolism-Based Herbicide Resistance to Mesosulfuron-methyl and Identification of Candidate Genes in Bromus japonicus.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {13}, pages = {}, pmid = {38999592}, issn = {2223-7747}, support = {23JCQNJC00450//Tianjin Natural Science Foundation/ ; 2021CXGC010811//Key R&D Program of Shandong Province, China/ ; }, abstract = {The evolved resistance of Bromus japonicus Houtt. to ALS-inhibiting herbicides is well established. Previous studies have primarily focused on target-site resistance; however, non-target-site resistance has not been well characterized. This investigation demonstrated that ALS gene sequencing did not detect any previously known resistance mutations in a mesosulfuron-methyl-resistant (MR) population, and notably, treatment with the P450 monooxygenase (P450) inhibitor malathion markedly heightened susceptibility to mesosulfuron-methyl. Utilizing UPLC-MS/MS analysis confirmed elevated mesosulfuron-methyl metabolism in MR plants. The integration of Isoform Sequencing (Iso-Seq) and RNA Sequencing (RNA-Seq) facilitated the identification of candidate genes associated with non-target sites in a subpopulation with two generations of herbicide selection. Through qRT-PCR analysis, 21 differentially expressed genes were characterized, and among these, 10 genes (comprising three P450s, two glutathione S-transferases, one glycosyltransferase, two ATP-binding cassette transporters, one oxidase, and one hydrolase) exhibited constitutive upregulation in resistant plants. Our findings substantiated that increased herbicide metabolism is a driving force behind mesosulfuron-methyl resistance in this B. japonicus population.}, } @article {pmid38999371, year = {2024}, author = {Dell'Anna, G and Fanti, L and Fanizza, J and Barà, R and Barchi, A and Fasulo, E and Elmore, U and Rosati, R and Annese, V and Laterza, L and Fuccio, L and Azzolini, F and Danese, S and Mandarino, FV}, title = {VAC-Stent in the Treatment of Post-Esophagectomy Anastomotic Leaks: A New "Kid on the Block" Who Marries the Best of Old Techniques-A Review.}, journal = {Journal of clinical medicine}, volume = {13}, number = {13}, pages = {}, pmid = {38999371}, issn = {2077-0383}, abstract = {Esophagectomy, while a pivotal treatment for esophageal cancer, is not without adverse events. Among these, anastomotic leak (AL) is the most feared complication, threatening patient lives and incurring significant healthcare costs. The management of AL is complex and lacks standardization. Given the high morbidity and mortality rates associated with redo-surgery, which poses risks for already fragile patients, various endoscopic treatments have been developed over time. Self-expandable metallic stents (SEMSs) were the most widely used treatment until the early 2000s. The mechanism of action of SEMSs includes covering the wall defect, protecting it from secretions, and promoting healing. In 2010, endoscopic vacuum therapy (EVT) emerged as a viable alternative for treating ALs, quickly gaining acceptance in clinical practice. EVT involves placing a dedicated sponge under negative pressure inside or adjacent to the wall defect, aiming to clear the leak and promote granulation tissue formation. More recently, the VAC-Stent entered the scenario of endoscopic treatment of post-esophagectomy ALs. This device combines a fully covered SEMS with an integrated EVT sponge, blending the ability of SEMSs to exclude defects and maintain the patency of the esophageal lumen with the capacity of EVT to aspirate secretions and promote the formation of granulation tissue. Although the literature on this new device is not extensive, early results from the application of VAC-Stent have shown promising outcomes. This review aims to synthesize the preliminary efficacy and safety data on the device, thoroughly analyze its advantages over traditional techniques and disadvantages, explore areas for improvement, and propose future directions.}, } @article {pmid38997748, year = {2024}, author = {Kato, C and Ueda, K and Morimoto, S and Takahashi, S and Nakamura, S and Ozawa, F and Ito, D and Daté, Y and Okada, K and Kobayashi, N and Nakahara, J and Okano, H}, title = {Proteomic insights into extracellular vesicles in ALS for therapeutic potential of Ropinirole and biomarker discovery.}, journal = {Inflammation and regeneration}, volume = {44}, number = {1}, pages = {32}, pmid = {38997748}, issn = {1880-9693}, support = {JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; JP20H00485//Japan Society for the Promotion of Science/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; }, abstract = {BACKGROUND: Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs.

METHODS: We collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment.

RESULTS: The findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search.

CONCLUSIONS: Despite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.}, } @article {pmid38997636, year = {2024}, author = {Karagianni, K and Dafou, D and Xanthopoulos, K and Sklaviadis, T and Kanata, E}, title = {RNA editing regulates glutamatergic synapses in the frontal cortex of a molecular subtype of Amyotrophic Lateral Sclerosis.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {30}, number = {1}, pages = {101}, pmid = {38997636}, issn = {1528-3658}, support = {01146//Hellenic Foundation for Research and Innovation (H.F.R.I.) under the "2nd Call for H.F.R.I. Research Projects to support Post-Doctoral Researchers"/ ; 10829//Hellenic Foundation for Research and Innovation (H.F.R.I.) under the 4th Call for H.F.R.I. PhD Fellowships/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *RNA Editing ; Humans ; *Frontal Lobe/metabolism ; *Synapses/metabolism/genetics ; Transcriptome ; Gene Expression Profiling ; Glutamic Acid/metabolism ; Computational Biology/methods ; Male ; Female ; Gene Expression Regulation ; Middle Aged ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a highly heterogenous neurodegenerative disorder that primarily affects upper and lower motor neurons, affecting additional cell types and brain regions. Underlying molecular mechanisms are still elusive, in part due to disease heterogeneity. Molecular disease subtyping through integrative analyses including RNA editing profiling is a novel approach for identification of molecular networks involved in pathogenesis.

METHODS: We aimed to highlight the role of RNA editing in ALS, focusing on the frontal cortex and the prevalent molecular disease subtype (ALS-Ox), previously determined by transcriptomic profile stratification. We established global RNA editing (editome) and gene expression (transcriptome) profiles in control and ALS-Ox cases, utilizing publicly available RNA-seq data (GSE153960) and an in-house analysis pipeline. Functional annotation and pathway analyses identified molecular processes affected by RNA editing alterations. Pearson correlation analyses assessed RNA editing effects on expression. Similar analyses on additional ALS-Ox and control samples (GSE124439) were performed for verification. Targeted re-sequencing and qRT-PCR analysis targeting CACNA1C, were performed using frontal cortex tissue from ALS and control samples (n = 3 samples/group).

RESULTS: We identified reduced global RNA editing in the frontal cortex of ALS-Ox cases. Differentially edited transcripts are enriched in synapses, particularly in the glutamatergic synapse pathway. Bioinformatic analyses on additional ALS-Ox and control RNA-seq data verified these findings. We identified increased recoding at the Q621R site in the GRIK2 transcript and determined positive correlations between RNA editing and gene expression alterations in ionotropic receptor subunits GRIA2, GRIA3 and the CACNA1C transcript, which encodes the pore forming subunit of a post-synaptic L-type calcium channel. Experimental data verified RNA editing alterations and editing-expression correlation in CACNA1C, highlighting CACNA1C as a target for further study.

CONCLUSIONS: We provide evidence on the involvement of RNA editing in the frontal cortex of an ALS molecular subtype, highlighting a modulatory role mediated though recoding and gene expression regulation on glutamatergic synapse related transcripts. We report RNA editing effects in disease-related transcripts and validated editing alterations in CACNA1C. Our study provides targets for further functional studies that could shed light in underlying disease mechanisms enabling novel therapeutic approaches.}, } @article {pmid38997630, year = {2024}, author = {Staderini, T and Bigi, A and Lagrève, C and Marzi, I and Bemporad, F and Chiti, F}, title = {Biophysical characterization of the phase separation of TDP-43 devoid of the C-terminal domain.}, journal = {Cellular & molecular biology letters}, volume = {29}, number = {1}, pages = {104}, pmid = {38997630}, issn = {1689-1392}, support = {AriSLA//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; project TDP-43-STRUCT//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; PRIN Project 2020PBS5MJ//Ministero dell'Università e della Ricerca/ ; Fondi di Ateneo 2021//Università degli studi di Firenze/ ; }, mesh = {*DNA-Binding Proteins/metabolism/chemistry ; Humans ; *Protein Domains ; Fluorescence Recovery After Photobleaching ; Phase Separation ; }, abstract = {BACKGROUND: Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP), amyotrophic lateral sclerosis (ALS) and limbic-predominant age-related TDP-43 encephalopathy (LATE) are associated with deposition of cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) in neurons. One complexity of this process lies in the ability of TDP-43 to form liquid-phase membraneless organelles in cells. Previous work has shown that the recombinant, purified, prion-like domain (PrLD) forms liquid droplets in vitro, but the behaviour of the complementary fragment is uncertain.

METHODS: We have purified such a construct without the PrLD (PrLD-less TDP-43) and have induced its phase separation using a solution-jump method and an array of biophysical techniques to study the morphology, state of matter and structure of the TDP-43 assemblies.

RESULTS: The fluorescent TMR-labelled protein construct, imaged using confocal fluorescence, formed rapidly (< 1 min) round, homogeneous and 0.5-1.0 µm wide assemblies which then coalesced into larger, yet round, species. When labelled with AlexaFluor488, they initially exhibited fluorescence recovery after photobleaching (FRAP), showing a liquid behaviour distinct from full-length TDP-43 and similar to PrLD. The protein molecules did not undergo major structural changes, as determined with circular dichroism and intrinsic fluorescence spectroscopies. This process had a pH and salt dependence distinct from those of full-length TDP-43 and its PrLD, which can be rationalized on the grounds of electrostatic forces.

CONCLUSIONS: Similarly to PrLD, PrLD-less TDP-43 forms liquid droplets in vitro through liquid-liquid phase separation (LLPS), unlike the full-length protein that rather undergoes liquid-solid phase separation (LSPS). These results offer a rationale of the complex electrostatic forces governing phase separation of full-length TDP-43 and its fragments. On the one hand, PrLD-less TDP-43 has a low pI and oppositively charged domains, and LLPS is inhibited by salts, which attenuate inter-domain electrostatic attractions. On the other hand, PrLD is positively charged due to a high isoionic point (pI) and LLPS is therefore promoted by salts and pH increases as they both reduce electrostatic repulsions. By contrast, full-length TDP-43 undergoes LSPS most favourably at its pI, with positive and negative salt dependences at lower and higher pH, respectively, depending on whether repulsive or attractive forces dominate, respectively.}, } @article {pmid38996790, year = {2024}, author = {Alqahtani, A and Alsubai, S and Sha, M and Dutta, AK and Zhang, YD}, title = {Intellectual assessment of amyotrophic lateral sclerosis using deep resemble forward neural network.}, journal = {Neural networks : the official journal of the International Neural Network Society}, volume = {178}, number = {}, pages = {106478}, doi = {10.1016/j.neunet.2024.106478}, pmid = {38996790}, issn = {1879-2782}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/complications ; Humans ; *Neural Networks, Computer ; Deep Learning ; Algorithms ; Reproducibility of Results ; Machine Learning ; }, abstract = {ALS (Amyotrophic Lateral Sclerosis) is a neurodegenerative disorder causing profound physical disability that severely impairs a patient's life expectancy and quality of life. It also leads to muscular atrophy and progressive weakness of muscles due to insufficient nutrition in the body. At present, there are no disease-modifying therapies to cure ALS, and there is a lack of preventive tools. The general clinical assessments are based on symptom reports, neurophysiological tests, neurological examinations, and neuroimaging. But, these techniques possess various limitations of low reliability, lack of standardized protocols, and lack of sensitivity, especially in the early stages of disease. So, effective methods are required to detect the progression of the disease and minimize the suffering of patients. Extensive studies concentrated on investigating the causes of neurological disease, which creates a barrier to precise identification and classification of genes accompanied with ALS disease. Hence, the proposed system implements a deep RSFFNNCNN (Resemble Single Feed Forward Neural Network-Convolutional Neural Network) algorithm to effectively classify the clinical associations of ALS. It involves the addition of custom weights to the kernel initializer and neutralizer 'k' parameter to each hidden layer in the network. This is done to increase the stability and learning ability of the classifier. Additionally, the comparison of the proposed approach is performed with SFNN (Single Feed NN) and ML (Machine Learning) based algorithms, namely, NB (Naïve Bayes), XGBoost (Extreme Gradient Boosting) and RF (Random Forest), to estimate the efficacy of the proposed model. The reliability of the proposed algorithm is measured by deploying performance metrics such as precision, recall, F1 score, and accuracy.}, } @article {pmid38996764, year = {2024}, author = {Montero, AS and Aliouat, I and Ribon, M and Canney, M and Goldwirt, L and Mourah, S and Berriat, F and Lobsiger, CS and Pradat, PF and Salachas, F and Bruneteau, G and Carpentier, A and Boillée, S}, title = {Effect of ultrasound-mediated blood-spinal cord barrier opening on survival and motor function in females in an amyotrophic lateral sclerosis mouse model.}, journal = {EBioMedicine}, volume = {106}, number = {}, pages = {105235}, pmid = {38996764}, issn = {2352-3964}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/therapy ; Female ; *Disease Models, Animal ; Mice ; *Spinal Cord/metabolism ; *Blood-Brain Barrier/metabolism ; *Insulin-Like Growth Factor I/metabolism ; Mice, Transgenic ; Humans ; Motor Neurons/metabolism ; Ultrasonic Waves ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. The limited efficacy of recent therapies in clinical development may be linked to lack of drug penetration to the affected motor neurons due to the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB).

METHODS: In this work, the safety and efficacy of repeated short transient opening of the BSCB by low intensity pulsed ultrasound (US, sonication) was studied in females of an ALS mouse model (B6.Cg-Tg(SOD1∗G93A)1Gur/J). The BSCB was disrupted using a 1 MHz ultrasound transducer coupled to the spinal cord, with and without injection of insulin-like growth factor 1 (IGF1), a neurotrophic factor that has previously shown efficacy in ALS models.

FINDINGS: Results in wild-type (WT) animals demonstrated that the BSCB can be safely disrupted and IGF1 concentrations significantly enhanced after a single session of transient BSCB disruption (176 ± 32 μg/g vs. 0.16 ± 0.008 μg/g, p < 0.0001). Five repeated weekly US sessions performed in female ALS mice demonstrated a survival advantage in mice treated with IGF1 and US (US IGF1) compared to treatment with IGF1 alone (176 vs. 166 days, p = 0.0038). Surprisingly, this survival advantage was also present in mice treated with US alone vs. untreated mice (178.5 vs. 166.5 days, p = 0.0061). Muscle strength did not show difference among the groups. Analysis of glial cell immunoreactivity and microglial transcriptome showing reduced cell proliferation pathways, in addition to lymphocyte infiltration, suggested that the beneficial effect of US or US IGF1 could act through immune cell modulation.

INTERPRETATION: These results show the first step towards a possible beneficial impact of transient BSCB opening for ALS therapy and suggest implication of immune cells.

FUNDING: Fondation pour la Recherche Médicale (FRM). Investissements d'avenirANR-10-IAIHU-06, Société Française de Neurochirurgie (SFNC), Fond d'étude et de Recherche du Corps Medical (FERCM), Aide à la Recherche des Maladies du Cerveau (ARMC), SLA Fondation Recherche (SLAFR), French Ministry for High Education and Research (MENR), Carthera, Laboratoire de Recherche en Technologies Chirurgicales Avancées (LRTCA).}, } @article {pmid38996643, year = {2024}, author = {Sheehan, Y and Cochrane, A and Treloar, C and Grebely, J and Tedla, N and Lloyd, AR and Lafferty, L}, title = {Understanding hepatitis C virus (HCV) health literacy and educational needs among people in prison to enhance HCV care in prisons.}, journal = {The International journal on drug policy}, volume = {130}, number = {}, pages = {104516}, doi = {10.1016/j.drugpo.2024.104516}, pmid = {38996643}, issn = {1873-4758}, mesh = {Humans ; Male ; *Health Literacy ; *Hepatitis C ; *Prisoners/psychology ; Adult ; Australia ; *Prisons ; Middle Aged ; Health Knowledge, Attitudes, Practice ; Substance Abuse, Intravenous ; }, abstract = {BACKGROUND: Hepatitis C virus (HCV) is a significant concern within prison populations. Provision of HCV testing and treatment for people in prison is expanding and a key component of global elimination efforts. Despite growing service availability, several challenges remain in HCV testing and treatment engagement during incarceration. The PIVOT study demonstrated that a 'one-stop-shop' intervention (point-of-care HCV RNA testing, Fibroscan®, nurse-led clinical assessment, and fast-tracked direct-acting antiviral prescription) enhanced HCV testing and treatment at a reception prison in Australia. Utilising Squier et al's Health Literacy Skills Framework, this analysis aimed to understand HCV health literacy and educational needs among people at a reception prison in Australia.

METHODS: Semi-structured interviews were conducted with twenty-four male PIVOT study participants. Purposive sampling ensured comparable representation of those with: 1) prior HCV testing history (standard pathology / no prior testing), and 2) injecting drug use history (IDU; ever / never).

RESULTS: Varied HCV health literacy levels and educational needs were evident amongst people in prison. Whilst those with multiple incarceration episodes and IDU history (prior knowledge) appeared to have stronger HCV health literacy than those without, substantial gaps in HCV health literacy were evident. Knowledge of HCV transmission risks in prison was high, and most understood the importance of HCV testing and treatment in prison (comprehension), but ability to engage with HCV testing and treatment services, participation in safe injecting behaviours (health-related behaviours), and knowledge of re-infection and re-treatment, within the context of the prison environment, were suboptimal. There was a general desire for increased HCV education in prison.

CONCLUSION: Gaps in HCV health literacy among people in prison were evident, indicating opportunities for improvement. A targeted HCV education program for people in prison, addressing the gaps identified in this analysis, may enhance HCV testing, treatment, and prevention by fostering stronger HCV health literacy among people in prison.}, } @article {pmid38995133, year = {2024}, author = {Bacigalupo, I and Finocchietti, M and Paoletti, O and Bargagli, AM and Brunori, P and Lombardi, N and Sciancalepore, F and Agabiti, N and Kirchmayer, U}, title = {Incidence and prevalence of Amyotrophic Lateral Sclerosis in three Italian Regions: a study based on health administrative databases.}, journal = {Epidemiologia e prevenzione}, volume = {48}, number = {3}, pages = {201-209}, doi = {10.19191/EP24.3.A710.055}, pmid = {38995133}, issn = {1120-9763}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Italy/epidemiology ; Incidence ; Prevalence ; Male ; Aged ; Female ; Retrospective Studies ; Middle Aged ; Adult ; Databases, Factual ; Aged, 80 and over ; Sex Distribution ; Adolescent ; Archives ; Algorithms ; Young Adult ; Age Distribution ; }, abstract = {OBJECTIVES: to estimate Amyotrophic Lateral Sclerosis (ALS) incidence and prevalence in three Italian Regions (Lazio, Tuscany, and Umbria), using health administrative databases.

DESIGN: retrospective population-based study.

SETTING AND PARTICIPANTS: ALS patients residing in Lazio, Umbria, and Tuscany were identified through an algorithm based on three different administrative databases: hospital discharge records, exemptions from health care co-payment, and emergency departments (study period 2014-2019). Crude, age- and gender-specific prevalence were calculated on 31.12.2019 and incidence rates of ALS were standardised by region, year, and gender between 2014-2019. Using a clinical dataset available in the Lazio Region, the proportion of individuals residing in the region correctly identified as ALS cases by the algorithm were calculated.

MAIN OUTCOMES MEASURES: prevalence and incidence rates.

RESULTS: a total of 1,031 ALS patients (>=18 years) were identified: 408 cases in Tuscany, 546 in Lazio, and 77 in Umbria. ALS standardised prevalence (per 100,000) was similar among regions: 12.31 in Tuscany, 11.52 in Lazio, and 9.90 in Umbria. The 5-year crude rates were higher in men, and in people aged 65-79 years. Among 310 patients included in the clinical dataset, 263 (84.8%) were correctly identified by the algorithm based on health administrative databases.

CONCLUSIONS: ALS prevalence and incidence in three Central Italy Regions are rather similar, but slightly higher than those previously reported. This finding is plausible, given that previous results relate to at least ten years ago and evidenced increasing trends. Overall, the results of this paper encourage the use of administrative data to produce occurrence estimates, useful to both epidemiological surveillance and research and healthcare policies.}, } @article {pmid38992244, year = {2024}, author = {Hunt von Herbing, I}, title = {Energetic Costs of Stress in Developing Fishes: Quantifying Allostasis and Allostatic Load.}, journal = {Integrative and comparative biology}, volume = {64}, number = {3}, pages = {1019-1033}, doi = {10.1093/icb/icae094}, pmid = {38992244}, issn = {1557-7023}, support = {GP64231//University of North Texas/ ; }, mesh = {Animals ; *Zebrafish/physiology/growth & development ; *Allostasis/physiology ; *Energy Metabolism ; *Stress, Physiological ; Larva/growth & development/physiology ; Yolk Sac/physiology ; Hypoxia ; }, abstract = {Stress exerts negative effects on fish health through stimulation of the hypothalamic-pituitary-interrenal axis and autonomic nervous system, resulting in heightened neural and neuroendocrine responses. Energetic investment and physiological adaptation are then required to re-establish homeostatic stability or reach a new allostatic state. The cost of the energetic investment is referred to as allostatic load (AL). While determining the sources of stress and assessing their consequences have resulted in estimates of AL, most of this work has been conducted in adult mammals and humans; no ALs exist for developing fish. From a series of experiments on a model species, zebrafish (Danio rerio), whose yolk-sac larvae were exposed to two chronic stressors (high-temperature and hypoxia), ALs were quantified based on biomarkers of ontogenetic changes in growth, morphometrics, and metabolic activities. Results showed that for zebrafish yolk-sac larvae, chronic stress imposed high AL and, thus, high total allostatic energetic costs, (Rt (AL)), because of prolonged energy demand in the face of limited resources (e.g., yolk). Under severe chronic stress, energetic costs were sufficiently large that energy-limited developing fish may not be able to fully compensate, resulting in maladaptive responses from allostatic overload, leading either to death or to novel allostatic states, possibly more resilient to environmental change.}, } @article {pmid38991324, year = {2024}, author = {Reis, J and Spencer, PS}, title = {An introduction to environmental neurotoxicology: Lessons from a clinical perspective.}, journal = {Journal of the neurological sciences}, volume = {463}, number = {}, pages = {123108}, doi = {10.1016/j.jns.2024.123108}, pmid = {38991324}, issn = {1878-5883}, mesh = {Humans ; *Environmental Exposure/adverse effects ; *Neurotoxicity Syndromes/etiology ; Animals ; }, abstract = {In 1992, the Committee on Neurotoxicology and Models for Assessing Risk of the National Academy of Sciences in Washington DC focused with a scientific perspective on the identification of substances with neurotoxic potential, studies of exposed populations, risk assessment, and biologic markers of disease. This Committee recommended: "all physicians should be trained to take a thorough occupational-exposure history and to be aware of other possible sources of toxic exposure". Although convened after several outbreaks of neurotoxic syndromes, clinical neurological considerations were lacking. After defining keys words, namely Environment, Neurotoxicology and Neurotoxicants, we present some demonstrative cases; e.g., the Epidemic Neuropathy in Cuba, Minamata disease, ALS/PDC on Guam, and the ALS hot spot in the French Alps. Always with a clinical and practical approach, we will then review the milieux that contain and convey potential neurotoxicants, the different exposure routes and the clinical presentations. Drawing lessons from clinical cases, we offer some thoughts concerning the future of Environmental Neurotoxicology (ENT). Pointing notably to the diffuse chemical contamination of ecosystems and living beings, including Homo sapiens, we question the real impact of agents with neurotoxic potential on the human brain, considering the effects, for example, of air pollution, endocrine disruptors and nanoparticles. Concern is expressed over the lack of knowledge of the non-monotonic kinetics of many of these chemicals, the major concern being related to mixtures and low-dose exposures, as well as the delayed appearance in clinical expression of prevalent neurodegenerative diseases.}, } @article {pmid38991167, year = {2024}, author = {Cave, R}, title = {How People Living With Amyotrophic Lateral Sclerosis Use Personalized Automatic Speech Recognition Technology to Support Communication.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {67}, number = {11}, pages = {4186-4202}, doi = {10.1044/2024_JSLHR-24-00097}, pmid = {38991167}, issn = {1558-9102}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; *Speech Recognition Software ; Male ; Female ; *Dysarthria/etiology/psychology/rehabilitation ; Middle Aged ; Aged ; Communication ; Communication Devices for People with Disabilities ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive, ultimately fatal disease causing progressive muscular weakness. Most people living with ALS (plwALS) experience dysarthria, eventually becoming unable to communicate using natural speech. Many wish to use speech for as long as possible. Personalized automated speech recognition (ASR) model technology, such as Google's Project Relate, is argued to better recognize speech with dysarthria, supporting maintenance of understanding through real-time captioning. The objectives of this study are how plwALS and communication partners use Relate in everyday conversation over a period of up to 12 months and how it may change with any decline in speech over time.

METHOD: This study videoed interactions between three plwALS and communication partners. We assessed ASR caption accuracy and how well they preserved meaning. Conversation analysis was used to identify participants' own organizational practices in the accomplishment of interaction. Thematic analysis was used to understand better the participants' experiences of using ASR captions.

RESULTS: All plwALS reported lower-than-expected ASR accuracy when used in conversation and felt ASR captioning was only useful in certain contexts. All participants liked the concept of live captioning and were hopeful that future improvements to ASR accuracy may support their communication in everyday life.

CONCLUSIONS: Training is needed on best practices for customization and practical use of ASR technology and for the limitations of ASR in conversational settings. Support is needed for those less confident with technology and to reduce misplaced allocation of ownership of captioning errors, risking negative effects on psychological well-being.}, } @article {pmid38990927, year = {2024}, author = {Srinivasan, V and Homer, V and Barton, D and Clutterbuck-James, A and Jenkins, S and Potter, C and Brock, K and Logan, A and Smith, D and Bruce, L and Nagy, Z and Bach, SP}, title = {A low molecular weight dextran sulphate, ILB®, for the treatment of amyotrophic lateral sclerosis (ALS): An open-label, single-arm, single-centre, phase II trial.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0291285}, pmid = {38990927}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Aged ; Prospective Studies ; Treatment Outcome ; Adult ; Neuroprotective Agents/therapeutic use/administration & dosage/adverse effects ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig´s disease, is a rare neurological condition and is the most common motor neurone disease. It is a fatal disease with specific loss of motor neurons in the spinal cord, brain stem, and motor cortex leading to progressive paralysis and usually death within five years of diagnosis. There remains no cure for ALS, and management is focused on a combination of neuroprotective medication, respiratory support, and management by multidisciplinary clinics.

PATIENTS AND METHODS: This prospective, single-arm, open-label phase II clinical trial of sustained weekly administration of 2 mg/kg ILB® (a low-molecular weight dextran sulphate) was conducted in a single UK hospital. Eligible patients were at least 18 years and had a definite diagnosis of ALS according to El Escorial Criteria. The co-primary outcomes were safety, tolerability, and quantity of ILB® administered. EudraCT number. 2018-000668-28.

FINDINGS: Between 18-Apr-2019 and 27-Mar-2020, 11 patients were recruited and treated for up to 38 weeks. There were no treatment terminations or withdrawals. One serious adverse event was reported, which was not related to ILB® and resolved without sequalae. 270 mild/moderate adverse events were reported with no intolerable events occurring during the trial. The total number of ILB® treatments administered per patient ranged from 4 to 38, with a cumulative dose ranging from 745 to 6668 mg. As a result of the COVID-19 pandemic and the high-risk status of study participants, recruitment and treatment was suspended early in Mar-2020. At the long-term follow-up, three patients had died after the trial was halted, between 53 and 62 weeks after their final ILB® injection.

INTERPRETATION: Long-term weekly ILB® injections of 2 mg/kg was well tolerated and had an acceptable safety profile in patients with ALS.

TRIAL REGISTRATION: EudraCT: 2018-000668-28. clinicaltrials.gov: NCT03705390. This trial adheres to the principles of GCP in the design, conduct, recording and reporting of clinical trials as listed in part 2, "Conditions and Principles which apply to all Clinical Trials" under the header "Principles based on Articles 2 to 5 of the EU GCP Directive" in the Medicines for Human Use Clinical Trials Regulations (as amended in SI 2006/1928). For clarity, the study did not conform to all aspects of the International Conference on Harmonisation (ICH) E6 R2 Guidelines for GCP (also known as 'ICH GCP'). Of note, we did not use an external database, perform 100% source data verification, and only primary outcome data were analysed in parallel by a second, independent statistician.}, } @article {pmid38990842, year = {2024}, author = {Yip, PK and Pizzasegola, C and Gladman, S and Biggio, ML and Marino, M and Jayasinghe, M and Ullah, F and Dyall, SC and Malaspina, A and Bendotti, C and Michael-Titus, A}, title = {Correction: The Omega-3 Fatty Acid Eicosapentaenoic Acid Accelerates Disease Progression in a Model of Amyotrophic Lateral Sclerosis.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0307246}, pmid = {38990842}, issn = {1932-6203}, abstract = {[This corrects the article DOI: 10.1371/journal.pone.0061626.].}, } @article {pmid38989937, year = {2025}, author = {Locatelli, M and Farina, C}, title = {Role of copper in central nervous system physiology and pathology.}, journal = {Neural regeneration research}, volume = {20}, number = {4}, pages = {1058-1068}, pmid = {38989937}, issn = {1673-5374}, abstract = {Copper is a transition metal and an essential element for the organism, as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs, including the central nervous system. Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B, Menkes disease and Wilson's disease, respectively, and also in multifactorial neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology, reports about unbalances in copper levels and/or distribution under disease, describes relevant animal models for human disorders where copper metabolism genes are dysregulated, and discusses relevant therapeutic approaches modulating copper availability. Overall, alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.}, } @article {pmid38989900, year = {2025}, author = {Marchica, V and Biasetti, L and Barnard, J and Li, S and Nikolaou, N and Frosch, MP and Lucente, DE and Eldaief, M and King, A and Fanto, M and Troakes, C and Houart, C and Smith, BN}, title = {Annexin A11 mutations are associated with nuclear envelope dysfunction in vivo and in human tissues.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {1}, pages = {276-290}, pmid = {38989900}, issn = {1460-2156}, support = {//Motor Neurone Disease Association UK/ ; /MRF/MRF/United Kingdom ; //Van Geest Foundation/ ; //MNDA Studentship/ ; //Project Grants/ ; 855-791//Project Grant by the MNDA/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Zebrafish ; *Nuclear Envelope/metabolism/genetics ; *Mutation ; *Annexins/genetics/metabolism ; Lamin Type B/genetics/metabolism ; Frontotemporal Dementia/genetics/pathology ; Male ; Spinal Cord/metabolism/pathology ; }, abstract = {Annexin A11 mutations are a rare cause of amyotrophic lateral sclerosis (ALS), wherein replicated protein variants P36R, G38R, D40G and D40Y are located in a small helix within the long, disordered N-terminus. To elucidate disease mechanisms, we characterized the phenotypes induced by a genetic loss-of-function and by misexpression of G38R and D40G in vivo. Loss of Annexin A11 results in a low-penetrant behavioural phenotype and aberrant axonal morphology in zebrafish homozygous knockout larvae, which is rescued by human wild-type Annexin A11. Both Annexin A11 knockout/down and ALS variants trigger nuclear dysfunction characterized by Lamin B2 mislocalization. The Lamin B2 signature also presented in anterior horn, spinal cord neurons from post-mortem ALS ± frontotemporal dementia patient tissue possessing G38R and D40G protein variants. These findings suggest mutant Annexin A11 acts as a dominant negative, revealing a potential early nucleopathy highlighting nuclear envelope abnormalities preceding behavioural abnormality in animal models.}, } @article {pmid38989463, year = {2024}, author = {Pasternack, N and Doucet-O'Hare, T and Johnson, K and , and Paulsen, O and Nath, A}, title = {Endogenous retroviruses are dysregulated in ALS.}, journal = {iScience}, volume = {27}, number = {7}, pages = {110147}, pmid = {38989463}, issn = {2589-0042}, abstract = {Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease with no cure. Human endogenous retroviruses (HERVs) have been implicated in its pathogenesis but their relevance to ALS is not fully understood. We examined bulk RNA-seq data from almost 2,000 ALS and unaffected control samples derived from the cortex and spinal cord. Using different methods of feature selection, including differential expression analysis and machine learning, we discovered that transcription of HERV-K loci 1q22 and 8p23.1 were significantly upregulated in the spinal cord of individuals with ALS. Additionally, we identified a subset of ALS patients with upregulated HERV-K expression in the cortex and spinal cord. We also found the expression of HERV-K loci 19q11 and 8p23.1 was correlated with protein coding genes previously implicated in ALS and dysregulated in ALS patients in this study. These results clarify the association of HERV-K and ALS and highlight specific genes in the pathobiology of late-stage ALS.}, } @article {pmid38988889, year = {2024}, author = {Ansari, U and Alam, M and Nadora, D and Muttalib, Z and Chen, V and Taguinod, I and FitzPatrick, M and Wen, J and Ansari, Z and Lui, F}, title = {Assessing the efficacy of amyotrophic lateral sclerosis drugs in slowing disease progression: A literature review.}, journal = {AIMS neuroscience}, volume = {11}, number = {2}, pages = {166-177}, pmid = {38988889}, issn = {2373-7972}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and intricate neurodegenerative disease that impacts upper and lower motor neurons within the central nervous system, leading to their progressive destruction. Despite extensive research, the pathogenesis of this multifaceted disease remains elusive. The United States Food and Drug Administration (FDA) has granted approval for seven medications designed to address ALS and mitigate its associated symptoms. These FDA-sanctioned treatments are Qalsody, Relyvrio, Radicava, Rilutek, Tiglutik, Exservan, and Nuedexta. In this review, the effects of these seven drugs on ALS based on their mechanism of action, dosing, and clinical presentations are comprehensively summarized. Each medication offers a distinct approach to manage ALS, aiming to alleviate the burdensome symptoms and slow the disease's progression, thereby improving the quality of life for individuals affected by this neurological condition. However, despite these advancements in pharmaceutical interventions, finding a definitive cure for ALS remains a significant challenge. Continuous investigation into ALS pathophysiology and therapeutic avenues remains imperative, necessitating further research collaborations and innovative approaches to unravel the complex mechanisms underlying this debilitating condition.}, } @article {pmid38988205, year = {2024}, author = {Arnaldi, P and Casarotto, E and Relucenti, M and Bellese, G and Gagliani, MC and Crippa, V and Castagnola, P and Cortese, K}, title = {A NSC-34 cell line-derived spheroid model: Potential and challenges for in vitro evaluation of neurodegeneration.}, journal = {Microscopy research and technique}, volume = {87}, number = {11}, pages = {2785-2800}, doi = {10.1002/jemt.24651}, pmid = {38988205}, issn = {1097-0029}, support = {PRIN2020PBS5MJ//Ministero dell'Università e della Ricerca/ ; PRIN2022KSJZF5//Ministero dell'Università e della Ricerca/ ; //University of Genoa/ ; 100008-2022-KC-FRA_ANATOMIA//Fondi Ricerca Ateneo/ ; //Italian Ministry of Health (Ricerca Corrente)/ ; }, mesh = {*Spheroids, Cellular/pathology ; Animals ; Mice ; *DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Cell Line ; Motor Neurons/pathology ; Cell Survival ; Neurodegenerative Diseases/pathology ; Cell Culture Techniques/methods ; Spinal Cord/cytology/pathology ; Hydrogels/chemistry ; Humans ; Mitochondria/metabolism ; }, abstract = {Three-dimensional (3D) spheroid models aim to bridge the gap between traditional two-dimensional (2D) cultures and the complex in vivo tissue environment. These models, created by self-clustering cells to mimic a 3D environment with surrounding extracellular framework, provide a valuable research tool. The NSC-34 cell line, generated by fusing mouse spinal cord motor neurons and neuroblastoma cells, is essential for studying neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), where abnormal protein accumulation, such as TAR-DNA-binding protein 43 (TDP-43), occurs in affected nerve cells. However, NSC-34 behavior in a 3D context remains underexplored, and this study represents the first attempt to create a 3D model to determine its suitability for studying pathology. We generated NSC-34 spheroids using a nonadhesive hydrogel-based template and characterized them for 6 days. Light microscopy revealed that NSC-34 cells in 3D maintained high viability, a distinct round shape, and forming stable membrane connections. Scanning electron microscopy identified multiple tunnel-like structures, while ultrastructural analysis highlighted nuclear bending and mitochondria alterations. Using inducible GFP-TDP-43-expressing NSC-34 spheroids, we explored whether 3D structure affected TDP-43 expression, localization, and aggregation. Spheroids displayed nuclear GFP-TDP-43 expression, albeit at a reduced level compared with 2D cultures and generated both TDP-35 fragments and TDP-43 aggregates. This study sheds light on the distinctive behavior of NSC-34 in 3D culture, suggesting caution in the use of the 3D model for ALS or TDP-43 pathologies. Yet, it underscores the spheroids' potential for investigating fundamental cellular mechanisms, cell adaptation in a 3D context, future bioreactor applications, and drug penetration studies. RESEARCH HIGHLIGHTS: 3D spheroid generation: NSC-34 spheroids, developed using a hydrogel-based template, showed high viability and distinct shapes for 6 days. Structural features: advanced microscopy identified tunnel-like structures and nuclear and mitochondrial changes in the spheroids. Protein dynamics: the study observed how 3D structures impact TDP-43 behavior, with altered expression but similar aggregation patterns to 2D cultures. Research implications: this study reveals the unique behavior of NSC-34 in 3D culture, suggests a careful approach to use this model for ALS or TDP-43 pathologies, and highlights its potential in cellular mechanism research and drug testing applications.}, } @article {pmid38988008, year = {2025}, author = {Murakami, A and Koga, S and Fujioka, S and White, AE and Bieniek, KF and Sekiya, H and DeJesus-Hernandez, M and Finch, NA and van Blitterswijk, M and Nakamura, M and Tsuboi, Y and Murray, ME and Wszolek, ZK and Dickson, DW}, title = {Upper motor neuron-predominant motor neuron disease presenting as atypical parkinsonism: A clinicopathological study.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {35}, number = {1}, pages = {e13286}, pmid = {38988008}, issn = {1750-3639}, support = {P01-AG03949/GF/NIH HHS/United States ; R01-AG062348/GF/NIH HHS/United States ; 1U19AG063911/GF/NIH HHS/United States ; P30-AG062677/GF/NIH HHS/United States ; FAIN: U19AG063911/GF/NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R01-NS121125/GF/NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; RF1-NS123052/GF/NIH HHS/United States ; RF1 NS123052/NS/NINDS NIH HHS/United States ; R01 NS121125/NS/NINDS NIH HHS/United States ; U54 NS100693/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; U54-NS100693/GF/NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; *Motor Neuron Disease/pathology/diagnosis ; *Parkinsonian Disorders/pathology/diagnosis ; Aged, 80 and over ; Motor Neurons/pathology ; Amyotrophic Lateral Sclerosis/pathology/diagnosis ; Supranuclear Palsy, Progressive/pathology/diagnosis ; DNA-Binding Proteins/metabolism ; Corticobasal Degeneration/pathology/diagnosis ; Diagnosis, Differential ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by upper and lower motor neuron signs. There are, however, cases where upper motor neurons (UMNs) are predominantly affected, leading to clinical presentations of UMN-dominant ALS or primary lateral sclerosis. Furthermore, cases exhibiting an UMN-predominant pattern of motor neuron disease (MND) presenting with corticobasal syndrome (CBS) have been sparsely reported. This study aims to clarify the clinicopathological features of patients with UMN-predominant MND. We reviewed 24 patients with UMN-predominant MND with TDP-43 pathology in the presence or absence of frontotemporal lobar degeneration. Additionally, we reviewed the medical records of patients with pathologically-confirmed corticobasal degeneration (CBD) who received a final clinical diagnosis of CBS (n = 10) and patients with pathologically-confirmed progressive supranuclear palsy (PSP) who received a final clinical diagnosis of PSP syndrome (n = 10). Of 24 UMN-predominant MND patients, 20 had a clinical diagnosis of an atypical parkinsonian disorder, including CBS (n = 11) and PSP syndrome (n = 8). Only two patients had antemortem diagnoses of motor neuron disease. UMN-predominant MND patients with CBS less frequently exhibited apraxia than those with CBD, and they were less likely to meet clinical criteria for possible or probable CBS. Similarly, UMN-predominant MND patients with PSP syndrome less often met clinical criteria for probable PSP than PSP patients with PSP syndrome. Our findings suggest that UMN-predominant MND can mimic atypical parkinsonism, and should be considered in the differential diagnosis of CBS and PSP syndrome, in particular when criteria are not met.}, } @article {pmid38987905, year = {2024}, author = {Bergem, AK and Aamotsmo, T}, title = {Navigating parenthood in the face of amyotrophic lateral sclerosis: A qualitative exploration of partner experiences.}, journal = {Scandinavian journal of caring sciences}, volume = {38}, number = {4}, pages = {835-843}, doi = {10.1111/scs.13282}, pmid = {38987905}, issn = {1471-6712}, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/psychology ; *Qualitative Research ; Adult ; Norway ; *Adaptation, Psychological ; Middle Aged ; *Parents/psychology ; Aged ; Child ; }, abstract = {INTRODUCTION: Among people diagnosed with Amyotrophic Lateral Sclerosis (ALS), there are parents with children living at home. Children in families experiencing severe illness are exposed to stress and health risks. Since 2010, healthcare personnel in Norway must assess whether patients have children under 18 years of age and make sure the children's needs for support are met. A child's ability to cope with family life affected by a serious illness depends on how the parent without the disease manages the situation. Little is known about how the partner of someone affected by ALS manages being next of kin and a parent simultaneously, and what kind of support they need.

METHODS: During 2021-2022, six semi-structured interviews were conducted with partners to persons with ALS, whom had children living at home. The interviews were transcribed verbatim and analysed through qualitative content analysis.

RESULTS: Three themes with subthemes emerged: (1) Together, yet alone; (a) restricted home life, (b) missing the sharing of responsibilities and tasks as equal parents, and (c) caught between children's and partner's needs; (2) Experience of coping while waiting for death; (a) cherishing the moments, (b) sense of coping and concern, and (c) ensuring to get recharged; and (3) Support in times of need; (a) difficult to ask the network for help and (b) the healthcare system does not see the whole family.

CONCLUSIONS: Our respondents felt alone, caught between the needs of their children and partner, without necessary support from the services, and were left to handle everyday life with all new challenges on their own. Future healthcare services need to consider the challenges faced by families dealing with life-limiting illnesses. A family-focused perspective is needed, so is peer support and interventions that address both emotional and practical aspects of life with an ill partner.}, } @article {pmid38987226, year = {2024}, author = {Luo, X and Heydari, A and Renfrey, D and Gardner, Z and He, S and Tang, Y and Weiss, GA and Rogers, ML and Raston, CL}, title = {Sustainability-Driven Accelerated Shear-Mediated Immunoassay for Amyotrophic Lateral Sclerosis Detection.}, journal = {ChemSusChem}, volume = {17}, number = {21}, pages = {e202401008}, doi = {10.1002/cssc.202401008}, pmid = {38987226}, issn = {1864-564X}, support = {DP200101106//Australian Research Council/ ; IC190100034//Australian Research Council/ ; //Flinders Health Seed Foundation/ ; //Australian Nanotechnology Network/ ; //Flinders University Research Investment Fund/ ; //Australian Microscopy and Microanalysis Research Facility/ ; //Australian National Fabrication Facility (ANFF)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Immunoassay/methods ; Limit of Detection ; Biomarkers ; }, abstract = {Healthcare facilities produce millions of tons of waste annually, with a significant portion consisting of diagnostic plasticware. Here, we introduce a new detection platform that completely replaces traditional assay plates with a piece of membrane, offering a much greener and more sustainable alternative. The membrane, integrated within the portable vortex fluidic device (P-VFD), enables rapid detection of a clinically relevant protein biomarker, urinary p75[ECD]. This biomarker is utilized to evaluate the prognosis, disease severity, and progression of amyotrophic lateral sclerosis (ALS). This assay has a limit-of-detection (LOD) of 4.03 pg, which is comparable to the plate-based assay (2.24 pg) and has been optimised through a full factorial design of experiments (DOE) and response surface methodology (RSM). P-VFD has great potential in quantifying p75[ECD] in human biofluids and can significantly reduce the assay time to 5 min compared to the current plate-based p75[ECD] ELISA assay (3 days), with at least a 4.4-fold reduction in the usage of the detection antibody.}, } @article {pmid38986433, year = {2025}, author = {Rifai, OM and Waldron, FM and Sleibi, D and O'Shaughnessy, J and Leighton, DJ and Gregory, JM}, title = {Clinicopathological analysis of NEK1 variants in amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {35}, number = {1}, pages = {e13287}, pmid = {38986433}, issn = {1750-3639}, support = {108890/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; R01 NS127186/NS/NINDS NIH HHS/United States ; 1R01NS127186/NS/NINDS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; BB-2022-C4-L2//Target ALS/ ; }, mesh = {Humans ; *NIMA-Related Kinase 1/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Male ; Female ; Middle Aged ; Aged ; DNA-Binding Proteins/genetics/metabolism ; Mutation ; Mutation, Missense ; Adult ; }, abstract = {Many genes have been linked to amyotrophic lateral sclerosis (ALS), including never in mitosis A (NIMA)-related kinase 1 (NEK1), a serine/threonine kinase that plays a key role in several cellular functions, such as DNA damage response and cell cycle regulation. Whole-exome sequencing studies have shown that NEK1 mutations are associated with an increased risk for ALS, where a significant enrichment of NEK1 loss-of-function (LOF) variants were found in individuals with ALS compared to controls. In particular, the p.Arg261His missense variant was associated with significantly increased disease susceptibility. This case series aims to understand the neuropathological phenotypes resulting from NEK1 mutations in ALS. We examined a cohort of three Scottish patients with a mutation in the NEK1 gene and evaluated the distribution and cellular expression of NEK1, as well as the abundance of phosphorylated TDP-43 (pTDP-43) aggregates, in the motor cortex compared to age- and sex-matched control tissue. We show pathological, cytoplasmic TDP-43 aggregates in all three NEK1-ALS cases. NEK1 protein staining revealed no immunoreactivity in two of the NEK1-ALS cases, indicating a LOF and corresponding to a reduction in NEK1 mRNA as detected by in situ hybridisation. However, the p.Arg261His missense mutation resulted in an increase in NEK1 mRNA molecules and abundant NEK1-positive cytoplasmic aggregates, with the same morphologic appearance, and within the same cells as co-occurring TDP-43 aggregates. Here we show the first neuropathological assessment of a series of ALS cases carrying mutations in the NEK1 gene. Specifically, we show that TDP-43 pathology is present in these cases and that potential NEK1 LOF can either be mediated through loss of NEK1 translation or through aggregation of NEK1 protein as in the case with p.Arg261His mutation, a potential novel pathological feature of NEK1-ALS.}, } @article {pmid38984697, year = {2024}, author = {Hasan, M and Alam, SM and Rahman, HZ and Khan, MAS and Huq, MR}, title = {Autonomic Dysfunction in Amyotrophic Lateral Sclerosis - A Case-Control Study.}, journal = {Acta medica academica}, volume = {53}, number = {1}, pages = {24-34}, pmid = {38984697}, issn = {1840-2879}, mesh = {Case-Control Studies ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Autonomic Nervous System Diseases/epidemiology ; Bangladesh/epidemiology ; Tertiary Care Centers ; Humans ; Male ; Female ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Upper Extremity/physiopathology ; Lower Extremity/physiopathology ; Sympathetic Nervous System ; }, abstract = {INTRODUCTION: This study aimed to explore autonomic nervous system involvement in amyotrophic lateral sclerosis (ALS) patients by evaluating sympathetic skin response (SSR).

MATERIALS AND METHODS: The study included 35 sporadic (ALS) patients (cases), and 35 healthy age and sex-matched participants (controls) aged <60 years. SSR was recorded in the electrophysiology lab of the Neurology Department of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Patients with diseases associated with peripheral or autonomic neuropathy were excluded. Prolonged latency (delayed SSR) or an absent response was considered abnormal SSR.

RESULTS: SSR was found to be abnormal in 17 (48.6 %) ALS cases, with an absent response in the upper limbs of six cases (17.1%). Abnormal SSR was more prevalent in the lower limbs, with 33 (94.3%) and 20 (57.1%) cases having a delayed or absent response, respectively. In comparison, SSR was normal in all control participants (P-value <0.05). Abnormal SSR was significantly more common in the lower limbs of ALS cases with bulbar palsy than those without bulbar palsy (P-value=0.04). There was no association of SSR with disease severity and duration.

CONCLUSION: ALS is significantly associated with abnormal SSR, indicating autonomic nervous system involvement. There could also be an association between bulbar palsy and abnormal SSR among ALS patients. Further studies should be carried out to determine the association of abnormal SSR with disease severity, duration, and type.}, } @article {pmid38984619, year = {2024}, author = {Olney, N and Weiss, MD}, title = {Real world experience with sodium phenylbutyrate-taurursodiol for ALS: Lessons learned from a failed drug.}, journal = {Muscle & nerve}, volume = {70}, number = {3}, pages = {299-301}, doi = {10.1002/mus.28203}, pmid = {38984619}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Phenylbutyrates/therapeutic use ; Male ; Female ; Middle Aged ; Treatment Failure ; Aged ; }, } @article {pmid38984582, year = {2025}, author = {Jiang, SS and Nie, HB and Hua, S and Xie, M and Xu, RS}, title = {Preliminary Analysis of Potentially Overlapping Differentially Expressed Proteins in Both the Spinal Cord and Brain of SOD1 G93A Mice.}, journal = {Current protein & peptide science}, volume = {26}, number = {1}, pages = {57-75}, pmid = {38984582}, issn = {1875-5550}, support = {30560042, 81160161, 81360198, 82160255//National Natural Science Foundation of China/ ; GJJ13198, GJJ170021//Education Department of Jiangxi Province/ ; [2014]-47, 20142BBG70062, 20171BAB- 215022, 20192BAB205043//Jiangxi provincial department of science and technology/ ; 20181019, 202210002, 202310119//Health and Family Planning Commission of Jiangxi province/ ; [2015] 108//Jiangxi Provincial Department of Science and Technology Gan Po Elite 555 (Jiangxi Finance Elite Education)/ ; }, mesh = {Animals ; *Spinal Cord/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Brain/metabolism/pathology ; *Proteomics/methods ; *Mice, Transgenic ; Superoxide Dismutase/metabolism/genetics ; Disease Models, Animal ; Gene Expression Regulation ; Superoxide Dismutase-1/genetics/metabolism ; Proteome/metabolism/genetics ; Computational Biology/methods ; Gene Ontology ; Humans ; }, abstract = {OBJECTIVE: Proteomic elucidation is an essential step in improving our understanding of the biological properties of proteins in amyotrophic lateral sclerosis (ALS).

METHODS: Preliminary proteomic analysis was performed on the spinal cord and brain of SOD1 G93A (TG) and wild-type (WT) mice using isobaric tags for relative and absolute quantitation.

RESULTS: Partial up- and downregulated proteins showing significant differences between TG and WT mice were identified, of which 105 proteins overlapped with differentially expressed proteins in both the spinal cord and brain of progression mice. Bioinformatic analyses using Gene Ontology, a cluster of orthologous groups, and Kyoto Encyclopedia of Genes and Genomes pathway revealed that the significantly up- and downregulated proteins represented multiple biological functions closely related to ALS, with 105 overlapping differentially expressed proteins in the spinal cord and brain at the progression stage of TG mice closely related to 122 pathways. Differentially expressed proteins involved in a set of molecular functions play essential roles in maintaining neural cell survival.

CONCLUSION: This study provides additional proteomic profiles of TG mice, including potential overlapping proteins in both the spinal cord and brain that participate in pathogenesis, as well as novel insights into the up- and downregulation of proteins involved in the pathogenesis of ALS.}, } @article {pmid38982381, year = {2024}, author = {Mioshi, E and Heal, S and Katangwe-Chigamba, T}, title = {'A lightbulb moment': carers' experiences of behavioural symptoms in motor neurone disease before and after MiNDToolkit.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {238}, pmid = {38982381}, issn = {1471-2377}, support = {934-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; 934-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Caregivers/psychology ; Male ; *Motor Neuron Disease/psychology/therapy ; Female ; Middle Aged ; *Behavioral Symptoms/therapy/etiology ; Aged ; Adult ; Qualitative Research ; }, abstract = {BACKGROUND: To explore carers' experiences of behavioural symptoms in Motor Neurone Disease (MND), before and after using the MiNDToolkit, a novel internet-based psychoeducational intervention to support management of behavioural symptoms (BehSymp) in MND. The study also investigated carers' views and acceptability of MiNDToolkit.

METHODS: A qualitative process evaluation of carers engagement with, and acceptability of, the MiNDToolkit conducted using semi-structured interviews with carers (n = 11). All interviews were audio-recorded, professionally transcribed verbatim and analysed thematically.

RESULTS: Five themes were identified: (1) In the dark: carers' experiences and reactions to BehSymp; (2) Others can see: the role of HCPs in identifying symptoms - and perceived opportunities for carers to receive support; (3) Shedding light: carers implementation and perceived impact of the MiNDToolkit content; (4) Acceptability and carers' engagement with MiNDToolkit; (5) Future implementation. Carers' experience of BehSymp was particularly distressing when symptoms were apparently out of context. MiNDToolkit appeared to support learning that BehSymp were part of MND. Content resonated with carers, who reported learning about the full picture of MND, which led to acceptance and use of newly learned strategies. Engagement with the platform was good, with varied input from HCPs. Greater and nuanced involvement from HCPs seem important to support management of BehSymp. Recommendations for a full-scale trial emerged, including adding a paper booklet to accompany the intervention and creation of new modules on emotional lability, changes in relationships, and transitioning to a care home.

CONCLUSIONS: MiNDToolkit was acceptable to carers overall. Recommended improvements should be actioned in a full-scale trial.}, } @article {pmid38981325, year = {2024}, author = {Asghar, H and Tariq, A and Rasool, G and Hayat, A}, title = {Fabrication of a salivary amylase electrochemical sensor based on surface confined MWCNTs/β-cyclodextrin/starch architect for dental caries in clinical samples.}, journal = {Bioelectrochemistry (Amsterdam, Netherlands)}, volume = {160}, number = {}, pages = {108774}, doi = {10.1016/j.bioelechem.2024.108774}, pmid = {38981325}, issn = {1878-562X}, mesh = {*beta-Cyclodextrins/chemistry ; Humans ; *Nanotubes, Carbon/chemistry ; *Biosensing Techniques/methods ; *Starch/chemistry ; *Electrochemical Techniques/methods ; *Dental Caries/diagnosis ; Saliva/chemistry ; Limit of Detection ; Salivary alpha-Amylases/analysis/metabolism ; Electrodes ; }, abstract = {Salivary α-amylase (α-ALS) has drawn attention as a possible bioindicator for dental caries. Herein, combining the synergistic properties of multi-walled carbon nanotubes (MWCNTs), β-cyclodextrin (β-CD) and starch, an electrochemical sensor is constructed employing ferrocene (FCN) as an electrochemical indicator to oversee the progression of the enzymatic catalysis of α-ALS. The method involves a two-step chemical reaction sequence on a screen-printed carbon electrode (SPCE). X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, Field emission scanning electron microscope (FE-SEM), and Dynamic light scattering (DLS) were used to characterize the synthesized material, while Static water Contact angle measurements, cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS) were performed to monitor each step of sensor fabrication. The electrochemical sensor permitted to detect α-ALS within the linear range of 0.5-280 U mL[-1], revealing detection (LOD), and quantification (LOQ) values of 0.041 U mL[-1], and 0.159 U mL[-1], respectively. Remarkably, the sensor demonstrated exceptional specificity and selectivity, effectively discriminating against other interfering substances in saliva. Validation of the method involved analyzing α-ALS levels in artificial saliva with an accuracy range of 97 % to 103 %, as well as in real clinical saliva samples across various age groups.}, } @article {pmid38979791, year = {2024}, author = {Stabellini, N and Cullen, J and Bittencourt, MS and Moore, JX and Sutton, A and Nain, P and Hamerschlak, N and Weintraub, NL and Dent, S and Tsai, MH and Banerjee, A and Ghosh, AK and Sadler, D and Coughlin, SS and Barac, A and Shanahan, J and Montero, AJ and Guha, A}, title = {Allostatic Load/Chronic Stress and Cardiovascular Outcomes in Patients Diagnosed With Breast, Lung, or Colorectal Cancer.}, journal = {Journal of the American Heart Association}, volume = {13}, number = {14}, pages = {e033295}, pmid = {38979791}, issn = {2047-9980}, mesh = {Humans ; Female ; *Colorectal Neoplasms/epidemiology ; *Breast Neoplasms/epidemiology ; *Lung Neoplasms/epidemiology/diagnosis ; Middle Aged ; Male ; Retrospective Studies ; Aged ; *Cardiovascular Diseases/epidemiology ; *Allostasis/physiology ; Risk Assessment ; Risk Factors ; Stress, Psychological/complications ; }, abstract = {BACKGROUND: Cardiovascular disease and cancer share a common risk factor: chronic stress/allostatic load (AL). A 1-point increase in AL is linked to up to a 30% higher risk of major cardiac events (MACE) in patients with prostate cancer. However, AL's role in MACE in breast cancer, lung cancer, or colorectal cancer remains unknown.

METHODS AND RESULTS: Patients ≥18 years of age diagnosed with the mentioned 3 cancers of interest (2010-2019) and followed up at a large, hybrid academic-community practice were included in this retrospective cohort study. AL was modeled as an ordinal measure (0-11). Adjusted Fine-Gray competing risks regressions estimated the impact of AL precancer diagnosis on 2-year MACE (a composite of heart failure, ischemic stroke, acute coronary syndrome, and atrial fibrillation). The effect of AL changes over time on MACE was calculated via piecewise Cox regression (before, and 2 months, 6 months, and 1 year after cancer diagnosis). Among 16 467 patients, 50.5% had breast cancer, 27.9% had lung cancer, and 21.4% had colorectal cancer. A 1-point elevation in AL before breast cancer diagnosis corresponded to a 10% heightened associated risk of MACE (adjusted hazard ratio, 1.10 [95% CI, 1.06-1.13]). Similar findings were noted in lung cancer (adjusted hazard ratio, 1.16 [95% CI, 1.12-1.20]) and colorectal cancer (adjusted hazard ratio, 1.13 [95% CI, 1.08-1.19]). When considering AL as a time-varying exposure, the peak associated MACE risk occurred with a 1-point AL rise between 6 and 12 months post- breast cancer, lung cancer, and colorectal cancer diagnosis.

CONCLUSIONS: AL warrants investigation as a potential marker in these patients to identify those at elevated cardiovascular risk and intervene accordingly.}, } @article {pmid38979291, year = {2024}, author = {Weiss, A and Gilbert, JW and Flores, IVR and Belgrad, J and Ferguson, C and Dogan, EO and Wightman, N and Mocarski, K and Echeverria, D and Summers, A and Bramato, B and McHugh, N and Furgal, R and Yamada, N and Cooper, D and Monopoli, K and Godinho, BMDC and Hassler, MR and Yamada, K and Greer, P and Henninger, N and Brown, RH and Khvorova, A}, title = {RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38979291}, issn = {2692-8205}, support = {R01 NS111990/NS/NINDS NIH HHS/United States ; S10 OD020012/OD/NIH HHS/United States ; R21 NR020231/NR/NINR NIH HHS/United States ; R21 NS131756/NS/NINDS NIH HHS/United States ; R01 NS104022/NS/NINDS NIH HHS/United States ; R35 GM131839/GM/NIGMS NIH HHS/United States ; U24 NS113844/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene lowering a promising approach, supported by preclinical data and the 2023 FDA approval of the GapmeR ASO targeting SOD1, tofersen. Despite the approval of an ASO and the optimism it brings to the field, the pharmacodynamics and pharmacokinetics of therapeutic SOD1 modulation can be improved. Here, we developed a chemically stabilized divalent siRNA scaffold (di-siRNA) that effectively suppresses SOD1 expression in vitro and in vivo. With optimized chemical modification, it achieves remarkable CNS tissue permeation and SOD1 silencing in vivo. Administered intraventricularly, di-siRNA[SOD1] extended survival in SOD1-G93A ALS mice, surpassing survival previously seen in these mice by ASO modalities, slowed disease progression, and prevented ALS neuropathology. These properties offer an improved therapeutic strategy for SOD1-mediated ALS and may extend to other dominantly inherited neurological disorders.}, } @article {pmid38979278, year = {2024}, author = {Arseni, D and Nonaka, T and Jacobsen, MH and Murzin, AG and Cracco, L and Peak-Chew, SY and Garringer, HJ and Kawakami, I and Suzuki, H and Onaya, M and Saito, Y and Murayama, S and Geula, C and Vidal, R and Newell, KL and Mesulam, M and Ghetti, B and Hasegawa, M and Ryskeldi-Falcon, B}, title = {Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.25.600403}, pmid = {38979278}, issn = {2692-8205}, support = {P30 AG013854/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; }, abstract = {Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system [1] . Human genetic studies established a causal role for protein assembly in neurodegeneration [2] . However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in electron cryo-microscopy (cryo-EM) have enabled the structures of the protein filaments to be determined from patient brains [1] . All diseases studied to date have been characterised by the self-assembly of a single intracellular protein in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) Types A and B [3,4] . Here, we used cryo-EM to determine filament structures from the brains of individuals with FTLD-TDP Type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/284-N345 and ANXA11 residues L39-L74 from their respective low-complexity domains (LCDs). Regions of TDP-43 and ANXA11 previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as a ∼22 kDa N-terminal fragment (NTF) lacking the annexin core domain. Immunohistochemistry of brain sections confirmed the co-localisation of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP Type C. This work establishes a central role for ANXA11 in FTLD-TDP Type C. The unprecedented formation of heteromeric amyloid filaments in human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.}, } @article {pmid38979270, year = {2024}, author = {Baghel, MS and Burns, GD and Tsapatsis, M and Mallika, AP and Cruz, ALF and Cao, T and Chen, XK and Rosa, I and Marx, SR and Ye, Y and Sun, S and Li, T and Wong, PC}, title = {Depletion of TDP-43 exacerbates tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-mediated endoproteolysis of tau in a mouse model of Multiple Etiology Dementia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38979270}, issn = {2692-8205}, support = {R01 NS095969/NS/NINDS NIH HHS/United States ; R61 NS115161/NS/NINDS NIH HHS/United States ; F31 NS135935/NS/NINDS NIH HHS/United States ; R33 NS115161/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; R01 AG078948/AG/NIA NIH HHS/United States ; }, abstract = {TDP-43 proteinopathy, initially disclosed in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coexists with tauopathy in a variety of neurodegenerative disorders, termed multiple etiology dementias (MEDs), including Alzheimer's Disease (AD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration and steeper cognitive decline, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. The loss of TDP-43 splicing repression that occurs in presymptomatic ALS-FTD individuals suggests that such early loss could facilitate the pathological conversion of tau to accelerate neuron loss. Here, we report that the loss of TDP-43 repression of cryptic exons in forebrain neurons (CaMKII-CreER;Tardbp [f/f] mice) is necessary to exacerbate tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-dependent cleavage of endogenous tau to promote tauopathy. Corroborating this finding within the human context, we demonstrate that loss of TDP-43 function in iPSC-derived cortical neurons promotes early cryptic exon inclusion and subsequent caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in CaMKII-CreER;Tardbp [f/f] mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed positively correlates with levels of caspase 3-cleaved tau. Importantly, we found that the vulnerability of hippocampal neurons to TDP-43 depletion is dependent on the amount of caspase 3-cleaved tau: from most vulnerable neurons in the CA2/3, followed by those in the dentate gyrus, to the least in CA1. Taken together, our findings strongly support the view that TDP-43 loss-of-function exacerbates tauopathy-dependent brain atrophy by increasing the sensitivity of vulnerable neurons to caspase 3-mediated endoproteolysis of tau, resulting in a greater degree of neurodegeneration in human disorders with co-pathologies of tau and TDP-43. Our work thus discloses novel mechanistic insights and therapeutic targets for human tauopathies harboring co-pathology of TDP-43 and provides a new MED model for testing therapeutic strategies.}, } @article {pmid38979232, year = {2024}, author = {Keuss, MJ and Harley, P and Ryadnov, E and Jackson, RE and Zanovello, M and Wilkins, OG and Barattucci, S and Mehta, PR and Oliveira, MG and Parkes, JE and Sinha, A and Correa-Sánchez, AF and Oliver, PL and Fisher, EMC and Schiavo, G and Shah, M and Burrone, J and Fratta, P}, title = {Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38979232}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; }, abstract = {TDP-43 loss of function induces multiple splicing changes, including a cryptic exon in the amyotrophic lateral sclerosis and fronto-temporal lobar degeneration risk gene UNC13A, leading to nonsense-mediated decay of UNC13A transcripts and loss of protein. UNC13A is an active zone protein with an integral role in coordinating pre-synaptic function. Here, we show TDP-43 depletion induces a severe reduction in synaptic transmission, leading to an asynchronous pattern of network activity. We demonstrate that these deficits are largely driven by a single cryptic exon in UNC13A. Antisense oligonucleotides targeting the UNC13A cryptic exon robustly rescue UNC13A protein levels and restore normal synaptic function, providing a potential new therapeutic approach for ALS and other TDP-43-related disorders.}, } @article {pmid38979013, year = {2024}, author = {Shi, W and Ding, R and Chen, Y and Ji, F and Ji, J and Ma, W and Jin, J}, title = {The HRD1-SEL1L ubiquitin ligase regulates stress granule homeostasis in couple with distinctive signaling branches of ER stress.}, journal = {iScience}, volume = {27}, number = {7}, pages = {110196}, pmid = {38979013}, issn = {2589-0042}, abstract = {Stress granules (SGs) are membrane-less cellular compartments which are dynamically assembled via biomolecular condensation mechanism when eukaryotic cells encounter environmental stresses. SGs are important for gene expression and cell fate regulation. Dysregulation of SG homeostasis has been linked to human neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we report that the HRD1-SEL1L ubiquitin ligase complex specifically regulates the homeostasis of heat shock-induced SGs through the ubiquitin-proteasome system (UPS) and the UPS-associated ATPase p97. Mechanistically, the HRD1-SEL1L complex mediates SG homeostasis through the BiP-coupled PERK-eIF2α signaling axis of endoplasmic reticulum (ER) stress, thereby coordinating the unfolded protein response (UPR) with SG dynamics. Furthermore, we show that the distinctive branches of ER stress play differential roles in SG homeostasis. Our study indicates that the UPS and the UPR together via the HRD1-SEL1L ubiquitin ligase to maintain SG homeostasis in a stressor-dependent manner.}, } @article {pmid38978682, year = {2024}, author = {Neumann, M and Kothare, H and Ramanarayanan, V}, title = {Multimodal Speech Biomarkers for Remote Monitoring of ALS Disease Progression.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38978682}, support = {R42 DC019877/DC/NIDCD NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that severely impacts affected persons' speech and motor functions, yet early detection and tracking of disease progression remain challenging. The current gold standard for monitoring ALS progression, the ALS functional rating scale - revised (ALSFRS-R), is based on subjective ratings of symptom severity, and may not capture subtle but clinically meaningful changes due to a lack of granularity. Multimodal speech measures which can be automatically collected from patients in a remote fashion allow us to bridge this gap because they are continuous-valued and therefore, potentially more granular at capturing disease progression. Here we investigate the responsiveness and sensitivity of multimodal speech measures in persons with ALS (pALS) collected via a remote patient monitoring platform in an effort to quantify how long it takes to detect a clinically-meaningful change associated with disease progression. We recorded audio and video from 278 participants and automatically extracted multimodal speech biomarkers (acoustic, orofacial, linguistic) from the data. We find that the timing alignment of pALS speech relative to a canonical elicitation of the same prompt and the number of words used to describe a picture are the most responsive measures at detecting such change in both pALS with bulbar (n = 36) and non-bulbar onset (n = 107). Interestingly, the responsiveness of these measures is stable even at small sample sizes. We further found that certain speech measures are sensitive enough to track bulbar decline even when there is no patient-reported clinical change, i.e. the ALSFRS-R speech score remains unchanged at 3 out of a total possible score of 4. The findings of this study have the potential to facilitate improved, accelerated and cost-effective clinical trials and care.}, } @article {pmid38978196, year = {2024}, author = {Huang, X and Wu, J and Zhang, N and Teng, J and Yang, Q and Zhang, Y and Yin, T and Zhou, W and Fan, D and Ye, S}, title = {Smell loss is associated with cognitive impairment in amyotrophic lateral sclerosis patients.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {7}, pages = {e14851}, pmid = {38978196}, issn = {1755-5949}, support = {82001350//National Natural Science Foundation of China/ ; 2021ZD0204200//STI2030-Major Projects/ ; JCTD-2021-06//The Chinese Academy of Sciences Grants/ ; YCXJ-JZ-2022-007//Beijing E-Town Cooperation & Development Foundation/ ; YJXJ-JZ-2021-0014//Beijing E-Town Cooperation & Development Foundation/ ; DL2019002//PUTH Cohort Construction Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology/epidemiology ; Male ; Female ; Middle Aged ; *Cognitive Dysfunction/epidemiology/etiology ; Aged ; *Olfaction Disorders/etiology/epidemiology ; Adult ; }, abstract = {BACKGROUND: Smell loss significantly impacts the quality of life in patients. However, there is limited research on smell loss in individuals with amyotrophic lateral sclerosis (ALS), and the correlation between smell loss and cognitive impairment is unclear. This study aimed to investigate the correlation between smell loss and cognition impairment in ALS patients.

METHODS: The study included 216 ALS patients. The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and smell identification test specifically for the Chinese population (CSIT) were administered to evaluate participants' cognitive and olfactory function, respectively.

RESULTS: After covarying for age, sex, BMI, education level, degree of hunger, dietary bias, eagerness for food, stress, smoking status, alcohol consumption, and upper respiratory tract infection (URTI) or rhinitis, CSIT scores were significantly correlated with ECAS scores (r = 0.162, p = 0.028), especially the ALS-specific scores (r = 0.158, p = 0.031). Even after excluding patients with URTI or rhinitis, the results were similar. CSIT scores were significantly correlated with ECAS scores (r = 0.224, p = 0.011), especially the ALS-specific scores (r = 0.205, p = 0.019).

CONCLUSION: In patients with ALS, smell loss is significantly correlated with cognitive impairment, particularly frontotemporal dysfunction. Cognitive dysfunction may lead to worse olfactory performance in ALS patients.}, } @article {pmid38978024, year = {2024}, author = {Endalamaw, A and Gilks, CF and Ambaw, F and Shiferaw, WS and Assefa, Y}, title = {Explaining inequity in knowledge, attitude, and services related to HIV/AIDS: a systematic review.}, journal = {BMC public health}, volume = {24}, number = {1}, pages = {1815}, pmid = {38978024}, issn = {1471-2458}, mesh = {Humans ; *HIV Infections/psychology ; *Health Knowledge, Attitudes, Practice ; Healthcare Disparities ; }, abstract = {BACKGROUND: Equitable service provision and coverage are important responses to end the threat of the HIV/AIDS pandemic. Understanding inequity supports policies and programmes to deliver tailored interventions. There is continuous evidence generation on inequity in HIV/AIDS services. However, there was a lack of evidence on the global picture of inequity in behavioural and biomedical services related to HIV/AIDS. This systematic review assessed inequities in knowledge, attitude, HIV testing, and ART coverage across individual-level social groups and multiple (dis)advantage categories.

METHODS: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline, with a PROSPERO registration number CRD42024521247. The risk of bias was assessed by using Hoy et al's and Joanna Brigg's quality appraisal checklists for cross-sectional quantitative and qualitative studies, respectively. The search date was from inception to the final database search date (May 29, 2023). The included articles were either quantitative or qualitative studies. We used mixed-methods approach to analyse the data from the review articles. Quantitative descriptive analysis was conducted to estimate frequency of articles published from different countries around the world. Qualitative content analysis of the findings from the original studies was conducted using the PROGRESS plus framework which stands for: place of residence, occupation or employment status, gender, religion, education status, socioeconomic status, and social capital.

RESULTS: Out of 6,029 articles that were accessed and screened, only 72 articles met the inclusion criteria. More articles on HIV-related equity in knowledge, attitude, testing, and ART were published in developed countries than in developing countries. Individuals from higher-income households had better knowledge about HIV/AIDS. Unfavourable attitudes towards people living with HIV and HIV/AIDS-associated stigma were common among women. HIV/AIDS service coverage (HIV testing or ART coverage) was higher among richer and urban residents. HIV/AIDS-associated stigma and lower levels of knowledge about HIV/AIDS were observed among multiple disadvantageous groups due to the intersection of two or more identities.

CONCLUSIONS: The current review revealed that there have been disparities in HIV/AIDS services between social classes. Ending service disparity towards the global threat of HIV/AIDS demands tailored interventions based on socially disadvantaged groups (e.g., poor, rural dwellers, and women) and intersectional determinants. There is a need to understand the deep-rooted causes of inequity and the challenges that an equity-oriented system faces over time. More studies on inequity are needed, including intersectional inequity, which has been rarely studied in developing countries.}, } @article {pmid38977678, year = {2024}, author = {M Amaral, D and Soares, DF and Gromicho, M and de Carvalho, M and Madeira, SC and Tomás, P and Aidos, H}, title = {Temporal stratification of amyotrophic lateral sclerosis patients using disease progression patterns.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {5717}, pmid = {38977678}, issn = {2041-1723}, support = {101017598//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; 101017598//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; 101017598//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; 101017598//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Humans ; *Disease Progression ; Male ; Cluster Analysis ; Female ; Middle Aged ; Aged ; }, abstract = {Identifying groups of patients with similar disease progression patterns is key to understand disease heterogeneity, guide clinical decisions and improve patient care. In this paper, we propose a data-driven temporal stratification approach, ClusTric, combining triclustering and hierarchical clustering. The proposed approach enables the discovery of complex disease progression patterns not found by univariate temporal analyses. As a case study, we use Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease with a non-linear and heterogeneous disease progression. In this context, we applied ClusTric to stratify a hospital-based population (Lisbon ALS Clinic dataset) and validate it in a clinical trial population. The results unravelled four clinically relevant disease progression groups: slow progressors, moderate bulbar and spinal progressors, and fast progressors. We compared ClusTric with a state-of-the-art method, showing its effectiveness in capturing the heterogeneity of ALS disease progression in a lower number of clinically relevant progression groups.}, } @article {pmid38977656, year = {2024}, author = {Han, M and Raymond, J and Larson, TC and Mehta, P and Horton, DK}, title = {Comparison of Demographics: National Amyotrophic Lateral Sclerosis Registry and Clinical Trials Data.}, journal = {Journal of racial and ethnic health disparities}, volume = {}, number = {}, pages = {}, pmid = {38977656}, issn = {2196-8837}, abstract = {OBJECTIVE: To characterize the participant demographics in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database compared with the web-portal National Amyotrophic Lateral Sclerosis (ALS) Registry (the Registry).

METHODS: Demographics and ALS symptom information were compared between the self-reported registrant data in the Registry web portal (2010-2021) and the latest available PRO-ACT data (updated August 2022), which is a collection of clinical trials data.

RESULTS: Greater percentages of younger (≤ 59 years old) but smaller percentages of older (60 + years old) participants were represented in PRO-ACT compared to Registry. Enrollment for minority race groups was greater in the Registry portal data, but race information was largely missing/unknown in PRO-ACT database. Median age at the time of diagnosis and age at the time of symptom onset were significantly higher for Registry enrollees compared to the participants of PRO-ACT. Symptom onset sites were similarly reported, but duration between self-noted symptom onset and diagnosis was slight, but significantly longer for the Registry enrollees (11 vs. 9 months). Hispanic were as likely as non-Hispanic to participate in research studies, based on the Registry data.

CONCLUSION: There was a notable difference in the age distribution and minority representation of enrollees between the PRO-ACT and Registry study populations. Age distribution in the PRO-ACT database skewed to a younger and less diverse cohort. Despite the clinical heterogeneity and complex disease mechanism of ALS, identifying the underrepresented demographic niche in the PRO-ACT and Registry study populations can help improve patient participation and criteria for patient selection to enhance generalizability.}, } @article {pmid38976599, year = {2024}, author = {Xu, Z and Xu, R}, title = {Current potential diagnostic biomarkers of amyotrophic lateral sclerosis.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {8}, pages = {917-931}, pmid = {38976599}, issn = {2191-0200}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Humans ; *Biomarkers/metabolism ; Oxidative Stress/physiology ; Proteomics/methods ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) currently lacks the useful diagnostic biomarkers. The current diagnosis of ALS is mainly depended on the clinical manifestations, which contributes to the diagnostic delay and be difficult to make the accurate diagnosis at the early stage of ALS, and hinders the clinical early therapeutics. The more and more pathogenesis of ALS are found at the last 30 years, including excitotoxicity, the oxidative stress, the mitochondrial dysfunction, neuroinflammation, the altered energy metabolism, the RNA misprocessing and the most recent neuroimaging findings. The findings of these pathogenesis bring the new clues for searching the diagnostic biomarkers of ALS. At present, a large number of relevant studies about the diagnostic biomarkers are underway. The ALS pathogenesis related to the diagnostic biomarkers might lessen the diagnostic reliance on the clinical manifestations. Among them, the cortical altered signatures of ALS patients derived from both structural and functional magnetic resonance imaging and the emerging proteomic biomarkers of neuronal loss and glial activation in the cerebrospinal fluid as well as the potential biomarkers in blood, serum, urine, and saliva are leading a new phase of biomarkers. Here, we reviewed these current potential diagnostic biomarkers of ALS.}, } @article {pmid38975625, year = {2024}, author = {Berkman, O and Raveh, E and Harpaz, E and Kreitman, R and Ben-Ami, E and Nechushtan, E and Birman, N and Drory, VE}, title = {Changes in saccadic intrusions over time as an objective biomarker to follow ALS disease progression.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {760-766}, doi = {10.1080/21678421.2024.2376732}, pmid = {38975625}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Disease Progression ; Female ; Middle Aged ; Male ; Aged ; *Saccades/physiology ; Ocular Motility Disorders/etiology/diagnosis/physiopathology ; Biomarkers ; }, abstract = {Objective: Saccadic Intrusions (SIs) are abnormal eye movements during gaze fixation. Studies have indicated the clinical relevance of SIs, especially of square wave jerks (SWJ) in ALS. We used a software-based platform to extract SIs as a part of an interventional drug trial. The objective was to examine SIs' change over time as a potential biomarker of ALS disease progression. Methods: 28 ALS patients (61.95 ± 8.6 years) were assessed with the revised ALS Functional Rating Scale (ALSFRS-R) and with an oculometric test. Changes of SIs over time and correlations with ALSFRS-R and its bulbar subscale were calculated. A power calculation was conducted to understand the practical implications of results. Results: A significant increase of SWJ over trial duration was observed, with an increase in frequency (mean rise of 0.14 ± 0.28, p < 0.01), amplitude (0.001 ± 0.0016 degrees, p < 0.005), overall duration of SWJ (0.13 ± 0.25, in %, p < 0.01), and in their relative part out of all intrusions (0.18 ± 0.32, in %, p < 0.005). Negative correlations were found with the bulbar subscale (R=-0.43, -0.41, -0.39 and -0.47, respectively, p < 0.001). The required sample size for observing a 40% reduction in bulbar aspects when using the oculometric test (α = 0.05 and β = 0.8), was found to be 150 patients per arm, compared with 200 patients using the bulbar subscale. Conclusions: Evaluation of saccadic intrusions during fixation was able to detect disease progression over time, correlated with ALSFRS-R bulbar subscale. Eye movements can potentially serve as an objective biomarker in ALS clinical trials and reduce the required sample size to show clinical effect of therapies.}, } @article {pmid38975145, year = {2024}, author = {Zhang, J and Xie, D and Jiao, D and Zhou, S and Liu, S and Ju, Z and Hu, L and Qi, L and Yao, C and Zhao, C}, title = {From inflammatory signaling to neuronal damage: Exploring NLR inflammasomes in ageing neurological disorders.}, journal = {Heliyon}, volume = {10}, number = {12}, pages = {e32688}, pmid = {38975145}, issn = {2405-8440}, abstract = {The persistence of neuronal degeneration and damage is a major obstacle in ageing medicine. Nucleotide-binding oligomerization domain (NOD)-like receptors detect environmental stressors and trigger the maturation and secretion of pro-inflammatory cytokines that can cause neuronal damage and accelerate cell death. NLR (NOD-like receptors) inflammasomes are protein complexes that contain NOD-like receptors. Studying the role of NLR inflammasomes in ageing-related neurological disorders can provide valuable insights into the mechanisms of neurodegeneration. This includes investigating their activation of inflammasomes, transcription, and capacity to promote or inhibit inflammatory signaling, as well as exploring strategies to regulate NLR inflammasomes levels. This review summarizes the use of NLR inflammasomes in guiding neuronal degeneration and injury during the ageing process, covering several neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and peripheral neuropathies. To improve the quality of life and slow the progression of neurological damage, NLR-based treatment strategies, including inhibitor-related therapies and physical therapy, are presented. Additionally, important connections between age-related neurological disorders and NLR inflammasomes are highlighted to guide future research and facilitate the development of new treatment options.}, } @article {pmid38974930, year = {2024}, author = {Aziz, S and Barratt, J and Wilson-Baig, N and Lachowycz, K and Major, R and Barnard, EBG and Rees, P}, title = {A protocol for the ERICA-ARREST feasibility study of Emergency Resuscitative Endovascular Balloon occlusion of the Aorta in Out-of-Hospital Cardiac Arrest.}, journal = {Resuscitation plus}, volume = {19}, number = {}, pages = {100688}, pmid = {38974930}, issn = {2666-5204}, abstract = {BACKGROUND: Fewer than one in ten out-of-hospital cardiac arrest (OHCA) patients survive to hospital discharge in the UK. For prehospital teams to improve outcomes in patients who remain in refractory OHCA despite advanced life support (ALS); novel strategies that increase the likelihood of return of spontaneous circulation, whilst preserving cerebral circulation, should be investigated. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) has been shown to improve coronary and cerebral perfusion during cardiopulmonary resuscitation. Early, prehospital initiation of REBOA may improve outcomes in patients who do not respond to standard ALS. However, there are significant clinical, technical, and logistical challenges with rapidly delivering prehospital REBOA in OHCA; and the feasibility of delivering this intervention in the UK urban-rural setting has not been evaluated.

METHODS: The Emergency Resuscitative Endovascular Balloon Occlusion of the Aorta in Out-of-Hospital Cardiac Arrest (ERICA-ARREST) study is a prospective, single-arm, interventional feasibility study. The trial will enrol 20 adult patients with non-traumatic OHCA. The primary objective is to assess the feasibility of performing Zone I (supra-coeliac) aortic occlusion in patients who remain in OHCA despite standard ALS in the UK prehospital setting. The trial's secondary objectives are to describe the hemodynamic and physiological responses to aortic occlusion; to report key time intervals; and to document adverse events when performing REBOA in this context.

DISCUSSION: Using compressed geography, and targeted dispatch, alongside a well-established femoral arterial access programme, the ERICA-ARREST study will assess the feasibility of deploying REBOA in OHCA in a mixed UK urban and rural setting.Trial registration.ClinicalTrials.gov (NCT06071910), registration date October 10, 2023, https://classic.clinicaltrials.gov/ct2/show/NCT06071910.}, } @article {pmid38973130, year = {2025}, author = {Corcia, P and Guy, N and Pradat, PF and Soriani, MH and Verschueren, A and Couratier, P}, title = {Treatment continuity of amyotrophic lateral sclerosis with available riluzole formulations: state of the art and current challenges in a 'real-world' setting.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {15-21}, doi = {10.1080/21678421.2024.2375330}, pmid = {38973130}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/complications ; *Riluzole/therapeutic use ; Humans ; *Neuroprotective Agents/therapeutic use ; Deglutition Disorders/drug therapy/etiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare multisystem neurodegenerative disease leading to death due to respiratory failure. Riluzole was the first disease modifying treatment approved in ALS. Randomized clinical trials showed a significant benefit of riluzole on survival in the months following randomization, with a good safety profile. 'Real-world' studies suggested that the survival benefit of riluzole is substantially greater, with an extended survival ranging between 6 and 19 months. The main limiting associated adverse effects of riluzole are non-severe gastrointestinal complications and an elevation of liver enzymes, observed in 10% of patients. While different classes of drugs have been approved in some countries, riluzole remains the gold standard of therapy. Dysphagia induced by ALS is a major challenge for food intake and riluzole administration. Tablet crushing is associated with a loss of drug intake and a risk of powder aspiration, which jeopardizes the benefits of riluzole. Riluzole oral suspension (ROS) and oral film (ROF) allow riluzole intake in patients with dysphagia. Both formulations are bioequivalent to riluzole tablets with a good safety profile albeit transient oral hypoaesthesia. In case of severe dysphagia, ROS can be used with percutaneous endoscopic gastrostomy. ROF, the last approved formulation, requires low swallowing capacities and may contribute to maintain the efficacy of riluzole when tablets are inadequate according to patient's status and/or preferences. To optimize treatment continuity in newly diagnosed patients, the expected psychological impact of formulation switching that may be perceived as the sign of disease progression should be anticipated.}, } @article {pmid38972779, year = {2024}, author = {Pelaez, MC and Fiore, F and Larochelle, N and Dabbaghizadeh, A and Comaduran, MF and Arbour, D and Minotti, S and Marcadet, L and Semaan, M and Robitaille, R and Nalbantoglu, JN and Sephton, CF and Durham, HD}, title = {Reversal of cognitive deficits in FUS[R521G] amyotrophic lateral sclerosis mice by arimoclomol and a class I histone deacetylase inhibitor independent of heat shock protein induction.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {5}, pages = {e00388}, pmid = {38972779}, issn = {1878-7479}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; Mice ; *Mice, Transgenic ; Heat-Shock Proteins/genetics/metabolism ; Hydroxylamines/pharmacology/therapeutic use ; Cognitive Dysfunction/drug therapy/metabolism ; Disease Models, Animal ; Spinal Cord/drug effects/metabolism ; Humans ; Mice, Inbred C57BL ; }, abstract = {Protein misfolding and mislocalization are common to both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Maintaining proteostasis through induction of heat shock proteins (HSP) to increase chaperoning capacity is a rational therapeutic strategy in the treatment of ALS. However, the threshold for upregulating stress-inducible HSPs remains high in neurons, presenting a therapeutic obstacle. This study used mouse models expressing the ALS variants FUS[R521G] or SOD1[G93A] to follow up on previous work in cultured motor neurons showing varied effects of the HSP co-inducer, arimoclomol, and class I histone deacetylase (HDAC) inhibitors on HSP expression depending on the ALS variant being expressed. As in cultured neurons, neither expression of the transgene nor drug treatments induced expression of HSPs in cortex, spinal cord or muscle of FUS[R521G] mice, indicating suppression of the heat shock response. Nonetheless, arimoclomol, and RGFP963, restored performance on cognitive tests and improved cortical dendritic spine densities. In SOD1[G93A] mice, multiple HSPs were upregulated in hindlimb skeletal muscle, but not in lumbar spinal cord with the exception of HSPB1 associated with astrocytosis. Drug treatments improved contractile force but reduced the increase in HSPs in muscle rather than facilitating their expression. The data point to mechanisms other than amplification of the heat shock response underlying recovery of cognitive function in ALS-FUS mice by arimoclomol and class I HDAC inhibition and suggest potential benefits in counteracting cognitive impairment in ALS, frontotemporal dementia and related disorders.}, } @article {pmid38972199, year = {2024}, author = {Rosén, C and Mitre, B and Nellgård, B and Axelsson, M and Constantinescu, R and Andersen, PM and Dalla, K and Blennow, K and Nilsson, G and Zetterberg, H and Rosén, H}, title = {High levels of neurofilament light and YKL-40 in cerebrospinal fluid are related to poor outcome in ALS.}, journal = {Journal of the neurological sciences}, volume = {463}, number = {}, pages = {123112}, doi = {10.1016/j.jns.2024.123112}, pmid = {38972199}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis/blood ; *Chitinase-3-Like Protein 1/cerebrospinal fluid/blood ; Female ; Male ; *Neurofilament Proteins/cerebrospinal fluid ; Middle Aged ; Aged ; *Biomarkers/cerebrospinal fluid ; Glial Fibrillary Acidic Protein/cerebrospinal fluid ; Disease Progression ; Adult ; Membrane Glycoproteins ; Receptors, Immunologic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease without effective treatment. No pathognomonic test can diagnose ALS in sporadic cases. Routine investigation in suspected cases includes neurological examination, imaging of the brain and spine and electromyography supported by blood and cerebrospinal fluid (CSF) analyses. The ALS diagnosis is made by clinical judgement and results from examinations. We aimed to study if the CSF biomarkers neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), YKL-40, soluble amyloid precursor protein (sAPP) α and β, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were associated with ALS diagnosis and could predict disease progression. Eighty-one patients with suspected ALS were included after referral to the neurological clinic at Sahlgrenska University Hospital. Fifty-nine patients were diagnosed having ALS, while 22 patients were given alternative diagnoses and labeled ALS mimics. Finally, 25 age-matched neurologically intact individuals were used as controls. ALS patients had significantly higher CSF levels of NFL than controls and mimics. Levels of YKL-40 and GFAP were significantly higher in ALS patients compared with controls. No difference was found between study groups when comparing levels of sAPPα, sAPPβ and sTREM2. Further, elevated levels of NFL and YKL-40 were associated with an increased hazard of death and the annual decline in ALSFRS-R. We also found that patients with elevated levels of both NFL and YKL-40 had a particularly poor prognosis. The results demonstrate the usefulness of CSF biomarkers in the diagnosis and prognostication of ALS.}, } @article {pmid38971939, year = {2024}, author = {Gomez, D and Selvaraj, MG and Casas, J and Mathiyazhagan, K and Rodriguez, M and Assefa, T and Mlaki, A and Nyakunga, G and Kato, F and Mukankusi, C and Girma, E and Mosquera, G and Arredondo, V and Espitia, E}, title = {Advancing common bean (Phaseolus vulgaris L.) disease detection with YOLO driven deep learning to enhance agricultural AI.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {15596}, pmid = {38971939}, issn = {2045-2322}, mesh = {*Phaseolus/virology/microbiology ; *Deep Learning ; *Plant Diseases/virology/microbiology ; Agriculture/methods ; Plant Leaves/virology/microbiology ; Africa ; Colombia ; }, abstract = {Common beans (CB), a vital source for high protein content, plays a crucial role in ensuring both nutrition and economic stability in diverse communities, particularly in Africa and Latin America. However, CB cultivation poses a significant threat to diseases that can drastically reduce yield and quality. Detecting these diseases solely based on visual symptoms is challenging, due to the variability across different pathogens and similar symptoms caused by distinct pathogens, further complicating the detection process. Traditional methods relying solely on farmers' ability to detect diseases is inadequate, and while engaging expert pathologists and advanced laboratories is necessary, it can also be resource intensive. To address this challenge, we present a AI-driven system for rapid and cost-effective CB disease detection, leveraging state-of-the-art deep learning and object detection technologies. We utilized an extensive image dataset collected from disease hotspots in Africa and Colombia, focusing on five major diseases: Angular Leaf Spot (ALS), Common Bacterial Blight (CBB), Common Bean Mosaic Virus (CBMV), Bean Rust, and Anthracnose, covering both leaf and pod samples in real-field settings. However, pod images are only available for Angular Leaf Spot disease. The study employed data augmentation techniques and annotation at both whole and micro levels for comprehensive analysis. To train the model, we utilized three advanced YOLO architectures: YOLOv7, YOLOv8, and YOLO-NAS. Particularly for whole leaf annotations, the YOLO-NAS model achieves the highest mAP value of up to 97.9% and a recall of 98.8%, indicating superior detection accuracy. In contrast, for whole pod disease detection, YOLOv7 and YOLOv8 outperformed YOLO-NAS, with mAP values exceeding 95% and 93% recall. However, micro annotation consistently yields lower performance than whole annotation across all disease classes and plant parts, as examined by all YOLO models, highlighting an unexpected discrepancy in detection accuracy. Furthermore, we successfully deployed YOLO-NAS annotation models into an Android app, validating their effectiveness on unseen data from disease hotspots with high classification accuracy (90%). This accomplishment showcases the integration of deep learning into our production pipeline, a process known as DLOps. This innovative approach significantly reduces diagnosis time, enabling farmers to take prompt management interventions. The potential benefits extend beyond rapid diagnosis serving as an early warning system to enhance common bean productivity and quality.}, } @article {pmid38971043, year = {2024}, author = {Malmström, N and Öhlén, J and Jakobsson Larsson, B and Nilsson, S and Nygren, I and M Andersen, P and Ozanne, A}, title = {Adolescents' challenging and grief-filled transitions when living with a parent with ALS: A qualitative interpretive study.}, journal = {Social science & medicine (1982)}, volume = {354}, number = {}, pages = {117063}, doi = {10.1016/j.socscimed.2024.117063}, pmid = {38971043}, issn = {1873-5347}, mesh = {Humans ; *Qualitative Research ; *Amyotrophic Lateral Sclerosis/psychology ; Sweden ; *Grief ; Female ; Male ; Adolescent ; Adult ; Adaptation, Psychological ; Child ; Young Adult ; Parents/psychology ; Parent-Child Relations ; }, abstract = {OBJECTIVE: The study aimed to explore the meaning for adolescents of living with a parent with amyotrophic lateral sclerosis (ALS).

METHODS: The design is qualitative. Interviews were conducted between December 2020 and April 2022 with 11 adolescents (8-25 y), living in households with a parent with ALS in Sweden. The analysis was phenomenologically hermeneutical.

RESULTS: The adolescents were in a difficult and exposed situation, especially if the parent had a severe disability and assistant care providers were in the home. Witnessing the gradual loss of the parent in an indefinite battle against time, while still needing them, elicited grief-filled and hard-to-manage emotions. Everyday life was turned upside down, resulting in greater responsibility for the adolescents, not only in helping with household chores and assisting the ill parent, but also in emotionally protecting both parents. It forced the adolescents to mature faster and put their own life on hold, triggering experiences of being limited. This, together with changing family roles yet being more attached to home, reinforced the imbalance in the adolescents' lives. The interpreted whole of the adolescents' narratives revealed that living with a parent with ALS meant a challenging and grieving transition during an already transition-filled adolescence, which left the adolescents struggling to keep a foothold on a life torn apart.

CONCLUSION: The unbalanced life situation may hinder the adolescents' identity formation and emancipation, which are developmentally important for managing a healthy and independent adulthood. The results emphasize the importance of early targeted support to reach this vulnerable group in order to secure their health.}, } @article {pmid38970668, year = {2024}, author = {Ludolph, AC and Dietrich, J and Dreyhaupt, J and Kassubek, J and Del Tredici, K and Rosenbohm, A}, title = {Clinical spreading of muscle weakness in amyotrophic lateral sclerosis (ALS): a study in 910 patients.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5357-5367}, pmid = {38970668}, issn = {1432-1459}, support = {LU 336/15-1//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology/diagnosis ; Male ; Female ; Middle Aged ; Aged ; *Muscle Weakness/physiopathology/etiology/pathology ; Disease Progression ; Cohort Studies ; Adult ; Germany/epidemiology ; }, abstract = {BACKGROUND: Neuroanatomical staging of sporadic amyotrophic lateral sclerosis (ALS) indicates that neurodegeneration may spread corticofugally.

METHODS: We conducted an observational study to define the initial sites of disease onset and the clinical progression ('spreading patterns') of motor deficits in a cohort of 910 ALS patients in Germany.

RESULTS: Mean age of ALS onset was 59.0 ± 12.6 years for males and 61.2 ± 10.5 years for females, the mean ALSFRS-R was 35.1 ± 9.2, and 7.7% of the cohort reported a family history. Onset of motor symptoms was bulbar/upper limb in 26.8%/35.9%, the right arm initially being slightly more often affected than the left (18.5% vs.16.3%). Testing on concordance of handedness and onset in the dominant arm did not reach significance. Lower limb onset was observed in 37.3%. Unilateral limb onset patients reported horizontal spreading about three times more often than vertical spreading. 71/244 bulbar onset patients reported spreading pattern to the legs, and 17/339 lumbar onset patients reported spreading secondarily to the bulbar region.

DISCUSSION: Our results indicate that, although the phenotype of so-called 'spinal' or 'intraspinal' spreading predominated, we also observed an additional clinical spreading pattern: 29.1% of patients with bulbar onset experienced spreading clinically to the legs (vice versa in 5.0% of lumbar onset patients). For obvious neuroanatomical reasons, this pattern hardly can be explained solely by a 'spinal' or an 'intraspinal' pattern of spreading. Instead, these findings complement insights from previous clinical and clinicopathological studies supporting a cortical initiation of ALS.}, } @article {pmid38970158, year = {2024}, author = {Li, Z and Wen, J and Wu, W and Dai, Z and Liang, X and Zhang, N and Cheng, Q and Zhang, H}, title = {Causal relationship and shared genes between air pollutants and amyotrophic lateral sclerosis: A large-scale genetic analysis.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {7}, pages = {e14812}, pmid = {38970158}, issn = {1755-5949}, support = {2023CQBSHTB3095//Chongqing Postdoctoral Research Special Funding Project/ ; CSTB2023NSCQBHX0002//Chongqing Postdoctoral Science Foundation/ ; 2023MD734131//China Postdoctoral Science Foundation/ ; 2023RC3074//Hunan Youth Science and Technology Talent Project/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Humans ; *Polymorphism, Single Nucleotide/genetics ; *Genome-Wide Association Study ; *Air Pollutants/adverse effects/toxicity ; *Mendelian Randomization Analysis ; Genetic Predisposition to Disease/genetics ; Particulate Matter/adverse effects ; }, abstract = {OBJECTIVE: Air pollutants have been reported to have a potential relationship with amyotrophic lateral sclerosis (ALS). The causality and underlying mechanism remained unknown despite several existing observational studies. We aimed to investigate the potential causality between air pollutants (PM2.5, NOX, and NO2) and the risk of ALS and elucidate the underlying mechanisms associated with this relationship.

METHODS: The data utilized in our study were obtained from publicly available genome-wide association study data sets, in which single nucleotide polymorphisms (SNPs) were employed as the instrumental variantswith three principles. Two-sample Mendelian randomization and transcriptome-wide association (TWAS) analyses were conducted to evaluate the effects of air pollutants on ALS and identify genes associated with both pollutants and ALS, followed by regulatory network prediction.

RESULTS: We observed that exposure to a high level of PM2.5 (OR: 2.40 [95% CI: 1.26-4.57], p = 7.46E-3) and NOx (OR: 2.35 [95% CI: 1.32-4.17], p = 3.65E-3) genetically increased the incidence of ALS in MR analysis, while the effects of NO2 showed a similar trend but without sufficient significance. In the TWAS analysis, TMEM175 and USP35 turned out to be the genes shared between PM2.5 and ALS in the same direction.

CONCLUSION: Higher exposure to PM2.5 and NOX might causally increase the risk of ALS. Avoiding exposure to air pollutants and air cleaning might be necessary for ALS prevention.}, } @article {pmid38969143, year = {2024}, author = {Jha, SK and Nelson, VK and Suryadevara, PR and Panda, SP and Pullaiah, CP and Nuli, MV and Kamal, M and Imran, M and Ausali, S and Abomughaid, MM and Srivastava, R and Deka, R and Pritam, P and Gupta, N and Shyam, H and Singh, IK and Pandey, BW and Dewanjee, S and Jha, NK and Jafari, SM}, title = {Cannabidiol and neurodegeneration: From molecular mechanisms to clinical benefits.}, journal = {Ageing research reviews}, volume = {100}, number = {}, pages = {102386}, doi = {10.1016/j.arr.2024.102386}, pmid = {38969143}, issn = {1872-9649}, mesh = {Humans ; *Cannabidiol/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis are severe and life-threatening conditions in which significant damage of functional neurons occurs to produce psycho-motor malfunctions. NDs are an important cause of death in the elderly population worldwide. These disorders are commonly associated with the progression of age, oxidative stress, and environmental pollutants, which are the major etiological factors. Abnormal aggregation of specific proteins such as α-synuclein, amyloid-β, huntingtin, and tau, and accumulation of the associated oligomers in neurons are the hallmark pathological features of NDs. Existing therapeutic options for NDs are only symptomatic relief and do not address root-causing factors, such as protein aggregation, oxidative stress, and neuroinflammation. Cannabidiol (CBD) is a non-psychotic natural cannabinoid obtained from Cannabis sativa that possesses multiple pharmacological actions, including antioxidant, anti-inflammatory, and neuroprotective effects in various NDs and other neurological disorders both in vitro and in vivo. CBD has gained attention as a promising drug candidate for the management of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, by inhibiting protein aggregation, free radicals, and neuroinflammation. In parallel, CBD has shown positive results in other neurological disorders, such as epilepsy, depression, schizophrenia, and anxiety, as well as adjuvant treatment with existing standard therapeutic agents. Hence, the present review focuses on exploring the possible molecular mechanisms in controlling various neurological disorders as well as the clinical applications of CBD in NDs including epilepsy, depression and anxiety. In this way, the current review will serve as a standalone reference for the researchers working in this area.}, } @article {pmid38968328, year = {2024}, author = {Gowrishankar, S and Smith, ME and Creber, N and Muzaffar, J and Borsetto, D}, title = {Immunosuppression in stem cell clinical trials of neural and retinal cell types: A systematic review.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0304073}, pmid = {38968328}, issn = {1932-6203}, mesh = {Humans ; *Stem Cell Transplantation/methods ; *Immunosuppression Therapy/methods ; Retina/immunology ; Immunosuppressive Agents/therapeutic use ; Clinical Trials as Topic ; }, abstract = {BACKGROUND: Pharmacologic immunosuppression regimes are commonly employed in stem cell clinical trials to mitigate host immune rejection and promote survival and viability of transplanted cells. Immunosuppression and cell survival has been extensively studied in retinal and spinal tissues. The applicability of stem cell therapy is rapidly expanding to other sensory organs such as the ear and hearing. As regenerative therapy is directed to new areas, a greater understanding of immunosuppression strategies and their efficacy is required to facilitate translation to organ-specific biologic microenvironments.

OBJECTIVE: This systematic review appraises the current literature regarding immunosuppression strategies employed in stem cell trials of retinal and neural cells.

METHODS: This systematic review was performed in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria included studies presenting data on neural or retinal cells as part of an in-human clinical trial that detailed the immunosuppression regime used. Exclusion criteria included non-English language studies, animal studies, review articles, case reports, editorials, and letters. The databases Medline, Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception to February 2024. Risk of bias was evaluated using the ROBINS-I tool.

RESULTS: Eighteen articles fit the inclusion criteria. Nine articles concerned retinal cells, 5 concerned spinal cord injury, and 4 concerned amyotrophic lateral sclerosis. A multi-drug and short-term immunosuppression regime were commonly employed in the identified studies. Detected immune responses in treated patients were rare. Common immunosuppression paradigms included tacrolimus, mycophenolate mofetil and tapering doses of steroids. Local immunosuppression with steroids was employed in some studies concerning retinal diseases.

DISCUSSION: A short-term course of systemic immunosuppression seemed efficacious for most included studies, with some showing grafted cells viable months to years after immunosuppression had stopped. Longer-term follow-up is required to see if this remains the case. Side effects related to immunosuppression were uncommon.}, } @article {pmid38967881, year = {2024}, author = {Rojas-López, JC and Estrada-Gualdron, PI and Ramírez-Guerrero, S and Velásquez-Cárdenas, MJ and Redondo-Escobar, J and Vargas-Arenas, S and Palacios-Sánchez, L and Palacios-Espinosa, X}, title = {Efficacy of pain management strategies in adults with Amyotrophic Lateral Sclerosis (ALS): A Systematic Review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {12}, pages = {5591-5604}, pmid = {38967881}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Pain Management/methods ; Adult ; Pain/etiology/drug therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness. Presence of pain in ALS patients is heterogeneously reported in studies, and mostly underrepresented in symptom scales. The aim of this study is to evaluate the efficacy of pharmacological and non-pharmacological therapeutic modalities for pain management in patients with ALS. A systematic review was conducted in four databases; PubMed, Scopus, Clinicaltrials.gov, and Cochrane-Ovid. Five randomized controlled clinical trials were included regarding pharmacological and non-pharmacological pain management interventions in adult patients with confirmed diagnosis of ALS in whom pain was objectively evaluated. Risk of bias assessment was evaluated using the RoB2.0 tool. Eligible studies were reported as a descriptive analysis. This systematic review was registered with PROSPERO ID: CRD42024495009. Five clinical trials regarding pain management strategies in ALS were eligible for analysis. Two out of five were non-pharmacological approaches whilst the remaining three provided pharmacological therapies. Of these, Mexiletine was efficient in terms of pain relief, particularly between 600 and 900 mg per day, whereas Mecasin showed no pain relief at both, high and low doses. Non-pharmacological therapies, such as exercise and osteopathic manual treatment also lacked efficacy in regard to pain management. Clinical trials focusing on pain management strategies for ALS patients are limited. Medical professionals, understandably focused on immediate life-threatening aspects, may inadvertently sideline the nuanced and intricate dimension of pain experienced by patients with ALS.}, } @article {pmid38967655, year = {2024}, author = {Müller, P and Draguhn, A and Egorov, AV}, title = {Persistent sodium currents in neurons: potential mechanisms and pharmacological blockers.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {476}, number = {10}, pages = {1445-1473}, pmid = {38967655}, issn = {1432-2013}, support = {HE8155/1-2//Deutsche Forschungsgemeinschaft/ ; EG134/2-1//Deutsche Forschungsgemeinschaft/ ; Treat-ION01GM1907A//Bundesministerium für Bildung und Forschung/ ; College for Clinician Scientists//Else Kröner-Fresenius-Stiftung/ ; }, mesh = {Humans ; Animals ; *Neurons/metabolism/drug effects/physiology ; Sodium Channel Blockers/pharmacology ; Sodium Channels/metabolism/drug effects ; }, abstract = {Persistent sodium current (INaP) is an important activity-dependent regulator of neuronal excitability. It is involved in a variety of physiological and pathological processes, including pacemaking, prolongation of sensory potentials, neuronal injury, chronic pain and diseases such as epilepsy and amyotrophic lateral sclerosis. Despite its importance, neither the molecular basis nor the regulation of INaP are sufficiently understood. Of particular significance is a solid knowledge and widely accepted consensus about pharmacological tools for analysing the function of INaP and for developing new therapeutic strategies. However, the literature on INaP is heterogeneous, with varying definitions and methodologies used across studies. To address these issues, we provide a systematic review of the current state of knowledge on INaP, with focus on mechanisms and effects of this current in the central nervous system. We provide an overview of the specificity and efficacy of the most widely used INaP blockers: amiodarone, cannabidiol, carbamazepine, cenobamate, eslicarbazepine, ethosuximide, gabapentin, GS967, lacosamide, lamotrigine, lidocaine, NBI-921352, oxcarbazepine, phenytoine, PRAX-562, propofol, ranolazine, riluzole, rufinamide, topiramate, valproaic acid and zonisamide. We conclude that there is strong variance in the pharmacological effects of these drugs, and in the available information. At present, GS967 and riluzole can be regarded bona fide INaP blockers, while phenytoin and lacosamide are blockers that only act on the slowly inactivating component of sodium currents.}, } @article {pmid38967638, year = {2024}, author = {Garau, J and Garofalo, M and Dragoni, F and Scarian, E and Di Gerlando, R and Diamanti, L and Zucca, S and Bordoni, M and Pansarasa, O and Gagliardi, S}, title = {RNA expression profiling in lymphoblastoid cell lines from mutated and non-mutated amyotrophic lateral sclerosis patients.}, journal = {The journal of gene medicine}, volume = {26}, number = {7}, pages = {e3711}, doi = {10.1002/jgm.3711}, pmid = {38967638}, issn = {1521-2254}, support = {//Ministero della Salute/ ; //Italian Agency for Research on ALS-ARiSLA/ ; //Italian Ministry of Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Gene Expression Profiling ; *Mutation ; *Transcriptome ; Female ; Male ; Middle Aged ; C9orf72 Protein/genetics/metabolism ; Leukocytes, Mononuclear/metabolism ; Superoxide Dismutase-1/genetics ; Cell Line ; Aged ; Gene Expression Regulation ; DNA-Binding Proteins ; RNA-Binding Protein FUS ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of upper and lower motor neurons with an unknown etiology. The difficulty of recovering biological material from patients led to employ lymphoblastoid cell lines (LCLs) as a model for ALS because many pathways, typically located in neurons, are also activated in these cells.

METHODS: To investigate the expression of coding and long non-coding RNAs in LCLs, a transcriptomic profiling of sporadic ALS (SALS) and mutated patients (FUS, TARDBP, C9ORF72 and SOD1) and matched controls was realized. Thus, differentially expressed genes (DEGs) were investigated among the different subgroups of patients. Peripheral blood mononuclear cells (PBMCs) were isolated and immortalized into LCLs via Epstein-Barr virus infection; RNA was extracted, and RNA-sequencing analysis was performed.

RESULTS: Gene expression profiles of LCLs were genetic-background-specific; indeed, only 12 genes were commonly deregulated in all groups. Nonetheless, pathways enriched by DEGs in each group were also compared, and a total of 89 Kyoto Encyclopedia of Genes and Genomes (KEGG) terms were shared among all patients. Eventually, the similarity of affected pathways was also assessed when our data were matched with a transcriptomic profile realized in the PBMCs of the same patients.

CONCLUSIONS: We conclude that LCLs are a good model for the study of RNA deregulation in ALS.}, } @article {pmid38967302, year = {2024}, author = {Sîrbulescu, RF and Nicholson, K and Kawai, K and Hilton, OM and Sobell, D and Jin, G and Verrill, DE and Dwyer, LJ and Xiong, Y and Bachanová, P and Kim, SE and Gallup, S and Gelevski, D and Daley, H and Hernandez Rodriguez, DE and Negre, H and Sturtevant, O and Nikiforow, S and Ritz, J and Chen, YB and Reeves, PM and Sluder, AE and Berry, JD and Sadri-Vakili, G and Cudkowicz, M and Poznansky, MC}, title = {Allogeneic B cell immunomodulatory therapy in amyotrophic lateral sclerosis.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {38}, number = {13}, pages = {e23796}, doi = {10.1096/fj.202302659R}, pmid = {38967302}, issn = {1530-6860}, support = {//Ward Family Foundation/ ; //Vaccine and Immunotherapy Center Innovation Fund/ ; //Vaccine and Immunotherapy Center Education Fund/ ; //Sean M. Healey and AMG Center for ALS/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/immunology ; Animals ; Mice ; Humans ; *B-Lymphocytes/immunology ; Disease Models, Animal ; Mice, Transgenic ; Male ; Female ; Mice, Inbred C57BL ; Immunomodulation ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease. Immune system dysregulation plays an essential role in ALS onset and progression. Our preclinical studies have shown that the administration of exogenous allogeneic B cells improves outcomes in murine models of skin and brain injury through a process termed pligodraxis, in which B cells adopt an immunoregulatory and neuroprotective phenotype in an injured environment. Here, we investigated the effects of B-cell therapy in the SOD1[G93A] mouse preclinical model of ALS and in a person living with ALS. Purified splenic mature naïve B cells from haploidentical donor mice were administered intravenously in SOD1[G93A] mice for a total of 10 weekly doses. For the clinical study in a person with advanced ALS, IgA gammopathy of unclear significance, and B lymphopenia, CD19[+] B cells were positively selected from a healthy haploidentical donor and infused intravenously twice, at a 60-day interval. Repeated intravenous B-cell administration was safe and significantly delayed disease onset, extended survival, reduced cellular apoptosis, and decreased astrogliosis in SOD1[G93A] mice. Repeated B-cell infusion in a person with ALS was safe and did not appear to generate a clinically evident inflammatory response. An improvement of 5 points on the ALSFRS-R scale was observed after the first infusion. Levels of inflammatory markers showed persistent reduction post-infusion. This represents a first demonstration of the efficacy of haploidentical B-cell infusion in the SOD1[G93A] mouse and the safety and feasibility of using purified haploidentical B lymphocytes as a cell-based therapeutic strategy for a person with ALS.}, } @article {pmid38967083, year = {2024}, author = {Nijs, M and Van Damme, P}, title = {The genetics of amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {560-569}, pmid = {38967083}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *C9orf72 Protein/genetics ; *Genetic Predisposition to Disease/genetics ; *RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; Superoxide Dismutase/genetics ; Proteins/genetics ; DNA-Binding Proteins/genetics ; Genetic Testing ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) has a strong genetic basis, but the genetic landscape of ALS appears to be complex. The purpose of this article is to review recent developments in the genetics of ALS.

RECENT FINDINGS: Large-scale genetic studies have uncovered more than 40 genes contributing to ALS susceptibility. Both rare variants with variable effect size and more common variants with small effect size have been identified. The most common ALS genes are C9orf72 , SOD1 , TARDBP and FUS . Some of the causative genes of ALS are shared with frontotemporal dementia, confirming the molecular link between both diseases. Access to diagnostic gene testing for ALS has to improve, as effective gene silencing therapies for some genetic subtypes of ALS are emerging, but there is no consensus about which genes to test for.

SUMMARY: Our knowledge about the genetic basis of ALS has improved and the first effective gene silencing therapies for specific genetic subtypes of ALS are underway. These therapeutic advances underline the need for better access to gene testing for people with ALS. Further research is needed to further map the genetic heterogeneity of ALS and to establish the best strategy for gene testing in a clinical setting.}, } @article {pmid38966756, year = {2024}, author = {Garg, V and Geurten, BRH}, title = {Diving deep: zebrafish models in motor neuron degeneration research.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1424025}, pmid = {38966756}, issn = {1662-4548}, abstract = {In the dynamic landscape of biomedical science, the pursuit of effective treatments for motor neuron disorders like hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA) remains a key priority. Central to this endeavor is the development of robust animal models, with the zebrafish emerging as a prime candidate. Exhibiting embryonic transparency, a swift life cycle, and significant genetic and neuroanatomical congruencies with humans, zebrafish offer substantial potential for research. Despite the difference in locomotion-zebrafish undulate while humans use limbs, the zebrafish presents relevant phenotypic parallels to human motor control disorders, providing valuable insights into neurodegenerative diseases. This review explores the zebrafish's inherent traits and how they facilitate profound insights into the complex behavioral and cellular phenotypes associated with these disorders. Furthermore, we examine recent advancements in high-throughput drug screening using the zebrafish model, a promising avenue for identifying therapeutically potent compounds.}, } @article {pmid38966655, year = {2024}, author = {Saito, S and Ikeguchi, R and Kitagawa, K}, title = {Chronic cerebrospinal fluid leak can cause amyotrophic lateral sclerosis mimic.}, journal = {Journal of general and family medicine}, volume = {25}, number = {4}, pages = {237-238}, pmid = {38966655}, issn = {2189-7948}, abstract = {Chronic cerebrospinal fluid leak with spinal cord compression can mimic the symptoms of ALS, with a snake-eyes appearance on MRI.}, } @article {pmid38966427, year = {2024}, author = {Couturier, N and Hörner, SJ and Nürnberg, E and Joazeiro, C and Hafner, M and Rudolf, R}, title = {Aberrant evoked calcium signaling and nAChR cluster morphology in a SOD1 D90A hiPSC-derived neuromuscular model.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1429759}, pmid = {38966427}, issn = {2296-634X}, abstract = {Familial amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder that is due to mutations in one of several target genes, including SOD1. So far, clinical records, rodent studies, and in vitro models have yielded arguments for either a primary motor neuron disease, or a pleiotropic pathogenesis of ALS. While mouse models lack the human origin, in vitro models using human induced pluripotent stem cells (hiPSC) have been recently developed for addressing ALS pathogenesis. In spite of improvements regarding the generation of muscle cells from hiPSC, the degree of maturation of muscle cells resulting from these protocols has remained limited. To fill these shortcomings, we here present a new protocol for an enhanced myotube differentiation from hiPSC with the option of further maturation upon coculture with hiPSC-derived motor neurons. The described model is the first to yield a combination of key myogenic maturation features that are consistent sarcomeric organization in association with complex nAChR clusters in myotubes derived from control hiPSC. In this model, myotubes derived from hiPSC carrying the SOD1 D90A mutation had reduced expression of myogenic markers, lack of sarcomeres, morphologically different nAChR clusters, and an altered nAChR-dependent Ca[2+] response compared to control myotubes. Notably, trophic support provided by control hiPSC-derived motor neurons reduced nAChR cluster differences between control and SOD1 D90A myotubes. In summary, a novel hiPSC-derived neuromuscular model yields evidence for both muscle-intrinsic and nerve-dependent aspects of neuromuscular dysfunction in SOD1-based ALS.}, } @article {pmid38965709, year = {2024}, author = {Arends, S and Drenthen, J and de Koning, L and van den Bergh, P and Hadden, RDM and Kuwabara, S and Reisin, RC and Shahrizaila, N and Ajroud-Driss, S and Antonini, G and Attarian, S and Balducci, C and Bertorini, T and Brannagan, TH and Cavaletti, G and Chao, CC and Chavada, G and Dillmann, KU and Dimachkie, MM and Galassi, G and Gutiérrez-Gutiérrez, G and Harbo, T and Islam, B and Islam, Z and Katzberg, H and Kusunoki, S and Manganelli, F and Miller, JAL and Pardo, J and Pereon, Y and Rajabally, YA and Sindrup, S and Stettner, M and Uncini, A and Verhamme, C and Vytopil, M and Waheed, W and Jacobs, BC and Cornblath, DR and , }, title = {Electrodiagnostic subtyping in Guillain-Barré syndrome patients in the International Guillain-Barré Outcome Study.}, journal = {European journal of neurology}, volume = {31}, number = {9}, pages = {e16335}, pmid = {38965709}, issn = {1468-1331}, mesh = {Humans ; *Guillain-Barre Syndrome/diagnosis/classification/physiopathology ; *Neural Conduction/physiology ; *Electrodiagnosis/methods ; Male ; Female ; Middle Aged ; Adult ; Amyotrophic Lateral Sclerosis/diagnosis/classification/physiopathology ; Aged ; Cohort Studies ; }, abstract = {BACKGROUND AND PURPOSE: Various electrodiagnostic criteria have been developed in Guillain-Barré syndrome (GBS). Their performance in a broad representation of GBS patients has not been evaluated. Motor conduction data from the International GBS Outcome Study (IGOS) cohort were used to compare two widely used criterion sets and relate these to diagnostic amyotrophic lateral sclerosis criteria.

METHODS: From the first 1500 patients in IGOS, nerve conduction studies from 1137 (75.8%) were available for the current study. These patients were classified according to nerve conduction studies criteria proposed by Hadden and Rajabally.

RESULTS: Of the 1137 studies, 68.3% (N = 777) were classified identically according to criteria by Hadden and Rajabally: 111 (9.8%) axonal, 366 (32.2%) demyelinating, 195 (17.2%) equivocal, 35 (3.1%) inexcitable and 70 (6.2%) normal. Thus, 360 studies (31.7%) were classified differently. The areas of differences were as follows: 155 studies (13.6%) classified as demyelinating by Hadden and axonal by Rajabally; 122 studies (10.7%) classified as demyelinating by Hadden and equivocal by Rajabally; and 75 studies (6.6%) classified as equivocal by Hadden and axonal by Rajabally. Due to more strictly defined cutoffs fewer patients fulfilled demyelinating criteria by Rajabally than by Hadden, making more patients eligible for axonal or equivocal classification by Rajabally. In 234 (68.6%) axonal studies by Rajabally the revised El Escorial (amyotrophic lateral sclerosis) criteria were fulfilled; in axonal cases by Hadden this was 1.8%.

CONCLUSIONS AND DISCUSSION: This study shows that electrodiagnosis in GBS is dependent on the criterion set utilized, both of which are based on expert opinion. Reappraisal of electrodiagnostic subtyping in GBS is warranted.}, } @article {pmid38965379, year = {2024}, author = {Jacob, SM and Lee, S and Kim, SH and Sharkey, KA and Pfeffer, G and Nguyen, MD}, title = {Brain-body mechanisms contribute to sexual dimorphism in amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {8}, pages = {475-494}, pmid = {38965379}, issn = {1759-4766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/epidemiology/metabolism ; *Sex Characteristics ; Male ; Female ; Animals ; Brain/metabolism/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of human motor neuron disease. It is characterized by the progressive degeneration of upper and lower motor neurons, leading to generalized motor weakness and, ultimately, respiratory paralysis and death within 3-5 years. The disease is shaped by genetics, age, sex and environmental stressors, but no cure or routine biomarkers exist for the disease. Male individuals have a higher propensity to develop ALS, and a different manifestation of the disease phenotype, than female individuals. However, the mechanisms underlying these sex differences remain a mystery. In this Review, we summarize the epidemiology of ALS, examine the sexually dimorphic presentation of the disease and highlight the genetic variants and molecular pathways that might contribute to sex differences in humans and animal models of ALS. We advance the idea that sexual dimorphism in ALS arises from the interactions between the CNS and peripheral organs, involving vascular, metabolic, endocrine, musculoskeletal and immune systems, which are strikingly different between male and female individuals. Finally, we review the response to treatments in ALS and discuss the potential to implement future personalized therapeutic strategies for the disease.}, } @article {pmid38964584, year = {2024}, author = {Peters, S and Bouma, F and Hoek, G and Janssen, N and Vermeulen, R}, title = {Air pollution exposure and mortality from neurodegenerative diseases in the Netherlands: A population-based cohort study.}, journal = {Environmental research}, volume = {259}, number = {}, pages = {119552}, doi = {10.1016/j.envres.2024.119552}, pmid = {38964584}, issn = {1096-0953}, mesh = {Humans ; Netherlands/epidemiology ; *Air Pollution/adverse effects/analysis ; Male ; *Air Pollutants/analysis/adverse effects ; *Neurodegenerative Diseases/mortality/chemically induced/epidemiology ; Middle Aged ; Female ; Cohort Studies ; *Environmental Exposure/adverse effects ; Aged ; *Particulate Matter/analysis/adverse effects ; Adult ; }, abstract = {BACKGROUND: Long-term exposure to ambient air pollution has been linked with all-cause mortality and cardiovascular and respiratory diseases. Suggestive associations between ambient air pollutants and neurodegeneration have also been reported, but due to the small effect and relatively rare outcomes evidence is yet inconclusive. Our aim was to investigate the associations between long-term air pollution exposure and mortality from neurodegenerative diseases.

METHODS: A Dutch national cohort of 10.8 million adults aged ≥30 years was followed from 2013 until 2019. Annual average concentrations of air pollutants (ultra-fine particles (UFP), nitrogen dioxide (NO2), fine particles (PM2.5 and PM10) and elemental carbon (EC)) were estimated at the home address at baseline, using land-use regression models. The outcome variables were mortality due to amyotrophic lateral sclerosis (ALS), Parkinson's disease, non-vascular dementia, Alzheimer's disease, and multiple sclerosis (MS). Hazard ratios (HR) were estimated using Cox models, adjusting for individual and area-level socio-economic status covariates.

RESULTS: We had a follow-up of 71 million person-years. The adjusted HRs for non-vascular dementia were significantly increased for NO2 (1.03; 95% confidence interval (CI) 1.02-1.05) and PM2.5 (1.02; 95%CI 1.01-1.03) per interquartile range (IQR; 6.52 and 1.47 μg/m[3], respectively). The association with PM2.5 was also positive for ALS (1.02; 95%CI 0.97-1.07). These associations remained positive in sensitivity analyses and two-pollutant models. UFP was not associated with any outcome. No association with air pollution was found for Parkinson's disease and MS. Inverse associations were found for Alzheimer's disease.

CONCLUSION: Our findings, using a cohort of more than 10 million people, provide further support for associations between long-term exposure to air pollutants (PM2.5 and particularly NO2) and mortality of non-vascular dementia. No associations were found for Parkinson and MS and an inverse association was observed for Alzheimer's disease.}, } @article {pmid38963716, year = {2024}, author = {Lima, PLGSB and Couto, EM and Nóbrega, PR}, title = {Response letter to: a homozygous p.Val120Leu (c.358G > C) SOD1 mutation led to slowly progressive amyotrophic lateral sclerosis in a Brazilian family.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {803-804}, doi = {10.1080/21678421.2024.2374372}, pmid = {38963716}, issn = {2167-9223}, } @article {pmid38963497, year = {2024}, author = {Yu, G and Bai, Y and Zhang, ZY}, title = {Valosin-Containing Protein (VCP)/p97 Oligomerization.}, journal = {Sub-cellular biochemistry}, volume = {104}, number = {}, pages = {485-501}, pmid = {38963497}, issn = {0306-0225}, mesh = {*Valosin Containing Protein/metabolism/genetics/chemistry ; Humans ; Protein Multimerization ; Animals ; Mutation ; Frontotemporal Dementia/genetics/metabolism ; Adenosine Triphosphatases/metabolism/genetics/chemistry ; Osteitis Deformans/genetics/metabolism ; Cell Cycle Proteins/metabolism/genetics/chemistry ; Myositis, Inclusion Body/genetics/metabolism ; Muscular Dystrophies, Limb-Girdle ; }, abstract = {Valosin-containing protein (VCP), also known as p97, is an evolutionarily conserved AAA+ ATPase essential for cellular homeostasis. Cooperating with different sets of cofactors, VCP is involved in multiple cellular processes through either the ubiquitin-proteasome system (UPS) or the autophagy/lysosomal route. Pathogenic mutations frequently found at the interface between the NTD domain and D1 ATPase domain have been shown to cause malfunction of VCP, leading to degenerative disorders including the inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS), and cancers. Therefore, VCP has been considered as a potential therapeutic target for neurodegeneration and cancer. Most of previous studies found VCP predominantly exists and functions as a hexamer, which unfolds and extracts ubiquitinated substrates from protein complexes for degradation. However, recent studies have characterized a new VCP dodecameric state and revealed a controlling mechanism of VCP oligomeric states mediated by the D2 domain nucleotide occupancy. Here, we summarize our recent knowledge on VCP oligomerization, regulation, and potential implications of VCP in cellular function and pathogenic progression.}, } @article {pmid38963135, year = {2024}, author = {Turano, E and Virla, F and Scambi, I and Dabrowska, S and Bankole, O and Mariotti, R}, title = {Adipose mesenchymal stem cells-derived extracellular vesicles exert their preferential action in damaged central sites of SOD1 mice rather than peripherally.}, journal = {European journal of histochemistry : EJH}, volume = {68}, number = {3}, pages = {}, pmid = {38963135}, issn = {2038-8306}, mesh = {Animals ; *Extracellular Vesicles/metabolism ; *Mesenchymal Stem Cells/metabolism ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/therapy/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Adipose Tissue/metabolism ; Motor Neurons/metabolism ; Neuromuscular Junction/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving motor neuron (MN) loss in the motor cortex, brainstem and spinal cord leading to progressive paralysis and death. Due to the pathogenetic complexity, there are no effective therapies available. In this context the use of mesenchymal stem cells and their vesicular counterpart is an emerging therapeutic strategy to counteract neurodegeneration. The extracellular vesicles derived from adipose stem cells (ASC-EVs) recapitulate and ameliorate the neuroprotective effect of stem cells and, thanks to their small dimensions, makes their use suitable to develop novel therapeutic approaches for neurodegenerative diseases as ALS. Here we investigate a therapeutic regimen of ASC-EVs injection in SOD1(G93A) mice, the most widely used murine model of ALS. Repeated intranasal administrations of high doses of ASC-EVs were able to ameliorate motor performance of injected SOD1(G93A) mice at the early stage of the disease and produce a significant improvement at the end-stage in the lumbar MNs rescue. Moreover, ASC-EVs preserve the structure of neuromuscular junction without counteracting the muscle atrophy. The results indicate that the intranasal ASC-EVs administration acts in central nervous system sites rather than at peripheral level in SOD1(G93A) mice. These considerations allow us to identify future applications of ASC-EVs that involve different targets simultaneously to maximize the clinical and neuropathological outcomes in ALS in vivo models.}, } @article {pmid38963090, year = {2024}, author = {Pearson, K and Dobak, S}, title = {Current practices in the nutrition management of people with amyotrophic lateral sclerosis (ALS): a survey of U.S. ALS care teams.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {653-660}, doi = {10.1080/21678421.2024.2374382}, pmid = {38963090}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diet therapy ; Cross-Sectional Studies ; United States/epidemiology ; Male ; Patient Care Team ; Female ; Surveys and Questionnaires ; Nutrition Therapy/methods ; Nutritionists/statistics & numerical data ; }, abstract = {OBJECTIVE: To assess current practices of U.S. professionals providing outpatient ALS nutrition care.

METHODS: A cross-sectional survey assessing nutrition care practices was distributed in February/March 2023 through electronic mailing lists of relevant professional organizations.

RESULTS: Of the 87 professionals completing the survey, 85.1% were registered dietitians and 50.6% had five or fewer years of experience in ALS care. Many (44.2%) professionals reported receiving no training on the nutrition care of people with ALS (PALS), and 40.2% reported having no other ALS dietitians in their close network. Methods utilized to estimate calorie and protein requirements in PALS varied widely. Although 95.4% of respondents reported that their clinic's dietitian participates in feeding tube discussions, many practitioners may be waiting until ALS symptoms negatively impact PALS' breathing, eating, swallowing, or weight to begin discussing feeding tubes. Additionally, few professionals reported institutional practices conducive for refeeding syndrome prevention or monitoring.

CONCLUSIONS: Many professionals providing outpatient nutrition care to PALS possess limited experience, received insufficient training, and are not connected to other ALS dietitians. Specific nutrition care practices, including nutrient need estimation, vary widely among health professionals. Practices surrounding feeding tube discussions and refeeding syndrome may be suboptimal at many institutions. These findings highlight the need for initiatives that educate and connect practitioners providing nutrition care to PALS.}, } @article {pmid38963079, year = {2024}, author = {Naruse, H and Iseki, C and Mitsui, J and Miki, J and Nagasawa, H and Kurokawa, K and Kobayashi, R and Sato, H and Goto, J and Satake, W and Ishiura, H and Tsuji, S and Ohta, Y and Toda, T}, title = {A novel TBK1 loss-of-function variant associated with ALS and parkinsonism phenotypes.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {791-794}, doi = {10.1080/21678421.2024.2374374}, pmid = {38963079}, issn = {2167-9223}, mesh = {Humans ; *Protein Serine-Threonine Kinases/genetics ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Parkinsonian Disorders/genetics ; Male ; Female ; Middle Aged ; *Phenotype ; Loss of Function Mutation/genetics ; Pedigree ; Aged ; Adult ; }, abstract = {Loss-of-function (LoF) variants in the TANK binding kinase 1 (TBK1) gene are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we present the first familial cases of ALS and parkinsonism associated with a novel TBK1 variant. We describe two siblings: one diagnosed with classical ALS and the other with a unique syndrome overlapping ALS and parkinsonism. Comprehensive clinical and imaging evaluations supported these diagnoses. Genetic analysis through whole-genome sequencing revealed a previously unknown heterozygous splice site variant in TBK1. Functional assessments demonstrated that this splice site variant leads to abnormal splicing and subsequent degradation of the mutated TBK1 allele by nonsense-mediated decay, confirming its pathogenic impact. Our findings suggest a broader involvement of TBK1 in neurodegenerative diseases and underscore the need for further research into TBK1's role, advocating for screening for TBK1 variants in similar familial cases.}, } @article {pmid38961496, year = {2024}, author = {Linse, K and Weber, C and Reilich, P and Schöberl, F and Boentert, M and Petri, S and Rödiger, A and Posa, A and Otto, M and Wolf, J and Zeller, D and Brunkhorst, R and Koch, J and Hermann, A and Großkreutz, J and Schröter, C and Groß, M and Lingor, P and Machetanz, G and Semmler, L and Dorst, J and Lulé, D and Ludolph, A and Meyer, T and Maier, A and Metelmann, M and Regensburger, M and Winkler, J and Schrank, B and Kohl, Z and Hagenacker, T and Brakemeier, S and Weyen, U and Weiler, M and Lorenzl, S and Bublitz, S and Weydt, P and Grehl, T and Kotterba, S and Lapp, HS and Freigang, M and Vidovic, M and Aust, E and Günther, R}, title = {Patients' and caregivers' perception of multidimensional and palliative care in amyotrophic lateral sclerosis - protocol of a German multicentre study.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {34}, pmid = {38961496}, issn = {2524-3489}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an inevitably fatal condition that leads to a progressive loss of physical functioning, which results in a high psychosocial burden and organizational challenges related to medical care. Multidimensional and multiprofessional care is advised to meet the complex needs of patients and their families. Many healthcare systems, including Germany, may not be able to meet these needs because non-medical services such as psychological support or social counselling are not regularly included in the care of patients with ALS (pwALS). Specialised neuropalliative care is not routinely implemented nor widely available. Caregivers of pwALS are also highly burdened, but there is still a lack of support services for them.

METHODS: This project aims to assess the perceptions and satisfaction with ALS care in Germany in pwALS and their caregivers. This will be achieved by means of a cross-sectional, multicentre survey. The examination will assess, to which extend the patients' needs in the six domains of physical, psychological, social, spiritual, practical and informational are being met by current care structures. This assessment will be linked to mental well-being, subjective quality of life, attitudes toward life-sustaining measures and physician-assisted suicide, and caregiver burden. The study aims to recruit 500 participants from nationwide ALS centres in order to draw comprehensive conclusions for Germany. A total of 29 centres, mostly acquired via the clinical and scientific German Network for Motor Neuron Diseases (MND-NET), will take part in the project, 25 of which have already started recruitment.

PERSPECTIVE: It is intended to provide data-based starting points on how current practice of care in Germany is perceived pwALS and their caregivers and how it can be improved according to their needs. Planning and initiation of the study has been completed.

TRIAL REGISTRATION: The study is registered at ClinicalTrails.gov; NCT06418646.}, } @article {pmid38960585, year = {2025}, author = {Dols-Icardo, O and Carbayo, Á and Jericó, I and Blasco-Martínez, O and Álvarez-Sánchez, E and López Pérez, MA and Bernal, S and Rodríguez-Santiago, B and Cusco, I and Turon-Sans, J and Cabezas-Torres, M and Caballero-Ávila, M and Vesperinas, A and Llansó, L and Pagola-Lorz, I and Torné, L and Valle-Tamayo, N and Muñoz, L and Rubio-Guerra, S and Illán-Gala, I and Cortés-Vicente, E and Gelpi, E and Rojas-García, R}, title = {Identification of a pathogenic mutation in ARPP21 in patients with amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {2}, pages = {132-139}, pmid = {38960585}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Middle Aged ; Spain ; *Mutation, Missense ; Aged ; Adult ; RNA-Binding Proteins/genetics ; Phosphoproteins/genetics ; Pedigree ; Whole Genome Sequencing ; }, abstract = {BACKGROUND AND OBJECTIVE: Between 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause after a comprehensive study of the known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region from Spain, the aim of this work was to identify novel ALS-related genes in ALS cases with negative genetic testing.

METHODS: We detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region.

RESULTS: We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 (ARPP21) gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes.

CONCLUSIONS: While previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene.}, } @article {pmid38960473, year = {2024}, author = {R, HC and Datta, A and S, UK and Zayed, H and D, TK and C, GPD}, title = {Decoding genetic and pathophysiological mechanisms in amyotrophic lateral sclerosis and primary lateral sclerosis: A comparative study of differentially expressed genes and implicated pathways in motor neuron disorders.}, journal = {Advances in protein chemistry and structural biology}, volume = {141}, number = {}, pages = {177-201}, doi = {10.1016/bs.apcsb.2023.12.008}, pmid = {38960473}, issn = {1876-1631}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Gene Expression Profiling ; Motor Neuron Disease/genetics/metabolism ; }, abstract = {Motor Neuron Disorders (MNDs), characterized by the degradation and loss of function of motor neurons, are recognized as fatal conditions with limited treatment options and no known cure. The present study aimed to identify the pathophysiological functions and affected genes in patients with MNDs, specifically Amyotrophic Lateral Sclerosis (ALS) and Primary Lateral Sclerosis (PLS). The GSE56808 dataset comprised three sample groups: six patients diagnosed with ALS (GSM1369650, GSM1369652, GSM1369654, GSM1369656, GSM1369657, GSM1369658), five patients diagnosed with PLS (GSM1369648, GSM1369649, GSM1369653, GSM1369655, GSM1369659), and six normal controls (GSM1369642, GSM1369643, GSM1369644, GSM1369645, GSM1369646, and GSM1369647). The application of computational analysis of microarray gene expression profiles enabled us to identify 346 significantly differentially expressed genes (DEGs), 169 genes for the ALS sample study, and 177 genes for the PLS sample study. Enrichment was carried out using MCODE, a Cytoscape plugin. Functional annotation of DEGs was carried out via ClueGO/CluePedia (v2.5.9) and further validated via the DAVID database. NRP2, SEMA3D, ROBO3 and, CACNB1, CACNG2 genes were identified as the gene of interest for ALS and PLS sample groups, respectively. Axonal guidance (GO:0007411) and calcium ion transmembrane transport (GO:0070588) were identified to be some of the significantly dysregulated gene ontology (GO) terms, with arrhythmogenic right ventricular cardiomyopathy (KEGG:05412) to be the top relevant KEGG pathway which is affected in MND patients. ROBO3 gene was observed to have distinctive roles in ALS and PLS-affected patients, hinting towards the differential progression of ALS from PLS. The insights derived from our comprehensive analysis accentuate the distinct variances in the underlying molecular pathogenesis of ALS and PLS. Further research should investigate the mechanistic roles of the identified DEGs and molecular pathways, leading to potential targeted therapies for ALS and PLS.}, } @article {pmid38960099, year = {2024}, author = {Bhandari, UR and Danish, SM and Ahmad, S and Ikram, M and Nadaf, A and Hasan, N and Kesharwani, P and Ahmad, FJ}, title = {New opportunities for antioxidants in amelioration of neurodegenerative diseases.}, journal = {Mechanisms of ageing and development}, volume = {221}, number = {}, pages = {111961}, doi = {10.1016/j.mad.2024.111961}, pmid = {38960099}, issn = {1872-6216}, mesh = {Humans ; *Antioxidants/pharmacology/therapeutic use ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Oxidative Stress/drug effects ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {This comprehensive review elucidates the critical role of antioxidants to mitigate oxidative stress, a common denominator in an array of neurodegenerative disorders. Oxidative stress-induced damage has been linked to the development of diseases such as Alzheimer's, Parkinson's, Huntington's disease and amyotrophic lateral sclerosis. This article examines a wide range of scientific literature and methodically delineates the several methods by which antioxidants exercise their neuroprotective benefits. It also explores into the complex relationship between oxidative stress and neuroinflammation, focusing on how antioxidants can alter signaling pathways and transcription factors to slow neurodegenerative processes. Key antioxidants, such as vitamins C and E, glutathione, and polyphenolic compounds, are tested for their ability to combat reactive oxygen and nitrogen species. The dual character of antioxidants, which operate as both direct free radical scavengers and regulators of cellular redox homeostasis, is investigated in terms of therapeutic potential. Furthermore, the study focuses on new antioxidant-based therapy techniques and their mechanisms including Nrf-2, PCG1α, Thioredoxin etc., which range from dietary interventions to targeted antioxidant molecules. Insights into ongoing clinical studies evaluating antioxidant therapies in neurodegenerative illnesses offer an insight into the translational potential of antioxidant research. Finally, this review summarizes our present understanding of antioxidant processes in neurodegenerative illnesses, providing important possibilities for future study and treatment development.}, } @article {pmid38958608, year = {2024}, author = {Lang, R and Hodgson, RE and Shelkovnikova, TA}, title = {TDP-43 in nuclear condensates: where, how, and why.}, journal = {Biochemical Society transactions}, volume = {52}, number = {4}, pages = {1809-1825}, pmid = {38958608}, issn = {1470-8752}, mesh = {Humans ; *DNA-Binding Proteins/metabolism ; *Cell Nucleus/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Biomolecular Condensates/metabolism ; Animals ; Neurodegenerative Diseases/metabolism ; }, abstract = {TDP-43 is an abundant and ubiquitously expressed nuclear protein that becomes dysfunctional in a spectrum of neurodegenerative diseases. TDP-43's ability to phase separate and form/enter biomolecular condensates of varying size and composition is critical for its functionality. Despite the high density of phase-separated assemblies in the nucleus and the nuclear abundance of TDP-43, our understanding of the condensate-TDP-43 relationship in this cellular compartment is only emerging. Recent studies have also suggested that misregulation of nuclear TDP-43 condensation is an early event in the neurodegenerative disease amyotrophic lateral sclerosis. This review aims to draw attention to the nuclear facet of functional and aberrant TDP-43 condensation. We will summarise the current knowledge on how TDP-43 containing nuclear condensates form and function and how their homeostasis is affected in disease.}, } @article {pmid38958573, year = {2024}, author = {Tu, S and Vucic, S and Kiernan, MC}, title = {Pathological insights derived from neuroimaging in amyotrophic lateral sclerosis: emerging clinical applications.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {577-584}, doi = {10.1097/WCO.0000000000001295}, pmid = {38958573}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Humans ; *Neuroimaging/methods ; Brain/diagnostic imaging/pathology ; }, abstract = {PURPOSE OF REVIEW: Neuroimaging has been instrumental in shaping current understanding of the pathoanatomical signature of amyotrophic lateral sclerosis (ALS) across clinically well defined patient cohorts. The potential utility of imaging as an objective disease marker, however, remains poorly defined.

RECENT FINDINGS: Increasingly advanced quantitative and computational imaging studies have highlighted emerging clinical applications for neuroimaging as a complementary clinical modality for diagnosis, monitoring, and modelling disease propagation. Multimodal neuroimaging has demonstrated novel approaches for capturing primary motor disease. Extra-motor subcortical dysfunction is increasingly recognized as key modulators of disease propagation.

SUMMARY: The neural signature of cortical and subcortical dysfunction in ALS has been well defined at the population level. Objective metrics of focal primary motor dysfunction are increasingly sensitive and translatable to the individual patient level. Integrity of extra-motor subcortical abnormalities are recognized to represent critical pathways of the ALS disease 'connectome', predicting pathological spread. Neuroimaging plays a pivotal role in capturing upper motor neuron pathology in ALS. Their potential clinical role as objective disease markers for disease classification, longitudinal monitoring, and prognosis in ALS have become increasingly well defined.}, } @article {pmid38957123, year = {2025}, author = {Ghaderi, S and Fatehi, F and Kalra, S and Mohammadi, S and Batouli, SAH}, title = {Quantitative susceptibility mapping in amyotrophic lateral sclerosis: automatic quantification of the magnetic susceptibility in the subcortical nuclei.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {73-84}, doi = {10.1080/21678421.2024.2372648}, pmid = {38957123}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism/pathology ; Male ; Female ; Middle Aged ; *Magnetic Resonance Imaging/methods ; Adult ; Brain Mapping/methods ; Image Processing, Computer-Assisted/methods ; }, abstract = {OBJECTIVE: Previous studies have suggested a link between dysregulation of cortical iron levels and neuronal loss in amyotrophic lateral sclerosis (ALS) patients. However, few studies have reported differences in quantitative susceptibility mapping (QSM) values in subcortical nuclei between patients with ALS and healthy controls (HCs).

METHODS: MRI was performed using a 3 Tesla Prisma scanner (64-channel head coil), including 3D T1-MPRAGE and multi-echo 3D GRE for QSM reconstruction. Automated QSM segmentation was used to measure susceptibility values in the subcortical nuclei, which were compared between the groups. Correlations with clinical scales were analyzed. Group comparisons were performed using independent t-tests, with p < 0.05 considered significant. Correlations were assessed using Pearson's correlation, with p < 0.05 considered significant. Cohen's d was reported to compare the standardized mean difference (SMD) of QSM.

RESULTS: Twelve patients with limb-onset ALS (mean age 48.7 years, 75% male) and 13 age-, sex-, and handedness-matched HCs (mean age 44.6 years, 69% male) were included. Compared to HCs, ALS patients demonstrated significantly lower susceptibility in the left caudate nucleus (CN) (SMD = -0.845), right CN (SMD = -0.851), whole CN (SMD = -1.016), and left subthalamic nucleus (STN) (SMD = -1.000). Susceptibility in the left putamen (SMD = -0.857), left thalamus (SMD = -1.081), and whole thalamus (SMD = -0.968) was significantly higher in the patients. The susceptibility of the substantia nigra (SN), CN, and pulvinar was positively correlated with disease duration.

CONCLUSIONS: QSM detects abnormal iron accumulation patterns in the subcortical gray matter of ALS patients, which correlates with disease characteristics, supporting its potential as a neuroimaging biomarker.}, } @article {pmid38956726, year = {2024}, author = {Ye, S and Chen, L and Murphy, D and Wu, J and Zhang, H and Liu, H and Zou, B and Hou, G and Zhang, N and Yin, T and Smith, RA and Fan, D}, title = {Validation of the Center for Neurologic Study Bulbar Function Scale-Chinese version in a population with amyotrophic lateral sclerosis.}, journal = {Orphanet journal of rare diseases}, volume = {19}, number = {1}, pages = {246}, pmid = {38956726}, issn = {1750-1172}, support = {82001350//National Natural Science Foundation of China/ ; 81873784//National Natural Science Foundation of China/ ; 82071426//National Natural Science Foundation of China/ ; YCXJ-JZ-2022-007//Beijing E-Town Cooperation & Development Foundation/ ; YJXJ-JZ-2021-0014//Beijing E-Town Cooperation & Development Foundation/ ; DL2019002//PUTH Cohort Construction Project/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/physiopathology ; }, abstract = {OBJECTIVE: The Center for Neurologic Study Bulbar Function Scale (CNS-BFS) was specifically designed as a self-reported measure of bulbar function. The purpose of this research was to validate the Chinese translation of the CNS-BFSC as an effective measurement for the Chinese population with ALS.

METHODS: A total of 111 ALS patients were included in this study. The CNS-BFSC score, three bulbar function items from the ALSFRS-R, and visual analog scale (VAS) score for speech, swallowing and salivation were assessed in the present study. Forty-six ALS patients were retested on the same scale 5-10 days after the first evaluation.

RESULTS: The CNS-BFSC sialorrhea, speech and swallowing subscores were separately correlated with the VAS subscores (p < 0.001). The CNS-BFSC total score and sialorrhea and speech scores were significantly correlated with the ALSFRS-R bulbar subscore (p < 0.001). The CNS-BFSC total score and ALSFRS-R bulbar subscale score were highly predictive of a clinician diagnosis of impaired bulbar function (area under the receiver operating characteristic curve, 0.947 and 0.911, respectively; p < 0.001). A cutoff value for the CNS-BFSC total score was selected by maximizing Youden's index; this cutoff score was 33, with 86.4% sensitivity and 93.3% specificity. The CNS-BFSC total score and the sialorrhea, speech and swallowing subscores had good-retest reliability (p > 0.05). The Cronbach's α of the CNS-BFSC was 0.972.

CONCLUSION: The Chinese version of the CNS-BFSC has acceptable efficacy and reliability for the assessment of bulbar dysfunction in ALS patients.}, } @article {pmid38956470, year = {2024}, author = {Cai, H and Jiang, H and Xie, D and Lai, Z and Wu, J and Chen, M and Yang, Z and Xu, R and Zeng, S and Ma, H}, title = {Enhancing image quality in computed tomography angiography follow-ups after endovascular aneurysm repair: a comparative study of reconstruction techniques.}, journal = {BMC medical imaging}, volume = {24}, number = {1}, pages = {162}, pmid = {38956470}, issn = {1471-2342}, support = {82202217//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Retrospective Studies ; Female ; *Computed Tomography Angiography/methods ; Aged ; Male ; *Endovascular Procedures/methods ; *Artifacts ; Middle Aged ; Aortic Aneurysm, Abdominal/surgery/diagnostic imaging ; Deep Learning ; Radiographic Image Interpretation, Computer-Assisted/methods ; Stents ; Endovascular Aneurysm Repair ; }, abstract = {BACKGROUND: The image quality of computed tomography angiography (CTA) images following endovascular aneurysm repair (EVAR) is not satisfactory, since artifacts resulting from metallic implants obstruct the clear depiction of stent and isolation lumens, and also adjacent soft tissues. However, current techniques to reduce these artifacts still need further advancements due to higher radiation doses, longer processing times and so on. Thus, the aim of this study is to assess the impact of utilizing Single-Energy Metal Artifact Reduction (SEMAR) alongside a novel deep learning image reconstruction technique, known as the Advanced Intelligent Clear-IQ Engine (AiCE), on image quality of CTA follow-ups conducted after EVAR.

MATERIALS: This retrospective study included 47 patients (mean age ± standard deviation: 68.6 ± 7.8 years; 37 males) who underwent CTA examinations following EVAR. Images were reconstructed using four different methods: hybrid iterative reconstruction (HIR), AiCE, the combination of HIR and SEMAR (HIR + SEMAR), and the combination of AiCE and SEMAR (AiCE + SEMAR). Two radiologists, blinded to the reconstruction techniques, independently evaluated the images. Quantitative assessments included measurements of image noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), the longest length of artifacts (AL), and artifact index (AI). These parameters were subsequently compared across different reconstruction methods.

RESULTS: The subjective results indicated that AiCE + SEMAR performed the best in terms of image quality. The mean image noise intensity was significantly lower in the AiCE + SEMAR group (25.35 ± 6.51 HU) than in the HIR (47.77 ± 8.76 HU), AiCE (42.93 ± 10.61 HU), and HIR + SEMAR (30.34 ± 4.87 HU) groups (p < 0.001). Additionally, AiCE + SEMAR exhibited the highest SNRs and CNRs, as well as the lowest AIs and ALs. Importantly, endoleaks and thrombi were most clearly visualized using AiCE + SEMAR.

CONCLUSIONS: In comparison to other reconstruction methods, the combination of AiCE + SEMAR demonstrates superior image quality, thereby enhancing the detection capabilities and diagnostic confidence of potential complications such as early minor endleaks and thrombi following EVAR. This improvement in image quality could lead to more accurate diagnoses and better patient outcomes.}, } @article {pmid38956107, year = {2024}, author = {Opie-Martin, S and Iacoangeli, A and Topp, SD and Abel, O and Mayl, K and Mehta, PR and Shatunov, A and Fogh, I and Bowles, H and Limbachiya, N and Spargo, TP and Al-Khleifat, A and Williams, KL and Jockel-Balsarotti, J and Bali, T and Self, W and Henden, L and Nicholson, GA and Ticozzi, N and McKenna-Yasek, D and Tang, L and Shaw, PJ and Chio, A and Ludolph, A and Weishaupt, JH and Landers, JE and Glass, JD and Mora, JS and Robberecht, W and Damme, PV and McLaughlin, R and Hardiman, O and van den Berg, L and Veldink, JH and Corcia, P and Stevic, Z and Siddique, N and Silani, V and Blair, IP and Fan, DS and Esselin, F and de la Cruz, E and Camu, W and Basak, NA and Siddique, T and Miller, T and Brown, RH and Al-Chalabi, A and Shaw, CE}, title = {Author Correction: The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {5560}, doi = {10.1038/s41467-024-49938-y}, pmid = {38956107}, issn = {2041-1723}, } @article {pmid38955238, year = {2024}, author = {Wang, M and Tang, Z}, title = {No causal relationship between serum urate and neurodegenerative diseases: A Mendelian randomization study.}, journal = {Experimental gerontology}, volume = {194}, number = {}, pages = {112503}, doi = {10.1016/j.exger.2024.112503}, pmid = {38955238}, issn = {1873-6815}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Uric Acid/blood ; *Neurodegenerative Diseases/genetics/blood ; *Amyotrophic Lateral Sclerosis/genetics/blood ; *Genome-Wide Association Study ; Parkinson Disease/genetics/blood ; Multiple Sclerosis/genetics/blood ; Alzheimer Disease/genetics/blood ; Polymorphism, Single Nucleotide ; Causality ; }, abstract = {OBJECTIVE: Observational studies have shown that increased serum urate is associated with a lower risk of neurodegenerative diseases (NDs), but the causality remains unclear. We employed a two-sample Mendelian randomization (MR) approach to assess the causal relationship between serum urate and four common subtypes of NDs, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS).

METHODS: Serum urate data came from the CKDGen Consortium. GWAS data for PD, AD, ALS, and MS were obtained from four databases in the primary analysis and then acquired statistics from the FinnGen consortium for replication and meta-analysis. Inverse variance weighted (IVW), weighted median (WM), and MR-Egger regression methods were applied in the MR analyses. Pleiotropic effects, heterogeneity, and leave-one-out analyses were evaluated to validate the results.

RESULTS: There was no evidence for the effect of serum urate on PD (OR: 1.00, 95 % CI: 0.90-1.11, P = 0.97), AD (OR: 1.02, 95 % CI: 1.00-1.04, P = 0.06), ALS (OR: 1.05, 95 % CI: 0.97-1.13, P = 0.22), and MS (OR: 1.01, 95 % CI: 0.89-1.14, P = 0.90) risk when combined with the FinnGen consortium, neither was any evidence of pleiotropy detected between the instrumental variables (IVs).

CONCLUSION: The MR analysis suggested that serum urate may not be causally associated with a risk of PD, AD, ALS, and MS.}, } @article {pmid38954274, year = {2024}, author = {Faltracco, V and Poletti, B and Aiello, EN and Telesca, A and Bella, ED and Bersano, E and Silani, V and Ticozzi, N and Lauria, G and Consonni, M}, title = {Emotional awareness in patients with amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {10}, pages = {5043-5046}, pmid = {38954274}, issn = {1590-3478}, support = {2015-0023//Fondazione Regionale per la Ricerca Biomedica, Regione Lombardia/ ; 1157625//Fondo Europeo di Sviluppo Regionale, Regione Lombardia (POR FESR 2014-2020)/ ; RRC//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; Female ; *Affective Symptoms/etiology/physiopathology ; Middle Aged ; Aged ; Emotions/physiology ; Awareness/physiology ; Neuropsychological Tests ; Cohort Studies ; }, abstract = {INTRODUCTION: It has been recently acknowledged that deficits in experiencing and processing one's own emotions, also termed alexithymia, may possibly feature the frontotemporal-spectrum disorders. This study aims to determine whether alexithymia could be included within the frontotemporal syndromes of amyotrophic lateral sclerosis (ALS).

METHODS: Alexithymic traits were estimated in a cohort of 68 non-demented ALS patients with the 20-item Toronto Alexithymia Scale (TAS-20). Patients were assessed for the identification of motor-phenotypes and frontotemporal syndromes based on current classification criteria. Spearman's coefficients explored the correlates of TAS-20 measures with motor-functional profiles, global cognitive, social-cognitive (emotion recognition and empathy) and behavioral status.

RESULTS: Abnormal TAS-20 scores were found in 13% of patients, and their distribution did not vary within motor and frontotemporal phenotypes. Significant associations were detected between TAS-20 and executive (p ≤ .011), memory (p = .006), state-anxiety (p ≤ .013) and depression measures (p ≤ .010). By contrast, TAS-20 scores were unrelated to social-cognitive performances, dysexecutive and apathetic profiles. Disease duration was the only motor-functional feature being related to the TAS-20 (p ≤ .008).

CONCLUSIONS: Alexithymia of potential clinical relevance occur in a minority of ALS patients, and its neuropsychological correlates mostly resemble those featuring the general population. Hence, it is unlikely that alexithymia is a specific feature of frontotemporal-spectrum characterizing ALS, rather it could be an expression of psychogenic factors as a reaction to the disease.}, } @article {pmid38954254, year = {2025}, author = {Wang, Y and Wang, Y and Yin, H and Xiao, Z and Ren, Z and Ma, X and Zhang, J and Fu, X and Zhang, F and Zeng, L}, title = {BI1 Activates Autophagy and Mediates TDP43 to Regulate ALS Pathogenesis.}, journal = {Molecular neurobiology}, volume = {62}, number = {1}, pages = {988-1030}, pmid = {38954254}, issn = {1559-1182}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Autophagy/physiology ; Animals ; *DNA-Binding Proteins/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Mice, Transgenic ; Humans ; Mitochondria/metabolism ; Apoptosis Regulatory Proteins/metabolism ; Apoptosis ; Mice ; Neuromuscular Junction/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disease in adults. Currently, there are no known drugs or clinical approaches that have demonstrated efficacy in treating ALS. Mitochondrial function and autophagy have been identified as crucial mechanisms in the development of ALS. While Bax inhibitor 1 (BI1) has been implicated in neurodegenerative diseases, its exact mechanism remains unknown. This study investigates the therapeutic impact of BI1 overexpression on ALS both in vivo and in vitro, revealing its ability to mitigate SOD1[G93A]-induced apoptosis, nuclear damage, mitochondrial dysfunction, and axonal degeneration of motor neurons. At the same time, BI1 prolongs onset time and lifespan of ALS mice, improves motor function, and alleviates neuronal damage, muscle damage, neuromuscular junction damage among other aspects. The findings indicate that BI1 can inhibit pathological TDP43 morphology and initially stimulate autophagy through interaction with TDP43. This study establishes a solid theoretical foundation for understanding the regulation of autophagy by BI1 and TDP43 while shedding light on the pathogenesis of ALS through their interaction - offering new concepts and targets for clinical implementation and drug development.}, } @article {pmid38953009, year = {2024}, author = {Rostás, R and Fekete, I and Horváth, L and Márton, S and Fekete, K}, title = {Correlation of single-fiber electromyography studies and functional status in patients with amyotrophic lateral sclerosis.}, journal = {Open medicine (Warsaw, Poland)}, volume = {19}, number = {1}, pages = {20240990}, pmid = {38953009}, issn = {2391-5463}, abstract = {OBJECTIVE: Our aim was to examine the significance of single-fiber electromyography (SFEMG) in patients diagnosed with amyotrophic lateral sclerosis (ALS) and determine the best correlating parameter with SFEMG parameters and clinical scales across different muscles including facial muscles.

METHODS: SFEMG examinations were conducted on the extensor digitorum (ED), frontalis, and orbicularis oculi muscles. Mean jitter, percentage of increased jitter, fiber density (FD), and impulse blocking percentage were compared to reference values and functional scales.

RESULTS: Significant differences (p < 0.001) were observed between the patients' SFEMG results and reference values in all muscles. Significant correlations were found between SFEMG parameters and clinical scales, particularly when considering both FD and jitter. A notable value of the ALS Functional Rating Scale Revised (ALSFRS-R) was detected in all muscles: 31 points in the ED muscle, 30 in the orbicularis oculi muscle, and 31 in the frontalis muscle. Below this ALSFRS-R threshold, the percentage of increased jitter was higher, while FD remained relatively low.

CONCLUSION: SFEMG examination emerges as a valuable tool for better understanding ALS and holds potential for assessing prognosis. Combined jitter and FD analysis showed the strongest correlation with clinical scales. In addition to the ED muscle, the orbicularis oculi muscle may be important in the assessment.}, } @article {pmid38951798, year = {2024}, author = {Pottinger, TD and Motelow, JE and Povysil, G and Moreno, CAM and Ren, Z and Phatnani, H and , and Aitman, TJ and Santoyo-Lopez, J and , and Mitsumoto, H and , and , and , and Goldstein, DB and Harms, MB}, title = {Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.}, journal = {BMC genomics}, volume = {25}, number = {1}, pages = {651}, pmid = {38951798}, issn = {1471-2164}, support = {P01 AG007232/AG/NIA NIH HHS/United States ; U19 AI067854/AI/NIAID NIH HHS/United States ; R01 AG037212/AG/NIA NIH HHS/United States ; UM1 AI100645/AI/NIAID NIH HHS/United States ; T32 HL144442/HL/NHLBI NIH HHS/United States ; }, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics ; Ethnicity/genetics ; Genetic Predisposition to Disease ; Genetic Variation ; European People ; East Asian People ; African People ; Hispanic or Latino ; Middle Eastern People ; South Asian People ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.

METHODS: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.

RESULTS: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR = 19.18, p = 3.67 × 10[-39]; OR = 4.73, p = 2 × 10[-10]; OR = 2.3, p = 7.49 × 10[-9], respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10[-7]), was protective for ALS in this model. An intolerant domain-based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR = 10.08, p = 3.62 × 10[-16]). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p = 8.38 × 10[-6]).

CONCLUSIONS: In a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.}, } @article {pmid38951432, year = {2024}, author = {Didcote, L and Vitoratou, S and Al-Chalabi, A and Goldstein, LH}, title = {Comparison of in-person vs. remote administration of cognitive screening tools for people with ALS.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {11}, pages = {5309-5317}, pmid = {38951432}, issn = {1590-3478}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; Goldstein/Oct17/892-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Middle Aged ; Aged ; *Neuropsychological Tests ; Videoconferencing ; Cognition Disorders/diagnosis/etiology ; Cognitive Dysfunction/diagnosis/etiology ; }, abstract = {OBJECTIVE: This study investigated whether cognitive screening tools used for people with amyotrophic lateral sclerosis (pwALS) are affected by the screen being administered face-to-face or remotely online. It also investigated whether demographic variables predicted total cognitive screen scores.

METHODS: The cognitive component of the Edinburgh Cognitive and Behavioural ALS Screen (ECASc), the cognitive component of the ALS Cognitive Behavioural Screen (ALS-CBSc), and the Mini Addenbrooke's Cognitive Examination (Mini-ACE) were administered to 41 pwALS and 41 controls face-to-face. Versions of the cognitive screens designed to be administered remotely were administered to 57 pwALS and 44 controls via videoconferencing methods. Backwards stepwise linear regressions were conducted to assess whether total scores on the ECASc, ALS-CBSc, and Mini-ACE scores were predicted by administration mode (face-to-face or remote) or demographic variables.

RESULTS: Mode of administration significantly affected scores on the ECASc and ALS-CBSc; remote administration was associated with better total scores. Administration mode did not significantly affect Mini-ACE scores. All cognitive screens were significantly affected by IQ scores; higher IQ scores predicted better screening tool scores. Only ECASc scores were significantly affected by age, with older age predicting poorer scores. Being female was associated with better Mini-ACE scores; sex did not predict ECASc and ALS-CBSc scores.

CONCLUSIONS: Our results suggest that videoconferencing versions of the ECASc and ALS-CBSc may function differently to the original, face-to-face versions. There are advantages to using remote versions of cognitive screening tools but clinicians and researchers who use them should consider that they may not yield equivalent scores.}, } @article {pmid38951089, year = {2024}, author = {Zhang, JH and Chen, ZH and Ling, L and Cheng, HM and Zhang, Y and Zhao, JR and Huang, XS}, title = {[Analysis of the characteristics of patients with amyotrophic lateral sclerosis with neuromuscular junction dysfunction prior to motor neuron degeneration].}, journal = {Zhonghua nei ke za zhi}, volume = {63}, number = {7}, pages = {660-665}, doi = {10.3760/cma.j.cn112138-20230811-00049}, pmid = {38951089}, issn = {0578-1426}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Electromyography ; *Motor Neurons/physiology ; Neuromuscular Junction/physiopathology ; Electric Stimulation ; Accessory Nerve/physiopathology ; Male ; Female ; Middle Aged ; }, abstract = {Objective: To investigate the clinical and electrophysiological characteristics of patients with amyotrophic lateral sclerosis (ALS) with positive repetitive nerve stimulation (RNS) test results on the accessory nerve and negative needle electromyography (EMG) test results on the sternocleidomastoid with the goal to enrich the knowledge of disease progression in patients with ALS. Methods: The clinical data of 612 patients diagnosed with ALS at the Neurology Department of the First Medical Center, Chinese PLA General Hospital from June 2016 to August 2022 were collected. In total, 267 cases had undergone EMG tests on the sternocleidomastoid following a positive 3 Hz RNS test result on the accessory nerve, who were selected as the study subjects. The differences in clinical indicators were compared between RNS (+)/EMG (-) group and RNS (+)/EMG (+) group. A binomial distribution model with multiple variables was built to quantitatively analyze the major factors and their effects. Results: At the initial visit, 15.8% of patients with ALS were 3 Hz RNS (+) on the accessory nerve and EMG (-) on the ipsilateral sternocleidomastoid, accounting for 36.3% of RNS (+) patients. The decremental range of the 3 Hz RNS test delivered to the accessory nerve in these patients [-14% (-19%, -12%)] was lower than that in patients with RNS (+)/EMG (+) [-17% (-23%, -13%)] (P<0.05), while the ratio of upper limb onset (64.9%) and non-definite diagnosis (28.9%) were higher [54.7% and 13.5% for patients with RNS (+)/EMG (+), P<0.05]. Furthermore, the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score [40 (37, 42)], body mass index (BMI) [23.8 (22.0, 25.4) kg/m[2]] and forced vital capacity (FVC) [92.8% (76.6%, 103.8%)] were higher in patients with RNS(+)/EMG(+) (P<0.05). The multivariate model suggested that, in patients with RNS (+)/EMG (-), the ratio of upper limb onset to lower limb onset was 1.04, while that of upper limb onset to bulbar onset was 2.02, and that of lower limb onset to bulbar onset was 1.94. The ratio of non-definite ALS to definite ALS was 1.13. The ALSFRS-R score, BMI, and FVC had a protective contribution to the electrophysiological function of the motor neurons. The ratio of the effect size of the ALSFRS-R or BMI to that of FVC was 3.37 and 1.14, respectively. Conclusions: Patients with ALS that were 3 Hz RNS (+) on the accessory nerve and EMG (-) on the ipsilateral sternocleidomastoid had a smaller decremental range of the compound muscle action potential amplitude, and a higher proportion of upper limb onset and non-definite ALS. A higher ALSFRS-R score, BMI, and FVC have a protective effect to the electrophysiological function of motor neurons. The effect size of the ALSFRS-R score is the largest, followed by BMI and FVC.}, } @article {pmid38948094, year = {2024}, author = {Haider, KH}, title = {Priming mesenchymal stem cells to develop "super stem cells".}, journal = {World journal of stem cells}, volume = {16}, number = {6}, pages = {623-640}, pmid = {38948094}, issn = {1948-0210}, abstract = {The stem cell pre-treatment approaches at cellular and sub-cellular levels encompass physical manipulation of stem cells to growth factor treatment, genetic manipulation, and chemical and pharmacological treatment, each strategy having advantages and limitations. Most of these pre-treatment protocols are non-combinative. This editorial is a continuum of Li et al's published article and Wan et al's editorial focusing on the significance of pre-treatment strategies to enhance their stemness, immunoregulatory, and immunosuppressive properties. They have elaborated on the intricacies of the combinative pre-treatment protocol using pro-inflammatory cytokines and hypoxia. Applying a well-defined multi-pronged combinatorial strategy of mesenchymal stem cells (MSCs), pre-treatment based on the mechanistic understanding is expected to develop "Super MSCs", which will create a transformative shift in MSC-based therapies in clinical settings, potentially revolutionizing the field. Once optimized, the standardized protocols may be used with slight modifications to pre-treat different stem cells to develop "super stem cells" with augmented stemness, functionality, and reparability for diverse clinical applications with better outcomes.}, } @article {pmid38946834, year = {2024}, author = {Taherifard, E and Saeed, A}, title = {Predicting liver function after hemihepatectomy in patients with hepatocellular carcinoma using different modalities.}, journal = {World journal of clinical oncology}, volume = {15}, number = {6}, pages = {783-785}, pmid = {38946834}, issn = {2218-4333}, abstract = {In response to Dr. Yue et al's study on prognostic factors for post-hemihepatectomy outcomes in hepatocellular carcinoma (HCC) patients, this critical review identifies methodological limitations and proposes enhancements for future research. While the study identifies liver stiffness measure and standard residual liver volume as potential predictors, concerns regarding small sample size, reliance on biochemical markers for safety assessment, and inadequate adjustment for confounding variables are raised. Recommendations for rigorous methodology, including robust statistical analysis, consideration of confounding factors, and selection of outcome measures with clinical components, are proposed to strengthen prognostic assessments. Furthermore, validation of novel evaluation models is crucial for enhancing clinical applicability and advancing understanding of postoperative outcomes in patients with HCC undergoing hemihepatectomy.}, } @article {pmid38946579, year = {2024}, author = {Trucco, AP and Backhouse, T and Mioshi, E}, title = {Describing and assessing behavioural symptoms in amyotrophic lateral sclerosis with and without frontotemporal dementia: a scoping review.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {603-610}, pmid = {38946579}, issn = {1473-6551}, mesh = {Humans ; *Frontotemporal Dementia/psychology/physiopathology/diagnosis ; *Amyotrophic Lateral Sclerosis/psychology/complications/diagnosis ; Behavioral Symptoms/etiology/diagnosis ; }, abstract = {PURPOSE OF REVIEW: Alongside motor and cognitive symptoms, amyotrophic lateral sclerosis (ALS) and ALS with frontotemporal dementia (ALSFTD) present with behavioural symptoms, which can be challenging for all affected by the disease. A scoping review of studies published between 2011 and 2024 was conducted to present the breadth of behavioural symptoms in ALS and ALSFTD, explore how they are described and assessed, and identify patterns in the literature.

FINDINGS: This scoping review identified 3939 articles, with 111/3939 meeting eligibility criteria. Most studies were from Australia (23.22%), Italy (16.94%) and the UK (14.29%); 75.67% were cross-sectional. Sample size ranged from 1 to 1013, as case studies were included. Overall mean age (100/111 studies) was 61.32 (SD = 4.15). Proportion of male patients (reported 102/111 studies) was 61.49%; mean disease duration (reported in 86/111 records) was 32.63 months (SD = 24.72). Papers described a broad range of behavioural symptoms (465 examples), which were thematically collated into seven categories: disinhibition (27.74%), apathy (25.16%), perseverative/compulsive behaviours (17.42%), hyperorality (10.53%), loss of sympathy or empathy (8.6%), psychotic symptoms (7.74%), and loss of insight about disease and changes (2.8%). Most studies (78.37%) used validated behavioural assessments that elicited carer's perspectives.

SUMMARY: Despite extensive evidence of behavioural symptoms in ALS, implementation of assessments and management of behavioural symptoms in clinical care remain limited. Clinicians must assess behavioural symptoms, as these can negatively affect disease prognosis, patient treatment engagement and increase family distress. Measures capturing carers' perspectives through interviews are ideal as they can reveal anosognosia, lack of sympathy and lack of empathy.}, } @article {pmid38944367, year = {2024}, author = {Wankhede, NL and Rajendra Kopalli, S and Dhokne, MD and Badnag, DJ and Chandurkar, PA and Mangrulkar, SV and Shende, PV and Taksande, BG and Upaganlawar, AB and Umekar, MJ and Koppula, S and Kale, MB}, title = {Decoding mitochondrial quality control mechanisms: Identifying treatment targets for enhanced cellular health.}, journal = {Mitochondrion}, volume = {78}, number = {}, pages = {101926}, doi = {10.1016/j.mito.2024.101926}, pmid = {38944367}, issn = {1872-8278}, mesh = {Humans ; *Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; Animals ; }, abstract = {Mitochondria are singular cell organelles essential for many cellular functions, which includes responding to stress, regulating calcium levels, maintaining protein homeostasis, and coordinating apoptosis response. The vitality of cells, therefore, hinges on the optimal functioning of these dynamic organelles. Mitochondrial Quality Control Mechanisms (MQCM) play a pivotal role in ensuring the integrity and functionality of mitochondria. Perturbations in these mechanisms have been closely associated with the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Compelling evidence suggests that targeting specific pathways within the MQCM could potentially offer a therapeutic avenue for rescuing mitochondrial integrity and mitigating the progression of neurodegenerative diseases. The intricate interplay of cellular stress, protein misfolding, and impaired quality control mechanisms provides a nuanced understanding of the underlying pathology. Consequently, unravelling the specific MQCM dysregulation in neurodegenerative disorders becomes paramount for developing targeted therapeutic strategies. This review delves into the impaired MQCM pathways implicated in neurodegenerative disorders and explores emerging therapeutic interventions. By shedding light on pharmaceutical and genetic manipulations aimed at restoring MQCM efficiency, the discussion aims to provide insights into novel strategies for ameliorating the progression of neurodegenerative diseases. Understanding and addressing mitochondrial quality control mechanisms not only underscore their significance in cellular health but also offer a promising frontier for advancing therapeutic approaches in the realm of neurodegenerative disorders.}, } @article {pmid38943180, year = {2024}, author = {Wiesner, D and Feldengut, S and Woelfle, S and Boeckers, TM and Ludolph, AC and Roselli, F and Del Tredici, K}, title = {Neuropeptide FF (NPFF)-positive nerve cells of the human cerebral cortex and white matter in controls, selected neurodegenerative diseases, and schizophrenia.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {108}, pmid = {38943180}, issn = {2051-5960}, support = {446067541//Deutsche Forschungsgemeinschaft/ ; 443642953//Deutsche Forschungsgemeinschaft/ ; 431995586//Deutsche Forschungsgemeinschaft/ ; 251293561//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *White Matter/pathology/metabolism ; Male ; *Schizophrenia/pathology/metabolism ; Female ; *Cerebral Cortex/pathology/metabolism ; Aged ; Middle Aged ; *Neurodegenerative Diseases/pathology/metabolism ; Aged, 80 and over ; Oligopeptides ; Adult ; Neurons/pathology/metabolism ; }, abstract = {We quantified and determined for the first time the distribution pattern of the neuropeptide NPFF in the human cerebral cortex and subjacent white matter. To do so, we studied n = 9 cases without neurological disorders and n = 22 cases with neurodegenerative diseases, including sporadic amyotrophic lateral sclerosis (ALS, n = 8), Alzheimer's disease (AD, n = 8), Pick's disease (PiD, n = 3), and schizophrenia (n = 3). NPFF-immunopositive cells were located chiefly, but not exclusively, in the superficial white matter and constituted there a subpopulation of white matter interstitial cells (WMIC): Pyramidal-like and multipolar somata predominated in the gyral crowns, whereas bipolar and ovoid somata predominated in the cortex surrounding the sulci. Their sparsely ramified axons were unmyelinated and exhibited NPFF-positive bead-like varicosities. We found significantly fewer NPFF-immunopositive cells in the gray matter of the frontal, cingulate, and superior temporal gyri of both sporadic ALS and late-stage AD patients than in controls, and significantly fewer NPFF-positive cells in the subjacent as well as deep white matter of the frontal gyrus of these patients compared to controls. Notably, the number of NPFF-positive cells was also significantly lower in the hippocampal formation in AD compared to controls. In PiD, NPFF-positive cells were present in significantly lower numbers in the gray and white matter of the cingulate and frontal gyrii in comparison to controls. In schizophrenic patients, lower wNPFF cell counts in the neocortex were significant and global (cingulate, frontal, superior temporal gyrus, medial, and inferior gyri). The precise functions of NPFF-positive cells and their relationship to the superficial corticocortical white matter U-fibers are currently unknown. Here, NPFF immunohistochemistry and expression characterize a previously unrecognized population of cells in the human brain, thereby providing a new entry-point for investigating their physiological and pathophysiological roles.}, } @article {pmid38943019, year = {2024}, author = {He, S and He, XX and Yang, HQ and Zhang, JW and Chen, S}, title = {Two new cases with the UBQLN2 gene mutation in Han Chinese.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {10}, pages = {5047-5051}, pmid = {38943019}, issn = {1590-3478}, mesh = {Humans ; Female ; Male ; *Autophagy-Related Proteins/genetics ; Middle Aged ; *Mutation ; Young Adult ; Amyotrophic Lateral Sclerosis/genetics ; Adaptor Proteins, Signal Transducing/genetics ; China ; Adult ; Pedigree ; East Asian People ; }, abstract = {Variations in the UBQLN2 gene are associated with a group of diseases with X-linked dominant inheritance and clinical phenotypes of amyotrophic lateral sclerosis (ALS) and/or frontal temporal lobe dementia (FTD). Cases with UBQLN2 variations have been rarely reported worldwide. The reported cases exhibit strong clinical heterogeneity. Here, we report two adult-onset cases with UBQLN2 variations in Han Chinese. Whole exome sequencing revealed the hemizygous P506S (c.1516C > T) and the heterozygous P509S variation (c.1525C > T), both of which were located within the hotspot mutation region. The patient with the P506S variation was a 24-year-old male. The clinical feature was spastic paraplegia without lower motor neuron damage. The patient's mother was an asymptomatic heterozygote carrier with skewed X-chromosome inactivation. The patient with the P509S variation was a 63-year-old female. Clinical features included ALS and parkinsonism. [18]F-fluorodopa PET-CT revealed presynaptic dopaminergic deficits in bilateral posterior putamen. These cases further highlight the clinical heterogeneity of UBQLN2 cases.}, } @article {pmid38942541, year = {2024}, author = {Shukla, H and John, D and Banerjee, S and Tiwari, AK}, title = {Drug repurposing for neurodegenerative diseases.}, journal = {Progress in molecular biology and translational science}, volume = {207}, number = {}, pages = {249-319}, doi = {10.1016/bs.pmbts.2024.03.035}, pmid = {38942541}, issn = {1878-0814}, mesh = {Humans ; *Drug Repositioning ; *Neurodegenerative Diseases/drug therapy ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) are neuronal problems that include the brain and spinal cord and result in loss of sensory and motor dysfunction. Common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS) etc. The occurrence of these diseases increases with age and is one of the challenging problems among elderly people. Though, several scientific research has demonstrated the key pathologies associated with NDDs still the underlying mechanisms and molecular details are not well understood and need to be explored and this poses a lack of effective treatments for NDDs. Several lines of evidence have shown that NDDs have a high prevalence and affect more than a billion individuals globally but still, researchers need to work forward in identifying the best therapeutic target for NDDs. Thus, several researchers are working in the directions to find potential therapeutic targets to alter the disease pathology and treat the diseases. Several steps have been taken to identify the early detection of the disease and drug repurposing for effective treatment of NDDs. Moreover, it is logical that current medications are being evaluated for their efficacy in treating such disorders; therefore, drug repurposing would be an efficient, safe, and cost-effective way in finding out better medication. In the current manuscript we discussed the utilization of drugs that have been repurposed for the treatment of AD, PD, HD, MS, and ALS.}, } @article {pmid38941189, year = {2024}, author = {Huang, WP and Ellis, BCS and Hodgson, RE and Sanchez Avila, A and Kumar, V and Rayment, J and Moll, T and Shelkovnikova, TA}, title = {Stress-induced TDP-43 nuclear condensation causes splicing loss of function and STMN2 depletion.}, journal = {Cell reports}, volume = {43}, number = {7}, pages = {114421}, doi = {10.1016/j.celrep.2024.114421}, pmid = {38941189}, issn = {2211-1247}, support = {MR/W028522/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *RNA Splicing/genetics ; *Cell Nucleus/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Stress, Physiological ; Animals ; Mice ; }, abstract = {TDP-43 protein is dysregulated in several neurodegenerative diseases, which often have a multifactorial nature and may have extrinsic stressors as a "second hit." TDP-43 undergoes reversible nuclear condensation in stressed cells including neurons. Here, we demonstrate that stress-inducible nuclear TDP-43 condensates are RNA-depleted, non-liquid assemblies distinct from the known nuclear bodies. Their formation requires TDP-43 oligomerization and ATP and is inhibited by RNA. Using a confocal nanoscanning assay, we find that amyotrophic lateral sclerosis (ALS)-linked mutations alter stress-induced TDP-43 condensation by changing its affinity to liquid-like ribonucleoprotein assemblies. Stress-induced nuclear condensation transiently inactivates TDP-43, leading to loss of interaction with its protein binding partners and loss of function in splicing. Splicing changes are especially prominent and persisting for STMN2 RNA, and STMN2 protein becomes rapidly depleted early during stress. Our results point to early pathological changes to TDP-43 in the nucleus and support therapeutic modulation of stress response in ALS.}, } @article {pmid38940407, year = {2024}, author = {Xu, A and Liu, T and Liu, D and Li, W and Huang, H and Wang, S and Xu, L and Liu, X and Jiang, S and Chen, Y and Sun, M and Luo, Q and Ding, T and Yao, T}, title = {Edge-Rich Pt-O-Ce Sites in CeO2 Supported Patchy Atomic-Layer Pt Enable a Non-CO Pathway for Efficient Methanol Oxidation.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {63}, number = {40}, pages = {e202410545}, doi = {10.1002/anie.202410545}, pmid = {38940407}, issn = {1521-3773}, support = {12025505//the National Natural Science Foundation of China/ ; 22179125//the National Natural Science Foundation of China/ ; 12205304//the National Natural Science Foundation of China/ ; KY9990000214//USTC research startup funds/ ; 2021YFA1600800//the National Key R&D Program of China/ ; XDB0450200//the Strategic Priority Research Program of the Chinese Academy of Sciences/ ; GXXT-2020-053//the University of China Innovation Program of Anhui Province/ ; 2022458//the Youth Innovation Promotion Association CAS/ ; 2021TQ0319//the Fellowship of China Postdoctoral Science Foundation/ ; BX20240350//the Fellowship of China Postdoctoral Science Foundation/ ; WK2060000038//the Fundamental Research Funds for the Central Universities/ ; WK2310000113//the Fundamental Research Funds for the Central Universities/ ; }, abstract = {Rational design of efficient methanol oxidation reaction (MOR) catalyst that undergo non-CO pathway is essential to resolve the long-standing poisoning issue. However, it remains a huge challenge due to the rather difficulty in maximizing the non-CO pathway by the selective coupling between the key *CHO and *OH intermediates. Here, we report a high-performance electrocatalyst of patchy atomic-layer Pt epitaxial growth on CeO2 nanocube (Pt ALs/CeO2) with maximum electronic metal-support interaction for enhancing the coupling selectively. The small-size monolayer material achieves an optimal geometrical distance between edge Pt-O-Ce sites and *OH absorbed on CeO2, which well restrains the dehydrogenation of *CHO, resulting in the non-CO pathway. Meanwhile, the *CHO/*CO intermediate generated at inner Pt-O-Ce sites can migrate to edge, inducing the subsequent coupling reaction, thus avoiding poisoning while promoting reaction efficiency. Consequently, Pt ALs/CeO2 exhibits exceptionally catalytic stability with negligible degradation even under 1000 s pure CO poisoning operation and high mass activity (14.87 A/mgPt), enabling it one of the best-performing alkali-stable MOR catalysts.}, } @article {pmid38939990, year = {2024}, author = {Song, XY and Fan, CX and Rahman, AU and Choudhary, MI and Wang, XP}, title = {Neuro-regeneration or Repair: Cell Therapy of Neurological Disorders as A Way Forward.}, journal = {Current neuropharmacology}, volume = {22}, number = {14}, pages = {2272-2283}, pmid = {38939990}, issn = {1875-6190}, mesh = {Humans ; *Nervous System Diseases/therapy ; Animals ; *Cell- and Tissue-Based Therapy/methods ; Nerve Regeneration/physiology ; Stem Cell Transplantation/methods ; }, abstract = {The human central nervous system (CNS) has a limited capacity for regeneration and repair, as many other organs do. Partly as a result, neurological diseases are the leading cause of medical burden globally. Most neurological disorders cannot be cured, and primary treatments focus on managing their symptoms and slowing down their progression. Cell therapy for neurological disorders offers several therapeutic potentials and provides hope for many patients. Here we provide a general overview of cell therapy in neurological disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Wilson's disease (WD), stroke and traumatic brain injury (TBI), involving many forms of stem cells, including embryonic stem cells and induced pluripotent stem cells. We also address the current concerns and perspectives for the future. Most studies for cell therapy in neurological diseases are in the pre-clinical stage, and there is still a great need for further research to translate neural replacement and regenerative therapies into clinical settings.}, } @article {pmid38939546, year = {2024}, author = {Kararia, N and Kararia, V and Sharma, D and Gupta, S and Chaturvedi, S and Chaturvedi, Y}, title = {Comparative evaluation of the accuracy of two electronic apex locators in detecting simulated incomplete vertical root fractures: An in vitro stereomicroscopic study.}, journal = {Journal of conservative dentistry and endodontics}, volume = {27}, number = {5}, pages = {540-544}, pmid = {38939546}, issn = {2950-4708}, abstract = {AIM: The aim of this study was to compare the accuracy of two different electronic apex locators (EALs) in detecting simulated incomplete vertical root fractures (VRFs).

MATERIALS AND METHODS: Thirty freshly extracted single-rooted teeth were randomly divided into three groups of 10 teeth each labeled as Groups A, B, and C. Incomplete VRFs were simulated in the coronal, middle, and apical one-third of the roots for Groups A, B, and C, respectively. The teeth were embedded in alginate mold and fracture location was determined with Root ZX and Propex EALs for each sample and each group. To calculate the actual length (AL), each sample was sectioned at the upper level of the vertical fracture, and the length was measured by setting the stopper of the #10 K file under a stereomicroscope at ×30 magnification. The electronic lengths and ALs were compared using computer software, and the results were analyzed using SPSS 28.0 at a 95% confidence level.

RESULTS: No significant differences were seen in the accuracy of the two EALs when compared with ALs. Root ZX showed significantly longer measurements than ALs in groups B and C.

CONCLUSION: The tested EALs showed low accuracy (20%) in detecting simulated incomplete VRFs with a tendency for longer measurements compared to ALs.}, } @article {pmid38937912, year = {2024}, author = {Verde, F and Licaj, S and Soranna, D and Ticozzi, N and Silani, V and Zambon, A}, title = {Cerebrospinal fluid and blood neurofilament light chain levels in amyotrophic lateral sclerosis and frontotemporal degeneration: A meta-analysis.}, journal = {European journal of neurology}, volume = {31}, number = {9}, pages = {e16371}, pmid = {38937912}, issn = {1468-1331}, support = {//Ministero della Salute/ ; //BIBLIOSAN/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood ; Humans ; *Neurofilament Proteins/blood/cerebrospinal fluid ; *Frontotemporal Lobar Degeneration/blood/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid/blood ; Frontotemporal Dementia/cerebrospinal fluid/blood ; }, abstract = {BACKGROUND AND PURPOSE: Neurofilament light chain (NFL) has been shown to be increased in amyotrophic lateral sclerosis (ALS) and, to a lesser extent, in frontotemporal dementia (FTD). A meta-analysis of NFL in ALS and FTD was performed.

METHODS: Available studies comparing cerebrospinal fluid and blood NFL levels in ALS versus neurologically healthy controls (NHCs), other neurological diseases (ONDs) and ALS mimics, as well as in FTD and related entities (behavioural variant of FTD and frontotemporal lobar degeneration syndromes) versus NHCs, ONDs and other dementias were evaluated.

RESULTS: In ALS, both cerebrospinal fluid and blood levels of NFL were higher compared to other categories. In FTD, behavioural variant of FTD and frontotemporal lobar degeneration syndromes, NFL levels were consistently higher compared to NHCs; however, several comparisons with ONDs and other dementias did not demonstrate significant differences.

DISCUSSION: Amyotrophic lateral sclerosis is characterized by higher NFL levels compared to most other conditions. In contrast, NFL is not as good at discriminating FTD from other dementias.}, } @article {pmid38936435, year = {2024}, author = {Tondo, G and Mazzini, L and Caminiti, SP and Gallo, C and Matheoud, R and Comi, C and Sacchetti, GM and Perani, D and De Marchi, F}, title = {Coupling motor evoked potentials and brain [[18]F]FDG-PET in Amyotrophic Lateral Sclerosis: preliminary findings on disease severity.}, journal = {Neurobiology of disease}, volume = {199}, number = {}, pages = {106579}, doi = {10.1016/j.nbd.2024.106579}, pmid = {38936435}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism/physiopathology ; Male ; Female ; Middle Aged ; *Fluorodeoxyglucose F18 ; *Positron-Emission Tomography/methods ; *Transcranial Magnetic Stimulation/methods ; Aged ; Retrospective Studies ; *Brain/diagnostic imaging/metabolism/physiopathology ; *Evoked Potentials, Motor/physiology ; Adult ; Severity of Illness Index ; }, abstract = {BACKGROUND: The diagnosis of amyotrophic lateral sclerosis (ALS) is primarily clinical, supported by the electromyographic examination to reveal signs of lower motor neuron damage. Identifying reliable markers of upper motor neuron (UMN) involvement is challenging. On this regard, the role of transcranial magnetic stimulation-induced motor-evoked potentials (TMS-MEPs), and its relationship with UMN burden, is still under investigation.

OBJECTIVE: To evaluate the ability of TMS-MEPs in delineating the neurophysiological UMN damage, and to determine the relationship between TMS-MEPs and [[18]F]FDG-PET measures of neural dysfunction.

METHODS: We retrospectively selected 13 ALS patients who underwent, during the diagnostic process, the TMS-MEPs and [[18]F]FDG-PET scans. Demographic and clinical data were collected. For the MEP evaluation, we considered normal MEP, absent MEP, or significantly increased central-motor-conduction-time. For [[18]F]FDG-PET, we conducted voxel-wise analyses, both at single-subject and group levels, exploring hypometabolism and hypermetabolism patterns in comparison with a large dataset of healthy controls (HC).

RESULTS: Based on TMS-MEPs, we identified 4/13 patients with normal MEP in all limbs (GROUP-NO), while 9/13 had an abnormal MEP in at least one limb (GROUP-AB). Despite the [[18]F]FDG-PET single-subject analysis revealed heterogenous expression of regional hypo- and hyper-metabolism patterns in the patients, the group-level analysis revealed a common hypometabolism, involving the precentral gyrus and the supplementary motor area, the paracentral lobule and the anterior cingulate cortex in the GROUP-AB. Moreover, exclusively for the GROUP-AB compared with HC, a relative hypermetabolism was observed in the right cerebellum, right inferior and middle temporal gyrus. The GROUP-NO showed no specific cluster of hypo- and hyper-metabolism compared to HC.

CONCLUSION: This study showed altered brain metabolism only in the ALS group with abnormal MEPs, suggesting an association between the two biomarkers in defining the UMN damage.}, } @article {pmid38935506, year = {2024}, author = {Halim, DO and Krishnan, G and Hass, EP and Lee, S and Verma, M and Almeida, S and Gu, Y and Kwon, DY and Fazzio, TG and Gao, FB}, title = {The exocyst subunit EXOC2 regulates the toxicity of expanded GGGGCC repeats in C9ORF72-ALS/FTD.}, journal = {Cell reports}, volume = {43}, number = {7}, pages = {114375}, pmid = {38935506}, issn = {2211-1247}, support = {RF1 NS101986/NS/NINDS NIH HHS/United States ; R21 NS119952/NS/NINDS NIH HHS/United States ; R01 HD104971/HD/NICHD NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; R21 NS112766/NS/NINDS NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *DNA Repeat Expansion/genetics ; Motor Neurons/metabolism/pathology ; }, abstract = {GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this genetic mutation leads to neurodegeneration remains largely unknown. Using CRISPR-Cas9 technology, we deleted EXOC2, which encodes an essential exocyst subunit, in induced pluripotent stem cells (iPSCs) derived from C9ORF72-ALS/FTD patients. These cells are viable owing to the presence of truncated EXOC2, suggesting that exocyst function is partially maintained. Several disease-relevant cellular phenotypes in C9ORF72 iPSC-derived motor neurons are rescued due to, surprisingly, the decreased levels of dipeptide repeat (DPR) proteins and expanded G4C2 repeats-containing RNA. The treatment of fully differentiated C9ORF72 neurons with EXOC2 antisense oligonucleotides also decreases expanded G4C2 repeats-containing RNA and partially rescued disease phenotypes. These results indicate that EXOC2 directly or indirectly regulates the level of G4C2 repeats-containing RNA, making it a potential therapeutic target in C9ORF72-ALS/FTD.}, } @article {pmid38934637, year = {2025}, author = {Tankus, A and Stern, E and Klein, G and Kaptzon, N and Nash, L and Marziano, T and Shamia, O and Gurevitch, G and Bergman, L and Goldstein, L and Fahoum, F and Strauss, I}, title = {A Speech Neuroprosthesis in the Frontal Lobe and Hippocampus: Decoding High-Frequency Activity into Phonemes.}, journal = {Neurosurgery}, volume = {96}, number = {2}, pages = {356-364}, doi = {10.1227/neu.0000000000003068}, pmid = {38934637}, issn = {1524-4040}, support = {17630//Ministry of Science and Technology, Israel/ ; }, mesh = {Humans ; Male ; Adult ; *Hippocampus/surgery/physiology ; *Frontal Lobe/surgery/physiology ; Speech/physiology ; Electrodes, Implanted ; Brain-Computer Interfaces ; Neural Prostheses ; }, abstract = {BACKGROUND AND OBJECTIVES: Loss of speech due to injury or disease is devastating. Here, we report a novel speech neuroprosthesis that artificially articulates building blocks of speech based on high-frequency activity in brain areas never harnessed for a neuroprosthesis before: anterior cingulate and orbitofrontal cortices, and hippocampus.

METHODS: A 37-year-old male neurosurgical epilepsy patient with intact speech, implanted with depth electrodes for clinical reasons only, silently controlled the neuroprosthesis almost immediately and in a natural way to voluntarily produce 2 vowel sounds.

RESULTS: During the first set of trials, the participant made the neuroprosthesis produce the different vowel sounds artificially with 85% accuracy. In the following trials, performance improved consistently, which may be attributed to neuroplasticity. We show that a neuroprosthesis trained on overt speech data may be controlled silently.

CONCLUSION: This may open the way for a novel strategy of neuroprosthesis implantation at earlier disease stages (eg, amyotrophic lateral sclerosis), while speech is intact, for improved training that still allows silent control at later stages. The results demonstrate clinical feasibility of direct decoding of high-frequency activity that includes spiking activity in the aforementioned areas for silent production of phonemes that may serve as a part of a neuroprosthesis for replacing lost speech control pathways.}, } @article {pmid38934512, year = {2024}, author = {Zhang, J and Cao, W and Xie, J and Pang, C and Gao, L and Zhu, L and Li, Y and Yu, H and Du, L and Fan, D and Deng, B}, title = {Metabolic Syndrome and Risk of Amyotrophic Lateral Sclerosis: Insights from a Large-Scale Prospective Study.}, journal = {Annals of neurology}, volume = {96}, number = {4}, pages = {788-801}, doi = {10.1002/ana.27019}, pmid = {38934512}, issn = {1531-8249}, support = {12101460//National Natural Science Foundation of China/ ; 81901273//National Natural Science Foundation of China/ ; LQ21H090018//Natural Science Foundation of Zhejiang Province/ ; LQ22A010005//Natural Science Foundation of Zhejiang Province/ ; LQ22H020003//Natural Science Foundation of Zhejiang Province/ ; ZCLY24H0903//Natural Science Foundation of Zhejiang Province/ ; KY2024-R054//Ethical Decision Committee of the Research Administration at First Affiliated Hospital of Wenzhou Medical University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Male ; Female ; *Metabolic Syndrome/epidemiology ; Middle Aged ; Prospective Studies ; Aged ; Risk Factors ; Adult ; United Kingdom/epidemiology ; Body Mass Index ; Hypertension/epidemiology/complications ; }, abstract = {OBJECTIVE: Although metabolic abnormalities are implicated in the etiology of neurodegenerative diseases, their role in the development of amyotrophic lateral sclerosis (ALS) remains a subject of controversy. We aimed to identify the association between metabolic syndrome (MetS) and the risk of ALS.

METHODS: This study included 395,987 participants from the UK Biobank to investigate the relationship between MetS and ALS. Cox regression model was used to estimate hazard ratios (HR). Stratified analyses were performed based on gender, body mass index (BMI), smoking status, and education level. Mediation analysis was conducted to explore potential mechanisms.

RESULTS: In this study, a total of 539 cases of ALS were recorded after a median follow-up of 13.7 years. Patients with MetS (defined harmonized) had a higher risk of developing ALS after adjusting for confounding factors (HR: 1.50, 95% CI: 1.19-1.89). Specifically, hypertension and high triglycerides were linked to a higher risk of ALS (HR: 1.53, 95% CI: 1.19-1.95; HR: 1.31, 95% CI: 1.06-1.61, respectively). Moreover, the quantity of metabolic abnormalities showed significant results. Stratified analysis revealed that these associations are particularly significant in individuals with a BMI <25. These findings remained stable after sensitivity analysis. Notably, mediation analysis identified potential metabolites and metabolomic mediators, including alkaline phosphatase, cystatin C, γ-glutamyl transferase, saturated fatty acids to total fatty acids percentage, and omega-6 fatty acids to omega-3 fatty acids ratio.

INTERPRETATION: MetS exhibits a robust association with an increased susceptibility to ALS, particularly in individuals with a lower BMI. Furthermore, metabolites and metabolomics, as potential mediators, provide invaluable insights into the intricate biological mechanisms. ANN NEUROL 2024;96:788-801.}, } @article {pmid38934400, year = {2025}, author = {Chen, Y and Wei, Y and Liu, J and Zhu, T and Zhou, C and Zhang, D}, title = {Spatial transcriptomics combined with single-nucleus RNA sequencing reveals glial cell heterogeneity in the human spinal cord.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3302-3316}, pmid = {38934400}, issn = {1673-5374}, abstract = {JOURNAL/nrgr/04.03/01300535-202511000-00032/figure1/v/2024-12-20T164640Z/r/image-tiff Glial cells play crucial roles in regulating physiological and pathological functions, including sensation, the response to infection and acute injury, and chronic neurodegenerative disorders. Glial cells include astrocytes, microglia, and oligodendrocytes in the central nervous system, and satellite glial cells and Schwann cells in the peripheral nervous system. Despite the greater understanding of glial cell types and functional heterogeneity achieved through single-cell and single-nucleus RNA sequencing in animal models, few studies have investigated the transcriptomic profiles of glial cells in the human spinal cord. Here, we used high-throughput single-nucleus RNA sequencing and spatial transcriptomics to map the cellular and molecular heterogeneity of astrocytes, microglia, and oligodendrocytes in the human spinal cord. To explore the conservation and divergence across species, we compared these findings with those from mice. In the human spinal cord, astrocytes, microglia, and oligodendrocytes were each divided into six distinct transcriptomic subclusters. In the mouse spinal cord, astrocytes, microglia, and oligodendrocytes were divided into five, four, and five distinct transcriptomic subclusters, respectively. The comparative results revealed substantial heterogeneity in all glial cell types between humans and mice. Additionally, we detected sex differences in gene expression in human spinal cord glial cells. Specifically, in all astrocyte subtypes, the levels of NEAT1 and CHI3L1 were higher in males than in females, whereas the levels of CST3 were lower in males than in females. In all microglial subtypes, all differentially expressed genes were located on the sex chromosomes. In addition to sex-specific gene differences, the levels of MT-ND4 , MT2A , MT-ATP6 , MT-CO3 , MT-ND2 , MT-ND3 , and MT-CO2 in all spinal cord oligodendrocyte subtypes were higher in females than in males. Collectively, the present dataset extensively characterizes glial cell heterogeneity and offers a valuable resource for exploring the cellular basis of spinal cord-related illnesses, including chronic pain, amyotrophic lateral sclerosis, and multiple sclerosis.}, } @article {pmid38934222, year = {2024}, author = {Kim, A and Lee, DY and Sung, JJ}, title = {Cdk5 inhibition in the SOD1[G93A] transgenic mouse model of amyotrophic lateral sclerosis suppresses neurodegeneration and extends survival.}, journal = {Journal of neurochemistry}, volume = {168}, number = {9}, pages = {2908-2925}, doi = {10.1111/jnc.16160}, pmid = {38934222}, issn = {1471-4159}, support = {2018R1A5A2025964//National Research Foundation of Korea/ ; 2019M3C7A1031867//National Research Foundation of Korea/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Cells, Cultured ; *Cyclin-Dependent Kinase 5/metabolism/genetics/antagonists & inhibitors ; Disease Models, Animal ; Mice, Transgenic ; Motor Neurons/pathology/metabolism ; Nerve Degeneration/pathology/genetics/metabolism ; Superoxide Dismutase ; *Superoxide Dismutase-1/genetics ; tau Proteins/metabolism/genetics ; }, abstract = {Deregulated cyclin-dependent kinase 5 (Cdk5) activity closely correlates with hyperphosphorylated tau, a common pathology found in neurodegenerative diseases. Previous postmortem studies had revealed increased Cdk5 immunoreactivity in amyotrophic lateral sclerosis (ALS); hence, we investigated the effects of Cdk5 inhibition on ALS model mice and neurons in this study. For the in vitro study, motor neuron cell lines with wild-type superoxide dismutase 1 (SOD1) or SOD1[G93A] and primary neuronal cultures from SOD1[G93A] transgenic (TG) mice or non-TG mice were compared for the expression of proteins involved in tau pathology, neuroinflammation, apoptosis, and neuritic outgrowth by applying Cdk5-small interfering RNA or Cdk5-short hairpin RNA (shRNA). For the in vivo study, SOD1[G93A] mice and non-TG mice were intrathecally injected with adeno-associated virus 9 (AAV9)-scramble (SCR)-shRNA or AAV9-Cdk5-shRNA at the age of 5 weeks. Weight and motor function were measured three times per week from 60 days of age, longevity was evaluated, and the tissues were collected from 90-day-old or 120-day-old mice. Neurons with SOD1[G93A] showed increased phosphorylated tau, attenuated neuritic growth, mislocalization of SOD1, and enhanced neuroinflammation and apoptosis, all of which were reversed by Cdk5 inhibition. Weights did not show significant differences among non-TG and SOD1[G93A] mice with or without Cdk5 silencing. SOD1[G93A] mice treated with AAV9-Cdk5-shRNA showed significantly delayed disease onset, delayed rotarod failure, and prolonged survival compared with those treated with AAV9-SCR-shRNA. The brain and spinal cord of SOD1[G93A] mice intrathecally injected with AAV9-Cdk5-shRNA exhibited suppressed tau pathology, neuroinflammation, apoptosis, and an increased number of motor neurons compared to those of SOD1[G93A] mice injected with AAV9-SCR-shRNA. Cdk5 inhibition could be an important mechanism in the development of a new therapeutic strategy for ALS.}, } @article {pmid38932502, year = {2024}, author = {Stegmann, G and Krantsevich, C and Liss, J and Charles, S and Bartlett, M and Shefner, J and Rutkove, S and Kawabata, K and Talkar, T and Berisha, V}, title = {Automated speech analytics in ALS: higher sensitivity of digital articulatory precision over the ALSFRS-R.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {767-775}, pmid = {38932502}, issn = {2167-9223}, support = {R01 DC006859/DC/NIDCD NIH HHS/United States ; R43 DC017625/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Male ; Female ; Middle Aged ; Aged ; Speech Disorders/etiology/diagnosis/physiopathology ; Speech/physiology ; Adult ; Speech Production Measurement/methods ; Algorithms ; Severity of Illness Index ; Disease Progression ; }, abstract = {Objective: Although studies have shown that digital measures of speech detected ALS speech impairment and correlated with the ALSFRS-R speech item, no study has yet compared their performance in detecting speech changes. In this study, we compared the performances of the ALSFRS-R speech item and an algorithmic speech measure in detecting clinically important changes in speech. Importantly, the study was part of a FDA submission which received the breakthrough device designation for monitoring ALS; we provide this paper as a roadmap for validating other speech measures for monitoring disease progression. Methods: We obtained ALSFRS-R speech subscores and speech samples from participants with ALS. We computed the minimum detectable change (MDC) of both measures; using clinician-reported listener effort and a perceptual ratings of severity, we calculated the minimal clinically important difference (MCID) of each measure with respect to both sets of clinical ratings. Results: For articulatory precision, the MDC (.85) was lower than both MCID measures (2.74 and 2.28), and for the ALSFRS-R speech item, MDC (.86) was greater than both MCID measures (.82 and .72), indicating that while the articulatory precision measure detected minimal clinically important differences in speech, the ALSFRS-R speech item did not. Conclusion: The results demonstrate that the digital measure of articulatory precision effectively detects clinically important differences in speech ratings, outperforming the ALSFRS-R speech item. Taken together, the results herein suggest that this speech outcome is a clinically meaningful measure of speech change.}, } @article {pmid38932488, year = {2024}, author = {Spencer, D and Polke, J and Campbell, J and Houlden, H and Radunovic, A}, title = {'Outcomes of genetic testing in the London MND Center: the importance of achieving timely results and correlations to family history'.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {737-742}, doi = {10.1080/21678421.2024.2370808}, pmid = {38932488}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; *Genetic Testing/methods ; London/epidemiology ; Middle Aged ; Aged ; Adult ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; Mutation/genetics ; Aged, 80 and over ; Genetic Predisposition to Disease/genetics ; Medical History Taking/methods ; }, abstract = {Background: Despite recognition of the importance of genetic factors in the pathogenesis of MND and the increasing availability of genetic testing, testing practice remains highly variable. With the arrival of gene-targeted therapies there is a growing need to promptly identify actionable genetic results and patient death before receipt of results raises ethical dilemmas and limits access to novel therapies. Objective: To identify pathogenic mutations within a London tertiary MND center and their correlation with family history. To record waiting times for genetic results and deaths prior to receipt of results. Methods: In this series of 100 cases, genetic testing was offered to all patients with an MND diagnosis from the tertiary clinic. Data on demographics, disease progression and a detailed family history were taken. Time to receipt of genetic results and patient deaths prior to this were recorded. Results: Of the 97 patients who accepted testing a genetic cause was identified in 10%, including seven C9orf72 and two positive SOD1 cases. Only three patients with positive genetic findings had a family history of MND, although alternative neurological diagnoses and symptoms in the family were frequently reported. 14% of patients who underwent testing were deceased by the time results were received, including one actionable SOD1 case. Conclusions: Genetic testing should be made available to all patients who receive an MND diagnosis as family history alone is inadequate to identify potential familial cases. Time to receipt of results remains a significant issue due to the limited life expectancy following diagnosis.}, } @article {pmid38929462, year = {2024}, author = {De Marchi, I and Buffone, F and Mauro, A and Bruini, I and Vismara, L}, title = {Manual Therapy of Dysphagia in a Patient with Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {6}, pages = {}, pmid = {38929462}, issn = {1648-9144}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Male ; *Deglutition Disorders/etiology/therapy ; Middle Aged ; Manipulation, Osteopathic/methods ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable rare neurodegenerative condition, with 45% of cases showing the symptom of dysphagia; its clinical signs are atrophy, weakness, and fasciculations of the facial muscles, tongue, and pharynx. Furthermore, dysphagia is the main cause of aspiration pneumonia. The traditional treatment for dysphagia varies based on the patient's difficulty of swallowing. The initial phase consists of dietary consistency adjustments, progressing to alternatives like nasogastric tubes or percutaneous endoscopic gastrostomy (PEG) in advanced stages. Osteopathic manipulative treatment (OMT) is a complementary 'hands-on' approach that has already shown positive results as an add-on therapy in various health conditions. This study is a case report of a man diagnosed with ALS with initial dysphagia, managed with a protocol that extraordinarily included OMT. The patient showed somatic dysfunctions in the mediastinal region, upper cervical region, and occipital area which are all anatomically related to the nervous system, especially the glossopharyngeal reflex. At the end of the rehabilitation protocol, there was a reduction in the swallowing problems measured with Strand Scale and swallowing tests, and the patient reported an improved psycho-physical well-being assessed with the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40). Instead, the neurological function measured with ALSFRS-S remained stable. Although the nature of this study design prevents any causal assumption, the positive results should lead to future randomized controlled trials to assess the effectiveness of OMT as an adjunctive therapeutic proposal to improve the health of ALS patients.}, } @article {pmid38929429, year = {2024}, author = {Hillaert, A and Sanmiguel Serpa, LC and Xu, Y and Hesta, M and Bogaert, S and Vanderperren, K and Pullens, P}, title = {Optimization of Fair Arterial Spin Labeling Magnetic Resonance Imaging (ASL-MRI) for Renal Perfusion Quantification in Dogs: Pilot Study.}, journal = {Animals : an open access journal from MDPI}, volume = {14}, number = {12}, pages = {}, pmid = {38929429}, issn = {2076-2615}, support = {01D27919//Special Research Fund of Ghent University, Belgium/ ; }, abstract = {Arterial spin labeling (ASL) MRI allows non-invasive quantification of renal blood flow (RBF) and shows great potential for renal assessment. To our knowledge, renal ASL-MRI has not previously been performed in dogs. The aim of this pilot study was to determine parameters essential for ALS-MRI-based quantification of RBF in dogs: T1, blood (longitudinal relaxation time), λ (blood tissue partition coefficient) and TI (inversion time). A Beagle was scanned at 3T with a multi-TI ASL sequence, with TIs ranging from 250 to 2500 ms, to determine the optimal TI value. The T1 of blood for dogs was determined by scanning a blood sample with a 2D IR TSE sequence. The water content of the dog's kidney was determined by analyzing kidney samples from four dogs with a moisture analyzer and was subsequently used to calculate λ. The optimal TI and the measured values for T1,blood, and λ were 2000 ms, 1463 ms and 0.91 mL/g, respectively. These optimized parameters for dogs resulted in lower RBF values than those obtained from inline generated RBF maps. In conclusion, this study determined preliminary parameters essential for ALS-MRI-based RBF quantification in dogs. Further research is needed to confirm these values, but it may help guide future research.}, } @article {pmid38928874, year = {2024}, author = {Szulc, A and Wiśniewska, K and Żabińska, M and Gaffke, L and Szota, M and Olendzka, Z and Węgrzyn, G and Pierzynowska, K}, title = {Effectiveness of Flavonoid-Rich Diet in Alleviating Symptoms of Neurodegenerative Diseases.}, journal = {Foods (Basel, Switzerland)}, volume = {13}, number = {12}, pages = {}, pmid = {38928874}, issn = {2304-8158}, support = {533-0C20-GS0D-24//University of Gdansk/ ; }, abstract = {Over the past decades, there has been a significant increase in the burden of neurological diseases, including neurodegenerative disorders, on a global scale. This is linked to a widespread demographic trend in which developed societies are aging, leading to an increased proportion of elderly individuals and, concurrently, an increase in the number of those afflicted, posing one of the main public health challenges for the coming decades. The complex pathomechanisms of neurodegenerative diseases and resulting varied symptoms, which differ depending on the disease, environment, and lifestyle of the patients, make searching for therapies for this group of disorders a formidable challenge. Currently, most neurodegenerative diseases are considered incurable. An important aspect in the fight against and prevention of neurodegenerative diseases may be broadly understood lifestyle choices, and more specifically, what we will focus on in this review, a diet. One proposal that may help in the fight against the spread of neurodegenerative diseases is a diet rich in flavonoids. Flavonoids are compounds widely found in products considered healthy, such as fruits, vegetables, and herbs. Many studies indicated not only the neuroprotective effects of these compounds but also their ability to reverse changes occurring during the progression of diseases such as Alzheimer's, Parkinson's and amyotrophic lateral sclerosis. Here, we present the main groups of flavonoids, discussing their characteristics and mechanisms of action. The most widely described mechanisms point to neuroprotective functions due to strong antioxidant and anti-inflammatory effects, accompanied with their ability to penetrate the blood-brain barrier, as well as the ability to inhibit the formation of protein aggregates. The latter feature, together with promoting removal of the aggregates is especially important in neurodegenerative diseases. We discuss a therapeutic potential of selected flavonoids in the fight against neurodegenerative diseases, based on in vitro studies, and their impact when included in the diet of animals (laboratory research) and humans (population studies). Thus, this review summarizes flavonoids' actions and impacts on neurodegenerative diseases. Therapeutic use of these compounds in the future is potentially possible but depends on overcoming key challenges such as low bioavailability, determining the therapeutic dose, and defining what a flavonoid-rich diet is and determining its potential negative effects. This review also suggests further research directions to address these challenges.}, } @article {pmid38928564, year = {2024}, author = {Lin, CY and Vanoverbeke, V and Trent, D and Willey, K and Lee, YS}, title = {The Spatiotemporal Expression of SOCS3 in the Brainstem and Spinal Cord of Amyotrophic Lateral Sclerosis Mice.}, journal = {Brain sciences}, volume = {14}, number = {6}, pages = {}, pmid = {38928564}, issn = {2076-3425}, support = {2022-040//Cleveland Clinic Technology Development Investment Project and Ohio Third Frontier Technology Validation and Start-up Fund/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons from the brain and spinal cord. The excessive neuroinflammation is thought to be a common determinant of ALS. Suppressor of cytokine signaling-3 (SOCS3) is pathologically upregulated after injury/diseases to negatively regulate a broad range of cytokines/chemokines that mediate inflammation; however, the role that SOCS3 plays in ALS pathogenesis has not been explored. Here, we found that SOCS3 protein levels were significantly increased in the brainstem of the superoxide dismutase 1 (SOD1)-G93A ALS mice, which is negatively related to a progressive decline in motor function from the pre-symptomatic to the early symptomatic stage. Moreover, SOCS3 levels in both cervical and lumbar spinal cords of ALS mice were also significantly upregulated at the pre-symptomatic stage and became exacerbated at the early symptomatic stage. Concomitantly, astrocytes and microglia/macrophages were progressively increased and reactivated over time. In contrast, neurons were simultaneously lost in the brainstem and spinal cord examined over the course of disease progression. Collectively, SOCS3 was first found to be upregulated during ALS progression to directly relate to both increased astrogliosis and increased neuronal loss, indicating that SOCS3 could be explored to be as a potential therapeutic target of ALS.}, } @article {pmid38928553, year = {2024}, author = {Di Martino, P and Marcozzi, V and Bibbò, S and Ghinassi, B and Di Baldassarre, A and Gaggi, G and Di Credico, A}, title = {Unraveling the Epigenetic Landscape: Insights into Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis.}, journal = {Brain sciences}, volume = {14}, number = {6}, pages = {}, pmid = {38928553}, issn = {2076-3425}, support = {MUR-Fondo Promozione e Sviluppo-DM 737/2021, DEFENDANTs, Developmental Neurotoxi-city of Endocrine Disruptors from Plastic Pollutants.//NextGenerationEU "MUR-Fondo Promozione e Sviluppo-DM 737/2021, DEFENDANTs, De-velopmental Neurotoxicity of Endocrine Disruptors from Plastic Pollutants./ ; }, abstract = {Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) are examples of neurodegenerative movement disorders (NMDs), which are defined by a gradual loss of motor function that is frequently accompanied by cognitive decline. Although genetic abnormalities have long been acknowledged as significant factors, new research indicates that epigenetic alterations are crucial for the initiation and development of disease. This review delves into the complex interactions that exist between the pathophysiology of NMDs and epigenetic mechanisms such DNA methylation, histone modifications, and non-coding RNAs. Here, we examine how these epigenetic changes could affect protein aggregation, neuroinflammation, and gene expression patterns, thereby influencing the viability and functionality of neurons. Through the clarification of the epigenetic terrain underpinning neurodegenerative movement disorders, this review seeks to enhance comprehension of the underlying mechanisms of the illness and augment the creation of innovative therapeutic strategies.}, } @article {pmid38927681, year = {2024}, author = {Adler, GL and Le, K and Fu, Y and Kim, WS}, title = {Human Endogenous Retroviruses in Neurodegenerative Diseases.}, journal = {Genes}, volume = {15}, number = {6}, pages = {}, pmid = {38927681}, issn = {2073-4425}, mesh = {Humans ; *Endogenous Retroviruses/genetics/pathogenicity ; *Neurodegenerative Diseases/virology/genetics ; Amyotrophic Lateral Sclerosis/virology/genetics ; Animals ; }, abstract = {Human endogenous retroviruses (HERVs) are DNA transposable elements that have integrated into the human genome via an ancestral germline infection. The potential importance of HERVs is underscored by the fact that they comprise approximately 8% of the human genome. HERVs have been implicated in the pathogenesis of neurodegenerative diseases, a group of CNS diseases characterized by a progressive loss of structure and function of neurons, resulting in cell death and multiple physiological dysfunctions. Much evidence indicates that HERVs are initiators or drivers of neurodegenerative processes in multiple sclerosis and amyotrophic lateral sclerosis, and clinical trials have been designed to target HERVs. In recent years, the role of HERVs has been explored in other major neurodegenerative diseases, including frontotemporal dementia, Alzheimer's disease and Parkinson's disease, with some interesting discoveries. This review summarizes and evaluates the past and current research on HERVs in neurodegenerative diseases. It discusses the potential role of HERVs in disease manifestation and neurodegeneration. It critically reviews antiretroviral strategies used in the therapeutic intervention of neurodegenerative diseases.}, } @article {pmid38927674, year = {2024}, author = {Gotte, G}, title = {Effects of Pathogenic Mutants of the Neuroprotective RNase 5-Angiogenin in Amyotrophic Lateral Sclerosis (ALS).}, journal = {Genes}, volume = {15}, number = {6}, pages = {}, pmid = {38927674}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; *Ribonuclease, Pancreatic/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; Animals ; Mutation ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that affects the motoneurons. More than 40 genes are related with ALS, and amyloidogenic proteins like SOD1 and/or TDP-43 mutants are directly involved in the onset of ALS through the formation of polymorphic fibrillogenic aggregates. However, efficacious therapeutic approaches are still lacking. Notably, heterozygous missense mutations affecting the gene coding for RNase 5, an enzyme also called angiogenin (ANG), were found to favor ALS onset. This is also true for the less-studied but angiogenic RNase 4. This review reports the substrate targets and illustrates the neuroprotective role of native ANG in the neo-vascularization of motoneurons. Then, it discusses the molecular determinants of many pathogenic ANG mutants, which almost always cause loss of function related to ALS, resulting in failures in angiogenesis and motoneuron protection. In addition, ANG mutations are sometimes combined with variants of other factors, thereby potentiating ALS effects. However, the activity of the native ANG enzyme should be finely balanced, and not excessive, to avoid possible harmful effects. Considering the interplay of these angiogenic RNases in many cellular processes, this review aims to stimulate further investigations to better elucidate the consequences of mutations in ANG and/or RNase 4 genes, in order to achieve early diagnosis and, possibly, successful therapies against ALS.}, } @article {pmid38927671, year = {2024}, author = {Carata, E and Muci, M and Mariano, S and Di Giulio, S and Nigro, A and Romano, A and Panzarini, E}, title = {Extracellular Vesicles from NSC-34 MN-like Cells Transfected with Mutant SOD1 Modulate Inflammatory Status of Raw 264.7 Macrophages.}, journal = {Genes}, volume = {15}, number = {6}, pages = {}, pmid = {38927671}, issn = {2073-4425}, mesh = {Animals ; *Extracellular Vesicles/metabolism/genetics ; Mice ; RAW 264.7 Cells ; *Superoxide Dismutase-1/genetics/metabolism ; *Macrophages/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Motor Neurons/metabolism ; Inflammation/genetics/metabolism/pathology ; Mutation ; Transfection ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease targeting the brain and spinal cord. Non-neuronal cells, including macrophages, may contribute to the disruption of motor neurons (MNs), neuromuscular junction dismantling and clinical signs of ALS. Understanding the modality and the effect of MNs-macrophage communication is pivotal. Here, we focus on extracellular vesicle (EVS)-mediated communication and, in particular, we analyze the response of macrophages. NSC-34 cells transfected with mutant SOD1 (G93A, A4V, G85R, G37R) and differentiated towards MN-like cells, and Raw 264.7 macrophages are the cellular models of the study. mSOD1 NSC-34 cells release a high number of vesicles, both large-lEVs (300 nm diameter) and small-sEVs (90 nm diameter), containing inflammation-modulating molecules, and are efficiently taken up by macrophages. RT-PCR analysis of inflammation mediators demonstrated that the conditioned medium of mSOD1 NSC-34 cells polarizes Raw 264.7 macrophages towards both pro-inflammatory and anti-inflammatory phenotypes. sEVs act on macrophages in a time-dependent manner: an anti-inflammatory response mediated by TGFβ firstly starts (12 h); successively, the response shifts towards a pro-inflammation IL-1β-mediated (48 h). The response of macrophages is strictly dependent on the SOD1 mutation type. The results suggest that EVs impact physiological and behavioral macrophage processes and are of potential relevance to MN degeneration.}, } @article {pmid38927616, year = {2024}, author = {Wang, H and Guan, L and Ma, X and Wang, Y and Wang, J and Zhang, P and Deng, M}, title = {Whole-Genome Sequencing Identified a Novel Mutation in the N-Terminal Domain of KIF5A in Chinese Patients with Familial Amyotrophic Lateral Sclerosis.}, journal = {Genes}, volume = {15}, number = {6}, pages = {}, pmid = {38927616}, issn = {2073-4425}, support = {82273915//National Natural Science Foundation of China/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; China ; East Asian People/genetics ; *Kinesins/genetics ; Mutation ; *Mutation, Missense ; Pedigree ; Phenotype ; *Whole Genome Sequencing ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive damage to both upper and lower motor neurons. Genetic factors are known to play a crucial role in ALS, as genetic studies not only advance our comprehension of disease mechanisms but also help unravel the complex phenotypes exhibited by patients. To gain further insights into the genetic landscape of ALS in the Chinese population and explore genotype-phenotype correlations among individuals, we conducted whole-genome sequencing to screen genes in 34 Chinese familial ALS (FALS) probands lacking the most common ALS-associated genes. Within this cohort, we identified a rare heterozygous missense mutation in the N-terminal domain of KIF5A (c.86A>G) in one of the probands. This finding is significant as mutations in the KIF5A gene have been implicated in ALS in European cohorts since 2018, predominantly characterized by C-terminal mutations. Analysis of the clinical phenotype within this familial lineage revealed a delayed onset of symptoms, an extended survival duration, and initial manifestations in both upper limbs. These observations underscore the clinical heterogeneity observed in ALS patients harboring KIF5A mutations. In conclusion, our study contributes to the growing body of evidence linking KIF5A to ALS and enhances our understanding of the intricate genetic landscape of this disease.}, } @article {pmid38927501, year = {2024}, author = {Parvanovova, P and Evinova, A and Grofik, M and Hnilicova, P and Tatarkova, Z and Turcanova-Koprusakova, M}, title = {Mitochondrial Dysfunction in Sporadic Amyotrophic Lateral Sclerosis Patients: Insights from High-Resolution Respirometry.}, journal = {Biomedicines}, volume = {12}, number = {6}, pages = {}, pmid = {38927501}, issn = {2227-9059}, abstract = {Amyotrophic lateral sclerosis is a severe neurodegenerative disease whose exact cause is still unclear. Currently, research attention is turning to the mitochondrion as a critical organelle of energy metabolism. Current knowledge is sufficient to confirm the involvement of the mitochondria in the pathophysiology of the disease, since the mitochondria are involved in many processes in the cell; however, the exact mechanism of involvement is still unclear. We used peripheral blood mononuclear cells isolated from whole fresh blood from patients with amyotrophic lateral sclerosis for measurement and matched an age- and sex-matched set of healthy subjects. The group of patients consisted of patients examined and diagnosed at the neurological clinic of the University Hospital Martin. The set of controls consisted of healthy individuals who were actively searched, and controls were selected on the basis of age and sex. The group consisted of 26 patients with sporadic forms of ALS (13 women, 13 men), diagnosed based on the definitive criteria of El Escorial. The average age of patients was 54 years, and the average age of healthy controls was 56 years. We used a high-resolution O2K respirometry method, Oxygraph-2k, to measure mitochondrial respiration. Basal respiration was lower in patients by 29.48%, pyruvate-stimulated respiration (respiratory chain complex I) was lower by 29.26%, and maximal respiratory capacity was lower by 28.15%. The decrease in succinate-stimulated respiration (respiratory chain complex II) was 26.91%. Our data confirm changes in mitochondrial respiration in ALS patients, manifested by the reduced function of complex I and complex II of the respiratory chain. These defects are severe enough to confirm this disease's hypothesized mitochondrial damage. Therefore, research interest in the future should be directed towards a deeper understanding of the involvement of mitochondria and respiratory complexes in the pathophysiology of the disease. This understanding could develop new biomarkers in diagnostics and subsequent therapeutic interventions.}, } @article {pmid38927130, year = {2024}, author = {Vilardo, B and De Marchi, F and Raineri, D and Manfredi, M and De Giorgis, V and Bebeti, A and Scotti, L and Kustrimovic, N and Cappellano, G and Mazzini, L and Chiocchetti, A}, title = {Shotgun Proteomics Links Proteoglycan-4[+] Extracellular Vesicles to Cognitive Protection in Amyotrophic Lateral Sclerosis.}, journal = {Biomolecules}, volume = {14}, number = {6}, pages = {}, pmid = {38927130}, issn = {2218-273X}, support = {953121//European Union's Horizon 2020 Research and Innovation Program/ ; FOHN//Ministero dell'Istruzione e del Merito/ ; AGING//Ministero dell'Istruzione e del Merito/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/blood ; *Extracellular Vesicles/metabolism ; *Proteomics/methods ; Male ; Middle Aged ; Female ; *Biomarkers/blood/metabolism ; Aged ; Proteoglycans/metabolism ; Cognition ; Case-Control Studies ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder lacking reliable biomarkers for early diagnosis and disease progression monitoring. This study aimed to identify the novel biomarkers in plasmatic extracellular vesicles (EVs) isolated from ALS patients and healthy controls (HCs). A total of 61 ALS patients and 30 age-matched HCs were enrolled in the study and the protein content of circulating EVs was analyzed by shotgun proteomics. The study was divided into a discovery phase (involving 12 ALS and 12 HC patients) and a validation one (involving 49 ALS and 20 HC patients). In the discovery phase, more than 300 proteins were identified, with 32 proteins showing differential regulation in ALS patients compared to HCs. In the validation phase, over 400 proteins were identified, with 20 demonstrating differential regulation in ALS patients compared to HCs. Notably, seven proteins were found to be common to both phases, all of which were significantly upregulated in EVs from ALS patients. Most of them have previously been linked to ALS since they have been detected in the serum or cerebrospinal fluid of ALS patients. Among them, proteoglycan (PRG)-4, also known as lubricin, was of particular interest since it was significantly increased in ALS patients with normal cognitive and motor functions. This study highlights the significance of EVs as a promising avenue for biomarker discovery in ALS. Moreover, it sheds light on the unexpected role of PRG-4 in relation to cognitive status in ALS patients.}, } @article {pmid38926444, year = {2024}, author = {Bhuyan, P and Chatterjee, K}, title = {Estimating prevalence of post-war health disorders using multiple systems data.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {14763}, pmid = {38926444}, issn = {2045-2322}, support = {Category-I Research Project Grant (No. 3878/RP: PSEISMC-RDA HIVS)//Indian Institute of Management Calcutta/ ; Core Research Grant (No. CRG/2019/003204)//Science and Engineering Research Board (SERB), Department of Science & Technology, Government of India/ ; }, mesh = {Humans ; Prevalence ; *Amyotrophic Lateral Sclerosis/epidemiology ; Veterans/statistics & numerical data ; Algorithms ; Monte Carlo Method ; Gulf War ; }, abstract = {Effective surveillance on the long-term public health impact due to war and terrorist attacks remains limited. Such health issues are commonly under-reported, specifically for a large group of individuals. For this purpose, efficient estimation of the size or undercount of the population under the risk of physical and mental health hazards is of utmost necessity. A novel trivariate Bernoulli model is developed allowing heterogeneity among the individuals and dependence between the sources of information, and an estimation methodology using a Monte Carlo-based EM algorithm is proposed. Simulation results show the superiority of the performance of the proposed method over existing competitors and robustness under model mis-specifications. The method is applied to analyse two real case studies on monitoring amyotrophic lateral sclerosis (ALS) cases for the Gulf War veterans and the 9/11 terrorist attack survivors at the World Trade Center, USA. The average annual cumulative incidence rate for ALS disease increases by 33 % and 16 % for deployed and no-deployed military personnel, respectively, after adjusting the undercount. The number of individuals exposed to the risk of physical and mental health effects due to WTC terrorist attacks increased by 42 % . These results provide interesting insights that can assist in effective decision-making and policy formulation for monitoring the health status of post-war survivors.}, } @article {pmid38925911, year = {2024}, author = {De La Cruz, E and Esselin, F and Polge, A and Mouzat, K and Guissart, C}, title = {Most SOD1 mutations are pathogenic, and their identification can lead to early access to treatment.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {12}, pages = {1219-1220}, doi = {10.1136/jnnp-2024-333939}, pmid = {38925911}, issn = {1468-330X}, } @article {pmid38925110, year = {2024}, author = {Wyse-Sookoo, K and Luo, S and Candrea, D and Schippers, A and Tippett, DC and Wester, B and Fifer, M and Vansteensel, MJ and Ramsey, NF and Crone, NE}, title = {Stability of ECoG high gamma signals during speech and implications for a speech BCI system in an individual with ALS: a year-long longitudinal study.}, journal = {Journal of neural engineering}, volume = {21}, number = {4}, pages = {}, pmid = {38925110}, issn = {1741-2552}, support = {T32 EB003383/EB/NIBIB NIH HHS/United States ; UH3 NS114439/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Brain-Computer Interfaces ; Longitudinal Studies ; *Electrocorticography/methods ; *Speech/physiology ; Male ; Gamma Rhythm/physiology ; Middle Aged ; Female ; Electrodes, Implanted ; }, abstract = {Objective.Speech brain-computer interfaces (BCIs) have the potential to augment communication in individuals with impaired speech due to muscle weakness, for example in amyotrophic lateral sclerosis (ALS) and other neurological disorders. However, to achieve long-term, reliable use of a speech BCI, it is essential for speech-related neural signal changes to be stable over long periods of time. Here we study, for the first time, the stability of speech-related electrocorticographic (ECoG) signals recorded from a chronically implanted ECoG BCI over a 12 month period.Approach.ECoG signals were recorded by an ECoG array implanted over the ventral sensorimotor cortex in a clinical trial participant with ALS. Because ECoG-based speech decoding has most often relied on broadband high gamma (HG) signal changes relative to baseline (non-speech) conditions, we studied longitudinal changes of HG band power at baseline and during speech, and we compared these with residual high frequency noise levels at baseline. Stability was further assessed by longitudinal measurements of signal-to-noise ratio, activation ratio, and peak speech-related HG response magnitude (HG response peaks). Lastly, we analyzed the stability of the event-related HG power changes (HG responses) for individual syllables at each electrode.Main Results.We found that speech-related ECoG signal responses were stable over a range of syllables activating different articulators for the first year after implantation.Significance.Together, our results indicate that ECoG can be a stable recording modality for long-term speech BCI systems for those living with severe paralysis.Clinical Trial Information.ClinicalTrials.gov, registration number NCT03567213.}, } @article {pmid38924779, year = {2024}, author = {Bratches, RWR and Cohen, J and Carpenter-Song, E and Mistler, L and Barr, PJ}, title = {The Feasibility and Acceptability of Sharing Video Recordings of Amyotrophic Lateral Sclerosis Clinical Encounters With Patients and Their Caregivers: Pilot Randomized Clinical Trial.}, journal = {JMIR formative research}, volume = {8}, number = {}, pages = {e57519}, pmid = {38924779}, issn = {2561-326X}, support = {T32 HS013852/HS/AHRQ HHS/United States ; }, abstract = {BACKGROUND: Multidisciplinary clinics (MDCs) provide benefits to patients with amyotrophic lateral sclerosis (ALS) and their caregivers, but MDC visits are information-heavy and can last 4 hours, with patients and caregivers meeting with multiple specialists within each MDC visit. There are questions about the effectiveness of current methods of sharing information from MDCs with patients. Video recordings are a promising new method of sharing information that may allow patients and caregivers to revisit the MDC and remind them of clinical recommendations and conversations.

OBJECTIVE: The objective of this trial is to determine the feasibility and acceptability of sharing information through video recordings of ALS MDC visits with patients and caregivers.

METHODS: This study was a randomized, controlled pilot trial with 3 months of follow-up from April 2021 to March 2022 in a rural multidisciplinary neurology clinic. We recruited patients with ALS, their caregivers, and their clinicians. Patients and their caregivers were randomized to either receive their normal after-visit summary (treatment as usual) or to receive their normal after-visit summary and a video recording of their MDC visit (video). Each specialist visit had its own recording and was accessible by patients and caregivers using a secure web-based platform called HealthPAL over a 3-month follow-up period. Primary study outcomes were feasibility and acceptability of the video intervention measured by recruitment rate (target: 70%), percentage of participants watching videos (target: 75%), and the Feasibility of Intervention Measure and Acceptability of Intervention Measure (targets: 3/5). We hypothesized that video recording would be feasible and acceptable to patients and their caregivers.

RESULTS: Of the 30 patients approached, 24 were recruited, while all caregivers (n=21) and clinicians (n=34) approached were recruited. A total of 144 specialist visits were recorded, approximately 12 specialist visits at a median of one MDC visit per patient. Of the recorded patients, 75% (9/12) viewed videos. High median intervention feasibility (4, SD 0.99) and acceptability (4, SD 1.22) of intervention measures were reported by patients and caregivers in the intervention arm. High median intervention feasibility (5, SD 0.21) and acceptability (4.88, SD 0.4) were reported by clinicians. Of the 24 patients, 50% (n=12) did not complete a 3-month follow-up, primarily due to death (n=10).

CONCLUSIONS: Video recording is highly feasible and acceptable for patients, caregivers, and clinicians at a rural ALS clinic. Our level of attrition is a useful benchmark for future studies in MDC populations. Despite high rates of patient death, 1-week assessments highlight the value of recordings for both patients and caregivers.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04719403; https://clinicaltrials.gov/study/NCT04719403.}, } @article {pmid38924719, year = {2024}, author = {Shaw, PJ and Cooper-Knock, J}, title = {Physical Activity as a Risk Factor for Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209689}, doi = {10.1212/WNL.0000000000209689}, pmid = {38924719}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Risk Factors ; *Exercise ; }, } @article {pmid38924713, year = {2024}, author = {Vaage, AM and Meyer, HE and Landgraff, IK and Myrstad, M and Holmøy, T and Nakken, O}, title = {Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis: A Prospective Cohort Study.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209575}, doi = {10.1212/WNL.0000000000209575}, pmid = {38924713}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/physiopathology ; Male ; Female ; Adult ; Middle Aged ; Prospective Studies ; Norway/epidemiology ; *Physical Fitness/physiology ; Risk Factors ; Heart Rate/physiology ; Exercise/physiology ; Cohort Studies ; Proportional Hazards Models ; Motor Activity/physiology ; }, abstract = {BACKGROUND AND OBJECTIVES: Observational studies have demonstrated an increased amyotrophic lateral sclerosis (ALS) risk among professional athletes in various sports. For moderately increased levels of physical activity and fitness, the results are diverging. Through a cohort study, we aimed to assess the relationship between indicators of physical activity and fitness (self-reported physical activity and resting heart rate) and long-term ALS risk.

METHODS: From a large Norwegian cardiovascular health survey (1985-1999), we collected information on self-reported physical activity in leisure time, resting heart rate, and other cardiovascular risk factors. Patients with ALS were identified through health registries covering the whole population. We fitted Cox proportional hazard models to assess the risk of ALS according to levels of self-reported physical activity in 3 categories (1: sedentary; 2: minimum 4 hours per week of walking or cycling; 3: minimum 4 hours per week of recreational sports or hard training), and resting heart rate modeled both on the continuous scale and as quartiles of distribution.

RESULTS: Out of 373,696 study participants (mean 40.9 [SD 1.1] years at inclusion), 504 (41.2% women) developed ALS during a mean follow-up time of 27.2 (SD 5.0) years. Compared with participants with the lowest level of physical activity, the hazard ratio was 0.71 (95% CI 0.53-0.95) for those with the highest level. There were no clear associations between resting heart rate and ALS in the total sample. In men, the hazard ratio of ALS was 0.71 (95% CI 0.53-0.95) for those reporting moderate levels of physical activity and 0.59 (95% CI 0.42-0.84) for those reporting high levels, compared with those reporting low levels. Men with resting heart rate in the lowest quartile had 32% reduced risk of ALS (hazard ratio 0.68, 95% CI 0.49-0.94) compared with those in the second highest quartile. In women, no association was detected between neither self-reported levels of physical activity nor resting heart rate and ALS risk.

DISCUSSION: Indicators of high levels of physical activity and fitness are associated with a reduced risk of ALS more than 30 years later in men, but not in women.}, } @article {pmid38924633, year = {2024}, author = {Wolf, J and Buckley, GJ and Rozanski, EA and Fletcher, DJ and Boller, M and Burkitt-Creedon, JM and Weigand, KA and Crews, M and Fausak, ED and , }, title = {2024 RECOVER Guidelines: Advanced Life Support. Evidence and knowledge gap analysis with treatment recommendations for small animal CPR.}, journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)}, volume = {34 Suppl 1}, number = {}, pages = {44-75}, doi = {10.1111/vec.13389}, pmid = {38924633}, issn = {1476-4431}, support = {//Zoetis Animal Health/ ; //Boehringer Ingelheim Animal Health/ ; }, mesh = {Animals ; Dogs ; Cats ; *Dog Diseases/therapy/drug therapy ; Cardiopulmonary Resuscitation/veterinary/standards ; Cat Diseases/therapy/drug therapy ; Veterinary Medicine/standards ; Heart Arrest/veterinary/therapy ; }, abstract = {OBJECTIVE: To systematically review the evidence and devise clinical recommendations on advanced life support (ALS) in dogs and cats and to identify critical knowledge gaps.

DESIGN: Standardized, systematic evaluation of literature pertinent to ALS following Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Prioritized questions were each reviewed by Evidence Evaluators, and findings were reconciled by ALS Domain Chairs and Reassessment Campaign on Veterinary Resuscitation (RECOVER) Co-Chairs to arrive at treatment recommendations commensurate to quality of evidence, risk:benefit relationship, and clinical feasibility. This process was implemented using an Evidence Profile Worksheet for each question that included an introduction, consensus on science, treatment recommendations, justification for these recommendations, and important knowledge gaps. A draft of these worksheets was distributed to veterinary professionals for comment for 4 weeks prior to finalization.

SETTING: Transdisciplinary, international collaboration in university, specialty, and emergency practice.

RESULTS: Seventeen questions pertaining to vascular access, vasopressors in shockable and nonshockable rhythms, anticholinergics, defibrillation, antiarrhythmics, and adjunct drug therapy as well as open-chest CPR were reviewed. Of the 33 treatment recommendations formulated, 6 recommendations addressed the management of patients with nonshockable arrest rhythms, 10 addressed shockable rhythms, and 6 provided guidance on open-chest CPR. We recommend against high-dose epinephrine even after prolonged CPR and suggest that atropine, when indicated, is used only once. In animals with a shockable rhythm in which initial defibrillation was unsuccessful, we recommend doubling the defibrillator dose once and suggest vasopressin (or epinephrine if vasopressin is not available), esmolol, lidocaine in dogs, and/or amiodarone in cats.

CONCLUSIONS: These updated RECOVER ALS guidelines clarify the approach to refractory shockable rhythms and prolonged CPR. Very low quality of evidence due to absence of clinical data in dogs and cats continues to compromise the certainty with which recommendations can be made.}, } @article {pmid38924627, year = {2024}, author = {Burkitt-Creedon, JM and Boller, M and Fletcher, DJ and Brainard, BM and Buckley, GJ and Epstein, SE and Fausak, ED and Hopper, K and Lane, SL and Rozanski, EA and Wolf, J}, title = {2024 RECOVER Guidelines: Updated treatment recommendations for CPR in dogs and cats.}, journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)}, volume = {34 Suppl 1}, number = {}, pages = {104-123}, doi = {10.1111/vec.13391}, pmid = {38924627}, issn = {1476-4431}, support = {//Boehringer Ingelheim Animal Health/ ; //Zoetis Animal Health/ ; }, mesh = {Dogs ; Animals ; Cats ; *Cardiopulmonary Resuscitation/veterinary/standards/methods ; *Cat Diseases/therapy ; Dog Diseases/therapy ; Heart Arrest/veterinary/therapy ; }, abstract = {OBJECTIVE: After the 2012 Reassessment Campaign on Veterinary Resuscitation (RECOVER) CPR Guidelines, this is an update of evidence-based consensus guidelines for Basic Life Support (BLS), advanced life support (ALS), and periarrest monitoring.

DESIGN: These RECOVER CPR Guidelines were generated using a modified version of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for evidence evaluation and translation of this evidence into clear and actionable clinical instructions. Prioritized clinical questions in the Population, Intervention, Comparator, and Outcome (PICO) format were used as the basis to conduct systematic literature searches by information specialists, to extract information from relevant publications, to assess this evidence for quality, and finally to translate the findings into treatment recommendations. These recommendations were reviewed by the RECOVER writing group and opened for comment by veterinary professionals for 4 weeks.

SETTING: Transdisciplinary, international collaboration in university, specialty, and emergency practice.

RESULTS: A total of 40 worksheets were prepared to evaluate questions across the 3 domains of BLS, ALS and Monitoring, resulting in 90 individual treatment recommendations. High-dose epinephrine is no longer recommended, and atropine, if used, is only administered once. Bag-mask ventilation is prioritized over mouth-to-nose ventilation in nonintubated animals. In addition, an algorithm for initial assessment, an updated CPR algorithm, a rhythm diagnosis tool, and an updated drug dosing table are provided.

CONCLUSIONS: While the majority of the BLS and ALS recommendations remain unchanged, some noteworthy changes were made due to new evidence that emerged over the past 10 years. Indirectness of evidence remains the largest impediment to the certainty of guidelines formulation and underscores an urgent need for more studies in the target species of dogs and cats.}, } @article {pmid38924530, year = {2024}, author = {Deutsch, AJ and Elbasiouny, SM}, title = {Dysregulation of persistent inward and outward currents in spinal motoneurons of symptomatic SOD1-G93A mice.}, journal = {The Journal of physiology}, volume = {602}, number = {15}, pages = {3715-3736}, pmid = {38924530}, issn = {1469-7793}, support = {NS131816-S2/NS/NINDS NIH HHS/United States ; R01 NS131816/NS/NINDS NIH HHS/United States ; AG067758/AG/NIA NIH HHS/United States ; NS091836/NS/NINDS NIH HHS/United States ; R01 NS091836/NS/NINDS NIH HHS/United States ; NS131816/NS/NINDS NIH HHS/United States ; R01 AG067758/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Motor Neurons/physiology ; *Amyotrophic Lateral Sclerosis/physiopathology/genetics/pathology ; Mice ; *Mice, Transgenic ; Spinal Cord/physiology ; Superoxide Dismutase-1/genetics ; Male ; Female ; Mice, Inbred C57BL ; Action Potentials ; }, abstract = {Persistent inward currents (PICs) and persistent outward currents (POCs) regulate the excitability and firing behaviours of spinal motoneurons (MNs). Given their potential role in MN excitability dysfunction in amyotrophic lateral sclerosis (ALS), PICs have been previously studied in superoxide dismutase 1 (SOD1)-G93A mice (the standard animal model of ALS); however, conflicting results have been reported on how the net PIC changes during disease progression. Also, individual PICs and POCs have never been examined before in symptomatic ALS. To fill this gap, we measured the net and individual PIC and POC components of wild-type (WT) and SOD MNs in current clamp and voltage clamp during disease progression (assessed by neuroscores). We show that SOD MNs of symptomatic mice experience a much larger net PIC, relative to WT cells from age-matched littermates. Specifically, the Na[+] and Ca[2+] PICs are larger, whereas the lasting SK-mediated (SKL) POC is smaller than WT (Na[+] PIC is the largest and SKL POC is the smallest components in SOD MNs). We also show that PIC dysregulation is present at symptom onset, is sustained throughout advanced disease stages and is proportional to SOD MN cell size (largest dysregulation is in the largest SOD cells, the most vulnerable in ALS). Additionally, we show that studying disease progression using neuroscores is more accurate than using SOD mouse age, which could lead to misleading statistics and age-based trends. Collectively, this study contributes novel PIC and POC data, reveals ionic mechanisms contributing to the vulnerability differential among MN types/sizes, and provides insights on the roles PIC and POC mechanisms play in MN excitability dysfunction in ALS. KEY POINTS: Individual persistent inward currents (PICs) and persistent outward currents (POCs) have never been examined before in spinal motoneurons (MNs) of symptomatic amyotrophic lateral sclerosis (ALS) mice. Thus, we contribute novel PIC and POC data to the ALS literature. Male SOD MNs of symptomatic mice have elevated net PIC, with larger Na[+] and Ca[2+] PICs but reduced SKL POC vs. wild-type littermates. Na[+] PIC is the largest and SKL POC is the smallest current in SOD cells. The PIC/POC dysregulation is present at symptom onset. PIC dysregulation is sustained throughout advanced disease, and is proportional to SOD MN size (largest dysregulation is in the largest cells, the most vulnerable in ALS). Thus, we reveal ionic mechanisms contributing to the vulnerability differential among MN types/sizes in ALS. Studying disease progression using SOD mice neuroscores is more accurate than using age, which could distort the statistical differences between SOD and WT PIC/POC data and the trends during disease progression.}, } @article {pmid38924023, year = {2024}, author = {Spoden, C and Wenzel, O and Erdmann, A and Neitzke, G and Hirschberg, I}, title = {Coping and end-of-life decision-making in ALS: A qualitative interview study.}, journal = {PloS one}, volume = {19}, number = {6}, pages = {e0306102}, pmid = {38924023}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Male ; Female ; Middle Aged ; *Adaptation, Psychological ; *Decision Making ; *Terminal Care/psychology ; Aged ; *Qualitative Research ; Adult ; Germany ; Interviews as Topic ; }, abstract = {How do people with amyotrophic lateral sclerosis (PALS) deal with their diagnosis and engage in end-of-life decision-making? What informational or supportive needs do they have for counselling about life-sustaining treatment and end-of-life care? Which correlating conditions and influences relate to these needs and how do they connect to the wish to die or wish to live? We conducted a qualitative interview study with 13 people with ALS in Germany from March 2019 to April 2021. Data collection and analysis followed a grounded theory-based approach and revealed close relationships between coping, informational needs and the preparedness for decision-making. We identified the coping strategies 'avoid thinking about end-of-life' and its counterpart, 'planning ahead to be well-prepared,' and differentiated the latter into the patterns 'withdrawing from life and taking precautions against life-prolongation' and 'searching for a new meaning in life and preparing for life-sustaining treatment'. The approaches are based on individual perceptions, attitudes and motives and can be positively/negatively reinforced by healthcare professionals (HCP), family and other interpersonal networks, but also by disease progression and in reaction to health care services. Type and degree of needs concerning information and counselling differed according to coping strategies. These strategies may vary over time, resulting in different support needs. Our findings signify that deep insight is needed into PALS' coping processes to understand their decision-making about life-sustaining treatment. Healthcare professionals should be sensitive to illness experiences beyond medical aspects and foster coping as a biographical process to better support people with ALS.}, } @article {pmid38923692, year = {2024}, author = {Snyder, A and Ryan, VH and Hawrot, J and Lawton, S and Ramos, DM and Qi, YA and Johnson, KR and Reed, X and Johnson, NL and Kollasch, AW and Duffy, MF and VandeVrede, L and Cochran, JN and Miller, BL and Toro, C and Bielekova, B and Marks, DS and Yokoyama, JS and Kwan, JY and Cookson, MR and Ward, ME}, title = {An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {20}, number = {8}, pages = {5220-5235}, pmid = {38923692}, issn = {1552-5279}, support = {K01AG049152//NIH National Institute on Aging/ ; K01 AG049152/AG/NIA NIH HHS/United States ; U54NS123985//NIH National Institute of Neurological Disorders and Stroke/ ; ZIAAG000534/AG/NIA NIH HHS/United States ; FI2 GM142475/GM/NIGMS NIH HHS/United States ; //Chan-Zuckerberg Initiative's Neurodegeneration Challenge Network/ ; P30AG062422//NIH National Institute on Aging/ ; ZIA AG000539/ImNIH/Intramural NIH HHS/United States ; 1ZIAAG000539-01//NIH National Institute on Aging/ ; R00 AG068271/AG/NIA NIH HHS/United States ; //Global Brain Health Institute/ ; //NIH Undiagnosed Diseases Program, Undiagnosed Diseases Network/ ; P50 AG023501/AG/NIA NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; R01 AG062588/AG/NIA NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; R00AG068271//NIH National Institute on Aging/ ; P01AG019724//NIH National Institute on Aging/ ; 75N95022C00031/DA/NIDA NIH HHS/United States ; U54 NS123985/NS/NINDS NIH HHS/United States ; U19 AG079774/AG/NIA NIH HHS/United States ; R01AG057234//NIH National Institute on Aging/ ; FI2GM142475//NIH National Institute of General Medical Sciences/ ; P30 AG062422/AG/NIA NIH HHS/United States ; K23AG073514//NIH National Institute on Aging/ ; P01 AG019724/AG/NIA NIH HHS/United States ; 2016-A-005-SUP//Larry L. Hillblom Foundation/ ; //NIH Office of Intramural Training and Education/ ; R01 AG057234/AG/NIA NIH HHS/United States ; //Rainwater Charitable Foundation/ ; //Bluefield Project to Cure Frontotemporal Dementia/ ; //French Foundation/ ; U19AG079774//NIH National Institute on Aging/ ; P50AG023501//NIH National Institute on Aging/ ; ZIA AG000534/ImNIH/Intramural NIH HHS/United States ; //Intramural Research Programs of the National Institute of Neurological Disorders and Stroke/ ; P01AG1972403//NIH National Institute on Aging/ ; //HudsonAlpha Foundation Memory and Mobility Fund/ ; R01AG062588//NIH National Institute on Aging/ ; K23 AG073514/AG/NIA NIH HHS/United States ; //Mary Oakley Foundation/ ; }, mesh = {Humans ; *DNA-Binding Proteins/genetics/metabolism ; *Annexins/genetics ; Male ; Mutation/genetics ; Female ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Neurons/metabolism/pathology ; Frontotemporal Dementia/genetics/pathology ; Middle Aged ; Aged ; }, abstract = {INTRODUCTION: Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene - in a corticobasal syndrome kindred. Established ANXA11 mutations cause ANXA11 aggregation, altered lysosomal-RNA granule co-trafficking, and transactive response DNA binding protein of 43 kDa (TDP-43) mis-localization.

METHODS: We described the clinical presentation and explored the phenotypic diversity of ANXA11 variants. P93S's effect on ANXA11 function and TDP-43 biology was characterized in induced pluripotent stem cell-derived neurons alongside multiomic neuronal and microglial profiling.

RESULTS: ANXA11 mutations were linked to corticobasal syndrome cases. P93S led to decreased lysosome colocalization, neuritic RNA, and nuclear TDP-43 with cryptic exon expression. Multiomic microglial signatures implicated immune dysregulation and interferon signaling pathways.

DISCUSSION: This study establishes ANXA11 P93S pathogenicity, broadens the phenotypic spectrum of ANXA11 mutations, underscores neuronal and microglial dysfunction in ANXA11 pathophysiology, and demonstrates the potential of cellular models to determine variant pathogenicity.

HIGHLIGHTS: ANXA11 P93S is a pathogenic variant. Corticobasal syndrome is part of the ANXA11 phenotypic spectrum. Hybridization chain reaction fluorescence in situ hybridization (HCR FISH) is a new tool for the detection of cryptic exons due to TDP-43-related loss of splicing regulation. Microglial ANXA11 and related immune pathways are important drivers of disease. Cellular models are powerful tools for adjudicating variants of uncertain significance.}, } @article {pmid38923364, year = {2024}, author = {Yang, XD and Gong, B and Chen, W and Chen, JJ and Qian, C and Lu, R and Min, Y and Jiang, T and Li, L and Yu, HQ}, title = {In Situ Quantitative Monitoring of Adsorption from Aqueous Phase by UV-vis Spectroscopy: Implication for Understanding of Heterogeneous Processes.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {11}, number = {32}, pages = {e2402732}, pmid = {38923364}, issn = {2198-3844}, support = {//Program for Changjiang Scholars and Innovative Research Team in University/ ; 51821006//National Natural Science Foundation of China/ ; 52027815//National Natural Science Foundation of China/ ; 52192684//National Natural Science Foundation of China/ ; 22276217//National Natural Science Foundation of China/ ; }, abstract = {The development of in situ techniques to quantitatively characterize the heterogeneous reactions is essential for understanding physicochemical processes in aqueous phase. In this work, a new approach coupling in situ UV-vis spectroscopy with a two-step algorithm strategy is developed to quantitatively monitor heterogeneous reactions in a compact closed-loop incorporation. The algorithm involves the inverse adding-doubling method for light scattering correction and the multivariate curve resolution-alternating least squares (MCR-ALS) method for spectral deconvolution. Innovatively, theoretical spectral simulations are employed to connect MCR-ALS solutions with chemical molecular structural evolution without prior information for reference spectra. As a model case study, the aqueous adsorption kinetics of bisphenol A onto polyamide microparticles are successfully quantified in a one-step UV-vis spectroscopic measurement. The practical applicability of this approach is confirmed by rapidly screening a superior adsorbent from commercial materials for antibiotic wastewater adsorption treatment. The demonstrated capabilities are expected to extend beyond monitoring adsorption systems to other heterogeneous reactions, significantly advancing UV-vis spectroscopic techniques toward practical integration into automated experimental platforms for probing aqueous chemical processes and beyond.}, } @article {pmid38923228, year = {2024}, author = {Koch, T and Fabian, R and Weinhold, L and Koch, FW and Barakat, S and Castro-Gomez, S and Grehl, T and Bernsen, S and Weydt, P}, title = {Cardiac troponin T as a serum biomarker of respiratory impairment in amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {8}, pages = {2063-2072}, pmid = {38923228}, issn = {2328-9503}, support = {//Boris Canessa Foundation/ ; 21060//Alzheimer Forschung Initiative e.V/ ; 2021-1A-12//Hertie Network of Excellence in Clinical Neuroscience/ ; //BONFOR-Forschungskommission der Medizinischen Fakultät Bonn/ ; //Neuro-aCSis Bonn Neuroscience Clinician Scientist Program/ ; EXC2151-390873048//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/physiopathology ; *Troponin T/blood ; Male ; Middle Aged ; Female ; *Biomarkers/blood ; Aged ; Retrospective Studies ; Vital Capacity/physiology ; Respiratory Insufficiency/blood/etiology ; Adult ; Neurofilament Proteins/blood ; }, abstract = {OBJECTIVE: Informative biomarkers are an urgent need in the management of amyotrophic lateral sclerosis. Serum cardiac troponin T is elevated in the majority of amyotrophic lateral sclerosis patients and increases with disease progression. We sought to establish the informative value of cardiac troponin T with regard to respiratory function, a major prognostic factor in amyotrophic lateral sclerosis.

METHODS: In this retrospective observation, we analyzed two independent hospital-based cohorts (d = discovery cohort; v = validation cohort) regarding serum cardiac troponin T (nd = 298; nv = 49), serum neurofilament light chain (nd = 117; nv = 17), and respiratory tests (nd = 93; nv = 49).

RESULTS: Serum cardiac troponin T, in contrast to serum neurofilament levels, was associated with the respiratory domain of the revised amyotrophic lateral sclerosis functional rating scale and with pulmonary function parameters, namely forced vital capacity % (r = -0.45, p = 0.001) and slow vital capacity % (r = -0.50, p = 0.001). Serum cardiac troponin T reliably discriminated benchmarks of slow vital capacity <80% (AUC 0.73, 95% CI 0.62-0.84) and <50% (AUC 0.80, 95% CI 0.68-0.93), forced vital capacity <80% (AUC 0.72, 95% CI 0.61-0.83) and <50% (AUC 0.79, 95% CI 0.67-0.91).

INTERPRETATION: Our findings position cardiac Troponin T as a valuable serum biomarker in amyotrophic lateral sclerosis, complementing neurofilaments and expanding the understanding of underlying physiological mechanisms. In clinical practice, serum cardiac troponin T can flag benchmarks of compromised respiratory function.}, } @article {pmid38922880, year = {2025}, author = {Goldschmidt-Clermont, PJ and Khan, A and Jimsheleishvili, G and Graham, P and Brooks, A and Silvera, R and Goldschmidt, AJP and Pearse, DD and Dietrich, WD and Levi, AD and Guest, JD}, title = {Treating amyotrophic lateral sclerosis with allogeneic Schwann cell-derived exosomal vesicles: a case report.}, journal = {Neural regeneration research}, volume = {20}, number = {4}, pages = {1207-1216}, pmid = {38922880}, issn = {1673-5374}, abstract = {Schwann cells are essential for the maintenance and function of motor neurons, axonal networks, and the neuromuscular junction. In amyotrophic lateral sclerosis, where motor neuron function is progressively lost, Schwann cell function may also be impaired. Recently, important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported. This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles, marking, to our knowledge, the first instance of such treatment. An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis. After initial diagnosis, the patient underwent a combination of generic riluzole, sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis, and taurursodiol. The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function. We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired (senescent) and that exposure of the patient's Schwann cells to allogeneic Schwann cell-derived exosomal vesicles, cultured expanded from a cadaver donor improved their growth capacity in vitro. After a period of observation lasting 10 weeks, during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored, the patient received weekly consecutive infusions of 1.54 × 10 12 (×2), and then consecutive infusions of 7.5 × 10 12 (×6) allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco's phosphate-buffered saline. None of the infusions were associated with adverse events such as infusion reactions (allergic or otherwise) or changes in vital signs. Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend. A more sensitive in-house assay suggested possible inflammasome activation during the disease course. A trend for clinical stabilization was observed during the infusion period. Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles. Initial findings suggest that this approach is safe.}, } @article {pmid38921286, year = {2024}, author = {Katz, L and Gur, A}, title = {Psychosocial Intervention for Family Caregivers of ALS Patients: A Systematic Review.}, journal = {Healthcare (Basel, Switzerland)}, volume = {12}, number = {12}, pages = {}, pmid = {38921286}, issn = {2227-9032}, abstract = {PROPOSAL: This systematic review aims to comprehensively examine all existing knowledge on psychosocial interventions for family caregivers for ALS patients. Also, the study will present the gaps in knowledge, recommendations for future research, and guidelines for psychosocial interventions that are focused and adapted to the needs of family caregivers of ALS patients.

MATERIALS AND METHODS: The systematic review was conducted according to the PRISMA guidelines and identified studies on psychosocial intervention for family caregivers of ALS patients, using five electronic databases: PsychNET, PubMed, EBSCO, PRIMO, and PROQUEST. Seven articles met the criteria and were included in the review. A thematic analysis was conducted to extract major themes.

RESULTS: Three major themes emerged from the data: (1) Personal benefits; (2) Interpersonal benefits; and (3) Charting challenges and pathways to improve psychosocial interventions.

CONCLUSIONS: Based on the findings, practical guidelines were formulated that focus on the group's composition, the facilitator's role, the contents, the relationships within the group, and the opportunities and limitations of online interventions.}, } @article {pmid38921029, year = {2024}, author = {Carata, E and Muci, M and Di Giulio, S and Di Giulio, T and Mariano, S and Panzarini, E}, title = {The Neuromuscular Disorder Mediated by Extracellular Vesicles in Amyotrophic Lateral Sclerosis.}, journal = {Current issues in molecular biology}, volume = {46}, number = {6}, pages = {5999-6017}, pmid = {38921029}, issn = {1467-3045}, abstract = {Amyotrophic lateral sclerosis (ALS) represents a neurodegenerative disorder characterized by the progressive loss of both upper and lower motor neurons, resulting in muscular atrophy and eventual paralysis. While much research has concentrated on investigating the impact of major mutations associated with ALS on motor neurons and central nervous system (CNS) cells, recent studies have unveiled that ALS pathogenesis extends beyond CNS imbalances, encompassing dysregulation in other tissues such as skeletal muscle. Evidence from animal models and patients supports this broader perspective. Skeletal muscle, once considered solely as an effector organ, is now recognized as possessing significant secretory activity capable of influencing motor neuron survival. However, the precise cellular and molecular mechanisms underlying the detrimental effects observed in muscle and its associated structures in ALS remain poorly understood. Additionally, emerging data suggest that extracellular vesicles (EVs) may play a role in the establishment and function of the neuromuscular junction (NMJ) under both physiological and pathological conditions and in wasting and regeneration of skeletal muscles, particularly in neurodegenerative diseases like ALS. This review aims to explore the key findings about skeletal muscle involvement in ALS, shedding light on the potential underlying mechanisms and contributions of EVs and their possible application for the design of biosensors.}, } @article {pmid38920997, year = {2024}, author = {Nowak, I and Paździor, M and Sarna, R and Madej, M}, title = {Molecular Mechanisms in the Design of Novel Targeted Therapies for Neurodegenerative Diseases.}, journal = {Current issues in molecular biology}, volume = {46}, number = {6}, pages = {5436-5453}, pmid = {38920997}, issn = {1467-3045}, abstract = {Neurodegenerative diseases are a diverse group of diseases characterized by a progressive loss of neurological function due to damage to nerve cells in the central nervous system. In recent years, there has been a worldwide increase in the expanding associated with increasing human life expectancy. Molecular mechanisms control many of the essential life processes of cells, such as replication, transcription, translation, protein synthesis and gene regulation. These are complex interactions that form the basis for understanding numerous processes in the organism and developing new diagnostic and therapeutic approaches. In the context of neurodegenerative diseases, molecular basis refers to changes at the molecular level that cause damage to or degeneration of nerve cells. These may include protein aggregates leading to pathological structures in brain cells, impaired protein transport in nerve cells, mitochondrial dysfunction, inflammatory processes or genetic mutations that impair nerve cell function. New medical therapies are based on these mechanisms and include gene therapies, reduction in inflammation and oxidative stress, and the use of miRNAs and regenerative medicine. The aim of this study was to bring together the current state of knowledge regarding selected neurodegenerative diseases, presenting the underlying molecular mechanisms involved, which could be potential targets for new forms of treatment.}, } @article {pmid38920691, year = {2024}, author = {Ilieva, MS}, title = {Non-Coding RNAs in Neurological and Neuropsychiatric Disorders: Unraveling the Hidden Players in Disease Pathogenesis.}, journal = {Cells}, volume = {13}, number = {12}, pages = {}, pmid = {38920691}, issn = {2073-4409}, mesh = {Humans ; *RNA, Untranslated/genetics/metabolism ; *Nervous System Diseases/genetics/metabolism ; *Mental Disorders/genetics/metabolism ; RNA, Circular/genetics/metabolism ; Animals ; RNA, Long Noncoding/genetics/metabolism ; Gene Expression Regulation ; MicroRNAs/genetics/metabolism ; }, abstract = {Neurological and neuropsychiatric disorders pose substantial challenges to public health, necessitating a comprehensive understanding of the molecular mechanisms underlying their pathogenesis. In recent years, the focus has shifted toward the intricate world of non-coding RNAs (ncRNAs), a class of RNA molecules that do not encode proteins but play pivotal roles in gene regulation and cellular processes. This review explores the emerging significance of ncRNAs in the context of neurological and neuropsychiatric disorders, shedding light on their diverse functions and regulatory mechanisms. The dysregulation of various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), has been implicated in the pathophysiology of conditions such as Alzheimer's disease, Parkinson's disease, schizophrenia, and mood disorders. This review delves into the specific roles these ncRNAs play in modulating key cellular processes, including synaptic plasticity, neuroinflammation, and apoptosis, providing a nuanced understanding of their impact on disease progression. Furthermore, it discusses the potential diagnostic and therapeutic implications of targeting ncRNAs in neurological and neuropsychiatric disorders. The identification of specific ncRNA signatures holds promise for the development of novel biomarkers for early disease detection, while the manipulation of ncRNA expression offers innovative therapeutic avenues. Challenges and future directions in the field are also considered, highlighting the need for continued research to unravel the complexities of ncRNA-mediated regulatory networks in the context of neurological and neuropsychiatric disorders. This review aims to provide a comprehensive overview of the current state of knowledge and stimulate further exploration into the fascinating realm of ncRNAs in the brain's intricate landscape.}, } @article {pmid38920626, year = {2024}, author = {Cihankaya, H and Bader, V and Winklhofer, KF and Vorgerd, M and Matschke, J and Stahlke, S and Theiss, C and Matschke, V}, title = {Elevated NLRP3 Inflammasome Activation Is Associated with Motor Neuron Degeneration in ALS.}, journal = {Cells}, volume = {13}, number = {12}, pages = {}, pmid = {38920626}, issn = {2073-4409}, support = {91753179//German Academic Exchange Service/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Motor Neurons/metabolism/pathology ; *Inflammasomes/metabolism ; Mice ; *MicroRNAs/metabolism/genetics ; Spinal Cord/pathology/metabolism ; Disease Models, Animal ; Nerve Degeneration/pathology/metabolism ; Microglia/metabolism/pathology ; Mice, Inbred C57BL ; Caspase 1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration in the central nervous system. Recent research has increasingly linked the activation of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome to ALS pathogenesis. NLRP3 activation triggers Caspase 1 (CASP 1) auto-activation, leading to the cleavage of Gasdermin D (GSDMD) and pore formation on the cellular membrane. This process facilitates cytokine secretion and ultimately results in pyroptotic cell death, highlighting the complex interplay of inflammation and neurodegeneration in ALS. This study aimed to characterize the NLRP3 inflammasome components and their colocalization with cellular markers using the wobbler mouse as an ALS animal model. Firstly, we checked the levels of miR-223-3p because of its association with NLRP3 inflammasome activity. The wobbler mice showed an increased expression of miR-223-3p in the ventral horn, spinal cord, and cerebellum tissues. Next, increased levels of NLRP3, pro-CASP 1, cleaved CASP 1 (c-CASP 1), full-length GSDMD, and cleaved GDSMD revealed NLRP3 inflammasome activation in wobbler spinal cords, but not in the cerebellum. Furthermore, we investigated the colocalization of the aforementioned proteins with neurons, microglia, and astrocyte markers in the spinal cord tissue. Evidently, the wobbler mice displayed microgliosis, astrogliosis, and motor neuron degeneration in this tissue. Additionally, we showed the upregulation of protein levels and the colocalization of NLRP3, c-CASP1, and GSDMD in neurons, as well as in microglia and astrocytes. Overall, this study demonstrated the involvement of NLRP3 inflammasome activation and pyroptotic cell death in the spinal cord tissue of wobbler mice, which could further exacerbate the motor neuron degeneration and neuroinflammation in this ALS mouse model.}, } @article {pmid38918634, year = {2024}, author = {Zhang, N and Westerhaus, A and Wilson, M and Wang, E and Goff, L and Sockanathan, S}, title = {Physiological regulation of neuronal Wnt activity is essential for TDP-43 localization and function.}, journal = {The EMBO journal}, volume = {43}, number = {16}, pages = {3388-3413}, pmid = {38918634}, issn = {1460-2075}, support = {T32GM007445//HHS | National Institutes of Health (NIH)/ ; T32 GM007445/GM/NIGMS NIH HHS/United States ; F31AG072745//HHS | National Institutes of Health (NIH)/ ; R01 AG068043/AG/NIA NIH HHS/United States ; 5RO1AG068043//HHS | National Institutes of Health (NIH)/ ; F31 AG072745/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; *Wnt Signaling Pathway ; *Neurons/metabolism ; Mice ; *Phosphoric Diester Hydrolases/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Active Transport, Cell Nucleus ; Cell Nucleus/metabolism ; }, abstract = {Nuclear exclusion of the RNA- and DNA-binding protein TDP-43 can induce neurodegeneration in different diseases. Diverse processes have been implicated to influence TDP-43 mislocalization, including disrupted nucleocytoplasmic transport (NCT); however, the physiological pathways that normally ensure TDP-43 nuclear localization are unclear. The six-transmembrane enzyme glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) cleaves the glycosylphosphatidylinositol (GPI) anchor that tethers some proteins to the membrane. Here we show that GDE2 maintains TDP-43 nuclear localization by regulating the dynamics of canonical Wnt signaling. Ablation of GDE2 causes aberrantly sustained Wnt activation in adult neurons, which is sufficient to cause NCT deficits, nuclear pore abnormalities, and TDP-43 nuclear exclusion. Disruption of GDE2 coincides with TDP-43 abnormalities in postmortem tissue from patients with amyotrophic lateral sclerosis (ALS). Further, GDE2 deficits are evident in human neural cell models of ALS, which display erroneous Wnt activation that, when inhibited, increases mRNA levels of genes regulated by TDP-43. Our study identifies GDE2 as a critical physiological regulator of Wnt signaling in adult neurons and highlights Wnt pathway activation as an unappreciated mechanism contributing to nucleocytoplasmic transport and TDP-43 abnormalities in disease.}, } @article {pmid38918466, year = {2024}, author = {Bahram Sangani, N and Koetsier, J and Mélius, J and Kutmon, M and Ehrhart, F and Evelo, CT and Curfs, LMG and Reutelingsperger, CP and Eijssen, LMT}, title = {A novel insight into neurological disorders through HDAC6 protein-protein interactions.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {14666}, pmid = {38918466}, issn = {2045-2322}, mesh = {*Histone Deacetylase 6/metabolism/genetics ; Humans ; *Protein Interaction Maps ; Nervous System Diseases/metabolism/genetics ; Alzheimer Disease/metabolism/genetics ; Phosphorylation ; Acetylation ; Parkinson Disease/metabolism/genetics/pathology ; }, abstract = {Due to its involvement in physiological and pathological processes, histone deacetylase 6 (HDAC6) is considered a promising pharmaceutical target for several neurological manifestations. However, the exact regulatory role of HDAC6 in the central nervous system (CNS) is still not fully understood. Hence, using a semi-automated literature screening technique, we systematically collected HDAC6-protein interactions that are experimentally validated and reported in the CNS. The resulting HDAC6 network encompassed 115 HDAC6-protein interactions divided over five subnetworks: (de)acetylation, phosphorylation, protein complexes, regulatory, and aggresome-autophagy subnetworks. In addition, 132 indirect interactions identified through HDAC6 inhibition were collected and categorized. Finally, to display the application of our HDAC6 network, we mapped transcriptomics data of Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis on the network and highlighted that in the case of Alzheimer's disease, alterations predominantly affect the HDAC6 phosphorylation subnetwork, whereas differential expression within the deacetylation subnetwork is observed across all three neurological disorders. In conclusion, the HDAC6 network created in the present study is a novel and valuable resource for the understanding of the HDAC6 regulatory mechanisms, thereby providing a framework for the integration and interpretation of omics data from neurological disorders and pharmacodynamic assessments.}, } @article {pmid38918327, year = {2024}, author = {Sharma, V and Sharma, P and Singh, TG}, title = {Mechanistic insights on TLR-4 mediated inflammatory pathway in neurodegenerative diseases.}, journal = {Pharmacological reports : PR}, volume = {76}, number = {4}, pages = {679-692}, pmid = {38918327}, issn = {2299-5684}, mesh = {Humans ; *Toll-Like Receptor 4/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; *Signal Transduction ; NF-kappa B/metabolism ; Inflammation/metabolism/drug therapy ; }, abstract = {Neurodegenerative diseases (NDDs) pose a significant issue in healthcare, needing a thorough knowledge of their complex molecular mechanisms. A diverse set of cell signaling mediators and their interactions play critical roles in neuroinflammation. The release of pro-inflammatory mediators in response to neural dysfunction is detrimental to normal cell survival. Moreover, the important role of nuclear factor-κB (NF-κB) in the central nervous system through Toll-like receptor (TLR) activation has been well established. Therefore, through a comprehensive review of current research and experimentation, this investigation elucidates the interactions between novel pharmacological agents (TLR-4/NF-κB inhibitors) and neurodegeneration encompassing Alzheimer's, Parkinson's, Huntington's disease, amyotrophic lateral sclerosis and stroke. Insights garnered from this exploration underscore the potential of TLR-4 as a therapeutic target. Through the revelation of these insights, our aim is to establish a foundation for the development of enhanced and focused therapeutic approaches in the continuous endeavor to combat neurodegeneration. This review thus serves as a roadmap, guiding future research endeavors toward innovative strategies for combatting the complex interplay between TLR-4 signaling and NDDs.}, } @article {pmid38917863, year = {2024}, author = {Chou, CZ and Everett, EA and McFarlin, J and Ramanathan, U}, title = {End-of-Life and Hospice Care in Neurologic Diseases.}, journal = {Seminars in neurology}, volume = {44}, number = {5}, pages = {523-533}, doi = {10.1055/s-0044-1787809}, pmid = {38917863}, issn = {1098-9021}, mesh = {Humans ; *Nervous System Diseases/therapy ; *Hospice Care ; *Terminal Care/methods ; Advance Care Planning ; }, abstract = {The care of a patient with neurologic disease at end-of-life requires expertise in addressing advance care planning, hospice, symptom management, and caregiver support. Neurologists caring for patients with advanced neurologic disease often identify changes in disease trajectory, functional status, or goals of care that prompt discussions of advance care planning and hospice. Patients nearing end-of-life may develop symptoms such as dyspnea, secretions, delirium, pain, and seizures. Neurologists may be the primary clinicians managing these symptoms, particularly in the hospitalized patient, though they may also lend their expertise to non-neurologists about expected disease trajectories and symptoms in advanced neurologic disease. This article aims to help neurologists guide patients and caregivers through the end-of-life process by focusing on general knowledge that can be applied across diseases as well as specific considerations in severe stroke and traumatic brain injury, amyotrophic lateral sclerosis, Parkinson's disease, and dementia.}, } @article {pmid38917432, year = {2024}, author = {Atkinson, RAK and Collins, JM and Sreedharan, J and King, AE and Fernandez-Martos, CM}, title = {Alterations to metabolic hormones in amyotrophic lateral sclerosis and frontotemporal dementia postmortem human tissue.}, journal = {Journal of neuropathology and experimental neurology}, volume = {83}, number = {11}, pages = {907-916}, pmid = {38917432}, issn = {1554-6578}, support = {//"la Caixa" Banking Foundation/ ; PR-HR18-000341b//Fundación Luzón/ ; //Victorian Brain Bank/ ; //The Florey, The Alfred, Victorian Institute of Forensic Medicine/ ; //Coroners Court of Victoria/ ; //Fundación Luzón/ ; //The Alfred, Victorian Institute of Forensic Medicine/ ; //Parkinson's Victoria/ ; //FightMND/ ; //Yulgilbar Foundation/ ; //Ian and Maria Cootes/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Male ; Female ; Aged ; *Frontotemporal Dementia/metabolism/pathology/genetics ; Middle Aged ; *Neuropeptide Y/metabolism ; Receptors, Leptin/metabolism/genetics ; Receptor, Insulin/metabolism ; Aged, 80 and over ; Spinal Cord/metabolism/pathology ; RNA, Messenger/metabolism ; Motor Cortex/metabolism/pathology ; Antigens, CD ; }, abstract = {Metabolic changes are observed in patients with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although regulation of metabolic processes in the CNS is predominantly carried out within the hypothalamus, extra-hypothalamic CNS areas contain metabolic hormone receptors, including those for leptin (LEPR), insulin (INSR), and neuropeptide Y (NPY), indicating that they may play a role in biological processes underlying pathogenic disease processes. The status of these hormones within regions vulnerable in ALS/FTD is not well described. This study sought to determine whether the expression of these hormones and their receptors is altered in pathology-rich regions in cases of human FTD (superior frontal gyrus and insular cortex) and ALS (primary motor cortex and lumbar spinal cord) with TDP-43 pathology compared to matched healthy controls. LEPR mRNA was increased within the superior frontal gyrus of FTD cases and within primary motor cortex and lumbar spinal cord of ALS cases; INSR mRNA was increased in superior frontal gyrus and insular cortex of FTD cases. NPY protein was decreased in primary motor cortex and lumbar spinal cord of ALS cases. Our results demonstrate that metabolic hormones undergo complex alterations in ALS and FTD and suggest that these hormones could play critical roles in the pathogenesis of these diseases.}, } @article {pmid38917317, year = {2024}, author = {LaBarbera, VA and Gill, E and Hill, NS and Sachs, G}, title = {The Louise Wilcox ALS Clinic at Rhode Island Hospital: 25th Anniversary (1999-2024).}, journal = {Rhode Island medical journal (2013)}, volume = {107}, number = {7}, pages = {51-53}, pmid = {38917317}, issn = {2327-2228}, mesh = {Rhode Island ; Humans ; *Amyotrophic Lateral Sclerosis/history ; Anniversaries and Special Events ; }, } @article {pmid38916909, year = {2024}, author = {Honda, H and Sadashima, S and Yoshimura, M and Sakurada, N and Koyama, S and Yagita, K and Hamasaki, H and Noguchi, H and Arahata, H and Sasagasako, N}, title = {Altered expression of human myxovirus resistance protein A in amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {83}, number = {9}, pages = {745-751}, doi = {10.1093/jnen/nlae052}, pmid = {38916909}, issn = {1554-6578}, mesh = {Humans ; *Myxovirus Resistance Proteins/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Female ; Male ; Middle Aged ; Aged ; *Spinal Cord/metabolism/pathology ; Adult ; Aged, 80 and over ; Anterior Horn Cells/pathology/metabolism ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. The etiology of sporadic ALS (sALS) has not yet been clarified. An increasing body of evidence suggests the involvement of viral infections and interferons (IFNs). Human myxovirus resistance protein A (MxA) is an IFN-induced dynamin-like GTPase that acts as a potent antiviral factor. This study examined MxA expression in ALS patient spinal cords using immunohistochemistry. Thirty-two cases of sALS (pathologically proven ALS-TDP), 10 non-ALS, other neurological disease control cases were examined. In most ALS cases, MxA cytoplasmic condensates were observed in the remaining spinal anterior horn neurons. The ALS group had a significantly higher rate of MxA-highly expressing neurons than the non-ALS group. Colocalization of MxA cytoplasmic condensate and transactive response DNA-binding protein 43 kDa (TDP-43)-positive inclusions was rarely observed. Because MxA has antiviral activity induced by IFNs, our results suggest that IFNs are involved in the pathogenesis of ALS in spinal cord anterior horn neurons. Our study also suggests that monitoring viral infections and IFN activation in patients with ALS may be critically important.}, } @article {pmid38916676, year = {2024}, author = {Schaub, A and Erdmann, H and Scholz, V and Timmer, M and Cordts, I and Günther, R and Reilich, P and Abicht, A and Schöberl, F}, title = {Analysis and occurrence of biallelic pathogenic repeat expansions in RFC1 in a German cohort of patients with a main clinical phenotype of motor neuron disease.}, journal = {Journal of neurology}, volume = {271}, number = {9}, pages = {5804-5812}, pmid = {38916676}, issn = {1432-1459}, mesh = {Humans ; *Motor Neuron Disease/genetics ; *Phenotype ; *Replication Protein C/genetics ; Male ; Female ; Cohort Studies ; Germany ; *DNA Repeat Expansion ; Middle Aged ; Aged ; Adult ; }, abstract = {Biallelic pathogenic repeat expansions in RFC1 were recently identified as molecular origin of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) as well as of one of the most common causes of adult-onset ataxia. In the meantime, the phenotypic spectrum has expanded massively and now includes mimics of multiple system atrophy or parkinsonism. After identifying a patient with a clinical diagnosis of amyotrophic lateral sclerosis (ALS) as a carrier of biallelic pathogenic repeat expansions in RFC1, we studied a cohort of 106 additional patients with a clinical main phenotype of motor neuron disease (MND) to analyze whether such repeat expansions are more common in MND patients. Indeed, two additional MND patients (one also with ALS and one with primary lateral sclerosis/PLS) have been identified as carrier of biallelic pathogenic repeat expansions in RFC1 in the absence of another genetic alteration explaining the phenotype, suggesting motor neuron disease as another extreme phenotype of RFC1 spectrum disorder. Therefore, MND might belong to the expanding phenotypic spectrum of pathogenic RFC1 repeat expansions, particularly in those MND patients with additional features such as sensory and/or autonomic neuropathy, vestibular deficits, or cerebellar signs. By systematically analyzing the RFC1 repeat array using Oxford nanopore technology long-read sequencing, our study highlights the high intra- and interallelic heterogeneity of this locus and allows the identification of the novel repeat motif 'ACAAG'.}, } @article {pmid38915796, year = {2024}, author = {Thonhoff, JR and Beers, DR and Zhao, W and Faridar, A and Thome, A and Wen, S and Zhang, A and Wang, J and Appel, SH}, title = {A phase 1 proof-of-concept study evaluating safety, tolerability, and biological marker responses with combination therapy of CTLA4-Ig and interleukin-2 in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1415106}, pmid = {38915796}, issn = {1664-2295}, abstract = {OBJECTIVE: To determine whether a combination therapy with abatacept (CTLA4-Ig) and interleukin-2 (IL-2) is safe and suppresses markers of oxidative stress, inflammation, and degeneration in ALS.

METHODS: In this open-label study, four participants with ALS received subcutaneous injections of low dose IL-2 (1 × 10[6] IU/injection/day) for 5 consecutive days every 2 weeks and one subcutaneous injection of CTLA4-Ig (125 mg/mL/injection) every 2 weeks coinciding with the first IL-2 injection of each treatment cycle. Participants received a total of 24 treatment cycles during the first 48 weeks in this 56-week study. They were closely monitored for treatment-emergent adverse events (TEAEs) and disease progression with the ALSFRS-R. Phenotypic changes within T cell populations and serum biological markers of oxidative stress [4-hydroxynonenal (4-HNE) and oxidized-LDL (ox-LDL)], inflammation (IL-18), and structural neuronal degeneration [neurofilament light chain (Nf-L)] were assessed longitudinally.

RESULTS: CTLA4-Ig/IL-2 therapy was safe and well-tolerated in all four participants over the 56-week study. During the first 24 weeks, the average rate of change in the ALSFRS-R was +0.04 points/month. Over the 48-week treatment period, the average rate of change was -0.13 points/month with one participant improving by 0.9 points/month while the other three participants experienced an average decrease of -0.47 points/month, which is slower than the average - 1.1 points/month prior to initiation of therapy. Treg suppressive function and numbers increased during treatment. Responses in the biological markers during the first 16 weeks coincided with minimal clinical progression. Mean levels of 4-HNE decreased by 30%, ox-LDL decreased by 19%, IL-18 decreased by 23%, and Nf-L remained the same, on average, in all four participants. Oxidized-LDL levels decreased in all four participants, 4-HNE and IL-18 levels decreased in three out of four participants, and Nf-L decreased in two out of four participants.

CONCLUSION: The combination therapy of CTLA4-Ig and IL-2 in ALS is safe and well-tolerated with promising results of clinical efficacy and suppression of biomarkers of oxidative stress, neuroinflammation and neuronal degeneration. In this open-label study, the efficacy as measured by the ALSFRS-R and corresponding biomarkers suggests the therapeutic potential of this treatment and warrants further study in a phase 2 double-blind, placebo-controlled trial.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT06307301.}, } @article {pmid38915767, year = {2024}, author = {Ambrosini, A and Dalla Bella, E and Ravasi, M and Melazzini, M and Lauria, G}, title = {New clinical insight in amyotrophic lateral sclerosis and innovative clinical development from the non-profit repurposing trial of the old drug guanabenz.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1407912}, pmid = {38915767}, issn = {2296-858X}, abstract = {Drug repurposing is considered a valid approach to accelerate therapeutic solutions for rare diseases. However, it is not as widely applied as it could be, due to several barriers that discourage both industry and academic institutions from pursuing this path. Herein we present the case of an academic multicentre study that considered the repurposing of the old drug guanabenz as a therapeutic strategy in amyotrophic lateral sclerosis. The difficulties encountered are discussed as an example of the barriers that academics involved in this type of study may face. Although further development of the drug for this target population was hampered for several reasons, the study was successful in many ways. Firstly, because the hypothesis tested was confirmed in a sub-population, leading to alternative innovative solutions that are now under clinical investigation. In addition, the study was informative and provided new insights into the disease, which are now giving new impetus to laboratory research. The message from this example is that even a repurposing study with an old product has the potential to generate innovation and interest from industry partners, provided it is based on a sound rationale, the study design is adequate to ensure meaningful results, and the investigators keep the full clinical development picture in mind.}, } @article {pmid38915526, year = {2024}, author = {Mackness, BC and Morgan, BR and Deveau, LM and Kathuria, SV and Zitzewitz, JA and Massi, F}, title = {A hydrophobic core stabilizes the residual structure in the RRM2 intermediate state of the ALS-linked protein TDP-43.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.12.598648}, pmid = {38915526}, issn = {2692-8205}, abstract = {Folding intermediates mediate both protein folding and the misfolding and aggregation observed in human diseases, including amyotrophic lateral sclerosis (ALS), and are prime targets for therapeutic interventions. In this study, we identified the core nucleus of structure for a folding intermediate in the second RNA recognition motif (RRM2) of the ALS-linked RNA-binding protein, TDP-43, using a combination of experimental and computational approaches. Urea equilibrium unfolding studies revealed that the RRM2 intermediate state consists of collapsed residual secondary structure localized to the N-terminal half of RRM2, while the C-terminus is largely disordered. Steered molecular dynamics simulations and mutagenesis studies yielded key stabilizing hydrophobic contacts that, when mutated to alanine, severely disrupt the overall fold of RRM2. In combination, these findings suggest a role for this RRM intermediate in normal TDP-43 function as well as serving as a template for misfolding and aggregation through the low stability and non-native secondary structure.}, } @article {pmid38914810, year = {2024}, author = {Manchia, M and Paribello, P and Pinna, M and Steardo, L and Carpiniello, B and Pinna, F and Pisanu, C and Squassina, A and Hajek, T}, title = {Lithium and its effects: does dose matter?.}, journal = {International journal of bipolar disorders}, volume = {12}, number = {1}, pages = {23}, pmid = {38914810}, issn = {2194-7511}, abstract = {BACKGROUND: Decades of clinical research have demonstrated the efficacy of lithium in treating acute episodes (both manic and depressive), as well as in preventing recurrences of bipolar disorder (BD). Specific to lithium is its antisuicidal effect, which appears to extend beyond its mood-stabilizing properties. Lithium's clinical effectiveness is, to some extent, counterbalanced by its safety and tolerability profile. Indeed, monitoring of lithium levels is required by its narrow therapeutic index. There is consensus that adequate serum levels should be above 0.6 mEq/L to achieve clinical effectiveness. However, few data support the choice of this threshold, and increasing evidence suggests that lithium might have clinical and molecular effects at much lower concentrations.

CONTENT: This narrative review is aimed at: (1) reviewing and critically interpreting the clinical evidence supporting the use of the 0.6 mEq/L threshold, (2) reporting a narrative synthesis of the evidence supporting the notion that lithium might be effective in much lower doses. Among these are epidemiological studies of lithium in water, evidence on the antisuicidal, anti-aggressive, and neuroprotective effects, including efficacy in preventing cognitive impairment progression, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS), of lithium; and (3) revieweing biological data supporting clinically viable uses of lithium at low levels with the delineation of a mechanistic hypothesis surrounding its purported mechanism of action. The study selection was based on the authors' preference, reflecting the varied and extensive expertise on the review subject, further enriched with an extensive pearl-growing strategy for relevant reviews and book sections.

CONCLUSIONS: Clinical and molecular effects of lithium are numerous, and its effects also appear to have a certain degree of specificity related to the dose administered. In sum, the clinical effects of lithium are maximal for mood stabilisation at concentrations higher than 0.6 mEq/l. However, lower levels may be sufficient for preventing depressive recurrences in older populations of patients, and microdoses could be effective in decreasing suicide risk, especially in patients with BD. Conversely, lithium's ability to counteract cognitive decline appears to be exerted at subtherapeutic doses, possibly corresponding to its molecular neuroprotective effects. Indeed, lithium may reduce inflammation and induce neuroprotection even at doses several folds lower than those commonly used in clinical settings. Nevertheless, findings surrounding its purported mechanism of action are missing, and more research is needed to investigate the molecular targets of low-dose lithium adequately.}, } @article {pmid38914784, year = {2024}, author = {Sang, A and Zhuo, S and Bochanis, A and Manautou, JE and Bahal, R and Zhong, XB and Rasmussen, TP}, title = {Mechanisms of Action of the US Food and Drug Administration-Approved Antisense Oligonucleotide Drugs.}, journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy}, volume = {38}, number = {4}, pages = {511-526}, pmid = {38914784}, issn = {1179-190X}, support = {R01 HL147028/HL/NHLBI NIH HHS/United States ; R35 GM140862/GM/NIGMS NIH HHS/United States ; R35GM140862/GM/NIGMS NIH HHS/United States ; R01HL147028/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use/pharmacology ; United States ; *United States Food and Drug Administration ; *Drug Approval ; RNA, Messenger/genetics/metabolism ; Animals ; RNA Splicing/drug effects ; }, abstract = {Antisense oligonucleotides (ASOs) are single stranded nucleic acids that target RNA. The US Food and Drug Administration has approved ASOs for several diseases. ASOs utilize three principal modes of action (MOA). The first MOA is initiated by base-pairing between the ASO and its target mRNA, followed by RNase H-dependent mRNA degradation. The second MOA is triggered by ASOs that occlude splice acceptor sites in pre-mRNAs leading to skipping of a mutation-bearing exon. The third MOA involves ASOs that sterically hinder mRNA function, often inhibiting translation. ASOs contain a variety of modifications to the sugar-phosphate backbone and bases that stabilize the ASO or render them resistant to RNase activity. RNase H-dependent ASOs include inotersen and eplontersen (for hereditary transthyretin amyloidosis), fomiversen (for opportunistic cytomegalovirus infection), mipomersen (for familial hypercholesterolemia), and tofersen [for amyotrophic lateral sclerosis (ALS)]. Splice modulating ASOs include nursinersen (for spinal muscular atrophy) and eteplirsen, golodirsen, viltolarsen, and casimersen (all for the treatment of Duchenne muscular dystrophy). In addition, a designer ASO, milasen, was used to treat a single individual afflicted with Batten disease. Since ASO design relies principally upon knowledge of mRNA sequence, the bench to bedside pipeline for ASOs is expedient compared with protein-directed drugs. [Graphical abstract available.].}, } @article {pmid38914219, year = {2024}, author = {Asahina, R and Takahashi, M and Takano, H and Yao, R and Abe, M and Goshima, Y and Ohshima, T}, title = {The role of CRMP4 in LPS-induced neuroinflammation.}, journal = {Brain research}, volume = {1841}, number = {}, pages = {149094}, doi = {10.1016/j.brainres.2024.149094}, pmid = {38914219}, issn = {1872-6240}, mesh = {Animals ; *Lipopolysaccharides/pharmacology ; *Microglia/metabolism/drug effects ; *Mice, Knockout ; *Nerve Tissue Proteins/metabolism/genetics ; Mice ; *Neuroinflammatory Diseases/metabolism/chemically induced ; Inflammation/metabolism/chemically induced ; Interleukin-10/metabolism ; Substantia Nigra/metabolism/drug effects ; Mice, Inbred C57BL ; Corpus Striatum/metabolism/drug effects ; Male ; Microfilament Proteins/metabolism ; Arginase/metabolism ; }, abstract = {Neuroinflammation has been gaining attention as one of the potential causes of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis in recent years. The suppression of excessive proinflammatory responses is expected to be a target for the treatment and prevention of neurodegenerative diseases. Collapsin response mediator protein 4 (CRMP4) is involved in cytoskeleton-associated axonal guidance in the developing brain. Recently, the involvement of CRMP4 in several pathological conditions, including inflammation induced by lipopolysaccharide (LPS), a widely used inflammatory molecule, has been reported. However, the role of CRMP4 in LPS-induced inflammation in vivo remains largely unknown. In this study, we generated microglia-specific CRMP4 knockout mice for the first time and examined the role of CRMP4 in an LPS-induced brain inflammation model. We found that microglia after LPS injection in substantia nigra was significantly reduced in Crmp4[-/-] mice compared to Crmp4[+/+]mice. The increased expression of IL-10 in striatum samples was downregulated in Crmp4[-/-] mice. A significant reduction in Iba1 expression was also observed in microglia-specific Crmp4 knockout mice compared with that in control mice. In contrast, the expression of IL-10 did not change in these mice, whereas arginase 1 (Arg1) expression was significantly suppressed. These results demonstrate the involvement of CRMP4 in LPS-induced inflammation in vivo, that CRMP4 suppresses microglial proliferation in a cell-autonomous manner.}, } @article {pmid38914173, year = {2024}, author = {Tortarolo, M and Re Cecconi, AD and Camporeale, L and Margotta, C and Nardo, G and Pasetto, L and Bonetto, V and Galbiati, M and Crippa, V and Poletti, A and Piccirillo, R and Bendotti, C}, title = {Sunitinib-mediated inhibition of STAT3 in skeletal muscle and spinal cord does not affect the disease in a mouse model of ALS.}, journal = {Neurobiology of disease}, volume = {199}, number = {}, pages = {106576}, doi = {10.1016/j.nbd.2024.106576}, pmid = {38914173}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; *Sunitinib/pharmacology ; *Muscle, Skeletal/drug effects/metabolism/pathology ; *STAT3 Transcription Factor/metabolism/antagonists & inhibitors ; *Mice, Transgenic ; *Indoles/pharmacology ; Mice ; *Disease Models, Animal ; *Spinal Cord/metabolism/drug effects/pathology ; *Mice, Inbred C57BL ; *Pyrroles/pharmacology ; Superoxide Dismutase/metabolism/genetics ; Muscular Atrophy/metabolism/pathology ; Motor Neurons/drug effects/metabolism/pathology ; Disease Progression ; }, abstract = {Variability in disease onset and progression is a hallmark of amyotrophic lateral sclerosis (ALS), both in sporadic and genetic forms. Recently, we found that SOD1-G93A transgenic mice expressing the same amount of mutant SOD1 but with different genetic backgrounds, C57BL/6JOlaHsd and 129S2/SvHsd, show slow and rapid muscle wasting and disease progression, respectively. Here, we investigated the different molecular mechanisms underlying muscle atrophy. Although both strains showed similar denervation-induced degradation of muscle proteins, only the rapidly progressing mice exhibited early and sustained STAT3 activation that preceded atrophy in gastrocnemius muscle. We therefore investigated the therapeutic potential of sunitinib, a tyrosine kinase inhibitor known to inhibit STAT3 and prevent cancer-induced muscle wasting. Although sunitinib treatment reduced STAT3 activation in the gastrocnemius muscle and lumbar spinal cord, it did not preserve spinal motor neurons, improve neuromuscular impairment, muscle atrophy and disease progression in the rapidly progressing SOD1-G93A mice. Thus, the effect of sunitinib is not equally positive in different diseases associated with muscle wasting. Moreover, given the complex role of STAT3 in the peripheral and central compartments of the neuromuscular system, the present study suggests that its broad inhibition may lead to opposing effects, ultimately preventing a potential positive therapeutic action in ALS.}, } @article {pmid38913386, year = {2024}, author = {Shamaskin-Garroway, AM and Shamaskin, J}, title = {Slowing Down-A Family's Experience With ALS.}, journal = {JAMA neurology}, volume = {81}, number = {9}, pages = {907-908}, doi = {10.1001/jamaneurol.2024.1922}, pmid = {38913386}, issn = {2168-6157}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Family/psychology ; Male ; Female ; Middle Aged ; }, } @article {pmid38911266, year = {2024}, author = {Huang, X and Lee, S and Chen, K and Kawaguchi, R and Wiskow, O and Ghosh, S and Frost, D and Perrault, L and Pandey, R and Klim, JR and Boivin, B and Hermawan, C and Livak, KJ and Geschwind, DH and Wainger, BJ and Eggan, KC and Bean, BP and Woolf, CJ}, title = {Downregulation of the silent potassium channel Kv8.1 increases motor neuron vulnerability in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {3}, pages = {fcae202}, pmid = {38911266}, issn = {2632-1297}, support = {P50 HD105351/HD/NICHD NIH HHS/United States ; R35 NS127216/NS/NINDS NIH HHS/United States ; }, abstract = {While voltage-gated potassium channels have critical roles in controlling neuronal excitability, they also have non-ion-conducting functions. Kv8.1, encoded by the KCNV1 gene, is a 'silent' ion channel subunit whose biological role is complex since Kv8.1 subunits do not form functional homotetramers but assemble with Kv2 to modify its ion channel properties. We profiled changes in ion channel expression in amyotrophic lateral sclerosis patient-derived motor neurons carrying a superoxide dismutase 1(A4V) mutation to identify what drives their hyperexcitability. A major change identified was a substantial reduction of KCNV1/Kv8.1 expression, which was also observed in patient-derived neurons with C9orf72 expansion. We then studied the effect of reducing KCNV1/Kv8.1 expression in healthy motor neurons and found it did not change neuronal firing but increased vulnerability to cell death. A transcriptomic analysis revealed dysregulated metabolism and lipid/protein transport pathways in KCNV1/Kv8.1-deficient motor neurons. The increased neuronal vulnerability produced by the loss of KCNV1/Kv8.1 was rescued by knocking down Kv2.2, suggesting a potential Kv2.2-dependent downstream mechanism in cell death. Our study reveals, therefore, unsuspected and distinct roles of Kv8.1 and Kv2.2 in amyotrophic lateral sclerosis-related neurodegeneration.}, } @article {pmid38909659, year = {2024}, author = {Issa, NT and Bunick, CG}, title = {In response to Reynolds et al's "guidelines of care for the management of acne vulgaris".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e113-e114}, doi = {10.1016/j.jaad.2024.05.091}, pmid = {38909659}, issn = {1097-6787}, mesh = {Humans ; *Acne Vulgaris/therapy/diagnosis/drug therapy ; *Practice Guidelines as Topic ; }, } @article {pmid38909349, year = {2024}, author = {Ketabforoush, A and Faghihi, F and Azedi, F and Ariaei, A and Habibi, MA and Khalili, M and Ashtiani, BH and Joghataei, MT and Arnold, WD}, title = {Sodium Phenylbutyrate and Tauroursodeoxycholic Acid: A Story of Hope Turned to Disappointment in Amyotrophic Lateral Sclerosis Treatment.}, journal = {Clinical drug investigation}, volume = {44}, number = {7}, pages = {495-512}, pmid = {38909349}, issn = {1179-1918}, mesh = {Humans ; *Taurochenodeoxycholic Acid/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; *Phenylbutyrates/therapeutic use/pharmacology ; Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {The absence of a definitive cure for amyotrophic lateral sclerosis (ALS) emphasizes the crucial need to explore new and improved treatment approaches for this fatal, progressive, and disabling neurodegenerative disorder. As at the end of 2023, five treatments - riluzole, edaravone, dextromethorphan hydrobromide + quinidine sulfate (DHQ), tofersen, and sodium phenylbutyrate-tauroursodeoxycholic acid (PB-TUDCA) - were FDA approved for the treatment of patients with ALS. Among them PB-TUDCA has been shown to impact DNA processing impairments, mitochondria dysfunction, endoplasmic reticulum stress, oxidative stress, and pathologic folded protein agglomeration defects, which have been associated with ALS pathophysiology. The Phase 2 CENTAUR trial demonstrated significant impact of PB-TUDCA on the ALS Functional Rating Scale-Revised (ALSFRS-R) risk of death, hospitalization, and the need for tracheostomy or permanent assisted ventilation in patients with ALS based on post hoc analyses. More recently, contrasting with the CENTAUR trial results, results from the Phase 3 PHOENIX trial (NCT05021536) showed no change in ALSFRS-R total score at 48 weeks. Consequently, the sponsor company initiated the process with the US FDA and Health Canada to voluntarily withdraw the marketing authorizations for PB-TUDCA. In the present article, we review ALS pathophysiology, with a focus on PB-TUDCA's proposed mechanisms of action and recent clinical trial results and discuss the implications of conflicting trial data for ALS and other neurological disorders.}, } @article {pmid38909342, year = {2024}, author = {Réginault, T and Wibart, P and Mathis, S and Le Masson, G and Pillet, O and Grassion, L}, title = {Factors associated with survival after early at-home NIV initiation in ALS patients.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5590-5597}, pmid = {38909342}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/mortality/physiopathology ; Male ; Female ; *Noninvasive Ventilation ; Middle Aged ; Retrospective Studies ; Aged ; Respiratory Insufficiency/therapy/mortality/etiology ; Home Care Services ; }, abstract = {BACKGROUND: The initiation of early non-invasive ventilation (NIV) often involves a careful balance between tolerance and effectiveness. In amyotrophic lateral sclerosis (ALS) patients, the establishment of a strategy, including the decision to focus on adhering to a cut-off, setting specific targets, or correcting all events, is crucial.

OBJECTIVE: To identify factors at 1 month after early at-home NIV initiation that are associated with improved survival in ALS patients. We explored the impacts of adherence (ADH), quality of treatment, and NIV parameters at 1 month after early at-home NIV initiation on patient survival.

METHODS: We conducted a retrospective study of 184 ALS patients at the Bordeaux ALS Centre for whom NIV was initiated between September 2017 and June 2021, and we collected data for a minimum period of 2 years after the last patient included. The primary outcome was the risk of death according to baseline characteristics of our population and the NIV parameters and monitoring during the early NIV initiation period. The secondary outcomes were association with NIV ADH during the early NIV initiation period on prognosis, and NIV ADH cut-off for good versus poor prognosis.

RESULTS: Among the 178 ALS patients analysed, we found that quality of NIV treatment and device settings did not significantly influence prognosis. However, low ADH was significantly associated with a higher risk of death. The use of NIV for > 5 h/day during the early NIV initiation period was linked to a decreased risk of death [hazard ratio = 0.4; 95% confidence interval: 0.27-0.9].

CONCLUSION: The use of NIV for > 5 h/day during the early NIV initiation period was associated with increased survival.}, } @article {pmid38909069, year = {2024}, author = {Ngo, TD and Kieu, HD and Nguyen, MH and Nguyen, TH and Can, VM and Nguyen, BH and Le, TH}, title = {An EEG & eye-tracking dataset of ALS patients & healthy people during eye-tracking-based spelling system usage.}, journal = {Scientific data}, volume = {11}, number = {1}, pages = {664}, pmid = {38909069}, issn = {2052-4463}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Brain-Computer Interfaces ; *Electroencephalography ; *Eye-Tracking Technology ; }, abstract = {This research presents a dataset consisting of electroencephalogram and eye tracking recordings obtained from six patients with amyotrophic lateral sclerosis (ALS) in a locked-in state and one hundred seventy healthy individuals. The ALS patients exhibited varying degrees of disease progression, ranging from partial mobility and weakened speech to complete paralysis and loss of speech. Despite these physical impairments, the ALS patients retained good eye function, which allowed them to use a virtual keyboard for communication. Data from ALS patients was recorded multiple times at their homes, while data from healthy individuals was recorded once in a laboratory setting. For each data recording, the experimental design involved nine recording sessions per participant, each corresponding to a common human action or demand. This dataset can serve as a valuable benchmark for several applications, such as improving spelling systems with brain-computer interfaces, investigating motor imagination, exploring motor cortex function, monitoring motor impairment progress in patients undergoing rehabilitation, and studying the effects of ALS on cognitive and motor processes.}, } @article {pmid38908354, year = {2024}, author = {Kim, K and Choi, D and Shim, H and Lee, CA}, title = {Effects of gamification in advanced life support training for clinical nurses: A cluster randomized controlled trial.}, journal = {Nurse education today}, volume = {140}, number = {}, pages = {106263}, doi = {10.1016/j.nedt.2024.106263}, pmid = {38908354}, issn = {1532-2793}, mesh = {Humans ; Female ; Adult ; Male ; *COVID-19/nursing ; Cardiopulmonary Resuscitation/education ; Clinical Competence/standards ; Advanced Cardiac Life Support/education ; Games, Experimental ; }, abstract = {BACKGROUND: Cardiopulmonary resuscitation training is a mandatory competency, especially for healthcare professionals. However, the spread of COVID-19 caused a sharp decline in the number of participants on advanced life support training, thereby accelerating the diversification of educational methods. Gamification is an increasingly popular method of diversifying instruction, but its effectiveness remains controversial.

AIM: To evaluate the effectiveness of gamification learning in advanced life support training.

DESIGN: A cluster randomized controlled trial.

SETTING: A single advanced life support training center.

PARTICIPANTS: Clinical nurses who are currently practicing in a hospital.

METHODS: A part of the existing advanced life support course was gamified using Kahoot! platform. Conventional learning and gamified learning were each conducted 11 times, and the level of knowledge after training was assessed. The assessment questions were categorized into advanced life support algorithms, teamwork, and cardiac arrest rhythms.

RESULTS: A total of 267 were enrolled in the study, and 148 and 139 learners were assigned to CL and GL, respectively. There was no difference in post-training knowledge related to teamwork, and cardiac arrest rhythms between the conventional learning and gamified learning groups, but knowledge related to the advanced life support algorithm was low in the gamified learning group.

CONCLUSIONS: Even if the learners are the same, advanced life support gamification training can lead to negative outcomes depending on the simplicity or goal of the training content. To improve the effectiveness of the training, various methods of gamification training should be applied depending on the goal and content of the training.}, } @article {pmid38908196, year = {2024}, author = {Donders, Z and Skorupska, IJ and Willems, E and Mussen, F and Broeckhoven, JV and Carlier, A and Schepers, M and Vanmierlo, T}, title = {Beyond PDE4 inhibition: A comprehensive review on downstream cAMP signaling in the central nervous system.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {177}, number = {}, pages = {117009}, doi = {10.1016/j.biopha.2024.117009}, pmid = {38908196}, issn = {1950-6007}, mesh = {Humans ; *Cyclic AMP/metabolism ; *Phosphodiesterase 4 Inhibitors/pharmacology ; Animals ; *Central Nervous System/drug effects/metabolism ; *Signal Transduction/drug effects ; *Central Nervous System Diseases/drug therapy/metabolism/enzymology ; *Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism ; }, abstract = {Cyclic adenosine monophosphate (cAMP) is a key second messenger that regulates signal transduction pathways pivotal for numerous biological functions. Intracellular cAMP levels are spatiotemporally regulated by their hydrolyzing enzymes called phosphodiesterases (PDEs). It has been shown that increased cAMP levels in the central nervous system (CNS) promote neuroplasticity, neurotransmission, neuronal survival, and myelination while suppressing neuroinflammation. Thus, elevating cAMP levels through PDE inhibition provides a therapeutic approach for multiple CNS disorders, including multiple sclerosis, stroke, spinal cord injury, amyotrophic lateral sclerosis, traumatic brain injury, and Alzheimer's disease. In particular, inhibition of the cAMP-specific PDE4 subfamily is widely studied because of its high expression in the CNS. So far, the clinical translation of full PDE4 inhibitors has been hampered because of dose-limiting side effects. Hence, focusing on signaling cascades downstream activated upon PDE4 inhibition presents a promising strategy, offering novel and pharmacologically safe targets for treating CNS disorders. Yet, the underlying downstream signaling pathways activated upon PDE(4) inhibition remain partially elusive. This review provides a comprehensive overview of the existing knowledge regarding downstream mediators of cAMP signaling induced by PDE4 inhibition or cAMP stimulators. Furthermore, we highlight existing gaps and future perspectives that may incentivize additional downstream research concerning PDE(4) inhibition, thereby providing novel therapeutic approaches for CNS disorders.}, } @article {pmid38908137, year = {2024}, author = {Cain, CN and Synovec, RE}, title = {Enhancing gas chromatography-mass spectrometry resolution and pure analyte discovery using intra-chromatogram elution profile matching.}, journal = {Talanta}, volume = {278}, number = {}, pages = {126453}, doi = {10.1016/j.talanta.2024.126453}, pmid = {38908137}, issn = {1873-3573}, abstract = {Chemometric decomposition methods like multivariate curve resolution-alternating least squares (MCR-ALS) are often employed in gas chromatography-mass spectrometry (GC-MS) to improve analyte identification and quantitation. However, these methods can perform poorly for analytes with a low chromatographic resolution (Rs) and a high degree of spectral contamination from noise and background interferences. Thus, we propose a novel computational algorithm, termed mzCompare, to improve analyte identification and quantitation when coupled to MCR-ALS. The mzCompare method utilizes an underlying requirement that the retention time and peak shape between mass channels (m/z) of the same analyte should be similar. By discovering the selective m/z for a given analyte in a chromatogram, a pure elution profile can be generated and used as an equality constraint in MCR-ALS. The performance of the mzCompare methodology is demonstrated with both experimental and simulated chromatograms. Experimentally, unresolved analytes with a Rs as low as 0.05 could be confidently identified with mzCompare assisted MCR-ALS. Furthermore, application of the mzCompare algorithm to a complex aerospace fuel resulted in the discovery of 335 analytes, a 44 % increase compared to conventional peak detection methods. GC-MS simulations of target-interferent analyte pairs demonstrated that the performance of MCR-ALS deteriorated below a Rs of ∼0.25. However, mzCompare assisted MCR-ALS showed excellent identification and acceptable quantitative accuracy at a Rs of ∼0.02. These results show that the mzCompare algorithm can help analysts overcome modeling ambiguities resulting from the chemometric multiplex disadvantage.}, } @article {pmid38907861, year = {2024}, author = {Yang, T and Wei, Q and Pang, D and Cheng, Y and Huang, J and Lin, J and Xiao, Y and Jiang, Q and Wang, S and Li, C and Shang, H}, title = {Clinical and genetic characteristics of ALS patients with variants in genes regulating DNA methylation.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5556-5566}, pmid = {38907861}, issn = {1432-1459}, support = {82371430//National Natural Science Foundation of China/ ; 2022ZDZX0023//Sichuan Science and Technology Program/ ; YCXJ-JZ-2022-007//Beijing E-town Coorperation & Development Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *DNA Methylation ; Female ; Male ; Middle Aged ; Aged ; China ; Genetic Predisposition to Disease/genetics ; DNA-Binding Proteins/genetics ; Cohort Studies ; Adult ; Dioxygenases ; Genetic Variation ; }, abstract = {BACKGROUND: Aberrant DNA methylation alterations are implicated in amyotrophic lateral sclerosis (ALS). Nevertheless, the influence of genetic variants in genes regulating DNA methylation on ALS patients is not well understood. Therefore, we aim to provide a comprehensive variant profile of genes related to DNA methylation (DNMT1, DNMT3A, DNMT3B, DNMT3L) and demethylation (TET1, TET2, TET3, TDG) and to investigate the association of these variants with ALS.

METHODS: Variants were screened in a cohort of 2240 ALS patients from Southwest China, using controls from the Genome Aggregation Database (n = 9976) and the China Metabolic Analytics Project (n = 10,588). The over-representation of rare variants and their association with ALS risk were evaluated using Fisher's exact test with Bonferroni correction at both allele and gene levels. Kaplan-Meier analysis and Cox regression analysis were employed to explore the relationship between variants and survival.

RESULTS: A total of 210 variants meeting the criteria were identified. Gene-based burden analysis identified a significant increase in ALS risk associated with rare variants in the TET2 gene (OR = 1.95, 95% CI = 1.29-2.88, P = 0.001). Survival analysis demonstrated that patients carrying variants in demethylation-related genes had a higher risk of death compared to those with methylation-related gene variants (HR = 1.29, 95% CI = 1.03-1.86, P = 0.039).

CONCLUSIONS: This study provides a genetic variant profile of genes involved in DNA methylation and demethylation regulation, along with the clinical characteristics of ALS patients carrying these variants. The findings offer genetic evidence implicating disrupted DNA methylation dynamics in ALS.}, } @article {pmid38907103, year = {2024}, author = {Limone, F and Mordes, DA and Couto, A and Joseph, BJ and Mitchell, JM and Therrien, M and Ghosh, SD and Meyer, D and Zhang, Y and Goldman, M and Bortolin, L and Cobos, I and Stevens, B and McCarroll, SA and Kadiu, I and Burberry, A and Pietiläinen, O and Eggan, K}, title = {Single-nucleus sequencing reveals enriched expression of genetic risk factors in extratelencephalic neurons sensitive to degeneration in ALS.}, journal = {Nature aging}, volume = {4}, number = {7}, pages = {984-997}, pmid = {38907103}, issn = {2662-8465}, support = {K08 NS104270/NS/NINDS NIH HHS/United States ; P50 AG005134/AG/NIA NIH HHS/United States ; P50 HD105351/HD/NICHD NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *Neurons/metabolism/pathology ; Risk Factors ; Microglia/metabolism/pathology ; Cell Nucleus/metabolism/genetics ; Oligodendroglia/metabolism/pathology ; Male ; Single-Cell Analysis ; Sequence Analysis, RNA ; Female ; Middle Aged ; Nerve Degeneration/genetics/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive loss of motor function linked to degenerating extratelencephalic neurons/Betz cells (ETNs). The reasons why these neurons are selectively affected remain unclear. Here, to understand the unique molecular properties that may sensitize ETNs to ALS, we performed RNA sequencing of 79,169 single nuclei from cortices of patients and controls. In both patients and unaffected individuals, we found significantly higher expression of ALS risk genes in THY1[+] ETNs, regardless of diagnosis. In patients, this was accompanied by the induction of genes involved in protein homeostasis and stress responses that were significantly induced in a wide collection of ETNs. Examination of oligodendroglial and microglial nuclei revealed patient-specific downregulation of myelinating genes in oligodendrocytes and upregulation of an endolysosomal reactive state in microglia. Our findings suggest that selective vulnerability of extratelencephalic neurons is partly connected to their intrinsic molecular properties sensitizing them to genetics and mechanisms of degeneration.}, } @article {pmid38906677, year = {2024}, author = {Au, WH and Miller-Fleming, L and Sanchez-Martinez, A and Lee, JA and Twyning, MJ and Prag, HA and Raik, L and Allen, SP and Shaw, PJ and Ferraiuolo, L and Mortiboys, H and Whitworth, AJ}, title = {Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes in C9orf72 ALS/FTD models.}, journal = {Life science alliance}, volume = {7}, number = {9}, pages = {}, pmid = {38906677}, issn = {2575-1077}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Oxidative Stress ; *NF-E2-Related Factor 2/metabolism/genetics ; *C9orf72 Protein/genetics/metabolism ; *Mitochondria/metabolism ; Animals ; *Disease Models, Animal ; *Kelch-Like ECH-Associated Protein 1/metabolism/genetics ; Humans ; *Signal Transduction ; *Frontotemporal Dementia/genetics/metabolism ; *Phenotype ; Drosophila Proteins/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Mitophagy/genetics ; Dimethyl Fumarate/pharmacology ; Male ; }, abstract = {Mitochondrial dysfunction is a common feature of C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this is a cause or consequence of the pathogenic process. Analysing multiple aspects of mitochondrial biology across several Drosophila models of C9orf72-ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss of locomotor performance. Notably, only genetic manipulations that reversed the oxidative stress levels were also able to rescue C9orf72 locomotor deficits, supporting a causative link between mitochondrial dysfunction, oxidative stress, and behavioural phenotypes. Targeting the key antioxidant Keap1/Nrf2 pathway, we found that genetic reduction of Keap1 or pharmacological inhibition by dimethyl fumarate significantly rescued the C9orf72-related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in C9orf72 patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. These results indicate that mitochondrial oxidative stress is an important mechanistic contributor to C9orf72 pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for C9orf72-related ALS/FTD.}, } @article {pmid38906263, year = {2024}, author = {Veenstra, J and Ozog, D}, title = {Response to Barbieri, "Response to Veenstra et al's 'benzoyl peroxide use in acne therapy: Evaluating the association with acute myeloid leukemia risk'".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e111-e112}, doi = {10.1016/j.jaad.2024.06.036}, pmid = {38906263}, issn = {1097-6787}, mesh = {Humans ; *Acne Vulgaris/drug therapy ; *Leukemia, Myeloid, Acute/drug therapy/chemically induced ; *Benzoyl Peroxide/therapeutic use/adverse effects ; Dermatologic Agents/adverse effects/therapeutic use ; }, } @article {pmid38906259, year = {2024}, author = {Barbieri, JS}, title = {Response to Veenstra et al's "Benzoyl peroxide use in acne therapy: Evaluating the association with acute myeloid leukemia risk".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e109-e110}, doi = {10.1016/j.jaad.2024.05.090}, pmid = {38906259}, issn = {1097-6787}, mesh = {Humans ; *Acne Vulgaris/drug therapy ; *Leukemia, Myeloid, Acute/drug therapy/chemically induced ; *Benzoyl Peroxide/therapeutic use/adverse effects ; Dermatologic Agents/adverse effects/therapeutic use ; }, } @article {pmid38905535, year = {2024}, author = {}, title = {Addendum: Relyvrio withdrawn.}, journal = {The Medical letter on drugs and therapeutics}, volume = {66}, number = {1704}, pages = {96}, doi = {10.58347/tml.2024.1704e}, pmid = {38905535}, issn = {1523-2859}, mesh = {Humans ; Phenylbutyrates ; }, } @article {pmid38905382, year = {2024}, author = {Jing, Z and Qi, X and Teng, J}, title = {Dietary factors and risk for amyotrophic lateral sclerosis: A two sample mendelian randomization study.}, journal = {Medicine}, volume = {103}, number = {25}, pages = {e38473}, pmid = {38905382}, issn = {1536-5964}, mesh = {*Mendelian Randomization Analysis/methods ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/etiology ; Humans ; *Diet ; Risk Factors ; Fruit ; Genome-Wide Association Study ; Vegetables ; Coffee/adverse effects ; Meat/adverse effects ; }, abstract = {Correlations between dietary factors and amyotrophic lateral sclerosis (ALS) have been found in previous observational studies. However, no further studies have used Mendelian randomization to further explore the causal relationship between dietary factors and ALS. Clarifying these relationships is a crucial part of developing nutritional recommendations for ALS prevention. The exposure and outcome datasets employed in this study were extracted from the IEU Open GWAS project (https://gwas.mrcieu.ac.uk/). The exposure datasets involved in our Mendelian analyses consisted of meat intake (processed meat intake, poultry intake, beef intake, pork intake, non-oily fish intake, and oily fish intake), staple foods intake (bread intake and cereal intake), vegetable intake (cooked vegetable intake, salad/raw vegetable intake), fruit intake (fresh fruit intake and dried fruit intake), and beverage intake (coffee intake and tea intake). The weighted median, MR-Egger, Inverse Variance Weighted, Simple mode and Weighted mode methods were all utilized. And we applied Inverse Variance Weighted method as the main judgement criterion for Mendelian randomization analysis. Heterogeneity and pleiotropy analyses were conducted to confirm the validity of the outcomes. Genetically predicted that oily fish intake (OR: 0.7648; 95% CI: 0.5905-0.9904; P = .0420), coffee intake (OR: 0.7385; 95% CI: 0.5660-0.9637; P = .0256), and fresh fruit intake (OR: 0.6165; 95% CI: 0.4007-0.9487; P = .0278) were causally associated with a decreased risk of ALS. Negative results (P > .05) were received for all other dietary factors. This study found that oily fish intake, coffee intake and fresh fruit intake reduced the risk of developing ALS. Additionally, other factors were not associated with ALS.}, } @article {pmid38905379, year = {2024}, author = {Park, BK and Oh, SI and Kang, M and Seok, HY and Park, JM and Kim, S and Kim, HI and Kim, JA and Park, JS}, title = {Reliability and Validity of the Korean version of the Center for Neurologic Study Bulbar Function Scale (K-CNS-BFS): An observational study.}, journal = {Medicine}, volume = {103}, number = {25}, pages = {e38216}, pmid = {38905379}, issn = {1536-5964}, mesh = {Humans ; Male ; Female ; Republic of Korea ; Middle Aged ; Reproducibility of Results ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; Aged ; *Severity of Illness Index ; Adult ; }, abstract = {Bulbar dysfunction in amyotrophic lateral sclerosis (ALS) significantly affects daily life, leading to weight loss and reduced survival. Methods for evaluating bulbar dysfunction, including videofluoroscopic swallowing studies and the bulbar component of the ALS Functional Rating Scale-Revised (ALSFRS-R), have been employed; however, Korean-specific tools are lacking. The Center for Neurologic Study Bulbar Function Scale (CNS-BFS) comprehensively evaluates bulbar symptoms. This study aimed to develop and validate the Korean version of the CNS-BFS (K-CNS-BFS) to assess bulbar dysfunction in Korean patients with ALS. Twenty-seven patients with ALS were recruited from a tertiary hospital in South Korea based on revised El Escorial criteria. Demographic, clinical, and measurement data were collected. The K-CNS-BFS was evaluated for reliability and validity. Reliability assessment revealed strong internal consistency (Cronbach alpha) for the K-CNS-BFS subscales and total score. Test-retest reliability showed significant correlation. Content validity index was excellent, and convergent validity demonstrated significant correlations between the K-CNS-BFS and relevant measures. Discriminant validity was observed between the K-CNS-BFS and motor/respiratory subscores of the ALSFRS-R. Construct validity demonstrated significant correlations between the K-CNS-BFS subscales and total score. This is the first study to investigate the reliability and validity of the Korean version of the CNS-BFS, which showed consistent and reliable scores that correlated with tests for bulbar or general dysfunction. The K-CNS-BFS effectively measured bulbar dysfunction similar to the original CNS-BFS. The K-CNS-BFS is a reliable and valid tool for assessing bulbar dysfunction in patients with ALS in South Korea.}, } @article {pmid38904901, year = {2024}, author = {Aiello, EN and Torre, S and Solca, F and Curti, B and De Luca, G and Gendarini, C and Cocuzza, A and Colombo, E and Maranzano, A and Verde, F and Morelli, C and Messina, S and Doretti, A and Silani, V and Ticozzi, N and Poletti, B}, title = {Ecological validity of performance-based cognitive screeners in amyotrophic lateral sclerosis: preliminary evidence.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {11}, pages = {5319-5325}, pmid = {38904901}, issn = {1590-3478}, support = {Ministero della Salute//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Male ; Female ; Middle Aged ; *Caregivers/psychology ; Aged ; *Neuropsychological Tests/standards ; Reproducibility of Results ; Cognition Disorders/diagnosis/etiology ; Adult ; }, abstract = {BACKGROUND: This study aimed at preliminarily assessing, in a cohort of non-demented amyotrophic lateral sclerosis (ALS) patients, the ecological validity, and more specifically the veridicality, of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and the ALS Cognitive Behavioral Screen (ALS-CBS™), by relating their scores to caregiver-report ratings of cognitive changes.

METHODS: N = 147 patient-caregiver dyads were recruited. Patients were administered the ECAS and ALS-CBS™, whilst caregiver the Caregiver Behavioral Questionnaire (CBQ) and Beaumont Behavioural Inventory (BBI). An Ecological Cognitive Functioning Index (ECFI) was derived from those items of the CBQ and BBI that tap on executive and language changes. Ecological validity was assessed via both correlational and predictive analyses net of caregiver-rated behavioural changes (as assessed by the ECAS-Carer Interview).

RESULTS: The ECFI was associated with the total scores on both the ECAS (p = .014) and ALS-CBS™ (p = .017). When looking at ECAS and ALS-CBS™ subscales, those assessing verbal fluency were selectively associated with the ECFI. The ECFI was higher in patients performing defectively on the ECAS (p = .004) and on the ALS-CBS™ (p = .027).

DISCUSSION: This study suggests that both the ECAS and the ALS-CBS™ represent a valid estimate of non-demented ALS patients' cognitive status in the real world, also highlighting the clinical relevance of cognitive changes reported by caregivers.}, } @article {pmid38904729, year = {2024}, author = {Portes E Silva, KR and Nogueira, EM and Jesus Mendes, AL and Pena, ALB and Simões E Silva, AC}, title = {The potential role of renin angiotensin system in acute leukemia: a narrative review.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {775}, pmid = {38904729}, issn = {1573-4978}, support = {304496/2023-5//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, mesh = {Humans ; *Renin-Angiotensin System/physiology ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism/pathology ; *Angiotensin II/metabolism ; Leukemia, Myeloid, Acute/metabolism/pathology ; Signal Transduction ; Angiotensin I/metabolism ; Neovascularization, Pathologic/metabolism ; Animals ; Peptide Fragments/metabolism ; }, abstract = {Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components.}, } @article {pmid38903602, year = {2024}, author = {Al-Kuraishy, HM and Jabir, MS and Sulaiman, GM and Mohammed, HA and Al-Gareeb, AI and Albuhadily, AK and Jawad, SF and Swelum, AA and Abomughaid, MM}, title = {The role of statins in amyotrophic lateral sclerosis: protective or not?.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1422912}, pmid = {38903602}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons characterized by muscle weakness, muscle twitching, and muscle wasting. ALS is regarded as the third-most frequent neurodegenerative disease, subsequent to Alzheimer's disease (AD) and Parkinson's disease (PD). The World Health Organization (WHO) in 2007 declared that prolonged use of statins may induce development of ALS-like syndrome and may increase ALS risk. Subsequently, different studies have implicated statins in the pathogenesis of ALS. In contrast, results from preclinical and clinical studies highlighted the protective role of statins against ALS neuropathology. Recently, meta-analyses and systematic reviews illustrated no association between long-term use of statins and ALS risk. These findings highlighted controversial points regarding the effects of statins on ALS pathogenesis and risk. The neuroprotective effects of statins against the development and progression of ALS may be mediated by regulating dyslipidemia and inflammatory changes. However, the mechanism for induction of ALS neuropathology by statins may be related to the dysregulation of liver X receptor signaling (LXR) signaling in the motor neurons and reduction of cholesterol, which has a neuroprotective effect against ALS neuropathology. Nevertheless, the exact role of statins on the pathogenesis of ALS was not fully elucidated. Therefore, this narrative review aims to discuss the role of statins in ALS neuropathology.}, } @article {pmid38903475, year = {2024}, author = {Dash, D and Teplansky, K and Ferrari, P and Babajani-Feremi, A and Calley, CS and Heitzman, D and Austin, SG and Wang, J}, title = {Automatic detection of ALS from single-trial MEG signals during speech tasks: a pilot study.}, journal = {Frontiers in psychology}, volume = {15}, number = {}, pages = {1114811}, pmid = {38903475}, issn = {1664-1078}, abstract = {Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, and fast-progressive neurodegenerative disease characterized by the degeneration of motor neurons. ALS patients often experience an initial misdiagnosis or a diagnostic delay due to the current unavailability of an efficient biomarker. Since impaired speech is typical in ALS, we hypothesized that functional differences between healthy and ALS participants during speech tasks can be explained by cortical pattern changes, thereby leading to the identification of a neural biomarker for ALS. In this pilot study, we collected magnetoencephalography (MEG) recordings from three early-diagnosed patients with ALS and three healthy controls during imagined (covert) and overt speech tasks. First, we computed sensor correlations, which showed greater correlations for speakers with ALS than healthy controls. Second, we compared the power of the MEG signals in canonical bands between the two groups, which showed greater dissimilarity in the beta band for ALS participants. Third, we assessed differences in functional connectivity, which showed greater beta band connectivity for ALS than healthy controls. Finally, we performed single-trial classification, which resulted in highest performance with beta band features (∼ 98%). These findings were consistent across trials, phrases, and participants for both imagined and overt speech tasks. Our preliminary results indicate that speech-evoked beta oscillations could be a potential neural biomarker for diagnosing ALS. To our knowledge, this is the first demonstration of the detection of ALS from single-trial neural signals.}, } @article {pmid38903116, year = {2024}, author = {Matera, AG and Steiner, RE and Mills, CA and Herring, LE and Garcia, EL}, title = {Chaperoning the chaperones: Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38903116}, issn = {2692-8205}, support = {P30 CA016086/CA/NCI NIH HHS/United States ; R35 GM136435/GM/NIGMS NIH HHS/United States ; }, abstract = {Molecular chaperones and co-chaperones are highly conserved cellular components that perform variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN. The Survival Motor Neuron (SMN) complex is an RNP assembly chaperone and serves as a paradigm for studying how specific small nuclear (sn)RNAs are identified and paired with their client substrate proteins. SMN protein is the eponymous component of a large complex required for the biogenesis of uridine-rich small nuclear ribonucleoproteins (U-snRNPs) and localizes to distinct membraneless organelles in both the nucleus and cytoplasm of animal cells. SMN forms the oligomeric core of this complex, and missense mutations in its YG box self-interaction domain are known to cause Spinal Muscular Atrophy (SMA). The basic framework for understanding how snRNAs are assembled into U-snRNPs is known, the pathways and mechanisms used by cells to regulate their biogenesis are poorly understood. Given the importance of these processes to normal development as well as neurodegenerative disease, we set out to identify and characterize novel SMN binding partners. Here, we carried out affinity purification mass spectrometry (AP-MS) of SMN using stable fly lines exclusively expressing either wildtype or SMA-causing missense alleles. Bioinformatic analyses of the pulldown data, along with comparisons to proximity labeling studies carried out in human cells, revealed conserved connections to at least two other major chaperone systems including heat shock folding chaperones (HSPs) and histone/nucleosome assembly chaperones. Notably, we found that heat shock cognate protein Hsc70-4 and other HspA family members preferentially interacted with SMA-causing alleles of SMN. Hsc70-4 is particularly interesting because its mRNA is aberrantly sequestered by a mutant form of TDP-43 in mouse and Drosophila ALS (Amyotrophic Lateral Sclerosis) disease models. Most important, a missense allele of Hsc70-4 (HspA8 in mammals) was recently identified as a bypass suppressor of the SMA phenotype in mice. Collectively, these findings suggest that chaperone-related dysfunction lies at the etiological root of both ALS and SMA.}, } @article {pmid38902980, year = {2024}, author = {Dratch, L and Kinnamon, DD and Harrington, EA and Goldman, J and Fong, JC and Jones, T and Uhlmann, WR and Roggenbuck, J}, title = {Response to "assessment of risk of ALS conferred by the GGGGCC hexanucleotide expansion in C9orf72 among first-degree relatives of patients with ALS carrying the repeat expansion".}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {797-799}, doi = {10.1080/21678421.2024.2362854}, pmid = {38902980}, issn = {2167-9223}, } @article {pmid38902734, year = {2024}, author = {Hu, Y and Hruscha, A and Pan, C and Schifferer, M and Schmidt, MK and Nuscher, B and Giera, M and Kostidis, S and Burhan, Ö and van Bebber, F and Edbauer, D and Arzberger, T and Haass, C and Schmid, B}, title = {Mis-localization of endogenous TDP-43 leads to ALS-like early-stage metabolic dysfunction and progressive motor deficits.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {50}, pmid = {38902734}, issn = {1750-1326}, mesh = {Animals ; *Zebrafish ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Disease Models, Animal ; *Motor Neurons/metabolism/pathology ; *Zebrafish Proteins/metabolism/genetics ; Animals, Genetically Modified ; Neuromuscular Junction/metabolism/pathology ; }, abstract = {BACKGROUND: The key pathological signature of ALS/ FTLD is the mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm. However, TDP-43 gain of function in the cytoplasm is still poorly understood since TDP-43 animal models recapitulating mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm are missing.

METHODS: CRISPR/Cas9 technology was used to generate a zebrafish line (called CytoTDP), that mis-locates endogenous TDP-43 from the nucleus to the cytoplasm. Phenotypic characterization of motor neurons and the neuromuscular junction was performed by immunostaining, microglia were immunohistochemically localized by whole-mount tissue clearing and muscle ultrastructure was analyzed by scanning electron microscopy. Behavior was investigated by video tracking and quantitative analysis of swimming parameters. RNA sequencing was used to identify mis-regulated pathways with validation by molecular analysis.

RESULTS: CytoTDP fish have early larval phenotypes resembling clinical features of ALS such as progressive motor defects, neurodegeneration and muscle atrophy. Taking advantage of zebrafish's embryonic development that solely relys on yolk usage until 5 days post fertilization, we demonstrated that microglia proliferation and activation in the hypothalamus is independent from food intake. By comparing CytoTDP to a previously generated TDP-43 knockout line, transcriptomic analyses revealed that mis-localization of endogenous TDP-43, rather than TDP-43 nuclear loss of function, leads to early onset metabolic dysfunction.

CONCLUSIONS: The new TDP-43 model mimics the ALS/FTLD hallmark of progressive motor dysfunction. Our results suggest that functional deficits of the hypothalamus, the metabolic regulatory center, might be the primary cause of weight loss in ALS patients. Cytoplasmic gain of function of endogenous TDP-43 leads to metabolic dysfunction in vivo that are reminiscent of early ALS clinical non-motor metabolic alterations. Thus, the CytoTDP zebrafish model offers a unique opportunity to identify mis-regulated targets for therapeutic intervention early in disease progression.}, } @article {pmid38902629, year = {2024}, author = {Takemoto, Y and Ito, D and Komori, S and Kishimoto, Y and Yamada, S and Hashizume, A and Katsuno, M and Nakatochi, M}, title = {Comparing preprocessing strategies for 3D-Gene microarray data of extracellular vesicle-derived miRNAs.}, journal = {BMC bioinformatics}, volume = {25}, number = {1}, pages = {221}, pmid = {38902629}, issn = {1471-2105}, support = {JP21wm0425013//Japan Agency for Medical Research and Development/ ; 23H00420//Japan Society for the Promotion of Science/ ; 16H06277//Japan Society for the Promotion of Science/ ; }, mesh = {*Extracellular Vesicles/metabolism/genetics ; *MicroRNAs/genetics/metabolism ; Humans ; *Oligonucleotide Array Sequence Analysis/methods ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Gene Expression Profiling/methods ; }, abstract = {BACKGROUND: Extracellular vesicle-derived (EV)-miRNAs have potential to serve as biomarkers for the diagnosis of various diseases. miRNA microarrays are widely used to quantify circulating EV-miRNA levels, and the preprocessing of miRNA microarray data is critical for analytical accuracy and reliability. Thus, although microarray data have been used in various studies, the effects of preprocessing have not been studied for Toray's 3D-Gene chip, a widely used measurement method. We aimed to evaluate batch effect, missing value imputation accuracy, and the influence of preprocessing on measured values in 18 different preprocessing pipelines for EV-miRNA microarray data from two cohorts with amyotrophic lateral sclerosis using 3D-Gene technology.

RESULTS: Eighteen different pipelines with different types and orders of missing value completion and normalization were used to preprocess the 3D-Gene microarray EV-miRNA data. Notable results were suppressed in the batch effects in all pipelines using the batch effect correction method ComBat. Furthermore, pipelines utilizing missForest for missing value imputation showed high agreement with measured values. In contrast, imputation using constant values for missing data exhibited low agreement.

CONCLUSIONS: This study highlights the importance of selecting the appropriate preprocessing strategy for EV-miRNA microarray data when using 3D-Gene technology. These findings emphasize the importance of validating preprocessing approaches, particularly in the context of batch effect correction and missing value imputation, for reliably analyzing data in biomarker discovery and disease research.}, } @article {pmid38902525, year = {2024}, author = {Kitamura, A and Fujimoto, A and Kawashima, R and Lyu, Y and Sasaki, K and Hamada, Y and Moriya, K and Kurata, A and Takahashi, K and Brielmann, R and Bott, LC and Morimoto, RI and Kinjo, M}, title = {Hetero-oligomerization of TDP-43 carboxy-terminal fragments with cellular proteins contributes to proteotoxicity.}, journal = {Communications biology}, volume = {7}, number = {1}, pages = {743}, pmid = {38902525}, issn = {2399-3642}, support = {JP22gm6410028//Japan Agency for Medical Research and Development (AMED)/ ; JP22ym0126814//Japan Agency for Medical Research and Development (AMED)/ ; 24H02286//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22H04826//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 16KK0156//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 18K06201//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22H02578//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22K19886//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JPMJSP2119//MEXT | Japan Science and Technology Agency (JST)/ ; JPMJFS2101//MEXT | Japan Science and Technology Agency (JST)/ ; }, mesh = {*DNA-Binding Proteins/metabolism/chemistry/genetics ; Humans ; Animals ; Protein Multimerization ; Caenorhabditis elegans/metabolism/genetics ; Intrinsically Disordered Proteins/chemistry/metabolism/genetics ; }, abstract = {Carboxy terminal fragments (CTFs) of TDP-43 contain an intrinsically disordered region (IDR) and form cytoplasmic condensates containing amyloid fibrils. Such condensates are toxic and associated with pathogenicity in amyotrophic lateral sclerosis. However, the molecular details of how the domain of TDP-43 CTFs leads to condensation and cytotoxicity remain elusive. Here, we show that truncated RNA/DNA-recognition motif (RRM) at the N-terminus of TDP-43 CTFs leads to the structural transition of the IDR, whereas the IDR itself of TDP-43 CTFs is difficult to assemble even if they are proximate intermolecularly. Hetero-oligomers of TDP-43 CTFs that have recruited other proteins are more toxic than homo-oligomers, implicating loss-of-function of the endogenous proteins by such oligomers is associated with cytotoxicity. Furthermore, such toxicity of TDP-43 CTFs was cell-nonautonomously affected in the nematodes. Therefore, misfolding and oligomeric characteristics of the truncated RRM at the N-terminus of TDP-43 CTFs define their condensation properties and toxicity.}, } @article {pmid38901111, year = {2024}, author = {Pavey, NA and Menon, P and Peterchev, AV and Kiernan, MC and Vucic, S}, title = {Abnormalities of cortical stimulation strength-duration time constant in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {164}, number = {}, pages = {161-167}, pmid = {38901111}, issn = {1872-8952}, support = {R01 MH128422/MH/NIMH NIH HHS/United States ; R01 NS117405/NS/NINDS NIH HHS/United States ; RF1 MH124943/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; *Transcranial Magnetic Stimulation/methods ; Middle Aged ; *Motor Cortex/physiopathology ; Aged ; *Evoked Potentials, Motor/physiology ; Adult ; Motor Neurons/physiology ; }, abstract = {OBJECTIVES: Strength-duration time constant (SDTC) may now be determined for cortical motor neurones, with activity mediated by transient Na[+] conductances. The present study determined whether cortical SDTC is abnormal and linked to the pathogenesis of amyotrophic lateral sclerosis.

METHODS: Cortical SDTC and rheobase were estimated from 17 ALS patients using a controllable pulse parameter transcranial magnetic stimulation (cTMS) device. Resting motor thresholds (RMTs) were determined at pulse widths (PW) of 30, 45, 60, 90 and 120 µs and M-ratio of 0.1, using a figure-of-eight coil applied to the primary motor cortex.

RESULTS: SDTC was significantly reduced in ALS patients (150.58 ± 9.98 µs; controls 205.94 ± 13.7 µs, P < 0.01). The reduced SDTC correlated with a rate of disease progression (Rho = -0.440, P < 0.05), ALS functional rating score (ALSFRS-R) score (Rho = 0.446, P < 0.05), and disease duration (R = 0.428, P < 0.05). The degree of change in SDTC was greater in patients with cognitive abnormalities as manifested by an abnormal total Edinburgh Cognitive ALS Screen score (140.5 ± 28.7 µs, P < 0.001) and ALS-specific subscore (141.7 ± 33.2 µs, P = 0.003).

CONCLUSIONS: Cortical SDTC reduction was associated with a more aggressive ALS phenotype, or with more prominent cognitive impairment.

SIGNIFICANCE: An increase in transient Na[+] conductances may account for the reduction in SDTC, linked to the pathogenesis of ALS.}, } @article {pmid38900989, year = {2024}, author = {Tahedl, M and Tan, EL and Kleinerova, J and Delaney, S and Hengeveld, JC and Doherty, MA and Mclaughlin, RL and Pradat, PF and Raoul, C and Ango, F and Hardiman, O and Chang, KM and Lope, J and Bede, P}, title = {Progressive Cerebrocerebellar Uncoupling in Sporadic and Genetic Forms of Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209623}, doi = {10.1212/WNL.0000000000209623}, pmid = {38900989}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/pathology/physiopathology ; Male ; Female ; Middle Aged ; *Cerebellum/diagnostic imaging/pathology ; Aged ; *C9orf72 Protein/genetics ; Prospective Studies ; Ataxin-2/genetics ; Magnetic Resonance Imaging ; Disease Progression ; Cerebral Cortex/diagnostic imaging/pathology/physiopathology ; Adult ; Longitudinal Studies ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is predominantly associated with motor cortex, corticospinal tract (CST), brainstem, and spinal cord degeneration, and cerebellar involvement is much less well characterized. However, some of the cardinal clinical features of ALS, such as dysarthria, dysphagia, gait impairment, falls, and impaired dexterity, are believed to be exacerbated by coexisting cerebellar pathology. Cerebellar pathology may also contribute to cognitive, behavioral, and pseudobulbar manifestations. Our objective was to systematically assess both intracerebellar pathology and cerebrocerebellar connectivity alterations in a genetically stratified cohort of ALS.

METHODS: A prospective, multimodal neuroimaging study was conducted to evaluate the longitudinal evolution of intracerebellar pathology and cerebrocerebellar connectivity, using structural and functional measures.

RESULTS: A total of 113 healthy controls and 212 genetically stratified individuals with ALS were included: (1) C9orf72 hexanucleotide carriers ("C9POS"), (2) sporadic patients who tested negative for ALS-associated genetic variants, and (3) intermediate-length CAG trinucleotide carriers in ATXN2 ("ATXN2"). Flocculonodular lobule (padj = 0.014, 95% CI -5.06e-5 to -3.98e-6) and crura (padj = 0.031, 95% CI -1.63e-3 to -5.55e-5) volume reductions were detected at baseline in sporadic patients. Cerebellofrontal and cerebelloparietal structural connectivity impairment was observed in both C9POS and sporadic patients at baseline, and both projections deteriorated further over time in sporadic patients (padj = 0.003, t(249) = 3.04 and padj = 0.05, t(249) = 1.93). Functional cerebelloparietal uncoupling was evident in sporadic patients at baseline (padj = 0.004, 95% CI -0.19 to -0.03). ATXN2 patients exhibited decreased cerebello-occipital functional connectivity at baseline (padj = 0.004, 95% CI -0.63 to -0.06), progressive cerebellotemporal functional disconnection (padj = 0.025, t(199) = -2.26), and progressive flocculonodular lobule degeneration (padj = 0.017, t(249) = -2.24). C9POS patients showed progressive ventral dentate atrophy (padj = 0.007, t(249) = -2.75). The CSTs (padj < 0.001, 95% CI 4.89e-5 to 1.14e-4) and transcallosal interhemispheric fibers (padj < 0.001, 95% CI 5.21e-5 to 1.31e-4) were affected at baseline in C9POS and exhibited rapid degeneration over the 4 time points. The rate of decline in CST and corpus callosum integrity was faster than the rate of cerebrocerebellar disconnection (padj = 0.001, t(190) = 6.93).

DISCUSSION: ALS is associated with accruing intracerebellar disease burden as well as progressive corticocerebellar uncoupling. Contrary to previous suggestions, we have not detected evidence of compensatory structural or functional changes in response to supratentorial degeneration. The contribution of cerebellar disease burden to dysarthria, dysphagia, gait impairment, pseudobulbar affect, and cognitive deficits should be carefully considered in clinical assessments, monitoring, and multidisciplinary interventions.}, } @article {pmid38900757, year = {2024}, author = {Serian, A and Finsel, J and Ludolph, AC and Uttner, I and Lulé, D}, title = {Screening instruments of cognition: The relation of the mini-mental state examination to the Edinburgh cognitive and behavioural ALS screen in amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {19}, number = {6}, pages = {e0304593}, pmid = {38900757}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology/complications/epidemiology ; Male ; Female ; Middle Aged ; Aged ; *Mental Status and Dementia Tests ; Cognition/physiology ; Cognitive Dysfunction/diagnosis/epidemiology ; Neuropsychological Tests ; Cognition Disorders/diagnosis ; }, abstract = {OBJECTIVE: The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) is an established cognitive screening instrument for patients with amyotrophic lateral sclerosis (ALS). Different from tools like the Mini-Mental State Examination (MMSE), it is adjusted for motor impairment, yet, the latter remains one of the most widely used screening instruments, also in ALS studies. Thus, it is of utmost importance to relate outcome scores of both instruments to allow for comparison in ALS patients. This study reports on the performance of ALS patients in both tests with regard to incidence and degree of cognitive impairment, and the correspondence of both, ECAS and MMSE scores.

METHODS: We examined N = 84 ALS patients with the German versions of the ECAS and the MMSE. Performance in both tests regarding incidence and degree of cognitive impairment, and correspondence of frequency of cognitive impairment according to both tests was examined. The relationship between ECAS and MMSE scores was modelled with a non-linear regression model.

RESULTS: All ALS patients were able to complete the ECAS, 89.3% (N = 75) were capable to complete the MMSE. Prevalence of cognitive impairment was in both tests 22.7%, however agreement was only 52.9%. Despite, regression analyses yielded a strong positive relationship (adjusted R2 = .68) between the ECAS total score and the MMSE total score. Both tests were able to identify all patients with dementia.

CONCLUSION: These results suggest that the MMSE is not ideal for cognitive screening in early-stage ALS patients. However, a rough translation of MMSE scores in ECAS scores is possible to estimate the cognitive performance level of patients, with the ECAS being more discriminative in the lower range of cognitive dysfunction (ECAS score: 80-136), for which the MMSE does not define cognitive impairment (corresponding MMSE score: 27-30).}, } @article {pmid38900570, year = {2024}, author = {Privado, J and Sanchis Sanchis, E and Sancho-Cantus, D and Cubero-Plazas, L and Navarro-Illana, E and de la Rubia Ortí, JE}, title = {Prediction of caregiver psychological distress in amyotrophic lateral sclerosis: A cross-sectional study.}, journal = {Rehabilitation psychology}, volume = {69}, number = {4}, pages = {364-374}, doi = {10.1037/rep0000554}, pmid = {38900570}, issn = {1939-1544}, support = {//Catholic University of Valencia San Vicente Mártir/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; *Caregivers/psychology ; Female ; Cross-Sectional Studies ; Middle Aged ; *Psychological Distress ; Aged ; Adult ; Stress, Psychological/psychology/complications ; }, abstract = {PURPOSE/OBJECTIVE: To propose a predictive model for caregivers' psychological distress (including anxiety, depression, and cognitive overload) based on different data gathered from amyotrophic lateral sclerosis (ALS) patients (cognitive level, psychological distress, type of ALS, and sex).

RESEARCH METHOD/DESIGN: A cross-sectional study with a sample of 51 ALS patients and their respective main carers. Various instruments were used such as the Beck Anxiety Inventory, ALS Depression Inventory-12, and the Edinburgh Cognitive and Behavioral ALS Screen, Zarit Burden Interview, Self-Rating Depression Scale, and Self-Rating Anxiety Scale for caregivers.

RESULTS: ALS type, sex, and cognition were predictive variables for caregiver distress, with the main explanatory variable being the distress of the patients themselves. Spinal ALS led to higher psychological distress in caregivers (β = .38), as did male patients with ALS and preserved cognition.

CONCLUSIONS/IMPLICATIONS: The proposed confirmatory model demonstrates that patients' psychological distress is the best predictor of psychological distress in their caregivers. (PsycInfo Database Record (c) 2024 APA, all rights reserved).}, } @article {pmid38898687, year = {2024}, author = {Lee, B and Lee, SM and Song, JW and Choi, JW}, title = {Gut Microbiota Metabolite Messengers in Brain Function and Pathology at a View of Cell Type-Based Receptor and Enzyme Reaction.}, journal = {Biomolecules & therapeutics}, volume = {32}, number = {4}, pages = {403-423}, pmid = {38898687}, issn = {1976-9148}, abstract = {The human gastrointestinal (GI) tract houses a diverse microbial community, known as the gut microbiome comprising bacteria, viruses, fungi, and protozoa. The gut microbiome plays a crucial role in maintaining the body's equilibrium and has recently been discovered to influence the functioning of the central nervous system (CNS). The communication between the nervous system and the GI tract occurs through a two-way network called the gut-brain axis. The nervous system and the GI tract can modulate each other through activated neuronal cells, the immune system, and metabolites produced by the gut microbiome. Extensive research both in preclinical and clinical realms, has highlighted the complex relationship between the gut and diseases associated with the CNS, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review aims to delineate receptor and target enzymes linked with gut microbiota metabolites and explore their specific roles within the brain, particularly their impact on CNS-related diseases.}, } @article {pmid38898538, year = {2024}, author = {Bravo-Miana, RDC and Arizaga-Echebarria, JK and Otaegui, D}, title = {Central nervous system-derived extracellular vesicles: the next generation of neural circulating biomarkers?.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {32}, pmid = {38898538}, issn = {2047-9158}, support = {PI20/1253//Instituto de Salud Carlos III/ ; KK-2021/00009//Departamento de Desarrollo Económico, Sostenibilidad y Medio Ambiente/ ; ECTRIMS Postdoctoral Research Fellowship 2023//European Committee for Treatment and Research in Multiple Sclerosis/ ; Predoctoral fellowship//Basque Government/ ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers/blood ; *Central Nervous System/metabolism ; *Neurodegenerative Diseases/blood/diagnosis/metabolism ; Animals ; }, abstract = {The central nervous system (CNS) is integrated by glial and neuronal cells, and both release extracellular vesicles (EVs) that participate in CNS homeostasis. EVs could be one of the best candidates to operate as nanosized biological platforms for analysing multidimensional bioactive cargos, which are protected during systemic circulation of EVs. Having a window into the molecular level processes that are happening in the CNS could open a new avenue in CNS research. This raises a particular point of interest: can CNS-derived EVs in blood serve as circulating biomarkers that reflect the pathological status of neurological diseases? L1 cell adhesion molecule (L1CAM) is a widely reported biomarker to identify CNS-derived EVs in peripheral blood. However, it has been demonstrated that L1CAM is also expressed outside the CNS. Given that principal data related to neurodegenerative diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease were obtained using L1CAM-positive EVs, efforts to overcome present challenges related to its specificity are required. In this sense, other surface biomarkers for CNS-derived EVs, such as glutamate aspartate transporter (GLAST) and myelin oligodendrocyte glycoprotein (MOG), among others, have started to be used. Establishing a panel of EV biomarkers to analyse CNS-derived EVs in blood could increase the specificity and sensitivity necessary for these types of studies. This review covers the main evidence related to CNS-derived EVs in cerebrospinal fluid and blood samples of patients with neurological diseases, focusing on the reported biomarkers and the technical possibilities for their isolation. EVs are emerging as a mirror of brain physiopathology, reflecting both localized and systemic changes. Therefore, when the technical hindrances for EV research and clinical applications are overcome, novel disease-specific panels of EV biomarkers would be discovered to facilitate transformation from traditional medicine to personalized medicine.}, } @article {pmid38898231, year = {2024}, author = {Gao, J and Gunasekar, S and Xia, ZJ and Shalin, K and Jiang, C and Chen, H and Lee, D and Lee, S and Pisal, ND and Luo, JN and Griciuc, A and Karp, JM and Tanzi, R and Joshi, N}, title = {Gene therapy for CNS disorders: modalities, delivery and translational challenges.}, journal = {Nature reviews. Neuroscience}, volume = {25}, number = {8}, pages = {553-572}, pmid = {38898231}, issn = {1471-0048}, mesh = {Humans ; *Genetic Therapy/methods/trends ; *Central Nervous System Diseases/therapy/genetics ; Animals ; Translational Research, Biomedical/methods ; Gene Transfer Techniques/trends ; }, abstract = {Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.}, } @article {pmid38898006, year = {2024}, author = {Nógrádi, B and Nógrádi-Halmi, D and Erdélyi-Furka, B and Kádár, Z and Csont, T and Gáspár, R}, title = {Mechanism of motoneuronal and pyramidal cell death in amyotrophic lateral sclerosis and its potential therapeutic modulation.}, journal = {Cell death discovery}, volume = {10}, number = {1}, pages = {291}, pmid = {38898006}, issn = {2058-7716}, support = {BO/00574/22//Magyar Tudományos Akadémia (Hungarian Academy of Sciences)/ ; ÚNKP-23-5 -SZTE-711//Emberi Eroforrások Minisztériuma (Ministry of Human Capacities)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder clinically characterized by muscle atrophy and progressive paralysis. Loss of motoneurons and pyramidal cells is thought to be the center piece of the complex and multifaceted ALS pathology, however, the exact mechanisms laying behind motoneuronal cell death in the spinal cord and motor cortex are still unknown. It was originally proposed that apoptosis plays a fundamental role in motoneuronal demise, nonetheless, later it became clear that other forms of regulated cell death, including necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death, may also contribute to motoneuron loss. Over the past years, multiple studies aimed to improve our understanding of the contributory role of these mechanisms as well as to offer novel targets for potential therapeutic interventions. The pharmacological inhibition of the ferroptotic pathway and the modulation of the autophagic machinery seem to have particularly promising effects, reducing motoneuron loss and slowing disease progression in transgenic models of ALS. Nevertheless, the potential beneficial effects of necroptosis-targeting interventions were mostly disproven in the latest studies. In this review we aim to summarize the current view on regulated cell death mechanisms that lead to motoneuronal and pyramidal cell degeneration in ALS and showcase their applicability as future drug targets.}, } @article {pmid38897956, year = {2025}, author = {Takahashi, R and Furuta, M and Nagashima, K and Ikeda, Y}, title = {Concurrent Amyotrophic Lateral Sclerosis and Huntington's Disease.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {64}, number = {2}, pages = {297-300}, pmid = {38897956}, issn = {1349-7235}, mesh = {Humans ; *Huntington Disease/genetics/complications/diagnosis ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/genetics ; Male ; Middle Aged ; Huntingtin Protein/genetics ; Trinucleotide Repeat Expansion/genetics ; }, abstract = {Huntington's disease (HD) is a dominantly inherited neurological disorder characterized by chorea, psychiatric symptoms, and cognitive decline but typically lacks muscular atrophy and weakness. We herein report a case of genetically confirmed HD showing progressive systemic weakness with findings of upper and lower motor neuron involvement due to amyotrophic lateral sclerosis (ALS). The current patient and the previously reported cases with complications of HD and ALS indicate that cytosine-adenine-guanine (CAG) repeat expansion in the huntingtin gene might have a pathogenic role in causing the two neurological disorders.}, } @article {pmid38896345, year = {2024}, author = {Robinson, JL and Suh, E and Xu, Y and Hurtig, HI and Elman, L and McMillan, CT and Irwin, DJ and Porta, S and Van Deerlin, VM and Lee, EB}, title = {Annexin A11 aggregation in FTLD-TDP type C and related neurodegenerative disease proteinopathies.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {104}, pmid = {38896345}, issn = {1432-0533}, support = {RF1 AG065341/AG/NIA NIH HHS/United States ; U19 AG062418/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; P01AG066597/AG/NIA NIH HHS/United States ; U19AG062418/AG/NIA NIH HHS/United States ; R01 AG075276/AG/NIA NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; P30AG072979/AG/NIA NIH HHS/United States ; RF1AG065341/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Aged ; *Annexins/genetics/metabolism ; Female ; Male ; *DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Lobar Degeneration/genetics/pathology/metabolism ; Middle Aged ; Aged, 80 and over ; TDP-43 Proteinopathies/pathology/genetics ; Neurodegenerative Diseases/pathology/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Inclusion Bodies/pathology/metabolism ; Brain/pathology/metabolism ; Protein Aggregation, Pathological/pathology/genetics/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein found within ribonucleoprotein granules tethered to lysosomes via annexin A11. TDP-43 protein forms inclusions in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Annexin A11 is also known to form aggregates in ALS cases with pathogenic variants in ANXA11. Annexin A11 aggregation has not been described in sporadic ALS, FTLD-TDP or LATE-NC cases. To explore the relationship between TDP-43 and annexin A11, genetic analysis of 822 autopsy cases was performed to identify rare ANXA11 variants. In addition, an immunohistochemical study of 368 autopsy cases was performed to identify annexin A11 aggregates. Insoluble annexin A11 aggregates which colocalize with TDP-43 inclusions were present in all FTLD-TDP Type C cases. Annexin A11 inclusions were also seen in a small proportion (3-6%) of sporadic and genetic forms of FTLD-TDP types A and B, ALS, and LATE-NC. In addition, we confirm the comingling of annexin A11 and TDP-43 aggregates in an ALS case with the pathogenic ANXA11 p.G38R variant. Finally, we found abundant annexin A11 inclusions as the primary pathologic finding in a case of progressive supranuclear palsy-like frontotemporal dementia with prominent striatal vacuolization due to a novel variant, ANXA11 p.P75S. By immunoblot, FTLD-TDP with annexinopathy and ANXA11 variant cases show accumulation of insoluble ANXA11 including a truncated fragment. These results indicate that annexin A11 forms a diverse and heterogeneous range of aggregates in both sporadic and genetic forms of TDP-43 proteinopathies. In addition, the finding of a primary vacuolar annexinopathy due to ANXA11 p.P75S suggests that annexin A11 aggregation is sufficient to cause neurodegeneration.}, } @article {pmid38896262, year = {2024}, author = {Shen, D and Yang, X and He, D and Zhang, K and Liu, S and Sun, X and Li, J and Cai, Z and Liu, M and Zhang, X and Liu, Q and Cui, L}, title = {Clinical and genetic characteristics of 1672 cases of amyotrophic lateral sclerosis in China: a single-center retrospective study.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5541-5548}, pmid = {38896262}, issn = {1432-1459}, support = {XDB39040100//Strategic Priority Research Program (Pilot study) "Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; 2022-PUMCH-B-017//High-level Hospital Construction Project of Guangdong Provincial People's Hospital/ ; 2022YFC2703904//Key Technologies Research and Development Program/ ; 2021-I2M-1-034//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 81971293//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Male ; Middle Aged ; Female ; Adult ; Aged ; Young Adult ; Adolescent ; Aged, 80 and over ; China/epidemiology ; Retrospective Studies ; *C9orf72 Protein/genetics ; Age of Onset ; Mutation ; Phenotype ; Exome Sequencing ; Genotype ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. In recent years, continuous discoveries of new ALS-causing genes have enhanced the understanding of the genotype-phenotype relationship in ALS, aiding in disease progression prediction and providing a more comprehensive basis for genetic diagnosis.

METHODS: A total of 1672 ALS patients who visited the Neurology Department of Peking Union Medical College Hospital between January 2014 and December 2022 and met the revised El Escorial diagnostic criteria were included. Clinical data were collected, whole exome sequencing and dynamic mutation screening of the C9ORF72 gene were performed, and the clinical phenotypes and genotypes of the patients were analyzed.

RESULTS: The average age of onset for the 1672 ALS patients was 52.6 ± 11.2 years (range 17-85 years), with a median disease duration of 14 months at the time of visit (interquartile range 9-24 months, range 2-204 months). The male to female ratio was 833:839. The patients included 297 (17.8%) with bulbar onset, 198 (11.8%) with flail arm/leg syndrome, 89 (5.3%) with familial ALS, and 52 (3.1%) with concomitant frontotemporal dementia (FTD). Pathogenic variants associated with ALS were detected in 175 patients (10.5% of the cohort), with the most common mutations being SOD1, FUS, and ANXA11. Among patients with familial ALS, 56.2% (50/89) had genetic mutations, compared to 7.9% (125/1583) in sporadic ALS cases. From the perspective of phenotype-genotype correlation, (1) In ALS-FTD patients, the most common genetic mutations were ANXA11 and C9ORF72 repeat expansions. Patients with flail arm/leg syndrome more frequently carried mutations in SOD1, ANXA11, and hnRNPA1; (2) Despite genetic heterogeneity, it was observed that mutations in FUS and NEK1 were more common in males, and patients with FUS mutations had a younger age of onset; mutations in SOD1 and SQSTM1 were more likely to present with lower limb onset.

CONCLUSION: This study provides comprehensive data on the genetic characteristics of ALS patients in China through large-scale clinical data and genetic analysis of 1672 cases. Differences in age of onset, onset site, and clinical phenotype among ALS patients with different genotypes can help clinicians better predict disease progression and provide a basis for precise diagnosis and individualized treatment.}, } @article {pmid38896163, year = {2024}, author = {Woodworth, DC and Nguyen, KM and Sordo, L and Scambray, KA and Head, E and Kawas, CH and Corrada, MM and Nelson, PT and Sajjadi, SA}, title = {Comprehensive assessment of TDP-43 neuropathology data in the National Alzheimer's Coordinating Center database.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {103}, pmid = {38896163}, issn = {1432-0533}, support = {P20 AG068053/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P20 AG068077/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; T32AG073088/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; T32 AG073088/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; R01 AG079280/AG/NIA NIH HHS/United States ; R01 AG062706/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P20 AG068024/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; RF1 AG082339/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; R01AG062706/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Female ; Aged ; Male ; *Alzheimer Disease/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; *TDP-43 Proteinopathies/pathology ; Aged, 80 and over ; Databases, Factual ; Frontotemporal Lobar Degeneration/pathology/metabolism ; Brain/pathology/metabolism ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; Hippocampus/pathology/metabolism ; Middle Aged ; }, abstract = {TDP-43 proteinopathy is a salient neuropathologic feature in a subset of frontotemporal lobar degeneration (FTLD-TDP), in amyotrophic lateral sclerosis (ALS-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and is associated with hippocampal sclerosis of aging (HS-A). We examined TDP-43-related pathology data in the National Alzheimer's Coordinating Center (NACC) in two parts: (I) availability of assessments, and (II) associations with clinical diagnoses and other neuropathologies in those with all TDP-43 measures available. Part I: Of 4326 participants with neuropathology data collected using forms that included TDP-43 assessments, data availability was highest for HS-A (97%) and ALS (94%), followed by FTLD-TDP (83%). Regional TDP-43 pathologic assessment was available for 77% of participants, with hippocampus the most common region. Availability for the TDP-43-related measures increased over time, and was higher in centers with high proportions of participants with clinical FTLD. Part II: In 2142 participants with all TDP-43-related assessments available, 27% of participants had LATE-NC, whereas ALS-TDP or FTLD-TDP (ALS/FTLD-TDP) was present in 9% of participants, and 2% of participants had TDP-43 related to other pathologies ("Other TDP-43"). HS-A was present in 14% of participants, of whom 55% had LATE-NC, 20% ASL/FTLD-TDP, 3% Other TDP-43, and 23% no TDP-43. LATE-NC, ALS/FTLD-TDP, and Other TDP-43, were each associated with higher odds of dementia, HS-A, and hippocampal atrophy, compared to those without TDP-43 pathology. LATE-NC was associated with higher odds for Alzheimer's disease (AD) clinical diagnosis, AD neuropathologic change (ADNC), Lewy bodies, arteriolosclerosis, and cortical atrophy. ALS/FTLD-TDP was associated with higher odds of clinical diagnoses of primary progressive aphasia and behavioral-variant frontotemporal dementia, and cortical/frontotemporal lobar atrophy. When using NACC data for TDP-43-related analyses, researchers should carefully consider the incomplete availability of the different regional TDP-43 assessments, the high frequency of participants with ALS/FTLD-TDP, and the presence of other forms of TDP-43 pathology.}, } @article {pmid38895672, year = {2024}, author = {Deng, J and Sun, WT and Gong, K and Wang, LP and Li, FZ}, title = {Internal limiting membrane peeling combined with silicone oil or air tamponade for highly myopic foveoschisis.}, journal = {International journal of ophthalmology}, volume = {17}, number = {6}, pages = {1079-1085}, pmid = {38895672}, issn = {2222-3959}, abstract = {AIM: To compare the efficacy of pars plana vitrectomy (PPV) combined with internal limiting membrane (ILM) and silicone oil or sterile air tamponade for the treatment of myopic foveoschisis (MF) in highly myopic eyes.

METHODS: This retrospective study included 48 myopic eyes of 40 patients with MF and axial lengths (ALs) ranging from 26-32 mm treated between January 2020 and January 2022. All patients were underwent PPV combined with ILM peeling followed by sterile air or silicone oil tamponade and followed up at least 12mo. Based on the features on spectral-domain optical coherence tomography (SD-OCT), the eyes were divided into the MF-only group (Group A, n=15 eyes), MF with central foveal detachment group (Group B, n=20 eyes), and MF with lamellar macular hole group (Group C, n=13 eyes). According to AL, eyes were further divided into three groups: Group D (26.01-28.00 mm, n=12 eyes), Group E (28.01-30.00 mm, n=26 eyes), and Group F (30.01-32.00 mm, n=10 eyes). The best-corrected visual acuity (BCVA), central foveal thickness (CFT), and complications were recorded.

RESULTS: The patients included 16 males and 24 females with the mean age of 56±9.82y. The BCVA and CFT improved in all groups after surgery (P<0.01), while there was no significant difference of the CFT in Group A, B, and C postoperatively (P>0.05). The intergroup differences of BCVA and CFT postoperatively were statistically significant in Group D, E, and F. Twenty eyes were injected with sterile air, and 28 eyes were injected with silicone oil for tamponade based on the AL. However, there was no statistically significant difference among Groups D, E, and F in terms of the results of sterile air or silicone oil tamponade. The mean recovery time was 5.9mo for MF patients subjected to silicone oil tamponade and 7.7mo for patients subjected to sterile air tamponade, and the difference was not statistically significant.

CONCLUSION: PPV and ILM peeling combined with silicone oil or sterile air tamponade can achieve good results for MF in highly myopic eyes with ALs≤32 mm.}, } @article {pmid38895610, year = {2024}, author = {Kaundun, SS and Martin-Sanz, A and Rodríguez, M and Serbanoiu, T and Moreno, J and Mcindoe, E and le Goupil, G}, title = {First case of evolved herbicide resistance in the holoparasite sunflower broomrape, Orobanche cumana Wallr.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1420009}, pmid = {38895610}, issn = {1664-462X}, abstract = {The development and commercialisation of sunflower varieties tolerant to acetolactate synthase (ALS)-inhibiting herbicides some 20 years ago provided farmers with an alternative method for the cost-effective control of Orobanche cumana. In 2020, however, two independent sunflower broomrape populations from Drama (GR-DRA) and Orestiada (GR-ORE), Greece, were reported to be heavily infested with O. cumana after application of the ALS-inhibiting herbicide imazamox. Here we have investigated the race of GR-DRA and GR-ORE and determined the basis of resistance to imazamox in the two Greek O. cumana samples. Using a set of five diagnostic sunflower varieties characterised by different resistant genes with respect to O. cumana infestation, we have clearly established that the GR-ORE and GR-DRA populations belong to the invasive broomrape races G and G+, respectively. Live underground tubercles and emerged shoots were identified at the recommended field rate of imazamox for GR-DRA and GR-ORE but not for two other standard sensitive populations in a whole plant dose response test using two different herbicide-tolerant sunflower hybrids as hosts. Sequencing of the ALS gene identified an alanine 205 to aspartate mutation in all GR-ORE samples. Most GR-DRA tubercles were characterised by a second serine 653 to asparagine ALS mutation whilst a few GR-DRA individuals contained the A205D mutation. Mutations at ALS codons 205 and 653 are known to impact on the binding and efficacy of imazamox and other imidazolinone herbicides. The knowledge generated here will be important for tracking and managing broomrape resistance to ALS-inhibiting herbicides in sunflower growing regions.}, } @article {pmid38895485, year = {2024}, author = {Sikirzhytskaya, A and Tyagin, I and Sutton, SS and Wyatt, MD and Safro, I and Shtutman, M}, title = {AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.06.597745}, pmid = {38895485}, issn = {2692-8205}, abstract = {UNLABELLED: Neurodegenerative pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, HIV-associated neurocognitive disorder, and others significantly affect individuals, their families, caregivers, and healthcare systems. While there are no cures yet, researchers worldwide are actively working on the development of novel treatments that have the potential to slow disease progression, alleviate symptoms, and ultimately improve the overall health of patients. Huge volumes of new scientific information necessitate new analytical approaches for meaningful hypothesis generation. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases, such as PubMed. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. Here we focus on drugs that can be repurposed for dementia treatment as an outcome of neurodegenerative diseases. Therefore, we determined dementia-associated genes statistically highly ranked in other disease classes. Additionally, we report a mechanism for detecting genes common to multiple health conditions. These sets of genes were classified based on their presence in biological pathways, aiding in selecting candidates and biological processes that are exploitable with drug repurposing.

AUTHOR SUMMARY: This manuscript outlines our project involving the application of AGATHA, an AI-based literature mining tool, to discover drugs with the potential for repurposing in the context of neurocognitive disorders. The primary objective is to identify connections between approved medications and specific health conditions through advanced statistical analysis, including techniques like Partial Least Squares Discriminant Analysis (PLSDA) and unsupervised clustering. The methodology involves grouping scientific terms related to different health conditions and genes, followed by building discrimination models to extract lists of disease-specific genes. These genes are then analyzed through pathway analysis to select candidates for drug repurposing.}, } @article {pmid38895380, year = {2024}, author = {König, LE and Rodriguez, S and Hug, C and Daneshvari, S and Chung, A and Bradshaw, GA and Sahin, A and Zhou, G and Eisert, RJ and Piccioni, F and Das, S and Kalocsay, M and Sokolov, A and Sorger, P and Root, DE and Albers, MW}, title = {TYK2 as a novel therapeutic target in Alzheimer's Disease with TDP-43 inclusions.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38895380}, issn = {2692-8205}, support = {R01 AG058063/AG/NIA NIH HHS/United States ; U54 CA225088/CA/NCI NIH HHS/United States ; }, abstract = {Neuroinflammation is a pathological feature of many neurodegenerative diseases, including Alzheimer's disease (AD)[1,2] and amyotrophic lateral sclerosis (ALS)[3], raising the possibility of common therapeutic targets. We previously established that cytoplasmic double-stranded RNA (cdsRNA) is spatially coincident with cytoplasmic pTDP-43 inclusions in neurons of patients with C9ORF72-mediated ALS[4]. CdsRNA triggers a type-I interferon (IFN-I)-based innate immune response in human neural cells, resulting in their death[4]. Here, we report that cdsRNA is also spatially coincident with pTDP-43 cytoplasmic inclusions in brain cells of patients with AD pathology and that type-I interferon response genes are significantly upregulated in brain regions affected by AD. We updated our machine-learning pipeline DRIAD-SP (Drug Repurposing In Alzheimer's Disease with Systems Pharmacology) to incorporate cryptic exon (CE) detection as a proxy of pTDP-43 inclusions and demonstrated that the FDA-approved JAK inhibitors baricitinib and ruxolitinib that block interferon signaling show a protective signal only in cortical brain regions expressing multiple CEs. Furthermore, the JAK family member TYK2 was a top hit in a CRISPR screen of cdsRNA-mediated death in differentiated human neural cells. The selective TYK2 inhibitor deucravacitinib, an FDA-approved drug for psoriasis, rescued toxicity elicited by cdsRNA. Finally, we identified CCL2, CXCL10, and IL-6 as candidate predictive biomarkers for cdsRNA-related neurodegenerative diseases. Together, we find parallel neuroinflammatory mechanisms between TDP-43 associated-AD and ALS and nominate TYK2 as a possible disease-modifying target of these incurable neurodegenerative diseases.}, } @article {pmid38895337, year = {2024}, author = {Vazquez-Sanchez, S and Tilkin, B and Gasset-Rosa, F and Zhang, S and Piol, D and McAlonis-Downes, M and Artates, J and Govea-Perez, N and Verresen, Y and Guo, L and Cleveland, DW and Shorter, J and Da Cruz, S}, title = {Frontotemporal dementia-like disease progression elicited by seeded aggregation and spread of FUS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.03.593639}, pmid = {38895337}, issn = {2692-8205}, abstract = {RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fu sed in s arcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic FTLD. Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.}, } @article {pmid38895204, year = {2024}, author = {Maitra, S and Baek, M and Choe, YJ and Kim, NC}, title = {FDA-approved PDE4 inhibitors reduce the dominant toxicity of ALS-FTD-associated CHCHD10 [S59L].}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.04.597429}, pmid = {38895204}, issn = {2692-8205}, abstract = {Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10(CHCHD10) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing C2C10H [S81L] , and human cell models expressing CHCHD10 [S59L] , we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10 [S59L] . Evidences using in vitro/ in vivo genetic and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10 [S59L] -induced diseases. Therefore, we have investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10 [S59L] -induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10 [S59L] -induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H [S81L] . Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10 [S59L] . These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10 [S59L] -induced ALS-FTD and possibly other related diseases.}, } @article {pmid38894936, year = {2024}, author = {Brown, SP}, title = {Diagnosis of Cervical Spinal Cord Multiple Sclerosis by a Chiropractic Physician: A Case Report.}, journal = {Cureus}, volume = {16}, number = {6}, pages = {e62618}, pmid = {38894936}, issn = {2168-8184}, abstract = {We present a case report of diagnosis of cervical spine multiple sclerosis by a chiropractic physician. This unique case contributes an account of a challenging differential diagnosis to the literature. A 30-year-old male presented with a three-year history of diffuse left upper extremity motor strength deficits and paresthesia (numbness and tingling). The patient had seen multiple physicians for these symptoms with no diagnosis of multiple sclerosis and no advanced imaging. The differential diagnosis included lower cervical spine nerve root compression or neurological disorders such as amyotrophic lateral sclerosis, cerebral lesion, motor neuropathy, multiple sclerosis, or spinal cord lesion. MRI of the cervical spine with and without IV contrast revealed evidence of spinal cord multiple sclerosis. The patient was referred to a neurologist where the diagnosis of multiple sclerosis was confirmed. A 10-year follow-up showed the patient was controlling his condition with medications and had no disability. This case underscores the importance for physicians to consider neurological conditions and advanced imaging in the presence of diffuse motor strength deficits and paresthesia in the absence of injury, pain, or any other symptoms.}, } @article {pmid38894913, year = {2024}, author = {Sabnis, RW and Sabnis, AR}, title = {Novel Compounds as S1P5 Modulators for Treating Neurodegenerative Diseases.}, journal = {ACS medicinal chemistry letters}, volume = {15}, number = {6}, pages = {750-751}, pmid = {38894913}, issn = {1948-5875}, abstract = {Provided herein are novel compounds as S1P5 modulators, pharmaceutical compositions, use of such compounds in treating neurodegenerative diseases, particularly Alzheimer's disease, multiple sclerosis, migraine and amyotrophic lateral sclerosis, and processes for preparing such compounds.}, } @article {pmid38894662, year = {2024}, author = {Jacobsen, AB and Bostock, H and Howells, J and Cengiz, B and Samusyte, G and Koltzenburg, M and Pia, H and Fuglsang-Frederiksen, A and Blicher, J and Obál, I and Andersen, H and Tankisi, H}, title = {Threshold tracking transcranial magnetic stimulation and neurofilament light chain as diagnostic aids in ALS.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {7}, pages = {1887-1896}, pmid = {38894662}, issn = {2328-9503}, support = {//Sundhedsvidenskabelige Fakultet, Aarhus Universitet/ ; R290-2018-751//Lundbeck Foundation/ ; R346-2020-1946//Lundbeck Foundation/ ; //William Demant Fonden/ ; //Familien Hede Nielsens Fond/ ; //Aage og Johanne Louis-Hansens Fond/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Middle Aged ; Male ; Female ; Aged ; *Neurofilament Proteins ; *Transcranial Magnetic Stimulation/methods ; *Biomarkers ; Electromyography ; Evoked Potentials, Motor/physiology ; }, abstract = {OBJECTIVE: There is a need for sensitive biomarkers in amyotrophic lateral sclerosis (ALS), to enable earlier diagnosis and to help assess potential treatments. The main objective of this study was to compare two potential biomarkers, threshold-tracking short-interval cortical inhibition (T-SICI), which has shown promise as a diagnostic aid, and neurofilament light chains (NfL).

METHODS: Ninety-seven patients with ALS (mean age 67.1 ± 11.5 years) and 53 ALS mimics (aged 62.4 ± 12.9) were included. Mean disease duration was 14 months ±14.1. Patients were evaluated with revised ALS functional rating score (ALSFRS-R), Penn upper motor neuron score (UMNS), muscle strength using the Medical Research Council (MRC) score and examined with T-SICI, quantitative electromyography (EMG), and NfL measured in spinal fluid.

RESULTS: NfL increased with increasing UMNS (rho = 0.45, p = 8.2 × 10[-6]) whereas T-SICI at 2.5 ms paradoxically increased toward normal values (rho = 0.53, p = 1.9 × 10[-7]). However, these two measures were uncorrelated. Discrimination between ALS patients and mimics was best for NfL (area under ROC curve 0.842, sensitivity 84.9%, specificity 83.5%), compared with T-SICI (0.675, 39.6%, 91.8%). For the patients with no UMN signs, NfL also discriminated best (0.884, 89.3%, 82.6%), compared with T-SICI (0.811, 71.4%, 82.6%). However, when combining NfL and T-SICI, higher AUCs of 0.854 and 0.922 and specificities of 93.8 and 100 were found when considering all patients and patients with no UMN signs, respectively.

INTERPRETATION: Both T-SICI and NfL correlated with UMN involvement and combined, they provided a strong discrimination between ALS patients and ALS mimics.}, } @article {pmid38892814, year = {2024}, author = {Barbato, F and Bombaci, A and Colacicco, G and Bruno, G and Ippolito, D and Pota, V and Dongiovanni, S and Sica, G and Bocchini, G and Valente, T and Scaglione, M and Mainenti, PP and Guarino, S}, title = {Chest Dynamic MRI as Early Biomarker of Respiratory Impairment in Amyotrophic Lateral Sclerosis Patients: A Pilot Study.}, journal = {Journal of clinical medicine}, volume = {13}, number = {11}, pages = {}, pmid = {38892814}, issn = {2077-0383}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neuromuscular progressive disorder characterized by limb and bulbar muscle wasting and weakness. A total of 30% of patients present a bulbar onset, while 70% have a spinal outbreak. Respiratory involvement represents one of the worst prognostic factors, and its early identification is fundamental for the early starting of non-invasive ventilation and for the stratification of patients. Due to the lack of biomarkers of early respiratory impairment, we aimed to evaluate the role of chest dynamic MRI in ALS patients. Methods: We enrolled 15 ALS patients and 11 healthy controls. We assessed the revised ALS functional rating scale, spirometry, and chest dynamic MRI. Data were analyzed by using the Mann-Whitney U test and Cox regression analysis. Results: We observed a statistically significant difference in both respiratory parameters and pulmonary measurements at MRI between ALS patients and healthy controls. Moreover, we found a close relationship between pulmonary measurements at MRI and respiratory parameters, which was statistically significant after multivariate analysis. A sub-group analysis including ALS patients without respiratory symptoms and with normal spirometry values revealed the superiority of chest dynamic MRI measurements in detecting signs of early respiratory impairment. Conclusions: Our data suggest the usefulness of chest dynamic MRI, a fast and economically affordable examination, in the evaluation of early respiratory impairment in ALS patients.}, } @article {pmid38892250, year = {2024}, author = {Cerantonio, A and Citrigno, L and Greco, BM and De Benedittis, S and Passarino, G and Maletta, R and Qualtieri, A and Montesanto, A and Spadafora, P and Cavalcanti, F}, title = {The Role of Mitochondrial Copy Number in Neurodegenerative Diseases: Present Insights and Future Directions.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38892250}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *DNA, Mitochondrial/genetics ; *DNA Copy Number Variations ; *Mitochondria/genetics/metabolism ; Huntington Disease/genetics/pathology ; Animals ; }, abstract = {Neurodegenerative diseases are progressive disorders that affect the central nervous system (CNS) and represent the major cause of premature death in the elderly. One of the possible determinants of neurodegeneration is the change in mitochondrial function and content. Altered levels of mitochondrial DNA copy number (mtDNA-CN) in biological fluids have been reported during both the early stages and progression of the diseases. In patients affected by neurodegenerative diseases, changes in mtDNA-CN levels appear to correlate with mitochondrial dysfunction, cognitive decline, disease progression, and ultimately therapeutic interventions. In this review, we report the main results published up to April 2024, regarding the evaluation of mtDNA-CN levels in blood samples from patients affected by Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). The aim is to show a probable link between mtDNA-CN changes and neurodegenerative disorders. Understanding the causes underlying this association could provide useful information on the molecular mechanisms involved in neurodegeneration and offer the development of new diagnostic approaches and therapeutic interventions.}, } @article {pmid38891895, year = {2024}, author = {Dabrowska, S and Turano, E and Scambi, I and Virla, F and Nodari, A and Pezzini, F and Galiè, M and Bonetti, B and Mariotti, R}, title = {A Cellular Model of Amyotrophic Lateral Sclerosis to Study the Therapeutic Effects of Extracellular Vesicles from Adipose Mesenchymal Stem Cells on Microglial Activation.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38891895}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/metabolism/pathology ; *Extracellular Vesicles/metabolism ; *Microglia/metabolism ; *Mesenchymal Stem Cells/metabolism ; Humans ; *Superoxide Dismutase-1/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Cell Line ; Adipose Tissue/cytology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons (MNs) in the brain and spinal cord, leading to progressive paralysis and death. Increasing evidence indicates that neuroinflammation plays an important role in ALS's pathogenesis and disease progression. Neuroinflammatory responses, primarily driven by activated microglia and astrocytes, and followed by infiltrating peripheral immune cells, contribute to exacerbate/accelerate MN death. In particular, the role of the microglia in ALS remains unclear, partly due to the lack of experimental models that can fully recapitulate the complexity of ALS's pathology. In this study, we developed and characterized a microglial cell line, SIM-A9-expressing human mutant protein Cu[+]/Zn[+] superoxide dismutase_1 (SIM-A9hSOD1(G93A)), as a suitable model in vitro mimicking the microglia activity in ALS. The expression of hSOD1(G93A) in SIM-A9 cells induced a change in their metabolic activity, causing polarization into a pro-inflammatory phenotype and enhancing reactive oxygen species production, which is known to activate cell death processes and apoptosis. Afterward, we used our microglial model as an experimental set-up to investigate the therapeutic action of extracellular vesicles isolated from adipose mesenchymal stem cells (ASC-EVs). ASC-EVs represent a promising therapeutic treatment for ALS due to their neuroprotective and immunomodulatory properties. Here, we demonstrated that treatment with ASC-EVs is able to modulate activated ALS microglia, reducing their metabolic activity and polarizing their phenotype toward an anti-inflammatory one through a mechanism of reduction of reactive oxygen species.}, } @article {pmid38891791, year = {2024}, author = {Tokuda, E and Sakashita, Y and Tokoro, N and Date, A and Kosuge, Y and Miyasaka, T}, title = {MS785-MS27 Reactive Misfolded/Non-Native Zn-Deficient SOD1 Species Exhibit Cytotoxicity and Adopt Heterozygous Conformations in Motor Neurons.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38891791}, issn = {1422-0067}, support = {2022-2025//The Takeda Science Foundation/ ; }, mesh = {Animals ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Motor Neurons/metabolism/pathology ; Mice ; *Zinc/metabolism/deficiency ; *Protein Folding ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; Mutation ; Mice, Transgenic ; Heterozygote ; Protein Conformation ; }, abstract = {Misfolding of superoxide dismutase-1 (SOD1) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) with SOD1 mutations. The development of antibodies specific for misfolded SOD1 deepens our understanding of how the protein participates in ALS pathogenesis. Since the term "misfolding" refers to various disordered conformers other than the natively folded one, which misfolded species are recognized by specific antibodies should be determined. Here, we molecularly characterized the recognition by MS785-MS27, an antibody cocktail experimentally confirmed to recognize over 100 ALS-linked SOD1 mutants. Indirect ELISA revealed that the antibody cocktail recognized Zn-deficient wild-type and mutated SOD1 species. It also recognized conformation-disordered wild-type and mutated SOD1 species, such as unfolded and oligomeric forms, but had less affinity for the aggregated form. Antibody-reactive SOD1 exhibited cytotoxicity to a motor neuron cell model, which was blocked by Zn treatment with Zn-deficient SOD1. Immunohistochemistry revealed antibody-reactive SOD1 mainly in spinal motor neurons of SOD1[G93A] mice throughout the disease course, and the distribution after symptomatic stages differed from that of other misfolded SOD1 species. This suggests that misfolded/non-native SOD1 species exist as heterogeneous populations. In conclusion, MS785-MS27 recognizes various conformation-disordered SOD1 species lacking the Zn ion.}, } @article {pmid38891774, year = {2024}, author = {Arnold, FJ and Putka, AF and Raychaudhuri, U and Hsu, S and Bedlack, RS and Bennett, CL and La Spada, AR}, title = {Revisiting Glutamate Excitotoxicity in Amyotrophic Lateral Sclerosis and Age-Related Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38891774}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Glutamic Acid/metabolism ; Animals ; Motor Neurons/metabolism/pathology ; Aging/metabolism ; Receptors, AMPA/metabolism ; Endoplasmic Reticulum Stress ; Mitochondria/metabolism ; Excitatory Amino Acid Transporter 2/metabolism ; Astrocytes/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder. While there are five FDA-approved drugs for treating this disease, each has only modest benefits. To design new and more effective therapies for ALS, particularly for sporadic ALS of unknown and diverse etiologies, we must identify key, convergent mechanisms of disease pathogenesis. This review focuses on the origin and effects of glutamate-mediated excitotoxicity in ALS (the cortical hyperexcitability hypothesis), in which increased glutamatergic signaling causes motor neurons to become hyperexcitable and eventually die. We characterize both primary and secondary contributions to excitotoxicity, referring to processes taking place at the synapse and within the cell, respectively. 'Primary pathways' include upregulation of calcium-permeable AMPA receptors, dysfunction of the EAAT2 astrocytic glutamate transporter, increased release of glutamate from the presynaptic terminal, and reduced inhibition by cortical interneurons-all of which have been observed in ALS patients and model systems. 'Secondary pathways' include changes to mitochondrial morphology and function, increased production of reactive oxygen species, and endoplasmic reticulum (ER) stress. By identifying key targets in the excitotoxicity cascade, we emphasize the importance of this pathway in the pathogenesis of ALS and suggest that intervening in this pathway could be effective for developing therapies for this disease.}, } @article {pmid38891289, year = {2024}, author = {Idziak, R and Waligóra, H and Majchrzak, L and Szulc, P}, title = {Multifunctional Adjuvants Affect Sulfonylureas with Synthetic Auxin Mixture in Weed and Maize Grain Yield.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {38891289}, issn = {2223-7747}, abstract = {A field study in the years 2017-2019 was carried out to evaluate the impact of novel adjuvant formulations on the efficacy of sulfonylurea and synthetic auxin herbicides. Treatments included nicosulfuron + rimsulfuron + dicamba (N+R+D) at full and reduced rates with three multicomponent (TEST-1, TEST-2, TEST-3) as well as standard (MSO, S) adjuvants. In this greenhouse study, Echinochloa crus-galli seeds were planted and treated with N+R+D at 2-3 leaf stages. The water with the desired pH (4, 7, and 9) for the preparation of the spray liquid was prepared by incorporating citric acid or K3PO4 to either lower or raise the pH of the water. Adjuvant TEST-1 added to the spray liquid at pH 4 increased the effectiveness to 68%, TEST-2 to 81%, and TEST-3 to 80%, compared to 73% and 66% with the MSO and S. The efficacy of N+R+D at pH 7 with TEST-1 increased to 83%, TEST-2 to 82%, and TEST-3 to 77%, but with MSO, it increased to 81%, and 71% with S. Adjuvants TEST-1, TEST-2, and TEST-3 in the liquid at pH 9 increased efficacy to 76 and 80%, compared to 79 and 63% with MSO or S adjuvants. N+R+D applied with TEST-1, TEST-2, and TEST-3 provided greater weed control than herbicides with surfactant (S) and similar or even better than with standard methylated seed oil (MSO) adjuvants. Maize grain yield after herbicide-with-tested-adjuvant application was higher than from an untreated check, and comparable to yield from herbicide-with-MSO treatment, but higher than from S treatment.}, } @article {pmid38891112, year = {2024}, author = {Santos, JR and Park, J}, title = {MATR3's Role beyond the Nuclear Matrix: From Gene Regulation to Its Implications in Amyotrophic Lateral Sclerosis and Other Diseases.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891112}, issn = {2073-4409}, support = {n/a//Canada Research Chairs/ ; 202104PJT-462444-NSB-CEAB-275899//CIHR/Canada ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Nuclear Matrix-Associated Proteins/metabolism/genetics ; *Gene Expression Regulation ; *Nuclear Matrix/metabolism ; Animals ; RNA-Binding Proteins/metabolism/genetics ; }, abstract = {Matrin-3 (MATR3) was initially discovered as a component of the nuclear matrix about thirty years ago. Since then, accumulating studies have provided evidence that MATR3 not only plays a structural role in the nucleus, but that it is also an active protein involved in regulating gene expression at multiple levels, including chromatin organization, DNA transcription, RNA metabolism, and protein translation in the nucleus and cytoplasm. Furthermore, MATR3 may play a critical role in various cellular processes, including DNA damage response, cell proliferation, differentiation, and survival. In addition to the revelation of its biological role, recent studies have reported MATR3's involvement in the context of various diseases, including neurodegenerative and neurodevelopmental diseases, as well as cancer. Moreover, sequencing studies of patients revealed a handful of disease-associated mutations in MATR3 linked to amyotrophic lateral sclerosis (ALS), which further elevated the gene's importance as a topic of study. In this review, we synthesize the current knowledge regarding the diverse functions of MATR3 in DNA- and RNA-related processes, as well as its involvement in various diseases, with a particular emphasis on ALS.}, } @article {pmid38891099, year = {2024}, author = {Hernan-Godoy, M and Rouaux, C}, title = {From Environment to Gene Expression: Epigenetic Methylations and One-Carbon Metabolism in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891099}, issn = {2073-4409}, support = {ANR-21-CE16-0024//Agence Nationale de la Recherche/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Epigenesis, Genetic ; *DNA Methylation/genetics ; *Carbon/metabolism ; Animals ; }, abstract = {The etiology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is complex and considered multifactorial. The majority of ALS cases are sporadic, but familial cases also exist. Estimates of heritability range from 8% to 61%, indicating that additional factors beyond genetics likely contribute to ALS. Numerous environmental factors are considered, which may add up and synergize throughout an individual's lifetime building its unique exposome. One level of integration between genetic and environmental factors is epigenetics, which results in alterations in gene expression without modification of the genome sequence. Methylation reactions, targeting DNA or histones, represent a large proportion of epigenetic regulations and strongly depend on the availability of methyl donors provided by the ubiquitous one-carbon (1C) metabolism. Thus, understanding the interplay between exposome, 1C metabolism, and epigenetic modifications will likely contribute to elucidating the mechanisms underlying altered gene expression related to ALS and to developing targeted therapeutic interventions. Here, we review evidence for 1C metabolism alterations and epigenetic methylation dysregulations in ALS, with a focus on the impairments reported in neural tissues, and discuss these environmentally driven mechanisms as the consequences of cumulative exposome or late environmental hits, but also as the possible result of early developmental defects.}, } @article {pmid38891059, year = {2024}, author = {Dashtmian, AR and Darvishi, FB and Arnold, WD}, title = {Chronological and Biological Aging in Amyotrophic Lateral Sclerosis and the Potential of Senolytic Therapies.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891059}, issn = {2073-4409}, support = {1R01AG067758, R01AG078129, and R01AG067758-02S2//national institute of health/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/therapy ; Humans ; *Aging/pathology ; Senotherapeutics/pharmacology/therapeutic use ; Animals ; Cellular Senescence ; Mitochondria/metabolism/pathology ; DNA Damage ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a group of sporadic and genetic neurodegenerative disorders that result in losses of upper and lower motor neurons. Treatment of ALS is limited, and survival is 2-5 years after disease onset. While ALS can occur in younger individuals, the risk significantly increases with advancing age. Notably, both sporadic and genetic forms of ALS share pathophysiological features overlapping hallmarks of aging including genome instability/DNA damage, mitochondrial dysfunction, inflammation, proteostasis, and cellular senescence. This review explores chronological and biological aging in the context of ALS onset and progression. Age-related muscle weakness and motor unit loss mirror aspects of ALS pathology and coincide with peak ALS incidence, suggesting a potential link between aging and disease development. Hallmarks of biological aging, including DNA damage, mitochondrial dysfunction, and cellular senescence, are implicated in both aging and ALS, offering insights into shared mechanisms underlying disease pathogenesis. Furthermore, senescence-associated secretory phenotype and senolytic treatments emerge as promising avenues for ALS intervention, with the potential to mitigate neuroinflammation and modify disease progression.}, } @article {pmid38891021, year = {2024}, author = {Nguyen, L}, title = {Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891021}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/drug therapy ; Animals ; C9orf72 Protein/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a motor neuron disease. In ALS, upper and lower motor neurons in the brain and spinal cord progressively degenerate during the course of the disease, leading to the loss of the voluntary movement of the arms and legs. Since its first description in 1869 by a French neurologist Jean-Martin Charcot, the scientific discoveries on ALS have increased our understanding of ALS genetics, pathology and mechanisms and provided novel therapeutic strategies. The goal of this review article is to provide a comprehensive summary of the recent findings on ALS mechanisms and related therapeutic strategies to the scientific audience. Several highlighted ALS research topics discussed in this article include the 2023 FDA approved drug for SOD1 ALS, the updated C9orf72 GGGGCC repeat-expansion-related mechanisms and therapeutic targets, TDP-43-mediated cryptic splicing and disease markers and diagnostic and therapeutic options offered by these recent discoveries.}, } @article {pmid38891002, year = {2024}, author = {Genchi, G and Lauria, G and Catalano, A and Carocci, A and Sinicropi, MS}, title = {Neuroprotective Effects of Curcumin in Neurodegenerative Diseases.}, journal = {Foods (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {38891002}, issn = {2304-8158}, abstract = {Curcumin, a hydrophobic polyphenol extracted from the rhizome of Curcuma longa, is now considered a candidate drug for the treatment of neurological diseases, including Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and prion disease, due to its potent anti-inflammatory, antioxidant potential, anticancerous, immunomodulatory, neuroprotective, antiproliferative, and antibacterial activities. Traditionally, curcumin has been used for medicinal and dietary purposes in Asia, India, and China. However, low water solubility, poor stability in the blood, high rate of metabolism, limited bioavailability, and little capability to cross the blood-brain barrier (BBB) have limited the clinical application of curcumin, despite the important pharmacological activities of this drug. A variety of nanocarriers, including liposomes, micelles, dendrimers, cubosome nanoparticles, polymer nanoparticles, and solid lipid nanoparticles have been developed with great success to effectively deliver the active drug to brain cells. Functionalization on the surface of nanoparticles with brain-specific ligands makes them target-specific, which should significantly improve bioavailability and reduce harmful effects. The aim of this review is to summarize the studies on curcumin and/or nanoparticles containing curcumin in the most common neurodegenerative diseases, highlighting the high neuroprotective potential of this nutraceutical.}, } @article {pmid38890532, year = {2024}, author = {}, title = {Molecular pathology markers of FTD and ALS in blood extracellular vesicles.}, journal = {Nature medicine}, volume = {30}, number = {6}, pages = {1545-1546}, pmid = {38890532}, issn = {1546-170X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/pathology ; *Extracellular Vesicles/metabolism/genetics ; *Biomarkers/blood ; *Frontotemporal Dementia/genetics/blood/pathology ; Pathology, Molecular ; }, } @article {pmid38890531, year = {2024}, author = {Chatterjee, M and Özdemir, S and Fritz, C and Möbius, W and Kleineidam, L and Mandelkow, E and Biernat, J and Doğdu, C and Peters, O and Cosma, NC and Wang, X and Schneider, LS and Priller, J and Spruth, E and Kühn, AA and Krause, P and Klockgether, T and Vogt, IR and Kimmich, O and Spottke, A and Hoffmann, DC and Fliessbach, K and Miklitz, C and McCormick, C and Weydt, P and Falkenburger, B and Brandt, M and Guenther, R and Dinter, E and Wiltfang, J and Hansen, N and Bähr, M and Zerr, I and Flöel, A and Nestor, PJ and Düzel, E and Glanz, W and Incesoy, E and Bürger, K and Janowitz, D and Perneczky, R and Rauchmann, BS and Hopfner, F and Wagemann, O and Levin, J and Teipel, S and Kilimann, I and Goerss, D and Prudlo, J and Gasser, T and Brockmann, K and Mengel, D and Zimmermann, M and Synofzik, M and Wilke, C and Selma-González, J and Turon-Sans, J and Santos-Santos, MA and Alcolea, D and Rubio-Guerra, S and Fortea, J and Carbayo, Á and Lleó, A and Rojas-García, R and Illán-Gala, I and Wagner, M and Frommann, I and Roeske, S and Bertram, L and Heneka, MT and Brosseron, F and Ramirez, A and Schmid, M and Beschorner, R and Halle, A and Herms, J and Neumann, M and Barthélemy, NR and Bateman, RJ and Rizzu, P and Heutink, P and Dols-Icardo, O and Höglinger, G and Hermann, A and Schneider, A}, title = {Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS.}, journal = {Nature medicine}, volume = {30}, number = {6}, pages = {1771-1783}, pmid = {38890531}, issn = {1546-170X}, support = {P30 AG066614/AG/NIA NIH HHS/United States ; R01 AG080470/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/pathology/genetics ; *tau Proteins/blood/metabolism ; *Extracellular Vesicles/metabolism ; *Frontotemporal Dementia/blood/diagnosis/genetics/pathology ; *Biomarkers/blood ; *DNA-Binding Proteins/blood/genetics ; Female ; Male ; Aged ; Middle Aged ; Supranuclear Palsy, Progressive/blood/diagnosis ; Protein Isoforms/blood ; }, abstract = {Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.}, } @article {pmid38890465, year = {2024}, author = {Brown, AL and Wilkins, OG and Keuss, MJ and Hill, SE and Zanovello, M and Lee, WC and Bampton, A and Lee, FCY and Masino, L and Qi, YA and Bryce-Smith, S and Gatt, A and Hallegger, M and Fagegaltier, D and Phatnani, H and , and Newcombe, J and Gustavsson, EK and Seddighi, S and Reyes, JF and Coon, SL and Ramos, D and Schiavo, G and Fisher, EMC and Raj, T and Secrier, M and Lashley, T and Ule, J and Buratti, E and Humphrey, J and Ward, ME and Fratta, P}, title = {Author Correction: TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A.}, journal = {Nature}, volume = {631}, number = {8020}, pages = {E7}, doi = {10.1038/s41586-024-07577-9}, pmid = {38890465}, issn = {1476-4687}, } @article {pmid38889636, year = {2024}, author = {Alkhazaali-Ali, Z and Sahab-Negah, S and Boroumand, AR and Tavakol-Afshari, J}, title = {MicroRNA (miRNA) as a biomarker for diagnosis, prognosis, and therapeutics molecules in neurodegenerative disease.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {177}, number = {}, pages = {116899}, doi = {10.1016/j.biopha.2024.116899}, pmid = {38889636}, issn = {1950-6007}, mesh = {Humans ; *MicroRNAs/genetics ; *Neurodegenerative Diseases/diagnosis/genetics/therapy ; *Biomarkers/metabolism ; Animals ; Prognosis ; }, abstract = {Neurodegenerative diseases that include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS) that arise due to numerous causes like protein accumulation and autoimmunity characterized by neurologic depletion which lead to incapacity in normal physiological function such as thinking and movement in these patients. Glial cells perform an important role in protective neuronal function; in the case of neuroinflammation, glial cell dysfunction can promote the development of neurodegenerative diseases. miRNA that participates in gene regulation and plays a vital role in many biological processes in the body; in the central nervous system (CNS), it can play an essential part in neural maturation and differentiation. In neurodegenerative diseases, miRNA dysregulation occurs, enhancing the development of these diseases. In this review, we discuss neurodegenerative disease (Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)) and how miRNA is preserved as a diagnostic biomarker or therapeutic agent in these disorders. Finally, we highlight miRNA as therapy.}, } @article {pmid38889523, year = {2024}, author = {Müller, HP and Abrahao, A and Beaulieu, C and Benatar, M and Dionne, A and Genge, A and Frayne, R and Graham, SJ and Gibson, S and Korngut, L and Luk, C and Welsh, RC and Zinman, L and Kassubek, J and Kalra, S}, title = {Temporal and spatial progression of microstructural cerebral degeneration in ALS: A multicentre longitudinal diffusion tensor imaging study.}, journal = {NeuroImage. Clinical}, volume = {43}, number = {}, pages = {103633}, pmid = {38889523}, issn = {2213-1582}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *Disease Progression ; *Diffusion Tensor Imaging/methods ; Longitudinal Studies ; Aged ; *Pyramidal Tracts/diagnostic imaging/pathology ; Adult ; Cross-Sectional Studies ; Anisotropy ; Prospective Studies ; }, abstract = {OBJECTIVE: The corticospinal tract (CST) reveals progressive microstructural alterations in ALS measurable by DTI. The aim of this study was to evaluate fractional anisotropy (FA) along the CST as a longitudinal marker of disease progression in ALS.

METHODS: The study cohort consisted of 114 patients with ALS and 110 healthy controls from the second prospective, longitudinal, multicentre study of the Canadian ALS Neuroimaging Consortium (CALSNIC-2). DTI and clinical data from a harmonized protocol across 7 centres were collected. Thirty-nine ALS patients and 61 controls completed baseline and two follow-up visits and were included for longitudinal analyses. Whole brain-based spatial statistics and hypothesis-guided tract-of-interest analyses were performed for cross-sectional and longitudinal analyses.

RESULTS: FA was reduced at baseline and longitudinally in the CST, mid-corpus callosum (CC), frontal lobe, and other ALS-related tracts, with alterations most evident in the CST and mid-CC. CST and pontine FA correlated with functional impairment (ALSFRS-R), upper motor neuron function, and clinical disease progression rate. Reduction in FA was largely located in the upper CST; however, the longitudinal decline was greatest in the lower CST. Effect sizes were dependent on region, resulting in study group sizes between 17 and 31 per group over a 9-month interval. Cross-sectional effect sizes were maximal in the upper CST; whereas, longitudinal effect sizes were maximal in mid-callosal tracts.

CONCLUSIONS: Progressive microstructural alterations in ALS are most prominent in the CST and CC. DTI can provide a biomarker of cerebral degeneration in ALS, with longitudinal changes in white matter demonstrable over a reasonable observation period, with a feasible number of participants, and within a multicentre framework.}, } @article {pmid38889403, year = {2024}, author = {Zhu, Y and Wang, F and Xia, Y and Wang, L and Lin, H and Zhong, T and Wang, X}, title = {Research progress on astrocyte-derived extracellular vesicles in the pathogenesis and treatment of neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {8}, pages = {855-875}, pmid = {38889403}, issn = {2191-0200}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; *Astrocytes/metabolism ; Animals ; Cell Communication/physiology ; }, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), pose significant global health risks and represent a substantial public health concern in the contemporary era. A primary factor in the pathophysiology of these disorders is aberrant accumulation and aggregation of pathogenic proteins within the brain and spinal cord. Recent investigations have identified extracellular vesicles (EVs) in the central nervous system (CNS) as potential carriers for intercellular transport of misfolded proteins associated with neurodegenerative diseases. EVs are involved in pathological processes that contribute to various brain disorders including neurodegenerative disorders. Proteins linked to neurodegenerative disorders are secreted and distributed from cell to cell via EVs, serving as a mechanism for direct intercellular communication through the transfer of biomolecules. Astrocytes, as active participants in CNS intercellular communication, release astrocyte-derived extracellular vesicles (ADEVs) that are capable of interacting with diverse target cells. This review primarily focuses on the involvement of ADEVs in the development of neurological disorders and explores their potential dual roles - both advantageous and disadvantageous in the context of neurological disorders. Furthermore, this review examines the current studies investigating ADEVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases. The prospects and challenges associated with the application of ADEVs in clinical settings were also comprehensively reviewed.}, } @article {pmid38888068, year = {2024}, author = {Shefner, JM and Cudkowicz, ME}, title = {Failures to Replicate: What Recent Negative Phase 3 Trials Have Taught Us about Amyotrophic Lateral Sclerosis Clinical Research.}, journal = {Annals of neurology}, volume = {96}, number = {2}, pages = {211-215}, doi = {10.1002/ana.26999}, pmid = {38888068}, issn = {1531-8249}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Clinical Trials, Phase III as Topic/methods ; Biomedical Research ; }, } @article {pmid38887944, year = {2024}, author = {Mendes, AE and Silva, GD and Jorge, FMH and Callegaro, D}, title = {Tongue pressure is a strong predictor of recommendation for gastrostomy in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {3}, pages = {409-412}, doi = {10.1002/mus.28174}, pmid = {38887944}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/therapy ; *Gastrostomy ; Female ; Male ; Middle Aged ; Aged ; Prospective Studies ; *Tongue/physiopathology ; Pressure ; ROC Curve ; Follow-Up Studies ; }, abstract = {INTRODUCTION/AIMS: Objective and practical biomarkers to determine the need for gastrostomy in patients with amyotrophic lateral sclerosis (ALS) are lacking. Tongue pressure (TP) is a promising biomarker because it is associated with bulbar dysfunction. The aims of this study were to evaluate the association of TP with the need for gastrostomy, and to determine its optimal cut-off value.

METHODS: This prospective observational study included participants with ALS taking nutrition orally. TP was evaluated using the Iowa Oral Performance Instrument. Need for gastrostomy as determined by a multidisciplinary team during a 12-month follow up period was recorded. Associations between TP and need for gastrostomy placement were performed. ROC curve analysis determined the optimal cut-off value of TP to predict gastrostomy.

RESULTS: Of 208 screened participants, 119 were included. Gastrostomy was indicated in 45% (53), in a 12-month follow up period. TP of ≤20 kPA was a strong predictor of gastrostomy indication (OR 11.8, CI 95% [4.61, 34.7], p < .001). The association persisted even after adjustment for weight loss, pneumonia, prolonged feeding duration, Revised ALS Functional Rating Scale score, and American Speech-Language-Hearing Association scale score (OR 4.51, CI 95% [1.50, 14.9], p = .009). By receiver operating characteristic curve analysis, 20 kPA represented the optimal cut-off value (sensitivity 0.75, specificity 0.89).

DISCUSSION: TP is a strong independent predictor of gastrostomy indication in the subsequent 12 months in patients with ALS, with good sensitivity and specificity at a cutoff value of ≤20 kPA, suggesting that it may be a promising biomarker in clinical practice.}, } @article {pmid38887384, year = {2024}, author = {Tang, X and Li, Q and Huang, G and Chen, Z and Huang, Y and Pei, X and Zhao, S and Liu, Z and Guo, T and Liang, F}, title = {Immediate Efficacy of Contralateral Acupuncture on SI3 Combined with Active Exercise for Acute Lumbar Sprains: Protocol for a Randomized Controlled Trial.}, journal = {Journal of pain research}, volume = {17}, number = {}, pages = {2099-2110}, pmid = {38887384}, issn = {1178-7090}, abstract = {PURPOSE: Acute lumbar sprain (ALS) is a common clinical disease characterized by persistent intolerable low back pain and limitation of movement, and quick pain relief and restoration of mobility in a short time are the main needs of patients when they visit the clinic. This study aims to evaluate the immediate efficacy of contralateral acupuncture (CAT) on SI3 combined with active exercise in treating ALS.

METHODS AND ANALYSIS: This study is a randomized controlled trial which will recruit 118 eligible participants aged 18 to 55 years with ALS at the Second Affiliated Hospital of Yunnan University of Chinese Medicine between March 2024 and December 2026. Participants will be randomly assigned to the acupuncture group or the sham-acupuncture group in a 1:1 ratio. The acupuncture group will receive a 10-minute acupuncture treatment combined with active exercise, while the sham-acupuncture group will receive a 10-minute sham acupuncture treatment combined with active exercise. Randomization will use a computer-generated sequence with allocation concealed in opaque envelopes. The primary outcome will be the pain visual analogue scale (VAS) scores after 10 minutes of treatment. Secondary outcomes will include the pain VAS scores at other time points (2, 4, 6, and 8 minutes post-treatment), the lumbar range of motion (ROM) scores at various time points, blinded assessment, the treatment effect expectancy scale, and the rescue analgesia rate. The analysis will follow the intention-to-treat principle. The primary outcome will be analyzed using ANCOVA, and secondary outcomes with repeated measures ANOVA. The rescue analgesia rate will be assessed using either the χ[2] test or Fisher's exact test.

DISCUSSION: This study is the first randomized controlled trial to assess the immediate efficacy of CAT in combination with active exercise for ALS. This study will provide a simple, rapid, and effective treatment for the clinical management of ALS.}, } @article {pmid38887187, year = {2024}, author = {Ghaderi, S and Fatehi, F and Kalra, S and Mohammadi, S and Zemorshidi, F and Ramezani, M and Hesami, O and Pezeshgi, S and Batouli, SAH}, title = {Volume loss in the left anterior-superior subunit of the hypothalamus in amyotrophic lateral sclerosis.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {6}, pages = {e14801}, pmid = {38887187}, issn = {1755-5949}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *Hypothalamus/diagnostic imaging/pathology ; Aged ; *Magnetic Resonance Imaging ; Adult ; }, abstract = {BACKGROUND AND OBJECTIVE: Amyotrophic lateral sclerosis (ALS) causes motor neuron loss and progressive paralysis. While traditionally viewed as motor neuron disease (MND), ALS also affects non-motor regions, such as the hypothalamus. This study aimed to quantify the hypothalamic subregion volumes in patients with ALS versus healthy controls (HCs) and examine their associations with demographic and clinical features.

METHODS: Forty-eight participants (24 ALS patients and 24 HCs) underwent structural MRI. A deep convolutional neural network was used for the automated segmentation of the hypothalamic subunits, including the anterior-superior (a-sHyp), anterior-inferior (a-iHyp), superior tuberal (supTub), inferior tuberal (infTub), and posterior (posHyp). The neural network was validated using FreeSurfer v7.4.1, with individual head size variations normalized using total intracranial volume (TIV) normalization. Statistical analyses were performed for comparisons using independent sample t-tests. Correlations were calculated using Pearson's and Spearman's tests (p < 0.05). The standard mean difference (SMD) was used to compare the mean differences between parametric variables.

RESULTS: The volume of the left a-sHyp hypothalamic subunit was significantly lower in ALS patients than in HCs (p = 0.023, SMD = -0.681). No significant correlation was found between the volume of the hypothalamic subunits, body mass index (BMI), and ALSFRS-R in patients with ALS. However, right a-sHyp (r = 0.420, p = 0.041) was correlated with disease duration, whereas right supTub (r = -0.471, p = 0.020) and left postHyp (r = -0.406, p = 0.049) were negatively correlated with age. There was no significant difference in the volume of hypothalamic subunits between males and females, and no significant difference was found between patients with revised ALS Functional Rating Scale (ALSFRS-R) scores ≤41 and >41 and those with a disease duration of 9 months or less.

DISCUSSION AND CONCLUSION: The main finding suggests atrophy of the left a-sHyp hypothalamic subunit in patients with ALS, which is supported by previous research as an extra-motor neuroimaging finding for ALS.}, } @article {pmid38886938, year = {2025}, author = {Helmold, BR and Ahrens, A and Fitzgerald, Z and Ozdinler, PH}, title = {Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets.}, journal = {Neural regeneration research}, volume = {20}, number = {3}, pages = {725-739}, pmid = {38886938}, issn = {1673-5374}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; }, abstract = {Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein-protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as "causative" for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration-approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.}, } @article {pmid38886047, year = {2024}, author = {Jiang, Q and Lin, J and Wei, Q and Yang, T and Hou, Y and Zhang, L and Ou, R and Xiao, Y and Wang, S and Zheng, X and Li, C and Shang, H}, title = {Amyotrophic lateral sclerosis patients with various gene mutations show diverse motor phenotypes and survival in China.}, journal = {Journal of medical genetics}, volume = {61}, number = {9}, pages = {839-846}, doi = {10.1136/jmg-2024-109909}, pmid = {38886047}, issn = {1468-6244}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/mortality/pathology ; Male ; Female ; *C9orf72 Protein/genetics ; *Mutation ; Middle Aged ; *Phenotype ; China/epidemiology ; *Superoxide Dismutase-1/genetics ; Adult ; *Genetic Association Studies/methods ; RNA-Binding Protein FUS/genetics ; DNA-Binding Proteins/genetics ; Aged ; Genotype ; Age of Onset ; Genetic Predisposition to Disease ; Proteins/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by progressive degeneration of motor neurons. Genetic factors have a substantial impact on ALS. Therefore, this study aimed to explore the correlation between genotype (SOD1, TARDBP, FUS, C9orf72) and phenotype in ALS.

METHODS: Genetic analysis was performed on 2038 patients with ALS, among which 1696 patients with sporadic ALS (SALS) as controls for genotype-phenotype analysis, and 1602 SALS as controls for survival analysis. Logistic regression and Cox proportional hazards models were used for statistical analysis.

RESULTS: A total of 172 patients with ALS with the gene mutations were included in the statistical analysis (SOD1, n=65; FUS, n=43; TARDBP, n=27; C9orf72, n=37). SOD1 mutations were more frequent in flail leg phenotype (OR 7.317, p=0.001) and less in bulbar phenotype (OR 0.222, p=0.038). C9orf72 expansions exhibited higher frequency in bulbar phenotype (OR 2.770, p=0.008). SOD1 and FUS mutations were significantly associated with earlier age of onset (HR 2.039, p<0.001; HR 1.762, p=0.001). The patients with SOD1 mutations, C9orf72 expansions and those carrying pathogenic FUS mutations had significantly increased death risk (HR 2.217, p<0.001; HR 1.694, p=0.008; HR 1.652, p=0.036). The increased risk of death in ALS with C9orf72 expansions was significant in females (HR 2.419, p=0.014) but not in males (HR 1.442, p=0.128).

CONCLUSION: Our study revealed distinct motor phenotypic tendencies in patients with ALS with different genotypes, indicating variations in the vulnerability of motor neurons during the disease's progression. Furthermore, we made novel discoveries regarding survival of different gene mutations, warranting further investigation.}, } @article {pmid38885838, year = {2024}, author = {López Sanz, P and Azaña Defez, JM}, title = {Is ILVEN a misnomer? Proposal of MALID as an accurate nomenclature. Response to Polubothu et al's "ILVEN should be genotyped to direct treatment and genetic counselling".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e107-e108}, doi = {10.1016/j.jaad.2024.05.084}, pmid = {38885838}, issn = {1097-6787}, mesh = {Humans ; *Terminology as Topic ; *Genetic Counseling ; Genotype ; }, } @article {pmid38884646, year = {2024}, author = {Mielke, JK and Klingeborn, M and Schultz, EP and Markham, EL and Reese, ED and Alam, P and Mackenzie, IR and Ly, CV and Caughey, B and Cashman, NR and Leavens, MJ}, title = {Seeding activity of human superoxide dismutase 1 aggregates in familial and sporadic amyotrophic lateral sclerosis postmortem neural tissues by real-time quaking-induced conversion.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {100}, pmid = {38884646}, issn = {1432-0533}, support = {5P30GM140963-03/GM/NIGMS NIH HHS/United States ; P20 GM152335/GM/NIGMS NIH HHS/United States ; Sloan Scholars Mentoring Network Seed Grant//Alfred P. Sloan Foundation/ ; R21 EY033057/EY/NEI NIH HHS/United States ; P30 GM140963/GM/NIGMS NIH HHS/United States ; 1P20GM152335-01/GM/NIGMS NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; C9orf72 Protein/genetics ; Motor Cortex/pathology/metabolism ; Mutation/genetics ; *Spinal Cord/pathology/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; *Biomarkers/analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with average lifespan of 2-5 years after diagnosis. The identification of novel prognostic and pharmacodynamic biomarkers are needed to facilitate therapeutic development. Metalloprotein human superoxide dismutase 1 (SOD1) is known to accumulate and form aggregates in patient neural tissue with familial ALS linked to mutations in their SOD1 gene. Aggregates of SOD1 have also been detected in other forms of ALS, including the sporadic form and the most common familial form linked to abnormal hexanucleotide repeat expansions in the Chromosome 9 open reading frame 72 (C9ORF72) gene. Here, we report the development of a real-time quaking-induced conversion (RT-QuIC) seed amplification assay using a recombinant human SOD1 substrate to measure SOD1 seeding activity in postmortem spinal cord and motor cortex tissue from persons with different ALS etiologies. Our SOD1 RT-QuIC assay detected SOD1 seeds in motor cortex and spinal cord dilutions down to 10[-5]. Importantly, we detected SOD1 seeding activity in specimens from both sporadic and familial ALS cases, with the latter having mutations in either their SOD1 or C9ORF72 genes. Analyses of RT-QuIC parameters indicated similar lag phases in spinal cords of sporadic and familial ALS patients, but higher ThT fluorescence maxima by SOD1 familial ALS specimens and sporadic ALS thoracic cord specimens. For a subset of sporadic ALS patients, motor cortex and spinal cords were examined, with seeding activity in both anatomical regions. Our results suggest SOD1 seeds are in ALS patient neural tissues not linked to SOD1 mutation, suggesting that SOD1 seeding activity may be a promising biomarker, particularly in sporadic ALS cases for whom genetic testing is uninformative.}, } @article {pmid38884572, year = {2024}, author = {Benkirane, M and Bonhomme, M and Morsy, H and Safgren, SL and Marelli, C and Chaussenot, A and Smedley, D and Cipriani, V and de Sainte-Agathe, JM and Ding, C and Larrieu, L and Vestito, L and Margot, H and Lesca, G and Ramond, F and Castrioto, A and Baux, D and Verheijen, J and Sansa, E and Giunti, P and Haetty, A and Bergougnoux, A and Pointaux, M and Ardouin, O and Van Goethem, C and Vincent, MC and Hadjivassiliou, M and Cossée, M and Rouaud, T and Bartsch, O and Freeman, WD and Wierenga, KJ and Klee, EW and Vandrovcova, J and Houlden, H and Debant, A and Koenig, M}, title = {De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {11}, pages = {3681-3689}, doi = {10.1093/brain/awae193}, pmid = {38884572}, issn = {1460-2156}, support = {//Connaître les Syndromes Cérébelleux/ ; }, mesh = {Humans ; *Tubulin/genetics ; Male ; Female ; Middle Aged ; *Muscle Spasticity/genetics ; *Mutation, Missense/genetics ; Adult ; Aged ; Cerebellar Ataxia/genetics ; Spinocerebellar Ataxias/genetics ; Pedigree ; Cohort Studies ; France ; Intellectual Disability ; Optic Atrophy ; }, abstract = {Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis and frontotemporal dementia, based on identification of likely pathogenic variants in patients from distinct amyotrophic lateral sclerosis and frontotemporal dementia cohorts. By screening a multicentric French cohort of 448 unrelated probands presenting with cerebellar ataxia, we identified ultra-rare TUBA4A missense variants, all being absent from public databases and predicted pathogenic by multiple in silico tools. In addition, gene burden analyses in the 100 000 Genomes project (100KGP) showed enrichment of TUBA4A rare variants in the inherited ataxia group compared to controls [odds ratio: 57.0847 (10.2-576.7); P = 4.02 ×10-7]. Taken together, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harbouring a predicted pathogenic TUBA4A missense mutation, including five confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. Cultured fibroblasts from three patients harbouring distinct TUBA4A missense showed significant alterations in microtubule organization and dynamics, providing insight of TUBA4A variants pathogenicity. Our data confirm the identification of a hereditary spastic ataxia disease gene with variable age of onset, expanding the clinical spectrum of TUBA4A associated phenotypes.}, } @article {pmid38883980, year = {2024}, author = {Azam, HMH and Rößling, RI and Geithe, C and Khan, MM and Dinter, F and Hanack, K and Prüß, H and Husse, B and Roggenbuck, D and Schierack, P and Rödiger, S}, title = {MicroRNA biomarkers as next-generation diagnostic tools for neurodegenerative diseases: a comprehensive review.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1386735}, pmid = {38883980}, issn = {1662-5099}, abstract = {Neurodegenerative diseases (NDs) are characterized by abnormalities within neurons of the brain or spinal cord that gradually lose function, eventually leading to cell death. Upon examination of affected tissue, pathological changes reveal a loss of synapses, misfolded proteins, and activation of immune cells-all indicative of disease progression-before severe clinical symptoms become apparent. Early detection of NDs is crucial for potentially administering targeted medications that may delay disease advancement. Given their complex pathophysiological features and diverse clinical symptoms, there is a pressing need for sensitive and effective diagnostic methods for NDs. Biomarkers such as microRNAs (miRNAs) have been identified as potential tools for detecting these diseases. We explore the pivotal role of miRNAs in the context of NDs, focusing on Alzheimer's disease, Parkinson's disease, Multiple sclerosis, Huntington's disease, and Amyotrophic Lateral Sclerosis. The review delves into the intricate relationship between aging and NDs, highlighting structural and functional alterations in the aging brain and their implications for disease development. It elucidates how miRNAs and RNA-binding proteins are implicated in the pathogenesis of NDs and underscores the importance of investigating their expression and function in aging. Significantly, miRNAs exert substantial influence on post-translational modifications (PTMs), impacting not just the nervous system but a wide array of tissues and cell types as well. Specific miRNAs have been found to target proteins involved in ubiquitination or de-ubiquitination processes, which play a significant role in regulating protein function and stability. We discuss the link between miRNA, PTM, and NDs. Additionally, the review discusses the significance of miRNAs as biomarkers for early disease detection, offering insights into diagnostic strategies.}, } @article {pmid38882692, year = {2024}, author = {Yang, T and Wei, Q and Li, C and Ou, R and Lin, J and Cheng, Y and Xiao, Y and Shang, H}, title = {Peripheral immunity involvement in the cognitive impairment of sporadic amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1405275}, pmid = {38882692}, issn = {1664-2295}, abstract = {BACKGROUND: Recent research has indicated the significance of immune activation in amyotrophic lateral sclerosis (ALS). However, the impact of peripheral immunity on cognitive impairment in sporadic ALS remains poorly characterized. Therefore, we aim to assess the relationship between peripheral immune parameters and cognitive impairment in patients with sporadic ALS.

METHODS: A case-control study involving 289 patients with sporadic ALS was conducted. All participants underwent cognitive assessment and measurements of blood immune parameters. The main outcomes included adjusted odds ratios (ORs) in multivariate logistic regression analysis and adjusted coefficients in a multivariate linear regression model. Sensitivity analysis was performed with stratification by the King's clinical stage.

RESULTS: Cognitive impairment was observed in 98 (33.9%) patients. Higher counts of leukocyte (OR, 0.53; 95% CI, 0.29 to 0.95; p = 0.03), neutrophil (OR, 0.48; 95% CI, 0.26 to 0.88; p = 0.02), and monocyte (OR, 0.33; 95% CI, 0.18 to 0.60; p < 0.001) were significantly associated with better cognitive preformence in sporadic ALS, particularly among patients in King's clinical stages 1 and 2. Conversely, a higher percentage of CD4+ T cells was linked to an increased risk of cognitive impairment (OR, 2.79; 95% CI, 1.52 to 5.09; p = 0.001), particularly evident in patients in King's clinical stage 3.

CONCLUSION: These results highlight the involvement of peripheral immunity in the cognitive impairment of sporadic ALS and suggest dynamic and intricate roles that vary across disease stages. Elucidating the links between immunity and ALS sheds light on the pathophysiological mechanisms underlying this fatal neurodegenerative disorder and informs potential immunotherapeutic strategies.}, } @article {pmid38879961, year = {2024}, author = {Milella, G and Zoccolella, S and Giugno, A and Filardi, M and D'Errico, E and Piccirilli, G and Nanni, AG and Urso, D and Nigro, S and Tafuri, B and Tamburrino, L and Gnoni, V and Logroscino, G}, title = {Mapping lower-limbs muscle vulnerability in patients with ALS: The role of upper and lower motor neurons.}, journal = {Journal of the neurological sciences}, volume = {462}, number = {}, pages = {123098}, doi = {10.1016/j.jns.2024.123098}, pmid = {38879961}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Muscle, Skeletal/physiopathology ; *Motor Neurons/physiology ; Aged ; *Muscle Strength/physiology ; *Lower Extremity/physiopathology ; Muscle Weakness/physiopathology/etiology ; Adult ; Cohort Studies ; }, abstract = {BACKGROUND: Several studies have reported disproportionate wasting of the flexor muscles of the lower limbs (LL) compared to the extensors in patients with amyotrophic lateral sclerosis (ALS). However, these studies have involved small sample sizes (n 〈100), and their findings have been inconsistent. Thus, it remains uncertain whether a distinct pattern of LL muscle weakness is specific to ALS.

AIMS: To investigate the muscle weakness pattern in the LL at the knee, ankle, and toes in a large cohort of ALS patients and evaluate the relationship between the pattern of muscle strength and the extent of upper (UMN) and lower (LMN) motoneuron impairment.

MATERIAL AND METHODS: The strength of flexor and extensor muscle was evaluated in 1250 legs of newly diagnosed ALS patients at the knee, ankle, and foot toes. UMN and LMN burden were assessed using validated scores. Within-subjects ANOVA considering the type of muscle (flexor/extensor) and anatomical sites (knee/ankle/toes) and mixed-factorial ANOVA were conducted to explore the impact of UMN and LMN impairments on the muscle weakness pattern.

RESULTS: Muscle strength showed a significant decline from proximal to distal regions. Indeed both flexor and extensor muscles at the knee outperformed those at the ankle and toes. Within each site, extensor muscles exhibited less strength than flexor, except at the knee. Patients with heightened UMN impairment showed a more marked difference between flexors and extensors within each site, with extensor muscles being more compromised at the ankle and toes. Higher LMN impairment corresponded to a more pronounced weakness in flexor muscles at the ankle and toes compared to those at the knee.

CONCLUSIONS: The extensor muscle at the knee and the flexors at the foot and toes displayed relative resistance to ALS disease. UMN impairment amplified the differences between flexor and extensor muscles within each site, while LMN impairment demonstrated a clear distal-to-proximal vulnerability.}, } @article {pmid38879765, year = {2024}, author = {Sharma, A and Kakkar, A and Khanna, M and Devi, S}, title = {Arbutin's Potential in Neuroprotection: A Promising Role in Mitigating Neurodegenerative Diseases.}, journal = {Current drug research reviews}, volume = {}, number = {}, pages = {}, doi = {10.2174/0125899775298987240528050110}, pmid = {38879765}, issn = {2589-9783}, abstract = {Naturally occurring glycosylated hydroquinone Arbutin, has drawn interest due to its possible function in reducing the risk of neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Arbutin is well-known for its anti-inflammatory and antioxidant properties, which are essential in preventing oxidative stress and neuroinflammation. Research has shown that arbutin might alter important physiological pathways connected to protein misfolding, synapse function, and neuronal survival processes linked to the development of neurodegenerative diseases. Arbutin can also penetrate the blood- -brain barrier, which increases its therapeutic potential. Arbutin's neuroprotective properties and promise as a therapeutic agent for neurodegenerative illnesses are summarized in this review, which also emphasizes the need for further study into the molecular processes behind these effects.}, } @article {pmid38879591, year = {2024}, author = {Lambert-Smith, IA and Shephard, VK and McAlary, L and Yerbury, JJ and Saunders, DN}, title = {High-content analysis of proteostasis capacity in cellular models of amyotrophic lateral sclerosis (ALS).}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {13844}, pmid = {38879591}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Proteostasis ; Humans ; *Superoxide Dismutase-1/metabolism/genetics ; *Protein Folding ; *Mutation ; Cell Line ; Mice ; Animals ; }, abstract = {Disrupted proteome homeostasis (proteostasis) in amyotrophic lateral sclerosis (ALS) has been a major focus of research in the past two decades. However, the proteostasis processes that become disturbed in ALS are not fully understood. Obtaining more detailed knowledge of proteostasis disruption in association with different ALS-causing mutations will improve our understanding of ALS pathophysiology and may identify novel therapeutic targets and strategies for ALS patients. Here we describe the development and use of a novel high-content analysis (HCA) assay to investigate proteostasis disturbances caused by the expression of several ALS-causing gene variants. This assay involves the use of conformationally-destabilised mutants of firefly luciferase (Fluc) to examine protein folding/re-folding capacity in NSC-34 cells expressing ALS-associated mutations in the genes encoding superoxide dismutase-1 (SOD1[A4V]) and cyclin F (CCNF[S621G]). We demonstrate that these Fluc isoforms can be used in high-throughput format to report on reductions in the activity of the chaperone network that result from the expression of SOD1[A4V], providing multiplexed information at single-cell resolution. In addition to SOD1[A4V] and CCNF[S621G], NSC-34 models of ALS-associated TDP-43, FUS, UBQLN2, OPTN, VCP and VAPB mutants were generated that could be screened using this assay in future work. For ALS-associated mutant proteins that do cause reductions in protein quality control capacity, such as SOD1[A4V], this assay has potential to be applied in drug screening studies to identify candidate compounds that can ameliorate this deficiency.}, } @article {pmid38879469, year = {2024}, author = {Dai, Z and Zhou, X}, title = {Associations between allostatic load and hepatic steatosis and liver fibrosis: evidence from NHANES 2017-2020.}, journal = {BMC public health}, volume = {24}, number = {1}, pages = {1602}, pmid = {38879469}, issn = {1471-2458}, mesh = {Humans ; Female ; Male ; *Allostasis/physiology ; Middle Aged ; *Liver Cirrhosis ; *Nutrition Surveys ; *Fatty Liver/physiopathology ; Adult ; Aged ; Cross-Sectional Studies ; Risk Factors ; }, abstract = {BACKGROUND: Allostatic load, the cumulative strain resulting from chronic stress responses, has been linked to disease occurrence and progression, yet research quantifying this relationship is limited. This study aimed to explore the relationship between allostatic load score (ALS) levels and the degree of hepatic steatosis and fibrosis.

METHODS: Data from the National Health and Nutrition Examination Survey 2017-2020 were analyzed. The ALS was based on the statistical distribution, assigning one point for each biomarker if it was in the highest risk quartile, and then summing them to generate the ALS score (range, 0-8). The multivariate linear regression was employed to analyze the association between the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) with ALS. Additionally, multinomial logistic regression was used to investigate the association between ALS and the degree of hepatic steatosis and fibrosis.

RESULTS: Participants had a weighted mean age of 52.69 years and 56.14% were female. In the multivariate linear regression analysis, ALS showed a significant positive correlation with CAP (β = 15.56, 95% CI: 14.50-16.62) and LSM (β = 0.58, 95% CI: 0.48-0.67). Age, healthy dietary level, and PIR had significant interactions with this positive correlation. In the multinomial logistic regression analysis, ALS exhibited a significant positive correlation with different degrees of hepatic steatosis and fibrosis. Consistency of the results was observed in sensitivity analyses using clinical thresholds of ALS.

CONCLUSIONS: Comprehensive clinical assessment targeting load adaptation may enhance the effectiveness of risk assessment in patients with hepatic steatosis and fibrosis.}, } @article {pmid38879333, year = {2024}, author = {Han, Y and Gao, H and Sun, Y and Wang, Y and Yan, C and Ma, H and Liu, X and Huang, Z}, title = {Target gene overexpression and enhanced metabolism confer resistance to nicosulfuron in Eriochloa villosa (Thunb.).}, journal = {Pesticide biochemistry and physiology}, volume = {202}, number = {}, pages = {105946}, doi = {10.1016/j.pestbp.2024.105946}, pmid = {38879333}, issn = {1095-9939}, mesh = {*Sulfonylurea Compounds/pharmacology ; *Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Pyridines/pharmacology ; Plant Proteins/genetics/metabolism ; Gene Expression Regulation, Plant/drug effects ; Poaceae/genetics/drug effects ; }, abstract = {Eriochloa villosa (Thunb.) Kunth is a troublesome weed widely distributed in maize (Zea mays L.) fields in Northeast China. Many populations of E. villosa have evolved resistance to nicosulfuron herbicides, which inhibit acetolactate synthase (ALS). The objectives of this research were to confirm that E. villosa is resistant to nicosulfuron and to investigate the basis of nicosulfuron resistance. Whole-plant dose-response studies revealed that the R population had not developed a high level of cross-resistance and exhibited greater resistant (25.62-fold) to nicosulfuron than that of the S population and had not yet developed a high level of cross-resistance. An in vitro ALS activity assay demonstrated that the I50 of nicosulfuron was 6.87-fold greater in the R population than the S population. However, based on ALS gene sequencing, the target ALS gene in the R population did not contain mutations. Quantitative real-time polymerase chain reaction (qRT-PCR) revealed that ALS gene expression between the R and S populations was significantly different after nicosulfuron application, but no differences were observed in the gene copy number. After the cytochrome P450 inhibitor malathion or the GST inhibitor NBD-Cl was applied, the resistant E. villosa population exhibited increased sensitivity to nicosulfuron. Based on the activities of GSTs and P450s, the activities of the R population were greater than those of the S population after nicosulfuron application. This is the first report that the resistance of E. villosa to ALS inhibitors results from increased target gene expression and increased metabolism. These findings provide a theoretical foundation for the effective control of herbicide-resistant E. villosa.}, } @article {pmid38879294, year = {2024}, author = {Xu, H and Cheng, J and Leng, Q and Liang, S and Sun, L and Su, W and Xue, F and Wu, R}, title = {Nontarget site-based resistance to nicosulfuron and identification of candidate genes in Cucumis melo L. var. agrestis Naud. via RNA-Seq transcriptome analysis.}, journal = {Pesticide biochemistry and physiology}, volume = {202}, number = {}, pages = {105912}, doi = {10.1016/j.pestbp.2024.105912}, pmid = {38879294}, issn = {1095-9939}, mesh = {*Herbicide Resistance/genetics ; *Sulfonylurea Compounds/pharmacology ; *Herbicides/pharmacology/toxicity ; *Acetolactate Synthase/genetics/metabolism ; *Cucumis melo/genetics/drug effects ; *Pyridines/pharmacology ; RNA-Seq ; Gene Expression Profiling ; Malathion/pharmacology ; Gene Expression Regulation, Plant/drug effects ; Plant Proteins/genetics/metabolism ; }, abstract = {Herbicide resistance is a worldwide concern for weed control. Cucumis melo L. var. agrestis Naud. (C. melo) is an annual trailing vine weed that is commonly controlled by nicosulfuron, acetolactate synthase (ALS)-inhibiting herbicides. However, long-term use of this herbicide has led to the emergence of resistance and several nicosulfuron resistant populations of C. melo have been found. Here we identified a resistant (R) C. melo population exhibiting 7.31-fold resistance to nicosulfuron compared with a reference sensitive (S) population. ALS gene sequencing of the target site revealed no amino acid substitution in R plants, and no difference in enzyme activity, as shown by ALS activity assays in vitro. ALS gene expression was not significantly different before and after the application of nicosulfuron. Pretreatment with the cytochrome P450 monooxygenase (P450) inhibitor malathion reduced nicosulfuron resistance in the R population. RNA-Seq transcriptome analysis was used to identify candidate genes that may confer metabolic resistance to nicosulfuron. We selected genes with annotations related to detoxification functions. A total of 20 candidate genes (7 P450 genes, 1 glutathione S-transferase (GST) gene, 2 ATP-binding cassette (ABC) transporters, and 10 glycosyltransferase (GT)) were identified; 12 of them (7 P450s, 1 GST, 2 ABC transporters, and 2 GTs) were demonstrated significantly differential expression between R and S by quantitative real-time RT-PCR (qRT-PCR). Our findings revealed that the resistance mechanism in C. melo was nontarget-site based. Our results also provide a valuable resource for studying the molecular mechanisms of weed resistance.}, } @article {pmid38879100, year = {2024}, author = {Viccaro, F and Lecci, A and Baccolini, V and Sciurti, A and Piamonti, D and Inghilleri, M and D'Antoni, L and Palange, P}, title = {Prediction of cough effectiveness in amyotrophic lateral sclerosis patients assessed by ultrasuond of the diaphragm during the cough expiration phase.}, journal = {Respiratory physiology & neurobiology}, volume = {327}, number = {}, pages = {104299}, doi = {10.1016/j.resp.2024.104299}, pmid = {38879100}, issn = {1878-1519}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnostic imaging ; *Cough/physiopathology ; Male ; *Diaphragm/physiopathology/diagnostic imaging ; Female ; Middle Aged ; Aged ; *Ultrasonography ; Exhalation/physiology ; Peak Expiratory Flow Rate/physiology ; Adult ; }, abstract = {Assessing cough effectiveness, using Cough Peak Flow, is crucial for patients with Neuromuscular Diseases, such as Amyotrophic Lateral Sclerosis. Impaired cough function can contribute to respiratory decline and failure. The goal of the study is to determine the correlation between diaphragmatic excursion and cough expiratory phase, potentially utilizing ultrasonographic indices to estimate Cough Peak Flow in these patients. Twenty-two patients were enrolled in this study. The upward displacement of the diaphragm was measured with ultrasonography during voluntary cough expiration and Cough Peak Flow was simultaneously measured. A multivariable linear regression model was built to quantify the association between Cough Peak Flow and diaphragm expiratory excursion. There is significative relationship between Cough Peak Flow and diaphragm excursion with a Pearson's r coefficient of 0.86 observed in the patients group. Multiple linear regression analysis for Cough Peak Flow (Adjusted R[2] = 0.86) revealed significant associations between Cough Peak Flow and expiratory excursion (adjusted β-coefficient: 64.78, 95 %, CI: 51.50-78.07, p<0.001) and sex (adjusted β-coefficient: -69.06; 95 % CI: -109.98 to -28.15, p=0.001). Our results predict the cough effectiveness by using M-mode diaphragmatic sonography with a potentially significant impact on therapeutic choices.}, } @article {pmid38879065, year = {2024}, author = {Ashrafzadeh-Kian, S and Figdore, D and Larson, B and Deters, R and Abou-Diwan, C and Bornhorst, J and Algeciras-Schimnich, A}, title = {Head-to-head comparison of four plasma neurofilament light chain (NfL) immunoassays.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {561}, number = {}, pages = {119817}, doi = {10.1016/j.cca.2024.119817}, pmid = {38879065}, issn = {1873-3492}, mesh = {Humans ; Immunoassay/methods ; *Neurofilament Proteins/blood ; Multiple Sclerosis/blood/diagnosis ; Biomarkers/blood ; Amyotrophic Lateral Sclerosis/blood/diagnosis ; Female ; Male ; Middle Aged ; }, abstract = {BACKGROUND: Neurofilament Light Chain (NfL) is an emerging blood biomarker of neuro-axonal injury and neurodegeneration with the potential to be used in the clinical management of various neurological conditions. Various NfL immunoassays are in development on high-throughput automated systems, but little information is available related to the comparability between assays. In this study, we performed a head-to-head comparison of four NfL immunoassays using plasma samples from individuals with various neurological conditions.

METHODS: EDTA plasma samples in which NfL was ordered clinically were stratified according to diagnosis. NfL concentrations (pg/mL) in plasma were obtained using the Quanterix Simoa®, the Roche Elecsys, the Siemens Healthineers Atellica®IM, and the Fujirebio Lumipulse® NfL assays. Passing-Bablok regression analyses were performed to assess the correlation and bias between methods. Additionally, the distribution of NfL concentrations for each assay was assessed in three disease groups: amyotrophic lateral sclerosis (ALS) upon initial diagnosis, ALS treated, and multiple sclerosis (MS).

RESULTS: The R[2] between assays were all ≥ 0.95, however, significant proportional bias was observed between some assays. In particular, the Roche Elecsys assay NfL concentrations were significantly lower (∼85 %) when compared against the other three assays. The four assays were comparable with regards to the percentage of patients that were identified as having an elevated NfL result in the various clinical groups: ALS initial diagnoses (83-94 %), ALS untreated (93-100 %), and MS (8-18 %).

CONCLUSIONS: This is the first study describing a head-to-head comparison of four automated NfL immunoassays. We demonstrate that there is a strong correlation between assays but a lack of standardization which is evident by the bias observed between some of the evaluated methods. These analytical differences will be important to consider when using NfL as a biomarker of neurodegeneration.}, } @article {pmid38878774, year = {2024}, author = {Kumbier, K and Roth, M and Li, Z and Lazzari-Dean, J and Waters, C and Hammerlindl, S and Rinaldi, C and Huang, P and Korobeynikov, VA and , and Phatnani, H and Shneider, N and Jacobson, MP and Wu, LF and Altschuler, SJ}, title = {Identifying FUS amyotrophic lateral sclerosis disease signatures in patient dermal fibroblasts.}, journal = {Developmental cell}, volume = {59}, number = {16}, pages = {2134-2142.e6}, doi = {10.1016/j.devcel.2024.05.011}, pmid = {38878774}, issn = {1878-1551}, support = {R01 NS106236/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Fibroblasts/metabolism/pathology ; *RNA-Binding Protein FUS/metabolism/genetics ; Mutation/genetics ; Male ; Female ; Skin/pathology/metabolism ; Machine Learning ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, highly heterogeneous neurodegenerative disease, underscoring the importance of obtaining information to personalize clinical decisions quickly after diagnosis. Here, we investigated whether ALS-relevant signatures can be detected directly from biopsied patient fibroblasts. We profiled familial ALS (fALS) fibroblasts, representing a range of mutations in the fused in sarcoma (FUS) gene and ages of onset. To differentiate FUS fALS and healthy control fibroblasts, machine-learning classifiers were trained separately on high-content imaging and transcriptional profiles. "Molecular ALS phenotype" scores, derived from these classifiers, captured a spectrum from disease to health. Interestingly, these scores negatively correlated with age of onset, identified several pre-symptomatic individuals and sporadic ALS (sALS) patients with FUS-like fibroblasts, and quantified "movement" of FUS fALS and "FUS-like" sALS toward health upon FUS ASO treatment. Taken together, these findings provide evidence that non-neuronal patient fibroblasts can be used for rapid, personalized assessment in ALS.}, } @article {pmid38878554, year = {2024}, author = {Mincic, AM and Antal, M and Filip, L and Miere, D}, title = {Modulation of gut microbiome in the treatment of neurodegenerative diseases: A systematic review.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {43}, number = {7}, pages = {1832-1849}, doi = {10.1016/j.clnu.2024.05.036}, pmid = {38878554}, issn = {1532-1983}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Neurodegenerative Diseases/microbiology/therapy ; *Probiotics/administration & dosage/therapeutic use ; *Prebiotics/administration & dosage ; *Dysbiosis/therapy/microbiology ; Animals ; Fecal Microbiota Transplantation ; }, abstract = {BACKGROUND AND AIMS: Microbiota plays an essential role in maintaining body health, through positive influences on metabolic, defensive, and trophic processes and on intercellular communication. Imbalance in intestinal flora, with the proliferation of harmful bacterial species (dysbiosis) is consistently reported in chronic illnesses, including neurodegenerative diseases (ND). Correcting dysbiosis can have a beneficial impact on the symptoms and evolution of ND. This review examines the effects of microbiota modulation through administration of probiotics, prebiotics, symbiotics, or prebiotics' metabolites (postbiotics) in patients with ND like multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).

METHODS: PubMed, Web of Science, Medline databases and ClinicalTrials.gov registry searches were performed using pre-/pro-/postbiotics and ND-related terms. Further references were obtained by checking relevant articles.

RESULTS: Although few compared to animal studies, the human studies generally show positive effects on disease-specific symptoms, overall health, metabolic parameters, on oxidative stress and immunological markers. Therapy with probiotics in various forms (mixtures of bacterial strains, fecal microbiota transplant, diets rich in fermented foods) exert favorable effects on patients' mental health, cognition, and quality of life, targeting pathogenetic ND mechanisms and inducing reparatory mechanisms at the cellular level. More encouraging results have been observed in prebiotic/postbiotic therapy in some ND.

CONCLUSIONS: The effects of probiotic-related interventions depend on the patients' ND stage and pre-existing allopathic medication. Further studies on larger cohorts and long term comprehensive neuropsychiatric, metabolic, biochemical testing, and neuroimaging monitoring are necessary to optimize therapeutic protocols in ND.}, } @article {pmid38878150, year = {2025}, author = {Wang, F and Wen, H and Liu, L and Aisa, HA and Xin, X}, title = {A Pair of Epimers of Lignan Alleviate Neuroinflammatory Effects by Modulating iNOS/COX-2 and MAPK/NF-κB Signaling Pathways.}, journal = {Inflammation}, volume = {48}, number = {1}, pages = {361-371}, pmid = {38878150}, issn = {1573-2576}, support = {2020YFE0205600//the National Key Research and Development Program of China/ ; U1703235//the National Natural Science Foundation of China/ ; }, mesh = {*Lignans/pharmacology ; *Cyclooxygenase 2/metabolism ; Animals ; *NF-kappa B/metabolism ; *Nitric Oxide Synthase Type II/metabolism ; Mice ; *Anti-Inflammatory Agents/pharmacology/chemistry ; MAP Kinase Signaling System/drug effects ; Signal Transduction/drug effects ; Artemisia/chemistry ; Cell Line ; Neuroinflammatory Diseases/drug therapy/metabolism ; Lipopolysaccharides ; Microglia/drug effects/metabolism ; }, abstract = {Neuroinflammation is a causative factor in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Previous studies have shown that Artemisia mongolica has anti-inflammatory properties. Aschantin (AM3) has been shown to have anti-inflammatory effects. However, the mechanism of AM3 and its epimer epi-aschantin (AM2) remains controversial. Therefore, the present study explored the mechanism of neuroinflammation by AM2 and AM3 and attempted to reveal the relationship between the structure of AM2 and AM3 and anti-neuroinflammatory activity. We isolated for the first time 12 lignans from A. mongolica that inhibited NO content at 10 μM in LPS-stimulated BV2 cells. Among them, epi-aschantin (AM2) and Aschantin (AM3) showed significant inhibition in NO screening. With further studies, we found that both AM2 and AM3 effectively inhibited the overproduction of NO, PGE2, IL-6, TNF-α and MCP-1, as well as the overexpression of COX-2 and iNOS. Mechanistic studies have shown AM2 and AM3 significantly inhibited the phosphorylation of ERK, JNK and P-38 in the MAPK signaling pathway and p-IκBα,p-p65 and blocked p65 entry into the nucleus. The results suggested that the pair of epimers (AM2 and AM3) can be used as potential therapeutic agents in the treatment of various brain disorders and that structural differences do not differ in anti-neuroinflammatory effects.}, } @article {pmid38878106, year = {2024}, author = {Chourpiliadis, C and Seitz, C and Lovik, A and Joyce, EE and Pan, L and Hu, Y and Kläppe, U and Samuelsson, K and Press, R and Ingre, C and Fang, F}, title = {Lifestyle and medical conditions in relation to ALS risk and progression-an introduction to the Swedish ALSrisc Study.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5447-5459}, pmid = {38878106}, issn = {1432-1459}, support = {R01TS000324-01-00//US Center for Disease Control and Prevention/ ; 2019-01088//Swedish Research Council/ ; 2023-02428//Swedish Research Council/ ; MegaALS 802091//European Research Council Starting Grant/ ; R01 TS000324/TS/ATSDR CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Male ; Sweden/epidemiology ; Female ; Middle Aged ; Aged ; *Life Style ; *Disease Progression ; *Body Mass Index ; Adult ; Risk Factors ; Smoking/epidemiology ; Diabetes Mellitus/epidemiology ; Hypertension/epidemiology ; Hypercholesterolemia/epidemiology ; }, abstract = {BACKGROUND: This study was an introduction to the Swedish ALSrisc Study and explored the association of lifestyle and medical conditions, with risk and progression of amyotrophic lateral sclerosis (ALS).

METHODS: We included 265 newly diagnosed ALS patients during 2016-2022 in Stockholm and 207 ALS-free siblings and partners of the patients as controls. Information on body mass index (BMI), smoking, and history of head injuries, diabetes mellitus, hypercholesterolemia, and hypertension was obtained through the Euro-MOTOR questionnaire at recruitment. Patients were followed from diagnosis until death, invasive ventilation, or November 30, 2022.

RESULTS: Higher BMI at recruitment was associated with lower risk for ALS (OR 0.89, 95%CI 0.83-0.95), especially among those diagnosed after 65 years. One unit increase in the average BMI during the 3 decades before diagnosis was associated with a lower risk for ALS (OR 0.94, 95%CI 0.89-0.99). Diabetes was associated with lower risk of ALS (OR 0.38, 95%CI 0.16-0.90), while hypercholesterolemia was associated with higher risk of ALS (OR 2.10, 95%CI 1.13-3.90). Higher BMI at diagnosis was associated with lower risk of death (HR 0.91, 95%CI 0.84-0.98), while the highest level of smoking exposure (in pack-years) (HR 1.90, 95%CI 1.20-3.00), hypercholesterolemia (HR 1.84, 95%CI 1.06-3.19), and hypertension (HR 1.76, 95%CI 1.03-3.01) were associated with higher risk of death, following ALS diagnosis.

CONCLUSIONS: Higher BMI and diabetes were associated with lower risk of ALS. Higher BMI was associated with lower risk of death, whereas smoking (especially in high pack-years), hypercholesterolemia, and hypertension were associated with higher risk of death after ALS diagnosis.}, } @article {pmid38877004, year = {2024}, author = {Costa, RG and Conceição, A and Matos, CA and Nóbrega, C}, title = {The polyglutamine protein ATXN2: from its molecular functions to its involvement in disease.}, journal = {Cell death & disease}, volume = {15}, number = {6}, pages = {415}, pmid = {38877004}, issn = {2041-4889}, mesh = {Humans ; *Ataxin-2/metabolism/genetics ; *Peptides/metabolism/genetics ; Animals ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Spinocerebellar Ataxias/metabolism/genetics/pathology ; }, abstract = {A CAG repeat sequence in the ATXN2 gene encodes a polyglutamine (polyQ) tract within the ataxin-2 (ATXN2) protein, showcasing a complex landscape of functions that have been progressively unveiled over recent decades. Despite significant progresses in the field, a comprehensive overview of the mechanisms governed by ATXN2 remains elusive. This multifaceted protein emerges as a key player in RNA metabolism, stress granules dynamics, endocytosis, calcium signaling, and the regulation of the circadian rhythm. The CAG overexpansion within the ATXN2 gene produces a protein with an extended poly(Q) tract, inducing consequential alterations in conformational dynamics which confer a toxic gain and/or partial loss of function. Although overexpanded ATXN2 is predominantly linked to spinocerebellar ataxia type 2 (SCA2), intermediate expansions are also implicated in amyotrophic lateral sclerosis (ALS) and parkinsonism. While the molecular intricacies await full elucidation, SCA2 presents ATXN2-associated pathological features, encompassing autophagy impairment, RNA-mediated toxicity, heightened oxidative stress, and disruption of calcium homeostasis. Presently, SCA2 remains incurable, with patients reliant on symptomatic and supportive treatments. In the pursuit of therapeutic solutions, various studies have explored avenues ranging from pharmacological drugs to advanced therapies, including cell or gene-based approaches. These endeavours aim to address the root causes or counteract distinct pathological features of SCA2. This review is intended to provide an updated compendium of ATXN2 functions, delineate the associated pathological mechanisms, and present current perspectives on the development of innovative therapeutic strategies.}, } @article {pmid38876745, year = {2024}, author = {van Selms, MKA and van der Linden, MW and van der Meijden, C and Lobbezoo, F}, title = {A call for optimal oral care in patients with ALS.}, journal = {The Lancet. Neurology}, volume = {23}, number = {7}, pages = {670}, doi = {10.1016/S1474-4422(24)00226-6}, pmid = {38876745}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Oral Hygiene ; }, } @article {pmid38876730, year = {2024}, author = {The Lancet Neurology, }, title = {Multidisciplinary care for amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {23}, number = {7}, pages = {649}, doi = {10.1016/S1474-4422(24)00227-8}, pmid = {38876730}, issn = {1474-4465}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Patient Care Team ; }, } @article {pmid38876108, year = {2024}, author = {Scaber, J and Thomas-Wright, I and Clark, AJ and Xu, Y and Vahsen, BF and Carcolé, M and Dafinca, R and Farrimond, L and Isaacs, AM and Bennett, DL and Talbot, K}, title = {Cellular and axonal transport phenotypes due to the C9ORF72 HRE in iPSC motor and sensory neurons.}, journal = {Stem cell reports}, volume = {19}, number = {7}, pages = {957-972}, pmid = {38876108}, issn = {2213-6711}, support = {MR/T020113/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Induced Pluripotent Stem Cells/metabolism/cytology ; *C9orf72 Protein/genetics/metabolism ; Humans ; *Motor Neurons/metabolism ; *Sensory Receptor Cells/metabolism ; *Axonal Transport ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Phenotype ; *DNA Repeat Expansion/genetics ; }, abstract = {Induced pluripotent stem cell (iPSC)-derived motor neurons (MNs) from patients with amyotrophic lateral sclerosis (ALS) and the C9ORF72 hexanucleotide repeat expansion (HRE) have multiple cellular phenotypes, but which of these accurately reflect the biology underlying the cell-specific vulnerability of ALS is uncertain. We therefore compared phenotypes due to the C9ORF72 HRE in MNs with sensory neurons (SNs), which are relatively spared in ALS. The iPSC models were able to partially reproduce the differential gene expression seen between adult SNs and MNs. We demonstrated that the typical hallmarks of C9ORF72-ALS, including RNA foci and dipeptide formation, as well as specific axonal transport defects, occurred equally in MNs and SNs, suggesting that these in vitro phenotypes are not sufficient to explain the cell-type selectivity of ALS in isolation.}, } @article {pmid38875517, year = {2024}, author = {Michielsen, A and van Veenhuijzen, K and Janse van Mantgem, MR and van Es, MA and Veldink, JH and van Eijk, RPA and van den Berg, LH and Westeneng, HJ}, title = {Association Between Hypothalamic Volume and Metabolism, Cognition, and Behavior in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209603}, pmid = {38875517}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *Hypothalamus/diagnostic imaging/metabolism/pathology ; *Magnetic Resonance Imaging ; Aged ; Cross-Sectional Studies ; Longitudinal Studies ; Disease Progression ; Cognition/physiology ; Adult ; Energy Metabolism/physiology ; }, abstract = {BACKGROUND AND OBJECTIVES: Dysfunction of energy metabolism, cognition, and behavior are important nonmotor symptoms of amyotrophic lateral sclerosis (ALS), negatively affecting survival and quality of life, but poorly understood. Neuroimaging is ideally suited to studying nonmotor neurodegeneration in ALS, but few studies have focused on the hypothalamus, a key region for regulating energy homeostasis, cognition, and behavior. We evaluated, therefore, hypothalamic neurodegeneration in ALS and explored the relationship between hypothalamic volumes and dysregulation of energy metabolism, cognitive and behavioral changes, disease progression, and survival.

METHODS: Patients with ALS and population-based controls were included for this cross-sectional and longitudinal MRI study. The hypothalamus was segmented into 5 subregions and their volumes were calculated. Linear (mixed) models, adjusted for age, sex, and total intracranial volume, were used to compare hypothalamic volumes between groups and to analyze associations with metabolism, cognition, behavior, and disease progression. Cox proportional hazard models were used to investigate the relationship of hypothalamic volumes with survival. Permutation-based corrections for multiple hypothesis testing were applied to all analyses to control the family-wise error rate.

RESULTS: Data were available for 564 patients with ALS and 356 controls. The volume of the anterior superior subregion of the hypothalamus was smaller in patients with ALS than in controls (β = -0.70 [-1.15 to -0.25], p = 0.013). Weight loss, memory impairments, and behavioral disinhibition were associated with a smaller posterior hypothalamus (β = -4.79 [-8.39 to -2.49], p = 0.001, β = -10.14 [-15.88 to -4.39], p = 0.004, and β = -12.09 [-18.83 to -5.35], p = 0.003, respectively). Furthermore, the volume of this subregion decreased faster over time in patients than in controls (β = -0.25 [0.42 to -0.09], p = 0.013), and a smaller volume of this structure was correlated with shorter survival (hazard ratio = 0.36 [0.21-0.61], p = 0.029).

DISCUSSION: We obtained evidence for hypothalamic involvement in ALS, specifically marked by atrophy of the anterior superior subregion. Moreover, we found that atrophy of the posterior hypothalamus was associated with weight loss, memory dysfunction, behavioral disinhibition, and survival, and that this subregion deteriorated faster in patients with ALS than in controls. These findings improve our understanding of nonmotor involvement in ALS and could contribute to the identification of new treatment targets for this devastating disease.}, } @article {pmid38875513, year = {2024}, author = {van Eijk, RPA and van den Berg, LH and Lu, Y}, title = {Cultivating Patient Preferences in ALS Clinical Trials: Reliability and Prognostic Value of the Patient-Ranked Order of Function.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209502}, pmid = {38875513}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; *Patient Preference ; Reproducibility of Results ; Prognosis ; Aged ; Netherlands ; Clinical Trials as Topic ; Surveys and Questionnaires ; Registries ; }, abstract = {BACKGROUND AND OBJECTIVES: The Patient-Ranked Order of Function (PROOF) is a novel approach to account for patient-reported preferences in the evaluation of treatments of amyotrophic lateral sclerosis (ALS). In this study, we assess the reliability and prognostic value of different sets of patient-reported preferences that can be used for the PROOF end point.

METHODS: Data were obtained through online surveys over the course of 12 months using the population-based registry of the Netherlands. Patients were asked to score functional domains of the ALS Functional Rating Scale (ALSFRS-R) and rank the order of importance of each domain. Two weeks after the initial invite, the questionnaire was repeated to evaluate test-retest reliability. Vital status was extracted from the municipal population register.

RESULTS: In total, 611 patients with ALS were followed up for survival and 382 patients were included in the test-retest reliability study. All versions of PROOF, using different sets of preferences, resulted in excellent reliability (intraclass correlation coefficients ranged from 0.89 [95% CI 0.87-0.91] to 0.97 [95% CI 0.97-0.98], all p < 0.001), without systematic differences between baseline and week 2 (mean rank difference range -1 to -3 [95% CI range -8 to 2], all p > 0.20). Preferences about future events were more variable than preferences about current symptoms. All versions of PROOF strongly predicted overall survival (hazard ratios per 10th rank percentile ranged from 0.80 to 0.83 [95% CI range 0.76-0.87], all p < 0.001) and had a more even separation of survival curves between rank-stratified subgroups compared with the ALSFRS-R total score.

DISCUSSION: In a large cohort of patients, we show how patient-reported preferences can be measured and integrated reliably with the ALSFRS-R without leading to systematic bias. Patient preferences may provide unique prognostic information in addition to what is already measured conventionally. This could provide a more comprehensive understanding of how medical interventions effectively address the patient's concerns and improve what matters most to them.}, } @article {pmid38875346, year = {2024}, author = {}, title = {Erratum for the Research Article: "Sulfated disaccharide protects membrane and DNA damages from arginine-rich dipeptide repeats in ALS" by Chang et al.}, journal = {Science advances}, volume = {10}, number = {24}, pages = {eadq7259}, doi = {10.1126/sciadv.adq7259}, pmid = {38875346}, issn = {2375-2548}, } @article {pmid38874845, year = {2024}, author = {Birbaumer, N}, title = {"Your Thoughts are (were) Free!": Brain-Computer-Interfaces, Neurofeedback, Detection of Deception, and the Future of Mind-Reading.}, journal = {Applied psychophysiology and biofeedback}, volume = {}, number = {}, pages = {}, pmid = {38874845}, issn = {1573-3270}, abstract = {This review describes the historical developement and rationale of clinically relevant research on neurophysiological "mind reading" paradims: Brain- Computer-Interfaces, detection of deception, brain stimulation and neurofeedback and the clinical applications in drug resistant epilepsy, chronic stroke, and communication with paralyzed locked-in persons. The emphasis lies on completely locked-in patients with amyotrophic lateral sclerosis using non-invasive and invasive brain computer interfaces and neurofeedback to restore verbal communication with the social environment. In the second part of the article we argue that success and failure of neurophysiological "mind reading" paradigms may be explained with a motor theory of thinking and emotion in combination with learning theory. The ethical implications of brain computer interface and neurofeedback approaches, particularly for severe chronic paralysis and loss of communication diseases and decisions on hastened death and euthanasia are discussed.}, } @article {pmid38873369, year = {2024}, author = {Hong, J and Kim, GC and Cha, JG and Park, J and Park, B and Park, SY and Kim, SU}, title = {Transcholecystic Duodenal Drainage as an Alternative Decompression Method for Afferent Loop Syndrome: Two Case Reports.}, journal = {Journal of the Korean Society of Radiology}, volume = {85}, number = {3}, pages = {661-667}, pmid = {38873369}, issn = {2951-0805}, abstract = {Afferent loop syndrome (ALS) is a rare complication of gastrectomies and gastrointestinal reconstruction. This can predispose patients to fatal conditions, such as cholangitis, pancreatitis, and duodenal perforation with peritonitis. Therefore, emergency decompression is necessary to prevent these complications. Herein, we report two cases in which transcholecystic duodenal drainage, an alternative decompression treatment, was performed in ALS patients without bile duct dilatation. Two patients who underwent distal gastrectomy with Billroth II anastomosis sought consultation in an emergency department for epigastric pain and vomiting. On CT, ALS with acute pancreatitis was diagnosed. However, biliary access could not be achieved because of the absence of bile duct dilatation. To overcome this problem, a duodenal drainage catheter was placed to decompress the afferent loop after traversing the cystic duct via a transcholecystic approach. The patients were discharged without additional surgical treatment 2 weeks and 1 month after drainage.}, } @article {pmid38872308, year = {2024}, author = {Çelik, MH and Gagneur, J and Lim, RG and Wu, J and Thompson, LM and Xie, X}, title = {Identifying dysregulated regions in amyotrophic lateral sclerosis through chromatin accessibility outliers.}, journal = {HGG advances}, volume = {5}, number = {3}, pages = {100318}, pmid = {38872308}, issn = {2666-2477}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Chromatin/metabolism/genetics ; Promoter Regions, Genetic/genetics ; Algorithms ; Gene Expression Regulation ; Chromatin Immunoprecipitation Sequencing ; Histones/metabolism/genetics ; }, abstract = {The high heritability of amyotrophic lateral sclerosis (ALS) contrasts with its low molecular diagnosis rate post-genetic testing, pointing to potential undiscovered genetic factors. To aid the exploration of these factors, we introduced EpiOut, an algorithm to identify chromatin accessibility outliers that are regions exhibiting divergent accessibility from the population baseline in a single or few samples. Annotation of accessible regions with histone chromatin immunoprecipitation sequencing and Hi-C indicates that outliers are concentrated in functional loci, especially among promoters interacting with active enhancers. Across different omics levels, outliers are robustly replicated, and chromatin accessibility outliers are reliable predictors of gene expression outliers and aberrant protein levels. When promoter accessibility does not align with gene expression, our results indicate that molecular aberrations are more likely to be linked to post-transcriptional regulation rather than transcriptional regulation. Our findings demonstrate that the outlier detection paradigm can uncover dysregulated regions in rare diseases. EpiOut is available at github.com/uci-cbcl/EpiOut.}, } @article {pmid38872258, year = {2024}, author = {Xiong, B and Yang, C and Yang, X and Luo, S and Li, S and Chen, C and He, K and Nie, L and Li, P and Li, S and Huang, H and Liu, J and Zhang, Z and Xie, Y and Zou, L and Yang, X}, title = {Arctigenin derivative A-1 ameliorates motor dysfunction and pathological manifestations in SOD1[G93A] transgenic mice via the AMPK/SIRT1/PGC-1α and AMPK/SIRT1/IL-1β/NF-κB pathways.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {6}, pages = {e14692}, pmid = {38872258}, issn = {1755-5949}, support = {SZSM201611090//Sanming Project of Medicine in Shenzhen/ ; 82171583//National Natural Science Foundation of China/ ; JCYJ20200109144418639//The Key Basic Research Program of Shenzhen Science and Technology Innovation Commission/ ; JCYJ20200109150717745//The Key Basic Research Program of Shenzhen Science and Technology Innovation Commission/ ; SZXK069//Shenzhen Key Medical Discipline Construction Fund/ ; }, mesh = {Animals ; *Mice, Transgenic ; *Sirtuin 1/metabolism ; Mice ; *NF-kappa B/metabolism ; *AMP-Activated Protein Kinases/metabolism ; *Furans/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; *Interleukin-1beta/metabolism ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Lignans/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; Male ; Motor Neurons/drug effects/pathology/metabolism ; Spinal Cord/drug effects/pathology/metabolism ; }, abstract = {AIM: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive death of upper and lower motor neurons, leading to generalized muscle atrophy, paralysis, and even death. Mitochondrial damage and neuroinflammation play key roles in the pathogenesis of ALS. In the present study, the efficacy of A-1, a derivative of arctigenin with AMP-activated protein kinase (AMPK) and silent information regulator 1 (SIRT1) activation for ALS, was investigated.

METHODS: A-1 at 33.3 mg/kg was administrated in SOD1[G93A] transgenic mice orally from the 13th week for a 6-week treatment period. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes, and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl, and immunohistochemistry staining. Protein expression was detected with proteomics analysis, Western blotting, and ELISA. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit.

RESULTS: A-1 administration in SOD1[G93A] mice enhanced mobility, decreased skeletal muscle atrophy and fibrosis, mitigated loss of spinal motor neurons, and reduced glial activation. Additionally, A-1 treatment improved mitochondrial function, evidenced by elevated ATP levels and increased expression of key mitochondrial-related proteins. The A-1 treatment group showed decreased levels of IL-1β, pIκBα/IκBα, and pNF-κB/NF-κB.

CONCLUSIONS: A-1 treatment reduced motor neuron loss, improved gastrocnemius atrophy, and delayed ALS progression through the AMPK/SIRT1/PGC-1α pathway, which promotes mitochondrial biogenesis. Furthermore, the AMPK/SIRT1/IL-1β/NF-κB pathway exerted neuroprotective effects by reducing neuroinflammation. These findings suggest A-1 as a promising therapeutic approach for ALS.}, } @article {pmid38871941, year = {2025}, author = {Naik, B and Sasikumar, J and Das, SP}, title = {From Skin and Gut to the Brain: The Infectious Journey of the Human Commensal Fungus Malassezia and Its Neurological Consequences.}, journal = {Molecular neurobiology}, volume = {62}, number = {1}, pages = {533-556}, pmid = {38871941}, issn = {1559-1182}, support = {GIA/2019/000620/PRCGIA//Indian Council of Medical Research/ ; }, mesh = {Animals ; Humans ; *Brain/microbiology/pathology ; *Malassezia/genetics/isolation & purification/pathogenicity ; *Nervous System Diseases/diagnosis/microbiology/pathology ; *Skin/microbiology ; }, abstract = {The human mycobiome encompasses diverse communities of fungal organisms residing within the body and has emerged as a critical player in shaping health and disease. While extensive research has focused on the skin and gut mycobiome, recent investigations have pointed toward the potential role of fungal organisms in neurological disorders. Among those fungal organisms, the presence of the commensal fungus Malassezia in the brain has created curiosity because of its commensal nature and primary association with the human skin and gut. This budding yeast is responsible for several diseases, such as Seborrheic dermatitis, Atopic dermatitis, Pityriasis versicolor, Malassezia folliculitis, dandruff, and others. However recent findings surprisingly show the presence of Malassezia DNA in the brain and have been linked to diseases like Alzheimer's disease, Parkinson's disease, Multiple sclerosis, and Amyotrophic lateral sclerosis. The exact role of Malassezia in these disorders is unknown, but its ability to infect human cells, travel through the bloodstream, cross the blood-brain barrier, and reside along with the lipid-rich neuronal cells are potential mechanisms responsible for pathogenesis. This also includes the induction of pro-inflammatory cytokines, disruption of the blood-brain barrier, gut-microbe interaction, and accumulation of metabolic changes in the brain environment. In this review, we discuss these key findings from studies linking Malassezia to neurological disorders, emphasizing the complex and multifaceted nature of these cases. Furthermore, we discuss potential mechanisms through which Malassezia might contribute to the development of neurological conditions. Future investigations will open up new avenues for our understanding of the fungal gut-brain axis and how it influences human behavior. Collaborative research efforts among microbiologists, neuroscientists, immunologists, and clinicians hold promise for unraveling the enigmatic connections between human commensal Malassezia and neurological disorders.}, } @article {pmid38870925, year = {2024}, author = {Hamdi, N and Ocab, O and Soliman, R and Ludolph, A and Anwar, W and Logroscino, G and Fahmy, N}, title = {Motor Neuron Disease Population-Based Registry in Egypt: Where Do We Stand?.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-13}, doi = {10.1159/000539468}, pmid = {38870925}, issn = {1423-0208}, abstract = {BACKGROUND: There is a growing body of evidence indicating that the worldwide distribution of amyotrophic lateral sclerosis (ALS) is far from uniform. This is evident through variations in the epidemiology, genetics, and phenotypical characteristics of ALS and other motor neuron diseases (MND) across different regions. However, comprehensive ALS epidemiological studies are still lacking in many parts of the world, especially in Africa. Therefore, we propose the establishment of a population-based register for ALS/MND in Egypt, an important part of Africa with a population of more than 100 millions of people.

SUMMARY: Given Egypt's distinctive social and demographic characteristics, it is highly recommended to employ specific, recently developed epidemiological techniques for assessing the prevalence and incidence of these diseases within the country. By utilizing these methods, we can gather invaluable data that will contribute to a deeper understanding of ALS and enable us to effectively address its impact on the population of Egypt.

KEY MESSAGES: Our goal with this pioneering ALS/MND population-based register in Egypt is to define the burden of ALS in this part of Africa and to increase the chances for this consanguineous population to get access to modern individualized genetic therapies. Additionally, we aspire to uncover potential environmental factors and gene-environment interactions that contribute to the development of ALS. This knowledge of MND individual and group risk in Egypt will not only open doors for interventions but also provide opportunities for future research and discovery.}, } @article {pmid38870470, year = {2024}, author = {McDool, E and Carlton, J and Powell, PA and Coates, E and Knox, L and Mayberry, E and Appleby, N and Griffiths, AW and Hobson, E and McDermott, CJ}, title = {Measuring Health-Related Quality of Life in Amyotrophic Lateral Sclerosis: A Systematic Review and Conceptual Framework.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209549}, pmid = {38870470}, issn = {1526-632X}, mesh = {*Amyotrophic Lateral Sclerosis/psychology/physiopathology ; Humans ; *Quality of Life/psychology ; Patient Reported Outcome Measures ; }, abstract = {BACKGROUND AND OBJECTIVES: The assessment of health-related quality of life (HRQoL) in patients with amyotrophic lateral sclerosis (ALS) is heterogeneous and inconsistent. The objectives of this study were (1) to develop a comprehensive conceptual framework of HRQoL in ALS and (2) map the content of existing patient-reported outcome measures (PROMs) used in ALS to this novel framework.

METHODS: Our model of HRQoL in ALS (Health-related Quality of life in Amyotrophic Lateral Sclerosis, QuALS) was developed from a systematic literature review and consultative input from key stakeholders (patients, carers, and health care professionals). Five electronic databases were searched in April 2022. Primary studies of any design that assessed HRQoL in ALS by using a multi-item PROM and/or qualitative methods were identified. Using an a priori framework, HRQoL themes were extracted and iteratively modified from the content of each PROM and qualitative study quotations identified in the literature. The conceptual framework was ratified by stakeholders with lived experience and clinical experts. The QuALS framework was used to map the content of identified PROMs and qualitative studies based on thematic coverage.

RESULTS: QuALS covers 3 high-level domains of HRQoL (physical, psychological, and social functioning) and consists of 7 themes (Activities; Physical Health; Autonomy; Cognition; Feelings and Emotions; Self-identity; Relationships), characterized by 42 subthemes. Of 8,220 studies identified, 274 were included in the review that informed QuALS. In these studies, 111 PROMs were used to assess at least 1 aspect of HRQoL, and 11 studies used qualitative methods. Of the 3 high-level domains, physical functioning was the most commonly assessed, particularly within ALS-specific PROMs where almost one-quarter of PROMs exclusively assessed physical functioning. None of the PROMs or qualitative studies identified assessed all aspects of HRQoL in the QuALS framework.

DISCUSSION: This study presents a new comprehensive conceptual framework of HRQoL in ALS (QuALS), informed by a robust systematic review of existing literature and stakeholder input, incorporating lived experience. QuALS provides a valuable resource for researchers and clinicians interested in taking a holistic approach to assessing and understanding the full impact of ALS on HRQoL and how this may be affected by treatments.}, } @article {pmid38869826, year = {2024}, author = {Wang, H and Zeng, R}, title = {Aberrant protein aggregation in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {4826-4851}, pmid = {38869826}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; *Protein Aggregation, Pathological/metabolism ; Protein Aggregates/physiology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease. As its pathological mechanisms are not well understood, there are no efficient therapeutics for it at present. While it is highly heterogenous both etiologically and clinically, it has a common salient hallmark, i.e., aberrant protein aggregation (APA). The upstream pathogenesis and the downstream effects of APA in ALS are sophisticated and the investigation of this pathology would be of consequence for understanding ALS. In this paper, the pathomechanism of APA in ALS and the candidate treatment strategies for it are discussed.}, } @article {pmid38869076, year = {2024}, author = {Ye, Y and Jia, P and Miao, J and Wang, Y and Li, Z and Lin, Y and He, M and Liu, S and Zheng, BR and Wu, J and Pan, J and Li, CM and Hou, P and Guo, D}, title = {CCDC50 mediates the clearance of protein aggregates to prevent cellular proteotoxicity.}, journal = {Autophagy}, volume = {20}, number = {11}, pages = {2529-2539}, pmid = {38869076}, issn = {1554-8635}, mesh = {Animals ; *Autophagy/physiology ; Humans ; Mice ; *Protein Aggregates ; Neurons/metabolism ; Cell Survival ; Brain/metabolism/pathology ; Proteostasis ; Neurodegenerative Diseases/metabolism/genetics ; Ubiquitination ; Protein Aggregation, Pathological/metabolism ; }, abstract = {Protein aggregation caused by the disruption of proteostasis will lead to cellular cytotoxicity and even cell death, which is implicated in multiple neurodegenerative diseases. The elimination of aggregated proteins is mediated by selective macroautophagy receptors, which is termed aggrephagy. However, the identity and redundancy of aggrephagy receptors in recognizing substrates remain largely unexplored. Here, we find that CCDC50, a highly expressed autophagy receptor in brain, is recruited to proteotoxic stresses-induced polyubiquitinated protein aggregates and ectopically expressed aggregation-prone proteins. CCDC50 recognizes and further clears these cytotoxic aggregates through autophagy. The ectopic expression of CCDC50 increases the tolerance to stress-induced proteotoxicity and hence improved cell survival in neuron cells, whereas CCDC50 deficiency caused accumulation of lipid deposits and polyubiquitinated protein conjugates in the brain of one-year-old mice. Our study illustrates how aggrephagy receptor CCDC50 combats proteotoxic stress for the benefit of neuronal cell survival, thus suggesting a protective role in neurotoxic proteinopathy.Abbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; ATG5: autophagy related 5; BODIPY: boron-dipyrromethene; CASP3: caspase 3; CCDC50: coiled-coil domain containing 50; CCT2: chaperonin containing TCP1 subunit 2; CHX: cycloheximide; CQ: chloroquine; CRISPR: clustered regulatory interspaced short palindromic repeat; Cas9: CRISPR-associated system 9; DAPI: 4',6-diamidino-2-phenylindole; FK2: Anti-ubiquitinylated proteins antibody, clone FK2; FUS: FUS RNA binding protein; GFP: green fluorescent protein; HD: Huntington disease; HTT: huntingtin; KEGG: Kyoto Encyclopedia of Genes and Genomes; LDS: LIR-docking site; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPT/tau: microtubule associated protein tau; MIU: motif interacting with ubiquitin; NBR1: NBR1, autophagy cargo receptor; OPTN: optineurin; PD: Parkinson disease; PI: propidium iodide; ROS: reactive oxygen species; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; Ub: ubiquitin; UDS: UIM-docking site; UIM: ubiquitin interacting motif; UPS: ubiquitin-proteasome system.}, } @article {pmid38868068, year = {2024}, author = {Nuredini, A and Bottignole, D and Stragliati, F and Anceschi, P and Romano, S and Pollara, I and Abramo, A and Rausa, F and Parrino, L and Zinno, L and Mutti, C}, title = {Unraveling sleep respiratory dysfunction in amyotrophic lateral sclerosis: Beyond the apnea-hypopnea index and sleep-related hypoxia.}, journal = {Heliyon}, volume = {10}, number = {11}, pages = {e32250}, pmid = {38868068}, issn = {2405-8440}, abstract = {The timely introduction of non-invasive ventilation (NIV) is extremely relevant in the multidisciplinary management of patients affected by amyotrophic lateral sclerosis (ALS) and is based on the proper identification of red flags for early diaphragmatic exhaustion. Polygraphic sleep recording may provide insightful information on the ongoing respiratory impairment; in particular, atypical breathing patterns need to be recognized, as the application of current guidelines for sleep-related hypoxemia or sleep apnea may be insufficient for detecting early signs of diaphragmatic fatigue. We report the case of a 51-year-old man affected by ALS who was asymptomatic for breathing impairment, but whose nocturnal polysomnographic recording, despite not significant for obstructive sleep apnea nor for conventional hypoventilatory patterns, strongly suggested initial respiratory failure, as lately confirmed by the pulmonary follow-up. We discuss the advantages of including sleep recording in the clinical work-up of patients affected by ALS.}, } @article {pmid38867220, year = {2024}, author = {Jia, Q and Song, Y and Zhang, C and Li, M and Feng, L and Sugimoto, K and Zhang, X and Liu, J and Gao, Y}, title = {Reasons and experience for patients with amyotrophic lateral sclerosis using traditional Chinese medicine: a CARE-TCM based mixed method study.}, journal = {BMC complementary medicine and therapies}, volume = {24}, number = {1}, pages = {231}, pmid = {38867220}, issn = {2662-7671}, support = {QN2021110001L//National Foreign Expert Project/ ; 2018, 12//Chinese Medicine Inheritance and Innovation Talent Project Leading Talent Support Program of National Traditional Chinese Medicine/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Medicine, Chinese Traditional/methods ; Female ; Male ; Middle Aged ; Surveys and Questionnaires ; Aged ; China ; Adult ; Quality of Life ; Qualitative Research ; }, abstract = {BACKGROUND AND AIM: Traditional Chinese medicine (TCM) is widely used by patients with amyotrophic lateral sclerosis (ALS). However, their reasons and experience in using TCM have received insufficient attention. Therefore, we conducted a mixed method study to gain insights into this issue.

MATERIALS AND METHODS: This study was conducted on the basis of the China Amyotrophic Lateral Sclerosis Registry of Patients with Traditional Chinese Medicine (CARE-TCM). Data were collected from Dongzhimen Hospital through a mixed method approach, including a questionnaire and a semi-structured interview. Patients with ALS who were using TCM when they were initially registered with CARE-TCM and who had been followed-up for over six months were recruited. The questionnaires' outcomes were statistically outlined, and the interview transcripts were thematically analysed to identify themes and sub-themes.

RESULTS: Fifty-two and sixteen patients were included in the questionnaire and semi-structured interview groups, respectively. Patients used TCM with the hope of regulating their body holistically to improve nonmotor symptoms and quality of life (QOL). Those who recognised TCM as ineffective tended to discontinue it after a three-month trial period. Although quality was a major concern, herbal medicine (HM) was the most frequently used modality among all participants (n = 52), with the majority (n = 44, 84.6%) continuing to use it. Patients emphasised in-person consultations as a crucial part of TCM treatment. However, the disability caused by disease often made this interaction unattainable.

CONCLUSION: Nonmotor symptoms and QOL hold substantial importance for patients with ALS using TCM. HM is a more suitable modality than other TCM treatment modalities, but patients are facing challenges in seeking HM treatment. It is necessary to promote the implementation of hierarchical diagnosis and treatment, thus making TCM more accessible.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04885374 (registered on May 13, 2021).}, } @article {pmid38866783, year = {2024}, author = {Di Timoteo, G and Giuliani, A and Setti, A and Biagi, MC and Lisi, M and Santini, T and Grandioso, A and Mariani, D and Castagnetti, F and Perego, E and Zappone, S and Lattante, S and Sabatelli, M and Rotili, D and Vicidomini, G and Bozzoni, I}, title = {M[6]A reduction relieves FUS-associated ALS granules.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {5033}, pmid = {38866783}, issn = {2041-1723}, support = {ERC-2019-SyG 855923-ASTRA//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; ERC-2018-CoG 818669-BrightEyes//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; AIRC IG 2019 Id. 23053//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; PRIN 2017 2017P352Z4//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; NextGenerationEU PNRR MUR//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; "National Center for Gene Therapy and Drugbased on RNA Technology" (CN00000041)//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; "National Center for Gene Therapy and Drug based on RNA Technology" (CN00000041)//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; NextGenerationEU PNRR MUR//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; "Sapienza" Ateneo Project 2021 n. RM12117A61C811CE//Sapienza Università di Roma (Sapienza University of Rome)/ ; Regione Lazio PROGETTI DI GRUPPI DI RICERCA 2020 - A0375-2020-36597//Regione Lazio (Region of Lazio)/ ; }, mesh = {*RNA-Binding Protein FUS/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; *Motor Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; Cytoplasmic Granules/metabolism ; Fibroblasts/metabolism ; Adenosine/metabolism/analogs & derivatives ; Methyltransferases/metabolism/genetics ; Mutation ; Inclusion Bodies/metabolism ; Stress Granules/metabolism ; Transcriptome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motoneurons (MN) degeneration. Among the processes associated to ALS pathogenesis, there is the formation of cytoplasmic inclusions produced by aggregation of mutant proteins, among which the RNA binding protein FUS. Here we show that, in neuronal cells and in iPSC-derived MN expressing mutant FUS, such inclusions are significantly reduced in number and dissolve faster when the RNA m[6]A content is diminished. Interestingly, stress granules formed in ALS conditions showed a distinctive transcriptome with respect to control cells, which reverted to similar to control after m[6]A downregulation. Notably, cells expressing mutant FUS were characterized by higher m[6]A levels suggesting a possible link between m[6]A homeostasis and pathological aggregates. Finally, we show that FUS inclusions are reduced also in patient-derived fibroblasts treated with STM-2457, an inhibitor of METTL3 activity, paving the way for its possible use for counteracting aggregate formation in ALS.}, } @article {pmid38865943, year = {2024}, author = {Ipek, L and Güneş Gencer, GY}, title = {Is caregiver burden of patients with amyotrophic lateral sclerosis related to caregivers' mindfulness, quality of life, and patients' functional level.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {126}, number = {}, pages = {95-100}, doi = {10.1016/j.jocn.2024.06.007}, pmid = {38865943}, issn = {1532-2653}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/nursing/therapy ; Female ; *Quality of Life/psychology ; Male ; Middle Aged ; *Mindfulness ; *Caregiver Burden/psychology ; Adult ; Caregivers/psychology ; Aged ; Cost of Illness ; }, abstract = {BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the caregiver burden, mindfulness, and quality of life (QoL) of caregivers of ALS patients and the patient's functional level.

METHODS: This study was conducted with 57 ALS patients and their primary caregivers. The data were collected using the Zarit Burden Interview, Mindful Attention Awareness Scale (MAAS), the Short Form-36 (SF-36), and the ALS Functional Rating Scale (ALS-FRS).

RESULTS: The mean age of the caregivers was 49.7 ± 12 years; 66 % were female, and 73.7 % were spouses of the patients. Around 65 % of caregivers experienced a moderate to severe caregiver burden. A low and negative correlation was found between the caregiver burden and mindfulness of caregivers of ALS patients. As the mindfulness levels of the caregivers increased, the caregiver burden decreased, and the physical role difficulty score, one of the sub-dimensions of the QoL, increased. Also, caregivers' QoL decreased as caregiver burden increased (except physical function QoL, p < 0.05). Moreover, there was a positive correlation between the caregiver burden and ALSFRS-R scores (bulbar, motor, respiratory, and total) of the caregivers of ALS patients (p < 0.05).

DISCUSSION: Improved technology for managing ALS disease has increased patient life expectancy. However, caregivers may experience a high burden as the patient's functional level declines. Increasing caregiver mindfulness can help reduce the burden and improve their QoL.}, } @article {pmid38865034, year = {2024}, author = {Rashed, HR and Staff, NP and Milone, M and Mauermann, ML and Berini, S and Cheshire, WP and Coon, EA and Fealey, RD and Sorenson, E and Cutsforth-Gregory, J and Benarroch, EE and Sandroni, P and Low, PA and Singer, W and Shouman, K}, title = {Autonomic impairment in primary lateral sclerosis.}, journal = {Clinical autonomic research : official journal of the Clinical Autonomic Research Society}, volume = {34}, number = {4}, pages = {421-425}, pmid = {38865034}, issn = {1619-1560}, mesh = {Humans ; Male ; Middle Aged ; Female ; *Autonomic Nervous System Diseases/physiopathology/diagnosis/etiology ; Adult ; Retrospective Studies ; Aged ; Sweating/physiology ; Motor Neuron Disease/physiopathology/diagnosis/complications ; Autonomic Nervous System/physiopathology ; }, abstract = {PURPOSE: Prior studies reported evidence of autonomic involvement in motor neuron disease and suggested more severe dysfunction in upper motor neuron predominant syndromes. Hence, we sought to characterize autonomic impairment in primary lateral sclerosis.

METHODS: Neurological evaluations, thermoregulatory sweat tests, and autonomic reflex screens were analyzed retrospectively in 34 primary lateral sclerosis patients (28 definite and 6 probable). Patients with other potential causes of autonomic failure and patients with autonomic testing results compromised by artifact were excluded.

RESULTS: A total of 17 patients reported autonomic symptoms. Orthostatic lightheadedness was most frequent (8 patients), followed by bladder (7), bowel (5), and erectile dysfunction (3). The autonomic reflex screens of 33 patients were reviewed; 20 patients had abnormal studies. The thermoregulatory sweat tests of 19 patients were reviewed; 11 patients had abnormal studies. Composite Autonomic Severity Score was calculated for 33 patients and found abnormal in 20/33 patients (60.6%): 15/20 patients (75%) had mild impairment, and 5/20 patients (25%) had moderate impairment. The frequencies of testing abnormalities were: sudomotor 18/20 (90%), cardiovagal 9/20 (45%), and adrenergic 6/20 (30%). Sweat loss pattern analysis showed global, regional, and mixed patterns to be more common than length-dependent and distal patterns.

CONCLUSION: We found evidence of frequent autonomic dysfunction in primary lateral sclerosis, which is generally of modest severity akin to prior reports for amyotrophic lateral sclerosis, but more commonly in a pattern consistent with preganglionic/ganglionic localization. This suggests that primary lateral sclerosis, as with amyotrophic lateral sclerosis, is a multisystem disease that affects the autonomic nervous system.}, } @article {pmid38864944, year = {2024}, author = {Wang, LY and Zhang, L and Bai, XY and Qiang, RR and Zhang, N and Hu, QQ and Cheng, JZ and Yang, YL and Xiang, Y}, title = {The Role of Ferroptosis in Amyotrophic Lateral Sclerosis Treatment.}, journal = {Neurochemical research}, volume = {49}, number = {10}, pages = {2653-2667}, pmid = {38864944}, issn = {1573-6903}, mesh = {*Ferroptosis/drug effects/physiology ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; Humans ; Animals ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; Iron/metabolism ; Antioxidants/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with a challenging treatment landscape, due to its complex pathogenesis and limited availability of clinical drugs. Ferroptosis, an iron-dependent form of programmed cell death (PCD), stands distinct from apoptosis, necrosis, autophagy, and other cell death mechanisms. Recent studies have increasingly highlighted the role of iron deposition, reactive oxygen species (ROS) accumulation, oxidative stress, as well as systemic Xc- and glutamate accumulation in the antioxidant system in the pathogenesis of amyotrophic lateral sclerosis. Therefore, targeting ferroptosis emerges as a promising strategy for amyotrophic lateral sclerosis treatment. This review introduces the regulatory mechanism of ferroptosis, the relationship between amyotrophic lateral sclerosis and ferroptosis, and the drugs used in the clinic, then discusses the current status of amyotrophic lateral sclerosis treatment, hoping to provide new directions and targets for its treatment.}, } @article {pmid38863235, year = {2024}, author = {Priyanka, and Raymandal, B and Mondal, S}, title = {Native State Stabilization of Amyloidogenic Proteins by Kinetic Stabilizers: Inhibition of Protein Aggregation and Clinical Relevance.}, journal = {ChemMedChem}, volume = {19}, number = {19}, pages = {e202400244}, doi = {10.1002/cmdc.202400244}, pmid = {38863235}, issn = {1860-7187}, support = {SRG/2023/000434//Science and Engineering Research Board, India/ ; }, mesh = {Humans ; Kinetics ; *Amyloidogenic Proteins/metabolism/antagonists & inhibitors/chemistry ; Protein Aggregates/drug effects ; Superoxide Dismutase-1/metabolism/chemistry/antagonists & inhibitors ; Prealbumin/metabolism/chemistry/antagonists & inhibitors ; Amyloidosis/drug therapy/metabolism ; Clinical Relevance ; }, abstract = {Proteinopathies or amyloidoses are a group of life-threatening disorders that result from misfolding of proteins and aggregation into toxic insoluble amyloid aggregates. Amyloid aggregates have low clearance from the body due to the insoluble nature, leading to their deposition in various organs and consequent organ dysfunction. While amyloid deposition in the central nervous system leads to neurodegenerative diseases that mostly cause dementia and difficulty in movement, several other organs, including heart, liver and kidney are also affected by systemic amyloidoses. Regardless of the site of amyloid deposition, misfolding and structural alteration of the precursor proteins play the central role in amyloid formation. Kinetic stabilizers are an emerging class of drugs, which act like pharmacological chaperones to stabilize the native state structure of amyloidogenic proteins and to increase the activation energy barrier that is required for adopting a misfolded structure or conformation, ultimately leading to the inhibition of protein aggregation. In this review, we discuss the kinetic stabilizers that stabilize the native quaternary structure of transthyretin, immunoglobulin light chain and superoxide dismutase 1 that cause transthyretin amyloidoses, light chain amyloidosis and familial amyotrophic lateral sclerosis, respectively.}, } @article {pmid38862967, year = {2024}, author = {Vazquez-Sanchez, S and Tilkin, B and Gasset-Rosa, F and Zhang, S and Piol, D and McAlonis-Downes, M and Artates, J and Govea-Perez, N and Verresen, Y and Guo, L and Cleveland, DW and Shorter, J and Da Cruz, S}, title = {Frontotemporal dementia-like disease progression elicited by seeded aggregation and spread of FUS.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {46}, pmid = {38862967}, issn = {1750-1326}, mesh = {Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; Brain/metabolism/pathology ; Disease Models, Animal ; *Disease Progression ; *Frontotemporal Dementia/pathology/metabolism/genetics ; *Mice, Transgenic ; Protein Aggregation, Pathological/metabolism ; *RNA-Binding Protein FUS/metabolism/genetics ; }, abstract = {RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic Frontotemporal lobar degeneration (FTLD). Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.}, } @article {pmid38861223, year = {2024}, author = {Parakh, S and Perri, ER and Vidal, M and Takalloo, Z and Jagaraj, CJ and Mehta, P and Yang, S and Thomas, CJ and Blair, IP and Hong, Y and Atkin, JD}, title = {Protein Disulfide Isomerase Endoplasmic Reticulum Protein 57 (ERp57) is Protective Against ALS-Associated Mutant TDP-43 in Neuronal Cells.}, journal = {Neuromolecular medicine}, volume = {26}, number = {1}, pages = {23}, pmid = {38861223}, issn = {1559-1174}, mesh = {*Protein Disulfide-Isomerases/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Humans ; *Inclusion Bodies/metabolism/genetics ; Animals ; Mice ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; Neurons/metabolism/drug effects ; Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease affecting motor neurons. Pathological forms of Tar-DNA binding protein-43 (TDP-43), involving its mislocalisation to the cytoplasm and the formation of misfolded inclusions, are present in almost all ALS cases (97%), and ~ 50% cases of the related condition, frontotemporal dementia (FTD), highlighting its importance in neurodegeneration. Previous studies have shown that endoplasmic reticulum protein 57 (ERp57), a member of the protein disulphide isomerase (PDI) family of redox chaperones, is protective against ALS-linked mutant superoxide dismutase (SOD1) in neuronal cells and transgenic SOD1[G93A] mouse models. However, it remains unclear whether ERp57 is protective against pathological TDP-43 in ALS. Here, we demonstrate that ERp57 is protective against key features of TDP-43 pathology in neuronal cells. ERp57 inhibited the mislocalisation of TDP-43[M337V] from the nucleus to the cytoplasm. In addition, ERp57 inhibited the number of inclusions formed by ALS-associated variant TDP-43[M337V] and reduced the size of these inclusions. ERp57 was also protective against ER stress and induction of apoptosis. Furthermore, ERp57 modulated the steady-state expression levels of TDP-43. This study therefore demonstrates a novel mechanism of action of ERp57 in ALS. It also implies that ERp57 may have potential as a novel therapeutic target to prevent the TDP-43 pathology associated with neurodegeneration.}, } @article {pmid38861034, year = {2024}, author = {Lehto, A and Schumacher, J and Kasper, E and Teipel, S and Hermann, A and Kurth, J and Krause, BJ and Prudlo, J}, title = {Cerebral glucose metabolic correlates of cognitive and behavioural impairments in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5290-5300}, pmid = {38861034}, issn = {1432-1459}, support = {13GW0482D//Bundesministerium für Bildung und Forschung/Verein Deutscher Ingenieure/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging ; Male ; Female ; Middle Aged ; *Positron-Emission Tomography ; *Fluorodeoxyglucose F18/metabolism ; Aged ; *Glucose/metabolism ; *Neuropsychological Tests ; Magnetic Resonance Imaging ; Cognition Disorders/diagnostic imaging/metabolism/etiology ; Mental Disorders/metabolism/diagnostic imaging ; Brain/diagnostic imaging/metabolism ; Cerebral Cortex/diagnostic imaging/metabolism ; }, abstract = {OBJECTIVE: Half of ALS patients are cognitively and/or behaviourally impaired. As cognition/behaviour and cerebral glucose metabolism can be correlated by means of [18]F-Fluorodeoxyglucose positron emission tomography (FDG-PET), we aimed to utilise FDG-PET, first, to replicate group-level differences in glucose metabolism between non-demented ALS patients separated into non-impaired (ALSni), cognitively impaired (ALSci), behaviourally impaired (ALSbi), and cognitively and behaviourally impaired (ALScbi) groups; second, to investigate glucose metabolism and performance in various cognitive domains; and third, to examine the impact of partial volume effects correction (PVEC) of the FDG-PET data on the results.

METHODS: We analysed neuropsychological, clinical, and imaging data from 67 ALS patients (30 ALSni, 21 ALSci, 5 ALSbi, and 11 ALScbi). Cognition was assessed with the Edinburgh Cognitive and Behavioural ALS Screen, and two social cognition tests. FDG-PET and structural MRI scans were acquired for each patient. Voxel-based statistical analyses were undertaken on grey matter volume (GMV) and non-corrected vs. PVE-corrected FDG-PET scans.

RESULTS: ALSci and ALScbi had lower cognitive scores than ALSni. In contrast to both ALSni and ALSci, ALScbi showed widespread hypometabolism in the superior- and middle-frontal gyri in addition to the right temporal pole. Correlations were observed between the GMV, the FDG-PET signal, and various cognitive scores. The FDG-PET results were largely unaffected by PVEC.

INTERPRETATION: Our study identified widespread differences in hypometabolism in the ALScbi-ni but not in the ALSci-ni group comparison, raising the possibility that cerebral metabolism may be more closely related to the presence of behavioural changes than to mild cognitive deficits.}, } @article {pmid38860943, year = {2024}, author = {Zhang, Y and Xia, Y and Sun, J}, title = {Probiotics and microbial metabolites maintain barrier and neuromuscular functions and clean protein aggregation to delay disease progression in TDP43 mutation mice.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2363880}, pmid = {38860943}, issn = {1949-0984}, support = {I01 BX004824/BX/BLRD VA/United States ; R01 DK105118/DK/NIDDK NIH HHS/United States ; R01 DK114126/DK/NIDDK NIH HHS/United States ; R01 DK134343/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy ; Blood-Brain Barrier/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Disease Progression ; *DNA-Binding Proteins/metabolism/genetics ; *Gastrointestinal Microbiome ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Neuroglia/metabolism ; *Probiotics/administration & dosage/pharmacology ; Spinal Cord/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. The ALS mice expressing human mutant of transactive response DNA binding protein of 43 kDa (hmTDP43) showed intestinal dysfunction before neuromuscular symptoms. We hypothesize that restoring the intestinal and microbial homeostasis with a bacterial metabolite or probiotics delays the ALS disease onset. We investigate the pathophysiological changes in the intestine and neurons, intestinal and blood-brain barriers, and inflammation during the ALS progression. We then cultured enteric glial cells (EGCs) isolated from TDP43 mice for mechanistic studies. TDP43 mice had significantly decreased intestinal mobility, increased permeability, and weakened muscle, compared with the age-matched wild-type mice. We observed increased hmTDP43 and Glial fibrillary acidic protein (GFAP), and decreased expression of α-smooth muscle actin (α-SMA), tight junction proteins (ZO-1 and Claudin-5) in the colon, spinal cord, and brain in TDP43 mice. TDP43 mice had reduced Butyryl-coenzyme A CoA transferase, decreased butyrate-producing bacteria Butyrivibrio fibrisolvens, and increased Bacteroides fragilis, compared to the WT mice. Serum inflammation cytokines (IL-6, IL-17, and IFN-γ) and LPS were elevated in TDP43 mice. EGCs from TDP43 mice showed aggregation of hmTDP43 associated with increased GFAP and ionized calcium-binding adaptor molecule (IBA1, a microglia marker). TDP43 mice treated with butyrate or probiotic VSL#3 had significantly increased rotarod time, increased intestinal mobility and decreased permeability, compared to the untreated group. Butyrate or probiotics treatment decreased the expression of GFAP, TDP43, and increased α-SMA, ZO-1, and Claudin-5 in the colon, spinal cord, and brain. Also, butyrate or probiotics treatment enhanced the Butyryl-coenzyme A CoA transferase, Butyrivibrio fibrisolvens, and reduced inflammatory cytokines in TDP43 mice. The TDP43 EGCs treated with butyrate or probiotics showed reduced GFAP, IBA1, and TDP43 aggregation. Restoring the intestinal and microbial homeostasis by beneficial bacteria and metabolites provide a potential therapeutic strategy to treat ALS.}, } @article {pmid38860430, year = {2024}, author = {Geng, Y and Liu, C and Xu, N and Suen, MC and Miao, H and Xie, Y and Zhang, B and Chen, X and Song, Y and Wang, Z and Cai, Q and Zhu, G}, title = {Crystal structure of a tetrameric RNA G-quadruplex formed by hexanucleotide repeat expansions of C9orf72 in ALS/FTD.}, journal = {Nucleic acids research}, volume = {52}, number = {13}, pages = {7961-7970}, pmid = {38860430}, issn = {1362-4962}, support = {32071188//National Scientific Foundation of China/ ; 16101120//Research Grants Council of the Hong Kong Special Administrative Region/ ; 3502Z20214001//Hong Kong University of Science and Technology/ ; 2021A1515220104//Guangdong Basic and Applied Basic Research Foundation/ ; }, mesh = {*C9orf72 Protein/genetics/chemistry ; *G-Quadruplexes ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; Humans ; *RNA/chemistry/genetics ; *DNA Repeat Expansion/genetics ; Crystallography, X-Ray ; Models, Molecular ; }, abstract = {The abnormal GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause the fatal neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal dementia. The transcribed RNA HREs, short for r(G4C2)n, can form toxic RNA foci which sequestrate RNA binding proteins and impair RNA processing, ultimately leading to neurodegeneration. Here, we determined the crystal structure of r(G4C2)2, which folds into a parallel tetrameric G-quadruplex composed of two four-layer dimeric G-quadruplex via 5'-to-5' stacking in coordination with a K+ ion. Notably, the two C bases locate at 3'- end stack on the outer G-tetrad with the assistance of two additional K+ ions. The high-resolution structure reported here lays a foundation in understanding the mechanism of neurological toxicity of RNA HREs. Furthermore, the atomic details provide a structural basis for the development of potential therapeutic agents against the fatal neurodegenerative diseases ALS/FTD.}, } @article {pmid38860134, year = {2024}, author = {Levison, LS and Jepsen, P and Andersen, H}, title = {Registration of Amyotrophic Lateral Sclerosis: Validity in the Danish National Patient Registry.}, journal = {Clinical epidemiology}, volume = {16}, number = {}, pages = {409-415}, pmid = {38860134}, issn = {1179-1349}, abstract = {PURPOSE: Health care databases are a valuable source for epidemiological research on amyotrophic lateral sclerosis (ALS) if diagnosis codes are valid. We evaluated the validity of the diagnostic codes for ALS in the Danish National Patient Registry (DNPR).

PATIENTS AND METHODS: We obtained data from the DNPR for all adult (>17 years) patients registered with ALS in Denmark between 1987 and 2022 (median population of 4.2 million during the study period). We randomly selected adult patients living in the North Denmark Region and Central Denmark Region (median population 1.4 million), with a primary discharge diagnosis code of ALS, diagnosed at three departments of neurology. We retrieved and reviewed medical records and estimated the positive predictive value (PPV) of the ALS diagnosis.

RESULTS: Over 36 years, we identified 5679 patients. From the validation cohort of 300 patients, we were able to retrieve 240 (80%) medical records, and 215 ALS diagnoses were confirmed. The overall positive predictive value was 89.6% (95% confidence interval (CI): 85.1-92.8). The highest PPV was achieved for diagnoses registered for patients aged ≥70 years (93.8; 95% CI: 86.2-97.3) compared to patients <60 years (83.4; 95% CI: 73.3-90.7).

CONCLUSION: We found a high PPV of primary diagnostic codes for ALS from Danish departments of neurology, demonstrating high validity. Thus, the DNPR is a well-suited data source for large-scale epidemiological research on ALS.}, } @article {pmid38859699, year = {2024}, author = {Finsterer, J and Strobl, W}, title = {Gastrointestinal involvement in neuromuscular disorders.}, journal = {Journal of gastroenterology and hepatology}, volume = {39}, number = {10}, pages = {1982-1993}, doi = {10.1111/jgh.16650}, pmid = {38859699}, issn = {1440-1746}, mesh = {Humans ; *Neuromuscular Diseases/complications/etiology ; *Gastrointestinal Diseases/etiology/therapy/diagnosis ; Myotonic Dystrophy/complications/diagnosis/physiopathology ; Mitochondrial Diseases/complications ; }, abstract = {Although not often discussed, many of the neuromuscular disorders (NMDs) affect the gastrointestinal tract (GIT). Depending on the type of NMD, the prevalence of GIT involvement ranges from <5% (e.g. hereditary neuropathies, myofibrillar myopathies) to 100% (e.g. MNGIE, OPMD). Particularly in NMDs with multisystem affection, involvement of the GIT can dominate the clinical presentation or at least make up a significant part of the clinical picture. The most prominent representatives of NMDs with multisystem involvement are the mitochondrial disorders (MIDs) and the myotonic dystrophies. The best known syndromic MIDs with GIT involvement are MNGIE, MELAS, Leigh, and Pearson syndromes. Among neuropathies, GIT involvement is most commonly found in ALS and GBS. GIT involvement may also be a feature of myasthenia. The clinical manifestations of GIT involvement are diverse and can affect the entire GIT, from the teeth to the rectum, including the liver and pancreas. The most well-known clinical manifestations of GIT involvement are dysphagia, nausea, vomiting, reflux, hollow organ dysmotility, hepatopathy, diabetes, diarrhea, constipation, and fecal incontinence. Even if treatment can usually only be symptomatic, the therapeutic options are diverse, are often effective, and can significantly and beneficially influence the course of the underlying NMD.}, } @article {pmid38859579, year = {2024}, author = {Meyer, T and Dreger, M and Grehl, T and Weyen, U and Kettemann, D and Weydt, P and Günther, R and Lingor, P and Petri, S and Koch, JC and Großkreutz, J and Rödiger, A and Baum, P and Hermann, A and Prudlo, J and Boentert, M and Weishaupt, JH and Löscher, WN and Dorst, J and Koc, Y and Bernsen, S and Cordts, I and Vidovic, M and Steinbach, R and Metelmann, M and Kleinveld, VE and Norden, J and Ludolph, A and Walter, B and Schumann, P and Münch, C and Körtvélyessy, P and Maier, A}, title = {Serum neurofilament light chain in distinct phenotypes of amyotrophic lateral sclerosis: A longitudinal, multicenter study.}, journal = {European journal of neurology}, volume = {31}, number = {9}, pages = {e16379}, pmid = {38859579}, issn = {1468-1331}, support = {//Bosis Canessa ALS Stiftung, Düsseldorf, Germany/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood ; *Neurofilament Proteins/blood ; Male ; Female ; Middle Aged ; *Phenotype ; Aged ; Longitudinal Studies ; Disease Progression ; Biomarkers/blood ; Adult ; Germany/epidemiology ; }, abstract = {OBJECTIVE: To assess the performance of serum neurofilament light chain (sNfL) in clinical phenotypes of amyotrophic lateral sclerosis (ALS).

METHODS: In 2949 ALS patients at 16 ALS centers in Germany and Austria, clinical characteristics and sNfL were assessed. Phenotypes were differentiated for two anatomical determinants: (1) upper and/or lower motor involvement (typical, typMN; upper/lower motor neuron predominant, UMNp/LMNp; primary lateral sclerosis, PLS) and (2) region of onset and propagation of motor neuron dysfunction (bulbar, limb, flail-arm, flail-leg, thoracic onset). Phenotypes were correlated to sNfL, progression, and survival.

RESULTS: Mean sNfL was - compared to typMN (75.7 pg/mL, n = 1791) - significantly lower in LMNp (45.1 pg/mL, n = 413), UMNp (58.7 pg/mL n = 206), and PLS (37.6 pg/mL, n = 84). Also, sNfL significantly differed in the bulbar (92.7 pg/mL, n = 669), limb (64.1 pg/mL, n = 1305), flail-arm (46.4 pg/mL, n = 283), flail-leg (53.6 pg/mL, n = 141), and thoracic (74.5 pg/mL, n = 96) phenotypes. Binary logistic regression analysis showed highest contribution to sNfL elevation for faster progression (odds ratio [OR] 3.24) and for the bulbar onset phenotype (OR 1.94). In contrast, PLS (OR 0.20), LMNp (OR 0.45), and thoracic onset (OR 0.43) showed reduced contributions to sNfL. Longitudinal sNfL (median 12 months, n = 2862) showed minor monthly changes (<0.2%) across all phenotypes. Correlation of sNfL with survival was confirmed (p < 0.001).

CONCLUSIONS: This study underscored the correlation of ALS phenotypes - differentiated for motor neuron involvement and region of onset/propagation - with sNfL, progression, and survival. These phenotypes demonstrated a significant effect on sNfL and should be recognized as independent confounders of sNfL analyses in ALS trials and clinical practice.}, } @article {pmid38857767, year = {2024}, author = {Bass, J and Hill, H and Jaworsky, C}, title = {Response to Hartman et al in reply to Bass et al's "Significant discordance in DermTech test results when paired with histopathology: Caveat emptor".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e103}, doi = {10.1016/j.jaad.2024.06.003}, pmid = {38857767}, issn = {1097-6787}, mesh = {Humans ; *Dermoscopy ; Skin Neoplasms/pathology ; }, } @article {pmid38856890, year = {2024}, author = {Tripathi, S and Bhawana, }, title = {Epigenetic Orchestration of Neurodegenerative Disorders: A Possible Target for Curcumin as a Therapeutic.}, journal = {Neurochemical research}, volume = {49}, number = {9}, pages = {2319-2335}, pmid = {38856890}, issn = {1573-6903}, mesh = {*Curcumin/therapeutic use/pharmacology ; Humans ; *Epigenesis, Genetic/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism/genetics ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; Mitochondria/metabolism/drug effects ; Oxidative Stress/drug effects ; }, abstract = {Epigenetic modulations play a major role in gene expression and thus are responsible for various physiological changes including age-associated neurological disorders. Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD), although symptomatically different, may share common underlying mechanisms. Most neurodegenerative diseases are associated with increased oxidative stress, aggregation of certain proteins, mitochondrial dysfunction, inactivation/dysregulation of protein degradation machinery, DNA damage and cell excitotoxicity. Epigenetic modulations has been reported to play a significant role in onset and progression of neurodegenerative diseases by regulating these processes. Previous studies have highlighted the marked antioxidant and neuroprotective abilities of polyphenols such as curcumin, by increased activity of detoxification systems like superoxide dismutase (SOD), catalase or glutathione peroxidase. The role of curcumin as an epigenetic modulator in neurological disorders and neuroinflammation apart from other chronic diseases have also been reported by a few groups. Nonetheless, the evidences for the role of curcumin mediated epigenetic modulation in its neuroprotective ability are still limited. This review summarizes the current knowledge of the role of mitochondrial dysfunction, epigenetic modulations and mitoepigenetics in age-associated neurological disorders such as PD, AD, HD, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), and describes the neuroprotective effects of curcumin in the treatment and/or prevention of these neurodegenerative diseases by regulation of the epigenetic machinery.}, } @article {pmid38856805, year = {2024}, author = {Zhang, Z and He, X and Cui, J and Wang, J and Shi, B}, title = {Translation and reliability and validity of the Chinese version of Amyotrophic Lateral Sclerosis-Specific Quality of Life-Short Form.}, journal = {Journal of patient-reported outcomes}, volume = {8}, number = {1}, pages = {57}, pmid = {38856805}, issn = {2509-8020}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; *Quality of Life/psychology ; Male ; Female ; Middle Aged ; Reproducibility of Results ; Cross-Sectional Studies ; China ; Surveys and Questionnaires ; Adult ; *Psychometrics/methods/instrumentation ; Translations ; Aged ; Translating ; }, abstract = {OBJECTIVE: To translate Amyotrophic Lateral Sclerosis-Specific Quality of Life-Short Form (ALSSQOL-SF) and test its reliability and validity, so that explore feasibility in Chinese mainland and make up the gap of specific tools for measuring quality of life of patients with ALS.

METHODS: This was a cross-sectional design. The Brislin translation model was used to translate ALSSQOL-SF, and the Chinese version of ALSSQOL-SF (C-ALSSQOL-SF) was revised through cultural adaptation and pre-test. The convenience sampling method was used to investigate 138 patients with ALS in Tianjin to test the reliability and validity of the C-ALSSQOL-SF.

RESULTS: The C-ALSSQOL-SF included 20 items, covering 6 dimensions: physical symptoms, bulbar function, negative emotion, interaction with people and the environment, religiosity and intimacy. The scale-level content validity index (S-CVI) of C-ALSSQOL-SF was 0.964, and the item-level content validity index (I-CVI) was between 0.857 to 1.000. The results of Confirmatory Factor Analysis (CFA) showed that CMIN/DF = 1.161, RMSEA = 0.034, GFI = 0.892, IFI = 0.976, TLI = 0.969, CFI = 0.975, and the 6-factor model fitted well. The scores of C-ALSSQOL-SF and WHOQOL-BREF were positively correlated (r = 0.745). The Cronbach's α coefficient of the scale was 0.85, the Cronbach's α coefficient of each dimension was between 0.59 to 0.86, and the split-half reliability was 0.78.

CONCLUSION: The Chinese version of ALSSQOL-SF has good reliability and validity, and can be used as a tool to evaluate the quality of life of patients with ALS in Chinese mainland.}, } @article {pmid38856793, year = {2025}, author = {Kumari, S and Kamiya, A and Karnik, SS and Rohilla, S and Dubey, SK and Taliyan, R}, title = {Novel Gene Therapy Approaches for Targeting Neurodegenerative Disorders: Focusing on Delivering Neurotrophic Genes.}, journal = {Molecular neurobiology}, volume = {62}, number = {1}, pages = {386-411}, pmid = {38856793}, issn = {1559-1182}, mesh = {Humans ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/therapy/genetics ; Animals ; *Nerve Growth Factors/genetics ; Gene Transfer Techniques ; Genetic Vectors ; }, abstract = {Neurodegenerative illnesses (NDDs) like Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, spinal muscular atrophy, and Huntington's disease have demonstrated considerable potential for gene therapy as a viable therapeutic intervention. NDDs are marked by the decline of neurons, resulting in changes in both behavior and pathology within the body. Strikingly, only symptomatic management is available without a cure for the NDDs. There is an unmet need for a permanent therapeutic approach. Many studies have been going on to target the newer therapeutic molecular targets for NDDs including gene-based therapy. Gene therapy has the potential to provide therapeutic benefits to a large number of patients with NDDs by offering mechanisms including neuroprotection, neuro-restoration, and rectification of pathogenic pathways. Gene therapy is a medical approach that aims to modify the biological characteristics of living cells by controlling the expression of specific genes in certain neurological disorders. Despite being the most complex and well-protected organ in the human body, there is clinical evidence to show that it is possible to specifically target the central nervous system (CNS). This provides hope for the prospective application of gene therapy in treating NDDs in the future. There are several advanced techniques available for using viral or non-viral vectors to deliver the therapeutic gene to the afflicted region. Neurotrophic factors (NTF) in the brain are crucial for the development, differentiation, and survival of neurons in the CNS, making them important in the context of various neurological illnesses. Gene delivery of NTF has the potential to be used as a therapeutic approach for the treatment of neurological problems in the brain. This review primarily focuses on the methodologies employed for delivering the genes of different NTFs to treat neurological disorders. These techniques are currently being explored as a viable therapeutic approach for neurodegenerative diseases. The article exclusively addresses gene delivery approaches and does not cover additional therapy strategies for NDDs. Gene therapy offers a promising alternative treatment for NDDs by stimulating neuronal growth instead of solely relying on symptom relief from drugs and their associated adverse effects. It can serve as a long-lasting and advantageous treatment choice for the management of NDDs. The likelihood of developing NDDs increases with age as a result of neuronal degradation in the brain. Gene therapy is an optimal approach for promoting neuronal growth through the introduction of nerve growth factor genes.}, } @article {pmid38855716, year = {2024}, author = {Morganroth, J and Bardakjian, TM and Dratch, L and Quinn, CC and Elman, LB}, title = {Enhancing Clinical Infrastructure for the Delivery of Intrathecal and Genetic Therapies: A Qalsody (Tofersen) Model for Patients With SOD1-ALS.}, journal = {Neurology. Clinical practice}, volume = {14}, number = {4}, pages = {e200303}, pmid = {38855716}, issn = {2163-0402}, abstract = {BACKGROUND: Qalsody (tofersen), an intrathecal therapy (IT) antisense oligonucleotide (ASO), was granted accelerated approval by the Food and Drug Administration for the treatment of SOD1-mediated amyotrophic lateral sclerosis (ALS) on April 25, 2023. Academic centers need to be prepared for expedited drug delivery. The purpose of this model was to predict the number of SOD1-ALS patients whom we expect to see at our center at the time of Qalsody approval and to use it to extrapolate to a model for a hypothetical sporadic IT ALS therapy.

RECENT FINDINGS: We predicted that 6 symptomatic and 14 presymptomatic SOD1 patients would come to our center, whereas a sporadic therapy would generate 108 patients, creating excess office visits, lumbar punctures, and genetic counseling visits.

IMPLICATIONS FOR PRACTICE: As new therapies for neurologic diseases come to market, preparing for increased office volume and complex drug delivery are essential for optimal care.}, } @article {pmid38855322, year = {2024}, author = {Tsekrekou, M and Giannakou, M and Papanikolopoulou, K and Skretas, G}, title = {Protein aggregation and therapeutic strategies in SOD1- and TDP-43- linked ALS.}, journal = {Frontiers in molecular biosciences}, volume = {11}, number = {}, pages = {1383453}, pmid = {38855322}, issn = {2296-889X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with severe socio-economic impact. A hallmark of ALS pathology is the presence of aberrant cytoplasmic inclusions composed of misfolded and aggregated proteins, including both wild-type and mutant forms. This review highlights the critical role of misfolded protein species in ALS pathogenesis, particularly focusing on Cu/Zn superoxide dismutase (SOD1) and TAR DNA-binding protein 43 (TDP-43), and emphasizes the urgent need for innovative therapeutic strategies targeting these misfolded proteins directly. Despite significant advancements in understanding ALS mechanisms, the disease remains incurable, with current treatments offering limited clinical benefits. Through a comprehensive analysis, the review focuses on the direct modulation of the misfolded proteins and presents recent discoveries in small molecules and peptides that inhibit SOD1 and TDP-43 aggregation, underscoring their potential as effective treatments to modify disease progression and improve clinical outcomes.}, } @article {pmid38854008, year = {2024}, author = {Rifai, OM and Waldron, FM and O'Shaughnessy, J and Read, FL and Gilodi, M and Pastore, A and Shneider, N and Tartaglia, GG and Zacco, E and Spence, H and Gregory, JM}, title = {Amygdala TDP-43 pathology is associated with behavioural dysfunction and ferritin accumulation in amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38854008}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 NS127186/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Cognitive and behavioural symptoms associated with amyotrophic lateral sclerosis and frontotemporal spectrum disorders (ALSFTSD) are thought to be driven, at least in part, by the pathological accumulation of TDP-43.

METHODS: Here we examine post-mortem tissue from six brain regions associated with cognitive and behavioural symptoms in a cohort of 30 people with sporadic ALS (sALS), a proportion of which underwent standardized neuropsychological behavioural assessment as part of the Edinburgh Cognitive ALS Screen (ECAS).

RESULTS: Overall, the behavioural screen performed as part of the ECAS predicted accumulation of pathological phosphorylated TDP-43 (pTDP-43) with 100% specificity and 86% sensitivity in behaviour-associated brain regions. Notably, of these regions, pathology in the amygdala was the most predictive correlate of behavioural dysfunction in sALS. In the amygdala of sALS patients, we show variation in morphology, cell type predominance, and severity of pTDP-43 pathology. Further, we demonstrate that the presence and severity of intra-neuronal pTDP-43 pathology, but not astroglial pathology, or phosphorylated Tau pathology, is associated with behavioural dysfunction. Cases were also evaluated using a TDP-43 aptamer (TDP-43[APT]), which revealed that pathology was not only associated with behavioural symptoms, but also with ferritin levels, a measure of brain iron.

CONCLUSIONS: Intra-neuronal pTDP-43 and cytoplasmic TDP-43[APT] pathology in the amygdala is associated with behavioural symptoms in sALS. TDP-43[APT] staining intensity is also associated with increased ferritin, regardless of behavioural phenotype, suggesting that ferritin increases may occur upstream of clinical manifestation, in line with early TDP-43[APT] pathology, representing a potential region-specific imaging biomarker of early disease in ALS.}, } @article {pmid38853969, year = {2024}, author = {Bingham, IN and Norel, R and Roitberg, EG and Peller, J and Trevisan, MA and Agurto, C and Shalom, DE and Aguirre, F and Embon, I and Taitz, A and Harris, D and Wright, A and Seaver, K and Sullivan, S and Green, JR and Ostrow, LW and Fraenkel, E and Berry, JD}, title = {Listener effort quantifies clinically meaningful progression of dysarthria in people living with amyotrophic lateral sclerosis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38853969}, support = {K24 DC016312/DC/NIDCD NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron disease that causes progressive muscle weakness. Progressive bulbar dysfunction causes dysarthria and thus social isolation, reducing quality of life. The Everything ALS Speech Study obtained longitudinal clinical information and speech recordings from 292 participants. In a subset of 120 participants, we measured speaking rate (SR) and listener effort (LE), a measure of dysarthria severity rated by speech pathologists from recordings. LE intra- and inter-rater reliability was very high (ICC 0.88 to 0.92). LE correlated with other measures of dysarthria at baseline. LE changed over time in participants with ALS (slope 0.77 pts/month; p<0.001) but not controls (slope 0.005 pts/month; p=0.807). The slope of LE progression was similar in all participants with ALS who had bulbar dysfunction at baseline, regardless of ALS site of onset. LE could be a remotely collected clinically meaningful clinical outcome assessment for ALS clinical trials.}, } @article {pmid38853922, year = {2024}, author = {Dilliott, AA and Costanzo, MC and Bandres-Ciga, S and Blauwendraat, C and Casey, B and Hoang, Q and Iwaki, H and Jang, D and Kim, JJ and Leonard, HL and Levine, KS and Makarious, M and Nguyen, TT and Rouleau, GA and Singleton, AB and Smadbeck, P and Solle, J and Vitale, D and Nalls, MA and Flannick, J and Burtt, NP and Farhan, SMK}, title = {The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38853922}, abstract = {Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathological mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across ten different phenotypic groups, including neurological conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively utilize the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use-cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open-science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for neurodegenerative disease patients.}, } @article {pmid38853763, year = {2024}, author = {Maranzano, A and Verde, F and Dubini, A and Torre, S and Colombo, E and Doretti, A and Gentile, F and Manini, A and Milone, I and Brusati, A and Peverelli, S and Santangelo, S and Spinelli, EG and Torresani, E and Gentilini, D and Messina, S and Morelli, C and Poletti, B and Agosta, F and Ratti, A and Filippi, M and Silani, V and Ticozzi, N}, title = {Association of APOE genotype and cerebrospinal fluid Aβ and tau biomarkers with cognitive and motor phenotype in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {9}, pages = {e16374}, pmid = {38853763}, issn = {1468-1331}, support = {RF-2021-12374238//Ministry of Health/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyloid beta-Peptides/cerebrospinal fluid ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/genetics ; *Apolipoproteins E/genetics/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; Cognition Disorders/cerebrospinal fluid/genetics/etiology ; Genotype ; Peptide Fragments/cerebrospinal fluid ; *Phenotype ; *tau Proteins/cerebrospinal fluid ; }, abstract = {OBJECTIVE: Little is known about amyotrophic lateral sclerosis (ALS)-nonspecific cognitive deficits - most notably memory disturbance - and their biological underpinnings. We investigated the associations of the Alzheimer's disease (AD) genetic risk factor APOE and cerebrospinal fluid (CSF) biomarkers Aβ and tau proteins with cognitive and motor phenotype in ALS.

METHODS: APOE haplotype was determined in 281 ALS patients; for 105 of these, CSF levels of Aβ42, Aβ40, total tau (T-tau), and phosphorylated tau (P-tau181) were quantified by chemiluminescence enzyme immunoassay (CLEIA). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was employed to evaluate the neuropsychological phenotype.

RESULTS: APOE-E4 allele was associated with worse ECAS memory score (median, 14.0 in carriers vs. 16.0 in non-carriers) and lower CSF Aβ42 (-0.8 vs. 0.1, log-transformed values) and Aβ42/40 ratio (-0.1 vs. 0.3). Some 37.1% of ALS patients showed low Aβ42 levels, possibly reflecting cerebral Aβ deposition. While lower Aβ42/40 correlated with lower memory score (β = 0.20), Aβ42 positively correlated with both ALS-specific (β = 0.24) and ALS-nonspecific (β = 0.24) scores. Although Aβ42/40 negatively correlated with T-tau (β = -0.29) and P-tau181 (β = -0.33), we found an unexpected positive association of Aβ42 and Aβ40 with both tau proteins. Regarding motor phenotype, lower levels of Aβ species were associated with lower motor neuron (LMN) signs (Aβ40: β = 0.34; Aβ42: β = 0.22).

CONCLUSIONS: APOE haplotype and CSF Aβ biomarkers are associated with cognitive deficits in ALS and particularly with memory impairment. This might partly reflect AD-like pathophysiological processes, but additional ALS-specific mechanisms could be involved.}, } @article {pmid38853167, year = {2024}, author = {Öijerstedt, L and Foucher, J and Lovik, A and Yazdani, S and Juto, A and Kläppe, U and Fang, F and Ingre, C}, title = {Repeated cognitive assessments show stable function over time in patients with ALS.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5267-5274}, pmid = {38853167}, issn = {1432-1459}, support = {SLS-986189//Svenska Läkaresällskapet/ ; 2023-02428//Vetenskapsrådet/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Male ; Female ; Middle Aged ; Aged ; *Cognitive Dysfunction/etiology/physiopathology/diagnosis ; Longitudinal Studies ; *Neuropsychological Tests ; Disease Progression ; Executive Function/physiology ; Sweden/epidemiology ; Follow-Up Studies ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multisystem disorder with not only motor symptoms but also extra-motor features including cognitive impairment. The most common cognitive profile observed in patients with ALS includes deficits in executive function, language, and social cognition. However, longitudinal studies on cognitive changes over time in ALS are sparse. We aimed to investigate the presence and nature of cognitive impairment at the time of ALS diagnosis and its association with survival as well as explore longitudinal cognitive change.

METHOD: Patients (n = 216) were recruited at the Karolinska University Hospital in Stockholm, Sweden. Follow-up visits (n = 307 in total) were performed every 6 months. Cognitive impairment was assessed using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and/or Montreal Cognitive Assessment (MoCA).

RESULTS: Cognitive impairment was observed in 38% of the patients at the time of ALS diagnosis, and the majority of these patients had deficits in executive function and/or language. Patients with cognitive impairment at the time of diagnosis had a more rapid decline in ALSFRS-R at 12- and 18-months follow-up, and a shorter survival. Cognitive function was stable during the first 2 years after diagnosis, and did not follow the trajectories of decline in motor functions.

CONCLUSION: Cognitive impairment in ALS was associated with a faster decline of motor functions, and shorter survival. However, cognitive function did not deteriorate over time. Cognitive assessment is essential for the patients and caregivers to understand the phenotypic expression of ALS.}, } @article {pmid38852806, year = {2024}, author = {Yazdani, S and Lovik, A and Seitz, C and Ingre, C and Fang, F and Andersson, J}, title = {T cell subset composition differs between blood and cerebrospinal fluid in amyotrophic lateral sclerosis.}, journal = {Clinical immunology (Orlando, Fla.)}, volume = {265}, number = {}, pages = {110270}, doi = {10.1016/j.clim.2024.110270}, pmid = {38852806}, issn = {1521-7035}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/immunology/blood ; Male ; Female ; Middle Aged ; *Flow Cytometry ; Aged ; *T-Lymphocyte Subsets/immunology ; Adult ; }, abstract = {Inflammation is a hallmark of amyotrophic lateral sclerosis (ALS) and is often assessed through biological samples. Due to the easier access, peripheral blood is more commonly phenotyped instead of cerebrospinal fluid (CSF) or affected tissues in ALS. Here, using flow cytometry, we compared the composition of T cell subsets in blood and CSF in ALS patients. We found consistent but weak correlations between blood and CSF for all T cell subsets examined. This finding implies that blood and CSF offer complementary information when characterizing T cell immunity in ALS and blood may not be used as a surrogate for CSF.}, } @article {pmid38852741, year = {2024}, author = {Moncayo, AK and Grossman, D and Kim, CC and Hartman, RI}, title = {Response to Bass et al's "Significant discordance in DermTech test results when paired with histopathology: Caveat emptor".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e101-e102}, doi = {10.1016/j.jaad.2024.05.079}, pmid = {38852741}, issn = {1097-6787}, mesh = {Humans ; *Skin Neoplasms/pathology ; Dermoscopy ; Melanoma/pathology ; }, } @article {pmid38852112, year = {2024}, author = {Leighton, DJ and Ansari, M and Newton, J and Cleary, E and Stephenson, L and Beswick, E and Carod Artal, J and Davenport, R and Duncan, C and Gorrie, GH and Morrison, I and Swingler, R and Deary, IJ and Porteous, M and Chandran, S and Pal, S and , }, title = {Genotypes and phenotypes of motor neuron disease: an update of the genetic landscape in Scotland.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5256-5266}, pmid = {38852112}, issn = {1432-1459}, support = {CAF/MND/15/01//Chief Scientist Office, Scottish Government Health and Social Care Directorate/ ; CAF/MND/15/01//MND Scotland/ ; CAF/MND/15/01/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; Scotland/epidemiology ; *Motor Neuron Disease/genetics/epidemiology ; Male ; Female ; Middle Aged ; Aged ; *Phenotype ; *C9orf72 Protein/genetics ; Genotype ; Adult ; DNA Repeat Expansion/genetics ; Cohort Studies ; Aged, 80 and over ; Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND: Using the Clinical Audit Research and Evaluation of Motor Neuron Disease (CARE-MND) database and the Scottish Regenerative Neurology Tissue Bank, we aimed to outline the genetic epidemiology and phenotypes of an incident cohort of people with MND (pwMND) to gain a realistic impression of the genetic landscape and genotype-phenotype associations.

METHODS: Phenotypic markers were identified from the CARE-MND platform. Sequence analysis of 48 genes was undertaken. Variants were classified using a structured evidence-based approach. Samples were also tested for C9orf72 hexanucleotide expansions using repeat-prime PCR methodology.

RESULTS: 339 pwMND donated a DNA sample: 44 (13.0%) fulfilled criteria for having a pathogenic variant/repeat expansion, 53.5% of those with a family history of MND and 9.3% of those without. The majority (30 (8.8%)) had a pathogenic C9orf72 repeat expansion, including two with intermediate expansions. Having a C9orf72 expansion was associated with a significantly lower Edinburgh Cognitive and Behavioural ALS Screen ALS-Specific score (p = 0.0005). The known pathogenic SOD1 variant p.(Ile114Thr), frequently observed in the Scottish population, was detected in 9 (2.7%) of total cases but in 17.9% of familial cases. Rare variants were detected in FUS and NEK1. One individual carried both a C9orf72 expansion and SOD1 variant.

CONCLUSIONS: Our results provide an accurate summary of MND demographics and genetic epidemiology. We recommend early genetic testing of people with cognitive impairment to ensure that C9orf72 carriers are given the best opportunity for informed treatment planning. Scotland is enriched for the SOD1 p.(Ile114Thr) variant and this has significant implications with regards to future genetically-targeted treatments.}, } @article {pmid38851229, year = {2024}, author = {Yu, Y and Zeng, L and Wu, M and Li, C and Qiu, Y and Liu, J and Yang, F and Xia, P}, title = {Exploring amyotrophic lateral sclerosis patients' experiences of psychological distress during the disease course in China: a qualitative study.}, journal = {BMJ open}, volume = {14}, number = {6}, pages = {e082398}, pmid = {38851229}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Female ; Male ; China ; Middle Aged ; *Qualitative Research ; *Psychological Distress ; *Quality of Life ; Adult ; Aged ; Stress, Psychological/psychology ; Interviews as Topic ; Social Stigma ; Adaptation, Psychological ; }, abstract = {OBJECTIVE: This study aims to explore the psychological distress course of Chinese amyotrophic lateral sclerosis (ALS) patients after the onset of the disease and to provide targeted nursing guidance.

DESIGN: The interview content was analysed qualitatively. We used seven steps of Colaizzi's method to analyse the participants' data.

SETTING: Wuhan, China, Traditional Chinese Medicine Hospital.

PARTICIPANTS: A semistructured face-to-face interview were performed among 22 people with ALS from the motor neuron disease rehabilitation centre of a tertiary Chinese medicine hospital in China.

RESULT: This study included a total of 22 participants, from whom three main themes regarding the psychological distress trajectory of ALS patients were extracted from the interview data: 'Time begins to run out' include tormented and restless waiting and shock and doubt in ALS disease confirmation, 'Family out of control' include the burden of stigma and function loss, the burden of missing family roles, the burden of marriage's emotional needs and the burden of offspring health, 'Way forward' include struggle between live and death and struggle between quality of life and the value of life.

CONCLUSION: This study outlines the psychologically distressing journey of ALS patients. Studies have pointed out the need for targeted care to address patients' various sources of psychological distress to improve their quality of life and coping ability, increase their psychological resilience and reconstruct their life beliefs.}, } @article {pmid38850875, year = {2024}, author = {Coen, M and Benyamine, A and Delmont, E and Kaplanski, G and Bouabdallah, R and Xerri, L and Attarian, S and Serratrice, J}, title = {Tell-tale immune-related neurological syndromes: Should we look for and underlying low-grade B-cell lymphoma? A retrospective study on 12 cases.}, journal = {Pathology, research and practice}, volume = {260}, number = {}, pages = {155377}, doi = {10.1016/j.prp.2024.155377}, pmid = {38850875}, issn = {1618-0631}, mesh = {Humans ; Retrospective Studies ; Male ; Female ; Middle Aged ; *Lymphoma, B-Cell/pathology/immunology ; Aged ; Adult ; }, abstract = {INTRODUCTION: Immune-related neurological syndromes (affecting both the central and peripheral nervous system, as well as the neuromuscular junction) can associate with low-grade B-cell lymphomas.

METHODS: We conducted a retrospective study on the records of patients with miscellaneous immune-related neuropathies followed by the "Referral Centre for Neuromuscular Diseases and ALS" in collaboration with the Services of Internal Medicine and Hematology (La Timone Hospital, and the Paoli Calmettes-Insitute, Marseille, France; Geneva University Hospitals, Geneva, Switzerland). Clinical, biological, immunological and histological work-up was carried out and data collected.

RESULTS: We identified 12 patients with neurological syndromes and atypical presentation/course. In all these patients multiple autoantibodies were found. This prompted us to perform thorough hematologic investigations, that led to the diagnosis of different type of Low-Grade B-Cell lymphomas [i.e. marginal zone lymphomas with lymphoplasmacytic differentiation (n=3), splenic marginal area lymphoma with secondary lymph node invasion (n=1), unclassified marginal area lymphomas (n=8)]. Treatment of the underling lymphoma resulted in an improvement (n=8) or stabilization (n=4) of neurological disease.

CONCLUSION: Atypical presentation of immune-related neurological syndromes, as well as the presence of antibodies with different antigenic targets should be regarded as "warning signs" and raise the suspicion of a paraneoplastic origin sustained by an underlying low-grade B-cell lymphoma that should be actively sought and treated. Close collaboration between internists, neurologists and hematologists allows for the appropriate management of each case.}, } @article {pmid38849544, year = {2024}, author = {Sun, H and Yang, B and Li, Q and Zhu, X and Song, E and Liu, C and Song, Y and Jiang, G}, title = {Polystyrene nanoparticles trigger aberrant condensation of TDP-43 and amyotrophic lateral sclerosis-like symptoms.}, journal = {Nature nanotechnology}, volume = {19}, number = {9}, pages = {1354-1365}, pmid = {38849544}, issn = {1748-3395}, support = {22176206, 22174116 and 22241604//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {*Polystyrenes/chemistry/toxicity ; *Amyotrophic Lateral Sclerosis/metabolism/chemically induced ; *DNA-Binding Proteins/metabolism ; Humans ; *Nanoparticles/chemistry ; Animals ; Mice ; Oxidative Stress/drug effects ; Motor Neurons/metabolism/drug effects/pathology ; HSP70 Heat-Shock Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the dysfunction and progressive death of cerebral and spinal motor neurons. Preliminary epidemiological research has hinted at a relationship between environmental risks and the escalation of ALS, but the underlying reasons remain mostly mysterious. Here we show that nanosize polystyrene plastics (PS) induce ALS-like symptoms and illustrate the related molecular mechanism. When exposed to PS, cells endure internal oxidative stress, which leads to the aggregation of TAR DNA-binding protein 43 kDa (TDP-43), triggering ALS-like characteristics. In addition, the oxidized heat shock protein 70 fails to escort TDP-43 back to the nucleus. The cytoplasmic accumulation of TDP-43 facilitates the formation of a complex between PS and TDP-43, enhancing the condensation and solidification of TDP-43. These findings are corroborated through in silico and in vivo assays. Altogether, our work illustrates a unique toxicological mechanism induced by nanoparticles and provides insights into the connection between environmental pollution and neurodegenerative disorders.}, } @article {pmid38849367, year = {2024}, author = {Mora, S and Stuckert, A and von Huth Friis, R and Pietersz, K and Noes-Holt, G and Montañana-Rosell, R and Wang, H and Sørensen, AT and Selvan, R and Verhaagen, J and Allodi, I}, title = {Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4867}, pmid = {38849367}, issn = {2041-1723}, support = {21-2B-9477/L102 and 18-2B-3570//Aage og Johanne Louis-Hansens Fond (Aage and Johanne Louis-Hansen Foundation)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/metabolism/therapy ; *Interneurons/metabolism ; *Motor Neurons/metabolism ; *Disease Models, Animal ; Mice ; *Mice, Transgenic ; *Synapses/metabolism ; Phenotype ; Male ; Genetic Therapy/methods ; Humans ; Female ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Loss of connectivity between spinal V1 inhibitory interneurons and motor neurons is found early in disease in the SOD1[G93A] mice. Such changes in premotor inputs can contribute to homeostatic imbalance of motor neurons. Here, we show that the Extended Synaptotagmin 1 (Esyt1) presynaptic organizer is downregulated in V1 interneurons. V1 restricted overexpression of Esyt1 rescues inhibitory synapses, increases motor neuron survival, and ameliorates motor phenotypes. Two gene therapy approaches overexpressing ESYT1 were investigated; one for local intraspinal delivery, and the other for systemic administration using an AAV-PHP.eB vector delivered intravenously. Improvement of motor functions is observed in both approaches, however systemic administration appears to significantly reduce onset of motor impairment in the SOD1[G93A] mice in absence of side effects. Altogether, we show that stabilization of V1 synapses by ESYT1 overexpression has the potential to improve motor functions in ALS, demonstrating that interneurons can be a target to attenuate ALS symptoms.}, } @article {pmid38849340, year = {2024}, author = {Caldi Gomes, L and Hänzelmann, S and Hausmann, F and Khatri, R and Oller, S and Parvaz, M and Tzeplaeff, L and Pasetto, L and Gebelin, M and Ebbing, M and Holzapfel, C and Columbro, SF and Scozzari, S and Knöferle, J and Cordts, I and Demleitner, AF and Deschauer, M and Dufke, C and Sturm, M and Zhou, Q and Zelina, P and Sudria-Lopez, E and Haack, TB and Streb, S and Kuzma-Kozakiewicz, M and Edbauer, D and Pasterkamp, RJ and Laczko, E and Rehrauer, H and Schlapbach, R and Carapito, C and Bonetto, V and Bonn, S and Lingor, P}, title = {Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4893}, pmid = {38849340}, issn = {2041-1723}, support = {01GM1917A//Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)/ ; SFB1192 PB8, and PC3//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism ; Humans ; Female ; Animals ; Male ; Mice ; *Mice, Transgenic ; *MAP Kinase Signaling System/drug effects ; *Disease Models, Animal ; Pyridones/pharmacology/therapeutic use ; RNA-Binding Protein FUS/metabolism/genetics ; Prefrontal Cortex/metabolism ; Transcriptome ; Superoxide Dismutase-1/genetics/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Middle Aged ; MicroRNAs/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; Sex Characteristics ; Aged ; Sex Factors ; Pyrimidinones ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating motor neuron disease and lacks effective disease-modifying treatments. This study utilizes a comprehensive multiomic approach to investigate the early and sex-specific molecular mechanisms underlying ALS. By analyzing the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, alongside four transgenic mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS), we have uncovered significant molecular alterations associated with the disease. Here, we show that males exhibit more pronounced changes in molecular pathways compared to females. Our integrated analysis of transcriptomes, (phospho)proteomes, and miRNAomes also identified distinct ALS subclusters in humans, characterized by variations in immune response, extracellular matrix composition, mitochondrial function, and RNA processing. The molecular signatures of human subclusters were reflected in specific mouse models. Our study highlighted the mitogen-activated protein kinase (MAPK) pathway as an early disease mechanism. We further demonstrate that trametinib, a MAPK inhibitor, has potential therapeutic benefits in vitro and in vivo, particularly in females, suggesting a direction for developing targeted ALS treatments.}, } @article {pmid38848664, year = {2024}, author = {Morioka, D and Sagisaka, R and Nakagawa, K and Takahashi, H and Tanaka, H}, title = {Effect of timing of advanced life support on out-of-hospital cardiac arrests at home.}, journal = {The American journal of emergency medicine}, volume = {82}, number = {}, pages = {94-100}, doi = {10.1016/j.ajem.2024.05.021}, pmid = {38848664}, issn = {1532-8171}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; Retrospective Studies ; Aged ; *Epinephrine/administration & dosage/therapeutic use ; Japan/epidemiology ; Middle Aged ; *Emergency Medical Services ; *Advanced Cardiac Life Support/methods ; Intubation, Intratracheal/statistics & numerical data ; Time-to-Treatment/statistics & numerical data ; Aged, 80 and over ; Registries ; Time Factors ; Return of Spontaneous Circulation ; Cardiopulmonary Resuscitation/methods ; }, abstract = {AIM: In cases of out-of-hospital cardiac arrests (OHCA) occurring at home, Japanese emergency medical services personnel decide whether to provide treatment on the scene or during transport based on their judgment. This study aimed to evaluate the association between the timing of advanced life support (ALS) (i.e., endotracheal intubation [ETI] or adrenaline administration) for OHCA at home and prognosis.

METHOD: This retrospective cohort study used data from the Japan Utstein Registry and emergency transport data collected from patients who underwent pre-hospital ETI (n = 6806) and received adrenaline (n = 22,636) between 2016 and 2019. The timing of ETI or adrenaline administration was determined as "on the scene" or "in the ambulance." Multiple logistic regression analysis was used to estimate the association among the timing of ALS implementation, pre-hospital return of spontaneous circulation (ROSC), and survival at 1 month.

RESULT: ETI on the scene was significantly positively associated with pre-hospital ROSC (adjusted odds ratio [AOR], 1.81; 95% confidence interval [CI], 1.57-2.09) and survival at 1 month (AOR, 1.81; 95% CI, 1.47-2.23). Adrenaline administration on the scene was significantly positively associated with pre-hospital ROSC (AOR, 2.51; 95% CI, 2.33-2.70) and survival at 1 month (AOR, 2.13; 95% CI, 1.89-2.40).

CONCLUSION: Our analysis suggests performing ALS on the scene was associated with pre-hospital ROSC and survival at 1 month. Further efforts are needed to increase the rate of ALS implementation on the scene by emergency life-saving technicians.}, } @article {pmid38848044, year = {2025}, author = {Samalia, P and Niederer, R}, title = {Letter to the Editor: Comment on Raad et al's "Adalimumab for the Treatment of Non-Infectious Uveitis: A Real Life Experience".}, journal = {Ocular immunology and inflammation}, volume = {33}, number = {3}, pages = {377}, doi = {10.1080/09273948.2024.2362879}, pmid = {38848044}, issn = {1744-5078}, } @article {pmid38848023, year = {2024}, author = {Fabi, JP}, title = {The connection between gut microbiota and its metabolites with neurodegenerative diseases in humans.}, journal = {Metabolic brain disease}, volume = {39}, number = {5}, pages = {967-984}, doi = {10.1007/s11011-024-01369-w}, pmid = {38848023}, issn = {1573-7365}, support = {2013/07914-8//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 307842/2022-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Neurodegenerative Diseases/metabolism/microbiology ; *Dysbiosis/metabolism ; *Brain-Gut Axis/physiology ; Animals ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; }, abstract = {The aging of populations is a global phenomenon that follows a possible increase in the incidence of neurodegenerative diseases. Alzheimer's, Parkinson's, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Huntington's diseases are some neurodegenerative disorders that aging could initiate or aggravate. Recent research has indicated that intestinal microbiota dysbiosis can trigger metabolism and brain functioning, contributing to the etiopathogenesis of those neurodegenerative diseases. The intestinal microbiota and its metabolites show significant functions in various aspects, such as the immune system modulation (development and maturation), the maintenance of the intestinal barrier integrity, the modulation of neuromuscular functions in the intestine, and the facilitation of essential metabolic processes for both the microbiota and humans. The primary evidence supporting the connection between intestinal microbiota and its metabolites with neurodegenerative diseases are epidemiological observations and animal models experimentation. This paper reviews up-to-date evidence on the correlation between the microbiota-gut-brain axis and neurodegenerative diseases, with a specially focus on gut metabolites. Dysbiosis can increase inflammatory cytokines and bacterial metabolites, altering intestinal and blood-brain barrier permeability and causing neuroinflammation, thus facilitating the pathogenesis of neurodegenerative diseases. Clinical data supporting this evidence still needs to be improved. Most of the works found are descriptive and associated with the presence of phyla or species of bacteria with neurodegenerative diseases. Despite the limitations of recent research, the potential for elucidating clinical questions that have thus far eluded clarification within prevailing pathophysiological frameworks of health and disease is promising through investigation of the interplay between the host and microbiota.}, } @article {pmid38847583, year = {2024}, author = {Zhou, M and Sheng, Z and Ji, G and Zhang, X}, title = {Aerogel-Involved Triple-State Gels Resemble Natural Living Leaves in Structure and Multi-Functions.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {36}, number = {32}, pages = {e2406007}, doi = {10.1002/adma.202406007}, pmid = {38847583}, issn = {1521-4095}, support = {52173052//National Natural Science Foundation of China/ ; SYC2022125//Suzhou Municipal Science and Technology Bureau/ ; }, mesh = {*Plant Leaves/chemistry/metabolism ; Gels/chemistry ; Silicon Dioxide/chemistry ; Hydrogels/chemistry ; Photosynthesis ; Polyvinyl Alcohol/chemistry ; Hydrophobic and Hydrophilic Interactions ; }, abstract = {Natural plant leaves with multiple functions, for example, spectral features, transpiration, photosynthesis, etc., have played a significant role in the ecosystem, and artificial synthesis of plant leaves with multiple functions of natural ones is still a great challenge. Herein, this work presents an aerogel-involved living leaf (AL), most similar to natural ones so far, by embedding super-hydrophobic SiO2 aerogel microparticles in polyvinyl alcohol hydrogel in the presence of hygroscopic salt and chlorophyllin copper sodium to form solid-liquid-vapor triple-state gel. The AL shows a high spectral similarity with all sampled 15 species of natural leaves and exhibits ≈4-7 times transpiration speed higher than natural leaves. More importantly, AL can achieve several times higher photosynthesis than natural leaves without the energy provided by the respiratory action of natural ones. This work demonstrates the feasibility of creating ALs with natural leaf-like triple-state gel structures and multiple functions, opening up new avenues for energy conversion, environmental engineering, and biomimetic applications.}, } @article {pmid38847056, year = {2024}, author = {Michelotti, G and Egger-Sigg, M and Bornstein, MM}, title = {[Komplexes Odontom im Unterkieferfrontzahnbereich bei einer 16-jährigen Patientin - Diagnostik, Therapie und Nachsorge].}, journal = {Swiss dental journal}, volume = {134}, number = {3}, pages = {}, doi = {10.61872/sdj-2024-03-08}, pmid = {38847056}, issn = {2296-6498}, mesh = {Adolescent ; Humans ; Diagnosis, Differential ; Mandibular Neoplasms/surgery/pathology/diagnosis ; Maxillary Neoplasms/surgery/pathology/diagnosis ; *Odontoma/surgery/diagnosis/pathology ; }, abstract = {Odontome gelten zusammen mit den Amelo- blastomen als die häufigsten odontogenen Tumoren. Sie entstehen während der embryo- nalen Zahnkeimentwicklung durch fehlerhaft differenziertes Keimgewebe und werden daher auch als Hamartome bezeichnet. Somit sind sie also strenggenommen keine klassischen Neoplasien.}, } @article {pmid38846716, year = {2024}, author = {Bradford, D and Rodgers, KE}, title = {Advancements and challenges in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1401706}, pmid = {38846716}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) continues to pose a significant challenge due to the disease complexity and heterogeneous manifestations. Despite recent drug approvals, there remains a critical need for the development of more effective therapies. This review explores the underlying mechanisms involved; including neuroinflammation, glutamate mediated excitotoxicity, mitochondrial dysfunction, and hypermetabolism, and how researchers are trying to develop novel drugs to target these pathways. While progress has been made, the unmet need of ALS patients highlights the urgency for continued research and resource allocation in the pursuit of effective treatments.}, } @article {pmid38846532, year = {2024}, author = {Murage, B and Tan, H and Mashimo, T and Jackson, M and Skehel, PA}, title = {Spinal cord neurone loss and foot placement changes in a rat knock-in model of amyotrophic lateral sclerosis Type 8.}, journal = {Brain communications}, volume = {6}, number = {3}, pages = {fcae184}, pmid = {38846532}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is an age-dependent cell type-selective degenerative disease. Genetic studies indicate that amyotrophic lateral sclerosis is part of a spectrum of disorders, ranging from spinal muscular atrophy to frontotemporal dementia that share common pathological mechanisms. Amyotrophic lateral sclerosis Type 8 is a familial disease caused by mis-sense mutations in VAPB. VAPB is localized to the cytoplasmic surface of the endoplasmic reticulum, where it serves as a docking point for cytoplasmic proteins and mediates inter-organelle interactions with the endoplasmic reticulum membrane. A gene knock-in model of amyotrophic lateral sclerosis Type 8 based on the VapB[P56S] mutation and VapB gene deletion has been generated in rats. These animals display a range of age-dependent phenotypes distinct from those previously reported in mouse models of amyotrophic lateral sclerosis Type 8. A loss of motor neurones in VapB[P56S/+] and VapB[P56S/P56S] animals is indicated by a reduction in the number of large choline acetyl transferase-staining cells in the spinal cord. VapB[-/-] animals exhibit a relative increase in cytoplasmic TDP-43 levels compared with the nucleus, but no large protein aggregates. Concomitant with these spinal cord pathologies VapB[P56S/+] , VapB[P56S/P56S] and VapB[-/-] animals exhibit age-dependent changes in paw placement and exerted pressures when traversing a CatWalk apparatus, consistent with a somatosensory dysfunction. Extramotor dysfunction is reported in half the cases of motor neurone disease, and this is the first indication of an associated sensory dysfunction in a rodent model of amyotrophic lateral sclerosis. Different rodent models may offer complementary experimental platforms with which to understand the human disease.}, } @article {pmid38845371, year = {2024}, author = {Rooney, J and Murray, D and Meldrum, D and Al-Chalabi, A and Bunte, T and Chiwera, T and Choudhury, M and Chio, A and Fenton, L and Fortune, J and Maidment, L and Manera, U and McDermott, CJ and Meyjes, M and Tattersall, R and Torrieri, MC and Van Damme, P and Vanderlinden, E and Wood, C and van den Berg, LH and Hardiman, O}, title = {REVEALS-a longitudinal cohort study of multifaceted respiratory assessment in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {661-671}, pmid = {38845371}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Male ; Female ; Middle Aged ; Aged ; Longitudinal Studies ; *Disease Progression ; Respiratory Function Tests/methods ; Vital Capacity/physiology ; Cohort Studies ; Cough/physiopathology/diagnosis ; }, abstract = {OBJECTIVE: To systematically assess decline in respiratory measures in amyotrophic lateral sclerosis (ALS) and to examine the impact of sex, disease onset type and baseline morbidity on progression.

METHODS: The REVEALS study (Registry of Endpoints and Validated Experiences in ALS) was conducted between April 2018 and February 2021 in six European ALS centers. Slow and forced vital capacity (S/FVC), sniff nasal inspiratory pressure (SNIP), peak cough flow, amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R), and respiratory morbidity were collected. Data were analyzed using a Bayesian multiple outcomes random effects model.

RESULTS: Two hundred and eighty participants had a median of three assessments (IQR 2.0, 5.0) over a median of 8 months (IQR 2.3, 14.1). There were 974 data collection timepoints. Differences in respiratory measures and rates of decline between disease-onset and sex subgroups were identified. Females had lower scores in all respiratory measures and females with bulbar onset ALS had faster decline compared with other sub-groups. These differences were not detected by the ALSFRS-r respiratory subscale. Dyspnea, orthopnea, and a higher King's stage at baseline were associated with lower respiratory scores throughout follow-up, while having a regular productive cough at baseline was associated with lower peak cough flow scores.

CONCLUSION: Respiratory function declines more quickly in females with ALS compared with males when measured by FVC, SVC, SNIP, or PCF, but not the ALSFRS-R respiratory sub-score. Higher baseline King's staging and the presence of clinical respiratory symptoms at baseline were associated with worse respiratory function. The ALSFRS-R respiratory sub-score is poorly correlated with objective respiratory measurements.}, } @article {pmid38845026, year = {2024}, author = {Kettunen, P and Koistinaho, J and Rolova, T}, title = {Contribution of CNS and extra-CNS infections to neurodegeneration: a narrative review.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {152}, pmid = {38845026}, issn = {1742-2094}, support = {334525//Research Council of Finland/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Central Nervous System Infections ; Animals ; }, abstract = {Central nervous system infections have been suggested as a possible cause for neurodegenerative diseases, particularly sporadic cases. They trigger neuroinflammation which is considered integrally involved in neurodegenerative processes. In this review, we will look at data linking a variety of viral, bacterial, fungal, and protozoan infections to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis and unspecified dementia. This narrative review aims to bring together a broad range of data currently supporting the involvement of central nervous system infections in the development of neurodegenerative diseases. The idea that no single pathogen or pathogen group is responsible for neurodegenerative diseases will be discussed. Instead, we suggest that a wide range of susceptibility factors may make individuals differentially vulnerable to different infectious pathogens and subsequent pathologies.}, } @article {pmid38844617, year = {2024}, author = {Tyr, A and Heldring, N and Zilg, B}, title = {Examining the use of alternative light sources in medico-legal assessments of blunt-force trauma: a systematic review.}, journal = {International journal of legal medicine}, volume = {138}, number = {5}, pages = {1925-1938}, pmid = {38844617}, issn = {1437-1596}, mesh = {Humans ; *Contusions ; *Wounds, Nonpenetrating ; Light ; Forensic Medicine/methods ; }, abstract = {The ability to analyze blunt-force trauma is crucial for deciphering valuable clues concerning mechanisms of injury and as evidence for medico-legal investigations. The use of alternate light sources (ALS) has been studied over the past decade, and is proposed to outperform conventional white light (CWL) during bruise assessments. In response to the growing interest of the technology worldwide, a systematic review of the literature was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) to address the ability of ALS to detect and visualize bruising. From an initial 4055 records identified, ten studies met the eligibly criteria and were selected for this review. Evaluation also included a novel framework, referred to as SPICOT, to further systematically assess both scientific evidence and risk of bias in forensic literature. Analysis reveals that narrowband wavelengths within in the infrared or ultraviolet spectral ranges do not significantly outperform CWL in visualizing or detecting bruising. However, wavelengths within the visible spectrum, particularly 415 nm combined with longpass or bandpass yellow filters, are more effective. However, the majority of selected studies only address the sensitivity of ALS, and therefore, results may only be considered valid when the location of a bruise is known. Further investigation is required to understand the specificity of ALS, in particular how the use of topical cosmetic products, previous wounds/scar-tissue, tattoos, moles and freckles may affect detection. The ethical concern regarding the interpretation of enhanced visualized trauma should also be considered in prospect discussions prior to implementing ALS into routine practice. Nevertheless, this review finds that narrowband ALS within the visible spectrum demonstrates potential for improved injury documentation, outperforming CWL in the detection and visualization of bruising.}, } @article {pmid38844339, year = {2024}, author = {Robinson, G}, title = {Neuropsychological assessment in ALS.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {8}, pages = {692}, pmid = {38844339}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis/complications ; *Neuropsychological Tests ; Cognition Disorders/diagnosis ; }, } @article {pmid38842106, year = {2024}, author = {Neel, DV and Baselga-Garriga, C and Benson, M and Keegan, M and Chase, M and D'Agostino, D and Drake, K and Hagar, JL and Hasenoehrl, MG and Kulesa-Kelley, J and Leite, A and Mohapatra, S and Portaro, SM and Pothier, LM and Rosenthal, J and Sherman, AV and Yu, H and McCaffrey, A and Ho, D and Luppino, S and Bedlack, R and Heitzman, D and Ajroud-Driss, S and Katz, J and Felice, K and Whitaker, C and Ladha, S and Alameda, G and Locatelli, E and Qureshi, IA and Hotchkin, MT and Hayden, MR and Cudkowicz, ME and Babu, S and Berry, JD and Paganoni, S}, title = {Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {2}, pages = {232-239}, doi = {10.1002/mus.28169}, pmid = {38842106}, issn = {1097-4598}, support = {//I AM ALS/ ; //Biohaven Pharmaceuticals, Inc/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; United States ; Male ; Female ; Middle Aged ; Aged ; Drugs, Investigational/therapeutic use ; United States Food and Drug Administration ; Adult ; Health Services Accessibility ; Adaptive Clinical Trials as Topic ; }, abstract = {INTRODUCTION/AIMS: Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers.

METHODS: A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration.

RESULTS: A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing.

DISCUSSION: Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.}, } @article {pmid38841627, year = {2024}, author = {Picher-Martel, V and Babu, S and Amato, AA}, title = {TARDBP Mutations in Facial-Onset Sensory and Motor Neuronopathy.}, journal = {Neurology. Genetics}, volume = {10}, number = {3}, pages = {e200160}, pmid = {38841627}, issn = {2376-7839}, abstract = {OBJECTIVES: Facial-onset sensory and motor neuronopathy (FOSMN) is a rare neuromuscular disorder characterized by progressive facial sensory impairment followed by motor dysfunction in a rostro-caudal distribution. FOSMN is clinically and pathologically associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In contrast to ALS/FTD, the genetic profile of patients with FOSMN and the role of genetic testing are poorly defined.

METHODS: A 66-year-old woman was evaluated in our neuromuscular clinic for progressive facial pain, dysphagia, and dysarthria. Her diagnostic evaluation included brain and cervical MRI, nerve conduction studies and EMG, and an ALS/FTD next-generation sequencing panel.

RESULTS: The patient was diagnosed with FOSMN, and we identified a N390D variant in transactive response DNA-binding protein (TDP-43/TARDBP). This variant has never been reported in FOSMN but was previously reported in 2 cases of ALS, and a N390S variant was also previously reported in FOSMN. A review of the literature revealed that TARDBP mutations are overrepresented in patients with FOSMN compared with patients with ALS/FTD. By contrast, other common familial forms of ALS, including C9ORF72 or SOD1, are respectively absent or rare in FOSMN.

DISCUSSION: FOSMN is pathologically and genetically associated with TDP-43. Therefore, ALS genetic testing that includes specifically TARDBP should be considered in patients with FOSMN.}, } @article {pmid38840222, year = {2024}, author = {Provasek, VE and Kodavati, M and Kim, B and Mitra, J and Hegde, ML}, title = {TDP43 interacts with MLH1 and MSH6 proteins in a DNA damage-inducible manner.}, journal = {Molecular brain}, volume = {17}, number = {1}, pages = {32}, pmid = {38840222}, issn = {1756-6606}, support = {RF1 NS112719/NS/NINDS NIH HHS/United States ; RF1NS112719/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism ; *MutL Protein Homolog 1/metabolism ; *DNA Damage ; *Protein Binding/drug effects ; Cell Line, Tumor ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Neurons/metabolism ; Middle Aged ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double-strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that the TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complementary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 h treatment of 10 μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS-affected neurons.}, } @article {pmid38839275, year = {2024}, author = {Palumbo, F and Iazzolino, B and Callegaro, S and Canosa, A and Manera, U and Vasta, R and Grassano, M and Matteoni, E and Cabras, S and Pellegrino, G and Salamone, P and Peotta, L and Casale, F and Fuda, G and Moglia, C and Chio, A and Calvo, A}, title = {Disentangling the relationship between social cognition, executive functions and behaviour changes in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {8}, pages = {722-729}, doi = {10.1136/jnnp-2023-332700}, pmid = {38839275}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/physiopathology ; *Executive Function ; Male ; Female ; *Social Cognition ; Middle Aged ; Cross-Sectional Studies ; *Theory of Mind/physiology ; Aged ; Neuropsychological Tests ; Cognitive Dysfunction/psychology/diagnosis ; Case-Control Studies ; }, abstract = {BACKGROUND: Social cognition (SC) deficits are included in the amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTDS) revised diagnostic criteria. However, the impact of SC assessment on cognitive classification and the cognitive-behavioural correlates of SC remain unclear. This cross-sectional study aimed to assess the impact of SC assessment on ALS-FTDS categorisation and explore the relationship of SC with executive functions (EF) and behaviour changes in a cohort of ALS patients.

METHODS: 121 patients and 56 healthy controls from the Turin ALS Centre underwent cognitive/behavioural testing, including the SC subdomains of facial emotion recognition, and cognitive and affective theory of mind (ToM).

RESULTS: Patients performed significantly worse than controls in all SC explored domains, and 45% of patients exhibited a deficit in at least one SC test, dissociated from the presence of EF deficits. In 13% of cases, the SC deficit was isolated and subclinical. SC assessment contributed to the attribution of cognitive impairment in 10% of patients. Through a statistical clustering approach, we found that ToM only partially overlaps with EF while behaviour changes are associated with emotional disorders (anxiety and depression).

CONCLUSIONS: SC is overall independent of EF in ALS, with ToM only partially associated with specific EF measures, and behaviour changes associated with emotional disorders. The influence of SC on cognitive categorisation and the frequent identification of a subclinical SC impairment have implications in a clinical setting, considering the substantial impact of cognitive impairment on disease burden and therapeutic choices.}, } @article {pmid38838600, year = {2024}, author = {Ou, H and Zhang, P and Wang, X and Lin, M and Li, Y and Wang, G}, title = {Gaining insights into the responses of individual yeast cells to ethanol fermentation using Raman tweezers and chemometrics.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {319}, number = {}, pages = {124584}, doi = {10.1016/j.saa.2024.124584}, pmid = {38838600}, issn = {1873-3557}, mesh = {*Spectrum Analysis, Raman/methods ; *Ethanol/metabolism ; *Saccharomyces cerevisiae/metabolism ; *Fermentation ; *Principal Component Analysis ; Least-Squares Analysis ; Optical Tweezers ; Single-Cell Analysis/methods ; }, abstract = {Saccharomyces cerevisiae is the most common microbe used for the industrial production of bioethanol, and it encounters various stresses that inhibit cell growth and metabolism during fermentation. However, little is currently known about the physiological changes that occur in individual yeast cells during ethanol fermentation. Therefore, in this work, Raman spectroscopy and chemometric techniques were employed to monitor the metabolic changes of individual yeast cells at distinct stages during high gravity ethanol fermentation. Raman tweezers was used to acquire the Raman spectra of individual yeast cells. Multivariate curve resolution-alternating least squares (MCR-ALS) and principal component analysis were employed to analyze the Raman spectra dataset. MCR-ALS extracted the spectra of proteins, phospholipids, and triacylglycerols and their relative contents in individual cells. Changes in intracellular biomolecules showed that yeast cells undergo three distinct physiological stages during fermentation. In addition, heterogeneity among yeast cells significantly increased in the late fermentation period, and different yeast cells may respond to ethanol stress via different mechanisms. Our findings suggest that the combination of Raman tweezers and chemometrics approaches allows for characterizing the dynamics of molecular components within individual cells. This approach can serve as a valuable tool in investigating the resistance mechanism and metabolic heterogeneity of yeast cells during ethanol fermentation.}, } @article {pmid38838248, year = {2024}, author = {Liss, J and Berisha, V}, title = {Operationalizing Clinical Speech Analytics: Moving From Features to Measures for Real-World Clinical Impact.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {67}, number = {11}, pages = {4226-4232}, doi = {10.1044/2024_JSLHR-24-00039}, pmid = {38838248}, issn = {1558-9102}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Speech Production Measurement/methods ; Speech ; Reproducibility of Results ; }, abstract = {OBJECTIVE: This research note advocates for a methodological shift in clinical speech analytics, emphasizing the transition from high-dimensional speech feature representations to clinically validated speech measures designed to operationalize clinically relevant constructs of interest. The aim is to enhance model generalizability and clinical applicability in real-world settings.

METHOD: We outline the challenges of using conventional supervised machine learning models in clinical speech analytics, particularly their limited generalizability and interpretability. We propose a new framework focusing on speech measures that are closely tied to specific speech constructs and have undergone rigorous validation. This research note discusses a case study involving the development of a measure for articulatory precision in amyotrophic lateral sclerosis (ALS), detailing the process from ideation through Food and Drug Administration (FDA) breakthrough status designation.

RESULTS: The case study demonstrates how the operationalization of the articulatory precision construct into a quantifiable measure yields robust, clinically meaningful results. The measure's validation followed the V3 framework (verification, analytical validation, and clinical validation), showing high correlation with clinical status and speech intelligibility. The practical application of these measures is exemplified in a clinical trial and designation by the FDA as a breakthrough status device, underscoring their real-world impact.

CONCLUSIONS: Transitioning from speech features to speech measures offers a more targeted approach for developing speech analytics tools in clinical settings. This shift ensures that models are not only technically sound but also clinically relevant and interpretable, thereby bridging the gap between laboratory research and practical health care applications. We encourage further exploration and adoption of this approach for developing interpretable speech representations tailored to specific clinical needs.}, } @article {pmid38838021, year = {2024}, author = {Ho, DM and Shaban, M and Mahmood, F and Ganguly, P and Todeschini, L and Van Vactor, D and Artavanis-Tsakonas, S}, title = {cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {24}, pages = {e2400732121}, pmid = {38838021}, issn = {1091-6490}, support = {R21 NS123207/NS/NINDS NIH HHS/United States ; R21NS123207//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; *Cyclic AMP/metabolism ; *Drosophila melanogaster/metabolism ; *Cyclic AMP-Dependent Protein Kinases/metabolism/genetics ; *Drosophila Proteins/metabolism/genetics ; *Signal Transduction ; *DNA-Binding Proteins/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Humans ; Motor Neurons/metabolism ; }, abstract = {Cytoplasmic mislocalization and aggregation of TDP-43 protein are hallmarks of amyotrophic lateral sclerosis (ALS) and are observed in the vast majority of both familial and sporadic cases. How these two interconnected processes are regulated on a molecular level, however, remains enigmatic. Genome-wide screens for modifiers of the ALS-associated genes TDP-43 and FUS have identified the phospholipase D (Pld) pathway as a key regulator of ALS-related phenotypes in the fruit fly Drosophila melanogaster [M. W. Kankel et al., Genetics 215, 747-766 (2020)]. Here, we report the results of our search for downstream targets of the enzymatic product of Pld, phosphatidic acid. We identify two conserved negative regulators of the cAMP/PKA signaling pathway, the phosphodiesterase dunce and the inhibitory subunit PKA-R2, as modifiers of pathogenic phenotypes resulting from overexpression of the Drosophila TDP-43 ortholog TBPH. We show that knockdown of either of these genes results in a mitigation of both TBPH aggregation and mislocalization in larval motor neuron cell bodies, as well as an amelioration of adult-onset motor defects and shortened lifespan induced by TBPH. We determine that PKA kinase activity is downstream of both TBPH and Pld and that overexpression of the PKA target CrebA can rescue TBPH mislocalization. These findings suggest a model whereby increasing cAMP/PKA signaling can ameliorate the molecular and functional effects of pathological TDP-43.}, } @article {pmid38837845, year = {2024}, author = {Huang, Q and Zhang, Q and Cao, B}, title = {Causal relationship between PCSK9 inhibitor and common neurodegenerative diseases: A drug target Mendelian randomization study.}, journal = {Brain and behavior}, volume = {14}, number = {6}, pages = {e3543}, pmid = {38837845}, issn = {2162-3279}, support = {2022NSFSC0749 to BC//the National Natural Science Fund of Sichuan/ ; }, mesh = {Humans ; Alzheimer Disease/genetics/drug therapy ; Amyotrophic Lateral Sclerosis/genetics/drug therapy/epidemiology ; Genome-Wide Association Study ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology/adverse effects ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/drug therapy/genetics ; Parkinson Disease/genetics/drug therapy ; *PCSK9 Inhibitors ; *Polymorphism, Single Nucleotide ; Proprotein Convertase 9 ; }, abstract = {BACKGROUND: In addition to lowering cholesterol levels, the proprotein convertase subtilis kexin 9 (PCSK9) inhibitor has a variety of effects, including anti-neuroapoptosis. However, the effects of PCSK9 inhibitors on neurodegenerative diseases are controversial. Therefore, we used drug-targeted Mendelian randomization (MR) analysis to investigate the effects of PCSK9 inhibitors on different neurodegenerative diseases.

METHODS: We collected single nucleotide polymorphisms (SNPs) of PCSK9 from published statistics of genome-wide association studies and performed drug target MR analyses to detect a causal relationship between PCSK9 inhibitors and the risk of neurodegenerative diseases. We utilized the effects of 3-Hydroxy -3- methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitors (statin targets) for comparison with PCSK9 inhibitors. Coronary heart disease risk was used as a positive control, and primary outcomes included amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD).

RESULTS: PCSK9 inhibitors marginally reduced the risk of ALS (OR [95%] = 0.89 [0.77 to 1.00], p = 0.048), while they increased the risk of PD (OR [95%] = 1.417 [1.178 to 1.657], p = 0.004). However, HMGCR inhibitors increased the risk of PD (OR [95%] = 1.907 [1.502 to 2.312], p = 0.001).

CONCLUSION: PCSK9 inhibitors significantly reduce the risk of ALS but increase the risk of PD. HMGCR inhibitors may be the risk factor for PD.}, } @article {pmid38837773, year = {2024}, author = {Connaghan, KP and Green, JR and Eshghi, M and Haenssler, AE and Scheier, ZA and Clark, A and Iyer, A and Richburg, BD and Rowe, HP and Okada, J and Johnson, SA and Onnela, JP and Burke, KM and Berry, JD}, title = {The relationship of rate and pause features to the communicative participation of people living with ALS.}, journal = {Muscle & nerve}, volume = {70}, number = {2}, pages = {217-225}, pmid = {38837773}, issn = {1097-4598}, support = {K23 DC019179/DC/NIDCD NIH HHS/United States ; DP2-MH103909/NH/NIH HHS/United States ; R15 DC018944/DC/NIDCD NIH HHS/United States ; 1R15DC018944/NH/NIH HHS/United States ; NIH-NIDCD K24DC016312/NH/NIH HHS/United States ; K23DC019179/NH/NIH HHS/United States ; DP2 MH103909/MH/NIMH NIH HHS/United States ; K24 DC016312/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology ; Female ; Male ; Middle Aged ; Aged ; Speech/physiology ; Adult ; Communication ; Self Report ; }, abstract = {INTRODUCTION/AIMS: Many people living with amyotrophic lateral sclerosis (PALS) report restrictions in their day-to-day communication (communicative participation). However, little is known about which speech features contribute to these restrictions. This study evaluated the effects of common speech symptoms in PALS (reduced overall speaking rate, slowed articulation rate, and increased pausing) on communicative participation restrictions.

METHODS: Participants completed surveys (the Communicative Participation Item Bank-short form; the self-entry version of the ALS Functional Rating Scale-Revised) and recorded themselves reading the Bamboo Passage aloud using a smartphone app. Rate and pause measures were extracted from the recordings. The association of various demographic, clinical, self-reported, and acoustic speech features with communicative participation was evaluated with bivariate correlations. The contribution of salient rate and pause measures to communicative participation was assessed using multiple linear regression.

RESULTS: Fifty seven people living with ALS participated in the study (mean age = 61.1 years). Acoustic and self-report measures of speech and bulbar function were moderately to highly associated with communicative participation (Spearman rho coefficients ranged from rs = 0.48 to rs = 0.77). A regression model including participant age, sex, articulation rate, and percent pause time accounted for 57% of the variance of communicative participation ratings.

DISCUSSION: Even though PALS with slowed articulation rate and increased pausing may convey their message clearly, these speech features predict communicative participation restrictions. The identification of quantitative speech features, such as articulation rate and percent pause time, is critical to facilitating early and targeted intervention and for monitoring bulbar decline in ALS.}, } @article {pmid38837229, year = {2024}, author = {Ó Murchú, SC and O'Halloran, KD}, title = {BREATHE DMD: boosting respiratory efficacy after therapeutic hypoxic episodes in Duchenne muscular dystrophy.}, journal = {The Journal of physiology}, volume = {602}, number = {14}, pages = {3255-3272}, doi = {10.1113/JP280280}, pmid = {38837229}, issn = {1469-7793}, support = {SFI FFP/19/6628 INSPIRE DMD/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {*Muscular Dystrophy, Duchenne/physiopathology/therapy ; Humans ; *Hypoxia/physiopathology ; Animals ; Respiration ; }, abstract = {Duchenne muscular dystrophy (DMD) is a fatal genetic neuromuscular disorder, characterised by progressive decline in skeletal muscle function due to the secondary consequences of dystrophin deficiency. Weakness extends to the respiratory musculature, and cardiorespiratory failure is the leading cause of death in men with DMD. Intermittent hypoxia has emerged as a potential therapy to counteract ventilatory insufficiency by eliciting long-term facilitation of breathing. Mechanisms of sensory and motor facilitation of breathing have been well delineated in animal models. Various paradigms of intermittent hypoxia have been designed and implemented in human trials culminating in clinical trials in people with spinal cord injury and amyotrophic lateral sclerosis. Application of therapeutic intermittent hypoxia to DMD is considered together with discussion of the potential barriers to progression owing to the complexity of this devastating disease. Notwithstanding the considerable challenges and potential pitfalls of intermittent hypoxia-based therapies for DMD, we suggest it is incumbent on the research community to explore the potential benefits in pre-clinical models. Intermittent hypoxia paradigms should be implemented to explore the proclivity to express respiratory plasticity with the longer-term aim of preserving and potentiating ventilation in pre-clinical models and people with DMD.}, } @article {pmid38836336, year = {2024}, author = {Foucher, J and Öijerstedt, L and Lovik, A and Sun, J and Ismail, MA and Sennfält, S and Savitcheva, I and Estenberg, U and Pagani, M and Fang, F and Pereira, JB and Ingre, C}, title = {ECAS correlation with metabolic alterations on FDG-PET imaging in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {708-716}, doi = {10.1080/21678421.2024.2361695}, pmid = {38836336}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Male ; Female ; *Fluorodeoxyglucose F18 ; Middle Aged ; *Positron-Emission Tomography/methods ; Aged ; Brain/metabolism/diagnostic imaging ; Cognitive Dysfunction/metabolism/diagnostic imaging ; Adult ; Neuropsychological Tests ; Glucose/metabolism ; Radiopharmaceuticals ; }, abstract = {Background: Cognitive impairment is observed in up to 50% of patients with amyotrophic lateral sclerosis (ALS). The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is an ALS-specific multi-domain screening tool. Few studies have examined the relationship between ECAS scores and [[18]F]fluorodeoxyglucose positron emission tomography ([[18]F]FDG-PET) findings. Objective: To assess the relationship between ECAS scores and glucose metabolism patterns on [[18]F]FDG -PET images in ALS. Methods: We collected [[18]F]FDG-PET images from 65 patients with ALS and 39 healthy controls. ECAS scores were collected on all patients and we calculated the correlation to [[18]F]FDG-PET in order to investigate the potential links between cognition and glucose metabolism. Results: We observed hypometabolism in the frontal cortex, insula, and limbic system, together with hypermetabolism in the cerebellum in patients with ALS compared to controls. A lower ECAS total score was associated with lower glucose metabolism in the right orbitofrontal gyrus and higher glucose metabolism in lateral occipital, medial occipital, and cerebellar regions, among patients with ALS. Similar results, although less widespread, were observed in the analyses of ECAS ALS-specific scores. Conclusions: The metabolic patterns in [[18]F]FDG -PET show that changes in the glucose metabolism of corresponding areas are related to cognitive dysfunction in ALS, and can be detected using the ECAS.}, } @article {pmid38836001, year = {2024}, author = {Rong, P and Heidrick, L and Pattee, GL}, title = {A multimodal approach to automated hierarchical assessment of bulbar involvement in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1396002}, pmid = {38836001}, issn = {1664-2295}, abstract = {INTRODUCTION: As a hallmark feature of amyotrophic lateral sclerosis (ALS), bulbar involvement leads to progressive declines of speech and swallowing functions, significantly impacting social, emotional, and physical health, and quality of life. Standard clinical tools for bulbar assessment focus primarily on clinical symptoms and functional outcomes. However, ALS is known to have a long, clinically silent prodromal stage characterized by complex subclinical changes at various levels of the bulbar motor system. These changes accumulate over time and eventually culminate in clinical symptoms and functional declines. Detection of these subclinical changes is critical, both for mechanistic understanding of bulbar neuromuscular pathology and for optimal clinical management of bulbar dysfunction in ALS. To this end, we developed a novel multimodal measurement tool based on two clinically readily available, noninvasive instruments-facial surface electromyography (sEMG) and acoustic techniques-to hierarchically assess seven constructs of bulbar/speech motor control at the neuromuscular and acoustic levels. These constructs, including prosody, pause, functional connectivity, amplitude, rhythm, complexity, and regularity, are both mechanically and clinically relevant to bulbar involvement.

METHODS: Using a custom-developed, fully automated data analytic algorithm, a variety of features were extracted from the sEMG and acoustic recordings of a speech task performed by 13 individuals with ALS and 10 neurologically healthy controls. These features were then factorized into 10 composite outcome measures using confirmatory factor analysis. Statistical and machine learning techniques were applied to these composite outcome measures to evaluate their reliability (internal consistency), validity (concurrent and construct), and efficacy for early detection and progress monitoring of bulbar involvement in ALS.

RESULTS: The composite outcome measures were demonstrated to (1) be internally consistent and structurally valid in measuring the targeted constructs; (2) hold concurrent validity with the existing clinical and functional criteria for bulbar assessment; and (3) outperform the outcome measures obtained from each constituent modality in differentiating individuals with ALS from healthy controls. Moreover, the composite outcome measures combined demonstrated high efficacy for detecting subclinical changes in the targeted constructs, both during the prodromal stage and during the transition from prodromal to symptomatic stages.

DISCUSSION: The findings provided compelling initial evidence for the utility of the multimodal measurement tool for improving early detection and progress monitoring of bulbar involvement in ALS, which have important implications in facilitating timely access to and delivery of optimal clinical care of bulbar dysfunction.}, } @article {pmid38835240, year = {2024}, author = {McAlary, L and Nan, JR and Shyu, C and Sher, M and Plotkin, SS and Cashman, NR}, title = {Amyloidogenic regions in beta-strands II and III modulate the aggregation and toxicity of SOD1 in living cells.}, journal = {Open biology}, volume = {14}, number = {6}, pages = {230418}, pmid = {38835240}, issn = {2046-2441}, support = {//R. Howard Webster Foundation/ ; //CIHR/ ; //Canadian Consortium for Neurodegeneration/ ; //Brain Canada/ ; }, mesh = {*Superoxide Dismutase-1/metabolism/genetics/chemistry ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Protein Aggregates ; Protein Aggregation, Pathological/genetics/metabolism ; Mutation ; Protein Conformation, beta-Strand ; Models, Molecular ; Proline/metabolism ; Amyloid/metabolism/chemistry ; Protein Folding ; }, abstract = {Mutations in the protein superoxide dismutase-1 (SOD1) promote its misfolding and aggregation, ultimately causing familial forms of the debilitating neurodegenerative disease amyotrophic lateral sclerosis (ALS). Currently, over 220 (mostly missense) ALS-causing mutations in the SOD1 protein have been identified, indicating that common structural features are responsible for aggregation and toxicity. Using in silico tools, we predicted amyloidogenic regions in the ALS-associated SOD1-G85R mutant, finding seven regions throughout the structure. Introduction of proline residues into β-strands II (I18P) or III (I35P) reduced the aggregation propensity and toxicity of SOD1-G85R in cells, significantly more so than proline mutations in other amyloidogenic regions. The I18P and I35P mutations also reduced the capability of SOD1-G85R to template onto previously formed non-proline mutant SOD1 aggregates as measured by fluorescence recovery after photobleaching. Finally, we found that, while the I18P and I35P mutants are less structurally stable than SOD1-G85R, the proline mutants are less aggregation-prone during proteasome inhibition, and less toxic to cells overall. Our research highlights the importance of a previously underappreciated SOD1 amyloidogenic region in β-strand II ([15]QGIINF[20]) to the aggregation and toxicity of SOD1 in ALS mutants, and suggests that β-strands II and III may be good targets for the development of SOD1-associated ALS therapies.}, } @article {pmid38835201, year = {2024}, author = {Tsai, CC and Tao, B and Wong, M and Suntharalingam, H and Abrahao, A and Barnett-Tapia, C}, title = {Sex, racial, and ethnic disparities in motor neuron disease: clinical trial enrolment.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {694-701}, doi = {10.1080/21678421.2024.2358793}, pmid = {38835201}, issn = {2167-9223}, mesh = {Female ; Humans ; Male ; Clinical Trials as Topic ; Ethnicity ; *Healthcare Disparities/ethnology/statistics & numerical data ; *Motor Neuron Disease/ethnology ; Sex Factors ; Racial Groups ; *Patient Selection ; }, abstract = {OBJECTIVE: Motor neuron disease (MND) is a group of neurological diseases, the majority being amyotrophic lateral sclerosis (ALS), with varying clinical presentations across demographics. Clinical trial enrollment reflecting global disease burden improves understanding of diverse presentations and aids personalized therapy development. We assessed the sex, racial, and ethnic composition of MND/ALS clinical trial participants relative to global disease burdens.

METHODS: We searched 'motor neuron disease OR amyotrophic lateral sclerosis' on ClinicalTrials.gov from 02/2000-04/2024. We extracted trial (start year, study site, sponsor location, phase, masking, intervention) and demographic data (sex, race, ethnicity) from randomized interventional studies. We obtained sex-based MND/ALS disease burden estimates from the Global Burden of Disease database. For females, we calculated pooled participation-to-prevalence ratio (PPR) with 95% confidence intervals (CIs), with PPR of 0.8-1.2 indicating adequate enrollment. We used Kruskal-Wallis tests to compare demographic groups across trial characteristics.

RESULTS: Of 85 trials, females comprised 37.47% (n = 5011) of 13,372 participants; the pooled female PPR was 0.97 (95% CI: 0.77-1.16). Of 41 trials (9340 participants) reporting race, 121 (1.30%) participants were Black or African American, 16 (0.17%) American Indian or Alaskan Native, and 6 (0.06%) Native Hawaiian or Other Pacific Islander. 24 trials (595 participants) reported ethnicity, with a minority of Hispanic participants (n = 153; 2.57%).

CONCLUSIONS: MND/ALS clinical trials had adequate female enrollment relative to global disease burdens. Race and ethnicity data were underreported. However, there were enrollment disparities of racial and ethnic groups. Increased trial leadership diversity, equitable enrollment policies, and addressing barriers to participation could improve enrollment diversity.}, } @article {pmid38835198, year = {2024}, author = {Trudel, P and Quesnel-Olivo, MH and Blais, M and Shoesmith, C and Dupré, N}, title = {ALS, MAiD and Tissue Donation: Case Reports from Six Patients' Care Journeys.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-2}, doi = {10.1017/cjn.2024.277}, pmid = {38835198}, issn = {0317-1671}, } @article {pmid38834164, year = {2024}, author = {Griñán-Ferré, C and Bellver-Sanchis, A and Guerrero, A and Pallàs, M}, title = {Advancing personalized medicine in neurodegenerative diseases: The role of epigenetics and pharmacoepigenomics in pharmacotherapy.}, journal = {Pharmacological research}, volume = {205}, number = {}, pages = {107247}, doi = {10.1016/j.phrs.2024.107247}, pmid = {38834164}, issn = {1096-1186}, mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/drug therapy/genetics ; *Pharmacogenetics/methods ; *Epigenesis, Genetic/drug effects ; Animals ; Epigenomics/methods ; }, abstract = {About 80 % of brain disorders have a genetic basis. The pathogenesis of most neurodegenerative diseases is associated with a myriad of genetic defects, epigenetic alterations (DNA methylation, histone/chromatin remodeling, miRNA dysregulation), and environmental factors. The emergence of new sequencing technologies and tools to study the epigenome has led to identifying predictive biomarkers for earlier diagnosis, opening up the possibility of prophylactical interventions. As a result, advances in pharmacogenetics and pharmacoepigenomics now allow for personalized treatments based on the profile of each patient and the specific genetic and epigenetic mechanisms involved. This Review highlights the complexity of neurodegenerative diseases and the variability in patient responses to pharmacotherapy, emphasizing the influence of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of drugs used to treat those conditions. We specifically discuss the potential modulatory effect of several genetic polymorphisms associated with an increased risk of developing different neurodegenerative diseases. We explore genetic and genomic technologies and the potential of analyzing individual-specific drug metabolism to predict and influence drug response and associated clinical outcomes. We also provide insights into the mechanism of action of the drugs under investigation and their potential impact on disease-modifying pathways. Finally, the Review underscores the great potential of this field to enhance the effectiveness and safety of drug treatments through personalized medicine.}, } @article {pmid38833116, year = {2024}, author = {Mubeen, H and Masood, A and Zafar, A and Khan, ZQ and Khan, MQ and Nisa, AU}, title = {Insights into AlphaFold's breakthrough in neurodegenerative diseases.}, journal = {Irish journal of medical science}, volume = {193}, number = {5}, pages = {2577-2588}, pmid = {38833116}, issn = {1863-4362}, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology ; Artificial Intelligence ; Deep Learning ; Parkinson Disease ; Alzheimer Disease ; Algorithms ; Frontotemporal Dementia/genetics ; }, abstract = {Neurodegenerative diseases (ND) are disorders of the central nervous system (CNS) characterized by impairment in neurons' functions, and complete loss, leading to memory loss, and difficulty in learning, language, and movement processes. The most common among these NDs are Alzheimer's disease (AD) and Parkinson's disease (PD), although several other disorders also exist. These are frontotemporal dementia (FTD), amyotrophic lateral syndrome (ALS), Huntington's disease (HD), and others; the major pathological hallmark of NDs is the proteinopathies, either of amyloid-β (Aβ), tauopathies, or synucleinopathies. Aggregation of proteins that do not undergo normal configuration, either due to mutations or through some disturbance in cellular pathway contributes to the diseases. Artificial Intelligence (AI) and deep learning (DL) have proven to be successful in the diagnosis and treatment of various congenital diseases. DL approaches like AlphaFold (AF) are a major leap towards success in CNS disorders. This 3D protein geometry modeling algorithm developed by DeepMind has the potential to revolutionize biology. AF has the potential to predict 3D-protein confirmation at an accuracy level comparable to experimentally predicted one, with the additional advantage of precisely estimating protein interactions. This breakthrough will be beneficial to identify diseases' advancement and the disturbance of signaling pathways stimulating impaired functions of proteins. Though AlphaFold has solved a major problem in structural biology, it cannot predict membrane proteins-a beneficial approach for drug designing.}, } @article {pmid38832321, year = {2024}, author = {Patel, JS and McCall, NS and Thomas, M and Zhou, J and Higgins, KA and Bradley, JD and Tian, S and McDonald, MW and Kesarwala, AH and Stokes, WA}, title = {Immune System Dose With Proton Versus Photon Radiotherapy for Treatment of Locally Advanced NSCLC.}, journal = {International journal of particle therapy}, volume = {12}, number = {}, pages = {100016}, pmid = {38832321}, issn = {2331-5180}, abstract = {PURPOSE: Emerging data have illuminated the impact of effective radiation dose to immune cells (EDIC) on outcomes in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) treated with intensity-modulated radiotherapy (IMRT). Hypothesizing that intensity-modulated proton therapy (IMPT) may reduce EDIC versus IMRT, we conducted a dosimetric analysis of patients treated at our institution.

MATERIALS AND METHODS: Data were retrospectively collected for 12 patients with locally advanced, unresectable NSCLC diagnosed between 2019 and 2021 who had physician-approved IMRT and IMPT plans. Data to calculate EDIC from both Jin et al (PMID: 34944813) and Ladbury et al's (PMID: 31175902) models were abstracted. Paired t tests were utilized to compare the difference in mean EDIC between IMPT and IMRT plans.

RESULTS: IMPT decreased EDIC for 11 of 12 patients (91.7%). The mean EDIC per the Jin model was significantly lower with IMPT than IMRT (3.04 GyE vs 4.99 Gy, P < .001). Similarly, the mean EDIC per the Ladbury model was significantly lower with IMPT than IMRT (4.50 GyE vs 7.60 Gy, P < .002). Modeled 2-year overall survival was significantly longer with IMPT than IMRT (median 71% vs 63%; P = .03).

CONCLUSION: IMPT offers a statistically significant reduction in EDIC compared to IMRT. Given the emergence of EDIC as a modifiable prognostic factor in treatment planning, our dosimetric study highlights a potential role for IMPT to address an unmet need in improving oncologic outcomes in patients with locoregionally advanced NSCLC.}, } @article {pmid38832104, year = {2024}, author = {Oh, HJ and Lee, WJ and Sung, JJ and Hong, YH and , }, title = {Individualized predictions for clinical milestone in amyotrophic lateral sclerosis: A multialgorithmic approach.}, journal = {Digital health}, volume = {10}, number = {}, pages = {20552076241260120}, pmid = {38832104}, issn = {2055-2076}, abstract = {OBJECTIVE: The phenotypic heterogeneity and complex disease trajectory complicate the ability to predict specific clinical milestone for individual patients with amyotrophic lateral sclerosis (ALS). Here we developed individualized prediction models to estimate the time to the loss of autonomy in swallowing function.

METHODS: Utilizing the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we built three models of distinct time-to-event prediction algorithms: accelerated failure time (AFT), cox proportional hazard (COX) and random survival forest (RSF) for an individualized risk assessment of the swallowing milestone. The target variable was defined as the time to a decline in the ALSFRS-R swallowing item score to 1 or below, indicating a need for supplementary tube feeding.

RESULTS: Internal cross-validation revealed the median concordance index (C-index) of 0.851 (IQR, 0.842-0.859) for AFT, 0.850 (0.841-0.859) for COX and 0.846 (0.839-0.854) for RSF, and all models demonstrated good distributional calibration with predicted and observed event probabilities closely matched across different time intervals. For external validation with a registry dataset with characteristics different from PRO-ACT, the discriminative power was replicated with comparable C-indices for all models, whereas the calibration revealed a left-skewed distribution suggesting a bias towards overestimation of event probabilities in real-world data. While all models were effective at stratifying patients, the results of RSF model, unlike AFT and COX, did not match well with the KM curves of the corresponding risk groups, supporting the importance of nuanced understanding of data structure and algorithmic properties.

CONCLUSION: Our models are implemented into a web application which could be applied to individualized counselling, management and clinical trial design for gastrostomy intervention. Further studies for model optimization will advance personalized care in patients with ALS.}, } @article {pmid38831349, year = {2024}, author = {López-Carbonero, JI and García-Toledo, I and Fernández-Hernández, L and Bascuñana, P and Gil-Moreno, MJ and Matías-Guiu, JA and Corrochano, S}, title = {In vivo diagnosis of TDP-43 proteinopathies: in search of biomarkers of clinical use.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {29}, pmid = {38831349}, issn = {2047-9158}, support = {2022-5A/BMD-24221//Consejería de Educación, Juventud y Deporte, Comunidad de Madrid/ ; PDI2020-1153-70RB-100/AEI/10.13039/501100011033//Ministerio de Ciencia e Innovación/ ; CM23/00094//Instituto de Salud Carlos III/ ; INT20/00079//Instituto de Salud Carlos III/ ; INT23/00017//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *TDP-43 Proteinopathies/diagnosis/metabolism/genetics ; *Biomarkers/analysis/metabolism ; *DNA-Binding Proteins/metabolism ; Brain/metabolism/pathology ; }, abstract = {TDP-43 proteinopathies are a heterogeneous group of neurodegenerative disorders that share the presence of aberrant, misfolded and mislocalized deposits of the protein TDP-43, as in the case of amyotrophic lateral sclerosis and some, but not all, pathological variants of frontotemporal dementia. In recent years, many other diseases have been reported to have primary or secondary TDP-43 proteinopathy, such as Alzheimer's disease, Huntington's disease or the recently described limbic-predominant age-related TDP-43 encephalopathy, highlighting the need for new and accurate methods for the early detection of TDP-43 proteinopathy to help on the stratification of patients with overlapping clinical diagnosis. Currently, TDP-43 proteinopathy remains a post-mortem pathologic diagnosis. Although the main aim is to determine the pathologic TDP-43 proteinopathy in the central nervous system (CNS), the ubiquitous expression of TDP-43 in biofluids and cells outside the CNS facilitates the use of other accessible target tissues that might reflect the potential TDP-43 alterations in the brain. In this review, we describe the main developments in the early detection of TDP-43 proteinopathies, and their potential implications on diagnosis and future treatments.}, } @article {pmid38830342, year = {2024}, author = {Li, J and Li, S and Fei, G}, title = {Potential Correlation between Tea Intake and the Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study.}, journal = {Neuro-degenerative diseases}, volume = {24}, number = {2}, pages = {45-53}, doi = {10.1159/000539590}, pmid = {38830342}, issn = {1660-2862}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Humans ; *Tea ; *Mendelian Randomization Analysis/methods ; *Polymorphism, Single Nucleotide/genetics ; Risk Factors ; }, abstract = {INTRODUCTION: There were limited observation studies on the association between tea intake and amyotrophic lateral sclerosis (ALS) with inconsistent results. This study aimed to determine the potential relationship between tea intake and ALS by a two-sample Mendelian randomization (MR) analysis.

METHODS: We identified 41 independent SNPs strongly associated with tea intake from 448,060 participants of European ancestry in the UK Biobank. Summary statistics associated with ALS were also obtained from the UK Biobank including 20,806 cases and 59,804 controls. The study used MR analysis to assess the potential effect of tea consumption on ALS, and several methods such as sensitivity analyses and MR-pleiotropy residual sum and outlier method were performed to further test the robustness of our findings.

RESULTS: The F statistic was more than 10 in each SNP, which meets the first assumption for the MR study. Using the inverse variance weighted MR analysis as the primary method, we found that a one standard deviation increase in tea consumption was associated with a 14% lower risk of ALS (OR = 0.86, 95% CI = 0.74-0.99, p < 0.05). Sensitivity analyses detected no potential pleiotropy and directional heterogeneity.

CONCLUSION: Our MR study supported the potential relationship between tea intake and ALS risk, suggesting the potential advantages of tea intake for preventing ALS. Future clinical trials and research are needed to further validate the results and elucidate possible mechanisms.}, } @article {pmid38830304, year = {2024}, author = {Chin, B and Um, J and Kim, MK and Kim, HS and Yim, HS and Cho, HJ and Lim, SY and Kim, Y and Jeon, J and Park, JS}, title = {Clinical presentation, viral shedding, and neutralizing antibody responses of mpox cases in South Korea: Single center experience.}, journal = {Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology}, volume = {173}, number = {}, pages = {105692}, doi = {10.1016/j.jcv.2024.105692}, pmid = {38830304}, issn = {1873-5967}, mesh = {Humans ; Male ; Female ; Adult ; Republic of Korea/epidemiology ; *Antibodies, Neutralizing/blood ; Middle Aged ; *Virus Shedding ; Young Adult ; *Antibodies, Viral/blood ; Disease Outbreaks ; DNA, Viral/blood ; Mpox, Monkeypox ; }, abstract = {BACKGROUND: A global mpox outbreak occurred in 2022, and a domestic outbreak started in South Korea in April 2023. This study aimed to evaluate the clinical characteristics, viral shedding, and immune response of mpox in South Korea.

METHODS: Patients hospitalized with mpox in the National Medical Center between September 2022 and June 2023 were included in this study. Oropharyngeal (OP), anogenital lesion (AL), and skin lesion (SL) swabs and blood samples were collected, and monkeypox virus (MPXV) DNA using real-time polymerase chain reaction (RT-PCR) and culture assays were performed. Neutralizing antibodies (NAbs) against MPXV A.2.1, B.1.1, and B.1.3 were detected using plaque reduction neutralization tests.

RESULTS: Eighteen patients were enrolled, of whom 17 (94.4 %) were male, with a median (IQR) age of 32.5 (24-51) years. While nine (50 %) were HIV-infected individuals, none of them revealed CD4+ counts less than 200 cells/μL. MPXV DNA was detected in 87.3 % and 82.7 % of patient's ALs and SLs, respectively, until 2 weeks after symptom onset. While MPXV was isolated for up to 15 days in all three sample types, the culture positivity decreased to 53.8 % and 42.9 % in ALs and SLs after 10 days, respectively, and 28.6 % and 22.2 %, respectively, after 2 weeks from symptom onset. The NAb titers against MPXV A.2.1 were significantly lower than those against B.1.1 and B.1.3.

CONCLUSIONS: Infectious MPXV was isolated from various anatomical sites up to 15 days after symptom onset. The MPXV NAb response was varied among different lineages, and this implies limited cross-lineage protection.}, } @article {pmid38830181, year = {2024}, author = {Weemering, DN and Beelen, A and Kliest, T and van Leeuwen, LAG and van den Berg, LH and van Eijk, RPA}, title = {Trial Participation in Neurodegenerative Diseases: Barriers and Facilitators: A Systematic Review and Meta-Analysis.}, journal = {Neurology}, volume = {103}, number = {1}, pages = {e209503}, pmid = {38830181}, issn = {1526-632X}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Clinical Trials as Topic ; *Patient Participation ; Patient Selection ; }, abstract = {BACKGROUND AND OBJECTIVES: Clinical trials in neurodegenerative diseases often encounter selective enrollment and under-representation of certain patient populations. This delays drug development and substantially limits the generalizability of clinical trial results. To inform recruitment and retention strategies, and to better understand the generalizability of clinical trial populations, we investigated which factors drive participation.

METHODS: We reviewed the literature systematically to identify barriers to and facilitators of trial participation in 4 major neurodegenerative disease areas: Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease. Inclusion criteria included original research articles published in a peer-reviewed journal and evaluating barriers to and/or facilitators of participation in a clinical trial with a drug therapy (either symptomatic or disease-modifying). The Critical Appraisal Skills Program checklist for qualitative studies was used to assess and ensure the quality of the studies. Qualitative thematic analyses were employed to identify key enablers of trial participation. Subsequently, we pooled quantitative data of each enabler using meta-analytical models.

RESULTS: Overall, we identified 36 studies, enrolling a cumulative sample size of 5,269 patients, caregivers, and health care professionals. In total, the thematic analysis resulted in 31 unique enablers of trial participation; the key factors were patient-related (own health benefit and altruism), study-related (treatment and study burden), and health care professional-related (information availability and patient-physician relationship). When meta-analyzed across studies, responders reported that the reason to participate was mainly driven by (1) the relationship with clinical staff (70% of the respondents; 95% CI 53%-83%), (2) the availability of study information (67%, 95% CI 38%-87%), and (3) the use or absence of a placebo or sham-control arm (53% 95% CI 32%-72%). There was, however, significant heterogeneity between studies (all p < 0.001).

DISCUSSION: We have provided a comprehensive list of reasons why patients participate in clinical trials for neurodegenerative diseases. These results may help to increase participation rates, better inform patients, and facilitate patient-centric approaches, thereby potentially reducing selection mechanisms and improving generalizability of trial results.}, } @article {pmid38829866, year = {2024}, author = {Laurido-Soto, OJ and Faust, IM and Nielsen, SS and Racette, BA}, title = {Adherence to practice parameters in Medicare beneficiaries with amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {19}, number = {6}, pages = {e0304083}, pmid = {38829866}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Medicare ; Male ; Female ; United States ; Aged ; Retrospective Studies ; Aged, 80 and over ; Guideline Adherence/statistics & numerical data ; Middle Aged ; Practice Patterns, Physicians'/statistics & numerical data ; }, abstract = {OBJECTIVE: Physician adherence to evidence-based clinical practice parameters impacts outcomes of amyotrophic lateral sclerosis (ALS) patients. We sought to investigate compliance with the 2009 practice parameters for treatment of ALS patients in the United States, and sociodemographic and provider characteristics associated with adherence.

METHODS: In this population-based, retrospective cohort study of incident ALS patients in 2009-2014, we included all Medicare beneficiaries age ≥20 with ≥1 International Classification of Diseases, Ninth Revision, Clinical Modification ALS code (335.20) in 2009 and no prior years (N = 8,575). Variables of interest included race/ethnicity, sex, age, urban residence, Area Deprivation Index (ADI), and provider specialty (neurologist vs. non-neurologist). Outcomes were use of practice parameters, which included feeding tubes, non-invasive ventilation (NIV), riluzole, and receiving care from a neurologist.

RESULTS: Overall, 42.9% of patients with ALS received neurologist care. Black beneficiaries (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.47-0.67), older beneficiaries (OR 0.964, 95% CI 0.961-0.968 per year), and those living in disadvantaged areas (OR 0.70, 95% CI 0.61-0.80) received less care from neurologists. Overall, only 26.7% of beneficiaries received a feeding tube, 19.2% NIV, and 15.3% riluzole. Neurologist-treated patients were more likely to receive interventions than other ALS patients: feeding tube (OR 2.80, 95% CI 2.52-3.11); NIV (OR 10.8, 95% CI 9.28-12.6); and riluzole (OR 7.67, 95% CI 6.13-9.58), after adjusting for sociodemographics. These associations remained marked and significant when we excluded ALS patients who subsequently received a code for other diseases that mimic ALS.

CONCLUSIONS: ALS patients treated by neurologists received care consistent with practice parameters more often than those not treated by a neurologist. Black, older, and disadvantaged beneficiaries received less care consistent with the practice parameters.}, } @article {pmid38829511, year = {2025}, author = {Jiang, S and Xu, R}, title = {The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {62}, number = {1}, pages = {221-232}, pmid = {38829511}, issn = {1559-1182}, support = {30560042//National Natural Science Foundation of China/ ; 81160161//National Natural Science Foundation of China/ ; 81360198//National Natural Science Foundation of China/ ; 82160255//National Natural Science Foundation of China/ ; GJJ13198//Education Department of Jiangxi Province/ ; GJJ170021//Education Department of Jiangxi Province/ ; 20192BAB205043//Jiangxi Provincial Department of Science and Technology/ ; 20181019//Health and Family Planning Commission of Jiangxi Province/ ; 202210002//Health and Family Planning Commission of Jiangxi Province/ ; 202310119//Health and Family Planning Commission of Jiangxi Province/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/microbiology/pathology/physiopathology ; Autophagy/physiology ; Dysbiosis/complications/microbiology/physiopathology ; Extracellular Vesicles/metabolism ; Gastrointestinal Microbiome/physiology ; Mitochondria/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease mainly characterized by the accumulation of ubiquitinated proteins in the affected motor neurons. At present, the accurate pathogenesis of ALS remains unclear and there are still no effective treatment measures for ALS. The potential pathogenesis of ALS mainly includes the misfolding of some pathogenic proteins, the genetic variation, mitochondrial dysfunction, autophagy disorders, neuroinflammation, the misregulation of RNA, the altered axonal transport, and gut microbial dysbiosis. Exploring the pathogenesis of ALS is a critical step in searching for the effective therapeutic approaches. The current studies suggested that the genetic variation, gut microbial dysbiosis, the activation of glial cells, and the transportation disorder of extracellular vesicles may play some important roles in the pathogenesis of ALS. This review conducts a systematic review of these current potential promising topics closely related to the pathogenesis of ALS; it aims to provide some new evidences and clues for searching the novel treatment measures of ALS.}, } @article {pmid38829431, year = {2024}, author = {Sabatelli, M and Cerri, F and Zuccarino, R and Patanella, AK and Bernardo, D and Bisogni, G and Tanel, R and Sansone, V and Filosto, M and Lattante, S and Martello, F and Doronzio, PN and Stano, S and Zanfini, BA and Coccia, M and Costantini, EM and Lizio, A and Lucioli, G and Padovani, A and Merlini, GP and Conte, A}, title = {Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5177-5186}, pmid = {38829431}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/blood ; Male ; Female ; Middle Aged ; Aged ; *Superoxide Dismutase-1/genetics ; Neurofilament Proteins/blood/cerebrospinal fluid ; Disease Progression ; Adult ; Retrospective Studies ; Treatment Outcome ; Cohort Studies ; }, abstract = {BACKGROUND: In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant.

METHODS: In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48 weeks (median period of 84 weeks, range 48-108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1 year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients.

RESULTS: Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p = 0.023 and p = 0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60% of patients. Such alterations were clinically asymptomatic in all but two patients who showed an acute pure motor radiculitis, which responded to steroid therapy.

CONCLUSIONS: Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients.}, } @article {pmid38829015, year = {2024}, author = {Negri, C and Usberti, N and Contaldo, G and Bracconi, M and Nova, I and Maestri, M and Tronconi, E}, title = {Quantitative Kinetic Insights from Operando-UV/Vis Spectroscopy: An Application to NH3-SCR of NOx on Cu-CHA Catalysts.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {63}, number = {41}, pages = {e202408328}, doi = {10.1002/anie.202408328}, pmid = {38829015}, issn = {1521-3773}, abstract = {We employ UV/Vis Diffuse Reflectance spectroscopy directly coupled with a packed bed flow reactor to extract quantitative kinetic information. We use as a show-case the Cu[II]/Cu[I] redox dynamics during the reduction half cycle of the NH3-Selective Catalytic Reduction (SCR) on Cu-CHA catalysts. Our measurements enable quantification of the fraction of oxidized Cu, reconstructed by Multivariate Curve Resolution (MCR) together with monitoring of the gas-phase evolution during the reaction. These data both on the dynamics of the gas-phase and of the active site oxidation state have been used to assess the reduction half cycle rate equation and estimate the rate constant. Our results in terms of reaction orders and kinetic constant are in line with previous findings in the literature. Overall, our results demonstrate that the combined analysis of the UV spectra and of the gas-phase dynamics provides converging and unparalleled kinetic insight: this approach effectively resolves ambiguities concerning RHC kinetics and mechanism. More in general, this work provides evidence that operando spectroscopy can be used to extract quantitative kinetic information on catalytic cycles.}, } @article {pmid38829007, year = {2024}, author = {Foucher, J and Bunte, TM and Bertone, V and Verschoor, RL and Couillard, M and Straub, C and Genge, A and Ingre, C and van den Berg, LH}, title = {International network for ALS research and care (INARC).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {795-796}, doi = {10.1080/21678421.2024.2362850}, pmid = {38829007}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Biomedical Research/methods/trends ; }, abstract = {The International Network for Amyotrophic Lateral Sclerosis (ALS) Research and Care (INARC) was founded in 2022. INARC's main goals are to offer a platform dedicated to staff members for ALS clinics and research teams who are not physicians. By nurturing experience and expertise exchanges to improve problem solving skills, the ultimate goal is to increase the standard ALS care and research. This brief report aims to describe the formation of INARC, the 2023 INARC meeting, as well as to report topics discussed, lessons learned and challenges raised by INARC members.}, } @article {pmid38828849, year = {2024}, author = {Mamarabadi, M and Fafoutis, E and Geronimo, A and Walsh, S and Simmons, Z}, title = {Sodium phenylbutyrate-taurursodiol access, adherence and adverse event in patients with amyotrophic lateral sclerosis: Experience at one center in the United States.}, journal = {Muscle & nerve}, volume = {70}, number = {2}, pages = {204-209}, doi = {10.1002/mus.28175}, pmid = {38828849}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/economics ; Male ; Female ; Middle Aged ; Aged ; Adult ; *Medication Adherence ; United States ; Aged, 80 and over ; Phenylbutyrates/therapeutic use/economics ; Health Expenditures ; Retrospective Studies ; }, abstract = {INTRODUCTION/AIMS: Sodium phenylbutyrate-taurursodiol (PB-TURSO) was recently approved for treating amyotrophic lateral sclerosis (ALS). Third-party payors' coverage policies are evolving, and adverse events are just being fully assessed. The goals of this study were to evaluate patients' experiences in obtaining and continuing PB-TURSO and assess adverse events and medication adherence.

METHODS: Medical records of 109 ALS patients who were considered PB-TURSO candidates by the treating physician at a tertiary ALS clinic from October 2022 to May 2023 were reviewed. Data was recorded for demographics, clinical, and insurance information. A survey was e-mailed to patients asking about out-of-pocket expenses for PB-TURSO, financial assistance, medication start and (if applicable) stop dates, and reasons for discontinuation.

RESULTS: Insurance information was available for 91 patients [57 males (62%); mean age 64.8 years (range 25.7-88)]. Of 79 who applied for insurance approval, 71 (90%) were approved; however, 19 required 1-3 appeals. Among 73 patients with available data about medication status, 54 started PB-TURSO and 19 did not, most commonly due to personal choice or out-of-pocket expenses. About 44% of patients (24/54) stopped taking PB-TURSO, primarily due to adverse events. Monthly out-of-pocket expenses varied from $0 to $3500 and 36 patients qualified for financial assistance. Administrative and nursing staff devoted 7.2 hours/week to the insurance authorization process.

DISCUSSION: Most patients received insurance approval for PB-TURSO, but one-fourth required appeals. Some out-of-pocket costs were very high. Investment of staff time was substantial. These findings have implications for insurance coverage of, and adherence to, future ALS treatments.}, } @article {pmid38827490, year = {2024}, author = {Yotsukura, E and Torii, H and Mori, K and Ogawa, M and Hanyuda, A and Negishi, K and Kurihara, T and Tsubota, K}, title = {Slowing of Greater Axial Length Elongation Stemming from the Coronavirus Disease 2019 Pandemic with Increasing Time Outdoors: The Tokyo Myopia Study.}, journal = {Ophthalmology science}, volume = {4}, number = {5}, pages = {100491}, pmid = {38827490}, issn = {2666-9145}, abstract = {PURPOSE: To investigate the changes in axial length (AL) elongation and other ocular parameters before and during the coronavirus disease 2019 pandemic.

DESIGN: A longitudinal school-based study.

PARTICIPANTS: Public elementary schoolchildren in Tokyo (grades 1-6; age, 6-12 years) participated in this study from 2018 to 2021.

METHODS: All participants underwent eye examinations and provided written consent to measurements of the noncycloplegic refraction and ocular biometry including AL, among others. The students' parents also completed a questionnaire about the students' lifestyles. We included the right eye in our analysis and compared the changes in the ocular parameters among the periods using a linear mixed-effects model for repeated measures and examined the univariate and step-wise multiple regression analyses to evaluate the associations between myopia and other covariates.

MAIN OUTCOME MEASURES: Changes in AL elongation and other ocular parameters from 2018 to 2019 (prepandemic), that of 2019 to 2020 (immediately after the pandemic onset), and that of 2020 to 2021 (during the pandemic).

RESULTS: A total of 578 students before the pandemic period, 432 immediately after the pandemic onset, and 457 during the pandemic period were evaluated. The changes in the ALs and spherical equivalents (SEs) a year before, immediately after onset, and during the pandemic were 0.31 mm/-0.20 diopter, 0.38 mm/-0.27 diopter, and 0.28 mm/-0.47 diopter, respectively (ALs, P < 0.001; SEs, P = 0.014). The results of the questionnaire showed that time spent outdoors daily had changed during the 3 years to 79, 63, and 77 minutes/day, respectively (P < 0.001). Time spent using smartphones or tablets increased year by year to 41, 52, and 62 minutes/day (P < 0.001). The greatest AL elongation occurred during the period when the shortest amount of time was spent outdoors during the 3 years.

CONCLUSIONS: These results suggested that the school closures and decreasing time spent outdoors might have caused greater AL elongation among schoolchildren in Tokyo; however, it is possible that, although the time spent in near work still increased, the return to the time spent outdoors to the prepandemic levels may have affected the slowing of AL elongation after lockdown.

FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.}, } @article {pmid38826647, year = {2024}, author = {Zhao, H and Xie, J and Chen, Y and Cao, J and Liao, WH and Cao, H}, title = {Diagnosis of neurodegenerative diseases with a refined Lempel-Ziv complexity.}, journal = {Cognitive neurodynamics}, volume = {18}, number = {3}, pages = {1153-1166}, pmid = {38826647}, issn = {1871-4080}, abstract = {The investigation into the distinctive difference of gait is of significance for the clinical diagnosis of neurodegenerative diseases. However, human gait is affected by many factors like behavior, occupation and so on, and they may confuse the gait differences among Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. For the purpose of examining distinctive gait differences of neurodegenerative diseases, this study extracts various features from both vertical ground reaction force and time intervals. Moreover, refined Lempel-Ziv complexity is proposed considering the detailed distribution of signals based on the median and quartiles. Basic features (mean, coefficient of variance, and the asymmetry index), nonlinear dynamic features (Hurst exponent, correlation dimension, largest Lyapunov exponent), and refined Lempel-Ziv complexity of different neurodegenerative diseases are compared statistically by violin plot and Kruskal-Wallis test to reveal distinction and regularities. The comparative analysis results illustrate the gait differences across these neurodegenerative diseases by basic features and nonlinear dynamic features. Classification results by random forest indicate that the refined Lempel-Ziv complexity can robustly enhance the diagnosis accuracy when combined with basic features.}, } @article {pmid38826483, year = {2024}, author = {Provasek, VE and Kodavati, M and Kim, B and Mitra, J and Hegde, ML}, title = {TDP43 Interacts with MLH1 and MSH6 Proteins in A DNA Damage-Inducible Manner.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38826483}, issn = {2693-5015}, support = {R35 CA220430/CA/NCI NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; P01 CA092584/CA/NCI NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complimentary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 hr treatment of 10μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS affected neurons.}, } @article {pmid38826246, year = {2024}, author = {Martínez, P and Silva, M and Abarzúa, S and Tevy, MF and Jaimovich, E and Constantine-Paton, M and Bustos, FJ and van Zundert, B}, title = {Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.05.24.595817}, pmid = {38826246}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1 [G93A] (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2+ transients and reactive oxygen species (i.e., H 2 O 2). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.}, } @article {pmid38826088, year = {2024}, author = {Mehta, P and Raymond, J and Nair, T and Han, M and Punjani, R and Larson, T and Berry, J and Mohidul, S and Horton, DK}, title = {Prevalence of ALS in all 50 states in the United States, data from the National ALS Registry, 2011-2018.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {687-693}, doi = {10.1080/21678421.2024.2358786}, pmid = {38826088}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology ; Humans ; United States/epidemiology ; *Registries ; Male ; Prevalence ; Aged ; Female ; Middle Aged ; Aged, 80 and over ; Adult ; Risk Factors ; }, abstract = {Objective: To summarize the prevalence of ALS in all 50 states and Washington, DC in the United States from 2011 to 2018 using data collected and analyzed by the National ALS Registry. In October 2010, the federal Agency for Toxic Substances and Disease Registry (ATSDR) launched the congressionally mandated Registry to determine the incidence and prevalence of ALS within the USA, characterize the demographics of persons with ALS, and identify the potential risk factors for the disease. This is the first analysis of state-level ALS prevalence estimates. Methods: ALS is not a notifiable disease in the USA, so the Registry uses a two-pronged approach to identify cases. The first approach uses existing national administrative databases (Medicare, Veterans Health Administration, and Veterans Benefits Administration). The second method uses a secure web portal to gather voluntary participant data and identify cases not included in the national administrative databases. Results: State-level age-adjusted average prevalence from 2011-2018 ranged from 2.6 per 100,000 persons (Hawaii) to 7.8 per 100,000 persons (Vermont), with an average of 4.4 per 100,000 persons in the US. New England and Midwest regions had higher prevalence rates than the national average. Conclusions: These findings summarize the prevalence of ALS for all 50 states from 2011 to 2018. This is a continuing effort to identify ALS cases on a national population basis. The establishment of the National ALS Registry has allowed for epidemiological trends of this disease and the assessment of potential risk factors that could cause ALS.}, } @article {pmid38826044, year = {2024}, author = {Rooney, JPK and Geoghegan, G and O'Reilly, F and Heverin, M and Bose-O'Reilly, S and Casale, F and Chio, A and Günther, K and Schuster, J and Klopstock, T and Ludolph, A and Hardiman, O and Rakete, S}, title = {Serum heat shock protein concentrations are not associated with amyotrophic lateral sclerosis risk or survival in three European populations.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {751-759}, doi = {10.1080/21678421.2024.2358805}, pmid = {38826044}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality/epidemiology/diagnosis ; Female ; Male ; Middle Aged ; Aged ; *Biomarkers/blood ; Germany/epidemiology ; HSP70 Heat-Shock Proteins/blood ; Ireland/epidemiology ; Italy/epidemiology ; Heat-Shock Proteins/blood ; HSP90 Heat-Shock Proteins/blood ; Cohort Studies ; Adult ; Europe/epidemiology ; }, abstract = {Introduction: Serum heat shock protein (HSP) concentrations have been reported as potential biomarkers for amyotrophic lateral sclerosis (ALS). Here, we investigate the role of serum HSP70, HSP90, and DNAJC7 as biomarkers for ALS. Methods: Serum samples were collected from ALS patients and volunteer controls from three different clinical cohorts (in Germany, Ireland, and Italy). Serum HSP concentrations were determined using enzyme-linked immunosorbent assay. Descriptive statistics, generalized logistic regression, and Cox proportional hazards models were used to model associations between log serum HSP concentrations and ALS risk. Results: In total, 251 ALS patients and 184 healthy volunteers were included. Logistic regression models failed to find associations between ALS risk and log serum concentration of HSP70 (OR 0.43, 95% CI: 0.10-1.78, p = 0.242), HSP90 (OR 0.95, 95% CI: 0.39-2.37, p = 0.904), or DNAJC7 (OR 1.55, 95% CI: 0.90-2.68, p = 0.118). Survival of ALS patients was not associated with log serum concentration of HSP HSP70 (HR1.06, 95% CI: 0.36-3.14, p = 0.916), HSP90 (HR 1.17, 95% CI: 0.67-2.02, p = 0.584), or DNAJC7 (HR 0.83, 95% CI: 0.57-1.21, p = 0.337). Discussion: We did not replicate previous findings that serum HSP70 and HSP90 concentrations were associated with risk of ALS. DNAJC7 was not associated with ALS risk, and there were no obvious longitudinal patterns in log serum concentrations of HSP70, HSP90, or DNAJC7. In addition, serum HSP concentrations were not associated with ALS survival.}, } @article {pmid38825034, year = {2024}, author = {Fang, T and Pacut, P and Bose, A and Sun, Y and Gao, J and Sivakumar, S and Bloom, B and Nascimento Andrade, EI and Trombetta, B and Ghasemi, M}, title = {Clinical and genetic factors affecting diagnostic timeline of amyotrophic lateral sclerosis: a 15-year retrospective study.}, journal = {Neurological research}, volume = {46}, number = {9}, pages = {859-867}, doi = {10.1080/01616412.2024.2362578}, pmid = {38825034}, issn = {1743-1328}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Genetic Testing/methods ; Adult ; Delayed Diagnosis ; Time Factors ; }, abstract = {OBJECTIVES: Amyotrophic Lateral Sclerosis (ALS) diagnosis can take 10-16 months from symptom onset, leading to delays in treatment and patient counselling. We studied the impact of clinical and genetic risk factors on the diagnostic timeline of ALS.

METHODS: Baseline characteristics, family history, gene testing, onset location, time from symptom onset to diagnosis, and time from first doctor visit to suspected ALS was collected. We used multiple regression to assess the interaction of these factors on ALS diagnostic timeline. We analysed a subgroup of patients with genetic testing and compared positive or negative tests, sporadic or familial and ALS-related genes to time for diagnosis.

RESULTS: Four hundred and forty-eight patients diagnosed with ALS at the University of Massachusetts Chan Medical Center between January 2007 and December 2021 were analysed. The median time to ALS diagnosis was 12 months and remained unchanged from 2007 to 2021 (p = 0.20). Diagnosis was delayed in patients with sporadic compared with familial ALS (mean months [standard deviation], 16.5[13.5] and 11.2[8.5], p < 0.001); cognitive onset (41[21.26]) had longer time to diagnosis than bulbar (11.9[8.2]), limb (15.9[13.2]), respiratory (19.7[13.9]) and ALS with multiple onset locations (20.77[15.71], p < 0.001). One hundred and thirty-four patients had gene testing and 32 tested positive (23.8%). Gene testing (p = 0.23), a positive genetic test (p = 0.16), different ALS genes (p = 0.25) and sporadic (p = 0.92) or familial (p = 0.85) ALS testing positive for ALS genes did not influence time to diagnosis.

DISCUSSION: Time for ALS diagnosis remained unchanged from 2007 to 2021, bulbar-onset and familial ALS made for faster diagnosis.}, } @article {pmid38824664, year = {2024}, author = {Ahmed, Z and Shahzadi, K and Jin, Y and Li, R and Momanyi, BM and Zulfiqar, H and Ning, L and Lin, H}, title = {[Not Available].}, journal = {Proteomics}, volume = {24}, number = {21-22}, pages = {e2400044}, doi = {10.1002/pmic.202400044}, pmid = {38824664}, issn = {1615-9861}, support = {62372088//National Natural Science Foundation of China/ ; }, mesh = {*RNA/metabolism ; Humans ; *Artificial Intelligence ; Proteins/metabolism/chemistry/analysis ; Databases, Protein ; Computational Biology/methods ; Phase Separation ; }, abstract = {RNA-dependent liquid-liquid phase separation (LLPS) proteins play critical roles in cellular processes such as stress granule formation, DNA repair, RNA metabolism, germ cell development, and protein translation regulation. The abnormal behavior of these proteins is associated with various diseases, particularly neurodegenerative disorders like amyotrophic lateral sclerosis and frontotemporal dementia, making their identification crucial. However, conventional biochemistry-based methods for identifying these proteins are time-consuming and costly. Addressing this challenge, our study developed a robust computational model for their identification. We constructed a comprehensive dataset containing 137 RNA-dependent and 606 non-RNA-dependent LLPS protein sequences, which were then encoded using amino acid composition, composition of K-spaced amino acid pairs, Geary autocorrelation, and conjoined triad methods. Through a combination of correlation analysis, mutual information scoring, and incremental feature selection, we identified an optimal feature subset. This subset was used to train a random forest model, which achieved an accuracy of 90% when tested against an independent dataset. This study demonstrates the potential of computational methods as efficient alternatives for the identification of RNA-dependent LLPS proteins. To enhance the accessibility of the model, a user-centric web server has been established and can be accessed via the link: http://rpp.lin-group.cn.}, } @article {pmid38823272, year = {2024}, author = {Bijl, I and Vianen, NJ and Van Lieshout, EMM and Beekers, CHJ and Van Der Waarden, NWPL and Pekbay, B and Maissan, IM and Verhofstad, MHJ and Van Vledder, MG}, title = {Emergency reflex action drill for traumatic cardiac arrest in a simulated pre-hospital setting; a one-group pre-post intervention study.}, journal = {Intensive & critical care nursing}, volume = {84}, number = {}, pages = {103731}, doi = {10.1016/j.iccn.2024.103731}, pmid = {38823272}, issn = {1532-4036}, mesh = {Humans ; Prospective Studies ; Female ; Adult ; *Emergency Medical Services/methods/standards/statistics & numerical data ; Male ; Heart Arrest/complications/therapy ; Middle Aged ; Simulation Training/methods/standards ; Patient Simulation ; }, abstract = {BACKGROUND: Emergency Reflex Action Drills (ERADs) are meant to decrease stress-associated cognitive demand in high urgency situations. The aim of this study was to develop and test an ERAD for witnessed traumatic cardiac arrest (TCA), an event in which potentially reversible causes need to be systematically addressed and treated in a short period of time. We hypothesize that this ERAD (the TCA-Drill) helps ground Emergency Medical Services (EMS) nurses in overcoming performance decline during this specific high-pressure situation.

METHODS: This was a prospective, experimental one-group pre-post intervention study. Ground EMS nurses participated in a session of four simulated scenarios, with an in-between educational session to teach the TCA-Drill. Scenarios were video recorded, after which adherence and time differences were analyzed. Self-confidence on clinical practice was measured before and after the scenarios.

RESULTS: Twelve ground EMS nurses participated in this study. Overall median time to address reversible causes of TCA decreased significantly using the TCA-Drill (132 vs. 110 s; p = 0.030) compared with the conventional ALS strategy. More specifically, participants adhering to the TCA-Drill showed a significantly lower time needed for hemorrhage control (58 vs. 37 s; p = 0.012). Eight of 12 (67 %) ground EMS nurses performed the ERAD without protocol deviations. Reported self-confidence significantly increased on 11 of the 13 surveyed items.

CONCLUSIONS: The use of an ERAD for TCA (the TCA-Drill) significantly reduces the time to address reversible causes for TCA without delaying chest compressions in a simulated environment and can be easily taught to ground EMS nurses and increases self-confidence.

The use of an ERAD for TCA (the TCA-Drill can significantly reduce the time to address reversible causes for TCA without delaying chest compression. This drill can be easily taught to ground EMS nurses and increases their self-confidence in addressing TCA-patients.}, } @article {pmid38823229, year = {2024}, author = {Roman-Pognuz, E and Rigutti, S and Colussi, G and Lena, E and Bonsano, M and Lucangelo, U}, title = {Acute esophageal necrosis following cardiac arrest: A rare and lethal syndrome with diagnostic challenges.}, journal = {International journal of surgery case reports}, volume = {120}, number = {}, pages = {109751}, pmid = {38823229}, issn = {2210-2612}, abstract = {Acute esophageal necrosis (AEN) is a condition characterized by the necrosis of the distal portion of the esophageal mucosa. Risk factors predisposing to this condition are associated to compromised vascular perfusion (e.g. diabetes mellitus, chronic kidney disease, advanced age, and hypertension, shock states). Complications of AEN can be severe including UGI stricture, perforation and overall increased mortality. The true incidence of AEN remains uncertain due to potential subclincal presentations and early resolution.

CASE PRESENTATION: The case outlined involves a 66-years-old obese male with history of alcoholism and lymph-edema of the left leg who presented to the emergency department with hematemesis, haemodynamic instability and impaired consciousness. Shortly after initial assessment, the patient went into cardiac arrest with pulse-less electrical activity (PEA). Return of spontaneous circulation (ROSC) was achieved following instigation of ALS protocol, fluid resuscitation and the administration of a total of 5 mg of adrenaline. Following stabilization, a CT scan was performed which reported a moderately enlarged esophagus with a thickened wall, liquid hypodense material within the esophagus and stomach, and liver cirrhosis. The emergent esophagogastroduodenoscopy (EGDS) revealed extensive mucosal findings indicative of diffuse necrosis with initial scarring, which was later diagnosed as AEN. The patient unfortunately deceased in ICU after developing progression of the AEN, post-cardiac arrest syndrome and liver failure.

CLINICAL DISCUSSION: The presented case highlights several crucial clinical issues and management problems related to AEN. To diagnose AEN, EGDS is still the gold-standard since it allows direct inspection of the esophageal mucosal layer. The management of AEN necessitates a multidisciplinary approach that includes aggressive resuscitation, treatment of underlying comorbidities, and supportive care (e.g. proton pump inhibitors). The mortality rate for AEN remains high despite improvements in diagnosis and treatment highlighting the need to recognize this condition early and intervene promptly in the patients affected. Moreover, long-term sequelae like stricture formation of the esophagus and impaired esophageal motility may contribute to morbidity requiring continuos monitoring. Therefore, to optimize outcomes while reducing complications among affected patients, prompt identification associated with appropriate medical measures are essential. More research needs to be done aiming to better understand the pathophysiology of AEN thereby identifying strategies for its prevention or cure.

CONCLUSIONS: AEN is a rare syndrome characterized by upper gastrointestinal bleeding and hypoxic damage of the esophageal mucosa, often associated with ischemia, gastric outlet obstruction, and compromised protective barriers. Treatment involves aggressive resuscitation, proton pump inhibitors, and monitoring for infection or perforation. However, despite intensive efforts, the mortality rate for AEN remains high at 32 %.}, } @article {pmid38822985, year = {2024}, author = {Faysal, M and Dehbia, Z and Zehravi, M and Sweilam, SH and Haque, MA and Kumar, KP and Chakole, RD and Shelke, SP and Sirikonda, S and Nafady, MH and Khan, SL and Nainu, F and Ahmad, I and Emran, TB}, title = {Flavonoids as Potential Therapeutics Against Neurodegenerative Disorders: Unlocking the Prospects.}, journal = {Neurochemical research}, volume = {49}, number = {8}, pages = {1926-1944}, pmid = {38822985}, issn = {1573-6903}, mesh = {*Flavonoids/therapeutic use/pharmacology ; Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Antioxidants/therapeutic use/pharmacology ; }, abstract = {Neurodegeneration, the decline of nerve cells in the brain, is a common feature of neurodegenerative disorders (NDDs). Oxidative stress, a key factor in NDDs such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease can lead to neuronal cell death, mitochondria impairment, excitotoxicity, and Ca[2+] stress. Environmental factors compromising stress response lead to cell damage, necessitating novel therapeutics for preventing or treating brain disorders in older individuals and an aging population. Synthetic medications offer symptomatic benefits but can have adverse effects. This research explores the potential of flavonoids derived from plants in treating NDDs. Flavonoids compounds, have been studied for their potential to enter the brain and treat NDDs. These compounds have diverse biological effects and are currently being explored for their potential in the treatment of central nervous system disorders. Flavonoids have various beneficial effects, including antiviral, anti-allergic, antiplatelet, anti-inflammatory, anti-tumor, anti-apoptotic, and antioxidant properties. Their potential to alleviate symptoms of NDDs is significant.}, } @article {pmid38822416, year = {2024}, author = {Yadav, S and Deepika, and Moar, K and Kumar, A and Khola, N and Pant, A and Kakde, GS and Maurya, PK}, title = {Reconsidering red blood cells as the diagnostic potential for neurodegenerative disorders.}, journal = {Biology of the cell}, volume = {116}, number = {7}, pages = {e2400019}, doi = {10.1111/boc.202400019}, pmid = {38822416}, issn = {1768-322X}, support = {//Council of Scientific and Industrial Research (CSIR), Government of India/ ; //University Grant Commission (UGC)/ ; HSCIT-3946//Haryana State Council for Science, Innovation, and Technology/ ; //Central University of Haryana, Mahendergarh/ ; //Indian Council of Medical Research (ICMR), Government of India/ ; }, mesh = {Humans ; *Erythrocytes/metabolism ; *Neurodegenerative Diseases/diagnosis/metabolism/blood ; *Biomarkers/metabolism/blood ; Oxidative Stress ; Animals ; Alzheimer Disease/diagnosis/metabolism/blood ; }, abstract = {BACKGROUND: Red blood cells (RBCs) are usually considered simple cells and transporters of gases to tissues.

HYPOTHESIS: However, recent research has suggested that RBCs may have diagnostic potential in major neurodegenerative disorders (NDDs).

RESULTS: This review summarizes the current knowledge on changes in RBC in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and other NDDs. It discusses the deposition of neuronal proteins like amyloid-β, tau, and α-synuclein, polyamines, changes in the proteins of RBCs like band-3, membrane transporter proteins, heat shock proteins, oxidative stress biomarkers, and altered metabolic pathways in RBCs during neurodegeneration. It also highlights the comparison of RBC diagnostic markers to other in-market diagnoses and discusses the challenges in utilizing RBCs as diagnostic tools, such as the need for standardized protocols and further validation studies.

SIGNIFICANCE STATEMENT: The evidence suggests that RBCs have diagnostic potential in neurodegenerative disorders, and this study can pave the foundation for further research which may lead to the development of novel diagnostic approaches and treatments.}, } @article {pmid38821351, year = {2024}, author = {Pocock, J and Vasilopoulou, F and Svensson, E and Cosker, K}, title = {Microglia and TREM2.}, journal = {Neuropharmacology}, volume = {257}, number = {}, pages = {110020}, doi = {10.1016/j.neuropharm.2024.110020}, pmid = {38821351}, issn = {1873-7064}, mesh = {Humans ; *Microglia/metabolism ; *Receptors, Immunologic/metabolism/genetics ; *Membrane Glycoproteins/metabolism/genetics ; Animals ; Neurodegenerative Diseases/metabolism/pathology/genetics ; Induced Pluripotent Stem Cells/metabolism ; Phagocytosis/physiology ; }, abstract = {TREM2 is a membrane receptor solely expressed on microglia in normal brain. In this review we outline recent advances in TREM2 biology and its implications for microglial function, with particular emphasis on findings from iPSC-derived microglia (iMG) expressing TREM2 loss-of-function mutations. Alterations in receptor proximal and distal signalling underlie TREM2 risk variants linked to neurodegenerative disease, principally NH-linked FTD, and late-onset AD, but emerging data suggest roles for TREM2 in PD, MS and ALS. TREM2 downstream functions include phagocytosis of myelin debris, amyloid beta peptides, and phosphatidylserine-expressing cells (resulting from damage or stress). Microglial survival, migration, DAMP signalling, inflammasome activation, and intercellular signalling including tau spreading via exosomes, as well as roles for sTREM2 in protection and as a biomarker are discussed. The role of TREM2 in metabolic homeostasis, and immunometabolic switching are discussed regarding microglial responses to damage and protection. The use of iPSC models to investigate the role of TREM2 in AD, PD, MS, ALS, and other neurodegenerative diseases could prove invaluable due to their ability to recapitulate human pathology, allowing a full understanding of TREM2 and microglial involvement in the underlying disease mechanisms and progression. This article is part of the Special Issue on "Microglia".}, } @article {pmid38820331, year = {2025}, author = {Dessie, G and Li, J and Nghiem, S and Doan, T}, title = {Prevalence and Determinants of Stunting-Anemia and Wasting-Anemia Comorbidities and Micronutrient Deficiencies in Children Under 5 in the Least-Developed Countries: A Systematic Review and Meta-analysis.}, journal = {Nutrition reviews}, volume = {83}, number = {2}, pages = {e178-e194}, pmid = {38820331}, issn = {1753-4887}, support = {//Australia National University/ ; }, mesh = {Child, Preschool ; Female ; Humans ; Infant ; *Anemia/epidemiology ; Comorbidity ; *Developing Countries/statistics & numerical data ; *Growth Disorders/epidemiology ; *Micronutrients/deficiency ; Prevalence ; *Wasting Syndrome/epidemiology ; }, abstract = {CONTEXT: Despite shifting from addressing isolated forms of malnutrition to recognizing its multifaceted nature, evidence on the prevalence and determinants of micronutrient deficiencies, and their coexistence with undernutrition in children under 5, remains insufficient, unsystematic, and incohesive.

OBJECTIVE: The aim of this systematic review and meta-analysis was to assess the prevalence and determinants of stunting-anemia and wasting-anemia comorbidities and micronutrient deficiencies in children under 5 in the least-developed countries (LDCs).

DATA SOURCES: Electronic searches took place from January 15, 2023, to February 14, 2024, across multiple databases, including PubMed, Embase, Web of Science, SCOPUS, African Index Medicus (AIM), World Health Organization's Institutional Repository for Information Sharing (IRIS), and African Journals Online. The search spanned the years 2000 to 2024, yet it yielded eligible full-text English research articles from only 2005 to 2021 conducted in LDCs. Studies lacking quantitative data on malnutrition types and their determinants were excluded.

DATA EXTRACTION: Two independent authors assessed articles for bias and quality using Hoy et al's 10-item scale and Newcastle-Ottawa Scale (NOS) criteria. Prevalence and other details were extracted using a Joanna Briggs Institute Excel template. Authors extracted adjusted odds ratios (aORs) for determinant factors such as sex and vitamin A and iron supplementation.

DATA ANALYSIS: The search yielded 6248 articles from 46 LDCs. Sixty-nine articles, with a total sample size of 181 605, met inclusion criteria for the final meta-analysis. Vitamin A deficiency affected 16.32% of children, and iodine deficiency affected 43.41% of children. The pooled prevalence of wasting-anemia and stunting-anemia comorbidity was 5.44% and 19.47%, respectively. Stunting was associated with vitamin A deficiency (aOR: 1.54; 95% CI: 1.01-2.37), and not taking vitamin A supplementation was associated with iron-deficiency anemia (aOR: 1.37; 95% CI: 1.21-1.55).

CONCLUSION: A significant proportion of children under 5 in LDCs experienced stunting-anemia and wasting-anemia comorbidities and micronutrient deficiencies. This study underscores the urgent need to address factors driving these burdens.

PROSPERO registration no. CRD42023409483.}, } @article {pmid38820149, year = {2024}, author = {Montañana-Rosell, R and Selvan, R and Hernández-Varas, P and Kaminski, JM and Sidhu, SK and Ahlmark, DB and Kiehn, O and Allodi, I}, title = {Spinal inhibitory neurons degenerate before motor neurons and excitatory neurons in a mouse model of ALS.}, journal = {Science advances}, volume = {10}, number = {22}, pages = {eadk3229}, pmid = {38820149}, issn = {2375-2548}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; Animals ; *Motor Neurons/metabolism/pathology ; *Disease Models, Animal ; Mice ; *Interneurons/metabolism/pathology ; *Spinal Cord/pathology/metabolism ; *Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism ; Humans ; Disease Progression ; Nerve Degeneration/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of somatic motor neurons. A major focus has been directed to motor neuron intrinsic properties as a cause for degeneration, while less attention has been given to the contribution of spinal interneurons. In the present work, we applied multiplexing detection of transcripts and machine learning-based image analysis to investigate the fate of multiple spinal interneuron populations during ALS progression in the SOD1[G93A] mouse model. The analysis showed that spinal inhibitory interneurons are affected early in the disease, before motor neuron death, and are characterized by a slow progressive degeneration, while excitatory interneurons are affected later with a steep progression. Moreover, we report differential vulnerability within inhibitory and excitatory subpopulations. Our study reveals a strong interneuron involvement in ALS development with interneuron specific degeneration. These observations point to differential involvement of diverse spinal neuronal circuits that eventually may be determining motor neuron degeneration.}, } @article {pmid38819717, year = {2024}, author = {Tappenden, P and Hardiman, O and Kwon, SH and Mon-Yee, M and Galvin, M and McDermott, C and , }, title = {A Model-Based Economic Evaluation of Hypothetical Treatments for Amyotrophic Lateral Sclerosis in the UK: Implications for Pricing of New and Emerging Health Technologies.}, journal = {PharmacoEconomics}, volume = {42}, number = {9}, pages = {1003-1016}, pmid = {38819717}, issn = {1179-2027}, mesh = {*Amyotrophic Lateral Sclerosis/economics/therapy/drug therapy ; Humans ; *Cost-Benefit Analysis ; *Quality-Adjusted Life Years ; United Kingdom ; *Models, Economic ; Disease Progression ; Biomedical Technology/economics ; Technology Assessment, Biomedical ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease which leads to loss of muscle function and paralysis. Historically, clinical drug development has been unsuccessful, but promising disease-modifying therapies (DMTs) may be on the horizon.

OBJECTIVES: The aims of this study were to estimate survival, quality-adjusted life-years (QALYs) and costs under current care, and to explore the conditions under which new therapies might be considered cost effective.

METHODS: We developed a health economic model to evaluate the cost effectiveness of future ALS treatments from a UK National Health Service and Personal Social Services perspective over a lifetime horizon using data from the ALS-CarE study. Costs were valued at 2021/22 prices. Two hypothetical interventions were evaluated: a DMT which delays progression and mortality, and a symptomatic therapy which improves utility only. Sensitivity analysis was conducted to identify key drivers of cost effectiveness.

RESULTS: Starting from King's stage 2, patients receiving current care accrue an estimated 2.27 life-years, 0.75 QALYs and lifetime costs of £68,047. Assuming a 50% reduction in progression rates and a UK-converted estimate of the price of edaravone, the incremental cost-effectiveness ratio for a new DMT versus current care is likely to exceed £735,000 per QALY gained. Symptomatic therapies may be more likely to achieve acceptable levels of cost effectiveness.

CONCLUSIONS: Regardless of efficacy, DMTs may struggle to demonstrate cost effectiveness, even at a low price. The cost effectiveness of DMTs is likely to be strongly influenced by drug price, the magnitude and durability of relative treatment effects, treatment starting/stopping rules and any additional utility benefits over current care.}, } @article {pmid38819491, year = {2024}, author = {Juarez, D and Handal-Silva, A and Morán-Perales, JL and Torres-Cifuentes, DM and Flores, G and Treviño, S and Moreno-Rodriguez, A and Guevara, J and Diaz, A}, title = {New insights into sodium phenylbutyrate as a pharmacotherapeutic option for neurological disorders.}, journal = {Synapse (New York, N.Y.)}, volume = {78}, number = {4}, pages = {e22301}, doi = {10.1002/syn.22301}, pmid = {38819491}, issn = {1098-2396}, support = {IN214117//PAPITT-UNAM/ ; DIFA-NAT24-G//Vicerrectoría de Investigación y Estudios de Posgrado, Benemérita Universidad Autónoma de Puebla/ ; TEMS-NAT24-G//Vicerrectoría de Investigación y Estudios de Posgrado, Benemérita Universidad Autónoma de Puebla/ ; }, mesh = {Humans ; *Phenylbutyrates/therapeutic use/pharmacology ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Neurological disorders (NDs) are diseases of the central and peripheral nervous systems that affect more than one billion people worldwide. The risk of developing an ND increases with age due to the vulnerability of the different organs and systems to genetic, environmental, and social changes that consequently cause motor and cognitive deficits that disable the person from their daily activities and individual and social productivity. Intrinsic factors (genetic factors, age, gender) and extrinsic factors (addictions, infections, or lifestyle) favor the persistence of systemic inflammatory processes that contribute to the evolution of NDs. Neuroinflammation is recognized as a common etiopathogenic factor of ND. The study of new pharmacological options for the treatment of ND should focus on improving the characteristic symptoms and attacking specific molecular targets that allow the delay of damage processes such as neuroinflammation, oxidative stress, cellular metabolic dysfunction, and deregulation of transcriptional processes. In this review, we describe the possible role of sodium phenylbutyrate (NaPB) in the pathogenesis of Alzheimer's disease, hepatic encephalopathy, aging, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis; in addition, we describe the mechanism of action of NaPB and its beneficial effects that have been shown in various in vivo and in vitro studies to delay the evolution of any ND.}, } @article {pmid38819416, year = {2024}, author = {Finsterer, J}, title = {Sleep Disorders Can Only be a Risk Factor for Breathing Disorders in Amyotrophic Lateral Sclerosis if All Other Risk Factors are Excluded.}, journal = {Annals of Indian Academy of Neurology}, volume = {27}, number = {4}, pages = {450-451}, pmid = {38819416}, issn = {0972-2327}, } @article {pmid38819224, year = {2024}, author = {Shen, J and Gu, X and Xiao, C and Yan, H and Feng, Y and Li, X}, title = {Genome-wide association analysis reveals potential genetic correlation and causality between circulating inflammatory proteins and amyotrophic lateral sclerosis.}, journal = {Aging}, volume = {16}, number = {11}, pages = {9470-9484}, pmid = {38819224}, issn = {1945-4589}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood ; Humans ; *Genome-Wide Association Study ; *Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; Mendelian Randomization Analysis ; Genetic Pleiotropy ; Inflammation/genetics/blood ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease, continues to elude complete comprehension of its pathological underpinnings. Recent focus on inflammation in ALS pathogenesis prompts this investigation into the genetic correlation and potential causal relationships between circulating inflammatory proteins and ALS.

METHODS: Genome-wide association study (GWAS) data encompassing 91 circulating inflammatory protein measures from 14,824 individuals of European ancestry, alongside records from 27,205 ALS cases and 110,881 controls, were employed. Assessment of genetic correlation and overlap utilized LD score regression (LDSC), high-definition likelihood (HDL), and genetic analysis integrating pleiotropy and annotation (GPA) methodologies. Identification of shared genetic loci involved pleiotropy analysis, functional mapping and annotation (FUMA), and co-localization analysis. Finally, Mendelian randomization was applied to probe causal relationships between inflammatory proteins and ALS.

RESULTS: Our investigation revealed significant genetic correlation and overlap between ALS and various inflammatory proteins, including C-C motif chemokine 28, Interleukin-18, C-X-C motif chemokine 1, and Leukemia inhibitory factor receptor (LIFR). Pleiotropy analysis uncovered shared variations at specific genetic loci, some of which bore potential harm. Mendelian randomization analysis suggested that alterations in specific inflammatory protein levels, notably LIFR, could impact ALS risk.

CONCLUSIONS: Our findings uncover a genetic correlation between certain circulating inflammatory proteins and ALS, suggesting their possible causal involvement in ALS pathogenesis. Moreover, the identification of LIFR as a crucial protein may yield new insights into ALS pathomechanisms and offer a promising avenue for therapeutic interventions. These discoveries provide novel perspectives for advancing the comprehension of ALS pathophysiology and exploring potential therapeutic avenues.}, } @article {pmid38818523, year = {2024}, author = {Shen, J and Wang, X and Wang, M and Zhang, H}, title = {Potential molecular mechanism of exercise reversing insulin resistance and improving neurodegenerative diseases.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1337442}, pmid = {38818523}, issn = {1664-042X}, abstract = {Neurodegenerative diseases are debilitating nervous system disorders attributed to various conditions such as body aging, gene mutations, genetic factors, and immune system disorders. Prominent neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Insulin resistance refers to the inability of the peripheral and central tissues of the body to respond to insulin and effectively regulate blood sugar levels. Insulin resistance has been observed in various neurodegenerative diseases and has been suggested to induce the occurrence, development, and exacerbation of neurodegenerative diseases. Furthermore, an increasing number of studies have suggested that reversing insulin resistance may be a critical intervention for the treatment of neurodegenerative diseases. Among the numerous measures available to improve insulin sensitivity, exercise is a widely accepted strategy due to its convenience, affordability, and significant impact on increasing insulin sensitivity. This review examines the association between neurodegenerative diseases and insulin resistance and highlights the molecular mechanisms by which exercise can reverse insulin resistance under these conditions. The focus was on regulating insulin resistance through exercise and providing practical ideas and suggestions for future research focused on exercise-induced insulin sensitivity in the context of neurodegenerative diseases.}, } @article {pmid38817709, year = {2024}, author = {Ghaderi, S and Batouli, SAH and Kalra, S and Mohammadi, S and Fatehi, F}, title = {A 65-year-old woman with ALS and bilateral precentral motor band sign.}, journal = {Clinical case reports}, volume = {12}, number = {6}, pages = {e9014}, pmid = {38817709}, issn = {2050-0904}, abstract = {Advanced MRI techniques, including SWI, MinIP, and QSM, are instrumental in detecting the "motor band sign" in ALS, aiding in the early diagnosis and assessment of upper motor neuron involvement, which is critical for therapeutic interventions.}, } @article {pmid38817347, year = {2024}, author = {Du, R and Zhu, Y and Chen, P and Li, M and Zhang, Y and Huang, X}, title = {Causal association between obstructive sleep apnea and amyotrophic lateral sclerosis: a Mendelian randomization study.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1357070}, pmid = {38817347}, issn = {1663-4365}, abstract = {BACKGROUND: Obstructive sleep apnea (OSA) had a high prevalence in the population. Whether OSA increases the risk of amyotrophic lateral sclerosis (ALS) is unknown. Our aim was to clarify this issue using two-sample Mendelian randomization (MR) analysis in a large cohort.

METHODS: Two-sample MR was used to evaluate the potential causality between OSA and ALS by selecting single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) from genome-wide association studies (GWAS). The inverse-variance weighted (IVW) method was chosen as the primary method to estimate causal association. Weighted median, weighted mode and simple mode methods were used as sensitivity analyses to ensure the robustness of the results.

RESULTS: In MR analysis, IVW mode showed genetic liability to OSA was found to be significantly associated with a higher ALS risk (OR, 1.220; 95% confidence interval, 1.031-1.443; p = 0.021). No evidence of heterogeneity and horizontal pleiotropy were suggested.

CONCLUSION: We found potential evidence for a causal effect of OSA on an increased risk of ALS.}, } @article {pmid38816946, year = {2024}, author = {Karas, M and Olsen, J and Straczkiewicz, M and Johnson, SA and Burke, KM and Iwasaki, S and Lahav, A and Scheier, ZA and Clark, AP and Iyer, AS and Huang, E and Berry, JD and Onnela, JP}, title = {Tracking amyotrophic lateral sclerosis disease progression using passively collected smartphone sensor data.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {6}, pages = {1380-1392}, pmid = {38816946}, issn = {2328-9503}, support = {//The research reported in this paper was financially supported in part by a grant from Mitsubishi Tanabe Pharma Holdings America, Inc. (MTPHA)./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Smartphone ; Male ; Female ; Middle Aged ; *Disease Progression ; Aged ; *Accelerometry/instrumentation ; Mobile Applications ; Walking/physiology ; Exercise/physiology ; }, abstract = {BACKGROUND: Passively collected smartphone sensor data provide an opportunity to study physical activity and mobility unobtrusively over long periods of time and may enable disease monitoring in people with amyotrophic lateral sclerosis (PALS).

METHODS: We enrolled 63 PALS who used Beiwe mobile application that collected their smartphone accelerometer and GPS data and administered the self-entry ALS Functional Rating Scale-Revised (ALSFRS-RSE) survey. We identified individual steps from accelerometer data and used the Activity Index to summarize activity at the minute level. Walking, Activity Index, and GPS outcomes were then aggregated into day-level measures. We used linear mixed effect models (LMMs) to estimate baseline and monthly change for ALSFRS-RSE scores (total score, subscores Q1-3, Q4-6, Q7-9, Q10-12) and smartphone sensor data measures, as well as the associations between them.

FINDINGS: The analytic sample (N = 45) was 64.4% male with a mean age of 60.1 years. The mean observation period was 292.3 days. The ALSFRS-RSE total score baseline mean was 35.8 and had a monthly rate of decline of -0.48 (p-value <0.001). We observed statistically significant change over time and association with ALSFRS-RSE total score for four smartphone sensor data-derived measures: walking cadence from top 1 min and log-transformed step count, step count from top 1 min, and Activity Index from top 1 min.

INTERPRETATION: Smartphone sensors can unobtrusively track physical changes in PALS, potentially aiding disease monitoring and future research.}, } @article {pmid38816580, year = {2024}, author = {Wu, Y and Zheng, W and Xu, G and Zhu, L and Li, Z and Chen, J and Wang, L and Chen, S}, title = {C9orf72 controls hepatic lipid metabolism by regulating SREBP1 transport.}, journal = {Cell death and differentiation}, volume = {31}, number = {8}, pages = {1070-1084}, pmid = {38816580}, issn = {1476-5403}, mesh = {Humans ; *C9orf72 Protein/metabolism/genetics ; *Lipid Metabolism ; *Sterol Regulatory Element Binding Protein 1/metabolism/genetics ; Animals ; *Endoplasmic Reticulum/metabolism ; *Liver/metabolism ; Monomeric GTP-Binding Proteins/metabolism/genetics ; Mice ; COP-Coated Vesicles/metabolism ; Vesicular Transport Proteins/metabolism/genetics ; Lipogenesis/genetics ; }, abstract = {Sterol regulatory element binding transcription factors (SREBPs) play a crucial role in lipid homeostasis. They are processed and transported to the nucleus via COPII, where they induce the expression of lipogenic genes. COPII maintains the homeostasis of organelles and plays an essential role in the protein secretion pathways in eukaryotes. The formation of COPII begins at endoplasmic reticulum exit sites (ERES), and is regulated by SEC16A, which provides a platform for the assembly of COPII. However, there have been few studies on the changes in SEC16A protein levels. The repetitive expansion of the hexanucleotide sequence GGGGCC within the chromosome 9 open reading frame 72 (C9orf72) gene is a prevalent factor in the development of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we found that the absence of C9orf72 leads to a decrease in SEC16A protein levels, resulting in reduced localization of the guanine nucleotide exchange factor SEC12 at the ERES. Consequently, the small GTP binding protein SAR1 is unable to bind the endoplasmic reticulum normally, impairing the assembly of COPII. Ultimately, the disruption of SREBPs transport decreases de novo lipogenesis. These results suggest that C9orf72 acts as a novel role in regulating lipid homeostasis and may serve as a potential therapeutic target for obesity.}, } @article {pmid38816479, year = {2024}, author = {Mathis, S and Beauvais, D and Duval, F and Solé, G and Le Masson, G}, title = {The various forms of hereditary motor neuron disorders and their historical descriptions.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {3978-3990}, pmid = {38816479}, issn = {1432-1459}, mesh = {Humans ; *Motor Neuron Disease/history/genetics ; History, 20th Century ; History, 19th Century ; Spastic Paraplegia, Hereditary/genetics/history ; }, abstract = {Motor neuron disorders comprise a clinically and pathologically heterogeneous group of neurologic diseases characterized by progressive degeneration of motor neurons (including both sporadic and hereditary diseases), affecting the upper motor neurons, lower motor neurons, or both. Hereditary motor neuron disorders themselves represent a vast and heterogeneous group, with numerous clinical and genetic overlaps that can be a source of error. This narrative review aims at providing an overview of the main types of inherited motor neuron disorders by recounting the stages in their historical descriptions. For practical purposes, this review of the literature sets out their various clinical characteristics and updates the list of all the genes involved in the various forms of inherited motor neuron disorders, including spinal muscular atrophy, familial amyotrophic lateral sclerosis, hereditary spastic paraplegia, distal hereditary motor neuropathies/neuronopathies, Kennedy's disease, riboflavin transporter deficiencies, VCPopathy and the neurogenic scapuloperoneal syndrome.}, } @article {pmid38814545, year = {2024}, author = {Sun, S and Chen, Y and Zhao, B and Zhu, J and Wen, T and Peng, B and Ren, Q and Sun, X and Lin, P and Zhang, D and Liu, S}, title = {Abnormal brain functional network dynamics in amyotrophic lateral sclerosis patients with depression.}, journal = {Brain imaging and behavior}, volume = {18}, number = {5}, pages = {1034-1043}, pmid = {38814545}, issn = {1931-7565}, support = {2020M672067//China postdoctoral science foundation/ ; NSFC82001354//National natural science foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology/complications/diagnostic imaging ; Female ; Male ; *Magnetic Resonance Imaging/methods ; Middle Aged ; *Brain/physiopathology/diagnostic imaging ; *Depression/physiopathology/diagnostic imaging ; *Nerve Net/physiopathology/diagnostic imaging ; Adult ; Neural Pathways/physiopathology/diagnostic imaging ; Aged ; Brain Mapping/methods ; }, abstract = {Since depression is common in amyotrophic lateral sclerosis (ALS) patients, we aimed to explore the specific brain functional network dynamics in ALS patients with depression (ALS-D) compared with healthy controls (HCs) and ALS patients without depressive symptoms (ALS-ND). According to the DSM-V, 32 ALS-D patients were selected from a large and newly diagnosed ALS cohort. Then, 32 demographic- and cognitive-matched ALS-ND patients were also selected, and 64 HCs were recruited. These participants underwent resting-state fMRI scans, and functional connectivity state analysis and dynamic graph theory were applied to evaluate brain functional network dynamics. Moreover, the Hamilton Depression Rating Scale (HDRS) was used to quantify depressive symptoms in the ALS-D patients. Four distinct states were identified in the ALS-D patients and controls. Compared with that in HCs, the fraction rate (FR) in state 2 was significantly decreased in ALS-D patients, and the FR in state 4 was significantly increased in ALS-D patients. Compared with that of HCs, the dwell time in state 4 was significantly increased in the ALS-D patients. Moreover, compared with that in the ALS-D patients, the FR in state 3 was significantly decreased in the ALS-ND patients. Among the ALS-D patients, there was the suggestion of a positive association between HDRS scores and dwell time of state 4, but this association did not reach statistical significance (r = 0.354; p = 0.055). Depression is an important feature of ALS patients, and we found a special pattern of brain functional network dynamics in ALS-D patients. Our findings may play an important role in understanding the mechanism underlying depression in ALS patients and help develop therapeutic interventions for depressed ALS patients.}, } @article {pmid38814471, year = {2024}, author = {Costantino, I and Meng, A and Ravits, J}, title = {Alternatively spliced ELAVL3 cryptic exon 4a causes ELAVL3 downregulation in ALS TDP-43 proteinopathy.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {93}, pmid = {38814471}, issn = {1432-0533}, support = {T32 AG066596/AG/NIA NIH HHS/United States ; P30 NS047101/RG/CSR NIH HHS/United States ; P30 NS047101/NS/NINDS NIH HHS/United States ; R21 NS121805/NS/NINDS NIH HHS/United States ; T32 AG066596/RG/CSR NIH HHS/United States ; R21 NS121805/RG/CSR NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Alternative Splicing/genetics ; *Exons/genetics ; *Down-Regulation ; TDP-43 Proteinopathies/genetics/pathology/metabolism ; Male ; Female ; Middle Aged ; DNA-Binding Proteins ; }, } @article {pmid38813817, year = {2024}, author = {Sprunger, ML and Jackrel, ME}, title = {The role of Matrin-3 in physiology and its dysregulation in disease.}, journal = {Biochemical Society transactions}, volume = {52}, number = {3}, pages = {961-972}, pmid = {38813817}, issn = {1470-8752}, support = {F31 NS120512/NS/NINDS NIH HHS/United States ; R21 AG080393/AG/NIA NIH HHS/United States ; R35 GM128772/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *RNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Nuclear Matrix-Associated Proteins/metabolism ; *Frontotemporal Dementia/metabolism/genetics ; DNA-Binding Proteins/metabolism ; Animals ; DNA Damage ; RNA-Binding Protein FUS/metabolism/chemistry ; }, abstract = {The dysfunction of many RNA-binding proteins (RBPs) that are heavily disordered, including TDP-43 and FUS, are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). These proteins serve many important roles in the cell, and their capacity to form biomolecular condensates (BMCs) is key to their function, but also a vulnerability that can lead to misregulation and disease. Matrin-3 (MATR3) is an intrinsically disordered RBP implicated both genetically and pathologically in ALS/FTD, though it is relatively understudied as compared with TDP-43 and FUS. In addition to binding RNA, MATR3 also binds DNA and is implicated in many cellular processes including the DNA damage response, transcription, splicing, and cell differentiation. It is unclear if MATR3 localizes to BMCs under physiological conditions, which is brought further into question due to its lack of a prion-like domain. Here, we review recent studies regarding MATR3 and its roles in numerous physiological processes, as well as its implication in a range of diseases.}, } @article {pmid38813358, year = {2024}, author = {Finsterer, J}, title = {A positive effect of Cerebrolysin on motor functions and spasticity in ALS with limb or bulbar onset is questionable.}, journal = {Journal of medicine and life}, volume = {17}, number = {2}, pages = {242}, pmid = {38813358}, issn = {1844-3117}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Muscle Spasticity/drug therapy ; *Amino Acids/therapeutic use/pharmacology ; Neuroprotective Agents/therapeutic use/pharmacology ; }, } @article {pmid38813353, year = {2024}, author = {Firstenfeld, AJ}, title = {A positive effect of Cerebrolysin on motor functions and spasticity in ALS with limb or bulbar onset is questionable.}, journal = {Journal of medicine and life}, volume = {17}, number = {2}, pages = {243}, pmid = {38813353}, issn = {1844-3117}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Muscle Spasticity/drug therapy ; *Amino Acids/therapeutic use/pharmacology ; Neuroprotective Agents/therapeutic use/pharmacology ; }, } @article {pmid38812975, year = {2024}, author = {Fu, J and Lai, X and Wei, Q and Chen, X and Shang, H}, title = {Associations of cerebrospinal fluid profiles with severity and mortality risk of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1375892}, pmid = {38812975}, issn = {1662-4548}, abstract = {BACKGROUND: The relationship between routine cerebrospinal fluid (CSF) testing and the disease phenotype of amyotrophic lateral sclerosis (ALS) is unclear, and there are some contradictions in current studies.

METHODS: This study aimed to analyze the relationship between CSF profiles and disease phenotype in ALS patients. We collected 870 ALS patients and 96 control subjects admitted to West China Hospital of Sichuan University. CSF microprotein, albumin, IgG, index of IgG (IgGindex), albumin quotient (QALB), and serum IgG were examined.

RESULTS: In ALS patients, CSF IgG, and QALB were significantly increased, while CSF IgGindex was decreased, compared with control subjects. Approximately one-third of ALS patients had higher CSF IgG levels. The multiple linear regression analysis identified that CSF IgGindex was weakly negatively associated with ALS functional rating scale revised (ALSFRS-R) scores (β = -0.062, p = 0.041). This significance was found in male ALS but not in female ALS. The Cox survival analyses found that upregulated CSF IgG was significantly associated with the increased mortality risk in ALS [HR = 1.219 (1.010-1.470), p = 0.039].

CONCLUSION: In the current study, the higher CFS IgG was associated with increased mortality risk of ALS. CSF IgGindex may be associated with the severity of ALS. These findings may be sex-specific.}, } @article {pmid38812793, year = {2024}, author = {Jadhav, SP}, title = {MicroRNAs in microglia: deciphering their role in neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1391537}, pmid = {38812793}, issn = {1662-5102}, abstract = {This review presents a comprehensive analysis of the role of microRNAs in microglia and their implications in the pathogenesis of neurodegenerative diseases. Microglia, as the resident immune cells of the central nervous system (CNS), are pivotal in maintaining neural homeostasis and responding to pathological changes. Recent studies have highlighted the significance of miRNAs, small non-coding RNA molecules, in regulating microglial functions. In neurodegenerative diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), dysregulated miRNA expression in microglia contributes to disease progression through various mechanisms such regulation of gene expression, as modulation of cytokine response and phagocytosis. This review synthesizes current knowledge on how miRNAs influence microglial activation, cytokine production, and phagocytic activity. Specific miRNAs, such as miR-155, are explored for their roles in modulating microglial responses in the context of neuroinflammation and neurodegeneration. The study also discusses the impact of miRNA dysregulation on the transition of microglia from a neuroprotective to a neurotoxic phenotype, a critical aspect in the progression of neurodegenerative diseases.}, } @article {pmid38812789, year = {2024}, author = {Sidisky, JM and Winters, A and Caratenuto, R and Babcock, DT}, title = {Synaptic defects in a drosophila model of muscular dystrophy.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1381112}, pmid = {38812789}, issn = {1662-5102}, abstract = {Muscular dystrophies are a devastating class of diseases that result in a progressive loss of muscle integrity. Duchenne Muscular Dystrophy, the most prevalent form of Muscular Dystrophy, is due to the loss of functional Dystrophin. While much is known regarding destruction of muscle tissue in these diseases, much less is known regarding the synaptic defects that also occur in these diseases. Synaptic defects are also among the earliest hallmarks of neurodegenerative diseases, including the neuromuscular disease Amyotrophic Lateral Sclerosis (ALS). Our current study investigates synaptic defects within adult muscle tissues as well as presynaptic motor neurons in Drosophila dystrophin mutants. Here we demonstrate that the progressive, age-dependent loss of flight ability in dystrophin mutants is accompanied by disorganization of Neuromuscular Junctions (NMJs), including impaired localization of both presynaptic and postsynaptic markers. We show that these synaptic defects, including presynaptic defects within motor neurons, are due to the loss of Dystrophin specifically within muscles. These results should help to better understand the early synaptic defects preceding cell loss in neuromuscular disorders.}, } @article {pmid38811997, year = {2024}, author = {Huang, M and Liu, YU and Yao, X and Qin, D and Su, H}, title = {Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {28}, pmid = {38811997}, issn = {2047-9158}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/epidemiology/diagnosis ; Humans ; *Superoxide Dismutase-1/genetics ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and limited post-diagnosis life expectancy. Although primarily sporadic, familial ALS (fALS) cases suggest a genetic basis. This review focuses on SOD1, the first gene found to be associated with fALS, which has been more recently confirmed by genome sequencing. While informative, databases such as ALSoD and STRENGTH exhibit regional biases. Through a systematic global examination of SOD1 mutations from 1993 to 2023, we found different geographic distributions and clinical presentations. Even though different SOD1 variants are expressed at different protein levels and have different half-lives and dismutase activities, these alterations lead to loss of function that is not consistently correlated with disease severity. Gain of function of toxic aggregates of SOD1 resulting from mutated SOD1 has emerged as one of the key contributors to ALS. Therapeutic interventions specifically targeting toxic gain of function of mutant SOD1, including RNA interference and antibodies, show promise, but a cure remains elusive. This review provides a comprehensive perspective on SOD1-associated ALS and describes molecular features and the complex genetic landscape of SOD1, highlighting its importance in determining diverse clinical manifestations observed in ALS patients and emphasizing the need for personalized therapeutic strategies.}, } @article {pmid38811858, year = {2024}, author = {Benatar, M and Wuu, J and Huey, ED and McMillan, CT and Petersen, RC and Postuma, R and McHutchison, C and Dratch, L and Arias, JJ and Crawley, A and Houlden, H and McDermott, MP and Cai, X and Thakur, N and Boxer, A and Rosen, H and Boeve, BF and Dacks, P and Cosentino, S and Abrahams, S and Shneider, N and Lingor, P and Shefner, J and Andersen, PM and Al-Chalabi, A and Turner, MR and , }, title = {Publisher Correction: The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {6}, pages = {377}, doi = {10.1038/s41582-024-00978-4}, pmid = {38811858}, issn = {1759-4766}, support = {K01 AG057796/AG/NIA NIH HHS/United States ; R01 AG062268/AG/NIA NIH HHS/United States ; R01 MH120794/MH/NIMH NIH HHS/United States ; U01 AG079850/AG/NIA NIH HHS/United States ; }, } @article {pmid38809826, year = {2024}, author = {Krajewski, E and Lee, J and Viswanathan, N and Olmstead, A and Simmons, Z}, title = {The Effects of Interactive Context on Acoustic Characteristics of Speech in People With Dysarthria: A Preliminary Study.}, journal = {American journal of speech-language pathology}, volume = {33}, number = {4}, pages = {1952-1964}, doi = {10.1044/2024_AJSLP-23-00372}, pmid = {38809826}, issn = {1558-9110}, mesh = {Humans ; *Dysarthria/etiology/physiopathology/diagnosis ; Male ; Female ; *Speech Acoustics ; Middle Aged ; Aged ; *Speech Production Measurement ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; *Phonetics ; Speech Intelligibility ; Voice Quality ; Preliminary Data ; Sound Spectrography ; Time Factors ; Aged, 80 and over ; Acoustics ; }, abstract = {PURPOSE: The current study compared temporal and spectral acoustic contrast between vowel segments produced by speakers with dysarthria across three speech tasks-interactive, solo habitual, and solo clear.

METHOD: Nine speakers with dysarthria secondary to amyotrophic lateral sclerosis participated in the study. Each speaker was paired with a typical interlocutor over videoconferencing software. The speakers produced the vowels /i, ɪ, ɛ, æ/ in /h/-vowel-/d/ words. For the solo tasks, speakers read the stimuli aloud in both their habitual and clear speaking styles. For the interactive task, speakers produced a target stimulus for their interlocutor to select among the four possibilities. We measured the duration difference between long and short vowels, as well as the F1/F2 Euclidean distance between adjacent vowels, and also determined how well the vowels could be classified based on their acoustic characteristics.

RESULTS: Temporal contrast between long and short vowels was higher in the interactive task than in both solo tasks. Spectral distance between adjacent vowel pairs was also higher for some pairs in the interactive task than the habitual speech task. Finally, vowel classification accuracy was highest in the interactive task.

CONCLUSIONS: Overall, we found evidence that individuals with dysarthria produced vowels with greater acoustic contrast in structured interactions than they did in solo tasks. Furthermore, the speech adjustments they made to the vowel segments differed from those observed in solo speech.}, } @article {pmid38809531, year = {2024}, author = {Yang, CN and Chen, WL and Yeh, HH and Chu, HS and Wu, JH and Hsieh, YT}, title = {Convolutional Neural Network-Based Prediction of Axial Length Using Color Fundus Photography.}, journal = {Translational vision science & technology}, volume = {13}, number = {5}, pages = {23}, pmid = {38809531}, issn = {2164-2591}, mesh = {Humans ; Male ; Female ; *Neural Networks, Computer ; Middle Aged ; Adult ; *Photography/methods ; Aged ; *Axial Length, Eye/diagnostic imaging ; Fundus Oculi ; Young Adult ; Aged, 80 and over ; }, abstract = {PURPOSE: To develop convolutional neural network (CNN)-based models for predicting the axial length (AL) using color fundus photography (CFP) and explore associated clinical and structural characteristics.

METHODS: This study enrolled 1105 fundus images from 467 participants with ALs ranging from 19.91 to 32.59 mm, obtained at National Taiwan University Hospital between 2020 and 2021. The AL measurements obtained from a scanning laser interferometer served as the gold standard. The accuracy of prediction was compared among CNN-based models with different inputs, including CFP, age, and/or sex. Heatmaps were interpreted by integrated gradients.

RESULTS: Using age, sex, and CFP as input, the mean ± standard deviation absolute error (MAE) for AL prediction by the model was 0.771 ± 0.128 mm, outperforming models that used age and sex alone (1.263 ± 0.115 mm; P < 0.001) and CFP alone (0.831 ± 0.216 mm; P = 0.016) by 39.0% and 7.31%, respectively. The removal of relatively poor-quality CFPs resulted in a slight MAE reduction to 0.759 ± 0.120 mm without statistical significance (P = 0.24). The inclusion of age and CFP improved prediction accuracy by 5.59% (P = 0.043), while adding sex had no significant improvement (P = 0.41). The optic disc and temporal peripapillary area were highlighted as the focused areas on the heatmaps.

CONCLUSIONS: Deep learning-based prediction of AL using CFP was fairly accurate and enhanced by age inclusion. The optic disc and temporal peripapillary area may contain crucial structural information for AL prediction in CFP.

TRANSLATIONAL RELEVANCE: This study might aid AL assessments and the understanding of the morphologic characteristics of the fundus related to AL.}, } @article {pmid38809094, year = {2024}, author = {Gafni, R and Nassar, JA and Matzrafi, M and Blank, L and Eizenberg, H}, title = {Unraveling the reasons for failure to control Amaranthus albus: insights into herbicide application at different growth stages, temperature effect, and herbicide resistance on a regional scale.}, journal = {Pest management science}, volume = {80}, number = {9}, pages = {4757-4769}, doi = {10.1002/ps.8192}, pmid = {38809094}, issn = {1526-4998}, support = {132187417//Chief Scientist, Israel Ministry of Agriculture and Rural Development/ ; }, mesh = {*Amaranthus/drug effects/growth & development/genetics ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Temperature ; *Acetolactate Synthase/metabolism/genetics ; Weed Control/methods ; Israel ; Triazines ; }, abstract = {BACKGROUND: This study investigates factors contributing Amaranthus albus control failure in processing tomato fields in northern Israel. The study region is characterized by a significant climate gradient from east to west, providing the opportunity to investigate the effect of critical elements of the agricultural environment, e.g., temperature. Eight populations were collected from commercial fields in this region. Post-emergence herbicide efficacy of metribuzin, a photosystem II inhibitor, and rimsulfuron, an acetolactate synthase (ALS) inhibitor, was assessed through dose-response analyses at various growth stages. Temperature effects on control efficacy and resistance mechanisms were also explored.

RESULTS: Standard metribuzin dose (X) was ineffective on A. albus plants with more than six true-leaves, whereas 2X dose proved effective. Rimsulfuron at 16X dose was ineffective on plants with more than four true-leaves. We report here the first case of target site resistance to ALS inhibitors in A. albus, due to point mutation in the ALS gene (Pro197 to Leu). Furthermore, our findings suggest potential involvement of CYT P450 enzymes in enhanced metabolizing of rimsulfuron. An overall decrease in dry weight was observed in response to both herbicides at 16/22 °C (P < 0.0001). Rimsulfuron was effective against only one population when applied at 28/34 °C. A possible fitness cost associated with target site-resistant biotypes was observed under low temperature conditions, leading to effective control.

CONCLUSION: This regional-scale study highlights the challenges faced by growers, emphasizes the need for adapting management practices to the local climatic conditions and lays the groundwork for implementing location-specific weed management strategies in commercial fields. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid38808993, year = {2024}, author = {Solomon, B}, title = {Bone marrow-derived microglia confer neuroprotection to a mouse model of amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {12}, pages = {2586-2587}, pmid = {38808993}, issn = {1673-5374}, } @article {pmid38807398, year = {2024}, author = {Kekenadze, M and Kvirkvelia, N and Beridze, M and Vashadze, S}, title = {SEROTONIN AND AMYOTROPHIC LATERAL SCLEROSIS.}, journal = {Georgian medical news}, volume = {}, number = {348}, pages = {87-90}, pmid = {38807398}, issn = {1512-0112}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Serotonin/metabolism ; Middle Aged ; Female ; Male ; Adult ; Aged ; Aged, 80 and over ; Adolescent ; Motor Neurons/pathology ; Electromyography ; Magnetic Resonance Imaging ; }, abstract = {Selective degeneration of motoneurons is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Does serotonin (5-HT) play a role in progression or development of disease is under the research. The topic of the present paper is pressing as there is no data available regarding the spread of amyotrophic lateral sclerosis. It is also noteworthy that previous studies have indicated that the pathogenesis of ALS is closely linked to 5-hydroxytryptamine (5-HT). The clinical research was conducted in Georgia. During the last five years, 60 patients from different parts of Georgia have been studied, searched, and examined by us. Including from Samegrolo, Kartli, Adjara, Abkhazia, Guria, Kakheti regions. The Georgian Neurologists Corps participated and helped us in finding patients. Brain MRI and electromyography were also performed. 60 patients with different forms of ALS participated in the study, including 34 (56.66%) men and 26 (43.33%) women. Their age ranges from 30 to 81 years. The study was conducted after obtaining the written consent of the patients, taking into account the ethical requirements for the study. We also compared the results of the serotonin level of patients with amyotrophic lateral sclerosis with a control group of 20 people (aged 18 to 50 years) who had no neurological disease in past medical history. Patients of the first group, with LMN damage, are observed with decreased amount of serotonin (61.3) %, compared to other pairs, followed by patients of the upper neuron and bulbar syndrome groups, the level of serotonin in the control group is quite high. Thus, the level of serotonin in the group of patients with bulbar events is higher than in the other groups. Low serotonin requires further investigation. According to our research, the longer the anamnesis of amyotrophic lateral sclerosis patients is, the lower the level of serotonin is observed. It should also be taken into account that a low level of serotonin may be due to the presence of depression, which requires additional research. We speculate that 5-HT could therefore be a potential therapeutic target for amyotrophic lateral sclerosis.}, } @article {pmid38807021, year = {2024}, author = {Rahimian, S and Najafi, H and Webber, CA and Jalali, H}, title = {Advances in Exosome-Based Therapies for the Repair of Peripheral Nerve Injuries.}, journal = {Neurochemical research}, volume = {49}, number = {8}, pages = {1905-1925}, pmid = {38807021}, issn = {1573-6903}, mesh = {*Exosomes/metabolism/transplantation ; Humans ; *Peripheral Nerve Injuries/therapy/metabolism ; Animals ; Nerve Regeneration/physiology ; }, abstract = {Peripheral nerve injuries (PNIs) are the term used to describe injuries that occur to the nerve fibers of the peripheral nervous system (PNS). Such injuries may be caused by trauma, infection, or aberrant immunological response. Although the peripheral nervous system has a limited capacity for self-repair, in cases of severe damage, this process is either interrupted entirely or is only partially completed. The evaluation of variables that promote the repair of peripheral nerves has consistently been a focal point. Exosomes are a subtype of extracellular vesicles that originate from cellular sources and possess abundant proteins, lipids, and nucleic acids, play a critical role in facilitating intercellular communication. Due to their modifiable composition, they possess exceptional capabilities as carriers for therapeutic compounds, including but not limited to mRNAs or microRNAs. Exosome-based therapies have gained significant attention in the treatment of several nervous system diseases due to their advantageous properties, such as low toxicity, high stability, and limited immune system activation. The objective of this review article is to provide an overview of exosome-based treatments that have been developed in recent years for a range of PNIs, including nerve trauma, diabetic neuropathy, amyotrophic lateral sclerosis (ALS), glaucoma, and Guillain-Barre syndrome (GBS). It was concluded that exosomes could provide favorable results in the improvement of peripheral PNIs by facilitating the transfer of regenerative factors. The development of bioengineered exosome therapy for PNIs should be given more attention to enhance the efficacy of exosome treatment for PNIs.}, } @article {pmid38806659, year = {2024}, author = {Xie, C and Chen, G and Li, M and Huang, P and Chen, Z and Lei, K and Li, D and Wang, Y and Cleetus, A and Mohamed, MA and Sonar, P and Feng, W and Ökten, Z and Ou, G}, title = {Neurons dispose of hyperactive kinesin into glial cells for clearance.}, journal = {The EMBO journal}, volume = {43}, number = {13}, pages = {2606-2635}, pmid = {38806659}, issn = {1460-2075}, support = {31991191//MOST | National Natural Science Foundation of China (NSFC)/ ; 32200612//MOST | National Natural Science Foundation of China (NSFC)/ ; 32071191//MOST | National Natural Science Foundation of China (NSFC)/ ; 31971160//MOST | National Natural Science Foundation of China (NSFC)/ ; 2019YFA0508401//MOST | National Key Research and Development Program of China (NKPs)/ ; XDB37020302//Strategic Priority Research Program of CAS/ ; }, mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics ; *Kinesins/metabolism/genetics ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Neuroglia/metabolism ; *Cilia/metabolism ; Neurons/metabolism ; Mutation ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; }, abstract = {Microtubule-based kinesin motor proteins are crucial for intracellular transport, but their hyperactivation can be detrimental for cellular functions. This study investigated the impact of a constitutively active ciliary kinesin mutant, OSM-3CA, on sensory cilia in C. elegans. Surprisingly, we found that OSM-3CA was absent from cilia but underwent disposal through membrane abscission at the tips of aberrant neurites. Neighboring glial cells engulf and eliminate the released OSM-3CA, a process that depends on the engulfment receptor CED-1. Through genetic suppressor screens, we identified intragenic mutations in the OSM-3CA motor domain and mutations inhibiting the ciliary kinase DYF-5, both of which restored normal cilia in OSM-3CA-expressing animals. We showed that conformational changes in OSM-3CA prevent its entry into cilia, and OSM-3CA disposal requires its hyperactivity. Finally, we provide evidence that neurons also dispose of hyperactive kinesin-1 resulting from a clinic variant associated with amyotrophic lateral sclerosis, suggesting a widespread mechanism for regulating hyperactive kinesins.}, } @article {pmid38806131, year = {2024}, author = {Oliveira, D and Assoni, AF and Alves, LM and Sakugawa, A and Melo, US and Teles E Silva, AL and Sertie, AL and Caires, LC and Goulart, E and Ghirotto, B and Carvalho, VM and Ferrari, MR and Zatz, M}, title = {ALS-associated VRK1 R321C mutation causes proteostatic imbalance and mitochondrial defects in iPSC-derived motor neurons.}, journal = {Neurobiology of disease}, volume = {198}, number = {}, pages = {106540}, doi = {10.1016/j.nbd.2024.106540}, pmid = {38806131}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; *Mitochondria/metabolism/genetics/pathology ; Male ; *Protein Serine-Threonine Kinases/genetics/metabolism ; Female ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Proteostasis/genetics ; Middle Aged ; Mutation, Missense ; Adult ; }, abstract = {Vaccinia-related kinase 1 (VRK1) is a gene which has been implicated in the pathological process of a broad range of neurodevelopmental disorders as well as neuropathies, such as Amyotrophic Lateral Sclerosis (ALS). Here we report a family presenting ALS in an autosomal recessive mode of inheritance, segregating with a homozygous missense mutation located in VRK1 gene (p.R321C; Arg321Cys). Proteomic analyses from iPSC-derived motor neurons identified 720 proteins eligible for subsequent investigation, and our exploration of protein profiles revealed significant enrichments in pathways such as mTOR signaling, E2F, MYC targets, DNA repair response, cell proliferation and energetic metabolism. Functional studies further validated such alterations, showing that affected motor neurons presented decreased levels of global protein output, ER stress and downregulation of mTOR signaling. Mitochondrial alterations also pointed to decreased reserve capacity and increased non-mitochondrial oxygen consumption. Taken together, our results present the main pathological alterations associated with VRK1 mutation in ALS.}, } @article {pmid38805448, year = {2024}, author = {Fernandes, APM and Holanda, LJ and Lucena, LC and Silva, KERD and Lopes, ACSM and Borges, DT and Nagem, DAP and Valentim, RAM and Bougrain, L and Rodrigues Lindquist, AR}, title = {Electromyography as a tool to motion analysis for people with Amyotrophic Lateral Sclerosis: A protocol for a systematic review.}, journal = {PloS one}, volume = {19}, number = {5}, pages = {e0302479}, pmid = {38805448}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Humans ; *Electromyography/methods ; Systematic Reviews as Topic ; Muscle, Skeletal/physiopathology ; Movement/physiology ; Biomechanical Phenomena ; }, abstract = {Biomechanical analysis of human movement plays an essential role in understanding functional changes in people with Amyotrophic Lateral Sclerosis (ALS), providing information on muscle impairment. Studies suggest that surface electromyography (sEMG) may be able to quantify muscle activity, identify levels of fatigue, assess muscle strength, and monitor variation in limb movement. In this article, a systematic review protocol will analyze the psychometric properties of the sEMG regarding the clinical data on the skeletal muscles of people with ALS. This protocol uses the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodological tool. A specific field structure was defined to reach each phase. Nine scientific databases (PubMed, Web of Science, Embase, Elsevier, IEEE, Google Scholar, SciELO, PEDro, LILACS E CENTRAL) were searched. The framework developed will extract data (i.e. study information, sample information, sEMG information, intervention, and outcomes) from the selected studies using a rigorous approach. The data will be described quantitatively using frequency and trend analysis methods, and heterogeneity between the included studies will be assessed using the I2 test. The risk of bias will be summarized using the most recent prediction model risk of bias assessment tool. Be sure to include relevant statistics here, such as sample sizes, response rates, P values or Confidence Intervals. Be specific (by stating the value) rather than general (eg, "there were differences between the groups"). This protocol will map out the construction of a systematic review that will identify and synthesize the advances in movement analysis of people with ALS through sEMG, using data extracted from articles.}, } @article {pmid38805282, year = {2024}, author = {Bell, AM and Utting, C and Dickie, AC and Kucharczyk, MW and Quillet, R and Gutierrez-Mecinas, M and Razlan, ANB and Cooper, AH and Lan, Y and Hachisuka, J and Weir, GA and Bannister, K and Watanabe, M and Kania, A and Hoon, MA and Macaulay, IC and Denk, F and Todd, AJ}, title = {Deep sequencing of Phox2a nuclei reveals five classes of anterolateral system neurons.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {23}, pages = {e2314213121}, pmid = {38805282}, issn = {1091-6490}, support = {BB/S017178/1//UKRI | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; 204820/Z/16/Z//Wellcome Trust (WT)/ ; MR/W004739/1//UKRI | Medical Research Council (MRC)/ ; MR/T01072X/1/MRC_/Medical Research Council/United Kingdom ; BBS/E/T/000PR9816//UKRI | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; MR/V033638/1//UKRI | Medical Research Council (MRC)/ ; 219433/Z/19/Z//Wellcome Trust (WT)/ ; MR/V033638/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; SGL025\1079//Academy of Medical Sciences (The Academy of Medical Sciences)/ ; BB/CCG1720/1//UKRI | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; MR/W002426/1//UKRI | Medical Research Council (MRC)/ ; MR/T01072X/1//UKRI | Medical Research Council (MRC)/ ; ZIADE000721-22//HHS | NIH | National Institute of Dental and Craniofacial Research (NIDCR)/ ; MRF-160-0015-ELP-DENK-C0844//UKRI | MRC | Medical Research Foundation/ ; }, mesh = {Animals ; Mice ; *Homeodomain Proteins/genetics/metabolism ; Spinal Cord/cytology/metabolism ; Neurons/metabolism ; High-Throughput Nucleotide Sequencing ; Male ; Cell Nucleus/metabolism/genetics ; Transcription Factors/genetics/metabolism ; }, abstract = {The anterolateral system (ALS) is a major ascending pathway from the spinal cord that projects to multiple brain areas and underlies the perception of pain, itch, and skin temperature. Despite its importance, our understanding of this system has been hampered by the considerable functional and molecular diversity of its constituent cells. Here, we use fluorescence-activated cell sorting to isolate ALS neurons belonging to the Phox2a-lineage for single-nucleus RNA sequencing. We reveal five distinct clusters of ALS neurons (ALS1-5) and document their laminar distribution in the spinal cord using in situ hybridization. We identify three clusters of neurons located predominantly in laminae I-III of the dorsal horn (ALS1-3) and two clusters with cell bodies located in deeper laminae (ALS4 and ALS5). Our findings reveal the transcriptional logic that underlies ALS neuronal diversity in the adult mouse and uncover the molecular identity of two previously identified classes of projection neurons. We also show that these molecular signatures can be used to target groups of ALS neurons using retrograde viral tracing. Overall, our findings provide a valuable resource for studying somatosensory biology and targeting subclasses of ALS neurons.}, } @article {pmid38805054, year = {2024}, author = {Beswick, E and Christides, A and Symonds, A and Johnson, M and Fawcett, T and Newton, J and Lyle, D and Weaver, C and Chandran, S and Pal, S}, title = {Exploratory study to evaluate the acceptability of a wearable accelerometer to assess motor progression in motor neuron disease.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5083-5101}, pmid = {38805054}, issn = {1432-1459}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Motor Neuron Disease/physiopathology/diagnosis ; Aged ; *Wearable Electronic Devices ; *Accelerometry/instrumentation ; *Disease Progression ; Patient Acceptance of Health Care ; Surveys and Questionnaires/standards ; }, abstract = {Motor neuron disease (MND) is a rapidly progressive condition traditionally assessed using a questionnaire to evaluate physical function, the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R). Its use can be associated with poor sensitivity in detecting subtle changes over time and there is an urgent need for more sensitive and specific outcome measures. The ActiGraph GT9X is a wearable device containing multiple sensors that can be used to provide metrics that represent physical activity. The primary aim of this study was to investigate the initial suitability and acceptability of limb-worn wearable devices to group of people with MND in Scotland. A secondary aim was to explore the preliminary associations between the accelerometer sensor data within the ActiGraph GT9X and established measures of physical function. 10 participants with MND completed a 12-week schedule of assessments including fortnightly study visits, both in-person and over videoconferencing software. Participants wore the device on their right wrist and right ankle for a series of movements, during a 6-min walking test and for a period of 24-h wear, including overnight. Participants also completed an ALSFRS-R and questionnaires on their experience with the devices. 80% of the participants found wearing these devices to be a positive experience and no one reported interference with daily living or added burden. However, 30% of the participants experienced technical issues with their devices. Data from the wearable devices correlated with established measures of physical function.}, } @article {pmid38805053, year = {2024}, author = {Bjelica, B and Bartels, MB and Hesebeck-Brinckmann, J and Petri, S}, title = {Non-motor symptoms in patients with amyotrophic lateral sclerosis: current state and future directions.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {3953-3977}, pmid = {38805053}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of both upper and lower motor neurons. A defining histopathological feature in approximately 97% of all ALS cases is the accumulation of phosphorylated trans-activation response (TAR) DNA-binding protein 43 protein (pTDP-43) aggregates in the cytoplasm of neurons and glial cells within the central nervous system. Traditionally, it was believed that the accumulation of TDP-43 aggregates and subsequent neurodegeneration primarily occurs in motor neurons. However, contemporary evidence suggests that as the disease progresses, other systems and brain regions are also affected. Despite this, there has been a limited number of clinical studies assessing the non-motor symptoms in ALS patients. These studies often employ various outcome measures, resulting in a wide range of reported frequencies of non-motor symptoms in ALS patients. The importance of assessing the non-motor symptoms reflects in a fact that they have a significant impact on patients' quality of life, yet they frequently go underdiagnosed and unreported during clinical evaluations. This review aims to provide an up-to-date overview of the current knowledge concerning non-motor symptoms in ALS. Furthermore, we address their diagnosis and treatment in everyday clinical practice.}, } @article {pmid38802624, year = {2024}, author = {Riva, N and Domi, T and Pozzi, L and Lunetta, C and Schito, P and Spinelli, EG and Cabras, S and Matteoni, E and Consonni, M and Bella, ED and Agosta, F and Filippi, M and Calvo, A and Quattrini, A}, title = {Update on recent advances in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {4693-4723}, pmid = {38802624}, issn = {1432-1459}, support = {IDEALS//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; Marazzina Project//Marazzina Foundation/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; Animals ; }, abstract = {In the last few years, our understanding of disease molecular mechanisms underpinning ALS has advanced greatly, allowing the first steps in translating into clinical practice novel research findings, including gene therapy approaches. Similarly, the recent advent of assistive technologies has greatly improved the possibility of a more personalized approach to supportive and symptomatic care, in the context of an increasingly complex multidisciplinary line of actions, which remains the cornerstone of ALS management. Against this rapidly growing background, here we provide an comprehensive update on the most recent studies that have contributed towards our understanding of ALS pathogenesis, the latest results from clinical trials as well as the future directions for improving the clinical management of ALS patients.}, } @article {pmid38802492, year = {2024}, author = {Watanabe, S and Amporndanai, K and Awais, R and Latham, C and Awais, M and O'Neill, PM and Yamanaka, K and Hasnain, SS}, title = {Ebselen analogues delay disease onset and its course in fALS by on-target SOD-1 engagement.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {12118}, pmid = {38802492}, issn = {2045-2322}, support = {WA1198//ALS Association/ ; }, mesh = {*Superoxide Dismutase-1/genetics/metabolism ; Animals ; *Organoselenium Compounds/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Isoindoles/pharmacology ; Mice ; *Azoles/pharmacology ; Humans ; Mice, Transgenic ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) selectively affects motor neurons. SOD1 is the first causative gene to be identified for ALS and accounts for at least 20% of the familial (fALS) and up to 4% of sporadic (sALS) cases globally with some geographical variability. The destabilisation of the SOD1 dimer is a key driving force in fALS and sALS. Protein aggregation resulting from the destabilised SOD1 is arrested by the clinical drug ebselen and its analogues (MR6-8-2 and MR6-26-2) by redeeming the stability of the SOD1 dimer. The in vitro target engagement of these compounds is demonstrated using the bimolecular fluorescence complementation assay with protein-ligand binding directly visualised by co-crystallography in G93A SOD1. MR6-26-2 offers neuroprotection slowing disease onset of SOD1[G93A] mice by approximately 15 days. It also protected neuromuscular junction from muscle denervation in SOD1[G93A] mice clearly indicating functional improvement.}, } @article {pmid38802184, year = {2024}, author = {Vucic, S and de Carvalho, M and Bashford, J and Alix, JJP}, title = {Contribution of neurophysiology to the diagnosis and monitoring of ALS.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {87-118}, doi = {10.1016/bs.irn.2024.04.001}, pmid = {38802184}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; *Transcranial Magnetic Stimulation/methods ; *Electromyography/methods ; *Neurophysiology/methods ; Disease Progression ; Motor Cortex/physiopathology ; }, abstract = {This chapter describes the role of neurophysiological techniques in diagnosing and monitoring amyotrophic lateral sclerosis (ALS). Despite many advances, electromyography (EMG) remains a keystone investigation from which to build support for a diagnosis of ALS, demonstrating the pathophysiological processes of motor unit hyperexcitability, denervation and reinnervation. We consider development of the different diagnostic criteria and the role of EMG therein. While not formally recognised by established diagnostic criteria, we discuss the pioneering studies that have demonstrated the diagnostic potential of transcranial magnetic stimulation (TMS) of the motor cortex and highlight the growing evidence for TMS in the diagnostic process. Finally, accurately monitoring disease progression is crucial for the successful implementation of clinical trials. Neurophysiological measures of disease state have been incorporated into clinical trials for over 20 years and we review prominent techniques for assessing disease progression.}, } @article {pmid38802183, year = {2024}, author = {Moll, T and Harvey, C and Alhathli, E and Gornall, S and O'Brien, D and Cooper-Knock, J}, title = {Non-coding genome contribution to ALS.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {75-86}, doi = {10.1016/bs.irn.2024.04.002}, pmid = {38802183}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; Animals ; Genetic Predisposition to Disease/genetics ; }, abstract = {The majority of amyotrophic lateral sclerosis (ALS) is caused by a complex gene-environment interaction. Despite high estimates of heritability, the genetic basis of disease in the majority of ALS patients are unknown. This limits the development of targeted genetic therapies which require an understanding of patient-specific genetic drivers. There is good evidence that the majority of these missing genetic risk factors are likely to be found within the non-coding genome. However, a major challenge in the discovery of non-coding risk variants is determining which variants are functional in which specific CNS cell type. We summarise current discoveries of ALS-associated genetic drivers within the non-coding genome and we make the case that improved cell-specific annotation of genomic function is required to advance this field, particularly via single-cell epigenetic profiling and spatial transcriptomics. We highlight the example of TBK1 where an apparent paradox exists between pathogenic coding variants which cause loss of protein function, and protective non-coding variants which cause reduced gene expression; the paradox is resolved when it is understood that the non-coding variants are acting primarily via change in gene expression within microglia, and the effect of coding variants is most prominent in neurons. We propose that cell-specific functional annotation of ALS-associated genetic variants will accelerate discovery of the genetic architecture underpinning disease in the vast majority of patients.}, } @article {pmid38802182, year = {2024}, author = {Al-Chalabi, A and Andrews, J and Farhan, S}, title = {Recent advances in the genetics of familial and sporadic ALS.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {49-74}, doi = {10.1016/bs.irn.2024.04.007}, pmid = {38802182}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genetic Predisposition to Disease/genetics ; }, abstract = {ALS shows complex genetic inheritance patterns. In about 5% to 10% of cases, there is a family history of ALS or a related condition such as frontotemporal dementia in a first or second degree relative, and for about 80% of such people a pathogenic gene variant can be identified. Such variants are also seen in people with no family history because of factor influencing the expression of genes, such as age. Genetic susceptibility factors also contribute to risk, and the heritability of ALS is between 40% and 60%. The genetic variants influencing ALS risk include single base changes, repeat expansions, copy number variants, and others. Here we review what is known of the genetic landscape and architecture of ALS.}, } @article {pmid38802181, year = {2024}, author = {De Cock, L and Bercier, V and Van Den Bosch, L}, title = {New developments in pre-clinical models of ALS to guide translation.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {477-524}, doi = {10.1016/bs.irn.2024.04.008}, pmid = {38802181}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/physiopathology/therapy ; Animals ; *Disease Models, Animal ; Humans ; Translational Research, Biomedical/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder in which selective death of motor neurons leads to muscle weakness and paralysis. Most research has focused on understanding and treating monogenic familial forms, most frequently caused by mutations in SOD1, FUS, TARDBP and C9orf72, although ALS is mostly sporadic and without a clear genetic cause. Rodent models have been developed to study monogenic ALS, but despite numerous pre-clinical studies and clinical trials, few disease-modifying therapies are available. ALS is a heterogeneous disease with complex underlying mechanisms where several genes and molecular pathways appear to play a role. One reason for the high failure rate of clinical translation from the current models could be oversimplification in pre-clinical studies. Here, we review advances in pre-clinical models to better capture the heterogeneous nature of ALS and discuss the value of novel model systems to guide translation and aid in the development of precision medicine.}, } @article {pmid38802180, year = {2024}, author = {Shelkovnikova, TA and Hautbergue, GM}, title = {RNP granules in ALS and neurodegeneration: From multifunctional membraneless organelles to therapeutic opportunities.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {455-479}, doi = {10.1016/bs.irn.2024.04.009}, pmid = {38802180}, issn = {2162-5514}, support = {MR/R024162/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Ribonucleoproteins/metabolism ; Animals ; *Cytoplasmic Granules/metabolism ; Neurodegenerative Diseases/metabolism ; Organelles/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases are characterised by dysfunction of a host of RNA-binding proteins (RBPs) and a severely disrupted RNA metabolism. Recently, RBP-harbouring phase-separated complexes, ribonucleoprotein (RNP) granules, have come into the limelight as "crucibles" of neuronal pathology in ALS. RNP granules are indispensable for the multitude of regulatory processes underlying cellular RNA metabolism and serve as critical organisers of cellular biochemistry. Neurons, highly specialised cells, heavily rely on RNP granules for efficient trafficking, signalling and stress responses. Multiple RNP granule components, primarily RBPs such as TDP-43 and FUS, are affected by ALS mutations. However, even in the absence of mutations, RBP proteinopathies represent pathophysiological hallmarks of ALS. Given the high local concentrations of RBPs and RNAs, their weakened or enhanced interactions within RNP granules disrupt their homeostasis. Thus, the physiological process of phase separation and RNP granule formation, vital for maintaining the high-functioning state of neuronal cells, becomes their Achilles heel. Here, we will review the recent literature on the causes and consequences of abnormal RNP granule functioning in ALS and related disorders. In particular, we will summarise the evidence for the network-level dysfunction of RNP granules in these conditions and discuss considerations for therapeutic interventions to target RBPs, RNP granules and their network as a whole.}, } @article {pmid38802179, year = {2024}, author = {Pandya, VA and Patani, R}, title = {The role of glial cells in amyotrophic lateral sclerosis.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {381-450}, doi = {10.1016/bs.irn.2024.04.005}, pmid = {38802179}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology/therapy ; Humans ; *Neuroglia/physiology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has traditionally been considered a neuron-centric disease. This view is now outdated, with increasing recognition of cell autonomous and non-cell autonomous contributions of central and peripheral nervous system glia to ALS pathomechanisms. With glial research rapidly accelerating, we comprehensively interrogate the roles of astrocytes, microglia, oligodendrocytes, ependymal cells, Schwann cells and satellite glia in nervous system physiology and ALS-associated pathology. Moreover, we highlight the inter-glial, glial-neuronal and inter-system polylogue which constitutes the healthy nervous system and destabilises in disease. We also propose classification based on function for complex glial reactive phenotypes and discuss the pre-requisite for integrative modelling to advance translation. Given the paucity of life-enhancing therapies currently available for ALS patients, we discuss the promising potential of harnessing glia in driving ALS therapeutic discovery.}, } @article {pmid38802177, year = {2024}, author = {Lee, J and Pye, N and Ellis, L and Vos, K and Mortiboys, H}, title = {Evidence of mitochondrial dysfunction in ALS and methods for measuring in model systems.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {269-325}, doi = {10.1016/bs.irn.2024.04.006}, pmid = {38802177}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Mitochondria/metabolism ; Animals ; Reactive Oxygen Species/metabolism ; Disease Models, Animal ; Oxidative Stress/physiology ; }, abstract = {Metabolic dysfunction is a hallmark of multiple amyotrophic lateral sclerosis (ALS) models with a majority of ALS patients exhibiting hypermetabolism. The central sites of metabolism in the cell are mitochondria, capable of utilising a multitude of cellular substrates in an array of ATP-generating reactions. With reactive oxygen species (ROS) production occurring during some of these reactions, mitochondria can contribute considerably to oxidative stress. Mitochondria are also very dynamic organelles, interacting with other organelles, undergoing fusion/fission in response to changing metabolic states and being turned over by the cell regularly. Disruptions to many of these mitochondrial functions and processes have been reported in ALS models, largely indicating compromised mitochondrial function, increased ROS production by mitochondria, disrupted interactions with the endoplasmic reticulum and reduced turnover. This chapter summarises methods routinely used to assess mitochondria in ALS models and the alterations that have been reported in these models.}, } @article {pmid38802176, year = {2024}, author = {Castelli, L and Vasta, R and Allen, SP and Waller, R and Chiò, A and Traynor, BJ and Kirby, J}, title = {From use of omics to systems biology: Identifying therapeutic targets for amyotrophic lateral sclerosis.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {209-268}, doi = {10.1016/bs.irn.2024.02.001}, pmid = {38802176}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/drug therapy/therapy ; *Systems Biology/methods ; *Genomics/methods ; Proteomics/methods ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous progressive neurodegenerative disorder with available treatments such as riluzole and edaravone extending survival by an average of 3-6 months. The lack of highly effective, widely available therapies reflects the complexity of ALS. Omics technologies, including genomics, transcriptomic and proteomics have contributed to the identification of biological pathways dysregulated and targeted by therapeutic strategies in preclinical and clinical trials. Integrating clinical, environmental and neuroimaging information with omics data and applying a systems biology approach can further improve our understanding of the disease with the potential to stratify patients and provide more personalised medicine. This chapter will review the omics technologies that contribute to a systems biology approach and how these components have assisted in identifying therapeutic targets. Current strategies, including the use of genetic screening and biosampling in clinical trials, as well as the future application of additional technological advances, will also be discussed.}, } @article {pmid38802175, year = {2024}, author = {Malaspina, A}, title = {Use of biomarkers in clinical trials and future developments that will help identify novel biomarkers.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {171-207}, doi = {10.1016/bs.irn.2024.04.010}, pmid = {38802175}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/genetics/metabolism/drug therapy ; *Biomarkers ; *Clinical Trials as Topic/methods ; }, abstract = {Engineering new solutions for therapeutic benefit in Amyotrophic Lateral Sclerosis (ALS) has proved a difficult task to accomplish. This is largely the reflection of complexities at multiple levels, that require solutions to improve cost-effectiveness and outcomes. The main obstacle related to the condition's clinical heterogeneity, chiefly the broad difference in survival observed among ALS patients, imposes large populations studies and long follow-up to evaluate any efficacy. The emerging solution is composite clinical and biological parameters enabling prognostic stratification into homogeneous phenotypes for more affordable studies. From a therapeutic development perspective, the choice of a medicinal product requires the availability of treatment-specific biomarkers of target engagement to identify off-target effects based on the compound's putative modality of action. More importantly, there are no established biomarkers of treatment response that can complement clinical outcome measures and support futility and end of treatment analyses of efficacy. Ultimately the onus rests on the development of biomarkers encompassing the unmet needs of clinical trial design, from inclusion to efficacy. These readouts of the pathological process may be used in combination with clinical and paraclinical outcome measured, significantly reducing the time and financial burden of clinical studies. Progress towards a biomarker-driven clinical trial design in ALS has been possible thanks to the accurate detection of neurofilaments and of other immunological mediators in biological fluids with the disease progression, a step change enabling the testing of novel therapeutic agents in a new clinical trial setting. However, further progress remains to be made to find treatment specific target engagement biomarkers along with readouts of treatment response that can be reliably applied to all emerging therapies and clinical studies. Here we will cover the basic notions of biomarker development in ALS clinical trials, the most crucial unanswered questions and the unmet needs in the ALS biomarkers space.}, } @article {pmid38802174, year = {2024}, author = {Hobson, E and McDermott, C}, title = {Advances in symptom management and in monitoring disease progression in motor neuron disease.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {119-169}, doi = {10.1016/bs.irn.2024.04.004}, pmid = {38802174}, issn = {2162-5514}, mesh = {Humans ; *Motor Neuron Disease/therapy/physiopathology ; *Disease Progression ; Disease Management ; Quality of Life ; }, abstract = {The aim of supportive management of motor neuron disease is to improve survival, promote good quality of life and patient independence and autonomy whilst preparing for future progression and the end of life. Multidisciplinary specialist care aims to address the multifaceted and interacting biopsychosocial problems associated with motor neuron disease that leads to proven benefits in both survival and quality of life. This chapter will explore principles, structure and details of treatment options, and make recommendations for practice and for future research.}, } @article {pmid38802173, year = {2024}, author = {Van Es, MA}, title = {Amyotrophic lateral sclerosis; clinical features, differential diagnosis and pathology.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {1-47}, doi = {10.1016/bs.irn.2024.04.011}, pmid = {38802173}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/pathology/physiopathology ; Diagnosis, Differential ; Frontotemporal Dementia/diagnosis/genetics/physiopathology/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset syndrome characterized by the progressive degeneration of both upper motor neurons (UMN) and lower motor neurons (LMN). ALS forms a clinical continuum with frontotemporal dementia (FTD), in which there are progressive language deficits or behavioral changes. The genetics and pathology underlying both ALS and FTD overlap as well, with cytoplasmatic misvocalization of TDP-43 as the hallmark. ALS is diagnosed by exclusion. Over the years several diagnostic criteria have been proposed, which in essence all require a history of slowly progressive motor symptoms, with UMN and LMN signs on neurological examination, clear spread of symptoms through the body, the exclusion of other disorder that cause similar symptoms and an EMG that it is compatible with LMN loss. ALS is heterogeneous disorder that may present in multitude ways, which makes the diagnosis challenging. Therefore, a systematic approach in the diagnostic process is required in line with the most common presentations. Subsequently, assessing whether there are cognitive and/or behavioral changes within the spectrum of FTD and lastly determining the cause is genetic. This chapter, an outline on how to navigate this 3 step process.}, } @article {pmid38799643, year = {2024}, author = {Xu, S and Ma, Q and Shen, J and Li, N and Sun, S and Wang, N and Chen, Y and Dong, C and Tam, KY and Prehn, JHM and Wang, H and Ying, Z}, title = {ALS-linked C9orf72 dipeptide repeats inhibit starvation-induced autophagy through modulating BCL2-BECN1 interaction.}, journal = {Acta pharmaceutica Sinica. B}, volume = {14}, number = {5}, pages = {2026-2038}, pmid = {38799643}, issn = {2211-3835}, abstract = {Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative disorders. The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72 (C9orf72) is the most genetic cause of both ALS and FTD. According to the previous studies, GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation, which produces dipeptide repeat (DPR) proteins. Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD, whether these DPRs can affect autophagy remains unclear. In the present study, we find that poly-GR and poly-PR, two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies, strongly inhibit starvation-induced autophagy. Moreover, our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation, therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells. Importantly, our study not only highlights the role of C9orf72 DPR in autophagy dysfunction, but also provides novel insight that pharmacological intervention of autophagy using SW063058, a small molecule compound that can disrupt the interaction between BECN1 and BCL2, may reduce C9orf72 DPR-induced neurotoxicity.}, } @article {pmid38798695, year = {2024}, author = {Conforti, FL and Renton, AE and Houlden, H}, title = {Editorial: Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia volume II.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1420029}, doi = {10.3389/fgene.2024.1420029}, pmid = {38798695}, issn = {1664-8021}, } @article {pmid38798645, year = {2024}, author = {Landry, C and Costanzo, J and Mitne-Neto, M and Zatz, M and Schaffer, A and Hatzoglou, M and Muotri, A and Miranda, HC}, title = {Mitochondrial dysfunction heightens the integrated stress response to drive ALS pathogenesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.05.13.594000}, pmid = {38798645}, issn = {2692-8205}, support = {R01 NS121374/NS/NINDS NIH HHS/United States ; R61 NS133212/NS/NINDS NIH HHS/United States ; }, abstract = {Vesicle-associated membrane protein-associated protein-B (VAPB) is an ER membrane bound protein. VAPB P56S causes a dominant, familial form of amyotrophic lateral sclerosis (ALS), however, the mechanism through which this mutation causes motor neuron (MN) disease remains unknown. Using inducible wild type (WT) and VAPB P56S expressing iPSC-derived MNs we show that VAPB P56S, but not WT, protein decreased neuronal firing and mitochondrial-ER contact (MERC) with an associated age-dependent decrease in mitochondrial membrane potential (MMP); all typical characteristics of MN-disease. We further show that VAPB P56S expressing iPSC-derived MNs have enhanced age-dependent sensitivity to ER stress. We identified elevated expression of the master regulator of the Integrated Stress Response (ISR) marker ATF4 and decreased protein synthesis in the VAPB P56S iPSC-derived MNs. Chemical inhibition of ISR with the compound, ISRIB, rescued all MN disease phenotype in VAPB P56S MNs. Thus, our results not only support ISR inhibition as a potential therapeutic target for ALS patients, but also provides evidence to pathogenesis.}, } @article {pmid38798341, year = {2024}, author = {Provasek, VE and Bacolla, A and Rangaswamy, S and Mitra, J and Kodavati, M and Yusuf, IO and Malojirao, VH and Vasquez, V and Britz, GW and Li, GM and Xu, Z and Mitra, S and Garruto, RM and Tainer, JA and Hegde, ML}, title = {RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38798341}, issn = {2692-8205}, support = {R35 CA220430/CA/NCI NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; P01 CA092584/CA/NCI NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {TAR DNA-binding protein 43 (TDP43) is increasingly recognized for its involvement in neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP43 proteinopathy, characterized by dysregulated nuclear export and cytoplasmic aggregation, is present in most ALS/FTD cases and is associated with a loss of nuclear function and genomic instability in neurons. Building on prior evidence linking TDP43 pathology to DNA double-strand breaks (DSBs), this study identifies a novel regulatory role for TDP43 in the DNA mismatch repair (MMR) pathway. We demonstrate that depletion or overexpression of TDP43 affects the expression of key MMR genes, including MLH1, MSH6, MSH2, MSH3, and PMS2. Specifically, TDP43 modulates the expression of MLH1 and MSH6 proteins through alternative splicing and transcript stability. These findings are validated in ALS mice models, patient-derived neural progenitor cells and autopsied brain tissues from ALS patients. Furthermore, MMR depletion showed a partial rescue of TDP43-induced DNA damage in neuronal cells. Bioinformatics analysis of TCGA cancer database reveals significant correlations between TDP43 and MMR gene expressions and mutational burden across various cancer subtypes. These results collectively establish TDP43 as a critical regulator of the MMR pathway, with broad implications for understanding the genomic instability underlying neurodegenerative and neoplastic diseases.}, } @article {pmid38796984, year = {2024}, author = {Jiang, L and Tracey, TJ and Gill, MK and Howe, SL and Power, DT and Bharti, V and McCombe, PA and Henderson, RD and Steyn, FJ and Ngo, ST}, title = {Generation of human induced pluripotent stem cell lines from sporadic, sporadic frontotemporal dementia, familial SOD1, and familial C9orf72 amyotrophic lateral sclerosis (ALS) patients.}, journal = {Stem cell research}, volume = {78}, number = {}, pages = {103447}, doi = {10.1016/j.scr.2024.103447}, pmid = {38796984}, issn = {1876-7753}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *C9orf72 Protein/genetics/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; Female ; Male ; Cell Line ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Clinical heterogeneity and complex genetics pose challenges to understanding disease mechanisms and producing effective cures. To model clinical heterogeneity, we generated human induced pluripotent stem cells (iPSCs) from two sporadic ALS patients (sporadic ALS and sporadic ALS with frontotemporal dementia), two familial ALS patients (familial SOD1 mutation positive and familial C9orf72 repeat expansion positive), and four age- and sex-matched healthy controls. These iPSCs can be used to generate 2D and 3D in vitro models of ALS to investigate mechanisms of disease and screen for therapeutics.}, } @article {pmid38796647, year = {2024}, author = {Chong, NF and Van de Wouw, AP and Idnurm, A}, title = {The ilv2 gene, encoding acetolactate synthase for branched chain amino acid biosynthesis, is required for plant pathogenicity by Leptosphaeria maculans.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {682}, pmid = {38796647}, issn = {1573-4978}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Plant Diseases/microbiology ; *Herbicides/pharmacology ; *Amino Acids, Branched-Chain/biosynthesis/metabolism ; *Leptosphaeria/genetics/pathogenicity ; Mutation/genetics ; Fungal Proteins/genetics/metabolism ; Gene Editing/methods ; Plant Leaves/microbiology ; CRISPR-Cas Systems/genetics ; Brassica/microbiology ; Ascomycota/pathogenicity/genetics ; }, abstract = {BACKGROUND: Control of blackleg disease of canola caused by the fungus Leptosphaeria maculans relies on strategies such as the inhibition of growth with fungicides. However, other chemicals are used during canola cultivation, including fertilizers and herbicides. There is widespread use of herbicides that target the acetolactate synthase (ALS) enzyme involved in branched chain amino acid synthesis and low levels of these amino acids within leaves of Brassica species. In L. maculans the ilv2 gene encodes ALS and thus ALS-inhibiting herbicides may inadvertently impact the fungus.

METHODS AND RESULTS: Here, the impact of a commercial herbicide targeting ALS and mutation of the homologous ilv2 gene in L. maculans was explored. Exposure to herbicide had limited impact on growth in vitro but reduced lesion sizes in plant disease experiments. Furthermore, the mutation of the ilv2 gene via CRISPR-Cas9 gene editing rendered the fungus non-pathogenic.

CONCLUSION: Herbicide applications can influence disease outcome, but likely to a minor extent.}, } @article {pmid38795957, year = {2024}, author = {Bhushan, NL and Romano, CD and Gras-Najjar, J and Reno, J and Rockwood, N and Quattrone, W and Adams, ET and Kelly, B and McLeod, L and Bhavnani, SP and Bocell, FD and Campbell, M and Kontson, K and Reasner, D and Zhang, C and Retzky, S}, title = {Remote-Use Applications of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised Clinical Outcome Assessment Tool: A Scoping Review.}, journal = {Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research}, volume = {27}, number = {10}, pages = {1454-1465}, doi = {10.1016/j.jval.2024.05.005}, pmid = {38795957}, issn = {1524-4733}, support = {75F40120A00017/FD/FDA HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/physiopathology ; Humans ; *Outcome Assessment, Health Care/methods ; Telemedicine ; Severity of Illness Index ; Videoconferencing ; }, abstract = {OBJECTIVES: In 2021, the US Congress passed the Accelerating Access to Critical Therapies for Amyotrophic Lateral Sclerosis Act. The law encourages development of "tools, methods, and processes" to improve clinical trial efficiency for neurodegenerative diseases. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is an outcome measure administered during in-person clinic visits and used to support investigational studies for persons living with amyotrophic lateral sclerosis. Availability of a standardized, remote-use version of the ALSFRS-R may promote more inclusive, decentralized clinical trials. A scoping literature review was conducted to identify existing remote-use ALSFRS-R tools, synthesize feasibility and comparability of administration modes, and summarize barriers and facilitators to inform development of a standardized remote-use ALSFRS-R tool.

METHODS: Included studies reported comparisons between remote and in-person, clinician-reported, ALSFRS-R administration and were published in English (2002-2022). References were identified by searching peer-reviewed and gray literature. Twelve studies met the inclusion criteria and were analyzed to compare findings within and across modes of administration.

RESULTS: Remote modes of ALSFRS-R administration were categorized into 4 nonmutually exclusive categories: telephone (n = 6), videoconferencing (n = 3), computer or online platforms (n = 3), mobile applications and wearables (n = 2), and 1 unspecified telemedicine modality (n = 1). Studies comparing in-person to telephone or videoconferencing administration reported high ALSFRS-R rating correlations and nonsignificant between-mode differences.

CONCLUSIONS: There is insufficient information in the ALSFRS-R literature to support remote clinician administration for collecting high quality data. Future research should engage persons living with amyotrophic lateral sclerosis, care partners, and providers to develop a standardized remote-use ALSFRS-R version.}, } @article {pmid38795892, year = {2024}, author = {Ridho, MR and Lubis, MAR and Nawawi, DS and Fatriasari, W}, title = {Optimization of areca leaf sheath nanolignin synthesis by a mechanical method for in situ modification of ultra-low molar ratio urea-formaldehyde adhesives.}, journal = {International journal of biological macromolecules}, volume = {271}, number = {Pt 1}, pages = {132614}, doi = {10.1016/j.ijbiomac.2024.132614}, pmid = {38795892}, issn = {1879-0003}, mesh = {*Formaldehyde/chemistry ; *Adhesives/chemistry ; *Urea/chemistry ; Plant Leaves/chemistry ; Particle Size ; Lignin/chemistry ; }, abstract = {This study addresses the optimization of the nanolignin preparation method from the areca leaf sheath (ALS) by a mechanical process using a high shear homogenizer at 13,000-16,000 rpm for 1-4 h and its application in enhancing the performance of ultralow molar ratio urea-formaldehyde (UF) adhesive. Response surface methodology (RSM) with a central composite design (CCD) model was used to determine the optimum nanolignin preparation method. The mathematical model obtained was quadratic for the particle size response and linear for the zeta potential response. Under the optimum conditions, a speed of 16,000 rpm for 4 h resulted in a particle size of 227.7 nm and a zeta potential of -18.57 mV with a high desirability value of 0.970. FE-SEM revealed that the characteristic changes of lignin to nanolignin occur from an irregular or nonuniform shape to an oval shape with uniform particles. Nanolignin was introduced during the addition reaction of UF resin synthesis. UF modified with nanolignin (UF-NL) was analyzed for its adhesive characteristics, functional groups, crystallinity, and thermomechanical properties. The UF-NL adhesive had a slightly greater solid content (73.23 %) than the UF adhesive, a gelation time of 4.10 min, and a viscosity of 1066 mPa[.]s. The UF-NL adhesive had similar functional groups as the UF adhesive, with a lower crystallinity of 59.73 %. Compared with the control plywood which has a tensile shear strength value of 0.79 MPa, the plywood bonded with UF-NL had a greater tensile shear strength of 1.07 MPa, with a lower formaldehyde emission of 0.065 mg/L.}, } @article {pmid38795640, year = {2024}, author = {Li, Z and Zhang, Y and Ji, M and Wu, C and Zhang, Y and Ji, S}, title = {Targeting ferroptosis in neuroimmune and neurodegenerative disorders for the development of novel therapeutics.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {176}, number = {}, pages = {116777}, doi = {10.1016/j.biopha.2024.116777}, pmid = {38795640}, issn = {1950-6007}, mesh = {*Ferroptosis/drug effects/physiology ; Humans ; *Neurodegenerative Diseases/drug therapy/immunology/metabolism/pathology ; Animals ; Neuroimmunomodulation ; }, abstract = {Neuroimmune and neurodegenerative ailments impose a substantial societal burden. Neuroimmune disorders involve the intricate regulatory interactions between the immune system and the central nervous system. Prominent examples of neuroimmune disorders encompass multiple sclerosis and neuromyelitis optica. Neurodegenerative diseases result from neuronal degeneration or demyelination in the brain or spinal cord, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The precise underlying pathogenesis of these conditions remains incompletely understood. Ferroptosis, a programmed form of cell death characterised by lipid peroxidation and iron overload, plays a pivotal role in neuroimmune and neurodegenerative diseases. In this review, we provide a detailed overview of ferroptosis, its mechanisms, pathways, and regulation during the progression of neuroimmune and neurodegenerative diseases. Furthermore, we summarise the impact of ferroptosis on neuroimmune-related cells (T cells, B cells, neutrophils, and macrophages) and neural cells (glial cells and neurons). Finally, we explore the potential therapeutic implications of ferroptosis inhibitors in diverse neuroimmune and neurodegenerative diseases.}, } @article {pmid38795036, year = {2024}, author = {Chen, X and Cao, Z and Wang, Y}, title = {Amyotrophic Lateral Sclerosis-Associated Mutants of SOD1 Perturb mRNA Splicing through Aberrant Interactions with SRSF2.}, journal = {Analytical chemistry}, volume = {96}, number = {23}, pages = {9713-9720}, pmid = {38795036}, issn = {1520-6882}, support = {R35 ES031707/ES/NIEHS NIH HHS/United States ; }, mesh = {*Serine-Arginine Splicing Factors/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; *RNA Splicing ; *Mutation ; RNA, Messenger/genetics/metabolism ; HEK293 Cells ; Biotinylation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that results in the degeneration of neurons in the brain and spinal cord. Although a substantial number of studies have been conducted, much remains to be learned about the cellular mechanisms underlying ALS. In this study, we employed an engineered ascorbate peroxidase (APEX)-based proximity biotinylation, together with affinity pull-down of the ensuing biotinylated peptides, to investigate the proximity proteomes of human SOD1 and its two ALS-linked mutants, G85R and G93A. We were able to identify 25 common biotinylated peptides with preferential enrichment in the proximity proteomes of SOD1[G85R] and SOD1[G93A] over wild-type SOD1. Our coimmunoprecipitation followed by Western blot analyses revealed that one of these proteins, SRSF2, binds more strongly with the two SOD1 mutants than its wild-type counterpart. We also observed aberrant splicing of mRNAs in cells with ectopic expression of the two SOD1 mutants relative to cells expressing the wild-type protein. In addition, the aberrations in splicing elicited by the SOD1 variants were markedly attenuated upon knockdown of SRSF2. Collectively, we uncovered that ALS-liked SOD1[G85R] and SOD1[G93A] mutants interact more strongly with SRSF2, where the aberrant interactions perturbed mRNA splicing. Thus, our work offered novel mechanistic insights into the contributions of the ALS-linked SOD1 mutants to disease etiology.}, } @article {pmid38791160, year = {2024}, author = {Bocheva, G and Bakalov, D and Iliev, P and Tafradjiiska-Hadjiolova, R}, title = {The Vital Role of Melatonin and Its Metabolites in the Neuroprotection and Retardation of Brain Aging.}, journal = {International journal of molecular sciences}, volume = {25}, number = {10}, pages = {}, pmid = {38791160}, issn = {1422-0067}, mesh = {*Melatonin/metabolism/pharmacology/therapeutic use ; Humans ; *Brain/metabolism/drug effects ; *Aging/metabolism/drug effects ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Neuroprotection/drug effects ; *Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Kynuramine/metabolism/analogs & derivatives ; }, abstract = {While primarily produced in the pineal gland, melatonin's influence goes beyond its well-known role in regulating sleep, nighttime metabolism, and circadian rhythms, in the field of chronobiology. A plethora of new data demonstrates melatonin to be a very powerful molecule, being a potent ROS/RNS scavenger with anti-inflammatory, immunoregulatory, and oncostatic properties. Melatonin and its metabolites exert multiple beneficial effects in cutaneous and systemic aging. This review is focused on the neuroprotective role of melatonin during aging. Melatonin has an anti-aging capacity, retarding the rate of healthy brain aging and the development of age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. Melatonin, as well as its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), can reduce oxidative brain damage by shielding mitochondria from dysfunction during the aging process. Melatonin could also be implicated in the treatment of neurodegenerative conditions, by modifying their characteristic low-grade neuroinflammation. It can either prevent the initiation of inflammatory responses or attenuate the ongoing inflammation. Drawing on the current knowledge, this review discusses the potential benefits of melatonin supplementation in preventing and managing cognitive impairment and neurodegenerative diseases.}, } @article {pmid38791099, year = {2024}, author = {Moțățăianu, A and Mănescu, IB and Șerban, G and Bărcuțean, L and Ion, V and Bălașa, R and Andone, S}, title = {Exploring the Role of Metabolic Hormones in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {10}, pages = {}, pmid = {38791099}, issn = {1422-0067}, support = {PN-III-P1-1.1-TE-2021-0960//Ministry of Research, Innovation and Digitization, CNCS - UEFISCDI, Romania/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/blood ; Male ; Female ; Middle Aged ; Aged ; *Islet Amyloid Polypeptide/metabolism/blood ; Cross-Sectional Studies ; *Biomarkers/blood ; *Insulin/metabolism/blood ; Disease Progression ; Leptin/blood/metabolism ; Glucagon-Like Peptide 1/metabolism/blood ; C-Peptide/blood/metabolism ; Ghrelin/metabolism/blood ; Glucagon/blood/metabolism ; Adult ; Hormones/metabolism/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of motor neurons. Emerging evidence suggests a potential link between metabolic dysregulation and ALS pathogenesis. This study aimed to investigate the relationship between metabolic hormones and disease progression in ALS patients. A cross-sectional study was conducted involving 44 ALS patients recruited from a tertiary care center. Serum levels of insulin, total amylin, C-peptide, active ghrelin, GIP (gastric inhibitory peptide), GLP-1 active (glucagon-like peptide-1), glucagon, PYY (peptide YY), PP (pancreatic polypeptide), leptin, interleukin-6, MCP-1 (monocyte chemoattractant protein-1), and TNFα (tumor necrosis factor alpha) were measured, and correlations with ALSFRS-R, evolution scores, and biomarkers were analyzed using Spearman correlation coefficients. Subgroup analyses based on ALS subtypes, progression pattern of disease, and disease progression rate patterns were performed. Significant correlations were observed between metabolic hormones and ALS evolution scores. Insulin and amylin exhibited strong correlations with disease progression and clinical functional outcomes, with insulin showing particularly robust associations. Other hormones such as C-peptide, leptin, and GLP-1 also showed correlations with ALS progression and functional status. Subgroup analyses revealed differences in hormone levels based on sex and disease evolution patterns, with male patients showing higher amylin and glucagon levels. ALS patients with slower disease progression exhibited elevated levels of amylin and insulin. Our findings suggest a potential role for metabolic hormones in modulating ALS progression and functional outcomes. Further research is needed to elucidate the underlying mechanisms and explore the therapeutic implications of targeting metabolic pathways in ALS management.}, } @article {pmid38790984, year = {2024}, author = {Zhdanov, DD and Gladilina, YA and Blinova, VG and Abramova, AA and Shishparenok, AN and Eliseeva, DD}, title = {Induction of FoxP3 Pre-mRNA Alternative Splicing to Enhance the Suppressive Activity of Regulatory T Cells from Amyotrophic Lateral Sclerosis Patients.}, journal = {Biomedicines}, volume = {12}, number = {5}, pages = {}, pmid = {38790984}, issn = {2227-9059}, support = {23-24-00326//Russian Science Foundation/ ; }, abstract = {Forkhead box protein 3 (FoxP3) is a key transcription factor responsible for the development, maturation, and function of regulatory T cells (Tregs). The FoxP3 pre-mRNA is subject to alternative splicing, resulting in the translation of multiple splice variants. We have shown that Tregs from patients with amyotrophic lateral sclerosis (ALS) have reduced expression of full-length (FL) FoxP3, while other truncated splice variants are expressed predominantly. A correlation was observed between the reduced number of Tregs in the peripheral blood of ALS patients, reduced total FoxP3 mRNA, and reduced mRNA of its FL splice variant. Induction of FL FoxP3 was achieved using splice-switching oligonucleotides capable of base pairing with FoxP3 pre-mRNA and selectively modulating the inclusion of exons 2 and 7 in the mature mRNA. Selective expression of FL FoxP3 resulted in the induction of CD127[low], CD152, and Helios-positive cells, while the cell markers CD4 and CD25 were not altered. Such Tregs had an increased proliferative activity and a higher frequency of cell divisions per day. The increased suppressive activity of Tregs with the induced FL FoxP3 splice variant was associated with the increased synthesis of the pro-apoptotic granzymes A and B, and perforin, IL-10, and IL-35, which are responsible for contact-independent suppression, and with the increased ability to suppress telomerase in target cells. The upregulation of Treg suppressive and proliferative activity using splice-switching oligonucleotides to induce the predominant expression of the FoxP3 FL variant is a promising approach for regenerative cell therapy in Treg-associated diseases.}, } @article {pmid38790979, year = {2024}, author = {Mishra, PS and Phaneuf, D and Boutej, H and Picher-Martel, V and Dupre, N and Kriz, J and Julien, JP}, title = {Inhibition of NF-κB with an Analog of Withaferin-A Restores TDP-43 Homeostasis and Proteome Profiles in a Model of Sporadic ALS.}, journal = {Biomedicines}, volume = {12}, number = {5}, pages = {}, pmid = {38790979}, issn = {2227-9059}, support = {143275/CAPMC/CIHR/Canada ; 231575//Canada Research Chairs/ ; }, abstract = {The current knowledge on pathogenic mechanisms in amyotrophic lateral sclerosis (ALS) has widely been derived from studies with cell and animal models bearing ALS-linked genetic mutations. However, it remains unclear to what extent these disease models are of relevance to sporadic ALS. Few years ago, we reported that the cerebrospinal fluid (CSF) from sporadic ALS patients contains toxic factors for disease transmission in mice via chronic intracerebroventricular (i.c.v.) infusion. Thus a 14-day i.c.v. infusion of pooled CSF samples from ALS cases in mice provoked motor impairment as well as ALS-like pathological features. This offers a unique paradigm to test therapeutics in the context of sporadic ALS disease. Here, we tested a new Withaferin-A analog (IMS-088) inhibitor of NF-κB that was found recently to mitigate disease phenotypes in mouse models of familial disease expressing TDP-43 mutant. Our results show that oral intake of IMS-088 ameliorated motor performance of mice infused with ALS-CSF and it alleviated pathological changes including TDP-43 proteinopathy, neurofilament disorganization, and neuroinflammation. Moreover, CSF infusion experiments were carried out with transgenic mice having neuronal expression of tagged ribosomal protein (hNfL-RFP mice), which allowed immunoprecipitation of neuronal ribosomes for analysis by mass spectrometry of the translational peptide signatures. The results indicate that treatment with IMS-088 prevented many proteomic alterations associated with exposure to ALS-CSF involving pathways related to cytoskeletal changes, inflammation, metabolic dysfunction, mitochondria, UPS, and autophagy dysfunction. The effective disease-modifying effects of this drug in a mouse model based on i.c.v. infusion of ALS-CSF suggest that the NF-κB signaling pathway represents a compelling therapeutic target for sporadic ALS.}, } @article {pmid38790450, year = {2024}, author = {Eisen, A and Pioro, EP and Goutman, SA and Kiernan, MC}, title = {Nanoplastics and Neurodegeneration in ALS.}, journal = {Brain sciences}, volume = {14}, number = {5}, pages = {}, pmid = {38790450}, issn = {2076-3425}, support = {R01 TS000327/TS/ATSDR CDC HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; }, abstract = {Plastic production, which exceeds one million tons per year, is of global concern. The constituent low-density polymers enable spread over large distances and micro/nano particles (MNPLs) induce organ toxicity via digestion, inhalation, and skin contact. Particles have been documented in all human tissues including breast milk. MNPLs, especially weathered particles, can breach the blood-brain barrier, inducing neurotoxicity. This has been documented in non-human species, and in human-induced pluripotent stem cell lines. Within the brain, MNPLs initiate an inflammatory response with pro-inflammatory cytokine production, oxidative stress with generation of reactive oxygen species, and mitochondrial dysfunction. Glutamate and GABA neurotransmitter dysfunction also ensues with alteration of excitatory/inhibitory balance in favor of reduced inhibition and resultant neuro-excitation. Inflammation and cortical hyperexcitability are key abnormalities involved in the pathogenic cascade of amyotrophic lateral sclerosis (ALS) and are intricately related to the mislocalization and aggregation of TDP-43, a hallmark of ALS. Water and many foods contain MNPLs and in humans, ingestion is the main form of exposure. Digestion of plastics within the gut can alter their properties, rendering them more toxic, and they cause gut microbiome dysbiosis and a dysfunctional gut-brain axis. This is recognized as a trigger and/or aggravating factor for ALS. ALS is associated with a long (years or decades) preclinical period and neonates and infants are exposed to MNPLs through breast milk, milk substitutes, and toys. This endangers a time of intense neurogenesis and establishment of neuronal circuitry, setting the stage for development of neurodegeneration in later life. MNPL neurotoxicity should be considered as a yet unrecognized risk factor for ALS and related diseases.}, } @article {pmid38788983, year = {2024}, author = {de Holanda Paranhos, L and Magalhães, RSS and de Araújo Brasil, A and Neto, JRM and Ribeiro, GD and Queiroz, DD and Dos Santos, VM and Eleutherio, ECA}, title = {The familial amyotrophic lateral sclerosis-associated A4V SOD1 mutant is not able to regulate aerobic glycolysis.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {1868}, number = {8}, pages = {130634}, doi = {10.1016/j.bbagen.2024.130634}, pmid = {38788983}, issn = {1872-8006}, mesh = {*Glycolysis ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Superoxide Dismutase-1/genetics/metabolism ; *Saccharomyces cerevisiae/genetics/metabolism ; Glucose/metabolism ; Mutation ; }, abstract = {Under certain stress conditions, astrocytes operate in aerobic glycolysis, a process controlled by pyruvate dehydrogenase (PDH) inhibition through its E1 α subunit (Pda1) phosphorylation. This supplies lactate to neurons, which save glucose to obtain NADPH to, among other roles, counteract reactive oxygen species. A failure in this metabolic cooperation causes severe damage to neurons. In this work, using humanized Saccharomyces cerevisiae cells in which its endogenous Cu/Zn Superoxide Dismutase (SOD1) was replaced by human ortholog, we investigated the role of human SOD1 (hSOD1) in aerobic glycolysis regulation and its implications to amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. Yeast cells ferment glucose even in the presence of oxygen and switch to respiratory metabolism after glucose exhaustion. However, like cells of SOD1-knockout strain, cells expressing A4V mutant of hSOD1 growing on glucose showed a respiratory phenotype, i.e., low glucose and high oxygen consumptions and low intracellular oxidation levels in response to peroxide stress, contrary to cells expressing wild-type (WT) SOD1 (yeast or human). The A4V mutation in hSOD1 is linked to ALS. In contrast to WT SOD1 strains, PDH activity of both sod1Δ and A4V hSOD1 cells did not change in response to a metabolic shift toward oxidative metabolism, which was associated to lower Pda1 phosphorylation levels under growth on glucose. Taken together, our results suggest that A4V mutant cannot regulate aerobic glycolysis via Pda1 phosphorylation the same way WT hSOD1, which might be linked to problems observed in the motor neurons of ALS patients with the SOD1 A4V mutation.}, } @article {pmid38788796, year = {2024}, author = {Togawa, N and Ayaki, T and Yoshii, D and Maki, T and Sawamoto, N and Takahashi, R}, title = {TMEM119-positive microglia were increased in the brains of patients with amyotrophic lateral sclerosis.}, journal = {Neuroscience letters}, volume = {833}, number = {}, pages = {137829}, doi = {10.1016/j.neulet.2024.137829}, pmid = {38788796}, issn = {1872-7972}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Microglia/metabolism/pathology ; Male ; Female ; Aged ; Middle Aged ; *Membrane Proteins/metabolism ; *Brain/pathology/metabolism ; Macrophages/metabolism/pathology ; Receptors, CCR2/metabolism ; White Matter/pathology/metabolism ; Spinal Cord/metabolism/pathology ; Aged, 80 and over ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that has been reported to be affected by inflammatory cells, such as microglia and macrophages, through the concept of non-cell autonomous neuronal death. Resident microglia in the human brain and monocyte-derived macrophages (MoDM) infiltrating in tissues are difficult to distinguish. Therefore, the effects of microglia and MoDMs in ALS remain poorly understood. This study aimed to investigate the role of resident microglia and MoDMs in the pathogenesis of ALS using postmortem brain and spinal cord samples. The samples used for immunohistochemical analysis included 11 cases of sporadic ALS and 11 age-matched controls. We stained the cells with TMEM119 to detect resident microglia and CCR2 to detect MoDMs. In ALS cases, TMEM119-immunopositive resident microglia were abundant in the motor cortex and subcortical white matter (SWM) of the motor area, whereas CCR2-immunopositive MoDM was similar to control cases. In addition, the mean density of CD68-immunopositive cells in the SWM significantly correlated with the mean density of pTDP-43-positive GCIs. These results suggest that resident microglial activation plays an important role in the cerebral pathogenesis of ALS and may provide novel therapeutic strategies to target excessive activation of resident microglia in ALS.}, } @article {pmid38788509, year = {2024}, author = {Valeriano, MC and Neto, AM and Batista, ACF and Mamián-López, MB}, title = {Raman spectra soft modeling of the biodiesel oxidation through evolving factor analysis & multivariate curve resolution.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {318}, number = {}, pages = {124498}, doi = {10.1016/j.saa.2024.124498}, pmid = {38788509}, issn = {1873-3557}, abstract = {The oxidative stability of biodiesel is defined by its relative resistance to the action of oxygen at room temperature. Its determination is an essential reference to the quality of biofuel and a significant parameter to be determined. This parameter concerns the quality of the biodiesel to be supplied to the consumer, and its determination is fundamental to maintaining the engine's proper functioning. Raman spectroscopy allows the rapid obtaining of structural information regarding biodiesel quality and, when aided by multivariate analysis methods, allows a quantitative determination of specific properties. This work uses Raman spectroscopy, Multivariate Curve Resolution with Alternative Least Squares (MCR-ALS) method, and Evolving Factor Analysis (EFA) to study biodiesel's oxidation kinetics. Also, the vibrational modes C = C, CH2, and CH3 were identified as the main structural groups involved in this process, corroborating previous studies. The MCR-ALS & EFA combination allowed modeling of the degradation kinetics following an A → B → C mechanism, where A corresponds to the biodiesel (starting material), B is related to the hydroperoxide mixture, and C is the final product. The results also suggested that this process follows a first-order reaction, with kinetic constant values of k1 = 0.0056 min[-1] and k2 = 0.0031 min[-1].}, } @article {pmid38788288, year = {2024}, author = {van Neerven, GJL and Schelling, WJ and van den Borne, K and Bijleveld, K and Baars, A and Flink, H and Gilissen, LPL}, title = {The periprocedural respiratory safety of propofol sedation in patients with a motor neuron disease undergoing percutaneous endoscopic gastrostomy insertion.}, journal = {Journal of the neurological sciences}, volume = {461}, number = {}, pages = {123049}, doi = {10.1016/j.jns.2024.123049}, pmid = {38788288}, issn = {1878-5883}, mesh = {Humans ; Male ; Female ; Aged ; *Gastrostomy/adverse effects/methods ; *Propofol/adverse effects/administration & dosage/therapeutic use ; Retrospective Studies ; *Motor Neuron Disease ; Middle Aged ; *Hypnotics and Sedatives/adverse effects ; Pneumonia, Aspiration/etiology ; Aged, 80 and over ; Enteral Nutrition/methods/adverse effects ; }, abstract = {Motor neuron diseases (MND), such as Amyotrophic Lateral Sclerosis (ALS) and Primary Lateral Sclerosis (PLS), may cause swallowing and respiratory problems, due to muscle weakness. Chronic enteral feeding via percutaneous endoscopic gastrostomy (PEG) is often indicated in these patients. PEG insertion is normally performed with sedation. Some guidelines withhold sedation in MND patients, due to the risk of respiratory complications. These guidelines seem to be defensive however and evidence is lacking. Our aim was to examine periprocedural respiratory complications occurring in MND patients undergoing PEG insertion with propofol sedation. A retrospective monocentre study was conducted in a referral hospital with an experienced PEG team. Patients with MND who underwent PEG insertion with propofol sedation between January 1. 2016 to January 1. 2023 were analysed to identify periprocedural respiratory complications. 46 patients were included. In five patients (10.9%) respiratory adverse events (AE) occurred, of which two serious (4.3%) and four AE (8.7%). Serious AE (SAE) were fatal in both cases: aspiration pneumonia (2.2%) and hypercapnia (2.2%) a few days after insertion. Sedation may have influenced the first case. Respiratory AE consisted of desaturation in two (4.3%), mild aspiration pneumonia in one (2.2%), and apnea in one patient (2.2%). Compared to previous studies respiratory complications and mortality had comparable prevalences.}, } @article {pmid38788085, year = {2024}, author = {Mohassel, P and Abdullah, M and Eichler, FS and Dunn, TM}, title = {Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders.}, journal = {Journal of neuromuscular diseases}, volume = {11}, number = {4}, pages = {735-747}, pmid = {38788085}, issn = {2214-3602}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Hereditary Sensory and Autonomic Neuropathies/genetics/metabolism/physiopathology ; *Neurodegenerative Diseases/metabolism ; *Neurodevelopmental Disorders ; *Serine C-Palmitoyltransferase/metabolism/genetics ; Spastic Paraplegia, Hereditary/genetics/metabolism ; Sphingolipids/metabolism ; }, abstract = {Motor neuron diseases and peripheral neuropathies are heterogeneous groups of neurodegenerative disorders that manifest with distinct symptoms due to progressive dysfunction or loss of specific neuronal subpopulations during different stages of development. A few monogenic, neurodegenerative diseases associated with primary metabolic disruptions of sphingolipid biosynthesis have been recently discovered. Sphingolipids are a subclass of lipids that form critical building blocks of all cellular and subcellular organelle membranes including the membrane components of the nervous system cells. They are especially abundant within the lipid portion of myelin. In this review, we will focus on our current understanding of disease phenotypes in three monogenic, neuromuscular diseases associated with pathogenic variants in components of serine palmitoyltransferase, the first step in sphingolipid biosynthesis. These include hereditary sensory and autonomic neuropathy type 1 (HSAN1), a sensory predominant peripheral neuropathy, and two neurodegenerative disorders: juvenile amyotrophic lateral sclerosis affecting the upper and lower motor neurons with sparing of sensory neurons, and a complicated form of hereditary spastic paraplegia with selective involvement of the upper motor neurons and more broad CNS neurodegeneration. We will also review our current understanding of disease pathomechanisms, therapeutic approaches, and the unanswered questions to explore in future studies.}, } @article {pmid38787599, year = {2024}, author = {Wong, JPH and Blazev, R and Ng, YK and Goodman, CA and Montgomery, MK and Watt, KI and Carl, CS and Watt, MJ and Voldstedlund, CT and Richter, EA and Crouch, PJ and Steyn, FJ and Ngo, ST and Parker, BL}, title = {Characterization of the skeletal muscle arginine methylome in health and disease reveals remodeling in amyotrophic lateral sclerosis.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {38}, number = {10}, pages = {e23647}, doi = {10.1096/fj.202400045R}, pmid = {38787599}, issn = {1530-6860}, support = {APP2009642//DHAC | National Health and Medical Research Council (NHMRC)/ ; 1185427//DHAC | National Health and Medical Research Council (NHMRC)/ ; //University of Melbourne Driving Research Momentum/ ; //Motor Neurone Disease Research Australia Charcot/ ; //Department of Anatomy and Physiology (The University of Melbourne) ECR Seeding Grant/ ; }, mesh = {*Muscle, Skeletal/metabolism/pathology ; *Arginine/metabolism/analogs & derivatives ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; Mice ; *Protein-Arginine N-Methyltransferases/metabolism/genetics ; Male ; Methylation ; Female ; Protein Processing, Post-Translational ; Mice, Inbred C57BL ; Proteome/metabolism ; }, abstract = {Arginine methylation is a protein posttranslational modification important for the development of skeletal muscle mass and function. Despite this, our understanding of the regulation of arginine methylation under settings of health and disease remains largely undefined. Here, we investigated the regulation of arginine methylation in skeletal muscles in response to exercise and hypertrophic growth, and in diseases involving metabolic dysfunction and atrophy. We report a limited regulation of arginine methylation under physiological settings that promote muscle health, such as during growth and acute exercise, nor in disease models of insulin resistance. In contrast, we saw a significant remodeling of asymmetric dimethylation in models of atrophy characterized by the loss of innervation, including in muscle biopsies from patients with myotrophic lateral sclerosis (ALS). Mass spectrometry-based quantification of the proteome and asymmetric arginine dimethylome of skeletal muscle from individuals with ALS revealed the largest compendium of protein changes with the identification of 793 regulated proteins, and novel site-specific changes in asymmetric dimethyl arginine (aDMA) of key sarcomeric and cytoskeletal proteins. Finally, we show that in vivo overexpression of PRMT1 and aDMA resulted in increased fatigue resistance and functional recovery in mice. Our study provides evidence for asymmetric dimethylation as a regulator of muscle pathophysiology and presents a valuable proteomics resource and rationale for numerous methylated and nonmethylated proteins, including PRMT1, to be pursued for therapeutic development in ALS.}, } @article {pmid38786016, year = {2024}, author = {Salzinger, A and Ramesh, V and Das Sharma, S and Chandran, S and Thangaraj Selvaraj, B}, title = {Neuronal Circuit Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {10}, pages = {}, pmid = {38786016}, issn = {2073-4409}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Humans ; *Motor Neurons/pathology/physiology ; Animals ; Nerve Net/physiopathology/pathology ; Neuromuscular Junction/physiopathology/pathology ; Disease Models, Animal ; Motor Cortex/physiopathology/pathology ; }, abstract = {The primary neural circuit affected in Amyotrophic Lateral Sclerosis (ALS) patients is the corticospinal motor circuit, originating in upper motor neurons (UMNs) in the cerebral motor cortex which descend to synapse with the lower motor neurons (LMNs) in the spinal cord to ultimately innervate the skeletal muscle. Perturbation of these neural circuits and consequent loss of both UMNs and LMNs, leading to muscle wastage and impaired movement, is the key pathophysiology observed. Despite decades of research, we are still lacking in ALS disease-modifying treatments. In this review, we document the current research from patient studies, rodent models, and human stem cell models in understanding the mechanisms of corticomotor circuit dysfunction and its implication in ALS. We summarize the current knowledge about cortical UMN dysfunction and degeneration, altered excitability in LMNs, neuromuscular junction degeneration, and the non-cell autonomous role of glial cells in motor circuit dysfunction in relation to ALS. We further highlight the advances in human stem cell technology to model the complex neural circuitry and how these can aid in future studies to better understand the mechanisms of neural circuit dysfunction underpinning ALS.}, } @article {pmid38785754, year = {2024}, author = {Alkhazaali-Ali, Z and Sahab-Negah, S and Boroumand, AR and Farkhad, NK and Khodadoust, MA and Tavakol-Afshari, J}, title = {Evaluation of the Safety and Efficacy of Repeated Mesenchymal Stem Cell Transplantations in ALS Patients by Investigating Patients' Specific Immunological and Biochemical Biomarkers.}, journal = {Diseases (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {38785754}, issn = {2079-9721}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable disease. There are vigorous attempts to develop treatments to reduce the effects of this disease, and among these treatments is the transplantation of stem cells. This study aimed to retrospectively evaluate a mesenchymal stem cell (MSC) therapy cohort as a promising novel treatment modality by estimating some additional new parameters, such as immunological and biochemical factors.

METHODS: This study was designed as an open-label, one-arm cohort retrospective study to evaluate potential diagnostic biomarkers of repeated infusions of autologous-bone marrow-derived mesenchymal stem cells (BM-MSCs) in 15 confirmed patients with ALS, administered at a dose of 1 × 106 cells/kg BW with a one-month interval, in equal amounts in both an intravenous (IV) and intrathecal (IT) capacity simultaneously, via various biochemical (iron (Fe), ferritin, total-iron-binding capacity (TIBC), transferrin, and creatine kinase (CK)) and immunological parameters (tumor necrosis factor-alpha (TNF-α), neurofilament light chain (NFL), and glial-cell-derived neurotrophic factor (GDNF) levels, evaluated during the three-month follow-up period in serum and cerebrospinal fluid (CSF).

RESULTS: Our study indicated that, in the case of immunological biomarkers, TNF-α levels in the CSF showed a significant decrease at month three after transplantation compared with levels at month zero, and the p-value was p < 0.01. No statistically significant changes were observed for other immunological as well as biochemical parameters and a p-value of p > 0.05.

CONCLUSIONS: These results can indicate the potential benefit of stem cell transfusion in patients with ALS and suggest some diagnostic biomarkers. Several studies are required to approve these results.}, } @article {pmid38785539, year = {2024}, author = {Pribac, M and Motataianu, A and Andone, S and Mardale, E and Nemeth, S}, title = {Bridging the Gap: Harnessing Plant Bioactive Molecules to Target Gut Microbiome Dysfunctions in Amyotrophic Lateral Sclerosis.}, journal = {Current issues in molecular biology}, volume = {46}, number = {5}, pages = {4471-4488}, pmid = {38785539}, issn = {1467-3045}, abstract = {The correlation between neurodegenerative diseases and the gut microbiome is increasingly evident, with amyotrophic lateral sclerosis (ALS) being particularly notable for its severity and lack of therapeutic options. The gut microbiota, implicated in the pathogenesis and development of ALS, plays a crucial role in the disease. Bioactive plant molecules, specifically volatile compounds in essential oils, offer a promising therapeutic avenue due to their anti-inflammatory properties and gut-modulating effects. Our narrative review aimed to identify microbiota-associated bacteria in ALS and analyze the benefits of administering bioactive plant molecules as much-needed therapeutic options in the management of this disease. A comprehensive search of PubMed database articles published before December 2023, encompassing research on cell, human, and animal ALS models, was conducted. After selecting, analyzing, and discussing key articles, bacteria linked to ALS pathogenesis and physiopathology were identified. Notably, positively highlighted bacteria included Akkermansia muciniphila (Verrucomicrobia phylum), Faecalibacterium prausnitzii, and Butyrivibrio spp. (Firmicutes phylum). Conversely, members of the Escherichia coli spp. (Proteobacteria phylum) and Ruminococcus spp. (Firmicutes phylum) stood out negatively in respect to ALS development. These bacteria were associated with molecular changes linked to ALS pathogenesis and evolution. Bioactive plant molecules can be directly associated with improvements in the microbiome, due to their role in reducing inflammation and oxidative stress, emerging as one of the most promising natural agents for enriching present-day ALS treatments.}, } @article {pmid38785530, year = {2024}, author = {Serrano, PL and Rodrigues, TPV and Pinto, LD and Pereira, IC and Farias, IB and Cavalheiro, RBR and Mendes, PM and Peixoto, KO and Barile, JP and Seneor, DD and Correa Silva, EG and Oliveira, ASB and Pinto, WBVR and Sgobbi, P}, title = {Assessing Chitinases and Neurofilament Light Chain as Biomarkers for Adult-Onset Leukodystrophies.}, journal = {Current issues in molecular biology}, volume = {46}, number = {5}, pages = {4309-4323}, pmid = {38785530}, issn = {1467-3045}, abstract = {Leukodystrophies represent a large and complex group of inherited disorders affecting the white matter of the central nervous system. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare leukodystrophy which still needs the proper identification of diagnostic, prognostic, and monitoring biomarkers. The aim of this study was to determine the diagnostic and prognostic value of chitinases and neurofilament light chain as biomarkers for ALSP. A cross-sectional study was performed to analyze cerebrospinal fluid levels of chitinases (chitotriosidase and chitinase 3-like 2) and neurofilament light chain in five different groups: (i) normal health individuals; (ii) patients with definitive diagnosis of ALSP and genetic confirmation; (iii) asymptomatic patients with CSF1R variants; (iv) patients with other adult-onset leukodystrophies; and (v) patients with amyotrophic lateral sclerosis (external control group). Chitinase levels showed a statistical correlation with clinical assessment parameters in ALSP patients. Chitinase levels were also distinct between ALSP and the other leukodystrophies. Significant differences were noted in the levels of chitinases and neurofilament light chain comparing symptomatic (ALSP) and asymptomatic individuals with CSF1R variants. This study is the first to establish chitinases as a potential biomarker for ALSP and confirms neurofilament light chain as a good biomarker for primary microgliopathies.}, } @article {pmid38784406, year = {2024}, author = {Keselica, M and Peřan, D and Renza, M and Duška, F and Omáčka, D and Schnaubelt, S and Lulic, I and Sýkora, R}, title = {Efficiency of two-member crews in delivering prehospital advanced life support cardiopulmonary resuscitation: A scoping review.}, journal = {Resuscitation plus}, volume = {18}, number = {}, pages = {100661}, pmid = {38784406}, issn = {2666-5204}, abstract = {BACKGROUND: Advanced Life Support (ALS) during cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrest (OHCA) is frequently administered by two-member crews. However, ALS CPR is mostly designed for larger crews, and the feasibility and efficacy of implementing ALS guidelines for only two rescuers remain unclear.

OBJECTIVE: This scoping review aims to examine the existing evidence and identify knowledge gaps in the efficiency of pre-hospital ALS CPR performed by two-member teams.

DESIGN: A comprehensive search was undertaken across the following databases: PubMed, Web of Science, SCOPUS, Cochrane Library Trials, and ClinicalTrials.gov. The search covered publications in English or German from January 1, 2005, to November 30, 2023. The review included studies that focused on ALS CPR procedures carried out by two-member teams in adult patients in either simulated or clinical settings.

RESULTS: A total of 22 articles were included in the qualitative synthesis. Seven topics in two-person prehospital ALS/CPR delivery were identified: 1) effect of team configuration on clinical outcome and CPR quality, 2) early airway management and ventilation techniques, 3) mechanical chest compressions, 4) prefilled syringes, 5) additional equipment, 6) adaptation of recommended ALS/CPR protocols, and 7) human factors.

CONCLUSION: There is a lack of comprehensive data regarding the adaptation of the recommended ALS algorithm in CPR for two-member crews. Although simulation studies indicate potential benefits arising from the employment of mechanical chest compression devices, prefilled syringes, and automation-assisted protocols, the current evidence is too limited to support specific modifications to existing guidelines.}, } @article {pmid38784093, year = {2024}, author = {Chen, W and Liu, X and Wan, P and Chen, Z and Chen, Y}, title = {Anti-artifacts techniques for neural recording front-ends in closed-loop brain-machine interface ICs.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1393206}, pmid = {38784093}, issn = {1662-4548}, abstract = {In recent years, thanks to the development of integrated circuits, clinical medicine has witnessed significant advancements, enabling more efficient and intelligent treatment approaches. Particularly in the field of neuromedical, the utilization of brain-machine interfaces (BMI) has revolutionized the treatment of neurological diseases such as amyotrophic lateral sclerosis, cerebral palsy, stroke, or spinal cord injury. The BMI acquires neural signals via recording circuits and analyze them to regulate neural stimulator circuits for effective neurological treatment. However, traditional BMI designs, which are often isolated, have given way to closed-loop brain-machine interfaces (CL-BMI) as a contemporary development trend. CL-BMI offers increased integration and accelerated response speed, marking a significant leap forward in neuromedicine. Nonetheless, this advancement comes with its challenges, notably the stimulation artifacts (SA) problem inherent to the structural characteristics of CL-BMI, which poses significant challenges on the neural recording front-ends (NRFE) site. This paper aims to provide a comprehensive overview of technologies addressing artifacts in the NRFE site within CL-BMI. Topics covered will include: (1) understanding and assessing artifacts; (2) exploring the impact of artifacts on traditional neural recording front-ends; (3) reviewing recent technological advancements aimed at addressing artifact-related issues; (4) summarizing and classifying the aforementioned technologies, along with an analysis of future trends.}, } @article {pmid38782644, year = {2025}, author = {Corcia, P and Couratier, P and Ingre, C}, title = {Could PLS represent a UMN-predominant ALS syndrome?.}, journal = {Revue neurologique}, volume = {181}, number = {1-2}, pages = {52-57}, doi = {10.1016/j.neurol.2024.04.006}, pmid = {38782644}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/pathology/complications ; *Motor Neurons/physiology/pathology ; *Motor Neuron Disease/diagnosis ; Diagnosis, Differential ; Syndrome ; }, abstract = {Primary lateral sclerosis (PLS) is a motor neuron condition marked by pure upper motor neuron (UMN) degeneration. PLS represents around 3% of all motor neuron diseases. Classically the prognosis of PLS is less severe than those of amyotrophic lateral sclerosis (ALS). This explains the necessity to distinguish both conditions as early as possible. The key hallmark between the two diseases is the involvement of the lower motor neuron (LMN) system which is classically considered spared in PLS contrary to ALS. Although it seemed clinically easy to distinguish PLS from ALS with the aid of clinical and complementary examinations, there is a large body of evidence highlighting that the LMN system might be impaired in PLS. This led us to suggest that PLS might be considered as an almost pure UMN ALS phenotype.}, } @article {pmid38782052, year = {2024}, author = {Bass, J and Hill, H and Jaworsky, C}, title = {Response to Green et al in reply to Bass et al's "Significant discordance in DermTech test results when paired with histopathology: Caveat emptor".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {3}, pages = {e81}, doi = {10.1016/j.jaad.2024.05.038}, pmid = {38782052}, issn = {1097-6787}, mesh = {Humans ; *Dermoscopy ; Skin Neoplasms/pathology ; }, } @article {pmid38782041, year = {2024}, author = {Hogan, DB and Maxwell, CJ and Dampf, H and McGrail, K and Estabrooks, CA and Poss, JW and Bakal, JA and Hoben, M}, title = {Excess Deaths in Assisted Living and Nursing Homes during the COVID-19 Pandemic in Alberta, Canada.}, journal = {Journal of the American Medical Directors Association}, volume = {25}, number = {7}, pages = {105032}, doi = {10.1016/j.jamda.2024.105032}, pmid = {38782041}, issn = {1538-9375}, mesh = {Humans ; *COVID-19/mortality/epidemiology ; *Nursing Homes ; Alberta/epidemiology ; *Assisted Living Facilities ; Male ; Female ; Aged ; Retrospective Studies ; Aged, 80 and over ; SARS-CoV-2 ; Pandemics ; Dementia/mortality/epidemiology ; Homes for the Aged/statistics & numerical data ; Cognitive Dysfunction/mortality/epidemiology ; Mortality/trends ; }, abstract = {OBJECTIVES: Assisted living (AL) is a significant and growing congregate care option for vulnerable older adults designed to reduce the use of nursing homes (NHs). However, work on excess mortality in congregate care during the COVID-19 pandemic has primarily focused on NHs with only a few US studies examining AL. The objective of this study was to assess excess mortality among AL and NH residents with and without dementia or significant cognitive impairment in Alberta, Canada, during the first 2 years of the COVID-19 pandemic, relative to the 3 years before.

DESIGN: Population-based, retrospective cohort study.

SETTING AND PARTICIPANTS: Residents who lived in an AL or NH facility operated or contracted by the Provincial health care system to provide publicly funded care in Alberta between January 1, 2017, and December 31, 2021.

METHODS: We used administrative health care data, including Resident Assessment Instrument - Home Care (RAI-HC, AL) and Minimum Data Set 2.0 (RAI-MDS 2.0, NHs) records, linked with data on residents' vital statistics, COVID-19 testing, emergency room registrations, and hospital stays. The outcome was excess deaths during COVID-19 (ie, the number of deaths beyond that expected based on pre-pandemic data), estimated, using overdispersed Poisson generalized linear models.

RESULTS: Overall, the risk of excess mortality [adjusted incidence rate ratio (95% confidence interval)] was higher in ALs than in NHs [1.20 (1.14-1.26) vs 1.10 (1.07-1.13)]. Weekly peaks in excess deaths coincided with COVID-19 pandemic waves and were higher among those with diagnosed dementia or significant cognitive impairment in both, AL and NHs.

CONCLUSIONS AND IMPLICATIONS: Finding excess mortality within both AL and NH facilities should lead to greater focus on infection prevention and control measures across all forms of congregate housing for vulnerable older adults. The specific needs of residents with dementia in particular will have to be addressed.}, } @article {pmid38782015, year = {2024}, author = {Benatar, M and Hansen, T and Rom, D and Geist, MA and Blaettler, T and Camu, W and Kuzma-Kozakiewicz, M and van den Berg, LH and Morales, RJ and Chio, A and Andersen, PM and Pradat, PF and Lange, D and Van Damme, P and Mora, G and Grudniak, M and Elliott, M and Petri, S and Olney, N and Ladha, S and Goyal, NA and Meyer, T and Hanna, MG and Quinn, C and Genge, A and Zinman, L and Jabari, D and Shoesmith, C and Ludolph, AC and Neuwirth, C and Nations, S and Shefner, JM and Turner, MR and Wuu, J and Bennett, R and Dang, H and Sundgreen, C and , }, title = {Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {7}, pages = {687-699}, doi = {10.1016/S1474-4422(24)00134-0}, pmid = {38782015}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Double-Blind Method ; Middle Aged ; Aged ; *Neuroprotective Agents/therapeutic use/adverse effects ; Treatment Outcome ; Adult ; Hydroxylamines/therapeutic use/adverse effects/pharmacology ; Oxadiazoles/therapeutic use/adverse effects ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.

METHODS: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.

FINDINGS: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).

INTERPRETATION: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.

FUNDING: Orphazyme.}, } @article {pmid38782014, year = {2024}, author = {Hardiman, O}, title = {Amyotrophic lateral sclerosis: a lesson in translation.}, journal = {The Lancet. Neurology}, volume = {23}, number = {7}, pages = {651-653}, doi = {10.1016/S1474-4422(24)00223-0}, pmid = {38782014}, issn = {1474-4465}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Translational Research, Biomedical ; }, } @article {pmid38781481, year = {2025}, author = {Zeng, Y and Guo, R and Cao, S and Chavarria Gonzalez, S and Pang, K and Liu, C and Yang, H}, title = {Mendelian randomization study supports relative carbohydrate intake as an independent risk factor for amyotrophic lateral sclerosis.}, journal = {Nutritional neuroscience}, volume = {28}, number = {1}, pages = {116-124}, doi = {10.1080/1028415X.2024.2352196}, pmid = {38781481}, issn = {1476-8305}, support = {G9815508/MRC_/Medical Research Council/United Kingdom ; MC_PC_15018/MRC_/Medical Research Council/United Kingdom ; MC_PC_19009/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Mendelian Randomization Analysis ; *Dietary Carbohydrates/administration & dosage ; Risk Factors ; *Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Diet ; Dietary Fats/administration & dosage ; Dietary Proteins/administration & dosage ; }, abstract = {OBJECTIVES: Observational studies suggested a potential correlation between dietary intake and amyotrophic lateral sclerosis (ALS), but conflicting findings exist and causality remains unclear. Here, we performed a Mendelian randomization (MR) analysis to evaluate the causal impact of relative intake of (i) carbohydrate, (ii) fat, and (iii) protein on ALS risk.

METHODS: The genome-wide association summary statistics of three dietary macronutrient intake traits and ALS were obtained. Initially, forward and reverse univariable MR (UVMR) analysis were conducted using the inverse variance weighted (IVW) method as the primary approach, supplemented by MR-Egger, weighted median, and maximum likelihood. Subsequently, multivariable MR (MVMR) analysis was performed to assess the independent causal effects of each dietary. Additionally, diverse sensitivity tests were conducted to evaluate the reliability of the MR analyses.

RESULTS: The forward UVMR analysis conducted by IVW indicated that relative carbohydrate intake significantly increased ALS risk. Furthermore, results from three other MR methods paralleled those from IVW. However, the other two dietary intake traits did not have a causative impact on ALS risk. The reverse UVMR analysis indicated that ALS did not causatively influence the three dietary intake traits. The MVMR analysis showed that after adjusting for the effects of the other two dietary intake traits, relative carbohydrate intake independently and significantly increased ALS risk. Sensitivity tests indicated no significant heterogeneity or horizontal pleiotropy.

DISCUSSION: MR analysis supported relative carbohydrate independently increasing ALS risk. Nevertheless, further validation of this finding in future large cohorts is required.}, } @article {pmid38780855, year = {2024}, author = {Burgio, F and Danesin, L and Wennberg, A and Tonini, E and Galetto, V and Sivieri, S and Giustiniani, A and Palmer, K and Meneghello, F and Sorarù, G and Zettin, M and Arcara, G and Benavides-Varela, S and Semenza, C}, title = {Financial and numerical abilities: patterns of dissociation in neurological and psychiatric diseases.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {10}, pages = {4779-4787}, pmid = {38780855}, issn = {1590-3478}, support = {GR-2018-12367927//Ministero della Salute/ ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; *Neuropsychological Tests ; Adult ; Aged ; Cognitive Dysfunction/etiology/physiopathology ; Mental Disorders/economics ; Schizophrenia/physiopathology/complications ; Brain Injuries, Traumatic/complications/psychology ; }, abstract = {The present work investigates whether financial abilities can be associated with numerical abilities and with general cognitive abilities. We compared performance on numerical and financial tests, and on tests routinely used to measure general cognitive performance, in healthy controls and in a group of people with heterogeneous pathological conditions including mild cognitive impairment, amyotrophic lateral sclerosis, traumatic brain injury, and schizophrenia. Patients showed lower performances in both numerical and financial abilities compared to controls. Numerical and financial skills were positively correlated in both groups, but they correlated poorly with measures of general cognitive functioning. Crucially, only basic financial tasks -such as counting currencies- but not advanced ones -like financial judgments- were associated with numerical or general cognitive functioning in logistic regression analyses. Conversely, advanced financial abilities, but not basic ones, were associated with abstract reasoning. At a qualitative analysis, we found that deficits in numerical and financial abilities might double dissociate. Similarly, we observed double dissociations between difficulties in financial abilities and cognitive deficits. In conclusion, financial abilities may be independent of numerical skills, and financial deficits are not always related to the presence of cognitive difficulties. These findings are important for both clinical and legal practice.}, } @article {pmid38780595, year = {2024}, author = {da Gama, NAS and Queiroz, GAMC and de Alcântara, C and Cruzeiro, MM and Alencar, MA and Martins de Araújo, C and Gomide, GFD and de Souza, LC and Jaeger, A}, title = {Memory for emotional information in sporadic and Type 8 amyotrophic lateral sclerosis.}, journal = {Neuropsychology}, volume = {38}, number = {5}, pages = {465-474}, doi = {10.1037/neu0000957}, pmid = {38780595}, issn = {1931-1559}, support = {//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; //Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/physiopathology ; Male ; Female ; Middle Aged ; *Emotions/physiology ; Aged ; *Recognition, Psychology/physiology ; Memory Disorders/etiology/diagnosis ; Adult ; Memory, Episodic ; Neuropsychological Tests ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is often shown to cause episodic memory deficits. Here, we investigated whether such memory deficits are differentially expressed according to the emotional valence of stimuli and whether they are similarly reproduced in both individuals with sporadic ALS (sALS) and familial Type 8 ALS (ALS8).

METHOD: Twenty individuals with sALS, 18 individuals with ALS8, and 19 healthy controls were recruited for the study. After a neuropsychological and psychopathological assessment, all participants responded to a recognition memory test wherein images varying in terms of valence were initially shown. After a short interval, the images were shown again intermixed with new images, and the participants' task was to indicate whether each image was "old" or "new" and to estimate the confidence in their responses.

RESULTS: Both the sALS and the ALS8 groups showed significantly lower recognition of positive relative to negative valence images (d = 0.92 and d = 0.74, respectively), an effect that was completely absent for healthy controls (d = 0.17). These effects were qualified by a significant interaction involving the factors of valence and group (ηp² = 0.12).

CONCLUSIONS: The current findings demonstrate that sALS and ALS8 are associated with decreased recognition of emotional information, an effect that is nonetheless restricted to positive valence stimuli. (PsycInfo Database Record (c) 2024 APA, all rights reserved).}, } @article {pmid38779803, year = {2024}, author = {Zhu, L and Bai, D and Wang, X and Ou, K and Li, B and Jia, Q and Tan, Z and Liang, J and He, D and Yan, S and Wang, L and Li, S and Li, XJ and Yin, P}, title = {Pathologic TDP-43 downregulates myelin gene expression in the monkey brain.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {6}, pages = {e13277}, pmid = {38779803}, issn = {1750-3639}, support = {32270564//National Natural Science Foundation of China/ ; 81830032//National Natural Science Foundation of China/ ; 82071421//National Natural Science Foundation of China/ ; 82394422//National Natural Science Foundation of China/ ; 2021ZT09Y007//Department of Science and Technology of Guangdong Province/ ; 2018B030337001//Department of Science and Technology of Guangdong Province/ ; 2022A1515011205//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023A1515010811//Basic and Applied Basic Research Foundation of Guangdong Province/ ; }, mesh = {Animals ; Male ; *Brain/metabolism/pathology ; Corpus Callosum/metabolism/pathology ; Demyelinating Diseases/pathology/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Down-Regulation ; Myelin Sheath/metabolism/pathology/genetics ; Oligodendroglia/metabolism/pathology ; Macaca fascicularis ; }, abstract = {Growing evidence indicates that non-neuronal oligodendrocyte plays an important role in Amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. In patient's brain, the impaired myelin structure is a pathological feature with the observation of TDP-43 in cytoplasm of oligodendrocyte. However, the mechanism underlying the gain of function by TDP-43 in oligodendrocytes, which are vital for the axonal integrity, remains unclear. Recently, we found that the primate-specific cleavage of truncated TDP-43 fragments occurred in cytoplasm of monkey neural cells. This finding opened up the avenue to investigate the myelin integrity affected by pathogenic TDP-43 in oligodendrocytes. In current study, we demonstrated that the truncated TDP-35 in oligodendrocytes specifically, could lead to the dysfunctional demyelination in corpus callosum of monkey. As a consequence of the interaction of myelin regulatory factor with the accumulated TDP-35 in cytoplasm, the downstream myelin-associated genes expression was downregulated at the transcriptional level. Our study aims to investigate the potential effect on myelin structure injury, affected by the truncated TDP-43 in oligodendrocyte, which provided the additional clues on the gain of function during the progressive pathogenesis and symptoms in TDP-43 related diseases.}, } @article {pmid38779353, year = {2024}, author = {Trubshaw, M and Gohil, C and Yoganathan, K and Kohl, O and Edmond, E and Proudfoot, M and Thompson, AG and Talbot, K and Stagg, CJ and Nobre, AC and Woolrich, M and Turner, MR}, title = {The cortical neurophysiological signature of amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {3}, pages = {fcae164}, pmid = {38779353}, issn = {2632-1297}, abstract = {The progressive loss of motor function characteristic of amyotrophic lateral sclerosis is associated with widespread cortical pathology extending beyond primary motor regions. Increasing muscle weakness reflects a dynamic, variably compensated brain network disorder. In the quest for biomarkers to accelerate therapeutic assessment, the high temporal resolution of magnetoencephalography is uniquely able to non-invasively capture micro-magnetic fields generated by neuronal activity across the entire cortex simultaneously. This study examined task-free magnetoencephalography to characterize the cortical oscillatory signature of amyotrophic lateral sclerosis for having potential as a pharmacodynamic biomarker. Eight to ten minutes of magnetoencephalography in the task-free, eyes-open state was recorded in amyotrophic lateral sclerosis (n = 36) and healthy age-matched controls (n = 51), followed by a structural MRI scan for co-registration. Extracted magnetoencephalography metrics from the delta, theta, alpha, beta, low-gamma, high-gamma frequency bands included oscillatory power (regional activity), 1/f exponent (complexity) and amplitude envelope correlation (connectivity). Groups were compared using a permutation-based general linear model with correction for multiple comparisons and confounders. To test whether the extracted metrics could predict disease severity, a random forest regression model was trained and evaluated using nested leave-one-out cross-validation. Amyotrophic lateral sclerosis was characterized by reduced sensorimotor beta band and increased high-gamma band power. Within the premotor cortex, increased disability was associated with a reduced 1/f exponent. Increased disability was more widely associated with increased global connectivity in the delta, theta and high-gamma bands. Intra-hemispherically, increased disability scores were particularly associated with increases in temporal connectivity and inter-hemispherically with increases in frontal and occipital connectivity. The random forest model achieved a coefficient of determination (R[2]) of 0.24. The combined reduction in cortical sensorimotor beta and rise in gamma power is compatible with the established hypothesis of loss of inhibitory, GABAergic interneuronal circuits in pathogenesis. A lower 1/f exponent potentially reflects a more excitable cortex and a pathology unique to amyotrophic lateral sclerosis when considered with the findings published in other neurodegenerative disorders. Power and complexity changes corroborate with the results from paired-pulse transcranial magnetic stimulation. Increased magnetoencephalography connectivity in worsening disability is thought to represent compensatory responses to a failing motor system. Restoration of cortical beta and gamma band power has significant potential to be tested in an experimental medicine setting. Magnetoencephalography-based measures have potential as sensitive outcome measures of therapeutic benefit in drug trials and may have a wider diagnostic value with further study, including as predictive markers in asymptomatic carriers of disease-causing genetic variants.}, } @article {pmid38778614, year = {2024}, author = {Zhou, H and Xia, Y and Zhu, R and Zhang, Y and Zhang, X and Zhang, Y and Wang, J}, title = {Ribosomal DNA and Neurological Disorders.}, journal = {Current molecular medicine}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115665240292079240513093708}, pmid = {38778614}, issn = {1875-5666}, abstract = {Ribosomal DNA (rDNA) is important in the nucleolus and nuclear organization of human cells. Defective rDNA repeat maintenance has been reported to be closely associated with neurological disorders, such as Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, depression, suicide, etc. However, there has not been a comprehensive review on the role of rDNA in these disorders. In this review, we have summarized the role of rDNA in major neurological disorders to sort out the correlation between rDNA and neurological diseases and provided insights for therapy with rDNA as a target.}, } @article {pmid38778595, year = {2025}, author = {Jayaprakash, B and Savira, M and Mahmood, AAR and Prasanna, M}, title = {The Role of Stem Cell Therapies in the Treatment of Neurodegenerative Diseases.}, journal = {Current stem cell research & therapy}, volume = {20}, number = {2}, pages = {146-165}, doi = {10.2174/011574888X313112240510160102}, pmid = {38778595}, issn = {2212-3946}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Stem Cell Transplantation/methods ; Animals ; Neural Stem Cells/transplantation ; Parkinson Disease/therapy ; }, abstract = {Cellular replacement therapy and genetic transfer in injured brains provide new pathways for treating human neurological illnesses. Current progress in the field focuses on the production of neurons and glial cells from many types of stem cells, such as embryonic, induced pluripotent, mesenchymal, and neural stem cells. This has led to a significant increase in research on brain transplantation treatments. Extended neurodegeneration results in the progressive decline of certain neuronal subtypes or whole neuronal cells. An analysis of the progress made in induced pluripotent and mesenchymal stem cells reveals their significant promise in disease modeling, regeneration, and medication screening. The requirement for stem cells in neurodegenerative disease studies has been crucial in recent years. Stem cells provide the potential for replacing impaired neurons, comprehending disease needs modeling, and creating efficient treatments, but they have many challenges in culturing and acceptability to the host immune cells. The need to use their potential in discovering novel therapies for diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis leads to promising therapy. This review examines the function of stem cells in the pathogenesis and treatment of Huntington's disease, Parkinson's disease, Alzheimer's disease, and multiple sclerosis. This review further examines hurdles such as immunological reactions and delivery systems intending to overcome these problems. This article offers a detailed viewpoint on the use of stem cell-based nanotherapies as revolutionary treatments for various neurological illnesses.}, } @article {pmid38778483, year = {2024}, author = {Yan, J and Chen, H and Zhang, Y and Peng, L and Wang, Z and Lan, X and Yu, S and Yang, Y}, title = {Fecal microbiota transplantation significantly improved respiratory failure of amyotrophic lateral sclerosis.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2353396}, pmid = {38778483}, issn = {1949-0984}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/microbiology ; Bacteroides ; Faecalibacterium prausnitzii ; *Fecal Microbiota Transplantation ; Feces/microbiology ; Gastrointestinal Microbiome ; Respiration, Artificial ; *Respiratory Insufficiency/therapy/microbiology ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to respiratory failure, and eventually death. However, there is a lack of effective treatments for ALS. Here we report the results of fecal microbiota transplantation (FMT) in two patients with late-onset classic ALS with a Japan ALS severity classification of grade 5 who required tracheostomy and mechanical ventilation. In both patients, significant improvements in respiratory function were observed following two rounds of FMT, leading to weaning off mechanical ventilation. Their muscle strength improved, allowing for assisted standing and mobility. Other notable treatment responses included improved swallowing function and reduced muscle fasciculations. Metagenomic and metabolomic analysis revealed an increase in beneficial Bacteroides species (Bacteroides stercoris, Bacteroides uniformis, Bacteroides vulgatus), and Faecalibacterium prausnitzii after FMT, as well as elevated levels of metabolites involved in arginine biosynthesis and decreased levels of metabolites involved in branched-chain amino acid biosynthesis. These findings offer a potential rescue therapy for ALS with respiratory failure and provide new insights into ALS in general.}, } @article {pmid38777640, year = {2024}, author = {Zhu, J and Yan, Y and Jiang, W and Zhang, S and Niu, X and Wan, S and Cong, Y and Hu, X and Zheng, B and Yang, Y}, title = {A Deep Learning Model for Automatically Quantifying the Anterior Segment in Ultrasound Biomicroscopy Images of Implantable Collamer Lens Candidates.}, journal = {Ultrasound in medicine & biology}, volume = {50}, number = {8}, pages = {1262-1272}, doi = {10.1016/j.ultrasmedbio.2024.05.004}, pmid = {38777640}, issn = {1879-291X}, mesh = {Humans ; *Microscopy, Acoustic/methods ; *Deep Learning ; *Anterior Eye Segment/diagnostic imaging ; Male ; Female ; Adult ; Phakic Intraocular Lenses ; Lens Implantation, Intraocular ; Young Adult ; Middle Aged ; Image Processing, Computer-Assisted/methods ; }, abstract = {OBJECTIVE: This study aimed to develop and evaluate a deep learning-based model that could automatically measure anterior segment (AS) parameters on preoperative ultrasound biomicroscopy (UBM) images of implantable Collamer lens (ICL) surgery candidates.

METHODS: A total of 1164 panoramic UBM images were preoperatively obtained from 321 patients who received ICL surgery in the Eye Center of Renmin Hospital of Wuhan University (Wuhan, China) to develop an imaging database. First, the UNet++ network was utilized to segment AS tissues automatically, such as corneal lens and iris. In addition, image processing techniques and geometric localization algorithms were developed to automatically identify the anatomical landmarks (ALs) of pupil diameter (PD), anterior chamber depth (ACD), angle-to-angle distance (ATA), and sulcus-to-sulcus distance (STS). Based on the results of the latter two processes, PD, ACD, ATA, and STS can be measured. Meanwhile, an external dataset of 294 images from Huangshi Aier Eye Hospital was employed to further assess the model's performance in other center. Lastly, a subset of 100 random images from the external test set was chosen to compare the performance of the model with senior experts.

RESULTS: Whether in the internal test dataset or external test dataset, using manual labeling as the reference standard, the models achieved a mean Dice coefficient exceeding 0.880. Additionally, the intra-class correlation coefficients (ICCs) of ALs' coordinates were all greater than 0.947, and the percentage of Euclidean distance distribution of ALs within 250 μm was over 95.24%.While the ICCs for PD, ACD, ATA, and STS were greater than 0.957, furthermore, the average relative error (ARE) of PD, ACD, ATA, and STS were below 2.41%. In terms of human versus machine performance, the ICCs between the measurements performed by the model and those by senior experts were all greater than 0.931.

CONCLUSION: A deep learning-based model could measure AS parameters using UBM images of ICL candidates, and exhibited a performance similar to that of a senior ophthalmologist.}, } @article {pmid38777186, year = {2024}, author = {Green, LJ and Brouha, B and Bhatia, N}, title = {Response to Bass et al's "Significant discordance in DermTech test results when paired with histopathology: Caveat emptor".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {3}, pages = {e79}, doi = {10.1016/j.jaad.2024.02.067}, pmid = {38777186}, issn = {1097-6787}, mesh = {Humans ; *Skin Neoplasms/pathology ; Dermoscopy ; Melanoma/pathology ; }, } @article {pmid38776614, year = {2024}, author = {López-Figueroa, C and Domingo, M and Duignan, PJ and Cuvertoret-Sanz, M and Martí-García, B and Pintado, E and Martinez, M and Martínez, J}, title = {Air leak syndrome in animals: definition and pathogenesis.}, journal = {Journal of comparative pathology}, volume = {211}, number = {}, pages = {42-51}, doi = {10.1016/j.jcpa.2024.04.005}, pmid = {38776614}, issn = {1532-3129}, mesh = {Animals ; Cats ; *Pneumothorax/veterinary/etiology ; Dogs ; Mediastinal Emphysema/veterinary ; Retrospective Studies ; Cat Diseases/pathology ; Dog Diseases/pathology ; Female ; Male ; Subcutaneous Emphysema/veterinary/etiology ; Pneumoperitoneum/veterinary ; }, abstract = {Air leak syndrome (ALS) is described in human medicine as a constellation of clinical disorders including pneumomediastinum, pneumopericardium, pulmonary interstitial emphysema, pneumothorax, pneumoperitoneum, pneumoretroperitoneum and subcutaneous emphysema. The pathogenesis of ALS depends on the anatomy of the mediastinum and its associations with thoracic, abdominal and cervical connective tissues, as well as a physical phenomenon referred to as the Macklin effect. Various animal species develop diverse combinations of these lesions, although ALS has not been recognized in animals. However, this term aids pathologists in addressing this disease compilation. The aim of this retrospective study is to illustrate examples of ALS in animals by arbitrarily selecting 13 cases in dogs, cats, pinnipeds, sea otters and harbour porpoises. ALS can be classified into three groups based on aetiology: iatrogenic, secondary or spontaneous. Iatrogenic ALS was diagnosed in two cats with tracheal laceration following endotracheal intubation. Secondary ALS was identified in two dogs, one with acute respiratory distress syndrome and the other due to grass awn migration. Secondary ALS in pinnipeds was diagnosed following severe pulmonary parasitism, uraemic pneumonia and oesophageal perforation. The other marine mammals developed ALS following trauma. Spontaneous ALS was also diagnosed in one cat and one dog without any apparent predisposing causes.}, } @article {pmid38776297, year = {2024}, author = {Issa, NP and Aydin, S and Polley, E and Carberry, N and Garret, MA and Smith, S and Habib, AA and Baumgartner, NW and Soliven, B and Rezania, K}, title = {Intermuscular coherence as an early biomarker for amyotrophic lateral sclerosis: The protocol for a prospective, multicenter study.}, journal = {PloS one}, volume = {19}, number = {5}, pages = {e0303053}, pmid = {38776297}, issn = {1932-6203}, support = {R01 NS116262/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Biomarkers/analysis ; *Electromyography/methods ; Motor Neurons/pathology ; Muscle, Skeletal/physiopathology/pathology ; Prospective Studies ; Multicenter Studies as Topic ; }, abstract = {OBJECTIVE: To describe the protocol of a prospective study to test the validity of intermuscular coherence (IMC) as a diagnostic tool and biomarker of upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS).

METHODS: This is a multicenter, prospective study. IMC of muscle pairs in the upper and lower limbs is gathered in ∼650 subjects across three groups using surface electrodes and conventional electromyography (EMG) machines. The following subjects will be tested: 1) neurotypical controls; 2) patients with symptomatology suggestive for early ALS but not meeting probable or definite ALS by Awaji Criteria; 3) patients with a known ALS mimic. The recruitment period is between 3/31/2021 and 12/31/2025. Written consent will be sought from the subject or the subject's legally authorized representative during enrollment.

RESULTS: The endpoints of this study include: 1) whether adding IMC to the Awaji ALS criteria improve its sensitivity in early ALS and can allow for diagnosis earlier; 2) constructing a database of IMC across different ages, genders, and ethnicities.

SIGNIFICANCE: This study may validate a new inexpensive, painless, and widely available tool for the diagnosis of ALS.}, } @article {pmid38775852, year = {2024}, author = {Ebrahimi, P and Davoudi, E and Sadeghian, R and Zadeh, AZ and Razmi, E and Heidari, R and Morowvat, MH and Sadeghian, I}, title = {In vivo and ex vivo gene therapy for neurodegenerative diseases: a promise for disease modification.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {397}, number = {10}, pages = {7501-7530}, pmid = {38775852}, issn = {1432-1912}, support = {29849//Shiraz University of Medical Sciences/ ; }, mesh = {Humans ; *Genetic Therapy/methods ; Animals ; *Neurodegenerative Diseases/therapy/genetics ; Gene Editing/methods ; }, abstract = {Neurodegenerative diseases (NDDs), including AD, PD, HD, and ALS, represent a growing public health concern linked to aging and lifestyle factors, characterized by progressive nervous system damage leading to motor and cognitive deficits. Current therapeutics offer only symptomatic management, highlighting the urgent need for disease-modifying treatments. Gene therapy has emerged as a promising approach, targeting the underlying pathology of diseases with diverse strategies including gene replacement, gene silencing, and gene editing. This innovative therapeutic approach involves introducing functional genetic material to combat disease mechanisms, potentially offering long-term efficacy and disease modification. With advancements in genomics, structural biology, and gene editing tools such as CRISPR/Cas9, gene therapy holds significant promise for addressing the root causes of NDDs. Significant progress in preclinical and clinical studies has demonstrated the potential of in vivo and ex vivo gene therapy to treat various NDDs, offering a versatile and precise approach in comparison to conventional treatments. The current review describes various gene therapy approaches employed in preclinical and clinical studies for the treatment of NDDs, including AD, PD, HD, and ALS, and addresses some of the key translational challenges in this therapeutic approach.}, } @article {pmid38775303, year = {2024}, author = {Zhang, J and Yang, F and Li, M and Zhu, Y and Huang, X}, title = {Quantitative evaluation of factors influencing the 3 Hz repetitive nerve stimulation test in patients with amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {2}, pages = {194-203}, doi = {10.1002/mus.28165}, pmid = {38775303}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; Aged ; Adult ; Electric Stimulation/methods ; Neuromuscular Junction/physiopathology ; Electromyography/methods ; }, abstract = {INTRODUCTION/AIMS: Previous studies have suggested that treatments targeting the neuromuscular junction (NMJ) may play a role in the treatment of amyotrophic lateral sclerosis (ALS). However, factors impacting repetitive nerve stimulation (RNS), a technique to evaluate NMJ function, have yet to be fully elucidated. We aimed to identify independent factors contributing to the decremental response of the accessory nerve and evaluated its value in ALS clinical practice.

METHODS: A total of 626 patients who were diagnosed with ALS and underwent 3 Hz RNS tests on the accessory nerve were enrolled. Data on their clinical and electrophysiological indicators were divided into a training set (collected from June 2016 to December 2022) and a test set (collected from January to August 2023). Stepwise regression was used in independent variable selection and model building.

RESULTS: Forty-two percent of patients had a decrement larger than 10% and 24% had a decrement larger than 15%. Onset age, sex, onset site, forced vital capacity (FVC) and motor unit potential (MUP) duration were independent factors contributing to the results of the RNS test. MUP duration had the greatest impact on decremental response, followed by FVC and onset age. The decremental response in females was larger than in males. Upper limb onset was found to contribute more to the decrement than lower limb or bulbar onset.

DISCUSSION: In patients with ALS, NMJ safety factor is reduced during re-innervation. Decremental response is affected by multiple factors, which needs to be considered in clinical trials targeting the NMJ in these patients.}, } @article {pmid38775192, year = {2024}, author = {Ju, W and Ban, JJ and Im, HR and Ko, SH and Seo, J and Min, YG and Hong, YH and Choi, SJ and Sung, JJ}, title = {Association of serum Spp1 levels with disease progression in ALS and SBMA.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {7}, pages = {1809-1818}, pmid = {38775192}, issn = {2328-9503}, support = {2018R1A5A2025964//National Research Foundation of Korea/ ; 2020R1C1C1005122//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/physiopathology/diagnosis ; *Osteopontin/blood ; Male ; Female ; Middle Aged ; *Disease Progression ; Aged ; Biomarkers/blood ; Adult ; Neuroinflammatory Diseases/blood ; Cytokines/blood ; }, abstract = {OBJECTIVE: In comparison with amyotrophic lateral sclerosis (ALS), the contribution of neuroinflammation in spinobulbar muscular atrophy (SBMA) has been less explored. We investigated the role of neuroinflammation in the pathogenesis of ALS and SBMA by analyzing systemic inflammatory markers and osteopontin (Spp1).

METHODS: This study involved 105 ALS, 77 SBMA, and 55 healthy controls. We measured their systemic inflammatory markers, serum Spp1, and cytokine levels (interferon-γ, interleukin [IL]-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α, and IL-17A), investigated correlations between Spp1 levels and clinical features, and evaluated ALS survival rates according to Spp1 levels.

RESULTS: In the ALS group, systemic inflammatory markers were significantly higher than in the control and SBMA groups. Spp1 levels were observed to be higher in ALS patients, but the difference was not statistically significant among the study groups. Cytokine profiles were comparable. In ALS, higher Spp1 levels were correlated with lower ALS Functional Rating Scale-Revised (ALSFRS-R) scores (r = -0.25, p = 0.02) and faster disease progression rate (r = 0.37, p < 0.001). After adjusting for other prognostic indicators, high Spp1 levels were independently associated with shorter survival in ALS patients (hazard ratio 13.65, 95% confidence interval 2.57-72.53, p < 0.01).

INTERPRETATION: Neuroinflammation does not appear to be a primary contributor to the pathogenesis of SBMA. Serum Spp1 levels may serve as a reliable biomarker for disease progression and prognosis in ALS. These findings expand our understanding of these two distinct motor neuron disorders and offer a potential biomarker for future studies.}, } @article {pmid38775181, year = {2024}, author = {Marriott, H and Spargo, TP and Al Khleifat, A and Andersen, PM and Başak, NA and Cooper-Knock, J and Corcia, P and Couratier, P and de Carvalho, M and Drory, V and Gotkine, M and Landers, JE and McLaughlin, R and Pardina, JSM and Morrison, KE and Pinto, S and Shaw, CE and Shaw, PJ and Silani, V and Ticozzi, N and van Damme, P and van den Berg, LH and Vourc'h, P and Weber, M and Veldink, JH and , and Dobson, RJ and Schwab, P and Al-Chalabi, A and Iacoangeli, A}, title = {Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {7}, pages = {1775-1786}, pmid = {38775181}, issn = {2328-9503}, support = {//Maudsley NHS Foundation Trust/ ; 22-PDF-609//ALS Association Milton Safenowitz Research/ ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; //BHF British Heart Foundation/ ; //Darby Rimmer MND Foundation/ ; NIHR202421//National Institute for Health Research/ ; Al Khleifat/Oct21/975-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; //MND Scotland/ ; ES/L008238/1//Economic and Social Research Council/ ; //Alan Davidson Foundation/ ; /WT_/Wellcome Trust/United Kingdom ; //Alzheimer's Research UK/ ; //Rosetrees Trust/ ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; //My Name'5 Doddie Foundation/ ; //GlaxoSmithKline/ ; //MRC Medical Research Council/ ; //The NIHR Maudsley Biomedical Research Centre/ ; //Spastic Paraplegia Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Genetic Predisposition to Disease/genetics ; Mutation ; Mutation, Missense ; *Neurofilament Proteins/genetics ; Protein Domains/genetics ; }, abstract = {OBJECTIVE: Neurofilament heavy-chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk.

METHODS: Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta-analyses of published case-control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole-genome sequencing data.

RESULTS: Fixed-effects meta-analysis found that rare (MAF <1%) missense variants in the tail domain of NEFH increase ALS risk (OR 4.55, 95% CI 2.13-9.71, p < 0.0001). In Project MinE, ultrarare NEFH variants increased ALS risk (OR 1.37 95% CI 1.14-1.63, p = 0.0007), with rod domain variants (mostly intronic) appearing to drive the association (OR 1.45 95% CI 1.18-1.77, pMadsen-Browning = 0.0007, pSKAT-O = 0.003). While in the tail domain, ultrarare (MAF <0.1%) pathogenic missense variants were also associated with higher risk of ALS (OR 1.94, 95% CI 0.86-4.37, pMadsen-Browning = 0.039), supporting the meta-analysis results. Finally, several tail in-frame deletions were also found to affect disease risk, however, both protective and pathogenic deletions were found in this domain, highlighting an intricate architecture that requires further investigation.

INTERPRETATION: We showed that NEFH tail missense and in-frame deletion variants, and intronic rod variants are risk factors for ALS. However, they are not variants of large effect, and their functional impact needs to be clarified in further studies. Therefore, their inclusion in routine genetic screening panels should be reconsidered.}, } @article {pmid38775138, year = {2024}, author = {Calma, AD and Pavey, N and Menon, P and Vucic, S}, title = {Neuroinflammation in amyotrophic lateral sclerosis: pathogenic insights and therapeutic implications.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {585-592}, pmid = {38775138}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/immunology/therapy/genetics ; Humans ; *Neuroinflammatory Diseases/immunology ; Animals ; Immunity, Innate/immunology ; Inflammation/immunology ; }, abstract = {PURPOSE OF REVIEW: Neuroinflammation appears to be an important pathogenic process in amyotrophic lateral sclerosis (ALS). Dysfunction of central immune pathways, including activation of microglia and astrocytes, and peripherally derived immune cells, initiate noncell autonomous inflammatory mechanisms leading to degeneration. Cell autonomous pathways linked to ALS genetic mutations have been recently identified as contributing mechanism for neurodegeneration. The current review provides insights into the pathogenic importance of central and peripheral inflammatory processes in ALS pathogenesis and appraises their potential as therapeutic targets.

RECENT FINDINGS: ALS is a multistep process mediated by a complex interaction of genetic, epigenetic, and environmental factors. Noncell autonomous inflammatory pathways contribute to neurodegeneration in ALS. Activation of microglia and astrocytes, along with central nervous system infiltration of peripherally derived pro-inflammatory innate (NK-cells/monocytes) and adaptive (cell-mediated/humoral) immune cells, are characteristic of ALS. Dysfunction of regulatory T-cells, elevation of pro-inflammatory cytokines and dysbiosis of gut microbiome towards a pro-inflammatory phenotype, have been reported as pathogenic mechanisms in ALS.

SUMMARY: Dysregulation of adaptive and innate immunity is pathogenic in ALS, being associated with greater disease burden, more rapid disease course and reduced survival. Strategies aimed at modulating the pro-inflammatory immune components could be of therapeutic utility.}, } @article {pmid38775034, year = {2024}, author = {Brooks, BR}, title = {Letter to the Editor: Glycemic Index/Load Effect on Amyotrophic Lateral Sclerosis Progression: Potential Interaction with Riluzole.}, journal = {Annals of neurology}, volume = {96}, number = {1}, pages = {208}, doi = {10.1002/ana.26970}, pmid = {38775034}, issn = {1531-8249}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Riluzole/therapeutic use ; *Disease Progression ; *Glycemic Index/drug effects ; Neuroprotective Agents/therapeutic use ; Blood Glucose/metabolism/drug effects ; }, } @article {pmid38774156, year = {2024}, author = {Canella, C and Braun, C and Witt, CM}, title = {Developing a digital mind body medicine supportive care intervention for people with amyotrophic lateral sclerosis using stakeholder engagement and design thinking.}, journal = {Digital health}, volume = {10}, number = {}, pages = {20552076241255928}, pmid = {38774156}, issn = {2055-2076}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis disease (ALS) is also called the disease of a thousand farewells. Consequently, it is important to offer supportive care interventions that can be applied continuously during the whole course of the disease. People with ALS are interested in complementary and integrative medicine. Due to ALS' progressive nature, digital solutions might be most feasible and accessible for people with ALS in the long-term.

OBJECTIVES: In our study, we explored with stakeholders which digital complementary and integrative medicine interventions and formats are considered as supportive for people with ALS, and which settings are needed by the people with ALS to incorporate the interventions in everyday life.

METHODS: We used a participatory research approach and conducted a stakeholder engagement process, applying a design thinking process with qualitative research methods (interviews, workshops).

RESULTS: Due to the unpredictable course of the disease on their loss of abilities, people with ALS welcome online settings because they are accessible and easy to implement in their daily life. Stakeholders considered the following implementation factors for a complementary and integrative medicine intervention as essential: short-term realization of planned interventions, short duration of interventions, and user-friendliness in terms of accessibility and applicability. Concerning the complementary and integrative medicine interventions, the people with ALS preferred mind body medicine interventions, such as breathing, mindfulness and relaxation exercises.

CONCLUSIONS: Short-term treatment intervals and short online mind body medicine interventions align with the needs of people with ALS. The complementary and integrative medicine interventions as well as the digital infrastructure must meet the special accessibility and applicability needs of people with ALS.}, } @article {pmid38772930, year = {2024}, author = {Kherbek, H and Itoh, CY and Daley, C and Eggers, SD and Hinson, S and Sarker, P and Staff, NP and Pittock, SJ and Dubey, D}, title = {Clinical and serological insights into paraneoplastic brachial amyotrophic diplegia.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {4620-4627}, pmid = {38772930}, issn = {1432-1459}, support = {238183//State of Minnesota's David J. Tomassoni ALS Research Grant Program/ ; }, mesh = {Humans ; Male ; Middle Aged ; Retrospective Studies ; Aged ; Female ; *Paraneoplastic Syndromes, Nervous System/immunology/diagnosis/blood ; Adult ; Autoantibodies/blood ; Brachial Plexus Neuropathies/etiology/diagnosis/physiopathology ; Carrier Proteins ; }, abstract = {BACKGROUND: Brachial amyotrophic diplegia (BAD) is typically linked to a neurodegenerative etiology such as amyotrophic lateral sclerosis (ALS). Clinical and serological characterizations of paraneoplastic neurologic syndromes resembling BAD are limited.

METHODS: A retrospective chart review of patients with BAD-like presentations was conducted. Clinical/paraclinical features of paraneoplastic BAD and neurodegenerative BAD cases were compared.

RESULTS: Between 2017 and 2023, 13 cases of BAD were identified, of these 10 were neurodegenerative BAD (ALS variant), and 3 cases associated with paraneoplastic autoimmunity. An additional paraneoplastic BAD case diagnosed in 2005 was included. LUZP4-IgG was detected in all four paraneoplastic cases, with coexisting KLHL11-IgG in three cases and ANNA1 (anti-Hu)-IgG in one case. Out of the four paraneoplastic cases, two patients had seminoma, while the remaining two had limited cancer investigation. Three patients exhibited bi-brachial weakness as the initial symptom before the onset of brainstem symptoms or seizures. Compared to BAD patients with a neurodegenerative etiology, a higher proportion of paraneoplastic cases had ataxia (75% vs 0%, p = 0.011). Other clinical features only detected in the paraneoplastic BAD group were vertigo (n = 2), hearing loss (n = 2) and ophthalmoplegia (n = 2). Electrodiagnostic studies in these patients revealed cervical myotome involvement, supportive of motor neuronopathy. All paraneoplastic cases but none of the neurodegenerative BAD cases exhibited inflammatory cerebrospinal fluid (CSF) findings (lymphocytic pleocytosis and/or supernumerary oligoclonal bands; p = 0.067). Despite the administration of immunotherapy and/or cancer treatment, none of the paraneoplastic patients reported clinical improvement.

DISCUSSION: BAD or bi-brachial neurogenic weakness is a rare phenotypic presentation associated with paraneoplastic autoimmunity. Co-existing features of brainstem dysfunction or cerebellar ataxia should prompt further paraneoplastic evaluation. Common serological and cancer associations among these cases include LUZP4-IgG and KLHL11-IgG, along with testicular germ cell tumors, respectively.}, } @article {pmid38772669, year = {2024}, author = {Martínez Bilesio, AR and Puig-Castellví, F and Tauler, R and Sciara, M and Fay, F and Rasia, RM and Burdisso, P and García-Reiriz, AG}, title = {Multivariate curve resolution-based data fusion approaches applied in [1]H NMR metabolomic analysis of healthy cohorts.}, journal = {Analytica chimica acta}, volume = {1309}, number = {}, pages = {342689}, doi = {10.1016/j.aca.2024.342689}, pmid = {38772669}, issn = {1873-4324}, mesh = {Humans ; *Metabolomics/methods ; Male ; Female ; Multivariate Analysis ; Healthy Volunteers ; Adult ; Proton Magnetic Resonance Spectroscopy ; Cohort Studies ; Middle Aged ; Least-Squares Analysis ; Young Adult ; }, abstract = {BACKGROUND: Metabolomics plays a critical role in deciphering metabolic alterations within individuals, demanding the use of sophisticated analytical methodologies to navigate its intricate complexity. While many studies focus on single biofluid types, simultaneous analysis of multiple matrices enhances understanding of complex biological mechanisms. Consequently, the development of data fusion methods enabling multiblock analysis becomes essential for comprehensive insights into metabolic dynamics.

RESULTS: This study introduces a novel guideline for jointly analyzing diverse metabolomic datasets (serum, urine, metadata) with a focus on metabolic differences between groups within a healthy cohort. The guideline presents two fusion strategies, 'Low-Level data fusion' (LLDF) and 'Mid-Level data fusion' (MLDF), employing a sequential application of Multivariate Curve Resolution with Alternating Least Squares (MCR-ALS), linking the outcomes of successive analyses. MCR-ALS is a versatile method for analyzing mixed data, adaptable at various stages of data processing-encompassing resonance integration, data compression, and exploratory analysis. The LLDF and MLDF strategies were applied to [1]H NMR spectral data extracted from urine and serum samples, coupled with biochemical metadata sourced from 145 healthy volunteers.

SIGNIFICANCE: Both methodologies effectively integrated and analysed multiblock datasets, unveiling the inherent data structure and variables associated with discernible factors among healthy cohorts. While both approaches successfully detected sex-related differences, the MLDF strategy uniquely revealed components linked to age. By applying this analysis, we aim to enhance the interpretation of intricate biological mechanisms and uncover variations that may not be easily discernible through individual data analysis.}, } @article {pmid38771698, year = {2024}, author = {Alarcan, H and Bruno, C and Emond, P and Raoul, C and Vourc'h, P and Corcia, P and Camu, W and Veyrune, JL and Garlanda, C and Locati, M and Juntas-Morales, R and Saker, S and Suehs, C and Masseguin, C and Kirby, J and Shaw, P and Malaspina, A and De Vos, J and Al-Chalabi, A and Leigh, PN and Tree, T and Bensimon, G and Blasco, H}, title = {Pharmacometabolomics applied to low-dose interleukin-2 treatment in amyotrophic lateral sclerosis.}, journal = {Annals of the New York Academy of Sciences}, volume = {1536}, number = {1}, pages = {82-91}, doi = {10.1111/nyas.15147}, pmid = {38771698}, issn = {1749-6632}, support = {//National Institute of Health and Medical Research/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Humans ; *Interleukin-2/administration & dosage/metabolism ; *Metabolomics/methods ; *T-Lymphocytes, Regulatory/metabolism/drug effects/immunology ; Male ; Middle Aged ; Female ; Kynurenine/metabolism ; Aged ; Metabolome/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2). We propose a pharmacometabolomics approach to decipher metabolic modifications occurring in patients treated with ld-IL-2 and its relationship with Treg response. Blood metabolomic profiles were determined on days D1, D64, and D85 from patients receiving 2 MIU of IL-2 (n = 12) and patients receiving a placebo (n = 12). We discriminated the three time points for the treatment group (average error rate of 42%). Among the important metabolites, kynurenine increased between D1 and D64, followed by a reduction at D85. The percentage increase of Treg number from D1 to D64, as predicted by the metabolome at D1, was highly correlated with the observed value. This study provided a proof of concept for metabolic characterization of the effect of ld-IL-2 in ALS. These data could present advances toward a personalized medicine approach and present pharmacometabolomics as a key tool to complement genomic and transcriptional data for drug characterization, leading to systems pharmacology.}, } @article {pmid38771230, year = {2024}, author = {Maccabeo, A and Salustro, E and Sanna, M and Garau, P and Maioli, MA and Coa, R and Puligheddu, M and Borghero, G}, title = {Scleroderma-Polymyositis Overlap Syndrome as a Potential Bulbar Amyotrophic Lateral Sclerosis Mimic.}, journal = {Journal of clinical neuromuscular disease}, volume = {25}, number = {4}, pages = {199-200}, doi = {10.1097/CND.0000000000000467}, pmid = {38771230}, issn = {1537-1611}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Diagnosis, Differential ; *Polymyositis/complications ; Scleroderma, Systemic/complications ; }, } @article {pmid38770222, year = {2024}, author = {Lagrange, E and Loriot, MA and Chaudhary, NK and Schultz, P and Dirks, AC and Guissart, C and James, TY and Vernoux, JP and Camu, W and Tripathi, A and Spencer, PS}, title = {Corrected speciation and gyromitrin content of false morels linked to ALS patients with mostly slow-acetylator phenotypes.}, journal = {eNeurologicalSci}, volume = {35}, number = {}, pages = {100502}, pmid = {38770222}, issn = {2405-6502}, abstract = {A case-control study of sporadic amyotrophic lateral sclerosis (ALS) in a mountainous village in the French Alps discovered an association of cases with a history of eating wild fungi (false morels) collected locally and initially identified and erroneously reported as Gyromitra gigas. Specialist re-examination of dried specimens of the ALS-associated fungi demonstrated they were members of the G. esculenta group, namely G. venenata and G. esculenta, species that have been reported to contain substantially higher concentrations of gyromitrin than present in G. gigas. Gyromitrin is metabolized to monomethylhydrazine, which is responsible not only for the acute oral toxic and neurotoxic properties of false morels but also has genotoxic potential with proposed mechanistic relevance to the etiology of neurodegenerative disease. Most ALS patients had a slow- or intermediate-acetylator phenotype predicted by N-acetyltransferase-2 (NAT2) genotyping, which would increase the risk for neurotoxic and genotoxic effects of gyromitrin metabolites.}, } @article {pmid38769202, year = {2024}, author = {Benatar, M and Wuu, J and Huey, ED and McMillan, CT and Petersen, RC and Postuma, R and McHutchison, C and Dratch, L and Arias, JJ and Crawley, A and Houlden, H and McDermott, MP and Cai, X and Thakur, N and Boxer, A and Rosen, H and Boeve, BF and Dacks, P and Cosentino, S and Abrahams, S and Shneider, N and Lingor, P and Shefner, J and Andersen, PM and Al-Chalabi, A and Turner, MR and , }, title = {The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {6}, pages = {364-376}, pmid = {38769202}, issn = {1759-4766}, support = {U01 AG079850/AG/NIA NIH HHS/United States ; R01 MH120794/MH/NIMH NIH HHS/United States ; K01 AG057796/AG/NIA NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; R01 NS105479/NS/NINDS NIH HHS/United States ; R01 AG062268/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/metabolism/pathology ; *Phenotype ; *Frontotemporal Dementia/genetics/diagnosis/metabolism ; Neurodegenerative Diseases/diagnosis/metabolism/genetics ; Biomarkers/metabolism ; }, abstract = {Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.}, } @article {pmid38768217, year = {2024}, author = {Petrauskas, A and Fortunati, DL and Kandi, AR and Pothapragada, SS and Agrawal, K and Singh, A and Huelsmeier, J and Hillebrand, J and Brown, G and Chaturvedi, D and Lee, J and Lim, C and Auburger, G and VijayRaghavan, K and Ramaswami, M and Bakthavachalu, B}, title = {Structured and disordered regions of Ataxin-2 contribute differently to the specificity and efficiency of mRNP granule formation.}, journal = {PLoS genetics}, volume = {20}, number = {5}, pages = {e1011251}, pmid = {38768217}, issn = {1553-7404}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Ataxin-2/genetics/metabolism ; Animals ; Humans ; *Ribonucleoproteins/genetics/metabolism ; *Drosophila Proteins/genetics/metabolism ; *Drosophila melanogaster/genetics/metabolism ; *RNA, Messenger/genetics/metabolism ; Poly(A)-Binding Proteins/metabolism/genetics ; Animals, Genetically Modified ; Cytoplasmic Granules/metabolism/genetics ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Protein Biosynthesis ; RNA-Binding Proteins/genetics/metabolism ; Intrinsically Disordered Proteins/genetics/metabolism ; Nerve Tissue Proteins/genetics/metabolism ; DNA-Binding Proteins ; }, abstract = {Ataxin-2 (ATXN2) is a gene implicated in spinocerebellar ataxia type II (SCA2), amyotrophic lateral sclerosis (ALS) and Parkinsonism. The encoded protein is a therapeutic target for ALS and related conditions. ATXN2 (or Atx2 in insects) can function in translational activation, translational repression, mRNA stability and in the assembly of mRNP-granules, a process mediated by intrinsically disordered regions (IDRs). Previous work has shown that the LSm (Like-Sm) domain of Atx2, which can help stimulate mRNA translation, antagonizes mRNP-granule assembly. Here we advance these findings through a series of experiments on Drosophila and human Ataxin-2 proteins. Results of Targets of RNA Binding Proteins Identified by Editing (TRIBE), co-localization and immunoprecipitation experiments indicate that a polyA-binding protein (PABP) interacting, PAM2 motif of Ataxin-2 may be a major determinant of the mRNA and protein content of Ataxin-2 mRNP granules. Experiments with transgenic Drosophila indicate that while the Atx2-LSm domain may protect against neurodegeneration, structured PAM2- and unstructured IDR- interactions both support Atx2-induced cytotoxicity. Taken together, the data lead to a proposal for how Ataxin-2 interactions are remodelled during translational control and how structured and non-structured interactions contribute differently to the specificity and efficiency of RNP granule condensation as well as to neurodegeneration.}, } @article {pmid38767564, year = {2024}, author = {Natung, T and Pandey, I and Nongrum, B and Sekhose, EK}, title = {Comparison of Hill-RBF 3.0 with Barrett Universal II, SRK/T, Hoffer Q, Haigis, and Holladay 1 to predict the accuracy of post-cataract surgery refractive outcomes in Indian eyes.}, journal = {Indian journal of ophthalmology}, volume = {72}, number = {9}, pages = {1261-1266}, pmid = {38767564}, issn = {1998-3689}, mesh = {Humans ; Prospective Studies ; Male ; Female ; India/epidemiology ; *Refraction, Ocular/physiology ; Middle Aged ; *Visual Acuity/physiology ; Aged ; Follow-Up Studies ; Lenses, Intraocular ; Phacoemulsification ; Postoperative Period ; Lens Implantation, Intraocular ; Refractive Errors/physiopathology/diagnosis/epidemiology ; }, abstract = {PURPOSE: To compare Hill-RBF 3.0 with Barrett Universal II (BU II), SRK/T, Hoffer Q, Haigis, and Holladay 1 in predicting the accuracy of post-cataract surgery refractive outcomes in Indian eyes.

METHODS: In this prospective, comparative, observational study, consecutive patients with uncomplicated age-related cataracts undergoing uneventful phacoemulsification with posterior chamber intraocular lens (IOL) implantation were included. The mean absolute errors (MAEs) and median absolute errors were used to determine the accuracy of predicted postoperative target refractions.

RESULTS: A total of 219 eyes of 173 patients were enrolled. Based on the axial lengths (AL), the patients were classified into: AL <22 mm (short), 22-24.5 mm (normal), and >24.5 mm (long). BU II exhibited the lowest MAE for normal ALs (0.2683 ± 0.2790 D) as well as for the entire population (0.2764 ± 0.2764 D). For the short ALs, Hill RBF 3.0 exhibited the lowest MAE (0.3268 ± 0.3268 D), while for the long ALs, SRK/T showed the lowest MAE (0.2823 ± 0.2642 D). BU II exhibited the highest percentage of eyes of 57.5%, 95.4%, and 98.6% within ±0.25, ±0.75, and ±1.0 D of postoperative target refractions respectively, whereas Hill RBF 3.0 had the highest percentages of eyes (88.1%) within ±0.5 D of postoperative target refraction.

CONCLUSION: Hill-RBF 3.0 exhibited the least MAE for patients with short ALs, while BU II showed the least MAE for normal ALs as well as for the entire population and SRK/T for long ALs. This study is likely to aid surgeons in selecting the most appropriate IOL power formula, which thereby improves the refractive outcomes with utmost accuracy.}, } @article {pmid38767482, year = {2025}, author = {Martinelli, I and Mandrioli, J and Ghezzi, A and Zucchi, E and Gianferrari, G and Simonini, C and Cavallieri, F and Valzania, F}, title = {Multifaceted superoxide dismutase 1 expression in amyotrophic lateral sclerosis patients: a rare occurrence?.}, journal = {Neural regeneration research}, volume = {20}, number = {1}, pages = {130-138}, pmid = {38767482}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex, brainstem, and spinal cord. While the typical clinical phenotype of ALS involves both upper and lower motor neurons, human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions, expanding the phenotype of ALS. Although superoxide dismutase 1 (SOD1) mutations represent a minority of ALS cases, the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies. Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1 (SOD1-ALS), no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation. In this narrative review, we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS. The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms, pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.}, } @article {pmid38767073, year = {2024}, author = {Napoletano, G and Circosta, F and Basile, G}, title = {Access to medically-assisted procreation: the withdrawal of paternal consent in the maze of law n. 40/2004.}, journal = {La Clinica terapeutica}, volume = {175}, number = {3}, pages = {163-167}, doi = {10.7417/CT.2024.5057}, pmid = {38767073}, issn = {1972-6007}, mesh = {Humans ; *Reproductive Techniques, Assisted/legislation & jurisprudence/ethics ; Italy ; Female ; Male ; Health Services Accessibility/legislation & jurisprudence ; Cryopreservation ; Parental Consent/legislation & jurisprudence ; Informed Consent/legislation & jurisprudence ; }, abstract = {The law (No.40/2004) stipulates that consent to Medically Assisted Procreation (MAP) remains irrevocable post ovum fertilization. Cryo-preservation introduces complexities, enabling embryo implantation requests after a couple's separation and the dissolution of the original parenthood plan. Constitutional Court Ruling No.161 in 2023 affirmed that the prohibition of revoking consent to MAP aligns with the Italian Constitution and the jurisprudence of the European Court of Human Rights. This delicate equilibrium of conflicting interests upholds human freedom, allowing consent revocation prior to ovocyte fertilization. Permitting revocation until implantation could inflict more significant harm: the infertile woman can in fact miss the opportunity to become a mother, impacting her psychophysical well-being and freedom of self-determination. Moreover, the embryo loses the chance to live, remaining in cryopreservation, which violates its dignity. Addressing this issue requires thorough communication by medical profession-als to inform couples about the limitations on consent revocation. An element of objectivity in terms of standards and evidence-based guidelines, from which norms must originate, is of utmost importance. Relying on broadly shared rules, especially at the international level, is vital in light of the unremitting scientific advances in MAP, as in other areas of medicine, which will open up new opportunities for which current legal/regulatory frameworks are inadequate.}, } @article {pmid38766825, year = {2025}, author = {Tedeschi, V and Sapienza, S and Ciancio, R and Canzoniero, LMT and Pannaccione, A and Secondo, A}, title = {Lysosomal Channels as New Molecular Targets in the Pharmacological Therapy of Neurodegenerative Diseases via Autophagy Regulation.}, journal = {Current neuropharmacology}, volume = {23}, number = {4}, pages = {375-383}, pmid = {38766825}, issn = {1875-6190}, support = {PE0000006//National Recovery and Resilience Plan (NRRP), project MNESYS/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Autophagy/drug effects/physiology ; *Lysosomes/drug effects/metabolism ; Animals ; *Transient Receptor Potential Channels/metabolism/drug effects ; Calcium Channels/metabolism/drug effects ; }, abstract = {Besides controlling several organellar functions, lysosomal channels also guide the catabolic "self-eating" process named autophagy, which is mainly involved in protein and organelle quality control. Neuronal cells are particularly sensitive to the rate of autophagic flux either under physiological conditions or during the degenerative process. Accordingly, neurodegeneration occurring in Parkinson's (PD), Alzheimer's (AD), and Huntington's Diseases (HD), and Amyotrophic Lateral Sclerosis (ALS) as well as Lysosomal Storage Diseases (LSD) is partially due to defective autophagy and accumulation of toxic aggregates. In this regard, dysfunction of lysosomal ionic homeostasis has been identified as a putative cause of aberrant autophagy. From a therapeutic perspective, Transient Receptor Potential Channel Mucolipin 1 (TRPML1) and Two-Pore Channel isoform 2 (TPC2), regulating lysosomal homeostasis, are now considered promising druggable targets in neurodegenerative diseases. Compelling evidence suggests that pharmacological modulation of TRPML1 and TPC2 may rescue the pathological phenotype associated with autophagy dysfunction in AD, PD, HD, ALS, and LSD. Although pharmacological repurposing has identified several already used drugs with the ability to modulate TPC2, and several tools are already available for the modulation of TRPML1, many efforts are necessary to design and test new entities with much higher specificity in order to reduce dysfunctional autophagy during neurodegeneration.}, } @article {pmid38765269, year = {2024}, author = {Cheng, J and Niu, X and Li, H and Yang, Q and Du, K}, title = {Evaluation of the therapeutic effects of rehabilitation therapy on patients with amyotrophic lateral sclerosis-a meta-analysis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1389146}, pmid = {38765269}, issn = {1664-2295}, abstract = {OBJECTIVE: To investigate the effect of rehabilitation therapy on the global function, respiratory function, and quality of life in patients with amyotrophic lateral sclerosis (ALS).

METHODS: PubMed, Web of Science, and The National Library of Medicine (NLM) were systematically searched and the search period was between the date of database establishment and December 31, 2023. The outcome measures finally analyzed included the ALS functional rating scale/revised (ALSFRS/ALSFRS-R), forced vital capacity percentage predicted (FVC%), fatigue severity scale (FSS), and maximal expiratory pressure (MEP).

RESULTS: A total of 13 randomized controlled trials (RCTs) were included, and 5 outcome measures were pooled and analyzed. A total of 657 patients with ALS were enrolled, with 299 in the experimental group (rehabilitation therapy, such as resistance training, endurance training, aerobic training, respiratory muscle training, and standard rehabilitation therapy) and 358 in the control group (conventional interventions, such as simple joint movements or daily stretching). The ALSFRS scores were better in the experimental group than in the control group at 0-4 months (MD = 3.36, 95% CI: 0.82, 5.91, Z = 2.59, p = 0.009) and at 5-8 months (MD = 5.00, 95% CI: -2.42, 7.58, Z = 3.80, p < 0.001). Moreover, the ALSFRS-R scores of the experimental group was better than that of the control group at 5-8 months (MD = 2.83, 95% CI: 1.21, 4.45, Z = 3.42, p < 0.001) and 9-12 months (MD = 1.87, 95% CI: -0.37, 4.11, Z = 1.63, p = 0.10). It was also found that the MEP value of the experimental group was significantly better than that of the control group after intervention (MD = 18.49, 95% CI: 1.47, 35.50, Z = 2.13, p = 0.03). However, there were no significant differences in FVC% value and FSS scores at 0-5 months and 6-12 months between the two groups.

CONCLUSION: Rehabilitation therapy is helpful in improving the short-, medium-, and long-term global function score of patients with ALS, with positive effects on respiratory function.}, } @article {pmid38765264, year = {2024}, author = {Colognesi, M and Shkodra, A and Gabbia, D and Kawamata, H and Manfredi, PL and Manfredi, G and De Martin, S}, title = {Sex-dependent effects of the uncompetitive N-methyl-D-aspartate receptor antagonist REL-1017 in G93A-SOD1 amyotrophic lateral sclerosis mice.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1384829}, pmid = {38765264}, issn = {1664-2295}, support = {R35 NS122209/NS/NINDS NIH HHS/United States ; }, abstract = {INTRODUCTION: The pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the demise of motor neurons has been linked to excitotoxicity caused by excessive calcium influx via N-methyl-D-aspartate receptors (NMDARs), suggesting that uncompetitive NMDAR antagonism could be a strategy to attenuate motor neuron degeneration. REL-1017, the dextro-isomer of racemic methadone, is a low-affinity uncompetitive NMDAR antagonist. Importantly, in humans REL-1017 has shown excellent tolerability in clinical trials for major depression.

METHODS: Here, we tested if REL-1017 improves the disease phenotypes in the G93A SOD1 mouse, a well-established model of familial ALS, by examining survival and motor functions, as well as the expression of genes and proteins involved in neuroplasticity.

RESULTS: We found a sex-dependent effect of REL-1017 in G93A SOD1 mice. A delay of ALS symptom onset, assessed as 10%-decrease of body weight (p < 0.01 vs. control untreated mice) and an extension of lifespan (p < 0.001 vs. control untreated mice) was observed in male G93A SOD1 mice. Female G93A SOD1 mice treated with REL-1017 showed an improvement of muscle strength (p < 0.01 vs. control untreated mice). Both males and females treated with REL-1017 showed a decrease in hind limb clasping. Sex-dependent effects of REL-1017 were also detected in molecular markers of neuronal plasticity (PSD95 and SYN1) in the spinal cord and in the GluN1 NMDAR subunit in quadricep muscles.

CONCLUSION: In conclusion, this study provides preclinical in vivo evidence supporting the clinical evaluation of REL-1017 in ALS.}, } @article {pmid38765173, year = {2024}, author = {Souayah, N and Chen, H and Chong, ZZ and Patel, T and Pahwa, A and Menkes, DL and Cunningham, T}, title = {Novel strategy: Identifying new markers for demyelination in diabetic distal symmetrical polyneuropathy.}, journal = {Heliyon}, volume = {10}, number = {9}, pages = {e30419}, pmid = {38765173}, issn = {2405-8440}, abstract = {OBJECTIVE: To develop a novel strategy for identifying acquired demyelination in diabetic distal symmetrical polyneuropathy (DSP).

BACKGROUND: Motor nerve conduction velocity (CV) slowing in diabetic DSP exceeds expectations for pure axonal loss thus implicating superimposed acquired demyelination.

METHODS: After establishing demyelination confidence intervals by regression analysis of nerve conduction data from chronic inflammatory demyelinating polyneuropathy (CIDP), we prospectively studied CV slowing in 90 diabetic DSP patients with and without at least one motor nerve exhibiting CV slowing (groups A and B) into the demyelination range by American Academy of Neurology (AAN) criteria respectively and 95 amyotrophic lateral sclerosis (ALS) patients. Simultaneously, secretory phospholipase A2 (sPLA2) activity was assessed in both diabetic groups and 46 healthy controls.

RESULTS: No ALS patient exhibited CV slowing in more than two motor nerves based on AAN criteria or the confidence intervals. Group A demonstrated a significantly higher percentage of patients as compared to group B fulfilling the above criteria, with an additional criterion of at least one motor nerve exhibiting CV slowing in the demyelinating range and a corresponding F response in the demyelinating range by AAN criteria (70.3 % vs. 1.9 %; p < 0.0001). Urine sPLA2 activity was increased significantly in diabetic groups as compared to healthy controls (942.9 ± 978.0 vs. 591.6 ± 390.2 pmol/min/ml, p < 0.05), and in group A compared to Group B (1328.3 ± 1274.2 vs. 673.8 ± 576.9 pmol/min/ml, p < 0.01). More patients with elevated sPLA2 activity and more than 2 motor nerves with CV slowing in the AAN or the confidence intervals were identified in group A as compared to group B (35.1 % vs. 5.7 %, p < 0.001). Furthermore, 13.5 % of patients in diabetic DSP Group A, and no patients in diabetic DSP Group B, fulfilled an additional criterion of more than one motor nerve with CV slowing into the demyelinating range with its corresponding F response into the demyelinating range by AAN criteria.

CONCLUSION: A combination of regression analysis of electrodiagnostic data and a urine biological marker of systemic inflammation identifies a subgroup of diabetic DSP with superimposed acquired demyelination that may respond favorably to immunomodulatory therapy.}, } @article {pmid38763702, year = {2024}, author = {Dorrity, TJ and Shin, H and Gertie, JA and Chung, H}, title = {The Sixth Sense: Self-nucleic acid sensing in the brain.}, journal = {Advances in immunology}, volume = {161}, number = {}, pages = {53-83}, pmid = {38763702}, issn = {1557-8445}, support = {R01 AR050026/AR/NIAMS NIH HHS/United States ; R01 NS127802/NS/NINDS NIH HHS/United States ; T32 AR076953/AR/NIAMS NIH HHS/United States ; T32 GM145440/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Brain/metabolism/immunology ; Animals ; *Receptors, Pattern Recognition/metabolism ; *Immunity, Innate ; *Nucleic Acids/immunology/metabolism ; Homeostasis ; Signal Transduction ; }, abstract = {Our innate immune system uses pattern recognition receptors (PRRs) as a first line of defense to detect microbial ligands and initiate an immune response. Viral nucleic acids are key ligands for the activation of many PRRs and the induction of downstream inflammatory and antiviral effects. Initially it was thought that endogenous (self) nucleic acids rarely activated these PRRs, however emerging evidence indicates that endogenous nucleic acids are able to activate host PRRs in homeostasis and disease. In fact, many regulatory mechanisms are in place to finely control and regulate sensing of self-nucleic acids by PRRs. Sensing of self-nucleic acids is particularly important in the brain, as perturbations to nucleic acid sensing commonly leads to neuropathology. This review will highlight the role of nucleic acid sensors in the brain, both in disease and homeostasis. We also indicate the source of endogenous stimulatory nucleic acids where known and summarize future directions for the study of this growing field.}, } @article {pmid38762759, year = {2024}, author = {Wang, Z and Xiong, S and Wu, Z and Wang, X and Gong, Y and Zhu, WG and Xu, X}, title = {VCP/p97 UFMylation stabilizes BECN1 and facilitates the initiation of autophagy.}, journal = {Autophagy}, volume = {20}, number = {9}, pages = {2041-2054}, pmid = {38762759}, issn = {1554-8635}, mesh = {*Autophagy/physiology/genetics ; Humans ; *Valosin Containing Protein/metabolism/genetics ; *Beclin-1/metabolism ; *Ubiquitination ; Ataxin-3/metabolism/genetics ; Ubiquitin-Protein Ligases/metabolism ; HeLa Cells ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Stability ; HEK293 Cells ; Intracellular Signaling Peptides and Proteins ; }, abstract = {Macroautophagy/autophagy is essential for the degradation and recycling of cytoplasmic materials. The initiation of this process is determined by phosphatidylinositol-3-kinase (PtdIns3K) complex, which is regulated by factor BECN1 (beclin 1). UFMylation is a novel ubiquitin-like modification that has been demonstrated to modulate several cellular activities. However, the role of UFMylation in regulating autophagy has not been fully elucidated. Here, we found that VCP/p97 is UFMylated on K109 by the E3 UFL1 (UFM1 specific ligase 1) and this modification promotes BECN1 stabilization and assembly of the PtdIns3K complex, suggesting a role for VCP/p97 UFMylation in autophagy initiation. Mechanistically, VCP/p97 UFMylation stabilizes BECN1 through ATXN3 (ataxin 3)-mediated deubiquitination. As a key component of the PtdIns3K complex, stabilized BECN1 facilitates assembly of this complex. Re-expression of VCP/p97, but not the UFMylation-defective mutant, rescued the VCP/p97 depletion-induced increase in MAP1LC3B/LC3B protein expression. We also showed that several pathogenic VCP/p97 mutations identified in a variety of neurological disorders and cancers were associated with reduced UFMylation, thus implicating VCP/p97 UFMylation as a potential therapeutic target for these diseases. Abbreviation: ATG14:autophagy related 14; Baf A1:bafilomycin A1;CMT2Y: Charcot-Marie-Toothdisease, axonal, 2Y; CYB5R3: cytochromeb5 reductase 3; DDRGK1: DDRGK domain containing 1; DMEM:Dulbecco'smodified Eagle's medium;ER:endoplasmic reticulum; FBS:fetalbovine serum;FTDALS6:frontotemporaldementia and/or amyotrophic lateral sclerosis 6; IBMPFD1:inclusion bodymyopathy with early-onset Paget disease with or withoutfrontotemporal dementia 1; LC-MS/MS:liquid chromatography tandem mass spectrometry; MAP1LC3B/LC3B:microtubule associated protein 1 light chain 3 beta; MS: massspectrometry; NPLOC4: NPL4 homolog, ubiquitin recognition factor;PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3;PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K:phosphatidylinositol 3-kinase; RPL26: ribosomal protein L26; RPN1:ribophorin I; SQSTM1/p62: sequestosome 1; UBA5: ubiquitin likemodifier activating enzyme 5; UFC1: ubiquitin-fold modifierconjugating enzyme 1; UFD1: ubiquitin recognition factor in ERassociated degradation 1; UFL1: UFM1 specific ligase 1; UFM1:ubiquitin fold modifier 1; UFSP2: UFM1 specific peptidase 2; UVRAG:UV radiation resistance associated; VCP/p97: valosin containingprotein; WT: wild-type.}, } @article {pmid38762656, year = {2024}, author = {Li, Z and Kang, H}, title = {Efficacy of non-pharmacological interventions for individuals with amyotrophic lateral sclerosis: systematic review and network meta-analysis of randomized control trials.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {11365}, pmid = {38762656}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/physiopathology ; Humans ; *Randomized Controlled Trials as Topic ; *Quality of Life ; *Network Meta-Analysis ; Exercise Therapy/methods ; Treatment Outcome ; Muscle Strength ; }, abstract = {This network meta-analysis (NMA) aimed to compare the efficacy of five non-pharmacological interventions, including exercise intervention (EI), nutritional intervention (NI), respiratory intervention (RI), psychological intervention (PSI), and integrated physical intervention (IPI), on functional status, quality of life, muscle strength, pulmonary function, and safety in patients with amyotrophic lateral sclerosis (ALS). We searched nine databases, PubMed, Cochrane, Embase, Scopus, Web of Science, CNKI, CBM, WFPD, and CSTJ, for randomized controlled trials of ALS patients. The primary outcome was the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score. Secondary outcomes were the McGill Quality of Life Questionnaire (McGill-QoL), Medical Research Council (MRC)-sum score, Forced Vital Capacity (FVC), and Fatigue Severity Scale (FSS) score. This NMA was conducted using random-effect models to calculate the standard mean difference (SMD) and 95% confidence interval (CI). All types of supplemental interventions had some benefit for patients with ALS. EI had a beneficial effect on the ALSFRS-R score (SMD: 1.01; 95% CI 0.50-1.51), FVC (SMD: 0.78; 95% CI 0.02-1.55), McGill-QoL (SMD: 0.71 95% CI 0.33-1.08), and MRC (SMD: 1.11; 95% CI 0.08-2.14). RI had a beneficial effect on the ALSFRS-R score (SMD: 0.83 95% CI 0.12-1.55). IPI had a beneficial effect on the ALSFRS-R score (SMD: 0.65 95% CI 0.06-1.24). NI had a beneficial effect on the McGill-QoL (SMD: 0.63 95% CI 0.02-1.23). The current study findings support a multimodal intervention strategy with an emphasis on EI for slowing disease progression in patients with ALS.}, } @article {pmid38762243, year = {2024}, author = {Ponzini, E}, title = {Tear biomarkers.}, journal = {Advances in clinical chemistry}, volume = {120}, number = {}, pages = {69-115}, doi = {10.1016/bs.acc.2024.03.002}, pmid = {38762243}, issn = {2162-9471}, mesh = {Humans ; *Tears/metabolism/chemistry ; *Biomarkers/analysis/metabolism ; Eye Diseases/diagnosis/metabolism ; }, abstract = {An extensive exploration of lacrimal fluid molecular biomarkers in understanding and diagnosing a spectrum of ocular and systemic diseases is presented. The chapter provides an overview of lacrimal fluid composition, elucidating the roles of proteins, lipids, metabolites, and nucleic acids within the tear film. Pooled versus single-tear analysis is discussed to underline the benefits and challenges associated with both approaches, offering insights into optimal strategies for tear sample analysis. Subsequently, an in-depth analysis of tear collection methods is presented, with a focus on Schirmer's test strips and microcapillary tubes methods. Alternative tear collection techniques are also explored, shedding light on their applicability and advantages. Variability factors, including age, sex, and diurnal fluctuations, are examined in the context of their impact on tear biomarker analysis. The main body of the chapter is dedicated to discussing specific biomarkers associated with ocular discomfort and a wide array of ocular diseases. From dry eye disease and thyroid-associated ophthalmopathy to keratoconus, age-related macular degeneration, diabetic retinopathy, and glaucoma, the intricate relationship between molecular biomarkers and these conditions is thoroughly dissected. Expanding beyond ocular pathologies, the chapter explores the applicability of tear biomarkers in diagnosing systemic diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and cancer. This broader perspective underscores the potential of lacrimal fluid analysis in offering non-invasive diagnostic tools for conditions with far-reaching implications.}, } @article {pmid38761668, year = {2024}, author = {Silani, V}, title = {Continuity of treatment in ALS: Benefits and challenges of maintaining riluzole over the course of the disease.}, journal = {Journal of the neurological sciences}, volume = {461}, number = {}, pages = {123038}, doi = {10.1016/j.jns.2024.123038}, pmid = {38761668}, issn = {1878-5883}, mesh = {Humans ; *Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neuroprotective Agents/therapeutic use ; Male ; Female ; Middle Aged ; }, } @article {pmid38760965, year = {2024}, author = {Lee, SY and Yoo, SH and Cho, B and Kim, KH and Jang, MS and Shin, J and Hwang, I and Choi, SJ and Sung, JJ and Kim, MS}, title = {Burden and preparedness of care partners of people living with amyotrophic lateral sclerosis at home in Korea: A care partner survey.}, journal = {Muscle & nerve}, volume = {70}, number = {3}, pages = {306-315}, doi = {10.1002/mus.28115}, pmid = {38760965}, issn = {1097-4598}, support = {HC21C0115//Patient-Centered Clinical Research Coordinating Center(PACEN) funded by the Ministry of Health and Welfare, Republic of Korea/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology/nursing ; Male ; Republic of Korea/epidemiology ; Female ; *Caregivers/psychology ; Middle Aged ; Aged ; Adult ; Surveys and Questionnaires ; Depression/psychology/therapy/epidemiology ; Home Care Services ; Cost of Illness ; Tracheostomy ; Spouses/psychology ; Caregiver Burden/psychology ; }, abstract = {INTRODUCTION/AIMS: The care burden of people living with amyotrophic lateral sclerosis (pALS) increases with disease progression. This study aimed to investigate the home care status and preparedness of care partners of pALS (cALS) in Korea.

METHODS: An online survey was conducted with family care partners of patients diagnosed with ALS for over 1 year in 2022. The data collected included care time, depression evaluated using the patient health questionnaire-9 (PHQ-9), preparedness for caregiving scale (PCS), and caregiver competence scale (CCS). Results were compared based on whether the pALS underwent a tracheostomy or not.

RESULTS: Ninety-eight cALS of 98 pALS participated in the study, of whom 59 pALS had undergone tracheostomy. Among the cALS, 60.2% were spouses, and 34.7% were children. The cALS took care of the patients for 13 (8-20) hours/day (median, interquartile range [IQR]) on weekdays and 15 (10-24) h/day on weekends. Among the cALS, 91.8% were depressed, and 28.6% had severe depression. The median (IQR) PCS and CCS scores were low (11/32 (8-15) and 8/20 (8-11), respectively), and both were lower in those caring for patients without than with tracheostomy (p < .001 and p < .02, respectively). Most cALS (77.6%) wished to continue caring for their pALS at home.

DISCUSSION: Family care partners of pALS spend more than half of each day caring for patients and are often depressed. Most cALS preferred providing care at home, but felt ill-prepared. Designing home-based medical care is necessary for pALS to thrive at home.}, } @article {pmid38760935, year = {2024}, author = {Fiadeiro, MB and Diogo, JC and Silva, AA and Kim, YS and Cristóvão, AC}, title = {NADPH Oxidases in Neurodegenerative Disorders: Mechanisms and Therapeutic Opportunities.}, journal = {Antioxidants & redox signaling}, volume = {41}, number = {7-9}, pages = {522-541}, doi = {10.1089/ars.2023.0002}, pmid = {38760935}, issn = {1557-7716}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *NADPH Oxidases/metabolism/antagonists & inhibitors ; *Reactive Oxygen Species/metabolism ; Animals ; Oxidative Stress ; }, abstract = {Significance: The nicotinamide adenine dinucleotide phosphate oxidase (NOX) enzyme family, located in the central nervous system, is recognized as a source of reactive oxygen species (ROS) in the brain. Despite its importance in cellular processes, excessive ROS generation leads to cell death and is involved in the pathogenesis of neurodegenerative disorders. Recent advances: NOX enzymes contribute to the development of neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and stroke, highlighting their potential as targets for future therapeutic development. This review will discuss NOX's contribution and therapeutic targeting potential in neurodegenerative diseases, focusing on PD, AD, ALS, and stroke. Critical issues: Homeostatic and physiological levels of ROS are crucial for regulating several processes, such as development, memory, neuronal signaling, and vascular homeostasis. However, NOX-mediated excessive ROS generation is deeply involved in the damage of DNA, proteins, and lipids, leading to cell death in the pathogenesis of a wide range of diseases, namely neurodegenerative diseases. Future directions: It is essential to understand the role of NOX homologs in neurodegenerative disorders and the pathological mechanisms undergoing neurodegeneration mediated by increased levels of ROS. This further knowledge will allow the development of new specific NOX inhibitors and their application for neurodegenerative disease therapeutics. Antioxid. Redox Signal. 41, 522-541.}, } @article {pmid38760174, year = {2024}, author = {Pal, A and Grossmann, D and Glaß, H and Zimyanin, V and Günther, R and Catinozzi, M and Boeckers, TM and Sterneckert, J and Storkebaum, E and Petri, S and Wegner, F and Grill, SW and Pan-Montojo, F and Hermann, A}, title = {Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS.}, journal = {Life science alliance}, volume = {7}, number = {8}, pages = {}, pmid = {38760174}, issn = {2575-1077}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *RNA-Binding Protein FUS/metabolism/genetics ; *Glycolates/metabolism/pharmacology ; *Mitochondria/metabolism ; *Protein Deglycase DJ-1/metabolism/genetics ; *Lactic Acid/metabolism ; *Superoxide Dismutase-1/metabolism/genetics ; Membrane Potential, Mitochondrial ; Motor Neurons/metabolism ; Lysosomes/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)-both putative products of the Parkinson's disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.}, } @article {pmid38759931, year = {2024}, author = {Guo, X and Zhang, Z and Gu, J and Ke, P and Liu, J and Meng, Y and Zheng, W and Que, W and Fan, R and Luo, J and Xiao, F}, title = {FUDNC1-dependent mitophagy ameliorate motor neuron death in an amyotrophic lateral sclerosis mouse model.}, journal = {Neurobiology of disease}, volume = {197}, number = {}, pages = {106534}, doi = {10.1016/j.nbd.2024.106534}, pmid = {38759931}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Mitophagy/physiology ; *Motor Neurons/metabolism/pathology ; *Mice, Transgenic ; Mice ; *Disease Models, Animal ; *Mitochondrial Proteins/metabolism/genetics ; Membrane Proteins/metabolism/genetics ; Humans ; Spinal Cord/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, yet effective treatment is lacking. Moreover, the underlying pathomechanisms of ALS remain unclear, with impaired mitophagy function being increasingly recognized as a contributing factor. FUN14 domain-containing protein 1 (FUNDC1) is an autophagy receptor localized to the outer mitochondrial membrane and a mitochondrial membrane protein that mediates mitophagy and therefore considered as important factor in neurodegenerative diseases. However, its specific role in ALS is not yet clear. Therefore, this study aimed to investigate the regulatory role of FUNDC1 in ALS and determine its regulatory mechanisms. ALS transgenic mice were obtained and maintained under standard conditions. Cell lines were generated by stable transfection with hSOD1[G93A] or control vectors. Mice received intrathecal injections of AAV9 vectors expressing FUNDC1 or EGFP. Motor function was assessed through behavioral tests, and histological and immunostaining analyses were performed. Colocalization analysis was conducted in transfected cells, and protein expression was evaluated via western blotting. We first observed that FUNDC1 was significantly downregulated in the spinal cord tissues of SOD1[G93A] mice. FUNDC1 overexpression considerably improved locomotor activity and prolonged survival time in SOD1[G93A] mice. Mechanistically, reduced expression of FUNDC1 resulted in decreased mitophagy, as indicated by decreased recruitment through LC3 in SOD1[G93A] mice and cellular models. Consequently, this led to increased mitochondrial accumulation and cell apoptosis, exacerbating the ALS phenotype. Furthermore, we identified transcription factor FOXD3 as an essential upstream factor of FUNDC1, resulting in reduced transcription of FUNDC1 in ALS lesions. This study suggests a novel strategy of targeting FUNDC1-mediated mitophagy for developing therapeutic interventions to mitigate disease progression and improve outcomes for ALS patients.}, } @article {pmid38759788, year = {2024}, author = {Kumar, RP and Sivan, V and Bachir, H and Sarwar, SA and Ruzicka, F and O'Malley, GR and Lobo, P and Morales, IC and Cassimatis, ND and Hundal, JS and Patel, NV}, title = {Can Artificial Intelligence Mitigate Missed Diagnoses by Generating Differential Diagnoses for Neurosurgeons?.}, journal = {World neurosurgery}, volume = {187}, number = {}, pages = {e1083-e1088}, doi = {10.1016/j.wneu.2024.05.052}, pmid = {38759788}, issn = {1878-8769}, mesh = {Humans ; Diagnosis, Differential ; *Artificial Intelligence ; *Neurosurgeons ; *Missed Diagnosis ; Neurosurgery ; Diagnostic Errors ; }, abstract = {BACKGROUND/OBJECTIVE: Neurosurgery emphasizes the criticality of accurate differential diagnoses, with diagnostic delays posing significant health and economic challenges. As large language models (LLMs) emerge as transformative tools in healthcare, this study seeks to elucidate their role in assisting neurosurgeons with the differential diagnosis process, especially during preliminary consultations.

METHODS: This study employed 3 chat-based LLMs, ChatGPT (versions 3.5 and 4.0), Perplexity AI, and Bard AI, to evaluate their diagnostic accuracy. Each LLM was prompted using clinical vignettes, and their responses were recorded to generate differential diagnoses for 20 common and uncommon neurosurgical disorders. Disease-specific prompts were crafted using Dynamed, a clinical reference tool. The accuracy of the LLMs was determined based on their ability to identify the target disease within their top differential diagnoses correctly.

RESULTS: For the initial differential, ChatGPT 3.5 achieved an accuracy of 52.63%, while ChatGPT 4.0 performed slightly better at 53.68%. Perplexity AI and Bard AI demonstrated 40.00% and 29.47% accuracy, respectively. As the number of considered differentials increased from 2 to 5, ChatGPT 3.5 reached its peak accuracy of 77.89% for the top 5 differentials. Bard AI and Perplexity AI had varied performances, with Bard AI improving in the top 5 differentials at 62.11%. On a disease-specific note, the LLMs excelled in diagnosing conditions like epilepsy and cervical spine stenosis but faced challenges with more complex diseases such as Moyamoya disease and amyotrophic lateral sclerosis.

CONCLUSIONS: LLMs showcase the potential to enhance diagnostic accuracy and decrease the incidence of missed diagnoses in neurosurgery.}, } @article {pmid38759454, year = {2024}, author = {Wei, Y and Zhong, S and Yang, H and Wang, X and Lv, B and Bian, Y and Pei, Y and Xu, C and Zhao, Q and Wu, Y and Luo, D and Wang, F and Sun, H and Chen, Y}, title = {Current therapy in amyotrophic lateral sclerosis (ALS): A review on past and future therapeutic strategies.}, journal = {European journal of medicinal chemistry}, volume = {272}, number = {}, pages = {116496}, doi = {10.1016/j.ejmech.2024.116496}, pmid = {38759454}, issn = {1768-3254}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the first and second motoneurons (MNs), associated with muscle weakness, paralysis and finally death. The exact etiology of the disease still remains unclear. Currently, efforts to develop novel ALS treatments which target specific pathomechanisms are being studied. The mechanisms of ALS pathogenesis involve multiple factors, such as protein aggregation, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, apoptosis, inflammation etc. Unfortunately, to date, there are only two FDA-approved drugs for ALS, riluzole and edavarone, without curative treatment for ALS. Herein, we give an overview of the many pathways and review the recent discovery and preclinical characterization of neuroprotective compounds. Meanwhile, drug combination and other therapeutic approaches are also reviewed. In the last part, we analyze the reasons of clinical failure and propose perspective on the treatment of ALS in the future.}, } @article {pmid38759021, year = {2024}, author = {Pupillo, E and Al-Chalabi, A and Sassi, S and Arippol, E and Tinti, L and Vitelli, E and Copetti, M and Leone, MA and Bianchi, E}, title = {Methodological Quality of Clinical Trials in Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Journal of neuromuscular diseases}, volume = {11}, number = {4}, pages = {749-765}, pmid = {38759021}, issn = {2214-3602}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Clinical Trials as Topic/standards ; *Research Design ; }, abstract = {BACKGROUND: More than 200 clinical trials have been performed worldwide in ALS so far, but no agents with substantial efficacy on disease progression have been found.

OBJECTIVE: To describe the methodological quality of all clinical trials performed in ALS and published before December 31, 2022.

METHODS: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta Analyses.

RESULTS: 213 trials were included. 47.4% manuscripts described preclinical study evaluation, with a positive effect in all. 67.6% of trials were conducted with a parallel-arm design, while 12.7% were cross-over studies; 77% were randomized, while in 5.6% historical-controls were used for comparison. 70% of trials were double blind. Participant inclusion allowed forced vital capacity (or corresponding slow vital capacity)<50% in 15% cases, between 55-65% in 21.6%, between 70-80% in 14.1% reports, and 49.3% of the evaluated manuscripts did not provide a minimum value for respiratory capacity at inclusion. Disease duration was < 6-months in 6 studies, 7-36 months in 68, 37-60 months in 24, 8 trials requested more than 1-month of disease duration, while in 107 reports a disease duration was not described. Dropout rate was ≥20% in 30.5% trials, while it was not reported for 8.5%.

CONCLUSION: The methodological quality of the included studies was highly variable. Major issues to be addressed in future ALS clinical trials include: the requirement for standard animal toxicology and phase I studies, the resource-intensive nature of phase II-III studies, adequate study methodology and design, a good results reporting.}, } @article {pmid38758376, year = {2024}, author = {Li, X and Song, C and Wang, Y and Wang, J and Tang, Q and Wu, Z and Zhou, Y and Sun, J and Jia, Y and Lin, Z and Li, S}, title = {Accuracy of 14 intraocular lens power calculation formulas in extremely long eyes.}, journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie}, volume = {262}, number = {11}, pages = {3619-3628}, pmid = {38758376}, issn = {1435-702X}, support = {2020SKC2002//Project Supported by Science and Technology Innovation Program of Socialization Investment of Hunan Province/ ; }, mesh = {Humans ; Retrospective Studies ; *Lenses, Intraocular ; *Refraction, Ocular/physiology ; *Axial Length, Eye ; Female ; Male ; Aged ; *Biometry/methods ; *Optics and Photonics ; Middle Aged ; Reproducibility of Results ; Visual Acuity ; Aged, 80 and over ; Adult ; Lens Implantation, Intraocular ; }, abstract = {PURPOSE: To compare the accuracy of 14 formulas in calculating intraocular lens (IOL) power in extremely long eyes with axial length (AL) over 30.0 mm.

METHODS: In this retrospective study, 211 eyes (211 patients) with ALs > 30.0 mm were successfully treated with cataract surgery without complications. Ocular biometric parameters were obtained from IOLMaster 700. Fourteen formulas were evaluated using the optimized A constants: Barrett Universal II (BUII), Kane, Emmetropia Verifying Optical (EVO) 2.0, PEARL-DGS, T2, SRK/T, Holladay 1, Holladay 2, Haigis and Wang-Koch AL adjusted formulas (SRK/Tmodified-W/K, Holladay 1modified-W/K, Holladay 1NP-modified-W/K, Holladay 2modified-W/K, Holladay 2NP-modified-W/K). The mean prediction error (PE) and standard deviation (SD), mean absolute errors (MAE), median absolute errors (MedAE), and the percentage of prediction errors (PEs) within ± 0.25 D, ± 0.50 D, ± 1.00 D were analyzed.

RESULTS: The Kane formula had the smallest MAE (0.43 D) and MedAE (0.34 D). The highest percentage of PE within ± 0.25 D was for EVO 2.0 (37.91%) and the Holladay 1NP-modified-W/K formulas (37.91%). The Kane formula had the highest percentage of PEs in the range of ± 0.50, ± 0.75, ± 1.00, and ± 2.00 D. There was no significant difference in PEs within ± 0.25, ± 0.50 ± 0.75 and ± 1.00 D between BUII, Kane, EVO 2.0 and Wang-Koch AL adjusted formulas (P > .05) by using Cochran's Q test. The Holladay 2modified-W/K formula has the lowest percentage of hyperopic outcomes (29.38%).

CONCLUSIONS: The BUII, Kane, EVO 2.0 and Wang-Koch AL adjusted formulas have comparable accuracy for IOL power calculation in eyes with ALs > 30.0 mm.}, } @article {pmid38758353, year = {2024}, author = {Mavroudis, I and Alexiou, P and Petridis, F and Ciobica, A and Balmus, IM and Gireadă, B and Gurzu, IL and Novac, O and Novac, B}, title = {Patients' and caregivers' attitudes towards patient assisted suicide or euthanasia in amyotrophic lateral sclerosis-a meta-analysis.}, journal = {Acta neurologica Belgica}, volume = {124}, number = {5}, pages = {1489-1498}, pmid = {38758353}, issn = {2240-2993}, mesh = {*Amyotrophic Lateral Sclerosis/psychology ; Humans ; *Suicide, Assisted/psychology ; *Caregivers/psychology ; *Euthanasia/psychology ; Attitude to Death ; }, abstract = {Assisted suicide and euthanasia are long debated topics in amyotrophic lateral sclerosis (ALS) patients care. We conducted a meta-analysis to evaluate the attitudes of ALS patients and their caregivers toward physician-assisted suicide (PAS) and euthanasia. Also, we were interested to identify the factors associated with the positive or negative attitude of patients and caregivers towards PAS/euthanasia. A thorough search of the online databases (PubMed, Cochrane Library, and Web of Science) was conducted and eligibility criteria according to the PRISMA guidelines were used to include the studies in the current meta-analysis. The assessment of the quality of the selected studies was carried out using a pre-specified set of criteria by Cochrane. The studies that were selected for this meta-analysis suggested that the expression of the wish to die is more likely correlated with depression, anxiety, hopelessness, and lack of optimism. The overall prevalence of considering PAS/euthanasia significantly varies in a dependent manner over the cultural, legal, and societal factors. In this context, we found that the opinion on this topic can be deeply personal and may vary widely among individuals and communities. Lower quality of life and lower religiosity were associated with a positive attitude toward PAS/euthanasia. On the other hand, patients who are more religious are less likely to choose PAS/euthanasia. Gender does not appear to play a significant role in determining attitudes towards PAS/euthanasia in ALS patients. Other factors, such as education and psychological state, could also be important. In conclusion, end-of-life decisions in ALS patients are complex and require careful consideration of individual values, beliefs, and preferences. Understanding the factors that influence a patient's attitude towards PAS/euthanasia can help healthcare providers to offer appropriate care and support for these patients and their families.}, } @article {pmid38758288, year = {2024}, author = {Qi, C and Kobayashi, R and Kawakatsu, S and Kametani, F and Scheres, SHW and Goedert, M and Hasegawa, M}, title = {Tau filaments with the chronic traumatic encephalopathy fold in a case of vacuolar tauopathy with VCP mutation D395G.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {86}, pmid = {38758288}, issn = {1432-0533}, support = {JSPS KAKENHI//Japanese society for the promotion of science/ ; MC_UP_A025_1013/MRC_/Medical Research Council/United Kingdom ; JPMH20GB1002//Ministry of Health, Labour and Welfare/ ; JPMH23GB1003//Ministry of Health, Labour and Welfare/ ; MC_UP_A025-1013/MRC_/Medical Research Council/United Kingdom ; JP20K07922//Japanese society for the promotion of science/ ; MC_U105184291/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Tauopathies/genetics/pathology ; *Chronic Traumatic Encephalopathy/pathology/genetics ; *tau Proteins/genetics/metabolism ; *Valosin Containing Protein/genetics ; *Mutation ; Vacuoles/pathology/ultrastructure ; Male ; Adenosine Triphosphatases/genetics ; Cell Cycle Proteins/genetics ; Middle Aged ; Frontotemporal Dementia/genetics/pathology ; Brain/pathology ; Female ; }, abstract = {Dominantly inherited mutation D395G in the gene encoding valosin-containing protein causes vacuolar tauopathy, a type of behavioural-variant frontotemporal dementia, with marked vacuolation and abundant filamentous tau inclusions made of all six brain isoforms. Here we report that tau inclusions were concentrated in layers II/III of the frontotemporal cortex in a case of vacuolar tauopathy. By electron cryomicroscopy, tau filaments had the chronic traumatic encephalopathy (CTE) fold. Tau inclusions of vacuolar tauopathy share this cortical location and the tau fold with CTE, subacute sclerosing panencephalitis and amyotrophic lateral sclerosis/parkinsonism-dementia complex, which are believed to be environmentally induced. Vacuolar tauopathy is the first inherited disease with the CTE tau fold.}, } @article {pmid38758193, year = {2024}, author = {Oliveira Santos, M and de Carvalho, M}, title = {Profiling tofersen as a treatment of superoxide dismutase 1 amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {24}, number = {6}, pages = {549-553}, doi = {10.1080/14737175.2024.2355983}, pmid = {38758193}, issn = {1744-8360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Oligonucleotides/therapeutic use ; Oligonucleotides, Antisense/therapeutic use ; Biomarkers/blood ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disorder with a fatal outcome 3-5 years after disease onset due to respiratory complications. Superoxide dismutase 1 (SOD1) mutations are found in about 2% of all patients. Tofersen is a novel oligonucleotide antisense drug specifically developed to treat SOD1-ALS patients.

AREAS COVERED: Our review covers and discusses tofersen pharmacological properties and its phase I/II and III clinical trials results. Other available drugs and their limitations are also addressed.

EXPERT OPINION: VALOR study failed to meet the primary endpoint (change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale score from baseline to week 28, tofersen arm vs. placebo), but a significant reduction in plasma neurofilament light chain (NfL) levels was observed in tofersen arm (60% vs. 20%). PrefALS study has proposed plasma NfL has a potential biomarker for presymptomatic treatment, since it increases 6-12 months before phenoconversion. There is probably a delay between plasma NfL reduction and the clinical benefit. ATLAS study will allow more insights regarding tofersen clinical efficacy in disease progression rate, survival, and even disease onset delay in presymptomatic SOD1 carriers.}, } @article {pmid38758158, year = {2024}, author = {Zou, X and Shi, Y and Zhang, T and Huang, A and Cui, H and Wang, T}, title = {Electroacupuncture Combined with Chinese Herbal Medicine, Qidong Huoluo Granule, for Amyotrophic Lateral Sclerosis: An 8-Month Case Report.}, journal = {Alternative therapies in health and medicine}, volume = {}, number = {}, pages = {}, pmid = {38758158}, issn = {1078-6791}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an adult neurodegenerative disorder characterized by progressive muscle weakness and eventual paralysis, for which there is currently no curative treatment. Mainstream medical interventions primarily focus on providing supportive care. However, acupuncture offers promising avenues for alleviating symptoms and enhancing quality of life. Specific acupuncture points are targeted to address bulbar paralysis as well as paralysis affecting the upper and lower extremities.

OBJECTIVE: To investigate the efficacy of electroacupuncture combined with Chinese herbal medicine in delaying disease progression and alleviating symptoms of bulbar paralysis in patients with ALS.

CASE PRESENTATION: A 51-year-old male presented with a 4-year and 8-month history of weakness in his left arm and both legs, accompanied by muscle cramps and diminished coordination, which had rapidly worsened over the past year. ALS was diagnosed, and the patient was initiated on oral Riluzole (50 mg) and Qidong Huoluo granule, a Chinese herbal compound, administered twice daily. Concurrently, he underwent acupuncture treatment sessions twice weekly for over 8 months.

RESULTS: Following acupuncture therapy, the patient experienced gradual stabilization of symptoms, notably improvement in swallowing function. The combination of electroacupuncture and Qidong Huoluo granule resulted in sustained clinical enhancements post-treatment, including improvements in speech, coughing, articulation, and breathing.

CONCLUSION: Electroacupuncture therapy demonstrates the potential to slow disease progression and ameliorate symptoms of bulbar paralysis in ALS patients. However, further robust clinical research is imperative to explain the precise therapeutic role of electroacupuncture in managing this debilitating condition. Continued investigation into the efficacy and safety profile of electroacupuncture holds promise for advancing treatment modalities for ALS.}, } @article {pmid38757649, year = {2024}, author = {Lee, I and Mitsumoto, H and Lee, S and Kasarskis, E and Rosenbaum, M and Factor-Litvak, P and Nieves, JW}, title = {Reply to Glycemic Index/Load Effect on ALS Progression: Potential Interaction with Riluzole.}, journal = {Annals of neurology}, volume = {96}, number = {1}, pages = {208-209}, doi = {10.1002/ana.26971}, pmid = {38757649}, issn = {1531-8249}, support = {K23NS131586/NS/NINDS NIH HHS/United States ; K23NS131586/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Riluzole/therapeutic use/pharmacology ; *Disease Progression ; *Glycemic Index/drug effects ; Neuroprotective Agents/therapeutic use/pharmacology ; Blood Glucose/drug effects/metabolism ; }, } @article {pmid38756356, year = {2024}, author = {Rennie, O and Sharma, M and Helwa, N}, title = {Colorectal anastomotic leakage: a narrative review of definitions, grading systems, and consequences of leaks.}, journal = {Frontiers in surgery}, volume = {11}, number = {}, pages = {1371567}, pmid = {38756356}, issn = {2296-875X}, abstract = {BACKGROUND: Anastomotic leaks (ALs) are a significant and feared postoperative complication, with incidence of up to 30% despite advances in surgical techniques. With implications such as additional interventions, prolonged hospital stays, and hospital readmission, ALs have important impacts at the level of individual patients and healthcare providers, as well as healthcare systems as a whole. Challenges in developing unified definitions and grading systems for leaks have proved problematic, despite acknowledgement that colorectal AL is a critical issue in intestinal surgery with serious consequences. The aim of this study was to construct a narrative review of literature surrounding definitions and grading systems for ALs, and consequences of this postoperative complication.

METHODS: A literature review was conducted by examining databases including PubMed, Web of Science, OVID Embase, Google Scholar, and Cochrane library databases. Searches were performed with the following keywords: anastomosis, anastomotic leak, colorectal, surgery, grading system, complications, risk factors, and consequences. Publications that were retrieved underwent further assessment to ensure other relevant publications were identified and included.

RESULTS: A universally accepted definition and grading system for ALs continues to be lacking, leading to variability in reported incidence in the literature. Additional factors add to variability in estimates, including differences in the anastomotic site and institutional/individual differences in operative technique. Various groups have worked to publish guidelines for defining and grading AL, with the International Study Group of Rectal Cancer (ISGRC/ISREC) definition the current most recommended universal definition for colorectal AL. The burden of AL on patients, healthcare providers, and hospitals is well documented in evidence from leak consequences, such as increased morbidity and mortality, higher reoperation rates, and increased readmission rates, among others.

CONCLUSIONS: Colorectal AL remains a significant challenge in intestinal surgery, despite medical advancements. Understanding the progress made in defining and grading leaks, as well as the range of negative outcomes that arise from AL, is crucial in improving patient care, reduce surgical mortality, and drive further advancements in earlier detection and treatment of AL.}, } @article {pmid38755145, year = {2024}, author = {Garcia-Montojo, M and Fathi, S and Rastegar, C and Simula, ER and Doucet-O'Hare, T and Cheng, YHH and Abrams, RPM and Pasternack, N and Malik, N and Bachani, M and Disanza, B and Maric, D and Lee, MH and Wang, H and Santamaria, U and Li, W and Sampson, K and Lorenzo, JR and Sanchez, IE and Mezghrani, A and Li, Y and Sechi, LA and Pineda, S and Heiman, M and Kellis, M and Steiner, J and Nath, A}, title = {TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4163}, pmid = {38755145}, issn = {2041-1723}, support = {I01 BX002466/BX/BLRD VA/United States ; NS003130//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; Female ; Humans ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Asparaginase/genetics/metabolism ; Autoantigens/genetics/metabolism ; Brain/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Motor Cortex/metabolism/pathology ; *Neurons/metabolism/pathology ; *TDP-43 Proteinopathies/metabolism/pathology/genetics ; Endogenous Retroviruses/genetics/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL1 gene harbors a copy of the human endogenous retrovirus HML-2, whose overexpression contributes to ALS pathogenesis. Here we show that ASRGL1 expression was diminished in ALS brain samples by RNA sequencing, immunohistochemistry, and western blotting. TDP-43 and ASRGL1 colocalized in neurons but, in the absence of ASRGL1, TDP-43 aggregated in the cytoplasm. TDP-43 was found to be prone to isoaspartate formation and a substrate for ASRGL1. ASRGL1 silencing triggered accumulation of misfolded, fragmented, phosphorylated and mislocalized TDP-43 in cultured neurons and motor cortex of female mice. Overexpression of ASRGL1 restored neuronal viability. Overexpression of HML-2 led to ASRGL1 silencing. Loss of ASRGL1 leading to TDP-43 aggregation may be a critical mechanism in ALS pathophysiology.}, } @article {pmid38753998, year = {2025}, author = {Yin, Z and Yang, Z and Liu, Y and Zhao, L and Liang, F}, title = {Oxidative stress and neurodegenerative diseases: a bidirectional Mendelian randomization study.}, journal = {Nutritional neuroscience}, volume = {28}, number = {1}, pages = {107-115}, doi = {10.1080/1028415X.2024.2352195}, pmid = {38753998}, issn = {1476-8305}, mesh = {*Mendelian Randomization Analysis ; Humans ; *Oxidative Stress ; *Neurodegenerative Diseases/genetics ; *Genome-Wide Association Study ; Alzheimer Disease/genetics ; Uric Acid/blood ; Zinc/blood ; Amyotrophic Lateral Sclerosis/genetics ; Parkinson Disease/genetics ; alpha-Tocopherol/blood ; Biomarkers/blood ; }, abstract = {INTRODUCTION: Oxidative stress (OS) has been linked to neurodegenerative diseases in numerous epidemiological studies; however, whether it is a pathogenesis or a downstream factor remains controversial.

METHODS: A two-sample bidirectional Mendelian randomization (MR) analysis was implemented to examine evidence of causality of 15 OS injury markers with 3 major neurodegenerative diseases using available genome-wide association studies statistics. As a main approach, inverse-variance weighted (IVW) analysis was performed. The weighted-median (WM) analysis was used to validate the relationship. In order to investigate the existence of horizontal pleiotropy and correct the IVW estimate, the Radial MR approach was applied. To gauge the consistency and robustness of the findings, several sensitivity and pleiotropy analyses were used. For this analysis, p < 0.05 indicates a nominally causal association; according to the Bonferroni correction test, p < 0.0011 indicates a statistically significant causal association.

RESULTS: Via IVW and WM, in directional MR, it was genetically predicted that zinc was nominally causally correlated with the risk of Parkinson's disease but not after Bonferroni correction test; alpha-tocopherol was nominally causally correlated with the risk of Amyotrophic lateral sclerosis (ALS) but not after Bonferroni correction test; furthermore, in reverse MR, it was genetically predicted that Alzheimer's disease was causally correlated with uric acid but not after Bonferroni correction test. These above findings were stable across sensitivity and pleiotropy analyses.

CONCLUSIONS: Based on the current study, there is no authentic genetic causal association between OS biomarkers and neurodegenerative diseases. The complex relationship is required to be confirmed in future experimental research.}, } @article {pmid38753768, year = {2024}, author = {Prasad, K and Hassan, MI and Raghuvanshi, S and Kumar, V}, title = {Understanding the relationship between cerebellum and the frontal-cortex region of C9orf72-related amyotrophic lateral sclerosis: A comparative analysis of genetic features.}, journal = {PloS one}, volume = {19}, number = {5}, pages = {e0301267}, pmid = {38753768}, issn = {1932-6203}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; C9orf72 Protein/genetics/metabolism ; *Cerebellum/metabolism/pathology ; *Frontal Lobe/metabolism/pathology ; Frontotemporal Dementia/genetics/pathology/metabolism ; MicroRNAs/genetics/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative diseases for which at present no cure is available. Despite the extensive research the progress from diagnosis to prognosis in ALS and frontotemporal dementia (FTD) has been slow which represents suboptimal understanding of disease pathophysiological processes. In recent studies, several genes have been associated with the ALS and FTD diseases such as SOD1, TDP43, and TBK1, whereas the hexanucleotide GGGGCC repeat expansion (HRE) in C9orf72 gene is a most frequent cause of ALS and FTD, that has changed the understanding of these diseases.

METHODS: The goal of this study was to identify and spatially determine differential gene expression signature differences between cerebellum and frontal cortex in C9orf72-associated ALS (C9-ALS), to study the network properties of these differentially expressed genes, and to identify miRNAs targeting the common differentially expressed genes in both the tissues. This study thus highlights underlying differential cell susceptibilities to the disease mechanisms in C9-ALS and suggesting therapeutic target selection in C9-ALS.

RESULTS: In this manuscript, we have identified that the genes involved in neuron development, protein localization and transcription are mostly enriched in cerebellum of C9-ALS patients, while the UPR-related genes are enriched in the frontal cortex. Of note, UPR pathway genes were mostly dysregulated both in the C9-ALS cerebellum and frontal cortex. Overall, the data presented here show that defects in normal RNA processing and the UPR pathway are the pathological hallmarks of C9-ALS. Interestingly, the cerebellum showed more strong transcriptome changes than the frontal cortex.

CONCLUSION: Interestingly, the cerebellum region showed more significant transcriptomic changes as compared to the frontal cortex region suggesting its active participation in the disease process. This nuanced understanding may offer valuable insights for the development of targeted therapeutic strategies aimed at mitigating disease progression in C9-ALS.}, } @article {pmid38751620, year = {2024}, author = {Shojaei, M and Zhou, Q and Palumbo, G and Schaefer, R and Kaskinoro, J and Vehmaan-Kreula, P and Bartenstein, P and Brendel, M and Edbauer, D and Lindner, S}, title = {Development and Preclinical Evaluation of a Copper-64-Labeled Antibody Targeting Glycine-Alanine Dipeptides for PET Imaging of C9orf72-Associated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {5}, pages = {1404-1414}, pmid = {38751620}, issn = {2575-9108}, abstract = {Aggregating poly(glycine-alanine) (poly-GA) is derived from the unconventional translation of the pathogenic intronic hexanucleotide repeat expansion in the C9orf72 gene, which is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Poly-GA accumulates predominantly in neuronal cytoplasmic inclusions unique to C9orf72 ALS/FTD patients. Poly-GA is, therefore, a promising target for PET/CT imaging of FTD/ALS to monitor disease progression and therapeutic interventions. A novel [64]Cu-labeled anti-GA antibody (mAb1A12) targeting the poly-GA protein was developed and evaluated in a transgenic mouse model. It was obtained with high radiochemical purity (RCP), radiochemical yield (RCY), and specific activity, and showed high stability in vitro and ex vivo and specifically bound to poly-GA. The affinity of NODAGA-mAb1A12 for poly-GA was not affected by this modification. [[64]Cu]Cu-NODAGA-mAb1A12 was injected into transgenic mice expressing GFP-(GA)175 in excitatory neurons driven by Camk2a-Cre and in control littermates. PET/CT imaging was performed at 2, 20, and 40 h post-injection (p.i.) and revealed a higher accumulation in the cortex in transgenic mice than in wild-type mice, as reflected by higher standardized uptake value ratios (SUVR) using the cerebellum as the reference region. The organs were isolated for biodistribution and ex vivo autoradiography. Autoradiography revealed a higher cortex-to-cerebellum ratio in the transgenic mice than in the controls. Results from autoradiography were validated by immunohistochemistry and poly-GA immunoassays. Moreover, we confirmed antibody uptake in the CNS in a pharmacokinetic study of the perfused tissues. In summary, [[64]Cu]Cu-NODAGA-mAb1A12 demonstrated favorable in vitro characteristics and an increased relative binding in poly-GA transgenic mice compared to wild-type mice in vivo. Our results with this first-in-class radiotracer suggested that targeting poly-GA is a promising approach for PET/CT imaging in FTD/ALS.}, } @article {pmid38751168, year = {2024}, author = {Raffaele, S and Nguyen, N and Milanese, M and Mannella, FC and Boccazzi, M and Frumento, G and Bonanno, G and Abbracchio, MP and Bonifacino, T and Fumagalli, M}, title = {Montelukast improves disease outcome in SOD1[G93A] female mice by counteracting oligodendrocyte dysfunction and aberrant glial reactivity.}, journal = {British journal of pharmacology}, volume = {181}, number = {18}, pages = {3303-3326}, doi = {10.1111/bph.16408}, pmid = {38751168}, issn = {1476-5381}, support = {GPR17ALS-1//AriSLA ETS - Fondazione Italiana di ricerca per la SLA/ ; 2017NSXP8J//Italian Ministry of University and Research (MUR)/ ; PE0000006//#NEXTGENERATIONEU (NGEU) and the Italian Ministry of University and Research (MUR), NRRP - National Recovery and Resilience Plan/ ; //Foundation Bellandi Bernardoni/ ; }, mesh = {Animals ; Female ; *Cyclopropanes/pharmacology ; *Quinolines/pharmacology ; *Acetates/pharmacology/therapeutic use ; *Oligodendroglia/drug effects/metabolism/pathology ; *Sulfides/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; *Mice, Transgenic ; Mice ; Male ; Receptors, Leukotriene/metabolism/genetics ; Receptors, G-Protein-Coupled/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; Spinal Cord/drug effects/metabolism/pathology ; Microglia/drug effects/metabolism/pathology ; Nerve Tissue Proteins ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron (MN) loss and consequent muscle atrophy, for which no effective therapies are available. Recent findings reveal that disease progression is fuelled by early aberrant neuroinflammation and the loss of oligodendrocytes with neuroprotective and remyelinating properties. On this basis, pharmacological interventions capable of restoring a pro-regenerative local milieu and re-establish proper oligodendrocyte functions may be beneficial.

EXPERIMENTAL APPROACH: Here, we evaluated the in vivo therapeutic effects of montelukast (MTK), an antagonist of the oligodendroglial G protein-coupled receptor 17 (GPR17) and of cysteinyl-leukotriene receptor 1 (CysLT1R) receptors on microglia and astrocytes, in the SOD1[G93A] ALS mouse model. We chronically treated SOD1[G93A] mice with MTK, starting from the early symptomatic disease stage. Disease progression was assessed by behavioural and immunohistochemical approaches.

KEY RESULTS: Oral MTK treatment significantly extended survival probability, delayed body weight loss and ameliorated motor functionalityonly in female SOD1[G93A] mice. Noteworthy, MTK significantly restored oligodendrocyte maturation and induced significant changes in the reactive phenotype and morphological features of microglia/macrophages and astrocytes in the spinal cord of female SOD1[G93A] mice, suggesting enhanced pro-regenerative functions. Importantly, concomitant MN preservation has been detected after MTK administration. No beneficial effects were observed in male mice, highlighting a sex-based difference in the protective activity of MTK.

CONCLUSIONS AND IMPLICATIONS: Our results provide the first preclinical evidence indicating that repurposing of MTK, a safe and marketed anti-asthmatic drug, may be a promising sex-specific strategy for personalized ALS treatment.}, } @article {pmid38750212, year = {2024}, author = {Leventoux, N and Morimoto, S and Ishikawa, M and Nakamura, S and Ozawa, F and Kobayashi, R and Watanabe, H and Supakul, S and Okamoto, S and Zhou, Z and Kobayashi, H and Kato, C and Hirokawa, Y and Aiba, I and Takahashi, S and Shibata, S and Takao, M and Yoshida, M and Endo, F and Yamanaka, K and Kokubo, Y and Okano, H}, title = {Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {84}, pmid = {38750212}, issn = {1432-0533}, support = {JP15J03921//Japan Society for the Promotion of Science/ ; JP18K07368//Japan Society for the Promotion of Science/ ; JP18KK0239//Japan Society for the Promotion of Science/ ; JP19K17002//Japan Society for the Promotion of Science/ ; JP19K08002//Japan Society for the Promotion of Science/ ; JP21H05278//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP17K10083//Japan Society for the Promotion of Science/ ; JP20H03567//Japan Society for the Promotion of Science/ ; JP22K18388//Japan Society for the Promotion of Science/ ; JP23H02882//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; JP21K06417//Japan Society for the Promotion of Science/ ; JP18K06506//Japan Society for the Promotion of Science/ ; JP22H04923//Japan Society for the Promotion of Science/ ; JP25305030//Japan Society for the Promotion of Science/ ; JP15K09364//Japan Society for the Promotion of Science/ ; JP17H01689//Japan Society for the Promotion of Science/ ; JP18K07514//Japan Society for the Promotion of Science/ ; JP18K07368//Japan Society for the Promotion of Science/ ; JP20H00485//Japan Society for the Promotion of Science/ ; JP21F21410//Japan Society for the Promotion of Science/ ; JP21H05273//Japan Society for the Promotion of Science/ ; JP22KF0333//Japan Society for the Promotion of Science/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP22bm0804023//Japan Agency for Medical Research and Development/ ; JP22gm6510006//Japan Agency for Medical Research and Development/ ; JP21wm0425019//Japan Agency for Medical Research and Development/ ; JP17ek0109139//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP20ek0109395//Japan Agency for Medical Research and Development/ ; JP20ek0109329//Japan Agency for Medical Research and Development/ ; JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; H29-Nanchi-Ippan-085//Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases/ ; JP18KK0239//Japanese Foundation for Research and Promotion of Endoscopy/ ; JP16H06277//MEXT/ ; }, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *Astrocytes/pathology/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Mitochondria/pathology/metabolism ; *Mitochondrial Proteins/genetics/metabolism ; *Transcription Factors/genetics/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.}, } @article {pmid38749729, year = {2025}, author = {Kunieda, K and Hayashi, Y and Fujishima, I and Shimohata, T}, title = {Weight and Muscle Mass Loss Associated with Acute Disease Can Be Reversed with Appropriate Nutrition Therapy and Exercise in a Patient with Amyotrophic Lateral Sclerosis.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {64}, number = {1}, pages = {133-136}, pmid = {38749729}, issn = {1349-7235}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/complications/rehabilitation/therapy/diet therapy/physiopathology ; Aged, 80 and over ; *Exercise Therapy/methods ; *Weight Loss/physiology ; Nutrition Therapy/methods ; Acute Disease ; Deglutition Disorders/etiology/rehabilitation/therapy/physiopathology ; Muscle Strength/physiology ; Body Composition ; Treatment Outcome ; }, abstract = {Nutritional interventions targeting weight loss are useful for the treatment of amyotrophic lateral sclerosis (ALS). However, the changes in body composition after nutritional intervention remain unclear. We herein present a patient with ALS who experienced an increased weight and muscle mass owing to nutritional therapy and physical exercise. An 86-year-old man presented with dysphagia and dysarthria. The patient was diagnosed with bulbar-type ALS. As weight loss progressed, a gastrostomy was performed. After 21 months of disease onset, gastrointestinal bleeding due to a bumper ulcer led to further weight loss (from 40.2 kg to 36.8 kg). The patient experienced difficulty walking and ingesting food orally. Although the total daily energy expenditure (TDEE) was estimated to be 1,122 kcal/day, an intake of 1,500 kcal/day beyond the calculated TDEE was administered. The patient continued to perform daily voluntary exercises in addition to his usual rehabilitation. After 5 months, his weight increased from 36.8 kg to 40.4 kg. Muscle mass increased from 25.1 kg to 30.1 kg, as measured using a multifrequency bioelectrical impedance device. Muscle strength improved from 8.5/10.0 kg to 15.0/18.0 kg in grip strength and from 15.2 kPa to 20.4 kPa in tongue pressure. The patient's physical and swallowing functions also improved. In patients with ALS, a decreased body weight and muscle mass due to acute disease may be improved by appropriate nutritional therapy and physical exercise.}, } @article {pmid38749539, year = {2024}, author = {Schwartze, JT and Das, S and Suggitt, D and Baxter, J and Tunstall, S and Ronan, N and Stannard, H and Rezgui, A and Jafar, W and Baxter, DN}, title = {Ward-based in situ simulation: lessons learnt from a UK District General Hospital.}, journal = {BMJ open quality}, volume = {13}, number = {2}, pages = {}, pmid = {38749539}, issn = {2399-6641}, mesh = {Humans ; United Kingdom ; Male ; Female ; *Patient Care Team/standards/statistics & numerical data ; Hospitals, General/statistics & numerical data ; Clinical Competence/statistics & numerical data/standards ; Simulation Training/methods/statistics & numerical data/standards ; Hospitals, District/statistics & numerical data ; Adult ; Patient Safety/standards/statistics & numerical data ; }, abstract = {INTRODUCTION: In situ simulation (ISS) enables multiprofessional healthcare teams to train for real emergencies in their own working environment and identify latent patient safety threats. This study aimed to determine ISS impact on teamwork, technical skill performance, healthcare staff perception and latent error identification during simulated medical emergencies.

MATERIALS AND METHODS: Unannounced ISS sessions (n=14, n=75 staff members) using a high-fidelity mannequin were conducted in medical, paediatric and rehabilitation wards at Stepping Hill Hospital (Stockport National Health Service Foundation Trust, UK). Each session encompassed a 15 min simulation followed by a 15 min faculty-led debrief.

RESULTS: The clinical team score revealed low overall teamwork performances during simulated medical emergencies (mean±SEM: 4.3±0.5). Linear regression analysis revealed that overall communication (r=0.9, p<0.001), decision-making (r=0.77, p<0.001) and overall situational awareness (r=0.73, p=0.003) were the strongest statistically significant predictors of overall teamwork performance. Neither the number of attending healthcare professionals, their professional background, age, gender, degree of clinical experience, level of resuscitation training or previous simulation experience statistically significantly impacted on overall teamwork performance. ISS positively impacted on healthcare staff confidence and clinical training. Identified safety threats included unknown location of intraosseous kits, poor/absent airway management, incomplete A-E assessments, inability to activate the major haemorrhage protocol, unknown location/dose of epinephrine for anaphylaxis management, delayed administration of epinephrine and delayed/absence of attachment of pads to the defibrillator as well as absence of accessing ALS algorithms, poor chest compressions and passive behaviour during simulated cardiac arrests.

CONCLUSION: Poor demonstration of technical/non-technical skills mandate regular ISS interventions for healthcare professionals of all levels. ISS positively impacts on staff confidence and training and drives identification of latent errors enabling improvements in workplace systems and resources.}, } @article {pmid38748878, year = {2024}, author = {Koopman, M and Güngördü, L and Janssen, L and Seinstra, RI and Richmond, JE and Okerlund, N and Wardenaar, R and Islam, P and Hogewerf, W and Brown, AEX and Jorgensen, EM and Nollen, EAA}, title = {Rebalancing the motor circuit restores movement in a Caenorhabditis elegans model for TDP-43 toxicity.}, journal = {Cell reports}, volume = {43}, number = {5}, pages = {114204}, doi = {10.1016/j.celrep.2024.114204}, pmid = {38748878}, issn = {2211-1247}, support = {P40 OD010440/OD/NIH HHS/United States ; }, mesh = {Animals ; *Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/metabolism/genetics ; Cholinergic Neurons/metabolism ; *Disease Models, Animal ; *DNA-Binding Proteins/metabolism/genetics ; GABAergic Neurons/metabolism ; Locomotion ; Motor Neurons/metabolism ; Movement ; Synaptic Transmission ; *TDP-43 Proteinopathies/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis can be caused by abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm of neurons. Here, we use a C. elegans model for TDP-43-induced toxicity to identify the biological mechanisms that lead to disease-related phenotypes. By applying deep behavioral phenotyping and subsequent dissection of the neuromuscular circuit, we show that TDP-43 worms have profound defects in GABA neurons. Moreover, acetylcholine neurons appear functionally silenced. Enhancing functional output of repressed acetylcholine neurons at the level of, among others, G-protein-coupled receptors restores neurotransmission, but inefficiently rescues locomotion. Rebalancing the excitatory-to-inhibitory ratio in the neuromuscular system by simultaneous stimulation of the affected GABA- and acetylcholine neurons, however, not only synergizes the effects of boosting individual neurotransmitter systems, but instantaneously improves movement. Our results suggest that interventions accounting for the altered connectome may be more efficient in restoring motor function than those solely focusing on diseased neuron populations.}, } @article {pmid38748695, year = {2024}, author = {Kim, HS and Woo, H and Choi, SJ and Baek, JG and Ryu, JS and Shin, HI and Park, KS and Beom, J}, title = {Factors associated with adherence to noninvasive positive pressure ventilation in amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {19}, number = {5}, pages = {e0302515}, pmid = {38748695}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology ; Female ; Male ; Middle Aged ; *Positive-Pressure Respiration/methods ; *Noninvasive Ventilation ; Aged ; Retrospective Studies ; Blood Gas Analysis ; Length of Stay ; Patient Compliance ; Respiratory Function Tests ; Adult ; }, abstract = {INTRODUCTION: This cohort study aimed to investigate the factors associated with noninvasive positive pressure ventilation adherence and assess the long-term effects of noninvasive positive pressure ventilation adherence in patients with amyotrophic lateral sclerosis (ALS).

METHODS: The medical records of patients with ALS admitted to a tertiary hospital for noninvasive positive pressure ventilation initiation were retrospectively reviewed. Pulmonary function parameters, variables of blood gas analysis, the site of symptom onset, the time from onset and diagnosis to noninvasive positive pressure ventilation application, ALS Functional Rating Scale-Revised, neurophysiological index, and the length of hospital stay were evaluated. The adherence to noninvasive positive pressure ventilation was defined as the use of noninvasive positive pressure ventilation for ≥ 2 h/day or ≥ 4 h/day. The correlations between noninvasive positive pressure ventilation adherence or length of hospital stay and other clinical parameters were analyzed.

RESULTS: Fifty-one patients with ALS were included in the study. The time from onset and diagnosis to NIPPV application was reduced by 16 months in the adherent group than that in the non-adherent group; however, the parameters of blood gas analysis and pulmonary function tests did not differ significantly between the groups. Furthermore, the neurophysiological index of the abductor digiti minimi muscle was higher by 4.05 in the adherent group than that in the non-adherent group. The adherence to noninvasive positive pressure ventilation prolonged tracheostomy-free survival compared to that of non-adherence. Desaturation events, lower forced vital capacity, last pCO2, bicarbonate, and base excess, and higher differences in pCO2, were associated with an increase in the length of hospital stay.

CONCLUSIONS: Noninvasive positive pressure ventilation application shortly after symptom onset and ALS diagnosis in patients with CO2 retention and reduced forced vital capacity can be considered for successful adherence. Adherence to noninvasive positive pressure ventilation may result in reduced tracheostomy conversion rates and prolonged tracheostomy-free survival.}, } @article {pmid38748065, year = {2024}, author = {Lu, T and Luo, L and Yang, J and Cheng, X and Sun, J}, title = {Circulating Levels of T-Cell Traits and the Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study.}, journal = {Molecular neurobiology}, volume = {61}, number = {12}, pages = {10529-10537}, pmid = {38748065}, issn = {1559-1182}, support = {WZ21M01 and WX20C35//the Wuhan Municipal Health Commission/ ; 2019YFC1708601//the National Key Research and Development Program of China/ ; SZ2021ZZ14//the Specific Fund of State Key Laboratory of Dampness Syndrome of Chinese Medicine/ ; 2017B030314176, 2018-75, and 2019-140//the Guangdong Provincial Key Laboratory of Research on Emergency in traditional Chinese medicine (TCM)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood ; Humans ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; Risk Factors ; Genetic Predisposition to Disease ; T-Lymphocytes/immunology/metabolism ; Polymorphism, Single Nucleotide/genetics ; Receptors, CCR7/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) represents a rare and potentially fatal neurodegenerative disease. Diverse T-cell subsets could potentially exert diametrically opposite impacts upon ALS development. A two-sample Mendelian randomization (MR) analysis was performed to investigate the correlation between 244 T-cell subsets and ALS risk. Genetic instrumental variables were procured from a standard genome-wide association study (GWAS) that encompassed 244 T-cell subsets in 3757 individuals of European lineage. ALS-related data were collected from a GWAS comprising 20,806 ALS instances and 59,804 European control participants. Multiple sensitivity analyses were performed to verify the robustness of the significant results. Reverse MR analysis was used for delineating the effects of ALS on the characteristics of T-cells. After multiple comparison corrections, 24 out of the 244 subtypes demonstrated a potential association with ALS risk. Significantly, 75% of these associations encompassed the expression of the CD3 on diverse T-cell subtypes, revealing a highly consistent inverse relation to ALS risk. The proportion of T regulatory cells (Tregs) in CD4+ T cells and secreting Tregs in CD4+ T cells demonstrated negative associations with the risk of ALS. CCR7 expression on naive CD4+ T cells and CCR7 expression on naive CD8+ T cells showed positive associations with ALS risk. Certain T-cell subsets, particularly those identified by CD3 expression on terminally differentiated CD8+ T cells, proportions of Tregs, and CCR7 expression, indicated an association with ALS risk. These findings harmonize with and extend previous observational studies investigating the involvement of T lymphocyte subset-induced immunological processes in ALS.}, } @article {pmid38747354, year = {2024}, author = {Borghero, G and Pierri, V and Pili, F and Muroni, A and Ercoli, T and Pateri, MI and Pilotto, S and Maccabeo, A and Chiò, A and Defazio, G}, title = {Percutaneous gastrostomy, mechanical ventilation and survival in amyotrophic lateral sclerosis: an observational study in an incident cohort.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {563-569}, doi = {10.1080/21678421.2024.2351185}, pmid = {38747354}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/therapy ; *Gastrostomy/methods ; Male ; Female ; Middle Aged ; Aged ; *Respiration, Artificial/statistics & numerical data ; Cohort Studies ; Retrospective Studies ; Enteral Nutrition/methods/statistics & numerical data ; Adult ; Noninvasive Ventilation/methods ; Survival Analysis ; }, abstract = {OBJECTIVE: To analyze disease-modifying effects of percutaneous endoscopic gastrostomy (PEG) insertion for supporting nutrition, noninvasive ventilation (NIV), and tracheostomy-assisted ('invasive') ventilation (TIV) in amyotrophic lateral sclerosis (ALS).

METHODS: We retrospectively analyzed survival in a large population-based incident cohort that was prospectively followed up in our center. Analysis considered several known ALS-related prognostic variables.

RESULTS: In this population, PEG and NIV in multivariable analysis significantly correlated to survival as computed by disease onset to death/tracheostomy. NIV was associated with better survival while PEG was associated with reduced survival. Other independent prognostic factors were age at ALS onset, diagnostic delay, and flail arm/leg and pure upper motor neuron (PUMN) phenotypes. The length of survival after TIV was significantly associated with age at ALS onset (inverse correlation) whereas other variables did not. The length of survival after TIV correlated to age at ALS onset in such a way that each additional year of age at ALS onset decreased survival by about 0.7 months. Patients who underwent both TIV and NIV did not experience a better survival than those who underwent TIV alone.

CONCLUSION: The lack of effect of enteral nutrition on ALS survival probably reflected the timing of PEG insertion in patients with more severe disease. By contrast, patients who used mechanical ventilation had an increased overall survival compared with non-ventilated ones. The study also provided new information showing that the combined use of NIV and TIV did not may prolong ALS survival as compared to TIV alone.}, } @article {pmid38747109, year = {2024}, author = {Bender, J and Kojeku, T and Preece, E}, title = {Grading lumbar foraminal stenosis - Interrater agreement of radiologists and radiology trainees before and after education of a standardised grading scale.}, journal = {Journal of medical imaging and radiation oncology}, volume = {68}, number = {5}, pages = {511-515}, doi = {10.1111/1754-9485.13669}, pmid = {38747109}, issn = {1754-9485}, mesh = {Humans ; *Spinal Stenosis/diagnostic imaging ; *Lumbar Vertebrae/diagnostic imaging ; *Observer Variation ; *Magnetic Resonance Imaging/methods ; *Radiologists ; Severity of Illness Index ; Radiology/education ; Reproducibility of Results ; Clinical Competence ; Male ; }, abstract = {INTRODUCTION: Lumbar foraminal stenosis is a key contributor to low back pain. Imaging, particularly MRI, is commonly used in the assessment of foraminal stenosis, contributing to treatment planning. The adoption of a standardised grading system to try and improve inter-rater agreement is thought to be of importance. Our study aims to assess the variability of grading lumbar foraminal stenosis amongst reporting doctors, determine whether education about a validated grading scale increases agreement, and determine if these changes persist over time.

METHODS: A single-site study involving MRI reporting registrars/radiologists was performed. Participants were shown select MRI images and asked to grade the degree of stenosis in each on a 4-point scale. Subsequently, they were educated about Lee et al's grading system and asked to re-grade the cases 1 and 6 weeks later. The level of agreement was calculated using Gwet's AC1 coefficient and Krippendorff's Alpha.

RESULTS: The baseline level of agreement was substantial (AC1 = 0.71). This decreased to a moderate level of agreement post-intervention (AC1 = 0.575 at 1-week, P-value 0.033 and AC1 = 0.598 at 6 weeks, P-value 0.012). A grading of severe stenosis was 21% more likely 6 weeks post-education.

CONCLUSION: The baseline agreement at our institution was substantial, thought to be due to the single-centre nature of the study. Moderate agreement was achieved after education regarding the Lee et al.'s scale, in-line with other studies, with changes maintained at 6 weeks, showing retention of the scale parameters. Grading of severe stenosis was more common post intervention.}, } @article {pmid38747014, year = {2024}, author = {Gale, J and Aizenman, E}, title = {The physiological and pathophysiological roles of copper in the nervous system.}, journal = {The European journal of neuroscience}, volume = {60}, number = {1}, pages = {3505-3543}, pmid = {38747014}, issn = {1460-9568}, support = {R01 NS043277/NS/NINDS NIH HHS/United States ; 5T32AG021885/NH/NIH HHS/United States ; R56 NS043277/NS/NINDS NIH HHS/United States ; NS043277/NH/NIH HHS/United States ; T32 GM144300/GM/NIGMS NIH HHS/United States ; T32 AG021885/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Copper/metabolism ; Animals ; Homeostasis/physiology ; Nervous System/metabolism ; }, abstract = {Copper is a critical trace element in biological systems due the vast number of essential enzymes that require the metal as a cofactor, including cytochrome c oxidase, superoxide dismutase and dopamine-β-hydroxylase. Due its key role in oxidative metabolism, antioxidant defence and neurotransmitter synthesis, copper is particularly important for neuronal development and proper neuronal function. Moreover, increasing evidence suggests that copper also serves important functions in synaptic and network activity, the regulation of circadian rhythms, and arousal. However, it is important to note that because of copper's ability to redox cycle and generate reactive species, cellular levels of the metal must be tightly regulated to meet cellular needs while avoiding copper-induced oxidative stress. Therefore, it is essential that the intricate system of copper transporters, exporters, copper chaperones and copper trafficking proteins function properly and in coordinate fashion. Indeed, disorders of copper metabolism such as Menkes disease and Wilson disease, as well as diseases linked to dysfunction of copper-requiring enzymes, such as SOD1-linked amyotrophic lateral sclerosis, demonstrate the dramatic neurological consequences of altered copper homeostasis. In this review, we explore the physiological importance of copper in the nervous system as well as pathologies related to improper copper handling.}, } @article {pmid38746326, year = {2024}, author = {Spencer, BE and Xie, SX and Elman, L and Quinn, CC and Amado, D and Baer, M and Lee, EB and Van Deerlin, VM and Dratch, L and Massimo, L and Irwin, DJ and McMillan, CT}, title = {C9orf72 repeat expansions modify risk for secondary motor and cognitive-behavioral symptoms in behavioral-variant frontotemporal degeneration and amyotrophic lateral sclerosis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.04.30.24306638}, pmid = {38746326}, abstract = {In behavioral-variant frontotemporal degeneration (bvFTD) and amyotrophic lateral sclerosis (ALS), secondary motor or cognitive-behavioral symptoms, respectively, are associated with shorter survival. However, factors influencing secondary symptom development remain largely unexplored. We performed a retrospective evaluation of the entire disease course of individuals with ALS (n=172) and bvFTD (n=69). Only individuals who had neuropathological confirmation of TDP-43 proteinopathy at autopsy or a C9orf72 hexanucleotide repeat expansion were included for analysis. We examined the odds and hazard of secondary symptom development and assessed whether each was modified by the presence of a C9orf72 expansion or initial clinical syndrome. Binary logistic regression and Cox proportional hazard analyses revealed increased odds (OR=4.25 [95% CI 1.97-9.14], p<0.001) and an increased hazard (HR= 4.77 [95% CI 2.33-9.79], p<0.001) for developing secondary symptoms in those with a C9orf72 expansion compared to those without. Initial clinical syndrome (bvFTD or ALS), age at symptom onset, and sex were not associated with development of secondary symptoms. These data highlight the need for clinician vigilance to detect the onset of secondary motor and cognitive-behavioral symptoms in patients carrying a C9orf72 expansion, regardless of initial clinical syndrome. C9orf72 clinical care can be enhanced through coordination between cognitive and neuromuscular clinics.}, } @article {pmid38745522, year = {2024}, author = {Mioshi, E and Grant, K and Flanagan, E and Heal, S and Copsey, H and Gould, RL and Hammond, M and Shepstone, L and Ashford, PA}, title = {An online intervention for carers to manage behavioral symptoms in motor neuron disease (MiNDToolkit): a randomized parallel multi-center feasibility trial.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {506-516}, pmid = {38745522}, issn = {2167-9223}, mesh = {Humans ; *Motor Neuron Disease/psychology/therapy ; Male ; Female ; *Caregivers/psychology ; *Feasibility Studies ; Middle Aged ; Aged ; Behavioral Symptoms/etiology/therapy ; Adult ; }, abstract = {BACKGROUND: Evidence on management of behavioral symptoms in motor neuron disease (MND) is lacking. The MiNDToolkit, an online psychoeducational platform, supports carers dealing with behavioral symptoms (BehSymp). The study objectives were to ascertain recruitment and retention rates, carer and healthcare professional (HCP) use of the platform, and completion of online assessments, to inform a full-scale trial. Design: Randomized, parallel, multi-center, feasibility trial.

SETTING: England and Wales, across diverse MND services; recruitment from July/21 to November/22; last participant follow-up in March/23.

PARTICIPANTS: Carers of people with motor neuron disease (PwMND) with BehSymp, recruited through MND services. After confirming eligibility, participants completed screening and baseline assessments online via the MiNDToolkit platform and were randomized centrally in a 1:1 ratio to MiNDToolkit or control.

INTERVENTION: MiNDToolkit offered tailored modules to carers for the 3-month study period. Carers in the intervention group could receive additional support from MiNDToolkit trained HCPs. The control group was offered access to the intervention at the end of the study. Data were collected on platform usage and psychosocial variables.

MAIN OUTCOMES: One hundred and fifty-one carers from 11 sites were invited to join the study (letter, face-to-face); 30 were screened; 29 were randomized. Fifteen people were allocated to the control arm; 14 to intervention. Carers were mostly female; median age for was 62.5 (IQR: 58, 68; intervention) and 57 (IQR: 56, 70; controls). Study retention was high (24/29 = 82.76%); carers engaged with the platform on average 14 times (median (IQR):14.0 (10.0, 18.5)) during the study period.

CONCLUSION: The MiNDToolkit study was feasible and well accepted by carers and trained HCPs. A definitive trial is warranted.}, } @article {pmid38745521, year = {2024}, author = {Fernandez, A and Guenegou, L and Corcia, P and Bailly, N}, title = {The effect of social support on the emotional well-being of people with amyotrophic lateral sclerosis: Exploring the mediating role of spirituality.}, journal = {Palliative & supportive care}, volume = {}, number = {}, pages = {1-8}, doi = {10.1017/S1478951524000610}, pmid = {38745521}, issn = {1478-9523}, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that, so far, is considered always fatal. Treatments mainly consist in increasing survival and aim to improve the quality of life of people with ALS (pwALS). Social support and spirituality have been shown to play a key role in pwALS' quality of life. Our study explored it in depth by investigating the underlying mechanisms linking social support, spirituality, and emotional well-being.

METHODS: Thirty-six pwALS underwent a battery of tests evaluating emotional well-being (emotional well-being scale of the 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire), social support (6-item Social Support Questionnaire), and spiritual well-being (12-item Functional Assessment of Chronic Illness Therapy - Spiritual well-being). Our recruitment was web-based through the FILSLAN and the ARSLA websites as well as through Facebook® advertisements (ALS groups). Data were analyzed by Pearson correlation analysis and Process macro was used in an SPSS program to analyze the mediator variable effect.

RESULTS: Availability of social support, spiritual well-being, and 2 of its dimensions, i.e., meaning and peace, were positively correlated with emotional well-being. The mediational analyses showed that spiritual well-being, meaning, and peace act as mediators in the association between availability of social support and good emotional well-being.

SIGNIFICANCE OF RESULTS: Availability of social support and spirituality are essential for the emotional well-being of pwALS. Spirituality as a mediator between availability of social support and emotional well-being appears as real novel finding which could be explored further. Spiritual well-being, meaning, and peace appear as coping resources for pwALS. We provide practical guidance for professionals working with pwALS.}, } @article {pmid38745475, year = {2024}, author = {Katangwe-Chigamba, T and Flanagan, E and Mioshi, E}, title = {Implementation of the MiNDToolkit intervention for the management of behavioral symptoms in MND by healthcare professionals: a mixed-methods process evaluation.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {496-505}, pmid = {38745475}, issn = {2167-9223}, mesh = {Humans ; *Health Personnel/psychology/education ; Male ; Female ; *Motor Neuron Disease/psychology/therapy ; *Caregivers/psychology ; Behavioral Symptoms/therapy/etiology ; Middle Aged ; Adult ; Surveys and Questionnaires ; Feasibility Studies ; }, abstract = {OBJECTIVE: MiNDToolkit is a novel psychoeducational intervention for carers to support management of behavioral symptoms in people living with motor neuron disease (PlwMND). Implementation of MiNDToolkit involves delivery of an online intervention to carers, which is reinforced by trained healthcare professionals (HCPs).

METHODS: A mixed-methods process evaluation of the MiNDToolkit feasibility trial was conducted, focusing on reinforcement of the intervention by HCPs. Quantitative data, descriptively analyzed, were included from platform analytics, questionnaire, and 10 semi-structured interviews with HCPs. Interviews were transcribed verbatim; data were inductively analyzed using Reflective Thematic Analysis.

RESULTS: The MiNDToolkit training and platform is a beneficial and acceptable resource for HCPs with potential to increase knowledge and confidence in identifying and managing behavioral symptoms in MND. Implementation barriers included HCPs' perceptions that highlighting behavior changes would be burdensome to carers and assumptions that carers would take the initiative to ask for support from clinicians. Degree of intervention reinforcement varied, with most HCPs delegating intervention delivery solely to the online platform.

CONCLUSIONS: Implementation of the MiNDToolkit was viewed to be feasible and the platform thought to increase accessibility of support to carers. The flexible approach to delivery (online platform and optional HCP reinforcement) is acceptable as an intervention for supporting carers of PlwMND with behavioral symptoms. However, MiNDToolkit should not negate HCP involvement in providing medical and practical information to PlwMND and families. Future research should explore ways to incorporate support for carers in the management of PlwMND alongside standard care, alongside tools such as the MiNDToolkit.}, } @article {pmid38745425, year = {2024}, author = {Nona, RJ and Henderson, RD and McCombe, PA}, title = {Neutrophil-to-lymphocyte ratio at diagnosis as a biomarker for survival of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {452-464}, doi = {10.1080/21678421.2024.2351187}, pmid = {38745425}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/blood/diagnosis/mortality ; Humans ; *Neutrophils ; *Lymphocytes ; Female ; Male ; Biomarkers/blood ; Middle Aged ; Aged ; }, abstract = {INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) has previously been reported to be associated with survival in ALS. To provide further information about the role of NLR as a biomarker in ALS, we performed a systematic review, analyzed data from our local cohort of ALS subjects and performed a meta-analysis.

METHODS: (1) The systematic review used established methods. (2) Using data from our cohort of subjects, we analyzed the association of NLR with survival. (3) Meta-analysis was performed using previous studies and our local data.

RESULTS: (1) In the systematic review, higher NLR was associated with shorter survival in all studies. (2) In our subjects, survival was significantly shorter in patients in the highest NLR groups. (3) Meta-analysis showed subjects with highest NLR tertile or with NLR >3 had significantly shorter survival than other subjects.

DISCUSSION: This study supports NLR as a biomarker in ALS; high NLR is associated with poor survival.}, } @article {pmid38744216, year = {2024}, author = {Trivedi, RR and Archambault, AS and Pavlak, C and Gastaldi, M and Cantoni, C and Ghezzi, L and Cross, AH and Miller, TM and Wu, GF}, title = {Prevalence of anti-myelin oligodendrocyte glycoprotein antibodies across neuroinflammatory and neurodegenerative diseases.}, journal = {Journal of the neurological sciences}, volume = {461}, number = {}, pages = {123041}, doi = {10.1016/j.jns.2024.123041}, pmid = {38744216}, issn = {1878-5883}, mesh = {*Myelin-Oligodendrocyte Glycoprotein/immunology ; Humans ; *Autoantibodies/blood ; Female ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/blood/immunology/diagnosis ; *Immunoglobulin G/blood ; Neurodegenerative Diseases/immunology/blood/diagnosis ; Aged ; Neuroinflammatory Diseases/immunology/blood ; Adult ; Multiple Sclerosis/immunology/blood ; Animals ; }, abstract = {Inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), are characterized by humoral immune abnormalities. Anti-MOG antibodies are not specific to MOGAD, with their presence described in MS. Autoantibodies may also be present and play a role in various neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease driven by motor neuron dysfunction. While immune involvement in ALS has been recognized, the presence of antibodies targeting CNS myelin antigens has not been established. We aimed to establish a live cell-based assay for quantification of serum anti-MOG IgG1 in patients with CNS diseases, including MS and ALS. In total, 771 serum samples from the John L. Trotter MS Center and the Northeast ALS Consortium were examined using a live cell-based assay for detection of anti-MOG IgG1. Samples from three cohorts were tested in blinded fashion: healthy control (HC) subjects, patients with clinically diagnosed MOGAD, and an experimental group of ALS and MS patients. All samples from established MOGAD cases were positive for anti-MOG antibodies, while all HC samples were negative. Anti-MOG IgG1 was detected in 65 of 658 samples (9.9%) from MS subjects and 4 of 108 (3.7%) samples from ALS subjects. The presence of serum anti-MOG IgG1 in MS and ALS patients raises questions about the contribution of these antibodies to disease pathophysiology as well as accuracy of diagnostic approaches for CNS inflammatory diseases.}, } @article {pmid38743595, year = {2024}, author = {Klose, V and Jesse, S and Lewerenz, J and Kassubek, J and Dorst, J and Rosenbohm, A and Nagel, G and Wernecke, D and Roselli, F and Tumani, H and Ludolph, AC}, title = {Blood-CSF barrier integrity in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {12}, pages = {4254-4264}, doi = {10.1093/brain/awae144}, pmid = {38743595}, issn = {1460-2156}, support = {443642953//Deutsche Zentrum für Neurodegenerative Erkrankungen (DZNE)/ ; 251293561//Danger Response, Disturbance Factors and Regenerative Potential after Acute Trauma/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Male ; Female ; Middle Aged ; Aged ; *Blood-Brain Barrier/metabolism ; Adult ; Albumins/metabolism ; Aged, 80 and over ; Cohort Studies ; }, abstract = {The integrity of the blood-CSF barrier plays a major role in inflammation, but also in shielding the CNS from external and systemic-potentially toxic-factors. Here we report results of measurements of the albumin quotient-which is thought to mirror the integrity of the blood-CSF barrier-in 1059 patients with amyotrophic lateral sclerosis. The results were compared with groups of patients suffering from Alzheimer's disease, facial palsy and tension headache. The albumin quotient, an accepted measure of the blood-CSF barrier integrity, was not significantly different from control populations. In addition, we found that the albumin quotient correlated with survival of the patients; this effect was mainly driven by male patients and influenced by age, body mass index and diabetes mellitus. We conclude that the blood-CSF barrier is intact in this large cohort of patients with amyotrophic lateral sclerosis and that the albumin quotient correlates with survival. Whether this is important for the pathogenesis of the disease, requires mechanistic studies.}, } @article {pmid38743390, year = {2024}, author = {Vignolo, M and Zuccarino, R and Truffelli, R and Gemelli, C and Giove, E and Ferraro, PM and Manunza, D and Trinchero, C and Cipollina, I and Lungu, M and Lizio, A and Gragnano, G and Cabona, C and Pardini, M and Caponnetto, C and Rao, F}, title = {Dog-assisted physiotherapy in amyotrophic lateral sclerosis: a randomized controlled pilot study.}, journal = {European journal of physical and rehabilitation medicine}, volume = {60}, number = {3}, pages = {470-476}, pmid = {38743390}, issn = {1973-9095}, mesh = {Humans ; Pilot Projects ; *Amyotrophic Lateral Sclerosis/rehabilitation ; Male ; Female ; Middle Aged ; *Animal Assisted Therapy/methods ; Aged ; *Physical Therapy Modalities ; Animals ; Dogs ; Treatment Outcome ; }, abstract = {BACKGROUND: Animal-assisted therapy (AAT) is an intervention in which the animal acts as a co-therapist. It has been mainly used in the context of patients with dementia, showing positive effects on psychological symptoms, but its potential as a physiotherapy treatment for patients with neuromuscular disorders, amyotrophic lateral sclerosis (ALS) in particular, has not yet been investigated.

AIM: The aim of the study was to evaluate the impact of AAT, specifically of dog-assisted therapy, on motor functions and psychological status in patients with ALS.

DESIGN: This study was a randomized controlled pilot study.

SETTING: The study was carried out at the Rehabilitation Unit NEuroMuscular Omnicenter (NEMO) of Arenzano, Genoa.

POPULATION: Sixty hospitalized ALS patients were enrolled.

METHODS: All patients ran a regular two-weeks neurorehabilitation program twice a day. For three days a week, in place of the morning traditional treatment, the AAT group performed a rehabilitation session with a simultaneous interaction with the therapy-dog, while the control group performed a traditional rehabilitation session. The outcome measures were the Timed Up and Go Test, the Short Physical Performance Battery (SPPB), the Six Minutes Walk Test, the Ten Meters walking Test and the Hospital Anxiety and Depression Scale.

RESULTS: Both groups showed an amelioration in motor scales. However, SPPB subscales as well as HADS scores showed a statistically significant improvement only in the AAT group (P values from <0.0001 to 0.0004). Additionally, across almost all motor and psychological measures, post-treatments values were significantly better for the AAT group (P values from <0.0001 to 0.01).

CONCLUSIONS: The obtained results not only suggest that AAT is comparable to traditional physiotherapy treatments, but also evidence that this type of treatment has greater beneficial effects on motor and psychological symptoms in patients with ALS.

This study provides first evidence that AAT is a powerful rehabilitation strategy in patients with ALS, improving both motor and psychological symptoms, and therefore possibly ameliorating quality of life.}, } @article {pmid38743164, year = {2024}, author = {Zoccolella, S and Milella, G and Giugno, A and Filardi, M and D'Errico, E and Tamburrino, L and Devitofrancesco, V and Damato, R and Piomboni, F and Misceo, S and Logroscino, G}, title = {Nerve conduction study on the split-hand plus index in Amyotrophic lateral sclerosis: correlations with lower motor neuron impairment.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {10}, pages = {4863-4870}, pmid = {38743164}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; *Neural Conduction/physiology ; Aged ; Case-Control Studies ; *Motor Neurons/physiology ; Hand/physiopathology ; Prospective Studies ; Action Potentials/physiology ; Median Nerve/physiopathology ; Adult ; Nerve Conduction Studies ; }, abstract = {INTRODUCTION: In the arms of patients with Amyotrophic lateral sclerosis (ALS) two peculiar patterns of dissociated muscular atrophy have been described: the split-hand sign (with predominant atrophy of the lateral aspect of the hand, compared to hypothenar eminence) and the split-hand-plus sign (SHPS), a predominant abductor pollicis brevis (ABP) atrophy with sparing of flexor pollicis longus (FPL).

AIMS: In this case-control study, we evaluated the diagnostic utility of a neurophysiological indicator of SHPS and assessed its association with clinical features.

METHODS: We prospectively studied 59 incident ALS patients, 61 patients with ALS-mimic disorders (OND) and 61 non-neurological controls (NNCs). ABP and FPL compound muscle action potentials (CMAP) amplitudes were obtained by supramaximal stimulation of median nerve at elbow. Split-hand plus index (SHPI) was calculated according to the formula: APB-CMAP/FPL-CMAP.

RESULTS: SHPI was significantly lower in ALS compared to OND patients and NNCs (p < 0.0001). SHPI value < 1 was observed in 2% of NNCs and 9% of OND patients and demonstrated an accuracy of 71% in differentiating ALS from OND and an accuracy of 74% in differentiating ALS from NNC. SHPI was associated with higher LMN score, and higher disease severity as quantified by the ALSFRS-r.

CONCLUSION: Our results indicate that SHPI is a reliable indicator to distinguish ALS patients from ONDs and NNCs. SHPI was significantly associated to the degree of lower motor neuron impairment but showed no association with upper motoneuron impairment.}, } @article {pmid38742757, year = {2024}, author = {Shephard, VK and Brown, ML and Thompson, BA and Harpur, A and McAlary, L}, title = {Rapid classification of a novel ALS-causing I149S variant in superoxide dismutase-1.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {608-614}, doi = {10.1080/21678421.2024.2351177}, pmid = {38742757}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Superoxide Dismutase-1/genetics ; Middle Aged ; Male ; Female ; Mutation/genetics ; }, abstract = {Variants of the oxygen free radical scavenging enzyme superoxide dismutase-1 (SOD1) are associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). These variants occur in roughly 20% of familial ALS cases, and 1% of sporadic ALS cases. Here, we identified a novel SOD1 variant in a patient in their 50s who presented with movement deficiencies and neuropsychiatric features. The variant was heterozygous and resulted in the isoleucine at position 149 being substituted with a serine (I149S). In silico analysis predicted the variant to be destabilizing to the SOD1 protein structure. Expression of the SOD1[I149S] variant with a C-terminal EGFP tag in neuronal-like NSC-34 cells resulted in extensive inclusion formation and reduced cell viability. Immunoblotting revealed that the intramolecular disulphide between Cys57 and Cys146 was fully reduced for SOD1[I149S]. Furthermore, SOD1[I149S] was highly susceptible to proteolytic digestion, suggesting a large degree of instability to the protein fold. Finally, fluorescence correlation spectroscopy and native-PAGE of cell lysates showed that SOD1[I149S] was monomeric in solution in comparison to the dimeric SOD1[WT]. This experimental data was obtained within 3 months and resulted in the rapid re-classification of the variant from a variant of unknown significance (VUS) to a clinically actionable likely pathogenic variant.}, } @article {pmid38742544, year = {2024}, author = {Donohue, C and Vasilopoulos, T and Wymer, JP and Plowman, EK}, title = {Relationship between pulmonary, cough, and swallowing functions in individuals with amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {1}, pages = {140-147}, pmid = {38742544}, issn = {1097-4598}, support = {//Nancy McEwans Wilkins Fellowship for ALS Research Fund/ ; 1R01NS100859/NS/NINDS NIH HHS/United States ; R01 NS100859/NS/NINDS NIH HHS/United States ; //ALS Association/ ; //University of Florida McKnight Brain Institute and BREATHING Research and Therapeutics Center/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; Male ; *Cough/physiopathology/etiology ; Female ; Middle Aged ; Aged ; *Deglutition/physiology ; *Deglutition Disorders/physiopathology/etiology ; Vital Capacity/physiology ; Adult ; Lung/physiopathology/diagnostic imaging ; Fluoroscopy ; Respiratory Function Tests ; }, abstract = {INTRODUCTION/AIMS: Evaluations of pulmonary, cough, and swallow function are frequently performed to assess disease progression in amyotrophic lateral sclerosis (ALS), yet the relationship between these functions remains unknown. We therefore aimed to determine relationships between these measures in individuals with ALS.

METHODS: One hundred individuals with ALS underwent standardized tests: forced vital capacity (FVC), maximum expiratory/inspiratory pressure (MEP, MIP), voluntary cough peak expiratory flow (PEF), and videofluoroscopic swallow evaluation (VF). Duplicate raters completed independent, blinded ratings using the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale. Descriptives, Spearman's Rho correlations, Kruskal-Wallis analyses, and Pearson's chi-squared tests were completed.

RESULTS: Mean and standard deviation across pulmonary and cough measures were FVC: 74.2% predicted (± 22.6), MEP: 91.6 cmH2O (± 46.4), MIP cmH2O: 61.1 (± 28.9), voluntary PEF: 352.7 L/min (± 141.6). DIGEST grades included: 0 (normal swallowing): 31%, 1 (mild dysphagia): 48%, 2 (moderate dysphagia): 10%, 3 (severe dysphagia): 10%, and 4 (life-threatening dysphagia): 1%. Positive correlations were observed: MEP-MIP: r = .76, MIP-PEF: r = .68, MEP-PEF: r = .61, MIP-FVC: r = .60, PEF-FVC: r = .49, and MEP-FVC: r = .46, p < .0001. MEP (p = .009) and PEF (p = .04) differed across DIGEST safety grades. Post hoc analyses revealed significant between group differences in MEP and PEF across DIGEST safety grades 0 versus 1 and grades 0 versus 3, (p < .05).

DISCUSSION: In this cohort of individuals with ALS, pulmonary function, and voluntary cough were associated. Expiratory metrics (MEP, PEF) were diminished in individuals with unsafe swallowing, increasing their risk for effectively defending the airway.}, } @article {pmid38742276, year = {2024}, author = {Cheung, SW and Bhavnani, E and Simmons, DG and Bellingham, MC and Noakes, PG}, title = {Perineuronal nets are phagocytosed by MMP-9 expressing microglia and astrocytes in the SOD1[G93A] ALS mouse model.}, journal = {Neuropathology and applied neurobiology}, volume = {50}, number = {3}, pages = {e12982}, doi = {10.1111/nan.12982}, pmid = {38742276}, issn = {1365-2990}, support = {GIC1842//Motor Neuron Disease Research Australia/ ; I2326//Motor Neuron Disease Research Australia/ ; GIV1842//Motor Neuron Disease Research Australia/ ; IG2326//Motor Neuron Disease Research Australia/ ; 1188169//National Health & Medical Research Council Australia/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Astrocytes/metabolism/pathology ; Disease Models, Animal ; Extracellular Matrix/metabolism/pathology ; *Matrix Metalloproteinase 9/metabolism ; Mice, Transgenic ; *Microglia/metabolism/pathology ; Motor Neurons/pathology/metabolism ; *Phagocytosis/physiology ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {AIMS: Perineuronal nets (PNNs) are an extracellular matrix structure that encases excitable neurons. PNNs play a role in neuroprotection against oxidative stress. Oxidative stress within motor neurons can trigger neuronal death, which has been implicated in amyotrophic lateral sclerosis (ALS). We investigated the spatio-temporal timeline of PNN breakdown and the contributing cellular factors in the SOD1[G93A] strain, a fast-onset ALS mouse model.

METHODS: This was conducted at the presymptomatic (P30), onset (P70), mid-stage (P130), and end-stage disease (P150) using immunofluorescent microscopy, as this characterisation has not been conducted in the SOD1[G93A] strain.

RESULTS: We observed a significant breakdown of PNNs around α-motor neurons in the ventral horn of onset and mid-stage disease SOD1[G93A] mice compared with wild-type controls. This was observed with increased numbers of microglia expressing matrix metallopeptidase-9 (MMP-9), an endopeptidase that degrades PNNs. Microglia also engulfed PNN components in the SOD1[G93A] mouse. Further increases in microglia and astrocyte number, MMP-9 expression, and engulfment of PNN components by glia were observed in mid-stage SOD1[G93A] mice. This was observed with increased expression of fractalkine, a signal for microglia engulfment, within α-motor neurons of SOD1[G93A] mice. Following PNN breakdown, α-motor neurons of onset and mid-stage SOD1[G93A] mice showed increased expression of 3-nitrotyrosine, a marker for protein oxidation, which could render them vulnerable to death.

CONCLUSIONS: Our observations suggest that increased numbers of MMP-9 expressing glia and their subsequent engulfment of PNNs around α-motor neurons render these neurons sensitive to oxidative damage and eventual death in the SOD1[G93A] ALS model mouse.}, } @article {pmid38741492, year = {2024}, author = {Kanda, S and Kanda, T}, title = {[Multifocal Motor Neuropathy].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {5}, pages = {526-533}, doi = {10.11477/mf.1416202639}, pmid = {38741492}, issn = {1881-6096}, mesh = {Humans ; *Polyneuropathies/physiopathology/diagnosis ; Immunoglobulins, Intravenous/therapeutic use/administration & dosage ; }, abstract = {Multifocal motor neuropathy (MMN), an acquired chronic progressive immune-mediated motor neuropathy, is characterized by asymmetrical distal upper limb muscle weakness and muscle atrophy without sensory impairment. Differentiation from amyotrophic lateral sclerosis is usually challenging, and electrophysiological studies show multifocal conduction blocks. Immunoglobulin (Ig)M GM1 antibodies are detected in approximately 50% of patients. In contrast to chronic inflammatory demyelinating polyneuropathy, corticosteroids are ineffective for management of MMN, and IVIg is the sole established treatment.}, } @article {pmid38741111, year = {2024}, author = {Maresova, P and Rezny, L and Bauer, P and Valko, M and Kuca, K}, title = {Nonpharmacological intervention therapies for dementia: potential break-even intervention price and savings for selected risk factors in the European healthcare system.}, journal = {BMC public health}, volume = {24}, number = {1}, pages = {1293}, pmid = {38741111}, issn = {1471-2458}, support = {ERDF No. CZ.02.1.01/0.0/0.0/18_069/0010054-IT4Neuro(degeneration)//Ministry of Education Youth and Sports/ ; Excellence 2022//UHK FIM/ ; }, mesh = {Humans ; *Dementia/economics/epidemiology/prevention & control ; Risk Factors ; Europe/epidemiology ; Cost Savings ; Aged ; Health Care Costs/statistics & numerical data ; Models, Theoretical ; Male ; Female ; Prevalence ; Aged, 80 and over ; Middle Aged ; }, abstract = {BACKGROUND: New effective treatments for dementia are lacking, and early prevention focusing on risk factors of dementia is important. Non-pharmacological intervention therapies aimed at these factors may provide a valuable tool for reducing the incidence of dementia. This study focused on the development of a mathematical model to predict the number of individuals with neurodegenerative diseases, specifically Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis. Scenarios for non-pharmacological intervention therapies based on risk factor reduction were also assessed. The estimated total costs and potential cost savings from societal were included.

METHODS: Based on demographic and financial data from the EU, a mathematical model was developed to predict the prevalence and resulting care costs of neurodegenerative diseases in the population. Each disease (Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis) used parameters that included prevalence, incidence, and death risk ratio, and the simulation is related to the age of the cohort and the disease stage.

RESULTS: A replicable simulation for predicting the prevalence and resulting cost of care for neurodegenerative diseases in the population exhibited an increase in treatment costs from 267 billion EUR in 2021 to 528 billion EUR by 2050 in the EU alone. Scenarios related to the reduction of the prevalence of dementia by up to 20% per decade led to total discounted treatment cost savings of up to 558 billion EUR.

CONCLUSION: The model indicates the magnitude of the financial burden placed on EU healthcare systems due to the growth in the population prevalence of neurodegenerative diseases in the coming decades. Lifestyle interventions based on reducing the most common risk factors could serve as a prevention strategy to reduce the incidence of dementia with substantial cost-savings potential. These findings could support the implementation of public health approaches throughout life to ultimately prevent premature mortality and promote a healthier and more active lifestyle in older individuals.}, } @article {pmid38739991, year = {2024}, author = {Li, X and Liu, N and Wu, D and Li, SC and Wang, Q and Zhang, DW and Song, LL and Huang, M and Chen, X and Li, W}, title = {Hippocampal transcriptomic analyses reveal the potential antiapoptotic mechanism of a novel anticonvulsant agent Q808 on pentylenetetrazol-induced epilepsy in rats.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {175}, number = {}, pages = {116746}, doi = {10.1016/j.biopha.2024.116746}, pmid = {38739991}, issn = {1950-6007}, mesh = {Animals ; *Pentylenetetrazole ; *Hippocampus/drug effects/metabolism/pathology ; *Apoptosis/drug effects ; *Anticonvulsants/pharmacology ; Male ; *Transcriptome/drug effects ; *Epilepsy/drug therapy/chemically induced/genetics ; *Gene Expression Profiling/methods ; Rats ; *Rats, Sprague-Dawley ; Disease Models, Animal ; Neurons/drug effects/metabolism/pathology ; Seizures/chemically induced/genetics/drug therapy ; }, abstract = {Brain apoptosis is one of the main causes of epileptogenesis. The antiapoptotic effect and potential mechanism of Q808, an innovative anticonvulsant chemical, have never been reported. In this study, the seizure stage and latency to reach stage 2 of pentylenetetrazol (PTZ) seizure rat model treated with Q808 were investigated. The morphological change and neuronal apoptosis in the hippocampus were detected by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, respectively. The hippocampal transcriptomic changes were observed using RNA sequencing (RNA-seq). The expression levels of hub genes were verified by quantitative reverse-transcription PCR (qRT-PCR). Results revealed that Q808 could allay the seizure score and prolong the stage 2 latency in seizure rats. The morphological changes of neurons and the number of apoptotic cells in the DG area were diminished by Q808 treatment. RNA-seq analysis revealed eight hub genes, including Map2k3, Nfs1, Chchd4, Hdac6, Siglec5, Slc35d3, Entpd1, and LOC103690108, and nine hub pathways among the control, PTZ, and Q808 groups. Hub gene Nfs1 was involved in the hub pathway sulfur relay system, and Map2k3 was involved in the eight remaining hub pathways, including Amyotrophic lateral sclerosis, Cellular senescence, Fc epsilon RI signaling pathway, GnRH signaling pathway, Influenza A, Rap1 signaling pathway, TNF signaling pathway, and Toll-like receptor signaling pathway. qRT-PCR confirmed that the mRNA levels of these hub genes were consistent with the RNA-seq results. Our findings might contribute to further studies exploring the new apoptosis mechanism and actions of Q808.}, } @article {pmid38739934, year = {2024}, author = {Xin, J and Huang, S and Wen, J and Li, Y and Li, A and Satyanarayanan, SK and Yao, X and Su, H}, title = {Drug Screening and Validation Targeting TDP-43 Proteinopathy for Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {16}, number = {2}, pages = {693-713}, pmid = {38739934}, issn = {2152-5250}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; Humans ; *TDP-43 Proteinopathies/metabolism/pathology/drug therapy ; Drug Evaluation, Preclinical ; DNA-Binding Proteins/metabolism ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) stands as a rare, yet severely debilitating disorder marked by the deterioration of motor neurons (MNs) within the brain and spinal cord, which is accompanied by degenerated corticobulbar/corticospinal tracts and denervation in skeletal muscles. Despite ongoing research efforts, ALS remains incurable, attributed to its intricate pathogenic mechanisms. A notable feature in the pathology of ALS is the prevalence of TAR DNA-binding protein 43 (TDP-43) proteinopathy, detected in approximately 97% of ALS cases, underscoring its significance in the disease's progression. As a result, strategies targeting the aberrant TDP-43 protein have garnered attention as a potential avenue for ALS therapy. This review delves into the existing drug screening systems aimed at TDP-43 proteinopathy and the models employed for drug efficacy validation. It also explores the hurdles encountered in the quest to develop potent medications against TDP-43 proteinopathy, offering insights into the intricacies of drug discovery and development for ALS. Through this comprehensive analysis, the review sheds light on the critical aspects of identifying and advancing therapeutic solutions for ALS.}, } @article {pmid38739752, year = {2024}, author = {Droppelmann, CA and Campos-Melo, D and Noches, V and McLellan, C and Szabla, R and Lyons, TA and Amzil, H and Withers, B and Kaplanis, B and Sonkar, KS and Simon, A and Buratti, E and Junop, M and Kramer, JM and Strong, MJ}, title = {Mitigation of TDP-43 toxic phenotype by an RGNEF fragment in amyotrophic lateral sclerosis models.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {6}, pages = {2053-2068}, pmid = {38739752}, issn = {1460-2156}, support = {P40 OD018537/OD/NIH HHS/United States ; //Temerty Family Foundation/ ; /CAPMC/CIHR/Canada ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; Humans ; *Disease Models, Animal ; *Guanine Nucleotide Exchange Factors/metabolism/genetics ; *Phenotype ; Drosophila ; Mice, Transgenic ; Drosophila Proteins/genetics/metabolism ; Male ; }, abstract = {Aggregation of the RNA-binding protein TAR DNA binding protein (TDP-43) is a hallmark of TDP-proteinopathies including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As TDP-43 aggregation and dysregulation are causative of neuronal death, there is a special interest in targeting this protein as a therapeutic approach. Previously, we found that TDP-43 extensively co-aggregated with the dual function protein GEF (guanine exchange factor) and RNA-binding protein rho guanine nucleotide exchange factor (RGNEF) in ALS patients. Here, we show that an N-terminal fragment of RGNEF (NF242) interacts directly with the RNA recognition motifs of TDP-43 competing with RNA and that the IPT/TIG domain of NF242 is essential for this interaction. Genetic expression of NF242 in a fruit fly ALS model overexpressing TDP-43 suppressed the neuropathological phenotype increasing lifespan, abolishing motor defects and preventing neurodegeneration. Intracerebroventricular injections of AAV9/NF242 in a severe TDP-43 murine model (rNLS8) improved lifespan and motor phenotype, and decreased neuroinflammation markers. Our results demonstrate an innovative way to target TDP-43 proteinopathies using a protein fragment with a strong affinity for TDP-43 aggregates and a mechanism that includes competition with RNA sequestration, suggesting a promising therapeutic strategy for TDP-43 proteinopathies such as ALS and FTD.}, } @article {pmid38738747, year = {2024}, author = {de Araújo, CM and de Alcântara, C and Alencar, MA and da Gama, NAS and Cruzeiro, MM and França, MC and Jaeger, A and Camargos, ST and Machado, TH and de Souza, LC}, title = {Language impairment in sporadic and familial (type 8) amyotrophic lateral sclerosis: A comparative study.}, journal = {Muscle & nerve}, volume = {70}, number = {1}, pages = {130-139}, doi = {10.1002/mus.28109}, pmid = {38738747}, issn = {1097-4598}, support = {//Brazilian National Council for Scientific and Technological Development (CNPq)/ ; 001//CAPES/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; Aged ; Language Disorders/etiology/diagnosis ; Adult ; Neuropsychological Tests ; Language Tests ; }, abstract = {INTRODUCTION/AIMS: Language is frequently affected in patients with sporadic amyotrophic lateral sclerosis (sALS), with reduced performance in naming, syntactic comprehension, grammatical expression, and orthographic processing. However, the language profile of patients with familial type 8 ALS (ALS8), linked to p.P56S VAPB mutation, remains unclear. We investigated language in patients with ALS8 by examining their auditory comprehension and verbal production.

METHODS: We included three groups of participants: (1) patients with sALS (n = 20), (2) patients with familial ALS8 (n = 22), and (3) healthy controls (n = 21). The groups were matched for age, sex, and education level. All participants underwent a comprehensive language battery, including the Boston Diagnostic Aphasia Examination, the reduced Token test, letter fluency, categorical fluency (animals), word definition from the Cambridge Semantic Memory Research Battery, and a narrative discourse analysis. Participants also were evaluated using Addenbrooke's Cognitive Exam-Revised Version, the Hospital Anxiety and Depression Scale, and the ALS Functional Rating Scale-Revised.

RESULTS: Compared to controls, sALS and ALS8 patients had impaired performance on oral (syntactic and phonological processing) comprehension and inappropriate discourse cohesion. sALS and ALS8 did not differ in any language measure. There was no correlation between language scores and functional and psychiatric scales.

DISCUSSION: ALS8 patients exhibit language deficits that are independent of motor features. These findings are consistent with the current evidence suggesting that ALS8 has prominent non-motor features.}, } @article {pmid38738727, year = {2024}, author = {Bhushan, B and Singh, K and Kumar, S and Bhardwaj, A}, title = {Advancements in CRISPR-Based Therapies for Genetic Modulation in Neurodegenerative Disorders.}, journal = {Current gene therapy}, volume = {25}, number = {1}, pages = {34-45}, pmid = {38738727}, issn = {1875-5631}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/genetics ; *Genetic Therapy/methods ; *CRISPR-Cas Systems/genetics ; *Gene Editing/methods ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; Amyotrophic Lateral Sclerosis/therapy/genetics ; Parkinson Disease/therapy/genetics ; Mutation ; Huntington Disease/therapy/genetics ; }, abstract = {Neurodegenerative disorders pose significant challenges in the realm of healthcare, as these conditions manifest in complex, multifaceted ways, often attributed to genetic anomalies. With the emergence of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology, a new frontier has been unveiled in the quest for targeted, precise genetic manipulation. This abstract explores the recent advancements and potential applications of CRISPR-based therapies in addressing genetic components contributing to various neurodegenerative disorders. The review delves into the foundational principles of CRISPR technology, highlighting its unparalleled ability to edit genetic sequences with unprecedented precision. In addition, it talks about the latest progress in using CRISPR to target specific genetic mutations linked to neurodegenerative diseases like Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease. It talks about the most important studies and trials that show how well and safely CRISPR-based therapies work. This shows how this technology can change genetic variants that cause diseases. Notably, the discussion emphasizes the challenges and ethical considerations associated with the implementation of CRISPR in clinical settings, including off-target effects, delivery methods, and long-term implications. Furthermore, the article explores the prospects and potential hurdles in the widespread application of CRISPR technology for treating neurodegenerative disorders. It touches upon the need for continued research, improved delivery mechanisms, and ethical frameworks to ensure responsible and equitable access to these groundbreaking therapies.}, } @article {pmid38738637, year = {2024}, author = {Błaszczyk, L and Ryczek, M and Das, B and Mateja-Pluta, M and Bejger, M and Śliwiak, J and Nakatani, K and Kiliszek, A}, title = {Antisense RNA C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms a triplex-like structure and binds small synthetic ligand.}, journal = {Nucleic acids research}, volume = {52}, number = {11}, pages = {6707-6717}, pmid = {38738637}, issn = {1362-4962}, support = {UMO-2022/45/B/NZ7/03543//National Science Centre/ ; 22H00351//Japan Society for the Promotion of Science/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; *C9orf72 Protein/genetics/metabolism ; Humans ; Ligands ; RNA, Antisense/genetics/chemistry/metabolism ; Nucleic Acid Conformation ; DNA Repeat Expansion/genetics ; Crystallography, X-Ray ; Models, Molecular ; }, abstract = {The abnormal expansion of GGGGCC/GGCCCC hexanucleotide repeats (HR) in C9orf72 is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Structural polymorphisms of HR result in the multifactorial pathomechanism of ALS/FTD. Consequently, many ongoing studies are focused at developing therapies targeting pathogenic HR RNA. One of them involves small molecules blocking sequestration of important proteins, preventing formation of toxic nuclear foci. However, rational design of potential therapeutics is hindered by limited number of structural studies of RNA-ligand complexes. We determined the crystal structure of antisense HR RNA in complex with ANP77 ligand (1.1 Å resolution) and in the free form (0.92 and 1.5 Å resolution). HR RNA folds into a triplex structure composed of four RNA chains. ANP77 interacted with two neighboring single-stranded cytosines to form pseudo-canonical base pairs by adopting sandwich-like conformation and adjusting the position of its naphthyridine units to the helical twist of the RNA. In the unliganded structure, the cytosines formed a peculiar triplex i-motif, assembled by trans C•C+ pair and a third cytosine located at the Hoogsteen edge of the C•C+ pair. These results extend our knowledge of the structural polymorphisms of HR and can be used for rational design of small molecules targeting disease-related RNAs.}, } @article {pmid38738213, year = {2023}, author = {Fan, C and Hahn, N and Kamdar, F and Avansino, D and Wilson, GH and Hochberg, L and Shenoy, KV and Henderson, JM and Willett, FR}, title = {Plug-and-Play Stability for Intracortical Brain-Computer Interfaces: A One-Year Demonstration of Seamless Brain-to-Text Communication.}, journal = {Advances in neural information processing systems}, volume = {36}, number = {}, pages = {42258-42270}, pmid = {38738213}, issn = {1049-5258}, support = {R01 DC014034/DC/NIDCD NIH HHS/United States ; R01 EB028171/EB/NIBIB NIH HHS/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; }, abstract = {Intracortical brain-computer interfaces (iBCIs) have shown promise for restoring rapid communication to people with neurological disorders such as amyotrophic lateral sclerosis (ALS). However, to maintain high performance over time, iBCIs typically need frequent recalibration to combat changes in the neural recordings that accrue over days. This requires iBCI users to stop using the iBCI and engage in supervised data collection, making the iBCI system hard to use. In this paper, we propose a method that enables self-recalibration of communication iBCIs without interrupting the user. Our method leverages large language models (LMs) to automatically correct errors in iBCI outputs. The self-recalibration process uses these corrected outputs ("pseudo-labels") to continually update the iBCI decoder online. Over a period of more than one year (403 days), we evaluated our Continual Online Recalibration with Pseudo-labels (CORP) framework with one clinical trial participant. CORP achieved a stable decoding accuracy of 93.84% in an online handwriting iBCI task, significantly outperforming other baseline methods. Notably, this is the longest-running iBCI stability demonstration involving a human participant. Our results provide the first evidence for long-term stabilization of a plug-and-play, high-performance communication iBCI, addressing a major barrier for the clinical translation of iBCIs.}, } @article {pmid38738022, year = {2024}, author = {De Jesus-Morales, K and De Jesús-Rojas, W and Ramos-Benitez, MJ}, title = {Neutrophil-to-Lymphocyte Ratio Dynamics From Pre-diagnosis to End-Stage Amyotrophic Lateral Sclerosis (ALS): A Case Study on Association With Progression and Clinical Events.}, journal = {Cureus}, volume = {16}, number = {4}, pages = {e58109}, pmid = {38738022}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by the progressive degeneration of motor neurons, resulting in muscle weakness and paralysis. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a potential marker for monitoring disease severity and progression in ALS, yet longitudinal analyses of NLR are limited. Our study conducts an in-depth examination of NLR dynamics from before diagnosis through the disease's progression to its end stage. We analyze the case of a 56-year-old Puerto Rican male with ALS, tracking his NLR over 13 years - six years before and seven years after his diagnosis - alongside assessments of clinical symptoms and lung function. Our findings indicate that NLR values were initially normal but significantly increased with the onset of symptoms. NLR remained elevated above the normal range, with a notable exception during a period of edaravone therapy when levels normalized. The study demonstrates a clear elevation in NLR associated with ALS progression and critical clinical events, such as symptom onset, diagnosis, and the initiation of respiratory support. This research is, to our knowledge, the first to provide a detailed characterization of NLR changes from the pre-diagnostic phase to end-stage ALS, showing its correlation with clinical deterioration, decreased pulmonary function, and key clinical events. Our results contribute to the body of evidence on NLR's role in ALS while enhancing our understanding of ALS's natural progression.}, } @article {pmid38735361, year = {2024}, author = {D'Agostino, F and Agrò, FE and Petrosino, P and Ferri, C and Ristagno, G}, title = {Are instructors correctly gauging ventilation competence acquired by course attendees?.}, journal = {Resuscitation}, volume = {200}, number = {}, pages = {110240}, doi = {10.1016/j.resuscitation.2024.110240}, pmid = {38735361}, issn = {1873-1570}, mesh = {Humans ; *Clinical Competence/standards ; *Cardiopulmonary Resuscitation/education/standards/methods ; Respiration, Artificial/standards/methods/instrumentation ; Educational Measurement/methods ; Male ; Female ; Manikins ; Tidal Volume/physiology ; }, abstract = {Achievement of adequate ventilation skills during training courses is mainly based on instructors' perception of attendees' capability to ventilate with correct rate and chest compression:ventilation ratio, while leading to chest raising, as evidence of adequate tidal volume. Accuracy in evaluating ventilation competence was assessed in 20 ACLS provider course attendees, by comparing course instructors' evaluation with measures from a ventilation feedback device. According to course instructors, all candidates acquired adequate ventilation competence. However, data from the feedback device indicated a ventilation not aligned with current guidelines, with higher tidal volume and lower rate (p < 0.01). Deploying quality ventilation during CPR is a skill whose acquisition starts with effective training. Therefore, course instructors' capability to accurately evaluate attendees' ventilation maneuvers is crucial.}, } @article {pmid38735299, year = {2024}, author = {Gould, RL and McDermott, CJ and Thompson, BJ and Rawlinson, CV and Bursnall, M and Bradburn, M and Kumar, P and Turton, EJ and White, DA and Serfaty, MA and Graham, CD and McCracken, LM and Goldstein, LH and Al-Chalabi, A and Orrell, RW and Williams, T and Noad, R and Baker, I and Faull, C and Lambert, T and Chhetri, SK and Ealing, J and Hanratty, A and Radunovic, A and Gunawardana, N and Meadows, G and Gorrie, GH and Young, T and Lawrence, V and Cooper, C and Shaw, PJ and Howard, RJ and , }, title = {Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND): a multicentre, parallel, randomised controlled trial in the UK.}, journal = {Lancet (London, England)}, volume = {403}, number = {10442}, pages = {2381-2394}, doi = {10.1016/S0140-6736(24)00533-6}, pmid = {38735299}, issn = {1474-547X}, support = {NIHR202421//NIHR/ ; }, mesh = {Humans ; *Quality of Life ; *Acceptance and Commitment Therapy/methods ; Male ; Female ; Middle Aged ; *Motor Neuron Disease/therapy/psychology ; United Kingdom ; Aged ; Treatment Outcome ; }, abstract = {BACKGROUND: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease.

METHODS: We conducted a parallel, multicentre, two-arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web-based system, stratified by site. Participants were followed up at 6 months and 9 months post-randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire-Revised (MQOL-R) at 6 months post-randomisation. Primary analyses were multi-level modelling and modified intention to treat among participants with available data. This trial was pre-registered with the ISRCTN Registry (ISRCTN12655391).

FINDINGS: Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63·1 years (SD 11·0). 155 (81%) participants had primary outcome data at 6 months post-randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0·66 [95% CI 0·22-1·10]; d=0·46 [0·16-0·77]; p=0·0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention.

INTERPRETATION: ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services.

FUNDING: National Institute for Health and Care Research Health Technology Assessment and Motor Neurone Disease Association.}, } @article {pmid38735139, year = {2024}, author = {Im, G and Choi, D}, title = {Molecular and physiological characterization of AIP1, encoding the acetolactate synthase regulatory subunit in rice.}, journal = {Biochemical and biophysical research communications}, volume = {718}, number = {}, pages = {150087}, doi = {10.1016/j.bbrc.2024.150087}, pmid = {38735139}, issn = {1090-2104}, mesh = {*Oryza/genetics/metabolism/enzymology ; *Acetolactate Synthase/genetics/metabolism ; *Plant Proteins/genetics/metabolism ; *Gene Expression Regulation, Plant ; Plants, Genetically Modified ; Stress, Physiological/genetics ; Amino Acids, Branched-Chain/metabolism ; Oxygen/metabolism ; Protein Subunits/metabolism/genetics ; }, abstract = {Flooding deprives plants of oxygen and thereby causes severe stress by interfering with energy production, leading to growth retardation. Enzymes and metabolites may help protect plants from waterlogging and hypoxic environmental conditions. Acetolactate synthase (ALS) is a key enzyme in the biosynthesis of branched-chain amino acids (BCAAs), providing the building blocks for proteins and various secondary metabolites. Additionally, under energy-poor conditions, free BCAAs can be used as an alternative energy source by mitochondria through a catabolic enzyme chain reaction. In this study, we characterized ALS-INTERACTING PROTEIN 1 (OsAIP1), which encodes the regulatory subunit of ALS in rice (Oryza sativa). This gene was expressed in all parts of the rice plant, and its expression level was significantly higher in submerged and low-oxygen environments. Rice transformants overexpressing OsAIP1 showed a higher survival rate under hypoxic stress than did non-transgenic control plants under the same conditions. The OsAIP1-overexpressing plants accumulated increased levels of BCAAs, demonstrating that OsAIP1 is an important factor in the hypoxia resistance mechanism. These results suggest that ALS proteins are part of a defense mechanism that improves the tolerance of plants to low-oxygen environments.}, } @article {pmid38734896, year = {2024}, author = {Sun, S and Shen, Y and Zhang, X and Ding, N and Xu, Z and Zhang, Q and Li, L}, title = {The MuSK agonist antibody protects the neuromuscular junction and extends the lifespan in C9orf72-ALS mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {32}, number = {7}, pages = {2176-2189}, pmid = {38734896}, issn = {1525-0024}, mesh = {Animals ; *Neuromuscular Junction/metabolism/drug effects ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/drug therapy ; *C9orf72 Protein/genetics/metabolism ; Humans ; *Disease Models, Animal ; *Receptor Protein-Tyrosine Kinases/metabolism/genetics ; Longevity/drug effects ; Motor Neurons/metabolism/drug effects ; Agrin/metabolism/genetics ; Mice, Transgenic ; Antibodies/pharmacology ; Receptors, Cholinergic/metabolism/genetics ; LDL-Receptor Related Proteins/metabolism/genetics ; }, abstract = {The disassembly of the neuromuscular junction (NMJ) is an early event in amyotrophic lateral sclerosis (ALS), ultimately leading to motor dysfunction and lethal respiratory paralysis. The hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most common genetic mutation, and the dipeptide repeat (DPR) proteins have been shown to cause neurodegeneration. While no drugs can treat ALS patients efficiently, new treatment strategies are urgently needed. Here, we report that a MuSK agonist antibody alleviates poly-PR-induced NMJ deficits in C9orf72-ALS mice. The HB9-PR[F/F] mice, which express poly-PR proteins in motor neurons, exhibited impaired motor behavior and NMJ deficits. Mechanistically, poly-PR proteins interacted with Agrin to disrupt the interaction between Agrin and Lrp4, leading to attenuated activation of MuSK. Treatment with a MuSK agonist antibody rescued NMJ deficits, and extended the lifespan of C9orf72-ALS mice. Moreover, impaired NMJ transmission was observed in C9orf72-ALS patients. These findings identify the mechanism by which poly-PR proteins attenuate MuSK activation and NMJ transmission, highlighting the potential of promoting MuSK activation with an agonist antibody as a therapeutic strategy to protect NMJ function and prolong the lifespan of ALS patients.}, } @article {pmid38734122, year = {2024}, author = {Panchalingam, S and Kasivelu, G}, title = {Exploring the impact of circular RNA on ALS progression: A systematic review.}, journal = {Brain research}, volume = {1838}, number = {}, pages = {148990}, doi = {10.1016/j.brainres.2024.148990}, pmid = {38734122}, issn = {1872-6240}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *RNA, Circular/metabolism/genetics ; Humans ; *Disease Progression ; Animals ; Motor Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease that damages motor neurons and causes gradual muscular weakening and paralysis. Although studies have linked a number of genetic and environmental factors to ALS, the specific causes and mechanisms of the disease are still unclear. The pivotal role of circular RNA in the pathogenesis of ALS is a newly emerging area of research. The term "circular RNA" describes a particular class of RNA molecule that, in contrast to most RNA molecules, has a closed-loop structure. According to recent research, circular RNA might be essential for the development and progression of ALS. It has been discovered that these circular RNAs support important cellular functions related to ALS, including protein turnover, mitochondrial function, RNA processing, and cellular transport. Gaining knowledge about the precise roles and processes of circular RNA in the development of ALS could assist in understanding the pathophysiology of the disease and possibly pave the way for the development of targeted therapies. However, the understanding of circular RNA in ALS is still limited, and more research is needed to fully elucidate its role. In order to gain a comprehensive understanding of the role of circRNAs in ALS, it is imperative to delve into the various mechanisms through which circRNAs may contribute to the development and progression of the disease. Examining the current status of circRNA research in ALS and offering insights into their potential as therapeutic targets and diagnostic markers are the primary objectives of this review.}, } @article {pmid38733435, year = {2024}, author = {Liu, S and Hong, Y and Wang, BR and Wei, ZQ and Zhao, HD and Jiang, T and Zhang, YD and Shi, JQ}, title = {The presence and clinical significance of autoantibodies in amyotrophic lateral sclerosis: a narrative review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {9}, pages = {4133-4149}, pmid = {38733435}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/immunology/blood ; Humans ; *Autoantibodies/immunology/blood ; Clinical Relevance ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease, which is characterized by the selective loss of the upper and lower motor neurons. The pathogenesis of ALS remains to be elucidated and has been connected to genetic, environmental and immune conditions. Evidence from clinical and experimental studies has suggested that the immune system played an important role in ALS pathophysiology. Autoantibodies are essential components of the immune system. Several autoantibodies directed at antigens associated with ALS pathogenesis have been identified in the serum and/or cerebrospinal fluid of ALS patients. The aim of this review is to summarize the presence and clinical significance of autoantibodies in ALS.}, } @article {pmid38733354, year = {2024}, author = {Emile, R and Krisjanous, J and Banga, M and Kadirov, D}, title = {Healthcare access for pregnant women in a rural developing country context: Formal and informal institutional challenges.}, journal = {Health marketing quarterly}, volume = {41}, number = {3}, pages = {294-312}, doi = {10.1080/07359683.2024.2347047}, pmid = {38733354}, issn = {1545-0864}, mesh = {Humans ; Female ; *Health Services Accessibility ; Pregnancy ; *Rural Population ; *Developing Countries ; Adult ; Pregnant People/psychology ; }, abstract = {This study examines healthcare access for pregnant women in a rural developing country context. Drawing upon institutional theory and Levesque et al's model of access, the study finds pregnant women face challenges both of a formal and informal nature in accessing healthcare. The findings suggest the need for integrated and collaborative workings across formal and informal institutional networks. Theoretically, the study makes two contributions. First, it adds value to institutional theory by incorporating a dimension of access. Second, it builds upon Levesque et al.'s healthcare access framework by highlighting the role and significance of a third dimension-that is informal institutions, in addition to the current two-formal institutions and individual factors.}, } @article {pmid38732386, year = {2024}, author = {Zhang, Y and Zhao, A and Mu, L and Teng, X and Ma, Y and Li, R and Lei, K and Ji, L and Wang, X and Li, P}, title = {First Clarification of the Involvement of Glycosyltransferase MdUGT73CG22 in the Detoxification Metabolism of Nicosulfuron in Apple.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {9}, pages = {}, pmid = {38732386}, issn = {2223-7747}, support = {No. ZR202102180037//Shandong Provincial Natural Science Foundation of China/ ; No. LCUGYTD2022-04//Guangyue Young Scholar Innovation Team of Liaocheng University/ ; }, abstract = {Nicosulfuron, an acetolactate synthase (ALS) inhibitor herbicide, is a broad-spectrum and highly effective post-emergence herbicide. Glycosyltransferases (GTs) are widely found in organisms and transfer sugar molecules from donors to acceptors to form glycosides or sugar esters, thereby altering the physicochemical properties of the acceptor molecule, such as participating in detoxification. In this study, nine glycosyltransferases in group D of the apple glycosyltransferase family I were predicted to possibly be involved in the detoxification metabolism of ALS-inhibiting herbicides based on gene chip data published online. In order to confirm this, we analysed whether the expression of the nine glycosyltransferase genes in group D was induced by the previously reported ALS-inhibiting herbicides by real-time PCR (polymerase chain reaction). It was found that the ALS-inhibiting herbicide nicosulfuron significantly increased the expression of the MdUGT73CG22 gene in group D. Further investigation of the mechanism of action revealed that the apple glycosyltransferase MdUGT73CG22 glycosylated and modified nicosulfuron both in vivo and ex vivo to form nicosulfuron glycosides, which were involved in detoxification metabolism. In conclusion, a new glycosyltransferase, MdUGT73CG22, was identified for the first time in this study, which can glycosylate modifications of the ALS-inhibiting herbicide nicosulfuron and may be involved in the detoxification process in plants, which can help to further improve the knowledge of the non-targeted mechanism of herbicides.}, } @article {pmid38732027, year = {2024}, author = {Cantara, S and Simoncelli, G and Ricci, C}, title = {Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade.}, journal = {International journal of molecular sciences}, volume = {25}, number = {9}, pages = {}, pmid = {38732027}, issn = {1422-0067}, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use ; *Motor Neuron Disease/genetics/therapy ; Animals ; Muscular Atrophy, Spinal/therapy/genetics ; Amyotrophic Lateral Sclerosis/genetics/therapy ; }, abstract = {Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins, and decrease levels of toxic proteins. ASOs are being developed for the treatment of motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MNDs, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.}, } @article {pmid38731036, year = {2024}, author = {Ueha, R and Miura, C and Matsumoto, N and Sato, T and Goto, T and Kondo, K}, title = {Vocal Fold Motion Impairment in Neurodegenerative Diseases.}, journal = {Journal of clinical medicine}, volume = {13}, number = {9}, pages = {}, pmid = {38731036}, issn = {2077-0383}, abstract = {Vocal fold motion impairment (VFMI) is the inappropriate movement of the vocal folds during respiration, leading to vocal fold adduction and/or abduction problems and causing respiratory and vocal impairments. Neurodegenerative diseases (NDDs) are a wide range of disorders characterized by progressive loss of neurons and deposition of altered proteins in the brain and peripheral organs. VFMI may be unrecognized in patients with NDDs. VFMI in NDDs is caused by the following: laryngeal muscle weakness due to muscular atrophy, caused by brainstem and motor neuron degeneration in amyotrophic lateral sclerosis; hyperactivity of laryngeal adductors in Parkinson's disease; and varying degrees of laryngeal adductor hypertonia and abductor paralysis in multiple system atrophy. Management of VFMI depends on whether there is a presence of glottic insufficiency or insufficient glottic opening with/without severe dysphagia. VFMI treatment options for glottic insufficiency range from surgical interventions, including injection laryngoplasty and medialization thyroplasty, to behavioral therapies; for insufficient glottic opening, various options are available based on the severity and underlying cause of the condition, including continuous positive airway pressure therapy, botulinum toxin injection, tracheostomy, vocal fold surgery, or a combination of interventions. In this review, we outline the mechanisms, clinical features, and management of VFMI in NDDs and provide a guide for physicians who may encounter these clinical features in their patients. NDDs are always progressive; hence, timely evaluation, proper diagnosis, and appropriate management of the patient will greatly affect their vocal, respiratory, and swallowing functions as well as their quality of life.}, } @article {pmid38728654, year = {2024}, author = {McFarlane, R and Heverin, M and Walsh, C and Hardiman, O}, title = {Irish Amyotrophic Lateral Sclerosis Incidence: Age, Period, and Cohort Effects Using a Partial Least Squares Regression Model.}, journal = {Neurology}, volume = {102}, number = {11}, pages = {e209391}, doi = {10.1212/WNL.0000000000209391}, pmid = {38728654}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Ireland/epidemiology ; Incidence ; Aged ; Middle Aged ; Male ; Female ; Adult ; Least-Squares Analysis ; Aged, 80 and over ; Registries ; Age Factors ; Cohort Effect ; Cohort Studies ; }, abstract = {BACKGROUND AND OBJECTIVES: To investigate the underlying reasons for variability in the incidence rate of amyotrophic lateral sclerosis (ALS) within the Irish population between the years 1996 and 2021.

METHODS: The Irish ALS register was used to calculate the incidence and to subsequently extract age at diagnosis (age), year of diagnosis (period), and date of birth (cohort) for all incident patients within the study period (n = 2,771). An age-period-cohort (APC) model using partial least squares regression was constructed to examine each component separately and their respective contribution to the incidence while minimizing the well-known identifiability problem of APC effects. A dummy regression model consisting of 5 periods, 19 cohorts, and 16 age groups was used to examine nonlinear relationships within the data over time. The CIs for each of these were estimated using the jackknife method.

RESULTS: The nonlinear model achieved R[2] of 99.43% with 2-component extraction. Age variation was evident with those in the ages 65-79 years contributing significantly to the incidence (βmax = 0.0746, SE = 0.000410, CI 0.00665-0.00826). However, those aged 25-60 years contributed significantly less (βmin = -0.00393, SE = 0.000291, CI -0.00454 to -0.00340). Each successive period showed an increase in the regression model coefficient suggesting an increasing incidence over time, independent of the other factors examined-an increase of β from -0.00489 (SE = 0.000264, CI -0.00541 to -0.00437) to 0.00973 (SE = 0.000418, CI 0.0105-0.00891). A cohort effect was demonstrated showing that the contribution of those born between 1927 and 1951 contributed to a significantly greater degree than the other birth cohorts (βmax = 0.00577, SE = 0.000432, CI 0.00493-0.00662).

DISCUSSION: Using the Irish population-based ALS Register, robust age, period, and cohort effects can be identified. The age effect may be accounted for by demographic shifts within the population. Changes in disease categorization, competing risks of death, and improved surveillance may account for period effects. The cohort effect may reflect lifestyle and environmental factors associated with the challenging economic circumstances in Ireland between 1927 and 1951. Age-period-cohort studies can help to account for changes in disease incidence and prevalence, providing additional insights into likely demographic and environmental factors that influence population-based disease risk.}, } @article {pmid38727285, year = {2024}, author = {Gao, Y and Lu, Y and Liang, X and Zhao, M and Yu, X and Fu, H and Yang, W}, title = {CD4[+] T-Cell Senescence in Neurodegenerative Disease: Pathogenesis and Potential Therapeutic Targets.}, journal = {Cells}, volume = {13}, number = {9}, pages = {}, pmid = {38727285}, issn = {2073-4409}, support = {20230505039ZP//Jilin Province Science and Technology Department/ ; }, mesh = {Animals ; Humans ; Aging/immunology/pathology ; *CD4-Positive T-Lymphocytes/immunology ; *Neurodegenerative Diseases/immunology/pathology/therapy ; *T-Cell Senescence ; }, abstract = {With the increasing proportion of the aging population, neurodegenerative diseases have become one of the major health issues in society. Neurodegenerative diseases (NDs), including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neurodegeneration associated with aging, leading to a gradual decline in cognitive, emotional, and motor functions in patients. The process of aging is a normal physiological process in human life and is accompanied by the aging of the immune system, which is known as immunosenescence. T-cells are an important part of the immune system, and their senescence is the main feature of immunosenescence. The appearance of senescent T-cells has been shown to potentially lead to chronic inflammation and tissue damage, with some studies indicating a direct link between T-cell senescence, inflammation, and neuronal damage. The role of these subsets with different functions in NDs is still under debate. A growing body of evidence suggests that in people with a ND, there is a prevalence of CD4[+] T-cell subsets exhibiting characteristics that are linked to senescence. This underscores the significance of CD4[+] T-cells in NDs. In this review, we summarize the classification and function of CD4[+] T-cell subpopulations, the characteristics of CD4[+] T-cell senescence, the potential roles of these cells in animal models and human studies of NDs, and therapeutic strategies targeting CD4[+] T-cell senescence.}, } @article {pmid38726604, year = {2024}, author = {López Gómez, JJ and Díaz Marín, C and Castillo-García, T and Larrad-Sainz, A and Gastaldo-Simeón, R and Juarros-Martínez, S and Leunda-Eizmendi, L and Civera Andrés, M and Matía Martín, P}, title = {[Medical nutrition therapy in amyotrophic lateral sclerosis - Do we act or react? A case report and multidisciplinary review].}, journal = {Nutricion hospitalaria}, volume = {41}, number = {3}, pages = {712-723}, doi = {10.20960/nh.05189}, pmid = {38726604}, issn = {1699-5198}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications ; *Malnutrition/etiology/therapy ; *Nutrition Therapy/methods ; Nutritional Status ; }, abstract = {Background: amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a progressive course. The current prevalence is between 3 and 6 cases/100,000. Malnutrition is closely related to patient prognosis in ALS. The implications of this conditions have been that we should recommend patient care in a multidisciplinary unit. Case report: the case presented shows the evolution of a patient with ALS. The patient was referred to different clinical departments after neurological evaluation and her nutritional, functional and respiratory status were assessed. There was no nutritional deterioration at diagnosis; however, intake was below energy-protein requirements. The clinical evolution of the patient showed a decrease in muscle mass with preservation of weight and fat mass. "Aggressive" measures to control nutritional status such as gastrostomy were rejected in the initial stages of the disease, but had to be carried out after development of dysphagia and associated malnutrition. This situation of progressive morphofunctional deterioration and the development of disease-related complications made essential the participation of different health services and professionals in its control. Dicussion: the management of ALS in a multidisciplinary manner allows to improve the course of the disease and the quality of life of both the patients and their families. Patient follow-up is based on the adjustment and management of complications. The basis of the relationship with these patients includes maintaining an adequate communication with them and their families, and ensuring joint decision-making about their condition.}, } @article {pmid38726482, year = {2024}, author = {Henden, L and Fearnley, LG and Southwood, D and Smith, A and Rowe, DB and Kiernan, MC and Pamphlett, R and Bahlo, M and Blair, IP and Williams, KL}, title = {Short tandem repeat expansions in LRP12 are absent in cohorts of familial and sporadic amyotrophic lateral sclerosis patients of European ancestry.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {644-647}, doi = {10.1080/21678421.2024.2348636}, pmid = {38726482}, issn = {2167-9223}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; Cohort Studies ; Trinucleotide Repeat Expansion ; *White People/genetics ; *Low Density Lipoprotein Receptor-Related Protein-1/genetics ; }, abstract = {In patients of Asian ancestry, a heterozygous CGG repeat expansion of >100 units in LRP12 is the cause of oculopharyngodistal myopathy type 1 (OPDM1). Repeat lengths of between 61 and 100 units have been associated with rare amyotrophic lateral sclerosis (ALS) cases of Asian ancestry, although with unusually long disease duration and without significant upper motor neuron involvement. This study sought to determine whether LRP12 CGG repeat expansions were also present in ALS patients of European ancestry. Whole-genome sequencing data from 608 sporadic ALS patients, 35 familial ALS probands, and 4703 neurologically normal controls were screened for LRP12 CGG expansions using ExpansionHunter v4. All individuals had LRP12 CGG repeat lengths within the normal range of 3-25 units. To date, LRP12 CGG repeat expansions have not been reported in ALS patients of European ancestry and may be limited to rare ALS patients of Asian ancestry and atypical clinical presentations.}, } @article {pmid38725125, year = {2024}, author = {Kim, D and Kim, S and Seok, JM and Shin, KJ and Oh, E and Jeon, MY and Park, J and Chang, HJ and Youn, J and Oh, J and Sohn, E and Park, J and Cho, JW and Kim, BJ}, title = {Establishment of a registry of clinical data and bioresources for rare nervous system diseases.}, journal = {Osong public health and research perspectives}, volume = {15}, number = {2}, pages = {174-181}, pmid = {38725125}, issn = {2210-9099}, support = {2023ER050600//National Institute of Health research/ ; }, abstract = {Rare diseases are predominantly genetic or inherited, and patients with these conditions frequently exhibit neurological symptoms. Diagnosing and treating many rare diseases is a complex challenge, and their low prevalence complicates the performance of research, which in turn hinders the advancement of therapeutic options. One strategy to address this issue is the creation of national or international registries for rare diseases, which can help researchers monitor and investigate their natural progression. In the Republic of Korea, we established a registry across 5 centers that focuses on 3 rare diseases, all of which are characterized by gait disturbances resulting from motor system dysfunction. The registry will collect clinical information and human bioresources from patients with amyotrophic lateral sclerosis, spinocerebellar ataxia, and hereditary spastic paraplegia. These resources will be stored at ICreaT and the National Biobank of Korea. Once the registry is complete, the data will be made publicly available for further research. Through this registry, our research team is dedicated to identifying genetic variants that are specific to Korean patients, uncovering biomarkers that show a strong correlation with clinical symptoms, and leveraging this information for early diagnosis and the development of treatments.}, } @article {pmid38724513, year = {2024}, author = {Zhou, T and Solis, NV and Marshall, M and Yao, Q and Garleb, R and Yang, M and Pearlman, E and Filler, SG and Liu, H}, title = {Hyphal Als proteins act as CR3 ligands to promote immune responses against Candida albicans.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {3926}, pmid = {38724513}, issn = {2041-1723}, support = {R01 GM117111/GM/NIGMS NIH HHS/United States ; R01 EY018612/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Mice ; beta-Glucans/metabolism/immunology ; Candida albicans/immunology ; *Candidiasis/immunology/microbiology ; CD11b Antigen/metabolism/immunology ; *CD18 Antigens/metabolism ; Dendritic Cells/immunology/metabolism ; *Fungal Proteins/metabolism/immunology ; *Lectins, C-Type/metabolism/immunology ; *Macrophages/immunology/metabolism ; Signal Transduction ; }, abstract = {Patients with decreased levels of CD18 (β2 integrins) suffer from life-threatening bacterial and fungal infections. CD11b, the α subunit of integrin CR3 (CD11b/CD18, αMβ2), is essential for mice to fight against systemic Candida albicans infections. Live elongating C. albicans activates CR3 in immune cells. However, the hyphal ligands that activate CR3 are not well defined. Here, we discovered that the C. albicans Als family proteins are recognized by the I domain of CD11b in macrophages. This recognition synergizes with the β-glucan-bound lectin-like domain to activate CR3, thereby promoting Syk signaling and inflammasome activation. Dectin-2 activation serves as the "outside-in signaling" for CR3 activation at the entry site of incompletely sealed phagosomes, where a thick cuff of F-actin forms to strengthen the local interaction. In vitro, CD18 partially contributes to IL-1β release from dendritic cells induced by purified hyphal Als3. In vivo, Als3 is vital for C. albicans clearance in mouse kidneys. These findings uncover a novel family of ligands for the CR3 I domain that promotes fungal clearance.}, } @article {pmid38723941, year = {2024}, author = {Doeleman, LC and Boomars, R and Radstok, A and Schober, P and Dellaert, Q and Hollmann, MW and Koster, RW and van Schuppen, H}, title = {Ventilation during cardiopulmonary resuscitation with mechanical chest compressions: How often are two insufflations being given during the 3-second ventilation pauses?.}, journal = {Resuscitation}, volume = {199}, number = {}, pages = {110234}, doi = {10.1016/j.resuscitation.2024.110234}, pmid = {38723941}, issn = {1873-1570}, mesh = {Humans ; *Cardiopulmonary Resuscitation/methods ; *Out-of-Hospital Cardiac Arrest/therapy ; Male ; Female ; *Insufflation/methods ; Middle Aged ; Prospective Studies ; *Heart Massage/methods ; Aged ; Netherlands ; Time Factors ; Respiration, Artificial/methods ; Emergency Medical Services/methods ; Registries ; }, abstract = {BACKGROUND: Mechanical chest compression devices in 30:2 mode provide 3-second pauses to allow for two insufflations. We aimed to determine how often two insufflations are provided in these ventilation pauses, in order to assess if prehospital providers are able to ventilate out-of-hospital cardiac arrest (OHCA) patients successfully during mechanical chest compressions.

METHODS: Data from OHCA cases of the regional ambulance service of Utrecht, The Netherlands, were prospectively collected in the UTrecht studygroup for OPtimal registry of cardIAc arrest database (UTOPIA). Compression pauses and insufflations were visualized on thoracic impedance and waveform capnography signals recorded by manual defibrillators. Ventilation pauses were analyzed for number of insufflations, duration of the subintervals of the ventilation cycles, and ratio of successfully providing two insufflations over the course of the resuscitation. Generalized linear mixed effects models were used to accurately estimate proportions and means.

RESULTS: In 250 cases, 8473 ventilation pauses were identified, of which 4305 (51%) included two insufflations. When corrected for non-independence of the data across repeated measures within the same subjects with a mixed effects analysis, two insufflations were successfully provided in 45% of ventilation pauses (95% CI: 40-50%). In 19% (95% CI: 16-22%) none were given.

CONCLUSION: Providing two insufflations during pauses in mechanical chest compressions is mostly unsuccessful. We recommend developing strategies to improve giving insufflations when using mechanical chest compression devices. Increasing the pause duration might help to improve insufflation success.}, } @article {pmid38723906, year = {2024}, author = {Koike, Y}, title = {Molecular mechanisms linking loss of TDP-43 function to amyotrophic lateral sclerosis/frontotemporal dementia-related genes.}, journal = {Neuroscience research}, volume = {208}, number = {}, pages = {1-7}, doi = {10.1016/j.neures.2024.05.001}, pmid = {38723906}, issn = {1872-8111}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Animals ; Polymorphism, Single Nucleotide ; Aging/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by nuclear depletion and cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43). TDP-43 plays a key role in regulating the splicing of numerous genes, including TARDBP. This review aims to delineate two aspects of ALS/FTD pathogenesis associated with TDP-43 function. First, we described novel mechanistic insights into the splicing of UNC13A, a TDP-43 target gene. Single nucleotide polymorphisms (SNPs) in UNC13A are the most common risk factors for ALS/FTD. We found that TDP-43 represses "cryptic exon" inclusion during UNC13A RNA splicing. A risk-associated SNP in this exon results in increased RNA levels of UNC13A retaining the cryptic exon. Second, we described the perturbation of the TDP-43 autoregulatory mechanism caused by age-related DNA demethylation. Aging is a major risk factor for sporadic ALS/FTD. Typically, TDP-43 levels are regulated via alternative splicing of TARDBP mRNA. This review focused on that TARDBP methylation is altered by aging, thereby disrupting TDP-43 autoregulation. It was found that demethylation reduces the efficiency of alternative splicing and increases TARDBP mRNA levels. Moreover, we demonstrated that, with aging, this region is demethylated in the human motor cortex and is associated with the early onset of ALS.}, } @article {pmid38723752, year = {2024}, author = {Singh, K and Sethi, P and Datta, S and Chaudhary, JS and Kumar, S and Jain, D and Gupta, JK and Kumar, S and Guru, A and Panda, SP}, title = {Advances in gene therapy approaches targeting neuro-inflammation in neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {98}, number = {}, pages = {102321}, doi = {10.1016/j.arr.2024.102321}, pmid = {38723752}, issn = {1872-9649}, mesh = {Humans ; *Genetic Therapy/methods/trends ; *Neurodegenerative Diseases/therapy/genetics ; *Neuroinflammatory Diseases/therapy ; Animals ; }, abstract = {Over the last three decades, neurodegenerative diseases (NDs) have increased in frequency. About 15% of the world's population suffers from NDs in some capacity, which causes cognitive and physical impairment. Neurodegenerative diseases, including Amyotrophic Lateral Sclerosis, Parkinson's disease, Alzheimer's disease, and others represent a significant and growing global health challenge. Neuroinflammation is recognized to be related to all NDs, even though NDs are caused by a complex mix of genetic, environmental, and lifestyle factors. Numerous genes and pathways such as NFκB, p38 MAPK, Akt/mTOR, caspase, nitric oxide, and COX are involved in triggering brain immune cells like astrocytes and microglia to secrete inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. In AD, the binding of Aβ with CD36, TLR4, and TLR6 receptors results in activation of microglia which start to produce proinflammatory cytokines and chemokines. Consequently, the pro-inflammatory cytokines worsen and spread neuroinflammation, causing the deterioration of healthy neurons and the impairment of brain functions. Gene therapy has emerged as a promising therapeutic approach to modulate the inflammatory response in NDs, offering potential neuroprotective effects and disease-modifying benefits. This review article focuses on recent advances in gene therapy strategies targeting neuroinflammation pathways in NDs. We discussed the molecular pathways involved in neuroinflammation, highlighted key genes and proteins implicated in these processes, and reviewed the latest preclinical and clinical studies utilizing gene therapy to modulate neuroinflammatory responses. Additionally, this review addressed the prospects and challenges in translating gene therapy approaches into effective treatments for NDs.}, } @article {pmid38722513, year = {2024}, author = {Sultana, J and Ragagnin, AMG and Parakh, S and Saravanabavan, S and Soo, KY and Vidal, M and Jagaraj, CJ and Ding, K and Wu, S and Shadfar, S and Don, EK and Deva, A and Nicholson, G and Rowe, DB and Blair, I and Yang, S and Atkin, JD}, title = {C9orf72-Associated Dipeptide Repeat Expansions Perturb ER-Golgi Vesicular Trafficking, Inducing Golgi Fragmentation and ER Stress, in ALS/FTD.}, journal = {Molecular neurobiology}, volume = {61}, number = {12}, pages = {10318-10338}, pmid = {38722513}, issn = {1559-1182}, support = {10305133//National Health and Medical Research Council/ ; 1086887//National Health and Medical Research Council/ ; 1095215//National Health and Medical Research Council/ ; 1176913//National Health and Medical Research Council/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Golgi Apparatus/metabolism ; *Endoplasmic Reticulum Stress/genetics ; *Endoplasmic Reticulum/metabolism ; *Dipeptides/metabolism ; *DNA Repeat Expansion/genetics ; Protein Transport ; }, abstract = {Hexanucleotide repeat expansions (HREs) in the chromosome 9 open reading frame 72 (C9orf72) gene are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both are debilitating neurodegenerative conditions affecting either motor neurons (ALS) in the brain and spinal cord or neurons in the frontal and/or temporal cortical lobes (FTD). HREs undergo repeat-associated non-ATG (RAN) translation on both sense and anti-sense strands, generating five distinct dipeptide repeat proteins (DPRs), poly-GA, -GR, -GP, -PA and -PR. Perturbed proteostasis is well-recognised in ALS pathogenesis, including processes affecting the endoplasmic reticulum (ER) and Golgi compartments. However, these mechanisms have not been well characterised for C9orf72-mediated ALS/FTD. In this study we demonstrate that C9orf72 DPRs polyGA, polyGR and polyGP (× 40 repeats) disrupt secretory protein transport from the ER to the Golgi apparatus in neuronal cells. Consistent with this finding, these DPRs also induce fragmentation of the Golgi apparatus, activate ER stress, and inhibit the formation of the omegasome, the precursor of the autophagosome that originates from ER membranes. We also demonstrate Golgi fragmentation in cells undergoing RAN translation that express polyGP. Furthermore, dysregulated ER-Golgi transport was confirmed in C9orf72 patient dermal fibroblasts. Evidence of aberrant ER-derived vesicles in spinal cord motor neurons from C9orf72 ALS patients compared to controls was also obtained. These data thus confirm that ER proteostasis and ER-Golgi transport is perturbed in C9orf72-ALS in the absence of protein over-expression. Hence this study identifies novel molecular mechanisms associated with the ER and Golgi compartments induced by the C9orf72 HRE.}, } @article {pmid38721655, year = {2024}, author = {Christoforidou, E and Moody, L and Joilin, G and Simoes, FA and Gordon, D and Talbot, K and Hafezparast, M}, title = {An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner.}, journal = {Disease models & mechanisms}, volume = {17}, number = {5}, pages = {}, pmid = {38721655}, issn = {1754-8411}, support = {//University of Sussex/ ; Hafezparast/Apr21/880-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; DOD/14/30-PF12794//My Name'5 Doddie Foundation/ ; }, mesh = {*Microglia/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *MicroRNAs/genetics/metabolism ; Animals ; Female ; *Mice, Transgenic ; Male ; *Mutation/genetics ; *Sex Characteristics ; DNA-Binding Proteins/genetics/metabolism ; Mice ; Extracellular Space/metabolism ; Humans ; Lipopolysaccharides/pharmacology ; Gene Expression Regulation ; }, abstract = {Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation originates from microglia. Furthermore, TDP-43 (encoded by TARDBP), involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of three candidate miRNAs, namely, miR-16-5p, miR-99a-5p and miR-191-5p, by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and identified their predicted targets, which primarily include genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia, which may in turn be a source of the miRNA dysregulation observed in the disease. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.}, } @article {pmid38721118, year = {2024}, author = {Lu, L and Deng, Y and Xu, R}, title = {Current potential therapeutics of amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1402962}, pmid = {38721118}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating motor neurological disorder for which there is still no cure. The disease seriously jeopardizes the health and lifespan of adult populations. The authors extensively retrieved the current literature about clinical and experimental ALS treatments. Based on them, this review primarily focused on summarizing the current potential clinical usage and trialing therapeutics of ALS. Currently, the clinical ALS treatments have focused primarily on relieving symptoms to improve the quality of life yet. There are a number of therapeutic approaches such as medicine, gene therapy, neuron protectants, combination therapy and stem cells. Among them, Stem cells including embryonic stem cells, mesenchymal stem cells, neural stem cells, and many other types of stem cells have been used in ALS treatment, and although the short-term efficacy is good, it is worth exploring whether this improved efficacy leads to prolonged patient survival. In addition, the supportive treatments also exert an important effect on improving the quality of life and prolong the survival of ALS patients in absence of effectively care for stopping or reversing the progression of ALS.}, } @article {pmid38720896, year = {2024}, author = {Zong, J and Yang, Y and Wang, H and Zhang, H and Yang, X and Yang, X}, title = {The two-directional prospective association between inflammatory bowel disease and neurodegenerative disorders: a systematic review and meta-analysis based on longitudinal studies.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1325908}, pmid = {38720896}, issn = {1664-3224}, mesh = {Humans ; *Inflammatory Bowel Diseases/complications ; *Neurodegenerative Diseases/epidemiology/etiology ; Longitudinal Studies ; Risk Factors ; Prospective Studies ; }, abstract = {OBJECTIVE: Previous studies reported possible connections between inflammatory bowel disease (IBD) and several neurodegenerative disorders. However, the comprehensive relationships between IBD and various neurodegenerative disorders were not summarized. We executed a meta-analysis of longitudinal studies to provide an estimate of the strength of the two-directional prospective association between IBD and neurodegenerative disorders.

METHODS: We accomplished a thorough bibliographic search of PubMed, Web of Science, Embase, PsycINFO, and Cochrane Library databases until June 2023 to locate relevant longitudinal studies. The extracted data were then analyzed via meta-analysis using either a fixed or random effects model.

RESULTS: The final analysis encompassed 27 studies. Individuals with IBD faced an increased risk of developing four neurodegenerative disorders than the general public, namely, Alzheimer's disease (hazard ratio[HR] = 1.35, 95% confidence interval [CI]: 1.03-1.77, P=0.031), dementia (HR =1.24, 95% CI: 1.13-1.36, P<0.001), multiple sclerosis (HR =2.07, 95% CI:1.42-3.02, P<0.001) and Parkinson's disease (HR =1.23, 95% CI:1.10-1.38, P<0.001). Two articles reported an increased incidence of amyotrophic lateral sclerosis or multiple system atrophy in IBD patients. Three studies investigated the prospective association between multiple sclerosis and IBD, revealing an elevated risk of the latter in patients with the former. (HR=1.87, 95% CI:1.66-2.10, P<0.001).

INTERPRETATION: These findings verified the two-directional relationship between the brain-gut axis, specifically demonstrating a heightened risk of various neurodegenerative diseases among IBD patients. It may be profitable to prepare screening strategies for IBD patients to find neurodegenerative diseases during the long-term course of treatment for IBD with a view to potential earlier diagnosis and treatment of neurodegenerative diseases, reducing public health and social burden.

PROSPERO (CRD42023437553).}, } @article {pmid38720484, year = {2024}, author = {Fernandes, JMA and Gondim, FAA}, title = {A homozygous p.Val120Leu (c.358G > C) SOD1 mutation led to slowly progressive amyotrophic lateral sclerosis in a Brazilian family.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {788-790}, doi = {10.1080/21678421.2024.2346824}, pmid = {38720484}, issn = {2167-9223}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Adult ; *Superoxide Dismutase-1/genetics ; Brazil ; *Mutation/genetics ; *Disease Progression ; Pedigree ; Superoxide Dismutase/genetics ; Homozygote ; Female ; Middle Aged ; Valine/genetics ; Leucine/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease usually associated with severe weakness and death within 2-5 years. SOD1 mutations cause hereditary ALS in autosomal dominant and rarely in recessive pattern. We describe a new phenotype of slowly progressive fALS due to homozygous SOD1 mutations (c.358G > C, p.Val120Leu) in a Brazilian family. We reviewed the medical chart and interviewed the index patient and other relatives. A 41-year-old man developed weakness in his legs, leading to frequent falls, followed over the next few months with progressive arm fasciculations and muscle atrophy. The SOD1 enzymatic activity in erythrocytes was slightly decreased. A genetic test panel disclosed homozygous SOD1 mutations (c.358G > C, p.Val120Leu). His asymptomatic parents also carried one mutant allele and 2 brothers and a sister had died with ALS. We reported a new family with homozygous SOD1 mutation and slowly progressive ALS course. Further studies are necessary to confirm whether this mutation can also lead to disease in heterozygosis with incomplete penetrance.}, } @article {pmid38720470, year = {2024}, author = {Didcote, L and Al-Chalabi, A and Goldstein, LH}, title = {How the coronavirus pandemic affected the lives of people with ALS and their spouses in the UK from spouses' perspectives: a qualitative study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {625-633}, pmid = {38720470}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/epidemiology ; *Spouses/psychology ; *COVID-19/psychology/epidemiology ; Male ; Female ; Middle Aged ; *Qualitative Research ; Aged ; United Kingdom/epidemiology ; SARS-CoV-2 ; Caregivers/psychology ; Adult ; Anxiety/psychology/epidemiology ; }, abstract = {OBJECTIVE: This study set out to investigate, using qualitative methodology, the experiences of spouses of people with Amyotrophic Lateral Sclerosis (ALS) during the coronavirus pandemic, with particular focus on spouse distress and cognitive and behavioral change in people with ALS (pwALS).

METHODS: Qualitative semi-structured interviews of nine spouses of pwALS living in England were conducted between 11/09/2020 and 20/04/2021, focusing on spouses' perspectives of how their lives and the lives of pwALS were affected by the pandemic and related lockdowns. Interviews were subject to thematic analysis.

RESULTS: Four superordinate themes were identified from the spouses' interviews: (i) pandemic behaviors, which encompassed accounts of cautious behavior, relaxation of cautious behavior, and other people's attitudes to shielding the person with ALS; (ii) changes to daily life caused by the pandemic and progression of ALS; (iii) distress in spouses, which included anxiety, depression, and burden; and (iv) ALS-related behavioral impairment. Spouses also provided mixed accounts of telehealth care, pointing out its convenience but some felt that face-to-face appointments were preferable.

CONCLUSIONS: While many reactions to the pandemic reported by spouses of pwALS may have been similar to those of the general population or other vulnerable groups, interviews indicated the potential for the pandemic to have made more apparent certain aspects of behavioral change in pwALS with which carers may require support. Clinicians need to acknowledge spouses' concerns about the potential limitations of remote clinical consultations, enquire about cognitive and behavioral change, and consider how input should be best provided in such limiting circumstances.}, } @article {pmid38719860, year = {2024}, author = {Cusaro, CM and Capelli, E and Picco, AM and Brusoni, M}, title = {Incidence of resistance to ALS and ACCase inhibitors in Echinochloa species and soil microbial composition in Northern Italy.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {10544}, pmid = {38719860}, issn = {2045-2322}, support = {ECS00000036//MUR - M4C2 1.5 of PNRR funded by the European Union - NextGenerationEU/ ; }, mesh = {*Soil Microbiology ; Italy/epidemiology ; *Herbicide Resistance ; *Herbicides/pharmacology ; *Acetolactate Synthase/antagonists & inhibitors/genetics ; *Echinochloa/drug effects ; *Acetyl-CoA Carboxylase/genetics/antagonists & inhibitors ; Plant Weeds/drug effects ; Microbiota/drug effects ; Biodiversity ; Bacteria/drug effects/genetics/isolation & purification/classification ; Soil/chemistry ; Fungi/drug effects/isolation & purification/genetics ; }, abstract = {The increasing amount of weeds surviving herbicide represents a very serious problem for crop management. The interaction between microbial community of soil and herbicide resistance, along with the potential evolutive consequences, are still poorly known and need to be investigated to better understand the impact on agricultural management. In our study, we analyzed the microbial composition of soils in 32 farms, located in the Northern Italy rice-growing area (Lombardy) with the aim to evaluate the relationship between the microbial composition and the incidence of resistance to acetolactate synthase (ALS) and acetyl-CoA carboxylase (ACCase) inhibiting herbicides in Echinochloa species. We observed that the coverage of weeds survived herbicide treatment was higher than 60% in paddy fields with a low microbial biodiversity and less than 5% in those with a high microbial biodiversity. Fungal communities showed a greater reduction in richness than Bacteria. In soils with a reduced microbial diversity, a significant increase of some bacterial and fungal orders (i.e. Lactobacillales, Malasseziales and Diaporthales) was observed. Interestingly, we identified two different microbial profiles linked to the two conditions: high incidence of herbicide resistance (H-HeR) and low incidence of herbicide resistance (L-HeR). Overall, the results we obtained allow us to make hypotheses on the greater or lesser probability of herbicide resistance occurrence based on the composition of the soil microbiome and especially on the degree of biodiversity of the microbial communities.}, } @article {pmid38718295, year = {2024}, author = {Huang, J and Fu, Y and Wang, A and Shi, K and Peng, Y and Yi, Y and Yu, R and Gao, J and Feng, J and Jiang, G and Song, Q and Jiang, J and Chen, H and Gao, X}, title = {Brain Delivery of Protein Therapeutics by Cell Matrix-Inspired Biomimetic Nanocarrier.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {36}, number = {31}, pages = {e2405323}, doi = {10.1002/adma.202405323}, pmid = {38718295}, issn = {1521-4095}, support = {2022YFC2502800//National Key Research and Development Program of China/ ; 2023ZKZD21//Innovation Program of Shanghai Municipal Education Commission/ ; 81973272//National Natural Science Foundation of China/ ; 92068111//National Natural Science Foundation of China/ ; 81801212//National Natural Science Foundation of China/ ; 23S41900100//Shanghai Science and Technology Development Foundation/ ; 22QA1405000//Shanghai Science and Technology Development Foundation/ ; 21XD1422200//Shanghai Science and Technology Development Foundation/ ; SHSMU-ZDCX20211201//Innovative Research Team of High-Level Local Universities in Shanghai/ ; }, mesh = {Animals ; Mice ; *Biomimetic Materials/chemistry ; *Drug Carriers/chemistry ; *Blood-Brain Barrier/metabolism ; *Hyaluronic Acid/chemistry ; *Catalase/metabolism/chemistry ; *Brain/metabolism ; Nanoparticles/chemistry ; Protamines/chemistry ; Amyotrophic Lateral Sclerosis/drug therapy ; Disease Models, Animal ; Humans ; Brain Injuries/drug therapy/metabolism ; Biomimetics/methods ; }, abstract = {Protein therapeutics are anticipated to offer significant treatment options for central nervous system (CNS) diseases. However, the majority of proteins are unable to traverse the blood-brain barrier (BBB) and reach their CNS target sites. Inspired by the natural environment of active proteins, the cell matrix components hyaluronic acid (HA) and protamine (PRTM) are used to self-assemble with proteins to form a protein-loaded biomimetic core and then incorporated into ApoE3-reconstituted high-density lipoprotein (rHDL) to form a protein-loaded biomimetic nanocarrier (Protein-HA-PRTM-rHDL). This cell matrix-inspired biomimetic nanocarrier facilitates the penetration of protein therapeutics across the BBB and enables their access to intracellular target sites. Specifically, CAT-HA-PRTM-rHDL facilitates rapid intracellular delivery and release of catalase (CAT) via macropinocytosis-activated membrane fusion, resulting in improved spatial learning and memory in traumatic brain injury (TBI) model mice (significantly reduces the latency of TBI mice and doubles the number of crossing platforms), and enhances motor function and prolongs survival in amyotrophic lateral sclerosis (ALS) model mice (extended the median survival of ALS mice by more than 10 days). Collectively, this cell matrix-inspired nanoplatform enables the efficient CNS delivery of protein therapeutics and provides a novel approach for the treatment of CNS diseases.}, } @article {pmid38717990, year = {2024}, author = {Yu, X and Sun, J and Yang, Y and Zhang, J and Lu, Y and Tang, W}, title = {Enhanced Herbicide Metabolism and Target Site Mutation Enabled the Multiple Resistance to Cyhalofop-butyl, Florpyrauxifen-benzyl, and Penoxsulam in Echinochloa crus-galli.}, journal = {Journal of agricultural and food chemistry}, volume = {72}, number = {20}, pages = {11405-11414}, doi = {10.1021/acs.jafc.4c02450}, pmid = {38717990}, issn = {1520-5118}, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology/metabolism ; *Mutation ; *Echinochloa/genetics/drug effects/metabolism/growth & development ; *Plant Proteins/genetics/metabolism ; *Cytochrome P-450 Enzyme System/genetics/metabolism ; Acetyl-CoA Carboxylase/genetics/metabolism ; Plant Weeds/drug effects/genetics/metabolism ; Acetolactate Synthase/genetics/metabolism ; Butanes ; Nitriles ; Sulfonamides ; Uridine/analogs & derivatives ; }, abstract = {This study investigated the multiple herbicide resistance (MHR) mechanism of one Echinochloa crus-galli population that was resistant to florpyrauxifen-benzyl (FPB), cyhalofop-butyl (CHB), and penoxsulam (PEX). This population carried an Ala-122-Asn mutation in the acetolactate synthase (ALS) gene but no mutation in acetyl-CoA carboxylase (ACCase) and transport inhibitor response1 (TIR1) genes. The metabolism rate of PEX was 2-fold higher, and the production of florpyrauxifen-acid and cyhalofop-acid was lower in the resistant population. Malathion and 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) could reverse the resistance, suggesting that cytochrome P450 (CYP450) and glutathione S-transferase (GST) contribute to the enhanced metabolism. According to RNA-seq and qRT-PCR validation, two CYP450 genes (CYP71C42 and CYP71D55), one GST gene (GSTT2), two glycosyltransferase genes (rhamnosyltransferase 1 and IAAGLU), and two ABC transporter genes (ABCG1 and ABCG25) were induced by CHB, FPB, and PEX in the resistant population. This study revealed that the target mutant and enhanced metabolism were involved in the MHR mechanism in E. crus-galli.}, } @article {pmid38717875, year = {2024}, author = {Chen, M and Zhou, P}, title = {2CFastICA: A Novel Method for High Density Surface EMG Decomposition Based on Kernel Constrained FastICA and Correlation Constrained FastICA.}, journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society}, volume = {32}, number = {}, pages = {2177-2186}, doi = {10.1109/TNSRE.2024.3398822}, pmid = {38717875}, issn = {1558-0210}, mesh = {*Electromyography/methods ; Humans ; *Algorithms ; *Signal-To-Noise Ratio ; Reproducibility of Results ; Signal Processing, Computer-Assisted ; Muscle, Skeletal/physiology ; Motor Neurons/physiology ; Computer Simulation ; Male ; Adult ; Female ; }, abstract = {This study presents a novel high density surface electromyography (EMG) decomposition method, named as 2CFastICA, because it incorporates two key algorithms: kernel constrained FastICA and correlation constrained FastICA. The former focuses on overcoming the local convergence of FastICA without requiring the peel-off strategy used in the progressive FastICA peel-off (PFP) framework. The latter further refines the output of kernel constrained FastICA by correcting possible erroneous or missed spikes. The two constrained FastICA algorithms supplement each other to warrant the decomposition performance. The 2CFastICA method was validated using simulated surface EMG signals with different motor unit numbers and signal to noise ratios (SNRs). Two source validation was also performed by simultaneous high density surface EMG and intramuscular EMG recordings, showing a matching rate (MR) of (97.2 ± 3.5)% for 170 common motor units. In addition, a different form of two source validation was also conducted taking advantages of the high density surface EMG characteristics of patients with amyotrophic lateral sclerosis, showing a MR of (99.4 ± 0.9)% for 34 common motor units from interference and sparse datasets. Both simulation and experimental results indicate that 2CFastICA can achieve similar decomposition performance to PFP. However, the efficiency of decomposition can be greatly improved by 2CFastICA since the complex signal processing procedures associated with the peel-off strategy are not required any more. Along with this paper, we also provide the MATLAB open source code of 2CFastICA for high density surface EMG decomposition.}, } @article {pmid38717430, year = {2024}, author = {Boyce, D and Raymond, J and Larson, TC and Kirkland, E and Horton, DK and Mehta, P}, title = {What do you think caused your ALS? An analysis of the CDC national amyotrophic lateral sclerosis patient registry qualitative risk factor data using artificial intelligence and qualitative methodology.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {615-624}, pmid = {38717430}, issn = {2167-9223}, support = {CC999999/ImCDC/Intramural CDC HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/psychology/epidemiology ; Humans ; *Artificial Intelligence ; *Registries ; Male ; Female ; United States/epidemiology ; Risk Factors ; Middle Aged ; Centers for Disease Control and Prevention, U.S. ; Aged ; Adult ; Qualitative Research ; Natural Language Processing ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is an incurable, progressive neurodegenerative disease with a significant health burden and poorly understood etiology. This analysis assessed the narrative responses from 3,061 participants in the Centers for Disease Control and Prevention's National ALS Registry who answered the question, "What do you think caused your ALS?"

METHODS: Data analysis used qualitative methods and artificial intelligence (AI) using natural language processing (NLP), specifically, Bidirectional Encoder Representations from Transformers (BERT) to explore responses regarding participants' perceptions of the cause of their disease.

RESULTS: Both qualitative and AI analysis methods revealed several, often aligned themes, which pointed to perceived causes including genetic, environmental, and military exposures. However, the qualitative analysis revealed detailed themes and subthemes, providing a more comprehensive understanding of participants' perceptions. Although there were areas of alignment between AI and qualitative analysis, AI's broader categories did not capture the nuances discovered using the more traditional, qualitative approach. The qualitative analysis also revealed that the potential causes of ALS were described within narratives that sometimes indicate self-blame and other maladaptive coping mechanisms.

CONCLUSIONS: This analysis highlights the diverse range of factors that individuals with ALS consider as perceived causes for their disease. Understanding these perceptions can help clinicians to better support people living with ALS (PLWALS). The analysis highlights the benefits of using traditional qualitative methods to supplement or improve upon AI-based approaches. This rapidly evolving area of data science has the potential to remove barriers to accessing the rich narratives of people with lived experience.}, } @article {pmid38717009, year = {2024}, author = {Zhang, X and Sun, Y and Zhang, X and Shen, D and Shu, S and Yang, X and Liu, M and Cui, L and Liu, Q and Zhang, X}, title = {Genotype-phenotype association and functional analysis of hnRNPA1 mutations in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {600-607}, doi = {10.1080/21678421.2024.2346502}, pmid = {38717009}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Heterogeneous Nuclear Ribonucleoprotein A1/genetics ; Male ; Middle Aged ; Female ; *Mutation/genetics ; *Genetic Association Studies/methods ; Adult ; Exome Sequencing ; Aged ; }, abstract = {BACKGROUND: Pathogenic variants in hnRNPA1 have been reported in amyotrophic lateral sclerosis (ALS) patients. However, studies on hnRNPA1 mutant spectrum and pathogenicity of variants were rare.

METHODS: We performed whole exome sequencing of ALS-associated genes and subsequent verification of rare variants in hnRNPA1 in our ALS patients. The hnRNPA1 mutations reported in literature were reviewed and combined with our results to determine the genotype-phenotype relationship. Functional analysis of the novel variant p.G195A was performed in vitro by transfection of mutant hnRNPA1 into 293T cell.

RESULTS: Among 207 ALS patients recruited, 3 rare hnRNPA1 variants were identified (mutant frequency 1.45%), including two recurrent mutations (p.P340S and p.G283R), and a novel rare variant p.G195A. In combination with previous reports, there are 27 ALS patients with 15 hnRNPA1 mutations identified. Disease onset age was 47.90 ± 1.52 years with predominant limb onset. The p.P340S mutation caused flail arm syndrome (FAS) in two independent families with extended life expectancy. The newly identified p.G195A mutation, lying at the start of the PrLD ("prion-like" domain)/LCD (low-complexity domain), causes local structural changes in 3D protein prediction. Upon sodium arsenite exposure, mutant hnRNPA1 retained in the nucleus but deficit of cytoplasmic G3BP1-positive stress granule clearance was observed. This is different from the p.P340S mutation which caused both cytoplasmic translocation and stress granule formation. No cytoplasmic TDP-43 translocation was observed.

CONCLUSION: Mutations in hnRNPA1 are overall minor in ALS patients. The p.P340S mutation is associated with manifestation of FAS. Mutations in LCD of hnRNPA1 cause stress granule misprocessing.}, } @article {pmid38716751, year = {2024}, author = {Schito, P and Manera, U and Russo, T and Cremona, G and Riboldi, E and Tettamanti, A and Agosta, F and Quattrini, A and Chiò, A and Filippi, M and Calvo, A and Riva, N}, title = {Use of the combination of spirometry, arterial blood gas analysis and overnight oximetry to predict the outcomes of patients affected by motor neuron disease: The Milan-Torin respiratory score (Mi-To-RS).}, journal = {European journal of neurology}, volume = {31}, number = {8}, pages = {e16316}, pmid = {38716751}, issn = {1468-1331}, support = {//Giovanni Marazzina Foundation/ ; }, mesh = {Humans ; Female ; Male ; Middle Aged ; Aged ; *Blood Gas Analysis/methods ; *Spirometry ; *Oximetry/methods ; *Motor Neuron Disease/blood/physiopathology/diagnosis ; Prognosis ; Retrospective Studies ; Adult ; }, abstract = {BACKGROUND AND PURPOSE: The use of multiple tests, including spirometry, arterial blood gas (ABG) analysis and overnight oximetry (OvOx), is highly recommended to monitor the respiratory function of patients with motor neuron disease (MND). In this study, we propose a composite score to simplify the respiratory management of MND patients and better stratify their prognosis.

MATERIALS AND METHODS: We screened the clinical charts of 471 non-ventilated MND patients referred to the Neuro-rehabilitation Unit of the San Raffaele Scientific Institute of Milan (January 2001-December 2019), collecting spirometric, ABG and OvOx parameters. To evaluate the prognostic role of each measurement, univariate Cox regression for death/tracheostomy was performed, and the variables associated with survival were selected to design a scoring system. Univariate and multivariate Cox regression analyses were then carried out to evaluate the prognostic role of the score. Finally, results were replicated in an independent cohort from the Turin ALS Center.

RESULTS: The study population included 450 patients. Six measurements were found to be significantly associated with survival and were selected to design a scoring system (maximum score = 8 points). Kaplan-Meier analysis showed significant stratification of survival and time to non-invasive mechanical ventilation adaptation according to score values, and multivariate analysis confirmed the independent effect of the respiratory score on survival of each cohort.

CONCLUSION: Forced vital capacity, ABG and OvOx parameters provide complementary information for the respiratory management and prognosis of MND patients and the combination of these parameters into a single score might help neurologists predict prognosis and guide decisions on the timing of the implementation of different diagnostic or therapeutic approaches.}, } @article {pmid38715656, year = {2024}, author = {Paul, S and Dansithong, W and Gandelman, M and Figueroa, KP and Scoles, DR and Pulst, SM}, title = {Cerebellar Micro-RNA Profile in a Mouse Model of Spinocerebellar Ataxia Type 2.}, journal = {Neurology. Genetics}, volume = {10}, number = {2}, pages = {e200144}, pmid = {38715656}, issn = {2376-7839}, support = {R35 NS127253/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Micro-RNAs (miRNAs) are critical for regulating the expression of genes in multiple neurodegenerative diseases, but miRNAs have not been investigated in spinocerebellar ataxia type 2 (SCA2). SCA2, a dominantly inherited progressive neurodegenerative polyglutamine (polyQ) disease, is caused by a CAG repeat expansion in the ataxin-2 (ATXN2) gene. In this study, we determined miRNA transcriptomes in SCA2-BAC-ATXN2[Q72] transgenic mice.

METHODS: We assessed the expression of miRNAs in SCA2 transgenic mouse cerebella using the HiSeq Illumina sequencer. We used the miRNA target filter tool in Qiagen Ingenuity Pathway Analysis (IPA) to identify target genes of differentially expressed miRNAs (DEmiRs) within in the SCA2 mouse transcriptomes and then performed pathway analyses.

RESULTS: Our analysis revealed significant changes in the expression levels of multiple miRNAs in mice with SCA2. We identified 81 DEmiRs in mice with SCA2, with 52 miRNAs upregulated and 29 miRNAs downregulated after onset of rotarod deficit. Subsequent IPA processing enabled us to establish connections between these DEmiRs and specific biological regulatory functions. Furthermore, by using the IPA miRNA target filter, we identified target genes of DEmiRs in the SCA2-BAC-ATXN2[Q72] transcriptome data set and demonstrated their significant impact on several biological functional and disease pathways.

DISCUSSION: Our study establishes the role of both DEmiRs and their targets in SCA2 pathogenesis. By expressing mutant ATXN2 under the control of its endogenous regulatory elements in the SCA2-BAC-ATXN2[Q72] mouse model, we identified a set of DEmiRs that are shared across multiple neurodegenerative diseases including other SCAs, Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). There was a significant overlap of both DEmiRs and their targets of BAC-ATXN2[Q72] transcriptomes in dysregulated pathways that characterize SCA2. This observation also extended to dysregulated pathways in ALS, AD, and PD. DEmiRs identified in this study may represent therapeutic targets for neurodegeneration or lead to biomarkers for characterizing various neurodegenerative diseases.}, } @article {pmid38713169, year = {2024}, author = {Nikel, LM and Talbot, K and Vahsen, BF}, title = {Recent insights from human induced pluripotent stem cell models into the role of microglia in amyotrophic lateral sclerosis.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {46}, number = {7}, pages = {e2400054}, doi = {10.1002/bies.202400054}, pmid = {38713169}, issn = {1521-1878}, support = {2023/MNDS/6400/753TALB//MND Scotland/ ; Talbot/Apr22/889-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism ; Humans ; *Microglia/metabolism/pathology ; *Motor Neurons/pathology/metabolism ; Coculture Techniques ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, primarily leading to the degeneration of motor neurons. The traditional focus on motor neuron-centric mechanisms has recently shifted towards understanding the contribution of non-neuronal cells, such as microglia, in ALS pathophysiology. Advances in induced pluripotent stem cell (iPSC) technology have enabled the generation of iPSC-derived microglia monocultures and co-cultures to investigate their role in ALS pathogenesis. Here, we briefly review the insights gained from these studies into the role of microglia in ALS. While iPSC-derived microglia monocultures have revealed intrinsic cellular dysfunction due to ALS-associated mutations, microglia-motor neuron co-culture studies have demonstrated neurotoxic effects of mutant microglia on motor neurons. Based on these findings, we briefly discuss currently unresolved questions and how they could be addressed in future studies. iPSC models hold promise for uncovering disease-relevant pathways in ALS and identifying potential therapeutic targets.}, } @article {pmid38712849, year = {2024}, author = {Ludolph, AC and Corcia, P and Desnuelle, C and Heiman-Patterson, T and Mora, JS and Mansfield, CD and Couratier, P}, title = {Categorization of the amyotrophic lateral sclerosis population via the clinical determinant of post-onset ΔFS for study design and medical practice.}, journal = {Muscle & nerve}, volume = {70}, number = {1}, pages = {36-41}, doi = {10.1002/mus.28101}, pmid = {38712849}, issn = {1097-4598}, support = {//AB Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Clinical Trials as Topic/methods ; Disease Progression ; Outcome Assessment, Health Care/standards ; *Research Design ; Severity of Illness Index ; }, abstract = {The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) has become the most widely utilized measure of disease severity in patients with ALS, with change in ALSFRS-R from baseline being a trusted primary outcome measure in ALS clinical trials. This is despite the scale having several established limitations, and although alternative scales have been proposed, it is unlikely that these will displace ALSFRS-R in the foreseeable future. Here, we discuss the merits of delta FS (ΔFS), the slope or rate of ALSFRS-R decline over time, as a relevant tool for innovative ALS study design, with an as yet untapped potential for optimization of drug effectiveness and patient management. In our view, categorization of the ALS population via the clinical determinant of post-onset ΔFS is an important study design consideration. It serves not only as a critical stratification factor and basis for patient enrichment but also as a tool to explore differences in treatment response across the overall population; thereby, facilitating identification of responder subgroups. Moreover, because post-onset ΔFS is derived from information routinely collected as part of standard patient care and monitoring, it provides a suitable patient selection tool for treating physicians. Overall, post-onset ΔFS is a very attractive enrichment tool that is, can and should be regularly incorporated into ALS trial design.}, } @article {pmid38712174, year = {2024}, author = {Ozkan, A and Padmanabhan, HK and Shipman, SL and Azim, E and Kumar, P and Sadegh, C and Basak, AN and Macklis, JD}, title = {Directed differentiation of functional corticospinal-like neurons from endogenous SOX6+/NG2+ cortical progenitors.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.04.21.590488}, pmid = {38712174}, issn = {2692-8205}, support = {DP1 NS106665/NS/NINDS NIH HHS/United States ; R01 NS045523/NS/NINDS NIH HHS/United States ; R01 NS049553/NS/NINDS NIH HHS/United States ; }, abstract = {Corticospinal neurons (CSN) centrally degenerate in amyotrophic lateral sclerosis (ALS), along with spinal motor neurons, and loss of voluntary motor function in spinal cord injury (SCI) results from damage to CSN axons. For functional regeneration of specifically affected neuronal circuitry in vivo , or for optimally informative disease modeling and/or therapeutic screening in vitro , it is important to reproduce the type or subtype of neurons involved. No such appropriate in vitro models exist with which to investigate CSN selective vulnerability and degeneration in ALS, or to investigate routes to regeneration of CSN circuitry for ALS or SCI, critically limiting the relevance of much research. Here, we identify that the HMG-domain transcription factor Sox6 is expressed by a subset of NG2+ endogenous cortical progenitors in postnatal and adult cortex, and that Sox6 suppresses a latent neurogenic program by repressing inappropriate proneural Neurog2 expression by progenitors. We FACS-purify these genetically accessible progenitors from postnatal mouse cortex and establish a pure culture system to investigate their potential for directed differentiation into CSN. We then employ a multi-component construct with complementary and differentiation-sharpening transcriptional controls (activating Neurog2, Fezf2 , while antagonizing Olig2 with VP16:Olig2). We generate corticospinal-like neurons from SOX6+/NG2+ cortical progenitors, and find that these neurons differentiate with remarkable fidelity compared with corticospinal neurons in vivo . They possess appropriate morphological, molecular, transcriptomic, and electrophysiological characteristics, without characteristics of the alternate intracortical or other neuronal subtypes. We identify that these critical specifics of differentiation are not reproduced by commonly employed Neurog2 -driven differentiation. Neurons induced by Neurog2 instead exhibit aberrant multi-axon morphology and express molecular hallmarks of alternate cortical projection subtypes, often in mixed form. Together, this developmentally-based directed differentiation from genetically accessible cortical progenitors sets a precedent and foundation for in vitro mechanistic and therapeutic disease modeling, and toward regenerative neuronal repopulation and circuit repair.}, } @article {pmid38712171, year = {2024}, author = {Islam, Z and Polash, A and Suzawa, M and Chim, B and Kuhn, S and Sultana, S and Cutrona, N and Smith, PT and Kabat, J and Ganesan, S and Foroushani, A and Hafner, M and Muljo, SA}, title = {MATRIN3 deficiency triggers autoinflammation via cGAS-STING activation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38712171}, issn = {2692-8205}, support = {ZIA AI001185/ImNIH/Intramural NIH HHS/United States ; ZIA AR041205/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Interferon-stimulated genes (ISGs) comprise a program of immune effectors important for host immune defense. When uncontrolled, ISGs play a central role in interferonopathies and other inflammatory diseases. The mechanisms responsible for turning on ISGs are not completely known. By investigating MATRIN3 (MATR3), a nuclear RNA-binding protein mutated in familial ALS, we found that perturbing MATR3 results in elevated expression of ISGs. Using an integrative approach, we elucidate a pathway that leads to activation of cGAS-STING. This outlines a plausible mechanism for pathogenesis in a subset of ALS, and suggests new diagnostic and therapeutic approaches for this fatal disease.}, } @article {pmid38711658, year = {2024}, author = {Otero, G and Bolatto, C and Isasi, E and Cerri, S and Rodríguez, P and Boragno, D and Marco, M and Parada, C and Stancov, M and Cuitinho, MN and Olivera-Bravo, S}, title = {Adult aberrant astrocytes submitted to late passage cultivation lost differentiation markers and decreased their pro-inflammatory profile.}, journal = {Heliyon}, volume = {10}, number = {9}, pages = {e30360}, pmid = {38711658}, issn = {2405-8440}, abstract = {In amyotrophic lateral sclerosis (ALS), astrocytes are considered key players in some non-cell non-neuronal autonomous mechanisms that underlie motor neuron death. However, it is unknown how much of these deleterious features were permanently acquired. To assess this point, we evaluated if the most remarkable features of neurotoxic aberrant glial phenotypes (AbAs) isolated from paralytic rats of the ALS model G93A Cu/Zn superoxide dismutase 1 (SOD1) could remain upon long lasting cultivation. Real time PCR, immunolabelling and zymography analysis showed that upon many passages, AbAs preserved the cell proliferation capacity, mitochondrial function and response to different compounds that inhibit some key astrocyte functions but decreased the expression of parameters associated to cell lineage, homeostasis and inflammation. As these results are contrary to the sustained inflammatory status observed along disease progression in SOD1G93A rats, we propose that the most AbAs remarkable features related to homeostasis and neurotoxicity were not permanently acquired and might depend on the signaling coming from the injuring microenvironment present in the degenerating spinal cord of terminal rats.}, } @article {pmid38711616, year = {2024}, author = {Chen, L and Chen, G and Zhang, M and Zhang, X}, title = {Modeling sporadic juvenile ALS in iPSC-derived motor neurons explores the pathogenesis of FUS[R503fs] mutation.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1364164}, pmid = {38711616}, issn = {1662-5102}, abstract = {INTRODUCTION: Fused in sarcoma (FUS) mutations represent the most common genetic etiology of juvenile amyotrophic lateral sclerosis (JALS), for which effective treatments are lacking. In a prior report, we identified a novel FUS mutation, c.1509dupA: p. R503fs (FUSR503fs), in a sporadic JALS patient.

METHODS: The physicochemical properties and structure of FUSR503fs protein were analyzed by software: Multi-electrode array (MEA) assay, calcium activity imaging assay and transcriptome analysis were used to explore the pathophysiological mechanism of iPSC derived motor neurons.

RESULTS: Structural analysis and predictions regarding physical and chemical properties of this mutation suggest that the reduction of phosphorylation and glycosylation sites, along with alterations in the amino acid sequence, may contribute to abnormal FUS accumulation within the cytoplasm and nucleus of induced pluripotent stem cell- derived motor neurons (MNs). Multi-electrode array and calcium activity imaging indicate diminished spontaneous electrical and calcium activity signals in MNs harboring the FUS[R503fs] mutation. Transcriptomic analysis reveals upregulation of genes associated with viral infection and downregulation of genes involved in neural function maintenance, such as the ATP6V1C2 gene. Treatment with ropinirole marginally mitigates the electrophysiological decline in FUS[R503fs] MNs, suggesting the utility of this cell model for mechanistic exploration and drug screening.

DISCUSSION: iPSCs-derived motor neurons from JALS patients are promising tools for drug screening. The pathological changes in motor neurons of FUS[R503fs] may occur earlier than in other known mutation types that have been reported.}, } @article {pmid38711277, year = {2024}, author = {Vakilipour, P and Fekrvand, S}, title = {Brain-to-brain interface technology: A brief history, current state, and future goals.}, journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience}, volume = {84}, number = {5}, pages = {351-367}, doi = {10.1002/jdn.10334}, pmid = {38711277}, issn = {1873-474X}, mesh = {Humans ; *Brain-Computer Interfaces ; *Brain/physiology ; History, 20th Century ; History, 21st Century ; }, abstract = {A brain-to-brain interface (BBI), defined as a combination of neuroimaging and neurostimulation methods to extract and deliver information between brains directly without the need for the peripheral nervous system, is a budding communication technique. A BBI system is made up of two parts known as the brain-computer interface part, which reads a sender's brain activity and digitalizes it, and the computer-brain interface part, which writes the delivered brain activity to a receiving brain. As with other technologies, BBI systems have gone through an evolutionary process since they first appeared. The BBI systems have been employed for numerous purposes, including rehabilitation for post-stroke patients, communicating with patients suffering from amyotrophic lateral sclerosis, locked-in syndrome and speech problems following stroke. Also, it has been proposed that a BBI system could play an important role on future battlefields. This technology was not only employed for communicating between two human brains but also for making a direct communication path among different species through which motor or sensory commands could be sent and received. However, the application of BBI systems has provoked significant challenges to human rights principles due to their ability to access and manipulate human brain information. In this study, we aimed to review the brain-computer interface and computer-brain interface technologies as components of BBI systems, the development of BBI systems, applications of this technology, arising ethical issues and expectations for future use.}, } @article {pmid38711257, year = {2024}, author = {Horty, LG and Martin, T}, title = {Synthesis of Radiolabeled [[14]C]Rimsulfuron and Stable Isotope Labeled Rimsulfuron-[M + 3] to Support Crop Metabolism Studies for Reregistration.}, journal = {Journal of labelled compounds & radiopharmaceuticals}, volume = {67}, number = {7}, pages = {263-272}, doi = {10.1002/jlcr.4096}, pmid = {38711257}, issn = {1099-1344}, mesh = {*Carbon Radioisotopes/chemistry ; *Crops, Agricultural/metabolism ; *Isotope Labeling ; *Pyridines/chemistry/chemical synthesis ; Herbicides/chemical synthesis/chemistry ; Sulfonamides ; }, abstract = {Rimsulfuron is a sulfonylurea herbicide that controls grass and broadleaf weeds in maize, potatoes, fruits, nuts, and other crops. It can also be used as a burndown herbicide to clear invasive weed species along roadsides and other nonagricultural land. Rimsulfuron acts as an acetolactase synthase (ALS) inhibitor, blocking the synthesis of essential amino acids required for plant growth. As is common practice, rimsulfuron has been subject to periodic reviews by regulatory agencies for reregistration since its introduction into the market in the early 1990s. The goal of these reviews is to ensure that the herbicide carries out its intended use without creating adverse side effects to humans and the environment. Since scientific methods are continually evolving and being developed, global regulatory agencies can require additional studies to address data gaps for pesticide renewals. During this reregistration process for rimsulfuron, a new confined rotational crop study was required to address a data gap requested by the European Food Safety Authority (EFSA). Consequently, the corresponding pyridine and pyrimidine radiolabeled [[14]C]rimsulfuron and [M + 3] stable isotopes of rimsulfuron were synthesized for this study to support the reregistration process.}, } @article {pmid38709603, year = {2024}, author = {Demaree, D and Brignone, J and Bromberg, M and Zhang, H}, title = {Preliminary Study on Effects of Neck Exoskeleton Structural Design in Patients With Amyotrophic Lateral Sclerosis.}, journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society}, volume = {32}, number = {}, pages = {1841-1850}, doi = {10.1109/TNSRE.2024.3397584}, pmid = {38709603}, issn = {1558-0210}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; *Exoskeleton Device ; Female ; Middle Aged ; *Neck Muscles/physiopathology ; Biomechanical Phenomena ; Aged ; Electromyography ; Head Movements ; Neck/physiopathology ; Equipment Design ; Adult ; Muscle Weakness/physiopathology ; }, abstract = {Neck muscle weakness due to amyotrophic lateral sclerosis (ALS) can result in dropped head syndrome, adversely impacting the quality of life of those affected. Static neck collars are currently prescribed to hold the head in a fixed upright position. However, these braces are uncomfortable and do not allow any voluntary head-neck movements. By contrast, powered neck exoskeletons have the potential to enable head-neck movements. Our group has recently improved the mechanical structure of a state-of-the-art neck exoskeleton through a weighted optimization. To evaluate the effect of the structural changes, we conducted an experiment in which patients with ALS were asked to perform head-neck tracking tasks while using the two versions of the neck exoskeleton. We found that the neck muscle activation was significantly reduced when assisted by the structurally enhanced design compared to no assistance provided. The improved structure also improved kinematics tracking performance, allowing users to better achieve the desired head poses. In comparison, the previous design did not help reduce the muscle effort required to perform these tasks and even slightly worsened the kinematic tracking performance. It was also found that biomechanical benefits gained from using the structurally improved design were consistent across participants with both mild and severe neck weakness. Furthermore, we observed that participants preferred to use the powered neck exoskeletons to voluntarily move their heads and make eye contact during a conversation task rather than remain in a fixed upright position. Each of these findings highlights the importance of the structural design of neck exoskeletons in achieving desired biomechanical benefits and suggests that neck exoskeletons can be a viable method to improve the daily life of patients with ALS.}, } @article {pmid38709037, year = {2024}, author = {Ketabforoush, A and Wang, M and Smith, CL and Arnold, WD and Nichols, NL}, title = {Assessing Rat Diaphragm Motor Unit Connectivity Outcome Measures as Quantitative Biomarkers of Phrenic Motor Neuron Degeneration and Compensation.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {206}, pages = {}, doi = {10.3791/66568}, pmid = {38709037}, issn = {1940-087X}, mesh = {Animals ; *Motor Neurons/pathology ; Rats ; *Phrenic Nerve ; *Diaphragm/innervation/physiopathology ; Biomarkers/analysis/metabolism ; Action Potentials/physiology ; Nerve Degeneration/pathology ; Rats, Sprague-Dawley ; }, abstract = {Loss of ventilatory muscle function is a consequence of motor neuron injury and neurodegeneration (e.g., cervical spinal cord injury and amyotrophic lateral sclerosis, respectively). Phrenic motor neurons are the final link between the central nervous system and muscle, and their respective motor units (groups of muscle fibers innervated by a single motor neuron) represent the smallest functional unit of the neuromuscular ventilatory system. Compound muscle action potential (CMAP), single motor unit potential (SMUP), and motor unit number estimation (MUNE) are established electrophysiological approaches that enable the longitudinal assessment of motor unit integrity in animal models over time but have mostly been applied to limb muscles. Therefore, the objectives of this study are to describe an approach in preclinical rodent studies that can be used longitudinally to quantify the phrenic MUNE, motor unit size (represented as SMUP), and CMAP, and then to demonstrate the utility of these approaches in a motor neuron loss model. Sensitive, objective, and translationally relevant biomarkers for neuronal injury, degeneration, and regeneration in motor neuron injury and diseases can significantly aid and accelerate experimental research discoveries to clinical testing.}, } @article {pmid38708921, year = {2024}, author = {Monteiro, KLC and Dos Santos Alcântara, MG and de Aquino, TM and da Silva-Júnior, EF}, title = {Insights on Natural Products Against Amyotrophic Lateral Sclerosis (ALS).}, journal = {Current neuropharmacology}, volume = {22}, number = {7}, pages = {1169-1188}, pmid = {38708921}, issn = {1875-6190}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Biological Products/therapeutic use/pharmacology ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; Plants, Medicinal/chemistry ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes the death of motor neurons and consequent muscle paralysis. Despite many efforts to address it, current therapy targeting ALS remains limited, increasing the interest in complementary therapies. Over the years, several herbal preparations and medicinal plants have been studied to prevent and treat this disease, which has received remarkable attention due to their blood-brain barrier penetration properties and low toxicity. Thus, this review presents the therapeutic potential of a variety of medicinal herbs and their relationship with ALS and their physiopathological pathways.}, } @article {pmid38708063, year = {2024}, author = {Maria, B and Massimo, G and Antonio, B and Giuseppe, S and Giovanna, BE}, title = {BerTime: A novel tool for supporting ALS algorithm application in clinical practice.}, journal = {Resuscitation plus}, volume = {18}, number = {}, pages = {100636}, pmid = {38708063}, issn = {2666-5204}, } @article {pmid38706964, year = {2024}, author = {Edman, S and Horwath, O and Van der Stede, T and Blackwood, SJ and Moberg, I and Strömlind, H and Nordström, F and Ekblom, M and Katz, A and Apró, W and Moberg, M}, title = {Pro-Brain-Derived Neurotrophic Factor (BDNF), but Not Mature BDNF, Is Expressed in Human Skeletal Muscle: Implications for Exercise-Induced Neuroplasticity.}, journal = {Function (Oxford, England)}, volume = {5}, number = {3}, pages = {zqae005}, pmid = {38706964}, issn = {2633-8823}, mesh = {Adult ; Female ; Humans ; Male ; Young Adult ; *Brain-Derived Neurotrophic Factor/metabolism/blood ; *Exercise/physiology ; Lactic Acid/blood/metabolism ; *Muscle, Skeletal/metabolism ; *Neuronal Plasticity ; Protein Precursors/metabolism ; }, abstract = {Exercise promotes brain plasticity partly by stimulating increases in mature brain-derived neurotrophic factor (mBDNF), but the role of the pro-BDNF isoform in the regulation of BDNF metabolism in humans is unknown. We quantified the expression of pro-BDNF and mBDNF in human skeletal muscle and plasma at rest, after acute exercise (+/- lactate infusion), and after fasting. Pro-BDNF and mBDNF were analyzed with immunoblotting, enzyme-linked immunosorbent assay, immunohistochemistry, and quantitative polymerase chain reaction. Pro-BDNF was consistently and clearly detected in skeletal muscle (40-250 pg mg[-1] dry muscle), whereas mBDNF was not. All methods showed a 4-fold greater pro-BDNF expression in type I muscle fibers compared to type II fibers. Exercise resulted in elevated plasma levels of mBDNF (55%) and pro-BDNF (20%), as well as muscle levels of pro-BDNF (∼10%, all P < 0.05). Lactate infusion during exercise induced a significantly greater increase in plasma mBDNF (115%, P < 0.05) compared to control (saline infusion), with no effect on pro-BDNF levels in plasma or muscle. A 3-day fast resulted in a small increase in plasma pro-BDNF (∼10%, P < 0.05), with no effect on mBDNF. Pro-BDNF is highly expressed in human skeletal muscle, particularly in type I fibers, and is increased after exercise. While exercising with higher lactate augmented levels of plasma mBDNF, exercise-mediated increases in circulating mBDNF likely derive partly from release and cleavage of pro-BDNF from skeletal muscle, and partly from neural and other tissues. These findings have implications for preclinical and clinical work related to a wide range of neurological disorders such as Alzheimer's, clinical depression, and amyotrophic lateral sclerosis.}, } @article {pmid38706539, year = {2024}, author = {Rungan, S and Smith-Merry, J and Liu, HM and Drinkwater, A and Eastwood, J}, title = {School-Based Integrated Care Within Sydney Local Health District: A Qualitative Study About Partnerships Between the Education and Health Sectors.}, journal = {International journal of integrated care}, volume = {24}, number = {2}, pages = {13}, pmid = {38706539}, issn = {1568-4156}, abstract = {INTRODUCTION: The unmet physical and mental health needs of school-aged children (5-18 years) in New South Wales (NSW), stemming from poor access and engagement with healthcare, can be addressed by school-based integrated care (SBIC) models.This research aims to understand why and how partnerships between the health and education sector, in SBIC models, are important in providing care for children, and to identify the facilitating factors and barriers for implementation.

METHODS: A qualitative study was conducted using semi-structured interviews and thematic analysis. The principles of the 'Integrated People-Centred Health Service (IPCHS)' framework and Looman et al's (2021) implementation strategies for integrated care were considered.

RESULTS: Themes within IPCHS framework: Strategy 1: Engaging and empowering people and communities - community-driven models, improved access to healthcare, positive outcomes for children and families, 'connection', and service provision for marginalised populations; Strategy 2: Strengthening governance and accountability - system integration and developing evidence base; Strategy 3: Reorienting the model of care - shifting healthcare to schools reduces inequity and provides culturally safe practice; Strategy 4: Coordinating services within and across sectors - integrating care and stable workforce; Strategy 5: Creating an enabling environment: leadership, stakeholder commitment, and adequate resourcing.

DISCUSSION: Potential strategies for implementing SBIC models across NSW include community consultation and co-design; building multidisciplinary teams with new competencies and roles e.g. linkers and coordinators; collaborative and shared leadership; and alignment of operational systems while maintaining a balance between structure and flexibility.

CONCLUSION: SBIC models require high-level collaboration across sectors and with communities to provide a shift towards child and family centred care that improves engagement, access and outcomes in health delivery.}, } @article {pmid38705796, year = {2024}, author = {Grangeon, L and Wallon, D and Bourre, B and Guillaume, M and Guegan-Massardier, E and Guyant-Marechal, L and Liard, A and Sibert, L and Maltete, D}, title = {Development of an Objective Structured Clinical Examination (OSCE) to evaluate the diagnosis announcement of chronic neurological disease by residents in neurology.}, journal = {Revue neurologique}, volume = {180}, number = {7}, pages = {655-660}, doi = {10.1016/j.neurol.2024.02.390}, pmid = {38705796}, issn = {0035-3787}, mesh = {Humans ; *Neurology/standards/education ; *Internship and Residency/standards ; *Nervous System Diseases/diagnosis ; *Educational Measurement/methods ; Chronic Disease ; Male ; Female ; Adult ; Clinical Competence/standards ; Prospective Studies ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: There is little consensus on how to make a diagnosis announcement of severe chronic disease in neurology. Other medical specialties, such as oncology, have developed assessment methods similar to the Objective Structured Clinical Examination (OSCE) to address this issue. Here we report the implementation of an OSCE focused on the diagnosis announcement of chronic disease in neurology by residents.

OBJECTIVE: We aimed to evaluate the acceptability, feasibility and validity in routine practice of an OSCE combined with a theoretical course focused on diagnosis announcement in neurology.

METHOD: Eighteen neurology residents were prospectively included between 2019 and 2022. First, they answered a questionnaire on their previous level of training in diagnosis announcement. Second, in a practical session with a simulated patient, they made a 15-min diagnosis announcement and then had 5mins of immediate feedback with an expert observer, present in the room. The OSCE consisted of 4 different stations, with standardized scenarios dedicated to the announcement of multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Third, in a theory session, expert observers covered the essential theoretical points. All residents and expert observers completed an evaluation of the "practical session" and the "theory session".

RESULTS: Residents estimated their previous level of diagnosis announcement training at 3.1/5. The most feared announcements were AD and ALS. The "practical session" was rated at a mean of 4.1/5 by the residents and 4.8/5 by the expert observers, and the "theory session" at a mean of 4.7/5 by the residents and 5/5 by the expert observers. After the OSCEs, 11 residents felt more confident about making an announcement.

CONCLUSION: This study has shown a benefit of using an OSCE to learn how to make a diagnosis announcement of severe chronic disease in neurology. OSCEs could be used in many departments in routine practice and seem adapted to residents.}, } @article {pmid38705786, year = {2024}, author = {Ishikawa, A and Takeda, T and Kokubun, S and Saito, Y and Isose, S and Ito, K and Arai, K and Sugiyama, A and Kuwabara, S and Honda, K}, title = {Putaminal hypointensity on T2-weighted MRI mimicking multiple system atrophy in amyotrophic lateral sclerosis: An autopsy case report.}, journal = {Journal of the neurological sciences}, volume = {460}, number = {}, pages = {123025}, doi = {10.1016/j.jns.2024.123025}, pmid = {38705786}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *Multiple System Atrophy/diagnostic imaging/pathology ; *Magnetic Resonance Imaging ; *Autopsy ; Putamen/diagnostic imaging/pathology ; Male ; Diagnosis, Differential ; Middle Aged ; Aged ; Female ; }, } @article {pmid38705318, year = {2024}, author = {Mororó, MCC and Mahnke, LC and Assis, CRD and da Silva, RA and Cabrera, MP and Bezerra, RP and Carvalho Júnior, LB and Alves, MHME}, title = {Acetylcholinesterase purification from human erythrocytes using magnetic nanoparticles containing procainamide.}, journal = {International journal of biological macromolecules}, volume = {269}, number = {Pt 1}, pages = {132094}, doi = {10.1016/j.ijbiomac.2024.132094}, pmid = {38705318}, issn = {1879-0003}, mesh = {Humans ; *Acetylcholinesterase/chemistry/metabolism/isolation & purification ; *Erythrocytes/enzymology ; *Magnetite Nanoparticles/chemistry ; *Procainamide/chemistry ; Aniline Compounds/chemistry ; }, abstract = {This work presents a magnetic purification method of human erythrocyte Acetylcholinesterase (EC 3.1.1.7; AChE) based on affinity binding to procainamide (Proca) as ligand. Acetylcholinesterase is an acetylcholine-regulating enzyme found in different areas of the body and associated with various neurological disorders, such as Parkinson, Alzheymer and Amyotrophic Lateral Sclerosis. AChE from human erythrocyte purification has been attempted in recent years with low degree of purity. Here, magnetic nanoparticles (MNP) were synthesized and coated with polyaniline (PANI) and procainamide (PROCA) was covalently linked to the PANI. The extracted human erythrocyte AChE formed a complex with the MNP@PANI-PROCA and an external magnet separated it from the undesired proteins. Finally, the enzyme was collected by increasing the ionic strength. Experimental Box-Behnken design was developed to optimize this process of human erythrocyte AChE purification protocol. The enzyme was purified in all fifteen experiments. However, the best AChE purification result was achieved, about 2000 times purified, when 100 mg of MNP@PANI-PROCA was incubated for one hour with 4 ml hemolysate extract. The SDS-PAGE of this preparation presented a molecular weight of approximately 70 kDa, corroborating with few previous studies of AChE from erythrocyte purification.}, } @article {pmid38705104, year = {2024}, author = {Dharmadasa, T and Pavey, N and Tu, S and Menon, P and Huynh, W and Mahoney, CJ and Timmins, HC and Higashihara, M and van den Bos, M and Shibuya, K and Kuwabara, S and Grosskreutz, J and Kiernan, MC and Vucic, S}, title = {Novel approaches to assessing upper motor neuron dysfunction in motor neuron disease/amyotrophic lateral sclerosis: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {163}, number = {}, pages = {68-89}, doi = {10.1016/j.clinph.2024.04.010}, pmid = {38705104}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Transcranial Magnetic Stimulation/methods ; *Motor Neuron Disease/physiopathology/diagnosis ; *Motor Neurons/physiology ; Evoked Potentials, Motor/physiology ; Motor Cortex/physiopathology/diagnostic imaging ; }, abstract = {Identifying upper motor neuron (UMN) dysfunction is fundamental to the diagnosis and understanding of disease pathogenesis in motor neuron disease (MND). The clinical assessment of UMN dysfunction may be difficult, particularly in the setting of severe muscle weakness. From a physiological perspective, transcranial magnetic stimulation (TMS) techniques provide objective biomarkers of UMN dysfunction in MND and may also be useful to interrogate cortical and network function. Single, paired- and triple pulse TMS techniques have yielded novel diagnostic and prognostic biomarkers in MND, and have provided important pathogenic insights, particularly pertaining to site of disease onset. Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation, has been associated with the onset of lower motor neuron degeneration, along with patterns of disease spread, development of specific clinical features such as the split hand phenomenon, and may provide an indication about the rate of disease progression. Additionally, reduction of SICI has emerged as a potential diagnostic aid in MND. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction in MND. Separately, sophisticated brain imaging techniques have uncovered novel biomarkers of neurodegeneration that have bene associated with progression. The present review will discuss the utility of TMS and brain neuroimaging derived biomarkers of UMN dysfunction in MND, focusing on recently developed TMS techniques and advanced neuroimaging modalities that interrogate structural and functional integrity of the corticomotoneuronal system, with an emphasis on pathogenic, diagnostic, and prognostic utility.}, } @article {pmid38703766, year = {2024}, author = {Alfahel, L and Gschwendtberger, T and Kozareva, V and Dumas, L and Gibbs, R and Kertser, A and Baruch, K and Zaccai, S and Kahn, J and Thau-Habermann, N and Eggenschwiler, R and Sterneckert, J and Hermann, A and Sundararaman, N and Vaibhav, V and Van Eyk, JE and Rafuse, VF and Fraenkel, E and Cantz, T and Petri, S and Israelson, A}, title = {Targeting low levels of MIF expression as a potential therapeutic strategy for ALS.}, journal = {Cell reports. Medicine}, volume = {5}, number = {5}, pages = {101546}, pmid = {38703766}, issn = {2666-3791}, mesh = {*Macrophage Migration-Inhibitory Factors/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology ; Animals ; Humans ; *Motor Neurons/metabolism/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Induced Pluripotent Stem Cells/metabolism ; Intramolecular Oxidoreductases/metabolism/genetics ; Mice, Transgenic ; Dependovirus/genetics ; Disease Models, Animal ; Male ; Mutation/genetics ; Female ; Protein Folding ; }, abstract = {Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neuron (MN) loss. We previously discovered that macrophage migration inhibitory factor (MIF), whose levels are extremely low in spinal MNs, inhibits mutant SOD1 misfolding and toxicity. In this study, we show that a single peripheral injection of adeno-associated virus (AAV) delivering MIF into adult SOD1[G37R] mice significantly improves their motor function, delays disease progression, and extends survival. Moreover, MIF treatment reduces neuroinflammation and misfolded SOD1 accumulation, rescues MNs, and corrects dysregulated pathways as observed by proteomics and transcriptomics. Furthermore, we reveal low MIF levels in human induced pluripotent stem cell-derived MNs from familial ALS patients with different genetic mutations, as well as in post mortem tissues of sporadic ALS patients. Our findings indicate that peripheral MIF administration may provide a potential therapeutic mechanism for modulating misfolded SOD1 in vivo and disease outcome in ALS patients.}, } @article {pmid38703699, year = {2024}, author = {Grapperon, AM and Harlay, V and Boucekine, M and Devos, D and Rolland, AS and Desnuelle, C and Delmont, E and Verschueren, A and Attarian, S}, title = {Could the motor unit number index be an early prognostic biomarker for amyotrophic lateral sclerosis?.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {163}, number = {}, pages = {47-55}, doi = {10.1016/j.clinph.2024.04.013}, pmid = {38703699}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality/diagnosis ; Male ; Female ; Middle Aged ; Aged ; Longitudinal Studies ; *Motor Neurons/physiology ; Prognosis ; *Disease Progression ; Biomarkers ; Adult ; Electromyography ; }, abstract = {OBJECTIVE: To evaluate the associations between motor unit number index (MUNIX) and disease progression and prognosis in amyotrophic lateral sclerosis (ALS) in a large-scale longitudinal study.

METHODS: MUNIX was performed at the patient's first visit, at 3, 6, and 12 months in 4 muscles. MUNIX data from the patients were compared with those from 38 age-matched healthy controls. Clinical data included the revised ALS functional rating scale (ALSFRS-R), the forced vital capacity (FVC), and the survival of the patients.

RESULTS: Eighty-two patients were included at baseline, 62 were evaluated at three months, 48 at six months, and 33 at twelve months. MUNIX score was lower in ALS patients compared to controls. At baseline, MUNIX was correlated with ALSFRS-R and FVC. Motor unit size index (MUSIX) was correlated with patient survival. Longitudinal analyses showed that MUNIX decline was greater than ALSFRS-R decline at each evaluation. A baseline MUNIX score greater than 378 predicted survival over the 12-month period with a sensitivity of 82% and a specificity of 56%.

CONCLUSIONS: This longitudinal study suggests that MUNIX could be an early quantitative marker of disease progression and prognosis in ALS.

SIGNIFICANCE: MUNIX might be considered as potential indicator for monitoring disease progression.}, } @article {pmid38703513, year = {2024}, author = {El Khalfi, R and Maupoint, E and Chiavassa-Gandois, H and Goumarre, C and Filliole, A and Lapègue, F and Fabry, V and Acket, B and Laforet, A and Sans, N and Cintas, P and Faruch-Bilfeld, M}, title = {Assessment of whole-body muscle MRI for the early diagnosis of Amyotrophic Lateral Sclerosis.}, journal = {European journal of radiology}, volume = {176}, number = {}, pages = {111481}, doi = {10.1016/j.ejrad.2024.111481}, pmid = {38703513}, issn = {1872-7727}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Male ; Female ; Middle Aged ; *Whole Body Imaging/methods ; *Muscle, Skeletal/diagnostic imaging/pathology ; *Sensitivity and Specificity ; *Early Diagnosis ; *Magnetic Resonance Imaging/methods ; Reproducibility of Results ; Adult ; Aged ; }, abstract = {OBJECTIVES: To evaluate muscle signal abnormalities on whole-body muscle MRI with T2 and diffusion-weighted imaging in early ALS stages.

METHODS: 101 muscles were analyzed in newly diagnosed ALS patients and healthy controls on a whole-body MRI protocol including four-point T2-Dixon imaging and diffusion-weighted imaging (b0 and b800). Sensitivity and inter-observer agreement were assessed.

RESULTS: 15 patients (mean age, 64 +/- 12 [SD], 9 men) who met the Awaji-Shima criteria for definite, probable or possible ALS and 9 healthy controls were assessed (mean age, 53 +/- 13 [SD], 2 men). 61 % of the muscles assessed in ALS patients (62/101) showed signal hyperintensities on T2-weighted imaging, mainly in the upper and lower extremities (legs, hands and feet). ALS patients had a significantly higher number of involved muscles compared to healthy controls (p = 0,006). Diffusion-weighted imaging allowed for the detection of additional involvement in 22 muscles, thus improving the sensitivity of whole-body MRI from 60 % (using T2-weighted imaging only) up to 80 % (with the combination of T2-weighted and diffusion-weighted imaging).

CONCLUSIONS: ALS patients exhibited significant muscle signal abnormalities on T2-weighted and diffusion-weighted imaging in early disease stages. Whole-body MRI could be used for pre-EMG mapping of muscle involvement in order to choose suitable targets, thus improving early diagnosis.}, } @article {pmid38703371, year = {2024}, author = {Thumbadoo, KM and Dieriks, BV and Murray, HC and Swanson, MEV and Yoo, JH and Mehrabi, NF and Turner, C and Dragunow, M and Faull, RLM and Curtis, MA and Siddique, T and Shaw, CE and Newell, KL and Henden, L and Williams, KL and Nicholson, GA and Scotter, EL}, title = {Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {10}, pages = {3547-3561}, pmid = {38703371}, issn = {1460-2156}, support = {//Amelia Pais-Rodriguez and Marcus Gerbich/ ; 16420//Michael J Fox Foundation/ ; //Health Research Council Sir Charles Hercus Health Research Fellowship/ ; //Marsden FastStart and Rutherford Discovery Fellowship/ ; 15-UOA-157//Royal Society of New Zealand/ ; //Alzheimer's Disease Research and Education/ ; //Sir Thomas and Lady Duncan Trust/ ; //Coker Family Trust/ ; 2011120//National Health and Medical Research Council of Australia/ ; //Neuron Disease NZ/ ; //Freemasons Foundation of New Zealand/ ; //Matteo de Nora/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; Humans ; *Autophagy-Related Proteins/genetics/metabolism ; *Hippocampus/pathology/metabolism ; Male ; *Adaptor Proteins, Signal Transducing/genetics/metabolism ; Middle Aged ; Female ; Aged ; DNA-Binding Proteins/genetics/metabolism ; Adult ; C9orf72 Protein/genetics ; Cell Cycle Proteins/genetics/metabolism ; }, abstract = {Pathogenic variants in the UBQLN2 gene cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia characterized by ubiquilin 2 aggregates in neurons of the motor cortex, hippocampus and spinal cord. However, ubiquilin 2 neuropathology is also seen in sporadic and familial amyotrophic lateral sclerosis and/or frontotemporal dementia cases not caused by UBQLN2 pathogenic variants, particularly C9orf72-linked cases. This makes the mechanistic role of mutant ubiquilin 2 protein and the value of ubiquilin 2 pathology for predicting genotype unclear. Here we examine a cohort of 44 genotypically diverse amyotrophic lateral sclerosis cases with or without frontotemporal dementia, including eight cases with UBQLN2 variants [resulting in p.S222G, p.P497H, p.P506S, p.T487I (two cases) and p.P497L (three cases)]. Using multiplexed (five-label) fluorescent immunohistochemistry, we mapped the co-localization of ubiquilin 2 with phosphorylated TDP-43, dipeptide repeat aggregates and p62 in the hippocampus of controls (n = 6), or amyotrophic lateral sclerosis with or without frontotemporal dementia in sporadic (n = 20), unknown familial (n = 3), SOD1-linked (n = 1), FUS-linked (n = 1), C9orf72-linked (n = 5) and UBQLN2-linked (n = 8) cases. We differentiate between (i) ubiquilin 2 aggregation together with phosphorylated TDP-43 or dipeptide repeat proteins; and (ii) ubiquilin 2 self-aggregation promoted by UBQLN2 pathogenic variants that cause amyotrophic lateral sclerosis and/or frontotemporal dementia. Overall, we describe a hippocampal protein aggregation signature that fully distinguishes mutant from wild-type ubiquilin 2 in amyotrophic lateral sclerosis with or without frontotemporal dementia, whereby mutant ubiquilin 2 is more prone than wild-type to aggregate independently of driving factors. This neuropathological signature can be used to assess the pathogenicity of UBQLN2 gene variants and to understand the mechanisms of UBQLN2-linked disease.}, } @article {pmid38702287, year = {2024}, author = {Tazir, M and Nouioua, S}, title = {Distal hereditary motor neuropathies.}, journal = {Revue neurologique}, volume = {180}, number = {10}, pages = {1031-1036}, doi = {10.1016/j.neurol.2023.09.005}, pmid = {38702287}, issn = {0035-3787}, mesh = {Humans ; *Hereditary Sensory and Motor Neuropathy/genetics/diagnosis/physiopathology ; Mutation ; Charcot-Marie-Tooth Disease/genetics/diagnosis/physiopathology/epidemiology ; }, abstract = {Distal hereditary motor neuropathies (dHMN) are a group of heterogeneous hereditary disorders characterized by a slowly progressive distal pure motor neuropathy. Electrophysiology, with normal motor and sensory conduction velocities, can suggest the diagnosis of dHMN and guide the genetic study. More than thirty genes are currently associated with HMNs, but around 60 to 70% of cases of dHMN remain uncharacterized genetically. Recent cohort studies showed that HSPB1, GARS, BICB2 and DNAJB2 are among the most frequent dHMN genes and that the prevalence of the disease was calculated as 2.14 and 2.3 per 100,000. The determination of the different genes involved in dHMNs made it possible to observe a genotypic overlap with some other neurogenetic disorders and other hereditary neuropathies such as CMT2, mainly with the HSPB1, HSPB8, BICD2 and TRPV4 genes of AD-inherited transmission and recently observed with SORD gene of AR transmission which seems relatively frequent and potentially curable. Distal hereditary motor neuropathy that predominates in the upper limbs is linked mainly to three genes: GARS, BSCL2 and REEP1, whereas dHMN with vocal cord palsy is associated with SLC5A7, DCTN1 and TRPV4 genes. Among the rare AR forms of dHMN like IGHMBP2 and DNAJB2, the SIGMAR1 gene mutations as well as VRK1 variants are associated with a motor neuropathy phenotype often associated with upper motoneuron involvement. The differential diagnosis of these latter arises with juvenile forms of amyotrophic lateral sclerosis, that could be caused also by variations of these genes, as well as hereditary spastic paraplegia. A differential diagnosis of dHMN related to Brown Vialetto Van Laere syndrome due to riboflavin transporter deficiency is important to consider because of the therapeutic possibility.}, } @article {pmid38700207, year = {2024}, author = {Keeley, O and Coyne, AN}, title = {Nuclear and degradative functions of the ESCRT-III pathway: implications for neurodegenerative disease.}, journal = {Nucleus (Austin, Tex.)}, volume = {15}, number = {1}, pages = {2349085}, pmid = {38700207}, issn = {1949-1042}, support = {R00 NS123242/NS/NINDS NIH HHS/United States ; R01 NS132836/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Endosomal Sorting Complexes Required for Transport/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Animals ; Cell Nucleus/metabolism ; Frontotemporal Dementia/metabolism/pathology/genetics ; Endosomes/metabolism ; }, abstract = {The ESCRT machinery plays a pivotal role in membrane-remodeling events across multiple cellular processes including nuclear envelope repair and reformation, nuclear pore complex surveillance, endolysosomal trafficking, and neuronal pruning. Alterations in ESCRT-III functionality have been associated with neurodegenerative diseases including Frontotemporal Dementia (FTD), Amyotrophic Lateral Sclerosis (ALS), and Alzheimer's Disease (AD). In addition, mutations in specific ESCRT-III proteins have been identified in FTD/ALS. Thus, understanding how disruptions in the fundamental functions of this pathway and its individual protein components in the human central nervous system (CNS) may offer valuable insights into mechanisms underlying neurodegenerative disease pathogenesis and identification of potential therapeutic targets. In this review, we discuss ESCRT components, dynamics, and functions, with a focus on the ESCRT-III pathway. In addition, we explore the implications of altered ESCRT-III function for neurodegeneration with a primary emphasis on nuclear surveillance and endolysosomal trafficking within the CNS.}, } @article {pmid38697975, year = {2024}, author = {Tsitkov, S and Valentine, K and Kozareva, V and Donde, A and Frank, A and Lei, S and , and E Van Eyk, J and Finkbeiner, S and Rothstein, JD and Thompson, LM and Sareen, D and Svendsen, CN and Fraenkel, E}, title = {Disease related changes in ATAC-seq of iPSC-derived motor neuron lines from ALS patients and controls.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {3606}, pmid = {38697975}, issn = {2041-1723}, support = {RF1 AG057331/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; Male ; Female ; Middle Aged ; Case-Control Studies ; Chromatin/metabolism/genetics ; Aged ; Epigenomics/methods ; Chromatin Immunoprecipitation Sequencing/methods ; Disease Progression ; Epigenesis, Genetic ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured by ATAC-seq, of motor neuron cultures derived from a diverse group of 380 ALS patients and 80 healthy controls. We find that chromatin accessibility is heavily influenced by sex, the iPSC cell type of origin, ancestry, and the inherent variance arising from sequencing. Once these covariates are corrected for, we are able to identify ALS-specific signals in the data. Additionally, we find that the ATAC-seq data is able to predict ALS disease progression rates with similar accuracy to methods based on biomarkers and clinical status. These results suggest that iPSC-derived motor neurons recapitulate important disease-relevant epigenomic changes.}, } @article {pmid38697285, year = {2024}, author = {Tuerxun, K and Tang, RH and Abudoumijiti, A and Yusupu, Z and Aikebaier, A and Mijiti, S and Ibrahim, I and Cao, YL and Yasheng, A and Wu, YQ}, title = {Comparative proteomics analysis of samples from hepatic cystic echinococcosis patients using data-independent acquisition approach.}, journal = {Journal of proteomics}, volume = {301}, number = {}, pages = {105191}, doi = {10.1016/j.jprot.2024.105191}, pmid = {38697285}, issn = {1876-7737}, mesh = {*Proteomics/methods ; Humans ; *Echinococcus granulosus/metabolism ; Animals ; Helminth Proteins/metabolism/analysis ; Echinococcosis, Hepatic/metabolism/parasitology ; Proteome/analysis/metabolism ; }, abstract = {Cystic echinococcosis is a zoonotic disease resulting from infection caused by the larval stage of Echinococcus granulosus. This study aimed to assess the specific proteins that are potential candidates for the development of a vaccine against E. granulosus. The data-independent acquisition approach was employed to identify differentially expressed proteins (DEPs) in E. granulosus samples. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was employed to identify several noteworthy proteins. Results: The DEPs in E. granulosus samples were identified (245 pericystic wall vs. parasite-free yellowish granuloma (PYG, 1725 PY vs. PYG, 2274 PN vs. PYG). Further examination of these distinct proteins revealed their predominant enrichment in metabolic pathways, amyotrophic lateral sclerosis, and neurodegeneration-associated pathways. Notably, among these DEPs, SH3BGRL, MST1, TAGLN2, FABP5, UBE2V2, and RARRES2 exhibited significantly higher expression levels in the PYG group compared with the PY group (P < 0.05). The findings may contribute to the understanding of the pathological mechanisms underlying echinococcosis, providing valuable insights into the development of more effective diagnostic tools, treatment modalities, and preventive strategies. SIGNIFICANCE: CE is a major public health hazard in the western regions of China, Central Asia, South America, the Mediterranean countries, and eastern Africa. Echinococcus granulosus is responsible for zoonotic disease through infection Our analysis focuses on the proteins in various samples by data-dependent acquisition (DIA) for proteomic analysis. The importance of this research is to develop new strategies and targets to protect against E. granulosus infections in humans.}, } @article {pmid38697002, year = {2024}, author = {Su, T and Gan, Y and Ma, S and Wu, H and Lu, S and Zhi, M and Wang, B and Lu, Y and Yao, J}, title = {Graves' disease and the risk of five autoimmune diseases: A Mendelian randomization and colocalization study.}, journal = {Diabetes & metabolic syndrome}, volume = {18}, number = {5}, pages = {103023}, doi = {10.1016/j.dsx.2024.103023}, pmid = {38697002}, issn = {1878-0334}, mesh = {Humans ; *Graves Disease/genetics/epidemiology ; *Mendelian Randomization Analysis ; *Autoimmune Diseases/genetics/epidemiology ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; Prognosis ; Risk Factors ; Crohn Disease/genetics/epidemiology ; Follow-Up Studies ; Lupus Erythematosus, Systemic/genetics/epidemiology ; Arthritis, Rheumatoid/genetics/epidemiology ; }, abstract = {BACKGROUND: Epidemiological studies have consistently demonstrated a high prevalence of concurrent autoimmune diseases in individuals with Graves' disease (GD).

OBJECTIVE: The objective of this study is to establish a causal association between GD and autoimmune diseases.

METHODS: We employed a two-sample Mendelian randomization (MR) to infer a causal association between GD and five autoimmune diseases, namely rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Crohn's disease (CD), ulcerative colitis (UC), and amyotrophic lateral sclerosis (ALS), in the East Asian and European population. Genetic correlations were explored through linkage disequilibrium score regression analysis (LDSC). Finally, colocalization analyses were performed to investigate possible genetic foundations.

RESULTS: Bidirectional MR analysis indicated that genetically predicted GD increased the risk of RA (Odds Ratio (OR): 1.34, 95 % Confidence Interval (CI): 1.21 to 1.47, P < 0.001) and SLE (OR: 1.21, 95%CI: 1.08 to 1.35, P < 0.001) in the East Asian population. In contrast, we found that genetically predicted RA (OR: 1.14, 95%CI: 1.05 to 1.24, P = 0.002) and SLE (OR: 1.10, 95%CI: 1.03 to 1.17, P = 0.003) were associated with a higher risk of GD. The results have been partially validated in European cohorts. Colocalization analysis suggested the potential existence of shared causal variants between GD and other autoimmune diseases. In particular, gene ARID5B may play an important role in the incidence of autoimmune diseases.

CONCLUSION: This study has confirmed that GD was associated with RA and SLE and found a possible key gene ARID5B. It may be necessary to strengthen detection to prevent the occurrence of comorbidities in clinical practice.}, } @article {pmid38696744, year = {2024}, author = {}, title = {Variation in Resting Metabolic Rate Affects Identification of Metabolic Change in Geographically Distinct Cohorts of Patients With ALS.}, journal = {Neurology}, volume = {102}, number = {10}, pages = {e209407}, doi = {10.1212/WNL.0000000000209407}, pmid = {38696744}, issn = {1526-632X}, } @article {pmid38696153, year = {2024}, author = {Chugunov, DA and Shmilovich, AA and Larina, MR and Goncharenko, SN and Moiseeva, TV and Ryauzova, ES and Fedorova, EV and Bukinich, AA}, title = {[Clinical and psychometric characteristics of cognitive and negative disorders in schizophrenia].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {4. Vyp. 2}, pages = {64-71}, doi = {10.17116/jnevro202412404264}, pmid = {38696153}, issn = {1997-7298}, mesh = {Humans ; Male ; Female ; Adult ; *Schizophrenia/diagnosis/complications ; *Psychometrics ; Middle Aged ; *Schizophrenic Psychology ; Cognition ; Neuropsychological Tests ; Cognition Disorders/diagnosis/etiology ; }, abstract = {OBJECTIVE: To establish the characteristics of clinical manifestations and cognitive tests in patients with schizophrenia, with a predominance of cognitive and negative disorders.

MATERIAL AND METHODS: We examined 76 patients, 66 in the main group, 10 in the comparison group, who were treated in Psychiatric Hospital No. 1 and Psychiatric Hospital No. 4 (Moscow). Clinical-psychopathological, psychometric and statistical methods were used. Features of cognitive functioning were studied using the Frontal Assessment Battery (FAB) and the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis (ALS) Screen (ECAS). Emotional intelligence scores were assessed using the Ekman Face Emotion Recognition (EFER) test.

RESULTS: Patients with schizophrenia showed dominance of one of 3 types of deficit symptoms: cognitive, emotional, and volitional. Cognitive functions were significantly reduced in patients with schizophrenia when compared with the comparison group (mean FAB score (M±SD) 13.44±2.97 in patients with schizophrenia vs. 16.10±1.70 in the comparison group; t=4.10; p<0.001). Cognitive functions were particularly reduced in patients with volitional deficit (mean EFER total score 42.40±9.0 in patients with volitional deficit vs. 47.21±633 in patients with cognitive deficit; t=2.12; p=0.039; mean FAB score 12.83±3.29 in patients with volitional deficit vs. 16.10±1.70 in the comparison group; t=4.24; p<0.001; mean ECAS score specific to ALS 78.80±9.07 in patients with volitional deficit vs. 84.50±6.71 in the comparison group; t=2.18; p=0.034).

CONCLUSION: The greatest contribution to the development of cognitive disorders in schizophrenia is made by dysfunction of frontal (especially) and temporal cortex. Executive functions, speech skills and verbal fluency are most severely damaged.}, } @article {pmid38695966, year = {2024}, author = {Mendes Ferreira, V and Caetano, A and Santos, L and Fernandes, M}, title = {FIG4-associated disease manifesting as rapidly progressive amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {9}, pages = {4609-4610}, pmid = {38695966}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Disease Progression ; Flavoproteins/genetics ; Male ; Middle Aged ; Female ; Phosphoric Monoester Hydrolases ; }, } @article {pmid38695638, year = {2024}, author = {Fullam, T and Hunt, SL and Han, M and Denesia, J and Chandrashekhar, S and Jawdat, O and Piccione, E and Fernandes, JA and Statland, J}, title = {Outcomes after intervention for enteral nutrition in patients with amyotrophic lateral sclerosis in multidisciplinary clinics.}, journal = {Muscle & nerve}, volume = {70}, number = {1}, pages = {94-100}, pmid = {38695638}, issn = {1097-4598}, support = {UL1 TR002366/TR/NCATS NIH HHS/United States ; 10.13039/100000002/NH/NIH HHS/United States ; 10.13039/100000002/NH/NIH HHS/United States ; 10.13039/100005202//Muscular Dystrophy Association/ ; //FSHD Society/ ; //Friends of FSH Research/ ; //and FSHD Canada/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications ; Male ; Female ; *Enteral Nutrition/methods ; Aged ; Retrospective Studies ; Middle Aged ; *Gastrostomy ; Treatment Outcome ; Malnutrition/etiology/therapy ; Vital Capacity/physiology ; }, abstract = {INTRODUCTION/AIMS: Patients with amyotrophic lateral sclerosis (ALS) are susceptible to malnutrition, with appropriate management of nutritional interventions an active area of investigation. We sought to determine the impact of gastrostomy tube placement in ALS patients, exploring the correlation between forced vital capacity (FVC), malnutrition, and perioperative complications.

METHODS: A retrospective review was performed of clinically diagnosed ALS patients treated at two multidisciplinary clinics (University of Kansas, University of Nebraska) from January 2009 to September 2020 who were referred for gastrostomy. Data collected included demographics, disease characteristics, and key gastrostomy related dates/outcomes.

RESULTS: Two hundred thirty-nine patients were included with a median age of 65 years and median of 589 days from symptom onset to gastrostomy (interquartile range, 404-943). The population was predominantly Non-Hispanic White with bulbar-onset ALS. 30-day mortality was 4% and 30-day morbidity was 13%. Weight loss, body mass index, and predicted FVC at placement showed no increased 30-day morbidity or mortality association. Bulbar-onset ALS patients exhibited higher overall mortality postplacement than limb onset (odds ratio: 1.85, 95% confidence interval: 1.03-3.33). There was a 5% incidence of symptoms suggestive of refeeding syndrome.

DISCUSSION: Rates of major/minor complications and 30-day mortality related to gastrostomy placement in our population were similar compared with prior studies in ALS. The lack of difference in outcomes based on FVC at procedure may suggest this is not predictive of outcome, or perhaps, high-quality perioperative respiratory management. Alternative reasons may account for the increased morbidity and mortality of gastrostomy placement in the ALS population.}, } @article {pmid38694387, year = {2024}, author = {Arora, H and Javed, B and Kutikuppala, LVS and Chaurasia, M and Khullar, K and Kannan, S and Golla, V}, title = {ST2 levels and neurodegenerative diseases: is this a significant relation?.}, journal = {Annals of medicine and surgery (2012)}, volume = {86}, number = {5}, pages = {2812-2817}, pmid = {38694387}, issn = {2049-0801}, abstract = {Interleukin-33 (IL-33), belonging to the interleukin-1 cytokine family, has a decoy receptor soluble ST2 (sST2). IL-33 is found in oligodendrocytes and astrocytes and is involved in central nervous system healing and repair, whereas ST2 is found in microglia and astrocytes. Some studies have found a link between changes in the IL-33/ST2 pathway and neurodegenerative disorders. This review article investigates the relationship between the interleukin-33 (IL-33)/ST2 pathway and neurodegenerative disorders. It was discovered that soluble st2 levels were increased. Furthermore, IL-33 levels were found to be lower in many neurodegenerative diseases such as Alzheimer's and amyotrophic lateral sclerosis (ALS). The association with other disorders, such as ankylosing spondylitis, multiple sclerosis, and systemic lupus erythematosus (SLE), was also observed. Various studies suggest that ST2/IL-33 signalling may be pivotal in the disease modulation of neurodegenerative disorders. The serum sST2 level test can be useful in determining the inflammatory status and severity of illness in many neurodegenerative disorders. In this review, we will discuss recent findings concerning the interleukin-33 (IL-33)/ST2 pathway and its role in the diagnosis and treatment of diseases with neurodegeneration.}, } @article {pmid38694349, year = {2024}, author = {Amjadi, N and Mohammadi, S and Paybast, S and Dadkhah, P and Talayeh, M and Asemi, Z}, title = {A pregnant woman with amyotrophic lateral sclerosis from Iran: a case report.}, journal = {Annals of medicine and surgery (2012)}, volume = {86}, number = {5}, pages = {3013-3015}, pmid = {38694349}, issn = {2049-0801}, abstract = {INTRODUCTION AND IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease, which is extremely rare during pregnancy. The severity of the disease affects the pregnancy outcome. The present study reports the first Iranian case of a woman with ALS overlapping pregnancy.

CASE PRESENTATION: The 27-year-old lady in her second pregnancy was admitted to the emergency department with labor pain at the 37th gestation week. Following a multidisciplinary team meeting, including a neurologist, maternal-fetal medicine specialist, and anesthesiologist, a decision was made for an emergent cesarean section under spinal anesthesia. The delivery was successful without any maternal or fetal complications. A 5-month follow-up revealed the stable neurologic status of the mother.

CLINICAL DISCUSSION: The combination of ALS and pregnancy is very rare because the disease is more common in elderly men. ALS management involves a multidisciplinary approach. Riluzole is a drug that can increase the survival of the patients. ALS does not affect on motor and sensory nerves of the uterus, so vaginal delivery might be possible. The main cause of cesarean section in patients with ALS is respiratory compromise, but four patients with uncomplicated vaginal deliveries have been reported. The neonatal outcome of most cases resulted in normal healthy infants.

CONCLUSION: Management of ALS in pregnancy is challenging because of respiratory concerns, so multidisciplinary team management is important.}, } @article {pmid38692734, year = {2024}, author = {van Tartwijk, FW and Wunderlich, LCS and Mela, I and Makarchuk, S and Jakobs, MAH and Qamar, S and Franze, K and Kaminski Schierle, GS and St George-Hyslop, PH and Lin, JQ and Holt, CE and Kaminski, CF}, title = {Mutation of the ALS-/FTD-Associated RNA-Binding Protein FUS Affects Axonal Development.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {44}, number = {27}, pages = {}, pmid = {38692734}, issn = {1529-2401}, support = {MR/K02292X/1/MRC_/Medical Research Council/United Kingdom ; 109145/WT_/Wellcome Trust/United Kingdom ; 772426/ERC_/European Research Council/International ; 215943/WT_/Wellcome Trust/United Kingdom ; MR/K015850/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {*RNA-Binding Protein FUS/genetics/metabolism ; *Axons/pathology/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *Mutation ; Female ; Male ; Xenopus laevis ; Growth Cones/metabolism ; Humans ; Disease Models, Animal ; }, abstract = {Aberrant condensation and localization of the RNA-binding protein (RBP) fused in sarcoma (FUS) occur in variants of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Changes in RBP function are commonly associated with changes in axonal cytoskeletal organization and branching in neurodevelopmental disorders. Here, we asked whether branching defects also occur in vivo in a model of FUS-associated disease. We use two reported Xenopus models of ALS/FTD (of either sex), the ALS-associated mutant FUS(P525L) and a mimic of hypomethylated FUS, FUS(16R). Both mutants strongly reduced axonal complexity in vivo. We also observed an axon looping defect for FUS(P525L) in the target area, which presumably arises due to errors in stop cue signaling. To assess whether the loss of axon complexity also had a cue-independent component, we assessed axonal cytoskeletal integrity in vitro. Using a novel combination of fluorescence and atomic force microscopy, we found that mutant FUS reduced actin density in the growth cone, altering its mechanical properties. Therefore, FUS mutants may induce defects during early axonal development.}, } @article {pmid38691665, year = {2024}, author = {Singh, P and Belliveau, P and Towle, J and Neculau, AE and Dima, L}, title = {Edaravone Oral Suspension: A Neuroprotective Agent to Treat Amyotrophic Lateral Sclerosis.}, journal = {American journal of therapeutics}, volume = {31}, number = {3}, pages = {e258-e267}, doi = {10.1097/MJT.0000000000001742}, pmid = {38691665}, issn = {1536-3686}, mesh = {*Edaravone/administration & dosage/pharmacology/therapeutic use ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neuroprotective Agents/administration & dosage/therapeutic use/adverse effects ; Administration, Oral ; Suspensions ; Biological Availability ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons due to degeneration of nerve cells within the brain and spinal cord. Early symptoms include limb weakness, twitching or muscle cramping, and slurred speech. As the disease progresses, difficulty breathing, swallowing, and paralysis can lead to death. Currently, there are no medications that cure ALS, and guidelines recommend treatments focused on symptom management. Intravenous (IV) edaravone was approved by the US Food and Drug Administration (FDA) in 2017 as a treatment to slow the progression of ALS. In May 2022, the FDA approved an oral suspension (ORS) formulation of edaravone.

MECHANISM OF ACTION: The mechanism of action of edaravone is not well defined. However, its neuroprotective effects are thought to result from antioxidant properties occurring through elimination of free radicals.

PHARMACOKINETICS: Edaravone ORS (105 mg) has a bioavailability of 57% when compared with edaravone IV (60 mg). The ORS should be taken on an empty stomach in the morning, with water and no food or beverages, for 1 hour. Edaravone is bound to albumin (92%), has a mean volume of distribution of 63.1 L, a half-life of 4.5-9 hours, and a total clearance of 35.9 L/h after intravenous administration. Edaravone is metabolized into nonactive sulfate and glucuronide conjugates.

CLINICAL TRIALS: The FDA approval was based on studies of the pharmacokinetics, safety, tolerability, and bioavailability of edaravone ORS. A phase III, global, multicenter, open-label safety study was conducted on edaravone ORS in 185 patients with ALS over 48 weeks. The most reported treatment-emergent adverse events were falls, muscular weakness, and constipation. Serious treatment-emergent adverse events included disease worsening, dysphagia, dyspnea, and respiratory failure.

THERAPEUTIC ADVANCE: Oral edaravone is an ALS treatment that can be self-administered or administered by a caregiver, precluding the need for administration by a health care professional in an institutional setting.}, } @article {pmid38689650, year = {2024}, author = {Swindell, WR}, title = {Meta-analysis of differential gene expression in lower motor neurons isolated by laser capture microdissection from post-mortem ALS spinal cords.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1385114}, pmid = {38689650}, issn = {1664-8021}, abstract = {INTRODUCTION: ALS is a fatal neurodegenerative disease for which underlying mechanisms are incompletely understood. The motor neuron is a central player in ALS pathogenesis but different transcriptome signatures have been derived from bulk analysis of post-mortem tissue and iPSC-derived motor neurons (iPSC-MNs).

METHODS: This study performed a meta-analysis of six gene expression studies (microarray and RNA-seq) in which laser capture microdissection (LCM) was used to isolate lower motor neurons from post-mortem spinal cords of ALS and control (CTL) subjects. Differentially expressed genes (DEGs) with consistent ALS versus CTL expression differences across studies were identified.

RESULTS: The analysis identified 222 ALS-increased DEGs (FDR <0.10, SMD >0.80) and 278 ALS-decreased DEGs (FDR <0.10, SMD < -0.80). ALS-increased DEGs were linked to PI3K-AKT signaling, innate immunity, inflammation, motor neuron differentiation and extracellular matrix. ALS-decreased DEGs were associated with the ubiquitin-proteosome system, microtubules, axon growth, RNA-binding proteins and synaptic membrane. ALS-decreased DEG mRNAs frequently interacted with RNA-binding proteins (e.g., FUS, HuR). The complete set of DEGs (increased and decreased) overlapped significantly with genes near ALS-associated SNP loci (p < 0.01). Transcription factor target motifs with increased proximity to ALS-increased DEGs were identified, most notably DNA elements predicted to interact with forkhead transcription factors (e.g., FOXP1) and motor neuron and pancreas homeobox 1 (MNX1). Some of these DNA elements overlie ALS-associated SNPs within known enhancers and are predicted to have genotype-dependent MNX1 interactions. DEGs were compared to those identified from SOD1-G93A mice and bulk spinal cord segments or iPSC-MNs from ALS patients. There was good correspondence with transcriptome changes from SOD1-G93A mice (r ≤ 0.408) but most DEGs were not differentially expressed in bulk spinal cords or iPSC-MNs and transcriptome-wide effect size correlations were weak (bulk tissue: r ≤ 0.207, iPSC-MN: r ≤ 0.037).

CONCLUSION: This study defines a robust transcriptome signature from LCM-based motor neuron studies of post-mortem tissue from ALS and CTL subjects. This signature differs from those obtained from analysis of bulk spinal cord segments and iPSC-MNs. Results provide insight into mechanisms underlying gene dysregulation in ALS and highlight connections between these mechanisms, ALS genetics, and motor neuron biology.}, } @article {pmid38689506, year = {2024}, author = {Parvizi, T and Klotz, S and Keritam, O and Caliskan, H and Imhof, S and König, T and Haider, L and Traub-Weidinger, T and Wagner, M and Brunet, T and Brugger, M and Zimprich, A and Rath, J and Stögmann, E and Gelpi, E and Cetin, H}, title = {Clinical heterogeneity within the ALS-FTD spectrum in a family with a homozygous optineurin mutation.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {6}, pages = {1579-1589}, pmid = {38689506}, issn = {2328-9503}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology/diagnosis ; *Membrane Transport Proteins/genetics ; *Cell Cycle Proteins/genetics ; *Frontotemporal Dementia/genetics/pathology/physiopathology ; Male ; Adult ; Female ; Pedigree ; Transcription Factor TFIIIA/genetics ; Siblings ; Frameshift Mutation ; Homozygote ; }, abstract = {OBJECTIVE: Mutations in the gene encoding for optineurin (OPTN) have been reported in the context of different neurodegenerative diseases including the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. Based on single case reports, neuropathological data in OPTN mutation carriers have revealed transactive response DNA-binding protein 43 kDa (TDP-43) pathology, in addition to accumulations of tau and alpha-synuclein. Herein, we present two siblings from a consanguineous family with a homozygous frameshift mutation in the OPTN gene and different clinical presentations.

METHODS: Both affected siblings underwent (i) clinical, (ii) neurophysiological, (iii) neuropsychological, (iv) radiological, and (v) laboratory examinations, and (vi) whole-exome sequencing (WES). Postmortem histopathological examination was conducted in the index patient, who deceased at the age of 41.

RESULTS: The index patient developed rapidly progressing clinical features of upper and lower motor neuron dysfunction as well as apathy and cognitive deterioration at the age of 41. Autopsy revealed an ALS-FTLD pattern associated with prominent neuronal and oligodendroglial TDP-43 pathology, and an atypical limbic 4-repeat tau pathology reminiscent of argyrophilic grain disease. The brother of the index patient exhibited behavioral changes and mnestic deficits at the age of 38 and was diagnosed with behavioral FTD 5 years later, without any evidence of motor neuron dysfunction. WES revealed a homozygous frameshift mutation in the OPTN gene in both siblings (NM_001008212.2: c.1078_1079del; p.Lys360ValfsTer18).

INTERPRETATION: OPTN mutations can be associated with extensive TDP-43 pathology and limbic-predominant tauopathy and present with a heterogeneous clinical phenotype within the ALS-FTD spectrum within the same family.}, } @article {pmid38687737, year = {2024}, author = {Lumi, R and Petri, S and Siwy, J and Latosinska, A and Raad, J and Zürbig, P and Skripuletz, T and Mischak, H and Beige, J}, title = {Small peptide CSF fingerprint of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {19}, number = {4}, pages = {e0302280}, pmid = {38687737}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid ; Female ; Male ; Middle Aged ; Aged ; *Peptides/cerebrospinal fluid ; Proteomics/methods ; Adult ; Biomarkers/cerebrospinal fluid ; Case-Control Studies ; Tandem Mass Spectrometry ; Chromatography, Liquid ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by abnormal protein aggregation in the motor neurons. Present and earlier proteomic studies to characterize peptides in cerebrospinal fluid (CSF) associated with motoneuron pathology did not target low molecular weight proteins and peptides. We hypothesized that specific changes in CSF peptides or low molecular weight proteins are significantly altered in ALS, and that these changes may support deciphering molecular pathophysiology and even guide approaches towards therapeutic interventions.

METHODS: Cerebrospinal fluid (CSF) from 50 ALS patients and 50 non-ALS controls was collected, centrifuged immediately after collection, aliquoted into polypropylene test tubes, frozen within 30-40 min after the puncture, and stored at -80°C until use. Peptides were sequenced using capillary electrophoresis or liquid chromatography/mass spectrometry (CE-MS/MS or LC-MS/MS).

FINDINGS: In the CSF of 50 patients and 50 non-ALS controls 33 peptides were found, of which 14 could be sequenced using a non-lytic single-pot proteomic detection method, CE/MS. ALS deregulated peptides vs. controls included Integral membrane protein 2B, Neurosecretory protein VGF, Osteopontin, Neuroendocrine protein 7B2 (Secretogranin-V), EGF-containing fibulin-like extracellular matrix protein 1, Xylosyltransferase 1 XT-1, Chromogranin-A, Superoxide dismutase SOD-1, Secretogranin-1 (Chromogranin B), NR2F2 Nuclear Receptor Subfamily 2 Group F Member 2 and Collagen alpha-1(VII) chain.

INTERPRETATION: Most striking deregulations in CSF from ALS patients were found in VGF, Osteopontin, SOD-1 and EFEMP1 peptides. No associations of disease severity, duration and region of onset with sequenced peptides were found.}, } @article {pmid38686337, year = {2024}, author = {Felix, C and Johnston, JD and Owen, K and Shirima, E and Hinds, SR and Mandl, KD and Milinovich, A and Alberts, JL}, title = {Explainable machine learning for predicting conversion to neurological disease: Results from 52,939 medical records.}, journal = {Digital health}, volume = {10}, number = {}, pages = {20552076241249286}, pmid = {38686337}, issn = {2055-2076}, abstract = {OBJECTIVE: This study assesses the application of interpretable machine learning modeling using electronic medical record data for the prediction of conversion to neurological disease.

METHODS: A retrospective dataset of Cleveland Clinic patients diagnosed with Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, or Parkinson's disease, and matched controls based on age, sex, race, and ethnicity was compiled. Individualized risk prediction models were created using eXtreme Gradient Boosting for each neurological disease at four timepoints in patient history. The prediction models were assessed for transparency and fairness.

RESULTS: At timepoints 0-months, 12-months, 24-months, and 60-months prior to diagnosis, Alzheimer's disease models achieved the area under the receiver operating characteristic curve on a holdout test dataset of 0.794, 0.742, 0.709, and 0.645; amyotrophic lateral sclerosis of 0.883, 0.710, 0.658, and 0.620; multiple sclerosis of 0.922, 0.877, 0.849, and 0.781; and Parkinson's disease of 0.809, 0.738, 0.700, and 0.651, respectively.

CONCLUSIONS: The results demonstrate that electronic medical records contain latent information that can be used for risk stratification for neurological disorders. In particular, patient-reported outcomes, sleep assessments, falls data, additional disease diagnoses, and longitudinal changes in patient health, such as weight change, are important predictors.}, } @article {pmid38685454, year = {2024}, author = {Gadri, Y and Avneri, A and Peleg, Z}, title = {Induced mutation in the SiALS gene offers new weed management opportunities for sesame crop.}, journal = {Plant science : an international journal of experimental plant biology}, volume = {345}, number = {}, pages = {112104}, doi = {10.1016/j.plantsci.2024.112104}, pmid = {38685454}, issn = {1873-2259}, mesh = {*Weed Control/methods ; *Herbicide Resistance/genetics ; *Sesamum/genetics/growth & development ; *Herbicides/pharmacology ; Acetolactate Synthase/genetics ; Plant Weeds/genetics/drug effects ; Plant Proteins/genetics/metabolism ; Mutation ; Crops, Agricultural/genetics/growth & development ; }, abstract = {Weeds are the primary biotic constraint affecting sesame growth and production. Here, we applied EMS mutagenesis to an elite sesame cultivar and discovered a novel point mutation in the sesame SiALS gene conferring resistance to imidazolinone, a group of acetolactate-synthase (ALS)-inhibitors. The mutant line exhibited high resistance to imazamox, an ALS-inhibitor, with hybrid plants displaying an intermediate response. Field-based validation confirmed the mutant line's substantial resistance, leading to a significantly higher yield under imazamox treatment. Under pre-emergence application of imazapic, the mutant plants sustained growth, whereas wild-type and weed were effectively controlled. Field trials using s-metolachlor and imazapic combined resulted in weed-free plots compared to untreated controls. Consequently, this treatment showed a significantly greater yield (2280 vs. 880 Kg ha[-1]) than the commercial practice (s-metolachlor). Overall, our study unveils the potential of utilizing this point mutation in sesame breeding programs, offering new opportunities for integrated weed management strategies for sesame cultivation. Developing herbicide-resistant crop plants holds promise for supporting sustainable production and addressing the challenges of weed infestations in sesame farming.}, } @article {pmid38685248, year = {2024}, author = {Chtourou, M and Osuna, MD and Vázquez-García, JG and Lozano-Juste, J and De Prado, R and Torra, J and Souissi, T}, title = {Pro197Ser and the new Trp574Leu mutations together with enhanced metabolism contribute to cross-resistance to ALS inhibiting herbicides in Sinapis alba.}, journal = {Pesticide biochemistry and physiology}, volume = {201}, number = {}, pages = {105882}, doi = {10.1016/j.pestbp.2024.105882}, pmid = {38685248}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Herbicides/pharmacology ; *Herbicide Resistance/genetics ; *Sinapis/drug effects/genetics ; *Malathion/pharmacology ; *Mutation ; Plant Proteins/genetics/metabolism ; Arylsulfonates/pharmacology ; Molecular Docking Simulation ; Imidazoles/pharmacology ; }, abstract = {White mustard, (Sinapis alba), a problematic broadleaf weed in many Mediterranean countries in arable fields has been detected as resistant to tribenuron-methyl in Tunisia. Greenhouse and laboratory studies were conducted to characterize Target-Site Resistance (TSR) and the Non-Target Site Resistance (NTSR) mechanisms in two suspected white mustard biotypes. Herbicide dose-response experiments confirmed that the two S. alba biotypes were resistant to four dissimilar acetolactate synthase (ALS)-pinhibiting herbicide chemistries indicating the presence of cross-resistance mechanisms. The highest resistance factor (>144) was attributed to tribenuron-methyl herbicide and both R populations survived up to 64-fold the recommended field dose (18.7 g ai ha[-1]). In this study, the metabolism experiments with malathion (a cytochrome P450 inhibitor) showed that malathion reduced resistance to tribenuron-methyl and imazamox in both populations, indicating that P450 may be involved in the resistance. Sequence analysis of the ALS gene detected target site mutations in the two R biotypes, with amino acid substitutions Trp574Leu, the first report for the species, and Pro197Ser. Molecular docking analysis showed that ALS[Pro197Ser] enzyme cannot properly bind to tribenuron-methyl's aromatic ring due to a reduction in the number of hydrogen bonds, while imazamox can still bind. However, Trp574Leu can weaken the binding affinity between the mutated ALS enzyme and both herbicides with the loss of crucial interactions. This investigation provides substantial evidence for the risk of evolving multiple resistance in S. alba to auxin herbicides while deciphering the TSR and NTSR mechanisms conferring cross resistance to ALS inhibitors.}, } @article {pmid38685231, year = {2024}, author = {Deng, W and Yao, S and Li, Y and Yin, H and Yang, Q and Yuan, S}, title = {An Asp376Glu substitution and P450s-involved metabolism endow resistance to ALS inhibitors in an Ammannia auriculata Willd. Population.}, journal = {Pesticide biochemistry and physiology}, volume = {201}, number = {}, pages = {105911}, doi = {10.1016/j.pestbp.2024.105911}, pmid = {38685231}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/antagonists & inhibitors ; *Herbicides/pharmacology ; *Herbicide Resistance/genetics ; *Cytochrome P-450 Enzyme System/genetics/metabolism ; Malathion/pharmacology ; Sulfonylurea Compounds/pharmacology ; Plant Weeds/drug effects/genetics ; Amino Acid Substitution ; }, abstract = {Ammannia auriculata Willd. is a noxious broadleaf weed, commonly infesting rice ecosystems across southern China. A putative resistant A. auriculata population (AHSC-5) was sampled from a rice field of Anhui Province, where bensulfuron-methyl (BM) was unable to control its occurrence. This study aimed to determine the sensitivities of the AHSC-5 population to common-use herbicides, and to investigate the underlying resistance mechanisms. The bioassays showed that the AHSC-5 population was 138.1-fold resistant to BM, compared with the susceptible population (JSGL-1). Pretreatment of malathion reduced the resistance index to 19.5. ALS sequencing revealed an Asp376Glu substitution in the AHSC-5 population, and in vitro ALS activity assays found that 50% activity inhibition (I50) of BM in AHSC-5 was 75.4 times higher than that of JSGL-1. Moreover, the AHSC-5 population displayed cross-resistance to pyrazosulfuron-ethyl (10.6-fold), bispyribac‑sodium (3.6-fold), and imazethapyr (2.2-fold), and was in the process of evolving multiple resistance to synthetic auxin herbicides fluroxypyr (2.3-fold) and florpyrauxifen-benzyl (3.1-fold). This study proved the BM resistance in A. auriculata caused by the Asp376Glu mutation and P450-regulated metabolism. This multi-resistant population can still be controlled by penoxsulam, MCPA, bentazone, and carfentrazone-ethyl, which aids in developing targeted and effective weed management strategies.}, } @article {pmid38684907, year = {2024}, author = {Nelson, AT and Cicardi, ME and Markandaiah, SS and Han, JY and Philp, NJ and Welebob, E and Haeusler, AR and Pasinelli, P and Manfredi, G and Kawamata, H and Trotti, D}, title = {Glucose hypometabolism prompts RAN translation and exacerbates C9orf72-related ALS/FTD phenotypes.}, journal = {EMBO reports}, volume = {25}, number = {5}, pages = {2479-2510}, pmid = {38684907}, issn = {1469-3178}, support = {RF1 NS114128/NS/NINDS NIH HHS/United States ; W81XWH-21-1-0134//DOD | USA | MEDCOM | MRDC | U.S. Army Medical Research Acquisition Activity (USAMRAA)/ ; F31-NS118838//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS109150/NS/NINDS NIH HHS/United States ; RF1-NS114128//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 628389//Muscular Dystrophy Association (MDA)/ ; R35 NS122209/NS/NINDS NIH HHS/United States ; R21 NS090912/NS/NINDS NIH HHS/United States ; RO1-NS109150//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; F31 NS118838/NS/NINDS NIH HHS/United States ; RF1-AG057882//HHS | NIH | National Institute on Aging (NIA)/ ; RF1 AG057882/AG/NIA NIH HHS/United States ; R21-NS090912//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; Mice ; Adenosine Triphosphate/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Brain/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; Disease Models, Animal ; DNA Repeat Expansion/genetics ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Glucose/metabolism ; Mice, Transgenic ; Neurons/metabolism ; *Phenotype ; Protein Biosynthesis ; *ran GTP-Binding Protein/metabolism ; }, abstract = {The most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC)n nucleotide repeat expansion (NRE) occurring in the first intron of the C9orf72 gene (C9). Brain glucose hypometabolism is consistently observed in C9-NRE carriers, even at pre-symptomatic stages, but its role in disease pathogenesis is unknown. Here, we show alterations in glucose metabolic pathways and ATP levels in the brains of asymptomatic C9-BAC mice. We find that, through activation of the GCN2 kinase, glucose hypometabolism drives the production of dipeptide repeat proteins (DPRs), impairs the survival of C9 patient-derived neurons, and triggers motor dysfunction in C9-BAC mice. We also show that one of the arginine-rich DPRs (PR) could directly contribute to glucose metabolism and metabolic stress by inhibiting glucose uptake in neurons. Our findings provide a potential mechanistic link between energy imbalances and C9-ALS/FTD pathogenesis and suggest a feedforward loop model with potential opportunities for therapeutic intervention.}, } @article {pmid38683778, year = {2024}, author = {Brennan, MR and Keast, DH and Bain, K and Bain, M and Lorentsen, B and Ayoub, N}, title = {Defining wound bed conformability: a new testing methodology to assess the relative swelling rise of foam dressings.}, journal = {Journal of wound care}, volume = {33}, number = {5}, pages = {312-323}, doi = {10.12968/jowc.2024.33.5.312}, pmid = {38683778}, issn = {0969-0700}, mesh = {Humans ; *Wound Healing ; *Bandages ; Reproducibility of Results ; Exudates and Transudates ; Materials Testing ; Wounds and Injuries/therapy ; }, abstract = {OBJECTIVE: Using a dressing that expands and conforms to the wound bed upon exudate absorption is one of the best ways to promote wound healing. While many products claim wound bed conformability, no externally replicated or verified test methodology had been developed to quantify a wound dressing's ability to conform to the wound bed. The Relative Swelling Rise (RSR) test methodology was developed to measure the relative swelling rise of foam dressings upon fluid absorption, and offers a quantifiable and easily replicated method to measure wound bed conformability.

METHOD: The RSR test method was developed, validated and reliability tested by Coloplast A/S, Denmark. External replication was provided by ALS Odense, Denmark (previously DB Lab). Circular fences provide a fixed diameter to apply and contain the fluid and prevent horizontal spreading in the test set-up. The swelling height is quantified relative to the fence's inner diameter, i.e., the ratio alpha (α), and allows evaluation of a material's ability to conform to the wound bed.

RESULTS: Biatain Silicone foam products (n=3, Coloplast A/S, Denmark) were tested, all afforded an average α-ratio from 0.30 to 0.60. The relative standard deviations were between 1-3%, demonstrating the strength of the test. Robustness of the methodology was demonstrated through the internal validation study, the reliability study, and both an internal and external replication study, as well as a systematic literature review and expert review of the construct, content, criterion and generalisability of the method.

CONCLUSION: Having a validated, effective and easily replicable testing method to quantify wound bed conformability of foam dressings is an important step towards achieving better healing outcomes.}, } @article {pmid38683209, year = {2024}, author = {Wohnrade, C and Seeliger, T and Gingele, S and Bjelica, B and Skripuletz, T and Petri, S}, title = {Diagnostic value of neurofilaments in differentiating motor neuron disease from multifocal motor neuropathy.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {4441-4452}, pmid = {38683209}, issn = {1432-1459}, mesh = {Humans ; *Motor Neuron Disease/diagnosis/blood/cerebrospinal fluid/physiopathology ; Male ; Female ; Middle Aged ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Retrospective Studies ; Diagnosis, Differential ; Aged ; *Biomarkers/blood/cerebrospinal fluid ; *Polyneuropathies/diagnosis/blood/cerebrospinal fluid/physiopathology ; Adult ; }, abstract = {OBJECTIVE: To evaluate the performance of serum neurofilament light chain (NfL) and cerebrospinal fluid (CSF) phosphorylated neurofilament heavy chain (pNfH) as diagnostic biomarkers for the differentiation between motor neuron disease (MND) and multifocal motor neuropathy (MMN).

METHODS: This retrospective, monocentric study included 16 patients with MMN and 34 incident patients with MND. A subgroup of lower motor neuron (MN) dominant MND patients (n = 24) was analyzed separately. Serum NfL was measured using Ella automated immunoassay, and CSF pNfH was measured using enzyme-linked immunosorbent assay. Area under the curve (AUC), optimal cutoff values (Youden's index), and correlations with demographic characteristics were calculated.

RESULTS: Neurofilament concentrations were significantly higher in MND compared to MMN (p < 0.001), and serum NfL and CSF pNfH correlated strongly with each other (Spearman's rho 0.68, p < 0.001). Serum NfL (AUC 0.946, sensitivity and specificity 94%) and CSF pNfH (AUC 0.937, sensitivity 90.0%, specificity 100%) performed excellent in differentiating MND from MMN. Optimal cutoff values were ≥ 44.15 pg/mL (serum NfL) and ≥ 715.5 pg/mL (CSF pNfH), respectively. Similar results were found when restricting the MND cohort to lower MN dominant patients. Only one MMN patient had serum NfL above the cutoff. Two MND patients presented with neurofilament concentrations below the cutoffs, both featuring a slowly progressive disease.

CONCLUSION: Neurofilaments are valuable supportive biomarkers for the differentiation between MND and MMN. Serum NfL and CSF pNfH perform similarly well and elevated neurofilaments in case of diagnostic uncertainty underpin MND diagnosis.}, } @article {pmid38682649, year = {2024}, author = {Zhou, Q and Jiang, X and Zhang, X and Wang, D and Yang, G and Zhou, H and Wu, Y and Guo, F and Chen, M and Diao, G and Ni, L}, title = {Polyoxomolybdate-Based Metal-Organic Framework-Derived Cu-Embedded Molybdenum Dioxide Hybrid Nanoparticles as Highly Efficient Electrocatalysts for Al-S Batteries.}, journal = {ChemSusChem}, volume = {17}, number = {19}, pages = {e202400424}, doi = {10.1002/cssc.202400424}, pmid = {38682649}, issn = {1864-564X}, support = {21971221//National Natural Science Foundation of China/ ; 21401162//National Natural Science Foundation of China/ ; 21773203//National Natural Science Foundation of China/ ; KYCX22_3467//Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; yzuxk202010//Yangzhou University Interdisciplinary Research Foundation for Chemistry Discipline/ ; //Colleges and Universities of Jiangsu Province/ ; //Lvyangjinfeng Talent Program of Yangzhou/ ; }, abstract = {High-performance rechargeable aluminum-sulfur batteries (RASB) have great potential for various applications owing to their high theoretical capacity, abundant sulfur resources, and good safety. Nevertheless, the practical application of RASB still faces several challenges, including the polysulfide shuttle phenomenon and low sulfur utilization efficiency. Here, we first developed a synergistic copper heterogeneous metal oxide MoO2 derived from polymolybdate-based metal-organic framework as an efficient catalyst for mitigating polysulfide diffusion. This composite enhances sulfur utilization and electrical conductivity of the cathode. DFT calculations and experimental results reveal the catalyst Cu/MoO2@C not only effectively anchors aluminum polysulfides (AlPSs) to mitigate the shuttle effect, but also significantly promotes the catalytic conversion of AlPSs on the sulfur cathode side during charging and discharging. The unique nanostructure contains abundant electrocatalytic active sites of oxide nanoparticles and Cu clusters, resulting in excellent electrochemical performance. Consequently, the established RASB exhibits an initial capacity of 875 mAh g[-1] at 500 mA g[-1] and maintains a capacity of 967 mAh g[-1] even at a high temperature of 50 °C.}, } @article {pmid38682227, year = {2024}, author = {Mohammadi, S and Ghaderi, S and Mohammadi, M and Najafi Asli Pashaki, Z and Khatyal, R and Mohammadian, F and Mohammadjani, S}, title = {Thalamic Alterations in Motor Neuron Diseases: A Systematic Review of MRI Findings.}, journal = {Journal of integrative neuroscience}, volume = {23}, number = {4}, pages = {77}, doi = {10.31083/j.jin2304077}, pmid = {38682227}, issn = {0219-6352}, mesh = {Humans ; *Thalamus/diagnostic imaging/pathology/physiopathology ; *Motor Neuron Disease/diagnostic imaging/pathology/physiopathology ; *Magnetic Resonance Imaging ; Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/physiopathology ; }, abstract = {BACKGROUND: Motor neuron diseases (MNDs) are progressive neurodegenerative disorders characterized by motor impairment and non-motor symptoms. The involvement of the thalamus in MNDs, especially in conditions such as amyotrophic lateral sclerosis (ALS), and its interaction with frontotemporal dementia (FTD), has garnered increasing research interest. This systematic review analyzed magnetic resonance imaging (MRI) studies that focused on thalamic alterations in MNDs to understand the significance of these changes and their correlation with clinical outcomes.

METHODS: Following PRISMA 2020 guidelines, the PubMed and Scopus databases were searched from inception to June 2023 for studies related to MRI findings in the thalamus of patients with MNDs. Eligible studies included adult patients diagnosed with ALS or other forms of MND who underwent brain MRI, with outcomes related to thalamic alterations. Studies were evaluated for risk of bias using the Newcastle-Ottawa scale.

RESULTS: A total of 52 studies (including 3009 MND patients and 2181 healthy controls) used various MRI techniques, including volumetric analysis, diffusion tensor imaging, and functional MRI, to measure thalamic volume, connectivity, and other alterations. This review confirmed significant thalamic changes in MNDs, such as atrophy and microstructural degradation, which are associated with disease severity, progression, and functional disability. Thalamic involvement varies across different MND subtypes and is influenced by the presence of cognitive impairment and mutations in genes including chromosome 9 open reading frame 72 (C9orf72). The synthesis of findings across studies indicates that thalamic pathology is a prevalent early biomarker of MNDs that contributes to motor and cognitive deficits. The thalamus is a promising target for monitoring as its dysfunction underpins a variety of clinical symptoms in MNDs.

CONCLUSIONS: Thalamic alterations provide valuable insights into the pathophysiology and progression of MNDs. Multimodal MRI techniques are potent tools for detecting dynamic thalamic changes, indicating structural integrity, connectivity disruption, and metabolic activity.}, } @article {pmid38682222, year = {2024}, author = {Huang, Q and Li, Q and Guo, JH}, title = {Causal Relationship between Sex Hormones and Risk of Developing Common Neurodegenerative Diseases: A Mendelian Randomization Study.}, journal = {Journal of integrative neuroscience}, volume = {23}, number = {4}, pages = {78}, doi = {10.31083/j.jin2304078}, pmid = {38682222}, issn = {0219-6352}, support = {2021ZD0201801//Science and Technology Innovation 2030 - Major program of "Brain Science and Brain-like Research"/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/epidemiology/genetics ; *Sex Hormone-Binding Globulin/analysis/metabolism ; Testosterone/blood ; Alzheimer Disease/epidemiology/genetics ; Estradiol/blood ; Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Parkinson Disease/genetics/epidemiology ; Gonadal Steroid Hormones/blood/metabolism ; Female ; Male ; }, abstract = {BACKGROUND: Neurodegenerative diseases are a group of unexplained disorders of the central nervous system, and studies have shown that a large number of genetic and environmental factors are associated with these diseases. Since these diseases show significant gender differences in epidemiology, sex hormones are thought to be strongly associated with these diseases. In this study, we used Mendelian randomization to explore the causal relationship between sex hormones and the risk of developing neurodegenerative diseases.

METHODS: We obtained genetic instrumental variables for sex hormones (sex hormone-binding globulin [SHBG], estradiol levels [EL], and bioavailable testosterone [BT]) separately through the Integrative Epidemiology Unit (IEU) database (https://gwas.mrcieu.ac.uk/). We analyzed the causal relationship of each with the risk of developing neurodegenerative diseases (Amyotrophic Lateral Sclerosis [ALS], Parkinson's disease [PD], and Alzheimer's disease [AD]) using inverse variance weighted (IVW) in Mendelian randomization. Data were then analyzed for sensitivity.

RESULTS: BT was negatively associated with the risk of developing ALS (odds ratio [OR] = 0.794; 95% confidence interval [95% CI] = 0.672-0.938; p = 0.006). EL and SHBG were not associated with a risk for developing neurodegenerative diseases (ALS, PD, AD).

CONCLUSIONS: Elevated BT is associated with a reduced risk of developing ALS. Further research is needed to investigate the underlying mechanisms of action for this correlation and how it can be used as a potential target of action to reduce the risk of developing ALS.}, } @article {pmid38681726, year = {2024}, author = {Grzanka, M and Joniec, A and Rogulski, J and Sobiech, Ł and Idziak, R and Loryś, B}, title = {Impact of novel herbicide based on synthetic auxins and ALS inhibitor on weed control.}, journal = {Open life sciences}, volume = {19}, number = {1}, pages = {20220868}, pmid = {38681726}, issn = {2391-5412}, abstract = {Delayed sowing of winter cereals or unfavorable weather conditions in autumn may make it impossible to carry out herbicide treatment in autumn. In such cases, weed control should be started in the spring. During this time, the plantation should be protected as effectively as possible because the weeds are at an advanced stage of growth. Therefore, they are less sensitive to applied herbicides. In the treatment, it is worth using a mixture of different mechanisms of action. Studies were conducted to evaluate the effectiveness of a band of tribenuron-methyl, and MCPA applied as soluble granules in spring control of dicotyledonous in winter cereals. The biological efficacy of herbicides was estimated in the 25 field experiments on winter cereals in Poland. Postemergence, a spring application of tribenuron-methyl + MCPA, effectively controls the majority of weed species present in spring: Anthemis arvensis, Brassica napus, Capsella bursa-pastoris, Centaurea cyanus, Lamium purpureum, Matricaria chamomilla, Tripleurospermum inodorum, Stellaria media and Thlaspi arvense. Satisfactory control was confirmed for Veronica persica, Viola arvensis, and Galium aparine. Tribenuron-methyl with MCPA is recommended for application to winter cereals in spring. To prevent the development of resistance in weeds, it is advantageous to combine two active substances.}, } @article {pmid38679739, year = {2024}, author = {Pérez Compte, D and Etourneau, L and Hesse, AM and Kraut, A and Barthelon, J and Sturm, N and Borges, H and Biennier, S and Courçon, M and de Saint Loup, M and Mignot, V and Costentin, C and Burger, T and Couté, Y and Bruley, C and Decaens, T and Jaquinod, M and Boursier, J and Brun, V}, title = {Plasma ALS and Gal-3BP differentiate early from advanced liver fibrosis in MASLD patients.}, journal = {Biomarker research}, volume = {12}, number = {1}, pages = {44}, pmid = {38679739}, issn = {2050-7771}, support = {[ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-10-INBS-08]//ProFI project/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-17-EURE-0003]//Chemistry Biology Health (CBH) Graduate School at University Grenoble Alpes/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-15-IDEX-02]//LIFE project/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; [ANR-19-P3IA-0003]//MIAI @ Grenoble Alpes/ ; }, abstract = {BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is estimated to affect 30% of the world's population, and its prevalence is increasing in line with obesity. Liver fibrosis is closely related to mortality, making it the most important clinical parameter for MASLD. It is currently assessed by liver biopsy - an invasive procedure that has some limitations. There is thus an urgent need for a reliable non-invasive means to diagnose earlier MASLD stages.

METHODS: A discovery study was performed on 158 plasma samples from histologically-characterised MASLD patients using mass spectrometry (MS)-based quantitative proteomics. Differentially abundant proteins were selected for verification by ELISA in the same cohort. They were subsequently validated in an independent MASLD cohort (n = 200).

RESULTS: From the 72 proteins differentially abundant between patients with early (F0-2) and advanced fibrosis (F3-4), we selected Insulin-like growth factor-binding protein complex acid labile subunit (ALS) and Galectin-3-binding protein (Gal-3BP) for further study. In our validation cohort, AUROCs with 95% CIs of 0.744 [0.673 - 0.816] and 0.735 [0.661 - 0.81] were obtained for ALS and Gal-3BP, respectively. Combining ALS and Gal-3BP improved the assessment of advanced liver fibrosis, giving an AUROC of 0.796 [0.731. 0.862]. The {ALS; Gal-3BP} model surpassed classic fibrosis panels in predicting advanced liver fibrosis.

CONCLUSIONS: Further investigations with complementary cohorts will be needed to confirm the usefulness of ALS and Gal-3BP individually and in combination with other biomarkers for diagnosis of liver fibrosis. With the availability of ELISA assays, these findings could be rapidly clinically translated, providing direct benefits for patients.}, } @article {pmid38679111, year = {2024}, author = {Thulasidharan, A and Garg, L and Tendulkar, S and Ratnaparkhi, GS}, title = {Age-dependent dynamics of neuronal VAPB[ALS] inclusions in the adult brain.}, journal = {Neurobiology of disease}, volume = {196}, number = {}, pages = {106517}, doi = {10.1016/j.nbd.2024.106517}, pmid = {38679111}, issn = {1095-953X}, mesh = {Animals ; *Aging/metabolism/pathology/physiology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Animals, Genetically Modified ; Autophagy/physiology ; *Brain/metabolism/pathology ; Disease Models, Animal ; Drosophila ; *Drosophila Proteins/metabolism/genetics ; *Inclusion Bodies/metabolism/pathology ; Neurons/metabolism/pathology ; Valosin Containing Protein/metabolism/genetics ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a relentlessly progressive and fatal disease, caused by the degeneration of upper and lower motor neurons within the brain and spinal cord in the ageing human. The dying neurons contain cytoplasmic inclusions linked to the onset and progression of the disease. Here, we use a Drosophila model of ALS8 (VAP[P58S]) to understand the modulation of these inclusions in the ageing adult brain. The adult VAP[P58S] fly shows progressive deterioration in motor function till its demise 25 days post-eclosion. The density of VAP[P58S]-positive brain inclusions is stable for 5-15 days of age. In contrast, adding a single copy of VAP[WT] to the VAP[P58S] animal leads to a large decrease in inclusion density with concomitant rescue of motor function and lifespan. ER stress, a contributing factor in disease, shows reduction with ageing for the disease model. Autophagy, rather than the Ubiquitin Proteasome system, is the dominant mechanism for aggregate clearance. We explored the ability of Drosophila Valosin-containing protein (VCP/TER94), the ALS14 locus, which is involved in cellular protein clearance, to regulate age-dependent aggregation. Contrary to expectation, TER94 overexpression increased VAP[P58S] punctae density, while its knockdown led to enhanced clearance. Expression of a dominant positive allele, TER94[R152H], further stabilised VAP[P58S] puncta, cementing roles for an ALS8-ALS14 axis. Our results are explained by a mechanism where autophagy is modulated by TER94 knockdown. Our study sheds light on the complex regulatory events involved in the neuronal maintenance of ALS8 aggregates, suggesting a context-dependent switch between proteasomal and autophagy-based mechanisms as the larvae develop into an adult. A deeper understanding of the nucleation and clearance of the inclusions, which affect cellular stress and function, is essential for understanding the initiation and progression of ALS.}, } @article {pmid38678262, year = {2024}, author = {Xu, C and Mei, Y and Yang, R and Luo, Q and Zhang, J and Kou, X and Hu, J and Wang, Y and Li, Y and Chen, R and Zhang, Z and Yao, Y and Sima, J}, title = {Edaravone Dexborneol mitigates pathology in animal and cell culture models of Alzheimer's disease by inhibiting neuroinflammation and neuronal necroptosis.}, journal = {Cell & bioscience}, volume = {14}, number = {1}, pages = {55}, pmid = {38678262}, issn = {2045-3701}, support = {82173804//National Natural Science Foundation of China/ ; 82001144//National Natural Science Foundation of China/ ; 3150120042//High-Level Talents Start-up Funding of China Pharmaceutical University/ ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with limited disease-modifying treatments. Drug repositioning strategy has now emerged as a promising approach for anti-AD drug discovery. Using 5×FAD mice and Aβ-treated neurons in culture, we tested the efficacy of Y-2, a compounded drug containing the antioxidant Edaravone (Eda), a pyrazolone and (+)-Borneol, an anti-inflammatory diterpenoid from cinnamon, approved for use in amyotrophic lateral sclerosis patients.

RESULTS: We examined effects of Y-2 versus Eda alone by i.p. administered in 8-week-old 5×FAD mice (females) for 4 months by comparing cognitive function, Aβ pathologies, neuronal necroptosis and neuroinflammation. Using primary neurons and astrocytes, as well as neuronal and astrocytic cell lines, we elucidated the molecular mechanisms of Y-2 by examining neuronal injury, astrocyte-mediated inflammation and necroptosis. Here, we find that Y-2 improves cognitive function in AD mice. Histopathological data show that Y-2, better than Eda alone, markedly ameliorates Aβ pathologies including Aβ burden, astrogliosis/microgliosis, and Tau phosphorylation. In addition, Y-2 reduces Aβ-induced neuronal injury including neurite damage, mitochondrial impairment, reactive oxygen species production and NAD[+] depletion. Notably, Y-2 inhibits astrocyte-mediated neuroinflammation and attenuates TNF-α-triggered neuronal necroptosis in cell cultures and AD mice. RNA-seq further demonstrates that Y-2, compared to Eda, indeed upregulates anti-inflammation pathways in astrocytes.

CONCLUSIONS: Our findings infer that Y-2, better than Eda alone, mitigates AD pathology and may provide a potential drug candidate for AD treatment.}, } @article {pmid38677733, year = {2024}, author = {Keul, J and Sperling, S and Rohde, V and Mielke, D and Ninkovic, M}, title = {Riluzole Reverses a Number of Undesirable Effects of Dexamethasone in Glioblastoma Cells.}, journal = {Anticancer research}, volume = {44}, number = {5}, pages = {1829-1835}, doi = {10.21873/anticanres.16984}, pmid = {38677733}, issn = {1791-7530}, mesh = {*Riluzole/pharmacology ; Humans ; *Glioblastoma/drug therapy/pathology/metabolism ; *Dexamethasone/pharmacology ; *Cell Movement/drug effects ; Cell Line, Tumor ; Brain Neoplasms/drug therapy/pathology/metabolism ; Cell Survival/drug effects ; }, abstract = {BACKGROUND/AIM: Glioblastoma multiforme (GBM)-induced oedema is a major cause of morbidity and mortality among patients with GBM. Dexamethasone (Dex) is the most common corticosteroid used pre-operatively to control cerebral oedema in patients with GBM. Dex is associated with many side effects, and shorter overall survival and progression-free survival of patients with GBM. These negative effects of Dex highlight the need for combinational therapy. Riluzole (Ril), a drug used to treat amyotrophic lateral sclerosis (ALS), is thought to have potential as a treatment for various cancers, with clinical trials underway. Here, we investigated whether Ril could reverse some of the undesirable effects of Dex.

MATERIALS AND METHODS: The effect of Dex, Ril, and Ril-Dex treatment on cell migration was monitored using the xCELLigence system. Cell viability assays were performed using 3-(4, 5-dimethylthiazol)-2, 5-diphenyltetrazolium bromide (MTT). The expression of genes involved in migration, glucose metabolism, and stemness was examined using real-time polymerase chain reaction (PCR).

RESULTS: Pre-treating GBM cells with Ril reduced Dex-induced cell migration and altered Dex-induced effects on cell invasion, stem cell, and glucose metabolism markers. Furthermore, Ril remained effective in killing GBM cells in combination with Dex.

CONCLUSION: Ril, which acts as an anti-tumorigenic drug, mediates some of the negative effects of Dex; therefore, it could be a potential drug to manage the side effects of Dex therapy in GBM.}, } @article {pmid38677657, year = {2024}, author = {Ko, VI and Ong, K and Cleveland, DW and Yu, H and Ravits, JM}, title = {CK1δ/ε kinases regulate TDP-43 phosphorylation and are therapeutic targets for ALS-related TDP-43 hyperphosphorylation.}, journal = {Neurobiology of disease}, volume = {196}, number = {}, pages = {106516}, doi = {10.1016/j.nbd.2024.106516}, pmid = {38677657}, issn = {1095-953X}, mesh = {Phosphorylation ; *DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Humans ; *Casein Kinase Idelta/metabolism ; *Casein Kinase 1 epsilon/metabolism ; HEK293 Cells ; }, abstract = {Hyperphosphorylated TAR DNA-binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons is the neuropathological hallmark of amyotrophic lateral sclerosis (ALS) and a group of neurodegenerative diseases collectively referred to as TDP-43 proteinopathies that includes frontotemporal dementia, Alzheimer's disease, and limbic onset age-related TDP-43 encephalopathy. The mechanism of TDP-43 phosphorylation is poorly understood. Previously we reported casein kinase 1 epsilon gene (CSNK1E gene encoding CK1ε protein) as being tightly correlated with phosphorylated TDP-43 (pTDP-43) pathology. Here we pursued studies to investigate in cellular models and in vitro how CK1ε and CK1δ (a closely related family sub-member) mediate TDP-43 phosphorylation in disease. We first validated the binding interaction between TDP-43 and either CK1δ and CK1ε using kinase activity assays and predictive bioinformatic database. We utilized novel inducible cellular models that generated translocated phosphorylated TDP-43 (pTDP-43) and cytoplasmic aggregation. Reducing CK1 kinase activity with siRNA or small molecule chemical inhibitors resulted in significant reduction of pTDP-43, in both soluble and insoluble protein fractions. We also established CK1δ and CK1ε are the primary kinases that phosphorylate TDP-43 compared to CK2α, CDC7, ERK1/2, p38α/MAPK14, and TTBK1, other identified kinases that have been implicated in TDP-43 phosphorylation. Throughout our studies, we were careful to examine both the soluble and insoluble TDP-43 protein fractions, the critical protein fractions related to protein aggregation diseases. These results identify CK1s as critical kinases involved in TDP-43 hyperphosphorylation and aggregation in cellular models and in vitro, and in turn are potential therapeutic targets by way of CK1δ/ε inhibitors.}, } @article {pmid38676932, year = {2024}, author = {Oppegaard, KR and Mayo, SJ and Armstrong, TS and Dokiparthi, V and Melisko, M and Levine, JD and Olshen, AB and Anguera, JA and Roy, R and Paul, S and Cooper, B and Conley, YP and Hammer, MJ and Miaskowski, C and Kober, KM}, title = {Neurodegenerative disease pathways are perturbed in patients with cancer who self-report cognitive changes and anxiety: A pathway impact analysis.}, journal = {Cancer}, volume = {130}, number = {16}, pages = {2834-2847}, doi = {10.1002/cncr.35336}, pmid = {38676932}, issn = {1097-0142}, support = {T32NR016920/NR/NINR NIH HHS/United States ; CA134900/CA/NCI NIH HHS/United States ; CA233774/CA/NCI NIH HHS/United States ; CA082103/CA/NCI NIH HHS/United States ; //International Society of Nurses in Genetics/ ; //Sigma Theta Tau International Honor Society of Nursing-Alpha Eta Chapter/ ; T32NR016920/NR/NINR NIH HHS/United States ; 5U54CA156734-12//University of Massachusetts Boston-Dana-Farber/Harvard Cancer Center U54 Comprehensive Partnership for Cancer Health Disparities Research/ ; //Leavitt PhD Student Scholarship/ ; CA134900/CA/NCI NIH HHS/United States ; CA233774/CA/NCI NIH HHS/United States ; CA082103/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; *Anxiety ; Middle Aged ; *Neoplasms/psychology/complications ; *Neurodegenerative Diseases/psychology ; *Self Report ; Aged ; Signal Transduction ; Cognitive Dysfunction/etiology ; Adult ; }, abstract = {BACKGROUND: Cancer-related cognitive impairment (CRCI) and anxiety co-occur in patients with cancer. Little is known about mechanisms for the co-occurrence of these two symptoms. The purposes of this secondary analysis were to evaluate for perturbed pathways associated with the co-occurrence of self-reported CRCI and anxiety in patients with low versus high levels of these two symptoms and to identify potential mechanisms for the co-occurrence of CRCI and anxiety using biological processes common across any perturbed neurodegenerative disease pathways.

METHODS: Patients completed the Attentional Function Index and the Spielberger State-Trait Anxiety Inventory six times over two cycles of chemotherapy. Based on findings from a previous latent profile analysis, patients were grouped into none versus both high levels of these symptoms. Gene expression was quantified, and pathway impact analyses were performed. Signaling pathways for evaluation were defined with the Kyoto Encyclopedia of Genes and Genomes database.

RESULTS: A total of 451 patients had data available for analysis. Approximately 85.0% of patients were in the none class and 15.0% were in the both high class. Pathway impact analyses identified five perturbed pathways related to neurodegenerative diseases (i.e., amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, prion disease, and pathways of neurodegeneration-multiple diseases). Apoptosis, mitochondrial dysfunction, oxidative stress, and endoplasmic reticulum stress were common biological processes across these pathways.

CONCLUSIONS: This study is the first to describe perturbations in neurodegenerative disease pathways associated with CRCI and anxiety in patients receiving chemotherapy. These findings provide new insights into potential targets for the development of mechanistically based interventions.}, } @article {pmid38676818, year = {2024}, author = {Kubat, GB and Picone, P}, title = {Skeletal muscle dysfunction in amyotrophic lateral sclerosis: a mitochondrial perspective and therapeutic approaches.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {9}, pages = {4121-4131}, pmid = {38676818}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/pathology ; *Muscle, Skeletal/physiopathology/pathology ; Animals ; Mitochondria/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease that results in the loss of motor neurons and severe skeletal muscle atrophy. The etiology of ALS is linked to skeletal muscle, which can activate a retrograde signaling cascade that destroys motor neurons. This is why satellite cells and mitochondria play a crucial role in the health and performance of skeletal muscles. This review presents current knowledge on the involvement of mitochondrial dysfunction, skeletal muscle atrophy, muscle satellite cells, and neuromuscular junction (NMJ) in ALS. It also discusses current therapeutic strategies, including exercise, drugs, stem cells, gene therapy, and the prospective use of mitochondrial transplantation as a viable therapeutic strategy.}, } @article {pmid38676672, year = {2024}, author = {Kutlubaev, MA}, title = {[Promising approaches to the pathogenetic therapy of amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {4}, pages = {13-21}, doi = {10.17116/jnevro202412404113}, pmid = {38676672}, issn = {1997-7298}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Neuroprotective Agents/therapeutic use ; Genetic Therapy ; Antioxidants/therapeutic use ; Stem Cell Transplantation ; Gastrointestinal Microbiome ; Immunologic Factors/therapeutic use ; Immunomodulating Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis is a severe incurable disease of the nervous system. Currently only methods of palliative care for the patients with this disease are available. Few medications for the pathogenetic therapy are registered in some countries, i.e. riluzole, edaravon, sodium phenylbutyrate/taurursodiol as well as tofersen (conditionally). Their efficacy is relatively low. The main directions in the development of pathogenetic therapy of ALS include gene therapy, use of stem cells, immunomodulators, agents affecting gut microbiota. A search is also underway for low-molecular compounds with neuroprotective and antioxidant properties. Perspective direction is prevention of ALS. This will be possible when biomarkers for identification of patients in pre-manifest/prodromal stage are detected.}, } @article {pmid38676626, year = {2024}, author = {Dash, BP and Freischmidt, A and Weishaupt, JH and Hermann, A}, title = {An integrative miRNA-mRNA expression analysis identifies miRNA signatures associated with SOD1 and TARDBP patient-derived motor neurons.}, journal = {Human molecular genetics}, volume = {33}, number = {15}, pages = {1300-1314}, doi = {10.1093/hmg/ddae072}, pmid = {38676626}, issn = {1460-2083}, support = {//Hermann and Lilly Schilling-Stiftung für medizinische Forschung im Stifterverband/ ; //Professorinnenprogramm III (University of Rostock) of the German/ ; }, mesh = {*MicroRNAs/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Motor Neurons/metabolism/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; *RNA, Messenger/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Gene Expression Profiling ; Gene Expression Regulation/genetics ; Transcriptome/genetics ; }, abstract = {MicroRNAs (miRNAs) are a subset of small non-coding single-stranded RNA molecules involved in the regulation of post-transcriptional gene expression of a variety of transcript targets. Therefore altered miRNA expression may result in the dysregulation of key genes and biological pathways that has been reported with the onset and progression of neurodegenerative diseases, such as Amyotrophic lateral sclerosis (ALS). ALS is marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Although the pathomechanism underlying molecular interactions of ALS remains poorly understood, alterations in RNA metabolism, including dysregulation of miRNA expression in familial as well as sporadic forms are still scarcely studied. In this study, we performed combined transcriptomic data and miRNA profiling in MN samples of the same samples of iPSC-derived MNs from SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls. We report a global upregulation of mature miRNAs, and suggest that differentially expressed (DE) miRNAs have a significant impact on mRNA-level in SOD1-, but not in TARDBP-linked ALS. Furthermore, in SOD1-ALS we identified dysregulated miRNAs such as miR-124-3p, miR-19b-3p and miR-218 and their potential targets previously implicated in important functional process and pathogenic pathways underlying ALS. These miRNAs may play key roles in the neuronal development and cell survival related functions in SOD1-ALS. Altogether, we provide evidence of miRNA regulated genes expression mainly in SOD1 rather than TDP43-ALS.}, } @article {pmid38676602, year = {2024}, author = {Presotto, A and Hernández, F and Vercellino, RB and Kruger, RD and Fontana, ML and Ureta, MS and Crepy, M and Auge, G and Caicedo, A}, title = {Introgression from local cultivars is a driver of agricultural adaptation in Argentinian weedy rice.}, journal = {Molecular ecology}, volume = {33}, number = {11}, pages = {e17368}, doi = {10.1111/mec.17368}, pmid = {38676602}, issn = {1365-294X}, support = {IOS-1032023//Division of Integrative Organismal Systems/ ; PICT 2019-00581//Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación/ ; }, mesh = {*Oryza/genetics ; *Herbicide Resistance/genetics ; Argentina ; *Acetolactate Synthase/genetics ; *Herbicides ; Plant Weeds/genetics ; Phenotype ; Genotype ; Adaptation, Physiological/genetics ; Crops, Agricultural/genetics ; Gene Flow ; Agriculture ; Mutation ; }, abstract = {Weedy rice, a pervasive and troublesome weed found across the globe, has often evolved through fertilization of rice cultivars with little importance of crop-weed gene flow. In Argentina, weedy rice has been reported as an important constraint since the early 1970s, and, in the last few years, strains with herbicide-resistance are suspected to evolve. Despite their importance, the origin and genetic composition of Argentinian weedy rice as well its adaptation to agricultural environments has not been explored so far. To study this, we conducted genotyping-by-sequencing on samples of Argentinian weedy and cultivated rice and compared them with published data from weedy, cultivated and wild rice accessions distributed worldwide. In addition, we conducted a phenotypic characterization for weedy-related traits, a herbicide resistance screening and genotyped accessions for known mutations in the acetolactate synthase (ALS) gene, which confers herbicide resistance. Our results revealed large phenotypic variability in Argentinian weedy rice. Most strains were resistant to ALS-inhibiting herbicides with a high frequency of the ALS mutation (A122T) present in Argentinian rice cultivars. Argentinian cultivars belonged to the three major genetic groups of rice: japonica, indica and aus while weeds were mostly aus or aus-indica admixed, resembling weedy rice strains from the Southern Cone region. Phylogenetic analysis supports a single origin for aus-like South American weeds, likely as seed contaminants from the United States, and then admixture with local indica cultivars. Our findings demonstrate that crop to weed introgression can facilitate rapid adaptation to agriculture environments.}, } @article {pmid38676303, year = {2024}, author = {Zhao, W and Wang, R and Chen, M}, title = {Clinical analysis of air-leak syndrome following allogeneic hematopoietic stem cell transplantation in pediatric patients.}, journal = {Pediatric blood & cancer}, volume = {71}, number = {7}, pages = {e31008}, doi = {10.1002/pbc.31008}, pmid = {38676303}, issn = {1545-5017}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Male ; Female ; Retrospective Studies ; Child ; Child, Preschool ; Adolescent ; Infant ; Prognosis ; Survival Rate ; Follow-Up Studies ; Transplantation, Homologous ; Bronchiolitis Obliterans/etiology/mortality/therapy ; Pneumonia/etiology/mortality ; }, abstract = {BACKGROUND: Air-leak syndrome (ALS) is considered as an independent risk factor for poor prognosis in adult patients who had received hematopoietic stem cell transplantation (HSCT), and the 5-year overall survival (OS) of ALS is less than 30%. However, the clinical features of ALS among post-transplant pediatric patients have rarely been explored.

PROCEDURES: We retrospectively reviewed 2206 pediatric patients who had received an allo-HSCT between January 2013 and December 2019 at the Hebei Yanda Lu Daopei Hospital, and analyzed the role of ALS in prognosis following HSCT.

RESULTS: In our research, ALS was divided into two categories: 15 cases of bronchiolitis obliterans syndrome (BOS) and 13 cases of idiopathic pneumonia syndrome (IPS). Following treatment of the ALS, 18 patients survived (18/28, 64.3%), and 10 patients died of respiratory failure or infection (10/28, 35.7%).

CONCLUSIONS: The OS of ALS in Hebei Yanda Lu Daopei Hospital is significantly higher than others, and they were cited to be related to early diagnosis and timely FAM treatment in previous reports.}, } @article {pmid38675428, year = {2024}, author = {Calenda, S and Catarzi, D and Varano, F and Vigiani, E and Volpini, R and Lambertucci, C and Spinaci, A and Trevisan, L and Grieco, I and Federico, S and Spalluto, G and Novello, G and Salmaso, V and Moro, S and Colotta, V}, title = {Structural Investigations on 2-Amidobenzimidazole Derivatives as New Inhibitors of Protein Kinase CK1 Delta.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {4}, pages = {}, pmid = {38675428}, issn = {1424-8247}, support = {RICATEN2021-2023Colotta//University of Florence/ ; 2017MT3993_004//Italian Ministry of University and Research-PRIN2017/ ; }, abstract = {Protein kinase CK1δ (CK1δ) is a serine-threonine/kinase that modulates different physiological processes, including the cell cycle, DNA repair, and apoptosis. CK1δ overexpression, and the consequent hyperphosphorylation of specific proteins, can lead to sleep disorders, cancer, and neurodegenerative diseases. CK1δ inhibitors showed anticancer properties as well as neuroprotective effects in cellular and animal models of Parkinson's and Alzheimer's diseases and amyotrophic lateral sclerosis. To obtain new ATP-competitive CK1δ inhibitors, three sets of benzimidazole-2-amino derivatives were synthesized (1-32), bearing different substituents on the fused benzo ring (R) and diverse pyrazole-containing acyl moieties on the 2-amino group. The best-performing derivatives were those featuring the (1H-pyrazol-3-yl)-acetyl moiety on the benzimidazol-2-amino scaffold (13-32), which showed CK1δ inhibitor activity in the low micromolar range. Among the R substituents, 5-cyano was the most advantageous, leading to a compound endowed with nanomolar potency (23, IC50 = 98.6 nM). Molecular docking and dynamics studies were performed to point out the inhibitor-kinase interactions.}, } @article {pmid38674921, year = {2024}, author = {Wang, W and Pan, D and Liu, Q and Chen, X and Wang, S}, title = {L-Carnitine in the Treatment of Psychiatric and Neurological Manifestations: A Systematic Review.}, journal = {Nutrients}, volume = {16}, number = {8}, pages = {}, pmid = {38674921}, issn = {2072-6643}, mesh = {Humans ; *Carnitine/therapeutic use ; Dietary Supplements ; *Mental Disorders/drug therapy ; *Nervous System Diseases/drug therapy ; }, abstract = {OBJECTIVE: L-carnitine (LC), a vital nutritional supplement, plays a crucial role in myocardial health and exhibits significant cardioprotective effects. LC, being the principal constituent of clinical-grade supplements, finds extensive application in the recovery and treatment of diverse cardiovascular and cerebrovascular disorders. However, controversies persist regarding the utilization of LC in nervous system diseases, with varying effects observed across numerous mental and neurological disorders. This article primarily aims to gather and analyze database information to comprehensively summarize the therapeutic potential of LC in patients suffering from nervous system diseases while providing valuable references for further research.

METHODS: A comprehensive search was conducted in PubMed, Web Of Science, Embase, Ovid Medline, Cochrane Library and Clinicaltrials.gov databases. The literature pertaining to the impact of LC supplementation on neurological or psychiatric disorders in patients was reviewed up until November 2023. No language or temporal restrictions were imposed on the search.

RESULTS: A total of 1479 articles were retrieved, and after the removal of duplicates through both automated and manual exclusion processes, 962 articles remained. Subsequently, a meticulous re-screening led to the identification of 60 relevant articles. Among these, there were 12 publications focusing on hepatic encephalopathy (HE), while neurodegenerative diseases (NDs) and peripheral nervous system diseases (PNSDs) were represented by 9 and 6 articles, respectively. Additionally, stroke was addressed in five publications, whereas Raynaud's syndrome (RS) and cognitive disorder (CD) each had three dedicated studies. Furthermore, migraine, depression, and amyotrophic lateral sclerosis (ALS) each accounted for two publications. Lastly, one article was found for other symptoms under investigation.

CONCLUSION: In summary, LC has demonstrated favorable therapeutic effects in the management of HE, Alzheimer's disease (AD), carpal tunnel syndrome (CTS), CD, migraine, neurofibromatosis (NF), PNSDs, RS, and stroke. However, its efficacy appears to be relatively limited in conditions such as ALS, ataxia, attention deficit hyperactivity disorder (ADHD), depression, chronic fatigue syndrome (CFS), Down syndrome (DS), and sciatica.}, } @article {pmid38674548, year = {2024}, author = {Bai, L and Li, X and Guo, X and Chen, J and Yu, H and Cui, H}, title = {Distribution and Mechanism of Japanese Brome (Bromus japonicus) Resistance to ALS-Inhibiting Herbicides in China.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {8}, pages = {}, pmid = {38674548}, issn = {2223-7747}, support = {2023YFD1400501//National Key Research and Development Program of China and Technology Innovation Project, Chinese Academy of Agricultural Sciences./ ; }, abstract = {Bromus japonicus is a common monocot weed that occurs in major winter wheat fields in the Huang-Huai-Hai region of China. Pyroxsulam is a highly efficient and safe acetolactate synthase (ALS)-inhibiting herbicide that is widely used to control common weeds in wheat fields. However, B. japonicus populations in China have evolved resistance to pyroxsulam by different mutations in the ALS gene. To understand the resistance distribution, target-site resistance mechanisms, and cross-resistance patterns, 208 B. japonicus populations were collected from eight provinces. In the resistant population screening experiment, 59 populations from six provinces showed different resistance levels to pyroxsulam compared with the susceptible population, of which 17 B. japonicus populations with moderate or high levels of resistance to pyroxsulam were mainly from the Hebei (4), Shandong (4) and Shanxi (9) Provinces. Some resistant populations were selected to investigate the target site-resistance mechanism to the ALS-inhibiting herbicide pyroxsulam. Three pairs of primers were designed to amplify the ALS sequence, which was assembled into the complete ALS sequence with a length of 1932 bp. DNA sequencing of ALS revealed that four different ALS mutations (Pro-197-Ser, Pro-197-Thr, Pro-197-Phe and Asp-376-Glu) were found in 17 moderately or highly resistant populations. Subsequently, five resistant populations, QM21-41 with Pro-197-Ser, QM20-8 with Pro-197-Thr and Pro-197-Phe, and QM21-72, QM21-76 and QM21-79 with Asp-376-Glu mutations in ALS genes, were selected to characterize their cross-resistance patterns to ALS inhibitors. The QM21-41, QM20-8, QM21-72, QM21-76 and QM21-79 populations showed broad-spectrum cross-resistance to pyroxsulam, mesosulfuron-methyl and flucarbazone-sodium. This study is the first to report evolving cross-resistance to ALS-inhibiting herbicides due to Pro-197-Phe mutations in B. japonicus.}, } @article {pmid38674431, year = {2024}, author = {Shahim, P and Norato, G and Sinaii, N and Zetterberg, H and Blennow, K and Chan, L and Grunseich, C}, title = {Neurofilaments in Sporadic and Familial Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {Genes}, volume = {15}, number = {4}, pages = {}, pmid = {38674431}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood/diagnosis/cerebrospinal fluid ; Humans ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Biomarkers/blood/cerebrospinal fluid ; Intermediate Filaments/metabolism/genetics ; Prognosis ; }, abstract = {BACKGROUND: Neurofilament proteins have been implicated to be altered in amyotrophic lateral sclerosis (ALS). The objectives of this study were to assess the diagnostic and prognostic utility of neurofilaments in ALS.

METHODS: Studies were conducted in electronic databases (PubMed/MEDLINE, Embase, Web of Science, and Cochrane CENTRAL) from inception to 17 August 2023, and investigated neurofilament light (NfL) or phosphorylated neurofilament heavy chain (pNfH) in ALS. The study design, enrolment criteria, neurofilament concentrations, test accuracy, relationship between neurofilaments in cerebrospinal fluid (CSF) and blood, and clinical outcome were recorded. The protocol was registered with PROSPERO, CRD42022376939.

RESULTS: Sixty studies with 8801 participants were included. Both NfL and pNfH measured in CSF showed high sensitivity and specificity in distinguishing ALS from disease mimics. Both NfL and pNfH measured in CSF correlated with their corresponding levels in blood (plasma or serum); however, there were stronger correlations between CSF NfL and blood NfL. NfL measured in blood exhibited high sensitivity and specificity in distinguishing ALS from controls. Both higher levels of NfL and pNfH either measured in blood or CSF were correlated with more severe symptoms as assessed by the ALS Functional Rating Scale Revised score and with a faster disease progression rate; however, only blood NfL levels were associated with shorter survival.

DISCUSSION: Both NfL and pNfH measured in CSF or blood show high diagnostic utility and association with ALS functional scores and disease progression, while CSF NfL correlates strongly with blood (either plasma or serum) and is also associated with survival, supporting its use in clinical diagnostics and prognosis. Future work must be conducted in a prospective manner with standardized bio-specimen collection methods and analytical platforms, further improvement in immunoassays for quantification of pNfH in blood, and the identification of cut-offs across the ALS spectrum and controls.}, } @article {pmid38672445, year = {2024}, author = {Esperante, IJ and Meyer, M and Banzan, C and Kruse, MS and Lima, A and Roig, P and Guennoun, R and Schumacher, M and De Nicola, AF and Gonzalez Deniselle, MC}, title = {Testosterone Reduces Myelin Abnormalities in the Wobbler Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Biomolecules}, volume = {14}, number = {4}, pages = {}, pmid = {38672445}, issn = {2218-273X}, support = {PICT 2019 Nº 3292//Ministerio de Ciencia, Tecnología e Innovación/ ; PIP 2022-2024 #11220210100091CO//CONICET/ ; }, mesh = {Animals ; Mice ; *Myelin Sheath/metabolism/drug effects ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Male ; *Disease Models, Animal ; *Testosterone/pharmacology ; Spinal Cord/metabolism/drug effects/pathology ; Excitatory Amino Acid Transporter 2/metabolism/genetics ; Microglia/drug effects/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron degenerative disease that is associated with demyelination. The Wobbler (WR) mouse exhibits motoneuron degeneration, gliosis and myelin deterioration in the cervical spinal cord. Since male WRs display low testosterone (T) levels in the nervous system, we investigated if T modified myelin-relative parameters in WRs in the absence or presence of the aromatase inhibitor, anastrozole (A). We studied myelin by using luxol-fast-blue (LFB) staining, semithin sections, electron microscopy and myelin protein expression, density of IBA1[+] microglia and mRNA expression of inflammatory factors, and the glutamatergic parameters glutamine synthetase (GS) and the transporter GLT1. Controls and WR + T showed higher LFB, MBP and PLP staining, lower g-ratios and compact myelin than WRs and WR + T + A, and groups showing the rupture of myelin lamellae. WRs showed increased IBA1[+] cells and mRNA for CD11b and inflammatory factors (IL-18, TLR4, TNFαR1 and P2Y12R) vs. controls or WR + T. IBA1[+] cells, and CD11b were not reduced in WR + T + A, but inflammatory factors' mRNA remained low. A reduction of GS[+] cells and GLT-1 immunoreactivity was observed in WRs and WR + T + A vs. controls and WR + T. Clinically, WR + T but not WR + T + A showed enhanced muscle mass, grip strength and reduced paw abnormalities. Therefore, T effects involve myelin protection, a finding of potential clinical translation.}, } @article {pmid38672428, year = {2024}, author = {Cox, SN and Lo Giudice, C and Lavecchia, A and Poeta, ML and Chiara, M and Picardi, E and Pesole, G}, title = {Mitochondrial and Nuclear DNA Variants in Amyotrophic Lateral Sclerosis: Enrichment in the Mitochondrial Control Region and Sirtuin Pathway Genes in Spinal Cord Tissue.}, journal = {Biomolecules}, volume = {14}, number = {4}, pages = {}, pmid = {38672428}, issn = {2218-273X}, support = {UNIBA148- project code C1A93B75-CUP H94I20000410008//Research for Innovation (REFIN)-POR PUGLIA FESR-FSE 2014/2020/ ; CN_00000013//National Research Centers: "High Performance Computing, Big Data and Quantum Computing"/ ; CN_00000041//National Research Centers: "Gene Therapy and Drugs based on RNA Technology"/ ; PE_0000006//National Research Centers-Extended Partnerships: MNESYS/ ; IR0000010//ELIXIR-IT ELIXIRNextGenIT/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Spinal Cord/metabolism/pathology ; *DNA, Mitochondrial/genetics ; *Sirtuins/genetics/metabolism ; Male ; Female ; Middle Aged ; Mitochondria/genetics/metabolism ; Cell Nucleus/genetics/metabolism ; Aged ; Exome Sequencing ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive disease with prevalent mitochondrial dysfunctions affecting both upper and lower motor neurons in the motor cortex, brainstem, and spinal cord. Despite mitochondria having their own genome (mtDNA), in humans, most mitochondrial genes are encoded by the nuclear genome (nDNA). Our study aimed to simultaneously screen for nDNA and mtDNA genomes to assess for specific variant enrichment in ALS compared to control tissues. Here, we analysed whole exome (WES) and whole genome (WGS) sequencing data from spinal cord tissues, respectively, of 6 and 12 human donors. A total of 31,257 and 301,241 variants in nuclear-encoded mitochondrial genes were identified from WES and WGS, respectively, while mtDNA reads accounted for 73 and 332 variants. Despite technical differences, both datasets consistently revealed a specific enrichment of variants in the mitochondrial Control Region (CR) and in several of these genes directly associated with mitochondrial dynamics or with Sirtuin pathway genes within ALS tissues. Overall, our data support the hypothesis of a variant burden in specific genes, highlighting potential actionable targets for therapeutic interventions in ALS.}, } @article {pmid38672416, year = {2024}, author = {Cheslow, L and Snook, AE and Waldman, SA}, title = {Biomarkers for Managing Neurodegenerative Diseases.}, journal = {Biomolecules}, volume = {14}, number = {4}, pages = {}, pmid = {38672416}, issn = {2218-273X}, support = {F30 NS125921/NS/NINDS NIH HHS/United States ; 1R01 CA204881, 1R01 CA206026, 1R21 1NS130388, 1R01 DK1388341/NH/NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/metabolism/diagnosis/therapy ; *Alzheimer Disease/metabolism/diagnosis/therapy ; Amyotrophic Lateral Sclerosis/metabolism/therapy/diagnosis ; Parkinson Disease/metabolism/diagnosis/therapy ; Animals ; }, abstract = {Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track responses to therapy, and parse the causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD).}, } @article {pmid38672412, year = {2024}, author = {Lachén-Montes, M and Cartas-Cejudo, P and Cortés, A and Anaya-Cubero, E and Peral, E and Ausín, K and Díaz-Peña, R and Fernández-Irigoyen, J and Santamaría, E}, title = {Involvement of Glucosamine 6 Phosphate Isomerase 2 (GNPDA2) Overproduction in β-Amyloid- and Tau P301L-Driven Pathomechanisms.}, journal = {Biomolecules}, volume = {14}, number = {4}, pages = {}, pmid = {38672412}, issn = {2218-273X}, support = {0011-1411-2020-000028 and 0011-1411-2023-000028//Gobierno de Navarra/ ; PID2019-110356RB-I00/AEI/10.13039/501100011033//Spanish Ministry of Science, Innovation and Universities/ ; }, mesh = {Animals ; Humans ; *Aldose-Ketose Isomerases/metabolism/genetics ; *Alzheimer Disease/metabolism/genetics/pathology ; *Amyloid beta-Peptides/metabolism ; Animals, Genetically Modified ; Cell Proliferation ; Epithelial Cells/metabolism ; Proteomics ; *tau Proteins/metabolism/genetics ; *Zebrafish/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative olfactory disorder affecting millions of people worldwide. Alterations in the hexosamine- or glucose-related pathways have been described through AD progression. Specifically, an alteration in glucosamine 6 phosphate isomerase 2 (GNPDA2) protein levels has been observed in olfactory areas of AD subjects. However, the biological role of GNPDA2 in neurodegeneration remains unknown. Using mass spectrometry, multiple GNPDA2 interactors were identified in human nasal epithelial cells (NECs) mainly involved in intraciliary transport. Moreover, GNPDA2 overexpression induced an increment in NEC proliferation rates, accompanied by transcriptomic alterations in Type II interferon signaling or cellular stress responses. In contrast, the presence of beta-amyloid or mutated Tau-P301L in GNPDA2-overexpressing NECs induced a slowdown in the proliferative capacity in parallel with a disruption in protein processing. The proteomic characterization of Tau-P301L transgenic zebrafish embryos demonstrated that GNPDA2 overexpression interfered with collagen biosynthesis and RNA/protein processing, without inducing additional changes in axonal outgrowth defects or neuronal cell death. In humans, a significant increase in serum GNPDA2 levels was observed across multiple neurological proteinopathies (AD, Lewy body dementia, progressive supranuclear palsy, mixed dementia and amyotrophic lateral sclerosis) (n = 215). These data shed new light on GNPDA2-dependent mechanisms associated with the neurodegenerative process beyond the hexosamine route.}, } @article {pmid38671434, year = {2024}, author = {Ohlenburg, H and Arnemann, PH and Hessler, M and Görlich, D and Zarbock, A and Friederichs, H}, title = {Flipped Classroom: Improved team performance during resuscitation training through interactive pre-course content - a cluster-randomised controlled study.}, journal = {BMC medical education}, volume = {24}, number = {1}, pages = {459}, pmid = {38671434}, issn = {1472-6920}, mesh = {Humans ; *Patient Care Team ; *Resuscitation/education ; Female ; Male ; *Curriculum ; Germany ; Clinical Competence ; Problem-Based Learning ; Students, Medical ; Education, Medical, Undergraduate/methods ; Adult ; Educational Measurement ; Simulation Training ; }, abstract = {BACKGROUND: Resuscitation is a team effort, and it is increasingly acknowledged that team cooperation requires training. Staff shortages in many healthcare systems worldwide, as well as recent pandemic restrictions, limit opportunities for collaborative team training. To address this challenge, a learner-centred approach known as flipped learning has been successfully implemented. This model comprises self-directed, asynchronous pre-course learning, followed by knowledge application and skill training during in-class sessions. The existing evidence supports the effectiveness of this approach for the acquisition of cognitive skills, but it is uncertain whether the flipped classroom model is suitable for the acquisition of team skills. The objective of this study was to determine if a flipped classroom approach, with an online workshop prior to an instructor-led course could improve team performance and key resuscitation variables during classroom training.

METHODS: A single-centre, cluster-randomised, rater-blinded study was conducted on 114 final year medical students at a University Hospital in Germany. The study randomly assigned students to either the intervention or control group using a computer script. Each team, regardless of group, performed two advanced life support (ALS) scenarios on a simulator. The two groups differed in the order in which they completed the flipped e-learning curriculum. The intervention group started with the e-learning component, and the control group started with an ALS scenario. Simulators were used for recording and analysing resuscitation performance indicators, while professionals assessed team performance as a primary outcome.

RESULTS: The analysis was conducted on the data of 96 participants in 21 teams, comprising of 11 intervention groups and 10 control groups. The intervention teams achieved higher team performance ratings during the first scenario compared to the control teams (Estimated marginal mean of global rating: 7.5 vs 5.6, p < 0.01; performance score: 4.4 vs 3.8, p < 0.05; global score: 4.4 vs 3.7, p < 0.001). However, these differences were not observed in the second scenario, where both study groups had used the e-learning tool.

CONCLUSION: Flipped classroom approaches using learner-paced e-learning prior to hands-on training can improve team performance.

TRIAL REGISTRATION: German Clinical Trials Register (https://drks.de/search/de/trial/DRKS00013096).}, } @article {pmid38671062, year = {2024}, author = {Angrick, M and Luo, S and Rabbani, Q and Candrea, DN and Shah, S and Milsap, GW and Anderson, WS and Gordon, CR and Rosenblatt, KR and Clawson, L and Tippett, DC and Maragakis, N and Tenore, FV and Fifer, MS and Hermansky, H and Ramsey, NF and Crone, NE}, title = {Online speech synthesis using a chronically implanted brain-computer interface in an individual with ALS.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {9617}, pmid = {38671062}, issn = {2045-2322}, support = {UH3 NS114439/NS/NINDS NIH HHS/United States ; NS114439/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Brain-Computer Interfaces ; *Amyotrophic Lateral Sclerosis/physiopathology/therapy ; Male ; *Speech/physiology ; Middle Aged ; Electrodes, Implanted ; Electrocorticography ; }, abstract = {Brain-computer interfaces (BCIs) that reconstruct and synthesize speech using brain activity recorded with intracranial electrodes may pave the way toward novel communication interfaces for people who have lost their ability to speak, or who are at high risk of losing this ability, due to neurological disorders. Here, we report online synthesis of intelligible words using a chronically implanted brain-computer interface (BCI) in a man with impaired articulation due to ALS, participating in a clinical trial (ClinicalTrials.gov, NCT03567213) exploring different strategies for BCI communication. The 3-stage approach reported here relies on recurrent neural networks to identify, decode and synthesize speech from electrocorticographic (ECoG) signals acquired across motor, premotor and somatosensory cortices. We demonstrate a reliable BCI that synthesizes commands freely chosen and spoken by the participant from a vocabulary of 6 keywords previously used for decoding commands to control a communication board. Evaluation of the intelligibility of the synthesized speech indicates that 80% of the words can be correctly recognized by human listeners. Our results show that a speech-impaired individual with ALS can use a chronically implanted BCI to reliably produce synthesized words while preserving the participant's voice profile, and provide further evidence for the stability of ECoG for speech-based BCIs.}, } @article {pmid38670927, year = {2024}, author = {Quinn, C and Baer, M and Amado, DA and Kelley, M and Elman, L}, title = {A single ALS center experience with clinical use of sodium phenylbutyrate-taurursodiol.}, journal = {Muscle & nerve}, volume = {70}, number = {1}, pages = {148-151}, doi = {10.1002/mus.28096}, pmid = {38670927}, issn = {1097-4598}, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy ; Middle Aged ; Aged ; Phenylbutyrates/therapeutic use ; Adult ; Retrospective Studies ; Drug Combinations ; }, abstract = {INTRODUCTION/AIMS: The aim of this study was to examine clinical utilization and discontinuation rates of sodium phenylbutyrate-taurursodiol (PB-TURSO) in a single Amyotrophic Lateral Sclerosis (ALS) center. PB-TURSO was approved by the United States Food and Drug Administration (FDA) in September 2022. Prior experience has been limited to clinical trials or expanded access protocols. In this manuscript, we discuss insurance approval rates, patient uptake, and discontinuation of PB-TURSO in a large academic center.

METHODS: Records of patients seen for clinical visits between January 2022 and May 2023 were reviewed. Demographic and clinical characteristics of our clinic population and those initiating PB-TURSO were obtained from our clinical database.

RESULTS: A total of 228 patients were seen during the observation period and 122 requested PB-TURSO prescriptions. 77% (94) were approved by insurance. 66% (65) of those who were approved or received free drug chose to start medication. 51% (34) of those who initiated PB-TURSO continued to take it through the end of the observation period. Four patients discontinued due to death during the observation period. Of the 29 patients who survived and discontinued, the main reasons for discontinuation were GI symptoms (17, 58.6%) and taste (8, 29.6%).

DISCUSSION: PB-TURSO was approved by insurance for most patients. The discontinuation rate was high and was driven largely by GI side effects and taste. Future considerations would include deeper examination of demographic trends, patient costs, side effects, and potential benefits in clinical practice.}, } @article {pmid38670433, year = {2024}, author = {Sitruk-Ware, R and Sussman, H and Brinton, R and Schumacher, M and Singer, P and Kumar, N and De Nicola, AF and El-Etr, M and Guennoun, R and V Borlongan, C}, title = {Nestorone (segesterone acetate) effects on neuroregeneration.}, journal = {Frontiers in neuroendocrinology}, volume = {73}, number = {}, pages = {101136}, doi = {10.1016/j.yfrne.2024.101136}, pmid = {38670433}, issn = {1095-6808}, mesh = {Animals ; Humans ; *Norprogesterones/pharmacology ; *Neuroprotective Agents/pharmacology ; Nerve Regeneration/drug effects/physiology ; Female ; }, abstract = {Nestorone® (segesterone acetate) is a progestin with a chemical structure closely related to progesterone with high affinity and selectivity for the progesterone receptor without significant interaction with other steroid receptors. It has been developed for female and male contraception and is FDA-approved in a first long-acting contraceptive vaginal system for female contraception. Its safety has been extensively demonstrated in both preclinical and clinical studies for contraceptive indications. Nestorone was found to display neuroprotective and neuroregenerative activity in animal models of various central nervous system diseases, including multiple sclerosis, stroke, and amyotrophic lateral sclerosis. Reviewed herein are neuroprotective and myelin- regenerating properties of Nestorone in various animal models and its translational potential as a therapeutic agent for debilitating neurological diseases for which limited therapeutic options are available (Table 1).}, } @article {pmid38668754, year = {2024}, author = {Dogan, M and Teralı, K and Eroz, R and Kılıç, H and Gezdirici, A and Gönüllü, B}, title = {Discovery of a novel homozygous SOD1 truncating variant bolsters infantile SOD1 deficiency syndrome.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {580}, pmid = {38668754}, issn = {1573-4978}, mesh = {Child ; Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics ; Exome Sequencing ; Homozygote ; Pedigree ; Phenotype ; *Superoxide Dismutase-1/genetics ; Turkey ; Adolescent ; }, abstract = {OBJECTIVE: Superoxide dismutase 1 (SOD1) is an important antioxidant enzyme whose main function is to neutralise superoxide free radicals in the cytoplasm. Heterozygous variants in SOD1 are responsible for a substantial percentage of familial amyotrophic lateral sclerosis (ALS) cases. Recently, several reports have shown that biallelic loss of SOD1 function results in a novel phenotype called infantile SOD1 deficiency syndrome, which is consistent with a recessive pattern of inheritance and can be distinguished from typical (adult-onset) ALS.

METHODS: We documented detailed family histories and clinical data, followed by whole-exome sequencing and family co-segregation analysis through Sanger sequencing. To facilitate comparisons, relevant data from fifteen previously reported patients with SOD1-related neurodevelopmental disorders were included.

RESULTS: This study presents a new Turkish family with two affected children exhibiting severe delayed motor development, infancy-onset loss of motor skills, axial hypotonia, tetraspasticity, and impaired cognitive functions. Genetic analysis revealed a novel homozygous frameshift variant in SOD1 (c.248dupG [p.Asp84Argfs*8]), with computational biochemical studies shedding light on the mechanistic aspects of SOD1 dysfunction.

CONCLUSIONS: Our findings contribute an affirmative report of a fourth biallelic variant resulting in a severe clinical phenotype, reminiscent of those induced by previously identified homozygous loss-of-function SOD1 variants. This research not only advances our understanding of the pathogenesis of this debilitating neurological syndrome but also aligns with ongoing intensive efforts to comprehend and address SOD1-linked ALS.}, } @article {pmid38667292, year = {2024}, author = {Ruffo, P and De Amicis, F and La Bella, V and Conforti, FL}, title = {Investigating Repeat Expansions in NIPA1, NOP56, and NOTCH2NLC Genes: A Closer Look at Amyotrophic Lateral Sclerosis Patients from Southern Italy.}, journal = {Cells}, volume = {13}, number = {8}, pages = {}, pmid = {38667292}, issn = {2073-4409}, support = {ex60%//Ministry for Instruction, University and Research/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; Case-Control Studies ; DNA Repeat Expansion/genetics ; Genetic Predisposition to Disease ; Italy ; Nuclear Proteins/genetics ; }, abstract = {The discovery of hexanucleotide repeats expansion (RE) in Chromosome 9 Open Reading frame 72 (C9orf72) as the major genetic cause of amyotrophic lateral sclerosis (ALS) and the association between intermediate repeats in Ataxin-2 (ATXN2) with the disorder suggest that repetitive sequences in the human genome play a significant role in ALS pathophysiology. Investigating the frequency of repeat expansions in ALS in different populations and ethnic groups is therefore of great importance. Based on these premises, this study aimed to define the frequency of REs in the NIPA1, NOP56, and NOTCH2NLC genes and the possible associations between phenotypes and the size of REs in the Italian population. Using repeat-primed-PCR and PCR-fragment analyses, we screened 302 El-Escorial-diagnosed ALS patients and compared the RE distribution to 167 age-, gender-, and ethnicity-matched healthy controls. While the REs distribution was similar between the ALS and control groups, a moderate association was observed between longer RE lengths and clinical features such as age at onset, gender, site of onset, and family history. In conclusion, this is the first study to screen ALS patients from southern Italy for REs in NIPA1, NOP56, and NOTCH2NLC genes, contributing to our understanding of ALS genetics. Our results highlighted that the extremely rare pathogenic REs in these genes do not allow an association with the disease.}, } @article {pmid38667285, year = {2024}, author = {Alzahrani, FA and Riza, YM and Eid, TM and Almotairi, R and Scherschinski, L and Contreras, J and Nadeem, M and Perez, SE and Raikwar, SP and Jha, RM and Preul, MC and Ducruet, AF and Lawton, MT and Bhatia, K and Akhter, N and Ahmad, S}, title = {Exosomes in Vascular/Neurological Disorders and the Road Ahead.}, journal = {Cells}, volume = {13}, number = {8}, pages = {}, pmid = {38667285}, issn = {2073-4409}, mesh = {*Exosomes/metabolism ; Humans ; Animals ; Neurodegenerative Diseases/metabolism/pathology ; Vascular Diseases/metabolism/pathology ; Nervous System Diseases/metabolism/pathology ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and aneurysms, are characterized by the abnormal accumulation and aggregation of disease-causing proteins in the brain and spinal cord. Recent research suggests that proteins linked to these conditions can be secreted and transferred among cells using exosomes. The transmission of abnormal protein buildup and the gradual degeneration in the brains of impacted individuals might be supported by these exosomes. Furthermore, it has been reported that neuroprotective functions can also be attributed to exosomes in neurodegenerative diseases. The potential neuroprotective functions may play a role in preventing the formation of aggregates and abnormal accumulation of proteins associated with the disease. The present review summarizes the roles of exosomes in neurodegenerative diseases as well as elucidating their therapeutic potential in AD, PD, ALS, HD, stroke, and aneurysms. By elucidating these two aspects of exosomes, valuable insights into potential therapeutic targets for treating neurodegenerative diseases may be provided.}, } @article {pmid38666827, year = {2024}, author = {Ismail, M and Großmann, D and Hermann, A}, title = {Increased Vulnerability to Ferroptosis in FUS-ALS.}, journal = {Biology}, volume = {13}, number = {4}, pages = {}, pmid = {38666827}, issn = {2079-7737}, support = {NA//Hermann und Lilly Schilling-Stiftung/ ; }, abstract = {Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxide accumulation, plays a pivotal role in various pathological conditions, including neurodegenerative diseases. While reasonable evidence for ferroptosis exists, e.g., in Parkinson's disease or Alzheimer's disease, there are only a few reports on amyotrophic lateral sclerosis (ALS), a fast progressive and incurable neurodegenerative disease characterized by progressive motor neuron degeneration. Interestingly, initial studies have suggested that ferroptosis might be significantly involved in ALS. Key features of ferroptosis include oxidative stress, glutathione depletion, and alterations in mitochondrial morphology and function, mediated by proteins such as GPX4, xCT, ACSL4 FSP1, Nrf2, and TfR1. Induction of ferroptosis involves small molecule compounds like erastin and RSL3, which disrupt system Xc[-] and GPX4 activity, respectively, resulting in lipid peroxidation and cellular demise. Mutations in fused in sarcoma (FUS) are associated with familial ALS. Pathophysiological hallmarks of FUS-ALS involve mitochondrial dysfunction and oxidative damage, implicating ferroptosis as a putative cell-death pathway in motor neuron demise. However, a mechanistic understanding of ferroptosis in ALS, particularly FUS-ALS, remains limited. Here, we investigated the vulnerability to ferroptosis in FUS-ALS cell models, revealing mitochondrial disturbances and increased susceptibility to ferroptosis in cells harboring ALS-causing FUS mutations. This was accompanied by an altered expression of ferroptosis-associated proteins, particularly by a reduction in xCT expression, leading to cellular imbalance in the redox system and increased lipid peroxidation. Iron chelation with deferoxamine, as well as inhibition of the mitochondrial calcium uniporter (MCU), significantly alleviated ferroptotic cell death and lipid peroxidation. These findings suggest a link between ferroptosis and FUS-ALS, offering potential new therapeutic targets.}, } @article {pmid38666665, year = {2024}, author = {Forsberg, K and Karlsborg, M and Salvesen, L and Svenstrup, K and Winroth, I and Berntsson, H and M Andersen, P}, title = {[SOD1 gene therapy delays ALS disease progression].}, journal = {Lakartidningen}, volume = {121}, number = {}, pages = {}, pmid = {38666665}, issn = {1652-7518}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; *Superoxide Dismutase-1/genetics ; *Genetic Therapy ; *Disease Progression ; Male ; Middle Aged ; Mutation ; Oligonucleotides, Antisense/therapeutic use/administration & dosage ; Oligonucleotides/therapeutic use/administration & dosage ; }, abstract = {We present a patient with familial amyotrophic lateral sclerosis caused by an aggressive A4S mutation in the SOD1 gene. In 2020, the patient was enrolled in the VALOR SOD1 gene therapy phase-3 trial. At screening, the ALSFRS-R score was 41 (48 is normal) and the level of CSF-neurofilament L (an indicator of ongoing neuronal damage) was 11 000 ng/L (ref <650 ng/L). In the four years following enrollment, the patient received monthly intrathecal treatment with tofersen, an antisense oligonucleotide compound that inhibits SOD1 protein expression and hence lowers the synthesis of toxic SOD1 protein species. Side effects have been minimal and mostly attributed to the spinal taps. The patient remains ambulatory with an active social lifestyle. The ALSFRS-R score has in the past 18 months stabilized around 35-37, CSF-NfL is 1 290 ng/L and plasma-NfL is 12 (reference <13). This is the first documented arresting intervention in a patient with ALS in Sweden.}, } @article {pmid38666601, year = {2024}, author = {Officer, L and Armon, C and Barkhaus, P and Beauchamp, M and Benatar, M and Bertorini, T and Bowser, R and Bromberg, M and Brown, A and Carbunar, OM and Carter, GT and Crayle, J and Denson, K and Feldman, E and Fullam, T and Heiman-Patterson, T and Jackson, C and Jhooty, S and Levinson, D and Li, X and Linares, A and Mallon, E and Mascias Cadavid, J and Mcdermott, C and Mushannen, T and Ostrow, L and Patel, R and Pattee, G and Ratner, D and Sun, Y and Sladky, J and Wicks, P and Bedlack, R}, title = {ALSUntangled #75: Portable neuromodulation stimulator therapy.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {648-652}, doi = {10.1080/21678421.2024.2346825}, pmid = {38666601}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Electric Stimulation Therapy/methods/instrumentation ; }, abstract = {Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment.}, } @article {pmid38665232, year = {2024}, author = {Yao, Y and Liu, H and Gu, Y and Xu, X and Zhang, X}, title = {A causal association between amyotrophic lateral sclerosis and atrial fibrillation: a two-sample Mendelian randomization study.}, journal = {Frontiers in cardiovascular medicine}, volume = {11}, number = {}, pages = {1351495}, pmid = {38665232}, issn = {2297-055X}, abstract = {OBJECTIVES: To look into the connection between amyotrophic lateral sclerosis (ALS) and atrial fibrillation (AF) using Mendelian randomization (MR).

METHODS: Two-sample MR was performed using genetic information from genome-wide association studies (GWAS). Genetic variants robustly associated with ALS and AF were used as instrumental variables. GWAS genetic data for ALS (n = 138,086, ncase = 27,205) and AF (n = 1,030,836, ncase = 60,620), publicly available from IEU Open. The specific MR protocols were Inverse variance-weighted (IVW), Simple mode, MR Egger, Weighted mode, and Weight median estimator (WME). Subsequently, the MR-Egger intercept and Cochran Q examine were used to evaluate instrumental variables (IVs)' heterogeneity and multiplicative effects (IVs). In addition, MR-PRESSO analysis was conducted to exclude any potential pleiotropy.

RESULTS: The IVW method demonstrated that ALS positively affected AF [OR: 1.062, 95% CI (1.004-1.122); P = 0.035]. Indeed, other MR methods were in accordance with the tendency of the IVW method (all OR > 1), and sensitivity testing verified the reliability of this MR result.

CONCLUSIONS: This MR study proves a positive causal connection between ALS and atrial fibrillation. Further studies are warranted to elucidate the mechanisms linking ALS and AF.}, } @article {pmid38664831, year = {2024}, author = {Sirtori, R and J Gregoire, M and M Potts, E and Collins, A and Donatelli, L and Fallini, C}, title = {LINC complex alterations are a key feature of sporadic and familial ALS/FTD.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {69}, pmid = {38664831}, issn = {2051-5960}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; R01 NS116143/NS/NINDS NIH HHS/United States ; R01NS116143/NS/NINDS NIH HHS/United States ; P20GM103430/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; Male ; Motor Neurons/pathology/metabolism ; Spinal Cord/pathology/metabolism ; Nuclear Envelope/metabolism/pathology ; Female ; Induced Pluripotent Stem Cells/metabolism/pathology ; Middle Aged ; Aged ; Motor Cortex/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects motor neurons, leading to progressive muscle weakness and loss of voluntary muscle control. While the exact cause of ALS is not fully understood, emerging research suggests that dysfunction of the nuclear envelope (NE) may contribute to disease pathogenesis and progression. The NE plays a role in ALS through several mechanisms, including nuclear pore defects, nucleocytoplasmic transport impairment, accumulation of mislocalized proteins, and nuclear morphology abnormalities. The LINC complex is the second biggest multi-protein complex in the NE and consists of the SUN1/2 proteins spanning the inner nuclear membrane and Nesprin proteins embedded in the outer membrane. The LINC complex, by interacting with both the nuclear lamina and the cytoskeleton, transmits mechanical forces to the nucleus regulating its morphology and functional homeostasis. In this study we show extensive alterations to the LINC complex in motor and cortical iPSC-derived neurons and spinal cord organoids carrying the ALS causative mutation in the C9ORF72 gene (C9). Importantly, we show that such alterations are present in vivo in a cohort of sporadic ALS and C9-ALS postmortem spinal cord and motor cortex specimens. We also found that LINC complex disruption strongly correlated with nuclear morphological alterations occurring in ALS neurons, independently of TDP43 mislocalization. Altogether, our data establish morphological and functional alterations to the LINC complex as important events in ALS pathogenic cascade, making this pathway a possible target for both biomarker and therapy development.}, } @article {pmid38664109, year = {2024}, author = {Hastings, RL and Valdez, G}, title = {Origin, identity, and function of terminal Schwann cells.}, journal = {Trends in neurosciences}, volume = {47}, number = {6}, pages = {432-446}, pmid = {38664109}, issn = {1878-108X}, support = {R56 AG077814/AG/NIA NIH HHS/United States ; T32 AG041688/AG/NIA NIH HHS/United States ; }, mesh = {*Schwann Cells/physiology ; Animals ; Humans ; }, abstract = {The highly specialized nonmyelinating glial cells present at somatic peripheral nerve endings, known collectively as terminal Schwann cells (TSCs), play critical roles in the development, function and repair of their motor and sensory axon terminals and innervating tissue. Over the past decades, research efforts across various vertebrate species have revealed that while TSCs are a diverse group of cells, they share a number of features among them. In this review, we summarize the state-of-knowledge about each TSC type and explore the opportunities that TSCs provide to treat conditions that afflict peripheral axon terminals.}, } @article {pmid38663103, year = {2024}, author = {Nozal, V and Fernández-Gómez, P and García-Rubia, A and Martínez-González, L and Cuevas, EP and Carro, E and Palomo, V and Martínez, A}, title = {Designing multitarget ligands for neurodegenerative diseases with improved permeability trough PLGA nanoencapsulation.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {175}, number = {}, pages = {116626}, doi = {10.1016/j.biopha.2024.116626}, pmid = {38663103}, issn = {1950-6007}, mesh = {*Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Ligands ; Humans ; *Blood-Brain Barrier/metabolism/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Permeability ; Nanoparticles/chemistry ; Drug Design ; Drug Compounding ; Amyloid beta-Peptides/metabolism ; Animals ; tau Proteins/metabolism ; }, abstract = {Multitarget ligands (MTLs) have emerged as an interesting alternative for addressing complex multifactorial pathologies such as neurodegenerative diseases. However, a common challenge associated with these compounds is often their high molecular weight and low solubility, which becomes a hurdle when trying to permeate over the blood-brain barrier (BBB). In this study, we have designed two new MTLs that modulate three pharmacological targets simultaneously (tau, beta-amyloid and TAR DNA-binding protein 43). To enhance their brain penetration, we have formulated organic polymeric nanoparticles using poly(lactic-co-glycolic acid). The characterization of the formulations, evaluation of their permeability through an in vitro BBB model, and assessment of their activity on disease-representative cellular models, such as Alzheimer's disease and amyotrophic lateral sclerosis, have been conducted. The results demonstrate the potential of the new MTLs and their nanoparticle encapsulation for the treatment of neurodegenerative diseases.}, } @article {pmid38663099, year = {2024}, author = {Polverino, A and Troisi Lopez, E and Liparoti, M and Minino, R and Romano, A and Cipriano, L and Trojsi, F and Jirsa, V and Sorrentino, G and Sorrentino, P}, title = {Altered spreading of fast aperiodic brain waves relates to disease duration in Amyotrophic Lateral Sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {163}, number = {}, pages = {14-21}, doi = {10.1016/j.clinph.2024.04.003}, pmid = {38663099}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Female ; Male ; Middle Aged ; *Magnetoencephalography/methods ; Aged ; Adult ; Brain Waves/physiology ; Brain/physiopathology ; }, abstract = {OBJECTIVE: To test the hypothesis that patients affected by Amyotrophic Lateral Sclerosis (ALS) show an altered spatio-temporal spreading of neuronal avalanches in the brain, and that this may related to the clinical picture.

METHODS: We obtained the source-reconstructed magnetoencephalography (MEG) signals from thirty-six ALS patients and forty-two healthy controls. Then, we used the construct of the avalanche transition matrix (ATM) and the corresponding network parameter nodal strength to quantify the changes in each region, since this parameter provides key information about which brain regions are mostly involved in the spreading avalanches.

RESULTS: ALS patients presented higher values of the nodal strength in both cortical and sub-cortical brain areas. This parameter correlated directly with disease duration.

CONCLUSIONS: In this work, we provide a deeper characterization of neuronal avalanches propagation in ALS, describing their spatio-temporal trajectories and identifying the brain regions most likely to be involved in the process. This makes it possible to recognize the brain areas that take part in the pathogenic mechanisms of ALS. Furthermore, the nodal strength of the involved regions correlates directly with disease duration.

SIGNIFICANCE: Our results corroborate the clinical relevance of aperiodic, fast large-scale brain activity as a biomarker of microscopic changes induced by neurophysiological processes.}, } @article {pmid38663088, year = {2024}, author = {Frost, B and Dubnau, J}, title = {The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders.}, journal = {Annual review of neuroscience}, volume = {47}, number = {1}, pages = {123-143}, doi = {10.1146/annurev-neuro-082823-020615}, pmid = {38663088}, issn = {1545-4126}, support = {RF1 NS112391/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Retroelements/genetics ; *Endogenous Retroviruses/genetics ; Animals ; *Aging/genetics ; DNA-Binding Proteins/genetics/metabolism ; tau Proteins/genetics/metabolism ; }, abstract = {Over 40% of the human genome is composed of retrotransposons, DNA species that hold the potential to replicate via an RNA intermediate and are evolutionarily related to retroviruses. Retrotransposons are most studied for their ability to jump within a genome, which can cause DNA damage and novel insertional mutations. Retrotransposon-encoded products, including viral-like proteins, double-stranded RNAs, and extrachromosomal circular DNAs, can also be potent activators of the innate immune system. A growing body of evidence suggests that retrotransposons are activated in age-related neurodegenerative disorders and that such activation causally contributes to neurotoxicity. Here we provide an overview of retrotransposon biology and outline evidence of retrotransposon activation in age-related neurodegenerative disorders, with an emphasis on those involving TAR-DNA binding protein-43 (TDP-43) and tau. Studies to date provide the basis for ongoing clinical trials and hold promise for innovative strategies to ameliorate the adverse effects of retrotransposon dysregulation in neurodegenerative disorders.}, } @article {pmid38662803, year = {2025}, author = {Martín-Rivada, Á and Martos-Moreno, GÁ and Guerra-Cantera, S and Campillo-Calatayud, A and Oxvig, C and Frystyk, J and Chowen, JA and Barrios, V and Argente, J}, title = {Prepubertal Children With Obesity Have High Free IGF-1 Levels and Accelerated Growth Despite Reduced Pappalysin Levels.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {110}, number = {3}, pages = {e622-e629}, doi = {10.1210/clinem/dgae288}, pmid = {38662803}, issn = {1945-7197}, support = {FIS-PI19/00166//Spanish Ministry of Health/ ; //Centro de Investigación Biomédica en Red Fisiopatología de Obesidad y Nutrición/ ; //Instituto Carlos III/ ; no. CD19/00008//Instituto de Salud Carlos III/ ; //Comunidad Autónoma de Madrid/ ; }, mesh = {Humans ; Female ; Male ; Child ; *Insulin-Like Growth Factor I/metabolism/analysis ; *Pregnancy-Associated Plasma Protein-A/metabolism/analysis ; *Pediatric Obesity/blood ; *Glycoproteins/blood ; Child, Preschool ; Intercellular Signaling Peptides and Proteins/blood ; Weight Loss/physiology ; Child Development/physiology ; Puberty/blood/physiology ; Insulin-Like Growth Factor II/metabolism/analysis ; Body Mass Index ; Insulin-Like Growth Factor Binding Protein 3/blood ; }, abstract = {BACKGROUND: Prepubertal children with obesity frequently have enhanced growth, accelerated skeletal maturation, and changes in the growth hormone-insulin-like growth factor (GH-IGF) axis. However, the involvement of pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC1, STC2) as regulators of IGF bioavailability has not been studied in obesity.

OBJECTIVE: We aimed to determine the effects of childhood obesity and weight reduction on serum levels of PAPP-A, PAPP-A2, STC1, and STC2 and their relationship with IGF bioavailability, growth, and other components of the GH-IGF system.

METHODS: Prepubertal children with severe obesity (150, 50% males/females, age: 7.72 ± 2.05 years, BMI z-score: 4.95 ± 1.70, height z-score: 1.28 ± 1.04) were studied at diagnosis and after a minimum of 0.5 BMI z-score reduction. Two hundred and six healthy age- and sex-matched children were used as controls.

RESULTS: Children with obesity had decreased serum concentrations of PAPP-A, PAPP-A2 and STC2, but increased total and free IGF-I, intact IGFBP-3, acid-labile subunit (ALS), IGF-II, and insulin levels, with no difference in the free IGF-I/total IGF-I ratio. Neither the standardized body mass index (BMI) nor height correlated with any biochemical parameter analyzed. A decrease in IGF-II, insulin, and ALS with an increase in IGFBP-2 and -5, STC2, and PAPP-A were observed after weight loss.

CONCLUSION: Increased circulating total and free IGF-I, insulin, and IGF-II may all contribute to the increased rate of prepubertal growth and bone maturation observed in children with obesity, with STC2 possibly being involved.}, } @article {pmid38662766, year = {2024}, author = {Stikvoort García, DJL and Goedee, HS and van Eijk, RPA and van Schelven, LJ and van den Berg, LH and Sleutjes, BTHM}, title = {Revisiting distinct nerve excitability patterns in patients with amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {8}, pages = {2842-2853}, pmid = {38662766}, issn = {1460-2156}, support = {AV20180012//Dutch ALS Foundation/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Male ; Female ; Middle Aged ; Aged ; *Motor Neurons/physiology ; Adult ; Action Potentials/physiology ; Principal Component Analysis ; Axons/physiology ; Membrane Potentials/physiology ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease, characterized by loss of central and peripheral motor neurons. Although the disease is clinically and genetically heterogeneous, axonal hyperexcitability is a commonly observed feature that has been suggested to reflect an early pathophysiological step linked to the neurodegenerative cascade. Therefore, it is important to clarify the mechanisms causing axonal hyperexcitability and how these relate to the clinical characteristics of patients. Measures derived directly from a nerve excitability recording are frequently used as study end points, although their biophysical basis is difficult to deduce. Mathematical models can aid in the interpretation but are reliable only when applied to group-averaged recordings. Consequently, model estimates of membrane properties cannot be compared with clinical characteristics or treatment effects in individual patients, posing a considerable limitation in heterogeneous diseases, such as amyotrophic lateral sclerosis. To address these challenges, we revisited nerve excitability using a new pattern analysis-based approach (principal component analysis). We evaluated disease-specific patterns of excitability changes and established their biophysical origins. Based on the observed patterns, we developed new compound measures of excitability that facilitate the implementation of this approach in clinical settings. We found that excitability changes in amyotrophic lateral sclerosis patients (n = 161, median disease duration = 11 months) were characterized by four unique patterns compared with controls (n = 50, age and sex matched). These four patterns were best explained by changes in resting membrane potential (modulated by Na+/K+ currents), slow potassium and sodium currents (modulated by their gating kinetics) and refractory properties of the nerve. Consequently, we were able to show that altered gating of slow potassium channels was associated with, and predictive of, the rate of progression of the disease on the amyotrophic lateral sclerosis functional rating scale. Based on these findings, we designed four composite measures that capture these properties to facilitate implementation outside this study. Our findings demonstrate that changes in nerve excitability in patients with amyotrophic lateral sclerosis are dominated by four distinct patterns, each with a distinct biophysical origin. Based on this new approach, we provide evidence that altered slow potassium-channel function might play a role in the rate of disease progression. The magnitudes of these patterns, quantified using a similar approach or our new composite measures, have potential as efficient measures to study membrane properties directly in amyotrophic lateral sclerosis patients, and thus aid prognostic stratification and trial design.}, } @article {pmid38661532, year = {2024}, author = {Li, A and Yi, J and Li, X and Dong, L and Ostrow, LW and Ma, J and Zhou, J}, title = {Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {38661532}, issn = {2050-084X}, support = {R01 NS105621/NS/NINDS NIH HHS/United States ; R01 AG071676/AG/NIA NIH HHS/United States ; R01NS105621/NH/NIH HHS/United States ; R01AG071676/NH/NIH HHS/United States ; R01NS129219/NH/NIH HHS/United States ; R01 NS129219/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Neuromuscular Junction/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Mice ; *Satellite Cells, Skeletal Muscle/metabolism ; *Disease Models, Animal ; *Transcriptome ; Mice, Transgenic ; Oculomotor Muscles/innervation/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder characterized by progressive weakness of almost all skeletal muscles, whereas extraocular muscles (EOMs) are comparatively spared. While hindlimb and diaphragm muscles of end-stage SOD1G93A (G93A) mice (a familial ALS mouse model) exhibit severe denervation and depletion of Pax7[+]satellite cells (SCs), we found that the pool of SCs and the integrity of neuromuscular junctions (NMJs) are maintained in EOMs. In cell sorting profiles, SCs derived from hindlimb and diaphragm muscles of G93A mice exhibit denervation-related activation, whereas SCs from EOMs of G93A mice display spontaneous (non-denervation-related) activation, similar to SCs from wild-type mice. Specifically, cultured EOM SCs contain more abundant transcripts of axon guidance molecules, including Cxcl12, along with more sustainable renewability than the diaphragm and hindlimb counterparts under differentiation pressure. In neuromuscular co-culture assays, AAV-delivery of Cxcl12 to G93A-hindlimb SC-derived myotubes enhances motor neuron axon extension and innervation, recapitulating the innervation capacity of EOM SC-derived myotubes. G93A mice fed with sodium butyrate (NaBu) supplementation exhibited less NMJ loss in hindlimb and diaphragm muscles. Additionally, SCs derived from G93A hindlimb and diaphragm muscles displayed elevated expression of Cxcl12 and improved renewability following NaBu treatment in vitro. Thus, the NaBu-induced transcriptomic changes resembling the patterns of EOM SCs may contribute to the beneficial effects observed in G93A mice. More broadly, the distinct transcriptomic profile of EOM SCs may offer novel therapeutic targets to slow progressive neuromuscular functional decay in ALS and provide possible 'response biomarkers' in pre-clinical and clinical studies.}, } @article {pmid38658168, year = {2024}, author = {Jaroszynska, N and Salzinger, A and Tsarouchas, TM and Becker, CG and Becker, T and Lyons, DA and MacDonald, RB and Keatinge, M}, title = {C9ORF72 Deficiency Results in Neurodegeneration in the Zebrafish Retina.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {44}, number = {25}, pages = {}, pmid = {38658168}, issn = {1529-2401}, mesh = {Animals ; *Zebrafish ; Female ; *C9orf72 Protein/genetics/metabolism ; *Retina/metabolism/pathology ; Animals, Genetically Modified ; Zebrafish Proteins/genetics/metabolism/deficiency ; Proteins/genetics/metabolism ; Retinal Degeneration/genetics/metabolism/pathology ; Neurodegenerative Diseases/genetics/metabolism/pathology ; Spinal Cord/metabolism/pathology ; }, abstract = {Hexanucleotide repeat expansions within the gene C9ORF72 are the most common cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This disease-causing expansion leads to a reduction in C9ORF72 expression levels in patients, suggesting loss of C9ORF72 function could contribute to disease. To further understand the consequences of C9ORF72 deficiency in vivo, we generated a c9orf72 mutant zebrafish line. Analysis of the adult female spinal cords revealed no appreciable neurodegenerative pathology such as loss of motor neurons or increased levels of neuroinflammation. However, detailed examination of adult female c9orf72[-/-] retinas showed prominent neurodegenerative features, including a decrease in retinal thickness, gliosis, and an overall reduction in neurons of all subtypes. Analysis of rod and cone cells within the photoreceptor layer showed a disturbance in their outer segment structure and rhodopsin mislocalization from rod outer segments to their cell bodies and synaptic terminals. Thus, C9ORF72 may play a previously unappreciated role in retinal homeostasis and suggests C9ORF72 deficiency can induce tissue specific neuronal loss.}, } @article {pmid38657911, year = {2024}, author = {Liguori, F and Alberti, F and Amadio, S and Angelini, DF and Pilesi, E and Vitale, G and Tesoriere, G and Borsellino, G and Vernì, F and Volonté, C}, title = {Pan-neuronal expression of human mutant SOD1 in Drosophila impairs survival and motor performance, induces early neuroinflammation and chromosome aberrations.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1870}, number = {5}, pages = {167192}, doi = {10.1016/j.bbadis.2024.167192}, pmid = {38657911}, issn = {1879-260X}, mesh = {Animals ; *Superoxide Dismutase-1/genetics/metabolism ; Humans ; *Drosophila melanogaster/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Animals, Genetically Modified ; *Mutation ; *Chromosome Aberrations ; Drosophila Proteins/genetics/metabolism ; Motor Neurons/metabolism/pathology ; Disease Models, Animal ; Neuroinflammatory Diseases/genetics/metabolism/pathology ; Neurons/metabolism/pathology ; }, abstract = {Several mutations in the SOD1 gene encoding for the antioxidant enzyme Superoxide Dismutase 1, are associated with amyotrophic lateral sclerosis, a rare and devastating disease characterized by motor neuron degeneration and patients' death within 2-5 years from diagnosis. Motor neuron loss and related symptomatology manifest mostly in adult life and, to date, there is still a gap of knowledge on the precise cellular and molecular events preceding neurodegeneration. To deepen our awareness of the early phases of the disease, we leveraged two Drosophila melanogaster models pan-neuronally expressing either the mutation A4V or G85R of the human gene SOD1 (hSOD1[A4V] or hSOD1[G85R]). We demonstrate that pan-neuronal expression of the hSOD1[A4V] or hSOD1[G85R] pathogenic construct impairs survival and motor performance in transgenic flies. Moreover, protein and transcript analysis on fly heads indicates that mutant hSOD1 induction stimulates the glial marker Repo, up-regulates the IMD/Toll immune pathways through antimicrobial peptides and interferes with oxidative metabolism. Finally, cytological analysis of larval brains demonstrates hSOD1-induced chromosome aberrations. Of note, these parameters are found modulated in a timeframe when neurodegeneration is not detected. The novelty of our work is twofold: we have expressed for the first time hSOD1 mutations in all neurons of Drosophila and confirmed some ALS-related pathological phenotypes in these flies, confirming the power of SOD1 mutations in generating ALS-like phenotypes. Moreover, we have related SOD1 pathogenesis to chromosome aberrations and antimicrobial peptides up-regulation. These findings were unexplored in the SOD1-ALS field.}, } @article {pmid38657488, year = {2024}, author = {Rezaee Semnani, M and Mirzaasgari, Z and Ariaei, A and Haghi Ashtiani, B}, title = {Evaluation of carotid Intima-Media Thickness (IMT) in amyotrophic lateral sclerosis disease using ultrasonography.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {124}, number = {}, pages = {67-72}, doi = {10.1016/j.jocn.2024.04.019}, pmid = {38657488}, issn = {1532-2653}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Male ; Female ; *Carotid Intima-Media Thickness ; Middle Aged ; Adult ; Aged ; Ultrasonography/methods ; Body Mass Index ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease with multi-mechanisms as; inflammation, oxidative stress, glutamate excitotoxicity, protein aggregation, etc. This study aimed to evaluate the carotid Intima-Media Thickness (IMT) in ALS and healthy groups, as a possible indicator of these mechanisms.

METHODS: 42 patients with ALS along with 53 normal age and body mass index (BMI) matched participants were recruited from the Firoozgar hospital. Carotid IMT values of the participants were measured using B-mode ultrasonography. Using Pearson correlation and logistic regression adjusting with age, BMI, and gender, the IMT values were assessed.

RESULTS: The mean right and left carotid IMT values of the ALS patients (0.66 ± 0.09) were significantly higher than normal participants (0.45 ± 0.10) (p < 0.001). In addition, the IMT values were highly correlated with the age (r = 0.632; p < 0.001) and the age of ALS onset (r = 0.595; p < 0.001), in contrast to the BMI. Moreover, the higher value of IMT was associated with an increasing risk of ALS with an odd ratio (OR) of 1.483 (95 % Confidence interval [1.026-2.144]). Eventually, evaluating IMT by classifying ALS patients based on the ALS Health State Scale (ALSHSS) from early to late stage revealed a non-linear increase in the OR (1.372, 1.898, 2.172, and 3.403).

CONCLUSION: The increased value of the carotid IMT independent of BMI in ALS could be assessed through ultrasonography as a convenient tool to evaluate the disease severity or possible systemic inflammation.}, } @article {pmid38657132, year = {2025}, author = {Washington, KT and Mechling, CA and Pitzer, KA and Maiser, S and Mehta, AK}, title = {Identifying the Unmet Needs of People Living With Amyotrophic Lateral Sclerosis: A National Survey to Inform Interdisciplinary Palliative Care.}, journal = {The American journal of hospice & palliative care}, volume = {42}, number = {4}, pages = {326-333}, doi = {10.1177/10499091241248653}, pmid = {38657132}, issn = {1938-2715}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Male ; Female ; *Palliative Care/organization & administration/psychology ; *Quality of Life ; Middle Aged ; Aged ; *Advance Care Planning/organization & administration ; Terminal Care/psychology/organization & administration ; Adult ; Aged, 80 and over ; Needs Assessment ; Surveys and Questionnaires ; Disease Progression ; }, abstract = {Introduction/Aims: This national survey builds on previous qualitative research examining potential palliative care needs among people living with ALS (pALS) by quantifying and investigating relationships among pALS' stage of illness progression; physical, emotional, social, spiritual, and intimacy-related concerns; advance care planning behaviors; perceptions of feeling heard and understood by healthcare providers; and overall quality of life. Methods: Researchers partnered with national organizations to recruit pALS to participate in a one-time survey comprising items from validated instruments (eg, the ALS Specific Quality of Life Instrument-Revised) and researcher-generated measures. Data were analyzed using logistic and linear regression. Results: Among pALS (n = 112), many respondents indicated they had discussed their wishes for end-of-life care with family or friends, shared their wishes with providers, and documented their wishes in writing (79.5%, 49.1%, and 63.4%, respectively). Mean (M) quality of life scores were moderate (M ≈ 6 of 10). Illness stage was associated with documentation of end-of-life care wishes but not with having discussed these wishes with others or with overall quality of life. Reported emotional intimacy received was comparable to that desired (difference = .01 of 10); however, a greater desire for physical intimacy relative to that received was indicated (difference = 1.75 of 10). Discussion: Interdisciplinary palliative care teams may enhance ALS care by promoting advance care planning behaviors (particularly discussing one's wishes with healthcare providers), providing interventions to improve quality of life, and supporting pALS in navigating challenges related to physical intimacy.}, } @article {pmid38655803, year = {2024}, author = {Temkin-Greener, H and Hua, Y and Cai, S}, title = {Assisted living residents with dementia: Disparities in mental health services pre and during COVID-19.}, journal = {Journal of the American Geriatrics Society}, volume = {72}, number = {6}, pages = {1760-1769}, pmid = {38655803}, issn = {1532-5415}, support = {RF1 AG063811/AG/NIA NIH HHS/United States ; R01HS026893//Agency for Healthcare Research and Quality/ ; RF1 AG073052/AG/NIA NIH HHS/United States ; RF1AG063811/AG/NIA NIH HHS/United States ; R01 HS026893/HS/AHRQ HHS/United States ; RF1AG073052/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/epidemiology ; United States/epidemiology ; Male ; Female ; *Assisted Living Facilities/statistics & numerical data ; Aged ; *Telemedicine/statistics & numerical data ; *Dementia/epidemiology/therapy ; *Medicare/statistics & numerical data ; *Mental Health Services/statistics & numerical data ; Aged, 80 and over ; *Healthcare Disparities/statistics & numerical data ; SARS-CoV-2 ; Medicaid/statistics & numerical data ; Health Services Accessibility/statistics & numerical data ; }, abstract = {BACKGROUND: Little is known about mental health among Medicare beneficiaries with Alzheimer's disease or related dementias (ADRD) who reside in assisted living (AL) communities. The COVID-19 pandemic may have curtailed ambulatory care access for these residents, but telehealth may have expanded it. We examined in-person and telehealth use of ambulatory mental health visits among AL residents with ADRD, pre and during the COVID pandemic, focusing on race/ethnicity and Medicare/Medicaid dual status.

METHODS: A CY2018 cohort of AL residents with ADRD was identified. Outcome was any quarterly in-person or telemedicine mental health visit based on national CY2019-2020 Medicare claims. Key independent variables were individual race/ethnicity and dual status and the AL-level proportion of dual residents. We estimated a linear probability model with random effects and robust standard errors. Quarterly indicators captured service use before and after the onset of the pandemic.

RESULTS: The study included 102,758 fee-for-service Medicare beneficiaries with ADRD in 13,400 ALs. One in five residents had any mental health visits prior to the COVID-19 pandemic. Black residents, and those with dual Medicare/Medicaid eligibility, were significantly less likely to use mental health services prior to and during the pandemic. There were no significant differences in visits via telemedicine by race/ethnicity or individual dual status. Residents in AL communities with a higher proportion of duals had a lower likelihood of visits before and during the pandemic.

CONCLUSIONS/IMPLICATIONS: Mental health service use among AL residents with ADRD was low and declining prior to the pandemic. Telehealth allowed for mental health visits to continue during the pandemic, albeit at a lower level. Residents in ALs with a higher proportion of duals were less likely to have in-person or telehealth visits. The results suggest that some ALs may find it difficult to assure mental health service provision to this vulnerable population.}, } @article {pmid38655443, year = {2024}, author = {Zubair, AS and Saab, L and Scharer, K and Khokhar, B}, title = {Patients' experiences with methylcobalamin injections in amyotrophic lateral sclerosis.}, journal = {Brain circulation}, volume = {10}, number = {1}, pages = {60-66}, pmid = {38655443}, issn = {2455-4626}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with no definitive treatment. Vitamin B12 is not a Food and Drug Administration-approved treatment in the United States, although it has been prescribed off-label as ultra-high-dose methylcobalamin, which has been shown to be safe and effective in slowing functional decline in patients with ALS. This study evaluates the impact of Vitamin B12 injections on the quality of life of five patients.

METHODS: Semi-structured interviews were conducted with the patients and caregivers. The data was carefully read, coded, and organized into themes and sub-themes by two independent researchers.

RESULTS: The study found four themes and 11 subthemes from the data, including initial circumstances, administration of the injection, subjective experience with Vitamin B12, and outcomes and expectations. All participants recognized some benefits from Vitamin B12 injections, specifically increased energy, reduced fatigue, and improved balance. However, some patients had difficulty monitoring its specific effect due to the progressive nature of the disease.

DISCUSSION: The flexibility offered by this intervention is beneficial for patients with declining mobility and strength who wish to adapt their treatment to their schedule. This work is a modest call to fill the existing gap in the literature and push for more randomized controlled trials investigating and clarifying the effects of Vitamin B12 injections on disease progression, muscle function, and quality of life in a small but diverse pool of patients with ALS.}, } @article {pmid38654338, year = {2024}, author = {Li, Y and Hu, Q and Wang, Q and Liu, T and Gao, M}, title = {Real-time ultrasound-guided sacral plexus block combined with mild sedation for hemorrhoidectomy and hemorrhoidal artery ligation in a patient with amyotrophic lateral sclerosis: a case report.}, journal = {Journal of medical case reports}, volume = {18}, number = {1}, pages = {205}, pmid = {38654338}, issn = {1752-1947}, mesh = {Humans ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications ; *Ultrasonography, Interventional ; *Hemorrhoidectomy/methods ; Ligation ; *Nerve Block/methods ; *Dexmedetomidine/administration & dosage ; *Lumbosacral Plexus/diagnostic imaging ; Hemorrhoids/surgery ; Hypnotics and Sedatives/administration & dosage ; Treatment Outcome ; }, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis present perioperative challenges for clinical anesthesiologists for anesthesia-associated complications.

CASE PRESENTATION: A 54-year-old Han woman with a 2-year history of amyotrophic lateral sclerosis was scheduled for hemorrhoidectomy and hemorrhoidal artery ligation. We performed real-time ultrasound-guided sacral plexus block with dexmedetomidine under standard monitoring. The anesthesia method met the surgical demands and avoided respiratory complications during the procedures. There was no neurological deterioration after the surgery and 3 months after, the patient was discharged.

CONCLUSIONS: Real-time ultrasound-guided sacral plexus block combined with mild sedation may be an effective and safe technique in patients with amyotrophic lateral sclerosis undergoing hemorrhoidectomy and hemorrhoidal artery ligation.}, } @article {pmid38652017, year = {2024}, author = {Rahman, MU and Bano, S and Hong, X and Gu, RX and Chen, HF}, title = {Early Aggregation Mechanism of SOD128-38 Based on Force Field Parameter of 5-Cyano-Tryptophan.}, journal = {Journal of chemical information and modeling}, volume = {64}, number = {9}, pages = {3942-3952}, doi = {10.1021/acs.jcim.4c00289}, pmid = {38652017}, issn = {1549-960X}, mesh = {Humans ; Kinetics ; Markov Chains ; Molecular Dynamics Simulation ; *Protein Aggregates ; Protein Multimerization ; *Superoxide Dismutase-1/chemistry/metabolism ; *Tryptophan/chemistry/metabolism ; }, abstract = {The aggregation of superoxide dismutase 1 (SOD1) results in amyloid deposition and is involved in familial amyotrophic lateral sclerosis, a fatal motor neuron disease. There have been extensive studies of its aggregation mechanism. Noncanonical amino acid 5-cyano-tryptophan (5-CN-Trp), which has been incorporated into the amyloid segments of SOD1 as infrared probes to increase the structural sensitivity of IR spectroscopy, is found to accelerate the overall aggregation rate and potentially modulate the aggregation process. Despite these observations, the underlying mechanism remains elusive. Here, we optimized the force field parameters of 5-CN-Trp and then used molecular dynamics simulation along with the Markov state model on the SOD128-38 dimer to explore the kinetics of key intermediates in the presence and absence of 5-CN-Trp. Our findings indicate a significantly increased probability of protein aggregate formation in 5CN-Trp-modified ensembles compared to wildtype. Dimeric β-sheets of different natures were observed exclusively in the 5CN-Trp-modified peptides, contrasting with wildtype simulations. Free-energy calculations and detailed analyses of the dimer structure revealed augmented interstrand interactions attributed to 5-CN-Trp, which contributed more to peptide affinity than any other residues. These results explored the key events critical for the early nucleation of amyloid-prone proteins and also shed light on the practice of using noncanonical derivatives to study the aggregation mechanism.}, } @article {pmid38648781, year = {2024}, author = {Ikegawa, Y and Fukuma, R and Sugano, H and Oshino, S and Tani, N and Tamura, K and Iimura, Y and Suzuki, H and Yamamoto, S and Fujita, Y and Nishimoto, S and Kishima, H and Yanagisawa, T}, title = {Text and image generation from intracranial electroencephalography using an embedding space for text and images.}, journal = {Journal of neural engineering}, volume = {21}, number = {3}, pages = {}, doi = {10.1088/1741-2552/ad417a}, pmid = {38648781}, issn = {1741-2552}, mesh = {Humans ; *Brain-Computer Interfaces ; Male ; Female ; *Electrocorticography/methods ; Adult ; Electroencephalography/methods ; Middle Aged ; Electrodes, Implanted ; Young Adult ; Photic Stimulation/methods ; }, abstract = {Objective.Invasive brain-computer interfaces (BCIs) are promising communication devices for severely paralyzed patients. Recent advances in intracranial electroencephalography (iEEG) coupled with natural language processing have enhanced communication speed and accuracy. It should be noted that such a speech BCI uses signals from the motor cortex. However, BCIs based on motor cortical activities may experience signal deterioration in users with motor cortical degenerative diseases such as amyotrophic lateral sclerosis. An alternative approach to using iEEG of the motor cortex is necessary to support patients with such conditions.Approach. In this study, a multimodal embedding of text and images was used to decode visual semantic information from iEEG signals of the visual cortex to generate text and images. We used contrastive language-image pretraining (CLIP) embedding to represent images presented to 17 patients implanted with electrodes in the occipital and temporal cortices. A CLIP image vector was inferred from the high-γpower of the iEEG signals recorded while viewing the images.Main results.Text was generated by CLIPCAP from the inferred CLIP vector with better-than-chance accuracy. Then, an image was created from the generated text using StableDiffusion with significant accuracy.Significance.The text and images generated from iEEG through the CLIP embedding vector can be used for improved communication.}, } @article {pmid38647433, year = {2024}, author = {Mousavi, H and Rimaz, M and Zeynizadeh, B}, title = {Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {9}, pages = {1828-1881}, doi = {10.1021/acschemneuro.4c00055}, pmid = {38647433}, issn = {1948-7193}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Molecular Docking Simulation/methods ; Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; Heterocyclic Compounds, 2-Ring/pharmacology/chemical synthesis/chemistry ; Structure-Activity Relationship ; }, abstract = {Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome and (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a-h), and hydrazine monohydrate (NH2NH2•H2O) for the regioselective preparation of some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a-h). After synthesis and characterization of the mentioned cinnolines (3a-h), the in silico multi-targeting inhibitory properties of these heterocyclic scaffolds have been investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2[(G2019S)], hGSK-3β, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, and hDHODH, which have confirmed their functions and roles in the neurodegenerative diseases (NDs), based on molecular docking studies, and the obtained results were compared with a wide range of approved drugs and well-known (with IC50, EC50, etc.) compounds. In addition, in silico ADMET prediction analysis was performed to examine the prospective drug properties of the synthesized heterocyclic compounds (3a-h). The obtained results from the molecular docking studies and ADMET-related data demonstrated that these series of 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines (3a-h), especially hit ones, can really be turned into the potent core of new drugs for the treatment of neurodegenerative diseases (NDs), and/or due to the having some reactionable locations, they are able to have further organic reactions (such as cross-coupling reactions), and expansion of these compounds (for example, with using other types of aryl(or heteroaryl)glyoxal monohydrates) makes a new avenue for designing novel and efficient drugs for this purpose.}, } @article {pmid38647181, year = {2024}, author = {Zejlon, C and Sennfält, S and Finnsson, J and Connolly, B and Petersson, S and Granberg, T and Ingre, C}, title = {Motor band sign is specific for amyotrophic lateral sclerosis and corresponds to motor symptoms.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {5}, pages = {1280-1289}, pmid = {38647181}, issn = {2328-9503}, support = {20190565//Region Stockholm and Karolinska Institutet through ALF Medicine/ ; 976444//Region Stockholm and Karolinska Institutet through ALF Medicine/ ; //Neuroförbundet/ ; //Svenska Frimurarorden/ ; //Ulla-Carin Lindquists stiftelse för ALS-forskning/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/genetics ; Male ; Female ; Middle Aged ; Aged ; *Magnetic Resonance Imaging ; *Motor Cortex/diagnostic imaging/physiopathology ; Prospective Studies ; Adult ; Sensitivity and Specificity ; C9orf72 Protein/genetics ; }, abstract = {OBJECTIVE: Magnetic resonance imaging can detect neurodegenerative iron accumulation in the motor cortex, called the motor band sign. This study aims to evaluate its sensitivity/specificity and correlations to symptomatology, biomarkers, and clinical outcome in amyotrophic lateral sclerosis.

METHODS: This prospective study consecutively enrolled 114 persons with amyotrophic lateral sclerosis and 79 mimics referred to Karolinska University Hospital, and also 31 healthy controls. All underwent 3-Tesla brain susceptibility-weighted imaging. Three raters independently assessed motor cortex susceptibility with total and regional motor band scores. Survival was evaluated at a median of 34.2 months after the imaging.

RESULTS: The motor band sign identified amyotrophic lateral sclerosis with a sensitivity of 59.6% and a specificity of 91.1% versus mimics and 96.8% versus controls. Higher motor band scores were more common with genetic risk factors (p = 0.032), especially with C9orf72 mutation, and were associated with higher neurofilament light levels (std. β 0.22, p = 0.019). Regional scores correlated strongly with focal symptoms (medial region vs. gross motor dysfunction, std. β -0.64, p = 0.001; intermediate region vs. fine motor dysfunction, std. β -0.51, p = 0.031; lateral region vs. bulbar symptoms std. β -0.71, p < 0.001). There were no associations with cognition, progression rate, or survival.

INTERPRETATION: In a real-life clinical setting, the motor band sign has high specificity but relatively low sensitivity for identifying amyotrophic lateral sclerosis. Associations with genetic risk factors, neurofilament levels and somatotopic correspondence to focal motor weakness suggest that the motor band sign could be a suitable biomarker for diagnostics and clinical trials in amyotrophic lateral sclerosis.}, } @article {pmid38646691, year = {2024}, author = {Flynn, MB and Flynn, JF and Palacios, AM}, title = {Capitalizing on Hope: Questionable Marketing Approval and Pricing of a New ALS Drug.}, journal = {International journal of social determinants of health and health services}, volume = {54}, number = {4}, pages = {405-411}, doi = {10.1177/27551938241247778}, pmid = {38646691}, issn = {2755-1946}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/economics ; Humans ; *Drug Approval ; United States ; United States Food and Drug Administration ; Cost-Benefit Analysis ; }, abstract = {Regulatory agencies must balance patient demands to access new treatments for fatal diseases with limited treatment options while ensuring drug safety and efficacy. However, questionable U.S. regulatory actions resulted in the early approval of AMX0035 to treat amyotrophic lateral sclerosis (ALS) by reconvening advisory commissions to obtain positive decisions and designating the drug as a new molecular entity. Data from one randomized clinical trial suggests minimal delays in disease progression and longer survivability, but debate remains about the lack of confirmatory evidence of effectiveness owing to study limitations. A patient's decision-making process details the experience of using the drug, including perspectives on access, cost, effectiveness, and adverse effects. In line with the "nichebuster" business model, the drugmaker, Amylyx Pharmaceuticals, is charging US$158,000/year/patient and thus forecast to turn a profit on a drug with debatable clinical effectiveness prior to completing a Phase 3 trial. Early marketing approval, despite community demands, is unnecessary and may have reduced access because of the end of a compassionate use program, and the high price tag results in restricted coverage and high out-of-pocket costs. Also, the drug's key ingredients are available as a generic and a supplement.}, } @article {pmid38646235, year = {2024}, author = {Hagino, T and Ochiai, S and Hagino, T and Furuya, N and Wako, M and Haro, H}, title = {Impacts of Segond Fractures on Anterior Cruciate Ligament Reconstruction Outcomes.}, journal = {Cureus}, volume = {16}, number = {3}, pages = {e56542}, pmid = {38646235}, issn = {2168-8184}, abstract = {INTRODUCTION: Segond fractures, characterized by avulsion injuries at the lateral tibial condyle's anterolateral structure (ALS) attachment, often coincide with anterior cruciate ligament (ACL) injuries, potentially leading to knee instability. However, the influence of Segond fractures on knee stability after ACL reconstruction remains uncertain. Despite documented ALS reconstructions, there is a lack of consensus regarding the assessment of ALS failure and the criteria for surgical interventions. This study aimed to determine if Segond fracture presence impacts ACL reconstruction outcomes, utilizing patient-reported subjective assessments and healthcare providers' objective evaluations.

MATERIALS AND METHODS: This retrospective study encompassed 639 patients (328 males, 311 females; mean age 26.9 years) who underwent ACL reconstruction, with a follow-up of at least one year. Subjects were divided into two groups: Segond fractures diagnosed through radiographic findings (Group S+, n = 17) and no Segond fractures (Group S-, n = 622). Clinical evaluation included the 36-item Short Form Survey (SF-36), Lysholm score, visual analog scale (VAS) for knee pain, knee injury and osteoarthritis outcome score (KOOS), and knee instability assessment via Telos SE (Telos Japan, Tokyo, Japan). Statistical comparisons were performed between the two groups.

RESULTS: At the final follow-up, all SF-36 subscales improved in all eight subscales compared to before surgery, reaching national standard scores; no significant inter-group differences were evident. Lysholm scores were 93.0 ± 12.1 (Group S+) and 91.7 ± 10.9 (Group S-) (P = 0.62), VAS for knee pain was 10.0 ± 18.0 (Group S+) and 11.9 ± 16.9 (Group S-) (P = 0.62), total KOOS was 89.0 ± 17.4 (Group S+) and 90.7 ± 9.9 (Group S-) (P = 0.39), and anterior tibial translation differences were 2.8 ± 3.0 mm (Group S+) and 2.7 ± 2.9 mm (Group S-) (P = 0.73). All these values represent postoperative measurements. No significant discrepancies existed between groups across evaluation methods.

CONCLUSIONS: This study's results suggest that Segond fractures have minimal impact on clinical ACL reconstruction outcomes, as assessed through both patient-reported subjective evaluations and objective healthcare provider evaluations. Segond fractures' significance in postoperative outcomes questions the necessity of ALS reconstruction.}, } @article {pmid38645254, year = {2024}, author = {Card, NS and Wairagkar, M and Iacobacci, C and Hou, X and Singer-Clark, T and Willett, FR and Kunz, EM and Fan, C and Nia, MV and Deo, DR and Srinivasan, A and Choi, EY and Glasser, MF and Hochberg, LR and Henderson, JM and Shahlaie, K and Brandman, DM and Stavisky, SD}, title = {An accurate and rapidly calibrating speech neuroprosthesis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38645254}, support = {DP2 DC021055/DC/NIDCD NIH HHS/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; U01 DC019430/DC/NIDCD NIH HHS/United States ; }, abstract = {Brain-computer interfaces can enable rapid, intuitive communication for people with paralysis by transforming the cortical activity associated with attempted speech into text on a computer screen. Despite recent advances, communication with brain-computer interfaces has been restricted by extensive training data requirements and inaccurate word output. A man in his 40's with ALS with tetraparesis and severe dysarthria (ALSFRS-R = 23) was enrolled into the BrainGate2 clinical trial. He underwent surgical implantation of four microelectrode arrays into his left precentral gyrus, which recorded neural activity from 256 intracortical electrodes. We report a speech neuroprosthesis that decoded his neural activity as he attempted to speak in both prompted and unstructured conversational settings. Decoded words were displayed on a screen, then vocalized using text-to-speech software designed to sound like his pre-ALS voice. On the first day of system use, following 30 minutes of attempted speech training data, the neuroprosthesis achieved 99.6% accuracy with a 50-word vocabulary. On the second day, the size of the possible output vocabulary increased to 125,000 words, and, after 1.4 additional hours of training data, the neuroprosthesis achieved 90.2% accuracy. With further training data, the neuroprosthesis sustained 97.5% accuracy beyond eight months after surgical implantation. The participant has used the neuroprosthesis to communicate in self-paced conversations for over 248 hours. In an individual with ALS and severe dysarthria, an intracortical speech neuroprosthesis reached a level of performance suitable to restore naturalistic communication after a brief training period.}, } @article {pmid38645132, year = {2024}, author = {Caggiano, C and Morselli, M and Qian, X and Celona, B and Thompson, M and Wani, S and Tosevska, A and Taraszka, K and Heuer, G and Ngo, S and Steyn, F and Nestor, P and Wallace, L and McCombe, P and Heggie, S and Thorpe, K and McElligott, C and English, G and Henders, A and Henderson, R and Lomen-Hoerth, C and Wray, N and McRae, A and Pellegrini, M and Garton, F and Zaitlen, N}, title = {Tissue informative cell-free DNA methylation sites in amyotrophic lateral sclerosis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38645132}, support = {T32 NS048004/NS/NINDS NIH HHS/United States ; }, abstract = {Cell-free DNA (cfDNA) is increasingly recognized as a promising biomarker candidate for disease monitoring. However, its utility in neurodegenerative diseases, like amyotrophic lateral sclerosis (ALS), remains underexplored. Existing biomarker discovery approaches are tailored to a specific disease context or are too expensive to be clinically practical. Here, we address these challenges through a new approach combining advances in molecular and computational technologies. First, we develop statistical tools to select tissue-informative DNA methylation sites relevant to a disease process of interest. We then employ a capture protocol to select these sites and perform targeted methylation sequencing. Multi-modal information about the DNA methylation patterns are then utilized in machine learning algorithms trained to predict disease status and disease progression. We applied our method to two independent cohorts of ALS patients and controls (n=192). Overall, we found that the targeted sites accurately predicted ALS status and replicated between cohorts. Additionally, we identified epigenetic features associated with ALS phenotypes, including disease severity. These findings highlight the potential of cfDNA as a non-invasive biomarker for ALS.}, } @article {pmid38644973, year = {2024}, author = {Gonzalez, D and Cuenca, X and Allende, ML}, title = {Knockdown of tgfb1a partially improves ALS phenotype in a transient zebrafish model.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1384085}, pmid = {38644973}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) corresponds to a neurodegenerative disorder marked by the progressive degeneration of both upper and lower motor neurons located in the brain, brainstem, and spinal cord. ALS can be broadly categorized into two main types: sporadic ALS (sALS), which constitutes approximately 90% of all cases, and familial ALS (fALS), which represents the remaining 10% of cases. Transforming growth factor type-β (TGF-β) is a cytokine involved in various cellular processes and pathological contexts, including inflammation and fibrosis. Elevated levels of TGF-β have been observed in the plasma and cerebrospinal fluid (CSF) of both ALS patients and mouse models. In this perspective, we explore the impact of the TGF-β signaling pathway using a transient zebrafish model for ALS. Our findings reveal that the knockdown of tgfb1a lead to a partial prevention of motor axon abnormalities and locomotor deficits in a transient ALS zebrafish model at 48 h post-fertilization (hpf). In this context, we delve into the proposed distinct roles of TGF-β in the progression of ALS. Indeed, some evidence suggests a dual role for TGF-β in ALS progression. Initially, it seems to exert a neuroprotective effect in the early stages, but paradoxically, it may contribute to disease progression in later stages. Consequently, we suggest that the TGF-β signaling pathway emerges as an attractive therapeutic target for treating ALS. Nevertheless, further research is crucial to comprehensively understand the nuanced role of TGF-β in the pathological context.}, } @article {pmid38644578, year = {2024}, author = {Yao, Q and Long, C and Yi, P and Zhang, G and Wan, W and Rao, X and Ying, J and Liang, W and Hua, F}, title = {C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {4}, pages = {e14721}, pmid = {38644578}, issn = {1755-5949}, support = {jxsq2019201023//Jiangxi Province "Double Thousand Plan"/ ; 82060219//National Natural Science Foundation of China/ ; 82271234//National Natural Science Foundation of China/ ; 20212ACB216009//Natural Science Foundation of Jiangxi Province/ ; 20212BAB216048//Natural Science Foundation of Jiangxi Province/ ; 2019YNTD12003//Youth Team Project of the Second Affiliated Hospital of Nanchang University/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *CCAAT-Enhancer-Binding Protein-beta/metabolism/genetics ; *Disease Progression ; Animals ; Amyloid beta-Peptides/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment.

AIMS: Several studies have demonstrated an elevation in the expression level of C/EBPβ among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBPβ expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBPβ can be a new therapeutic target for AD.

METHODS: A systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded.

RESULTS: Overexpression of C/EBPβ exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including δ-secretase, apolipoprotein E4 (APOE4), acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO).

DISCUSSION: The correlation between overexpression of C/EBPβ and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBPβ regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBPβ overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS).

CONCLUSION: The overexpression of C/EBPβ accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBPβ plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBPβ could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.}, } @article {pmid38644373, year = {2024}, author = {Niccolai, E and Pedone, M and Martinelli, I and Nannini, G and Baldi, S and Simonini, C and Di Gloria, L and Zucchi, E and Ramazzotti, M and Spezia, PG and Maggi, F and Quaranta, G and Masucci, L and Bartolucci, G and Stingo, FC and Mandrioli, J and Amedei, A}, title = {Amyotrophic lateral sclerosis stratification: unveiling patterns with virome, inflammation, and metabolism molecules.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {4310-4325}, pmid = {38644373}, issn = {1432-1459}, support = {Grant-No. RF-2016-02361616//Ministero della Salute/ ; Grant no. B008-P00634//University of Florence/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/immunology ; Male ; Female ; Middle Aged ; Aged ; *Inflammation/blood ; *Virome ; Cytokines/blood ; Torque teno virus/genetics ; Fatty Acids, Nonesterified/blood ; Adult ; Biomarkers/blood ; DNA, Viral/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an untreatable and clinically heterogeneous condition primarily affecting motor neurons. The ongoing quest for reliable biomarkers that mirror the disease status and progression has led to investigations that extend beyond motor neurons' pathology, encompassing broader systemic factors such as metabolism, immunity, and the microbiome. Our study contributes to this effort by examining the potential role of microbiome-related components, including viral elements, such as torque tenovirus (TTV), and various inflammatory factors, in ALS. In our analysis of serum samples from 100 ALS patients and 34 healthy controls (HC), we evaluated 14 cytokines, TTV DNA load, and 18 free fatty acids (FFA). We found that the evaluated variables are effective in differentiating ALS patients from healthy controls. In addition, our research identifies four unique patient clusters, each characterized by distinct biological profiles. Intriguingly, no correlations were found with site of onset, sex, progression rate, phenotype, or C9ORF72 expansion. A remarkable aspect of our findings is the discovery of a gender-specific relationship between levels of 2-ethylhexanoic acid and patient survival. In addition to contributing to the growing body of evidence suggesting altered peripheral immune responses in ALS, our exploratory research underscores metabolic diversity challenging conventional clinical classifications. If our exploratory findings are validated by further research, they could significantly impact disease understanding and patient care customization. Identifying groups based on biological profiles might aid in clustering patients with varying responses to treatments.}, } @article {pmid38643758, year = {2024}, author = {Aiello, EN and Solca, F and Torre, S and Colombo, E and Maranzano, A and De Lorenzo, A and Patisso, V and Treddenti, M and Curti, B and Morelli, C and Doretti, A and Verde, F and Ferrucci, R and Barbieri, S and Ruggiero, F and Priori, A and Silani, V and Ticozzi, N and Poletti, B}, title = {Longitudinal Feasibility of the Montreal Cognitive Assessment (MoCA) in Non-Demented ALS Patients.}, journal = {European neurology}, volume = {87}, number = {2}, pages = {79-83}, doi = {10.1159/000538828}, pmid = {38643758}, issn = {1421-9913}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Male ; Female ; *Feasibility Studies ; *Mental Status and Dementia Tests/standards ; Middle Aged ; Aged ; Longitudinal Studies ; Reproducibility of Results ; Cognitive Dysfunction/etiology/diagnosis ; Disease Progression ; Italy ; Neuropsychological Tests/standards ; }, abstract = {INTRODUCTION: The present study aimed at testing the longitudinal feasibility of the Montreal Cognitive Assessment (MoCA) in an Italian cohort of non-demented amyotrophic lateral sclerosis (ALS) patients.

METHODS: N = 39 non-demented ALS patients were followed-up at a 5-to-10-month interval (M = 6.8; SD = 1.4) with the MoCA and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Practice effects, test-retest reliability, and predictive validity (against follow-up ECAS scores) were assessed. Reliable change indices (RCIs) were derived via a regression-based approach by accounting for retest interval and baseline confounders (i.e., demographics, disease duration, and severity and progression rate).

RESULTS: At retest, 100% and 69.2% of patients completed the ECAS and the MoCA, respectively. Patients who could not complete the MoCA showed a slightly more severe and fast-progressing disease. The MoCA was not subject to practice effects (t[32] = -0.80; p = 0.429) and was reliable at retest (intra-class correlation = 0.82). Moreover, baseline MoCA scores predicted the ECAS at retest. RCIs were successfully derived - with baseline MoCA scores being the only significant predictor of retest performances (ps < 0.001).

CONCLUSIONS: As long as motor disabilities do not undermine its applicability, the MoCA appears to be longitudinally feasible at a 5-to-10-month interval in non-demented ALS patients. However, ALS-specific screeners - such as the ECAS - should be preferred whenever possible.}, } @article {pmid38643177, year = {2024}, author = {Jeszka, J and Hummel, D and Woźniewicz, M and Morinaka, T and Sone, Y and Crews, DE}, title = {Allostatic load and frailty do not covary significantly among older residents of Greater Poland.}, journal = {Journal of physiological anthropology}, volume = {43}, number = {1}, pages = {12}, pmid = {38643177}, issn = {1880-6805}, mesh = {Male ; Humans ; Female ; Aged ; *Allostasis/physiology ; *Frailty/epidemiology ; Poland/epidemiology ; Biomarkers ; Cohort Studies ; }, abstract = {BACKGROUND: Physiological dysregulation/allostatic load and the geriatric syndrome frailty increase with age. As a neurophysiological response system, allostasis supports survival by limiting stressor-related damage. Frailty reflects decreased strength, endurance, and physical abilities secondary to losses of muscle and bone with age. One suggestion, based on large cohort studies of person's ages 70 + years, is that frailty contributes to allostatic load at older ages. However, small community-based research has not confirmed this specific association.

METHODS: To further explore possible associations between allostatic load and frailty, we enrolled 211 residents of Greater Poland aged 55-91 years living in a small village (Nekla, N = 104) and an urban center and capital of Greater Poland (Poznan, N = 107). For each, we recorded age, self-reported sex, and residence and estimated a 10-biomarker allostatic load score (ALS) and an 8-biomarker frailty index. We anticipated the following: higher ALS and frailty among men and rural residents; for frailty but not ALS to be higher at older ages; significant associations of ALS with sex and place of residence, but not with age or frailty. The significance of observed associations was evaluated by t-tests and multivariate regression.

RESULTS: ALS did not vary significantly between men and women nor between Nekla and Poznan residents overall. However, women showed significantly higher frailty than men. Nekla men showed significantly higher ALS but not frailty, while Nekla women showed nonsignificantly higher ALS and lower frailty than Poznan. In multivariate analyses, neither age, nor sex, nor residence was associated with ALS. Conversely, age, sex, and residence, but not ALS, are associated significantly with frailty. In Nekla, both age and sex, but in Poznan only age, are associated with ALS. Among women, both age and residence, but among men, neither associated with ALS. In no case did ALS associate significantly with frailty.

CONCLUSION: In this sample, lifestyle factors associated with residence, age, and sex influence stress-related physiology, less so in women, while ALS and frailty do not covary, suggesting their underlying promoters are distinct. Similar complex associations of physiological dysregulation with frailty, age, sex, and residence likely exist within many local settings. Knowledge of this variation likely will aid in supporting health and healthcare services among seniors.}, } @article {pmid38643019, year = {2024}, author = {Guo, J and You, L and Zhou, Y and Hu, J and Li, J and Yang, W and Tang, X and Sun, Y and Gu, Y and Dong, Y and Chen, X and Sato, C and Zinman, L and Rogaeva, E and Wang, J and Chen, Y and Zhang, M}, title = {Spatial enrichment and genomic analyses reveal the link of NOMO1 with amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {8}, pages = {2826-2841}, doi = {10.1093/brain/awae123}, pmid = {38643019}, issn = {1460-2156}, support = {82071430//National Natural Science Foundation of China/ ; 22ZR1466400//Shanghai Municipal Natural Science Foundation General Program/ ; //Fundamental Research Funds/ ; //Central Universities/ ; #2021ZD0201100//Science Innovation 2030 - Brain Science and Brain-Inspired Intelligence Technology Major Project/ ; //Ministry of Science and Technology/ ; //ALS Society of Canada and Canadian Consortium on Neurodegeneration in Aging/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; Mice ; Animals ; *Motor Cortex/metabolism/pathology ; Transcriptome ; Genomics/methods ; Prefrontal Cortex/metabolism/pathology ; Motor Neurons/metabolism/pathology ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease with uncertain genetic predisposition in most sporadic cases. The spatial architecture of cell types and gene expression are the basis of cell-cell interactions, biological function and disease pathology, but are not well investigated in the human motor cortex, a key ALS-relevant brain region. Recent studies indicated single nucleus transcriptomic features of motor neuron vulnerability in ALS motor cortex. However, the brain regional vulnerability of ALS-associated genes and the genetic link between region-specific genes and ALS risk remain largely unclear. Here, we developed an entropy-weighted differential gene expression matrix-based tool (SpatialE) to identify the spatial enrichment of gene sets in spatial transcriptomics. We benchmarked SpatialE against another enrichment tool (multimodal intersection analysis) using spatial transcriptomics data from both human and mouse brain tissues. To investigate regional vulnerability, we analysed three human motor cortex and two dorsolateral prefrontal cortex tissues for spatial enrichment of ALS-associated genes. We also used Cell2location to estimate the abundance of cell types in ALS-related cortex layers. To dissect the link of regionally expressed genes and ALS risk, we performed burden analyses of rare loss-of-function variants detected by whole-genome sequencing in ALS patients and controls, then analysed differential gene expression in the TargetALS RNA-sequencing dataset. SpatialE showed more accurate and specific spatial enrichment of regional cell type markers than multimodal intersection analysis in both mouse brain and human dorsolateral prefrontal cortex. Spatial transcriptomic analyses of human motor cortex showed heterogeneous cell types and spatial gene expression profiles. We found that 260 manually curated ALS-associated genes are significantly enriched in layer 5 of the motor cortex, with abundant expression of upper motor neurons and layer 5 excitatory neurons. Burden analyses of rare loss-of-function variants in Layer 5-associated genes nominated NOMO1 as a novel ALS-associated gene in a combined sample set of 6814 ALS patients and 3324 controls (P = 0.029). Gene expression analyses in CNS tissues revealed downregulation of NOMO1 in ALS, which is consistent with a loss-of-function disease mechanism. In conclusion, our integrated spatial transcriptomics and genomic analyses identified regional brain vulnerability in ALS and the association of a layer 5 gene (NOMO1) with ALS risk.}, } @article {pmid38643008, year = {2024}, author = {Zheng, Q and Zeng, Z and Tang, X and Ma, L}, title = {Impact of an ICU bed capacity optimisation method on the average length of stay and average cost of hospitalisation following implementation of China's open policy with respect to COVID-19: a difference-in-differences analysis based on information management system data from a tertiary hospital in southwest China.}, journal = {BMJ open}, volume = {14}, number = {4}, pages = {e078069}, pmid = {38643008}, issn = {2044-6055}, mesh = {Humans ; *COVID-19/epidemiology ; Length of Stay ; Tertiary Care Centers ; Hospitalization ; Intensive Care Units ; China/epidemiology ; Information Management ; }, abstract = {OBJECTIVES: Following the implementation of China's open policy with respect to COVID-19 on 7 December 2022, the influx of patients with infectious diseases has surged rapidly, necessitating hospitals to adopt temporary requisition and modification of ward beds to optimise hospital bed capacity and alleviate the burden of overcrowded patients. This study aims to investigate the effect of an intensive care unit (ICU) bed capacity optimisation method on the average length of stay (ALS) and average cost of hospitalisation (ACH) after the open policy of COVID-19 in China.

DESIGN AND SETTING: A difference-in-differences (DID) approach is employed to analyse and compare the ALS and ACH of patients in four modified ICUs and eight non-modified ICUs within a tertiary hospital located in southwest China. The analysis spans 2 months before and after the open policy, specifically from 5 October 2022 to 6 December 2022, and 7 December 2022 to 6 February 2023.

PARTICIPANTS: We used the daily data extracted from the hospital's information management system for a total of 5944 patients admitted by the outpatient and emergency access during the 2-month periods before and after the release of the open policy in China.

RESULTS: The findings indicate that the ICU bed optimisation method implemented by the tertiary hospital led to a significant reduction in ALS (HR -0.6764, 95% CI -1.0328 to -0.3201, p=0.000) and ACH (HR -0.2336, 95% CI -0.4741 to -0.0068, p=0.057) among ICU patients after implementation of the open policy. These results were robust across various sensitivity analyses. However, the effect of the optimisation method exhibits heterogeneity among patients admitted through the outpatient and emergency channels.

CONCLUSIONS: This study corroborates a significant positive impact of ICU bed optimisation in mitigating the shortage of medical resources following an epidemic outbreak. The findings hold theoretical and practical implications for identifying effective emergency coordination strategies in managing hospital bed resources during sudden public health emergency events. These insights contribute to the advancement of resource management practices and the promotion of experiences in dealing with public health emergencies.}, } @article {pmid38642323, year = {2024}, author = {Ferrari, V and Conti, M and Bovenzi, R and Cerroni, R and Pierantozzi, M and Mercuri, NB and Stefani, A}, title = {Rare association between spinocerebellar ataxia and amyotrophic lateral sclerosis: a case series.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {9}, pages = {4367-4371}, pmid = {38642323}, issn = {1590-3478}, mesh = {Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/complications ; *Spinocerebellar Ataxias/genetics/complications/physiopathology ; *Ataxin-2/genetics ; Trinucleotide Repeat Expansion/genetics ; }, abstract = {INTRODUCTION: In this work, we describe a new case of association between SCA2 and MND.

CASE REPORT: A 58-year-old man who was diagnosed with spinocerebellar ataxia type 2 presented dysphagia and a significant decline in his ability to walk, with a reduction in autonomy and the need to use a wheelchair. We performed electromyography and electroneurography of the four limbs and of the cranial district and motor-evoked potentials to study upper and lower motor neurons. Referring to the revised El Escorial criteria of 2015, ALS diagnosis was made.

DISCUSSION: Considering different cases described in literature over the years, SCA2 could represent an important risk factor for developing ALS. In particular, the presence of alleles of ATXN2 with 27 and 28 CAG repeats seems to slightly decrease the risk of developing the disease, which would instead be progressively increased by the presence of alleles with 29, 30, 31, 32, and 33 repeats. The exact physiopathological mechanism by which the mutation increases the risk of developing the disease is currently unknown. Transcriptomic studies on mouse models have demonstrated the involvement of several pathways, including the innate immunity regulation by STING and the biosynthesis of fatty acid and cholesterol by SREBP.

CONCLUSION: CAG repeat expansions in the ATXN2 gene have been associated with variable neurological presentations, which include SCA2, ALS, Parkinsonism, or a combination of them. Further research is needed to understand the relationship between SCA2 and ALS better and explore molecular underlying mechanisms.}, } @article {pmid38641715, year = {2024}, author = {Udine, E and DeJesus-Hernandez, M and Tian, S and das Neves, SP and Crook, R and Finch, NA and Baker, MC and Pottier, C and Graff-Radford, NR and Boeve, BF and Petersen, RC and Knopman, DS and Josephs, KA and Oskarsson, B and Da Mesquita, S and Petrucelli, L and Gendron, TF and Dickson, DW and Rademakers, R and van Blitterswijk, M}, title = {Abundant transcriptomic alterations in the human cerebellum of patients with a C9orf72 repeat expansion.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {73}, pmid = {38641715}, issn = {1432-0533}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; R01 NS120992/NS/NINDS NIH HHS/United States ; R35 NS097261/NS/NINDS NIH HHS/United States ; R21 NS110994/NS/NINDS NIH HHS/United States ; UH3 NS103870/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R01 AG037491/AG/NIA NIH HHS/United States ; UG3 NS103870/NS/NINDS NIH HHS/United States ; R01 NS121125/NS/NINDS NIH HHS/United States ; RF1 NS123052/NS/NINDS NIH HHS/United States ; RF1 NS120992/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; *Cerebellum/pathology ; DNA Repeat Expansion/genetics ; *Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; Gene Expression Profiling ; Transcriptome ; }, abstract = {The most prominent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a repeat expansion in the gene C9orf72. Importantly, the transcriptomic consequences of the C9orf72 repeat expansion remain largely unclear. Here, we used short-read RNA sequencing (RNAseq) to profile the cerebellar transcriptome, detecting alterations in patients with a C9orf72 repeat expansion. We focused on the cerebellum, since key C9orf72-related pathologies are abundant in this neuroanatomical region, yet TDP-43 pathology and neuronal loss are minimal. Consistent with previous work, we showed a reduction in the expression of the C9orf72 gene and an elevation in homeobox genes, when comparing patients with the expansion to both patients without the C9orf72 repeat expansion and control subjects. Interestingly, we identified more than 1000 alternative splicing events, including 4 in genes previously associated with ALS and/or FTLD. We also found an increase of cryptic splicing in C9orf72 patients compared to patients without the expansion and controls. Furthermore, we demonstrated that the expression level of select RNA-binding proteins is associated with cryptic splice junction inclusion. Overall, this study explores the presence of widespread transcriptomic changes in the cerebellum, a region not confounded by severe neurodegeneration, in post-mortem tissue from C9orf72 patients.}, } @article {pmid38640582, year = {2024}, author = {Ceccanti, M and Libonati, L and Moret, F and D'Andrea, E and Gori, MC and Bersani, FS and Inghilleri, M and Cambieri, C}, title = {Emotion recognition in amyotrophic lateral sclerosis in a dynamic environment.}, journal = {Journal of the neurological sciences}, volume = {460}, number = {}, pages = {123019}, doi = {10.1016/j.jns.2024.123019}, pmid = {38640582}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/physiopathology/complications ; Male ; Female ; Middle Aged ; *Emotions/physiology ; Aged ; *Facial Expression ; Neuropsychological Tests ; Recognition, Psychology/physiology ; Facial Recognition/physiology ; Adult ; }, abstract = {OBJECTIVE: The aim of our study was to measure the ability of ALS patients to process dynamic facial expressions as compared to a control group of healthy subjects and to correlate this ability in ALS patients with neuropsychological, clinical and neurological measures of the disease.

METHODS: Sixty-three ALS patients and 47 healthy controls were recruited. All the ALS patients also underwent i) the Geneva Emotion Recognition Test (GERT) in which ten actors express 14 types of dynamic emotions in brief video clips with audio, ii) the Edimburgh Cognitive and Behavioral ALS Screen (ECAS) test; iii) the ALS Functional Rating Scale Revised (ALSFRS-R) and iv) the Medical Research Council (MRC) for the evaluation of muscle strength. All the healthy subjects enrolled in the study underwent the GERT.

RESULTS: The recognition of irritation and pleasure was significantly different between ALS patients and the control group. The amusement, despair, irritation, joy, sadness and surprise had been falsely recognized differently between the two groups. Specific ALS cognitive impairment was associated with bulbar-onset phenotype (OR = 14,3889; 95%CI = 3,96-52,16). No association was observed between false emotion recognition and cognitive impairment (F(1,60)=,56,971, p=,45,333). The number of categorical errors was significantly higher in the ALS patients than in the control group (27,66 ± 7,28 vs 17,72 ± 5,29; t = 8723; p = 0.001).

CONCLUSIONS: ALS patients show deficits in the dynamic processing of a wide range of emotions. These deficits are not necessarily associated with a decline in higher cognitive functions: this could therefore lead to an underestimation of the phenomenon.}, } @article {pmid38638511, year = {2024}, author = {Finsel, J and Rosenbohm, A and Peter, RS and Bäzner, H and Börtlein, A and Dempewolf, S and Schabet, M and Hecht, M and Kohler, A and Opherk, C and Nägele, A and Sommer, N and Lindner, A and Rothenbacher, D and Ludolph, AC and Nagel, G and Lulé, DE}, title = {Coping as a resource to allow for psychosocial adjustment in fatal disease: results from patients with amyotrophic lateral sclerosis.}, journal = {Frontiers in psychology}, volume = {15}, number = {}, pages = {1361767}, pmid = {38638511}, issn = {1664-1078}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal disorder, which imposes a severe emotional burden on patients. Appropriate coping mechanisms may alleviate this burden and facilitate wellbeing, with social support known to be a successful coping strategy. This observational study aimed to determine the interplay of general coping traits of hope for success and fear of failure, coping behavior of social activity, and patients' wellbeing.

METHODS: In this cross-sectional study, patients with ALS from a clinical-epidemiological registry in Southwestern Germany were interviewed regarding coping traits (achievement-motivated behavior: hope for success and fear of failure), coping behavior of social activity, and psychosocial adjustment, determined using measures of depressiveness, anxiety [both measured by Hospital Anxiety and Depression Scale (HADS)], and quality of life [Anamnestic Comparative Self-Assessment (ACSA)]. Demographics, clinical [ALS Functional Rating Scale revised version (ALSFRS-R)], and survival data were recorded.

RESULTS: A total of 868 patients [60.70% male patients, mean age: 64.70 (±10.83) years, mean ALSFRS-R: 37.36 ± 7.07] were interviewed. Anxiety in patients was found to be associated with a high fear of failure. In contrast, a generally positive attitude in patients exemplified in high hopes for success was associated with better wellbeing. Finally, coping behavior of social activity explained up to 65% of the variance of depressiveness among the patients with ALS.

CONCLUSION: In this study, we present evidence that the wellbeing of patients with ALS is not an immediate fatalistic consequence of physical degradation but rather determined by coping traits and behavior, which may be trained to substantially increase the wellbeing of patients with ALS.}, } @article {pmid38638178, year = {2023}, author = {Fotouhi, M and Worrall, D and Ayoubi, R and Southern, K and McPherson, PS and Laflamme, C and , and , }, title = {A guide to selecting high-performing antibodies for RNA-binding protein TIA1 for use in Western Blot, immunoprecipitation and immunofluorescence.}, journal = {F1000Research}, volume = {12}, number = {}, pages = {745}, pmid = {38638178}, issn = {2046-1402}, mesh = {T-Cell Intracellular Antigen-1/genetics ; *RNA-Binding Proteins ; Blotting, Western ; Fluorescent Antibody Technique ; Immunoprecipitation ; }, abstract = {A member of the RNA-binding protein family, T-cell intracellular antigen-1 (TIA1) regulates mRNA translation and splicing as well as cellular stress by promoting stress granule formation. Variants of the TIA1 gene have implications in neurogenerative disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Reproducible research on TIA1 would be enhanced with the availability of high-quality anti-TIA1 antibodies. In this study, we characterized twelve TIA1 commercial antibodies for Western Blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.}, } @article {pmid38636451, year = {2024}, author = {Khalil, B and Da Cruz, S}, title = {14-3-3θ, a novel player in TDP-43 pathophysiology: Implications for ALS/FTD.}, journal = {Neuron}, volume = {112}, number = {8}, pages = {1197-1199}, doi = {10.1016/j.neuron.2024.03.025}, pmid = {38636451}, issn = {1097-4199}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; DNA-Binding Proteins/genetics ; *Frontotemporal Dementia/genetics ; Mice, Transgenic ; Neurons/pathology ; *TDP-43 Proteinopathies/genetics ; Disease Models, Animal ; }, abstract = {In this issue of Neuron, Ke et al.[1] report a novel non-canonical interaction between 14-3-3θ and TDP-43 that impacts loss-of-function and gain-of-toxic pathology in TDP-43 proteinopathies. The authors further provide proof of principle for a 14-3-3θ-targeted gene therapy to reduce TDP-43-induced deficits in transgenic TDP-43 mutant mice.}, } @article {pmid38636436, year = {2024}, author = {Suazo, KF and Mishra, V and Maity, S and Auger, SA and Justyna, K and Petre, AM and Ottoboni, L and Ongaro, J and Corti, SP and Lotti, F and Przedborski, S and Distefano, MD}, title = {Improved synthesis and application of an alkyne-functionalized isoprenoid analogue to study the prenylomes of motor neurons, astrocytes and their stem cell progenitors.}, journal = {Bioorganic chemistry}, volume = {147}, number = {}, pages = {107365}, pmid = {38636436}, issn = {1090-2120}, support = {R01 NS107442/NS/NINDS NIH HHS/United States ; P30 CA077598/CA/NCI NIH HHS/United States ; R21 NS101575/NS/NINDS NIH HHS/United States ; T32 AG029796/AG/NIA NIH HHS/United States ; T32 GM132029/GM/NIGMS NIH HHS/United States ; R35 GM141853/GM/NIGMS NIH HHS/United States ; }, mesh = {*Astrocytes/metabolism/cytology ; Animals ; *Protein Prenylation ; *Alkynes/chemistry/chemical synthesis ; *Motor Neurons/metabolism/cytology ; Terpenes/chemistry/chemical synthesis/metabolism ; Mice ; Molecular Structure ; Cells, Cultured ; }, abstract = {Protein prenylation is one example of a broad class of post-translational modifications where proteins are covalently linked to various hydrophobic moieties. To globally identify and monitor levels of all prenylated proteins in a cell simultaneously, our laboratory and others have developed chemical proteomic approaches that rely on the metabolic incorporation of isoprenoid analogues bearing bio-orthogonal functionality followed by enrichment and subsequent quantitative proteomic analysis. Here, several improvements in the synthesis of the alkyne-containing isoprenoid analogue C15AlkOPP are reported to improve synthetic efficiency. Next, metabolic labeling with C15AlkOPP was optimized to obtain useful levels of metabolic incorporation of the probe in several types of primary cells. Those conditions were then used to study the prenylomes of motor neurons (ES-MNs), astrocytes (ES-As), and their embryonic stem cell progenitors (ESCs), which allowed for the identification of 54 prenylated proteins from ESCs, 50 from ES-MNs, and 84 from ES-As, representing all types of prenylation. Bioinformatic analysis revealed specific enriched pathways, including nervous system development, chemokine signaling, Rho GTPase signaling, and adhesion. Hierarchical clustering showed that most enriched pathways in all three cell types are related to GTPase activity and vesicular transport. In contrast, STRING analysis showed significant interactions in two populations that appear to be cell type dependent. The data provided herein demonstrates that robust incorporation of C15AlkOPP can be obtained in ES-MNs and related primary cells purified via magnetic-activated cell sorting allowing the identification and quantification of numerous prenylated proteins. These results suggest that metabolic labeling with C15AlkOPP should be an effective approach for investigating the role of prenylated proteins in primary cells in both normal cells and disease pathologies, including ALS.}, } @article {pmid38635657, year = {2024}, author = {Castellanos Otero, P and Todd, TW and Shao, W and Jones, CJ and Huang, K and Daughrity, LM and Yue, M and Sheth, U and Gendron, TF and Prudencio, M and Oskarsson, B and Dickson, DW and Petrucelli, L and Zhang, YJ}, title = {Generation and characterization of monoclonal antibodies against pathologically phosphorylated TDP-43.}, journal = {PloS one}, volume = {19}, number = {4}, pages = {e0298080}, pmid = {38635657}, issn = {1932-6203}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; RF1 AG062171/AG/NIA NIH HHS/United States ; RF1 AG062077/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R21 NS127331/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R01 NS117461/NS/NINDS NIH HHS/United States ; P01 NS099114/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; }, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/pathology ; Antibodies, Monoclonal ; HEK293 Cells ; DNA-Binding Proteins/genetics ; *TDP-43 Proteinopathies ; }, abstract = {Inclusions containing TAR DNA binding protein 43 (TDP-43) are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). One of the disease-specific features of TDP-43 inclusions is the aberrant phosphorylation of TDP-43 at serines 409/410 (pS409/410). Here, we developed rabbit monoclonal antibodies (mAbs) that specifically detect pS409/410-TDP-43 in multiple model systems and FTD/ALS patient samples. Specifically, we identified three mAbs (26H10, 2E9 and 23A1) from spleen B cell clones that exhibit high specificity and sensitivity to pS409/410-TDP-43 peptides in an ELISA assay. Biochemical analyses revealed that pS409/410 of recombinant TDP-43 and of exogenous 25 kDa TDP-43 C-terminal fragments in cultured HEK293T cells are detected by all three mAbs. Moreover, the mAbs detect pS409/410-positive TDP-43 inclusions in the brains of FTD/ALS patients and mouse models of TDP-43 proteinopathy by immunohistochemistry. Our findings indicate that these mAbs are a valuable resource for investigating TDP-43 pathology both in vitro and in vivo.}, } @article {pmid38633814, year = {2024}, author = {Zhang, S and Moll, T and Rubin-Sigler, J and Tu, S and Li, S and Yuan, E and Liu, M and Butt, A and Harvey, C and Gornall, S and Alhalthli, E and Shaw, A and Souza, CDS and Ferraiuolo, L and Hornstein, E and Shelkovnikova, T and van Dijk, CH and Timpanaro, IS and Kenna, KP and Zeng, J and Tsao, PS and Shaw, PJ and Ichida, JK and Cooper-Knock, J and Snyder, MP}, title = {Deep learning modeling of rare noncoding genetic variants in human motor neurons defines CCDC146 as a therapeutic target for ALS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38633814}, support = {/WT_/Wellcome Trust/United Kingdom ; P50 HG007735/HG/NHGRI NIH HHS/United States ; R01 NS097850/NS/NINDS NIH HHS/United States ; R01 NS131409/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease caused by the selective and progressive death of motor neurons (MNs). Understanding the genetic and molecular factors influencing ALS survival is crucial for disease management and therapeutics. In this study, we introduce a deep learning-powered genetic analysis framework to link rare noncoding genetic variants to ALS survival. Using data from human induced pluripotent stem cell (iPSC)-derived MNs, this method prioritizes functional noncoding variants using deep learning, links cis-regulatory elements (CREs) to target genes using epigenomics data, and integrates these data through gene-level burden tests to identify survival-modifying variants, CREs, and genes. We apply this approach to analyze 6,715 ALS genomes, and pinpoint four novel rare noncoding variants associated with survival, including chr7:76,009,472:C>T linked to CCDC146. CRISPR-Cas9 editing of this variant increases CCDC146 expression in iPSC-derived MNs and exacerbates ALS-specific phenotypes, including TDP-43 mislocalization. Suppressing CCDC146 with an antisense oligonucleotide (ASO), showing no toxicity, completely rescues ALS-associated survival defects in neurons derived from sporadic ALS patients and from carriers of the ALS-associated G4C2-repeat expansion within C9ORF72. ASO targeting of CCDC146 may be a broadly effective therapeutic approach for ALS. Our framework provides a generic and powerful approach for studying noncoding genetics of complex human diseases.}, } @article {pmid38632611, year = {2024}, author = {Dai, T and Lou, J and Kong, D and Li, J and Ren, Q and Chen, Y and Sun, S and Yun, Y and Sun, X and Yang, Y and Shao, K and Li, W and Zhao, Y and Meng, X and Yan, C and Lin, P and Liu, S}, title = {Choroid plexus enlargement in amyotrophic lateral sclerosis patients and its correlation with clinical disability and blood-CSF barrier permeability.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {36}, pmid = {38632611}, issn = {2045-8118}, support = {22-8-7-smjk-1-nsh//Qingdao Science and Technology Benefit People Demonstration Guide Special Project/ ; 2020M672067//China Postdoctoral Science Foundation/ ; NSFC82001354//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Humans ; Choroid Plexus ; *Amyotrophic Lateral Sclerosis ; Retrospective Studies ; *Neurodegenerative Diseases ; Capillary Permeability ; }, abstract = {BACKGROUND: Using in vivo neuroimaging techniques, growing evidence has demonstrated that the choroid plexus (CP) volume is enlarged in patients with several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. However, although animal and postmortem findings suggest that CP abnormalities are likely important pathological mechanisms underlying amyotrophic lateral sclerosis (ALS), the third most common neurodegenerative disease, no available study has been conducted to thoroughly assess CP abnormalities and their clinical relevance in vivo in ALS patients to date. Thus, we aimed to determine whether in vivo CP enlargement may occur in ALS patients. We also aimed to identify the relationships of CP volume with clinical disabilities and blood-CSF barrier (BCSFB) permeability in ALS patients.

METHODS: In this retrospective study, based on structural MRI data, CP volume was assessed using a Gaussian mixture model and underwent further manual correction in 155 ALS patients and 105 age- and sex-matched HCs from October 2021 to April 2023. The ALS Functional Rating Scale-Revised (ALSFRS-R) was used to assess clinical disability. The CSF/serum albumin quotient (Qalb) was used to assess BCSFB permeability. Moreover, all the ALS patients completed genetic testing, and according to genetic testing, the ALS patients were further divided into genetic ALS subgroup and sporadic ALS subgroup.

RESULTS: We found that compared with HCs, ALS patients had a significantly higher CP volume (p < 0.001). Moreover, compared with HCs, CP volume was significantly increased in both ALS patients with and without known genetic mutations after family-wise error correction (p = 0.006 and p < 0.001, respectively), while there were no significant differences between the two ALS groups. Furthermore, the CP volume was significantly correlated with the ALSFRS-r score (r = -0.226; p = 0.005) and the Qalb (r = 0.479; p < 0.001) in ALS patients.

CONCLUSION: Our study first demonstrates CP enlargement in vivo in ALS patients, and continues to suggest an important pathogenetic role for CP abnormalities in ALS. Moreover, assessing CP volume is likely a noninvasive and easy-to-implement approach for screening BCSFB dysfunction in ALS patients.}, } @article {pmid38632300, year = {2024}, author = {Shiramasa, Y and Yamamoto, R and Kashiwagi, N and Sasaki, F and Imai, S and Ike, M and Kitazawa, S and Kameda, T and Kitahara, R}, title = {An aberrant fused in sarcoma liquid droplet of amyotrophic lateral sclerosis pathological variant, R495X, accelerates liquid-solid phase transition.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {8914}, pmid = {38632300}, issn = {2045-2322}, support = {JP23H02626//JSPS KAKENHI/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Phase Transition ; *RNA-Binding Protein FUS/genetics/metabolism ; *Sarcoma ; }, abstract = {Intracellular aggregation of fused in sarcoma (FUS) is associated with the pathogenesis of familial amyotrophic lateral sclerosis (ALS). Under stress, FUS forms liquid droplets via liquid-liquid phase separation (LLPS). Two types of wild-type FUS LLPS exist in equilibrium: low-pressure LLPS (LP-LLPS) and high-pressure LLPS (HP-LLPS); the former dominates below 2 kbar and the latter over 2 kbar. Although several disease-type FUS variants have been identified, the molecular mechanism underlying accelerated cytoplasmic granule formation in ALS patients remains poorly understood. Herein, we report the reversible formation of the two LLPS states and the irreversible liquid-solid transition, namely droplet aging, of the ALS patient-type FUS variant R495X using fluorescence microscopy and ultraviolet-visible absorption spectroscopy combined with perturbations in pressure and temperature. Liquid-to-solid phase transition was accelerated in the HP-LLPS of R495X than in the wild-type variant; arginine slowed the aging of droplets at atmospheric conditions by inhibiting the formation of HP-LLPS more selectively compared to that of LP-LLPS. Our findings provide new insight into the mechanism by which R495X readily forms cytoplasmic aggregates. Targeting the aberrantly formed liquid droplets (the HP-LLPS state) of proteins with minimal impact on physiological functions could be a novel therapeutic strategy for LLPS-mediated protein diseases.}, } @article {pmid38631798, year = {2024}, author = {Gerecht, RB and Nable, JV}, title = {Out-of-Hospital Cardiac Arrest.}, journal = {Cardiology clinics}, volume = {42}, number = {2}, pages = {317-331}, doi = {10.1016/j.ccl.2024.02.014}, pmid = {38631798}, issn = {1558-2264}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest ; *Cardiopulmonary Resuscitation ; *Emergency Medical Services ; }, abstract = {Survival from out-of-hospital cardiac arrest (OHCA) is predicated on a community and system-wide approach that includes rapid recognition of cardiac arrest, capable bystander CPR, effective basic and advanced life support (BLS and ALS) by EMS providers, and coordinated postresuscitation care. Management of these critically ill patients continues to evolve. This article focuses on the management of OHCA by EMS providers.}, } @article {pmid38631307, year = {2024}, author = {Büssing, A and Recchia, DR and Ortiz, M}, title = {[Validierung eines Fragebogeninstrumentes zur Erfassung des Erlebens von Natur: Die Experience of Nature Scale].}, journal = {Complementary medicine research}, volume = {31}, number = {4}, pages = {309-318}, doi = {10.1159/000538807}, pmid = {38631307}, issn = {2504-2106}, mesh = {Humans ; Surveys and Questionnaires/standards ; Female ; Male ; Cross-Sectional Studies ; Adult ; Middle Aged ; Reproducibility of Results ; *Nature ; Psychometrics ; Aged ; Young Adult ; Adolescent ; }, abstract = {UNLABELLED: Hintergrund: In den letzten Jahren ist insbesondere die Natur als Ressource in das Interesse der gesundheitspsychologischen Forschung gerückt. In Ergänzung zum etablierten Konzept der Naturzuwendung als Haltung wurde ein For-schungsinstrument zum Naturerleben entwickelt, welches das subjektive, teilweise intentionale Erleben von Natur unter unterschiedlichen Aspekten beleuchtet. Dazu gehören insbesondere Natur als Erlebensraum, um sich von der Alltagsbelastung distanzieren zu können, um Auszeiten durch Ruhe und Stille finden zu können, um emotionale Ausgeglichenheit zu erlangen, Natur als Ort der Faszination und des Staunens, Naturerleben als Basis für einen verantwortlichen Umgang mit der Natur. Das Manuskript zeigt die Ergebnisse der Validierung des neu entwickelten Fragebogeninstrumentes zum Naturerleben. Methoden: Eine anonyme Online-Querschnittsstudie unter 441 Teilnehmenden wurde mit standardisierten Fragebogeninstrumenten zur Validie-rung der Experience of Nature Scale (ENS) mittels explorativer Faktoren- (Hauptkomponentenanalyse mit Varimax-Rotation) und Reliabilitätsanalysen (Cronbachs α) durchgeführt. Ergebnisse: Die explorative Faktorenanalyse der Naturerlebens-Skala mit 11 Items ergab drei Hauptfaktoren mit guter interner Kongruenz, die 71% der Varianz erklären: (1) Alltagsdistanzierung/Entspannung (Cronbachs α = 0,87), (2) Faszination Natur/Staunen (Cronbachs α = 0,82) und (3) Verantwortungsempfinden für Natur (Cronbachs α = 0,85). Diese Faktoren korrelierten stark mit der Naturverbundenheit (NR-6) und moderat bis stark mit Ehrfurcht/Dankbarkeit (GrAw-7) im Sinne der Konvergenzvalidität, aber nur marginal bis schwach mit psychologischem Wohlbefinden (WHO-5). Schlussfolgerungen: Die ENS zur Erfassung des affektiven Erlebens von Natur hat gute psychometrische Qua-litätsindizes und kann in künftigen Studien zur Bedeutung dieses Erlebens von Natur zum Beispiel als Prädiktor- oder Prozessvariable eingesetzt werden.

BACKGROUND: In recent years, nature as a resource in particular has become of interest in health psychology research. In addition to the established concept of nature-relatedness as an attitude, a research instrument was developed that focuses on the subjective experience of nature in different aspects. This includes nature as an area for experiencing, to distance oneself from the stress of everyday life, to find times for peace and quietness, as a place of fascination and amazement, resulting in greater emotional balance, and experiencing nature as a basis for a responsible approach to nature. Therefore, the newly developed instrument to assess nature experiences should be validated in a cohort of healthy volunteers.

METHODS: We conducted an anonymous cross-sectional analysis among 441 participants with standardized instruments to validate the Experience of Nature Scale (ENS) using exploratory factor analysis (principal component analysis with Varimax rotation) and reliability analysis (Cronbach’s α).

RESULTS: The exploratory factor analysis of the 11-item ENS revealed three main factors with good internal congruence, explaining 71% of the variance: (1) detachment from everyday life/relaxation (Cronbach’s α = 0.87), (2) fascination with nature/wondering (Cronbach’s α = 0.82), and (3) sense of responsibility for nature (Cronbach’s α = 0.85). In terms of convergent validity, the three factors correlated strongly with nature-relatedness (NR-6) and moderately to strongly with awe/gratitude (GrAw-7), but only marginally to weakly with psychological well-being (WHO-5).

CONCLUSIONS: The ENS for assessing the affective experience of nature shows good psychometric quality indices and could be used as a predictor and process variable in future studies addressing the meaning of this experience of nature.}, } @article {pmid38630299, year = {2024}, author = {Wolff, A and Demleitner, AF and Feneberg, E and Lingor, P}, title = {[Smell the smoke before one sees the fire-The oligosymptomatic prodromal phase of neurodegenerative diseases].}, journal = {Der Nervenarzt}, volume = {95}, number = {8}, pages = {689-696}, pmid = {38630299}, issn = {1433-0407}, mesh = {*Neurodegenerative Diseases/diagnosis ; *Prodromal Symptoms ; Humans ; *Early Diagnosis ; *Biomarkers/blood ; Disease Progression ; }, abstract = {BACKGROUND: With the increasing development of disease-modifying causative treatment, the importance of early diagnosis and detection of asymptomatic or oligosymptomatic early stages of neurodegenerative diseases is increasing.

OBJECTIVE: Presentation of early stages of neurodegenerative diseases, diagnostic procedures for the early detection and possible treatment consequences.

MATERIAL AND METHODS: Selective literature search, discussion of basic research and expert recommendations.

RESULTS: Many neurodegenerative diseases have a prodromal phase preceding the manifest disease that can be diagnosed with current criteria. In this prodromal phase, those affected are often oligosymptomatic but in some cases can already be identified using biomarkers. These developments are already taken into account in diagnostic criteria for some of these prodromal phases. The prodromal phase, in turn, is preceded by an asymptomatic phase which, however, already shows molecular changes and can be identified by biomarkers in some diseases. The early identification and stratification of patients is particularly important when planning studies for disease-modifying treatment, and biomarkers are already being used in clinical trials for this purpose.

DISCUSSION: Biomarker-based identification of individuals in the prodromal phase of neurodegenerative diseases is already possible for some entities. People who show the first signs of a neurodegenerative disease can be referred to centers for clinical trials and observational studies.}, } @article {pmid38628839, year = {2023}, author = {Uzunoglu-Ozyurek, E and Önal, G and Dökmeci, S}, title = {Investigating the Therapeutics Effects of Oral Cavity Derived Stem Cells on Neurodegenerative Diseases: A Systematic Review.}, journal = {Basic and clinical neuroscience}, volume = {14}, number = {5}, pages = {565-584}, pmid = {38628839}, issn = {2008-126X}, abstract = {INTRODUCTION: Published data obtained from in vitro and in vivo studies was reviewed systematically and analyzed critically to evaluate the effect of oral cavity-derived stem cells (OCDSCs) on the recovery or therapy of neurodegenerative diseases (NDs), such as Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), Huntington (HD) diseases, and Parkinson disease (PD).

METHODS: An electronic search was accomplished. References of included articles were also manually searched. Studies were critically evaluated for suitability against the inclusion/exclusion criteria and the data was extracted. Bias risk evaluation of the studies and evidence synthesis were conducted.

RESULTS: A total of 14 in vivo and 10 in vitro studies met the inclusion criteria. PD was induced in 10 in vivo and 7 in vitro studies, while AD was induced in 2 in vivo and 4 in vitro studies. Two studies (1 in vitro and 1 in vivo) evaluated ALS disease and 1 in vivo study evaluated HD. Moderate evidence was found for in vitro studies reporting the positive effect of OCDSCs on PD or AD recovery. Strong evidence was found for in vivo studies in which PD animal models were used; meanwhile, moderate evidence was found for the impact of OCDSCs on AD recovery. Limited evidence was found for in vivo studies evaluating HD and ALS.

CONCLUSION: Although studies reported favorable data regarding the OCDSCs on NDs, they presented a considerable risk of bias. Because of heterogeneous study characteristics, the current study recommends improving standardized methods to evaluate the therapeutic effects of OCDSCs on the NDs.}, } @article {pmid38628797, year = {2024}, author = {Sabnis, RW}, title = {Novel Isoxazolidines as RIPK1 Inhibitors for Treating Alzheimer's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis.}, journal = {ACS medicinal chemistry letters}, volume = {15}, number = {4}, pages = {447-448}, pmid = {38628797}, issn = {1948-5875}, abstract = {Provided herein are novel isoxazolidines as RIPK1 inhibitors, pharmaceutical compositions, use of such compounds in treating Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS), and processes for preparing such compounds.}, } @article {pmid38628764, year = {2024}, author = {Zhao, T and Duan, S and Li, J and Zheng, H and Liu, C and Zhang, H and Luo, H and Xu, Y}, title = {Mapping of repeat-associated non-AUG (RAN) translation knowledge: A bibliometric analysis.}, journal = {Heliyon}, volume = {10}, number = {8}, pages = {e29141}, pmid = {38628764}, issn = {2405-8440}, abstract = {Over 50 genetic human disorders are attributed to the irregular expansion of microsatellites. These expanded microsatellite sequences can experience bidirectional transcription, leading to new reading frames. Beyond the standard AUG initiation or adjacent start codons, they are translated into proteins characterized by disease-causing amino acid repeats through repeat-associated non-AUG translation. Despite its significance, there's a discernible gap in comprehensive and objective articles on RAN translation. This study endeavors to evaluate and delineate the contemporary landscape and progress of RAN translation research via a bibliometric analysis. We sourced literature on RAN translation from the Web of Science Core Collection. Utilizing two bibliometric analysis tools, CiteSpace and VOSviewer, we gauged individual impacts and interactions by examining annual publications, journals, co-cited journals, countries/regions, institutions, authors, and co-cited authors. Following this, we assessed the co-occurrence and bursts of keywords and co-cited references to pinpoint research hotspots and trending in RAN translation. Between 2011 and 2022, 1317 authors across 359 institutions from 34 countries/regions contributed to 250 publications on RAN translation, spread across 118 academic journals. This article presents a systematic, objective, and comprehensive analysis of the current literature on RAN translation. Our findings emphasize that mechanisms related to C9orf72 ALS/FTD are pivotal topics in the realm of RAN translation, with cellular stress and the utilization of small molecule marking the trending research areas.}, } @article {pmid38628040, year = {2025}, author = {Howard, J and Forrest Keenan, K and Mazanderani, F and Turner, MR and Locock, L}, title = {Experiences of predictive genetic testing in inherited motor neuron disease: Findings from a qualitative interview study.}, journal = {Journal of genetic counseling}, volume = {34}, number = {1}, pages = {e1904}, pmid = {38628040}, issn = {1573-3599}, support = {Locock/Sept19/941-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; //University of Aberdeen/ ; }, mesh = {Humans ; *Motor Neuron Disease/genetics/psychology ; *Genetic Testing/methods ; Female ; Qualitative Research ; Male ; Adult ; Middle Aged ; Genetic Predisposition to Disease ; Interviews as Topic ; }, abstract = {Predictive genetic testing is increasingly available for individuals with a heightened risk of motor neuron disease (MND). However, little is known about how they decide whether or not to get tested, and how they experience this process. This paper reports findings from a constructivist grounded theory-informed interview study with 24 family members of people with identified or suspected inherited MND (iMND). Fourteen did not know their genetic status, and nine had decided to have predictive testing, of whom six tested positive for the pathogenic gene variant identified in their family and three tested negative. One additional person was identified as negative through a parent's negative result. This paper explores the diverse ways people approached testing, and the many factors and motivations involved, based on personal attitudes and goals, experiences of living with genetic risk, and wider family considerations and circumstances. Results were met with a range of emotions; whatever the outcome, the news disrupted each person's view of the future, and they adapted in their own way and time. Support after results was variable and a perceived lack of support impacted coping and the ability to move forwards. This paper situates findings against literature on other genetic conditions, highlighting experiences as grounded in the unique characteristics of iMND. Thus, it emphasizes the need for disease-specific guidelines and support structures around predictive genetic testing in this context. Understanding people's experiences and responding to these needs is particularly timely given the uptake of testing amongst this group is anticipated to rise with increasing access to genetic testing for people with MND, and gene-specific clinical trials.}, } @article {pmid38627418, year = {2024}, author = {Bales, I and Zhang, H}, title = {A six degrees-of-freedom cable-driven robotic platform for head-neck movement.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {8750}, pmid = {38627418}, issn = {2045-2322}, support = {2240508//National Science Foundation/ ; }, mesh = {Humans ; *Robotics/methods ; *Robotic Surgical Procedures ; Movement/physiology ; Head Movements/physiology ; *Exoskeleton Device ; *Nervous System Diseases ; }, abstract = {This paper introduces a novel cable-driven robotic platform that enables six degrees-of-freedom (DoF) natural head-neck movements. Poor postural control of the head-neck can be a debilitating symptom of neurological disorders such as amyotrophic lateral sclerosis and cerebral palsy. Current treatments using static neck collars are inadequate, and there is a need to develop new devices to empower movements and facilitate physical rehabilitation of the head-neck. State-of-the-art neck exoskeletons using lower DoF mechanisms with rigid linkages are limited by their hard motion constraints imposed on head-neck movements. By contrast, the cable-driven robot presented in this paper does not constrain motion and enables wide-range, 6-DoF control of the head-neck. We present the mechatronic design, validation, and control implementations of this robot, as well as a human experiment to demonstrate a potential use case of this versatile robot for rehabilitation. Participants were engaged in a target reaching task while the robot applied both assistive and resistive moments on the head during the task. Our results show that neck muscle activation increased by 19% when moving the head against resistance and decreased by 28-43% when assisted by the robot. Overall, these results provide a scientific justification for further research in enabling movement and identifying personalized rehabilitation for motor training. Beyond rehabilitation, other applications such as applying force perturbations on the head to study sensory integration and applying traction to achieve pain relief may benefit from the innovation of this robotic platform which is capable of applying controlled 6-DoF forces/moments on the head.}, } @article {pmid38627359, year = {2024}, author = {Magrì, A and Lipari, CLR and Caccamo, A and Battiato, G and Conti Nibali, S and De Pinto, V and Guarino, F and Messina, A}, title = {AAV-mediated upregulation of VDAC1 rescues the mitochondrial respiration and sirtuins expression in a SOD1 mouse model of inherited ALS.}, journal = {Cell death discovery}, volume = {10}, number = {1}, pages = {178}, pmid = {38627359}, issn = {2058-7716}, abstract = {Mitochondrial dysfunction represents one of the most common molecular hallmarks of both sporadic and familial forms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder caused by the selective degeneration and death of motor neurons. The accumulation of misfolded proteins on and within mitochondria, as observed for SOD1 G93A mutant, correlates with a drastic reduction of mitochondrial respiration and the inhibition of metabolites exchanges, including ADP/ATP and NAD[+]/NADH, across the Voltage-Dependent Anion-selective Channel 1 (VDAC1), the most abundant channel protein of the outer mitochondrial membrane. Here, we show that the AAV-mediated upregulation of VDAC1 in the spinal cord of transgenic mice expressing SOD1 G93A completely rescues the mitochondrial respiratory profile. This correlates with the increased activity and levels of key regulators of mitochondrial functions and maintenance, namely the respiratory chain Complex I and the sirtuins (Sirt), especially Sirt3. Furthermore, the selective increase of these mitochondrial proteins is associated with an increase in Tom20 levels, the receptor subunit of the TOM complex. Overall, our results indicate that the overexpression of VDAC1 has beneficial effects on ALS-affected tissue by stabilizing the Complex I-Sirt3 axis.}, } @article {pmid38627298, year = {2024}, author = {Hamad, AA and Amer, BE}, title = {Safety of masitinib in patients with neurodegenerative diseases: a meta-analysis of randomized controlled trials.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {7}, pages = {3503-3507}, pmid = {38627298}, issn = {1590-3478}, mesh = {Humans ; *Randomized Controlled Trials as Topic ; *Thiazoles/adverse effects/administration & dosage/therapeutic use ; *Neurodegenerative Diseases/drug therapy ; *Piperidines/adverse effects/therapeutic use/administration & dosage ; *Benzamides/adverse effects/administration & dosage ; *Pyridines/adverse effects/administration & dosage/therapeutic use ; Protein Kinase Inhibitors/adverse effects/administration & dosage ; }, abstract = {OBJECTIVES: This meta-analysis aimed to examine the safety of masitinib in patients with neurodegenerative diseases.

METHODS: We considered randomized controlled trials (RCTs) comparing different doses of masitinib versus placebo. We performed our analysis using the R (v.4.3.0) programming language and the incidence of adverse events was pooled using risk ratio (RR) and 95% confidence interval (CI).

RESULTS: We included five RCTs, focusing on multiple sclerosis (MS), Alzheimer's disease (AD), and amyotrophic lateral sclerosis. The meta-analysis revealed a significantly higher incidence of adverse events in the masitinib group compared to the control group, regardless of adverse event grade and masitinib dose (RR = 1.12, 95% CI [1.07 to 1.17], P < 0.01). Adverse events categorized as severe, non-fatal serious, leading to dose reduction, and leading to permanent discontinuation also showed a higher incidence in the masitinib group (P ≤ 0.01). Subgroup analysis for AD and MS supported these findings. The pooled incidence of adverse events, regardless of their grade, was higher in the masitinib group for both the 3 mg/kg/d dose (RR = 1.13, P = 0.01) and the 4.5 mg/kg/d dose (RR = 1.11, P < 0.01). However, there was no significant difference between masitinib 3 mg/kg/d dose and placebo regarding severe and non-fatal serious adverse events for the.

CONCLUSION: Masitinib use in neurodegenerative diseases presents safety concerns that may impact patients' quality of life and require management. Further research is recommended to determine the optimal dose with minimal safety concerns in this patient population.}, } @article {pmid38627230, year = {2024}, author = {Taufik, SA and Ramli, N and Tan, AH and Lim, SY and Ghani, MTA and Shahrizaila, N}, title = {Longitudinal Changes in the Retinal Nerve Fiber Layer Thickness in Amyotrophic Lateral Sclerosis and Parkinson's Disease.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {20}, number = {3}, pages = {285-292}, pmid = {38627230}, issn = {1738-6586}, abstract = {BACKGROUND AND PURPOSE: There is increasing evidence that the anterior visual pathways are involved in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). This study investigated longitudinal changes in retinal nerve fiber layer (RNFL) thickness in patients with ALS and PD with the aim of better understanding their roles as biomarkers of disease progression.

METHODS: This study recruited 21 ALS patients, 19 age-matched PD patients, and 21 agematched healthy controls. Patient demographics and clinical scores relating to the respective diseases were documented. The RNFL thickness was measured using optical coherence tomography at baseline and after 6 months.

RESULTS: At baseline, the RNFL in the superior quadrant was significantly thinner in the patients with ALS than in healthy controls (109.90±22.41 µm vs. 127.81±17.05 µm [mean±standard deviation], p=0.008). The RNFL thickness did not differ significantly between the ALS and PD patients or between the PD patients and healthy controls. At 6 months, there was further significant RNFL thinning in patients with ALS, for both the overall thickness (baseline: median=94.5 µm, range=83.0-106.0 µm; follow-up: median=93.5 µm, range=82.5-104.5 µm, p=0.043) and the thickness in the inferior quadrant (median=126 µm, range=109.5-142.5 µm; and median=117.5 µm, range=98.5-136.5 µm; respectively, p=0.032). However, these changes were not correlated with the ALS functional scores. In contrast, the patients with PD did not demonstrate a significant change in RNFL thickness between the two time points.

CONCLUSIONS: The RNFL thickness is a promising biomarker of disease progression in patients with ALS but not in those with PD, which has a slower disease progression.}, } @article {pmid38626361, year = {2024}, author = {Murdock, BJ and Zhao, B and Pawlowski, KD and Famie, JP and Piecuch, CE and Webber-Davis, IF and Teener, SJ and Feldman, EL and Zhao, L and Goutman, SA}, title = {Peripheral Immune Profiles Predict ALS Progression in an Age- and Sex-Dependent Manner.}, journal = {Neurology(R) neuroimmunology & neuroinflammation}, volume = {11}, number = {3}, pages = {e200241}, pmid = {38626361}, issn = {2332-7812}, support = {R01 TS000327/TS/ATSDR CDC HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; UL1 TR002240/TR/NCATS NIH HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R21 NS102960/NS/NINDS NIH HHS/United States ; }, mesh = {Male ; Humans ; Female ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases ; Disease Progression ; Prognosis ; Biomarkers ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease whose pathobiology associates with peripheral blood immune cell levels and activation patterns in an age and sex-dependent manner. This study's objective was to identify immune profile associations with ALS progression, whether the associations are age and sex-specific, and whether immune profiles can predict a future disease course.

METHODS: Flow cytometry immune profiles (a combination of 22 peripheral blood immune markers) were generated for 241 participants with ALS and linked to ALS progression, using progression-free survival, which is a composite combining the revised ALS Functional Rating Scale and survival. Participants were first grouped by immune profiles using unsupervised hierarchical clustering, and clusters were associated with subsequent progression-free survival. Next, individual immune markers were associated with progression-free survival using least absolute shrinkage and selection operator-Cox regression. Analyses were stratified by age and sex to identify demographic-specific immune mechanisms. Finally, random forest determined the predictive power of immune profiles on ALS progression in the whole population and again stratified by age and sex.

RESULTS: Progression-free survival differed between clusters of participants with similar immune profiles, particularly reduced natural killer (NK)-cell activation associated with slower progression. Individual markers such as neutrophil levels and NK-cell NKp46 expression associated with faster ALS progression while overall NK-cell levels and NK-cell subpopulations associated with slower progression; the strength of these associations varied by age and sex. Adding these immune markers to prediction models dramatically increased short-term prediction compared with routine clinical prognostic variables alone, and the addition of NK-cell markers further improved the prediction accuracy in female participants.

DISCUSSION: Specific immune profiles likely contribute to ALS progression in an age and sex-dependent manner, and peripheral immune markers enhance the prediction of short-term clinical outcomes. These findings suggest a complex milieu of immune profiles associated with ALS progression, and more detailed immunophenotyping in ALS will facilitate personalized immunotherapeutics in ALS.}, } @article {pmid38625841, year = {2024}, author = {Savant, R and Pradhan, RK and Bhagat, S and Mythri, RB and Varghese, AM and Vengalil, S and Nalini, A and Sathyaprabha, TN and Raju, TR and Vijayalakshmi, K}, title = {Enhanced levels of fractalkine and HSP60 in cerebrospinal fluid of sporadic amyotrophic lateral sclerosis patients.}, journal = {The International journal of neuroscience}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/00207454.2024.2344581}, pmid = {38625841}, issn = {1563-5279}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a multifactorial neurodegenerative disorder with a significant contribution of non-cell autonomous mechanisms to motor neuronal degeneration. Amongst a plethora of molecules, fractalkine (C-X3-C motif chemokine ligand 1), and Heat Shock Protein 60 (HSP60), are key modulators of microglial activation. The contribution of these molecules in Sporadic ALS (SALS) remains unexplored. To investigate this, fractalkine levels were estimated in Cerebrospinal fluid (CSF) of SALS patients (ALS-CSF; n = 44) by Enzyme-linked Immunosorbent Assay (ELISA) and correlated with clinical parameters including disease severity and duration. CSF HSP60 levels were estimated by Western blotting (ALS-CSF; n = 19). Also, CSF levels of Chitotriosidase-1 (CHIT-1), a microglia-specific neuroinflammatory molecule, were measured and its association, if any, with fractalkine and HSP60 was investigated. Both fractalkine and HSP60 levels were significantly elevated in ALS-CSF. Similar to our earlier observation, CHIT-1 levels were also upregulated. Fractalkine showed a moderate negative correlation with the ALS-Functional Rating Scale (ALSFRS) score indicating its significant rise in mild cases which plateaued in cases with high disease severity. However, no obvious correlation was found between fractalkine, HSP60, and CHIT-1. Our study hints that high fractalkine levels in mild cases might be conferring neuroprotection by combating microglial activation and highlights its importance as a novel therapeutic target for SALS. On the other hand, significantly enhanced levels of HSP60, a pro-inflammatory molecule, hint towards its role in accentuating microgliosis, although, it doesn't act synergistically with CHIT-1. Our study suggests that fractalkine and HSP60 act independently of CHIT-1 to suppress and accentuate neuroinflammation, respectively.}, } @article {pmid38625649, year = {2024}, author = {Chen, L and Ye, S and Murphy, D and Wu, J and Zhang, H and Liu, H and Zou, B and Hou, G and Zhang, N and Yin, T and Smith, RA and Fan, D}, title = {Chinese Translation and Validation of the Center for Neurologic Study Lability Scale.}, journal = {Neurology and therapy}, volume = {13}, number = {3}, pages = {739-747}, pmid = {38625649}, issn = {2193-8253}, support = {81873784//National Natural Science Foundation of China/ ; 82071426//National Natural Science Foundation of China/ ; }, abstract = {INTRODUCTION: Pseudobulbar palsy is a common symptom in patients with amyotrophic lateral sclerosis (ALS), but it is often underdiagnosed or misdiagnosed as other diseases. The Center for Neurologic Study Lability Scale (CNS-LS) is a self-report scale consisting of seven questions designed for evaluating pseudobulbar affect (PBA). The current study aimed to validate a Chinese version of the CNS-LS.

METHODS: The Chinese version of the CNS-LS was obtained through a standardized forward-backward translation and cultural adaptation. A total of 105 patients with ALS were recruited from the ALS database of Peking University Third Hospital in Beijing, China, to complete the CNS-LS. The reliability of the Chinese version was determined by the test-retest method, and receiver operating characteristic (ROC) analysis was performed for criterion validity.

RESULTS: Of 105 patients with ALS, 37 had symptoms of PBA and were diagnosed with that condition by neurologists. Forty-two patients completed the CNS-LS twice, and there was no statistically significant difference between the scores (Z = -0.896, p = 0.37). The Spearman correlation coefficient between the test and retest scores was 0.940 (p < 0.0005), and the Cronbach alpha coefficient was high (α = 0.905, n = 105). Scores of 12 or higher on the CNS-LS identified PBA with sensitivity of 0.919 and specificity of 0.882. The area under the ROC curve was 0.924.

CONCLUSION: The Chinese version of the CNS-LS demonstrated good sensitivity and specificity in the group of patients with ALS enrolled in this study. The CNS-LS should be a useful instrument for clinical and research purposes for patients in this language group.}, } @article {pmid38625400, year = {2024}, author = {Barel, D and Marom, D and Ponger, P and Kurolap, A and Bar-Shira, A and Kaplan-Ber, I and Mory, A and Abramovich, B and Yaron, Y and Drory, V and Baris Feldman, H}, title = {Genetic diagnosis and detection rates using C9orf72 repeat expansion and a multi-gene panel in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {4258-4266}, pmid = {38625400}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/epidemiology ; *C9orf72 Protein/genetics ; Middle Aged ; Male ; Female ; *DNA Repeat Expansion/genetics ; Aged ; *Genetic Testing ; Israel/epidemiology ; Jews/genetics ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. It is mostly sporadic, with the C9orf72 repeat expansion being the most common genetic cause. While the prevalence of C9orf72-ALS in patients from different populations has been studied, data regarding the yield of C9orf72 compared to an ALS gene panel testing is limited.We aimed to explore the application of C9orf72 versus a gene panel in the general Israeli population. A total of 140 ALS patients attended our Neurogenetics Clinic throughout 2018-2023. Disease onset was between ages 60 and 69 years for most patients (34%); however, a quarter had an early-onset disease (< 50 years). Overall, 119 patients (85%) were genetically evaluated: 116 (97%) were tested for the C9orf72 repeat expansion and 64 (54%) underwent gene panel testing. The C9orf72 repeat expansion had a prevalence of 21% among Ashkenazi Jewish patients compared to 5.7% in non-Ashkenazi patients, while the gene panel had a higher yield in non-Ashkenazi patients with 14% disease-causing variants compared to 5.7% in Ashkenazi Jews. Among early-onset ALS patients, panel testing was positive in 12% compared to 2.9% for C9orf72.We suggest a testing strategy for the Israeli ALS patients: C9orf72 should be the first-tier test in Ashkenazi Jewish patients, while a gene panel should be considered as the first step in non-Ashkenazi and early-onset patients. Tiered testing has important implications for patient management, including prognosis, ongoing clinical trials, and prevention in future generations. Similar studies should be implemented worldwide to uncover the diverse ALS genetic architecture and facilitate tailored care.}, } @article {pmid38623842, year = {2024}, author = {Kaul, CM and Haller, M and Yang, J and Solomon, S and Khan, MR and Pitts, RA and Phillips, MS}, title = {The authors' reply to Jensen et al's Letter to the Editor.}, journal = {Infection control and hospital epidemiology}, volume = {45}, number = {6}, pages = {799-800}, doi = {10.1017/ice.2024.59}, pmid = {38623842}, issn = {1559-6834}, } @article {pmid38623278, year = {2024}, author = {Inci, OK and Basırlı, H and Can, M and Yanbul, S and Seyrantepe, V}, title = {Gangliosides as Therapeutic Targets for Neurodegenerative Diseases.}, journal = {Journal of lipids}, volume = {2024}, number = {}, pages = {4530255}, pmid = {38623278}, issn = {2090-3030}, abstract = {Gangliosides, sialic acid-containing glycosphingolipids, are abundant in cell membranes and primarily involved in controlling cell signaling and cell communication. The altered ganglioside pattern has been demonstrated in several neurodegenerative diseases, characterized during early-onset or infancy, emphasizing the significance of gangliosides in the brain. Enzymes required for the biosynthesis of gangliosides are linked to several devastating neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP). In this review, we summarized not only the critical roles of biosynthetic enzymes and their inhibitors in ganglioside metabolism but also the efficacy of treatment strategies of ganglioside to address their significance in those diseases.}, } @article {pmid38622643, year = {2024}, author = {Filipe, CB and Carreira, NR and Reis-Pina, P}, title = {Optimizing breathlessness management in amyotrophic lateral sclerosis: insights from a comprehensive systematic review.}, journal = {BMC palliative care}, volume = {23}, number = {1}, pages = {100}, pmid = {38622643}, issn = {1472-684X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Dyspnea/etiology/therapy ; Palliative Care/methods/standards ; Noninvasive Ventilation/methods/standards ; Quality of Life ; Analgesics, Opioid/therapeutic use ; }, abstract = {BACKGROUND: Breathlessness is a prevalent symptom affecting the quality of life (QOL) of Amyotrophic Lateral Sclerosis (ALS) patients. This systematic review explored the interventions for controlling breathlessness in ALS patients, emphasizing palliative care (PALC), non-invasive ventilation (NIV), opioids, and non-pharmacological strategies.

METHODS: A comprehensive search of PubMed, Cochrane Library, and Web of Science databases was conducted. Eligibility criteria encompassed adults with ALS or motor neuron disease experiencing breathlessness. Outcomes included QOL and symptom control. Study designs comprised qualitative studies, cohort studies, and randomized controlled trials.

RESULTS: Eight studies were included, most exhibiting low bias risk, comprising one randomized controlled trial, three cohort studies, two comparative retrospective studies, and two qualitative studies (interviews). Most studies originated from Europe, with one from the United States of America. The participants totaled 3423, with ALS patients constituting 95.6%. PALC consultations significantly improved symptom assessment, advance care planning, and discussions about goals of care. NIV demonstrated efficacy in managing breathlessness, with considerations for device limitations. Opioids were effective, though predominantly studied in non-ALS patients. Non-pharmacological strategies varied in efficacy among patients.

CONCLUSION: The findings underscore the need for individualized approaches in managing breathlessness in ALS. PALC, NIV, opioids, and non-pharmacological strategies each play a role, with unique considerations. Further research, especially ALS-specific self-management studies, is warranted.}, } @article {pmid38621750, year = {2024}, author = {Kosmachevskaya, OV and Novikova, NN and Yakunin, SN and Topunov, AF}, title = {Formation of Supplementary Metal-Binding Centers in Proteins under Stress Conditions.}, journal = {Biochemistry. Biokhimiia}, volume = {89}, number = {Suppl 1}, pages = {S180-S204}, doi = {10.1134/S0006297924140104}, pmid = {38621750}, issn = {1608-3040}, mesh = {*Metals/chemistry/metabolism ; *Oxidative Stress ; Oxidation-Reduction ; Protein Processing, Post-Translational ; }, abstract = {In many proteins, supplementary metal-binding centers appear under stress conditions. They are known as aberrant or atypical sites. Physico-chemical properties of proteins are significantly changed after such metal binding, and very stable protein aggregates are formed, in which metals act as "cross-linking" agents. Supplementary metal-binding centers in proteins often arise as a result of posttranslational modifications caused by reactive oxygen and nitrogen species and reactive carbonyl compounds. New chemical groups formed as a result of these modifications can act as ligands for binding metal ions. Special attention is paid to the role of cysteine SH-groups in the formation of supplementary metal-binding centers, since these groups are the main target for the action of reactive species. Supplementary metal binding centers may also appear due to unmasking of amino acid residues when protein conformation changing. Appearance of such centers is usually considered as a pathological process. Such unilateral approach does not allow to obtain an integral view of the phenomenon, ignoring cases when formation of metal complexes with altered proteins is a way to adjust protein properties, activity, and stability under the changed redox conditions. The role of metals in protein aggregation is being studied actively, since it leads to formation of non-membranous organelles, liquid condensates, and solid conglomerates. Some proteins found in such aggregates are typical for various diseases, such as Alzheimer's and Huntington's diseases, amyotrophic lateral sclerosis, and some types of cancer.}, } @article {pmid38621743, year = {2024}, author = {Rezvykh, A and Shteinberg, D and Bronovitsky, E and Ustyugov, A and Funikov, S}, title = {Animal Models of FUS-Proteinopathy: A Systematic Review.}, journal = {Biochemistry. Biokhimiia}, volume = {89}, number = {Suppl 1}, pages = {S34-S56}, doi = {10.1134/S0006297924140037}, pmid = {38621743}, issn = {1608-3040}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; RNA-Binding Protein FUS/genetics/metabolism ; Motor Neurons/metabolism/pathology ; Cytoplasm/metabolism ; Mutation ; Disease Models, Animal ; }, abstract = {Mutations that disrupt the function of the DNA/RNA-binding protein FUS could cause amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. One of the key features in ALS pathogenesis is the formation of insoluble protein aggregates containing aberrant isoforms of the FUS protein in the cytoplasm of upper and lower motor neurons. Reproduction of human pathology in animal models is the main tool for studying FUS-associated pathology and searching for potential therapeutic agents for ALS treatment. In this review, we provide a systematic analysis of the role of FUS protein in ALS pathogenesis and an overview of the results of modelling FUS-proteinopathy in animals.}, } @article {pmid38621696, year = {2025}, author = {Müller, F and Proske, A and Füchtmeier, B and Wulbrand, C}, title = {Are Process Changes Measurable? An Analysis of 4136 Proximal Femur Fractures over 16 Year.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {163}, number = {1}, pages = {27-34}, doi = {10.1055/a-2276-6440}, pmid = {38621696}, issn = {1864-6743}, mesh = {Humans ; Retrospective Studies ; Female ; Male ; Aged ; *Reoperation/statistics & numerical data ; Germany ; COVID-19/epidemiology ; Middle Aged ; Aged, 80 and over ; Fracture Fixation, Intramedullary/methods ; Femoral Fractures/surgery ; Fracture Fixation, Internal ; Blood Transfusion/statistics & numerical data ; Adult ; Postoperative Complications ; Hip Fractures/surgery/mortality ; Trauma Centers ; Proximal Femoral Fractures ; }, abstract = {Prozessänderungen im perioperativen Setting werden selten analysiert, weil ihre Ergebnisse nicht unmittelbar fassbar sind und es einer hohen Fallzahl bedarf. Primäres Ziel war es, Prozessänderungen retrospektiv anhand proximaler Femurfrakturen (PF) zu evaluieren und deren Effekt mit verschiedenen Zielkriterien zu überprüfen. Sekundäres Ziel war die Definition möglicher Qualitätskriterien für die Versorgung von PF.Retrospektive Analyse der Datenbank eines Level-1-Traumazentrums zu PF. Eingeschlossen wurden alle osteosynthetisch und endoprothetisch versorgten PF im Behandlungszeitraum vom 01.01.2006 bis 31.12.2021. Der Zeitraum von 16 Jahren wurde für die Statistik trichotom aufgeteilt und die ersten 6 Jahre als Ausgangsbasis verwendet. Insgesamt 10 Prozessänderungen wurden in den folgenden 10 Jahren vorgenommen. Die Auswirkungen dieser Änderungen wurden anhand 1. der operativen Revisionsrate, 2. der Infektionsrate, 3. der perioperativen Transfusionsrate sowie 4. der 1-Jahres-Letalität überprüft.Insgesamt 4163 PF wurden analysiert. Hinsichtlich der Zielkriterien zeigten die Änderungen der ersten 5 Jahre (2012-2016; intramedulläres Verfahren für Osteosynthesen sowie Einwegabdeckung und Einwegkittel) den stärksten Effekt mit einer erstmaligen Senkung der operativen Revisionsrate unter 10% auf Dauer. Weitere Prozessoptimierungen der letzten 5 Jahre (2017-2021) erbrachten ebenfalls messbare Verbesserungen (Senkung der Infektions- und Transfusionsrate). Die 1-Jahres-Letalität blieb unverändert, auch während der COVID-19-Pandemie.Prozessänderungen bei PF führen nicht unmittelbar zu objektiv messbaren Verbesserungen. Rückblickend erscheint der Paradigmenwechsel von extra- auf intramedulläre Osteosynthese den höchsten Effekt erzielt zu haben, wenngleich über die letzten 10 Jahre eine schrittweise Besserung aller Zielkriterien eintrat - mit Ausnahme der Letalität. Als objektive Qualitätskontrolle sollte eine 1-Jahres-Revisionsrate unter 10% angestrebt sein.}, } @article {pmid38621442, year = {2024}, author = {Dewangan, D and Joshi, A and Padhi, AK}, title = {Long-timescale atomistic simulations uncover loss-of-function mechanisms of uncharacterized Angiogenin mutants associated with ALS.}, journal = {Archives of biochemistry and biophysics}, volume = {756}, number = {}, pages = {110000}, doi = {10.1016/j.abb.2024.110000}, pmid = {38621442}, issn = {1096-0384}, mesh = {*Ribonuclease, Pancreatic/chemistry/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Molecular Dynamics Simulation ; Loss of Function Mutation ; Molecular Docking Simulation ; Mutation ; Protein Conformation ; Thermodynamics ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive degeneration of motor neurons, resulting in respiratory failure and mortality within 3-5 years. Mutations in the Angiogenin (ANG) cause loss of ribonucleolytic and nuclear translocation activities, contributing to ALS pathogenesis. This study focused on investigating two uncharacterized ANG mutations, T11S and R122H, newly identified in the Project Mine consortium. Using extensive computational analysis, including structural modeling and microsecond-timescale molecular dynamics (MD) simulations, we observed conformational changes in the catalytic residue His114 of ANG induced by T11S and R122H mutations. These alterations impaired ribonucleolytic activity, as inferred through molecular docking and binding free energy calculations. Gibbs free energy landscape and residue-residue interaction network analysis further supported our findings, revealing the energetic states and allosteric pathway from the mutated site to His114. Additionally, we assessed the binding of NCI-65828, an inhibitor of ribonucleolytic activity of ANG, and found reduced effectiveness in binding to T11S and R122H mutants when His114 assumed a non-native conformation. This highlights the crucial role of His114 and its association with ALS. Elucidating the relationship between physical structure and functional dynamics of frequently mutated ANG mutants is essential for understanding ALS pathogenesis and developing more effective therapeutic interventions.}, } @article {pmid38621131, year = {2024}, author = {Sachdev, A and Gill, K and Sckaff, M and Birk, AM and Aladesuyi Arogundade, O and Brown, KA and Chouhan, RS and Issagholian-Lewin, PO and Patel, E and Watry, HL and Bernardi, MT and Keough, KC and Tsai, YC and Smith, AST and Conklin, BR and Clelland, CD}, title = {Reversal of C9orf72 mutation-induced transcriptional dysregulation and pathology in cultured human neurons by allele-specific excision.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {17}, pages = {e2307814121}, pmid = {38621131}, issn = {1091-6490}, support = {K08 NS112330/NS/NINDS NIH HHS/United States ; U19 NS132303/NS/NINDS NIH HHS/United States ; TL1 TR001871/TR/NCATS NIH HHS/United States ; R01 HL130533/HL/NHLBI NIH HHS/United States ; RF1 AG072052/AG/NIA NIH HHS/United States ; R01 AG072052/AG/NIA NIH HHS/United States ; R03 TR004009/TR/NCATS NIH HHS/United States ; U01 NS134062/NS/NINDS NIH HHS/United States ; P01 HL146366/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; C9orf72 Protein/genetics/metabolism ; Alleles ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia/metabolism ; Motor Neurons/metabolism ; Mutation ; DNA Repeat Expansion/genetics ; Dipeptides/metabolism ; }, abstract = {Efforts to genetically reverse C9orf72 pathology have been hampered by our incomplete understanding of the regulation of this complex locus. We generated five different genomic excisions at the C9orf72 locus in a patient-derived induced pluripotent stem cell (iPSC) line and a non-diseased wild-type (WT) line (11 total isogenic lines), and examined gene expression and pathological hallmarks of C9 frontotemporal dementia/amyotrophic lateral sclerosis in motor neurons differentiated from these lines. Comparing the excisions in these isogenic series removed the confounding effects of different genomic backgrounds and allowed us to probe the effects of specific genomic changes. A coding single nucleotide polymorphism in the patient cell line allowed us to distinguish transcripts from the normal vs. mutant allele. Using digital droplet PCR (ddPCR), we determined that transcription from the mutant allele is upregulated at least 10-fold, and that sense transcription is independently regulated from each allele. Surprisingly, excision of the WT allele increased pathologic dipeptide repeat poly-GP expression from the mutant allele. Importantly, a single allele was sufficient to supply a normal amount of protein, suggesting that the C9orf72 gene is haplo-sufficient in induced motor neurons. Excision of the mutant repeat expansion reverted all pathology (RNA abnormalities, dipeptide repeat production, and TDP-43 pathology) and improved electrophysiological function, whereas silencing sense expression did not eliminate all dipeptide repeat proteins, presumably because of the antisense expression. These data increase our understanding of C9orf72 gene regulation and inform gene therapy approaches, including antisense oligonucleotides (ASOs) and CRISPR gene editing.}, } @article {pmid38621087, year = {2024}, author = {Zhuang, Y and Wang, Y and Yang, X and Ma, T}, title = {Visible light positioning system using a smartphone's built-in ambient light sensor and inertial measurement unit.}, journal = {Optics letters}, volume = {49}, number = {8}, pages = {2105-2108}, doi = {10.1364/OL.519674}, pmid = {38621087}, issn = {1539-4794}, abstract = {In recent years, the visible light positioning field has experienced remarkable advancements. However, smartphones find it difficult to identify light-emitting diode (LED) and extract each LED's light signal intensity due to the low-frequency and uneven sampling of built-in ambient light sensors (ALS, which is a photodiode that measures ambient light in lux units). Thus, traditional visible light positioning systems cannot be directly applied to smartphones. In this Letter, we propose a single-light visible light positioning system using a non-modulated LED as an emitter, the built-in ALS as the receiver, and the inertial measurement unit of the smartphone to assist in measuring the smartphone's attitude. It only requires the user to turn the smartphone by a few angles in a stationary position to estimate its current three-dimensional (3D) spatial position. This method does not require modification of the existing lighting system and consumes less power than the camera-based visible light positioning (VLP) systems. We have built an experimental site measuring 5 m × 5 m × 2.2 m to evaluate the performance of the positioning system, and the preliminary results show that the proposed system achieves sub-meter-level positioning accuracy.}, } @article {pmid38617354, year = {2024}, author = {Lynch, EM and Pittman, S and Daw, J and Ikenaga, C and Chen, S and Dhavale, DD and Jackrel, ME and Ayala, YM and Kotzbauer, P and Ly, CV and Pestronk, A and Lloyd, TE and Weihl, CC}, title = {Seeding competent TDP-43 persists in human patient and mouse muscle.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38617354}, issn = {2692-8205}, support = {F32 NS124841/NS/NINDS NIH HHS/United States ; K24 AR073317/AR/NIAMS NIH HHS/United States ; R01 AG031867/AG/NIA NIH HHS/United States ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous system of some neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy (IBM). TDP-43 aggregates from ALS and FTD brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in IBM patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis and changes in TDP-43-related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with IBM, IMNM and ALS we found that TDP-43 seeding capacity was specific to IBM. Surprisingly, TDP-43 seeding capacity anti-correlated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.}, } @article {pmid38617322, year = {2024}, author = {Lowry, ER and Patel, T and Costa, JA and Chang, E and Tariq, S and Melikyan, H and Davis, IM and Aziz, S and Dermentzaki, G and Lotti, F and Wichterle, H}, title = {Embryonic motor neuron programming factors reactivate immature gene expression and suppress ALS pathologies in postnatal motor neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38617322}, issn = {2692-8205}, support = {R01 NS109217/NS/NINDS NIH HHS/United States ; K99 NS121136/NS/NINDS NIH HHS/United States ; R21 NS101575/NS/NINDS NIH HHS/United States ; R01 NS116141/NS/NINDS NIH HHS/United States ; R01 AG084965/AG/NIA NIH HHS/United States ; }, abstract = {Aging is a major risk factor in amyotrophic lateral sclerosis (ALS) and other adult-onset neurodegenerative disorders. Whereas young neurons are capable of buffering disease-causing stresses, mature neurons lose this ability and degenerate over time. We hypothesized that the resilience of young motor neurons could be restored by re-expression of the embryonic motor neuron selector transcription factors ISL1 and LHX3. We found that viral re-expression of ISL1 and LHX3 reactivates aspects of the youthful gene expression program in mature motor neurons and alleviates key disease-relevant phenotypes in the SOD1[G93A] mouse model of ALS. Our results suggest that redeployment of lineage-specific neuronal selector transcription factors can be an effective strategy to attenuate age-dependent phenotypes in neurodegenerative disease.}, } @article {pmid38617277, year = {2024}, author = {Liu, D and Webber, HC and Bian, F and Xu, Y and Prakash, M and Feng, X and Yang, M and Yang, H and You, IJ and Li, L and Liu, L and Liu, P and Huang, H and Chang, CY and Liu, L and Shah, SH and Torre, A and Welsbie, DS and Sun, Y and Duan, X and Goldberg, JL and Braun, M and Lansky, Z and Hu, Y}, title = {Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38617277}, issn = {2692-8205}, support = {R01 EY034353/EY/NEI NIH HHS/United States ; P30 EY026877/EY/NEI NIH HHS/United States ; R01 EY024932/EY/NEI NIH HHS/United States ; S10 OD025091/OD/NIH HHS/United States ; R01 EY032518/EY/NEI NIH HHS/United States ; R01 EY023295/EY/NEI NIH HHS/United States ; F32 EY029567/EY/NEI NIH HHS/United States ; R01 EY032159/EY/NEI NIH HHS/United States ; R01 EY025295/EY/NEI NIH HHS/United States ; S10 OD030452/OD/NIH HHS/United States ; }, abstract = {Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We found that OPTN C-terminus truncation (OPTN∆C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a striking decrease of axonal mitochondria. Surprisingly, we discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C-terminus dependent manner. Encouragingly, overexpressing OPTN/TRAK1/KIF5B reverses not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes striking ON regeneration. Therefore, in addition to generating new animal models for NTG and ALS, our results establish OPTN as a novel facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.}, } @article {pmid38615685, year = {2024}, author = {Beckers, J and Van Damme, P}, title = {Toxic gain-of-function mechanisms in C9orf72 ALS-FTD neurons drive autophagy and lysosome dysfunction.}, journal = {Autophagy}, volume = {20}, number = {9}, pages = {2102-2104}, pmid = {38615685}, issn = {1554-8635}, mesh = {*C9orf72 Protein/genetics/metabolism ; *Autophagy/genetics/physiology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Lysosomes/metabolism ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; Gain of Function Mutation/genetics ; DNA-Binding Proteins/metabolism/genetics ; Neurons/metabolism ; Sequestosome-1 Protein/metabolism/genetics ; }, abstract = {Hexanucleotide repeat expansions in the C9orf72 gene are the primary genetic cause for both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two related neurodegenerative diseases. Significant advances in the elucidation of the disease mechanisms responsible for C9orf72 ALS-FTD have revealed both a toxic gain-of-function and a loss-of-function mechanism as possible underlying disease cause. As the differential contribution of both gain and loss of function in C9orf72 ALS-FTD pathogenesis remains debated, we investigated disease mechanisms in motor neurons derived from both authentic human patient C9orf72 ALS-FTD iPSCs as well as a C9orf72 knockout iPSC line. We found that patient neurons presented with less motile and enlarged lysosomes, a decrease in autophagic flux and an increase in SQSTM1/p62 puncta and insoluble TARDBP/TDP-43 species. Importantly, we found that C9orf72 knockout barely has any influence on these phenotypes and mainly results in impaired endosomal maturation. Together, our data suggest that toxic gain-of-function, rather than loss-of-function, mechanisms in C9orf72 ALS-FTD impair the autophagy-lysosome system in neurons.}, } @article {pmid38615537, year = {2024}, author = {Xu, Z and Zhang, J and Tang, J and Gong, Y and Zou, Y and Zhang, Q}, title = {Dissecting the effect of ALS mutation S375G on the conformational properties and aggregation dynamics of TDP-43370-375 fragment.}, journal = {Biophysical chemistry}, volume = {310}, number = {}, pages = {107230}, doi = {10.1016/j.bpc.2024.107230}, pmid = {38615537}, issn = {1873-4200}, mesh = {*Molecular Dynamics Simulation ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *DNA-Binding Proteins/chemistry/genetics/metabolism ; *Mutation ; Protein Conformation ; Protein Aggregates ; Peptide Fragments/chemistry/genetics/metabolism ; }, abstract = {The aggregation of transactive response deoxyribonucleic acid (DNA) binding protein of 43 kDa (TDP-43) into ubiquitin-positive inclusions is closely associated with amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and chronic traumatic encephalopathy. The 370-375 fragment of TDP-43 ([370]GNNSYS[375], TDP-43370-375), the amyloidogenic hexapeptides, can be prone to forming pathogenic amyloid fibrils with the characteristic of steric zippers. Previous experiments reported the ALS-associated mutation, serine 375 substituted by glycine (S375G) is linked to early onset disease and protein aggregation of TDP-43. Based on this, it is necessary to explore the underlying molecular mechanisms. By utilizing all-atom molecular dynamics (MD) simulations of 102 μs in total, we investigated the impact of S375G mutation on the conformational ensembles and oligomerization dynamics of TDP-43370-375 peptides. Our replica exchange MD simulations show that S375G mutation could promote the unstructured conformation formation and induce peptides to form a loose packed oligomer, thus inhibiting the aggregation of TDP-43370-375. Further analyses suggest that S375G mutation displays a reduction effect on the number of total hydrogen bonds and contacts among TDP-43370-375 peptides. Hydrogen bonding and polar interactions among TDP-43370-375 peptides, as well as Y374-Y374 π-π stacking interaction, are attenuated by S375G mutation. Additional microsecond MD simulations demonstrate that S375G mutation could prohibit the conformational conversion to β-structure-rich aggregates and possess an inhibitory effect on the oligomerization dynamics of TDP-43370-375. This study offers for the first time of molecular insights into the S375G mutation affecting the aggregation of TDP-43370-375 at the atomic level, and may open new avenues in the development of future site-specific mutation therapeutics.}, } @article {pmid38614367, year = {2024}, author = {Roghani, AK and Garcia, RI and Roghani, A and Reddy, A and Khemka, S and Reddy, RP and Pattoor, V and Jacob, M and Reddy, PH and Sehar, U}, title = {Treating Alzheimer's disease using nanoparticle-mediated drug delivery strategies/systems.}, journal = {Ageing research reviews}, volume = {97}, number = {}, pages = {102291}, doi = {10.1016/j.arr.2024.102291}, pmid = {38614367}, issn = {1872-9649}, support = {R01 AG069333/AG/NIA NIH HHS/United States ; RF1 AG079264/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Drug Delivery Systems/methods ; Animals ; *Blood-Brain Barrier/drug effects/metabolism ; *Nanoparticles/administration & dosage ; Nanoparticle Drug Delivery System ; }, abstract = {The administration of promising medications for the treatment of neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) is significantly hampered by the blood-brain barrier (BBB). Nanotechnology has recently come to light as a viable strategy for overcoming this obstacle and improving drug delivery to the brain. With a focus on current developments and prospects, this review article examines the use of nanoparticles to overcome the BBB constraints to improve drug therapy for AD The potential for several nanoparticle-based approaches, such as those utilizing lipid-based, polymeric, and inorganic nanoparticles, to enhance drug transport across the BBB are highlighted. To shed insight on their involvement in aiding effective drug transport to the brain, methods of nanoparticle-mediated drug delivery, such as surface modifications, functionalization, and particular targeting ligands, are also investigated. The article also discusses the most recent findings on innovative medication formulations encapsulated within nanoparticles and the therapeutic effects they have shown in both preclinical and clinical testing. This sector has difficulties and restrictions, such as the need for increased safety, scalability, and translation to clinical applications. However, the major emphasis of this review aims to provide insight and contribute to the knowledge of how nanotechnology can potentially revolutionize the worldwide treatment of NDDs, particularly AD, to enhance clinical outcomes.}, } @article {pmid38613988, year = {2024}, author = {Ruotolo, G and D'Anzi, A and Casamassa, A and Mazzoni, M and Ferrari, D and Lombardi, I and Carletti, RM and D'Asdia, C and Torrente, I and Frezza, K and Lattante, S and Sabatelli, M and Pennuto, M and Vescovi, AL and Rosati, J}, title = {Generation of induced pluripotent stem cells (CSSi017-A)(12862) from an ALS patient carrying a repeat expansion in the C9orf72 gene.}, journal = {Stem cell research}, volume = {77}, number = {}, pages = {103412}, doi = {10.1016/j.scr.2024.103412}, pmid = {38613988}, issn = {1876-7753}, mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *DNA Repeat Expansion ; Cell Differentiation ; Fibroblasts/metabolism ; Cell Line ; Male ; }, abstract = {Genetic expansions of the hexanucleotide repeats (GGGGCC) in the C9orf72 gene appear in approximately 40% of patients with familial ALS and 7% of patients with sporadic ALS in the European population, making this mutation one of the most prevalent genetic mutations in ALS. Here, we generated a human induced pluripotent stem cell (hiPSC) line from the dermal fibroblasts of a patient carrying a 56-repeat expansion in an ALS disease-causing allele of C9orf72. These iPSCs showed stable amplification in vitro with normal karyotype and high expression of pluripotent markers and differentiated spontaneously in vivo into three germ layers.}, } @article {pmid38613779, year = {2024}, author = {Huang, Z and Zhou, Y and Liu, Y and Wang, J}, title = {Protocol to identify DNA-binding proteins recognizing nucleotide repeat dsDNAs.}, journal = {STAR protocols}, volume = {5}, number = {2}, pages = {103013}, pmid = {38613779}, issn = {2666-1667}, mesh = {*DNA/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; Electrophoretic Mobility Shift Assay/methods ; C9orf72 Protein/genetics/metabolism ; Isotope Labeling/methods ; }, abstract = {DNA-binding proteins perform diverse functions, including regulating cellular growth and orchestrating chromatin architecture. Here, we present a protocol to discover proteins specifically interacting with a hexanucleotide repeat DNA, the expansion of which is known as the most frequent genetic cause of familial C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia. We describe steps to fish out DNA-binding proteins recognizing double-stranded repeat DNAs using a SILAC (stable isotope labelling by amino acids in cell culture)-based approach and validate the results using electrophoretic mobility shift assay. For complete details on the use and execution of this protocol, please refer to Liu et al.[1].}, } @article {pmid38613054, year = {2024}, author = {López-Gómez, JJ and Izaola-Jauregui, O and Almansa-Ruiz, L and Jiménez-Sahagún, R and Primo-Martín, D and Pedraza-Hueso, MI and Ramos-Bachiller, B and González-Gutiérrez, J and De Luis-Román, D}, title = {Use of Muscle Ultrasonography in Morphofunctional Assessment of Amyotrophic Lateral Sclerosis (ALS).}, journal = {Nutrients}, volume = {16}, number = {7}, pages = {}, pmid = {38613054}, issn = {2072-6643}, mesh = {Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Body Mass Index ; *Deglutition Disorders ; *Malnutrition ; Quadriceps Muscle/diagnostic imaging ; Prospective Studies ; }, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a progressive disease with a high prevalence of malnutrition that can influence prognosis. The main objective of this study is to compare the validity of muscle ultrasonography in the diagnosis of malnutrition and the prognosis of patients with ALS.

METHODS: This is a prospective observational study that analyzes the nutritional status of patients at the beginning of nutritional monitoring. The morphofunctional assessment included the examination of anthropometric variables such as weight, height, body mass index (BMI), arm circumference, and calf circumference. Additionally, electrical bioimpedanciometry (BIA) was used to measure electrical parameters and estimate other relevant metrics. Muscle ultrasonography[®] (quadriceps rectus femoris (QRF)) assessed muscle mass parameters, including muscle area index (MARAI), anteroposterior diameter of the QRF (Y-axis) (cm), transverse diameter of the QRF (X-axis) (cm), and the sum of the quadriceps thickness (RF+VI) (cm), as well as muscle quality parameters such as echogenicity and the Y-X index.

RESULTS: A total of 37 patients diagnosed with amyotrophic lateral sclerosis (ALS) were included in this study. Of these patients, 51.4% were men. The mean age was 64.27 (12.59) years. A total of 54.1% of the patients had a bulbar onset of amyotrophic lateral sclerosis, and 45.9% had spinal onset. The percentage of subjects with malnutrition diagnosed by the Global Leadership Initiative on Malnutrition (GLIM) criteria was 45.9% of patients. There was a direct correlation between muscle mass parameters assessed by muscle ultrasonography (RF+VI) and active mass markers measured by bioimpedanciometry (body cellular mass index (BCMI) (r = 0.62; p < 0.01), fat-free mass index (FFMI) (r = 0.75; p < 0.01), and appendicular skeletal mass index (ASMI) (r = 0.69; p < 0.01)). There was a direct correlation between echogenicity and resistance (r = 0.44; p = 0.02), as well as between the fat-free mass index and the Y-X index (r = 0.36; p = 0.14). Additionally, there was a negative correlation between echogenicity and BCMI (r = -0.46; p < 0.01) and ASMI (r = 0.34; p = 0.06). Patients with low quadriceps thickness (male < 2.49 cm; female < 1.84 cm) showed an increased risk of hospital admission adjusted by age, sex, and presence of dysphagia (OR: 7.84 (CI 95%: 1.09-56.07); p-value = 0.04), and patients with low-quality mass (Y-X index < 0.35) had a higher risk of hospital admission adjusted by age, sex, and presence of dysphagia (OR: 19.83 (CI 95%: 1.77-222.46); p-value = 0.02).

CONCLUSIONS: In patients with ALS, ultrasonography echogenicity was inversely related to BCMI, FFMI, and ASMI, and the Y-X index was directly related to FFMI. The lowest quartiles of quadriceps thickness and Y-X index are risk factors for hospital admission.}, } @article {pmid38612804, year = {2024}, author = {Giri, PM and Banerjee, A and Ghosal, A and Layek, B}, title = {Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications.}, journal = {International journal of molecular sciences}, volume = {25}, number = {7}, pages = {}, pmid = {38612804}, issn = {1422-0067}, support = {P20 GM109024/GM/NIGMS NIH HHS/United States ; 2P20M109024/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Neuroinflammatory Diseases ; Inflammation/therapy ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; Central Nervous System ; }, abstract = {Neurodegenerative disorders (NDs) have become increasingly common during the past three decades. Approximately 15% of the total population of the world is affected by some form of NDs, resulting in physical and cognitive disability. The most common NDs include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Although NDs are caused by a complex interaction of genetic, environmental, and lifestyle variables, neuroinflammation is known to be associated with all NDs, often leading to permanent damage to neurons of the central nervous system. Furthermore, numerous emerging pieces of evidence have demonstrated that inflammation not only supports the progression of NDs but can also serve as an initiator. Hence, various medicines capable of preventing or reducing neuroinflammation have been investigated as ND treatments. While anti-inflammatory medicine has shown promising benefits in several preclinical models, clinical outcomes are often questionable. In this review, we discuss various NDs with their current treatment strategies, the role of neuroinflammation in the pathophysiology of NDs, and the use of anti-inflammatory agents as a potential therapeutic option.}, } @article {pmid38612745, year = {2024}, author = {Ke, H and Chen, Y and Zhang, B and Duan, S and Ma, X and Ren, B and Wang, Y}, title = {Odorant Receptors Expressing and Antennal Lobes Architecture Are Linked to Caste Dimorphism in Asian Honeybee, Apis cerana (Hymenoptera: Apidae).}, journal = {International journal of molecular sciences}, volume = {25}, number = {7}, pages = {}, pmid = {38612745}, issn = {1422-0067}, support = {2023YFE0113600//National Key Research and Development Program "Intergovernmental international cooperation on science, technology and innovation"/ ; 20200402001NC//Natural Science Foundation of Jilin Province/ ; 20190301047NY//Natural Science Foundation of Jilin Province/ ; }, mesh = {Bees/genetics ; Animals ; *Hymenoptera ; Sex Characteristics ; Cell Communication ; Food ; *Receptors, Odorant/genetics ; }, abstract = {Insects heavily rely on the olfactory system for food, mating, and predator evasion. However, the caste-related olfactory differences in Apis cerana, a eusocial insect, remain unclear. To explore the peripheral and primary center of the olfactory system link to the caste dimorphism in A. cerana, transcriptome and immunohistochemistry studies on the odorant receptors (ORs) and architecture of antennal lobes (ALs) were performed on different castes. Through transcriptomesis, we found more olfactory receptor genes in queens and workers than in drones, which were further validated by RT-qPCR, indicating caste dimorphism. Meanwhile, ALs structure, including volume, surface area, and the number of glomeruli, demonstrated a close association with caste dimorphism. Particularly, drones had more macroglomeruli possibly for pheromone recognition. Interestingly, we found that the number of ORs and glomeruli ratio was nearly 1:1. Also, the ORs expression distribution pattern was very similar to the distribution of glomeruli volume. Our results suggest the existence of concurrent plasticity in both the peripheral olfactory system and ALs among different castes of A. cerana, highlighting the role of the olfactory system in labor division in insects.}, } @article {pmid38612591, year = {2024}, author = {Moțățăianu, A and Andone, S and Stoian, A and Bălașa, R and Huțanu, A and Sărmășan, E}, title = {A Potential Role of Interleukin-5 in the Pathogenesis and Progression of Amyotrophic Lateral Sclerosis: A New Molecular Perspective.}, journal = {International journal of molecular sciences}, volume = {25}, number = {7}, pages = {}, pmid = {38612591}, issn = {1422-0067}, support = {293/5/2020//University of Medicine and Pharmacy of Târgu Mureş/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Cytokines ; Disease Progression ; *Interleukin-5 ; Upper Extremity ; }, abstract = {Cumulative data suggest that neuroinflammation plays a prominent role in amyotrophic lateral sclerosis (ALS) pathogenesis. The purpose of this work was to assess if patients with ALS present a specific peripheral cytokine profile and if it correlates with neurological disability assessed by ALSFRS-R, the rate of disease progression, and the pattern of disease progression (horizontal spreading [HSP] versus vertical spreading [VSP]). We determined the levels of 15 cytokines in the blood of 59 patients with ALS and 40 controls. We identified a positive correlation between levels of pro-inflammatory cytokines (interleukin [IL]-17F, IL-33, IL-31) and the age of ALS patients, as well as a positive correlation between IL-12p/70 and survival from ALS onset and ALS diagnosis. Additionally, there was a positive correlation between the ALSFRS-R score in the upper limb and respiratory domain and IL-5 levels. In our ALS cohort, the spreading pattern was 42% horizontal and 58% vertical, with patients with VSP showing a faster rate of ALS progression. Furthermore, we identified a negative correlation between IL-5 levels and the rate of disease progression, as well as a positive correlation between IL-5 and HSP of ALS. To the best of our knowledge, this is the first study reporting a "protective" role of IL-5 in ALS.}, } @article {pmid38612448, year = {2024}, author = {Homma, H and Tanaka, H and Fujita, K and Okazawa, H}, title = {Necrosis Links Neurodegeneration and Neuroinflammation in Neurodegenerative Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {7}, pages = {}, pmid = {38612448}, issn = {1422-0067}, mesh = {Humans ; *HMGB1 Protein ; *Neurodegenerative Diseases ; Neuroinflammatory Diseases ; Necrosis ; Cell Death ; }, abstract = {The mechanisms of neuronal cell death in neurodegenerative disease remain incompletely understood, although recent studies have made significant advances. Apoptosis was previously considered to be the only mechanism of neuronal cell death in neurodegenerative diseases. However, recent findings have challenged this dogma, identifying new subtypes of necrotic neuronal cell death. The present review provides an updated summary of necrosis subtypes and discusses their potential roles in neurodegenerative cell death. Among numerous necrosis subtypes, including necroptosis, paraptosis, ferroptosis, and pyroptosis, transcriptional repression-induced atypical cell death (TRIAD) has been identified as a potential mechanism of neuronal cell death. TRIAD is induced by functional deficiency of TEAD-YAP and self-amplifies via the release of HMGB1. TRIAD is a feasible potential mechanism of neuronal cell death in Alzheimer's disease and other neurodegenerative diseases. In addition to induction of cell death, HMGB1 released during TRIAD activates brain inflammatory responses, which is a potential link between neurodegeneration and neuroinflammation.}, } @article {pmid38610601, year = {2024}, author = {Piñar-Gutiérrez, A and González-Gracia, L and Vázquez Gutiérrez, R and García-Rey, S and Jiménez-Sánchez, A and González-Navarro, I and Tatay-Domínguez, D and Garrancho-Domínguez, P and Remón-Ruiz, PJ and Martínez-Ortega, AJ and Serrano-Aguayo, P and Giménez-Andreu, MD and García-Fernández, FJ and Bozada-García, JM and Nacarino-Mejías, V and López-Iglesias, Á and Pereira-Cunill, JL and García-Luna, PP}, title = {Percutaneous Gastrostomies: Associated Complications in PUSH vs. PULL Techniques over 12 Years in a Referral Centre.}, journal = {Journal of clinical medicine}, volume = {13}, number = {7}, pages = {}, pmid = {38610601}, issn = {2077-0383}, abstract = {Objectives: To compare complications associated with percutaneous gastrostomies performed using PUSH and PULL techniques, whether endoscopic (PEG) or radiological (PRG), in a tertiary-level hospital. Methods: This was a prospective observational study. Adult patients who underwent percutaneous PULL or PUSH gastrostomy using PEG or PRG techniques at the Virgen del Rocio University Hospital and subsequently followed up in the Nutrition Unit between 2009-2020 were included. X2 tests or Fisher's test were used for the comparison of proportions when necessary. Univariate analysis was conducted to study risk factors for PRG-associated complications. Results: n = 423 (PULL = 181; PUSH = 242). The PULL technique was associated with a higher percentage of total complications (37.6% vs. 23.8%; p = 0.005), exudate (18.2% vs. 11.2%; p = 0.039), and irritation (3.3% vs. 0%; p = 0.006). In the total sample, there were 5 (1.1%) cases of peritonitis, 3 (0.7%) gastrocolic fistulas, and 1 (0.2%) death due to complications associated with gastrostomy. Gender, age, and different indications were not risk factors for a higher number of complications. The most common indications were neurological diseases (35.9%), head and neck cancer (29%), and amyotrophic lateral sclerosis (17.2%). Conclusions: The PULL technique was associated with more total complications than the PUSH technique, but both were shown to be safe techniques, as the majority of complications were minor.}, } @article {pmid38610566, year = {2024}, author = {Maset-Roig, R and Caplliure-Llopis, J and de Bernardo, N and Privado, J and Alarcón-Jiménez, J and Martín-Ruiz, J and Botella-Navas, M and Villarón-Casales, C and Sancho-Cantus, D and de la Rubia Ortí, JE}, title = {Analysis of Heart Rate Variability in Individuals Affected by Amyotrophic Lateral Sclerosis.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {7}, pages = {}, pmid = {38610566}, issn = {1424-8220}, support = {2017-216-001//Catholic University of Valencia/ ; }, mesh = {Male ; Humans ; Female ; *Amyotrophic Lateral Sclerosis ; Heart Rate ; Autonomic Nervous System ; Health Status ; Heart ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) produces alterations in the autonomic nervous system (ANS), which explains the cardiac manifestations observed in patients. The assessment of heart rate variability (HRV) is what best reflects the activity of the ANS on heart rate. The Polar H7 Bluetooth[®] device proves to be a non-invasive and much faster technology than existing alternatives for this purpose.

OBJECTIVE: The goal of this study is to determine HRV using Polar H7 Bluetooth technology in ALS patients, comparing the obtained measurements with values from healthy individuals.

METHOD: The sample consisted of 124 participants: 68 diagnosed with ALS and 56 healthy individuals. Using Polar H7 Bluetooth technology and the ELITE HRV application, various HRV measurements were determined for all participants, specifically the HRV index, RMSSD, RMSSD LN, SDNN index, PNN50, LF, HF, LF/HF ratio, HR average, and HF peak frequency.

RESULTS: Statistically significant differences were observed between ALS patients and healthy individuals in the HRV index, RMSSD, RMSSD LN, SDNN index, PNN50, HF, and LF, where healthy individuals exhibited higher scores. For the HR average, the ALS group showed a higher value. Values were similar when comparing men and women with ALS, with only a higher HF peak frequency observed in women.

CONCLUSION: The Polar H7 Bluetooth[®] device is effective in determining heart rate variability alterations in ALS, being a promising prognostic tool for the disease.}, } @article {pmid38610192, year = {2024}, author = {Papadopoulou, M and Papapostolou, A and Dimakopoulos, R and Salakou, S and Koropouli, E and Fanouraki, S and Bakola, E and Moschovos, C and Tsivgoulis, G}, title = {Non-Pharmacological Interventions on Pain in Amyotrophic Lateral Sclerosis Patients: A Systematic Review and Meta-Analysis.}, journal = {Healthcare (Basel, Switzerland)}, volume = {12}, number = {7}, pages = {}, pmid = {38610192}, issn = {2227-9032}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motor neurons. Some ALS patients exhibit concomitant nonmotor signs; thus, ALS is considered a multisystemic disorder. Pain is an important nonmotor symptom. Observational and case-control studies report high frequency of pain in ALS patients and it has been correlated with depression and quality of life. There are no specific scales for the assessment of pain and no randomized controlled trials (RCTs) regarding the drug management of pain in ALS.

AIM: To systematically review the evidence for the nonpharmacological interventions (NPIs) in relieving pain in ALS, on March 2024, we searched the following databases: Pubmed, Scopus, Web of Science, and Cochrane. We also checked the bibliographies of trials identified to include further published or unpublished trials.

MAIN RESULTS: A total of 1003 records were identified. Finally, five RCTs including 131 patients (64 in the intervention group and 67 in the control group) were included for meta-analysis. The interventions of the included RCTs consisted of muscle exercise, combined aerobics-strength intervention, and osteopathic manual treatment. The meta-analysis did not find a statistically significant difference in favor of NPIs for alleviating pain in ALS patients.

CONCLUSIONS: ALS has a fulminant course and irreversibly leads to death. Pain in ALS patients, although a common nonmotor symptom, is often unrecognized and undertreated, and this is underlined by the lack of any RCTs on drug therapy for pain. Albeit NPIs are considered safe, as adverse effects are rarely reported, this systematic review did not provide sufficient evidence for a beneficial effect on pain. The scarceness of relevant literature highlights the need for future studies, with larger samples, more homogeneous in terms of interventions and population characteristics (stage of disease), and better choice of measurement scales to further investigate the efficacy, if any, of various pain interventions in ALS patients.}, } @article {pmid38610119, year = {2024}, author = {Vandenbogaerde, I and Van den Block, L and Deliens, L and Carduff, E and van der Heide, A and De Bleecker, J and De Vleminck, A}, title = {Experiences with advance care planning in amyotrophic lateral sclerosis: Qualitative longitudinal study with people with amyotrophic lateral sclerosis and their family carers.}, journal = {Palliative medicine}, volume = {38}, number = {5}, pages = {572-581}, doi = {10.1177/02692163241242320}, pmid = {38610119}, issn = {1477-030X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Advance Care Planning ; Male ; Female ; *Caregivers/psychology ; Middle Aged ; Longitudinal Studies ; Aged ; *Qualitative Research ; Adult ; Aged, 80 and over ; Terminal Care/psychology ; }, abstract = {BACKGROUND: It is unclear when people with amyotrophic lateral sclerosis and their family carers think about their future, what they would prefer in terms of care, and how their ideas change over time.

AIM: Understanding experiences with advance care planning of persons with amyotrophic lateral sclerosis and their family carers-and if, when, how, and why these experiences change over time.

DESIGN: A qualitative longitudinal interview study. Analysis involved content analysis, followed by a two-step timeline method to describe changes in advance care planning experiences within and across participants.

SETTING/PARTICIPANTS: Nine persons with amyotrophic lateral sclerosis and nine family carers who were interviewed three times over a 9-month period.

RESULTS: All participants thought about future care, but few talked about it. Over time, advance care planning experiences were influenced by intertwined elements: (1) experienced physical decline and related future care needs; (2) how persons with amyotrophic lateral sclerosis identify themselves as patients; (3) obtaining information about diagnosis and prognosis; (4) professionals initiating conversations about medical aspects of end-of-life decisions; (5) balancing between hope to remain stable and worry about the future; and (6) protecting themselves and each other from worries about the future.

CONCLUSION: This study emphasizes how factors such as coping with the disease and relational dynamics shape individuals' thoughts about future care over time and how psychological, social, and medical factors are interwoven in advance care planning. The findings advocate for a process-oriented perspective, portraying advance care planning as an ongoing dialog, encompassing the needs, concerns, and emotions of both people with amyotrophic lateral sclerosis and their family carers.}, } @article {pmid38610012, year = {2024}, author = {Liu, X and Shen, L and Wan, M and Xie, H and Wang, Z}, title = {Peripheral extracellular vesicles in neurodegeneration: pathogenic influencers and therapeutic vehicles.}, journal = {Journal of nanobiotechnology}, volume = {22}, number = {1}, pages = {170}, pmid = {38610012}, issn = {1477-3155}, support = {82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 82301625; 81801395; 82125023; 82072504; 81871822; U22A20300, 81971029//National Natural Science Foundation of China/ ; 2020YFC2008500//National Key R&D Program of China/ ; }, mesh = {Humans ; Prospective Studies ; *Extracellular Vesicles ; *Exosomes ; *Parkinson Disease ; *Alzheimer Disease ; }, abstract = {Neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis epitomize a class of insidious and relentless neurological conditions that are difficult to cure. Conventional therapeutic regimens often fail due to the late onset of symptoms, which occurs well after irreversible neurodegeneration has begun. The integrity of the blood-brain barrier (BBB) further impedes efficacious drug delivery to the central nervous system, presenting a formidable challenge in the pharmacological treatment of NDDs. Recent scientific inquiries have shifted focus toward the peripheral biological systems, investigating their influence on central neuropathology through the lens of extracellular vesicles (EVs). These vesicles, distinguished by their ability to breach the BBB, are emerging as dual operatives in the context of NDDs, both as conveyors of pathogenic entities and as prospective vectors for therapeutic agents. This review critically summarizes the burgeoning evidence on the role of extracerebral EVs, particularly those originating from bone, adipose tissue, and gut microbiota, in modulating brain pathophysiology. It underscores the duplicity potential of peripheral EVs as modulators of disease progression and suggests their potential as novel vehicles for targeted therapeutic delivery, positing a transformative impact on the future landscape of NDD treatment strategies. Search strategy A comprehensive literature search was conducted using PubMed, Web of Science, and Scopus from January 2000 to December 2023. The search combined the following terms using Boolean operators: "neurodegenerative disease" OR "Alzheimer's disease" OR "Parkinson's disease" OR "Amyotrophic lateral sclerosis" AND "extracellular vesicles" OR "exosomes" OR "outer membrane vesicles" AND "drug delivery systems" AND "blood-brain barrier". MeSH terms were employed when searching PubMed to refine the results. Studies were included if they were published in English, involved human subjects, and focused on the peripheral origins of EVs, specifically from bone, adipose tissue, and gut microbiota, and their association with related diseases such as osteoporosis, metabolic syndrome, and gut dysbiosis. Articles were excluded if they did not address the role of EVs in the context of NDDs or did not discuss therapeutic applications. The titles and abstracts of retrieved articles were screened using a dual-review process to ensure relevance and accuracy. The reference lists of selected articles were also examined to identify additional relevant studies.}, } @article {pmid38609957, year = {2024}, author = {Charrin, L and Romain-Scelle, N and Di-Filippo, C and Mercier, E and Balen, F and Tazarourte, K and Benhamed, A}, title = {Impact of delayed mobile medical team dispatch for respiratory distress calls: a propensity score matched study from a French emergency communication center.}, journal = {Scandinavian journal of trauma, resuscitation and emergency medicine}, volume = {32}, number = {1}, pages = {27}, pmid = {38609957}, issn = {1757-7241}, mesh = {Adult ; Humans ; Male ; Aged ; Cross-Sectional Studies ; Propensity Score ; *Communication ; *Catecholamines ; Dyspnea ; }, abstract = {BACKGROUND: Shortness of breath is a common complaint among individuals contacting emergency communication center (EMCCs). In some prehospital system, emergency medical services include an advanced life support (ALS)-capable team. Whether such team should be dispatched during the phone call or delayed until the BLS-capable paramedic team reports from the scene is unclear. We aimed to evaluate the impact of delayed MMT dispatch until receiving the paramedic review compared to immediate dispatch at the time of the call on patient outcomes.

METHODS: A cross-sectional study conducted in Lyon, France, using data obtained from the departmental EMCC during the period from January to December 2019. We included consecutive calls related to adult patients experiencing acute respiratory distress. Patients from the two groups (immediate mobile medical team (MMT) dispatch or delayed MMT dispatch) were matched on a propensity score, and a conditional weighted logistic regression assessed the adjusted odds ratios (ORs) for each outcome (mortality on days 0, 7 and 30).

RESULTS: A total of 870 calls (median age 72 [57-84], male 466 53.6%) were sought for analysis [614 (70.6%) "immediate MMT dispatch" and 256 (29.4%) "delayed MMT" groups]. The median time before MMT dispatch was 25.1 min longer in the delayed MMT group (30.7 [26.4-36.1] vs. 5.6 [3.9-8.8] min, p < 0.001). Patients subjected to a delayed MMT intervention were older (median age 78 [66-87] vs. 69 [53-83], p < 0.001) and more frequently highly dependent (16.3% vs. 8.6%, p < 0.001). A higher proportion of patients in the delayed MMT group required bag valve mask ventilation (47.3% vs. 39.1%, p = 0.03), noninvasive ventilation (24.6% vs. 20.0%, p = 0.13), endotracheal intubation (7.0% vs. 4.1%, p = 0.07) and catecholamine infusion (3.9% vs. 1.3%, p = 0.01). After propensity score matching, mortality at day 0 was higher in the delayed MMT group (9.8% vs. 4.2%, p = 0.002). Immediate MMT dispatch at the call was associated with a lower risk of mortality on day 0 (0.60 [0.38;0.82], p < 0.001) day 7 (0.50 [0.27;0.72], p < 0.001) and day 30 (0.56 [0.35;0.78], p < 0.001) CONCLUSIONS: This study suggests that the deployment of an MMT at call in patients in acute respiratory distress may result in decreased short to medium-term mortality compared to a delayed MMT following initial first aid assessment.}, } @article {pmid38609750, year = {2024}, author = {Sellier, C and Corcia, P and Vourc'h, P and Dupuis, L}, title = {C9ORF72 hexanucleotide repeat expansion: From ALS and FTD to a broader pathogenic role?.}, journal = {Revue neurologique}, volume = {180}, number = {5}, pages = {417-428}, doi = {10.1016/j.neurol.2024.03.008}, pmid = {38609750}, issn = {0035-3787}, mesh = {Humans ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; *DNA Repeat Expansion ; Phenotype ; Genetic Association Studies/methods ; Proteins/genetics ; }, abstract = {The major gene underlying monogenic forms of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) is C9ORF72. The causative mutation in C9ORF72 is an abnormal hexanucleotide (G4C2) repeat expansion (HRE) located in the first intron of the gene. The aim of this review is to propose a comprehensive update on recent developments on clinical, biological and therapeutics aspects related to C9ORF72 in order to highlight the current understanding of genotype-phenotype correlations, and also on biological machinery leading to neuronal death. We will particularly focus on the broad phenotypic presentation of C9ORF72-related diseases, that goes well beyond the classical phenotypes observed in ALS and FTD patients. Last, we will comment the possible therapeutical hopes for patients carrying a C9ORF72 HRE.}, } @article {pmid38609711, year = {2024}, author = {Lin, Y and Wang, S and Yang, Q}, title = {Identification of hub genes and diagnostic efficacy for triple-negative breast cancer through WGCNA and Mendelian randomization.}, journal = {Discover oncology}, volume = {15}, number = {1}, pages = {117}, pmid = {38609711}, issn = {2730-6011}, support = {3502Z20227344//Xiamen Science and Technology Plan Project/ ; }, abstract = {OBJECTIVE: Triple-negative breast cancer (TNBC) represents a particularly aggressive form of breast cancer with a poor prognosis due to a lack of targeted treatments resulting from limited a understanding of the underlying mechanisms. The aim of this study was the identification of hub genes for TNBC and assess their clinical applicability in predicting the disease.

METHODS: This study employed a combination of weighted gene co-expression network analysis (WGCNA) and differentially expressed genes (DEGs) to identify new susceptible modules and central genes in TNBC. The potential functional roles of the central genes were investigated using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. Furthermore, a predictive model and ROC curve were developed to assess the diagnostic performance of the identified central genes. The correlation between CCNB1 and immune cells proportion was also investigated. At last, a Mendelian randomization (MR) analysis utilizing Genome-Wide Association Study (GWAS) data was analyzed to establish the causal effect of CCNB1 level on TNBC.

RESULTS: WGCNA was applied to determine gene co-expression maps and identify the most relevant module. Through a screening process, 1585 candidate hub genes were subsequently identified with WGCNA and DEGs. GO and KEGG function enrichment analysis indicated that these core genes were related to various biological processes, such as organelle fission, chromosome segregation, nuclear division, mitotic cell cycle phase transition, the cell cycle, amyotrophic lateral sclerosis, and motor proteins. Using STRING and Cytoscape, the top five genes with high degrees were identified as CDC2, CCNB1, CCNA2, TOP2A, and CCNB2. The nomogram model demonstrated good performance in predicting TNBC risk and was proven effective in diagnosis, as evidenced by the receiver operating characteristic (ROC) curve. Further investigation revealed a causal association between CCNB1 and immune cell infiltrates in TNBC. Survival analysis revealed high expression of the CCNB1 gene leads to poorer prognosis in TNBC patients. Additionally, analysis using inverse variance weighting revealed that CCNB1 was linked to a 2.8% higher risk of TNBC (OR: 1.028, 95% CI 1.002-1.055, p = 0.032).

CONCLUSION: We established a co-expression network using the WGCNA methodology to detect pivotal genes associated with TNBC. This finding holds promise for advancing the creation of pre-symptomatic diagnostic tools and deepening our comprehension of the pathogenic mechanisms involved in TNBC risk genes.}, } @article {pmid38609644, year = {2024}, author = {Khalil, M and Teunissen, CE and Lehmann, S and Otto, M and Piehl, F and Ziemssen, T and Bittner, S and Sormani, MP and Gattringer, T and Abu-Rumeileh, S and Thebault, S and Abdelhak, A and Green, A and Benkert, P and Kappos, L and Comabella, M and Tumani, H and Freedman, MS and Petzold, A and Blennow, K and Zetterberg, H and Leppert, D and Kuhle, J}, title = {Neurofilaments as biomarkers in neurological disorders - towards clinical application.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {5}, pages = {269-287}, pmid = {38609644}, issn = {1759-4766}, mesh = {Humans ; *Biomarkers/metabolism/blood ; *Intermediate Filaments/metabolism ; *Nervous System Diseases/diagnosis/metabolism/blood ; *Neurofilament Proteins/blood/metabolism ; }, abstract = {Neurofilament proteins have been validated as specific body fluid biomarkers of neuro-axonal injury. The advent of highly sensitive analytical platforms that enable reliable quantification of neurofilaments in blood samples and simplify longitudinal follow-up has paved the way for the development of neurofilaments as a biomarker in clinical practice. Potential applications include assessment of disease activity, monitoring of treatment responses, and determining prognosis in many acute and chronic neurological disorders as well as their use as an outcome measure in trials of novel therapies. Progress has now moved the measurement of neurofilaments to the doorstep of routine clinical practice for the evaluation of individuals. In this Review, we first outline current knowledge on the structure and function of neurofilaments. We then discuss analytical and statistical approaches and challenges in determining neurofilament levels in different clinical contexts and assess the implications of neurofilament light chain (NfL) levels in normal ageing and the confounding factors that need to be considered when interpreting NfL measures. In addition, we summarize the current value and potential clinical applications of neurofilaments as a biomarker of neuro-axonal damage in a range of neurological disorders, including multiple sclerosis, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, stroke and cerebrovascular disease, traumatic brain injury, and Parkinson disease. We also consider the steps needed to complete the translation of neurofilaments from the laboratory to the management of neurological diseases in clinical practice.}, } @article {pmid38608469, year = {2024}, author = {Lee, AF and Chang, YH and Chien, LT and Yang, SC and Chiang, WC}, title = {A comparison between intraosseous and intravenous access in patients with out-of-hospital cardiac arrest: A retrospective cohort study.}, journal = {The American journal of emergency medicine}, volume = {80}, number = {}, pages = {162-167}, doi = {10.1016/j.ajem.2024.04.009}, pmid = {38608469}, issn = {1532-8171}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy ; Retrospective Studies ; *Infusions, Intraosseous/methods ; Male ; Female ; Middle Aged ; Aged ; Taiwan ; Cardiopulmonary Resuscitation/methods ; Emergency Medical Services/methods ; Aged, 80 and over ; }, abstract = {INTRODUCTION: The optimal vascular access for patients with out-of-hospital cardiac arrest (OHCA) remains controversial. Increasing evidence supports intraosseous (IO) access due to faster medication administration and higher first-attempt success rates compared to intravenous (IV) access. However, the impact on patient outcomes has been inconclusive.

METHODS: This retrospective cohort study in Taoyuan City, Taiwan, from January 1, 2019, to December 31, 2022, included patients aged ≥18 years with non-traumatic OHCA resuscitated by emergency medical technician paramedics (EMT-Ps) with either IVs or IOs for final vascular access. The exclusion criteria were cardiac arrest en route to the hospital and resuscitation during the coronavirus pandemic (from May 1, 2022, to October 31, 2022). The primary and secondary outcomes were sustained ROSC (≥2 h) and cerebral performance category (CPC) 1-2, respectively. Univariate logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CI) for the primary analysis. Multivariable logistic regression was employed, with variables selected based on a p-value of <0.05 in the univariate analysis. The survival benefits of different insertion sites and subgroups like general ambulance teams (with a composition that includes fewer EMT-Ps and limited experience in using IO access) were also analyzed.

RESULTS: A total of 2003 patients were enrolled; 1602 received IV access and 401 IO access. The median patient age was 70 years, and most were male (66.6%). Compared to patients receiving IV access, the adjusted odds ratios (aORs) for primary and secondary outcomes in patients with IOs were 0.83 (95% confidence interval [CI], 0.61-1.11; p = 0.20) and 0.96 (95% CI, 0.39-2.40; p = 0.93), respectively. Different insertion sites showed no outcome differences. In the subgroups of females and patients resuscitated by general ambulance teams, the aORs for sustained ROSC were 0.55 (95% CI, 0.33-0.92; p = 0.02) and 0.62 (95% CI, 0.41-0.94; p = 0.02), respectively.

CONCLUSIONS: For patients with OHCA resuscitated by EMT-Ps, IO access was comparable to IV access regarding patient outcomes. However, in females and patients resuscitated by general ambulance teams, IV access might be favorable.}, } @article {pmid38608255, year = {2024}, author = {Igarashi, S and Hioki, S and Sakamaru, N and Suzuki, A and Kurokawa, M and Kato, E}, title = {Flavan-3-ols, flavonoids, anthocyanidins and triterpenoids induces TIE2 phosphorylation -a candidate target for the vascular protective effects.}, journal = {Natural product research}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/14786419.2024.2340049}, pmid = {38608255}, issn = {1478-6427}, abstract = {Vascular system is essential for the body to maintain health. Dysregulated vascular system leads to cardiovascular diseases and are observed in ischaemic stroke, Alzheimer's disease, amyotrophic lateral sclerosis, and diabetes. TIE2 is a tyrosine kinase receptor expressed on vascular endothelial cells and contributes to the maintenance of a vascular system. In this paper, we screened for natural products with an activity to induce phosphorylation of TIE2, which will be beneficial for protection of a vascular system. Employing HeLa cells expressing TIE2, flavan-3-ols, flavonoids, anthocyanidins and triterpenoids were identified as active compounds that induce TIE2 phosphorylation. Several of the identified compounds are previously reported to protect endothelial cells from inflammation. Thus, the result provided TIE2 as the candidate receptor protein of those compounds for the protective effect of endothelial cells and the identified compounds will be a good candidate for maintenance of a vascular system.}, } @article {pmid38607533, year = {2024}, author = {Trinchillo, A and Valente, V and Esposito, M and Migliaccio, M and Iovino, A and Picciocchi, M and Cuomo, N and Caccavale, C and Nocerino, C and De Rosa, L and Salvatore, E and Pierantoni, GM and Menchise, V and Paladino, S and Criscuolo, C}, title = {Expanding SPG18 clinical spectrum: autosomal dominant mutation causes complicated hereditary spastic paraplegia in a large family.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {9}, pages = {4373-4381}, pmid = {38607533}, issn = {1590-3478}, support = {PE0000006//Italian Ministry for University and Research/ ; }, mesh = {Humans ; *Spastic Paraplegia, Hereditary/genetics ; Female ; Male ; *Pedigree ; Adult ; *Membrane Proteins/genetics ; *Mutation ; Middle Aged ; Phenotype ; Young Adult ; Adolescent ; Genes, Dominant ; Child ; Aged ; }, abstract = {BACKGROUND: SPG18 is caused by mutations in the endoplasmic reticulum lipid raft associated 2 (ERLIN2) gene. Autosomal recessive (AR) mutations are usually associated with complicated hereditary spastic paraplegia (HSP), while autosomal dominant (AD) mutations use to cause pure SPG18.

AIM: To define the variegate clinical spectrum of the SPG18 and to evaluate a dominant negative effect of erlin2 (encoded by ERLIN2) on oligomerization as causing differences between AR and AD phenotypes.

METHODS: In a four-generation pedigree with an AD pattern, a spastic paraplegia multigene panel test was performed. Oligomerization of erlin2 was analyzed with velocity gradient assay in fibroblasts of the proband and healthy subjects.

RESULTS: Despite the common p.V168M mutation identified in ERLIN2, a phenoconversion to amyotrophic lateral sclerosis (ALS) was observed in the second generation, pure HSP in the third generation, and a complicated form with psychomotor delay and epilepsy in the fourth generation. Erlin2 oligomerization was found to be normal.

DISCUSSION: We report the first AD SPG18 family with a complicated phenotype, and we ruled out a dominant negative effect of V168M on erlin2 oligomerization. Therefore, our data do not support the hypothesis of a relationship between the mode of inheritance and the phenotype, but confirm the multifaceted nature of SPG18 on both genetic and clinical point of view. Clinicians should be aware of the importance of conducting an in-depth clinical evaluation to unmask all the possible manifestations associated to an only apparently pure SPG18 phenotype. We confirm the genotype-phenotype correlation between V168M and ALS emphasizing the value of close follow-up.}, } @article {pmid38607083, year = {2024}, author = {Tamberi, L and Belloni, A and Pugnaloni, A and Rippo, MR and Olivieri, F and Procopio, AD and Bronte, G}, title = {The Influence of Myeloid-Derived Suppressor Cell Expansion in Neuroinflammation and Neurodegenerative Diseases.}, journal = {Cells}, volume = {13}, number = {7}, pages = {}, pmid = {38607083}, issn = {2073-4409}, mesh = {Humans ; *Myeloid-Derived Suppressor Cells/pathology ; Neuroinflammatory Diseases ; *Neurodegenerative Diseases/pathology ; Inflammation/pathology ; Cell Proliferation ; }, abstract = {The neuro-immune axis has a crucial function both during physiological and pathological conditions. Among the immune cells, myeloid-derived suppressor cells (MDSCs) exert a pivotal role in regulating the immune response in many pathological conditions, influencing neuroinflammation and neurodegenerative disease progression. In chronic neuroinflammation, MDSCs could lead to exacerbation of the inflammatory state and eventually participate in the impairment of cognitive functions. To have a complete overview of the role of MDSCs in neurodegenerative diseases, research on PubMed for articles using a combination of terms made with Boolean operators was performed. According to the search strategy, 80 papers were retrieved. Among these, 44 papers met the eligibility criteria. The two subtypes of MDSCs, monocytic and polymorphonuclear MDSCs, behave differently in these diseases. The initial MDSC proliferation is fundamental for attenuating inflammation in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), but not in amyotrophic lateral sclerosis (ALS), where MDSC expansion leads to exacerbation of the disease. Moreover, the accumulation of MDSC subtypes in distinct organs changes during the disease. The proliferation of MDSC subtypes occurs at different disease stages and can influence the progression of each neurodegenerative disorder differently.}, } @article {pmid38606777, year = {2024}, author = {Babu, S and Nicholson, KA and Rothstein, JD and Swenson, A and Sampognaro, PJ and Pant, P and Macklin, EA and Spruill, S and Paganoni, S and Gendron, TF and Prudencio, M and Petrucelli, L and Nix, D and Landrette, S and Nkrumah, E and Fandrick, K and Edwards, J and Young, PR}, title = {Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {9}, pages = {2998-3008}, doi = {10.1093/brain/awae109}, pmid = {38606777}, issn = {1460-2156}, support = {//OrphAI Therapeutics/ ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Double-Blind Method ; Adult ; Aged ; *C9orf72 Protein/genetics ; Pyrazoles/therapeutic use/pharmacokinetics ; Treatment Outcome ; Biomarkers/blood ; Hydrazones ; Morpholines ; Pyrimidines ; }, abstract = {Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated. This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansions were randomly assigned (2:1) to receive twice-daily oral treatment with 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent or serious adverse events attributable to the study drug and tolerability at trial completion or treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod dimesylate and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition [soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) upregulation] and disease-specific CNS target engagement [poly(GP)] were measured. Between 16 December 2021 and 7 July 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance [n = 9 (90%) apilimod dimesylate; n = 5 (100%) placebo]. At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/ml [standard deviation (SD): 0.937]. At Week 12, apilimod dimesylate increased plasma sGPNMB by >2.5-fold (P < 0.001), indicating PIKfyve inhibition, and lowered CSF poly(GP) protein levels by 73% (P < 0.001), indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker end-points in this phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to result in the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.}, } @article {pmid38606235, year = {2024}, author = {Frolov, A and Guzman, MA and Hayat, G and Martin, JR}, title = {Two Cases of Sporadic Amyotrophic Lateral Sclerosis With Contrasting Clinical Phenotypes: Genetic Insights.}, journal = {Cureus}, volume = {16}, number = {3}, pages = {e56023}, pmid = {38606235}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease that affects individuals of diverse racial and ethnic backgrounds. There is currently no cure for ALS, and the number of efficient disease-modifying drugs for ALS is limited to a few, despite the large number of clinical trials conducted in recent years. The latter could be attributed to the significant heterogeneity of ALS clinical phenotypes even in their familial forms. To address this issue, we conducted postmortem genetic screening of two female patients with sporadic ALS (sALS) and contrasting clinical phenotypes. The results demonstrated that despite their contrasting clinical phenotypes, both patients had rare pathologic/deleterious mutations in five genes: ACSM5, BBS12, HLA-DQB1, MUC20, and OBSCN, with mutations in three of those genes being identical: BBS12, HLA-DQB1, and MUC20. Additional groups of mutated genes linked to ALS, other neurologic disorders, and ALS-related pathologies were also identified. These data are consistent with a hypothesis that an individual could be primed for ALS via mutations in a specific set of genes not directly linked to ALS. The disease could be initiated by a concerted action of several mutated genes linked to ALS and the disease's clinical phenotype will evolve further through accessory gene mutations associated with other neurological disorders and ALS-related pathologies.}, } @article {pmid38605366, year = {2024}, author = {Aragón-González, A and Shaw, AC and Kok, JR and Roussel, FS and Santos Souza, CD and Granger, SM and Vetter, T and de Diego, Y and Meyer, KC and Beal, SN and Shaw, PJ and Ferraiuolo, L}, title = {C9ORF72 patient-derived endothelial cells drive blood-brain barrier disruption and contribute to neurotoxicity.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {34}, pmid = {38605366}, issn = {2045-8118}, support = {MR/W00416X/1/MRC_/Medical Research Council/United Kingdom ; 765704//Horizon 2020/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Blood-Brain Barrier/metabolism ; C9orf72 Protein/genetics/metabolism ; *Endothelial Cells/metabolism ; }, abstract = {The blood-brain barrier (BBB) serves as a highly intricate and dynamic interface connecting the brain and the bloodstream, playing a vital role in maintaining brain homeostasis. BBB dysfunction has been associated with multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS); however, the role of the BBB in neurodegeneration is understudied. We developed an ALS patient-derived model of the BBB by using cells derived from 5 patient donors carrying C9ORF72 mutations. Brain microvascular endothelial-like cells (BMEC-like cells) derived from C9ORF72-ALS patients showed altered gene expression, compromised barrier integrity, and increased P-glycoprotein transporter activity. In addition, mitochondrial metabolic tests demonstrated that C9ORF72-ALS BMECs display a significant decrease in basal glycolysis accompanied by increased basal and ATP-linked respiration. Moreover, our study reveals that C9-ALS derived astrocytes can further affect BMECs function and affect the expression of the glucose transporter Glut-1. Finally, C9ORF72 patient-derived BMECs form leaky barriers through a cell-autonomous mechanism and have neurotoxic properties towards motor neurons.}, } @article {pmid38603949, year = {2024}, author = {Shin-Yi Lin, C and Howells, J and Rutkove, S and Nandedkar, S and Neuwirth, C and Noto, YI and Shahrizaila, N and Whittaker, RG and Bostock, H and Burke, D and Tankisi, H}, title = {Neurophysiological and imaging biomarkers of lower motor neuron dysfunction in motor neuron diseases/amyotrophic lateral sclerosis: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {162}, number = {}, pages = {91-120}, doi = {10.1016/j.clinph.2024.03.015}, pmid = {38603949}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; *Motor Neurons/physiology ; *Motor Neuron Disease/physiopathology/diagnostic imaging/diagnosis ; *Biomarkers ; *Electromyography/methods ; *Neural Conduction/physiology ; }, abstract = {This chapter discusses comprehensive neurophysiological biomarkers utilised in motor neuron disease (MND) and, in particular, its commonest form, amyotrophic lateral sclerosis (ALS). These encompass the conventional techniques including nerve conduction studies (NCS), needle and high-density surface electromyography (EMG) and H-reflex studies as well as novel techniques. In the last two decades, new methods of assessing the loss of motor units in a muscle have been developed, that are more convenient than earlier methods of motor unit number estimation (MUNE),and may use either electrical stimulation (e.g. MScanFit MUNE) or voluntary activation (MUNIX). Electrical impedance myography (EIM) is another novel approach for the evaluation that relies upon the application and measurement of high-frequency, low-intensity electrical current. Nerve excitability techniques (NET) also provide insights into the function of an axon and reflect the changes in resting membrane potential, ion channel dysfunction and the structural integrity of the axon and myelin sheath. Furthermore, imaging ultrasound techniques as well as magnetic resonance imaging are capable of detecting the constituents of morphological changes in the nerve and muscle. The chapter provides a critical description of the ability of each technique to provide neurophysiological insight into the complex pathophysiology of MND/ALS. However, it is important to recognise the strengths and limitations of each approach in order to clarify utility. These neurophysiological biomarkers have demonstrated reliability, specificity and provide additional information to validate and assess lower motor neuron dysfunction. Their use has expanded the knowledge about MND/ALS and enhanced our understanding of the relationship between motor units, axons, reflexes and other neural circuits in relation to clinical features of patients with MND/ALS at different stages of the disease. Taken together, the ultimate goal is to aid early diagnosis, distinguish potential disease mimics, monitor and stage disease progression, quantify response to treatment and develop potential therapeutic interventions.}, } @article {pmid38602336, year = {2024}, author = {Zhang, QJ and Lin, J and Wang, YL and Chen, L and Ding, Y and Zheng, FZ and Song, HH and Lv, AW and Li, YY and Guo, QF and Lin, MT and Hu, W and Xu, LQ and Zhao, WL and Fang, L and Cui, MC and Fu, ZF and Chen, WJ and Zhang, J and Wang, ZQ and Wang, N and Fu, Y}, title = {Detection of pTDP-43 via routine muscle biopsy: A promising diagnostic biomarker for amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {6}, pages = {e13261}, pmid = {38602336}, issn = {1750-3639}, support = {2020Y9129//Joint Funds for the Innovation of Science and Technology of Fujian Province/ ; 2021J01209//Joint Funds for the Innovation of Science and Technology of Fujian Province/ ; 2021Y9156//Joint Funds for the Innovation of Science and Technology of Fujian Province/ ; BPB-LMT2021//2021 Provincial Special Subsidy Funds for Health (Biobank Construction Project for Neurological Diseases)/ ; 82230039//National Natural Science Foundation of China/ ; 82371409//National Natural Science Foundation of China/ ; U2005201//National Natural Science Foundation of China/ ; U21A20360//National Natural Science Foundation of China/ ; 2022ZQNZD005//Major Scientific Research Program for Young and Middle-aged Health Professionals of Fujian Province/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnosis/genetics/metabolism ; Male ; Female ; Middle Aged ; Aged ; *Biomarkers/metabolism ; *DNA-Binding Proteins/metabolism ; Biopsy/methods ; *Muscle, Skeletal/pathology/metabolism ; Adult ; C9orf72 Protein/genetics ; Cohort Studies ; Phosphorylation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 (pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; p < 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS.}, } @article {pmid38601850, year = {2024}, author = {Xiao, C and Gu, X and Feng, Y and Shen, J}, title = {Two-sample Mendelian randomization analysis of 91 circulating inflammatory protein levels and amyotrophic lateral sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1367106}, pmid = {38601850}, issn = {1663-4365}, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with poorly understood pathophysiology. Recent studies have highlighted systemic inflammation, especially the role of circulating inflammatory proteins, in ALS.

METHODS: This study investigates the potential causal link between these proteins and ALS. We employed a two-sample Mendelian Randomization(MR) approach, analyzing data from large-scale genome-wide association studies to explore the relationship between 91 circulating inflammatory proteins and ALS. This included various MR methods like MR Egger, weighted median, and inverse-variance weighted, complemented by sensitivity analyses for robust results.

RESULTS: Significant associations were observed between levels of inflammatory proteins, including Adenosine Deaminase, Interleukin-17C, Oncostatin-M, Leukemia Inhibitory Factor Receptor, and Osteoprotegerin, and ALS risk. Consistencies were noted across different P-value thresholds. Bidirectional MR suggested that ALS risk might influence levels of certain inflammatory proteins.

DISCUSSION: Our findings, via MR analysis, indicate a potential causal relationship between circulating inflammatory proteins and ALS. This sheds new light on ALS pathophysiology and suggests possible therapeutic targets. Further research is required to confirm these results and understand the specific roles of these proteins in ALS.}, } @article {pmid38601572, year = {2024}, author = {Urigüen, JA and Ruiz de Gauna, S and Gutiérrez, JJ and Azcárate, I and Leturiondo, M and Redondo, K and Russell, JK and Daya, MR}, title = {Metrics of impulsiveness of manual chest compressions for out-of-hospital cardiopulmonary resuscitation.}, journal = {Heliyon}, volume = {10}, number = {7}, pages = {e28739}, pmid = {38601572}, issn = {2405-8440}, abstract = {AIM: Propose new metrics of impulsiveness of manual chest compressions (CCs) that account for shape and duration, separate the characteristics of the compressive part of the CC cycle from those of the recoil part, and are uncorrelated to CC depth and rate.

METHODS: We conducted a retrospective analysis of adult out-of-hospital cardiac arrest monitor-defibrillator recordings having CPR data. Specifically, episodes of adult patients with ≥ 1000 compressions free of leaning were examined. CCs were obtained from the depth signal of the valid episodes, and we calculated the novel metrics: compression area index (CAI), recoil area index (RAI), compression impulsiveness index (CII) and recoil impulsiveness index (RII). Generalized linear mixed-effects models and Jonckheere-Terpstra trend analyses were employed to measure differences between populations and trends, and the absolute value of Pearson's correlation coefficient |r| was used to report dependence between variables. Statistics are reported as median and interquartile range.

RESULTS: We analyzed 982,340 CCs corresponding to 453 episodes, for which we calculated their CAI, RAI and duty cycle (DC). We analyzed the metrics for various populations: age, sex, any ROSC achieved and disposition, and found that CAI was significantly different according to patient disposition and RAI relative to age and sex (p<0.05). None of the metrics was correlated strongly to depth or rate (|r| values of 0.22 or smaller), and all of them varied for CC series corresponding to the same rescuer over the course of resuscitation (ptrend<0.05). However, we observed that the metrics are not balanced, in that for any value of DC, CAI and RAI span almost their entire ranges.

CONCLUSION: The proposed metrics correctly and completely describe manual CC waveforms, improve upon the DC, since they depend on the signal waveform, and provide additional information to current indicators of quality CPR, depth and rate. Furthermore, they allow to differentiate the compressive and recoil parts of the CC cycle, reflecting influence of the rescuer (via CAI or CII) and of the biomechanics of the patient's chest (via RAI or RII). Thus, they have the potential to contribute to better understanding CPR dynamics and, eventually, to enhanced quality of CPR practice as additional indicators of proper manual CC technique.}, } @article {pmid38601155, year = {2024}, author = {Du, R and Chen, P and Li, M and Zhu, Y and He, Z and Huang, X}, title = {Developing a novel immune infiltration-associated mitophagy prediction model for amyotrophic lateral sclerosis using bioinformatics strategies.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1360527}, pmid = {38601155}, issn = {1664-3224}, mesh = {Animals ; Mice ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Mitophagy/genetics ; *Neurodegenerative Diseases ; Computational Biology ; Databases, Factual ; Disease Models, Animal ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which leads to muscle weakness and eventual paralysis. Numerous studies have indicated that mitophagy and immune inflammation have a significant impact on the onset and advancement of ALS. Nevertheless, the possible diagnostic and prognostic significance of mitophagy-related genes associated with immune infiltration in ALS is uncertain. The purpose of this study is to create a predictive model for ALS using genes linked with mitophagy-associated immune infiltration.

METHODS: ALS gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. Univariate Cox analysis and machine learning methods were applied to analyze mitophagy-associated genes and develop a prognostic risk score model. Subsequently, functional and immune infiltration analyses were conducted to study the biological attributes and immune cell enrichment in individuals with ALS. Additionally, validation of identified feature genes in the prediction model was performed using ALS mouse models and ALS patients.

RESULTS: In this study, a comprehensive analysis revealed the identification of 22 mitophagy-related differential expression genes and 40 prognostic genes. Additionally, an 18-gene prognostic signature was identified with machine learning, which was utilized to construct a prognostic risk score model. Functional enrichment analysis demonstrated the enrichment of various pathways, including oxidative phosphorylation, unfolded proteins, KRAS, and mTOR signaling pathways, as well as other immune-related pathways. The analysis of immune infiltration revealed notable distinctions in certain congenital immune cells and adaptive immune cells between the low-risk and high-risk groups, particularly concerning the T lymphocyte subgroup. ALS mouse models and ALS clinical samples demonstrated consistent expression levels of four mitophagy-related immune infiltration genes (BCKDHA, JTB, KYNU, and GTF2H5) with the results of bioinformatics analysis.

CONCLUSION: This study has successfully devised and verified a pioneering prognostic predictive risk score for ALS, utilizing eighteen mitophagy-related genes. Furthermore, the findings indicate that four of these genes exhibit promising roles in the context of ALS prognostic.}, } @article {pmid38601118, year = {2024}, author = {Patel, GD and Liu, L and Li, A and Yang, YH and Shen, CC and Brand-Saberi, B and Yang, X}, title = {Mesenchymal stem cell-based therapies for treating well-studied neurological disorders: a systematic review.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1361723}, pmid = {38601118}, issn = {2296-858X}, abstract = {BACKGROUND: Millions of people across the globe are affected by conditions like Amyotrophic Lateral Sclerosis (ALS), Parkinson's Disease (PD), Multiple Sclerosis (MS), Spinal Cord Injury (SCI), and Traumatic Brain Injury (TBI), although most occurrences are common in the elderly population. This systematic review aims to highlight the safety of the procedures, their tolerability, and efficacy of the available therapies conducted over the years using mesenchymal stem cells (MSCs) in treating the neurological conditions mentioned above.

METHODS: PubMed was used to search for published data from clinical trials performed using mesenchymal stem cells. Studies that provided the necessary information that mentioned the efficacy and adverse effects of the treatment in patients were considered for this review.

RESULTS: In total, 43 manuscripts were selected after a strategic search, and these studies have been included in this systematic review. Most included studies reported the safety of the procedures used and the treatment's good tolerability, with mild adverse events such as fever, headache, mild pain at the injection site, or nausea being common. A few studies also reported death of some patients, attributed to the progression of the disease to severe stages before the treatment. Other severe events, such as respiratory or urinary infections reported in some studies, were not related to the treatment. Different parameters were used to evaluate the efficacy of the treatment based on the clinical condition of the patient.

CONCLUSION: Mesenchymal stem cells transplantation has so far proven to be safe and tolerable in select studies and patient types. This systematic review includes the results from the 43 selected studies in terms of safety and tolerability of the procedures, and several adverse events and therapeutic benefits during the follow-up period after administration of MSCs.}, } @article {pmid38600725, year = {2024}, author = {Madhubala, D and Patra, A and Khan, MR and Mukherjee, AK}, title = {Phytomedicine for neurodegenerative diseases: The road ahead.}, journal = {Phytotherapy research : PTR}, volume = {38}, number = {6}, pages = {2993-3019}, doi = {10.1002/ptr.8192}, pmid = {38600725}, issn = {1099-1573}, support = {//IASST/ ; EMR/2017/001829//Science and Engineering Research Board/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Catechin/analogs & derivatives/therapeutic use/pharmacology ; *Phytotherapy ; Curcumin/therapeutic use/pharmacology ; Quercetin/pharmacology/therapeutic use ; Animals ; Cannabinoids/therapeutic use/pharmacology ; Apigenin/pharmacology/therapeutic use ; Blood-Brain Barrier/drug effects ; Phytochemicals/pharmacology/therapeutic use ; Plant Extracts/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative disorders (NDs) are among the most common causes of death across the globe. NDs are characterized by progressive damage to CNS neurons, leading to defects in specific brain functions such as memory, cognition, and movement. The most common NDs are Parkinson's, Alzheimer's, Huntington's, and amyotrophic lateral sclerosis (ALS). Despite extensive research, no therapeutics or medications against NDs have been proven to be effective. The current treatment of NDs involving symptom-based targeting of the disease pathogenesis has certain limitations, such as drug resistance, adverse side effects, poor blood-brain barrier permeability, and poor bioavailability of drugs. Some studies have shown that plant-derived natural compounds hold tremendous promise for treating and preventing NDs. Therefore, the primary objective of this review article is to critically analyze the properties and potency of some of the most studied phytomedicines, such as quercetin, curcumin, epigallocatechin gallate (EGCG), apigenin, and cannabinoids, and highlight their advantages and limitations for developing next-generation alternative treatments against NDs. Further extensive research on pre-clinical and clinical studies for developing plant-based drugs against NDs from bench to bedside is warranted.}, } @article {pmid38600555, year = {2024}, author = {Liu, Y and Yan, D and Yang, L and Chen, X and Hu, C and Chen, M}, title = {Stathmin 2 is a potential treatment target for TDP-43 proteinopathy in amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {20}, pmid = {38600555}, issn = {2047-9158}, support = {2023A1515010477//Guangdong Basic and Applied Basic Research Foundation/ ; 32000690//National Natural Science Foundation of China/ ; 2019B030335001//The Key-Area Research and Development Program of Guangdong Province,China/ ; 2023-Z04-103//The Key Medical and Health Projects of Panyu District Science and Technology Plan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; DNA-Binding Proteins/genetics ; *Stathmin/antagonists & inhibitors ; *TDP-43 Proteinopathies/drug therapy ; }, } @article {pmid38599171, year = {2024}, author = {Castro-Gomez, S and Heneka, MT}, title = {Innate immune activation in neurodegenerative diseases.}, journal = {Immunity}, volume = {57}, number = {4}, pages = {790-814}, doi = {10.1016/j.immuni.2024.03.010}, pmid = {38599171}, issn = {1097-4180}, mesh = {Humans ; *Neurodegenerative Diseases ; Receptors, Pattern Recognition ; Immune System ; Inflammation Mediators ; Immunity, Innate ; }, abstract = {Activation of the innate immune system following pattern recognition receptor binding has emerged as one of the major pathogenic mechanisms in neurodegenerative disease. Experimental, epidemiological, pathological, and genetic evidence underscores the meaning of innate immune activation during the prodromal as well as clinical phases of several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Importantly, innate immune activation and the subsequent release of inflammatory mediators contribute mechanistically to other hallmarks of neurodegenerative diseases such as aberrant proteostatis, pathological protein aggregation, cytoskeleton abnormalities, altered energy homeostasis, RNA and DNA defects, and synaptic and network disbalance and ultimately to the induction of neuronal cell death. In this review, we discuss common mechanisms of innate immune activation in neurodegeneration, with particular emphasis on the pattern recognition receptors (PRRs) and other receptors involved in the detection of damage-associated molecular patterns (DAMPs).}, } @article {pmid38598868, year = {2024}, author = {Zhan, Y and Liu, H and Cao, Z and Qi, J and Bai, L and Pan, L}, title = {Target-site and non-target-site resistance mechanisms confer mesosulfuron-methyl resistance in Alopecurus aequalis.}, journal = {Plant physiology and biochemistry : PPB}, volume = {210}, number = {}, pages = {108597}, doi = {10.1016/j.plaphy.2024.108597}, pmid = {38598868}, issn = {1873-2690}, mesh = {*Herbicide Resistance/genetics ; *Sulfonylurea Compounds/pharmacology ; *Acetolactate Synthase/genetics/metabolism ; *Herbicides/pharmacology ; *Poaceae/genetics/drug effects/metabolism ; Cytochrome P-450 Enzyme System/genetics/metabolism ; Plant Proteins/genetics/metabolism ; Glutathione Transferase/metabolism/genetics ; Imidazoles/pharmacology ; Gene Expression Regulation, Plant/drug effects ; Mutation ; Molecular Docking Simulation ; Benzoates ; Pyrimidines ; }, abstract = {BACKGROUND: Shortawn foxtail (Alopecurus aequalis Sobol.) is a noxious weed in China. The resistance of A. aequalis developed rapidly due to the long-term application of acetolactate synthase (ALS)-inhibiting herbicides. Here, a suspected mesosulfuron-methyl-resistant A. aequalis population, Aa-R, was collected from a wheat field in China.

RESULTS: A dose‒response test showed that the Aa-R population has evolved a high level of resistance to mesosulfuron-methyl, and its growth was suppressed by imazamox, pyroxsulam and bispyribac-sodium. ALS gene sequence analysis revealed that a known resistance-related mutation (Pro-197-Thr) was present in the Aa-R population. Moreover, ALS gene overexpression was detected in the Aa-R population. The mesosulfuron-methyl resistance could be reversed by cytochrome P450 monooxygenase (CYP450) and glutathione S-transferase (GST) inhibitors. In addition, enhanced metabolism of mesosulfuron-methyl was detected in the Aa-R population compared with the susceptible population. NADPH-cytochrome P450 reductase and GST activities were strongly inducible in the Aa-R population. One CYP450 gene, CYP74A2, and one GST gene, GST4, were constitutively upregulated in the Aa-R population. Molecular docking results showed the binding affinity of CYP74A2 and GST4 for the tested ALS-inhibiting herbicides, respectively.

CONCLUSION: This study confirmed that target-site resistance and non-target-site resistance involving CYP450 and GST were the main mechanisms involved in resistance in the mesosulfuron-methyl-resistant A. aequalis population.}, } @article {pmid38598318, year = {2024}, author = {Peng, J and Gao, S and Bi, JH and Shi, J and Jia, L and Pang, QF and Zhao, DM and Fu, Y and Ye, F}, title = {Design, Synthesis, and Biological Evaluation of Novel Purine Derivatives as Herbicide Safeners.}, journal = {Journal of agricultural and food chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jafc.3c08138}, pmid = {38598318}, issn = {1520-5118}, abstract = {Mesosulfuron-methyl, an inhibitor of acetolactate synthase (ALS), has been extensively used in wheats. However, it can damage wheat (Triticum aestivum) and even lead to crop death. Herbicide safeners selectively shield crops from such damage without compromising weed control. To mitigate the phytotoxicity of mesosulfuron-methyl in crops, several purine derivatives were developed based on active substructure splicing. The synthesized title compounds underwent thorough characterization using infrared spectroscopy, [1]H nuclear magnetic resonance ([1]H NMR), [13]C nuclear magnetic resonance ([13]C NMR), and high-resolution mass spectrometry. We evaluated chlorophyll and glutathione contents as well as various enzyme activities to evaluate the safer activity of these compounds. Compounds III-3 and III-7 exhibited superior activity compared with the safener mefenpyr-diethyl. Molecular structure analysis, along with predictions of absorption, distribution, metabolism, excretion, and toxicity, indicated that compound III-7 shared pharmacokinetic traits with the commercial safener mefenpyr-diethyl. Molecular docking simulations revealed that compound III-7 competitively bound to the ALS active site with mesosulfuron-methyl, elucidating the protective mechanism of the safeners. Overall, this study highlights purine derivatives as potential candidates for novel safener development.}, } @article {pmid38597682, year = {2024}, author = {Kojak, N and Kuno, J and Fittipaldi, KE and Khan, A and Wenger, D and Glasser, M and Donnianni, RA and Tang, Y and Zhang, J and Huling, K and Ally, R and Mujica, AO and Turner, T and Magardino, G and Huang, PY and Kerk, SY and Droguett, G and Prissette, M and Rojas, J and Gomez, T and Gagliardi, A and Hunt, C and Rabinowitz, JS and Gong, G and Poueymirou, W and Chiao, E and Zambrowicz, B and Siao, CJ and Kajimura, D}, title = {Somatic and intergenerational G4C2 hexanucleotide repeat instability in a human C9orf72 knock-in mouse model.}, journal = {Nucleic acids research}, volume = {52}, number = {10}, pages = {5732-5755}, pmid = {38597682}, issn = {1362-4962}, mesh = {Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/genetics ; *C9orf72 Protein/genetics ; Disease Models, Animal ; DNA Breaks, Double-Stranded ; *DNA Repeat Expansion/genetics ; Frontotemporal Dementia/genetics ; Gene Knock-In Techniques ; *Genomic Instability/genetics ; MutS Homolog 2 Protein/genetics ; }, abstract = {Expansion of a G4C2 repeat in the C9orf72 gene is associated with familial Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). To investigate the underlying mechanisms of repeat instability, which occurs both somatically and intergenerationally, we created a novel mouse model of familial ALS/FTD that harbors 96 copies of G4C2 repeats at a humanized C9orf72 locus. In mouse embryonic stem cells, we observed two modes of repeat expansion. First, we noted minor increases in repeat length per expansion event, which was dependent on a mismatch repair pathway protein Msh2. Second, we found major increases in repeat length per event when a DNA double- or single-strand break (DSB/SSB) was artificially introduced proximal to the repeats, and which was dependent on the homology-directed repair (HDR) pathway. In mice, the first mode primarily drove somatic repeat expansion. Major changes in repeat length, including expansion, were observed when SSB was introduced in one-cell embryos, or intergenerationally without DSB/SSB introduction if G4C2 repeats exceeded 400 copies, although spontaneous HDR-mediated expansion has yet to be identified. These findings provide a novel strategy to model repeat expansion in a non-human genome and offer insights into the mechanism behind C9orf72 G4C2 repeat instability.}, } @article {pmid38596778, year = {2024}, author = {Ramírez-Jarquín, JO and Tecalco-Cruz, AC and Lopez-Huerta, VG and Ramírez-Jarquín, UN}, title = {Editorial: Over 60 years of neurochemistry, the heritage of Dr. Ricardo Tapia.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1398127}, doi = {10.3389/fnmol.2024.1398127}, pmid = {38596778}, issn = {1662-5099}, } @article {pmid38596666, year = {2024}, author = {Sini, P and Galleri, G and Ciampelli, C and Galioto, M and Padedda, BM and Lugliè, A and Iaccarino, C and Crosio, C}, title = {Evaluation of cyanotoxin L-BMAA effect on α-synuclein and TDP43 proteinopathy.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1360068}, pmid = {38596666}, issn = {1664-3224}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; alpha-Synuclein ; Cyanobacteria Toxins ; *Amino Acids, Diamino/toxicity ; *Parkinson Disease ; *Cyanobacteria ; }, abstract = {The complex interplay between genetic and environmental factors is considered the cause of neurodegenerative diseases including Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS). Among the environmental factors, toxins produced by cyanobacteria have received much attention due to the significant increase in cyanobacteria growth worldwide. In particular, L-BMAA toxin, produced by diverse taxa of cyanobacteria, dinoflagellates and diatoms, has been extensively correlated to neurodegeneration. The molecular mechanism of L-BMAA neurotoxicity is still cryptic and far from being understood. In this research article, we have investigated the molecular pathways altered by L-BMAA exposure in cell systems, highlighting a significant increase in specific stress pathways and an impairment in autophagic processes. Interestingly, these changes lead to the accumulation of both α-synuclein and TDP43, which are correlated with PD and ALS proteinopathy, respectively. Finally, we were able to demonstrate specific alterations of TDP43 WT or pathological mutants with respect to protein accumulation, aggregation and cytoplasmic translocation, some of the typical features of both sporadic and familial ALS.}, } @article {pmid38596495, year = {2024}, author = {Dirjayanto, VJ and Audrey, J and Simadibrata, DM}, title = {Vonoprazan-amoxicillin dual regimen with Saccharomyces boulardii as a rescue therapy for Helicobacter pylori: Current perspectives and implications.}, journal = {World journal of gastroenterology}, volume = {30}, number = {10}, pages = {1280-1286}, pmid = {38596495}, issn = {2219-2840}, mesh = {Humans ; Amoxicillin/therapeutic use ; Anti-Bacterial Agents/adverse effects ; *Helicobacter pylori ; *Saccharomyces boulardii ; *Helicobacter Infections/drug therapy ; Clarithromycin/therapeutic use ; Drug Therapy, Combination ; Proton Pump Inhibitors/adverse effects ; H(+)-K(+)-Exchanging ATPase ; Ions/pharmacology/therapeutic use ; Treatment Outcome ; *Pyrroles ; *Sulfonamides ; }, abstract = {Yu et al's study in the World Journal of Gastroenterology (2023) introduced a novel regimen of Vonoprazan-amoxicillin dual therapy combined with Saccharomyces boulardii (S. boulardii) for the rescue therapy against Helicobacter pylori (H. pylori), a pathogen responsible for peptic ulcers and gastric cancer. Vonoprazan is a potassium-competitive acid blocker renowned for its rapid and long-lasting acid suppression, which is minimally affected by mealtime. Compared to proton pump inhibitors, which bind irreversibly to cysteine residues in the H[+]/K[+]-ATPase pump, Vonoprazan competes with the K[+] ions, prevents the ions from binding to the pump and blocks acid secretion. Concerns with increasing antibiotic resistance, effects on the gut microbiota, patient compliance, and side effects have led to the advent of a dual regimen for H. pylori. Previous studies suggested that S. boulardii plays a role in stabilizing the gut barrier which improves H. pylori eradication rate. With an acceptable safety profile, the dual-adjunct regimen was effective regardless of prior treatment failure and antibiotic resistance profile, thereby strengthening the applicability in clinical settings. Nonetheless, S. boulardii comes in various formulations and dosages, warranting further exploration into the optimal dosage for supplementation in rescue therapy. Additionally, larger, randomized, double-blinded controlled trials are warranted to confirm these promising results.}, } @article {pmid38596406, year = {2024}, author = {Tanaka, Y and Kozuma, L and Hino, H and Takeya, K and Eto, M}, title = {Abemaciclib and Vacuolin-1 decrease aggregate-prone TDP-43 accumulation by accelerating autophagic flux.}, journal = {Biochemistry and biophysics reports}, volume = {38}, number = {}, pages = {101705}, pmid = {38596406}, issn = {2405-5808}, abstract = {(Macro)autophagy is a cellular degradation system for unnecessary materials, such as aggregate-prone TDP-43, a central molecule in neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Abemaciclib (Abe) and vacuolin-1 (Vac) treatments are known to induce vacuoles characterized by an autophagosome and a lysosome component, suggesting that they facilitate autophagosome-lysosome fusion. However, it remains unknown whether Abe and Vac suppress the accumulation of aggregate-prone TDP-43 by accelerating autophagic flux. In the present study, the Abe and Vac treatment dose-dependently reduced the GFP/RFP ratio in SH-SY5Y neuroblastoma cells stably expressing the autophagic flux marker GFP-LC3-RFP-LC3ΔG. Abe and Vac also increased the omegasome marker GFP-ATG13 signal and the autophagosome marker mCherry-LC3 localized to the lysosome marker LAMP1-GFP. The Abe and Vac treatment decreased the intracellular level of the lysosome marker LAMP1-GFP in SH-SY5Y cells stably expressing LAMP1-GFP, but did not increase the levels of LAMP1-GFP, the autophagosome marker LC3-II, or the multivesicular body marker TSG101 in the extracellular vesicle-enriched fraction. Moreover, Abe and Vac treatment autophagy-dependently inhibited GFP-tagged aggregate-prone TDP-43 accumulation. The results of a PI(3)P reporter assay using the fluorescent protein tagged-2 × FYVE and LAMP1-GFP indicated that Abe and Vac increased the intensity of the PI(3)P signal on lysosomes. A treatment with the VPS34 inhibitor wortmannin (WM) suppressed Abe-/Vac-facilitated autophagic flux and the degradation of GFP-tagged aggregate-prone TDP-43. Collectively, these results suggest that Abe and Vac degrade aggregate-prone TDP-43 by accelerating autophagosome formation and autophagosome-lysosome fusion through the formation of PI(3)P.}, } @article {pmid38596011, year = {2024}, author = {Xu, CZ and Huan, X and Luo, SS and Zhong, HH and Zhao, CB and Chen, Y and Zou, ZY and Chen, S}, title = {Serum cytokines profile changes in amyotrophic lateral sclerosis.}, journal = {Heliyon}, volume = {10}, number = {7}, pages = {e28553}, pmid = {38596011}, issn = {2405-8440}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder, characterized by progressive limb weakness, dysphagia, dysphonia, and respiratory failure due to degeneration of upper and lower motor neurons. The pathogenesis of ALS is still unclear. Neuroinflammation has been found to be involved in its development and progression. Cytokines play a significant role in the inflammatory process. This study aims to identify novel biomarkers that may assist in the diagnosis of ALS.

METHODS: In Fujian Medical University Union Hospital and Huashan Hospital Fudan University, two independent centers, we prospectively recruited 50 ALS patients, and 41 healthy controls (25 ALS and 26 controls in the first stage and 25 ALS and 15 controls in the validation stage). An 18-plex Luminex kit was used to screen the serum cytokines levels in the first stage. Commercial ELISA kits were used to measure the levels of target cytokines in the validation stage. A single-molecule array HD-X platform was applied to assess the levels of serum neurofilament light chain (NFL).

RESULTS: The levels of serum IL-18 were markedly increased in patients with ALS in the first stage (p = 0.016). The ROC curve showed an area under the curve at 0.695 (95% CI 0.50-0.84) in distinguishing ALS patients from healthy controls. The IL-21 was decreased in elderly patients when grouped by 55 years old (the medium age). Furthermore, the IL-5, IL-13, IL-18, and NFL had a positive relationship with the disease progression of ALS. We also found that serum IL-18 was markedly increased in ALS patients in the validation stage (167.67 [148.25-175.59] vs 116.44 [102.43-122.19]pg/ml, p < 0.0015).

CONCLUSION: In this study, we identified systemic cytokine profile changes in the serum of ALS patients, especially the elevated IL-18, as well as the decreased IL-21 in elder patients. These changes in serum cytokine profiles may shed new light on an in-depth understanding of the immunopathogenic characteristics of ALS.}, } @article {pmid38595972, year = {2024}, author = {Zhou, L and Xie, M and Wang, X and Xu, R}, title = {The usage and advantages of several common amyotrophic lateral sclerosis animal models.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1341109}, pmid = {38595972}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis is a fatal, multigenic, multifactorial neurodegenerative disease characterized by upper and lower motor neuron loss. Animal models are essential for investigating pathogenesis and reflecting clinical manifestations, particularly in developing reasonable prevention and therapeutic methods for human diseases. Over the decades, researchers have established a host of different animal models in order to dissect amyotrophic lateral sclerosis (ALS), such as yeast, worms, flies, zebrafish, mice, rats, pigs, dogs, and more recently, non-human primates. Although these models show different peculiarities, they are all useful and complementary to dissect the pathological mechanisms of motor neuron degeneration in ALS, contributing to the development of new promising therapeutics. In this review, we describe several common animal models in ALS, classified by the naturally occurring and experimentally induced, pointing out their features in modeling, the onset and progression of the pathology, and their specific pathological hallmarks. Moreover, we highlight the pros and cons aimed at helping the researcher select the most appropriate among those common experimental animal models when designing a preclinical ALS study.}, } @article {pmid38595767, year = {2024}, author = {Jia, H and Omar, AA and Xu, J and Dalmendray, J and Wang, Y and Feng, Y and Wang, W and Hu, Z and Grosser, JW and Wang, N}, title = {Generation of transgene-free canker-resistant Citrus sinensis cv. Hamlin in the T0 generation through Cas12a/CBE co-editing.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1385768}, pmid = {38595767}, issn = {1664-462X}, abstract = {Citrus canker disease affects citrus production. This disease is caused by Xanthomonas citri subsp. citri (Xcc). Previous studies confirmed that during Xcc infection, PthA4, a transcriptional activator like effector (TALE), is translocated from the pathogen to host plant cells. PthA4 binds to the effector binding elements (EBEs) in the promoter region of canker susceptibility gene LOB1 (EBEPthA4-LOBP) to activate its expression and subsequently cause canker symptoms. Previously, the Cas12a/CBE co-editing method was employed to disrupt EBEPthA4-LOBP of pummelo, which is highly homozygous. However, most commercial citrus cultivars are heterozygous hybrids and more difficult to generate homozygous/biallelic mutants. Here, we employed Cas12a/CBE co-editing method to edit EBEPthA4-LOBP of Hamlin (Citrus sinensis), a commercial heterozygous hybrid citrus cultivar grown worldwide. Binary vector GFP-p1380N-ttLbCas12a:LOBP1-mPBE:ALS2:ALS1 was constructed and shown to be functional via Xcc-facilitated agroinfiltration in Hamlin leaves. This construct allows the selection of transgene-free regenerants via GFP, edits ALS to generate chlorsulfuron-resistant regenerants as a selection marker for genome editing resulting from transient expression of the T-DNA via nCas9-mPBE:ALS2:ALS1, and edits gene(s) of interest (i.e., EBEPthA4-LOBP in this study) through ttLbCas12a, thus creating transgene-free citrus. Totally, 77 plantlets were produced. Among them, 8 plantlets were transgenic plants (#HamGFP1 - #HamGFP8), 4 plantlets were transgene-free (#HamNoGFP1 - #HamNoGFP4), and the rest were wild type. Among 4 transgene-free plantlets, three lines (#HamNoGFP1, #HamNoGFP2 and #HamNoGFP3) contained biallelic mutations in EBEpthA4, and one line (#HamNoGFP4) had homozygous mutations in EBEpthA4. We achieved 5.2% transgene-free homozygous/biallelic mutation efficiency for EBEPthA4-LOBP in C. sinensis cv. Hamlin, compared to 1.9% mutation efficiency for pummelo in a previous study. Importantly, the four transgene-free plantlets and 3 transgenic plantlets that survived were resistant against citrus canker. Taken together, Cas12a/CBE co-editing method has been successfully used to generate transgene-free canker-resistant C. sinensis cv. Hamlin in the T0 generation via biallelic/homozygous editing of EBEpthA4 of the canker susceptibility gene LOB1.}, } @article {pmid38595691, year = {2024}, author = {McMackin, R and Tadjine, Y and Fasano, A and Mitchell, M and Heverin, M and Awiszus, F and Nasseroleslami, B and Carson, RG and Hardiman, O}, title = {Examining short interval intracortical inhibition with different transcranial magnetic stimulation-induced current directions in ALS.}, journal = {Clinical neurophysiology practice}, volume = {9}, number = {}, pages = {120-129}, pmid = {38595691}, issn = {2467-981X}, abstract = {OBJECTIVE: To establish if induced current direction across the motor cortex alters the sensitivity of transcranial magnetic stimulation (TMS)-evoked short-interval intracortical inhibition (SICI) as an ALS biomarker.

METHODS: Threshold tracking-TMS was undertaken in 35 people with ALS and 39 controls. Using a coil orientation which induces posterior-anterior (PA)-directed current across the motor cortex, SICI (1 ms and 3 ms interstimulus intervals) and intracortical facilitation (ICF, 10 ms interstimulus interval) were recorded. SICI3ms was also recorded using a coil orientation which induces anterior-posterior (AP)-directed current across the motor cortex.

RESULTS: At group level, SICI3ms-PA (AUROC = 0.7), SICI3ms-AP (AUROC = 0.8) and SICI1ms (AUROC = 0.66) were substantially lower in those with ALS, although there was considerable interindividual heterogeneity. Averaging across interstimulus intervals (ISIs) marginally improved SICIPA sensitivity (AUROC = 0.76). Averaging SICI values across ISIs and orientations into a single SICI measure did not substantially improve sensitivity (AUROC = 0.81) compared to SICI3ms-AP alone. SICI3ms-AP and SICI3ms-PA did not significantly correlate (rho = 0.19, p = 0.313), while SICI1ms-PA and SICI3ms-PA did (rho = 0.37, p = 0.006). Further, those with ALS with the lowest SICI3ms-PA were not those with the lowest SICI3ms-AP. ICF was similar between groups (AUROC = 0.50).

CONCLUSIONS: SICIPA and SICIAP are uncorrelated measures of motor cortical inhibitory functions which are useful as distinct, unequally affected, measures of disinhibition in ALS.

SIGNIFICANCE: Examining both SICIPA and SICIAP may facilitate more comprehensive characterisation of motor cortical disinhibition in ALS.}, } @article {pmid38593618, year = {2024}, author = {Chen, Y and Pei, X and Chen, L and Chen, L}, title = {A dynamic regulatory switch for phase separation of FUS protein: Zinc ions and zinc finger domain.}, journal = {Biochemical and biophysical research communications}, volume = {710}, number = {}, pages = {149862}, doi = {10.1016/j.bbrc.2024.149862}, pmid = {38593618}, issn = {1090-2104}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Cysteine/genetics ; Mutation ; Phase Separation ; *RNA-Binding Protein FUS/chemistry/genetics/metabolism ; Zinc/metabolism ; Zinc Fingers ; Protein Aggregates ; }, abstract = {Zinc is an important trace element in the human body, and its homeostasis is closely related to amyotrophic lateral sclerosis (ALS). Cytoplasmic FUS proteins from patients with ALS aggregate their important pathologic markers. Liquid-liquid phase separation (LLPS) of FUS can lead to its aggregation. However, whether and how zinc homeostasis affects the aggregation of disease-associated FUS proteins in the cytoplasm remains unclear. Here, we found that zinc ion enhances LLPS and promotes the aggregation in the cytoplasm for FUS protein. In the FUS, the cysteine of the zinc finger (ZnF), recognizes and binds to zinc ions, reducing droplet mobility and enhancing protein aggregation in the cytoplasm. The mutation of FUS cysteine disrupts the dynamic regulatory switch of zinc ions and ZnF, resulting in insensitivity to zinc ions. These results suggest that the dynamic regulation of LLPS by binding with zinc ions may be a widespread mechanism and provide a new understanding of neurological diseases such as ALS and other ZnF protein-related diseases.}, } @article {pmid38593537, year = {2024}, author = {Vijayakumar, S and Schwaighofer, A and Ramer, G and Lendl, B}, title = {Multivariate curve resolution -alternating least squares augmented with partial least squares baseline correction applied to mid-IR laser spectra resolves protein denaturation by reducing rotational ambiguity.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {315}, number = {}, pages = {124228}, doi = {10.1016/j.saa.2024.124228}, pmid = {38593537}, issn = {1873-3557}, abstract = {High spectral power density provided by advances in external cavity quantum cascade lasers (EC-QCL) have enabled increased transmission path lengths in mid-infrared (mid-IR) spectroscopy for more sensitive measurement of proteins in aqueous solutions. These extended path lengths also facilitate flow through measurements by avoiding congestion of the flow cell by protein aggregates. Despite the advantages presented by laser-based mid-IR spectroscopy of proteins, extraction of secondary structure information from spectra, especially in the presence of complex multi-component matrices with overlapping spectral features, remains an impediment that requires fine tuning of evaluation algorithms (e.g., band fitting, interpretation of second derivative spectra etc.). In this work, the use of multivariate curve resolution alternating least squares (MCR-ALS) for the analysis of a chemical de- and renaturation experiment has been demonstrated, since this technique offers the second-order advantage of extracting spectral signatures and concentration profiles even in the presence of unknown, uncalibrated constituents. Furthermore, we exhibit a partial least squares regression (PLSR) based subtraction of matrix component spectra prior to MCR-ALS as a method to obtain secondary structure information even in the absence of reference spectra. These approaches are showcased using the online reaction monitoring of the titration of β-lactoglobulin (β-LG) in water against the surfactants sodium dodecyl sulfate (SDS) and octaethylene glyol monododecyl ether (C12E8), using a commercially available laser-based IR spectrometer. Results for the automated PLSR correction plus MCR-ALS approach compare favorably to an MCR-ALS standalone approach using initial estimates as well as analysis of secondary structure using data processed with a manual baseline correction. The herein described chemometric approach suggests a way to simplify the challenge of handling complex matrices in protein structure analysis by isolating the background from the protein contributions, prior to analysis via other soft-modelling techniques. Consequently, the findings of this study indicate the suitability of online reaction monitoring through mid-IR spectroscopy combined with chemometric techniques as a potential tool in downstream quality control and process automation.}, } @article {pmid38593477, year = {2024}, author = {Lindborg, SR and Goyal, NA and Katz, J and Burford, M and Li, J and Kaspi, H and Abramov, N and Boulanger, B and Berry, JD and Nicholson, K and Mozaffar, T and Miller, R and Jenkins, L and Baloh, RH and Lewis, R and Staff, NP and Owegi, MA and Dagher, B and Blondheim-Shraga, NR and Gothelf, Y and Levy, YS and Kern, R and Aricha, R and Windebank, AJ and Bowser, R and Brown, RH and Cudkowicz, ME}, title = {Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes.}, journal = {Muscle & nerve}, volume = {69}, number = {6}, pages = {719-729}, doi = {10.1002/mus.28093}, pmid = {38593477}, issn = {1097-4598}, support = {//California Institute for Regenerative Medicine/ ; //I AM ALS/ ; //ALS Association/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/drug therapy/diagnosis ; *Biomarkers/cerebrospinal fluid ; Double-Blind Method ; *Neurofilament Proteins/cerebrospinal fluid ; Treatment Outcome ; }, abstract = {INTRODUCTION/AIMS: Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint.

METHODS: A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty-five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale-Revised (ALSFRS-R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS-R.

RESULTS: We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel-treated participants (baseline NfL, baseline latency-associated peptide/transforming growth factor beta1 [LAP/TGFβ1], change galectin-1, all p < .01), with baseline NfL and LAP/TGFβ1 remaining (p < .05) when disease characteristics (p < .005) were incorporated. Change from baseline to the last measurement showed debamestrocel-driven reductions in NfL were associated with less decline in ALSFRS-R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p = .037).

DISCUSSION: Following debamestrocel treatment, many biomarkers showed increases (anti-inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These results offer preliminary insights that need to be confirmed.}, } @article {pmid38592845, year = {2024}, author = {Lerose, V and Ponticelli, M and Benedetto, N and Carlucci, V and Lela, L and Tzvetkov, NT and Milella, L}, title = {Withania somnifera (L.) Dunal, a Potential Source of Phytochemicals for Treating Neurodegenerative Diseases: A Systematic Review.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {6}, pages = {}, pmid = {38592845}, issn = {2223-7747}, support = {CUP: B34I20000320005//Project RESO - REsilienza e SOstenibilità delle filiere ortofrutticole e cerealicole per valorizzare i territori" - cod. identif. ARS01_01224 -/ ; CUP: G49J19001350004//Project SPIA-Valorization of by-products from the agro-food chain/ ; CUP: ECS00000036//Project NODES - Ecosistema dell'Innovazione "Nord Ovest Digitale e Sostenibile"/ ; }, abstract = {Withania somnifera (L.) Dunal is a medicinal plant belonging to the traditional Indian medical system, showing various therapeutic effects such as anti-cancer, anti-inflammatory, anti-microbial, anti-diabetic, and hepatoprotective activity. Of great interest is W. somnifera's potential beneficial effect against neurodegenerative diseases, since the authorized medicinal treatments can only delay disease progression and provide symptomatic relief and are not without side effects. A systematic search of PubMed and Scopus databases was performed to identify preclinical and clinical studies focusing on the applications of W. somnifera in preventing neurodegenerative diseases. Only English articles and those containing the keywords (Withania somnifera AND "neurodegenerative diseases", "neuroprotective effects", "Huntington", "Parkinson", "Alzheimer", "Amyotrophic Lateral Sclerosis", "neurological disorders") in the title or abstract were considered. Reviews, editorials, letters, meta-analyses, conference papers, short surveys, and book chapters were not considered. Selected articles were grouped by pathologies and summarized, considering the mechanism of action. The quality assessment and the risk of bias were performed using the Cochrane Handbook for Systematic Reviews of Interventions checklist. This review uses a systematic approach to summarize the results from 60 investigations to highlight the potential role of W. somnifera and its specialized metabolites in treating or preventing neurodegenerative diseases.}, } @article {pmid38591790, year = {2024}, author = {Lochner, RH and Arumanayagam, AS and Powell, SZ and Masdeu, JC and Pascual, B and Cykowski, MD}, title = {Anterior insula is more vulnerable than posterior insula to TDP-43 pathology in common dementias and ALS.}, journal = {Journal of neuropathology and experimental neurology}, volume = {83}, number = {5}, pages = {307-317}, pmid = {38591790}, issn = {1554-6578}, support = {RF1 NS118584/NS/NINDS NIH HHS/United States ; RF1NS118584/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/pathology ; *Dementia ; DNA-Binding Proteins ; Neurons/pathology ; *TDP-43 Proteinopathies/pathology ; }, abstract = {Based on the anatomic proximity, connectivity, and functional similarities between the anterior insula and amygdala, we tested the hypothesis that the anterior insula is an important focus in the progression of TDP-43 pathology in LATE-NC. Blinded to clinical and neuropathologic data, phospho-TDP (pTDP) inclusion pathology was assessed in paired anterior and posterior insula samples in 105 autopsied patients with Alzheimer disease, Lewy body disease, LATE-NC and hippocampal sclerosis (HS), amyotrophic lateral sclerosis (ALS), and other conditions. Insular pTDP pathology was present in 34.3% of the study cohort, most commonly as neuronal inclusions and/or short neurites in lamina II, and less commonly as subpial processes resembling those described in the amygdala region. Among positive samples, pTDP pathology was limited to the anterior insula (41.7%), or occurred in both anterior and posterior insula (58.3%); inclusion density was greater in anterior insula across all diseases (p < .001). pTDP pathology occurred in 46.7% of ALS samples, typically without a widespread TDP-43 proteinopathy. In LATE-NC, it was seen in 30.4% of samples (mostly LATE-NC stages 2 and 3), often co-occurring with basal forebrain pathology and comorbid HS, suggesting this is an important step in the evolution of this pathology beyond the medial temporal lobe.}, } @article {pmid38591728, year = {2024}, author = {Koysuren, A and Temucin, CM}, title = {Concentric needle jitter analysis of the genioglossus muscle in patients with motor neuron disease.}, journal = {Neurological research}, volume = {46}, number = {6}, pages = {578-582}, doi = {10.1080/01616412.2024.2339096}, pmid = {38591728}, issn = {1743-1328}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Electromyography/methods ; *Motor Neuron Disease/physiopathology/diagnosis ; Aged ; *Muscle, Skeletal/physiopathology ; Adult ; Needles ; Tongue/physiopathology ; }, abstract = {OBJECTIVES: Difficulty relaxing the genioglossus muscle makes the evaluation of spontaneous activity problematic in patients with motor neuron disease (MND). We performed jitter analysis using conventional disposable concentric needle electrodes (CNEs) of the voluntarily activated genioglossus muscle in patients with and without MND to detect the denervation-reinnervation process.

METHODS: CNE jitter analysis was performed at the genioglossus muscle in 21 MND(+) patients and 22 MND(-) subjects. The jitter analysis was considered abnormal if the jitter values exceeded these limits for the mean consecutive difference (MCD) or the individual MCD in more than 10% of readings.

RESULTS: Seventeen MND(+) patients (81%) had at least three abnormal individual jitter values whereas denervation findings were obtained in eleven of them during the needle electromyographic examination at genioglossus muscle. None of the MND(-) subjects showed CNE jitter abnormality.

CONCLUSION: CNE jitter analysis of genioglossus muscle may provide an useful information that may be suggestive of a diagnosis of MND/ALS.}, } @article {pmid38591201, year = {2024}, author = {Roy, T and Padhi, S and Mazumder, R and Majee, C and Das, S and Monika, and Mishra, R and Kapoor, B}, title = {Alleviating Neurodegenerative Diseases Associated with Mitochondrial Defects by Therapeutic Biomolecules.}, journal = {Current topics in medicinal chemistry}, volume = {24}, number = {16}, pages = {1377-1407}, pmid = {38591201}, issn = {1873-4294}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Mitochondria/metabolism/drug effects ; *Antioxidants/pharmacology/chemistry ; Reactive Oxygen Species/metabolism ; Animals ; }, abstract = {Neurodegenerative diseases are emerging as a global health concern in the current scenario, and their association with mitochondrial defects has been a potential area of research. Mitochondria, one of the essential organelles of the cell, serve as the cell's powerhouse, producing energy and ensuring cellular health. Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and Pelizaeus-Merzbacher disease have been found to be primarily triggered by mitochondrial malfunction. One of the key byproducts of mitochondrial respiration, reactive oxygen species, also contributes significantly to mitochondrial DNA mutations that eventually cause mitochondrial breakdown. This review paper comprehensively examines the potential of therapeutic biomolecules, specifically mitochondria-specific antioxidants, in mitigating the impact of mitochondrial defects on neurodegenerative diseases. It provides a detailed analysis of the mechanisms involved in mitochondrial dysfunction, the potential therapeutic targets of these biomolecules, and their structureactivity relationship information are also discussed in this review. Various research articles and publications were used extensively in compiling the data, and the structures of biomolecules were prepared using software such as ChemDraw and ChemSketch. Crucial elements triggering mitochondrial abnormalities were identified and a tabular compilation of bioactive antioxidant compounds along with their therapeutic targets, was presented. Mitochondria-specific antioxidant therapy is an innovative and promising strategy for the management of neurodegenerative diseases associated with mitochondrial defects. This review provides a thorough summary of the current state of research and promising avenues of research and development in this field, emphasizing the importance of further investigations and clinical trials to elucidate their therapeutic benefits.}, } @article {pmid38591193, year = {2024}, author = {Rhodes, E and Alfa, S and Jin, HA and Massimo, L and Elman, L and Amado, D and Baer, M and Quinn, C and McMillan, CT}, title = {Cognitive reserve in ALS: the role of occupational skills and requirements.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {486-495}, pmid = {38591193}, issn = {2167-9223}, support = {K23 AG083124/AG/NIA NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; P30 AG073105/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/physiopathology/complications/diagnosis ; *Cognitive Reserve/physiology ; Male ; Female ; Middle Aged ; Aged ; Neuropsychological Tests ; Cognitive Dysfunction/etiology/physiopathology/diagnosis/psychology ; Adult ; Occupations ; }, abstract = {OBJECTIVE: Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative condition featuring variable degrees of motor and cognitive impairment. We assessed the impact of specific, empirically derived occupational skills and requirements on cognitive and motor functioning in ALS.

METHODS: Individuals with ALS (n = 150) were recruited from the University of Pennsylvania's Comprehensive ALS Clinic. The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) measured cognition, and the Penn Upper Motor Neuron (PUMNS) and ALS Functional Rating Scales (ALSFRS-R) measured motor symptoms. We derived 17 factors representing distinct occupational skills and requirements from the Occupational Information Network (O*NET), which were related to cognitive and motor scores using multiple linear regression.

RESULTS: Occupational roles involving greater reasoning ability (β = 2.12, p < .05), social ability (β = 1.73, p < .05), analytic skills, (β = 3.12, p < .01) and humanities knowledge (β = 1.83, p<.01) were associated with better performance on the ECAS, while jobs involving more exposure to environmental hazards (β=-2.57, p < .01) and technical skills (β=-2.16, p<.01) were associated with lower ECAS scores. Jobs requiring more precision skills (β = 1.91, p < .05) were associated with greater motor dysfunction on the PUMNS.

CONCLUSIONS: Occupational histories involving more cognitively complex skills and activities were related to preserved cognitive functioning in ALS consistent with the cognitive reserve hypothesis, while jobs with greater exposure to environmental hazards and technical demands were linked to poorer cognitive functioning. Jobs involving more repetitive movements were associated with worse motor functioning, possibly due to overuse. Occupational history provides insight into protective and risk factors for variable degrees of cognitive and motor dysfunction in ALS.}, } @article {pmid38591179, year = {2024}, author = {Talbott, EO and Malek, AM and Arena, VC and Wu, F and Steffes, K and Sharma, RK and Buchanich, J and Rager, JR and Bear, T and Hoffman, CA and Lacomis, D and Donnelly, C and Mauna, J and Vena, JE}, title = {Case-control study of environmental toxins and risk of amyotrophic lateral sclerosis involving the national ALS registry.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {533-542}, doi = {10.1080/21678421.2024.2336108}, pmid = {38591179}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/blood/chemically induced ; Male ; Female ; Middle Aged ; Case-Control Studies ; *Registries ; Aged ; Risk Factors ; *Environmental Exposure/adverse effects/statistics & numerical data ; Occupational Exposure/adverse effects/statistics & numerical data ; Pesticides/blood/adverse effects ; United States/epidemiology ; }, abstract = {OBJECTIVE: Neurotoxic chemicals are suggested in the etiology of amyotrophic lateral sclerosis (ALS). We examined the association of environmental and occupational risk factors including persistent organochlorine pesticides (OCPs) and ALS risk among cases from the Centers for Disease Control and Prevention National ALS Registry and age, sex, and county-matched controls.

METHODS: Participants completed a risk factor survey and provided a blood sample for OCP measurement. ALS cases were confirmed through the Registry. Conditional logistic regression assessed associations between ALS and risk factors including OCP levels.

RESULTS: 243 matched case-control pairs (61.7% male, mean [SD] age = 62.9 [10.1]) were included. Fifteen of the 29 OCPs examined had sufficient detectable levels for analysis. Modest correlations of self-reported years of exposure to residential pesticide mixtures and OCP serum levels were found (p<.001). Moreover, occupational exposure to lead including soldering and welding with lead/metal dust and use of lead paint/gasoline were significantly related to ALS risk (OR = 1.77, 95% CI: 1.11-2.83). Avocational gardening was a significant risk factor for ALS (OR = 1.57, 95% CI: 1.04-2.37). ALS risk increased for each 10 ng/g of α-Endosulfan (OR = 1.42, 95% CI: 1.14-1.77) and oxychlordane (OR = 1.24, 95% CI: 1.01-1.53). Heptachlor (detectable vs. nondetectable) was also associated with ALS risk (OR = 3.57, 95% CI: 1.50-8.52).

CONCLUSION: This national case-control study revealed both survey and serum levels of OCPs as risk factors for ALS. Despite the United States banning many OCPs in the 1970s and 1980s, their use abroad and long half-lives continue to exert possible neurotoxic health effects.}, } @article {pmid38590640, year = {2024}, author = {Scaricamazza, S and Nesci, V and Salvatori, I and Fenili, G and Rosina, M and Gloriani, M and Paronetto, MP and Madaro, L and Ferri, A and Valle, C}, title = {Endurance exercise has a negative impact on the onset of SOD1-G93A ALS in female mice and affects the entire skeletal muscle-motor neuron axis.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1360099}, pmid = {38590640}, issn = {1663-9812}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease characterized by the degeneration of motor neurons that leads to muscle wasting and atrophy. Epidemiological and experimental evidence suggests a causal relationship between ALS and physical activity (PA). However, the impact of PA on motor neuron loss and sarcopenia is still debated, probably because of the heterogeneity and intensities of the proposed exercises. With this study, we aimed to clarify the effect of intense endurance exercise on the onset and progression of ALS in the SOD1-G93A mouse model.

METHODS: We randomly selected four groups of twelve 35-day-old female mice. SOD1-G93A and WT mice underwent intense endurance training on a motorized treadmill for 8 weeks, 5 days a week. During the training, we measured muscle strength, weight, and motor skills and compared them with the corresponding sedentary groups to define the disease onset. At the end of the eighth week, we analyzed the skeletal muscle-motor neuron axis by histological and molecular techniques.

RESULTS: Intense endurance exercise anticipates the onset of the disease by 1 week (age of the onset: trained SOD1-G93A = 63.17 ± 2.25 days old; sedentary SOD1-G93A = 70.75 ± 2.45 days old). In SOD1-G93A mice, intense endurance exercise hastens the muscular switch to a more oxidative phenotype and worsens the denervation process by dismantling neuromuscular junctions in the tibialis anterior, enhancing the Wallerian degeneration in the sciatic nerve, and promoting motor neuron loss in the spinal cord. The training exacerbates neuroinflammation, causing immune cell infiltration in the sciatic nerve and a faster activation of astrocytes and microglia in the spinal cord.

CONCLUSION: Intense endurance exercise, acting on skeletal muscles, worsens the pathological hallmarks of ALS, such as denervation and neuroinflammation, brings the onset forward, and accelerates the progression of the disease. Our findings show the potentiality of skeletal muscle as a target for both prognostic and therapeutic strategies; the preservation of skeletal muscle health by specific intervention could counteract the dying-back process and protect motor neurons from death. The physiological characteristics and accessibility of skeletal muscle further enhance its appeal as a therapeutic target.}, } @article {pmid38589279, year = {2024}, author = {Iwasaki, Y}, title = {[Neuropathology of the Neurodegenerative Diseases].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {4}, pages = {343-351}, doi = {10.11477/mf.1416202611}, pmid = {38589279}, issn = {1881-6096}, mesh = {Humans ; tau Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; *Tauopathies/metabolism/pathology ; *Pick Disease of the Brain/metabolism/pathology ; *Frontotemporal Dementia ; *Frontotemporal Lobar Degeneration ; *Multiple System Atrophy ; DNA-Binding Proteins/metabolism ; }, abstract = {A definite diagnosis of neurodegenerative diseases is required for neuropathological examination during an autopsy. Each neurodegenerative disease has specific vulnerable regions and affected systems (system degeneration), and is typified by an accumulation of abnormal protein with the formation of characteristic morphological aggregates in the nerve and glial cells, called proteinopathy. The most common neurodegenerative diseases are tauopathy, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD); α-synucleinopathy, including multiple system atrophy (MSA); and TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). PSP and CBD show characteristic tau-positive astrocytic inclusions known as tufted astrocytes and astrocytic plaques, respectively. PiD shows tau-positive neuronal inclusions termed Pick bodies. MSA is characterized by α-synuclein-positive oligodendroglial inclusions, called glial cytoplasmic inclusions. ALS- and FTLD-TDP show TDP-43-positive neuronal inclusions, such as skein-like and round inclusions. Huntington's disease shows polyglutamine-positive neuronal inclusions, and Creutzfeldt-Jakob disease shows diffuse deposition of granular prions in the neuropil. The atypical proteins in these diseases have abnormal conformational properties. A comprehensive comparison of the clinical findings and neuropathological observations, including neuroanatomy and images acquired during life, is important to improve the sensitivity of clinical diagnosis.}, } @article {pmid38588013, year = {2024}, author = {El Hajj, R and Al Sagheer, T and Ballout, N}, title = {Optogenetics in chronic neurodegenerative diseases, controlling the brain with light: A systematic review.}, journal = {Journal of neuroscience research}, volume = {102}, number = {4}, pages = {e25321}, doi = {10.1002/jnr.25321}, pmid = {38588013}, issn = {1097-4547}, mesh = {*Optogenetics/methods ; Animals ; *Neurodegenerative Diseases/therapy/genetics ; Humans ; *Brain/metabolism ; Disease Models, Animal ; Neurons/physiology/metabolism ; Deep Brain Stimulation/methods ; }, abstract = {Neurodegenerative diseases are progressive disorders characterized by synaptic loss and neuronal death. Optogenetics combines optical and genetic methods to control the activity of specific cell types. The efficacy of this approach in neurodegenerative diseases has been investigated in many reviews, however, none of them tackled it systematically. Our study aimed to review systematically the findings of optogenetics and its potential applications in animal models of chronic neurodegenerative diseases and compare it with deep brain stimulation and designer receptors exclusively activated by designer drugs techniques. The search strategy was performed based on the PRISMA guidelines and the risk of bias was assessed following the Systematic Review Centre for Laboratory Animal Experimentation tool. A total of 247 articles were found, of which 53 were suitable for the qualitative analysis. Our data revealed that optogenetic manipulation of distinct neurons in the brain is efficient in rescuing memory impairment, alleviating neuroinflammation, and reducing plaque pathology in Alzheimer's disease. Similarly, this technique shows an advanced understanding of the contribution of various neurons involved in the basal ganglia pathways with Parkinson's disease motor symptoms and pathology. However, the optogenetic application using animal models of Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis was limited. Optogenetics is a promising technique that enhanced our knowledge in the research of neurodegenerative diseases and addressed potential therapeutic solutions for managing these diseases' symptoms and delaying their progression. Nevertheless, advanced investigations should be considered to improve optogenetic tools' efficacy and safety to pave the way for their translatability to the clinic.}, } @article {pmid38586597, year = {2024}, author = {Zhang, T and Bao, L and Chen, H}, title = {Review of Phenotypic Heterogeneity of Neuronal Intranuclear Inclusion Disease and NOTCH2NLC-Related GGC Repeat Expansion Disorders.}, journal = {Neurology. Genetics}, volume = {10}, number = {2}, pages = {e200132}, pmid = {38586597}, issn = {2376-7839}, abstract = {Neuronal intranuclear inclusion disease (NIID) is an underdiagnosed neurodegenerative disorder caused by pathogenic GGC expansions in NOTCH2NLC. However, an increasing number of reports of NOTCH2NLC GGC expansions in patients with Alzheimer disease, essential tremor, Parkinson disease, amyotrophic lateral sclerosis, and oculopharyngodistal myopathy have led to the proposal of a new concept known as NOTCH2NLC-related GGC repeat expansion disorders (NREDs). The majority of studies have mainly focused on screening for NOTCH2NLC GGC repeat variation in populations previously diagnosed with the associated disease, subsequently presenting it as a novel causative gene for the condition. These studies appear to be clinically relevant but do have their limitations because they may incorrectly regard the lack of MRI abnormalities as an exclusion criterion for NIID or overlook concomitant clinical presentations not typically observed in the associated diseases. Besides, in many instances within these reports, patients lack pathologic evidence or undergo long-term follow-up to conclusively rule out NIID. In this review, we will systematically review the research on NOTCH2NLC 5' untranslated region GGC repeat expansions and their association with related neurologic disorders, explaining the limitations of the relevant reports. Furthermore, we will integrate subsequent studies to further demonstrate that these patients actually experienced distinct clinical phenotypes of NIID.}, } @article {pmid38585945, year = {2024}, author = {Haider, R and Shipley, B and Surewicz, K and Hinczewski, M and Surewicz, WK}, title = {Pathological C-terminal phosphomimetic substitutions alter the mechanism of liquid-liquid phase separation of TDP-43 low complexity domain.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38585945}, issn = {2692-8205}, support = {RF1 AG061797/AG/NIA NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; T32 NS077888/NS/NINDS NIH HHS/United States ; }, abstract = {C-terminally phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) marks the proteinaceous inclusions that characterize a number of age-related neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration and Alzheimer's disease. TDP-43 phosphorylation at S403/S404, and especially at S409/S410, is in fact accepted as a biomarker of proteinopathy. These residues are located within the low complexity domain (LCD), which also drives the protein's liquid-liquid phase separation (LLPS). The impact of phosphorylation at these LCD sites on phase separation of the protein is a topic of great interest, as these post-translational modifications and LLPS are both implicated in proteinopathies. Here, we employed a combination of experimental and simulation-based approaches to explore this question on a phosphomimetic model of the TDP-43 LCD. Our turbidity and fluorescence microscopy data show that Ser-to-Asp substitutions at residues S403, S404, S409 and S410 alter the LLPS behavior of TDP-43 LCD. In particular, in contrast to the unmodified protein, the phosphomimetic variants display a biphasic dependence on salt concentration. Through coarse-grained modeling, we find that this biphasic salt dependence is derived from an altered mechanism of phase separation, in which LLPS-driving short-range intermolecular hydrophobic interactions are modulated by long-range attractive electrostatic interactions. Overall, this in vitro and in silico study provides a physiochemical foundation for understanding the impact of pathologically-relevant C-terminal phosphorylation on the LLPS of the TDP-43 in a more complex cellular environment.}, } @article {pmid38585915, year = {2024}, author = {Martin, EJ and Santacruz, C and Mitevska, A and Jones, IE and Krishnan, G and Gao, FB and Finan, JD and Kiskinis, E}, title = {Traumatic injury causes selective degeneration and TDP-43 mislocalization in human iPSC-derived C9orf72-associated ALS/FTD motor neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38585915}, issn = {2692-8205}, support = {RF1 NS101986/NS/NINDS NIH HHS/United States ; R01 NS134166/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; R01 NS113935/NS/NINDS NIH HHS/United States ; R01 NS104219/NS/NINDS NIH HHS/United States ; }, abstract = {A hexanucleotide repeat expansion (HRE) in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, patients with the HRE exhibit a wide disparity in clinical presentation and age of symptom onset suggesting an interplay between genetic background and environmental stressors. Neurotrauma as a result of traumatic brain or spinal cord injury has been shown to increase the risk of ALS/FTD in epidemiological studies. Here, we combine patient-specific induced pluripotent stem cells (iPSCs) with a custom-built device to deliver biofidelic stretch trauma to C9orf72 patient and isogenic control motor neurons (MNs) in vitro. We find that mutant but not control MNs exhibit selective degeneration after a single incident of severe trauma, which can be partially rescued by pretreatment with a C9orf72 antisense oligonucleotide. A single incident of mild trauma does not cause degeneration but leads to cytoplasmic accumulation of TDP-43 in C9orf72 MNs. This mislocalization, which only occurs briefly in isogenic controls, is eventually restored in C9orf72 MNs after 6 days. Lastly, repeated mild trauma ablates the ability of patient MNs to recover. These findings highlight alterations in TDP-43 dynamics in C9orf72 ALS/FTD patient MNs following traumatic injury and demonstrate that neurotrauma compounds neuropathology in C9orf72 ALS/FTD. More broadly, our work establishes an in vitro platform that can be used to interrogate the mechanistic interactions between ALS/FTD and neurotrauma.}, } @article {pmid38585910, year = {2024}, author = {Jin, W and Boss, J and Bakulski, KM and Goutman, SA and Feldman, EL and Fritsche, LG and Mukherjee, B}, title = {Improving prediction models of amyotrophic lateral sclerosis (ALS) using polygenic, pre-existing conditions, and survey-based risk scores in the UK Biobank.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38585910}, support = {K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R01TS000344/ACL/ACL HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) causes profound impairments in neurological function and a cure for this devastating disease remains elusive. Early detection and risk stratification are crucial for timely intervention and improving patient outcomes. This study aimed to identify predisposing genetic, phenotypic, and exposure-related factors for Amyotrophic lateral sclerosis using multi-modal data and assess their joint predictive potential.

METHODS: Utilizing data from the UK Biobank, we analyzed an unrelated set of 292 ALS cases and 408,831 controls of European descent. Two polygenic risk scores (PRS) are constructed: "GWAS Hits PRS" and "PRS-CS," reflecting oligogenic and polygenic ALS risk profiles, respectively. Time-restricted phenome-wide association studies (PheWAS) were performed to identify pre-existing conditions increasing ALS risk, integrated into phenotypic risk scores (PheRS). A poly-exposure score ("PXS") captures the influence of environmental exposures measured through survey questionnaires. We evaluate the performance of these scores for predicting ALS incidence and stratifying risk, adjusting for baseline demographic covariates.

RESULTS: Both PRSs modestly predicted ALS diagnosis, but with increased predictive power when combined (covariate-adjusted receiver operating characteristic [AAUC] = 0.584 [0.525, 0.639]). PheRS incorporated diagnoses 1 year before ALS onset (PheRS1) modestly discriminated cases from controls (AAUC = 0.515 [0.472, 0.564]). The "PXS" did not significantly predict ALS. However, a model incorporating PRSs and PheRS1 improved prediction of ALS (AAUC = 0.604 [0.547, 0.667]), outperforming a model combining all risk scores. This combined risk score identified the top 10% of risk score distribution with a 4-fold higher ALS risk (95% CI: [2.04, 7.73]) versus those in the 40%-60% range.

DISCUSSIONS: By leveraging UK Biobank data, our study uncovers predisposing ALS factors, highlighting the improved effectiveness of multi-factorial prediction models to identify individuals at highest risk for ALS.}, } @article {pmid38585891, year = {2024}, author = {Antonucci, S and Caron, G and Dikwella, N and Krishnamurty, SS and Harster, A and Zarrin, H and Tahanis, A and Heuvel, FO and Danner, SM and Ludolph, AC and Grycz, K and Bączyk, M and Zytnicki, D and Roselli, F}, title = {Spinal motoneuron excitability is homeostatically-regulated through β-adrenergic neuromodulation in wild-type and presymptomatic SOD1 mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38585891}, issn = {2692-8205}, support = {R01 NS110953/NS/NINDS NIH HHS/United States ; R01 NS112304/NS/NINDS NIH HHS/United States ; R01 NS115900/NS/NINDS NIH HHS/United States ; }, abstract = {Homeostatic feedback loops are essential to stabilize the activity of neurons and neuronal networks. It has been hypothesized that, in the context of Amyotrophic Lateral Sclerosis (ALS), an excessive gain in feedback loops might hyper- or hypo-excite motoneurons (MNs) and contribute to the pathogenesis. Here, we investigated how the neuromodulation of MN intrinsic properties is homeostatically controlled in presymptomatic adult SOD1(G93A) mice and in the age-matched control WT mice. First, we determined that β2 and β3- adrenergic receptors, which are Gs-coupled receptors and subject to tight and robust feedback loops, are specifically expressed in spinal MNs of both SOD1 and WT mice at P45. We then demonstrated that these receptors elicit a so-far overlooked neuromodulation of the firing and excitability properties of MNs. These electrical properties are homeostatically regulated following receptor engagement, which triggers ion channel transcriptional changes and downregulates those receptors. These homeostatic feedbacks are not dysregulated in presymptomatic SOD1 mice, and they set the MN excitability upon β-adrenergic neuromodulation.}, } @article {pmid38585774, year = {2024}, author = {Yu, M and Xu, J and Dutta, R and Trapp, B and Pieper, AA and Cheng, F}, title = {Network medicine informed multi-omics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38585774}, issn = {2692-8205}, support = {R21 AG083003/AG/NIA NIH HHS/United States ; R01 AG082118/AG/NIA NIH HHS/United States ; R56 AG074001/AG/NIA NIH HHS/United States ; RF1 AG082211/AG/NIA NIH HHS/United States ; R01 AG084250/AG/NIA NIH HHS/United States ; RF1 NS133812/NS/NINDS NIH HHS/United States ; U01 AG073323/AG/NIA NIH HHS/United States ; R01 AG066707/AG/NIA NIH HHS/United States ; R01 AG076448/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. To date, the challenge to establishing effective treatment for ALS remains formidable, partly due to inadequate translation of existing human genetic findings into actionable ALS-specific pathobiology for subsequent therapeutic development. This study evaluates the feasibility of network medicine methodology via integrating human brain-specific multi-omics data to prioritize drug targets and repurposable treatments for ALS. Using human brain-specific genome-wide quantitative trait loci (x-QTLs) under a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in various known ALS pathobiological pathways, including regulation of T cell activation, monocyte differentiation, and lymphocyte proliferation. Specifically, we leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on brain-specific expression quantitative trait loci (QTL) (eQTL), protein QTLs (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Applying network proximity analysis of predicted ALS-associated gene-coding targets and existing drug-target networks under the human protein-protein interactome (PPI) model, we identified a set of potential repurposable drugs (including Diazoxide, Gefitinib, Paliperidone, and Dimethyltryptamine) for ALS. Subsequent validation established preclinical and clinical evidence for top-prioritized repurposable drugs. In summary, we presented a network-based multi-omics framework to identify potential drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.}, } @article {pmid38585725, year = {2024}, author = {Sinha, IR and Sandal, PS and Burns, GD and Mallika, AP and Irwin, KE and Cruz, ALF and Wang, V and Rodríguez, JL and Wong, PC and Ling, JP}, title = {Large-scale RNA-seq mining reveals ciclopirox triggers TDP-43 cryptic exons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38585725}, issn = {2692-8205}, support = {R01 NS095969/NS/NINDS NIH HHS/United States ; R33 NS115161/NS/NINDS NIH HHS/United States ; U01 FD008129/FD/FDA HHS/United States ; UH3 NS115608/NS/NINDS NIH HHS/United States ; }, abstract = {Nuclear clearance and cytoplasmic aggregation of TDP-43 in neurons, initially identified in ALS-FTD, are hallmark pathological features observed across a spectrum of neurodegenerative diseases. We previously found that TDP-43 loss-of-function leads to the transcriptome-wide inclusion of deleterious cryptic exons in brains and biofluids post-mortem as well as during the presymptomatic stage of ALS-FTD, but upstream mechanisms that lead to TDP-43 dysregulation remain unclear. Here, we developed a web-based resource (SnapMine) to determine the levels of TDP-43 cryptic exon inclusion across hundreds of thousands of publicly available RNA sequencing datasets. We established cryptic exon inclusion across a variety of human cells and tissues to provide ground truth references for future studies on TDP-43 dysregulation. We then explored studies that were entirely unrelated to TDP-43 or neurodegeneration and found that ciclopirox olamine (CPX), an FDA-approved antifungal, can trigger the inclusion of TDP-43-associated cryptic exons in a variety of mouse and human primary cells. CPX induction of cryptic exon occurs via heavy metal toxicity and oxidative stress, suggesting that similar vulnerabilities could play a role in neurodegeneration. Our work demonstrates how diverse datasets can be linked through common biological features and underscores that public archives of sequencing data represent a vastly underutilized resource with tremendous potential for uncovering novel insights into complex biological mechanisms and diseases.}, } @article {pmid38585670, year = {2024}, author = {Cipriano, L and Minino, R and Liparoti, M and Polverino, A and Romano, A and Bonavita, S and Pirozzi, MA and Quarantelli, M and Jirsa, V and Sorrentino, G and Sorrentino, P and Troisi Lopez, E}, title = {Flexibility of brain dynamics is increased and predicts clinical impairment in relapsing-remitting but not in secondary progressive multiple sclerosis.}, journal = {Brain communications}, volume = {6}, number = {2}, pages = {fcae112}, pmid = {38585670}, issn = {2632-1297}, abstract = {Large-scale brain activity has long been investigated under the erroneous assumption of stationarity. Nowadays, we know that resting-state functional connectivity is characterized by aperiodic, scale-free bursts of activity (i.e. neuronal avalanches) that intermittently recruit different brain regions. These different patterns of activity represent a measure of brain flexibility, whose reduction has been found to predict clinical impairment in multiple neurodegenerative diseases such as Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease. Brain flexibility has been recently found increased in multiple sclerosis, but its relationship with clinical disability remains elusive. Also, potential differences in brain dynamics according to the multiple sclerosis clinical phenotypes remain unexplored so far. We performed a brain dynamics study quantifying brain flexibility utilizing the 'functional repertoire' (i.e. the number of configurations of active brain areas) through source reconstruction of magnetoencephalography signals in a cohort of 25 multiple sclerosis patients (10 relapsing-remitting multiple sclerosis and 15 secondary progressive multiple sclerosis) and 25 healthy controls. Multiple sclerosis patients showed a greater number of unique reconfigurations at fast time scales as compared with healthy controls. This difference was mainly driven by the relapsing-remitting multiple sclerosis phenotype, whereas no significant differences in brain dynamics were found between secondary progressive multiple sclerosis and healthy controls. Brain flexibility also showed a different predictive power on clinical disability according to the multiple sclerosis type. For the first time, we investigated brain dynamics in multiple sclerosis patients through high temporal resolution techniques, unveiling differences in brain flexibility according to the multiple sclerosis phenotype and its relationship with clinical disability.}, } @article {pmid38585669, year = {2024}, author = {Novy, C and Busk, ØL and Tysnes, OB and Landa, SS and Aanjesen, TN and Alstadhaug, KB and Bjerknes, TL and Bjørnå, IK and Bråthen, G and Dahl, E and Demic, N and Fahlström, M and Flemmen, HØ and Hallerstig, E and HogenEsch, I and Kampman, MT and Kleveland, G and Kvernmo, HB and Ljøstad, U and Maniaol, A and Morsund, AH and Nakken, O and Olsen, CG and Schlüter, K and Utvik, MS and Yaseen, R and Holla, ØL and Holmøy, T and Høyer, H}, title = {Repeat expansions in AR, ATXN1, ATXN2 and HTT in Norwegian patients diagnosed with amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {2}, pages = {fcae087}, pmid = {38585669}, issn = {2632-1297}, abstract = {Genetic repeat expansions cause neuronal degeneration in amyotrophic lateral sclerosis as well as other neurodegenerative disorders such as spinocerebellar ataxia, Huntington's disease and Kennedy's disease. Repeat expansions in the same gene can cause multiple clinical phenotypes. We aimed to characterize repeat expansions in a Norwegian amyotrophic lateral sclerosis cohort. Norwegian amyotrophic lateral sclerosis patients (n = 414) and neurologically healthy controls adjusted for age and gender (n = 713) were investigated for repeat expansions in AR, ATXN1, ATXN2 and HTT using short read exome sequencing and the ExpansionHunter software. Five amyotrophic lateral sclerosis patients (1.2%) and two controls (0.3%) carried ≥36 repeats in HTT (P = 0.032), and seven amyotrophic lateral sclerosis patients (1.7%) and three controls (0.4%) carried ≥29 repeats in ATXN2 (P = 0.038). One male diagnosed with amyotrophic lateral sclerosis carried a pathogenic repeat expansion in AR, and his diagnosis was revised to Kennedy's disease. In ATXN1, 50 amyotrophic lateral sclerosis patients (12.1%) and 96 controls (13.5%) carried ≥33 repeats (P = 0.753). None of the patients with repeat expansions in ATXN2 or HTT had signs of Huntington's disease or spinocerebellar ataxia type 2, based on a re-evaluation of medical records. The diagnosis of amyotrophic lateral sclerosis was confirmed in all patients, with the exception of one patient who had primary lateral sclerosis. Our findings indicate that repeat expansions in HTT and ATXN2 are associated with increased likelihood of developing amyotrophic lateral sclerosis. Further studies are required to investigate the potential relationship between HTT repeat expansions and amyotrophic lateral sclerosis.}, } @article {pmid38585660, year = {2024}, author = {Zhang, H and Chen, C and Zhang, EE and Huang, X}, title = {TDP-43 deficiency in suprachiasmatic nucleus perturbs rhythmicity of neuroactivity in prefrontal cortex.}, journal = {iScience}, volume = {27}, number = {4}, pages = {109522}, pmid = {38585660}, issn = {2589-0042}, abstract = {Individuals within the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD) often experience disruptive mental behaviors and sleep-wake disturbances. The hallmark of ALS/FTD is the pathological involvement of TAR DNA-binding protein 43 (TDP-43). Understanding the role of TDP-43 in the circadian clock holds promise for addressing these behavioral abnormalities. In this study, we unveil TDP-43 as a pivotal regulator of the circadian clock. TDP-43 knockdown induces intracellular arrhythmicity, disrupts transcriptional activation regulation, and diminishes clock genes expression. Moreover, our experiments in adult mouse reveal that TDP-43 knockdown, specifically within the suprachiasmatic nucleus (SCN), induces locomotor arrhythmia, arrhythmic c-Fos expression, and depression-like behavior. This observation offers valuable insights into the substantial impact of TDP-43 on the behavioral aberrations associated with ALS/FTD. In summary, our study illuminates the significance of TDP-43 in circadian regulation, shedding light on the circadian regulatory mechanisms that may elucidate the pathological underpinnings of ALS/FTD.}, } @article {pmid38585631, year = {2024}, author = {Pinilla-González, V and Montecinos-Barrientos, B and Martin-Kommer, C and Chichiarelli, S and Saso, L and Rodrigo, R}, title = {Exploring antioxidant strategies in the pathogenesis of ALS.}, journal = {Open life sciences}, volume = {19}, number = {1}, pages = {20220842}, pmid = {38585631}, issn = {2391-5412}, abstract = {The central nervous system is essential for maintaining homeostasis and controlling the body's physiological functions. However, its biochemical characteristics make it highly vulnerable to oxidative damage, which is a common factor in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). ALS is a leading cause of motor neuron disease, characterized by a rapidly progressing and incurable condition. ALS often results in death from respiratory failure within 3-5 years from the onset of the first symptoms, underscoring the urgent need to address this medical challenge. The aim of this study is to present available data supporting the role of oxidative stress in the mechanisms underlying ALS and to discuss potential antioxidant therapies currently in development. These therapies aim to improve the quality of life and life expectancy for patients affected by this devastating disease.}, } @article {pmid38585517, year = {2023}, author = {Firstenfeld, AJ and Listorti, J and Jalaff, N and Loaiza Orozco, CP and Navarrete Gosdenovich, F and Schurr, T}, title = {Add-on treatment with Cerebrolysin improves clinical symptoms in patients with ALS: results from a prospective, single-center, placebo-controlled, randomized, double-blind, phase II study.}, journal = {Journal of medicine and life}, volume = {16}, number = {12}, pages = {1750-1755}, pmid = {38585517}, issn = {1844-3117}, mesh = {Humans ; *Amino Acids ; *Amyotrophic Lateral Sclerosis/drug therapy/diagnosis ; *Neuroprotective Agents/therapeutic use ; Prospective Studies ; Riluzole/therapeutic use ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating and progressive neurodegenerative disease with limited treatment options available. Cerebrolysin is a drug candidate for the treatment of ALS because of its neuroprotective and neuroregenerative effects. We initiated a pilot clinical study of a combination of Cerebrolysin and riluzole to assess the therapeutic benefit of Cerebrolysin as an add-on treatment on clinical signs and symptoms in outpatients with ALS. Twenty patients with a clinically definitive diagnosis of ALS were enrolled and randomly assigned in a 1:1 ratio to receive Cerebrolysin or placebo. All patients received 50 mg of riluzole PO twice daily as a standard treatment. Patients in the Cerebrolysin group received intravenous injections of 10 mL of Cerebrolysin once daily, five days a week for the first month and three days a week for the next two months. Analysis of the ALS Functional Rating Scale - revised at Month 1 (primary outcome measure), showed a significant treatment effect in favor of Cerebrolysin with a 2.3-point improvement from baseline to Month 1 compared to a 0.9-point decrease in patients on placebo (P=0.005). The effect was maintained over the three-month study period, and the beneficial effect of Cerebrolysin over placebo was also evident in the secondary outcome measures. The safety analysis showed that the combination of riluzole and Cerebrolyisn was well tolerated. Our results demonstrate for the first time a significant clinical effect of Cerebrolysin in improving functional outcomes in patients with ALS and suggest that Cerebrolysin has potential as a novel therapeutic option for ALS.}, } @article {pmid38585368, year = {2024}, author = {Jamet, M and Dupuis, L and Gonzalez De Aguilar, JL}, title = {Oligodendrocytes in amyotrophic lateral sclerosis and frontotemporal dementia: the new players on stage.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1375330}, pmid = {38585368}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal adult-onset neurodegenerative disorders that share clinical, neuropathological and genetic features, which forms part of a multi-system disease spectrum. The pathological process leading to ALS and FTD is the result of the combination of multiple mechanisms that operate within specific populations of neurons and glial cells. The implication of oligodendrocytes has been the subject of a number of studies conducted on patients and related animal models. In this review we summarize our current knowledge on the alterations specific to myelin and the oligodendrocyte lineage occurring in ALS and FTD. We also consider different ways by which specific oligodendroglial alterations influence neurodegeneration and highlight the important role of oligodendrocytes in these two intrinsically associated neurodegenerative diseases.}, } @article {pmid38583866, year = {2024}, author = {Lee, SH and Hong, WP and Kim, YS and Park, J and Lim, HJ}, title = {Dual-dispatch protocols and return of spontaneous circulation in patients with out-of-hospital cardiac arrest: a nationwide observational study.}, journal = {Clinical and experimental emergency medicine}, volume = {11}, number = {3}, pages = {276-285}, pmid = {38583866}, issn = {2383-4625}, abstract = {OBJECTIVE: The Korean National Fire Agency conducted a pilot project examining Advanced Life Support (ALS) protocols, including epinephrine administration, to improve survival among patients suffering out-of-hospital cardiac arrest (OHCA). In this study, we aimed to evaluate the effects of the Korean National Fire Agency ALS protocol on prehospital return of spontaneous circulation (ROSC) in patients with OHCA.

METHODS: This study included patients with adult-presumed cardiac arrest between January and December 2020. The main factor of interest was ambulance type according to ALS protocol, which was divided into dedicated ALS ambulance (DA), smartphone-based ALS ambulance (SALS), and non-DA, and the main analysis factor was prehospital ROSC. Multivariate logistic regression analysis was performed.

RESULTS: During the study period, a total of 18,031 adult patients with OHCA was treated by the emergency medical services, including 7,520 DAs (41.71%), 2,622 SALSs (14.54%), and 7,889 non-DAs (43.75%). The prehospital ROSC ratio was 13.19% for DA, 11.17% for SALS, and 7.91% for non-DA (P<0.01). Compared with that of the DA group, the odds ratios (95% confidence interval) for prehospital ROSC ratio were 0.97 (0.82-1.15) in the SALS group and 0.57 (0.50-0.65) in the non-DA group. The prehospital ROSC ratio of the DA group was higher than those of the non-DA group and the SALS group.

CONCLUSION: ALS protocol intervention was associated with prehospital ROSC rates. Therefore, continuous efforts to promote systemic implementation of the ALS protocol to improve OHCA outcomes are necessary.}, } @article {pmid38583639, year = {2024}, author = {Genin, EC and di Borgo, PP and Lorivel, T and Hugues, S and Farinelli, M and Mauri-Crouzet, A and Lespinasse, F and Godin, L and Paquis-Flucklinger, V and Petit-Paitel, A}, title = {CHCHD10[S59L/+] mouse model: Behavioral and neuropathological features of frontotemporal dementia.}, journal = {Neurobiology of disease}, volume = {195}, number = {}, pages = {106498}, doi = {10.1016/j.nbd.2024.106498}, pmid = {38583639}, issn = {1095-953X}, mesh = {Animals ; *Frontotemporal Dementia/pathology/genetics ; *Disease Models, Animal ; Mice ; *Mitochondrial Proteins/genetics/metabolism ; Mice, Transgenic ; Behavior, Animal/physiology ; Male ; Long-Term Potentiation/physiology ; Mice, Inbred C57BL ; Hippocampus/pathology/metabolism ; }, abstract = {CHCHD10-related disease causes a spectrum of clinical presentations including mitochondrial myopathy, cardiomyopathy, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We generated a knock-in mouse model bearing the p.Ser59Leu (S59L) CHCHD10 variant. Chchd10[S59L/+] mice have been shown to phenotypically replicate the disorders observed in patients: myopathy with mtDNA instability, cardiomyopathy and typical ALS features (protein aggregation, neuromuscular junction degeneration and spinal motor neuron loss). Here, we conducted a comprehensive behavioral, electrophysiological and neuropathological assessment of Chchd10[S59L/+] mice. These animals show impaired learning and memory capacities with reduced long-term potentiation (LTP) measured at the Perforant Pathway-Dentate Gyrus (PP-DG) synapses. In the hippocampus of Chchd10[S59L/+] mice, neuropathological studies show the involvement of protein aggregates, activation of the integrated stress response (ISR) and neuroinflammation in the degenerative process. These findings contribute to decipher mechanisms associated with CHCHD10 variants linking mitochondrial dysfunction and neuronal death. They also validate the Chchd10[S59L/+] mice as a relevant model for FTD, which can be used for preclinical studies to test new therapeutic strategies for this devastating disease.}, } @article {pmid38583636, year = {2024}, author = {do Prado Schneidewind, FCC and de Castilho, PF and Galvão, F and de Andrade Dos Santos, JV and da Silva Dantas, FG and Negri, M and da Silva Pinto, L and Moraes, CAF and Freitas, J and de Souza, PRB and Nogueira, CR and de Oliveira, KMP}, title = {Effects of bioconversion by Battus polydamas on the chemical composition of Aristolochia spp. and evaluation of antimicrobial activity and biocompatibility.}, journal = {Fitoterapia}, volume = {175}, number = {}, pages = {105949}, doi = {10.1016/j.fitote.2024.105949}, pmid = {38583636}, issn = {1873-6971}, mesh = {*Aristolochia/chemistry ; Animals ; *Plant Extracts/pharmacology/chemistry ; Larva/drug effects ; Phytochemicals/pharmacology/isolation & purification ; Microbial Sensitivity Tests ; Humans ; Antioxidants/pharmacology ; Bacillus cereus/drug effects ; Anti-Infective Agents/pharmacology/chemistry ; Anti-Bacterial Agents/pharmacology/chemistry ; Moths/drug effects ; }, abstract = {Aristolochia plants are emblematic from an ethnopharmacological viewpoint and are know to possess numerous biological properties, including antiseptic. However, the medicinal potential of these species is debatable because of their representative chemical constituents, aristolochic acids (AAs) and aristolactams (ALs), which are associated, for instance, with nephropathy and cancer. These contrasting issues have stimulated the development of approaches intended to detoxification of aristoloquiaceous biomasses, among which is included the bioconversion method using larvae of the specialist phytophagous insect Battus polydamas, previously shown to be viable for chemical diversification and to reduce toxicity. Thus, eleven Aristolochia spp. were bioconverted, and the antimicrobial activities of the plant methanolic extracts and its respective bioconversion products were evaluated. The best results were found for Aristolochia esperanzae, Aristolochia gibertii, and Aristolochia ringens against Bacillus cereus, with MIC ranging from 7.8 to 31.25 μg/mL. These three species were selected for chemical, antioxidant, cytotoxic, hemolytic, and mutagenic analyses. Chemical analysis revealed 65 compounds, 21 of them possible bioconversion products. The extracts showed potential to inhibit the formation and degradation of B. cereus biofilms. Extracts of A. gibertii and its bioconverted biomass showed antioxidant activity comparable to dibutylhydroxytoluene (BHT) standard. Bioconversion decreased the hemolytic activity of A. esperanzae and the cytotoxicities of A. esperanzae and A. gibertii. None of the extracts was found to be mutagenic. The bioactivities of the fecal extracts were maintained, and biocompatibility was improved. Therefore, the results obtained in this study reveal positive expectations about the natural detoxification process of the Aristolochia species.}, } @article {pmid38583622, year = {2024}, author = {Newell, ME and Babbrah, A and Aravindan, A and Rathnam, R and Kiernan, R and Driver, EM and Bowes, DA and Halden, RU}, title = {Prevalence rates of neurodegenerative diseases versus human exposures to heavy metals across the United States.}, journal = {The Science of the total environment}, volume = {928}, number = {}, pages = {172260}, doi = {10.1016/j.scitotenv.2024.172260}, pmid = {38583622}, issn = {1879-1026}, mesh = {*Metals, Heavy/analysis ; Humans ; United States/epidemiology ; *Environmental Exposure/statistics & numerical data ; Prevalence ; *Neurodegenerative Diseases/epidemiology/chemically induced ; Environmental Monitoring ; }, abstract = {Novel means are needed to identify individuals and subpopulations susceptible to and afflicted by neurodegenerative diseases (NDDs). This study aimed to utilize geographic distribution of heavy metal sources and sinks to investigate a potential human health risk of developing NDDs. Known or hypothesized environmental factors driving disease prevalence of Alzheimer's Disease (AD), Parkinson's Disease (PD), and amyotrophic lateral sclerosis (ALS) are heavy metals, including arsenic (As), cadmium (Cd), manganese (Mn) and mercury (Hg). Lead (Pb) has been associated with AD and ALS. Analyzable mediums of human exposure to heavy metals (i.e., toxic metals and metalloids), or proxies thereof, include infant blood, topsoil, sewage sludge, and well water. U.S. concentrations of heavy metals in topsoil, sewage sludge, well water, and infant blood were mapped and compared to prevalence rates of major NDDs. Data from federal and state agencies (i.e., CDC, EPA, and the US Geological Survey) on heavy metal concentrations, age distribution, and NDD prevalence rates were geographically represented and statistically analyzed to quantify possible correlations. Aside from an expected significant association between NDD prevalence and age (p < 0.0001), we found significant associations between the prevalence of the sum of three major NDDs with: Pb in topsoil (p = 0.0433); Cd (p < 0.0001) and Pb (p < 0.0001) in sewage sludge; Pb in infant blood (p < 0.0001). Concentrations in sewage sludge of Cd and Pb were significantly correlated with NDD prevalence rates with an odds ratio of 2.91 (2.04, 4.225 95%CI) and 4.084 (3.14, 5.312 95%CI), respectively. The presence of toxic metals in the U.S. environment in multiple matrices, including sewage sludge, was found to be significantly associated with NDD prevalence. This is the first use of sewage sludge as an environmental proxy matrix to infer risk of developing NDDs.}, } @article {pmid38583129, year = {2024}, author = {Thal, DR and Gawor, K and Moonen, S}, title = {Regulated cell death and its role in Alzheimer's disease and amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {69}, pmid = {38583129}, issn = {1432-0533}, support = {22-AAIIA-963171/ALZ/Alzheimer's Association/United States ; }, mesh = {Humans ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; *Regulated Cell Death ; Cell Death ; Motor Neurons ; }, abstract = {Despite considerable research efforts, it is still not clear which mechanisms underlie neuronal cell death in neurodegenerative diseases. During the last 20 years, multiple pathways have been identified that can execute regulated cell death (RCD). Among these RCD pathways, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-related cell death, and lysosome-dependent cell death have been intensively investigated. Although RCD consists of numerous individual pathways, multiple common proteins have been identified that allow shifting from one cell death pathway to another. Another layer of complexity is added by mechanisms such as the endosomal machinery, able to regulate the activation of some RCD pathways, preventing cell death. In addition, restricted axonal degeneration and synaptic pruning can occur as a result of RCD activation without loss of the cell body. RCD plays a complex role in neurodegenerative processes, varying across different disorders. It has been shown that RCD is differentially involved in Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), among the most common neurodegenerative diseases. In AD, neuronal loss is associated with the activation of not only necroptosis, but also pyroptosis. In ALS, on the other hand, motor neuron death is not linked to canonical necroptosis, whereas pyroptosis pathway activation is seen in white matter microglia. Despite these differences in the activation of RCD pathways in AD and ALS, the accumulation of protein aggregates immunoreactive for p62/SQSTM1 (sequestosome 1) is a common event in both diseases and many other neurodegenerative disorders. In this review, we describe the major RCD pathways with clear activation in AD and ALS, the main interactions between these pathways, as well as their differential and similar involvement in these disorders. Finally, we will discuss targeting RCD as an innovative therapeutic concept for neurodegenerative diseases, such as AD and ALS. Considering that the execution of RCD or "cellular suicide" represents the final stage in neurodegeneration, it seems crucial to prevent neuronal death in patients by targeting RCD. This would offer valuable time to address upstream events in the pathological cascade by keeping the neurons alive.}, } @article {pmid38582774, year = {2024}, author = {Zhang, H and Guo, H and Li, D and Zhang, Y and Zhang, S and Kang, W and Liu, C and Le, W and Wang, L and Li, D and Dai, B}, title = {Halogen doped graphene quantum dots modulate TDP-43 phase separation and aggregation in the nucleus.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {2980}, pmid = {38582774}, issn = {2041-1723}, support = {82188101//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32171236//National Natural Science Foundation of China (National Science Foundation of China)/ ; 92353302//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32170683//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; *Graphite ; Phase Separation ; *Quantum Dots ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/metabolism ; }, abstract = {TDP-43 is implicated in the dynamic formation of nuclear bodies and stress granules through phase separation. In diseased states, it can further condense into pathological aggregates in the nucleus and cytoplasm, contributing to the onset of amyotrophic lateral sclerosis. In this study, we evaluate the effect of graphene quantum dots (GQDs) with different functional groups on TDP-43's phase separation and aggregation in various cellular locations. We find that halogen atom-doped GQDs (GQDs-Cl, Cl-GQDs-OH) penetrate the nuclear envelope, inhibiting the assembly of TDP-43 nuclear bodies and stress granules under oxidative stress or hyperosmotic environments, and reduce amyloid aggregates and disease-associated phosphorylation of TDP-43. Mechanistic analysis reveals GQDs-Cl and Cl-GQDs-OH modulate TDP-43 phase separation through hydrophobic and electrostatic interactions. Our findings highlight the potential of GQDs-Cl and Cl-GQDs-OH in modulating nuclear protein condensation and pathological aggregation, offering direction for the innovative design of GQDs to modulate protein phase separation and aggregation.}, } @article {pmid38582030, year = {2024}, author = {van Unnik, JWJ and Meyjes, M and Janse van Mantgem, MR and van den Berg, LH and van Eijk, RPA}, title = {Remote monitoring of amyotrophic lateral sclerosis using wearable sensors detects differences in disease progression and survival: a prospective cohort study.}, journal = {EBioMedicine}, volume = {103}, number = {}, pages = {105104}, pmid = {38582030}, issn = {2352-3964}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis/physiopathology ; Male ; Female ; *Disease Progression ; *Wearable Electronic Devices ; Middle Aged ; Prospective Studies ; Aged ; Accelerometry/instrumentation ; Prognosis ; Remote Sensing Technology/instrumentation/methods ; Adult ; }, abstract = {BACKGROUND: There is an urgent need for objective and sensitive measures to quantify clinical disease progression and gauge the response to treatment in clinical trials for amyotrophic lateral sclerosis (ALS). Here, we evaluate the ability of an accelerometer-derived outcome to detect differential clinical disease progression and assess its longitudinal associations with overall survival in patients with ALS.

METHODS: Patients with ALS wore an accelerometer on the hip for 3-7 days, every 2-3 months during a multi-year observation period. An accelerometer-derived outcome, the Vertical Movement Index (VMI), was calculated, together with predicted disease progression rates, and jointly analysed with overall survival. The clinical utility of VMI was evaluated using comparisons to patient-reported functionality, while the impact of various monitoring schemes on empirical power was explored through simulations.

FINDINGS: In total, 97 patients (70.1% male) wore the accelerometer for 1995 days, for a total of 27,701 h. The VMI was highly discriminatory for predicted disease progression rates, revealing faster rates of decline in patients with a worse predicted prognosis compared to those with a better predicted prognosis (p < 0.0001). The VMI was strongly associated with the hazard for death (HR 0.20, 95% CI: 0.09-0.44, p < 0.0001), where a decrease of 0.19-0.41 unit was associated with reduced ambulatory status. Recommendations for future studies using accelerometery are provided.

INTERPRETATION: The results serve as motivation to incorporate accelerometer-derived outcomes in clinical trials, which is essential for further validation of these markers to meaningful endpoints.

FUNDING: Stichting ALS Nederland (TRICALS-Reactive-II).}, } @article {pmid38580817, year = {2024}, author = {Irwin, KE and Jasin, P and Braunstein, KE and Sinha, IR and Garret, MA and Bowden, KD and Chang, K and Troncoso, JC and Moghekar, A and Oh, ES and Raitcheva, D and Bartlett, D and Miller, T and Berry, JD and Traynor, BJ and Ling, JP and Wong, PC}, title = {Author Correction: A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS-FTD.}, journal = {Nature medicine}, volume = {30}, number = {5}, pages = {1504}, doi = {10.1038/s41591-024-02966-z}, pmid = {38580817}, issn = {1546-170X}, } @article {pmid38579683, year = {2024}, author = {Lai, JD and Berlind, JE and Fricklas, G and Lie, C and Urenda, JP and Lam, K and Sta Maria, N and Jacobs, R and Yu, V and Zhao, Z and Ichida, JK}, title = {KCNJ2 inhibition mitigates mechanical injury in a human brain organoid model of traumatic brain injury.}, journal = {Cell stem cell}, volume = {31}, number = {4}, pages = {519-536.e8}, doi = {10.1016/j.stem.2024.03.004}, pmid = {38579683}, issn = {1875-9777}, support = {RF1 NS122060/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/etiology/pathology ; Brain/metabolism ; *Brain Injuries, Traumatic/drug therapy/metabolism/therapy ; C9orf72 Protein/metabolism ; DNA-Binding Proteins/metabolism ; *Frontotemporal Dementia/etiology/pathology ; *Neurodegenerative Diseases/etiology/pathology ; *Potassium Channels, Inwardly Rectifying/antagonists & inhibitors/metabolism ; }, abstract = {Traumatic brain injury (TBI) strongly correlates with neurodegenerative disease. However, it remains unclear which neurodegenerative mechanisms are intrinsic to the brain and which strategies most potently mitigate these processes. We developed a high-intensity ultrasound platform to inflict mechanical injury to induced pluripotent stem cell (iPSC)-derived cortical organoids. Mechanically injured organoids elicit classic hallmarks of TBI, including neuronal death, tau phosphorylation, and TDP-43 nuclear egress. We found that deep-layer neurons were particularly vulnerable to injury and that TDP-43 proteinopathy promotes cell death. Injured organoids derived from C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) patients displayed exacerbated TDP-43 dysfunction. Using genome-wide CRISPR interference screening, we identified a mechanosensory channel, KCNJ2, whose inhibition potently mitigated neurodegenerative processes in vitro and in vivo, including in C9ORF72 ALS/FTD organoids. Thus, targeting KCNJ2 may reduce acute neuronal death after brain injury, and we present a scalable, genetically flexible cerebral organoid model that may enable the identification of additional modifiers of mechanical stress.}, } @article {pmid38577970, year = {2024}, author = {Barreto-Núñez, R and Béland, LC and Boutej, H and Picher-Martel, V and Dupré, N and Barbeito, L and Kriz, J}, title = {Chronically activated microglia in ALS gradually lose their immune functions and develop unconventional proteome.}, journal = {Glia}, volume = {72}, number = {7}, pages = {1319-1339}, doi = {10.1002/glia.24531}, pmid = {38577970}, issn = {1098-1136}, support = {//ALS Society of Canada/ ; //Fondation Brain Canada/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/immunology/pathology/genetics ; *Microglia/metabolism/immunology ; Animals ; *Proteome/metabolism ; Mice ; *Mice, Transgenic ; Spinal Cord/metabolism/pathology/immunology ; Disease Models, Animal ; Phagocytosis/physiology ; Humans ; Female ; Mice, Inbred C57BL ; Male ; }, abstract = {Neuroinflammation and chronic activation of microglial cells are the prominent features of amyotrophic lateral sclerosis (ALS) pathology. While alterations in the mRNA profile of diseased microglia have been well documented, the actual microglia proteome remains poorly characterized. Here we performed a functional characterization together with proteome analyses of microglial cells at different stages of disease in the SOD1-G93A model of ALS. Functional analyses of microglia derived from the lumbar spinal cord of symptomatic mice revealed: (i) remarkably high mitotic index (close to 100% cells are Ki67+) (ii) significant decrease in phagocytic capacity when compared to age-matched control microglia, and (iii) diminished response to innate immune challenges in vitro and in vivo. Proteome analysis revealed a development of two distinct molecular signatures at early and advanced stages of disease. While at early stages of disease, we identified several proteins implicated in microglia immune functions such as GPNMB, HMBOX1, at advanced stages of disease microglia signature at protein level was characterized with a robust upregulation of several unconventional proteins including rootletin, major vaults proteins and STK38. Upregulation of GPNMB and rootletin has been also found in the spinal cord samples of sporadic ALS. Remarkably, the top biological functions of microglia, in particular in the advanced disease, were not related to immunity/immune response, but were highly enriched in terms linked to RNA metabolism. Together, our results suggest that, over the course of disease, chronically activated microglia develop unconventional protein signatures and gradually lose their immune identity ultimately turning into functionally inefficient immune cells.}, } @article {pmid38577753, year = {2024}, author = {Yellepeddi, VK and Race, JA and McFarland, MM and Constance, JE and Fanaeian, E and Murphy, NA}, title = {Effectiveness of atropine in managing sialorrhea: A systematic review and meta-analysis.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {62}, number = {6}, pages = {267-277}, doi = {10.5414/CP204538}, pmid = {38577753}, issn = {0946-1965}, mesh = {*Sialorrhea/drug therapy ; Humans ; *Atropine/therapeutic use ; Treatment Outcome ; Salivation/drug effects ; }, abstract = {OBJECTIVES: To describe the efficacy of atropine in controlling salivary flow in patients with sialorrhea or drooling.

MATERIALS AND METHODS: We included randomized controlled studies, quasi-randomized trials, case reports, clinical trials, systematic reviews, and meta-analyses assessing the use of atropine in patients with sialorrhea or drooling. The endpoints were reduction in salivary flow rate, amount of saliva secreted, reduction in clinical symptoms of sialorrhea, death rattle intensity, or reduction in drooling intensity as measured by an objective scale such as the drooling intensity scale.

RESULTS: A total of 56 studies with 2,378 patients were included in the systematic review. The underlying disease states included brain injury, amyotrophic lateral sclerosis, cerebral palsy, clozapine- and perphenazine-induced sialorrhea, Parkinson's disease, and terminal illness. The routes of atropine administration included sublingual, intravenous, subcutaneous, oral tablet or solution, and direct injection of atropine into parotid glands or at the base of the tongue. The generalized estimated equation regression models showed that sublingual administration is superior to oral and subcutaneous routes.

CONCLUSION: Atropine is efficacious in managing sialorrhea in most disease states. Sublingual administration of atropine is superior to other routes of administration in reducing salivary flow in patients with sialorrhea.}, } @article {pmid38576758, year = {2024}, author = {Gonzalez, FM and Cohens, FG}, title = {Predicting outcomes after kidney transplantation: Can Pareto's rules help us to do so?.}, journal = {World journal of transplantation}, volume = {14}, number = {1}, pages = {90149}, pmid = {38576758}, issn = {2220-3230}, abstract = {Kidney transplantation is the best option for kidney replacement therapy, even considering that most of the times the grafts do not survive as long as their recipients. In the Khalil et al's experience, published in this issue of the Journal, they analyze their second kidney graft survival and describe those significant predictors of early loss. This editorial comments on the results and put in perspec tive that most of the times, long-term graft survival could be inadvertently jeopardized if the immunosuppressive therapy is reduced or withdrawn for any reason, and that it could happen frequently if the transplant physician intends to innovate with the clinical care without proper evidence-based data.}, } @article {pmid38576194, year = {2024}, author = {Rutkove, SB and McIlduff, CE and Stommel, E and Levy, S and Smith, C and Gutierrez, H and Verga, S and Samaan, S and Yator, C and Nanda, A and Pastel, L and Doussan, A and Phipps, K and Murphy, E and Halter, R}, title = {Assessing pulmonary function in ALS using electrical impedance tomography.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {581-588}, pmid = {38576194}, issn = {2167-9223}, support = {R21 NS118434/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/diagnosis ; Female ; Male ; Middle Aged ; *Electric Impedance ; *Respiratory Function Tests/methods ; Aged ; Tomography/methods ; Adult ; Reproducibility of Results ; Vital Capacity/physiology ; Lung/physiopathology/diagnostic imaging ; }, abstract = {OBJECTIVE: We sought to determine whether thoracic electrical impedance tomography (EIT) could characterize pulmonary function in amyotrophic lateral sclerosis (ALS) patients, including those with facial weakness. Thoracic EIT is a noninvasive, technology in which a multi-electrode belt is placed across the chest, producing real-time impedance imaging of the chest during breathing.

METHODS: We enrolled 32 ALS patients and 32 age- and sex-matched healthy controls (HCs) without underlying lung disease. All participants had EIT measurements performed simultaneously with standard pulmonary function tests (PFTs), including slow and forced vital capacity (SVC and FVC) in upright and supine positions and maximal inspiratory and expiratory pressures (MIPs and MEPs, respectively). Intraclass correlation coefficients (ICCs) were calculated to assess the immediate reproducibility of EIT measurements and Pearson's correlations were used to explore the relationships between EIT and PFT values.

RESULTS: Data from 30 ALS patients and 27 HCs were analyzed. Immediate upright SVC reproducibility was very high (ICC 0.98). Correlations were generally strongest between EIT and spirometry measures, with R values ranging from 0.64 to 0.82 (p < 0.001) in the ALS cohort. There were less robust correlations between EIT values and both MIPs and MEPs in the ALS patients, with R values ranging from 0.33 to 0.44. There was no significant difference for patients with and without facial weakness. There were no reported adverse events.

CONCLUSION: EIT-based pulmonary measures hold the promise of providing an alternative approach for lung function assessment in ALS patients. Based on these early results, further development and study of this technology are warranted.}, } @article {pmid38575965, year = {2024}, author = {Daudelin, D and Westerhaus, A and Zhang, N and Leyder, E and Savonenko, A and Sockanathan, S}, title = {Loss of GDE2 leads to complex behavioral changes including memory impairment.}, journal = {Behavioral and brain functions : BBF}, volume = {20}, number = {1}, pages = {7}, pmid = {38575965}, issn = {1744-9081}, support = {RF1AG062671/NH/NIH HHS/United States ; F31 AG079539/AG/NIA NIH HHS/United States ; T32NS091018/NH/NIH HHS/United States ; T32GM007445/NH/NIH HHS/United States ; RF1 AG062671/AG/NIA NIH HHS/United States ; T32 NS091018/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Animals ; Female ; Humans ; Mice ; *Alzheimer Disease/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; Memory ; Memory Disorders/genetics ; Mice, Transgenic ; *Neurodegenerative Diseases/genetics ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are debilitating neurodegenerative diseases for which there are currently no cures. Familial cases with known genetic causes make up less than 10% of these diseases, and little is known about the underlying mechanisms that contribute to sporadic disease. Accordingly, it is important to expand investigations into possible pathways that may contribute to disease pathophysiology. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a membrane-bound enzyme that acts at the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers distinct proteins to the membrane. GDE2 abnormally accumulates in intracellular compartments in the brain of patients with AD, ALS, and ALS/FTD, indicative of GDE2 dysfunction. Mice lacking GDE2 (Gde2KO) show neurodegenerative changes such as neuronal loss, reduced synaptic proteins and synapse loss, and increased Aβ deposition, raising the possibility that GDE2 disruption in disease might contribute to disease pathophysiology. However, the effect of GDE2 loss on behavioral function and learning/memory has not been characterized.

RESULTS: Here, we show that GDE2 is expressed throughout the adult mouse brain in areas including the cortex, hippocampus, habenula, thalamus, and amygdala. Gde2KO and WT mice were tested in a set of behavioral tasks between 7 and 16 months of age. Compared to WT, Gde2KO mice display moderate hyperactivity that becomes more pronounced with age across a variety of behavioral tests assessing novelty-induced exploratory activity. Additionally, Gde2KO mice show reduced startle response, with females showing additional defects in prepulse inhibition. No changes in anxiety-associated behaviors were found, but Gde2KOs show reduced sociability. Notably, aged Gde2KO mice demonstrate impaired short/long-term spatial memory and cued fear memory/secondary contextual fear acquisition.

CONCLUSIONS: Taken together, these observations suggest that loss of GDE2 leads to behavioral deficits, some of which are seen in neurodegenerative disease models, implying that loss of GDE2 may be an important contributor to phenotypes associated with neurodegeneration.}, } @article {pmid38575486, year = {2024}, author = {Chandran, SK and Doucet, M}, title = {Neurogenic Dysphagia.}, journal = {Otolaryngologic clinics of North America}, volume = {57}, number = {4}, pages = {589-597}, doi = {10.1016/j.otc.2024.02.023}, pmid = {38575486}, issn = {1557-8259}, mesh = {Humans ; *Deglutition Disorders/etiology/therapy/diagnosis ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Multiple Sclerosis/complications ; Parkinson Disease/complications ; Stroke/complications ; }, abstract = {This article provides an overview of neurogenic dysphagia, describing the evaluation and management of swallowing dysfunction in various neurologic diseases. The article will focus on stroke, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis.}, } @article {pmid38575127, year = {2024}, author = {Zhang, T and Wang, Z and Li, Y and Zhou, B and Liu, Y and Li, J and Wang, R and Lv, Q and Li, C and Zhang, Y and Su, R}, title = {Genetic diversity and population structure in five Inner Mongolia cashmere goat populations using whole-genome genotyping.}, journal = {Animal bioscience}, volume = {37}, number = {7}, pages = {1168-1176}, pmid = {38575127}, issn = {2765-0189}, support = {2021ZD0012//Science and technology major project of Inner Mongolia Autonomous Region/ ; 2021GG0086//Inner Mongolia Autonomous Region Science and Technology Research Project/ ; NJYT22038//Inner Mongolia Inner Mongolia Autonomous Region/ ; NMGIRT2322//Program for Innovative Research Team in Universities of Inner Mongolia Autonomous Region/ ; CARS-39//China Agriculture Research System of MOF and MARA/ ; }, abstract = {OBJECTIVE: As a charismatic species, cashmere goats have rich genetic resources. In the Inner Mongolia Autonomous Region, there are three cashmere goat varieties named and approved by the state. These goats are renowned for their high cashmere production and superior cashmere quality. Therefore, it is vitally important to protect their genetic resources as they will serve as breeding material for developing new varieties in the future.

METHODS: Three breeds including Inner Mongolia cashmere goats (IMCG), Hanshan White cashmere goats (HS), and Ujimqin white cashmere goats (WZMQ) were studied. IMCG were of three types: Aerbas (AEBS), Erlangshan (ELS), and Alashan (ALS). Nine DNA samples were collected for each population, and they were genomically re-sequenced to obtain high-depth data. The genetic diversity parameters of each population were estimated to determine selection intensity. Principal component analysis, phylogenetic tree construction and genetic differentiation parameter estimation were performed to determine genetic relationships among populations.

RESULTS: Samples from the 45 individuals from the five goat populations were sequenced, and 30,601,671 raw single nucleotide polymorphisms (SNPs) obtained. Then, variant calling was conducted using the reference genome, and 17,214,526 SNPs were retained after quality control. Individual sequencing depth of individuals ranged from 21.13× to 46.18×, with an average of 28.5×. In the AEBS, locus polymorphism (79.28) and expected heterozygosity (0.2554) proportions were the lowest, and the homologous consistency ratio (0.1021) and average inbreeding coefficient (0.1348) were the highest, indicating that this population had strong selection intensity. Conversely, ALS and WZMQ selection intensity was relatively low. Genetic distance between HS and the other four populations was relatively high, and genetic exchange existed among the other four populations.

CONCLUSION: The Inner Mongolia cashmere goat (AEBS type) population has a relatively high selection intensity and a low genetic diversity. The IMCG (ALS type) and WZMQ populations had relatively low selection intensity and high genetic diversity. The genetic distance between HS and the other four populations was relatively high, with a moderate degree of differentiation. Overall, these genetic variations provide a solid foundation for resource identification of Inner Mongolia Autonomous Region cashmere goats in the future.}, } @article {pmid38575115, year = {2024}, author = {Temkin-Greener, H and Guo, W and McGarry, B and Cai, S}, title = {Serious Mental Illness in Assisted Living Communities: Association with Nursing Home Placement.}, journal = {Journal of the American Medical Directors Association}, volume = {25}, number = {5}, pages = {917-922}, pmid = {38575115}, issn = {1538-9375}, support = {R01 HS026893/HS/AHRQ HHS/United States ; }, mesh = {Humans ; *Mental Disorders ; Medicare ; Aged ; Aged, 80 and over ; Dementia/epidemiology ; United States ; *Nursing Homes ; *Assisted Living Facilities ; Depressive Disorder, Major/epidemiology ; Bipolar Disorder/epidemiology ; Schizophrenia/epidemiology ; Retrospective Studies ; Male ; Female ; }, abstract = {OBJECTIVES: Assess prevalence of serious mental illness (SMI) alone, and co-occurring with Alzheimer disease and related dementias (ADRD), among Medicare beneficiaries in assisted living (AL). Examine the association between permanent nursing home (NH) placement and SMI, among residents with and without ADRD.

DESIGN: 2018-2019 retrospective cohort of Medicare beneficiaries in AL. Residents were followed for up to 2 years to track their NH placement. We used data from the Medicare Enrollment Database, the Medicare Beneficiary Summary File, Minimum Data Set, and a national directory of state-licensed AL communities. AL residents were identified using a validated, previously reported 9-digit zip code methodology.

SETTING AND PARTICIPANTS: A cross-sectional study sample included 289,350 Medicare beneficiaries in 17,265 AL communities across 50 states and in the District of Columbia.

METHODS: The outcome was permanent NH placement: a continuous stay for more than 90 days. Key independent variable was presence of SMI-schizophrenia, bipolar disorder, and major depression. Other covariates included sociodemographic factors and presence of other chronic conditions, including ADRD. A linear probability model with robust SEs, and AL-level random effects, was used to test the association between SMI diagnoses, ADRD, and their interactions on NH placement.

RESULTS: More than half (55.65%) of AL residents had a diagnosis of SMI, among them 93.2% had major depression, 28.5% schizophrenia, and 22.2% bipolar disorder. Individuals with schizophrenia and bipolar disorder had a significantly lower probability of NH placement, a 32% and a 15% decrease relative to the cohort mean, respectively. Placement risk was significantly greater for residents with ADRD compared to those without, increasing for those who also had schizophrenia or bipolar disorder, 12.9% and 1.5% relative to the sample mean, respectively.

CONCLUSION AND IMPLICATIONS: Presence of schizophrenia and bipolar disorder, in conjunction with ADRD, significantly increases the risk of long-term NH placement, suggesting that ALs may not be well prepared to care for these residents.}, } @article {pmid38574876, year = {2024}, author = {Watt, CL and Smith, IC and Rice, J and Murphy, R and Breiner, A and Duff, MLV and Nogo, D and Bush, SH and McNeely, S and Buenger, U and Zehrt, B and Zwicker, J}, title = {Qualitative Analysis of Initial Palliative Care Consultations in Amyotrophic Lateral Sclerosis.}, journal = {Journal of pain and symptom management}, volume = {68}, number = {1}, pages = {43-52.e2}, doi = {10.1016/j.jpainsymman.2024.03.024}, pmid = {38574876}, issn = {1873-6513}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Palliative Care ; Male ; Female ; Middle Aged ; *Caregivers/psychology ; Aged ; *Referral and Consultation ; Prospective Studies ; *Qualitative Research ; COVID-19 ; Adult ; Advance Care Planning ; Feasibility Studies ; }, abstract = {BACKGROUND: Palliative care (PC) benefits patients with amyotrophic lateral sclerosis (ALS), however the needs of patients and caregivers and the optimal timing of PC discussions remains unclear. This study reports the analysis of PC consult notes from a larger feasibility trial. The specific aims of this analysis were to i) identify the PC needs of patients with ALS via qualitative analysis and ii) identify characteristics of patients and caregivers that could predict specific PC needs.

METHODS: This study was nested within a nonrandomized, prospective study of patients with ALS (and their caregivers) being treated at a multidisciplinary ALS clinic. Exclusion criteria of the main study were age <18 years, inability to complete questionnaires, and prior receipt of PC. All patients were offered a PC consultation (PCC); those who accepted were included in this nested study. Consultation notes were reviewed and thematic and content analyses were conducted. The occurrence of themes across patient and caregiver contextual variables were examined.

RESULTS: Thirty-two PCCs were completed between October 2020 and April 2022. Six major themes were identified: PC roles (with subthemes encompassing the spectrum of specialist PC practice including symptom management and advance care planning), engagement with PC, patients' concerns for their caregivers, caregiver-specific concerns, finances, and COVID-19. An average of 12 topics were discussed per PCC (range = 3-22). Discussion of advance care planning, care coordination, and symptom management was common, and these topics were not discussed more frequently in PCCs with patients with lower functional status, more bulbar symptoms, or lower quality of life. Time from diagnosis did not impact topics of discussion. Patients reporting more symptoms of depression more frequently required psychological support, particularly regarding loss of independence, employment, and leisure activities.

DISCUSSION: Patients with ALS and their caregivers have a wide range of PC needs. These needs vary irrespective of time from diagnosis, functional status, or quality of life, therefore PCC is recommended for all patients with ALS. PCC should be individualized based on patient and caregiver preferences.

The study was registered with ClinicalTrials.gov (NCT04257760; https://clinicaltrials.gov/ct2/show/NCT04257760) on February 6, 2020. The first enrollment occurred on October 20, 2020.}, } @article {pmid38574339, year = {2024}, author = {Meyers, EE and Brizzi, KT}, title = {Analgesic Strategies in Patients With Amyotrophic Lateral Sclerosis #477.}, journal = {Journal of palliative medicine}, volume = {27}, number = {4}, pages = {565-566}, doi = {10.1089/jpm.2024.0014}, pmid = {38574339}, issn = {1557-7740}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Patients ; }, } @article {pmid38570593, year = {2024}, author = {van Stuijvenberg, OC and Broekman, MLD and Wolff, SEC and Bredenoord, AL and Jongsma, KR}, title = {Developer perspectives on the ethics of AI-driven neural implants: a qualitative study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {7880}, pmid = {38570593}, issn = {2045-2322}, support = {17619//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; }, mesh = {*Artificial Intelligence ; Reproducibility of Results ; Qualitative Research ; Focus Groups ; *Cochlear Implants ; }, abstract = {Convergence of neural implants with artificial intelligence (AI) presents opportunities for the development of novel neural implants and improvement of existing neurotechnologies. While such technological innovation carries great promise for the restoration of neurological functions, they also raise ethical challenges. Developers of AI-driven neural implants possess valuable knowledge on the possibilities, limitations and challenges raised by these innovations; yet their perspectives are underrepresented in academic literature. This study aims to explore perspectives of developers of neurotechnology to outline ethical implications of three AI-driven neural implants: a cochlear implant, a visual neural implant, and a motor intention decoding speech-brain-computer-interface. We conducted semi-structured focus groups with developers (n = 19) of AI-driven neural implants. Respondents shared ethically relevant considerations about AI-driven neural implants that we clustered into three themes: (1) design aspects; (2) challenges in clinical trials; (3) impact on users and society. Developers considered accuracy and reliability of AI-driven neural implants conditional for users' safety, authenticity, and mental privacy. These needs were magnified by the convergence with AI. Yet, the need for accuracy and reliability may also conflict with potential benefits of AI in terms of efficiency and complex data interpretation. We discuss strategies to mitigate these challenges.}, } @article {pmid38570009, year = {2024}, author = {Fernández Comaduran, M and Minotti, S and Jacob-Tomas, S and Rizwan, J and Larochelle, N and Robitaille, R and Sephton, CF and Vera, M and Nalbantoglu, JN and Durham, HD}, title = {Impact of histone deacetylase inhibition and arimoclomol on heat shock protein expression and disease biomarkers in primary culture models of familial ALS.}, journal = {Cell stress & chaperones}, volume = {29}, number = {3}, pages = {359-380}, pmid = {38570009}, issn = {1466-1268}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/drug therapy ; *Histone Deacetylase Inhibitors/pharmacology ; *Biomarkers/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Humans ; *Motor Neurons/metabolism/drug effects/pathology ; Animals ; HSP70 Heat-Shock Proteins/metabolism/genetics ; HSC70 Heat-Shock Proteins/metabolism/genetics ; Hydroxylamines/pharmacology ; Cells, Cultured ; RNA-Binding Protein FUS/metabolism/genetics ; Superoxide Dismutase-1/metabolism/genetics ; }, abstract = {Protein misfolding and mislocalization are common themes in neurodegenerative disorders, including motor neuron disease, and amyotrophic lateral sclerosis (ALS). Maintaining proteostasis is a crosscutting therapeutic target, including the upregulation of heat shock proteins (HSP) to increase chaperoning capacity. Motor neurons have a high threshold for upregulating stress-inducible HSPA1A, but constitutively express high levels of HSPA8. This study compared the expression of these HSPs in cultured motor neurons expressing three variants linked to familial ALS: TAR DNA binding protein 43 kDa (TDP-43)[G348C], fused in sarcoma (FUS)[R521G], or superoxide dismutase I (SOD1)[G93A]. All variants were poor inducers of Hspa1a, and reduced levels of Hspa8 mRNA and protein, indicating multiple compromises in chaperoning capacity. To promote HSP expression, cultures were treated with the putative HSP coinducer, arimoclomol, and class I histone deacetylase inhibitors, to promote active chromatin for transcription, and with the combination. Treatments had variable, often different effects on the expression of Hspa1a and Hspa8, depending on the ALS variant expressed, mRNA distribution (somata and dendrites), and biomarker of toxicity measured (histone acetylation, maintaining nuclear TDP-43 and the neuronal Brm/Brg-associated factor chromatin remodeling complex component Brg1, mitochondrial transport, FUS aggregation). Overall, histone deacetylase inhibition alone was effective on more measures than arimoclomol. As in the FUS model, arimoclomol failed to induce HSPA1A or preserve Hspa8 mRNA in the TDP-43 model, despite preserving nuclear TDP-43 and Brg1, indicating neuroprotective properties other than HSP induction. The data speak to the complexity of drug mechanisms against multiple biomarkers of ALS pathogenesis, as well as to the importance of HSPA8 for neuronal proteostasis in both somata and dendrites.}, } @article {pmid38568213, year = {2024}, author = {Feichtner, A and Enzler, F and Kugler, V and Hoppe, K and Mair, S and Kremser, L and Lindner, H and Huber, RG and Stelzl, U and Stefan, E and Torres-Quesada, O}, title = {Phosphorylation of the compartmentalized PKA substrate TAF15 regulates RNA-protein interactions.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {162}, pmid = {38568213}, issn = {1420-9071}, support = {255310//Österreichische Krebshilfe Tirol/ ; P32960//Austrian Science Fund/ ; P 30441/FWF_/Austrian Science Fund FWF/Austria ; I5406//Austrian Science Fund/ ; 235872//Tiroler Wissenschaftsförderung/ ; P 35159/FWF_/Austrian Science Fund FWF/Austria ; P 32960/FWF_/Austrian Science Fund FWF/Austria ; P30441//Austrian Science Fund/ ; Concrete//Horizon 2020 Framework Programme/ ; P35159//Austrian Science Fund/ ; }, mesh = {Humans ; Cyclic AMP-Dependent Protein Kinases ; Phosphorylation ; Cyclic AMP ; *Amyotrophic Lateral Sclerosis ; RNA ; *TATA-Binding Protein Associated Factors ; }, abstract = {Spatiotemporal-controlled second messengers alter molecular interactions of central signaling nodes for ensuring physiological signal transmission. One prototypical second messenger molecule which modulates kinase signal transmission is the cyclic-adenosine monophosphate (cAMP). The main proteinogenic cellular effectors of cAMP are compartmentalized protein kinase A (PKA) complexes. Their cell-type specific compositions precisely coordinate substrate phosphorylation and proper signal propagation which is indispensable for numerous cell-type specific functions. Here we present evidence that TAF15, which is implicated in the etiology of amyotrophic lateral sclerosis, represents a novel nuclear PKA substrate. In cross-linking and immunoprecipitation experiments (iCLIP) we showed that TAF15 phosphorylation alters the binding to target transcripts related to mRNA maturation, splicing and protein-binding related functions. TAF15 appears to be one of multiple PKA substrates that undergo RNA-binding dynamics upon phosphorylation. We observed that the activation of the cAMP-PKA signaling axis caused a change in the composition of a collection of RNA species that interact with TAF15. This observation appears to be a broader principle in the regulation of molecular interactions, as we identified a significant enrichment of RNA-binding proteins within endogenous PKA complexes. We assume that phosphorylation of RNA-binding domains adds another layer of regulation to binary protein-RNAs interactions with consequences to RNA features including binding specificities, localization, abundance and composition.}, } @article {pmid38568048, year = {2024}, author = {Grassano, M and Moglia, C and Palumbo, F and Koumantakis, E and Cugnasco, P and Callegaro, S and Canosa, A and Manera, U and Vasta, R and De Mattei, F and Matteoni, E and Fuda, G and Salamone, P and Marchese, G and Casale, F and De Marchi, F and Mazzini, L and Mora, G and Calvo, A and Chiò, A}, title = {Sex Differences in Amyotrophic Lateral Sclerosis Survival and Progression: A Multidimensional Analysis.}, journal = {Annals of neurology}, volume = {96}, number = {1}, pages = {159-169}, doi = {10.1002/ana.26933}, pmid = {38568048}, issn = {1531-8249}, support = {2017SNW5MB//Ministero dell'Università e della Ricerca/ ; RF-2016-02362405//Ministero della Salute/ ; //American Academy of Neurology/ ; //Joint Programme Neurodegenerative Disease Research (JPND)/ ; 259867//Seventh Framework Programme/ ; //ALS Association/ ; //American Brain Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology ; Male ; Female ; *Disease Progression ; Middle Aged ; Aged ; *Sex Characteristics ; Vital Capacity/physiology ; Cohort Studies ; Registries ; Sex Factors ; Prognosis ; Survival Analysis ; Adult ; }, abstract = {OBJECTIVE: To investigate sex-related differences in amyotrophic lateral sclerosis (ALS) prognosis and their contributing factors.

METHODS: Our primary cohort was the Piemonte and Aosta Register for ALS (PARALS); the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) and the Answer ALS databases were used for validation. Survival analyses were conducted accounting for age and onset site. The roles of forced vital capacity and weight decline were explored through a causal mediation analysis. Survival and disease progression rates were also evaluated after propensity score matching.

RESULTS: The PARALS cohort included 1,890 individuals (44.8% women). Men showed shorter survival when stratified by onset site (spinal onset HR 1.20, 95% CI 1.00-1.44, p = 0.0439; bulbar onset HR 1.36, 95% CI 1.09-1.70, p = 0.006917), although women had a steeper functional decline (+0.10 ALSFRS-R points/month, 95% CI 0.07-0.15, p < 0.00001) regardless of onset site. Instead, men showed worse respiratory decline (-4.2 forced vital capacity%/month, 95% CI -6.3 to -2.2, p < 0.0001) and faster weight loss (-0.15 kg/month, 95% CI -0.25 to -0.05, p = 0.0030). Causal mediation analysis showed that respiratory function and weight loss were pivotal in sex-related survival differences. Analysis of patients from PRO-ACT (n = 1,394, 40.9% women) and Answer ALS (n = 849, 37.2% women) confirmed these trends.

INTERPRETATION: The shorter survival in men is linked to worse respiratory function and weight loss rather than a faster disease progression. These findings emphasize the importance of considering sex-specific factors in understanding ALS pathophysiology and designing tailored therapeutic strategies. ANN NEUROL 2024;96:159-169.}, } @article {pmid38568044, year = {2024}, author = {Calvo, A and Moglia, C and Canosa, A and Manera, U and Vasta, R and Grassano, M and Daviddi, M and De Mattei, F and Matteoni, E and Gallone, S and Brunetti, M and Sbaiz, L and Cabras, S and Peotta, L and Palumbo, F and Iazzolino, B and Mora, G and Chiò, A}, title = {High Frequency of Cognitive and Behavioral Impairment in Amyotrophic Lateral Sclerosis Patients with SOD1 Pathogenic Variants.}, journal = {Annals of neurology}, volume = {96}, number = {1}, pages = {150-158}, doi = {10.1002/ana.26928}, pmid = {38568044}, issn = {1531-8249}, support = {RF-2016-02362405//Ministero della Salute/ ; 101017598//HORIZON EUROPE Health/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; 259867//FP7 Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/psychology/complications ; Male ; Female ; *Superoxide Dismutase-1/genetics ; Aged ; Middle Aged ; *Cognitive Dysfunction/genetics/psychology ; Adult ; }, abstract = {OBJECTIVE: While the cognitive-behavioral characteristics of amyotrophic lateral sclerosis (ALS) patients carrying C9orf72 pathological repeat expansion have been extensively studied, our understanding of those carrying SOD1 variants is mostly based on case reports. The aim of this paper is to extensively explore the cognitive-behavioral characteristics of a cohort of ALS patients carrying pathogenetic variants of SOD1 gene, comparing them to patients without pathogenetic variants of 46 ALS-related genes (wild-type [WT]-ALS) and healthy controls.

METHODS: All ALS patients seen at the Turin ALS expert center in the 2009-2021 period who underwent both cognitive/behavioral and extensive genetic testing were eligible to be included in the study. Only patients with SOD1 pathogenetic variants (n = 28) (SOD1-ALS) and WT-ALS (n = 829) were enrolled in the study. A series of 129 controls was also included.

RESULTS: Among the 28 SOD1-ALS patients, 16 (57.1%) had normal cognitive function, 5 (17.9%) isolated cognitive impairment (ALSci) (17.9%), 6 (21.4%) isolated behavioral impairment (ALSbi), 1 (3.6%) cognitive and behavioral impairment (ALScbi), and no one ALS-FTD. SOD1-ALS performed worse than controls in all explored domains, in particular Social Cognition and Language domains. SOD1-ALS patients had similar scores in all tests compared to WT-ALS, except the Story-based Empathy Task (SET), where they performed worse.

INTERPRETATION: Cognitive-behavioral impairment is much more common in SOD1 patients than previously assumed. SOD1-ALS are characterized by a more frequent impairment of Social Cognition and, less markedly, of Language domains. These findings have relevant implication both in the clinical and in the research setting, also considering recently approved treatment for SOD1-ALS. ANN NEUROL 2024;96:150-158.}, } @article {pmid38567799, year = {2024}, author = {Wang, XJ and Cornell, PY and Belanger, E and Thomas, KS}, title = {Do end-of-life outcomes differ by assisted living memory-care designation?.}, journal = {Journal of the American Geriatrics Society}, volume = {72}, number = {8}, pages = {2491-2499}, pmid = {38567799}, issn = {1532-5415}, support = {R01 AG057746/AG/NIA NIH HHS/United States ; R01 AG066902/AG/NIA NIH HHS/United States ; R01AG066902/AG/NIA NIH HHS/United States ; R01AG057746/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Assisted Living Facilities/statistics & numerical data ; Aged, 80 and over ; United States ; *Terminal Care/statistics & numerical data ; Aged ; *Medicare/statistics & numerical data ; Prospective Studies ; *Hospice Care/statistics & numerical data ; Alzheimer Disease/mortality/therapy ; Dementia/mortality/therapy ; }, abstract = {BACKGROUND: Residential care/assisted living (RC/AL) is an increasingly common place of end-of-life care for persons with Alzheimer's disease and related dementia (ADRD), who have unique care needs as their health declines. Approximately 22% of RC/ALs provide specialized memory care (memory-care RC/AL). Understanding how end-of-life outcomes differ by memory care among residents with ADRD could facilitate aging/dying in place for this population. The objective of this paper is to examine if end-of-life outcomes (i.e., mortality, hospice use, and number of days receiving hospice in the last month of life) differ between residents with ADRD who moved to memory-care RC/AL, compared with residents with ADRD who moved to RC/AL without memory care (general RC/AL).

METHODS: Prospective cohort of 15,152 fee-for-service Medicare beneficiaries with ADRD who moved to large RC/AL (> = 25 beds) between 2016 and 2018. We used inverse probability treatment weighting to account for observable differences between memory-care and general RC/AL residents. Two-part models estimated the difference by memory care in the number of days receiving hospice care in the last months of life among RC/AL decedents.

RESULTS: The unadjusted mortality rates were 13.4% in general RC/AL and 15.8% in memory-care RC/AL with an adjusted difference of 1.3 percentage points higher mortality among memory-care RC/AL residents (p = 0.04). Hospice use was 8% and 10.6% among general and memory-care RC/AL residents, respectively, with an adjusted difference of 1.4 percentage points (p = 0.01) higher in memory care. Two-part models showed that decedents in memory-care RC/AL spent about 1.4 more days receiving hospice care in the last month of life (p = 0.02).

CONCLUSION: We find a higher mortality rate and higher rate of hospice use among memory-care RC/AL residents. These findings suggest that memory care may attract residents closer to the end of life and/or promote hospice use at the end of life.}, } @article {pmid38565306, year = {2024}, author = {Zhang, Y and Li, J and Guo, K and Wang, T and Gao, L and Sun, Z and Ma, C and Wang, C and Tian, Y and Zheng, X}, title = {Strigolactones alleviate AlCl3 stress by vacuolar compartmentalization and cell wall blocking in apple.}, journal = {The Plant journal : for cell and molecular biology}, volume = {119}, number = {1}, pages = {197-217}, doi = {10.1111/tpj.16753}, pmid = {38565306}, issn = {1365-313X}, support = {//Breeding Plan of Shandong Provincial Qingchuang Research Team/ ; SDAIT-06-06//Modern Agricultural Technology Industry System of Shandong province/ ; 32001336//National Natural Science Foundation of China/ ; 32102351//National Natural Science Foundation of China/ ; 32172542//National Natural Science Foundation of China/ ; 32372674//National Natural Science Foundation of China/ ; }, mesh = {*Malus/genetics/metabolism/drug effects ; *Vacuoles/metabolism ; *Cell Wall/metabolism/drug effects ; *Aluminum Chloride ; *Plant Proteins/genetics/metabolism ; *Gene Expression Regulation, Plant/drug effects ; Lactones/metabolism/pharmacology ; Plants, Genetically Modified ; Stress, Physiological ; Plant Roots/metabolism/genetics/drug effects ; Heterocyclic Compounds, 3-Ring/metabolism/pharmacology ; Transcription Factors/metabolism/genetics ; Promoter Regions, Genetic ; }, abstract = {Poor management and excess fertilization of apple (Malus domestica Borkh.) orchards are causing increasingly serious soil acidification, resulting in Al toxicity and direct poisoning of roots. Strigolactones (SLs) are reported to be involved in plant responses to abiotic stress, but their role and mechanism under AlCl3 stress remain unknown. Here, we found that applying 1 μm GR24 (an SL analoge) significantly alleviated AlCl3 stress of M26 apple rootstock, mainly by blocking the movement of Al through cell wall and by vacuolar compartmentalization of Al. RNA-seq analysis identified the core transcription factor gene MdWRKY53, and overexpressing MdWRKY53 enhanced AlCl3 tolerance in transgenic apple plants through the same mechanism as GR24. Subsequently, we identified MdPMEI45 (encoding pectin methylesterase inhibitor) and MdALS3 (encoding an Al transporter) as downstream target genes of MdWRKY53 using chromatin immunoprecipitation followed by sequencing (ChIP-seq). GR24 enhanced the interaction between MdWRKY53 and the transcription factor MdTCP15, further increasing the binding of MdWRKY53 to the MdPMEI45 promoter and inducing MdPMEI45 expression to prevent Al from crossing cell wall. MdWRKY53 also bound to the promoter of MdALS3 and enhanced its transcription to compartmentalize Al in vacuoles under AlCl3 stress. We therefore identified two modules involved in alleviating AlCl3 stress in woody plant apple: the SL-WRKY+TCP-PMEI module required for excluding external Al by blocking the entry of Al[3+] into cells and the SL-WRKY-ALS module allowing internal detoxification of Al through vacuolar compartmentalization. These findings lay a foundation for the practical application of SLs in agriculture.}, } @article {pmid38565200, year = {2024}, author = {Stierwalt, J and Stierwalt, JAG and Clark, H and Burda, A and Benavidez Kiley, H and Collins, E and Kortemeyer, M and Miller, E and Peckenschneider, G and Schieltz, E and Shah, Y and Simon, K}, title = {Factors Affecting Performance on a Screening Tool in Persons with Amyotrophic Lateral Sclerosis.}, journal = {Seminars in speech and language}, volume = {45}, number = {3}, pages = {228-241}, doi = {10.1055/s-0044-1785447}, pmid = {38565200}, issn = {1098-9056}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/complications ; Male ; Female ; Middle Aged ; Aged ; Retrospective Studies ; Cognitive Dysfunction/diagnosis ; Neuropsychological Tests ; Frontotemporal Dementia/diagnosis/psychology ; Adult ; Aged, 80 and over ; }, abstract = {Persons with amyotrophic lateral sclerosis (PALS) are at risk of developing cognitive impairments and frontotemporal dementia (FTD). This study examined the relationship between performance of the ALS-Cognitive Behavioral Screen (ALS-CBS) and the demographic parameters of sex, education, time post-ALS diagnosis, and severity of symptoms. Data were collected retrospectively from 69 participants seen at the Mayo Clinic. Correlations were conducted on the ALS-CBS total scores and subsection scores and the above listed parameters; t-tests were conducted between participant subgroups. No statistically significant relationships or differences occurred between the ALS-CBS or its subsections and the variables measured with exception of age and the attention subsection. Older participants had lower ALS-CBS attention subsection scores. Based on the ALS-CBS scores, most participants had some degree of cognitive impairments: 43 had suspected cognitive impairment, 8 had suspected FTD; 18 fell within the normal range of cognitive function. Overall, the variables of sex, education, time post-diagnosis, and severity of symptoms do not appear to influence ALS-CBS scores. It is recommended cognitive screenings be completed for all PALS due to the high risk for developing cognitive impairments and FTD. Such knowledge can help clinicians develop assessment and treatment plans.}, } @article {pmid38564847, year = {2024}, author = {Rajagopalan, V and Pioro, EP}, title = {Differing patterns of cortical grey matter pathology identified by multifractal analysis in UMN-predominant ALS patients with and without corticospinal tract hyperintensity.}, journal = {Journal of the neurological sciences}, volume = {459}, number = {}, pages = {122945}, doi = {10.1016/j.jns.2024.122945}, pmid = {38564847}, issn = {1878-5883}, mesh = {Humans ; *Gray Matter/diagnostic imaging/pathology ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging/pathology ; Pyramidal Tracts/diagnostic imaging ; Brain/pathology ; Magnetic Resonance Imaging/methods ; }, abstract = {The pathological hallmarks of amyotrophic lateral sclerosis (ALS) are degeneration of the primary motor cortex grey matter (GM) and corticospinal tract (CST) resulting in upper motor neuron (UMN) dysfunction. Conventional brain magnetic resonance imaging (MRI) shows abnormal CST hyperintensity in some UMN-predominant ALS patients (ALS-CST+) but not in others (ALS-CST-). In addition to the CST differences, we aimed to determine whether GM degeneration differs between ALS-CST+ and ALS-CST- patients by cortical thickness (CT), voxel-based morphometry (VBM) and fractal dimension analyses. We hypothesized that MRI multifractal (MF) measures could differentiate between neurologic controls (n = 14) and UMN-predominant ALS patients as well as between patient subgroups (ALS-CST+, n = 21 vs ALS-CST-, n = 27). No significant differences were observed in CT or GM VBM in any brain regions between patients and controls or between ALS subgroups. MF analyses were performed separately on GM of the whole brain, of frontal, parietal, occipital, and temporal lobes as well as of cerebellum. Estimating MF measures D (Q = 0), D (Q = 1), D (Q = 2), Δf, Δα of frontal lobe GM classified neurologic controls, ALS-CST+ and ALS-CST- groups with 98% accuracy and > 95% in F1, recall, precision and specificity scores. Classification accuracy was only 74% when using whole brain MF measures and < 70% for other brain lobes. We demonstrate that MF analysis can distinguish UMN-predominant ALS subgroups based on GM changes, which the more commonly used quantitative approaches of CT and VBM cannot.}, } @article {pmid38563162, year = {2024}, author = {Pastora, LE and Namburu, NS and Arora, K and Christov, PP and Wilson, JT}, title = {STING-Pathway Inhibiting Nanoparticles (SPINs) as a Platform for Treatment of Inflammatory Diseases.}, journal = {ACS applied bio materials}, volume = {7}, number = {8}, pages = {4867-4878}, pmid = {38563162}, issn = {2576-6422}, support = {T32 DK101003/DK/NIDDK NIH HHS/United States ; P30 DK058404/DK/NIDDK NIH HHS/United States ; }, mesh = {*Membrane Proteins/metabolism/antagonists & inhibitors ; *Nanoparticles/chemistry ; Animals ; Mice ; Inflammation/drug therapy ; Humans ; Biocompatible Materials/chemistry/pharmacology ; Particle Size ; Materials Testing ; Nucleotidyltransferases/antagonists & inhibitors/metabolism ; Signal Transduction/drug effects ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; }, abstract = {Aberrant activation of the cyclic GMP-AMP synthase (cGAS)/Stimulator of Interferon Genes (STING) pathway has been implicated in the development and progression of a myriad of inflammatory diseases including colitis, nonalcoholic steatohepatitis, amyotrophic lateral sclerosis (ALS), and age-related macular degeneration. Thus, STING pathway inhibitors could have therapeutic application in many of these inflammatory conditions. The cGAS inhibitor RU.521 and the STING inhibitor H-151 have shown promise as therapeutics in mouse models of colitis, ALS, and more. However, these agents require frequent high-dose intraperitoneal injections, which may limit translatability. Furthermore, long-term use of systemically administered cGAS/STING inhibitors may leave patients vulnerable to viral infections and cancer. Thus, localized or targeted inhibition of the cGAS/STING pathway may be an attractive, broadly applicable treatment for a variety of STING pathway-driven ailments. Here we describe STING-Pathway Inhibiting Nanoparticles (SPINS)-poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with RU.521 and H-151-as a platform for enhanced and sustained inhibition of cGAS/STING signaling. We demonstrate that SPINs are equally or more effective at inhibiting type-I interferon responses induced by cytosolic DNA than free H-151 or RU.521. Additionally, we describe a SPIN formulation in which PLGA is coemulsified with poly(benzoyloxypropyl methacrylamide) (P(HPMA-Bz)), which significantly improves drug loading and allows for tunable release of H-151 over a period of days to over a week by varying P(HPMA-Bz) content. Finally, we find that all SPIN formulations were as potent or more potent in inhibiting cGAS/STING signaling in primary murine macrophages, resulting in decreased expression of inflammatory M1-like macrophage markers. Therefore, our study provides an in vitro proof-of-concept for nanoparticle delivery of STING pathway inhibitors and positions SPINs as a potential platform for slowing or reversing the onset or progression of cGAS/STING-driven inflammatory conditions.}, } @article {pmid38563056, year = {2024}, author = {Umar, TP and Jain, N and Papageorgakopoulou, M and Shaheen, RS and Alsamhori, JF and Muzzamil, M and Kostiks, A}, title = {Artificial intelligence for screening and diagnosis of amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {425-436}, doi = {10.1080/21678421.2024.2334836}, pmid = {38563056}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Humans ; *Artificial Intelligence ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurological disease that leads to progressive motor function degeneration. Diagnosing ALS is challenging due to the absence of a specific detection test. The use of artificial intelligence (AI) can assist in the investigation and treatment of ALS.

METHODS: We searched seven databases for literature on the application of AI in the early diagnosis and screening of ALS in humans. The findings were summarized using random-effects summary receiver operating characteristic curve. The risk of bias (RoB) analysis was carried out using QUADAS-2 or QUADAS-C tools.

RESULTS: In the 34 analyzed studies, a meta-prevalence of 47% for ALS was noted. For ALS detection, the pooled sensitivity of AI models was 94.3% (95% CI - 63.2% to 99.4%) with a pooled specificity of 98.9% (95% CI - 92.4% to 99.9%). For ALS classification, the pooled sensitivity of AI models was 90.9% (95% CI - 86.5% to 93.9%) with a pooled specificity of 92.3% (95% CI - 84.8% to 96.3%). Based on type of input for classification, the pooled sensitivity of AI models for gait, electromyography, and magnetic resonance signals was 91.2%, 92.6%, and 82.2%, respectively. The pooled specificity for gait, electromyography, and magnetic resonance signals was 94.1%, 96.5%, and 77.3%, respectively.

CONCLUSIONS: Although AI can play a significant role in the screening and diagnosis of ALS due to its high sensitivities and specificities, concerns remain regarding quality of evidence reported in the literature.}, } @article {pmid38563035, year = {2024}, author = {Fu, Y and Huang, XQ and Qu, HB and Ge, YZ and Ru, XL}, title = {Tandem Mass Tag-Based Proteomic Analysis of Normal and Degenerated Human Intervertebral Discs.}, journal = {Journal of pain research}, volume = {17}, number = {}, pages = {1313-1326}, pmid = {38563035}, issn = {1178-7090}, abstract = {BACKGROUND: Intervertebral disc degeneration (IVDD) is the main cause of low back pain (LBP), but the specific regulatory factors, pathways and specific molecular mechanisms remain unclear.

METHODS: We identified and quantitatively analyzed Pfirrmann Grade II (n=3) and Pfirrmann Grade IV (n=3) pulposus samples via MRI. The differential abundance of proteins in the samples was determined and quantitatively analyzed by relative and absolute quantitative analysis of the isotope marker levels combined with the liquid chromatography-tandem mass spectrometry (LC‒MSMS/MS).

RESULTS: A total of 70 proteins (30 significantly increased proteins (> 1.2-fold change) and 40 significantly decreased proteins (< 0.8-fold change)) showed different levels among the groups. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology (GO) enrichment analyses and Western blot analysis showed that CYCS, RAC1, and PSMD14 may play important roles in IVDD and that Epstein‒Barr virus infection, viral myocarditis, colorectal cancer, nonalcoholic fatty liver disease (NAFLD) and amyotrophic lateral sclerosis (ALS) are the main pathways involved in IVDD.

CONCLUSION: CYCS, RAC1 and PSMD14 may play important roles in IVDD, and Epstein‒Barr virus infection, viral myocarditis, colorectal cancer, NAFLD and ALS may be the main pathways involved in IVDD.}, } @article {pmid38562780, year = {2024}, author = {Krus, KL and Benitez, AM and Strickland, A and Milbrandt, J and Bloom, AJ and DiAntonio, A}, title = {Reduced STMN2 and pathogenic TDP-43, two hallmarks of ALS, synergize to accelerate motor decline in mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38562780}, issn = {2692-8205}, support = {R37 NS065053/NS/NINDS NIH HHS/United States ; R01 NS087632/NS/NINDS NIH HHS/United States ; RF1 AG013730/AG/NIA NIH HHS/United States ; R01 NS119812/NS/NINDS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; }, abstract = {Pathological TDP-43 loss from the nucleus and cytoplasmic aggregation occurs in almost all cases of ALS and half of frontotemporal dementia patients. Stathmin2 (Stmn2) is a key target of TDP-43 regulation and aberrantly spliced Stmn2 mRNA is found in patients with ALS, frontotemporal dementia, and Alzheimer's Disease. STMN2 participates in the axon injury response and its depletion in vivo partially replicates ALS-like symptoms including progressive motor deficits and distal NMJ denervation. The interaction between STMN2 loss and TDP-43 dysfunction has not been studied in mice because TDP-43 regulates human but not murine Stmn2 splicing. Therefore, we generated trans-heterozygous mice that lack one functional copy of Stmn2 and express one mutant TDP-43[Q331K] knock-in allele to investigate whether reduced STMN2 function exacerbates TDP-43-dependent pathology. Indeed, we observe synergy between these two alleles, resulting in an early onset, progressive motor deficit. Surprisingly, this behavioral defect is not accompanied by detectable neuropathology in the brain, spinal cord, peripheral nerves or at neuromuscular junctions (NMJs). However, the trans-heterozygous mice exhibit abnormal mitochondrial morphology in their distal axons and NMJs. As both STMN2 and TDP-43 affect mitochondrial dynamics, and neuronal mitochondrial dysfunction is a cardinal feature of many neurodegenerative diseases, this abnormality likely contributes to the observed motor deficit. These findings demonstrate that partial loss of STMN2 significantly exacerbates TDP-43-associated phenotypes, suggesting that STMN2 restoration could ameliorate TDP-43 related disease before the onset of degeneration.}, } @article {pmid38561605, year = {2024}, author = {Singh, K and Gupta, JK and Kumar, S and Soni, U}, title = {A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Bioactive Peptides.}, journal = {Current protein & peptide science}, volume = {25}, number = {7}, pages = {507-526}, pmid = {38561605}, issn = {1875-5550}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Peptides/therapeutic use/chemistry/pharmacology ; Animals ; Alzheimer Disease/drug therapy/metabolism/pathology ; Parkinson Disease/drug therapy/metabolism/pathology ; Neuroprotective Agents/therapeutic use/pharmacology/chemistry ; Oxidative Stress/drug effects ; Huntington Disease/drug therapy/metabolism/pathology ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Cholinesterase Inhibitors/therapeutic use/pharmacology/chemistry ; }, abstract = {Neurodegenerative disorders, which include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a significant and growing global health challenge. Current therapies predominantly focus on symptom management rather than altering disease progression. In this review, we discuss the major therapeutic strategies in practice for these disorders, highlighting their limitations. For AD, the mainstay treatments are cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. For PD, dopamine replacement therapies, including levodopa, are commonly used. HD is managed primarily with symptomatic treatments, and reusable extends survival in ALS. However, none of these therapies halts or substantially slows the neurodegenerative process. In contrast, this review highlights emerging research into bioactive peptides as potential therapeutic agents. These naturally occurring or synthetically designed molecules can interact with specific cellular targets, potentially modulating disease processes. Preclinical studies suggest that bioactive peptides may mitigate oxidative stress, inflammation, and protein misfolding, which are common pathological features in neurodegenerative diseases. Clinical trials using bioactive peptides for neurodegeneration are limited but show promising initial results. For instance, hemiacetal, a γ-secretase inhibitor peptide, has shown potential in AD by reducing amyloid-beta production, though its development was discontinued due to side effects. Despite these advancements, many challenges remain, including identifying optimal peptides, confirming their mechanisms of action, and overcoming obstacles related to their delivery to the brain. Future research should prioritize the discovery and development of novel bioactive peptides and improve our understanding of their pharmacokinetics and pharmacodynamics. Ultimately, this approach may lead to more effective therapies for neurodegenerative disorders, moving beyond symptom management to potentially modify the course of these devastating diseases.}, } @article {pmid38561079, year = {2024}, author = {Liu, X and Yu, Y and Garcia, LA and Au, ML and Tran, M and Zhang, J and Lou, A and Liu, Y and Wu, H}, title = {A grape-supplemented diet prevented ultraviolet (UV) radiation-induced cataract by regulating Nrf2 and XIAP pathways.}, journal = {The Journal of nutritional biochemistry}, volume = {129}, number = {}, pages = {109636}, pmid = {38561079}, issn = {1873-4847}, support = {R21 EY033941/EY/NEI NIH HHS/United States ; R25 HL125447/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Mice ; Anthocyanins/pharmacology ; *Cataract/prevention & control/metabolism/etiology ; *Dietary Supplements ; Glutathione/metabolism ; Lens, Crystalline/metabolism/radiation effects/drug effects ; Mice, Inbred C57BL ; *NF-E2-Related Factor 2/metabolism ; Resveratrol/pharmacology ; Signal Transduction/drug effects ; *Ultraviolet Rays/adverse effects ; *Vitis/chemistry ; *X-Linked Inhibitor of Apoptosis Protein/metabolism ; }, abstract = {The purpose of this study is to investigate if grape consumption, in the form of grape powder (GP), could protect against ultraviolet (UV)-induced cataract. Mice were fed with the regular diet, sugar placebo diet, or a grape diet (regular diet supplemented with 5%, 10%, and 15% GP) for 3 months. The mice were then exposed to UV radiation to induce cataract. The results showed that the GP diet dose-dependently inhibited UV-induced cataract and preserved glutathione pools. Interestingly, UV-induced Nrf2 activation was abolished in the groups on the GP diet, suggesting GP consumption may improve redox homeostasis in the lens, making Nrf2 activation unnecessary. For molecular target prediction, a total of 471 proteins regulated by GP were identified using Agilent Literature Search (ALS) software. Among these targets, the X-linked inhibitor of apoptosis (XIAP) was correlated with all of the main active ingredients of GP, including resveratrol, catechin, quercetin, and anthocyanins. Our data confirmed that GP prevented UV-induced suppression of XIAP, indicating that XIAP might be one of the critical molecular targets of GP. In conclusion, this study demonstrated that GP protected the lens from UV-induced cataract development in mice. The protective effects of GP may be attributed to its ability to improve redox homeostasis and activate the XIAP-mediated antiapoptotic pathway.}, } @article {pmid38560980, year = {2024}, author = {Xiang, SR and Ma, Q and Dong, J and Ren, YF and Lin, JZ and Zheng, C and Xiao, P and You, FM}, title = {Contrasting Effects of Music Therapy and Aromatherapy on Perioperative Anxiety: A Systematic Review and Meta-Analysis.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {278-291}, doi = {10.1159/000538425}, pmid = {38560980}, issn = {2504-2106}, mesh = {*Aromatherapy ; *Music Therapy ; Humans ; *Anxiety/therapy ; Heart Rate ; }, abstract = {INTRODUCTION: Music therapy and aromatherapy have been demonstrated effective for perioperative anxiety. However, the available studies have indicated discordant results about which adjunct treatment is better for perioperative anxiety. Therefore, we conducted this meta-analysis to explore the contrasting effects between them.

METHODS: Six electronic databases were searched for clinical trials evaluating the efficacy of music therapy compared with aromatherapy in alleviating perioperative anxiety. The primary outcome was the postintervention anxiety level. Secondary outcomes included differences in blood pressure and heart rate before and after the intervention as well as pain scores at intraoperative and postoperative time points. The study protocol was registered on PROSPERO (CRD42021249737).

RESULTS: Twelve studies (894 patients) were included. The anxiety level showed no statistically significant difference (SMD, 0.28; 95% CI: -0.12, 0.68; p = 0.17). The analysis of blood pressure and heart rate also did not identify statistically significant differences. Notably, the pain scores at the intraoperative time point suggested that aromatherapy was superior to music therapy (WMD, 0.29 cm; 95% CI: 0.05, 0.52; p = 0.02), while those at 4 h after surgery indicated the opposite results (WMD, -0.48 cm; 95% CI: -0.60, -0.36; p < 0.001).

CONCLUSION: Low-to-moderate quality evidence suggests that music therapy and aromatherapy have similar potential to relieve perioperative anxiety. The potential data indicate that the two therapies have different benefits in intervention duration and age distribution. More direct high-quality comparisons are encouraged in the future to verify this point.

UNLABELLED: EinleitungMusik- und Aromatherapie haben sich bei perioperativen Angstzuständen als wirksam erwiesen. Die verfügbaren Studien zeigten jedoch widersprüchliche Ergebnisse zur Frage, welche adjuvante Therapie bei perioperativen Angstzuständen besser ist. Daher führten wir die vorliegende Metaanalyse durch, um die unterschiedlichen Effekte der beiden Therapien zu untersuchen.MethodenSechs (6) elektronische Datenbanken wurden nach klinischen Studien zur Wirksamkeit von Musiktherapie im Vergleich zur Aromatherapie bei der Linderung perioperativer Angstzustände durchsucht. Primäres Zielkriterium war das Angstniveau nach der Intervention. Die sekundären Zielkriterien umfassten die Unterschiede bei Blutdruck und Herzfrequenz vor und nach der Intervention sowie die Schmerz-Scores zu intra- und postoperativen Zeitpunkten. Das Studienprotokoll wurde auf PROSPERO (CRD42021249737) registriert.ErgebnisseZwölf (12) Studien (894 Patienten) wurden eingeschlossen. Das Angstniveau zeigte keinen statistisch signifikanten Unterschied (SMD, 0,28; 95%-KI: −0,12, 0,68, p = 0,17) und auch die Analyse von Blutdruck und Herzfrequenz ergab keine statistisch signifikanten Unterschiede. Insbesondere die Schmerz-Scores zum intraoperativen Zeitpunkt sprachen dafür, dass die Aromatherapie gegenüber der Musiktherapie überlegen war (WMD, 0,29 cm; 95%-KI: 0,05, 0,52; p = 0,02), während die Werte 4 Stunden nach der Operation gegenteilige Ergebnisse zeigten (WMD, −0,48 cm; 95%-KI: −0,60, −0,36, p < 0,001).SchlussfolgerungEvidenzen von geringer bis mässiger Qualität deuten darauf hin, dass Musik- und Aromatherapie ein vergleichbares Potenzial bei der Linderung perioperativer Ängste besitzen. Die potenziellen Daten zeigen, dass die beiden Therapien unterschiedliche Vorteile hinsichtlich Interventionsdauer und Altersverteilung haben. Künftig sollten mehr direkte und qualitativ hochwertige Vergleiche durchgeführt werden, um diesen Aspekt zu überprüfen.}, } @article {pmid38560897, year = {2024}, author = {Minatoguchi, S and Fujita, Y and Niizuma, K and Tominaga, T and Yamashita, T and Abe, K and Dezawa, M}, title = {Donor Muse Cell Treatment Without HLA-Matching Tests and Immunosuppressant Treatment.}, journal = {Stem cells translational medicine}, volume = {13}, number = {6}, pages = {532-545}, pmid = {38560897}, issn = {2157-6580}, support = {//New Energy and Industrial Technology Development Organization/ ; //Japan Agency for Medical Research and Development/ ; //Ministry of Education, Culture, Sports, Science and Technology/ ; //Japan Society for the Promotion of Science/ ; //SENSHIN Medical Research Foundation/ ; //Life Science Institute Inc/ ; }, mesh = {Humans ; *Mesenchymal Stem Cells/cytology/metabolism ; Mesenchymal Stem Cell Transplantation/methods ; Immunosuppressive Agents/pharmacology/therapeutic use ; HLA Antigens/metabolism ; Cell Differentiation ; Animals ; Histocompatibility Testing/methods ; }, abstract = {The strength of stem cell therapy is the regeneration of tissues by synergistic pleiotropic effects. Among many stem cell types, mesenchymal stem cells (MSCs) that are comprised of heterogenous population are widely used for clinical applications with the expectation of pleiotropic bystander effects. Muse cells are pluripotent-like/macrophage-like stem cells distributed in the bone marrow, peripheral blood, and organ connective tissues as cells positive for the pluripotent surface marker stage-specific-embryonic antigen -3. Muse cells comprise ~1% to several percent of MSCs. While Muse cells and MSCs share several characteristics, such as mesenchymal surface marker expression and their bystander effects, Muse cells exhibit unique characteristics not observed in MSCs. These unique characteristics of Muse cells include selective homing to damaged tissue after intravenous injection rather than being trapped in the lung like MSCs, replacement of a wide range of damaged/apoptotic cells by differentiation through phagocytosis, and long-lasting immunotolerance for donor cell use. In this review, we focus on the basic properties of Muse cells clarified through preclinical studies and clinical trials conducted by intravenous injection of donor-Muse cells without HLA-matching tests or immunosuppressant treatment. MSCs are considered to differentiate into osteogenic, chondrogenic, and adipogenic cells, whereas the range of their differentiation has long been debated. Muse cells may provide clues to the wide-ranging differentiation potential of MSCs that are observed with low frequency. Furthermore, the utilization of Muse cells may provide a novel strategy for clinical treatment.}, } @article {pmid38559706, year = {2024}, author = {Bhor, S and Tonny, SH and Dinesh, S and Sharma, S}, title = {Computational screening of damaging nsSNPs in human SOD1 genes associated with amyotrophic lateral sclerosis identifies destabilising effects of G38R and G42D mutations through in silico evaluation.}, journal = {In silico pharmacology}, volume = {12}, number = {1}, pages = {20}, pmid = {38559706}, issn = {2193-9616}, abstract = {Amyotrophic lateral sclerosis (ALS), a complicated neurodegenerative disorder affected by hereditary and environmental variables, is a condition. In this study, the genetic makeup of ALS is investigated, with a focus on the SOD1 gene's single-nucleotide polymorphisms (SNPs) and their ability to affect disease risk. Eleven high-risk missense variations that may impair the functionality of the SOD1 protein were discovered after a thorough examination of SNPs in the SOD1 gene. These mutations were chosen using a variety of prediction approaches, highlighting their importance in the aetiology of ALS. Notably, it was discovered that the stability of the SOD1 wild-type protein structure was compromised by the G38R and G42D SOD1 variants. Additionally, Edaravone, a possible ALS medication, showed a greater affinity for binding mutant SOD1 structures, pointing to potential personalised treatment possibilities. The high-risk SNPs discovered in this investigation seem to have functional effects, especially on the stability of proteins and their interactions with other molecules. This study clarifies the complex genetics of ALS and offers insights into how these genetic variations may affect the effectiveness of therapeutic interventions, particularly in the context of edaravone. In this study advances our knowledge of the genetic mechanisms causing ALS vulnerability and prospective therapeutic strategies. Future studies are necessary to confirm these results and close the gap between individualised clinical applications and improved ALS care.}, } @article {pmid38559165, year = {2024}, author = {Sirtori, R and Gregoire, M and Potts, E and Collins, A and Donatelli, L and Fallini, C}, title = {LINC complex alterations are a hallmark of sporadic and familial ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.03.08.584123}, pmid = {38559165}, issn = {2692-8205}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects motor neurons, leading to progressive muscle weakness and loss of voluntary muscle control. While the exact cause of ALS is not fully understood, emerging research suggests that dysfunction of the nuclear envelope (NE) may contribute to disease pathogenesis and progression. The NE plays a role in ALS through several mechanisms, including nuclear pore defects, nucleocytoplasmic transport impairment, accumulation of mislocalized proteins, and nuclear morphology abnormalities. The LINC complex is the second biggest multi-protein complex in the NE and consists of the SUN1/2 proteins spanning the inner nuclear membrane and Nesprin proteins embedded in the outer membrane. The LINC complex, by interacting with both the nuclear lamina and the cytoskeleton, transmits mechanical forces to the nucleus regulating its morphology and functional homeostasis. In this study we show extensive alterations to the LINC complex in motor and cortical iPSC-derived neurons and spinal cord organoids carrying the ALS causative mutation in the C9ORF72 gene (C9). Importantly, we show that such alterations are present in vivo in a cohort of sporadic ALS and C9-ALS postmortem spinal cord and motor cortex biopsies. We also found that LINC complex disruption strongly correlated with nuclear morphological alterations occurring in ALS neurons, independently of TDP43 mislocalization. Altogether, our data establish morphological and functional alterations to the LINC complex as important events in ALS pathogenic cascade, making this pathway a possible target for both biomarker and therapy development.}, } @article {pmid38558260, year = {2024}, author = {Fonteh, CN and Patnaik, JL and Grove, NC and Lynch, AM and Pantcheva, MB and Christopher, KL}, title = {Refractive outcomes using Barrett formulas and patient characteristics of cataract surgery patients with and without prior LASIK/PRK.}, journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie}, volume = {262}, number = {9}, pages = {2937-2944}, pmid = {38558260}, issn = {1435-702X}, mesh = {Humans ; Retrospective Studies ; Female ; Male ; *Photorefractive Keratectomy/methods ; *Visual Acuity/physiology ; *Refraction, Ocular/physiology ; *Keratomileusis, Laser In Situ/methods ; Aged ; *Lasers, Excimer/therapeutic use ; Middle Aged ; Cataract Extraction/methods ; Follow-Up Studies ; Refractive Errors/physiopathology/diagnosis ; Treatment Outcome ; Myopia/surgery/physiopathology ; Axial Length, Eye/pathology ; }, abstract = {PURPOSE: The goal of this study is to describe characteristics of cataract surgery patients who previously underwent laser in situ keratomileusis/photorefractive keratectomy (LASIK/PRK) in comparison to non-LASIK/PRK cataract surgery patients including psychiatric comorbidities, as well as describe refractive prediction error after cataract surgery while accounting for axial length (AL) using the Barrett True-K and Barrett Universal II formulas.

METHODS: This was a retrospective study of patients from the University of Colorado Cataract Outcomes Registry. The primary outcomes were refraction prediction error (RPE), mean absolute RPE, and median absolute RPE. Outcomes were stratified by five axial length groups. Univariate and multivariate models for RPE were stratified by the AL group.

RESULTS: Two hundred eighty-one eyes with prior LASIK/PRK and 3101 eyes without are included in the study. Patients with prior LASIK/PRK were significantly younger: 67.0 vs 69.9 years, p < 0.0001. The LASIK/PRK group had significantly better mean pre-operative BCVA in comparison to the non-LASIK group, logMAR 0.204 vs logMAR 0.288, p = 0.003. The LASIK/PRK group had significantly lower rates of cardiovascular disease (18.5% vs 29.3%, p < 0.001), hypertension (49.1% vs 59.3%, p < 0.012), and type 2 diabetes (10.7% vs 26.0%, p < 0.001), and no significant difference in psychiatric disease. The absolute RPE was higher for the LASIK group for all ALs, but only significantly higher for eyes with AL less than 25 mm.

CONCLUSION: Patient eyes with prior LASIK/PRK surgery undergoing cataract surgery were significantly younger, had significantly less comorbidities, and a significantly better pre-operative BCVA. Using the Barrett formulas, absolute prediction error for eyes with longer ALs was not significantly worse for LASIK/PRK eyes than those without and the difference was smaller for eyes with longer AL.}, } @article {pmid38558150, year = {2024}, author = {Pensato, U and Cortelli, P}, title = {Soccer (football) and brain health.}, journal = {Journal of neurology}, volume = {271}, number = {6}, pages = {3019-3029}, pmid = {38558150}, issn = {1432-1459}, mesh = {Humans ; *Soccer/injuries ; *Brain Concussion/complications/epidemiology/etiology ; Athletic Injuries/complications ; Brain/physiopathology ; Chronic Traumatic Encephalopathy/etiology ; }, abstract = {Soccer is one of the most popular sports worldwide, played by over 270 million people and followed by many more. Several brain health benefits are promoted by practising soccer and physical exercise at large, which helps contrast the cognitive decline associated with ageing by enhancing neurogenesis processes. However, sport-related concussions have been increasingly recognised as a pressing public health concern, not only due to their acute impact but also, more importantly, due to mounting evidence indicating an elevated risk for the development of neurological sequelae following recurrent head traumas, especially chronic traumatic encephalopathy (CTE). While soccer players experience less frequent concussions compared with other contact or combat sports, such as American football or boxing, it stands alone in its purposeful use of the head to hit the ball (headings), setting its players apart as the only athletes exposed to intentional, sub-concussive head impacts. Additionally, an association between soccer and amyotrophic lateral sclerosis has been consistently observed, suggesting a potential "soccer-specific" risk factor. In this review, we discuss the neurological sequelae related to soccer playing, the emerging evidence of a detrimental effect related to recurrent headings, and the need for implementation of comprehensive strategies aimed at preventing and managing the burden of head impact in soccer.}, } @article {pmid38557405, year = {2024}, author = {Goutman, SA and Boss, J and Jang, DG and Piecuch, C and Farid, H and Batra, M and Mukherjee, B and Feldman, EL and Batterman, SA}, title = {Residential exposure associations with ALS risk, survival, and phenotype: a Michigan-based case-control study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {543-553}, pmid = {38557405}, issn = {2167-9223}, support = {K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; UL1 TR002240/TR/NCATS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/mortality ; Female ; Male ; Michigan/epidemiology ; Case-Control Studies ; *Environmental Exposure/adverse effects/statistics & numerical data ; Middle Aged ; Aged ; Risk Factors ; *Phenotype ; Adult ; }, abstract = {BACKGROUND: Environmental exposures impact amyotrophic lateral sclerosis (ALS) risk and progression, a fatal and progressive neurodegenerative disease. Better characterization of these exposures is needed to decrease disease burden.

OBJECTIVE: To identify exposures in the residential setting that associate with ALS risk, survival, and onset segment.

METHODS: ALS and control participants recruited from University of Michigan completed a survey that ascertained exposure risks in the residential setting. ALS risk was assessed using logistic regression models followed by latent profile analysis to consider exposure profiles. A case-only analysis considered the contribution of the residential exposure variables via a Cox proportional hazards model for survival outcomes and multinomial logistic regression for onset segment, a polytomous outcome.

RESULTS: This study included 367 ALS and 255 control participants. Twelve residential variables were associated with ALS risk after correcting for multiple comparison testing, with storage in an attached garage of chemical products including gasoline or kerosene (odds ratio (OR) = 1.14, padjusted < 0.001), gasoline-powered equipment (OR = 1.16, padjusted < 0.001), and lawn care products (OR = 1.15, padjusted < 0.001) representing the top three risk factors sorted by padjusted. Latent profile analysis indicated that storage of these chemical products in both attached and detached garages increased ALS risk. Although residential variables were not associated with poorer ALS survival following multiple testing corrections, storing pesticides, lawn care products, and woodworking supplies in the home were associated with shorter ALS survival using nominal p values. No exposures were associated with ALS onset segment.

CONCLUSION: Residential exposures may be important modifiable components of the ALS susceptibility and prognosis exposome.}, } @article {pmid38557366, year = {2024}, author = {Sopranzi, FM and Faragalli, A and Pompili, M and Carle, F and Gesuita, R and Ceravolo, MG}, title = {Incidence of amyotrophic lateral sclerosis before and during the COVID-19 pandemic: evidence from an 8-year population-based study in Central Italy based on healthcare utilization databases.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {554-562}, doi = {10.1080/21678421.2024.2336127}, pmid = {38557366}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Italy/epidemiology ; Male ; Female ; Aged ; *COVID-19/epidemiology ; Incidence ; Middle Aged ; Longitudinal Studies ; Databases, Factual ; Aged, 80 and over ; Patient Acceptance of Health Care/statistics & numerical data ; Adult ; SARS-CoV-2 ; Hospitalization/statistics & numerical data ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder with a high multidimensional burden, with an obscure etiopathogenesis.

METHODS: We designed a longitudinal, population-based study of people residing in Central Italy (Marche Region) who were beneficiaries of the National Health System. People with an unprecedented ALS hospitalization (335.20 ICD-9 CM) or tagged with an ALS exemption between 2014 and 2021 were considered incident cases. ALS cases residing in the region for <3 years or with an active ALS exemption or hospitalized for ALS before 2014 were excluded. We used secondary sources to identify new ALS diagnoses. The regional referral center for ALS's database was used to test the accuracy of secondary sources in detecting cases. ALS mean incidence was compared to that reported in similar studies conducted in Italy. The incidence rate trend adjusted by sex and age was evaluated using the Poisson regression model.

RESULTS: We detected 425 new ALS cases (median age: 70y) in the 2014-2021 period, with a mean incidence of 3.5:100,000 py (95%CI: 3.2-3.8; M:F = 1.2), similar to that reported in similar studies conducted in Italy. No trend was observed during 2014-2019. After including 2020-2021 in the model, we observed a mean decrease in incidence of 5.8% (95% CI 2.0%; 9.5%, p = 0.003).

CONCLUSION: We show a decrease in the incidence rate of ALS in Marche, during the 2014-2021 period, as a possible outcome of a delayed neurological assessment and diagnosis during the pandemic. An ad hoc developed identification algorithm, based on healthcare utilization databases, is a valuable tool to assess the health impact of global contingencies.}, } @article {pmid38556190, year = {2024}, author = {Fu, X and Zhang, Z and Hayes, LR and Wright, N and Asbury, J and Li, S and Ye, Y and Sun, S}, title = {DDX3X overexpression decreases dipeptide repeat proteins in a mouse model of C9ORF72-ALS/FTD.}, journal = {Experimental neurology}, volume = {376}, number = {}, pages = {114768}, pmid = {38556190}, issn = {1090-2430}, support = {R21 AG072078/AG/NIA NIH HHS/United States ; R01 NS123538/NS/NINDS NIH HHS/United States ; R01 NS107347/NS/NINDS NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; *DEAD-box RNA Helicases/genetics/metabolism ; Dipeptides/metabolism ; *Disease Models, Animal ; DNA Repeat Expansion/genetics ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Mice, Transgenic ; }, abstract = {Hexanucleotide repeat expansion in C9ORF72 (C9) is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One of the proposed pathogenic mechanisms is the neurotoxicity arising from dipeptide repeat (DPR) proteins produced by repeat-associated non-AUG (RAN) translation. Therefore, reducing DPR levels emerges as a potential therapeutic strategy for C9ORF72-ALS/FTD. We previously identified an RNA helicase, DEAD-box helicase 3 X-linked (DDX3X), modulates RAN translation. DDX3X overexpression decreases poly-GP accumulation in C9ORF72-ALS/FTD patient-derived induced pluripotent stem cell (iPSC)-differentiated neurons (iPSNs) and reduces the glutamate-induced neurotoxicity. In this study, we examined the in vivo efficacy of DDX3X overexpression using a mouse model. We expressed exogenous DDX3X or GFP in the central nervous system (CNS) of the C9-500 ALS/FTD BAC transgenic or non-transgenic control mice using adeno-associated virus serotype 9 (AAV9). The DPR levels were significantly reduced in the brains of DDX3X-expressing C9-BAC mice compared to the GFP control even twelve months after virus delivery. Additionally, p62 aggregation was also decreased. No neuronal loss or neuroinflammatory response were detected in the DDX3X overexpressing C9-BAC mice. This work demonstrates that DDX3X overexpression effectively reduces DPR levels in vivo without provoking neuroinflammation or neurotoxicity, suggesting the potential of increasing DDX3X expression as a therapeutic strategy for C9ORF72-ALS/FTD.}, } @article {pmid38555304, year = {2024}, author = {Cheng, CJ and Su, JJ}, title = {Detecting muscle-specific kinase myasthenia gravis in atypical presentations.}, journal = {Acta neurologica Belgica}, volume = {124}, number = {5}, pages = {1733-1735}, pmid = {38555304}, issn = {2240-2993}, } @article {pmid38554281, year = {2024}, author = {Dermentzaki, G and Furlan, M and Tanaka, I and Leonardi, T and Rinchetti, P and Passos, PMS and Bastos, A and Ayala, YM and Hanna, JH and Przedborski, S and Bonanomi, D and Pelizzola, M and Lotti, F}, title = {Depletion of Mettl3 in cholinergic neurons causes adult-onset neuromuscular degeneration.}, journal = {Cell reports}, volume = {43}, number = {4}, pages = {113999}, pmid = {38554281}, issn = {2211-1247}, support = {R01 AG084965/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; Adenosine/metabolism/analogs & derivatives ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Cholinergic Neurons/metabolism/pathology ; DNA-Binding Proteins/metabolism/genetics ; *Methyltransferases/metabolism/genetics ; Motor Neurons/metabolism/pathology ; *Neuromuscular Diseases/metabolism/pathology ; }, abstract = {Motor neuron (MN) demise is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Post-transcriptional gene regulation can control RNA's fate, and defects in RNA processing are critical determinants of MN degeneration. N[6]-methyladenosine (m[6]A) is a post-transcriptional RNA modification that controls diverse aspects of RNA metabolism. To assess the m[6]A requirement in MNs, we depleted the m[6]A methyltransferase-like 3 (METTL3) in cells and mice. METTL3 depletion in embryonic stem cell-derived MNs has profound and selective effects on survival and neurite outgrowth. Mice with cholinergic neuron-specific METTL3 depletion display a progressive decline in motor behavior, accompanied by MN loss and muscle denervation, culminating in paralysis and death. Reader proteins convey m[6]A effects, and their silencing phenocopies METTL3 depletion. Among the m[6]A targets, we identified transactive response DNA-binding protein 43 (TDP-43) and discovered that its expression is under epitranscriptomic control. Thus, impaired m[6]A signaling disrupts MN homeostasis and triggers neurodegeneration conceivably through TDP-43 deregulation.}, } @article {pmid38554151, year = {2024}, author = {Campos-Díaz, A and Morejón-García, P and Monte-Serrano, E and Ros-Pardo, D and Marcos-Alcalde, I and Gómez-Puertas, P and Lazo, PA}, title = {Pathogenic effects of Leu200Pro and Arg387His VRK1 protein variants on phosphorylation targets and H4K16 acetylation in distal hereditary motor neuropathy.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {102}, number = {6}, pages = {801-817}, pmid = {38554151}, issn = {1432-1440}, support = {PID2019-105610RB-I00//Agencia Estatal de Investigación/ ; PID2022-139598OB-I00//Agencia Estatal de Investigación/ ; RED2018-102801-T//Agencia Estatal de Investigación/ ; RTC-2017-6494-1//Agencia Estatal de Investigación/ ; RTI2018-094434-B-I00//Agencia Estatal de Investigación/ ; CSI264P20//Consejería de Educación, Junta de Castilla y León/ ; CLC-2017-01//Consejería de Educación, Junta de Castilla y León/ ; CSI004-18//Consejería de Educación, Junta de Castilla y León/ ; FPU20/02978//Ministerio de Universidades/ ; FPU16/01883//Ministerio de Universidades/ ; }, mesh = {Humans ; Acetylation ; *Histones/metabolism ; Phosphorylation ; *Protein Serine-Threonine Kinases/metabolism/genetics ; *Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Male ; Female ; DNA-Binding Proteins/genetics/metabolism ; Middle Aged ; Motor Neuron Disease/genetics/metabolism ; Nuclear Proteins/genetics/metabolism ; }, abstract = {Rare recessive variants in the human VRK1 gene are associated with several motor neuron diseases (MND), such as amyotrophic lateral sclerosis, spinal muscular atrophy, or distal hereditary motor neuropathies (dHMN). A case with dHMN carrying two novel VRK1 gene variants, expressing Leu200Pro (L200P) and Arg387His (R387H) variant proteins, identified that these protein variants are functionally different. The Leu200Pro variant shares with several variants in the catalytic domain the loss of the kinase activity on different substrates, such as histones, p53, or coilin. However, the distal Arg387His variant and the distal Trp375* (W375X) chinese variant, both located at the end of the low complexity C-terminal region and proximal to the termination codon, retain their catalytic activity on some substrates, and mechanistically their functional impairment is different. The L200P variant, as well as most VRK1 pathogenic variants, impairs the phosphorylation of BAF and histone H4K16 acetylation, which are required for DNA attachment to the nuclear envelope and chromatin accessibility to DNA repair mechanisms, respectively. The R387H variant impairs phosphorylation of H2AX, an early step in different types of DNA damage responses. The functional variability of VRK1 protein variants and their different combinations are a likely contributor to the clinical phenotypic heterogeneity of motor neuron and neurological diseases associated with rare VRK1 pathogenic variants. KEY MESSAGES: VRK1 variants implicated in motor neuron diseases are functionally different. The L200P variant is kinase inactive, and the R387H variant is partially active. VRK1 variants alter H4K16 acetylation and loss of coilin and BAF phosphorylation. VRK1 variants alter Cajal bodies and DNA damage responses. VRK1 variant combination determines the neurological phenotype heterogeneity.}, } @article {pmid38553272, year = {2024}, author = {Desmaison, A and Truffert, A and Pereira, B and Camdessanché, JP and Moisset, X and Guy, N}, title = {Upper motor neuron assessment in amyotrophic lateral sclerosis using the patellar tendon reflex and motor-evoked potentials to the lower limbs.}, journal = {Revue neurologique}, volume = {180}, number = {7}, pages = {632-641}, doi = {10.1016/j.neurol.2024.01.006}, pmid = {38553272}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/pathology ; Male ; Middle Aged ; Female ; Aged ; *Evoked Potentials, Motor/physiology ; *Motor Neurons/physiology ; Adult ; *Lower Extremity/physiopathology ; Electromyography/methods ; Reflex, Stretch/physiology ; Aged, 80 and over ; Sensitivity and Specificity ; Reflex/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) diagnosis relies on signs of progressive damage to both lower motoneuron (LMN), given by clinical examination and electromyography (EMG), and upper motoneuron (UMN), given by clinical examination only. Recognition of UMN involvement, however, is still difficult, so that diagnostic delay often remains too long. Shortening the time to clinical and genetic diagnosis is essential in order to provide accurate information to patients and families, avoid time-consuming investigations and for appropriate care management. This study investigates whether combined patellar tendon reflex recording with motor-evoked potentials to the lower limbs (T-MEP-LL) is relevant to assess corticospinal function in ALS, so that it might serve as a tool improving diagnosis. T-MEP-LL were recorded in 135 patients with suspected motor neuron disease (MND) from February 2010 to March 2021. The sensitivity, specificity, and ability to improve diagnosis when added to Awaji and Gold Coast criteria were determined. The main finding of the study is that T-MEP-LL can detect UMN dysfunction with a 70% sensitivity and 63% specificity when UMN clinical signs are lacking. The sensitivity reaches 82% when considering all MND patients. Moreover, at first evaluation, using T-MEP-LL to quantify reflex briskness and to measure central conduction time, can improve the diagnostic accuracy. T-MEP-LL is easy to perform and does not need any electrical stimulation, making the test rapid, and painless. By the simultaneous quantification of both UMN and LMN system, it could also help to identify different phenotype with more accuracy than clinical examination in this broad-spectrum pathology. The question whether T-MEP-LL could further be a real biomarker need further prospective studies.}, } @article {pmid38552851, year = {2024}, author = {Yang, L and Guttman, L and Dawson, VL and Dawson, TM}, title = {Parthanatos: Mechanisms, modulation, and therapeutic prospects in neurodegenerative disease and stroke.}, journal = {Biochemical pharmacology}, volume = {228}, number = {}, pages = {116174}, pmid = {38552851}, issn = {1873-2968}, support = {R01 AG085688/AG/NIA NIH HHS/United States ; R01 NS067525/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Stroke/drug therapy/metabolism/therapy ; *Parthanatos/drug effects/physiology ; Neuroprotective Agents/therapeutic use ; }, abstract = {Parthanatos is a cell death signaling pathway that has emerged as a compelling target for pharmaceutical intervention. It plays a pivotal role in the neuron loss and neuroinflammation that occurs in Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), and stroke. There are currently no treatments available to humans to prevent cell death in any of these diseases. This review provides an in-depth examination of the current understanding of the Parthanatos mechanism, with a particular focus on its implications in neuroinflammation and various diseases discussed herein. Furthermore, we thoroughly review potential intervention targets within the Parthanatos pathway. We dissect recent progress in inhibitory strategies, complimented by a detailed structural analysis of key Parthanatos executioners, PARP-1, AIF, and MIF, along with an assessment of their established inhibitors. We hope to introduce a new perspective on the feasibility of targeting components within the Parthanatos pathway, emphasizing its potential to bring about transformative outcomes in therapeutic interventions. By delineating therapeutic opportunities and known targets, we seek to emphasize the imperative of blocking Parthanatos as a precursor to developing disease-modifying treatments. This comprehensive exploration aims to catalyze a paradigm shift in our understanding of potential neurodegenerative disease therapeutics, advocating for the pursuit of effective interventions centered around Parthanatos inhibition.}, } @article {pmid38552475, year = {2024}, author = {Offroy, M and Marchetti, M and Kauffmann, TH and Bourson, P and Duponchel, L and Savarese, L and Mechling, JM}, title = {Using clustering as pre-processing in the framework of signal unmixing for exhaustive exploration of archaeological artefacts in Raman imaging.}, journal = {Talanta}, volume = {274}, number = {}, pages = {125955}, doi = {10.1016/j.talanta.2024.125955}, pmid = {38552475}, issn = {1873-3573}, abstract = {Analytical chemistry on archaeological material is an essential part of modern archaeological investigations and from year to year, instrumental improvement has made it possible to generate data at a high spatial and temporal frequency. In particular, Raman spectral imaging can be successfully applied in archaeological research by its simplicity of implementation to study past human societies through the analysis of their material remains. This technique makes it possible to simultaneously obtain spatial and spectral information by preserving sample integrity. However, because of the inherent complexity of the samples in Archaeology (e.g. seniority, fragility, lack or full absence of any information about its composition), chemical interpretation can be difficult at first glance. Indeed, specific problems of spectral selectivity related to unexpected chemical compounds could appear due to their state of conservation. Furthermore, detecting minor compounds becomes challenging as major components impose their contributions in the acquired spectra. Therefore, a relevant chemometric approach has been introduced in this context to characterize distinct spectral sources in a Raman imaging dataset of an archaeological specimen - a mosaic fragment. The fragment was unearthed during the Ruscino archaeological dig on the outskirts of Perpignan, France. It dates back to the oppidum period. The aim is to extract selective spectral information from pixel clustering analysis in order to enhance the initial optimisation step within the Multivariate Curve Resolution and Alternating Least-Squares (MCR-ALS) algorithm, a well-known signal unmixing technique. The underlying principle of the MCR-ALS is that the acquired spectra can be expressed as linear combinations of pure spectra of all individual components present in the chemical system under study. Sometimes it can be difficult to obtain the desired results through the algorithm, particularly if initial estimates of spectral or concentration profiles are inaccurate due to complex signals, noise or lack of selectivity, resulting in rank deficiency (i.e. a poor estimation of the total number of pure signals). For this reason, an innovative threshold-based clustering algorithm, combined with multiple Orthogonal Projection Approaches (OPA), has been developed to improve matrix rank investigation and thus the initialisation step of the MCR-ALS approach before optimisation. The effective analysis of Raman imaging data for an archaeological mosaic played a crucial role in uncovering significant chemical information about a particular biogenic material. This insight sheds light on the origins of mortar manufacture during the oppidum period.}, } @article {pmid38552376, year = {2024}, author = {Donayeva, A and Abdelazim, IA and Amanzholkyzy, A}, title = {Regarding cornual pregnancy as a rare entity of ectopic pregnancy: A case report.}, journal = {International journal of surgery case reports}, volume = {118}, number = {}, pages = {109574}, pmid = {38552376}, issn = {2210-2612}, abstract = {The published Toumi et al's article is somewhat confusing to the readers. The cornual pregnancy (CP) defined as a pregnancy that occurs in a rudimentary horn of a uterus with a Müllerian anomaly according to William's textbook. The interstitial ectopic pregnancy (IEP) occurs in the interstitial part of the fallopian tube where it crosses the uterine muscular to enter the uterine cavity. The IEP sonographic findings include an empty uterus with an eccentrically placed gestational sac, located ≥1 cm from the endometrial margin and bordered by ≤ 5 mm myometrial rim.}, } @article {pmid38551974, year = {2024}, author = {Jiménez-García, AM and Bonnel, G and Álvarez-Mota, A and Arias, N}, title = {Current perspectives on neuromodulation in ALS patients: A systematic review and meta-analysis.}, journal = {PloS one}, volume = {19}, number = {3}, pages = {e0300671}, pmid = {38551974}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Quality of Life ; *Neurodegenerative Diseases ; Exercise Therapy/methods ; Muscle Spasticity ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, resulting in muscle weakness, paralysis, and eventually patient mortality. In recent years, neuromodulation techniques have emerged as promising potential therapeutic approaches to slow disease progression and improve the quality of life of ALS patients. A systematic review was conducted until August 8, 2023, to evaluate the neuromodulation methods used and their potential in the treatment of ALS. The search strategy was applied in the Cochrane Central database, incorporating results from other databases such as PubMed, Embase, CTgov, CINAHL, and ICTRP. Following the exclusion of papers that did not fulfil the inclusion criteria, a total of 2090 records were found, leaving a total of 10 studies. R software was used to conduct meta-analyses based on the effect sizes between the experimental and control groups. This revealed differences in muscle stretch measures with manual muscle testing (p = 0.012) and resting motor threshold (p = 0.0457), but not with voluntary isometric contraction (p = 0.1883). The functionality of ALS was also different (p = 0.007), but not the quality of life. Although intracortical facilitation was not seen in motor cortex 1 (M1) (p = 0.1338), short-interval intracortical inhibition of M1 was significant (p = 0.0001). BDNF showed no differences that were statistically significant (p = 0.2297). Neuromodulation-based treatments are proposed as a promising therapeutic approach for ALS that can produce effects on muscle function, spasticity, and intracortical connections through electrical, magnetic, and photonic stimulation. Photobiomodulation stands out as an innovative approach that uses specific wavelengths to influence mitochondria, with the aim of improving mitochondrial function and reducing excitotoxicity. The lack of reliable placebo controls and the variation in stimulation frequency are some of the drawbacks of neuromodulation.}, } @article {pmid38550565, year = {2024}, author = {Di Nardo, AA and Prochiantz, A}, title = {Therapeutic value of homeoprotein signaling pathways.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1359523}, pmid = {38550565}, issn = {1662-4548}, abstract = {Cell signaling based on homeoprotein transfer is a pathway with developmental and physiological functions. For a few transcription factors of this family, primarily ENGRAILED1, ENGRAILED2 and OTX2, their physiological functions have led to therapeutic strategies in animal models of human diseases, including Parkinson's disease, amyotrophic lateral sclerosis, amblyopia and anxiety-related disorders. In mesencephalic dopaminergic neurons which degenerate in Parkinson's disease, ENGRAILED1/2 have cell autonomous activities, but their transducing properties enables their use as therapeutic proteins. In contrast, in spinal alpha-motoneurons, which are lost in amyotrophic lateral sclerosis, ENGRAILED1 is supplied by V1 interneurons. Thus, its use as a therapeutic protein to protect alpha-motoneurons against degeneration mimics its normal non-cell autonomous neurotrophic activity. OTX2, synthesized and secreted by the choroid plexus, is transferred to parvalbumin interneurons and exerts regulatory functions controlling cerebral cortex plasticity. Understanding the latter OTX2 function has led to strategies for manipulating visual acuity and anxiety-like behavior in adult mice. In this review, we describe these cases and what is known about the involved molecular mechanisms. Because the transduction sequences are conserved in most of the few hundred homeoproteins, we argue how this family of molecules constitutes an important reservoir of physiological knowledge, with potential consequences in the search for new therapeutic strategies.}, } @article {pmid38549627, year = {2024}, author = {Turner, M and Belli, A and Castellani, RJ}, title = {Changes in Brain Structure and Function in a Multisport Cohort of Retired Female and Male Athletes, Many Years after Suffering a Concussion: Implications for Neuroplasticity and Neurodegenerative Disease Pathogenesis.}, journal = {Journal of Alzheimer's disease reports}, volume = {8}, number = {1}, pages = {501-516}, pmid = {38549627}, issn = {2542-4823}, support = {P30 AG072977/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Cumulative effects of traumatic brain injury is of increasing concern, especially with respect to its role in the etiology and pathogenesis of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

OBJECTIVE: Compare regional brain volume and connectivity between athletes with a history of concussion and controls.

METHODS: We evaluated whole-brain volumetric effects with Bayesian regression models and functional connectivity with network-based statistics, in 125 retired athletes (a mean of 11 reported concussions) and 36 matched controls.

RESULTS: Brain regions significantly lower in volume in the concussed group included the middle frontal gyrus, hippocampus, supramarginal gyrus, temporal pole, and inferior frontal gyrus. Conversely, brain regions significantly larger included the hippocampal and collateral sulcus, middle occipital gyrus, medial orbital gyrus, caudate nucleus, lateral orbital gyrus, and medial postcentral gyrus. Functional connectivity analyses revealed increased edge strength, most marked in motor domains. Numerous edges of this network strengthened in athletes were significantly weakened with concussion. Aligned to meta-analytic neuroimaging data, the observed changes suggest functional enhancement within the motor, sensory, coordination, balance, and visual processing domains in athletes, attenuated by concussive head injury with a negative impact on memory and language.

CONCLUSIONS: These findings suggest that engagement in sport may benefit the brain across numerous domains, but also highlights the potentially damaging effects of concussive head injury. Future studies with longitudinal cohorts including autopsy examination are needed to determine whether the latter reflects tissue loss from brain shearing, or the onset of a progressive Alzheimer's disease like proteinopathy.}, } @article {pmid38548902, year = {2024}, author = {Cicardi, ME and Kankate, V and Sriramoji, S and Krishnamurthy, K and Markandaiah, SS and Verdone, BM and Girdhar, A and Nelson, A and Rivas, LB and Boehringer, A and Haeusler, AR and Pasinelli, P and Guo, L and Trotti, D}, title = {The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD.}, journal = {Communications biology}, volume = {7}, number = {1}, pages = {376}, pmid = {38548902}, issn = {2399-3642}, support = {RF1 NS114128/NS/NINDS NIH HHS/United States ; R21 NS090912/NS/NINDS NIH HHS/United States ; RF1 AG057882/AG/NIA NIH HHS/United States ; R01 NS109150/NS/NINDS NIH HHS/United States ; R35 GM138109/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Active Transport, Cell Nucleus ; C9orf72 Protein/genetics ; DNA-Binding Proteins/genetics/metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism ; }, abstract = {Expanded intronic G4C2 repeats in the C9ORF72 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These intronic repeats are translated through a non-AUG-dependent mechanism into five different dipeptide repeat proteins (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone and neurotoxic. Here, we report that Kapβ2 and GR interact, co-aggregating, in cultured neurons in-vitro and CNS tissue in-vivo. Importantly, this interaction significantly decreased the risk of death of cultured GR-expressing neurons. Downregulation of Kapβ2 is detrimental to their survival, whereas increased Kapβ2 levels mitigated GR-mediated neurotoxicity. As expected, GR-expressing neurons displayed TDP-43 nuclear loss. Raising Kapβ2 levels did not restore TDP-43 into the nucleus, nor did alter the dynamic properties of GR aggregates. Overall, our findings support the design of therapeutic strategies aimed at up-regulating Kapβ2 expression levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD.}, } @article {pmid38548323, year = {2024}, author = {Goldacre, R and Trubshaw, M and Morris, EJA and Talbot, K and Goldacre, MJ and Thompson, AG and Turner, MR}, title = {Venous thromboembolism risk in amyotrophic lateral sclerosis: a hospital record-linkage study.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {10}, pages = {912-918}, pmid = {38548323}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/complications ; *Venous Thromboembolism/epidemiology/prevention & control ; Male ; Female ; Aged ; Middle Aged ; Retrospective Studies ; Incidence ; England/epidemiology ; Risk Factors ; Adult ; Aged, 80 and over ; Medical Record Linkage ; Case-Control Studies ; Pulmonary Embolism/epidemiology ; }, abstract = {BACKGROUND: Venous thromboembolism (VTE) can occur in amyotrophic lateral sclerosis (ALS) and pulmonary embolism causes death in a minority of cases. The benefits of preventing VTE must be weighed against the risks. An accurate estimate of the incidence of VTE in ALS is crucial to assessing this balance.

METHODS: This retrospective record-linkage cohort study derived data from the Hospital Episode Statistics database, covering admissions to England's hospitals from 1 April 2003 to 31 December 2019 and included 21 163 patients with ALS and 17 425 337 controls. Follow-up began at index admission and ended at VTE admission, death or 2 years (whichever came sooner). Adjusted HRs (aHRs) for VTE were calculated, controlling for confounders.

RESULTS: The incidence of VTE in the ALS cohort was 18.8/1000 person-years. The relative risk of VTE in ALS was significantly greater than in controls (aHR 2.7, 95% CI 2.4 to 3.0). The relative risk of VTE in patients with ALS under 65 years was five times higher than controls (aHR 5.34, 95% CI 4.6 to 6.2), and higher than that of patients over 65 years compared with controls (aHR 1.86, 95% CI 1.62 to 2.12).

CONCLUSIONS: Patients with ALS are at a higher risk of developing VTE, but this is similar in magnitude to that reported in other chronic neurological conditions associated with immobility, such as multiple sclerosis, which do not routinely receive VTE prophylaxis. Those with ALS below the median age of symptom onset have a notably higher relative risk. A reappraisal of the case for routine antithrombotic therapy in those diagnosed with ALS now requires a randomised controlled trial.}, } @article {pmid38548305, year = {2024}, author = {Tilsley, P and Moutiez, A and Brodovitch, A and Mendili, MME and Testud, B and Zaaraoui, W and Verschueren, A and Attarian, S and Guye, M and Boucraut, J and Grapperon, AM and Stellmann, JP}, title = {Neurofilament Light Chain Levels Interact with Neurodegenerative Patterns and Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {AJNR. American journal of neuroradiology}, volume = {45}, number = {4}, pages = {494-503}, pmid = {38548305}, issn = {1936-959X}, mesh = {Male ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Retrospective Studies ; Prospective Studies ; *Neurodegenerative Diseases ; Intermediate Filaments ; Motor Neurons/pathology ; Magnetic Resonance Imaging/methods ; Atrophy/pathology ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving rapid motor neuron degeneration leading to brain, primarily precentral, atrophy. Neurofilament light chains are a robust prognostic biomarker highly specific to ALS, yet associations between neurofilament light chains and MR imaging outcomes are not well-understood. We investigated the role of neurofilament light chains as mediators among neuroradiologic assessments, precentral neurodegeneration, and disability in ALS.

MATERIALS AND METHODS: We retrospectively analyzed a prospective cohort of 29 patients with ALS (mean age, 56 [SD, 12] years; 18 men) and 36 controls (mean age, 49 [SD, 11] years; 18 men). Patients underwent 3T (n = 19) or 7T (n = 10) MR imaging, serum (n = 23) and CSF (n = 15) neurofilament light chains, and clinical (n = 29) and electrophysiologic (n = 27) assessments. The control group had equivalent 3T (n = 25) or 7T (n = 11) MR imaging. Two trained neuroradiologists performed blinded qualitative assessments of MR imaging anomalies (n = 29 patients, n = 36 controls). Associations between precentral cortical thickness and neurofilament light chains and clinical and electrophysiologic data were analyzed.

RESULTS: We observed extensive cortical thinning in patients compared with controls. MR imaging analyses showed significant associations between precentral cortical thickness and bulbar or arm impairment following distributions corresponding to the motor homunculus. Finally, uncorrected results showed positive interactions among precentral cortical thickness, serum neurofilament light chains, and electrophysiologic outcomes. Qualitative MR imaging anomalies including global atrophy (P = .003) and FLAIR corticospinal tract hypersignal anomalies (P = .033), correlated positively with serum neurofilament light chains.

CONCLUSIONS: Serum neurofilament light chains may be an important mediator between clinical symptoms and neuronal loss according to cortical thickness. Furthermore, MR imaging anomalies might have underestimated prognostic value because they seem to indicate higher serum neurofilament light chain levels.}, } @article {pmid38548126, year = {2024}, author = {Krut', VG and Kalinichenko, AL and Maltsev, DI and Jappy, D and Shevchenko, EK and Podgorny, OV and Belousov, VV}, title = {Optogenetic and chemogenetic approaches for modeling neurological disorders in vivo.}, journal = {Progress in neurobiology}, volume = {235}, number = {}, pages = {102600}, doi = {10.1016/j.pneurobio.2024.102600}, pmid = {38548126}, issn = {1873-5118}, mesh = {Animals ; Humans ; Optogenetics/methods ; *Epilepsy ; Models, Animal ; *Parkinson Disease ; Neuropathology ; }, abstract = {Animal models of human neurological disorders provide valuable experimental tools which enable us to study various aspects of disorder pathogeneses, ranging from structural abnormalities and disrupted metabolism and signaling to motor and mental deficits, and allow us to test novel therapies in preclinical studies. To be valid, these animal models should recapitulate complex pathological features at the molecular, cellular, tissue, and behavioral levels as closely as possible to those observed in human subjects. Pathological states resembling known human neurological disorders can be induced in animal species by toxins, genetic factors, lesioning, or exposure to extreme conditions. In recent years, novel animal models recapitulating neuropathologies in humans have been introduced. These animal models are based on synthetic biology approaches: opto- and chemogenetics. In this paper, we review recent opto- and chemogenetics-based animal models of human neurological disorders. These models allow for the creation of pathological states by disrupting specific processes at the cellular level. The artificial pathological states mimic a range of human neurological disorders, such as aging-related dementia, Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, epilepsy, and ataxias. Opto- and chemogenetics provide new opportunities unavailable with other animal models of human neurological disorders. These techniques enable researchers to induce neuropathological states varying in severity and ranging from acute to chronic. We also discuss future directions for the development and application of synthetic biology approaches for modeling neurological disorders.}, } @article {pmid38544185, year = {2024}, author = {Albán-Escobar, M and Navarrete-Arroyo, P and De la Cruz-Guevara, DR and Tobar-Quevedo, J}, title = {Assistance Device Based on SSVEP-BCI Online to Control a 6-DOF Robotic Arm.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {6}, pages = {}, pmid = {38544185}, issn = {1424-8220}, mesh = {Humans ; *Brain-Computer Interfaces ; *Robotic Surgical Procedures ; Electroencephalography/methods ; *Self-Help Devices ; Evoked Potentials, Visual ; Photic Stimulation ; }, abstract = {This paper explores the potential benefits of integrating a brain-computer interface (BCI) utilizing the visual-evoked potential paradigm (SSVEP) with a six-degrees-of-freedom (6-DOF) robotic arm to enhance rehabilitation tools. The SSVEP-BCI employs electroencephalography (EEG) as a method of measuring neural responses inside the occipital lobe in reaction to pre-established visual stimulus frequencies. The BCI offline and online studies yielded accuracy rates of 75% and 83%, respectively, indicating the efficacy of the system in accurately detecting and capturing user intent. The robotic arm achieves planar motion by utilizing a total of five control frequencies. The results of this experiment exhibited a high level of precision and consistency, as indicated by the recorded values of ±0.85 and ±1.49 cm for accuracy and repeatability, respectively. Moreover, during the performance tests conducted with the task of constructing a square within each plane, the system demonstrated accuracy of 79% and 83%. The use of SSVEP-BCI and a robotic arm together shows promise and sets a solid foundation for the development of assistive technologies that aim to improve the health of people with amyotrophic lateral sclerosis, spina bifida, and other related diseases.}, } @article {pmid38542501, year = {2024}, author = {Niu, Y and Pal, A and Szewczyk, B and Japtok, J and Naumann, M and Glaß, H and Hermann, A}, title = {Cell-Type-Dependent Recruitment Dynamics of FUS Protein at Laser-Induced DNA Damage Sites.}, journal = {International journal of molecular sciences}, volume = {25}, number = {6}, pages = {}, pmid = {38542501}, issn = {1422-0067}, support = {na//Nomis Foundation/ ; na//Hermann und Lilly Schilling-Stiftung/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; DNA Damage ; Mutation ; }, abstract = {Increased signs of DNA damage have been associated to aging and neurodegenerative diseases. DNA damage repair mechanisms are tightly regulated and involve different pathways depending on cell types and proliferative vs. postmitotic states. Amongst them, fused in sarcoma (FUS) was reported to be involved in different pathways of single- and double-strand break repair, including an early recruitment to DNA damage. FUS is a ubiquitously expressed protein, but if mutated, leads to a more or less selective motor neurodegeneration, causing amyotrophic lateral sclerosis (ALS). Of note, ALS-causing mutation leads to impaired DNA damage repair. We thus asked whether FUS recruitment dynamics differ across different cell types putatively contributing to such cell-type-specific vulnerability. For this, we generated engineered human induced pluripotent stem cells carrying wild-type FUS-eGFP and analyzed different derivatives from these, combining a laser micro-irradiation technique and a workflow to analyze the real-time process of FUS at DNA damage sites. All cells showed FUS recruitment to DNA damage sites except for hiPSC, with only 70% of cells recruiting FUS. In-depth analysis of the kinetics of FUS recruitment at DNA damage sites revealed differences among cellular types in response to laser-irradiation-induced DNA damage. Our work suggests a cell-type-dependent recruitment behavior of FUS during the DNA damage response and repair procedure. The presented workflow might be a valuable tool for studying the proteins recruited at the DNA damage site in a real-time course.}, } @article {pmid38542497, year = {2024}, author = {Nemeth, C and Banik, NL and Haque, A}, title = {Disruption of Neuromuscular Junction Following Spinal Cord Injury and Motor Neuron Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {6}, pages = {}, pmid = {38542497}, issn = {1422-0067}, support = {R21 NS118393/NS/NINDS NIH HHS/United States ; I01 BX001262/BX/BLRD VA/United States ; 1R21NS118393-01/NH/NIH HHS/United States ; I01 BX004269/BX/BLRD VA/United States ; I01 BX006101/BX/BLRD VA/United States ; IK6 BX005964/BX/BLRD VA/United States ; }, mesh = {Humans ; Neuromuscular Junction/metabolism ; Motor Neurons/metabolism ; Muscle Fibers, Skeletal/metabolism ; Spinal Cord/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *Spinal Cord Injuries/metabolism ; }, abstract = {The neuromuscular junction (NMJ) is a crucial structure that connects the cholinergic motor neurons to the muscle fibers and allows for muscle contraction and movement. Despite the interruption of the supraspinal pathways that occurs in spinal cord injury (SCI), the NMJ, innervated by motor neurons below the injury site, has been found to remain intact. This highlights the importance of studying the NMJ in rodent models of various nervous system disorders, such as amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease (CMT), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). The NMJ is also involved in myasthenic disorders, such as myasthenia gravis (MG), and is vulnerable to neurotoxin damage. Thus, it is important to analyze the integrity of the NMJ in rodent models during the early stages of the disease, as this may allow for a better understanding of the condition and potential treatment options. The spinal cord also plays a crucial role in the functioning of the NMJ, as the junction relays information from the spinal cord to the muscle fibers, and the integrity of the NMJ could be disrupted by SCI. Therefore, it is vital to study SCI and muscle function when studying NMJ disorders. This review discusses the formation and function of the NMJ after SCI and potential interventions that may reverse or improve NMJ dysfunction, such as exercise, nutrition, and trophic factors.}, } @article {pmid38542306, year = {2024}, author = {Marshall Moscon, SL and Connor, JR}, title = {HFE Mutations in Neurodegenerative Disease as a Model of Hormesis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {6}, pages = {}, pmid = {38542306}, issn = {1422-0067}, mesh = {Mice ; Animals ; *Neurodegenerative Diseases/genetics ; Hemochromatosis Protein/genetics ; Histocompatibility Antigens Class I/genetics ; Hormesis ; Mutation ; Iron/metabolism ; }, abstract = {Common variants in the iron regulatory protein HFE contribute to systematically increased iron levels, yet the effects in the brain are not fully characterized. It is commonly believed that iron dysregulation is a key contributor to neurodegenerative disease due to iron's ability to catalyze reactive oxygen species production. However, whether HFE variants exacerbate or protect against neurodegeneration has been heavily debated. Some claim that mutated HFE exacerbates oxidative stress and neuroinflammation, thus predisposing carriers to neurodegeneration-linked pathologies. However, H63D HFE has also been shown to slow the progression of multiple neurodegenerative diseases and to protect against environmental toxins that cause neurodegeneration. These conflicting results showcase the need to further understand the contribution of HFE variants to neurodegenerative disease heterogeneity. Data from mouse models consistently demonstrate robust neuroprotection against toxins known to increase the risk of neurodegenerative disease. This may represent an adaptive, or hormetic, response to increased iron, which leaves cells better protected against future stressors. This review describes the current research regarding the contribution of HFE variants to neurodegenerative disease prognosis in the context of a hormetic model. To our knowledge, this is the first time that a hormetic model for neurodegenerative disease has been presented.}, } @article {pmid38542223, year = {2024}, author = {Salvatori, I and Nesci, V and Spalloni, A and Marabitti, V and Muzzi, M and Zenuni, H and Scaricamazza, S and Rosina, M and Fenili, G and Goglia, M and Boffa, L and Massa, R and Moreno, S and Mercuri, NB and Nazio, F and Longone, P and Ferri, A and Valle, C}, title = {Trimetazidine Improves Mitochondrial Dysfunction in SOD1[G93A] Cellular Models of Amyotrophic Lateral Sclerosis through Autophagy Activation.}, journal = {International journal of molecular sciences}, volume = {25}, number = {6}, pages = {}, pmid = {38542223}, issn = {1422-0067}, support = {CNR IFT DBA.AD005.225 -NUTRAGE- FOE2021//National Research Council/ ; RF-2019-12369105//Ministero della Salute/ ; HyperALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; 'Unraveling the protective effects of NOS1AP in the rescue of TDP-43 loss of function pathological mechanisms//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; Ref. 27019//Italian Association for Cancer Research/ ; Prot. GeCoWEB n. A0375-2020- 36668//Regione Lazio/ ; The Grant of Excellence Departments 2023-2027//Ministero dell'Università e Ricerca Italy/ ; }, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/metabolism ; *Trimetazidine/pharmacology/therapeutic use ; Mice, Transgenic ; Leukocytes, Mononuclear/metabolism ; Superoxide Dismutase/metabolism ; Autophagy ; *Mitochondrial Diseases ; Disease Models, Animal ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is considered the prototype of motor neuron disease, characterized by motor neuron loss and muscle waste. A well-established pathogenic hallmark of ALS is mitochondrial failure, leading to bioenergetic deficits. So far, pharmacological interventions for the disease have proven ineffective. Trimetazidine (TMZ) is described as a metabolic modulator acting on different cellular pathways. Its efficacy in enhancing muscular and cardiovascular performance has been widely described, although its molecular target remains elusive. We addressed the molecular mechanisms underlying TMZ action on neuronal experimental paradigms. To this aim, we treated murine SOD1[G93A]-model-derived primary cultures of cortical and spinal enriched motor neurons, as well as a murine motor-neuron-like cell line overexpressing SOD1[G93A], with TMZ. We first characterized the bioenergetic profile of the cell cultures, demonstrating significant mitochondrial dysfunction that is reversed by acute TMZ treatments. We then investigated the effect of TMZ in promoting autophagy processes and its impact on mitochondrial morphology. Finally, we demonstrated the effectiveness of TMZ in terms of the mitochondrial functionality of ALS-rpatient-derived peripheral blood mononuclear cells (PBMCs). In summary, our results emphasize the concept that targeting mitochondrial dysfunction may represent an effective therapeutic strategy for ALS. The findings demonstrate that TMZ enhances mitochondrial performance in motor neuron cells by activating autophagy processes, particularly mitophagy. Although further investigations are needed to elucidate the precise molecular pathways involved, these results hold critical implications for the development of more effective and specific derivatives of TMZ for ALS treatment.}, } @article {pmid38540795, year = {2024}, author = {Gascón, E and Zaragoza, P and Calvo, AC and Osta, R}, title = {Sporadic Amyotrophic Lateral Sclerosis Skeletal Muscle Transcriptome Analysis: A Comprehensive Examination of Differentially Expressed Genes.}, journal = {Biomolecules}, volume = {14}, number = {3}, pages = {}, pmid = {38540795}, issn = {2218-273X}, support = {PI17/00949//Instituto de Salud Carlos III/ ; A19_23R//"LAGENBIO GRUPO INVESTIGACION"/ ; CIBER-358 NED-612-CB18/05/00037//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; }, mesh = {Humans ; Transcriptome/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; Muscle, Skeletal/metabolism ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) that comprises sporadic (sALS) and familial (fALS) cases, is a devastating neurodegenerative disorder characterized by progressive degeneration of motor neurons, leading to muscle atrophy and various clinical manifestations. However, the complex underlying mechanisms affecting this disease are not yet known. On the other hand, there is also no good prognosis of the disease due to the lack of biomarkers and therapeutic targets. Therefore, in this study, by means of bioinformatics analysis, sALS-affected muscle tissue was analyzed using the GEO GSE41414 dataset, identifying 397 differentially expressed genes (DEGs). Functional analysis revealed 320 up-regulated DEGs associated with muscle development and 77 down-regulated DEGs linked to energy metabolism. Protein-protein interaction network analysis identified 20 hub genes, including EIF4A1, HNRNPR and NDUFA4. Furthermore, miRNA target gene networks revealed 17 miRNAs linked to hub genes, with hsa-mir-206, hsa-mir-133b and hsa-mir-100-5p having been previously implicated in ALS. This study presents new potential biomarkers and therapeutic targets for ALS by correlating the information obtained with a comprehensive literature review, providing new potential targets to study their role in ALS.}, } @article {pmid38540776, year = {2024}, author = {Hughes, LS and Fröhlich, A and Pfaff, AL and Bubb, VJ and Quinn, JP and Kõks, S}, title = {Exploring SVA Insertion Polymorphisms in Shaping Differential Gene Expressions in the Central Nervous System.}, journal = {Biomolecules}, volume = {14}, number = {3}, pages = {}, pmid = {38540776}, issn = {2218-273X}, support = {1234//Andrzej Wlodarski Memorial Research Fund/ ; 1234//Multiple Sclerosis Western Australia/ ; }, mesh = {Humans ; *Retroelements ; *Amyotrophic Lateral Sclerosis/genetics ; Minisatellite Repeats ; DNA Transposable Elements ; Central Nervous System ; Gene Expression ; }, abstract = {Transposable elements (TEs) are repetitive elements which make up around 45% of the human genome. A class of TEs, known as SINE-VNTR-Alu (SVA), demonstrate the capacity to mobilise throughout the genome, resulting in SVA polymorphisms for their presence or absence within the population. Although studies have previously highlighted the involvement of TEs within neurodegenerative diseases, such as Parkinson's disease and amyotrophic lateral sclerosis (ALS), the exact mechanism has yet to be identified. In this study, we used whole-genome sequencing and RNA sequencing data of ALS patients and healthy controls from the New York Genome Centre ALS Consortium to elucidate the influence of reference SVA elements on gene expressions genome-wide within central nervous system (CNS) tissues. To investigate this, we applied a matrix expression quantitative trait loci analysis and demonstrate that reference SVA insertion polymorphisms can significantly modulate the expression of numerous genes, preferentially in the trans position and in a tissue-specific manner. We also highlight that SVAs significantly regulate mitochondrial genes as well as genes within the HLA and MAPT loci, previously associated within neurodegenerative diseases. In conclusion, this study continues to bring to light the effects of polymorphic SVAs on gene regulation and further highlights the importance of TEs within disease pathology.}, } @article {pmid38540709, year = {2024}, author = {Stoklund Dittlau, K and Freude, K}, title = {Astrocytes: The Stars in Neurodegeneration?.}, journal = {Biomolecules}, volume = {14}, number = {3}, pages = {}, pmid = {38540709}, issn = {2218-273X}, support = {R434-2023-242//Lundbeck Foundation/ ; 2078-00002B//Innovation Fund Denmark/ ; NNF21OC0071571//Novo Nordisk Foundation/ ; N/A//Alzheimer Foundation Denmark/ ; }, mesh = {Humans ; Astrocytes/physiology ; *Neurodegenerative Diseases ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis/therapy ; }, abstract = {Today, neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) affect millions of people worldwide, and as the average human lifespan increases, similarly grows the number of patients. For many decades, cognitive and motoric decline has been explained by the very apparent deterioration of neurons in various regions of the brain and spinal cord. However, more recent studies show that disease progression is greatly influenced by the vast population of glial cells. Astrocytes are traditionally considered star-shaped cells on which neurons rely heavily for their optimal homeostasis and survival. Increasing amounts of evidence depict how astrocytes lose their supportive functions while simultaneously gaining toxic properties during neurodegeneration. Many of these changes are similar across various neurodegenerative diseases, and in this review, we highlight these commonalities. We discuss how astrocyte dysfunction drives neuronal demise across a wide range of neurodegenerative diseases, but rather than categorizing based on disease, we aim to provide an overview based on currently known mechanisms. As such, this review delivers a different perspective on the disease causes of neurodegeneration in the hope to encourage further cross-disease studies into shared disease mechanisms, which might ultimately disclose potentially common therapeutic entry points across a wide panel of neurodegenerative diseases.}, } @article {pmid38540591, year = {2024}, author = {Brito, O and Fregonezi, G and Pondofe, K and Vieira, RGDS and Ribeiro, T and Dourado Júnior, ME and Fidelix, EC and Nagem, D and Valentim, R and Sarmento, A and Resqueti, V}, title = {Assessment of the Clinical and Functional Health Status of Patients with Amyotrophic Lateral Sclerosis during the COVID-19 Pandemic in Brazil Using Telemedicine.}, journal = {Healthcare (Basel, Switzerland)}, volume = {12}, number = {6}, pages = {}, pmid = {38540591}, issn = {2227-9032}, support = {2021OB805920//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 305960/2021-0//National Council for Scientific and Technological Development/ ; 316937/2021-5//National Council for Scientific and Technological Development/ ; }, abstract = {This study aimed to monitor the clinical and functional progression of patients with amyotrophic lateral sclerosis (ALS) and adjust ventilatory support during the COVID-19 pandemic in Brazil using telemedicine. This longitudinal case series included five evaluations from January 2019 to June 2021. The first and second assessments were performed in person and consisted of pulmonary function, respiratory muscle strength, functionality (ALS Functional Rating Scale-Revised [ALSFRS-R]) and disease staging (King's College criteria). The use of non-invasive ventilation (NIV), ALSFRS-R, and disease staging were assessed in the third, fourth, and fifth assessments during the COVID-19 pandemic, using telemedicine. The rate of functional decline was calculated by the difference in the total score of ALSFRS-R between evaluations. A cutoff of 0.77 in the ALSFRS-R was used to characterize the speed of functional decline. Eleven patients (mean age of 51 years, eight males) were assessed. The total score of the ALSFRS-R (p < 0.01) and its motor domain (p < 0.01) reduced significantly during the pandemic. NIV prescription increased from 54.4% to 83.3%. Telemedicine helped with the clinical and functional follow-up of patients with ALS.}, } @article {pmid38540370, year = {2024}, author = {Ivantsik, O and John, A and Kydonopoulou, K and Mitropoulos, K and Gerou, S and Ali, BR and Patrinos, GP}, title = {Novel Pathogenic Variants Leading to Sporadic Amyotrophic Lateral Sclerosis in Greek Patients.}, journal = {Genes}, volume = {15}, number = {3}, pages = {}, pmid = {38540370}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Mutation ; Superoxide Dismutase-1/genetics ; Greece ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease that affects motor neurons, leading to paralysis and death usually 3-5 years after the onset of symptoms. The investigation of both sporadic and familial ALS highlighted four main genes that contribute to the pathogenesis of the disease: SOD1, FUS, TARDBP and C9orf72. This study aims to provide a comprehensive investigation of genetic variants found in SOD1, FUS and TARDBP genes in Greek sporadic ALS (sALS) cases. Our sequencing analysis of the coding regions of the abovementioned genes that include the majority of the variants that lead to ALS in 32 sALS patients and 3 healthy relatives revealed 6 variants in SOD1, 19 variants in FUS and 37 variants in TARDBP, of which the SOD1 p.D90A and the FUS c.*356G>A (rs886051940) variants have been previously associated with ALS, while two novel nonsense pathogenic variants were also identified, namely FUS p.R241* and TDP-43 p.Y214*. Our study contributes to the worldwide effort toward clarifying the genetic basis of sALS to better understand the disease's molecular pathology.}, } @article {pmid38540369, year = {2024}, author = {Souza, PVS and Serrano, PL and Farias, IB and Machado, RIL and Badia, BML and Oliveira, HB and Barbosa, AS and Pereira, CA and Moreira, VF and Chieia, MAT and Barbosa, AR and Braga, VL and Pinto, WBVR and Oliveira, ASB}, title = {Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges.}, journal = {Genes}, volume = {15}, number = {3}, pages = {}, pmid = {38540369}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Motor Neurons ; Neuroimaging ; }, abstract = {Juvenile Amyotrophic Lateral Sclerosis is a genetically heterogeneous neurodegenerative disorder, which is frequently misdiagnosed due to low clinical suspicion and little knowledge about disease characteristics. More than 20 different genetic loci have been associated with both sporadic and familial juvenile Amyotrophic Lateral Sclerosis. Currently, almost 40% of cases have an identifiable monogenic basis; type 6, associated with FUS gene variants, is the most prevalent globally. Despite several upper motor neuron-dominant forms being generally associated with long-standing motor symptoms and slowly progressive course, certain subtypes with lower motor neuron-dominant features and early bulbar compromise lead to rapidly progressive motor handicap. For some monogenic forms, there is a well-established genotypic-phenotypic correlation. There are no specific biochemical and neuroimaging biomarkers for the diagnosis of juvenile Amyotrophic Lateral Sclerosis. There are several inherited neurodegenerative and neurometabolic disorders which can lead to the signs of motor neuron impairment. This review emphasizes the importance of high clinical suspicion, assessment, and proper diagnostic work-up for juvenile Amyotrophic Lateral Sclerosis.}, } @article {pmid38538647, year = {2024}, author = {Wang, X and Chen, H and Chang, Z and Zhang, J and Xie, D}, title = {Genetic causal role of body mass index in multiple neurological diseases.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {7256}, pmid = {38538647}, issn = {2045-2322}, support = {82274493//National Natural Science Foundation of China/ ; 81874389//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Body Mass Index ; *Amyotrophic Lateral Sclerosis/genetics ; Genome-Wide Association Study ; *Nervous System Diseases/genetics ; *Parkinson Disease/genetics ; *Multiple Sclerosis/genetics ; *Alzheimer Disease/genetics ; *Ischemic Stroke ; Mendelian Randomization Analysis ; Obesity/genetics ; }, abstract = {Body mass index (BMI) is a crucial health indicator for obesity. With the progression of socio-economic status and alterations in lifestyle, an increasing number of global populations are at risk of obesity. Given the complexity and severity of neurological diseases, early identification of risk factors is vital for the diagnosis and prognosis of such diseases. In this study, we employed Mendelian randomization (MR) analysis utilizing the most comprehensive genome-wide association study (GWAS) data to date. We selected single nucleotide polymorphisms (SNPs) that are unaffected by confounding factors and reverse causality as instrumental variables. These variables were used to evaluate the genetic and causal relationships between Body Mass Index (BMI) and various neurological diseases, including Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Ischemic Stroke (IS), and Epilepsy (EP). The Inverse Variance Weighted (IVW) analysis indicated that there was no significant causal relationship between Body Mass Index (BMI) indicators and PD (P-value = 0.511), AD (P-value = 0.076), ALS (P-value = 0.641), EP (P-value = 0.380). However, a causal relationship was found between BMI indicators and MS (P-value = 0.035), and IS (P-value = 0.000), with the BMI index positively correlated with the risk of both diseases. The Cochran's Q test for MR-IVW showed no heterogeneity in the MR analysis results between the BMI index and the neurological diseases (P > 0.05). The Egger intercept test for pleiotropy revealed no horizontal pleiotropy detected in any of the neurological diseases studied (P > 0.05). It was found that there was no causal relationship between BMI and PD, AD, ALS, EP, and a genetic causal association with MS, and IS. Meanwhile, the increase in BMI can lead to a higher risk of MS and IS, which reveals the critical role of obesity as a risk factor for specific neurological diseases in the pathogenesis of the diseases.}, } @article {pmid38538275, year = {2024}, author = {Ceccarelli, L and Verriello, L and Pauletto, G and Valente, M and Spadea, L and Salati, C and Zeppieri, M and Ius, T}, title = {The Role of Human Pluripotent Stem Cells in Amyotrophic Lateral Sclerosis: From Biological Mechanism to Practical Implications.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {29}, number = {3}, pages = {114}, doi = {10.31083/j.fbl2903114}, pmid = {38538275}, issn = {2768-6698}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Motor Neurons/metabolism ; *Pluripotent Stem Cells/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder, characterized by progressive loss of both upper and lower motor neurons, resulting in clinical features such as muscle weakness, paralysis, and ultimately, respiratory failure. Nowadays, there is not effective treatment to reverse the progression of the disease, that leads to death within 3-5 years after the onset. Nevertheless, the induced pluripotent stem cells (iPS) technology could be the answer, providing disease modelling, drug testing, and cell-based therapies for this pathology. The aim of this work was to conduct a literature review of the past 5 years about the role of iPS in ALS, to better define the neurobiological mechanisms involved in the pathogenesis and the potential future therapies. The review also deals with advanced and currently available technologies used to reprogram cell lines and generate human motor neurons in vitro, which represent the source to study the pathological processes, the relationship between phenotype and genotype, the disease progression and the potential therapeutic targets of these group of disorders. Specific treatment options with stem cells involve Advance Gene Editing Technology, neuroprotective agents, and cells or exosomes transplantation, aimed to replace dead or damaged nerve cells. In summary, this review comprehensively addresses the role of human pluripotent stem cells (hPSCs) in motor neuron diseases (MND), with a focus on physiopathology, diagnostic and prognostic implications, specific and potential future treatment options. Understanding the biological mechanisms and practical implications of hPSCs in MND is crucial for advancing therapeutic strategies and improving outcomes for patients affected by these devastating diseases.}, } @article {pmid38538227, year = {2024}, author = {Tan, EL and Lope, J and Bede, P}, title = {Harnessing Big Data in Amyotrophic Lateral Sclerosis: Machine Learning Applications for Clinical Practice and Pharmaceutical Trials.}, journal = {Journal of integrative neuroscience}, volume = {23}, number = {3}, pages = {58}, doi = {10.31083/j.jin2303058}, pmid = {38538227}, issn = {0219-6352}, support = {HRB EIA-2017-019/HRBI_/Health Research Board/Ireland ; JPND-Cofund-2-2019-/HRBI_/Health Research Board/Ireland ; SFI SP20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Big Data ; Biomarkers ; Machine Learning ; }, abstract = {The arrival of genotype-specific therapies in amyotrophic lateral sclerosis (ALS) signals the dawn of precision medicine in motor neuron diseases (MNDs). After decades of academic studies in ALS, we are now witnessing tangible clinical advances. An ever increasing number of well-designed descriptive studies have been published in recent years, characterizing typical disease-burden patterns in vivo and post mortem. Phenotype- and genotype-associated traits and "typical" propagation patterns have been described based on longitudinal clinical and biomarker data. The practical caveat of these studies is that they report "group-level", stereotyped trajectories representative of ALS as a whole. In the clinical setting, however, "group-level" biomarker signatures have limited practical relevance and what matters is the meaningful interpretation of data from a single individual. The increasing availability of large normative data sets, national registries, extant academic data, consortium repositories, and emerging data platforms now permit the meaningful interpretation of individual biomarker profiles and allow the categorization of single patients into relevant diagnostic, phenotypic, and prognostic categories. A variety of machine learning (ML) strategies have been recently explored in MND to demonstrate the feasibility of interpreting data from a single patient. Despite the considerable clinical prospects of classification models, a number of pragmatic challenges need to be overcome to unleash the full potential of ML in ALS. Cohort size limitations, administrative hurdles, data harmonization challenges, regulatory differences, methodological obstacles, and financial implications and are just some of the barriers to readily implement ML in routine clinical practice. Despite these challenges, machine-learning strategies are likely to be firmly integrated in clinical decision-making and pharmacological trials in the near future.}, } @article {pmid38536565, year = {2024}, author = {Vernikouskaya, I and Müller, HP and Ludolph, AC and Kassubek, J and Rasche, V}, title = {AI-assisted automatic MRI-based tongue volume evaluation in motor neuron disease (MND).}, journal = {International journal of computer assisted radiology and surgery}, volume = {19}, number = {8}, pages = {1579-1587}, pmid = {38536565}, issn = {1861-6429}, mesh = {Humans ; *Tongue/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; *Motor Neuron Disease/diagnostic imaging/diagnosis ; Male ; Female ; Middle Aged ; Aged ; *Neural Networks, Computer ; Pilot Projects ; Imaging, Three-Dimensional/methods ; Amyotrophic Lateral Sclerosis/diagnostic imaging/diagnosis ; Adult ; }, abstract = {PURPOSE: Motor neuron disease (MND) causes damage to the upper and lower motor neurons including the motor cranial nerves, the latter resulting in bulbar involvement with atrophy of the tongue muscle. To measure tongue atrophy, an operator independent automatic segmentation of the tongue is crucial. The aim of this study was to apply convolutional neural network (CNN) to MRI data in order to determine the volume of the tongue.

METHODS: A single triplanar CNN of U-Net architecture trained on axial, coronal, and sagittal planes was used for the segmentation of the tongue in MRI scans of the head. The 3D volumes were processed slice-wise across the three orientations and the predictions were merged using different voting strategies. This approach was developed using MRI datasets from 20 patients with 'classical' spinal amyotrophic lateral sclerosis (ALS) and 20 healthy controls and, in a pilot study, applied to the tongue volume quantification to 19 controls and 19 ALS patients with the variant progressive bulbar palsy (PBP).

RESULTS: Consensus models with softmax averaging and majority voting achieved highest segmentation accuracy and outperformed predictions on single orientations and consensus models with union and unanimous voting. At the group level, reduction in tongue volume was not observed in classical spinal ALS, but was significant in the PBP group, as compared to controls.

CONCLUSION: Utilizing single U-Net trained on three orthogonal orientations with consequent merging of respective orientations in an optimized consensus model reduces the number of erroneous detections and improves the segmentation of the tongue. The CNN-based automatic segmentation allows for accurate quantification of the tongue volumes in all subjects. The application to the ALS variant PBP showed significant reduction of the tongue volume in these patients and opens the way for unbiased future longitudinal studies in diseases affecting tongue volume.}, } @article {pmid38535081, year = {2024}, author = {Liampas, I and Danga, F and Kyriakoulopoulou, P and Siokas, V and Stamati, P and Messinis, L and Dardiotis, E and Nasios, G}, title = {The Contribution of Functional Near-Infrared Spectroscopy (fNIRS) to the Study of Neurodegenerative Disorders: A Narrative Review.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {14}, number = {6}, pages = {}, pmid = {38535081}, issn = {2075-4418}, abstract = {Functional near-infrared spectroscopy (fNIRS) is an innovative neuroimaging method that offers several advantages over other commonly used modalities. This narrative review investigated the potential contribution of this method to the study of neurodegenerative disorders. Thirty-four studies involving patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), frontotemporal dementia (FTD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS) and healthy controls were reviewed. Overall, it was revealed that the prefrontal cortex of individuals with MCI may engage compensatory mechanisms to support declining brain functions. A rightward shift was suggested to compensate for the loss of the left prefrontal capacity in the course of cognitive decline. In parallel, some studies reported the failure of compensatory mechanisms in MCI and early AD; this lack of appropriate hemodynamic responses may serve as an early biomarker of neurodegeneration. One article assessing FTD demonstrated a heterogeneous cortical activation pattern compared to AD, indicating that fNIRS may contribute to the challenging distinction of these conditions. Regarding PD, there was evidence that cognitive resources (especially executive function) were recruited to compensate for locomotor impairments. As for ALS, fNIRS data support the involvement of extra-motor networks in ALS, even in the absence of measurable cognitive impairment.}, } @article {pmid38535014, year = {2024}, author = {Goudie, A and Blaivas, M and Horn, R and Lien, WC and Michels, G and Wastl, D and Dietrich, CF}, title = {Ultrasound during Advanced Life Support-Help or Harm?.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {14}, number = {6}, pages = {}, pmid = {38535014}, issn = {2075-4418}, abstract = {Ultrasound is used in cardiopulmonary resuscitation (CPR) and advanced life support (ALS). However, there is divergence between the recommendations of many emergency and critical care societies who support its use and the recommendations of many international resuscitation organizations who either recommend against its use or recommend it only in limited circumstances. Ultrasound offers potential benefits of detecting reversable causes of cardiac arrest, allowing specific interventions. However, it also risks interfering with ALS protocols and increasing unhelpful interventions. As with many interventions in ALS, the evidence base for ultrasound use is weak, and well-designed randomized trials are needed. This paper reviews the current theory and evidence for harms and benefits.}, } @article {pmid38534355, year = {2024}, author = {Cohen, J and Mathew, A and Dourvetakis, KD and Sanchez-Guerrero, E and Pangeni, RP and Gurusamy, N and Aenlle, KK and Ravindran, G and Twahir, A and Isler, D and Sosa-Garcia, SR and Llizo, A and Bested, AC and Theoharides, TC and Klimas, NG and Kempuraj, D}, title = {Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders.}, journal = {Cells}, volume = {13}, number = {6}, pages = {}, pmid = {38534355}, issn = {2073-4409}, mesh = {Humans ; Neuroinflammatory Diseases ; Endothelial Cells ; *Induced Pluripotent Stem Cells ; *Neurodegenerative Diseases ; Inflammation ; }, abstract = {Neuroinflammatory and neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood. These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood-brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration. Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders.}, } @article {pmid38534336, year = {2024}, author = {Sonkodi, B}, title = {Progressive Irreversible Proprioceptive Piezo2 Channelopathy-Induced Lost Forced Peripheral Oscillatory Synchronization to the Hippocampal Oscillator May Explain the Onset of Amyotrophic Lateral Sclerosis Pathomechanism.}, journal = {Cells}, volume = {13}, number = {6}, pages = {}, pmid = {38534336}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Syndecan-3 ; Mechanotransduction, Cellular ; *Channelopathies ; *Neurodegenerative Diseases ; Protons ; Proprioception/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a mysterious lethal multisystem neurodegenerative disease that gradually leads to the progressive loss of motor neurons. A recent non-contact dying-back injury mechanism theory for ALS proposed that the primary damage is an acquired irreversible intrafusal proprioceptive terminal Piezo2 channelopathy with underlying genetic and environmental risk factors. Underpinning this is the theory that excessively prolonged proprioceptive mechanotransduction under allostasis may induce dysfunctionality in mitochondria, leading to Piezo2 channelopathy. This microinjury is suggested to provide one gateway from physiology to pathophysiology. The chronic, but not irreversible, form of this Piezo2 channelopathy is implicated in many diseases with unknown etiology. Dry eye disease is one of them where replenishing synthetic proteoglycans promote nerve regeneration. Syndecans, especially syndecan-3, are proposed as the first critical link in this hierarchical ordered depletory pathomechanism as proton-collecting/distributing antennas; hence, they may play a role in ALS pathomechanism onset. Even more importantly, the shedding or charge-altering variants of Syndecan-3 may contribute to the Piezo2 channelopathy-induced disruption of the Piezo2-initiated proton-based ultrafast long-range signaling through VGLUT1 and VGLUT2. Thus, these alterations may not only cause disruption to ultrafast signaling to the hippocampus in conscious proprioception, but could disrupt the ultrafast proprioceptive signaling feedback to the motoneurons. Correspondingly, an inert Piezo2-initiated proton-based ultrafast signaled proprioceptive skeletal system is coming to light that is suggested to be progressively lost in ALS. In addition, the lost functional link of the MyoD family of inhibitor proteins, as auxiliary subunits of Piezo2, may not only contribute to the theorized acquired Piezo2 channelopathy, but may explain how these microinjured ion channels evolve to be principal transcription activators.}, } @article {pmid38533934, year = {2024}, author = {Deutsch, AJ}, title = {PICking out progressive PIC alterations in amyotrophic lateral sclerosis.}, journal = {Journal of neurophysiology}, volume = {131}, number = {5}, pages = {822-824}, pmid = {38533934}, issn = {1522-1598}, support = {NS091836//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS131816/NS/NINDS NIH HHS/United States ; R01 AG067758/AG/NIA NIH HHS/United States ; AG067758//HHS | NIH | National Institute on Aging (NIA)/ ; R01 NS091836/NS/NINDS NIH HHS/United States ; NS131816//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Humans ; *Motor Neurons/physiology/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motoneuron death. Alterations to motoneuron excitability in ALS are suspected to contribute to motoneuron degeneration. Therefore, mechanisms underlying changes in motoneuron excitability are being thoroughly investigated. A recent publication from Trajano et al. (Trajano GS, Orssatto LB, McCombe PA, Rivlin W, Tang L, Henderson RD. J Physiol 601: 4723-4735, 2023) examined temporal changes to persistent inward currents (PICs) in ALS patients. They show that delta frequency (ΔF, an estimate of PICs) has opposite temporal trends in stronger and weaker muscles of ALS patients. This study is very important to aid in the understanding of disease mechanisms. This Neuro Forum article explores some important considerations for interpreting the results of this study, including treatment effects, potential sex differences, and a lack of comparison to healthy individuals.}, } @article {pmid38533726, year = {2024}, author = {Alix, JJP and Plesia, M and Dudgeon, AP and Kendall, CA and Hewamadduma, C and Hadjivassiliou, M and Gorman, GS and Taylor, RW and McDermott, CJ and Shaw, PJ and Mead, RJ and Day, JC}, title = {Conformational fingerprinting with Raman spectroscopy reveals protein structure as a translational biomarker of muscle pathology.}, journal = {The Analyst}, volume = {149}, number = {9}, pages = {2738-2746}, pmid = {38533726}, issn = {1364-5528}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Spectrum Analysis, Raman/methods ; Humans ; Animals ; *Biomarkers/analysis ; *Muscular Dystrophy, Duchenne/pathology/diagnosis ; Muscle, Skeletal/chemistry/pathology ; Mice ; Amyotrophic Lateral Sclerosis/diagnosis/pathology ; Male ; }, abstract = {Neuromuscular disorders are a group of conditions that can result in weakness of skeletal muscles. Examples include fatal diseases such as amyotrophic lateral sclerosis and conditions associated with high morbidity such as myopathies (muscle diseases). Many of these disorders are known to have abnormal protein folding and protein aggregates. Thus, easy to apply methods for the detection of such changes may prove useful diagnostic biomarkers. Raman spectroscopy has shown early promise in the detection of muscle pathology in neuromuscular disorders and is well suited to characterising the conformational profiles relating to protein secondary structure. In this work, we assess if Raman spectroscopy can detect differences in protein structure in muscle in the setting of neuromuscular disease. We utilise in vivo Raman spectroscopy measurements from preclinical models of amyotrophic lateral sclerosis and the myopathy Duchenne muscular dystrophy, together with ex vivo measurements of human muscle samples from individuals with and without myopathy. Using quantitative conformation profiling and matrix factorisation we demonstrate that quantitative 'conformational fingerprinting' can be used to identify changes in protein folding in muscle. Notably, myopathic conditions in both preclinical models and human samples manifested a significant reduction in α-helix structures, with concomitant increases in β-sheet and, to a lesser extent, nonregular configurations. Spectral patterns derived through non-negative matrix factorisation were able to identify myopathy with a high accuracy (79% in mouse, 78% in human tissue). This work demonstrates the potential of conformational fingerprinting as an interpretable biomarker for neuromuscular disorders.}, } @article {pmid38533300, year = {2024}, author = {Moskvin, SV}, title = {A brief literature review of low-level laser therapy for treating amyotrophic lateral sclerosis and confirmation of its effectiveness.}, journal = {BioMedicine}, volume = {14}, number = {1}, pages = {1-9}, pmid = {38533300}, issn = {2211-8020}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a steadily progressive course due to the death of central and peripheral motor neurons responsible for voluntary movements. Low-level laser therapy (LLLT) is a treatment method unique in its universality and efficacy, particularly for neurodegenerative diseases.

METHODS: In this review, we discuss the effect and application of LLLT in the treatment of ALS. A literature search for English and Russian publications for the keywords "Amyotrophic Lateral Sclerosis", "Low-Level Laser Therapy" was performed using PubMed, Scopus, Google Scholar, Web of Science and Russian Science Citation Index (RSCI) databases.

RESULTS: The article provided a brief literature review, substantiated the potential use of low-level laser therapy for ALS. The particular techniques of LLLT were developed.

CONCLUSION: Based on the results of several studies and many years of successful experience with low-level laser therapy in Russia we conclude that a LLLT technique, including intravenous laser blood illumination (ILBI), noninvasive laser blood illumination (NLBI), and local exposure, is a promising treatment method for ALS.}, } @article {pmid38532923, year = {2023}, author = {Howson, PJ}, title = {Foreign language acquisition of perceptually similar segments: evidence from Lower Sorbian.}, journal = {Open research Europe}, volume = {3}, number = {}, pages = {56}, pmid = {38532923}, issn = {2732-5121}, abstract = {Lower Sorbian is a moribund language spoken in Eastern Germany that features a three-way sibilant contrast, /s, ʂ, ɕ/. The vast majority of L1 speakers are above eighty years of age and virtually no young Sorbians learn Lower Sorbian as their first language. There are language revitalization programs in place, but this means that virtually all Lower Sorbian speakers are L2 learners whose first language is German. German, as opposed to Lower Sorbian, has a two-way sibilant contrast, /s, ʃ/. So, Lower Sorbian learners need to acquire a perceptually similar sibilant contrast, /ʂ, ɕ/, that commonly assimilates with a single L1 segment, /ʃ/. The two-to-one assimilation makes acquisition difficult. In this project, I examine the acquisition of the three-way sibilant contrast using ultrasound technology. The ultrasound data revealed that learners in the contemporary context do not produce a distinction between /ʂ, ɕ/ and only learners at an advanced level who had significant exposure to L1 speakers have acquired a three-way sibilant distinction. The findings are put into the context of models of L2 acquisition and generalized implications for foreign language acquisition are discussed.}, } @article {pmid38531942, year = {2024}, author = {Son, B and Lee, J and Ryu, S and Park, Y and Kim, SH}, title = {Timing and impact of percutaneous endoscopic gastrostomy insertion in patients with amyotrophic lateral sclerosis: a comprehensive analysis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {7103}, pmid = {38531942}, issn = {2045-2322}, support = {BK21 FOUR//National Research Foundation of Korea/ ; RS-2023-00265515//National Research Foundation of Korea/ ; }, mesh = {Humans ; Gastrostomy/methods ; *Amyotrophic Lateral Sclerosis ; Retrospective Studies ; *Deglutition Disorders ; Weight Loss ; }, abstract = {Dysphagia is common in amyotrophic lateral sclerosis (ALS) patients, often requiring percutaneous endoscopic gastrostomy (PEG) for enteral nutrition. We retrospectively analyzed data from 188 Korean patients with ALS who underwent PEG tube insertion at five-time points: symptom onset (t1), diagnosis (t2), recommended time for gastrostomy (t3), PEG insertion (t4), and one-year post-insertion (t5). The recommended time point for gastrostomy (T-rec for gastrostomy) was defined as the earlier time point between a weight loss of more than 10% and advanced dysphagia indicated by the ALSFRS-R swallowing subscore of 2 or less. The T-rec for gastrostomy was reached at 22 months after symptom onset, followed by PEG insertion at 30 months, resulting in an 8-month delay. During the delay, the ALSFRS-R declined most rapidly at 1.7 points/month, compared to 0.8 points/month from symptom onset to diagnosis, 0.7 points/month from diagnosis to T-rec for gastrostomy, and 0.6 points/month after the PEG insertion. It is crucial to discuss PEG insertion before significant weight loss or severe dysphagia occurs and minimize the delay between the recommended time for gastrostomy and the actual PEG insertion. A stratified and individualized multidisciplinary team approach with careful symptom monitoring and proactive management plans, including early PEG insertion, should be prioritized to improve patient outcomes.}, } @article {pmid38531462, year = {2024}, author = {Oliveira, NAS and Pinho, BR and Pinto, J and Guedes de Pinho, P and Oliveira, JMA}, title = {Edaravone counteracts redox and metabolic disruptions in an emerging zebrafish model of sporadic ALS.}, journal = {Free radical biology & medicine}, volume = {217}, number = {}, pages = {126-140}, doi = {10.1016/j.freeradbiomed.2024.03.016}, pmid = {38531462}, issn = {1873-4596}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Edaravone ; Zebrafish ; *Neurodegenerative Diseases ; Oxidation-Reduction ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which the death of motor neurons leads to loss of muscle function. Additionally, cognitive and circadian disruptions are common in ALS patients, contributing to disease progression and burden. Most ALS cases are sporadic, and environmental exposures contribute to their aetiology. However, animal models of these sporadic ALS cases are scarce. The small vertebrate zebrafish is a leading organism to model neurodegenerative diseases; previous studies have proposed bisphenol A (BPA) or β-methylamino-l-alanine (BMAA) exposure to model sporadic ALS in zebrafish, damaging motor neurons and altering motor responses. Here we characterise the face and predictive validity of sporadic ALS models, showing their potential for the mechanistic study of ALS drugs. We phenotypically characterise the BPA and BMAA-induced models, going beyond motor activity and motor axon morphology, to include circadian, redox, proteostasis, and metabolomic phenotypes, and assessing their predictive validity for ALS modelling. BPA or BMAA exposure induced concentration-dependent activity impairments. Also, exposure to BPA but not BMAA induced motor axonopathy and circadian alterations in zebrafish larvae. Our further study of the BPA model revealed loss of habituation to repetitive startles, increased oxidative damage, endoplasmic reticulum (ER) stress, and metabolome abnormalities. The BPA-induced model shows predictive validity, since the approved ALS drug edaravone counteracted BPA-induced motor phenotypes, ER stress, and metabolic disruptions. Overall, BPA exposure is a promising model of ALS-related redox and ER imbalances, contributing to fulfil an unmet need for validated sporadic ALS models.}, } @article {pmid38531340, year = {2024}, author = {Lee, KH and Kim, MH and Kim, J and Nam, HJ}, title = {Acupuncture for Tinnitus: A Scoping Review of Clinical Studies.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {292-301}, pmid = {38531340}, issn = {2504-2106}, mesh = {Humans ; *Acupuncture Therapy/methods ; *Tinnitus/therapy ; Randomized Controlled Trials as Topic ; Acupuncture Points ; }, abstract = {BACKGROUND: Acupuncture treatment for tinnitus has received attention owing to its potential as an alternative to conventional treatment modalities. We conducted a scoping review to identify detailed information on acupuncture treatment methods used in clinical studies and to provide useful information for practitioners, patients, and researchers.

METHODS: MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Oriental Medicine Advanced Searching Integrated System (OASIS), Korean Research Information Sharing Service (RISS), DataBase Periodical Information Academic (DBPIA), and the China National Knowledge Infrastructure (CNKI) were searched from their inception to December 2023. This review included single-arm trials, open-label randomized controlled trials (RCTs), and double-blind RCTs using needle-type acupuncture to treat tinnitus in English, Chinese, and Korean. We investigated basic and detailed information on the acupuncture treatment methods, assessment methods, and study outcomes. Network analysis was also conducted to evaluate the centrality between acupoints in the double-blind RCTs.

RESULTS: We included 106 articles. There were 11 single-arm trials, 90 open-label RCTs, and 5 double-blind RCTs. Most (89.6%) of these studies were conducted in China. Manual acupuncture was the most common type of acupuncture in treatment group. A total of 119 acupuncture points were used 1,138 times. The most frequently used acupoints were local points around the ear (TE17, GB2, SI19, and TE21). Both local and distant acupoints were used simultaneously in these studies. The treatment duration of 20-39 days, 10 to 19 sessions of treatment, the mean acupuncture duration of 30 min, needle diameter of 0.30 mm × 40 mm, and needling depth over 30 mm and less than 50 mm were confirmed as the most common.

CONCLUSION: These study outcomes will enable future acupuncture studies on tinnitus to perform more effective and standardized acupuncture treatments in selecting acupoints and procedures. Furthermore, the study has implications for informing clinicians and students about more impactful acupuncture strategies for addressing tinnitus.

UNLABELLED: HintergrundDie Anwendung von Akupunktur bei Tinnitus erhält seit einiger Zeit Aufmerksamkeit als potenzielle Alternative zu konventionellen Behandlungsmodalitäten. Wir führten einen Scoping-Review durch, um detaillierte Informationen zu den in klinischen Studien angewandten Akupunktur-Behandlungsmethoden zu sammeln und nützliche Informationen für Praktiker, Patienten und Forscher bereitzustellen.MethodenMEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Oriental Medicine Advanced Searching Integrated System (OASIS), Korean Research Information Sharing Service (RISS), DataBase Periodical Information Academic (DBPIA) und die China National Knowledge Infrastructure (CNKI) wurden von ihrem jeweiligen Beginn bis Dezember 2023 durchsucht. In diese Übersichtsarbeit wurden einarmige Studien, offene, randomisierte, kontrollierte Studien (RCTs) sowie doppelt verblindete RCTs zu Nadel-Akupunktur zur Behandlung von Tinnitus in englischer, chinesischer und koreanischer Sprache einbezogen. Wir untersuchten grundlegende und detaillierte Informationen zu den Akupunktur-Behandlungsmethoden, Untersuchungsmethoden und Studienergebnissen. Außerdem wurden Netzwerkanalysen zur Beurteilung der Zentralität zwischen Akupunkten in den doppelt verblindeten RCTs durchgeführt.Ergebnisse106 Artikel wurden eingeschlossen. Sie behandelten 11 einarmige Studien, 90 offene RCTs und 5 doppelt verblindete RCTs. Die meisten (89,6%) dieser Studien waren in China durchgeführt worden. Manuelle Akupunktur war die häufigste Form der Akupunktur in den Behandlungsgruppen. 119 Akupunkturpunkte wurden insgesamt 1’138 Mal verwendet. Die am häufigsten verwendeten Akupunkte waren lokale Punkte im Bereich des Ohrs (TE17, GB2, SI19 und TE21). Jedoch wurden in den Studien lokale und entfernte Akupunkte gleichzeitig angewendet. Außerdem wurde festgestellt, dass die Behandlungsdauer am häufigsten 20 bis 39 Tage betrug, die Zahl der Sitzungen 10 bis 19, die mittlere Akupunkturdauer 30 Minuten, die Nadelgröße 0.30 mm × 40 mm und die Einstichtiefe zwischen 30 mm und weniger als 50 mm.SchlussfolgerungDiese Studienergebnisse bieten eine Grundlage für künftige Studien zu Akupunktur bei Tinnitus, um durch die Auswahl der Akupunkte und Verfahren wirksamere und standardisierte Akupunkturbehandlungen durchzuführen. Darüber hinaus hat die Studie Implikationen für die Aufklärung von Praktikern und Schülern über wirkungsvollere Akupunkturstrategien zur Behandlung von Tinnitus.}, } @article {pmid38528673, year = {2024}, author = {Howard, J and Mazanderani, F and Keenan, KF and Turner, MR and Locock, L}, title = {Fluctuating salience in those living with genetic risk of motor neuron disease: A qualitative interview study.}, journal = {Health expectations : an international journal of public participation in health care and health policy}, volume = {27}, number = {2}, pages = {e14024}, pmid = {38528673}, issn = {1369-7625}, support = {Locock/Sept19/941-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Adult ; Child ; Humans ; *Motor Neuron Disease/genetics/diagnosis/psychology ; *Amyotrophic Lateral Sclerosis/diagnosis/pathology ; Qualitative Research ; Uncertainty ; Emotions ; }, abstract = {BACKGROUND: Motor neuron disease (MND) (also known as amyotrophic lateral sclerosis) is a life-limiting neurodegenerative condition. In up to 20% of people with MND, a pathogenic variant associated with autosomal dominant inheritance can be identified. Children of people carrying a pathogenic variant have a 50% chance of inheriting this and a higher, although harder to predict, chance of developing the disease compared to the general adult population. This paper explores the experience of living with the genetic risk of MND.

METHODS: We undertook a UK-based interview study with 35 individuals, including: 7 people living with genetically-mediated forms of MND; 24 asymptomatic relatives, the majority of whom had an increased risk of developing the disease; and 4 unrelated partners.

RESULTS: We explore how individuals make sense of genetic risk, unpacking the interplay between genetic knowledge, personal perception, experiences of the disease in the family, age and life stage and the implications that living with risk has for different aspects of their lives. We balance an emphasis on the emotional and psychological impact described by participants, with a recognition that the salience of risk fluctuates over time. Furthermore, we highlight the diverse strategies and approaches people employ to live well in the face of uncertainty and the complex ways they engage with the possibility of developing symptoms in the future. Finally, we outline the need for open-ended, tailored support and information provision.

CONCLUSIONS: Drawing on wider literature on genetic risk, we foreground how knowledge of MND risk can disrupt individuals' taken-for-granted assumptions on life and perceptions of the future, but also its contextuality, whereby its relevance becomes more prominent at critical junctures. This research has been used in the development of a public-facing resource on the healthtalk.org website.

People with experience of living with genetic risk were involved throughout the design and conduct of the study and advised on aspects including the topic guide, sampling and recruitment and the developing analysis. Two patient and public involvement contributors joined a formal advisory panel.}, } @article {pmid38527450, year = {2023}, author = {Cheong, I and Du, Y and Smith, G and Hua, J and Li, X and Pantelyat, A}, title = {Cerebral Tau Deposition in Comorbid Progressive Supranuclear Palsy and Amyotrophic Lateral Sclerosis: An [18F]-Flortaucipir and 7T MRI Study.}, journal = {Neuro-degenerative diseases}, volume = {23}, number = {3-4}, pages = {35-42}, pmid = {38527450}, issn = {1660-2862}, support = {K23 AG059891/AG/NIA NIH HHS/United States ; R01 AG059390/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Brain/diagnostic imaging/metabolism ; *Carbolines ; *Magnetic Resonance Imaging/methods ; *Positron-Emission Tomography/methods ; *Supranuclear Palsy, Progressive/diagnostic imaging/metabolism ; *tau Proteins/metabolism ; }, abstract = {INTRODUCTION: Progressive supranuclear palsy (PSP) is a four-repeat tauopathy characterized by multiple clinicopathologic subtypes. Advanced neuroimaging techniques have shown an early ability to distinguish PSP subtypes noninvasively for improved diagnosis. This study utilized tau PET imaging and MRI techniques at 7T to determine the neuroimaging profile of a participant with comorbid PSP and amyotrophic lateral sclerosis (ALS).

METHOD: [18F]-flortaucipir PET imaging was performed on one participant with PSP-ALS, one participant with typical PSP (Richardson's syndrome; PSP-RS), and 15 healthy control volunteers. Standardized uptake value ratio (SUVR) in each brain region was compared between PSP participants and controls. Quantitative susceptibility mapping (QSM) and inflow-based vascular-space occupancy MRI at 7T were performed on the two PSP participants and on two age-matched healthy controls to evaluate for differences in regional brain iron content and arteriolar cerebral blood volume (CBVa), respectively.

RESULTS: In the participant with PSP-ALS, the precentral gyrus demonstrated the highest [18F]-flortaucipir uptake of all brain regions relative to controls (z-score 1.94). In the participant with PSP-RS, [18F]-flortaucipir uptake relative to controls was highest in subcortical regions, including the pallidum, thalamus, hippocampus, and brainstem (z-scores 1.08, 1.41, 1.49, 1.32, respectively). Susceptibility values as a measure of brain iron content were higher in the globus pallidus and substantia nigra than in the midbrain and pons in each participant, regardless of group. CBVa values tended to be higher in the subcortical gray matter in PSP participants than in controls, although large measurement variability was noted in controls across multiple regions.

CONCLUSION: In vivo tau PET imaging of an individual with PSP-ALS overlap demonstrated increased tau burden in the motor cortex that was not observed in PSP-RS or control participants. Consistent with prior PET studies, tau burden in PSP-RS was mainly observed in subcortical regions, including the brainstem and basal ganglia. QSM data suggest that off-target binding to iron may account for some but not all of the increased [18F]-flortaucipir uptake in the basal ganglia in PSP-RS. These findings support existing evidence that tau PET imaging can distinguish among PSP subtypes by detecting distinct regional patterns of tau deposition in the brain. Larger studies are needed to determine whether CBVa is sensitive to changes in brain microvasculature in PSP.}, } @article {pmid38526287, year = {2024}, author = {Chen, W and Jiang, S and Li, S and Li, C and Xu, R}, title = {OSMR is a potential driver of inflammation in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {11}, pages = {2513-2521}, pmid = {38526287}, issn = {1673-5374}, abstract = {JOURNAL/nrgr/04.03/01300535-202419110-00031/figure1/v/2024-03-08T184507Z/r/image-tiff Amyotrophic lateral sclerosis is a neurodegenerative disease, and the molecular mechanism underlying its pathology remains poorly understood. However, inflammation is known to play an important role in the development of this condition. To identify driver genes that affect the inflammatory response in amyotrophic lateral sclerosis, as well as potential treatment targets, it is crucial to analyze brain tissue samples from patients with both sporadic amyotrophic lateral sclerosis and C9orf72-related amyotrophic lateral sclerosis. Therefore, in this study we used a network-driven gene analysis tool, NetBID2.0, which is based on SJARACNe, a scalable algorithm for the reconstruction of accurate cellular networks, to experimentally analyze sequencing data from patients with sporadic amyotrophic lateral sclerosis. The results showed that the OSMR gene is pathogenic in amyotrophic lateral sclerosis and participates in the progression of amyotrophic lateral sclerosis by mediating the neuroinflammatory response. Furthermore, there were differences in OSMR activity and expression between patients with sporadic amyotrophic lateral sclerosis and those with C9orf72-related amyotrophic lateral sclerosis. These findings suggest that OSMR may be a diagnostic and prognostic marker for amyotrophic lateral sclerosis.}, } @article {pmid38525704, year = {2024}, author = {Shirai, R and Yamauchi, J}, title = {Emerging Evidence of Golgi Stress Signaling for Neuropathies.}, journal = {Neurology international}, volume = {16}, number = {2}, pages = {334-348}, pmid = {38525704}, issn = {2035-8385}, abstract = {The Golgi apparatus is an intracellular organelle that modifies cargo, which is transported extracellularly through the nucleus, endoplasmic reticulum, and plasma membrane in order. First, the general function of the Golgi is reviewed and, then, Golgi stress signaling is discussed. In addition to the six main Golgi signaling pathways, two pathways that have been increasingly reported in recent years are described in this review. The focus then shifts to neurological disorders, examining Golgi stress reported in major neurological disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. The review also encompasses findings related to other diseases, including hypomyelinating leukodystrophy, frontotemporal spectrum disorder/amyotrophic lateral sclerosis, microcephaly, Wilson's disease, and prion disease. Most of these neurological disorders cause Golgi fragmentation and Golgi stress. As a result, strong signals may act to induce apoptosis.}, } @article {pmid38525545, year = {2024}, author = {Alpert, EA and Assaf, J and Nama, A and Pliner, R and Jaffe, E}, title = {Secondary Ambulance Transfers During the Mass-Casualty Terrorist Attack in Israel on October 7, 2023.}, journal = {Prehospital and disaster medicine}, volume = {39}, number = {2}, pages = {224-227}, doi = {10.1017/S1049023X24000153}, pmid = {38525545}, issn = {1945-1938}, mesh = {Israel ; Humans ; *Mass Casualty Incidents ; *Ambulances ; *Terrorism ; Emergency Medical Services/organization & administration ; Patient Transfer ; }, abstract = {On October 7, 2023, Israel experienced the worst terror attack in its history - 1,200 people were killed, 239 people were taken hostage, and 1,455 people were wounded. This mass-casualty event (MCE) was more specifically a mega terrorist attack. Due to the overwhelming number of victims who arrived at the two closest hospitals, it became necessary to implement secondary transfers to centers in other areas of the country. Historically, secondary transfer has been implemented in MCEs but usually for the transfer of critical patients from a Level 2 or Level 3 Trauma Center to a Level 1 Center. Magen David Adom (MDA), Israel's National Emergency Pre-Hospital Medical Organization, is designated by the Health Ministry as the incident command at any MCE. On October 7, in addition to the primary transport of victims by ambulance to hospitals throughout Israel, they secondarily transported patients from the two closest hospitals - the Soroka Medical Center (SMC; Level 1 Trauma Center) in Beersheba and the Barzilai Medical Center (BMC; Level 2 Trauma Center) in Ashkelon. Secondary transport began five hours after the event started and continued for approximately 12 hours. During this time, the terrorist infiltration was still on-going. Soroka received 650 victims and secondarily transferred 26, including five in Advanced Life Support (ALS) ambulances. Barzilai received 372 and secondarily transferred 38. These coordinated secondary transfers helped relieve the overwhelmed primary hospitals and are an essential component of any MCE strategy.}, } @article {pmid38525350, year = {2024}, author = {Gosik, R and Caldara, R and Toševski, I and Skuhrovec, J}, title = {Description of immature stages of Rhinusa species (Coleoptera, Curculionidae, Mecinini) with a focus on diagnostic morphological characters at the species and genus levels.}, journal = {ZooKeys}, volume = {1195}, number = {}, pages = {1-94}, pmid = {38525350}, issn = {1313-2989}, abstract = {The mature larvae of the following fourteen Rhinusa species are described and illustrated: Rhinusaantirrhini (Paykull, 1800), R.asellus (Gravenhorst, 1807), R.collina (Gyllenhal, 1813), R.eversmanni (Rosenschoeld, 1838), R.florum (Rubsaamen, 1895), R.herbarum (H. Brisout de Barneville, 1862), R.incana (Kirsch, 1881), R.linariae (Panzer, 1796), R.melas (Boheman, 1838), R.neta (Germar, 1821), R.pilosa (Gyllenhal, 1838), R.rara Toševski & Caldara, 2015, R.tetra (Fabricius, 1792), and R.vestita (Germar, 1821). The pupae of thirteen of them (except R.incana) were also described. The comparison of larval morphological characters and plant preferences provides evidence supporting the existence of different species groups previously established according to a phylogenetic analysis based on adult morphological characters. The following diagnostic attributes distinguishing the genus Rhinusa are highlighted. For the larvae: (1) pronotal shield indistinct; (2) thoracic prodorsal fold small or even vestigial; (3) abdominal postdorsal folds (especially of segments III-VII) high or even in the form of conical protuberances; (4) cuticle of abdominal segments densely covered with asperities; (5) cuticle without dark spots or dark pigmentation; (6) head suboval, rarely round; (7) labrum usually with 2 als; (8) des1 short or absent, rarely elongated; and (9) fs1-3 usually absent or minute. For the pupae: (1) body stout; (2) head protuberances always present; (3) pronotal protuberances (if present), separated at bases of the pronotum, always wider than higher; (4) abdominal protuberance usually present, wide or round; (5) femora usually with a single fes; and (6) urogomphi short or vestigial. Keys to the larvae and pupae described here are provided. All the characters used for identification are illustrated by photographs or drawings. Biological and distribution data, including new information, are provided for all the species studied.}, } @article {pmid38524582, year = {2024}, author = {Yamamoto, Y and Fujita, K and Yamazaki, H and Haji, S and Osaki, Y and Izumi, Y}, title = {Constipation in patients with motor neuron disease: A retrospective longitudinal study.}, journal = {Heliyon}, volume = {10}, number = {6}, pages = {e27951}, pmid = {38524582}, issn = {2405-8440}, abstract = {BACKGROUND: Constipation has been recently recognized as a complication associated with motor and autonomic dysfunction in patients with motor neuron disease (MND), typified by amyotrophic lateral sclerosis (ALS). However, the long-term characteristics of constipation remain unclear in patients with MND. We longitudinally investigated the prevalence and risk factors of constipation in a consecutive cohort of patients with MND.

METHODS: Data from Japanese patients with MND enrolled in a single-center registry from June 2017 to December 2021 were retrospectively investigated. The diagnosis of ALS was based on the updated Awaji criteria, and other MND subtypes were also included. The presence or absence of constipation symptoms was determined by referring to the Rome III criteria. The clinical backgrounds and symptoms of patients with and without constipation were compared.

RESULTS: Among 155 consecutive patients (female, 63; age, 66.5 ± 12.4 years), 30.3% had constipation at diagnosis and 52.9% after a median follow-up of 18 months. Univariate analysis showed that female sex, use of tracheostomy and invasive ventilation, and delivery of enteral nutrition were more frequent in the constipation group. The Revised Amyotrophic Lateral Sclerosis Functional Rating Scale score was significantly lower in the constipation group, especially for the sub-items related to physical motor function. Multivariate analysis showed that the use of enteral nutrition was an independent risk of constipation, with an odds ratio of 3.69 (95% CI, 1.49-9.17; p = 0.005).

CONCLUSION: Constipation had a high prevalence in patients with MND with impaired motor function. Controlling defecation is important in patients with MND, especially during enteral nutrition.}, } @article {pmid38524510, year = {2024}, author = {Liu, YX and Xu, Y}, title = {Enhancing competency of clinical research nurses: A comprehensive training and evaluation framework.}, journal = {World journal of clinical cases}, volume = {12}, number = {7}, pages = {1378-1381}, pmid = {38524510}, issn = {2307-8960}, abstract = {The Sun et al's training program for clinical research nurses (CRNs) in the World Journal of Clinical Cases is a comprehensive and scientific approach. It includes structured frameworks for CRN training, aiming to improve CRN competency. This program emphasizes practical abilities, updates training content, and improves evaluation methods. The cultivation of CRN talents focuses on enhancing the training system, establishing a multifaceted evaluation framework, and continuously refining the training programs. Regular feedback and evaluation are essential to improve CRNs' competency in practical settings.}, } @article {pmid38524401, year = {2024}, author = {Pota, V and Sansone, P and De Sarno, S and Aurilio, C and Coppolino, F and Barbarisi, M and Barbato, F and Fiore, M and Cosenza, G and Passavanti, MB and Pace, MC}, title = {Amyotrophic Lateral Sclerosis and Pain: A Narrative Review from Pain Assessment to Therapy.}, journal = {Behavioural neurology}, volume = {2024}, number = {}, pages = {1228194}, pmid = {38524401}, issn = {1875-8584}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Pain Measurement ; Quality of Life ; *Neurodegenerative Diseases/complications ; Pain/drug therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most frequent neurodegenerative disease of the motor system that affects upper and lower motor neurons, leading to progressive muscle weakness, spasticity, atrophy, and respiratory failure, with a life expectancy of 2-5 years after symptom onset. In addition to motor symptoms, patients with ALS have a multitude of nonmotor symptoms; in fact, it is currently considered a multisystem disease. The purpose of our narrative review is to evaluate the different types of pain, the correlation between pain and the disease's stages, the pain assessment tools in ALS patients, and the available therapies focusing above all on the benefits of cannabis use. Pain is an underestimated and undertreated symptom that, in the last few years, has received more attention from research because it has a strong impact on the quality of life of these patients. The prevalence of pain is between 15% and 85% of ALS patients, and the studies on the type and intensity of pain are controversial. The absence of pain assessment tools validated in the ALS population and the dissimilar study designs influence the knowledge of ALS pain and consequently the pharmacological therapy. Several studies suggest that ALS is associated with changes in the endocannabinoid system, and the use of cannabis could slow the disease progression due to its neuroprotective action and act on pain, spasticity, cramps, sialorrhea, and depression. Our research has shown high patients' satisfaction with the use of cannabis for the treatment of spasticity and related pain. However, especially due to the ethical problems and the lack of interest of pharmaceutical companies, further studies are needed to ensure the most appropriate care for ALS patients.}, } @article {pmid38522911, year = {2024}, author = {Urushitani, M and Warita, H and Atsuta, N and Izumi, Y and Kano, O and Shimizu, T and Nakayama, Y and Narita, Y and Nodera, H and Fujita, T and Mizoguchi, K and Morita, M and Aoki, M}, title = {The clinical practice guideline for the management of amyotrophic lateral sclerosis in Japan-update 2023.}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {64}, number = {4}, pages = {252-271}, doi = {10.5692/clinicalneurol.cn-001946}, pmid = {38522911}, issn = {1882-0654}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis ; Disease Progression ; Evidence-Based Medicine ; Japan ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset intractable motor neuron disease characterized by selective degeneration of cortical neurons in the frontotemporal lobe and motor neurons in the brainstem and spinal cord. Impairment of these neural networks causes progressive muscle atrophy and weakness that spreads throughout the body, resulting in life-threatening bulbar palsy and respiratory muscle paralysis. However, no therapeutic strategy has yet been established to halt ALS progression. Although evidence for clinical practice in ALS remains insufficient, novel research findings have steadily accumulated in recent years. To provide updated evidence-based or expert consensus recommendations for the diagnosis and management of ALS, the ALS Clinical Practice Guideline Development Committee, approved by the Japanese Society of Neurology, revised and published the Japanese clinical practice guidelines for the management of ALS in 2023. In this guideline, disease-modifying therapies that have accumulated evidence from randomized controlled trials were defined as "Clinical Questions," in which the level of evidence was determined by systematic reviews. In contrast, "Questions and Answers" were defined as issues of clinically important but insufficient evidence, according to reports of a small number of cases, observational studies, and expert opinions. Based on a literature search performed in February 2022, recommendations were reached by consensus, determined by an independent panel, reviewed by external reviewers, and submitted for public comments by Japanese Society of Neurology members before publication. In this article, we summarize the revised Japanese guidelines for ALS, highlighting the regional and cultural diversity of care processes and decision-making. The guidelines cover a broad range of essential topics such as etiology, diagnostic criteria, disease monitoring and treatments, management of symptoms, respiration, rehabilitation, nutrition, metabolism, patient instructions, and various types of care support. We believe that this summary will help improve the daily clinical practice for individuals living with ALS and their caregivers.}, } @article {pmid38522733, year = {2024}, author = {Rupp, D and Heuser, N and Sassen, MC and Betz, S and Volberg, C and Glass, S}, title = {Resuscitation (un-)wanted: Does anyone care? A retrospective real data analysis.}, journal = {Resuscitation}, volume = {198}, number = {}, pages = {110189}, doi = {10.1016/j.resuscitation.2024.110189}, pmid = {38522733}, issn = {1873-1570}, mesh = {Humans ; Retrospective Studies ; *Out-of-Hospital Cardiac Arrest/therapy ; Male ; Female ; Aged ; Aged, 80 and over ; *Cardiopulmonary Resuscitation/statistics & numerical data/methods ; *Emergency Medical Services/statistics & numerical data/methods ; Germany ; *Resuscitation Orders ; Middle Aged ; Advance Directives/statistics & numerical data ; }, abstract = {BACKGROUND AND OBJECTIVES: In case of out-of-hospital cardiac arrest (OHCA) personnel of the emergency medical services (EMS) are regularly confronted with advanced directives (AD) and do-not-attempt-resuscitation (DNACPR) orders. The authors conducted a retrospective analysis of EMS operation protocols to examine the prevalence of DNACPR in case of OHCA and the influence of a presented DNACPR on CPR-duration, performed Advanced-Life-Support (ALS) measures and decision making.

MATERIALS AND METHODS: Retrospective analysis of prehospital medical documentation of all resuscitation incidents in a German county with 250,000 inhabitants from 1 January 2016 to 31 December 2022. Combined with data from the structured CPR team-feedback database patients characteristics, measures and course of the CPR were analysed. Statistic testing with significance level p < 0.05.

RESULTS: In total n = 1,474 CPR events were analysed. Patients with DNACPR vs. no DNACPR: n = 263 (17.8%) vs. n = 1,211 (82.2%). Age: 80.0 ± 10.3 years vs. 68.0 ± 13.9 years; p < 0.001. Patients with ASA-status III/IV: n = 214 (81.3%) vs. n = 616 (50.9%); p < 0.001. Initial layperson-CPR: n = 148 (56.3%) vs. n = 647 (55.7%); p = 0.40. Airway management: n = 185 (70.3%) vs. n = 1,069 (88.3%); p < 0.001. With DNACPR CPR-duration initiated layperson-CPR vs. no layperson-CPR: 19:14 min (10:43-25:55 min) vs. 12:40 min (06:35-20:03 min); p < 0.001.

CONCLUSION: In case of CPR EMS-personnel are often confronted with DNACPR-orders. Patients are older and have more previous diseases than patients without DNACPR. Initiated layperson-CPR might lead to misinterpretation of patients will with impact on CPR-duration and unwanted measures. Awareness of this issue should be created through measures such as training programs in particular to train staff in the interpretation and legal admissibility of ADs.}, } @article {pmid38522514, year = {2024}, author = {Pokrishevsky, E and DuVal, MG and McAlary, L and Louadi, S and Pozzi, S and Roman, A and Plotkin, SS and Dijkstra, A and Julien, JP and Allison, WT and Cashman, NR}, title = {Tryptophan residues in TDP-43 and SOD1 modulate the cross-seeding and toxicity of SOD1.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {5}, pages = {107207}, pmid = {38522514}, issn = {1083-351X}, mesh = {Humans ; *Tryptophan/metabolism ; *Zebrafish ; Animals ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; *DNA-Binding Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Protein Folding ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons. Neuronal superoxide dismutase-1 (SOD1) inclusion bodies are characteristic of familial ALS with SOD1 mutations, while a hallmark of sporadic ALS is inclusions containing aggregated WT TAR DNA-binding protein 43 (TDP-43). We show here that co-expression of mutant or WT TDP-43 with SOD1 leads to misfolding of endogenous SOD1 and aggregation of SOD1 reporter protein SOD1[G85R]-GFP in human cell cultures and promotes synergistic axonopathy in zebrafish. Intriguingly, this pathological interaction is modulated by natively solvent-exposed tryptophans in SOD1 (tryptophan-32) and TDP-43 RNA-recognition motif RRM1 (tryptophan-172), in concert with natively sequestered TDP-43 N-terminal domain tryptophan-68. TDP-43 RRM1 intrabodies reduce WT SOD1 misfolding in human cell cultures, via blocking tryptophan-172. Tryptophan-68 becomes antibody-accessible in aggregated TDP-43 in sporadic ALS motor neurons and cell culture. 5-fluorouridine inhibits TDP-43-induced G85R-GFP SOD1 aggregation in human cell cultures and ameliorates axonopathy in zebrafish, via its interaction with SOD1 tryptophan-32. Collectively, our results establish a novel and potentially druggable tryptophan-mediated mechanism whereby two principal ALS disease effector proteins might directly interact in disease.}, } @article {pmid38522245, year = {2024}, author = {Geronimo, A and Simmons, Z}, title = {Remote pulmonary function testing allows for early identification of need for non-invasive ventilation in a subset of persons with ALS.}, journal = {Journal of the neurological sciences}, volume = {459}, number = {}, pages = {122971}, doi = {10.1016/j.jns.2024.122971}, pmid = {38522245}, issn = {1878-5883}, mesh = {Humans ; *Noninvasive Ventilation ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; *Respiratory Insufficiency/diagnosis/etiology/therapy ; Respiratory Function Tests ; Physical Examination ; }, abstract = {The traditional ALS multidisciplinary clinical practice of quarterly respiratory assessment may leave some individuals in danger of developing untreated respiratory insufficiency between visits or beginning non-invasive ventilation (NIV) later than would be optimal. Remote, or home-based, pulmonary function testing (rPFT) allows patients with ALS to perform regular respiratory testing at more frequent intervals in the home. The aim of this study was to determine the clinical benefit of weekly rPFT compared to standard, quarterly in-clinic respiratory assessments: the number of individuals with earlier identification of NIV need, the magnitude of this advance notice, and the individual factors predicting benefit. Participants with ALS (n = 39) completed rPFT training via telemedicine and then completed one year of weekly self-guided assessments in the home. Over this period, 17 individuals exhibited remotely-measured FVC dropping below 50% of predicted, the value often used for recommendation of NIV initiation. In 13 individuals with clinical detection of this event, the median and range of advance notice of need for NIV was 53 (-61-294) days. Prescription of NIV occurred for 21 individuals on the study, six of whom began NIV as a result of remote testing, prior to indication of need as determined by in-person assessments. Weekly home assessments appeared to be of greatest clinical value in a subset of patients with low baseline respiratory test values and rapid respiratory decline. This has potential implications for clinical management of ALS as well as the conduct of clinical trials that rely on respiratory endpoints.}, } @article {pmid38522244, year = {2024}, author = {Swash, M}, title = {Timing initiation of non-invasive ventilation in management of ALS.}, journal = {Journal of the neurological sciences}, volume = {459}, number = {}, pages = {122972}, doi = {10.1016/j.jns.2024.122972}, pmid = {38522244}, issn = {1878-5883}, mesh = {Humans ; *Noninvasive Ventilation ; *Amyotrophic Lateral Sclerosis/therapy ; *Respiratory Insufficiency ; }, } @article {pmid38521615, year = {2024}, author = {Ramos, R and Kaouk, J}, title = {Reply to Alessandro Guercio, Antonio Franco, Elisa Mancini, et al's Letter to the Editor re: Roxana Ramos, Ethan Ferguson, Mahmoud Abou Zeinab, et al. Single-port Transvesical Robot-assisted Simple Prostatectomy: Surgical Technique and Clinical Outcomes. Eur Urol. 2024;85:445-456.}, journal = {European urology}, volume = {85}, number = {6}, pages = {e171-e172}, doi = {10.1016/j.eururo.2024.03.020}, pmid = {38521615}, issn = {1873-7560}, mesh = {Humans ; Male ; *Prostatectomy/methods ; *Robotic Surgical Procedures ; Treatment Outcome ; }, } @article {pmid38521060, year = {2024}, author = {Pineda, SS and Lee, H and Ulloa-Navas, MJ and Linville, RM and Garcia, FJ and Galani, K and Engelberg-Cook, E and Castanedes, MC and Fitzwalter, BE and Pregent, LJ and Gardashli, ME and DeTure, M and Vera-Garcia, DV and Hucke, ATS and Oskarsson, BE and Murray, ME and Dickson, DW and Heiman, M and Belzil, VV and Kellis, M}, title = {Single-cell dissection of the human motor and prefrontal cortices in ALS and FTLD.}, journal = {Cell}, volume = {187}, number = {8}, pages = {1971-1989.e16}, pmid = {38521060}, issn = {1097-4172}, support = {R35 NS127327/NS/NINDS NIH HHS/United States ; R01 NS127187/NS/NINDS NIH HHS/United States ; F32 NS128067/NS/NINDS NIH HHS/United States ; T32 EB019940/EB/NIBIB NIH HHS/United States ; R01 AG067151/AG/NIA NIH HHS/United States ; U01 NS110453/NS/NINDS NIH HHS/United States ; R56 AG067151/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Frontotemporal Dementia/genetics ; *Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; Gene Expression Profiling ; Neurons/metabolism ; *Prefrontal Cortex/metabolism/pathology ; Single-Cell Gene Expression Analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) share many clinical, pathological, and genetic features, but a detailed understanding of their associated transcriptional alterations across vulnerable cortical cell types is lacking. Here, we report a high-resolution, comparative single-cell molecular atlas of the human primary motor and dorsolateral prefrontal cortices and their transcriptional alterations in sporadic and familial ALS and FTLD. By integrating transcriptional and genetic information, we identify known and previously unidentified vulnerable populations in cortical layer 5 and show that ALS- and FTLD-implicated motor and spindle neurons possess a virtually indistinguishable molecular identity. We implicate potential disease mechanisms affecting these cell types as well as non-neuronal drivers of pathogenesis. Finally, we show that neuron loss in cortical layer 5 tracks more closely with transcriptional identity rather than cellular morphology and extends beyond previously reported vulnerable cell types.}, } @article {pmid38520939, year = {2024}, author = {Ko, S and Yamasaki, R and Okui, T and Shiraishi, W and Watanabe, M and Hashimoto, Y and Kobayakawa, Y and Kusunoki, S and Kira, JI and Isobe, N}, title = {A nationwide survey of facial onset sensory and motor neuronopathy in Japan.}, journal = {Journal of the neurological sciences}, volume = {459}, number = {}, pages = {122957}, doi = {10.1016/j.jns.2024.122957}, pmid = {38520939}, issn = {1878-5883}, mesh = {Humans ; Japan/epidemiology ; *Amyotrophic Lateral Sclerosis ; Neurologic Examination ; Face ; }, abstract = {The epidemiology and etiology of facial onset sensory and motor neuronopathy (FOSMN), a rare syndrome that initiates with facial sensory disturbances followed by bulbar symptoms, remain unknown. To estimate the prevalence of FOSMN in Japan and establish the characteristics of this disease, we conducted a nationwide epidemiological survey. In the primary survey, we received answers from 604 facilities (49.8%), leading to an estimated number of 35.8 (95% confidential interval: 21.5-50.2) FOSMN cases in Japan. The secondary survey collected detailed clinical and laboratory data from 21 cases. Decreased or absent corneal and pharyngeal reflexes were present in over 85% of the cases. Electrophysiological analyses detected blink reflex test abnormalities in 94.1% of the examined cases. Immunotherapy was administered in 81% of cases and all patients received intravenous immunoglobulin. Among them, 35.3% were judged to have temporary beneficial effects evaluated by the physicians in charge. Immunotherapy tended to be effective in the early stage of disease. The spreading pattern of motor and sensory symptoms differed between cases and the characteristics of the motor-dominant and sensory-dominant cases were distinct. Cases with motor-dominant progression appeared to mimic amyotrophic lateral sclerosis. This is the first nationwide epidemiological survey of FOSMN in Japan. The clinical course of FOSMN is highly variable and motor-dominant cases developed a more severe condition than other types of cases. Because clinical interventions tend to be effective in the early phase of the disease, an early diagnosis is desirable.}, } @article {pmid38519870, year = {2024}, author = {Genuis, SK and Luth, W and Magnussen, C and Vande Velde, C and Taylor, D and , and Johnston, WS}, title = {Patient engagement in research: lessons learned from CAPTURE ALS, a longitudinal observational ALS study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {634-643}, doi = {10.1080/21678421.2024.2328599}, pmid = {38519870}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Longitudinal Studies ; *Patient Participation/psychology/statistics & numerical data ; Canada/epidemiology ; Male ; Biomedical Research ; Female ; }, abstract = {OBJECTIVE: There are compelling ethical and practical reasons for patient engagement in research (PEIR), however, evidence for best practices remains limited. We investigated PEIR as implemented in CAPTURE ALS, a longitudinal observational study, from study inception through the first 2.5 years of operations.

METHODS: Data were drawn from three engagement initiatives: a community-led letter-writing campaign; consultation with patient and caregiver focus groups; and a study-embedded 'participant partner advisory council' (PPAC). Data were derived retrospectively from study documentation. We used the International Association of Public Participation (IAP2) participation spectrum as a framework for investigation.

RESULTS: 2401 letters from community members to the Canadian government affirmed study objectives and advocated for funding. Feedback from focus group consultation influenced study design and supported the study's data-sharing plan. PPAC collaboration shaped all aspects of the study. Contributions included: co-creation of governance documents, input on study protocols and public-facing communication, and development of engagement webinars for study participants and feedback surveys. Effective communication practices fostered collaboration and helped avoid tokenistic engagement. CAPTURE ALS encompassed all IAP2 participation levels.

CONCLUSIONS: CAPTURE ALS was shaped by meaningful engagement initiatives over the course of the study. Lessons learned included: begin early and embed PEIR within research; build relationships and foster mutual learning; be flexible, open to adaptation, and seek diversity. Primary challenges included funding for early implementation, time needed to maintain relationships, and attrition due to disease progression. All IAP2 participation levels contributed to meaningful PEIR. 'Empowerment' was demonstrated through advocacy.}, } @article {pmid38519722, year = {2024}, author = {Gowda, VK and Babu, S and Kinhal, U and Srinivasan, VM}, title = {Amyotrophic Lateral Sclerosis due to ALS2 Pathogenic Variant Masquerading as Cerebral Palsy: Authors' Reply.}, journal = {Indian journal of pediatrics}, volume = {91}, number = {9}, pages = {989}, pmid = {38519722}, issn = {0973-7693}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Cerebral Palsy/diagnosis ; Diagnosis, Differential ; }, } @article {pmid38517792, year = {2024}, author = {Calderón-Garcidueñas, L and Ayala, A and Mukherjee, PS}, title = {2024 United States Elections: Air Pollution, Neurodegeneration, Neuropsychiatric, and Neurodevelopmental Disorders. Who Cares?.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {98}, number = {4}, pages = {1277-1282}, pmid = {38517792}, issn = {1875-8908}, mesh = {Humans ; United States/epidemiology ; Adult ; *Air Pollutants/adverse effects ; *Air Pollution/adverse effects/analysis ; Particulate Matter ; *Alzheimer Disease ; *Neurodevelopmental Disorders/epidemiology/etiology ; }, abstract = {Air pollution exposures ought to be of significant interest for the United States (US) public as health issues will play a role in the 2024 elections. Citizens are not aware of the harmful brain impact of exposures to ubiquitous anthropogenic combustion emissions and friction-derived nanoparticles, industrial nanoplastics, the growing risk of wildfires, and the smoke plumes of soot. Ample consideration of pediatric and early adulthood hallmarks of Alzheimer's disease, Parkinson's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis and associations with neuropsychiatric and neurodevelopmental disorders in the process of setting, reviewing, and implementing standards for particulate matter (PM)2.5, ultrafine PM, and industrial nanoparticles must be of interest to US citizens.}, } @article {pmid38517530, year = {2024}, author = {Kotsia, E and Chroni, E and Alexandropoulou, A and Mills, C and Veltsista, D and Kefalopoulou, ZM and Michou, E}, title = {Dysphagia Assessments as Criteria in the 'Decision-Making Process' for Percutaneous Endoscopic Gastrostomy Placement in People with Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Dysphagia}, volume = {39}, number = {6}, pages = {977-988}, pmid = {38517530}, issn = {1432-0460}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; *Deglutition Disorders/etiology ; *Gastrostomy/methods ; *Clinical Decision-Making/methods ; Male ; Female ; }, abstract = {To review the assessment methods of dysphagia as a criterion for the decision-making process for Percutaneous Endoscopic Gastrostomy (PEG) placement in patients with Amyotrophic Lateral Sclerosis (ALS). Systematic review. A search was conducted in three databases (EMBASE, CINAHL, PUBMED) in December 2022 and updated in July 2023. Two reviewers independently screened, selected, and extracted data. Study quality was appraised using the Joanna Briggs Institute Critical Appraisal Tools. Systematic review registration number in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42022385461. The searches identified 240 records. The 10 eligible studies included 2 case reports, 4 retrospective studies, 3 prospective studies, and 1 cohort observational study. Study quality was low, with most studies having moderate to high risk of bias. Dysphagia is a common criterion for decision-making. Dysphagia assessment is usually in the form of either self-reports, objective instrumental assessments, or both. Dysphagia is a common criterion for the decision-making process, yet is missing in clinical guidelines. Establishing the optimal means of dysphagia assessment is important for timely decision-making procedures, so that life-threatening consequences of dysphagia are minimized.}, } @article {pmid38517332, year = {2024}, author = {Brenner, D and Sieverding, K and Srinidhi, J and Zellner, S and Secker, C and Yilmaz, R and Dyckow, J and Amr, S and Ponomarenko, A and Tunaboylu, E and Douahem, Y and Schlag, JS and Rodríguez Martínez, L and Kislinger, G and Niemann, C and Nalbach, K and Ruf, WP and Uhl, J and Hollenbeck, J and Schirmer, L and Catanese, A and Lobsiger, CS and Danzer, KM and Yilmazer-Hanke, D and Münch, C and Koch, P and Freischmidt, A and Fetting, M and Behrends, C and Parlato, R and Weishaupt, JH}, title = {A TBK1 variant causes autophagolysosomal and motoneuron pathology without neuroinflammation in mice.}, journal = {The Journal of experimental medicine}, volume = {221}, number = {5}, pages = {}, pmid = {38517332}, issn = {1540-9538}, support = {//Medical Faculty Mannheim of Heidelberg University/ ; //University of Ulm/ ; 10.22.2.022MN//Fritz Thyssen Foundation/ ; 2022_EKES.18//Else Kröner-Fresenius-Stiftung/ ; //Frick Foundation for ALS Research/ ; WE 2791/7-1//Deutsche Forschungsgemeinschaft/ ; //Agence Nationale de la Recherche/ ; //Charité/ ; //Stifterverband für die Deutsche Wissenschaft/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Motor Neurons/pathology ; Mutation ; Neuroinflammatory Diseases ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics/metabolism ; }, abstract = {Heterozygous mutations in the TBK1 gene can cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The majority of TBK1-ALS/FTD patients carry deleterious loss-of-expression mutations, and it is still unclear which TBK1 function leads to neurodegeneration. We investigated the impact of the pathogenic TBK1 missense variant p.E696K, which does not abolish protein expression, but leads to a selective loss of TBK1 binding to the autophagy adaptor protein and TBK1 substrate optineurin. Using organelle-specific proteomics, we found that in a knock-in mouse model and human iPSC-derived motor neurons, the p.E696K mutation causes presymptomatic onset of autophagolysosomal dysfunction in neurons precipitating the accumulation of damaged lysosomes. This is followed by a progressive, age-dependent motor neuron disease. Contrary to the phenotype of mice with full Tbk1 knock-out, RIPK/TNF-α-dependent hepatic, neuronal necroptosis, and overt autoinflammation were not detected. Our in vivo results indicate autophagolysosomal dysfunction as a trigger for neurodegeneration and a promising therapeutic target in TBK1-ALS/FTD.}, } @article {pmid38516846, year = {2024}, author = {Kanazawa, T and Sato, W and Raveney, BJE and Takewaki, D and Kimura, A and Yamaguchi, H and Yokoi, Y and Saika, R and Takahashi, Y and Fujita, T and Saiki, S and Tamaoka, A and Oki, S and Yamamura, T}, title = {Pathogenic Potential of Eomesodermin-Expressing T-Helper Cells in Neurodegenerative Diseases.}, journal = {Annals of neurology}, volume = {95}, number = {6}, pages = {1093-1098}, doi = {10.1002/ana.26920}, pmid = {38516846}, issn = {1531-8249}, support = {16ek0109097h0002//Japan Multiple Sclerosis Society/ ; 17ek0109097h0003//Kato Memorial Trust for Nambyo Research/ ; 16ek0109155h0002//Mitsubishi Foundation/ ; 17ek0109155h0003//Practical Research Project for Rare/intractable Diseases from Japan Agency for Medical Research and Development, AMED/ ; 20FC0201//JSPS KAKENHI/ ; 30-5//National Institute of Neuroscience Intramural Research/ ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Alzheimer Disease/immunology/pathology/metabolism ; Amyotrophic Lateral Sclerosis/immunology ; Granzymes/metabolism ; *Neurodegenerative Diseases/immunology ; *T-Box Domain Proteins/metabolism ; *T-Lymphocytes, Helper-Inducer/immunology ; }, abstract = {Eomesodermin-expressing (Eomes[+]) T-helper (Th) cells show cytotoxic characteristics in secondary progressive multiple sclerosis. We found that Eomes[+] Th cell frequency was increased in the peripheral blood of amyotrophic lateral sclerosis and Alzheimer's disease patients. Furthermore, granzyme B production by Th cells from such patients was high compared with controls. A high frequency of Eomes[+] Th cells was observed in the initial (acutely progressive) stage of amyotrophic lateral sclerosis, and a positive correlation between Eomes[+] Th cell frequency and cognitive decline was observed in Alzheimer's disease patients. Therefore, Eomes[+] Th cells may be involved in the pathology of amyotrophic lateral sclerosis and Alzheimer's disease. ANN NEUROL 2024;95:1093-1098.}, } @article {pmid38516735, year = {2024}, author = {Li, X and Bedlack, R}, title = {Evaluating emerging drugs in phase II & III for the treatment of amyotrophic lateral sclerosis.}, journal = {Expert opinion on emerging drugs}, volume = {29}, number = {2}, pages = {93-102}, doi = {10.1080/14728214.2024.2333420}, pmid = {38516735}, issn = {1744-7623}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Humans ; *Drug Development ; *Drugs, Investigational/pharmacology ; Animals ; *Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; Drug Design ; Molecular Targeted Therapy ; Research Design ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis is a rapidly progressive motor neuron disorder causing severe disability and premature death. Owing to the advances in uncovering ALS pathophysiology, efficient clinical trial design and research advocacy program, several disease-modifying drugs have been approved for treating ALS. Despite this progress, ALS remains a rapidly disabling and life shortening condition. There is a critical need for more effective therapies.

AREAS COVERED: Here, we reviewed the emerging ALS therapeutics undergoing phase II & III clinical trials. To identify the investigational drugs, we searched ALS and phase II/III trials that are active and recruiting or not yet recruiting on clinicaltrials.gov and Pharmaprojects database.

EXPERT OPINION: The current pipeline is larger and more diverse than ever, with drugs targeting potential genetic and retroviral causes of ALS and drugs targeting a wide array of downstream pathways, including RNA metabolism, protein aggregation, integrated stress response and neuroinflammation.We remain most excited about those that target direct causes of ALS, e.g. antisense oligonucleotides targeting causative genes. Drugs that eliminate abnormal protein aggregates are also up-and-coming. Eventually, because of the heterogeneity of ALS pathophysiology, biomarkers that determine which biological events are most important for an individual ALS patient are needed.}, } @article {pmid38516553, year = {2023}, author = {Aishwarya, R and Abdullah, CS and Remex, NS and Nitu, S and Hartman, B and King, J and Bhuiyan, MAN and Rom, O and Miriyala, S and Panchatcharam, M and Orr, AW and Kevil, CG and Bhuiyan, MS}, title = {Pathological Sequelae Associated with Skeletal Muscle Atrophy and Histopathology in G93A*SOD1 Mice.}, journal = {Muscles (Basel, Switzerland)}, volume = {2}, number = {1}, pages = {51-74}, pmid = {38516553}, issn = {2813-0413}, support = {R00 HL150233/HL/NHLBI NIH HHS/United States ; K99 HL150233/HL/NHLBI NIH HHS/United States ; R01 DK134011/DK/NIDDK NIH HHS/United States ; R21 AA026708/AA/NIAAA NIH HHS/United States ; R01 HL152723/HL/NHLBI NIH HHS/United States ; P20 GM121307/GM/NIGMS NIH HHS/United States ; R01 HL098435/HL/NHLBI NIH HHS/United States ; R01 HL133497/HL/NHLBI NIH HHS/United States ; R01 HL149264/HL/NHLBI NIH HHS/United States ; R15 HL141998/HL/NHLBI NIH HHS/United States ; R01 HL145753/HL/NHLBI NIH HHS/United States ; R01 HL141155/HL/NHLBI NIH HHS/United States ; R21 AA025744/AA/NIAAA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex systemic disease that primarily involves motor neuron dysfunction and skeletal muscle atrophy. One commonly used mouse model to study ALS was generated by transgenic expression of a mutant form of human superoxide dismutase 1 (SOD1) gene harboring a single amino acid substitution of glycine to alanine at codon 93 (G93A*SOD1). Although mutant-SOD1 is ubiquitously expressed in G93A*SOD1 mice, a detailed analysis of the skeletal muscle expression pattern of the mutant protein and the resultant muscle pathology were never performed. Using different skeletal muscles isolated from G93A*SOD1 mice, we extensively characterized the pathological sequelae of histological, molecular, ultrastructural, and biochemical alterations. Muscle atrophy in G93A*SOD1 mice was associated with increased and differential expression of mutant-SOD1 across myofibers and increased MuRF1 protein level. In addition, high collagen deposition and myopathic changes sections accompanied the reduced muscle strength in the G93A*SOD1 mice. Furthermore, all the muscles in G93A*SOD1 mice showed altered protein levels associated with different signaling pathways, including inflammation, mitochondrial membrane transport, mitochondrial lipid uptake, and antioxidant enzymes. In addition, the mutant-SOD1 protein was found in the mitochondrial fraction in the muscles from G93A*SOD1 mice, which was accompanied by vacuolized and abnormal mitochondria, altered OXPHOS and PDH complex protein levels, and defects in mitochondrial respiration. Overall, we reported the pathological sequelae observed in the skeletal muscles of G93A*SOD1 mice resulting from the whole-body mutant-SOD1 protein expression.}, } @article {pmid38516187, year = {2024}, author = {Dudas, EF and Tully, MD and Foldes, T and Kelly, G and Tartaglia, GG and Pastore, A}, title = {The structural properties of full-length annexin A11.}, journal = {Frontiers in molecular biosciences}, volume = {11}, number = {}, pages = {1347741}, pmid = {38516187}, issn = {2296-889X}, abstract = {Annexin A11 (ANXA11) is a calcium-dependent phospholipid-binding protein belonging to the annexin protein family and implicated in the neurodegenerative amyotrophic lateral sclerosis. Structurally, ANXA11 contains a conserved calcium-binding C-terminal domain common to all annexins and a putative intrinsically unfolded N-terminus specific for ANXA11. Little is known about the structure and functions of this region of the protein. By analogy with annexin A1, it was suggested that residues 38 to 59 within the ANXA11 N-terminus could form a helical region that would be involved in interactions. Interestingly, this region contains residues that, when mutated, may lead to clinical manifestations. In the present study, we have studied the structural features of the full-length protein with special attention to the N-terminal region using a combination of biophysical techniques which include nuclear magnetic resonance and small angle X-ray scattering. We show that the N-terminus is intrinsically disordered and that the overall features of the protein are not markedly affected by the presence of calcium. We also analyzed the 38-59 helix hypothesis using synthetic peptides spanning both the wild-type sequence and clinically relevant mutations. We show that the peptides have a remarkable character typical of a native helix and that mutations do not alter the behaviour suggesting that they are required for interactions rather than being structurally important. Our work paves the way to a more thorough understanding of the ANXA11 functions.}, } @article {pmid38515787, year = {2024}, author = {Wang, L and Fang, X and Ling, B and Wang, F and Xia, Y and Zhang, W and Zhong, T and Wang, X}, title = {Research progress on ferroptosis in the pathogenesis and treatment of neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1359453}, pmid = {38515787}, issn = {1662-5102}, abstract = {Globally, millions of individuals are impacted by neurodegenerative disorders including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD). Although a great deal of energy and financial resources have been invested in disease-related research, breakthroughs in therapeutic approaches remain elusive. The breakdown of cells usually happens together with the onset of neurodegenerative diseases. However, the mechanism that triggers neuronal loss is unknown. Lipid peroxidation, which is iron-dependent, causes a specific type of cell death called ferroptosis, and there is evidence its involvement in the pathogenic cascade of neurodegenerative diseases. However, the specific mechanisms are still not well known. The present article highlights the basic processes that underlie ferroptosis and the corresponding signaling networks. Furthermore, it provides an overview and discussion of current research on the role of ferroptosis across a variety of neurodegenerative conditions.}, } @article {pmid38515451, year = {2024}, author = {Zoccolella, S and Milella, G and Giugno, A and Devitofrancesco, V and Damato, R and Tamburrino, L and Misceo, S and Filardi, M and Logroscino, G}, title = {Neurophysiological indices for split phenomena: correlation with age and sex and potential implications in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1371953}, pmid = {38515451}, issn = {1664-2295}, abstract = {BACKGROUND: Split phenomena (SP) are characterized by patterns of differential muscle wasting and atrophy, which are highly prevalent in amyotrophic lateral sclerosis (ALS) patients. Several neurophysiological indicators, including the split-hand index (SHI), split-leg index (SLI), and split-elbow index (SEI), have been proposed to assess SP. Nevertheless, their cutoff values and the impact of age and sex on these measures remain unclear.

METHODS: We prospectively collected neurophysiological data from 300 healthy adult subjects. The following indices were measured from compound muscle action potentials (CMAPs): SHI [abductor pollicis brevis (APBcmap) x first dorsal interosseous (FDI)cmap/adductor digiti minimi (ADMcmap)], SEI (BICEPScmap/TRICEPScmap), SLI (extensor digit brevis (EDB)cmap/abductor Hallucis (AH)cmap), and the neurophysiological ratios APBcmap /ADMcmap and FDIcmap/ADMcmap. Multiple linear regression analysis was used to investigate the association between age, sex, CMAPs, and neurophysiological indicators.

RESULTS: The median SHI was 10.4, with a median APBcmap/ADMcmap ratio of 0.9 and a median FDIcmap/ADMcmap ratio of 1.2. The median SEI was 1.6 (IQR:1.1-2.4) and the median SLI was 0.7 (IQR:0.5-1.0). Negative associations were observed between age, most of the CMAPs, and all the neurophysiological indices, except for SLI. The male subjects exhibited significantly higher CMAP values for the first dorsal interosseous (FDI), biceps, and SHI compared to the female participants.

CONCLUSION: Our findings highlight the importance of age- and sex-adjusted normative data for SP indices, which could enhance their diagnostic accuracy and clinical utility in patients with ALS. The SL index appears to be the most reliable indicator, as it showed no significant association with age or sex.}, } @article {pmid38515326, year = {2024}, author = {Lee, DY and Kwon, YN and Lee, K and Kim, SJ and Sung, JJ}, title = {Dual effects of TGF-β inhibitor in ALS - inhibit contracture and neurodegeneration.}, journal = {Journal of neurochemistry}, volume = {168}, number = {9}, pages = {2495-2514}, doi = {10.1111/jnc.16102}, pmid = {38515326}, issn = {1471-4159}, support = {2018R1A5A2025964//National Research Foundation of Korea (NRF) Grant/ ; 2019M3C7A1031867//National Research Foundation of Korea (NRF) Grant/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; Mice ; *Transforming Growth Factor beta/metabolism/antagonists & inhibitors ; *Contracture/drug therapy/prevention & control ; Mice, Transgenic ; Male ; Mice, Inbred C57BL ; Piperidines/pharmacology/therapeutic use ; Humans ; }, abstract = {As persistent elevation of transforming growth factor-β (TGF-β) promotes fibrosis of muscles and joints and accelerates disease progression in amyotrophic lateral sclerosis (ALS), we investigated whether inhibition of TGF-β would be effective against both exacerbations. The effects of TGF-β and its inhibitor on myoblasts and fibroblasts were tested in vitro and confirmed in vivo, and the dual action of a TGF-β inhibitor in ameliorating the pathogenic role of TGF-β in ALS mice was identified. In the peripheral neuromuscular system, fibrosis in the muscles and joint cavities induced by excessive TGF-β causes joint contracture and muscular degeneration, which leads to motor dysfunction. In an ALS mouse model, an increase in TGF-β in the central nervous system (CNS), consistent with astrocyte activity, was associated with M1 microglial activity and pro-inflammatory conditions, as well as with neuronal cell death. Treatment with the TGF-β inhibitor halofuginone could prevent musculoskeletal fibrosis, resulting in the alleviation of joint contracture and delay of motor deterioration in ALS mice. Halofuginone could also reduce glial cell-induced neuroinflammation and neuronal apoptosis. These dual therapeutic effects on both the neuromuscular system and the CNS were observed from the beginning to the end stages of ALS; as a result, treatment with a TGF-β inhibitor from the early stage of disease delayed the time of symptom exacerbation in ALS mice, which led to prolonged survival.}, } @article {pmid38514815, year = {2024}, author = {Baxter, RC}, title = {Endocrine and cellular physiology and pathology of the insulin-like growth factor acid-labile subunit.}, journal = {Nature reviews. Endocrinology}, volume = {20}, number = {7}, pages = {414-425}, pmid = {38514815}, issn = {1759-5037}, mesh = {Humans ; Animals ; *Glycoproteins/metabolism ; Carrier Proteins/metabolism ; Insulin-Like Growth Factor I/metabolism ; Mice ; Insulin-Like Growth Factor Binding Proteins/metabolism/physiology ; Insulin-Like Growth Factor II/metabolism ; Endocrine System/metabolism ; Insulin-Like Peptides ; }, abstract = {The acid-labile subunit (ALS) of the insulin-like growth factor (IGF) binding protein (IGFBP) complex, encoded in humans by IGFALS, has a vital role in regulating the endocrine transport and bioavailability of IGF-1 and IGF-2. Accordingly, ALS has a considerable influence on postnatal growth and metabolism. ALS is a leucine-rich glycoprotein that forms high-affinity ternary complexes with IGFBP-3 or IGFBP-5 when they are occupied by either IGF-1 or IGF-2. These complexes constitute a stable reservoir of circulating IGFs, blocking the potentially hypoglycaemic activity of unbound IGFs. ALS is primarily synthesized by hepatocytes and its expression is lower in non-hepatic tissues. ALS synthesis is strongly induced by growth hormone and suppressed by IL-1β, thus potentially serving as a marker of growth hormone secretion and/or activity and of inflammation. IGFALS mutations in humans and Igfals deletion in mice cause modest growth retardation and pubertal delay, accompanied by decreased osteogenesis and enhanced adipogenesis. In hepatocellular carcinoma, IGFALS is described as a tumour suppressor; however, its contribution to other cancers is not well delineated. This Review addresses the endocrine physiology and pathology of ALS, discusses the latest cell and proteomic studies that suggest emerging cellular roles for ALS and outlines its involvement in other disease states.}, } @article {pmid38514515, year = {2024}, author = {Finsterer, J}, title = {Amyotrophic Lateral Sclerosis due to ALS2 Pathogenic Variant Masquerading as Cerebral Palsy: Correspondence.}, journal = {Indian journal of pediatrics}, volume = {91}, number = {9}, pages = {988}, pmid = {38514515}, issn = {0973-7693}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Cerebral Palsy/diagnosis ; Diagnosis, Differential ; Guanine Nucleotide Exchange Factors/genetics ; Female ; Child, Preschool ; }, } @article {pmid38512820, year = {2024}, author = {Bartolomé-Nafría, A and García-Pardo, J and Ventura, S}, title = {Mutations in human prion-like domains: pathogenic but not always amyloidogenic.}, journal = {Prion}, volume = {18}, number = {1}, pages = {28-39}, pmid = {38512820}, issn = {1933-690X}, mesh = {Humans ; *Prions/metabolism ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Mutation ; }, abstract = {Heterogeneous nuclear ribonucleoproteins (hnRNPs) are multifunctional proteins with integral roles in RNA metabolism and the regulation of alternative splicing. These proteins typically contain prion-like domains of low complexity (PrLDs or LCDs) that govern their assembly into either functional or pathological amyloid fibrils. To date, over 60 mutations targeting the LCDs of hnRNPs have been identified and associated with a spectrum of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). The cryo-EM structures of pathological and functional fibrils formed by different hnRNPs have been recently elucidated, including those of hnRNPA1, hnRNPA2, hnRNPDL-2, TDP-43, and FUS. In this review, we discuss the structural features of these amyloid assemblies, placing particular emphasis on scrutinizing the impact of prevalent disease-associated mutations mapping within their LCDs. By performing systematic energy calculations, we reveal a prevailing trend of destabilizing effects induced by these mutations in the amyloid structure, challenging the traditionally assumed correlation between pathogenicity and amyloidogenic propensity. Understanding the molecular basis of this discrepancy might provide insights for developing targeted therapeutic strategies to combat hnRNP-associated diseases.}, } @article {pmid38512130, year = {2024}, author = {Pak, V and Adewale, Q and Bzdok, D and Dadar, M and Zeighami, Y and Iturria-Medina, Y}, title = {Distinctive whole-brain cell types predict tissue damage patterns in thirteen neurodegenerative conditions.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {38512130}, issn = {2050-084X}, support = {CIHR Project Grant 2020/CAPMC/CIHR/Canada ; }, mesh = {Humans ; Brain ; *Neurodegenerative Diseases ; Neurons ; *Parkinson Disease ; Brain Mapping ; }, abstract = {For over a century, brain research narrative has mainly centered on neuron cells. Accordingly, most neurodegenerative studies focus on neuronal dysfunction and their selective vulnerability, while we lack comprehensive analyses of other major cell types' contribution. By unifying spatial gene expression, structural MRI, and cell deconvolution, here we describe how the human brain distribution of canonical cell types extensively predicts tissue damage in 13 neurodegenerative conditions, including early- and late-onset Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, mutations in presenilin-1, and 3 clinical variants of frontotemporal lobar degeneration (behavioral variant, semantic and non-fluent primary progressive aphasia) along with associated three-repeat and four-repeat tauopathies and TDP43 proteinopathies types A and C. We reconstructed comprehensive whole-brain reference maps of cellular abundance for six major cell types and identified characteristic axes of spatial overlapping with atrophy. Our results support the strong mediating role of non-neuronal cells, primarily microglia and astrocytes, in spatial vulnerability to tissue loss in neurodegeneration, with distinct and shared across-disorder pathomechanisms. These observations provide critical insights into the multicellular pathophysiology underlying spatiotemporal advance in neurodegeneration. Notably, they also emphasize the need to exceed the current neuro-centric view of brain diseases, supporting the imperative for cell-specific therapeutic targets in neurodegeneration.}, } @article {pmid38511674, year = {2024}, author = {Amesaka, H and Hara, M and Sakai, Y and Shintani, A and Sue, K and Yamanaka, T and Tanaka, SI and Furukawa, Y}, title = {Engineering a monobody specific to monomeric Cu/Zn-superoxide dismutase associated with amyotrophic lateral sclerosis.}, journal = {Protein science : a publication of the Protein Society}, volume = {33}, number = {4}, pages = {e4961}, pmid = {38511674}, issn = {1469-896X}, support = {19H05765//Grants-in-Aid for Scientific Research on Innovative Areas/ ; 20H05516//Grants-in-Aid for Scientific Research on Innovative Areas/ ; 22H02768//Scientific Research (B)/ ; 21K05386//Scientific Research (C)/ ; 22K19389//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; }, mesh = {Humans ; Superoxide Dismutase-1/chemistry ; *Amyotrophic Lateral Sclerosis/genetics ; Protein Folding ; Superoxide Dismutase/chemistry ; Saccharomyces cerevisiae/metabolism ; Zinc/metabolism ; Mutation ; }, abstract = {Misfolding of mutant Cu/Zn-superoxide dismutase (SOD1) has been implicated in familial form of amyotrophic lateral sclerosis (ALS). A natively folded SOD1 forms a tight homodimer, and the dimer dissociation has been proposed to trigger the oligomerization/aggregation of SOD1. Besides increasing demand for probes allowing the detection of monomerized forms of SOD1 in various applications, the development of probes has been limited to conventional antibodies. Here, we have developed Mb(S4) monobody, a small synthetic binding protein based on the fibronectin type III scaffold, that recognizes a monomeric but not dimeric form of SOD1 by performing combinatorial library selections using phage and yeast-surface display methods. Although Mb(S4) was characterized by its excellent selectivity to the monomeric conformation of SOD1, the monomeric SOD1/Mb(S4) complex was not so stable (apparent Kd ~ μM) as to be detected in conventional pull-down experiments. Instead, the complex of Mb(S4) with monomeric but not dimeric SOD1 was successfully trapped by proximity-enabled chemical crosslinking even when reacted in the cell lysates. We thus anticipate that Mb(S4) binding followed by chemical crosslinking would be a useful strategy for in vitro and also ex vivo detection of the monomeric SOD1 proteins.}, } @article {pmid38511649, year = {2024}, author = {Craig, RA and De Vicente, J and Estrada, AA and Feng, JA and Lexa, KW and Canet, MJ and Dowdle, WE and Erickson, RI and Flores, BN and Haddick, PCG and Kane, LA and Lewcock, JW and Moerke, NJ and Poda, SB and Sweeney, Z and Takahashi, RH and Tong, V and Wang, J and Yulyaningsih, E and Solanoy, H and Scearce-Levie, K and Sanchez, PE and Tang, L and Xu, M and Zhang, R and Osipov, M}, title = {Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases.}, journal = {Journal of medicinal chemistry}, volume = {67}, number = {7}, pages = {5758-5782}, doi = {10.1021/acs.jmedchem.3c02422}, pmid = {38511649}, issn = {1520-4804}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Mutation ; Eukaryotic Initiation Factor-2B/genetics/metabolism ; Brain/metabolism ; *Leukoencephalopathies/metabolism ; }, abstract = {Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and stress granule formation in response to cellular insult. Modulation of the ISR has been proposed as a therapeutic strategy for treatment of neurodegenerative diseases such as vanishing white matter (VWM) disease and amyotrophic lateral sclerosis (ALS) based on its ability to improve cellular homeostasis and prevent neuronal degeneration. Herein, we report the small-molecule discovery campaign that identified potent, selective, and CNS-penetrant eIF2B activators using both structure- and ligand-based drug design. These discovery efforts culminated in the identification of DNL343, which demonstrated a desirable preclinical drug profile, including a long half-life and high oral bioavailability across preclinical species. DNL343 was progressed into clinical studies and is currently undergoing evaluation in late-stage clinical trials for ALS.}, } @article {pmid38511172, year = {2024}, author = {Rossi, JJ}, title = {Accessory oligos for neuronal delivery of therapeutic siRNAs for ALS.}, journal = {Molecular therapy. Nucleic acids}, volume = {35}, number = {2}, pages = {102153}, pmid = {38511172}, issn = {2162-2531}, } @article {pmid38511059, year = {2024}, author = {Casado Gama, H and Amorós, MA and Andrade de Araújo, M and Sha, CM and Vieira, MPS and Torres, RGD and Souza, GF and Junkes, JA and Dokholyan, NV and Leite Góes Gitaí, D and Duzzioni, M}, title = {Systematic review and meta-analysis of dysregulated microRNAs derived from liquid biopsies as biomarkers for amyotrophic lateral sclerosis.}, journal = {Non-coding RNA research}, volume = {9}, number = {2}, pages = {523-535}, pmid = {38511059}, issn = {2468-0540}, abstract = {The discovery of disease-specific biomarkers, such as microRNAs (miRNAs), holds the potential to transform the landscape of Amyotrophic Lateral Sclerosis (ALS) by facilitating timely diagnosis, monitoring treatment response, and accelerating drug discovery. Such advancement could ultimately improve the quality of life and survival rates for ALS patients. Despite more than a decade of research, no miRNA biomarker candidate has been translated into clinical practice. We conducted a systematic review and meta-analysis to quantitatively synthesize data from original studies that analyzed miRNA expression from liquid biopsies via PCR and compared them to healthy controls. Our analysis encompasses 807 miRNA observations from 31 studies, stratified according to their source tissue. We identified consistently dysregulated miRNAs in serum (hsa-miR-3665, -4530, -4745-5p, -206); blood (hsa-miR-338-3p, -183-5p); cerebrospinal fluid (hsa-miR-34a-3p); plasma (hsa-miR-206); and neural-enriched extracellular vesicles from plasma (hsa-miR-146a-5p, -151a-5p, -10b-5p, -29b-3p, and -4454). The meta-analyses provided further support for the upregulation of hsa-miR-206, hsa-miR-338-3p, hsa-miR-146a-5p and hsa-miR-151a-5p, and downregulation of hsa-miR-183-5p, hsa-miR-10b-5p, hsa-miR-29b-3p, and hsa-miR-4454 as consistent indicators of ALS across independent studies. Our findings provide valuable insights into the current understanding of miRNAs' dysregulated expression in ALS patients and on the researchers' choices of methodology. This work contributes to the ongoing efforts towards discovering disease-specific biomarkers.}, } @article {pmid38510000, year = {2024}, author = {Ditan, ID and Turalde, CWR}, title = {Treatment gaps in the care of amyotrophic lateral sclerosis in the Philippines: A scoping review.}, journal = {Heliyon}, volume = {10}, number = {6}, pages = {e27944}, pmid = {38510000}, issn = {2405-8440}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease affecting both the upper and lower motor neurons. Much of the management of ALS is supportive with the goal of maximizing patient quality of life. While the Philippines was participative in the "Ice Bucket Challenge" in 2014, it is up for investigation whether substantial changes occurred to improve healthcare for ALS patients. This study aims to evaluate the treatment gaps in the management of ALS in the Philippines through a scoping review. Data on epidemiology, health systems, and pharmacotherapy available regarding ALS in the local setting were synthesized. Nine articles were included. As of July 2023, there were only four indexed studies on ALS from the Philippines. Five of the included articles investigated ALS in Filipino populations but were not authored by Filipinos nor affiliated with Philippine institutions. The available literature showed a distinct lack of local ALS epidemiologic data, as well as limited availability in diagnostic centers, medications, health financing options, and digestible information for Filipinos. The limitations in managing ALS in the country are multifactorial - from political, medical, and social. It is imperative to establish a national database, financing systems, support groups, and accessible diagnostic centers for ALS patients.}, } @article {pmid38509062, year = {2024}, author = {Funes, S and Jung, J and Gadd, DH and Mosqueda, M and Zhong, J and Shankaracharya, and Unger, M and Stallworth, K and Cameron, D and Rotunno, MS and Dawes, P and Fowler-Magaw, M and Keagle, PJ and McDonough, JA and Boopathy, S and Sena-Esteves, M and Nickerson, JA and Lutz, C and Skarnes, WC and Lim, ET and Schafer, DP and Massi, F and Landers, JE and Bosco, DA}, title = {Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {2497}, pmid = {38509062}, issn = {2041-1723}, support = {RF1 AG068281/AG/NIA NIH HHS/United States ; R21 NS120126/NS/NINDS NIH HHS/United States ; R01 GM147677/GM/NIGMS NIH HHS/United States ; R01 NS108769/NS/NINDS NIH HHS/United States ; R01 MH113743/MH/NIMH NIH HHS/United States ; R01 NS117533/NS/NINDS NIH HHS/United States ; R01 GM137529/GM/NIGMS NIH HHS/United States ; U54 OD020351/OD/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Microglia/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Profilins/metabolism ; *Neurodegenerative Diseases ; Mutation ; }, abstract = {Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be elucidated. To investigate the effect of neurodegenerative disease-linked genes on the intrinsic properties of microglia, we studied microglia-like cells derived from human induced pluripotent stem cells (iPSCs), termed iMGs, harboring mutations in profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs exhibited evidence of lipid dysmetabolism, autophagy dysregulation and deficient phagocytosis, a canonical microglia function. Mutant PFN1 also displayed enhanced binding affinity for PI3P, a critical signaling molecule involved in autophagic and endocytic processing. Our cumulative data implicate a gain-of-toxic function for mutant PFN1 within the autophagic and endo-lysosomal pathways, as administration of rapamycin rescued phagocytic dysfunction in ALS-PFN1 iMGs. These outcomes demonstrate the utility of iMGs for neurodegenerative disease research and implicate microglial vesicular degradation pathways in the pathogenesis of these disorders.}, } @article {pmid38508480, year = {2024}, author = {Bager, P and Hvas, CL and Dahlerup, JF}, title = {Severe Fatigue in Inflammatory Bowel Disease: Dopaminergic Therapy With Modafinil or Vitamin Therapy With Thiamine.}, journal = {Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association}, volume = {22}, number = {11}, pages = {2348-2349}, doi = {10.1016/j.cgh.2024.03.002}, pmid = {38508480}, issn = {1542-7714}, mesh = {Humans ; *Modafinil/therapeutic use ; *Fatigue/drug therapy ; *Inflammatory Bowel Diseases/drug therapy/complications ; *Thiamine/therapeutic use ; Treatment Outcome ; Male ; Female ; Middle Aged ; }, abstract = {We found Moulton et al's[1] illustrative case series of 10 patients with inflammatory bowel disease (IBD) and chronic fatigue, all presenting with depression, particularly interesting. [1] Among the patients, 8 previously had undergone treatment with multiple psychotropic medications, and 2 had active IBD as indicated by increased fecal calprotectin levels. Remarkably, all 10 patients responded positively to open-label treatment with modafinil, a central nervous system stimulant that blocks dopamine reuptake transport, which resulted in an impressive improvement in their fatigue symptoms. At baseline, the self-reported mean fatigue score was 16, measured on the IBD Fatigue Assessment Scale (IBD-FAS), which ranges up to 20, and with levels higher than 11 indicating severe fatigue. After 6 months of modafinil treatment, the mean fatigue score was 6.7.[1].}, } @article {pmid38506473, year = {2024}, author = {Lillo, P and Zitko, P and Godoy-Reyes, G and Asenjo, G and Sáez, D and Cea, G and Navarrete, P and Valenzuela, D and Hughes, R and Heverin, M and Logroscino, G and Hardiman, O}, title = {Incidence of amyotrophic lateral sclerosis in Chile.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {528-532}, doi = {10.1080/21678421.2024.2329706}, pmid = {38506473}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Male ; Female ; Chile/epidemiology ; Incidence ; Middle Aged ; Aged ; Adult ; Cohort Studies ; Aged, 80 and over ; Survival Rate/trends ; Registries ; }, abstract = {OBJECTIVE: This study aimed to estimate amyotrophic lateral sclerosis (ALS) incidence and survival rates in the Metropolitan region of Chile.

METHODS: We conducted a cohort study of ALS cases in the Metropolitan Region from 2016 to 2019. A total of 219 ALS patients were recruited from Corporación ELA-Chile registry, in collaboration with neurologists from Sociedad de Neurología, Psiquiatría y Neurocirugía de Chile. We calculated incidence rates by sex and age and determined median survival from onset and diagnosis. Survival analysis used the Kaplan-Meier statistic, estimating hazard ratios for age, sex, time from symptom onset and from diagnosis using a Weibull regression model. All analyses were done using R 4.1.0.

RESULTS: Overall, ALS diagnosis incidence was 0.97 cases per 100,000 inhabitants, peaking in the 70-79 age group and declining thereafter. The male-to-female ratio was 1.23. The median time to death from diagnosis was 2.3 years (95% confidence interval [CI]: 1.9-2.5), and from the first symptom, it was 3.1 years (95% CI: 2.8-3.5).

CONCLUSIONS: This is the first population-based study reporting ALS incidence and survival rates in Chile's Metropolitan region. Incidence resembled other Latin American studies. Median survival from diagnosis and from the first symptom were in line with previous findings. Our results corroborated lower ALS rates in Latin America, consistent with prior research.}, } @article {pmid38505945, year = {2024}, author = {Kutlubaev, MA and Areprintseva, DK and Radakovic, R and Pervushina, EV}, title = {Psychometric properties of the Russian version of the Edinburgh cognitive and behavioral amyotrophic lateral sclerosis screen.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {785-787}, doi = {10.1080/21678421.2024.2328579}, pmid = {38505945}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis/complications ; Male ; Female ; Middle Aged ; *Psychometrics/methods ; Aged ; Russia/epidemiology ; Reproducibility of Results ; *Neuropsychological Tests/statistics & numerical data ; Adult ; Cognitive Dysfunction/diagnosis/etiology/psychology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition with observable cognitive and behavioral impairment. The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is a tool developed specifically for people with ALS (pwALS) and previously translated into Russian, but the psychometric properties have not yet been explored. The aim was to explore and determine the psychometric properties of the Russian-version of ECAS (ECAS-R).

METHODS: 56 Russian speaking pwALS, 32 of their caregivers and 26 healthy controls were recruited for the study. They completed the ECAS-R, Patient Health Questionnaire-9 (PHQ-9) and Montreal Cognitive Assessment (MoCA). King Staging System was also utilized. Internal consistency, divergent and convergent validity, as well as culturally-derived cutoff scores of ECAS-R were determined.

RESULTS: The internal consistency of ECAS-R was good (Cronbach's alpha = 0.73). Convergent validity was observed though a strong correlation between the ECAS-R and MoCA scores. No correlation between ECAS-R and PHQ-9 were observed in terms of divergent validity. Based on culturally-derived cutoff scores, 64.2% (N = 36) of pwALS displayed cognitive impairment, with the most affected cognitive domains as executive function and language. Apathy was the most common behavioral impairment for pwALS followed by a loss of sympathy/empathy.

CONCLUSIONS: The ECAS-R is valid and reliable tool for the screening for the cognitive and behavioral impairment in Russian-speaking pwALS, with culturally-derived cutoffs presented.}, } @article {pmid38505770, year = {2024}, author = {Shi, J and Wang, Z and Yi, M and Xie, S and Zhang, X and Tao, D and Liu, Y and Yang, Y}, title = {Evidence based on Mendelian randomization and colocalization analysis strengthens causal relationships between structural changes in specific brain regions and risk of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1333782}, pmid = {38505770}, issn = {1662-4548}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of motor neurons in the brain and spinal cord with a poor prognosis. Previous studies have observed cognitive decline and changes in brain morphometry in ALS patients. However, it remains unclear whether the brain structural alterations contribute to the risk of ALS. In this study, we conducted a bidirectional two-sample Mendelian randomization (MR) and colocalization analysis to investigate this causal relationship.

METHODS: Summary data of genome-wide association study were obtained for ALS and the brain structures, including surface area (SA), thickness and volume of subcortical structures. Inverse-variance weighted (IVW) method was used as the main estimate approach. Sensitivity analysis was conducted detect heterogeneity and pleiotropy. Colocalization analysis was performed to calculate the posterior probability of causal variation and identify the common genes.

RESULTS: In the forward MR analysis, we found positive associations between the SA in four cortical regions (lingual, parahippocampal, pericalcarine, and middle temporal) and the risk of ALS. Additionally, decreased thickness in nine cortical regions (caudal anterior cingulate, frontal pole, fusiform, inferior temporal, lateral occipital, lateral orbitofrontal, pars orbitalis, pars triangularis, and pericalcarine) was significantly associated with a higher risk of ALS. In the reverse MR analysis, genetically predicted ALS was associated with reduced thickness in the bankssts and increased thickness in the caudal middle frontal, inferior parietal, medial orbitofrontal, and superior temporal regions. Colocalization analysis revealed the presence of shared causal variants between the two traits.

CONCLUSION: Our results suggest that altered brain morphometry in individuals with high ALS risk may be genetically mediated. The causal associations of widespread multifocal extra-motor atrophy in frontal and temporal lobes with ALS risk support the notion of a continuum between ALS and frontotemporal dementia. These findings enhance our understanding of the cortical structural patterns in ALS and shed light on potentially viable therapeutic targets.}, } @article {pmid38505661, year = {2023}, author = {Alix, JJP and Plesia, M and Schooling, CN and Dudgeon, AP and Kendall, CA and Kadirkamanathan, V and McDermott, CJ and Gorman, GS and Taylor, RW and Mead, RJ and Shaw, PJ and Day, JC}, title = {Non-negative matrix factorisation of Raman spectra finds common patterns relating to neuromuscular disease across differing equipment configurations, preclinical models and human tissue.}, journal = {Journal of Raman spectroscopy : JRS}, volume = {54}, number = {3}, pages = {258-268}, pmid = {38505661}, issn = {0377-0486}, support = {/WT_/Wellcome Trust/United Kingdom ; MC_PC_15034/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Raman spectroscopy shows promise as a biomarker for complex nerve and muscle (neuromuscular) diseases. To maximise its potential, several challenges remain. These include the sensitivity to different instrument configurations, translation across preclinical/human tissues and the development of multivariate analytics that can derive interpretable spectral outputs for disease identification. Nonnegative matrix factorisation (NMF) can extract features from high-dimensional data sets and the nonnegative constraint results in physically realistic outputs. In this study, we have undertaken NMF on Raman spectra of muscle obtained from different clinical and preclinical settings. First, we obtained and combined Raman spectra from human patients with mitochondrial disease and healthy volunteers, using both a commercial microscope and in-house fibre optic probe. NMF was applied across all data, and spectral patterns common to both equipment configurations were identified. Linear discriminant models utilising these patterns were able to accurately classify disease states (accuracy 70.2-84.5%). Next, we applied NMF to spectra obtained from the mdx mouse model of a Duchenne muscular dystrophy and patients with dystrophic muscle conditions. Spectral fingerprints common to mouse/human were obtained and able to accurately identify disease (accuracy 79.5-98.8%). We conclude that NMF can be used to analyse Raman data across different equipment configurations and the preclinical/clinical divide. Thus, the application of NMF decomposition methods could enhance the potential of Raman spectroscopy for the study of fatal neuromuscular diseases.}, } @article {pmid38505513, year = {2023}, author = {Kamp, N and Krenn, P and Avian, M and Sass, O}, title = {Comparability of multi-temporal DTMs derived from different LiDAR platforms: Error sources and uncertainties in the application of geomorphic impact studies.}, journal = {Earth surface processes and landforms}, volume = {48}, number = {6}, pages = {1152-1175}, pmid = {38505513}, issn = {1096-9837}, abstract = {Multi-temporal digital terrain models (DTMs) derived from airborne or uncrewed aerial vehicle (UAV)-borne light detection and ranging (LiDAR) platforms are frequently used tools in geomorphic impact studies. Accurate estimation of mobilized sediments from multi-temporal DTMs is indispensable for hazard assessment. To study volumetric changes in alpine environments it is crucial to identify and discuss different kind of error sources in multi-temporal data. We subdivided errors into those caused by data acquisition, data processing, and spatial properties of the terrain. In terms of the quantification of surface changes, the propagation of errors can lead to high uncertainties. Three alpine catchments with different LiDAR point clouds of different origins (airborne laser scanning [ALS], UAV-borne laser scanning [ULS]), varying point densities, accuracies and qualities were analysed, and used as basis for interpolating DTMs. The workflow was developed in the Schöttlbach area in Styria and later applied to further catchments in Austria. The main aim of the presented work is a comprehensive DTM uncertainty analysis specially designed for geomorphic impact studies, with a resulting uncertainty analysis serving as input for a change detection tool. Our findings reveal that geomorphic impact studies need the careful distinction between actual surface changes and different data uncertainties. ULS combines the benefits of terrestrial laser scanning with all the benefits of ALS. However, the use of ULS data does not necessarily improve the results of the analysis since the high level of detail is not always helpful in geomorphic impact studies. In order to make the different point clouds and DTMs comparable the quality of the ULS point cloud had to be reduced to fit the accuracy of the reference data (older ALS point clouds). Using a point cloud with a high point density with a regular planimetric point spacing and less data gaps, in the best case collected during leaf-off conditions (e.g., cross-flight strategy) turned out to be sufficient for our geomorphic research purposes.}, } @article {pmid38504981, year = {2024}, author = {Cao, W and Cao, Z and Tang, L and Xu, C and Fan, D}, title = {Immune-mediated diseases are associated with a higher risk of ALS incidence: a prospective cohort study from the UK Biobank.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1356132}, pmid = {38504981}, issn = {1664-3224}, mesh = {Male ; Female ; Humans ; Prospective Studies ; UK Biobank ; *Amyotrophic Lateral Sclerosis/epidemiology ; Biological Specimen Banks ; Incidence ; *Immune System Diseases ; }, abstract = {OBJECTIVE: The occurrence of immune-mediated diseases (IMDs) in amyotrophic lateral sclerosis (ALS) patients is widely reported. However, whether IMDs and ALS is a simple coexistence or if there exists causal relationships between the two has been a subject of great interest to researchers.

METHODS: A total of 454,444 participants from the prospective cohort of UK Biobank were recruited to investigate the longitudinal association between IMDs and ALS. Previously any IMDs and organ specific IMDs were analyzed in relation to the following incident ALS by Cox-proportional hazard models. Subgroup analyses were performed to explore the covariates of these relationships.

RESULTS: After adjusting for potential covariates, the multivariate analysis showed that any IMDs were associated with an increased risk of ALS incidence (HR:1.42, 95%CI:1.03-1.94). IMDs of the endocrine-system and the intestinal-system were associated with increased risk of ALS incidence (endocrine-system IMDs: HR:3.01, 95%CI:1.49-6.06; intestinal system IMDs: HR:2.07, 95%CI: 1.14-3.77). Subgroup analyses revealed that immune burden, including IMD duration and the severity of inflammation had specific effects on the IMD-ALS association. In participants with IMD duration≥10 years or CRP≥1.3mg/L or females, previous IMDs increased the risk of incident ALS; however, in participants with IMD duration <10 years or CRP<1.3mg/L or males, IMDs had no effect on incident ALS.

INTERPRETATION: Our study provides evidence that previous any IMDs and endocrine-system and the intestinal-system specific IMDs are associated with an increased risk of developing ALS in females, but not in males.}, } @article {pmid38504632, year = {2024}, author = {Higashihara, M and Pavey, N and Menon, P and van den Bos, M and Shibuya, K and Kuwabara, S and Kiernan, MC and Koinuma, M and Vucic, S}, title = {Reduction in short interval intracortical inhibition from the early stage reflects the pathophysiology in amyotrophic lateral sclerosis: A meta-analysis study.}, journal = {European journal of neurology}, volume = {31}, number = {7}, pages = {e16281}, pmid = {38504632}, issn = {1468-1331}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; *Transcranial Magnetic Stimulation ; *Neural Inhibition/physiology ; *Motor Cortex/physiopathology ; Evoked Potentials, Motor/physiology ; }, abstract = {BACKGROUND AND PURPOSE: Cortical hyperexcitability has been identified as a diagnostic and pathogenic biomarker of amyotrophic lateral sclerosis (ALS). Cortical excitability is assessed by transcranial magnetic stimulation (TMS), a non-invasive neurophysiological technique. The TMS biomarkers exhibiting highest sensitivity for cortical hyperexcitability in ALS remain to be elucidated. A meta-analysis was performed to determine the TMS biomarkers exhibiting the highest sensitivity for cortical hyperexcitability in ALS.

METHODS: A systematic literature review was conducted of all relevant studies published in the English language by searching PubMed, MEDLINE, Embase and Scopus electronic databases from 1 January 2006 to 28 February 2023. Inclusion criteria included studies reporting the utility of threshold tracking TMS (serial ascending method) in ALS and controls.

RESULTS: In total, more than 2500 participants, incorporating 1530 ALS patients and 1102 controls (healthy, 907; neuromuscular, 195) were assessed with threshold tracking TMS across 25 studies. Significant reduction of mean short interval intracortical inhibition (interstimulus interval 1-7 ms) exhibited the highest standardized mean difference with moderate heterogeneity (-0.994, 95% confidence interval -1.12 to -0.873, p < 0.001; Q = 38.61, p < 0.05; I[2] = 40%). The reduction of cortical silent period duration along with an increase in motor evoked potential amplitude and intracortical facilitation also exhibited significant, albeit smaller, standardized mean differences.

CONCLUSION: This large meta-analysis study disclosed that mean short interval intracortical inhibition reduction exhibited the highest sensitivity for cortical hyperexcitability in ALS. Combined findings from this meta-analysis suggest that research strategies aimed at understanding the cause of inhibitory interneuronal circuit dysfunction could enhance understanding of ALS pathogenesis.}, } @article {pmid38504592, year = {2024}, author = {Hamilton, HL and Akther, M and Anis, S and Colwell, CB and Vargas, MR and Pehar, M}, title = {Nicotinamide Adenine Dinucleotide Precursor Supplementation Modulates Neurite Complexity and Survival in Motor Neurons from Amyotrophic Lateral Sclerosis Models.}, journal = {Antioxidants & redox signaling}, volume = {41}, number = {7-9}, pages = {573-589}, pmid = {38504592}, issn = {1557-7716}, support = {R01 NS089640/NS/NINDS NIH HHS/United States ; R01 NS100835/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *Motor Neurons/metabolism/pathology/drug effects ; Mice ; Humans ; *Disease Models, Animal ; *NAD/metabolism ; *Induced Pluripotent Stem Cells/metabolism/cytology ; *Neurites/metabolism/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Nicotinamide Mononucleotide/pharmacology/metabolism ; Neuroprotective Agents/pharmacology ; DNA-Binding Proteins/metabolism/genetics ; Cell Survival/drug effects ; Dietary Supplements ; }, abstract = {Aims: Increasing nicotinamide adenine dinucleotide (NAD[+]) availability has been proposed as a therapeutic approach to prevent neurodegeneration in amyotrophic lateral sclerosis (ALS). Accordingly, NAD[+] precursor supplementation appears to exert neuroprotective effects in ALS patients and mouse models. The mechanisms mediating neuroprotection remain uncertain but could involve changes in multiple cell types. We investigated a potential direct effect of the NAD[+] precursor nicotinamide mononucleotide (NMN) on the health of cultured induced pluripotent stem cell (iPSC)-derived human motor neurons and in motor neurons isolated from two ALS mouse models, that is, mice overexpressing wild-type transactive response DNA binding protein-43 (TDP-43) or the ALS-linked human superoxide dismutase 1 with the G93A mutation (hSOD1[G93A]). Results: NMN treatment increased the complexity of neuronal processes in motor neurons isolated from both mouse models and in iPSC-derived human motor neurons. In addition, NMN prevented neuronal death induced by trophic factor deprivation. In mouse and human motor neurons expressing ALS-linked mutant superoxide dismutase 1, NMN induced an increase in glutathione levels, but this effect was not observed in nontransgenic or TDP-43 overexpressing motor neurons. In contrast, NMN treatment normalized the TDP-43 cytoplasmic mislocalization induced by its overexpression. Innovation: NMN can directly act on motor neurons to increase the growth and complexity of neuronal processes and prevent the death induced by trophic factor deprivation. Conclusion: Our results support a direct beneficial effect of NAD[+] precursor supplementation on the maintenance of the neuritic arbor in motor neurons. Importantly, this was observed in motor neurons isolated from two different ALS models, with and without involvement of TDP-43 pathology, supporting its therapeutic potential in sporadic and familial ALS. Antioxid. Redox Signal. 41, 573-589.}, } @article {pmid38504285, year = {2024}, author = {Papaiz, F and Dourado, MET and de Medeiros Valentim, RA and Pinto, R and de Morais, AHF and Arrais, JP}, title = {Ensemble-imbalance-based classification for amyotrophic lateral sclerosis prognostic prediction: identifying short-survival patients at diagnosis.}, journal = {BMC medical informatics and decision making}, volume = {24}, number = {1}, pages = {80}, pmid = {38504285}, issn = {1472-6947}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Prognosis ; Machine Learning ; }, abstract = {Prognosticating Amyotrophic Lateral Sclerosis (ALS) presents a formidable challenge due to patients exhibiting different onset sites, progression rates, and survival times. In this study, we have developed and evaluated Machine Learning (ML) algorithms that integrate Ensemble and Imbalance Learning techniques to classify patients into Short and Non-Short survival groups based on data collected during diagnosis. We aimed to identify individuals at high risk of mortality within 24 months of symptom onset through analysis of patient data commonly encountered in daily clinical practice. Our Ensemble-Imbalance approach underwent evaluation employing six ML algorithms as base classifiers. Remarkably, our results outperformed those of individual algorithms, achieving a Balanced Accuracy of 88% and a Sensitivity of 96%. Additionally, we used the Shapley Additive Explanations framework to elucidate the decision-making process of the top-performing model, pinpointing the most important features and their correlations with the target prediction. Furthermore, we presented helpful tools to visualize and compare patient similarities, offering valuable insights. Confirming the obtained results, our approach could aid physicians in devising personalized treatment plans at the time of diagnosis or serve as an inclusion/exclusion criterion in clinical trials.}, } @article {pmid38503116, year = {2024}, author = {Opitz, DL}, title = {Editorial: Re-enchanting the vocation of science.}, journal = {Endeavour}, volume = {48}, number = {1}, pages = {100920}, doi = {10.1016/j.endeavour.2024.100920}, pmid = {38503116}, issn = {1873-1929}, mesh = {Occupations ; Retirement ; *Science ; }, abstract = {This editorial introduces the collection, "Specialists with Spirit: Re-Enchanting the Vocation of Science," co-edited by Dorien Daling and Hanneke Hoekstra. The collection offers a tribute to the eminent historian of science, Klaas van Berkel, commemorating his retirement from the University of Groningen. The papers compel us to consider the ongoing tensions between knowledge production and the social, political, and economic constraints faced by scholars, a theme that Max Weber famously addressed in his 1917 lecture, Wissenschaft als Beruf, which the collection's contributors revisit as they consider a range of historical and contemporary questions concerning science and its study by historians.}, } @article {pmid38501453, year = {2024}, author = {Erb, MK and Calcagno, N and Brown, R and Burke, KM and Scheier, ZA and Iyer, AS and Clark, A and Higgins, MP and Keegan, M and Gupta, AS and Johnson, SA and Chew, S and Berry, JD}, title = {Longitudinal comparison of the self-administered ALSFRS-RSE and ALSFRS-R as functional outcome measures in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {570-580}, doi = {10.1080/21678421.2024.2322549}, pmid = {38501453}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/psychology ; Male ; Female ; Longitudinal Studies ; Middle Aged ; Aged ; Self Report ; Outcome Assessment, Health Care/methods ; Smartphone ; Mobile Applications ; Adult ; }, abstract = {OBJECTIVE: Test the feasibility, adherence rates and optimal frequency of digital, remote assessments using the ALSFRS-RSE via a customized smartphone-based app.

METHODS: This fully remote, longitudinal study was conducted over a 24-week period, with virtual visits every 3 months and weekly digital assessments. 19 ALS participants completed digital assessments via smartphone, including a digital version of the ALSFRS-RSE and mood survey. Interclass correlation coefficients (ICC) and Bland-Altman plots were used to assess agreement between staff-administered and self-reported ALSFRS-R pairs. Longitudinal change was evaluated using ANCOVA models and linear mixed models, including impact of mood and time of day. Impact of frequency of administration of the ALSFRS-RSE on precision of the estimate slope was tested using a mixed effects model.

RESULTS: In our ALS cohort, digital assessments were well-accepted and adherence was robust, with completion rates of 86%. There was excellent agreement between the digital self-entry and staff-administered scores computing multiple ICCs (ICC range = 0.925-0.961), with scores on the ALSFRS-RSE slightly higher (1.304 points). Digital assessments were associated with increased precision of the slope, resulting in higher standardized response mean estimates for higher frequencies, though benefit appeared to diminish at biweekly and weekly frequency. Effects of participant mood and time of day on total ALSFRS-RSE score were evaluated but were minimal and not statistically significant.

CONCLUSION: Remote collection of digital patient-reported outcomes of functional status such as the ALSFRS-RSE yield more accurate estimates of change over time and provide a broader understanding of the lived experience of people with ALS.}, } @article {pmid38500808, year = {2024}, author = {, }, title = {Retraction: CSF p-tau as a potential cognition impairment biomarker in ALS.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1392563}, doi = {10.3389/fneur.2024.1392563}, pmid = {38500808}, issn = {1664-2295}, abstract = {[This retracts the article DOI: 10.3389/fneur.2022.991143.].}, } @article {pmid38500677, year = {2024}, author = {Zhou, L and Xu, R}, title = {Invertebrate genetic models of amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1328578}, pmid = {38500677}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) is a common adult-onset neurodegenerative disease characterized by the progressive death of motor neurons in the cerebral cortex, brain stem, and spinal cord. The exact mechanisms underlying the pathogenesis of ALS remain unclear. The current consensus regarding the pathogenesis of ALS suggests that the interaction between genetic susceptibility and harmful environmental factors is a promising cause of ALS onset. The investigation of putative harmful environmental factors has been the subject of several ongoing studies, but the use of transgenic animal models to study ALS has provided valuable information on the onset of ALS. Here, we review the current common invertebrate genetic models used to study the pathology, pathophysiology, and pathogenesis of ALS. The considerations of the usage, advantages, disadvantages, costs, and availability of each invertebrate model will also be discussed.}, } @article {pmid38499535, year = {2024}, author = {Chen, S and Puri, A and Bell, B and Fritsche, J and Palacios, HH and Balch, M and Sprunger, ML and Howard, MK and Ryan, JJ and Haines, JN and Patti, GJ and Davis, AA and Jackrel, ME}, title = {HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {2436}, pmid = {38499535}, issn = {2041-1723}, support = {R35 GM128772/GM/NIGMS NIH HHS/United States ; K08 NS101118/NS/NINDS NIH HHS/United States ; F31 NS120512/NS/NINDS NIH HHS/United States ; F31 GM140622/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *alpha-Synuclein/genetics/metabolism ; Amyloid/metabolism ; High-Temperature Requirement A Serine Peptidase 1/genetics/metabolism ; *Parkinson Disease/genetics/metabolism ; Lewy Bodies/metabolism ; }, abstract = {Parkinson's disease (PD) is closely linked to α-synuclein (α-syn) misfolding and accumulation in Lewy bodies. The PDZ serine protease HTRA1 degrades fibrillar tau, which is associated with Alzheimer's disease, and inactivating mutations to mitochondrial HTRA2 are implicated in PD. Here, we report that HTRA1 inhibits aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The protease domain of HTRA1 is necessary and sufficient for inhibiting aggregation, yet this activity is proteolytically-independent. Further, HTRA1 disaggregates preformed α-syn fibrils, rendering them incapable of seeding aggregation of endogenous α-syn, while reducing HTRA1 expression promotes α-syn seeding. HTRA1 remodels α-syn fibrils by targeting the NAC domain, the key domain catalyzing α-syn amyloidogenesis. Finally, HTRA1 detoxifies α-syn fibrils and prevents formation of hyperphosphorylated α-syn accumulations in primary neurons. Our findings suggest that HTRA1 may be a therapeutic target for a range of neurodegenerative disorders.}, } @article {pmid38499486, year = {2024}, author = {Jia, J and Fan, H and Wan, X and Fang, Y and Li, Z and Tang, Y and Zhang, Y and Huang, J and Fang, D}, title = {FUS reads histone H3K36me3 to regulate alternative polyadenylation.}, journal = {Nucleic acids research}, volume = {52}, number = {10}, pages = {5549-5571}, pmid = {38499486}, issn = {1362-4962}, support = {2022YFA1302800//National Key R&D Program of China/ ; 32361133547//National Natural Science Foundation of China/ ; 2019QN81005//Fundamental Research Funds for the Central Universities/ ; LZ24C060001//Natural Science Foundation of China/ ; 2022SKLS-KFKT002//Shanghai Jiao Tong University School of Medicine/ ; }, mesh = {Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Cell Differentiation/genetics ; Chromatin/metabolism/genetics ; HEK293 Cells ; *Histones/metabolism/genetics ; Mitochondria/metabolism/genetics ; Mouse Embryonic Stem Cells ; Mutation ; *Polyadenylation/genetics ; *RNA-Binding Protein FUS/genetics/metabolism ; Cell Line ; Protein Domains ; }, abstract = {Complex organisms generate differential gene expression through the same set of DNA sequences in distinct cells. The communication between chromatin and RNA regulates cellular behavior in tissues. However, little is known about how chromatin, especially histone modifications, regulates RNA polyadenylation. In this study, we found that FUS was recruited to chromatin by H3K36me3 at gene bodies. The H3K36me3 recognition of FUS was mediated by the proline residues in the ZNF domain. After these proline residues were mutated or H3K36me3 was abolished, FUS dissociated from chromatin and bound more to RNA, resulting in an increase in polyadenylation sites far from stop codons genome-wide. A proline mutation corresponding to a mutation in amyotrophic lateral sclerosis contributed to the hyperactivation of mitochondria and hyperdifferentiation in mouse embryonic stem cells. These findings reveal that FUS is an H3K36me3 reader protein that links chromatin-mediated alternative polyadenylation to human disease.}, } @article {pmid38499333, year = {2024}, author = {Turner, MR}, title = {We need to talk about brain donation.}, journal = {Practical neurology}, volume = {24}, number = {3}, pages = {183-184}, doi = {10.1136/pn-2024-004102}, pmid = {38499333}, issn = {1474-7766}, mesh = {Humans ; *Tissue and Organ Procurement ; Tissue Donors ; Brain/diagnostic imaging ; Brain Death/diagnosis ; }, } @article {pmid38499161, year = {2024}, author = {Bashir, S and Aiman, A and Shahid, M and Chaudhary, AA and Sami, N and Basir, SF and Hassan, I and Islam, A}, title = {Amyloid-induced neurodegeneration: A comprehensive review through aggregomics perception of proteins in health and pathology.}, journal = {Ageing research reviews}, volume = {96}, number = {}, pages = {102276}, doi = {10.1016/j.arr.2024.102276}, pmid = {38499161}, issn = {1872-9649}, mesh = {Humans ; Amyloid/metabolism ; *Amyloidosis/metabolism ; *Neurodegenerative Diseases/metabolism ; *Parkinson Disease/metabolism ; Amyloidogenic Proteins ; Perception ; }, abstract = {Amyloidosis of protein caused by fibrillation and aggregation are some of the most exciting new edges not only in protein sciences but also in molecular medicines. The present review discusses recent advancements in the field of neurodegenerative diseases and therapeutic applications with ongoing clinical trials, featuring new areas of protein misfolding resulting in aggregation. The endogenous accretion of protein fibrils having fibrillar morphology symbolizes the beginning of neuro-disorders. Prognostic amyloidosis is prominent in numerous degenerative infections such as Alzheimer's and Parkinson's disease, Amyotrophic lateral sclerosis (ALS), etc. However, the molecular basis determining the intracellular or extracellular evidence of aggregates, playing a significant role as a causative factor in neurodegeneration is still unclear. Structural conversions and protein self-assembly resulting in the formation of amyloid oligomers and fibrils are important events in the pathophysiology of the disease. This comprehensive review sheds light on the evolving landscape of potential treatment modalities, highlighting the ongoing clinical trials and the potential socio-economic impact of novel therapeutic interventions in the realm of neurodegenerative diseases. Furthermore, many drugs are undergoing different levels of clinical trials that would certainly help in treating these disorders and will surely improve the socio-impact of human life.}, } @article {pmid38498721, year = {2024}, author = {Kertesz, A and Finger, E and Munoz, DG}, title = {Progress in Primary Progressive Aphasia: A Review.}, journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology}, volume = {37}, number = {1}, pages = {3-12}, pmid = {38498721}, issn = {1543-3641}, mesh = {Humans ; *Frontotemporal Dementia/diagnosis/genetics ; *Supranuclear Palsy, Progressive/genetics/pathology ; Syndrome ; *Aphasia, Primary Progressive ; }, abstract = {We present a review of the definition, classification, and epidemiology of primary progressive aphasia (PPA); an update of the taxonomy of the clinical syndrome of PPA; and recent advances in the neuroanatomy, pathology, and genetics of PPA, as well as the search for biomarkers and treatment. PPA studies that have contributed to concepts of language organization and disease propagation in neurodegeneration are also reviewed. In addition, the issues of heterogeneity versus the relationships of the clinical phenotypes and their relationship to biological, pathological, and genetic advances are discussed, as is PPA's relationship to other conditions such as frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, Pick disease, and amyotrophic lateral sclerosis. Arguments are presented in favor of considering these conditions as one entity versus many.}, } @article {pmid38498118, year = {2024}, author = {Khanna, RK and Catanese, S and Blasco, H and Pisella, PJ and Corcia, P}, title = {Corneal nerves and amyotrophic lateral sclerosis: an in vivo corneal confocal imaging study.}, journal = {Journal of neurology}, volume = {271}, number = {6}, pages = {3370-3377}, pmid = {38498118}, issn = {1432-1459}, support = {2021//Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone/ ; 2021//Novartis-Société Française d'Ophtalmologie./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/physiopathology ; *Microscopy, Confocal ; Male ; *Cornea/innervation/diagnostic imaging/pathology ; Female ; Middle Aged ; Aged ; Case-Control Studies ; Prospective Studies ; Nerve Fibers/pathology ; Adult ; }, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disorder. Diagnosis is challenging due to its clinical heterogeneity and the absence of definitive diagnostic tools, leading to delays averaging between 9.1 and 27 months. In vivo corneal confocal microscopy, assessing the sub-basal nerve plexus of the cornea, has been proposed as a potential biomarker for ALS. We aimed to determine whether the assessment of corneal nerves using in vivo confocal microscopy can serve as an imaging biomarker for ALS.

METHODS: A single-centre prospective case-control study was conducted in France from September 2021 to March 2023 including patients with ALS according to the revised EI Escorial criteria. The corneal sub-basal nerve plexus was analysed using in vivo confocal microscopy. An automated algorithm (ACCMetrics) was used to evaluate corneal parameters: nerve fibre density, nerve branch density, nerve fibre length, nerve fibre area, nerve total branch density, nerve fibre width, and nerve fractal dimension.

RESULTS: Twenty-two patients with ALS and 30 controls were included. No significant differences were found between ALS and control groups for all corneal parameters (p > 0.05). Corneal sensitivity did not differ between groups, and no correlation was identified between corneal nerve parameters and ALS disease duration, severity and rate of progression (p > 0.05).

CONCLUSIONS: The present study does not support the use of in vivo corneal confocal microscopy as an early diagnostic or prognostic tool for ALS. Further research, especially longitudinal investigations, is needed to understand any potential corneal innervation changes as ALS progresses.}, } @article {pmid38496572, year = {2024}, author = {Cameron, B and Torres-Hernandez, L and Montague, VL and Lewis, KA and Smith, H and Fox, J and Guo, X and Kalb, RG and George, L}, title = {Titin is a nucleolar protein in neurons.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38496572}, issn = {2693-5015}, support = {P20 GM103474/GM/NIGMS NIH HHS/United States ; R15 NS090384/NS/NINDS NIH HHS/United States ; }, abstract = {Titin is the largest protein produced by living cells and its function as a molecular spring in striated muscle is well characterized (1, 2). Here we demonstrate that titin isoforms in the same size range as found in muscle are prominent neuronal proteins in both the central and peripheral nervous systems, including motor neurons in the spinal cord and brain. Within these neurons, titin localizes to the dense fibrillar component of the nucleolus, the site of ribosomal RNA biogenesis and modification, and a critical site of dysfunction in neurodegenerative disease (3-5). Additionally, we show that the levels of both titin mRNA and protein are altered in the spinal cord of SOD1[G93A] mice, a commonly used model of amyotrophic lateral sclerosis, indicating that titin mediated nucleolar events may in fact contribute to the pathobiology of disease.}, } @article {pmid38496415, year = {2024}, author = {Suazo, KF and Mishra, V and Maity, S and Auger, SA and Justyna, K and Petre, A and Ottoboni, L and Ongaro, J and Corti, SP and Lotti, F and Przedborski, S and Distefano, MD}, title = {Improved synthesis and application of an alkyne-functionalized isoprenoid analogue to study the prenylomes of motor neurons, astrocytes and their stem cell progenitors.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38496415}, issn = {2692-8205}, support = {R01 NS107442/NS/NINDS NIH HHS/United States ; P30 CA077598/CA/NCI NIH HHS/United States ; R21 NS101575/NS/NINDS NIH HHS/United States ; T32 AG029796/AG/NIA NIH HHS/United States ; T32 GM132029/GM/NIGMS NIH HHS/United States ; R35 GM141853/GM/NIGMS NIH HHS/United States ; }, abstract = {Protein prenylation is one example of a broad class of post-translational modifications where proteins are covalently linked to various hydrophobic moieties. To globally identify and monitor levels of all prenylated proteins in a cell simultaneously, our laboratory and others have developed chemical proteomic approaches that rely on the metabolic incorporation of isoprenoid analogues bearing bio-orthogonal functionality followed by enrichment and subsequent quantitative proteomic analysis. Here, several improvements in the synthesis of the alkyne-containing isoprenoid analogue C15AlkOPP are reported to improve synthetic efficiency. Next, metabolic labeling with C15AlkOPP was optimized to obtain useful levels of metabolic incorporation of the probe in several types of primary cells. Those conditions were then used to study the prenylomes of motor neurons (ES-MNs), astrocytes (ES-As), and their embryonic stem cell progenitors (ESCs), which allowed for the identification of 54 prenylated proteins from ESCs, 50 from ES-MNs and 84 from ES-As, representing all types of prenylation. Bioinformatic analysis revealed specific enriched pathways, including nervous system development, chemokine signaling, Rho GTPase signaling, and adhesion. Hierarchical clustering showed that most enriched pathways in all three cell types are related to GTPase activity and vesicular transport. In contrast, STRING analysis showed significant interactions in two populations that appear to be cell type dependent. The data provided herein demonstrates that robust incorporation of C15AlkOPP can be obtained in ES-MNs and related primary cells purified via magnetic-activated cell sorting allowing the identification and quantification of numerous prenylated proteins. These results suggest that metabolic labeling with C15AlkOPP should be an effective approach for investigating the role of prenylated proteins in primary cells in both normal cells and disease pathologies, including ALS.}, } @article {pmid38496202, year = {2024}, author = {da Silva Alves, C and Barroso, T and Gerardo, A and Almeida, T and Maduro, S and Boléo-Tomé, JP and Liberato, H}, title = {Forced Expiratory Volume in One Second Quotient (FEV1Q) as a Prognostic Factor in Amyotrophic Lateral Sclerosis Patients: Comparing Its Predictive Value to Other Lung Function Measurements.}, journal = {Cureus}, volume = {16}, number = {2}, pages = {e54176}, pmid = {38496202}, issn = {2168-8184}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting the first and second motor neurons. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) have conventionally served as indicators of respiratory muscle strength. Recently, FEV1Q (FEV1 divided by the sex-specific first percentile values of absolute FEV1 in adults with lung disease) has been suggested as a predictor of mortality. While FVC has been utilized as a prognostic factor, FEV1Q has not yet been examined.

METHODS: This retrospective unicenter study evaluated FEV1Q as a predictor of mortality in ALS patients, comparing its predictive efficacy with other measurements, including FEV1, FVC, sniff nasal inspiratory pressure, and maximal inspiratory pressure. The study utilized univariate analysis for each variable employing the Cox proportional hazards model to determine the statistical significance and predictive power of each measurement.

RESULTS: Forty-five patients were included, female predominant (60%) and an average age at diagnosis of 69.2 ± 11 years. Almost all (95%) met the criteria for non-invasive ventilation (NIV) and initiated (93%) during the study period, a mean of 137 days after diagnosis. The mortality rate observed was 57%, occurring at a median of 398 days post-diagnosis. On average, patients underwent 1.7 pulmonary function tests, revealing a decline in various parameters, including FEV1, FEV1Q, and FVC. However, only FEV1Q was a statistically significant predictor of mortality (p < 0.0083) in a Cox regression analysis. A negative coefficient for FEV1Q indicated that higher values were associated with a reduced mortality risk, with an average FEV1Q of 2.68 observed at the time of death.

CONCLUSION: FEV1Q emerged as the only statistically significant predictor of mortality among the evaluated respiratory measurements in ALS patients. This study is the first to focus on applying FEV1Q in the clinical evaluation of ALS, marking an initial step in understanding its potential role in patient follow-up. However, further studies are needed before these findings can be incorporated into clinical practice.}, } @article {pmid38495583, year = {2024}, author = {Uy, G and Farrell, LN and Faheem, SF and Kinne, LE and Adore, MG and Im, SH and Fairman, R}, title = {The Effects of poly-GA and poly-PR C9orf72 Dipeptide Repeats on Sleep Patterns in Drosophila melanogaster.}, journal = {microPublication biology}, volume = {2024}, number = {}, pages = {}, pmid = {38495583}, issn = {2578-9430}, abstract = {C9orf72 is the most common familial gene associated with amyotrophic lateral sclerosis (ALS). Dipeptide repeats (DPRs) encoded by an expanded nucleotide repeat sequence in the C9orf72 gene were found in the sleep-related neurons of patients, indicating a role of DPRs in ALS-associated sleep disruptions. Poly-GA or poly-PR DPRs were expressed in male Drosophila melanogaster to study their effect on sleep . Poly-PR expression caused sleep disruptions while poly-GA expression did not. This study validates the use of Drosophila as an in vivo model system for exploring the roles of DPRs in perturbing the underlying molecular mechanisms in sleep regulation.}, } @article {pmid38493058, year = {2024}, author = {Milani, M and Della Valle, I and Rossi, S and Fabbrizio, P and Margotta, C and Nardo, G and Cozzolino, M and D'Ambrosi, N and Apolloni, S}, title = {Neuroprotective effects of niclosamide on disease progression via inflammatory pathways modulation in SOD1-G93A and FUS-associated amyotrophic lateral sclerosis models.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {3}, pages = {e00346}, pmid = {38493058}, issn = {1878-7479}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Disease Models, Animal ; *Disease Progression ; Inflammation/drug therapy ; Mice, Transgenic ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Niclosamide/pharmacology/therapeutic use ; RNA-Binding Protein FUS/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease influenced by genetic, epigenetic, and environmental factors, resulting in dysfunction in cellular and molecular pathways. The limited efficacy of current treatments highlights the need for combination therapies targeting multiple aspects of the disease. Niclosamide, an anthelminthic drug listed as an essential medicine, has been repurposed in clinical trials for different diseases due to its anti-inflammatory and anti-fibrotic properties. Niclosamide can inhibit various molecular pathways (e.g., STAT3, mTOR) that are dysregulated in ALS, suggesting its potential to disrupt these altered mechanisms associated with the pathology. We administered niclosamide intraperitoneally to two transgenic murine models, SOD1-G93A and FUS mice, mimicking key pathological processes of ALS. The treatment was initiated at the onset of symptoms, and we assessed disease progression by neurological scores, rotarod and wire tests, and monitored survival. Furthermore, we investigated cellular and molecular mechanisms affected by niclosamide in the spinal cord and muscle of ALS mice. In both models, the administration of niclosamide resulted in a slowdown of disease progression, an increase in survival rates, and an improvement in tissue pathology. This was characterised by reduced gliosis, motor neuron loss, muscle atrophy, and inflammatory pathways. Based on these results, our findings demonstrate that niclosamide can impact multiple pathways involved in ALS. This multi-targeted approach leads to a slowdown in the progression of the disease, positioning niclosamide as a promising candidate for repurposing in the treatment of ALS.}, } @article {pmid38492239, year = {2024}, author = {Johnson, CN and Sojitra, KA and Sohn, EJ and Moreno-Romero, AK and Baudin, A and Xu, X and Mittal, J and Libich, DS}, title = {Insights into Molecular Diversity within the FUS/EWS/TAF15 Protein Family: Unraveling Phase Separation of the N-Terminal Low-Complexity Domain from RNA-Binding Protein EWS.}, journal = {Journal of the American Chemical Society}, volume = {146}, number = {12}, pages = {8071-8085}, pmid = {38492239}, issn = {1520-5126}, support = {R01 GM136917/GM/NIGMS NIH HHS/United States ; R01 GM140127/GM/NIGMS NIH HHS/United States ; R35 GM153388/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; RNA-Binding Protein EWS/metabolism ; RNA-Binding Protein FUS/metabolism ; Phase Separation ; *Sarcoma, Ewing/genetics/metabolism/pathology ; Proteins/metabolism ; Tyrosine ; *TATA-Binding Protein Associated Factors/genetics/metabolism ; }, abstract = {The FET protein family, comprising FUS, EWS, and TAF15, plays crucial roles in mRNA maturation, transcriptional regulation, and DNA damage response. Clinically, they are linked to Ewing family tumors and neurodegenerative diseases such as amyotrophic lateral sclerosis. The fusion protein EWS::FLI1, the causative mutation of Ewing sarcoma, arises from a genomic translocation that fuses a portion of the low-complexity domain (LCD) of EWS (EWS[LCD]) with the DNA binding domain of the ETS transcription factor FLI1. This fusion protein modifies transcriptional programs and disrupts native EWS functions, such as splicing. The exact role of the intrinsically disordered EWS[LCD] remains a topic of active investigation, but its ability to phase separate and form biomolecular condensates is believed to be central to EWS::FLI1's oncogenic properties. Here, we used paramagnetic relaxation enhancement NMR, microscopy, and all-atom molecular dynamics (MD) simulations to better understand the self-association and phase separation tendencies of the EWS[LCD]. Our NMR data and mutational analysis suggest that a higher density and proximity of tyrosine residues amplify the likelihood of condensate formation. MD simulations revealed that the tyrosine-rich termini exhibit compact conformations with unique contact networks and provided critical input on the relationship between contacts formed within a single molecule (intramolecular) and inside the condensed phase (intermolecular). These findings enhance our understanding of FET proteins' condensate-forming capabilities and underline differences between EWS, FUS, and TAF15.}, } @article {pmid38491246, year = {2024}, author = {Musarò, A and Dobrowolny, G and Cambieri, C and Libonati, L and Moret, F and Casola, I and Laurenzi, G and Garibaldi, M and Inghilleri, M and Ceccanti, M}, title = {MiR206 and 423-3p Are Differently Modulated in Fast and Slow-Progressing Amyotrophic Lateral Sclerosis Patients.}, journal = {Neuromolecular medicine}, volume = {26}, number = {1}, pages = {5}, pmid = {38491246}, issn = {1559-1174}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Disease Progression ; *MicroRNAs/genetics ; Research Design ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neuromuscular disease with a wide disease progression. Despite several efforts to develop efficient biomarkers, many concerns about the available ones still need to be addressed. MicroRNA (miR) are non-coding RNAs that can modulate molecular circuits and are involved in ALS pathogenic mechanisms. 22 fast and 23 slow-progressing-defined ALS patients were recruited. ALSFRS-R, strength, respiratory function, nerve conduction studies, and creatine kinase were evaluated at the baseline and after 6 months of follow-up. The mean monthly reduction of the previous variables (progression index - PI) was calculated. MiR206, 133a-3p, 151a-5p, 199a-5p, and 423-3p were dosed. The univariate analysis showed an independent reduction of miR206 and an increase of miR423-3p in patients with a slow slope of ALSFRS-R and weakness, respectively. MiR206 and 423-3p are differently modulated in fast and slow-progressing ALS patients, suggesting a role for microRNAs in prognosis and therapeutic target.}, } @article {pmid38491210, year = {2024}, author = {He, D and Yang, X and Liu, L and Shen, D and Liu, Q and Liu, M and Zhang, X and Cui, L}, title = {Dysregulated N[6]-methyladenosine modification in peripheral immune cells contributes to the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Frontiers of medicine}, volume = {18}, number = {2}, pages = {285-302}, pmid = {38491210}, issn = {2095-0225}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/immunology ; *Adenosine/analogs & derivatives/metabolism ; Humans ; Animals ; Female ; Mice ; Male ; Middle Aged ; Aged ; Case-Control Studies ; RAW 264.7 Cells ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurogenerative disorder with uncertain origins. Emerging evidence implicates N6-methyladenosine (m[6]A) modification in ALS pathogenesis. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and liquid chromatography-mass spectrometry were utilized for m[6]A profiling in peripheral immune cells and serum proteome analysis, respectively, in patients with ALS (n = 16) and controls (n = 6). The single-cell transcriptomic dataset (GSE174332) of primary motor cortex was further analyzed to illuminate the biological implications of differentially methylated genes and cell communication changes. Analysis of peripheral immune cells revealed extensive RNA hypermethylation, highlighting candidate genes with differential m[6]A modification and expression, including C-X3-C motif chemokine receptor 1 (CX3CR1). In RAW264.7 macrophages, disrupted CX3CR1 signaling affected chemotaxis, potentially influencing immune cell migration in ALS. Serum proteome analysis demonstrated the role of dysregulated immune cell migration in ALS. Cell type-specific expression variations of these genes in the central nervous system (CNS), particularly microglia, were observed. Intercellular communication between neurons and glial cells was selectively altered in ALS CNS. This integrated approach underscores m[6]A dysregulation in immune cells as a potential ALS contributor.}, } @article {pmid38490348, year = {2024}, author = {Chatterjee, A and Kumar, S and Roy Sarkar, S and Halder, R and Kumari, R and Banerjee, S and Sarkar, B}, title = {Dietary polyphenols represent a phytotherapeutic alternative for gut dysbiosis associated neurodegeneration: A systematic review.}, journal = {The Journal of nutritional biochemistry}, volume = {129}, number = {}, pages = {109622}, doi = {10.1016/j.jnutbio.2024.109622}, pmid = {38490348}, issn = {1873-4847}, mesh = {*Polyphenols/pharmacology ; *Dysbiosis/drug therapy ; *Gastrointestinal Microbiome/drug effects ; Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; Oxidative Stress/drug effects ; Phytotherapy ; Prebiotics ; Diet ; }, abstract = {Globally, neurodegeneration and cerebrovascular disease are common and growing causes of morbidity and mortality. Pathophysiology of this group of diseases encompasses various factors from oxidative stress to gut microbial dysbiosis. The study of the etiology and mechanisms of oxidative stress as well as gut dysbiosis-induced neurodegeneration in Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, autism spectrum disorder, and Huntington's disease has recently received a lot of attention. Numerous studies lend credence to the notion that changes in the intestinal microbiota and enteric neuroimmune system have an impact on the initiation and severity of these diseases. The prebiotic role of polyphenols can influence the makeup of the gut microbiota in neurodegenerative disorders by modulating intracellular signalling pathways. Metabolites of polyphenols function directly as neurotransmitters by crossing the blood-brain barrier or indirectly via influencing the cerebrovascular system. This assessment aims to bring forth an interlink between the consumption of polyphenols biotransformed by gut microbiota which in turn modulate the gut microbial diversity and biochemical changes in the brain. This systematic review will further augment research towards the association of dietary polyphenols in the management of gut dysbiosis-associated neurodegenerative diseases.}, } @article {pmid38490215, year = {2024}, author = {Reilich, P}, title = {[Multidimensional care for people with ALS and their families].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {92}, number = {3}, pages = {70-71}, doi = {10.1055/a-2240-8802}, pmid = {38490215}, issn = {1439-3522}, } @article {pmid38490025, year = {2024}, author = {Turco, A and Primiceri, E and Chiriacò, MS and La Pesa, V and Ferrara, F and Riva, N and Quattrini, A and Romano, A and Maruccio, G}, title = {Advancing amyotrophic lateral sclerosis disease diagnosis: A lab-on-chip electrochemical immunosensor for ultra-sensitive TDP-43 protein detection and monitoring in serum patients'.}, journal = {Talanta}, volume = {273}, number = {}, pages = {125866}, doi = {10.1016/j.talanta.2024.125866}, pmid = {38490025}, issn = {1873-3573}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Polymers ; *Biosensing Techniques ; *Neurodegenerative Diseases ; Reproducibility of Results ; Immunoassay ; Pyrroles ; DNA-Binding Proteins/metabolism ; Biomarkers/metabolism ; }, abstract = {The global increase in population aging has led to a rise in neurodegenerative diseases (NDs), posing significant challenges to public health. Developing selective and specific biomarkers for early diagnosis and drug development is crucial addressing the growing burden of NDs. In this context, the RNA-binding protein TDP-43 has emerged as a promising biomarker for amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and TDP-43-associated proteinopathies. However, existing detection methods suffer from limitations such as cost, complexity, and operator dependence. Here, we present a novel electrochemical biosensor integrated into a lab-on-chip (LoC) platform to detect TDP-43. The sensor utilizes electrosynthesized polypyrrole derivatives with carboxylic groups for transducer functionalization, enabling targeted immobilization of TDP-43 antibodies. Differential pulsed voltammetry (DPV) is used for the indirect detection and quantification of TDP-43. The chip exhibits rapid response, good reproducibility, a linear detection range, and sensitivity from 0.01 ng/mL to 25 ng/mL of TDP-43 protein concentration with a LOD = 10 pg/mL. Furthermore, successful TDP-43 detection in complex matrices like serum of ALS patients and healthy individuals demonstrates its potential as a point-of-care diagnostic device. This electrochemical biosensor integrated into a chip offers good sensitivity, rapid response, and robust performance, providing a promising avenue for advancing neurodegenerative disease diagnostics and therapeutic development.}, } @article {pmid38489867, year = {2024}, author = {Tausendfreund, O and Bidlingmaier, M and Martini, S and Müller, K and Rippl, M and Schilbach, K and Schmidmaier, R and Drey, M}, title = {Growth hormone treatment in aged patients with comorbidities: A systematic review.}, journal = {Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {75}, number = {}, pages = {101584}, doi = {10.1016/j.ghir.2024.101584}, pmid = {38489867}, issn = {1532-2238}, mesh = {Aged ; Humans ; Comorbidity ; Growth Hormone ; *Human Growth Hormone/adverse effects/therapeutic use ; Insulin-Like Growth Factor I ; Quality of Life ; Randomized Controlled Trials as Topic ; *Aging/pathology ; }, abstract = {OBJECTIVE: Hormonal substitution with growth hormone in aged patients remains a debated research topic and is rarely initiated in clinical practice. This reluctance may originate from concerns about adverse effects and the uncritical use as an anti-aging agent. Nevertheless, beneficial effects for selected patients suffering from certain acute and chronic illnesses could justify its use at an advanced age. This systematic review analyzes randomized controlled studies of GH interventions in older patients with different comorbidities to assess both, beneficial and harmful effects.

DESIGN: A systematic search strategy was implemented to identify relevant studies from PubMed, MEDLINE, and The Cochrane Library.

INCLUSION CRITERIA: participants aged over 65 years, randomized controlled trials involving human growth hormone (GH) and presence of at least one additional comorbidity independent of a flawed somatotropic axis.

RESULTS: The eight eligible studies encompassed various comorbidities including osteoporosis, frailty, chronic heart failure, hip fracture, amyotrophic lateral sclerosis and hemodialysis. Outcomes varied, including changes in body composition, physical performance, strength, bone mineral density, cardiovascular parameters, quality of life and housing situation. Study protocols differed greatly in GH application frequency (daily, 2nd day or 3×/week), doses (0.41 mg-2.6 mg; mean 1.3 mg per 60 kg patient) and duration (1-12 months; mean 7 months). Mild dose-related side effects were reported, alongside noticeable positive impacts particularly on body composition, functionality, and quality of life.

CONCLUSION: Despite limited evidence, GH treatment might offer diverse benefits with few adverse effects. Further research with IGF-I dependent indication and clear outcomes, incorporating IGF-I dependent GH titration in older adults is warranted.}, } @article {pmid38488546, year = {2024}, author = {Yang, Y and Cheng, Q and Gao, J and Kim, WS}, title = {Status of biomarker development for frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {10}, pages = {2117-2118}, pmid = {38488546}, issn = {1673-5374}, } @article {pmid38487578, year = {2024}, author = {Cortes-Flores, H and Torrandell-Haro, G and Brinton, RD}, title = {Association between CNS-active drugs and risk of Alzheimer's and age-related neurodegenerative diseases.}, journal = {Frontiers in psychiatry}, volume = {15}, number = {}, pages = {1358568}, pmid = {38487578}, issn = {1664-0640}, support = {P01 AG026572/AG/NIA NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; R01 AG057931/AG/NIA NIH HHS/United States ; }, abstract = {OBJECTIVE: As neuropsychiatric conditions can increase the risk of age-related neurodegenerative diseases (NDDs), the impact of CNS-active drugs on the risk of developing Alzheimer's Disease (AD), non-AD dementia, Multiple Sclerosis (MS), Parkinson's Disease (PD) and Amyotrophic Lateral Sclerosis (ALS) was investigated.

RESEARCH DESIGN AND METHODS: A retrospective cohort analysis of a medical claims dataset over a 10 year span was conducted in patients aged 60 years or older. Participants were propensity score matched for comorbidity severity and demographic parameters. Relative risk (RR) ratios and 95% confidence intervals (CI) were determined for age-related NDDs. Cumulative hazard ratios and treatment duration were determined to assess the association between CNS-active drugs and NDDs at different ages and treatment duration intervals.

RESULTS: In 309,128 patients who met inclusion criteria, exposure to CNS-active drugs was associated with a decreased risk of AD (0.86% vs 1.73%, RR: 0.50; 95% CI: 0.47-0.53; p <.0001) and all NDDs (3.13% vs 5.76%, RR: 0.54; 95% CI: 0.53-0.56; p <.0001). Analysis of impact of drug class on risk of AD indicated that antidepressant, sedative, anticonvulsant, and stimulant medications were associated with significantly reduced risk of AD whereas atypical antipsychotics were associated with increased AD risk. The greatest risk reduction for AD and NDDs occurred in patients aged 70 years or older with a protective effect only in patients with long-term therapy (>3 years). Furthermore, responders to these therapeutics were characterized by diagnosed obesity and higher prescriptions of anti-inflammatory drugs and menopausal hormonal therapy, compared to patients with a diagnosis of AD (non-responders). Addition of a second CNS-active drug was associated with greater reduction in AD risk compared to monotherapy, with the combination of a Z-drug and an SNRI associated with greatest AD risk reduction.

CONCLUSION: Collectively, these findings indicate that CNS-active drugs were associated with reduced risk of developing AD and other age-related NDDs. The exception was atypical antipsychotics, which increased risk. Potential use of combination therapy with atypical antipsychotics could mitigate the risk conferred by these drugs. Evidence from these analyses advance precision prevention strategies to reduce the risk of age-related NDDs in persons with neuropsychiatric disorders.}, } @article {pmid38487377, year = {2024}, author = {Hirsch, AG and Wright, EA and Nordberg, CM and DeWalle, J and Stains, EL and Kennalley, AL and Zhang, J and Tusing, LD and Piper, BJ}, title = {Dispensaries and Medical Marijuana Certifications and Indications: Unveiling the Geographic Connections in Pennsylvania, USA.}, journal = {Medical cannabis and cannabinoids}, volume = {7}, number = {1}, pages = {34-43}, pmid = {38487377}, issn = {2504-3889}, abstract = {INTRODUCTION: Pennsylvania opened its first medical marijuana (MMJ) dispensary in 2018. Qualifying conditions include six conditions determined to have no or insufficient evidence to support or refute MMJ effectiveness. We conducted a study to describe MMJ dispensary access in Pennsylvania and to determine whether dispensary proximity was associated with MMJ certifications and community demographics.

METHODS: Using data from the Pennsylvania Department of Health, we geocoded MMJ dispensary locations and linked them to US Census Bureau data. We created dispensary access measures from the population-weighted centroid of Zip Code Tabulation Areas (ZCTAs): distance to nearest dispensary and density of dispensaries within a 15-min drive. We evaluated associations between dispensary access and the proportion of adults who received MMJ certification and the proportion of certifications for low evidence conditions (amyotrophic lateral sclerosis, epilepsy, glaucoma, Huntington's disease, opioid use disorder, and Parkinson's disease) using negative binomial modeling, adjusting for community features. To evaluate associations racial and ethnic composition of communities and distance to nearest dispensary, we used logistic regression to estimate the odds ratios (OR) and 95% confidence intervals (CI), adjusting for median income.

RESULTS: Distance and density of MMJ dispensaries were associated with the proportion of the ZCTA population certified and the proportion of certifications for insufficient evidence conditions. Compared to ZCTAs with no dispensary within 15 min, the proportion of adults certified increased by up to 31% and the proportion of certifications for insufficient evidence decreased by up to 22% for ZCTAs with two dispensaries. From 2018 to 2021, the odds of being within five miles of a dispensary was up to 20 times higher in ZCTAs with the highest proportions of individuals who were not White (2019: OR: 20.14, CI: 10.7-37.8) and more than double in ZCTAs with the highest proportion of Hispanic individuals (2018: OR: 2.81, CI: 1.51-5.24), compared to ZCTAs with the lowest proportions.

CONCLUSIONS: Greater dispensary access was associated with the proportions of certified residents and certifications for low evidence conditions. Whether these patterns are due to differences in accessibility or demand is unknown. Associations between community demographics and dispensary proximity may indicate MMJ access differences.}, } @article {pmid38487369, year = {2024}, author = {Fagnani, E and Bonì, F and Seneci, P and Gornati, D and Muzio, L and Mastrangelo, E and Milani, M}, title = {Stabilization of the retromer complex: Analysis of novel binding sites of bis-1,3-phenyl guanylhydrazone 2a to the VPS29/VPS35 interface.}, journal = {Computational and structural biotechnology journal}, volume = {23}, number = {}, pages = {1088-1093}, pmid = {38487369}, issn = {2001-0370}, abstract = {The stabilization of the retromer protein complex can be effective in the treatment of different neurological disorders. Following the identification of bis-1,3-phenyl guanylhydrazone 2a as an effective new compound for the treatment of amyotrophic lateral sclerosis, in this work we analyze the possible binding sites of this molecule to the VPS35/VPS29 dimer of the retromer complex. Our results show that the affinity for different sites of the protein assembly depends on compound charge and therefore slight changes in the cell microenvironment could promote different binding states. Finally, we describe a novel binding site located in a deep cleft between VPS29 and VPS35 that should be further explored to select novel molecular chaperones for the stabilization of the retromer complex.}, } @article {pmid38484224, year = {2024}, author = {Sun, Y and Pahwa, S and Vasireddy, RP and Barty, A and Raslau, FD}, title = {Pearls & Oy-sters: Bibrachial Amyotrophy From a Dural Tear.}, journal = {Neurology}, volume = {102}, number = {7}, pages = {e209256}, doi = {10.1212/WNL.0000000000209256}, pmid = {38484224}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Spinal Cord Diseases ; *Intracranial Hypotension ; Magnetic Resonance Imaging ; Neck ; }, abstract = {Bibrachial amyotrophy signifies a clinical phenotype characterized by weakness in both upper extremities with preserved strength in the face, neck, and lower extremities. The underlying causes of bibrachial amyotrophy are broad. We report a patient exhibiting bibrachial amyotrophy who initially received a diagnosis of amyotrophic lateral sclerosis (ALS); however, his clinical course and NCS/EMG were atypical for ALS. Further evaluation demonstrated dural tears with CSF leak, resulting in a compressive extradural fluid collection, ventral myelopathy, and intracranial hypotension. Dural tear and ALS have overlapping features, including the manifestation of the bibrachial amyotrophy phenotype and the presence of T2 hyperintensities in the anterior horn cells, recognized by an "owl's eye" appearance on spine MRI. Clinical and radiologic vigilance is required to identify rare cases of dural tear causing ventral myelopathy that manifest as bibrachial amyotrophy.}, } @article {pmid38483631, year = {2024}, author = {Perera, A and Brock, O and Ahmed, A and Shaw, C and Ashkan, K}, title = {Taking the knife to neurodegeneration: a review of surgical gene therapy delivery to the CNS.}, journal = {Acta neurochirurgica}, volume = {166}, number = {1}, pages = {136}, pmid = {38483631}, issn = {0942-0940}, mesh = {Humans ; *Central Nervous System ; Genetic Therapy/methods ; Genetic Vectors ; *Neurodegenerative Diseases/genetics/therapy ; }, abstract = {Gene supplementation and editing for neurodegenerative disorders has emerged in recent years as the understanding of the genetic mechanisms underlying several neurodegenerative disorders increases. The most common medium to deliver genetic material to cells is via viral vectors; and with respect to the central nervous system, adeno-associated viral (AAV) vectors are a popular choice. The most successful example of AAV-based gene therapy for neurodegenerative disorders is Zolgensma© which is a transformative intravenous therapy given to babies with spinal muscular atrophy. However, the field has stalled in achieving safe drug delivery to the central nervous system in adults for which treatments for disorders such as amyotrophic lateral sclerosis are desperately needed. Surgical gene therapy delivery has been proposed as a potential solution to this problem. While the field of the so-called regenerative neurosurgery has yielded pre-clinical optimism, several challenges have emerged. This review seeks to explore the field of regenerative neurosurgery with respect to AAV-based gene therapy for neurodegenerative diseases, its progress so far and the challenges that need to be overcome.}, } @article {pmid38483313, year = {2024}, author = {Jafarinia, H and van der Giessen, E and Onck, PR}, title = {C9orf72 polyPR directly binds to various nuclear transport components.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {38483313}, issn = {2050-084X}, support = {Building Blocks of Life//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; }, mesh = {Active Transport, Cell Nucleus ; C9orf72 Protein/genetics ; *Nuclear Localization Signals ; *Amino Acids ; Arginine ; }, abstract = {The disruption of nucleocytoplasmic transport (NCT) is an important mechanism in neurodegenerative diseases. In the case of C9orf72-ALS, trafficking of macromolecules through the nuclear pore complex (NPC) might get frustrated by the binding of C9orf72-translated arginine-containing dipeptide repeat proteins (R-DPRs) to the Kapβ family of nuclear transport receptors. Besides Kapβs, several other types of transport components have been linked to NCT impairments in R-DPR-expressed cells, but the molecular origin of these observations has not been clarified. Here, we adopt a coarse-grained molecular dynamics model at amino acid resolution to study the direct interaction between polyPR, the most toxic DPR, and various nuclear transport components to elucidate the binding mechanisms and provide a complete picture of potential polyPR-mediated NCT defects. We found polyPR to directly bind to several isoforms of the Impα family, CAS (the specific exporter of Impα) and RanGAP. We observe no binding between polyPR and Ran. Longer polyPRs at lower salt concentrations also make contact with RanGEF and NTF2. Analyzing the polyPR contact sites on the transport components reveals that polyPR potentially interferes with RanGTP/RanGDP binding, with nuclear localization signal (NLS)-containing cargoes (cargo-NLS) binding to Impα, with cargo-NLS release from Impα, and with Impα export from the nucleus. The abundance of polyPR-binding sites on multiple transport components combined with the inherent polyPR length dependence makes direct polyPR interference of NCT a potential mechanistic pathway of C9orf72 toxicity.}, } @article {pmid38483107, year = {2024}, author = {Adari, MD and Pandian, BA and Gaines, TA and Prasad, PV and Jugulam, M}, title = {Confirmation and characterization of the first case of acetolactate synthase (ALS)-inhibitor resistance in Japanese brome (Bromus japonicus) in the US.}, journal = {Pest management science}, volume = {80}, number = {8}, pages = {3717-3725}, doi = {10.1002/ps.8074}, pmid = {38483107}, issn = {1526-4998}, mesh = {*Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Bromus/enzymology/drug effects/genetics ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Kansas ; *Plant Proteins/genetics/metabolism/antagonists & inhibitors ; Plant Weeds/drug effects/genetics/enzymology ; }, abstract = {BACKGROUND: Japanese brome (Bromus japonicus Thumb.) is one of the problematic annual weeds in winter wheat (Triticum aestivum L.) and is generally controlled by acetolactate synthase (ALS) inhibitors. Repeated use of the ALS inhibitor propoxycarbazone-Na resulted in the evolution of resistance to this herbicide in three B. japonicus populations, i.e., R1, R2, and R3 in Kansas (KS). However, the level of resistance and mechanism conferring resistance in these populations is unknown. The objectives of this research were to (i) evaluate the level of resistance to propoxycarbazone-Na in R1, R2, and R3 in comparison with a known susceptible population (S1), (ii) investigate the mechanism of resistance involved in conferring ALS-inhibitor resistance, and (iii) investigate the cross-resistance to other ALS inhibitors.

RESULTS: Dose-response (0 to 16x; x = 44 g ai ha[-1] of propoxycarbazone-Na) assay indicated 167, 125, and 667-fold resistance in R1, R2 and R3 populations, respectively, compared to S1 population. ALS gene sequencing confirmed the mutations resulting in amino acid substitutions, i.e., Pro-197-Thr (R3, R1)/Ser (R2, R1) bestowing resistance to these ALS inhibitors. Such amino acid substitutions also showed differential cross-resistance to sulfosulfuron, mesosulfuron-methyl, pyroxsulam, and imazamox among resistant populations. Pretreatment with malathion (a cytochrome P450 enzyme-inhibitor) followed by imazamox treatment suggested cross-resistance to this herbicide possibly via metabolism only in R3 population.

CONCLUSION: Overall, these results confirm the first case of target-site based resistance to ALS inhibitors in B. japonicus in the US, highlighting the need for exploring herbicides with alternative modes of action to enhance weed control in winter wheat. © 2024 Society of Chemical Industry.}, } @article {pmid38481899, year = {2024}, author = {El-Ghanem, M and Abdulrazeq, H and Brasiliense, L and Abbad, H and Aguilar-Salinas, P and Al-Mufti, F and Dumont, T}, title = {Outcomes of Mechanical Thrombectomy in Patients With Neurological Disorders: A National Inpatient Sample Database Analysis.}, journal = {Cureus}, volume = {16}, number = {2}, pages = {e54063}, pmid = {38481899}, issn = {2168-8184}, abstract = {INTRODUCTION: Mechanical thrombectomy (MT) has changed the standard of care for patients presenting with acute ischemic stroke (AIS). The window of treatment has significantly increased the number of patients who would benefit from intervention and operators may be confronted with patients harboring preexistent neurological disorders. Still, the epidemiology of patients with AIS and neurological disorders has not been established.

METHODS: This is a retrospective study, which utilizes data from the National Inpatient Sample (NIS) between 2012 and 2016. Patients with the major neurological comorbidities in the study were included: Alzheimer's dementia (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and myasthenia gravis (MG). These patients were divided into groups and analyzed based on discharged home status, length of hospital stay (LOS), and inpatient mortality. These outcomes were also compared between patients who underwent MT versus those who did not.

RESULTS: In this study, 460,070 patients with AIS were identified and included. MT was performed less often when the patient had a neurological diagnosis compared to those without a neurological disease (p<0.0001). However, patients with AIS who have underlying neurological disorders such as AD, PD, and MS have shown similar outcomes after MT to those who do not have these disorders.

CONCLUSION: Patients with preexisting neurological disorders were less likely to undergo MT. Further studies are required to elucidate the implications of having a neurological disorder in the setting of an AIS.}, } @article {pmid38481294, year = {2024}, author = {Laforest, M and Martin, SL and Bisaillon, K and Soufiane, B and Meloche, S and Tardif, FJ and Page, E}, title = {The ancestral karyotype of the Heliantheae Alliance, herbicide resistance, and human allergens: Insights from the genomes of common and giant ragweed.}, journal = {The plant genome}, volume = {17}, number = {2}, pages = {e20442}, doi = {10.1002/tpg2.20442}, pmid = {38481294}, issn = {1940-3372}, support = {J-001751//Agriculture and Agri-Food Canada/ ; J-002275//Agriculture and Agri-Food Canada/ ; }, mesh = {*Ambrosia/genetics ; *Allergens/genetics ; *Herbicide Resistance/genetics ; *Genome, Plant ; Humans ; Karyotype ; Herbicides/pharmacology ; Chromosomes, Plant ; }, abstract = {Ambrosia artemisiifolia and Ambrosia trifida (Asteraceae) are important pest species and the two greatest sources of aeroallergens globally. Here, we took advantage of a hybrid to simplify genome assembly and present chromosome-level assemblies for both species. These assemblies show high levels of completeness with Benchmarking Universal Single-Copy Ortholog (BUSCO) scores of 94.5% for A. artemisiifolia and 96.1% for A. trifida and long terminal repeat (LTR) Assembly Index values of 26.6 and 23.6, respectively. The genomes were annotated using RNA data identifying 41,642 genes in A. artemisiifolia and 50,203 in A. trifida. More than half of the genome is composed of repetitive elements, with 62% in A. artemisiifolia and 69% in A. trifida. Single copies of herbicide resistance-associated genes PPX2L, HPPD, and ALS were found, while two copies of the EPSPS gene were identified; this latter observation may reveal a possible mechanism of resistance to the herbicide glyphosate. Ten of the 12 main allergenicity genes were also localized, some forming clusters with several copies, especially in A. artemisiifolia. The evolution of genome structure has differed among these two species. The genome of A. trifida has undergone greater rearrangement, possibly the result of chromoplexy. In contrast, the genome of A. artemisiifolia retains a structure that makes the allotetraploidization of the most recent common ancestor of the Heliantheae Alliance the clearest feature of its genome. When compared to other Heliantheae Alliance species, this allowed us to reconstruct the common ancestor's karyotype-a key step for furthering of our understanding of the evolution and diversification of this economically and allergenically important group.}, } @article {pmid38479182, year = {2024}, author = {Nie, L and He, K and Qiu, C and Li, Q and Xiong, B and Gao, C and Zhang, X and Jing, M and Wu, W and Liu, J and Zhang, G and Zhang, Z and Yang, X and Sun, Y and Wang, Y}, title = {Tetramethylpyrazine Nitrone alleviates D-galactose-induced murine skeletal muscle aging and motor deficits by activating the AMPK signaling pathway.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {173}, number = {}, pages = {116415}, doi = {10.1016/j.biopha.2024.116415}, pmid = {38479182}, issn = {1950-6007}, mesh = {Mice ; Animals ; *Galactose ; AMP-Activated Protein Kinases ; *Neuroprotective Agents/pharmacology ; Aging ; Signal Transduction ; Muscle, Skeletal ; *Pyrazines ; }, abstract = {Tetramethylpyrazine nitrone (TBN), a novel derivative of tetramethylpyrazine (TMP) designed and synthesized by our group, possesses multi-functional mechanisms of action and displays broad protective effects in vitro and in animal models of age-related brain disorders such as stroke, Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Parkinson's disease (PD). In the present report, we investigated the effects of TBN on aging, specifically on muscle aging and the associated decline of motor functions. Using a D-galactose-induced aging mouse model, we found that TBN could reverse the levels of several senescence and aging markers including p16, p21, ceramides, and telomere length and increase the wet-weight ratio of gastrocnemius muscle tissue, demonstrating its efficacy in ameliorating muscle aging. Additionally, the pharmacological effects of TBN on motor deficits (gait analysis, pole-climbing test and grip strength test), muscle fibrosis (hematoxylin & eosin (HE), Masson staining, and αSMA staining), inflammatory response (IL-1β, IL-6, and TNF-α), and mitochondrial function (ATP, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were also confirmed in the D-galactose-induced aging models. Further experiments demonstrated that TBN alleviated muscle aging and improved the decline of age-related motor deficits through an AMPK-dependent mechanism. These findings highlight the significance of TBN as a potential anti-aging agent to combat the occurrence and development of aging and age-related diseases.}, } @article {pmid38478631, year = {2024}, author = {Scekic-Zahirovic, J and Benetton, C and Brunet, A and Ye, X and Logunov, E and Douchamps, V and Megat, S and Andry, V and Kan, VWY and Stuart-Lopez, G and Gilet, J and Guillot, SJ and Dirrig-Grosch, S and Gorin, C and Trombini, M and Dieterle, S and Sinniger, J and Fischer, M and René, F and Gunes, Z and Kessler, P and Dupuis, L and Pradat, PF and Goumon, Y and Goutagny, R and Marchand-Pauvert, V and Liebscher, S and Rouaux, C}, title = {Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency.}, journal = {Science translational medicine}, volume = {16}, number = {738}, pages = {eadg3665}, doi = {10.1126/scitranslmed.adg3665}, pmid = {38478631}, issn = {1946-6242}, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Spinal Cord/metabolism ; Norepinephrine/*deficiency ; Disease Models, Animal ; Mice, Transgenic ; Superoxide Dismutase/metabolism ; *Autonomic Nervous System Diseases ; Dopamine beta-Hydroxylase/*deficiency ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability, which precedes symptom onset, negatively correlates with survival, and is sufficient to trigger neurodegeneration in rodents. Using electrocorticography in the Sod1[G86R] and Fus[ΔNLS/+] ALS mouse models and standard electroencephalography recordings in patients with sporadic ALS, we demonstrate a deficit in theta-gamma phase-amplitude coupling (PAC) in ALS. In mice, PAC deficits started before symptom onset, and in patients, PAC deficits correlated with the rate of disease progression. Using mass spectrometry analyses of CNS neuropeptides, we identified a presymptomatic reduction of noradrenaline (NA) in the motor cortex of ALS mouse models, further validated by in vivo two-photon imaging in behaving SOD1[G93A] and Fus[ΔNLS/+] mice, that revealed pronounced reduction of locomotion-associated NA release. NA deficits were also detected in postmortem tissues from patients with ALS, along with transcriptomic alterations of noradrenergic signaling pathways. Pharmacological ablation of noradrenergic neurons with DSP-4 reduced theta-gamma PAC in wild-type mice and administration of a synthetic precursor of NA augmented theta-gamma PAC in ALS mice. Our findings suggest theta-gamma PAC as means to assess and monitor cortical dysfunction in ALS and warrant further investigation of the NA system as a potential therapeutic target.}, } @article {pmid38478117, year = {2024}, author = {Marques, C and Held, A and Dorfman, K and Sung, J and Song, C and Kavuturu, AS and Aguilar, C and Russo, T and Oakley, DH and Albers, MW and Hyman, BT and Petrucelli, L and Lagier-Tourenne, C and Wainger, BJ}, title = {Neuronal STING activation in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {56}, pmid = {38478117}, issn = {1432-0533}, support = {RF1 NS127407/NS/NINDS NIH HHS/United States ; DP2 NS106664/NS/NINDS NIH HHS/United States ; I01 BX002466/BX/BLRD VA/United States ; RF1NS127407/NH/NIH HHS/United States ; DP2-NS106664/NH/NIH HHS/United States ; F32 NS114319/NS/NINDS NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; F32NS114319/NH/NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; C9orf72 Protein/genetics ; *Frontotemporal Dementia/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; *Pick Disease of the Brain ; }, abstract = {The stimulator of interferon genes (STING) pathway has been implicated in neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis (ALS). While prior studies have focused on STING within immune cells, little is known about STING within neurons. Here, we document neuronal activation of the STING pathway in human postmortem cortical and spinal motor neurons from individuals affected by familial or sporadic ALS. This process takes place selectively in the most vulnerable cortical and spinal motor neurons but not in neurons that are less affected by the disease. Concordant STING activation in layer V cortical motor neurons occurs in a mouse model of C9orf72 repeat-associated ALS and frontotemporal dementia (FTD). To establish that STING activation occurs in a neuron-autonomous manner, we demonstrate the integrity of the STING signaling pathway, including both upstream activators and downstream innate immune response effectors, in dissociated mouse cortical neurons and neurons derived from control human induced pluripotent stem cells (iPSCs). Human iPSC-derived neurons harboring different familial ALS-causing mutations exhibit increased STING signaling with DNA damage as a main driver. The elevated downstream inflammatory markers present in ALS iPSC-derived neurons can be suppressed with a STING inhibitor. Our results reveal an immunophenotype that consists of innate immune signaling driven by the STING pathway and occurs specifically within vulnerable neurons in ALS/FTD.}, } @article {pmid38477424, year = {2025}, author = {Steigerwald, CG and Bertolini, C and McElhiney, M and Bergner, AL and Harms, MB and Harrington, EA}, title = {Individuals' experiences in genetic counseling and predictive testing for familial amyotrophic lateral sclerosis.}, journal = {Journal of genetic counseling}, volume = {34}, number = {1}, pages = {e1890}, doi = {10.1002/jgc4.1890}, pmid = {38477424}, issn = {1573-3599}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/psychology ; *Genetic Counseling/psychology ; *Genetic Testing/methods ; Male ; Female ; Middle Aged ; Adult ; Surveys and Questionnaires ; Aged ; }, abstract = {As clinical genetic testing in the amyotrophic lateral sclerosis (ALS) diagnostic setting increases, the identification of at-risk family members has also expanded. No practice guidelines specifically for predictive genetic testing exist, and few studies about the psychological impacts of testing in this subgroup have occurred, limiting the ability to tailor recommendations and counseling in this community. We surveyed asymptomatic individuals at risk for inheriting an ALS-associated gene mutation. The 80-question survey was designed using a combination of validated measures (General Anxiety Disorder; FACToR; Decision Regret Scale) and original items. Ninety participants completed the survey, including those who completed predictive genetic testing (N = 42) and those who did not (N = 48). Gene positive individuals experienced greater negativity, uncertainty, and overall psychological impairment (p = 0.002; p < 0.001; p = 0.001). Individuals who had not undergone testing reported thinking about their risk multiple times per day and experiencing more decisional regret than those who tested (p = 0.006). In terms of decision-making, being prepared for potential clinical drug trials was a more important potential benefit among those who underwent testing (p = 0.026). Participants valuing preparedness for clinical drug trials supports the concept that genetic testing for ALS will increase as research in gene-targeted therapeutics progresses. This study describes factors relevant to the genetic testing decision-making process and adaptation to results from the perspective of at-risk individuals, which can ultimately guide genetic counseling practice in this population.}, } @article {pmid38477419, year = {2024}, author = {de Fátima Dos Santos Sampaio, M and de Paiva, YB and Sampaio, TB and Pereira, MG and Coimbra, NC}, title = {Therapeutic applicability of cannabidiol and other phytocannabinoids in epilepsy, multiple sclerosis and Parkinson's disease and in comorbidity with psychiatric disorders.}, journal = {Basic & clinical pharmacology & toxicology}, volume = {134}, number = {5}, pages = {574-601}, doi = {10.1111/bcpt.13997}, pmid = {38477419}, issn = {1742-7843}, support = {2014/11869-0//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2020/15050-7//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; PDJ grant 155489/2018-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; Research Grant (NAP-USP-NuPNE; process IaPq2012-15//Universidade de São Paulo/ ; 374/2022//Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo/ ; 302605/2021-5//CNPq/ ; 301341/2015-0//CNPq/ ; 301905/2010-0//CNPq/ ; 155489/2018-6//CNPq/ ; }, mesh = {Humans ; *Cannabidiol/pharmacology/therapeutic use ; *Parkinson Disease/drug therapy ; *Multiple Sclerosis/drug therapy ; Receptor, Serotonin, 5-HT1A/therapeutic use ; *Cannabinoids/pharmacology/therapeutic use ; *Epilepsy/drug therapy ; *Mental Disorders/drug therapy ; Comorbidity ; }, abstract = {Studies have demonstrated the neuroprotective effect of cannabidiol (CBD) and other Cannabis sativa L. derivatives on diseases of the central nervous system caused by their direct or indirect interaction with endocannabinoid system-related receptors and other molecular targets, such as the 5-HT1A receptor, which is a potential pharmacological target of CBD. Interestingly, CBD binding with the 5-HT1A receptor may be suitable for the treatment of epilepsies, parkinsonian syndromes and amyotrophic lateral sclerosis, in which the 5-HT1A serotonergic receptor plays a key role. The aim of this review was to provide an overview of cannabinoid effects on neurological disorders, such as epilepsy, multiple sclerosis and Parkinson's diseases, and discuss their possible mechanism of action, highlighting interactions with molecular targets and the potential neuroprotective effects of phytocannabinoids. CBD has been shown to have significant therapeutic effects on epilepsy and Parkinson's disease, while nabiximols contribute to a reduction in spasticity and are a frequent option for the treatment of multiple sclerosis. Although there are multiple theories on the therapeutic potential of cannabinoids for neurological disorders, substantially greater progress in the search for strong scientific evidence of their pharmacological effectiveness is needed.}, } @article {pmid38474719, year = {2024}, author = {Noor Eddin, A and Alfuwais, M and Noor Eddin, R and Alkattan, K and Yaqinuddin, A}, title = {Gut-Modulating Agents and Amyotrophic Lateral Sclerosis: Current Evidence and Future Perspectives.}, journal = {Nutrients}, volume = {16}, number = {5}, pages = {}, pmid = {38474719}, issn = {2072-6643}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Dysbiosis/etiology ; *Gastrointestinal Microbiome/physiology ; *Microbiota ; Disease Progression ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a highly fatal neurodegenerative disorder characterized by the progressive wasting and paralysis of voluntary muscle. Despite extensive research, the etiology of ALS remains elusive, and effective treatment options are limited. However, recent evidence implicates gut dysbiosis and gut-brain axis (GBA) dysfunction in ALS pathogenesis. Alterations to the composition and diversity of microbial communities within the gut flora have been consistently observed in ALS patients. These changes are often correlated with disease progression and patient outcome, suggesting that GBA modulation may have therapeutic potential. Indeed, targeting the gut microbiota has been shown to be neuroprotective in several animal models, alleviating motor symptoms and mitigating disease progression. However, the translation of these findings to human patients is challenging due to the complexity of ALS pathology and the varying diversity of gut microbiota. This review comprehensively summarizes the current literature on ALS-related gut dysbiosis, focusing on the implications of GBA dysfunction. It delineates three main mechanisms by which dysbiosis contributes to ALS pathology: compromised intestinal barrier integrity, metabolic dysfunction, and immune dysregulation. It also examines preclinical evidence on the therapeutic potential of gut-microbiota-modulating agents (categorized as prebiotics, probiotics, and postbiotics) in ALS.}, } @article {pmid38474416, year = {2024}, author = {Tzeplaeff, L and Jürs, AV and Wohnrade, C and Demleitner, AF}, title = {Unraveling the Heterogeneity of ALS-A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials.}, journal = {Cells}, volume = {13}, number = {5}, pages = {}, pmid = {38474416}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Treatment Outcome ; Clinical Trials as Topic ; }, abstract = {Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be a single disease entity but rather may represent a clinical syndrome, with diverse genetic and molecular causes, histopathological alterations, and subsequent clinical presentations contributing to its complexity and variability among individuals. Defining a way to subcluster ALS patients is becoming a central endeavor in the field. Identifying specific clusters and applying them in clinical trials could enable the development of more effective treatments. This review aims to summarize the available data on heterogeneity in ALS with regard to various aspects, e.g., clinical, genetic, and molecular.}, } @article {pmid38474399, year = {2024}, author = {Manora, L and Borlongan, CV and Garbuzova-Davis, S}, title = {Cellular and Noncellular Approaches for Repairing the Damaged Blood-CNS-Barrier in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {5}, pages = {}, pmid = {38474399}, issn = {2073-4409}, support = {R01 NS090962/NS/NINDS NIH HHS/United States ; R21 NS132576/NS/NINDS NIH HHS/United States ; 1R21NS132576-01/NS/NINDS NIH HHS/United States ; 1R01NS090962/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Endothelial Cells/metabolism ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Stem Cells/metabolism ; }, abstract = {Numerous reports have demonstrated the breakdown of the blood-CNS barrier (B-CNS-B) in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Re-establishing barrier integrity in the CNS is critical to prevent further motor neuron degeneration from harmful components in systemic circulation. Potential therapeutic strategies for repairing the B-CNS-B may be achieved by the replacement of damaged endothelial cells (ECs) via stem cell administration or enhancement of endogenous EC survival through the delivery of bioactive particles secreted by stem cells. These cellular and noncellular approaches are thoroughly discussed in the present review. Specific attention is given to certain stem cell types for EC replacement. Also, various nanoparticles secreted by stem cells as well as other biomolecules are elucidated as promising agents for endogenous EC repair. Although the noted in vitro and in vivo studies show the feasibility of the proposed therapeutic approaches to the repair of the B-CNS-B in ALS, further investigation is needed prior to clinical transition.}, } @article {pmid38933502, year = {2024}, author = {Chen, BR and Wu, T and Chen, TH and Wang, Y}, title = {Neuroimmune interactions and their roles in neurodegenerative diseases.}, journal = {Fundamental research}, volume = {4}, number = {2}, pages = {251-261}, pmid = {38933502}, issn = {2667-3258}, abstract = {The nervous system possesses bidirectional, sophisticated and delicate communications with the immune system. These neuroimmune interactions play a vitally important role in the initiation and development of many disorders, especially neurodegenerative diseases. Although scientific advancements have made tremendous progress in this field during the last few years, neuroimmune communications are still far from being elucidated. By organizing recent research, in this review, we discuss the local and intersystem neuroimmune interactions and their roles in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Unveiling these will help us gain a better understanding of the process of interplay inside the body and how the organism maintains homeostasis. It will also facilitate a view of the diseases from a holistic, pluralistic and interconnected perspective, thus providing a basis of developing novel and effective methods to diagnose, intervene and treat diseases.}, } @article {pmid38933387, year = {2022}, author = {Li, X and Lu, S and Lu, B and Sun, X}, title = {Optogenetic control of GGGGCC repeat-containing RNA phase transition.}, journal = {Fundamental research}, volume = {2}, number = {6}, pages = {843-850}, pmid = {38933387}, issn = {2667-3258}, abstract = {The GGGGCC (G4C2) hexanucleotide repeat expansion in the C9ORF72 gene is a major cause of both hereditary amyotrophic lateral sclerosis and familial frontotemporal dementia. Recent studies have shown that G4C2 hexanucleotide repeat-containing RNA transcripts ((G4C2)n RNA) could go through liquid-liquid phase separation to form RNA foci, which may elicit neurodegeneration. However, the direct causality between these abnormal RNA foci and neuronal toxicity remains to be demonstrated. Here we introduce an optogenetic control system that can induce the assembly and phase separation of (G4C2)n RNA foci with blue light illumination in human cells, by fusing a specific (G4C2)n RNA binding protein as the linker domain to Cry2, a protein that oligomerizes in response to blue light. Our results demonstrate that a higher number of G4C2 repeats have the potential to be induced into more RNA foci in the cells. Both spontaneous and induced RNA foci display liquid-like properties according to FRAP measurements. Computational simulation shows strong consistency with the experimental results and supports the effect of our system to promote the propensity of (G4C2)n RNA towards phase separation. This system can thus be used to investigate whether (G4C2)n RNA foci would disrupt normal cellular processes and lead to pathological phenotypes relevant to repeat expansion disorders.}, } @article {pmid38505242, year = {2022}, author = {Mendive-Tapia, L and Mendive-Tapia, D and Zhao, C and Gordon, D and Benson, S and Bromley, MJ and Wang, W and Wu, J and Kopp, A and Ackermann, L and Vendrell, M}, title = {Rationales Design von Phe-BODIPY-Aminosäuren als fluorogene Bausteine für den peptidbasierten Nachweis von Candida-Infektionen im Harntrakt.}, journal = {Angewandte Chemie (Weinheim an der Bergstrasse, Germany)}, volume = {134}, number = {17}, pages = {e202117218}, pmid = {38505242}, issn = {0044-8249}, } @article {pmid38715858, year = {2021}, author = {Gupta, S and Sharma, U}, title = {Metabolomics of neurological disorders in India.}, journal = {Analytical science advances}, volume = {2}, number = {11-12}, pages = {594-610}, pmid = {38715858}, issn = {2628-5452}, abstract = {Metabolomics is the comprehensive study of the metabolome and its alterations within biological fluids and tissues. Over the years, applications of metabolomics have been explored in several areas, including personalised medicine in diseases, metabolome-wide association studies (MWAS), pharmacometabolomics and in combination with other branches of omics such as proteomics, transcriptomics and genomics. Mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy are the major analytical techniques widely employed in metabolomics. In addition, MS is coupled with chromatography techniques like gas chromatography (GC) and liquid chromatography (LC) to separate metabolites before analysis. These analytical techniques have made possible identification and quantification of large numbers of metabolites, encompassing characterization of diseases and facilitating a systematic and rational therapeutic strategy based on metabolic patterns. In recent years, the metabolomics approach has been used to obtain a deeper insight into the underlying biochemistry of neurodegenerative disorders and the discovery of biomarkers of clinical implications. The current review mainly focuses on an Indian perspective of metabolomics for the identification of metabolites and metabolic alterations serving as potential diagnostic biomarkers for neurological diseases including acute spinal cord injury, amyotrophic lateral sclerosis, tethered cord syndrome, spina bifida, stroke, Parkinson's disease, glioblastoma and neurological disorders with inborn errors of metabolism.}, } @article {pmid38505660, year = {2021}, author = {Romero, E and Jones, BS and Hogg, BN and Rué Casamajo, A and Hayes, MA and Flitsch, SL and Turner, NJ and Schnepel, C}, title = {Enzymkatalysierte späte Modifizierungen: Besser spät als nie.}, journal = {Angewandte Chemie (Weinheim an der Bergstrasse, Germany)}, volume = {133}, number = {31}, pages = {16962-16993}, pmid = {38505660}, issn = {0044-8249}, } @article {pmid38474336, year = {2024}, author = {Aksoy, YA and Cole, AJ and Deng, W and Hesselson, D}, title = {Zebrafish CCNF and FUS Mediate Stress-Specific Motor Responses.}, journal = {Cells}, volume = {13}, number = {5}, pages = {}, pmid = {38474336}, issn = {2073-4409}, support = {APP1095215//NHMRC/ ; APP1063981//NHMRC/ ; DP140103233/ARC/Ames Research Center NASA/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Cyclins/metabolism ; Motor Neurons/pathology ; *Neurodegenerative Diseases/metabolism ; Proteins/metabolism ; *RNA-Binding Protein FUS/genetics/metabolism ; *Zebrafish/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of motor neurons. Mutations in the cyclin F (CCNF) and fused in sarcoma (FUS) genes have been associated with ALS pathology. In this study, we aimed to investigate the functional role of CCNF and FUS in ALS by using genome editing techniques to generate zebrafish models with genetic disruptions in these genes. Sequence comparisons showed significant homology between human and zebrafish CCNF and FUS proteins. We used CRISPR/Cas9 and TALEN-mediated genome editing to generate targeted disruptions in the zebrafish ccnf and fus genes. Ccnf-deficient zebrafish exhibited abnormal motor neuron development and axonal outgrowth, whereas Fus-deficient zebrafish did not exhibit developmental abnormalities or axonopathies in primary motor neurons. However, Fus-deficient zebrafish displayed motor impairments in response to oxidative and endoplasmic reticulum stress. The Ccnf-deficient zebrafish were only sensitized to endoplasmic reticulum stress, indicating that ALS genes have overlapping as well as unique cellular functions. These zebrafish models provide valuable platforms for studying the functional consequences of CCNF and FUS mutations in ALS pathogenesis. Furthermore, these zebrafish models expand the drug screening toolkit used to evaluate possible ALS treatments.}, } @article {pmid38474192, year = {2024}, author = {Yamashita, T and Abe, K}, title = {Update on Antioxidant Therapy with Edaravone: Expanding Applications in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {5}, pages = {}, pmid = {38474192}, issn = {1422-0067}, support = {23K08543, 21K19572//Grant-in-Aid for Scientific Research/ ; }, mesh = {Animals ; Female ; Pregnancy ; *Amyotrophic Lateral Sclerosis/drug therapy ; Antioxidants/therapeutic use ; Antipyrine ; Edaravone/pharmacology/therapeutic use ; Free Radical Scavengers/pharmacology ; *Neurodegenerative Diseases/drug therapy ; *Neuroprotective Agents/pharmacology ; Placenta ; }, abstract = {The brain is susceptible to oxidative stress, which is associated with various neurological diseases. Edaravone (MCI-186, 3-methyl-1 pheny-2-pyrazolin-5-one), a free radical scavenger, has promising effects by quenching hydroxyl radicals (∙OH) and inhibiting both ∙OH-dependent and ∙OH-independent lipid peroxidation. Edaravone was initially developed in Japan as a neuroprotective agent for acute cerebral infarction and was later applied clinically to treat amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. There is accumulating evidence for the therapeutic effects of edaravone in a wide range of diseases related to oxidative stress, including ischemic stroke, ALS, Alzheimer's disease, and placental ischemia. These neuroprotective effects have expanded the potential applications of edaravone. Data from experimental animal models support its safety for long-term use, implying broader applications in various neurodegenerative diseases. In this review, we explain the unique characteristics of edaravone, summarize recent findings for specific diseases, and discuss its prospects for future therapeutic applications.}, } @article {pmid38473944, year = {2024}, author = {Scarian, E and Viola, C and Dragoni, F and Di Gerlando, R and Rizzo, B and Diamanti, L and Gagliardi, S and Bordoni, M and Pansarasa, O}, title = {New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {5}, pages = {}, pmid = {38473944}, issn = {1422-0067}, support = {Ricerca Corrente 2022-2024//Ministero della Salute/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Oxidative Stress/physiology ; Antioxidants/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Inflammation/drug therapy ; }, abstract = {Oxidative stress (OS) and inflammation are two important and well-studied pathological hallmarks of neurodegenerative diseases (NDDs). Due to elevated oxygen consumption, the high presence of easily oxidizable polyunsaturated fatty acids and the weak antioxidant defenses, the brain is particularly vulnerable to oxidative injury. Uncertainty exists over whether these deficits contribute to the development of NDDs or are solely a consequence of neuronal degeneration. Furthermore, these two pathological hallmarks are linked, and it is known that OS can affect the inflammatory response. In this review, we will overview the last findings about these two pathways in the principal NDDs. Moreover, we will focus more in depth on amyotrophic lateral sclerosis (ALS) to understand how anti-inflammatory and antioxidants drugs have been used for the treatment of this still incurable motor neuron (MN) disease. Finally, we will analyze the principal past and actual clinical trials and the future perspectives in the study of these two pathological mechanisms.}, } @article {pmid38472280, year = {2024}, author = {Safren, N and Dao, TP and Mohan, HM and Huang, C and Trotter, B and Castañeda, CA and Paulson, H and Barmada, S and Sharkey, LM}, title = {Pathogenic mutations in UBQLN2 exhibit diverse aggregation propensity and neurotoxicity.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {6049}, pmid = {38472280}, issn = {2045-2322}, support = {R01 GM136946/GM/NIGMS NIH HHS/United States ; R01GM136946./GF/NIH HHS/United States ; R01NS097542-01/GF/NIH HHS/United States ; R35 NS122302/NS/NINDS NIH HHS/United States ; R35NS122302/GF/NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/metabolism ; Autophagy-Related Proteins/genetics ; Mutation ; Adaptor Proteins, Signal Transducing/metabolism ; }, abstract = {The ubiquitin-adaptor protein UBQLN2 promotes degradation of several aggregate-prone proteins implicated in neurodegenerative diseases. Missense UBQLN2 mutations also cause X-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previously we demonstrated that the liquid-like properties of UBQLN2 molecular assemblies are altered by a specific pathogenic mutation, P506T, and that the propensity of UBQLN2 to aggregate correlated with neurotoxicity. Here, we systematically assess the effects of multiple, spatially distinct ALS/FTD-linked missense mutations on UBQLN2 aggregation propensity, neurotoxicity, phase separation, and autophagic flux. In contrast to what we observed for the P506T mutation, no other tested pathogenic mutant exhibited a clear correlation between aggregation propensity and neurotoxicity. These results emphasize the unique nature of pathogenic UBQLN2 mutations and argue against a generalizable link between aggregation propensity and neurodegeneration in UBQLN2-linked ALS/FTD.}, } @article {pmid38472048, year = {2024}, author = {Silva-Hucha, S and Fernández de Sevilla, ME and Humphreys, KM and Benson, FE and Franco, JM and Pozo, D and Pastor, AM and Morcuende, S}, title = {VEGF expression disparities in brainstem motor neurons of the SOD1[G93A] ALS model: Correlations with neuronal vulnerability.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {3}, pages = {e00340}, pmid = {38472048}, issn = {1878-7479}, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Brain Stem/metabolism ; Disease Models, Animal ; Mice, Transgenic ; *Motor Neurons/metabolism/pathology ; Superoxide Dismutase/metabolism/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; *Vascular Endothelial Growth Factor A/metabolism/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neuromuscular disease characterized by severe muscle weakness mainly due to degeneration and death of motor neurons. A peculiarity of the neurodegenerative processes is the variable susceptibility among distinct neuronal populations, exemplified by the contrasting resilience of motor neurons innervating the ocular motor system and the more vulnerable facial and hypoglossal motor neurons. The crucial role of vascular endothelial growth factor (VEGF) as a neuroprotective factor in the nervous system is well-established since a deficit of VEGF has been related to motoneuronal degeneration. In this study, we investigated the survival of ocular, facial, and hypoglossal motor neurons utilizing the murine SOD1[G93A] ALS model at various stages of the disease. Our primary objective was to determine whether the survival of the different brainstem motor neurons was linked to disparate VEGF expression levels in resilient and susceptible motor neurons throughout neurodegeneration. Our findings revealed a selective loss of motor neurons exclusively within the vulnerable nuclei. Furthermore, a significantly higher level of VEGF was detected in the more resistant motor neurons, the extraocular ones. We also examined whether TDP-43 dynamics in the brainstem motor neuron of SOD mice was altered. Our data suggests that the increased VEGF levels observed in extraocular motor neurons may potentially underlie their resistance during the neurodegenerative processes in ALS in a TDP-43-independent manner. Our work might help to better understand the underlying mechanisms of selective vulnerability of motor neurons in ALS.}, } @article {pmid38471489, year = {2024}, author = {D'Souza, A and Zink, K and Langhorst, J and Wildner, M and Stupp, C and Keil, T}, title = {How Effective Is Drinking Natural Mineral Water against Heartburn from Functional Dyspepsia, Gastroesophageal Reflux Disease, or Other Causes? A Systematic Review of Clinical Intervention Studies.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {253-265}, pmid = {38471489}, issn = {2504-2106}, mesh = {Humans ; *Mineral Waters/therapeutic use ; *Gastroesophageal Reflux/therapy/drug therapy ; *Heartburn/drug therapy ; *Dyspepsia/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: For centuries, spring and other natural waters have been recommended as external or internal remedies for numerous diseases. For studies that examined the effects of drinking mineral waters against heartburn, gastroesophageal reflux disease (GERD), or functional dyspepsia, a systematic review is lacking.

OBJECTIVES: The main aim of this systematic review was to examine the effects of drinking natural mineral waters on heartburn from various causes by identifying all published intervention studies and critically appraising their methods as well as summarizing their results.

METHODS: We systematically searched the largest medical literature database MEDLINE, further relevant web sources, and gray literature for randomized and nonrandomized trials, with or without control groups, up to September 2021 and no language restrictions. Further inclusion criteria were adult patients with heartburn, drinking cure with natural mineral water as the intervention, compared to no or other interventions (care-as-usual, waiting list). We defined the reduction of heartburn symptoms and duration of disease episodes as primary and quality of life as secondary outcomes. Two reviewers independently carried out the study quality assessments (risk of bias) using the National Institutes of Health-Study Quality Assessment Tools.

RESULTS: Nine trials comprising 393 patients from Italy, Russia, Ukraine, and Germany fulfilled all inclusion criteria. We identified three randomized controlled trials (all with poor methodological quality), plus six before-after (pre/post) intervention studies without a control group. The intervention groups of the three comparative trials seemed to show a stronger reduction of self-reported heartburn symptoms, and duration of heartburn episodes than the respective control groups; however, they all had poor methodological quality.

CONCLUSION: Based on the best available evidence of clinical studies, we cannot recommend or advise against drinking natural mineral waters as a treatment for heartburn. The potential benefits of natural mineral waters that were reported in some studies with a lower evidence level (e.g., lacking a control group) should be verified by good quality randomized clinical trials with adequate comparison groups and longer follow-up periods.

UNLABELLED: HintergrundSeit Jahrhunderten werden Quell- und andere natürliche Wässer als äußerliche oder innerliche Heilmittel für zahlreiche Krankheiten empfohlen. Für Studien, die die Wirkung des Trinkens von Mineralwasser gegen Sodbrennen, gastroösophageale Refluxkrankheit (GERD) oder funktionelle Dyspepsie untersuchten, fehlt eine systematische Übersicht.ZielsetzungDas Hauptziel dieser systematischen Übersichtsarbeit war es, die Auswirkungen von Trinkkuren mit natürlichen Mineralwässern auf Sodbrennen verschiedener Ursachen zu untersuchen, indem alle veröffentlichten Interventionsstudien identifiziert und ihre Methoden kritisch bewertet sowie ihre Ergebnisse zusammengefasst wurden.MethodenWir durchsuchten systematisch die größte medizinische Literaturdatenbank MEDLINE, weitere relevante Internetquellen und graue Literatur nach randomisierten und nicht-randomisierten Studien, mit oder ohne Kontrollgruppen, bis September 2021 und ohne sprachliche Einschränkungen. Weitere Einschlusskriterien waren erwachsene Patienten mit Sodbrennen, Trinkkur mit natürlichem Mineralwasser als Intervention, im Vergleich zu keiner oder anderen Interventionen (care-as-usual, Warteliste). Wir definierten die Abnahme der Symptome des Sodbrennens und die Dauer der Krankheitsepisoden als primäre und die Lebensqualität als sekundäre Endpunkte. Zwei Gutachter bewerteten unabhängig voneinander die Qualität der Studien (Verzerrungsrisiko) anhand der National Institutes of Health-Study Quality Assessment Tools.ErgebnisseNeun Studien mit 393 Patienten aus Italien, Russland, der Ukraine und Deutschland erfüllten alle Einschlusskriterien. Wir identifizierten drei randomisierte kontrollierte Studien (alle mit schlechter methodischer Qualität) sowie sechs Vorher-Nachher-Studien (Prä-/Post-Studien) ohne Kontrollgruppe. Die Interventionsgruppen der drei randomisierten Vergleichsstudien schienen eine stärkere Verringerung der selbstberichteten Symptome und der Dauer der Episoden des Sodbrennens zu zeigen als die jeweiligen Kontrollgruppen, allerdings waren sie alle von schlechter methodischer Qualität.SchlussfolgerungAuf der Grundlage der besten verfügbaren Belege aus klinischen Studien können wir das Trinken natürlicher Mineralwässer zur Behandlung von Sodbrennen weder empfehlen noch davon abraten. Die potenziellen Vorteile natürlicher Mineralwässer, die in einigen Studien mit geringerer Evidenz (z. B. ohne Kontrollgruppe) berichtet wurden, sollten durch qualitativ hochwertige randomisierte klinische Studien mit angemessenen Vergleichsgruppen und längeren Nachbeobachtungszeiträumen überprüft werden.}, } @article {pmid38470574, year = {2024}, author = {Pan, H and Wang, Y and Li, Z and Chu, X and Teng, B and Gao, H}, title = {A Complete Scheme for Multi-Character Classification Using EEG Signals From Speech Imagery.}, journal = {IEEE transactions on bio-medical engineering}, volume = {71}, number = {8}, pages = {2454-2462}, doi = {10.1109/TBME.2024.3376603}, pmid = {38470574}, issn = {1558-2531}, mesh = {Humans ; *Electroencephalography/methods ; *Signal Processing, Computer-Assisted ; *Speech/physiology ; *Brain-Computer Interfaces ; Algorithms ; Wavelet Analysis ; Imagination/physiology ; Adult ; Male ; Female ; Neural Networks, Computer ; }, abstract = {Some classification studies of brain-computer interface (BCI) based on speech imagery show potential for improving communication skills in patients with amyotrophic lateral sclerosis (ALS). However, current research on speech imagery is limited in scope and primarily focuses on vowels or a few selected words. In this paper, we propose a complete research scheme for multi-character classification based on EEG signals derived from speech imagery. Firstly, we record 31 speech imagery contents, including 26 alphabets and five commonly used punctuation marks, from seven subjects using a 32-channel electroencephalogram (EEG) device. Secondly, we introduce the wavelet scattering transform (WST), which shares a structural resemblance to Convolutional Neural Networks (CNNs), for feature extraction. The WST is a knowledge-driven technique that preserves high-frequency information and maintains the deformation stability of EEG signals. To reduce the dimensionality of wavelet scattering coefficient features, we employ Kernel Principal Component Analysis (KPCA). Finally, the reduced features are fed into an Extreme Gradient Boosting (XGBoost) classifier within a multi-classification framework. The XGBoost classifier is optimized through hyperparameter tuning using grid search and 10-fold cross-validation, resulting in an average accuracy of 78.73% for the multi-character classification task. We utilize t-Distributed Stochastic Neighbor Embedding (t-SNE) technology to visualize the low-dimensional representation of multi-character speech imagery. This visualization effectively enables us to observe the clustering of similar characters. The experimental results demonstrate the effectiveness of our proposed multi-character classification scheme. Furthermore, our classification categories and accuracy exceed those reported in existing research.}, } @article {pmid38470552, year = {2024}, author = {Zou, W and Li, M and Wang, X and Lu, H and Hao, Y and Chen, D and Zhu, S and Ji, D and Zhang, Z and Zhou, P and Cao, Y}, title = {Preimplantation genetic testing for monogenic disorders (PGT-M) offers an alternative strategy to prevent children from being born with hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes: a retrospective study.}, journal = {Journal of assisted reproduction and genetics}, volume = {41}, number = {5}, pages = {1245-1259}, pmid = {38470552}, issn = {1573-7330}, support = {82001635//the National Natural Science Foundation of China/ ; 2021YFC2700901//the National Key R&D Program of China/ ; 202204295107020012//the Clinical Medical research transformation Project of Anhui Province/ ; 2022LCX015//the Foundation for Selected Scientists Studying Abroad of Anhui Province/ ; gxyqZD2022027//Program for Outstanding Young Talents in University of Anhui/ ; 202003a07020012//Major Science and Technology Project of Anhui province/ ; }, mesh = {Humans ; *Preimplantation Diagnosis/methods ; Female ; Pregnancy ; *Genetic Testing/methods ; *Metabolic Diseases/genetics/pathology ; Retrospective Studies ; Male ; Nervous System Diseases/genetics ; Phenotype ; Adult ; Child ; Embryo Transfer ; Mutation/genetics ; }, abstract = {BACKGROUND: Preimplantation genetic testing for monogenic disorders (PGT-M) is now widely used as an effective strategy to prevent various monogenic or chromosomal diseases.

MATERIAL AND METHODS: In this retrospective study, couples with a family history of hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes and/or carrying the pathogenic genes underwent PGT-M to prevent children from inheriting disease-causing gene mutations from their parents and developing known genetic diseases. After PGT-M, unaffected (i.e., normal) embryos after genetic detection were transferred into the uterus of their corresponding mothers.

RESULTS: A total of 43 carrier couples with the following hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes underwent PGT-M: Duchenne muscular dystrophy (13 families); methylmalonic acidemia (7 families); spinal muscular atrophy (5 families); infantile neuroaxonal dystrophy and intellectual developmental disorder (3 families each); Cockayne syndrome (2 families); Menkes disease, spinocerebellar ataxia, glycine encephalopathy with epilepsy, Charcot-Marie-Tooth disease, mucopolysaccharidosis, Aicardi-Goutieres syndrome, adrenoleukodystrophy, phenylketonuria, amyotrophic lateral sclerosis, and Dravet syndrome (1 family each). After 53 PGT-M cycles, the final transferable embryo rate was 12.45%, the clinical pregnancy rate was 74.19%, and the live birth rate was 89.47%; a total of 18 unaffected (i.e., healthy) children were born to these families.

CONCLUSIONS: This study highlights the importance of PGT-M in preventing children born with hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes.}, } @article {pmid38470068, year = {2024}, author = {Van Damme, P and Al-Chalabi, A and Andersen, PM and Chiò, A and Couratier, P and De Carvalho, M and Hardiman, O and Kuźma-Kozakiewicz, M and Ludolph, A and McDermott, CJ and Mora, JS and Petri, S and Probyn, K and Reviers, E and Salachas, F and Silani, V and Tysnes, OB and van den Berg, LH and Villanueva, G and Weber, M}, title = {European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).}, journal = {European journal of neurology}, volume = {31}, number = {6}, pages = {e16264}, pmid = {38470068}, issn = {1468-1331}, support = {//ERN Euro-NMD/ ; //European Academy of Neurology/ ; //ALS Liga Belgium/ ; //EUpALS/ ; //ENCALS/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Europe ; Neurology/standards/methods ; Neuromuscular Diseases/therapy ; }, abstract = {BACKGROUND: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS).

METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available.

RESULTS: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease-modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end-of-life management.

CONCLUSIONS: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available.}, } @article {pmid38469975, year = {2024}, author = {Nigri, A and Stanziano, M and Fedeli, D and Manera, U and Ferraro, S and Medina Carrion, JP and Palermo, S and Lequio, L and Denegri, F and Agosta, F and Spinelli, EG and Filippi, M and Grisoli, M and Valentini, MC and De Mattei, F and Canosa, A and Calvo, A and Chiò, A and Bruzzone, MG and Moglia, C}, title = {Distinct neural signatures of pulvinar in C9orf72 amyotrophic lateral sclerosis mutation carriers and noncarriers.}, journal = {European journal of neurology}, volume = {31}, number = {6}, pages = {e16266}, pmid = {38469975}, issn = {1468-1331}, support = {2017SNW5MB//Ministero dell'Università e della Ricerca/ ; FP7/2007-2013//European Commission's Health Seventh Framework Programme/ ; 259867//European Commission's Health Seventh Framework Programme/ ; GR-2019-12371291//Ministero della Salute/ ; RF-2016-02362405//Ministero della Salute/ ; RRC//Ministero della Salute/ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/physiopathology/pathology ; *C9orf72 Protein/genetics ; Frontotemporal Dementia/genetics/physiopathology/diagnostic imaging/pathology ; Heterozygote ; *Magnetic Resonance Imaging ; *Mutation ; *Pulvinar/diagnostic imaging/physiopathology/pathology ; }, abstract = {BACKGROUND AND PURPOSE: Thalamic alterations have been reported as a major feature in presymptomatic and symptomatic patients carrying the C9orf72 mutation across the frontotemporal dementia-amyotrophic lateral sclerosis (ALS) spectrum. Specifically, the pulvinar, a high-order thalamic nucleus and timekeeper for large-scale cortical networks, has been hypothesized to be involved in C9orf72-related neurodegenerative diseases. We investigated whether pulvinar volume can be useful for differential diagnosis in ALS C9orf72 mutation carriers and noncarriers and how underlying functional connectivity changes affect this region.

METHODS: We studied 19 ALS C9orf72 mutation carriers (ALSC9+) accurately matched with wild-type ALS (ALSC9-) and ALS mimic (ALSmimic) patients using structural and resting-state functional magnetic resonance imaging data. Pulvinar volume was computed using automatic segmentation. Seed-to-voxel functional connectivity analyses were performed using seeds from a pulvinar functional parcellation.

RESULTS: Pulvinar structural integrity had high discriminative values for ALSC9+ patients compared to ALSmimic (area under the curve [AUC] = 0.86) and ALSC9- (AUC = 0.77) patients, yielding a volume cutpoint of approximately 0.23%. Compared to ALSmimic, ALSC9- showed increased anterior, inferior, and lateral pulvinar connections with bilateral occipital-temporal-parietal regions, whereas ALSC9+ showed no differences. ALSC9+ patients when compared to ALSC9- patients showed reduced pulvinar-occipital connectivity for anterior and inferior pulvinar seeds.

CONCLUSIONS: Pulvinar volume could be a differential biomarker closely related to the C9orf72 mutation. A pulvinar-cortical circuit dysfunction might play a critical role in disease progression and development, in both the genetic phenotype and ALS wild-type patients.}, } @article {pmid38469573, year = {2024}, author = {Broce, IJ and Sirkis, DW and Nillo, RM and Bonham, LW and Lee, SE and Miller, BL and Castruita, PA and Sturm, VE and Sugrue, LS and Desikan, RS and Yokoyama, JS}, title = {C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1258996}, pmid = {38469573}, issn = {1662-4548}, support = {R01 AG052496/AG/NIA NIH HHS/United States ; T32 AG058529/AG/NIA NIH HHS/United States ; R25 NS117367/NS/NINDS NIH HHS/United States ; R01 AG058233/AG/NIA NIH HHS/United States ; K01 AG070376/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: A hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis.

METHODS: We leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, and cerebellum) with average gene expression values for 15,633 protein-coding genes, including 54 genes known to be associated with ALS, FTD, or ALS-FTD. We then performed imaging transcriptomic analyses to evaluate whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n = 19) compared to controls (n = 23). Lastly, we explored whether genes with significant C9orf72 imaging transcriptomic correlations (i.e., "C9orf72 imaging transcriptomic network") were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways.

RESULTS: A total of 2,120 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 imaging transcriptomic network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic neurons in the spinal cord and brainstem and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with protein ubiquitination, autophagy, cellular response to DNA damage, endoplasmic reticulum to Golgi vesicle-mediated transport, among others.

CONCLUSION: Considered together, we identified a network of C9orf72 associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.}, } @article {pmid38468173, year = {2024}, author = {Yu, Z and Zhang, H and Wang, Y}, title = {In Reply to the Letter to the Editor Regarding "Cervical Spondylotic Amyotrophy Initially Misdiagnosed as Amyotrophic Lateral Sclerosis".}, journal = {World neurosurgery}, volume = {183}, number = {}, pages = {270}, doi = {10.1016/j.wneu.2023.12.140}, pmid = {38468173}, issn = {1878-8769}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Muscular Atrophy ; Muscle, Skeletal ; *Spondylosis/diagnosis ; Diagnostic Errors ; }, } @article {pmid38468172, year = {2024}, author = {Chang, MC}, title = {Letter to the Editor Regarding "Cervical Spondylotic Amyotrophy Initially Misdiagnosed as Amyotrophic Lateral Sclerosis".}, journal = {World neurosurgery}, volume = {183}, number = {}, pages = {269}, doi = {10.1016/j.wneu.2023.10.122}, pmid = {38468172}, issn = {1878-8769}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Muscular Atrophy ; Muscle, Skeletal ; *Spondylosis/diagnosis ; Diagnostic Errors ; Cervical Vertebrae ; }, } @article {pmid38468041, year = {2024}, author = {Davidson, JM and Zhang, L and Yue, GH and Di Ieva, A}, title = {Fractal Dimension Studies of the Brain Shape in Aging and Neurodegenerative Diseases.}, journal = {Advances in neurobiology}, volume = {36}, number = {}, pages = {329-363}, pmid = {38468041}, issn = {2190-5215}, mesh = {Humans ; Adult ; *Neurodegenerative Diseases/diagnostic imaging/pathology ; Fractals ; Gray Matter/diagnostic imaging/pathology ; Aging ; Cerebellum/diagnostic imaging/pathology ; }, abstract = {The fractal dimension is a morphometric measure that has been used to investigate the changes of brain shape complexity in aging and neurodegenerative diseases. This chapter reviews fractal dimension studies in aging and neurodegenerative disorders in the literature. Research has shown that the fractal dimension of the left cerebral hemisphere increases until adolescence and then decreases with aging, while the fractal dimension of the right hemisphere continues to increase until adulthood. Studies in neurodegenerative diseases demonstrated a decline in the fractal dimension of the gray matter and white matter in Alzheimer's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia. In multiple sclerosis, the white matter fractal dimension decreases, but conversely, the fractal dimension of the gray matter increases at specific stages of disease. There is also a decline in the gray matter fractal dimension in frontotemporal dementia and multiple system atrophy of the cerebellar type and in the white matter fractal dimension in epilepsy and stroke. Region-specific changes in fractal dimension have also been found in Huntington's disease and Parkinson's disease. Associations were found between the fractal dimension and clinical scores, showing the potential of the fractal dimension as a marker to monitor brain shape changes in normal or pathological processes and predict cognitive or motor function.}, } @article {pmid38467696, year = {2024}, author = {Hilton, JBW and Kysenius, K and Liddell, JR and Mercer, SW and Paul, B and Beckman, JS and McLean, CA and White, AR and Donnelly, PS and Bush, AI and Hare, DJ and Roberts, BR and Crouch, PJ}, title = {Evidence for disrupted copper availability in human spinal cord supports Cu[II](atsm) as a treatment option for sporadic cases of ALS.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {5929}, pmid = {38467696}, issn = {2045-2322}, mesh = {Humans ; Mice ; Animals ; Copper/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Mice, Transgenic ; Spinal Cord/metabolism ; Ceruloplasmin/metabolism ; Disease Models, Animal ; *Thiosemicarbazones ; *Coordination Complexes ; }, abstract = {The copper compound Cu[II](atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Cu[II](atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential copper. However, SOD1 mutations cause only ~ 2% of ALS cases and therapeutic relevance of copper availability in sporadic ALS is unresolved. Herein we assessed spinal cord tissue from human cases of sporadic ALS for copper-related changes. We found that when compared to control cases the natural distribution of spinal cord copper was disrupted in sporadic ALS. A standout feature was decreased copper levels in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Altered expression of genes involved in copper handling indicated disrupted copper availability, and this was evident in decreased copper-dependent ferroxidase activity despite increased abundance of the ferroxidases ceruloplasmin and hephaestin. Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for Cu[II](atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for Cu[II](atsm) involving copper availability may also be pertinent to sporadic cases of ALS.}, } @article {pmid38467605, year = {2024}, author = {Zhong, J and Wang, C and Zhang, D and Yao, X and Zhao, Q and Huang, X and Lin, F and Xue, C and Wang, Y and He, R and Li, XY and Li, Q and Wang, M and Zhao, S and Afridi, SK and Zhou, W and Wang, Z and Xu, Y and Xu, Z}, title = {PCDHA9 as a candidate gene for amyotrophic lateral sclerosis.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {2189}, pmid = {38467605}, issn = {2041-1723}, support = {32061143026, 31921002,32330038, 32394030//National Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund (NSFC-Yunnan Joint Fund)/ ; 82171412//National Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund (NSFC-Yunnan Joint Fund)/ ; 2021ZD0202300//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; }, mesh = {Humans ; Mice ; Animals ; Aged ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; Mice, Transgenic ; Motor Neurons/metabolism ; Spinal Cord/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. To identify additional genetic factors, we analyzed exome sequences in a large cohort of Chinese ALS patients and found a homozygous variant (p.L700P) in PCDHA9 in three unrelated patients. We generated Pcdhα9 mutant mice harboring either orthologous point mutation or deletion mutation. These mice develop progressive spinal motor loss, muscle atrophy, and structural/functional abnormalities of the neuromuscular junction, leading to paralysis and early lethality. TDP-43 pathology is detected in the spinal motor neurons of aged mutant mice. Mechanistically, we demonstrate that Pcdha9 mutation causes aberrant activation of FAK and PYK2 in aging spinal cord, and dramatically reduced NKA-α1 expression in motor neurons. Our single nucleus multi-omics analysis reveals disturbed signaling involved in cell adhesion, ion transport, synapse organization, and neuronal survival in aged mutant mice. Together, our results present PCDHA9 as a potential ALS gene and provide insights into its pathogenesis.}, } @article {pmid38466778, year = {2024}, author = {Salaikumaran, MR and Gopal, PP}, title = {Rational Design of TDP-43 Derived α-Helical Peptide Inhibitors: An In Silico Strategy to Prevent TDP-43 Aggregation in Neurodegenerative Disorders.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {6}, pages = {1096-1109}, pmid = {38466778}, issn = {1948-7193}, support = {R01 NS122907/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Protein Conformation, alpha-Helical ; Molecular Docking Simulation ; *Peptides/pharmacology ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/metabolism ; }, abstract = {TDP-43, an essential RNA/DNA-binding protein, is central to the pathology of neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia. Pathological mislocalization and aggregation of TDP-43 disrupt RNA splicing, mRNA stability, and mRNA transport, thereby impairing neuronal function and survival. The formation of amyloid-like TDP-43 filaments is largely facilitated by the destabilization of an α-helical segment within the disordered C-terminal region. In this study, we hypothesized that preventing the destabilization of the α-helical domain could potentially halt the growth of these pathological filaments. To explore this, we utilized a range of in silico techniques to design and evaluate peptide-based therapeutics that bind to pathological TDP-43 amyloid-like filament crystal structures and resist β sheet conversion. Our computational approaches, including biophysical and secondary structure property prediction, molecular docking, 3D structure prediction, and molecular dynamics simulations, were used to assess the structure, stability, and binding affinity of these peptides in relation to pathological TDP-43 filaments. The results of our in silico analyses identified a selection of promising peptides which displayed a stable α-helical structure, exhibited an increased number of intramolecular hydrogen bonds within the helical domain, and demonstrated high binding affinities for pathological TDP-43 amyloid-like filaments. Molecular dynamics simulations provided further support for the structural and thermodynamic stability of these peptides, as they exhibited lower root-mean-square deviation and more favorable free energy landscapes over 300 ns. These findings establish α-helical propensity peptides as potential lead molecules for the development of novel therapeutics against TDP-43 aggregation. This structure-based computational approach for the rational design of peptide inhibitors opens a new direction in the search for effective interventions for ALS, FTD, and other related neurodegenerative diseases. The peptides identified as the most promising candidates in this study are currently subject to further testing and validation through both in vitro and in vivo experiments.}, } @article {pmid38466738, year = {2024}, author = {Pelletier, C and Shaw, S and Alsayegh, S and Brown, AJP and Lorenz, A}, title = {Candida auris undergoes adhesin-dependent and -independent cellular aggregation.}, journal = {PLoS pathogens}, volume = {20}, number = {3}, pages = {e1012076}, pmid = {38466738}, issn = {1553-7374}, support = {MR/M026663/1/MRC_/Medical Research Council/United Kingdom ; MR/M026663/2/MRC_/Medical Research Council/United Kingdom ; MR/V033417/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Antifungal Agents/therapeutic use ; *Candida/genetics ; Candida auris ; Virulence ; Drug Resistance, Fungal ; Adhesins, Bacterial/metabolism ; Microbial Sensitivity Tests ; }, abstract = {Candida auris is a fungal pathogen of humans responsible for nosocomial infections with high mortality rates. High levels of resistance to antifungal drugs and environmental persistence mean these infections are difficult to treat and eradicate from a healthcare setting. Understanding the life cycle and the genetics of this fungus underpinning clinically relevant traits, such as antifungal resistance and virulence, is of the utmost importance to develop novel treatments and therapies. Epidemiological and genomic studies have identified five geographical clades (I-V), which display phenotypic and genomic differences. Aggregation of cells, a phenotype primarily of clade III strains, has been linked to reduced virulence in some infection models. The aggregation phenotype has thus been associated with conferring an advantage for (skin) colonisation rather than for systemic infection. However, strains with different clade affiliations were compared to infer the effects of different morphologies on virulence. This makes it difficult to distinguish morphology-dependent causes from clade-specific or even strain-specific genetic factors. Here, we identify two different types of aggregation: one induced by antifungal treatment which is a result of a cell separation defect; and a second which is controlled by growth conditions and only occurs in strains with the ability to aggregate. The latter aggregation type depends on an ALS-family adhesin which is differentially expressed during aggregation in an aggregative C. auris strain. Finally, we demonstrate that macrophages cannot clear aggregates, suggesting that aggregation might after all provide a benefit during systemic infection and could facilitate long-term persistence in the host.}, } @article {pmid38465877, year = {2024}, author = {Young, CA and Chaouch, A and Mcdermott, CJ and Al-Chalabi, A and Chhetri, SK and Talbot, K and Harrower, T and Orrell, RW and Annadale, J and Hanemann, CO and Scalfari, A and Tennant, A and Mills, R and , }, title = {Dyspnea (breathlessness) in amyotrophic lateral sclerosis/motor neuron disease: prevalence, progression, severity, and correlates.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {475-485}, pmid = {38465877}, issn = {2167-9223}, mesh = {Humans ; *Dyspnea/physiopathology/diagnosis/epidemiology/etiology ; Male ; Female ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis/physiopathology/complications ; Middle Aged ; Aged ; *Disease Progression ; Prevalence ; *Severity of Illness Index ; Motor Neuron Disease/epidemiology/physiopathology/diagnosis/complications ; Quality of Life ; Adult ; }, abstract = {OBJECTIVE: Dyspnea, or breathlessness, is an important symptom in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). We examined the measurement properties of the Dyspnea-12.

METHODS: Rasch analysis enabled conversion of raw Dyspnea-12 scores to interval level metric equivalents. Converted data were used to perform trajectory modeling; those following different trajectories were compared for demographic, clinical, symptom, and functioning characteristics. Logistic regression examined differences between distinct trajectories.

RESULTS: In 1022 people, at baseline, mean metric Dyspnea-12 was 7.6 (SD 9.3). 49.8% had dyspnea, severe in 12.6%. Trajectory analysis over 28 months revealed three breathlessness trajectories: group 1 reported none at baseline/follow-up (42.7%); group 2 significantly increased over time (9.4%); group 3 had a much higher level at baseline which rose over follow-up (47.9%). Group 3 had worse outcomes on all symptoms, functioning and quality of life; compared to group 1, their odds of: respiratory onset sixfold greater; King's stage ≥3 2.9 greater; increased odds of being bothered by choking, head drop, fasciculations, and muscle cramps; fatigue and anxiety also elevated (p < .01).

CONCLUSION: Dyspnea is a cardinal symptom in ALS/MND and can be quickly measured using the Dyspnea-12. Raw scores can easily be converted to interval level measurement, for valid change scores and trajectory modeling. Dyspnea trajectories reveal different patterns, showing that clinical services must provide monitoring which is customized to individual patient need. Almost half of this large population had worsening dyspnea, confirming the importance of respiratory monitoring and interventions being integrated into routine ALS care.}, } @article {pmid38465478, year = {2024}, author = {Wendebourg, MJ and Weigel, M and Weidensteiner, C and Sander, L and Kesenheimer, E and Naumann, N and Haas, T and Madoerin, P and Braun, N and Neuwirth, C and Weber, M and Jahn, K and Kappos, L and Granziera, C and Schweikert, K and Sinnreich, M and Bieri, O and Schlaeger, R}, title = {Cervical and thoracic spinal cord gray matter atrophy is associated with disability in patients with amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {6}, pages = {e16268}, pmid = {38465478}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/physiopathology/complications ; Female ; Middle Aged ; Male ; *Gray Matter/diagnostic imaging/pathology ; Aged ; *Magnetic Resonance Imaging ; *Atrophy/pathology ; Cervical Cord/diagnostic imaging/pathology ; Thoracic Vertebrae/diagnostic imaging ; Spinal Cord/diagnostic imaging/pathology ; Cervical Vertebrae/diagnostic imaging ; White Matter/diagnostic imaging/pathology ; }, abstract = {BACKGROUND AND PURPOSE: In amyotrophic lateral sclerosis (ALS), there is an unmet need for more precise patient characterization through quantitative, ideally operator-independent, assessments of disease extent and severity. Radially sampled averaged magnetization inversion recovery acquisitions (rAMIRA) magnetic resonance imaging enables gray matter (GM) and white matter (WM) area quantitation in the cervical and thoracic spinal cord (SC) with optimized contrast. We aimed to investigate rAMIRA-derived SC GM and SC WM areas and their association with clinical phenotype and disability in ALS.

METHODS: A total of 36 patients with ALS (mean [SD] age 61.7 [12.6] years, 14 women) and 36 healthy, age- and sex-matched controls (HCs; mean [SD] age 63.1 [12.1] years, 14 women) underwent two-dimensional axial rAMIRA imaging at the inter-vertebral disc levels C2/3-C5/C6 and the lumbar enlargement level Tmax. ALS Functional Rating Scale-revised (ALSFRS-R) score, muscle strength, and sniff nasal inspiratory pressure (SNIP) were assessed.

RESULTS: Compared to HCs, GM and WM areas were reduced in patients at all cervical levels (p < 0.0001). GM area (p = 0.0001), but not WM area, was reduced at Tmax. Patients with King's Stage 3 showed significant GM atrophy at all levels, while patients with King's Stage 1 showed significant GM atrophy selectively at Tmax. SC GM area was significantly associated with muscle force at corresponding myotomes. GM area at C3/C4 was associated with ALSFRS-R (p < 0.001) and SNIP (p = 0.0016).

CONCLUSION: Patients with ALS assessed by rAMIRA imaging show significant cervical and thoracic SC GM and SC WM atrophy. SC GM area correlates with muscle strength and clinical disability. GM area reduction at Tmax may be an early disease sign. Longitudinal studies are warranted.}, } @article {pmid38464738, year = {2023}, author = {Kekenadze, M and Rocca, C and Turchetti, V and Nagy, S and Kvirkvelia, N and Vashadze, S and Kvaratskhelia, E and Beridze, M and Kaiyrzhanov, R and Houlden, H}, title = {Analysis of C9orf72 repeat expansions in Georgian patients with Amyotrophic lateral sclerosis (ALS).}, journal = {F1000Research}, volume = {12}, number = {}, pages = {1113}, pmid = {38464738}, issn = {2046-1402}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; Proteins/genetics ; DNA Repeat Expansion ; *Frontotemporal Dementia/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder that affects the upper and lower motor neurons. Several genetic risk factors have been identified in the past decade with a hexanucleotide repeat expansion in the C9orf72 gene being the most significant. However, the presence of C9orf72 repeat expansion has not been examined in the Transcaucasian region, therefore we aimed to analyse its frequency in Georgian patients with ALS.

METHODS: We included 64 self-reported Georgian patients with ALS from different parts of the country, fulfilling the Gold Coast criteria. To investigate the presence of an expanded GGGGCC hexanucleotide repeat in the non-coding region of the C9orf72 gene, we performed Repeat-Primed PCR (RP-PCR).

RESULTS: In total, 62 sporadic and two familial ALS cases were identified. Patients were aged 26 to 84 years with a mean age of 58.3 years at disease onset. Bulbar onset was observed in 21.88%, upper limb onset in 34.38%, and lower limb onset in 43.75% of the patients. Frontotemporal dementia (FTD) fulfilling the Strong criteria was diagnosed in seven patients (10.94%). C9orf72 repeat expansion was detected in only one case using RP-PCR; the patient had a family history of dementia.

CONCLUSIONS: Our results indicate that C9orf72 hexanucleotide expansion does not belong to the major genetic risk factor of ALS in Georgian patients. Further genetic studies in a bigger study population are needed to reveal the genetic causes of ALS in the Transcaucasian population.}, } @article {pmid38464233, year = {2024}, author = {Jang, DG and Dou, J and Koubek, EJ and Teener, S and Zhao, L and Bakulski, KM and Mukherjee, B and Batterman, SA and Feldman, EL and Goutman, SA}, title = {Metal mixtures associate with higher amyotrophic lateral sclerosis risk and mortality independent of genetic risk and correlate to self-reported exposures: a case-control study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38464233}, support = {R01 ES030049/ES/NIEHS NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; R01TS000344/ACL/ACL HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; }, abstract = {BACKGROUND: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both genetic and environmental factors. This study investigates associations between metal measures in plasma and urine, ALS risk and survival, and exposure sources.

METHODS: Participants with and without ALS from Michigan provided plasma and urine samples for metal measurement via inductively coupled plasma mass spectrometry. Odds and hazard ratios for each metal were computed using risk and survival models. Environmental risk scores (ERS) were created to evaluate the association between exposure mixtures and ALS risk and survival and exposure source. ALS (ALS-PGS) and metal (metal-PGS) polygenic risk scores were constructed from an independent genome-wide association study and relevant literature-selected SNPs.

RESULTS: Plasma and urine samples from 454 ALS and 294 control participants were analyzed. Elevated levels of individual metals, including copper, selenium, and zinc, significantly associated with ALS risk and survival. ERS representing metal mixtures strongly associated with ALS risk (plasma, OR=2.95, CI=2.38-3.62, p<0.001; urine, OR=3.10, CI=2.43-3.97, p<0.001) and poorer ALS survival (plasma, HR=1.42, CI=1.24-1.63, p<0.001; urine, HR=1.52, CI=1.31-1.76, p<0.001). Addition of the ALS-PGS or metal-PGS did not alter the significance of metals with ALS risk and survival. Occupations with high potential of metal exposure associated with elevated ERS. Additionally, occupational and non-occupational metal exposures associated with measured plasma and urine metals.

CONCLUSION: Metals in plasma and urine associated with increased ALS risk and reduced survival, independent of genetic risk, and correlated with occupational and non-occupational metal exposures. These data underscore the significance of metal exposure in ALS risk and progression.}, } @article {pmid38464104, year = {2025}, author = {Das, T and Zaidi, FK and Farag, M and Ruff, KM and Mahendran, TS and Singh, A and Gui, X and Messing, J and Taylor, JP and Banerjee, PR and Pappu, RV and Mittag, T}, title = {Tunable metastability of condensates reconciles their dual roles in amyloid fibril formation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.02.28.582569}, pmid = {38464104}, issn = {2692-8205}, abstract = {Stress granules form via co-condensation of RNA-binding proteins containing prion-like low complexity domains (PLCDs) with RNA molecules. Homotypic interactions among PLCDs can drive amyloid fibril formation that is enhanced by ALS-associated mutations. We report that condensation-versus fibril-driving homotypic interactions are separable for A1-LCD, the PLCD of hnRNPA1. Separable interactions lead to thermodynamically metastable condensates and globally stable fibrils. Interiors of condensates suppress fibril formation whereas interfaces have the opposite effect. ALS-associated mutations enhance the stability of fibrils and weaken condensate metastability, thus enhancing the rate of fibril formation. We designed mutations to enhance A1-LCD condensate metastability and discovered that stress granule disassembly in cells can be restored even when the designed variants carry ALS-causing mutations. Therefore, fibril formation can be suppressed by condensate interiors that function as sinks. Condensate sink potentials are influenced by their metastability, which is tunable through separable interactions even among minority components of stress granules.}, } @article {pmid38464028, year = {2024}, author = {Silvestri, B and Mochi, M and Mawrie, D and de Turris, V and Colantoni, A and Borhy, B and Medici, M and Anderson, EN and Garone, MG and Zammerilla, CP and Pandey, UB and Rosa, A}, title = {HuD (ELAVL4) gain-of-function impairs neuromuscular junctions and induces apoptosis in in vitro and in vivo models of amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38464028}, issn = {2692-8205}, support = {R01 NS081303/NS/NINDS NIH HHS/United States ; }, abstract = {Early defects at the neuromuscular junction (NMJ) are among the first hallmarks of the progressive neurodegenerative disease amyotrophic lateral sclerosis (ALS). According to the "dying back" hypothesis, disruption of the NMJ not only precedes, but is also a trigger for the subsequent degeneration of the motoneuron in both sporadic and familial ALS, including ALS caused by the severe FUS pathogenic variant P525L. However, the mechanisms linking genetic and environmental factors to NMJ defects remain elusive. By taking advantage of co-cultures of motoneurons and skeletal muscle derived from human induced pluripotent stem cells (iPSCs), we show that the neural RNA binding protein HuD (ELAVL4) may underlie NMJ defects and apoptosis in FUS-ALS. HuD overexpression in motoneurons phenocopies the severe FUS[P525L] mutation, while HuD knockdown in FUS[P525L] co-cultures produces phenotypic rescue. We validated these findings in vivo in a Drosophila FUS-ALS model. Neuronal-restricted overexpression of the HuD-related gene, elav, produces per se a motor phenotype, while neuronal-restricted elav knockdown significantly rescues motor dysfunction caused by FUS. Finally, we show that HuD levels increase upon oxidative stress in human motoneurons and in sporadic ALS patients with an oxidative stress signature. On these bases, we propose HuD as an important player downstream of FUS mutation in familial ALS, with potential implications for sporadic ALS related to oxidative stress.}, } @article {pmid38463699, year = {2024}, author = {Van Schoor, E and Strubbe, D and Braems, E and Weishaupt, J and Ludolph, AC and Van Damme, P and Thal, DR and Bercier, V and Van Den Bosch, L}, title = {TUBA4A downregulation as observed in ALS post-mortem motor cortex causes ALS-related abnormalities in zebrafish.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1340240}, pmid = {38463699}, issn = {1662-5102}, abstract = {Disease-associated variants of TUBA4A (alpha-tubulin 4A) have recently been identified in familial ALS. Interestingly, a downregulation of TUBA4A protein expression was observed in familial as well as sporadic ALS brain tissue. To investigate whether a decreased TUBA4A expression could be a driving factor in ALS pathogenesis, we assessed whether TUBA4A knockdown in zebrafish could recapitulate an ALS-like phenotype. For this, we injected an antisense oligonucleotide morpholino in zebrafish embryos targeting the zebrafish TUBA4A orthologue. An antibody against synaptic vesicle 2 was used to visualize motor axons in the spinal cord, allowing the analysis of embryonic ventral root projections. Motor behavior was assessed using the touch-evoked escape response. In post-mortem ALS motor cortex, we observed reduced TUBA4A levels. The knockdown of the zebrafish TUBA4A orthologue induced a motor axonopathy and a significantly disturbed motor behavior. Both phenotypes were dose-dependent and could be rescued by the addition of human wild-type TUBA4A mRNA. Thus, TUBA4A downregulation as observed in ALS post-mortem motor cortex could be modeled in zebrafish and induced a motor axonopathy and motor behavior defects reflecting a motor neuron disease phenotype, as previously described in embryonic zebrafish models of ALS. The rescue with human wild-type TUBA4A mRNA suggests functional conservation and strengthens the causal relation between TUBA4A protein levels and phenotype severity. Furthermore, the loss of TUBA4A induces significant changes in post-translational modifications of tubulin, such as acetylation, detyrosination and polyglutamylation. Our data unveil an important role for TUBA4A in ALS pathogenesis, and extend the relevance of TUBA4A to the majority of ALS patients, in addition to cases bearing TUBA4A mutations.}, } @article {pmid38463392, year = {2024}, author = {Chen, Y and Mateski, J and Gerace, L and Wheeler, J and Burl, J and Prakash, B and Svedin, C and Amrick, R and Adams, BD}, title = {Non-coding RNAs and neuroinflammation: implications for neurological disorders.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {249}, number = {}, pages = {10120}, pmid = {38463392}, issn = {1535-3699}, mesh = {Humans ; Neuroinflammatory Diseases ; *Nervous System Diseases/genetics ; Microglia/metabolism ; *MicroRNAs/genetics/metabolism ; Cytokines/metabolism ; Chemokines/metabolism ; }, abstract = {Neuroinflammation is considered a balanced inflammatory response important in the intrinsic repair process after injury or infection. Under chronic states of disease, injury, or infection, persistent neuroinflammation results in a heightened presence of cytokines, chemokines, and reactive oxygen species that result in tissue damage. In the CNS, the surrounding microglia normally contain macrophages and other innate immune cells that perform active immune surveillance. The resulting cytokines produced by these macrophages affect the growth, development, and responsiveness of the microglia present in both white and gray matter regions of the CNS. Controlling the levels of these cytokines ultimately improves neurocognitive function and results in the repair of lesions associated with neurologic disease. MicroRNAs (miRNAs) are master regulators of the genome and subsequently control the activity of inflammatory responses crucial in sustaining a robust and acute immunological response towards an acute infection while dampening pathways that result in heightened levels of cytokines and chemokines associated with chronic neuroinflammation. Numerous reports have directly implicated miRNAs in controlling the abundance and activity of interleukins, TGF-B, NF-kB, and toll-like receptor-signaling intrinsically linked with the development of neurological disorders such as Parkinson's, ALS, epilepsy, Alzheimer's, and neuromuscular degeneration. This review is focused on discussing the role miRNAs play in regulating or initiating these chronic neurological states, many of which maintain the level and/or activity of neuron-specific secondary messengers. Dysregulated miRNAs present in the microglia, astrocytes, oligodendrocytes, and epididymal cells, contribute to an overall glial-specific inflammatory niche that impacts the activity of neuronal conductivity, signaling action potentials, neurotransmitter robustness, neuron-neuron specific communication, and neuron-muscular connections. Understanding which miRNAs regulate microglial activation is a crucial step forward in developing non-coding RNA-based therapeutics to treat and potentially correct the behavioral and cognitive deficits typically found in patients suffering from chronic neuroinflammation.}, } @article {pmid38462589, year = {2024}, author = {Ding, F and Sun, Q and Long, C and Rasmussen, RN and Peng, S and Xu, Q and Kang, N and Song, W and Weikop, P and Goldman, SA and Nedergaard, M}, title = {Dysregulation of extracellular potassium distinguishes healthy ageing from neurodegeneration.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {5}, pages = {1726-1739}, pmid = {38462589}, issn = {1460-2156}, support = {U19 NS128613/NS/NINDS NIH HHS/United States ; R01AT012312/NH/NIH HHS/United States ; R01 AT011439/AT/NCCIH NIH HHS/United States ; R01 AT012312/AT/NCCIH NIH HHS/United States ; R01 HL122578/HL/NHLBI NIH HHS/United States ; R01 AG072298/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Potassium/metabolism ; *Aging/metabolism ; Mice ; *Neurodegenerative Diseases/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Alzheimer Disease/metabolism/genetics ; Mice, Transgenic ; Potassium Channels, Inwardly Rectifying/metabolism/genetics ; Male ; Mice, Inbred C57BL ; Neurons/metabolism ; Humans ; Disease Models, Animal ; Cerebral Cortex/metabolism ; Huntington Disease/metabolism/genetics ; Female ; Astrocytes/metabolism ; Kcnj10 Channel ; }, abstract = {Progressive neuronal loss is a hallmark feature distinguishing neurodegenerative diseases from normal ageing. However, the underlying mechanisms remain unknown. Extracellular K+ homeostasis is a potential mediator of neuronal injury as K+ elevations increase excitatory activity. The dysregulation of extracellular K+ and potassium channel expressions during neurodegeneration could contribute to this distinction. Here we measured the cortical extracellular K+ concentration ([K+]e) in awake wild-type mice as well as murine models of neurodegeneration using K+-sensitive microelectrodes. Unexpectedly, aged wild-type mice exhibited significantly lower cortical [K+]e than young mice. In contrast, cortical [K+]e was consistently elevated in Alzheimer's disease (APP/PS1), amyotrophic lateral sclerosis (ALS) (SOD1G93A) and Huntington's disease (R6/2) models. Cortical resting [K+]e correlated inversely with neuronal density and the [K+]e buffering rate but correlated positively with the predicted neuronal firing rate. Screening of astrocyte-selective genomic datasets revealed a number of potassium channel genes that were downregulated in these disease models but not in normal ageing. In particular, the inwardly rectifying potassium channel Kcnj10 was downregulated in ALS and Huntington's disease models but not in normal ageing, while Fxyd1 and Slc1a3, each of which acts as a negative regulator of potassium uptake, were each upregulated by astrocytes in both Alzheimer's disease and ALS models. Chronic elevation of [K+]e in response to changes in gene expression and the attendant neuronal hyperexcitability may drive the neuronal loss characteristic of these neurodegenerative diseases. These observations suggest that the dysregulation of extracellular K+ homeostasis in a number of neurodegenerative diseases could be due to aberrant astrocytic K+ buffering and as such, highlight a fundamental role for glial dysfunction in neurodegeneration.}, } @article {pmid38461796, year = {2024}, author = {Saranya, KR and Vimina, ER and Pinto, FR}, title = {TransNeT-CGP: A cluster-based comorbid gene prioritization by integrating transcriptomics and network-topological features.}, journal = {Computational biology and chemistry}, volume = {110}, number = {}, pages = {108038}, doi = {10.1016/j.compbiolchem.2024.108038}, pmid = {38461796}, issn = {1476-928X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Protein Interaction Maps/genetics ; Cluster Analysis ; Transcriptome/genetics ; Algorithms ; Gene Regulatory Networks ; Female ; Computational Biology ; Comorbidity ; Muscular Atrophy, Spinal/genetics ; Ovarian Neoplasms/genetics ; }, abstract = {The local disruptions caused by the genes of one disease can influence the pathways associated with the other diseases resulting in comorbidity. For gene therapies, it is necessary to prioritize the key genes that regulate common biological mechanisms to tackle the issues caused by overlapping diseases. This work proposes a clustering-based computational approach for prioritising the comorbid genes within the overlapping disease modules by analyzing Protein-Protein Interaction networks. For this, a sub-network with gene interactions of the disease pair was extracted from the interactome. The edge weights are assigned by combining the pairwise gene expression correlation and betweenness centrality scores. Further, a weighted graph clustering algorithm is applied and dominant nodes of high-density clusters are ranked based on clustering coefficients and neighborhood connectivity. Case studies based on neurodegenerative diseases such as Amyotrophic Lateral Sclerosis- Spinal Muscular Atrophy (ALS-SMA) pair and cancers such as Ovarian Carcinoma-Invasive Ductal Breast Carcinoma (OC-IDBC) pair were conducted to examine the efficacy of the proposed method. To identify the mechanistic role of top-ranked genes, we used Functional and Pathway enrichment analysis, connectivity analysis with leave-one-out (LOO) method, analysis of associated disease-related protein complexes, and prioritization tools such as TOPPGENE and Heml2.0. From pathway analysis, it was observed that the top 10 genes obtained using the proposed method were associated with 10 pathways in ALS-SMA comorbidity and 15 in the case of OC-IDBC, while that in similar methods like SAPDSB and S2B were 4, 6 respectively for ALS-SMA and 9, 10 respectively for OC-IDBC. In both case studies, 70 % of the disease-specific benchmark protein complexes were linked to top-ranked genes of the proposed method while that of SAPDSB and S2B were 55 % and 60 % respectively. Additionally, it was found that the removal of the top 10 genes disconnect the network into 14 distinct components in the case of ALS-SMA and 9 in the case of OC-IDBC. The experimental results shows that the proposed method can be effectively used for identifying key genes in comorbidity and can offer insights about the intricate molecular relationship driving comorbid diseases.}, } @article {pmid38461753, year = {2024}, author = {Eceiza, MV and Jimenez-Martinez, C and Gil-Monreal, M and Barco-Antoñanzas, M and Font-Farre, M and Huybrechts, M and van der Hoorn, RL and Cuypers, A and Royuela, M and Zabalza, A}, title = {Role of glutathione S-transferases in the mode of action of herbicides that inhibit amino acid synthesis in Amaranthus palmeri.}, journal = {Plant physiology and biochemistry : PPB}, volume = {208}, number = {}, pages = {108506}, doi = {10.1016/j.plaphy.2024.108506}, pmid = {38461753}, issn = {1873-2690}, mesh = {*Herbicides/pharmacology/metabolism ; *Amaranthus ; Hydrogen Peroxide/metabolism ; Herbicide Resistance ; Glyphosate ; Glutathione/metabolism ; Transferases/metabolism ; }, abstract = {Acetolactate synthase inhibitors (ALS inhibitors) and glyphosate are two classes of herbicides that act by inhibiting an enzyme in the biosynthetic pathway of branched-chain or aromatic amino acids, respectively. Besides amino acid synthesis inhibition, both herbicides trigger similar physiological effects in plants. The main aim of this study was to evaluate the role of glutathione metabolism, with special emphasis on glutathione S-transferases (GSTs), in the mode of action of glyphosate and ALS inhibitors in Amaranthus palmeri. For that purpose, plants belonging to a glyphosate-sensitive (GLS) and a glyphosate-resistant (GLR) population were treated with different doses of glyphosate, and plants belonging to an ALS-inhibitor sensitive (AIS) and an ALS-inhibitor resistant (AIR) population were treated with different doses of the ALS inhibitor nicosulfuron. Glutathione-related contents, GST activity, and related gene expressions (glutamate-cysteine ligase, glutathione reductase, Phi GST and Tau GST) were analysed in leaves. According to the results of the analytical determinations, there were virtually no basal differences between GLS and GLR plants or between AIS and AIR plants. Glutathione synthesis and turnover did not follow a clear pattern in response to herbicides, but GST activity and gene expression (especially Phi GSTs) increased with both herbicides in treated sensitive plants, possibly related to the rocketing H2O2 accumulation. As GSTs offered the clearest results, these were further investigated with a multiple resistant (MR) population, compressing target-site resistance to both glyphosate and the ALS inhibitor pyrithiobac. As in single-resistant plants, measured parameters in the MR population were unaffected by herbicides, meaning that the increase in GST activity and expression occurs due to herbicide interactions with the target enzymes.}, } @article {pmid38461154, year = {2024}, author = {Kodavati, M and Wang, H and Guo, W and Mitra, J and Hegde, PM and Provasek, V and Rao, VHM and Vedula, I and Zhang, A and Mitra, S and Tomkinson, AE and Hamilton, DJ and Van Den Bosch, L and Hegde, ML}, title = {FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {2156}, pmid = {38461154}, issn = {2041-1723}, support = {R01 NS094535/NS/NINDS NIH HHS/United States ; R01 ES012512/ES/NIEHS NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA, Mitochondrial/genetics ; Ligases/metabolism ; Mice, Transgenic ; *Mitochondrial Diseases ; *Motor Neuron Disease/genetics/metabolism ; Mutation ; *RNA-Binding Protein FUS/genetics/metabolism ; DNA Ligase ATP/genetics/metabolism ; }, abstract = {This study establishes the physiological role of Fused in Sarcoma (FUS) in mitochondrial DNA (mtDNA) repair and highlights its implications to the pathogenesis of FUS-associated neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Endogenous FUS interacts with and recruits mtDNA Ligase IIIα (mtLig3) to DNA damage sites within mitochondria, a relationship essential for maintaining mtDNA repair and integrity in healthy cells. Using ALS patient-derived FUS mutant cell lines, a transgenic mouse model, and human autopsy samples, we discovered that compromised FUS functionality hinders mtLig3's repair role, resulting in increased mtDNA damage and mutations. These alterations cause various manifestations of mitochondrial dysfunction, particularly under stress conditions relevant to disease pathology. Importantly, rectifying FUS mutations in patient-derived induced pluripotent cells (iPSCs) preserves mtDNA integrity. Similarly, targeted introduction of human DNA Ligase 1 restores repair mechanisms and mitochondrial activity in FUS mutant cells, suggesting a potential therapeutic approach. Our findings unveil FUS's critical role in mitochondrial health and mtDNA repair, offering valuable insights into the mechanisms underlying mitochondrial dysfunction in FUS-associated motor neuron disease.}, } @article {pmid38459794, year = {2024}, author = {Campagne, S}, title = {U1 snRNP Biogenesis Defects in Neurodegenerative Diseases.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {25}, number = {9}, pages = {e202300864}, doi = {10.1002/cbic.202300864}, pmid = {38459794}, issn = {1439-7633}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Ribonucleoprotein, U1 Small Nuclear/metabolism/chemistry ; }, abstract = {The U1 small ribonucleoprotein (U1 snRNP) plays a pivotal role in the intricate process of gene expression, specifically within nuclear RNA processing. By initiating the splicing reaction and modulating 3'-end processing, U1 snRNP exerts precise control over RNA metabolism and gene expression. This ribonucleoparticle is abundantly present, and its complex biogenesis necessitates shuttling between the nuclear and cytoplasmic compartments. Over the past three decades, extensive research has illuminated the crucial connection between disrupted U snRNP biogenesis and several prominent human diseases, notably various neurodegenerative conditions. The perturbation of U1 snRNP homeostasis has been firmly established in diseases such as Spinal Muscular Atrophy, Pontocerebellar hypoplasia, and FUS-mediated Amyotrophic Lateral Sclerosis. Intriguingly, compelling evidence suggests a potential correlation in Fronto-temporal dementia and Alzheimer's disease as well. Although the U snRNP biogenesis pathway is conserved across all eukaryotic cells, neurons, in particular, appear to be highly susceptible to alterations in spliceosome homeostasis. In contrast, other cell types exhibit a greater resilience to such disturbances. This vulnerability underscores the intricate relationship between U1 snRNP dynamics and the health of neuronal cells, shedding light on potential avenues for understanding and addressing neurodegenerative disorders.}, } @article {pmid38459455, year = {2024}, author = {Nandeep, ER and Mamidi, RS and Pagidoju, S and Pamidi, S and Mummadi, MK and Reddy G, VR and Babu, CK and Reddy N, S and Geddam, JB}, title = {Comparison of Janani Suraksha Yojana (JSY) and augmented Arogya Laxmi scheme (ALS) in improving maternal and child health outcomes in urban settlements of Hyderabad, South India.}, journal = {BMC pregnancy and childbirth}, volume = {24}, number = {1}, pages = {188}, pmid = {38459455}, issn = {1471-2393}, support = {Grant A/C No. 241//ICMR-ICSSR Joint Research Programme/ ; Grant A/C No. 241//ICMR-ICSSR Joint Research Programme/ ; }, mesh = {Infant, Newborn ; Child ; Pregnancy ; Female ; Humans ; *Maternal Health Services ; Cross-Sectional Studies ; Prenatal Care ; India/epidemiology ; Outcome Assessment, Health Care ; Delivery, Obstetric ; }, abstract = {BACKGROUND: India accounts for the largest number of global neonatal deaths with around 20 per 1000 live births. To improve the utilization of government services for institutional deliveries, Augmented Arogya Laxmi Scheme (ALS) was launched in Telangana state of southern India. This study assessed the effectiveness of the Janani Suraksha Yojana (JSY), which combines cash assistance with delivery and post-delivery care, in comparison to ALS in improving the outcomes related to antenatal, natal, and postnatal care in urban settlements of Hyderabad, Telangana, southern India.

METHODS: This was a two-year cross-sectional study conducted in 14 urban settlements of Hyderabad city from September 2017- August 2019. All mothers delivered during the 18 months preceding the survey were enrolled after a written informed consent. Field investigators collected data on variables related to socio-demographic characteristics, awareness, and utilization of JSY and ALS programs. Variables related to antenatal history, antenatal care, complications during birth, delivery outcomes, newborn care, and postnatal care till 28 days were assessed. We used multivariable logistic regression model to examine the association between the different maternal, child, and socio-demographic characteristics of the two study groups.

RESULTS: A total of 926 mothers were beneficiaries of Janani Suraksha Yojana (JSY) program while 933 mothers were beneficiaries of augmented Arogya Laxmi Scheme (ALS). Mothers in ALS group (AOR 1.71; 95% CI 1.21-2.43) were at increased odds of having more than eight antenatal care (ANC) visits compared to the mothers availing JSY. Mothers in ALS group were at decreased odds of having complications like severe pain in the abdomen (AOR 0.43; 95% CI 0.22-0.86), swelling of legs or feet (AOR 0.59; 95% CI 0.44-0.80) compared to mothers in JSY group. Children of mothers in the ALS group had increased odds of receiving breastfeeding within 30 minutes of birth (AOR 1.46; 95% CI 1.13-1.88) compared to children of mothers in JSY group.

CONCLUSIONS: The newly launched augmented ALS led to the increased utilization of the government health facilities and improved the maternal and child health outcomes.}, } @article {pmid38458688, year = {2024}, author = {Xu, X and Zhao, B and Li, B and Shen, B and Qi, Z and Wang, J and Cui, H and Chen, S and Wang, G and Liu, X}, title = {Diverse ALS mutations and cross-and multiple-resistance to ALS and EPSPS inhibitors in flucarbazone‑sodium-resistant Bromus japonicus populations from Hebei province, China.}, journal = {Pesticide biochemistry and physiology}, volume = {199}, number = {}, pages = {105794}, doi = {10.1016/j.pestbp.2024.105794}, pmid = {38458688}, issn = {1095-9939}, mesh = {Bromus/metabolism ; *Herbicides/pharmacology ; Mutation ; China ; Herbicide Resistance/genetics ; *Acetolactate Synthase/metabolism ; *Sulfonamides ; *Triazoles ; }, abstract = {Japanese brome (Bromus japonicus) has become one of the main weeds in wheat fields in Hebei province of China and causes a large decrease of wheat production. A total of 44 putative resistant and 2 susceptible Japanese brome populations were collected in the 2021/2022 crop season from Hebei province of China to determine resistance levels to flucarbazone‑sodium and to investigate the diversity of acetolactate synthase (ALS) mutations, as well as to confirm the cross-and multiple-resistance levels to ALS and EPSPS (5-enolpyruvate shikimate-3-phosphate synthetase) inhibitors. Whole plant bioassay results showed that 15 out of 44 populations tested or 34% were resistant to flucarbazone‑sodium. The resistance indices of Japanese brome to flucarbazone‑sodium ranged from 43 to 1977. The resistant populations were mainly distributed in Baoding and Shijiazhuang districts, and there was only one resistant population in Langfang district. Resistant Japanese brome had diverse ALS mutations, including Pro-197-Ser, -Thr, -Arg and Asp-376-Glu. The incidence of Pro-197-Ser mutation was the highest at 68%. Application of the CYP450 inhibitor malathion suggested that CYP450 was involved in metabolic resistance in a population without an ALS mutation. The population with Pro-197-Thr mutation evolved weak cross-resistance to mesosulfuron-methyl and pyroxsulam, and it is in the process of evolving multiple-resistance to glyphosate.}, } @article {pmid38457872, year = {2024}, author = {Chaghazardi, M and Kashanian, S and Nazari, M and Omidfar, K and Shariati-Rad, M and Joseph, Y and Rahimi, P}, title = {Mercury (II) sensing using a simple turn-on fluorescent graphene oxide based aptasensor in serum and water samples.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {313}, number = {}, pages = {124057}, doi = {10.1016/j.saa.2024.124057}, pmid = {38457872}, issn = {1873-3557}, mesh = {*Mercury ; Fluorescence Resonance Energy Transfer/methods ; Fluorometry/methods ; Water ; Limit of Detection ; Oligonucleotides ; *Graphite ; *Biosensing Techniques/methods ; *Aptamers, Nucleotide/metabolism ; }, abstract = {A simple, highly sensitive, and selective fluorometric aptasensing platform based on aptamer and graphene oxide (GO) is proposed for the determination of mercury (II) ion (Hg[2+]). In the designed assay, two aptamer probes, a carboxy-fluorescein (FAM) labeled aptamer (aptamer A) and its complementary (aptamer B) with partial complement containing several mismatches and GO as the quencher were used. In the absence of Hg[2+], both A and B aptamers were adsorbed on the surface of GO by π-π-stacking, leading to fluorescence quenching of FAM due to fluorescence resonance energy transfer (FRET). Upon exposure to Hg[2+], the A and B aptamer strands bind Hg[2+] and form T-Hg[2+]-T complexes, leading to the formation of a stable double-stranded aptamer. The double-stranded aptamer is detached from the GO surface, resulting in the recovery of FAM fluorescence. The fluorescence intensity (FI) of the developed sensor was correlated with the Hg[2+] concentration under optimized experimental conditions in two wide linear ranges, even in the presence of 10 divalent cations as interferences. The linear ranges were obtained from 200.0 to 900.0 fM and 5.0 to 33.0 pM, a limit of detection (LOD) of 106.0 fM, and a limit of quantification (LOQ) of 321.3 fM. The concentration of Hg[2+] was determined in five real samples containing three water and two serum samples, using spiking and standard addition methods and the results were compared with the spiked amounts and atomic absorption (AAS) as standard method respectively, with acceptable recoveries. Furthermore, in the standard addition method, to overcome the effects of matrix influence of real samples in quantitative predictions, the excitation-emission matrix (EEM) data for samples was simultaneously analyzed by multivariate curve resolution with alternating least squares (MCR-ALS) as a second-order standard addition method (SOSAM).}, } @article {pmid38457412, year = {2024}, author = {Nowicka, N and Zglejc-Waszak, K and Juranek, J and Korytko, A and Wąsowicz, K and Chmielewska-Krzesińska, M and Wojtkiewicz, J}, title = {Novel insights into RAGE signaling pathways during the progression of amyotrophic lateral sclerosis in RAGE-deficient SOD1 G93A mice.}, journal = {PloS one}, volume = {19}, number = {3}, pages = {e0299567}, pmid = {38457412}, issn = {1932-6203}, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Disease Models, Animal ; Disease Progression ; Mice, Transgenic ; *Neurodegenerative Diseases ; Prospective Studies ; Receptor for Advanced Glycation End Products/genetics ; Signal Transduction ; Superoxide Dismutase/genetics/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is neurodegenerative disease characterized by a progressive loss of motor neurons resulting in paralysis and muscle atrophy. One of the most prospective hypothesis on the ALS pathogenesis suggests that excessive inflammation and advanced glycation end-products (AGEs) accumulation play a crucial role in the development of ALS in patients and SOD1 G93A mice. Hence, we may speculate that RAGE, receptor for advanced glycation end-products and its proinflammatory ligands such as: HMGB1, S100B and CML contribute to ALS pathogenesis. The aim of our studies was to decipher the role of RAGE as well as provide insight into RAGE signaling pathways during the progression of ALS in SOD1 G93A and RAGE-deficient SOD1 G93A mice. In our study, we observed alternations in molecular pattern of proinflammatory RAGE ligands during progression of disease in RAGE KO SOD1 G93A mice compared to SOD1 G93A mice. Moreover, we observed that the amount of beta actin (ACTB) as well as Glial fibrillary acidic protein (GFAP) was elevated in SOD1 G93A mice when compared to mice with deletion of RAGE. These data contributes to our understanding of implications of RAGE and its ligands in pathogenesis of ALS and highlight potential targeted therapeutic interventions at the early stage of this devastating disease. Moreover, inhibition of the molecular cross-talk between RAGE and its proinflammatory ligands may abolish neuroinflammation, gliosis and motor neuron damage in SOD1 G93A mice. Hence, we hypothesize that attenuated interaction of RAGE with its proinflammatory ligands may improve well-being and health status during ALS in SOD1 G93A mice. Therefore, we emphasize that the inhibition of RAGE signaling pathway may be a therapeutic target for neurodegenerative diseases.}, } @article {pmid38457337, year = {2024}, author = {Fiore, APZP and Maity, S and Jeffery, L and An, D and Rendleman, J and Iannitelli, D and Choi, H and Mazzoni, E and Vogel, C}, title = {Identification of molecular signatures defines the differential proteostasis response in induced spinal and cranial motor neurons.}, journal = {Cell reports}, volume = {43}, number = {3}, pages = {113885}, pmid = {38457337}, issn = {2211-1247}, support = {R01 GM113237/GM/NIGMS NIH HHS/United States ; R35 GM127089/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Proteostasis/physiology ; Proteome/metabolism ; Motor Neurons/metabolism ; *Amyotrophic Lateral Sclerosis/genetics ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum Stress ; }, abstract = {Amyotrophic lateral sclerosis damages proteostasis, affecting spinal and upper motor neurons earlier than a subset of cranial motor neurons. To aid disease understanding, we exposed induced cranial and spinal motor neurons (iCrMNs and iSpMNs) to proteotoxic stress, under which iCrMNs showed superior survival, quantifying the transcriptome and proteome for >8,200 genes at 0, 12, and 36 h. Two-thirds of the proteome showed cell-type differences. iSpMN-enriched proteins related to DNA/RNA metabolism, and iCrMN-enriched proteins acted in the endoplasmic reticulum (ER)/ER chaperone complex, tRNA aminoacylation, mitochondria, and the plasma/synaptic membrane, suggesting that iCrMNs expressed higher levels of proteins supporting proteostasis and neuronal function. When investigating the increased proteasome levels in iCrMNs, we showed that the activity of the 26S proteasome, but not of the 20S proteasome, was higher in iCrMNs than in iSpMNs, even after a stress-induced decrease. We identified Ublcp1 as an iCrMN-specific regulator of the nuclear 26S activity.}, } @article {pmid38456112, year = {2024}, author = {Saidi, NA and Abdul Karim, NS and Ismail, A and Raja Othman, RNF and Kasah, NHA and Yaakub, A and Ngoo, QZ}, title = {Does the Difference in Axial Length Affect the Refractive Outcome?.}, journal = {The Malaysian journal of medical sciences : MJMS}, volume = {31}, number = {1}, pages = {71-75}, pmid = {38456112}, issn = {1394-195X}, abstract = {BACKGROUND: The purpose of this study is to compare axial length (AL) and the refractive outcome after phacoemulsification surgery from 2014 to 2019 at Hospital Sultanah Nur Zahirah, Terengganu, Malaysia.

METHOD: This was a retrospective record review of all cataract patients who met the inclusion criteria and underwent uneventful superior wound phacoemulsification with nontoric intraocular lens (IOL) by a single surgeon from 2014 to 2019. Using optical biometry or immersion technique, the preoperative AL determined solely via the Sanders, Retzlaff and Kraff 2 (SRK2) formula was selected. The postoperative spherical equivalent (SE) at 6 weeks-12 weeks was retrieved. Using Statistical Package for the Social Sciences version 24.0, the mean differences between targeted and actual postoperative SE were analysed based on the AL.

RESULT: In this study, 490 eyes of 472 patients aged 25 years old-88 years old (mean age 65.72 years old [SD 8.83]) were involved. There were 162 eyes (33%) in Group A (< 23 mm), 189 eyes (39%) in Group B (23.01 mm-24.0 mm) and 139 eyes (28%) in Group C (> 24.0 mm). The mean AL was 23.63 mm (SD 1.19). The mean differences between the targeted and actual postoperative SE were: -0.09 D (SD 0.60) in Group A, -0.07 D (SD 0.53) in Group B and -0.16 D (SD 0.52) in Group C. No significant difference was found between these groups (P = 0.327).

CONCLUSION: There was no significant difference in the refractive outcome using the SRK2 formula in different ALs after phacoemulsification surgery. Hence, there is no reason to modify or adjust the targeted SE based on AL.}, } @article {pmid38455726, year = {2024}, author = {Liu, L and Wu, L and Li, Z and Fang, Y and Ju, B and Zhang, S and Bai, L and Pan, L}, title = {The Pro-197-Thr mutation in the ALS gene confers novel resistance patterns to ALS-inhibiting herbicides in Bromus japonicus in China.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1348815}, pmid = {38455726}, issn = {1664-462X}, abstract = {INTRODUCTION: Bromus japonicus is one of the most notorious agricultural weeds in China. The long-term use of ALS-inhibiting herbicides has led to rapid evolution of herbicide resistance in B. japonicus. B. japonicus population (BJ-R) surviving mesosulfuron-methyl treatment was collected from wheatland. Here, we aimed to confirm the resistance mechanisms in this putative resistant population.

METHODS: The dose-reponse tests were used to test the resistance level of the B. japonicus to ALS-inhibiting herbicides. Pretreatment with P450 and GST inhibitors and GST activity assays were used to determine whether P450 or GST was involved in the resistance of the BJ-R population. Sanger sequencing was used to analyse the ALS mutation of the BJ-R population. RT-qPCR was used to confirm the the expression levels of the ALS gene in mesosulfuron-methyl -resistant (BJ-R) and-susceptible (BJ-S) B. japonicus. An in vitro ALS activity assay was used to determine the ALS activity of the BJ-R and BJ-S populations. Homology modelling and docking were used to determine the binding energy of the BJ-R and BJ-S populations with ALS-inhibiting herbicides.

RESULTS: B. japonicus population (BJ-R) was confirmed to be 454- and 2.7-fold resistant to the SU herbicides mesosulfuron-methyl and nicosulfuron, and 7.3-, 2.3-, 1.1- and 10.8-fold resistant to the IMI herbicide imazamox, the TP herbicide penoxsulam, the PTB herbicide pyribenzoxim and the SCT herbicide flucarbazone-sodium, respectively, compared with its susceptible counterpart (BJ-S). Neither a P450 inhibitor nor a GST inhibitor could reverse the level of resistance to mesosulfuron-methyl in BJ-R. In addition, no significant differences in GST activity were found between the BJ-R and BJ-S. ALS gene sequencing revealed a Pro-197-Thr mutation in BJ-R, and the gene expression had no significant differences between the BJ-R and BJ-S. The ALS activity of BJ-R was 106-fold more tolerant to mesosulfuron-methyl than that of BJ-S. Molecular docking showed that the binding energy of the ALS active site and mesosulfuron-methyl was changed from -6.67 to -4.57 kcal mol[-1] due to the mutation at position 197.

DISCUSSION: These results suggested that the Pro-197-Thr mutation was the main reason for the high resistance level of BJ-R to mesosulfuron-methyl. Unlike previous reports of the cross-resistance pattern conferred by this mutation, we firstly documented that the Pro-197-Thr mutation confers broad cross-resistance spectrums to ALS-inhibiting herbicides in B. japonicus.}, } @article {pmid38452377, year = {2024}, author = {Rajabi, D and Khanmohammadi, S and Rezaei, N}, title = {The role of long noncoding RNAs in amyotrophic lateral sclerosis.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {5}, pages = {533-547}, pmid = {38452377}, issn = {2191-0200}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *RNA, Long Noncoding/genetics/metabolism ; Animals ; RNA-Binding Protein FUS/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a poor prognosis leading to death. The diagnosis and treatment of ALS are inherently challenging due to its complex pathomechanism. Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides involved in different cellular processes, incisively gene expression. In recent years, more studies have been conducted on lncRNA classes and interference in different disease pathologies, showing their promising contribution to diagnosing and treating neurodegenerative diseases. In this review, we discussed the role of lncRNAs like NEAT1 and C9orf72-as in ALS pathogenesis mechanisms caused by mutations in different genes, including TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), superoxide dismutase type 1 (SOD1). NEAT1 is a well-established lncRNA in ALS pathogenesis; hence, we elaborate on its involvement in forming paraspeckles, stress response, inflammatory response, and apoptosis. Furthermore, antisense lncRNAs (as-lncRNAs), a key group of transcripts from the opposite strand of genes, including ZEB1-AS1 and ATXN2-AS, are discussed as newly identified components in the pathology of ALS. Ultimately, we review the current standing of using lncRNAs as biomarkers and therapeutic agents and the future vision of further studies on lncRNA applications.}, } @article {pmid38451707, year = {2024}, author = {Clayton, EL and Huggon, L and Cousin, MA and Mizielinska, S}, title = {Synaptopathy: presynaptic convergence in frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {7}, pages = {2289-2307}, pmid = {38451707}, issn = {1460-2156}, support = {P2003//Epilepsy Research UK/ ; /ALZS_/Alzheimer's Society/United Kingdom ; //UK Dementia Research Institute/ ; //UK Medical Research Council/ ; 529508//Simons Foundation/ ; 204954/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; //Alzheimer's Research UK/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; *Frontotemporal Dementia/genetics/pathology/physiopathology ; *Synapses/pathology ; *Presynaptic Terminals/pathology/metabolism ; Animals ; Mutation ; }, abstract = {Frontotemporal dementia and amyotrophic lateral sclerosis are common forms of neurodegenerative disease that share overlapping genetics and pathologies. Crucially, no significantly disease-modifying treatments are available for either disease. Identifying the earliest changes that initiate neuronal dysfunction is important for designing effective intervention therapeutics. The genes mutated in genetic forms of frontotemporal dementia and amyotrophic lateral sclerosis have diverse cellular functions, and multiple disease mechanisms have been proposed for both. Identification of a convergent disease mechanism in frontotemporal dementia and amyotrophic lateral sclerosis would focus research for a targetable pathway, which could potentially effectively treat all forms of frontotemporal dementia and amyotrophic lateral sclerosis (both familial and sporadic). Synaptopathies are diseases resulting from physiological dysfunction of synapses, and define the earliest stages in multiple neuronal diseases, with synapse loss a key feature in dementia. At the presynapse, the process of synaptic vesicle recruitment, fusion and recycling is necessary for activity-dependent neurotransmitter release. The unique distal location of the presynaptic terminal means the tight spatio-temporal control of presynaptic homeostasis is dependent on efficient local protein translation and degradation. Recently, numerous publications have shown that mutations associated with frontotemporal dementia and amyotrophic lateral sclerosis present with synaptopathy characterized by presynaptic dysfunction. This review will describe the complex local signalling and membrane trafficking events that occur at the presynapse to facilitate neurotransmission and will summarize recent publications linking frontotemporal dementia/amyotrophic lateral sclerosis genetic mutations to presynaptic function. This evidence indicates that presynaptic synaptopathy is an early and convergent event in frontotemporal dementia and amyotrophic lateral sclerosis and illustrates the need for further research in this area, to identify potential therapeutic targets with the ability to impact this convergent pathomechanism.}, } @article {pmid38450645, year = {2024}, author = {Roychowdhury, S and Joshi, D and Singh, VK and Faruq, M and Das, P}, title = {Genetic and in silico analysis of Indian sporadic young onset patient with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {589-599}, doi = {10.1080/21678421.2024.2324896}, pmid = {38450645}, issn = {2167-9223}, mesh = {Humans ; Age of Onset ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/diagnosis ; *Computer Simulation ; Exome Sequencing ; India/epidemiology ; Mutation, Missense/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an old onset devastating neurodegenerative disorder. Young-onset ALS cases especially sporadic ones who are between 25 and 45 years are rarely affected by the disease. Despite the identification of numerous candidate genes associated with ALS, the etiology of the disease remains elusive due to extreme genetic and phenotypic variability. The advent of affordable whole exome sequencing (WES) has opened new avenues for unraveling the disease's pathophysiology better.

METHODS AND RESULTS: We aimed to determine the genetic basis of an Indian-origin, young onset sporadic ALS patient with very rapid deterioration of the disease course without any cognitive decline who was screened for mutations in major ALS candidate genes by WES. Variants detected were reconfirmed by Sanger sequencing. The clinicopathological features were investigated and two heterozygous missense variants were identified: R452W, not previously associated with ALS, present in one of the four conserved C terminal domains in ANXA11 and R208W in SIGMAR1, respectively. Both of these variants were predicted to be damaging by pathogenicity prediction tools and various in silico methods.

CONCLUSION: Our study revealed two potentially pathogenic variants in two ALS candidate genes. The genetic makeup of ALS patients from India has been the subject of a few prior studies, but none of them examined ANXA11 and SIGMAR1 genes so far. These results establish the framework for additional research into the pathogenic processes behind these variations that result in sporadic ALS disease and further our understanding of the genetic makeup of Indian ALS patients.}, } @article {pmid38448302, year = {2024}, author = {Heskamp, L and Birkbeck, MG and Hall, J and Schofield, IS and Bashford, J and Williams, TL and De Oliveira, HM and Whittaker, RG and Blamire, AM}, title = {Whole-body fasciculation detection in amyotrophic lateral sclerosis using motor unit MRI.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {161}, number = {}, pages = {246-255}, doi = {10.1016/j.clinph.2024.02.016}, pmid = {38448302}, issn = {1872-8952}, support = {BASHFORD/JUN16/947-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/P000983/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Male ; Female ; Middle Aged ; *Fasciculation/physiopathology/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Aged ; *Electromyography/methods ; Muscle, Skeletal/physiopathology/diagnostic imaging ; Adult ; Motor Neurons/physiology ; Tongue/physiopathology/diagnostic imaging ; }, abstract = {OBJECTIVE: Compare fasciculation rates between amyotrophic lateral sclerosis (ALS) patients and healthy controls in body regions relevant for diagnosing ALS using motor unit MRI (MUMRI) at baseline and 6 months follow-up, and relate this to single-channel surface EMG (SEMG).

METHODS: Tongue, biceps brachii, paraspinals and lower legs were assessed with MUMRI and biceps brachii and soleus with SEMG in 10 healthy controls and 10 patients (9 typical ALS, 1 primary lateral sclerosis [PLS]).

RESULTS: MUMRI-detected fasciculation rates in typical ALS patients were higher compared to healthy controls for biceps brachii (2.40 ± 1.90 cm[-3]min[-1]vs. 0.04 ± 0.10 cm[-3]min[-1], p = 0.004), paraspinals (1.14 ± 1.61 cm[-3]min[-1]vs. 0.02 ± 0.02 cm[-3]min[-1], p = 0.016) and lower legs (1.42 ± 1.27 cm[-3]min[-1]vs. 0.13 ± 0.10 cm[-3]min[-1], p = 0.004), but not tongue (1.41 ± 1.94 cm[-3]min[-1]vs. 0.18 ± 0.18 cm[-3]min[-1], p = 0.556). The PLS patient showed no fasciculation. At baseline, 6/9 ALS patients had increased fasciculation rates compared to healthy controls in at least 2 body regions. At follow-up every patient had increased fasciculation rates in at least 2 body regions. The MUMRI-detected fasciculation rate correlated with SEMG-detected fasciculation rates (τ = 0.475, p = 0.006).

CONCLUSION: MUMRI can non-invasively image fasciculation in multiple body regions and appears sensitive to disease progression in individual patients.

SIGNIFICANCE: MUMRI has potential as diagnostic tool for ALS.}, } @article {pmid38447450, year = {2024}, author = {Malacarne, C and Giagnorio, E and Chirizzi, C and Cattaneo, M and Saraceno, F and Cavalcante, P and Bonanno, S and Mantegazza, R and Moreno-Manzano, V and Lauria, G and Metrangolo, P and Bombelli, FB and Marcuzzo, S}, title = {FM19G11-loaded nanoparticles modulate energetic status and production of reactive oxygen species in myoblasts from ALS mice.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {173}, number = {}, pages = {116380}, doi = {10.1016/j.biopha.2024.116380}, pmid = {38447450}, issn = {1950-6007}, mesh = {Mice ; Animals ; Superoxide Dismutase-1/metabolism ; Reactive Oxygen Species/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neurodegenerative Diseases/pathology ; Myoblasts/metabolism ; *Nanoparticles ; Atrophy/pathology ; Mice, Transgenic ; Disease Models, Animal ; Superoxide Dismutase/metabolism ; *Benzamides ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Considerable evidence indicates that early skeletal muscle atrophy plays a crucial role in the disease pathogenesis, leading to an altered muscle-motor neuron crosstalk that, in turn, may contribute to motor neuron degeneration. Currently, there is no effective treatment for ALS, highlighting the need to dig deeper into the pathological mechanisms for developing innovative therapeutic strategies. FM19G11 is a novel drug able to modulate the global cellular metabolism, but its effects on ALS skeletal muscle atrophy and mitochondrial metabolism have never been evaluated, yet. This study investigated whether FM19G11-loaded nanoparticles (NPs) may affect the bioenergetic status in myoblasts isolated from G93A-SOD1 mice at different disease stages. We found that FM19G1-loaded NP treatment was able to increase transcriptional levels of Akt1, Akt3, Mef2a, Mef2c and Ucp2, which are key genes associated with cell proliferation (Akt1, Akt3), muscle differentiation (Mef2c), and mitochondrial activity (Ucp2), in G93A-SOD1 myoblasts. These cells also showed a significant reduction of mitochondrial area and networks, in addition to decreased ROS production after treatment with FM19G11-loaded NPs, suggesting a ROS clearance upon the amelioration of mitochondrial dynamics. Our overall findings demonstrate a significant impact of FM19G11-loaded NPs on muscle cell function and bioenergetic status in G93A-SOD1 myoblasts, thus promising to open new avenues towards possible adoption of FM19G11-based nanotherapies to slow muscle degeneration in the frame of ALS and muscle disorders.}, } @article {pmid38446760, year = {2024}, author = {Unni, S and Kommu, P and Aouti, S and Nalli, Y and Bharath, MMS and Ali, A and Padmanabhan, B}, title = {Structural insights into the modulation Of SOD1 aggregation By a fungal metabolite Phialomustin-B: Therapeutic potential in ALS.}, journal = {PloS one}, volume = {19}, number = {3}, pages = {e0298196}, pmid = {38446760}, issn = {1932-6203}, mesh = {Humans ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Cytoskeleton ; Muscular Atrophy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal human motor neuron disease leading to muscle atrophy and paralysis. Mutations in superoxide dismutase 1 (SOD1) are associated with familial ALS (fALS). The SOD1 mutants in ALS have a toxic-gain of function by destabilizing the functional SOD1 homodimer, consequently inducing fibril-like aggregation with a cytotoxic non-native trimer intermediate. Therefore, reducing SOD1 oligomerization via chemical modulators is an optimal therapy in ALS. Here, we report the discovery of Phialomustin-B, an unsaturated secondary metabolite from the endophytic fungus Phialophora mustea, as a modulator of SOD1 aggregation. The crystal structure of the SOD1-Phialomustin complex refined to 1.90 Å resolution demonstrated for the first time that the ligand binds to the dimer interface and the lateral region near the electrostatic loop. The aggregation analyses of SOD1WT and the disease mutant SOD1A4V revealed that Phialomustin-B reduces cytotoxic trimerization. We propose that Phialomustin-B is a potent lead molecule with therapeutic potential in fALS.}, } @article {pmid38445369, year = {2024}, author = {Nishimura, K and Sanchez-Molano, J and Kerr, N and Pressman, Y and Silvera, R and Khan, A and Gajavelli, S and Bramlett, HM and Dietrich, WD}, title = {Beneficial Effects of Human Schwann Cell-Derived Exosomes in Mitigating Secondary Damage After Penetrating Ballistic-Like Brain Injury.}, journal = {Journal of neurotrauma}, volume = {41}, number = {21-22}, pages = {2395-2412}, pmid = {38445369}, issn = {1557-9042}, support = {R37 NS133195/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Rats, Sprague-Dawley ; Male ; Rats ; *Exosomes/metabolism/transplantation ; Humans ; *Schwann Cells/metabolism ; *Head Injuries, Penetrating ; }, abstract = {There is a growing body of evidence that the delivery of cell-derived exosomes normally involved in intracellular communication can reduce secondary injury mechanisms after brain and spinal cord injury and improve outcomes. Exosomes are nanometer-sized vesicles that are released by Schwann cells and may have neuroprotective effects by reducing post-traumatic inflammatory processes as well as promoting tissue healing and functional recovery. The purpose of this study was to evaluate the beneficial effects of human Schwann-cell exosomes (hSC-Exos) in a severe model of penetrating ballistic-like brain injury (PBBI) in rats and investigate effects on multiple outcomes. Human Schwann cell processing protocols followed Current Good Manufacturing Practices (cGMP) with exosome extraction and purification steps approved by the Food and Drug Administration for an expanded access single ALS patient Investigational New Drug. Anesthetized male Sprague-Dawley rats (280-350g) underwent PBBI surgery or Sham procedures and, starting 30 min after injury, received either a dose of hSC-Exos or phosphate-buffered saline through the jugular vein. At 48h after PBBI, flow cytometry analysis of cortical tissue revealed that hSC-Exos administration reduced the number of activated microglia and levels of caspase-1, a marker of inflammasome activation. Neuropathological analysis at 21 days showed that hSC-Exos treatment after PBBI significantly reduced overall contusion volume and decreased the frequency of Iba-1 positive activated and amoeboid microglia by immunocytochemical analysis. This study revealed that the systemic administration of hSC-Exos is neuroprotective in a model of severe TBI and reduces secondary inflammatory injury mechanisms and histopathological damage. The administration of hSC-Exos represents a clinically relevant cell-based therapy to limit the detrimental effects of neurotrauma or other progressive neurological injuries by impacting multiple pathophysiological events and promoting neurological recovery.}, } @article {pmid38445096, year = {2024}, author = {Shabber, SM and Sumesh, EP}, title = {AFM signal model for dysarthric speech classification using speech biomarkers.}, journal = {Frontiers in human neuroscience}, volume = {18}, number = {}, pages = {1346297}, pmid = {38445096}, issn = {1662-5161}, abstract = {Neurological disorders include various conditions affecting the brain, spinal cord, and nervous system which results in reduced performance in different organs and muscles throughout the human body. Dysarthia is a neurological disorder that significantly impairs an individual's ability to effectively communicate through speech. Individuals with dysarthria are characterized by muscle weakness that results in slow, slurred, and less intelligible speech production. An efficient identification of speech disorders at the beginning stages helps doctors suggest proper medications. The classification of dysarthric speech assumes a pivotal role as a diagnostic tool, enabling accurate differentiation between healthy speech patterns and those affected by dysarthria. Achieving a clear distinction between dysarthric speech and the speech of healthy individuals is made possible through the application of advanced machine learning techniques. In this work, we conducted feature extraction by utilizing the Amplitude and frequency modulated (AFM) signal model, resulting in the generation of a comprehensive array of unique features. A method involving Fourier-Bessel series expansion is employed to separate various components within a complex speech signal into distinct elements. Subsequently, the Discrete Energy Separation Algorithm is utilized to extract essential parameters, namely the Amplitude envelope and Instantaneous frequency, from each component within the speech signal. To ensure the robustness and applicability of our findings, we harnessed data from various sources, including TORGO, UA Speech, and Parkinson datasets. Furthermore, the classifier's performance was evaluated based on multiple measures such as the area under the curve, F1-Score, sensitivity, and accuracy, encompassing KNN, SVM, LDA, NB, and Boosted Tree. Our analyses resulted in classification accuracies ranging from 85 to 97.8% and the F1-score ranging between 0.90 and 0.97.}, } @article {pmid38444607, year = {2024}, author = {Uozumi, R and Mori, K and Gotoh, S and Miyamoto, T and Kondo, S and Yamashita, T and Kawabe, Y and Tagami, S and Akamine, S and Ikeda, M}, title = {PABPC1 mediates degradation of C9orf72-FTLD/ALS GGGGCC repeat RNA.}, journal = {iScience}, volume = {27}, number = {3}, pages = {109303}, pmid = {38444607}, issn = {2589-0042}, abstract = {GGGGCC hexanucleotide repeat expansion in C9orf72 causes frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Expanded GGGGCC repeat RNA accumulates within RNA foci and is translated into toxic dipeptide repeat proteins; thus, efficient repeat RNA degradation may alleviate diseases. hnRNPA3, one of the repeat RNA-binding proteins, has been implicated in the destabilization of repeat RNA. Using APEX2-mediated proximity biotinylation, here, we demonstrate PABPC1, a cytoplasmic poly (A)-binding protein, interacts with hnRNPA3. Knockdown of PABPC1 increased the accumulation of repeat RNA and RNA foci to the same extent as the knockdown of hnRNPA3. Proximity ligation assays indicated PABPC1-hnRNPA3 and PABPC1-RNA exosomes, a complex that degrades repeat RNA, preferentially co-localized when repeat RNA was present. Our results suggest that PABPC1 functions as a mediator of polyadenylated GGGGCC repeat RNA degradation through interactions with hnRNPA3 and RNA exosome complex.}, } @article {pmid38443977, year = {2024}, author = {Duan, QQ and Wang, H and Su, WM and Gu, XJ and Shen, XF and Jiang, Z and Ren, YL and Cao, B and Li, GB and Wang, Y and Chen, YP}, title = {TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro.}, journal = {BMC medicine}, volume = {22}, number = {1}, pages = {96}, pmid = {38443977}, issn = {1741-7015}, support = {2022YFC2703101//the National Key Research and Development Program of China/ ; 2021YFS0051//Sichuan Province Science and Technology Support Program/ ; 2023YFS0269//Sichuan Province Science and Technology Support Program/ ; 81971188//the National Natural Science Fund of China/ ; 2022NSFSC0749//the National Natural Science Fund of Sichuan/ ; 2023HXFH032//the 1·3·5 project for disciplines of excellence Clinical Research Fund, West China Hospital, Sichuan University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Drug Repositioning ; Mendelian Randomization Analysis ; Protein Serine-Threonine Kinases/genetics ; *Aminopyridines ; }, abstract = {BACKGROUND: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment.

METHODS: To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models.

RESULTS: Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation.

CONCLUSIONS: Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.}, } @article {pmid38443601, year = {2024}, author = {Spence, H and Waldron, FM and Saleeb, RS and Brown, AL and Rifai, OM and Gilodi, M and Read, F and Roberts, K and Milne, G and Wilkinson, D and O'Shaughnessy, J and Pastore, A and Fratta, P and Shneider, N and Tartaglia, GG and Zacco, E and Horrocks, MH and Gregory, JM}, title = {RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides with STMN-2 cryptic splicing and precedes clinical manifestation in ALS.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {50}, pmid = {38443601}, issn = {1432-0533}, support = {MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; R01 NS127186/NS/NINDS NIH HHS/United States ; R01NS127186/GF/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Aptamers, Nucleotide ; DNA-Binding Proteins/genetics ; RNA Splicing ; Antibodies ; }, abstract = {TDP-43 is an aggregation-prone protein which accumulates in the hallmark pathological inclusions of amyotrophic lateral sclerosis (ALS). However, the analysis of deeply phenotyped human post-mortem samples has shown that TDP-43 aggregation, revealed by standard antibody methods, correlates poorly with symptom manifestation. Recent identification of cryptic-splicing events, such as the detection of Stathmin-2 (STMN-2) cryptic exons, are providing evidence implicating TDP-43 loss-of-function as a potential driving pathomechanism but the temporal nature of TDP-43 loss and its relation to the disease process and clinical phenotype is not known. To address these outstanding questions, we used a novel RNA aptamer, TDP-43[APT], to detect TDP-43 pathology and used single molecule in situ hybridization to sensitively reveal TDP-43 loss-of-function and applied these in a deeply phenotyped human post-mortem tissue cohort. We demonstrate that TDP-43[APT] identifies pathological TDP-43, detecting aggregation events that cannot be detected by classical antibody stains. We show that nuclear TDP-43 pathology is an early event, occurring prior to cytoplasmic accumulation and is associated with loss-of-function measured by coincident STMN-2 cryptic splicing pathology. Crucially, we show that these pathological features of TDP-43 loss-of-function precede the clinical inflection point and are not required for region specific clinical manifestation. Furthermore, we demonstrate that gain-of-function in the form of extensive cytoplasmic accumulation, but not loss-of-function, is the primary molecular correlate of clinical manifestation. Taken together, our findings demonstrate implications for early diagnostics as the presence of STMN-2 cryptic exons and early TDP-43 aggregation events could be detected prior to symptom onset, holding promise for early intervention in ALS.}, } @article {pmid38443479, year = {2024}, author = {Fyfe, I}, title = {α-Synuclein seeds in amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {4}, pages = {203}, pmid = {38443479}, issn = {1759-4766}, mesh = {Humans ; *alpha-Synuclein ; *Amyotrophic Lateral Sclerosis ; }, } @article {pmid38441935, year = {2024}, author = {Finsterer, J}, title = {Whether Clenbuterol Is Beneficial in Sporadic ALS Can Only Be Answered Through Appropriately Designed Studies.}, journal = {Journal of clinical neuromuscular disease}, volume = {25}, number = {3}, pages = {150-151}, doi = {10.1097/CND.0000000000000475}, pmid = {38441935}, issn = {1537-1611}, mesh = {Humans ; *Clenbuterol/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; }, } @article {pmid38441932, year = {2024}, author = {Gomathy, SB and Das, A and Srivastava, AK}, title = {Flail Leg Phenotype in Familial Amyotrophic Lateral Sclerosis: Think of a Cause With Something to Offer.}, journal = {Journal of clinical neuromuscular disease}, volume = {25}, number = {3}, pages = {144-145}, doi = {10.1097/CND.0000000000000471}, pmid = {38441932}, issn = {1537-1611}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/genetics ; Leg ; }, } @article {pmid38435594, year = {2024}, author = {Wei, J and Yan, H and Shao, X and Zhao, L and Han, L and Yan, P and Wang, S}, title = {A machine learning-based hybrid recommender framework for smart medical systems.}, journal = {PeerJ. Computer science}, volume = {10}, number = {}, pages = {e1880}, pmid = {38435594}, issn = {2376-5992}, abstract = {This article presents a hybrid recommender framework for smart medical systems by introducing two methods to improve service level evaluations and doctor recommendations for patients. The first method uses big data techniques and deep learning algorithms to develop a registration review system in medical institutions. This system outperforms conventional evaluation methods, thus achieving higher accuracy. The second method implements the term frequency and inverse document frequency (TF-IDF) algorithm to construct a model based on the patient's symptom vector space, incorporating score weighting, modified cosine similarity, and K-means clustering. Then, the alternating least squares (ALS) matrix decomposition and user collaborative filtering algorithm are applied to calculate patients' predicted scores for doctors and recommend top-performing doctors. Experimental results show significant improvements in metrics called precision and recall rates compared to conventional methods, making the proposed approach a practical solution for department triage and doctor recommendation in medical appointment platforms.}, } @article {pmid38435120, year = {2024}, author = {Duan, C and Kang, M and Pan, X and Gan, Z and Huang, V and Li, G and Place, RF and Li, LC}, title = {Intrathecal administration of a novel siRNA modality extends survival and improves motor function in the SOD1[G93A] ALS mouse model.}, journal = {Molecular therapy. Nucleic acids}, volume = {35}, number = {1}, pages = {102147}, pmid = {38435120}, issn = {2162-2531}, abstract = {Antisense oligonucleotides (ASOs) were the first modality to pioneer targeted gene knockdown in the treatment of amyotrophic lateral sclerosis (ALS) caused by mutant superoxide dismutase 1 (SOD1). RNA interference (RNAi) is another mechanism of gene silencing in which short interfering RNAs (siRNAs) effectively degrade complementary transcripts. However, delivery to extrahepatic tissues like the CNS has been a bottleneck in the clinical development of RNAi. Herein, we identify potent siRNA duplexes for the knockdown of human SOD1 in which medicinal chemistry and conjugation to an accessory oligonucleotide (ACO) enable activity in CNS tissues. Local delivery via intracerebroventricular or intrathecal injection into SOD1[G93A] mice delayed disease progression and extended animal survival with superior efficacy compared with an ASO resembling tofersen in sequence and chemistry. Treatment also prevented disease-related declines in motor function, including improvements in animal mobility, muscle strength, and coordination. The ACO itself does not target any specific complementary nucleic acid sequence; rather, it imparts benefits conducive to bioavailability and delivery through its chemistry. The complete conjugate (i.e., siRNA-ACO) represents a novel modality for delivery of duplex RNA (e.g., siRNA) to the CNS that is currently being tested in the clinic for treatment of ALS.}, } @article {pmid38435055, year = {2024}, author = {Peterson, IL and Thompson, AD and Scholpa, NE and Largent-Milnes, T and Schnellmann, RG}, title = {Isolation and monoculture of functional primary astrocytes from the adult mouse spinal cord.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1367473}, pmid = {38435055}, issn = {1662-4548}, support = {T32 ES007091/ES/NIEHS NIH HHS/United States ; P30 ES006694/ES/NIEHS NIH HHS/United States ; IK2 BX005218/BX/BLRD VA/United States ; I01 BX004868/BX/BLRD VA/United States ; T32 HL007249/HL/NHLBI NIH HHS/United States ; R01 NS126752/NS/NINDS NIH HHS/United States ; }, abstract = {Astrocytes are a widely heterogenic cell population that play major roles in central nervous system (CNS) homeostasis and neurotransmission, as well as in various neuropathologies, including spinal cord injury (SCI), traumatic brain injury, and neurodegenerative diseases, such as amyotrophic lateral sclerosis. Spinal cord astrocytes have distinct differences from those in the brain and accurate modeling of disease states is necessary for understanding disease progression and developing therapeutic interventions. Several limitations to modeling spinal cord astrocytes in vitro exist, including lack of commercially available adult-derived cells, lack of purchasable astrocytes with different genotypes, as well as time-consuming and costly in-house primary cell isolations that often result in low yield due to small tissue volume. To address these issues, we developed an efficient adult mouse spinal cord astrocyte isolation method that utilizes enzymatic digestion, debris filtration, and multiple ACSA-2 magnetic microbead purification cycles to achieve an astrocyte monoculture purity of ≅93-98%, based on all markers assessed. Importantly, the isolated cells contain active mitochondria and express key astrocyte markers including ACSA-1, ACSA-2, EAAT2, and GFAP. Furthermore, this isolation method can be applied to the spinal cord of male and female mice, mice subjected to SCI, and genetically modified mice. We present a primary adult mouse spinal cord astrocyte isolation protocol focused on purity, viability, and length of isolation that can be applied to a multitude of models and aid in targeted research on spinal-cord related CNS processes and pathologies.}, } @article {pmid38434715, year = {2024}, author = {Kumar, R and Blackband, J and Wagle Shukla, A}, title = {Rhythmic Jaw Movements in Amyotrophic Lateral Sclerosis: Is It Clonus or Tremor?.}, journal = {Tremor and other hyperkinetic movements (New York, N.Y.)}, volume = {14}, number = {}, pages = {8}, pmid = {38434715}, issn = {2160-8288}, mesh = {Humans ; Tremor/etiology ; *Essential Tremor/diagnosis ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis/complications ; Movement ; Reflex, Abnormal ; }, abstract = {BACKGROUND: Jaw clonus refers to involuntary, rhythmic jaw contractions induced by a hyperactive trigeminal nerve stretch reflex; however, the movements, when triggered without a stretch, can be confused with a tremor.

PHENOMENOLOGY SHOWN: This video demonstrates a patient with amyotrophic lateral sclerosis presenting with rapid rhythmic jaw movements seen at rest, alongside a power spectrum analysis revealing a narrow high-frequency peak of 10 Hz.

EDUCATIONAL VALUE: Rhythmic jaw movements are seen in many disorders such as Parkinson's disease, essential tremor, tardive syndromes, and cranial myorhythmias; however, a high-frequency movement, regardless of clonus or tremor, can indicate amyotrophic lateral sclerosis when accompanied by typical upper and lower motor neuron signs.

HIGHLIGHTS: The presented video abstract shows a patient with amyotrophic lateral sclerosis with rhythmic jaw movements seen at rest. A power spectrum analysis of the rhythmic movements revealed a 10 Hz peak, a frequency higher than those seen in patients with Parkinson's disease, essential tremor, myorhythmia, and tardive syndromes.}, } @article {pmid38433895, year = {2024}, author = {Lépine, S and Nauleau-Javaudin, A and Deneault, E and Chen, CX and Abdian, N and Franco-Flores, AK and Haghi, G and Castellanos-Montiel, MJ and Maussion, G and Chaineau, M and Durcan, TM}, title = {Homozygous ALS-linked mutations in TARDBP/TDP-43 lead to hypoactivity and synaptic abnormalities in human iPSC-derived motor neurons.}, journal = {iScience}, volume = {27}, number = {3}, pages = {109166}, pmid = {38433895}, issn = {2589-0042}, abstract = {Cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43 is a pathological hallmark of the motor neuron (MN) disease amyotrophic lateral sclerosis (ALS). Furthermore, while mutations in TARDBP (encoding TDP-43) have been associated with ALS, the pathogenic consequences of these mutations remain poorly understood. Using CRISPR-Cas9, we engineered two homozygous knock-in induced pluripotent stem cell lines carrying mutations in TARDBP encoding TDP-43[A382T] and TDP-43[G348C], two common yet understudied ALS TDP-43 variants. Motor neurons (MNs) differentiated from knock-in iPSCs had normal viability and displayed no significant changes in TDP-43 subcellular localization, phosphorylation, solubility, or aggregation compared with isogenic control MNs. However, our results highlight synaptic impairments in both TDP-43[A382T] and TDP-43[G348C] MN cultures, as reflected in synapse abnormalities and alterations in spontaneous neuronal activity. Collectively, our findings suggest that MN dysfunction may precede the occurrence of TDP-43 pathology and neurodegeneration in ALS and further implicate synaptic and excitability defects in the pathobiology of this disease.}, } @article {pmid38432083, year = {2024}, author = {Straczkiewicz, M and Karas, M and Johnson, SA and Burke, KM and Scheier, Z and Royse, TB and Calcagno, N and Clark, A and Iyer, A and Berry, JD and Onnela, JP}, title = {Upper limb movements as digital biomarkers in people with ALS.}, journal = {EBioMedicine}, volume = {101}, number = {}, pages = {105036}, pmid = {38432083}, issn = {2352-3964}, support = {U01 HL145386/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Upper Extremity ; Wrist ; Disease Progression ; Biomarkers ; }, abstract = {BACKGROUND: Objective evaluation of people with amyotrophic lateral sclerosis (PALS) in free-living settings is challenging. The introduction of portable digital devices, such as wearables and smartphones, may improve quantifying disease progression and hasten therapeutic development. However, there is a need for tools to characterize upper limb movements in neurologic disease and disability.

METHODS: Twenty PALS wore a wearable accelerometer, ActiGraph Insight Watch, on their wrist for six months. They also used Beiwe, a smartphone application that collected self-entry ALS Functional Rating Scale-Revised (ALSFRS-RSE) survey responses every 1-4 weeks. We developed several measures that quantify count and duration of upper limb movements: flexion, extension, supination, and pronation. New measures were compared against ALSFRS-RSE total score (Q1-12), and individual responses to specific questions related to handwriting (Q4), cutting food (Q5), dressing and performing hygiene (Q6), and turning in bed and adjusting bed clothes (Q7). Additional analysis considered adjusting for total activity counts (TAC).

FINDINGS: At baseline, PALS with higher Q1-12 performed more upper limb movements, and these movements were faster compared to individuals with more advanced disease. Most upper limb movement metrics had statistically significant change over time, indicating declining function either by decreasing count metrics or by increasing duration metric. All count and duration metrics were significantly associated with Q1-12, flexion and extension counts were significantly associated with Q6 and Q7, supination and pronation counts were also associated with Q4. All duration metrics were associated with Q6 and Q7. All duration metrics retained their statistical significance after adjusting for TAC.

INTERPRETATION: Wearable accelerometer data can be used to generate digital biomarkers on upper limb movements and facilitate patient monitoring in free-living environments. The presented method offers interpretable monitoring of patients' functioning and versatile tracking of disease progression in the limb of interest.

FUNDING: Mitsubishi-Tanabe Pharma Holdings America, Inc.}, } @article {pmid38432041, year = {2024}, author = {Yu, W and Wang, H and Li, M and Yang, F and Bai, J and Song, H and Huang, X}, title = {Prognostic value of geriatric nutritional risk index in patients with amyotrophic lateral sclerosis.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {122}, number = {}, pages = {19-24}, doi = {10.1016/j.jocn.2024.02.011}, pmid = {38432041}, issn = {1532-2653}, mesh = {Humans ; Aged ; Prognosis ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Delayed Diagnosis ; Nutritional Status ; Disease Progression ; Risk Factors ; Retrospective Studies ; }, abstract = {BACKGROUND: The geriatric nutritional risk index (GNRI) is a prognostic indicator for several diseases, meanwhile, nutrition and inflammation play important roles in the disease progression of amyotrophic lateral sclerosis (ALS). However, the association between the GNRI and ALS remains unknown.

METHODS: 443 patients diagnosed with ALS were divided into two groups based on the GNRI levels. Associations between GNRI and survival time were analyzed using Kaplan-Meier curves and compared by the log-rank test. Univariate and multivariate analyses were used to assess their prognostic values for survival time. Spearman correlation analysis was used to evaluate the correlation coefficients between GNRI and other clinical variables.

RESULTS: No significant differences were found in diagnostic delay between the two groups. The onset age and disease progression rate (DPR) were significantly lower in high GNRI group while forced vital capacity (FVC), revised version of the ALS functional rating scale (ALSFRS-R), serum albumin and body mass index (BMI) were significantly lower in low GNRI group. Lower GNRI levels were linked with shorter ALS patients' survival time by Kaplan-Meier curves. The univariate and multivariate analysis identified the onset age, gender, onset site, diagnostic delay, DRP and GNRI as predictors of survival time in patients with ALS.

CONCLUSION: Nutritional status was closely corelated with ALS progression. The GNRI may be used as a potential prognostic indictor for ALS patients.}, } @article {pmid38431841, year = {2024}, author = {Gao, C and Shi, Q and Pan, X and Chen, J and Zhang, Y and Lang, J and Wen, S and Liu, X and Cheng, TL and Lei, K}, title = {Neuromuscular organoids model spinal neuromuscular pathologies in C9orf72 amyotrophic lateral sclerosis.}, journal = {Cell reports}, volume = {43}, number = {3}, pages = {113892}, doi = {10.1016/j.celrep.2024.113892}, pmid = {38431841}, issn = {2211-1247}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology ; Proteins/genetics ; Dipeptides/pharmacology/metabolism ; DNA Repeat Expansion ; }, abstract = {Hexanucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Due to the lack of trunk neuromuscular organoids (NMOs) from ALS patients' induced pluripotent stem cells (iPSCs), an organoid system was missing to model the trunk spinal neuromuscular neurodegeneration. With the C9orf72 ALS patient-derived iPSCs and isogenic controls, we used an NMO system containing trunk spinal cord neural and peripheral muscular tissues to show that the ALS NMOs could model peripheral defects in ALS, including contraction weakness, neural denervation, and loss of Schwann cells. The neurons and astrocytes in ALS NMOs manifested the RNA foci and dipeptide repeat proteins. Acute treatment with the unfolded protein response inhibitor GSK2606414 increased the glutamatergic muscular contraction 2-fold and reduced the dipeptide repeat protein aggregation and autophagy. This study provides an organoid system for spinal neuromuscular pathologies in ALS and its application for drug testing.}, } @article {pmid38431830, year = {2024}, author = {Li, R and Han, X and Wang, Q and Wang, C and Jing, W and Zhang, H and Wang, J and Pan, W}, title = {Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part 3: Alleviation of hypoxia, muscle-wasting, and modulation of redox functions in amyotrophic lateral sclerosis.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {62}, number = {4}, pages = {169-177}, doi = {10.5414/CP204520}, pmid = {38431830}, issn = {0946-1965}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/diagnosis ; Medicine, Chinese Traditional ; Network Pharmacology ; Treatment Outcome ; Hypoxia ; Cholecalciferol ; Muscles ; Disease Progression ; }, abstract = {OBJECTIVE: The aim of this clinical study is to obtain evidence for the clinical efficacy of Bu-Shen-Jian-Pi formula (BSJP), a traditional Chinese medicine, used for the treatment of amyotrophic lateral sclerosis, a relatively rare, progressive and usually fatal disease possibly associated with alterations in tissue redox status, hypoxia, and muscular injury.

BACKGROUND: The active agents in BSJP formula[†] causing apoptosis, modulation of redox changes, and alterations in the immune status have been studied previously by us using cell cultures. The findings from these investigations have been incorporated into pharmacology databases employed in our analysis of BSJP using network pharmacology analysis/artifical intelligence. This information has been used here in the design of the investigation and to optimize evaluation of the clinical efficacy and usefulness of this herbal medicine, as far as possible using evidence-based medicine criteria.

MATERIALS AND METHODS: The design of the study was a randomized multi-center, controlled clinical trial in 127 patients with confirmed diagnoses of amyotrophic lateral sclerosis. Patients and investigator were double-blinded. Clinical efficacy was determined using the Amyotrophic Lateral Sclerosis Symptom Score in Integrative Treatment Scale (ALS-SSIT) and the Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R), together with tests of limb muscle strength using the manual muscle test (MMT), forced vital capacity (FVC), and clinical chemistry laboratory tests over a 20-week observation period.

RESULTS: The scores of ALS-SSIT in the BSJP group increased significantly (22%) after treatment. The ALSFRS-R score in the BSJP group decreased significantly after treatment (19%). The rate of decrease in muscle function (MMT score) in most BSJP patients was lower than that in the control group, where the differences in the scores for the trapezius and triceps brachii were statistically significant compared to the control group. The fall in FVC in the BJSP group was significantly slower than in the control group. There were no marked differences observed in the frequency of side effects. Serum vitamin D3 levels in the BSJP group showed greater increases compared to the control group.

CONCLUSION: BSJP treatment reduced the rate of progression of amyotrophic lateral sclerosis according to the ALS-SSITS and ALSFRS scores and significantly reduced the rate of deterioration in muscle function in the limbs of amyotrophic lateral sclerosis patients. The modes of action of BSJP in treating amyotrophic lateral sclerosis are probably diverse and multi targeted, some of which may involve regulation of serum vitamin D3 and alleviation of the impairments in liver and kidney function.}, } @article {pmid38431829, year = {2024}, author = {Yuan, W and Lin, J and Wang, J and Wang, C and Shan, Y and Jing, W and Fei, Z and Pan, W}, title = {Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part 2: Modulation of hypoxia, redox status, and mitochondrial protection in a neuroblastoma cell line, SH-SY5Y.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {62}, number = {4}, pages = {162-168}, doi = {10.5414/CP204505}, pmid = {38431829}, issn = {0946-1965}, mesh = {Humans ; *Medicine, Chinese Traditional ; Kaempferols/pharmacology ; Cell Line, Tumor ; Network Pharmacology ; *Neuroblastoma/drug therapy/metabolism ; Oxidation-Reduction ; Hypoxia/drug therapy ; Treatment Outcome ; }, abstract = {OBJECTIVE: To examine the mitochondrial protective effects of icariin, naringenin, kaempferol, and formononetin, potentially active agents in Bu-Shen-Jian-Pi formula (BSJP) identified using network pharmacology analysis.

MATERIALS AND METHODS: Mitochondrial protection activity was determined using a hypoxia-reoxygenation in vitro model based on the neuroblastoma cell line SH-SY5Y and measurements of anti-ferroptotic activity.

RESULTS: Icariin, naringenin, kaempferol, and formononetin showed mitochondrial protective activity involving diverse signaling pathways. The cytoprotective effects of formononetin depended on the inhibition of ferroptosis. Hypoxia-reoxygenation stimulation induced ferroptosis in SH-SY5Y cells.

DISCUSSION: Ferroptosis is a key mechanism in nervous system diseases and is associated with hypoxia-reoxygenation injury. Naringenin and kaempferol were devoid of anti-ferroptotic activity.

CONCLUSION: Evidence has been obtained showing that the core components: icariin, naringenin, kaempferol, and formononetin in BSJP formula have anti-hypoxic and mitochondrial protective activity of potential clinical importance in the treatment of amyotrophic lateral sclerosis and patients with symptoms of hypoxia.}, } @article {pmid38431694, year = {2024}, author = {Mouhamed, AA and Nadim, AH and Mostafa, NM and Eltanany, BM}, title = {Application of smart chemometric models for spectra resolution and determination of challenging multi-action quaternary mixture: statistical comparison with greenness assessment.}, journal = {BMC chemistry}, volume = {18}, number = {1}, pages = {44}, pmid = {38431694}, issn = {2661-801X}, abstract = {A multivariate spectrophotometric method is a potential approach that enables discrimination of spectra of components in complex matrices (e.g., pharmaceutical formulation) serving as a substitution method for chromatography. Four green smart multivariate spectrophotometric models were proposed and validated, including principal component regression (PCR), partial least-squares (PLS), multivariate curve resolution-alternating least squares (MCR-ALS), and artificial neural networks (ANN). The developed chemometric models were compared to resolve highly overlapping spectra of Paracetamol (PARA), Chlorpheniramine maleate (CPM), Caffeine (CAF), and Ascorbic acid (ASC). The four multivariate calibration models were assessed via recoveries percent, and root mean square error of prediction. Hence, the proposed models were efficiently applied with no need for any preliminary separation step. The models were utilized to analyze the studied components in their combined pharmaceutical formulation (Grippostad® C capsules). Analytical GREEnness Metric Approach (AGREE) and eco-scale tools were applied to assess the greenness of the established models and found to be 0.77 and 85, respectively. Moreover, the proposed models have been compared to official ones showing no considerable variations in accuracy and precision. Therefore, these models can be highly advantageous for conducting standard pharmaceutical analysis of the substances researched within product testing laboratories.}, } @article {pmid38430933, year = {2024}, author = {Li, D and Zhou, L and Cao, Z and Wang, J and Yang, H and Lyu, M and Zhang, Y and Yang, R and Wang, J and Bian, Y and Xu, W and Wang, Y}, title = {Associations of environmental factors with neurodegeneration: An exposome-wide Mendelian randomization investigation.}, journal = {Ageing research reviews}, volume = {95}, number = {}, pages = {102254}, doi = {10.1016/j.arr.2024.102254}, pmid = {38430933}, issn = {1872-9649}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Exposome ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Alzheimer Disease/genetics ; *Parkinson Disease ; *Multiple Sclerosis/genetics ; }, abstract = {Neurodegenerative diseases (NDDs) remain a global health challenge. Previous studies have reported potential links between environmental factors and NDDs, however, findings remain controversial across studies and elusive to be interpreted as evidence of robust causal associations. In this study, we comprehensively explored the causal associations of the common environmental factors with major NDDs including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), based on updated large-scale genome-wide association study data through two-sample Mendelian randomization (MR) approach. Our results indicated that, overall, 28 significant sets of exposure-outcome causal association evidence were detected, 12 of which were previously underestimated and newly identified, including average weekly beer plus cider intake, strenuous sports or other exercises, diastolic blood pressure, and body fat percentage with AD, alcohol intake frequency with PD, apolipoprotein B, systolic blood pressure, and forced expiratory volume in 1 s (FEV1) with ALS, and alcohol intake frequency, hip circumference, forced vital capacity, and FEV1 with MS. Moreover, the causal effects of several environmental factors on NDDs were found to overlap. From a triangulation perspective, our investigation provided insights into understanding the associations of environmental factors with NDDs, providing causality-oriented evidence to establish the risk profile of NDDs.}, } @article {pmid38430277, year = {2024}, author = {Jagaraj, CJ and Shadfar, S and Kashani, SA and Saravanabavan, S and Farzana, F and Atkin, JD}, title = {Molecular hallmarks of ageing in amyotrophic lateral sclerosis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {111}, pmid = {38430277}, issn = {1420-9071}, support = {1095215//National Institute for Dementia Research/ ; Peter Stearne Familial MND Research Grant//Motor Neurone Disease Australia/ ; Linda Rynalski Bridge Funding Grant//Motor Neurone Disease Australia/ ; 51909/00//FightMND/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Longevity ; Autophagy/genetics ; Brain ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, severely debilitating and rapidly progressing disorder affecting motor neurons in the brain, brainstem, and spinal cord. Unfortunately, there are few effective treatments, thus there remains a critical need to find novel interventions that can mitigate against its effects. Whilst the aetiology of ALS remains unclear, ageing is the major risk factor. Ageing is a slowly progressive process marked by functional decline of an organism over its lifespan. However, it remains unclear how ageing promotes the risk of ALS. At the molecular and cellular level there are specific hallmarks characteristic of normal ageing. These hallmarks are highly inter-related and overlap significantly with each other. Moreover, whilst ageing is a normal process, there are striking similarities at the molecular level between these factors and neurodegeneration in ALS. Nine ageing hallmarks were originally proposed: genomic instability, loss of telomeres, senescence, epigenetic modifications, dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, stem cell exhaustion, and altered inter-cellular communication. However, these were recently (2023) expanded to include dysregulation of autophagy, inflammation and dysbiosis. Hence, given the latest updates to these hallmarks, and their close association to disease processes in ALS, a new examination of their relationship to pathophysiology is warranted. In this review, we describe possible mechanisms by which normal ageing impacts on neurodegenerative mechanisms implicated in ALS, and new therapeutic interventions that may arise from this.}, } @article {pmid38430248, year = {2024}, author = {Ullah, I and Uddin, S and Zhao, L and Wang, X and Li, H}, title = {Autophagy and UPS pathway contribute to nicotine-induced protection effect in Parkinson's disease.}, journal = {Experimental brain research}, volume = {242}, number = {4}, pages = {971-986}, pmid = {38430248}, issn = {1432-1106}, support = {81403145//National Natural Science Foundation of China/ ; 20JR10RA602//Natural Science Foundation of Gansu Province/ ; lzujbky- 2017-206//Fundamental Research Funds for the Central Universities/ ; lzujbky-2018-136//Fundamental Research Funds for the Central Universities/ ; 2019HZ-02//Science and Technology Program of Gansu Province/ ; 2010-1-154//Science and Technology Program of Gansu Province/ ; }, mesh = {Animals ; Humans ; Aged ; *Parkinson Disease/drug therapy/metabolism ; Nicotine/pharmacology/metabolism ; Caenorhabditis elegans/metabolism ; Lipofuscin/metabolism/pharmacology ; alpha-Synuclein/metabolism/pharmacology ; *Neurodegenerative Diseases/metabolism ; Dopaminergic Neurons/metabolism ; Autophagy ; }, abstract = {The gradual nature of age-related neurodegeneration causes Parkinson's disease (PD) and impairs movement, memory, intellectual ability, and social interaction. One of the most prevalent neurodegenerative conditions affecting the central nervous system (CNS) among the elderly is PD. PD affects both motor and cognitive functions. Degeneration of dopaminergic (DA) neurons and buildup of the protein α-synuclein (α-Syn) in the substantia nigra pars compacta (SNpc) are two major causes of this disorder. Both UPS and ALS systems serve to eliminate α-Syn. Autophagy and UPS deficits, shortened life duration, and lipofuscin buildup accelerate PD. This sickness has no cure. Innovative therapies are halting PD progression. Bioactive phytochemicals may provide older individuals with a natural substitute to help delay the onset of neurodegenerative illnesses. This study examines whether nicotine helps transgenic C. elegans PD models. According to numerous studies, nicotine enhances synaptic plasticity and dopaminergic neuronal survival. Upgrades UPS pathways, increases autophagy, and decreases oxidative stress and mitochondrial dysfunction. At 100, 150, and 200 µM nicotine levels, worms showed reduced α-Syn aggregation, repaired DA neurotoxicity after 6-OHDA intoxication, increased lifetime, and reduced lipofuscin accumulation. Furthermore, nicotine triggered autophagy and UPS. We revealed nicotine's potential as a UPS and autophagy activator to prevent PD and other neurodegenerative diseases.}, } @article {pmid38429929, year = {2024}, author = {Schuster, KH and Zalon, AJ and DiFranco, DM and Putka, AF and Stec, NR and Jarrah, SI and Naeem, A and Haque, Z and Zhang, H and Guan, Y and McLoughlin, HS}, title = {ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {32}, number = {5}, pages = {1359-1372}, pmid = {38429929}, issn = {1525-0024}, support = {R01 NS122751/NS/NINDS NIH HHS/United States ; R35 GM133346/GM/NIGMS NIH HHS/United States ; U01 NS106670/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Oligodendroglia/metabolism ; Mice ; *Machado-Joseph Disease/genetics/therapy/pathology/metabolism ; *Oligonucleotides, Antisense ; *Disease Models, Animal ; *Ataxin-3/genetics/metabolism ; Humans ; Repressor Proteins/genetics/metabolism ; Mice, Transgenic ; }, abstract = {Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia. Currently, no preventive or disease-modifying treatments exist for this progressive neurodegenerative disorder, although efforts using gene silencing approaches are under clinical trial investigation. The disease is caused by a CAG repeat expansion in the mutant gene, ATXN3, producing an enlarged polyglutamine tract in the mutant protein. Similar to other paradigmatic neurodegenerative diseases, studies evaluating the pathogenic mechanism focus primarily on neuronal implications. Consequently, therapeutic interventions often overlook non-neuronal contributions to disease. Our lab recently reported that oligodendrocytes display some of the earliest and most progressive dysfunction in SCA3 mice. Evidence of disease-associated oligodendrocyte signatures has also been reported in other neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. Here, we assess the effects of anti-ATXN3 antisense oligonucleotide (ASO) treatment on oligodendrocyte dysfunction in premanifest and symptomatic SCA3 mice. We report a severe, but modifiable, deficit in oligodendrocyte maturation caused by the toxic gain-of-function of mutant ATXN3 early in SCA3 disease that is transcriptionally, biochemically, and functionally rescued with anti-ATXN3 ASO. Our results highlight the promising use of an ASO therapy across neurodegenerative diseases that requires glial targeting in addition to affected neuronal populations.}, } @article {pmid38429818, year = {2024}, author = {Darabi, S and Ariaei, A and Rustamzadeh, A and Afshari, D and Charkhat Gorgich, EA and Darabi, L}, title = {Cerebrospinal fluid and blood exosomes as biomarkers for amyotrophic lateral sclerosis; a systematic review.}, journal = {Diagnostic pathology}, volume = {19}, number = {1}, pages = {47}, pmid = {38429818}, issn = {1746-1596}, mesh = {Humans ; *Exosomes ; *Amyotrophic Lateral Sclerosis/diagnosis ; Superoxide Dismutase-1 ; Biomarkers ; DNA-Binding Proteins ; Disease Progression ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease. Due to the limited knowledge about potential biomarkers that help in early diagnosis and monitoring disease progression, today's diagnoses are based on ruling out other diseases, neurography, and electromyography examination, which takes a time-consuming procedure.

METHODS: PubMed, ScienceDirect, and Web of Science were explored to extract articles published from January 2015 to June 2023. In the searching strategy following keywords were included; amyotrophic lateral sclerosis, biomarkers, cerebrospinal fluid, serum, and plama.

RESULTS: A total number of 6 studies describing fluid-based exosomal biomarkers were included in this study. Aggregated proteins including SOD1, TDP-43, pTDP-43, and FUS could be detected in the microvesicles (MVs). Moreover, TDP-43 and NFL extracted from plasma exosomes could be used as prognostic biomarkers. Also, downregulated miR-27a-3p detected through exoEasy Maxi and exoQuick Kit in the plasma could be measured as a diagnostic biomarker. Eventually, the upregulated level of CORO1A could be used to monitor disease progression.

CONCLUSION: Based on the results, each biomarker alone is insufficient to evaluate ALS. CNS-derived exosomes contain multiple ALS-related biomarkers (SOD1, TDP-43, pTDP-43, FUS, and miRNAs) that are detectable in cerebrospinal fluid and blood is a proper alternation. Exosome detecting kits listed as exoEasy, ExoQuick, Exo-spin, ME kit, ExoQuick Plus, and Exo-Flow, are helpful to reach this purpose.}, } @article {pmid38429713, year = {2024}, author = {Hagenaar, DA and Bindels-de Heus, KGCB and van Gils, MM and van den Berg, L and Ten Hoopen, LW and Affourtit, P and Pel, JJM and Joosten, KFM and Hillegers, MHJ and Moll, HA and de Wit, MY and Dieleman, GC and Mous, SE}, title = {Outcome measures in Angelman syndrome.}, journal = {Journal of neurodevelopmental disorders}, volume = {16}, number = {1}, pages = {6}, pmid = {38429713}, issn = {1866-1955}, support = {B17-04A//Stichting Vrienden van het Sophia/ ; }, mesh = {Child ; Humans ; *Angelman Syndrome/complications/diagnosis ; Reproducibility of Results ; Body Composition ; Plethysmography/methods ; Electric Impedance ; }, abstract = {BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe intellectual disability, little to no expressive speech, visual and motor problems, emotional/behavioral challenges, and a tendency towards hyperphagia and weight gain. The characteristics of AS make it difficult to measure these children's functioning with standard clinical tests. Feasible outcome measures are needed to measure current functioning and change over time, in clinical practice and clinical trials.

AIM: Our first aim is to assess the feasibility of several functional tests. We target domains of neurocognitive functioning and physical growth using the following measurement methods: eye-tracking, functional Near-Infrared Spectroscopy (fNIRS), indirect calorimetry, bio-impedance analysis (BIA), and BOD POD (air-displacement plethysmography). Our second aim is to explore the results of the above measures, in order to better understand the AS phenotype.

METHODS: The study sample consisted of 28 children with AS aged 2-18 years. We defined an outcome measure as feasible when (1) at least 70% of participants successfully finished the measurement and (2) at least 60% of those participants had acceptable data quality. Adaptations to the test procedure and reasons for early termination were noted. Parents rated acceptability and importance and were invited to make recommendations to increase feasibility. The results of the measures were explored.

RESULTS: Outcome measures obtained with eye-tracking and BOD POD met the definition of feasibility, while fNIRS, indirect calorimetry, and BIA did not. The most important reasons for early termination of measurements were showing signs of protest, inability to sit still and poor/no calibration (eye-tracking specific). Post-calibration was often applied to obtain valid eye-tracking results. Parents rated the BOD POD als most acceptable and fNIRS as least acceptable for their child. All outcome measures were rated to be important. Exploratory results indicated longer reaction times to high salient visual stimuli (eye-tracking) as well as high body fat percentage (BOD POD).

CONCLUSIONS: Eye-tracking and BOD POD are feasible measurement methods for children with AS. Eye-tracking was successfully used to assess visual orienting functions in the current study and (with some practical adaptations) can potentially be used to assess other outcomes as well. BOD POD was successfully used to examine body composition.

TRIAL REGISTRATION: Registered d.d. 23-04-2020 under number 'NL8550' in the Dutch Trial Register: https://onderzoekmetmensen.nl/en/trial/23075.}, } @article {pmid38429379, year = {2024}, author = {de Luzy, IR and Lee, MK and Mobley, WC and Studer, L}, title = {Lessons from inducible pluripotent stem cell models on neuronal senescence in aging and neurodegeneration.}, journal = {Nature aging}, volume = {4}, number = {3}, pages = {309-318}, pmid = {38429379}, issn = {2662-8465}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; R01 AG054720/AG/NIA NIH HHS/United States ; R01 AG070154/AG/NIA NIH HHS/United States ; ASAP-020370//Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases ; Aging ; Cellular Senescence/physiology ; Neurons ; *Pluripotent Stem Cells ; }, abstract = {Age remains the central risk factor for many neurodegenerative diseases including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Although the mechanisms of aging are complex, the age-related accumulation of senescent cells in neurodegeneration is well documented and their clearance can alleviate disease-related features in preclinical models. Senescence-like characteristics are observed in both neuronal and glial lineages, but their relative contribution to aging and neurodegeneration remains unclear. Human pluripotent stem cell-derived neurons provide an experimental model system to induce neuronal senescence. However, the extensive heterogeneity in the profile of senescent neurons and the methods to assess senescence remain major challenges. Here, we review the evidence of cellular senescence in neuronal aging and disease, discuss human pluripotent stem cell-based model systems used to investigate neuronal senescence and propose a panel of cellular and molecular hallmarks to characterize senescent neurons. Understanding the role of neuronal senescence may yield novel therapeutic opportunities in neurodegenerative disease.}, } @article {pmid38429156, year = {2024}, author = {Corcia, P and Couratier, P}, title = {Spreading of motor neuron degeneration in ALS is not so random.}, journal = {Revue neurologique}, volume = {180}, number = {6}, pages = {475-476}, doi = {10.1016/j.neurol.2024.02.384}, pmid = {38429156}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnosis ; *Motor Neurons/pathology/physiology ; *Nerve Degeneration/pathology ; }, } @article {pmid38428880, year = {2024}, author = {Hu, CJ and Chen, PC and Padmanabhan, N and Zahn, A and Ho, CM and Wang, K and Yen, Y}, title = {A new potential therapeutic approach for ALS: A case report with NGS analysis.}, journal = {Medicine}, volume = {103}, number = {9}, pages = {e37401}, pmid = {38428880}, issn = {1536-5964}, mesh = {Humans ; Male ; Aged ; Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/genetics ; Artificial Intelligence ; Treatment Outcome ; *Hypotension/drug therapy ; }, abstract = {RATIONALE: Amyotrophic lateral sclerosis (ALS) poses a significant clinical challenge due to its rapid progression and limited treatment options, often leading to deadly outcomes. Looking for effective therapeutic interventions is critical to improve patient outcomes in ALS.

PATIENT CONCERNS: The patient, a 75-year-old East Asian male, manifested an insidious onset of right-hand weakness advancing with dysarthria. Comprehensive Next-generation sequencing analysis identified variants in specific genes consistent with ALS diagnosis.

DIAGNOSES: ALS diagnosis is based on El Escorial diagnostic criteria.

INTERVENTIONS: This study introduces a novel therapeutic approach using artificial intelligence phenotypic response surface (AI-PRS) technology to customize personalized drug-dose combinations for ALS. The patient underwent a series of phases of AI-PRS-assisted trials, initially incorporating a 4-drug combination of Ibudilast, Riluzole, Tamoxifen, and Ropinirole. Biomarkers and regular clinical assessments, including nerve conduction velocity, F-wave, H-reflex, electromyography, and motor unit action potential, were monitored to comprehensively evaluate treatment efficacy.

OUTCOMES: Neurophysiological assessments supported the ALS diagnosis and revealed the co-presence of diabetic polyneuropathy. Hypotension during the trial necessitated an adaptation to a 2-drug combinational trial (ibudilast and riluzole). Disease progression assessment shifted exclusively to clinical tests of muscle strength, aligning with the patient's well-being.

LESSONS: The study raises the significance of personalized therapeutic strategies in ALS by AI-PRS. It also emphasizes the adaptability of interventions based on patient-specific responses. The encountered hypotension incident highlights the importance of attentive monitoring and personalized adjustments in treatment plans. The described therapy using AI-PRS, offering personalized drug-dose combinations technology is a potential approach in treating ALS. The promising outcomes warrant further evaluation in clinical trials for searching a personalized, more effective combinational treatment for ALS patients.}, } @article {pmid38428228, year = {2024}, author = {Masroor, A and Zaidi, N and Nabi, F and Malik, S and Zehra, S and Arjmand, F and Naseem, N and Khan, RH}, title = {Biophysical insight into anti-amyloidogenic nature of novel ionic Co(II)(phen)(H2O)4][+][glycinate][-] chemotherapeutic drug candidate against human lysozyme aggregation.}, journal = {Biophysical chemistry}, volume = {308}, number = {}, pages = {107214}, doi = {10.1016/j.bpc.2024.107214}, pmid = {38428228}, issn = {1873-4200}, mesh = {Humans ; *Amyloid/chemistry ; Muramidase/chemistry ; Molecular Docking Simulation ; *Amyloidosis/drug therapy/metabolism ; Dynamic Light Scattering ; Protein Aggregates ; }, abstract = {In the recent past, there has been an ever-increasing interest in the search for metal-based therapeutic drug candidates for protein misfolding disorders (PMDs) particularly neurodegenerative disorders such as Alzheimer's, Parkinson's, Prion's diseases, and amyotrophic lateral sclerosis. Also, different amyloidogenic variants of human lysozyme (HL) are involved in hereditary systemic amyloidosis. Metallo-therapeutic agents are extensively studied as antitumor agents, however, they are relatively unexplored for the treatment of non-neuropathic amyloidoses. In this work, inhibition potential of a novel ionic cobalt(II) therapeutic agent (CoTA) of the formulation [Co(phen)(H2O)4][+][glycinate][-] is evaluated against HL fibrillation. Various biophysical techniques viz., dye-binding assays, dynamic light scattering (DLS), differential scanning calorimetry (DSC), electron microscopy, and molecular docking experiments validate the proposed mechanism of inhibition of HL fibrillation by CoTA. The experimental corroborative results of these studies reveal that CoTA can suppress and slow down HL fibrillation at physiological temperature and pH. DLS and 1-anilino-8-naphthalenesulfonate (ANS) assay show that reduced fibrillation in the presence of CoTA is marked by a significant decrease in the size and hydrophobicity of the aggregates. Fluorescence quenching and molecular docking results demonstrate that CoTA binds moderately to the aggregation-prone region of HL (Kb = 6.6 × 10[4] M[-1]), thereby, inhibiting HL fibrillation. In addition, far-UV CD and DSC show that binding of CoTA to HL does not cause any change in the stability of HL. More importantly, CoTA attenuates membrane damaging effects of HL aggregates against RBCs. This study identifies inorganic metal complexes as a therapeutic intervention for systemic amyloidosis.}, } @article {pmid38428126, year = {2024}, author = {Wahbeh, F and Restifo, D and Laws, S and Pawar, A and Parikh, NS}, title = {Impact of tobacco smoking on disease-specific outcomes in common neurological disorders: A scoping review.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {122}, number = {}, pages = {10-18}, pmid = {38428126}, issn = {1532-2653}, support = {K23 AG073524/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Smoking Cessation ; Smoking/adverse effects/epidemiology ; Tobacco Smoking ; *Stroke/epidemiology/etiology/therapy ; *Multiple Sclerosis ; }, abstract = {Although the association of smoking with the risk of incident neurological disorders is well established, less is known about the impact of smoking and smoking cessation on outcomes of these conditions. The objective of this scoping review was to synthesize what is known about the impact of smoking and smoking cessation on disease-specific outcomes for seven common neurological disorders. We included 67 studies on the association of smoking and smoking cessation on disease-specific outcomes. For multiple sclerosis, smoking was associated with greater clinical and radiological disease progression, relapses, risk for disease-related death, cognitive decline, and mood symptoms, in addition to reduced treatment effectiveness. For stroke and transient ischemic attack, smoking was associated with greater rates of stroke recurrence, post-stroke cardiovascular outcomes, post-stroke mortality, post-stroke cognitive impairment, and functional impairment. In patients with cognitive impairment and dementia, smoking was associated with faster cognitive decline, and smoking was also associated with greater cognitive decline in Parkinson's disease, but not motor symptom worsening. Patients with amyotrophic lateral sclerosis who smoked faced increased mortality. Last, in patients with cluster headache, smoking was associated with more frequent and longer cluster attack periods. Conversely, for multiple sclerosis and stroke, smoking cessation was associated with improved disease-specific outcomes. In summary, whereas smoking is detrimentally associated with disease-specific outcomes in common neurological conditions, there is growing evidence that smoking cessation may improve outcomes. Effective smoking cessation interventions should be leveraged in the management of common neurological disorders to improve patient outcomes.}, } @article {pmid38427990, year = {2024}, author = {El-Hajj, VG and Daller, C and Fletcher-Sandersjöö, A and Gharios, M and Bydon, M and Söderman, M and Jabbour, P and Edström, E and Elmi-Terander, A and Arnberg, F}, title = {The negative impact of treatment delays on the long-term neurological outcomes of spinal dural arteriovenous fistulas: a longitudinal cohort study.}, journal = {Neurosurgical focus}, volume = {56}, number = {3}, pages = {E14}, doi = {10.3171/2023.12.FOCUS23703}, pmid = {38427990}, issn = {1092-0684}, mesh = {Humans ; Male ; Aged ; Female ; Cohort Studies ; Longitudinal Studies ; Retrospective Studies ; *Treatment Delay ; *Central Nervous System Vascular Malformations/complications/surgery ; }, abstract = {OBJECTIVE: Dural arteriovenous fistulas are rare vascular malformations that affect the brain and spinal cord. Spinal dural arteriovenous fistulas (sdAVFs) are the most frequently encountered vascular malformation affecting the spinal cord. The object of this study was to evaluate the impact of treatment delays on the long-term neurological outcomes of either open surgical or interventional treatment of sdAVFs.

METHODS: In this retrospective, population-based cohort study, the authors examined consecutive patients with diagnosed sdAVFs at a tertiary care center between 2005 and 2020. Patients were assessed using the Aminoff-Logue disability scale (ALS) at various time points including symptom onset, primary care visit, first specialist outpatient visit, as well as both short and long-term follow-ups. The postoperative long-term ALS gait and bladder grades constituted the primary outcomes of the study.

RESULTS: Among the 34 patients included in the study, the median age was 65 years, and there was a male predominance (71%). Most lesions were in the lumbar region (47%). Significant worsening in ALS gait and bladder grades was observed preoperatively, followed by postoperative improvements (p < 0.05). There was no difference in outcomes between surgical and endovascular treatments. Older age (OR 1.10, 95% CI 1.03-1.17, p = 0.007), worse preoperative ALS gait grades (OR 5.12, 95% CI 2.18-12.4, p < 0.001), and longer time from first specialist outpatient visit to first treatment (OR 1.00, 95% CI 1.00-1.01, p = 0.040) were independently associated with worse long-term gait outcomes. Only the preoperative ALS bladder score was a predictor of worse long-term bladder function (OR 92.7, 95% CI 28.0-306.7, p < 0.001).

CONCLUSIONS: Both surgical and endovascular treatments for sdAVFs led to significant neurological improvements. However, treatment delays were associated with less favorable long-term outcomes. Prompt diagnosis and early intervention prior to symptom progression may enhance recovery and help to preserve neurological function.}, } @article {pmid38427252, year = {2024}, author = {Rajaratnam, S and Pradhan, SS and Naik, AA and Sivaramakrishnan, V}, title = {Integrated Multi-Omics Analysis and Validation in Yeast Model of Amyotrophic Lateral Sclerosis.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2761}, number = {}, pages = {397-419}, pmid = {38427252}, issn = {1940-6029}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Saccharomyces cerevisiae/genetics ; Multiomics ; Software ; Gene Expression Profiling ; }, abstract = {Transcriptomics is a complex process that involves raw data extraction, normalization, differential gene expression, and analysis. The Gene Expression Omnibus (GEO) database at the National Center for Biotechnology Information (NCBI) is a repository of experimental datasets. Amyotrophic lateral sclerosis (ALS) datasets are deposited by various scientists and research investigators to expand the horizon of scientific knowledge. R-statistical tools are the most common ways for conducting these kinds of studies. The first step is the identification of appropriate datasets. Since the raw data is available in a variety of formats, a large array of software is used for extraction and analysis. Normalization is conducted for the datasets using NetworkAnalyst. Differential analysis is further conducted on the normalized data to identify significantly enriched genes. The significant genes are then grouped into pathways. The results were validated using yeast model of ALS in which the yeast is transformed with ALS plasmids encoding genes associated with ALS. The resulting GFP-tagged protein aggregates are imaged using fluorescence microscopy and subsequently validated using filter retardation assay and quantified using ImageJ software. Functional role of different genes is studied using metabolite treatment and knockout studies.}, } @article {pmid38427251, year = {2024}, author = {Niccolai, E and Martinelli, I and Quaranta, G and Nannini, G and Zucchi, E and De Maio, F and Gianferrari, G and Bibbò, S and Cammarota, G and Mandrioli, J and Masucci, L and Amedei, A}, title = {Fecal Microbiota Transplantation in Amyotrophic Lateral Sclerosis: Clinical Protocol and Evaluation of Microbiota Immunity Axis.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2761}, number = {}, pages = {373-396}, pmid = {38427251}, issn = {1940-6029}, mesh = {Humans ; Fecal Microbiota Transplantation ; *Amyotrophic Lateral Sclerosis/therapy ; *Microbiota ; *Gastrointestinal Microbiome/physiology ; Clinical Protocols ; Multicenter Studies as Topic ; Randomized Controlled Trials as Topic ; }, abstract = {The fecal microbial transplantation (FMT) is a therapeutic transplant of fecal microbiota from healthy donors to patients. This practice is aimed at restoring eubiosis and rebalancing the enteric and systemic immune responses, and then eliminating pathogenic triggers of multiple disease, including neurodegenerative diseases. Alterations of gut microbiota (GM) affect the central nervous system (CNS) health, impacting neuro-immune interactions, synaptic plasticity, myelination, and skeletal muscle function. T-regulatory lymphocytes (Treg) are among the most important players in the pathogenesis of amyotrophic lateral sclerosis (ALS), altering the disease course. Along with circulating neuropeptides, other immune cells, and the gut-brain axis, the GM influences immunological tolerance and controls Treg's number and suppressive functions. A double-blind, controlled, multicenter study on FMT in ALS patients has been designed to evaluate if FMT can modulate neuroinflammation, by restoring Treg number, thus modifying disease activity and progression.}, } @article {pmid38427163, year = {2024}, author = {Cioffi, E and Gioiosa, V and Tessa, A and Petrucci, A and Trovato, R and Santorelli, FM and Casali, C}, title = {Hereditary spastic paraparesis type 18 (SPG18): new ERLIN2 variants in a series of Italian patients, shedding light upon genetic and phenotypic variability.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {8}, pages = {3845-3852}, pmid = {38427163}, issn = {1590-3478}, mesh = {Humans ; Italy ; Male ; Female ; *Phenotype ; Adult ; *Membrane Proteins/genetics ; Middle Aged ; Mutation ; Spastic Paraplegia, Hereditary/genetics ; }, abstract = {INTRODUCTION: Hereditary spastic paraparesis (HSP) is a group of central nervous system diseases primarily affecting the spinal upper motor neurons, with different inheritance patterns and phenotypes. SPG18 is a rare, early-onset, complicated HSP, first reported as linked to biallelic ERLIN2 mutations. Recent cases of late-onset, pure HSP with monoallelic ERLIN2 variants prompt inquiries into the zygosity of such genetic conditions. The observed relationship between phenotype and mode of inheritance suggests a potential dominant negative effect of mutated ERLIN2 protein, potentially resulting in a milder phenotype. This speculation suggests that a wider range of HSP genes could be linked to various inheritance patterns.

PURPOSE AND BACKGROUND: With documented cases of HSP loci exhibiting both dominant and recessive patterns, this study emphasizes that the concept of zygosity is no longer a limiting factor in the establishment of molecular diagnoses for HSP. Recent cases have demonstrated phenoconversion in SPG18, from HSP to an amyotrophic lateral sclerosis (ALS)-like syndrome.

METHODS AND RESULTS: This report highlights two cases out of five exhibiting HSP-ALS phenoconversion, discussing an observed prevalence in autosomal dominant SPG18. Additionally, the study emphasizes the relatively high incidence of the c.502G>A variant in monoallelic SPG18 cases. This mutation appears to be particularly common in cases of HSPALS phenoconversion, indicating its potential role as a hotspot for a distinctive SPG18 phenotype with an ALS-like syndrome.

CONCLUSIONS: Clinicians need to be aware that patients with HSP may show ALS signs and symptoms. On the other hand, HSP panels must be included in genetic testing methods for instances of familial ALS.}, } @article {pmid38426720, year = {2024}, author = {Pei, Y and Liu, S and Wang, L and Chen, C and Hu, M and Xue, Y and Guan, D and Xie, L and Liao, H and Zhou, J and Zhang, H}, title = {Design, Synthesis, and Biological Evaluation of Eukaryotic Initiation Factor 2B (eIF2B) Activators.}, journal = {ChemMedChem}, volume = {19}, number = {11}, pages = {e202300716}, doi = {10.1002/cmdc.202300716}, pmid = {38426720}, issn = {1860-7187}, support = {LG202103-02-08//Lingang Laboratory/ ; }, mesh = {Humans ; *Activating Transcription Factor 4/metabolism ; *Drug Design ; HeLa Cells ; Structure-Activity Relationship ; *Eukaryotic Initiation Factor-2B/metabolism/antagonists & inhibitors ; Molecular Structure ; Dose-Response Relationship, Drug ; Oxadiazoles/pharmacology/chemistry/chemical synthesis ; }, abstract = {The eukaryotic initiation factor 2B (eIF2B) is a key regulator in protein-regulated signaling pathways and is closely related to the function of the central nervous system. Modulating eIF2B could retard the process of neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and vanishing white matter disease (VWM) et al. Here, we designed and synthesized a series of novel eIF2B activators containing oxadiazole fragments. The activating effects of compounds on eIF2B were investigated through testing the inhibition of ATF4 expression. Of all the targeted compounds, compounds 21 and 29 exhibited potent inhibition on ATF4 expression with IC50 values of 32.43 nM and 47.71 nM, respectively, which were stronger than that of ISRIB (IC50=67.90 nM). ATF4 mRNA assay showed that these two compounds could restore ATF4 mRNA to normal levels in thapsigargin-stimulated HeLa cells. Protein Translation assay showed that both compounds were effective in restoring protein synthesis. Compound potency assay showed that both compounds had similar potency to ISRIB with EC50 values of 5.844 and 37.70 nM. Cytotoxicity assay revealed that compounds 21 and 29 had low toxicity and were worth further investigation.}, } @article {pmid38426489, year = {2024}, author = {Rotem, RS and Bellavia, A and Paganoni, S and Weisskopf, MG}, title = {Medication use and risk of amyotrophic lateral sclerosis: using machine learning for an exposome-wide screen of a large clinical database.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {367-375}, pmid = {38426489}, issn = {2167-9223}, support = {P30 ES000002/ES/NIEHS NIH HHS/United States ; R21 NS099910/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/etiology ; *Exposome ; Bayes Theorem ; Machine Learning ; Vitamin E ; }, abstract = {BACKGROUND: Accumulating evidence suggests that non-genetic factors have important etiologic roles in amyotrophic lateral sclerosis (ALS), yet identification of specific culprit factors has been challenging. Many medications target biological pathways implicated in ALS pathogenesis, and screening large pharmacologic datasets for signals could greatly accelerate the identification of risk-modulating pharmacologic factors for ALS.

METHOD: We conducted a high-dimensional screening of patients' history of medication use and ALS risk using an advanced machine learning approach based on gradient-boosted decision trees coupled with Bayesian model optimization and repeated data sampling. Clinical and medication dispensing data were obtained from a large Israeli health fund for 501 ALS cases and 4,998 matched controls using a lag period of 3 or 5 years prior to ALS diagnosis for ascertaining medication exposure.

RESULTS: Of over 1,000 different medication classes, we identified 8 classes that were consistently associated with increased ALS risk across independently trained models, where most are indicated for control of symptoms implicated in ALS. Some suggestive protective effects were also observed, notably for vitamin E.

DISCUSSION: Our results indicate that use of certain medications well before the typically recognized prodromal period was associated with ALS risk. This could result because these medications increase ALS risk or could indicate that ALS symptoms can manifest well before suggested prodromal periods. The results also provide further evidence that vitamin E may be a protective factor for ALS. Targeted studies should be performed to elucidate the possible pathophysiological mechanisms while providing insights for therapeutics design.}, } @article {pmid38426231, year = {2024}, author = {Young, CA and Chaouch, A and Mcdermott, CJ and Al-Chalabi, A and Chhetri, SK and Talbot, K and Malaspina, A and Mills, R and Tennant, A}, title = {Improving the measurement properties of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R): deriving a valid measurement total for the calculation of change.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {400-409}, pmid = {38426231}, issn = {2167-9223}, support = {MALASPINA/APR13/817-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Factor Analysis, Statistical ; Disease Progression ; }, abstract = {BACKGROUND: The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score is a widely used measure of functional status in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS), but recent evidence has raised doubts about its validity. The objective was to examine the measurement properties of the ALSFRS-R, aiming to produce valid measurement from all 12 scale items.

METHOD: Longitudinal ALSFRS-R data were collected between 2013-2020 from 1120 people with ALS recruited from 35 centers, together with other scales in the Trajectories of Outcomes in Neurological Conditions-ALS (TONiC-ALS) study. The ALSFRS-R was analyzed by confirmatory factor analysis (CFA), Rasch Analysis (RA) and Mokken scaling.

RESULTS: No definite factor structure of the ALSFRS-R was confirmed by CFA. RA revealed the raw score total to be invalid even at the ordinal level because of multidimensionality; valid interval level subscale measures could be found for the Bulbar, Fine-Motor and Gross-Motor domains but the Respiratory domain was only valid at an ordinal level. All four domains resolved into a single valid, interval level measure by using a bifactor RA. The smallest detectable difference was 10.4% of the range of the interval scale.

CONCLUSION: A total ALSFRS-R ordinal raw score can lead to inferential bias in clinical trial results due to its non-linear nature. On the interval level transformation, more than 5 points difference is required before a statistically significant detectable difference can be observed. Transformation to interval level data should be mandatory in clinical trials.}, } @article {pmid38424324, year = {2024}, author = {Milioto, C and Carcolé, M and Giblin, A and Coneys, R and Attrebi, O and Ahmed, M and Harris, SS and Lee, BI and Yang, M and Ellingford, RA and Nirujogi, RS and Biggs, D and Salomonsson, S and Zanovello, M and de Oliveira, P and Katona, E and Glaria, I and Mikheenko, A and Geary, B and Udine, E and Vaizoglu, D and Anoar, S and Jotangiya, K and Crowley, G and Smeeth, DM and Adams, ML and Niccoli, T and Rademakers, R and van Blitterswijk, M and Devoy, A and Hong, S and Partridge, L and Coyne, AN and Fratta, P and Alessi, DR and Davies, B and Busche, MA and Greensmith, L and Fisher, EMC and Isaacs, AM}, title = {PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons.}, journal = {Nature neuroscience}, volume = {27}, number = {4}, pages = {643-655}, pmid = {38424324}, issn = {1546-1726}, support = {MR/V003585/1/MRC_/Medical Research Council/United Kingdom ; G0801110/MRC_/Medical Research Council/United Kingdom ; G0601056/MRC_/Medical Research Council/United Kingdom ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; MC_EX_MR/N501931/1/MRC_/Medical Research Council/United Kingdom ; MR/S017003/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Humans ; Mice ; *Frontotemporal Dementia/pathology ; *Amyotrophic Lateral Sclerosis/metabolism ; Transforming Growth Factor beta1 ; C9orf72 Protein/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; Drosophila ; Extracellular Matrix/metabolism ; Dipeptides/metabolism ; DNA Repeat Expansion/genetics ; }, abstract = {Dipeptide repeat proteins are a major pathogenic feature of C9orf72 amyotrophic lateral sclerosis (C9ALS)/frontotemporal dementia (FTD) pathology, but their physiological impact has yet to be fully determined. Here we generated C9orf72 dipeptide repeat knock-in mouse models characterized by expression of 400 codon-optimized polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice recapitulate key features of C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. TGF-β1 was one of the top predicted regulators of this ECM signature and polyGR expression in human induced pluripotent stem cell neurons was sufficient to induce TGF-β1 followed by COL6A1. Knockdown of TGF-β1 or COL6A1 orthologues in polyGR model Drosophila exacerbated neurodegeneration, while expression of TGF-β1 or COL6A1 in induced pluripotent stem cell-derived motor neurons of patients with C9ALS/FTD protected against glutamate-induced cell death. Altogether, our findings reveal a neuroprotective and conserved ECM signature in C9ALS/FTD.}, } @article {pmid38424114, year = {2024}, author = {Bridges, LR}, title = {RNA as a component of scrapie fibrils.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {5011}, pmid = {38424114}, issn = {2045-2322}, support = {P41 GM103311/GM/NIGMS NIH HHS/United States ; R01 GM129325/GM/NIGMS NIH HHS/United States ; }, mesh = {Cricetinae ; Animals ; Sheep ; Humans ; *Scrapie ; RNA ; Cytoskeleton ; *Alzheimer Disease ; Microscopy, Electron ; Cryoelectron Microscopy ; Amyloid/chemistry ; }, abstract = {Recently, electron cryo-microscopy (cryo-EM) maps of fibrils from the brains of mice and hamsters with five infectious scrapie strains have been published and deposited in the electron microscopy data bank (EMDB). As noted by the primary authors, the fibrils contain a second component other than protein. The aim of the present study was to identify the nature of this second component in the published maps using an in silico approach. Extra densities (EDs) containing this component were continuous, straight, axial, at right angles to protein rungs and within hydrogen-bonding distance of protein, consistent with a structural role. EDs co-located with strips of basic residues, notably lysines, and formed a conspicuous cladding over parts of the N-terminal lobe of the protein. A Y-shaped polymer consistent with RNA was found, in places forming a single chain and at one location forming a duplex, comprising two antiparallel chains, and raising the intriguing possibility of replicative behaviour. To reflect the monotonous nature of the protein interface, it is suggested that the RNA may be a short tandem repeat. Fibrils from brains of patients with Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other neurodegenerations also contain EDs and may be of a similar aetiology.}, } @article {pmid38421827, year = {2024}, author = {Zhang, Y and Li, Y and Bin, S and Cheng, X and Niu, Q}, title = {A Neglected Gene: The Role of the ANG Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {16}, number = {1}, pages = {13-32}, pmid = {38421827}, issn = {2152-5250}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with a poor prognosis. To date, more than 40 ALS-related genes have been identified. However, there is still a lack of targeted therapeutic drugs for the treatment of ALS, especially for patients with acute onset and severe disease. A series of studies reported missense heterozygous mutations with loss of function in the coding region of the ANG gene in ALS patients. ANG deficiency is related to the pathogenesis of ALS, but the underlying mechanism has not been determined. This article aimed to synthesize and consolidate the knowledge of the pathological mechanism of ALS induced by ANG mutation and provide a theoretical basis for ALS diagnosis and targeted therapy. This article further delves into the mechanisms underlying the current understanding of the structure and function of the ANG gene, the association between ANG and ALS, and its pathogenesis. Mutations in ANG may lead to the development of ALS through the loss of neuroprotective function, induction of oxidative stress, or inhibition of rRNA synthesis. ANG mutations and genetic and environmental factors may cause disease heterogeneity and more severe disease than in ALS patients with the wild-type gene. Exploring this mechanism is expected to provide a new approach for ALS treatment through increasing ANG expression or angiogenin activity. However, the related study is still in its infancy; therefore, this article also highlights the need for further exploration of the application of ANG gene mutations in clinical trials and animal experiments is needed to achieve improved early diagnosis and treatment of ALS.}, } @article {pmid38421467, year = {2024}, author = {Zhong, X and Li, C and Li, Y and Huang, Y and Liu, J and Jiang, A and Chen, J and Peng, Y}, title = {IRAK-M Plays A Role in the Pathology of Amyotrophic Lateral Sclerosis Through Suppressing the Activation of Microglia.}, journal = {Molecular neurobiology}, volume = {61}, number = {10}, pages = {7603-7610}, pmid = {38421467}, issn = {1559-1182}, support = {81901239//National Natural Science Foundation of China/ ; 82171354//National Natural Science Foundation of China/ ; 202201010924//Science and Technology Projects in Guangzhou/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Microglia/metabolism/pathology ; *Interleukin-1 Receptor-Associated Kinases/metabolism/genetics ; *Mice, Transgenic ; *Spinal Cord/pathology/metabolism ; Motor Neurons/pathology/metabolism ; Dependovirus/genetics ; Mice ; RNA, Messenger/metabolism/genetics ; Interleukin-1beta/metabolism ; Disease Models, Animal ; Mice, Inbred C57BL ; Humans ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Microglial activation plays a crucial role in the disease progression in amyotrophic lateral sclerosis (ALS). Interleukin receptor-associated kinases-M (IRAK-M) is an important negative regulatory factor in the Toll-like receptor 4 (TLR4) pathway during microglia activation, and its mechanism in this process is still unclear. In the present study, we aimed to investigate the dynamic changes of IRAK-M and its protective effects for motor neurons in SOD1-G93A mouse model of ALS. qPCR (Real-time Quantitative PCR Detecting System) were used to examine the mRNA levels of IRAK-M in the spinal cord in both SOD1-G93A mice and their age-matched wild type (WT) littermates at 60, 100 and 140 days of age. We established an adeno-associated virus 9 (AAV9)-based platform by which IRAK-M was targeted mostly to microglial cells to investigate whether this approach could provide a protection in the SOD1-G93A mouse. Compared with age-matched WT mice, IRAK-M mRNA level was elevated at 100 and 140 days in the anterior horn region of spinal cords in the SOD1-G93A mouse. AAV9-IRAK-M treated SOD1-G93A mice showed reduction of IL-1β mRNA levels and significant improvements in the numbers of spinal motor neurons in spinal cord. Mice also showed previously reduction of muscle atrophy. Our data revealed the dynamic changes of IRAK-M during ALS pathological progression and demonstrated that an AAV9-IRAK-M delivery was an effective and translatable therapeutic approach for ALS. These findings may help identify potential molecular targets for ALS therapy.}, } @article {pmid38418587, year = {2024}, author = {Thiry, L and Sirois, J and Durcan, TM and Stifani, S}, title = {Generation of human iPSC-derived phrenic-like motor neurons to model respiratory motor neuron degeneration in ALS.}, journal = {Communications biology}, volume = {7}, number = {1}, pages = {238}, pmid = {38418587}, issn = {2399-3642}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/physiology ; Diaphragm ; *Respiration Disorders/metabolism ; Nerve Degeneration ; }, abstract = {The fatal motor neuron (MN) disease Amyotrophic Lateral Sclerosis (ALS) is characterized by progressive MN degeneration. Phrenic MNs (phMNs) controlling the activity of the diaphragm are prone to degeneration in ALS, leading to death by respiratory failure. Understanding of the mechanisms of phMN degeneration in ALS is limited, mainly because human experimental models to study phMNs are lacking. Here we describe a method enabling the derivation of phrenic-like MNs from human iPSCs (hiPSC-phMNs) within 30 days. This protocol uses an optimized combination of small molecules followed by cell-sorting based on a cell-surface protein enriched in hiPSC-phMNs, and is highly reproducible using several hiPSC lines. We show further that hiPSC-phMNs harbouring ALS-associated amplification of the C9orf72 gene progressively lose their electrophysiological activity and undergo increased death compared to isogenic controls. These studies establish a previously unavailable protocol to generate human phMNs offering a disease-relevant system to study mechanisms of respiratory MN dysfunction.}, } @article {pmid38418571, year = {2024}, author = {Kumar, S and Bhowmik, R and Oh, JM and Abdelgawad, MA and Ghoneim, MM and Al-Serwi, RH and Kim, H and Mathew, B}, title = {Machine learning driven web-based app platform for the discovery of monoamine oxidase B inhibitors.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {4868}, pmid = {38418571}, issn = {2045-2322}, mesh = {Humans ; Molecular Docking Simulation ; *Mobile Applications ; Monoamine Oxidase/metabolism ; Monoamine Oxidase Inhibitors/chemistry ; *Neurodegenerative Diseases/drug therapy ; Dopamine Agents/pharmacology ; Internet ; Structure-Activity Relationship ; }, abstract = {Monoamine oxidases (MAOs), specifically MAO-A and MAO-B, play important roles in the breakdown of monoamine neurotransmitters. Therefore, MAO inhibitors are crucial for treating various neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). In this study, we developed a novel cheminformatics pipeline by generating three diverse molecular feature-based machine learning-assisted quantitative structural activity relationship (ML-QSAR) models concerning MAO-B inhibition. PubChem fingerprints, substructure fingerprints, and one-dimensional (1D) and two-dimensional (2D) molecular descriptors were implemented to unravel the structural insights responsible for decoding the origin of MAO-B inhibition in 249 non-reductant molecules. Based on a random forest ML algorithm, the final PubChem fingerprint, substructure fingerprint, and 1D and 2D molecular descriptor prediction models demonstrated significant robustness, with correlation coefficients of 0.9863, 0.9796, and 0.9852, respectively. The significant features of each predictive model responsible for MAO-B inhibition were extracted using a comprehensive variance importance plot (VIP) and correlation matrix analysis. The final predictive models were further developed as a web application, MAO-B-pred (https://mao-b-pred.streamlit.app/), to allow users to predict the bioactivity of molecules against MAO-B. Molecular docking and dynamics studies were conducted to gain insight into the atomic-level molecular interactions between the ligand-receptor complexes. These findings were compared with the structural features obtained from the ML-QSAR models, which supported the mechanistic understanding of the binding phenomena. The presented models have the potential to serve as tools for identifying crucial molecular characteristics for the rational design of MAO-B target inhibitors, which may be used to develop effective drugs for neurodegenerative disorders.}, } @article {pmid38418214, year = {2024}, author = {Otani, R and Shibuya, K and Suzuki, YI and Suichi, T and Morooka, M and Aotsuka, Y and Ogushi, M and Kuwabara, S}, title = {Effects of motor cortical and peripheral axonal hyperexcitability on survival in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {8}, pages = {730-736}, doi = {10.1136/jnnp-2023-333039}, pmid = {38418214}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality ; Male ; Female ; Middle Aged ; *Motor Cortex/physiopathology ; *Transcranial Magnetic Stimulation ; *Axons/physiology ; Aged ; Motor Neurons/physiology ; Evoked Potentials, Motor/physiology ; Adult ; Prognosis ; }, abstract = {BACKGROUND: Increased 'cortical' and 'peripheral' excitability are reportedly associated with shorter survival in amyotrophic lateral sclerosis (ALS) patients, suggesting that hyperexcitability contributes to motor neuron death. However, whether upper or lower motor function has a greater impact on survival is unclear. We aimed to investigate the component that strongly impacts the prognosis of ALS.

METHODS: A total of 103 consecutive patients with ALS who underwent cortical (threshold tracking transcranial magnetic stimulation (TMS)) and motor nerve excitability tests were included. Motor cortical excitability was evaluated using short-interval intracortical inhibition (SICI) during TMS. Motor axonal excitability was assessed using the strength-duration time constant (SDTC). Survival time was defined as the time from examination to death or tracheostomy.

RESULTS: Compared with healthy subjects, patients with ALS had lower SICI and longer SDTC (p<0.05), indicating increased excitability of cortical motor neurons and motor axons. According to the SICI and SDTC findings, patients were divided into the following four groups: 'cortical high and peripheral high (high-high)', 'high-low', 'low-high' and 'low-low' groups. In Kaplan-Meier curves, the 'high-high' and 'low-high' groups showed significantly shorter survival than the other groups. Multivariate analysis revealed that increased cortical (HR=5.3, p<0.05) and peripheral (HR=20.0, p<0.001) excitability were significantly associated with shorter survival.

CONCLUSIONS: In patients with ALS, both motor cortical and peripheral hyperexcitability independently affected survival time, with peripheral hyperexcitability having a greater impact on shorter survival. The modulation of neuronal/axonal excitability is a potential therapeutic target for ALS.}, } @article {pmid38417517, year = {2024}, author = {Li, M and Qiu, J and Yan, G and Zheng, X and Li, A}, title = {How does the neurotoxin β-N-methylamino-L-alanine exist in biological matrices and cause toxicity?.}, journal = {The Science of the total environment}, volume = {922}, number = {}, pages = {171255}, doi = {10.1016/j.scitotenv.2024.171255}, pmid = {38417517}, issn = {1879-1026}, mesh = {Animals ; Humans ; *Neurotoxins/chemistry ; *Amino Acids, Diamino/toxicity/chemistry ; Cyanobacteria Toxins ; Oxidative Stress ; }, abstract = {The neurotoxin β-N-methylamino-L-alanine (BMAA) has been deemed as a risk factor for some neurodegenerative diseases such as amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC). This possible link has been proved in some primate models and cell cultures with the appearance that BMAA exposure can cause excitotoxicity, formation of protein aggregates, and/or oxidative stress. The neurotoxin BMAA extensively exists in the environment and can be transferred through the food web to human beings. In this review, the occurrence, toxicological mechanisms, and characteristics of BMAA were comprehensively summarized, and proteins and peptides were speculated as its possible binding substances in biological matrices. It is difficult to compare the published data from previous studies due to the inconsistent analytical methods and components of BMAA. The binding characteristics of BMAA should be focused on to improve our understanding of its health risk to human health in the future.}, } @article {pmid38417402, year = {2024}, author = {Hu, N and Soh, KL and Japar, S and Li, T}, title = {Ear-Marking Relief: A Meta-Analysis on the Efficacy of Auricular Acupressure in Alleviating Anxiety Disorders.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {266-277}, doi = {10.1159/000537734}, pmid = {38417402}, issn = {2504-2106}, mesh = {Humans ; *Acupressure ; *Anxiety Disorders/therapy ; Randomized Controlled Trials as Topic ; Auriculotherapy/methods ; }, abstract = {BACKGROUND: The increasing worldwide mental health crisis, notably anxiety, emphasizes the urgency for available and effective interventions. Traditional therapies, although beneficial, pose limitations due to their considerable costs and possible adverse effects, thereby inviting alternative treatments such as auricular acupressure (AA). This non-pharmacological, integrative method, underpinned by Eastern and Western medical principles, presents a significant prospect for managing anxiety.

OBJECTIVE: This study aims to evaluate the existing evidence on the efficacy of AA in reducing anxiety, as elucidated through a systematic review.

METHODS: A comprehensive search of randomized controlled trials was conducted across various databases: the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Web of Science, Chinese National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), Wan Fang, and Database for Chinese Technical Periodicals (VIP). Two reviewers retrieved the pertinent studies and assessed their methodological quality. A meta-analysis was then conducted, incorporating data from all relevant time points.

RESULTS: Upon examining 25 studies encompassing 1,909 participants, it was discerned that AA significantly diminished anxiety (SMD = -1.1074; 95% confidence interval, -1.348 to -0.801; z = 7.70, p < 0.01). Subgroup analyses indicated that neither an increased number of auricular points nor extended intervention augmented effects. Larger effect sizes were associated with probing and avoidance of sham acupressure. Notably, 23 of the 25 studies exhibited some bias, suggesting further research is necessary.

CONCLUSIONS: The extant evidence advocates for AA as an effective supplementary intervention that reduces patient anxiety. The results hint at a potential placebo effect elicited by sham acupressure, necessitating rigorous control group definitions in future inquiries. The study findings suggest that fewer acupressure points and shorter intervention durations could effectively alleviate anxiety symptoms. Nonetheless, the significant heterogeneity across the studies underscores the requirement for more stringent research methodologies to substantiate these conclusions.

UNLABELLED: HintergrundDie weltweit zunehmende Krise der psychischen Gesundheit, vor allem von Angstzuständen, zeigt, dass dringend verfügbare und wirksame Interventionen erforderlich sind. Herkömmliche Therapien sind zwar hilfreich, werden aber durch ihre hohen Kosten und möglichen unerwünschten Wirkungen eingeschränkt, so dass alternative Behandlungen wie die Ohrakupressur gefragt sind. Diese nicht-pharmakologische, integrative Methode, die sich auf östliche und westliche medizinische Prinzipien stützt, stellt eine bedeutsame Perspektive für die Behandlung von Angstzuständen dar.ZielZiel dieser Studie ist es, die vorhandenen Evidenzen für die Wirksamkeit der Ohrakupressur (auricular acupressure, AA) zur Verringerung von Angstzuständen, die in einer systematischen Übersichtsarbeit ermittelt wurden, zu bewerten.MethodenEs wurde eine umfassende Suche nach randomisierten kontrollierten Studien in verschiedenen Datenbanken durchgeführt: Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Web of Science, Chinese National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), Wan Fang und Database for Chinese Technical Periodicals (VIP). Zwei Gutachter suchten die einschlägigen Studien heraus und bewerteten ihre methodische Qualität. Anschliessend erfolgte eine Metaanalyse, bei der Daten aller relevanten Zeitpunkte berücksichtigt wurden.Ergebnisse:Die Untersuchung von 25 Studien mit 1’909 Teilnehmern ergab, dass die Ohrakupressur (AA) Angstzustände signifikant verringerte (SMD = −1,1074; 95%-KI: −1,348 bis −0,801; z = 7,70, p < 0,01). Subgruppenanalysen zeigten, dass die Effekte weder durch eine höhere Anzahl von Ohrpunkten noch durch eine längere Intervention verstärkt wurden. Grössere Effektstärken waren mit Sondenverwendung und Vermeidung von Scheinakupressur assoziiert. Hervorzuheben ist, dass 23 der 25 Studien eine gewisse Verzerrung aufwiesen, weshalb weitere Untersuchungen erforderlich sind.SchlussfolgerungenDie vorhandene Evidenzlage stützt die Ohrakupressur (AA) als wirksame unterstützende Intervention, die die Angst der Patienten verringert. Die Ergebnisse deuten auf einen potenziellen Placeboeffekt durch Scheinakupressur hin, so dass in künftigen Untersuchungen strenge Kontrollgruppendefinitionen erforderlich sind. Die Studienergebnisse sprechen dafür, dass eine geringere Anzahl von Akupressurpunkten und kürzere Interventionszeiten die Angstsymptome wirksam lindern können. Die starke Heterogenität der Studien zeigt allerdings, dass strengere wissenschaftliche Methoden erforderlich sind, um diese Schlussfolgerungen zu untermauern.}, } @article {pmid38416402, year = {2024}, author = {Wolff, AW and Peine, J and Höfler, J and Zurek, G and Hemker, C and Lingor, P}, title = {SAFE-ROCK: A Phase I Trial of an Oral Application of the ROCK Inhibitor Fasudil to Assess Bioavailability, Safety, and Tolerability in Healthy Participants.}, journal = {CNS drugs}, volume = {38}, number = {4}, pages = {291-302}, pmid = {38416402}, issn = {1179-1934}, support = {2017_T05//Else Kröner-Fresenius-Stiftung/ForTra GmbH/ ; }, mesh = {Male ; Humans ; Female ; *rho-Associated Kinases ; Biological Availability ; Healthy Volunteers ; *Protein Kinase Inhibitors/adverse effects ; Chronic Disease ; Administration, Oral ; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/*analogs & derivatives ; }, abstract = {BACKGROUND: The intravenous (IV) formulation of Rho-kinase (ROCK) inhibitor fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995. Additionally, fasudil has shown promising preclinical results for various chronic diseases, including neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and dementia, in which long-term intravenous (IV) administration might not be suitable.

OBJECTIVE: The objective of this study was to assess the absolute bioavailability of oral, in comparison to IV, application of the approved formulation of fasudil (ERIL®) and to evaluate the safety and tolerability of the oral application of fasudil.

METHODS: This was a phase I, single-center, open-label, randomized, two period cross-over clinical trial in healthy women and men. By applying a cross-over design, each subject served as their own control. Two treatments were investigated, separated by a wash out phase of at least 3 days. Oral fasudil was administered once on day 1 to assess pharmacokinetics and three times on day 2, at an interval of 8 ± 1 h, to assess safety and gastrointestinal tolerability. For pharmacometrics of IV fasudil, it was administered once on day 1. Plasma profiles of fasudil and its active metabolite hydroxyfasudil after oral or IV administration were measured by liquid chromatography electrospray tandem mass spectrometry. Tolerability was assessed as proportion of subjects without significant drug intolerance, and safety was assessed by the proportion of subjects without clinical or laboratory treatment-associated serious adverse events. Gastrointestinal safety was assessed by applying the gastrointestinal symptom rating scale (GSRS).

RESULTS: Fourteen subjects aged 30-70 years were included in this trial. After oral administration, fasudil concentrations in blood were mostly very low [1.4 g/L; coefficient of variation (CV) 41.0%]. After IV application, the peak concentration was 100.6 µg/L (CV 74.2%); however, a high variance in peak concentrations were assessed for both treatments. The maximal concentrations of hydroxyfasudil in blood were similar after oral and IV treatment [111.6 µg/L (CV 24.1%) and 108.4 µg/L (CV 19.7%), respectively]. Exposure of hydroxyfasudil (assessed as AUC0-tz) differed between both treatments, with 449 µg × h/L after IV treatment and 309 µg × h/L after oral treatment. Therefore, the absolute bioavailability of hydroxyfasudil after the oral treatment was approximately 69% of the IV treatment. No serious adverse events (SAEs) occurred during this trial, and good tolerability of oral fasudil (90 mg/day) was documented.

CONCLUSIONS: Oral fasudil was generally well tolerated in the studied population, and no safety concerns were identified. However, systemic bioavailability of oral hydroxyfasudil corresponded to 69%, and dose adjustments need to considered. The results presented here lay grounds for future trials of fasudil in chronic diseases, which require an oral long-term application. This trial was registered with EudraCT (no. 2019-001805-26).}, } @article {pmid38415696, year = {2024}, author = {Didcote, L and Vitoratou, S and Al-Chalabi, A and Goldstein, LH}, title = {What is the extent of reliability and validity evidence for screening tools for cognitive and behavioral change in people with ALS? A systematic review.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {437-451}, pmid = {38415696}, issn = {2167-9223}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis/complications ; Reproducibility of Results ; Neuropsychological Tests/standards ; Cognitive Dysfunction/diagnosis/etiology ; }, abstract = {OBJECTIVE: This systematic review provides an updated summary of the existing literature on the validity of screening tools for cognitive and behavioral impairment in people with Amyotrophic Lateral Sclerosis (pwALS), and also focuses on their reliability.

METHOD: The following cognitive and behavioral screening tools were assessed in this review: the Edinburgh Cognitive and Behavioral ALS Screen (ECAS); the ALS Cognitive Behavioral Screen (ALS-CBS), the Mini Addenbrooke's Cognitive Examination (Mini-ACE), the Beaumont Behavioral Interview (BBI); the MND Behavior Scale (MiND-B); and the ALS-FTD Questionnaire (ALS-FTD-Q). A search, using Medline, PsychINFO and Embase (21/09/2023), generated 37 results after exclusion criteria were applied. Evidence of internal consistency, item-total correlations, inter-rater reliability, clinical validity, convergent validity, and structural validity were extracted and assessed and risk of bias was evaluated.

RESULTS: The cognitive component of the ECAS was the tool with most evidence of reliability and validity for the assessment of cognitive impairment in ALS. It is well-suited to accommodate physical symptoms of ALS. For behavioral assessment, the BBI or ALS-FTD-Q had the most evidence of reliability and validity. The BBI is more thorough, but the ALS-FTD-Q is briefer.

CONCLUSIONS: There is good but limited evidence for the reliability and validity of cognitive and behavioral screens. Further evidence of clinical and convergent validity would increase confidence in their clinical and research use.}, } @article {pmid38415587, year = {2024}, author = {Koehn, LM and Steele, JR and Schittenhelm, RB and Turner, BJ and Nicolazzo, JA}, title = {Sex-Dependent Changes to the Intestinal and Hepatic Abundance of Drug Transporters and Metabolizing Enzymes in the SOD1[G93A] Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Molecular pharmaceutics}, volume = {21}, number = {4}, pages = {1756-1767}, doi = {10.1021/acs.molpharmaceut.3c01089}, pmid = {38415587}, issn = {1543-8392}, mesh = {Animals ; Female ; Humans ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; Disease Models, Animal ; Liver/metabolism ; Mice, Transgenic ; *Organic Anion Transporters/metabolism ; Proteomics ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by death and dysfunction of motor neurons that result in a rapidly progressing loss of motor function. While there are some data on alterations at the blood-brain barrier (BBB) in ALS and their potential impact on CNS trafficking of drugs, little is reported on the impact of this disease on the expression of drug-handling proteins in the small intestine and liver. This may impact the dosing of the many medicines that individuals with ALS are prescribed. In the present study, a proteomic evaluation was performed on small intestine and liver samples from postnatal day 120 SOD1[G93A] mice (a model of familial ALS that harbors a human mutant form of superoxide dismutase 1) and wild-type (WT) littermates (n = 7/genotype/sex). Untargeted, quantitative proteomics was undertaken using either label-based [tandem mass tag (TMT)] or label-free [data-independent acquisition (DIA)] acquisition strategies on high-resolution mass spectrometric instrumentation. Copper chaperone for superoxide dismutase (CCS) was significantly higher in SOD1[G93A] samples compared to the WT samples for both sexes and tissues, therefore representing a potential biomarker for ALS in this mouse model. Relative to WT mice, male SOD1[G93A] mice had significantly different proteins (Padj < 0.05, |fold-change|>1.2) in the small intestine (male 22, female 1) and liver (male 140, female 3). This included an up-regulation of intestinal transporters for dietary glucose [solute carrier (SLC) SLC5A1] and cholesterol (Niemann-Pick c1-like 1), as well as for several drugs (e.g., SLC15A1), in the male SOD1[G93A] mice. There was both an up-regulation (e.g., SLCO2A1) and down-regulation (ammonium transporter rh type b) of transporters in the male SOD1[G93A] liver. In addition, there was both an up-regulation (e.g., phosphoenolpyruvate carboxykinase) and down-regulation (e.g., carboxylesterase 1) of metabolizing enzymes in the male SOD1[G93A] liver. This proteomic data set identified male-specific changes to key small intestinal and hepatic transporters and metabolizing enzymes that may have important implications for the bioavailability of nutrients and drugs in individuals with ALS.}, } @article {pmid38414054, year = {2024}, author = {Ma, YY and Li, X and Yu, JT and Wang, YJ}, title = {Therapeutics for neurodegenerative diseases by targeting the gut microbiome: from bench to bedside.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {12}, pmid = {38414054}, issn = {2047-9158}, support = {92249305//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Gastrointestinal Microbiome ; *Amyotrophic Lateral Sclerosis ; *Alzheimer Disease ; *Parkinson Disease/therapy ; }, abstract = {The aetiologies and origins of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), are complex and multifaceted. A growing body of evidence suggests that the gut microbiome plays crucial roles in the development and progression of neurodegenerative diseases. Clinicians have come to realize that therapeutics targeting the gut microbiome have the potential to halt the progression of neurodegenerative diseases. This narrative review examines the alterations in the gut microbiome in AD, PD, ALS and HD, highlighting the close relationship between the gut microbiome and the brain in neurodegenerative diseases. Processes that mediate the gut microbiome-brain communication in neurodegenerative diseases, including the immunological, vagus nerve and circulatory pathways, are evaluated. Furthermore, we summarize potential therapeutics for neurodegenerative diseases that modify the gut microbiome and its metabolites, including diets, probiotics and prebiotics, microbial metabolites, antibacterials and faecal microbiome transplantation. Finally, current challenges and future directions are discussed.}, } @article {pmid38413232, year = {2024}, author = {Chun, C and Lee, JH and Bothwell, M and Nghiem, P and Smith, AST and Mack, DL}, title = {Human Motor Neurons Elicit Pathological Hallmarks of ALS and Reveal Potential Biomarkers of the Disease in Response to Prolonged IFNγ Exposure.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {44}, number = {16}, pages = {}, pmid = {38413232}, issn = {1529-2401}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; R03 TR004009/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; B7-H1 Antigen/metabolism ; Biomarkers ; DNA-Binding Proteins/genetics ; *Induced Pluripotent Stem Cells/metabolism ; Interferon-gamma/metabolism/pharmacology ; Motor Neurons/drug effects/metabolism/pathology ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder marked by progressive motor neuron degeneration and muscle denervation. A recent transcriptomic study integrating a wide range of human ALS samples revealed that the upregulation of p53, a downstream target of inflammatory stress, is commonly detected in familial and sporadic ALS cases by a mechanism linked to a transactive response DNA-binding protein 43 (TDP-43) dysfunction. In this study, we show that prolonged interferon-gamma (IFNγ) treatment of human induced pluripotent stem cell-derived spinal motor neurons results in a severe cytoplasmic aggregation of TDP-43. TDP-43 dysfunction resulting from either IFNγ exposure or an ALS-associated TDP-43 mutation was associated with the activation of the p53 pathway. This was accompanied by the hyperactivation of neuronal firing, followed by the complete loss of their electrophysiological function. Through a comparative single-cell transcriptome analysis, we have identified significant alterations in ALS-associated genes in motor neurons exposed to IFNγ, implicating their direct involvement in ALS pathology. Interestingly, IFNγ was found to induce significant levels of programmed death-ligand 1 (PD-L1) expression in motor neurons without affecting the levels of any other immune checkpoint proteins. This finding suggests a potential role of excessive PD-L1 expression in ALS development, given that PD-L1 was recently reported to impair neuronal firing ability in mice. Our findings suggest that exposing motor neurons to IFNγ could directly derive ALS pathogenesis, even without the presence of the inherent genetic mutation or functional glia component. Furthermore, this study provides a comprehensive list of potential candidate genes for future immunotherapeutic targets with which to treat sporadic forms of ALS, which account for 90% of all reported cases.}, } @article {pmid38412787, year = {2024}, author = {Zhan, ZQ and Huang, ZM and Zhou, HB and Xie, ZX and Chen, YZ and Luo, YH and Chen, PZ and Kang, JQ and Cheng, ZJ and Sun, B}, title = {Gastroesophageal reflux disease with 6 neurodegenerative and psychiatric disorders: Genetic correlations, causality, and potential molecular mechanisms.}, journal = {Journal of psychiatric research}, volume = {172}, number = {}, pages = {244-253}, doi = {10.1016/j.jpsychires.2024.02.030}, pmid = {38412787}, issn = {1879-1379}, mesh = {Humans ; *Sleep Initiation and Maintenance Disorders ; *Depressive Disorder, Major/epidemiology/genetics ; *Mental Disorders/epidemiology/genetics ; Anxiety Disorders/epidemiology/genetics ; *Gastroesophageal Reflux/epidemiology/genetics ; Genome-Wide Association Study ; }, abstract = {The comorbidities between gastroesophageal reflux disease (GERD) and various neurodegenerative and psychiatric disorders have been widely reported. However, the genetic correlations, causal relationships, and underlying mechanisms linking GERD to these disorders remain largely unknown. Here, we conducted a bidirectional Mendelian randomization (MR) analysis to determine the causality between GERD and 6 neurodegenerative and psychiatric disorders. Sensitivity analyses and multivariable MR were performed to test the robustness of our findings. Linkage disequilibrium score regression was used to assess the genetic correlation between these diseases as affected by heredity. Multiple bioinformatics tools combining two machine learning algorithms were applied to further investigate the potential mechanisms underlying these diseases. We found that genetically predicted GERD significantly increased the risk of Alzheimer's disease, major depressive disorder, and anxiety disorders. There might be a bidirectional relationship between GERD and insomnia. GERD has varying degrees of genetic correlations with AD, ALS, anxiety disorders, insomnia, and depressive disorder. Bioinformatics analyses revealed the hub shared genes and the common pathways between GERD and 6 neurodegenerative and psychiatric disorders. Our findings demonstrated the complex nature of the genetic architecture across these diseases and clarified their causality, highlighting that treatments for the cure or remission of GERD may serve as potential strategies for preventing and managing neurodegenerative and psychiatric disorders.}, } @article {pmid38412259, year = {2024}, author = {Tseng, YJ and Krans, A and Malik, I and Deng, X and Yildirim, E and Ovunc, S and Tank, EMH and Jansen-West, K and Kaufhold, R and Gomez, NB and Sher, R and Petrucelli, L and Barmada, SJ and Todd, PK}, title = {Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats.}, journal = {Nucleic acids research}, volume = {52}, number = {10}, pages = {5928-5949}, pmid = {38412259}, issn = {1362-4962}, support = {//Alzheimer's Association Research Fellowship/ ; RF1 AG062077/AG/NIA NIH HHS/United States ; BX004842//VA BLRD/ ; I01 BX004842/BX/BLRD VA/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; //Cellular and Molecular Biology Graduate Program, University of Michigan/ ; R35 NS097273/NS/NINDS NIH HHS/United States ; P50HD104463/GF/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Ataxia ; *C9orf72 Protein/genetics/metabolism ; DNA Repeat Expansion/genetics ; Fragile X Mental Retardation Protein/genetics/metabolism ; Fragile X Syndrome/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; GC Rich Sequence ; HEK293 Cells ; Induced Pluripotent Stem Cells/metabolism ; Neurons/metabolism ; *Protein Biosynthesis ; Ribosomes/metabolism/genetics ; Tremor ; *Trinucleotide Repeat Expansion/genetics ; *Ribosomal Proteins/metabolism ; }, abstract = {A GGGGCC (G4C2) hexanucleotide repeat expansion in C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), while a CGG trinucleotide repeat expansion in FMR1 leads to the neurodegenerative disorder Fragile X-associated tremor/ataxia syndrome (FXTAS). These GC-rich repeats form RNA secondary structures that support repeat-associated non-AUG (RAN) translation of toxic proteins that contribute to disease pathogenesis. Here we assessed whether these same repeats might trigger stalling and interfere with translational elongation. We find that depletion of ribosome-associated quality control (RQC) factors NEMF, LTN1 and ANKZF1 markedly boost RAN translation product accumulation from both G4C2 and CGG repeats while overexpression of these factors reduces RAN production in both reporter assays and C9ALS/FTD patient iPSC-derived neurons. We also detected partially made products from both G4C2 and CGG repeats whose abundance increased with RQC factor depletion. Repeat RNA sequence, rather than amino acid content, is central to the impact of RQC factor depletion on RAN translation-suggesting a role for RNA secondary structure in these processes. Together, these findings suggest that ribosomal stalling and RQC pathway activation during RAN translation inhibits the generation of toxic RAN products. We propose augmenting RQC activity as a therapeutic strategy in GC-rich repeat expansion disorders.}, } @article {pmid38411425, year = {2024}, author = {D'Urso, B and Weil, R and Génin, P}, title = {[Optineurin and mitochondrial dysfunction in neurodegeneration].}, journal = {Medecine sciences : M/S}, volume = {40}, number = {2}, pages = {167-175}, doi = {10.1051/medsci/2023220}, pmid = {38411425}, issn = {1958-5381}, mesh = {Humans ; Ubiquitin ; *Amyotrophic Lateral Sclerosis/genetics ; Cytosol ; Mitochondria/genetics ; *Mitochondrial Diseases ; }, abstract = {Optineurin (OPTN) is a multifunctional protein playing a crucial role as a receptor in selective autophagy. OPTN gene mutations are linked to diseases such as normal-tension glaucoma and amyotrophic lateral sclerosis. Recognized as a critical receptor for mitophagy, OPTN is pivotal in selectively degrading damaged mitochondria. This process is essential to prevent their accumulation, the generation of reactive oxygen species, and the release of pro-apoptotic factors. Mitophagy's quality control is governed by the PINK1 kinase and the cytosolic ubiquitin ligase Parkin, whose mutations are associated with Parkinson's disease. This review highlights recent insights emphasizing OPTN's role in mitophagy and its potential involvement in neurodegenerative diseases.}, } @article {pmid38411261, year = {2024}, author = {Sakowski, SA and Koubek, EJ and Chen, KS and Goutman, SA and Feldman, EL}, title = {Role of the Exposome in Neurodegenerative Disease: Recent Insights and Future Directions.}, journal = {Annals of neurology}, volume = {95}, number = {4}, pages = {635-652}, pmid = {38411261}, issn = {1531-8249}, support = {R01TS000327/CC/CDC HHS/United States ; R01 TS000289/TS/ATSDR CDC HHS/United States ; R01 TS000327/TS/ATSDR CDC HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R01TS000289/CC/CDC HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; P30 DK020572/DK/NIDDK NIH HHS/United States ; K23ES027221/NH/NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Exposome ; *Alzheimer Disease/genetics ; *Parkinson Disease/genetics ; }, abstract = {Neurodegenerative diseases are increasing in prevalence and place a significant burden on society. The causes are multifactorial and complex, and increasing evidence suggests a dynamic interplay between genes and the environment, emphasizing the importance of identifying and understanding the role of lifelong exposures, known as the exposome, on the nervous system. This review provides an overview of recent advances toward defining neurodegenerative disease exposomes, focusing on Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. We present the current state of the field based on emerging data, elaborate on key themes and potential mechanisms, and conclude with limitations and future directions. ANN NEUROL 2024;95:635-652.}, } @article {pmid38410712, year = {2024}, author = {Moretti, A and Pietersen, PI and Hassan, M and Shafiek, H and Prosch, H and Tarnoki, AD and Annema, JT and Munavvar, M and Bonta, PI and de Wever, W and Juul, AD}, title = {ERS International Congress 2023: highlights from the Clinical Techniques, Imaging and Endoscopy Assembly.}, journal = {ERJ open research}, volume = {10}, number = {1}, pages = {}, pmid = {38410712}, issn = {2312-0541}, abstract = {The Clinical Techniques, Imaging and Endoscopy Assembly is involved in the diagnosis and treatment of several pulmonary diseases, as demonstrated at the 2023 European Respiratory Society (ERS) International Congress in Milan, Italy. From interventional pulmonology, the congress included several exciting results for the use of bronchoscopy in lung cancer, including augmented fluoroscopy, robotic-assisted bronchoscopy and cryobiopsies. In obstructive lung disease, the latest results on bronchoscopic treatment of emphysema with hyperinflation and chronic bronchitis were presented. Research on using cryobiopsies to diagnose interstitial lung disease was further explored, with the aims of elevating diagnostic yield and minimising risk. For imaging, the latest updates in using artificial intelligence to overcome the increased workload of radiologists were of great interest. Novel imaging in sarcoidosis explored the use of magnetic resonance imaging, photon-counting computed tomography and positron emission tomography/computed tomography in the diagnostic work-up. Lung cancer screening is still a hot topic and new results were presented regarding incorporation of biomarkers, identifying knowledge gaps and improving screening programmes. The use of ultrasound in respiratory medicine is an expanding field, which was demonstrated by the large variety in studies presented at the 2023 ERS Congress. Ultrasound of the diaphragm in patients with amyotrophic lateral sclerosis and myasthenia gravis was used to assess movements and predict respiratory fatigue. Furthermore, studies using ultrasound to diagnose or monitor pulmonary disease were presented. The congress also included studies regarding the training and assessment of competencies as an important part of implementing ultrasound in clinical practice.}, } @article {pmid38409777, year = {2024}, author = {Rabadi, MH and Russell, KC and Xu, C}, title = {Predictors of Mortality in Veterans with Amyotrophic Lateral Sclerosis: Respiratory Status and Speech Disorder at Presentation.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {30}, number = {}, pages = {e943288}, pmid = {38409777}, issn = {1643-3750}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Speech ; Dysarthria ; *Veterans ; Disease Progression ; }, abstract = {BACKGROUND There is a lack of accurate models to predict amyotrophic lateral sclerosis (ALS) disease course and outcomes. As a result, risk assessment and counseling, the timing of interventions, and their stratification in clinical trials are difficult. This study aimed to evaluate the association between symptoms at presentation and mortality. MATERIAL AND METHODS A single veterans hospital reviewed the electronic records of 105 veterans with ALS who were periodically followed in our ALS clinic between 2010 and 2021. A survival decision tree (≤3 or >3 years) was generated based on the statistical median survival of our data. The variables known to influence survival when alive were compared to patients who died. RESULTS The (mean±SD) age at onset was 62±11 years, M/F ratio 101: 4, and 90% were non-Hispanic whites. The initial score for the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) was 31±8.3. Dysarthria and shortness of breath (SOB) were present on initial presentation in 52 (49.5%) and 32 (30.5%) patients, respectively. Deaths occurred in 80 (76.2%) patients during the study period. The main cause of death was respiratory disease (failure and pneumonia, n=43 53.75%). Patients survived for >3 years on initial presentation with normal respiration and speech, compared to ≤3 years of survival in patients with dysarthria and SOB, irrespective of age. CONCLUSIONS This study suggests that for veterans with ALS, the main predictors of shorter survival were respiratory status and speech disorder on initial presentation to the clinic.}, } @article {pmid38409193, year = {2024}, author = {Chang, HY and Wang, IF}, title = {Restoring functional TDP-43 oligomers in ALS and laminopathic cellular models through baicalein-induced reconfiguration of TDP-43 aggregates.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {4620}, pmid = {38409193}, issn = {2045-2322}, support = {ND-01-003//Garage Brain Science/ ; ND-01-003//Garage Brain Science/ ; TDP-01//YeeFan Med Inc./ ; TDP-01//YeeFan Med Inc./ ; }, mesh = {Humans ; *Progeria/genetics ; Lamin Type A/genetics ; *Aging, Premature ; DNA-Binding Proteins/genetics ; *Flavanones ; }, abstract = {A group of misfolded prone-to-aggregate domains in disease-causing proteins has recently been shown to adopt unique conformations that play a role in fundamental biological processes. These processes include the formation of membrane-less sub-organelles, alternative splicing, and gene activation and silencing. The cellular responses are regulated by the conformational switching of prone-to-aggregate domains, independently of changes in RNA or protein expression levels. Given this, targeting the misfolded states of disease-causing proteins to redirect them towards their physiological conformations is emerging as an effective therapeutic strategy for diseases caused by protein misfolding. In our study, we successfully identified baicalein as a potent structure-correcting agent. Our findings demonstrate that baicalein can reconfigure existing TDP-43 aggregates into an oligomeric state both in vitro and in disease cells. This transformation effectively restores the bioactivity of misfolded TDP-43 proteins in cellular models of ALS and premature aging in progeria. Impressively, in progeria cells where defective lamin A interferes with TDP-43-mediated exon skipping, the formation of pathological TDP-43 aggregates is promoted. Baicalein, however, restores the functionality of TDP-43 and mitigates nuclear shape defects in these laminopathic cells. This establishes a connection between lamin A and TDP-43 in the context of aging. Our findings suggest that targeting physiological TDP-43 oligomers could offer a promising therapeutic avenue for treating aging-associated disorders.}, } @article {pmid38408864, year = {2024}, author = {Odierna, GL and Vucic, S and Dyer, M and Dickson, T and Woodhouse, A and Blizzard, C}, title = {How do we get from hyperexcitability to excitotoxicity in amyotrophic lateral sclerosis?.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {5}, pages = {1610-1621}, pmid = {38408864}, issn = {1460-2156}, support = {//Motor Neuron Disease Research Australia/ ; //National Health and Medical Research Council of Australia/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; *Motor Neurons/physiology ; *Glutamic Acid/metabolism ; Animals ; Motor Cortex/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease that, at present, has no effective cure. Evidence of increased circulating glutamate and hyperexcitability of the motor cortex in patients with amyotrophic lateral sclerosis have provided an empirical support base for the 'dying forward' excitotoxicity hypothesis. The hypothesis postulates that increased activation of upper motor neurons spreads pathology to lower motor neurons in the spinal cord in the form of excessive glutamate release, which triggers excitotoxic processes. Many clinical trials have focused on therapies that target excitotoxicity via dampening neuronal activation, but not all are effective. As such, there is a growing tension between the rising tide of evidence for the 'dying forward' excitotoxicity hypothesis and the failure of therapies that target neuronal activation. One possible solution to these contradictory outcomes is that our interpretation of the current evidence requires revision in the context of appreciating the complexity of the nervous system and the limitations of the neurobiological assays we use to study it. In this review we provide an evaluation of evidence relevant to the 'dying forward' excitotoxicity hypothesis and by doing so, identify key gaps in our knowledge that need to be addressed. We hope to provide a road map from hyperexcitability to excitotoxicity so that we can better develop therapies for patients suffering from amyotrophic lateral sclerosis. We conclude that studies of upper motor neuron activity and their synaptic output will play a decisive role in the future of amyotrophic lateral sclerosis therapy.}, } @article {pmid38408684, year = {2024}, author = {Dithmar, S and Zare, A and Salehi, S and Briese, M and Sendtner, M}, title = {hnRNP R regulates mitochondrial movement and membrane potential in axons of motoneurons.}, journal = {Neurobiology of disease}, volume = {193}, number = {}, pages = {106454}, doi = {10.1016/j.nbd.2024.106454}, pmid = {38408684}, issn = {1095-953X}, mesh = {Membrane Potentials ; *Motor Neurons/metabolism ; *Axons/pathology ; Heterogeneous-Nuclear Ribonucleoproteins/genetics/metabolism ; Mitochondria/metabolism ; }, abstract = {Axonal mitochondria defects are early events in the pathogenesis of motoneuron disorders such as spinal muscular atrophy and amyotrophic lateral sclerosis. The RNA-binding protein hnRNP R interacts with different motoneuron disease-related proteins such as SMN and TDP-43 and has important roles in axons of motoneurons, including axonal mRNA transport. However, whether hnRNP R also modulates axonal mitochondria is currently unknown. Here, we show that axonal mitochondria exhibit altered function and motility in hnRNP R-deficient motoneurons. Motoneurons lacking hnRNP R show decreased anterograde and increased retrograde transport of mitochondria in axons. Furthermore, hnRNP R-deficiency leads to mitochondrial hyperpolarization, caused by decreased complex I and reversed complex V activity within the respiratory chain. Taken together, our data indicate a role for hnRNP R in regulating transport and maintaining functionality of axonal mitochondria in motoneurons.}, } @article {pmid38405340, year = {2024}, author = {Sun, W and Wei, C}, title = {Causal Relationship Between Ferritin and Neuropsychiatric Disorders: A Two-Sample Mendelian Randomization Study.}, journal = {Journal of Alzheimer's disease reports}, volume = {8}, number = {1}, pages = {257-266}, pmid = {38405340}, issn = {2542-4823}, abstract = {BACKGROUND: Previous observational research has indicated a correlation between ferritin levels and neuropsychiatric disorders, although the causal relationship remains uncertain.

OBJECTIVE: The objective of this study was to investigate the potential causal link between plasma ferritin levels and neuropsychiatric disorders.

METHODS: A two-sample Mendelian randomization (MR) study was conducted, wherein genetic instruments associated with ferritin were obtained from a previously published genome-wide association study (GWAS). Summary statistics pertaining to neuropsychiatric disorders were derived from five distinct GWAS datasets. The primary MR analysis employed the inverse variance weighted (IVW) method and was corroborated by additional methods including MR-Egger, weighted median, simple mode, and weighted mode. Sensitivity analyses were employed to identify potential pleiotropy and heterogeneity in the results.

RESULTS: The fixed effects IVW method revealed a statistically significant causal relationship between plasma ferritin level and the occurrence of Alzheimer's disease (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.00-1.12, p = 0.037), as well as Parkinson's disease (OR = 1.06, 95% CI: 1.00-1.13, p = 0.041). Various sensitivity analyses were conducted, which demonstrated no substantial heterogeneity or pleiotropy. Conversely, no compelling evidence was found to support a causal association between ferritin and amyotrophic lateral sclerosis, schizophrenia, or major depressive disorder.

CONCLUSIONS: This MR study provides evidence at the genetic level for a causal relationship between plasma ferritin and an increased risk of Alzheimer's disease and Parkinson's disease. The exact genetic mechanisms underlying this connection necessitate further investigation.}, } @article {pmid38405076, year = {2024}, author = {Dittlau, KS and Chandrasekaran, A and Freude, K and Van Den Bosch, L}, title = {Generation of Human Induced Pluripotent Stem Cell (hiPSC)-Derived Astrocytes for Amyotrophic Lateral Sclerosis and Other Neurodegenerative Disease Studies.}, journal = {Bio-protocol}, volume = {14}, number = {4}, pages = {e4936}, pmid = {38405076}, issn = {2331-8325}, abstract = {Astrocytes are increasingly recognized for their important role in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). In ALS, astrocytes shift from their primary function of providing neuronal homeostatic support towards a reactive and toxic role, which overall contributes to neuronal toxicity and cell death. Currently, our knowledge on these processes is incomplete, and time-efficient and reproducible model systems in a human context are therefore required to understand and therapeutically modulate the toxic astrocytic response for future treatment options. Here, we present an efficient and straightforward protocol to generate human induced pluripotent stem cell (hiPSC)-derived astrocytes implementing a differentiation scheme based on small molecules. Through an initial 25 days, hiPSCs are differentiated into astrocytes, which are matured for 4+ weeks. The hiPSC-derived astrocytes can be cryopreserved at every passage during differentiation and maturation. This provides convenient pauses in the protocol as well as cell banking opportunities, thereby limiting the need to continuously start from hiPSCs. The protocol has already proven valuable in ALS research but can be adapted to any desired research field where astrocytes are of interest. Key features • This protocol requires preexisting experience in hiPSC culturing for a successful outcome. • The protocol relies on a small molecule differentiation scheme and an easy-to-follow methodology, which can be paused at several time points. • The protocol generates >50 × 10[6] astrocytes per differentiation, which can be cryopreserved at every passage, ensuring a large-scale experimental output.}, } @article {pmid38404827, year = {2024}, author = {Liu, Y and Chang, Y and Jiang, X and Mei, H and Cao, Y and Wu, D and Xie, R and Jiang, W and Vasquez, E and Wu, Y and Lin, S and Cao, Y}, title = {Analysis of the role of PANoptosis in seizures via integrated bioinformatics analysis and experimental validation.}, journal = {Heliyon}, volume = {10}, number = {4}, pages = {e26219}, pmid = {38404827}, issn = {2405-8440}, abstract = {BACKGROUND: Epilepsy is recognized as the most common chronic neurological condition among children, and hippocampal neuronal cell death has been identified as a crucial factor in the pathophysiological processes underlying seizures. In recent studies, PANoptosis, a newly characterized form of cell death, has emerged as a significant contributor to the development of various neurological disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. PANoptosis involves the simultaneous activation of pyroptosis, apoptosis, and necroptosis within the same population of cells. However, its specific role in the context of seizures remains to be fully elucidated. Further investigation is required to uncover the precise involvement of PANoptosis in the pathogenesis of seizures and to better understand its potential implications for the development of targeted therapeutic approaches in epilepsy.

METHODS: In this study, the gene expression data of the hippocampus following the administration of kainic acid (KA) or NaCl was obtained from the Gene Expression Omnibus (GEO) database. The PANoptosis-related gene set was compiled from the GeneCards database and previous literature. Time series analysis was performed to analyze the temporal expression patterns of the PANoptosis-related genes. Gene set variation analysis (GSVA), Gene ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) were employed to explore potential biological mechanisms underlying PANoptosis and its role in seizures. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were utilized to identify pivotal gene modules and PANoptosis-related genes associated with the pathophysiological processes underlying seizures. To validate the expression of PANoptosis-related genes, Western blotting or quantitative real-time polymerase chain reaction (qRT-PCR) assays were conducted. These experimental validations were performed in human blood samples, animal models, and cell models to verify the expression patterns of the PANoptosis-related genes and their relevance to epilepsy.

RESULTS: The GSVA analysis performed in this study demonstrated that PANoptosis-related genes have the potential to distinguish between the control group and KA-induced epileptic mice. This suggests that the expression patterns of these genes are significantly altered in response to KA-induced epilepsy. Furthermore, the Weighted gene co-expression network analysis (WGCNA) identified the blue module as being highly associated with epileptic phenotypes. This module consists of genes that exhibit correlated expression patterns specifically related to epilepsy. Within the blue module, 10 genes were further identified as biomarker genes for epilepsy. These genes include MLKL, IRF1, RIPK1, GSDMD, CASP1, CASP8, ZBP1, CASP6, PYCARD, and IL18. These genes likely play critical roles in the pathophysiology of epilepsy and could serve as potential biomarkers for diagnosing or monitoring the condition.

CONCLUSION: In conclusion, our study suggests that the hippocampal neuronal cell death in epilepsy may be closely related to PANoptosis, a novel form of cell death, which provides insights into the underlying pathophysiological processes of epilepsy and helps the development of novel therapeutic approaches for epilepsy.}, } @article {pmid38404440, year = {2024}, author = {Lee, SH and Pham, D and Kosa, E and Agbas, A}, title = {Human Platelet Derived Mitochondrial OPA-1 Isoforms and Interaction With TDP-43 in Neurodegenerative Diseases.}, journal = {Missouri medicine}, volume = {121}, number = {1}, pages = {87-92}, pmid = {38404440}, issn = {0026-6620}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA, Mitochondrial/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Mitochondria/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Protein Isoforms/metabolism ; *GTP Phosphohydrolases/genetics/metabolism ; }, abstract = {Optic atrophy 1(OPA1) is a GTPase protein that controls mitochondrial fusion, cristae integrity, and mtDNA maintenance. In neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), the mitochondrial network morphology is compromised. Studies on TAR-DNA binding protein 43 (TDP-43) has been the focus in our lab. OPA1 and TDP-43 interaction may shed a light on how aberrant TDP-43 interacts with OPA1, which will lead to mitochondrial dysfunction. The preliminary study tested the idea of whether OPA1 and TDP-43 are physically interacting in human platelet derived mitochondria obtained from healthy human subjects.}, } @article {pmid38404316, year = {2024}, author = {Dunn, KJ and Matlock, A and Funkenbusch, G and Yaqoob, Z and So, PTC and Berger, AJ}, title = {Optical diffraction tomography for assessing single cell models in angular light scattering.}, journal = {Biomedical optics express}, volume = {15}, number = {2}, pages = {973-990}, pmid = {38404316}, issn = {2156-7085}, abstract = {Angularly resolved light scattering (ALS) has become a useful tool for assessing the size and refractive index of biological scatterers at cellular and organelle length scales. Sizing organelle populations with ALS relies on Mie scattering theory models, which require significant assumptions about the object, including spherical scatterers and a homogeneous medium. These assumptions may incur greater error at the single cell level, where there are fewer scatterers to be averaged over. We investigate the validity of these assumptions using 3D refractive index (RI) tomograms measured via optical diffraction tomography (ODT). We compute the angular scattering on digitally manipulated tomograms with increasingly strong model assumptions, including RI-matched immersion media, homogeneous cytosol, and spherical organelles. We also compare the tomogram-computed angular scattering to experimental measurements of angular scattering from the same cells to ensure that the ODT-based approach accurately models angular scattering. We show that enforced RI-matching with the immersion medium and a homogeneous cytosol significantly affects the angular scattering intensity shape, suggesting that these assumptions can reduce the accuracy of size distribution estimates.}, } @article {pmid38403672, year = {2024}, author = {Wang, H and Chen, N and Jian, F and Zhang, Z and Tai, H and Pan, H}, title = {Amyotrophic lateral sclerosis and myasthenia gravis overlaps syndrome: a series of case report.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {7}, pages = {3549-3553}, pmid = {38403672}, issn = {1590-3478}, mesh = {Humans ; *Myasthenia Gravis/diagnosis/complications ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Middle Aged ; Male ; Female ; Aged ; }, } @article {pmid38403286, year = {2024}, author = {Fan, H and Zhang, M and Wen, J and Wang, S and Yuan, M and Sun, H and Shu, L and Yang, X and Pu, Y and Cai, Z}, title = {Microglia in brain aging: An overview of recent basic science and clinical research developments.}, journal = {Journal of biomedical research}, volume = {38}, number = {2}, pages = {122-136}, pmid = {38403286}, issn = {1674-8301}, abstract = {Aging is characterized by progressive degeneration of tissues and organs, and it is positively associated with an increased mortality rate. The brain, as one of the most significantly affected organs, experiences age-related changes, including abnormal neuronal activity, dysfunctional calcium homeostasis, dysregulated mitochondrial function, and increased levels of reactive oxygen species. These changes collectively contribute to cognitive deterioration. Aging is also a key risk factor for neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. For many years, neurodegenerative disease investigations have primarily focused on neurons, with less attention given to microglial cells. However, recently, microglial homeostasis has emerged as an important mediator in neurological disease pathogenesis. Here, we provide an overview of brain aging from the perspective of the microglia. In doing so, we present the current knowledge on the correlation between brain aging and the microglia, summarize recent progress of investigations about the microglia in normal aging, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, and then discuss the correlation between the senescent microglia and the brain, which will culminate with a presentation of the molecular complexity involved in the microglia in brain aging with suggestions for healthy aging.}, } @article {pmid38402886, year = {2024}, author = {Baudin, E and Goichot, B and Berruti, A and Hadoux, J and Moalla, S and Laboureau, S and Nölting, S and de la Fouchardière, C and Kienitz, T and Deutschbein, T and Zovato, S and Amar, L and Haissaguerre, M and Timmers, H and Niccoli, P and Faggiano, A and Angokai, M and Lamartina, L and Luca, F and Cosentini, D and Hahner, S and Beuschlein, F and Attard, M and Texier, M and Fassnacht, M and , and , }, title = {Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial.}, journal = {Lancet (London, England)}, volume = {403}, number = {10431}, pages = {1061-1070}, doi = {10.1016/S0140-6736(23)02554-0}, pmid = {38402886}, issn = {1474-547X}, mesh = {Adult ; Humans ; Adolescent ; Sunitinib/therapeutic use ; *Pheochromocytoma/drug therapy/etiology ; Progression-Free Survival ; *Hypertension/etiology ; *Adrenal Gland Neoplasms/drug therapy/etiology ; Double-Blind Method ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; }, abstract = {BACKGROUND: No randomised controlled trial has ever been done in patients with metastatic phaeochromocytomas and paragangliomas. Preclinical and first clinical evidence suggested beneficial effects of sunitinib. We aimed to evaluate the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas.

METHODS: FIRSTMAPPP is a multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial done at 14 academic centres across four European countries. Eligible participants were adults (aged ≥18 years) with sporadic or inherited progressive metastatic phaeochromocytomas and paragangliomas. Patients were randomly assigned (1:1) to receive either oral sunitinib (37·5 mg per day) or placebo. Randomisation was stratified according to SDHB status (mutation present vs wild type) and number of previous systemic therapies (0 vs ≥1). Primary endpoint was the rate of progression-free survival at 12 months according to real-time central review (Response Evaluation Criteria in Solid Tumours version 1.1). On the basis of a two-step Simon model, we aimed for the accrual of 78 patients, assuming a 20% improvement of the 12-month progression-free survival rate from 20% to 40%, to conclude that sunitinib is effective. Crossover from the placebo group was allowed. This trial is registered with ClinicalTrials.gov, number NCT01371201, and is closed for enrolment.

FINDINGS: From Dec 1, 2011, to Jan 31, 2019, a total of 78 patients with progressive metastatic phaeochromocytomas and paragangliomas were enrolled (39 patients per group). 25 (32%) of 78 patients had germline SDHx variants and 54 (69%) had used previous therapies. The primary endpoint was met, with a 12-month progression-free survival in 14 of 39 patients (36% [90% CI 23-50]) in the sunitinib group. In the placebo group, the 12-month progression-free survival in seven of 39 patients was 19% (90% CI 11-31), validating the hypotheses of our study design. The most frequent grade 3 or 4 adverse events were asthenia (seven [18%] of 39 and one [3%] of 39), hypertension (five [13%] and four [10%]), and back or bone pain (one [3%] and three [8%]) in the sunitinib and placebo groups, respectively. Three deaths occurred in the sunitinib group: these deaths were due to respiratory insufficiency, amyotrophic lateral sclerosis, and rectal bleeding. Only the latter event was considered drug related. Two deaths occurred in the placebo group due to aspiration pneumonia and septic shock.

INTERPRETATION: This first randomised trial supports the use of sunitinib as the medical option with the highest level of evidence for anti-tumour efficacy in progressive metastatic phaeochromocytomas and paragangliomas.

FUNDING: French Ministry of Health, through the National Institute for Cancer, German Ministry of Education and Research, and the German Research Foundation within the CRC/Transregio 205/2, EU Seventh Framework Programme, and a private donator grant.}, } @article {pmid38401571, year = {2024}, author = {Cheng, F and Chapman, T and Zhang, S and Morsch, M and Chung, R and Lee, A and Rayner, SL}, title = {Understanding age-related pathologic changes in TDP-43 functions and the consequence on RNA splicing and signalling in health and disease.}, journal = {Ageing research reviews}, volume = {96}, number = {}, pages = {102246}, doi = {10.1016/j.arr.2024.102246}, pmid = {38401571}, issn = {1872-9649}, mesh = {Humans ; RNA Splicing ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Frontotemporal Dementia/genetics ; DNA-Binding Proteins/genetics/metabolism ; Neurons/metabolism ; }, abstract = {TAR DNA binding protein-43 (TDP-43) is a key component in RNA splicing which plays a crucial role in the aging process. In neurodegenerative diseases such as amyotrophic lateral sclerosis, frontotemporal dementia and limbic-predominant age-related TDP-43 encephalopathy, TDP-43 can be mutated, mislocalised out of the nucleus of neurons and glial cells and form cytoplasmic inclusions. These TDP-43 alterations can lead to its RNA splicing dysregulation and contribute to mis-splicing of various types of RNA, such as mRNA, microRNA, and circular RNA. These changes can result in the generation of an altered transcriptome and proteome within cells, ultimately changing the diversity and quantity of gene products. In this review, we summarise the findings of novel atypical RNAs resulting from TDP-43 dysfunction and their potential as biomarkers or targets for therapeutic development.}, } @article {pmid38401191, year = {2024}, author = {Lemon, R}, title = {The Corticospinal System and Amyotrophic Lateral Sclerosis: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {160}, number = {}, pages = {56-67}, doi = {10.1016/j.clinph.2024.02.001}, pmid = {38401191}, issn = {1872-8952}, mesh = {Animals ; Humans ; *Pyramidal Tracts/physiology ; *Amyotrophic Lateral Sclerosis ; Motor Neurons/physiology ; Primates ; Axons ; }, abstract = {Corticospinal neurons located in motor areas of the cerebral neocortex project corticospinal axons which synapse with the spinal network; a parallel corticobulbar system projects to the cranial motor network and to brainstem motor pathways. The primate corticospinal system has a widespread cortical origin and an extensive range of different fibre diameters, including thick, fast-conducting axons. Direct cortico-motoneuronal (CM) projections from the motor cortex to arm and hand alpha motoneurons are a recent evolutionary feature, that is well developed in dexterous primates and particularly in humans. Many of these projections originate from the caudal subdivision of area 4 ('new' M1: primary motor cortex). They arise from corticospinal neurons of varied soma size, including those with fast- and relatively slow-conducting axons. This CM system has been shown to be involved in the control of skilled movements, carried out with fractionation of the distal extremities and at low force levels. During movement, corticospinal neurons are activated quite differently from 'lower' motoneurons, and there is no simple or fixed functional relationship between a so-called 'upper' motoneuron and its target lower motoneuron. There are key differences in the organisation and function of the corticospinal and CM system in primates versus non-primates, such as rodents. These differences need to be recognized when making the choice of animal model for understanding disorders such as amyotrophic lateral sclerosis (ALS). In this neurodegenerative brain disease there is a selective loss of fast-conducting corticospinal axons, and their synaptic connections, and this is reflected in responses to non-invasive cortical stimuli and measures of cortico-muscular coherence. The loss of CM connections influencing distal limb muscles results in a differential loss of muscle strength or 'split-hand' phenotype. Importantly, there is also a unique impairment in the coordination of skilled hand tasks that require fractionation of digit movement. Scores on validated tests of skilled hand function could be used to assess disease progression.}, } @article {pmid38400897, year = {2024}, author = {Pirasteh, A and Shamseini Ghiyasvand, M and Pouladian, M}, title = {EEG-based brain-computer interface methods with the aim of rehabilitating advanced stage ALS patients.}, journal = {Disability and rehabilitation. Assistive technology}, volume = {19}, number = {8}, pages = {3183-3193}, doi = {10.1080/17483107.2024.2316312}, pmid = {38400897}, issn = {1748-3115}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology ; *Brain-Computer Interfaces ; *Electroencephalography ; Support Vector Machine ; Neural Networks, Computer ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that leads to progressive muscle weakness and paralysis, ultimately resulting in the loss of ability to communicate and control the environment. EEG-based Brain-Computer Interface (BCI) methods have shown promise in providing communication and control with the aim of rehabilitating ALS patients. In particular, P300-based BCI has been widely studied and used for ALS rehabilitation. Other EEG-based BCI methods, such as Motor Imagery (MI) based BCI and Hybrid BCI, have also shown promise in ALS rehabilitation. Nonetheless, EEG-based BCI methods hold great potential for improvement. This review article introduces and reviews FFT, WPD, CSP, CSSP, CSP, and GC feature extraction methods. The Common Spatial Pattern (CSP) is an efficient and common technique for extracting data properties used in BCI systems. In addition, Linear Discriminant Analysis (LDA), Support Vector Machine (SVM), Neural Networks (NN), and Deep Learning (DL) classification methods were introduced and reviewed. SVM is the most appropriate classifier due to its insensitivity to the curse of dimensionality. Also, DL is used in the design of BCI systems and is a good choice for BCI systems based on motor imagery with big datasets. Despite the progress made in the field, there are still challenges to overcome, such as improving the accuracy and reliability of EEG signal detection and developing more intuitive and user-friendly interfaces By using BCI, disabled patients can communicate with their caregivers and control their environment using various devices, including wheelchairs, and robotic arms.}, } @article {pmid38400247, year = {2024}, author = {Cano, LA and Albarracín, AL and Pizá, AG and García-Cena, CE and Fernández-Jover, E and Farfán, FD}, title = {Assessing Cognitive Workload in Motor Decision-Making through Functional Connectivity Analysis: Towards Early Detection and Monitoring of Neurodegenerative Diseases.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {4}, pages = {}, pmid = {38400247}, issn = {1424-8220}, mesh = {Male ; Female ; Humans ; Young Adult ; Adult ; *Neurodegenerative Diseases/diagnosis ; Cerebral Cortex ; Muscle, Skeletal/physiology ; Electromyography ; Electroencephalography/methods ; Cognition ; }, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and frontotemporal dementia, among others, are increasingly prevalent in the global population. The clinical diagnosis of these NDs is based on the detection and characterization of motor and non-motor symptoms. However, when these diagnoses are made, the subjects are often in advanced stages where neuromuscular alterations are frequently irreversible. In this context, we propose a methodology to evaluate the cognitive workload (CWL) of motor tasks involving decision-making processes. CWL is a concept widely used to address the balance between task demand and the subject's available resources to complete that task. In this study, multiple models for motor planning during a motor decision-making task were developed by recording EEG and EMG signals in n=17 healthy volunteers (9 males, 8 females, age 28.66±8.8 years). In the proposed test, volunteers have to make decisions about which hand should be moved based on the onset of a visual stimulus. We computed functional connectivity between the cortex and muscles, as well as among muscles using both corticomuscular and intermuscular coherence. Despite three models being generated, just one of them had strong performance. The results showed two types of motor decision-making processes depending on the hand to move. Moreover, the central processing of decision-making for the left hand movement can be accurately estimated using behavioral measures such as planning time combined with peripheral recordings like EMG signals. The models provided in this study could be considered as a methodological foundation to detect neuromuscular alterations in asymptomatic patients, as well as to monitor the process of a degenerative disease.}, } @article {pmid38399543, year = {2024}, author = {Karagul, S and Senol, S and Karakose, O and Uzunoglu, K and Kayaalp, C}, title = {One Anastomosis Gastric Bypass versus Roux-en-Y Gastric Bypass: A Randomized Prospective Trial.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {2}, pages = {}, pmid = {38399543}, issn = {1648-9144}, mesh = {Humans ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged ; *Gastric Bypass/methods ; Prospective Studies ; *Obesity, Morbid/surgery ; Comorbidity ; Weight Loss ; Retrospective Studies ; }, abstract = {Background and Objectives: One anastomosis gastric bypass (OAGB) and Roux-en-Y gastric bypass (RYGB) surgeries are effective methods used in bariatric surgery. There are limited randomized studies comparing these procedures over more than 2 years. Here, we aimed to compare the 3-year results of two bariatric procedures. Materials and Methods: Patients included in this randomized prospective study were compared in OAGB and RYGB groups. A total of 55 patients, aged between 18 and 65, were eligible for the study. Thirteen patients who did not accept randomization were excluded. Patients were evaluated at 6, 12, 24, and 36 months postoperatively. Results: Three patients were excluded from the study due to loss of communication during the clinical follow-up and one due to death by amyotrophic lateral sclerosis, which started in the eighth month after surgery. The study was completed with a total of 38 patients (OAGB; n = 20, RYGB; n = 18). Patients in the two groups were similar in terms of age, gender, body mass index (BMI), and obesity-related comorbidities. At the end of 3-year follow-up, BMI in the OAGB and RYGB groups was 28.80 ± 4.53 kg/m[2] and 29.17 ± 5.36 kg/m[2], respectively (p = 0.822). Percentage total weight loss (TWL%) was similar. No significant differences were found between the groups regarding percentage excess weight loss (EWL%). Remission of comorbidities was similar. De novo refluxes developed in four OAGB patients; there were no occurrences of these in RYGB patients (p = 0.066). Conclusions: Both OAGB and RYGB are effective in the treatment of morbid obesity. The two procedures are similarly successful in terms of obesity-related comorbidities.}, } @article {pmid38399458, year = {2024}, author = {Al Shaer, D and Al Musaimi, O and Albericio, F and de la Torre, BG}, title = {2023 FDA TIDES (Peptides and Oligonucleotides) Harvest.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {2}, pages = {}, pmid = {38399458}, issn = {1424-8247}, abstract = {A total of nine TIDES (pepTIDES and oligonucleoTIDES) were approved by the FDA during 2023. The four approved oligonucleotides are indicated for various types of disorders, including amyotrophic lateral sclerosis, geographic atrophy, primary hyperoxaluria type 1, and polyneuropathy of hereditary transthyretin-mediated amyloidosis. All oligonucleotides show chemically modified structures to enhance their stability and therapeutic effectiveness as antisense or aptamer oligomers. Some of them demonstrate various types of conjugation to driving ligands. The approved peptides comprise various structures, including linear, cyclic, and lipopeptides, and have diverse applications. Interestingly, the FDA has granted its first orphan drug designation for a peptide-based drug as a highly selective chemokine antagonist. Furthermore, Rett syndrome has found its first-ever core symptoms treatment, which is also peptide-based. Here, we analyze the TIDES approved in 2023 on the basis of their chemical structure, medical target, mode of action, administration route, and common adverse effects.}, } @article {pmid38399373, year = {2024}, author = {Cha, Y and Kagalwala, MN and Ross, J}, title = {Navigating the Frontiers of Machine Learning in Neurodegenerative Disease Therapeutics.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {2}, pages = {}, pmid = {38399373}, issn = {1424-8247}, abstract = {Recent advances in machine learning hold tremendous potential for enhancing the way we develop new medicines. Over the years, machine learning has been adopted in nearly all facets of drug discovery, including patient stratification, lead discovery, biomarker development, and clinical trial design. In this review, we will discuss the latest developments linking machine learning and CNS drug discovery. While machine learning has aided our understanding of chronic diseases like Alzheimer's disease and Parkinson's disease, only modest effective therapies currently exist. We highlight promising new efforts led by academia and emerging biotech companies to leverage machine learning for exploring new therapies. These approaches aim to not only accelerate drug development but to improve the detection and treatment of neurodegenerative diseases.}, } @article {pmid38397958, year = {2024}, author = {Borrego-Hernández, D and Vázquez-Costa, JF and Domínguez-Rubio, R and Expósito-Blázquez, L and Aller, E and Padró-Miquel, A and García-Casanova, P and Colomina, MJ and Martín-Arriscado, C and Osta, R and Cordero-Vázquez, P and Esteban-Pérez, J and Povedano-Panadés, M and García-Redondo, A}, title = {Intermediate Repeat Expansion in the ATXN2 Gene as a Risk Factor in the ALS and FTD Spanish Population.}, journal = {Biomedicines}, volume = {12}, number = {2}, pages = {}, pmid = {38397958}, issn = {2227-9059}, support = {17/00491//Instituto de Salud Carlos III/ ; 21/00286//Instituto de Salud Carlos III/ ; JR19/00030//Instituto de Salud Carlos III/ ; 2021/00737//Instituto de Salud Carlos III/ ; 2017/0653//STOPELA/ ; BOCM142-17/09/2019 pg.105//Spanish Health Ministry/ ; }, abstract = {Intermediate CAG expansions in the gene ataxin-2 (ATXN2) are a known risk factor for ALS, but little is known about their role in FTD risk. Moreover, their contribution to the risk and phenotype of patients might vary in populations with different genetic backgrounds. The aim of this study was to assess the relationship of intermediate CAG expansions in ATXN2 with the risk and phenotype of ALS and FTD in the Spanish population. Repeat-primed PCR was performed in 620 ALS and 137 FTD patients in three referral centers in Spain to determine the exact number of CAG repeats. In our cohort, ≥27 CAG repeats in ATXN2 were associated with a higher risk of developing ALS (odds ratio [OR] = 2.666 [1.471-4.882]; p = 0.0013) but not FTD (odds ratio [OR] = 1.446 [0.558-3.574]; p = 0.44). Moreover, ALS patients with ≥27 CAG repeats in ATXN2 showed a shorter survival rate compared to those with <27 repeats (hazard ratio [HR] 1.74 [1.18, 2.56], p = 0.005), more frequent limb onset (odds ratio [OR] = 2.34 [1.093-4.936]; p = 0.028) and a family history of ALS (odds ratio [OR] = 2.538 [1.375-4.634]; p = 0.002). Intermediate CAG expansions of ≥27 repeats in ATXN2 are associated with ALS risk but not with FTD in the Spanish population. ALS patients carrying an intermediate expansion in ATXN2 show more frequent limb onset but a worse prognosis than those without expansions. In patients carrying C9orf72 expansions, the intermediate ATXN2 expansion might increase the penetrance and modify the phenotype.}, } @article {pmid38397838, year = {2024}, author = {Peggion, C and Calì, T and Brini, M}, title = {Mitochondria Dysfunction and Neuroinflammation in Neurodegeneration: Who Comes First?.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {2}, pages = {}, pmid = {38397838}, issn = {2076-3921}, abstract = {Neurodegenerative diseases (NDs) encompass an assorted array of disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, each characterised by distinct clinical manifestations and underlying pathological mechanisms. While some cases have a genetic basis, many NDs occur sporadically. Despite their differences, these diseases commonly feature chronic neuroinflammation as a hallmark. Consensus has recently been reached on the possibility that mitochondria dysfunction and protein aggregation can mutually contribute to the activation of neuroinflammatory response and thus to the onset and progression of these disorders. In the present review, we discuss the contribution of mitochondria dysfunction and neuroinflammation to the aetiology and progression of NDs, highlighting the possibility that new potential therapeutic targets can be identified to tackle neurodegenerative processes and alleviate the progression of these pathologies.}, } @article {pmid38396996, year = {2024}, author = {Firdaus, Z and Li, X}, title = {Unraveling the Genetic Landscape of Neurological Disorders: Insights into Pathogenesis, Techniques for Variant Identification, and Therapeutic Approaches.}, journal = {International journal of molecular sciences}, volume = {25}, number = {4}, pages = {}, pmid = {38396996}, issn = {1422-0067}, support = {R01 DK126662/DK/NIDDK NIH HHS/United States ; R01 DK129241/DK/NIDDK NIH HHS/United States ; R01 DK129241 and DK126662/NH/NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics/therapy/pathology ; *Parkinson Disease/genetics/therapy/pathology ; *Alzheimer Disease/pathology ; *Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Genetic abnormalities play a crucial role in the development of neurodegenerative disorders (NDDs). Genetic exploration has indeed contributed to unraveling the molecular complexities responsible for the etiology and progression of various NDDs. The intricate nature of rare and common variants in NDDs contributes to a limited understanding of the genetic risk factors associated with them. Advancements in next-generation sequencing have made whole-genome sequencing and whole-exome sequencing possible, allowing the identification of rare variants with substantial effects, and improving the understanding of both Mendelian and complex neurological conditions. The resurgence of gene therapy holds the promise of targeting the etiology of diseases and ensuring a sustained correction. This approach is particularly enticing for neurodegenerative diseases, where traditional pharmacological methods have fallen short. In the context of our exploration of the genetic epidemiology of the three most prevalent NDDs-amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease, our primary goal is to underscore the progress made in the development of next-generation sequencing. This progress aims to enhance our understanding of the disease mechanisms and explore gene-based therapies for NDDs. Throughout this review, we focus on genetic variations, methodologies for their identification, the associated pathophysiology, and the promising potential of gene therapy. Ultimately, our objective is to provide a comprehensive and forward-looking perspective on the emerging research arena of NDDs.}, } @article {pmid38396946, year = {2024}, author = {Anilkumar, AK and Vij, P and Lopez, S and Leslie, SM and Doxtater, K and Khan, MM and Yallapu, MM and Chauhan, SC and Maestre, GE and Tripathi, MK}, title = {Long Non-Coding RNAs: New Insights in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {4}, pages = {}, pmid = {38396946}, issn = {1422-0067}, support = {DP1 AG069870/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; R16 GM146696/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics/pathology ; *RNA, Long Noncoding/genetics ; *Alzheimer Disease ; *Parkinson Disease/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are gradually becoming a burden to society. The adverse effects and mortality/morbidity rates associated with these NDDs are a cause of many healthcare concerns. The pathologic alterations of NDDs are related to mitochondrial dysfunction, oxidative stress, and inflammation, which further stimulate the progression of NDDs. Recently, long non-coding RNAs (lncRNAs) have attracted ample attention as critical mediators in the pathology of NDDs. However, there is a significant gap in understanding the biological function, molecular mechanisms, and potential importance of lncRNAs in NDDs. This review documents the current research on lncRNAs and their implications in NDDs. We further summarize the potential implication of lncRNAs to serve as novel therapeutic targets and biomarkers for patients with NDDs.}, } @article {pmid38396337, year = {2024}, author = {Genge, A and Cedarbaum, JM and Shefner, J and Chio, A and Al-Chalabi, A and Van Damme, P and McDermott, C and Glass, J and Berry, J and van Eijk, RPA and Fournier, C and Grosskreutz, J and Andrews, J and Bertone, V and Bunte, TM and Couillard, M and Cummings, C and Kittle, G and Polzer, J and Salmon, K and Straub, C and van den Berg, LH}, title = {The ALSFRS-R Summit: a global call to action on the use of the ALSFRS-R in ALS clinical trials.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {382-387}, doi = {10.1080/21678421.2024.2320880}, pmid = {38396337}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Severity of Illness Index ; Disease Progression ; }, abstract = {The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) was developed more than 25 years ago as an instrument to monitor functional change over time in patients with ALS. It has since been revised and extended to meet the needs of high data quality in ALS trials (ALSFRS-R), however a full re-validation of the scale was not completed. Despite this, the scale has remained a primary outcome measure in clinical trials. We convened a group of clinical trialists to discuss and explore opportunities to improve the scale and propose alternative measures. In this meeting report, we present a call to action on the use of the ALSFRS-Revised scale in clinical trials, focusing on the need for (1) harmonization of the ALSFRS-R administration globally, (2) alignment on a set of recommendations for clinical trial design and statistical analysis plans (SAPs), and (3) use of additional outcome measures.}, } @article {pmid38395965, year = {2024}, author = {Markovinovic, A and Martín-Guerrero, SM and Mórotz, GM and Salam, S and Gomez-Suaga, P and Paillusson, S and Greig, J and Lee, Y and Mitchell, JC and Noble, W and Miller, CCJ}, title = {Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca[2+] and synaptic defects.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {32}, pmid = {38395965}, issn = {2051-5960}, support = {MR/R022666/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Calcium/metabolism ; Endoplasmic Reticulum/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism ; Protein Tyrosine Phosphatases/metabolism ; Synapses/pathology ; TDP-43 Proteinopathies/metabolism ; *Vesicular Transport Proteins/genetics ; }, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are clinically linked major neurodegenerative diseases. Notably, TAR DNA-binding protein-43 (TDP43) accumulations are hallmark pathologies of FTD/ALS and mutations in the gene encoding TDP43 cause familial FTD/ALS. There are no cures for FTD/ALS. FTD/ALS display damage to a broad range of physiological functions, many of which are regulated by signaling between the endoplasmic reticulum (ER) and mitochondria. This signaling is mediated by the VAPB-PTPIP51 tethering proteins that serve to recruit regions of ER to the mitochondrial surface so as to facilitate inter-organelle communications. Several studies have now shown that disrupted ER-mitochondria signaling including breaking of the VAPB-PTPIP51 tethers are features of FTD/ALS and that for TDP43 and other familial genetic FTD/ALS insults, this involves activation of glycogen kinase-3β (GSK3β). Such findings have prompted suggestions that correcting damage to ER-mitochondria signaling and the VAPB-PTPIP51 interaction may be broadly therapeutic. Here we provide evidence to support this notion. We show that overexpression of VAPB or PTPIP51 to enhance ER-mitochondria signaling corrects mutant TDP43 induced damage to inositol 1,4,5-trisphosphate (IP3) receptor delivery of Ca[2+] to mitochondria which is a primary function of the VAPB-PTPIP51 tethers, and to synaptic function. Moreover, we show that ursodeoxycholic acid (UDCA), an FDA approved drug linked to FTD/ALS and other neurodegenerative diseases therapy and whose precise therapeutic target is unclear, corrects TDP43 linked damage to the VAPB-PTPIP51 interaction. We also show that this effect involves inhibition of TDP43 mediated activation of GSK3β. Thus, correcting damage to the VAPB-PTPIP51 tethers may have therapeutic value for FTD/ALS and other age-related neurodegenerative diseases.}, } @article {pmid38395927, year = {2024}, author = {Baranova, A and Zhao, Q and Cao, H and Chandhoke, V and Zhang, F}, title = {Causal influences of neuropsychiatric disorders on Alzheimer's disease.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {114}, pmid = {38395927}, issn = {2158-3188}, mesh = {Humans ; *Alzheimer Disease/genetics ; *Schizophrenia/epidemiology/genetics ; *Parkinson Disease/genetics ; *Attention Deficit Disorder with Hyperactivity/genetics ; *Migraine Disorders/genetics ; Genome-Wide Association Study ; }, abstract = {Previous studies have observed a significant comorbidity between Alzheimer's disease (AD) and some other neuropsychiatric disorders. However, the mechanistic connections between neuropsychiatric disorders and AD are not well understood. We conducted a Mendelian randomization analysis to appraise the potential influences of 18 neurodegenerative and neuropsychiatric disorders on AD. We found that four disorders are causally associated with increased risk for AD, including bipolar disorder (BD) (OR: 1.09), migraine (OR: 1.09), schizophrenia (OR: 1.05), and Parkinson's disease (PD) (OR: 1.07), while attention-deficit/hyperactivity disorder (ADHD) was associated with a decreased risk for AD (OR: 0.80). In case of amyotrophic lateral sclerosis (OR: 1.04) and Tourette's syndrome (OR: 1.05), there was suggestive evidence of their causal effects of on AD. Our study shows that genetic components predisposing to BD, migraine, schizophrenia, and PD may promote the development of AD, while ADHD may be associated with a reduced risk of AD. The treatments aimed at alleviating neuropsychiatric diseases with earlier onset may also influence the risk of AD-related cognitive decline, which is typically observed later in life.}, } @article {pmid38394955, year = {2024}, author = {Lim, JX and Fong, E and Goh, C and Ng, LP and Low, DCY and Seow, WT and Low, SYY}, title = {Complex lumbosacral spinal cord lipomas: A longitudinal study on outcomes from a Singapore children's hospital.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {121}, number = {}, pages = {119-128}, doi = {10.1016/j.jocn.2024.02.017}, pmid = {38394955}, issn = {1532-2653}, mesh = {Child ; Humans ; Infant ; Longitudinal Studies ; Retrospective Studies ; Treatment Outcome ; Singapore/epidemiology ; *Spinal Cord Neoplasms/diagnostic imaging/surgery ; Spinal Cord ; *Lipoma/surgery ; Hospitals ; Lumbosacral Region/surgery ; }, abstract = {BACKGROUND: Total/near-total resection (TR/NTR) of complex lumbosacral lipomas (CSL) is reported to be associated with better long-term functional outcomes and lower symptomatic re-tethering rates. We report our institutional experience for CSL resection in affected children.

METHODS: This is a single-institution, retrospective study. Inclusion criteria consist of patients with CSL with dorsal, transitional and chaotic lipomas based on Pang et al's classification. The study population is divided into 2 groups: asymptomatic patients with a normal preoperative workup referred to as 'prophylactic intent' and 'therapeutic intent' for those with pre-existing neuro-urological symptoms. Primary aims are to review factors that affect post-operative clean intermittent catheterization (CIC), functional outcomes based on Necker functional score (NFS), and re-tethering rates.

RESULTS: 122 patients were included from 2000 to 2021. There were 32 dorsal lipomas (26.2 %), 74 transitional lipomas (60.7 %), and 16 chaotic lipomas (13.1 %). 82 % patients achieved TR/NTR. Favourable NFS at 1-year was 48.2 %. The re-tethering rate was 6.6 %. After multivariable analysis, post-operative CIC was associated with median age at surgery (p = 0.026), lipoma type (p = 0.029), conus height (p = 0.048) and prophylactic intent (p < 0.001). Next, extent of lipoma resection (p = 0.012) and the post-operative CSF leak (p = 0.004) were associated with re-tethering. Favourable NFS was associated with lipoma type (p = 0.047) and prophylactic intent surgery (p < 0.001).

CONCLUSIONS: Our experience shows that TR/NTR for CSL is a feasible option to prevent functional deterioration and re-tethering. Efforts are needed to work on factors associated with post-operative CIC.}, } @article {pmid38394210, year = {2024}, author = {Chang, YJ and Lin, KT and Shih, O and Yang, CH and Chuang, CY and Fang, MH and Lai, WB and Lee, YC and Kuo, HC and Hung, SC and Yao, CK and Jeng, US and Chen, YR}, title = {Sulfated disaccharide protects membrane and DNA damages from arginine-rich dipeptide repeats in ALS.}, journal = {Science advances}, volume = {10}, number = {8}, pages = {eadj0347}, pmid = {38394210}, issn = {2375-2548}, mesh = {Animals ; Mice ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Dipeptides/pharmacology ; Arginine/genetics ; Sulfates ; Drosophila/genetics ; DNA Damage ; DNA Repeat Expansion ; C9orf72 Protein/genetics/metabolism ; }, abstract = {Hexanucleotide repeat expansion in C9ORF72 (C9) is the most prevalent mutation among amyotrophic lateral sclerosis (ALS) patients. The patients carry over ~30 to hundreds or thousands of repeats translated to dipeptide repeats (DPRs) where poly-glycine-arginine (GR) and poly-proline-arginine (PR) are most toxic. The structure-function relationship is still unknown. Here, we examined the minimal neurotoxic repeat number of poly-GR and found that extension of the repeat number led to a loose helical structure disrupting plasma and nuclear membrane. Poly-GR/PR bound to nucleotides and interfered with transcription. We screened and identified a sulfated disaccharide that bound to poly-GR/PR and rescued poly-GR/PR-induced toxicity in neuroblastoma and C9-ALS-iPSC-derived motor neurons. The compound rescued the shortened life span and defective locomotion in poly-GR/PR expressing Drosophila model and improved motor behavior in poly-GR-injected mouse model. Overall, our results reveal structural and toxicity mechanisms for poly-GR/PR and facilitate therapeutic development for C9-ALS.}, } @article {pmid38393638, year = {2024}, author = {Gowda, VK and Babu, S and Kinhal, U and Srinivasan, VM}, title = {Amyotrophic Lateral Sclerosis due to ALS2 Pathogenic Variant Masquerading as Cerebral Palsy.}, journal = {Indian journal of pediatrics}, volume = {91}, number = {8}, pages = {872}, pmid = {38393638}, issn = {0973-7693}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Cerebral Palsy/diagnosis ; Diagnosis, Differential ; Male ; Guanine Nucleotide Exchange Factors/genetics ; }, } @article {pmid38393299, year = {2024}, author = {García-Parra, B and Guiu, JM and Povedano, M and Mariño, EL and Modamio, P}, title = {Geographical distribution of clinical trials in amyotrophic lateral sclerosis: a scoping review.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {376-381}, doi = {10.1080/21678421.2024.2320881}, pmid = {38393299}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics/therapy ; Belgium ; France ; Germany ; United Kingdom ; }, abstract = {Introduction: Clinical trials location is determined by many factors, including the availability of patient populations, regulatory environment, scientific expertise, and cost considerations. In clinical drug development of amyotrophic lateral sclerosis (ALS), where genetic differences have been described and may be related to geographic setting, this could have implications for the clinical interpretation of results in underrepresented geographic settings. Objective: The aim of this study was to review country participation in ALS clinical research based on available data from clinical trial registries and databases. Methods: We performed a scoping review with available information about clinical trials on ALS in ClinicalTrials.gov (CT), EU clinical trials register (EudraCT), WHO International Clinical Trials Registry Platform (ICTRP) and Web of Science (WOS). Inclusion criteria were clinical trials in phase 2 and 3 to treat ALS, recruiting or active not recruiting, from 23/06/2018 to 23/06/2023. Results: The total number of clinical trials identified were 188; 54 studies in CT, 38 in EudraCT, 47 in ICTRP and 49 in WOS. We identified 77 clinical trials after deleting duplicates and applying exclusion criteria. The countries with most studies conducted were the US with 35 studies (10.9%), followed by the United Kingdom, Belgium, France and Germany with 21 studies each one of them (6.5%). Conclusion: The data obtained in our review showed a non-homogeneous distribution in clinical trials at the international level, which may influence the interpretation of the results obtained.}, } @article {pmid38392311, year = {2024}, author = {Dratch, L and Bardakjian, TM and Johnson, K and Babaian, N and Gonzalez-Alegre, P and Elman, L and Quinn, C and Guo, MH and Scherer, SS and Amado, DA}, title = {The Importance of Offering Exome or Genome Sequencing in Adult Neuromuscular Clinics.}, journal = {Biology}, volume = {13}, number = {2}, pages = {}, pmid = {38392311}, issn = {2079-7737}, abstract = {Advances in gene-specific therapeutics for patients with neuromuscular disorders (NMDs) have brought increased attention to the importance of genetic diagnosis. Genetic testing practices vary among adult neuromuscular clinics, with multi-gene panel testing currently being the most common approach; follow-up testing using broad-based methods, such as exome or genome sequencing, is less consistently offered. Here, we use five case examples to illustrate the unique ability of broad-based testing to improve diagnostic yield, resulting in identification of SORD-neuropathy, HADHB-related disease, ATXN2-ALS, MECP2 related progressive gait decline and spasticity, and DNMT1-related cerebellar ataxia, deafness, narcolepsy, and hereditary sensory neuropathy type 1E. We describe in each case the technological advantages that enabled identification of the causal gene, and the resultant clinical and personal implications for the patient, demonstrating the importance of offering exome or genome sequencing to adults with NMDs.}, } @article {pmid38392286, year = {2024}, author = {Jackson, WS and Bauer, S and Kaczmarczyk, L and Magadi, SS}, title = {Selective Vulnerability to Neurodegenerative Disease: Insights from Cell Type-Specific Translatome Studies.}, journal = {Biology}, volume = {13}, number = {2}, pages = {}, pmid = {38392286}, issn = {2079-7737}, support = {grant # 990868//the Konung Gustaf V:s och Drottning Victorias Stiftelse; the Wallenberg Center for Molecular Medicine;the Hereditary Disease Foundation/ ; }, abstract = {Neurodegenerative diseases (NDs) manifest a wide variety of clinical symptoms depending on the affected brain regions. Gaining insights into why certain regions are resistant while others are susceptible is vital for advancing therapeutic strategies. While gene expression changes offer clues about disease responses across brain regions, the mixture of cell types therein obscures experimental results. In recent years, methods that analyze the transcriptomes of individual cells (e.g., single-cell RNA sequencing or scRNAseq) have been widely used and have provided invaluable insights into specific cell types. Concurrently, transgene-based techniques that dissect cell type-specific translatomes (CSTs) in model systems, like RiboTag and bacTRAP, offer unique advantages but have received less attention. This review juxtaposes the merits and drawbacks of both methodologies, focusing on the use of CSTs in understanding conditions like amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Alzheimer's disease (AD), and specific prion diseases like fatal familial insomnia (FFI), genetic Creutzfeldt-Jakob disease (gCJD), and acquired prion disease. We conclude by discussing the emerging trends observed across multiple diseases and emerging methods.}, } @article {pmid38392208, year = {2024}, author = {Fukatsu, S and Okawa, M and Okabe, M and Cho, M and Isogai, M and Yokoi, T and Shirai, R and Oizumi, H and Yamamoto, M and Ohbuchi, K and Miyamoto, Y and Yamauchi, J}, title = {Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148Tyr.}, journal = {Current issues in molecular biology}, volume = {46}, number = {2}, pages = {1398-1412}, pmid = {38392208}, issn = {1467-3045}, abstract = {Some charged multivesicular body protein 2B (CHMP2B) mutations are associated with autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 7 (FTDALS7). The main aim of this study is to clarify the relationship between the expression of mutated CHMP2B protein displaying FTD symptoms and defective neuronal differentiation. First, we illustrate that the expression of CHMP2B with the Asp148Tyr (D148Y) mutation, which preferentially displays FTD phenotypes, blunts neurite process elongation in rat primary cortical neurons. Similar results were observed in the N1E-115 cell line, a model that undergoes neurite elongation. Second, these effects were also accompanied by changes in neuronal differentiation marker protein expression. Third, wild-type CHMP2B protein was indeed localized in the endosomal sorting complexes required to transport (ESCRT)-like structures throughout the cytoplasm. In contrast, CHMP2B with the D148Y mutation exhibited aggregation-like structures and accumulated in the Golgi body. Fourth, among currently known Golgi stress regulators, the expression levels of Hsp47, which has protective effects on the Golgi body, were decreased in cells expressing CHMP2B with the D148Y mutation. Fifth, Arf4, another Golgi stress-signaling molecule, was increased in mutant-expressing cells. Finally, when transfecting Hsp47 or knocking down Arf4 with small interfering (si)RNA, cellular phenotypes in mutant-expressing cells were recovered. These results suggest that CHMP2B with the D148Y mutation, acting through Golgi stress signaling, is negatively involved in the regulation of neuronal cell morphological differentiation, providing evidence that a molecule controlling Golgi stress may be one of the potential FTD therapeutic targets at the molecular and cellular levels.}, } @article {pmid38391754, year = {2024}, author = {Leão Batista Simões, J and Webler Eichler, S and Raitz Siqueira, ML and de Carvalho Braga, G and Bagatini, MD}, title = {Amyotrophic Lateral Sclerosis in Long-COVID Scenario and the Therapeutic Potential of the Purinergic System in Neuromodulation.}, journal = {Brain sciences}, volume = {14}, number = {2}, pages = {}, pmid = {38391754}, issn = {2076-3425}, support = {Proj. No 404256/2021-0 and 310606/2021-7).//National Council for Scientific and Technological Development/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) involves the degeneration of motor neurons and debilitating and possibly fatal symptoms. The COVID-19 pandemic directly affected the quality of life of this group, and the SARS-CoV-2 infection accelerated the present neuroinflammatory process. Furthermore, studies indicate that the infection may have led to the development of the pathology. Thus, the scenario after this pandemic presents "long-lasting COVID" as a disease that affects people who have been infected. From this perspective, studying the pathophysiology behind ALS associated with SARS-CoV-2 infection and possible supporting therapies becomes necessary when we understand the impact on the quality of life of these patients. Thus, the purinergic system was trained to demonstrate how its modulation can add to the treatment, reduce disease progression, and result in better prognoses. From our studies, we highlight the P2X7, P2X4, and A2AR receptors and how their activity can directly influence the ALS pathway.}, } @article {pmid38391732, year = {2024}, author = {Yang, K and Liu, Y and Zhang, M}, title = {The Diverse Roles of Reactive Astrocytes in the Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {14}, number = {2}, pages = {}, pmid = {38391732}, issn = {2076-3425}, support = {82271478//National Natural Science Foundation of China/ ; }, abstract = {Astrocytes displaying reactive phenotypes are characterized by their ability to remodel morphologically, molecularly, and functionally in response to pathological stimuli. This process results in the loss of their typical astrocyte functions and the acquisition of neurotoxic or neuroprotective roles. A growing body of research indicates that these reactive astrocytes play a pivotal role in the pathogenesis of amyotrophic lateral sclerosis (ALS), involving calcium homeostasis imbalance, mitochondrial dysfunction, abnormal lipid and lactate metabolism, glutamate excitotoxicity, etc. This review summarizes the characteristics of reactive astrocytes, their role in the pathogenesis of ALS, and recent advancements in astrocyte-targeting strategies.}, } @article {pmid38391731, year = {2024}, author = {Manera, U and Torrieri, MC and Moglia, C and Canosa, A and Vasta, R and Palumbo, F and Matteoni, E and Cabras, S and Grassano, M and Bombaci, A and Mattei, A and Bellocchia, M and Tabbia, G and Ribolla, F and Chiò, A and Calvo, A}, title = {Calculated Maximal Volume Ventilation (cMVV) as a Marker of Early Respiratory Failure in Amyotrophic Lateral Sclerosis (ALS).}, journal = {Brain sciences}, volume = {14}, number = {2}, pages = {}, pmid = {38391731}, issn = {2076-3425}, support = {GA101017598//European Union's Horizon 2020/ ; RF-2016-02362405//the Italian Ministry of Health/ ; 2017SNW5MB//Italian Ministry of Education, University and Research/ ; 259867//European Commission's Health Seventh Framework Programme/ ; Strength, ALS-Care and Brain-Mend projects//Joint Programme-Neurodegenerative Disease Research/ ; Department of Excellence grant//Italian Ministry of University and Research/ ; }, abstract = {Respiratory failure assessment is among the most debatable research topics in amyotrophic lateral sclerosis (ALS) clinical research due to the wide heterogeneity of its presentation. Among the different pulmonary function tests (PFTs), maximal voluntary ventilation (MVV) has shown potential utility as a diagnostic and monitoring marker, able to capture early respiratory modification in neuromuscular disorders. In the present study, we explored calculated MVV (cMVV) as a prognostic biomarker in a center-based, retrospective ALS population belonging to the Piemonte and Valle d'Aosta registry for ALS (PARALS). A Spearman's correlation analysis with clinical data and PFTs showed a good correlation of cMVV with forced vital capacity (FVC) and a moderate correlation with some other features such as bulbar involvement, ALSFRS-R total score, blood oxygen (pO2), carbonate (HCO3[-]), and base excess (BE), measured with arterial blood gas analysis. Both the Cox proportional hazard models for survival and the time to non-invasive ventilation (NIV) measurement highlighted that cMVV at diagnosis (considering cMVV(40) ≥ 80) is able to stratify patients across different risk levels for death/tracheostomy and NIV indication, especially considering patients with FVC% ≥ 80. In conclusion, cMVV is a useful marker of early respiratory failure in ALS, and is easily derivable from standard PFTs, especially in asymptomatic ALS patients with normal FVC measures.}, } @article {pmid38390994, year = {2024}, author = {Nájera-Maldonado, JM and Salazar, R and Alvarez-Fitz, P and Acevedo-Quiroz, M and Flores-Alfaro, E and Hernández-Sotelo, D and Espinoza-Rojo, M and Ramírez, M}, title = {Phenolic Compounds of Therapeutic Interest in Neuroprotection.}, journal = {Journal of xenobiotics}, volume = {14}, number = {1}, pages = {227-246}, pmid = {38390994}, issn = {2039-4713}, support = {A1-S-34290 to Monica Ramirez//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; }, abstract = {The number of elderly people is projected to double in the next 50 years worldwide, resulting in an increased prevalence of neurodegenerative diseases. Aging causes changes in brain tissue homeostasis, thus contributing to the development of neurodegenerative disorders. Current treatments are not entirely effective, so alternative treatments or adjuvant agents are being actively sought. Antioxidant properties of phenolic compounds are of particular interest for neurodegenerative diseases whose psychopathological mechanisms strongly rely on oxidative stress at the brain level. Moreover, phenolic compounds display other advantages such as the permeability of the blood-brain barrier (BBB) and the interesting molecular mechanisms that we reviewed in this work. We began by briefly outlining the physiopathology of neurodegenerative diseases to understand the mechanisms that result in irreversible brain damage, then we provided an overall classification of the phenolic compounds that would be addressed later. We reviewed in vitro and in vivo studies, as well as some clinical trials in which neuroprotective mechanisms were demonstrated in models of different neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), ischemia, and traumatic brain injury (TBI).}, } @article {pmid38390945, year = {2024}, author = {Fukatsu, S and Sashi, H and Shirai, R and Takagi, N and Oizumi, H and Yamamoto, M and Ohbuchi, K and Miyamoto, Y and Yamauchi, J}, title = {Rab11a Controls Cell Shape via C9orf72 Protein: Possible Relationships to Frontotemporal Dementia/Amyotrophic Lateral Sclerosis (FTDALS) Type 1.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {31}, number = {1}, pages = {100-116}, pmid = {38390945}, issn = {1873-149X}, abstract = {Abnormal nucleotide insertions of C9orf72, which forms a complex with Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8) protein and WD repeat-containing protein 41 (WDR41) protein, are associated with an autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 1 (FTDALS1). The differentially expressed in normal and neoplastic cells (DENN) domain-containing C9orf72 and its complex with SMCR8 and WDR41 function as a guanine-nucleotide exchange factor for Rab GTP/GDP-binding proteins (Rab GEF, also called Rab activator). Among Rab proteins serving as major effectors, there exists Rab11a. However, it remains to be established which Rab protein is related to promoting or sustaining neuronal morphogenesis or homeostasis. In this study, we describe that the knockdown of Rab11a decreases the expression levels of neuronal differentiation marker proteins, as well as the elongation of neurite-like processes, using N1E-115 cells, a well-utilized neuronal differentiation model. Similar results were obtained in primary cortical neurons. In contrast, the knockdown of Rab11b, a Rab11a homolog, did not significantly affect their cell morphological changes. It is of note that treatment with hesperetin, a citrus flavonoid (also known as Vitamin P), recovered the neuronal morphological phenotypes induced by Rab11a knockdown. Also, the knockdown of Rab11a or Rab11b led to a decrease in glial marker expression levels and in morphological changes in FBD-102b cells, which serve as the oligodendroglial differentiation model. Rab11a is specifically involved in the regulation of neuronal morphological differentiation. The knockdown effect mimicking the loss of function of C9orf72 is reversed by treatment with hesperetin. These findings may reveal a clue for identifying one of the potential molecular and cellular phenotypes underlying FTDALS1.}, } @article {pmid38389786, year = {2024}, author = {Berthiaume, AA and Reda, SM and Kleist, KN and Setti, SE and Wu, W and Johnston, JL and Taylor, RW and Stein, LR and Moebius, HJ and Church, KJ}, title = {ATH-1105, a small-molecule positive modulator of the neurotrophic HGF system, is neuroprotective, preserves neuromotor function, and extends survival in preclinical models of ALS.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1348157}, pmid = {38389786}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disorder, primarily affects the motor neurons of the brain and spinal cord. Like other neurodegenerative conditions, ongoing pathological processes such as increased inflammation, excitotoxicity, and protein accumulation contribute to neuronal death. Hepatocyte growth factor (HGF) signaling through the MET receptor promotes pro-survival, anti-apoptotic, and anti-inflammatory effects in multiple cell types, including the neurons and support cells of the nervous system. This pleiotropic system is therefore a potential therapeutic target for treatment of neurodegenerative disorders such as ALS. Here, we test the effects of ATH-1105, a small-molecule positive modulator of the HGF signaling system, in preclinical models of ALS.

METHODS: In vitro, the impact of ATH-1105 on HGF-mediated signaling was assessed via phosphorylation assays for MET, extracellular signal-regulated kinase (ERK), and protein kinase B (AKT). Neuroprotective effects of ATH-1105 were evaluated in rat primary neuron models including spinal motor neurons, motor neuron-astrocyte cocultures, and motor neuron-human muscle cocultures. The anti-inflammatory effects of ATH-1105 were evaluated in microglia- and macrophage-like cell systems exposed to lipopolysaccharide (LPS). In vivo, the impact of daily oral treatment with ATH-1105 was evaluated in Prp-TDP43[A315T] hemizygous transgenic ALS mice.

RESULTS: In vitro, ATH-1105 augmented phosphorylation of MET, ERK, and AKT. ATH-1105 attenuated glutamate-mediated excitotoxicity in primary motor neurons and motor neuron- astrocyte cocultures, and had protective effects on motor neurons and neuromuscular junctions in motor neuron-muscle cocultures. ATH-1105 mitigated LPS-induced inflammation in microglia- and macrophage-like cell systems. In vivo, ATH-1105 treatment resulted in improved motor and nerve function, sciatic nerve axon and myelin integrity, and survival in ALS mice. Treatment with ATH-1105 also led to reductions in levels of plasma biomarkers of inflammation and neurodegeneration, along with decreased pathological protein accumulation (phospho-TDP-43) in the sciatic nerve. Additionally, both early intervention (treatment initiation at 1 month of age) and delayed intervention (treatment initiation at 2 months of age) with ATH-1105 produced benefits in this preclinical model of ALS.

DISCUSSION: The consistent neuroprotective and anti-inflammatory effects demonstrated by ATH-1105 preclinically provide a compelling rationale for therapeutic interventions that leverage the positive modulation of the HGF pathway as a treatment for ALS.}, } @article {pmid38389507, year = {2024}, author = {Al Ojaimi, Y and Slek, C and Osman, S and Alarcan, H and Marouillat, S and Corcia, P and Vourc'h, P and Lanznaster, D and Blasco, H}, title = {The effect of pH alterations on TDP-43 in a cellular model of amyotrophic lateral sclerosis.}, journal = {Biochemistry and biophysics reports}, volume = {38}, number = {}, pages = {101664}, pmid = {38389507}, issn = {2405-5808}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. The pathophysiology of ALS is not well understood but TDP-43 proteinopathy (aggregation and mislocalization) is one of the major phenomena described. Several factors can influence TDP-43 behavior such as mild pH alterations that can induce conformational changes in recombinant TDP-43, increasing its propensity to aggregate. However to our knowledge, no studies have been conducted yet in a cellular setting, in the context of ALS. We therefore tested the effect of cellular pH alterations on the localization, aggregation, and phosphorylation of TDP-43. HEK293T cells overexpressing wildtype TDP-43 were incubated for 1 h with solutions of different pH (6.4, 7.2, and 8). Incubation of cells for 1 h in solutions of pH 6.4 and 8 led to an increase in TDP-43-positive puncta. This was accompanied by the mislocalization of TDP-43 from the nucleus to the cytoplasm. Our results suggest that small alterations in cellular pH affect TDP-43 and increase its mislocalization into cytoplasmic TDP-43-positive puncta, which might suggest a role of TDP-43 in the response of cells to pH alterations.}, } @article {pmid38389222, year = {2024}, author = {Consonni, M and Faltracco, V and Dalla Bella, E and Telesca, A and Bersano, E and Nigri, A and Demichelis, G and Medina, JP and Bruzzone, MG and Lauria, G}, title = {Loneliness as neurobehavioral issue in amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {5}, pages = {1122-1134}, pmid = {38389222}, issn = {2328-9503}, support = {2015-0023//Fondazione Regionale per la Ricerca Biomedica, Regione Lombardia/ ; 1157625//Fondo Europeo di Sviluppo Regionale, Regione Lombardia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology/diagnostic imaging ; Male ; *Loneliness/psychology ; Female ; Aged ; Middle Aged ; *Quality of Life ; Magnetic Resonance Imaging ; Cognitive Dysfunction/etiology/physiopathology/diagnostic imaging ; Depression/physiopathology ; }, abstract = {OBJECTIVE: In elderly people loneliness represents a risk factor for dementia and may negatively impact on mental and physical health. The specific contribute of loneliness to cognitive and behavioral functioning have not yet been determined in amyotrophic lateral sclerosis (ALS). Our hypothesis was that loneliness may be related to motor dysfunction with a negative impact on cognitive and behavioral decline, possibly related to specific cortical involvement.

METHODS: In 200 ALS patients (ALSpts) and 50 healthy controls (HCs) we measured loneliness, mood, and quality of life (QoL). ALSpts underwent comprehensive clinical, genetic, and neuropsychological assessment to define phenotypes. Seventy-seven ALSpts performed 3T MRI scans to measure cortical thickness. Between-group, partial correlation and regression analyses were used to examined clinical, neuropsychological, and cortical signatures of loneliness.

RESULTS: Feelings of loneliness were documented in 38% of ALSpts (ALS/L+pts) and in 47% of HCs. In both groups loneliness was associated with anxiety (P < 0.001), depression (P ≤ 0.005), and poor QoL (P < 0.001). ALS/L+pts had similar motor dysfunctions and cognitive abilities than non-lonely ALSpts, but distinct behavioral profiles (P ≤ 0.005) and frontoparietal involvement (P < 0.05). Loneliness in ALS is related to behavioral changes, apathy, and emotional dysregulation (P < 0.001).

INTERPRETATION: Our cross-sectional study indicates that, in ALS, the satisfaction of social environment is associated with a sense of life well-being that is not limited to the motor status, proving instead that loneliness can impact on disease-related neurobehavioral changes with a possible flashback on brain architecture. This suggests that sociality could promote personal resilience against behavioral and affective decline in ALS.}, } @article {pmid38389123, year = {2024}, author = {Sainouchi, M and Oginezawa, S and Tada, M and Ishihara, T and Onodera, O and Kakita, A}, title = {Slow disease progression and characteristic TDP-43 inclusions in a patient with familial amyotrophic lateral sclerosis carrying a TARDBP G357S variant.}, journal = {Neuropathology and applied neurobiology}, volume = {50}, number = {1}, pages = {e12966}, doi = {10.1111/nan.12966}, pmid = {38389123}, issn = {1365-2990}, support = {22H02995//JSPS/ ; 23H00434//JSPS/ ; 21K07272//JSPS/ ; JP23jm0210097//AMED-SICORP/ ; //Grants-in Aid from the Research Committee of CNS Degenerative Diseases/ ; //Research on Policy Planning and Evaluation for Rare and Intractable Diseases/ ; //Health, Labour and Welfare Sciences Research Grants/ ; //Ministry of Health, Labour and Welfare, Japan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Disease Progression ; DNA-Binding Proteins/genetics ; Mutation ; }, } @article {pmid38388775, year = {2024}, author = {Pang, D and Yu, Y and Zhao, B and Huang, J and Cui, Y and Li, T and Li, C and Shang, H}, title = {The Long Non-Coding RNA NR3C2-8:1 Promotes p53-Mediated Apoptosis through the miR-129-5p/USP10 Axis in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {61}, number = {10}, pages = {7466-7480}, pmid = {38388775}, issn = {1559-1182}, support = {81871000//National Natural Science Foundation of China/ ; 2022NSFSC0750//Sichuan Province Science and Technology Support Program/ ; }, mesh = {*RNA, Long Noncoding/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Tumor Suppressor Protein p53/metabolism/genetics ; *Apoptosis/genetics ; *MicroRNAs/genetics/metabolism ; *Ubiquitin Thiolesterase/genetics/metabolism ; Male ; Signal Transduction/genetics ; Up-Regulation/genetics ; Base Sequence ; }, abstract = {Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is a form of apoptosis, but the mechanisms underlying this neuronal cell death remain unclear. Numerous studies demonstrate abnormally elevated and active p53 in the central nervous system of ALS patients. Activation of p53-regulated pro-apoptotic signaling pathways may trigger motor neuron death. We previously reported decreased expression of the long non-coding RNA NR3C2-8:1 (Lnc-NR3C) in leukocytes of ALS patients. Here, we show lnc-NR3C promotes p53-mediated cell death in ALS by upregulating USP10 and promoting lnc-NR3C-triggered p53 activation, resulting in cell death. Conversely, lnc-NR3C knockdown inhibited USP10-triggered p53 activation, thereby protecting cells against oxidative stress. As a competitive endogenous RNA, lnc-NR3C competitively binds miR-129-5p, regulating the usp10/p53 axis. Elucidating the link between Lnc-NR3C and the USP10/p53 axis in an ALS cell model reveals a role for long non-coding RNAs in activating apoptosis. This provides new therapeutic opportunities in ALS.}, } @article {pmid38386047, year = {2024}, author = {Imrell, S and Fang, F and Ingre, C and Sennfält, S}, title = {Increased incidence of motor neuron disease in Sweden: a population-based study during 2002-2021.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2730-2735}, pmid = {38386047}, issn = {1432-1459}, support = {Swedish Research Grant DNR 2019-01088//Vetenskapsrådet/ ; }, mesh = {Humans ; Sweden/epidemiology ; Male ; Female ; Incidence ; Aged ; *Motor Neuron Disease/epidemiology ; Middle Aged ; Aged, 80 and over ; Adult ; *Registries ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Motor neuron diseases (MND), with amyotrophic lateral sclerosis constituting most cases, are rare conditions of unknown etiology. There have been reports of an increase in incidence during the latter half of the twentieth century in various Western countries, including Sweden. This study provides updated data on the incidence of MND in Sweden during the last 20 years.

METHODS: Data was obtained from the Swedish National Patient Register on individuals diagnosed with MND from 2002 to 2021 and analysed in relation to group level data for the entire Swedish population. Incidence rates were calculated and presented in relation to year, age, sex, and region.

RESULTS: In the early 2000s, there was a crude incidence rate of 3.5-3.7 per 100,000 person-years, which then increased to 4.0-4.6 from 2008 onward. Age standardization to the starting year (2002) partially mitigated this increase. The incidence rate was greater among men compared to women and was highest within the age range of 70 to 84 years. There were indications of a higher incidence rate in the northernmost parts of the country, although the difference was not statistically significant.

CONCLUSIONS: The incidence rate of MND in Sweden now seems to have surpassed 4 cases per 100,000 person-years. This is higher when compared to both other European countries and previous Swedish studies. It remains to be determined if this increase reflects an actual increasing incidence of MND in Sweden or is due to other factors such as better registry coverage.}, } @article {pmid38385052, year = {2024}, author = {Cherin, N and Patel, S and Jukic, M}, title = {Delayed amyotrophic lateral sclerosis diagnosis with subtle cardiac manifestations: Was anchoring bias contributory?.}, journal = {Clinical case reports}, volume = {12}, number = {2}, pages = {e8544}, pmid = {38385052}, issn = {2050-0904}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disease affecting both upper and lower motor neurons. Throughout medical training, it is taught that the most recognizable clinical presentation involves both motor and bulbar changes. Given the complexity of the diagnosis however, it is no surprise that there is significant multisystem involvement secondary to the autonomic dysfunction associated with the disease. The clinical cognitive biases that exist due to prior educational training and patient provided chief complaint can mislead clinicians and prevent a holistic, inclusive approach toward each patient encounter. This can delay diagnosis and increase unnecessary healthcare spending. In a disease with such a poor prognosis, this effect can be catastrophic, resulting in unacceptable medical, functional, and psychosocial outcomes. As clinicians, it is imperative to acknowledge these cognitive biases through introspection, which can improve clinical outcomes and ultimately patient quality of life for those facing this devastating disease. We report a case of a 55-year-old female who presented with a chief complaint of palpitations and minimal slurred speech on multiple encounters, subsequently leading to a focused cardiovascular workup. It was not until after several hospital encounters that a thorough functional and neuromuscular exam was performed, which ultimately helped to broaden the differential and lead to the diagnosis of ALS. Unfortunately, due to this delayed diagnosis, the patient's functionality was beyond repair. Given the underlying cognitive biases that are present in all clinicians, we hypothesize this patient's sex, presenting symptom, and primary chief complaint misled clinicians to perform limited history and physical examinations, therefore, leading to a narrowed differential. If diagnosed in a timely fashion, vital services such as rehabilitation could have provided this patient with the necessary medical, functional, and psychosocial support to face this devastating disease.}, } @article {pmid38384337, year = {2024}, author = {Wiesenfarth, M and Dorst, J and Brenner, D and Elmas, Z and Parlak, Ö and Uzelac, Z and Kandler, K and Mayer, K and Weiland, U and Herrmann, C and Schuster, J and Freischmidt, A and Müller, K and Siebert, R and Bachhuber, F and Simak, T and Günther, K and Fröhlich, E and Knehr, A and Regensburger, M and German, A and Petri, S and Grosskreutz, J and Klopstock, T and Reilich, P and Schöberl, F and Hagenacker, T and Weyen, U and Günther, R and Vidovic, M and Jentsch, M and Haarmeier, T and Weydt, P and Valkadinov, I and Hesebeck-Brinckmann, J and Conrad, J and Weishaupt, JH and Schumann, P and Körtvélyessy, P and Meyer, T and Ruf, WP and Witzel, S and Senel, M and Tumani, H and Ludolph, AC}, title = {Effects of tofersen treatment in patients with SOD1-ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program.}, journal = {EClinicalMedicine}, volume = {69}, number = {}, pages = {102495}, pmid = {38384337}, issn = {2589-5370}, abstract = {BACKGROUND: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated.

METHODS: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events.

FINDINGS: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported.

INTERPRETATION: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction.

FUNDING: No funding was received towards this study.}, } @article {pmid38383591, year = {2024}, author = {Verheijen, BM and Chung, C and Thompson, B and Kim, H and Nakahara, A and Anink, JJ and Mills, JD and , and Lee, JH and Aronica, E and Oyanagi, K and Kakita, A and Gout, JF and Vermulst, M}, title = {The cycad genotoxin methylazoxymethanol, linked to Guam ALS/PDC, induces transcriptional mutagenesis.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {30}, pmid = {38383591}, issn = {2051-5960}, support = {R01 AG054641/AG/NIA NIH HHS/United States ; R01AG054641/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Mutagens ; Guam ; Methylazoxymethanol Acetate/*analogs & derivatives ; Mutagenesis ; *Amyotrophic Lateral Sclerosis/genetics ; }, } @article {pmid38383503, year = {2024}, author = {Vidovic, M and Menschikowski, M and Freigang, M and Lapp, HS and Günther, R}, title = {Macrophage inclusions in cerebrospinal fluid following treatment initiation with antisense oligonucleotide therapies in motor neuron diseases.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {11}, pmid = {38383503}, issn = {2524-3489}, abstract = {5q-associated spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are two distinct neurological disorders leading to degeneration of lower motor neurons. The antisense oligonucleotides (ASOs) nusinersen and tofersen are novel disease-modifying agents for these diseases, respectively. In the context of ASO treatment, the cytological characteristics and composition of cerebrospinal fluid (CSF) have recently garnered particular interest. This report presents a case series of CSF cytology findings in two patients with SMA and ALS revealing comparable unspecified macrophage inclusions following treatment initiation with nusinersen and tofersen. Yet, the presence of these "asophages" in the treatment course of two different ASOs is of unclear significance. While both treatments have been well tolerated, this phenomenon warrants attention, given the long-term nature of these treatments.}, } @article {pmid38383499, year = {2024}, author = {Halcrow, PW and Quansah, DNK and Kumar, N and Steiner, JP and Nath, A and Geiger, JD}, title = {HERV-K (HML-2) Envelope Protein Induces Mitochondrial Depolarization and Neurotoxicity via Endolysosome Iron Dyshomeostasis.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {44}, number = {14}, pages = {}, pmid = {38383499}, issn = {1529-2401}, support = {R01 NS065957/NS/NINDS NIH HHS/United States ; U54 GM115458/GM/NIGMS NIH HHS/United States ; R01 MH119000/MH/NIMH NIH HHS/United States ; R01 DA032444/DA/NIDA NIH HHS/United States ; R01 GM100329/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Endogenous Retroviruses ; *Amyotrophic Lateral Sclerosis/pathology ; Iron ; Reactive Oxygen Species ; *Neuroblastoma ; *Neurotoxicity Syndromes ; Arginine ; }, abstract = {Human endogenous retroviruses (HERVs) are associated with the pathogenesis of amyotrophic lateral sclerosis (ALS); a disease characterized by motor neuron degeneration and cell death. The HERV-K subtype HML-2 envelope protein (HERV-K Env) is expressed in the brain, spinal cord, and cerebrospinal fluid of people living with ALS and through CD98 receptor-linked interactions causes neurodegeneration. HERV-K Env-induced increases in oxidative stress are implicated in the pathogenesis of ALS, and ferrous iron (Fe[2+]) generates reactive oxygen species (ROS). Endolysosome stores of Fe[2+] are central to iron trafficking and endolysosome deacidification releases Fe[2+] into the cytoplasm. Because HERV-K Env is an arginine-rich protein that is likely endocytosed and arginine is a pH-elevating amino acid, it is important to determine HERV-K Env effects on endolysosome pH and whether HERV-K Env-induced neurotoxicity is downstream of Fe[2+] released from endolysosomes. Here, we showed using SH-SY5Y human neuroblastoma cells and primary cultures of human cortical neurons (HCNs, information on age and sex was not available) that HERV-K Env (1) is endocytosed via CD98 receptors, (2) concentration dependently deacidified endolysosomes, (3) decreased endolysosome Fe[2+] concentrations, (4) increased cytosolic and mitochondrial Fe[2+] and ROS levels, (5) depolarized mitochondrial membrane potential, and (6) induced cell death, effects blocked by an antibody against the CD98 receptor and by the endolysosome iron chelator deferoxamine. Thus, HERV-K Env-induced increases in cytosolic and mitochondrial Fe[2+] and ROS as well as cell death appear to be mechanistically caused by HERV-K Env endocytosis, endolysosome deacidification, and endolysosome Fe[2+] efflux into the cytoplasm.}, } @article {pmid38382884, year = {2024}, author = {Jiao, LL and Dong, HL and Liu, MM and Wu, PL and Cao, Y and Zhang, Y and Gao, FG and Zhu, HY}, title = {The potential roles of salivary biomarkers in neurodegenerative diseases.}, journal = {Neurobiology of disease}, volume = {193}, number = {}, pages = {106442}, doi = {10.1016/j.nbd.2024.106442}, pmid = {38382884}, issn = {1095-953X}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis ; Reproducibility of Results ; *Parkinson Disease/metabolism ; *Alzheimer Disease ; *Huntington Disease/diagnosis ; Biomarkers ; }, abstract = {Current research efforts on neurodegenerative diseases are focused on identifying novel and reliable biomarkers for early diagnosis and insight into disease progression. Salivary analysis is gaining increasing interest as a promising source of biomarkers and matrices for measuring neurodegenerative diseases. Saliva collection offers multiple advantages over the currently detected biofluids as it is easily accessible, non-invasive, and repeatable, allowing early diagnosis and timely treatment of the diseases. Here, we review the existing findings on salivary biomarkers and address the potential value in diagnosing neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Based on the available research, β-amyloid, tau protein, α-synuclein, DJ-1, Huntington protein in saliva profiles display reliability and validity as the biomarkers of neurodegenerative diseases.}, } @article {pmid38382647, year = {2024}, author = {Huang, TN and Shih, YT and Yen, TL and Hsueh, YP}, title = {Vcp overexpression and leucine supplementation extend lifespan and ameliorate neuromuscular junction phenotypes of a SOD1G93A-ALS mouse model.}, journal = {Human molecular genetics}, volume = {33}, number = {11}, pages = {935-944}, pmid = {38382647}, issn = {1460-2083}, support = {AS-CFII-108-104//Transgenic Core Facility/ ; //Animal Facility of the Institute of Molecular Biology, Academia Sinica/ ; }, mesh = {Animals ; *Valosin Containing Protein/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Disease Models, Animal ; Mice ; *Neuromuscular Junction/metabolism ; Female ; Male ; *Longevity/genetics ; *Mice, Transgenic ; *Leucine/pharmacology/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; *Phenotype ; Superoxide Dismutase/genetics/metabolism ; Cell Cycle Proteins/genetics/metabolism ; Humans ; Adenosine Triphosphatases/genetics/metabolism ; }, abstract = {Many genes with distinct molecular functions have been linked to genetically heterogeneous amyotrophic lateral sclerosis (ALS), including SuperOxide Dismutase 1 (SOD1) and Valosin-Containing Protein (VCP). SOD1 converts superoxide to oxygen and hydrogen peroxide. VCP acts as a chaperon to regulate protein degradation and synthesis and various other cellular responses. Although the functions of these two genes differ, in the current report we show that overexpression of wild-type VCP in mice enhances lifespan and maintains the size of neuromuscular junctions (NMJs) of both male and female SOD1G93A mice, a well-known ALS mouse model. Although VCP exerts multiple functions, its regulation of ER formation and consequent protein synthesis has been shown to play the most important role in controlling dendritic spine formation and social and memory behaviors. Given that SOD1 mutation results in protein accumulation and aggregation, it may direct VCP to the protein degradation pathway, thereby impairing protein synthesis. Since we previously showed that the protein synthesis defects caused by Vcp deficiency can be improved by leucine supplementation, to confirm the role of the VCP-protein synthesis pathway in SOD1-linked ALS, we applied leucine supplementation to SOD1G93A mice and, similar to Vcp overexpression, we found that it extends SOD1G93A mouse lifespan. In addition, the phenotypes of reduced muscle strength and fewer NMJs of SOD1G93A mice are also improved by leucine supplementation. These results support the existence of crosstalk between SOD1 and VCP and suggest a critical role for protein synthesis in ASL. Our study also implies a potential therapeutic treatment for ALS.}, } @article {pmid38382562, year = {2024}, author = {Berezutskyi, V and Berezutska, M}, title = {Rare Example of abnormal vocal resonance: a case from Balzac's novel.}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {78}, number = {8}, pages = {556-560}, doi = {10.1055/a-2248-9672}, pmid = {38382562}, issn = {1438-8790}, mesh = {Adolescent ; Humans ; Male ; Diagnosis, Differential ; Rare Diseases ; *Singing ; Tuberculosis, Pulmonary/diagnosis ; Voice Disorders/diagnosis/etiology ; Medicine in Literature ; }, abstract = {Ungewöhnliche klinische Fälle wecken bei praktizierenden Ärzten immer wieder Interesse und ermöglichen es ihnen, ihre Wissensbasis zu erweitern und ihre Fähigkeiten zum klinischen Denken zu verbessern. Der Zweck dieser Studie besteht darin, einen klinischen Fall von Stimmresonanz beim Singen bei einem schwindsüchtigen Teenager aus dem Roman "Der Landarzt" von Honoré de Balzac unter Verwendung induktiver und deduktiver Methoden des klinischen Denkens zu analysieren. Stimmresonanzen beim Singen in Schwindsucht können als pathognomonisches Zeichen für eine kavernöse Tuberkulose gewertet werden, da nur mit dem Bronchus verbundene Hohlräume als Helmholtz-Resonator wirken. Trotz der Einzigartigkeit ist das Gehäuse durchaus realistisch, da es nicht im Widerspruch zu den Gesetzen der Akustik steht. Praktizierende Ärzte verfügen über die Kenntnisse der medizinischen Physik, Morphologie und Physiologie, die zum Verständnis der Pathogenese der klinischen Manifestation einer Lungenhöhle erforderlich sind. Dieser Fall zeigt deutlich die Vor- und Nachteile klinischer Denkmethoden, die in der Praxis eingesetzt werden. Dank der Kombination aus Originalität und Realismus kann der Fall von Stimmresonanz aus Balzacs Roman "Der Landarzt" seinen rechtmäßigen Platz in der persönlichen Sammlung klinischer Fälle eines jeden Lungenarztes einnehmen.}, } @article {pmid38382464, year = {2024}, author = {Smith, HL and Chaytow, H and Gillingwater, TH}, title = {Excitotoxicity and ALS: New therapy targets an old mechanism.}, journal = {Cell reports. Medicine}, volume = {5}, number = {2}, pages = {101423}, pmid = {38382464}, issn = {2666-3791}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Mice, Transgenic ; Motor Neurons/metabolism ; Superoxide Dismutase/metabolism ; Disease Models, Animal ; }, abstract = {Excitotoxicity-induced cell death in motor neurons is a major therapeutic target for amyotrophic lateral sclerosis (ALS). Yan et al.[1] present a novel compound to specifically disrupt extra-synaptic NMDAR complexes, extending the lifespan of the SOD1[G93A] ALS mouse and ameliorating cell death.}, } @article {pmid38381656, year = {2024}, author = {Wang, XX and Chen, WZ and Li, C and Xu, RS}, title = {Current potential pathogenic mechanisms of copper-zinc superoxide dismutase 1 (SOD1) in amyotrophic lateral sclerosis.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {5}, pages = {549-563}, pmid = {38381656}, issn = {2191-0200}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Superoxide Dismutase-1/metabolism/genetics ; Animals ; Motor Neurons/metabolism/pathology ; Oxidative Stress/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease which damages upper and lower motor neurons (UMN and LMN) innervating the muscles of the trunk, extremities, head, neck and face in cerebrum, brain stem and spinal cord, which results in the progressive weakness, atrophy and fasciculation of muscle innervated by the related UMN and LMN, accompanying with the pathological signs leaded by the cortical spinal lateral tract lesion. The pathogenesis about ALS is not fully understood, and no specific drugs are available to cure and prevent the progression of this disease at present. In this review, we reviewed the structure and associated functions of copper-zinc superoxide dismutase 1 (SOD1), discuss why SOD1 is crucial to the pathogenesis of ALS, and outline the pathogenic mechanisms of SOD1 in ALS that have been identified at recent years, including glutamate-related excitotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, axonal transport disruption, prion-like propagation, and the non-cytologic toxicity of glial cells. This review will help us to deeply understand the current progression in this field of SOD1 pathogenic mechanisms in ALS.}, } @article {pmid38381447, year = {2024}, author = {Bahr, T and Vu, TA and Tuttle, JJ and Iezzi, R}, title = {Deep Learning and Machine Learning Algorithms for Retinal Image Analysis in Neurodegenerative Disease: Systematic Review of Datasets and Models.}, journal = {Translational vision science & technology}, volume = {13}, number = {2}, pages = {16}, pmid = {38381447}, issn = {2164-2591}, mesh = {Humans ; Algorithms ; *Alzheimer Disease/diagnostic imaging ; *Deep Learning ; Machine Learning ; *Neurodegenerative Diseases/diagnostic imaging ; Datasets as Topic ; *Retina/diagnostic imaging ; }, abstract = {PURPOSE: Retinal images contain rich biomarker information for neurodegenerative disease. Recently, deep learning models have been used for automated neurodegenerative disease diagnosis and risk prediction using retinal images with good results.

METHODS: In this review, we systematically report studies with datasets of retinal images from patients with neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and others. We also review and characterize the models in the current literature which have been used for classification, regression, or segmentation problems using retinal images in patients with neurodegenerative diseases.

RESULTS: Our review found several existing datasets and models with various imaging modalities primarily in patients with Alzheimer's disease, with most datasets on the order of tens to a few hundred images. We found limited data available for the other neurodegenerative diseases. Although cross-sectional imaging data for Alzheimer's disease is becoming more abundant, datasets with longitudinal imaging of any disease are lacking.

CONCLUSIONS: The use of bilateral and multimodal imaging together with metadata seems to improve model performance, thus multimodal bilateral image datasets with patient metadata are needed. We identified several deep learning tools that have been useful in this context including feature extraction algorithms specifically for retinal images, retinal image preprocessing techniques, transfer learning, feature fusion, and attention mapping. Importantly, we also consider the limitations common to these models in real-world clinical applications.

TRANSLATIONAL RELEVANCE: This systematic review evaluates the deep learning models and retinal features relevant in the evaluation of retinal images of patients with neurodegenerative disease.}, } @article {pmid38381392, year = {2024}, author = {Miah, MM and Zinnia, MA and Tabassum, N and Islam, ABMMK}, title = {Association between DPP6 gene rs10260404 polymorphism and increased risk of sporadic amyotrophic lateral sclerosis (sALS): a meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {7}, pages = {3225-3243}, pmid = {38381392}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *Genetic Predisposition to Disease/genetics ; *Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics ; *Polymorphism, Single Nucleotide ; Case-Control Studies ; Nerve Tissue Proteins ; Potassium Channels ; }, abstract = {BACKGROUND: Sporadic amyotrophic lateral sclerosis (sALS) is a severe neurodegenerative disease characterized by continuous diminution of motor neurons in the brain and spinal cord. Earlier studies indicated that the DPP6 gene variant has a role in the development of sALS. This meta-analysis was designed to uncover the role of rs10260404 polymorphism of the DPP6 gene and its association with sALS.

METHODS: All case-control articles published prior to October 2022 on the association between DPP6 (rs10260404) polymorphism and sALS risk were systematically extracted from different databases which include PubMed, PubMed Central, and Google Scholar. Overall odds ratios (ORs) and "95% confidence intervals (CIs)" were summarized for various genetic models. Subgroup and heterogeneity assessments were performed. Egger's and "Begg's tests were applied to evaluate publication bias. Trial sequential analysis (TSA) and false-positive report probability (FPRP) were performed.

RESULTS: Nine case-control studies containing 4202 sALS cases and 4444 healthy controls were included in the meta-analysis. A significant association of the DPP6 (rs10260404) variant with an increased sALS risk in overall pooled subjects under allelic model [C allele vs. T allele, OR = 1.149, 95% CI (1.010-1.307), p-value = 0.035], dominant model [CC + CT vs. TT, OR = 1.165, 95% CI (1.067-1.273), p-value = 0.001], and homozygote comparison [CC vs. TT, OR = 1.421, 95% CI (1.003-2.011), p-value = 0.048] were observed. Moreover, in subgroup analysis by nationality, remarkable associations were detected in Dutch, Irish, American, and Swedish under allelic, dominant, and homozygote models. Additionally, stratification analysis by ethnicity exhibited an association with sALS risk among Caucasians and Americans under different genetic models. Interestingly, none of the models found any significant association with Asians.

CONCLUSION: The present meta-analysis indicates that DPP6 (rs10260404) polymorphism could be a candidate risk factor for sALS predisposition.}, } @article {pmid38381071, year = {2024}, author = {Scherer, NM and Maurel, C and Graus, MS and McAlary, L and Richter, G and Radford, RAW and Hogan, A and Don, EK and Lee, A and Yerbury, J and Francois, M and Chung, RS and Morsch, M}, title = {RNA-binding properties orchestrate TDP-43 homeostasis through condensate formation in vivo.}, journal = {Nucleic acids research}, volume = {52}, number = {9}, pages = {5301-5319}, pmid = {38381071}, issn = {1362-4962}, support = {//Bill Gole Postdoctoral Fellowship/ ; //Motor Neuron Disease Research Australia/ ; //FightMND funding/ ; R21DA056320/NS/NINDS NIH HHS/United States ; //Snow Foundation Fellowship/ ; /MH/NIMH NIH HHS/United States ; //Macquarie University/ ; //Snow Foundation/ ; //National Health and Medical Research Council/ ; //NHMRC/ ; R21 DA056320/DA/NIDA NIH HHS/United States ; //ALS Foundation Netherlands/ ; }, mesh = {Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Biomolecular Condensates/metabolism ; Cell Nucleus/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Homeostasis ; *Motor Neurons/metabolism ; Mutation ; Protein Binding ; Protein Processing, Post-Translational ; RNA/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; }, abstract = {Insoluble cytoplasmic aggregate formation of the RNA-binding protein TDP-43 is a major hallmark of neurodegenerative diseases including Amyotrophic Lateral Sclerosis. TDP-43 localizes predominantly in the nucleus, arranging itself into dynamic condensates through liquid-liquid phase separation (LLPS). Mutations and post-translational modifications can alter the condensation properties of TDP-43, contributing to the transition of liquid-like biomolecular condensates into solid-like aggregates. However, to date it has been a challenge to study the dynamics of this process in vivo. We demonstrate through live imaging that human TDP-43 undergoes nuclear condensation in spinal motor neurons in a living animal. RNA-binding deficiencies as well as post-translational modifications can lead to aberrant condensation and altered TDP-43 compartmentalization. Single-molecule tracking revealed an altered mobility profile for RNA-binding deficient TDP-43. Overall, these results provide a critically needed in vivo characterization of TDP-43 condensation, demonstrate phase separation as an important regulatory mechanism of TDP-43 accessibility, and identify a molecular mechanism of how functional TDP-43 can be regulated.}, } @article {pmid38380436, year = {2024}, author = {Nakaso, K}, title = {Roles of Microglia in Neurodegenerative Diseases.}, journal = {Yonago acta medica}, volume = {67}, number = {1}, pages = {1-8}, pmid = {38380436}, issn = {0513-5710}, abstract = {In recent years, microglia have attracted attention owing to their roles in various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Microglia, which are brain-resident macrophages, not only act as immune cells but also perform other functions in the body. Interestingly, they exert contrasting effects on different neurodegenerative diseases. In addition to the previously reported M1 (toxic) and M2 (protective) types, microglia now also include disease-associated microglia owing to a more elaborate classification. Understanding this detailed classification is necessary to elucidate the association between microglia and neurodegenerative diseases. In this review, we discuss the diverse roles of microglia in neurodegenerative diseases and highlight their potential as therapeutic targets.}, } @article {pmid38379946, year = {2024}, author = {El-Mastouri, Z and Košnarová, P and Hamouzová, K and Alimi, E and Soukup, J}, title = {Insight into the herbicide resistance patterns in Lolium rigidum populations in Tunisian and Moroccan wheat regions.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1331725}, pmid = {38379946}, issn = {1664-462X}, abstract = {Rigid ryegrass (Lolium rigidum Gaud.) is one of the most troublesome weeds in Moroccan and Tunisian cereal crop fields. In total, 19 rigid ryegrass field populations were randomly selected in northern wheat crop areas of Morocco and Tunisia to examine the patterns of herbicide resistance to acetolactate synthase (ALS)- and acetyl-CoA carboxylase (ACCase)-inhibiting herbicides. Greenhouse experiments confirmed reduced sensitivity to ALS- and/or ACCase-inhibiting herbicides in all L. rigidum populations. The occurrence of target-site resistance (TSR) was tested using high-throughput genotyping. The advent of next-generation sequencing (NGS) has enabled easy identification of causal mutations and confirmed the presence of ALS and ACCase mutations at specific codons conferring TSR. Thirteen populations showed resistance to ALS-inhibiting herbicides associated with point mutations in positions Pro-197-Thr, Pro-197-Ser, Pro-197-Leu, Pro-197-Gln and Trp-574-Leu, while resistance to ACCase-inhibiting herbicides was detected in 18 populations in positions Asp-2078-Val, Trp-2027-Cys, Ile-1781-Leu, Gly-2096-Ala, and Ile-2041-Asn of the enzymes conferring TSR. Additionally, dose-response experiments with pyroxsulam applied after the inhibition of cytochrome P450 monooxygenase by malathion showed an increase in sensitivity in two out of seven highly resistant (HR) rigid ryegrass populations. This demonstrates the presence of non-target-site resistance (NTSR) in some ryegrass populations. Further evidence of NTSR was investigated in dose-response experiments with pyroxsulam, following pretreatment with the glutathione S-transferase (GST) inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl), which partially reversed resistance in only a few individuals of two L. rigidum populations. Hence, our study confirms the existence of multiple and cross-resistance to ALS- and ACCase-inhibiting herbicides in L. rigidum from Morocco and Tunisia with both TSR and NTSR mechanisms. These results emphasize local resistance management as an important tool to detect and mitigate gene flow from rigid ryegrass populations where resistance has evolved.}, } @article {pmid38378992, year = {2024}, author = {Song, M and Qiang, Y and Zhao, X and Song, F}, title = {Cyclin-dependent Kinase 5 and Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {61}, number = {10}, pages = {7287-7302}, pmid = {38378992}, issn = {1559-1182}, mesh = {Humans ; *Neurodegenerative Diseases/enzymology/metabolism ; *Cyclin-Dependent Kinase 5/metabolism ; Animals ; Oxidative Stress/physiology ; Mitochondria/metabolism ; }, abstract = {Neurodegenerative diseases are a group of diseases characterized by the progressive loss of neurons, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. These diseases have a high incidence and mortality rate globally, placing a heavy burden on patients and their families. The pathogenesis of neurodegenerative diseases is complex, and there are no effective treatments at present. Cyclin-dependent kinase 5 is a proline-directed serine/threonine protein kinase that is closely related to the development and function of the nervous system. Under physiological conditions, it is involved in regulating the process of neuronal proliferation, differentiation, migration, and synaptic plasticity. Moreover, there is increasing evidence that cyclin-dependent kinase 5 also plays an important role in the pathogenesis of neurodegenerative diseases. In this review, we address the biological characteristics of cyclin-dependent kinase 5 and its role in neurodegenerative diseases. In particular, this review highlights the underlying mechanistic linkages between cyclin-dependent kinase 5 and mitochondrial dysfunction, oxidative stress and neuroinflammation in the context of neurodegeneration. Finally, we also summarize the currently available cyclin-dependent kinase 5 inhibitors and their prospects for the treatment of neurodegenerative diseases. Taken together, a better understanding of the molecular mechanisms of cyclin-dependent kinase 5 involved in neurodegenerative diseases can lead to the development of new strategies for the prevention and treatment of these devastating diseases.}, } @article {pmid38378788, year = {2024}, author = {Rim, C and You, MJ and Nahm, M and Kwon, MS}, title = {Emerging role of senescent microglia in brain aging-related neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {10}, pmid = {38378788}, issn = {2047-9158}, support = {2023R1A2C1006622//National Research Foundation (NRF)/ ; RS-2023-00265515//National Research Foundation (NRF)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; Microglia/pathology ; Brain/pathology ; Cellular Senescence ; *Amyotrophic Lateral Sclerosis/pathology ; }, abstract = {Brain aging is a recognized risk factor for neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), but the intricate interplay between brain aging and the pathogenesis of these conditions remains inadequately understood. Cellular senescence is considered to contribute to cellular dysfunction and inflammaging. According to the threshold theory of senescent cell accumulation, the vulnerability to neurodegenerative diseases is associated with the rates of senescent cell generation and clearance within the brain. Given the role of microglia in eliminating senescent cells, the accumulation of senescent microglia may lead to the acceleration of brain aging, contributing to inflammaging and increased vulnerability to neurodegenerative diseases. In this review, we propose the idea that the senescence of microglia, which is notably vulnerable to aging, could potentially serve as a central catalyst in the progression of neurodegenerative diseases. The senescent microglia are emerging as a promising target for mitigating neurodegenerative diseases.}, } @article {pmid38378504, year = {2024}, author = {Pollmann, AS and Nguyen, MTD and Keyeutat, M and Danis, É and Durr, GM and Agoumi, Y and Jabbour, S}, title = {Refractive outcomes of immediately sequential bilateral cataract surgery in eyes with long and short axial lengths.}, journal = {BMC ophthalmology}, volume = {24}, number = {1}, pages = {77}, pmid = {38378504}, issn = {1471-2415}, mesh = {Humans ; Visual Acuity ; Lens Implantation, Intraocular/adverse effects ; Retrospective Studies ; *Lenses, Intraocular/adverse effects ; Refraction, Ocular ; *Refractive Errors/etiology ; Biometry ; Axial Length, Eye ; *Cataract/complications ; *Cataract Extraction/adverse effects ; }, abstract = {PURPOSE: To report the refractive outcomes of long (≥25.00 mm) and short (≤22.00 mm) axial length (AL) eyes undergoing immediately sequential bilateral cataract surgery (ISBCS).

METHODS: In this retrospective cohort study, patients who underwent ISBCS were identified and eyes of patients with bilateral long and short ALs were included. Pre- and postoperative biometry, autorefraction, and ocular comorbidities or complications were recorded. The primary outcome was the mean refractive prediction error.

RESULTS: Thirty-seven patients (74 eyes) with long ALs and 18 patients (36 eyes) with short ALs were included. The means ± standard deviations of the ALs were 26.40 ± 1.38 mm and 21.44 ± 0.46 mm in the long and short AL groups, respectively. In long AL eyes, the mean absolute error from the biometry-predicted refraction was - 0.16 ± 0.46 D, corresponding to 74% of eyes achieving a refraction within ±0.50 D of the predicted value. In short AL eyes, the mean absolute error was - 0.63 ± 0.73 D, corresponding to 44% of eyes achieving a refraction within ±0.50 D of the predicted value. Eight (44.4%) patients with short AL eyes had a myopic deviation greater than ±0.50 D from the predicted result in both eyes.

CONCLUSIONS: Compared to patients with long AL eyes, ISBCS in patients with short ALs had a wider variance in refractive outcome and a lower rate of achieving a postoperative refraction within ±0.50 D of the predicted target.}, } @article {pmid38377980, year = {2024}, author = {Ariana, S and Amjadi, N and Kazemi, SN and Ahmadli, Z}, title = {The Use of Evening Primrose Oil for Cervical Ripening in Low-Risk Women with Term Pregnancy: A Randomized Double-Blinded Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {3}, pages = {215-221}, doi = {10.1159/000535585}, pmid = {38377980}, issn = {2504-2106}, mesh = {Humans ; Female ; Pregnancy ; Adult ; Double-Blind Method ; *Plant Oils/therapeutic use ; *Oenothera biennis ; *gamma-Linolenic Acid/therapeutic use/administration & dosage ; *Linoleic Acids/therapeutic use ; *Cervical Ripening/drug effects ; Young Adult ; Iran ; }, abstract = {BACKGROUND: Several methods have been developed for cervical ripening. The data regarding the efficiency of evening primrose oil (EPO) are inconsistent. The purpose of this study was to investigate the outcomes of EPO use on cervical ripening in low-risk women with term pregnancy.

PATIENTS AND METHODS: Low-risk term pregnant women referred to the obstetrics clinic of Imam Hossein Hospital in Tehran who were eligible according to the inclusion were randomized either to the case or control group. The case group received 1,000 mg vaginal EPO capsule, and the other group received a vaginal placebo capsule daily, similar to the original drug. The primary outcome was Bishop score, while the duration of labor phases and the inducing procedures were the secondary outcomes.

RESULTS: Forty-eight participants were randomized to each group and were considered for data analysis. Although Bishop score was not statistically different before the intervention, it was significantly higher in case group compared to the placebo group after the intervention (EPO = 5.83 ± 1.68, placebo = 5.19 ± 1.52, p value = 0.002). Four participants in the case group and two in the control group underwent cesarean section (p value = 0.677). The need for labor induction was significantly higher in the placebo group than EPO group (oxytocin injection: 10.4% vs. 31.3%, p value = 0.012, amniotomy: 75% vs. 41.7, p value = 0.001).

CONCLUSION: The vaginal use of EPO could be considered as a safe and efficient approach for cervical ripening in low-risk term pregnant women.

UNLABELLED: HintergrundEs wurden verschiedene Methoden zur Zervixreifung entwickelt. Die Daten zur Wirksamkeit von Nachtkerzenöl (evening primrose oil, EPO) sind uneinheitlich. Mit dieser Studie sollen die Ergebnisse der Anwendung von EPO zur Zervixreifung bei Frauen mit niedrigem Risiko und termingerechter Schwangerschaft untersucht werden.Patientinnen und MethodenSchwangere Frauen mit niedrigem Risiko und termingerechter Schwangerschaft, die in die Geburtsklinik des Imam-Hossein-Krankenhauses in Teheran eingewiesen wurden und gemäss den Einschlusskriterien für die Teilnahme infrage kamen, wurden randomisiert der Fall- oder der Kontrollgruppe zugewiesen. Die Fallgruppe erhielt 1.000 mg EPO als Vaginalkapseln, während die andere Gruppe täglich eine vaginale Placebokapsel erhielt, die dem Originalpräparat ähnelte. Primäres Zielkriterium war der Bishop-Score und sekundäre Zielkriterien waren die Dauer der Wehenphasen sowie die Verfahren zur Geburtseinleitung.ErgebnisseJeder Gruppe wurden randomisiert 48 Teilnehmerinnen zugewiesen und bei der Datenanalyse berücksichtigt. Während vor der Intervention kein statistisch signifikanter Unterschied im Bishop-Score bestand, fiel dieser nach der Intervention in der Fallgruppe signifikant höher aus als in der Placebogruppe (EPO = 5,83 ± 1,68, Placebo = 5,19 ± 1,52, p-Wert = 0,002). Bei vier Teilnehmerinnen in der Fallgruppe und zwei in der Kontrollgruppe wurde ein Kaiserschnitt durchgeführt (p-Wert = 0,677). Die Notwendigkeit einer Weheneinleitung war in der Placebogruppe signifikant höher als in der EPO-Gruppe (Oxytocin-Injektion: 10,4% vs. 31,3%, p-Wert = 0,012, Amniotomie: 75% vs. 41,7%, p-Wert = 0,001).SchlussfolgerungDie vaginale Anwendung von EPO kann als sicherer und wirksamer Ansatz zur Zervixreifung bei Frauen mit niedrigem Risiko und termingerechter Schwangerschaft angesehen werden.}, } @article {pmid38377779, year = {2024}, author = {Sapienza, S and Tedeschi, V and Apicella, B and Pannaccione, A and Russo, C and Sisalli, MJ and Magliocca, G and Loffredo, S and Secondo, A}, title = {Ultrafine particulate matter pollution and dysfunction of endoplasmic reticulum Ca[2+] store: A pathomechanism shared with amyotrophic lateral sclerosis motor neurons?.}, journal = {Ecotoxicology and environmental safety}, volume = {273}, number = {}, pages = {116104}, doi = {10.1016/j.ecoenv.2024.116104}, pmid = {38377779}, issn = {1090-2414}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/chemically induced/genetics/metabolism ; Endoplasmic Reticulum/metabolism ; Motor Neurons/metabolism ; Proteomics ; Primary Cell Culture ; *Particulate Matter/adverse effects ; Endoplasmic Reticulum Stress ; Calcium/metabolism ; Disease Models, Animal ; }, abstract = {Increased risk of neurodegenerative diseases has been envisaged for air pollution exposure. On the other hand, environmental risk factors, including air pollution, have been suggested for Amyotrophic Lateral Sclerosis (ALS) pathomechanism. Therefore, the neurotoxicity of ultrafine particulate matter (PM0.1) (PM < 0.1 μm size) and its sub-20 nm nanoparticle fraction (NP20) has been investigated in motor neuronal-like cells and primary cortical neurons, mainly affected in ALS. The present data showed that PM0.1 and NP20 exposure induced endoplasmic reticulum (ER) stress, as occurred in cortex and spinal cord of ALS mice carrying G93A mutation in SOD1 gene. Furthermore, NSC-34 motor neuronal-like cells exposed to PM0.1 and NP20 shared the same proteomic profile on some apoptotic factors with motor neurons treated with the L-BMAA, a neurotoxin inducing Amyotrophic Lateral Sclerosis/Parkinson-Dementia Complex (ALS/PDC). Of note ER stress induced by PM0.1 and NP20 in motor neurons was associated to pathological changes in ER morphology and dramatic reduction of organellar Ca[2+] level through the dysregulation of the Ca[2+]-pumps SERCA2 and SERCA3, the Ca[2+]-sensor STIM1, and the Ca[2+]-release channels RyR3 and IP3R3. Furthermore, the mechanism deputed to ER Ca[2+] refilling (e.g. the so called store operated calcium entry-SOCE) and the relative currents ICRAC were also altered by PM0.1 and NP20 exposure. Additionally, these carbonaceous particles caused the exacerbation of L-BMAA-induced ER stress and Caspase-9 activation. In conclusion, this study shows that PM0.1 and NP20 induced the aberrant expression of ER proteins leading to dysmorphic ER, organellar Ca[2+] dysfunction, ER stress and neurotoxicity, providing putative correlations with the neurodegenerative process occurring in ALS.}, } @article {pmid38377583, year = {2024}, author = {Zhao, S and Solem, C}, title = {Thiamine-Starved Lactococcus lactis for Producing Food-Grade Pyruvate.}, journal = {Journal of agricultural and food chemistry}, volume = {72}, number = {9}, pages = {4858-4868}, doi = {10.1021/acs.jafc.3c09216}, pmid = {38377583}, issn = {1520-5118}, mesh = {*Pyruvic Acid/metabolism ; *Lactococcus lactis/genetics/metabolism ; Thiamine/metabolism ; Diacetyl/metabolism ; L-Lactate Dehydrogenase/metabolism ; Lactic Acid/metabolism ; Butter ; *Lactates ; }, abstract = {Lactococcus lactis is a safe lactic acid bacterium widely used in dairy fermentations. Normally, its main fermentation product is lactic acid; however, L. lactis can be persuaded into producing other compounds, e.g., through genetic engineering. Here, we have explored the possibility of rewiring the metabolism of L. lactis into producing pyruvate without using genetic tools. Depriving the thiamine-auxotrophic and lactate dehydrogenase-deficient L. lactis strain RD1M5 of thiamine efficiently shut down two enzymes at the pyruvate branch, the thiamine pyrophosphate (TPP) dependent pyruvate dehydrogenase (PDHc) and α-acetolactate synthase (ALS). After eliminating the remaining enzyme acting on pyruvate, the highly oxygen-sensitive pyruvate formate lyase (PFL), by simple aeration, the outcome was pyruvate production. Pyruvate could be generated by nongrowing cells and cells growing in a substrate low in thiamine, e.g., Florisil-treated milk. Pyruvate is a precursor for the butter aroma compound diacetyl. Using an α-acetolactate decarboxylase deficient L. lactis strain, pyruvate could be converted to α-acetolactate and diacetyl. Summing up, by starving L. lactis for thiamine, secretion of pyruvate could be attained. The food-grade pyruvate produced has many applications, e.g., as an antioxidant or be used to make butter aroma.}, } @article {pmid38377183, year = {2024}, author = {Brar, S and Ganesh, S and Karegowda, M}, title = {Clinical outcomes and rotational stability after implantation of a monofocal toric intraocular lens with textured haptics in normal vs high axial lengths.}, journal = {Journal of cataract and refractive surgery}, volume = {50}, number = {7}, pages = {718-723}, doi = {10.1097/j.jcrs.0000000000001429}, pmid = {38377183}, issn = {1873-4502}, mesh = {Humans ; Retrospective Studies ; *Lens Implantation, Intraocular ; *Lenses, Intraocular ; *Visual Acuity/physiology ; Female ; *Phacoemulsification ; Male ; *Axial Length, Eye/pathology ; *Refraction, Ocular/physiology ; *Pseudophakia/physiopathology ; Middle Aged ; *Astigmatism/physiopathology/surgery ; Prosthesis Design ; Aged ; Rotation ; Treatment Outcome ; }, abstract = {PURPOSE: To compare the clinical outcomes and rotational stability after implantation of a toric intraocular lens (IOL) with textured haptics in eyes with normal vs high axial lengths (ALs).

SETTING: Nethradhama Superspeciality Eye Hospital, Bangalore, India.

DESIGN: 2-arm, retrospective comparative study.

METHODS: This retrospective study included 114 eyes of 114 patients who underwent femtolaser cataract surgery followed by implantation of the HOYA Vivinex Toric monofocal IOL (Model XY1A-SP), of which 62 and 52 eyes belonged to normal (≤23.9 mm) and high (≥24 mm) AL groups, respectively. 1 week and 3 months postoperatively, clinical outcomes and rotational stability of the toric IOL was evaluated.

RESULTS: 3 months postoperatively, % eyes achieving refractive astigmatism accuracy within ≤0.50 diopter, was 100% (n = 62) in the normal vs 94% (n = 49) in the high AL group. All eyes that is, 100% (n = 62) in the normal and 96.15% (n = 50) eyes in the high myopia group were <5 degrees of the intended axis. The mean change in postoperative rotation from 1 week to 3 months was 0.28 ± 0.09 degrees in the normal, and 0.30 ± 1.11 degrees in the high AL group (P = .80). No significant correlation was observed between AL and white-to-white diameter with 1-week postoperative rotation values. No eye required repositioning of toric IOL for significant misalignment.

CONCLUSIONS: No significant differences were observed for clinical outcomes and postoperative rotational stability between eyes with normal and high ALs, suggesting excellent rotational stability of the Vivinex Toric IOL with textured haptics in all eyes, irrespective of the preoperative AL measurements.}, } @article {pmid38376500, year = {2024}, author = {Krajewski, E and Lee, J and Olmstead, AJ and Simmons, Z}, title = {Comparison of Vowel and Sentence Intelligibility in People With Dysarthria Secondary to Amyotrophic Lateral Sclerosis.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {}, number = {}, pages = {1-10}, doi = {10.1044/2024_JSLHR-23-00497}, pmid = {38376500}, issn = {1558-9102}, abstract = {PURPOSE: In this study, we examined the utility of vowel intelligibility testing for assessing the impact of dysarthria on speech characteristics in people with amyotrophic lateral sclerosis (ALS). We tested the sensitivity and specificity of overall vowel identification, as well as that of vowel-specific identification, to dysarthria presence and severity. We additionally examined the relationship between vowel intelligibility and sentence intelligibility.

METHOD: Twenty-three people with ALS and 22 age- and sex-matched control speakers produced sentences from the Speech Intelligibility Test (SIT), as well as 10 American English monophthongs in /h/-vowel-/d/ words for the vowel intelligibility test (VIT). Data for SIT and VIT scores came from 135 listeners. Diagnostic accuracy of VIT measures was evaluated using the area under the curve of receiver operator characteristics. We then examined differences between control speakers, speakers with mild dysarthria, and speakers with severe dysarthria in their relationship between SIT and VIT scores.

RESULTS: The results suggest that the overall vowel intelligibility score showed high sensitivity and specificity in differentiating between speakers with and without dysarthria, even those with milder symptoms. In addition, single-vowel identification scores showed at least acceptable group differentiation between the mild and severe dysarthria groups, though fewer single vowels were acceptable discriminators between the control group and the group with mild dysarthria. Identification accuracy of /ɪ/ in particular showed excellent discrimination across all groups. Examination of the relationship between SIT and VIT scores suggests a severity-specific relationship. Speakers with SIT scores above 70% generally had higher SIT than VIT scores, whereas speakers with SIT below 70% generally had higher VIT than SIT scores.

DISCUSSION: Vowel intelligibility testing can detect speech impairments in speakers with mild dysarthria and residual articulatory function in speakers with severe dysarthria. Vowel intelligibility testing may, therefore, be a useful addition to intelligibility testing for individuals with dysarthria.}, } @article {pmid38376483, year = {2024}, author = {Lee, D and Jeong, HC and Kim, SY and Chung, JY and Cho, SH and Kim, KA and Cho, JH and Ko, BS and Cha, IJ and Chung, CG and Kim, ES and Lee, SB}, title = {A comparison study of pathological features and drug efficacy between Drosophila models of C9orf72 ALS/FTD.}, journal = {Molecules and cells}, volume = {47}, number = {1}, pages = {100005}, pmid = {38376483}, issn = {0219-1032}, mesh = {Animals ; Drosophila/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; *Frontotemporal Dementia ; *Neurodegenerative Diseases ; Levamisole/*analogs & derivatives ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease with a complex genetic basis, presenting both in familial and sporadic forms. The hexanucleotide (G4C2) repeat expansion in the C9orf72 gene, which triggers distinct pathogenic mechanisms, has been identified as a major contributor to familial and sporadic Amyotrophic lateral sclerosis cases. Animal models have proven pivotal in understanding these mechanisms; however, discrepancies between models due to variable transgene sequence, expression levels, and toxicity profiles complicate the translation of findings. Herein, we provide a systematic comparison of 7 publicly available Drosophila transgenes modeling the G4C2 expansion under uniform conditions, evaluating variations in their toxicity profiles. Further, we tested 3 previously characterized disease-modifying drugs in selected lines to uncover discrepancies among the tested strains. Our study not only deepens our understanding of the C9orf72 G4C2 mutations but also presents a framework for comparing constructs with minute structural differences. This work may be used to inform experimental designs to better model disease mechanisms and help guide the development of targeted interventions for neurodegenerative diseases, thus bridging the gap between model-based research and therapeutic application.}, } @article {pmid38375749, year = {2024}, author = {Awassa, J and Soulé, S and Cornu, D and Ruby, C and El-Kirat-Chatel, S}, title = {Understanding the nanoscale adhesion forces between the fungal pathogen Candida albicans and antimicrobial zinc-based layered double hydroxides using single-cell and single-particle force spectroscopy.}, journal = {Nanoscale}, volume = {16}, number = {10}, pages = {5383-5394}, doi = {10.1039/d3nr06027f}, pmid = {38375749}, issn = {2040-3372}, mesh = {Humans ; *Candida albicans ; *Antifungal Agents/pharmacology ; Hydroxides/pharmacology/chemistry ; Zinc/pharmacology/chemistry ; Spectrum Analysis ; *Zinc Compounds ; }, abstract = {Antifungal resistance has become a very serious concern, and Candida albicans is considered one of the most opportunistic fungal pathogens responsible for several human infections. In this context, the use of new antifungal agents such as zinc-based layered double hydroxides to fight such fungal pathogens is considered one possible means to help limit the problem of antifungal resistance. In this study, we show that ZnAl LDH nanoparticles exhibit remarkable antifungal properties against C. albicans and cause serious cell wall damage, as revealed by growth tests and atomic force microscopy (AFM) imaging. To further link the antifungal activity of ZnAl LDHs to their adhesive behaviors toward C. albicans cells, AFM-based single-cell spectroscopy and single-particle force spectroscopy were used to probe the nanoscale adhesive interactions. The force spectroscopy analysis revealed that antimicrobial ZnAl LDHs exhibit specific surface interactions with C. albicans cells, demonstrating remarkable force magnitudes and adhesion frequencies in comparison with non-antifungal negative controls, e.g., Al-coated substrates and MgAl LDHs, which showed limited interactions with C. albicans cells. Force signatures suggest that such adhesive interactions may be attributed to the presence of agglutinin-like sequence (Als) adhesive proteins at the cell wall surface of C. albicans cells. Our findings propose the presence of a strong correlation between the antifungal effect provided by ZnAl LDHs and their nanoscale adhesive interactions with C. albicans cells at both the single-cell and single-particle levels. Therefore, ZnAl LDHs could interact with C. albicans fungal pathogens by specific adhesive interactions through which they adhere to fungal cells, leading to their damage and subsequent growth inhibition.}, } @article {pmid38374770, year = {2024}, author = {Pavey, N and Hannaford, A and van den Bos, M and Kiernan, MC and Menon, P and Vucic, S}, title = {Distinct neuronal circuits mediate cortical hyperexcitability in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {7}, pages = {2344-2356}, doi = {10.1093/brain/awae049}, pmid = {38374770}, issn = {1460-2156}, support = {//MND Research Australia/ ; 2001261//NHMRC/ ; 2010812//National Health & Medical Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Transcranial Magnetic Stimulation/methods ; *Motor Cortex/physiopathology ; Aged ; *Evoked Potentials, Motor/physiology ; Adult ; Nerve Net/physiopathology ; Neural Inhibition/physiology ; Electromyography ; }, abstract = {Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial magnetic stimulation (TMS) stimulus within the primary motor cortex can be utilized to influence descending corticospinal volleys and to thereby provide information about distinct interneuronal circuits. Cortical motor function and cognition was assessed in 29 ALS patients with results compared to healthy volunteers. Cortical dysfunction was assessed using threshold-tracking TMS to explore alterations in short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), the index of excitation and stimulus response curves using a figure-of-eight coil with the coil oriented relative to the primary motor cortex in a posterior-anterior, lateral-medial and anterior-posterior direction. Mean SICI, between interstimulus interval of 1-7 ms, was significantly reduced in ALS patients compared to healthy controls when assessed with the coil oriented in posterior-anterior (P = 0.044) and lateral-medial (P = 0.005) but not the anterior-posterior (P = 0.08) directions. A significant correlation between mean SICI oriented in a posterior-anterior direction and the total Edinburgh Cognitive and Behavioural ALS Screen score (Rho = 0.389, P = 0.037) was evident. In addition, the mean SICF, between interstimulus interval 1-5 ms, was significantly increased in ALS patients when recorded with TMS coil oriented in posterior-anterior (P = 0.035) and lateral-medial (P < 0.001) directions. In contrast, SICF recorded with TMS coil oriented in the anterior-posterior direction was comparable between ALS and controls (P = 0.482). The index of excitation was significantly increased in ALS patients when recorded with the TMS coil oriented in posterior-anterior (P = 0.041) and lateral-medial (P = 0.003) directions. In ALS patients, a significant increase in the stimulus response curve gradient was evident compared to controls when recorded with TMS coil oriented in posterior-anterior (P < 0.001), lateral-medial (P < 0.001) and anterior-posterior (P = 0.002) directions. The present study has established that dysfunction of distinct interneuronal circuits mediates the development of cortical hyperexcitability in ALS. Specifically, complex interplay between inhibitory circuits and facilitatory interneuronal populations, that are preferentially activated by stimulation in posterior-to-anterior or lateral-to-medial directions, promotes cortical hyperexcitability in ALS. Mechanisms that underlie dysfunction of these specific cortical neuronal circuits will enhance understanding of the pathophysiological processes in ALS, with the potential to uncover focussed therapeutic targets.}, } @article {pmid38374589, year = {2025}, author = {Mehdipour, A and Teshler, L and Dal Bello-Haas, V and Bouchard, V and Kuspinar, A}, title = {Translation of the Preference-Based Amyotrophic Lateral Sclerosis Scale into French.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {52}, number = {1}, pages = {129-131}, doi = {10.1017/cjn.2024.18}, pmid = {38374589}, issn = {0317-1671}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis ; Canada ; Male ; Female ; Translating ; Middle Aged ; Language ; Translations ; Surveys and Questionnaires ; Aged ; }, abstract = {The objective of this study was to translate the Preference-Based Amyotrophic Lateral Sclerosis Scale to French-Canadian. After the scale underwent forward and back translations, the expert committee examined the translated versions and found minor grammatical errors and suggested idioms to be changed to better represent French-Canadian language. Cognitive debriefing interviews were carried out to assess the pre-final version for clarity, and minor changes were made. Consensus from the expert committee and people with amyotrophic lateral sclerosis on the measure's clarity, word choice, and meaning were achieved, resulting in the final French version of the Preference-Based Amyotrophic Lateral Sclerosis Scale.}, } @article {pmid38374041, year = {2024}, author = {San Gil, R and Pascovici, D and Venturato, J and Brown-Wright, H and Mehta, P and Madrid San Martin, L and Wu, J and Luan, W and Chui, YK and Bademosi, AT and Swaminathan, S and Naidoo, S and Berning, BA and Wright, AL and Keating, SS and Curtis, MA and Faull, RLM and Lee, JD and Ngo, ST and Lee, A and Morsch, M and Chung, RS and Scotter, E and Lisowski, L and Mirzaei, M and Walker, AK}, title = {A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {1508}, pmid = {38374041}, issn = {2041-1723}, support = {1140386//Department of Health | National Health and Medical Research Council (NHMRC)/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/metabolism ; *Frontotemporal Lobar Degeneration/metabolism ; Neurons/metabolism ; Proteomics ; *TDP-43 Proteinopathies/metabolism ; *Protein Aggregates ; }, abstract = {Understanding the mechanisms that drive TDP-43 pathology is integral to combating amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases. Here we generated a longitudinal quantitative proteomic map of the cortex from the cytoplasmic TDP-43 rNLS8 mouse model of ALS and FTLD, and developed a complementary open-access webtool, TDP-map (https://shiny.rcc.uq.edu.au/TDP-map/). We identified distinct protein subsets enriched for diverse biological pathways with temporal alterations in protein abundance, including increases in protein folding factors prior to disease onset. This included increased levels of DnaJ homolog subfamily B member 5, DNAJB5, which also co-localized with TDP-43 pathology in diseased human motor cortex. DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures, and knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in mice. Together, these findings reveal molecular mechanisms at distinct stages of ALS and FTLD progression and suggest that protein folding factors could be protective in neurodegenerative diseases.}, } @article {pmid38372843, year = {2024}, author = {Katerelos, A and Alexopoulos, P and Economou, P and Polychronopoulos, P and Chroni, E}, title = {Correction to: Cognitive function in amyotrophic lateral sclerosis: a cross‑sectional and prospective pragmatic clinical study with review of the literature.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {5}, pages = {2407}, doi = {10.1007/s10072-024-07408-9}, pmid = {38372843}, issn = {1590-3478}, } @article {pmid38372747, year = {2024}, author = {Yang, T and Li, C and Wei, Q and Pang, D and Cheng, Y and Huang, J and Lin, J and Xiao, Y and Jiang, Q and Wang, S and Shang, H}, title = {Genome-wide DNA methylation analysis related to ALS patient progression and survival.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2672-2683}, pmid = {38372747}, issn = {1432-1459}, support = {82371430//National Natural Science Foundation of China/ ; 82101485//National Natural Science Foundation of China/ ; 2022ZDZX0023//Sichuan Science and Technology Program/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/mortality ; *DNA Methylation ; Male ; Female ; *Disease Progression ; Middle Aged ; Aged ; Epigenesis, Genetic ; Genome-Wide Association Study ; Follow-Up Studies ; }, abstract = {BACKGROUND: Epigenetics contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS). We aimed to characterize the DNA methylation profiles associated with clinical heterogeneity in disease progression and survival among patients.

METHODS: We included a cohort of 41 patients with sporadic ALS, with a median follow-up of 86.9 months, and 27 rigorously matched healthy controls. Blood-based genome-wide DNA methylation analysis was conducted.

RESULTS: A total of 948 progression rate-associated differentially methylated positions, 298 progression rate-associated differentially methylated regions (R-DMRs), 590 survival time-associated DMPs, and 197 survival time-associated DMRs (S-DMRs) were identified, using complementary grouping strategies. Enrichment analysis of differentially methylated genes highlighted the involvement of synapses and axons in ALS progression and survival. Clinical analysis revealed a positive correlation between the average methylation levels of the R-DMR in PRDM8 and disease progression rate (r = 0.479, p = 0.002). Conversely, there was an inverse correlation between the average methylation levels of the R-DMR in ANKRD33 and disease progression rate (r = - 0.476, p = 0.002). In addition, patients with higher methylation levels within the S-DMR of ZNF696 experienced longer survival (p = 0.016), while those with elevated methylation levels in the S-DMR of RAI1 had shorter survival (p = 0.006).

CONCLUSION: DNA methylation holds promise as a potential biomarker for tracking disease progression and predicting survival outcome and also offers targets for precision medicine.}, } @article {pmid38372421, year = {2024}, author = {Miquel, E and Villarino, R and Martínez-Palma, L and Cassina, A and Cassina, P}, title = {Pyruvate dehydrogenase kinase 2 knockdown restores the ability of amyotrophic lateral sclerosis-linked SOD1G93A rat astrocytes to support motor neuron survival by increasing mitochondrial respiration.}, journal = {Glia}, volume = {72}, number = {5}, pages = {999-1011}, doi = {10.1002/glia.24516}, pmid = {38372421}, issn = {1098-1136}, support = {//Programa de Desarrollo de las Ciencias Básicas (PEDECIBA)/ ; FCE_1_2019_1_156461//Agencia Nacional de Investigación e Innovación/ ; }, mesh = {Animals ; Rats ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Astrocytes/metabolism ; Cells, Cultured ; Disease Models, Animal ; Motor Neurons/metabolism ; *Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics/metabolism ; Respiration ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration. Various studies using cellular and animal models of ALS indicate that there is a complex interplay between MN and neighboring non-neuronal cells, such as astrocytes, resulting in noncell autonomous neurodegeneration. Astrocytes in ALS exhibit a lower ability to support MN survival than nondisease-associated ones, which is strongly correlated with low-mitochondrial respiratory activity. Indeed, pharmacological inhibition of pyruvate dehydrogenase kinase (PDK) led to an increase in the mitochondrial oxidative phosphorylation pathway as the primary source of cell energy in SOD1G93A astrocytes and restored the survival of MN. Among the four PDK isoforms, PDK2 is ubiquitously expressed in astrocytes and presents low expression levels in neurons. Herein, we hypothesize whether selective knockdown of PDK2 in astrocytes may increase mitochondrial activity and, in turn, reduce SOD1G93A-associated toxicity. To assess this, cultured neonatal SOD1G93A rat astrocytes were incubated with specific PDK2 siRNA. This treatment resulted in a reduction of the enzyme expression with a concomitant decrease in the phosphorylation rate of the pyruvate dehydrogenase complex. In addition, PDK2-silenced SOD1G93A astrocytes exhibited restored mitochondrial bioenergetics parameters, adopting a more complex mitochondrial network. This treatment also decreased lipid droplet content in SOD1G93A astrocytes, suggesting a switch in energetic metabolism. Significantly, PDK2 knockdown increased the ability of SOD1G93A astrocytes to support MN survival, further supporting the major role of astrocyte mitochondrial respiratory activity in astrocyte-MN interactions. These results suggest that PDK2 silencing could be a cell-specific therapeutic tool to slow the progression of ALS.}, } @article {pmid38371486, year = {2024}, author = {Strang, P and Schultz, T and Ozanne, A}, title = {Partly unequal receipt of healthcare in last month of life in amyotrophic lateral sclerosis: a retrospective cohort study of the Stockholm region.}, journal = {Upsala journal of medical sciences}, volume = {129}, number = {}, pages = {}, pmid = {38371486}, issn = {2000-1967}, mesh = {Aged ; Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/therapy ; Delivery of Health Care ; *Dementia/therapy ; *Frailty ; Palliative Care ; Retrospective Studies ; }, abstract = {CONTEXT: In amyotrophic lateral sclerosis (ALS), equal care is important, given that the disease often has complex symptoms at the end of life.

OBJECTIVES: The aim was to study the possible associations between demographic and clinical factors, including age, sex, and frailty, with acute healthcare utilization in the last month of life, measured by emergency room (ER) visits, admissions to acute hospitals and, acute hospitals as place of death, among patients with ALS. A second aim was to study whether receipt of specialized palliative care (SPC) affects above-mentioned healthcare utilization.

METHODS: Observational, retrospective study based on Region Stockholm's administrative data warehouse (VAL) in Sweden. Data were retrieved for 2015-2021 and analyzed with descriptive statistics and logistic regression models.

RESULTS: All deceased patients (n = 448) ≥18 years with ALS were included. The mean age was 70.5 years, 46% were women and 58% had risk of frailty according to Hospital Frailty Risk Score (HFRS). Ninety-nine (22%) were nursing home residents and 49% received SPC. The receipt of SPC in patients with ALS was equal in relation to gender, socio-economic standing, frailty, and age <75 years. Patients ≥75 years, those with dementia and/or residing in nursing homes (NH) were less likely to receive SPC (P = 0.01, P = 0.03 and P = 0.002, respectively). Receipt of SPC reduced ER visits (29% vs. 48%, P < 0.001) and deaths at hospital (12% vs. 48%, P <0.001). Patients who were frail, had a higher risk of ER visits and were more likely to die at an acute hospital setting (P < 0.001 and P = 0.004). NH residents were less likely to have ER visits and to die in hospital (P = 0.002 and P = 0.005).

CONCLUSIONS: The results indicate partly unequal distribution of palliative care, however the actual, individual preferences cannot be deducted from registry studies. All patients with ALS should be offered SPC when needed.

KEY MESSAGE: This register study shows that receipt of SPC in patients with ALS is equal in relation to gender, socioeconomic standing, frailty, and age <75 years, while those ≥75 years, with dementia, or residing in NH were somewhat less likely to receive SPC. Receipt of SPC reduces ER visits and acute hospital admissions.}, } @article {pmid38371336, year = {2024}, author = {Barnabe, A and Genestet, S and Gut-Gobert, C and Rivalain, C and Noury, JB and Goret, M and Barnier, A and De Moreuil, C and Espinasse, B and Le Mao, R and Leroyer, C and Couturaud, F and Tromeur, C}, title = {Venous thromboembolism and amyotrophic lateral sclerosis: the Venous Thrombo-Embolism and Sclerosis Lateral Amyotrophic study.}, journal = {Research and practice in thrombosis and haemostasis}, volume = {8}, number = {1}, pages = {102287}, pmid = {38371336}, issn = {2475-0379}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease. Given the inflammatory nature of ALS and the high number of ALS-related clinical circumstances (eg, prolonged immobilization and infections), patients with ALS may have a high risk of venous thromboembolism (VTE).

OBJECTIVES: To determine the annual incidence rate of VTE and the predictors of VTE in patients with ALS.

METHODS: We analyzed a prospective cohort of patients with ALS diagnosed between 2009 and 2019 followed in the Brest University Hospital ALS Centre.

RESULTS: Among 227 patients with ALS, VTE occurred in 19 patients during a median follow-up period of 717 days (IQR, 488-1308), yielding an annual incidence rate of 2.93% (95% CI, 1.88%-4.53%). Predictors for VTE were a family history of VTE (hazard ratio [HR], 15.24; 95% CI, 1.72-134.84; P = .01), the presence of noninvasive ventilation at ALS diagnosis (HR, 6.98; 95% CI, 1.09-44.59; P = .04) and a short time (ie, <213 days) between first symptoms and ALS diagnosis (HR, 5.48; 95% CI, 1.57-19.11; P = .01). Recurrent VTE occurred within 3 months after stopping anticoagulation in 5 patients (26.3%).

CONCLUSION: The annual incidence of VTE in patients with ALS is high. Predictive factors of VTE were a VTE history, noninvasive ventilation, and a short time between first symptoms of ALS and ALS diagnosis.}, } @article {pmid38370434, year = {2024}, author = {Chen, C and Qi, J and Li, Y and Li, D and Wu, L and Li, R and Chen, Q and Sun, N}, title = {Applications of Raman spectroscopy in the diagnosis and monitoring of neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1301107}, pmid = {38370434}, issn = {1662-4548}, abstract = {Raman scattering is an inelastic light scattering that occurs in a manner reflective of the molecular vibrations of molecular structures and chemical conditions in a given sample of interest. Energy changes in the scattered light can be assessed to determine the vibration mode and associated molecular and chemical conditions within the sample, providing a molecular fingerprint suitable for sample identification and characterization. Raman spectroscopy represents a particularly promising approach to the molecular analysis of many diseases owing to clinical advantages including its instantaneous nature and associated high degree of stability, as well as its ability to yield signal outputs corresponding to a single molecule type without any interference from other molecules as a result of its narrow peak width. This technology is thus ideally suited to the simultaneous assessment of multiple analytes. Neurodegenerative diseases represent an increasingly significant threat to global public health owing to progressive population aging, imposing a severe physical and social burden on affected patients who tend to develop cognitive and/or motor deficits beginning between the ages of 50 and 70. Owing to a relatively limited understanding of the etiological basis for these diseases, treatments are lacking for the most common neurodegenerative diseases, which include Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The present review was formulated with the goal of briefly explaining the principle of Raman spectroscopy and discussing its potential applications in the diagnosis and evaluation of neurodegenerative diseases, with a particular emphasis on the research prospects of this novel technological platform.}, } @article {pmid38369520, year = {2024}, author = {Adashek, JJ and Pandya, C and Maragakis, NJ and De, P and Cohen, PR and Kato, S and Kurzrock, R}, title = {Neuregulin-1 and ALS19 (ERBB4): at the crossroads of amyotrophic lateral sclerosis and cancer.}, journal = {BMC medicine}, volume = {22}, number = {1}, pages = {74}, pmid = {38369520}, issn = {1741-7015}, support = {U10 CA180888/CA/NCI NIH HHS/United States ; UG1 CA233198/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Neoplasms/genetics ; *Neuregulin-1/genetics/metabolism ; *Receptor, ErbB-4/genetics/metabolism ; Signal Transduction ; }, abstract = {BACKGROUND: Neuregulin-1 (NRG1) is implicated in both cancer and neurologic diseases such as amyotrophic lateral sclerosis (ALS); however, to date, there has been little cross-field discussion between neurology and oncology in regard to these genes and their functions.

MAIN BODY: Approximately 0.15-0.5% of cancers harbor NRG1 fusions that upregulate NRG1 activity and hence that of the cognate ERBB3/ERBB4 (HER3/HER4) receptors; abrogating this activity with small molecule inhibitors/antibodies shows preliminary tissue-agnostic anti-cancer activity. Notably, ERBB/HER pharmacologic suppression is devoid of neurologic toxicity. Even so, in ALS, attenuated ERBB4/HER4 receptor activity (due to loss-of-function germline mutations or other mechanisms in sporadic disease) is implicated; indeed, ERBB4/HER4 is designated ALS19. Further, secreted-type NRG1 isoforms may be upregulated (perhaps via a feedback loop) and could contribute to ALS pathogenesis through aberrant glial cell stimulation via enhanced activity of other (e.g., ERBB1-3/HER1-3) receptors and downstream pathways. Hence, pan-ERBB inhibitors, already in use for cancer, may be agents worthy of testing in ALS.

CONCLUSION: Common signaling cascades between cancer and ALS may represent novel therapeutic targets for both diseases.}, } @article {pmid38368936, year = {2024}, author = {Herman, M and Randall, GW and Spiegel, JL and Maldonado, DJ and Simoes, S}, title = {Endo-lysosomal dysfunction in neurodegenerative diseases: opinion on current progress and future direction in the use of exosomes as biomarkers.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {379}, number = {1899}, pages = {20220387}, pmid = {38368936}, issn = {1471-2970}, support = {R01 AG071868/AG/NIA NIH HHS/United States ; R21 AG070768/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Exosomes ; *Alzheimer Disease/diagnosis ; Lysosomes/metabolism ; Biomarkers/metabolism ; }, abstract = {Over the past two decades, increased research has highlighted the connection between endosomal trafficking defects and neurodegeneration. The endo-lysosomal network is an important, complex cellular system specialized in the transport of proteins, lipids, and other metabolites, essential for cell homeostasis. Disruption of this pathway is linked to a wide range of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and frontotemporal dementia. Furthermore, there is strong evidence that defects in this pathway create opportunities for diagnostic and therapeutic intervention. In this Opinion piece, we concisely address the role of endo-lysosomal dysfunction in five neurodegenerative diseases and discuss how future research can investigate this intracellular pathway, including extracellular vesicles with a specific focus on exosomes for the identification of novel disease biomarkers. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.}, } @article {pmid38367882, year = {2024}, author = {Godoy-Corchuelo, JM and Ali, Z and Brito Armas, JM and Martins-Bach, AB and García-Toledo, I and Fernández-Beltrán, LC and López-Carbonero, JI and Bascuñana, P and Spring, S and Jimenez-Coca, I and Muñoz de Bustillo Alfaro, RA and Sánchez-Barrena, MJ and Nair, RR and Nieman, BJ and Lerch, JP and Miller, KL and Ozdinler, HP and Fisher, EMC and Cunningham, TJ and Acevedo-Arozena, A and Corrochano, S}, title = {TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43.}, journal = {Neurobiology of disease}, volume = {193}, number = {}, pages = {106437}, pmid = {38367882}, issn = {1095-953X}, support = {MC_EX_MR/N501931/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Child, Preschool ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Brain/metabolism ; Cognition ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology ; *TDP-43 Proteinopathies/genetics/pathology ; }, abstract = {TDP-43 pathology is found in several neurodegenerative disorders, collectively referred to as "TDP-43 proteinopathies". Aggregates of TDP-43 are present in the brains and spinal cords of >97% of amyotrophic lateral sclerosis (ALS), and in brains of ∼50% of frontotemporal dementia (FTD) patients. While mutations in the TDP-43 gene (TARDBP) are usually associated with ALS, many clinical reports have linked these mutations to cognitive impairments and/or FTD, but also to other neurodegenerative disorders including Parkinsonism (PD) or progressive supranuclear palsy (PSP). TDP-43 is a ubiquitously expressed, highly conserved RNA-binding protein that is involved in many cellular processes, mainly RNA metabolism. To investigate systemic pathological mechanisms in TDP-43 proteinopathies, aiming to capture the pleiotropic effects of TDP-43 mutations, we have further characterised a mouse model carrying a point mutation (M323K) within the endogenous Tardbp gene. Homozygous mutant mice developed cognitive and behavioural deficits as early as 3 months of age. This was coupled with significant brain structural abnormalities, mainly in the cortex, hippocampus, and white matter fibres, together with progressive cortical interneuron degeneration and neuroinflammation. At the motor level, progressive phenotypes appeared around 6 months of age. Thus, cognitive phenotypes appeared to be of a developmental origin with a mild associated progressive neurodegeneration, while the motor and neuromuscular phenotypes seemed neurodegenerative, underlined by a progressive loss of upper and lower motor neurons as well as distal denervation. This is accompanied by progressive elevated TDP-43 protein and mRNA levels in cortex and spinal cord of homozygous mutant mice from 3 months of age, together with increased cytoplasmic TDP-43 mislocalisation in cortex, hippocampus, hypothalamus, and spinal cord at 12 months of age. In conclusion, we find that Tardbp M323K homozygous mutant mice model many aspects of human TDP-43 proteinopathies, evidencing a dual role for TDP-43 in brain morphogenesis as well as in the maintenance of the motor system, making them an ideal in vivo model system to study the complex biology of TDP-43.}, } @article {pmid38367748, year = {2024}, author = {La Cognata, V and Morello, G and Guarnaccia, M and Cavallaro, S}, title = {The multifaceted role of the CXC chemokines and receptors signaling axes in ALS pathophysiology.}, journal = {Progress in neurobiology}, volume = {235}, number = {}, pages = {102587}, doi = {10.1016/j.pneurobio.2024.102587}, pmid = {38367748}, issn = {1873-5118}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Signal Transduction ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disease with complex genetic basis and still no clear etiology. Multiple intertwined layers of immune system-related dysfunctions and neuroinflammatory mechanisms are emerging as substantial determinants in ALS onset and progression. In this review, we collect the increasingly arising evidence implicating four main CXC chemokines/cognate receptors signaling axes (CXCR1/2-CXCL1/2/8; CXCR3-CXCL9/10/11; CXCR4/7-CXCL12; CXCR5-CXCL13) in the pathophysiology of ALS. Findings in preclinical models implicate these signaling pathways in motor neuron toxicity and neuroprotection, while in ALS patients dysregulation of CXCLs/CXCRs has been shown at both central and peripheral levels. Immunological monitoring of CXC-ligands in ALS may allow tracking of disease progression, while pharmacological modulation of CXC-receptors provides a novel therapeutic strategy. A deeper understanding of the interplay between CXC-mediated neuroinflammation and ALS is crucial to advance research into treatments for this debilitating uncurable disorder.}, } @article {pmid38367681, year = {2024}, author = {Arsuffi-Marcon, R and Souza, LG and Santos-Miranda, A and Joviano-Santos, JV}, title = {Neurotoxicity of Pyrethroids in neurodegenerative diseases: From animals' models to humans' studies.}, journal = {Chemico-biological interactions}, volume = {391}, number = {}, pages = {110911}, doi = {10.1016/j.cbi.2024.110911}, pmid = {38367681}, issn = {1872-7786}, mesh = {Animals ; Humans ; *Pyrethrins/toxicity ; *Insecticides/toxicity ; *Neurodegenerative Diseases/chemically induced ; *Neurotoxicity Syndromes ; *Pesticides/toxicity ; Mammals ; }, abstract = {Neurodegenerative diseases are associated with diverse symptoms, both motor and mental. Genetic and environmental factors can trigger neurodegenerative diseases. Chemicals as pesticides are constantly used in agriculture and also domestically. In this regard, pyrethroids (PY), are a class of insecticides in which its main mechanism of action is through disruption of voltage-dependent sodium channels function in insects. However, in mammals, they can also induce oxidative stress and enzyme dysfunction. This review investigates the association between PY and neurodegenerative diseases as Alzheimer's, Huntington's, Parkinson's, Amyotrophic Lateral Sclerosis, and Autism in animal models and humans. Published works using specific and non-specific models for these diseases were selected. We showed a tendency toward the development and/or aggravating of these neurodegenerative diseases following exposure to PYs. In animal models, the biochemical mechanisms of the diseases and their interaction with the insecticides are more deeply investigated. Nonetheless, only a few studies considered the specific model for each type of disease to analyze the impacts of the exposure. The choice of a specific model during the research is an important step and our review highlights the knowledge gaps of PYs effects using these models reinforcing the importance of them during the design of the experiments.}, } @article {pmid38367047, year = {2024}, author = {Sun, W and Liu, SH and Wei, XJ and Sun, H and Ma, ZW and Yu, XF}, title = {Potential of neuroimaging as a biomarker in amyotrophic lateral sclerosis: from structure to metabolism.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2238-2257}, pmid = {38367047}, issn = {1432-1459}, support = {No. JLSWSRCZX2023-13//the Medical and Health Talents Special Foundation of Jilin Province/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Humans ; *Neuroimaging/methods/standards ; *Biomarkers/metabolism ; Brain/diagnostic imaging/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration. The development of ALS involves metabolite alterations leading to tissue lesions in the nervous system. Recent advances in neuroimaging have significantly improved our understanding of the underlying pathophysiology of ALS, with findings supporting the corticoefferent axonal disease progression theory. Current studies on neuroimaging in ALS have demonstrated inconsistencies, which may be due to small sample sizes, insufficient statistical power, overinterpretation of findings, and the inherent heterogeneity of ALS. Deriving meaningful conclusions solely from individual imaging metrics in ALS studies remains challenging, and integrating multimodal imaging techniques shows promise for detecting valuable ALS biomarkers. In addition to giving an overview of the principles and techniques of different neuroimaging modalities, this review describes the potential of neuroimaging biomarkers in the diagnosis and prognostication of ALS. We provide an insight into the underlying pathology, highlighting the need for standardized protocols and multicenter collaborations to advance ALS research.}, } @article {pmid38366598, year = {2024}, author = {Ke, YD and van Hummel, A and Au, C and Chan, G and Lee, WS and van der Hoven, J and Przybyla, M and Deng, Y and Sabale, M and Morey, N and Bertz, J and Feiten, A and Ippati, S and Stevens, CH and Yang, S and Gladbach, A and Haass, NK and Kril, JJ and Blair, IP and Delerue, F and Ittner, LM}, title = {Targeting 14-3-3θ-mediated TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal dementia mice.}, journal = {Neuron}, volume = {112}, number = {8}, pages = {1249-1264.e8}, doi = {10.1016/j.neuron.2024.01.022}, pmid = {38366598}, issn = {1097-4199}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/metabolism ; Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by cytoplasmic deposition of the nuclear TAR-binding protein 43 (TDP-43). Although cytoplasmic re-localization of TDP-43 is a key event in the pathogenesis of ALS/FTD, the underlying mechanisms remain unknown. Here, we identified a non-canonical interaction between 14-3-3θ and TDP-43, which regulates nuclear-cytoplasmic shuttling. Neuronal 14-3-3θ levels were increased in sporadic ALS and FTD with TDP-43 pathology. Pathogenic TDP-43 showed increased interaction with 14-3-3θ, resulting in cytoplasmic accumulation, insolubility, phosphorylation, and fragmentation of TDP-43, resembling pathological changes in disease. Harnessing this increased affinity of 14-3-3θ for pathogenic TDP-43, we devised a gene therapy vector targeting TDP-43 pathology, which mitigated functional deficits and neurodegeneration in different ALS/FTD mouse models expressing mutant or non-mutant TDP-43, including when already symptomatic at the time of treatment. Our study identified 14-3-3θ as a mediator of cytoplasmic TDP-43 localization with implications for ALS/FTD pathogenesis and therapy.}, } @article {pmid38364912, year = {2024}, author = {Du, L and Roy, S and Wang, P and Li, Z and Qiu, X and Zhang, Y and Yuan, J and Guo, B}, title = {Unveiling the future: Advancements in MRI imaging for neurodegenerative disorders.}, journal = {Ageing research reviews}, volume = {95}, number = {}, pages = {102230}, doi = {10.1016/j.arr.2024.102230}, pmid = {38364912}, issn = {1872-9649}, mesh = {Humans ; *Diffusion Tensor Imaging/methods ; Artificial Intelligence ; Brain/pathology ; Magnetic Resonance Imaging/methods ; *Neurodegenerative Diseases/pathology ; }, abstract = {Neurodegenerative disorders represent a significant and growing global health challenge, necessitating continuous advancements in diagnostic tools for accurate and early detection. This work explores the recent progress in Magnetic Resonance Imaging (MRI) techniques and their application in the realm of neurodegenerative disorders. The introductory section provides a comprehensive overview of the study's background, significance, and objectives. Recognizing the current challenges associated with conventional MRI, the manuscript delves into advanced imaging techniques such as high-resolution structural imaging (HR-MRI), functional MRI (fMRI), diffusion tensor imaging (DTI), and positron emission tomography-MRI (PET-MRI) fusion. Each technique is critically examined regarding its potential to address theranostic limitations and contribute to a more nuanced understanding of the underlying pathology. A substantial portion of the work is dedicated to exploring the applications of advanced MRI in specific neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis (ALS). In addressing the future landscape, the manuscript examines technological advances, including the integration of machine learning and artificial intelligence in neuroimaging. The conclusion summarizes key findings, outlines implications for future research, and underscores the importance of these advancements in reshaping our understanding and approach to neurodegenerative disorders.}, } @article {pmid38363426, year = {2024}, author = {Tziortzouda, P and Steyaert, J and Scheveneels, W and Sicart, A and Stoklund Dittlau, K and Barbosa Correia, AM and Burg, T and Pal, A and Hermann, A and Van Damme, P and Moens, TG and Van Den Bosch, L}, title = {PP2A and GSK3 act as modifiers of FUS-ALS by modulating mitochondrial transport.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {41}, pmid = {38363426}, issn = {1432-0533}, support = {P40 OD018537/OD/NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; Glycogen Synthase Kinase 3/genetics/metabolism ; Protein Phosphatase 2/genetics/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; *Neurodegenerative Diseases/pathology ; Kinesins/genetics/metabolism ; Motor Neurons/metabolism ; Drosophila/genetics/metabolism ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which currently lacks effective treatments. Mutations in the RNA-binding protein FUS are a common cause of familial ALS, accounting for around 4% of the cases. Understanding the mechanisms by which mutant FUS becomes toxic to neurons can provide insight into the pathogenesis of both familial and sporadic ALS. We have previously observed that overexpression of wild-type or ALS-mutant FUS in Drosophila motor neurons is toxic, which allowed us to screen for novel genetic modifiers of the disease. Using a genome-wide screening approach, we identified Protein Phosphatase 2A (PP2A) and Glycogen Synthase Kinase 3 (GSK3) as novel modifiers of FUS-ALS. Loss of function or pharmacological inhibition of either protein rescued FUS-associated lethality in Drosophila. Consistent with a conserved role in disease pathogenesis, pharmacological inhibition of both proteins rescued disease-relevant phenotypes, including mitochondrial trafficking defects and neuromuscular junction failure, in patient iPSC-derived spinal motor neurons (iPSC-sMNs). In FUS-ALS flies, mice, and human iPSC-sMNs, we observed reduced GSK3 inhibitory phosphorylation, suggesting that FUS dysfunction results in GSK3 hyperactivity. Furthermore, we found that PP2A acts upstream of GSK3, affecting its inhibitory phosphorylation. GSK3 has previously been linked to kinesin-1 hyperphosphorylation. We observed this in both flies and iPSC-sMNs, and we rescued this hyperphosphorylation by inhibiting GSK3 or PP2A. Moreover, increasing the level of kinesin-1 expression in our Drosophila model strongly rescued toxicity, confirming the relevance of kinesin-1 hyperphosphorylation. Our data provide in vivo evidence that PP2A and GSK3 are disease modifiers, and reveal an unexplored mechanistic link between PP2A, GSK3, and kinesin-1, that may be central to the pathogenesis of FUS-ALS and sporadic forms of the disease.}, } @article {pmid38362496, year = {2024}, author = {Hoyer, LL and Freeman, BA and Hogan, EK and Hernandez, AG}, title = {Use of a Candida albicans SC5314 PacBio HiFi reads dataset to close gaps in the reference genome assembly, reveal a subtelomeric gene family, and produce accurate phased allelic sequences.}, journal = {Frontiers in cellular and infection microbiology}, volume = {14}, number = {}, pages = {1329438}, pmid = {38362496}, issn = {2235-2988}, support = {R15 DE026401/DE/NIDCR NIH HHS/United States ; }, mesh = {*Candida albicans/genetics ; *Genome, Fungal ; Base Sequence ; Repetitive Sequences, Nucleic Acid ; Telomere/genetics ; Sequence Analysis, DNA/methods ; High-Throughput Nucleotide Sequencing ; }, abstract = {Candida albicans SC5314 is the most-often used strain for molecular manipulation of the species. The SC5314 reference genome sequence is the result of considerable effort from many scientists and has advanced research into fungal biology and pathogenesis. Although the resource is highly developed and presented in a phased diploid format, the sequence includes gaps and does not extend to the telomeres on its eight chromosome pairs. Accurate SC5314 genome assembly is complicated by the presence of extensive repeated sequences and considerable allelic length variation at some loci. Advances in genome sequencing technology provide the tools to obtain highly accurate long-read data that span even the most-difficult-to-assemble genome regions. Here, we describe derivation of a PacBio HiFi data set and creation of a collapsed haploid telomere-to-telomere assembly of the SC5314 genome (ASM3268872v1) that revealed previously unknown features of the strain. ASM3268872v1 subtelomeric distances were up to 19 kb larger than in the reference genome and revealed a family of highly conserved DNA helicase-encoding genes at 10 of the 16 chromosome ends. We also describe alignments of individual HiFi reads to deduce accurate diploid sequences for the most notoriously difficult-to-assemble C. albicans genes: the agglutinin-like sequence (ALS) gene family. We provide a tutorial that demonstrates how the HiFi reads can be visualized to explore any region of interest. Availability of the HiFi reads data set and the ASM3268872v1 comparative guide assembly will streamline research efforts because accurate diploid sequences can be derived using simple in silico methods rather than time-consuming laboratory-bench approaches.}, } @article {pmid38360060, year = {2024}, author = {El-Ghazouly, DE and Yassien, RI}, title = {Bisphosphonate's effect on the tongue in adult male albino rats and the possible protective role of rutin: light and scanning electron microscopic study.}, journal = {Anatomy & cell biology}, volume = {57}, number = {1}, pages = {129-142}, pmid = {38360060}, issn = {2093-3665}, abstract = {Alendronate sodium (ALS) is a nitrogen-containing bisphosphonate used for the treatment of different bone disorders. However, its adverse effect on oral soft tissue has been detected. Rutin (RUT) is natural flavonoid with antioxidant and anti-inflammatory properties. This work aimed to investigate the possible effect of ALS on the tongue of adult male albino rats and to evaluate the possible protective role of RUT. Forty adult male albino rats were equally divided into four groups: group I (control), group II (RUT): Received RUT 50 mg/kg, group III (ALS): Received ALS 1 mg/kg, group IV (ALS+RUT): Received ALS and RUT with the same doses as pervious groups. The drugs were given once daily for 5 weeks. Tongue specimens were taken and processed for light and scanning electron microscopic inspection. ALS treated group revealed structural changes in the tongue in the form of decrease in the height of the filiform papillae with blunt ends, marked atrophy in some papillae with areas of focal loss, loss of some epithelial cells, pyknotic nuclei and cytoplasmic vacuoles in some epithelial cells. The lamina propria showed inflammatory cellular infiltration with congested blood vessels. Statistically, there were highly significant decrease in the number of proliferating cell nuclear antigen immunopositive cells, area percentage of Bcl-2 immunoexpression and highly significant increase in the collagen content compared to control group. Administration of RUT with ALS minimizes these changes. RUT protected the rat tongue against the histological and immunohistochemical changes induced by ALS through its antioxidant and anti-inflammatory properties.}, } @article {pmid38359044, year = {2024}, author = {Vieira, FG and Tassinari, VR and Kidd, JD and Moreno, A and Thompson, K and Perrin, S and Gill, A and Hatzipetros, T}, title = {PERK modulation, with GSK2606414, Sephin1 or salubrinal, failed to produce therapeutic benefits in the SOD1G93A mouse model of ALS.}, journal = {PloS one}, volume = {19}, number = {2}, pages = {e0292190}, pmid = {38359044}, issn = {1932-6203}, mesh = {Mice ; Humans ; Animals ; *Guanabenz/pharmacology/therapeutic use/*analogs & derivatives ; eIF-2 Kinase/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Clonidine ; Unfolded Protein Response ; Adrenergic alpha-2 Receptor Agonists ; Adenine/*analogs & derivatives ; *Cinnamates ; *Indoles ; Thiourea/*analogs & derivatives ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has been linked to overactivity of the protein kinase RNA-like ER kinase (PERK) branch of the unfolded protein response (UPR) pathway, both in ALS patients and mouse models. However, attempts to pharmacologically modulate PERK for therapeutic benefit have yielded inconsistent and often conflicting results. This study sought to address these discrepancies by comprehensively evaluating three commonly used, CNS-penetrant, PERK modulators (GSK2606414, salubrinal, and Sephin1) in the same experimental models, with the goal of assessing the viability of targeting the PERK pathway as a therapeutic strategy for ALS. To achieve this goal, a tunicamycin-challenge assay was developed using wild-type mice to monitor changes in liver UPR gene expression in response to PERK pathway modulation. Subsequently, multiple dosing regimens of each PERK modulator were tested in standardized, well-powered, gender-matched, and litter-matched survival efficacy studies using the SOD1G93A mouse model of ALS. The alpha-2-adrenergic receptor agonist clonidine was also tested to elucidate the results obtained from the Sephin1, and of the previously reported guanabenz studies, by comparing the effects of presence or absence of α-2 agonism. The results revealed that targeting PERK may not be an ideal approach for ALS treatment. Inhibiting PERK with GSK2606414 or activating it with salubrinal did not confer therapeutic benefits. While Sephin1 showed some promising therapeutic effects, it appears that these outcomes were mediated through PERK-independent mechanisms. Clonidine also produced some favorable therapeutic effects, which were unexpected and not linked to the UPR. In conclusion, this study highlights the challenges of pharmacologically targeting PERK for therapeutic purposes in the SOD1G93A mouse model and suggests that exploring other targets within, and outside, the UPR may be more promising avenues for ALS treatment.}, } @article {pmid38358553, year = {2024}, author = {Brakemeier, S and Lipka, J and Schlag, M and Kleinschnitz, C and Hagenacker, T}, title = {Risdiplam improves subjective swallowing quality in non-ambulatory adult patients with 5q-spinal muscular atrophy despite advanced motor impairment.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2649-2657}, pmid = {38358553}, issn = {1432-1459}, mesh = {Humans ; Male ; Female ; Middle Aged ; Adult ; *Deglutition Disorders/etiology/physiopathology/drug therapy ; Pyrimidines/therapeutic use/pharmacology ; Aged ; Spinal Muscular Atrophies of Childhood/drug therapy/physiopathology/complications ; Treatment Outcome ; Deglutition/physiology/drug effects ; Prospective Studies ; Muscular Atrophy, Spinal/drug therapy/physiopathology ; Young Adult ; *Azo Compounds ; }, abstract = {BACKGROUND: 5q-associated spinal muscular atrophy (SMA) is characterized by the progressive loss of motor neurons with consecutive weakness and atrophy of the limb, respiratory, and bulbar muscles. While trunk and limb motor function improve or stabilize in adults with SMA under nusinersen and risdiplam treatment, the efficacy on bulbar function in this age group of patients remains uncertain. However, it is important to assess bulbar dysfunction, which frequently occurs in the disease course and is associated with increased morbidity and mortality.

METHODS: Bulbar function was evaluated prospectively in 25 non-ambulatory adults with type 2 and 3 SMA before and 4 and 12 months after risdiplam treatment initiation using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (b-ALSFRS-R). Extremity function was assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM).

RESULTS: Subjective swallowing quality, measured with the SSQ, improved after 12 months of therapy with risdiplam. For the b-ALSFRS-R, a non-significant trend towards improvement was observed. The RULM score improved after 12 months of risdiplam therapy, but not the HFMSE score. HFMSE and RULM scores did not correlate with the SSQ but the b-ALSFRS-R score at baseline.

CONCLUSIONS: The improvement in subjective swallowing quality under risdiplam treatment, despite an advanced disease stage with severe motor deficits, strengthens the importance of a standardized bulbar assessment in addition to established motor scores. This may reveal relevant treatment effects and help individualize treatment decisions in the future.}, } @article {pmid38358049, year = {2024}, author = {Milani, A and Panozzo, S and Grazia, TM and Scarabel, L}, title = {Development of a rapid detection assay for acetolactate synthase inhibitors resistance in three Amaranthus weed species through loop-mediated isothermal amplification.}, journal = {Journal of the science of food and agriculture}, volume = {104}, number = {9}, pages = {5522-5532}, doi = {10.1002/jsfa.13385}, pmid = {38358049}, issn = {1097-0010}, support = {//Regione Emilia-Romagna/ ; }, mesh = {*Amaranthus/genetics/drug effects ; *Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Nucleic Acid Amplification Techniques/methods ; *Herbicide Resistance/genetics ; *Plant Weeds/drug effects/genetics ; *Plant Proteins/genetics/metabolism ; *Herbicides/pharmacology ; Enzyme Inhibitors/pharmacology ; Molecular Diagnostic Techniques ; }, abstract = {BACKGROUND: The early detection of herbicide resistance in weeds is a key factor to avoid herbicide waste and improve agriculture sustainability. The present study aimed to develop and validate an allele-specific loop-mediated isothermal amplification (AS-LAMP) assay for the quick on-site detection of the resistance-endowing point mutation Trp-574-Leu in the acetolactate synthase (ALS) gene in three widely diffused Amaranthus weed species: Amaranthus retroflexus, Amaranthus hybridus and Amaranthus tuberculatus.

RESULTS: The AS-LAMP protocol was developed on wild-type and ALS-mutant plants of the three species and revealed that the amplification approach with only the primer set specific for the mutant allele (574-Leu) was the most promising. The validation and estimation of the AS-LAMP performance evaluated by comparing the results with those of the molecular marker (cleaved amplified polymorphic sequences) indicated that, although the sensitivity and specificity were relatively high in all species (overall 100 and > 65%, respectively), precision was high for A. hybridus L. and A. retroflexus L. (75 and 79%, respectively), but quite low for A. tuberculatus (Moq.) J. D. Sauer (59%). The LAMP assay was also effective on crude genomic DNA extraction, allowing the quick detection of mutant plants in field situation (on site resistance detection).

CONCLUSION: The proposed AS-LAMP method has proven to be a promising technique for rapid detection of resistance as a result of Trp-574-Leu on the two monoecious weedy Amaranthus species but resulted less effective in the genetically variable dioecious species A. tuberculatus. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid38357638, year = {2024}, author = {Gerritzen, EV and Lee, AR and McDermott, O and Coulson, N and Orrell, M}, title = {Online peer support for people with Amyotrophic Lateral Sclerosis (ALS): a narrative synthesis systematic review.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1138530}, pmid = {38357638}, issn = {2673-253X}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) significantly impacts the lives of people with the diagnosis and their families. A supportive social environment is important for people with ALS to adopt effective coping strategies and health behaviours, and reduce depressive symptoms. Peer support can provide a supportive social environment and can happen in-person and online. Advantages of online peer support are that people can engage from their own home, at their own time and pace, and that it offers a variety of different platforms and modes of communication.

OBJECTIVES: To (1) explore the benefits and challenges of online peer support for people with ALS, and (2) identify successful elements of online peer support for people with ALS.

METHODS: The method selected for this systematic review was a narrative synthesis. Six databases were systematically searched in April 2020 for articles published between 1989 and 2020. The search was updated in June 2022. The quality of the included studies was assessed with the Critical Appraisal Skills Programme qualitative research checklist.

RESULTS: 10,987 unique articles were identified through the systematic database search. Of those, 9 were included in this review. One of the main benefits of online peer support was that people could communicate using text rather than needing verbal communication, which can be challenging for some with ALS. Successful elements included using profile pages and graphics to identify others with similar or relevant experiences. Challenges included ALS symptoms which could make it difficult to use technological devices.

CONCLUSIONS: Peer support can provide a non-judgmental and supportive environment for people with ALS, in which they can exchange experiences and emotional support, which can help people in developing adaptive coping strategies. However, ALS symptoms may make it more difficult for people to use technological devices and engage in online peer support. More research is needed to identify what kind of specific barriers people with ALS experience, and how these could be overcome.}, } @article {pmid38356886, year = {2024}, author = {Giardina, E and Mandich, P and Ghidoni, R and Ticozzi, N and Rossi, G and Fenoglio, C and Tiziano, FD and Esposito, F and Capellari, S and Nacmias, B and Mineri, R and Campopiano, R and Di Pilla, L and Sammarone, F and Zampatti, S and Peconi, C and De Angelis, F and Palmieri, I and Galandra, C and Nicodemo, E and Origone, P and Gotta, F and Ponti, C and Nicsanu, R and Benussi, L and Peverelli, S and Ratti, A and Ricci, M and Di Fede, G and Magri, S and Serpente, M and Lattante, S and Domi, T and Carrera, P and Saltimbanco, E and Bagnoli, S and Ingannato, A and Albanese, A and Tagliavini, F and Lodi, R and Caltagirone, C and Gambardella, S and Valente, EM and Silani, V}, title = {Distribution of the C9orf72 hexanucleotide repeat expansion in healthy subjects: a multicenter study promoted by the Italian IRCCS network of neuroscience and neurorehabilitation.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1284459}, pmid = {38356886}, issn = {1664-2295}, abstract = {INTRODUCTION: High repeat expansion (HRE) alleles in C9orf72 have been linked to both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); ranges for intermediate allelic expansions have not been defined yet, and clinical interpretation of molecular data lacks a defined genotype-phenotype association. In this study, we provide results from a large multicenter epidemiological study reporting the distribution of C9orf72 repeats in healthy elderly from the Italian population.

METHODS: A total of 967 samples were collected from neurologically evaluated healthy individuals over 70 years of age in the 13 institutes participating in the RIN (IRCCS Network of Neuroscience and Neurorehabilitation) based in Italy. All samples were genotyped using the AmplideXPCR/CE C9orf72 Kit (Asuragen, Inc.), using standardized protocols that have been validated through blind proficiency testing.

RESULTS: All samples carried hexanucleotide G4C2 expansion alleles in the normal range. All samples were characterized by alleles with less than 25 repeats. In particular, 93.7% of samples showed a number of repeats ≤10, 99.9% ≤20 repeats, and 100% ≤25 repeats.

CONCLUSION: This study describes the distribution of hexanucleotide G4C2 expansion alleles in an Italian healthy population, providing a definition of alleles associated with the neurological healthy phenotype. Moreover, this study provides an effective model of federation between institutes, highlighting the importance of sharing genomic data and standardizing analysis techniques, promoting translational research. Data derived from the study may improve genetic counseling and future studies on ALS/FTD.}, } @article {pmid38356047, year = {2024}, author = {Wimmer, N and Müller, HP and Metze, P and Rasche, V and Ludolph, AC and Kassubek, J}, title = {The central pattern of weakness of ALS: Morphological correlates in whole-body muscle MRI.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {4}, pages = {1000-1010}, pmid = {38356047}, issn = {2328-9503}, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Whole Body Imaging ; Muscle, Skeletal/pathology ; Paresis ; }, abstract = {OBJECTIVE: Monosynaptically cortically innervated α-motoneurons are early and strongly involved in amyotrophic lateral sclerosis (ALS). Consequently, the muscles that receive the strongest direct corticomotoneuronal input are the clinically most affected. To objectify this concept in vivo through morphological image correlates, whole-body magnetic resonance imaging (MRI) with muscle signal analysis was performed in patients with ALS compared to healthy controls.

METHODS: Modified Dixon-based whole-body MRI was acquired in patients with ALS (n = 33) and matched healthy controls (n = 30). Manual labeling of limb muscle MRI was performed, and a specific subset of nine muscles, selected as pairs of muscle groups with different corticomotoneuronal input, was analyzed per subject based on their volume, fat fraction, and functional remaining muscle area (fRMA).

RESULTS: Statistical analysis of 978 muscles in total revealed significantly decreased volumes, decreased fRMA, and increased fat fraction in the muscles of patients with ALS compared to controls. The clinical degree of pareses of directly innervated muscles was significantly worse than that of less directly innervated muscles in each comparison. The muscles receiving stronger direct corticomotoneuronal input showed more pronounced morphological involvement compared to those with less monosynaptic corticomotoneuronal input (fRMA, significant in three pairwise comparisons).

INTERPRETATION: In conclusion, whole-body MRI-based muscle analysis provided additional evidence for a characteristic pattern of pareses in ALS. This technical approach (parameterization and quantification of muscle alterations from MRI) to patients with ALS could pave the way for the future establishment of a diagnostic algorithm of muscle MRI for ALS and may serve as a biomarker.}, } @article {pmid38355792, year = {2024}, author = {Hruska-Plochan, M and Wiersma, VI and Betz, KM and Mallona, I and Ronchi, S and Maniecka, Z and Hock, EM and Tantardini, E and Laferriere, F and Sahadevan, S and Hoop, V and Delvendahl, I and Pérez-Berlanga, M and Gatta, B and Panatta, M and van der Bourg, A and Bohaciakova, D and Sharma, P and De Vos, L and Frontzek, K and Aguzzi, A and Lashley, T and Robinson, MD and Karayannis, T and Mueller, M and Hierlemann, A and Polymenidou, M}, title = {A model of human neural networks reveals NPTX2 pathology in ALS and FTLD.}, journal = {Nature}, volume = {626}, number = {8001}, pages = {1073-1083}, pmid = {38355792}, issn = {1476-4687}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *C-Reactive Protein/metabolism ; *DNA-Binding Proteins/deficiency/metabolism ; *Frontotemporal Lobar Degeneration/metabolism/pathology ; *Nerve Net/metabolism/pathology ; *Nerve Tissue Proteins/metabolism ; Neural Stem Cells/cytology ; Neuroglia/cytology ; *Neurons/cytology/metabolism ; Reproducibility of Results ; }, abstract = {Human cellular models of neurodegeneration require reproducibility and longevity, which is necessary for simulating age-dependent diseases. Such systems are particularly needed for TDP-43 proteinopathies[1], which involve human-specific mechanisms[2-5] that cannot be directly studied in animal models. Here, to explore the emergence and consequences of TDP-43 pathologies, we generated induced pluripotent stem cell-derived, colony morphology neural stem cells (iCoMoNSCs) via manual selection of neural precursors[6]. Single-cell transcriptomics and comparison to independent neural stem cells[7] showed that iCoMoNSCs are uniquely homogenous and self-renewing. Differentiated iCoMoNSCs formed a self-organized multicellular system consisting of synaptically connected and electrophysiologically active neurons, which matured into long-lived functional networks (which we designate iNets). Neuronal and glial maturation in iNets was similar to that of cortical organoids[8]. Overexpression of wild-type TDP-43 in a minority of neurons within iNets led to progressive fragmentation and aggregation of the protein, resulting in a partial loss of function and neurotoxicity. Single-cell transcriptomics revealed a novel set of misregulated RNA targets in TDP-43-overexpressing neurons and in patients with TDP-43 proteinopathies exhibiting a loss of nuclear TDP-43. The strongest misregulated target encoded the synaptic protein NPTX2, the levels of which are controlled by TDP-43 binding on its 3' untranslated region. When NPTX2 was overexpressed in iNets, it exhibited neurotoxicity, whereas correcting NPTX2 misregulation partially rescued neurons from TDP-43-induced neurodegeneration. Notably, NPTX2 was consistently misaccumulated in neurons from patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 pathology. Our work directly links TDP-43 misregulation and NPTX2 accumulation, thereby revealing a TDP-43-dependent pathway of neurotoxicity.}, } @article {pmid38354985, year = {2024}, author = {Zamani, A and Thomas, E and Wright, DK}, title = {Sex biology in amyotrophic lateral sclerosis.}, journal = {Ageing research reviews}, volume = {95}, number = {}, pages = {102228}, doi = {10.1016/j.arr.2024.102228}, pmid = {38354985}, issn = {1872-9649}, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Brain/pathology ; Biology ; }, abstract = {Although sex differences in amyotrophic lateral sclerosis (ALS) have not been studied systematically, numerous clinical and preclinical studies have shown sex to be influential in disease prognosis. Moreover, with the development of advanced imaging tools, the difference between male and female brain in structure and function and their response to neurodegeneration are more definitive. As discussed in this review, ALS patients exhibit a sex bias pertaining to the features of the disease, and their clinical, pathological, (and pathophysiological) phenotypes. Several epidemiological studies have indicated that this sex disparity stems from various aetiologies, including sex-specific brain structure and neural functioning, genetic predisposition, age, gonadal hormones, susceptibility to traumatic brain injury (TBI)/head trauma and lifestyle factors.}, } @article {pmid38354672, year = {2024}, author = {Aradhye, P and Jha, S and Saha, P and Patwardhan, RS and Noothalapati, H and Krishna, CM and Patwardhan, S}, title = {Distinct spectral signatures unfold ECM stiffness-triggered biochemical changes in breast cancer cells.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {311}, number = {}, pages = {123994}, doi = {10.1016/j.saa.2024.123994}, pmid = {38354672}, issn = {1873-3557}, mesh = {Humans ; Female ; *Breast Neoplasms/metabolism ; Extracellular Matrix/chemistry/metabolism ; Collagen/analysis ; }, abstract = {Cancer progression often accompanies the stiffening of extracellular matrix (ECM) in and around the tumor, owing to extra deposition and cross-linking of collagen. Stiff ECM has been linked with poor prognosis and is known to fuel invasion and metastasis, notably in breast cancer. However, the underlying biochemical or metabolic changes and the cognate molecular signatures remain elusive. Here, we explored Raman spectroscopy to unveil the spectral fingerprints of breast cancer cells in response to extracellular mechanical cues. Using stiffness-tuneable hydrogels, we showed that cells grown on stiff ECM displayed morphological changes with high proliferation. We further demonstrated that Raman Spectroscopy, a label-free and non-invasive technique, could provide comprehensive information about the biochemical environment of breast cancer cells in response to varying ECM stiffness. Raman spectroscopic analysis classified the cells into distinct clusters based on principal component-based linear discriminant analysis (PC-LDA). Multivariate curve resolution-alternating least squares (MCR-ALS) analysis indicated that cells cultured on stiff ECM exhibited elevated nucleic acid content and lesser lipids. Interestingly, increased intensity of Raman bands corresponding to cytochrome-c was also observed in stiff ECM conditions, suggesting mitochondrial modulation. The key findings harboured by spectral profiles were also corroborated by transmission electron microscopy, confirming altered metabolic status as reflected by increased mitochondria number and decreased lipid droplets in response to ECM stiffening. Collectively, these findings not only give the spectral signatures for mechanoresponse but also provide the landscape of biochemical changes in response to ECM stiffening.}, } @article {pmid38354654, year = {2024}, author = {Li, M and Zhao, Z and Zhang, Y and Guo, X and Zhang, Y and Wang, J and Liu, Y and Yang, L and Mou, W and Zhang, X and Gao, H}, title = {Chemometrics combined with comprehensive two-dimensional gas chromatography-mass spectrometry for the identification of Baijiu vintage.}, journal = {Food chemistry}, volume = {444}, number = {}, pages = {138690}, doi = {10.1016/j.foodchem.2024.138690}, pmid = {38354654}, issn = {1873-7072}, mesh = {Gas Chromatography-Mass Spectrometry/methods ; *Chemometrics ; Least-Squares Analysis ; }, abstract = {The identification of baijiu vintage is crucial for quality assessment and economic value determination. However, its complex composition and multifaceted influences pose significant technical challenges, necessitating research into its aging mechanisms and the development of related identification methods. This study utilized Chemometrics in conjunction with GC × GC-TOFMS for Baijiu Vintage identification. Data compression achieved a reduction of over 1000-fold without compromising key information, enabling analysis on many samples and get their changing regular in a big matrix by MCR. Subsequently, MCR-ALS facilitated the extraction of physical and chemical meaningful information related to baijiu vintage. Key MCR principal components suitable for qualitative and quantitative assessments were selected using CARS-PLS. The regression model demonstrated errors of less than one year. Furthermore, a PLS-DA model provided 30 MCR principal components as potential markers. The research results provide technical support for baijiu vintage identification and lay the groundwork for studying the changing patterns of flavor compounds in baijiu.}, } @article {pmid38353166, year = {2024}, author = {Hart, AA and Swenson, A and Narayanan, NS and Simmering, JE}, title = {Rurality modifies the association between symptoms and the diagnosis of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {517-527}, pmid = {38353166}, issn = {2167-9223}, support = {K12 TR004382/TR/NCATS NIH HHS/United States ; P30 ES005605/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Male ; Female ; Middle Aged ; *Rural Population/statistics & numerical data ; Aged ; Adult ; United States/epidemiology ; Urban Population/statistics & numerical data ; }, abstract = {OBJECTIVE: We utilized national claims-based data to identify the change in odds of diagnosis of ALS following possible-ALS-symptoms-and whether the change varies in urban/rural areas.

METHODS: Insurance claims were obtained from the Merative MarketScan databases, 2001-2021 in the United States. Individuals with incident ALS were identified and matched on age, sex, and enrollment period to individuals without ALS. For all individuals, claims for 8 possible-ALS-symptoms in the time before any ALS diagnosis were identified. We then used conditional logistic regression to estimate the odds of being diagnosed with ALS following these symptoms and whether the association varied by urban/rural location.

RESULTS: 19,226 individuals with ALS were matched to 96,126 controls. Patients with ALS were more likely to live in an urban area (87.0% vs 84.5%). Of those with ALS 84% had 1+ of our 8 possible-ALS-symptom compared to 51% of controls. After adjustment for confounders, having possible-ALS-symptoms increased the odds of a future ALS diagnosis by nearly 5-fold. A dose-response pattern was present with increasing odds as the number of symptoms increased. In all models, urban areas were associated with increased odds of diagnosis with ALS while the effect of having a symptom was smaller in urban places. Urban cases of ALS are diagnosed at younger ages.

CONCLUSIONS: These results suggest symptoms may appear and be noted years before the diagnosis of ALS. Additionally, rural patients are diagnosed at later ages with a greater dependence on symptoms than urban patients. These results highlight potential improvements for screening for ALS.}, } @article {pmid38352429, year = {2024}, author = {Alessandrini, F and Wright, M and Kurosaki, T and Maquat, LE and Kiskinis, E}, title = {ALS-Associated TDP-43 Dysfunction Compromises UPF1-Dependent mRNA Metabolism Pathways Including Alternative Polyadenylation and 3'UTR Length.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.01.31.578311}, pmid = {38352429}, issn = {2692-8205}, abstract = {UPF1-mediated decay entails several mRNA surveillance pathways that play a crucial role in cellular homeostasis. However, the precise role of UPF1 in postmitotic neurons remains unresolved, as does its activity in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease characterized by TDP-43 pathology and disrupted mRNA metabolism. Here, we used human iPSC-derived spinal motor neurons (MNs) to identify mRNAs subject to UPF1 degradation by integrating RNA-seq before and after UPF1 knockdown with RIP-seq to identify RNAs that co-immunoprecipitate with the active form of phosphorylated UPF1. We define a stringent set of bona fide UPF1 targets in MNs that are functionally enriched for autophagy and structurally enriched for GC-rich and long 3' UTRs but not for premature termination codon (PTC)-containing transcripts. TDP-43 depletion in iPSC-derived MNs reduces UPF1 phosphorylation and consequently post-transcriptional upregulation of UPF1 targets, suggesting that TDP-43 dysfunction compromises UPF1-mediated mRNA surveillance. Intriguingly, our datasets reveal that UPF1 and TDP-43 regulate alternative polyadenylation and 3'UTR length of mRNAs associated with synaptic and axonal function, a process that we find to be compromised in ALS models in vitro and ALS patient tissue. Our study provides a comprehensive description of UPF1-mediated mRNA decay activity in neurons, reveals overlapping roles between UPF1 and TDP-43 in regulating 3'UTR length, and offers novel insight into the intricate interplay between RNA metabolism and neurodegeneration in ALS.}, } @article {pmid38352403, year = {2024}, author = {Sirtori, R and Gregoire, M and Collins, A and Santangelo, S and Chatragadda, B and Cullen, R and Ratti, A and Fallini, C}, title = {Altered nuclear envelope homeostasis is a key pathogenic event in C9ORF72-linked ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.02.01.578318}, pmid = {38352403}, issn = {2692-8205}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; R01 NS116143/NS/NINDS NIH HHS/United States ; }, abstract = {ALS and FTD are complex neurodegenerative disorders that primarily affects motor neurons in the brain and spinal cord, and cortical neurons in the frontal lobe. Although the pathogenesis of ALS/FTD is unclear, recent research spotlights nucleocytoplasmic transport impairment, DNA damage, and nuclear abnormalities as drivers of neuronal death. In this study, we show that loss of nuclear envelope (NE) integrity is a key pathology associated with nuclear pore complex (NPC) injury in C9ORF72 mutant neurons. Importantly, we show that mechanical stresses generated by cytoskeletal forces on the NE can lead to NPC injury, loss of nuclear integrity, and accumulation of DNA damage. Importantly, we demonstrate that restoring NE tensional homeostasis, by disconnecting the nucleus from the cytoskeleton, can rescue NPC injury and reduce DNA damage in C9ORF72 mutant cells. Together, our data suggest that modulation of NE homeostasis and repair may represent a novel and promising therapeutic target for ALS/FTD.}, } @article {pmid38352376, year = {2024}, author = {Amado, DA and Robbins, AB and Smith, AR and Whiteman, KR and Chillon Bosch, G and Chen, Y and Fuller, JA and Izda, A and Nelson, S and Dichter, AI and Monteys, AM and Davidson, BL}, title = {AAV-based delivery of RNAi targeting Ataxin-2 improves survival, strength, and pathology in mouse models of rapidly and slowly progressive sporadic ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.01.31.578314}, pmid = {38352376}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron death due to nuclear loss and cytoplasmic aggregation of the splice factor TDP-43. Pathologic TDP-43 associates with stress granules (SGs) and downregulating the SG-associated protein Ataxin-2 (Atxn2) using antisense oligonucleotides (ASO) prolongs survival in the TAR4/4 sporadic ALS mouse model, a strategy now in clinical trials. Here, we used AAV-mediated RNAi delivery to achieve lasting and targeted Atxn2 knockdown after a single injection. To achieve this, a novel AAV with improved transduction potency of our target cells was used to deliver Atxn2 -targeting miRNAs. Mouse dosing studies demonstrated 55% Atxn2 knockdown in frontal cortex and 25% knockdown throughout brainstem and spinal cord after intracerebroventricular injection at a dose 40x lower than used in other recent studies. In TAR4/4 mice, miAtxn2 treatment increased mean and median survival by 54% and 45% respectively (p<0.0003). Mice showed robust improvement across strength-related measures ranging from 24-75%. Interestingly, treated mice showed increased vertical activity above wildtype, suggesting unmasking of an FTD phenotype with improved strength. Histologically, lower motor neuron survival improved with a concomitant reduction in CNS inflammatory markers. Additionally, phosphorylated TDP-43 was reduced to wildtype levels. Bulk RNA sequencing revealed correction of 153 genes in the markedly dysregulated transcriptome of mutant mice, several of which are described in the human ALS literature. In slow progressing hemizygous mice, treatment rescued weight loss and improved gait at late time points. Cumulatively the data support the utility of AAV-mediated RNAi against Atxn2 as a robust and translatable treatment strategy for sporadic ALS.}, } @article {pmid38352350, year = {2024}, author = {Gomez, N and Hsieh, C and Li, X and Dykstra, M and Waksmacki, J and Altheim, C and Bechar, Y and Klim, J and Zaepfel, B and Rothstein, J and Tank, EE and Barmada, SJ}, title = {Counter-regulation of RNA stability by UPF1 and TDP43.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.01.31.578310}, pmid = {38352350}, issn = {2692-8205}, support = {R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; T32 GM145470/GM/NIGMS NIH HHS/United States ; }, abstract = {RNA quality control is crucial for proper regulation of gene expression. Disruption of nonsense mediated mRNA decay (NMD), the primary RNA decay pathway responsible for the degradation of transcripts containing premature termination codons (PTCs), can disrupt development and lead to multiple diseases in humans and other animals. Similarly, therapies targeting NMD may have applications in hematological, neoplastic and neurological disorders. As such, tools capable of accurately quantifying NMD status could be invaluable for investigations of disease pathogenesis and biomarker identification. Toward this end, we assemble, validate, and apply a next-generation sequencing approach (NMDq) for identifying and measuring the abundance of PTC-containing transcripts. After validating NMDq performance and confirming its utility for tracking RNA surveillance, we apply it to determine pathway activity in two neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) characterized by RNA misprocessing and abnormal RNA stability. Despite the genetic and pathologic evidence implicating dysfunctional RNA metabolism, and NMD in particular, in these conditions, we detected no significant differences in PTC-encoding transcripts in ALS models or disease. Contrary to expectations, overexpression of the master NMD regulator UPF1 had little effect on the clearance of transcripts with PTCs, but rather restored RNA homeostasis through differential use and decay of alternatively poly-adenylated isoforms. Together, these data suggest that canonical NMD is not a significant contributor to ALS/FTD pathogenesis, and that UPF1 promotes neuronal survival by regulating transcripts with abnormally long 3'UTRs.}, } @article {pmid38351547, year = {2024}, author = {Park, JJ and Chow, SM and Epskamp, S and Molenaar, PCM}, title = {Subgrouping with Chain Graphical VAR Models.}, journal = {Multivariate behavioral research}, volume = {59}, number = {3}, pages = {543-565}, pmid = {38351547}, issn = {1532-7906}, support = {U24 AA027684/AA/NIAAA NIH HHS/United States ; UL1 TR002014/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Monte Carlo Method ; *Models, Statistical ; *Computer Simulation/statistics & numerical data ; Data Interpretation, Statistical ; Least-Squares Analysis ; }, abstract = {Recent years have seen the emergence of an "idio-thetic" class of methods to bridge the gap between nomothetic and idiographic inference. These methods describe nomothetic trends in idiographic processes by pooling intraindividual information across individuals to inform group-level inference or vice versa. The current work introduces a novel "idio-thetic" model: the subgrouped chain graphical vector autoregression (scGVAR). The scGVAR is unique in its ability to identify subgroups of individuals who share common dynamic network structures in both lag(1) and contemporaneous effects. Results from Monte Carlo simulations indicate that the scGVAR shows promise over similar approaches when clusters of individuals differ in their contemporaneous dynamics and in showing increased sensitivity in detecting nuanced group differences while keeping Type-I error rates low. In contrast, a competing approach-the Alternating Least Squares VAR (ALS VAR) performs well when groups were separated by larger distances. Further considerations are provided regarding applications of the ALS VAR and scGVAR on real data and the strengths and limitations of both methods.}, } @article {pmid38350967, year = {2024}, author = {Rodriguez-Mogeda, C and van Ansenwoude, CMJ and van der Molen, L and Strijbis, EMM and Mebius, RE and de Vries, HE}, title = {The role of CD56[bright] NK cells in neurodegenerative disorders.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {48}, pmid = {38350967}, issn = {1742-2094}, mesh = {Humans ; Killer Cells, Natural ; Cytokines ; Cell Differentiation ; *Antineoplastic Agents ; *Neurodegenerative Diseases ; }, abstract = {Emerging evidence suggests a potential role for natural killer (NK) cells in neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. However, the precise function of NK cells in these diseases remains ambiguous. The existence of two NK cell subsets, CD56[bright] and CD56[dim] NK cells, complicates the understanding of the contribution of NK cells in neurodegeneration as their functions within the context of neurodegenerative diseases may differ significantly. CD56[bright] NK cells are potent cytokine secretors and are considered more immunoregulatory and less terminally differentiated than their mostly cytotoxic CD56[dim] counterparts. Hence, this review focusses on NK cells, specifically on CD56[bright] NK cells, and their role in neurodegenerative diseases. Moreover, it explores the mechanisms underlying their ability to enter the central nervous system. By consolidating current knowledge, we aim to provide a comprehensive overview on the role of CD56[bright] NK cells in neurodegenerative diseases. Elucidating their impact on neurodegeneration may have implications for future therapeutic interventions, potentially ameliorating disease pathogenesis.}, } @article {pmid38350049, year = {2024}, author = {Urushitani, M and Nakamura, R}, title = {Hypermetabolism in Amyotrophic Lateral Sclerosis: Step Ahead Toward Global Consensus.}, journal = {Neurology}, volume = {102}, number = {5}, pages = {e209179}, doi = {10.1212/WNL.0000000000209179}, pmid = {38350049}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Consensus ; }, } @article {pmid38350046, year = {2024}, author = {Holdom, CJ and Janse van Mantgem, MR and He, J and Howe, SL and McCombe, PA and Fan, D and van den Berg, LH and Henderson, RD and van Eijk, R and Steyn, FJ and Ngo, ST}, title = {Variation in Resting Metabolic Rate Affects Identification of Metabolic Change in Geographically Distinct Cohorts of Patients With ALS.}, journal = {Neurology}, volume = {102}, number = {5}, pages = {e208117}, doi = {10.1212/WNL.0000000000208117}, pmid = {38350046}, issn = {1526-632X}, mesh = {Humans ; *Basal Metabolism ; Energy Metabolism ; *Amyotrophic Lateral Sclerosis/epidemiology/metabolism ; Australia/epidemiology ; Body Composition ; }, abstract = {BACKGROUND AND OBJECTIVES: Altered metabolism is observed in amyotrophic lateral sclerosis (ALS). However, without a standardized methodology to define metabolic changes, our understanding of factors contributing to and the clinical significance of altered metabolism in ALS is limited.

METHODS: We aimed to determine how geographic variation in metabolic rates influences estimates and accuracy of predicted resting energy expenditure (REE) in patients with ALS and controls, while validating the effectiveness of cohort-specific approaches in predicting altered metabolic rate in ALS. Participants from 3 geographically distinct sites across Australia, China, and the Netherlands underwent REE assessments, and we considered 22 unique equations for estimating REE. Analyses evaluated equation performance and the influence of demographics on metabolic status. Comparisons were made using standardized and local reference values to identify metabolic alterations.

RESULTS: 606 participants were included from Australia (patients with ALS: 140, controls: 154), the Netherlands (patients with ALS: 79, controls: 37) and China (patients with ALS: 67, controls: 129). Measured REE was variable across geographic cohorts, with fat-free mass contributing to this variation across all patients (p = 0.002 to p < 0.001). Of the 22 predication equations assessed, the Sabounchi Structure 4 (S4) equation performed relatively well across all control cohorts. Use of prediction thresholds generated using data from Australian controls generally increased the prevalence of hypermetabolism in Chinese (55%, [43%-67%]) and Dutch (44%, [33%-55%]) cases when compared with Australian cases (30%, [22%-38%]). Adjustment of prediction thresholds to consider geographically distinct characteristics from matched control cohorts resulted in a decrease in the proportion of hypermetabolic cases in Chinese and Dutch cohorts (25%-31% vs 55% and 20%-34% vs 43%-44%, respectively), and increased prevalence of hypometabolism in Dutch cases with ALS (1% to 8%-10%).

DISCUSSION: The identification of hypermetabolism in ALS is influenced by the formulae and demographic-specific prediction thresholds used for defining alterations in metabolic rate. A consensus approach is needed for identification of metabolic changes in ALS and will facilitate improved understanding of the cause and clinical significance of this in ALS.}, } @article {pmid38349516, year = {2024}, author = {Xin, Z and Xin, C and Huo, J and Liu, Q and Dong, H and Li, R and Liu, Y}, title = {Neuroprotective Effect of a Multistrain Probiotic Mixture in SOD1[G93A] Mice by Reducing SOD1 Aggregation and Targeting the Microbiota-Gut-Brain Axis.}, journal = {Molecular neurobiology}, volume = {61}, number = {12}, pages = {10051-10071}, pmid = {38349516}, issn = {1559-1182}, support = {H2021206310//the Natural Science Foundation of Hebei Province/ ; zh2018004//the Key Project of Technical Health Research and Achievement Transformation of Hebei Provincial Department of Health/ ; }, mesh = {Animals ; *Probiotics/pharmacology ; *Gastrointestinal Microbiome/drug effects ; *Superoxide Dismutase-1/metabolism/genetics ; *Mice, Transgenic ; *Neuroprotective Agents/pharmacology ; *Amyotrophic Lateral Sclerosis/pathology ; Brain-Gut Axis/drug effects/physiology ; Mice ; Autophagy/drug effects ; Brain/drug effects/metabolism ; Spinal Cord/drug effects/metabolism/pathology ; Protein Aggregates/drug effects ; Mice, Inbred C57BL ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the selective loss of motor neurons. A bidirectional communication system known as the "microbiota-gut-brain" axis has a regulatory function in neurodegenerative disorders. The impact of probiotics on ALS through the "microbiota-gut-brain" axis remains uncertain. A longitudinal investigation was conducted to examine the alterations in the structure of the ileum and colon in mutant superoxide dismutase 1 (SOD1[G93A]) transgenic mice models of ALS by using immunofluorescence and Western blotting. Subsequently, the mice were administered a multistrain probiotic mixture (LBE) or vehicle orally, starting from 60 days of age until the terminal stage of the disease. The effects of these agents on the behavior, gut microbiota, microbial metabolites, and pathological processes of the spinal and intestine of SOD1[G93A] mice were analyzed, with a focus on exploring potential protective mechanisms. SOD1[G93A] mice exhibit various structural abnormalities in the intestine. Oral administration of LBE improved the proinflammatory response, reduced aberrant superoxide dismutase 1 (SOD1) aggregation, and protected neuronal cells in the intestine and spinal cord of SOD1[G93A] mice. Furthermore, LBE treatment resulted in a change in intestinal microbiota, an increase in short-chain fatty acid levels, and an enhancement in autophagy flux. SOD1[G93A] mice exhibited various structural abnormalities in the intestine. LBE can improve the proinflammatory response, reduce aberrant SOD1 aggregation, and protect neuronal cells in the spinal cord and intestine of SOD1[G93A] mice. The positive effect of LBE can be attributed to increased short-chain fatty acids and enhanced autophagy flux.}, } @article {pmid38349514, year = {2024}, author = {Xu, Y and Lin, F and Liao, G and Sun, J and Chen, W and Zhang, L}, title = {Ripks and Neuroinflammation.}, journal = {Molecular neurobiology}, volume = {61}, number = {9}, pages = {6771-6787}, pmid = {38349514}, issn = {1559-1182}, support = {81971098//National Natural Science Foundation of China/ ; 82104144//National Natural Science Foundation of China/ ; }, mesh = {*Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Humans ; Animals ; *Neuroinflammatory Diseases/metabolism/pathology ; Inflammation/pathology/metabolism ; }, abstract = {Neuroinflammation is an immune response in the central nervous system and poses a significant threat to human health. Studies have shown that the receptor serine/threonine protein kinase family (RIPK) family, a popular research target in inflammation, has been shown to play an essential role in neuroinflammation. It is significant to note that the previous reviews have only examined the link between RIPK1 and neuroinflammation. However, it has yet to systematically analyze the relationship between the RIPK family and neuroinflammation. Activation of RIPK1 promotes neuroinflammation. RIPK1 and RIPK3 are responsible for the control of cell death, including apoptosis, necrosis, and inflammation. RIPK1 and RIPK3 regulate inflammatory responses through the release of damage in necroptosis. RIPK1 and RIPK3 regulate inflammatory responses by releasing damage-associated molecular patterns (DAMPs) during necrosis. In addition, activated RIPK1 nuclear translocation and its interaction with the BAF complex leads to upregulation of chromatin modification and inflammatory gene expression, thereby triggering inflammation. Although RIPK2 is not directly involved in regulating cell death, it is considered an essential target for treating neurological inflammation. When the peptidoglycan receptor detects peptidoglycan IE-DAP or MDP in bacteria, it prompts NOD1 and NOD2 to recruit RIPK2 and activate the XIAP E3 ligase. This leads to the K63 ubiquitination of RIPK2. This is followed by LUBAC-mediated linear ubiquitination, which activates NF-KB and MAPK pathways to produce cytokines and chemokines. In conclusion, there are seven known members of the RIPK family, but RIPK4, RIPK5, RIPK6, and RIPK7 have not been linked to neuroinflammation. This article seeks to explore the potential of RIPK1, RIPK2, and RIPK3 kinases as therapeutic interventions for neuroinflammation, which is associated with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), ischemic stroke, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI).}, } @article {pmid38349395, year = {2024}, author = {Soni, S and Lukhey, MS and Thawkar, BS and Chintamaneni, M and Kaur, G and Joshi, H and Ramniwas, S and Tuli, HS}, title = {A current review on P2X7 receptor antagonist patents in the treatment of neuroinflammatory disorders: a patent review on antagonists.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {397}, number = {7}, pages = {4643-4656}, pmid = {38349395}, issn = {1432-1912}, mesh = {*Patents as Topic ; Humans ; *Receptors, Purinergic P2X7/metabolism ; *Purinergic P2X Receptor Antagonists/therapeutic use/pharmacology ; Animals ; *Neuroinflammatory Diseases/drug therapy ; }, abstract = {Chronic inflammation is defined by an activated microglial state linked to all neurological disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (a motor neuron disease that affects the brain and spinal cord). P2X7 receptors (P2X7R) are ATP-activated ion-gated channels present on microglial surfaces. Prolonged ATP release under pathological settings results in sustained P2X7R activation, which leads to inflammasome development and cytokine release. P2X7R and its enabling roles have recently been linked to neurodegenerative diseases, making it a potential research subject. This research provides an overview of current patents for chemicals, biologics, and medicinal applications. The World Intellectual Property Organization (WIPO), European Patent Office (EPO, Espacenet), and the United States Patent and Trademark Office (USPTO) databases were searched for patents using the keywords "P2X7R and Neuroinflammation." During the study period from 2015 to 2021, 103 patents were examined. The countries that protected these innovations were the United States, PCT (Patent Cooperation Treaty states), Europe, Canada, Australia, and India. Janssen Pharmaceutica NV had the most applications, followed by Acetelion Pharmaceuticals LTD., Renovis Inc., Kelly Michael G, Kincaid Jhon, Merck Patent GMBH, H Lundbeck A/S, and many more. The P2X7R is a possible diagnostic and therapeutic target for cancer, pain disorders, and inflammation. For P2X7 R, several compounds have been discovered and are presently the subject of clinical trial investigations. This study featured patents for P2X7R antagonists, which help treat conditions including neuroinflammation.}, } @article {pmid38348223, year = {2024}, author = {Orfali, R and Alwatban, AZ and Orfali, RS and Lau, L and Chea, N and Alotaibi, AM and Nam, YW and Zhang, M}, title = {Oxidative stress and ion channels in neurodegenerative diseases.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1320086}, pmid = {38348223}, issn = {1664-042X}, support = {R33 NS101182/NS/NINDS NIH HHS/United States ; }, abstract = {Numerous neurodegenerative diseases result from altered ion channel function and mutations. The intracellular redox status can significantly alter the gating characteristics of ion channels. Abundant neurodegenerative diseases associated with oxidative stress have been documented, including Parkinson's, Alzheimer's, spinocerebellar ataxia, amyotrophic lateral sclerosis, and Huntington's disease. Reactive oxygen and nitrogen species compounds trigger posttranslational alterations that target specific sites within the subunits responsible for channel assembly. These alterations include the adjustment of cysteine residues through redox reactions induced by reactive oxygen species (ROS), nitration, and S-nitrosylation assisted by nitric oxide of tyrosine residues through peroxynitrite. Several ion channels have been directly investigated for their functional responses to oxidizing agents and oxidative stress. This review primarily explores the relationship and potential links between oxidative stress and ion channels in neurodegenerative conditions, such as cerebellar ataxias and Parkinson's disease. The potential correlation between oxidative stress and ion channels could hold promise for developing innovative therapies for common neurodegenerative diseases.}, } @article {pmid38348026, year = {2024}, author = {Tang, C and Lei, X and Ding, Y and Yang, S and Ma, Y and He, D}, title = {Causal relationship between immune cells and neurodegenerative diseases: a two-sample Mendelian randomisation study.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1339649}, pmid = {38348026}, issn = {1664-3224}, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; *Alzheimer Disease/genetics ; *Parkinson Disease/genetics ; Causality ; *Multiple Sclerosis/genetics ; }, abstract = {BACKGROUND: There is increasing evidence that the types of immune cells are associated with various neurodegenerative diseases. However, it is currently unclear whether these associations reflect causal relationships.

OBJECTIVE: To elucidate the causal relationship between immune cells and neurodegenerative diseases, we conducted a two-sample Mendelian randomization (MR) analysis.

MATERIALS AND METHODS: The exposure and outcome GWAS data used in this study were obtained from an open-access database (https://gwas.mrcieu.ac.uk/), the study employed two-sample MR analysis to assess the causal relationship between 731 immune cell features and four neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). All immune cell data was obtained from Multiple MR methods were used to minimize bias and obtain reliable estimates of the causal relationship between the variables of interest and the outcomes. Instrumental variable selection criteria were restricted to ensure the accuracy and effectiveness of the causal relationship between species of immune cells and the risk of these neurodegenerative diseases.

RESULTS: The study identified potential causal relationships between various immune cells and different neurodegenerative diseases. Specifically, we found that 8 different types of immune cells have potential causal relationships with AD, 1 type of immune cells has potential causal relationships with PD, 6 different types of immune cells have potential causal relationships with ALS, and 6 different types of immune cells have potential causal relationships with MS.

CONCLUSION: Our study, through genetic means, demonstrates close causal associations between the specific types of immune cells and AD, PD, ALS and MS, providing useful guidance for future clinical researches.}, } @article {pmid38347888, year = {2024}, author = {Aoun, SM and O'Brien, MR and Knighting, K}, title = {Using the Carers' Alert Thermometer tool to identify needs and support family caregivers of people with motor neurone disease: moving beyond needs assessments.}, journal = {Palliative care and social practice}, volume = {18}, number = {}, pages = {26323524241228306}, pmid = {38347888}, issn = {2632-3524}, abstract = {BACKGROUND: Family caregivers of people with motor neurone disease (MND) experience adverse health outcomes as a result of their caregiving experience. This may be alleviated if their support needs are identified and addressed in a systematic and timely manner. The objective of this pilot study was to assess the feasibility and relevance of the Carers' Alert Thermometer (CAT) in home-based care, from the perspective of MND family caregivers. The tool provides a formal structure to facilitate discussions with caregivers to enable needs to be addressed.

METHODS: This mixed-method study was conducted in Western Australia (2020-2021). Forty-one caregivers and five MND Advisors participated in trialling the CAT intervention which consisted of two encounters with Advisors (6-8 weeks apart) to identify and address support needs through action plans. Caregivers' feedback was obtained via telephone interviews and a thematic analysis was undertaken.

RESULTS: Thirty caregivers completed two CAT assessments. Caregivers identified support priorities of managing their feelings and worries, providing emotional or spiritual care, information about the person's condition and how their care needs might change. Seventeen caregivers were interviewed and found that this assessment process adequately addressed their needs and it should be continued, it brought the focus onto them to clarify problems and work through solutions. The improvements that were suggested by them, including better information/education in palliative care, led to the development of an online support/information toolkit, which served to empower caregivers and staff by accessing relevant information and resources.

CONCLUSIONS: The CAT demonstrated utility for triaging caregivers most in need of additional support and those whom signposting to additional information and self-directed access to support was most appropriate. For any tool to become an integrated part of care, service provider support is key for implementation, allowing for the time resource required and an appropriate education and support structure. MND Associations have an important role in building stronger partnerships with supportive community networks, through compassionate communities models of care, to address the identified needs of MND families in a more sustainable and wholistic manner. Needs assessment is a means towards building this capacity between formal and informal networks.}, } @article {pmid38347806, year = {2024}, author = {Lao, Z and Tang, Y and Dong, X and Tan, Y and Li, X and Liu, X and Li, L and Guo, C and Wei, G}, title = {Elucidating the reversible and irreversible self-assembly mechanisms of low-complexity aromatic-rich kinked peptides and steric zipper peptides.}, journal = {Nanoscale}, volume = {16}, number = {8}, pages = {4025-4038}, doi = {10.1039/d3nr05130g}, pmid = {38347806}, issn = {2040-3372}, mesh = {Protein Conformation ; *Amyloid/chemistry ; *Peptides/chemistry ; Molecular Dynamics Simulation ; Protein Conformation, beta-Strand ; }, abstract = {Many RNA-binding proteins such as fused-in sarcoma (FUS) can self-assemble into reversible liquid droplets and fibrils through the self-association of their low-complexity (LC) domains. Recent experiments have revealed that SYG-rich segments in the FUS LC domains play critical roles in the reversible self-assembly behaviors of FUS. These FUS LC segments alone can self-assemble into reversible kinked fibrils, which are markedly different from the canonical irreversible steric zipper β-sheet fibrils. However, the molecular determinants underlying the reversible and irreversible self-assembly are poorly understood. Herein we conducted extensive all-atom and coarse-grained molecular dynamics simulations of four representative hexapeptides: two low-complexity aromatic-rich kinked peptides from the amyotrophic lateral sclerosis-related FUS protein, FUS37-42 (SYSGYS) and FUS54-59 (SYSSYG); and two steric zipper peptides from Alzheimer's-associated Aβ and Tau proteins, Aβ16-21 (KLVFFA) and Tau306-311 (VQIVYK). We dissected their reversible and irreversible self-assembly dynamics, predicted their phase separation behaviors, and elucidated the underpinning molecular interactions. Our simulations showed that alternating stickers (Tyr) and spacers (Gly and Ser) in FUS37-42 and FUS54-59 facilitate the formation of highly dynamic coil-rich oligomers and lead to reversible self-assembly, while consecutive hydrophobic residues of LVFF in Aβ16-21 and IVY in Tau306-311 act as hydrophobic patches, favoring the formation of stable β-sheet-rich oligomers and driving the irreversible self-assembly. Intriguingly, we found that FUS37-42 and FUS54-59 peptides, possessing the same amino acid composition and the same number of sticker and spacer residues, display differential self-assembly propensities. This finding suggests that the self-assembly behaviors of FUS peptides are fine-tuned by the site-specific patterning of spacer residues (Ser and Gly). This study provides significant mechanistic insights into reversible and irreversible peptide self-assembly, which would be helpful for understanding the molecular mechanisms underlying the formation of biological liquid condensates and pathological solid amyloid fibrils.}, } @article {pmid38347638, year = {2024}, author = {Li, W and Li, HL and Wang, JZ and Liu, R and Wang, X}, title = {Abnormal protein post-translational modifications induces aggregation and abnormal deposition of protein, mediating neurodegenerative diseases.}, journal = {Cell & bioscience}, volume = {14}, number = {1}, pages = {22}, pmid = {38347638}, issn = {2045-3701}, support = {92049107//National Natural Science Foundation of China/ ; 82071440//National Natural Science Foundation of China/ ; 31929002//National Natural Science Foundation of China/ ; }, abstract = {Protein post-translational modifications (PPTMs) refer to a series of chemical modifications that occur after the synthesis of protein. Proteins undergo different modifications such as phosphorylation, acetylation, ubiquitination, and so on. These modifications can alter the protein's structure, function, and interaction, thereby regulating its biological activity. In neurodegenerative diseases, several proteins undergo abnormal post-translational modifications, which leads to aggregation and abnormal deposition of protein, thus resulting in neuronal death and related diseases. For example, the main pathological features of Alzheimer's disease are the aggregation of beta-amyloid protein and abnormal phosphorylation of tau protein. The abnormal ubiquitination and loss of α-synuclein are related to the onset of Parkinson's disease. Other neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis, and so on are also connected with abnormal PPTMs. Therefore, studying the abnormal PPTMs in neurodegenerative diseases is critical for understanding the mechanism of these diseases and the development of significant therapeutic strategies. This work reviews the implications of PPTMs in neurodegenerative diseases and discusses the relevant therapeutic strategies.}, } @article {pmid38347315, year = {2024}, author = {Huang, SL and Shen, YL and Peng, WY and Ye, K and Zheng, H}, title = {Edaravone for patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Acta neurologica Belgica}, volume = {124}, number = {3}, pages = {895-904}, pmid = {38347315}, issn = {2240-2993}, support = {no. 2021JDTD0007//Sichuan Province Science and Technology Support Program/ ; }, mesh = {*Edaravone/therapeutic use ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Free Radical Scavengers/therapeutic use ; Randomized Controlled Trials as Topic/methods ; Treatment Outcome ; }, abstract = {BACKGROUND AND OBJECTIVE: The effectiveness and long-term efficacy of edaravone, a recommended treatment for amyotrophic lateral sclerosis (ALS), has not been examined in real-world settings. This study aims to evaluate the effectiveness and long-term efficacy of edaravone.

METHODS: The OVID Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases were searched for articles published between January 1, 2000, and May 1, 2023. Two investigators independently screened the retrieved articles for randomized controlled trials (RCTs), cohort studies, or single-arm trials that evaluated the effect of edaravone on amyotrophic lateral sclerosis (ALS). The risk of bias was evaluated using the revised Cochrane Risk-of-Bias (RoB 2.0) tool for randomized controlled trials (RCTs) and the Risk-of-Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for observational studies. The primary outcome was the ALSFRS-R score assessed at month 6, with secondary outcomes including the ALSFRS-R scores evaluated at months 9, 12, and 18, forced vital capacity (FVC), and adverse events. The certainty of evidence was assessed using the GRADE approach.

RESULTS: The analysis included 16 studies with a total of 4828 participants. Among these, four were randomized controlled trials (RCTs) and 12 were observational studies. Of the RCTs, four were rated as having a low risk of bias, while six of the observational studies were rated as having a low risk of bias. Edaravone was associated with slightly slower progression in the reduction of ALSFRS-R score at month 6 compared to placebo (mean difference 1.01, 95%CI -0.87 to 3.09, p = 0.293), as shown by evidence from RCTs. However, observational studies did not show any benefit of adding edaravone to routine practice (mean difference 1.85, 95%CI -2.05 to 5.75, p = 0.352). The change from baseline in ALSFRS-R score was -2.1, -4.04, -7.5, -6.82, and -7.9 at months 3, 6, 9, 12, and 18, respectively. The GRADE assessment indicated moderate certainty for evidence from RCTs, while evidence from observational studies had very low certainty.

CONCLUSION: Due to the limited number of studies and confounding issues in observational studies, further examination of the added benefits of edaravone to routine practice is necessary through RCTs, particularly regarding its long-term efficacy.}, } @article {pmid38345477, year = {2024}, author = {Zhu, H and Dalvi, U and Cazenave, W and Cattaert, D and Branchereau, P}, title = {Excitatory action of low frequency depolarizing GABA/glycine synaptic inputs is prevalent in prenatal spinal SOD1[G93A] motoneurons.}, journal = {The Journal of physiology}, volume = {602}, number = {5}, pages = {913-932}, doi = {10.1113/JP285105}, pmid = {38345477}, issn = {1469-7793}, support = {AAP2018//Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone/ ; 23185//AFM-TELETHON/ ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis ; Glycine/pharmacology ; Superoxide Dismutase-1/genetics ; Spinal Cord/physiology ; Chlorides ; *Neurodegenerative Diseases ; Mice, Transgenic ; Motor Neurons/physiology ; gamma-Aminobutyric Acid/pharmacology ; Disease Models, Animal ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by progressive motor neuron degeneration and muscle paralysis. Recent evidence suggests the dysfunction of inhibitory signalling in ALS motor neurons. We have shown that embryonic day (E)17.5 spinal motoneurons (MNs) of the SOD1[G93A] mouse model of ALS exhibit an altered chloride homeostasis. At this prenatal stage, inhibition of spinal motoneurons (MNs) is mediated by depolarizing GABAergic/glycinergic postsynaptic potentials (dGPSPs). Here, using an ex vivo preparation and patch clamp recording from MNs with a chloride equilibrium set below spike threshold, we report that low input resistance (Rin) E17.5 MNs from the SOD1[G93A] ALS mouse model do not correctly integrate dGPSPs evoked by electrical stimulations of GABA/glycine inputs at different frequencies. Indeed, firing activity of most wild-type (WT) MNs with low Rin was inhibited by incoming dGPSPs, whereas low Rin SOD1[G93A] MNs were excited or exhibited a dual response (excited by low frequency dGPSPs and inhibited by high frequency dGPSPs). Simulation highlighted the importance of the GABA/glycine input density and showed that pure excitation could be obtained in SOD-like MNs by moving GABA/glycine input away from the cell body to dendrites. This was in agreement with confocal imaging showing a lack of peri-somatic inhibitory terminals in SOD1[G93A] MNs compared to WT littermates. Putative fast ALS-vulnerable MNs with low Rin are therefore lacking functional inhibition at the near-term prenatal stage. KEY POINTS: We analysed the integration of GABAergic/glycinergic synaptic events by embryonic spinal motoneurons (MNs) in a mouse model of the amyotrophic lateral sclerosis (ALS) neurodegenerative disease. We found that GABAergic/glycinergic synaptic events do not properly inhibit ALS MNs with low input resistance, most probably corresponding to future vulnerable MNs. We used a neuron model to highlight the importance of the GABA/glycine terminal location and density in the integration of the GABAergic/glycinergic synaptic events. Confocal imaging showed a lack of GABA/glycine terminals on the cell body of ALS MNs. The present study suggests that putative ALS vulnerable MNs with low Rin lack functional inhibition at the near-term stage.}, } @article {pmid38343852, year = {2024}, author = {Mitra, J and Dharmalingam, P and Kodavati, M and Guerrero, EN and Rao, KS and Garruto, RM and Hegde, ML}, title = {Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38343852}, issn = {2693-5015}, support = {R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {TDP-43 mislocalization and aggregation are key pathological features of motor neuron diseases (MND) including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, transgenic hTDP-43 WT or ΔNLS-overexpression animal models mainly capture late-stages TDP-43 proteinopathy, and do not provide a complete understanding of early motor neuron-specific pathology during pre-symptomatic phases. We have now addressed this shortcoming by generating a new endogenous knock-in (KI) mouse model using a combination of CRISPR/Cas9 and FLEX Cre-switch strategy for the conditional expression of a mislocalized Tdp-43ΔNLS variant of mouse Tdp-43. This variant is either expressed conditionally in whole mice or specifically in the motor neurons. The mice exhibit loss of nuclear Tdp-43 concomitant with its cytosolic accumulation and aggregation in targeted cells, leading to increased DNA double-strand breaks (DSBs), signs of inflammation and DNA damage-associated cellular senescence. Notably, unlike WT Tdp43 which functionally interacts with Xrcc4 and DNA Ligase 4, the key DSB repair proteins in the non-homologous end-joining (NHEJ) pathway, the Tdp-43ΔNLS mutant sequesters them into cytosolic aggregates, exacerbating neuronal damage in mice brain. The mutant mice also exhibit myogenic degeneration in limb muscles and distinct motor deficits, consistent with the characteristics of MND. Our findings reveal progressive degenerative mechanisms in motor neurons expressing endogenous Tdp-43ΔNLS mutant, independent of TDP-43 overexpression or other confounding etiological factors. Thus, this unique Tdp-43 KI mouse model, which displays key molecular and phenotypic features of Tdp-43 proteinopathy, offers a significant opportunity to further characterize the early-stage progression of MND and also opens avenues for developing DNA repair-targeted approaches for treating TDP-43 pathology-linked neurodegenerative diseases.}, } @article {pmid38343836, year = {2024}, author = {Hobson, R and Levy, SHS and Flaherty, D and Xiao, H and Ciener, B and Reddy, H and Singal, C and Kim, CY and Teich, AF and Shneider, NA and Bradshaw, EM and Elyaman, W}, title = {Clonal CD8 T Cells Accumulate in the Leptomeninges and Communicate with Microglia in Human Neurodegeneration.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38343836}, issn = {2693-5015}, support = {P30 CA013696/CA/NCI NIH HHS/United States ; R01 AG067581/AG/NIA NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; }, abstract = {Murine studies have highlighted a crucial role for immune cells in the meninges in surveilling the central nervous system (CNS) and influencing neuroinflammation. However, how meningeal immunity is altered in human neurodegeneration and its effects on CNS inflammation is understudied. We performed the first single-cell analysis of the transcriptomes and T cell receptor (TCR) repertoire of 104,635 immune cells from 55 postmortem human brain and leptomeningeal tissues from donors with neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. RNA and TCR sequencing from paired leptomeninges and brain allowed us to perform lineage tracing to identify the spatial trajectory of clonal T cells in the CNS and its borders. We propose that T cells activated in the brain emigrate to and establish residency in the leptomeninges where they likely contribute to impairments in lymphatic drainage and remotely to CNS inflammation by producing IFNγ and other cytokines. We identified regulatory networks local to the meninges including NK cell-mediated CD8 T cell killing which likely help to control meningeal inflammation. Collectively, these findings provide not only a foundation for future studies into brain border immune surveillance but also highlight important intercellular dynamics that could be leveraged to modulate neuroinflammation.}, } @article {pmid38343431, year = {2024}, author = {Olesen, LK and la Cour, K and Nimmon, L and With, H and Handberg, C}, title = {Experiences of an Online Palliative Rehabilitation Programme for Spousal Caregivers of People With Amyotrophic Lateral Sclerosis and Cognitive and/or Behavioural Impairments: A Qualitative Interpretive Study.}, journal = {Advances in rehabilitation science and practice}, volume = {13}, number = {}, pages = {27536351241227860}, pmid = {38343431}, issn = {2753-6351}, abstract = {PURPOSE: The purpose of this study was to understand how spousal caregivers of people with amyotrophic lateral sclerosis and cognitive and/or behavioural impairments felt about the EMBRACE intervention.

MATERIALS AND METHODS: A qualitative interpretive study, using individual semi-structured interviews pre- and post-participation in a palliative rehabilitation blended learning programme, was applied. In total, 13 spousal caregivers were interviewed pre-intervention and 10 of them post-intervention.

RESULTS: Three overarching themes were identified: Striving to Obtain Control in Everyday Life, Peer support Across the Illness Trajectory and The Complexity of Relations. Information provided in targeted videos and sharing experiences with peers in virtual group meetings were beneficial to comprehend, manage and find meaning in everyday challenges related to being a caregiver.

CONCLUSION: The EMBRACE intervention helped spousal caregivers cope with everyday needs and challenges related to being a caregiver. EMBRACE was found to support and strengthen the participants in gaining more control in everyday life, creating a sense of coherence. Through targeted videos and discussions with peers, the participants felt prepared for the illness trajectory of their relative. Peer support promoted resilient functioning and reduced their feelings of loneliness.

CLINICAL TRIAL REGISTRATION: This study was registered on clinicaltrials.gov under the name: A Complex Intervention Study on a Palliative Rehabilitation Blended Learning Programme to Support Relatives and Health Care Providers of People with ALS and Cognitive Impairments in Coping with Challenges. ID no. NCT04638608. URL: https://clinicaltrials.gov/ct2/results?cond=&term=NCT04638608&cntry=&state=&city=&dist=.}, } @article {pmid38342829, year = {2024}, author = {Bottinelli, C and Baradian, P and Poly, A and Hoizey, G and Chatenay, C}, title = {Identification and quantification of both isomers of hexahydrocannabinol, (9R)-hexahydrocannabinol and (9S)-hexahydrocannabinol, in three different matrices by mass spectrometry.}, journal = {Rapid communications in mass spectrometry : RCM}, volume = {38}, number = {7}, pages = {e9711}, doi = {10.1002/rcm.9711}, pmid = {38342829}, issn = {1097-0231}, mesh = {Tandem Mass Spectrometry/methods ; Reproducibility of Results ; *Cannabinoids/analysis ; *Cannabidiol/analysis ; Gas Chromatography-Mass Spectrometry/methods ; Dronabinol ; }, abstract = {CONTEXT: Hexahydrocannabinol (HHC), a compound derived from synthetic production using cannabidiol (CBD) or delta-9-tetrahydrocannabinol (Δ[9] -THC), has gained recent attention due to its presence in seized materials across Europe. Sold legally in various forms, HHC poses potential health risks, particularly as a legal alternative to THC in some countries. Despite its historical description in the 1940s, limited toxicology data, pharmacological understanding, and analytical methods for HHC exist.

METHOD: This study proposes analytical techniques using mass spectrometry to detect, identify, and quantify (9R)-HHC and (9S)-HHC, concurrently with THC and CBD in various matrices, including oral fluid, whole blood, and seized material. Three distinct methods were employed for different matrices: GC/MS for seized material, GC/MS/MS for whole blood, and UHPLC/MS/MS for oral fluid. Methods were validated qualitatively for oral fluid with a FLOQSwab® device and quantitatively in whole blood and seized material according to Peters et al's recommendations and ICH guidelines.

RESULTS: Validated methods were considered reliable in detecting and quantifying HHC isomers in terms of repeatability, reproducibility, and linearity with r[2] systematically >0.992. These methods were applied to authentic cases, including seized materials and biological samples from traffic control (whole blood and oral fluid). In seized materials, (9R)-HHC levels ranged from 2.09% to 8.85% and (9R)-HHC/(9S)-HHC ratios varied from 1.36 to 2.68. In whole blood sample, (9R)-HHC and (9S)-HHC concentrations were, respectively, 2.38 and 1.39 ng/mL. For all analyzed samples, cannabinoids such as THC and CBD were also detected.

CONCLUSION: This research contributes analytical insights into differentiating and simultaneously analyzing (9R)-HHC and (9S)-HHC, using widely applicable mass spectrometric methods. The study emphasizes the need for vigilance among toxicologists, as new semisynthetic cannabinoids continue to emerge in Europe, with potential health implications. The findings underscore the importance of reliable analytical methods for monitoring these compounds in forensic and clinical settings.}, } @article {pmid38340017, year = {2024}, author = {Kim, JS and Park, M and Park, S and Chae, J and Hong, YH and Park, KS and Sung, JJ and Choi, SJ}, title = {Prognosis of amyotrophic lateral sclerosis patients after tracheostomy invasive ventilation in Korea.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {271-281}, doi = {10.1080/21678421.2024.2314064}, pmid = {38340017}, issn = {2167-9223}, mesh = {Humans ; Male ; Middle Aged ; Female ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/surgery ; *Noninvasive Ventilation ; Retrospective Studies ; Tracheostomy ; Prognosis ; Republic of Korea/epidemiology ; }, abstract = {Background: Tracheostomy invasive ventilation (TIV) is applied to a subset of amyotrophic lateral sclerosis (ALS) patients; however, its frequency and impact on prognosis vary across countries. Methods: We conducted a nationwide retrospective cohort study using Korean National Health Insurance claims data. All patients diagnosed with sporadic ALS from 2012 to 2017 were included, with the observation period until 2020. The survival time between the TIV and non-TIV groups was compared using propensity score matching analysis, and prognostic factors were assessed within the TIV group. Results: This study included 3484 ALS patients (mean [standard deviation] age, 62.4 [11.9] years, 60.4% male), among whom 1230 (35.3%) underwent TIV. After 1:1 propensity score matching, the survival duration between the two groups was not significantly different (28 vs. 25 months, p = 0.057). Cox regression indicated that older age (hazard ratios [HRs] for each decade compared to <40 years: 3.89, 3.83, 5.30, 6.78, and 8.40 [≥80 years]; p < 0.005 for all) and lower income (HR, 1.28; 95% confidence interval [CI], 1.09-1.52; p = 0.003) negatively impacted survival, while gastrostomy (HR, 0.57; 95% CI, 0.50-0.66; p < 0.001) and supportive care services (HR, 0.43; 95% CI, 0.32-0.59; p < 0.001) were associated with prolonged survival. Conclusions: TIV was administered to more than one-third of Korean ALS patients without significant survival prolongation. Older age, lower income, lack of gastrostomy, and insufficient supportive care were independent poor prognostic factors for survival, underscoring the importance of comprehensive management for ALS patients.}, } @article {pmid38339149, year = {2024}, author = {Lee, A and Henderson, R and Aylward, J and McCombe, P}, title = {Gut Symptoms, Gut Dysbiosis and Gut-Derived Toxins in ALS.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38339149}, issn = {1422-0067}, support = {There were no grant numbers//Wesley Medical Research/ ; There were no grant numbers//MND Research Australia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/etiology ; Dysbiosis/etiology ; *Gastrointestinal Microbiome/physiology ; Brain ; }, abstract = {Many pathogenetic mechanisms have been proposed for amyotrophic lateral sclerosis (ALS). Recently, there have been emerging suggestions of a possible role for the gut microbiota. Gut microbiota have a range of functions and could influence ALS by several mechanisms. Here, we review the possible role of gut-derived neurotoxins/excitotoxins. We review the evidence of gut symptoms and gut dysbiosis in ALS. We then examine a possible role for gut-derived toxins by reviewing the evidence that these molecules are toxic to the central nervous system, evidence of their association with ALS, the existence of biochemical pathways by which these molecules could be produced by the gut microbiota and existence of mechanisms of transport from the gut to the blood and brain. We then present evidence that there are increased levels of these toxins in the blood of some ALS patients. We review the effects of therapies that attempt to alter the gut microbiota or ameliorate the biochemical effects of gut toxins. It is possible that gut dysbiosis contributes to elevated levels of toxins and that these could potentially contribute to ALS pathogenesis, but more work is required.}, } @article {pmid38339035, year = {2024}, author = {Sun, Y and Islam, S and Michikawa, M and Zou, K}, title = {Presenilin: A Multi-Functional Molecule in the Pathogenesis of Alzheimer's Disease and Other Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38339035}, issn = {1422-0067}, support = {C19K07846//The Grant-in-Aid for Scientific Research/ ; 22K07352//The Ministry of Education, Culture, Sports, Science, and Technology, Japan./ ; JP20dk0207050h0001 and JP20de010702//AMED/ ; no//The 24th General Assembly of the Japanese Association of Medical Sciences/ ; no//Daiko Foundation/ ; no//Hirose International Scholarship Foundation/ ; no//Hori Sciences and Arts Foundation/ ; no//Daiwa Securities Foundation/ ; no//Hirose Foundation/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; *Neurodegenerative Diseases/etiology ; Amyloid Precursor Protein Secretases/metabolism ; Presenilin-1/genetics/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Apolipoproteins E ; Presenilin-2/genetics/metabolism ; }, abstract = {Presenilin, a transmembrane protein primarily known for its role in Alzheimer's disease (AD) as part of the γ-secretase complex, has garnered increased attention due to its multifaceted functions in various cellular processes. Recent investigations have unveiled a plethora of functions beyond its amyloidogenic role. This review aims to provide a comprehensive overview of presenilin's diverse roles in AD and other neurodegenerative disorders. It includes a summary of well-known substrates of presenilin, such as its involvement in amyloid precursor protein (APP) processing and Notch signaling, along with other functions. Additionally, it highlights newly discovered functions, such as trafficking function, regulation of ferritin expression, apolipoprotein E (ApoE) secretion, the interaction of ApoE and presenilin, and the Aβ42-to-Aβ40-converting activity of ACE. This updated perspective underscores the evolving landscape of presenilin research, emphasizing its broader impact beyond established pathways. The incorporation of these novel findings accentuates the dynamic nature of presenilin's involvement in cellular processes, further advancing our comprehension of its multifaceted roles in neurodegenerative disorders. By synthesizing evidence from a range of studies, this review sheds light on the intricate web of presenilin functions and their implications in health and disease.}, } @article {pmid38339026, year = {2024}, author = {Potenza, RL and Armida, M and Popoli, P}, title = {Can Some Anticancer Drugs Be Repurposed to Treat Amyotrophic Lateral Sclerosis? A Brief Narrative Review.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38339026}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Motor Neuron Disease ; *Antineoplastic Agents/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare progressive motor neuron disease that, due to its high complexity, still lacks effective treatments. Development of a new drug is a highly costly and time-consuming process, and the repositioning of approved drugs can represent an efficient strategy to provide therapeutic opportunities. This is particularly true for rare diseases, which are characterised by small patient populations and therefore attract little commercial interest. Based on the overlap between the biological background of cancer and neurodegeneration, the repurposing of antineoplastic drugs for ALS has been suggested. The objective of this narrative review was to summarise the current experimental evidence on the use of approved anticancer drugs in ALS. Specifically, anticancer drugs belonging to different classes were found to act on mechanisms involved in the ALS pathogenesis, and some of them proved to exert beneficial effects in ALS models. However, additional studies are necessary to confirm the real therapeutic potential of anticancer drugs for repositioning in ALS treatment.}, } @article {pmid38338912, year = {2024}, author = {Duranti, E and Cordani, N and Villa, C}, title = {Edaravone: A Novel Possible Drug for Cancer Treatment?.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38338912}, issn = {1422-0067}, mesh = {Humans ; Edaravone/therapeutic use ; *Neuroprotective Agents/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy ; Antioxidants/therapeutic use ; *Neoplasms/drug therapy/chemically induced ; Free Radical Scavengers/pharmacology ; }, abstract = {Despite significant advancements in understanding the causes and progression of tumors, cancer remains one of the leading causes of death worldwide. In light of advances in cancer therapy, there has been a growing interest in drug repurposing, which involves exploring new uses for medications that are already approved for clinical use. One such medication is edaravone, which is currently used to manage patients with cerebral infarction and amyotrophic lateral sclerosis. Due to its antioxidant and anti-inflammatory properties, edaravone has also been investigated for its potential activities in treating cancer, notably as an anti-proliferative and cytoprotective drug against side effects induced by traditional cancer therapies. This comprehensive review aims to provide updates on the various applications of edaravone in cancer therapy. It explores its potential as a standalone antitumor drug, either used alone or in combination with other medications, as well as its role as an adjuvant to mitigate the side effects of conventional anticancer treatments.}, } @article {pmid38338857, year = {2024}, author = {Venegas, S and Alarcón, C and Araya, J and Gatica, M and Morin, V and Tarifeño-Saldivia, E and Uribe, E}, title = {Biodegradation of Polystyrene by Galleria mellonella: Identification of Potential Enzymes Involved in the Degradative Pathway.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38338857}, issn = {1422-0067}, support = {VRID 220.037.026-M//University of Concepción/ ; }, mesh = {Animals ; *Polystyrenes/metabolism ; Chromatography, Liquid ; Proteomics ; Tandem Mass Spectrometry ; *Moths/microbiology ; Larva/metabolism ; Biodegradation, Environmental ; }, abstract = {Galleria mellonella is a lepidopteran whose larval stage has shown the ability to degrade polystyrene (PS), one of the most recalcitrant plastics to biodegradation. In the present study, we fed G. mellonella larvae with PS for 54 days and determined candidate enzymes for its degradation. We first confirmed the biodegradation of PS by Fourier transform infrared spectroscopy- Attenuated total reflectance (FTIR-ATR) and then identified candidate enzymes in the larval gut by proteomic analysis using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Two of these proteins have structural similarities to the styrene-degrading enzymes described so far. In addition, potential hydrolases, isomerases, dehydrogenases, and oxidases were identified that show little similarity to the bacterial enzymes that degrade styrene. However, their response to a diet based solely on polystyrene makes them interesting candidates as a potential new group of polystyrene-metabolizing enzymes in eukaryotes.}, } @article {pmid38338823, year = {2024}, author = {Moreno-Martinez, L and Macías-Redondo, S and Strunk, M and Guillén-Antonini, MI and Lunetta, C and Tarlarini, C and Penco, S and Calvo, AC and Osta, R and Schoorlemmer, J}, title = {New Insights into Endogenous Retrovirus-K Transcripts in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {3}, pages = {}, pmid = {38338823}, issn = {1422-0067}, support = {Ayuda de Colegios de Farmacéuticos//Fundación Mehuer, Sevilla, Spain/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Endogenous Retroviruses/genetics ; Leukocytes, Mononuclear/metabolism ; Brain/metabolism ; Brain Stem/metabolism ; }, abstract = {Retroviral reverse transcriptase activity and the increased expression of human endogenous retroviruses (HERVs) are associated with amyotrophic lateral sclerosis (ALS). We were interested in confirming HERVK overexpression in the ALS brain, its use as an accessory diagnostic marker for ALS, and its potential interplay with neuroinflammation. Using qPCR to analyze HERVK expression in peripheral blood mononuclear cells (PBMCs) and in postmortem brain samples from ALS patients, no significant differences were observed between patients and control subjects. By contrast, we report alterations in the expression patterns of specific HERVK copies, especially in the brainstem. Out of 27 HERVK copies sampled, the relative expression of 17 loci was >1.2-fold changed in samples from ALS patients. In particular, the relative expression of two HERVK copies (Chr3-3 and Chr3-5) was significantly different in brainstem samples from ALS patients compared with controls. Further qPCR analysis of inflammation markers in brain samples revealed a significant increase in NLRP3 levels, while TNFA, IL6, and GZMB showed slight decreases. We cannot confirm global HERVK overexpression in ALS, but we can report the ALS-specific overexpression of selected HERVK copies in the ALS brain. Our data are compatible with the requirement for better patient stratification and support the potential importance of particular HERVK copies in ALS.}, } @article {pmid38337635, year = {2024}, author = {Carrera-Juliá, S and Estrela, JM and Zacarés, M and Navarro, MÁ and Vega-Bello, MJ and de la Rubia Ortí, JE and Moreno, ML and Drehmer, E}, title = {Nutritional, Clinical and Sociodemographic Profiles of Spanish Patients with Amyotrophic Lateral Sclerosis.}, journal = {Nutrients}, volume = {16}, number = {3}, pages = {}, pmid = {38337635}, issn = {2072-6643}, support = {2017-216-001//Valencia Catholic University Saint Vincent Martyr/ ; OTR2017-18255INVES//University of Valencia/ ; }, mesh = {Male ; Female ; Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Energy Intake ; Cross-Sectional Studies ; *Neurodegenerative Diseases ; Nutritional Status ; Diet/adverse effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic and progressive neurodegenerative disease that leads to the loss of motor neurons. The dietary intake of ALS patients is thought to influence the prognosis and progression of the disease. The aim of this study was to examine the nutritional, clinical and sociodemographic characteristics of ALS patients in Spain. A cross-sectional descriptive study with demographics, clinical anamnesis and anthropometric assessment was carried out. Nutritional intake was recorded and compared with dietary reference intakes (DRI). Forty subjects (25 males; 15 females) aged 54.7 ± 10.17 were included in the study. The mean weight and height were 67.99 ± 8.85 kg and 167.83 ± 8.79 cm, respectively. Clinical phenotype, time to diagnosis, year of onset and family history were not associated with the place of origin. Clinical phenotype had no influence on time of diagnosis. Caloric and protein intakes were adequate, while carbohydrate, vitamin B8 and iodine intakes were significantly lower than the DRI. Lipids; vitamins B1, B2, B3, B5, B6, B12, C and E; sodium; phosphorus; and selenium intakes were significantly higher than the recommended nutritional standards. ALS patients, who are homogeneously distributed throughout our national territory, should modify their dietary habits to minimize ultra-processed products and prioritize foods rich in healthy fats and fiber.}, } @article {pmid38337170, year = {2024}, author = {White, S and O'Cathain, A and Halliday, V and Bradburn, M and McDermott, CJ}, title = {Supporting people with Motor Neuron Disease (MND) to make decisions about gastrostomy feeding tube placement: a survey of UK healthcare professionals' practice and beliefs.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {290-298}, pmid = {38337170}, issn = {2167-9223}, mesh = {Humans ; Gastrostomy ; *Amyotrophic Lateral Sclerosis ; Cross-Sectional Studies ; *Motor Neuron Disease/surgery ; United Kingdom ; Delivery of Health Care ; }, abstract = {OBJECTIVE: Understand the practice and beliefs of healthcare professionals (HCPs) supporting the decision-making of people with MND (pwMND) about gastrostomy placement, including identifying differences between professions.

METHODS: An online cross-sectional survey disseminated to HCPs who support the decision-making of pwMND about gastrostomy placement.

RESULTS: A total of 139 participants completed the survey including representation from a range of healthcare professions. A third (36/101, 36%) initiated discussions about gastrostomy later in practice than they believed was ideal. In relation to the outcome of declining compared to accepting gastrostomy, participants were more likely to discuss aspiration (80% vs. 68%), choking (76% vs. 58%) and prognosis (36% vs. 22%). Participants believed gastrostomies should be placed after a mean 8.1% weight loss since symptom-onset. More participants favored gastrostomy placement before pwMND presented with respiratory symptoms (45%) compared to onset of dysphagia (11%). Half believed pwMND placed gastrostomies too late. Participants were more likely to 'often'/'always' recommend pwMND to have a gastrostomy (23%) than continue without (7%) or decline (4%) gastrostomy, when believing these were the best option for pwMND. Nurses and dietitians discussed the broadest range of information, while doctors were more likely to discuss mortality risk and prognosis.

CONCLUSION: There is variation in HCPs practice and beliefs about initiating discussions, the sharing of information and recommendations, and timing, about gastrostomy placement. The information shared varies by profession and there is evidence of sub-optimal communication between HCPs. Further research is required to understand how these findings may impact on the decision-making of pwMND about gastrostomy.}, } @article {pmid38337058, year = {2024}, author = {Choi, BJ and Park, MH and Jin, HK and Bae, JS}, title = {Acid sphingomyelinase as a pathological and therapeutic target in neurological disorders: focus on Alzheimer's disease.}, journal = {Experimental & molecular medicine}, volume = {56}, number = {2}, pages = {301-310}, pmid = {38337058}, issn = {2092-6413}, mesh = {Animals ; Humans ; Mice ; *Alzheimer Disease/drug therapy ; Brain ; *Multiple Sclerosis ; *Nervous System Diseases ; Sphingomyelin Phosphodiesterase/genetics ; }, abstract = {Over the past decade, numerous studies have highlighted the importance of acid sphingomyelinase (ASM) in disease treatment in humans. This enzyme functions primarily to generate ceramide, maintain the cellular membrane, and regulate cellular function. However, in the blood and brain of patients with neurological disorders, including major depression, ischemic stroke, amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer's disease (AD), elevated ASM levels significantly suggest disease onset or progression. In these diseases, increased ASM is profoundly involved in neuronal death, abnormal autophagy, neuroinflammation, blood-brain barrier disruption, hippocampal neurogenesis loss, and immune cell dysfunction. Moreover, genetic and pharmacological inhibition of ASM can prevent or ameliorate various diseases. The therapeutic effects of ASM inhibition have prompted the urgent need to develop ASM inhibitors, and several ASM inhibitors have been identified. In this review, we summarize the current knowledge on the critical roles and mechanisms of ASM in brain cells and blood that are associated with different neuropathological features, especially those observed in AD. Furthermore, we elucidate the potential possibility and limitations of existing ASM-targeting drugs according to experimental studies in neurological disorder mouse models.}, } @article {pmid38336911, year = {2024}, author = {Menšíková, K and Rosales, R and Colosimo, C and Spencer, P and Lannuzel, A and Ugawa, Y and Sasaki, R and Giménez-Roldán, S and Matej, R and Tuckova, L and Hrabos, D and Kolarikova, K and Vodicka, R and Vrtel, R and Strnad, M and Hlustik, P and Otruba, P and Prochazka, M and Bares, M and Boluda, S and Buee, L and Ransmayr, G and Kaňovský, P}, title = {Reply to: Questioning the cycad theory of Kii ALS-PDC causation.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {3}, pages = {195-196}, pmid = {38336911}, issn = {1759-4766}, mesh = {Humans ; *Parkinsonian Disorders ; *Amyotrophic Lateral Sclerosis/etiology/complications ; }, } @article {pmid38336910, year = {2024}, author = {Kokubo, Y and Morimoto, S and Yoshida, M}, title = {Questioning the cycad theory of Kii ALS-PDC causation.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {3}, pages = {194}, pmid = {38336910}, issn = {1759-4766}, mesh = {Humans ; *Parkinsonian Disorders ; *Amyotrophic Lateral Sclerosis/etiology/complications ; }, } @article {pmid38336286, year = {2024}, author = {Lomeli, N and Pearre, DC and Cruz, M and Di, K and Ricks-Oddie, JL and Bota, DA}, title = {Cisplatin induces BDNF downregulation in middle-aged female rat model while BDNF enhancement attenuates cisplatin neurotoxicity.}, journal = {Experimental neurology}, volume = {375}, number = {}, pages = {114717}, pmid = {38336286}, issn = {1090-2430}, support = {TL1 TR001415/TR/NCATS NIH HHS/United States ; T32 NS082174/NS/NINDS NIH HHS/United States ; R01 CA263806/CA/NCI NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; T32 CA060396/CA/NCI NIH HHS/United States ; P30 CA062203/CA/NCI NIH HHS/United States ; K08 NS072234/NS/NINDS NIH HHS/United States ; }, mesh = {Rats ; Animals ; Female ; *Cisplatin/toxicity ; *Brain-Derived Neurotrophic Factor/metabolism ; Rats, Sprague-Dawley ; Down-Regulation ; Quality of Life ; Riluzole/pharmacology ; Hippocampus/metabolism ; Disks Large Homolog 4 Protein ; }, abstract = {Cancer-related cognitive impairments (CRCI) are neurological complications associated with cancer treatment, and greatly affect cancer survivors' quality of life. Brain-derived neurotrophic factor (BDNF) plays an essential role in neurogenesis, learning and memory. The reduction of BDNF is associated with the decrease in cognitive function in various neurological disorders. Few pre-clinical studies have reported on the effects of chemotherapy and medical stress on BDNF levels and cognition. The present study aimed to compare the effects of medical stress and cisplatin on serum BDNF levels and cognitive function in 9-month-old female Sprague Dawley rats to age-matched controls. Serum BDNF levels were collected longitudinally during cisplatin treatment, and cognitive function was assessed by novel object recognition (NOR) 14 weeks post-cisplatin initiation. Terminal BDNF levels were collected 24 weeks after cisplatin initiation. In cultured hippocampal neurons, we screened three neuroprotective agents, riluzole (an approved treatment for amyotrophic lateral sclerosis), as well as the ampakines CX546 and CX1739. We assessed dendritic arborization by Sholl analysis and dendritic spine density by quantifying postsynaptic density-95 (PSD-95) puncta. Cisplatin and exposure to medical stress reduced serum BDNF levels and impaired object discrimination in NOR compared to age-matched controls. Pharmacological BDNF augmentation protected neurons against cisplatin-induced reductions in dendritic branching and PSD-95. Ampakines (CX546 and CX1739) and riluzole did not affect the antitumor efficacy of cisplatin in vitro. In conclusion, we established the first middle-aged rat model of cisplatin-induced CRCI, assessing the contribution of medical stress and longitudinal changes in BDNF levels on cognitive function, although future studies are warranted to assess the efficacy of BDNF enhancement in vivo on synaptic plasticity. Collectively, our results indicate that cancer treatment exerts long-lasting changes in BDNF levels, and support BDNF enhancement as a potential preventative approach to target CRCI with therapeutics that are FDA approved and/or in clinical study for other indications.}, } @article {pmid38336279, year = {2024}, author = {Costa-Pinto, S and Gonçalves-Ribeiro, J and Tedim-Moreira, J and Socodato, R and Relvas, JB and Sebastião, AM and Vaz, SH}, title = {Communication defects with astroglia contribute to early impairments in the motor cortex plasticity of SOD1[G93A] mice.}, journal = {Neurobiology of disease}, volume = {193}, number = {}, pages = {106435}, doi = {10.1016/j.nbd.2024.106435}, pmid = {38336279}, issn = {1095-953X}, mesh = {Mice ; Animals ; Astrocytes/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; *Motor Cortex ; *Neurodegenerative Diseases/metabolism ; Proteomics ; Disease Models, Animal ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, involving the selective degeneration of cortical upper synapses in the primary motor cortex (M1). Excitotoxicity in ALS occurs due to an imbalance between excitation and inhibition, closely linked to the loss/gain of astrocytic function. Using the ALS SOD1[G93A] mice, we investigated the astrocytic contribution for the electrophysiological alterations observed in the M1 of SOD1[G93A] mice, throughout disease progression. Results showed that astrocytes are involved in synaptic dysfunction observed in presymptomatic SOD1[G93A] mice, since astrocytic glutamate transport currents are diminished and pharmacological inhibition of astrocytes only impaired long-term potentiation and basal transmission in wild-type mice. Proteomic analysis revealed major differences in neuronal transmission, metabolism, and immune system in upper synapses, confirming early communication deficits between neurons and astroglia. These results provide valuable insights into the early impact of upper synapses in ALS and the lack of supportive functions of cortical astrocytes, highlighting the possibility of manipulating astrocytes to improve synaptic function.}, } @article {pmid38335961, year = {2024}, author = {Klickstein, JA and Johnson, MA and Antonoudiou, P and Maguire, J and Paulo, JA and Gygi, SP and Weihl, C and Raman, M}, title = {ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons.}, journal = {Stem cell reports}, volume = {19}, number = {3}, pages = {366-382}, pmid = {38335961}, issn = {2213-6711}, support = {R01 GM127557/GM/NIGMS NIH HHS/United States ; R01 NS102937/NS/NINDS NIH HHS/United States ; P50 MH122379/MH/NIMH NIH HHS/United States ; R01 GM067945/GM/NIGMS NIH HHS/United States ; R01 AA026256/AA/NIAAA NIH HHS/United States ; R01 MH128235/MH/NIMH NIH HHS/United States ; K24 AR073317/AR/NIAMS NIH HHS/United States ; R01 AG031867/AG/NIA NIH HHS/United States ; R21 NS123631/NS/NINDS NIH HHS/United States ; K12 GM133314/GM/NIGMS NIH HHS/United States ; R01 GM132129/GM/NIGMS NIH HHS/United States ; R01 NS105628/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Induced Pluripotent Stem Cells ; Macroautophagy ; Motor Neurons ; Mutation ; }, abstract = {Mutations in the AAA+ ATPase p97 cause multisystem proteinopathy 1, which includes amyotrophic lateral sclerosis; however, the pathogenic mechanisms that contribute to motor neuron loss remain obscure. Here, we use two induced pluripotent stem cell models differentiated into spinal motor neurons to investigate how p97 mutations perturb the motor neuron proteome. Using quantitative proteomics, we find that motor neurons harboring the p97 R155H mutation have deficits in the selective autophagy of lysosomes (lysophagy). p97 R155H motor neurons are unable to clear damaged lysosomes and have reduced viability. Lysosomes in mutant motor neurons have increased pH compared with wild-type cells. The clearance of damaged lysosomes involves UBXD1-p97 interaction, which is disrupted in mutant motor neurons. Finally, inhibition of the ATPase activity of p97 using the inhibitor CB-5083 rescues lysophagy defects in mutant motor neurons. These results add to the evidence that endo-lysosomal dysfunction is a key aspect of disease pathogenesis in p97-related disorders.}, } @article {pmid38295729, year = {2024}, author = {Bhatt, N and Puangmalai, N and Sengupta, U and Jerez, C and Kidd, M and Gandhi, S and Kayed, R}, title = {C9orf72-associated dipeptide protein repeats form A11-positive oligomers in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {2}, pages = {105628}, pmid = {38295729}, issn = {1083-351X}, support = {R01 AG054025/AG/NIA NIH HHS/United States ; R01 NS094557/NS/NINDS NIH HHS/United States ; R01 AG060718/AG/NIA NIH HHS/United States ; RF1 AG055771/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; DNA Repeat Expansion ; Dipeptides/chemistry ; Arginine ; Amyloidogenic Proteins ; Glycine ; }, abstract = {Hexanucleotide repeat expansion in C9orf72 is one of the most common causes of amyotrophic lateral sclerosis and frontotemporal dementia. The hexanucleotide expansion, formed by GGGGCC (G4C2) repeats, leads to the production of five dipeptide protein repeats (DPRs) via repeat-associated non-AUG translation. Among the five dipeptide repeats, Gly-Arg, Pro-Arg, and Gly-Ala form neuronal inclusions that contain aggregates of the peptides. Several studies have attempted to model DPR-associated toxicity using various repeat lengths, which suggests a unique conformation that is cytotoxic and is independent of the repeat length. However, the structural characteristics of DPR aggregates have yet to be determined. Increasing evidence suggests that soluble species, such as oligomers, are the main cause of toxicity in proteinopathies, such as Alzheimer's and Parkinson's disease. To investigate the ability of DPRs to aggregate and form toxic oligomers, we adopted a reductionist approach using small dipeptide repeats of 3, 6, and 12. This study shows that DPRs, particularly glycine-arginine and proline-arginine, form oligomers that exhibit distinct dye-binding properties and morphologies. Importantly, we also identified toxic DPR oligomers in amyotrophic lateral sclerosis and frontotemporal dementia postmortem brains that are morphologically similar to those generated recombinantly. This study demonstrates that, similar to soluble oligomers formed by various amyloid proteins, DPR oligomers are toxic, independent of their repeat length.}, } @article {pmid38334818, year = {2024}, author = {Hoek, AG and Dal Canto, E and Wenker, E and Bindraban, N and Handoko, ML and Elders, PJM and Beulens, JWJ}, title = {Epidemiology of heart failure in diabetes: a disease in disguise.}, journal = {Diabetologia}, volume = {67}, number = {4}, pages = {574-601}, pmid = {38334818}, issn = {1432-0428}, support = {91718304/ZONMW_/ZonMw/Netherlands ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/epidemiology/complications ; *Heart Failure/epidemiology/physiopathology ; Incidence ; Prevalence ; Stroke Volume/physiology ; Ventricular Dysfunction, Left/epidemiology/physiopathology ; Echocardiography ; }, abstract = {Left ventricular diastolic dysfunction (LVDD) without symptoms, and heart failure (HF) with preserved ejection fraction (HFpEF) represent the most common phenotypes of HF in individuals with type 2 diabetes mellitus, and are more common than HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF) and left ventricular systolic dysfunction (LVSD) in these individuals. However, diagnostic criteria for HF have changed over the years, resulting in heterogeneity in the prevalence/incidence rates reported in different studies. We aimed to give an overview of the diagnosis and epidemiology of HF in type 2 diabetes, using both a narrative and systematic review approach; we focus narratively on diagnosing (using the 2021 European Society of Cardiology [ESC] guidelines) and screening for HF in type 2 diabetes. We performed an updated (2016-October 2022) systematic review and meta-analysis of studies reporting the prevalence and incidence of HF subtypes in adults ≥18 years with type 2 diabetes, using echocardiographic data. Embase and MEDLINE databases were searched and data were assessed using random-effects meta-analyses, with findings presented as forest plots. From the 5015 studies found, 209 were screened using the full-text article. In total, 57 studies were included, together with 29 studies that were identified in a prior meta-analysis; these studies reported on the prevalence of LVSD (n=25 studies, 24,460 individuals), LVDD (n=65 studies, 25,729 individuals), HFrEF (n=4 studies, 4090 individuals), HFmrEF (n=2 studies, 2442 individuals) and/or HFpEF (n=8 studies, 5292 individuals), and on HF incidence (n=7 studies, 17,935 individuals). Using Hoy et al's risk-of-bias tool, we found that the studies included generally had a high risk of bias. They showed a prevalence of 43% (95% CI 37%, 50%) for LVDD, 17% (95% CI 7%, 35%) for HFpEF, 6% (95% CI 3%, 10%) for LVSD, 7% (95% CI 3%, 15%) for HFrEF, and 12% (95% CI 7%, 22%) for HFmrEF. For LVDD, grade I was found to be most prevalent. Additionally, we reported a higher incidence rate of HFpEF (7% [95% CI 4%, 11%]) than HFrEF 4% [95% CI 3%, 7%]). The evidence is limited by the heterogeneity of the diagnostic criteria over the years. The systematic section of this review provides new insights on the prevalence/incidence of HF in type 2 diabetes, unveiling a large pre-clinical target group with LVDD/HFpEF in which disease progression could be halted by early recognition and treatment.Registration PROSPERO ID CRD42022368035.}, } @article {pmid38334639, year = {2024}, author = {Cunha-Oliveira, T and Montezinho, L and Simões, RF and Carvalho, M and Ferreiro, E and Silva, FSG}, title = {Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {3}, pages = {}, pmid = {38334639}, issn = {2073-4409}, support = {PTDC/MED-FAR/29391/2017//Fundação para a Ciência e Tecnologia/ ; POCI-01-0145-FEDER-029391//Fundação para a Ciência e Tecnologia/ ; PTDC/BTM-SAL/29297/2017//Fundação para a Ciência e Tecnologia/ ; POCI-01-0145-FEDER-029297//Fundação para a Ciência e Tecnologia/ ; PTDC/BTM-ORG/0055/2021//Fundação para a Ciência e Tecnologia/ ; DL57/2016/CP1448/CT0016//Fundação para a Ciência e Tecnologia/ ; CEECIND/00322/2017//Fundação para a Ciência e Tecnologia/ ; 2022.00011.CEECIND//Fundação para a Ciência e Tecnologia/ ; UIDP/04539/2020//Fundação para a Ciência e Tecnologia/ ; UIDB/04539/2020//Fundação para a Ciência e Tecnologia/ ; UIDB/00081/2020//Fundação para a Ciência e Tecnologia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; Motor Neurons/pathology ; Apoptosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, for which current treatment options are limited. Recent studies have shed light on the role of mitochondria in ALS pathogenesis, making them an attractive therapeutic intervention target. This review contains a very comprehensive critical description of the involvement of mitochondria and mitochondria-mediated mechanisms in ALS. The review covers several key areas related to mitochondria in ALS, including impaired mitochondrial function, mitochondrial bioenergetics, reactive oxygen species, metabolic processes and energy metabolism, mitochondrial dynamics, turnover, autophagy and mitophagy, impaired mitochondrial transport, and apoptosis. This review also highlights preclinical and clinical studies that have investigated various mitochondria-targeted therapies for ALS treatment. These include strategies to improve mitochondrial function, such as the use of dichloroacetate, ketogenic and high-fat diets, acetyl-carnitine, and mitochondria-targeted antioxidants. Additionally, antiapoptotic agents, like the mPTP-targeting agents minocycline and rasagiline, are discussed. The paper aims to contribute to the identification of effective mitochondria-targeted therapies for ALS treatment by synthesizing the current understanding of the role of mitochondria in ALS pathogenesis and reviewing potential convergent therapeutic interventions. The complex interplay between mitochondria and the pathogenic mechanisms of ALS holds promise for the development of novel treatment strategies to combat this devastating disease.}, } @article {pmid38334609, year = {2024}, author = {Noori, L and Saqagandomabadi, V and Di Felice, V and David, S and Caruso Bavisotto, C and Bucchieri, F and Cappello, F and Conway de Macario, E and Macario, AJL and Scalia, F}, title = {Putative Roles and Therapeutic Potential of the Chaperone System in Amyotrophic Lateral Sclerosis and Multiple Sclerosis.}, journal = {Cells}, volume = {13}, number = {3}, pages = {}, pmid = {38334609}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Multiple Sclerosis/therapy ; Molecular Chaperones/metabolism ; Heat-Shock Proteins/metabolism ; }, abstract = {The putative pathogenic roles and therapeutic potential of the chaperone system (CS) in amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are reviewed to provide a bibliographic and conceptual platform for launching research on the diagnostic and therapeutic applications of CS components. Various studies suggest that dysfunction of the CS contributes to the pathogenesis of ALS and MS, and here, we identify some of the implicated CS members. The physiology and pathophysiology of the CS members can be properly understood if they are studied or experimentally or clinically manipulated for diagnostic or therapeutic purposes, bearing in mind that they belong to a physiological system with multiple interacting and dynamic components, widespread throughout the body, intra- and extracellularly. Molecular chaperones, some called heat shock protein (Hsp), are the chief components of the CS, whose canonical functions are cytoprotective. However, abnormal chaperones can be etiopathogenic factors in a wide range of disorders, chaperonopathies, including ALS and MS, according to the data reviewed. Chaperones typically form teams, and these build functional networks to maintain protein homeostasis, the canonical role of the CS. However, members of the CS also display non-canonical functions unrelated to protein homeostasis. Therefore, chaperones and other members of the CS, if abnormal, may disturb not only protein synthesis, maturation, and migration but also other physiological processes. Thus, in elucidating the role of CS components in ALS and MS, one must look at protein homeostasis abnormalities and beyond, following the clues emerging from the works discussed here.}, } @article {pmid38334356, year = {2024}, author = {Kleinveld, VEA and Keritam, O and Horlings, CGC and Cetin, H and Wanschitz, J and Hotter, A and Zirch, LS and Zimprich, F and Topakian, R and Müller, P and Oel, D and Quasthoff, S and Erdler, M and Rauschka, H and Grinzinger, S and Jecel, J and Gaulhofer, P and Castek, B and Stadler, K and Löscher, WN}, title = {Multifocal motor neuropathy as a mimic of amyotrophic lateral sclerosis: Serum neurofilament light chain as a reliable diagnostic biomarker.}, journal = {Muscle & nerve}, volume = {69}, number = {4}, pages = {422-427}, doi = {10.1002/mus.28054}, pmid = {38334356}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Biomarkers ; Intermediate Filaments ; Prognosis ; *Polyneuropathies/diagnosis ; Neurofilament Proteins ; }, abstract = {INTRODUCTION/AIMS: The clinical presentation of multifocal motor neuropathy (MMN) may mimic early amyotrophic lateral sclerosis (ALS) with predominant lower motor neuron (LMN) involvement, posing a diagnostic challenge. Both diseases have specific treatments and prognoses, highlighting the importance of early diagnosis. The aim of this study was to assess the diagnostic value of serum neurofilament light chain (NfL) in differentiating MMN from LMN dominant ALS.

METHODS: NfL was measured in serum in n = 37 patients with MMN and n = 37 age- and sex-matched patients with LMN dominant ALS, to determine the diagnostic accuracy. Clinical and demographic data were obtained at the time of NfL sampling.

RESULTS: Serum NfL concentration was significantly lower in MMN patients compared to ALS patients (mean 20.7 pg/mL vs. 59.4 pg/mL, p < .01). NfL demonstrated good diagnostic value in discriminating the two groups (AUC 0.985 [95% CI 0.963-1.000], sensitivity 94.6%, specificity 100%, cut-off 44.00 pg/mL).

DISCUSSION: NfL could be a helpful tool in differentiating MMN from LMN dominant ALS in those patients in whom electrophysiological and clinical examinations remain inconclusive early in the diagnostic process.}, } @article {pmid38334254, year = {2024}, author = {Mohammadi, S and Ghaderi, S and Fatehi, F}, title = {MRI biomarkers and neuropsychological assessments of hippocampal and parahippocampal regions affected by ALS: A systematic review.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {2}, pages = {e14578}, pmid = {38334254}, issn = {1755-5949}, mesh = {Humans ; *Hippocampus/diagnostic imaging/pathology ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/psychology/pathology/metabolism ; *Magnetic Resonance Imaging ; *Neuropsychological Tests ; *Biomarkers/metabolism ; Parahippocampal Gyrus/diagnostic imaging/pathology ; }, abstract = {BACKGROUND AND OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive motor and extra-motor neurodegenerative disease. This systematic review aimed to examine MRI biomarkers and neuropsychological assessments of the hippocampal and parahippocampal regions in patients with ALS.

METHODS: A systematic review was conducted in the Scopus and PubMed databases for studies published between January 2000 and July 2023. The inclusion criteria were (1) MRI studies to assess hippocampal and parahippocampal regions in ALS patients, and (2) studies reporting neuropsychological data in patients with ALS.

RESULTS: A total of 46 studies were included. Structural MRI revealed hippocampal atrophy, especially in ALS-FTD, involving specific subregions (CA1, dentate gyrus). Disease progression and genetic factors impacted atrophy patterns. Diffusion tensor imaging (DTI) showed increased mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and decreased fractional anisotropy (FA) in the hippocampal tracts and adjacent regions, indicating loss of neuronal and white matter integrity. Functional MRI (fMRI) revealed reduced functional connectivity (FC) between the hippocampus, parahippocampus, and other regions, suggesting disrupted networks. Perfusion MRI showed hypoperfusion in parahippocampal gyri. Magnetic resonance spectroscopy (MRS) found changes in the hippocampus, indicating neuronal loss. Neuropsychological tests showed associations between poorer memory and hippocampal atrophy or connectivity changes. CA1-2, dentate gyrus, and fimbria atrophy were correlated with worse memory.

CONCLUSIONS: The hippocampus and the connected regions are involved in ALS. Hippocampal atrophy disrupted connectivity and metabolite changes correlate with cognitive and functional decline. Specific subregions can be particularly affected. The hippocampus is a potential biomarker for disease monitoring and prognosis.}, } @article {pmid38334027, year = {2024}, author = {Cao, YB and Wu, Y and Dong, QY and Huang, NX and Zou, ZY and Chen, HJ}, title = {Neurite orientation dispersion and density imaging quantifies microstructural impairment in the thalamus and its connectivity in amyotrophic lateral sclerosis.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {2}, pages = {e14616}, pmid = {38334027}, issn = {1755-5949}, support = {2022QNA022//Fujian Provincial Health Technology Project/ ; 2023CXA009//Fujian Provincial Health Technology Project/ ; 62201265//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurites ; Diffusion Tensor Imaging/methods ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Thalamus/diagnostic imaging ; Neural Pathways/diagnostic imaging ; }, abstract = {AIMS: To evaluate microstructural impairment in the thalamus and thalamocortical connectivity using neurite orientation dispersion and density imaging (NODDI) in amyotrophic lateral sclerosis (ALS).

METHODS: This study included 47 healthy controls and 43 ALS patients, whose structural and diffusion-weighted data were collected. We used state-of-the-art parallel transport tractography to identify thalamocortical pathways in individual spaces. Thalamus was then parcellated into six subregions based on its connectivity pattern with the priori defined cortical (i.e., prefrontal/motor/somatosensory/temporal/posterior-parietal/occipital) regions. For each of the thalamic and cortical subregions and thalamo-cortical tracts, we compared the following NODDI metrics between groups: orientation dispersion index (ODI), neurite density index (NDI), and isotropic volume fraction (ISO). We also used these metrics to conduct receiver operating characteristic curve (ROC) analyses and Spearman correlation.

RESULTS: In ALS patients, we found decreased ODI and increased ISO in the thalamic subregion connecting the left motor cortex and other extramotor (e.g., somatosensory and occipital) cortex (Bonferroni-corrected p < 0.05). NDI decreased in the bilateral thalamo-motor and thalamo-somatosensory tracts and in the right thalamo-posterior-parietal and thalamo-occipital tracts (Bonferroni-corrected p < 0.05). NDI reduction in the bilateral thalamo-motor tract (p = 0.017 and 0.009) and left thalamo-somatosensory tract (p = 0.029) was correlated with disease severity. In thalamo-cortical tracts, NDI yielded a higher effect size during between-group comparisons and a greater area under ROC (p < 0.05) compared with conventional diffusion tensor imaging metrics.

CONCLUSIONS: Microstructural impairment in the thalamus and thalamocortical connectivity is the hallmark of ALS. NODDI improved the detection of disrupted thalamo-cortical connectivity in ALS.}, } @article {pmid38332900, year = {2024}, author = {Du, L and Pang, Y}, title = {Identifying Regenerated Saplings by Stratifying Forest Overstory Using Airborne LiDAR Data.}, journal = {Plant phenomics (Washington, D.C.)}, volume = {6}, number = {}, pages = {0145}, pmid = {38332900}, issn = {2643-6515}, abstract = {Identifying the spatiotemporal distributions and phenotypic characteristics of understory saplings is beneficial in exploring the internal mechanisms of plant regeneration and providing technical assistances for continues cover forest management. However, it is challenging to detect the understory saplings using 2-dimensional (2D) spectral information produced by conventional optical remotely sensed data. This study proposed an automatic method to detect the regenerated understory saplings based on the 3D structural information from aerial laser scanning (ALS) data. By delineating individual tree crown using the improved spectral clustering algorithm, we successfully removed the overstory canopy and associated trunk points. Then, individual understory saplings were segmented using an adaptive-mean-shift-based clustering algorithm. This method was tested in an experimental forest farm of North China. Our results showed that the detection rates of understory saplings ranged from 94.41% to 152.78%, and the matching rates increased from 62.59% to 95.65% as canopy closure went down. The ALS-based sapling heights well captured the variations of field measurements [R[2] = 0.71, N = 3,241, root mean square error (RMSE) = 0.26 m, P < 0.01] and terrestrial laser scanning (TLS)-based measurements (R[2] = 0.78, N =443, RMSE = 0.23 m, P < 0.01). The ALS-based sapling crown width was comparable with TLS-based measurements (R[2] = 0.64, N = 443, RMSE = 0.24 m). This study provides a solution for the quantification of understory saplings, which can be used to improve forest ecosystem resilence through regulating the dynamics of forest gaps to better utilize light resources.}, } @article {pmid38332698, year = {2024}, author = {Sung, JH and Baek, SH and Park, JW and Lee, JH and Son, MH and Kim, BJ}, title = {Dynamic suprahyoid muscle ultrasound in assessing oropharyngeal dysphagia in neurological disorders.}, journal = {European journal of physical and rehabilitation medicine}, volume = {60}, number = {2}, pages = {233-244}, pmid = {38332698}, issn = {1973-9095}, mesh = {Humans ; *Deglutition Disorders/diagnostic imaging/etiology ; Cross-Sectional Studies ; Deglutition/physiology ; *Stroke/complications/diagnostic imaging ; Ultrasonography ; Muscles ; }, abstract = {BACKGROUND: Appropriate evaluation and management of dysphagia are essential in neurological disorders. However, there is currently a lack of a simple yet reliable method for dysphagia evaluation.

AIM: This study aimed to investigate the usefulness of new dynamic M-mode ultrasonography (US) parameters of suprahyoid muscle (SHM) to evaluate dysphagia.

DESIGN: Prospective observational, cross-sectional study.

SETTING: Inpatient setting at neurology department of tertiary medical center.

POPULATION: A total of 89 patients with dysphagia and 175 healthy volunteers were enrolled in the study. Patients were subdivided into mild and severe dysphagia groups depending on the need for dietary changes and disease classification, which included amyotrophic lateral sclerosis, peripheral neuromuscular diseases, and stroke.

METHODS: Dynamic M-mode US was performed during swallowing to obtain the SHM thickness (the baseline thickness of the SHM), SHM displacement (peak-to-peak amplitude of SHM movement), SHM difference (SHM displacement - SHM thickness), SHM ratio (SHM displacement/SHM thickness), peak-to-peak time, and total duration. A videofluoroscopic swallowing study (VFSS) was performed.

RESULTS: Significant differences were found in SHM displacement and SHM difference according to dysphagia severity (P<0.001). The SHM ratio, total duration (P<0.001), and peak-to-peak time (P=0.001) differed significantly according to the patients' underlying diseases. The pharyngeal delay time and penetration-aspiration scale from the VFSS demonstrated significant negative correlations with SHM displacement and difference (P<0.001). By combining SHM difference and total duration, patients with dysphagia could be distinguished from healthy controls, with the highest negative predictive value of 95.6%.

CONCLUSIONS: Dynamic M-mode US of the SHM provided added value in evaluating the severity of dysphagia and differentiating swallowing mechanics of dysphagia related to underlying neurological disorders.

Dynamic M-mode US of the SHM can serve as a supportive tool for rapid screening and repetitive follow-up of patients with dysphagia, which would contribute to dysphagia rehabilitation in patients with various neurological disorders.}, } @article {pmid38332489, year = {2024}, author = {Dandl, S and Bender, A and Hothorn, T}, title = {Heterogeneous treatment effect estimation for observational data using model-based forests.}, journal = {Statistical methods in medical research}, volume = {33}, number = {3}, pages = {392-413}, pmid = {38332489}, issn = {1477-0334}, mesh = {Humans ; *Treatment Effect Heterogeneity ; Riluzole ; *Amyotrophic Lateral Sclerosis ; Linear Models ; }, abstract = {The estimation of heterogeneous treatment effects has attracted considerable interest in many disciplines, most prominently in medicine and economics. Contemporary research has so far primarily focused on continuous and binary responses where heterogeneous treatment effects are traditionally estimated by a linear model, which allows the estimation of constant or heterogeneous effects even under certain model misspecifications. More complex models for survival, count, or ordinal outcomes require stricter assumptions to reliably estimate the treatment effect. Most importantly, the noncollapsibility issue necessitates the joint estimation of treatment and prognostic effects. Model-based forests allow simultaneous estimation of covariate-dependent treatment and prognostic effects, but only for randomized trials. In this paper, we propose modifications to model-based forests to address the confounding issue in observational data. In particular, we evaluate an orthogonalization strategy originally proposed by Robinson (1988, Econometrica) in the context of model-based forests targeting heterogeneous treatment effect estimation in generalized linear models and transformation models. We found that this strategy reduces confounding effects in a simulated study with various outcome distributions. We demonstrate the practical aspects of heterogeneous treatment effect estimation for survival and ordinal outcomes by an assessment of the potentially heterogeneous effect of Riluzole on the progress of Amyotrophic Lateral Sclerosis.}, } @article {pmid38331161, year = {2024}, author = {Golia, MT and Frigerio, R and Pucci, S and Sironi, F and Margotta, C and Pasetto, L and Testori, C and Berrone, E and Ingravalle, F and Chiari, M and Gori, A and Duchi, R and Perota, A and Bergamaschi, L and D'Angelo, A and Cagnotti, G and Galli, C and Corona, C and Bonetto, V and Bendotti, C and Cretich, M and Colombo, SF and Verderio, C}, title = {Changes in glial cell activation and extracellular vesicles production precede the onset of disease symptoms in transgenic hSOD1[G93A] pigs.}, journal = {Experimental neurology}, volume = {374}, number = {}, pages = {114716}, doi = {10.1016/j.expneurol.2024.114716}, pmid = {38331161}, issn = {1090-2430}, mesh = {Mice ; Animals ; Humans ; Swine ; Superoxide Dismutase-1/genetics ; Motor Neurons/metabolism ; Superoxide Dismutase/genetics ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/pathology ; Spinal Cord/pathology ; Neuroglia/pathology ; *Extracellular Vesicles ; Biomarkers/metabolism ; Peptides/metabolism ; Disease Models, Animal ; }, abstract = {SOD1 gene is associated with progressive motor neuron degeneration in the familiar forms of amyotrophic lateral sclerosis. Although studies on mutant human SOD1 transgenic rodent models have provided important insights into disease pathogenesis, they have not led to the discovery of early biomarkers or effective therapies in human disease. The recent generation of a transgenic swine model expressing the human pathological hSOD1[G93A] gene, which recapitulates the course of human disease, represents an interesting tool for the identification of early disease mechanisms and diagnostic biomarkers. Here, we analyze the activation state of CNS cells in transgenic pigs during the disease course and investigate whether changes in neuronal and glial cell activation state can be reflected by the amount of extracellular vesicles they release in biological fluids. To assess the activation state of neural cells, we performed a biochemical characterization of neurons and glial cells in the spinal cords of hSOD1[G93A] pigs during the disease course. Quantification of EVs of CNS cell origin was performed in cerebrospinal fluid and plasma of transgenic pigs at different disease stages by Western blot and peptide microarray analyses. We report an early activation of oligodendrocytes in hSOD1[G93A] transgenic tissue followed by astrocyte and microglia activation, especially in animals with motor symptoms. At late asymptomatic stage, EV production from astrocytes and microglia is increased in the cerebrospinal fluid, but not in the plasma, of transgenic pigs reflecting donor cell activation in the spinal cord. Estimation of EV production by biochemical analyses is corroborated by direct quantification of neuron- and microglia-derived EVs in the cerebrospinal fluid by a Membrane Sensing Peptide enabled on-chip analysis that provides fast results and low sample consumption. Collectively, our data indicate that alteration in astrocytic EV production precedes the onset of disease symptoms in the hSOD[G93A] swine model, mirroring donor cell activation in the spinal cord, and suggest that EV measurements from the cells first activated in the ALS pig model, i.e. OPCs, may further improve early disease detection.}, } @article {pmid38330934, year = {2024}, author = {Yang, L and Li, Y and Zhang, S and Qian, H and Xu, W and Yu, J}, title = {Efficacy of Acupuncture Combined with Traditional Chinese Medicine Fumigation Therapy in Sequelae of Pelvic Inflammatory Disease: A Systematic Review and Meta-Analysis.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {175-186}, doi = {10.1159/000536101}, pmid = {38330934}, issn = {2504-2106}, abstract = {BACKGROUND AND OBJECTIVE: Acupuncture combined with traditional Chinese medicine fumigation is increasingly being used in treating sequelae of pelvic inflammatory disease (SPID). However, there is a lack of meta-analysis on the effectiveness of acupuncture combined with traditional Chinese medicine fumigation in treating SPID. The aim of this study was to assess the feasibility of combining acupuncture with traditional Chinese medicine fumigation in the treatment of SPID.

METHODS: We searched eight databases for studies on acupuncture combined with traditional Chinese medicine fumigation for the treatment of SPID from the date of establishment to October 29, 2022. We assessed the quality of included studies by using the Cochrane bias risk tool. Pooled results were expressed as risk ratios (RRs), with a 95% confidence interval (CI). In addition, we identified sources of heterogeneity by sensitivity analysis, assessed publication bias by Egger's test, and assessed the quality of the evidence by Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). All statistical analyses were performed by Review Manager 5.3 and Stata 14.

RESULTS: Finally, seven studies with a total of 663 participants were included. We found a significant difference in the total effective rate in the acupuncture combined with the fumigation group compared with the acupuncture group in the treatment of SPID (RR = 1.17, 95% CI [1.09, 1.25], p = 0.0001 < 0.05; I2 = 0%; 6 trials), and a significant difference in the total effective rate in the acupuncture combined with fumigation group compared with the fumigation group in the treatment of SPID (RR = 1.42, 95% CI [1.21, 1.66], p = 0.0001 < 0.05; 5 trials).

CONCLUSION: The clinical efficacy of acupuncture combined with herbal fumigation in the treatment of SPID is relatively good. Larger scale studies are needed in the future.

UNLABELLED: Hintergrund und ZielAkupunktur in Kombination mit Fumigation, einem Verfahren der Traditionellen Chinesischen Medizin, wird zunehmend in der Behandlung von Folgeerscheinungen von Beckenentzündungen (SPID; sequelae of pelvic inflammatory disease) eingesetzt. Es mangelt jedoch an Metaanalysen zur Wirksamkeit der Akupunktur in Kombination mit Fumigation gemäß der Traditionellen Chinesischen Medizin in der Behandlung von SPID. Das Ziel dieser Studie ist die Beurteilung der Machbarkeit der Kombination aus Akupunktur und Fumigation gemäß der Traditionellen Chinesischen Medizin in der Behandlung von SPID.MethodenWir durchsuchten acht Datenbanken nach Studien zur Akupunktur in Kombination mit Fumigation gemäß der Traditionellen Chinesischen Medizin in der Behandlung von Folgeerscheinungen von SPID von der Einrichtung bis zum 29. Oktober 2022. Wir beurteilten die Qualität der eingeschlossenen Studien mit dem Cochrane-Tool zur Bewertung des Bias-Risikos. Die gepoolten Ergebnisse wurden als Risikoquotient (RR; risk ratio) mit 95%-Konfidenzintervall (KI) ausgedrückt. Zusätzlich identifizierten wir Quellen für Heterogenität mittels Sensitivitätsanalyse, beurteilten den Publikations-Bias mittels Egger-Test und bewerteten die Qualität der Evidenz nach Grad der Empfehlungsstärke, Beurteilung, Entwicklung und Evaluierung (GRADE). Alle statistischen Analysen erfolgten mit Review Manager 5.3 und Stata 14.ErgebnisseIm Endeffekt wurden 7 Studien mit insgesamt 663 Teilnehmern eingeschlossen. Wir fanden einen signifikanten Unterschied in der Gesamt-Effektivitätsrate bei der Gruppe, die zur Behandlung von SPID Akupunktur in Kombination mit Fumigation erhielt, im Vergleich zur reinen Akupunkturgruppe (RR = 1,17; 95%-KI [1,09; 1,25]; p = 0,0001 < 0,05; I2-Wert = 0%; 6 Studien), und einen signifikanten Unterschied in der Gesamt-Effektivitätsrate bei der Gruppe, die zur Behandlung von SPID Akupunktur in Kombination mit Fumigation erhielt, im Vergleich zur reinen Fumigationsgruppe (RR = 1,42; 95%-KI [1,21; 1,66]; p = 0,0001 < 0,05; 5 Studien).SchlussfolgerungDie klinische Wirksamkeit der Akupunktur in Kombination mit Kräuter-Fumigation zur Behandlung von SPID ist relativ gut. Zukünftig sind größere Studien erforderlich.}, } @article {pmid38330929, year = {2024}, author = {Fronczek, M and Kopacz, K and Kopacz, Ł and Padula, G}, title = {The Role of Objective Movement Analysis in the Control of Yoga Asanas: A Case Study.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {201-209}, doi = {10.1159/000535312}, pmid = {38330929}, issn = {2504-2106}, abstract = {INTRODUCTION: Yoga is classified as a form of complementary and alternative medicine. It can be used in many disciplines including physiotherapy, medicine, and sport. The objective of the study was to identify possible biomechanical problems during yoga practice and to minimize the risk of injury.

CASE PRESENTATION: Objective evaluation of the symmetry of asanas, balance, stability, and muscle tension was provided in case of a 37-year-old woman, practicing mainly aerial and Hatha yoga for 6 years. The bigger body tilt and deviations in center of pressure (COP) parameters were observed in tadasana during forward examinations. In tadasana, the highest muscle activity was observed in the rectus femoris. In case of forward tadasana observation, the highest activity was found in the gastrocnemius and in the lumbar portion of the erector spinae. During backward tadasana trial, the most active were the tibialis anterior and rectus femoris muscles. In garudasana and natarajasana, the symmetry of the trunk position in relation to the lower limbs was observed, regardless of the supporting limb. In the same way, COP parameters in garudasana were similar regardless of the supporting limb. However, in natarajasana, the higher COP displacement parameters were observed in the case of the nondominant supporting limb. As for the electromyographic evaluation of garudasana and natarajasana, the highest muscle activity was observed in the lumbar portion of the erector spinae. In chakrasana, a slightly greater angle of the hip extension was observed in the left hip. A higher muscle activity in chakrasana was observed in the lumbar portion of the right erector spinae. In sirsasana, no significant displacements of the cervical spine were observed, but a higher activity of the left sternocleidomastoid muscle was found.

CONCLUSION: With the use of objective movement analysis, possible biomechanical problems were identified. Attention should be paid to the normalization of the tension in the lumbar part of the right erector spinae and the right sternocleidomastoid muscle, as well as to the balance training in positions on the nondominant lower limb. Objective movement analysis can be a useful tool for instructors or physiotherapists to adjust yoga programs and correct asanas in order to avoid future injuries.

UNLABELLED: EinleitungYoga gilt als Form der Komplementär- und Alternativmedizin. Es ist in vielen Disziplinen einsetzbar, von Physiotherapie über Medizin bis Sport. Das Ziel dieser Studie war es, mögliche biomechanische Probleme bei der Ausübung von Yoga zu identifizieren, um das Verletzungsrisiko zu minimieren.Vorstellung des FallsEine objektive Beurteilung der Symmetrie der Asanas, des Gleichgewichts, der Stabilität und der Muskelspannung erfolgte bei einer 37-jährigen Frau, die seit 6 Jahren hauptsächlich Aerial- und Hatha-Yoga praktiziert. Stärkere Körperneigung und Abweichungen bei Druckmittelpunkt-Parametern wurden in Tadasana bei der Vorwärts-Beobachtung festgestellt. In Tadasana wurde die höchste Muskelaktivität im Rectus femoris beobachtet. Bei der Tadasana-Vorwärts-Beobachtung war die höchste Aktivität im Gastrocnemius und im lumbalen Anteil des Erector spinae zu verzeichnen. Während der Tadasana-Rückwärts-Übung waren die aktivsten Muskeln der Tibialis anterior und Rectus femoris. In Garudasana und Natarajasana wurde die Symmetrie der Rumpfposition im Verhältnis zu den unteren Gliedmaßen unabhängig von der belasteten Gliedmaße beobachtet. Ebenso waren die Parameter des Druckmittelpunkts (DMP) in Garudasana unabhängig von der belasteten Gliedmaße vergleichbar. In Natarajasana wurden jedoch höhere Parameter der DMP-Verschiebung bei der nicht-dominanten belasteten Gliedmaße beobachtet. Bei der elektromyografischen Auswertung von Garudasana und Natarajasana wurde die höchste Muskelaktivität im lumbalen Anteil des Erector spinae beobachtet. In Chakrasana wurde ein etwas größerer Winkel der Hüftstreckung im linken Hüftgelenk beobachtet. Eine höhere Muskelaktivität in Chakrasana wurde im lumbalen Anteil des rechten Erector spinae beobachtet. In Sirsasana wurden keine signifikanten Verschiebungen der Halswirbelsäule beobachtet, jedoch war eine höhere Aktivität des linken Sternocleidomastoideus zu verzeichnen.SchlussfolgerungMit Hilfe einer objektiven Bewegungsanalyse wurden mögliche biomechanische Probleme identifiziert. Mit besonderer Aufmerksamkeit sollte auf die Normalisierung der Spannung im lumbalen Anteil des rechten Erector spinae und des rechten Sternocleidomastoideus sowie auf die Schulung des Gleichgewichts in Positionen auf der nicht-dominanten unteren Extremität geachtet werden. Die objektive Bewegungsanalyse kann ein nützliches Instrument für Instruktoren oder Physiotherapeuten sein, um Yoga-Programme anzupassen und Asanas zu korrigieren, um Verletzungen vorzubeugen.}, } @article {pmid38330924, year = {2024}, author = {Leedasawat, P and Sangvatanakul, P and Tungsukruthai, P and Kamalashiran, C and Phetkate, P and Patarajierapun, P and Sriyakul, K}, title = {The Efficacy and Safety of Chinese Eye Exercise of Acupoints in Dry Eye Patients: A Randomized Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {149-159}, doi = {10.1159/000536516}, pmid = {38330924}, issn = {2504-2106}, abstract = {INTRODUCTION: Dry eye disorder (DED) is a growing global issue linked to excessive digital screen time. Chinese eye exercise of acupoint (CEA), a set of self-massages on shared Chinese acupuncture (CA), has been used to reduce visual-related ocular symptoms and possibly as an alternative treatment for DED. This study aimed to assess the efficacy and safety of CEA.

METHODS: A single-blind randomized controlled trial was conducted at Thammasat University Hospital in Thailand, recruiting 56 participants aged 20-60 years, equally divided into two groups: the treatment group with CEA and the control group with standard lid hygiene treatment (STD). The intervention program lasted 12 weeks.

MAIN OUTCOME MEASURES: Ocular Surface Disease Index (OSDI), tear break-up time (TBUT), Schirmer-I test (SIT), corneal surface staining (CSS), and self-recorded forms for safety and adverse effects were measured at baseline, week 4, and week 12. An independent sample t test, paired t test, and repeated measures (ANOVA) were used to compare results between both groups, study visits, and primary and secondary outcome measurements, respectively. The p values <0.05 were considered statistically significant.

RESULTS: The characteristics were not statistically different between both groups at the baseline. The mean OSDI scores were significantly reduced in both groups at week 4 and week 12 compared to baseline (p value <0.05). Additionally, both CEA and STD showed significant improvement in TBUT and SIT (p value <0.05). CSS was significantly improved only in the CEA groups (p value <0.05). No significant differences were observed between the study groups, except for SIT at week 12 (p value <0.05). For the safety, there were no adverse side effects in either group.

CONCLUSION: CEA seemed to be as effective as STD in improving the OSDI, TBUT, and SIT of DED without causing any side effects.

UNLABELLED: EinleitungDas Trockene Auge (Dry eye disorder, DED) ist weltweit ein zunehmendes Problem, das mit übermässiger Bildschirmarbeit zusammenhängt. Die chinesische Augenübung der Akupunkturpunkte (Chinese eye exercise of acupoint, CEA), eine Reihe von Selbstmassagen an gemeinsamen CA-Akupunkturpunkten, wird zur Linderung visusbezogener Augensymptome und als mögliche alternative Behandlung für DED eingesetzt. Mit dieser Studie sollte die Wirksamkeit und Sicherheit von CEA bewertet werden.MethodenAm Thammasat-Universitätsklinikum in Thailand wurde eine einfach verblindete, randomisierte, kontrollierte Studie mit 56 Teilnehmern im Alter von 20 bis 60 Jahren durchgeführt, die zu gleichen Teilen zwei Gruppen zugewiesen wurden: die Behandlungsgruppe mit CEA und die Kontrollgruppe, die die Standard-Lidhygienebehandlung erhielt (STD). Das Interventionsprogramm dauerte 12 Wochen. Die Haupt-Zielkriterien, der Ocular Surface Disease Index (OSDI), die Tränenfilmaufreisszeit (tear break-up time, TBUT), der Schirmer-I-Test (SIT), das Corneal Surface Staining (CSS) und Selbstauskunftsformulare zur Sicherheit und zu unerwünschten Wirkungen wurden zu Beginn der Behandlung, in Woche 4 und in Woche 12 ermittelt. Für den Vergleich der Ergebnisse zwischen den beiden Gruppen, den Studienvisiten bzw. den primären und sekundären Zielkriterien wurden ein t Test für unabhängige Stichproben, ein t Test für paarige Stichproben und eine ANOVA mit Messwiederholungen verwendet. p-Werte <0,05 galten als statistisch signifikant.ErgebnisseHinsichtlich der Merkmale bestand zwischen den beiden Gruppen kein statistischer Unterschied bei Studienbeginn. In beiden Gruppen fielen die mittleren OSDI-Scores in Woche 4 und Woche 12 im Vergleich zum Ausgangswert signifikant geringer aus (p-Wert <0,05). Darüber hinaus zeigten sowohl die CEA- als auch die STD-Gruppe eine signifikante Verbesserung der TBUT- und SIT-Werte (p-Wert <0,05). Das CSS verbesserte sich nur in der CEA-Gruppe signifikant (p-Wert <0,05). Zwischen den Studiengruppen waren keine signifikanten Unterschiede zu beobachten, ausser beim SIT in Woche 12 (p-Wert <0,05). Was die Sicherheit betrifft, so traten in beiden Gruppen keine unerwünschten Nebenwirkungen auf.SchlussfolgerungDie CEA schien die OSDI-, TBUT- und SIT-Werte bei DED ebenso wirksam zu verbessern wie die Standardbehandlung, ohne Nebenwirkungen zu verursachen.}, } @article {pmid38330475, year = {2024}, author = {Stavros, K}, title = {Genetic Myelopathies.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {30}, number = {1}, pages = {119-132}, pmid = {38330475}, issn = {1538-6899}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Muscular Atrophy, Spinal/diagnosis ; *Spastic Paraplegia, Hereditary/diagnosis ; *Spinal Cord Diseases/diagnosis/genetics/therapy ; }, abstract = {OBJECTIVE: This article provides an overview of genetic myelopathies, a diverse group of inherited, degenerative conditions that may be broadly categorized as motor neuron disorders, disorders of spinocerebellar degeneration, leukodystrophies, and hereditary spastic paraplegia. Clinical examples from each category are provided to illustrate the spectrum of genetic myelopathies and their distinguishing features that aid in differentiating genetic myelopathies from potentially treatable acquired causes of myelopathy.

LATEST DEVELOPMENTS: Advances in genetic testing have vastly enhanced current knowledge of genetic myelopathies and the ability to diagnose and provide appropriate counseling to patients and their families. However, potential health care disparities in access to genetic testing is a topic that must be further explored. Although treatment for most of these conditions is typically supportive, there have been recent therapeutic breakthroughs in treatments for amyotrophic lateral sclerosis, spinal muscular atrophy, and Friedreich ataxia.

ESSENTIAL POINTS: Genetic myelopathies may present with chronic and progressive symptoms, a family history of similar symptoms, and involvement of other structures outside of the spinal cord. Imaging often shows spinal cord atrophy, but cord signal change is rare. Exclusion of reversible causes of myelopathy is a key step in the diagnosis. There are many different causes of genetic myelopathies, and in some cases, symptoms may overlap, which underscores the utility of genetic testing in confirming the precise underlying neurologic condition.}, } @article {pmid38329887, year = {2024}, author = {Sanghai, N and Vuong, B and Burak Berk, A and Afridi, MSK and Tranmer, GK}, title = {Current Small Molecule-Based Medicinal Chemistry Approaches for Neurodegeneration Therapeutics.}, journal = {ChemMedChem}, volume = {19}, number = {9}, pages = {e202300705}, doi = {10.1002/cmdc.202300705}, pmid = {38329887}, issn = {1860-7187}, support = {//Department of Human Anatomy and Cell Science, University of Manitoba/ ; //College of Pharmacy, Department of Pharmacology & Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Small Molecule Libraries/chemistry/pharmacology/chemical synthesis ; *Neuroprotective Agents/chemistry/pharmacology/chemical synthesis ; Blood-Brain Barrier/metabolism/drug effects ; Chemistry, Pharmaceutical ; Molecular Structure ; }, abstract = {Neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS) possess multifactorial aetiologies. In recent years, our understanding of the biochemical and molecular pathways across NDDs has increased, however, new advances in small molecule-based therapeutic strategies targeting NDDs are obscure and scarce. Moreover, NDDs have been studied for more than five decades, however, there is a paucity of drugs that can treat NDDs. Further, the highly lipoidal blood-brain barrier (BBB) limits the uptake of many therapeutic molecules into the brain and is a complicating factor in the development of new agents to treat neurodegeneration. Considering the highly complex nature of NDDs, the association of multiple risk factors, and the challenges to overcome the BBB junction, medicinal chemists have developed small organic molecule-based novel approaches to target NDDs over the last few decades, such as designing lipophilic molecules and applying prodrug strategies. Attempts have been made to utilize a multitarget approach to modulate different biochemical molecular pathways involved in NDDs, in addition to, medicinal chemists making better decisions in identifying optimized drug candidates for the central nervous system (CNS) by using web-based computational tools. To increase the clinical success of these drug candidates, an in vitro assay modeling the BBB has been utilized by medicinal chemists in the pre-clinical phase as a further screening measure of small organic molecules. Herein, we examine some of the intriguing strategies taken by medicinal chemists to design small organic molecules to combat NDDs, with the intention of increasing our awareness of neurodegenerative therapeutics.}, } @article {pmid38328178, year = {2024}, author = {Arnold, FJ and Cui, Y and Michels, S and Colwin, MR and Stockford, C and Ye, W and Tam, OH and Menon, S and Situ, WG and Ehsani, KCK and Howard, S and Hammell, MG and Li, W and La Spada, AR}, title = {TDP-43 dysregulation of polyadenylation site selection is a defining feature of RNA misprocessing in ALS/FTD and related disorders.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.01.22.576709}, pmid = {38328178}, issn = {2692-8205}, support = {RF1 NS118570/NS/NINDS NIH HHS/United States ; }, abstract = {Nuclear clearance and cytoplasmic aggregation of the RNA-binding protein TDP-43 are observed in many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and fronto- temporal dementia (FTD). Although TDP-43 dysregulation of splicing has emerged as a key event in these diseases, TDP-43 can also regulate polyadenylation; yet, this has not been adequately studied. Here, we applied the dynamic analysis of polyadenylation from RNA-seq (DaPars) tool to ALS/FTD transcriptome datasets, and report extensive alternative polyadenylation (APA) upon TDP-43 alteration in ALS/FTD cell models and postmortem ALS/FTD neuronal nuclei. Importantly, many identified APA genes highlight pathways implicated in ALS/FTD pathogenesis. To determine the functional significance of APA elicited by TDP-43 nuclear depletion, we examined microtubule affinity regulating kinase 3 (MARK3). Nuclear loss of TDP-43 yielded increased expression of MARK3 transcripts with longer 3'UTRs, resulting in greater transcript stability and elevated MARK3 protein levels, which promotes increased neuronal tau S262 phosphorylation. Our findings define changes in polyadenylation site selection as a previously unrecognized feature of TDP-43-driven disease pathology in ALS/FTD and highlight a potentially novel mechanistic link between TDP-43 dysfunction and tau regulation.}, } @article {pmid38328059, year = {2024}, author = {Zeng, Y and Lovchykova, A and Akiyama, T and Liu, C and Guo, C and Jawahar, VM and Sianto, O and Calliari, A and Prudencio, M and Dickson, DW and Petrucelli, L and Gitler, AD}, title = {TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38328059}, issn = {2692-8205}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; R01 NS120992/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; RF1 AG064690/AG/NIA NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; T32 AG047126/AG/NIA NIH HHS/United States ; RF1 NS120992/NS/NINDS NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; R35 NS097263/NS/NINDS NIH HHS/United States ; }, abstract = {In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus. TDP-43 loss leads to cryptic exon inclusion but a role in other RNA processing events remains unresolved. Here, we show that loss of TDP-43 causes widespread changes in alternative polyadenylation, impacting expression of disease-relevant genes (e.g., ELP1, NEFL, and TMEM106B) and providing evidence that alternative polyadenylation is a new facet of TDP-43 pathology.}, } @article {pmid38328053, year = {2024}, author = {Yan, X and Kuster, D and Mohanty, P and Nijssen, J and Pombo-García, K and Rizuan, A and Franzmann, TM and Sergeeva, A and Passos, PM and George, L and Wang, SH and Shenoy, J and Danielson, HL and Honigmann, A and Ayala, YM and Fawzi, NL and Mittal, J and Alberti, S and Hyman, AA}, title = {Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38328053}, issn = {2692-8205}, support = {R01 NS114289/NS/NINDS NIH HHS/United States ; }, abstract = {Cytosolic aggregation of the nuclear protein TDP-43 is associated with many neurodegenerative diseases, but the triggers for TDP-43 aggregation are still debated. Here, we demonstrate that TDP-43 aggregation requires a double event. One is up-concentration in stress granules beyond a threshold, and the other is oxidative stress. These two events collectively induce intra-condensate demixing, giving rise to a dynamic TDP-43 enriched phase within stress granules, which subsequently transitions into pathological aggregates. Mechanistically, intra-condensate demixing is triggered by local unfolding of the RRM1 domain for intermolecular disulfide bond formation and by increased hydrophobic patch interactions in the C-terminal domain. By engineering TDP-43 variants resistant to intra-condensate demixing, we successfully eliminate pathological TDP-43 aggregates in cells. We conclude that up-concentration inside condensates and simultaneous exposure to environmental stress could be a general pathway for protein aggregation, with intra-condensate demixing constituting a key intermediate step.}, } @article {pmid38325718, year = {2024}, author = {Cuevas, EP and Martinez-Gonzalez, L and Gordillo, C and Tosat-Bitrián, C and Pérez de la Lastra, C and Sáenz, A and Gil, C and Palomo, V and Martin-Requero, Á and Martinez, A}, title = {Casein kinase 1 inhibitor avoids TDP-43 pathology propagation in a patient-derived cellular model of amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {192}, number = {}, pages = {106430}, doi = {10.1016/j.nbd.2024.106430}, pmid = {38325718}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Casein Kinase I ; *Neurodegenerative Diseases ; *Neuroblastoma ; DNA-Binding Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease without a cure to reverse its progression. Its main hallmark is the nuclear protein TDP-43, which undergoes different post-translational modifications leading to a loss of function in the nucleus and an increase in toxicity in the cytoplasm. Previous reports have indicated that pathogenic TDP-43 exhibits prion-like propagation in various contexts. With the aim of advancing therapeutics focused on preventing the propagation of TDP-43 pathology, we studied the potential role of pathogenic TDP-43 in lymphoblasts from sporadic ALS patients. We used lymphoblastoid cell lines from sporadic ALS patients as a source of pathogenic forms of TDP-43, and healthy human cells (lymphoblasts, myoblasts, neuroblastoma SH-SY5Y, or osteosarcoma U2OS) as recipient cells to investigate the seeding and spread of TDP-43 proteinopathy. Furthermore, we evaluated the potential of targeting TDP-43 phosphorylation with a CK-1 inhibitor to prevent the propagation of the pathology. The results presented herein indicate that pathogenic forms of TDP-43 are secreted into the extracellular medium of sporadic ALS lymphoblasts and could be transported by extracellular vesicles, spreading TDP-43 pathology to healthy cells. Moreover, tunneling nanotubes have also been discovered in pathological cells and may be involved in the transport of TDP-43. Interestingly, targeting TDP-43 phosphorylation with an in-house designed CK-1 inhibitor (IGS2.7) was sufficient to halt TDP-43 pathology transmission, in addition to its known effects on restoring the homeostasis of TDP-43 protein in patients-derived cells.}, } @article {pmid38325473, year = {2024}, author = {Xu, Y and Nie, J and Lu, C and Hu, C and Chen, Y and Ma, Y and Huang, Y and Lu, L}, title = {Effects and mechanisms of bisphenols exposure on neurodegenerative diseases risk: A systemic review.}, journal = {The Science of the total environment}, volume = {919}, number = {}, pages = {170670}, doi = {10.1016/j.scitotenv.2024.170670}, pmid = {38325473}, issn = {1879-1026}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/chemically induced ; *Alzheimer Disease ; *Parkinson Disease/etiology/metabolism ; Brain/metabolism ; Oxidative Stress/physiology ; }, abstract = {Environmental bisphenols (BPs) pose a global threat to human health because of their extensive use as additives in plastic products. BP residues are increasing in various environmental media (i.e., water, soil, and indoor dust) and biological and human samples (i.e., serum and brain). Both epidemiological and animal studies have determined an association between exposure to BPs and an increased risk of neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis), including cognitive abnormalities and behavioral disturbances. Hence, understanding the biological responses to different BPs is essential for prevention, and treatment. This study provides an overview of the underlying pathogenic molecular mechanisms as a valuable basis for understanding neurodegenerative disease responses to BPs, including accumulation of misfolded proteins, reduction of tyrosine hydroxylase and dopamine, abnormal hormone signaling, neuronal death, oxidative stress, calcium homeostasis, and inflammation. These findings provide new insights into the neurotoxic potential of BPs and ultimately contribute to a comprehensive health risk evaluation.}, } @article {pmid38325382, year = {2024}, author = {Yan, J and Wang, YM and Hellwig, A and Bading, H}, title = {TwinF interface inhibitor FP802 stops loss of motor neurons and mitigates disease progression in a mouse model of ALS.}, journal = {Cell reports. Medicine}, volume = {5}, number = {2}, pages = {101413}, pmid = {38325382}, issn = {2666-3791}, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology ; Superoxide Dismutase/metabolism/pharmacology/therapeutic use ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Disease Models, Animal ; Disease Progression ; *TRPM Cation Channels ; }, abstract = {Toxic signaling by extrasynaptic NMDA receptors (eNMDARs) is considered an important promoter of amyotrophic lateral sclerosis (ALS) disease progression. To exploit this therapeutically, we take advantage of TwinF interface (TI) inhibition, a pharmacological principle that, contrary to classical NMDAR pharmacology, allows selective elimination of eNMDAR-mediated toxicity via disruption of the NMDAR/TRPM4 death signaling complex while sparing the vital physiological functions of synaptic NMDARs. Post-disease onset treatment of the SOD1[G93A] ALS mouse model with FP802, a modified TI inhibitor with a safe pharmacology profile, stops the progressive loss of motor neurons in the spinal cord, resulting in a reduction in the serum biomarker neurofilament light chain, improved motor performance, and an extension of life expectancy. FP802 also effectively blocks NMDA-induced death of neurons in ALS patient-derived forebrain organoids. These results establish eNMDAR toxicity as a key player in ALS pathogenesis. TI inhibitors may provide an effective treatment option for ALS patients.}, } @article {pmid38324182, year = {2024}, author = {Jiang, Z and Gu, XJ and Su, WM and Duan, QQ and Yin, KF and Ren, YL and Wang, Y and Cao, B and Chen, YP}, title = {Discovery and Exploration of Lipid-Modifying Drug Targets for ALS by Mendelian Randomization.}, journal = {Molecular neurobiology}, volume = {61}, number = {9}, pages = {6572-6583}, pmid = {38324182}, issn = {1559-1182}, support = {2022YFC2703101//the National Key Research and Development Program of China/ ; 2022NSFSC0749//the National Natural Science Fund of Sichuan/ ; 2021YFS0051//the Science and Technology Bureau Fund of Sichuan Province/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Mendelian Randomization Analysis ; Phenotype ; Drug Discovery ; Polymorphism, Single Nucleotide/genetics ; Lipids/blood ; Molecular Targeted Therapy ; Genetic Predisposition to Disease ; }, abstract = {Observational studies have faced challenges in identifying replicable causes for amyotrophic lateral sclerosis (ALS). To address this, we employed an unbiased and data-driven approach to discover and explore potential causal exposures using two-sample Mendelian randomization (MR) analyses. In the phenotype discovery stage, we assessed 3948 environmental exposures from the UK Biobank and utilized ALS summary statistics (Europeans, 20,806 cases, 59,804 controls) as the outcome within a phenome-wide MR pipeline. Through a range of sensitivity analyses, two medication traits were identified to be protective for ALS. In the target exploration stage, we further conducted drug target MR analyses using the latest and trans-ethnic summary data on lipid-related traits and ALS (Europeans, 27,205 cases, 110,881 controls; East Asians, 1234 cases, 2850 controls). Our aim was to explore potential causal drug targets through six lipid-modifying effects. These comprehensive analyses revealed significant findings. Specifically, "cholesterol-lowering medication" and "atorvastatin" survived predefined criteria in the phenotype discovery stage and exhibited a protective effect on ALS. Further in the target exploration stage, we demonstrated that the therapeutic effect of APOB through LDL-lowering was associated with reduced ALS liability in Europeans (OR = 0.835, P = 5.61E - 5). Additionally, the therapeutic effect of APOA1 and LDLR through TC-lowering was associated with reduced ALS liability in East Asians (APOA1, OR = 0.859, P = 5.38E - 4; LDLR, OR = 0.910, P = 2.73E - 5). Overall, we propose potential protective effects of cholesterol-lowering drugs or statins on ALS risk from thousands of exposures. Our research also suggests APOB, APOA1, and LDLR as novel therapeutic targets for ALS and supports their potential protective mechanisms may be mediated by LDL-lowering or TC-lowering effects.}, } @article {pmid38324041, year = {2024}, author = {Harris, CM and Higgins, C and Mehta, AK}, title = {Trends in Specialty Palliative Care Service Utilization and In-Hospital Outcomes for Patients With Amyotrophic Lateral Sclerosis.}, journal = {Journal of palliative medicine}, volume = {27}, number = {4}, pages = {521-525}, doi = {10.1089/jpm.2023.0444}, pmid = {38324041}, issn = {1557-7740}, mesh = {Humans ; United States ; *Palliative Care ; *Amyotrophic Lateral Sclerosis/therapy ; Hospitals ; Hospitalization ; Patients ; }, abstract = {Background: Hospitalized people with amyotrophic lateral sclerosis (ALS) may benefit from specialty palliative care services (sPCS). Objective: To describe access to in-hospital sPCS for people with ALS (pALS). Methods: We compared years 2010-2011 to 2018-2019, and conducted trend analyses of sPCS from 2010 to 2019 stratified by race. Results: Of 103,193 pALS admitted during the study period, 13,885 (13.4%) received sPCS. Rates of sPCS increased over time (2010-2011: 8.9% vs. 2018-2019: 16.6%; p < 0.01). From 2010 to 2019, there was an increase in sPCS (p-trend<0.01) for all studied racial groups. Conclusions: Access to palliative care has increased over time for pALS admitted to hospitals in the United States.}, } @article {pmid38323662, year = {2024}, author = {Garcés, P and Amaro, A and Montecino, M and van Zundert, B}, title = {Inorganic polyphosphate: from basic research to diagnostic and therapeutic opportunities in ALS/FTD.}, journal = {Biochemical Society transactions}, volume = {52}, number = {1}, pages = {123-135}, doi = {10.1042/BST20230257}, pmid = {38323662}, issn = {1470-8752}, mesh = {Animals ; Mice ; Humans ; *Frontotemporal Dementia/metabolism/therapy ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/metabolism ; Polyphosphates ; *Alzheimer Disease ; *Parkinson Disease ; Mammals ; }, abstract = {Inorganic polyphosphate (polyP) is a simple, negatively charged biopolymer with chain lengths ranging from just a few to over a thousand ortho-phosphate (Pi) residues. polyP is detected in every cell type across all organisms in nature thus far analyzed. Despite its structural simplicity, polyP has been shown to play important roles in a remarkably broad spectrum of biological processes, including blood coagulation, bone mineralization and inflammation. Furthermore, polyP has been implicated in brain function and the neurodegenerative diseases amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease and Parkinson's disease. In this review, we first address the challenges associated with identifying mammalian polyP metabolizing enzymes, such as Nudt3, and quantifying polyP levels in brain tissue, cultured neural cells and cerebrospinal fluid. Subsequently, we focus on recent studies that unveil how the excessive release of polyP by human and mouse ALS/FTD astrocytes contributes to these devastating diseases by inducing hyperexcitability, leading to motoneuron death. Potential implications of elevated polyP levels in ALS/FTD patients for innovative diagnostic and therapeutic approaches are explored. It is emphasized, however, that caution is required in targeting polyP in the brain due to its diverse physiological functions, serving as an energy source, a chelator for divalent cations and a scaffold for amyloidogenic proteins. Reducing polyP levels, especially in neurons, might thus have adverse effects in brain functioning. Finally, we discuss how activated mast cells and platelets also can significantly contribute to ALS progression, as they can massively release polyP.}, } @article {pmid38323575, year = {2024}, author = {Hamatani, T and Atsuta, N and Sano, F and Nakamura, R and Hayashi, Y and Sobue, G}, title = {ALSFRS-R decline rate prior to baseline is not useful for stratifying subsequent progression of functional decline.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {388-399}, doi = {10.1080/21678421.2024.2309989}, pmid = {38323575}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Disease Progression ; Prognosis ; Registries ; Databases, Factual ; }, abstract = {OBJECTIVE: One of the difficulties in developing a novel drug for patients with amyotrophic lateral sclerosis (ALS) is the significant variation in the clinical course. To control this variation, a 12-week run-in period is used in some clinical trials. Based on the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) change during the run-in period, only moderate progressors are selected in some clinical trials. Some reports showed that the ALSFRS-R progression rate was associated with survival. However, it is unclear whether the ALSFRS-R change in the run-in period is a useful prognostic factor of the ALSFRS-R change from baseline. In addition, we explore the inclusion criteria that could control the variability in ALS-function progression without setting a run-in period.

METHODS: We utilized the Japanese and US ALS registry databases (JaCALS and PRO-ACT). Patients were classified into three populations (rapid, moderate, and slow progressors) based on the ALSFRS-R change prior to baseline. We also classified patients into three prognostic populations based on the ALSFRS-R change from baseline. We confirmed whether each of the three populations were matched with their respective three prognostic populations.

RESULTS: Our data showed that the three groups classified by the ALSFRS-R change during the 12 weeks prior to baseline or by the rate of progression from onset to baseline did not accord with the three prognostic groups.

CONCLUSIONS: Our results showed that the ALSFRS-R change in the run-in period or from onset to baseline is not useful for stratifying subsequent progression of functional decline in clinical trials.}, } @article {pmid38323488, year = {2024}, author = {Downing, NR and Scafide, KN and Ali, Z and Hayat, MJ}, title = {Visibility of inflicted bruises by alternate light: Results of a randomized controlled trial.}, journal = {Journal of forensic sciences}, volume = {69}, number = {3}, pages = {880-887}, doi = {10.1111/1556-4029.15481}, pmid = {38323488}, issn = {1556-4029}, support = {2016-DN-BX-0147//National Institute of Justice, Office of Justice Programs, U.S. Department of Justice/ ; }, mesh = {Humans ; *Contusions/pathology ; Male ; Female ; Adult ; *Cross-Over Studies ; *Skin Pigmentation ; *Light ; Young Adult ; Middle Aged ; }, abstract = {Difficulty visualizing bruises resulting from interpersonal violence, especially in individuals with dark skin, contributes to disparities in access to justice. The purpose of this analysis was to compare bruise visibility of detected injuries using white light versus alternate light sources (ALS). Visibility was assessed using the 5-point Bruise Visibility Scale (BVS) for white light and the ALS Visibility Scale (AVS) for ALS. Bruises were induced using controlled application of a paintball to the upper arm on 157 healthy adults across six skin color categories. Using a crossover design, the light source used first to assess the bruise (white light or ALS) was randomized. Each bruise was examined up to 21 times over 4 weeks using white light and 10 combinations of wavelengths (350 nanometer [nm] - 535 nm) and colored filters (yellow, orange, and red). Multilevel modeling was used to analyze the repeated measures data with a total 20,103 bruise assessments. Results revealed 415 nm with yellow filter resulted in an almost 0.5-point increase in BVS/AVS score across all skin colors (Estimate = 0.46; 95% CI: 0.43, 0.49; p < 0.001), a clinically significant improvement in ability to visualize bruises. Conversely, 515 nm (Estimate = -0.80; 95% CI: -0.84, -0.76; p < 0.001) and 535 nm (Estimate = -0.64, 95% CI: -0.67, -0.60; p < 0.001) with red filter resulted in more than 0.5-point decrease in BVS/AVS score. The use of ALS is supported by the data and results in improved bruise visibility during medical forensic examinations.}, } @article {pmid38322130, year = {2023}, author = {Polverino, F and Sampaolo, S and Capuozzo, A and Fasolino, M and Aliberti, M and Satta, E and Santoriello, C and Polverino, M}, title = {Diagnosis of amyotrophic lateral sclerosis by respiratory function test.}, journal = {Multidisciplinary respiratory medicine}, volume = {18}, number = {1}, pages = {941}, pmid = {38322130}, issn = {1828-695X}, abstract = {The diagnostic criterion for amyotrophic lateral sclerosis (ALS) based on the findings of concomitant clinical and electrophysiological evidence of upper and lower motor neuron involvement may remain unsatisfied for months and in some patients, even for years in the early stage of the disease. Since respiratory involvement is an onset symptom of ALS in only 1-3% of patients, pulmonary assessment has never been considered useful in the early diagnosis of ALS. However, studies on pulmonary function are lacking, especially in those early stages where neurologic tests are also inconclusive. In contrast to the scarcity of data in the early stages, as the disease progresses, it is increasingly enriched by a rich set of symptoms and positive respiratory tests until respiratory failure occurs, which represents the main cause of death in ALS. Hereby we analyze the main pulmonary function tests (PFT) in the various stages of the disease, up to the recent evidence for the possibility of an early diagnosis.}, } @article {pmid38321352, year = {2024}, author = {Sathyamurthy, VH and Nagarajan, Y and Parvathi, VD}, title = {Mitochondria-Endoplasmic Reticulum Contact Sites (MERCS): A New Axis in Neuronal Degeneration and Regeneration.}, journal = {Molecular neurobiology}, volume = {61}, number = {9}, pages = {6528-6538}, pmid = {38321352}, issn = {1559-1182}, mesh = {Humans ; Animals ; *Mitochondria/metabolism ; *Endoplasmic Reticulum/metabolism ; Nerve Degeneration/pathology ; Nerve Regeneration/physiology ; Neurons/metabolism/pathology ; Neurodegenerative Diseases/metabolism/pathology ; Mitochondria Associated Membranes ; }, abstract = {Mitochondria-Endoplasmic Reticulum Contact Sites (MERCS) are dynamic structures whose physiological interaction is vital to direct life and death of the cell. A bevy of tethering proteins, mitofusin-1/2 (Mfn-1/2), glucose-regulated protein-75 (Grp-75), voltage-dependent anion channel-1 (VDAC1), and dynamic-related protein-1 (Drp1), plays an integral role in establishing and regulating this intricate intracellular communication. Dysregulation of this interplay leads to various neurodegenerative disorders, like Alzheimer's disease (AD), Parkinson's disease (PD), stroke, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Although there is an absence of a well-defined molecular background that dictates the pathway of MERCS, adequate exploration has resulted in preliminary data that suggests its cardinal role in neuroregeneration. The juxtaposition of mitochondria and ER has a critical function in cell senescence, thus regulating regeneration. Axonal regeneration and brain tissue regeneration, using reactive astrocytes, are studied most extensively. Overexpression of Grp-75 promoted axonal regeneration post a nerve injury. Attempts have been made to exploit MERCS as potential therapeutic drug targets for enhancing neuroregeneration and impeding neurodegeneration. Novel strategies have been developed to aid the delivery of mitochondria into the neuronal cell body, which in turn establishes a network with the presiding ER resulting in contact site formation. The fascinating aspect of this mechanism is that despite the lack of inherent regenerative capacity in neurons, it can be induced by modifying MERCS.}, } @article {pmid38320753, year = {2024}, author = {Khan, M and Chen, XXL and Dias, M and Santos, JR and Kour, S and You, J and van Bruggen, R and Youssef, MMM and Wan, YW and Liu, Z and Rosenfeld, JA and Tan, Q and Pandey, UB and Yalamanchili, HK and Park, J}, title = {MATR3 pathogenic variants differentially impair its cryptic splicing repression function.}, journal = {FEBS letters}, volume = {598}, number = {4}, pages = {415-436}, doi = {10.1002/1873-3468.14806}, pmid = {38320753}, issn = {1873-3468}, support = {58-3092-0-001//National Institute of Food and Agriculture/ ; //Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Exons/genetics ; RNA-Binding Proteins/genetics/metabolism ; RNA ; Nuclear Matrix-Associated Proteins/genetics ; }, abstract = {Matrin-3 (MATR3) is an RNA-binding protein implicated in neurodegenerative and neurodevelopmental diseases. However, little is known regarding the role of MATR3 in cryptic splicing within the context of functional genes and how disease-associated variants impact this function. We show that loss of MATR3 leads to cryptic exon inclusion in many transcripts. We reveal that ALS-linked S85C pathogenic variant reduces MATR3 solubility but does not impair RNA binding. In parallel, we report a novel neurodevelopmental disease-associated M548T variant, located in the RRM2 domain, which reduces protein solubility and impairs RNA binding and cryptic splicing repression functions of MATR3. Altogether, our research identifies cryptic events within functional genes and demonstrates how disease-associated variants impact MATR3 cryptic splicing repression function.}, } @article {pmid38320749, year = {2024}, author = {Lee, I and Nandakumar, R and Haeusler, RA}, title = {Alteration of serum bile acids in amyotrophic lateral sclerosis.}, journal = {Lipids}, volume = {59}, number = {4}, pages = {85-91}, pmid = {38320749}, issn = {1558-9307}, support = {K23NS131586/NH/NIH HHS/United States ; R01 DK115825/DK/NIDDK NIH HHS/United States ; //American Brain Foundation/ ; //American Academy of Neurology/ ; ULTR001873//National Center for Advancing Translational Sciences, National Institutes of Health/ ; K23 NS131586/NS/NINDS NIH HHS/United States ; R01DK115825/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics ; Male ; Female ; Middle Aged ; *Bile Acids and Salts/blood ; Case-Control Studies ; Adult ; Aged ; }, abstract = {Hydrophilic endogenous bile acids ursodeoxycholic acid (UDCA), tauroursodeoxycholic acid (TUDCA), and glucourosodeoxycholic acid (GUDCA) have suggested neuroprotective effects. We performed a case-control study to examine the association between ALS diagnosis and serum levels of bile acids. Sporadic and familial ALS patients, age- and sex-matched healthy controls, and presymptomatic gene carriers who donated blood samples were included. Non-fasted serum samples stored at -80°C were used for the analysis. Serum bile acid levels were measured by liquid chromatography-mass spectrometry (LC-MS). Concentrations of 15 bile acids were obtained, 5 non-conjugated and 10 conjugated, and compared between ALS versus control groups (presymptomatic gene carriers + healthy controls) using the Wilcoxon-Rank-Sum test. In total, 80 participants were included: 31 ALS (17 sporadic and 14 familial ALS); 49 controls (22 gene carriers, 27 healthy controls). The mean age was 50 years old and 50% were male. In the ALS group, 45% had familial disease with a pathogenic variant in C9orf72 (29%), TARDBP (10%), FUS (3%), and CHCHD10 (3%) genes. In the control group, 43% carried pathogenic variants: C9orf72 (27%), SOD1 (10%), and FUS (6%). The serum levels of UDCA, TUDCA, and GUDCA trended higher in the ALS group compared to controls (median 27 vs. 7 nM, 4 vs. 3 nM, 110 vs. 47 nM, p-values 0.04, 0.06, 0.04, respectively). No significant group differences were found in other bile acids serum levels. In conclusion, the serum level of UDCA, TUDCA, GUDCA trended higher in ALS patients compared to controls, and no evidence of deficiencies was found.}, } @article {pmid38318860, year = {2024}, author = {Jhooty, S and Barkhaus, P and Brown, A and Mascias Cadavid, J and Carter, GT and Crayle, J and Heiman-Patterson, T and Li, X and Mallon, E and Mcdermott, C and Mushannen, T and Pattee, G and Ratner, D and Wicks, P and Wiedau, M and Bedlack, R}, title = {ALSUntangled #74: Withania Somnifera (Ashwagandha).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {805-808}, doi = {10.1080/21678421.2024.2311721}, pmid = {38318860}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Withania ; Animals ; *Plant Extracts/therapeutic use ; Phytotherapy/methods ; }, abstract = {ALSUntangled reviews alternative and off-label treatments on behalf of people with ALS (PALS) who ask about them. Here, we review withania somnifera (WS) commonly known as ashwagandha or winter cherry. WS has plausible mechanisms for slowing ALS progression because of its effects on inflammation, oxidative stress, autophagy, mitochondrial function, and apoptosis. Preclinical trials demonstrate that WS slows disease progression in multiple different animal models of ALS. Of the five individuals we found who described using WS for their ALS, two individuals reported moderate benefit while none reported experiencing any significant side effects. There is currently one clinical trial using WS to treat PALS; the results are not yet published. There are no serious side effects associated with WS and the associated cost of this treatment is low. Based on the above information, WS appears to us to be a good candidate for future ALS trials.}, } @article {pmid38318827, year = {2024}, author = {Motamedy, S and Soltani, B and Kameshki, H and Kermani, AA and Amleshi, RS and Nazeri, M and Shabani, M}, title = {The Therapeutic Potential and Molecular Mechanisms Underlying the Neuroprotective Effects of Sativex[®] - A Cannabis-derived Spray.}, journal = {Mini reviews in medicinal chemistry}, volume = {24}, number = {15}, pages = {1427-1448}, pmid = {38318827}, issn = {1875-5607}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/chemistry ; *Cannabidiol/pharmacology/therapeutic use/chemistry ; *Plant Extracts/chemistry/pharmacology ; *Dronabinol/pharmacology/chemistry/therapeutic use ; Animals ; Multiple Sclerosis/drug therapy ; Cannabis/chemistry ; Drug Combinations ; }, abstract = {Sativex is a cannabis-based medicine that comes in the form of an oromucosal spray. It contains equal amounts of Δ9-tetrahydrocannabinol and cannabidiol, two compounds derived from cannabis plants. Sativex has been shown to have positive effects on symptoms of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and sleep disorders. It also has analgesic, antiinflammatory, antitumoral, and neuroprotective properties, which make it a potential treatment option for other neurological disorders. The article reviews the results of recent preclinical and clinical studies that support the therapeutic potential of Sativex and the molecular mechanisms behind its neuroprotective benefits in various neurological disorders. The article also discusses the possible advantages and disadvantages of using Sativex as a neurotherapeutic agent, such as its safety, efficacy, availability, and legal status.}, } @article {pmid38318532, year = {2024}, author = {Geng, Y and Cai, Q}, title = {Role of C9orf72 hexanucleotide repeat expansions in ALS/FTD pathogenesis.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1322720}, pmid = {38318532}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurological disorders that share neurodegenerative pathways and features. The most prevalent genetic causes of ALS/FTD is the GGGGCC hexanucleotide repeat expansions in the first intron region of the chromosome 9 open reading frame 72 (C9orf72) gene. In this review, we comprehensively summarize the accumulating evidences elucidating the pathogenic mechanism associated with hexanucleotide repeat expansions in ALS/FTD. These mechanisms encompass the structural polymorphism of DNA and transcribed RNA, the formation of RNA foci via phase separation, and the cytoplasmic accumulation and toxicities of dipeptide-repeat proteins. Additionally, the formation of G-quadruplex structures significantly impairs the expression and normal function of the C9orf72 protein. We also discuss the sequestration of specific RNA binding proteins by GGGGCC RNA, which further contributes to the toxicity of C9orf72 hexanucleotide repeat expansions. The deeper understanding of the pathogenic mechanism of hexanucleotide repeat expansions in ALS/FTD provides multiple potential drug targets for these devastating diseases.}, } @article {pmid38318443, year = {2024}, author = {Plasencia-Salini, R and Havens, AP and Miller, KM}, title = {Biometry challenges in the longest eyes we have encountered to date.}, journal = {American journal of ophthalmology case reports}, volume = {33}, number = {}, pages = {101997}, pmid = {38318443}, issn = {2451-9936}, abstract = {PURPOSE: This report aims to present biometry challenges and solutions for a patient with the longest eyes we have encountered to date.

OBSERVATIONS: A 41-year-old woman with a history of Crouzon syndrome, extreme axial myopia, and posterior segment staphylomas was referred for cataract evaluation. Optical biometry was attempted using two partial coherence interferometry and optical low-coherence reflectometry devices that were available in 2011. Neither device could measure the axial length (AL) of either eye, unfortunately. We were able to measure them by A scan ultrasound, however, with results of 40.59 mm for the right eye and 38.29 mm for the left eye. Shortly thereafter, she underwent uncomplicated phacoemulsification with posterior chamber intraocular lens implantation under topical anesthesia. Twelve years later, she returned for repeat optical biometry with 3 newer generation devices, 2 of which utilized swept-source optical coherence tomography (SS-OCT). Only 1 SS-OCT device, the Argos biometer, was able to obtain AL measurements, and they were 40.54 mm and 40.84 mm for the right and left eyes, respectively.

CONCLUSIONS AND IMPORTANCE: Biometry measurement using optical biometers on a patient with ALs greater than 40 mm was impossible in 2011 because of the relatively short gate for acceptable readings. Ultrasound biometry can also be challenging due to the presence of posterior staphylomas. However, a newer SS-OCT with a longer AL measurement capability enabled readings to be obtained more recently.}, } @article {pmid38318390, year = {2024}, author = {Komine, O and Ohnuma, S and Hinohara, K and Hara, Y and Shimada, M and Akashi, T and Watanabe, S and Sobue, A and Kawade, N and Ogi, T and Yamanaka, K}, title = {Genetic background variation impacts microglial heterogeneity and disease progression in amyotrophic lateral sclerosis model mice.}, journal = {iScience}, volume = {27}, number = {2}, pages = {108872}, pmid = {38318390}, issn = {2589-0042}, abstract = {Recent single-cell analyses have revealed the complexity of microglial heterogeneity in brain development, aging, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Disease-associated microglia (DAMs) have been identified in ALS mice model, but their role in ALS pathology remains unclear. The effect of genetic background variations on microglial heterogeneity and functions remains unknown. Herein, we established and analyzed two mice models of ALS with distinct genetic backgrounds of C57BL/6 and BALB/c. We observed that the change in genetic background from C57BL/6 to BALB/c affected microglial heterogeneity and ALS pathology and its progression, likely due to the defective induction of neurotrophic factor-secreting DAMs and impaired microglial survival. Single-cell analyses of ALS mice revealed new markers for each microglial subtype and a possible association between microglial heterogeneity and systemic immune environments. Thus, we highlighted the role of microglia in ALS pathology and importance of genetic background variations in modulating microglial functions.}, } @article {pmid38318246, year = {2024}, author = {Izquierdo-Condoy, JS and Arias Rodríguez, FD and Duque-Sánchez, E and Alegría N, N and Rojas Cadena, M and Naranjo-Lara, P and Mendoza, AP and Jima-Sanmartín, J and Casanova, DA and García, B and Giraldo, NC}, title = {Assessment of preparedness and proficiency in basic and advanced life support among nursing professionals: a cross-sectional study.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1328573}, pmid = {38318246}, issn = {2296-858X}, abstract = {BACKGROUND: Cardiac diseases are among the leading causes of death worldwide, including sudden cardiac arrest in particular. Nursing professionals are often the first to encounter these scenarios in various settings. Adequate preparation and competent knowledge among nurses significantly impact survival rates positively.

AIM: To describe the state of knowledge about Basic and Advanced Life Support guidelines among Ecuadorian nursing professionals.

METHODOLOGY: A nationwide, descriptive, cross-sectional study was conducted from February to April 2023 among Ecuadorian nursing professionals. Participants were invited through official social media groups such as WhatsApp and Facebook. The study utilized a self-administered online questionnaire to evaluate theoretical knowledge of Basic Life Support (BLS) and Advanced Life Support (ALS). Knowledge scores were assigned based on the number of correct answers on the tests. T-tests and one-way ANOVA were used to examine relationships between knowledge scores and demographic and academic training variables.

RESULTS: A total of 217 nursing professionals participated in the study. The majority of the participants were female (77.4%) and held a university degree (79.9%). Among them, only 44.7% claimed to have obtained a BLS training certificate at least once, and 19.4% had ALS certification. The overall BLS knowledge score (4.8/10 ± 1.8 points) was higher than the ALS score (4.3/10 ± 1.8 points). Participants who had obtained BLS certification and those who used evidence-based summaries as a source of extracurricular training achieved higher BLS and ALS knowledge scores.

CONCLUSION: Ecuadorian nursing professionals in this study exhibited a significant deficiency in theoretical knowledge of BLS and ALS. Formal training and preparation positively impact life support knowledge. Support and inclusion of Ecuadorian nurses in training and academic preparation programs beginning at the undergraduate level are essential for promoting life support knowledge and improving outcomes.}, } @article {pmid38317984, year = {2024}, author = {Harvey, C and Weinreich, M and Lee, JAK and Shaw, AC and Ferraiuolo, L and Mortiboys, H and Zhang, S and Hop, PJ and Zwamborn, RAJ and van Eijk, K and Julian, TH and Moll, T and Iacoangeli, A and Al Khleifat, A and Quinn, JP and Pfaff, AL and Kõks, S and Poulton, J and Battle, SL and Arking, DE and Snyder, MP and , and Veldink, JH and Kenna, KP and Shaw, PJ and Cooper-Knock, J}, title = {Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis.}, journal = {Heliyon}, volume = {10}, number = {3}, pages = {e24975}, pmid = {38317984}, issn = {2405-8440}, support = {S10 OD025212/OD/NIH HHS/United States ; R56 NS073873/NS/NINDS NIH HHS/United States ; R01 NS073873/NS/NINDS NIH HHS/United States ; R01 HL101388/HL/NHLBI NIH HHS/United States ; P50 HL083800/HL/NHLBI NIH HHS/United States ; P30 DK116074/DK/NIDDK NIH HHS/United States ; R01 HL122939/HL/NHLBI NIH HHS/United States ; UM1 HG009442/HG/NHGRI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving selective vulnerability of energy-intensive motor neurons (MNs). It has been unclear whether mitochondrial function is an upstream driver or a downstream modifier of neurotoxicity. We separated upstream genetic determinants of mitochondrial function, including genetic variation within the mitochondrial genome or autosomes; from downstream changeable factors including mitochondrial DNA copy number (mtCN). Across three cohorts including 6,437 ALS patients, we discovered that a set of mitochondrial haplotypes, chosen because they are linked to measurements of mitochondrial function, are a determinant of ALS survival following disease onset, but do not modify ALS risk. One particular haplotype appeared to be neuroprotective and was significantly over-represented in two cohorts of long-surviving ALS patients. Causal inference for mitochondrial function was achievable using mitochondrial haplotypes, but not autosomal SNPs in traditional Mendelian randomization (MR). Furthermore, rare loss-of-function genetic variants within, and reduced MN expression of, ACADM and DNA2 lead to ∼50 % shorter ALS survival; both proteins are implicated in mitochondrial function. Both mtCN and cellular vulnerability are linked to DNA2 function in ALS patient-derived neurons. Finally, MtCN responds dynamically to the onset of ALS independently of mitochondrial haplotype, and is correlated with disease severity. We conclude that, based on the genetic measures we have employed, mitochondrial function is a therapeutic target for amelioration of disease severity but not prevention of ALS.}, } @article {pmid38317639, year = {2024}, author = {Verma, S and Vats, A and Ahuja, V and Vats, K and Khurana, S and Vats, Y and Gourie-Devi, M and Wajid, S and Ganguly, NK and Chakraborti, P and Taneja, V}, title = {Functional consequences of familial ALS-associated SOD1[L84F] in neuronal and muscle cells.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {38}, number = {3}, pages = {e23461}, doi = {10.1096/fj.202301979R}, pmid = {38317639}, issn = {1530-6860}, support = {09/591(0150)/2018-EMR-I//Council of Scientific and Industrial Research, India (CSIR)/ ; 3/1/2/151/Neuro/2021-NCD-I//Indian Council of Medical Research (ICMR)/ ; 2020-2641/CMB/ADHOC-BMS//Indian Council of Medical Research (ICMR)/ ; 211610027970//University Grants Commission (UGC)/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Muscle Cells/metabolism ; Mutation ; *Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder characterized by progressive skeletal muscle denervation and loss of motor neurons that results in muscle atrophy and eventual death due to respiratory failure. Previously, we identified a novel SOD1[L84F] variation in a familial ALS case. In this study, we examined the functional consequences of SOD1[L84F] overexpression in the mouse motor neuron cell line (NSC-34). The cells expressing SOD1[L84F] showed increased oxidative stress and increased cell death. Interestingly, SOD1[L84F] destabilized the native dimer and formed high molecular weight SDS-resistant protein aggregates. Furthermore, SOD1[L84F] also decreased the percentage of differentiated cells and significantly reduced neurite length. A plethora of evidence suggested active involvement of skeletal muscle in disease initiation and progression. We observed differential processing of the mutant SOD1 and perturbations of cellular machinery in NSC-34 and muscle cell line C2C12. Unlike neuronal cells, mutant protein failed to accumulate in muscle cells probably due to the activated autophagy, as evidenced by increased LC3-II and reduced p62. Further, SOD1[L84F] altered mitochondrial dynamics only in NSC-34. In addition, microarray analysis also revealed huge variations in differentially expressed genes between NSC-34 and C2C12. Interestingly, SOD1[L84F] hampered the endogenous FUS autoregulatory mechanism in NSC-34 by downregulating retention of introns 6 and 7 resulting in a two-fold upregulation of FUS. No such changes were observed in C2C12. Our findings strongly suggest the differential processing and response towards the mutant SOD1 in neuronal and muscle cell lines.}, } @article {pmid38317225, year = {2024}, author = {Liddell, JR and Hilton, JBW and Kysenius, K and Billings, JL and Nikseresht, S and McInnes, LE and Hare, DJ and Paul, B and Mercer, SW and Belaidi, AA and Ayton, S and Roberts, BR and Beckman, JS and McLean, CA and White, AR and Donnelly, PS and Bush, AI and Crouch, PJ}, title = {Microglial ferroptotic stress causes non-cell autonomous neuronal death.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {14}, pmid = {38317225}, issn = {1750-1326}, mesh = {Mice ; Animals ; Humans ; Microglia/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/metabolism ; *Neurodegenerative Diseases/metabolism ; Cell Death ; Disease Models, Animal ; }, abstract = {BACKGROUND: Ferroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved.

METHODS: To elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). We utilised the SOD1[G37R] mouse model of ALS and a CNS-permeant ferroptosis inhibitor to verify pharmacological significance in vivo.

RESULTS: We found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from human cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Further, we show the molecular correlation between ferroptosis and neurotoxic astrocytes evident in human ALS-affected spinal cord is recapitulated in the SOD1[G37R] mouse model where treatment with a CNS-permeant ferroptosis inhibitor, Cu[II](atsm), ameliorated these markers and was neuroprotective.

CONCLUSIONS: By showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pathophysiological role for ferroptosis in disease.}, } @article {pmid38316966, year = {2024}, author = {Naruse, H and Ishiura, H and Esaki, K and Mitsui, J and Satake, W and Greimel, P and Shingai, N and Machino, Y and Kokubo, Y and Hamaguchi, H and Oda, T and Ikkaku, T and Yokota, I and Takahashi, Y and Suzuki, Y and Matsukawa, T and Goto, J and Koh, K and Takiyama, Y and Morishita, S and Yoshikawa, T and Tsuji, S and Toda, T}, title = {SPTLC2 variants are associated with early-onset ALS and FTD due to aberrant sphingolipid synthesis.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {4}, pages = {946-957}, pmid = {38316966}, issn = {2328-9503}, support = {21K07512//Japan Society for the Promotion of Science/ ; 22K15724//Japan Society for the Promotion of Science/ ; //Ministry of Health, Labour and Welfare/ ; JP22ek0109617//Japan Agency for Medical Research and Development/ ; JP23ek0109617//Japan Agency for Medical Research and Development/ ; }, mesh = {Adult ; Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Serine C-Palmitoyltransferase/genetics ; *Neurodegenerative Diseases ; Sphingolipids ; Ceramides ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating, incurable neurodegenerative disease. A subset of ALS patients manifests with early-onset and complex clinical phenotypes. We aimed to elucidate the genetic basis of these cases to enhance our understanding of disease etiology and facilitate the development of targeted therapies.

METHODS: Our research commenced with an in-depth genetic and biochemical investigation of two specific families, each with a member diagnosed with early-onset ALS (onset age of <40 years). This involved whole-exome sequencing, trio analysis, protein structure analysis, and sphingolipid measurements. Subsequently, we expanded our analysis to 62 probands with early-onset ALS and further included 440 patients with adult-onset ALS and 1163 healthy controls to assess the prevalence of identified genetic variants.

RESULTS: We identified heterozygous variants in the serine palmitoyltransferase long chain base subunit 2 (SPTLC2) gene in patients with early-onset ALS. These variants, located in a region closely adjacent to ORMDL3, bear similarities to SPTLC1 variants previously implicated in early-onset ALS. Patients with ALS carrying these SPTLC2 variants displayed elevated plasma ceramide levels, indicative of increased serine palmitoyltransferase (SPT) activity leading to sphingolipid overproduction.

INTERPRETATION: Our study revealed novel SPTLC2 variants in patients with early-onset ALS exhibiting frontotemporal dementia. The combination of genetic evidence and the observed elevation in plasma ceramide levels establishes a crucial link between dysregulated sphingolipid metabolism and ALS pathogenesis. These findings expand our understanding of ALS's genetic diversity and highlight the distinct roles of gene defects within SPT subunits in its development.}, } @article {pmid38316400, year = {2024}, author = {Taule, T and Tysnes, OB and Aßmus, J and Rekand, T}, title = {A prospective study for using cognitive decline as a predictor for survival and use of feeding/respiratory support for patients with motor neuron disease in Norway.}, journal = {Annals of palliative medicine}, volume = {13}, number = {1}, pages = {86-92}, doi = {10.21037/apm-23-386}, pmid = {38316400}, issn = {2224-5839}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Prospective Studies ; *Motor Neuron Disease/complications/therapy ; *Cognitive Dysfunction ; Enteral Nutrition ; }, abstract = {BACKGROUND: There is a need for knowledge regarding the medical management of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) with and without cognitive decline. It has scarcely been studied whether cognitive decline will influence the course of disease or interfere with the use of life-prolonging aids for respiration and nutrition. Cognitive decline may impact the length of illness.

METHODS: Patients were prospectively recruited from an ALS outpatient clinic at Haukeland University Hospital. Participants underwent the standardized cognitive test Edinburgh Cognitive and Behavioral ALS Screen Norwegian version (ECAS-N), clinical examination, and were functionally assessed by the ALS Functioning Rating Scale-revised version (ALS-FRS-R). The time and indication for installation of a feeding tube [percutaneous endoscopic gastrostomy (PEG)] and/or respiratory aid [bilevel positive airway pressure device (BiPAP)] or invasive respirator were retrieved from the medical records. Kaplan-Meier tests were used to study the risk of death and the probability for implementing PEG and/or BiPAP in relation to time from diagnosis. The individual assessment was used for analyzing the establishment of aids in relation to point of death.

RESULTS: A total of 40 patients were evaluated for the study, 31 of whom were finally included. None of the included patients did not use an invasive respirator. The patients were divided into two subgroups (normal cognition or cognitive decline, cut-off 92 points) according to their performance in the ECAS-N. The course of the disease, shown as a risk of death, was higher among the ALS/MND patients with cognitive decline compared to those with cognitive intact function throughout the study period. The cognitive status did not influence the fitting of aids. Use of aids did not influence the survival in subgroups significantly.

CONCLUSIONS: The study demonstrated shorter survival for the patients with ALS/MND with cognitive decline compared to those without cognitive decline. The practice and implementation of both BiPAP and PEG did not differ among the ALS/MND patients with and without cognitive decline in Norway.}, } @article {pmid38314348, year = {2023}, author = {Watts, ME and Giadone, RM and Ordureau, A and Holton, KM and Harper, JW and Rubin, LL}, title = {Analyzing the ER stress response in ALS patient derived motor neurons identifies druggable neuroprotective targets.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1327361}, pmid = {38314348}, issn = {1662-5102}, support = {F32 AG079593/AG/NIA NIH HHS/United States ; R01 NS083524/NS/NINDS NIH HHS/United States ; R01 NS110395/NS/NINDS NIH HHS/United States ; R37 NS083524/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron (MN) disease with severely limited treatment options. Identification of effective treatments has been limited in part by the lack of predictive animal models for complex human disorders. Here, we utilized pharmacologic ER stressors to exacerbate underlying sensitivities conferred by ALS patient genetics in induced pluripotent stem cell (iPSC)-derived motor neurons (MNs). In doing so, we found that thapsigargin and tunicamycin exposure recapitulated ALS-associated degeneration, and that we could rescue this degeneration via MAP4K4 inhibition (MAP4K4i). We subsequently identified mechanisms underlying MAP4K4i-mediated protection by performing phosphoproteomics on iPSC-derived MNs treated with ER stressors ±MAP4K4i. Through these analyses, we found JNK, PKC, and BRAF to be differentially modulated in MAP4K4i-protected MNs, and that inhibitors to these proteins could also rescue MN toxicity. Collectively, this study highlights the value of utilizing ER stressors in ALS patient MNs to identify novel druggable targets.}, } @article {pmid38314277, year = {2024}, author = {Mohan, S and Alhazmi, HA and Hassani, R and Khuwaja, G and Maheshkumar, VP and Aldahish, A and Chidambaram, K}, title = {Role of ferroptosis pathways in neuroinflammation and neurological disorders: From pathogenesis to treatment.}, journal = {Heliyon}, volume = {10}, number = {3}, pages = {e24786}, pmid = {38314277}, issn = {2405-8440}, abstract = {Ferroptosis is a newly discovered non-apoptotic and iron-dependent type of cell death. Ferroptosis mainly takes place owing to the imbalance of anti-oxidation and oxidation in the body. It is regulated via a number of factors and pathways both inside and outside the cell. Ferroptosis is closely linked with brain and various neurological disorders (NDs). In the human body, the brain contains the highest levels of polyunsaturated fatty acids, which are known as lipid peroxide precursors. In addition, there is also a connection of glutathione depletion and lipid peroxidation with NDs. There is growing evidence regarding the possible link between neuroinflammation and multiple NDs, such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and stroke. Recent studies have demonstrated that disruptions of lipid reactive oxygen species (ROS), glutamate excitatory toxicity, iron homeostasis, and various other manifestations linked with ferroptosis can be identified in various neuroinflammation-mediated NDs. It has also been reported that damage-associated molecular pattern molecules including ROS are generated during the events of ferroptosis and can cause glial activation via activating neuroimmune pathways, which subsequently leads to the generation of various inflammatory factors that play a role in various NDs. This review summarizes the regulation pathways of ferroptosis, the link between ferroptosis as well as inflammation in NDs, and the potential of a range of therapeutic agents that can be used to target ferroptosis and inflammation in the treatment of neurological disorders.}, } @article {pmid38313873, year = {2024}, author = {Hill, J and Sanghani, N and Li, Y}, title = {Features Suggestive of Coexisting Amyotrophic Lateral Sclerosis in Patients With Spinal Stenosis and Influence of Spinal Decompression.}, journal = {Cureus}, volume = {16}, number = {1}, pages = {e51587}, pmid = {38313873}, issn = {2168-8184}, abstract = {BACKGROUND: Spinal stenosis and amyotrophic lateral sclerosis (ALS) can co-occur and both manifest as signs of dysfunction of lower and/or upper motor neurons. Few studies have identified factors that alert the diagnosis of ALS in patients with spinal stenosis, and the influence of spinal decompression surgery on ALS progression remains unclear.

OBJECTIVE: The objective of this study is to describe factors that are suggestive of an ALS diagnosis in patients with spinal stenosis and influence of spinal decompression surgery on the progression of ALS  Materials and methods: A retrospective review of the institutional ALS database and electronic medical records was performed to identify patients with coexisting diagnoses of ALS and moderate to severe cervical and/or lumbosacral spine stenosis. Identified patients were divided into two subgroups: those with spinal decompression surgery and those without. Comparisons of clinical features and progression of ALS were made between subgroups.

RESULTS:  A total of 77 patients with ALS and coexisting moderate to severe cervical or lumbosacral spine stenosis were included. Among them, 50 patients underwent spinal decompression surgery and 27 did not. In comparison to patients with spinal decompression, patients without spinal decompression surgery were seen more frequently by neurologists (74% versus 26%), had less prominent radicular pain (19% versus 50%), demonstrated more frequent bulbar signs (30% versus 8%), experienced more likely weight loss (41% versus 4%), and disclosed more noticeable axonal loss changes on electromyography. Spinal decompression surgery did not modify the progression of ALS based on ALSFRS-R score change and analysis of survival duration.

CONCLUSION: Our study identified a number of useful features that are suggestive of an ALS diagnosis when evaluating patients with spinal stenosis and may support the performance of spinal decompression surgery in a subset of selected ALS patients with symptomatic spinal stenosis.}, } @article {pmid38313408, year = {2023}, author = {Monov, D and Molodozhnikova, N}, title = {Biochemical parameters as a tool to assess the nutritional status of patients with amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1258224}, pmid = {38313408}, issn = {1664-2295}, abstract = {BACKGROUND: The research aimed to analyze blood biochemical parameters in patients with amyotrophic lateral sclerosis and to determine whether they can be used to assess their nutritional status.

METHODS: The study included 45 patients diagnosed with amyotrophic lateral sclerosis (ALS): 28 (62.2%) were men and 17 (37.8%) were women. The mean age of the study participants was 50.69 ± 7.24 years. The control group consisted of 30 practically healthy individuals.

RESULTS: Compared with practically healthy individuals, patients with ALS had significantly lower blood parameters, including total lymphocyte count (1.49 ± 0.11 vs. 2.86 ± 0.25, p < 0.05), total protein (60.55 ± 2.38 vs. 77.80 ± 4.41, p < 0.05), albumin (33.70 ± 2.03 vs. 46.49 ± 3.22, p < 0.05), urea (3.09 ± 0.36 vs. 5.37 ± 0.50, p < 0.05), creatinine (51.28 ± 4.42 vs. 70.91 ± 5.13, p < 0.05), and transferrin (1.84 ± 0.12 vs. 2.32 ± 0.10, p < 0.05). These parameters correspond to first-degree malnutrition. There were direct correlations between anthropometric and biochemical parameters in the ALS group. BMI correlated with the blood levels of total protein (r = 0.22, p < 0.05), albumin (r = 0.27, p < 0.05), urea (r = 0.33, p < 0.05), creatinine (r = 0.30, p < 0.05), transferrin (r = 0.18, p < 0.05), and total lymphocyte count (r = 0.20, p < 0.05). PNI correlated with the blood levels of total protein (r = 0.53, p < 0.05), albumin (r = 0.87, p < 0.05), total cholesterol (r = 0.34, p < 0.05), transferrin (r = 0.40, p < 0.05), total lymphocyte count (r = 0.79, p < 0.05), urea (r = 0, 37, p < 0.05), and creatinine (r = 0.32, p < 0.05).

CONCLUSION: The study presents compelling evidence supporting the utilization of biochemical parameters, including total protein, albumin, urea, creatinine, transferrin, and total lymphocyte count, for potentially evaluating the nutritional status of individuals diagnosed with ALS.}, } @article {pmid38313254, year = {2024}, author = {Bryce-Smith, S and Brown, AL and Mehta, PR and Mattedi, F and Mikheenko, A and Barattucci, S and Zanovello, M and Dattilo, D and Yome, M and Hill, SE and Qi, YA and Wilkins, OG and Sun, K and Ryadnov, E and Wan, Y and , and Vargas, JNS and Birsa, N and Raj, T and Humphrey, J and Keuss, M and Ward, M and Secrier, M and Fratta, P}, title = {TDP-43 loss induces extensive cryptic polyadenylation in ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38313254}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; MC_PC_MR/S022708/1/MRC_/Medical Research Council/United Kingdom ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; }, abstract = {Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 is the hallmark of ALS, occurring in over 97% of cases. A key consequence of TDP-43 nuclear loss is the de-repression of cryptic exons. Whilst TDP-43 regulated cryptic splicing is increasingly well catalogued, cryptic alternative polyadenylation (APA) events, which define the 3' end of last exons, have been largely overlooked, especially when not associated with novel upstream splice junctions. We developed a novel bioinformatic approach to reliably identify distinct APA event types: alternative last exons (ALE), 3'UTR extensions (3'Ext) and intronic polyadenylation (IPA) events. We identified novel neuronal cryptic APA sites induced by TDP-43 loss of function by systematically applying our pipeline to a compendium of publicly available and in house datasets. We find that TDP-43 binding sites and target motifs are enriched at these cryptic events and that TDP-43 can have both repressive and enhancing action on APA. Importantly, all categories of cryptic APA can also be identified in ALS and FTD post mortem brain regions with TDP-43 proteinopathy underlining their potential disease relevance. RNA-seq and Ribo-seq analyses indicate that distinct cryptic APA categories have different downstream effects on transcript and translation. Intriguingly, cryptic 3'Exts occur in multiple transcription factors, such as ELK1, SIX3, and TLX1, and lead to an increase in wild-type protein levels and function. Finally, we show that an increase in RNA stability leading to a higher cytoplasmic localisation underlies these observations. In summary, we demonstrate that TDP-43 nuclear depletion induces a novel category of cryptic RNA processing events and we expand the palette of TDP-43 loss consequences by showing this can also lead to an increase in normal protein translation.}, } @article {pmid38312023, year = {2024}, author = {Stoccoro, A and Smith, AR and Mosca, L and Marocchi, A and Gerardi, F and Lunetta, C and Lunnon, K and Migliore, L and Coppedè, F}, title = {Mitochondrial D-loop methylation levels inversely correlate with disease duration in amyotrophic lateral sclerosis.}, journal = {Epigenomics}, volume = {16}, number = {4}, pages = {203-214}, doi = {10.2217/epi-2023-0265}, pmid = {38312023}, issn = {1750-192X}, support = {Researcher's intramural funds (ATENEO Funds, Uni)//Università di Pisa/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Mutation ; DNA Methylation ; DNA, Mitochondrial/genetics ; Mitochondria/genetics ; }, abstract = {Aim: To correlate mitochondrial D-loop region methylation levels and mtDNA copy number with disease duration in familial amyotrophic lateral sclerosis (ALS) patients. Patients & methods: The study population included 12 ALS patients with a mutation in SOD1 and 13 ALS patients with the C9orf72 hexanucleotide repeat expansion. Methylation levels of the D-loop region and mtDNA copy number were quantified using pyrosequencing and quantitative PCR, respectively. Results: We observed that D-loop methylation levels inversely correlated while mtDNA copy number positively correlated with disease duration. Conclusion: Considering the central role played by mitochondria in ALS, this preliminary study provides new knowledge for future studies aimed at identifying biomarkers of disease progression and new targets for therapeutic interventions.}, } @article {pmid38311779, year = {2024}, author = {Ueda, T and Takeuchi, T and Fujikake, N and Suzuki, M and Minakawa, EN and Ueyama, M and Fujino, Y and Kimura, N and Nagano, S and Yokoseki, A and Onodera, O and Mochizuki, H and Mizuno, T and Wada, K and Nagai, Y}, title = {Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {20}, pmid = {38311779}, issn = {2051-5960}, support = {21H02840//Japan Society for the Promotion of Science/ ; 22H02792//Japan Society for the Promotion of Science/ ; 24659438//Japan Society for the Promotion of Science/ ; 17H05699//Japan Society for the Promotion of Science/ ; 20H05927//Japan Society for the Promotion of Science/ ; 11013026//Japan Society for the Promotion of Science/ ; JP15dm0107026//Japan Agency for Medical Research and Development/ ; JP20dm0107061//Japan Agency for Medical Research and Development/ ; JP16ek0109018//Japan Agency for Medical Research and Development/ ; JP19ek0109222//Japan Agency for Medical Research and Development/ ; JP20ek0109316//Japan Agency for Medical Research and Development/ ; JPMJPR17H8//Precursory Research for Embryonic Science and Technology/ ; RGY0066/2017//Human Frontier Science Program/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *DNA-Binding Proteins/genetics/metabolism ; Drosophila/metabolism ; *Dynactin Complex/genetics ; *Frontotemporal Dementia/pathology ; Stress Granules ; *Drosophila Proteins/genetics ; }, abstract = {The abnormal aggregation of TDP-43 into cytoplasmic inclusions in affected neurons is a major pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 is aberrantly accumulated in the neurons of most patients with sporadic ALS/FTD and other TDP-43 proteinopathies, how TDP-43 forms cytoplasmic aggregates remains unknown. In this study, we show that a deficiency in DCTN1, a subunit of the microtubule-associated motor protein complex dynactin, perturbs the dynamics of stress granules and drives the formation of TDP-43 cytoplasmic aggregation in cultured cells, leading to the exacerbation of TDP-43 pathology and neurodegeneration in vivo. We demonstrated using a Drosophila model of ALS/FTD that genetic knockdown of DCTN1 accelerates the formation of ubiquitin-positive cytoplasmic inclusions of TDP-43. Knockdown of components of other microtubule-associated motor protein complexes, including dynein and kinesin, also increased the formation of TDP-43 inclusions, indicating that intracellular transport along microtubules plays a key role in TDP-43 pathology. Notably, DCTN1 knockdown delayed the disassembly of stress granules in stressed cells, leading to an increase in the formation of pathological cytoplasmic inclusions of TDP-43. Our results indicate that a deficiency in DCTN1, as well as disruption of intracellular transport along microtubules, is a modifier that drives the formation of TDP-43 pathology through the dysregulation of stress granule dynamics.}, } @article {pmid38311731, year = {2024}, author = {Simmatis, LER and Robin, J and Spilka, MJ and Yunusova, Y}, title = {Detecting bulbar amyotrophic lateral sclerosis (ALS) using automatic acoustic analysis.}, journal = {Biomedical engineering online}, volume = {23}, number = {1}, pages = {15}, pmid = {38311731}, issn = {1475-925X}, support = {R01 DC013547/DC/NIDCD NIH HHS/United States ; R01DC013547/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Bayes Theorem ; Speech ; Speech Disorders/diagnosis ; ROC Curve ; }, abstract = {Automatic speech assessments have the potential to dramatically improve ALS clinical practice and facilitate patient stratification for ALS clinical trials. Acoustic speech analysis has demonstrated the ability to capture a variety of relevant speech motor impairments, but implementation has been hindered by both the nature of lab-based assessments (requiring travel and time for patients) and also by the opacity of some acoustic feature analysis methods. These challenges and others have obscured the ability to distinguish different ALS disease stages/severities. Validation of automated acoustic analysis tools could enable detection of early signs of ALS, and these tools could be deployed to screen and monitor patients without requiring clinic visits. Here, we sought to determine whether acoustic features gathered using an automated assessment app could detect ALS as well as different levels of speech impairment severity resulting from ALS. Speech samples (readings of a standardized, 99-word passage) from 119 ALS patients with varying degrees of disease severity as well as 22 neurologically healthy participants were analyzed, and 53 acoustic features were extracted. Patients were stratified into early and late stages of disease (ALS-early/ALS-E and ALS-late/ALS-L) based on the ALS Functional Ratings Scale-Revised bulbar score (FRS-bulb) (median [interquartile range] of FRS-bulbar scores: 11[3]). The data were analyzed using a sparse Bayesian logistic regression classifier. It was determined that the current relatively small set of acoustic features could distinguish between ALS and controls well (area under receiver-operating characteristic curve/AUROC = 0.85), that the ALS-E patients could be separated well from control participants (AUROC = 0.78), and that ALS-E and ALS-L patients could be reasonably separated (AUROC = 0.70). These results highlight the potential for automated acoustic analyses to detect and stratify ALS.}, } @article {pmid38311174, year = {2024}, author = {Demongin, C and Tranier, S and Joshi, V and Ceschi, L and Desforges, B and Pastré, D and Hamon, L}, title = {RNA and the RNA-binding protein FUS act in concert to prevent TDP-43 spatial segregation.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {3}, pages = {105716}, pmid = {38311174}, issn = {1083-351X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Peptide Fragments/metabolism ; *RNA/metabolism ; RNA, Messenger/genetics/metabolism ; *RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {FUS and TDP-43 are two self-adhesive aggregation-prone mRNA-binding proteins whose pathological mutations have been linked to neurodegeneration. While TDP-43 and FUS form reversible mRNA-rich compartments in the nucleus, pathological mutations promote their respective cytoplasmic aggregation in neurons with no apparent link between the two proteins except their intertwined function in mRNA processing. By combining analyses in cellular context and at high resolution in vitro, we unraveled that TDP-43 is specifically recruited in FUS assemblies to form TDP-43-rich subcompartments but without reciprocity. The presence of mRNA provides an additional scaffold to promote the mixing between TDP-43 and FUS. Accordingly, we also found that the pathological truncated form of TDP-43, TDP-25, which has an impaired RNA-binding ability, no longer mixes with FUS. Together, these results suggest that the binding of FUS along nascent mRNAs enables TDP-43, which is highly aggregation-prone, to mix with FUS phase to form mRNA-rich subcompartments. A functional link between FUS and TDP-43 may explain their common implication in amyotrophic lateral sclerosis.}, } @article {pmid38309276, year = {2024}, author = {Ku, J and Lee, K and Ku, D and Kim, S and Lee, J and Bang, H and Kim, N and Do, H and Lee, H and Lim, C and Han, J and Lee, YS and Kim, Y}, title = {Alternative polyadenylation determines the functional landscape of inverted Alu repeats.}, journal = {Molecular cell}, volume = {84}, number = {6}, pages = {1062-1077.e9}, doi = {10.1016/j.molcel.2024.01.008}, pmid = {38309276}, issn = {1097-4164}, mesh = {Humans ; Mice ; Animals ; *Tumor Suppressor Protein p53/genetics ; *Polyadenylation ; 3' Untranslated Regions/genetics ; Gene Expression Regulation ; Introns ; }, abstract = {Inverted Alu repeats (IRAlus) are abundantly found in the transcriptome, especially in introns and 3' untranslated regions (UTRs). Yet, the biological significance of IRAlus embedded in 3' UTRs remains largely unknown. Here, we find that 3' UTR IRAlus silences genes involved in essential signaling pathways. We utilize J2 antibody to directly capture and map the double-stranded RNA structure of 3' UTR IRAlus in the transcriptome. Bioinformatic analysis reveals alternative polyadenylation as a major axis of IRAlus-mediated gene regulation. Notably, the expression of mouse double minute 2 (MDM2), an inhibitor of p53, is upregulated by the exclusion of IRAlus during UTR shortening, which is exploited to silence p53 during tumorigenesis. Moreover, the transcriptome-wide UTR lengthening in neural progenitor cells results in the global downregulation of genes associated with neurodegenerative diseases, including amyotrophic lateral sclerosis, via IRAlus inclusion. Our study establishes the functional landscape of 3' UTR IRAlus and its role in human pathophysiology.}, } @article {pmid38308916, year = {2024}, author = {Pietrobon, D and Conti, F}, title = {Astrocytic Na[+], K[+] ATPases in physiology and pathophysiology.}, journal = {Cell calcium}, volume = {118}, number = {}, pages = {102851}, doi = {10.1016/j.ceca.2024.102851}, pmid = {38308916}, issn = {1532-1991}, mesh = {Humans ; Mice ; Animals ; Sodium-Potassium-Exchanging ATPase/genetics/metabolism ; *Migraine with Aura/genetics/metabolism ; Astrocytes/metabolism ; *Alzheimer Disease/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; }, abstract = {The Na[+], K[+] ATPases play a fundamental role in the homeostatic functions of astrocytes. After a brief historic prologue and discussion of the subunit composition and localization of the astrocytic Na[+], K[+] ATPases, the review focuses on the role of the astrocytic Na[+], K[+] pumps in extracellular K[+] and glutamate homeostasis, intracellular Na[+] and Ca[2+] homeostasis and signaling, regulation of synaptic transmission and neurometabolic coupling between astrocytes and neurons. Loss-of-function mutations in the gene encoding the astrocytic α2 Na[+], K[+] ATPase cause a rare monogenic form of migraine with aura (familial hemiplegic migraine type 2). On the other hand, the α2 Na[+], K[+] ATPase is upregulated in spinal cord and brain samples from amyotrophic lateral sclerosis and Alzheimer disease patients, respectively. In the last part, the review focuses on i) the migraine relevant phenotypes shown by familial hemiplegic migraine type 2 knock-in mice with 50 % reduced expression of the astrocytic α2 Na[+], K[+] ATPase and the insights into the pathophysiology of migraine obtained from these genetic mouse models, and ii) the evidence that upregulation of the astrocytic α2 Na[+], K[+] ATPase in mouse models of amyotrophic lateral sclerosis and Alzheimer disease promotes neuroinflammation and contributes to progressive neurodegeneration.}, } @article {pmid38308282, year = {2024}, author = {Cai, R and Yang, J and Wu, L and Liu, Y and Wang, X and Zheng, Q and Li, L}, title = {Accelerating drug development for amyotrophic lateral sclerosis: construction and application of a disease course model using historical placebo group data.}, journal = {Orphanet journal of rare diseases}, volume = {19}, number = {1}, pages = {40}, pmid = {38308282}, issn = {1750-1172}, support = {82174229//the National Natural Science Funds of China/ ; 2022YFC3502000//China national key research and development program/ ; ZY [2021-2023]-0401//Shanghai 3-year Action Plan for Inheritance, Innovation, and Development of traditional Chinese Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Drug Development ; *Riluzole/therapeutic use ; Male ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an irreversible degenerative disease. Placebo-controlled randomized trials are currently the main trial design to assess the clinical efficacy of drugs for ALS treatment. The aim of this study was to establish models to quantitatively describe the course of ALS, explore influencing factors, and provide the necessary information for ALS drug development.

METHODS: We conducted a comprehensive search of PubMed and the Cochrane Library Central Register for placebo-controlled trials that evaluated treatments for ALS. From these trials, we extracted the clinical and demographic characteristics of participants in the placebo group, as well as outcome data, which encompassed overall survival (OS) and Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores, at various time points.

RESULTS: In total, 47 studies involving 6118 participants were included. Disease duration and the proportion of patients receiving riluzole were identified as significant factors influencing OS in the placebo group. Specifically, the median OS was 35.5 months for a disease duration of 9 months, whereas it was 20.0 months for a disease duration of 36 months. Furthermore, for every 10% increase in the proportion of patients treated with riluzole (100 mg daily), there was an association with a median OS extension of approximately 0.4 months. The estimated time for the ALSFRS-R score in the placebo group to decrease to 50% of its maximum effect from baseline level was approximately 17.5 months, and the time to reach a plateau was about 40 months.

CONCLUSIONS: The established disease course model of the historical placebo group is valuable in the decision-making process for the clinical development of ALS drugs. It serves not only as an external control to evaluate the efficacy of the tested drug in single-arm trials but also as prior information that aids in accurately estimating the posterior distribution of the disease course in the placebo group during small-sample clinical trials.}, } @article {pmid38306019, year = {2024}, author = {Kasper, E and Temp, AGM and Köckritz, V and Meier, L and Machts, J and Vielhaber, S and Hermann, A and Prudlo, J}, title = {Verbal expressive language minimally affected in non-demented people living with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {308-316}, doi = {10.1080/21678421.2024.2307512}, pmid = {38306019}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Bayes Theorem ; Dysarthria/etiology ; Language ; *Language Disorders ; *Communication Disorders ; Neuropsychological Tests ; }, abstract = {Objective: Language dysfunction is one of the most common cognitive impairments in amyotrophic lateral sclerosis (ALS). Although discourse capacities are essential for daily functioning, verbal expressive language has not been widely investigated in ALS. The existing research available suggests that discourse impairments are prevalent. This study investigates verbal expressive language in people living with ALS (plwALS) in contrast to healthy controls (HC).Methods: 64 plwALS and 49 age, gender and education-matched healthy controls were ask to describe the Cookie Theft Picture Task. The recordings were analyzed for discourse productivity, discourse content, syntactic complexity, speech fluency and verb processing. We applied the Bayesian hypothesis-testing framework, incorporating the effects of dysarthria, cognitive impairment status (CIS), and premorbid crystalline verbal IQ.Results: Compared to HC, plwALS only showed a single impairment: speech dysfluency. Discourse productivity, discourse content, syntactic complexity and verb processing were not impaired. Cognition and dysarthria exceeded the influence of verbal IQ for total words spoken and content density. Cognition alone seemed to explain dysfluency. Body-agent verbs were produced at even higher rates than other verb types. For the remaining outcomes, verbal IQ was the most decisive factor.Conclusions: In contrast to existing research, our data demonstrates no discernible impairment in verbal expressive language in ALS. What our findings show to be decisive is accounting for the influence of dysarthria, cognitive impairment status, and verbal IQ as variables on spontaneous verbal expressive language. Minor impairments in verbal expressive language appear to be influenced to a greater degree by executive dysfunctioning and dysarthria than by language impairment.}, } @article {pmid38305586, year = {2024}, author = {Raghav, Y and Dilliott, AA and Petrozziello, T and Kim, SE and Berry, JD and Cudkowicz, ME and Vakili, K and , and Fraenkel, E and Farhan, SMK and Sadri-Vakili, G}, title = {Identification of gene fusions associated with amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {69}, number = {4}, pages = {477-489}, doi = {10.1002/mus.28043}, pmid = {38305586}, issn = {1097-4598}, support = {//ALS Finding a Cure/ ; //Active Against ALS/ ; //Answer ALS Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Neurodegenerative Diseases ; Motor Neurons/pathology ; Gene Fusion ; }, abstract = {INTRODUCTION/AIMS: Genetics is an important risk factor for amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. Recent findings demonstrate that in addition to specific genetic mutations, structural variants caused by genetic instability can also play a causative role in ALS. Genomic instability can lead to deletions, duplications, insertions, inversions, and translocations in the genome, and these changes can sometimes lead to fusion of distinct genes into a single transcript. Gene fusion events have been studied extensively in cancer; however, they have not been thoroughly investigated in ALS. The aim of this study was to determine whether gene fusions are present in ALS.

METHODS: Gene fusions were identified using STAR Fusion v1.10.0 software in bulk RNA-Seq data from human postmortem samples from publicly available data sets from Target ALS and the New York Genome Center ALS Consortium.

RESULTS: We report the presence of gene fusion events in several brain regions as well as in spinal cord samples in ALS. Although most gene fusions were intra-chromosomal events between neighboring genes and present in both ALS and control samples, there was a significantly greater number of unique gene fusions in ALS compared to controls. Lastly, we identified specific gene fusions with a significant burden in ALS, that were absent from both control samples and known cancer gene fusion databases.

DISCUSSION: Collectively, our findings reveal an enrichment of gene fusions in ALS and suggest that these events may be an additional genetic cause linked to ALS pathogenesis.}, } @article {pmid38304795, year = {2024}, author = {Matsuura, S and Tatebe, H and Higuchi, M and Tokuda, T}, title = {Validation of a newly developed immunoassay for TDP-43 in human plasma.}, journal = {Heliyon}, volume = {10}, number = {2}, pages = {e24672}, pmid = {38304795}, issn = {2405-8440}, abstract = {The level of TAR DNA-binding protein 43 (TDP-43) in human blood was reported to have potential for use as a specific fluid biomarker, which represents disease-specific pathologies, for TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), which involves the aggregation and deposition of TDP-43 in the nervous system. However, at present, no reliable immunoassay can precisely quantify TDP-43 in human plasma and detect the difference in plasma TDP-43 levels between patients with ALS and controls. We recently developed a novel ultrasensitive immunoassay to quantify TDP-43 in human plasma, and in this study, we analytically validated this assay for application as a diagnostic biomarker for TDP-43 proteinopathies. The novel TDP-43 assay was assessed for the limit of detection, lower limit of quantification, intra- and interassay variation, linearity, parallelism, and analytical spike recoveries. Additionally, 17 pilot plasma samples obtained from patients with ALS and age-matched controls were analyzed using the assay. Our novel TDP-43 assay showed sufficient analytical performance to quantify TDP-43 in human plasma, with high sensitivity (LOD and LLOQ of 0.109 and 0.759 pg/mL, respectively) and high intra- and interassay precision (%CV) below 15 %. The experimental results for spike recovery, parallelism, and dilution linearity were also acceptable. In addition, despite a small sample size, significant differences in the plasma levels of TDP-43 were found between patients with ALS and controls (ALS, 66.63 ± 20.52 pg/mL; control, 42.70 ± 23.06 pg/mL, p = 0.0330). These results support that our novel TDP-43 assay is a reliable and innovative method for the quantification of TDP-43 in human plasma and can be a potential blood-based biomarker for the diagnosis of TDP-43 proteinopathies. Further large-scale studies are warranted to validate its usefulness.}, } @article {pmid38304328, year = {2023}, author = {Phillips, MCL and Johnston, SE and Simpson, P and Chang, DK and Mather, D and Dick, RJ}, title = {Time-restricted ketogenic diet in amyotrophic lateral sclerosis: a case study.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1329541}, pmid = {38304328}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder. The most devastating variant is bulbar-onset ALS, which portends a median survival of 24 months from the onset of symptoms. Abundant evidence indicates that neuron metabolism and mitochondrial function are impaired in ALS. Metabolic strategies, particularly fasting and ketogenic diet protocols, alter neuron metabolism and mitochondria function in a manner that may mitigate the symptoms of this disorder. We report the case of a 64-year-old man with a 21-month history of progressive, deteriorating bulbar-onset ALS, with an associated pseudobulbar affect, who implemented a time-restricted ketogenic diet (TRKD) for 18 months. During this time, he improved in ALS-related function (7% improvement from baseline), forced expiratory volume (17% improvement), forced vital capacity (13% improvement), depression (normalized), stress levels (normalized), and quality of life (19% improvement), particularly fatigue (23% improvement). His swallowing impairment and neurocognitive status remained stable. Declines were measured in physical function, maximal inspiratory pressure, and maximal expiratory pressure. Weight loss was attenuated and no significant adverse effects occurred. This case study represents the first documented occurrence of a patient with ALS managed with either a fasting or ketogenic diet protocol, co-administered as a TRKD. We measured improved or stabilized ALS-related function, forced expiratory volume, forced vital capacity, swallowing, neurocognitive status, mood, and quality of life. Measurable declines were restricted to physical function, maximal inspiratory pressure, and maximal expiratory pressure. Now over 45 months since symptom onset, our patient remains functionally independent and dedicated to his TRKD.}, } @article {pmid38304180, year = {2024}, author = {Kreiml, V and Sauter, A and Abu-Omar, K and Eickmann, S and Herrmann-Johns, A}, title = {"That's like therapy"-A qualitative study on socially disadvantaged women's views on the effects of a community-based participatory research project on their health and health behavior.}, journal = {Frontiers in public health}, volume = {12}, number = {}, pages = {1339556}, pmid = {38304180}, issn = {2296-2565}, mesh = {Humans ; Female ; *Community-Based Participatory Research ; *Health Behavior ; Health Promotion/methods ; Exercise ; Social Support ; }, abstract = {BACKGROUND: Regular physical activity has positive effects on both physical and mental health. Nevertheless, socially disadvantaged women are often insufficiently physically active. Through needs-based physical activity offers, community-based participatory research (CBPR) projects have the potential to reach these women and increase the effectiveness of physical activity interventions by supporting women's empowerment, health, and health behaviors. This study aimed to examine socially disadvantaged women's views on the effects of long-term participation in Bewegung als Investition in Gesundheit (BIG, i.e., movement as an investment in health), a long-standing German CBPR project, on their health and health behavior.

METHODS: Semi-structured qualitative interviews were conducted with 30 participating women at five BIG sites across Germany between April and August 2022. The interviews were recorded, transcribed verbatim, and analyzed using framework analysis.

RESULTS: Women reported that participation in BIG classes contributed to their physical, mental, and social health. For many women, the positive effects on their mental and social wellbeing were most important. In addition to increased fitness and improved physical endurance, many participating women were able to expand their social networks, thus receiving further social support, and improve their self-esteem, self-confidence, and self-efficacy. Furthermore, participation in BIG physical activity classes positively influenced the health awareness of many women helping them to improve their activity level and diet over time.

CONCLUSION: Our results suggest that CBPR projects, such as the BIG project, can increase physical activity among socially disadvantaged groups and contribute to their overall health and wellbeing. CBPR projects could thus be considered a key element of health promotion for this target group. Future interventional research is required to confirm and further explore the effects of CBPR interventions and to examine whether the effects can be replicated in other settings.}, } @article {pmid38302810, year = {2024}, author = {Teixeira, LCR and Mamede, I and Luizon, MR and Gomes, KB}, title = {Role of long non-coding RNAs in the pathophysiology of Alzheimer's disease and other dementias.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {270}, pmid = {38302810}, issn = {1573-4978}, mesh = {Humans ; *Alzheimer Disease/genetics ; *RNA, Long Noncoding/genetics ; Amyloid beta-Peptides ; *Frontotemporal Dementia ; }, abstract = {Dementia is the term used to describe a group of cognitive disorders characterized by a decline in memory, thinking, and reasoning abilities that interfere with daily life activities. Examples of dementia include Alzheimer's Disease (AD), Frontotemporal dementia (FTD), Amyotrophic lateral sclerosis (ALS), Vascular dementia (VaD) and Progressive supranuclear palsy (PSP). AD is the most common form of dementia. The hallmark pathology of AD includes formation of β-amyloid (Aβ) oligomers and tau hyperphosphorylation in the brain, which induces neuroinflammation, oxidative stress, synaptic dysfunction, and neuronal apoptosis. Emerging studies have associated long non-coding RNAs (lncRNAs) with the pathogenesis and progression of the neurodegenerative diseases. LncRNAs are defined as RNAs longer than 200 nucleotides that lack the ability to encode functional proteins. LncRNAs play crucial roles in numerous biological functions for their ability to interact with different molecules, such as proteins and microRNAs, and subsequently regulate the expression of their target genes at transcriptional and post-transcriptional levels. In this narrative review, we report the function and mechanisms of action of lncRNAs found to be deregulated in different types of dementia, with the focus on AD. Finally, we discuss the emerging role of lncRNAs as biomarkers of dementias.}, } @article {pmid38302474, year = {2024}, author = {Fernández-Beltrán, LC and Ali, Z and Larrad-Sanz, A and Lopez-Carbonero, JI and Godoy-Corchuelo, JM and Jimenez-Coca, I and Garcia-Toledo, I and Bentley, L and Gomez-Pinedo, U and Matias-Guiu, JA and Gil-Moreno, MJ and Matias-Guiu, J and Corrochano, S}, title = {Leptin haploinsufficiency exerts sex-dependent partial protection in SOD1[G93A] mice by reducing inflammatory pathways in the adipose tissue.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {2671}, pmid = {38302474}, issn = {2045-2322}, support = {2018-T1/BMD-10731//Consejeria de Educacion, Ciencia y Universidades de la Comunidad de Madrid/ ; 2018-T1/BMD-10731//Consejeria de Educacion, Ciencia y Universidades de la Comunidad de Madrid/ ; INT20/00079//European Regional Development/ ; }, mesh = {Animals ; Female ; Humans ; Male ; Mice ; Adipose Tissue/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Disease Models, Animal ; Haploinsufficiency ; Leptin/metabolism ; Mice, Transgenic ; Spinal Cord/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by significant metabolic disruptions, including weight loss and hypermetabolism in both patients and animal models. Leptin, an adipose-derived hormone, displays altered levels in ALS. Genetically reducing leptin levels (Lepob/+) to maintain body weight improved motor performance and extended survival in female SOD1G93A mice, although the exact molecular mechanisms behind these effects remain elusive. Here, we corroborated the sexual dimorphism in circulating leptin levels in ALS patients and in SOD1G93A mice. We reproduced a previous strategy to generate a genetically deficient leptin SOD1G93A mice (SOD1G93ALepob/+) and studied the transcriptomic profile in the subcutaneous adipose tissue and the spinal cord. We found that leptin deficiency reduced the inflammation pathways activated by the SOD1G93A mutation in the adipose tissue, but not in the spinal cord. These findings emphasize the importance of considering sex-specific approaches in metabolic therapies and highlight the role of leptin in the systemic modulation of ALS by regulating immune responses outside the central nervous system.}, } @article {pmid38302116, year = {2024}, author = {Ikeda, T and Yamazaki, K and Okumura, F and Kamura, T and Nakatsukasa, K}, title = {Role of the San1 ubiquitin ligase in the heat stress-induced degradation of nonnative Nup1 in the nuclear pore complex.}, journal = {Genetics}, volume = {226}, number = {4}, pages = {}, doi = {10.1093/genetics/iyae017}, pmid = {38302116}, issn = {1943-2631}, support = {//Toray Science Foundation/ ; //Toyoaki Scholarship Foundation/ ; 15K18503//JSPS KAKENHI/ ; //Institute for Fermentation, Osaka/ ; //Hori Science and Arts Foundation/ ; }, mesh = {Nuclear Pore/genetics/chemistry/metabolism ; Nuclear Pore Complex Proteins/genetics/metabolism ; *Proteasome Endopeptidase Complex/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; Ubiquitin/analysis/genetics/metabolism ; Ubiquitin-Protein Ligases/genetics/metabolism ; }, abstract = {The nuclear pore complex (NPC) mediates the selective exchange of macromolecules between the nucleus and the cytoplasm. Neurodegenerative diseases such as amyotrophic lateral sclerosis are characterized by mislocalization of nucleoporins (Nups), transport receptors, and Ras-related nuclear proteins into nucleoplasmic or cytosolic aggregates, underscoring the importance of precise assembly of the NPC. The assembly state of large protein complexes is strictly monitored by the protein quality control system. The ubiquitin-proteasome system may eliminate aberrant, misfolded, and/or orphan components; however, the involvement of the ubiquitin-proteasome system in the degradation of nonnative Nups in the NPC remains unclear. Here, we show that in Saccharomyces cerevisiae, although Nup1 (the FG-Nup component of the central core of the NPC) was stable, C-terminally green fluorescent protein-tagged Nup1, which had been incorporated into the NPC, was degraded by the proteasome especially under heat stress conditions. The degradation was dependent on the San1 ubiquitin ligase and Cdc48/p97, as well as its cofactor Doa1. We also demonstrate that San1 weakly but certainly contributes to the degradation of nontagged endogenous Nup1 in cells defective in NPC biogenesis by the deletion of NUP120. In addition, the overexpression of SAN1 exacerbated the growth defect phenotype of nup120Δ cells, which may be caused by excess degradation of defective Nups due to the deletion of NUP120. These biochemical and genetic data suggest that San1 is involved in the degradation of nonnative Nups generated by genetic mutation or when NPC biogenesis is impaired.}, } @article {pmid38301895, year = {2024}, author = {Gotoh, S and Mori, K and Fujino, Y and Kawabe, Y and Yamashita, T and Omi, T and Nagata, K and Tagami, S and Nagai, Y and Ikeda, M}, title = {eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {3}, pages = {105703}, pmid = {38301895}, issn = {1083-351X}, support = {P40 OD018537/OD/NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology ; *C9orf72 Protein/genetics ; Dipeptides/genetics ; *DNA Repeat Expansion/genetics ; Drosophila/genetics/metabolism ; *Eukaryotic Initiation Factor-5/genetics/metabolism ; *Frontotemporal Lobar Degeneration/genetics/physiopathology ; HeLa Cells ; Humans ; Disease Models, Animal ; }, abstract = {Tandem GGGGCC repeat expansion in C9orf72 is a genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeats are translated into dipeptide repeat proteins via repeat-associated non-AUG (RAN) translation. However, the regulatory mechanism of RAN translation remains unclear. Here, we reveal a GTPase-activating protein, eukaryotic initiation factor 5 (eIF5), which allosterically facilitates the conversion of eIF2-bound GTP into GDP upon start codon recognition, as a novel modifier of C9orf72 RAN translation. Compared to global translation, eIF5, but not its inactive mutants, preferentially stimulates poly-GA RAN translation. RAN translation is increased during integrated stress response, but the stimulatory effect of eIF5 on poly-GA RAN translation was additive to the increase of RAN translation during integrated stress response, with no further increase in phosphorylated eIF2α. Moreover, an alteration of the CUG near cognate codon to CCG or AUG in the poly-GA reading frame abolished the stimulatory effects, indicating that eIF5 primarily acts through the CUG-dependent initiation. Lastly, in a Drosophila model of C9orf72 FTLD/ALS that expresses GGGGCC repeats in the eye, knockdown of endogenous eIF5 by two independent RNAi strains significantly reduced poly-GA expressions, confirming in vivo effect of eIF5 on poly-GA RAN translation. Together, eIF5 stimulates the CUG initiation of poly-GA RAN translation in cellular and Drosophila disease models of C9orf72 FTLD/ALS.}, } @article {pmid38301596, year = {2024}, author = {Wang, H and Liu, YT and Ren, YL and Guo, XY and Wang, Y}, title = {Association of peripheral immune activation with amyotrophic lateral sclerosis and Parkinson's disease: A systematic review and meta-analysis.}, journal = {Journal of neuroimmunology}, volume = {388}, number = {}, pages = {578290}, doi = {10.1016/j.jneuroim.2024.578290}, pmid = {38301596}, issn = {1872-8421}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology ; Biomarkers ; *Neurodegenerative Diseases/immunology ; *Parkinson Disease/immunology ; }, abstract = {BACKGROUND: Recent studies have revealed the link between immune activation and neurodegenerative diseases.

METHODS: By employing meta-analysis, we estimated the standardized mean difference (SMD) and their corresponding 95% confidence intervals (CIs) between the groups.

RESULTS: According to the pre-set criteria, a total of 21 published articles including 2377 ALS patients and 1244 HCs, as well as 60 articles including 5111 PD patients and 4237 HCs, were identified. This study provided evidence of peripheral immune activation in the pathogenesis of ALS and PD.

CONCLUSION: Our results suggested monitoring changes in peripheral blood immune cell populations, particularly lymphocyte subsets, will benefit understanding the developments and exploring reliable and specific biomarkers of these two diseases.}, } @article {pmid38300375, year = {2024}, author = {Sarkar, S and Patranabis, S}, title = {Emerging Role of Extracellular Vesicles in Intercellular Communication in the Brain: Implications for Neurodegenerative Diseases and Therapeutics.}, journal = {Cell biochemistry and biophysics}, volume = {82}, number = {2}, pages = {379-398}, pmid = {38300375}, issn = {1559-0283}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; *Cell Communication ; *Brain/metabolism/pathology ; Animals ; }, abstract = {Extracellular vesicles (EVs) are minute lipid-bilayer sacs discharged by cells, encompassing a diverse array of proteins, nucleic acids, and lipids. The identification of EVs as pivotal agents in intercellular communication has sparked compelling research pathways in the realms of cell biology and neurodegenerative diseases. Utilizing EVs for medicinal reasons has garnered interest due to the adaptability of EV-mediated communication. EVs can be classified based on their physical characteristics, biochemical composition, or cell of origin following purification. This review delves into the primary sub-types of EVs, providing an overview of the biogenesis of each type. Additionally, it explores the diverse environmental conditions triggering EV release and the originating cells, including stem cells and those from the Central Nervous System. Within the brain, EVs play a pivotal role as essential mediators of intercellular communication, significantly impacting synaptic plasticity, brain development, and the etiology of neurological diseases. Their potential diagnostic and therapeutic applications in various brain-related conditions are underscored, given their ability to carry specific cargo. Specially engineered EVs hold promise for treating diverse diseases, including neurodegenerative disorders. This study primarily emphasizes the diagnostic and potential therapeutic uses of EVs in neurological disorders such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Prions disease. It also summarizes innovative techniques for detecting EVs in the brain, suggesting that EVs could serve as non-invasive biomarkers for early detection, disease monitoring, and prognosis in neurological disorders.}, } @article {pmid38299458, year = {2024}, author = {Villarruel, FD and Denofrio, MP and de León, TS and Erra-Balsells, R and Wolcan, E and García Einschlag, FS and Cabrerizo, FM}, title = {Exploring potooxidative degradation pathways of harmol and harmalol alkaloids in water: effects of pH, excitation sources and atmospheric conditions.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {26}, number = {7}, pages = {6068-6079}, doi = {10.1039/d3cp05223k}, pmid = {38299458}, issn = {1463-9084}, mesh = {*Water ; *Alkaloids ; Indoles ; Hydrogen-Ion Concentration ; Harmaline/*analogs & derivatives ; Harmine/*analogs & derivatives ; }, abstract = {This work explores the photochemical degradation of cationic species of 7-hydroxy-1-methyl-2H-pyrido[3,4-b]indole or harmol (1C) and the corresponding partially hydrogenated derivative 7-hydroxy-1-methyl-3,4-dihydro-2H-pyrido[3,4-b]indole or harmalol (2C) in aqueous solution. UV-visible absorption and fluorescence emission spectroscopy coupled with multivariate data analysis (MCR-ALS and PARAFAC), HPLC and HRESI-MS techniques were used for both quantitative and qualitative analysis. The formation of hydrogen peroxide reactive oxygen species (ROS) was quantified, and the influence of pH, oxygen partial pressure and photoexcitation source on the photochemical degradation of both compounds was assessed. The potential implications on the biosynthesis of βCs and their biological role in living systems are discussed.}, } @article {pmid38297405, year = {2024}, author = {Larson, KC and Martens, LH and Marconi, M and Dejesus, C and Bruhn, S and Miller, TA and Tate, B and Levenson, JM}, title = {Preclinical translational platform of neuroinflammatory disease biology relevant to neurodegenerative disease.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {37}, pmid = {38297405}, issn = {1742-2094}, mesh = {Humans ; Mice ; Animals ; *Neurodegenerative Diseases/metabolism ; Neuroinflammatory Diseases ; Microglia/metabolism ; Inflammasomes/metabolism ; Biology ; }, abstract = {Neuroinflammation is a key driver of neurodegenerative disease, however the tools available to model this disease biology at the systems level are lacking. We describe a translational drug discovery platform based on organotypic culture of murine cortical brain slices that recapitulate disease-relevant neuroinflammatory biology. After an acute injury response, the brain slices assume a chronic neuroinflammatory state marked by transcriptomic profiles indicative of activation of microglia and astrocytes and loss of neuronal function. Microglia are necessary for manifestation of this neuroinflammation, as depletion of microglia prior to isolation of the brain slices prevents both activation of astrocytes and robust loss of synaptic function genes. The transcriptomic pattern of neuroinflammation in the mouse platform is present in published datasets derived from patients with amyotrophic lateral sclerosis, Huntington's disease, and frontotemporal dementia. Pharmacological utility of the platform was validated by demonstrating reversal of microglial activation and the overall transcriptomic signature with transforming growth factor-β. Additional anti-inflammatory targets were screened and inhibitors of glucocorticoid receptors, COX-2, dihydrofolate reductase, and NLRP3 inflammasome all failed to reverse the neuroinflammatory signature. Bioinformatics analysis of the neuroinflammatory signature identified protein tyrosine phosphatase non-receptor type 11 (PTPN11/SHP2) as a potential target. Three structurally distinct inhibitors of PTPN11 (RMC-4550, TN0155, IACS-13909) reversed the neuroinflammatory disease signature. Collectively, these results highlight the utility of this novel neuroinflammatory platform for facilitating identification and validation of targets for neuroinflammatory neurodegenerative disease drug discovery.}, } @article {pmid38297144, year = {2024}, author = {Sun, K and Ray, S and Gupta, N and Aldworth, Z and Stopfer, M}, title = {Olfactory system structure and function in newly hatched and adult locusts.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {2608}, pmid = {38297144}, issn = {2045-2322}, support = {Intramural Grant//National Institute of Child Health and Human Development/ ; }, mesh = {Animals ; *Grasshoppers ; Odorants ; Olfactory Pathways/physiology ; *Olfactory Receptor Neurons/physiology ; Interneurons ; Smell/physiology ; }, abstract = {An important question in neuroscience is how sensory systems change as animals grow and interact with the environment. Exploring sensory systems in animals as they develop can reveal how networks of neurons process information as the neurons themselves grow and the needs of the animal change. Here we compared the structure and function of peripheral parts of the olfactory pathway in newly hatched and adult locusts. We found that populations of olfactory sensory neurons (OSNs) in hatchlings and adults responded with similar tunings to a panel of odors. The morphologies of local neurons (LNs) and projection neurons (PNs) in the antennal lobes (ALs) were very similar in both age groups, though they were smaller in hatchlings, they were proportional to overall brain size. The odor evoked responses of LNs and PNs were also very similar in both age groups, characterized by complex patterns of activity including oscillatory synchronization. Notably, in hatchlings, spontaneous and odor-evoked firing rates of PNs were lower, and LFP oscillations were lower in frequency, than in the adult. Hatchlings have smaller antennae with fewer OSNs; removing antennal segments from adults also reduced LFP oscillation frequency. Thus, consistent with earlier computational models, the developmental increase in frequency is due to increasing intensity of input to the oscillation circuitry. Overall, our results show that locusts hatch with a fully formed olfactory system that structurally and functionally matches that of the adult, despite its small size and lack of prior experience with olfactory stimuli.}, } @article {pmid38296522, year = {2025}, author = {Kamiya, K and Hanashiro, S and Kano, O and Uchida, W and Kamagata, K and Aoki, S and Hori, M}, title = {Surface-based Analyses of Diffusional Kurtosis Imaging in Amyotrophic Lateral Sclerosis: Relationship with Onset Subtypes.}, journal = {Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine}, volume = {24}, number = {1}, pages = {122-132}, pmid = {38296522}, issn = {1880-2206}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; Aged ; *Diffusion Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/pathology ; Anisotropy ; Adult ; Image Processing, Computer-Assisted/methods ; Diffusion Tensor Imaging/methods ; }, abstract = {PURPOSE: Here, we aimed to characterize the cortical and subcortical microstructural alterations in the brains of patients with amyotrophic lateral sclerosis (ALS). In particular, we compared these features between bulbar-onset ALS (b-ALS) and limb-onset ALS (l-ALS).

METHODS: Diffusion MRI data (b = 0, 700, 2000 ms/mm[2], 1.7-mm isotropic voxel) from 28 patients with ALS (9 b-ALS and 19 l-ALS) and 17 healthy control subjects (HCs) were analyzed. Diffusional kurtosis imaging (DKI) metrics were sampled at the mid-cortical and subcortical surfaces. We used permutation testing with a nonparametric combination of mean diffusivity (MD), fractional anisotropy (FA), and mean kurtosis (MK) to assess intergroup differences over the cerebrum. We also carried out an atlas-based analysis focusing on Brodmann Area 4 and 6 (primary motor and premotor areas) and investigated the correlation between MRI metrics and clinical parameters.

RESULTS: At both the mid-cortical and subcortical surfaces, b-ALS was associated with significantly greater MD, smaller FA, and smaller MK in the motor and premotor areas than HC. In contrast, the patients with l-ALS showed relatively moderate differences relative to HCs. The ALS Functional Rating Scale-Revised bulbar subscore was significantly correlated with the diffusion metrics in Brodmann Area 4.

CONCLUSION: The distribution of abnormalities over the cerebral hemispheres and the more severe microstructural alteration in b-ALS compared to l-ALS were in good agreement with findings from postmortem histology. Our results suggest the feasibility of surface-based DKI analyses for exploring brain microstructural pathologies in ALS. The observed differences between b-ALS and l-ALS and their correlations with functional bulbar impairment support the clinical relevance of DKI measurement in the cortical and juxtacortical regions of patients with ALS.}, } @article {pmid38295187, year = {2024}, author = {Limone, F and Couto, A and Wang, JY and Zhang, Y and McCourt, B and Huang, C and Minkin, A and Jani, M and McNeer, S and Keaney, J and Gillet, G and Gonzalez, RL and Goodman, WA and Kadiu, I and Eggan, K and Burberry, A}, title = {Myeloid and lymphoid expression of C9orf72 regulates IL-17A signaling in mice.}, journal = {Science translational medicine}, volume = {16}, number = {732}, pages = {eadg7895}, pmid = {38295187}, issn = {1946-6242}, support = {R01 NS089742/NS/NINDS NIH HHS/United States ; R01 DK128143/DK/NIDDK NIH HHS/United States ; S10 OD021559/OD/NIH HHS/United States ; R01 AG085316/AG/NIA NIH HHS/United States ; R00 AG057808/AG/NIA NIH HHS/United States ; R35 NS097303/NS/NINDS NIH HHS/United States ; K99 AG057808/AG/NIA NIH HHS/United States ; R03 AG080175/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *C9orf72 Protein/genetics ; Endothelial Cells/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Interleukin-17 ; Neuroinflammatory Diseases ; }, abstract = {A mutation in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Patients with ALS or FTD often develop autoimmunity and inflammation that precedes or coincides with the onset of neurological symptoms, but the underlying mechanisms are poorly understood. Here, we knocked out murine C9orf72 in seven hematopoietic progenitor compartments by conditional mutagenesis and found that myeloid lineage C9orf72 prevents splenomegaly, loss of tolerance, and premature mortality. Furthermore, we demonstrated that C9orf72 plays a role in lymphoid cells to prevent interleukin-17A (IL-17A) production and neutrophilia. Mass cytometry identified early and sustained elevation of the costimulatory molecule CD80 expressed on C9orf72-deficient mouse macrophages, monocytes, and microglia. Enrichment of CD80 was similarly observed in human spinal cord microglia from patients with C9ORF72-mediated ALS compared with non-ALS controls. Single-cell RNA sequencing of murine spinal cord, brain cortex, and spleen demonstrated coordinated induction of gene modules related to antigen processing and presentation and antiviral immunity in C9orf72-deficient endothelial cells, microglia, and macrophages. Mechanistically, C9ORF72 repressed the trafficking of CD80 to the cell surface in response to Toll-like receptor agonists, interferon-γ, and IL-17A. Deletion of Il17a in C9orf72-deficient mice prevented CD80 enrichment in the spinal cord, reduced neutrophilia, and reduced gut T helper type 17 cells. Last, systemic delivery of an IL-17A neutralizing antibody augmented motor performance and suppressed neuroinflammation in C9orf72-deficient mice. Altogether, we show that C9orf72 orchestrates myeloid costimulatory potency and provide support for IL-17A as a therapeutic target for neuroinflammation associated with ALS or FTD.}, } @article {pmid38294285, year = {2024}, author = {Castro-Rodriguez, E and Azagra-Ledesma, R and Gómez-Batiste, X and Aguyé-Batista, A and Clemente-Azagra, C and Díaz-Herrera, MA}, title = {Complexity of needs in amyotrophic lateral sclerosis (ALS) patients using the ENP-E scale in the north-eastern region of Spain.}, journal = {Palliative & supportive care}, volume = {22}, number = {3}, pages = {460-469}, doi = {10.1017/S1478951523001773}, pmid = {38294285}, issn = {1478-9523}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy/complications ; Male ; Spain ; Female ; Aged ; Middle Aged ; Longitudinal Studies ; Palliative Care/methods/statistics & numerical data/standards/psychology ; Needs Assessment/statistics & numerical data ; Aged, 80 and over ; Surveys and Questionnaires ; Terminal Care/methods/psychology/statistics & numerical data/standards ; }, abstract = {OBJECTIVES: This study aimed to explore the clinical characteristics of amyotrophic lateral sclerosis (ALS) patients in Spain's north-eastern region, their inclusion in chronic care programmes, and their psychosocial and spiritual needs (PSNs).

METHODS: A longitudinal descriptive study in adult patients with ALS. We analyzed clinical variables and participation in chronicity and PSNs assessment using the tool Psychosocial and Spiritual Needs Evaluation scale in end-of-life patients (ENP-E scale).

RESULTS: 81 patients (average age 65.6 ± 11.7) were studied. At the study's outset, 29.7% employed non-invasive ventilation (NIV), increasing to 51.9% by its conclusion. Initial percutaneous endoscopic gastrostomy (PEG) utilization was 14.8%, rising to 35.85%. Chronic care programme participation was as follows: home care (24.7% initially, 50.6% end), palliative care (16% initially, 40.7% end), case management (13.6% initially, 50.6% end), and advance care planning registration (6.2% initially, 35.8% end). At study start, 47.8% of patients (n = 46) showed moderate-to-severe complexity in PSNs assessment using the ENP-E scale, without showing differences in age, sex, and time of evolution; whereas, on the evolutionary analysis, it was 75% (n = 24). A higher evolutionary complexity was observed in males <60 and >70 years, with no PEG and evolution of ALS of <2 and ≥5 years, and not included in chronicity programmes. When assessing concerns, physical pain and family aspects stand out in all measurements. Forty-eight percent of patients at study start and 71% at end of study showed external signs of emotional distress.

SIGNIFICANCE OF RESULTS: Most ALS patients showed a high degree of complexity and were not integrated in chronicity programmes. A "care path" is proposed to integrate ALS patients in these programmes and systematically assess their needs.}, } @article {pmid38293807, year = {2024}, author = {Tang, D and Bao, H and Qi, S}, title = {The C9orf72-SMCR8 complex suppresses primary ciliogenesis as a RAB8A GAP.}, journal = {Autophagy}, volume = {20}, number = {5}, pages = {1205-1207}, pmid = {38293807}, issn = {1554-8635}, mesh = {*rab GTP-Binding Proteins/metabolism/genetics ; *Cilia/metabolism ; Humans ; *C9orf72 Protein/genetics/metabolism ; *Autophagy/genetics ; Animals ; Signal Transduction ; Hedgehog Proteins/metabolism ; HEK293 Cells ; GTPase-Activating Proteins/metabolism/genetics ; Protein Binding ; Mice ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Carrier Proteins ; }, abstract = {Approximately half of the familial cases of amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD) are attributed to the abnormal GGGGCC repeat expansion within the first intron of C9orf72, potentializing C9orf72 and its product as the most promising target for ALS therapeutics. Nevertheless, the biological function of C9orf72 remains unclear. Previously, we reported that C9orf72 and its binding partner, SMCR8, form a GTPase-activating protein (GAP) complex, which is proposed to regulate membrane trafficking and autophagy. Hereby, we found that the C9orf72-SMCR8 complex negatively regulates primary ciliogenesis and hedgehog (HH) signaling. Furthermore, the biochemical analysis and cell biology experiments identified C9orf72 as the RAB8A binding subunit and SMCR8 as the GAP subunit within the complex. Further, we discussed the relationship among the C9orf72-SMCR8 complex, primary ciliogenesis, and autophagy.}, } @article {pmid38293619, year = {2023}, author = {Lu, B and Meng, R and Wang, Y and Xiong, W and Ma, Y and Gao, P and Ren, J and Zhang, L and Zhao, Z and Fan, G and Wen, Y and Yuan, X}, title = {Distinctive physiological and molecular responses of foxtail millet and maize to nicosulfuron.}, journal = {Frontiers in plant science}, volume = {14}, number = {}, pages = {1308584}, pmid = {38293619}, issn = {1664-462X}, abstract = {INTRODUCTION: Nicosulfuron is the leading acetolactate synthase inhibitor herbicide product, and widely used to control gramineous weeds. Here, we investigated the metabolic process of nicosulfuron into foxtail millet and maize, in order to clarify the mechanism of the difference in sensitivity of foxtail millet and maize to nicosulfuron from the perspective of physiological metabolism and provide a theoretical basis for the breeding of nicosulfuron-resistant foxtail millet varieties.

METHODS: We treated foxtail millet (Zhangzagu 10, Jingu 21) and maize (Nongda 108, Ditian 8) with various doses of nicosulfuron in both pot and field experiments. The malonaldehyde (MDA) content, target enzymes, detoxification enzymes, and antioxidant enzymes, as well as related gene expression levels in the leaf tissues of foxtail millet and maize were measured, and the yield was determined after maturity.

RESULTS: The results showed that the recommended dose of nicosulfuron caused Zhangzagu 10 and Jingu 21 to fail to harvest; the yield of the sensitive maize variety (Ditian 8) decreased by 37.09%, whereas that of the resistant maize variety (Nongda 108) did not decrease. Nicosulfuron stress increased the CYP450 enzyme activity, MDA content, and antioxidant enzyme activity of foxtail millet and maize, reduced the acetolactate synthase (ALS) activity and ALS gene expression of foxtail millet and Ditian 8, and reduced the glutathione S-transferase (GST) activity and GST gene expression of foxtail millet. In conclusion, target enzymes, detoxification enzymes, and antioxidant enzymes were involved in the detoxification metabolism of nicosulfuron in plants. ALS and GST are the main factors responsible for the metabolic differences among foxtail millet, sensitive maize varieties, and resistant maize varieties.

DISCUSSION: These findings offer valuable insights for exploring the target resistance (TSR) and non-target resistance (NTSR) mechanisms in foxtail millet under herbicide stress and provides theoretical basis for future research of develop foxtail millet germplasm with diverse herbicide resistance traits.}, } @article {pmid38292603, year = {2024}, author = {Weerawarna, PM and Schiefer, IT and Soares, P and Fox, S and Morimoto, RI and Melani, RD and Kelleher, NL and Luan, CH and Silverman, RB}, title = {Target Identification of a Class of Pyrazolone Protein Aggregation Inhibitor Therapeutics for Amyotrophic Lateral Sclerosis.}, journal = {ACS central science}, volume = {10}, number = {1}, pages = {87-103}, pmid = {38292603}, issn = {2374-7943}, support = {P41 GM108569/GM/NIGMS NIH HHS/United States ; R01 AG061708/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure, and current treatment options are very limited. Previously, we performed a high-throughput screen to identify small molecules that inhibit protein aggregation caused by a mutation in the gene that encodes superoxide dismutase 1 (SOD1), which is responsible for about 25% of familial ALS. This resulted in three hit series of compounds that were optimized over several years to give three compounds that were highly active in a mutant SOD1 ALS model. Here we identify the target of two of the active compounds (6 and 7) with the use of photoaffinity labeling, chemical biology reporters, affinity purification, proteomic analysis, and fluorescent/cellular thermal shift assays. Evidence is provided to demonstrate that these two pyrazolone compounds directly interact with 14-3-3-E and 14-3-3-Q isoforms, which have chaperone activity and are known to interact with mutant SOD1[G93A] aggregates and become insoluble in the subcellular JUNQ compartment, leading to apoptosis. Because protein aggregation is the hallmark of all neurodegenerative diseases, knowledge of the target compounds that inhibit protein aggregation allows for the design of more effective molecules for the treatment of ALS and possibly other neurodegenerative diseases.}, } @article {pmid38292023, year = {2023}, author = {Ratano, P and Cocozza, G and Pinchera, C and Busdraghi, LM and Cantando, I and Martinello, K and Scioli, M and Rosito, M and Bezzi, P and Fucile, S and Wulff, H and Limatola, C and D'Alessandro, G}, title = {Reduction of inflammation and mitochondrial degeneration in mutant SOD1 mice through inhibition of voltage-gated potassium channel Kv1.3.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1333745}, pmid = {38292023}, issn = {1662-5099}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no effective therapy, causing progressive loss of motor neurons in the spinal cord, brainstem, and motor cortex. Regardless of its genetic or sporadic origin, there is currently no cure for ALS or therapy that can reverse or control its progression. In the present study, taking advantage of a human superoxide dismutase-1 mutant (hSOD1-G93A) mouse that recapitulates key pathological features of human ALS, we investigated the possible role of voltage-gated potassium channel Kv1.3 in disease progression. We found that chronic administration of the brain-penetrant Kv1.3 inhibitor, PAP-1 (40 mg/Kg), in early symptomatic mice (i) improves motor deficits and prolongs survival of diseased mice (ii) reduces astrocyte reactivity, microglial Kv1.3 expression, and serum pro-inflammatory soluble factors (iii) improves structural mitochondrial deficits in motor neuron mitochondria (iv) restores mitochondrial respiratory dysfunction. Taken together, these findings underscore the potential significance of Kv1.3 activity as a contributing factor to the metabolic disturbances observed in ALS. Consequently, targeting Kv1.3 presents a promising avenue for modulating disease progression, shedding new light on potential therapeutic strategies for ALS.}, } @article {pmid38291418, year = {2024}, author = {Cai, Y and Peng, Z and He, Q and Sun, P}, title = {Behavioral variant frontotemporal dementia associated with GRN and ErbB4 gene mutations: a case report and literature review.}, journal = {BMC medical genomics}, volume = {17}, number = {1}, pages = {43}, pmid = {38291418}, issn = {1755-8794}, mesh = {Male ; Humans ; Middle Aged ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Positron Emission Tomography Computed Tomography ; Progranulins/genetics ; Mutation ; }, abstract = {OBJECTIVE: To report the clinical manifestation and genetic characteristics of a patient having frontotemporal dementia (FTD) with abnormal behavior and unstable walking.

METHODS: The clinical and imaging features of a patient who was eventually diagnosed with FTD were analyzed. The patient's neuropsychological, PET-CT, electromyography, and genetic data were collected. Furthermore, the patient's blood samples were examined for FTD-related genes.

RESULTS: The patient was a 52-year-old man with hidden onset. The symptoms progressed gradually, presenting with abnormal behaviors, including repeated shopping, taking away other people's things, constantly eating snacks, and frequently calling friends at night. The patient also exhibited executive dysfunction, such as the inability to cook and multiple driving problems, e.g., constantly deviates from his lane while driving. In addition, the patient showed personality changes such as irritability, indifference, and withdrawal, as well as motor symptoms, including unstable walking and frequent falls when walking. Brain magnetic resonance imaging revealed hippocampal sclerosis along with widening and deepening of the bilateral temporal lobe sulcus. Brain metabolic imaging via PET-CT demonstrated decreased metabolism in the bilateral prefrontal lobe, with the abnormal energy metabolism indicating FTD. Lastly, blood sample analysis detected mutations in the amyotrophic lateral sclerosis (ALS)-related GRN gene c.1352C > T (p.P451L) and ErbB4 gene c.256 T > C (p.Y86H).

CONCLUSION: This is the first case of heterozygous mutations in the GRN and ErbB4 genes in FTD alone. The GRN and ErbB4 genes are likely to be important in the pathogenesis of FTD, expanding the common genetic profile of ALS and FTD.}, } @article {pmid38290651, year = {2024}, author = {Lõhelaid, H and Saarma, M and Airavaara, M}, title = {CDNF and ER stress: Pharmacology and therapeutic possibilities.}, journal = {Pharmacology & therapeutics}, volume = {254}, number = {}, pages = {108594}, doi = {10.1016/j.pharmthera.2024.108594}, pmid = {38290651}, issn = {1879-016X}, mesh = {Animals ; Humans ; *Parkinson Disease/drug therapy ; Nerve Growth Factors/therapeutic use/metabolism ; Recombinant Proteins/therapeutic use ; }, abstract = {Cerebral dopamine neurotrophic factor (CDNF) is an endogenous protein in humans and other vertebrates, and it has been shown to have protective and restorative effects on cells in various disease models. Although it is named as a neurotrophic factor, its actions are drastically different from classical neurotrophic factors such as neurotrophins or the glial cell line-derived neurotrophic family of proteins. Like all secreted proteins, CDNF has a signal sequence at the N-terminus, but unlike common growth factors it has a KDEL-receptor retrieval sequence at the C-terminus. Thus, CDNF is mainly located in the ER. In response to adverse effects, such as ER stress, the expression of CDNF is upregulated and can alleviate ER stress. Also different from other neurotrophic factors, CDNF reduces protein aggregation and inflammation in disease models. Although it is an ER luminal protein, it can surprisingly directly interact with alpha-synuclein, a protein involved in the pathogenesis of synucleinopathies e.g., Parkinson's disease. Pleiotropic CDNF has therapeutic potential and has been tested as a recombinant human protein and gene therapy. The neuroprotective and neurorestorative effects have been described in a number of preclinical studies of Parkinson's disease, stroke and amyotrophic lateral sclerosis. Currently, it was successfully evaluated for safety in a phase 1/2 clinical trial for Parkinson's disease. Collectively, based on recent findings on the mode of action and therapeutic potential of CDNF, its use as a drug could be expanded to other ER stress-related diseases.}, } @article {pmid38290377, year = {2024}, author = {Takeda, T and Koreki, A and Kokubun, S and Saito, Y and Ishikawa, A and Isose, S and Ito, K and Arai, K and Kitagawa, K and Kuwabara, S and Honda, K}, title = {Deep vein thrombosis and its risk factors in neurodegenerative diseases: A markedly higher incidence in Parkinson's disease.}, journal = {Journal of the neurological sciences}, volume = {457}, number = {}, pages = {122896}, doi = {10.1016/j.jns.2024.122896}, pmid = {38290377}, issn = {1878-5883}, mesh = {Humans ; Female ; *Parkinson Disease/complications/diagnostic imaging/epidemiology ; *Amyotrophic Lateral Sclerosis ; Incidence ; *Supranuclear Palsy, Progressive ; *Multiple System Atrophy ; Risk Factors ; *Venous Thrombosis/diagnostic imaging/epidemiology ; }, abstract = {BACKGROUND: Information on the incidence and risk factors of deep vein thrombosis (DVT) in neurodegenerative diseases is limited. We aimed to determine the incidence of DVT among neurodegenerative disorders (amyotrophic lateral sclerosis [ALS], Parkinson's disease [PD], multiple system atrophy [MSA], and progressive supranuclear palsy [PSP]-corticobasal syndrome [CBS]) and the risk factors for the development of DVT.

METHODS: Overall, 229 hospitalized patients with neurodegenerative diseases (65 patients with ALS, 61 with PD, 53 with MSA, and 50 with PSP-CBS) were included in this study. D-dimer value and ultrasonography of the leg vein were assessed to determine the presence or absence of leg DVT. We compared the DVT incidence among each disease group. To identify the risk factors for DVT, a multivariate analysis was performed.

RESULTS: Of 229 patients, 34 had leg DVT; the incidence was significantly higher in patients with PD (38%) than in those with ALS (2%), MSA (5%), or PSP-CBS (4%). Patients with DVT were older, had a smaller waist circumference, had a longer disease duration, and had a high blood pressure (BP) variability. Multivariate analysis revealed that a PD diagnosis and female sex, with a high BP variability were predictive of leg DVT.

CONCLUSIONS: Among the neurodegenerative diseases, the DVT incidence was markedly higher in PD than in ALS, MSA, and PSP-CBS. Several risk factors have been identified in patients with leg DVT. Recognition of these risk factors will improve patient care and guide the appropriate use of anticoagulants.}, } @article {pmid38290242, year = {2024}, author = {Shadish, JA and Lee, JC}, title = {Genetically encoded lysine photocage for spatiotemporal control of TDP-43 nuclear import.}, journal = {Biophysical chemistry}, volume = {307}, number = {}, pages = {107191}, pmid = {38290242}, issn = {1873-4200}, support = {ZIA HL001055/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; Active Transport, Cell Nucleus ; *Amyotrophic Lateral Sclerosis/genetics ; DNA-Binding Proteins/chemistry ; HEK293 Cells ; *Lysine/metabolism ; }, abstract = {Intracellular aggregation of transactive response DNA binding protein of 43 kDa (TDP-43) is a hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis. While primarily a nuclear protein, TDP-43 translocates to the cytosol during cellular stress. Consequences of cytosolic accumulation of TDP-43 is difficult to evaluate in the absence of exogenous toxins. Here, we demonstrate spatiotemporal control over the nuclear import of TDP-43 by installing a photocage (ortho-nitrobenzyl ester) on a single lysine residue (K84) through amber codon suppression in HEK293T cells. Translocation of this cytosolic construct is photo-triggerable in a dose-dependent manner with 355 nm light. Interestingly, both fluid- and solid-like puncta were found based on fluorescence recovery after photobleaching experiments, similar to what is expected of stress granules and intracellular aggregates, respectively. This optogenetic method is advantageous as it is minimally perturbative and broadly applicable to other studies of protein translocation between cellular compartments.}, } @article {pmid38289969, year = {2024}, author = {Hossain, MA and Sarin, R and Donnelly, DP and Miller, BC and Weiss, A and McAlary, L and Antonyuk, SV and Salisbury, JP and Amin, J and Conway, JB and Watson, SS and Winters, JN and Xu, Y and Alam, N and Brahme, RR and Shahbazian, H and Sivasankar, D and Padmakumar, S and Sattarova, A and Ponmudiyan, AC and Gawde, T and Verrill, DE and Yang, W and Kannapadi, S and Plant, LD and Auclair, JR and Makowski, L and Petsko, GA and Ringe, D and Agar, NYR and Greenblatt, DJ and Ondrechen, MJ and Chen, Y and Yerbury, JJ and Manetsch, R and Hasnain, SS and Brown, RH and Agar, JN}, title = {Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS.}, journal = {PLoS biology}, volume = {22}, number = {1}, pages = {e3002462}, pmid = {38289969}, issn = {1545-7885}, support = {P30 GM124166/GM/NIGMS NIH HHS/United States ; R01 NS065263/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Cysteine/genetics ; Mutation ; Superoxide Dismutase/genetics/chemistry/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, "S-XL6," was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A's in vivo half-life; and that S-XL6 crosses the blood-brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS.}, } @article {pmid38289193, year = {2024}, author = {Nolan, M and Scott, C and Hof, PR and Ansorge, O}, title = {Betz cells of the primary motor cortex.}, journal = {The Journal of comparative neurology}, volume = {532}, number = {1}, pages = {e25567}, pmid = {38289193}, issn = {1096-9861}, support = {ANSORGE/OCT14/877-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L022656/1/MRC_/Medical Research Council/United Kingdom ; 14/877-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Adult ; Humans ; Animals ; *Motor Cortex ; *Amyotrophic Lateral Sclerosis ; Pyramidal Cells ; Motor Neurons ; Primates ; Mammals ; }, abstract = {Betz cells, named in honor of Volodymyr Betz (1834-1894), who described them as "giant pyramids" in the primary motor cortex of primates and other mammalian species, are layer V extratelencephalic projection (ETP) neurons that directly innervate α-motoneurons of the brainstem and spinal cord. Despite their large volume and circumferential dendritic architecture, to date, no single molecular criterion has been established that unequivocally distinguishes adult Betz cells from other layer V ETP neurons. In primates, transcriptional signatures suggest the presence of at least two ETP neuron clusters that contain mature Betz cells; these are characterized by an abundance of axon guidance and oxidative phosphorylation transcripts. How neurodevelopmental programs drive the distinct positional and morphological features of Betz cells in humans remains unknown. Betz cells display a distinct biphasic firing pattern involving early cessation of firing followed by delayed sustained acceleration in spike frequency and magnitude. Few cell type-specific transcripts and electrophysiological characteristics are conserved between rodent layer V ETP neurons of the motor cortex and primate Betz cells. This has implications for the modeling of disorders that affect the motor cortex in humans, such as amyotrophic lateral sclerosis (ALS). Perhaps vulnerability to ALS is linked to the evolution of neural networks for fine motor control reflected in the distinct morphomolecular architecture of the human motor cortex, including Betz cells. Here, we discuss histological, molecular, and functional data concerning the position of Betz cells in the emerging taxonomy of neurons across diverse species and their role in neurological disorders.}, } @article {pmid38288970, year = {2024}, author = {Lini, RS and Scanferla, DTP and de Oliveira, NG and Aguera, RG and Santos, TDS and Teixeira, JJV and Kaneshima, AMS and Mossini, SAG}, title = {Fungicides as a risk factor for the development of neurological diseases and disorders in humans: a systematic review.}, journal = {Critical reviews in toxicology}, volume = {54}, number = {1}, pages = {35-54}, doi = {10.1080/10408444.2024.2303481}, pmid = {38288970}, issn = {1547-6898}, mesh = {Humans ; *Fungicides, Industrial/toxicity ; *Nervous System Diseases/chemically induced ; Risk Factors ; Brazil ; }, abstract = {Although studies show that pesticides, especially insecticides, may be toxic to humans, publications on the neurological effects of fungicides are scarce. As fungicides are used widely in Brazil, it is necessary to gather evidence to support actions aimed at safely using of these chemicals. We investigated through a systematic review of publications on the use of fungicides and consequences of exposure related to nervous system diseases or neurological disorders in humans. The protocol review was registered on PROSPERO and followed the guidelines of the PRISMA-Statement. As far as it is known, there is no apparent systematic review in the literature on this topic. The search was comprised of the following databases: PubMed; Web of Science; Scopus and EMBASE, using groups of Mesh terms and strategies specific to each database. Thirteen articles were selected for this review. Regarding the substances analyzed in the studies, some reported the use of fungicides in general, without separating them by type, while others summarized the categories of all pesticides by their function (insecticides, herbicides, fungicides, etc.) or chemical class (dithiocarbamate, dicarboximide, inorganic, etc.). However, most of the articles referred to fungicides that contain the metal manganese (Mn) in their composition. As for neurological disorders, articles addressed Parkinson's disease (PD), neurodevelopmental outcomes, extrapyramidal syndrome resembling PD, cognitive disorders, depression, neural tube defects, motor neurone disease, and amyotrophic lateral sclerosis. Most investigations pointed to exposure to fungicides, mainly maneb and mancozeb, leading to the development of at least one neurological disease, which suggests the need for further multicentric clinical trials and prospective studies for greater clarity of the research problem.}, } @article {pmid38288843, year = {2024}, author = {Fatima, J and Siddique, YH}, title = {Application of Nanocomposites and Nanoparticles in Treating Neurodegenerative Disorders.}, journal = {CNS & neurological disorders drug targets}, volume = {23}, number = {10}, pages = {1217-1233}, pmid = {38288843}, issn = {1996-3181}, support = {211610179057//University Grants Commission/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Nanoparticles/therapeutic use ; *Nanocomposites/therapeutic use ; Animals ; Drug Delivery Systems/methods ; Blood-Brain Barrier/drug effects/metabolism ; Neuroprotective Agents/therapeutic use ; }, abstract = {Neurodegenerative diseases represent a formidable global health challenge, affecting millions and imposing substantial burdens on healthcare systems worldwide. Conditions, like Alzheimer's, Parkinson's, and Huntington's diseases, among others, share common characteristics, such as neuronal loss, misfolded protein aggregation, and nervous system dysfunction. One of the major obstacles in treating these diseases is the presence of the blood-brain barrier, limiting the delivery of therapeutic agents to the central nervous system. Nanotechnology offers promising solutions to overcome these challenges. In Alzheimer's disease, NPs loaded with various compounds have shown remarkable promise in preventing amyloid-beta (Aβ) aggregation and reducing neurotoxicity. Parkinson's disease benefits from improved dopamine delivery and neuroprotection. Huntington's disease poses its own set of challenges, but nanotechnology continues to offer innovative solutions. The promising developments in nanoparticle-based interventions for neurodegenerative diseases, like amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), have offered new avenues for effective treatment. Nanotechnology represents a promising frontier in biomedical research, offering tailored solutions to the complex challenges posed by neurodegenerative diseases. While much progress has been made, ongoing research is essential to optimize nanomaterial designs, improve targeting, and ensure biocompatibility and safety. Nanomaterials possess unique properties that make them excellent candidates for targeted drug delivery and neuroprotection. They can effectively bypass the blood-brain barrier, opening doors to precise drug delivery strategies. This review explores the extensive research on nanoparticles (NPs) and nanocomposites in diagnosing and treating neurodegenerative disorders. These nanomaterials exhibit exceptional abilities to target neurodegenerative processes and halt disease progression.}, } @article {pmid38288290, year = {2023}, author = {Aussenac, R and Monnet, JM and Klopčič, M and Hawryło, P and Socha, J and Mahnken, M and Gutsch, M and Cordonnier, T and Vallet, P}, title = {Diameter, height and species of 42 million trees in three European landscapes generated from field data and airborne laser scanning data.}, journal = {Open research Europe}, volume = {3}, number = {}, pages = {32}, pmid = {38288290}, issn = {2732-5121}, abstract = {Ecology and forestry sciences are using an increasing amount of data to address a wide variety of technical and research questions at the local, continental and global scales. However, one type of data remains rare: fine-grain descriptions of large landscapes. Yet, this type of data could help address the scaling issues in ecology and could prove useful for testing forest management strategies and accurately predicting the dynamics of ecosystem services. Here we present three datasets describing three large European landscapes in France, Poland and Slovenia down to the tree level. Tree diameter, height and species data were generated combining field data, vegetation maps and airborne laser scanning (ALS) data following an area-based approach. Together, these landscapes cover more than 100 000 ha and consist of more than 42 million trees of 51 different species. Alongside the data, we provide here a simple method to produce high-resolution descriptions of large landscapes using increasingly available data: inventory and ALS data. We carried out an in-depth evaluation of our workflow including, among other analyses, a leave-one-out cross validation. Overall, the landscapes we generated are in good agreement with the landscapes they aim to reproduce. In the most favourable conditions, the root mean square error (RMSE) of stand basal area (BA) and mean quadratic diameter (Dg) predictions were respectively 5.4 m [2].ha [-1] and 3.9 cm, and the generated main species corresponded to the observed main species in 76.2% of cases.}, } @article {pmid38287907, year = {2024}, author = {Pan, MT and Zhang, H and Li, XJ and Guo, XY}, title = {Genetically modified non-human primate models for research on neurodegenerative diseases.}, journal = {Zoological research}, volume = {45}, number = {2}, pages = {263-274}, pmid = {38287907}, issn = {2095-8137}, mesh = {Humans ; Animals ; Chlorocebus aethiops ; *Neurodegenerative Diseases/genetics/therapy/veterinary ; Animals, Genetically Modified ; Disease Models, Animal ; *Parkinson Disease/pathology/veterinary ; Macaca mulatta ; }, abstract = {Neurodegenerative diseases (NDs) are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Currently, there are no therapies available that can delay, stop, or reverse the pathological progression of NDs in clinical settings. As the population ages, NDs are imposing a huge burden on public health systems and affected families. Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments. While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms, the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap. Old World non-human primates (NHPs), such as rhesus, cynomolgus, and vervet monkeys, are phylogenetically, physiologically, biochemically, and behaviorally most relevant to humans. This is particularly evident in the similarity of the structure and function of their central nervous systems, rendering such species uniquely valuable for neuroscience research. Recently, the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms. This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained, as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.}, } @article {pmid38287331, year = {2024}, author = {Oh, J and An, J and Park, K and Park, Y}, title = {Psychosocial interventions for people with amyotrophic lateral sclerosis and motor neuron disease and their caregivers: a scoping review.}, journal = {BMC nursing}, volume = {23}, number = {1}, pages = {75}, pmid = {38287331}, issn = {1472-6955}, support = {2022R1F1A1064038//National Research Foundation of Korea grant funded by the Korea government/ ; }, abstract = {BACKGROUND: As amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) is a fatal progressive neurodegenerative disorder, patients experience severe impairments, with patients and family caregivers facing emotional distress and exhaustion. Several psychosocial interventions are aimed at providing tailored support for ALS/MND patients and caregivers. The aim of this study was to conduct a scoping review and present a comprehensive overview of psychosocial interventions designed for individuals and families affected by ALS/MND, while also pinpointing research gaps.

METHODS: This scoping review utilized Arksey and O'Malley's methodological framework to investigate psychosocial interventions designed for individuals with ALS/MND and their families. The study adhered to the PRISMA-ScR checklist for reporting.

RESULTS: A total of 27 articles describing 25 interventions met the inclusion criteria. The predominant interventions observed in the research encompassed education-related strategies, closely followed by behavior therapy, counseling, social support interventions, and psychotherapy interventions. Across the majority of the studies, findings indicated promising feasibility and acceptability of these interventions. Notably, a significant proportion of quantitative investigations yielded one or more statistically significant effects, while qualitative studies consistently reported favorable outcomes, including enhancements in well-being and heightened awareness of individual circumstances.

CONCLUSIONS: Given the progressive and debilitating nature of this condition, coupled with the absence of a cure, the adoption of a psychosocial approach can prove beneficial for both ALS/MND patients and their families. However, high-quality RCTs with a large sample size are recommended to examine and confirm the effectiveness.}, } @article {pmid38287112, year = {2024}, author = {Wang, J and Wang, Y and Zhang, Q and Li, SZ and He, MG and Wang, N and Zhang, Y}, title = {Quantitative analysis of dynamic iris changes in primary angle-closure disease with long axial lengths: the Handan Eye Study.}, journal = {Eye (London, England)}, volume = {38}, number = {7}, pages = {1362-1367}, pmid = {38287112}, issn = {1476-5454}, mesh = {Humans ; *Glaucoma, Angle-Closure/physiopathology/diagnosis ; Cross-Sectional Studies ; Female ; Male ; *Tomography, Optical Coherence/methods ; Middle Aged ; *Axial Length, Eye/pathology/diagnostic imaging ; *Iris/pathology/diagnostic imaging ; Aged ; Adult ; Intraocular Pressure/physiology ; Gonioscopy ; Anterior Chamber/pathology/diagnostic imaging ; }, abstract = {OBJECTIVE: To investigate dynamic iris changes in patients with primary angle-closure disease (PACD) with long axial length (AL) compared to those with short and medium AL.

METHODS: This observational cross-sectional study enrolled participants aged 35 years or older from the Handan Eye Study follow-up examination who were diagnosed with PACD and underwent Visante anterior segment optical coherence tomography (ASOCT) imaging under light and dark conditions. The right eye of each participant was included in the analysis. AL was categorized as short (<22.0 mm), medium (≥22.0 to ≤23.5 mm), or long (>23.5 mm). Anterior segment parameters, including iris dynamic changes, were compared among the three groups with different ALs.

RESULTS: Data from 448 patients with PACD were analyzed. We found that 10.9% of included eyes had a long AL with a flatter cornea; larger central anterior chamber depth, angle opening distance, anterior chamber width, anterior chamber area, and volume; and smaller lens thickness and lens vault (LV) (P < 0.05) than those with short AL. No significant difference existed between the three groups in iris thickness, iris cross-sectional area (IA), iris curvature, or pupil diameter (PD) change between light and dark (P > 0.05). The significant associated factors for IA changes were area recess area (ARA) in the dark, LV in the dark, and PD change from light to dark (P < 0.05).

CONCLUSIONS: Dynamic and static iris parameters were consistent across patients with PACD with short, medium, or long AL and may contribute to the pathogenesis of angle closure in atypical PACD.}, } @article {pmid38286832, year = {2024}, author = {Lu, J and He, AX and Jin, ZY and Zhang, M and Li, ZX and Zhou, F and Ma, L and Jin, HM and Wang, JY and Shen, X}, title = {Desloratadine alleviates ALS-like pathology in hSOD1[G93A] mice via targeting 5HTR2A on activated spinal astrocytes.}, journal = {Acta pharmacologica Sinica}, volume = {45}, number = {5}, pages = {926-944}, pmid = {38286832}, issn = {1745-7254}, mesh = {Animals ; *Astrocytes/drug effects/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Spinal Cord/drug effects/pathology/metabolism ; Mice ; *Mice, Transgenic ; *Superoxide Dismutase-1/genetics/metabolism ; *Loratadine/*analogs & derivatives/pharmacology/therapeutic use ; Humans ; Receptor, Serotonin, 5-HT2A/metabolism ; Disease Models, Animal ; Male ; Serotonin 5-HT2 Receptor Antagonists/pharmacology/therapeutic use ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive loss of motor neurons in the spinal cord, cerebral cortex and brain stem. ALS is characterized by gradual muscle atrophy and dyskinesia. The limited knowledge on the pathology of ALS has impeded the development of therapeutics for the disease. Previous studies have shown that autophagy and astrocyte-mediated neuroinflammation are involved in the pathogenesis of ALS, while 5HTR2A participates in the early stage of astrocyte activation, and 5HTR2A antagonism may suppress astrocyte activation. In this study, we evaluated the therapeutic effects of desloratadine (DLT), a selective 5HTR2A antagonist, in human SOD1[G93A] (hSOD1[G93A]) ALS model mice, and elucidated the underlying mechanisms. HSOD1[G93A] mice were administered DLT (20 mg·kg[-1]·d[-1], i.g.) from the age of 8 weeks for 10 weeks or until death. ALS onset time and lifespan were determined using rotarod and righting reflex tests, respectively. We found that astrocyte activation accompanying with serotonin receptor 2 A (5HTR2A) upregulation in the spinal cord was tightly associated with ALS-like pathology, which was effectively attenuated by DLT administration. We showed that DLT administration significantly delayed ALS symptom onset time, prolonged lifespan and ameliorated movement disorders, gastrocnemius injury and spinal motor neuronal loss in hSOD1[G93A] mice. Spinal cord-specific knockdown of 5HTR2A by intrathecal injection of adeno-associated virus9 (AAV9)-si-5Htr2a also ameliorated ALS pathology in hSOD1[G93A] mice, and occluded the therapeutic effects of DLT administration. Furthermore, we demonstrated that DLT administration promoted autophagy to reduce mutant hSOD1 levels through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocyte neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1[G93A] mice. In summary, 5HTR2A antagonism shows promise as a therapeutic strategy for ALS, highlighting the potential of DLT in the treatment of the disease. DLT as a 5HTR2A antagonist effectively promoted autophagy to reduce mutant hSOD1 level through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocytic neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1[G93A] mice.}, } @article {pmid38286389, year = {2024}, author = {Rayner, SL and Hogan, A and Davidson, JM and Chapman, T and Cheng, F and Luu, L and Wu, S and Zhang, S and Yang, S and Blair, I and Morsch, M and Chung, R and Lee, A}, title = {Cyclin F can alter the turnover of TDP-43.}, journal = {Neurobiology of disease}, volume = {192}, number = {}, pages = {106421}, doi = {10.1016/j.nbd.2024.106421}, pmid = {38286389}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Zebrafish ; DNA-Binding Proteins/metabolism ; Ubiquitination ; Cyclins/genetics/metabolism ; }, abstract = {Previously, we demonstrated that the SCF[cyclin F] complex directly mediates the poly-ubiquitylation of TDP-43, raising the question of whether cyclin F can be used to enhance the turnover of TDP-43. A hurdle to the use of cyclin F, however, is that the overexpression of cyclin F can lead to the initiation of cell death pathways. Accordingly, the aim of this study was to identify and evaluate a less toxic variant of cyclin F. To do so, we first confirmed and validated our previous findings that cyclin F binds to TDP-43 in an atypical manner. Additionally, we demonstrated that mutating the canonical substrate region in cyclin F (to generate cyclin F[MRL/AAA]) led to reduced binding affinity to known canonical substrates without impacting the interaction between cyclin F and TDP-43. Notably, both wild-type and cyclin F[MRL/AAA] effectively reduced the abundance of TDP-43 in cultured cells whilst cyclin F[MRL/AAA] also demonstrated reduced cell death compared to the wild-type control. The decrease in toxicity also led to a reduction in morphological defects in zebrafish embryos. These results suggest that cyclin F can be modified to enhance its targeting of TDP-43, which in turn reduces the toxicity associated with the overexpression of cyclin F. This study provides greater insights into the interaction that occurs between cyclin F and TDP-43 in cells and in vivo.}, } @article {pmid38286113, year = {2024}, author = {Dutta, A and Manna, A and Ghosh, S and Mundle, M and Saha, M and Gourav, K and Maiti, S and Chattopadhyay, B}, title = {Prespecified Homeopathic Medicines in the Prevention of Confirmed and Suspected Cases of COVID-19: A Community-Based, Double-Blind, Randomized, Placebo-Controlled Prophylaxis Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {140-148}, doi = {10.1159/000536395}, pmid = {38286113}, issn = {2504-2106}, abstract = {INTRODUCTION: Homeopathic medicines have been used for decades in the prevention and treatment of infectious diseases. However, the preventive efficacy of specific homeopathic medicines in COVID-19 is not well characterized. This study aimed to evaluate the comparative efficacy of prespecified homeopathic medicines in preventing COVID-19.

METHODS: A community-based, double-blind, randomized, placebo-controlled trial was conducted on 4,034 participants residing in Ward No. 27 of the Howrah Municipal Corporation in India. Participants were randomized to receive one of three prespecified homeopathic medicines [Influenzinum 30C, Arsenicum album 30C, Anas barbariae hepatis et cordis extractum 200K (Oscillococcinum®)], or placebo. The outcomes were the incidence of laboratory-confirmed and suspected cases of COVID-19 during a follow-up period of 1 month.

RESULTS: During the follow-up period, a total of 13 new laboratory-confirmed COVID-19 cases were reported in the study population. Among these, 5 cases in Influenzinum group, 2 cases in Arsenicum album group, 1 case in Oscillococcinum® group, and 5 cases in Placebo group were reported. On the other hand, number of suspected COVID-19 cases was significantly less in all the three homeopathic medicine groups compared to placebo. The least number of suspected cases reported in the Oscillococcinum® group (aOR: 0.058; 95% confidence interval [CI]: 0.029, 0.114), followed by the Arsenicum album (aOR: 0.337; 95% CI: 0.238, 0.475) and Influenzinum (aOR: 0.539; 95% CI: 0.401, 0.726) groups.

CONCLUSION: Prespecified homeopathic medicines, particularly Oscillococcinum® and Arsenicum album 30C, may have a role in preventing COVID-19, especially in reducing the incidence of suspected or COVID-19-like respiratory illnesses. However, the result failed to demonstrate a statistically significant difference in the occurrence of confirmed cases of COVID-19 between the study groups. Further research is needed to evaluate the efficacy of these medicines in different populations and settings.

UNLABELLED: EinleitungHomöopathische Arzneimittel werden seit Jahrzehnten zur Prävention und Behandlung von Infektionskrankheiten eingesetzt. Die Wirksamkeit spezifischer homöopathischer Arzneimittel zur Prophylaxe von COVID-19 ist jedoch nicht gut untersucht. Mit dieser Studie sollte die vergleichende Wirksamkeit spezifischer homöopathischer Arzneimittel bei der Prävention von COVID-19 untersucht werden.MethodenEs handelte sich um eine gemeindebasierte, doppelblinde, randomisierte, placebokontrollierte Studie mit 4.034 Teilnehmern, die im Bezirk Nr. 27 der Howrah Municipal Corporation in Indien lebten. Die Teilnehmer erhielten randomisiert eines von drei zuvor festgelegten homöopathischen Arzneimitteln [Influenzinum 30C, Arsenicum album 30C, Anas barbariae hepatis et cordis extractum 200K (Oscillococcinum®)] oder Placebo. Zielkriterien waren die Inzidenz von laborchemisch bestätigten und vermuteten COVID-19-Fällen während des Follow-up-Zeitraums von einem Monat.ErgebnisseWährend des Follow-up-Zeitraums wurden insgesamt 13 neue, laborchemisch bestätigte COVID-19-Fälle in der Studienpopulation berichtet, davon 5 Fälle in der Influenzinum-Gruppe, 2 Fälle in der Arsenicum album-Gruppe, 1 Fall in der Oscillococcinum®-Gruppe und 5 Fälle in der Placebo-Gruppe. Demgegenüber fiel Zahl der COVID-19-Verdachtsfälle in allen drei homöopathischen Arzneimittelgruppen signifikant geringer aus als in der Placebogruppe. Die wenigsten Verdachtsfälle wurden in der Oscillococcinum®-Gruppe berichtet (aOR: 0.058; 95%-KI: 0.029, 0.114), gefolgt von der Arsenicum album- (aOR: 0.337; 95%-KI: 0.238, 0.475) und der Influenzinum- (aOR: 0.539; 95%-KI: 0.401, 0.726) Gruppe.SchlussfolgerungSpezifische homöopathische Arzneimittel, insbesondere Oscillococcinum® und Arsenicum album 30C, könnten bei der Prävention von COVID-19 eine Rolle spielen, vor allem bei der Senkung der Inzidenz von COVID-19-Verdachtsfällen oder COVID-19-ähnlichen Atemwegserkrankungen. Allerdings war kein statistisch signifikanter Unterschied im Auftreten von bestätigten COVID-19-Fällen zwischen den Studiengruppen nachweisbar. Weitere Untersuchungen sind erforderlich, um die Wirksamkeit dieser Arzneimittel in verschiedenen Populationen und Umgebungen zu bewerten.}, } @article {pmid38286111, year = {2024}, author = {Wang, M and Wang, T and Gu, F}, title = {Efficacy of Huanglian Jiedu Decoction for Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {187-200}, doi = {10.1159/000536453}, pmid = {38286111}, issn = {2504-2106}, abstract = {OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder, and there is an increasing interest in the potential benefits of traditional Chinese medicine, such as Huanglian Jiedu decoction (HJD), for its management. This meta-analysis aimed to determine the efficacy and safety of HJD in the treatment of T2DM.

METHODS: A systematic review was conducted across six databases including PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang, from their inception to August 24, 2023. We focused on randomized controlled trials (RCTs) that evaluated HJD as both a monotherapy and in combination treatments for T2DM patients. Data analysis was performed using RevMan 5.3 and Stata 17.0, with evaluations for heterogeneity and publication bias. Additionally, subgroup analyses were stratified based on the duration of treatment.

RESULTS: A total of 40 studies involving 3,934 participants were included in the meta-analysis. Both HJD monotherapy and combined with other therapies significantly reduced hemoglobin A1C (HbA1c) fasting blood glucose (FBG) and 2-h postprandial glucose (2hPG) levels, as well as improved insulin resistance. Furthermore, combination therapy enhanced the efficacy rate and favorably altered lipid profiles, including increasing HDL-C and decreasing LDL-C, TC, and TG levels. It was worth noting that the results of the subgroup analysis indicated that, in terms of reducing HbA1c and 2hPG, the efficacy of HJD alone for a duration of less than 3 months was found to be potentially superior to that observed in treatments exceeding 3 months. Adverse event assessment suggested that HJD did not increase the incidence of side effects, including diarrhea, affirming its safety.

CONCLUSION: HJD appears to be an effective and safe alternative or adjunctive therapy for T2DM, showing significant improvements in glycemic control and lipid profiles without increasing adverse events. Further rigorous, multicenter RCTs outside China are warranted to validate these findings.

UNLABELLED: ZielDiabetes mellitus Typ 2 (DMT2) ist eine weit verbreitete Stoffwechselerkrankung, und es besteht ein steigendes Interesse an den potenziellen Vorteilen der traditionellen chinesischen Medizin, wie beispielsweise Huanglian Jiedu-Dekokt (HJD), zu seiner Behandlung. Mit dieser Metaanalyse sollten die Wirksamkeit und Sicherheit von HJD zur Behandlung von DMT2 ermittelt werden.MethodenEs wurde eine systematische Recherche in sechs Datenbanken durchgeführt, darunter PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure (CNKI) und Wanfang, für die Zeit vom Beginn der Datenbank bis zum 24. August 2023. Dabei lag unser Hauptaugenmerk auf randomisierten kontrollierten Studien (RCTs), die HJD sowohl als Monotherapie als auch in Kombinationstherapien bei Patienten mit DMT2 untersuchten. Die Datenanalyse erfolgte mithilfe von RevMan 5.3 und Stata 17.0 mit Untersuchungen auf Heterogenität und Publikationsverzerrungen. Darüber hinaus wurden Subgruppenanalysen stratifiziert nach Behandlungsdauer durchgeführt.ErgebnisseInsgesamt wurden 40 Studien mit 3.934 Teilnehmern in die Metaanalyse eingeschlossen. HJD führte sowohl als Monotherapie als auch in Kombination mit anderen Therapien zu einer signifikanten Senkung des HbA1c-Nüchternblutzuckerspiegels (fasting blood glucose, FBG) und der postprandialen Blutzuckerwerte 2 Stunden nach dem Essen (2-h postprandial glucose, 2hPG) sowie zu einer Verbesserung der Insulinresistenz. Darüber hinaus verbesserte die Kombinationstherapie die Wirksamkeitsrate und führte zu einer positiven Veränderung der Lipidprofile, die eine Erhöhung der HDL-Cholesterinwerte und eine Senkung der LDL-, Gesamtcholesterin- und Trigylceridwerte einschloss. Erwähnenswert ist, dass nach den Ergebnissen der Subgruppenanalyse die Wirksamkeit von HJD als Monotherapie in Hinblick auf die Senkung der HbA1c- und 2hPG-Werte bei einer Behandlungsdauer von weniger als drei Monaten gegenüber derjenigen von Behandlungen, die länger als drei Monate dauerten, potenziell überlegen war. Die Bewertung der unerwünschten Ereignisse zeigte, dass HJD nicht zu einem Anstieg der Nebenwirkungen wie Durchfall führte, was seine Sicherheit bestätigte.SchlussfolgerungHJD scheint eine wirksame und sichere Alternative oder Zusatztherapie bei DMT2 zu sein, die signifikante Verbesserungen der Blutzuckerkontrolle und der Lipidprofile ohne Zunahme der unerwünschten Ereignisse bewirkt. Weitere rigorose, multizentrische RCTs außerhalb Chinas sind erforderlich, um diese Ergebnisse zu validieren.}, } @article {pmid38285093, year = {2024}, author = {Díaz, M and Fabelo, N and Martín, MV and Santos, G and Ferrer, I}, title = {Evidence for alterations in lipid profiles and biophysical properties of lipid rafts from spinal cord in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {102}, number = {3}, pages = {391-402}, pmid = {38285093}, issn = {1432-1440}, support = {SAF2014-52582-R//Ministerio de Ciencia e Innovación/ ; SAF2017-84454-R//Ministerio de Ciencia e Innovación/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Neurodegenerative Diseases/metabolism ; Lipids ; Membrane Microdomains/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an age-dependent neurodegenerative disease affecting motor neurons in the spinal cord and brainstem whose etiopathogenesis remains unclear. Recent studies have linked major neurodegenerative diseases with altered function of multimolecular lipid-protein complexes named lipid rafts. In the present study, we have isolated lipid rafts from the anterior horn of the spinal cords of controls and ALS individuals and analysed their lipid composition. We found that ALS affects levels of different fatty acids, lipid classes and related ratios and indexes. The most significant changes affected the contents of n-9/n-7 monounsaturated fatty acids and arachidonic acid, the main n-6 long-chain polyunsaturated fatty acid (LCPUFA), which were higher in ALS lipid rafts. Paralleling these findings, ALS lipid rafts lower saturates-to-unsaturates ratio compared to controls. Further, levels of cholesteryl ester (SE) and anionic-to-zwitterionic phospholipids ratio were augmented in ALS lipid rafts, while sulfatide contents were reduced. Further, regression analyses revealed augmented SE esterification to (mono)unsaturated fatty acids in ALS, but to saturates in controls. Overall, these changes indicate that lipid rafts from ALS spinal cord undergo destabilization of the lipid structure, which might impact their biophysical properties, likely leading to more fluid membranes. Indeed, estimations of membrane microviscosity confirmed less viscous membranes in ALS, as well as more mobile yet smaller lipid rafts compared to surrounding membranes. Overall, these results demonstrate that the changes in ALS lipid rafts are unrelated to oxidative stress, but to anomalies in lipid metabolism and/or lipid raft membrane biogenesis in motor neurons. KEY MESSAGES: The lipid matrix of multimolecular membrane complexes named lipid rafts are altered in human spinal cord in sporadic amyotrophic lateral sclerosis (ALS). Lipid rafts from ALS spinal cord contain higher levels of n-6 LCPUFA (but not n-3 LCPUFA), n-7/n-9 monounsaturates and lower saturates-to-unsaturates ratio. ALS lipid rafts display increased contents of cholesteryl esters, anomalous anionic-to-zwitterionic phospholipids and phospholipid remodelling and reduced sulphated and total sphingolipid levels, compared to control lipid rafts. Destabilization of the lipid structure of lipid raft affects their biophysical properties and leads to more fluid, less viscous membrane microdomains. The changes in ALS lipid rafts are unlikely related to increased oxidative stress, but to anomalies in lipid metabolism and/or raft membrane biogenesis in motor neurons.}, } @article {pmid38284771, year = {2024}, author = {Grassano, M and Koumantakis, E and Manera, U and Canosa, A and Vasta, R and Palumbo, F and Fuda, G and Salamone, P and Marchese, G and Casale, F and Charrier, L and Mora, G and Moglia, C and Calvo, A and Chiò, A}, title = {Giving Breath to Motor Neurons: Noninvasive Mechanical Ventilation Slows Disease Progression in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {95}, number = {4}, pages = {817-822}, doi = {10.1002/ana.26875}, pmid = {38284771}, issn = {1531-8249}, support = {2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 259867//Seventh Framework Programme/ ; RF-2016-02362405//Ministero della Salute/ ; //EU Joint Programme - Neurodegenerative Disease Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Respiration, Artificial ; Disease Progression ; Quality of Life ; Motor Neurons ; }, abstract = {OBJECTIVE: Noninvasive mechanical ventilation (NIMV) improves amyotrophic lateral sclerosis (ALS) quality of life and survival. However, data about its effect on disease progression are still lacking. Here, we test whether NIMV use changed the rate of functional decline among ALS patients.

METHODS: In this retrospective observational study, we included 448 ALS patients followed up at the ALS Center in Turin, Italy, who underwent NIMV during the disease course. The primary outcome was the change in functional decline after NIMV initiation adjusting for covariates. Functional decline was based on the nonrespiratory items of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R).

RESULTS: NIMV initiation resulted in a slower functional decline (mean improvement = 0.16 points per month, 95% confidence interval = 0.12-0.19, p < 0.001), with consistent effects observed across various demographic factors, including sex, age at diagnosis, and disease duration before NIMV initiation. This finding was replicated using the PRO-ACT (Pooled Resource Open-Access ALS Clinical Trials) dataset. The favorable impact of NIMV on ALSFRS-R progression was evident independently of disease stages. Notably, NIMV benefits were not dose-dependent but were particularly prominent for nighttime respiratory support.

INTERPRETATION: NIMV significantly influences the rate of motor progression in ALS, and this effect is not determined by the nonlinearity of ALSFRS-R trajectory. The functional decline slowed following NIMV initiation, independently of the site of disease onset or disease severity at the time of NIMV initiation. Our findings underscore the importance of timely NIMV initiation for all ALS patients and highlight the need to consider NIMV-induced slowing of disease progression when evaluating clinical trial outcomes. ANN NEUROL 2024;95:817-822.}, } @article {pmid38284068, year = {2024}, author = {Sunildutt, N and Ahmed, F and Chethikkattuveli Salih, AR and Lim, JH and Choi, KH}, title = {Integrating Transcriptomic and Structural Insights: Revealing Drug Repurposing Opportunities for Sporadic ALS.}, journal = {ACS omega}, volume = {9}, number = {3}, pages = {3793-3806}, pmid = {38284068}, issn = {2470-1343}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disorder characterized by the loss of upper and lower motor neurons, resulting in debilitating muscle weakness and atrophy. Currently, there are no effective treatments available for ALS, posing significant challenges in managing the disease that affects approximately two individuals per 100,000 people annually. To address the urgent need for effective ALS treatments, we conducted a drug repurposing study using a combination of bioinformatics tools and molecular docking techniques. We analyzed sporadic ALS-related genes from the GEO database and identified key signaling pathways involved in sporadic ALS pathogenesis through pathway analysis using DAVID. Subsequently, we utilized the Clue Connectivity Map to identify potential drug candidates and performed molecular docking using AutoDock Vina to evaluate the binding affinity of short-listed drugs to key sporadic ALS-related genes. Our study identified Cefaclor, Diphenidol, Flubendazole, Fluticasone, Lestaurtinib, Nadolol, Phenamil, Temozolomide, and Tolterodine as potential drug candidates for repurposing in sporadic ALS treatment. Notably, Lestaurtinib demonstrated high binding affinity toward multiple proteins, suggesting its potential as a broad-spectrum therapeutic agent for sporadic ALS. Additionally, docking analysis revealed NOS3 as the gene that interacts with all the short-listed drugs, suggesting its possible involvement in the mechanisms underlying the therapeutic potential of these drugs in sporadic ALS. Overall, our study provides a systematic framework for identifying potential drug candidates for sporadic ALS therapy and highlights the potential of drug repurposing as a promising strategy for discovering new therapies for neurodegenerative diseases.}, } @article {pmid38283093, year = {2023}, author = {Calderón-Garcidueñas, L and Stommel, EW and Torres-Jardón, R and Hernández-Luna, J and Aiello-Mora, M and González-Maciel, A and Reynoso-Robles, R and Pérez-Guillé, B and Silva-Pereyra, HG and Tehuacanero-Cuapa, S and Rodríguez-Gómez, A and Lachmann, I and Galaz-Montoya, C and Doty, RL and Roy, A and Mukherjee, PS}, title = {Alzheimer and Parkinson diseases, frontotemporal lobar degeneration and amyotrophic lateral sclerosis overlapping neuropathology start in the first two decades of life in pollution exposed urbanites and brain ultrafine particulate matter and industrial nanoparticles, including Fe, Ti, Al, V, Ni, Hg, Co, Cu, Zn, Ag, Pt, Ce, La, Pr and W are key players. Metropolitan Mexico City health crisis is in progress.}, journal = {Frontiers in human neuroscience}, volume = {17}, number = {}, pages = {1297467}, pmid = {38283093}, issn = {1662-5161}, abstract = {The neuropathological hallmarks of Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS) are present in urban children exposed to fine particulate matter (PM2.5), combustion and friction ultrafine PM (UFPM), and industrial nanoparticles (NPs). Metropolitan Mexico City (MMC) forensic autopsies strongly suggest that anthropogenic UFPM and industrial NPs reach the brain through the nasal/olfactory, lung, gastrointestinal tract, skin, and placental barriers. Diesel-heavy unregulated vehicles are a key UFPM source for 21.8 million MMC residents. We found that hyperphosphorylated tau, beta amyloid1-42, α-synuclein, and TAR DNA-binding protein-43 were associated with NPs in 186 forensic autopsies (mean age 27.45 ± 11.89 years). The neurovascular unit is an early NPs anatomical target, and the first two decades of life are critical: 100% of 57 children aged 14.8 ± 5.2 years had AD pathology; 25 (43.9%) AD+TDP-43; 11 (19.3%) AD + PD + TDP-43; and 2 (3.56%) AD +PD. Fe, Ti, Hg, Ni, Co, Cu, Zn, Cd, Al, Mg, Ag, Ce, La, Pr, W, Ca, Cl, K, Si, S, Na, and C NPs are seen in frontal and temporal lobes, olfactory bulb, caudate, substantia nigra, locus coeruleus, medulla, cerebellum, and/or motor cortical and spinal regions. Endothelial, neuronal, and glial damages are extensive, with NPs in mitochondria, rough endoplasmic reticulum, the Golgi apparatus, and lysosomes. Autophagy, cell and nuclear membrane damage, disruption of nuclear pores and heterochromatin, and cell death are present. Metals associated with abrasion and deterioration of automobile catalysts and electronic waste and rare earth elements, i.e., lanthanum, cerium, and praseodymium, are entering young brains. Exposure to environmental UFPM and industrial NPs in the first two decades of life are prime candidates for initiating the early stages of fatal neurodegenerative diseases. MMC children and young adults-surrogates for children in polluted areas around the world-exhibit early AD, PD, FTLD, and ALS neuropathological hallmarks forecasting serious health, social, economic, academic, and judicial societal detrimental impact. Neurodegeneration prevention should be a public health priority as the problem of human exposure to particle pollution is solvable. We are knowledgeable of the main emission sources and the technological options to control them. What are we waiting for?}, } @article {pmid38282082, year = {2024}, author = {Parnianpour, P and Benatar, M and Briemberg, H and Dey, A and Dionne, A and Dupré, N and Evans, KC and Frayne, R and Genge, A and Graham, SJ and Korngut, L and McLaren, DG and Seres, P and Welsh, RC and Wilman, A and Zinman, L and Kalra, S}, title = {Mismatch between clinically defined classification of ALS stage and the burden of cerebral pathology.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2547-2559}, pmid = {38282082}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *Disease Progression ; Aged ; *Magnetic Resonance Imaging ; Adult ; Brain/diagnostic imaging/pathology ; Severity of Illness Index ; Longitudinal Studies ; Cerebral Cortex/diagnostic imaging/pathology ; }, abstract = {This study aimed to investigate the clinical stratification of amyotrophic lateral sclerosis (ALS) patients in relation to in vivo cerebral degeneration. One hundred forty-nine ALS patients and one hundred forty-four healthy controls (HCs) were recruited from the Canadian ALS Neuroimaging Consortium (CALSNIC). Texture analysis was performed on T1-weighted scans to extract the texture feature "autocorrelation" (autoc), an imaging biomarker of cerebral degeneration. Patients were stratified at baseline into early and advanced disease stages based on criteria adapted from ALS clinical trials and the King's College staging system, as well as into slow and fast progressors (disease progression rates, DPR). Patients had increased autoc in the internal capsule. These changes extended beyond the internal capsule in early-stage patients (clinical trial-based criteria), fast progressors, and in advanced-stage patients (King's staging criteria). Longitudinal increases in autoc were observed in the postcentral gyrus, corticospinal tract, posterior cingulate cortex, and putamen; whereas decreases were observed in corpus callosum, caudate, central opercular cortex, and frontotemporal areas. Both longitudinal increases and decreases of autoc were observed in non-overlapping regions within insula and precentral gyrus. Within-criteria comparisons of autoc revealed more pronounced changes at baseline and longitudinally in early- (clinical trial-based criteria) and advanced-stage (King's staging criteria) patients and fast progressors. In summary, comparative patterns of baseline and longitudinal progression in cerebral degeneration are dependent on sub-group selection criteria, with clinical trial-based stratification insufficiently characterizing disease stage based on pathological cerebral burden.}, } @article {pmid38281010, year = {2024}, author = {Fouda, AES and Etaiw, SEH and Abd El-Aziz, DM and El-Hossiany, AA and Elbaz, UA}, title = {Experimental and theoretical studies of the efficiency of metal-organic frameworks (MOFs) in preventing aluminum corrosion in hydrochloric acid solution.}, journal = {BMC chemistry}, volume = {18}, number = {1}, pages = {21}, pmid = {38281010}, issn = {2661-801X}, abstract = {Aluminum corrosion inhibitors "{[CuI (CN)2(phen) CuII (CN)2(phen)]5H2O}, (MOF1) and {[CuI(CN)2(phen)CuII(CN)2(phen)]5H2O} @TiO2 (MOF1@TiO2) were studied in one molar HCl solution". The ML results for three different temperatures (25-45 °C) were compared with the results of PDP and EIS analyses. The adsorption of inhibitors on Al surfaces has been calculated and discussed by a Langmuir isotherm. The inhibitors that were created showed great effectiveness, with a noticeable increase in their inhibitory efficiency as the dosage was raised and the temperature was lowered. Inhibition efficiency each amounted to 88.6%, 84.5% at 400 ppm and 25 °C for MOF1@TiO2 and MOF1, respectively. Analyzing the polarization curves of synthesized inhibitors revealed that they were mixed-type inhibitors. Al was found to be surface inhibited when coated with a thin film of inhibitors, and "Al's surface morphology was assessed by different techniques such as scanning electron microscopy (SEM), energy dispersive X-ray (EDX) and atomic force microscope (AFM)". "Theoretical models like quantum chemical and molecular dynamics simulation authenticated the experimental observation". The MOFs exhibit exceptional corrosion resistance against Al when exposed to acidic environments, according to several tests.}, } @article {pmid38280780, year = {2024}, author = {Karimvand, SK and Pahlevan, A and Zade, SV and Jafari, JM and Abdollahi, H}, title = {Multivariate curve resolution-soft independent modelling of class analogy (MCR-SIMCA).}, journal = {Analytica chimica acta}, volume = {1291}, number = {}, pages = {342205}, doi = {10.1016/j.aca.2024.342205}, pmid = {38280780}, issn = {1873-4324}, abstract = {BACKGROUND: Various classification, class modeling, and clustering techniques operate within abstract spaces, utilizing Principal Components (e.g., Linear Discriminant Analysis (LDA), Principal Component Analysis (PCA)) or latent variable spaces (e.g., Partial Least Squares Discriminant Analysis (PLS-DA)). It's important to note that PCA, despite being a mathematical tool, defines its Principal Components under certain mathematical constraints, it has a wide range of applications in the analysis of real-world systems. In this research, we assess the viability of employing the Multivariate Curve Resolution (MCR) subspace within class modeling techniques, as an alternative to the PC subspace. (92).

RESULTS: This study evaluates the use of the MCR subspace in class modeling methods, specifically in tandem with soft independent modeling of class analogy (SIMCA), to investigate the advantages of employing the meaningful physico-chemical subspace of MCR over the mathematical subspace of PCA. In the MCR-SIMCA strategy, the model is constructed by applying MCR to training samples from a target class. The MCR model effectively partitions the data into two smaller sub-matrices: the contribution matrix and the corresponding response matrix. In the next step, the contribution matrix resulting from the decomposition of the training set develops a distance plot (DP). First, the theory of the MCR-SIMCA model is discussed in detail. Next, two real experimental datasets were analyzed, and their performance was compared with the DD-SIMCA model. In most cases, the results were as good as or even more satisfactory than those obtained with the DD-SIMCA model. (146).

SIGNIFICANCE: The suggested class modeling method presents a promising avenue for the analysis of real-world natural systems. The study's results emphasize the practical utility of the MCR approach, underscoring the significance of the MCR subspace advantages over the PCA subspace. (39).}, } @article {pmid38279584, year = {2024}, author = {Lai, C and Chuang, LH and Lai, CC and Liu, CF and Yang, JW and Chen, HSL}, title = {Longitudinal changes in optical coherence tomography angiography characteristics in normal-tension glaucoma with or without high myopia.}, journal = {Acta ophthalmologica}, volume = {102}, number = {5}, pages = {e762-e773}, doi = {10.1111/aos.16644}, pmid = {38279584}, issn = {1755-3768}, mesh = {Humans ; *Tomography, Optical Coherence/methods ; *Low Tension Glaucoma/physiopathology/diagnosis ; Male ; Female ; *Visual Fields/physiology ; Middle Aged ; *Fluorescein Angiography/methods ; *Retinal Ganglion Cells/pathology ; *Nerve Fibers/pathology ; *Intraocular Pressure/physiology ; *Optic Disk/blood supply ; Retinal Vessels/diagnostic imaging/pathology ; Aged ; Follow-Up Studies ; Disease Progression ; Myopia, Degenerative/physiopathology/diagnosis/complications ; Retrospective Studies ; Fundus Oculi ; }, abstract = {PURPOSE: To evaluate the structural, microvascular, and functional progression of normal tension glaucoma (NTG) with or without high myopia by examining longitudinal changes in optical coherence tomography angiography (OCTA) and visual field (VF) parameters.

METHODS: We evaluated 61 NTG eyes and classified 25 of the eyes with axial lengths (ALs) of ≥26 mm as highly myopic. We assessed the rate of change in OCTA parameters, namely radial peripapillary capillary (RPC) vessel density (VD), parafovea VD, deep parafovea VD, retinal nerve fibre layer (RNFL) thickness, and ganglion cell complex thickness. We evaluated the correlation of the rate of change in OCTA parameters with VF loss and AL.

RESULTS: Among the 61 NTG eyes, rates of loss of RPC VD, parafovea VD, deep parafovea VD, and RNFL thickness were significantly different from zero despite the nonsignificant rate of change in VF mean deviation (MD). Changes in these OCTA parameters did not differ significantly in highly myopic NTG eyes. The rate of change in VF MD was significantly correlated with the rate of change in parafovea VD in highly myopic and non-highly myopic NTG eyes. In highly myopic NTG eyes, AL was negatively correlated with the rates of loss of RNFL thickness, VF MD, and VF PSD.

CONCLUSION: NTG eyes with a relatively stable VF exhibited loss of VD and RNFL thickness. VF progression in NTG was correlated with decreasing parafovea VD, indicating a structure-function correlation. Greater AL may indicate faster VF loss and RNFL thinning in highly myopic NTG eyes.}, } @article {pmid38278991, year = {2024}, author = {Irwin, KE and Jasin, P and Braunstein, KE and Sinha, IR and Garret, MA and Bowden, KD and Chang, K and Troncoso, JC and Moghekar, A and Oh, ES and Raitcheva, D and Bartlett, D and Miller, T and Berry, JD and Traynor, BJ and Ling, JP and Wong, PC}, title = {A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS-FTD.}, journal = {Nature medicine}, volume = {30}, number = {2}, pages = {382-393}, pmid = {38278991}, issn = {1546-170X}, support = {T32 GM136577/GM/NIGMS NIH HHS/United States ; R33 NS115161/NS/NINDS NIH HHS/United States ; RF1 NS095969/NS/NINDS NIH HHS/United States ; R01 NS095969/NS/NINDS NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; U01 FD008129/FD/FDA HHS/United States ; ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; UH3 NS115608/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; DNA-Binding Proteins/genetics/metabolism ; Biomarkers/cerebrospinal fluid ; }, abstract = {Although loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well documented in postmortem tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects loss of function of TDP-43, and thus detection of proteins containing cryptic exon-encoded neoepitopes in cerebrospinal fluid (CSF) or blood could reveal the earliest stages of TDP-43 dysregulation in patients. Here we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2) to show that loss of TDP-43 splicing repression occurs in ALS-FTD, including in presymptomatic C9orf72 mutation carriers. Cryptic hepatoma-derived growth factor-like protein 2 (HDGFL2) accumulates in CSF at significantly higher levels in familial ALS-FTD and sporadic ALS compared with controls and is elevated earlier than neurofilament light and phosphorylated neurofilament heavy chain protein levels in familial disease. Cryptic HDGFL2 can also be detected in blood of individuals with ALS-FTD, including in presymptomatic C9orf72 mutation carriers, and accumulates at levels highly correlated with those in CSF. Our findings indicate that loss of TDP-43 cryptic splicing repression occurs early in disease progression, even presymptomatically, and that detection of the HDGFL2 cryptic neoepitope serves as a potential diagnostic biomarker for ALS, which should facilitate patient recruitment and measurement of target engagement in clinical trials.}, } @article {pmid38278691, year = {2024}, author = {Kwon, Y and Kang, M and Jeon, YM and Lee, S and Lee, HW and Park, JS and Kim, HJ}, title = {Identification and characterization of novel ERBB4 variant associated with sporadic amyotrophic lateral sclerosis (ALS).}, journal = {Journal of the neurological sciences}, volume = {457}, number = {}, pages = {122885}, doi = {10.1016/j.jns.2024.122885}, pmid = {38278691}, issn = {1878-5883}, mesh = {Male ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/metabolism ; Mutation/genetics ; Receptor, ErbB-4/genetics/metabolism ; Tyrosine ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common type of motor neuron disease characterized by progressive motor neuron degeneration in brain and spinal cord. Most cases are sporadic in ALS and 5-10% of cases are familiar. >50 genes are known to be associated with ALS and one of them is ERBB4. In this paper, we report the case of a 53-year-old ALS patient with progressive muscle weakness and fasciculation, but he had no cognitive decline. We performed the next generation sequencing (NGS) and in silico analysis, it predicted a highly pathogenic variant, c.2116 A > G, p.Asn706Asp (N706D) in the ERBB4 gene. The amino acid residue is highly conserved among species. ERBB4 is a member of the ERBB family of receptor tyrosine kinases. ERBB4 has multiple tyrosine phosphorylation sites, including an autophosphorylation site at tyrosine 1284 residue. Autophosphorylation of ERBB4 promotes biological activity and it associated with NRG-1/ERBB4 pathway. It is already known that tyrosine 128 phosphorylation of ERBB4 is decreased in patients who have ALS-associated ERBB4 mutations. We generated ERBB4 N706D construct using site-directed mutagenesis and checked the phosphorylation level of ERBB4 N706D in NSC-34 cells. We found that the phosphorylation of ERBB4 N706D was decreased compared to ERBB4 wild-type, indicating a loss of function mutation in ERBB4. We report a novel variant in ERBB4 gene leading to ALS through dysfunction of ERBB4.}, } @article {pmid38278093, year = {2024}, author = {Goutman, SA and Boss, J and Jang, DG and Piecuch, C and Farid, H and Batra, M and Mukherjee, B and Feldman, EL and Batterman, SA}, title = {Avocational exposure associations with ALS risk, survival, and phenotype: A Michigan-based case-control study.}, journal = {Journal of the neurological sciences}, volume = {457}, number = {}, pages = {122899}, pmid = {38278093}, issn = {1878-5883}, support = {R01 TS000327/TS/ATSDR CDC HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; UL1 TR002240/TR/NCATS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; }, mesh = {Humans ; Middle Aged ; Case-Control Studies ; Michigan/epidemiology ; Risk Factors ; *Environmental Exposure ; Phenotype ; *Amyotrophic Lateral Sclerosis/epidemiology ; }, abstract = {INTRODUCTION: Environmental exposures strongly influence ALS risk and identification is needed to reduce ALS burden. Participation in hobbies and exercise may alter ALS risk and phenotype, warranting an assessment to understand their contribution to the ALS exposome.

METHODS: Participants with ALS and healthy controls were recruited from University of Michigan and self-completed a survey to ascertain hobbies, exercise, and avocational exposures. Exposure variables were associated with ALS risk, survival, onset segment, and onset age.

RESULTS: ALS (n = 400) and control (n = 287) participants self-reported avocational activities. Cases were slightly older (median age 63.0 vs. 61.1 years, p = 0.019) and had a lower educational attainment (p < 0.001) compared to controls; otherwise, demographics were well balanced. Risks associating with ALS after multiple comparison correction included golfing (odds ratio (OR) 3.48, padjusted = 0.004), recreational dancing (OR 2.00, padjusted = 0.040), performing gardening or yard work (OR 1.71, padjusted = 0.040) five years prior to ALS and personal (OR 1.76, padjusted = 0.047) or family (OR 2.21, padjusted = 0.040) participation in woodworking, and personal participation in hunting and shooting (OR 1.89, padjusted = 0.040). No exposures associated with ALS survival and onset. Those reporting swimming (3.86 years, padjusted = 0.016) and weightlifting (3.83 years, padjusted = 0.020) exercise 5 years prior to ALS onset had an earlier onset age.

DISCUSSION: The identified exposures in this study may represent important modifiable ALS factors that influence ALS phenotype. Thus, exposures related to hobbies and exercise should be captured in studies examining the ALS exposome.}, } @article {pmid38277781, year = {2024}, author = {Hirsch, E and Bornemissza, Z and Nagy, ZK and Marosi, GJ and Farkas, A}, title = {Quantitative and qualitative analysis of cell culture media powders for mammalian cells by Raman microscopy.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {310}, number = {}, pages = {123906}, doi = {10.1016/j.saa.2024.123906}, pmid = {38277781}, issn = {1873-3557}, mesh = {Animals ; Powders ; *Microscopy ; *Cell Culture Techniques/methods ; Recombinant Proteins ; Least-Squares Analysis ; Spectrum Analysis, Raman/methods ; Culture Media/chemistry ; Multivariate Analysis ; Mammals ; }, abstract = {Cell culture media are essential for large-scale recombinant protein production using mammalian cell cultures. The composition and quality of media significantly impact cell growth and product formation. Analyzing media poses challenges due to complex compositions and undisclosed exact compositions. Traditional methods like NMR and chromatography offer sensitivity but require time-consuming sample preparation and lack spatial information. Raman chemical mapping characterizes solids, but its use in cell culture media analysis is limited so far. We present a chemometric evaluation for Raman maps to qualify and quantify media components, evaluate powder homogeneity, and perform lot-to-lot comparisons. Three lots of a marketed cell culture media powder were measured with Raman mapping technique. Chemometrics techniques have outlined a strategy to extract information from complex data. First, a spectral library has been structured. In addition to the 23 spectra for presumed ingredients, we obtained another 9 pure components with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS). Then the Spectral Angle Mapper-Orthogonal Projection (SAM-OP) algorithm revealed whether references actually occur in the mapped media powders. Finally, a quantification was provided by Classical Least Squares (CLS) modelling. Quantities of 18 significant amino acids mostly correlated with the reference method. The proposed method can be generally applied even for such complicated samples. Leveraging Raman mapping and innovative chemometric methods enhance recombinant protein production by improving the understanding of the spatial distribution and composition of cell culture media in mammalian cell cultivations.}, } @article {pmid38277467, year = {2024}, author = {Seddighi, S and Qi, YA and Brown, AL and Wilkins, OG and Bereda, C and Belair, C and Zhang, YJ and Prudencio, M and Keuss, MJ and Khandeshi, A and Pickles, S and Kargbo-Hill, SE and Hawrot, J and Ramos, DM and Yuan, H and Roberts, J and Sacramento, EK and Shah, SI and Nalls, MA and Colón-Mercado, JM and Reyes, JF and Ryan, VH and Nelson, MP and Cook, CN and Li, Z and Screven, L and Kwan, JY and Mehta, PR and Zanovello, M and Hallegger, M and Shantaraman, A and Ping, L and Koike, Y and Oskarsson, B and Staff, NP and Duong, DM and Ahmed, A and Secrier, M and Ule, J and Jacobson, S and Reich, DS and Rohrer, JD and Malaspina, A and Dickson, DW and Glass, JD and Ori, A and Seyfried, NT and Maragkakis, M and Petrucelli, L and Fratta, P and Ward, ME}, title = {Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.}, journal = {Science translational medicine}, volume = {16}, number = {734}, pages = {eadg7162}, pmid = {38277467}, issn = {1946-6242}, support = {RF1 AG062171/AG/NIA NIH HHS/United States ; T32 GM136577/GM/NIGMS NIH HHS/United States ; RF1 AG062077/AG/NIA NIH HHS/United States ; MR/M023664/1/MRC_/Medical Research Council/United Kingdom ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; MR/T046015/1/MRC_/Medical Research Council/United Kingdom ; P01 NS084974/NS/NINDS NIH HHS/United States ; R35 NS097273/NS/NINDS NIH HHS/United States ; CC0102/ARC_/Arthritis Research UK/United Kingdom ; MC_PC_MR/S022708/1/MRC_/Medical Research Council/United Kingdom ; U19 AG063911/AG/NIA NIH HHS/United States ; MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; FI2 GM142475/GM/NIGMS NIH HHS/United States ; ZIA NS003155/ImNIH/Intramural NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; MR/W005190/1/MRC_/Medical Research Council/United Kingdom ; MALASPINA/APR13/817-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/J009482/1/MRC_/Medical Research Council/United Kingdom ; HALLEGGER/OCT15/959-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics ; Peptides ; Proteomics ; }, abstract = {Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.}, } @article {pmid38276084, year = {2024}, author = {Vacchiano, V and Bonan, L and Liguori, R and Rizzo, G}, title = {Primary Lateral Sclerosis: An Overview.}, journal = {Journal of clinical medicine}, volume = {13}, number = {2}, pages = {}, pmid = {38276084}, issn = {2077-0383}, abstract = {Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder which causes the selective deterioration of the upper motor neurons (UMNs), sparing the lower motor neuron (LMN) system. The clinical course is defined by a progressive motor disability due to muscle spasticity which typically involves lower extremities and bulbar muscles. Although classically considered a sporadic disease, some familiar cases and possible causative genes have been reported. Despite it having been recognized as a rare but distinct entity, whether it actually represents an extreme end of the motor neuron diseases continuum is still an open issue. The main knowledge gap is the lack of specific biomarkers to improve the clinical diagnostic accuracy. Indeed, the diagnostic imprecision, together with some uncertainty about overlap with UMN-predominant ALS and Hereditary Spastic Paraplegia (HSP), has become an obstacle to the development of specific therapeutic trials. In this study, we provided a comprehensive analysis of the existing literature, including neuropathological, clinical, neuroimaging, and neurophysiological features of the disease, and highlighting the controversies still unsolved in the differential diagnoses and the current diagnostic criteria. We also discussed the current knowledge gaps still present in both diagnostic and therapeutic fields when approaching this rare condition.}, } @article {pmid38274887, year = {2023}, author = {Ito, M and Fujii, N and Kohara, S and Tanaka, M and Takao, M and Mihara, B and Saito, Y and Mizuma, A and Nakayama, T and Netsu, S and Suzuki, N and Kakita, A and Nagata, E}, title = {Elevation of inositol pyrophosphate IP7 in the mammalian spinal cord of amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1334004}, pmid = {38274887}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive impairment of spinal motor neurons. Continuous research endeavor is underway to fully understand the molecular mechanisms associating with this disorder. Although several studies have implied the involvement of inositol pyrophosphate IP7 in ALS, there is no direct experimental evidence proving this notion. In this study, we analyzed inositol pyrophosphate IP7 and its precursor IP6 in the mouse and human ALS biological samples to directly assess whether IP7 level and/or its metabolism are altered in ALS disease state.

METHODS: We used a liquid chromatography-mass spectrometry (LC-MS) protocol originally-designed for mammalian IP6 and IP7 analysis. We measured the abundance of these molecules in the central nervous system (CNS) of ALS mouse model SOD1(G93A) transgenic (TG) mice as well as postmortem spinal cord of ALS patients. Cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) from ALS patients were also analyzed to assess if IP7 status in these biofluids is associated with ALS disease state.

RESULTS: SOD1(G93A) TG mice showed significant increase of IP7 level in the spinal cord compared with control mice at the late stage of disease progression, while its level in cerebrum and cerebellum remains constant. We also observed significantly elevated IP7 level and its product-to-precursor ratio (IP7/IP6) in the postmortem spinal cord of ALS patients, suggesting enhanced enzymatic activity of IP7-synthesizing kinases in the human ALS spinal cord. In contrast, human CSF did not contain detectable level of IP6 and IP7, and neither the IP7 level nor the IP7/IP6 ratio in human PBMCs differentiated ALS patients from age-matched healthy individuals.

CONCLUSION: By directly analyzing IP7 in the CNS of ALS mice and humans, the findings of this study provide direct evidence that IP7 level and/or the enzymatic activity of IP7-generating kinases IP6Ks are elevated in ALS spinal cord. On the other hand, this study also showed that IP7 is not suitable for biofluid-based ALS diagnosis. Further investigation is required to elucidate a role of IP7 in ALS pathology and utilize IP7 metabolism on the diagnostic application of ALS.}, } @article {pmid38271732, year = {2024}, author = {Sample, C and Rahmim, A and Benard, F and Wu, J and Clark, H}, title = {PSMA PET/CT as a predictive tool for subregional importance estimates in the parotid gland.}, journal = {Biomedical physics & engineering express}, volume = {10}, number = {2}, pages = {}, doi = {10.1088/2057-1976/ad229c}, pmid = {38271732}, issn = {2057-1976}, mesh = {Humans ; Head ; *Parotid Gland/diagnostic imaging ; *Positron Emission Tomography Computed Tomography ; Positron-Emission Tomography ; }, abstract = {Objective. Xerostomia and radiation-induced salivary gland dysfunction remain a common side effect for head-and-neck radiotherapy patients, and attempts have been made to quantify the heterogeneity of the dose response within parotid glands. Prostate Specific Membrane Antigen (PSMA) ligands have demonstrated high uptake in salivary glands, which has been shown to correlate with gland functionality. Here we compare several models of parotid gland subregional relative importance with PSMA positron emission tomography (PET) uptake. We then develop a predictive model for Clarket al's relative importance estimates using PSMA PET and CT radiomic features, and demonstrate a methodology for predicting patient-specific importance deviations from the population.Approach. Intra-parotid gland uptake was compared with four regional importance models using 30 [18F]DCFPyL PSMA PET images. The correlation of uptake and importance was ascertained when numerous non-overlapping subregions were defined, while a paired t-test was used to compare binary region pairs. A radiomics-based predictive model of population importance was developed using a double cross-validation methodology. A model was then devised for supplementing population-level subregional importance estimates for each patient using patient-specific radiomic features.Main Results. Anticorrelative relationships were found to exist between PSMA PET uptake and four independent models of subregional parotid gland importance from the literature. Kernel Ridge Regression with principal component analysis feature selection performed best over test sets (Mean Absolute Error = 0.08), with gray level co-occurrence matrix (GLCM) features being particularly important. Deblurring PSMA PET images with neural blind deconvolution strengthened correlations and improved model performance.Significance. This study suggests that regions of relatively low PSMA PET uptake in parotid glands may exhibit relatively high dose-sensitivity. We've demonstrated the utility of PSMA PET radiomic features for predicting relative importance within subregions of parotid glands. PSMA PET appears to be a promising quantitative imaging modality for analyzing salivary gland functionality.}, } @article {pmid38270797, year = {2024}, author = {Singh, S and Borkar, MR and Bhatt, LK}, title = {Transposable Elements: Emerging Therapeutic Targets in Neurodegenerative Diseases.}, journal = {Neurotoxicity research}, volume = {42}, number = {1}, pages = {9}, pmid = {38270797}, issn = {1476-3524}, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; DNA Transposable Elements/genetics ; *Amyotrophic Lateral Sclerosis ; *Alzheimer Disease ; *Parkinson Disease ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by the progressive loss of neuronal function and structure. While several genetic and environmental factors have been implicated in the pathogenesis of these disorders, emerging evidence suggests that transposable elements (TEs), once considered "junk DNA," play a significant role in their development and progression. TEs are mobile genetic elements capable of moving within the genome, and their dysregulation has been associated with genomic instability, altered gene expression, and neuroinflammation. This review provides an overview of TEs, including long interspersed nuclear elements (LINEs), short interspersed nuclear elements (SINEs), and endogenous retroviruses (ERVs), mechanisms of repression and derepression, and their potential impact on neurodegeneration. The evidence linking TEs to AD, PD, and ALS by shedding light on the complex interactions between TEs and neurodegeneration has been discussed. Furthermore, the therapeutic potential of targeting TEs in neurodegenerative diseases has been explored. Understanding the role of TEs in neurodegeneration holds promise for developing novel therapeutic strategies aimed at mitigating disease progression and preserving neuronal health.}, } @article {pmid38270730, year = {2024}, author = {Abbasi, A and Fryk, H and Rudnik, J and White, R and Vanderkelen, M and Scowcroft, A and Bonar, K}, title = {Using an expanded algorithm to estimate prevalence of amyotrophic lateral sclerosis in U.S. and UK.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {5}, pages = {2321-2324}, pmid = {38270730}, issn = {1590-3478}, mesh = {Humans ; Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/diagnosis ; Prevalence ; *Motor Neuron Disease ; Algorithms ; United Kingdom/epidemiology ; }, abstract = {BACKGROUND: There is an increasing need to better understand the burden of amyotrophic lateral sclerosis (ALS) using real-world data (RWD). However, identifying ALS cases using RWD presents several challenges due to the rarity of ALS and the differences in database coding systems.

METHODS: MarketScan claims, and the UK Clinical Practice Research Datalink (CPRD) databases were searched for diagnosis codes of ALS or MND, the only drugs approved for treating ALS (riluzole and edaravone) and clinical visits with 12-month enrolment prior to 1 January 2011. The main algorithm required ≥ 1 ALS diagnosis code together with prescriptions or clinical visits. We expanded the existing algorithm to identify unspecific (possible) ALS group that had codes for motor neuron disease (MND) and the ALS drugs. The study period was from 1 January 2011 until 31 December 2020.

RESULTS: We identified 16,246 patients with ≥ 1 ALS code in Marketscan (denominator n = 85,279,619), yet only 184 were found in the UK CPRD (denominator n = 21,318,589). Using the main algorithm 9,433 ALS patients were included in MarketScan, with a prevalence ranged between 4.5 per 100,000 in 2019 and 6.2 in 2015. In MarketScan, 3,658 (4.3 per 100,000) had ≥ 1 MND code and the ALS drug codes (possible cases). In CPRD, 47.9% of 2,785 patients with ≥ 1 MND code had a prescription for riluzole (6.3 per 100,000), regarded as possible ALS cases.

CONCLUSIONS: The expanded algorithm enabled the identification of a large population with ALS, or possible ALS, and the estimation of ALS prevalence in MarketScan and CPRD.}, } @article {pmid38270442, year = {2024}, author = {Smith, R and Hovren, H and Bowser, R and Bakkar, N and Garruto, R and Ludolph, A and Ravits, J and Gaertner, L and Murphy, D and Lebovitz, R}, title = {Misfolded alpha-synuclein in amyotrophic lateral sclerosis: Implications for diagnosis and treatment.}, journal = {European journal of neurology}, volume = {31}, number = {4}, pages = {e16206}, pmid = {38270442}, issn = {1468-1331}, mesh = {Humans ; *alpha-Synuclein/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Lewy Bodies/metabolism/pathology ; Superoxide Dismutase-1 ; }, abstract = {BACKGROUND: Alpha-synuclein (α-Syn) oligomers and fibrils have been shown to augment the aggregation of TAR DNA-binding Protein 43 (TDP-43) monomers in vitro, supporting the idea that TDP-43 proteinopathies such as ALS may be modulated by the presence of toxic forms of α-Syn. Recently, parkinsonian features were reported in a study of European patients and Lewy bodies have been demonstrated pathologically in a similar series of patients. Based on these and other considerations, we sought to determine whether seed-competent α-Syn can be identified in spinal fluid of patients with ALS including familial, sporadic, and Guamanian forms of the disease.

METHODS: Based on the finding that α-Syn has been found to be a prion-like protein, we have utilized a validated α-Synuclein seed amplification assay to determine if seed-competent α-Syn could be detected in the spinal fluid of patients with ALS.

RESULTS: Toxic species of α-Syn were detected in CSF in 18 of 127 ALS patients, 5 of whom were from Guam. Two out of twenty six samples from patients with C9orf72 variant ALS had positive seed-amplification assays (SAAs). No positive tests were noted in superoxide dismutase type 1 ALS subjects (n = 14). The SAA was negative in 31 control subjects.

CONCLUSIONS: Our findings suggest that a sub-group of ALS occurs in which self-replicating α-Syn is detectable and likely contributes to its pathogenesis. This finding may have implications for the diagnosis and treatment of this disorder.}, } @article {pmid38270154, year = {2024}, author = {Jiang, Q and Wei, Q and Zhang, L and Yang, T and Lin, J and Xiao, Y and Li, C and Hou, Y and Ou, R and Liu, K and Zhao, B and Wu, Y and Lai, X and Shang, H}, title = {Peripheral immunity relate to disease progression and prognosis in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {5-6}, pages = {465-474}, doi = {10.1080/21678421.2024.2306969}, pmid = {38270154}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/blood/mortality ; Male ; Female ; Middle Aged ; *Disease Progression ; Aged ; Prognosis ; Adult ; CD4-Positive T-Lymphocytes/immunology ; Immunoglobulin G/blood ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Abnormalities in the peripheral immune system in ALS have been paid attention; however, the results of changes in peripheral immune parameters were inconsistent.

METHODS: A total of 1109 ALS patients were enrolled in the study. All patients received clinical evaluation and peripheral immune parameters measurement. The outcomes were analyzed by correlation analysis, multiple linear regression and cox survival analysis.

RESULTS: We found that ALS patients had significantly higher percentage of CD4[+] T cells (39.3 vs. 37.1%, p < 0.001) and CD4[+]/CD8[+] ratio (1.88 vs. 1.72, p = 0.011), significantly lower IgG (11.73 vs.12.82, p < 0.001) and IgA (2130.70 vs. 2284.8, p = 0.013) compared with the health controls. In the multivariate linear model, we found that each increase of 1.262, 0.278, and 4.44E-4 in ALSFRS-R scores were significantly associated with each increment of lymphocyte count, IgG, and IgA, respectively. However, each decrease of 0.341, 0.068, and 0.682 in ALSFRS-R score was associated with each increment in neutrophils, CD4[+] T cells, and CD4[+]/CD8[+] ratio, respectively. Cox survival regression analysis showed that the death risk of ALS patients was related to the levels of C3 (HR 0.592, 95% CI 0.361-0.973).

CONCLUSION: We found that there were differences in peripheral immune parameters of ALS patients with the severity of the disease, especially neutrophil, lymphocyte, CD4[+] T, and IgG; C3 is an independent predictor of survival in ALS patients. More studies are needed to elucidate the mechanisms associated with altered immune parameters in ALS.}, } @article {pmid38268041, year = {2024}, author = {Cascella, M and Monaco, F and Vittori, A and Elshazly, M and Carlucci, A and Piazza, O}, title = {Bridging knowledge gaps: a bibliometric analysis of non-invasive ventilation in palliative care studies.}, journal = {Journal of anesthesia, analgesia and critical care}, volume = {4}, number = {1}, pages = {5}, pmid = {38268041}, issn = {2731-3786}, abstract = {BACKGROUND: Despite being a useful strategy for providing respiratory support to patients with advanced or terminal illnesses, non-invasive ventilation (NIV) requires in-depth investigation in several key aspects.

OBJECTIVES: This bibliometric analysis seeks to comprehensively examine the existing research on the subject. Its goal is to uncover valuable insights that can inform the prediction trajectory of studies, guide the implementation of corrective measures, and contribute to the improvement of research networks.

METHODS: A comprehensive review of literature on NIV in the context of palliative care was conducted using the Web of Science core collection online database. The search utilized the key terms "non-invasive ventilation" and "palliative care" to identify the most relevant articles. All data were gathered on November 7, 2023. Relevant information from documents meeting the specified criteria was extracted, and Journal Citation Reports™ 2022 (Clarivate Analytics) served as the data source. The analysis employed literature analysis and knowledge visualization tools, specifically CiteScope (version 6.2.R4) and VOSviewer (version 1.6.20).

RESULTS: A dataset with bibliometric findings from 192 items was analyzed. We found a consistent upward of the scientific output trend over time. Guidelines on amyotrophic lateral sclerosis management received the highest number of citations. Most documents were published in top-ranked journals. Less than one-third of the documents pertain to clinical studies, especially retrospective analyses (25%). Key topics such as "decision making", and "communication" were less addressed.

CONCLUSIONS: Given the substantial clinical implications, further high-quality studies on this subject are recommended. Encouraging international collaborations is needed. Despite the growing volume of documents in the field, this bibliometric analysis indicates a decline in collaborative networks.}, } @article {pmid38267984, year = {2024}, author = {Irwin, KE and Sheth, U and Wong, PC and Gendron, TF}, title = {Fluid biomarkers for amyotrophic lateral sclerosis: a review.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {9}, pmid = {38267984}, issn = {1750-1326}, support = {R01 NS095969/NS/NINDS NIH HHS/United States ; T32 GM136577/GM/NIGMS NIH HHS/United States ; P01NS084974/NH/NIH HHS/United States ; U19AG063911/NH/NIH HHS/United States ; RF1 NS095969/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Neurodegenerative Diseases ; Biomarkers ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Presently, three FDA-approved drugs are available to help slow functional decline for patients with ALS, but no cure yet exists. With an average life expectancy of only two to five years after diagnosis, there is a clear need for biomarkers to improve the care of patients with ALS and to expedite ALS treatment development. Here, we provide a review of the efforts made towards identifying diagnostic, prognostic, susceptibility/risk, and response fluid biomarkers with the intent to facilitate a more rapid and accurate ALS diagnosis, to better predict prognosis, to improve clinical trial design, and to inform interpretation of clinical trial results. Over the course of 20 + years, several promising fluid biomarker candidates for ALS have emerged. These will be discussed, as will the exciting new strategies being explored for ALS biomarker discovery and development.}, } @article {pmid38267577, year = {2024}, author = {Obara, CJ and Nixon-Abell, J and Moore, AS and Riccio, F and Hoffman, DP and Shtengel, G and Xu, CS and Schaefer, K and Pasolli, HA and Masson, JB and Hess, HF and Calderon, CP and Blackstone, C and Lippincott-Schwartz, J}, title = {Motion of VAPB molecules reveals ER-mitochondria contact site subdomains.}, journal = {Nature}, volume = {626}, number = {7997}, pages = {169-176}, pmid = {38267577}, issn = {1476-4687}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/genetics ; *Endoplasmic Reticulum/chemistry/metabolism/ultrastructure ; *Mitochondria/chemistry/metabolism/ultrastructure ; *Mitochondrial Membranes/chemistry/metabolism/ultrastructure ; Signal Transduction ; *Vesicular Transport Proteins/genetics/metabolism/ultrastructure ; Microscopy, Electron ; Imaging, Three-Dimensional ; Binding Sites ; Diffusion ; Time Factors ; Mutation ; Homeostasis ; *Movement ; }, abstract = {To coordinate cellular physiology, eukaryotic cells rely on the rapid exchange of molecules at specialized organelle-organelle contact sites[1,2]. Endoplasmic reticulum-mitochondrial contact sites (ERMCSs) are particularly vital communication hubs, playing key roles in the exchange of signalling molecules, lipids and metabolites[3,4]. ERMCSs are maintained by interactions between complementary tethering molecules on the surface of each organelle[5,6]. However, due to the extreme sensitivity of these membrane interfaces to experimental perturbation[7,8], a clear understanding of their nanoscale organization and regulation is still lacking. Here we combine three-dimensional electron microscopy with high-speed molecular tracking of a model organelle tether, Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), to map the structure and diffusion landscape of ERMCSs. We uncovered dynamic subdomains within VAPB contact sites that correlate with ER membrane curvature and undergo rapid remodelling. We show that VAPB molecules enter and leave ERMCSs within seconds, despite the contact site itself remaining stable over much longer time scales. This metastability allows ERMCSs to remodel with changes in the physiological environment to accommodate metabolic needs of the cell. An amyotrophic lateral sclerosis-associated mutation in VAPB perturbs these subdomains, likely impairing their remodelling capacity and resulting in impaired interorganelle communication. These results establish high-speed single-molecule imaging as a new tool for mapping the structure of contact site interfaces and reveal that the diffusion landscape of VAPB at contact sites is a crucial component of ERMCS homeostasis.}, } @article {pmid38267456, year = {2024}, author = {Feró, O and Varga, D and Nagy, É and Karányi, Z and Sipos, É and Engelhardt, J and Török, N and Balogh, I and Vető, B and Likó, I and Fóthi, Á and Szabó, Z and Halmos, G and Vécsei, L and Arányi, T and Székvölgyi, L}, title = {DNA methylome, R-loop and clinical exome profiling of patients with sporadic amyotrophic lateral sclerosis.}, journal = {Scientific data}, volume = {11}, number = {1}, pages = {123}, pmid = {38267456}, issn = {2052-4463}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; DNA ; Epigenome ; Exome ; R-Loop Structures ; *DNA Methylation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the death of motor neurons, the aetiology of which is essentially unknown. Here, we present an integrative epigenomic study in blood samples from seven clinically characterised sporadic ALS patients to elucidate molecular factors associated with the disease. We used clinical exome sequencing (CES) to study DNA variants, DNA-RNA hybrid immunoprecipitation sequencing (DRIP-seq) to assess R-loop distribution, and reduced representation bisulfite sequencing (RRBS) to examine DNA methylation changes. The above datasets were combined to create a comprehensive repository of genetic and epigenetic changes associated with the ALS cases studied. This repository is well-suited to unveil new correlations within individual patients and across the entire patient cohort. The molecular attributes described here are expected to guide further mechanistic studies on ALS, shedding light on the underlying genetic causes and facilitating the development of new epigenetic therapies to combat this life-threatening disease.}, } @article {pmid38267282, year = {2024}, author = {Tortorella, MEC and Alves, I and Gromicho, M and Santos, MO and de Carvalho, M}, title = {Proton pump inhibitors and amyotrophic lateral sclerosis: A case-control study.}, journal = {Journal of the neurological sciences}, volume = {457}, number = {}, pages = {122895}, doi = {10.1016/j.jns.2024.122895}, pmid = {38267282}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Case-Control Studies ; Proton Pump Inhibitors/adverse effects ; Disease Progression ; }, } @article {pmid38267040, year = {2024}, author = {Fukui, Y and Shirakawa, H and Kaneko, S and Nagayasu, K}, title = {Wild-Type DCTN1 Suppresses the Aggregation of DCTN1 Mutants Associated with Perry Disease.}, journal = {Biological & pharmaceutical bulletin}, volume = {47}, number = {1}, pages = {253-258}, doi = {10.1248/bpb.b23-00828}, pmid = {38267040}, issn = {1347-5215}, mesh = {Humans ; Dynactin Complex/genetics ; HEK293 Cells ; Cytosol ; Mutation ; *Motor Neuron Disease ; }, abstract = {Perry disease, a rare autosomal dominant neurodegenerative disorder, is characterized by parkinsonism, depression or apathy, unexpected weight loss, and central hypoventilation. Genetic analyses have revealed a strong association between point mutations in the dynactin I gene (DCTN1) coding p150[glued] and Perry disease. Although previous reports have suggested a critical role of p150[glued] aggregation in Perry disease pathology, whether and how p150[glued] mutations affect protein aggregation is not fully understood. In this study, we comprehensively investigated the intracellular distribution of the p150[glued] mutants in HEK293T cells. We further assessed the effect of co-overexpression of the wild-type p150[glued] protein with mutants on the formation of mutant aggregates. Notably, overexpression of p150[glued] mutants identified in healthy controls, which is also associated with amyotrophic lateral sclerosis, showed a thread-like cytoplasmic distribution, similar to the wild-type p150[glued]. In contrast, p150[glued] mutants in Perry disease and motor neuron disease caused aggregation. In addition, the co-overexpression of the wild-type protein with p150[glued] mutants in Perry disease suppressed aggregate formation. In contrast, the p150[glued] aggregation of motor neuron disease mutants was less affected by the wild-type p150[glued]. Further investigation of the mechanism of aggregate formation, contents of the aggregates, and biological mechanisms of Perry disease could help develop novel therapeutics.}, } @article {pmid38266764, year = {2024}, author = {Lundt, S and Zhang, N and Polo-Parada, L and Wang, X and Ding, S}, title = {Dietary NMN supplementation enhances motor and NMJ function in ALS.}, journal = {Experimental neurology}, volume = {374}, number = {}, pages = {114698}, doi = {10.1016/j.expneurol.2024.114698}, pmid = {38266764}, issn = {1090-2430}, support = {R01 NS069726/NS/NINDS NIH HHS/United States ; R01 NS094539/NS/NINDS NIH HHS/United States ; R01 NS123023/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; NAD/metabolism ; Neuromuscular Junction/metabolism ; Dietary Supplements ; Mice, Transgenic ; Disease Models, Animal ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease that causes the degeneration of motor neurons in the motor cortex and spinal cord. Patients with ALS experience muscle weakness and atrophy in the limbs which eventually leads to paralysis and death. NAD[+] is critical for energy metabolism, such as glycolysis and oxidative phosphorylation, but is also involved in non-metabolic cellular reactions. In the current study, we determined whether the supplementation of nicotinamide mononucleotide (NMN), an NAD[+] precursor, in the diet had beneficial impacts on disease progression using a SOD1[G93A] mouse model of ALS. We found that the ALS mice fed with an NMN-supplemented diet (ALS[+NMN] mice) had modestly extended lifespan and exhibited delayed motor dysfunction. Using electrophysiology, we studied the effect of NMN on synaptic transmission at neuromuscular junctions (NMJs) in symptomatic of ALS mice (18 weeks old). ALS[+NMN] mice had larger end-plate potential (EPP) amplitudes and maintained better responses than ALS mice, and also had restored EPP facilitation. While quantal content was not affected by NMN, miniature EPP (mEPP) amplitude and frequency were elevated in ALS[+NMN] mice. NMN supplementation in diet also improved NMJ morphology, innervation, mitochondrial structure, and reduced reactive astrogliosis in the ventral horn of the lumbar spinal cord. Overall, our results indicate that dietary consumption of NMN can slow motor impairment, enhance NMJ function and improve healthspan of ALS mice.}, } @article {pmid38266701, year = {2024}, author = {Eisen, A and Nedergaard, M and Gray, E and Kiernan, MC}, title = {The glymphatic system and Amyotrophic lateral sclerosis.}, journal = {Progress in neurobiology}, volume = {234}, number = {}, pages = {102571}, doi = {10.1016/j.pneurobio.2024.102571}, pmid = {38266701}, issn = {1873-5118}, mesh = {Humans ; *Glymphatic System/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/metabolism ; Brain/metabolism ; *Alzheimer Disease/metabolism ; Sleep ; }, abstract = {The glymphatic system and the meningeal lymphatic vessels provide a pathway for transport of solutes and clearance of toxic material from the brain. Of specific relevance to ALS, this is applicable for TDP-43 and glutamate, both major elements in disease pathogenesis. Flow is propelled by arterial pulsation, respiration, posture, as well as the positioning and proportion of aquaporin-4 channels (AQP4). Non-REM slow wave sleep is the is key to glymphatic drainage which discontinues during wakefulness. In Parkinson's disease and Alzheimer's disease, sleep impairment is known to predate the development of characteristic clinical features by several years and is associated with progressive accumulation of toxic proteinaceous products. While sleep issues are well described in ALS, consideration of preclinical sleep impairment or the potential of a failing glymphatic system in ALS has rarely been considered. Here we review how the glymphatic system may impact ALS. Preclinical sleep impairment as an unrecognized major risk factor for ALS is considered, while potential therapeutic options to improve glymphatic flow are explored.}, } @article {pmid38265475, year = {2024}, author = {Xiang, Y and Song, X and Long, D}, title = {Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases.}, journal = {Archives of toxicology}, volume = {98}, number = {3}, pages = {579-615}, pmid = {38265475}, issn = {1432-0738}, support = {81673227//National Natural Science Foundation of China/ ; 2020JJ4080//Natural Science Foundation of Hunan Province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases ; NF-E2-Related Factor 2/metabolism ; *Ferroptosis ; Oxidative Stress/physiology ; Antioxidants/metabolism ; }, abstract = {This article provides an overview of the background knowledge of ferroptosis in the nervous system, as well as the key role of nuclear factor E2-related factor 2 (Nrf2) in regulating ferroptosis. The article takes Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) as the starting point to explore the close association between Nrf2 and ferroptosis, which is of clear and significant importance for understanding the mechanism of neurodegenerative diseases (NDs) based on oxidative stress (OS). Accumulating evidence links ferroptosis to the pathogenesis of NDs. As the disease progresses, damage to the antioxidant system, excessive OS, and altered Nrf2 expression levels, especially the inhibition of ferroptosis by lipid peroxidation inhibitors and adaptive enhancement of Nrf2 signaling, demonstrate the potential clinical significance of Nrf2 in detecting and identifying ferroptosis, as well as targeted therapy for neuronal loss and mitochondrial dysfunction. These findings provide new insights and possibilities for the treatment and prevention of NDs.}, } @article {pmid38264389, year = {2023}, author = {Gouveia, C and Araújo, L and Freitas, S and Correia, J and Passos, V and Camacho, G and Gomes, L and Fragoeiro, H and Camacho, C and Chambino, B}, title = {A Palliative Care Approach to Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {15}, number = {12}, pages = {e51048}, pmid = {38264389}, issn = {2168-8184}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a degenerative disease characterized by motor dysfunction. Currently, treatment options are limited and management is based mostly on symptom control and quality of life optimization, so palliative care plays a fundamental role. Our objective was to characterize the ALS population in Madeira Island that was referenced and/or followed by a palliative care unit over a five-year period.

METHODS: Longitudinal, retrospective, descriptive, and observational study to analyze patients with ALS who were referred and/or followed by a palliative care unit during a five-year period, between 2017 and 2021. Patient's medical electronic and physical records were analyzed to gather data. Descriptive and inferential statistical analysis was done using Microsoft Excel and Statistical Package for the Social Sciences (version 28.0.1).

RESULTS: During this five-year period, a total of 38 patients were diagnosed with ALS in Madeira Island and 23 (60.53%) were referred to palliative care. Three patients died before assessment, so 20 (50.63%) were followed by the palliative care team. They had a median life expectancy of 425 days and the median time spent in palliative care was 137 days. Of this population, 56.52% (n=13) was male with an average age of 64 years. The median period from diagnosis to referral was 167 days, with most referrals being made by family medicine (39.13%; n=9) motivated by uncontrolled symptoms (95.65%; n=22). The median period from referral to first assessment by a palliative care physician was 19 days. The Palliative Performance Scale (PPS) and Confusion Assessment Method (CAM) applied on the first visit had a median score of 40% in the former and was negative in 95.00% (n=19) of patients in the latter. Advanced care directives were present in 55.00% (n=11) of patients and all provided care was in accordance with the patient's wishes. The most common symptoms were dysphagia, dyspnea, pain, anxiety, and sialorrhea. The most used drugs were morphine, riluzole, butylscopolamine, bisacodyl, and midazolam. As for other interventions, 55.00% (n=11) of patients underwent noninvasive ventilation (NIV), 15.00% (n=3) were submitted to percutaneous endoscopic gastrostomy (PEG), and one patient (5.00%) was nasogastrically intubated. The death rate was 95.00% (n=19) with 73.68% (n=14) of deaths occurring in the palliative care unit.

CONCLUSION: Literature has shown that there are many advantages to the early inclusion of palliative care in ALS management, achieving effective symptom control and greater quality of life, but also reducing caregiver burden. However, in this study, we found that referrals to palliative care were late and included mostly cases of advanced disease with uncontrolled symptoms.}, } @article {pmid38263228, year = {2024}, author = {Ayyappan, MV and Kishore, P and Panda, SK and Kumar, A and Uchoi, D and Nadella, RK and Priyadarshi, H and Obaiah, MC and George, D and Hamza, M and Ramannathan, SK and Ravishankar, CN}, title = {Emergence of multidrug resistant, ctx negative seventh pandemic Vibrio cholerae O1 El Tor sequence type (ST) 69 in coastal water of Kerala, India.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {2031}, pmid = {38263228}, issn = {2045-2322}, mesh = {Animals ; *Vibrio cholerae O1 ; Ecosystem ; Pandemics ; Phylogeny ; *Cholera ; India ; *Lepidoptera ; Water ; }, abstract = {Seventh pandemic Vibrio choleare O1 El Tor strain is responsible for the on-going pandemic outbreak of cholera globally. This strain evolved from non-pathogenic V. cholerae by acquiring seventh pandemic gene (VC 2346), pandemic Islands (VSP1 and VSP2), pathogenicity islands (VP1 and VP2) and CTX prophage region. The cholera toxin production is mainly attributed to the presence of ctx gene in these strains. However, several variants of this strain emerged as hybrid strains or atypical strains. The present study aimed to assess the aquatic environment of Cochin, India, over a period of 5 years for the emergence of multidrug resistant V. cholerae and its similarity with seventh pandemic strain. The continuous surveillance and monitoring resulted in the isolation of ctx negative, O1 positive V. cholerae isolate (VC6) from coastal water, Cochin, Kerala. The isolate possessed the biotype specific O1 El Tor tcpA gene and lacked other biotype specific ctx, zot, ace and rst genes. Whole genome analysis revealed the isolate belongs to pandemic sequence type (ST) 69 with the possession of pandemic VC2346 gene, pathogenic island VPI1, VPI2, and pandemic island VSP1 and VSP2. The isolate possessed several insertion sequences and the SXT/R391 family related Integrative Conjugative Elements (ICEs). In addition to this, the isolate genome carried virulence genes such as VgrG, mshA, ompT, toxR, ompU, rtxA, als, VasX, makA, and hlyA and antimicrobial resistance genes such as gyrA, dfrA1, strB, parE, sul2, parC, strA, VC1786ICE9-floR, and catB9. Moreover, the phylogenetic analysis suggests that the isolate genome is more closely related to seventh pandemic V. cholerae O1 N16961 strain. This study reports the first incidence of environmental ctx negative seventh pandemic V. choleare O1 El Tor isolate, globally and its presence in the aquatic system likely to induce toxicity in terms of public health point of view. The presence of this isolate in the aquatic environment warns the strict implementation of the epidemiological surveillance on the occurrence of emerging strains and the execution of flagship program for the judicious use of antibiotics in the aquatic ecosystem.}, } @article {pmid38262892, year = {2024}, author = {Adams-Mitchell, CJ and Smith, WR and Wilkie, DJ}, title = {Dysphagia in patients with sickle cell disease: An understudied problem.}, journal = {Journal of the National Medical Association}, volume = {116}, number = {2 Pt 1}, pages = {126-130}, doi = {10.1016/j.jnma.2023.11.005}, pmid = {38262892}, issn = {1943-4693}, mesh = {Humans ; *Deglutition Disorders/complications/diagnosis ; *Anemia, Sickle Cell/complications ; *Stroke/complications ; *Nervous System Diseases/complications ; *Parkinson Disease ; }, abstract = {Dysphagia which is defined as disordered swallowing is well known as one of the most common and dangerous symptoms of many diseases, including neurological disorders such as Parkinson's disease, amyotrophic lateral sclerosis, myasthenia gravis, and most commonly, stroke. Strokes are a potentially devastating complication of sickle cell disease (SCD), the most common genetic hemoglobinopathy worldwide, yet little is known about dysphagia as it relates to SCD. Thus, the purposes of this article are to review briefly the primary causes and health consequences of dysphagia, to highlight the relevance of dysphagia to SCD, to review what little is known about dysphagia in SCD, to recommend, based on our consensus and the available literature, when to screen, evaluate, and monitor dysphagia in patients with SCD, and to outline unanswered questions where research on dysphagia in SCD might improve health outcomes.}, } @article {pmid38262101, year = {2024}, author = {Masegosa, VM and Navarro, X and Herrando-Grabulosa, M}, title = {ICA-27243 improves neuromuscular function and preserves motoneurons in the transgenic SOD1[G93A] mice.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {2}, pages = {e00319}, pmid = {38262101}, issn = {1878-7479}, mesh = {Mice ; Animals ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase-1/genetics ; *Neurodegenerative Diseases ; Motor Neurons ; Spinal Cord ; Disease Models, Animal ; Superoxide Dismutase ; *Benzamides ; *Pyridines ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the death of upper and lower motor neurons (MNs). Excessive neuronal excitability has been implicated in MN degeneration; thus, modulation of hyperexcitability appears as a promising therapeutic strategy. Potassium channels are attractive targets since they can be activated at subthreshold voltages and can regulate neuronal excitability. In this study, we assayed the effects of N-(6-Chloro-pyridin-3-yl)-3,4-difluorobenzamide compound, known as ICA-27243, as a potential treatment for ALS. ICA-27243 is a highly selective Kv7.2/7.3 opener used mainly in epilepsy models. In the in vitro model of spinal cord organotypic cultures (SCOCs) exposed to acute excitotoxicity, ICA-27243 prevented MN degeneration at a dose-of 10 μM. Administration of ICA-27243 to transgenic SOD1[G93A] ALS mice improved the decline of neuromuscular function, maintained locomotion and coordination in the rotarod, decreased spinal MN death and attenuated glial reactivity. In conclusion, we report here for the first time that ICA-27243 is an effective treatment for ALS, emphasizing the potential of targeting Kv channels to reduce neuronal hyperexcitability.}, } @article {pmid38261982, year = {2024}, author = {Moglia, C and Calvo, A and Canosa, A and Manera, U and Vasta, R and Di Pede, F and Daviddi, M and Matteoni, E and Brunetti, M and Sbaiz, L and Cabras, S and Gallone, S and Grassano, M and Peotta, L and Palumbo, F and Mora, G and Iazzolino, B and Chio, A}, title = {Cognitive and Behavioral Features of Patients With Amyotrophic Lateral Sclerosis Who Are Carriers of the TARDBP Pathogenic Variant.}, journal = {Neurology}, volume = {102}, number = {4}, pages = {e208082}, pmid = {38261982}, issn = {1526-632X}, mesh = {Aged ; Female ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis ; *Apathy ; Cognition ; *Frontotemporal Dementia ; Memory, Short-Term ; Male ; }, abstract = {BACKGROUND AND OBJECTIVES: TARDBP patients are considered particularly prone to cognitive involvement, but no systematic studies of cognitive impairment in TARDBP patients are available. The aim of this article was to depict in depth the cognitive-behavioral characteristics of a cohort of patients with amyotrophic lateral sclerosis (ALS) carrying TARDBP pathogenetic variants followed by an ALS referral center.

METHODS: We enrolled all patients with ALS seen at the Turin ALS expert center in the 2009-2021 period who underwent extensive genetic testing and a neuropsychological battery encompassing executive function, verbal memory, language, visual memory, visuoconstructive abilities, attention/working memory, psychomotor speed, nonverbal intelligence, cognitive flexibility, social cognition, and behavior. Tests were compared with the Mann-Whitney U test on age-corrected, sex-corrected, and education-corrected scores. Cognition was classified as normal (ALS-CN); isolated cognitive impairment (ALSci), that is, evidence of executive and/or language dysfunction; isolated behavioral impairment (ALSbi), that is, identification of apathy; cognitive and behavioral impairment (ALScbi), that is, evidence meeting the criteria for both ALSci and ALSbi; and frontotemporal dementia (ALS-FTD).

RESULTS: This study includes 33 patients with TARDBP pathogenetic variants (TARDBP-ALS) (median age 61 years [interquartile range (IQR) 53-67], 8 female [24.2%]) and 928 patients with ALS not carrying the pathogenic variant (WT-ALS) (median age 67 years [IQR 59-74], 386 female [41.6%]). TARDBP-ALS cases were also compared with 129 matched controls (median age 66 years [IQR 57.5-71.5], 55 female [42.6%]). TARDBP-ALS and WT-ALS patients were cognitively classified as ALS-CN (54% vs 58.8%, respectively), ALSci (21.2% vs 18.3%), ALSci (9.1% vs 9.5%), ALScbi (6.1% vs 6.0%), and ALS-FTD (9.1 vs 6.7%), with no significant difference (p = 0.623). Compared with controls, TARDBP-ALS had a worse performance in executive functions, visual memory, visuoconstructive abilities, verbal fluency, and the apathy behavioral component of FrSBe. The scores of performed tests, including all Edinburgh Cognitive and Behavioral ALS Screen subdomains, were similar in TARDBP-ALS and WT-ALS.

DISCUSSION: TARDBP-ALS patients were significantly more impaired than controls in most examined domains but do not show any specific pattern of cognitive impairment compared with WT-ALS. Our findings are relevant both clinically, considering the effect of cognitive impairment on patients' decision-making and caregivers' burden, and in designing clinical trials for the treatment of patients carrying TARDBP pathogenetic variants.}, } @article {pmid38261942, year = {2024}, author = {Sumera, K and Ilczak, T and Bakkerud, M and Lane, JD and Pallas, J and Martorell, SO and Sumera, A and Webster, CA and Quinn, T and Sandars, J and Niroshan Siriwardena, A}, title = {CPR Quality Officer role to improve CPR quality: A multi-centred international simulation randomised control trial.}, journal = {Resuscitation plus}, volume = {17}, number = {}, pages = {100537}, pmid = {38261942}, issn = {2666-5204}, abstract = {BACKGROUND: An out-of-hospital cardiac arrest requires early recognition, prompt and quality clinical interventions, and coordination between different clinicians to improve outcomes. Clinical team leaders and clinical teams have high levels of cognitive burden. We aimed to investigate the effect of a dedicated Cardio-Pulmonary Resuscitation (CPR) Quality Officer role on team performance.

METHODS: This multi-centre randomised control trial used simulation in universities from the UK, Poland, and Norway. Student Paramedics participated in out-of-hospital cardiac arrest scenarios before randomisation to either traditional roles or assigning one member as the CPR Quality Officer. The quality of CPR was measured using QCPR® and Advanced Life Support (ALS) elements were evaluated.

RESULTS: In total, 36 teams (108 individuals) participated. CPR quality from the first attempt (72.45%, 95% confidence interval [CI] 64.94 to 79.97) significantly increased after addition of the CPR Quality role (81.14%, 95% CI 74.20 to 88.07, p = 0.045). Improvement was not seen in the control group. The time to first defibrillation had no significant difference in the intervention group between the first attempt (53.77, 95% CI 36.57-70.98) and the second attempt (48.68, 95% CI 31.31-66.05, p = 0.84). The time to manage an obstructive airway in the intervention group showed significant difference (p = 0.006) in the first attempt (168.95, 95% CI 110.54-227.37) compared with the second attempt (136.95, 95% CI 87.03-186.88, p = 0.1).

CONCLUSION: A dedicated CPR Quality Officer in simulated scenarios improved the quality of CPR compressions without a negative impact on time to first defibrillation, managing the airway, or adherence to local ALS protocols.}, } @article {pmid38261358, year = {2024}, author = {}, title = {Correction to: Persistence of Kii amyotrophic lateral sclerosis after the 2000s and its characteristic aging-related tau astrogliopathy.}, journal = {Journal of neuropathology and experimental neurology}, volume = {83}, number = {9}, pages = {795}, doi = {10.1093/jnen/nlae006}, pmid = {38261358}, issn = {1554-6578}, } @article {pmid38261295, year = {2024}, author = {Khabibrakhmanov, AN and Zueva, IV and Petrov, KA and Bogdanov, EI and Mukhamedyarov, MA}, title = {[Plasma and salivary acetylcholinesterase activity in amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {1}, pages = {128-134}, doi = {10.17116/jnevro2024124011128}, pmid = {38261295}, issn = {1997-7298}, mesh = {Animals ; Humans ; Mice ; Middle Aged ; *Acetylcholinesterase ; *Amyotrophic Lateral Sclerosis/diagnosis ; Mice, Transgenic ; Saliva ; }, abstract = {OBJECTIVE: Assessment of plasma and salivary acetylcholinesterase (AChE) activity in patients with amyotrophic lateral sclerosis (ALS) and in an animal model of the disease.

MATERIAL AND METHODS: We studied 41 participants, aged 31 to 71 years, including 17 patients with diagnosed ALS (ALS group, average age 62.3±2.2), 9 patients with ALS mimics (disease control, average age 58.1±2.9), and 15 healthy people (normal control, average age 57.7±2.3). Plasma and salivary AChE activity was measured by using the Ellman colorimetric method. ALS severity was assessed using the ALSFRS-R scale. The King's College staging system and the Milano-Torino Scale (MiToS) were used to determine the stage of the disease. Transgenic FUS-mice were used as ALS model.

RESULTS: Plasma AChE activity in the ALS group did not significantly differ from the control groups. There was also no significant correlation between plasma AChE activity and disease parameters such as the stage, duration, rate of progression, and severity. In transgenic FUS-mice plasma AChE activity also did not differ from wild-type mice. However, it has been shown that patients with ALS have significantly higher saliva AChE activity compared to normal controls. However, patients with the bulbar form of ALS had significantly higher values of salivary AChE activity compared to healthy controls.

CONCLUSION: In patients with the bulbar form of ALS, an increase in salivary AChE activity was noted, which can be used for diagnostic and prognostic purposes. There is no significant change in plasma AChE activity in ALS patients.}, } @article {pmid38261256, year = {2024}, author = {Ouyang, J and Peng, S and Wu, G and Liu, R}, title = {Association Between Neurodegenerative Diseases and an Increased Risk of Epilepsy Based on Single Nucleotide Polymorphisms: A Mendelian Randomization Study.}, journal = {Molecular neurobiology}, volume = {61}, number = {8}, pages = {5950-5957}, pmid = {38261256}, issn = {1559-1182}, mesh = {Humans ; *Polymorphism, Single Nucleotide/genetics ; *Mendelian Randomization Analysis ; *Epilepsy/genetics ; *Genetic Predisposition to Disease ; *Neurodegenerative Diseases/genetics/epidemiology ; Genome-Wide Association Study ; Risk Factors ; }, abstract = {Epilepsy is a common neurological disorder characterized by transient brain dysfunction, attributed to a multitude of factors. The purpose of this study is to explore whether neurodegenerative diseases, specifically Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), have a causal effect on epilepsy. Mendelian randomization (MR) methods were used to analyze the causal association between neurodegenerative diseases (AD, PD, ALS, and MS) and epilepsy based on single nucleotide polymorphisms from genome-wide association studies, including inverse-variance weighted, weighted median, MR-Egger, and weighted mode methods. The reliability and stability of the MR analysis results were assessed by the MR-Egger intercept, MR-PRESSO, and heterogeneity tests. Forty-three SNPs were selected for the MR analysis of MS and epilepsy. The inverse-variance weighted method showed a significant causal association between MS and increased risk of epilepsy (odds ratio 1.046; 95% confidence interval 1.001-1.093; P = 0.043). However, AD (P = 0.986), PD (P = 0.894), and ALS (P = 0.533) were not causally associated with epilepsy. Sensitivity analysis showed that the results were robust. The MR study confirmed the causal relationship between genetically predicted MS and epilepsy but did not support the causal relationship between genetically predicted AD, PD, and ALS on epilepsy.}, } @article {pmid38261034, year = {2024}, author = {Sian-Hulsmann, J and Riederer, P}, title = {Virus-induced brain pathology and the neuroinflammation-inflammation continuum: the neurochemists view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {131}, number = {12}, pages = {1429-1453}, pmid = {38261034}, issn = {1435-1463}, mesh = {Humans ; *Neuroinflammatory Diseases/pathology/immunology/metabolism ; Animals ; Neurodegenerative Diseases/pathology/metabolism/immunology ; Brain/pathology/metabolism/immunology ; Inflammation/pathology/metabolism/immunology ; }, abstract = {Fascinatingly, an abundance of recent studies has subscribed to the importance of cytotoxic immune mechanisms that appear to increase the risk/trigger for many progressive neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis, and multiple sclerosis. Events associated with the neuroinflammatory cascades, such as ageing, immunologic dysfunction, and eventually disruption of the blood-brain barrier and the "cytokine storm", appear to be orchestrated mainly through the activation of microglial cells and communication with the neurons. The inflammatory processes prompt cellular protein dyshomeostasis. Parkinson's and Alzheimer's disease share a common feature marked by characteristic pathological hallmarks of abnormal neuronal protein accumulation. These Lewy bodies contain misfolded α-synuclein aggregates in PD or in the case of AD, they are Aβ deposits and tau-containing neurofibrillary tangles. Subsequently, these abnormal protein aggregates further elicit neurotoxic processes and events which contribute to the onset of neurodegeneration and to its progression including aggravation of neuroinflammation. However, there is a caveat for exclusively linking neuroinflammation with neurodegeneration, since it's highly unlikely that immune dysregulation is the only factor that contributes to the manifestation of many of these neurodegenerative disorders. It is unquestionably a complex interaction with other factors such as genetics, age, and environment. This endorses the "multiple hit hypothesis". Consequently, if the host has a genetic susceptibility coupled to an age-related weakened immune system, this makes them more susceptible to the virus/bacteria-related infection. This may trigger the onset of chronic cytotoxic neuroinflammatory processes leading to protein dyshomeostasis and accumulation, and finally, these events lead to neuronal destruction. Here, we differentiate "neuroinflammation" and "inflammation" with regard to the involvement of the blood-brain barrier, which seems to be intact in the case of neuroinflammation but defect in the case of inflammation. There is a neuroinflammation-inflammation continuum with regard to virus-induced brain affection. Therefore, we propose a staging of this process, which might be further developed by adding blood- and CSF parameters, their stage-dependent composition and stage-dependent severeness grade. If so, this might be suitable to optimise therapeutic strategies to fight brain neuroinflammation in its beginning and avoid inflammation at all.}, } @article {pmid38261020, year = {2024}, author = {Ricci, V and Mezian, K and Chang, KV and Onishi, K and Kara, M and Naňka, O and Özçakar, L}, title = {Ultrasound-guided injection of the ankle joint: cadaveric investigation of the anterolateral approach.}, journal = {Surgical and radiologic anatomy : SRA}, volume = {46}, number = {2}, pages = {241-248}, pmid = {38261020}, issn = {1279-8517}, mesh = {Humans ; *Ankle Joint/diagnostic imaging ; Cadaver ; Injections, Intra-Articular/methods ; Ultrasonography, Interventional/methods ; }, abstract = {OBJECTIVE: Injection of the tibiotalar (TT) joint is commonly performed in clinical practice under ultrasound (US) guidance using an anteromedial approach. However, in some patients, this approach may be technically challenging due to post-traumatic and/or degenerative bony changes. Therefore, the aim of this cadaveric investigation was to demonstrate the feasibility of the ultrasound-guided (USG) injection of the ankle joint via the anterolateral sulcus (ALS) by confirming the dye placement/distribution inside the articular space. Likewise, the safety of the procedure has also been evaluated by measuring the distance between the needle and the intermediate dorsal cutaneous nerve of the foot.

DESIGN: A descriptive laboratory study with eight embalmed cadaveric ankles using the Fix for Life (F4L) method was performed at the setting of an academic institution. The interventional technique and the related anatomical findings were illustrated. During the injection, the needle was advanced into the TT joint through the ALS under US guidance, i.e., in-plane anterior-to-posterior approach. With the objective to confirm its correct placement, the needle was kept in situ and-to demonstrate the location of the dye inside the articular space-all eight ankles were injected with 3 mL of green color dye. Thereafter, a layer-by-layer anatomical dissection was performed on all four cadavers.

RESULTS: The position of the needle's tip within the ALS was confirmed in all specimens. Accurate placement of the dye inside the articular space of the ankle was confirmed in seven of the eight cadaveric ankles, with 87.5% of accuracy. Herewith, unintentional spilling of the dye within the superficial soft tissues was reported in two of the eight ankles (25.0%). The mean distance between the needle and the intermediate dorsal cutaneous nerve of the foot, measured in all eight procedures, was 3 cm.

CONCLUSION: USG injection of the ALS using the in-plane, anterior-to-posterior approach can accurately place the injectate inside the articular space.

CLINICAL RELEVANCE: This cadaveric investigation described the accuracy and potential pitfalls of USG injection of the ankle via the anterolateral approach which represents an alternative technique in patients with reduced accessibility of the anteromedial recess due to degenerative and/or post-traumatic bony changes.}, } @article {pmid38260713, year = {2023}, author = {Geraci, J and Bhargava, R and Qorri, B and Leonchyk, P and Cook, D and Cook, M and Sie, F and Pani, L}, title = {Machine learning hypothesis-generation for patient stratification and target discovery in rare disease: our experience with Open Science in ALS.}, journal = {Frontiers in computational neuroscience}, volume = {17}, number = {}, pages = {1199736}, pmid = {38260713}, issn = {1662-5188}, abstract = {INTRODUCTION: Advances in machine learning (ML) methodologies, combined with multidisciplinary collaborations across biological and physical sciences, has the potential to propel drug discovery and development. Open Science fosters this collaboration by releasing datasets and methods into the public space; however, further education and widespread acceptance and adoption of Open Science approaches are necessary to tackle the plethora of known disease states.

MOTIVATION: In addition to providing much needed insights into potential therapeutic protein targets, we also aim to demonstrate that small patient datasets have the potential to provide insights that usually require many samples (>5,000). There are many such datasets available and novel advancements in ML can provide valuable insights from these patient datasets.

PROBLEM STATEMENT: Using a public dataset made available by patient advocacy group AnswerALS and a multidisciplinary Open Science approach with a systems biology augmented ML technology, we aim to validate previously reported drug targets in ALS and provide novel insights about ALS subpopulations and potential drug targets using a unique combination of ML methods and graph theory.

METHODOLOGY: We use NetraAI to generate hypotheses about specific patient subpopulations, which were then refined and validated through a combination of ML techniques, systems biology methods, and expert input.

RESULTS: We extracted 8 target classes, each comprising of several genes that shed light into ALS pathophysiology and represent new avenues for treatment. These target classes are broadly categorized as inflammation, epigenetic, heat shock, neuromuscular junction, autophagy, apoptosis, axonal transport, and excitotoxicity. These findings are not mutually exclusive, and instead represent a systematic view of ALS pathophysiology. Based on these findings, we suggest that simultaneous targeting of ALS has the potential to mitigate ALS progression, with the plausibility of maintaining and sustaining an improved quality of life (QoL) for ALS patients. Even further, we identified subpopulations based on disease onset.

CONCLUSION: In the spirit of Open Science, this work aims to bridge the knowledge gap in ALS pathophysiology to aid in diagnostic, prognostic, and therapeutic strategies and pave the way for the development of personalized treatments tailored to the individual's needs.}, } @article {pmid38260655, year = {2024}, author = {Chen, D and Philippidou, P and Brenha, BF and Schaffer, AE and Miranda, HC}, title = {Scalable, optically-responsive human neuromuscular junction model reveals convergent mechanisms of synaptic dysfunction in familial ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.01.11.575304}, pmid = {38260655}, issn = {2692-8205}, support = {K01 NS116119/NS/NINDS NIH HHS/United States ; R01 NS114510/NS/NINDS NIH HHS/United States ; R01 NS121374/NS/NINDS NIH HHS/United States ; }, abstract = {Neuromuscular junctions (NMJs) are specialized synapses that mediate communication between motor neurons and skeletal muscles and are essential for movement. The degeneration of this system can lead to symptoms observed in neuromuscular and motor neuron diseases. Studying these synapses and their degeneration has proven challenging. Prior NMJ studies heavily relied upon the use of mouse, chick, or isolated primary human cells, which have demonstrated limited fidelity for disease modeling. To enable the study of NMJ dysfunction and model genetic diseases, we, and others, have developed methods to generate human NMJs from pluripotent stem cells (PSCs), embryonic stem cells, and induced pluripotent stem cells. However, published studies have highlighted technical limitations associated with these complex in vitro NMJ models. In this study, we developed a robust PSC-derived motor neuron and skeletal muscle co-culture method, and demonstrated its sensitivity in modeling motor neuron disease. Our method spontaneously and reproducibly forms human NMJs. We developed multiwell-multielectrode array (MEA) parameters to quantify the activity of PSC-derived skeletal muscles, as well as measured the electrophysiological activity of functional human PSC-derived NMJs. We further leveraged our method to morphologically and functionally assess NMJs from the familial amyotrophic lateral sclerosis (fALS) PSCs, C9orf72 hexanucleotide (G4C2)n repeat expansion (HRE), SOD1 [A5V] , and TDP43 [G298S] to define the reproducibility and sensitivity of our system. We observed a significant decrease in the numbers and activity of PSC-derived NMJs developed from the different ALS lines compared to their respective controls. Furthermore, we evaluated a therapeutic candidate undergoing clinical trials and observed a variant-dependent rescue of functionality of NMJs. Our newly developed method provides a platform for the systematic investigation of genetic causes of NMJ neurodegeneration and highlights the need for therapeutic avenues to consider patient genotype.}, } @article {pmid38260601, year = {2024}, author = {Bosco, DB and Kremen, V and Haruwaka, K and Zhao, S and Wang, L and Ebner, BA and Zheng, J and Dheer, A and Perry, JF and Xie, M and Nguyen, AT and Worrell, GA and Wu, LJ}, title = {Impaired microglial phagocytosis promotes seizure development.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38260601}, issn = {2692-8205}, support = {R01 NS088627/NS/NINDS NIH HHS/United States ; R01 NS112144/NS/NINDS NIH HHS/United States ; R35 NS132326/NS/NINDS NIH HHS/United States ; }, abstract = {In the central nervous system, triggering receptor expressed on myeloid cells 2 (TREM2) is exclusively expressed by microglia and is critical for microglial proliferation, migration, and phagocytosis. TREM2 plays an important role in neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis. However, little is known about the role TREM2 plays in epileptogenesis. To investigate this, we utilized TREM2 knockout (KO) mice within the murine intra-amygdala kainic acid seizure model. Electroencephalographic analysis, immunocytochemistry, and RNA sequencing revealed that TREM2 deficiency significantly promoted seizure-induced pathology. We found that TREM2 KO increased both acute status epilepticus and spontaneous recurrent seizures characteristic of chronic focal epilepsy. Mechanistically, phagocytic clearance of damaged neurons by microglia was impaired in TREM2 KO mice and the reduced phagocytic capacity correlated with increased spontaneous seizures. Analysis of human tissue from patients who underwent surgical resection for drug resistant temporal lobe epilepsy also showed a negative correlation between microglial phagocytic activity and focal to bilateral tonic-clonic generalized seizure history. These results indicate that microglial TREM2 and phagocytic activity may be important to epileptogenesis and the progression of focal temporal lobe epilepsy.}, } @article {pmid38260395, year = {2024}, author = {Evangelista, BA and Ragusa, JV and Pellegrino, K and Wu, Y and Quiroga-Barber, IY and Cahalan, SR and Arooji, OK and Madren, JA and Schroeter, S and Cozzarin, J and Xie, L and Chen, X and White, KK and Ezzell, JA and Iannone, MA and Cohen, S and Traub, RE and Li, X and Bedlack, R and Phanstiel, DH and Meeker, R and Stanley, N and Cohen, TJ}, title = {TDP-43 pathology links innate and adaptive immunity in amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.01.07.574541}, pmid = {38260395}, issn = {2692-8205}, support = {R21 AG071229/AG/NIA NIH HHS/United States ; T35 AG038047/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis is the most common fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, Transactive Response DNA Binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 pathology elicits disease-modifying immune responses in ALS remains underexplored. In this study, we demonstrate that TDP-43 pathology is internalized by antigen presenting cells, causes vesicle rupture, and leads to innate and adaptive immune cell activation. Using a multiplex imaging platform, we observed interactions between innate and adaptive immune cells near TDP-43 pathological lesions in ALS brain. We used a mass cytometry-based whole-blood stimulation assay to provide evidence that ALS patient peripheral immune cells exhibit responses to TDP-43 aggregates. Taken together, this study provides a novel link between TDP-43 pathology and ALS immune dysfunction, and further highlights the translational and diagnostic implications of monitoring and manipulating the ALS immune response.}, } @article {pmid38260379, year = {2024}, author = {Zhu, Y and Cho, K and Lacin, H and Zhu, Y and DiPaola, JT and Wilson, BA and Patti, GJ and Skeath, JB}, title = {Loss of dihydroceramide desaturase drives neurodegeneration by disrupting endoplasmic reticulum and lipid droplet homeostasis in glial cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38260379}, issn = {2692-8205}, support = {P30 DK020579/DK/NIDDK NIH HHS/United States ; R01 NS036570/NS/NINDS NIH HHS/United States ; R01 NS122903/NS/NINDS NIH HHS/United States ; }, abstract = {Dihydroceramide desaturases convert dihydroceramides to ceramides, the precursors of all complex sphingolipids. Reduction of DEGS1 dihydroceramide desaturase function causes pediatric neurodegenerative disorder hypomyelinating leukodystrophy-18 (HLD-18). We discovered that infertile crescent (ifc), the Drosophila DEGS1 homolog, is expressed primarily in glial cells to promote CNS development by guarding against neurodegeneration. Loss of ifc causes massive dihydroceramide accumulation and severe morphological defects in cortex glia, including endoplasmic reticulum (ER) expansion, failure of neuronal ensheathment, and lipid droplet depletion. RNAi knockdown of the upstream ceramide synthase schlank in glia of ifc mutants rescues ER expansion, suggesting dihydroceramide accumulation in the ER drives this phenotype. RNAi knockdown of ifc in glia but not neurons drives neuronal cell death, suggesting that ifc function in glia promotes neuronal survival. Our work identifies glia as the primary site of disease progression in HLD-18 and may inform on juvenile forms of ALS, which also feature elevated dihydroceramide levels.}, } @article {pmid38260082, year = {2023}, author = {Norgren, J and Kåreholt, I and Sindi, S}, title = {Is there evidence of a ketogenic effect of coconut oil? Commentary: Effect of the Mediterranean diet supplemented with nicotinamide riboside and pterostilbene and/or coconut oil on anthropometric variables in amyotrophic lateral sclerosis. A pilot study.}, journal = {Frontiers in nutrition}, volume = {10}, number = {}, pages = {1333933}, pmid = {38260082}, issn = {2296-861X}, } @article {pmid38259506, year = {2023}, author = {Gallo, JM and Nishimura, A and Haapasalo, A}, title = {Editorial: Molecular mechanisms underlying C9orf72 neurodegeneration, volume II.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1357319}, pmid = {38259506}, issn = {1662-5102}, } @article {pmid38259504, year = {2023}, author = {Rashid, S and Dimitriadi, M}, title = {Autophagy in spinal muscular atrophy: from pathogenic mechanisms to therapeutic approaches.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1307636}, pmid = {38259504}, issn = {1662-5102}, abstract = {Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by the depletion of the ubiquitously expressed survival motor neuron (SMN) protein. While the genetic cause of SMA has been well documented, the exact mechanism(s) by which SMN depletion results in disease progression remain elusive. A wide body of evidence has highlighted the involvement and dysregulation of autophagy in SMA. Autophagy is a highly conserved lysosomal degradation process which is necessary for cellular homeostasis; defects in the autophagic machinery have been linked with a wide range of neurodegenerative disorders, including amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease. The pathway is particularly known to prevent neurodegeneration and has been suggested to act as a neuroprotective factor, thus presenting an attractive target for novel therapies for SMA patients. In this review, (a) we provide for the first time a comprehensive summary of the perturbations in the autophagic networks that characterize SMA development, (b) highlight the autophagic regulators which may play a key role in SMA pathogenesis and (c) propose decreased autophagic flux as the causative agent underlying the autophagic dysregulation observed in these patients.}, } @article {pmid38256091, year = {2024}, author = {Iskusnykh, IY and Zakharova, AA and Kryl'skii, ED and Popova, TN}, title = {Aging, Neurodegenerative Disorders, and Cerebellum.}, journal = {International journal of molecular sciences}, volume = {25}, number = {2}, pages = {}, pmid = {38256091}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases ; Cerebellum ; *Alzheimer Disease ; *Huntington Disease ; Aging ; }, abstract = {An important part of the central nervous system (CNS), the cerebellum is involved in motor control, learning, reflex adaptation, and cognition. Diminished cerebellar function results in the motor and cognitive impairment observed in patients with neurodegenerative disorders such as Alzheimer's disease (AD), vascular dementia (VD), Parkinson's disease (PD), Huntington's disease (HD), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Friedreich's ataxia (FRDA), and multiple sclerosis (MS), and even during the normal aging process. In most neurodegenerative disorders, impairment mainly occurs as a result of morphological changes over time, although during the early stages of some disorders such as AD, the cerebellum also serves a compensatory function. Biological aging is accompanied by changes in cerebellar circuits, which are predominantly involved in motor control. Despite decades of research, the functional contributions of the cerebellum and the underlying molecular mechanisms in aging and neurodegenerative disorders remain largely unknown. Therefore, this review will highlight the molecular and cellular events in the cerebellum that are disrupted during the process of aging and the development of neurodegenerative disorders. We believe that deeper insights into the pathophysiological mechanisms of the cerebellum during aging and the development of neurodegenerative disorders will be essential for the design of new effective strategies for neuroprotection and the alleviation of some neurodegenerative disorders.}, } @article {pmid38256050, year = {2024}, author = {Bruno, A and Milillo, C and Anaclerio, F and Buccolini, C and Dell'Elice, A and Angilletta, I and Gatta, M and Ballerini, P and Antonucci, I}, title = {Perinatal Tissue-Derived Stem Cells: An Emerging Therapeutic Strategy for Challenging Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {2}, pages = {}, pmid = {38256050}, issn = {1422-0067}, mesh = {Female ; Pregnancy ; Humans ; *Neurodegenerative Diseases/therapy ; *Alzheimer Disease ; *Huntington Disease/therapy ; *Parkinson Disease/therapy ; Stem Cells ; }, abstract = {Over the past 20 years, stem cell therapy has been considered a promising option for treating numerous disorders, in particular, neurodegenerative disorders. Stem cells exert neuroprotective and neurodegenerative benefits through different mechanisms, such as the secretion of neurotrophic factors, cell replacement, the activation of endogenous stem cells, and decreased neuroinflammation. Several sources of stem cells have been proposed for transplantation and the restoration of damaged tissue. Over recent decades, intensive research has focused on gestational stem cells considered a novel resource for cell transplantation therapy. The present review provides an update on the recent preclinical/clinical applications of gestational stem cells for the treatment of protein-misfolding diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). However, further studies should be encouraged to translate this promising therapeutic approach into the clinical setting.}, } @article {pmid38254647, year = {2023}, author = {Lauria, G and Curcio, R and Tucci, P}, title = {A Machine Learning Approach for Highlighting microRNAs as Biomarkers Linked to Amyotrophic Lateral Sclerosis Diagnosis and Progression.}, journal = {Biomolecules}, volume = {14}, number = {1}, pages = {}, pmid = {38254647}, issn = {2218-273X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Biomarkers ; Machine Learning ; *MicroRNAs/genetics ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord. The early diagnosis of ALS can be challenging, as it usually depends on clinical examination and the exclusion of other possible causes. In this regard, the analysis of miRNA expression profiles in biofluids makes miRNAs promising non-invasive clinical biomarkers. Due to the increasing amount of scientific literature that often provides controversial results, this work aims to deepen the understanding of the current state of the art on this topic using a machine-learning-based approach. A systematic literature search was conducted to analyze a set of 308 scientific articles using the MySLR digital platform and the Latent Dirichlet Allocation (LDA) algorithm. Two relevant topics were identified, and the articles clustered in each of them were analyzed and discussed in terms of biomolecular mechanisms, as well as in translational and clinical settings. Several miRNAs detected in the tissues and biofluids of ALS patients, including blood and cerebrospinal fluid (CSF), have been linked to ALS diagnosis and progression. Some of them may represent promising non-invasive clinical biomarkers. In this context, future scientific priorities and goals have been proposed.}, } @article {pmid38254150, year = {2024}, author = {Khalil, B and Linsenmeier, M and Smith, CL and Shorter, J and Rossoll, W}, title = {Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {8}, pmid = {38254150}, issn = {1750-1326}, support = {R33NS110960/NS/NINDS NIH HHS/United States ; R21AG061784/AG/NIA NIH HHS/United States ; RF1AG076122/AG/NIA NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; R33 NS110960/NS/NINDS NIH HHS/United States ; R21 AG065854/AG/NIA NIH HHS/United States ; R01GM099836/GM/NIGMS NIH HHS/United States ; R21 AG079609/AG/NIA NIH HHS/United States ; R21AG065854/AG/NIA NIH HHS/United States ; R01 AG077771/AG/NIA NIH HHS/United States ; RF1AG068581/AG/NIA NIH HHS/United States ; W81XWH-20–1-0242//Department of Defense/ ; }, mesh = {Humans ; *Frontotemporal Dementia ; *Amyotrophic Lateral Sclerosis ; Active Transport, Cell Nucleus ; DNA-Binding Proteins ; *Prions ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that are characterized by the cytoplasmic mislocalization and aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation of TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), and other nuclear RBPs in detergent-insoluble aggregates in the cytoplasm of degenerating neurons in ALS/FTD is connected to nuclear pore dysfunction and other defects in the nucleocytoplasmic transport machinery. Recent advances suggest that beyond their canonical role in the nuclear import of protein cargoes, nuclear-import receptors (NIRs) can prevent and reverse aberrant phase transitions of TDP-43, FUS, and related prion-like RBPs and restore their nuclear localization and function. Here, we showcase the NIR family and how they recognize cargo, drive nuclear import, and chaperone prion-like RBPs linked to ALS/FTD. We also discuss the promise of enhancing NIR levels and developing potentiated NIR variants as therapeutic strategies for ALS/FTD and related neurodegenerative proteinopathies.}, } @article {pmid38254109, year = {2024}, author = {Nagy, ZF and Pál, M and Engelhardt, JI and Molnár, MJ and Klivényi, P and Széll, M}, title = {Beyond C9orf72: repeat expansions and copy number variations as risk factors of amyotrophic lateral sclerosis across various populations.}, journal = {BMC medical genomics}, volume = {17}, number = {1}, pages = {30}, pmid = {38254109}, issn = {1755-8794}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *C9orf72 Protein/genetics ; DNA Copy Number Variations ; Genes, Regulator ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which is characterized by the loss of both upper and lower motor neurons in the central nervous system. In a significant fraction of ALS cases - irrespective of family history- a genetic background may be identified. The genetic background of ALS shows a high variability from one ethnicity to another. The most frequent genetic cause of ALS is the repeat expansion of the C9orf72 gene. With the emergence of next-generation sequencing techniques and copy number alteration calling tools the focus in ALS genetics has shifted from disease causing genes and mutations towards genetic susceptibility and risk factors.In this review we aimed to summarize the most widely recognized and studied ALS linked repeat expansions and copy number variations other than the hexanucleotide repeat expansion in the C9orf72 gene. We compare and contrast their involvement and phenotype modifying roles in ALS among different populations.}, } @article {pmid38253707, year = {2024}, author = {El-Malla, SF and Hamza, AA and Elagamy, SH}, title = {Simultaneous determination of meloxicam and bupivacaine via a novel modified dual wavelength method and an advanced chemometric approach.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {1893}, pmid = {38253707}, issn = {2045-2322}, mesh = {Meloxicam ; *Chemometrics ; *Bupivacaine ; Chromatography, High Pressure Liquid ; Spectrophotometry ; }, abstract = {This study presents two spectrophotometric methods; a novel dual wavelength-derivative spectrophotometry and multivariate curve resolution-alternating least squares (MCR-ALS) for the simultaneous determination of a fixed dose combination of bupivacaine (BUP) and meloxicam (MEL) in a ratio of 30:1. The extended UV spectrum of MEL enables its direct determination at λmax 360 nm with no interference from BUP. The determination of BUP was unfeasible directly because the UV spectra of both drugs are moderately overlapped over the wavelength range of 250-450 nm, thus new chemometric based spectrophotometric methods should be developed for its determination. Dual wavelength-derivative method was employed based on using first derivative spectra. The selected dual wavelengths for determination BUP were 274.6 nm and 374.6 nm where the dA/dλ amplitudes differences for MET are equal to zero. MCR-ALS is advanced chemometric tool that enables analysis of multicomponent samples in complex matrices with high resolution based on the decomposition of signal/spectral data into the pure spectra and corresponding concentration profile. The figures of merits for MCR model show that there is a good agreement between the actual and predicted concentrations for MEL and BUP. The methods were validated and statistically compared with a reported HPLC method.}, } @article {pmid38253550, year = {2024}, author = {Voorhees, J and Bailey, S and Waterman, H and Checkland, K}, title = {A paradox of problems in accessing general practice: a qualitative participatory case study.}, journal = {The British journal of general practice : the journal of the Royal College of General Practitioners}, volume = {74}, number = {739}, pages = {e104-e112}, pmid = {38253550}, issn = {1478-5242}, mesh = {Humans ; *General Practice ; Qualitative Research ; Family Practice ; Focus Groups ; England ; }, abstract = {BACKGROUND: Despite longstanding problems of access to general practice, attempts to understand and address the issues do not adequately include perspectives of the people providing or using care, nor do they use established theories of access to understand complexity.

AIM: To understand problems of access to general practice from the multiple perspectives of service users and staff using an applied theory of access.

DESIGN AND SETTING: A qualitative participatory case study in an area of northwest England.

METHOD: A community-based participatory approach was used with qualitative interviews, focus groups, and observation to understand perspectives about accessing general practice. Data were collected between October 2015 and October 2016. Inductive and abductive analysis, informed by Levesque et al's theory of access, allowed the team to identify complexities and relationships between interrelated problems.

RESULTS: This study presents a paradox of problems in accessing general practice, in which the demand on general practice both creates and hides unmet need in the population. Data show how reactive rules to control demand have undermined important aspects of care, such as continuity. The layers of rules and decreased continuity create extra work for practice staff, clinicians, and patients. Complicated rules, combined with a lack of capacity to reach out or be flexible, leave many patients, including those with complex and/or unrecognised health needs, unable to navigate the system to access care. This relationship between demand and unmet need exacerbates existing health inequities.

CONCLUSION: Understanding the paradox of access problems allows for different targets for change and different solutions to free up capacity in general practice to address the unmet need in the population.}, } @article {pmid38253209, year = {2024}, author = {Yusuf, IO and Parsi, S and Ostrow, LW and Brown, RH and Thompson, PR and Xu, Z}, title = {PAD2 dysregulation and aberrant protein citrullination feature prominently in reactive astrogliosis and myelin protein aggregation in sporadic ALS.}, journal = {Neurobiology of disease}, volume = {192}, number = {}, pages = {106414}, pmid = {38253209}, issn = {1095-953X}, support = {R01 NS118145/NS/NINDS NIH HHS/United States ; R35 GM118112/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; *Citrullination ; Gliosis/metabolism ; Hydrolases/genetics/metabolism ; Myelin Proteins/metabolism ; Myelin Sheath/pathology ; Protein Aggregates ; Protein-Arginine Deiminase Type 2/metabolism ; Protein-Arginine Deiminases/metabolism ; Proteins/metabolism ; Spinal Cord/pathology ; }, abstract = {Alteration in protein citrullination (PC), a common posttranslational modification (PTM), contributes to pathogenesis in various inflammatory disorders. We previously reported that PC and protein arginine deiminase 2 (PAD2), the predominant enzyme isoform that catalyzes this PTM in the central nervous system (CNS), are altered in mouse models of amyotrophic lateral sclerosis (ALS). We now demonstrate that PAD2 expression and PC are altered in human postmortem ALS spinal cord and motor cortex compared to controls, increasing in astrocytes while trending lower in neurons. Furthermore, PC is enriched in protein aggregates that contain the myelin proteins PLP and MBP in ALS. These results confirm our findings in ALS mouse models and suggest that altered PAD2 and PC contribute to neurodegeneration in ALS.}, } @article {pmid38252383, year = {2024}, author = {Vassileff, N and Spiers, JG and Lee, JD and Woodruff, TM and Ebrahimie, E and Mohammadi Dehcheshmeh, M and Hill, AF and Cheng, L}, title = {A Panel of miRNA Biomarkers Common to Serum and Brain-Derived Extracellular Vesicles Identified in Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {61}, number = {8}, pages = {5901-5915}, pmid = {38252383}, issn = {1559-1182}, support = {GNT1041413//National Health and Medical Research Council/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/blood/genetics/pathology/metabolism ; *Extracellular Vesicles/metabolism ; *MicroRNAs/genetics/metabolism/blood ; *Disease Models, Animal ; *Biomarkers/blood/metabolism ; *Brain/metabolism/pathology ; Mice ; Mice, Transgenic ; DNA-Binding Proteins/metabolism/genetics ; Male ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease characterised by the deposition of aggregated proteins including TAR DNA-binding protein 43 (TDP-43) in vulnerable motor neurons and the brain. Extracellular vesicles (EVs) facilitate the spread of neurodegenerative diseases and can be easily accessed in the bloodstream. This study aimed to identify a panel of EV miRNAs that can capture the pathology occurring in the brain and peripheral circulation. EVs were isolated from the cortex (BDEVs) and serum (serum EVs) of 3 month-old and 6-month-old TDP-43*Q331K and TDP-43*WT mice. Following characterisation and miRNA isolation, the EVs underwent next-generation sequencing where 24 differentially packaged miRNAs were identified in the TDP-43*Q331K BDEVs and 7 in the TDP-43*Q331K serum EVs. Several miRNAs, including miR-183-5p, were linked to ALS. Additionally, miR-122-5p and miR-486b-5p were identified in both panels, demonstrating the ability of the serum EVs to capture the dysregulation occurring in the brain. This is the first study to identify miRNAs common to both the serum EVs and BDEVs in a mouse model of ALS.}, } @article {pmid38251257, year = {2024}, author = {Garamszegi, SP and Brzostowicki, DJ and Coyne, TM and Vontell, RT and Davis, DA}, title = {TDP-43 and Alzheimer's Disease Pathology in the Brain of a Harbor Porpoise Exposed to the Cyanobacterial Toxin BMAA.}, journal = {Toxins}, volume = {16}, number = {1}, pages = {}, pmid = {38251257}, issn = {2072-6651}, support = {GR012556 DAVIS//Herbert W. Hoover Foundation/ ; }, mesh = {Animals ; *Phocoena ; *Alzheimer Disease/chemically induced ; *Neurodegenerative Diseases ; Brain ; DNA-Binding Proteins ; }, abstract = {Cetaceans are well-regarded as sentinels for toxin exposure. Emerging studies suggest that cetaceans can also develop neuropathological changes associated with neurodegenerative disease. The occurrence of neuropathology makes cetaceans an ideal species for examining the impact of marine toxins on the brain across the lifespan. Here, we describe TAR DNA-binding protein 43 (TDP-43) proteinopathy and Alzheimer's disease (AD) neuropathological changes in a beached harbor porpoise (Phocoena phocoena) that was exposed to a toxin produced by cyanobacteria called β-N-methylamino-L-alanine (BMAA). We found pathogenic TDP-43 cytoplasmic inclusions in neurons throughout the cerebral cortex, midbrain and brainstem. P62/sequestosome-1, responsible for the autophagy of misfolded proteins, was observed in the amygdala, hippocampus and frontal cortex. Genes implicated in AD and TDP-43 neuropathology such as APP and TARDBP were expressed in the brain. AD neuropathological changes such as amyloid-β plaques, neurofibrillary tangles, granulovacuolar degeneration and Hirano bodies were present in the hippocampus. These findings further support the development of progressive neurodegenerative disease in cetaceans and a potential causative link to cyanobacterial toxins. Climate change, nutrient pollution and industrial waste are increasing the frequency of harmful cyanobacterial blooms. Cyanotoxins like BMAA that are associated with neurodegenerative disease pose an increasing public health risk.}, } @article {pmid38250776, year = {2024}, author = {Du, P and Zhang, X and Lian, X and Hölscher, C and Xue, G}, title = {O-GlcNAcylation and Its Roles in Neurodegenerative Diseases.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {97}, number = {3}, pages = {1051-1068}, doi = {10.3233/JAD-230955}, pmid = {38250776}, issn = {1875-8908}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Protein Processing, Post-Translational ; Proteins/metabolism ; *Alzheimer Disease/pathology ; Acetylglucosamine/metabolism ; Disease Progression ; N-Acetylglucosaminyltransferases/metabolism ; }, abstract = {As a non-classical post-translational modification, O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is widely found in human organ systems, particularly in our brains, and is indispensable for healthy cell biology. With the increasing age of the global population, the incidence of neurodegenerative diseases is increasing, too. The common characteristic of these disorders is the aggregation of abnormal proteins in the brain. Current research has found that O-GlcNAcylation dysregulation is involved in misfolding or aggregation of these abnormal proteins to mediate disease progression, but the specific mechanism has not been defined. This paper reviews recent studies on O-GlcNAcylation's roles in several neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, Machado-Joseph's disease, and giant axonal neuropathy, and shows that O-GlcNAcylation, as glucose metabolism sensor, mediating synaptic function, participating in oxidative stress response and signaling pathway conduction, directly or indirectly regulates characteristic pathological protein toxicity and affects disease progression. The existing results suggest that targeting O-GlcNAcylation will provide new ideas for clinical diagnosis, prevention, and treatment of neurodegenerative diseases.}, } @article {pmid38250183, year = {2024}, author = {Xia, J and Guo, S and Hu, F and Fan, L and Yu, L and Ye, J}, title = {Changes in Corneal Higher-Order Aberrations and Ocular Biometric Measurements after Phacoemulsification Combined with Goniosynechialysis in Primary Angle Closure/Glaucoma Patients.}, journal = {Journal of ophthalmology}, volume = {2024}, number = {}, pages = {5833543}, pmid = {38250183}, issn = {2090-004X}, abstract = {PURPOSE: To compare corneal higher-order aberrations (HOAs), refractive error, and ocular biological parameters before and after phacoemulsification combined with goniosynechialysis (Phaco-GSL) in primary angle closure/glaucoma (PAC/PACG) patients with different axial lengths (ALs).

METHODS: In this prospective study, cataract patients diagnosed with PAC/PACG were categorized into two groups based on their ALs: the short AL group (AL ≤ 22.5 mm) and the normal AL group (22.5 < AL ≤ 24.5 mm). The pre- and postsurgery measurements of intraocular pressure (IOP) and best-corrected visual acuity (BCVA) were conducted at 1 day, 1 week, 1 month, 3 months, 6 months, and 12 months. Additionally, the assessments included corneal HOAs, the number of antiglaucoma medications, visual field parameters, manifest refraction, and other ocular biological parameters before surgery and at the final follow-up.

RESULTS: Prior to surgery, the two groups exhibited no significant differences, except for AL, curvature value, and Z (4, 0) of the posterior corneal surface (all P < 0.01). Following surgery, BCVA improved, and IOP decreased significantly in both groups (P < 0.01). Both anterior and total corneal HOAs, along with Z (3, -3), increased in the two groups (all P < 0.05), with the normal AL group exhibiting a significantly greater increase in total cornea Z (3, -3) than the short AL group (P=0.047). The normal AL group also exhibited a slight tendency towards hyperopia (P < 0.01). Significant changes were observed in the visual field index and mean deviation in both groups (P < 0.05).

CONCLUSIONS: Phaco-GSL resulted in an increased corneal HOAs, particularly trefoil, with variations based on the patient's AL. Patients with normal ALs tended to shift towards hyperopia after surgery.}, } @article {pmid38249779, year = {2024}, author = {de Carvalho, M and Swash, M}, title = {[Not Available].}, journal = {Clinical neurophysiology practice}, volume = {9}, number = {}, pages = {27-38}, pmid = {38249779}, issn = {2467-981X}, abstract = {Accurate and rapid diagnosis of amyotrophic lateral sclerosis (ALS) is essential in order to provide accurate information for patient and family, to avoid time-consuming investigations and to permit an appropriate management plan. ALS is variable regarding presentation, disease progression, genetic profile and patient reaction to the diagnosis. It is obviously important to exclude treatable conditions but, in most patients, for experienced neurologists the diagnosis is clear-cut, depending on the presence of progressive upper and lower motor neuron signs. Patients with signs of restricted lower motor neuron (LMN) or upper motor neuron (UMN) dysfunction may present diagnostic difficulty, but electromyography (EMG) is often a determinant diagnostic test since it may exclude other disorders. Transcranial magnetic stimulation may aid detection of UMN dysfunction, and brain and spinal cord MRI, ultrasound and blood neurofilament measurements, have begun to have clinical impact, although none are themselves diagnostic tests. Several sets of diagnostic criteria have been proposed in the past; all rely on clinical LMN and UMN signs in different anatomic territories, EMG changes, exclusion of other disorders, and disease progression, in particular evidence of spreading to other anatomic territories. Fasciculations are a characteristic clinical feature and increased importance is now attached to fasciculation potentials detected by EMG, when associated with classical signs of denervation and reinnervation. The Gold Coast diagnostic criteria rely on the presence of UMN and LMN signs in one (or more) anatomic territory, or LMN signs in two (or more) anatomic territories, recognizing the fundamental clinical requirements of disease progression and exclusion of other diseases. Recent studies confirm a high sensitivity without loss of specificity using these Gold Coast criteria. In considering the diagnosis of ALS a critical question for future understanding is whether ALS should be considered a syndrome or a specific clinico-pathologic entity; this can only be addressed in the light of more complete knowledge.}, } @article {pmid38249738, year = {2023}, author = {Croucher, KM and Fleming, SM}, title = {ATP13A2 (PARK9) and basal ganglia function.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1252400}, pmid = {38249738}, issn = {1664-2295}, support = {R01 ES031124/ES/NIEHS NIH HHS/United States ; }, abstract = {ATP13A2 is a lysosomal protein involved in polyamine transport with loss of function mutations associated with multiple neurodegenerative conditions. These include early onset Parkinson's disease, Kufor-Rakeb Syndrome, neuronal ceroid lipofuscinosis, hereditary spastic paraplegia, and amyotrophic lateral sclerosis. While ATP13A2 mutations may result in clinical heterogeneity, the basal ganglia appear to be impacted in the majority of cases. The basal ganglia is particularly vulnerable to environmental exposures such as heavy metals, pesticides, and industrial agents which are also established risk factors for many neurodegenerative conditions. Not surprisingly then, impaired function of ATP13A2 has been linked to heavy metal toxicity including manganese, iron, and zinc. This review discusses the role of ATP13A2 in basal ganglia function and dysfunction, potential common pathological mechanisms in ATP13A2-related disorders, and how gene x environment interactions may contribute to basal ganglia dysfunction.}, } @article {pmid38249592, year = {2023}, author = {Jiang, Q and Guo, Y and Yang, T and Li, S and Hou, Y and Lin, J and Xiao, Y and Ou, R and Wei, Q and Shang, H}, title = {Cystatin C is associated with poor survival in amyotrophic lateral sclerosis patients.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1309568}, pmid = {38249592}, issn = {1662-4548}, abstract = {BACKGROUND: Cystatin C (CysC) levels in amyotrophic lateral sclerosis (ALS) have been found changes, however, the associations between serum CysC levels and the progression and survival of ALS remain largely unknown.

METHODS: A total of 1,086 ALS patients and 1,026 sex-age matched healthy controls (HCs) were enrolled in this study. Serum CysC, other renal function, and metabolic parameters were measured. Correlation analysis and binary logistic regression were used to explore the factors related to serum CysC. Kaplan-Meier curve and Cox regression model were used for survival analysis.

RESULTS: CysC levels were significantly higher in ALS patients compared to HCs (0.94 vs. 0.85 mg/L, p < 0.001). Compared with ALS patients with lower CysC levels, those with higher CysC levels had an older age of onset, significantly lower ALSFRS-R scores (40.1 vs. 41.3, p < 0.001), a faster disease progression rate (0.75 vs. 0.67, p = 0.011), and lower frontal lobe function scores (15.8 vs. 16.1, p = 0.020). In the correlation analysis, CysC levels were significantly negatively correlated with ALSFRS-R scores (r = -0.16, p < 0.001). Additionally, ALS patients with higher CysC levels had significantly shorter survival time (40.0 vs. 51.8, p < 0.001) compared to patients with lower CysC levels. Higher CysC levels were associated with a higher risk of death in Cox analysis (HR: 1.204, 95% CI: 1.012-1.433). However, when treatment was included in the model, the result was no longer significant.

CONCLUSION: CysC levels in ALS patients were higher compared to HCs. Higher CysC levels were associated with greater disease severity, faster progression rate and shorter survival, needing early intervention.}, } @article {pmid38249293, year = {2023}, author = {Krishnamurthy, K and Pradhan, RK}, title = {Emerging perspectives of synaptic biomarkers in ALS and FTD.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1279999}, pmid = {38249293}, issn = {1662-5099}, abstract = {Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are debilitating neurodegenerative diseases with shared pathological features like transactive response DNA-binding protein of 43 kDa (TDP-43) inclusions and genetic mutations. Both diseases involve synaptic dysfunction, contributing to their clinical features. Synaptic biomarkers, representing proteins associated with synaptic function or structure, offer insights into disease mechanisms, progression, and treatment responses. These biomarkers can detect disease early, track its progression, and evaluate therapeutic efficacy. ALS is characterized by elevated neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) and blood, correlating with disease progression. TDP-43 is another key ALS biomarker, its mislocalization linked to synaptic dysfunction. In FTD, TDP-43 and tau proteins are studied as biomarkers. Synaptic biomarkers like neuronal pentraxins (NPs), including neuronal pentraxin 2 (NPTX2), and neuronal pentraxin receptor (NPTXR), offer insights into FTD pathology and cognitive decline. Advanced technologies, like machine learning (ML) and artificial intelligence (AI), aid biomarker discovery and drug development. Challenges in this research include technological limitations in detection, variability across patients, and translating findings from animal models. ML/AI can accelerate discovery by analyzing complex data and predicting disease outcomes. Synaptic biomarkers offer early disease detection, personalized treatment strategies, and insights into disease mechanisms. While challenges persist, technological advancements and interdisciplinary efforts promise to revolutionize the understanding and management of ALS and FTD. This review will explore the present comprehension of synaptic biomarkers in ALS and FTD and discuss their significance and emphasize the prospects and obstacles.}, } @article {pmid38249102, year = {2024}, author = {Bakaeva, M and Chetverikov, S and Starikov, S and Kendjieva, A and Khudaygulov, G and Chetverikova, D}, title = {Effect of Plant Growth-Promoting Bacteria on Antioxidant Status, Acetolactate Synthase Activity, and Growth of Common Wheat and Canola Exposed to Metsulfuron-Methyl.}, journal = {Journal of xenobiotics}, volume = {14}, number = {1}, pages = {79-95}, pmid = {38249102}, issn = {2039-4713}, support = {23-26-00097//Russian Science Foundation/ ; }, abstract = {Metsulfuron-methyl, a widely used herbicide, could cause damage to the sensitive plants in crop-rotation systems at extremely low levels in the soil. The potential of plant growth-promoting bacteria (PGPB) for enhancing the resistance of plants against herbicide stress has been discovered recently. Therefore, it is poorly understood how physiological processes occur in plants, while PGPB reduce the phytotoxicity of herbicides for agricultural crops. In greenhouse studies, the effect of strains Pseudomonas protegens DA1.2 and Pseudomonas chlororaphis 4CH on oxidative damage, acetolactate synthase (ALS), enzymatic and non-enzymatic antioxidants in canola (Brassica napus L.), and wheat (Triticum aestivum L.) were investigated under two levels (0.05 and 0.25 mg∙kg[-1]) of metsulfuron-methyl using spectrophotometric assays. The inoculation of herbicide-exposed wheat with bacteria significantly increased the shoots fresh weight (24-28%), amount of glutathione GSH (60-73%), and flavonoids (5-14%), as well as activity of ascorbate peroxidase (129-140%), superoxide dismutase SOD (35-49%), and ALS (50-57%). Bacterial treatment stimulated the activity of SOD (37-94%), ALS (65-73%), glutathione reductase (19-20%), and the accumulation of GSH (61-261%), flavonoids (17-22%), and shoots weight (27-33%) in herbicide-exposed canola. Simultaneous inoculation prevented lipid peroxidation induced by metsulfuron-methyl in sensitive plants. Based on the findings, it is possible that the protective role of bacterial strains against metsulfuron-metil is linked to antioxidant system activation.}, } @article {pmid38247879, year = {2024}, author = {Shehjar, F and Almarghalani, DA and Mahajan, R and Hasan, SA and Shah, ZA}, title = {The Multifaceted Role of Cofilin in Neurodegeneration and Stroke: Insights into Pathogenesis and Targeting as a Therapy.}, journal = {Cells}, volume = {13}, number = {2}, pages = {}, pmid = {38247879}, issn = {2073-4409}, support = {R01 NS112642/NS/NINDS NIH HHS/United States ; R01NS112642/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Actin Depolymerizing Factors ; alpha-Synuclein ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; *Parkinson Disease ; *Stroke/metabolism ; }, abstract = {This comprehensive review explores the complex role of cofilin, an actin-binding protein, across various neurodegenerative diseases (Alzheimer's, Parkinson's, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's) and stroke. Cofilin is an essential protein in cytoskeletal dynamics, and any dysregulation could lead to potentially serious complications. Cofilin's involvement is underscored by its impact on pathological hallmarks like Aβ plaques and α-synuclein aggregates, triggering synaptic dysfunction, dendritic spine loss, and impaired neuronal plasticity, leading to cognitive decline. In Parkinson's disease, cofilin collaborates with α-synuclein, exacerbating neurotoxicity and impairing mitochondrial and axonal function. ALS and frontotemporal dementia showcase cofilin's association with genetic factors like C9ORF72, affecting actin dynamics and contributing to neurotoxicity. Huntington's disease brings cofilin into focus by impairing microglial migration and influencing synaptic plasticity through AMPA receptor regulation. Alzheimer's, Parkinson's, and schizophrenia exhibit 14-3-3 proteins in cofilin dysregulation as a shared pathological mechanism. In the case of stroke, cofilin takes center stage, mediating neurotoxicity and neuronal cell death. Notably, there is a potential overlap in the pathologies and involvement of cofilin in various diseases. In this context, referencing cofilin dysfunction could provide valuable insights into the common pathologies associated with the aforementioned conditions. Moreover, this review explores promising therapeutic interventions, including cofilin inhibitors and gene therapy, demonstrating efficacy in preclinical models. Challenges in inhibitor development, brain delivery, tissue/cell specificity, and long-term safety are acknowledged, emphasizing the need for precision drug therapy. The call to action involves collaborative research, biomarker identification, and advancing translational efforts. Cofilin emerges as a pivotal player, offering potential as a therapeutic target. However, unraveling its complexities requires concerted multidisciplinary efforts for nuanced and effective interventions across the intricate landscape of neurodegenerative diseases and stroke, presenting a hopeful avenue for improved patient care.}, } @article {pmid38247869, year = {2024}, author = {Smeele, PH and Cesare, G and Vaccari, T}, title = {ALS' Perfect Storm: C9orf72-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis.}, journal = {Cells}, volume = {13}, number = {2}, pages = {}, pmid = {38247869}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *C9orf72 Protein/genetics ; Dipeptides ; *Frontotemporal Dementia/genetics ; *Proteostasis ; }, abstract = {Protein homeostasis is essential for neuron longevity, requiring a balanced regulation between protein synthesis and degradation. The clearance of misfolded and aggregated proteins, mediated by autophagy and the ubiquitin-proteasome systems, maintains protein homeostasis in neurons, which are post-mitotic and thus cannot use cell division to diminish the burden of misfolded proteins. When protein clearance pathways are overwhelmed or otherwise disrupted, the accumulation of misfolded or aggregated proteins can lead to the activation of ER stress and the formation of stress granules, which predominantly attempt to restore the homeostasis by suppressing global protein translation. Alterations in these processes have been widely reported among studies investigating the toxic function of dipeptide repeats (DPRs) produced by G4C2 expansion in the C9orf72 gene of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this review, we outline the modalities of DPR-induced disruptions in protein homeostasis observed in a wide range of models of C9orf72-linked ALS/FTD. We also discuss the relative importance of each DPR for toxicity, possible synergies between DPRs, and discuss the possible functional relevance of DPR aggregation to disease pathogenesis. Finally, we highlight the interdependencies of the observed effects and reflect on the importance of feedback and feedforward mechanisms in their contribution to disease progression. A better understanding of DPR-associated disease pathogenesis discussed in this review might shed light on disease vulnerabilities that may be amenable with therapeutic interventions.}, } @article {pmid38246117, year = {2024}, author = {de Jonge, S and Potters, WV and Verhamme, C}, title = {Artificial intelligence for automatic classification of needle EMG signals: A scoping review.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {159}, number = {}, pages = {41-55}, doi = {10.1016/j.clinph.2023.12.134}, pmid = {38246117}, issn = {1872-8952}, mesh = {Humans ; *Artificial Intelligence ; *Amyotrophic Lateral Sclerosis ; Electromyography ; Needles ; }, abstract = {OBJECTIVE: This scoping review provides an overview of artificial intelligence (AI), including machine and deep learning techniques, in the interpretation of clinical needle electromyography (nEMG) signals.

METHODS: A comprehensive search of Medline, Embase and Web of Science was conducted to find peer-reviewed journal articles. All papers published after 2010 were included. The methodological quality of the included studies was assessed with CLAIM (checklist for artificial intelligence in medical imaging).

RESULTS: 51 studies were identified that fulfilled the inclusion criteria. 61% used open-source EMGlab data set to develop models to classify nEMG signal in healthy, amyotrophic lateral sclerosis (ALS) and myopathy (25 subjects). Only two articles developed models to classify signals recorded at rest. Most articles reported high performance accuracies, but many were subject to bias and overtraining.

CONCLUSIONS: Current AI-models of nEMG signals are not sufficient for clinical implementation. Suggestions for future research include emphasizing the need for an optimal training and validation approach using large datasets of clinical nEMG data from a diverse patient population.

SIGNIFICANCE: The outcomes of this study and the suggestions made aim to contribute to developing AI-models that can effectively handle signal quality variability and are suitable for daily clinical practice in interpreting nEMG signals.}, } @article {pmid38245992, year = {2024}, author = {Robertson, DJ and Jeziorczak, PM and Aprahamian, CJ}, title = {Diaphragmatic pacing for respiratory failure in children.}, journal = {Seminars in pediatric surgery}, volume = {33}, number = {1}, pages = {151386}, doi = {10.1016/j.sempedsurg.2024.151386}, pmid = {38245992}, issn = {1532-9453}, mesh = {Child ; Humans ; *Amyotrophic Lateral Sclerosis/complications ; Diaphragm ; Phrenic Nerve/surgery ; *Respiratory Insufficiency/etiology/therapy ; }, abstract = {Diaphragm pacing is a ventilation strategy in respiratory failure. Most of the literature on pacing involves adults with common indications being spinal cord injury and amyotrophic lateral sclerosis (ALS). Previous reports in pediatric patients consist of case reports or small series; most describe direct phrenic nerve stimulation for central hypoventilation syndrome. This differs from adult reports that focus most commonly on spinal cord injuries and the rehabilitative nature of diaphragm pacing. This review describes the current state of diaphragm pacing in pediatric patients. Indications, current available technologies, surgical techniques, advantages, and pitfalls/problems are discussed.}, } @article {pmid38244886, year = {2024}, author = {DSouza, AA and Kulkarni, P and Ferris, CF and Amiji, MM and Bleier, BS}, title = {Mild repetitive TBI reduces brain-derived neurotrophic factor (BDNF) in the substantia nigra and hippocampus: A preclinical model for testing BDNF-targeted therapeutics.}, journal = {Experimental neurology}, volume = {374}, number = {}, pages = {114696}, pmid = {38244886}, issn = {1090-2430}, support = {P30 EY003790/EY/NEI NIH HHS/United States ; R01 NS108968/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Female ; Male ; Rats ; *Brain Concussion/complications ; *Brain Injuries, Traumatic/drug therapy/complications ; Brain-Derived Neurotrophic Factor/metabolism ; Hippocampus/metabolism ; Substantia Nigra/metabolism ; }, abstract = {Clinical studies have consistently shown that neurodegenerative diseases (NDs) such as Parkinson's disease, Alzheimer's disease, Amyotrophic Lateral Sclerosis, and Huntington's disease show absent or low levels of brain-derived neurotrophic factor (BDNF). Despite this relationship between BDNF and ND, only a few ND animal models have been able to recapitulate the low BDNF state, thereby hindering research into the therapeutic targeting of this important neurotrophic factor. In order to address this unmet need, we sought to develop a reproducible model of BDNF reduction by inducing traumatic brain injury (TBI) using a closed head momentum exchange injury model in mature 9-month-old male and female rats. Head impacts were repetitive and varied in intensity from mild to severe. BDNF levels, as assessed by ELISA, were significantly reduced in the hippocampus of both males and females as well as in the substantia nigra of males 12 days after mild TBI. However, we observed significant sexual dimorphism in multiple sequelae, including magnetic resonance imaging-determined vasogenic edema, astrogliosis (GFAP-activation), and microgliosis (Iba1 activation). This study provides an opportunity to investigate the mechanism of BDNF reduction in rodent models and provides a reliable paradigm to test BDNF-targeted therapeutics for the treatment of ND.}, } @article {pmid38244235, year = {2024}, author = {Kim, SH and Oh, KW and Noh, MY and Kwon, MS}, title = {Optimal Therapeutic Strategy of Bone Marrow-Originated Autologous Mesenchymal Stromal/Stem Cells for ALS.}, journal = {Stem cells translational medicine}, volume = {13}, number = {4}, pages = {309-316}, pmid = {38244235}, issn = {2157-6580}, support = {NRF//National Research Foundation/ ; MSIT; RS-2023-00265515//Korean government/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Bone Marrow ; Biomarkers ; *Mesenchymal Stem Cells ; *Mesenchymal Stem Cell Transplantation/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by selective and progressive neurodegenerative changes in motor neural networks. Given the system complexity, including anatomically distributed sites of degeneration from the motor cortex to the spinal cord and chronic pro-inflammatory conditions, a cell-based therapeutic strategy could be an alternative approach to treating ALS. Lessons from previous mesenchymal stromal/stem cell (MSC) trials in ALS realized the importance of 3 aspects in current and future MSC therapy, including the preparation of MSCs, administration routes and methods, and recipient-related factors. This review briefly describes the current status and future prerequisites for an optimal strategy using bone-marrow-originated MSCs to treat ALS. We suggest mandatory factors in the optimized therapeutic strategy focused on advanced therapy medicinal products produced according to Good Manufacturing Practice, an optimal administration method, the selection of proper patients, and the importance of biomarkers.}, } @article {pmid38244210, year = {2024}, author = {Xu, C and Diemant, T and Mariani, A and Di Pietro, ME and Mele, A and Liu, X and Passerini, S}, title = {Locally Concentrated Ionic Liquid Electrolytes for Wide-Temperature-Range Aluminum-Sulfur Batteries.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {63}, number = {10}, pages = {e202318204}, doi = {10.1002/anie.202318204}, pmid = {38244210}, issn = {1521-3773}, support = {//China Sponsorship Council/ ; //Helmholtz Association/ ; MSCA EF Master Class 2018//Politecnico di Milano/ ; }, abstract = {Aluminum-sulfur (Al-S) batteries are promising energy storage devices due to their high theoretical capacity, low cost, and high safety. However, the high viscosity and inferior ion transport of conventionally used ionic liquid electrolytes (ILEs) limit the kinetics of Al-S batteries, especially at sub-zero temperatures. Herein, locally concentrated ionic liquid electrolytes (LCILE) formed via diluting the ILEs with non-solvating 1,2-difluorobenzene (dFBn) co-solvent are proposed for wide-temperature-range Al-S batteries. The addition of dFBn effectively promotes the fluidity and ionic conductivity without affecting the AlCl4 [-] /Al2 Cl7 [-] equilibrium, which preserves the reversible stripping/plating of aluminum and further promotes the overall kinetics of Al-S batteries. As a result, Al-S cells employing the LCILE exhibit higher specific capacity, better cyclability, and lower polarization with respect to the neat ILE in a wide temperature range from -20 to 40 °C. For instance, Al-S batteries employing the LCILE sustain a remarkable capacity of 507 mAh g[-1] after 300 cycles at 20 °C, while only 229 mAh g[-1] is delivered with the dFBn-free electrolyte under the same condition. This work demonstrates the favorable use of LCILEs for wide-temperature Al-S batteries.}, } @article {pmid38243956, year = {2024}, author = {Singh, S and Ahuja, A and Pathak, S}, title = {Potential Role of Oxidative Stress in the Pathophysiology of Neurodegenerative Disorders.}, journal = {Combinatorial chemistry & high throughput screening}, volume = {27}, number = {14}, pages = {2043-2061}, pmid = {38243956}, issn = {1875-5402}, mesh = {Humans ; *Oxidative Stress/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Antioxidants/pharmacology ; Reactive Oxygen Species/metabolism ; Animals ; Neuroprotective Agents/pharmacology/chemistry ; }, abstract = {Neurodegeneration causes premature death in the peripheral and central nervous system. Neurodegeneration leads to the accumulation of oxidative stress, inflammatory responses, and the generation of free radicals responsible for nervous disorders like amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disorders. Therefore, focus must be diverted towards treating and managing these disorders, as it is very challenging. Furthermore, effective therapies are also lacking, so the growing interest of the global market must be inclined towards developing newer therapeutic approaches that can intercept the progression of neurodegeneration. Emerging evidences of research findings suggest that antioxidant therapy has significant potential in modulating disease phenotypes. This makes them promising candidates for further investigation. This review focuses on the role of oxidative stress and reactive oxygen species in the pathological mechanisms of various neurodegenerative diseases, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disorders and their neuroprotection. Additionally, it highlights the potential of antioxidant-based therapeutics in mitigating disease severity in humans and improving patient compliance. Ongoing extensive global research further sheds light on exploring new therapeutic targets for a deeper understanding of disease mechanisms in the field of medicine and biology targeting neurogenerative disorders.}, } @article {pmid38242131, year = {2024}, author = {Shum, C and Hedges, EC and Allison, J and Lee, YB and Arias, N and Cocks, G and Chandran, S and Ruepp, MD and Shaw, CE and Nishimura, AL}, title = {Mutations in FUS lead to synaptic dysregulation in ALS-iPSC derived neurons.}, journal = {Stem cell reports}, volume = {19}, number = {2}, pages = {187-195}, pmid = {38242131}, issn = {2213-6711}, support = {MR/N013255/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; Mutation ; Glutamates/metabolism ; RNA-Binding Protein FUS/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset neurodegenerative disorder characterized by progressive muscular weakness due to the selective loss of motor neurons. Mutations in the gene Fused in Sarcoma (FUS) were identified as one cause of ALS. Here, we report that mutations in FUS lead to upregulation of synaptic proteins, increasing synaptic activity and abnormal release of vesicles at the synaptic cleft. Consequently, FUS-ALS neurons showed greater vulnerability to glutamate excitotoxicity, which raised neuronal swellings (varicose neurites) and led to neuronal death. Fragile X mental retardation protein (FMRP) is an RNA-binding protein known to regulate synaptic protein translation, and its expression is reduced in the FUS-ALS lines. Collectively, our data suggest that a reduction of FMRP levels alters the synaptic protein dynamics, leading to synaptic dysfunction and glutamate excitotoxicity. Here, we present a mechanistic hypothesis linking dysregulation of peripheral translation with synaptic vulnerability in the pathogenesis of FUS-ALS.}, } @article {pmid38242117, year = {2024}, author = {Rautila, OS and Kaivola, K and Rautila, H and Hokkanen, L and Launes, J and Strandberg, TE and Laaksovirta, H and Palmio, J and Tienari, PJ}, title = {The shared ancestry between the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles using haplotype sharing trees and HAPTK.}, journal = {American journal of human genetics}, volume = {111}, number = {2}, pages = {383-392}, pmid = {38242117}, issn = {1537-6605}, mesh = {Humans ; Alleles ; *Amyotrophic Lateral Sclerosis/genetics ; *C9orf72 Protein/genetics ; DNA Repeat Expansion/genetics ; Haplotypes/genetics ; Receptor Protein-Tyrosine Kinases/genetics ; *Trees/genetics ; }, abstract = {The C9orf72 hexanucleotide repeat expansion (HRE) is a common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The inheritance is autosomal dominant, but a high proportion of subjects with the mutation are simplex cases. One possible explanation is de novo expansions of unstable intermediate-length alleles (IAs). Using haplotype sharing trees (HSTs) with the haplotype analysis tool kit (HAPTK), we derived majority-based ancestral haplotypes of HRE samples and discovered that IAs containing ≥18-20 repeats share large haplotypes in common with the HRE. Using HSTs of HRE and IA samples, we demonstrate that the longer IA haplotypes are largely indistinguishable from HRE haplotypes and that several ≥18-20 IA haplotypes share over 5 Mb (>600 markers) haplotypes in common with the HRE haplotypes. These analysis tools allow physical understanding of the haplotype blocks shared with the majority-based ancestral haplotype. Our results demonstrate that the haplotypes with longer IAs belong to the same pool of haplotypes as the HRE and suggest that longer IAs represent potential premutation alleles.}, } @article {pmid38241787, year = {2024}, author = {Hromas, G and Jackson, CE and Cooper, DB and Sullivan, AC}, title = {Primary progressive aphasia and amyotrophic lateral sclerosis (PPA-ALS): A longitudinal case study.}, journal = {Applied neuropsychology. Adult}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/23279095.2024.2302833}, pmid = {38241787}, issn = {2327-9109}, abstract = {OBJECTIVE: Approximately 50% of patients with amyotrophic lateral sclerosis (ALS) experience cognitive decline, with frontotemporal dementia (FTD) accounting for up to 15% of these cases. Despite this, there is considerable delay in diagnosis, which affects patient care.

METHODS: We report longitudinal results of neuropsychological evaluations in a patient diagnosed with non-fluent/agrammatic primary progressive aphasia (nfvPPA) and amyotrophic lateral sclerosis (ALS). The patient, Ms. X, presented with progressive speech difficulties starting in her late-60's. Initial diagnosis was nfvPPA. After 4-5 years of progressive swallowing difficulties, as well as facial weakness, her diagnosis was modified to PPA-ALS.

RESULTS: Ms. X underwent neuropsychological evaluations three times over a period of five years. Results of evaluations were intact and stable over time, except for progressive loss of speech impacting her performance on a sentence repetition task.

CONCLUSION: This case study provides valuable insight into the overlap between PPA-ALS from a neuropsychological standpoint. The results reflect preserved cognitive skills in the context of loss of speech and motor abilities. This case study also shows the length of time between onset of symptoms and clear diagnosis, which often requires an immense amount of health literacy and personal advocacy on the part of the patient.}, } @article {pmid38241161, year = {2024}, author = {Klemmensen, MM and Borrowman, SH and Pearce, C and Pyles, B and Chandra, B}, title = {Mitochondrial dysfunction in neurodegenerative disorders.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {1}, pages = {e00292}, pmid = {38241161}, issn = {1878-7479}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/drug therapy ; Mitochondria ; Reactive Oxygen Species/therapeutic use ; *Alzheimer Disease/pathology ; *Mitochondrial Diseases/genetics/therapy ; }, abstract = {Recent advances in understanding the role of mitochondrial dysfunction in neurodegenerative diseases have expanded the opportunities for neurotherapeutics targeting mitochondria to alleviate symptoms and slow disease progression. In this review, we offer a historical account of advances in mitochondrial biology and neurodegenerative disease. Additionally, we summarize current knowledge of the normal physiology of mitochondria and the pathogenesis of mitochondrial dysfunction, the role of mitochondrial dysfunction in neurodegenerative disease, current therapeutics and recent therapeutic advances, as well as future directions for neurotherapeutics targeting mitochondrial function. A focus is placed on reactive oxygen species and their role in the disruption of telomeres and their effects on the epigenome. The effects of mitochondrial dysfunction in the etiology and progression of Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease are discussed in depth. Current clinical trials for mitochondria-targeting neurotherapeutics are discussed.}, } @article {pmid38241160, year = {2024}, author = {López-Blanch, R and Salvador-Palmer, R and Oriol-Caballo, M and Moreno-Murciano, P and Dellinger, RW and Estrela, JM and Obrador, E}, title = {Nicotinamide riboside, pterostilbene and ibudilast protect motor neurons and extend survival in ALS mice.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {1}, pages = {e00301}, pmid = {38241160}, issn = {1878-7479}, mesh = {Mice ; Animals ; Humans ; Superoxide Dismutase-1 ; *Amyotrophic Lateral Sclerosis/drug therapy ; Neuroinflammatory Diseases ; Tumor Necrosis Factor-alpha ; Endothelial Cells ; Hydrogen Peroxide ; Pilot Projects ; Motor Neurons ; Niacinamide/pharmacology/therapeutic use/*analogs & derivatives ; Mice, Transgenic ; Disease Models, Animal ; Superoxide Dismutase ; Spinal Cord ; *Indolizines ; *Pyrazoles ; *Pyridinium Compounds ; }, abstract = {Oxidative stress and neuroinflammation are major contributors to the pathophysiology of ALS. Nicotinamide riboside (a NAD[+] precursor) and pterostilbene (a natural antioxidant) were efficacious in a human pilot study of ALS patients and in ALS SOD1[G93A] transgenic mice. Ibudilast targets different phosphodiesterases and the macrophage migration inhibitory factor, reduces neuroinflammation, and in early-phase studies improved survival and slowed progression in ALS patients. Using two ALS murine models (SOD1[G93A], FUS[R521C]) the effects of nicotinamide riboside, pterostilbene, and ibudilast on disease onset, progression and survival were studied. In both models ibudilast enhanced the effects of nicotinamide riboside and pterostilbene on survival and neuromotor functions. The triple combination reduced microgliosis and astrogliosis, and the levels of different proinflammatory cytokines in the CSF. TNFα, IFNγ and IL1β increased H2O2 and NO generation by motor neurons, astrocytes, microglia and endothelial cells isolated from ALS mice. Nicotinamide riboside and pterostilbene decreased H2O2 and NO generation in all these cells. Ibudilast specifically decreased TNFα levels and H2O2 generation by microglia and endothelial cells. Unexpectedly, pathophysiological concentrations of H2O2 or NO caused minimal motor neuron cytotoxicity. H2O2-induced cytotoxicity was increased by NO via a trace metal-dependent formation of potent oxidants (i.e. OH and [-]OONO radicals). In conclusion, our results show that the combination of nicotinamide riboside, pterostilbene and ibudilast improve neuromotor functions and survival in ALS murine models. Studies on the underlying mechanisms show that motor neuron protection involves the decrease of oxidative and nitrosative stress, the combination of which is highly damaging to motor neurons.}, } @article {pmid38240416, year = {2024}, author = {Schuster, J and Dreyhaupt, J and Mönkemöller, K and Dupuis, L and Dieterlé, S and Weishaupt, JH and Kassubek, J and Petri, S and Meyer, T and Grosskreutz, J and Schrank, B and Boentert, M and Emmer, A and Hermann, A and Zeller, D and Prudlo, J and Winkler, AS and Grehl, T and Heneka, MT and Johannesen, S and Göricke, B and Witzel, S and Dorst, J and Ludolph, AC and , }, title = {In-depth analysis of data from the RAS-ALS study reveals new insights in rasagiline treatment for amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {4}, pages = {e16204}, pmid = {38240416}, issn = {1468-1331}, support = {//Teva Pharmaceutical Industries/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Indans/therapeutic use ; Disease Progression ; }, abstract = {BACKGROUND AND PURPOSE: In 2016, we concluded a randomized controlled trial testing 1 mg rasagiline per day add-on to standard therapy in 252 amyotrophic lateral sclerosis (ALS) patients. This article aims at better characterizing ALS patients who could possibly benefit from rasagiline by reporting new subgroup analysis and genetic data.

METHODS: We performed further exploratory in-depth analyses of the study population and investigated the relevance of single nucleotide polymorphisms (SNPs) related to the dopaminergic system.

RESULTS: Placebo-treated patients with very slow disease progression (loss of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R] per month before randomization of ≤0.328 points) showed a per se survival probability after 24 months of 0.85 (95% confidence interval = 0.65-0.94). The large group of intermediate to fast progressing ALS patients showed a prolonged survival in the rasagiline group compared to placebo after 6 and 12 months (p = 0.02, p = 0.04), and a reduced decline of ALSFRS-R after 18 months (p = 0.049). SNP genotypes in the MAOB gene and DRD2 gene did not show clear associations with rasagiline treatment effects.

CONCLUSIONS: These results underline the need to consider individual disease progression at baseline in future ALS studies. Very slow disease progressors compromise the statistical power of studies with treatment durations of 12-18 months using clinical endpoints. Analysis of MAOB and DRD2 SNPs revealed no clear relationship to any outcome parameter. More insights are expected from future studies elucidating whether patients with DRD2CC genotype (Rs2283265) show a pronounced benefit from treatment with rasagiline, pointing to the opportunities precision medicine could open up for ALS patients in the future.}, } @article {pmid38240367, year = {2024}, author = {Hobin, F and De Vocht, J and Lamaire, N and Beyens, H and Ombelet, F and Van Damme, P}, title = {Specialized multidisciplinary care improves ALS survival in Belgium: a population-based retrospective study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {282-289}, doi = {10.1080/21678421.2024.2304058}, pmid = {38240367}, issn = {2167-9223}, mesh = {Humans ; Retrospective Studies ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/therapy ; Belgium/epidemiology ; *Neurodegenerative Diseases ; Prognosis ; }, abstract = {ALS is a neurodegenerative disease characterized by loss of motor neurons, resulting in progressive weakness and wasting of muscles. The average survival time is 2-5 years, mostly due to respiratory failure. Since current therapies can prolong survival time by only a few months, multidisciplinary care remains the cornerstone of the management of ALS. At the ALS Expert Centre of University Hospitals Leuven, a large proportion of Belgian ALS patients are seen for diagnosis and a significant number is also in follow-up with the multidisciplinary team. In this retrospective study, we compared the outcome of incident patients who were in follow-up at our site with patients who were not in follow-up. We included 659 patients of which 557 (84.5%) received specialized care at the ALS Expert Centre. After adjusting for clinically relevant prognostic parameters, multidisciplinary follow-up significantly prolonged survival (p = 0.004; HR = 0.683; CI 95% [0.528 - 0.884]). This increase in survival is mainly driven by patients with spinal onset (p = 0.035; HR = 0.746; CI 95% [0.568 - 0.980]), since no significant increased survival time was observed in patients with bulbar onset (p = 0.28; HR = 0.778; CI 95% [0.495 - 1.223]). These data confirm that multidisciplinary follow-up contributes to a better outcome of patients, emphasizing the importance of multidisciplinary specialized care in ALS.}, } @article {pmid38239833, year = {2023}, author = {Eck, RJ and Stair, JG and Kraemer, BC and Liachko, NF}, title = {Simple models to understand complex disease: 10 years of progress from Caenorhabditis elegans models of amyotrophic lateral sclerosis and frontotemporal lobar degeneration.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1300705}, pmid = {38239833}, issn = {1662-4548}, support = {P40 OD010440/OD/NIH HHS/United States ; F31 AG082391/AG/NIA NIH HHS/United States ; I01 BX005762/BX/BLRD VA/United States ; I01 BX004044/BX/BLRD VA/United States ; RF1 AG055474/AG/NIA NIH HHS/United States ; T32 GM136534/GM/NIGMS NIH HHS/United States ; I01 BX002619/BX/BLRD VA/United States ; R01 AG066729/AG/NIA NIH HHS/United States ; IK6 BX006467/BX/BLRD VA/United States ; R01 NS064131/NS/NINDS NIH HHS/United States ; }, abstract = {The nematode Caenorhabditis elegans are a powerful model system to study human disease, with numerous experimental advantages including significant genetic and cellular homology to vertebrate animals, a short lifespan, and tractable behavioral, molecular biology and imaging assays. Beginning with the identification of SOD1 as a genetic cause of amyotrophic lateral sclerosis (ALS), C. elegans have contributed to a deeper understanding of the mechanistic underpinnings of this devastating neurodegenerative disease. More recently this work has expanded to encompass models of other types of ALS and the related disease frontotemporal lobar degeneration (FTLD-TDP), including those characterized by mutation or accumulation of the proteins TDP-43, C9orf72, FUS, HnRNPA2B1, ALS2, DCTN1, CHCHD10, ELP3, TUBA4A, CAV1, UBQLN2, ATXN3, TIA1, KIF5A, VAPB, GRN, and RAB38. In this review we summarize these models and the progress and insights from the last ten years of using C. elegans to study the neurodegenerative diseases ALS and FTLD-TDP.}, } @article {pmid38239560, year = {2023}, author = {Wang, G and Jin, S and Liu, J and Li, X and Dai, P and Wang, Y and Hou, SX}, title = {A neuron-immune circuit regulates neurodegeneration in the hindbrain and spinal cord of Arf1-ablated mice.}, journal = {National science review}, volume = {10}, number = {12}, pages = {nwad222}, pmid = {38239560}, issn = {2053-714X}, abstract = {Neuroimmune connections have been revealed to play a central role in neurodegenerative diseases (NDs). However, the mechanisms that link the central nervous system (CNS) and peripheral immune cells are still mostly unknown. We recently found that specific ablation of the Arf1 gene in hindbrain and spinal cord neurons promoted NDs through activating the NLRP3 inflammasome in microglia via peroxided lipids and adenosine triphosphate (ATP) releasing. Here, we demonstrate that IL-1β with elevated chemokines in the neuronal Arf1-ablated mouse hindbrain and spinal cord recruited and activated γδ T cells in meninges. The activated γδ T cells then secreted IFN-γ that entered into parenchyma to activate the microglia-A1 astrocyte-C3-neuronal C3aR neurotoxic pathway. Remarkably, the neurodegenerative phenotypes of the neuronal Arf1-ablated mice were strongly ameliorated by IFN-γ or C3 knockout. Finally, we show that the Arf1-reduction-induced neuroimmune-IFN-γ-gliosis pathway exists in human NDs, particularly in amyotrophic lateral sclerosis and multiple sclerosis. Together, our results uncover a previously unknown mechanism that links the CNS and peripheral immune cells to promote neurodegeneration.}, } @article {pmid38239315, year = {2024}, author = {Kim, K and Ko, DS and Kim, JW and Lee, D and Son, E and Kim, HW and Song, TJ and Kim, YH}, title = {Association of smoking with amyotrophic lateral sclerosis: A systematic review, meta-analysis, and dose-response analysis.}, journal = {Tobacco induced diseases}, volume = {22}, number = {}, pages = {}, pmid = {38239315}, issn = {1617-9625}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder primarily affecting the voluntary motor nervous system. Several observational studies have provided conflicting results regarding the association between smoking and ALS. Therefore, our objective was to investigate this association through a systematic review, meta-analysis, and dose-response analysis.

METHODS: On 16 January 2023, we initially extracted records from medical databases, which included Medline, Embase, Web of Science, Scopus, and ScienceDirect. We included case-control and cohort studies as eligible studies. Subgroup analyses were performed based on sex, study design, and current smoking. Restricted cubic-spline analysis was utilized to assess the dose-response relationship between smoking (pack-years) and ALS.

RESULTS: Twenty-eight case-control and four cohort studies met the inclusion criteria. The unadjusted OR for the overall association between smoking and ALS was 1.14 (95% CI: 1.06-1.22, I[2]=44%, p<0.001), and the adjusted OR (AOR) was 1.12 (95% CI: 1.03-1.21, I[2]=49%, p=0.009). Subgroup analysis revealed a more pronounced association among current smokers, with an AOR of 1.28 (95% CI: 1.10-1.49, I[2]=66%, p<0.001) and AOR of 1.28 (95% CI: 1.10-1.48, I[2]=58%, p=0.001). In the dose-response analysis, the non-linear model revealed an inverted U-shaped curve.

CONCLUSIONS: Our study provides evidence of a positive relationship between smoking and the risk of ALS. To mitigate the risk of developing ALS, discontinuing smoking, which is a modifiable risk factor, may be crucial.TRIAL REGISTRATION: The study was registered in PROSPERO.IDENTIFIER: CRD42023388822.}, } @article {pmid38239147, year = {2024}, author = {Lin, J and Wang, J and Wang, C and Shan, Y and Jing, W and Fei, Z and Pan, W}, title = {Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part 1: Biogenic components and identification of targets and signaling pathways in amyotrophic lateral sclerosis patients.}, journal = {International journal of clinical pharmacology and therapeutics}, volume = {62}, number = {4}, pages = {155-161}, doi = {10.5414/CP204501}, pmid = {38239147}, issn = {0946-1965}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Medicine, Chinese Traditional ; Network Pharmacology ; Treatment Outcome ; Busulfan ; Signal Transduction ; Molecular Docking Simulation ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: There is evidence that Bu-Shen-Jian-Pi (BSJP), a traditional Chinese medicine, has curative effects in patients suffering from amyotrophic lateral sclerosis (ALS), a progressive and potentially fatal hypoxic condition.

OBJECTIVE: To identify biogenic components in BSJP extracts having potential pharmacological efficacy in ALS.

MATERIALS AND METHODS: Biogenic components in BSJP and their potential pharmacological targets and signaling pathways in ALS were identified and assessed using network pharmacology/hub node analysis.

RESULTS: Network pharmacology analysis identified icariin, naringenin, kaempferol, quercetin, and formononetin as core components in BSJP with potential activity involving mitochondrial protection in patients with ALS.

CONCLUSION: Network pharmacology analysis proved to be a successful screening tool for obtaining information from scientific databases on the pharmacology of biogenic components in BSJP showing potential therapeutic activity in ALS.}, } @article {pmid38238759, year = {2024}, author = {Séguin, P and Maby, E and Fouillen, M and Otman, A and Luauté, J and Giraux, P and Morlet, D and Mattout, J}, title = {The challenge of controlling an auditory BCI in the case of severe motor disability.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {21}, number = {1}, pages = {9}, pmid = {38238759}, issn = {1743-0003}, support = {DEA20140629858//Fondation pour la Recherche Médicale/ ; ING20121226307//Fondation pour la Recherche Médicale/ ; ANR-17-CE40-0005//Agence Nationale de la Recherche/ ; Labex Cortex (ANR-11-LABX-0042)//Agence Nationale de la Recherche/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Brain-Computer Interfaces ; *Persons with Disabilities ; Electroencephalography ; *Locked-In Syndrome ; *Motor Disorders ; }, abstract = {BACKGROUND: The locked-in syndrome (LIS), due to a lesion in the pons, impedes communication. This situation can also be met after some severe brain injury or in advanced Amyotrophic Lateral Sclerosis (ALS). In the most severe condition, the persons cannot communicate at all because of a complete oculomotor paralysis (Complete LIS or CLIS). This even prevents the detection of consciousness. Some studies suggest that auditory brain-computer interface (BCI) could restore a communication through a « yes-no» code.

METHODS: We developed an auditory EEG-based interface which makes use of voluntary modulations of attention, to restore a yes-no communication code in non-responding persons. This binary BCI uses repeated speech sounds (alternating "yes" on the right ear and "no" on the left ear) corresponding to either frequent (short) or rare (long) stimuli. Users are instructed to pay attention to the relevant stimuli only. We tested this BCI with 18 healthy subjects, and 7 people with severe motor disability (3 "classical" persons with locked-in syndrome and 4 persons with ALS).

RESULTS: We report online BCI performance and offline event-related potential analysis. On average in healthy subjects, online BCI accuracy reached 86% based on 50 questions. Only one out of 18 subjects could not perform above chance level. Ten subjects had an accuracy above 90%. However, most patients could not produce online performance above chance level, except for two people with ALS who obtained 100% accuracy. We report individual event-related potentials and their modulation by attention. In addition to the classical P3b, we observed a signature of sustained attention on responses to frequent sounds, but in healthy subjects and patients with good BCI control only.

CONCLUSIONS: Auditory BCI can be very well controlled by healthy subjects, but it is not a guarantee that it can be readily used by the target population of persons in LIS or CLIS. A conclusion that is supported by a few previous findings in BCI and should now trigger research to assess the reasons of such a gap in order to propose new and efficient solutions.

CLINICAL TRIAL REGISTRATIONS: No. NCT02567201 (2015) and NCT03233282 (2013).}, } @article {pmid38237070, year = {2024}, author = {Goto, S and Maeda, N and Ohnuma, K and Lawu, T and Ogawa, K and Sugiyama, S and Matsumaru, M and Noda, T}, title = {Impact of segmented optical axial length on the performance of intraocular lens power calculation formulas.}, journal = {Journal of cataract and refractive surgery}, volume = {50}, number = {5}, pages = {492-497}, doi = {10.1097/j.jcrs.0000000000001397}, pmid = {38237070}, issn = {1873-4502}, mesh = {Humans ; *Axial Length, Eye/pathology/diagnostic imaging ; *Lenses, Intraocular ; Retrospective Studies ; *Biometry/methods ; *Optics and Photonics ; Male ; Female ; *Tomography, Optical Coherence/methods ; *Phacoemulsification ; *Refraction, Ocular/physiology ; Lens Implantation, Intraocular ; Aged ; Middle Aged ; Aged, 80 and over ; Visual Acuity/physiology ; Pseudophakia/physiopathology ; }, abstract = {PURPOSE: To investigate the difference between the segmented axial length (AL) and the composite AL on a swept-source optical coherence tomography biometer and to evaluate the subsequent effects on artificial intelligence intraocular lens (IOL) power calculations: the Kane and Hill-RBF 3.0 formulas compared with established vergence formulas.

SETTING: National Hospital Organization, Tokyo Medical Center, Japan.

DESIGN: Retrospective case series.

METHODS: Consecutive patients undergoing cataract surgery with a single-piece IOL were reviewed. The prediction accuracy of the Barrett Universal II, Haigis, Hill-RBF 3.0, Hoffer Q, Holladay 1, Kane, and SRK/T formulas based on 2 ALs were compared for each formula. The heteroscedastic test was used with the SD of prediction errors as the endpoint for formula performance.

RESULTS: The study included 145 eyes of 145 patients. The segmented AL (24.83 ± 1.89) was significantly shorter than the composite AL (24.88 ± 1.96, P < .001). Bland-Altman analysis revealed a negative proportional bias for the differences between the segmented AL and the composite AL. The SD values obtained by Hoffer Q, Holladay 1, and SRK/T formulas based on the segmented AL (0.52 diopters [D], 0.54 D, and 0.50 D, respectively) were significantly lower than those based on the composite AL (0.57 D, 0.60 D, and 0.52 D, respectively, P < .01).

CONCLUSIONS: The segmented ALs were longer in short eyes and shorter in long eyes than the composite ALs. The refractive accuracy can be improved in the Hoffer Q, Holladay 1, and SRK/T formulas by changing the composite ALs to the segmented ALs.}, } @article {pmid38236205, year = {2024}, author = {Bryson, JB and Kourgiantaki, A and Jiang, D and Demosthenous, A and Greensmith, L}, title = {An optogenetic cell therapy to restore control of target muscles in an aggressive mouse model of amyotrophic lateral sclerosis.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {38236205}, issn = {2050-084X}, support = {Bryson 965-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R011648/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Mice ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Optogenetics ; Muscle, Skeletal ; Paralysis ; Cell- and Tissue-Based Therapy ; Disease Models, Animal ; }, abstract = {Breakdown of neuromuscular junctions (NMJs) is an early pathological hallmark of amyotrophic lateral sclerosis (ALS) that blocks neuromuscular transmission, leading to muscle weakness, paralysis and, ultimately, premature death. Currently, no therapies exist that can prevent progressive motor neuron degeneration, muscle denervation, or paralysis in ALS. Here, we report important advances in the development of an optogenetic, neural replacement strategy that can effectively restore innervation of severely affected skeletal muscles in the aggressive SOD1[G93A] mouse model of ALS, thus providing an interface to selectively control the function of targeted muscles using optical stimulation. We also identify a specific approach to confer complete survival of allogeneic replacement motor neurons. Furthermore, we demonstrate that an optical stimulation training paradigm can prevent atrophy of reinnervated muscle fibers and results in a tenfold increase in optically evoked contractile force. Together, these advances pave the way for an assistive therapy that could benefit all ALS patients.}, } @article {pmid38235854, year = {2024}, author = {Dukic, S and Fasano, A and Coffey, A and Buxó, T and McMackin, R and Chipika, R and Heverin, M and Bede, P and Muthuraman, M and Lowery, M and Carson, RG and Hardiman, O and Nasseroleslami, B}, title = {Electroencephalographic β-band oscillations in the sensorimotor network reflect motor symptom severity in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {4}, pages = {e16201}, pmid = {38235854}, issn = {1468-1331}, support = {/WT_/Wellcome Trust/United Kingdom ; 16/ERCD/3854/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Electroencephalography ; Motor Neurons ; Brain ; Brain Mapping ; }, abstract = {BACKGROUND AND PURPOSE: Resting-state electroencephalography (EEG) holds promise for assessing brain networks in amyotrophic lateral sclerosis (ALS). We investigated whether neural β-band oscillations in the sensorimotor network could serve as an objective quantitative measure of progressive motor impairment and functional disability in ALS patients.

METHODS: Resting-state EEG was recorded in 18 people with ALS and 38 age- and gender-matched healthy controls. We estimated source-localized β-band spectral power in the sensorimotor cortex. Clinical evaluation included lower (LMN) and upper motor neuron scores, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, fine motor function (FMF) subscore, and progression rate. Correlations between clinical scores and β-band power were analysed and corrected using a false discovery rate of q = 0.05.

RESULTS: β-Band power was significantly lower in people with ALS than controls (p = 0.004), and correlated with LMN score (R = -0.65, p = 0.013), FMF subscore (R = -0.53, p = 0.036), and FMF progression rate (R = 0.52, p = 0.036).

CONCLUSIONS: β-Band spectral power in the sensorimotor cortex reflects clinically evaluated motor impairment in ALS. This technology merits further investigation as a biomarker of progressive functional disability.}, } @article {pmid38235844, year = {2024}, author = {Zhang, L and Li, Y and Niu, J and Hu, N and Ding, J and Cui, L and Liu, M}, title = {Neuromuscular ultrasound in combination with nerve conduction studies helps identify inflammatory motor neuropathies from lower motor neuron syndromes.}, journal = {European journal of neurology}, volume = {31}, number = {4}, pages = {e16202}, pmid = {38235844}, issn = {1468-1331}, support = {CIFMS 2021-I2M-1-003//CAMS Innovation Fund for Medical Sciences/ ; 2022-PUMCH-B-017//National High Level Hospital Clinical Research Funding/ ; 2016YFC0905103//National Key Research and Development Program of China/ ; grant XDB39040000//the Strategic Priority Research Program (Pilot study) "Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/therapy ; Nerve Conduction Studies ; Neural Conduction/physiology ; Motor Neurons ; *Polyneuropathies ; *Motor Neuron Disease ; }, abstract = {BACKGROUND AND PURPOSE: Identifying patients with inflammatory motor neuropathies (IMNs) is warranted since effective treatments are available and the prognosis of these patients differs from that of amyotrophic lateral sclerosis patients.

METHODS: Between January 2019 and May 2022, 102 consecutive treatment-naïve lower motor neuron syndrome (LMNS) patients were recruited; these patients were suspected of having multifocal motor neuropathy, pure motor chronic inflammatory demyelinating polyneuropathy or amyotrophic lateral sclerosis with initial lower motor neuron presentation. Neuromuscular ultrasound (US) and nerve conduction studies (NCSs) were conducted at baseline. Relevant diagnostic investigations were performed if clinically warranted. The proposed US evidence of IMN was as follows: (i) nerve enlargement at ≥1 of the predetermined sites or (ii) absence of high intensity fasciculations in predefined muscle groups. Final diagnoses were made by experienced physicians after a prolonged follow-up period (≥12 months). IMN patients were defined as LMNS patients who experienced convincing improvements in response to immunotherapies. IMN patients without electrodiagnostic demyelinating features were diagnosed with treatment-responsive LMNS (TR-LMNS).

RESULTS: In total, 16 patients were classified as IMN, including nine chronic inflammatory demyelinating polyneuropathy/multifocal motor neuropathy patients and seven TR-LMNS patients. Six TR-LMNS patients were identified by neuromuscular US. The sensitivity and specificity of NCSs, nerve US and muscle US were 56.3% and 100%, 43.8% and 90.7% and 68.8% and 97.7%, respectively. When these three modalities were combined, the sensitivity and specificity were 93.8% and 88.4%, respectively.

CONCLUSION: Neuromuscular US studies are supplementary modalities to NCSs, and the combined use of these techniques might improve the identification of IMNs in LMNS patients.}, } @article {pmid38235589, year = {2024}, author = {Gebrehiwet, P and Aggarwal, S and Topaloglu, O and Chiò, A}, title = {Feasibility assessment of using the MiToS staging system for conducting economic evaluation in amyotrophic lateral sclerosis.}, journal = {Expert review of pharmacoeconomics & outcomes research}, volume = {24}, number = {3}, pages = {447-458}, doi = {10.1080/14737167.2024.2306819}, pmid = {38235589}, issn = {1744-8379}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Cost-Benefit Analysis ; Feasibility Studies ; Mitochondria Associated Membranes ; Disease Progression ; Quality-Adjusted Life Years ; }, abstract = {OBJECTIVES: This study assessed the feasibility of using the Milano-Torino staging (MiToS) system for conducting economic evaluation to measure health outcomes in amyotrophic lateral sclerosis (ALS).

METHODS: A Markov model was developed using the MiToS system and evaluated with a hypothetical treatment versus standard of care. Health utilities and transition probabilities were derived from the literature. Four-time horizons (1, 5, 10, and 20 years) were examined. Treatment effects of 20-35% relative risk reduction (RRR) of progressing to the next MiToS stage were assessed. Three patient distribution scenarios were tested: (1) all patients began in stage 0; (2) patient distribution based on real-world TONiC study; (3) distribution based on the PRO-ACT database. Health outcomes (quality-adjusted life-years [QALYs], life-years [LYs]) were reported with a 3% discount rate.

RESULTS: A time horizon of 10 years fully captured treatment benefits: incremental QALYs were 0.28-0.60, 0.21-0.45, and 0.26-0.55 for scenarios 1-3, respectively; incremental LYs were 0.56-1.17, 0.46-0.97, and 0.53-1.11, respectively.

CONCLUSION: MiToS-based staging can be used for conducting economic analyses in ALS. Estimated incremental QALY and LY gains were meaningful within the context of ALS, for hypothetical treatments with RRR of 20-35%.}, } @article {pmid38234062, year = {2024}, author = {Stanziano, M and Fedeli, D and Manera, U and Ferraro, S and Medina Carrion, JP and Palermo, S and Sciortino, P and Cogoni, M and Agosta, F and Basaia, S and Filippi, M and Grisoli, M and Valentini, MC and De Mattei, F and Canosa, A and Calvo, A and Bruzzone, MG and Chiò, A and Nigri, A and Moglia, C}, title = {Resting-state fMRI functional connectome of C9orf72 mutation status.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {3}, pages = {686-697}, pmid = {38234062}, issn = {2328-9503}, support = {GR-2019-12371291//Italian Ministry of Health/ ; RF-2016-02362405//Italian Ministry of Health/ ; RRC//Italian Ministry of Health/ ; //Ministero della Salute/ ; //Ricerca Sanitaria Finalizzata/ ; //Giovani ricercatori/ ; 259867//European Commission's Health Seventh Framework Programme/ ; //Italian Ministry of Education, University and Research/ ; 2017SNW5MB//Progetti di Ricerca di Rilevante Interesse Nazionale, PRIN/ ; //Joint Programme - Neurodegenerative Disease Research/ ; //Department of Excellence/ ; //'Rita Levi Montalcini' Department of Neuroscience/ ; //University of Torino, Italy/ ; }, mesh = {Humans ; Magnetic Resonance Imaging ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics/pathology ; C9orf72 Protein/genetics ; *Connectome ; DNA Repeat Expansion/genetics ; Proteins/genetics ; Mutation ; }, abstract = {OBJECTIVE: The resting-state functional connectome has not been extensively investigated in amyotrophic lateral sclerosis (ALS) spectrum disease, in particular in relationship with patients' genetic status.

METHODS: Here we studied the network-to-network connectivity of 19 ALS patients carrying the C9orf72 hexanucleotide repeat expansion (C9orf72+), 19 ALS patients not affected by C9orf72 mutation (C9orf72-), and 19 ALS-mimic patients (ALSm) well-matched for demographic and clinical variables.

RESULTS: When compared with ALSm, we observed greater connectivity of the default mode and frontoparietal networks with the visual network for C9orf72+ patients (P = 0.001). Moreover, the whole-connectome showed greater node degree (P < 0.001), while sensorimotor cortices resulted isolated in C9orf72+.

INTERPRETATION: Our results suggest a crucial involvement of extra-motor functions in ALS spectrum disease. In particular, alterations of the visual cortex may have a pathogenic role in C9orf72-related ALS. The prominent feature of these patients would be increased visual system connectivity with the networks responsible of the functional balance between internal and external attention.}, } @article {pmid38233111, year = {2025}, author = {Kunji Koya, R and Branston, JR and Gallagher, AWA and Bui, WKT and Ross, H and Mohamed Nor, N}, title = {Improving estimates of the illicit cigarette trade through collaboration: lessons from two studies of Malaysia.}, journal = {Tobacco control}, volume = {34}, number = {2}, pages = {242-247}, doi = {10.1136/tc-2023-058333}, pmid = {38233111}, issn = {1468-3318}, mesh = {Malaysia ; *Tobacco Products/economics/legislation & jurisprudence ; Humans ; *Commerce/legislation & jurisprudence ; *Taxes ; Crime/statistics & numerical data ; }, abstract = {This paper critically analyses contrasting estimates of Malaysia's illicit cigarette trade in 2011, 2015 and 2019 by Bui et al and Koya et al who previously produced independent estimates at about the same time using tax gap analysis. Collaboration between the two authors' teams emerged due to the discrepancies in their results, generating this paper to explore the methodological issues identified and hence produce revised estimates of the rate of illicit. Key issues identified were: Bui et al's assessment of legally imported cigarettes impacting all years; their exclusion of ad valorem duty affecting the 2011 and 2015 estimates; Koya et al overlooked the value of cigarettes for export market in their ad valorem calculation and used the sales value of imported tobacco/tobacco products, not just cigarettes, both of which impact estimates for 2011 and 2015. Recalculations using Koya et al's consumption data reveal that in 2019, illicit cigarettes accounted for about 70% of the market, which is higher than Bui et al's estimate (38%) but slightly lower than Koya et al's (72%). For 2011 and 2015 where ad valorem applied, the corrected estimates show a share of the illicit cigarette market of approximately 41.1% and 52.7%, respectively, differing from Bui et al's 0% in 2011 and 29.6% in 2015, and Koya et al's 51% in 2011 and 55% in 2015. This paper provides essential lessons for addressing methodological issues between authors' teams and updated estimates of Malaysia's illicit cigarette trade, verifying that Malaysia faces a substantial illicit cigarette trade problem.}, } @article {pmid38229740, year = {2024}, author = {Rosse, G}, title = {Novel Pyrazolopyridine Inhibitors of Monoacylglycerol Lipase for the Treatment of Neurodegenerative Diseases and Neuroinflammation.}, journal = {ACS medicinal chemistry letters}, volume = {15}, number = {1}, pages = {19-20}, pmid = {38229740}, issn = {1948-5875}, abstract = {This work highlights the use of bicyclic heterocyclic compounds as monoacylglycerol lipase inhibitors potentially in the treatment of Alzheimer's disease, Parkinson's disease, ALS, traumatic brain injury, and multiple sclerosis.}, } @article {pmid38229533, year = {2024}, author = {Feng, Y and Xu, Z and Jin, H and Chen, Y and Fu, C and Zhang, Y and Yin, Y and Wang, H and Cheng, W}, title = {Metformin ameliorates mitochondrial damage induced by C9orf72 poly(GR) via upregulating AKT phosphorylation.}, journal = {Journal of cellular biochemistry}, volume = {125}, number = {3}, pages = {e30526}, doi = {10.1002/jcb.30526}, pmid = {38229533}, issn = {1097-4644}, support = {23ZR1441200//Natural Science Foundation of Shanghai/ ; 20QA1406300//Shanghai Rising-Star Program/ ; 81901162//National Natural Science Foundation of China/ ; 81974270//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Frontotemporal Dementia/drug therapy/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; Phosphorylation ; Dipeptides ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases with no effective cure. GGGGCC repeat expansion in C9orf72 is the most common genetic cause of both ALS and FTD. A key pathological feature of C9orf72 related ALS/FTD is the presence of abnormal dipeptide repeat proteins translated from GGGGCC repeat expansion, including poly Glycine-Arginine (GR). In this study, we observed that (GR)50 conferred significant mitochondria damage and cytotoxicity. Metformin, the most widely used clinical drug, successfully relieved (GR)50 induced mitochondrial damage and inhibited (GR)50 related cytotoxicity. Further research revealed metformin effectively restored mitochondrial function by upregulating AKT phosphorylation in (GR)50 expressed cells. Taken together, our results indicated restoring mitochondrial function with metformin may be a rational therapeutic strategy to reduce poly(GR) toxicity in C9orf72 ALS/FTD patients.}, } @article {pmid38229194, year = {2024}, author = {Jadhav, PA and Hole, A and Ingle, A and Govekar, R and Noothalapati, H and Krishna, CM}, title = {Serum Raman spectroscopy: Evaluation of tumour load variations in experimental carcinogenesis.}, journal = {Journal of biophotonics}, volume = {17}, number = {4}, pages = {e202300424}, doi = {10.1002/jbio.202300424}, pmid = {38229194}, issn = {1864-0648}, mesh = {Animals ; Cricetinae ; Humans ; *Spectrum Analysis, Raman/methods ; Tumor Burden ; Multivariate Analysis ; Discriminant Analysis ; *Cell Transformation, Neoplastic ; Least-Squares Analysis ; }, abstract = {Several serum Raman spectroscopy (RS) studies have demonstrated its potential as an oral cancer screening tool. This study investigates influence of low tumour load (LTL) and high tumour load (HTL) on serum RS using hamster buccal pouch model of experimental oral carcinogenesis. Sera of untreated control, LTL, and HTL groups at week intervals during malignant transformation were employed. Serum Raman spectra were subjected to multivariate analyses-principal component analysis, principal component-based linear discriminant analysis (for stratification of study groups), and multivariate curve resolution-alternating least squares (MCR-ALS) (to comprehend biomolecular differences). Multivariate analysis revealed misclassifications between LTL and HTL at all week intervals. MCR-ALS components showed statistically significant abundances between control versus LTL and control versus HTL, but could not discern LTL and HTL. MCR-ALS components exhibited spectral mixtures of proteins, lipids, heme and nucleic acids. Thus, these findings support use of serum RS as a screening tool as varying tumour load is not a confounding factor influencing the technique.}, } @article {pmid38227807, year = {2024}, author = {Carbayo, Á and Borrego-Écija, S and Turon-Sans, J and Cortés-Vicente, E and Molina-Porcel, L and Gascón-Bayarri, J and Rubio, MÁ and Povedano, M and Gámez, J and Sotoca, J and Juntas-Morales, R and Almendrote, M and Marquié, M and Sánchez-Valle, R and Illán-Gala, I and Dols-Icardo, O and Rubio-Guerra, S and Bernal, S and Caballero-Ávila, M and Vesperinas, A and Gelpi, E and Rojas-García, R}, title = {Clinicopathological correlates in the frontotemporal lobar degeneration-motor neuron disease spectrum.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {7}, pages = {2357-2367}, pmid = {38227807}, issn = {1460-2156}, support = {CM21/00057//Río Hortega Contract/ ; //Instituto de Salud Carlos III/ ; //Atlantic Fellow for Equity in Brain Health/ ; //Global Brain Health Institute/ ; /ALZ/Alzheimer's Association/United States ; ALZ UK-21-720973/ALZS_/Alzheimer's Society/United Kingdom ; JR20/0018//Juan Rodés Contract/ ; JR19/00037//Juan Rodés Contract/ ; }, mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; *Frontotemporal Lobar Degeneration/pathology/genetics ; Retrospective Studies ; *Motor Neuron Disease/pathology/genetics ; Amyotrophic Lateral Sclerosis/pathology/genetics ; Frontotemporal Dementia/pathology/genetics ; Brain/pathology ; DNA-Binding Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease (MND) that shares a common clinical, genetic and pathologic spectrum with frontotemporal dementia (FTD). It is highly heterogeneous in its presentation and features. Up to 50% of patients with MND develop cognitive-behavioural symptoms during the course of the disease, meeting criteria for FTD in 10%-15% of cases. In the absence of a precise biomarker, neuropathology is still a valuable tool to understand disease nosology, reach a definite diagnostic confirmation and help define specific subgroups of patients with common phenotypic, genetic and biomarker profiles. However, few neuropathological series have been published, and the frequency of frontotemporal lobar degeneration (FTLD) in MND is difficult to estimate. In this work we describe a large clinicopathological series of MND patients, analysing the frequency of concurrent FTLD changes and trying to define specific subgroups of patients based on their clinical, genetic and pathological characteristics. We performed an observational, retrospective, multicentre case study. We included all cases meeting neuropathological criteria for MND from the Neurological Tissue Bank of the FRCB-IDIBAPS-Hospital Clínic Barcelona Biobank between 1994 and 2022, regardless of their last clinical diagnosis. While brain donation is encouraged in all patients, it is performed in very few, and representativeness of the cohort might not be precise for all patients with MND. We retrospectively reviewed clinical and neuropathological data and describe the main clinical, genetic and pathogenic features, comparing neuropathologic groups between MND with and without FTLD changes and aiming to define specific subgroups. We included brain samples from 124 patients, 44 of whom (35.5%) had FTLD neuropathologic features (i.e. FTLD-MND). Pathologic TDP-43 aggregates were present in 93.6% of the cohort and were more extensive (higher Brettschneider stage) in those with concurrent FTLD (P < 0.001). Motor symptom onset was more frequent in the bulbar region in FTLD-MND cases than in those with isolated MND (P = 0.023), with no differences in survival. We observed a better clinicopathological correlation in the MND group than in the FTLD-MND group (93.8% versus 61.4%; P < 0.001). Pathogenic genetic variants were more common in the FTLD-MND group, especially C9orf72. We describe a frequency of FTLD of 35.5% in our series of neuropathologically confirmed cases of MND. The FTLD-MND spectrum is highly heterogeneous in all aspects, especially in patients with FTLD, in whom it is particularly difficult to define specific subgroups. In the absence of definite biomarkers, neuropathology remains a valuable tool for a definite diagnosis, increasing our knowledge in disease nosology.}, } @article {pmid38227505, year = {2024}, author = {Goswami, A and Carra, S}, title = {PML nuclear bodies: new players in familial amyotrophic lateral sclerosis-frontotemporal dementia?.}, journal = {Neural regeneration research}, volume = {19}, number = {9}, pages = {1875-1876}, pmid = {38227505}, issn = {1673-5374}, } @article {pmid38226616, year = {2024}, author = {Otani, R and Shibuya, K and Shimizu, T and Kitaoji, T and Noto, YI and Bokuda, K and Kimura, H and Suichi, T and Nakamura, K and Kano, H and Morooka, M and Aotsuka, Y and Ogushi, M and Misawa, S and Kuwabara, S}, title = {Diagnostic utility of Gold Coast criteria for amyotrophic lateral sclerosis in Asia.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {264-270}, doi = {10.1080/21678421.2024.2303062}, pmid = {38226616}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Asia ; Electromyography ; Sensitivity and Specificity ; }, abstract = {Objective: This study aimed to reveal the diagnostic utility of Gold Coast (GC) criteria in Japanese patients with amyotrophic lateral sclerosis (ALS) by comparing the sensitivity/specificity with revised El Escorial (R-EE) and Awaji criteria, because its utility has not been studied in Asian ALS. Methods: Consecutive 639 patients (529 with ALS and 110 with ALS mimics), who were suspected of ALS and referred to three Japanese ALS centers, were enrolled. Diagnostic accuracy and characteristics of false positive and negative in GC criteria were compared with those of the Awaji and R-EE criteria. Patients were categorized as definite, probable or possible ALS according to each criterion. Results: The sensitivity of GC criteria (96.8%, 95% confidence interval [CI]: 95.3-98.3%) was higher than that of Awaji (89.6%, 95% CI: 87.0-92.2%) and R-EEC (89.2, 95% CI: 86.6-91.8%) criteria (both, p < 0.001). The specificity was also higher with GC criteria (77.3%, 95% CI: 69.5-85.1%) than Awaji (65.5%, 95% CI: 56.6-74.4%) and R-EEC (66.4, 95% CI: 57.6-75.2%) criteria (both, p < 0.01). Using GC criteria, patients with cervical spondylosis and Parkinson's syndrome tended to be diagnosed with ALS (i.e. "false positive"). Additionally, ALS patients diagnosed only by GC criteria less frequently had upper motor neuron (UMN) signs, compared with the other two criteria. Conclusion: Gold Coast criteria improve diagnostic accuracy for ALS in an Asian population, especially in patients with subtle UMN signs.}, } @article {pmid38226245, year = {2024}, author = {Sharma, S and Mehan, S and Khan, Z and Gupta, GD and Narula, AS}, title = {Icariin prevents methylmercury-induced experimental neurotoxicity: Evidence from cerebrospinal fluid, blood plasma, brain samples, and in-silico investigations.}, journal = {Heliyon}, volume = {10}, number = {1}, pages = {e24050}, pmid = {38226245}, issn = {2405-8440}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that causes significant neurodegeneration. Methylmercury (MeHg+) is a neurotoxin that induces axonal neurodegeneration and motor nerve degeneration by destroying oligodendrocytes, degenerating white matter, inducing apoptosis, excitotoxicity, and reducing myelin basic protein (MBP). This study examines the inhibition of SIRT-1 (silence information regulator 1), Nrf-2 (nuclear factor E2-related factor 2), HO-1 (heme oxygenase 1), and TDP-43 (TAR-DNA-binding protein 43) accumulation in the context of ALS, as well as the modulation of these proteins by icariin (15 and 30 mg/kg, orally), a glycoside flavonoid with neuroprotective properties. Neuroprotective icariin activates SIRT-1, Nrf-2, and HO-1, mitigating inflammation and neuronal injury in neurodegenerative disorders. In-vivo and in-silico testing of experimental ALS models confirmed icariin efficacy in modulating these cellular targets. The addition of sirtinol 10 mg/kg, an inhibitor of SIRT-1, helps determine the effectiveness of icariin. In this study, we also examined neurobehavioral, neurochemical, histopathological, and LFB (Luxol fast blue) markers in various biological samples, including Cerebrospinal fluid (CSF), blood plasma, and brain homogenates (Cerebral Cortex, Hippocampus, Striatum, mid-brain, and Cerebellum). These results demonstrate that the administration of icariin ameliorates experimental ALS and that the mechanism underlying these benefits is likely related to regulating the SIRT-1, Nrf-2, and HO-1 signaling pathways.}, } @article {pmid38226086, year = {2023}, author = {AlMadan, N and AlMajed, A and AlAbbad, M and AlNashmi, F and Aleissa, A}, title = {Dental Management of Patients With Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {15}, number = {12}, pages = {e50602}, pmid = {38226086}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons with upper and lower motor neuron manifestations. It is divided into two variants: a spinal onset and a bulbar onset. The first starts as focal muscle weakness and wasting that spreads with disease progression, while the second phenotype presents with dysarthria, dysphonia, and dysphagia. Moreover, an extra-motor manifestation could be reported with the most commonly reported symptoms being the change in cognition and sleep disorder. Oral manifestations include increased salivation, limited mouth opening, and dysphagia. Patients with ALS have difficulty maintaining oral hygiene, and it is important for the practitioner and the caregiver to take care of this group of population. We herein provide a short review of the disease with a focus on the oral manifestations and dental considerations for management for this group.}, } @article {pmid38226024, year = {2024}, author = {de Jongh, CA and Bikker, FJ and de Vries, TJ and Werner, A and Gibbs, S and Krom, BP}, title = {Porphyromonas gingivalis interaction with Candida albicans allows for aerobic escape, virulence and adherence.}, journal = {Biofilm}, volume = {7}, number = {}, pages = {100172}, pmid = {38226024}, issn = {2590-2075}, abstract = {In the oral cavity Candida albicans interacts with many oral bacteria, including Porphyromonas gingivalis, both physically and metabolically. The aim of this in vitro study was to characterize these interactions and study their effects on the survival of P. gingivalis. First, metabolic interactions were evaluated by counting the colony forming units (CFU) after co-culturing. The results indicated that the anaerobic bacterium P. gingivalis survives under aerobic conditions when co-cultured with C. albicans. This is due to the oxygen consumption by C. albicans as determined by a reduction in survival upon the addition of Antimycin A. By measuring the protease activity, it was found that the presence of C. albicans induced gingipain activity by P. gingivalis, which is an important virulence factor. Adherence of P. gingivalis to hyphae of C. albicans was observed with a dynamic flow system. Using various C. albicans mutants, it was shown that the mechanism of adhesion was mediated by the cell wall adhesins, members of the agglutinin-like sequence (Als) family: Als3 and Als1. Furthermore, the two microorganisms could be co-cultured into forming a biofilm in which P. gingivalis can survive under aerobic culturing conditions, which was imaged using scanning electron microscopy. This study has further elucidated mechanisms of interaction, virulence acquisition and survival of P. gingivalis when co-cultured with C. albicans. Such survival could be essential for the pathogenicity of P. gingivalis in the oxygen-rich niches of the oral cavity. This study has emphasized the importance of interaction between different microbes in promoting survival, virulence and attachment of pathogens, which could be essential in facilitating penetration into the environment of the host.}, } @article {pmid38225089, year = {2024}, author = {Unan, R and Azapoglu, O and Deligoz, İ and Mennan, H and Al-Khatib, K}, title = {Gene flow and spontaneous mutations are responsible for imidazolinone herbicide-resistant weedy rice (Oryza sativa L.).}, journal = {Pesticide biochemistry and physiology}, volume = {198}, number = {}, pages = {105746}, doi = {10.1016/j.pestbp.2023.105746}, pmid = {38225089}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology ; *Oryza/genetics ; Gene Flow ; Plant Weeds/genetics ; Herbicide Resistance/genetics ; Mutation ; }, abstract = {For more than two decades, weedy rice (Oryza sativa L.) has been controlled in rice fields by using imidazolinone (IMI) herbicide-resistant rice technology (Clearfield®). Outcrossing in weedy rice populations and spontaneous mutations are potential problems with herbicide-resistant crop management technologies, such as the IMI-resistant rice. The aim of this study was to characterize the mechanism of IMI herbicide resistance in weedy rice through dose-response bioassay study and evaluating amino acid substitutions in acetolactate synthase (ALS) protein. A total of 118 suspected IMI-resistant weedy rice samples, which survived in the field after an IMI herbicide application, were collected at harvest time from Türkiye in 2020 and 2021. Single-dose imazamox application experiment revealed that 38 plants survived herbicide treatment. The imazamox resistance of the surviving plants was confirmed by dose-response experiment. ALS gene region underwent a sanger DNA partial sequencing. No substitution was found in 10 samples, however, amino acid substitutions were found in 26 samples with S563N, one sample with S653T, and one sample with E630D. The S653N point is the same substitution point that serves as the origin of resistance for the Clearfield® rice varieties that are commonly cultivated in the region. It has been hypothesized that the gene flow from IMI-resistant rice may be the cause of resistance in the IMI resistant weedy rice samples with S653N. The other substitution, S653T, were considered spontaneous mutation to IMI resistance. Interestingly, the S653T mutation was detected for the first time in weedy rice. The mechanism of resistance of 10 resistant weedy rice was not confirmed in this study, however, it may be a non-target resistance or another mutation point in target site, but evidently, they did not acquire resistance by gene flow from IMI-resistant rice. It has been concluded that the effectiveness of IMI-resistant rice technology in controlling weedy rice has drastically decreased due to possible gene flow, spontaneous mutation and non-target resistance. In addition to cultural controls like clean seed, clean machinery and crop rotation, other herbicide-tolerant rice systems such as Provisia® and Roxy-RPS® rice are needed to create a diverse weedy rice management ensemble available for rice production and move towards sustainable rice farming.}, } @article {pmid38225088, year = {2024}, author = {Ohta, K and Sada, Y}, title = {Inheritance and stacking effect of mutant ALS genes in Schoenoplectiella juncoides (Roxb.) Lye (Cyperaceae).}, journal = {Pesticide biochemistry and physiology}, volume = {198}, number = {}, pages = {105745}, doi = {10.1016/j.pestbp.2023.105745}, pmid = {38225088}, issn = {1095-9939}, mesh = {*Lye/pharmacology ; *Cyperaceae/genetics ; *Herbicides/pharmacology ; Mutation ; Alleles ; Herbicide Resistance/genetics ; *Acetolactate Synthase/genetics ; }, abstract = {Schoenoplectiella juncoides, a noxious sedge weed in Japanese rice paddy, has two ALS genes, and ALS-inhibitor-resistant plants have a mutation in one of the ALS genes. The authors aimed (a) to quantitate the effect of the number of mutant alleles of ALS genes on whole-plant resistance of S. juncoides and (b) to clarify a mode of inheritance of the resistance by investigating resistance levels of the progenies of a hybrid between two S. juncoides plants with Trp574Leu substitution in different ALS. A dose-response analysis on the parental lines and the F1 population suggested that the two ALS genes contribute equally to whole-plant resistant levels. A dose-response study on the F2 population indicated that it could be classified into five groups based on the sensitivities to metsulfuron-methyl. The five groups (in ascending order of resistance levels) were considered to have zero, one, two, three, and four mutant alleles. The stacking effect of mutant alleles on resistance enhancement was more significant when the number of mutant alleles was low than when it was high; in other words, each additional mutant allele stacking increases plant resistance, but the effect saturates as the number of mutant alleles increases. A chi-square test supported that the segregation ratio of the five groups corresponds to 1:4:6:4:1 of Mendelian independence for the two ALS loci.}, } @article {pmid38225062, year = {2024}, author = {Xu, X and Zhao, B and Li, B and Shen, B and Qi, Z and Wang, J and Cui, H and Chen, S and Wang, G and Liu, X}, title = {Trp-574-Leu mutation and metabolic resistance by cytochrome P450 gene conferred high resistance to ALS-inhibiting herbicides in Descurainia sophia.}, journal = {Pesticide biochemistry and physiology}, volume = {198}, number = {}, pages = {105708}, doi = {10.1016/j.pestbp.2023.105708}, pmid = {38225062}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/antagonists & inhibitors/metabolism ; *Arylsulfonates ; *Brassicaceae/drug effects/genetics ; Cytochrome P-450 Enzyme System/genetics ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Mutation ; }, abstract = {Descurainia sophia (flixweed) is a troublesome weed in winter wheat fields in North China. Resistant D. sophia populations with different acetolactate synthetase (ALS) mutations have been reported in recent years. In addition, metabolic resistance to ALS-inhibiting herbicides has also been identified. In this study, we collected and purified two resistant D. sophia populations (R1 and R2), which were collected from winter wheat fields where tribenuron-methyl provided no control of D. sophia at 30 g a.i. ha[-1]. Whole plant bioassay and ALS activity assay results showed the R1 and R2 populations had evolved high-level resistance to tribenuron-methyl and florasulam and cross-resistance to imazethapyr and pyrithiobac‑sodium. The two ALS genes were cloned from the leaves of R1 and R2 populations, ALS1 (2004 bp) and ALS2 (1998 bp). A mutation of Trp 574 to Leu in ALS1 was present in both R1 and R2. ALS1 and ALS2 were cloned from R1 and R2 populations respectively and transferred into Arabidopsis thaliana. Homozygous T3 transgenic seedlings with ALS1 of R1 or R2 were resistant to ALS-inhibiting herbicides and the resistant levels were the same. Transgenic seedlings with ALS2 from R1 or R2 were susceptible to ALS-inhibiting herbicides. Treatment with cytochrome P450 inhibitor malathion decreased the resistant levels to tribenuron-methyl in R1 and R2. RNA-Seq was used to identify target cytochrome P450 genes possibly involved in resistance to ALS-inhibiting herbicides. There were five up-regulated differentially expressed cytochrome P450 genes: CYP72A15, CYP83B1, CYP81D8, CYP72A13 and CYP71A12. Among of them, CYP72A15 had the highest expression level in R1 and R2 populations. The R1 and R2 populations of D. sophia have evolved resistance to ALS-inhibiting herbicides due to Trp 574 Leu mutation in ALS1 and possibly other mechanisms. The resistant function of CYP72A15 needs further research.}, } @article {pmid38224498, year = {2024}, author = {Urban, MW and Charsar, BA and Heinsinger, NM and Markandaiah, SS and Sprimont, L and Zhou, W and Brown, EV and Henderson, NT and Thomas, SJ and Ghosh, B and Cain, RE and Trotti, D and Pasinelli, P and Wright, MC and Dalva, MB and Lepore, AC}, title = {EphrinB2 knockdown in cervical spinal cord preserves diaphragm innervation in a mutant SOD1 mouse model of ALS.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {38224498}, issn = {2050-084X}, support = {R01 NS079702/NS/NINDS NIH HHS/United States ; R01 NS110385/NS/NINDS NIH HHS/United States ; R01NS109150/NS/NINDS NIH HHS/United States ; R21 NS090912/NS/NINDS NIH HHS/United States ; T32 GM144302/GM/NIGMS NIH HHS/United States ; R01 NS109150/NS/NINDS NIH HHS/United States ; R01NS110385/NS/NINDS NIH HHS/United States ; R01NS079702/NS/NINDS NIH HHS/United States ; RF1AG057882/NS/NINDS NIH HHS/United States ; R21NS090912/NS/NINDS NIH HHS/United States ; RF1 AG057882/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; Astrocytes/metabolism ; *Cervical Cord/metabolism/pathology ; Diaphragm/innervation ; Disease Models, Animal ; *Ephrin-B2/genetics ; Mice, Transgenic ; *Neurodegenerative Diseases/pathology ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss. Importantly, non-neuronal cell types such as astrocytes also play significant roles in disease pathogenesis. However, mechanisms of astrocyte contribution to ALS remain incompletely understood. Astrocyte involvement suggests that transcellular signaling may play a role in disease. We examined contribution of transmembrane signaling molecule ephrinB2 to ALS pathogenesis, in particular its role in driving motor neuron damage by spinal cord astrocytes. In symptomatic SOD1[G93A] mice (a well-established ALS model), ephrinB2 expression was dramatically increased in ventral horn astrocytes. Reducing ephrinB2 in the cervical spinal cord ventral horn via viral-mediated shRNA delivery reduced motor neuron loss and preserved respiratory function by maintaining phrenic motor neuron innervation of diaphragm. EphrinB2 expression was also elevated in human ALS spinal cord. These findings implicate ephrinB2 upregulation as both a transcellular signaling mechanism in mutant SOD1-associated ALS and a promising therapeutic target.}, } @article {pmid38223824, year = {2024}, author = {Lee, MY and Kim, M}, title = {Effects of Red ginseng on neuroinflammation in neurodegenerative diseases.}, journal = {Journal of ginseng research}, volume = {48}, number = {1}, pages = {20-30}, pmid = {38223824}, issn = {1226-8453}, abstract = {Red ginseng (RG) is widely used as a herbal medicine. As the human lifespan has increased, numerous diseases have developed, and RG has also been used to treat various diseases. Neurodegenerative diseases are major problems that modern people face through their lives. Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are featured by progressive nerve system damage. Recently, neuroinflammation has emerged as a degenerative factor and is an immune response in which cytokines with nerve cells that constitute the nervous system. RG, a natural herbal medicine with fewer side effects than chemically synthesized drugs, is currently in the spotlight. Therefore, we reviewed studies reporting the roles of RG in treating neuroinflammation and neurodegenerative diseases and found that RG might help alleviate neurodegenerative diseases by regulating neuroinflammation.}, } @article {pmid38222431, year = {2023}, author = {Turabieh, H and Afshar, AS and Statland, J and Song, X and , }, title = {Towards a Machine Learning Empowered Prognostic Model for Predicting Disease Progression for Amyotrophic Lateral Sclerosis.}, journal = {AMIA ... Annual Symposium proceedings. AMIA Symposium}, volume = {2023}, number = {}, pages = {718-725}, pmid = {38222431}, issn = {1942-597X}, mesh = {Humans ; Prognosis ; *Amyotrophic Lateral Sclerosis/diagnosis ; Disease Progression ; Algorithms ; Machine Learning ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disorder that is highly heterogeneous and invariably fatal. Due to the unpredictable nature of its progression, accurate tools and algorithms are needed to predict disease progression and improve patient care. To address this need, we developed and compared an extensive set of screener-learner machine learning models to accurately predict the ALS Function-Rating-Scale (ALSFRS) score reduction between 3 and 12 months, by paring 5 state-of-arts feature selection algorithms with 17 predictive models and 4 ensemble models using the publicly available Pooled Open Access Clinical Trials Database (PRO-ACT). Our experiment showed promising results with the blender-type ensemble model achieving the best prediction accuracy and highest prognostic potential.}, } @article {pmid38220602, year = {2023}, author = {Seow-Choen, F and Ng, PKL}, title = {On the correct lectotype for Marmessoidea unicolor Redtenbacher, 1908 (Insecta: Phasmatodea).}, journal = {Zootaxa}, volume = {5360}, number = {3}, pages = {448-450}, doi = {10.11646/zootaxa.5360.3.8}, pmid = {38220602}, issn = {1175-5334}, mesh = {Animals ; *Insecta ; *Neoptera ; }, abstract = {Hennemann, F.H., Conle, O.V. & Brock, P.D. (2023) The types of Phasmatodea (= Phasmida) deposited in the Eidgenssisches Technisches Hochschulzentrum, Zrich, Switzerland (ETHZ). Zootaxa, 5278 (1), 176188. https://doi.org/10.11646/zootaxa.5278.1.10 Hovinga, H. (2010) The Sumatra Railroad: Final destination Pakan Baroe, 19431945. Brill, Leiden, 391 pp. https://doi.org/10.1163/9789004253711 ICZN [International Commission on Zoological Nomenclature] (1999) International Code of Zoological Nomenclature. International Commission of Zoological Nomenclature. 4th Edition. Adopted by the XXI General Assembly of the International Union of Biological Sciences. International Trust for Zoological Nomenclature, in association with the British Museum (Natural History), London, 338 pp. Redtenbacher, J. (1908) Die Insektenfamilie der Phasmiden. III. Phasmidae Anareolatae (Phibalosomini, Acrophyllini, Necrosciini). Wilhelm Engelmann, Leipzig, pp. 341589, pls. 1627. Seow-Choen, F. (2021) A Taxonomic Guide to Stick Insects of Peninsular Malaysia. Vol. 1. Natural History Publications, Borneo, Kota Kinabalu, 944 pp. Weidmann, W. (1936) Der Schweizer als Pionier und Kolonist in Sumatra. In: Der Schweizer Verein Deli-Sumatra (Ed.), Der Schweizer Verein Deli-Sumatra: Zum fnfzigjhrigen Bestehen, 18861936. Buchdruckerei der Neuen Zrcher Zeitung, Zrich, pp. 3348.}, } @article {pmid38220456, year = {2024}, author = {Li, Y and Guo, Y and Xia, CX and Meng, XY and Wang, X and Xu, T and Zhong, Y and Wang, F}, title = {[Echocardiographic two-dimensional strain evaluation of right ventricular function in healthy adults].}, journal = {Zhonghua xin xue guan bing za zhi}, volume = {52}, number = {1}, pages = {58-63}, doi = {10.3760/cma.j.cn112148-20231019-00348}, pmid = {38220456}, issn = {0253-3758}, support = {2020YFC2002700//National Key R & D Program/ ; BJ-2019-133//Scientific Research Project of Beijing Hospital/ ; }, mesh = {Adult ; Female ; Humans ; Male ; Cross-Sectional Studies ; *Echocardiography/methods ; Heart Ventricles/diagnostic imaging ; *Ventricular Dysfunction, Right/diagnosis ; Ventricular Function, Right ; Feasibility Studies ; }, abstract = {Objective: To explore the feasibility of using two-dimensional speckle tracking echocardiography for measuring right ventricular strain and function in healthy adults, and to analyze the impact of age and gender. Methods: This study is a cross-sectional study. Healthy adults who underwent physical examination in the Physical Examination Center of Beijing Hospital from January 1, 2020 to January 1, 2021 were included. Two researchers independently measured various right ventricular longitudinal strain indices using the Echopac software, including (global longitudinal strain (GLS), apical longitudinal strain (ALS), midventricle longitudinal strain (MLS), basal longitudinal strain (BLS), free wall GLS (FWGLS), free wall ALS (FWALS), free wall MLS (FWMLS) and free wall BLS (FWBLS)) as well as tricuspid annular plane systolic excursion (TAPSE) and right ventricle-fraction of area change (RVFAC). The above indicators were taken as the average of two physicians. The consistency of the measurements by two physicians was evaluated by the within-group correlation coefficient (ICC). Results: A total of 233 subjects were included, including 137 males, aged (58.5±14.2) years. ICC values was all above 0.8 with excellent agreement. The values of FWGLS and GLS in healthy adults were -26.63% and -21.89%, respectively. There was no statistically significant difference in TAPSE ((2.06±0.41)cm vs. (2.10±0.39)cm, P=0.510) and RVFAC ((51.17±9.91)% vs. (50.89±8.65)%, P=0.826) between males and females. The values of various right ventricular long axis strain indicators (GLS, ALS, MLS, BLS, FWGLS, FWMLS, FWMLS, FWBLS) in females aged 18 to 40 and 41 to 65 years were higher than those in males of the same age (all P<0.05), while there was no statistically significant difference in the values of various right ventricular long axis strain indicators between the sexes in subjects aged 65 years and above (all P>0.05). In females, the right ventricular GLS, ALS, MLS, FWGLS, FWALS, FWMLS, and FWBLS values in the groups aged 18 to 40 and 41 to 65 years were significantly higher than those in the group aged 65 years and above (all P<0.05). In contrast, no significant differences were found in these indices among different age groups in males (all P>0.05). Conclusions: Using two-dimensional speckle tracking technology in echocardiography to measure right ventricular strain indicators is feasible and highly reproducible. Gender and age have an impact on right ventricular strain indicators.}, } @article {pmid38220307, year = {2024}, author = {Carabajal, MD and Bortolato, SA and Lisandrini, FT and Olivieri, AC}, title = {An exhaustive analysis of the use of image moments for second-order calibration. A comparison with multivariate curve resolution-alternating least-squares.}, journal = {Analytica chimica acta}, volume = {1288}, number = {}, pages = {342177}, doi = {10.1016/j.aca.2023.342177}, pmid = {38220307}, issn = {1873-4324}, abstract = {BACKGROUND: the chemometric processing of second-order chromatographic-spectral data is usually carried out with the aid of multivariate curve resolution-alternating least-squares (MCR-ALS). Recently, an alternative procedure was described based on the estimation of image moments for each data matrix and subsequent application of multiple linear regression after suitable variable selection.

RESULTS: The analysis of both simulated and experimental data leads to the conclusion that the image moment method, although can cope with chromatographic lack of reproducibility across injections, it only performs well in the absence of uncalibrated interferents. MCR-ALS, on the other hand, provides good analytical results in all studied situations, whether the test samples contain uncalibrated interferents or not.

SIGNIFICANCE: The results are useful to assess the real usefulness of newly proposed methodologies for second-order calibration in the case of chromatographic-spectral data sets, especially when samples contain unexpected chemical constituents.}, } @article {pmid38220221, year = {2024}, author = {Castro, J and Oliveira Santos, M and Swash, M and de Carvalho, M}, title = {Segmental motor neuron dysfunction in amyotrophic lateral sclerosis: Insights from H reflex paradigms.}, journal = {Muscle & nerve}, volume = {69}, number = {3}, pages = {303-312}, doi = {10.1002/mus.28035}, pmid = {38220221}, issn = {1097-4598}, support = {//Biogen/ ; }, mesh = {Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis ; H-Reflex/physiology ; Motor Neurons/physiology ; Muscle, Skeletal ; Spine ; }, abstract = {INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS), the role of spinal interneurons in ALS is underrecognized. We aimed to investigate pre- and post-synaptic modulation of spinal motor neuron excitability by studying the H reflex, to understand spinal interneuron function in ALS.

METHODS: We evaluated the soleus H reflex, and three different modulation paradigms, to study segmental spinal inhibitory mechanisms. Homonymous recurrent inhibition (H'RI) was assessed using the paired H reflex technique. Presynaptic inhibition of Ia afferents (H'Pre) was evaluated using D1 inhibition after stimulation of the common peroneal nerve. We also studied inhibition of the H reflex after cutaneous stimulation of the sural nerve (H'Pos).

RESULTS: Fifteen ALS patients (median age 57.0 years), with minimal signs of lower motor neuron involvement and good functional status, and a control group of 10 healthy people (median age 57.0 years) were studied. ALS patients showed reduced inhibition, compared to controls, in all paradigms (H'RI 0.35 vs. 0.11, p = .036; H'Pre 1.0 vs. 5.0, p = .001; H'Pos 0.0 vs. 2.5, p = .031). The clinical UMN score was a significant predictor of the amount of recurrent and presynaptic inhibition.

DISCUSSION: Spinal inhibitory mechanisms are impaired in ALS. We argue that hyperreflexia could be associated with dysfunction of spinal inhibitory interneurons. In this case, an interneuronopathy could be deemed a major feature of ALS.}, } @article {pmid38218903, year = {2024}, author = {Lee, MH and Kang, S and Um, KH and Lee, SW and Hwang, H and Baek, K and Choi, JW}, title = {Brain-targeted delivery of neuroprotective survival gene minimizing hematopoietic cell contamination: implications for Parkinson's disease treatment.}, journal = {Journal of translational medicine}, volume = {22}, number = {1}, pages = {53}, pmid = {38218903}, issn = {1479-5876}, support = {NRF-2017R1A5A2014768//Ministry of Science and ICT, South Korea/ ; NRF-2022R1A2C2009281//Ministry of Science and ICT, South Korea/ ; NRF-2019R1A2C1006752//Ministry of Science and ICT, South Korea/ ; 21153MFDS601//Ministry of Food and Drug Safety/ ; }, mesh = {Animals ; *Parkinson Disease/genetics/therapy ; Leukocytes, Mononuclear ; Brain/metabolism ; Genetic Therapy/methods ; Transgenes ; Genetic Vectors ; Dependovirus/genetics ; }, abstract = {BACKGROUND: Neurodegenerative diseases, including Parkinson's disease, Amyotropic Lateral Sclerosis (ALS) and Alzheimer's disease, present significant challenges for therapeutic development due to drug delivery restrictions and toxicity concerns. Prevailing strategies often employ adeno-associated viral (AAV) vectors to deliver neuroprotective survival genes directly into the central nervous system (CNS). However, these methods have been limited by triggering immunogenic responses and risk of tumorigenicity, resulting from overexpression of survival genes in peripheral blood mononuclear cells (PBMC), thereby increasing the risk of tumorigenicity in specific immune cells. Thus, by coding selectively suppressive microRNA (miRNA) target sequences in AAV genome, we designed CNS-targeted neuroprotective gene expression vector system without leakage to blood cells.

METHODS: To minimize the potential for transgene contamination in the blood, we designed a CNS-specific AAV system. Our system utilized a self-complementary AAV (scAAV), encoding a quadruple repeated target sequence of the hematopoietic cell-specific miR142-3p at the 3' untranslated region (UTR). As a representative therapeutic survival gene for Parkinson's disease treatment, we integrated DX2, an antagonistic splice variant of the apoptotic gene AIMP2, known to be implicated in Parkinson's disease, into the vector.

RESULTS: This configuration ensured that transgene expression was stringently localized to the CNS, even if the vector found its way into the blood cells. A single injection of scAAV-DX2 demonstrated marked improvement in behavior and motor activity in animal models of Parkinson's disease induced by either Rotenone or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Importantly, comprehensive preclinical data adhering to Good Laboratory Practice (GLP) standards revealed no adverse effects in the treated animals.

CONCLUSIONS: Our CNS-specific vector system, which encodes a survival transgene DX2, signifies a promising avenue for safe gene therapy, avoiding unintended expression of survival gene in blood cells, applicable to various neurodegenerative diseases.}, } @article {pmid38218579, year = {2024}, author = {Huo, D and Liang, W and Wang, D and Liu, Q and Wang, H and Wang, Y and Zhang, C and Cong, C and Su, X and Tan, X and Zhang, W and Han, L and Zhang, D and Wang, M and Feng, H}, title = {Roflupram alleviates autophagy defects and reduces mutant hSOD1-induced motor neuron damage in cell and mouse models of amyotrophic lateral sclerosis.}, journal = {Neuropharmacology}, volume = {247}, number = {}, pages = {109812}, doi = {10.1016/j.neuropharm.2023.109812}, pmid = {38218579}, issn = {1873-7064}, mesh = {Mice ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; AMP-Activated Protein Kinases/metabolism ; Superoxide Dismutase/genetics/metabolism ; Motor Neurons ; Spinal Cord/metabolism ; Mice, Transgenic ; Autophagy ; Disease Models, Animal ; *Benzene Derivatives ; *Furans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and incurable disease involving motor neuron (MN) degeneration and is characterized by ongoing myasthenia and amyotrophia in adults. Most ALS patients die of respiratory muscle paralysis after an average of 3-5 years. Defective autophagy in MNs is considered an important trigger of ALS pathogenesis. Roflupram (ROF) was demonstrated to activate autophagy in microglial cells and exert protective effects against Parkinson's disease (PD) and Alzheimer's disease (AD). Therefore, our research aimed to investigate the efficacy and mechanism of ROF in treating ALS both in vivo and in vitro. We found that ROF could delay disease onset and prolong the survival of hSOD1-G93A transgenic mice. Moreover, ROF protected MNs in the anterior horn of the spinal cord, activated the AMPK/ULK1 signaling pathway, increased autophagic flow, and reduced SOD1 aggregation. In an NSC34 cell line stably transfected with hSOD1-G93A, ROF protected against cellular damage caused by hSOD1-G93A. Moreover, we have demonstrated that ROF inhibited gliosis in ALS model mice. Collectively, our study suggested that ROF is neuroprotective in ALS models and the AMPK/ULK1 signaling pathway is a potential therapeutic target in ALS, which increases autophagic flow and reduces SOD1 aggregation.}, } @article {pmid38218077, year = {2024}, author = {Di Lazzaro, V and Ranieri, F and Bączyk, M and de Carvalho, M and Dileone, M and Dubbioso, R and Fernandes, S and Kozak, G and Motolese, F and Ziemann, U}, title = {Novel approaches to motoneuron disease/ALS treatment using non-invasive brain and spinal stimulation: IFCN handbook chapter.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {158}, number = {}, pages = {114-136}, doi = {10.1016/j.clinph.2023.12.012}, pmid = {38218077}, issn = {1872-8952}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; *Transcranial Direct Current Stimulation ; *Motor Neuron Disease/diagnosis/therapy ; Motor Neurons/physiology ; Brain ; Transcranial Magnetic Stimulation/methods ; }, abstract = {Non-invasive brain stimulation techniques have been exploited in motor neuron disease (MND) with multifold objectives: to support the diagnosis, to get insights in the pathophysiology of these disorders and, more recently, to slow down disease progression. In this review, we consider how neuromodulation can now be employed to treat MND, with specific attention to amyotrophic lateral sclerosis (ALS), the most common form with upper motoneuron (UMN) involvement, taking into account electrophysiological abnormalities revealed by human and animal studies that can be targeted by neuromodulation techniques. This review article encompasses repetitive transcranial magnetic stimulation methods (including low-frequency, high-frequency, and pattern stimulation paradigms), transcranial direct current stimulation as well as experimental findings with the newer approach of trans-spinal direct current stimulation. We also survey and discuss the trials that have been performed, and future perspectives.}, } @article {pmid38217607, year = {2024}, author = {Mázala, DAG and Chen, D and Chin, ER}, title = {SERCA1 Overexpression in Skeletal Muscle Attenuates Muscle Atrophy and Improves Motor Function in a Mouse Model of ALS.}, journal = {Journal of neuromuscular diseases}, volume = {11}, number = {2}, pages = {315-326}, pmid = {38217607}, issn = {2214-3602}, support = {T32 AG000268/AG/NIA NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis ; Endoplasmic Reticulum Chaperone BiP ; Calcium/metabolism ; Fura-2/metabolism ; Muscle, Skeletal ; Mice, Transgenic ; Muscular Atrophy/metabolism ; Calcium-Transporting ATPases/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of muscle mass and muscle function. Previous work from our lab demonstrated that skeletal muscles from a mouse model of ALS show elevated intracellular calcium (Ca2+) levels and heightened endoplasmic reticulum (ER) stress.

OBJECTIVE: To investigate whether overexpression of sarcoplasmic reticulum (SR) Ca2+ ATPase 1 (SERCA1) in skeletal muscle would improve intracellular Ca2+ handling, attenuate ER stress, and improve motor function ALS transgenic mice.

METHODS: B6SJL-Tg (SOD1*G93A)1Gur/J (ALS-Tg) mice were bred with skeletal muscle α-actinin SERCA1 overexpressing mice to generate wild type (WT), SERCA1 overexpression (WT/+SERCA1), ALS-Tg, and SERCA1 overexpressing ALS-Tg (ALS-Tg/+SERCA1) mice. Motor function (grip test) was assessed weekly and skeletal muscles were harvested at 16 weeks of age to evaluate muscle mass, SR-Ca2+ ATPase activity, levels of SERCA1 and ER stress proteins - protein disulfide isomerase (PDI), Grp78/BiP, and C/EBP homologous protein (CHOP). Single muscle fibers were also isolated from the flexor digitorum brevis muscle to assess changes in resting and peak Fura-2 ratios.

RESULTS: ALS-Tg/+SERCA1 mice showed improved motor function, delayed onset of disease, and improved muscle mass compared to ALS-Tg. Further, ALS-Tg/+SERCA1 mice returned levels of SERCA1 protein and SR-Ca2+ ATPase activity back to levels in WT mice. Unexpectedly, SERCA-1 overexpression increased levels of the ER stress maker Grp78/BiP in both WT and ALS-Tg mice, while not altering protein levels of PDI or CHOP. Lastly, single muscle fibers from ALS-Tg/+SERCA1 had similar resting but lower peak Fura-2 levels (at 30 Hz and 100 Hz) compared to ALS-Tg mice.

CONCLUSIONS: These data indicate that SERCA1 overexpression attenuates the progressive loss of muscle mass and maintains motor function in ALS-Tg mice while not lowering resting Ca2+ levels or ER stress.}, } @article {pmid38217066, year = {2024}, author = {Tsagakis, I and Yamanaka, K}, title = {An open chat with… Koji Yamanaka.}, journal = {FEBS open bio}, volume = {14}, number = {2}, pages = {162-164}, pmid = {38217066}, issn = {2211-5463}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Koji Yamanaka is a Professor at the Research Institute of Environmental Medicine at Nagoya University of Japan. His research interests lie in understanding the mechanism of onset and progression of motor neuron disease as well as the role of glial cells in Alzheimer's disease neuroinflammation. Koji has been serving on the FEBS Open Bio Editorial Board since 2013. In this interview, he explains the implications of recent findings in neurobiology for amyotrophic lateral sclerosis, provides updates on the research environment in Japan and discusses how editors might use their position to positively influence academic culture.}, } @article {pmid38216448, year = {2024}, author = {Van Daele, SH and Masrori, P and Van Damme, P and Van Den Bosch, L}, title = {The sense of antisense therapies in ALS.}, journal = {Trends in molecular medicine}, volume = {30}, number = {3}, pages = {252-262}, doi = {10.1016/j.molmed.2023.12.003}, pmid = {38216448}, issn = {1471-499X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; Oligonucleotides, Antisense/therapeutic use ; RNA Splicing ; }, abstract = {Treatment of patients with amyotrophic lateral sclerosis (ALS) has entered a new era now that encouraging results about antisense oligonucleotides (ASOs) are becoming available and a first ASO therapy for ALS has been approved by the FDA. Moreover, there is hope not only that ALS can be stopped but also that symptoms can be reversed. Until now, degrading ASOs seemed to be successful mostly for rarer forms of familial ALS. However, the first attempts to correct mis-splicing events in sporadic ALS are underway, as well as a clinical trial examining interference with a genetic modifier. In this review, we discuss the current status of using ASOs in ALS and the possibilities and pitfalls of this therapeutic strategy.}, } @article {pmid38214845, year = {2024}, author = {Fang, A and Zhao, Y and Yang, P and Zhang, X and Giovannucci, EL}, title = {Vitamin D and human health: evidence from Mendelian randomization studies.}, journal = {European journal of epidemiology}, volume = {39}, number = {5}, pages = {467-490}, pmid = {38214845}, issn = {1573-7284}, support = {81803219//National Natural Science Foundation of China/ ; 2018A030310335//Natural Science Foundation of Guangdong Province/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Vitamin D/blood/analogs & derivatives ; Vitamin D Deficiency/epidemiology/complications/genetics ; }, abstract = {We summarized the current evidence on vitamin D and major health outcomes from Mendelian randomization (MR) studies. PubMed and Embase were searched for original MR studies on vitamin D in relation to any health outcome from inception to September 1, 2022. Nonlinear MR findings were excluded due to concerns about the validity of the statistical methods used. A meta-analysis was preformed to synthesize study-specific estimates after excluding overlapping samples, where applicable. The methodological quality of the included studies was evaluated according to the STROBE-MR checklist. A total of 133 MR publications were eligible for inclusion in the analyses. The causal association between vitamin D status and 275 individual outcomes was examined. Linear MR analyses showed genetically high 25-hydroxyvitamin D (25(OH)D) concentrations were associated with reduced risk of multiple sclerosis incidence and relapse, non-infectious uveitis and scleritis, psoriasis, femur fracture, leg fracture, amyotrophic lateral sclerosis, anorexia nervosa, delirium, heart failure, ovarian cancer, non-alcoholic fatty liver disease, dyslipidemia, and bacterial pneumonia, but increased risk of Behçet's disease, Graves' disease, kidney stone disease, fracture of radium/ulna, basal cell carcinoma, and overall cataracts. Stratified analyses showed that the inverse association between genetically predisposed 25(OH)D concentrations and multiple sclerosis risk was significant and consistent regardless of the genetic instruments GIs selected. However, the associations with most of the other outcomes were only pronounced when using genetic variants not limited to those in the vitamin D pathway as GIs. The methodological quality of the included MR studies was substantially heterogeneous. Current evidence from linear MR studies strongly supports a causal role of vitamin D in the development of multiple sclerosis. Suggestive support for a number of other health conditions could help prioritize conditions where vitamin D may be beneficial or harmful.}, } @article {pmid38213752, year = {2024}, author = {}, title = {Erratum: Estimated Familial Amyotrophic Lateral Sclerosis Proportion: A Literature Review and Meta-Analysis.}, journal = {Neurology. Genetics}, volume = {10}, number = {1}, pages = {e200131}, pmid = {38213752}, issn = {2376-7839}, abstract = {[This corrects the article DOI: 10.1212/NXG.0000000000200109.].}, } @article {pmid38213309, year = {2024}, author = {Eisen, A and Vucic, S and Mitsumoto, H}, title = {History of ALS and the competing theories on pathogenesis: IFCN handbook chapter.}, journal = {Clinical neurophysiology practice}, volume = {9}, number = {}, pages = {1-12}, pmid = {38213309}, issn = {2467-981X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the human motor system, first described in the 19th Century. The etiology of ALS appears to be multifactorial, with a complex interaction of genetic, epigenetic, and environmental factors underlying the onset of disease. Importantly, there are no known naturally occurring animal models, and transgenic mouse models fail to faithfully reproduce ALS as it manifests in patients. Debate as to the site of onset of ALS remain, with three competing theories proposed, including (i) the dying-forward hypothesis, whereby motor neuron degeneration is mediated by hyperexcitable corticomotoneurons via an anterograde transsynaptic excitotoxic mechanism, (ii) dying-back hypothesis, proposing the ALS begins in the peripheral nervous system with a toxic factor(s) retrogradely transported into the central nervous system and mediating upper motor neuron dysfunction, and (iii) independent hypothesis, suggesting that upper and lower motor neuron degenerated independently. Transcranial magnetic stimulation studies, along with pathological and genetic findings have supported the dying forward hypothesis theory, although the science is yet to be settled. The review provides a historical overview of ALS, discusses phenotypes and likely pathogenic mechanisms.}, } @article {pmid38213020, year = {2024}, author = {Chen, M and Guo, X and Guo, J and Shi, C and Wu, Y and Chen, L and Mao, R and Fan, Y}, title = {Cytoplasmic Accumulation of Histones Induced by BET Inhibition Protects Cells from C9orf72 Poly(PR)-Induced Cell Death.}, journal = {Advanced biology}, volume = {8}, number = {3}, pages = {e2300334}, doi = {10.1002/adbi.202300334}, pmid = {38213020}, issn = {2701-0198}, support = {31970616//National Natural Science Foundation of China/ ; 81873531//National Natural Science Foundation of China/ ; BK20211330//Jiangsu Provincial Natural Science Foundation/ ; KYCX20_2796//Graduate Research and Innovation Projects of Jiangsu Province/ ; KYCX22_3362//Graduate Research and Innovation Projects of Jiangsu Province/ ; }, mesh = {*Histones/genetics/metabolism/pharmacology ; C9orf72 Protein/genetics/metabolism/pharmacology ; *Nuclear Proteins/genetics/metabolism/pharmacology ; DNA Repeat Expansion ; Transcription Factors/genetics/metabolism/pharmacology ; Dipeptides/genetics/metabolism/pharmacology ; Cell Death/genetics ; }, abstract = {Repeat dipeptides such as poly(proline-arginine) (polyPR) are generated from the hexanucleotide GGGGCC repeat expansions in the C9orf72 gene. These dipeptides are often considered as the genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In the study, fluorescein isothiocyanate (FITC) labeled PR20 is used to investigate PR20-induced cell death. The findings reveal that the cell death induced by PR20 is dependent on its nuclear distribution and can be blocked by a nuclear import inhibitor called importazole. Further investigation reveals that BRD4 inhibitors, such as JQ-1 and I-BET762, restrict cytoplasmic localization of PR20, thereby reducing its cytotoxic effect. Mechanistically, the inhibition of BRD4 leads to an increase in the expression of numerous histones, resulting in the accumulation of histones in the cytoplasm. These cytoplasmic histones associate with PR20 and limit its distribution within the nucleus. Notably, the ectopic expression of histones alone is enough to confer protection to cells treated with PR20. In addition, phenylephrine (PE) induces cellular hypertrophy and cytoplasmic distribution of histone, which also helps protect cells from PR20-induced cell death. The research suggests that temporarily inducing the presence of cytoplasmic histones may alleviate the neurotoxic effects of dipeptide repeat proteins.}, } @article {pmid38212835, year = {2024}, author = {Zaccai, S and Nemirovsky, A and Lerner, L and Alfahel, L and Eremenko, E and Israelson, A and Monsonego, A}, title = {CD4 T-cell aging exacerbates neuroinflammation in a late-onset mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {17}, pmid = {38212835}, issn = {1742-2094}, support = {3-16148//Ministry of Science, Technology and Space/ ; 284/19//Israel Science Foundation grant/ ; }, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; CD4-Positive T-Lymphocytes/metabolism ; Mice, Transgenic ; Neuroinflammatory Diseases ; T-Cell Senescence ; Superoxide Dismutase/genetics/metabolism ; Spinal Cord/metabolism ; Disease Progression ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons in the brain and spinal cord. Accumulating evidence suggests that ALS is not solely a neuronal cell- or brain tissue-autonomous disease and that neuroinflammation plays a key role in disease progression. Furthermore, whereas both CD4 and CD8 T cells were observed in spinal cords of ALS patients and in mouse models of the disease, their role in the neuroinflammatory process, especially considering their functional changes with age, is not fully explored. In this study, we revealed the structure of the CD4 T-cell compartment during disease progression of early-onset SOD1[G93A] and late-onset SOD1[G37R] mouse models of ALS. We show age-related changes in the CD4 T-cell subset organization between these mutant SOD1 mouse models towards increased frequency of effector T cells in spleens of SOD1[G37R] mice and robust infiltration of CD4 T cells expressing activation markers and the checkpoint molecule PD1 into the spinal cord. The frequency of infiltrating CD4 T cells correlated with the frequency of infiltrating CD8 T cells which displayed a more exhausted phenotype. Moreover, RNA-Seq and immunohistochemistry analyses of spinal cords from SOD1[G37R] mice with early clinical symptoms demonstrated immunological trajectories reminiscent of a neurotoxic inflammatory response which involved proinflammatory T cells and antigen presentation related pathways. Overall, our findings suggest that age-related changes of the CD4 T cell landscape is indicative of a chronic inflammatory response, which aggravates the disease process and can be therapeutically targeted.}, } @article {pmid38212665, year = {2024}, author = {Jang, MS and Yoo, SH and Kim, MS and Cho, B and Kim, KH and Shin, J and Hwang, I and Choi, SJ and Sung, JJ and Lee, SY}, title = {Healthcare Utilization and Supportive Care Timing in South Korean People Living With Amyotrophic Lateral Sclerosis: A Single-Center Retrospective Study.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {20}, number = {2}, pages = {166-174}, pmid = {38212665}, issn = {1738-6586}, support = {27302C0115/ES/NIEHS NIH HHS/United States ; }, abstract = {BACKGROUND AND PURPOSE: Despite the growing demands and challenges faced by patients with amyotrophic lateral sclerosis (ALS) in accessing healthcare services, our understanding of this access remains poor. This study aimed to investigate the healthcare utilization patterns and timing of nutritional and respiration support in patients with ALS in South Korea.

METHODS: A retrospective cohort study was conducted on patients diagnosed with ALS at a single tertiary hospital between 2016 and 2019 and followed up for 2 years. We evaluated patient characteristics, healthcare utilization (hospital admissions, outpatient visits, and emergency department [ED] visits), and the timing of nutritional and respiration support (noninvasive positive pressure ventilation [NIPPV], tracheostomy, gastrostomy, and nasogastric tube) at 6-month intervals from the first outpatient visit.

RESULTS: Among the 143 included patients, 73.4% were admitted at least once, 18.9% experienced unplanned admissions, and 30.1% visited the ED at least once during the study period. The most-common reason for ED visits was neurological symptoms during the first 6 months (59.1%), followed by respiratory symptoms. One fifth of patients who visited the ED underwent tracheostomy (20.9%) or NIPPV (20.9%). Two years after the first visit, 32.2% used a ventilator, and 13.3%, 26.6%, and 6.3% had undergone tracheostomy, gastrostomy, and nasogastric tube insertion, respectively.

CONCLUSIONS: During the 2 years following their first outpatient visit, 20% of patients with ALS experienced unplanned admissions and 30% visited the ED. An active and prompt supportive-care program should be implemented to ensure timely functional support in order to reduce these risks of unplanned admissions.}, } @article {pmid38212334, year = {2024}, author = {Sharma, K and Stockert, F and Shenoy, J and Berbon, M and Abdul-Shukkoor, MB and Habenstein, B and Loquet, A and Schmidt, M and Fändrich, M}, title = {Cryo-EM observation of the amyloid key structure of polymorphic TDP-43 amyloid fibrils.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {486}, pmid = {38212334}, issn = {2041-1723}, mesh = {Humans ; Amyloid/metabolism ; Cryoelectron Microscopy ; Amyloidogenic Proteins ; *Frontotemporal Lobar Degeneration/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; DNA-Binding Proteins/metabolism ; }, abstract = {The transactive response DNA-binding protein-43 (TDP-43) is a multi-facet protein involved in phase separation, RNA-binding, and alternative splicing. In the context of neurodegenerative diseases, abnormal aggregation of TDP-43 has been linked to amyotrophic lateral sclerosis and frontotemporal lobar degeneration through the aggregation of its C-terminal domain. Here, we report a cryo-electron microscopy (cryo-EM)-based structural characterization of TDP-43 fibrils obtained from the full-length protein. We find that the fibrils are polymorphic and contain three different amyloid structures. The structures differ in the number and relative orientation of the protofilaments, although they share a similar fold containing an amyloid key motif. The observed fibril structures differ from previously described conformations of TDP-43 fibrils and help to better understand the structural landscape of the amyloid fibril structures derived from this protein.}, } @article {pmid38206346, year = {2024}, author = {Vosough, M and Salemi, A and Rockel, S and Schmidt, TC}, title = {Enhanced efficiency of MS/MS all-ion fragmentation for non-targeted analysis of trace contaminants in surface water using multivariate curve resolution and data fusion.}, journal = {Analytical and bioanalytical chemistry}, volume = {416}, number = {5}, pages = {1165-1177}, pmid = {38206346}, issn = {1618-2650}, support = {520243139//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Data-independent acquisition-all-ion fragmentation (DIA-AIF) mode of mass spectrometry can facilitate wide-scope non-target analysis of contaminants in surface water due to comprehensive spectral identification. However, because of the complexity of the resulting MS[2] AIF spectra, identifying unknown pollutants remains a significant challenge, with a significant bottleneck in translating non-targeted chemical signatures into environmental impacts. The present study proposes to process fused MS[1] and MS[2] data sets obtained from LC-HRMS/MS measurements in non-targeted AIF workflows on surface water samples using multivariate curve resolution-alternating least squares (MCR-ALS). This enables straightforward assignment between precursor ions obtained from resolved MS[1] spectra and their corresponding MS[2] spectra. The method was evaluated for two sets of tap water and surface water contaminated with 14 target chemicals as a proof of concept. The data set of surface water samples consisting of 3506 MS[1] and 2170 MS[2] AIF mass spectral features was reduced to 81 components via a fused MS[1]-MS[2] MCR model that describes at least 98.8% of the data. Each component summarizes the distinct chromatographic elution of components together with their corresponding MS[1] and MS[2] spectra. MS[2] spectral similarity of more than 82% was obtained for most target chemicals. This highlights the potential of this method for unraveling the composition of MS/MS complex data in a water environment. Ultimately, the developed approach was applied to the retrospective non-target analysis of an independent set of surface water samples.}, } @article {pmid38205130, year = {2024}, author = {Izquierdo-Condoy, JS and Naranjo-Lara, P and Arias Rodríguez, FD and Puglla-Mendoza, AG and Jima-Sanmartín, J and Andrade Casanova, D and Duque-Sánchez, EP and Alegría N, N and Rojas Cadena, MG and Ortiz-Prado, E}, title = {Assessing the Proficiency in Basic and Advanced Life Support Among Physicians in Ecuador: A Cross-Sectional Study.}, journal = {Advances in medical education and practice}, volume = {15}, number = {}, pages = {25-35}, pmid = {38205130}, issn = {1179-7258}, abstract = {PURPOSE: Cardiorespiratory arrest's unpredictability poses a global health challenge, with gaps in physicians' life support knowledge potentially leading to poor patient outcomes, a factor yet unstudied among Ecuadorian physicians. This study aims to elucidate the state of physicians' theoretical knowledge in Ecuador based on Basic Life Support (BLS) and Advanced Life Support (ALS) guidelines.

PATIENTS AND METHODS: A national cross-sectional online 35-questions survey was conducted between February and March 2023 using a self-administered, expert-validated questionnaire. Participants' responses were obtained through official social media groups (WhatsApp and Facebook). The survey evaluated the theoretical knowledge of BLS and ALS, with scores based on the number of correct answers out of a maximum of 10.0 points. For descriptive analysis, frequencies, percentages, means, and standard deviations (SD) were used. The T-test and one-way ANOVA were utilized to analyze the associations between knowledge levels and demographic and academic training variables of Ecuadorian doctors. Values of p < 0.05 were considered statistically significant for all analyses.

RESULTS: The survey garnered responses from 385 physicians, with a majority being female (56.6%) and possessing less than 3 years of work experience (75.1%). Of these, 71.7% and 51.9% held BLS and ALS certifications, respectively. Knowledge scores for BLS (5.8/10 ± 1.6) surpassed those for ALS (4.7/10 ± 1.8) (p < 0.001). Physicians with less than 3 years of work experience exhibited higher knowledge scores in both BLS and ALS tests (p < 0.05).

CONCLUSION: This study revealed a notable deficiency in the theoretical knowledge of BLS and ALS among surveyed Ecuadorian physicians. Factors such as prior certification and years of work experience appeared to influence knowledge levels. Continual training and updates in life support protocols at universities and healthcare institutions are key to enhancing physicians' skills and patient outcomes.}, } @article {pmid38203614, year = {2023}, author = {Wu, Y and Chen, Y and Yu, X and Zhang, M and Li, Z}, title = {Towards Understanding Neurodegenerative Diseases: Insights from Caenorhabditis elegans.}, journal = {International journal of molecular sciences}, volume = {25}, number = {1}, pages = {}, pmid = {38203614}, issn = {1422-0067}, support = {2002472//National Health and Medical Research Council/ ; }, mesh = {Animals ; Caenorhabditis elegans/genetics ; *Neurodegenerative Diseases/genetics ; *Alzheimer Disease ; *Huntington Disease ; *Parkinson Disease ; Mammals ; }, abstract = {The elevated occurrence of debilitating neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD) and Machado-Joseph disease (MJD), demands urgent disease-modifying therapeutics. Owing to the evolutionarily conserved molecular signalling pathways with mammalian species and facile genetic manipulation, the nematode Caenorhabditis elegans (C. elegans) emerges as a powerful and manipulative model system for mechanistic insights into neurodegenerative diseases. Herein, we review several representative C. elegans models established for five common neurodegenerative diseases, which closely simulate disease phenotypes specifically in the gain-of-function aspect. We exemplify applications of high-throughput genetic and drug screenings to illustrate the potential of C. elegans to probe novel therapeutic targets. This review highlights the utility of C. elegans as a comprehensive and versatile platform for the dissection of neurodegenerative diseases at the molecular level.}, } @article {pmid38203300, year = {2023}, author = {Wei, J and Wong, LC and Boland, S}, title = {Lipids as Emerging Biomarkers in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {1}, pages = {}, pmid = {38203300}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis ; *Alzheimer Disease/diagnosis ; *Parkinson Disease ; Biomarkers ; Monoglycerides ; }, abstract = {Biomarkers are molecules that can be used to observe changes in an individual's biochemical or medical status and provide information to aid diagnosis or treatment decisions. Dysregulation in lipid metabolism in the brain is a major risk factor for many neurodegenerative disorders, including frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Thus, there is a growing interest in using lipids as biomarkers in neurodegenerative diseases, with the anionic phospholipid bis(monoacylglycerol)phosphate and (glyco-)sphingolipids being the most promising lipid classes thus far. In this review, we provide a general overview of lipid biology, provide examples of abnormal lysosomal lipid metabolism in neurodegenerative diseases, and discuss how these insights might offer novel and promising opportunities in biomarker development and therapeutic discovery. Finally, we discuss the challenges and opportunities of lipid biomarkers and biomarker panels in diagnosis, prognosis, and/or treatment response in the clinic.}, } @article {pmid38202942, year = {2023}, author = {Kosmyna, N and Hauptmann, E and Hmaidan, Y}, title = {A Brain-Controlled Quadruped Robot: A Proof-of-Concept Demonstration.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {1}, pages = {}, pmid = {38202942}, issn = {1424-8220}, mesh = {Humans ; Animals ; Dogs ; *Robotics ; Brainwashing ; Proof of Concept Study ; *Amyotrophic Lateral Sclerosis ; Brain ; }, abstract = {Coupling brain-computer interfaces (BCIs) and robotic systems in the future can enable seamless personal assistant systems in everyday life, with the requests that can be performed in a discrete manner, using one's brain activity only. These types of systems might be of a particular interest for people with locked-in syndrome (LIS) or amyotrophic lateral sclerosis (ALS) because they can benefit from communicating with robotic assistants using brain sensing interfaces. In this proof-of-concept work, we explored how a wireless and wearable BCI device can control a quadruped robot-Boston Dynamics' Spot. The device measures the user's electroencephalography (EEG) and electrooculography (EOG) activity of the user from the electrodes embedded in the glasses' frame. The user responds to a series of questions with YES/NO answers by performing a brain-teaser activity of mental calculus. Each question-answer pair has a pre-configured set of actions for Spot. For instance, Spot was prompted to walk across a room, pick up an object, and retrieve it for the user (i.e., bring a bottle of water) when a sequence resolved to a YES response. Our system achieved at a success rate of 83.4%. To the best of our knowledge, this is the first integration of wireless, non-visual-based BCI systems with Spot in the context of personal assistant use cases. While this BCI quadruped robot system is an early prototype, future iterations may embody friendly and intuitive cues similar to regular service dogs. As such, this project aims to pave a path towards future developments in modern day personal assistant robots powered by wireless and wearable BCI systems in everyday living conditions.}, } @article {pmid38202163, year = {2023}, author = {Ueha, R and Cotaoco, C and Kondo, K and Yamasoba, T}, title = {Management and Treatment for Dysphagia in Neurodegenerative Disorders.}, journal = {Journal of clinical medicine}, volume = {13}, number = {1}, pages = {}, pmid = {38202163}, issn = {2077-0383}, abstract = {Patients with neurodegenerative disorders (NDDs) often experience functional dysphagia, which may involve dysfunction in a specific phase of swallowing or in the entire process. This review outlines the approach to dysphagia in the setting of NDDs. Distinguishing the etiology of dysphagia can be difficult, and it is important to always look out for signs pointing to NDD as the cause. Thorough diagnostic work-up is essential, and it includes a comprehensive history and physical examination, alongside swallowing function tests, such as fiberoptic endoscopic evaluation of swallowing, videofluoroscopic swallowing study, and high-resolution manometry. Management requires a multidisciplinary approach with a treatment plan tailored to each patient. This involves dietary guidance, swallowing rehabilitation, and surgery in cases in which improvement with rehabilitation is inadequate. Surgery may involve altering certain pharyngolaryngeal structures to facilitate swallowing and reduce the risk of aspiration (swallowing improvement surgery) or separating the airway and digestive tract while sacrificing laryngeal function, with the main goal of preventing aspiration (aspiration prevention surgery). Proper management stems from recognizing the impact of these disorders on swallowing and consistently finding ways to improve the quality of life of patients.}, } @article {pmid38201932, year = {2023}, author = {Sharma, H and Sharma, N and An, SSA}, title = {Unique Bioactives from Zombie Fungus (Cordyceps) as Promising Multitargeted Neuroprotective Agents.}, journal = {Nutrients}, volume = {16}, number = {1}, pages = {}, pmid = {38201932}, issn = {2072-6643}, support = {RS-2023-00251396 and 2021R1A6A1A03038996//National Research Foundation of Korea/ ; }, mesh = {*Neuroprotective Agents/pharmacology ; *Cordyceps ; *Agaricales ; Neuroprotection ; Adenosine ; }, abstract = {Cordyceps, also known as "zombie fungus", is a non-poisonous mushroom that parasitizes insects for growth and development by manipulating the host system in a way that makes the victim behave like a "zombie". These species produce promising bioactive metabolites, like adenosine, β-glucans, cordycepin, and ergosterol. Cordyceps has been used in traditional medicine due to its immense health benefits, as it boosts stamina, appetite, immunity, longevity, libido, memory, and sleep. Neuronal loss is the typical feature of neurodegenerative diseases (NDs) (Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS)) and neurotrauma. Both these conditions share common pathophysiological features, like oxidative stress, neuroinflammation, and glutamatergic excitotoxicity. Cordyceps bioactives (adenosine, N[6]-(2-hydroxyethyl)-adenosine, ergosta-7, 9 (11), 22-trien-3β-ol, active peptides, and polysaccharides) exert potential antioxidant, anti-inflammatory, and anti-apoptotic activities and display beneficial effects in the management and/or treatment of neurodegenerative disorders in vitro and in vivo. Although a considerable list of compounds is available from Cordyceps, only a few have been evaluated for their neuroprotective potential and still lack information for clinical trials. In this review, the neuroprotective mechanisms and safety profile of Cordyceps extracts/bioactives have been discussed, which might be helpful in the identification of novel potential therapeutic entities in the future.}, } @article {pmid38201303, year = {2024}, author = {Chen, L and Zhang, S and Liu, S and Gao, S}, title = {Amyotrophic Lateral Sclerosis Mechanism: Insights from the Caenorhabditis elegans Models.}, journal = {Cells}, volume = {13}, number = {1}, pages = {}, pmid = {38201303}, issn = {2073-4409}, support = {32020103007//Major International (Regional) Joint Research Project/ ; 2022YFA1206001//National Key Research and Development Program of China/ ; 32371189, 32300984//the National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Caenorhabditis elegans ; Motor Neurons ; Protein Aggregates ; Signal Transduction ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a debilitating neurodegenerative condition characterized by the progressive degeneration of motor neurons. Despite extensive research in various model animals, the cellular signal mechanisms of ALS remain elusive, impeding the development of efficacious treatments. Among these models, a well-characterized and diminutive organism, Caenorhabditis elegans (C. elegans), has emerged as a potent tool for investigating the molecular and cellular dimensions of ALS pathogenesis. This review summarizes the contributions of C. elegans models to our comprehension of ALS, emphasizing pivotal findings pertaining to genetics, protein aggregation, cellular pathways, and potential therapeutic strategies. We analyze both the merits and constraints of the C. elegans system in the realm of ALS research and point towards future investigations that could bridge the chasm between C. elegans foundational discoveries and clinical applications.}, } @article {pmid38200884, year = {2024}, author = {Fürmann, A and Syring, C and Becker, J and Sarbach, A and Weber, J and Welham Ruiters, M and Steiner, A}, title = {Prevalence of Painful Lesions of the Digits and Risk Factors Associated with Digital Dermatitis, Ulcers and White Line Disease on Swiss Cattle Farms.}, journal = {Animals : an open access journal from MDPI}, volume = {14}, number = {1}, pages = {}, pmid = {38200884}, issn = {2076-2615}, abstract = {The first aim of this study was to calculate the prevalence of painful lesions of the digits ("alarm" lesions; ALs) in Swiss dairy herds and cow-calf operations over a three-year study period. The following ALs were included in the calculation: the M2 stage of digital dermatitis (DD M2), ulcers (U), white line fissures (WLF) of moderate and high severity, white line abscesses (WLA), interdigital phlegmon (IP) and swelling of the coronet and/or bulb (SW). Between February 2020 and February 2023, digit disorders were electronically recorded during routine trimmings by 40 specially trained hoof trimmers on Swiss cattle farms participating in the national claw health programme. The data set used consisted of over 35,000 observations from almost 25,000 cows from 702 herds. While at the herd-level, the predominant AL documented in 2022 was U with 50.3% followed by WLF with 38.1%, at the cow-level, in 2022, it was DD M2 with 5.4% followed by U with 3.7%. During the study period, within-herd prevalences of ALs ranged from 0.0% to a maximum of 66.1% in 2020. The second aim of this study was to determine herd- and cow-level risk factors associated with digital dermatitis (DD), U and white line disease (WL) in dairy cows using data from 2022. While for DD, analysed herd-level factors appeared to have a greater effect on the probability of its occurrence, the presence of U and WL was mainly associated with the analysed cow-level factors. The risk for DD increased with a higher herd trimming frequency. Herds kept in tie stalls had a lower risk for DD and WL and a higher risk for U compared to herds kept in loose housing systems. Herds with predominantly Holstein Friesian cows as well as Holstein Friesian cows had a higher risk for the occurrence of DD compared to herds and cows of other breeds. With increasing parity, cows had a higher risk of developing U and WL, whereas for DD, parity was negatively associated with prevalence. Cows trimmed during the grazing period had a higher risk of U and WL than cows trimmed during the housing period. These findings may contribute to improve management measures affecting the health of the digits in farms with structures similar to those evaluated in the current study, such as small herds with frequent access to pasture. Further research is warranted to demonstrate how measures addressing the current results combined with those of individual herd risk assessments might contribute to an improvement in the health of the digits in the respective dairy herds.}, } @article {pmid38200398, year = {2024}, author = {Stenson, K and Fecteau, TE and O'Callaghan, L and Bryden, P and Mellor, J and Wright, J and Earl, L and Thomas, O and Iqbal, H and Barlow, S and Parvanta, S}, title = {Health-related quality of life across disease stages in patients with amyotrophic lateral sclerosis: results from a real-world survey.}, journal = {Journal of neurology}, volume = {271}, number = {5}, pages = {2390-2404}, pmid = {38200398}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology/complications ; *Quality of Life ; Male ; Female ; Middle Aged ; Cross-Sectional Studies ; *Disease Progression ; Aged ; Adult ; Severity of Illness Index ; Surveys and Questionnaires ; Caregivers/psychology ; Neurologists ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by a rapid disease course, with disease severity being associated with declining health-related quality of life (HRQoL) in persons living with ALS (pALS). The main objective of this study was to assess the impact of disease progression on HRQoL across King's, Milano-Torino Staging (MiToS), and physician-judgement clinical staging. Additionally, we evaluated the impact of the disease on the HRQoL of care partners (cALS).

METHODS: Data were sourced from the Adelphi ALS Disease Specific Programme (DSP)™, a cross-sectional survey of neurologists, pALS and cALS presenting in a real-world clinical setting between July 2020 and March 2021 in Europe and the United States.

RESULTS: Neurologists (n = 142) provided data for 880 pALS. There were significant negative correlations between all three clinical staging systems and EuroQol (European Quality of Life) Five Dimension Five Level Scale (EQ-5D-5L) utility scores and visual analogue scale (VAS) ratings. Although not all differences were significant, 5-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5) scores showed a stepwise increase in HRQoL impairment at each stage of the disease regardless of the staging system. At later stages, high levels of fatigue and substantial activity impairment were reported. As pALS disease states progressed, cALS also experienced a decline in HRQoL and increased burden.

CONCLUSIONS: Across outcomes, pALS and cALS generally reported worse outcomes at later stages of the disease, highlighting an unmet need in this population for strategies to maximise QoL despite disease progression. Recognition and treatment of symptoms such as pain and fatigue may lead to improved outcomes for pALS and cALS.}, } @article {pmid38198547, year = {2024}, author = {Perlegos, AE and Durkin, J and Belfer, SJ and Rodriguez, A and Shcherbakova, O and Park, K and Luong, J and Bonini, NM and Kayser, MS}, title = {TDP-43 impairs sleep in Drosophila through Ataxin-2-dependent metabolic disturbance.}, journal = {Science advances}, volume = {10}, number = {2}, pages = {eadj4457}, pmid = {38198547}, issn = {2375-2548}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; T32 HL007953/HL/NHLBI NIH HHS/United States ; P40 OD018537/OD/NIH HHS/United States ; F31 AG063470/AG/NIA NIH HHS/United States ; T32 MH014654/MH/NIMH NIH HHS/United States ; R01 AG071777/AG/NIA NIH HHS/United States ; R56 AG071777/AG/NIA NIH HHS/United States ; R01 GM084947/GM/NIGMS NIH HHS/United States ; F30 AG058409/AG/NIA NIH HHS/United States ; P40 OD010949/OD/NIH HHS/United States ; F32 NS117785/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis ; Ataxin-2 ; DNA-Binding Proteins/genetics ; Drosophila ; *Neurodegenerative Diseases ; }, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia are associated with substantial sleep disruption, which may accelerate cognitive decline and brain degeneration. Here, we define a role for trans-activation response element (TAR) DNA binding protein 43 (TDP-43), a protein associated with human neurodegenerative disease, in regulating sleep using Drosophila. Expression of TDP-43 severely disrupts sleep, and the sleep deficit is rescued by Atx2 knockdown. Brain RNA sequencing revealed that Atx2 RNA interference regulates transcripts enriched for small-molecule metabolic signaling in TDP-43 brains. Focusing on these Atx2-regulated genes, we identified suppressors of the TDP-43 sleep phenotype enriched for metabolism pathways. Knockdown of Atx2 or treatment with rapamycin attenuated the sleep phenotype and mitigated the disruption of small-molecule glycogen metabolism caused by TDP-43. Our findings provide a connection between toxicity of TDP-43 and sleep disturbances and highlight key aspects of metabolism that interplay with TDP-43 toxicity upon Atx2 rescue.}, } @article {pmid38197966, year = {2024}, author = {Dzik, KP and Flis, DJ and Kaczor-Keller, KB and Bytowska, ZK and Karnia, MJ and Ziółkowski, W and Kaczor, JJ}, title = {Spinal cord abnormal autophagy and mitochondria energy metabolism are modified by swim training in SOD1-G93A mice.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {102}, number = {3}, pages = {379-390}, pmid = {38197966}, issn = {1432-1440}, support = {(2018/29/N/NZ7/01627)//Narodowe Centrum Nauki/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Autophagy ; Disease Models, Animal ; Energy Metabolism ; Insulin-Like Growth Factor I ; Mice, Transgenic ; Mitochondria/metabolism ; Motor Neurons/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) may result from the dysfunctions of various mechanisms such as protein accumulation, mitophagy, and biogenesis of mitochondria. The purpose of the study was to evaluate the molecular mechanisms in ALS development and the impact of swim training on these processes. In the present study, an animal model of ALS, SOD1-G93A mice, was used with the wild-type mice as controls. Mice swam five times per week for 30 min. Mice were analyzed before ALS onset (70 days old), at ALS 1 disease onset (116 days old), and at the terminal stage of the disease ALS (130 days old), and compared with the corresponding ALS untrained groups and normalized to the wild-type group. Enzyme activity and protein content were analyzed in the spinal cord homogenates. The results show autophagy disruptions causing accumulation of p62 accompanied by low PGC-1α and IGF-1 content in the spinal cord of SOD1-G93A mice. Swim training triggered a neuroprotective effect, attenuation of NF-l degradation, less accumulated p62, and lower autophagy initiation. The IGF-1 pathway induces pathophysiological adaptation to maintain energy demands through anaerobic metabolism and mitochondrial protection. KEY MESSAGES: The increased protein content of p62 in the spinal cord of SOD1-G93A mice suggests that autophagic clearance and transportation are disrupted. Swim training attenuates neurofilament light destruction in the spinal cord of SOD1-G93A mice. Swim training reducing OGDH provokes suppression of ATP-consuming anabolic pathways. Swim training induces energy metabolic changes and mitochondria protection through the IGF-1 signaling pathway.}, } @article {pmid38197897, year = {2024}, author = {Iguchi, Y and Takahashi, Y and Li, J and Araki, K and Amakusa, Y and Kawakami, Y and Kobayashi, K and Yokoi, S and Katsuno, M}, title = {IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation.}, journal = {The Journal of cell biology}, volume = {223}, number = {2}, pages = {}, pmid = {38197897}, issn = {1540-8140}, support = {JP20H03589//Japan Society for the Promotion of Science/ ; JP21wm0425013//Japan Agency for Medical Research and Development/ ; //SERIKA/ ; //Japan ALS Association/ ; //Takeda Science Foundation/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; Disease Models, Animal ; *DNA-Binding Proteins/genetics ; *Frontotemporal Dementia ; *Frontotemporal Lobar Degeneration ; *I-kappa B Kinase/genetics ; Proteasome Endopeptidase Complex ; Humans ; }, abstract = {Cytoplasmic aggregation of TDP-43 in neurons is a pathological feature common to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We demonstrate that the IκB kinase (IKK) complex promotes the degradation of cytoplasmic TDP-43 through proteasomes. While IKKβ is a major factor in TDP-43 degradation, IKKα acts as a cofactor, and NEMO functions as a scaffold for the recruitment of TDP-43 to the IKK complex. Furthermore, we identified IKKβ-induced phosphorylation sites of TDP-43 and found that phosphorylation at Thr8 and Ser92 is important for the reduction of TDP-43 by IKK. TDP-43 phosphorylation at Ser92 was detected in a pattern different from that of C-terminal phosphorylation in the pathological inclusion of ALS. IKKβ was also found to significantly reduce the expression level and toxicity of the disease-causing TDP-43 mutation. Finally, the favorable effect of IKKβ on TDP-43 aggregation was confirmed in the hippocampus of mice. IKK and the N-terminal phosphorylation of TDP-43 are potential therapeutic targets for ALS and FTLD.}, } @article {pmid38196621, year = {2023}, author = {Pottinger, TD and Motelow, JE and Povysil, G and Moreno, CAM and Ren, Z and Phatnani, H and , and Aitman, TJ and Santoyo-Lopez, J and , and Mitsumoto, H and , and Goldstein, DB and Harms, MB}, title = {Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38196621}, issn = {2693-5015}, support = {K01 MH098126/MH/NIMH NIH HHS/United States ; RC2 MH089915/MH/NIMH NIH HHS/United States ; P01 HD080642/HD/NICHD NIH HHS/United States ; R01 MH097971/MH/NIMH NIH HHS/United States ; RC2 NS070344/NS/NINDS NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UM1 AI100645/AI/NIAID NIH HHS/United States ; P30 AG028377/AG/NIA NIH HHS/United States ; U54 NS078059/NS/NINDS NIH HHS/United States ; P01 AG007232/AG/NIA NIH HHS/United States ; MC_PC_15080/MRC_/Medical Research Council/United Kingdom ; RF1 AG054023/AG/NIA NIH HHS/United States ; R01 HD048805/HD/NICHD NIH HHS/United States ; U01 HG007672/HG/NHGRI NIH HHS/United States ; U01 NS053998/NS/NINDS NIH HHS/United States ; U01 NS077303/NS/NINDS NIH HHS/United States ; U19 AI067854/AI/NIAID NIH HHS/United States ; R01 AG037212/AG/NIA NIH HHS/United States ; R01 ES016348/ES/NIEHS NIH HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 30,000 people in the United States. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms, such as antisense oligonucleotides, continue to develop, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.

METHODS: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger cohort of 6,970 ALS patients from a large multi-ethnic cohort as well as 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.

RESULTS: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR=19.18, p = 3.67 × 10[-39]; OR=4.73, p = 2 × 10[-10]; OR=2.3, p = 7.49 × 10[-9], respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10[-7]), was protective for ALS in this model. An intolerant domain based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR=10.08, p = 3.62 × 10[-16]). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p=8.38 × 10[-6]).

CONCLUSIONS: In a large multi-ethnic cohort of 6,970 ALS patients, rare variant burden testing validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.}, } @article {pmid38196030, year = {2024}, author = {Mohammadi, S and Seyedalipour, B and Hashemi, SZ and Hosseinkhani, S and Mohseni, M}, title = {Implications of ALS-Associated Mutations on Biochemical and Biophysical Features of hSOD1 and Aggregation Formation.}, journal = {Biochemical genetics}, volume = {62}, number = {5}, pages = {3658-3680}, pmid = {38196030}, issn = {1573-4927}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Mutation ; Amyloid/metabolism ; Protein Aggregates ; Protein Aggregation, Pathological/genetics ; }, abstract = {One of the recognized motor neuron degenerative disorders is amyotrophic lateral sclerosis (ALS). By now, several mutations have been reported and linked to ALS patients, some of which are induced by mutations in the human superoxide dismutase (hSOD1) gene. The ALS-provoking mutations are located throughout the structure of hSOD1 and promote the propensity to aggregate. Despite numerous investigations, the underlying mechanism related to the toxicity of mutant hSOD1 through the gain of a toxic function is still vague. We surveyed two mutant forms of hSOD1 by removing and adding cysteine at positions 146 and 72, respectively, to investigate the biochemical characterization and amyloid formation. Our findings predicted the harmful and destabilizing impact of two SOD1 mutants using multiple programs. The specific activity of the wild-type form was about 1.42- and 1.92-fold higher than that of C146R and G72C mutants, respectively. Comparative structural studies using CD spectropolarimetry, and intrinsic and ANS fluorescence showed alterations in secondary structure content, exposure of hydrophobic patches, and structural compactness of WT-hSOD1 vs. mutants. We demonstrated that two mutants were able to promote amyloid-like aggregates under amyloid induction circumstances (50-mM Tris-HCl pH 7.4, 0.2-M KSCN, 50-mM DTT, 37 °C, 190 rpm). Monitoring aggregates were done using an enhancement in thioflavin T fluorescence and alterations in Congo red absorption. The mutants accelerated fibrillation with subsequently greater fluorescence amplitude and a shorter lag time compared to WT-SOD1. These findings support the aggregation of ALS-associated SOD1 mutants as an integral part of ALS pathology.}, } @article {pmid38195712, year = {2024}, author = {Ravichandran, KA and Heneka, MT}, title = {Inflammasomes in neurological disorders - mechanisms and therapeutic potential.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {2}, pages = {67-83}, pmid = {38195712}, issn = {1759-4766}, mesh = {Humans ; Inflammasomes/metabolism ; *Nervous System Diseases/drug therapy ; *Stroke ; *Multiple Sclerosis ; Brain/metabolism ; }, abstract = {Inflammasomes are molecular scaffolds that are activated by damage-associated and pathogen-associated molecular patterns and form a key element of innate immune responses. Consequently, the involvement of inflammasomes in several diseases that are characterized by inflammatory processes, such as multiple sclerosis, is widely appreciated. However, many other neurological conditions, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, stroke, epilepsy, traumatic brain injury, sepsis-associated encephalopathy and neurological sequelae of COVID-19, all involve persistent inflammation in the brain, and increasing evidence suggests that inflammasome activation contributes to disease progression in these conditions. Understanding the biology and mechanisms of inflammasome activation is, therefore, crucial for the development of inflammasome-targeted therapies for neurological conditions. In this Review, we present the current evidence for and understanding of inflammasome activation in neurological diseases and discuss current and potential interventional strategies that target inflammasome activation to mitigate its pathological consequences.}, } @article {pmid38194904, year = {2024}, author = {Nassar, J and Rizk, C and Fares, G and Tohme, C and Braidy, C and Farah, J}, title = {Clinical image quality assessment and mean glandular dose for full field digital mammography.}, journal = {Journal of radiological protection : official journal of the Society for Radiological Protection}, volume = {44}, number = {1}, pages = {}, doi = {10.1088/1361-6498/ad1cd4}, pmid = {38194904}, issn = {1361-6498}, mesh = {Humans ; Female ; Radiation Dosage ; Retrospective Studies ; Mammography ; *Radiation Exposure ; Diagnostic Reference Levels ; *Breast Neoplasms/diagnostic imaging ; Radiographic Image Enhancement/methods ; }, abstract = {This study aims to assess the image quality (IQ) of 12 mammographic units and to identify units with potential optimisation needs. Data for 350 mammography examinations meeting inclusion criteria were collected retrospectively from April 2021 to April 2022. They were categorised based on the medical reports into 10 normal cases, 10 cases displaying calcifications and 10 cases presenting lesions. Two radiologists assessed the IQ of 1400 mammograms, evaluating system performance per Boitaet al's study and positioning performance following European guidelines. To measure agreement between the two radiologists, the Cohen's Kappa coefficient (κ) was computed, quantifying the excess of agreement beyond chance. The visual grading analysis score (VGAS) was computed to compare system and positioning performance assessments across different categories and facilities. Median average glandular dose (AGD) values for cranio caudal and medio lateral oblique views were calculated for each category and facility and compared to the national diagnostic reference levels. The health facilities were categorised by considering both IQ VGAS and AGD levels. Inter-rater agreement between radiologists ranged from poor (κ< 0.20) to moderate (0.41 <κ< 0.60), likely influenced by inherent biases and distinct IQ expectations. 50% of the facilities were classified as needing corrective actions for their system performance as they had IQ or high AGD that could increase recall rate and radiation risk and 50% of the health facilities exhibited insufficient positioning performance that could mask tumour masses and microcalcifications. The study's findings emphasise the importance of implementing quality assurance programs to ensure optimal IQ for accurate diagnoses while adhering to radiation exposure guidelines. Additionally, comprehensive training for technologists is essential to address positioning challenges. These initiatives collectively aim to enhance the overall quality of breast imaging services, contributing to improved patient care.}, } @article {pmid38194198, year = {2024}, author = {Xu, A and Luo, Y and Tang, Y and Yang, F and Gao, X and Qiao, G and Zhu, X and Zhou, J}, title = {Chitinases as a potential diagnostic and prognostic biomarker for amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {6}, pages = {2489-2503}, pmid = {38194198}, issn = {1590-3478}, support = {2023AFD128//Hubei Provincial Natural Science Foundation and the Innovation and Development of Traditional Chinese Medicine of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis/blood ; Humans ; *Biomarkers/cerebrospinal fluid/blood ; *Chitinases/cerebrospinal fluid/blood ; Prognosis ; Hexosaminidases/cerebrospinal fluid/blood ; Chitinase-3-Like Protein 1/cerebrospinal fluid/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons, and there is currently a lack of reliable diagnostic biomarkers. This meta-analysis aimed to evaluate CHIT1, CHI3L1, and CHI3L2 levels in the cerebrospinal fluid (CSF) or blood and their diagnostic potential in ALS patients. A systematic, comprehensive search was performed of peer-reviewed English-language articles published before April 1, 2023, in PubMed, Scopus, Embase, Cochrane Library, and Web of Science. After a thorough screening, 13 primary articles were included, and their chitinases-related data were extracted for systematic review and meta-analysis. In ALS patients, the CSF CHIT1 levels were significantly elevated compared to controls with healthy control (HC) (SMD, 1.92; 95% CI, 0.78 - 3.06; P < 0.001). CHIT1 levels were elevated in the CSF of ALS patients compared to other neurodegenerative diseases (ONDS) control (SMD, 0.74; 95% CI, 0.22 - 1.27; P < 0.001) and exhibited an even more substantial increase when compared to ALS-mimicking diseases (AMDS) (SMD, 1.15; 95% CI, 0.35 - 1.94, P < 0.001). Similarly, the CSF CHI3L1 levels were significantly higher in ALS patients compared to HC (SMD, 3.16; 95% CI, 1.26 - 5.06, P < 0.001). CHI3L1 levels were elevated in the CSF of ALS patients compared to ONDS (SMD, 0.75; 95% CI, 0.32 - 1.19; P = 0.017) and exhibited a more pronounced increase when compared to AMDS (SMD, 1.92; 95% CI, 0.41 - 3.42; P < 0.001). The levels of CSF chitinases in the ALS patients showed a significant increase, supporting the role of CSF chitinases as diagnostic biomarkers for ALS.}, } @article {pmid38194085, year = {2024}, author = {Zhu, L and Deng, F and Bai, D and Hou, J and Jia, Q and Zhang, C and Ou, K and Li, S and Li, XJ and Yin, P}, title = {Loss of TDP-43 mediates severe neurotoxicity by suppressing PJA1 gene transcription in the monkey brain.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {16}, pmid = {38194085}, issn = {1420-9071}, support = {32270564//National Natural Science Foundation of China/ ; 81830032//National Natural Science Foundation of China/ ; 82071421//National Natural Science Foundation of China/ ; 2023A1515010811//Guangdong Basic and Applied Basic Research/ ; 2022A1515011205//Guangdong Basic and Applied Basic Research/ ; 2021ZT09Y007//Department of Science and Technology of Guangdong Province/ ; 2018B030337001//Department of Science and Technology of Guangdong Province/ ; 202007030008//Guangzhou Key Research Program on Brain Science/ ; 21622113//Fundamental Research Funds for the Central Universities/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics ; *Brain ; *DNA-Binding Proteins/genetics ; Haplorhini ; Transcription, Genetic ; *Ubiquitin-Protein Ligases/genetics ; Disease Models, Animal ; }, abstract = {The nuclear loss and cytoplasmic accumulation of TDP-43 (TAR DNA/RNA binding protein 43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previously, we reported that the primate-specific cleavage of TDP-43 accounts for its cytoplasmic mislocalization in patients' brains. This prompted us to investigate further whether and how the loss of nuclear TDP-43 mediates neuropathology in primate brain. In this study, we report that TDP-43 knockdown at the similar effectiveness, induces more damage to neuronal cells in the monkey brain than rodent mouse. Importantly, the loss of TDP-43 suppresses the E3 ubiquitin ligase PJA1 expression in the monkey brain at transcriptional level, but yields an opposite upregulation of PJA1 in the mouse brain. This distinct effect is due to the species-dependent binding of nuclear TDP-43 to the unique promoter sequences of the PJA1 genes. Further analyses reveal that the reduction of PJA1 accelerates neurotoxicity, whereas overexpressing PJA1 diminishes neuronal cell death by the TDP-43 knockdown in vivo. Our findings not only uncover a novel primate-specific neurotoxic contribution to the loss of function theory of TDP-43 proteinopathy, but also underscore a potential therapeutic approach of PJA1 to the loss of nuclear TDP-43.}, } @article {pmid38193795, year = {2024}, author = {Corrales-Guerrero, L and Díaz-Moreno, I}, title = {Deciphering the role of Zn[2+]-binding histidines from TIA-1 on the assembly and dynamics of stress granules.}, journal = {BioFactors (Oxford, England)}, volume = {50}, number = {4}, pages = {750-755}, doi = {10.1002/biof.2037}, pmid = {38193795}, issn = {1872-8081}, support = {DOC_00796//Agencia de Innovación y Desarrollo de Andalucía/ ; P18-FR-3487//Agencia de Innovación y Desarrollo de Andalucía/ ; PID2021-126663NB-I00//Ministerio de Ciencia e Innovación/ ; }, mesh = {*T-Cell Intracellular Antigen-1/metabolism/genetics ; *Zinc/metabolism ; *Histidine/metabolism/genetics/chemistry ; *Stress Granules/metabolism/genetics ; Humans ; Protein Binding ; Binding Sites ; Cytoplasmic Granules/metabolism/genetics ; }, abstract = {T-cell intracellular antigen-1 (TIA-1) is a key RNA-binding protein that participates in translation regulation and RNA splicing. TIA-1 undergoes liquid-liquid phase separation as a fundamental mechanism that enables the condensation of RNA and proteins into membraneless organelles called stress granules (SGs). However, this dynamic behavior can lead to aberrant fibril formation, implicated in neurodegenerative disorders, and must be tightly regulated. In this study, we investigated the role in the cell of histidine residues His94 and His96, responsible for Zn[2+] binding. Using fluorescence microscopy, we found that the specific binding site formed by these residues is critical for SG assembly. Furthermore, it also plays a role maintaining the dynamic behavior of SG-assembled TIA-1. Collectively, our findings confirm the physiological relevance of TIA-1 His94 and His96 in the Zn[2+]-mediated regulatory mechanism for protection against fibril formation in SGs.}, } @article {pmid38193356, year = {2024}, author = {Tsuji, K and Nakayama, Y and Taruya, J and Ito, H}, title = {Persistence of Kii amyotrophic lateral sclerosis after the 2000s and its characteristic aging-related tau astrogliopathy.}, journal = {Journal of neuropathology and experimental neurology}, volume = {83}, number = {2}, pages = {79-93}, doi = {10.1093/jnen/nlad113}, pmid = {38193356}, issn = {1554-6578}, support = {18H02743//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Brain/pathology ; *Dementia/pathology ; Japan/epidemiology ; *Parkinsonian Disorders ; Tauopathies/pathology ; TDP-43 Proteinopathies/pathology ; }, abstract = {Kii amyotrophic lateral sclerosis (ALS) is a unique disease that occurs in the southern portion of the Kii Peninsula and exhibits a dual pathology of TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy and tauopathy. The incidence of ALS in this region was very high in the 1960s, briefly decreased through the 1980s, but began increasing again after 2000 with a change of high-concentration geographic foci. It is unclear, however, whether the unique pathological features have changed along with the incidence changes. This study analyzed postmortem specimens from neuropathologically confirmed Kii ALS cases from the 1970s (n = 4) and those after 1999 (n = 12) from the southern Kii Peninsula or outside of the area. Our results confirm the continued occurrence of Kii ALS after 2000 in the southern Kii Peninsula and the preservation of disease-specific neuronal tau pathology, including the widespread occurrence throughout the brain and spinal cord, sparse neuropil threads, and predominance in superficial layers. Furthermore, we assessed the glial tau pathology of Kii and non-Kii ALS in accordance with the aging-related tau astrogliopathy classification method for the first time and detected a unique brainstem predominant appearance of gray matter aging-related tau astrogliopathy in Kii ALS cases, which may provide clues to pathogenetic mechanisms.}, } @article {pmid38191942, year = {2024}, author = {Hernandez-Candia, CN and Brady, BR and Harrison, E and Tucker, CL}, title = {A platform to induce and mature biomolecular condensates using chemicals and light.}, journal = {Nature chemical biology}, volume = {20}, number = {4}, pages = {452-462}, pmid = {38191942}, issn = {1552-4469}, support = {R21 MH134019/MH/NIMH NIH HHS/United States ; R35 GM136367/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Biomolecular Condensates ; *Huntington Disease/genetics ; Optogenetics ; Proteostasis ; }, abstract = {Biomolecular condensates are membraneless compartments that impart spatial and temporal organization to cells. Condensates can undergo maturation, transitioning from dynamic liquid-like states into solid-like states associated with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Huntington's disease. Despite their important roles, many aspects of condensate biology remain incompletely understood, requiring tools for acutely manipulating condensate-relevant processes within cells. Here we used the BCL6 BTB domain and its ligands BI-3802 and BI-3812 to create a chemical genetic platform, BTBolig, allowing inducible condensate formation and dissolution. We also developed optogenetic and chemical methods for controlled induction of condensate maturation, where we surprisingly observed recruitment of chaperones into the condensate core and formation of dynamic biphasic condensates. Our work provides insights into the interaction of condensates with proteostasis pathways and introduces a suite of chemical-genetic approaches to probe the role of biomolecular condensates in health and disease.}, } @article {pmid38191789, year = {2024}, author = {Salomonsson, SE and Maltos, AM and Gill, K and Aladesuyi Arogundade, O and Brown, KA and Sachdev, A and Sckaff, M and Lam, KJK and Fisher, IJ and Chouhan, RS and Van Laar, VS and Marley, CB and McLaughlin, I and Bankiewicz, KS and Tsai, YC and Conklin, BR and Clelland, CD}, title = {Validated assays for the quantification of C9orf72 human pathology.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {828}, pmid = {38191789}, issn = {2045-2322}, support = {K08 NS112330/NS/NINDS NIH HHS/United States ; U19 NS132303/NS/NINDS NIH HHS/United States ; TL1 TR001871/TR/NCATS NIH HHS/United States ; R01 HL130533/HL/NHLBI NIH HHS/United States ; AACSF-17-531484/ALZ/Alzheimer's Association/United States ; RF1 AG072052/AG/NIA NIH HHS/United States ; R01 AG072052/AG/NIA NIH HHS/United States ; U01 NS134062/NS/NINDS NIH HHS/United States ; P01 HL146366/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Mice ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; *Frontotemporal Dementia ; Antibodies ; *Craniocerebral Trauma ; Mice, Transgenic ; DNA ; RNA ; }, abstract = {A repeat expansion mutation in the C9orf72 gene is the leading known genetic cause of FTD and ALS. The C9orf72-ALS/FTD field has been plagued by a lack of reliable tools to monitor this genomic locus and its RNA and protein products. We have validated assays that quantify C9orf72 pathobiology at the DNA, RNA and protein levels using knock-out human iPSC lines as controls. Here we show that single-molecule sequencing can accurately measure the repeat expansion and faithfully report on changes to the C9orf72 locus in what has been a traditionally hard to sequence genomic region. This is of particular value to sizing and phasing the repeat expansion and determining changes to the gene locus after gene editing. We developed ddPCR assays to quantify two major C9orf72 transcript variants, which we validated by selective excision of their distinct transcriptional start sites. Using validated knock-out human iPSC lines, we validated 4 commercially available antibodies (of 9 tested) that were specific for C9orf72 protein quantification by Western blot, but none were specific for immunocytochemistry. We tested 15 combinations of antibodies against dipeptide repeat proteins (DPRs) across 66 concentrations using MSD immunoassay, and found two (against poly-GA and poly-GP) that yielded a 1.5-fold or greater signal increase in patient iPSC-motor neurons compared to knock-out control, and validated them in human postmortem and transgenic mouse brain tissue. Our validated DNA, RNA and protein assays are applicable to discovery research as well as clinical trials.}, } @article {pmid38189756, year = {2024}, author = {Zeng, Y and Cao, S and Pang, K and Tang, J and Lin, G}, title = {Causal Association Between Sepsis and Neurodegenerative Diseases: A Bidirectional Two-Sample Mendelian Randomization Study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {97}, number = {1}, pages = {229-237}, doi = {10.3233/JAD-230954}, pmid = {38189756}, issn = {1875-8908}, mesh = {Humans ; *Neurodegenerative Diseases/complications/epidemiology/genetics ; *Alzheimer Disease/genetics ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Reproducibility of Results ; *Sepsis/complications/genetics ; }, abstract = {BACKGROUND: Previous observational studies suggested an association between sepsis and neurodegenerative diseases, but causality remains unclear.

OBJECTIVE: Determining the causal association between sepsis and four neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Lewy body dementia) through bidirectional two-sample Mendelian randomization (MR) analysis.

METHODS: Genome-wide association study summary statistics for all traits were obtained from publicly available databases. Inverse variance weighted (IVW) was the primary method for evaluating causal associations. In addition, three additional MR methods (MR-Egger, weighted median, and maximum likelihood method) were employed to supplement IVW. Furthermore, various sensitivity tests were conducted to assess the reliability: 1) Cochrane's Q test for assessing heterogeneity; 2) MR-Egger intercept test and MR-PRESSO global test for evaluating horizontal pleiotropy; 3) leave-one-out sensitivity test for determining the stability.

RESULTS: The results of IVW indicated that sepsis significantly increased the risk of Alzheimer's disease (OR = 1.11, 95% CI: 1.01-1.21, p = 0.025). In addition, three additional MR methods suggested parallel results. However, no causal effect of sepsis on the three other neurodegenerative diseases was identified. Subsequently, reverse MR analysis indicated that the four neurodegenerative diseases do not causally affect sepsis. Furthermore, sensitivity tests demonstrated the reliability of the MR analyses, suggesting no heterogeneity or horizontal pleiotropy.

CONCLUSIONS: The present study contributes to a deeper comprehension of the intricate interplay between sepsis and neurodegenerative disorders, thereby offering potential avenues for the development of therapeutic agents that can effectively mitigate the multifarious complications associated with sepsis.}, } @article {pmid38189364, year = {2025}, author = {Lim, SJ and Muhd Noor, ND and Sabri, S and Mohamad Ali, MS and Salleh, AB and Oslan, SN}, title = {Features of the rare pathogen Meyerozyma guilliermondii strain SO and comprehensive in silico analyses of its adherence-contributing virulence factor agglutinin-like sequences.}, journal = {Journal of biomolecular structure & dynamics}, volume = {43}, number = {7}, pages = {3728-3748}, doi = {10.1080/07391102.2023.2300757}, pmid = {38189364}, issn = {1538-0254}, mesh = {*Virulence Factors/chemistry/metabolism/genetics ; Animals ; *Zebrafish ; Agglutinins/chemistry/metabolism ; Fungal Proteins/chemistry/genetics/metabolism ; Biofilms/drug effects ; Virulence ; Mucorales/pathogenicity/metabolism ; Computer Simulation ; Candida albicans/pathogenicity/genetics ; }, abstract = {Meyerozyma guilliermondii is a rare yeast pathogen contributing to the deadly invasive candidiasis. M. guilliermondii strain SO, as a promising protein expression host, showed 99% proteome similarity with the clinically isolated ATCC 6260 (type strain) in a recent comparative genomic analysis. However, their in vitro virulence features and in vivo pathogenicity were uncharacterized. This study aimed to characterize the in vitro and in vivo pathogenicity of M. guilliermondii strain SO and analyze its Als proteins (MgAls) via comprehensive bioinformatics approaches. M. guilliermondii strain SO showed lower and higher sensitivity towards β-mercaptoethanol and lithium, respectively than the avirulent S. cerevisiae but exhibited the same tolerance towards cell wall-perturbing Congo Red with C. albicans. With 7.5× higher biofilm mass, M. guilliermondii strain SO also demonstrated 75% higher mortality rate in the zebrafish embryos with a thicker biofilm layer on the chorion compared to the avirulent S. cerevisiae. Being one of the most important Candida adhesins, sequence and structural analyses of four statistically identified MgAls showed that MgAls1056 was predicted to exhibit the most conserved amyloid-forming regions, tandem repeat domain and peptide binding cavity (PBC) compared to C. albicans Als3. Favoured from the predicted largest ligand binding site and druggable pockets, it showed the highest affinity towards hepta-threonine. Non-PBC druggable pockets in the most potent virulence contributing MgAls1056 provide new insights into developing antifungal drugs targeting non-albicans Candida spp. Virtual screening of available synthetic or natural bioactive compounds and MgAls1056 deletion from the fungal genome should be further performed and validated experimentally.}, } @article {pmid38189033, year = {2023}, author = {Moreno-Roco, J and Del Valle, L and Jiménez, D and Acosta, I and Castillo, JL and Dharmadasa, T and Kiernan, MC and Matamala, JM}, title = {Diagnostic utility of transcranial magnetic stimulation for neurodegenerative disease: a critical review.}, journal = {Dementia & neuropsychologia}, volume = {17}, number = {}, pages = {e20230048}, pmid = {38189033}, issn = {1980-5764}, abstract = {Neurodegenerative diseases pose significant challenges due to their impact on brain structure, function, and cognition. As life expectancy rises, the prevalence of these disorders is rapidly increasing, resulting in substantial personal, familial, and societal burdens. Efforts have been made to optimize the diagnostic and therapeutic processes, primarily focusing on clinical, cognitive, and imaging characterization. However, the emergence of non-invasive brain stimulation techniques, specifically transcranial magnetic stimulation (TMS), offers unique functional insights and diagnostic potential. TMS allows direct evaluation of brain function, providing valuable information inaccessible through other methods. This review aims to summarize the current and potential diagnostic utility of TMS in investigating neurodegenerative diseases, highlighting its relevance to the field of cognitive neuroscience. The findings presented herein contribute to the growing body of research focused on improving our understanding and management of these debilitating conditions, particularly in regions with limited resources and a pressing need for innovative approaches.}, } @article {pmid38188422, year = {2023}, author = {Doyle, JJ and Parker, JA}, title = {Genetic Interactions of Progranulin Across the ALS-FTD Spectrum and Beyond.}, journal = {microPublication biology}, volume = {2023}, number = {}, pages = {}, pmid = {38188422}, issn = {2578-9430}, support = {P40 OD010440/OD/NIH HHS/United States ; }, abstract = {Progranulin (PGRN) is a growth factor in which mutations are one of the leading causes of frontotemporal dementia (FTD), and has been implicated in an assortment of neurodegenerative diseases. Conversely, higher levels of the protein have shown potential as a general neuronal protective factor. While examining its neuroprotective applications on a broader scale would be unfeasible in mammalian models, we turned to the nematode C. elegans to map the interactions of PGRN across multiple genetic models of neurodegenerative diseases. Our results indicate that while the overexpression of PGRN appears to be protective across all models tested, the loss of PGRN exacerbated the disease phenotypes of all but three of the models tested. Given the ease of genetic analysis in nematodes, we propose this model organism as an efficient tool to build a comprehensive map of PGRN's genetic interactions.}, } @article {pmid38188233, year = {2023}, author = {Lockard, G and Gordon, J and Schimmel, S and Sayed, BE and Monsour, M and Garbuzova-Davis, S and Borlongan, CV}, title = {Attenuation of amyotrophic lateral sclerosis via stem cell and extracellular vesicle therapy: An updated review.}, journal = {Neuroprotection}, volume = {1}, number = {2}, pages = {130-138}, pmid = {38188233}, issn = {2770-730X}, support = {R21 NS132576/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly fatal neurological disease characterized by upper and lower motor neuron degeneration. Though typically idiopathic, familial forms of ALS are commonly comprised of a superoxide dismutase 1 (SOD1) mutation. Basic science frequently utilizes SOD1 models in vitro and in vivo to replicate ALS conditions. Therapies are sparse; those that exist on the market extend life minimally, thus driving the demand for research to identify novel therapeutics. Transplantation of stem cells is a promising approach for many diseases and has shown efficacy in SOD1 models and clinical trials. The underlying mechanism for stem cell therapy presents an exciting venue for research investigations. Most notably, the paracrine actions of stem cell-derived extracellular vesicles (EVs) have been suggested as a potent mitigating factor. This literature review focuses on the most recent preclinical research investigating cell-free methods for treating ALS. Various avenues are being explored, differing on the EV contents (protein, microRNA, etc.) and on the cell target (astrocyte, endothelial cell, motor neuron-like cells, etc.), and both molecular and behavioral outcomes are being examined. Unfortunately, EVs may also play a role in propagating ALS pathology. Nonetheless, the overarching goal remains clear; to identify efficient cell-free techniques to attenuate the deadly consequences of ALS.}, } @article {pmid38188146, year = {2024}, author = {Shao, BZ and Jiang, JJ and Zhao, YC and Zheng, XR and Xi, N and Zhao, GR and Huang, XW and Wang, SL}, title = {Neutrophil extracellular traps in central nervous system (CNS) diseases.}, journal = {PeerJ}, volume = {12}, number = {}, pages = {e16465}, pmid = {38188146}, issn = {2167-8359}, mesh = {Humans ; *Extracellular Traps ; *Central Nervous System Diseases ; *Multiple Sclerosis ; Central Nervous System ; Neutrophils ; }, abstract = {Excessive induction of inflammatory and immune responses is widely considered as one of vital factors contributing to the pathogenesis and progression of central nervous system (CNS) diseases. Neutrophils are well-studied members of inflammatory and immune cell family, contributing to the innate and adaptive immunity. Neutrophil-released neutrophil extracellular traps (NETs) play an important role in the regulation of various kinds of diseases, including CNS diseases. In this review, current knowledge on the biological features of NETs will be introduced. In addition, the role of NETs in several popular and well-studied CNS diseases including cerebral stroke, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and neurological cancers will be described and discussed through the reviewing of previous related studies.}, } @article {pmid38188028, year = {2023}, author = {Hu, Z and Zuo, C and Mao, C and Shi, C and Xu, Y}, title = {Peripheral immune markers and amyotrophic lateral sclerosis: a Mendelian randomization study.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1269354}, pmid = {38188028}, issn = {1662-4548}, abstract = {INTRODUCTION: The peripheral immune system changes in amyotrophic lateral sclerosis (ALS), but the causal relationship between the two is still controversial.

METHODS: In this study, we aimed to estimate the causal relationship between peripheral immune markers and ALS using a two-sample Mendelian randomization method. Genome-wide association study (GWAS) data on peripheral blood immune traits from European populations were used for exposure, and ALS summary statistics were used as the outcome. The causal relationship was evaluated by inverse variance weighting, MR-Egger, and weighted median methods and verified by multiple sensitivity analysis.

RESULTS: We found that the increase of one standard deviation of lymphocyte count is related to reducing ALS risk. CD3 on effector memory CD4[+] T cell, HLA DR[+] CD4[+] T cell, effector memory CD8[+] T cell, terminally differentiated CD8[+] T cell and CD28- CD8[+] T cell is also a protective factor for ALS. Among the circulating immune protein, the increase of one standard deviation of α-2-macroglobulin receptor-associated protein (α-2-MRAP) and C4b showed associated with low risk of ALS, while Interleukin-21 (IL-21) increases the risk of ALS.

DISCUSSION: Our study further reveals the important role of peripheral immune activity in ALS.}, } @article {pmid38188011, year = {2023}, author = {Ansari, U and Chen, V and Sedighi, R and Syed, B and Muttalib, Z and Ansari, K and Ansari, F and Nadora, D and Razick, D and Lui, F}, title = {Role of the UNC13 family in human diseases: A literature review.}, journal = {AIMS neuroscience}, volume = {10}, number = {4}, pages = {388-400}, pmid = {38188011}, issn = {2373-7972}, abstract = {This literature review explores the pivotal roles of the Uncoordinated-13 (UNC13) protein family, encompassing UNC13A, UNC13B, UNC13C, and UNC13D, in the pathogenesis of various human diseases. These proteins, which are evolutionarily conserved and crucial for synaptic vesicle priming and exocytosis, have been implicated in a range of disorders, spanning from neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) to immune-related conditions such as familial hemophagocytic lymphohistiocytosis (FHL). The involvement of UNC13A in neurotransmitter release and synaptic plasticity is linked to ALS and FTD, with genetic variations affecting disease progression. UNC13B, which is closely related to UNC13A, plays a role in autism spectrum disorders (ASD), epilepsy, and schizophrenia. UNC13C is implicated in oral squamous cell carcinoma (OSCC) and hepatocellular carcinoma (HCC), and has a neuroprotective role in Alzheimer's disease (AD). UNC13D has an essential role in immune cell function, making it a key player in FHL. This review highlights the distinct molecular functions of each UNC13 family member and their implications in disease contexts, shedding light on potential therapeutic strategies and avenues for future research. Understanding these proteins' roles offers new insights into the management and treatment of neurological and immunological disorders.}, } @article {pmid38188002, year = {2023}, author = {Ansari, U and Wen, J and Taguinod, I and Nadora, D and Nadora, D and Lui, F}, title = {Exploring dietary approaches in the prevention and management of Amyotrophic Lateral Sclerosis: A literature review.}, journal = {AIMS neuroscience}, volume = {10}, number = {4}, pages = {376-387}, pmid = {38188002}, issn = {2373-7972}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and complex neurodegenerative disease of upper and lower motor neurons of the central nervous system. The pathogenesis of this multifaceted disease is unknown. However, diet has emerged as a modifiable risk factor that has neuroprotective effects towards other neurological disorders such as Alzheimer's, Parkinson's and dementia. Thus, this review aims to explore how diet can potentially influence ALS onset and/or progression. In this review, five popular diets (Mediterranean, Vegan, Carnivore, Paleolithic and Ketogenic) and their distinct macromolecule composition, nutritional profile, biochemical pathways and their potential therapeutic effects for ALS are thoroughly examined. However, the composition of these diets varies, and the data is controversial, with conflicting studies on the effectiveness of nutrient intake of several of these diets. Although these five diets show that a higher intake of foods containing anti-inflammatory and antioxidant compounds have a positive correlation towards reducing the oxidative stress of ALS, further research is needed to directly compare the effects of these diets and the mechanisms leading to ALS and its progression.}, } @article {pmid38187588, year = {2024}, author = {McKeever, PM and Sababi, AM and Sharma, R and Xu, Z and Xiao, S and McGoldrick, P and Ketela, T and Sato, C and Moreno, D and Visanji, N and Kovacs, GG and Keith, J and Zinman, L and Rogaeva, E and Goodarzi, H and Bader, GD and Robertson, J}, title = {Single-nucleus transcriptome atlas of orbitofrontal cortex in amyotrophic lateral sclerosis with a deep learning-based decoding of alternative polyadenylation mechanisms.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.12.22.573083}, pmid = {38187588}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two age-related and fatal neurodegenerative disorders that lie on a shared disease spectrum. While both disorders involve complex interactions between neuronal and glial cells, the specific cell-type alterations and their contributions to disease pathophysiology remain incompletely understood. Here, we applied single-nucleus RNA sequencing of the orbitofrontal cortex, a region affected in ALS-FTLD, to map cell-type specific transcriptional signatures in C9orf72-related ALS (with and without FTLD) and sporadic ALS cases. Our findings reveal disease- and cell-type-specific transcriptional changes, with neurons exhibiting the most pronounced alterations, primarily affecting mitochondrial function, protein homeostasis, and chromatin remodeling. A comparison with independent datasets from different cortical regions of C9orf72 and sporadic ALS cases showed concordance in several pathways, with neuronal STMN2 and NEFL showing consistent up-regulation between brain regions and disease subtypes. We also interrogated alternative polyadenylation (APA) as an additional layer of transcriptional regulation, demonstrating that APA events are not correlated with identified gene expression changes. To interpret these events, we developed APA-Net, a deep learning model that integrates transcript sequences with RNA-binding protein expression profiles, revealing cell type-specific patterns of APA regulation. Our atlas illuminates cell type-specific pathomechanisms of ALS/FTLD, providing a valuable resource for further investigation.}, } @article {pmid38187158, year = {2023}, author = {Yang, J and Liu, T and Zhang, L and Li, X and Du, FP and Liu, Q and Dong, H and Liu, Y}, title = {Eosinophils at diagnosis are elevated in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1289467}, pmid = {38187158}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare, devastating neurodegenerative disease that affects upper and lower motor neurons. To date, no effective treatment or reliable biomarker for ALS has been developed. In recent years, many factors have been proposed as possible biomarkers of ALS; however, no consensus has been reached. Therefore, a reliable biomarker is urgently needed. Eosinophils may play a crucial role in healthy humans and diseases, and serve as a biomarker for many chronic diseases.

METHODS: Routine blood test results were collected from 66 healthy controls and 59 patients with ALS. The percentages and total numbers of each cell population were analyzed, and the correlation between these indicators and patient ALS functional rating scale-revised (ALSFRS-R) score or disease progression rate (ΔFS score) was analyzed.

RESULTS: Compared to healthy controls, the number of blood leukocytes, neutrophils, monocytes, and basophils was significantly decreased in patients with ALS (p = 0.002, p = 0.001, p = 0.049, and p < 0.0001, respectively). There was an increase in the number of eosinophils (p < 0.0001), but no difference in the number of lymphocytes between patients with ALS and healthy controls was found (p = 0.563). Compared to healthy controls, the percentage of neutrophils was decreased and the percentage of lymphocytes and eosinophils was increased in patients with ALS (p = 0.01, p = 0.012, and p = 0.001, respectively). There was no difference between patients with ALS and healthy controls in the percentage of monocytes and basophils (p = 0.622 and p = 0.09, respectively). However, only the percentage and number of eosinophils had a correlation with the ΔFS score. Further multivariate analysis revealed a significant correlation between the disease duration, eosinophil count and percentage, and the disease progression rate (p < 0.0001, p = 0.048, and p = 0.023, respectively). The neutrophil-to-eosinophil ratio (NER), lymphocyte-to-eosinophil ratio (LER), and monocyte-to-eosinophil ratio (MER) were significantly lower in patients with ALS than in healthy controls. However, only the LER was significantly correlated with the ΔFS score.

CONCLUSION: These observations implicate neutrophils, lymphocytes, and eosinophils as important factors, and increasing eosinophil counts were negatively correlated with the ΔFS score in patients with ALS.}, } @article {pmid38187117, year = {2023}, author = {Dorça, A and Vergara, J and Skoretz, SA and Brenner, MJ and Diniz, DS and Zeredo, JL and Sarmet, M}, title = {Respiratory support effect on pharyngeal area in patients with amyotrophic lateral sclerosis: A fluoroscopic comparison of NIV, helmet/CPAP, and high-flow nasal cannula.}, journal = {Respiratory medicine case reports}, volume = {46}, number = {}, pages = {101958}, pmid = {38187117}, issn = {2213-0071}, abstract = {The global use of noninvasive respiratory support provided by different supportive ventilation delivery methods (SVDMs) has increased, but the impact of these devices on the upper airway structures of patients with amyotrophic lateral sclerosis (ALS) is not known. We aimed to compare the pharyngeal cross-sectional area during spontaneous breathing with four different SVDMs: intranasal masks, oronasal masks, high-flow nasal cannula (HFNC), and helmet in patients with ALS. We compared measures of the pharyngeal area during spontaneous breathing and SVDM use. The greatest increase was observed with intranasal mask use, followed by HFNC, oronasal mask, and helmet respectively. In conclusion, upper airway opening in patients with ALS is enhanced by positive pressure with intranasal masks and HFNC, showing promise for increasing pharyngeal patency. Future studies should explore its applicability and effectiveness in maintaining long-term pharyngeal patency, especially in this population with bulbar weakness.}, } @article {pmid38185999, year = {2024}, author = {Liu, Z and Qiang, Y and Shan, S and Wang, S and Song, F}, title = {Carbon disulfide induces accumulation of TDP-43 in the cytoplasm and mitochondrial dysfunction in rat spinal cords.}, journal = {Cerebral cortex (New York, N.Y. : 1991)}, volume = {34}, number = {2}, pages = {}, doi = {10.1093/cercor/bhad526}, pmid = {38185999}, issn = {1460-2199}, support = {82173552//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Rats ; Animals ; *Carbon Disulfide/metabolism ; *Neuroblastoma/metabolism/pathology ; Cytoplasm/metabolism ; DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/chemically induced/pathology ; Spinal Cord/pathology ; *Neurodegenerative Diseases/metabolism ; *Mitochondrial Diseases/metabolism/pathology ; }, abstract = {The relationship between environmental neurotoxicant exposure and neurodegenerative diseases is being extensively investigated. Carbon disulfide, a classic neurotoxicant and prototype of dithiocarbamates fungicides and anti-inflammatory agents, has been detected in urban adults, raising questions about whether exposure to carbon disulfide is associated with a high incidence of neurodegenerative diseases. Here, using rat models and SH-SY5Y cells, we investigated the possible mechanistic linkages between carbon disulfide neurotoxicity and the expression of TDP-43 protein, a marker of amyotrophic lateral sclerosis/frontotemporal lobar degeneration. Our results showed that rats exhibited severe dyskinesia and increased TDP-43 expression in the spinal cord following carbon disulfide exposure. Moreover, carbon disulfide exposure induced abnormal cytoplasmic localization and phosphorylation of TDP-43 in motor neurons. Importantly, carbon disulfide treatment led to the accumulation of TDP-43 in the mitochondria of motor neurons and resulted in subsequent mitochondrial damage, including mitochondrial structural disruption, mitochondrial respiratory chain complex I inhibition, and impaired VCP/p97-dependent mitophagy. In summary, our study provides support for carbon disulfide exposure-mediated TDP-43 mislocalization and mitochondrial dysfunction, contributes to understanding the pathogenesis of environmental neurotoxin-induced neurodegeneration, and provides inspiration for potential therapeutic strategies.}, } @article {pmid38185916, year = {2024}, author = {Barber, S and Gomez-Godinez, V and Young, J and Wei, A and Chen, S and Snissarenko, A and Chan, SS and Wu, C and Shi, L}, title = {Impacts of H2O2, SARM1 inhibition, and high NAm concentrations on Huntington's disease laser-induced degeneration.}, journal = {Journal of biophotonics}, volume = {17}, number = {3}, pages = {e202300370}, doi = {10.1002/jbio.202300370}, pmid = {38185916}, issn = {1864-0648}, support = {//Beckman Laser Inc/ ; }, mesh = {Animals ; Mice ; Humans ; *Hydrogen Peroxide ; Niacinamide ; *Huntington Disease ; Mice, Knockout ; Neurons/metabolism ; Cytoskeletal Proteins/metabolism ; Armadillo Domain Proteins/genetics/metabolism ; }, abstract = {Axonal degeneration is a key component of neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease, and amyotrophic lateral sclerosis. Nicotinamide, an NAD+ precursor, has long since been implicated in axonal protection and reduction of degeneration. However, studies on nicotinamide (NAm) supplementation in humans indicate that NAm has no protective effect. Sterile alpha and toll/interleukin receptor motif-containing protein 1 (SARM1) regulates several cell responses to axonal damage and has been implicated in promoting neuronal degeneration. SARM1 inhibition seems to result in protection from neuronal degeneration while hydrogen peroxide has been implicated in oxidative stress and axonal degeneration. The effects of laser-induced axonal damage in wild-type and HD dorsal root ganglion cells treated with NAm, hydrogen peroxide (H2O2), and SARM1 inhibitor DSRM-3716 were investigated and the cell body width, axon width, axonal strength, and axon shrinkage post laser-induced injury were measured.}, } @article {pmid38185101, year = {2024}, author = {Huber, T and Krüerke, D and Simões-Wüst, AP}, title = {How Physicians and Nursing Staff Perceive Effectiveness and Tolerability of Bryophyllum Preparations: An Online Survey in an Anthroposophic Hospital.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {116-123}, pmid = {38185101}, issn = {2504-2106}, abstract = {BACKGROUND: Bryophyllum preparations are widely used in anthroposophic medicine, most often for mental and behavioural disorders. Three prospective studies have revealed positive effects of Bryophyllum pinnatum on sleep quality, and various trials have shown very good tolerability. Results from animal models have indicated CNS depressant and anxiolytic effects. This survey was conducted at the hospital "Klinik Arlesheim" in Switzerland to find out how the physicians and the nursing staff perceive the effectiveness and the tolerability of the Bryophyllum preparations they most frequently use.

DESIGN: Internal, anonymous online survey of healthcare professionals (April 8-May 31, 2022). The questionnaire comprised 105 multiple-choice questions. Answering the questions was taken as consent to participate in the survey.

PARTICIPANTS AND METHODS: All physicians and nursing staff with a valid email address at the hospital "Klinik Arlesheim AG" were invited via email to participate in this REDCap survey. The data were analysed descriptively.

RESULTS: Out of 266 invited participants, 48 answered some and 36 answered all questions (response rate between 18.0% and 13.5%). The participants had long experience with Bryophyllum preparations and were comprised approximately equal numbers of physicians and nursing staff. Various Bryophyllum preparations from the hospital's own production and Wala Heilmittel GmbH (in both cases produced from the species B. daigremontianum) and from Weleda AG (species B. pinnatum) were used. The indications for which most participants had prescribed or administered Bryophyllum preparations "very frequently" were anxiety, sleep disorders, crisis situations in oncology, posttraumatic stress disorder, benzodiazepine dependence/withdrawal, and depression. Improvements such as relief from restlessness, decreased anxiety, balance, easier falling asleep, better sleeping through, increased resilience, mood elevation, and less urge to move one's legs were reported "frequently" or "very frequently." Almost all participants agreed that Bryophyllum can be used to reduce the intake of synthetic sedatives or psychotropic drugs, but only approximately half believed that it could replace them. The majority of participants mentioned good tolerability of the various products, but a few reported occasional stomach or intestinal irritation, daytime fatigue, drowsiness, diarrhoea, and nausea.

CONCLUSION: Bryophyllum preparations are perceived as helpful in the treatment of various mental disorders, particularly anxiety, and are generally well tolerated. Most of these preparations are used for indications that have not yet been clinically investigated.

UNLABELLED: HintergrundBryophyllum-Präparate werden in der Anthroposophischen Medizin sehr häufig zur Behandlung von psychischen und Verhaltensstörungen eingesetzt. Drei prospektive Studien zeigten zudem positive Wirkungen von Bryophyllum pinnatum (BP) auf die Schlafqualität. Auch die Verträglichkeit wurde in allen bisherigen Studien als sehr gut bewertet. In Tiermodellen wurden ZNS-depressive und anxiolytische Effekte von BP festgestellt. Die hier durchgeführte Umfrage fand an der Klinik Arlesheim (Schweiz) statt. Sie diente dazu herauszufinden, wie Ärztinnen und Ärzte sowie das Pflegepersonal die Wirksamkeit und Verträglichkeit der von ihnen am häufigsten verwendeten Bryophyllum-Präparate wahrnehmen.DesignInterne, anonyme, Online-Befragung unter ärztlichen und pflegerischen Fachkräften (8. April–31. Mai 2022). Der Fragebogen umfasste 105 Multiple-Choice-Fragen. Die Beantwortung der Fragen wurde als Zustimmung zur Teilnahme an der Umfrage interpretiert.Teilnehmende und MethodenAlle Ärztinnen, Ärzte und Pflegefachpersonen mit einer gültigen E-Mail-Adresse der “Klinik Arlesheim AG” wurden per E-Mail eingeladen, an dieser REDCap-Umfrage teilzunehmen. Die Daten wurden deskriptiv ausgewertet.ErgebnisseVon den 266 eingeladenen Teilnehmenden beantworteten 48 einige und 36 alle Fragen (Antwortquote zwischen 18.0% und 13.5%). Die Teilnehmenden hatten langjährige Erfahrung mit Bryophyllum-Präparaten und setzten sich etwa zu gleichen Teilen aus ärztlichen und pflegerischen Fachkräften zusammen. Die Resultate zeigen, dass verschiedenste Bryophyllum-Präparate aus klinikeigener Herstellung, von der Wala Heilmittel GmbH (Art B. daigremontianum) und von der Weleda AG (Art B. pinnatum) verwendet werden. Zu den Indikationen, bei denen die meisten Teilnehmenden Bryophyllum-Präparate “sehr häufig” verordnet oder angewendet haben, gehören Angstzustände, Schlafstörungen, Krisensituationen in der Onkologie, Posttraumatische Belastungsstörung, Benzodiazepin-Abhängigkeit/Entzug und Depressionen. Gesundheitsverbesserungen wie Linderung von Unruhe, verminderte Angst, Ausgeglichenheit, leichteres Einschlafen, besseres Durchschlafen, erhöhte Belastbarkeit, Stimmungsaufhellung und weniger Drang, die Beine zu bewegen, wurden als “häufig” oder “sehr häufig” angegeben. Fast alle Teilnehmenden waren sich einig, dass Bryophyllum verwendet werden kann, um die Einnahme von synthetischen Beruhigungsmitteln oder Psychopharmaka zu reduzieren, aber nur etwa die Hälfte gab an, dass es diese ersetzen kann. Die Mehrheit der Teilnehmenden spricht von einer guten Verträglichkeit der verschiedenen Produkte. Einige wenige berichteten von gelegentlicher Magen- oder Darmreizung, Tagesmüdigkeit, Schläfrigkeit, Durchfall und Übelkeit.SchlussfolgerungBryophyllum-Präparate werden als hilfreich bei der Behandlung verschiedener psychischen Störungen, insbesondere bei Angstzuständen, angesehen und im Allgemeinen gut vertragen. Die meisten der angegebenen Präparate werden für Indikationen verwendet, die noch nicht klinisch untersucht worden sind.}, } @article {pmid38184629, year = {2024}, author = {Klíčová, K and Mareš, J and Menšíková, K and Kaiserová, M and Friedecký, D and Kaňovský, P and Strnad, M and Matěj, R}, title = {Utilizing neurodegenerative markers for the diagnostic evaluation of amyotrophic lateral sclerosis.}, journal = {European journal of medical research}, volume = {29}, number = {1}, pages = {31}, pmid = {38184629}, issn = {2047-783X}, support = {CZ.02.1.01 / 0.0 / 0.0 / 16_019 / 0000868//European Regional Development Fund - ENOCH project/ ; NV19-04-00090//Grant Agency of the Ministry of Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Clusterin ; Delayed Diagnosis ; tau Proteins ; Biomarkers ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive deterioration of upper and lower motor neurons. A definitive diagnostic test or biomarker for ALS is currently unavailable, leading to a diagnostic delay following the onset of initial symptoms. Our study focused on cerebrospinal fluid (CSF) concentrations of clusterin, tau protein, phosphorylated tau protein, and beta-amyloid1-42 in ALS patients and a control group.

METHODS: Our study involved 54 ALS patients and 58 control subjects. Among the ALS patients, 14 presented with bulbar-onset ALS, and 40 with limb-onset ALS. We quantified biomarker levels using enzyme-linked immunosorbent assay (ELISA) and compared the results using the Mann-Whitney U-test.

RESULTS: Significant elevations in neurodegenerative markers, including tau protein (p < 0.0001), phosphorylated tau protein (p < 0.0001), and clusterin (p = 0.038), were observed in ALS patients compared to controls. Elevated levels of tau protein and phosphorylated tau protein were also noted in both bulbar and limb-onset ALS patients. However, no significant difference was observed for beta-amyloid1-42. ROC analysis identified tau protein (AUC = 0.767) and p-tau protein (AUC = 0.719) as statistically significant predictors for ALS.

CONCLUSION: Our study demonstrates that neurodegenerative marker levels indicate an ongoing neurodegenerative process in ALS. Nonetheless, the progression of ALS cannot be predicted solely based on these markers. The discovery of a specific biomarker could potentially complement existing diagnostic criteria for ALS.}, } @article {pmid38183652, year = {2024}, author = {Guise, AJ and Misal, SA and Carson, R and Chu, JH and Boekweg, H and Van Der Watt, D and Welsh, NC and Truong, T and Liang, Y and Xu, S and Benedetto, G and Gagnon, J and Payne, SH and Plowey, ED and Kelly, RT}, title = {TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis.}, journal = {Cell reports}, volume = {43}, number = {1}, pages = {113636}, pmid = {38183652}, issn = {2211-1247}, support = {R01 GM138931/GM/NIGMS NIH HHS/United States ; R33 CA225248/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; DNA-Binding Proteins/metabolism ; Motor Neurons/metabolism ; Proteome/metabolism ; Proteomics ; }, abstract = {A limitation of conventional bulk-tissue proteome studies in amyotrophic lateral sclerosis (ALS) is the confounding of motor neuron (MN) signals by admixed non-MN proteins. Here, we leverage laser capture microdissection and nanoPOTS single-cell mass spectrometry-based proteomics to query changes in protein expression in single MNs from postmortem ALS and control tissues. In a follow-up analysis, we examine the impact of stratification of MNs based on cytoplasmic transactive response DNA-binding protein 43 (TDP-43)+ inclusion pathology on the profiles of 2,238 proteins. We report extensive overlap in differentially abundant proteins identified in ALS MNs with or without overt TDP-43 pathology, suggesting early and sustained dysregulation of cellular respiration, mRNA splicing, translation, and vesicular transport in ALS. Together, these data provide insights into proteome-level changes associated with TDP-43 proteinopathy and begin to demonstrate the utility of pathology-stratified trace sample proteomics for understanding single-cell protein dynamics in human neurologic diseases.}, } @article {pmid38183365, year = {2024}, author = {Barć, K and Finsel, J and Helczyk, O and Baader, S and Aho-Özhan, H and Ludolph, AC and Lulé, D and Kuźma-Kozakiewicz, M}, title = {One third of physicians discuss exit strategies with patients with amyotrophic lateral sclerosis: Results from nationwide surveys among German and Polish neurologists.}, journal = {Brain and behavior}, volume = {14}, number = {2}, pages = {e3243}, pmid = {38183365}, issn = {2162-3279}, support = {NEEDSinALS 01ED1405//EU Joint Programme-Neurodegenerative Disease Research/ ; FTLDc O1GI1007A//Bundesministerium für Bildung und Forschung/ ; MND-Net 01GM1103A//Bundesministerium für Bildung und Forschung/ ; PaCeMed 01DS18031//Bundesministerium für Bildung und Forschung/ ; K.N.K.B.008.04//Kompetenznetzwerk Präventivmedizin Baden-Württemberg/ ; //Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)/ ; }, abstract = {OBJECTIVE: This paper examines neurologists' approaches to exit strategies (ESs), such as euthanasia and physician-assisted suicide, in patients with amyotrophic lateral sclerosis (PALS) in two European countries.

METHODS: In a nationwide anonymous survey, we collected responses from 237 Polish and 228 German neurologists, focusing on their practices and beliefs about ESs, as well as their viewpoints on life-sustaining measures (LSMs) (percutaneous endoscopic gastrostomy, non-invasive, and invasive ventilation). To analyze the data, we employed statistical methods, including Mann-Whitney U, Kruskal-Wallis, chi-square tests, Spearman's rank correlation, and multiple regression analysis.

RESULTS: One third of the neurologists initiated the discussion about ESs with PALS. Half were ready to have this conversation upon patient's request. Age, gender, religiousness, and nationality were closely associated with this approach. One in 9 neurologists received a request to terminate an LSM, whereas 1 in 10 to implement an ES. German neurologists and palliative care trainees acquired both demands more commonly. Neurologists quoted a low quality of life, decreased mood, and being a burden to the family/closest ones as primary reasons for a wish to hasten death among PALS. Although the majority expressed a willingness to terminate an LSM at a request of the patient, most opposed the legalization of euthanasia. Younger and less religious individuals were more likely to favor accepting euthanasia.

CONCLUSION: Neurologists vary significantly in their approaches to terminal care. Complex relationships exist among personal indices, shared beliefs, and current practices.}, } @article {pmid38182485, year = {2024}, author = {Mainous, RO and Dunlap, JJ and Brewer, TL}, title = {Author Response to Kesten et al's Letter to the Editor.}, journal = {Nursing outlook}, volume = {72}, number = {2}, pages = {102106}, doi = {10.1016/j.outlook.2023.102106}, pmid = {38182485}, issn = {1528-3968}, } @article {pmid38182429, year = {2024}, author = {Lee, YJ and Rio, DC}, title = {A mutation in the low-complexity domain of splicing factor hnRNPA1 linked to amyotrophic lateral sclerosis disrupts distinct neuronal RNA splicing networks.}, journal = {Genes & development}, volume = {38}, number = {1-2}, pages = {11-30}, pmid = {38182429}, issn = {1549-5477}, support = {S10 RR026866/RR/NCRR NIH HHS/United States ; R35 GM118121/GM/NIGMS NIH HHS/United States ; S10 RR029668/RR/NCRR NIH HHS/United States ; S10 RR025622/RR/NCRR NIH HHS/United States ; R01 GM097352/GM/NIGMS NIH HHS/United States ; S10 RR027303/RR/NCRR NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/metabolism ; Mutation ; *Neurodegenerative Diseases ; RNA Splicing/genetics ; RNA Splicing Factors/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by loss of motor neurons. Human genetic studies have linked mutations in RNA-binding proteins as causative for this disease. The hnRNPA1 protein, a known pre-mRNA splicing factor, is mutated in some ALS patients. Here, two human cell models were generated to investigate how a mutation in the C-terminal low-complexity domain (LCD) of hnRNPA1 can cause splicing changes of thousands of transcripts that collectively are linked to the DNA damage response, cilium organization, and translation. We show that the hnRNPA1 D262V mutant protein binds to new binding sites on differentially spliced transcripts from genes that are linked to ALS. We demonstrate that this ALS-linked hnRNPA1 mutation alters normal RNA-dependent protein-protein interactions. Furthermore, cells expressing this hnRNPA1 mutant exhibit a cell aggregation phenotype, markedly reduced growth rates, changes in stress granule kinetics, and aberrant growth of neuronal processes. This study provides insight into how a single amino acid mutation in a splicing factor can alter RNA splicing networks of genes linked to ALS.}, } @article {pmid38181731, year = {2024}, author = {Alvarado, CX and Makarious, MB and Weller, CA and Vitale, D and Koretsky, MJ and Bandres-Ciga, S and Iwaki, H and Levine, K and Singleton, A and Faghri, F and Nalls, MA and Leonard, HL}, title = {omicSynth: An open multi-omic community resource for identifying druggable targets across neurodegenerative diseases.}, journal = {American journal of human genetics}, volume = {111}, number = {1}, pages = {150-164}, pmid = {38181731}, issn = {1537-6605}, support = {Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; ZIA AG000534/ImNIH/Intramural NIH HHS/United States ; ZIA NS003154/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics ; Community Resources ; Multiomics ; *Neurodegenerative Diseases/drug therapy/genetics ; *Parkinson Disease ; Mendelian Randomization Analysis ; }, abstract = {Treatments for neurodegenerative disorders remain rare, but recent FDA approvals, such as lecanemab and aducanumab for Alzheimer disease (MIM: 607822), highlight the importance of the underlying biological mechanisms in driving discovery and creating disease modifying therapies. The global population is aging, driving an urgent need for therapeutics that stop disease progression and eliminate symptoms. In this study, we create an open framework and resource for evidence-based identification of therapeutic targets for neurodegenerative disease. We use summary-data-based Mendelian randomization to identify genetic targets for drug discovery and repurposing. In parallel, we provide mechanistic insights into disease processes and potential network-level consequences of gene-based therapeutics. We identify 116 Alzheimer disease, 3 amyotrophic lateral sclerosis (MIM: 105400), 5 Lewy body dementia (MIM: 127750), 46 Parkinson disease (MIM: 605909), and 9 progressive supranuclear palsy (MIM: 601104) target genes passing multiple test corrections (pSMR_multi < 2.95 × 10[-6] and pHEIDI > 0.01). We created a therapeutic scheme to classify our identified target genes into strata based on druggability and approved therapeutics, classifying 41 novel targets, 3 known targets, and 115 difficult targets (of these, 69.8% are expressed in the disease-relevant cell type from single-nucleus experiments). Our novel class of genes provides a springboard for new opportunities in drug discovery, development, and repurposing in the pre-competitive space. In addition, looking at drug-gene interaction networks, we identify previous trials that may require further follow-up such as riluzole in Alzheimer disease. We also provide a user-friendly web platform to help users explore potential therapeutic targets for neurodegenerative diseases, decreasing activation energy for the community.}, } @article {pmid38181637, year = {2024}, author = {Wen, S and Fu, S and Gao, C and Lei, K and Liu, X}, title = {Generation of two induced pluripotent stem cell lines from two sporadic amyotrophic lateral sclerosis patients.}, journal = {Stem cell research}, volume = {74}, number = {}, pages = {103288}, doi = {10.1016/j.scr.2023.103288}, pmid = {38181637}, issn = {1876-7753}, mesh = {Male ; Female ; Humans ; Middle Aged ; *Induced Pluripotent Stem Cells/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Leukocytes, Mononuclear/metabolism ; Kruppel-Like Factor 4 ; Cell Differentiation ; }, abstract = {Peripheral blood mononuclear cells were obtained from two patients diagnosed with amyotrophic lateral sclerosis (ALS), a 47-year-old female and a 45-year-old male. Induced pluripotent stem cells (iPSCs) were generated using a non-integrating SeV-based method, delivering the transcription factors OCT4, SOX2, c-MYC, and KLF4. These transgene-free iPSC lines exhibited typical pluripotent cell morphology, expressed pluripotency-associated markers, and had tri-lineage differentiation potential. Both iPSC lines were free of mycoplasma contamination and displayed normal karyotypes. The availability of these two cell lines provides a promising opportunity to use sporadic ALS models for investigating the intricate pathological mechanisms of ALS.}, } @article {pmid38180612, year = {2024}, author = {Lin, CY and Wu, HE and Weng, EF and Wu, HC and Su, TP and Wang, SM}, title = {Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB.}, journal = {Molecular neurobiology}, volume = {61}, number = {8}, pages = {5282-5294}, pmid = {38180612}, issn = {1559-1182}, mesh = {*Sigma-1 Receptor ; *Fluvoxamine/pharmacology ; *Receptors, sigma/metabolism ; *Autophagy/drug effects ; *Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Humans ; *Active Transport, Cell Nucleus/drug effects ; Animals ; Mice ; Cell Nucleus/metabolism/drug effects ; C9orf72 Protein/metabolism/genetics ; Cell Line ; }, abstract = {Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alzheimer's disease. Nevertheless, the mechanisms underlying Sigma-1R activation and its effect on (G4C2)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and stabilize the protein expression of Pom121 in (G4C2)31-RNA-expressing NSC34 cells, leading to increased colocalization at the nuclear envelope. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In C9orf72-ALS, the nuclear translocation of TFEB autophagy factor decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted the shuttling of TFEB into the nucleus and elevated the expression of LC3-II compared to the overexpression of (G4C2)31-RNA alone. Additionally, even when used alone, fluvoxamine increases Pom121 expression and TFEB translocation. To summarize, fluvoxamine may act as a promising repurposed medicine for patients with C9orf72-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (G4C2)31-RNA-expressing NSC34 cells.}, } @article {pmid38180358, year = {2024}, author = {Ferguson, R and van Es, MA and van den Berg, LH and Subramanian, V}, title = {Neural stem cell homeostasis is affected in cortical organoids carrying a mutation in Angiogenin.}, journal = {The Journal of pathology}, volume = {262}, number = {4}, pages = {410-426}, doi = {10.1002/path.6244}, pmid = {38180358}, issn = {1096-9896}, support = {084562/Z/07/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics/pathology ; *Neural Stem Cells/metabolism ; Mutation ; Homeostasis ; *Ribonuclease, Pancreatic ; }, abstract = {Mutations in Angiogenin (ANG) and TARDBP encoding the 43 kDa transactive response DNA binding protein (TDP-43) are associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). ANG is neuroprotective and plays a role in stem cell dynamics in the haematopoietic system. We obtained skin fibroblasts from members of an ALS-FTD family, one with mutation in ANG, one with mutation in both TARDBP and ANG, and one with neither mutation. We reprogrammed these fibroblasts to induced pluripotent stem cells (iPSCs) and generated cortical organoids as well as induced stage-wise differentiation of the iPSCs to neurons. Using these two approaches we investigated the effects of FTD-associated mutations in ANG and TARDBP on neural precursor cells, neural differentiation, and response to stress. We observed striking neurodevelopmental defects such as abnormal and persistent rosettes in the organoids accompanied by increased self-renewal of neural precursor cells. There was also a propensity for differentiation to later-born neurons. In addition, cortical neurons showed increased susceptibility to stress, which is exacerbated in neurons carrying mutations in both ANG and TARDBP. The cortical organoids and neurons generated from patient-derived iPSCs carrying ANG and TARDBP gene variants recapitulate dysfunctions characteristic of frontotemporal lobar degeneration observed in FTD patients. These dysfunctions were ameliorated upon treatment with wild type ANG. In addition to its well-established role during the stress response of mature neurons, ANG also appears to play a role in neural progenitor dynamics. This has implications for neurogenesis and may indicate that subtle developmental defects play a role in disease susceptibility or onset. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.}, } @article {pmid38179776, year = {2023}, author = {Yang, EJ and Lee, SH}, title = {Anti-Inflammatory Effects of Chaenomeles sinensis Extract in an ALS Animal Model.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {28}, number = {12}, pages = {326}, doi = {10.31083/j.fbl2812326}, pmid = {38179776}, issn = {2768-6698}, support = {NRF-2020R1A2C2006703//National Research Foundation of Korea, South Korea/ ; KSN2212010//KIOM, South Korea/ ; C18040//KIOM, South Korea/ ; }, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; Mice, Transgenic ; Disease Models, Animal ; Spinal Cord ; *Rosaceae/chemistry ; Antioxidants/pharmacology/therapeutic use ; Plant Extracts/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a systemic disease with multiple pathological effects, including neuroinflammation, oxidative stress, autophagy, mitochondrial dysfunction, and endoplasmic reticulum stress. Despite many studies seeking to identify and develop effective therapies, effective ALS treatment has yet to be approved. Hence, patients with ALS ultimately experience muscle atrophy and loss of motor neurons. Herbal medicines have been used to treat numerous diseases by modulating multiple biological processes and exerting pharmacological effects, including anti-inflammatory and antioxidant properties. In particular, Chaenomeles sinensis Koehne (CS) exhibits anti-hyperuricemic and nephroprotective effects and is used to treat anaphylaxis, viral infections, and neurodegenerative diseases, such as Alzheimer's disease. This study monitored the effects of CS supplementation on muscle function and motor neurons in hSOD1G93A mice, an established ALS animal model.

METHODS: Body weight measurements and behavioral tests were performed; additionally, western blotting and immunohistochemistry analyses were conducted using the mice gastrocnemius, tibialis anterior, and spinal cord.

RESULTS: CS augmented anti-inflammatory and antioxidant effects in the muscle and spinal cord of hSOD1G93A mice. Furthermore, CS improved motor function and regulated autophagy in the muscles of the hSOD1G93A mice.

CONCLUSIONS: CS might represent a promising supplement for improving motor function and delaying ALS progression. However, its development for clinical use warrants further investigation.}, } @article {pmid38179454, year = {2023}, author = {Li, H and Liu, S and Zhang, K and Zhu, X and Dai, J and Lu, Y}, title = {Gut microbiome and plasma metabolome alterations in myopic mice.}, journal = {Frontiers in microbiology}, volume = {14}, number = {}, pages = {1251243}, pmid = {38179454}, issn = {1664-302X}, abstract = {BACKGROUND: Myopia is one of the most common eye diseases leading to blurred distance vision. Inflammatory diseases could trigger or exacerbate myopic changes. Although gut microbiota bacteria are associated with various inflammatory diseases, little is known about its role in myopia.

MATERIALS AND METHODS: The mice were randomly divided into control and model groups, with the model group being attached-30D lens onto the eyes for 3 weeks. Then, mouse cecal contents and plasma were collected to analyze their intestinal microbiota and plasma metabolome.

RESULTS: We identified that the microbial composition differed considerably between the myopic and non-myopic mice, with the relative abundance of Firmicutes phylum decreased obviously while that of Actinobacteria phylum was increased in myopia. Furthermore, Actinobacteria and Bifidobacterium were positively correlated with axial lengths (ALs) of eyeballs while negatively correlated with refractive diopters. Untargeted metabolomic analysis identified 141 differentially expressed metabolites, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed considerable enrichment mainly in amino acid metabolism pathways. Notably, pathways involved glutamate metabolism including "Glutamine and D-glutamate metabolism" and "Alanine, aspartate and glutamate metabolism" was changed dramatically, which presented as the concentrations of L-Glutamate and L-Glutamine decreased obviously in myopia. Interestingly, microbiome dysbiosis and metabolites alternations in myopia have a disrupting gut barrier feature. We further demonstrated that the gut barrier function was impaired in myopic mice manifesting in decreased expression of Occludin, ZO-1 and increased permeation of FITC-dextran.

DISCUSSION: Myopic mice had obviously altered gut microbiome and metabolites profiles compared to non-myopic mice. The dysbiosis and plasma metabolomics shift in myopia had an interrupting gut barrier feature. Our study provides new insights into the possible role of the gut microbiota in myopia and reinforces the potential feasibility of microbiome-based therapies in myopia.}, } @article {pmid38179225, year = {2023}, author = {Ji, X and Walczak, P and Boltze, J}, title = {Exploring novel experimental treatments for major neurodegenerative disorders.}, journal = {Neuroprotection}, volume = {1}, number = {2}, pages = {81-83}, pmid = {38179225}, issn = {2770-730X}, support = {R01 DA056739/DA/NIDA NIH HHS/United States ; }, } @article {pmid38178841, year = {2023}, author = {Zhao, S and Chen, R and Gao, Y and Lu, Y and Bai, X and Zhang, J}, title = {Fundamental roles of the Optineurin gene in the molecular pathology of Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1319706}, pmid = {38178841}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons (MNs) in the brain and spinal cord. It is caused by multiple factors, including mutations in any one of several specific genes. Optineurin (OPTN) mutation is an essential cause of some familial and sporadic ALS. Besides, as a multifunctional protein, OPTN is highly expressed and conserved in the central nervous system. OPTN exerts its functions by interacting with various proteins, often acting as an adaptor to provide a link between two or more core proteins related to autophagy and inflammation, etc. OPTN mutation mainly results in its function deficiency, which alters these interactions, leading to functional impairment in many processes. Meanwhile, OPTN immunopositive inclusions are also confirmed in the cases of ALS due to C9ORF72, FUS, TARDBP, and SOD1 mutations. Therefore, OPTN gene may play fundamental roles in the molecular pathology of ALS in addition to OPTN mutation. In this review, we summarize the recent advances in the ALS pathology of OPTN defect, such as mitophagy disorder, neuroinflammation, neuronal axonal degeneration, vesicular transport dysfunction, etc., which will provide a reference for research on the pathogenesis and treatment of ALS.}, } @article {pmid38178788, year = {2024}, author = {Noda, I}, title = {Two-Dimensional Correlation Spectroscopy (2D-COS) Analysis of Evolving Hyperspectral Images.}, journal = {Applied spectroscopy}, volume = {}, number = {}, pages = {37028231222011}, doi = {10.1177/00037028231222011}, pmid = {38178788}, issn = {1943-3530}, abstract = {The evolutionary behavior is examined for heterogeneously distributed hyperspectral images of a simulated biological tissue sample comprising lipid-like and protein-like components during the aging process. Taking a simple planar average of a spectral image loses useful information about the spatially resolved nature of the data. In contrast, multivariate curve resolution (MCR) analysis of a spectral image at a given stage of aging produces a set of loadings of major component groups. Each loading represents the combined spectral contributions of a mixture of similar but not identical constituents (i.e., lipid-like and protein-like components). Temporal analysis of individual component groups using two-dimensional correlation spectroscopy (2D-COS) and MCR provides much-streamlined results without interferences from the overlapped contributions. Grouping of data into separate components also allows for the effective comparison of the parallel processes of lipid oxidation and protein denaturation involving a number of constituents using the heterocomponent 2D-COS analysis. The complex interplays of lipid constituents and protein secondary structures during the tissue aging process are unambiguously highlighted. The possibility of extending this approach to a much more general form of applications using a moving window analysis is also discussed.}, } @article {pmid38178578, year = {2024}, author = {Haider, R and Penumutchu, S and Boyko, S and Surewicz, WK}, title = {Phosphomimetic substitutions in TDP-43's transiently α-helical region suppress phase separation.}, journal = {Biophysical journal}, volume = {123}, number = {3}, pages = {361-373}, pmid = {38178578}, issn = {1542-0086}, support = {S10 OD024996/OD/NIH HHS/United States ; F30 AG071339/AG/NIA NIH HHS/United States ; T32 NS077888/NS/NINDS NIH HHS/United States ; RF1 AG061797/AG/NIA NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; DNA-Binding Proteins/metabolism ; *Frontotemporal Lobar Degeneration/metabolism ; Phase Separation ; Phosphorylation ; }, abstract = {Phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) is present within the aggregates of several age-related neurodegenerative disorders, such as amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Alzheimer's disease, to the point that the presence of phosphorylated TDP-43 is considered a hallmark of some of these diseases. The majority of known TDP-43 phosphorylation sites detected in amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients is located in the low-complexity domain (LCD), the same domain that has been shown to be critical for TDP-43 liquid-liquid phase separation (LLPS). However, the effect of these LCD phosphorylation sites on TDP-43 LLPS has been largely unexplored, and any work that has been done has mainly focused on sites near the C-terminal end of the LCD. Here, we used a phosphomimetic approach to explore the impact of phosphorylation at residues S332 and S333, sites located within the transiently α-helical region of TDP-43 that have been observed to be phosphorylated in disease, on protein LLPS. Our turbidimetry and fluorescence microscopy data demonstrate that these phosphomimetic substitutions greatly suppress LLPS, and solution NMR data strongly suggest that this effect is at least in part due to the loss of α-helical propensity of the phosphomimetic protein variant. We also show that the S332D and S333D substitutions slow TDP-43 LCD droplet aging and fibrillation of the protein. Overall, these findings provide a biophysical basis for understanding the effect of phosphorylation within the transiently α-helical region of TDP-43 LCD on protein LLPS and fibrillation, suggesting that phosphorylation at residues 332 and 333 is not necessarily directly related to the pathogenic process.}, } @article {pmid38178278, year = {2024}, author = {Meira, MDV and Silva, RSD and Chochinov, HM and Medeiros, MOSF and Ferreira, MMM and de Góes Salvetti, M}, title = {Effects of Dignity Therapy on individuals with amyotrophic lateral sclerosis: Case studies.}, journal = {Palliative & supportive care}, volume = {22}, number = {3}, pages = {517-525}, doi = {10.1017/S1478951523001888}, pmid = {38178278}, issn = {1478-9523}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/therapy ; Female ; Male ; Middle Aged ; Aged ; Qualitative Research ; Respect ; Personhood ; Surveys and Questionnaires ; Quality of Life/psychology ; Dignity Therapy ; }, abstract = {OBJECTIVES: To analyze the effects of Dignity Therapy (DT) on the physical, existential, and psychosocial symptoms of individuals with amyotrophic lateral sclerosis (ALS).

METHODS: This is a mixed-methods case study research that used the concurrent triangulation strategy to analyze the effects of DT on 3 individuals with ALS. Data collection included 3 instances of administering validated scales to assess multiple physical symptoms, anxiety, depression, spiritual well-being, and the Patient Dignity Inventory (PDI), followed by the implementation of DT and a semi-structured interview.

RESULTS: The scale results indicate that DT led to an improvement in the assessment of physical, social, emotional, spiritual, and existential symptoms according to the score results. It is worth noting that the patient with a recent diagnosis showed higher scores for anxiety and depression after DT. Regarding the PDI, the scores indicate improvements in the sense of dignity in all 3 cases, which aligns with the positive verbal reports after the implementation of DT.

SIGNIFICANCE OF RESULTS: This study allowed us to analyze the effects of DT on the physical, existential, and psychosocial symptoms of individuals with ALS, suggesting the potential benefits of this approach for this group of patients. Participants reported positive effects regarding pain and fatigue, could reflect on their life trajectories, and regained their value and meaning.}, } @article {pmid38178044, year = {2024}, author = {Peng, Q and Zhu, T and Huang, J and Liu, Y and Huang, J and Zhang, W}, title = {Factors and a model to predict three-month mortality in patients with acute fatty liver of pregnancy from two medical centers.}, journal = {BMC pregnancy and childbirth}, volume = {24}, number = {1}, pages = {27}, pmid = {38178044}, issn = {1471-2393}, support = {2023JJ40980//Natural Science Foundation of Hunan Province/ ; 2022JJ40789//Natural Science Foundation of Hunan Province/ ; 82301927//National Natural Science Foundation of China/ ; 82371700//National Natural Science Foundation of China/ ; }, mesh = {Female ; Humans ; Pregnancy ; *Fatty Liver/diagnosis/mortality ; Prognosis ; Retrospective Studies ; ROC Curve ; Severity of Illness Index ; *Pregnancy Complications/diagnosis/mortality ; Models, Biological ; }, abstract = {BACKGROUND: Acute fatty liver of pregnancy (AFLP) is an uncommon but potentially life-threatening complication. Lacking of prognostic factors and models renders prediction of outcomes difficult. This study aims to explore factors and develop a prognostic model to predict three-month mortality of AFLP.

METHODS: This retrospective study included 78 consecutive patients fulfilling both clinical and laboratory criteria and Swansea criteria for diagnosis of AFLP. Univariate and multivariate cox regression analyses were used to identify predictive factors of mortality. Predictive efficacy of prognostic index for AFLP (PI-AFLP) was compared with the other four liver disease models using receiver operating characteristic (ROC) curve.

RESULTS: AFLP-related three-month mortality of two medical centers was 14.10% (11/78). International normalised ratio (INR, hazard ratio [HR] = 3.446; 95% confidence interval [CI], 1.324-8.970), total bilirubin (TBIL, HR = 1.005; 95% CI, 1.000-1.010), creatine (Scr, HR = 1.007; 95% CI, 1.001-1.013), low platelet (PLT, HR = 0.964; 95% CI, 0.931-0.997) at 72 h postpartum were confirmed as significant predictors of mortality. Artificial liver support (ALS, HR = 0.123; 95% CI, 0.012-1.254) was confirmed as an effective measure to improve severe patients' prognosis. Predictive accuracy of PI-AFLP was 0.874. Area under the receiver operating characteristic curves (AUCs) of liver disease models for end-stage liver disease (MELD), MELD-Na, integrated MELD (iMELD) and pregnancy-specific liver disease (PSLD) were 0.781, 0.774, 0.744 and 0.643, respectively.

CONCLUSION: TBIL, INR, Scr and PLT at 72 h postpartum are significant predictors of three-month mortality in AFLP patients. ALS is an effective measure to improve severe patients' prognosis. PI-AFLP calculated by TBIL, INR, Scr, PLT and ALS was a sensitive and specific model to predict mortality of AFLP.}, } @article {pmid38177242, year = {2024}, author = {Shi, Y and Huang, L and Dong, H and Yang, M and Ding, W and Zhou, X and Lu, T and Liu, Z and Zhou, X and Wang, M and Zeng, B and Sun, Y and Zhong, S and Wang, B and Wang, W and Yin, C and Wang, X and Wu, Q}, title = {Decoding the spatiotemporal regulation of transcription factors during human spinal cord development.}, journal = {Cell research}, volume = {34}, number = {3}, pages = {193-213}, pmid = {38177242}, issn = {1748-7838}, support = {81891001//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32122037//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Animals ; Humans ; *Transcription Factors/genetics ; *Amyotrophic Lateral Sclerosis ; Neurogenesis ; Central Nervous System ; }, abstract = {The spinal cord is a crucial component of the central nervous system that facilitates sensory processing and motor performance. Despite its importance, the spatiotemporal codes underlying human spinal cord development have remained elusive. In this study, we have introduced an image-based single-cell transcription factor (TF) expression decoding spatial transcriptome method (TF-seqFISH) to investigate the spatial expression and regulation of TFs during human spinal cord development. By combining spatial transcriptomic data from TF-seqFISH and single-cell RNA-sequencing data, we uncovered the spatial distribution of neural progenitor cells characterized by combinatorial TFs along the dorsoventral axis, as well as the molecular and spatial features governing neuronal generation, migration, and differentiation along the mediolateral axis. Notably, we observed a sandwich-like organization of excitatory and inhibitory interneurons transiently appearing in the dorsal horns of the developing human spinal cord. In addition, we integrated data from 10× Visium to identify early and late waves of neurogenesis in the dorsal horn, revealing the formation of laminas in the dorsal horns. Our study also illuminated the spatial differences and molecular cues underlying motor neuron (MN) diversification, and the enrichment of Amyotrophic Lateral Sclerosis (ALS) risk genes in MNs and microglia. Interestingly, we detected disease-associated microglia (DAM)-like microglia groups in the developing human spinal cord, which are predicted to be vulnerable to ALS and engaged in the TYROBP causal network and response to unfolded proteins. These findings provide spatiotemporal transcriptomic resources on the developing human spinal cord and potential strategies for spinal cord injury repair and ALS treatment.}, } @article {pmid38177103, year = {2024}, author = {Bapat, O and Purimetla, T and Kruessel, S and Shah, M and Fan, R and Thum, C and Rupprecht, F and Langer, JD and Rangaraju, V}, title = {VAP spatially stabilizes dendritic mitochondria to locally support synaptic plasticity.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {205}, pmid = {38177103}, issn = {2041-1723}, mesh = {*Actins/metabolism ; *Dendritic Spines/metabolism ; Neuronal Plasticity ; Synapses/metabolism ; Mitochondria/metabolism ; }, abstract = {Synapses are pivotal sites of plasticity and memory formation. Consequently, synapses are energy consumption hotspots susceptible to dysfunction when their energy supplies are perturbed. Mitochondria are stabilized near synapses via the cytoskeleton and provide the local energy required for synaptic plasticity. However, the mechanisms that tether and stabilize mitochondria to support synaptic plasticity are unknown. We identified proteins exclusively tethering mitochondria to actin near postsynaptic spines. We find that VAP, the vesicle-associated membrane protein-associated protein implicated in amyotrophic lateral sclerosis, stabilizes mitochondria via actin near the spines. To test if the VAP-dependent stable mitochondrial compartments can locally support synaptic plasticity, we used two-photon glutamate uncaging for spine plasticity induction and investigated the induced and adjacent uninduced spines. We find VAP functions as a spatial stabilizer of mitochondrial compartments for up to ~60 min and as a spatial ruler determining the ~30 μm dendritic segment supported during synaptic plasticity.}, } @article {pmid38177100, year = {2024}, author = {Liu, ML and Ma, S and Tai, W and Zhong, X and Ni, H and Zou, Y and Wang, J and Zhang, CL}, title = {Screens in aging-relevant human ALS-motor neurons identify MAP4Ks as therapeutic targets for the disease.}, journal = {Cell death & disease}, volume = {15}, number = {1}, pages = {4}, pmid = {38177100}, issn = {2041-4889}, support = {R01 NS092616/NS/NINDS NIH HHS/United States ; R01 NS111776/NS/NINDS NIH HHS/United States ; R01 NS117065/NS/NINDS NIH HHS/United States ; R01 NS127375/NS/NINDS NIH HHS/United States ; }, mesh = {Mice ; Animals ; Adult ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Aging ; Disease Models, Animal ; Mice, Transgenic ; }, abstract = {Effective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant motor neurons, we identify a neuroprotective compound and show that MAP4Ks may serve as therapeutic targets for treating ALS. The lead compound broadly improves survival and function of motor neurons directly converted from human ALS patients. Mechanistically, it works as an inhibitor of MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, and normalizes subcellular distribution of RANGAP1 and TDP-43. Finally, in an ALS mouse model we show that inhibiting MAP4Ks preserves motor neurons and significantly extends animal lifespan.}, } @article {pmid38176936, year = {2023}, author = {Windhorst, U and Dibaj, P}, title = {Plastic Spinal Motor Circuits in Health and Disease.}, journal = {Journal of integrative neuroscience}, volume = {22}, number = {6}, pages = {167}, doi = {10.31083/j.jin2206167}, pmid = {38176936}, issn = {0219-6352}, mesh = {Animals ; Humans ; Spinal Cord ; *Amyotrophic Lateral Sclerosis ; *Muscular Atrophy, Spinal/pathology ; *Spinal Cord Injuries/pathology ; Disease Models, Animal ; *Stroke/pathology ; }, abstract = {In the past, the spinal cord was considered a hard-wired network responsible for spinal reflexes and a conduit for long-range connections. This view has changed dramatically over the past few decades. It is now recognized as a plastic structure that has the potential to adapt to changing environments. While such changes occur under physiological conditions, the most dramatic alterations take place in response to pathological events. Many of the changes that occur following such pathological events are maladaptive, but some appear to help adapt to the new conditions. Although a number of studies have been devoted to elucidating the underlying mechanisms, in humans and animal models, the etiology and pathophysiology of various diseases impacting the spinal cord are still not well understood. In this review, we summarize current understanding and outstanding challenges for a number of diseases, including spinal muscular atrophy (SMA), amyotrophic laterals sclerosis (ALS), and spinal cord injury (SCI), with occasional relations to stroke. In particular, we focus on changes resulting from SCI (and stroke), and various influencing factors such as cause, site and extent of the afflicted damage.}, } @article {pmid38175301, year = {2024}, author = {Agra Almeida Quadros, AR and Li, Z and Wang, X and Ndayambaje, IS and Aryal, S and Ramesh, N and Nolan, M and Jayakumar, R and Han, Y and Stillman, H and Aguilar, C and Wheeler, HJ and Connors, T and Lopez-Erauskin, J and Baughn, MW and Melamed, Z and Beccari, MS and Olmedo Martínez, L and Canori, M and Lee, CZ and Moran, L and Draper, I and Kopin, AS and Oakley, DH and Dickson, DW and Cleveland, DW and Hyman, BT and Das, S and Ertekin-Taner, N and Lagier-Tourenne, C}, title = {Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer's disease.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {9}, pmid = {38175301}, issn = {1432-0533}, support = {P50 AG025711/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; R01 NS080820/NS/NINDS NIH HHS/United States ; R01 AG061796/AG/NIA NIH HHS/United States ; T32 GM008666/GM/NIGMS NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; R01 NS112503/NS/NINDS NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; C06 RR016574/RR/NCRR NIH HHS/United States ; T32 AG066592/AG/NIA NIH HHS/United States ; R01 AG018023/AG/NIA NIH HHS/United States ; R38 AG065762/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; R01 AG032990/AG/NIA NIH HHS/United States ; T32 AG066596/AG/NIA NIH HHS/United States ; U19 AG074879/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; P01 AG017216/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics ; *Amyotrophic Lateral Sclerosis ; DNA-Binding Proteins/genetics ; *Frontotemporal Dementia ; *Pick Disease of the Brain ; RNA Splicing ; RNA, Messenger/genetics ; Stathmin/genetics ; }, abstract = {Nuclear clearance and cytoplasmic accumulations of the RNA-binding protein TDP-43 are pathological hallmarks in almost all patients with amyotrophic lateral sclerosis (ALS) and up to 50% of patients with frontotemporal dementia (FTD) and Alzheimer's disease. In Alzheimer's disease, TDP-43 pathology is predominantly observed in the limbic system and correlates with cognitive decline and reduced hippocampal volume. Disruption of nuclear TDP-43 function leads to abnormal RNA splicing and incorporation of erroneous cryptic exons in numerous transcripts including Stathmin-2 (STMN2, also known as SCG10) and UNC13A, recently reported in tissues from patients with ALS and FTD. Here, we identify both STMN2 and UNC13A cryptic exons in Alzheimer's disease patients, that correlate with TDP-43 pathology burden, but not with amyloid-β or tau deposits. We also demonstrate that processing of the STMN2 pre-mRNA is more sensitive to TDP-43 loss of function than UNC13A. In addition, full-length RNAs encoding STMN2 and UNC13A are suppressed in large RNA-seq datasets generated from Alzheimer's disease post-mortem brain tissue. Collectively, these results open exciting new avenues to use STMN2 and UNC13A as potential therapeutic targets in a broad range of neurodegenerative conditions with TDP-43 proteinopathy including Alzheimer's disease.}, } @article {pmid38175192, year = {2024}, author = {Wu, Z and Li, H and Zhang, Z and Su, X and Shi, H and Huang, YN}, title = {Design of Deep-Ultraviolet Zero-Order Waveplate Materials by Rational Assembly of [AlO2F4] and [SO4] Groups.}, journal = {Inorganic chemistry}, volume = {63}, number = {3}, pages = {1674-1681}, doi = {10.1021/acs.inorgchem.3c03904}, pmid = {38175192}, issn = {1520-510X}, abstract = {Zero-order waveplates are widely used in the manufacture of laser polarizer waves, which are important in polarimetry and the laser industry. However, there are still challenges in designing deep-ultraviolet (DUV) waveplate materials that satisfy large band gaps and small optical anisotropy simultaneously. Herein, three cases of aluminum sulfate fluorides: Na2AlSO4F3, Li4NH4Al(SO4)2F4, and Li6K3Al(SO4)4F4, with novel [AlSO4F3] layers or isolated [AlS2O8F4] trimers were designed and synthesized by the rational assembly of [AlO2F4] and [SO4] groups through a hydrothermal method. Experiments and theoretical calculations imply that these three possess short cutoff edges (λ < 200 nm) and small birefringence (0.0014-0.0076 @ 1064 nm), which fulfils the prerequisite for potential DUV zero-order waveplate materials. This work extends the exploration of DUV zero-order waveplate materials to the aluminum sulfate fluoride systems.}, } @article {pmid38174670, year = {2023}, author = {Maksymowicz-Śliwińska, A and Lulé, D and Nieporęcki, K and Ciećwierska, K and Ludolph, AC and Kuźma-Kozakiewicz, M}, title = {Attitudes of caregivers towards prolonging and shortening life in advanced stages of amyotrophic lateral sclerosis.}, journal = {Folia neuropathologica}, volume = {61}, number = {4}, pages = {349-359}, doi = {10.5114/fn.2023.130444}, pmid = {38174670}, issn = {1509-572X}, mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/therapy ; Quality of Life ; Caregivers ; Death ; Disease Progression ; }, abstract = {INTRODUCTION: Inevitable disease progression in amyotrophic lateral sclerosis (ALS) forces patients and their caregivers (CGs) to reflect on end-of-life treatment. The CGs are often heavily burdened with their role of surrogate decision-makers. The aim of the study was to analyze attitudes of CGs and presumable attitudes of ALS patients from the CGs' perspective towards palliative care in advanced disease stages.

MATERIAL AND METHODS: One hundred and sixty four CGs from Germany and Poland were interviewed regarding their own preferences and patients' ideational attitudes towards life-prolonging (invasive and non-invasive ventilation, tube feeding) and life-shortening methods (termination of measures, active measures if permitted by law). The data were correlated with patient- and CG-related factors: demographic and clinical data, care commitment, depression and quality of life (QoL).

RESULTS: The CGs were mostly female spouses of ALS patients, with secondary/higher education. Nearly 70% (81% in Poland, 57% in Germany; p = 0.0001) reported positive attitudes towards life-prolonging methods, which positively correlated with religiousness and negatively with patients' age. Approximately 40% of CGs (25% and 51% respectively; p = 0.001) reported positive attitudes towards life-shortening methods. It positively correlated with time since diagnosis and negatively with the CG's QoL, religiosity and religious/spiritual faith as factors that significantly influenced end-of-life decisions. There was a strongly positive correlation between CGs' positive attitudes towards life-shortening methods and presumed positive patients' attitudes assessed by their CGs (p < 0.000001).

CONCLUSIONS: Although attitudes towards treatment differed between countries, the CGs of ALS patients were generally positive towards life-prolonging treatment. A greater acceptance of life-shortening methods in the case of longer disease duration and poorer QoL may indicate worse coping with disease progression and weaker adaptation mechanisms in CGs compared to those previously reported in ALS patients. A close resemblance of the CGs' answers to probable patients' attitudes reported by the CGs indicates that many GCs might actually express their own culturally shaped attitudes towards end-of-life methods. In light of earlier-reported discrepancies between presumed opinions of the CGs and of patients themselves, a greater focus should be placed on thorough discussions on future treatment options with ALS patients in the presence of their CGs, to stay in line with the patient's authentic will.}, } @article {pmid38174587, year = {2024}, author = {Hung, C and Patani, R}, title = {4R tau drives endolysosomal and autophagy dysfunction in frontotemporal dementia.}, journal = {Autophagy}, volume = {20}, number = {5}, pages = {1201-1202}, pmid = {38174587}, issn = {1554-8635}, support = {MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Frontotemporal Dementia/metabolism/genetics/pathology ; *Autophagy/physiology ; *tau Proteins/metabolism ; *Lysosomes/metabolism ; Endosomes/metabolism ; Neurons/metabolism ; Mutation/genetics ; Valosin Containing Protein/metabolism/genetics ; }, abstract = {Dysfunction of the neuronal endolysosome and macroautophagy/autophagy pathway is emerging as an important pathogenic mechanism in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The VCP (valosin-containing protein) gene is of significant relevance, directly implicated in both FTD and ALS. In our recent study, we used patient-derived stem cells to study the effects of VCP mutations on the endolysosome and autophagy system in human cortical excitatory neurons. We found that VCP mutations cause an abnormal accumulation of enlarged endosomes and lysosomes, accompanied by reduced autophagy flux. VCP mutations also lead to the spatial dissociation of intra-nuclear RNA-binding proteins, FUS and SFPQ, which correlates with alternative splicing of the MAPT pre-mRNA and increased tau phosphorylation. Importantly, we found that an increase in the 4R-tau isoform is sufficient to drive toxic changes in healthy human cortical excitatory neurons, including tau hyperphosphorylation, endolysosomal dysfunction, lysosomal membrane rupture, endoplasmic reticulum stress, and apoptosis. Together, our data suggest that endolysosomal and autophagy dysfunction could represent a convergent pathogenic "design principle" shared by both FTD and ALS.}, } @article {pmid38174271, year = {2024}, author = {Aguila-Rosas, J and García-Martínez, BA and Ríos, C and Diaz-Ruiz, A and Obeso, JL and Quirino-Barreda, CT and Ibarra, IA and Guzmán-Vargas, A and Lima, E}, title = {Copper release by MOF-74(Cu): a novel pharmacological alternative to diseases with deficiency of a vital oligoelement.}, journal = {RSC advances}, volume = {14}, number = {2}, pages = {855-862}, pmid = {38174271}, issn = {2046-2069}, abstract = {Copper deficiency can trigger various diseases such as Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease (PD) and even compromise the development of living beings, as manifested in Menkes disease (MS). Thus, the regulated administration (controlled release) of copper represents an alternative to reduce neuronal deterioration and prevent disease progression. Therefore, we present, to the best of our knowledge, the first experimental in vitro investigation for the kinetics of copper release from MOF-74(Cu) and its distribution in vivo after oral administration in male Wistar rats. Taking advantage of the abundance and high periodicity of copper within the crystalline-nanostructured metal-organic framework material (MOF-74(Cu)), it was possible to control the release of copper due to the partial degradation of the material. Thus, we simultaneously corroborated a low accumulation of copper in the liver (the main detoxification organ) and a slight increase of copper in the brain (striatum and midbrain), demonstrating that MOF-74(Cu) is a promising pharmacological alternative (controlled copper source) to these diseases.}, } @article {pmid38171451, year = {2024}, author = {Halon-Golabek, M and Flis, DJ and Zischka, H and Akdogan, B and Wieckowski, MR and Antosiewicz, J and Ziolkowski, W}, title = {Amyotrophic lateral sclerosis associated disturbance of iron metabolism is blunted by swim training-role of AKT signaling pathway.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1870}, number = {3}, pages = {167014}, doi = {10.1016/j.bbadis.2023.167014}, pmid = {38171451}, issn = {1879-260X}, mesh = {Mice ; Animals ; Humans ; Proto-Oncogene Proteins c-akt/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Superoxide Dismutase-1/metabolism ; *Neuroblastoma ; Signal Transduction ; Iron/metabolism ; Disease Models, Animal ; Ferritins/metabolism ; RNA-Binding Proteins/metabolism ; }, abstract = {Swim training has increased the life span of the transgenic animal model of amyotrophic lateral sclerosis (ALS). Conversely, the progress of the disease is associated with the impairment of iron metabolism and insulin signaling. We used transgenic hmSOD1 G93A (ALS model) and non-transgenic mice in the present study. The study was performed on the muscles taken from trained (ONSET and TERMINAL) and untrained animals at three stages of the disease: BEFORE, ONSET, and TERMINAL. In order to study the molecular mechanism of changes in iron metabolism, we used SH-SY5Y and C2C12 cell lines expression vector pcDNA3.1 and transiently transfected with specific siRNAs. The progress of ALS resulted in decreased P-Akt/Akt ratio, which is associated with increased proteins responsible for iron storage ferritin L, ferritin H, PCBP1, and skeletal muscle iron at ONSET. Conversely, proteins responsible for iron export- TAU significantly decrease. The training partially reverses changes in proteins responsible for iron metabolism. AKT silencing in the SH-SY5Y cell line decreased PCBP2 and ferroportin and increased ferritin L, H, PCBP1, TAU, transferrin receptor 1, and APP. Moreover, silencing APP led to an increase in ferritin L and H. Our data suggest that swim training in the mice ALS model is associated with significant changes in iron metabolism related to AKT activity. Down-regulation of AKT mainly upregulates proteins involved in iron import and storage but decreases proteins involved in iron export.}, } @article {pmid38170745, year = {2024}, author = {Aubrey, LD and Ninkina, N and Ulamec, SM and Abramycheva, NY and Vasili, E and Devine, OM and Wilkinson, M and Mackinnon, E and Limorenko, G and Walko, M and Muwanga, S and Amadio, L and Peters, OM and Illarioshkin, SN and Outeiro, TF and Ranson, NA and Brockwell, DJ and Buchman, VL and Radford, SE}, title = {Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {2}, pages = {e2309700120}, pmid = {38170745}, issn = {1091-6490}, support = {MR/T011149/1/MRC_/Medical Research Council/United Kingdom ; P40 OD018537/OD/NIH HHS/United States ; MC_PC_16030/2/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; 204963/WT_/Wellcome Trust/United Kingdom ; 204963/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Humans ; Amyloid/chemistry ; *Amyotrophic Lateral Sclerosis/genetics ; gamma-Synuclein/genetics ; alpha-Synuclein/metabolism ; *Parkinson Disease/metabolism ; Amyloidogenic Proteins ; }, abstract = {α-, β-, and γ-Synuclein are intrinsically disordered proteins implicated in physiological processes in the nervous system of vertebrates. α-synuclein (αSyn) is the amyloidogenic protein associated with Parkinson's disease and certain other neurodegenerative disorders. Intensive research has focused on the mechanisms that cause αSyn to form amyloid structures, identifying its NAC region as being necessary and sufficient for amyloid assembly. Recent work has shown that a 7-residue sequence (P1) is necessary for αSyn amyloid formation. Although γ-synuclein (γSyn) is 55% identical in sequence to αSyn and its pathological deposits are also observed in association with neurodegenerative conditions, γSyn is resilient to amyloid formation in vitro. Here, we report a rare single nucleotide polymorphism (SNP) in the SNCG gene encoding γSyn, found in two patients with amyotrophic lateral sclerosis (ALS). The SNP results in the substitution of Met38 with Ile in the P1 region of the protein. These individuals also had a second, common and nonpathological, SNP in SNCG resulting in the substitution of Glu110 with Val. In vitro studies demonstrate that the Ile38 variant accelerates amyloid fibril assembly. Contrastingly, Val110 retards fibril assembly and mitigates the effect of Ile38. Substitution of residue 38 with Leu had little effect, while Val retards, and Ala increases the rate of amyloid formation. Ile38 γSyn also results in the formation of γSyn-containing inclusions in cells. The results show how a single point substitution can enhance amyloid formation of γSyn and highlight the P1 region in driving amyloid formation in another synuclein family member.}, } @article {pmid38170440, year = {2024}, author = {Kumar, S and Mehan, S and Khan, Z and Das Gupta, G and Narula, AS}, title = {Guggulsterone Selectively Modulates STAT-3, mTOR, and PPAR-Gamma Signaling in a Methylmercury-Exposed Experimental Neurotoxicity: Evidence from CSF, Blood Plasma, and Brain Samples.}, journal = {Molecular neurobiology}, volume = {61}, number = {8}, pages = {5161-5193}, pmid = {38170440}, issn = {1559-1182}, support = {DST-SERB//DST-SERB, Govt. of India; Core Research Grant/ ; Govt. of India; Core Research Grant - CRG/2021/001009//DST-SERB, Govt. of India; Core Research Grant/ ; }, mesh = {Animals ; *TOR Serine-Threonine Kinases/metabolism ; *PPAR gamma/metabolism ; *STAT3 Transcription Factor/metabolism ; *Methylmercury Compounds/toxicity ; Male ; *Brain/drug effects/pathology/metabolism ; *Signal Transduction/drug effects ; Rats ; *Pregnenediones/pharmacology ; Rats, Wistar ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a paralytic disease that damages the brain and spinal cord motor neurons. Several clinical and preclinical studies have found that methylmercury (MeHg[+]) causes ALS. In ALS, MeHg[+]-induced neurotoxicity manifests as oligodendrocyte destruction; myelin basic protein (MBP) deficiency leads to axonal death. ALS development has been connected to an increase in signal transducer and activator of transcription-3 (STAT-3), a mammalian target of rapamycin (mTOR), and a decrease in peroxisome proliferator-activated receptor (PPAR)-gamma. Guggulsterone (GST), a plant-derived chemical produced from Commiphorawhighitii resin, has been found to protect against ALS by modulating these signaling pathways. Vitamin D3 (VitD3) deficiency has been related to oligodendrocyte precursor cells (OPC) damage, demyelination, and white matter deterioration, which results in motor neuron death. As a result, the primary goal of this work was to investigate the therapeutic potential of GST by altering STAT-3, mTOR, and PPAR-gamma levels in a MeHg[+]-exposed experimental model of ALS in adult rats. The GST30 and 60 mg/kg oral treatments significantly improved the behavioral, motor, and cognitive dysfunctions and increased remyelination, as proven by the Luxol Fast Blue stain (LFB), and reduced neuroinflammation as measured by histological examinations. Furthermore, the co-administration of VitD3 exhibits moderate efficacy when administered in combination with GST60. Our results show that GST protects neurons by decreasing STAT-3 and mTOR levels while increasing PPAR-gamma protein levels in ALS rats.}, } @article {pmid38170217, year = {2024}, author = {Zhu, Y and Burg, T and Neyrinck, K and Vervliet, T and Nami, F and Vervoort, E and Ahuja, K and Sassano, ML and Chai, YC and Tharkeshwar, AK and De Smedt, J and Hu, H and Bultynck, G and Agostinis, P and Swinnen, JV and Van Den Bosch, L and da Costa, RFM and Verfaillie, C}, title = {Disruption of MAM integrity in mutant FUS oligodendroglial progenitors from hiPSCs.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {6}, pmid = {38170217}, issn = {1432-0533}, support = {12ZG121N//Fonds Wetenschappelijk Onderzoek/ ; SBO-S001221N//Fonds Wetenschappelijk Onderzoek/ ; 12AIK24N//Fonds Wetenschappelijk Onderzoek/ ; W001422N//Fonds Wetenschappelijk Onderzoek/ ; W001422N//Fonds Wetenschappelijk Onderzoek/ ; 201908440360//China Scholarship Council/ ; C14-17-107//Universitaire Ziekenhuizen Leuven, KU Leuven/ ; C14/22/132//Universitaire Ziekenhuizen Leuven, KU Leuven/ ; ALS-OL//Fondation Thierry Latran/ ; C14/19/099//Research Council of the KU Leuven/ ; AKUL/19/34//Research Council of the KU Leuven/ ; iBOF/23/02//the ALS Liga ('A Cure for ALS')/ ; IDN/22/012//Generet Award for Rare Diseases/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; Mutation ; Oligodendroglia/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder, characterized by selective loss of motor neurons (MNs). A number of causative genetic mutations underlie the disease, including mutations in the fused in sarcoma (FUS) gene, which can lead to both juvenile and late-onset ALS. Although ALS results from MN death, there is evidence that dysfunctional glial cells, including oligodendroglia, contribute to neurodegeneration. Here, we used human induced pluripotent stem cells (hiPSCs) with a R521H or a P525L mutation in FUS and their isogenic controls to generate oligodendrocyte progenitor cells (OPCs) by inducing SOX10 expression from a TET-On SOX10 cassette. Mutant and control iPSCs differentiated efficiently into OPCs. RNA sequencing identified a myelin sheath-related phenotype in mutant OPCs. Lipidomic studies demonstrated defects in myelin-related lipids, with a reduction of glycerophospholipids in mutant OPCs. Interestingly, FUS[R521H] OPCs displayed a decrease in the phosphatidylcholine/phosphatidylethanolamine ratio, known to be associated with maintaining membrane integrity. A proximity ligation assay further indicated that mitochondria-associated endoplasmic reticulum membranes (MAM) were diminished in both mutant FUS OPCs. Moreover, both mutant FUS OPCs displayed increased susceptibility to ER stress when exposed to thapsigargin, and exhibited impaired mitochondrial respiration and reduced Ca[2+] signaling from ER Ca[2+] stores. Taken together, these results demonstrate a pathological role of mutant FUS in OPCs, causing defects in lipid metabolism associated with MAM disruption manifested by impaired mitochondrial metabolism with increased susceptibility to ER stress and with suppressed physiological Ca[2+] signaling. As such, further exploration of the role of oligodendrocyte dysfunction in the demise of MNs is crucial and will provide new insights into the complex cellular mechanisms underlying ALS.}, } @article {pmid38169680, year = {2023}, author = {Zhang, Z and Liu, N and Pan, X and Zhang, C and Yang, Y and Li, X and Shao, Y}, title = {Assessing causal associations between neurodegenerative diseases and neurological tumors with biological aging: a bidirectional Mendelian randomization study.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1321246}, pmid = {38169680}, issn = {1662-4548}, abstract = {BACKGROUND: Aging is a significant risk factor for many neurodegenerative diseases and neurological tumors. Previous studies indicate that the frailty index, facial aging, telomere length (TL), and epigenetic aging clock acceleration are commonly used biological aging proxy indicators. This study aims to comprehensively explore potential relationships between biological aging and neurodegenerative diseases and neurological tumors by integrating various biological aging proxy indicators, employing Mendelian randomization (MR) analysis.

METHODS: Two-sample bidirectional MR analyses were conducted using genome-wide association study (GWAS) data. Summary statistics for various neurodegenerative diseases and neurological tumors, along with biological aging proxy indicators, were obtained from extensive meta-analyses of GWAS. Genetic single-nucleotide polymorphisms (SNPs) associated with the exposures were used as instrumental variables, assessing causal relationships between three neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), two benign neurological tumors (vestibular schwannoma and meningioma), one malignant neurological tumor (glioma), and four biological aging indicators (frailty index, facial aging, TL, and epigenetic aging clock acceleration). Sensitivity analyses were also performed.

RESULTS: Our analysis revealed that genetically predicted longer TL reduces the risk of Alzheimer's disease but increases the risk of vestibular schwannoma and glioma (All Glioma, GBM, non-GBM). In addition, there is a suggestive causal relationship between some diseases (PD and GBM) and DNA methylation GrimAge acceleration. Causal relationships between biological aging proxy indicators and other neurodegenerative diseases and neurological tumors were not observed.

CONCLUSION: Building upon prior investigations into the causal relationships between telomeres and neurodegenerative diseases and neurological tumors, our study validates these findings using larger GWAS data and demonstrates, for the first time, that Parkinson's disease and GBM may promote epigenetic age acceleration. Our research provides new insights and evidence into the causal relationships between biological aging and the risk of neurodegenerative diseases and neurological tumors.}, } @article {pmid38168440, year = {2023}, author = {Ugalde, MV and Alecki, C and Rizwan, J and Le, P and Jacob-Tomas, S and Xu, JM and Minotti, S and Wu, T and Durham, H and Yeo, G}, title = {Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38168440}, issn = {2693-5015}, support = {RF1 MH126719/MH/NIMH NIH HHS/United States ; U41 HG009889/HG/NHGRI NIH HHS/United States ; U24 HG009889/HG/NHGRI NIH HHS/United States ; R01 HG004659/HG/NHGRI NIH HHS/United States ; R01 HG011864/HG/NHGRI NIH HHS/United States ; R01 NS103172/NS/NINDS NIH HHS/United States ; }, abstract = {Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal projections because of their polarized morphology and constant synaptic proteome remodeling. Using high-resolution fluorescence microscopy, we discovered that neurons localize a subset of chaperone mRNAs to their dendrites and use microtubule-based transport to increase this asymmetric localization following proteotoxic stress. The most abundant dendritic chaperone mRNA encodes a constitutive heat shock protein 70 family member (HSPA8). Proteotoxic stress also enhanced HSPA8 mRNA translation efficiency in dendrites. Stress-mediated HSPA8 mRNA localization to the dendrites was impaired by depleting fused in sarcoma-an amyotrophic lateral sclerosis-related protein-in cultured mouse motor neurons and expressing a pathogenic variant of heterogenous nuclear ribonucleoprotein A2/B1 in neurons derived from human induced pluripotent stem cells. These results reveal a crucial and unexpected neuronal stress response in which RNA-binding proteins increase the dendritic localization of HSPA8 mRNA to maintain proteostasis and prevent neurodegeneration.}, } @article {pmid38168426, year = {2023}, author = {Talaia, G and Bentley-DeSousa, A and Ferguson, SM}, title = {Lysosomal TBK1 Responds to Amino Acid Availability to Relieve Rab7-Dependent mTORC1 Inhibition.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38168426}, issn = {2692-8205}, support = {R01 GM105718/GM/NIGMS NIH HHS/United States ; }, abstract = {Lysosomes play a pivotal role in coordinating macromolecule degradation and regulating cell growth and metabolism. Despite substantial progress in identifying lysosomal signaling proteins, understanding the pathways that synchronize lysosome functions with changing cellular demands remains incomplete. This study uncovers a role for TANK-binding kinase 1 (TBK1), well known for its role in innate immunity and organelle quality control, in modulating lysosomal responsiveness to nutrients. Specifically, we identify a pool of TBK1 that is recruited to lysosomes in response to elevated amino acid levels. At lysosomes, this TBK1 phosphorylates Rab7 on serine 72. This is critical for alleviating Rab7-mediated inhibition of amino acid-dependent mTORC1 activation. Furthermore, a TBK1 mutant (E696K) associated with amyotrophic lateral sclerosis and frontotemporal dementia constitutively accumulates at lysosomes, resulting in elevated Rab7 phosphorylation and increased mTORC1 activation. This data establishes the lysosome as a site of amino acid regulated TBK1 signaling that is crucial for efficient mTORC1 activation. This lysosomal pool of TBK1 has broader implications for lysosome homeostasis, and its dysregulation could contribute to the pathogenesis of ALS-FTD.}, } @article {pmid38168388, year = {2023}, author = {Cheemala, A and Kimble, AL and Tyburski, JD and Leclair, NK and Zuberi, AR and Murphy, M and Jellison, ER and Reese, B and Hu, X and Lutz, CM and Yan, R and Murphy, PA}, title = {Loss of Endothelial TDP-43 Leads to Blood Brain Barrier Defects in Mouse Models of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38168388}, issn = {2692-8205}, support = {R00 HL125727/HL/NHLBI NIH HHS/United States ; K99 HL125727/HL/NHLBI NIH HHS/United States ; U54 OD020351/OD/NIH HHS/United States ; P30 CA034196/CA/NCI NIH HHS/United States ; RF1 NS117449/NS/NINDS NIH HHS/United States ; }, abstract = {Loss of nuclear TDP-43 occurs in a wide range of neurodegenerative diseases, and specific mutations in the TARDBP gene that encodes the protein are linked to familial Frontal Temporal Lobar Dementia (FTD), and Amyotrophic Lateral Sclerosis (ALS). Although the focus has been on neuronal cell dysfunction caused by TDP-43 variants, TARDBP mRNA transcripts are expressed at similar levels in brain endothelial cells (ECs). Since increased permeability across the blood brain barrier (BBB) precedes cognitive decline, we postulated that altered functions of TDP-43 in ECs contributes to BBB dysfunction in neurodegenerative disease. To test this hypothesis, we examined EC function and BBB properties in mice with either knock-in mutations found in ALS/FTLD patients (TARDBP[G348C] and GRN[R493X]) or EC-specific deletion of TDP-43 throughout the endothelium (Cdh5(PAC)CreERT2; Tardbp[ff]) or restricted to brain endothelium (Slco1c1(BAC)CreERT2; Tardbp[ff]). We found that TARDBP[G348C] mice exhibited increased permeability to 3kDa Texas Red dextran and NHS-biotin, relative to their littermate controls, which could be recapitulated in cultured brain ECs from these mice. Nuclear levels of TDP-43 were reduced in vitro and in vivo in ECs from TARDBP[G348C] mice. This coincided with a reduction in junctional proteins VE-cadherin, claudin-5 and ZO-1 in isolated ECs, supporting a cell autonomous effect on barrier function through a loss of nuclear TDP-43. We further examined two models of Tardbp deletion in ECs, and found that the loss of TDP-43 throughout the endothelium led to systemic endothelial activation and permeability. Deletion specifically within the brain endothelium acutely increased BBB permeability, and eventually led to hallmarks of FTD, including fibrin deposition, microglial and astrocyte activation, and behavioral defects. Together, these data show that TDP-43 dysfunction specifically within brain ECs would contribute to the BBB defects observed early in the progression of ALS/FTLD.}, } @article {pmid38168370, year = {2023}, author = {McCallister, TX and Lim, CKW and Terpstra, WM and Alejandra Zeballos C, M and Zhang, S and Powell, JE and Gaj, T}, title = {A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38168370}, issn = {2692-8205}, support = {R01 GM141296/GM/NIGMS NIH HHS/United States ; R01 NS123556/NS/NINDS NIH HHS/United States ; T32 EB019944/EB/NIBIB NIH HHS/United States ; U01 NS122102/NS/NINDS NIH HHS/United States ; }, abstract = {An abnormal expansion of a GGGGCC hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving transcribed forms of the repeat expansion. By utilizing a Cas13 variant with reduced collateral effects, we developed a high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to the brain of a transgenic rodent model, this Cas13-based platform effectively curbed the expression of the GGGGCC repeat-containing RNA without affecting normal C9ORF72 levels, which in turn decreased the formation of RNA foci and reversed transcriptional deficits. This high-fidelity Cas13 variant possessed improved transcriptome-wide specificity compared to its native form and mediated efficient targeting in motor neuron-like cells derived from a patient with ALS. Our results lay the foundation for the implementation of RNA-targeting CRISPR technologies for C9ORF72-linked ALS/FTD.}, } @article {pmid38168312, year = {2023}, author = {Rothstein, JD and Warlick, C and Coyne, AN}, title = {Highly variable molecular signatures of TDP-43 loss of function are associated with nuclear pore complex injury in a population study of sporadic ALS patient iPSNs.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38168312}, issn = {2692-8205}, support = {RF1 AG062171/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; R01 NS122236/NS/NINDS NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; R00 NS123242/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R01 NS132836/NS/NINDS NIH HHS/United States ; }, abstract = {The nuclear depletion and cytoplasmic aggregation of the RNA binding protein TDP-43 is widely considered a pathological hallmark of Amyotrophic Lateral Sclerosis (ALS) and related neurodegenerative diseases. Recent studies have artificially reduced TDP-43 in wildtype human neurons to replicate loss of function associated events. Although this prior work has defined a number of gene expression and mRNA splicing changes that occur in a TDP-43 dependent manner, it is unclear how these alterations relate to authentic ALS where TDP-43 is not depleted from the cell but miscompartmentalized to variable extents. Here, in this population study, we generate ~30,000 qRT-PCR data points spanning 20 genes in induced pluripotent stem cell (iPSC) derived neurons (iPSNs) from >150 control, C9orf72 ALS/FTD, and sALS patients to examine molecular signatures of TDP-43 dysfunction. This data set defines a time dependent and variable profile of individual molecular hallmarks of TDP-43 loss of function within and amongst individual patient lines. Importantly, nearly identical changes are observed in postmortem CNS tissues obtained from a subset of patients whose iPSNs were examined. Notably, these studies provide evidence that induction of nuclear pore complex (NPC) injury via reduction of the transmembrane Nup POM121 in wildtype iPSNs is sufficient to phenocopy disease associated signatured of TDP-43 loss of function thereby directly linking NPC integrity to TDP-43 loss of function. Therapeutically, we demonstrate that the expression of all mRNA species associated with TDP-43 loss of function can be restored in sALS iPSNs via two independent methods to repair NPC injury. Collectively, this data 1) represents a substantial resource for the community to examine TDP-43 loss of function events in authentic sALS patient iPSNs, 2) demonstrates that patient derived iPSNs can accurately reflect actual TDP-43 associated alterations in patient brain, and 3) that targeting NPC injury events can be preclinically and reliably accomplished in an iPSN based platform of a sporadic disease.}, } @article {pmid38168276, year = {2023}, author = {Omar, OMF and Kimble, AL and Cheemala, A and Tyburski, JD and Pandey, S and Wu, Q and Reese, B and Jellison, ER and Li, Y and Hao, B and Yan, R and Murphy, PA}, title = {Targeted inCITE-Seq Analysis Identifies the Loss of Nuclear TDP-43 in Endothelium as a Mediator of Blood Brain Barrier Signaling Pathway Dysfunction in Neurodegeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38168276}, issn = {2692-8205}, support = {K99 HL125727/HL/NHLBI NIH HHS/United States ; R00 HL125727/HL/NHLBI NIH HHS/United States ; R01 GM135592/GM/NIGMS NIH HHS/United States ; RF1 NS117449/NS/NINDS NIH HHS/United States ; }, abstract = {Despite the importance of the endothelium in the regulation of the blood brain barrier (BBB) in aging and neurodegenerative disease, difficulties in extracting endothelial cell (EC) nuclei have limited analysis of these cells. In addition, nearly all Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Degeneration (FTD), and a large portion of Alzheimer's Disease (AD) exhibit neuronal TDP-43 aggregation, leading to loss of nuclear function, but whether TDP-43 is similarly altered in human BBB ECs is unknown. Here we utilize a novel technique for the enrichment of endothelial and microglial nuclei from human cortical brain tissues, combined with inCITE-seq, to analyze nuclear proteins and RNA transcripts in a large cohort of healthy and diseased donors. Our findings reveal a unique transcriptional signature in nearly half of the capillary endothelial cells across neurodegenerative states, characterized by reduced levels of nuclear β-Catenin and canonical downstream genes, and an increase in TNF/NF-kB target genes. We demonstrate that this does not correlate with increased nuclear p65/NF-kB, but rather a specific loss of nuclear TDP-43 in these disease associated ECs. Comparative analysis in animal models with targeted disruption of TDP-43 shows that this is sufficient to drive these transcriptional alterations. This work reveals that TDP-43 is a critical governor of the transcriptional output from nuclear p65/NF-kB, which has paradoxical roles in barrier maintenance and also barrier compromising inflammatory responses, and suggests that disease specific loss in ECs contributes to BBB defects observed in the progression of AD, ALS and FTD.}, } @article {pmid38168171, year = {2023}, author = {Maltby, CJ and Krans, A and Grudzien, SJ and Palacios, Y and Muiños, J and Suárez, A and Asher, M and Khurana, V and Barmada, SJ and Dijkstra, AA and Todd, PK}, title = {AAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS Neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38168171}, issn = {2692-8205}, support = {R01 NS086810/NS/NINDS NIH HHS/United States ; P50 HD104463/HD/NICHD NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R21 NS129096/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; }, abstract = {Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late onset, recessively inherited neurodegenerative disorder caused by biallelic, non-reference pentameric AAGGG(CCCTT) repeat expansions within the second intron of replication factor complex subunit 1 (RFC1). To investigate how these repeats cause disease, we generated CANVAS patient induced pluripotent stem cell (iPSC) derived neurons (iNeurons) and utilized calcium imaging and transcriptomic analysis to define repeat-elicited gain-of-function and loss-of-function contributions to neuronal toxicity. AAGGG repeat expansions do not alter neuronal RFC1 splicing, expression, or DNA repair pathway functions. In reporter assays, AAGGG repeats are translated into pentapeptide repeat proteins that selectively accumulate in CANVAS patient brains. However, neither these proteins nor repeat RNA foci were detected in iNeurons, and overexpression of these repeats in isolation did not induce neuronal toxicity. CANVAS iNeurons exhibit defects in neuronal development and diminished synaptic connectivity that is rescued by CRISPR deletion of a single expanded allele. These phenotypic deficits were not replicated by knockdown of RFC1 in control neurons and were not rescued by ectopic expression of RFC1. These findings support a repeat-dependent but RFC1-independent cause of neuronal dysfunction in CANVAS, with important implications for therapeutic development in this currently untreatable condition.}, } @article {pmid38167886, year = {2024}, author = {Le, MUT and Park, JH and Son, JG and Shon, HK and Joh, S and Chung, CG and Cho, JH and Pirkl, A and Lee, SB and Lee, TG}, title = {Monitoring lipid alterations in Drosophila heads in an amyotrophic lateral sclerosis model with time-of-flight secondary ion mass spectrometry.}, journal = {The Analyst}, volume = {149}, number = {3}, pages = {846-858}, doi = {10.1039/d3an01670f}, pmid = {38167886}, issn = {1364-5528}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Drosophila ; Spectrometry, Mass, Secondary Ion ; Lipids ; }, abstract = {Lipid alterations in the brain are well-documented in disease and aging, but our understanding of their pathogenic implications remains incomplete. Recent technological advances in assessing lipid profiles have enabled us to intricately examine the spatiotemporal variations in lipid compositions within the complex brain characterized by diverse cell types and intricate neural networks. In this study, we coupled time-of-flight secondary ion mass spectrometry (ToF-SIMS) to an amyotrophic lateral sclerosis (ALS) Drosophila model, for the first time, to elucidate changes in the lipid landscape and investigate their potential role in the disease process, serving as a methodological and analytical complement to our prior approach that utilized matrix-assisted laser desorption/ionization mass spectrometry. The expansion of G4C2 repeats in the C9orf72 gene is the most prevalent genetic factor in ALS. Our findings indicate that expressing these repeats in fly brains elevates the levels of fatty acids, diacylglycerols, and ceramides during the early stages (day 5) of disease progression, preceding motor dysfunction. Using RNAi-based genetic screening targeting lipid regulators, we found that reducing fatty acid transport protein 1 (FATP1) and Acyl-CoA-binding protein (ACBP) alleviates the retinal degeneration caused by G4C2 repeat expression and also markedly restores the G4C2-dependent alterations in lipid profiles. Significantly, the expression of FATP1 and ACBP is upregulated in G4C2-expressing flies, suggesting their contribution to lipid dysregulation. Collectively, our novel use of ToF-SIMS with the ALS Drosophila model, alongside methodological and analytical improvements, successfully identifies crucial lipids and related genetic factors in ALS pathogenesis.}, } @article {pmid38166850, year = {2024}, author = {Yu, W and Yu, F and Li, M and Yang, F and Wang, H and Song, H and Huang, X}, title = {Quantitative association between lead exposure and amyotrophic lateral sclerosis: a Bayesian network-based predictive study.}, journal = {Environmental health : a global access science source}, volume = {23}, number = {1}, pages = {2}, pmid = {38166850}, issn = {1476-069X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Bayes Theorem ; Lead ; Retrospective Studies ; Risk Factors ; }, abstract = {BACKGROUND: Environmental lead (Pb) exposure have been suggested as a causative factor for amyotrophic lateral sclerosis (ALS). However, the role of Pb content of human body in ALS outcomes has not been quantified clearly. The purpose of this study was to apply Bayesian networks to forecast the risk of Pb exposure on the disease occurrence.

METHODS: We retrospectively collected medical records of ALS inpatients who underwent blood Pb testing, while matched controlled inpatients on age, gender, hospital ward and admission time according to the radio of 1:9. Tree Augmented Naïve Bayes (TAN), a semi-naïve Bayes classifier, was established to predict probability of ALS or controls with risk factors.

RESULTS: A total of 140 inpatients were included in this study. The whole blood Pb levels of ALS patients (57.00 μg/L) were more than twice as high as the controls (27.71 μg/L). Using the blood Pb concentrations to calculate probability of ALS, TAN produced the total coincidence rate of 90.00%. The specificity, sensitivity of Pb for ALS prediction was 0.79, or 0.74, respectively.

CONCLUSION: Therefore, these results provided quantitative evidence that Pb exposure may contribute to the development of ALS. Bayesian networks may be used to predict the ALS early onset with blood Pb levels.}, } @article {pmid38165347, year = {2024}, author = {}, title = {Observing Patterns in MRI With QSM in Patients With SOD1 Genetic ALS (5047).}, journal = {Neurology}, volume = {102}, number = {2}, pages = {e208121}, doi = {10.1212/WNL.0000000000208121}, pmid = {38165347}, issn = {1526-632X}, mesh = {Humans ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics ; Magnetic Resonance Imaging ; Patients ; }, } @article {pmid38165325, year = {2024}, author = {Spinelli, EG and Ghirelli, A and Basaia, S and Canu, E and Castelnovo, V and Cividini, C and Russo, T and Schito, P and Falzone, YM and Riva, N and Filippi, M and Agosta, F}, title = {Structural and Functional Brain Network Connectivity at Different King's Stages in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {102}, number = {2}, pages = {e207946}, pmid = {38165325}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Basal Ganglia ; Brain/diagnostic imaging ; Diffusion ; Motor Neurons ; Male ; Female ; }, abstract = {BACKGROUND AND OBJECTIVES: There is currently no validated disease-stage biomarker for amyotrophic lateral sclerosis (ALS). The identification of quantitative and reproducible markers of disease stratification in ALS is fundamental for study design definition and inclusion of homogenous patient cohorts into clinical trials. Our aim was to assess the rearrangements of structural and functional brain connectivity underlying the clinical stages of ALS, to suggest objective, reproducible measures provided by MRI connectomics mirroring disease staging.

METHODS: In this observational study, patients with ALS and healthy controls (HCs) underwent clinical evaluation and brain MRI on a 3T scanner. Patients were classified into 4 groups, according to the King's staging system. Structural and functional brain connectivity matrices were obtained using diffusion tensor and resting-state fMRI data, respectively. Whole-brain network-based statistics (NBS) analysis and comparisons of intraregional and inter-regional connectivity values using analysis of covariance models were performed between groups. Correlations between MRI and clinical/cognitive measures were tested using Pearson coefficient.

RESULTS: One hundred four patients with ALS and 61 age-matched and sex-matched HCs were included. NBS and regional connectivity analyses demonstrated a progressive decrease of intranetwork and internetwork structural connectivity of sensorimotor regions at increasing ALS stages in our cohort, compared with HCs. By contrast, functional connectivity showed divergent patterns between King's stages 3 (increase in basal ganglia and temporal circuits [p = 0.04 and p = 0.05, respectively]) and 4 (frontotemporal decrease [p = 0.03]), suggesting a complex interplay between opposite phenomena in late stages of the disease. Intraregional sensorimotor structural connectivity was correlated with ALS Functional Rating Scale-revised (ALSFRS-r) score (r = 0.31, p < 0.001) and upper motor neuron burden (r = -0.25, p = 0.01). Inter-regional frontal-sensorimotor structural connectivity was also correlated with ALSFRS-r (r = 0.24, p = 0.02). No correlations with cognitive measures were found.

DISCUSSION: MRI of the brain allows to demonstrate and quantify increasing disruption of structural connectivity involving the sensorimotor networks in ALS, mirroring disease stages. Frontotemporal functional disconnection seems to characterize only advanced disease phases. Our findings support the utility of MRI connectomics to stratify patients and stage brain pathology in ALS in a reproducible way, which may mirror clinical progression.}, } @article {pmid38165299, year = {2024}, author = {Nelke, C}, title = {Right Brain: The Strangeness of a Good Diagnosis.}, journal = {Neurology}, volume = {102}, number = {3}, pages = {e208103}, doi = {10.1212/WNL.0000000000208103}, pmid = {38165299}, issn = {1526-632X}, mesh = {Humans ; Female ; Male ; *Cerebral Cortex ; *Amyotrophic Lateral Sclerosis ; Emotions ; Face ; Fasciculation ; }, abstract = {Coffee, black with a spritz of milk. I enjoyed routine, and today was no different. We were on the 12th floor of the "tower", as our hospital is lovingly called. It was my second year of residency, and I was charged with admissions to our neurological ward. Sighing with the expectation of a long day, I walked over to our patients. The first was a woman in her sixties. She complained of trouble swallowing for the past 2 months that was getting worse. She was otherwise healthy. Asked about her social background, she looked over to her husband with an impish grin and replied: "happily married for almost thirty years." Physical examination was next. There was no apparent muscle weakness, but, strangely enough, the Babinski sign was clearly positive. Looking at her tongue, I noticed a single, delicate strain of muscle twitching. It was subtle, but impossible to miss. The twitching was adamant. It was not rhythmic, but it was unrelenting. I could not help but stare, and eventually, the patient closed her mouth, looking at me puzzled. I did not make the connection at first. But, walking back to our room, I realized that the concert of neurological dysfunction was spelling out the diagnosis. I caught myself feeling excited despite my knowledge of the potential outcome. Reporting my findings to my consultant, I remember him saying: "Sure sounds like amyotrophic lateral sclerosis, but we still have to complete our work-up." And so we did, dutifully.}, } @article {pmid38165188, year = {2023}, author = {Altuwaijri, F}, title = {Simulation-based Comparison of British and Australian Advanced Life Support Guidelines.}, journal = {The western journal of emergency medicine}, volume = {24}, number = {6}, pages = {1064-1068}, pmid = {38165188}, issn = {1936-9018}, mesh = {Humans ; Australia ; *Cardiopulmonary Resuscitation/methods ; *Emergency Medical Services ; *Heart Arrest/therapy ; }, abstract = {INTRODUCTION: Cardiac arrest is a major health concern that has been linked to poor disease outcomes. Cardiopulmonary resuscitation (CPR) is a critical protocol for restoring spontaneous circulation. The guidelines used by medical staff differ across different countries. A comparison of these guidelines can help in designing more efficient Advanced Life Support (ALS) protocols. The goal in this study was to compare the guidelines for interruption of compression during CPR (hands-off time) for ALS protocols provided by Australian and United Kingdom (UK) resuscitation councils.

METHODS: The author designed a simulation-based study using a mannequin and a defibrillator, and then recruited six participants. Three participants were certified ALS practitioners who followed UK guidelines, and three were certified ALS practitioners who followed Australian guidelines. Each participant received a random task assignment for each scenario, as a team leader, performer of cardiopulmonary resuscitation, or assistant. The team leader and the chest compressor were unaware of the shockability of each case's rhythm. Eight minutes total were spent on 10 CPR trials, each lasting four cycles. A video of the simulation was recorded for automated timekeeping. An independent sample t-test was used to compare the amount of hands-off time (seconds) throughout each cycle between two procedures. For purposes of calculating statistical significance, a 0.05 P-value was employed.

RESULTS: The mean duration of second cycle hands-off time (seconds) in the UK ALS protocol was statistically significantly longer than the Australian ALS (t = -2.100; P = 0.05). For shockable rhythms, the hands-off time of the UK ALS protocol was significantly longer than Australian ALS protocol, as reflected in the second cycle (t = -0.621; P < 0.001), third cycle (t = -8.083; P < 0.001), and fourth cycle (t = -5.814; p < 0.001), while the difference in the first cycle between groups was not statistically significant. (t = -0.258; P = 0.803).

CONCLUSION: This simulation-based study demonstrated that the UK ALS guidelines led to an increased duration of hands-off time during the second cycle. The hands-off time in the shockable rhythms was also higher during the second, third, and fourth cycles in the UK ALS protocol compared to the Australian ALS protocol. These points must be focused on in future revisions of the UK ALS guidelines. For better results, it is critical to limit hands-off time between chest compression cycles.}, } @article {pmid38162906, year = {2024}, author = {Beswick, E and Forbes, D and Johnson, M and Newton, J and Dakin, R and Glasmcher, S and Abrahams, S and Carson, A and Chandran, S and Pal, S}, title = {Non-motor symptoms in motor neuron disease: prevalence, assessment and impact.}, journal = {Brain communications}, volume = {6}, number = {1}, pages = {fcad336}, pmid = {38162906}, issn = {2632-1297}, abstract = {People with motor neuron disease often experience non-motor symptoms that may occur secondary to, or distinct from, motor degeneration and that may significantly reduce quality of life, despite being under-recognized and evaluated in clinical practice. Non-motor symptoms explored in this population-based study include pain, fatigue, gastrointestinal issues, poor sleep, low mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction. People registered on the Clinical Audit Research and Evaluation of motor neuron disease platform, the Scottish Motor Neuron Disease Register, were invited to complete a questionnaire on non-motor symptoms and a self-reported Amyotrophic Lateral Sclerosis Functional Rating Scale. The questionnaire comprised a pre-defined list of 11 potential non-motor symptoms, with the opportunity to list additional symptoms. A total of 120 individuals participated in this cross-sectional study, a 39% response rate of those sent questionnaires (n = 311); 99% of participants recruited (n = 120) experienced at least one non-motor symptom, with 72% (n = 120) reporting five or more. The symptoms most often reported were pain and fatigue (reported by 76% of participants, respectively). The symptoms reported to be most impactful were gastrointestinal issues (reported as 'severe' by 54% of participants who experienced them), followed by pain and problematic saliva (51%, respectively). Lower Amyotrophic Lateral Sclerosis Functional Rating Scale scores, indicating more advanced disease and being a long survivor [diagnosed over 8 years ago; Black et al. (Genetic epidemiology of motor neuron disease-associated variants in the Scottish population. Neurobiol Aging. 2017;51:178.e11-178.e20.)], were significantly associated with reporting more symptoms; 73% of respondents were satisfied with the frequency that non-motor symptoms were discussed in clinical care; 80% of participants indicated they believe evaluation of non-motor symptom is important to include as outcomes in trials, independent of their personal experience of these symptoms. The preferred method of assessment was completing questionnaires, at home. The overwhelming majority of people with motor neuron disease report non-motor symptoms and these frequently co-occur. Pain, fatigue, gastrointestinal issues, sleep, mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction are prevalent. People with motor neuron disease who had worse physical function and those who were long survivors were more likely to report more symptoms. Where reported, these symptoms are frequent, impactful and a priority for people with motor neuron disease in clinical care and trial design.}, } @article {pmid38162899, year = {2024}, author = {Waller, R and Bury, JJ and Appleby-Mallinder, C and Wyles, M and Loxley, G and Babel, A and Shekari, S and Kazoka, M and Wollff, H and Al-Chalabi, A and Heath, PR and Shaw, PJ and Kirby, J}, title = {Establishing mRNA and microRNA interactions driving disease heterogeneity in amyotrophic lateral sclerosis patient survival.}, journal = {Brain communications}, volume = {6}, number = {1}, pages = {fcad331}, pmid = {38162899}, issn = {2632-1297}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease, associated with the degeneration of both upper and lower motor neurons of the motor cortex, brainstem and spinal cord. Death in most patients results from respiratory failure within 3-4 years from symptom onset. However, due to disease heterogeneity some individuals survive only months from symptom onset while others live for several years. Identifying specific biomarkers that aid in establishing disease prognosis, particularly in terms of predicting disease progression, will help our understanding of amyotrophic lateral sclerosis pathophysiology and could be used to monitor a patient's response to drugs and therapeutic agents. Transcriptomic profiling technologies are continually evolving, enabling us to identify key gene changes in biological processes associated with disease. MicroRNAs are small non-coding RNAs typically associated with regulating gene expression, by degrading mRNA or reducing levels of gene expression. Being able to associate gene expression changes with corresponding microRNA changes would help to distinguish a more complex biomarker signature enabling us to address key challenges associated with complex diseases such as amyotrophic lateral sclerosis. The present study aimed to investigate the transcriptomic profile (mRNA and microRNA) of lymphoblastoid cell lines from amyotrophic lateral sclerosis patients to identify key signatures that are distinguishable in those patients who suffered a short disease duration (<12 months) (n = 22) compared with those that had a longer disease duration (>6 years) (n = 20). Transcriptional profiling of microRNA-mRNA interactions from lymphoblastoid cell lines in amyotrophic lateral sclerosis patients revealed differential expression of genes involved in cell cycle, DNA damage and RNA processing in patients with longer survival from disease onset compared with those with short survival. Understanding these particular microRNA-mRNA interactions and the pathways in which they are involved may help to distinguish potential therapeutic targets that could exert neuroprotective effects to prolong the life expectancy of amyotrophic lateral sclerosis patients.}, } @article {pmid38161591, year = {2023}, author = {Li, J and Ma, C and Huang, H and Liao, H}, title = {Amyotrophic lateral sclerosis and osteoporosis: a two-sample Mendelian randomization study.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1305040}, pmid = {38161591}, issn = {1663-4365}, abstract = {BACKGROUND: A few observational studies revealed that amyotrophic lateral sclerosis (ALS) was tightly connected with osteoporosis. However, the results of previous studies were inconsistent, and the causal effect of ALS on osteoporosis has not been investigated. To do so, the two-sample Mendelian randomization (MR) method was employed to estimate the causality.

METHODS: The instrumental variables (IVs) for ALS were selected from one GWAS summary dataset (27,205 ALS cases and 110,881 controls), and bone mineral density (BMD) in the femoral neck (FN), lumbar spine (LS), and forearm, extracted from another large-scale GWAS summary database (53,236 cases), were used as phenotypes for osteoporosis. Random-effects inverse variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode were conducted to evaluate the causality. Sensitivity analyses were further performed to explore heterogeneity and pleiotropy.

RESULTS: A total of 10 qualified SNPs were finally selected as proxies for ALS. The results of random effects from IVW revealed that ALS has no causal effect on FN-BMD (beta: -0.038, 95% CI: -0.090 to 0.015, SE: 0.027, p = 0.158), LS-BMD (beta: -0.015, 95% CI: -0.076 to 0.046, SE: 0.031, p = 0.629), and forearm BMD (beta: 0.044, 95% CI: -0.063 to 0.152, SE: 0.055, p = 0.418). These results were confirmed using the MR-Egger, weighted median, simple model, and weighted model. No heterogeneity or pleiotropy was detected (p > 0.05 for all).

CONCLUSION: Contrary to previous observational studies, our study figured out that no causal effect existed between ALS and osteoporosis. The disparity in results is probably attributed to secondary effects such as physical inactivity and muscle atrophy caused by ALS.}, } @article {pmid38160320, year = {2024}, author = {Mohanty, P and Rizuan, A and Kim, YC and Fawzi, NL and Mittal, J}, title = {A complex network of interdomain interactions underlies the conformational ensemble of monomeric TDP-43 and modulates its phase behavior.}, journal = {Protein science : a publication of the Protein Society}, volume = {33}, number = {2}, pages = {e4891}, pmid = {38160320}, issn = {1469-896X}, support = {R01 NS116176/NS/NINDS NIH HHS/United States ; /NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Protein Domains ; *Frontotemporal Dementia ; DNA-Binding Proteins/chemistry ; RNA/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a multidomain protein involved in the regulation of RNA metabolism, and its aggregates have been observed in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Numerous studies indicate TDP-43 can undergo liquid-liquid phase separation (LLPS) in vitro and is a component of biological condensates. Homo-oligomerization via the folded N-terminal domain (aa:1-77) and the conserved helical region (aa:319-341) of the disordered, C-terminal domain is found to be an important driver of TDP-43 phase separation. However, a comprehensive molecular view of TDP-43 phase separation, particularly regarding the nature of heterodomain interactions, is lacking due to the challenges associated with its stability and purification. Here, we utilize all-atom and coarse-grained (CG) molecular dynamics (MD) simulations to uncover the network of interdomain interactions implicated in TDP-43 phase separation. All-atom simulations uncovered the presence of transient, interdomain interactions involving flexible linkers, RNA-recognition motif (RRM) domains and a charged segment of disordered C-terminal domain (CTD). CG simulations indicate these inter-domain interactions which affect the conformational landscape of TDP-43 in the dilute phase are also prevalent in the condensed phase. Finally, sequence and surface charge distribution analysis coupled with all-atom simulations (at high salt) confirmed that the transient interdomain contacts are predominantly electrostatic in nature. Overall, our findings from multiscale simulations lead to a greater appreciation of the complex interaction network underlying the structural landscape and phase separation of TDP-43.}, } @article {pmid38159460, year = {2024}, author = {Soontrapa, P and Seven, NA and Liewluck, T and Cui, G and Mer, G and Milone, M}, title = {Adolescent-onset multisystem proteinopathy due to a novel VCP variant.}, journal = {Neuromuscular disorders : NMD}, volume = {34}, number = {}, pages = {89-94}, doi = {10.1016/j.nmd.2023.11.014}, pmid = {38159460}, issn = {1873-2364}, mesh = {Adolescent ; Adult ; Child ; Humans ; Cell Cycle Proteins/genetics ; *Muscular Diseases ; Mutation/genetics ; *Myositis, Inclusion Body/diagnosis/genetics/pathology ; *Osteitis Deformans/diagnosis/genetics/pathology ; *Proteostasis Deficiencies ; Valosin Containing Protein/genetics ; }, abstract = {Valosin-containing protein (VCP) pathogenic variants are the most common cause of multisystem proteinopathy presenting with inclusion body myopathy, amyotrophic lateral sclerosis/frontotemporal dementia, and Paget disease of bone in isolation or in combination. We report a patient manifesting with adolescent-onset myopathy caused by a novel heterozygous VCP variant (c.467G > T, p.Gly156Val). The myopathy manifested asymmetrically in lower limbs and extended to proximal, axial, and upper limb muscles, with loss of ambulation at age 35. Creatine kinase value was normal. Alkaline phosphatase was elevated. Electromyography detected mixed low amplitude, short duration and high amplitude, long duration motor unit potentials. Muscle biopsy showed features of inclusion body myopathy, which in combination with newly diagnosed Paget disease of bone, supported the VCP variant pathogenicity. In conclusion, VCP-multisystem proteinopathy is not only a disease of adulthood but can have a pediatric onset and should be considered in differential diagnosis of neuromuscular weakness in the pediatric population.}, } @article {pmid38159307, year = {2024}, author = {Lalechère, E and Monnet, JM and Breen, J and Fuhr, M}, title = {Assessing the potential of remote sensing-based models to predict old-growth forests on large spatiotemporal scales.}, journal = {Journal of environmental management}, volume = {351}, number = {}, pages = {119865}, doi = {10.1016/j.jenvman.2023.119865}, pmid = {38159307}, issn = {1095-8630}, mesh = {*Ecosystem ; Remote Sensing Technology ; Retrospective Studies ; *Biological Phenomena ; }, abstract = {Old-growth forests provide a broad range of ecosystem services. However, due to poor knowledge of their spatiotemporal distribution, implementing conservation and restoration strategies is challenging. The goal of this study is to compare the predictive ability of socioecological factors and different sources of remotely sensed data that determine the spatiotemporal scales at which forest maturity attributes can be predicted. We evaluated various remotely sensed data that cover a broad range of spatial (from local to global) and temporal (from current to decades) extents, from Airborne Laser Scanning (ALS), aerial multispectral and stereo-imagery, Sentinel-1, Sentinel-2 and Landsat data. Using random forests, remotely sensed data were related to a forest maturity index available in 688 forest plots across four ranges of the French Alps. Each model also includes socioecological predictors related to topography, socioeconomy, pedology and climatology. We found that the different remotely sensed data provide information on the main forest structural characteristics as defined by ALS, except for Landsat, which has a too coarse resolution, and Sentinel-1, which responds differently to vegetation structure. The predictions were quite similar considering aerial remotely sensed data, on the one hand, and satellite remotely sensed data, on the other hand. Socioecological variables are the most important predictors compared to the remote sensing metrics. In conclusion, our results indicate that a wide range of remotely sensed data can be used to study old-growth forests beyond the use of ALS and despite different abilities to predict forest structure. Accounting for socioecological predictors is indispensable to avoid a significant loss of predictive accuracy. Remotely sensed data can allow for predictions to be made at different spatiotemporal resolutions and extents. This study paves the way to large-scale monitoring of forest maturity, as well as for retrospective analyses which will show to what extent predicted maturity change at different dates.}, } @article {pmid38158701, year = {2024}, author = {Izumi, R and Ikeda, K and Niihori, T and Suzuki, N and Shirota, M and Funayama, R and Nakayama, K and Warita, H and Tateyama, M and Aoki, Y and Aoki, M}, title = {Nuclear pore pathology underlying multisystem proteinopathy type 3-related inclusion body myopathy.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {3}, pages = {577-592}, pmid = {38158701}, issn = {2328-9503}, support = {KAKENHI (20K16571)//Grant-in-Aid for Early-Career Scientists from Japan Society for the Promotion of Science (JSPS)/ ; KAKENHI (20H03586)//Grant-in-Aid for Scientific Research (B) from Japan Society for the Promotion of Science (JSPS)/ ; KAKENHI (23H02821)//Grant-in-Aid for Scientific Research (B) from Japan Society for the Promotion of Science (JSPS)/ ; KAKENHI (20K07897)//Grant-in-Aid for Scientific Research (C) from Japan Society for the Promotion of Science (JSPS)/ ; 23FC1008//Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour and Welfare Sciences Research Grants, the Ministry of Health, Labour and Welfare, Japan/ ; 23FC1010//Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour and Welfare Sciences Research Grants, the Ministry of Health, Labour and Welfare, Japan/ ; 20FC1036//Grants-in-Aid for Research on Rare and Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan/ ; 23FC1014//Grants-in-Aid for Research on Rare and Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan/ ; //Haruki ALS Research Foundation/ ; 2-5//Intramural Research Grant for Neurological and Psychiatric Disorders Provided from National Center of Neurology and Psychiatry of Japan/ ; 5-6//Intramural Research Grant for Neurological and Psychiatric Disorders Provided from National Center of Neurology and Psychiatry of Japan/ ; }, mesh = {Humans ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics ; Nuclear Pore/metabolism/pathology ; Muscle, Skeletal/metabolism ; Inclusion Bodies/metabolism/pathology ; *Muscular Diseases/metabolism ; Nuclear Pore Complex Proteins/genetics/metabolism ; }, abstract = {OBJECTIVE: Multisystem proteinopathy type 3 (MSP3) is an inherited, pleiotropic degenerative disorder caused by a mutation in heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which can affect the muscle, bone, and/or nervous system. This study aimed to determine detailed histopathological features and transcriptomic profile of HNRNPA1-mutated skeletal muscles to reveal the core pathomechanism of hereditary inclusion body myopathy (hIBM), a predominant phenotype of MSP3.

METHODS: Histopathological analyses and RNA sequencing of HNRNPA1-mutated skeletal muscles harboring a c.940G > A (p.D314N) mutation (NM_031157) were performed, and the results were compared with those of HNRNPA1-unlinked hIBM and control muscle tissues.

RESULTS: RNA sequencing revealed aberrant alternative splicing events that predominantly occurred in myofibril components and mitochondrial respiratory complex. Enrichment analyses identified the nuclear pore complex (NPC) and nucleocytoplasmic transport as suppressed pathways. These two pathways were linked by the hub genes NUP50, NUP98, NUP153, NUP205, and RanBP2. In immunohistochemistry, these nucleoporin proteins (NUPs) were mislocalized to the cytoplasm and aggregated mostly with TAR DNA-binding protein 43 kDa and, to a lesser extent, with hnRNPA1. Based on ultrastructural observation, irregularly shaped myonuclei with deep invaginations were frequently observed in atrophic fibers, consistent with the disorganization of NPCs. Additionally, regarding the expression profiles of overall NUPs, reduced expression of NUP98, NUP153, and RanBP2 was shared with HNRNPA1-unlinked hIBMs.

INTERPRETATION: The shared subset of altered NUPs in amyotrophic lateral sclerosis (ALS), as demonstrated in prior research, HNRNPA1-mutated, and HNRNPA1-unlinked hIBM muscle tissues may provide evidence regarding the underlying common nuclear pore pathology of hIBM, ALS, and MSP.}, } @article {pmid38158673, year = {2023}, author = {Luo, S and Yang, L and Ma, B and Wang, X and Lu, Y and Ma, S and Wang, D and Qu, H and Zou, L}, title = {Explore the pharmacological basis of ShengJiYiSui decoction in the treatment of amyotrophic lateral sclerosis based on network pharmacology and molecular docking technology.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {69}, number = {13}, pages = {156-161}, doi = {10.14715/cmb/2023.69.13.24}, pmid = {38158673}, issn = {1165-158X}, mesh = {Humans ; Network Pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Molecular Docking Simulation ; Phosphatidylinositol 3-Kinases/genetics ; Proto-Oncogene Proteins c-akt ; Medicine, Chinese Traditional ; Technology ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative illnesses have long been handled clinically by traditional Chinese medicine. This study is the first time to explore the pharmacological basis of application in amyotrophic lateral sclerosis (ALS) through network pharmacology and molecular docking techniques. In the present investigation, the TCMSP database and HIT2 database were examined for 9 TCM constituents of Sheng Ji Yu Sui Decoction (SJYSD), and the desired sites for the components were searched in the Drugbank database. and the Sjysd-target network was constructed. Associated targets for Amyotrophic lateral sclerosis (ALS) were then retrieved and collected in the OMIM, TTD, Genecards and DisGeNET databases. Protein-protein interaction and enrichment analysis were performed for the common targets of drugs and diseases, and molecular anchoring for the chosen core targets and related molecules was carried out. The results showed that SJYSD had 100 active compounds corresponding to 598 targets. ALS has a total of 5,325 genes. SJYSD and ALS share 163 genes, and these targets involve PI3K-AKT signaling, p53 signaling and IL-17 signaling, etc. The core components of luteolin and quercetin were discovered and may be used to treat ALS by regulating PI3K-AKT signaling pathway by HSP90AB1 protein.}, } @article {pmid38157654, year = {2024}, author = {Halseth, M and Mahoney, R and Hsiou, J and Jones, HN and Kimonis, V}, title = {Remote respiratory resistance exercise training improves respiratory function in individuals with VCP multisystem proteinopathy.}, journal = {Neuromuscular disorders : NMD}, volume = {34}, number = {}, pages = {68-74}, doi = {10.1016/j.nmd.2023.12.001}, pmid = {38157654}, issn = {1873-2364}, mesh = {Adult ; Humans ; Valosin Containing Protein/genetics ; *Resistance Training ; *Muscular Diseases ; Respiration ; *Frontotemporal Dementia ; *Amyotrophic Lateral Sclerosis ; Mutation ; Cell Cycle Proteins/genetics ; }, abstract = {Valosin-containing protein (VCP) disease is an autosomal dominant multisystem proteinopathy associated with hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Myopathy frequently results in respiratory muscle weakness, leading to early mortality due to respiratory failure. We investigated the effects of a remotely administered inspiratory muscle training program in individuals with VCP disease. Nine adults with VCP mutation-positive familial myopathy without evidence of dementia were recruited for a 40-week remotely administered study. Baseline performance was established during the first 8 weeks, followed by 32 weeks of inspiratory muscle training. The primary outcome was maximum inspiratory pressure (MIP). The secondary and exploratory endpoints included spirometry, grip strength, Inclusion Body Myopathy Functional Rating Scale (IBMFRS), Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS), timed up and go, and six-minute walk test (6MWT). During the treatment phase, MIP increased significantly by a weekly mean of 0.392cm. H2O (p=0.023). In contrast, grip strength and ALSFRS significantly decreased by 0.088 lbs. (p=0.031) and 0.043 points (p=0.004) per week, respectively, as expected from the natural progression of this disease. A remotely administered inspiratory muscle training program is therefore feasible, safe, and well-tolerated in individuals with VCP disease and results in improved inspiratory muscle strength.}, } @article {pmid38157256, year = {2023}, author = {Kang, Q and Jiang, S and Min, J and Hu, F and Xu, R}, title = {Parvalbumin interneurons dysfunction is potentially associated with FαMNs decrease and NRG1-ErbB4 signaling inhibition in spinal cord in amyotrophic lateral sclerosis.}, journal = {Aging}, volume = {15}, number = {24}, pages = {15324-15339}, pmid = {38157256}, issn = {1945-4589}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; *Interneurons/metabolism ; Matrix Metalloproteinase 9/metabolism ; Mice, Transgenic ; Parvalbumins/metabolism ; Receptor, ErbB-4/genetics/metabolism ; Neuregulin-1/genetics/metabolism ; }, abstract = {OBJECTIVE: To investigate the alteration of PV interneurons in ALS mainly focusing its dynamic changes and its relationship with motor neurons and ErbB4 signaling.

METHODS: SOD1G93A mice were used as ALS model. ALS animals were divided into different groups according to birth age: symptomatic prophase (50~60 days), symptomatic phase (90~100 days), and symptomatic progression (130~140 days). Immunofluorescence was performed for measurement of PV-positive interneurons, MMP-9, ChAT, NeuN and ErbB4. RT-qPCR and western blot were used to determine the expression of PV and MMP-9.

RESULTS: PV expression was remarkably higher in the anterior horn of gray matter compared with posterior horn and area in the middle of gray matter in control mice. In ALS mice, PV, MMP-9 and ErbB4 levels were gradually decreased along with onset. PV, MMP-9 and ErbB4 levels in ALS mice were significantly down-regulated than control mice after onset, indicating the alteration of PV interneurons, FαMNs and ErbB4. SαMNs levels only decreased remarkably at symptomatic progression in ALS mice compared with control mice, while γMNs levels showed no significant change during whole period in all mice. MMP-9 and ErbB4 were positively correlated with PV. NRG1 treatment significantly enhanced the expression of ErBb4, PV and MMP-9 in ALS mice.

CONCLUSION: PV interneurons decrease is along with FαMNs and ErbB4 decrease in ALS mice.}, } @article {pmid38156828, year = {2024}, author = {Gebrehiwet, P and Brekke, J and Rudnicki, SA and Mellor, J and Wright, J and Earl, L and Ball, N and Iqbal, H and Thomas, O and Castellano, G}, title = {Time from amyotrophic lateral sclerosis symptom onset to key disease milestones: analysis of data from a multinational cross-sectional survey.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {345-357}, doi = {10.1080/21678421.2023.2297795}, pmid = {38156828}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Disease Progression ; Cross-Sectional Studies ; Body Mass Index ; Time Factors ; }, abstract = {OBJECTIVE: To determine the average time from Amyotrophic Lateral Sclerosis (ALS) symptom onset to 11 pre-defined milestones, overall and according to ALS progression rate and geographic location.

METHODS: Data were drawn from the Adelphi Real World ALS Disease-Specific Programme[TM], a point-in-time survey of neurologists caring for people living with ALS (pALS) conducted in France, Germany, Italy, Spain, the United Kingdom and the United States from 2020-2021. ALS progression rate was calculated using time since symptom onset and ALS Functional Rating Scale Revised score.

RESULTS: Survey results were available for N = 1003 pALS (progression rate for N = 867). Mean time from symptom onset was 3.8 months to first consultation, 8.0 months to diagnosis, 16.2 months to employment change (part-time/sick leave/retirement/unemployment), 17.5 months to use of a walking aid, 18.5 months to first occurrence of caregiver support, 22.8 months to use of a wheelchair, 24.6 months to use of a communication aid, 27.3 months to use of a respiratory aid, 28.6 months to use of gastrostomy feeding, 29.7 months to use of eye gaze technology and 30.3 months to entering a care facility. Multivariate analysis indicated significant effects of fast (versus slow) progression rate on time to reach all 11 milestones, as well as US (versus European) location, age, body mass index and bulbar onset (versus other) on time to reach milestones.

CONCLUSIONS: pALS rapidly reached clinical and disease-related milestones within 30 months from symptom onset. Milestones were reached significantly faster by pALS with fast versus slow progression. Geographic differences were observed.}, } @article {pmid38156274, year = {2023}, author = {Zheng, Q and Wang, D and Lin, R and Chen, Y and Huang, H and Xu, Z and Zheng, C and Xu, W}, title = {Mendelian randomization analysis suggests no associations of human herpes viruses with amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1299122}, pmid = {38156274}, issn = {1662-4548}, abstract = {BACKGROUND: The causal associations between infections with human herpes viruses (HHVs) and amyotrophic lateral sclerosis (ALS) has been disputed. This study investigated the causal associations between herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), HHV-6, and HHV-7 infections and ALS through a bidirectional Mendelian randomization (MR) method.

METHODS: The genome-wide association studies (GWAS) database were analyzed by inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods. MR-Egger intercept test, MR-PRESSO test, Cochran's Q test, funnel plots, and leaveone-out analysis were used to verify the validity and robustness of the MR results.

RESULTS: In the forward MR analysis of the IVW, genetically predicted HSV infections [odds ratio (OR) = 0.9917; 95% confidence interval (CI): 0.9685-1.0154; p = 0.4886], HSV keratitis and keratoconjunctivitis (OR = 0.9897; 95% CI: 0.9739-1.0059; p = 0.2107), anogenital HSV infection (OR = 1.0062; 95% CI: 0.9826-1.0304; p = 0.6081), VZV IgG (OR = 1.0003; 95% CI: 0.9849-1.0160; p = 0.9659), EBV IgG (OR = 0.9509; 95% CI: 0.8879-1.0183; p = 0.1497), CMV (OR = 0.9481; 95% CI: 0.8680-1.0357; p = 0.2374), HHV-6 IgG (OR = 0.9884; 95% CI: 0.9486-1.0298; p = 0.5765) and HHV-7 IgG (OR = 0.9991; 95% CI: 0.9693-1.0299; p = 0.9557) were not causally associated with ALS. The reverse MR analysis of the IVW revealed comparable findings, indicating no link between HHVs infections and ALS. The reliability and validity of the findings were verified by the sensitivity analysis.

CONCLUSION: According to the MR study, there is no evidence of causal associations between genetically predicted HHVs (HSV, VZV, EBV, CMV, HHV-6, and HHV-7) and ALS.}, } @article {pmid38154301, year = {2024}, author = {Li, X and Gao, X and Fu, B and Lu, C and Han, H and Zhou, Q and Xu, H}, title = {Study on the toxicity prediction model ofacetolactate synthase inhibitor herbicides based on human serum albumin and superoxide dismutase binding information.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {309}, number = {}, pages = {123789}, doi = {10.1016/j.saa.2023.123789}, pmid = {38154301}, issn = {1873-3557}, mesh = {Animals ; Humans ; *Herbicides/toxicity/metabolism ; Serum Albumin, Human/metabolism ; Molecular Docking Simulation ; *Pesticides ; Protein Binding ; Enzyme Inhibitors/toxicity ; Carrier Proteins ; Superoxide Dismutase/metabolism ; Spectrometry, Fluorescence ; }, abstract = {Toxicity significantly influences the successful development of drugs. Based on the toxicity prediction method (carrier protein binding information-toxicity relationship) previously established by the our group, this paper introduces information on the interaction between pesticides and environmental markers (SOD) into the model for the first time, so that the toxicity prediction model can not only predict the toxicity of pesticides to humans and animals, but also predict the toxicity of pesticides to the environment. Firstly, the interaction of acetolactate synthase inhibitor herbicides (ALS inhibitor herbicides) with human serum albumin (HSA) and superoxide dismutase (SOD) was investigated systematically from theory combined with experiments by spectroscopy methods and molecular docking, and important fluorescence parameters were obtained. Then, the fluorescence parameters, pesticides acute toxicity LD50 and structural splitting information were used to construct predictive modeling of ALS inhibitor herbicides based on the carrier protein binding information (R[2] = 0.977) and the predictive modeling of drug acute toxicity based on carrier protein binding information and conformational relationship (R[2] = 0.991), which had effectively predicted pesticides toxicity in humans and animals. To predict potential environmental toxicity, the predictive modeling of drug acute toxicity based on superoxide dismutase binding information was established (R[2] = 0.883) by ALS inhibitor herbicides-SOD binding information, which has a good predictive ability in the potential toxicity of pesticides to the environment. This study lays the foundation for developing low toxicity pesticides.}, } @article {pmid38152653, year = {2023}, author = {Vacchiano, V and Palombo, F and Ormanbekova, D and Fiorini, C and Fiorentino, A and Caporali, L and Mastrangelo, A and Valentino, ML and Capellari, S and Liguori, R and Carelli, V}, title = {The genetic puzzle of a SOD1-patient with ocular ptosis and a motor neuron disease: a case report.}, journal = {Frontiers in genetics}, volume = {14}, number = {}, pages = {1322067}, pmid = {38152653}, issn = {1664-8021}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a complex genetic architecture, showing monogenic, oligogenic, and polygenic inheritance. In this study, we describe the case of a 71 years-old man diagnosed with ALS with atypical clinical features consisting in progressive ocular ptosis and sensorineural deafness. Genetic analyses revealed two heterozygous variants, in the SOD1 (OMIM*147450) and the TBK1 (OMIM*604834) genes respectively, and furthermore mitochondrial DNA (mtDNA) sequencing identified the homoplasmic m.14484T>C variant usually associated with Leber's Hereditary Optic Neuropathy (LHON). We discuss how all these variants may synergically impinge on mitochondrial function, possibly contributing to the pathogenic mechanisms which might ultimately lead to the neurodegenerative process, shaping the clinical ALS phenotype enriched by adjunctive clinical features.}, } @article {pmid38152548, year = {2023}, author = {Neurology, B}, title = {Retracted: Classification of Myopathy and Amyotrophic Lateral Sclerosis Electromyograms Using Bat Algorithm and Deep Neural Networks.}, journal = {Behavioural neurology}, volume = {2023}, number = {}, pages = {9769130}, pmid = {38152548}, issn = {1875-8584}, abstract = {[This retracts the article DOI: 10.1155/2022/3517872.].}, } @article {pmid38151890, year = {2024}, author = {Talebi, S and Khodagholi, F and Bahaeddin, Z and Ansari Dezfouli, M and Zeinaddini-Meymand, A and Berchi Kankam, S and Foolad, F and Alijaniha, F and Fayazi Piranghar, F}, title = {Does hazelnut consumption affect brain health and function against neurodegenerative diseases?.}, journal = {Nutritional neuroscience}, volume = {27}, number = {9}, pages = {1008-1024}, doi = {10.1080/1028415X.2023.2296164}, pmid = {38151890}, issn = {1476-8305}, mesh = {*Corylus ; Humans ; *Neurodegenerative Diseases/prevention & control ; *Brain ; Nuts ; Antioxidants/administration & dosage ; Neuroprotective Agents/administration & dosage ; Animals ; Diet ; Nutritive Value ; }, abstract = {INTRODUCTION: A healthy daily diet and consuming certain nutrients, such as polyphenols, vitamins, and unsaturated fatty acids, may help neuronal health maintenance. Polyphenolic chemicals, which have antioxidant and anti-inflammatory properties, are involved in the neuroprotective pathway. Because of their nutritional value, nuts have been shown in recent research to be helpful in neuroprotection.

OBJECTIVE: Hazelnut is often consumed worldwide in various items, including processed foods, particularly in bakery, chocolate, and confectionery products. This nut is an excellent source of vitamins, amino acids, tocopherols, phytosterols, polyphenols, minerals, and unsaturated fatty acids. Consuming hazelnut may attenuate the risk of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease due to its anti-inflammatory and anti-oxidant qualities.

RESULTS: Many documents introduce hazelnut as an excellent choice to provide neuroprotection against neurodegenerative disorders and there is some direct proof of its neuroprotective effects.

DISCUSSION: So hazelnut consumption in daily diet may reduce neurodegenerative disease risk and be advantageous in reducing the imposed costs of dealing with neurodegenerative diseases.}, } @article {pmid38151605, year = {2024}, author = {Molin, J and Hartmann, J and Pærregaard, MM and Thygesen, CB and Sillesen, AS and Raja, AA and Vøgg, ROB and Iversen, KK and Bundgaard, H and Christensen, AH}, title = {The Neonatal QRS Complex and Its Association with Left Ventricular Mass.}, journal = {Pediatric cardiology}, volume = {45}, number = {2}, pages = {248-256}, pmid = {38151605}, issn = {1432-1971}, support = {NNF20OC0065799//The Novo Nordisk Foundation/ ; Grant 0134-00363B//The Independent Research Fund Denmark/ ; }, mesh = {Male ; Infant, Newborn ; Humans ; Female ; *Hypertrophy, Left Ventricular/diagnosis ; Prospective Studies ; *Electrocardiography/methods ; Heart ; Echocardiography ; }, abstract = {To evaluate QRS complex features during the first month of life and the association with echocardiographic measurements of left ventricular mass in neonates. Prospective cohort study of neonates with electrocardiography (ECG) and echocardiography performed during the first month of life. Left ventricular mass index (LVMI) was determined by echocardiography and the correlation with electrocardiographic markers of LVMI outliers (≥ 98th percentile) were analyzed. We included 17,450 neonates (52% boys; median age at examination 11 days) and found an increase in median QRS duration and LVMI during the first month of life (54 vs. 56 ms and 24.7 vs. 28.6 g/m[2] at days 0-4 and 25-30, respectively; both p < 0.001). All investigated ECG features (QRS duration, QRS area in V1/V6, maximum amplitudes of S-V1/R-V6, and the Sokolow-Lyon voltage product) showed no to low correlation with LVMI, resulting in low sensitivities (0-9.0%), but high specificities (97.2-98.1%), and area under the curve values close to the identity line (0.49-0.61) for identifying LVMI outliers. Adjustment of outlier definition for LVMI and threshold for QRS features had no significant effect on sensitivity. We present reference values for QRS complex features and their association with LVMI in neonates from a large, unselected, population-based cohort. The QRS complex gradually evolved during the first month of life but had a low correlation with LVMI. Our results indicate a poor diagnostic value of using ECG features to identify LVMI outliers in neonates.Trial Registry Copenhagen Baby Heart, NCT02753348, https://clinicaltri-als.gov/ct2/show/NCT02753348?cond=Copenhagen+Baby+Heart&draw=2&rank=1 , deidentified individual participant data will not be made available.}, } @article {pmid38151482, year = {2024}, author = {Taha, MA and Morren, JA}, title = {The role of artificial intelligence in electrodiagnostic and neuromuscular medicine: Current state and future directions.}, journal = {Muscle & nerve}, volume = {69}, number = {3}, pages = {260-272}, doi = {10.1002/mus.28023}, pmid = {38151482}, issn = {1097-4598}, mesh = {Humans ; *Artificial Intelligence ; Machine Learning ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Brain ; Electromyography ; }, abstract = {The rapid advancements in artificial intelligence (AI), including machine learning (ML), and deep learning (DL) have ushered in a new era of technological breakthroughs in healthcare. These technologies are revolutionizing the way we utilize medical data, enabling improved disease classification, more precise diagnoses, better treatment selection, therapeutic monitoring, and highly accurate prognostication. Different ML and DL models have been used to distinguish between electromyography signals in normal individuals and those with amyotrophic lateral sclerosis and myopathy, with accuracy ranging from 67% to 99.5%. DL models have also been successfully applied in neuromuscular ultrasound, with the use of segmentation techniques achieving diagnostic accuracy of at least 90% for nerve entrapment disorders, and 87% for inflammatory myopathies. Other successful AI applications include prediction of treatment response, and prognostication including prediction of intensive care unit admissions for patients with myasthenia gravis. Despite these remarkable strides, significant knowledge, attitude, and practice gaps persist, including within the field of electrodiagnostic and neuromuscular medicine. In this narrative review, we highlight the fundamental principles of AI and draw parallels with the intricacies of human brain networks. Specifically, we explore the immense potential that AI holds for applications in electrodiagnostic studies, neuromuscular ultrasound, and other aspects of neuromuscular medicine. While there are exciting possibilities for the future, it is essential to acknowledge and understand the limitations of AI and take proactive steps to mitigate these challenges. This collective endeavor holds immense potential for the advancement of healthcare through the strategic and responsible integration of AI technologies.}, } @article {pmid38149762, year = {2024}, author = {Lopes, CS and Pronto-Laborinho, AC and Conceição, VA and Freitas, T and Matias, GL and Gromicho, M and Santos, NC and de Carvalho, M and Carvalho, FA}, title = {Erythrocytes' surface properties and stiffness predict survival and functional decline in ALS patients.}, journal = {BioFactors (Oxford, England)}, volume = {50}, number = {3}, pages = {558-571}, doi = {10.1002/biof.2030}, pmid = {38149762}, issn = {1872-8081}, support = {COVID/BD/151823/2021//Fundação para a Ciência e a Tecnologia/ ; PD/BD/135045/2017//Fundação para a Ciência e a Tecnologia/ ; PTDC/EMD-TLM/7289/2020//Fundação para a Ciência e a Tecnologia/ ; UID/BIM/50005/2019//Fundação para a Ciência e a Tecnologia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology/mortality/blood ; Female ; Middle Aged ; Male ; *Erythrocytes/metabolism/pathology ; *Microscopy, Atomic Force ; Aged ; Surface Properties ; Erythrocyte Membrane/metabolism ; Adult ; Vital Capacity ; Disease Progression ; }, abstract = {Erythrocytes play a fundamental role in oxygen delivery to tissues and binding to inflammatory mediators. Evidences suggest that dysregulated erythrocyte function could contribute to the pathophysiology of several neurodegenerative diseases. We aimed to evaluate changes in morphological, biomechanical, and biophysical properties of erythrocytes from amyotrophic lateral sclerosis (ALS) patients, as new areas of study in this disease. Blood samples were collected from ALS patients, comparing with healthy volunteers. Erythrocytes were assessed using atomic force microscopy (AFM) and zeta potential analysis. The patients' motor and respiratory functions were evaluated using the revised ALS Functional Rating Scale (ALSFRS-R) and percentage of forced vital capacity (%FVC). Patient survival was also assessed. Erythrocyte surface roughness was significantly smoother in ALS patients, and this parameter was a predictor of faster decline in ALSFRS-R scores. ALS patients exhibited higher erythrocyte stiffness, as indicated by reduced AFM tip penetration depth, which predicted a faster ALSFRS-R score and respiratory subscore decay. A lower negative charge on the erythrocyte membrane was predictor of a faster ALSFRS-R and FVC decline. Additionally, a larger erythrocyte surface area was an independent predictor of lower survival. These changes in morphological and biophysical membrane properties of ALS patients' erythrocytes, lead to increased cell stiffness and morphological variations. We speculate that these changes might precipitate motoneurons dysfunction and accelerate disease progression. Further studies should explore the molecular alterations related to these observations. Our findings may contribute to dissect the complex interplay between respiratory function, tissue hypoxia, progression rate, and survival in ALS.}, } @article {pmid38149648, year = {2024}, author = {Nicholas, R and Magliozzi, R and Marastoni, D and Howell, O and Roncaroli, F and Muraro, P and Reynolds, R and Friede, T}, title = {High Levels of Perivascular Inflammation and Active Demyelinating Lesions at Time of Death Associated with Rapidly Progressive Multiple Sclerosis Disease Course: A Retrospective Postmortem Cohort Study.}, journal = {Annals of neurology}, volume = {95}, number = {4}, pages = {706-719}, doi = {10.1002/ana.26870}, pmid = {38149648}, issn = {1531-8249}, mesh = {Humans ; *Multiple Sclerosis/pathology ; Cohort Studies ; Retrospective Studies ; Inflammation/complications ; Brain/pathology ; *Multiple Sclerosis, Chronic Progressive/pathology ; }, abstract = {OBJECTIVE: Analysis of postmortem multiple sclerosis (MS) tissues combined with in vivo disease milestones suggests that whereas perivascular white matter infiltrates are associated with demyelinating activity in the initial stages, leptomeningeal immune cell infiltration, enriched in B cells, and associated cortical lesions contribute to disease progression. We systematically examine the association of inflammatory features and white matter demyelination at postmortem with clinical milestones.

METHODS: In 269 MS brains, 20 sites were examined using immunohistochemistry for active lesions (ALs) and perivenular inflammation (PVI). In a subset of 22, a detailed count of CD20+ B cells and CD3+ T cells in PVIs was performed.

RESULTS: ALs were detected in 22%, whereas high levels of PVI were detected in 52% of cases. ALs were present in 35% of cases with high levels of PVI. Shorter time from onset of progression to death was associated with increased prevalence and higher levels of PVI (both p < 0.0001). Shorter time from onset of progression to wheelchair use was associated with higher prevalence of ALs (odds ratio [OR] = 0.921, 95% confidence interval [CI] = 0.858-0.989, p = 0.0230) and higher level of PVI (OR = 0.932, 95% CI = 0.886-0.981, p = 0.0071). High levels of PVI were associated with meningeal inflammation and increased cortical demyelination and significantly higher levels of B lymphocytes within the PVI.

INTERPRETATION: ALs, a feature of early disease stage, persist up to death in a subgroup with high levels of PVI. These features link to a rapid progressive phase and higher levels of meningeal inflammation and B-cell infiltrates, supporting the hypothesis that chronic inflammation drives progression in MS. ANN NEUROL 2024;95:706-719.}, } @article {pmid38149039, year = {2024}, author = {Ryan, M and Doherty, MA and Al Khleifat, A and Costello, E and Hengeveld, JC and Heverin, M and Al-Chalabi, A and Mclaughlin, RL and Hardiman, O}, title = {C9orf72 Repeat Expansion Discordance in 6 Multigenerational Kindreds.}, journal = {Neurology. Genetics}, volume = {10}, number = {1}, pages = {e200112}, pmid = {38149039}, issn = {2376-7839}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {BACKGROUND AND OBJECTIVES: A hexanucleotide repeat expansion in the noncoding region of the C9orf72 gene is the most common genetically identifiable cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in populations of European ancestry. Pedigrees associated with this expansion exhibit phenotypic heterogeneity and incomplete disease penetrance, the basis of which is poorly understood. Relatives of those carrying the C9orf72 repeat expansion exhibit a characteristic cognitive endophenotype independent of carrier status. To examine whether additional shared genetic or environmental risks within kindreds could compel this observation, we have conducted a detailed cross-sectional study of the inheritance within multigenerational Irish kindreds carrying the C9orf72 repeat expansion.

METHODS: One hundred thirty-one familial ALS pedigrees, 59 of which carried the C9orf72 repeat expansion (45.0% [95% CI 36.7-53.5]), were identified through the Irish population-based ALS register. C9orf72 genotyping was performed using repeat-primed PCR with amplicon fragment length analysis. Pedigrees were further investigated using SNP, targeted sequencing data, whole-exome sequencing, and whole-genome sequencing.

RESULTS: We identified 21 kindreds where at least 1 family member with ALS carried the C9orf72 repeat expansion and from whom DNA was available from multiple affected family members. Of these, 6 kindreds (28.6% [95% CI 11.8-48.3]) exhibited discordant segregation. The C9orf72 haplotype was studied in 2 families and was found to segregate with the C9orf72-positive affected relative but not the C9orf72-negative affected relative. No other ALS pathogenic variants were identified within these discordant kindreds.

DISCUSSION: Family members of kindreds associated with the C9orf72 repeat expansion may carry an increased risk of developing ALS independent of their observed carrier status. This has implications for assessment and counseling of asymptomatic individuals regarding their genetic risk.}, } @article {pmid38148722, year = {2023}, author = {Kiernan, MC and Halliday, GM and Rowe, DB and Tan, RH}, title = {The importance of patient-centred drug development for amyotrophic lateral sclerosis.}, journal = {Neuropathology and applied neurobiology}, volume = {49}, number = {6}, pages = {e12944}, doi = {10.1111/nan.12944}, pmid = {38148722}, issn = {1365-2990}, support = {//FightMND/ ; //National Health and Medical Research Council./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Drug Development ; }, } @article {pmid38148559, year = {2024}, author = {Gautam, S and Latif, S and Kang, YS}, title = {Effect of Various Pathological Conditions on Nitric Oxide Level and L-Citrulline Uptake in Motor Neuron-Like (NSC-34) Cell Lines.}, journal = {Biomolecules & therapeutics}, volume = {32}, number = {1}, pages = {154-161}, pmid = {38148559}, issn = {1976-9148}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder that causes progressive paralysis. L-Citrulline is a non-essential neutral amino acid produced by L-arginine via nitric oxide synthase (NOS). According to previous studies, the pathogenesis of ALS entails glutamate toxicity, oxidative stress, protein misfolding, and neurofilament disruption. In addition, L-citrulline prevents neuronal cell death in brain ischemia; therefore, we investigated the change in the transport of L-citrulline under various pathological conditions in a cell line model of ALS. We examined the uptake of [[14]C]L-citrulline in wild-type (hSOD1wt/WT) and mutant NSC-34/ SOD1[G93A] (MT) cell lines. The cell viability was determined via MTT assay. A transport study was performed to determine the uptake of [[14]C]L-citrulline. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed to determine the expression levels of rat large neutral amino acid transported 1 (rLAT1) in ALS cell lines. Nitric oxide (NO) assay was performed using Griess reagent. L-Citrulline had a restorative effect on glutamate induced cell death, and increased [[14]C]L-citrulline uptake and mRNA levels of the large neutral amino acid transporter (LAT1) in the glutamate-treated ALS disease model (MT). NO levels increased significantly when MT cells were pretreated with glutamate for 24 h and restored by co-treatment with L-citrulline. Co-treatment of MT cells with L-arginine, an NO donor, increased NO levels. NSC-34 cells exposed to high glucose conditions showed a significant increase in [[14]C]L-citrulline uptake and LAT1 mRNA expression levels, which were restored to normal levels upon co-treatment with unlabeled L-citrulline. In contrast, exposure of the MT cell line to tumor necrosis factor alpha, lipopolysaccharides, and hypertonic condition decreased the uptake significantly which was restored to the normal level by co-treating with unlabeled L-citrulline. L-Citrulline can restore NO levels and cellular uptake in ALS-affected cells with glutamate cytotoxicity, pro-inflammatory cytokines, or other pathological states, suggesting that L-citrulline supplementation in ALS may play a key role in providing neuroprotection.}, } @article {pmid38147116, year = {2024}, author = {Louro, H and Vettorazzi, A and López de Cerain, A and Spyropoulou, A and Solhaug, A and Straumfors, A and Behr, AC and Mertens, B and Žegura, B and Fæste, CK and Ndiaye, D and Spilioti, E and Varga, E and Dubreil, E and Borsos, E and Crudo, F and Eriksen, GS and Snapkow, I and Henri, J and Sanders, J and Machera, K and Gaté, L and Le Hegarat, L and Novak, M and Smith, NM and Krapf, S and Hager, S and Fessard, V and Kohl, Y and Silva, MJ and Dirven, H and Dietrich, J and Marko, D}, title = {Hazard characterization of Alternaria toxins to identify data gaps and improve risk assessment for human health.}, journal = {Archives of toxicology}, volume = {98}, number = {2}, pages = {425-469}, pmid = {38147116}, issn = {1432-0738}, support = {101057014//European Commission/ ; }, mesh = {Humans ; *Perylene ; Alternaria/metabolism ; *Mycotoxins/toxicity/analysis ; Mutagens/toxicity/metabolism ; Lactones/toxicity/metabolism ; Risk Assessment ; Food Contamination/analysis ; }, abstract = {Fungi of the genus Alternaria are ubiquitous plant pathogens and saprophytes which are able to grow under varying temperature and moisture conditions as well as on a large range of substrates. A spectrum of structurally diverse secondary metabolites with toxic potential has been identified, but occurrence and relative proportion of the different metabolites in complex mixtures depend on strain, substrate, and growth conditions. This review compiles the available knowledge on hazard identification and characterization of Alternaria toxins. Alternariol (AOH), its monomethylether AME and the perylene quinones altertoxin I (ATX-I), ATX-II, ATX-III, alterperylenol (ALP), and stemphyltoxin III (STTX-III) showed in vitro genotoxic and mutagenic properties. Of all identified Alternaria toxins, the epoxide-bearing analogs ATX-II, ATX-III, and STTX-III show the highest cytotoxic, genotoxic, and mutagenic potential in vitro. Under hormone-sensitive conditions, AOH and AME act as moderate xenoestrogens, but in silico modeling predicts further Alternaria toxins as potential estrogenic factors. Recent studies indicate also an immunosuppressive role of AOH and ATX-II; however, no data are available for the majority of Alternaria toxins. Overall, hazard characterization of Alternaria toxins focused, so far, primarily on the commercially available dibenzo-α-pyrones AOH and AME and tenuazonic acid (TeA). Limited data sets are available for altersetin (ALS), altenuene (ALT), and tentoxin (TEN). The occurrence and toxicological relevance of perylene quinone-based Alternaria toxins still remain to be fully elucidated. We identified data gaps on hazard identification and characterization crucial to improve risk assessment of Alternaria mycotoxins for consumers and occupationally exposed workers.}, } @article {pmid38144173, year = {2023}, author = {Simmatis, LE and Robin, J and Pommée, T and McKinlay, S and Sran, R and Taati, N and Truong, J and Koyani, B and Yunusova, Y}, title = {Validation of automated pipeline for the assessment of a motor speech disorder in amyotrophic lateral sclerosis (ALS).}, journal = {Digital health}, volume = {9}, number = {}, pages = {20552076231219102}, pmid = {38144173}, issn = {2055-2076}, support = {R01 DC013547/DC/NIDCD NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVE: Amyotrophic lateral sclerosis (ALS) frequently causes speech impairments, which can be valuable early indicators of decline. Automated acoustic assessment of speech in ALS is attractive, and there is a pressing need to validate such tools in line with best practices, including analytical and clinical validation. We hypothesized that data analysis using a novel speech assessment pipeline would correspond strongly to analyses performed using lab-standard practices and that acoustic features from the novel pipeline would correspond to clinical outcomes of interest in ALS.

METHODS: We analyzed data from three standard speech assessment tasks (i.e., vowel phonation, passage reading, and diadochokinesis) in 122 ALS patients. Data were analyzed automatically using a pipeline developed by Winterlight Labs, which yielded 53 acoustic features. First, for analytical validation, data were analyzed using a lab-standard analysis pipeline for comparison. This was followed by univariate analysis (Spearman correlations between individual features in Winterlight and in-lab datasets) and multivariate analysis (sparse canonical correlation analysis (SCCA)). Subsequently, clinical validation was performed. This included univariate analysis (Spearman correlation between automated acoustic features and clinical measures) and multivariate analysis (interpretable autoencoder-based dimensionality reduction).

RESULTS: Analytical validity was demonstrated by substantial univariate correlations (Spearman's ρ > 0.70) between corresponding pairs of features from automated and lab-based datasets, as well as interpretable SCCA feature groups. Clinical validity was supported by strong univariate correlations between automated features and clinical measures (Spearman's ρ > 0.70), as well as associations between multivariate outputs and clinical measures.

CONCLUSION: This novel, automated speech assessment feature set demonstrates substantial promise as a valid tool for analyzing impaired speech in ALS patients and for the further development of these technologies.}, } @article {pmid38143564, year = {2023}, author = {Quillet, R and Gutierrez-Mecinas, M and Polgár, E and Dickie, AC and Boyle, KA and Watanabe, M and Todd, AJ}, title = {Synaptic circuits involving gastrin-releasing peptide receptor-expressing neurons in the dorsal horn of the mouse spinal cord.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1294994}, pmid = {38143564}, issn = {1662-5099}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/V033638/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {The superficial dorsal horn (SDH) of the spinal cord contains a diverse array of neurons. The vast majority of these are interneurons, most of which are glutamatergic. These can be assigned to several populations, one of which is defined by expression of gastrin-releasing peptide receptor (GRPR). The GRPR cells are thought to be "tertiary pruritoceptors," conveying itch information to lamina I projection neurons of the anterolateral system (ALS). Surprisingly, we recently found that GRPR-expressing neurons belong to a morphological class known as vertical cells, which are believed to transmit nociceptive information to lamina I ALS cells. Little is currently known about synaptic circuits engaged by the GRPR cells. Here we combine viral-mediated expression of PSD95-tagRFP fusion protein with super-resolution microscopy to reveal sources of excitatory input to GRPR cells. We find that they receive a relatively sparse input from peptidergic and non-peptidergic nociceptors in SDH, and a limited input from A- and C-low threshold mechanoreceptors on their ventral dendrites. They receive synapses from several excitatory interneuron populations, including those defined by expression of substance P, neuropeptide FF, cholecystokinin, neurokinin B, and neurotensin. We investigated downstream targets of GRPR cells by chemogenetically exciting them and identifying Fos-positive (activated) cells. In addition to lamina I projection neurons, many ALS cells in lateral lamina V and the lateral spinal nucleus were Fos-positive, suggesting that GRPR-expressing cells target a broader population of projection neurons than was previously recognised. Our findings indicate that GRPR cells receive a diverse synaptic input from various types of primary afferent and excitatory interneuron, and that they can activate ALS cells in both superficial and deep regions of the dorsal horn.}, } @article {pmid38143551, year = {2023}, author = {Kasindi, A and Carstarphen, KJ}, title = {Bulbar Onset Amyotrophic Lateral Sclerosis in an African American Older Adult.}, journal = {Ochsner journal}, volume = {23}, number = {4}, pages = {353-356}, pmid = {38143551}, issn = {1524-5012}, abstract = {Background: Amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease, affects the motor tracts and anterior horn cells of the spinal cord, causing both upper and lower motor neuron dysfunction. ALS typically involves progressive peripheral weakness and mobility issues. Case Report: An African American male in his early 70s presented to his primary care provider (PCP) with bulbar weakness and urinary tract symptoms. At presentation, and even later in the disease course, he ambulated well and did not report any limb issues. After some months of worsening symptoms of dyspnea, dysarthria, dysphagia, and urinary incontinence, a diagnosis of ALS was made via collaborative work between the PCP, a medical student, and various medical specialists including a neurosurgeon and neurologist. Because of the absence of limb abnormalities, the patient had difficulty accepting a diagnosis of ALS, thus delaying treatment onset. Conclusion: Clinicians must consider the patient's presentation holistically so that they do not miss insidious, complex, or unique presentations. ALS can present with bulbar symptoms early in the disease course with no upper motor neuron/lower motor neuron involvement. Older adult African American males can present with ALS. Mistrust of health care systems and resistance to science based on religious beliefs can impact patient acceptance of diagnoses and engagement in treatments. Having a long-term relationship with a PCP who also represents the patient's community can influence patient willingness to accept diagnoses, especially those that are life-limiting.}, } @article {pmid38143367, year = {2024}, author = {Gao, J and Leinonen, H and Wang, EJ and Ding, M and Perry, G and Palczewski, K and Wang, X}, title = {Sex-Specific Early Retinal Dysfunction in Mutant TDP-43 Transgenic Mice.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {97}, number = {2}, pages = {927-937}, pmid = {38143367}, issn = {1875-8908}, support = {P30 EY034070/EY/NEI NIH HHS/United States ; R01 EY009339/EY/NEI NIH HHS/United States ; RF1 AG056320/AG/NIA NIH HHS/United States ; }, mesh = {Mice ; Humans ; Male ; Female ; Animals ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia ; *Neurodegenerative Diseases ; DNA-Binding Proteins/genetics/metabolism ; Retina/pathology ; }, abstract = {BACKGROUND: Increasing evidence has highlighted retinal impairments in neurodegenerative diseases. Dominant mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the accumulation of TDP-43 in the cytoplasm is a pathological hallmark of ALS, frontotemporal dementia (FTD), and many other neurodegenerative diseases.

OBJECTIVE: While homozygous transgenic mice expressing the disease-causing human TDP-43 M337V mutant (TDP-43M337V mice) experience premature death, hemizygous TDP-43M337V mice do not suffer sudden death, but they exhibit age-dependent motor-coordinative and cognitive deficits. This study aims to leverage the hemizygous TDP-43M337V mice as a valuable ALS/FTD disease model for the assessment also of retinal changes during the disease progression.

METHODS: We evaluated the retinal function of young TDP-43M337V mice by full field electroretinogram (ERG) recordings.

RESULTS: At 3-4 months of age, well before the onset of brain dysfunction at 8 months, the ERG responses were notably impaired in the retinas of young female TDP-43M337V mice in contrast to their male counterparts and age-matched non-transgenic mice. Mitochondria have been implicated as critical targets of TDP-43. Further investigation revealed that significant changes in the key regulators of mitochondrial dynamics and bioenergetics were only observed in the retinas of young female TDP-43M337V mice, while these alterations were not present in the brains of either gender.

CONCLUSIONS: Together our findings suggest a sex-specific vulnerability within the retina in the early disease stage, and highlight the importance of retinal changes and mitochondrial markers as potential early diagnostic indicators for ALS, FTD, and other TDP-43 related neurodegenerative conditions.}, } @article {pmid38143357, year = {2024}, author = {de Boer, SCM and Riedl, L and Fenoglio, C and Rue, I and Landin-Romero, R and Matis, S and Chatterton, Z and Galimberti, D and Halliday, G and Diehl-Schmid, J and Piguet, O and Pijnenburg, YAL and Ducharme, S}, title = {Rationale and Design of the "DIagnostic and Prognostic Precision Algorithm for behavioral variant Frontotemporal Dementia" (DIPPA-FTD) Study: A Study Aiming to Distinguish Early Stage Sporadic FTD from Late-Onset Primary Psychiatric Disorders.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {97}, number = {2}, pages = {963-973}, pmid = {38143357}, issn = {1875-8908}, mesh = {Humans ; *Frontotemporal Dementia/genetics ; Prospective Studies ; Prognosis ; Neuropsychological Tests ; Biomarkers ; *Acetamides ; *Isothiocyanates ; }, abstract = {BACKGROUND: The behavioral variant of frontotemporal dementia (bvFTD) is very heterogeneous in pathology, genetics, and disease course. Unlike Alzheimer's disease, reliable biomarkers are lacking and sporadic bvFTD is often misdiagnosed as a primary psychiatric disorder (PPD) due to overlapping clinical features. Current efforts to characterize and improve diagnostics are centered on the minority of genetic cases.

OBJECTIVE: The multi-center study DIPPA-FTD aims to develop diagnostic and prognostic algorithms to help distinguish sporadic bvFTD from late-onset PPD in its earliest stages.

METHODS: The prospective DIPPA-FTD study recruits participants with late-life behavioral changes, suspect for bvFTD or late-onset PPD diagnosis with a negative family history for FTD and/or amyotrophic lateral sclerosis. Subjects are invited to participate after diagnostic screening at participating memory clinics or recruited by referrals from psychiatric departments. At baseline visit, participants undergo neurological and psychiatric examination, questionnaires, neuropsychological tests, and brain imaging. Blood is obtained to investigate biomarkers. Patients are informed about brain donation programs. Follow-up takes place 10-14 months after baseline visit where all examinations are repeated. Results from the DIPPA-FTD study will be integrated in a data-driven approach to develop diagnostic and prognostic models.

CONCLUSIONS: DIPPA-FTD will make an important contribution to early sporadic bvFTD identification. By recruiting subjects with ambiguous or prodromal diagnoses, our research strategy will allow the characterization of early disease stages that are not covered in current sporadic FTD research. Results will hopefully increase the ability to diagnose sporadic bvFTD in the early stage and predict progression rate, which is pivotal for patient stratification and trial design.}, } @article {pmid38142663, year = {2024}, author = {Castro, J and Pedrosa, T and Alves, I and Simão, S and Swash, M and de Carvalho, M}, title = {A neurophysiological approach to mirror movements in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {158}, number = {}, pages = {27-34}, doi = {10.1016/j.clinph.2023.12.002}, pmid = {38142663}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Muscle, Skeletal ; *Movement Disorders ; Neurophysiology ; Transcranial Magnetic Stimulation/methods ; }, abstract = {OBJECTIVE: To investigate mirror activity in amyotrophic lateral sclerosis (ALS) patients, using a simple paradigm of signal quantification.

METHODS: Patients were asked to perform a brief isometric maximum contraction of the abductor digiti minimi (ADM) or tibialis anterior (TA) on one side, while relaxing the contralateral side of the body. Both sides were investigated. Signals were stored and analyzed offline, for quantification of electromyographic signal. Clinical signs of upper motor neuron (UMN) dysfunction, transcranial magnetic stimulation (TMS) for the upper (UL) and lower limbs (LL), the ADM ipsilateral cortical silent period (iSP) and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) cognitive scale were also investigated.

RESULTS: 42 ALS patients were included. In the 4 investigated muscles the amount of mirror activity was significantly higher than in the matched healthy group. The amount of mirror activity was similar between sides, but significantly higher in UL and LL with abnormal TMS results for ADM (p = 0.005) and TA (p = 0.002), as well as in UL with abnormal iSP values (p = 0.009). No association was found between mirror activity and clinical signs of UMN involvement.

CONCLUSIONS: Mirror activity is a common phenomenon in ALS. Mirror activity intensity corresponds to the severity of UMN dysfunction, as measured by TMS, and probably derives from the abnormal transcallosal inhibition as mirrored by iSP abnormality.

SIGNIFICANCE: Mirror activity is increased in ALS and is associated with abnormal transcallosal inhibition and UMN dysfunction.}, } @article {pmid38141357, year = {2024}, author = {Tang, M and Xiong, M and Zhou, W and Lei, J and Huang, M and Huang, C and Wang, F and Liu, J and Li, J and Xu, X}, title = {Generation of a human induced pluripotent stem cell line (SMUSHi002-A) from an ALS patient carrying a heterozygous mutation c.1562G > A in the FUS gene.}, journal = {Stem cell research}, volume = {74}, number = {}, pages = {103286}, doi = {10.1016/j.scr.2023.103286}, pmid = {38141357}, issn = {1876-7753}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Mutation/genetics ; RNA-Binding Protein FUS/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Affected patients experience gradual loss of their spinal cord and cortical motor neurons with consequent muscle weakness and emaciation, and eventual respiratory failure. The pathogenesis of ALS remains largely unknown although the FUS (sarcoma fusion gene) gene is known to be one of the major pathogenic genes. We have generated an induced pluripotent stem cell line SMUSHi002-A from an ALS patient who carries a heterozygous mutation c.1562G > A in FUS. This cell line will serve as a useful model to investigate disease pathogenesis and develop potential therapeutic approaches for ALS.}, } @article {pmid38141272, year = {2024}, author = {Sancho-Cantus, D and Cubero-Plazas, L and Privado, J and García-Iturrospe, EJA and Cañabate Ros, M and Navarro-Illana, E and Ortí, JER}, title = {Spanish adaptation and validation of the ALS Depression Inventory-12 (ADI-12) in patients with Amyotrophic Lateral Sclerosis.}, journal = {Archives of medical research}, volume = {55}, number = {1}, pages = {102936}, doi = {10.1016/j.arcmed.2023.102936}, pmid = {38141272}, issn = {1873-5487}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; Depression/diagnosis/etiology/epidemiology ; Surveys and Questionnaires ; Mood Disorders ; Reproducibility of Results ; }, abstract = {BACKGROUND: Patients with Amyotrophic Lateral Sclerosis (ALS) have a higher prevalence of mood disorders, including depression, than the general population. Non-specific measurement instruments have been used to evaluate depression in these patients, which complicates accurate diagnosis. The ALS Depression Inventory (ADI-12) exclusively assesses depressive symptoms in patients with ALS.

AIM: To adapt and validate the ADI-12 in a Spanish sample.

METHODS: A selective design was used with 74 patients with ALS, using the ADI-12 questionnaire. The original instrument was translated and back-translated into Spanish. The internal structure, temporal stability, convergent, and discriminant validity of the instrument were analyzed.

RESULTS: Two confirmatory models showed internal validity (p = 0.502 for the one-factor model, p = 0.507 for the two-factor model). The Cronbach's alpha (0.900 in the first measurement and 0.889 in the second one) indicated a high internal consistency of the test. The Pearson correlation (0.90) indicated high temporal stability. In terms of convergent validity, the ADI-12 showed moderate correlations with the Beck Anxiety Inventory (BAI) (0.51-0.58), and low correlations with time since ALS diagnosis (-0.26 to -0.27).

LIMITATIONS: The main limitation of the present study was the small sample size.

CONCLUSIONS: The ADI-12 is fitted to a single general factor of depression, and the scale shows high internal consistency and high temporal stability, therefore, its use is recommended for the diagnosis of depression in patients with ALS.}, } @article {pmid38141002, year = {2024}, author = {Muhanna, M and Lund, I and Bromberg, M and Wicks, P and Benatar, M and Barnes, B and Pierce, K and Ratner, D and Brown, A and Bertorini, T and Barkhaus, P and Carter, G and Mascias Cadavid, J and McDermott, C and Glass, JD and Pattee, G and Armon, C and Bedlack, R and Li, X}, title = {ALSUntangled #73: Lion's Mane.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {420-423}, doi = {10.1080/21678421.2023.2296557}, pmid = {38141002}, issn = {2167-9223}, mesh = {Animals ; Humans ; *Agaricales ; *Amyotrophic Lateral Sclerosis ; Europe ; *Neurodegenerative Diseases ; }, abstract = {Lion's Mane (Hericium erinaceus) has historically been used as traditional medicine in Asia and Europe for its potential benefits in fighting infection and cancer. It has gained interest in the neurodegenerative disease field because of its mechanisms of action; these include anti-inflammation, neuroprotection, and promoting neurite growth demonstrated in various cell and animal models. A very small, double-blind, placebo-controlled trial in patients with mild cognitive impairment showed a temporary improvement in cognitive function; this finding has yet to be replicated. However, there have been no studies in ALS cell or animal models or in humans with ALS. Lion's Mane appears safe and inexpensive when consumed in powder or capsule, but one anaphylactic case was reported after a patient consumed fresh Lion's Mane mushroom. Currently, we do not have enough information to support the use of Lion's Mane for treating ALS. We support further research in ALS disease models and clinical trials to study its efficacy.}, } @article {pmid38140224, year = {2023}, author = {Park, JS and Ahmad, R and Choe, K and Kang, MH and Park, TJ and Kim, MO}, title = {Immunization Effects of a Novel α-Synuclein-Based Peptide Epitope Vaccine in Parkinson's Disease-Associated Pathology.}, journal = {Vaccines}, volume = {11}, number = {12}, pages = {}, pmid = {38140224}, issn = {2076-393X}, support = {2020M3E5D9080660//National Research Foundation of Korea/ ; }, abstract = {Parkinson's disease (PD) is a chronic neurodegenerative disease that affects the central nervous system, specifically the motor system. It is mainly caused by the loss of dopamine due to the accumulation of α-synuclein (α-syn) protein in the striatum and substantia nigra pars compacta (SNpc). Previous studies have reported that immunization may be a potential preventive strategy for neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Therefore, the aim of the study was to design an α-syn specific epitope vaccine and investigate its effect in PD-related pathophysiology using an α-syn-induced mouse model. We used an in silico model to identify and design a non-toxic α-syn-based peptide epitope vaccine and, to overcome poor immunogenicity, the vaccine was coupled with immunogenic carrier proteins, i.e., ovalbumin (OVA) and keyhole limpet haemocyanin (KLH). Our results showed that vaccinated PD mouse models, especially with vaccines with carrier proteins, improved in motor functions compared with the non-vaccinated PD model. Additionally, the vaccinated groups showed increased immunoglobulin G (IgG) levels in the spleen and plasma as well as decreased interleukin-10 (IL-10) levels in the plasma. Furthermore, vaccinated groups, especially OVA and KLH groups, showed decrease in α-syn levels and increased dopamine-related markers, i.e., tyrosine hydroxylase (TH), vesicle monoamine transporter 2 (VMAT2), and dopamine transporter (DAT), and autophagy activities in the striatum and SNpc. Lastly, our data showed decreased neuroinflammation by reducing the activation of microglia and astrocytes and pro-inflammatory cytokines in the immunized groups, especially with OVA and KLH carrier proteins. Overall, these results suggest that vaccination, especially with immunogenic carrier proteins, is effective in reducing the accumulation of α-syn aggregates in the brain and ameliorate PD-related pathophysiology. Hence, further development of this approach might have a potential role in preventing the development of PD.}, } @article {pmid38139294, year = {2023}, author = {Peggion, C and Massimino, ML and Pereira, D and Granuzzo, S and Righetto, F and Bortolotto, R and Agostini, J and Sartori, G and Bertoli, A and Lopreiato, R}, title = {Structural Integrity of Nucleolin Is Required to Suppress TDP-43-Mediated Cytotoxicity in Yeast and Human Cell Models.}, journal = {International journal of molecular sciences}, volume = {24}, number = {24}, pages = {}, pmid = {38139294}, issn = {1422-0067}, support = {DOR2395544/23; BIRD202151/20; DOR2331994/23//University of Padova/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA ; *DNA-Binding Proteins/metabolism ; *Frontotemporal Lobar Degeneration/genetics/metabolism ; *Nucleolin/metabolism ; RNA ; Saccharomyces cerevisiae/genetics/metabolism ; }, abstract = {The Transactivating response (TAR) element DNA-binding of 43 kDa (TDP-43) is mainly implicated in the regulation of gene expression, playing multiple roles in RNA metabolism. Pathologically, it is implicated in amyotrophic lateral sclerosis and in a class of neurodegenerative diseases broadly going under the name of frontotemporal lobar degeneration (FTLD). A common hallmark of most forms of such diseases is the presence of TDP-43 insoluble inclusions in the cell cytosol. The molecular mechanisms of TDP-43-related cell toxicity are still unclear, and the contribution to cell damage from either loss of normal TDP-43 function or acquired toxic properties of protein aggregates is yet to be established. Here, we investigate the effects on cell viability of FTLD-related TDP-43 mutations in both yeast and mammalian cell models. Moreover, we focus on nucleolin (NCL) gene, recently identified as a genetic suppressor of TDP-43 toxicity, through a thorough structure/function characterization aimed at understanding the role of NCL domains in rescuing TDP-43-induced cytotoxicity. Using functional and biochemical assays, our data demonstrate that the N-terminus of NCL is necessary, but not sufficient, to exert its antagonizing effects on TDP-43, and further support the relevance of the DNA/RNA binding central region of the protein. Concurrently, data suggest the importance of the NCL nuclear localization for TDP-43 trafficking, possibly related to both TDP-43 physiology and toxicity.}, } @article {pmid38136980, year = {2023}, author = {Bouike, Y and Sakima, M and Taninishi, Y and Matsutani, T and Noguchi, Y and Bo, R and Awano, H and Nishio, H}, title = {Real-Time PCR-Based Screening for Homozygous SMN2 Deletion Using Residual Dried Blood Spots.}, journal = {Genes}, volume = {14}, number = {12}, pages = {}, pmid = {38136980}, issn = {2073-4425}, support = {23K07279//the Ministry of Education, Culture, Sports, Science, and Technology, Japan/ ; }, mesh = {Infant ; Infant, Newborn ; Humans ; Real-Time Polymerase Chain Reaction/methods ; Retrospective Studies ; Prospective Studies ; Gene Deletion ; *Muscular Atrophy, Spinal/diagnosis/genetics ; Motor Neurons ; Neonatal Screening/methods ; Survival of Motor Neuron 2 Protein/genetics ; }, abstract = {The survival motor neuron 2 (SMN2) gene is a recognized modifier gene of spinal muscular atrophy (SMA). However, our knowledge about the role of SMN2-other than its modification of SMA phenotypes-is very limited. Discussions regarding the relationship between homozygous SMN2 deletion and motor neuron diseases, including amyotrophic lateral sclerosis, have been mainly based on retrospective epidemiological studies of the diseases, and the precise relationship remains inconclusive. In the present study, we first estimated that the frequency of homozygous SMN2 deletion was ~1 in 20 in Japan. We then established a real-time polymerase chain reaction (PCR)-based screening method using residual dried blood spots to identify infants with homozygous SMN2 deletion. This method can be applied to a future prospective cohort study to clarify the relationship between homozygous SMN2 deletion and motor neuron diseases. In our real-time PCR experiment, both PCR (low annealing temperatures) and blood (high hematocrit values and low white blood cell counts) conditions were associated with incorrect results (i.e., false negatives and positives). Together, our findings not only help to elucidate the role of SMN2, but also aid in our understanding of the pitfalls of current SMA newborn screening programs for detecting homozygous SMN1 deletions.}, } @article {pmid38136659, year = {2023}, author = {Cilleros-Holgado, P and Gómez-Fernández, D and Piñero-Pérez, R and Romero-Domínguez, JM and Reche-López, D and López-Cabrera, A and Álvarez-Córdoba, M and Munuera-Cabeza, M and Talaverón-Rey, M and Suárez-Carrillo, A and Romero-González, A and Sánchez-Alcázar, JA}, title = {Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.}, journal = {Biomolecules}, volume = {13}, number = {12}, pages = {}, pmid = {38136659}, issn = {2218-273X}, support = {FIS PI19/00377 and PI22/00142 grants//Instituto de Salud Carlos III/ ; CTS-5725, PY18-850, and UPO-FEDER 2018 (UPO-1380614)//Regional Government of Andalusia/ ; }, mesh = {Animals ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; *Mitochondrial Diseases ; Aging ; Unfolded Protein Response ; }, abstract = {Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.}, } @article {pmid38136561, year = {2023}, author = {Cotet, C and Alarcan, H and Hérault, O and Corcia, P and Vourc'h, P and Andres, CR and Blasco, H and Veyrat-Durebex, C}, title = {Neutrophil to Lymphocyte Ratio as a Prognostic Marker in Amyotrophic Lateral Sclerosis.}, journal = {Biomolecules}, volume = {13}, number = {12}, pages = {}, pmid = {38136561}, issn = {2218-273X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Neutrophils ; Retrospective Studies ; Prognosis ; Disease Progression ; Lymphocytes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative motor neuron disease and remains misunderstood with a difficult diagnosis and prognosis. The implication of the immune system is recognized in ALS pathophysiology, hence the interest in leucocyte count as lymphocytes and neutrophils. The neutrophil-to-lymphocyte ratio (NLR) has recently been used as a prognosis factor to assess the progression of ALS. Thus, the aim of this study was to analyze the evolution of the NLR during disease evolution in a French cohort of ALS patients and its relation with survival. In this monocentric retrospective study, clinical parameters and NLR were collected in ALS patients followed at the University Hospital of Tours (France). ALS patients were subdivided into three groups regarding their NLR value at inclusion: group 1 (NLR < 2); group 2 (NLR: 2-3); group 3 (NLR > 3). A comparison of qualitative and quantitative clinical and biological variables between NLR groups was performed. Then, Cox regressions were carried out to determine the association of NLR with survival. We observed a significant correlation of NLR with ALSFRS-r score (p < 0.0001) and with vital forced capacity (p = 0.0004) at inclusion. We observed that increased NLR at diagnosis is associated with decreased ALS patients' survival.}, } @article {pmid38135852, year = {2024}, author = {Huang, J and Yu, Y and Pang, D and Li, C and Wei, Q and Cheng, Y and Cui, Y and Ou, R and Shang, H}, title = {Lnc-HIBADH-4 Regulates Autophagy-Lysosome Pathway in Amyotrophic Lateral Sclerosis by Targeting Cathepsin D.}, journal = {Molecular neurobiology}, volume = {61}, number = {7}, pages = {4768-4782}, pmid = {38135852}, issn = {1559-1182}, support = {81871000//National Natural Science Foundation of China/ ; 82101485//National Natural Science Foundation of China/ ; 2022ZYD0051//Sichuan Province Science and Technology Support Program/ ; No.2022NSFSC0750//Sichuan Province Science and Technology Support Program/ ; }, mesh = {Humans ; *Autophagy/physiology ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; *Lysosomes/metabolism ; *Cathepsin D/metabolism/genetics ; Male ; Female ; Signal Transduction ; MicroRNAs/genetics/metabolism ; Apoptosis/genetics ; Middle Aged ; Cell Proliferation ; Down-Regulation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most prevalent and lethal class of severe motor neuron diseases (MND) with no efficacious treatment. The pathogenic mechanisms underlying ALS remain unclear. Nearly 90% of patients exhibit sporadic onset (sALS). Therefore, elucidating the pathophysiology of ALS is imperative. Long non-coding RNA (lncRNA) is a large class of non-coding RNAs that regulate transcription, translation, and post-translational processes. LncRNAs contribute to the pathogenesis of diverse neurodegenerative disorders and hold promise as targets for interference in the realm of neurodegeneration. However, the mechanisms of which lncRNAs are involved in ALS have not been thoroughly investigated. We identified and validated a downregulated lncRNA, lnc-HIBADH-4, in ALS which correlated with disease severity and overall survival. Lnc-HIBADH-4 acted as a "molecular sponge" regulating lysosomal function through the lnc-HIBADH-4/miR-326/CTSD pathway, thereby impacting autophagy-lysosome dynamics and the levels of cell proliferation and apoptosis. Therefore, this study discovered and revealed the role of lnc-HIBADH-4 in the pathogenesis of ALS. With further research, lnc-HIBADH-4 is expected to provide a new biomarker in the diagnosis and treatment of ALS.}, } @article {pmid38134913, year = {2024}, author = {Wicke, F and Lorenz, E and Pokora, RM}, title = {[Schätzung der Wirksamkeit der Grippeimpfung anhand von Sekundärdaten: Eine Kohortenstudie und Propensity-Score-Matching-Analyse von Leistungsdaten aus Baden-Württemberg].}, journal = {Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany))}, volume = {86}, number = {S 03}, pages = {S205-S211}, doi = {10.1055/a-2173-8160}, pmid = {38134913}, issn = {1439-4421}, mesh = {Humans ; Germany/epidemiology ; *Influenza, Human/prevention & control/epidemiology ; *Influenza Vaccines/administration & dosage ; Male ; *Propensity Score ; Female ; Middle Aged ; Adult ; Aged ; Adolescent ; Young Adult ; Cohort Studies ; Aged, 80 and over ; Hospitalization/statistics & numerical data ; Vaccine Efficacy/statistics & numerical data ; Treatment Outcome ; Age Distribution ; Sex Distribution ; Reproducibility of Results ; }, abstract = {Ziel war es die Wirksamkeit der Influenza-Impfung (VE) für die Grippesaison 2014/2015 auf Grundlage von Routinedaten aus Krankenkassendatensatz zu schätzen und zu replizieren. Zusätzlich sollten methodische Aspekte untersucht werden. Es wurden Abrechnungsdaten von 2,64 Millionen Versicherten der AOK Baden-Württemberg mit dortigem Wohnsitz ab 15 Jahren analysiert. Basierend auf Abrechnungsdaten für die Influenza-Impfung 2014, wurden die Teilnehmer als ungeimpft oder geimpft klassifiziert. Kovariablen, die den Zusammenhang zwischen Impfung und Influenzainfektion beeinträchtigen könnten, wurden berücksichtigt. Hierzu gehörten Alter, Geschlecht, Wohnort sowie Kovariablen, die auf den Gesundheitszustand und die Inanspruchnahme von Gesundheitsdienstleistungen hinweisen. Der primäre Endpunkt war ein Krankenhausaufenthalt wegen Influenza während der Grippesaison 2015. Zu den sekundären Endpunkten gehörten unter anderem Krankenhausaufenthalte wegen Lungenentzündung und die Gesamtmortalität. Um eine vergleichbare Gruppe von geimpften und ungeimpften Teilnehmern zu ermitteln, wurde ein Propensity-Score-Matching (PSM) durchgeführt. Es wurde eine Bias-Analyse durchgeführt, bei der die VE vor und nach der Grippesaison geschätzt wurde, also zu Zeitpunkten, in denen angenommen wurde, dass die Influenza nicht in der Bevölkerung zirkulierte und die Impfung nicht wirken konnte. Insgesamt konnten 839.706 Teilnehmer 1:1 gematcht werden. Die geschätzte VE (basierend auf Influenza bedingten Krankenhausaufenthalten) betrug 27% [95%Konfidenzintervall (KI): 17%; 36%], was der Schätzung des RKI für dieselbe Saison (27% [95%KI: -1%; 47%]) entspricht. Die Bias-Analyse zeigte, dass das Ergebnis teilweise durch residuale Konfundierung erklärt werden kann, was zu einer potenziellen Überschätzung des zugrunde liegenden Effekts führt. Die Ergebnisse der sekundären Endpunkte zeigten ähnliche Ergebnisse, obwohl sie wahrscheinlich in höherem Maße durch residuale Konfundierung bedingt sind. Zusammenfassend zeigt sich, dass (1) sekundäre Daten der deutschen Krankenkassen verwendet werden können, um plausible VE-Schätzungen abzuleiten, und dass (2) das PSM eine nützliche und transparente Methode zur Ableitung dieser Schätzungen ist. Darüber hinaus ist (3) residuale Konfundierung ein relevantes Problem in Beobachtungsstudien zu VE und (4) Bias-Analysen vor- und nach der Grippesaison sind eine wesentliche Ergänzung für die Interpretation der Ergebnisse.}, } @article {pmid38134563, year = {2024}, author = {Dave, U and Narain, P and Mishra, D and Gomes, J}, title = {Aggregation of E121K mutant D-amino acid oxidase and ubiquitination-mediated autophagy mechanisms leading to amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {456}, number = {}, pages = {122845}, doi = {10.1016/j.jns.2023.122845}, pmid = {38134563}, issn = {1878-5883}, mesh = {Adult ; Humans ; Amino Acids ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Autophagy/genetics ; Mutation/genetics ; *Neuroblastoma ; Oxidoreductases ; Protein Aggregates ; Ubiquitin/metabolism ; Ubiquitination ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a terminal adult-onset neuromuscular disorder. Our group has been studying this illness and previously reported novel mutations and rare mutations in a study using next-generation sequencing of DNA samples from Indian ALS patients. In this paper, we focus on the E121K mutation in the DAO gene to understand how it leads to ALS. Our experiments in SH-SY5Y cells indicate that the E121K mutation results in the accumulation of mutant protein aggregates, a change in cell morphology, and the death of neuronal cells. These protein aggregates get ubiquitinated and cause an imbalance in autophagy regulation. We observed an increase in the cellular concentrations of p62, OPTN, and LC3II. Through confocal microscopy studies, we show that the binding of p62 with ubiquitinated aggregates and its recruitment to LC3II mediates autophagosome generation. These relative changes in the key partners in autophagy increase cell death in cells harboring the E121K mutation and is a probable mechanism leading to ALS.}, } @article {pmid38132330, year = {2023}, author = {Spisni, E and Valerii, MC and Massimino, ML}, title = {Essential Oil Molecules Can Break the Loop of Oxidative Stress in Neurodegenerative Diseases.}, journal = {Biology}, volume = {12}, number = {12}, pages = {}, pmid = {38132330}, issn = {2079-7737}, support = {0000//Xeda international (1397 Route Nationale 7, Zac la Crau, 13670 Saint Andiol, France)./ ; }, abstract = {Essential oils (EOs) are mixtures of volatile compounds, extracted from aromatic plants, with multiple activities including antioxidant and anti-inflammatory ones. EOs are complex mixtures easy to find on the market and with low costs. In this mini narrative review, we have collected the results of in vitro and in vivo studies, which tested these EOs on validated models of neurodegeneration and in particular of the two main neurodegenerative diseases (NDs) that afflict humans: Alzheimer's and Parkinson's. Since EO compositions can vary greatly, depending on the environmental conditions, plant cultivar, and extraction methods, we focused our attention to studies involving single EO molecules, and in particular those that have demonstrated the ability to cross the blood-brain barrier. These single EO molecules, alone or in defined mixtures, could be interesting new therapies to prevent or slow down oxidative and inflammatory processes which are common mechanisms that contribute to neuronal death in all NDs.}, } @article {pmid38132101, year = {2023}, author = {Liu, T and Wetzel, L and Zhu, Z and Kumaraguru, P and Gorthi, V and Yan, Y and Bukhari, MZ and Ermekbaeva, A and Jeon, H and Kee, TR and Woo, JA and Kang, DE}, title = {Disruption of Mitophagy Flux through the PARL-PINK1 Pathway by CHCHD10 Mutations or CHCHD10 Depletion.}, journal = {Cells}, volume = {12}, number = {24}, pages = {}, pmid = {38132101}, issn = {2073-4409}, support = {I01 BX004680/BX/BLRD VA/United States ; R21 AG070299/AG/NIA NIH HHS/United States ; R01 AG080924/AG/NIA NIH HHS/United States ; R01AG080924/NH/NIH HHS/United States ; R21 AG077735/AG/NIA NIH HHS/United States ; R01NS122350/NH/NIH HHS/United States ; R21AG070299/NH/NIH HHS/United States ; R01 AG059721/AG/NIA NIH HHS/United States ; R01AG059721/NH/NIH HHS/United States ; R01 NS122350/NS/NINDS NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; RF1AG053060/NH/NIH HHS/United States ; RF1 AG053060/AG/NIA NIH HHS/United States ; R01AG067741/NH/NIH HHS/United States ; RF1 NS122218/NS/NINDS NIH HHS/United States ; R01 AG067741/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia/genetics/pathology ; Mitophagy/genetics ; Mitochondrial Proteins/genetics/metabolism ; Mutation/genetics ; DNA-Binding Proteins/genetics/metabolism ; Protein Kinases/genetics ; Mammals/metabolism ; Metalloproteases/genetics ; }, abstract = {Coiled-coil-helix-coiled-coil-helix domain-containing 10 (CHCHD10) is a nuclear-encoded mitochondrial protein which is primarily mutated in the spectrum of familial and sporadic amyotrophic lateral sclerosis (ALS)-frontotemporal dementia (FTD). Endogenous CHCHD10 levels decline in the brains of ALS-FTD patients, and the CHCHD10[S59L] mutation in Drosophila induces dominant toxicity together with PTEN-induced kinase 1 (PINK1), a protein critical for the induction of mitophagy. However, whether and how CHCHD10 variants regulate mitophagy flux in the mammalian brain is unknown. Here, we demonstrate through in vivo and in vitro models, as well as human FTD brain tissue, that ALS/FTD-linked CHCHD10 mutations (R15L and S59L) impair mitophagy flux and mitochondrial Parkin recruitment, whereas wild-type CHCHD10 (CHCHD10[WT]) normally enhances these measures. Specifically, we show that CHCHD10[R15L] and CHCHD10[S59L] mutations reduce PINK1 levels by increasing PARL activity, whereas CHCHD10[WT] produces the opposite results through its stronger interaction with PARL, suppressing its activity. Importantly, we also demonstrate that FTD brains with TAR DNA-binding protein-43 (TDP-43) pathology demonstrate disruption of the PARL-PINK1 pathway and that experimentally impairing mitophagy promotes TDP-43 aggregation. Thus, we provide herein new insights into the regulation of mitophagy and TDP-43 aggregation in the mammalian brain through the CHCHD10-PARL-PINK1 pathway.}, } @article {pmid38131803, year = {2023}, author = {Miteva, D and Vasilev, GV and Velikova, T}, title = {Role of Specific Autoantibodies in Neurodegenerative Diseases: Pathogenic Antibodies or Promising Biomarkers for Diagnosis.}, journal = {Antibodies (Basel, Switzerland)}, volume = {12}, number = {4}, pages = {}, pmid = {38131803}, issn = {2073-4468}, support = {BG-RRP-2.004-0008//the European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria/ ; }, abstract = {Neurodegenerative diseases (NDDs) affect millions of people worldwide. They develop due to the pathological accumulation and aggregation of various misfolded proteins, axonal and synaptic loss and dysfunction, inflammation, cytoskeletal abnormalities, defects in DNA and RNA, and neuronal death. This leads to the activation of immune responses and the release of the antibodies against them. Recently, it has become clear that autoantibodies (Aabs) can contribute to demyelination, axonal loss, and brain and cognitive dysfunction. This has significantly changed the understanding of the participation of humoral autoimmunity in neurodegenerative disorders. It is crucial to understand how neuroinflammation is involved in neurodegeneration, to aid in improving the diagnostic and therapeutic value of Aabs in the future. This review aims to provide data on the immune system's role in NDDs, the pathogenic role of some specific Aabs against molecules associated with the most common NDDs, and their potential role as biomarkers for monitoring and diagnosing NDDs. It is suggested that the autoimmune aspects of NDDs will facilitate early diagnosis and help to elucidate previously unknown aspects of the pathobiology of these diseases.}, } @article {pmid38131496, year = {2023}, author = {Lynch, HF}, title = {Big Mistake: Knowing and Doing Better in Patient Engagement.}, journal = {The Hastings Center report}, volume = {53}, number = {6}, pages = {2}, doi = {10.1002/hast.1537}, pmid = {38131496}, issn = {1552-146X}, mesh = {Humans ; Female ; Patient Participation ; *Bioethics ; Ethicists ; Dissent and Disputes ; *Amyotrophic Lateral Sclerosis/therapy ; }, abstract = {Pushing back on policies favored by dying patients is a challenging endeavor, requiring tact, engagement, openness to bidirectional learning, and willingness to offer alternative solutions. It's easy to make missteps, especially in the age of social media. Holly Fernandez Lynch shares her experience learning with and from the amyotrophic lateral sclerosis (ALS) community, first as a caricature of an ivory tower bioethicist and more recently as a trusted advisor, at least for some. Patient-engaged bioethics doesn't mean taking the view that patients are always right, but even when disagreement continues, progress is possible if academics and patients recognize the unique expertise each has to offer.}, } @article {pmid38129934, year = {2023}, author = {Marriott, H and Kabiljo, R and Hunt, GP and Khleifat, AA and Jones, A and Troakes, C and , and , and Pfaff, AL and Quinn, JP and Koks, S and Dobson, RJ and Schwab, P and Al-Chalabi, A and Iacoangeli, A}, title = {Unsupervised machine learning identifies distinct ALS molecular subtypes in post-mortem motor cortex and blood expression data.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {208}, pmid = {38129934}, issn = {2051-5960}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; Motor Neurone Disease Association/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Unsupervised Machine Learning ; *Motor Cortex/metabolism ; Brain/pathology ; Autopsy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) displays considerable clinical and genetic heterogeneity. Machine learning approaches have previously been utilised for patient stratification in ALS as they can disentangle complex disease landscapes. However, lack of independent validation in different populations and tissue samples have greatly limited their use in clinical and research settings. We overcame these issues by performing hierarchical clustering on the 5000 most variably expressed autosomal genes from motor cortex expression data of people with sporadic ALS from the KCL BrainBank (N = 112). Three molecular phenotypes linked to ALS pathogenesis were identified: synaptic and neuropeptide signalling, oxidative stress and apoptosis, and neuroinflammation. Cluster validation was achieved by applying linear discriminant analysis models to cases from TargetALS US motor cortex (N = 93), as well as Italian (N = 15) and Dutch (N = 397) blood expression datasets, for which there was a high assignment probability (80-90%) for each molecular subtype. The ALS and motor cortex specificity of the expression signatures were tested by mapping KCL BrainBank controls (N = 59), and occipital cortex (N = 45) and cerebellum (N = 123) samples from TargetALS to each cluster, before constructing case-control and motor cortex-region logistic regression classifiers. We found that the signatures were not only able to distinguish people with ALS from controls (AUC 0.88 ± 0.10), but also reflect the motor cortex-based disease process, as there was perfect discrimination between motor cortex and the other brain regions. Cell types known to be involved in the biological processes of each molecular phenotype were found in higher proportions, reinforcing their biological interpretation. Phenotype analysis revealed distinct cluster-related outcomes in both motor cortex datasets, relating to disease onset and progression-related measures. Our results support the hypothesis that different mechanisms underpin ALS pathogenesis in subgroups of patients and demonstrate potential for the development of personalised treatment approaches. Our method is available for the scientific and clinical community at https://alsgeclustering.er.kcl.ac.uk .}, } @article {pmid38129650, year = {2023}, author = {Ito, H and Machida, K and Hasumi, M and Ueyama, M and Nagai, Y and Imataka, H and Taguchi, H}, title = {Reconstitution of C9orf72 GGGGCC repeat-associated non-AUG translation with purified human translation factors.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {22826}, pmid = {38129650}, issn = {2045-2322}, support = {JPMJFS2112//Japan Science and Technology Agency/ ; JP26116002//Ministry of Education, Culture, Sports, Science and Technology/ ; JP18H03984//Ministry of Education, Culture, Sports, Science and Technology/ ; JP21H04763//Ministry of Education, Culture, Sports, Science and Technology/ ; JP20H05925//Ministry of Education, Culture, Sports, Science and Technology/ ; 2019-25//Mitsubishi Foundation/ ; 2019//Uehara Memorial Foundation/ ; }, mesh = {Peptide Chain Elongation, Translational ; Peptide Elongation Factors/metabolism ; Humans ; *C9orf72 Protein/genetics ; Frameshifting, Ribosomal ; Peptide Chain Initiation, Translational ; In Vitro Techniques ; HeLa Cells ; *Protein Biosynthesis ; Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia/genetics ; }, abstract = {Nucleotide repeat expansion of GGGGCC (G4C2) in the non-coding region of C9orf72 is the most common genetic cause underlying amyotrophic lateral sclerosis and frontotemporal dementia. Transcripts harboring this repeat expansion undergo the translation of dipeptide repeats via a non-canonical process known as repeat-associated non-AUG (RAN) translation. In order to ascertain the essential components required for RAN translation, we successfully recapitulated G4C2-RAN translation using an in vitro reconstituted translation system comprising human factors, namely the human PURE system. Our findings conclusively demonstrate that the presence of fundamental translation factors is sufficient to mediate the elongation from the G4C2 repeat. Furthermore, the initiation mechanism proceeded in a 5' cap-dependent manner, independent of eIF2A or eIF2D. In contrast to cell lysate-mediated RAN translation, where longer G4C2 repeats enhanced translation, we discovered that the expansion of the G4C2 repeats inhibited translation elongation using the human PURE system. These results suggest that the repeat RNA itself functions as a repressor of RAN translation. Taken together, our utilization of a reconstituted RAN translation system employing minimal factors represents a distinctive and potent approach for elucidating the intricacies underlying RAN translation mechanism.}, } @article {pmid38129120, year = {2024}, author = {Allison, RL and Ebert, AD}, title = {ALS iPSC-derived microglia and motor neurons respond to astrocyte-targeted IL-10 and CCL2 modulation.}, journal = {Human molecular genetics}, volume = {33}, number = {6}, pages = {530-542}, doi = {10.1093/hmg/ddad209}, pmid = {38129120}, issn = {1460-2083}, support = {//Medical College of Wisconsin Center for Immunology/ ; //Neuroscience Research Center/ ; }, mesh = {Humans ; Interleukin-10/genetics ; Astrocytes ; C9orf72 Protein ; Microglia ; *Amyotrophic Lateral Sclerosis/genetics ; *Induced Pluripotent Stem Cells ; *Neurodegenerative Diseases ; Superoxide Dismutase-1/genetics ; Motor Neurons ; Chemokine CCL2/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs). The loss of MNs in ALS leads to muscle weakness and wasting, respiratory failure, and death often within two years of diagnosis. Glial cells in ALS show aberrant expression of pro-inflammatory and neurotoxic proteins associated with activation and have been proposed as ideal therapeutic targets. In this study, we examined astrocyte-targeted treatments to reduce glial activation and neuron pathology using cells differentiated from ALS patient-derived iPSC carrying SOD1 and C9ORF72 mutations. Specifically, we tested the ability of increasing interleukin 10 (IL-10) and reducing C-C motif chemokine ligand 2 (CCL2/MCP-1) signaling targeted to astrocytes to reduce activation phenotypes in both astrocytes and microglia. Overall, we found IL10/CCL2NAb treated astrocytes to support anti-inflammatory phenotypes and reduce neurotoxicity, through different mechanisms in SOD1 and C9ORF72 cultures. We also found altered responses of microglia and motor neurons to astrocytic influences when cells were cultured together rather than in isolation. Together these data support IL-10 and CCL2 as non-mutation-specific therapeutic targets for ALS and highlight the role of glial-mediated pathology in this disease.}, } @article {pmid38128275, year = {2024}, author = {Alcaraz, MR and Espinosa-Mansilla, A and Durán-Merás, I and Muñoz de la Peña, A}, title = {An optimized methodology for the determination of multiclass organic ultraviolet sunscreens and metabolites in human milk through chromatographic and chemometric resolution.}, journal = {Talanta}, volume = {270}, number = {}, pages = {125560}, doi = {10.1016/j.talanta.2023.125560}, pmid = {38128275}, issn = {1873-3573}, mesh = {Humans ; *Milk, Human ; Sunscreening Agents ; Chemometrics ; Ecosystem ; Chromatography, Reverse-Phase ; *Liquid Phase Microextraction/methods ; Chromatography, High Pressure Liquid/methods ; }, abstract = {Organic UV filters (UVFS) are used to mitigate the dermal effects associated with health risks from UV radiation, making them essential in personal care products. UVFS are frequently identified in environmental samples due to their high lipophilicity and persistence, underscoring the urgency of comprehensive assessments and regulatory measures aimed at safeguarding ecosystems and human health. The present study reports a multiclass analytical method for determining 16 UV sunscreens and metabolites in breast milk based on an ultrasound-assisted-dispersive liquid-liquid micro-extraction (UA-DLLME) with further chromatographic and chemometric resolution. The experimental conditions of the UA-DLLME were optimized through the implementation of the Design of Experiment tools. To model the responses, least-squares and artificial neural network methodologies were implemented. The optimal conditions were found by employing the desirability function. The samples were analyzed through reverse-phase liquid chromatographic separation, UV diode array, and fast-scanning fluorescence detection. The chromatographic analysis enabled the resolution of 16 analytes in a total time of 13.0 min. Multivariate curve resolution-alternating least-square (MCR-ALS) modelling was implemented to resolve analytes that were not fully resolved and to determine analytes that coeluted with endogenous components of the breast milk samples. An enrichment factor of 5-fold concentration was obtained with this methodology, reaching recoveries between 65 % and 105 % for 13 multiclass UV sunscreens and metabolites in breast milk samples with RSD % and REP % lower than 12 %.}, } @article {pmid38128171, year = {2024}, author = {Manrique Rabelo, CM}, title = {[Resistance to the use of a wheelchair and gait aids by patients with amyotrophic ALS: Learned beliefs and attitudes].}, journal = {Rehabilitacion}, volume = {58}, number = {1}, pages = {100830}, doi = {10.1016/j.rh.2023.100830}, pmid = {38128171}, issn = {1578-3278}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Gait ; *Wheelchairs ; Muscular Atrophy ; }, } @article {pmid38127306, year = {2023}, author = {Ho, DT and Berry, JD}, title = {The Intense Psychological Burden of ALS, the Enduring Strength of People Living With ALS, and the Tools We Can Use to Help.}, journal = {The Journal of clinical psychiatry}, volume = {85}, number = {1}, pages = {}, doi = {10.4088/JCP.23com15173}, pmid = {38127306}, issn = {1555-2101}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; }, } @article {pmid38127305, year = {2023}, author = {Lester, EG and Vitolo, OV and Flaherty, A and Beaussant, Y and Cramer, M and Harley, R and Cohen, JN}, title = {"When Will All of This End?": A 65-Year-Old Man With Amyotrophic Lateral Sclerosis and Psychiatric Distress.}, journal = {The Journal of clinical psychiatry}, volume = {85}, number = {1}, pages = {}, doi = {10.4088/JCP.23ct15038}, pmid = {38127305}, issn = {1555-2101}, mesh = {Aged ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/therapy ; *Cognitive Behavioral Therapy ; Psychotherapy ; *Psychological Distress ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) are impacted both physically and psychiatrically during their illness. Emotional distress (ie, anxiety, depression, stress) is common in patients diagnosed with ALS, as prognosis is poor and there are very few effective treatments. The progression of symptoms is unpredictable, and all cases are terminal. Neuropsychiatric symptoms are also increasingly recognized as part of ALS symptomatology. There are currently no empirically supported interventions or best practices for adjustment to ALS. This case presents both the psychological and pharmacologic aspects of caring for a patient with ALS. Psychotherapy utilized a cognitive behavioral therapy-informed approach, and pharmacotherapy was tailored to the specific needs of the patient. We explore how these approaches impacted our patient, as well as how ALS-specific challenges presented throughout the course of treatment.}, } @article {pmid38127186, year = {2024}, author = {Guo, R and Chen, Y and Zhang, J and Zhou, Z and Feng, B and Du, X and Liu, X and Ma, J and Cui, H}, title = {Neural Differentiation and spinal cord organoid generation from induced pluripotent stem cells (iPSCs) for ALS modelling and inflammatory screening.}, journal = {Molecular neurobiology}, volume = {61}, number = {7}, pages = {4732-4749}, pmid = {38127186}, issn = {1559-1182}, support = {81801278//Natural Science Foundation of China/ ; 201608130015//China National Textile and Apparel Council/ ; H2019206637//Natural Science Foundation of Hebei Province/ ; H2015206409//Natural Science Foundation of Hebei Province/ ; H2020206557//Key Natural Science Foundation of Hebei Province/ ; C20190509//Overseas researcher Program in Hebei Provincial Department of human resources and social security/ ; }, mesh = {*Induced Pluripotent Stem Cells/metabolism ; Humans ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *Organoids/metabolism/pathology ; *Cell Differentiation ; *Spinal Cord/pathology ; *Motor Neurons/pathology/metabolism ; Astrocytes/metabolism/pathology ; Inflammation/pathology ; C9orf72 Protein/genetics/metabolism ; Models, Biological ; Neurons/metabolism/pathology ; }, abstract = {C9orf72 genetic mutation is the most common genetic cause of ALS/FTD accompanied by abnormal protein insufficiency. Induced pluripotent stem cell (iPSC)-derived two-dimensional (2D) and three-dimensional (3D) cultures are providing new approaches. Therefore, this study established neuronal cell types and generated spinal cord organoids (SCOs) derived from C9orf72 knockdown human iPSCs to model ALS disease and screen the unrevealed phenotype. Wild-type (WT) iPSC lines from three healthy donor fibroblasts were established, and pluripotency and differentiation ability were identified by RT-PCR, immunofluorescence and flow cytometry. After infection by the lentivirus with C9orf72-targeting shRNA, stable C9-knockdown iPSC colonies were selected and differentiated into astrocytes, motor neurons and SCOs. Finally, we analyzed the extracted RNA-seq data of human C9 mutant/knockout iPSC-derived motor neurons and astrocytes from the GEO database and the inflammatory regulation-related genes in function and pathways. The expression of inflammatory factors was measured by qRT-PCR. The results showed that both WT-iPSCs and edited C9-iPSCs maintained a similar ability to differentiate into the three germ layers, astrocytes and motor neurons, forming SCOs in a 3D culture system. The constructed C9-SCOs have features of spinal cord development and multiple neuronal cell types, including sensory neurons, motor neurons, and other neurons. Based on the bioinformatics analysis, proinflammatory factors were confirmed to be upregulated in C9-iPSC-derived 2D cells and 3D cultured SCOs. The above differentiated models exhibited low C9orf72 expression and the pathological characteristics of ALS, especially neuroinflammation.}, } @article {pmid38126188, year = {2025}, author = {Alamri, SH and Haque, S and Alghamdi, BS and Tayeb, HO and Azhari, S and Farsi, RM and Elmokadem, A and Alamri, TA and Harakeh, S and Prakash, A and Kumar, V}, title = {Comprehensive mapping of mutations in TDP-43 and α-Synuclein that affect stability and binding.}, journal = {Journal of biomolecular structure & dynamics}, volume = {43}, number = {4}, pages = {1818-1830}, doi = {10.1080/07391102.2023.2293258}, pmid = {38126188}, issn = {1538-0254}, mesh = {*alpha-Synuclein/genetics/metabolism/chemistry ; *DNA-Binding Proteins/genetics/chemistry/metabolism ; *Protein Binding ; Humans ; *Protein Stability ; *Molecular Dynamics Simulation ; *Mutation ; Mutation, Missense ; Binding Sites ; Protein Interaction Domains and Motifs ; }, abstract = {Abnormal aggregation and amyloid inclusions of TAR DNA-binding protein 43 (TDP-43) and α-Synuclein (α-Syn) are frequently co-observed in amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Several reports showed TDP-43 C-terminal domain (CTD) and α-Syn interact with each other and the aggregates of these two proteins colocalized together in different cellular and animal models. Molecular dynamics simulation was conducted to elucidate the stability of the TDP-43 and Syn complex structure. The interfacial mutations in protein complexes changes the stability and binding affinity of the protein that may cause diseases. Here, we have utilized the computational saturation mutagenesis approach including structure-based stability and binding energy calculations to compute the systemic effects of missense mutations of TDP-43 CTD and α-Syn on protein stability and binding affinity. Most of the interfacial mutations of CTD and α-Syn were found to destabilize the protein and reduced the protein binding affinity. The results thus shed light on the functional consequences of missense mutations observed in TDP-43 associated proteinopathies and may provide the mechanisms of co-morbidities involving these two proteins.Communicated by Ramaswamy H. Sarma.}, } @article {pmid38124685, year = {2024}, author = {Strunge, K and Bostock, H and Howells, J and Cengiz, B and Samusyte, G and Koltzenburg, M and Tankisi, H}, title = {Caffeine and cortical excitability, as measured with paired-pulse transcranial magnetic stimulation.}, journal = {Muscle & nerve}, volume = {69}, number = {2}, pages = {206-212}, doi = {10.1002/mus.28027}, pmid = {38124685}, issn = {1097-4598}, support = {//Lundbeck Foundation/ ; //Grosserer L. F. Foghts Fond/ ; //Aase og Ejnar Danielsens Fond/ ; //Dagmar Marshalls Fond/ ; }, mesh = {Female ; Humans ; Male ; Caffeine/pharmacology ; Chewing Gum ; *Cortical Excitability ; Evoked Potentials, Motor/physiology ; *Motor Cortex/physiology ; Neural Inhibition/physiology ; Transcranial Magnetic Stimulation/methods ; Young Adult ; Adult ; }, abstract = {INTRODUCTION/AIMS: The transcranial magnetic stimulation tests of short-interval intracortical inhibition (SICI) by both conventional amplitude measurements (A-SICI) and threshold-tracking (T-SICI) are important methods to investigate intracortical inhibitory circuits, and T-SICI has been proposed to aid the diagnosis of amyotrophic lateral sclerosis. Beverages containing caffeine are widely consumed, and caffeine has been reported to affect cortical excitability. The aim of this study was to determine whether these SICI tests are affected by caffeine.

METHODS: Twenty-four healthy subjects (13 females, 11 males, aged from 19 to 31, mean: 26.2 ± 2.4 years) were studied in a single fixed-dose randomized double-blind placebo-controlled cross-over trial of 200 mg caffeine or placebo ingested as chewing gum. A-SICI and T-SICI, using parallel tracking (T-SICIp), were performed before and after chewing gum.

RESULTS: There was no significant change in SICI parameters after placebo in A-SICI (p > .10) or T-SICIp (p > .30), and no significant effect of caffeine was found on A-SICI (p > .10) or T-SICIp (p > .50) for any of the interstimulus intervals.

DISCUSSION: There is no need for caffeine abstention before measurements of SICI by either the T-SICI or A-SICI measurements.}, } @article {pmid38123999, year = {2024}, author = {Douglas, AGL and Baralle, D}, title = {Reduced penetrance of gene variants causing amyotrophic lateral sclerosis.}, journal = {Journal of medical genetics}, volume = {61}, number = {3}, pages = {294-297}, doi = {10.1136/jmg-2023-109580}, pmid = {38123999}, issn = {1468-6244}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics/pathology ; *Frontotemporal Dementia/epidemiology/genetics ; C9orf72 Protein/genetics ; Penetrance ; Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis overlaps aetiologically and genetically with frontotemporal dementia and occurs in both familial and apparently sporadic forms. The most commonly implicated genes are C9orf72, SOD1, TARDBP and FUS. Penetrance of disease-causing variants in these genes is known to be incomplete, but has not been well studied at population level.

OBJECTIVE: We sought to determine the population-level penetrance of pathogenic and likely pathogenic variants in genes commonly causing amyotrophic lateral sclerosis.

METHODS: Published epidemiological data for amyotrophic lateral sclerosis and frontotemporal dementia were used to calculate expected frequencies of disease-causing variants per gene at population level. Variant data from gnomAD and ClinVar databases were used to ascertain observed numbers of disease-causing variants and to estimate population-level penetrance per gene. Data for C9orf72 were obtained from the published literature.

RESULTS: Maximum population penetrance for either amyotrophic lateral sclerosis or frontotemporal dementia was found to be 33% for C9orf72 (95% CI (20.9 to 53.2)), 54% for SOD1 (95% CI (32.7 to 88.6)), 38% for TARDBP (95% CI (21.1 to 69.8)) and 19% for FUS (95% CI (13.0 to 28.4)).

CONCLUSION: Population-level penetrance of amyotrophic lateral sclerosis disease genes is reduced. This finding has implications for the genetic testing and counselling of affected individuals and their unaffected relatives.}, } @article {pmid38123494, year = {2024}, author = {Nolano, M and Provitera, V and Caporaso, G and Fasolino, I and Borreca, I and Stancanelli, A and Iuzzolino, VV and Senerchia, G and Vitale, F and Tozza, S and Ruggiero, L and Iodice, R and Ferrari, S and Santoro, L and Manganelli, F and Dubbioso, R}, title = {Skin innervation across amyotrophic lateral sclerosis clinical stages: new prognostic biomarkers.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {5}, pages = {1740-1750}, doi = {10.1093/brain/awad426}, pmid = {38123494}, issn = {1460-2156}, support = {//Istituti Clinici Scientifici Maugeri IRCCS/ ; //Italian Ministry of Health/ ; //Ministry of University and Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Male ; Female ; Middle Aged ; *Skin/innervation/pathology ; Aged ; Prognosis ; Biomarkers/blood ; Neural Conduction/physiology ; Adult ; Disease Progression ; Neurofilament Proteins/blood/metabolism ; Longitudinal Studies ; }, abstract = {Over recent decades, peripheral sensory abnormalities, including the evidence of cutaneous denervation, have been reported among the non-motor manifestations in amyotrophic lateral sclerosis (ALS). However, a correlation between cutaneous innervation and clinical features has not been found. The aims of this study were to assess sensory involvement by applying a morpho-functional approach to a large population of ALS patients stratified according to King's stages and correlate these findings with the severity and prognosis of the disease. We recruited 149 ALS patients and 41 healthy controls. Patients undertook clinical questionnaires for small fibre neuropathy symptoms (Small Fiber Neuropathy Symptoms Inventory Questionnaire) and underwent nerve conductions studies (NCS) and 3-mm punch skin biopsies from leg, thigh and fingertip. We assessed intraepidermal nerve fibre (IENF) and Meissner corpuscle (MC) density by applying an indirect immunofluorescence technique. Moreover, a subset of 65 ALS patients underwent a longitudinal study with repeat biopsies from the thigh at 6- and 12-month follow-ups. Serum NfL levels were measured in 40 patients. Sensory symptoms and sensory NCS abnormalities were present in 32.2% and 24% of patients, respectively, and increased across clinical stages. Analogously, we observed a progressive reduction in amplitude of the sensory and motor ulnar nerve potential from stage 1 to stage 4. Skin biopsy showed a significant loss of IENFs and MCs in ALS compared with healthy controls (all P < 0.001). Across the clinical stages, we found a progressive reduction in MCs (P = 0.004) and an increase in IENFs (all P < 0.027). The increase in IENFs was confirmed by the longitudinal study. Interestingly, the MC density inversely correlated with NfL level (r = -0.424, P = 0.012), and survival analysis revealed that low MC density, higher NfL levels and increasing IENF density over time were associated with a poorer prognosis (all P < 0.024). To summarize, in patients with ALS, peripheral sensory involvement worsens in parallel with motor disability. Furthermore, the correlation between skin innervation and disease activity may suggest the use of skin innervation as a putative prognostic biomarker.}, } @article {pmid38123099, year = {2024}, author = {Stackhouse, LA and Coops, NC and Kuiper, SD and Hinch, SG and White, JC and Tompalski, P and Nonis, A and Gergel, SE}, title = {Modeling instream temperature from solar insolation under varying timber harvesting intensities using RPAS laser scanning.}, journal = {The Science of the total environment}, volume = {912}, number = {}, pages = {169459}, doi = {10.1016/j.scitotenv.2023.169459}, pmid = {38123099}, issn = {1879-1026}, abstract = {Stream temperatures are influenced by the amount of solar insolation they receive. Increasing stream temperatures associated with climate warming pose detrimental health risks to freshwater ecosystems. In British Columbia (BC), Canada, timber harvesting along forested streams is managed using riparian buffer zones of varying widths and designations. Within buffer zones, depending on distance from the stream, selective thinning may be permitted or harvest may be forbidden. In this study, we used airborne laser scanning (ALS) point cloud data acquired via a remotely piloted aircraft system (RPAS) to derive forest canopy characteristics that were then used to estimate daily incoming summer and fall solar insolation for five stream reaches in coastal conifer-dominated temperate forests in Vancouver Island, BC, Canada. We then examined empirical relationships between estimated insolation and actual instream temperature measurements. Based on these empirical relationships, the potential effects of timber harvest on instream temperatures were simulated by comparing scenarios of different riparian forest harvest intensities. Our results indicated that modeled solar insolation explained 43-90 % of the variation in observed stream reach temperatures, and furthermore, when a single cold-water stream reach was excluded explained an overall 81 % of variation. Simulated harvesting scenarios generally projected increases in maximum stream reach temperatures 1-2 °C in summer and early fall months. However, in a full clearcut scenario (i.e. where all trees were removed), maximum stream reach temperatures increased as much as 5.8 °C. Our results emphasize the importance of retaining riparian vegetation for the maintenance of habitable temperatures for freshwater-reliant fish with thermal restrictions. In addition, we demonstrate the feasibility of RPAS-based monitoring of stream reach shading and canopy cover, enabling detailed assessment of environmental stressors faced by fish populations under climate warming.}, } @article {pmid38117120, year = {2024}, author = {Vaage, AM and Benth, JŠ and Meyer, HE and Holmøy, T and Nakken, O}, title = {Premorbid lipid levels and long-term risk of ALS-a population-based cohort study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {358-366}, doi = {10.1080/21678421.2023.2295455}, pmid = {38117120}, issn = {2167-9223}, mesh = {Female ; Humans ; Male ; Cholesterol, LDL ; Cohort Studies ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Triglycerides ; Cholesterol, HDL ; Risk Factors ; }, abstract = {OBJECTIVE: To assess the temporal relationship between premorbid lipid levels and long-term amyotrophic lateral sclerosis (ALS) risk.

METHODS: From Norwegian cardiovascular health surveys (1974-2003), we collected information on total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glucose, and other cardiovascular risk factors. ALS incidence and mortality were identified through validated Norwegian health registries. The relation between premorbid lipid levels and ALS risk was assessed by Cox regression models.

RESULTS: Out of 640,066 study participants (51.5% females), 974 individuals (43.5% females) developed ALS. Mean follow-up time was 23.7 (SD 7.1) years among ALS cases. One mmol/l increase in LDL-C was associated with 6% increase in risk for ALS (hazard ratio 1.06 [95% CI: 1.01-1.09]). Higher levels of TC and TG were also associated with increased ALS risk, but only within the last 6-7 years prior to ALS diagnosis or death. No association between HDL-C and ALS risk was found. Adjusting for body mass index, birth cohort, smoking, and physical activity did not alter the results.

CONCLUSIONS: Higher levels of LDL-C are associated with increased ALS risk over 40 years later, compatible with a causal relationship. The temporal relationship between TG, TC, and ALS risk suggests that increased levels of these lipid biomarkers represent consequences of ALS.}, } @article {pmid38116771, year = {2023}, author = {Máčová, L and Kancheva, R and Bičíková, M}, title = {Molecular Regulation of the CNS by Vitamin D.}, journal = {Physiological research}, volume = {72}, number = {S4}, pages = {S339-S356}, doi = {10.33549/physiolres.935248}, pmid = {38116771}, issn = {1802-9973}, mesh = {Humans ; Vitamin D/therapeutic use ; Vitamins ; *Alzheimer Disease ; *Nervous System Diseases ; *Parkinson Disease ; }, abstract = {Vitamin D is a lipid-soluble vitamin that can be found in some foods. It is also produced endogenously (in the presence of ultraviolet light), transported through the blood to the targets organs and this is the reason to consider vitamin D as a hormone. It is known that vitamin D has genomic and non-genomic effects. This review is focused mainly on the vitamin D receptors, the importance of vitamin D as a neuromodulator, the role of vitamin D in the pathophysiology of devastating neurological disorders such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and the benefit of vitamin D and its derivates in alleviating these disorders.}, } @article {pmid38115557, year = {2024}, author = {Nementzik, LR and Thumbadoo, KM and Murray, HC and Gordon, D and Yang, S and Blair, IP and Turner, C and Faull, RLM and Curtis, MA and McLean, C and Nicholson, GA and Swanson, MEV and Scotter, EL}, title = {Distribution of ubiquilin 2 and TDP-43 aggregates throughout the CNS in UBQLN2 p.T487I-linked amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {3}, pages = {e13230}, pmid = {38115557}, issn = {1750-3639}, support = {//Amelia Pais-Rodriguez and Marcus Gerbich/ ; //Freemasons Foundation of New Zealand/ ; //Health Education Trust/ ; 15-UOA-157//Marsden Fund/ ; //Matteo de Nora/ ; //Motor Neuron Disease NZ/ ; //PaR NZ Golfing/ ; 15-UOA-003//Royal Society Te Apārangi/ ; }, mesh = {Humans ; Adaptor Proteins, Signal Transducing/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Autophagy-Related Proteins/metabolism ; DNA-Binding Proteins/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Mutation ; Transcription Factors/metabolism ; }, abstract = {Mutations in the UBQLN2 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of such UBQLN2-linked cases of ALS/FTD is characterised by aggregates of the ubiquilin 2 protein in addition to aggregates of the transactive response DNA-binding protein of 43 kDa (TDP-43). ALS and FTD without UBQLN2 mutations are also characterised by TDP-43 aggregates, that may or may not colocalise with wildtype ubiquilin 2. Despite this, the relative contributions of TDP-43 and ubiquilin 2 to disease pathogenesis remain largely under-characterised, as does their relative deposition as aggregates across the central nervous system (CNS). Here we conducted multiplex immunohistochemistry of three UBQLN2 p.T487I-linked ALS/FTD cases, three non-UBQLN2-linked (sporadic) ALS cases, and 8 non-neurodegenerative disease controls, covering 40 CNS regions. We then quantified ubiquilin 2 aggregates, TDP-43 aggregates and aggregates containing both proteins in regions of interest to determine how UBQLN2-linked and non-UBQLN2-linked proteinopathy differ. We find that ubiquilin 2 aggregates that are negative for TDP-43 are predominantly small and punctate and are abundant in the hippocampal formation, spinal cord, all tested regions of neocortex, medulla and substantia nigra in UBQLN2-linked ALS/FTD but not sporadic ALS. Curiously, the striatum harboured small punctate ubiquilin 2 aggregates in all cases examined, while large diffuse striatal ubiquilin 2 aggregates were specific to UBQLN2-linked ALS/FTD. Overall, ubiquilin 2 is mainly deposited in clinically unaffected regions throughout the CNS such that symptomology in UBQLN2-linked cases maps best to the aggregation of TDP-43.}, } @article {pmid38112783, year = {2024}, author = {Libonati, L and Cambieri, C and Colavito, D and Moret, F and D'Andrea, E and Del Giudice, E and Leon, A and Inghilleri, M and Ceccanti, M}, title = {Genetics screening in an Italian cohort of patients with Amyotrophic Lateral Sclerosis: the importance of early testing and its implication.}, journal = {Journal of neurology}, volume = {271}, number = {4}, pages = {1921-1936}, pmid = {38112783}, issn = {1432-1459}, mesh = {Humans ; Mutation ; *Amyotrophic Lateral Sclerosis/epidemiology ; Superoxide Dismutase-1/genetics ; C9orf72 Protein/genetics ; *Neurodegenerative Diseases ; Italy ; Heat-Shock Proteins/genetics ; Molecular Chaperones/genetics ; }, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with an elusive etiology. While environmental factors have been considered, familial ALS cases have raised the possibility of genetic involvement. This genetic connection is increasingly evident, even in patients with sporadic ALS. We allowed access to the genetic test to all patients attending our clinic to identify the prevalence and the role of genetic variants in the development of the disease and to identify patients with potentially treatable forms of the disease.

MATERIALS AND METHODS: 194 patients with probable or definite ALS, were enrolled. A comprehensive genetic testing was performed, including sequencing all exons of the SOD1 gene and testing for hexanucleotide intronic repeat expansions (G4C2) in the C9orf72 gene using fluorescent repeat-primed PCR (RP-PCR). Whole Exome NGS Sequencing (WES) was performed, followed by an in silico multigene panel targeting neuromuscular diseases, spastic paraplegia, and motor distal neuropathies. We conducted statistical analyses to compare different patient groups.

RESULTS: Clinically significant pathogenetic variants were detected in 14.43% of cases. The highest prevalence of pathogenetic variants was observed in fALS patients, but a substantial proportion of sALS patients also displayed at least one variant, either pathogenetic or of uncertain significance (VUS). The most observed pathogenetic variant was the expansion of the C9orf72 gene, which was associated with a shorter survival. SOD1 variants were found in 1.6% of fALS and 2.5% of sALS patients.

DISCUSSION: The study reveals a significant number of ALS patients carrying pathogenic or likely pathogenic variants, with a higher prevalence in familial ALS cases. The expansion of the C9orf72 gene emerges as the most common genetic cause of ALS, affecting familial and sporadic cases. Additionally, SOD1 variants are detected at an unexpectedly higher rate, even in patients without a familial history of ALS, underscoring the crucial role of genetic testing in treatment decisions and potential participation in clinical trials. We also investigated variants in genes such as TARDBP, FUS, NEK1, TBK1, and DNAJC7, shedding light on their potential involvement in ALS. These findings underscore the complexity of interpreting variants of uncertain significance (VUS) and their ethical implications in patient communication and genetic counseling for patients' relatives.

CONCLUSION: This study emphasizes the diverse genetic basis of ALS and advocates for integrating comprehensive genetic testing into diagnostic protocols. The evolving landscape of genetic therapies requires identifying all eligible patients transcending traditional familial boundaries. The presence of VUS highlights the multifaceted nature of ALS genetics, prompting further exploration of complex interactions among genetic variants, environmental factors, and disease development.}, } @article {pmid38112636, year = {2024}, author = {Wang, Y and Shen, O and Xu, Q and Sun, L and Jia, Y and Liu, Y and He, Y and Chang, X and Guo, D and Shi, M and Chen, GC and Zheng, J and Zhu, Z}, title = {Genetic analyses identify brain imaging-derived phenotypes associated with the risk of amyotrophic lateral sclerosis.}, journal = {Cerebral cortex (New York, N.Y. : 1991)}, volume = {34}, number = {1}, pages = {}, doi = {10.1093/cercor/bhad496}, pmid = {38112636}, issn = {1460-2199}, support = {82103917//National Natural Science Foundation of China/ ; 21KJB330006//Natural Science Research Project of Jiangsu Provincial Higher Education/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics ; Brain/diagnostic imaging ; Genome-Wide Association Study ; Neuroimaging ; Phenotype ; Polymorphism, Single Nucleotide ; Mendelian Randomization Analysis ; }, abstract = {Brain imaging-derived phenotypes have been suggested to be associated with amyotrophic lateral sclerosis in observational studies, but whether these associations are causal remains unclear. We aimed to assess the potential bidirectional causal associations between imaging-derived phenotypes and amyotrophic lateral sclerosis using bidirectional 2-sample Mendelian randomization analyses. Summary statistics for 469 imaging-derived phenotypes (33,224 individuals) and amyotrophic lateral sclerosis (20,806 cases and 59,804 controls) were obtained from 2 large-scale genome-wide association studies of European ancestry. We used the inverse-variance weighted Mendelian randomization method in the main analysis to assess the bidirectional associations between imaging-derived phenotypes and amyotrophic lateral sclerosis, followed by several sensitivity analyses for robustness validation. In the forward Mendelian randomization analyses, we found that genetically determined high orientation dispersion index in the right cerebral peduncle was associated with the increased risk of amyotrophic lateral sclerosis (odds ratio = 1.30, 95% confidence interval = 1.16-1.45, P = 2.26 × 10-6). In addition, the reverse Mendelian randomization analysis indicated that amyotrophic lateral sclerosis had no effect on 469 imaging-derived phenotypes. Mendelian randomization-Egger regression analysis showed no directional pleiotropy for the association between high orientation dispersion index in the right cerebral peduncle and amyotrophic lateral sclerosis, and sensitivity analyses with different Mendelian randomization models further confirmed these findings. The present systematic bidirectional Mendelian randomization analysis showed that high orientation dispersion index in the right cerebral peduncle might be the potential causal mediator of amyotrophic lateral sclerosis, which may provide predictive guidance for the prevention of amyotrophic lateral sclerosis. Further studies are warranted to replicate our findings and clarify the underlying mechanisms.}, } @article {pmid38112345, year = {2024}, author = {Battaglini, M and Marino, A and Montorsi, M and Carmignani, A and Ceccarelli, MC and Ciofani, G}, title = {Nanomaterials as Microglia Modulators in the Treatment of Central Nervous System Disorders.}, journal = {Advanced healthcare materials}, volume = {13}, number = {12}, pages = {e2304180}, doi = {10.1002/adhm.202304180}, pmid = {38112345}, issn = {2192-2659}, mesh = {*Microglia/drug effects/metabolism ; Humans ; *Nanostructures/chemistry ; Animals ; *Central Nervous System Diseases/drug therapy/metabolism ; Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {Microglia play a pivotal role in the central nervous system (CNS) homeostasis, acting as housekeepers and defenders of the surrounding environment. These cells can elicit their functions by shifting into two main phenotypes: pro-inflammatory classical phenotype, M1, and anti-inflammatory alternative phenotype, M2. Despite their pivotal role in CNS homeostasis, microglia phenotypes can influence the development and progression of several CNS disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, ischemic stroke, traumatic brain injuries, and even brain cancer. It is thus clear that the possibility of modulating microglia activation has gained attention as a therapeutic tool against many CNS pathologies. Nanomaterials are an unprecedented tool for manipulating microglia responses, in particular, to specifically target microglia and elicit an in situ immunomodulation activity. This review focuses the discussion on two main aspects: analyzing the possibility of using nanomaterials to stimulate a pro-inflammatory response of microglia against brain cancer and introducing nanostructures able to foster an anti-inflammatory response for treating neurodegenerative disorders. The final aim is to stimulate the analysis of the development of new microglia nano-immunomodulators, paving the way for innovative and effective therapeutic approaches for the treatment of CNS disorders.}, } @article {pmid38112253, year = {2023}, author = {Juranek, J and Osowski, A and Wojtkiewicz, J and Banach, M}, title = {Plasma levels of soluble RAGE, AGEs and AOPPs at the early stage of amyotrophic lateral sclerosis: A preliminary study.}, journal = {Polimery w medycynie}, volume = {53}, number = {2}, pages = {105-110}, doi = {10.17219/pim/175544}, pmid = {38112253}, issn = {0370-0747}, mesh = {Humans ; Receptor for Advanced Glycation End Products/metabolism ; *Advanced Oxidation Protein Products/metabolism ; *Amyotrophic Lateral Sclerosis ; Longitudinal Studies ; Oxidative Stress ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with largely unknown pathogenesis and no effective cure. It is believed that several, not mutually exclusive mechanisms contribute to the pathogenesis and progression of this disease, including, among others, elevated oxidative stress, excitotoxicity, increased neuroinflammation, and protein aggregation. Receptor for advanced glycation end products (RAGE) is a part of immunoglobulin superfamily; it is believed to participate in ALS pathogenesis.

OBJECTIVES: Our previous studies on ALS demonstrated that RAGE is likely one of the key players in ALS, acting on its own and in tandem with its oxidative stress and pro-inflammatory ligands, such as advanced glycation end products (AGEs) or advanced oxidation protein products (AOPPs). In this study, based on our previous results, we aimed to establish blood levels of soluble RAGE, AGE and AOPP in ALS patients.

MATERIAL AND METHODS: Forty-six coded and anonymized surplus plasma samples from ALS patients and non-neurological control were used in the study. The plasma levels of RAGE, AGE and AOPP were measured using enzyme-linked immunosorbent assay (ELISA) commercially available kits. Statistical evaluation of data was performed using one-way non-parametric analysis of variance (ANOVA) with Kruskal-Wallis post hoc test.

RESULTS: Our results revealed a decline in soluble RAGE level, concurrent with an increase in the levels of AGEs and AOPPs in blood samples from ALS patients, signifying a loss of neuroprotective form of RAGE and a simultaneous increase in AGE and AOPP production and uptake at the early stage of the disease.

CONCLUSIONS: The results obtained from our study indicate that further longitudinal study of RAGE, AGE and AOPP levels would be beneficial, outlining the dynamics between RAGE and its ligand levels as the disease progresses, and making them valuable diagnostic tools and potential therapeutic targets.}, } @article {pmid38111871, year = {2023}, author = {Poletti, B and Aiello, EN and Tagini, S and Solca, F and Torre, S and Colombo, E and Maranzano, A and Bonetti, R and Schevegher, F and Morelli, C and Doretti, A and Verde, F and Barbieri, S and Mameli, F and Priori, A and Ferrucci, R and Silani, V and Cherubini, P and Pravettoni, G and Ticozzi, N}, title = {An exploratory study on counterfactual thinking in amyotrophic lateral sclerosis.}, journal = {Frontiers in psychology}, volume = {14}, number = {}, pages = {1281976}, pmid = {38111871}, issn = {1664-1078}, abstract = {OBJECTIVES: This study aimed at exploring (1) the motor and non-motor correlates of counterfactual thinking (CFT) abilities in non-demented amyotrophic lateral sclerosis (ALS) patients and (2) the ability of CFT measures to discriminate these patients from healthy controls (HCs) and patients with and without cognitive impairment.

METHODS: N = 110 ALS patients and N = 51 HCs were administered two CFT tasks, whose sum, resulting in a CFT Index (CFTI), was addressed as the outcome. Patients further underwent an in-depth cognitive, behavioral, and motor-functional evaluation. Correlational analyses were run to explore the correlates of the CFTI in patients. Logistic regressions were performed to test whether the CFTI could discriminate patients from HCs.

RESULTS: The CFTI was selectively associated (p ≤ 0.005) with fluency and memory subscales of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), but not with other variables. CFTI scores discriminated patients from HCs (p < 0.001) with high accuracy (82%), but not patients with a normal vs. defective performance on the ECAS-Total.

CONCLUSION: CFT measures in non-demented ALS patients were associated with verbal fluency and memory functions, and they were also able to discriminate them from HCs.}, } @article {pmid38111121, year = {2024}, author = {}, title = {Erratum to "Suicide among veterans with amyotrophic lateral sclerosis".}, journal = {Muscle & nerve}, volume = {69}, number = {2}, pages = {246-247}, doi = {10.1002/mus.28011}, pmid = {38111121}, issn = {1097-4598}, } @article {pmid38111057, year = {2023}, author = {Zhao, B and Cowan, CM and Coutts, JA and Christy, DD and Saraph, A and Hsueh, SCC and Plotkin, SS and Mackenzie, IR and Kaplan, JM and Cashman, NR}, title = {Targeting RACK1 to alleviate TDP-43 and FUS proteinopathy-mediated suppression of protein translation and neurodegeneration.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {200}, pmid = {38111057}, issn = {2051-5960}, support = {SRA F16-05805//ProMIS Neurosciences/ ; PJT-159546//Canadian Institute of Health Research/ ; CCNA-20R04367//Canadian Institute of Health Research/ ; 20R74974//Fondation Brain Canada/ ; F20-04056//Fondation Brain Canada/ ; F17-00928//William A. Lambert donation/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Drosophila melanogaster/genetics/metabolism ; HEK293 Cells ; Motor Neurons/metabolism ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/pathology ; *Frontotemporal Lobar Degeneration/pathology ; Protein Biosynthesis ; *Sarcoma/metabolism/pathology ; RNA-Binding Protein FUS/genetics/metabolism ; Receptors for Activated C Kinase/genetics/metabolism ; Neoplasm Proteins/genetics ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) and Fused in Sarcoma/Translocated in Sarcoma (FUS) are ribonucleoproteins associated with pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Under physiological conditions, TDP-43 and FUS are predominantly localized in the nucleus, where they participate in transcriptional regulation, RNA splicing and metabolism. In disease, however, they are typically mislocalized to the cytoplasm where they form aggregated inclusions. A number of shared cellular pathways have been identified that contribute to TDP-43 and FUS toxicity in neurodegeneration. In the present study, we report a novel pathogenic mechanism shared by these two proteins. We found that pathological FUS co-aggregates with a ribosomal protein, the Receptor for Activated C-Kinase 1 (RACK1), in the cytoplasm of spinal cord motor neurons of ALS, as previously reported for pathological TDP-43. In HEK293T cells transiently transfected with TDP-43 or FUS mutant lacking a functional nuclear localization signal (NLS; TDP-43[ΔNLS] and FUS[ΔNLS]), cytoplasmic TDP-43 and FUS induced co-aggregation with endogenous RACK1. These co-aggregates sequestered the translational machinery through interaction with the polyribosome, accompanied by a significant reduction of global protein translation. RACK1 knockdown decreased cytoplasmic aggregation of TDP-43[ΔNLS] or FUS[ΔNLS] and alleviated associated global translational suppression. Surprisingly, RACK1 knockdown also led to partial nuclear localization of TDP-43[ΔNLS] and FUS[ΔNLS] in some transfected cells, despite the absence of NLS. In vivo, RACK1 knockdown alleviated retinal neuronal degeneration in transgenic Drosophila melanogaster expressing hTDP-43[WT] or hTDP-43[Q331K] and improved motor function of hTDP-43[WT] flies, with no observed adverse effects on neuronal health in control knockdown flies. In conclusion, our results revealed a novel shared mechanism of pathogenesis for misfolded aggregates of TDP-43 and FUS mediated by interference with protein translation in a RACK1-dependent manner. We provide proof-of-concept evidence for targeting RACK1 as a potential therapeutic approach for TDP-43 or FUS proteinopathy associated with ALS and FTLD.}, } @article {pmid38110839, year = {2024}, author = {Benatar, M and Ostrow, LW and Lewcock, JW and Bennett, F and Shefner, J and Bowser, R and Larkin, P and Bruijn, L and Wuu, J}, title = {Biomarker Qualification for Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: Theory and Practice.}, journal = {Annals of neurology}, volume = {95}, number = {2}, pages = {211-216}, pmid = {38110839}, issn = {1531-8249}, support = {U01 NS107027/NS/NINDS NIH HHS/United States ; U01 NS107027/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Superoxide Dismutase-1 ; Intermediate Filaments ; Biomarkers ; Prognosis ; Neurofilament Proteins ; }, abstract = {OBJECTIVE: To explore whether the utility of neurofilament light chain (NfL), as a biomarker to aid amyotrophic lateral sclerosis (ALS) therapy development, would be enhanced by obtaining formal qualification from the US Food and Drug Administration for a defined context-of-use.

METHODS: Consensus discussion among academic, industry, and patient advocacy group representatives.

RESULTS: A wealth of scientific evidence supports the use of NfL as a prognostic, response, and potential safety biomarker in the broad ALS population, and as a risk/susceptibility biomarker among the subset of SOD1 pathogenic variant carriers. Although NfL has not yet been formally qualified for any of these contexts-of-use, the US Food and Drug Administration has provided accelerated approval for an SOD1-lowering antisense oligonucleotide, based partially on the recognition that a reduction in NfL is reasonably likely to predict a clinical benefit.

INTERPRETATION: The increasing incorporation of NfL into ALS therapy development plans provides evidence that its utility-as a prognostic, response, risk/susceptibility, and/or safety biomarker-is already widely accepted by the community. The willingness of the US Food and Drug Administration to base regulatory decisions on rigorous peer-reviewed data-absent formal qualification, leads us to conclude that formal qualification, despite some benefits, is not essential for ongoing and future use of NfL as a tool to aid ALS therapy development. Although the balance of considerations for and against seeking NfL biomarker qualification will undoubtedly vary across different diseases and contexts-of-use, the robustness of the published data and careful deliberations of the ALS community may offer valuable insights for other disease communities grappling with the same issues. ANN NEUROL 2024;95:211-216.}, } @article {pmid38110502, year = {2023}, author = {Ludolph, AC and Grandjean, H and Reviers, E and De Micheli, V and Bianchi, C and Cardosi, L and Russ, H and Silani, V}, title = {The preferences of people with amyotrophic lateral sclerosis on riluzole treatment in Europe.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {22497}, pmid = {38110502}, issn = {2045-2322}, mesh = {Humans ; Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Suspensions ; Europe ; *Airway Obstruction ; Tablets ; *Neuroprotective Agents ; }, abstract = {The Patient Preference Survey aims to understand unmet needs related to riluzole management in people with Amyotrophic Lateral Sclerosis (ALS) and to identify which characteristics of a new formulation could better match their preferences. The survey involved 117 people with ALS (PALS) treated with riluzole in four European countries. The dysphagic PALS were least satisfied with the riluzole tablet and oral suspension and with ease in self-administration; up to 68% of respondents postponed or missed the treatment due to swallowing difficulties and need of caregiver assistance. Overall, 51% of tablet and 53% of oral suspension users regularly crushed or mixed riluzole with beverages, respectively; PALS who always manipulated riluzole showed low satisfaction with the formulation and considered the risk of choking and pneumonia the most worrisome event. The survey evaluated the driving factors in choosing/switching the therapy: 67% of PALS declared a low risk of choking. The research finally evaluated which attributes of a new formulation would be preferred: the most relevant were ease of use (4.3/5), convenient/portable packaging (4.0/5) and oral-dissolving properties without tongue motility (3.9/5). The Patient Preference Survey suggests that patients have several unmet needs and preferences that could be addressed by a different formulation, e.g. using oral film technologies.}, } @article {pmid38110419, year = {2023}, author = {Chen, ZS and Ou, M and Taylor, S and Dafinca, R and Peng, SI and Talbot, K and Chan, HYE}, title = {Mutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {8420}, pmid = {38110419}, issn = {2041-1723}, mesh = {Humans ; *Frontotemporal Dementia/genetics ; RNA ; beta Catenin/genetics/metabolism ; C9orf72 Protein/genetics ; DNA Repeat Expansion ; *Amyotrophic Lateral Sclerosis/genetics ; YY1 Transcription Factor/genetics/metabolism ; }, abstract = {The GGGGCC hexanucleotide repeat expansion mutation in the chromosome 9 open reading frame 72 (C9orf72) gene is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). In this study, we demonstrate that the zinc finger (ZF) transcriptional regulator Yin Yang 1 (YY1) binds to the promoter region of the planar cell polarity gene Fuzzy to regulate its transcription. We show that YY1 interacts with GGGGCC repeat RNA via its ZF and that this interaction compromises the binding of YY1 to the Fuzzy[YY1] promoter sites, resulting in the downregulation of Fuzzy transcription. The decrease in Fuzzy protein expression in turn activates the canonical Wnt/β-catenin pathway and induces synaptic deficits in C9ALS/FTD neurons. Our findings demonstrate a C9orf72 GGGGCC RNA-initiated perturbation of YY1-Fuzzy transcriptional control that implicates aberrant Wnt/β-catenin signalling in C9ALS/FTD-associated neurodegeneration. This pathogenic cascade provides a potential new target for disease-modifying therapy.}, } @article {pmid38110144, year = {2024}, author = {Hafner, C and Manschein, V and Klaus, DA and Schaubmayr, W and Tiboldi, A and Scharner, V and Gleiss, A and Thal, B and Krammel, M and Hamp, T and Willschke, H and Hermann, M}, title = {Live stream of prehospital point-of-care ultrasound during cardiopulmonary resuscitation - A feasibility trial.}, journal = {Resuscitation}, volume = {194}, number = {}, pages = {110089}, doi = {10.1016/j.resuscitation.2023.110089}, pmid = {38110144}, issn = {1873-1570}, support = {21044//Medical Scientific Fund of the Mayor of the City of Vienna/ ; }, mesh = {Humans ; *Cardiopulmonary Resuscitation/methods ; *Emergency Medical Services/methods ; Feasibility Studies ; *Out-of-Hospital Cardiac Arrest/diagnostic imaging/therapy ; Point-of-Care Systems ; }, abstract = {BACKGROUND: Current resuscitation guidelines recommend that skilled persons could use ultrasound to detect reversible causes during cardiopulmonary resuscitation (CPR) where the examination can be safely integrated into the Advanced Life Support (ALS) algorithm. However, in a prehospital setting performing and rapidly interpreting ultrasound can be challenging for physicians. Implementing remote, expert-guided, and real-time transmissions of ultrasound examinations offers the opportunity for tele-support, even during an out-of-hospital cardiac arrest (OHCA). The aim of this feasibility study was to evaluate the impact of tele-supported ultrasound in ALS on hands-off time during an OHCA.

METHODS: In an urban setting, physicians performed point-of-care ultrasound (POCUS) on patients during OHCA using a portable device, either with tele-support (n = 30) or without tele-support (n = 12). Where tele-support was used, the ultrasound image was transmitted via a remote real-time connection to an on-call specialist in anaesthesia and intensive care medicine with an advanced level of critical care ultrasound expertise. The primary safety endpoint of this study was to evaluate whether POCUS can be safely integrated into the algorithm, and to provide an analysis of hands-off time before, during, and after POCUS during OHCA.

RESULTS: In all 42 cases it was possible to perform POCUS during regular rhythm analyses, and no additional hands-off time was required. In 40 of these 42 cases, the physicians were able to perform POCUS during a single regular rhythm analysis, with two periods required only in two cases. The median hands-off time during these rhythm analyses for POCUS with tele-support was 10 (8-13) seconds, and 11 (9-14) seconds for POCUS without tele-support. Furthermore, as a result of POCUS, in a quarter of all cases the physician on scene altered their diagnosis of the primary suspected cause of cardiac arrest, leading to a change in treatment strategy.

CONCLUSIONS: This feasibility study demonstrated that POCUS with tele-support can be safely performed during OHCA in an urban environment. Trial Registration (before patient enrolment): ClinicalTrials.gov, NCT04817475.}, } @article {pmid38109536, year = {2023}, author = {Qin, F and Cai, B and Cao, R and Bai, X and Yuan, J and Zhang, Y and Liu, Y and Chen, T and Liu, F and Sun, W and Zheng, Y and Qi, X and Zhao, W and Liu, B and Gao, C}, title = {Listerin promotes cGAS protein degradation through the ESCRT pathway to negatively regulate cGAS-mediated immune response.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {52}, pages = {e2308853120}, pmid = {38109536}, issn = {1091-6490}, support = {32230033//MOST | National Natural Science Foundation of China (NSFC)/ ; 81930039//MOST | National Natural Science Foundation of China (NSFC)/ ; 82222027//MOST | National Natural Science Foundation of China (NSFC)/ ; 32270918//MOST | National Natural Science Foundation of China (NSFC)/ ; 31900680//MOST | National Natural Science Foundation of China (NSFC)/ ; 2021YFC2300603//MOST | National Key Research and Development Program of China (NKPs)/ ; ZR201911140289//| Natural Science Foundation of Shandong Province ()/ ; ZR2021YQ48//| Natural Science Foundation of Shandong Province ()/ ; ZR2018BC021//| Natural Science Foundation of Shandong Province ()/ ; ZR2021ZD08//| Natural Science Foundation of Shandong Province ()/ ; 82321002//MOST | National Natural Science Foundation of China (NSFC)/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/immunology ; Endosomal Sorting Complexes Required for Transport/metabolism ; Immunity, Innate/genetics ; Nucleotidyltransferases/metabolism ; Proteolysis ; Signal Transduction/physiology ; Disease Models, Animal ; *Ubiquitin-Protein Ligases/antagonists & inhibitors/immunology/metabolism ; }, abstract = {The enzyme cyclic GMP-AMP synthase (cGAS) is a key sensor for detecting misplaced double-stranded DNA (dsDNA) of genomic, mitochondrial, and microbial origin. It synthesizes 2'3'-cGAMP, which in turn activates the stimulator of interferon genes pathway, leading to the initiation of innate immune responses. Here, we identified Listerin as a negative regulator of cGAS-mediated innate immune response. We found that Listerin interacts with cGAS on endosomes and promotes its K63-linked ubiquitination through recruitment of the E3 ligase TRIM27. The polyubiquitinated cGAS is then recognized by the endosomal sorting complexes required for transport machinery and sorted into endosomes for degradation. Listerin deficiency enhances the innate antiviral response to herpes simplex virus 1 infection. Genetic deletion of Listerin also deteriorates the neuroinflammation and the ALS disease progress in an ALS mice model; overexpression of Listerin can robustly ameliorate disease progression in ALS mice. Thus, our work uncovers a mechanism for cGAS regulation and suggests that Listerin may be a promising therapeutic target for ALS disease.}, } @article {pmid38109186, year = {2023}, author = {Nimma, S and Gans, A and Wardhan, R and Allen, W}, title = {Remimazolam Sedation and Neuraxial Anesthesia in a Patient with Amyotrophic Lateral Sclerosis Undergoing an Open Colectomy: A Case Report.}, journal = {A&A practice}, volume = {17}, number = {12}, pages = {e01733}, doi = {10.1213/XAA.0000000000001733}, pmid = {38109186}, issn = {2575-3126}, mesh = {Male ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/surgery ; *Neurodegenerative Diseases ; Benzodiazepines ; *Anesthesia, Conduction ; Colectomy ; *Respiratory Insufficiency ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving the upper and lower motor neurons. Perioperative management of patients with ALS can be challenging due to the risk of hemodynamic instability, aspiration, and ventilatory failure. We discuss a 58-year-old male patient with ALS who underwent open abdominal surgery under regional anesthesia utilizing a remimazolam infusion for sedation. While various sedation agents have been used successfully in patients with ALS, remimazolam, a new short-acting benzodiazepine with unique pharmacologic properties and reversible anxiolysis, provides amnesia while avoiding ventilatory depression.}, } @article {pmid38108952, year = {2024}, author = {Xiao, X and Rui, Y and Jin, Y and Chen, M}, title = {Relationship of Sleep Disorder with Neurodegenerative and Psychiatric Diseases: An Updated Review.}, journal = {Neurochemical research}, volume = {49}, number = {3}, pages = {568-582}, pmid = {38108952}, issn = {1573-6903}, support = {82371541//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Alzheimer Disease/metabolism ; Brain/metabolism ; *Huntington Disease/metabolism ; *Sleep Wake Disorders/metabolism ; }, abstract = {Sleep disorders affect many people worldwide and can accompany neurodegenerative and psychiatric diseases. Sleep may be altered before the clinical manifestations of some of these diseases appear. Moreover, some sleep disorders affect the physiological organization and function of the brain by influencing gene expression, accelerating the accumulation of abnormal proteins, interfering with the clearance of abnormal proteins, or altering the levels of related hormones and neurotransmitters, which can cause or may be associated with the development of neurodegenerative and psychiatric diseases. However, the detailed mechanisms of these effects are unclear. This review mainly focuses on the relationship between and mechanisms of action of sleep in Alzheimer's disease, depression, and anxiety, as well as the relationships between sleep and Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. This summary of current research hotspots may provide researchers with better clues and ideas to develop treatment solutions for neurodegenerative and psychiatric diseases associated with sleep disorders.}, } @article {pmid38108666, year = {2024}, author = {Clemente-Gutierrez, U and Pieterman, CRC and Lui, MS and Yamashita, TS and Tame-Elorduy, A and Huang, BL and Shirali, AS and Erstad, DJ and Lee, JE and Fisher, SB and Graham, PH and Grubbs, EG and Waguespack, SG and Ng, CS and Perrier, N}, title = {Beyond the three P's: adrenal involvement in MEN1.}, journal = {Endocrine-related cancer}, volume = {31}, number = {2}, pages = {}, pmid = {38108666}, issn = {1479-6821}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Adult ; Middle Aged ; *Multiple Endocrine Neoplasia Type 1/pathology ; Retrospective Studies ; *Adrenal Gland Neoplasms/epidemiology ; *Adrenocortical Carcinoma ; *Adrenal Cortex Neoplasms ; }, abstract = {Adrenal lesions (ALs) are often detected in patients with multiple endocrine neoplasia type 1 (MEN1). However, they are not well described in MEN1, making their clinical management unclear. This study examined the prevalence and outcomes of ALs found in MEN1. We performed a retrospective chart review of patients diagnosed with MEN1 from 1990 to 2021. ALs were diagnosed using abdominal or thoracic imaging and classified as being unilateral or bilateral, having single or multiple nodules, and as having diffuse enlargement or not. Measurable nodular lesions were analyzed for their size and growth over time. Patients' clinical and radiographic characteristics were collected. We identified 382 patients with MEN1, 89 (23.3%) of whom had ALs. The mean age at detection was 47 ± 11.9 years. We documented 101 measurable nodular lesions (mean size, 17.5 mm; range, 3-123 mm). Twenty-seven nodules (26.7%) were smaller than 1 cm. Watchful waiting was indicated in 79 (78.2%) patients, of whom 28 (35.4%) had growing lesions. Functional lesions were diagnosed in 6 (15.8%) of 38 that had functional work-up (diagnoses: pheochromocytoma (n = 2), adrenocorticotropic hormone-dependent hypercortisolism (n = 2), hyperandrogenism (n = 1), hyperaldosteronism (n = 1)); surgery was indicated for 5 (83.3%; n = 12 nodules), 2 of whom had bilateral, diffuse adrenal enlargement. Two patients were diagnosed with adrenocortical carcinoma and two with neoplasms of uncertain malignant potential. Radiographic or clinical progression of ALs is uncommon. Malignancy should be suspected on the basis of a lesion's growth rate and size. A baseline hormonal work-up is recommended, and no further biochemical work-up is suggested when the initial assessment shows nonfunctioning lesions.}, } @article {pmid38106242, year = {2023}, author = {Wang, S and Man, X and Chen, Y and Gong, T and Gao, F and Chen, W and Wang, G and Zhao, B and Chhabra, A}, title = {Three-dimensional magnetic resonance neurography aids in detection of brachial plexus nerve root signal and size alterations in patients with amyotrophic lateral sclerosis: a case-control study.}, journal = {Quantitative imaging in medicine and surgery}, volume = {13}, number = {12}, pages = {8694-8703}, pmid = {38106242}, issn = {2223-4292}, abstract = {BACKGROUND: Since previous histopathological studies have shown a distal to proximal gradient of axonal damage in peripheral nerves of patients with amyotrophic lateral sclerosis (ALS), it would be worthwhile to evaluate consequence of such changes on magnetic resonance imaging (MRI). The aim of this study was to assess proximal-distal longitudinal signal and size alterations of brachial plexus nerve roots in ALS patients using 3-dimensional (3D) magnetic resonance neurography (MRN).

METHODS: A total of 21 ALS patients and 19 controls were evaluated. The diameters and signal-to-noise (SNR) ratio values of C5-C8 roots were measured at five points from proximal to distal sites. Student's t-test was performed to compare the differences at each point between two groups. Linear regression was performed for each nerve root, and the differences in linear regression slopes between two groups were analyzed. Receiver operating characteristic (ROC) analysis was performed for the diameter and SNR value ratio of the distal to the proximal points.

RESULTS: Interobserver agreement was excellent [intraclass correlation coefficient (ICC): 0.802-0.913]. The diameters and SNR values of C5-C8 roots showed a significant decrease (P<0.05) from proximal to distal except SNR value of C5 root in controls. The slope values of diameters in ALS were -0.01924 for C5, -0.04404 for C6, -0.06228 for C7, and -0.06464 for C8. The slope values of SNR values in ALS were -10.14 for C5, -12.86 for C6, -15.99 for C7, and -19.06 for C8. The slope of nerve diameters and SNR values for ALS patients were more negatively sloped than controls (P<0.05) except SNR values of C5 and C7 roots. The ROC analysis confirmed that the diameter and SNR value ratio could differentiate ALS patients from controls with high accuracy. The cutoff values of diameter ratio were 0.7418 for C5, 0.6952 for C6, 0.6431 for C7, and 0.7147 for C8. The cutoff values of SNR value ratio were 0.5989 for C5, 0.6516 for C6, 0.6065 for C7, and 0.6758 for C8.

CONCLUSIONS: Proximal-distal longitudinal diameters and SNR values decreased significantly for brachial plexus nerve roots in ALS patients with larger differences in slopes compared to controls. These results reflect pathophysiological changes of ALS and may be helpful in improving the diagnosis of ALS.}, } @article {pmid38105925, year = {2023}, author = {Mimic, S and Aru, B and Pehlivanoğlu, C and Sleiman, H and Andjus, PR and Yanıkkaya Demirel, G}, title = {Immunology of amyotrophic lateral sclerosis - role of the innate and adaptive immunity.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1277399}, pmid = {38105925}, issn = {1662-4548}, abstract = {This review aims to summarize the latest evidence about the role of innate and adaptive immunity in Amyotrophic Lateral Sclerosis (ALS). ALS is a devastating neurodegenerative disease affecting upper and lower motor neurons, which involves essential cells of the immune system that play a basic role in innate or adaptive immunity, that can be neurotoxic or neuroprotective for neurons. However, distinguishing between the sole neurotoxic or neuroprotective function of certain cells such as astrocytes can be challenging due to intricate nature of these cells, the complexity of the microenvironment and the contextual factors. In this review, in regard to innate immunity we focus on the involvement of monocytes/macrophages, microglia, the complement, NK cells, neutrophils, mast cells, and astrocytes, while regarding adaptive immunity, in addition to humoral immunity the most important features and roles of T and B cells are highlighted, specifically different subsets of CD4[+] as well as CD8[+] T cells. The role of autoantibodies and cytokines is also discussed in distinct sections of this review.}, } @article {pmid38105307, year = {2024}, author = {Hamad, AA and Amer, BE and Hawas, Y and Mabrouk, MA and Meshref, M}, title = {Masitinib as a neuroprotective agent: a scoping review of preclinical and clinical evidence.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {5}, pages = {1861-1873}, pmid = {38105307}, issn = {1590-3478}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; *Benzamides/pharmacology/therapeutic use ; *Thiazoles/pharmacology/therapeutic use ; *Piperidines/pharmacology/therapeutic use ; *Pyridines/pharmacology/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; }, abstract = {OBJECTIVES: Masitinib, originally developed as a tyrosine kinase inhibitor for cancer treatment, has shown potential neuroprotective effects in various neurological disorders by modulating key pathways implicated in neurodegeneration. This scoping review aimed to summarize the current evidence of masitinib's neuroprotective activities from preclinical to clinical studies.

METHODS: This scoping review was conducted following the guidelines described by Arksey and O'Malley and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The inclusion criteria covered all original studies reporting on the neuroprotective effects of masitinib, including clinical studies, animal studies, and in vitro studies.

RESULTS: A total of 16 studies met the inclusion criteria and were included in the review. These comprised five randomized controlled trials (RCTs), one post-hoc analysis study, one case report, and nine animal studies. The RCTs focused on Alzheimer's disease (two studies), multiple sclerosis (two studies), and amyotrophic lateral sclerosis (one study). Across all included studies, masitinib consistently demonstrated neuroprotective properties. However, the majority of RCTs reported concerns regarding the safety profile of masitinib. Preclinical studies revealed the neuroprotective mechanisms of masitinib, which include inhibition of certain kinases interfering with cell proliferation and survival, reduction of neuroinflammation, and exhibition of antioxidant activity.

CONCLUSION: The current evidence suggests a promising therapeutic benefit of masitinib in neurodegenerative diseases. However, further research is necessary to validate and expand upon these findings, particularly regarding the precise mechanisms through which masitinib exerts its therapeutic effects. Future studies should also focus on addressing the safety concerns associated with masitinib use.}, } @article {pmid38105306, year = {2024}, author = {Katerelos, A and Alexopoulos, P and Economou, P and Polychronopoulos, P and Chroni, E}, title = {Cognitive function in amyotrophic lateral sclerosis: a cross-sectional and prospective pragmatic clinical study with review of the literature.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {5}, pages = {2075-2085}, pmid = {38105306}, issn = {1590-3478}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; *Cognition Disorders/etiology/complications ; Neuropsychological Tests ; Prospective Studies ; Quality of Life ; Cross-Sectional Studies ; Cognition/physiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) can present with either bulbar or spinal symptoms, and in some cases, both types of symptoms may be present. In addition, cognitive impairment has been observed in ALS. The study aimed to evaluate the frontal and general cognitive performance in ALS not only cross-sectionally but also longitudinally.

METHODS AND MATERIALS: The Frontal Assessment Battery (FAB) and the Montreal Cognitive Assessment (MoCA) were employed to assess cognitive function in 52 adults with ALS and 52 cognitively healthy individuals. The statistical analyses encompassed the Pearson Chi square test, the Skillings-Mack test, the Spearman's rank correlation coefficient, and the Proportional Odds Logistic Regression Model (POLR).

RESULTS: Cross-sectionally, lower cognitive performance was associated with ALS diagnosis, older age, and motor functional decline. The cognitive impairment of individuals with bulbar and spinal-bulbar symptoms showed faster deterioration compared to those with spinal symptoms. The spinal subgroup consistently performed worst in delayed recall and attention, while the spinal-bulbar and bulbar subgroups exhibited inferior scores in delayed recall, attention, visuospatial skills, orientation, and verbal fluency.

CONCLUSION: The incorporation of cognitive screening in the diagnostic workup of ALS may be beneficial, as early detection can enhance symptom management and improve the quality of life for both individuals with ALS and their care partners.}, } @article {pmid38103252, year = {2024}, author = {He, L and Zhou, Q and Xiu, C and Shao, Y and Shen, D and Meng, H and Le, W and Chen, S}, title = {Circulating proteomic biomarkers for diagnosing sporadic amyotrophic lateral sclerosis: a cross-sectional study.}, journal = {Neural regeneration research}, volume = {19}, number = {8}, pages = {1842-1848}, pmid = {38103252}, issn = {1673-5374}, abstract = {JOURNAL/nrgr/04.03/01300535-202408000-00039/figure1/v/2023-12-16T180322Z/r/image-tiff Biomarkers are required for the early detection, prognosis prediction, and monitoring of amyotrophic lateral sclerosis, a progressive disease. Proteomics is an unbiased and quantitative method that can be used to detect neurochemical signatures to aid in the identification of candidate biomarkers. In this study, we used a label-free quantitative proteomics approach to screen for substantially differentially regulated proteins in ten patients with sporadic amyotrophic lateral sclerosis compared with five healthy controls. Substantial upregulation of serum proteins related to multiple functional clusters was observed in patients with sporadic amyotrophic lateral sclerosis. Potential biomarkers were selected based on functionality and expression specificity. To validate the proteomics profiles, blood samples from an additional cohort comprising 100 patients with sporadic amyotrophic lateral sclerosis and 100 healthy controls were subjected to enzyme-linked immunosorbent assay. Eight substantially upregulated serum proteins in patients with sporadic amyotrophic lateral sclerosis were selected, of which the cathelicidin-related antimicrobial peptide demonstrated the best discriminative ability between patients with sporadic amyotrophic lateral sclerosis and healthy controls (area under the curve [AUC] = 0.713, P < 0.0001). To further enhance diagnostic accuracy, a multi-protein combined discriminant algorithm was developed incorporating five proteins (hemoglobin beta, cathelicidin-related antimicrobial peptide, talin-1, zyxin, and translationally-controlled tumor protein). The algorithm achieved an AUC of 0.811 and a P-value of < 0.0001, resulting in 79% sensitivity and 71% specificity for the diagnosis of sporadic amyotrophic lateral sclerosis. Subsequently, the ability of candidate biomarkers to discriminate between early-stage amyotrophic lateral sclerosis patients and controls, as well as patients with different disease severities, was examined. A two-protein panel comprising talin-1 and translationally-controlled tumor protein effectively distinguished early-stage amyotrophic lateral sclerosis patients from controls (AUC = 0.766, P < 0.0001). Moreover, the expression of three proteins (FK506 binding protein 1A, cathelicidin-related antimicrobial peptide, and hemoglobin beta-1) was found to increase with disease progression. The proteomic signatures developed in this study may help facilitate early diagnosis and monitor the progression of sporadic amyotrophic lateral sclerosis when used in combination with current clinical-based parameters.}, } @article {pmid38103219, year = {2024}, author = {Ma, S and Zhang, CL}, title = {MAP4K inhibition as a potential therapy for amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {8}, pages = {1639-1640}, pmid = {38103219}, issn = {1673-5374}, support = {R01 NS092616/NS/NINDS NIH HHS/United States ; R01 NS111776/NS/NINDS NIH HHS/United States ; R01 NS117065/NS/NINDS NIH HHS/United States ; R01 NS127375/NS/NINDS NIH HHS/United States ; }, } @article {pmid38103074, year = {2023}, author = {Villavicencio-Tejo, F and Olesen, MA and Navarro, L and Calisto, N and Iribarren, C and García, K and Corsini, G and Quintanilla, RA}, title = {Gut-Brain Axis Deregulation and Its Possible Contribution to Neurodegenerative Disorders.}, journal = {Neurotoxicity research}, volume = {42}, number = {1}, pages = {4}, pmid = {38103074}, issn = {1476-3524}, support = {1200178//Agencia Nacional de Investigación y Desarrollo/ ; }, mesh = {Animals ; Humans ; Brain-Gut Axis ; *Amyotrophic Lateral Sclerosis ; *Gastrointestinal Microbiome/physiology ; *Neurodegenerative Diseases/pathology ; Central Nervous System ; *Parkinson Disease/pathology ; *Huntington Disease/pathology ; *Alzheimer Disease ; }, abstract = {The gut-brain axis is an essential communication pathway between the central nervous system (CNS) and the gastrointestinal tract. The human microbiota is composed of a diverse and abundant microbial community that compasses more than 100 trillion microorganisms that participate in relevant physiological functions such as host nutrient metabolism, structural integrity, maintenance of the gut mucosal barrier, and immunomodulation. Recent evidence in animal models has been instrumental in demonstrating the possible role of the microbiota in neurodevelopment, neuroinflammation, and behavior. Furthermore, clinical studies suggested that adverse changes in the microbiota can be considered a susceptibility factor for neurological disorders (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). In this review, we will discuss evidence describing the role of gut microbes in health and disease as a relevant risk factor in the pathogenesis of neurodegenerative disorders, including AD, PD, HD, and ALS.}, } @article {pmid38102715, year = {2023}, author = {Stringer, RN and Weiss, N}, title = {Pathophysiology of ion channels in amyotrophic lateral sclerosis.}, journal = {Molecular brain}, volume = {16}, number = {1}, pages = {82}, pmid = {38102715}, issn = {1756-6606}, support = {#22-23242S//Grantová Agentura České Republiky/ ; VEGA #2/0073/22//Agentúra Ministerstva Školstva, Vedy, Výskumu a Športu SR/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Motor Neurons ; Ion Channels ; Muscle Weakness ; }, abstract = {Amyotrophic lateral sclerosis (ALS) stands as the most prevalent and severe form of motor neuron disease, affecting an estimated 2 in 100,000 individuals worldwide. It is characterized by the progressive loss of cortical, brainstem, and spinal motor neurons, ultimately resulting in muscle weakness and death. Although the etiology of ALS remains poorly understood in most cases, the remodelling of ion channels and alteration in neuronal excitability represent a hallmark of the disease, manifesting not only during the symptomatic period but also in the early pre-symptomatic stages. In this review, we delve into these alterations observed in ALS patients and preclinical disease models, and explore their consequences on neuronal activities. Furthermore, we discuss the potential of ion channels as therapeutic targets in the context of ALS.}, } @article {pmid38102515, year = {2024}, author = {Shen, D and Ji, Y and Qiu, C and Wang, K and Gao, Z and Liu, B and Shen, Y and Gong, L and Yang, X and Chen, X and Sun, H and Yao, X}, title = {Single-Cell RNA Sequencing Analysis of Microglia Dissected the Energy Metabolism and Revealed Potential Biomarkers in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {61}, number = {7}, pages = {4473-4487}, pmid = {38102515}, issn = {1559-1182}, support = {92068112//National Natural Science Foundation of China/ ; 82072160//National Natural Science Foundation of China/ ; 32130060//National Natural Science Foundation of China/ ; 81901933//National Natural Science Foundation of China/ ; 20KJA310012//Major Natural Science Research Projects in Universities of Jiangsu Province/ ; BK20202013//Natural Science Foundation of Jiangsu Province/ ; BK20201209//Natural Science Foundation of Jiangsu Province/ ; JC22022037//Priority Academic Program Development of Jiangsu Higher Education Institutions/ ; MS22022010//Priority Academic Program Development of Jiangsu Higher Education Institutions/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Microglia/metabolism/pathology ; Animals ; *Energy Metabolism/genetics ; Humans ; *Biomarkers/metabolism ; *Single-Cell Analysis ; Sequence Analysis, RNA/methods ; Mice ; Mice, Transgenic ; Male ; Superoxide Dismutase-1/genetics/metabolism ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease, accompanied by the gradual loss of motor neuron, even life-threatening. However, the pathogenesis, early diagnosis, and effective strategies of ALS are not yet completely understood. In this study, the function of differentially expressed genes (DEGs) in non-neuronal cells of the primary motor cortex of ALS patients (DATA1), the brainstem of SOD1 mutant ALS mice (DATA2), and the whole blood tissue of ALS patients (DATA3) were explored. The results showed that the functions of DEGs in non-neuronal cells were mainly related to energy metabolism (such as oxidative phosphorylation) and protein synthesis. In non-neuronal cells, six upregulated DEGs (HSPA8, SOD1, CALM1, CALM2, NEFL, COX6C) and three downregulated DEGs (SNRNP70, HSPA1A, HSPA1B) might be key factors in regulating ALS. Microglia played a key role in the development of ALS. The expression of SOD1 and TUBA4A in microglia in DATA1 was significantly increased. The integration analysis of DEGs in DATA1 and DATA2 showed that SOD1 and CALM1 might be potential biomarkers. The integration analysis of DEGs in DATA1 and DATA3 showed that CALM2 and HSPA1A might be potential biomarkers. Cell interaction showed that the interaction between microglia and other cells was reduced in high oxidative phosphorylation states, which might be a risk factor in ALS. Our research provided evidence for the pathogenesis, early diagnosis, and potential targeted therapy for ALS.}, } @article {pmid38101818, year = {2024}, author = {Ryan, L and Rubinsztein, DC}, title = {The autophagy of stress granules.}, journal = {FEBS letters}, volume = {598}, number = {1}, pages = {59-72}, doi = {10.1002/1873-3468.14787}, pmid = {38101818}, issn = {1873-3468}, support = {//Raymond and Beverly Sackler Fund/ ; NIHR203312//NIHR Cambridge Biomedical Research Centre/ ; //UK Dementia Research Institute/ ; }, mesh = {Humans ; *Stress Granules ; Proteins ; Autophagy ; *Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Our understanding of stress granule (SG) biology has deepened considerably in recent years, and with this, increased understanding of links has been made between SGs and numerous neurodegenerative diseases. One of the proposed mechanisms by which SGs and any associated protein aggregates may become pathological is based upon defects in their autophagic clearance, and so the precise processes governing the degradation of SGs are important to understand. Mutations and disease-associated variants implicated in amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and frontotemporal lobar dementia compromise autophagy, whilst autophagy-inhibiting drugs or knockdown of essential autophagy proteins result in the persistence of SGs. In this review, we will consider the current knowledge regarding the autophagy of SG.}, } @article {pmid38100415, year = {2023}, author = {Qi, C and Verheijen, BM and Kokubo, Y and Shi, Y and Tetter, S and Murzin, AG and Nakahara, A and Morimoto, S and Vermulst, M and Sasaki, R and Aronica, E and Hirokawa, Y and Oyanagi, K and Kakita, A and Ryskeldi-Falcon, B and Yoshida, M and Hasegawa, M and Scheres, SHW and Goedert, M}, title = {Tau filaments from amyotrophic lateral sclerosis/parkinsonism-dementia complex adopt the CTE fold.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {51}, pages = {e2306767120}, pmid = {38100415}, issn = {1091-6490}, support = {MC_UP_A025_1013/MRC_/Medical Research Council/United Kingdom ; R01 AG054641/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; MC_U105184291/MRC_/Medical Research Council/United Kingdom ; MC_UP_1201/25/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; *Dementia/etiology ; *Chronic Traumatic Encephalopathy ; *Neurodegenerative Diseases ; *Parkinsonian Disorders/complications ; *Tauopathies ; Japan ; tau Proteins ; }, abstract = {The amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the island of Guam and the Kii peninsula of Japan is a fatal neurodegenerative disease of unknown cause that is characterized by the presence of abundant filamentous tau inclusions in brains and spinal cords. Here, we used electron cryo-microscopy to determine the structures of tau filaments from the cerebral cortex of three cases of ALS/PDC from Guam and eight cases from Kii, as well as from the spinal cord of two of the Guam cases. Tau filaments had the chronic traumatic encephalopathy (CTE) fold, with variable amounts of Type I and Type II filaments. Paired helical tau filaments were also found in three Kii cases and tau filaments with the corticobasal degeneration fold in one Kii case. We identified a new Type III CTE tau filament, where protofilaments pack against each other in an antiparallel fashion. ALS/PDC is the third known tauopathy with CTE-type filaments and abundant tau inclusions in cortical layers II/III, the others being CTE and subacute sclerosing panencephalitis. Because these tauopathies are believed to have environmental causes, our findings support the hypothesis that ALS/PDC is caused by exogenous factors.}, } @article {pmid38100267, year = {2024}, author = {Qi, S and Peng, Y and Wang, G and Zhang, X and Liu, M and He, L}, title = {A tale of dual functions of SERF family proteins in regulating amyloid formation.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {25}, number = {5}, pages = {e202300727}, doi = {10.1002/cbic.202300727}, pmid = {38100267}, issn = {1439-7633}, support = {2018YFE0202301//National Key R&D Program of China/ ; 2018YFE0202300//National Key R&D Program of China/ ; 22174151//National Natural Sciences Foundation of China/ ; 21991080//National Natural Sciences Foundation of China/ ; XDB0540000//Strategic Priority Research Program of the Chinese Academy of Sciences/ ; 2023AFA041//Hubei Provincial Natural Science Foundation of China/ ; }, mesh = {Animals ; Caenorhabditis elegans ; *Neurodegenerative Diseases ; Amyloidogenic Proteins ; Amyloid beta-Peptides ; *Alzheimer Disease ; *Caenorhabditis elegans Proteins ; }, abstract = {The abnormal aggregation of proteins is a significant pathological hallmark of diseases, such as the amyloid formation associated with fused in sarcoma protein (FUS) in frontotemporal lobar degeneration and amyotrophic lateral sclerosis diseases. Understanding which cellular components and how these components regulate the process of abnormal protein aggregation in living organisms is crucial for the prevention and treatment of neurodegenerative diseases. MOAG-4/SERF is a conserved family of proteins with rich positive charged residues, which was initially identified as an enhancer for the formation of amyloids in C. elegans. Knocking out SERF impedes the amyloid formation of various proteins, including α-synuclein and β-amyloid, which are linked to Parkinson's and Alzheimer's diseases, respectively. However, recent studies revealed SERF exhibited dual functions, as it could both promote and inhibit the fibril formation of the neurodegenerative disease-related amyloidogenic proteins. The connection between functions and structure basis of SERF in regulating the amyloid formation is still unclear. This review will outline the hallmark proteins in neurodegenerative diseases, summarize the contradictory role of the SERF protein family in promoting and inhibiting the aggregation of neurodegenerative proteins, and finally explore the potential structural basis and functional selectivity of the SERF protein.}, } @article {pmid38099851, year = {2024}, author = {Rong, P and Heidrick, L}, title = {Hierarchical Temporal Structuring of Speech: A Multiscale, Multimodal Framework to Inform the Assessment and Management of Neuromotor Speech Disorder.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {67}, number = {1}, pages = {92-115}, doi = {10.1044/2023_JSLHR-23-00219}, pmid = {38099851}, issn = {1558-9102}, mesh = {Humans ; *Speech ; Speech Intelligibility ; *Amyotrophic Lateral Sclerosis/complications ; Jaw ; Speech Disorders ; Speech Production Measurement ; Tongue ; Speech Acoustics ; }, abstract = {PURPOSE: Hierarchical temporal structuring of speech is the key to multiscale linguistic information transfer toward effective communication. This study investigated and linked the hierarchical temporal cues of the kinematic and acoustic modalities of natural, unscripted speech in neurologically healthy and impaired speakers.

METHOD: Thirteen individuals with amyotrophic lateral sclerosis (ALS) and 10 age-matched healthy controls performed a story-telling task. The hierarchical temporal structure of the speech stimulus was measured by (a) 26 articulatory-kinematic features characterizing the depth, phase synchronization, and coherence of temporal modulation of the tongue tip, tongue body, lower lip, and jaw, at three hierarchically nested timescales corresponding to prosodic stress, syllables, and onset-rime/phonemes, and (b) 25 acoustic features characterizing the parallel aspects of temporal modulation of five critical-spectral-band envelopes. All features were compared between groups. For each aspect of temporal modulation, the contributions of all articulatory features to the parallel acoustic features were evaluated by group.

RESULTS: Generally consistent disease impacts were identified on the articulatory and acoustic features, manifested by reduced modulation depths of most articulators and critical-spectral-band envelopes, primarily at the timescales of syllables and onset-rime/phonemes. For healthy speakers, the strongest articulatory-acoustic relationships were found for (a) jaw and lip, in modulating stress timing, and (b) tongue tip, in modulating the timing relation between onset-rime/phonemes and syllables. For speakers with ALS, the tongue body, tongue tip, and jaw all showed the greatest contributions to modulating syllable timing.

CONCLUSIONS: The observed disease impacts likely reflect reduced entrainment of speech motor activities to finer-grained linguistic events, presumably due to the dynamic constraints of the neuromuscular system. To accommodate these restrictions, speakers with ALS appear to use their residual articulatory motor capacities to accentuate and convey the perceptually most salient temporal cues underpinned by the syllable-centric parsing mechanism. This adaptive strategy has potential implications in managing neuromotor speech disorders.}, } @article {pmid38099605, year = {2024}, author = {Peverelli, S and Brusati, A and Casiraghi, V and Sorce, MN and Invernizzi, S and Santangelo, S and Morelli, C and Verde, F and Silani, V and Ticozzi, N and Ratti, A}, title = {Analysis of normal C9orf72 repeat length as possible disease modifier in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {207-210}, doi = {10.1080/21678421.2023.2273965}, pmid = {38099605}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; DNA Repeat Expansion/genetics ; C9orf72 Protein/genetics ; Mutation/genetics ; Genotype ; }, abstract = {The C9orf72 hexanucleotide repeat (HR) expansion is the main genetic cause of amyotrophic lateral sclerosis (ALS), with expansion size from 30 to >4000 units. Normal C9orf72 HR length is polymorphic (2-23 repeats) with alleles >8 units showing a low frequency in the general population. This study aimed to investigate if the normal C9orf72 HR length influences C9orf72 gene expression and acts as disease modifier in ALS patients negative for C9orf72 mutation (ALS-C9Neg). We found that the distribution of HR alleles was similar in 325 ALS-C9Neg and 303 healthy controls. Gene expression analysis in blood revealed a significant increase of total C9orf72 and V3 mRNA levels in ALS-C9Neg carrying two long alleles (L/L; ≥8 units) compared to patients homozygous for the 2-unit short allele (S/S). However, HR allele genotypes (L/L, S/L, S/S) correlated with no clinical parameters. Our data suggest that normal C9orf72 HR length does not act as disease modifier in ALS-C9Neg despite increasing gene expression.}, } @article {pmid38097873, year = {2024}, author = {Seo, J and Saurkar, S and Fernandez, GS and Das, A and Goutman, SA and Heidenreich, S}, title = {Preferences of Patients with Amyotrophic Lateral Sclerosis for Intrathecal Drug Delivery: Choosing between an Implanted Drug-Delivery Device and Therapeutic Lumbar Puncture.}, journal = {The patient}, volume = {17}, number = {2}, pages = {161-177}, pmid = {38097873}, issn = {1178-1661}, mesh = {Humans ; Middle Aged ; *Choice Behavior ; *Amyotrophic Lateral Sclerosis/drug therapy ; Spinal Puncture/adverse effects ; Patient Preference ; Europe ; }, abstract = {BACKGROUND: Novel intrathecal treatments for amyotrophic lateral sclerosis (ALS) may require delivery using lumbar puncture (LP). Implanted drug-delivery devices (IDDDs) could be an alternative but little is known about patients' preferences for intrathecal drug-delivery methods.

OBJECTIVE: We aimed to elicit preferences of patients with ALS for routine LP and IDDD use.

METHODS: A discrete choice experiment (DCE) and a threshold technique (TT) exercise were conducted online among patients with ALS in the US and Europe. In the DCE, patients made trade-offs between administration attributes. Attributes were identified from qualitative interviews. The TT elicited maximum acceptable risks (MARs) of complications from device implantation surgery. DCE data were analyzed using mixed logit to quantify relative attribute importance (RAI) as the maximum contribution of each attribute to a preference, and to estimate MARs of device failure. TT data were analyzed using interval regression. Four scenarios of LP and IDDD were compared.

RESULTS: Participants (N = 295) had a mean age of 57.7 years; most (74.2%) were diagnosed < 3 years ago. Preferences were affected by device failure risk (RAI 28.6%), administration frequency (26.4%), administration risk (19.7%), overall duration (17.8%), and appointment location (7.5%). Patients accepted a 5.6% device failure risk to reduce overall duration from 2 h to 30 min and a 3.6% risk for administration in a local clinic instead of a hospital. The average MAR of complications from implantation surgery was 29%. Patients preferred IDDD over LP in three of four scenarios.

CONCLUSION: Patients considered an IDDD as a valuable alternative to LP in multiple clinical settings.}, } @article {pmid38097540, year = {2023}, author = {Ikeda, T and Takahashi, K and Higashi, M and Komiya, H and Asano, T and Ogasawara, A and Kubota, S and Hashiguchi, S and Kunii, M and Tanaka, K and Tada, M and Doi, H and Takeuchi, H and Takei, K and Tanaka, F}, title = {Lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor antagonist, ameliorates disease progression in amyotrophic lateral sclerosis model mice.}, journal = {Cell death discovery}, volume = {9}, number = {1}, pages = {454}, pmid = {38097540}, issn = {2058-7716}, support = {17H03561//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 18K07532//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 20H03342//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 20K07761//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; }, abstract = {Nogo-Nogo receptor 1 (NgR1) signaling is significantly implicated in neurodegeneration in amyotrophic lateral sclerosis (ALS). We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of NgR1 that prevents all myelin-associated inhibitors (MAIs), including Nogo, from binding to NgR1. Here we investigated the role of LOTUS in ALS pathogenesis by analyzing G93A-mutated human superoxide dismutase 1 (SOD1) transgenic (Tg) mice, as an ALS model, as well as newly generated LOTUS-overexpressing SOD1 Tg mice. We examined expression profiles of LOTUS and MAIs and compared motor functions and survival periods in these mice. We also investigated motor neuron survival, glial proliferation in the lumbar spinal cord, and neuromuscular junction (NMJ) morphology. We analyzed downstream molecules of NgR1 signaling such as ROCK2, LIMK1, cofilin, and ataxin-2, and also neurotrophins. In addition, we investigated LOTUS protein levels in the ventral horn of ALS patients. We found significantly decreased LOTUS expression in both SOD1 Tg mice and ALS patients. LOTUS overexpression in SOD1 Tg mice increased lifespan and improved motor function, in association with prevention of motor neuron loss, reduced gliosis, increased NMJ innervation, maintenance of cofilin phosphorylation dynamics, decreased levels of ataxin-2, and increased levels of brain-derived neurotrophic factor (BDNF). Reduced LOTUS expression may enhance neurodegeneration in SOD1 Tg mice and ALS patients by activating NgR1 signaling, and in this study LOTUS overexpression significantly ameliorated ALS pathogenesis. LOTUS might serve as a promising therapeutic target for ALS.}, } @article {pmid38097227, year = {2023}, author = {Ebihara, S and Katsumata, T and Park, U}, title = {[Rehabilitation for Amyotrophic Lateral Sclerosis and ALS clinic].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {75}, number = {12}, pages = {1349-1353}, doi = {10.11477/mf.1416202539}, pmid = {38097227}, issn = {1881-6096}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Exercise Therapy ; *Medicine ; }, abstract = {The dysfunctions of amyotrophic lateral sclerosis (ALS) are highly variable. Rehabilitation medicine for movement disorders differs in accordance with the degree of severity. Exercise therapy should be performed while the disease is mild, with compensatory training increasing as the severity increases. Exercise therapy with a Hybrid Assistive Limb®(HAL®) is generally thought to preserve lower extremity function compared to those without HAL®. The mechanism may be effective on disused muscle fibers. ALS clinic may improve the prognosis of ALS patients.}, } @article {pmid38096766, year = {2024}, author = {Arslan, BT and Görkem Özyurt, M and İşak, B and Cecen, S and Türker, KS}, title = {Single motor unit estimation of the cutaneous silent period in ALS.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {157}, number = {}, pages = {110-119}, doi = {10.1016/j.clinph.2023.11.013}, pmid = {38096766}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Motor Neurons/physiology ; Electromyography/methods ; Spine ; }, abstract = {OBJECTIVE: Recent evidence indicated that amyotrophic lateral sclerosis (ALS) also impairs spinal circuits, including those mediating cutaneous silent period (CSP). However, most studies utilised surface electromyography (sEMG), which needs more resolution to pinpoint changes at the single motoneuron level. We aimed to investigate CSP properties using single motor unit discharges in ALS.

METHODS: In mild and severe ALS patients and controls, CSP was recorded in the first dorsal interosseus and analysed using the discharge rate method, which accurately shows the inhibitory postsynaptic potentials (IPSPs) profile.

RESULTS: Our findings confirmed that the CSP latency was prolonged only in severe ALS patients. Moreover, the CSP duration was similar in each group, but late-stage ALS patients tend to have a longer CSP duration. The discharge rate method revealed a significantly longer duration (up to 150 ms) than the duration detected using sEMG. Strikingly, the motoneuron discharge rate - IPSP duration inverse relationship is lost in ALS patients, indicating a possible impairment in the motoneuron integrative properties.

CONCLUSIONS: Our data support previous findings of prolonged latency, presented input-output modifications of motoneurons, and revealed the entire course of the CSP, representing a much stronger inhibitory event than previously thought.

SIGNIFICANCE: Motoneuron integrative property modification assessed by CSP could be a new biomarker for ALS.}, } @article {pmid38096601, year = {2024}, author = {Chiba, K and Niwa, S}, title = {Autoinhibition and activation of kinesin-1 and their involvement in amyotrophic lateral sclerosis.}, journal = {Current opinion in cell biology}, volume = {86}, number = {}, pages = {102301}, doi = {10.1016/j.ceb.2023.102301}, pmid = {38096601}, issn = {1879-0410}, mesh = {Humans ; *Kinesins/metabolism ; *Amyotrophic Lateral Sclerosis ; Neurons/metabolism ; Biological Transport ; }, abstract = {Kinesin-1, composed of kinesin heavy chain and kinesin light chain, is a founding member of kinesin superfamily and transports various neuronal cargos. Kinesin-1 is one of the most abundant ATPases in the cell and thus need to be tightly regulated to avoid wastage of energy. It has been well established that kinesin-1 is regulated by the autoinhibition mechanism. This review focuses on the recent researches that have contributed to the understanding of mechanisms for the autoinhibition of kinesin-1 and its unlocking. Recent electron microscopic studies have shown an unanticipated structure of autoinhibited kinesin-1. Biochemical reconstitution have revealed detailed molecular mechanisms how the autoinhibition is unlocked. Importantly, misregulation of kinesin-1 is emerging as one of the major causes of amyotrophic lateral sclerosis.}, } @article {pmid38094423, year = {2023}, author = {Methods In Medicine, CAM}, title = {Retracted: Amyotrophic Lateral Sclerosis Symptom Score in Integrative Treatments (ALS-SSIT) for Evaluating Therapeutic Effect of Traditional Chinese Medicine: A Prospective Study.}, journal = {Computational and mathematical methods in medicine}, volume = {2023}, number = {}, pages = {9763080}, pmid = {38094423}, issn = {1748-6718}, abstract = {[This retracts the article DOI: 10.1155/2022/7594481.].}, } @article {pmid38093670, year = {2024}, author = {Oliveira Santos, M and Swash, M and de Carvalho, M}, title = {Current challenges in primary lateral sclerosis diagnosis.}, journal = {Expert review of neurotherapeutics}, volume = {24}, number = {1}, pages = {45-53}, doi = {10.1080/14737175.2023.2295010}, pmid = {38093670}, issn = {1744-8360}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis ; *Motor Neuron Disease/diagnosis ; Neuroimaging ; Diagnosis, Differential ; Biomarkers ; Multicenter Studies as Topic ; }, abstract = {INTRODUCTION: Primary lateral sclerosis (PLS) is a rare, adult-onset and slowly progressive motor neuron disorder whose clinical core is characterized by upper motor neuron (UMN) dysfunction. Its formal diagnosis is clinically based and disease duration-dependent. Differentiating PLS from other disorders involving UMN can be challenging, particularly in the early stages.

AREAS COVERED: Our review covers and discusses different aspects of the PLS field, including the diagnostic criteria and its limitations, its differential diagnosis and their major pitfalls, and the actual role of neurophysiology, neuroimaging, genetics, and molecular biomarkers. Symptomatic treatment of the different manifestations is also addressed. The authors searched MEDLINE and Scopus. They also searched the reference lists of articles identified by our search strategy and reviewed and selected those deemed relevant. They selected papers and studies based on the quality of the report, significance of the findings, and on the author's critical appraise and expertise.

EXPERT OPINION: It is important to investigate novel molecular biomarkers and plan multicenter clinical trials for PLS. However, this will require a large international project to recruit enough patients, particularly given the diagnostic uncertainty of the current clinical criteria. A better understanding of PLS pathophysiology is crucial for designing disease-targeted therapies.}, } @article {pmid38093132, year = {2023}, author = {Grigoriev, VV and Shevtsova, EF and Aksinenko, AY and Veselov, IM and Goreva, TV and Gabrelyan, AV and Bachurin, SO}, title = {New Hybrid Structures Based on Memanthine and Edaravone Molecules.}, journal = {Doklady. Biochemistry and biophysics}, volume = {512}, number = {1}, pages = {284-287}, pmid = {38093132}, issn = {1608-3091}, mesh = {*Memantine/pharmacology/chemistry ; Edaravone ; Receptors, N-Methyl-D-Aspartate ; *Adamantane/pharmacology ; }, abstract = {New hybrid structures based on memantine and edaravone molecules, in which the pyrazolone ring and adamantane fragments are linked by an alkyl linker, were synthesized. It was found that, in addition to the ability to block the intrachannel site of NMDA receptors, the new hybrid compounds exhibit the property of blockers of the allosteric site of NMDA receptors, which is not inherent in memantine and edaravone preparations. The most active hit compound was determined, which, along with the properties of a two-site blocker of the NMDA receptor, exhibits a pronounced activity as an inhibitor of lipid peroxidation, similarly to the drug edaravone.}, } @article {pmid38092849, year = {2023}, author = {Ou, Y and Zhao, Y}, title = {On enhancing the noise-reduction performance of the acoustic lined duct utilizing the phase-modulating metasurface.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {22184}, pmid = {38092849}, issn = {2045-2322}, abstract = {This work proposes a noise-reduction structure that integrates phase-modulating metasurface (PMM) with acoustic liners (ALs) to enhance the narrow band absorption performance of a duct with relatively small length-diameter ratio. The PMM manipulates the wavefront by introducing different transmission phase shifts based on an array of Helmholtz resonators, so that the spinning wave within the duct can be generated. Compared with the plane wave, the generated spinning wave has a lower group velocity, which results in a greater traveling distance over the ALs in the duct. The optimization design is performed to determine the final structural parameters of the PMM, which is based on the predictions of the amplitude and phase shift of the acoustic wave at the outlet of the PMM using the theory of passive phased array. With the manipulation of the PMM, the incident plane wave is modulated into a spinning wave, and then enters into the acoustic liner duct (ALD), whose structural parameters are optimized by maximizing the transmission loss using the mode-matching technique. Finally, the noise-reduction performance of this combined structure is evaluated by numerical simulations in the presence of grazing flow. The results demonstrate that, compared with the traditional ALD, the proposed structure exhibits a significant increase in transmission loss within the considered frequency band, especially near the peak frequency of the narrow band noise.}, } @article {pmid38092738, year = {2023}, author = {Raguseo, F and Wang, Y and Li, J and Petrić Howe, M and Balendra, R and Huyghebaert, A and Vadukul, DM and Tanase, DA and Maher, TE and Malouf, L and Rubio-Sánchez, R and Aprile, FA and Elani, Y and Patani, R and Di Michele, L and Di Antonio, M}, title = {The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {8272}, pmid = {38092738}, issn = {2041-1723}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; MR/S033947/1/MRC_/Medical Research Council/United Kingdom ; SGL027\1022/AMS_/Academy of Medical Sciences/United Kingdom ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; RNA/genetics/chemistry ; *G-Quadruplexes ; C9orf72 Protein/genetics ; DNA Repeat Expansion/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause of ALS/FTD is expansion of the intronic hexanucleotide repeat (GGGGCC)n in C9orf72. Here, we investigate the formation of nucleic acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of ALS/FTD. We observe significant aggregation of the hexanucleotide sequence (GGGGCC)n, which we associate to the formation of multimolecular G-quadruplexes (mG4s) by using a range of biophysical techniques. Exposing the condensates to G4-unfolding conditions leads to prompt disassembly, highlighting the key role of mG4-formation in the condensation process. We further validate the biological relevance of our findings by detecting an increased prevalence of G4-structures in C9orf72 mutant human motor neurons when compared to healthy motor neurons by staining with a G4-selective fluorescent probe, revealing signal in putative condensates. Our findings strongly suggest that RNA G-rich repetitive sequences can form protein-free condensates sustained by multimolecular G-quadruplexes, highlighting their potential relevance as therapeutic targets for C9orf72 mutation-related ALS/FTD.}, } @article {pmid38092667, year = {2024}, author = {Canosa, A and Cabras, S and Di Pede, F and Manera, U and Vasta, R and Moglia, C and Calvo, A and Gallone, S and Chiò, A}, title = {A mother and her daughter carrying a pathogenic expansion of the HTT gene with a phenotype encompassing motor neuron disease and Huntington's disease.}, journal = {Clinical genetics}, volume = {105}, number = {4}, pages = {430-433}, doi = {10.1111/cge.14472}, pmid = {38092667}, issn = {1399-0004}, support = {PRIN-2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; RF-2016-02362405//Ministero della Salute/ ; }, mesh = {Female ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Huntington Disease/genetics/pathology ; Mothers ; Nuclear Family ; *Frontotemporal Dementia ; *Motor Neuron Disease/genetics ; Phenotype ; Huntingtin Protein/genetics ; }, abstract = {Recently, pathogenic expansions (range 40-64 CAG repeats) in the HTT gene have been found in patients diagnosed with pure frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). We report a mother with Huntington's disease (HD) associated with motor neuron disease (MND) signs and her daughter suffering from ALS with subtle signs of HD, both carrying a pathogenic allele of the HTT gene (i.e., >39 repeats). The co-occurrence of MND and chorea has been reported in previous cases. Subjects showing both ALS and HD signs and carrying HTT pathogenic expansions in two generations of the same kindred have never been reported so far. The study of the overlap of disease mechanisms at the cellular level between TDP-43 and Huntingtin is relevant in an era offering promising strategies of targeted treatments in neurodegenerative disorders.}, } @article {pmid38092270, year = {2024}, author = {Deng, C and Chen, H}, title = {Brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling in spinal muscular atrophy and amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {190}, number = {}, pages = {106377}, doi = {10.1016/j.nbd.2023.106377}, pmid = {38092270}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Brain-Derived Neurotrophic Factor ; Motor Neurons/physiology ; Tropomyosin ; *Muscular Atrophy, Spinal ; Receptor, trkB ; }, abstract = {Tropomyosin receptor kinase B (TrkB) and its primary ligand brain-derived neurotrophic factor (BDNF) are expressed in the neuromuscular system, where they affect neuronal survival, differentiation, and functions. Changes in BDNF levels and full-length TrkB (TrkB-FL) signaling have been revealed in spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), two common forms of motor neuron diseases that are characterized by defective neuromuscular junctions in early disease stages and subsequently progressive muscle weakness. This review summarizes the current understanding of BDNF/TrkB-FL-related research in SMA and ALS, with an emphasis on their alterations in the neuromuscular system and possible BDNF/TrkB-FL-targeting therapeutic strategies. The limitations of current studies and future directions are also discussed, giving the hope of discovering novel and effective treatments.}, } @article {pmid38090719, year = {2023}, author = {Brusati, A and Peverelli, S and Calzari, L and Tiloca, C and Casiraghi, V and Sorce, MN and Invernizzi, S and Carbone, E and Cavagnola, R and Verde, F and Silani, V and Ticozzi, N and Ratti, A and Gentilini, D}, title = {Exploring epigenetic drift and rare epivariations in amyotrophic lateral sclerosis by epigenome-wide association study.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1272135}, pmid = {38090719}, issn = {1663-4365}, abstract = {During the last decades, our knowledge about the genetic architecture of sporadic amyotrophic lateral sclerosis (sALS) has significantly increased. However, besides the recognized genetic risk factors, also the environment is supposed to have a role in disease pathogenesis. Epigenetic modifications reflect the results of the interaction between environmental factors and genes and may play a role in the development and progression of ALS. A recent epigenome-wide association study (EWAS) in blood identified differentially methylated positions mapping to 42 genes involved in cholesterol biosynthesis and immune-related pathways. Here we performed a genome-wide DNA methylation analysis in the blood of an Italian cohort of 61 sALS patients and 61 healthy controls. Initially, a conventional genome-wide association analysis was performed, and results were subsequently integrated with the findings from the previous EWAS using a meta-analytical approach. To delve deeper into the significant outcomes, over-representation analysis (ORA) was employed. Moreover, the epigenetic signature obtained from the meta-analysis was examined to determine potential associations with chemical compounds, utilizing the Toxicogenomic Database. Expanding the scope of the epigenetic analysis, we explored both epigenetic drift and rare epivariations. Notably, we observed an elevated epigenetic drift in sALS patients compared to controls, both at a global and single gene level. Interestingly, epigenetic drift at a single gene level revealed an enrichment of genes related to the neurotrophin signaling pathway. Moreover, for the first time, we identified rare epivariations exclusively enriched in sALS cases associated with 153 genes, 88 of whom with a strong expression in cerebral areas. Overall, our study reinforces the evidence that epigenetics may contribute to the pathogenesis of ALS and that epigenetic drift may be a useful diagnostic marker. Moreover, this study suggests the potential role of epivariations in ALS.}, } @article {pmid38090405, year = {2023}, author = {Gupta, D and Vagha, S and Dhingra, H and Shirsath, H}, title = {Advances in Understanding and Treating Amyotrophic Lateral Sclerosis (ALS): A Comprehensive Review.}, journal = {Cureus}, volume = {15}, number = {11}, pages = {e48691}, pmid = {38090405}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a deadly CNS neurodegenerative disease. The way ALS is now managed, from diagnosis to prognosis, is still not ideal despite many studies. Early diagnosis can help ALS patients live longer since prompt treatment can halt the disease's development. Two medications, riluzole and edaravone, have recently been licensed for use in therapy, and they very slightly increase life expectancy. Still, a lot of cutting-edge experimental medications are being developed. In the following article, we give a synopsis of the innovative medications and genetic remodeling that have emerged recently and help to halt the course of the illness. Studies have also been conducted on a few symptomatic and rehabilitative therapies that enhance the quality of life for ALS patients.}, } @article {pmid38090276, year = {2023}, author = {}, title = {Correction to: Urinary biomarkers for amyotrophic lateral sclerosis: candidates, opportunities and considerations.}, journal = {Brain communications}, volume = {5}, number = {6}, pages = {fcad334}, doi = {10.1093/braincomms/fcad334}, pmid = {38090276}, issn = {2632-1297}, abstract = {[This corrects the article DOI: 10.1093/braincomms/fcad287.].}, } @article {pmid38088823, year = {2023}, author = {Hannan, AJ}, title = {Expanding horizons of tandem repeats in biology and medicine: Why 'genomic dark matter' matters.}, journal = {Emerging topics in life sciences}, volume = {7}, number = {3}, pages = {239-247}, pmid = {38088823}, issn = {2397-8554}, abstract = {Approximately half of the human genome includes repetitive sequences, and these DNA sequences (as well as their transcribed repetitive RNA and translated amino-acid repeat sequences) are known as the repeatome. Within this repeatome there are a couple of million tandem repeats, dispersed throughout the genome. These tandem repeats have been estimated to constitute ∼8% of the entire human genome. These tandem repeats can be located throughout exons, introns and intergenic regions, thus potentially affecting the structure and function of tandemly repetitive DNA, RNA and protein sequences. Over more than three decades, more than 60 monogenic human disorders have been found to be caused by tandem-repeat mutations. These monogenic tandem-repeat disorders include Huntington's disease, a variety of ataxias, amyotrophic lateral sclerosis and frontotemporal dementia, as well as many other neurodegenerative diseases. Furthermore, tandem-repeat disorders can include fragile X syndrome, related fragile X disorders, as well as other neurological and psychiatric disorders. However, these monogenic tandem-repeat disorders, which were discovered via their dominant or recessive modes of inheritance, may represent the 'tip of the iceberg' with respect to tandem-repeat contributions to human disorders. A previous proposal that tandem repeats may contribute to the 'missing heritability' of various common polygenic human disorders has recently been supported by a variety of new evidence. This includes genome-wide studies that associate tandem-repeat mutations with autism, schizophrenia, Parkinson's disease and various types of cancers. In this article, I will discuss how tandem-repeat mutations and polymorphisms could contribute to a wide range of common disorders, along with some of the many major challenges of tandem-repeat biology and medicine. Finally, I will discuss the potential of tandem repeats to be therapeutically targeted, so as to prevent and treat an expanding range of human disorders.}, } @article {pmid38087950, year = {2024}, author = {Metzger, M and Dukic, S and McMackin, R and Giglia, E and Mitchell, M and Bista, S and Costello, E and Peelo, C and Tadjine, Y and Sirenko, V and Plaitano, S and Coffey, A and McManus, L and Farnell Sharp, A and Mehra, P and Heverin, M and Bede, P and Muthuraman, M and Pender, N and Hardiman, O and Nasseroleslami, B}, title = {Functional network dynamics revealed by EEG microstates reflect cognitive decline in amyotrophic lateral sclerosis.}, journal = {Human brain mapping}, volume = {45}, number = {1}, pages = {e26536}, pmid = {38087950}, issn = {1097-0193}, support = {/WT_/Wellcome Trust/United Kingdom ; 16/ERCD/3854/SFI_/Science Foundation Ireland/Ireland ; URF\R1\221917/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Electroencephalography ; Retrospective Studies ; Brain ; Brain Mapping ; *Cognitive Dysfunction/etiology ; }, abstract = {Recent electroencephalography (EEG) studies have shown that patterns of brain activity can be used to differentiate amyotrophic lateral sclerosis (ALS) and control groups. These differences can be interrogated by examining EEG microstates, which are distinct, reoccurring topographies of the scalp's electrical potentials. Quantifying the temporal properties of the four canonical microstates can elucidate how the dynamics of functional brain networks are altered in neurological conditions. Here we have analysed the properties of microstates to detect and quantify signal-based abnormality in ALS. High-density resting-state EEG data from 129 people with ALS and 78 HC were recorded longitudinally over a 24-month period. EEG topographies were extracted at instances of peak global field power to identify four microstate classes (labelled A-D) using K-means clustering. Each EEG topography was retrospectively associated with a microstate class based on global map dissimilarity. Changes in microstate properties over the course of the disease were assessed in people with ALS and compared with changes in clinical scores. The topographies of microstate classes remained consistent across participants and conditions. Differences were observed in coverage, occurrence, duration, and transition probabilities between ALS and control groups. The duration of microstate class B and coverage of microstate class C correlated with lower limb functional decline. The transition probabilities A to D, C to B and C to B also correlated with cognitive decline (total ECAS) in those with cognitive and behavioural impairments. Microstate characteristics also significantly changed over the course of the disease. Examining the temporal dependencies in the sequences of microstates revealed that the symmetry and stationarity of transition matrices were increased in people with late-stage ALS. These alterations in the properties of EEG microstates in ALS may reflect abnormalities within the sensory network and higher-order networks. Microstate properties could also prospectively predict symptom progression in those with cognitive impairments.}, } @article {pmid38087504, year = {2024}, author = {Dellar, ER and Vendrell, I and Talbot, K and Kessler, BM and Fischer, R and Turner, MR and Thompson, AG}, title = {Data-independent acquisition proteomics of cerebrospinal fluid implicates endoplasmic reticulum and inflammatory mechanisms in amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {168}, number = {2}, pages = {115-127}, pmid = {38087504}, issn = {1471-4159}, support = {TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0701923/MRC_/Medical Research Council/United Kingdom ; TURNER/JAN13/944-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/K01014X/1/MRC_/Medical Research Council/United Kingdom ; MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; Thompson/Jan20/952-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Proteomics/methods ; Biomarkers/cerebrospinal fluid ; Prognosis ; Mass Spectrometry ; }, abstract = {While unbiased proteomics of human cerebrospinal fluid (CSF) has been used successfully to identify biomarkers of amyotrophic lateral sclerosis (ALS), high-abundance proteins mask the presence of lower abundance proteins that may have diagnostic and prognostic value. However, developments in mass spectrometry (MS) proteomic data acquisition methods offer improved protein depth. In this study, MS with library-free data-independent acquisition (DIA) was used to compare the CSF proteome of people with ALS (n = 40), healthy (n = 15) and disease (n = 8) controls. Quantified protein groups were subsequently correlated with clinical variables. Univariate analysis identified 7 proteins, all significantly upregulated in ALS versus healthy controls, and 9 with altered abundance in ALS versus disease controls (FDR < 0.1). Elevated chitotriosidase-1 (CHIT1) was common to both comparisons and was proportional to ALS disability progression rate (Pearson r = 0.41, FDR-adjusted p = 0.035) but not overall survival. Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1; upregulated in ALS versus healthy controls) was proportional to disability progression rate (Pearson r = 0.53, FDR-adjusted p = 0.003) and survival (Kaplan Meier log-rank p = 0.013) but not independently in multivariate proportional hazards models. Weighted correlation network analysis was used to identify functionally relevant modules of proteins. One module, enriched for inflammatory functions, was associated with age at symptom onset (Pearson r = 0.58, FDR-adjusted p = 0.005) and survival (Hazard Ratio = 1.78, FDR = 0.065), and a second module, enriched for endoplasmic reticulum proteins, was negatively correlated with disability progression rate (r = -0.42, FDR-adjusted p = 0.109). DIA acquisition methodology therefore strengthened the biomarker candidacy of CHIT1 and UCHL1 in ALS, while additionally highlighted inflammatory and endoplasmic reticulum proteins as novel sources of prognostic biomarkers.}, } @article {pmid38087359, year = {2023}, author = {Nayab, DE and Din, FU and Ali, H and Kausar, WA and Urooj, S and Zafar, M and Khan, I and Shabbir, K and Khan, GM}, title = {Nano biomaterials based strategies for enhanced brain targeting in the treatment of neurodegenerative diseases: an up-to-date perspective.}, journal = {Journal of nanobiotechnology}, volume = {21}, number = {1}, pages = {477}, pmid = {38087359}, issn = {1477-3155}, support = {20-14604/NRPU/R&D/HEC/2021//Higher Education Commision, Pakistan/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Brain ; Blood-Brain Barrier ; Drug Delivery Systems/methods ; Nanotechnology ; }, abstract = {Neurons and their connecting axons gradually degenerate in neurodegenerative diseases (NDs), leading to dysfunctionality of the neuronal cells and eventually their death. Drug delivery for the treatment of effected nervous system is notoriously complicated because of the presence of natural barriers, i.e., the blood-brain barrier and the blood cerebrospinal fluid barrier. Palliative care is currently the standard care for many diseases. Therefore, treatment programs that target the disease's origin rather than its symptoms are recommended. Nanotechnology-based drug delivery platforms offer an innovative way to circumvent these obstacles and deliver medications directly to the central nervous system, thereby enabling treatment of several common neurological problems, i.e., Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. Interestingly, the combination of nanomedicine and gene therapy enables targeting of selective mutant genes responsible for the progression of NDs, which may provide a much-needed boost in the struggle against these diseases. Herein, we discussed various central nervous system delivery obstacles, followed by a detailed insight into the recently developed techniques to restore neurological function via the differentiation of neural stem cells. Moreover, a comprehensive background on the role of nanomedicine in controlling neurogenesis via differentiation of neural stem cells is explained. Additionally, numerous phytoconstituents with their neuroprotective properties and molecular targets in the identification and management of NDs are also deliberated. Furthermore, a detailed insight of the ongoing clinical trials and currently marketed products for the treatment of NDs is provided in this manuscript.}, } @article {pmid38086894, year = {2024}, author = {Kraft, S and Mease, C and Jillapalli, D and Fermaglich, LJ and Miller, KL}, title = {Trends in drug development for amyotrophic lateral sclerosis.}, journal = {Nature reviews. Drug discovery}, volume = {23}, number = {2}, pages = {99-100}, doi = {10.1038/d41573-023-00199-2}, pmid = {38086894}, issn = {1474-1784}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Drug Development ; }, } @article {pmid38086800, year = {2023}, author = {Wei, J and Li, M and Ye, Z and Hu, X and He, X and Wang, J and Chen, G and Zou, C and Xu, D and Zhang, H and Yuan, J and Zha, Y}, title = {Elevated peripheral levels of receptor-interacting protein kinase 1 (RIPK1) and IL-8 as biomarkers of human amyotrophic lateral sclerosis.}, journal = {Signal transduction and targeted therapy}, volume = {8}, number = {1}, pages = {451}, pmid = {38086800}, issn = {2059-3635}, support = {WJ2021M257//Health and Family Planning Commission of Hubei Province (Hubei Provincial Health Department)/ ; 2019SHZDZX02//Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission)/ ; 32070737//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82188101, 91849204, 21837004, 92049303 and 32170755//National Natural Science Foundation of China (National Science Foundation of China)/ ; 20JC1411600//Shanghai Science and Technology Development Foundation (Shanghai Science and Technology Development Fund)/ ; 20QA1411500//Shanghai Science and Technology Development Foundation (Shanghai Science and Technology Development Fund)/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Biomarkers ; Interleukin-8/genetics ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; *Neurodegenerative Diseases/metabolism ; Primidone/metabolism/pharmacology/therapeutic use ; Protein Kinases/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics/metabolism/pharmacology ; Superoxide Dismutase/metabolism/pharmacology/therapeutic use ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease with no cure. Receptor-interacting protein kinase 1 (RIPK1) has been proposed to mediate pathogenesis of ALS. Primidone has been identified as an old drug that can also inhibit RIPK1 kinase. We conducted a drug-repurposing biomarker study of primidone as a RIPK1 inhibitor using SOD1[G93A] mice and ALS patients. SOD1[G93A] mice treated with primidone showed significant delay of symptomatic onset and improved motor performance. One-hundred-sixty-two ALS participants dosed daily with primidone (62.5 mg) completed 24-week follow-up. A significant reduction was showed in serum levels of RIPK1 and IL-8, which were significantly higher in ALS patients than that of healthy controls (P < 0.0001). Serum RIPK1 levels were correlated positively with the severity of bulbar symptoms (P < 0.05). Our study suggests that serum levels of RIPK1 and IL-8 in peripheral can be used as clinical biomarkers for the activation of RIPK1 in central nervous system in human ALS patients. Repurposing primidone may provide a promising therapeutic strategy for ALS. The effect of primidone for the treatment of other inflammatory diseases may also be considered, since the activation of RIPK1 has been implicated in mediating a variety of inflammatory diseases including COVID-19-associated cytokine release syndrome (CRS). (ChiCTR2200060149).}, } @article {pmid38084484, year = {2023}, author = {Reniers, PWA and Leontjevas, R and Declercq, IJN and Molog, M and Enders-Slegers, MJ and Gerritsen, DL and Hediger, K}, title = {[Not Available].}, journal = {Tijdschrift voor gerontologie en geriatrie}, volume = {}, number = {4}, pages = {}, doi = {10.54195/tgg.18095}, pmid = {38084484}, issn = {0167-9228}, abstract = {Achtergrond: Huisdieren zijn belangrijk in het leven van thuiswonende ouderen en van degenen die langdurige thuiszorg (LTZ) ontvangen. Het doel van dit project was om de betekenis van huisdieren voor thuiswonende ouderen te verkennen en te onderzoeken of deze ook van toepassing zijn op LTZ-cliënten. Daarnaast exploreerden we mogelijke huisdiergerelateerde uitdagingen en de invloed van huisdierbezit op zorgrelaties in de LTZ. Methoden: Het project startte met een systematische kwalitatieve literatuur review gevolgd door een studie met de Consensual Qualitative Research (CQR) methode en een onlinevragenlijst om de resultaten van de review in de LTZ te toetsen. LTZ-cliënten, mantelzorgers en professionele zorgverleners namen deel aan de CQR-studie en vragenlijst. De vragenlijst bevatte daarnaast open vragen over mogelijke huisdiergerelateerde uitdagingen en hun invloed op zorgrelaties in de LTZ. Resultaten: De review bevatte vijftien artikelen die achtentwintig rollen gerelateerd aan de betekenis van huisdieren beschreven, onderverdeeld in zeven categorieën. De uitkomsten van de CQR-studie en vragenlijst toonden dat huisdieren een vergelijkbare betekenis hebben voor thuiswonende ouderen en LTZ-cliënten. Deelnemers rapporteerden mogelijke uitdagingen en zowel positieve als negatieve effecten van huisdieren op zorgrelaties. Conclusies: Huisdieren hebben een vergelijkbare betekenis voor thuiswonende ouderen en LTZ-cliënten. Bovendien ervaren LTZ-cliënten mogelijke specifieke huisdiergerelateerde uitdagingen en kunnen huisdieren zorgrelaties beïnvloeden. Daarom is het noodzakelijk om rekening te houden met huisdieren in de LTZ.}, } @article {pmid38084253, year = {2023}, author = {Minić, R and Arsić, A and Kojadinović, M and Palibrk, A and Đorđević, B and Stević, Z}, title = {Erythrocyte fatty acid aberrations in Amyotrophic Lateral Sclerosis: Correlation with disease duration.}, journal = {Journal of medical biochemistry}, volume = {42}, number = {4}, pages = {621-629}, pmid = {38084253}, issn = {1452-8258}, abstract = {BACKGROUND: Recent literature data highlights metabolic changes in amyotrophic lateral sclerosis (ALS). To explore possible early metabolic changes, we aimed to analyse the fatty acids (FA) composition of erythrocytes in newly diagnosed als patients and to see whether fatty acid levels correlate with the ALSFRS-R score or disease duration.

METHODS: The severity of motor function involvement was assessed by the ALSFRS-R scale at the initial evaluation. The fatty acid profile of erythrocyte membranes was analysed by gas-liquid chromatography. The study comprised 26 clinically diagnosed als patients, with mean ALSFRS-R 38±8. The control group included 26 healthy volunteers.}, } @article {pmid38083843, year = {2024}, author = {Zhang, S and Li, L and Liu, X and Zhong, Q}, title = {The hookup model of the HOPS complex in autophagosome-lysosome fusion.}, journal = {Autophagy}, volume = {20}, number = {3}, pages = {714-715}, pmid = {38083843}, issn = {1554-8635}, mesh = {*Macroautophagy ; C9orf72 Protein/metabolism ; *Autophagy ; Autophagosomes/metabolism ; Membrane Fusion/physiology ; SNARE Proteins/metabolism ; Lysosomes/metabolism ; }, abstract = {Macroautophagy/autophagy is a highly conserved process that involves the degradation of proteins, damaged organelles, and other cytoplasmic macromolecules. Autophagosome-lysosome fusion is critical for successful substrate degradation and is mediated by SNARE proteins. The fusion process requires additional vesicle docking and tethering-regulating factors. Our recent work has uncovered a functional model of autophagosome-lysosome fusion. We demonstrated that the six-subunit homotypic fusion and vacuole protein sorting (HOPS) complex can be assembled by two subcomplexes, the VPS39-VPS11 subcomplex (HOPS-2) and the VPS41-VPS16-VPS18-VPS33A subcomplex (HOPS-4). VPS39 binds with RAB2 on the autophagosome and VPS41 binds with RAB39A on the lysosome, which then promotes membrane tethering and autophagic SNARE-mediated membrane fusion. Moreover, we have revealed that ALS- and FTD-related C9orf72 is a guanine exchange factor (GEF) for RAB39A. In this punctum, we discuss how the C9orf72-RAB39A-HOPS axis function regulates autophagosome-lysosome fusion.}, } @article {pmid38083694, year = {2023}, author = {Migliorelli, L and Moccia, S and Berardini, D and Frontoni, E and Coccia, M and Villani, L and Bandini, A}, title = {A preliminary study on self-care telemonitoring of dysarthria in spinal muscular atrophy.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2023}, number = {}, pages = {1-4}, doi = {10.1109/EMBC40787.2023.10340908}, pmid = {38083694}, issn = {2694-0604}, mesh = {Humans ; Dysarthria/diagnosis/etiology ; Self Care ; *Muscular Atrophy, Spinal/complications/diagnosis ; *Amyotrophic Lateral Sclerosis/complications ; Rare Diseases ; }, abstract = {Spinal muscular atrophy (SMA) is a rare neuromuscular disease which may cause impairments in oro-facial musculature. Most of the individuals with SMA present bulbar signs such as flaccid dysarthria which mines their abilities to speak and, as consequence, their psychic balance. To support clinicians, recent work has demonstrated the feasibility of video-based techniques for assessing the oro-facial functions in patients with neurological disorders such as amyotrophic lateral sclerosis. However, no work has so far focused on automatic and quantitative monitoring of dysarthria in SMA. To overcome limitations this work's aim is to propose a cloud-based store-and-forward telemonitoring system for automatic and quantitative evaluation of oro-facial muscles in individuals with SMA. The system integrates a convolutional neural network (CNN) aimed at identifying the position of facial landmarks from video recordings acquired via a web application by an SMA patient.Clinical relevance- The proposed work is in the preliminary stage, but it represents the first step towards a better understanding of the bulbar-functions' evolution in patients with SMA.}, } @article {pmid38082727, year = {2023}, author = {Khan, SU and Majid, M and Linguraru, MG and Muhammad Anwar, S}, title = {Upper Limb Movement Execution Classification using Electroencephalography for Brain Computer Interface.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2023}, number = {}, pages = {1-4}, doi = {10.1109/EMBC40787.2023.10341008}, pmid = {38082727}, issn = {2694-0604}, mesh = {Humans ; *Brain-Computer Interfaces ; Upper Extremity ; Electroencephalography/methods ; Movement ; Motion ; }, abstract = {An accurate classification of upper limb movements using electroencephalogram (EEG) signals is gaining significant importance in recent years due to the prevalence of brain-computer interfaces. The upper limbs in the human body are crucial since different skeletal segments combine to make a range of motions that helps us in our trivial daily tasks. Decoding EEG-based upper limb movements can be of great help to people with spinal cord injury (SCI) or other neuro-muscular diseases such as amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and periodic paralysis. This can manifest in a loss of sensory and motor function, which could make a person reliant on others to provide care in day-to-day activities. We can detect and classify upper limb movement activities, whether they be executed or imagined using an EEG-based brain-computer interface (BCI). Toward this goal, we focus our attention on decoding movement execution (ME) of the upper limb in this study. For this purpose, we utilize a publicly available EEG dataset that contains EEG signal recordings from fifteen subjects acquired using a 61-channel EEG device. We propose a method to classify four ME classes for different subjects using spectrograms of the EEG data through pre-trained deep learning (DL) models. Our proposed method of using EEG spectrograms for the classification of ME has shown significant results, where the highest average classification accuracy (for four ME classes) obtained is 87.36%, with one subject achieving the best classification accuracy of 97.03%.Clinical relevance- This research shows that movement execution of upper limbs is classified with significant accuracy by employing a spectrogram of the EEG signals and a pre-trained deep learning model which is fine-tuned for the downstream task.}, } @article {pmid38082598, year = {2023}, author = {Zhang, C and Deng, F and Li, Y and Hall, T and Goldys, E}, title = {Paper-based lateral flow assay for the point-of-care detection of neurofilament light chain.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2023}, number = {}, pages = {1-4}, doi = {10.1109/EMBC40787.2023.10340109}, pmid = {38082598}, issn = {2694-0604}, mesh = {Humans ; *Point-of-Care Systems ; Intermediate Filaments/metabolism ; Reproducibility of Results ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Biomarkers ; }, abstract = {Neurofilament light chain (NF-L) is a protein found in neurons of the nervous system and is widely used as a biomarker for neurological disorders. However, the current methods for detecting NF-L levels are complicated, expensive, and require specialized equipment, making it challenging to implement in a point-of-care (POC) setting. In this study, we developed a gold nanoshell (AuNS)-assisted lateral flow assay (LFA) based test strip for the POC detection of NF-L at a low ng/mL level (8 ng/mL = 117.65 pM). The test strip is a simple, rapid, and cost-effective method for detecting NF-L, making it suitable for use in a POC setting for the diagnosis and treatment of various neurological disorders. With its ease of use and reliability, the paper-based LFA is a valuable tool for the diagnosis and management of neurological conditions.Clinical Relevance- The AuNS-assisted LFA test strip developed in this study offers a rapid, cost-effective, and simple method for detecting NF-L levels, making it of great interest to practicing clinicians for the diagnosis of various neurological diseases such as HIV-associated dementia (HID), Amyotrophic Lateral Sclerosis (ALS), and Creutzfeldt-Jakob disease (CJD).}, } @article {pmid38082513, year = {2023}, author = {Lluch-Galcerá, JJ and Alcoverro, C and Prat, E and Martinez-Molina, M and Bielsa, I and Quer, A and Bassas, J}, title = {[Refraktärer IgA-Pemphigus erfolgreich mit Adalimumab als Monotherapie behandelt].}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {21}, number = {12}, pages = {1560-1562}, doi = {10.1111/ddg.15232_g}, pmid = {38082513}, issn = {1610-0387}, } @article {pmid38081672, year = {2023}, author = {Xiong, S and Klesges, L and Doering, M and Pratt, RJ}, title = {Applications of implementation science frameworks, models and theories in disparities-focused cancer screening interventions: a scoping review protocol.}, journal = {BMJ open}, volume = {13}, number = {12}, pages = {e078212}, pmid = {38081672}, issn = {2044-6055}, support = {T32 CA190194/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Early Detection of Cancer ; Implementation Science ; *Neoplasms/diagnosis/prevention & control ; Research Design ; Scoping Reviews As Topic ; }, abstract = {BACKGROUND: Implementation science (IS) frameworks, models and theories (FMTs) have gained popularity in guiding the implementation and evaluation of evidence-based interventions (EBIs) for cancer screening. However, there are significant research gaps in understanding their applications in cancer health disparities contexts. This paper outlines a scoping review protocol designed to explore the utilisation of IS FMTs in cancer screening EBIs to inform intervention designs and adaptations.

METHODS AND ANALYSIS: This scoping review protocol adheres to Arksey and O'Malley's five-step methodological framework for conducting scoping studies. Search strategies were conducted in five bibliographic databases: Ovid MEDLINE, PubMed, Scopus, Web of Science and EMBASE. The search was run on 22 June 2023 with an English language filter and a date limit of 2001-current. Two reviewers will independently screen studies for inclusion and exclusion criteria. A third reviewer will be consulted, where appropriate at any of the review stages, to achieve consensus or resolve conflicts. Data will be collected, managed and analysed using Covidence. A narrative synthesis, based on Popay et al's methodology, will guide reporting and summarisation of results. The review will adhere to the PRISMA Extension for Scoping Reviews guidelines.

ETHICS AND DISSEMINATION: This scoping review is a novel approach for examining a growing corpus of research literature on IS FMT applications used in cancer screening EBIs. As a secondary analysis, this scoping review does not require approval from an institutional review board. We anticipate the review will produce insightful information (eg, challenges, key areas for future directions) on the applications of IS TMFs in designing, deploying and testing EBIs for populations experiencing cancer screening disparities. We will disseminate the results through journals and conferences targeting IS and cancer prevention researchers and practitioners.}, } @article {pmid38079474, year = {2024}, author = {Zibold, J and Lessard, LER and Picard, F and da Silva, LG and Zadorozhna, Y and Streichenberger, N and Belotti, E and Osseni, A and Emerit, A and Errazuriz-Cerda, E and Michel-Calemard, L and Menassa, R and Coudert, L and Wiessner, M and Stucka, R and Klopstock, T and Simonetti, F and Hutten, S and Nonaka, T and Hasegawa, M and Strom, TM and Bernard, E and Ollagnon, E and Urtizberea, A and Dormann, D and Petiot, P and Schaeffer, L and Senderek, J and Leblanc, P}, title = {The new missense G376V-TDP-43 variant induces late-onset distal myopathy but not amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {5}, pages = {1768-1783}, pmid = {38079474}, issn = {1460-2156}, support = {//CNRS/ ; //Fondation pour la Recherche Médicale/ ; //Federal Ministry of Education and Research/ ; //German Research Foundation/ ; //Core/ ; //CLSM/ ; }, mesh = {Humans ; *Mutation, Missense/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Male ; *Distal Myopathies/genetics/pathology ; *DNA-Binding Proteins/genetics ; Female ; Middle Aged ; Aged ; Pedigree ; Muscle, Skeletal/pathology/metabolism ; }, abstract = {TAR DNA binding protein of 43 kDa (TDP-43)-positive inclusions in neurons are a hallmark of several neurodegenerative diseases including familial amyotrophic lateral sclerosis (fALS) caused by pathogenic TARDBP variants as well as more common non-Mendelian sporadic ALS (sALS). Here we report a G376V-TDP-43 missense variant in the C-terminal prion-like domain of the protein in two French families affected by an autosomal dominant myopathy but not fulfilling diagnostic criteria for ALS. Patients from both families presented with progressive weakness and atrophy of distal muscles, starting in their fifth to seventh decade. Muscle biopsies revealed a degenerative myopathy characterized by accumulation of rimmed (autophagic) vacuoles, disruption of sarcomere integrity and severe myofibrillar disorganization. The G376V variant altered a highly conserved amino acid residue and was absent in databases on human genome variation. Variant pathogenicity was supported by in silico analyses and functional studies. The G376V mutant increased the formation of cytoplasmic TDP-43 condensates in cell culture models, promoted assembly into high molecular weight oligomers and aggregates in vitro, and altered morphology of TDP-43 condensates arising from phase separation. Moreover, the variant led to the formation of cytoplasmic TDP-43 condensates in patient-derived myoblasts and induced abnormal mRNA splicing in patient muscle tissue. The identification of individuals with TDP-43-related myopathy, but not ALS, implies that TARDBP missense variants may have more pleiotropic effects than previously anticipated and support a primary role for TDP-43 in skeletal muscle pathophysiology. We propose to include TARDBP screening in the genetic work-up of patients with late-onset distal myopathy. Further research is warranted to examine the precise pathogenic mechanisms of TARDBP variants causing either a neurodegenerative or myopathic phenotype.}, } @article {pmid38078970, year = {2024}, author = {Sun, Z and Zhang, B and Peng, Y}, title = {Development of novel treatments for amyotrophic lateral sclerosis.}, journal = {Metabolic brain disease}, volume = {39}, number = {3}, pages = {467-482}, pmid = {38078970}, issn = {1573-7365}, support = {No. 82073835, and 81872855//National Natural Sciences Foundation of China/ ; No. 2021-I2M-1-054//CAMS Innovation Fund for Medical Sciences/ ; 201920200802//Disciplines construction project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology ; *Neurodegenerative Diseases ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes paralysis whose etiology and pathogenesis have not been fully elucidated. Presently it is incurable and rapidly progressive with a survival of 2-5 years from onset, and no treatments could cure it. Therefore, it is urgent to identify which therapeutic target(s) are more promising to develop treatments that could effectively treat ALS. So far, more than 90 novel treatments for ALS patients have been registered on ClinicalTrials.gov, of which 23 are in clinical trials, 12 have been terminated and the rest suspended. This review will systematically summarize the possible targets of these novel treatments under development or failing based on published literature and information released by sponsors, so as to provide basis and support for subsequent drug research and development.}, } @article {pmid38078426, year = {2023}, author = {Handberg, C and Werlauff, U}, title = {People with neuromuscular diseases and their relatives' perspectives on challenges in everyday life and healthcare.}, journal = {Neurodegenerative disease management}, volume = {13}, number = {5}, pages = {289-302}, doi = {10.2217/nmt-2023-0008}, pmid = {38078426}, issn = {1758-2032}, mesh = {Humans ; *Delivery of Health Care ; *Neuromuscular Diseases ; }, abstract = {Objective: People with a neuromuscular disease (NMD) often experience challenges in everyday life and healthcare. Aim: To investigate experiences of and perspectives on challenges in everyday life and healthcare of people with NMDs and their relatives to gain new insights into how life-long rehabilitation can be tailored. Patients & methods: The design was qualitative using the interpretive description methodology and the Sense of Coherence theory. An ethnographic fieldwork was conducted where 45 persons with NMD and their relatives were included for interviews and participant observations. Results & conclusion: People with NMDs continually adapt to a changing functioning and balance their need for knowledge with their dependency on help when navigating the healthcare system. Structured, professionally facilitated peer support is needed.}, } @article {pmid38078079, year = {2023}, author = {Shi, J and Yu, H and Fu, Y and Wang, T and Zhang, Y and Huang, J and Li, S and Zheng, T and Ni, X and Zhao, J}, title = {Development and validation of functional kompetitive allele-specific PCR markers for herbicide resistance in Brassica napus.}, journal = {Frontiers in plant science}, volume = {14}, number = {}, pages = {1213476}, pmid = {38078079}, issn = {1664-462X}, abstract = {Effective weed control in the field is essential for maintaining favorable growing conditions and rapeseed yields. Sulfonylurea herbicides are one kind of most widely used herbicides worldwide, which control weeds by inhibiting acetolactate synthase (ALS). Molecular markers have been designed from polymorphic sites within the sequences of ALS genes, aiding marker-assisted selection in breeding herbicide-resistant rapeseed cultivars. However, most of them are not breeder friendly and have relatively limited application due to higher costs and lower throughput in the breeding projects. The aims of this study were to develop high throughput kompetitive allele-specific PCR (KASP) assays for herbicide resistance. We first cloned and sequenced BnALS1 and BnALS3 genes from susceptible cultivars and resistant 5N (als1als1/als3als3 double mutant). Sequence alignments of BnALS1 and BnALS3 genes for cultivars and 5N showed single nucleotide polymorphisms (SNPs) at positions 1676 and 1667 respectively. These two SNPs for BnALS1 and BnALS3 resulted in amino acid substitutions and were used to develop a KASP assay. These functional markers were validated in three distinct BC1F2 populations. The KASP assay developed in this study will be valuable for the high-throughput selection of elite materials with high herbicide resistance in rapeseed breeding programs.}, } @article {pmid38077951, year = {2023}, author = {Adachi, K and Miyata, K and Chida, Y and Hirose, M and Morisaki, Y and Yamanaka, K and Misawa, H}, title = {Depletion of perivascular macrophages delays ALS disease progression by ameliorating blood-spinal cord barrier impairment in SOD1[G93A] mice.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1291673}, pmid = {38077951}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease in which non-cell-autonomous processes have been proposed as its cause. Non-neuronal cells that constitute the environment around motor neurons are known to mediate the pathogenesis of ALS. Perivascular macrophages (PVM) are immune cells that reside between the blood vessels of the central nervous system and the brain parenchyma; PVM are components of the neurovascular unit and regulate the integrity of the blood-spinal cord barrier (BSCB). However, it is not known whether regulation of BSCB function by PVM is involved in the pathogenesis of ALS. Here, we used SOD1[G93A] mice to investigate whether PVM is involved in the pathogenesis of ALS. Immunostaining revealed that the number of PVM was increased during the disease progression of ALS in the spinal cord. We also found that both anti-inflammatory Lyve1[+] PVM and pro-inflammatory MHCII[+] PVM subtypes were increased in SOD1[G93A] mice, and that subtype heterogeneity was shifted toward MHCII[+] PVM compared to wild-type (WT) mice. Then we depleted PVM selectively and continuously in SOD1[G93A] mice by repeated injection of clodronate liposomes into the cerebrospinal fluid and assessed motor neuron number, neurological score, and survival. Results showed that PVM depletion prevented the loss of motoneurons, slowed disease progression, and prolonged survival. Further histological analysis showed that PVM depletion prevents BSCB collapse by ameliorating the reduction of extracellular matrix proteins necessary for the maintenance of barrier function. These results indicate that PVM are involved in the pathogenesis of ALS, as PVM degrades the extracellular matrix and reduces BSCB function, which may affect motor neuron loss and disease progression. Targeting PVM interventions may represent a novel ALS therapeutic strategy.}, } @article {pmid38077871, year = {2023}, author = {Methods In Medicine, CAM}, title = {Retracted: Study on the Diagnostic Value of Neuroelectrophysiological Examination in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Computational and mathematical methods in medicine}, volume = {2023}, number = {}, pages = {9858143}, pmid = {38077871}, issn = {1748-6718}, abstract = {[This retracts the article DOI: 10.1155/2022/3907751.].}, } @article {pmid38077837, year = {2023}, author = {Bekdik, P and Baslo, MB}, title = {Investigation of Ongoing Denervation and Reinnervation in Amyotrophic Lateral Sclerosis by Using Concentric Needle Electrode with Single Fiber Electromyography Method.}, journal = {Noro psikiyatri arsivi}, volume = {60}, number = {4}, pages = {298-303}, pmid = {38077837}, issn = {1300-0667}, abstract = {INTRODUCTION: The aim of this study is to demonstrate the conduction disturbance at the neuromuscular junction in a cranial muscle by measuring jitter with a concentric needle (CN) electrode in the diagnosis of Amyotrophic Lateral Sclerosis (ALS) and to investigate the utility of evaluating the peak number as an ongoing reinnervation marker.

METHOD: Twelve patients diagnosed with ALS were included in this study. Single fiber electromyography (SFEMG) was performed using a CN electrode during the voluntary contraction of the right extensor digitorum communis (EDC) and left frontalis muscles.

RESULTS: In SFEMG from the right EDC muscle, the mean jitter value was high in all of them. The average jitter calculated in EDC muscles was 57.76±24.17 μs. The mean jitter value in the frontal muscles was 28.91±10.21 μs. In all patients, the number of CN electrode peaks was more than 4 in the EDC muscle and above 4 in 91.67% of the frontal muscle.

CONCLUSION: Detection of high jitter in SFEMG examination indicates that the examined muscle undergoes a denervation-reinnervation process in the case of increased peak number values. When such a determination is made in the extremity muscles, it becomes important for the diagnosis of ALS.}, } @article {pmid38077003, year = {2023}, author = {Zhou, Z and Kim, J and Huang, AY and Nolan, M and Park, J and Doan, R and Shin, T and Miller, MB and Chhouk, B and Morillo, K and Yeh, RC and Kenny, C and Neil, JE and Lee, CZ and Ohkubo, T and Ravits, J and Ansorge, O and Ostrow, LW and Lagier-Tourenne, C and Lee, EA and Walsh, CA}, title = {Somatic Mosaicism in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Reveals Widespread Degeneration from Focal Mutations.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38077003}, issn = {2692-8205}, support = {R56 AG079857/AG/NIA NIH HHS/United States ; DP2 AG072437/AG/NIA NIH HHS/United States ; K01 AG051791/AG/NIA NIH HHS/United States ; R01 NS032457/NS/NINDS NIH HHS/United States ; DP2 AG086138/AG/NIA NIH HHS/United States ; R01 AG082346/AG/NIA NIH HHS/United States ; K08 AG065502/AG/NIA NIH HHS/United States ; R01 AG070921/AG/NIA NIH HHS/United States ; R01 AG088082/AG/NIA NIH HHS/United States ; }, abstract = {Although mutations in dozens of genes have been implicated in familial forms of amyotrophic lateral sclerosis (fALS) and frontotemporal degeneration (fFTD), most cases of these conditions are sporadic (sALS and sFTD), with no family history, and their etiology remains obscure. We tested the hypothesis that somatic mosaic mutations, present in some but not all cells, might contribute in these cases, by performing ultra-deep, targeted sequencing of 88 genes associated with neurodegenerative diseases in postmortem brain and spinal cord samples from 404 individuals with sALS or sFTD and 144 controls. Known pathogenic germline mutations were found in 20.6% of ALS, and 26.5% of FTD cases. Predicted pathogenic somatic mutations in ALS/FTD genes were observed in 2.7% of sALS and sFTD cases that did not carry known pathogenic or novel germline mutations. Somatic mutations showed low variant allele fraction (typically <2%) and were often restricted to the region of initial discovery, preventing detection through genetic screening in peripheral tissues. Damaging somatic mutations were preferentially enriched in primary motor cortex of sALS and prefrontal cortex of sFTD, mirroring regions most severely affected in each disease. Somatic mutation analysis of bulk RNA-seq data from brain and spinal cord from an additional 143 sALS cases and 23 controls confirmed an overall enrichment of somatic mutations in sALS. Two adult sALS cases were identified bearing pathogenic somatic mutations in DYNC1H1 and LMNA, two genes associated with pediatric motor neuron degeneration. Our study suggests that somatic mutations in fALS/fFTD genes, and in genes associated with more severe diseases in the germline state, contribute to sALS and sFTD, and that mosaic mutations in a small fraction of cells in focal regions of the nervous system can ultimately result in widespread degeneration.}, } @article {pmid38076820, year = {2024}, author = {Worthy, AE and Anderson, JT and Lane, AR and Gomez-Perez, L and Wang, AA and Griffith, RW and Rivard, AF and Bikoff, JB and Alvarez, FJ}, title = {Spinal V1 inhibitory interneuron clades differ in birthdate, projections to motoneurons, and heterogeneity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.11.29.569270}, pmid = {38076820}, issn = {2692-8205}, support = {R01 NS047357/NS/NINDS NIH HHS/United States ; }, abstract = {UNLABELLED: Spinal cord interneurons play critical roles shaping motor output, but their precise identity and connectivity remain unclear. Focusing on the V1 interneuron cardinal class we defined four major V1 subsets according to neurogenesis timing, genetic lineage-tracing, synaptic output to motoneurons, and synaptic inputs from muscle afferents. Birthdate delineates two early born (Renshaw and Pou6f2) and two late born (Foxp2 and Sp8) V1 clades, showing that sequential neurogenesis produces different V1 subsets. Early born Renshaw cells and late born Foxp2-V1 interneurons are tightly coupled to motoneurons, while early born Pou6f2-V1 and late born Sp8-V1 interneurons are not, indicating that timing of neurogenesis does not correlate with motoneuron targeting. V1 clades also differ in cell numbers and diversity. Lineage labeling shows that the Foxp2-V1 clade contains over half of all V1 interneurons, provides the largest inhibitory input to motoneuron cell bodies and includes subgroups that differ in birthdate, location, and proprioceptive input. Notably, one Foxp2-V1 subgroup, defined by postnatal Otp expression is positioned near the lateral motor column and receives substantial input from proprioceptors, consistent with an involvement in reciprocal inhibitory pathways. Combined tracing of ankle flexor sensory afferents and interneurons monosynaptically connected to ankle extensors confirmed placement of Foxp2-V1 interneurons in reciprocal inhibitory pathways. Our results validate previously proposed V1 clades as unique functional subtypes that differ in circuit placement, with Foxp2-V1 cells forming the most heterogeneous subgroup. We discuss how V1 organizational diversity enables understanding of their roles in motor control, with implications for their diverse ontogenetic and phylogenetic origins.

SIGNIFICANCE STATEMENT: The complexity of spinal interneuron diversity and circuit organization represents a challenge to understand neural control of movement in normal adults as well as during motor development and in disease. Inhibitory interneurons are a core element of these spinal circuits. V1 interneurons comprise the largest group of inhibitory interneurons in the ventral horn, and their organization remains unclear. Here we present a comprehensive examination of V1 subtypes according to neurogenesis, placement in spinal motor circuits, and motoneuron synaptic targeting. V1 diversity increases during evolution from axial-swimming fishes to limb-based mammalian terrestrial locomotion. This increased diversity is reflected in the size and heterogeneity of the Foxp2-V1 clade, a group closely associated with limb motor pools. We show that Foxp2-V1 interneurons establish the densest direct inhibitory input to motoneurons, especially on cell bodies. These findings are particularly significant because recent studies have shown that motor neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) affect inhibitory V1 synapses on motoneuron cell bodies and Foxp2-V1 interneurons themselves in the earliest stages of pathology.}, } @article {pmid38073637, year = {2023}, author = {Mitsi, E and Christodoulou, CC and Nicolaou, P and Christodoulou, K and Zamba-Papanicolaou, E}, title = {The influence of environmental risk factors in the development of ALS in the Mediterranean Island of Cyprus.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1264743}, pmid = {38073637}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal degenerative disease of motor neurons, presenting with relentlessly progressive muscle atrophy and weakness. The etiology of ALS remains unexplained for over 85% of all cases, suggesting that besides the genetic basis of the disease, various environmental factors are implicated in the pathogenesis of ALS. This study aimed to investigate the contribution of known environmental risk factors of ALS in the Cypriot population.

METHODS: We conducted a case-control study with a total of 56 ALS cases and 56 healthy gender/age-matched controls of Cypriot nationality. Demographic, lifestyle characteristics, medical conditions, and environmental exposures were collected through the use of a detailed questionnaire. Statistical analyses using the R programming language examined the association between the above environmental factors and ALS.

RESULTS: A chi-square test analysis revealed a statistically significant (p = 0.000461) difference in smoking status between the two groups. In addition, univariate logistic regression analysis showed a statistically significant association between ALS cases for head trauma/injury (p = 0.0398) and exposure to chemicals (p = 0.00128), compared to controls.

CONCLUSION: This case-control investigation has shed some light on the epidemiological data of ALS in Cyprus, by identifying environmental determinants of ALS, such as smoking, head trauma, and chemical exposure, in the Cypriot population.}, } @article {pmid38072540, year = {2023}, author = {Yu, H and Guo, X and Peng, L and Li, X and Chen, J and Cui, H}, title = {Target gene mutations endowed cross-resistance to acetolactate synthase-inhibiting herbicides in wild Brassica juncea.}, journal = {Pesticide biochemistry and physiology}, volume = {197}, number = {}, pages = {105683}, doi = {10.1016/j.pestbp.2023.105683}, pmid = {38072540}, issn = {1095-9939}, mesh = {Amino Acids ; Mustard Plant/genetics/metabolism ; *Herbicides/pharmacology ; *Acetolactate Synthase/metabolism ; Herbicide Resistance/genetics ; Sodium ; Mutation ; Amyotrophic Lateral Sclerosis ; }, abstract = {Wild Brassica juncea is a troublesome weed that infests wheat fields in China. Two suspected wild B. juncea populations (19-5 and 19-6) resistant to acetolactate synthase (ALS) inhibitors were collected from wheat fields in China. To clarify their resistance profiles and resistance mechanism, the resistance levels of populations 19-5 and 19-6 to ALS-inhibiting herbicides and their underlying target-site resistance mechanism were investigated. The results showed that the 19-5 population exhibited resistance to tribenuron-methyl, pyrithiobac‑sodium and florasulam, while the 19-6 population was resistant to tribenuron-methyl, pyrithiobac‑sodium, imazethapyr and florasulam. Using the homologous cloning method, two ALS genes were identified in wild B. juncea, with one gene (ALS1) encoding 652 amino acids and the other (ALS2) encoding 655 amino acids. Pro-197-Arg mutation on ALS2 and Trp-574-Leu mutation on ALS1, together with the combination of these two mutations in a single plant, were observed in both 19-5 and 19-6 populations. ALS2 enzymes carrying the Pro-197-Arg mutation were cross-resistant to tribenuron-methyl, pyrithiobac‑sodium, imazerthapyr and florasulam, with resistance index (RI) values of 6.23, 32.81, 7.97 and 1162.50, respectively. Similarly, ALS1 enzymes with Trp-574-leu substitutions also displayed high resistance to these four herbicides (RI values ranging from 132.61 to 3375.00). In addition, the combination of Pro-197-Arg (ALS2) and Trp-574-Leu (ALS1) mutations increased the resistance level of the ALS enzyme to ALS inhibitors, with its RI values 3.83-214.19, 6.88-37.34, 1.91-31.82 and 2.03-5.90-fold higher than a single mutation for tribenuron-methyl, pyrithiobac‑sodium, imazerthapyr and florasulam, respectively. Collectively, Pro-197-Arg mutation on ALS2, Trp-574-Leu mutation on ALS1 and the combination of Pro-197-Arg (ALS2) and Trp-574-Leu (ALS1) mutations in wild B. juncea could endow broad-spectrum resistance to ALS inhibitors, which might provide guides for establishing effective strategies to prevent or delay such resistance evolution in this weed.}, } @article {pmid38072525, year = {2023}, author = {Han, Y and Sun, Y and Ma, H and Wang, R and Lan, Y and Gao, H and Huang, Z}, title = {Target-site and non-target-site based resistance to clodinafop-propargyl in wild oats (Avena fatua L.).}, journal = {Pesticide biochemistry and physiology}, volume = {197}, number = {}, pages = {105650}, doi = {10.1016/j.pestbp.2023.105650}, pmid = {38072525}, issn = {1095-9939}, mesh = {*Avena/genetics ; Poaceae/genetics ; Plant Proteins/genetics/metabolism ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Acetyl-CoA Carboxylase/genetics/metabolism ; Mutation ; }, abstract = {Wild oat (Avena fatua L.) is a common and problematic weed in wheat fields in China. In recent years, farmers found it increasingly difficult to control A. fatua using acetyl-CoA carboxylase (ACCase)-inhibiting herbicides. The purpose of this study was to identify the molecular basis of clodinafop-propargyl resistance in A. fatua. In comparison to the S1496 population, whole dose response studies revealed that the R1623 and R1625 populations were 71.71- and 67.76-fold resistant to clodinafop-propargyl, respectively. The two resistant A. fatua populations displayed high resistance to fenoxaprop-p-ethyl (APP) and low resistance to clethodim (CHD) and pinoxaden (PPZ), but they were still sensitive to the ALS inhibitors mesosulfuron-methyl and pyroxsulam. An Ile-2041-Asn mutation was identified in both resistant individual plants. The copy number and relative expression of the ACCase gene in the resistant population were not significantly different from those in the S1496 population. Under the application of 2160 g ai ha [-1] of clodinafop-propargyl, the fresh weight of the R1623 population was reduced to 74.9%; however, pretreatment with the application of the cytochrome P450 inhibitor malathion and the GST inhibitor NBD-Cl reduced the fresh weight to 50.91% and 47.16%, respectively, which proved the presence of metabolic resistance. This is the first report of an Ile-2041-Asn mutation and probable metabolic resistance in A. fatua, resulting in resistance to clodinafop-propargyl.}, } @article {pmid38072442, year = {2024}, author = {Matsushita, M and Nakamura, Y and Hosokawa, T and Takahashi, Y and Mizusawa, H and Arawaka, S}, title = {[Spinocerebellar ataxia 2 develop lower motor neuron involvement as an initial symptom: a case report].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {64}, number = {1}, pages = {28-32}, doi = {10.5692/clinicalneurol.cn-001910}, pmid = {38072442}, issn = {1882-0654}, mesh = {Male ; Humans ; Adult ; *Trinucleotide Repeat Expansion ; *Spinocerebellar Ataxias/diagnosis/genetics ; Ataxia ; Motor Neurons ; Atrophy ; }, abstract = {A 36-year-old man has developed weakness of left thumb and atrophy of left thenar muscle and left first dorsal interosseous muscle without sensory disturbance for a year. A nerve conduction study revealed decreases in the amplitude of compound muscle action potentials and occurrence of F-waves on left medial nerve. Needle electromyography examination revealed positive sharp waves and later recruited motor units on left abductor pollicis brevis muscle. Brain MRI showed atrophy of bilateral cerebellar hemisphere. His grandmother and his two uncles have been diagnosed as spinocerebellar degeneration. After discharge, he developed bilateral lower limb ataxia. Genetic analysis showed heterozygous CAG repeat expansion (19/39) in ATXN2 gene, being diagnosed as spinocerebellar ataxia 2 (SCA2). A previous report has shown that motor neuron involvement is recognized as part of SCA2 in the same pedigree with full CAG repeat expansions in ATXN2 gene. We here report the patient with lower motor neuron involvement as an initial symptom of SCA2.}, } @article {pmid38072117, year = {2024}, author = {Alaoui Mansouri, M and Kharbach, M and Bouklouze, A}, title = {Current Applications of Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) in Pharmaceutical Analysis: Review.}, journal = {Journal of pharmaceutical sciences}, volume = {113}, number = {4}, pages = {856-865}, doi = {10.1016/j.xphs.2023.12.004}, pmid = {38072117}, issn = {1520-6017}, mesh = {Least-Squares Analysis ; *Biopharmaceutics ; Pharmaceutical Preparations ; Multivariate Analysis ; }, abstract = {The present review encompasses various applications of multivariate curve resolution- alternating least squares (MCR-ALS) as a promising data handling, which is issued by analytical techniques in pharmaceutics. It involves different sections starting from a concise theory of MCR-ALS and four detailed applications in drugs analysis. Dissolution, stability, polymorphism, and quantification are the main four detailed applications. The data generated by analytical techniques associated with MCR-ALS deals accurately with different challenges compared to other chemometric tools. For each reviewed purpose, it was explained how MCR-ALS was applied and detailed information was given. Different approaches were introduced to overcome challenges that limit the use of MCR-ALS efficiently in pharmaceutical mixture were also discussed.}, } @article {pmid38072051, year = {2024}, author = {Lu, J and Ge, P and Sawaya, MR and Hughes, MP and Boyer, DR and Cao, Q and Abskharon, R and Cascio, D and Tayeb-Fligelman, E and Eisenberg, DS}, title = {Cryo-EM structures of the D290V mutant of the hnRNPA2 low-complexity domain suggests how D290V affects phase separation and aggregation.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {2}, pages = {105531}, pmid = {38072051}, issn = {1083-351X}, support = {RF1 AG065407/AG/NIA NIH HHS/United States ; R01 AG070895/AG/NIA NIH HHS/United States ; R01 AG048120/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Cryoelectron Microscopy ; Phase Separation ; Protein Domains ; Mutation ; Hydrogen-Ion Concentration ; *Models, Molecular ; Protein Stability ; Protein Structure, Tertiary ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B/chemistry/metabolism ; }, abstract = {Heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2) is a human ribonucleoprotein that transports RNA to designated locations for translation via its ability to phase separate. Its mutated form, D290V, is implicated in multisystem proteinopathy known to afflict two families, mainly with myopathy and Paget's disease of bone. Here, we investigate this mutant form of hnRNPA2 by determining cryo-EM structures of the recombinant D290V low complexity domain. We find that the mutant form of hnRNPA2 differs from the WT fibrils in four ways. In contrast to the WT fibrils, the PY-nuclear localization signals in the fibril cores of all three mutant polymorphs are less accessible to chaperones. Also, the mutant fibrils are more stable than WT fibrils as judged by phase separation, thermal stability, and energetic calculations. Similar to other pathogenic amyloids, the mutant fibrils are polymorphic. Thus, these structures offer evidence to explain how a D-to-V missense mutation diverts the assembly of reversible, functional amyloid-like fibrils into the assembly of pathogenic amyloid, and may shed light on analogous conversions occurring in other ribonucleoproteins that lead to neurological diseases such as amyotrophic lateral sclerosis and frontotemporal dementia.}, } @article {pmid38071852, year = {2024}, author = {Musso, G and Blasi, L and Mion, MM and Fortuna, A and Sabbatini, D and Zaninotto, M and Bello, L and Pegoraro, E and Basso, D and Plebani, M and Sorarù, G}, title = {Troponin T in spinal and bulbar muscular atrophy (SBMA).}, journal = {Journal of the neurological sciences}, volume = {456}, number = {}, pages = {122816}, doi = {10.1016/j.jns.2023.122816}, pmid = {38071852}, issn = {1878-5883}, mesh = {Adult ; Humans ; Troponin T ; *Bulbo-Spinal Atrophy, X-Linked ; *Muscular Atrophy, Spinal/diagnosis ; Biomarkers ; *Neuromuscular Diseases ; *Amyotrophic Lateral Sclerosis ; *Spinal Muscular Atrophies of Childhood ; }, abstract = {Serum biomarkers that might detect clinical progression are currently lacking for Spinal and bulbar muscular atrophy (SBMA), thus limiting the effectiveness of possible future pharmacological trials. Elevation of cardiac troponin T (cTnT) unrelated to myocardial damage in a motor neuron (MN) disease as amyotrophic lateral sclerosis (ALS) was associated to disease severity. We enrolled 47 SBMA patients and 5 Spinal muscular atrophy (SMA) type 3 adult patients as control group; each SBMA patient was evaluated at baseline and at one-year follow-up visit. Demographic and clinical data including functional scores (SBMAFRS) were collected; serum was collected as standard of care and tested for cardiac troponins. Levels of cTnT but not cTnI were increased in SBMA with respect to reference values; unlike other neuromuscular diseases, SMA patients had overall normal cTnT values. Median cTnT concentrations did not change after one year and values were correlated to motor function, particularly with lower limb subdomain, at baseline only. Variations of cTnT and of SBMAFRS were unrelated. The cautiously promising results of cTnT as potential biomarker should undergo a more extensive clinical validation, including studies with longer follow-up period. When evaluating SBMA patients for a potential cardiac damage cTnI testing should be coupled or preferred to cTnT.}, } @article {pmid38070961, year = {2023}, author = {Krall, JTW and Chakravartty, A and Caress, JB and Files, DC}, title = {Identification and Management of Acute Neuromuscular Respiratory Failure in the ICU.}, journal = {Chest}, volume = {164}, number = {6}, pages = {1454-1461}, doi = {10.1016/j.chest.2023.09.009}, pmid = {38070961}, issn = {1931-3543}, mesh = {Humans ; *Neuromuscular Diseases/complications/diagnosis/therapy ; *Respiratory Insufficiency/diagnosis/etiology/therapy ; Prognosis ; Intensive Care Units ; }, abstract = {Respiratory failure is a common and potentially life-threatening complication of neuromuscular diseases. Prompt recognition and accurate diagnosis of new or worsening chronic neuromuscular disease have important clinical management and prognostic implications. In this article, we present an approach to the acute presentation of undifferentiated neuromuscular respiratory failure in the ICU and guidance for determination and respiratory management of the underlying disorder.}, } @article {pmid38070417, year = {2024}, author = {Ur Rahman, S and Han, JC and Ahmad, M and Ashraf, MN and Khaliq, MA and Yousaf, M and Wang, Y and Yasin, G and Nawaz, MF and Khan, KA and Du, Z}, title = {Aluminum phytotoxicity in acidic environments: A comprehensive review of plant tolerance and adaptation strategies.}, journal = {Ecotoxicology and environmental safety}, volume = {269}, number = {}, pages = {115791}, doi = {10.1016/j.ecoenv.2023.115791}, pmid = {38070417}, issn = {1090-2414}, mesh = {*Aluminum/toxicity/metabolism ; Malates/metabolism ; Plant Breeding ; Plants/metabolism ; *Alkaloids/pharmacology ; Organic Chemicals/metabolism ; Soil/chemistry ; Plant Roots/metabolism ; Gene Expression Regulation, Plant ; }, abstract = {Aluminum (Al), a non-essential metal for plant growth, exerts significant phytotoxic effects, particularly on root growth. Anthropogenic activities would intensify Al's toxic effects by releasing Al[3+] into the soil solution, especially in acidic soils with a pH lower than 5.5 and rich mineral content. The severity of Al-induced phytotoxicity varies based on factors such as Al concentration, ionic form, plant species, and growth stages. Al toxicity leads to inhibited root and shoot growth, reduced plant biomass, disrupted water uptake causing nutritional imbalance, and adverse alterations in physiological, biochemical, and molecular processes. These effects collectively lead to diminished plant yield and quality, along with reduced soil fertility. Plants employ various mechanisms to counter Al toxicity under stress conditions, including sequestering Al in vacuoles, exuding organic acids (OAs) like citrate, oxalate, and malate from root tip cells to form Al-complexes, activating antioxidative enzymes, and overexpressing Al-stress regulatory genes. Recent advancements focus on enhancing the exudation of OAs to prevent Al from entering the plant, and developing Al-tolerant varieties. Gene transporter families, such as ATP-Binding Cassette (ABC), Aluminum-activated Malate Transporter (ALMT), Natural resistance-associated macrophage protein (Nramp), Multidrug and Toxic compounds Extrusion (MATE), and aquaporin, play a crucial role in regulating Al toxicity. This comprehensive review examined recent progress in understanding the cytotoxic impact of Al on plants at the cellular and molecular levels. Diverse strategies developed by both plants and scientists to mitigate Al-induced phytotoxicity were discussed. Furthermore, the review explored recent genomic developments, identifying candidate genes responsible for OAs exudation, and delved into genome-mediated breeding initiatives, isolating transgenic and advanced breeding lines to cultivate Al-tolerant plants.}, } @article {pmid38069659, year = {2024}, author = {Sommers-Spijkerman, M and Stukker, A and Kavanaugh, MS and Ketelaar, M and Visser-Meily, JMA and Beelen, A}, title = {What, how and when do families communicate about ALS? A qualitative exploration of parents' and children's perceptions.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {256-263}, doi = {10.1080/21678421.2023.2290738}, pmid = {38069659}, issn = {2167-9223}, mesh = {Child ; Humans ; Adolescent ; Young Adult ; Adult ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Parents ; Communication ; Qualitative Research ; }, abstract = {Objectives: In families with a parent diagnosed with amyotrophic lateral sclerosis (ALS), children's adaptation depends among others on how their parents communicate with them about the disease and its trajectory. The aim of this study was to explore parents' and children's perceptions of ALS-related family communication. Methods: A qualitative analysis using a conventional content analysis approach was applied to interview data previously collected from 21 parents (8 with ALS) and 15 children (age 13-23 years) about their experiences living with ALS. Results: Three themes emerged from the interviews: communication topics, styles and timing. Communication topics include facts about disease and prognosis, feelings, care and equipment, and the end. Although most parents perceived the familial communication style concerning ALS as open, the interviews revealed that both parents and children sometimes avoid interactions about ALS, because they do not know what to say or how to open the dialogue, are afraid to burden other family members, or are unwilling to discuss. Communication timing is directed by changes in the disease trajectory and/or questions of children. A family-level analysis showed that ALS-related family communication is sometimes perceived differently by parents and children. Conclusions: The study provides a better understanding of what, how and when parents and children in families living with ALS communicate about the disease. Most families opened the dialogue about ALS yet encountered challenges which may hamper good familial communication. Through addressing those challenges, healthcare professionals may facilitate better communication and adaptation in families with a parent with ALS.}, } @article {pmid38069599, year = {2024}, author = {Hansen, G and Burton-MacLeod, S and Schellenberg, KL}, title = {ALS Health care provider wellness.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {299-307}, doi = {10.1080/21678421.2023.2291710}, pmid = {38069599}, issn = {2167-9223}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/epidemiology ; Pandemics ; Canada/epidemiology ; Health Personnel/psychology ; *Physicians/psychology ; *Burnout, Professional/epidemiology/psychology ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Interest in health care provider (HCP) wellness and burnout is increasing; however, minimal literature explores HCP wellness in the context of Amyotrophic Lateral Sclerosis (ALS) care.

OBJECTIVES: We sought to determine rates of burnout and resiliency, as well as challenges and rewards in the provision of ALS care.

METHODS: A survey link was sent to physicians at all Canadian ALS centers for distribution to ALS HCPs in their network. The survey included demographics questions, and validated measures for resiliency and burnout; the Brief Resilient Coping Scale (BRCS) and the Single Item Burnout Score (SIBS). Participants were asked to describe challenges and rewards of ALS care, impact of COVID-19 pandemic, and how their workplace could better support them.

RESULTS: There were 85 respondents across multiple disciplines. The rate of burnout was 47%. Burnout for female respondents was significantly higher (p = 0.007), but not for age, role, or years in ALS clinic. Most participants were medium resilient copers n = 48 (56.5%), but resiliency was not related to burnout. Challenges included feeling helpless while patients relentlessly progressed to death, and emotionally charged interactions. Participants found fulfillment in providing care, and through relationships with patients and colleagues. There was a strongly expressed desire for increased resources, team building/debriefing, and formal training in emotional exhaustion and burnout.

CONCLUSIONS: The high rate of burnout and challenges of ALS care highlight the need for additional resources, team-building, and formal education around wellness.}, } @article {pmid38069329, year = {2023}, author = {Kim, H and Kim, GS and Hyun, SH and Kim, E}, title = {Advancements in 2D and 3D In Vitro Models for Studying Neuromuscular Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {23}, pages = {}, pmid = {38069329}, issn = {1422-0067}, support = {NRF-2021R1C1C2007132//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Neuromuscular Diseases ; Muscle, Skeletal ; Neuromuscular Junction ; Motor Neurons ; Organoids ; }, abstract = {Neuromuscular diseases (NMDs) are a genetically or clinically heterogeneous group of diseases that involve injury or dysfunction of neuromuscular tissue components, including peripheral motor neurons, skeletal muscles, and neuromuscular junctions. To study NMDs and develop potential therapies, remarkable progress has been made in generating in vitro neuromuscular models using engineering approaches to recapitulate the complex physical and biochemical microenvironments of 3D human neuromuscular tissues. In this review, we discuss recent studies focusing on the development of in vitro co-culture models of human motor neurons and skeletal muscles, with the pros and cons of each approach. Furthermore, we explain how neuromuscular in vitro models recapitulate certain aspects of specific NMDs, including amyotrophic lateral sclerosis and muscular dystrophy. Research on neuromuscular organoids (NMO) will continue to co-develop to better mimic tissues in vivo and will provide a better understanding of the development of the neuromuscular tissue, mechanisms of NMD action, and tools applicable to preclinical studies, including drug screening and toxicity tests.}, } @article {pmid38069154, year = {2023}, author = {Belosludtseva, NV and Matveeva, LA and Belosludtsev, KN}, title = {Mitochondrial Dyshomeostasis as an Early Hallmark and a Therapeutic Target in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {23}, pages = {}, pmid = {38069154}, issn = {1422-0067}, support = {23-25-00286//Russian Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Mitochondria/metabolism ; Motor Neurons/metabolism ; Energy Metabolism ; Disease Progression ; Superoxide Dismutase-1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal multisystem disease characterized by progressive death of motor neurons, loss of muscle mass, and impaired energy metabolism. More than 40 genes are now known to be associated with ALS, which together account for the majority of familial forms of ALS and only 10% of sporadic ALS cases. To date, there is no consensus on the pathogenesis of ALS, which makes it difficult to develop effective therapy. Accumulating evidence indicates that mitochondria, which play an important role in cellular homeostasis, are the earliest targets in ALS, and abnormalities in their structure and functions contribute to the development of bioenergetic stress and disease progression. Mitochondria are known to be highly dynamic organelles, and their stability is maintained through a number of key regulatory pathways. Mitochondrial homeostasis is dynamically regulated via mitochondrial biogenesis, clearance, fission/fusion, and trafficking; however, the processes providing "quality control" and distribution of the organelles are prone to dysregulation in ALS. Here, we systematically summarized changes in mitochondrial turnover, dynamics, calcium homeostasis, and alterations in mitochondrial transport and functions to provide in-depth insights into disease progression pathways, which may have a significant impact on current symptomatic therapies and personalized treatment programs for patients with ALS.}, } @article {pmid38068696, year = {2023}, author = {Sun, J and Yu, X and Xu, H and Yang, Y and Liu, M and Zhang, Y and Lu, Y and Tang, W}, title = {Post-Emergence Water-Dispersal Application Provides Equal Herbicidal Activity against Echinochloa crus-galli and Rice Safety as Foliar Spraying of Penoxsulam.}, journal = {Plants (Basel, Switzerland)}, volume = {12}, number = {23}, pages = {}, pmid = {38068696}, issn = {2223-7747}, support = {LGN21C140003//Zhejiang Provincial Natural Science Foundation/ ; 32071508//National Natural Science Foundation of China/ ; CARS-01//the China Agriculture Research System/ ; }, abstract = {Penoxsulam is an acetolactate synthase (ALS)-inhibiting herbicide usually applied by post-emergence foliar spraying (PFS) for the control of Echinochloa crus-galli and numerous annual weeds in paddy fields. Herbicides applied by foliar spraying can have negative impacts on the environment, ecosystems, and human health. In this study, the response of E. crus-galli and rice to the PFS and post-emergence water-dispersal (PWD) applications of penoxsulam, and the differences in the detoxification displayed by them between the two treatment methods were compared. The results showed that the PWD application of penoxsulam provides a similar control efficacy against E. crus-galli as PFS at the 1-, 3-, and 5-leaf stages. Meanwhile, the PWD application had a higher safety for the rice. After being treated with 30 g a.i. ha[-1] penoxsulam, residues were not detected in the rice treated by the PWD application method, whereas, with the PFS treatment, there was 59.0 µg/kg penoxsulam remaining. With the PFS application, there were many more residues of penoxsulam in the E. crus-galli than with the PWD method; the amount of residues was 32-fold higher 12 h after treatment. The in vitro enzyme activity assays revealed that the activities of ALS, glutathione-S-transferase (GST), and cytochrome P450 monooxygenases (P450) were increased in the PWD treatments, and were 1.5-, 1.3-, and 2.3-fold higher than with PFS 72 h after treatment. The real-time quantitative PCR (qRT-PCR) revealed that the GST1 and P450 genes, CYP81A14, CYP81A12, CYP81A18, and CYP81A21 were upregulated with the PWD application versus PFS in the E. crus-galli. In summary, these results demonstrate that the herbicidal activity was not affected by the upregulation of target and metabolic enzyme activities with the PWD application of penoxsulam. This research could contribute to application strategies reducing the risk of rice injury and environmental impacts by using water-dispersal formulations of penoxsulam.}, } @article {pmid38068637, year = {2023}, author = {Roth, IS and Singer, A and Yadid, I and Sibony, M and Peleg, Z and Rubin, B}, title = {Do Traits Travel? Multiple-Herbicide-Resistant A. tuberculatus, an Alien Weed Species in Israel.}, journal = {Plants (Basel, Switzerland)}, volume = {12}, number = {23}, pages = {}, pmid = {38068637}, issn = {2223-7747}, support = {3011002657//Israel Cotton Board/ ; 811-0210-98//The Chief Scientist Fund, Ministry of Agriculture, Israel/ ; }, abstract = {Amaranthus tuberculatus is the most common weed in soybean and corn in the USA and Canada. In Israel, it has been a minor riverbank weed. However, in recent years, growing densities of this plant have been observed in field crops, orchards, and roadsides. Between 2017 and 2022, we surveyed the distribution of A. tuberculatus and collected seeds for further study. We identified three main distribution zones in Israel: the Jezreel Valley, Hula Valley, and Coastal Plain. Most of the populations were found near water sources, fishponds, barns, dairies, or bird-feeding sites, suggesting the involvement of imported grain in introducing A. tuberculatus to Israel. Populations were screened for their responses to various post-emergence herbicides (i.e., ALS, EPSPS, PPO, HPPD, and PSII inhibitors). Several populations from the Jezreel Valley were found to be putatively resistant to ALS, EPSPS, and PPO inhibitors. The responses of those populations to trifloxysulfuron, glyphosate, and carfentrazone-ethyl were also studied. A single ALS-, EPSPS- and PPO-resistant plant was vegetatively propagated to create a clonal population, which was treated with foramsulfuron, glyphosate, and carfentrazone-ethyl. No resistance to PSII or HPPD inhibitors was observed, but resistance to herbicides that inhibit ALS, EPSPS, and PPO was observed. A clonal propagation assay revealed the existence of a population that was resistant to ALS, EPSPS, and PPO inhibitors. Since the local A. tuberculatus populations have not been exposed to herbicide selection pressure, these traits probably reached Israel through seed-mediated gene flow via imported grain.}, } @article {pmid38067180, year = {2023}, author = {Stella, R and Bonadio, RS and Cagnin, S and Andreotti, R and Massimino, ML and Bertoli, A and Peggion, C}, title = {Secreted Metabolome of ALS-Related hSOD1(G93A) Primary Cultures of Myocytes and Implications for Myogenesis.}, journal = {Cells}, volume = {12}, number = {23}, pages = {}, pmid = {38067180}, issn = {2073-4409}, support = {BIRD 202151/20//University of Padova/ ; DOR2331994/2//University of Padova/ ; 2016-1006//The Cariplo Foundation/ ; }, mesh = {Mice ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Motor Neurons/pathology ; Mice, Transgenic ; Superoxide Dismutase-1/metabolism ; *Motor Neuron Disease/metabolism ; Muscle Cells/metabolism ; Metabolome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron (MN) disease associated with progressive muscle atrophy, paralysis, and eventually death. Growing evidence demonstrates that the pathological process leading to ALS is the result of multiple altered mechanisms occurring not only in MNs but also in other cell types inside and outside the central nervous system. In this context, the involvement of skeletal muscle has been the subject of a few studies on patients and ALS animal models. In this work, by using primary myocytes derived from the ALS transgenic hSOD1(G93A) mouse model, we observed that the myogenic capability of such cells was defective compared to cells derived from control mice expressing the nonpathogenic hSOD1(WT) isoform. The correct in vitro myogenesis of hSOD1(G93A) primary skeletal muscle cells was rescued by the addition of a conditioned medium from healthy hSOD1(WT) myocytes, suggesting the existence of an in trans activity of secreted factors. To define a dataset of molecules participating in such safeguard action, we conducted comparative metabolomic profiling of a culture medium collected from hSOD1(G93A) and hSOD1(WT) primary myocytes and report here an altered secretion of amino acids and lipid-based signaling molecules. These findings support the urgency of better understanding the role of the skeletal muscle secretome in the regulation of the myogenic program and mechanisms of ALS pathogenesis and progression.}, } @article {pmid38066647, year = {2024}, author = {Barrios, V and Martín-Rivada, Á and Guerra-Cantera, S and Campillo-Calatayud, A and Camarneiro, RA and Graell, M and Chowen, JA and Argente, J}, title = {Reduction in Pappalysin-2 Levels and Lower IGF-I Bioavailability in Female Adolescents With Anorexia Nervosa.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {109}, number = {3}, pages = {e920-e931}, doi = {10.1210/clinem/dgad713}, pmid = {38066647}, issn = {1945-7197}, support = {FIS-PI19/00166//Ministerio de Ciencia e Innovación/ ; //European Union/ ; //Centro de Investigación Biomédica en Red Fisiopatología de Obesidad y Nutrición/ ; CD19/00008//Instituto de Salud Carlos III/ ; //Comunidad Autónoma de Madrid/ ; }, mesh = {Humans ; Female ; Adolescent ; Insulin-Like Growth Factor I/metabolism ; Insulin-Like Growth Factor Binding Protein 4 ; Insulin-Like Growth Factor Binding Protein 3 ; Insulin-Like Growth Factor Binding Protein 2 ; *Anorexia Nervosa ; Biological Availability ; Amenorrhea ; Insulin-Like Growth Factor Binding Proteins ; *Peptide Hormones ; Pregnancy-Associated Plasma Protein-A/metabolism ; }, abstract = {CONTEXT: Anorexia nervosa (AN) can cause severe undernutrition associated with alterations in the IGF axis. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) modulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implications in AN are unknown.

OBJECTIVE: We determined serum levels of PAPP-As and STCs in relationship with classical IGF axis parameters in female adolescents with AN and their association with nutritional status and secondary amenorrhea.

METHODS: Parameters of the IGF axis were determined in fasting serum samples of 68 female adolescents with AN at diagnosis and 62 sex- and age-matched controls. Standardized body mass index (BMI) and bone mineral density (BMD) were calculated.

RESULTS: Patients with AN had lower concentrations of total and free IGF-I, total IGFBP-3, acid-labile subunit (ALS), insulin, PAPP-A2, STC-1, and STC-2 and higher levels of IGF-II and IGFBP-2. Their free/total IGF-I ratio was decreased and the intact/total IGFBP-3 and -4 ratios increased. BMI was directly related to total IGF-I and intact IGFBP-3 and inversely with IGFBP-2 and intact IGFBP-4. Weight loss was directly correlated with intact IGFBP-4 and negatively with intact IGFBP-3, ALS, STC-2, and PAPP-A2 concentrations. BMD was directly related to intact IGFBP-3 and inversely with intact IGFBP-4 and PAPP-A2 levels. Patients with amenorrhea had lower levels of total IGF-I and IGFBP-3 than those with menses.

CONCLUSION: The reduction of PAPP-A2 in patients with AN may be involved in a decline in IGFBP cleavage, which could underlie the decrease in IGF-I bioavailability that is influenced by nutritional status and amenorrhea.}, } @article {pmid38066205, year = {2024}, author = {Reilich, P and Schöberl, F and Hiebeler, M and Tonon, M and Ludolph, AC and Senel, M}, title = {Myelitis as a side effect of tofersen therapy in SOD1-associated ALS.}, journal = {Journal of neurology}, volume = {271}, number = {4}, pages = {2114-2118}, pmid = {38066205}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Mutation ; *Myelitis/genetics ; Oligonucleotides/adverse effects ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/antagonists & inhibitors/genetics ; }, } @article {pmid38065418, year = {2024}, author = {Yuan, Y and Bailey, JM and Rivera-Lopez, GM and Atchison, WD}, title = {Preferential potentiation of AMPA-mediated currents in brainstem hypoglossal motoneurons by subchronic exposure of mice expressing the human superoxide dismutase 1 G93A gene mutation to neurotoxicant methylmercury in vivo.}, journal = {Neurotoxicology}, volume = {100}, number = {}, pages = {72-84}, pmid = {38065418}, issn = {1872-9711}, support = {R01 ES024064/ES/NIEHS NIH HHS/United States ; }, mesh = {Mice ; Humans ; Animals ; Superoxide Dismutase-1 ; *Amyotrophic Lateral Sclerosis/chemically induced/genetics ; *Methylmercury Compounds/toxicity ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology ; Superoxide Dismutase/metabolism ; Mice, Transgenic ; Motor Neurons/metabolism ; Brain Stem/metabolism ; Mutation ; Disease Models, Animal ; Spinal Cord/metabolism ; }, abstract = {The exact causes of Amyotrophic lateral sclerosis (ALS), a progressive and fatal neurological disorder due to loss of upper and/or lower motoneurons, remain elusive. Gene-environment interactions are believed to be an important factor in the development of ALS. We previously showed that in vivo exposure of mice overexpressing the human superoxide dismutase 1 (hSOD1) gene mutation (hSOD1G93A; G93A), a mouse model for ALS, to environmental neurotoxicant methylmercury (MeHg) accelerated the onset of ALS-like phenotype. Here we examined the time-course of effects of MeHg on AMPA receptor (AMPAR)-mediated currents in hypoglossal motoneurons in brainstem slices prepared from G93A, hSOD1wild-type (hWT) and non-carrier WT mice following in vivo exposure to MeHg. Mice were exposed daily to 3 ppm (approximately 0.7 mg/kg/day) MeHg via drinking water beginning at postnatal day 28 (P28) and continued until P47, 64 or 84, then acute brainstem slices were prepared, and spontaneous excitatory postsynaptic currents (sEPSCs) or AMPA-evoked currents were examined using whole cell patch-clamp recording technique. Brainstem slices of untreated littermates were prepared at the same time points to serve as control. MeHg exposure had no significant effect on either sEPSCs or AMPA-evoked currents in slices from hWT or WT mice during any of those exposure time periods under our experimental conditions. MeHg also did not cause any significant effect on sEPSCs or AMPA-currents in G93A hypoglossal motoneurons at P47 and P64. However, at P84, MeHg significantly increased amplitudes of both sEPSCs and AMPA-evoked currents in hypoglossal motineurons from G93A mice (p < 0.05), but not the sEPSC frequency, suggesting a postsynaptic action on AMPARs. MeHg exposure did not cause any significant effect on GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs). Therefore, MeHg exposure in vivo caused differential effects on AMPARs in hypoglossal motoneurons from mice with different genetic backgrounds. MeHg appears to preferentially stimulate the AMPAR-mediated currents in G93A hypoglossal motoneurons in an exposure time-dependent manner, which may contribute to the AMPAR-mediated motoneuron excitotoxicity, thereby facilitating development of ALS-like phenotype.}, } @article {pmid38064644, year = {2024}, author = {Rong, P and Rasmussen, L}, title = {A Fine-Grained Temporal Analysis of Multimodal Oral Diadochokinetic Performance to Assess Speech Impairment in Amyotrophic Lateral Sclerosis.}, journal = {American journal of speech-language pathology}, volume = {33}, number = {1}, pages = {307-332}, doi = {10.1044/2023_AJSLP-23-00177}, pmid = {38064644}, issn = {1558-9110}, mesh = {Humans ; *Speech/physiology ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Jaw ; Speech Disorders/complications ; Speech Production Measurement ; }, abstract = {PURPOSE: This study used a semiautomated fine-grained temporal analysis to extract features of temporal oral diadochokinetic (DDK) performance across multiple modalities and tasks, from neurologically healthy and impaired individuals secondary to amyotrophic lateral sclerosis (ALS). The aims were to (a) delineate temporal oral DDK deficits relating to the neuromotor pathology of ALS and (b) identify the optimal task-feature combinations to detect speech impairment in ALS.

METHOD: Mandibular myoelectric, kinematic, and acoustic data were acquired from 13 individuals with ALS and 10 healthy controls producing three alternating motion rate tasks and one sequential motion rate task. Twenty-seven features were extracted from the multimodal data, characterizing three temporal constructs: duration/rate, variability, and coordination. The disease impacts on these features were assessed across tasks, and the task eliciting the greatest disease-related change was identified for each feature. Such "optimal" task-feature combinations were fed into logistic regression to differentiate individuals with ALS from healthy controls.

RESULTS: Temporal deficits in ALS were characterized by (a) increased duration and variability and reduced coordination of jaw muscle activities, (b) increased duration and variability and altered temporal symmetry of jaw velocity profile, (c) increased muscle-burst-to-peak-velocity duration, and (d) increased motion-to-voice onset duration. These temporal features were differentially affected across tasks. The optimal task-feature combinations, which were further clustered into three composite factors reflecting temporal variability, coarser-grained duration, and finer-grained duration, differentiated ALS from controls with an F1 score of 0.86 (precision = 1.00, recall = 0.75).

CONCLUSIONS: Temporal oral DDK deficits are likely attributed to a hierarchy of interrelated neurophysiological and biomechanical factors associated with the neuromotor pathology of ALS. These deficits, as assessed crossmodally, provide previously unavailable insights into the multifaceted timing impairment of oromotor performance in ALS. The optimal task-feature combinations targeting these deficits show promise as quantitative markers for (early) detection of speech impairment in ALS.}, } @article {pmid38064514, year = {2023}, author = {Tang, D and Zheng, K and Zhu, J and Jin, X and Bao, H and Jiang, L and Li, H and Wang, Y and Lu, Y and Liu, J and Liu, H and Tang, C and Feng, S and Dong, X and Xu, L and Yin, Y and Dang, S and Wei, X and Ren, H and Dong, B and Dai, L and Cheng, W and Wan, M and Li, Z and Chen, J and Li, H and Kong, E and Wang, K and Lu, K and Qi, S}, title = {ALS-linked C9orf72-SMCR8 complex is a negative regulator of primary ciliogenesis.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {50}, pages = {e2220496120}, pmid = {38064514}, issn = {1091-6490}, support = {32071214//MOST | National Natural Science Foundation of China (NSFC)/ ; 32022020//MOST | National Natural Science Foundation of China (NSFC)/ ; 31970693//MOST | National Natural Science Foundation of China (NSFC)/ ; ZYYC20016//the 135 Project for Disciplines of Excellence, West China Hospital, Sichuan University/ ; ZYYC20015//the 135 Project for Disciplines of Excellence, West China Hospital, Sichuan University/ ; ZYJC18015//the 135 Project for Disciplines of Excellence, West China Hospital, Sichuan University/ ; 2022SCU12041//the Fundamental Research Funds for the Central Universities/ ; 2022NSFSC0049//the Natural Science Foundation of Sichuan, China/ ; 32201025//MOST | National Natural Science Foundation of China (NSFC)/ ; ZYGD18011//the 135 Project for Disciplines of Excellence, West China Hospital, Sichuan University/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; *C9orf72 Protein/genetics/metabolism ; *Cilia/metabolism ; DNA Repeat Expansion ; *Frontotemporal Dementia/metabolism ; GTPase-Activating Proteins/metabolism ; Humans ; HEK293 Cells ; }, abstract = {Massive GGGGCC (G4C2) repeat expansion in C9orf72 and the resulting loss of C9orf72 function are the key features of ~50% of inherited amyotrophic lateral sclerosis and frontotemporal dementia cases. However, the biological function of C9orf72 remains unclear. We previously found that C9orf72 can form a stable GTPase activating protein (GAP) complex with SMCR8 (Smith-Magenis chromosome region 8). Herein, we report that the C9orf72-SMCR8 complex is a major negative regulator of primary ciliogenesis, abnormalities in which lead to ciliopathies. Mechanistically, the C9orf72-SMCR8 complex suppresses the primary cilium as a RAB8A GAP. Moreover, based on biochemical analysis, we found that C9orf72 is the RAB8A binding subunit and that SMCR8 is the GAP subunit in the complex. We further found that the C9orf72-SMCR8 complex suppressed the primary cilium in multiple tissues from mice, including but not limited to the brain, kidney, and spleen. Importantly, cells with C9orf72 or SMCR8 knocked out were more sensitive to hedgehog signaling. These results reveal the unexpected impact of C9orf72 on primary ciliogenesis and elucidate the pathogenesis of diseases caused by the loss of C9orf72 function.}, } @article {pmid38064278, year = {2024}, author = {Mao, Y and Li, Y and McGarry, B and Wang, J and Temkin-Greener, H}, title = {Home time and state regulations among Medicare beneficiaries in assisted living communities.}, journal = {Journal of the American Geriatrics Society}, volume = {72}, number = {3}, pages = {742-752}, pmid = {38064278}, issn = {1532-5415}, support = {R01 HS026893/HS/AHRQ HHS/United States ; }, mesh = {Aged ; Humans ; United States ; *Medicare ; *Quality of Life ; Nursing Homes ; Medicaid ; Chronic Disease ; }, abstract = {BACKGROUND: Home time is an important patient-centric quality metric, which has been largely unexamined among assisted living (AL) residents. Our objectives were to assess variation in home time among AL residents in the year following admission and to examine the associations with state regulations for direct care workers (DCW) training and staffing and for licensed nurse staffing.

METHODS: Medicare beneficiaries who entered AL communities in 2018 were identified, and their home time in the year following admission was measured. Home time was calculated as the percentage of time spent at home per day being alive. Resident characteristics and state regulations in DCW staffing, DCW training, and licensed staffing were measured. We used a multivariate linear regression model with AL-level fixed effects to estimate the relationship between person-level characteristics and home time. Linear regression models adjusting for resident characteristics were used to estimate the association between state regulations and residents' home time.

RESULTS: The study sample included 59,831 new Medicare beneficiary residents in 12,143 ALs. In the year following AL admission, residents spent 94% (standard deviation = 14.6) of their time at home. Several resident characteristics were associated with lower home time: Medicare-Medicaid dual eligibility, having more chronic conditions, and specific chronic conditions, for example, dementia. In states with greater regulatory specificity for DCW training and staffing, and lower specificity for licensed staffing, residents had longer adjusted home time.

CONCLUSION/IMPLICATIONS: Home time varied substantially among AL residents depending on resident characteristics and state-level regulatory specificity. AL residents eligible for Medicare and Medicaid had substantially shorter home time than the Medicare-only residents, largely due to longer time spent in nursing homes. State AL regulatory specificity for DCWs and licensed staff also impacted AL residents' home time. These findings may guide AL operators and state legislators in efforts to improve this important quality of life metric.}, } @article {pmid38063868, year = {2024}, author = {Luib, E and Demleitner, AF and Cordts, I and Westenberg, E and Rau, P and Pürner, D and Haller, B and Lingor, P}, title = {Reduced tear fluid production in neurological diseases: a cohort study in 708 patients.}, journal = {Journal of neurology}, volume = {271}, number = {4}, pages = {1824-1836}, pmid = {38063868}, issn = {1432-1459}, mesh = {Humans ; Cohort Studies ; *Nervous System Diseases ; *Motor Neuron Disease ; *Amyotrophic Lateral Sclerosis/pathology ; Brain/pathology ; *Parkinson Disease ; }, abstract = {BACKGROUND: Tear fluid (TF) production is an important component of normal ocular function. It is regulated by parasympathetic and sympathetic innervation. Because parasympathetic nerve fibers originate in the brainstem, pathology in this brain region may affect TF production. For example, a reduction in TF production has been described in patients with Parkinson's disease (PD).

METHODS: TF was collected at one center from 772 individuals, 708 of which were patients with different neurological diseases, and 64 healthy controls. Wetting lengths (WL) were recorded using Schirmer test strips with a collection time of 10 min.

RESULTS: WL correlated negatively with age and was significantly reduced in subgroups of patients with neurodegenerative diseases (NDDs) (PD, Amyotrophic lateral sclerosis (ALS), other motor neuron diseases (MNDs)), as well as inflammatory/autoimmune/infectious central nervous system (CNS) diseases and vascular CNS diseases (VCDs), even if corrected for age or sex. While temperature had a significant negative effect on TF production, other environmental factors, such as hours of sunlight and humidity, did not.

CONCLUSION: WL was altered in many neurological diseases compared to healthy controls. Most importantly, we observed a reduction of WL in NDDs, independent of age or sex. This study highlights the potential of WL as an easily obtainable parameter and suggests functional alterations in the autonomic innervation in various neurological disorders.}, } @article {pmid38063178, year = {2023}, author = {Xu, C and Zarrabeitia, M and Li, Y and Biskupek, J and Kaiser, U and Liu, X and Passerini, S}, title = {Three-Dimensional Nitrogen-Doped Carbonaceous Networks Anchored with Cobalt as Separator Modification Layers for Low-Polarization and Long-Lifespan Aluminum-Sulfur Batteries.}, journal = {ACS nano}, volume = {17}, number = {24}, pages = {25234-25242}, doi = {10.1021/acsnano.3c08476}, pmid = {38063178}, issn = {1936-086X}, abstract = {Aluminum-sulfur (Al-S) batteries have attracted extensive interest due to their high theoretical energy density, inherent safety, and low cost. However, severe polarization and poor cycling performance significantly limit the development of Al-S batteries. Herein, three-dimensional (3D) nitrogen-doped carbonaceous networks anchored with cobalt (Co@CMel-ZIF) is proposed as a separator modification layer to mitigate these issues, prepared via carbonizations of a mixture of ZIF-7, melamine, and CoCl2. It exhibits a 3D network structure with a moderate surface area and high average pore diameter, which is demonstrated to be effective in adsorbing the aluminum polysulfides and hindering the mobility of polysulfides across the separator for enhanced cyclic stability of Al-S batteries. Meanwhile, Co@CMel-ZIF are characterized by abundant catalytic pyridinic-N and Co-Nx active sites that effectively eliminate the barrier of sulfides' conversion and thereby facilitate the polarization reduction. As a result, Al-S cells based on the separator modified with Co@CMel-ZIF exhibit a low voltage polarization of 0.47 V under the current density of 50 mA g[-1] at 20 °C and a high discharge specific capacity of 503 mAh g[-1] after 150 cycles. In contrast, the cell employing a bare separator exhibits a polarization of 1.01 V and a discharge capacity of 300 mAh g[-1] after 70 cycles under the same conditions. This work demonstrates that modifying the separators is a promising strategy to mitigate the high polarization and poor cyclability of Al-S batteries.}, } @article {pmid38062520, year = {2023}, author = {Rahman, MAA and Elghobashy, MR and Zaazaa, HE and El-Mosallamy, SS}, title = {Novel analytical method based on chemometric models applied to UV-Vis spectrophotometric data for simultaneous determination of Etoricoxib and Paracetamol in presence of Paracetamol impurities.}, journal = {BMC chemistry}, volume = {17}, number = {1}, pages = {176}, pmid = {38062520}, issn = {2661-801X}, abstract = {The multivariate models that are used for spectral data analysis have many beneficial applications, and one of the important applications is the analysis of drugs and their impurities. Three Chemometrically-assisted spectrophotometric models have been proposed and validated. The proposed models are Partial Least Squares (PLS), Artificial Neural Networks (ANN), and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS). The advanced chemometric models were applied to resolve the significantly overlapping spectra of Etoricoxib (ETO) and Paracetamol (PCM), along with impurities of PCM namely; P-aminophenol (PAP) and P-hydroxy acetophenone (PHA). The proposed models succeeded in simultaneously analyzing the mixture of ETO and PCM along with the impurities of PCM. So, the proposed techniques can be used without requiring a separation step in the analysis of pharmaceutical formulation. Moreover, no significant differences were found when the results of the suggested and published chemometric models were compared statistically with the reported HPLC method.}, } @article {pmid38062485, year = {2023}, author = {Shen, T and Vogel, JW and Duda, J and Phillips, JS and Cook, PA and Gee, J and Elman, L and Quinn, C and Amado, DA and Baer, M and Massimo, L and Grossman, M and Irwin, DJ and McMillan, CT}, title = {Novel data-driven subtypes and stages of brain atrophy in the ALS-FTD spectrum.}, journal = {Translational neurodegeneration}, volume = {12}, number = {1}, pages = {57}, pmid = {38062485}, issn = {2047-9158}, support = {K08 NS114106/NS/NINDS NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; R01 NS109260/NS/NINDS NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics ; *Frontotemporal Dementia/diagnostic imaging/genetics ; *Neurodegenerative Diseases/pathology ; Brain/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Atrophy/genetics/complications/pathology ; }, abstract = {BACKGROUND: TDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS-FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study was aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS-FTD spectrum.

METHODS: We used a data-driven procedure to identify 13 anatomic clusters of brain volume for 57 behavioral variant FTD (bvFTD; with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants), 103 ALS, and 47 ALS-FTD patients with likely TDP-43. A Subtype and Stage Inference (SuStaIn) model was trained to identify subtypes of individuals along the ALS-FTD spectrum with distinct brain atrophy patterns, and we related subtypes and stages to clinical, genetic, and neuropathological features of disease.

RESULTS: SuStaIn identified three novel subtypes: two disease subtypes with predominant brain atrophy in either prefrontal/somatomotor regions or limbic-related regions, and a normal-appearing group without obvious brain atrophy. The limbic-predominant subtype tended to present with more impaired cognition, higher frequencies of pathogenic variants in TBK1 and TARDBP genes, and a higher proportion of TDP-43 types B, E and C. In contrast, the prefrontal/somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A. The normal-appearing brain group showed higher frequency of ALS relative to ALS-FTD and bvFTD patients, higher cognitive capacity, higher proportion of lower motor neuron onset, milder motor symptoms, and lower frequencies of genetic pathogenic variants. The overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration, higher King's stage, and cognitive decline. Additionally, SuStaIn stages differed across clinical phenotypes, genotypes and types of TDP-43 pathology.

CONCLUSIONS: Our findings suggest distinct neurodegenerative subtypes of disease along the ALS-FTD spectrum that can be identified in vivo, each with distinct brain atrophy, clinical, genetic and pathological patterns.}, } @article {pmid38062079, year = {2023}, author = {Bowden, M and Beswick, E and Tam, J and Perry, D and Smith, A and Newton, J and Chandran, S and Watts, O and Pal, S}, title = {A systematic review and narrative analysis of digital speech biomarkers in Motor Neuron Disease.}, journal = {NPJ digital medicine}, volume = {6}, number = {1}, pages = {228}, pmid = {38062079}, issn = {2398-6352}, abstract = {Motor Neuron Disease (MND) is a progressive and largely fatal neurodegeneritve disorder with a lifetime risk of approximately 1 in 300. At diagnosis, up to 25% of people with MND (pwMND) exhibit bulbar dysfunction. Currently, pwMND are assessed using clinical examination and diagnostic tools including the ALS Functional Rating Scale Revised (ALS-FRS(R)), a clinician-administered questionnaire with a single item on speech intelligibility. Here we report on the use of digital technologies to assess speech features as a marker of disease diagnosis and progression in pwMND. Google Scholar, PubMed, Medline and EMBASE were systematically searched. 40 studies were evaluated including 3670 participants; 1878 with a diagnosis of MND. 24 studies used microphones, 5 used smartphones, 6 used apps, 2 used tape recorders and 1 used the Multi-Dimensional Voice Programme (MDVP) to record speech samples. Data extraction and analysis methods varied but included traditional statistical analysis, CSpeech, MATLAB and machine learning (ML) algorithms. Speech features assessed also varied and included jitter, shimmer, fundamental frequency, intelligible speaking rate, pause duration and syllable repetition. Findings from this systematic review indicate that digital speech biomarkers can distinguish pwMND from healthy controls and can help identify bulbar involvement in pwMND. Preliminary evidence suggests digitally assessed acoustic features can identify more nuanced changes in those affected by voice dysfunction. No one digital speech biomarker alone is consistently able to diagnose or prognosticate MND. Further longitudinal studies involving larger samples are required to validate the use of these technologies as diagnostic tools or prognostic biomarkers.}, } @article {pmid38061694, year = {2024}, author = {Ai, Y and Li, F and Hou, Y and Li, X and Li, W and Qin, K and Suo, X and Lei, D and Shang, H and Gong, Q}, title = {Differential cortical gray matter changes in early- and late-onset patients with amyotrophic lateral sclerosis.}, journal = {Cerebral cortex (New York, N.Y. : 1991)}, volume = {34}, number = {1}, pages = {}, doi = {10.1093/cercor/bhad426}, pmid = {38061694}, issn = {1460-2199}, support = {2022YFC2009900//National Key Research and Development Program of China/ ; 81621003//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Gray Matter/diagnostic imaging/pathology ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; Brain/pathology ; *Motor Cortex/pathology ; }, abstract = {Age at onset may be an important feature associated with distinct subtypes of amyotrophic lateral sclerosis (ALS). Little is known about the neuropathological mechanism of early-onset ALS (EO-ALS) and late-onset ALS (LO-ALS). Ninety ALS patients were divided into EO-ALS and LO-ALS group, and 128 healthy controls were matched into young controls(YCs) and old controls (OCs). A voxel-based morphometry approach was employed to investigate differences in gray matter volume (GMV). Significant age at onset-by-diagnosis interactions were found in the left parietal operculum, left precentral gyrus, bilateral postcentral gyrus, right occipital gyrus, and right orbitofrontal cortex. Post hoc analysis revealed a significant decrease in GMV in all affected regions of EO-ALS patients compared with YCs, with increased GMV in 5 of the 6 brain regions, except for the right orbitofrontal cortex, in LO-ALS patients compared with OCs. LO-ALS patients had a significantly increased GMV than EO-ALS patients after removing the aging effect. Correspondingly, GMV of the left postcentral gyrus correlated with disease severity in the 2 ALS groups. Our findings suggested that the pathological mechanisms in ALS patients with different ages at onset might differ. These findings provide unique insight into the clinical and biological heterogeneity of the 2 ALS subtypes.}, } @article {pmid38061331, year = {2023}, author = {Yadav, A and Matson, KJE and Lee, D and Alkaslasi, MR and Roome, RB and Ward, ME and Phatnani, H and Le Pichon, CE and Menon, V and Levine, AJ}, title = {A reproducible signature of cytoskeletal and ALS-related genes in human motoneurons.}, journal = {Neuron}, volume = {111}, number = {23}, pages = {3742-3744}, doi = {10.1016/j.neuron.2023.10.034}, pmid = {38061331}, issn = {1097-4199}, support = {R01 NS116350/NS/NINDS NIH HHS/United States ; }, } @article {pmid38059522, year = {2024}, author = {Xu, R and Wang, X and Zhu, S and Jiang, B and Wan, J and Ma, J and Yu, Y and Yu, L and Fang, Q and Hu, C and Zhu, M}, title = {Assessment of Cerebral White Matter Involvement in Amyotrophic Lateral Sclerosis Patients With Disease Progression and Cognitive Impairment by Fixel-Based Analysis and Neurite Orientation Dispersion and Density Imaging.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {60}, number = {3}, pages = {900-908}, doi = {10.1002/jmri.29171}, pmid = {38059522}, issn = {1522-2586}, support = {LK2021017//Application Fundamental Research Program of the Jiangsu Provincial Health Commission's Elderly Health Project/ ; UTPIE2023006//the Undergraduate Training Program for Innovation and Entrepreneurship, Soochow University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Female ; Male ; Middle Aged ; *Disease Progression ; *White Matter/diagnostic imaging/pathology ; *Neurites/pathology ; *Cognitive Dysfunction/diagnostic imaging ; Aged ; Prospective Studies ; Image Processing, Computer-Assisted/methods ; Brain/diagnostic imaging/pathology ; Magnetic Resonance Imaging/methods ; Diffusion Tensor Imaging/methods ; Diffusion Magnetic Resonance Imaging ; }, abstract = {BACKGROUND: Previous studies using emerging diffusion MRI techniques have revealed damage to the white matter (WM) microstructure in amyotrophic lateral sclerosis (ALS), particularly the influence of crossed fibers, but there is a lack of subgroup analyses.

PURPOSE: To detect WM microstructural changes in ALS patients using fixel-based analysis (FBA) and neurite orientation dispersion and density imaging (NODDI) MRI.

STUDY TYPE: Prospective.

POPULATION: Thirty-six ALS patients (aged 60.50 ± 9.5 years) and 25 healthy controls (HCs) (aged 58.90 ± 8.1 years).

FIELD STRENGTH/SEQUENCE: 3 T; NODDI and FBA (b-values = 0, 1000, and 2500 seconds/mm[2]).

ASSESSMENT: Subgroups were performed according to progression rate and cognition, including fast and slow progression (FP/SP), ALS with and without cognitive impairment (ALS-ci/ALS-nci). Fiber density (FD), fiber-bundle cross-section (FC), combined fiber density and cross-section (FDC), neurite density index (NDI), orientation dispersion index (ODI), isotropic volume fraction (ISO), and fractional anisotropy (FA) were calculated and their correlation with clinical variables examined.

STATISTICAL TESTING: Chi-square test, Mann-Whitney U test, two-sample t test, partial correlation analysis, and false discovery rate (FDR) corrected. A P-value <0.05 was considered significant.

RESULTS: ALS patients had lower FD and FDC values predominantly in the corticospinal tract (CST) and corpus callosum (CC) regions, as well as lower NDI value in the CC, radial crown, and internal capsule compared to HCs. Subgroup analysis based on progression rate and cognitive function showed significant differences in FBA results. The FC in the right CST region was significantly lower in the FP than SP, and the FD in the CC region was significantly lower in the ALS-ci than ALS-nci. Furthermore, a negative correlation was found between the mean FC value and the rate of progression in ALS patients (r = -0.408).

DATA CONCLUSION: FBA is a powerful tool for detecting complex cerebral WM microstructural damage for evaluating ALS cognition and disease progression.}, } @article {pmid38057503, year = {2023}, author = {Vernikouskaya, I and Müller, HP and Roselli, F and Ludolph, AC and Kassubek, J and Rasche, V}, title = {AI-assisted quantification of hypothalamic atrophy in amyotrophic lateral sclerosis by convolutional neural network-based automatic segmentation.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {21505}, pmid = {38057503}, issn = {2045-2322}, support = {LU 336/15-1//Deutsche Forschungsgemeinschaft/ ; 01GM1103A//German Network for Motor Neuron Diseases/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Neural Networks, Computer ; Magnetic Resonance Imaging/methods ; Neuroimaging/methods ; Atrophy ; Image Processing, Computer-Assisted/methods ; }, abstract = {The hypothalamus is a small structure of the brain with an essential role in metabolic homeostasis, sleep regulation, and body temperature control. Some neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and dementia syndromes are reported to be related to hypothalamic volume alterations. Despite its crucial role in human body regulation, neuroimaging studies of this structure are rather scarce due to work-intensive operator-dependent manual delineations from MRI and lack of automated segmentation tools. In this study we present a fully automatic approach based on deep convolutional neural networks (CNN) for hypothalamic segmentation and volume quantification. We applied CNN of U-Net architecture with EfficientNetB0 backbone to allow for accurate automatic hypothalamic segmentation in seconds on a GPU. We further applied our approach for the quantification of the normalized hypothalamic volumes to a large neuroimaging dataset of 432 ALS patients and 112 healthy controls (without the ground truth labels). Using the automated volumetric analysis, we could reproduce hypothalamic atrophy findings associated with ALS by detecting significant volume differences between ALS patients and controls at the group level. In conclusion, a fast and unbiased AI-assisted hypothalamic quantification method is introduced in this study (whose acceptance rate based on the outlier removal strategy was estimated to be above 95%) and made publicly available for researchers interested in the conduction of hypothalamus studies at a large scale.}, } @article {pmid38056528, year = {2024}, author = {Camiña-Conforto, G and Vilarrasa, E and Cabo, F and Fernández-Vela, J and Pousa, M and Romaní, J}, title = {Response letter to "Tracing the origins of setons in hidradenitis suppurativa: A commentary to Vilarrasa et al's 'Drainage setons for the management of sinus tracts in hidradenitis suppurativa'".}, journal = {Journal of the American Academy of Dermatology}, volume = {90}, number = {4}, pages = {e141-e142}, doi = {10.1016/j.jaad.2023.11.049}, pmid = {38056528}, issn = {1097-6787}, mesh = {Humans ; *Hidradenitis Suppurativa ; Inflammation ; }, } @article {pmid38056310, year = {2024}, author = {Guo, Y and Guan, T and Yu, Q and Sanghai, N and Shafiq, K and Li, M and Jiao, X and Na, D and Zhang, G and Kong, J}, title = {ALS-linked SOD1 mutations impair mitochondrial-derived vesicle formation and accelerate aging.}, journal = {Redox biology}, volume = {69}, number = {}, pages = {102972}, pmid = {38056310}, issn = {2213-2317}, mesh = {Animals ; Humans ; Infant ; Mice ; Middle Aged ; Aging/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Motor Neurons ; Mutation ; *Sirtuins/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Oxidative stress (OS) is regarded as the dominant theory for aging. While compelling correlative data have been generated to support the OS theory, a direct cause-and-effect relationship between the accumulation of oxidation-mediated damage and aging has not been firmly established. Superoxide dismutase 1 (SOD1) is a primary antioxidant in all cells. It is, however, susceptible to oxidation due to OS and gains toxic properties to cells. This study investigates the role of oxidized SOD1 derived from amyotrophic lateral sclerosis (ALS) linked SOD1 mutations in cell senescence and aging. Herein, we have shown that the cell line NSC34 expressing the G93A mutation of human SOD1 (hSOD1[G93A]) entered premature senescence as evidenced by a decreased number of the 5-ethynyl-2'-deoxyuridine (EdU)-positive cells. There was an upregulation of cellular senescence markers compared to cells expressing the wild-type human SOD1 (hSOD1[WT]). Transgenic mice carrying the hSOD1[G93A] gene showed aging phenotypes at an early age (135 days) with high levels of P53 and P16 but low levels of SIRT1 and SIRT6 compared with age-matched hSOD1[WT] transgenic mice. Notably, the levels of oxidized SOD1 were significantly elevated in both the senescent NSC34 cells and 135-day hSOD1[G93A] mice. Selective removal of oxidized SOD1 by our CT4-directed autophagy significantly decelerated aging, indicating that oxidized SOD1 is a causal factor of aging. Intriguingly, mitochondria malfunctioned in both senescent NSC34 cells and middle-aged hSOD[G93A] transgenic mice. They exhibited increased production of mitochondrial-derived vesicles (MDVs) in response to mild OS in mutant humanSOD1 (hSOD1) transgenic mice at a younger age; however, the mitochondrial response gradually declined with aging. In conclusion, our data show that oxidized SOD1 derived from ALS-linked SOD1 mutants is a causal factor for cellular senescence and aging. Compromised mitochondrial responsiveness to OS may serve as an indicator of premature aging.}, } @article {pmid38056247, year = {2024}, author = {Jiang, H and Zhang, Y and Hu, J and Wang, Z and Li, G and Lu, Y}, title = {An alternative spliced UPF2 transcript in pancreatic inflammatory myofibroblastic tumors.}, journal = {Biochemical and biophysical research communications}, volume = {691}, number = {}, pages = {149306}, doi = {10.1016/j.bbrc.2023.149306}, pmid = {38056247}, issn = {1090-2104}, mesh = {Humans ; *Neoplasms ; Nonsense Mediated mRNA Decay ; RNA, Messenger/genetics/metabolism ; RNA-Binding Proteins/metabolism ; }, abstract = {BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are characterized by myofibroblast proliferation and an inflammatory cell infiltrate. Our previous study on IMTs reveals that disrupt NMD pathway causes to lower the threshold for triggering the immune cell infiltration, thereby resulting in inappropriate immune activation. However, myofibroblast differentiation and proliferation is not yet known.

METHODS: RT-PCR, RT-qPCR, DNA sequence, western bolt, 5'race analysis and site-specific mutagenesis were used in this study.

RESULTS: Here, an alternative spliced (ALS) UPF2 mRNA skipping exon 2 and 3 and corresponding to the truncated UPF2 protein were found in 2 pancreatic IMTs. We showed that the uORF present in the 5'UTR of UPF2 mRNA is responsible for the translation inhibition, whiles ALS UPF2 is more facilitated to be translated into the truncated UPF2 protein. Several mRNA targets of the NMD were upregulated in IMT samples, indicating that the truncated UPF2 function is strongly perturbed, resulted in disrupted NMD pathway in IMTs. These upregulated NMD targets included cdkn1a expression and the generation of high levels of p21 (waf1/cip1), which may contribute to triggering IMTs.

CONCLUSION: The disrupt UPFs/NMD pathway may link to molecular alteration associated with differentiation and proliferation for IMTs.}, } @article {pmid38056214, year = {2024}, author = {Jia, F and Zhang, B and Yu, W and Chen, Z and Xu, W and Zhao, W and Wang, Z}, title = {Exploring the cuproptosis-related molecular clusters in the peripheral blood of patients with amyotrophic lateral sclerosis.}, journal = {Computers in biology and medicine}, volume = {168}, number = {}, pages = {107776}, doi = {10.1016/j.compbiomed.2023.107776}, pmid = {38056214}, issn = {1879-0534}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Neurodegenerative Diseases ; Algorithms ; Calibration ; Cluster Analysis ; Apoptosis ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and lethal neurodegenerative disease. Several studies have suggested the involvement of cuproptosis in its pathogenesis. In this research, we intend to explore the cuproptosis-related molecular clusters in ALS and develop a novel cuproptosis-related genes prediction model.

METHODS: The peripheral blood gene expression data was downloaded from the Gene Expression Omnibus (GEO) online database. Based on the GSE112681 dataset, we investigated the critical cuproptosis-related genes (CuRGs) and pathological clustering of ALS. The immune microenvironment features of the peripheral blood in ALS patients were also examined using the CIBERSORT algorithm. Cluster-specific hub genes were determined by the WGCNA. The most accurate prediction model was selected by comparing the performance of four machine learning techniques. ROC curves and two independent datasets were applied to validate the prediction accuracy. The available compounds targeting these hub genes were filtered to investigate their efficacy in treating ALS.

RESULTS: We successfully determined four critical cuproptosis-related genes and two pathological clusters with various immune profiles and biological characteristics in ALS. Functional analysis showed that genes in Cluster1 were primarily enriched in pathways closely associated with immunity. The Support Vector Machine (SVM) model exhibited the best discrimination properties with a large area under the curve (AUC = 0.862). Five hub prediction genes (BAP1, SMG1, BCLAF1, DHX15, EIF4G2) were selected to establish a nomogram model, suggesting significant risk prediction potential for ALS. The accuracy of this model in predicting ALS incidence was also demonstrated through calibration curves, nomograms, and decision curve analysis. Finally, three drugs targeting BAP1 were determined through drug-gene interactions.

CONCLUSION: This study elucidated the complex associations between cuproptosis and ALS and constructed a satisfactory predictive model to explore the pathological characteristics of different clusters in ALS patients.}, } @article {pmid38053196, year = {2023}, author = {Lombardo, FL and Spila Alegiani, S and Mayer, F and Cipriani, M and Lo Giudice, M and Ludolph, AC and McDermott, CJ and Corcia, P and Van Damme, P and Van den Berg, LH and Hardiman, O and Nicolini, G and Vanacore, N and Dickie, B and Albanese, A and Puopolo, M and , }, title = {A randomized double-blind clinical trial on safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS): the statistical analysis plan of TUDCA-ALS trial.}, journal = {Trials}, volume = {24}, number = {1}, pages = {792}, pmid = {38053196}, issn = {1745-6215}, support = {755094//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Riluzole ; *Neuroprotective Agents/adverse effects ; Reproducibility of Results ; Double-Blind Method ; Treatment Outcome ; Disease Progression ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a highly debilitating neurodegenerative condition. Despite recent advancements in understanding the molecular mechanisms underlying ALS, there have been no significant improvements in therapeutic options for ALS patients in recent years. Currently, there is no cure for ALS, and the only approved treatment in Europe is riluzole, which has been shown to slow the disease progression and prolong survival by approximately 3 months. Recently, tauroursodeoxycholic acid (TUDCA) has emerged as a promising and effective treatment for neurodegenerative diseases due to its neuroprotective activities.

METHODS: The ongoing TUDCA-ALS study is a double-blinded, parallel arms, placebo-controlled, randomized multicenter phase III trial with the aim to assess the efficacy and safety of TUDCA as add-on therapy to riluzole in patients with ALS. The primary outcome measure is the treatment response defined as a minimum of 20% improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) slope during the randomized treatment period (18 months) compared to the lead-in period (3 months). Randomization will be stratified by country. Primary analysis will be conducted based on the intention-to-treat principle through an unadjusted logistic regression model. Patient recruitment commenced on February 22, 2019, and was closed on December 23, 2021. The database will be locked in September 2023.

DISCUSSION: This paper provides a comprehensive description of the statistical analysis plan in order to ensure the reproducibility of the analysis and avoid selective reporting of outcomes and data-driven analysis. Sensitivity analyses have been included in the protocol to assess the impact of intercurrent events related to the coronavirus disease 2019. By focusing on clinically meaningful and robust outcomes, this trial aims to determine whether TUDCA can be effective in slowing the disease progression in patients with ALS.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03800524 . Registered on January 11, 2019.}, } @article {pmid38052682, year = {2024}, author = {Festa, LK and Grinspan, JB and Jordan-Sciutto, KL}, title = {White matter injury across neurodegenerative disease.}, journal = {Trends in neurosciences}, volume = {47}, number = {1}, pages = {47-57}, pmid = {38052682}, issn = {1878-108X}, support = {R01 MH098742/MH/NIMH NIH HHS/United States ; R01 MH126773/MH/NIMH NIH HHS/United States ; R21 MH118121/MH/NIMH NIH HHS/United States ; T32 AI007632/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *White Matter/metabolism ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis ; }, abstract = {Oligodendrocytes (OLs), the myelin-generating cells of the central nervous system (CNS), are active players in shaping neuronal circuitry and function. It has become increasingly apparent that injury to cells within the OL lineage plays a central role in neurodegeneration. In this review, we focus primarily on three degenerative disorders in which white matter loss is well documented: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We discuss clinical data implicating white matter injury as a key feature of these disorders, as well as shared and divergent phenotypes between them. We examine the cellular and molecular mechanisms underlying the alterations to OLs, including chronic neuroinflammation, aggregation of proteins, lipid dysregulation, and organellar stress. Last, we highlight prospects for therapeutic intervention targeting the OL lineage to restore function.}, } @article {pmid38052485, year = {2024}, author = {Din Abdul Jabbar, MA and Guo, L and Nag, S and Guo, Y and Simmons, Z and Pioro, EP and Ramasamy, S and Yeo, CJJ}, title = {Predicting amyotrophic lateral sclerosis (ALS) progression with machine learning.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {242-255}, doi = {10.1080/21678421.2023.2285443}, pmid = {38052485}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Bayes Theorem ; Disease Progression ; Machine Learning ; Databases, Factual ; }, abstract = {OBJECTIVE: To predict ALS progression with varying observation and prediction window lengths, using machine learning (ML).

METHODS: We used demographic, clinical, and laboratory parameters from 5030 patients in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database to model ALS disease progression as fast (at least 1.5 points decline in ALS Functional Rating Scale-Revised (ALSFRS-R) per month) or non-fast, using Extreme Gradient Boosting (XGBoost) and Bayesian Long Short Term Memory (BLSTM). XGBoost identified predictors of progression while BLSTM provided a confidence level for each prediction.

RESULTS: ML models achieved area under receiver-operating-characteristics curve (AUROC) of 0.570-0.748 and were non-inferior to clinician assessments. Performance was similar with observation lengths of a single visit, 3, 6, or 12 months and on a holdout validation dataset, but was better for longer prediction lengths. 21 important predictors were identified, with the top 3 being days since disease onset, past ALSFRS-R and forced vital capacity. Nonstandard predictors included phosphorus, chloride and albumin. BLSTM demonstrated higher performance for the samples about which it was most confident. Patient screening by models may reduce hypothetical Phase II/III clinical trial sizes by 18.3%.

CONCLUSION: Similar accuracies across ML models using different observation lengths suggest that a clinical trial observation period could be shortened to a single visit and clinical trial sizes reduced. Confidence levels provided by BLSTM gave additional information on the trustworthiness of predictions, which could aid decision-making. The identified predictors of ALS progression are potential biomarkers and therapeutic targets for further research.}, } @article {pmid38052188, year = {2024}, author = {Crowe, AL and Kerr, K and McAneney, H and McMullan, J and Duffy, G and McKnight, AJ}, title = {Stakeholder Perceptions of Complementary and Integrative Medicines from People Living with Rare Diseases in Northern Ireland: A Mixed Methods Study.}, journal = {Complementary medicine research}, volume = {31}, number = {2}, pages = {107-115}, pmid = {38052188}, issn = {2504-2106}, abstract = {INTRODUCTION: Only 5% of rare diseases have an approved treatment available, therefore patients often utilise complementary and integrative medicines (CIMs) to help manage their condition. Limited high-quality evidence-based studies are available which support the effectiveness of CIM, as it is difficult to show that an outcome is a direct result of the CIM intervention and not due to bias. Patients and healthcare professionals must weigh up the evidence quality, safety, efficacy, practical logistics, and financial implications of utilising CIM for rare diseases. This study aimed to elucidate perspectives of stakeholders (individuals with rare diseases, carers, family members, CIM practitioners and healthcare professionals), on the usage of CIM for rare diseases across Northern Ireland.

METHODS: This was a mixed methods study. An online survey was open from January to February 2019 (n = 29 responses). Themes identified from the survey were then discussed with stakeholders in a semi-structured discussion workshop in March 2019.

RESULTS: A limited number of participants responded to the survey (n = 29). Some individuals with rare diseases reported CIM as effective in the management of their condition, in particular acupuncture, dietary supplements, herbal medicines, homoeopathy, hydrotherapy, kinesiology, mindfulness, pilates, reflexology, tai chi, and yoga. However, a number of respondents (n = 7) experienced a negative side effect from CIM. Workshop participants raised concerns over the lack of information available about CIM and rare disease. Both the survey and workshop identified inequality of access with participants reporting CIM to be expensive.

CONCLUSIONS: More information, high-quality research, and education about CIM are required for patients and healthcare professionals to help make informed decisions about the usage of CIM for rare diseases. Improved communication, information, and health and social care in general would help individuals be more confident and knowledgeable about therapeutic options in relation to their rare disease(s).

UNLABELLED: EinleitungNur für fünf Prozent der seltenen Erkrankungen existiert eine zugelassene Behandlung, weshalb Patienten häufig komplementäre und integrative Medizin (CIM) nutzen, um ihre Krankheit zu behandeln. Es liegen nur wenige qualitativ hochwertige evidenzbasierte Studien vor, die die Wirksamkeit von CIM stützen, da sich schwer nachweisen lässt, dass ein Behandlungsergebnis direkt durch die CIM-Intervention bedingt und nicht Folge einer Verzerrung ist. Patienten und Angehörige der Gesundheitsberufe müssen die Qualität der Evidenz, die Sicherheit und Wirksamkeit sowie praktische logistische Aspekte und die finanziellen Folgen der Anwendung von CIM bei seltenen Erkrankungen abwägen. Mit der vorliegenden Studie sollte die Perspektive der Betroffenen (Menschen mit seltenen Erkrankungen, Betreuungspersonen, Familienangehörige, CIM-Praktiker und Angehörige der Gesundheitsberufe) in Bezug auf die Anwendung von CIM bei seltenen Erkrankungen in Nordirland untersucht werden.MethodenEs handelte sich um eine Studie mit gemischten Methoden. Eine Online-Umfrage war von Januar bis Februar 2019 geöffnet (n = 29 Antworten). Die in der Umfrage ermittelten Themen wurden anschließend im März 2019 im Rahmen eines halbstrukturierten Diskussionsworkshops mit den Betroffenen erörtert.ErgebnisseEine begrenzte Anzahl von Teilnehmern antwortete auf die Umfrage (n = 29). Einige Personen mit seltenen Erkrankungen gaben an, dass CIM bei der Behandlung ihrer Erkrankung wirksam war, insbesondere Akupunktur, Nahrungsergänzungsmittel, pflanzliche Arzneimittel, Homöopathie, Hydrotherapie, Kinesiologie, Achtsamkeit, Pilates, Reflexologie, Tai Chi und Yoga. Einige Befragte (n = 7) berichteten jedoch über negative Nebenwirkungen der CIM. Die Workshop-Teilnehmer äußerten Bedenken in Bezug auf den Mangel an Informationen über CIM und seltene Erkrankungen. Sowohl in der Umfrage als auch im Workshop zeigte sich eine Ungleichheit beim Zugang zu CIM und die Teilnehmer berichteten, dass CIM teuer sei.SchlussfolgerungenPatienten und Angehörige der Gesundheitsberufe benötigen mehr Informationen, qualitativ hochwertige Forschung und Aufklärung über CIM, um fundierte Entscheidungen über die Anwendung von CIM bei seltenen Erkrankungen treffen zu können. Eine bessere Kommunikation, Information sowie gesundheitliche und soziale Versorgung im Allgemeinen würden zu mehr Selbstvertrauen und Wissen der Betroffenen über die therapeutischen Möglichkeiten im Zusammenhang mit ihrer seltenen Erkrankung beitragen.}, } @article {pmid38051886, year = {2024}, author = {Liang, S and Zhou, J and Yu, X and Lu, S and Liu, R}, title = {Neuronal conversion from glia to replenish the lost neurons.}, journal = {Neural regeneration research}, volume = {19}, number = {7}, pages = {1446-1453}, pmid = {38051886}, issn = {1673-5374}, abstract = {Neuronal injury, aging, and cerebrovascular and neurodegenerative diseases such as cerebral infarction, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Huntington's disease are characterized by significant neuronal loss. Unfortunately, the neurons of most mammals including humans do not possess the ability to self-regenerate. Replenishment of lost neurons becomes an appealing therapeutic strategy to reverse the disease phenotype. Transplantation of pluripotent neural stem cells can supplement the missing neurons in the brain, but it carries the risk of causing gene mutation, tumorigenesis, severe inflammation, and obstructive hydrocephalus induced by brain edema. Conversion of neural or non-neural lineage cells into functional neurons is a promising strategy for the diseases involving neuron loss, which may overcome the above-mentioned disadvantages of neural stem cell therapy. Thus far, many strategies to transform astrocytes, fibroblasts, microglia, Müller glia, NG2 cells, and other glial cells to mature and functional neurons, or for the conversion between neuronal subtypes have been developed through the regulation of transcription factors, polypyrimidine tract binding protein 1 (PTBP1), and small chemical molecules or are based on a combination of several factors and the location in the central nervous system. However, some recent papers did not obtain expected results, and discrepancies exist. Therefore, in this review, we discuss the history of neuronal transdifferentiation, summarize the strategies for neuronal replenishment and conversion from glia, especially astrocytes, and point out that biosafety, new strategies, and the accurate origin of the truly converted neurons in vivo should be focused upon in future studies. It also arises the attention of replenishing the lost neurons from glia by gene therapies such as up-regulation of some transcription factors or down-regulation of PTBP1 or drug interference therapies.}, } @article {pmid38051885, year = {2024}, author = {Helgudóttir, SS and Mørkholt, AS and Lichota, J and Bruun-Nyzell, P and Andersen, MC and Kristensen, NMJ and Johansen, AK and Zinn, MR and Jensdóttir, HM and Nieland, JDV}, title = {Rethinking neurodegenerative diseases: neurometabolic concept linking lipid oxidation to diseases in the central nervous system.}, journal = {Neural regeneration research}, volume = {19}, number = {7}, pages = {1437-1445}, pmid = {38051885}, issn = {1673-5374}, abstract = {Currently, there is a lack of effective medicines capable of halting or reversing the progression of neurodegenerative disorders, including amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, or Alzheimer's disease. Given the unmet medical need, it is necessary to reevaluate the existing paradigms of how to target these diseases. When considering neurodegenerative diseases from a systemic neurometabolic perspective, it becomes possible to explain the shared pathological features. This innovative approach presented in this paper draws upon extensive research conducted by the authors and researchers worldwide. In this review, we highlight the importance of metabolic mitochondrial dysfunction in the context of neurodegenerative diseases. We provide an overview of the risk factors associated with developing neurodegenerative disorders, including genetic, epigenetic, and environmental factors. Additionally, we examine pathological mechanisms implicated in these diseases such as oxidative stress, accumulation of misfolded proteins, inflammation, demyelination, death of neurons, insulin resistance, dysbiosis, and neurotransmitter disturbances. Finally, we outline a proposal for the restoration of mitochondrial metabolism, a crucial aspect that may hold the key to facilitating curative therapeutic interventions for neurodegenerative disorders in forthcoming advancements.}, } @article {pmid38051870, year = {2024}, author = {Hartopp, N and Markovinovic, A and Miller, CC and Gomez-Suaga, P}, title = {Insight into endoplasmic reticulum-mitochondria contacts in human amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {7}, pages = {1407-1408}, pmid = {38051870}, issn = {1673-5374}, support = {MR/R022666/1/MRC_/Medical Research Council/United Kingdom ; }, } @article {pmid38050971, year = {2024}, author = {Shellikeri, S and Cho, S and Ash, S and Gonzalez-Recober, C and Mcmillan, CT and Elman, L and Quinn, C and Amado, DA and Baer, M and Irwin, DJ and Massimo, L and Olm, CA and Liberman, MY and Grossman, M and Nevler, N}, title = {Digital markers of motor speech impairments in spontaneous speech of patients with ALS-FTD spectrum disorders.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {317-325}, pmid = {38050971}, issn = {2167-9223}, support = {K99 AG073510/AG/NIA NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; R01 NS109260/NS/NINDS NIH HHS/United States ; K08 NS114106/NS/NINDS NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 AG054519/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/diagnosis/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Speech ; Magnetic Resonance Imaging ; *Dystonic Disorders ; }, abstract = {OBJECTIVE: To evaluate automated digital speech measures, derived from spontaneous speech (picture descriptions), in assessing bulbar motor impairments in patients with ALS-FTD spectrum disorders (ALS-FTSD).

METHODS: Automated vowel algorithms were employed to extract two vowel acoustic measures: vowel space area (VSA), and mean second formant slope (F2 slope). Vowel measures were compared between ALS with and without clinical bulbar symptoms (ALS + bulbar (n = 49, ALSFRS-r bulbar subscore: x¯ = 9.8 (SD = 1.7)) vs. ALS-nonbulbar (n = 23), behavioral variant frontotemporal dementia (bvFTD, n = 25) without a motor syndrome, and healthy controls (HC, n = 32). Correlations with bulbar motor clinical scales, perceived listener effort, and MRI cortical thickness of the orobuccal primary motor cortex (oral PMC) were examined. We compared vowel measures to speaking rate, a conventional metric for assessing bulbar dysfunction.

RESULTS: ALS + bulbar had significantly reduced VSA and F2 slope than ALS-nonbulbar (|d|=0.94 and |d|=1.04, respectively), bvFTD (|d|=0.89 and |d|=1.47), and HC (|d|=0.73 and |d|=0.99). These reductions correlated with worse bulbar clinical scores (VSA: R = 0.33, p = 0.043; F2 slope: R = 0.38, p = 0.011), greater listener effort (VSA: R=-0.43, p = 0.041; F2 slope: p > 0.05), and cortical thinning in oral PMC (F2 slope: β = 0.0026, p = 0.017). Vowel measures demonstrated greater sensitivity and specificity for bulbar impairment than speaking rate, while showing independence from cognitive and respiratory impairments.

CONCLUSION: Automatic vowel measures are easily derived from a brief spontaneous speech sample, are sensitive to mild-moderate stage of bulbar disease in ALS-FTSD, and may present better sensitivity to bulbar impairment compared to traditional assessments such as speaking rate.}, } @article {pmid38050862, year = {2023}, author = {Liu, X and Duan, S and Jin, Y and Walker, E and Tsao, M and Jang, JH and Chen, Z and Singh, AK and Cantrell, KL and Ingolfsson, HI and Buratto, SK and Bowers, MT}, title = {Computationally Designed Molecules Modulate ALS-Related Amyloidogenic TDP-43307-319 Aggregation.}, journal = {ACS chemical neuroscience}, volume = {14}, number = {24}, pages = {4395-4408}, doi = {10.1021/acschemneuro.3c00582}, pmid = {38050862}, issn = {1948-7193}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Frontotemporal Dementia ; *Frontotemporal Lobar Degeneration ; *Alzheimer Disease ; DNA-Binding Proteins/metabolism ; }, abstract = {Abnormal cytosolic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is observed in multiple diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease. Previous studies have shown that TDP-43307-319 located at the C-terminal of TDP-43 can form higher-order oligomers and fibrils. Of particular interest are the hexamers that adopt a cylindrin structure that has been strongly correlated to neurotoxicity. In this study, we use the joint pharmacophore space (JPS) model to identify and generate potential TDP-43 inhibitors. Five JPS-designed molecules are evaluated using both experimental and computational methods: ion mobility mass spectrometry, thioflavin T fluorescence assay, circular dichroism spectroscopy, atomic force microscopy, and molecular dynamics simulations. We found that all five molecules can prevent the amyloid fibril formation of TDP-43307-319, but their efficacy varies significantly. Furthermore, among the five molecules, [AC0101] is the most efficient in preventing the formation of higher-order oligomers and dissociating preformed higher-order oligomers. Molecular dynamics simulations show that [AC0101] both is the most flexible and forms the most hydrogen bonds with the TDP-43307-319 monomer. The JPS-designed molecules can insert themselves between the β-strands in the hexameric cylindrin structure of TDP-43307-319 and can open its structure. Possible mechanisms for JPS-designed molecules to inhibit and dissociate TDP-43307-319 oligomers on an atomistic scale are proposed.}, } @article {pmid38050178, year = {2024}, author = {Megens, M and de Souza, A}, title = {Amyotrophic lateral sclerosis with demyelinating neurophysiology and a motor band sign.}, journal = {Practical neurology}, volume = {24}, number = {3}, pages = {219-222}, doi = {10.1136/pn-2023-003963}, pmid = {38050178}, issn = {1474-7766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Aged ; Neural Conduction/physiology ; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/physiopathology/diagnosis/diagnostic imaging ; Magnetic Resonance Imaging/methods ; Demyelinating Diseases/diagnostic imaging/physiopathology ; }, abstract = {We describe an unusual case of clinical amyotrophic lateral sclerosis (ALS) with initial neurophysiological studies suggesting demyelination, along with neuroimaging findings that helped to support the eventual diagnosis. An otherwise well 68-year-old man had 8 weeks of left upper limb weakness. On examination, there were widespread lower and upper motor neurone findings suggesting ALS. However, nerve conduction studies identified sensorimotor demyelinating changes suggesting chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a diagnosis further supported by cerebrospinal fluid analysis. MR scan of the brain revealed a 'motor band', a feature seen commonly in ALS. His condition was refractory to immunotherapy with clinical progression in-keeping with ALS, establishing the diagnosis. ALS is rarely associated with demyelinating neurophysiological changes resembling CIDP. The clinical phenotype is crucial to support the correct diagnosis and imaging findings may help.}, } @article {pmid38050140, year = {2024}, author = {Thompson, AG and Taschler, B and Smith, SM and Turner, MR}, title = {Premorbid brain structure influences risk of amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {4}, pages = {360-365}, pmid = {38050140}, issn = {1468-330X}, support = {/WT_/Wellcome Trust/United Kingdom ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics ; Brain/diagnostic imaging ; Gray Matter/diagnostic imaging ; Magnetic Resonance Imaging ; *White Matter/diagnostic imaging ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease of the motor network associated with brain structure and functional connectivity alterations that are implicated in disease progression. Whether such changes have a causal role in ALS, fitting with a postulated influence of premorbid cerebral architecture on the phenotypes associated with neurodegenerative disorders is not known.

METHODS: This study considered causal effects and shared genetic risk of 2240 structural and functional MRI brain scan imaging-derived phenotypes (IDPs) on ALS using two sample Mendelian randomisation, with putative associations further examined with extensive sensitivity analysis. Shared genetic predisposition between IDPs and ALS was explored using genetic correlation analysis.

RESULTS: Increased white matter volume in the cerebral hemispheres was causally associated with ALS. Weaker causal associations were observed for brain stem grey matter volume, parieto-occipital white matter surface and volume of the left thalamic ventral anterior nucleus. Genetic correlation was observed between ALS and intracellular volume fraction and isotropic free water volume fraction within the posterior limb of the internal capsule.

CONCLUSIONS: This study provides evidence that premorbid brain structure, in particular white matter volume, contributes to the risk of ALS.}, } @article {pmid38050066, year = {2024}, author = {Bowser, R and An, J and Mehta, L and Chen, J and Timmons, J and Cudkowicz, M and Paganoni, S}, title = {Effect of sodium phenylbutyrate and taurursodiol on plasma concentrations of neuroinflammatory biomarkers in amyotrophic lateral sclerosis: results from the CENTAUR trial.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {7}, pages = {605-608}, pmid = {38050066}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/drug therapy ; *Biomarkers/blood ; *Chitinase-3-Like Protein 1/blood ; *C-Reactive Protein/analysis ; *Phenylbutyrates/therapeutic use ; Female ; Male ; Middle Aged ; Hexosaminidases/blood ; Aged ; Double-Blind Method ; Chitinases/blood ; }, abstract = {BACKGROUND: An oral sodium phenylbutyrate and taurursodiol combination (PB and TURSO) significantly reduced functional decline in people living with amyotrophic lateral sclerosis (ALS) in the CENTAUR trial. Biomarkers linking clinical therapeutic effect with biological changes are of high interest in ALS. We performed analyses of neuroinflammatory biomarkers associated with ALS in the literature, including YKL-40 (also known as chitinase-3-like protein 1), chitinase 1 (CHIT1) and C reactive protein (CRP), in plasma samples collected in CENTAUR.

METHODS: Log10-transformed plasma biomarker measurements were analysed using a linear mixed-effects model. Correlation between paired biomarker concentrations and ALS Functional Rating Scale-Revised (ALSFRS-R) total scores was assessed via Pearson correlation coefficients.

RESULTS: By week 24, geometric least squares mean YKL-40 plasma concentration decreased by approximately 20% (p=0.008) and CRP by 30% (p=0.048) in the PB and TURSO versus placebo group. YKL-40 (r of -0.21; p<0.0001) and CRP (r of -0.19; p=0.0002) concentration correlated with ALSFRS-R total score. CHIT1 levels were not significantly different between groups.

CONCLUSIONS: YKL-40 and CRP plasma levels were significantly reduced in participants with ALS receiving PB and TURSO in CENTAUR and correlated with disease progression. These findings suggest YKL-40 and CRP could be treatment-sensitive biomarkers in ALS, pending further confirmatory studies.

TRIAL REGISTRATION NUMBER: https://clinicaltrials.gov/study/NCT03127514.}, } @article {pmid38049694, year = {2024}, author = {Sequeira, M and Godinho, F and Lourenço, J}, title = {Amyotrophic Lateral Sclerosis with SOD1 Mutation Presenting with Progressive Cerebellar Ataxia.}, journal = {Cerebellum (London, England)}, volume = {23}, number = {4}, pages = {1702-1704}, pmid = {38049694}, issn = {1473-4230}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Superoxide Dismutase-1/genetics ; *Cerebellar Ataxia/genetics/diagnostic imaging ; *Mutation ; *Superoxide Dismutase/genetics ; Male ; Middle Aged ; Female ; }, abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder that affects upper and lower motor neurons. SOD1 mutations are the second most commonly found in familial and sporadic cases. We describe a patient with a homozygous pathogenic mutation in SOD1 gene that presented with a progressive cerebellar ataxia and ultimately developed a complex phenotype of cerebellar ataxia and motor neuron disease. The linkage between the cerebellum and ALS is shortly discussed.}, } @article {pmid38049641, year = {2024}, author = {Kiani, L}, title = {ALS pathogenesis linked to actin barrier collapse.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {1}, pages = {1}, pmid = {38049641}, issn = {1759-4766}, mesh = {Humans ; *Actins ; *Amyotrophic Lateral Sclerosis/etiology ; }, } @article {pmid38049549, year = {2024}, author = {Wu, T and Li, H}, title = {A case of Mills' syndrome: initially characterized by one cerebral hemisphere atrophy and decreased brain metabolism then evolving into amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {3}, pages = {1311-1313}, pmid = {38049549}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging/pathology ; *Motor Neuron Disease ; Brain/diagnostic imaging/pathology ; Chronic Disease ; Atrophy/pathology ; Muscular Atrophy ; *Cerebrum ; }, abstract = {This article reports a case of Mills' syndrome that initially manifested as atrophy of one cerebral hemisphere and decreased brain metabolism, which developed into amyotrophic lateral sclerosis in the fourth year of the disease. Mills' syndrome is a rare type of motor neuron disease, with only over 20 cases reported since 1990, but most lack imaging such as PET and DTI. This article provides a complete report of the 18F-FDG-PET and DTI images consistent with the characteristics of Mills' syndrome. In addition, we have discovered some new phenomena, which have certain clinical and teaching values. Firstly, the frontal, parietal and temporal lobes on the side of the lesion in the pyramidal tract of this patient were significantly atrophic, indicating that unilateral brain lobe atrophy may be a new feature of Mills' syndrome. Secondly, although there were no abnormalities in three EMG tests taken during the 4 years prior to the onset of the disease, amyotrophy and ALS-like EMG features appeared in the fourth year, suggesting that some Mills' syndrome may progress more rapidly to ALS. This highlights the importance of regular follow-up electromyography in Mills' syndrome patients.}, } @article {pmid38049418, year = {2023}, author = {Megat, S and Mora, N and Sanogo, J and Roman, O and Catanese, A and Alami, NO and Freischmidt, A and Mingaj, X and De Calbiac, H and Muratet, F and Dirrig-Grosch, S and Dieterle, S and Van Bakel, N and Müller, K and Sieverding, K and Weishaupt, J and Andersen, PM and Weber, M and Neuwirth, C and Margelisch, M and Sommacal, A and Van Eijk, KR and Veldink, JH and , and Lautrette, G and Couratier, P and Camuzat, A and Le Ber, I and Grassano, M and Chio, A and Boeckers, T and Ludolph, AC and Roselli, F and Yilmazer-Hanke, D and Millecamps, S and Kabashi, E and Storkebaum, E and Sellier, C and Dupuis, L}, title = {Author Correction: Integrative genetic analysis illuminates ALS heritability and identifies risk genes.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {8026}, doi = {10.1038/s41467-023-43710-4}, pmid = {38049418}, issn = {2041-1723}, } @article {pmid38049069, year = {2024}, author = {Navarro-Fernandez, I}, title = {Tracing the origins of setons in hidradenitis suppurativa: A commentary to Vilarrasa et al's "Drainage setons for the management of sinus tracts in hidradenitis suppurativa".}, journal = {Journal of the American Academy of Dermatology}, volume = {90}, number = {4}, pages = {e139}, doi = {10.1016/j.jaad.2023.10.068}, pmid = {38049069}, issn = {1097-6787}, mesh = {Humans ; *Hidradenitis Suppurativa ; Inflammation ; }, } @article {pmid38049068, year = {2024}, author = {Wang, B and Huang, Y and Li, J}, title = {Response to John et al's comments of "paroxetine is an effective treatment for refractory erythema of rosacea: Primary results from the prospective rosacea refractory erythema randomized clinical trial".}, journal = {Journal of the American Academy of Dermatology}, volume = {90}, number = {4}, pages = {e143-e144}, doi = {10.1016/j.jaad.2023.11.050}, pmid = {38049068}, issn = {1097-6787}, mesh = {Humans ; *Paroxetine/therapeutic use ; Prospective Studies ; *Rosacea/drug therapy ; Erythema/drug therapy/etiology ; Treatment Outcome ; }, } @article {pmid38046608, year = {2023}, author = {Wang, R and Sun, Y and Lan, Y and Wei, S and Huang, H and Li, X and Huang, Z}, title = {ALS gene overexpression and enhanced metabolism conferring Digitaria sanguinalis resistance to nicosulfuron in China.}, journal = {Frontiers in plant science}, volume = {14}, number = {}, pages = {1290600}, pmid = {38046608}, issn = {1664-462X}, abstract = {Crabgrass (Digitaria sanguinalis) is a common malignant weed in corn fields in China. Recently, the acetolactate synthase (ALS) inhibitor, nicosulfuron, has shown decreasing efficacy against crabgrass. In order to elucidate the molecular basis of resistance to nicosulfuron in crabgrass, we conducted bioassays, combined with gene sequence analysis, relative expression and relative copy number analysis, to characterize resistance in crabgrass populations collected from Beijing, Heilongjiang, Jilin and Anhui provinces. Whole-plant dose-response results indicated that only population collected in Heilongjiang province (HLJ) had developed low level of resistance to nicosulfuron compared with the sensitive population (SD22). No known resistant mutation of ALS gene was found in HLJ population. The real-time fluorescence quantitative PCR results showed that the ALS gene copy number did not differ significantly between the HLJ and SD22 populations. However, the ALS gene expression in the HLJ was 2.07-fold higher than that of the SD22 population at 24 h after treatment with nicosulfuron. Pretreatment with the cytochrome P450 (CYP450) inhibitor malathion, piperonyl butoxide (PBO), and the glutathione S-transferase (GST) inhibitor 4-Chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) all partially reversed HLJ resistance. Among them, the synergistic effect of PBO and nicosulfuron is the most significant. This is the first report of resistance to nicosulfuron in crabgrass through ALS gene overexpression and possible metabolic resistance.}, } @article {pmid38046601, year = {2023}, author = {Quan, W and Chan, Z and Wei, P and Mao, Y and Bartels, D and Liu, X}, title = {PHD finger proteins function in plant development and abiotic stress responses: an overview.}, journal = {Frontiers in plant science}, volume = {14}, number = {}, pages = {1297607}, pmid = {38046601}, issn = {1664-462X}, abstract = {The plant homeodomain (PHD) finger with a conserved Cys4-His-Cys3 motif is a common zinc-binding domain, which is widely present in all eukaryotic genomes. The PHD finger is the "reader" domain of methylation marks in histone H3 and plays a role in the regulation of gene expression patterns. Numerous proteins containing the PHD finger have been found in plants. In this review, we summarize the functional studies on PHD finger proteins in plant growth and development and responses to abiotic stresses in recent years. Some PHD finger proteins, such as VIN3, VILs, and Ehd3, are involved in the regulation of flowering time, while some PHD finger proteins participate in the pollen development, for example, MS, TIP3, and MMD1. Furthermore, other PHD finger proteins regulate the plant tolerance to abiotic stresses, including Alfin1, ALs, and AtSIZ1. Research suggests that PHD finger proteins, as an essential transcription regulator family, play critical roles in various plant biological processes, which is helpful in understanding the molecular mechanisms of novel PHD finger proteins to perform specific function.}, } @article {pmid38046408, year = {2023}, author = {Liu, J and Li, H and Zhou, Y and Zhang, Y and Song, S and Gu, X and Xu, J and Yu, X}, title = {Deep learning-based estimation of axial length using macular optical coherence tomography images.}, journal = {Frontiers in medicine}, volume = {10}, number = {}, pages = {1308923}, pmid = {38046408}, issn = {2296-858X}, abstract = {BACKGROUND: This study aimed to develop deep learning models using macular optical coherence tomography (OCT) images to estimate axial lengths (ALs) in eyes without maculopathy.

METHODS: A total of 2,664 macular OCT images from 444 patients' eyes without maculopathy, who visited Beijing Hospital between March 2019 and October 2021, were included. The dataset was divided into training, validation, and testing sets with a ratio of 6:2:2. Three pre-trained models (ResNet 18, ResNet 50, and ViT) were developed for binary classification (AL ≥ 26 mm) and regression task. Ten-fold cross-validation was performed, and Grad-CAM analysis was employed to visualize AL-related macular features. Additionally, retinal thickness measurements were used to predict AL by linear and logistic regression models.

RESULTS: ResNet 50 achieved an accuracy of 0.872 (95% Confidence Interval [CI], 0.840-0.899), with high sensitivity of 0.804 (95% CI, 0.728-0.867) and specificity of 0.895 (95% CI, 0.861-0.923). The mean absolute error for AL prediction was 0.83 mm (95% CI, 0.72-0.95 mm). The best AUC, and accuracy of AL estimation using macular OCT images (0.929, 87.2%) was superior to using retinal thickness measurements alone (0.747, 77.8%). AL-related macular features were on the fovea and adjacent regions.

CONCLUSION: OCT images can be effectively utilized for estimating AL with good performance via deep learning. The AL-related macular features exhibit a localized pattern in the macula, rather than continuous alterations throughout the entire region. These findings can lay the foundation for future research in the pathogenesis of AL-related maculopathy.}, } @article {pmid38045991, year = {2023}, author = {Barberio, J and Lally, C and Kupelian, V and Hardiman, O and Flanders, WD}, title = {Estimated Familial Amyotrophic Lateral Sclerosis Proportion: A Literature Review and Meta-analysis.}, journal = {Neurology. Genetics}, volume = {9}, number = {6}, pages = {e200109}, pmid = {38045991}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder. Familial (fALS) cases are usually reported to constitute 5%-10% of all ALS cases; however, no recent literature review or meta-analysis of this proportion (referred to throughout as "proportion fALS") has been conducted. Our objective was to estimate the proportion fALS by geographic region and to assess the effect of study characteristics on the estimates.

METHODS: A comprehensive literature review was performed to identify all original studies reporting the number of fALS cases in an ALS cohort. The results were stratified by geographic region, study design (case series or population-based), and decade of study publication. Subgroup analyses were conducted according to family history criteria used to define fALS. We report pooled estimates of the proportion fALS from random-effects meta-analyses when >2 studies are available and I[2] is < 90%; weighted averages and ranges are otherwise presented.

RESULTS: The overall pooled proportion fALS based on a total 165 studies was 8% (0%, 71%). The proportion fALS was 9% (0%, 71%) among 107 case series and 5% (4%, 6%) among 58 population-based studies. Among population-based studies, proportion fALS by geographic region was 6% (5%, 7%; N = 37) for Europe, 5% (3%, 7%; N = 5) for Latin America, and 5% (4%, 7%; N = 12) for North America. Criteria used to define fALS were reported by 21 population-based studies (36%), and proportion fALS was 5% (4%, 5%; N = 9) for first-degree relative, 7% (4%, 11%; N = 4) for first or second-degree relative, and 11% (N = 1) for more distant ALS family history. Population-based studies published in the 2000s or earlier generated a lower pooled proportion fALS than studies published in the 2010s or later.

DISCUSSION: The results suggest that variability in the reported proportion fALS in the literature may be, in part, due to the differences in geography, study design, fALS definition, and decade of case ascertainment. Few studies outside of European ancestral populations were available. The proportion fALS was marginally higher among case series compared with population-based studies, likely because of referral bias. Criteria used to define fALS were largely unreported. Consensus criteria for fALS and additional population-based studies in non-European ancestral populations are needed.}, } @article {pmid38043854, year = {2024}, author = {Pourzand, P and Moore, J and Metzger, A and Salverda, B and Suresh, M and Arango, S and Rosenhagen, H and Kaizer, A and Duval, S and Debaty, G and Lurie, K}, title = {Hemodynamics, survival and neurological function with early versus delayed automated head-up CPR in a porcine model of prolonged cardiac arrest.}, journal = {Resuscitation}, volume = {194}, number = {}, pages = {110067}, doi = {10.1016/j.resuscitation.2023.110067}, pmid = {38043854}, issn = {1873-1570}, support = {R43HL158361/NH/NIH HHS/United States ; }, mesh = {Animals ; *Cardiopulmonary Resuscitation/methods ; Disease Models, Animal ; Epinephrine ; *Heart Arrest ; Hemodynamics ; Swine ; }, abstract = {AIM: To determine if controlled head and thorax elevation, active compression-decompression cardiopulmonary resuscitation (CPR), and an impedance threshold device combined, termed automated head-up positioning CPR (AHUP-CPR), should be initiated early, as a basic (BLS) intervention, or later, as an advanced (ALS) intervention, in a severe porcine model of cardiac arrest.

METHODS: Yorkshire pigs (n = 22) weighing ∼40 kg were anesthetized and ventilated. After 15 minutes of untreated ventricular fibrillation, pigs were randomized to AHUP-CPR for 25 minutes (BLS group) or conventional CPR for 10 minutes, followed by 15 minutes of AHUP-CPR (ALS group). Thereafter, epinephrine, amiodarone, and defibrillation were administered. Neurologic function, the primary endpoint, was assessed 24-hours later with a Neurological Deficit Score (NDS, 0 = normal and 260 = worst deficit score or death). Secondary outcomes included return of spontaneous circulation (ROSC), cumulative survival, hemodynamics and epinephrine responsivity. Data, expressed as mean ± standard deviation, were compared using Fisher's Exact, log-rank, Mann-Whitney U and unpaired t-tests.

RESULTS: ROSC was achieved in 10/11 pigs with early AHUP-CPR versus 6/11 with delayed AHUP-CPR (p = 0.14), and cumulative 24-hour survival was 45.5% versus 9.1%, respectively (p < 0.02). The NDS was 203 ± 80 with early AHUP-CPR versus 259 ± 3 with delayed AHUP-CPR (p = 0.035). ETCO2, rSO2, and responsiveness to epinephrine were significantly higher in the early versus delayed AHUP-CPR.

CONCLUSION: When delivered early rather than late, AHUP-CPR resulted in significantly increased hemodynamics, 24-hour survival, and improved neurological function in pigs after prolonged cardiac arrest. Based on these findings, AHUP-CPR should be considered a BLS intervention.}, } @article {pmid38043051, year = {2024}, author = {Graber, DJ and Cook, WJ and Sentman, ML and Murad-Mabaera, JM and Sentman, CL}, title = {Human CD4+CD25+ T cells expressing a chimeric antigen receptor against aberrant superoxide dismutase 1 trigger antigen-specific immunomodulation.}, journal = {Cytotherapy}, volume = {26}, number = {2}, pages = {126-135}, pmid = {38043051}, issn = {1477-2566}, support = {P30 CA023108/CA/NCI NIH HHS/United States ; R21 NS102556/NS/NINDS NIH HHS/United States ; R21 NS117895/NS/NINDS NIH HHS/United States ; }, mesh = {Mice ; Animals ; Humans ; Superoxide Dismutase-1/genetics/metabolism/therapeutic use ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Receptors, Chimeric Antigen/therapeutic use ; Interleukin-10/genetics ; Superoxide Dismutase/metabolism ; Mice, Transgenic ; CD4-Positive T-Lymphocytes/metabolism ; Immunomodulation ; Disease Models, Animal ; }, abstract = {BACKGROUND AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal disease associated with motor neuron degeneration, accumulation of aggregated misfolded proteins and neuroinflammation in motor regions of the central nervous system (CNS). Clinical trials using regulatory T cells (Tregs) are ongoing because of Tregs' immunomodulatory function, ability to traffic to the CNS, high numbers correlating with slower disease in ALS and disease-modifying activity in ALS mouse models. In the current study, a chimeric antigen receptor (CAR) was developed and characterized in human Tregs to enhance their immunomodulatory activity when in contact with an ALS protein aggregate.

METHODS: A CAR (DG05-28-3z) consisting of a human superoxide dismutase 1 (hSOD1)-binding single-chain variable fragment, CD28 hinge, transmembrane and co-stimulatory domain and CD3ζ signaling domain was created and expressed in human Tregs. Human Tregs were isolated by either magnetic enrichment for CD4+CD25[hi] cells (Enr-Tregs) or cell sorting for CD4+CD25[hi]CD127[lo] cells (FP-Tregs), transduced and expanded for 17 days.

RESULTS: The CAR bound preferentially to the ALS mutant G93A-hSOD1 protein relative to the wild-type hSOD1 protein. The CAR Tregs produced IL-10 when cultured with aggregated G93A-hSOD1 proteins or spinal cord explants from G93A-hSOD1 transgenic mice. Co-culturing DG05-28-3z CAR Tregs with human monocytes/macrophages inhibited production of tumor necrosis factor alpha and reactive oxygen species. Expanded FP-Tregs resulted in more robust Tregs compared with Enr-Tregs. FP-Tregs produced similar IL-10 and less interferon gamma, had lower Treg-specific demethylated region methylation and expressed higher FoxP3 and CD39.

CONCLUSIONS: Taken together, this study demonstrates that gene-modified Tregs can be developed to target an aggregated ALS-relevant protein to elicit CAR-mediated Treg effector functions and provides an approach for generating Treg therapies for ALS with the goal of enhanced disease site-specific immunomodulation.}, } @article {pmid38042502, year = {2024}, author = {Ma, H and Huo, J and Xin, C and Yang, J and Liu, Q and Dong, H and Li, R and Liu, Y}, title = {RABGGTB plays a critical role in ALS pathogenesis.}, journal = {Brain research bulletin}, volume = {206}, number = {}, pages = {110833}, doi = {10.1016/j.brainresbull.2023.110833}, pmid = {38042502}, issn = {1873-2747}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Spinal Cord/metabolism ; DNA-Binding Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with unknown causes, which mainly affects motor neurons in the anterior horn of the spinal cord, brain stem, and cerebral cortex, also known as motor neuron disease. An important pathological feature of ALS is the formation of aggregates of mutant SOD1 protein, CTF25 of TDP-43, or other abnormal proteins in motor neurons, which require autophagy for degradation. Protein prenylation is known to participate in membrane association and proper localization of proteins. RABGGTB is the β subunit of GGTase II (one of the prenyltransferases) that can regulate autophagy via Rab7 geranylgeranylation. In this study, we overexpressed RABGGTB via lentiviral transfection in NSC34-hSOD1G93A and TDP-43 cells. Overexpression of RABGGTB improved ALS cell proliferation by facilitating autophagosome-lysosome fusion. Furthermore, the abnormal aggregation of SOD1 protein was reduced. This indicates that protein prenylation is important for the proliferation and autophagy of cells autophagy. Enhanced autophagy has been observed in two of the most widely used ALS cell models. These findings indicate the widespread applicability of prenylation in ALS. In summary, overexpression of RABGGTB improved the geranylgeranylation of the Rab7 protein and had a positive effect on cells. These findings provide insights into the development of a novel therapeutic strategy for ALS.}, } @article {pmid38041684, year = {2024}, author = {Dohrn, MF and Beijer, D and Lone, MA and Bayraktar, E and Oflazer, P and Orbach, R and Donkervoort, S and Foley, AR and Rose, A and Lyons, M and Louie, RJ and Gable, K and Dunn, T and Chen, S and Danzi, MC and Synofzik, M and Bönnemann, CG and Nazlı Başak, A and Hornemann, T and Zuchner, S}, title = {Recurrent de-novo gain-of-function mutation in SPTLC2 confirms dysregulated sphingolipid production to cause juvenile amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {3}, pages = {201-205}, pmid = {38041684}, issn = {1468-330X}, support = {R01 NS072248/NS/NINDS NIH HHS/United States ; R01 NS105755/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Ceramides ; Gain of Function Mutation ; Mutation/genetics ; *Serine C-Palmitoyltransferase/genetics/chemistry ; Sphingolipids ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) leads to paralysis and death by progressive degeneration of motor neurons. Recently, specific gain-of-function mutations in SPTLC1 were identified in patients with juvenile form of ALS. SPTLC2 encodes the second catalytic subunit of the serine-palmitoyltransferase (SPT) complex.

METHODS: We used the GENESIS platform to screen 700 ALS whole-genome and whole-exome data sets for variants in SPTLC2. The de-novo status was confirmed by Sanger sequencing. Sphingolipidomics was performed using liquid chromatography and high-resolution mass spectrometry.

RESULTS: Two unrelated patients presented with early-onset progressive proximal and distal muscle weakness, oral fasciculations, and pyramidal signs. Both patients carried the novel de-novo SPTLC2 mutation, c.203T>G, p.Met68Arg. This variant lies within a single short transmembrane domain of SPTLC2, suggesting that the mutation renders the SPT complex irresponsive to regulation through ORMDL3. Confirming this hypothesis, ceramide and complex sphingolipid levels were significantly increased in patient plasma. Accordingly, excessive sphingolipid production was shown in mutant-expressing human embryonic kindney (HEK) cells.

CONCLUSIONS: Specific gain-of-function mutations in both core subunits affect the homoeostatic control of SPT. SPTLC2 represents a new Mendelian ALS gene, highlighting a key role of dysregulated sphingolipid synthesis in the pathogenesis of juvenile ALS. Given the direct interaction of SPTLC1 and SPTLC2, this knowledge might open new therapeutic avenues for motor neuron diseases.}, } @article {pmid38041679, year = {2024}, author = {Syeda, SB and Lone, MA and Mohassel, P and Donkervoort, S and Munot, P and França, MC and Galarza-Brito, JE and Eckenweiler, M and Asamoah, A and Gable, K and Majumdar, A and Schumann, A and Gupta, SD and Lakhotia, A and Shieh, PB and Foley, AR and Jackson, KE and Chao, KR and Winder, TL and Catapano, F and Feng, L and Kirschner, J and Muntoni, F and Dunn, TM and Hornemann, T and Bönnemann, CG}, title = {Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {2}, pages = {103-113}, pmid = {38041679}, issn = {1468-330X}, support = {R01 HG009141/HG/NHGRI NIH HHS/United States ; UM1 HG008900/HG/NHGRI NIH HHS/United States ; }, mesh = {Child ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Neurodegenerative Diseases ; Sphingolipids ; Serine C-Palmitoyltransferase/genetics/metabolism ; *Hereditary Sensory and Autonomic Neuropathies/genetics ; Serine ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons with varying ages of onset, progression and pathomechanisms. Monogenic childhood-onset ALS, although rare, forms an important subgroup of ALS. We recently reported specific SPTLC1 variants resulting in sphingolipid overproduction as a cause for juvenile ALS. Here, we report six patients from six independent families with a recurrent, de novo, heterozygous variant in SPTLC2 c.778G>A [p.Glu260Lys] manifesting with juvenile ALS.

METHODS: Clinical examination of the patients along with ancillary and genetic testing, followed by biochemical investigation of patients' blood and fibroblasts, was performed.

RESULTS: All patients presented with early-childhood-onset progressive weakness, with signs and symptoms of upper and lower motor neuron degeneration in multiple myotomes, without sensory neuropathy. These findings were supported on ancillary testing including nerve conduction studies and electromyography, muscle biopsies and muscle ultrasound studies. Biochemical investigations in plasma and fibroblasts showed elevated levels of ceramides and unrestrained de novo sphingolipid synthesis. Our studies indicate that SPTLC2 variant [c.778G>A, p.Glu260Lys] acts distinctly from hereditary sensory and autonomic neuropathy (HSAN)-causing SPTLC2 variants by causing excess canonical sphingolipid biosynthesis, similar to the recently reported SPTLC1 ALS associated pathogenic variants. Our studies also indicate that serine supplementation, which is a therapeutic in SPTLC1 and SPTCL2-associated HSAN, is expected to exacerbate the excess sphingolipid synthesis in serine palmitoyltransferase (SPT)-associated ALS.

CONCLUSIONS: SPTLC2 is the second SPT-associated gene that underlies monogenic, juvenile ALS and further establishes alterations of sphingolipid metabolism in motor neuron disease pathogenesis. Our findings also have important therapeutic implications: serine supplementation must be avoided in SPT-associated ALS, as it is expected to drive pathogenesis further.}, } @article {pmid38041669, year = {2024}, author = {Guissart, C and De la Cruz, E and Flabeau, O and Grapperon, AM and Corazza, G and Junilhon, L and Delmas, JC and Millecamps, S and Polge, A and Amador, MDM and Salachas, F and Rochat, J and Goizet, C and Juntas Morales, R and Lumbroso, S and Philibert, P and Cheillan, D and Mouzat, K}, title = {Heterozygous SPTLC1 p.Leu39del is a major cause of slow-progressing juvenile ALS.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {3}, pages = {288-290}, doi = {10.1136/jnnp-2023-331753}, pmid = {38041669}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Mutation ; *Serine C-Palmitoyltransferase/genetics ; }, } @article {pmid38041662, year = {2024}, author = {Shy, ME}, title = {Genetics, cell biology and a novel mechanism for ALS.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {3}, pages = {199-200}, doi = {10.1136/jnnp-2023-332720}, pmid = {38041662}, issn = {1468-330X}, mesh = {Humans ; Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Motor Neurons ; Disease Models, Animal ; *Motor Neuron Disease ; }, } @article {pmid38041659, year = {2024}, author = {Kiernan, MC and Farrar, MA}, title = {Emerging role for sphingolipids in the genetics of amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {2}, pages = {101-102}, doi = {10.1136/jnnp-2023-332719}, pmid = {38041659}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Sphingolipids ; *Motor Neuron Disease ; }, } @article {pmid38038225, year = {2024}, author = {Sanghani, N and Claytor, B and Li, Y}, title = {Electrodiagnostic findings in amyotrophic lateral sclerosis: Variation with region of onset and utility of thoracic paraspinal muscle examination.}, journal = {Muscle & nerve}, volume = {69}, number = {2}, pages = {172-178}, doi = {10.1002/mus.28012}, pmid = {38038225}, issn = {1097-4598}, mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis ; Retrospective Studies ; Paraspinal Muscles ; Electromyography ; Electrodiagnosis ; }, abstract = {INTRODUCTION/AIMS: Limited data exist regarding variation of electrodiagnostic (EDX) findings in amyotrophic lateral sclerosis (ALS) patients with different onset regions and specificity of thoracic paraspinal muscle (TPSP) examination for confirming a diagnosis of ALS. We aimed to demonstrate the variation of EDX features and characterize the utility of TPSP muscle examination in the electrodiagnosis of ALS.

METHODS: This is a retrospective study of a large cohort of ALS patients who had a comprehensive EDX evaluation.

RESULTS: The study included 448 patients; all fulfilled the Gold Coast criteria for ALS. The average age at the time of EDX study was 64 years, and 41.1% were women. The onset region was identified as follows: bulbar (N = 149), cervical (N = 127), lumbosacral (N = 162), and other (N = 10). In contrast to limb onset, bulbar-onset patients more frequently demonstrated a pattern of normal or near normal needle electromyography (EMG) (p < .0001) and less frequently had abnormalities on EMG of TPSP (p = .002). Clinical or EDX diagnosis of sensory polyneuropathy was present in 12.6% patients, more frequently in the lumbosacral onset subgroup (p < .03). EMG showed active denervation in 9.6% and chronic denervation in 59% of craniobulbar muscles examined, without observed difference among different onset regions. TPSP showed higher frequencies of active and chronic denervation in ALS than a group of patients with non-ALS neuromuscular disorders.

DISCUSSION: EDX features may differ among ALS patients of different onset regions. TPSP EMG is highly useful in differentiating ALS from non-ALS neuromuscular disorders while the yield of craniobulbar muscles, especially for active denervation, is low.}, } @article {pmid38037913, year = {2024}, author = {Zhong, G and Wang, X and Li, J and Xie, Z and Wu, Q and Chen, J and Wang, Y and Chen, Z and Cao, X and Li, T and Liu, J and Wang, Q}, title = {Insights Into the Role of Copper in Neurodegenerative Diseases and the Therapeutic Potential of Natural Compounds.}, journal = {Current neuropharmacology}, volume = {22}, number = {10}, pages = {1650-1671}, pmid = {38037913}, issn = {1875-6190}, support = {81973918, 82274616//National Natural Science Foundation of China/ ; 2019KSYS005//Key laboratory project of colleges and universities in Guangdong Province/ ; 2020A0505100052//Guangdong province science and technology plan international cooperation project/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Copper/metabolism ; Animals ; Biological Products/therapeutic use/pharmacology ; Homeostasis/drug effects ; Chelating Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases encompass a collection of neurological disorders originating from the progressive degeneration of neurons, resulting in the dysfunction of neurons. Unfortunately, effective therapeutic interventions for these diseases are presently lacking. Copper (Cu), a crucial trace element within the human body, assumes a pivotal role in various biological metabolic processes, including energy metabolism, antioxidant defense, and neurotransmission. These processes are vital for the sustenance, growth, and development of organisms. Mounting evidence suggests that disrupted copper homeostasis contributes to numerous age-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Wilson's disease (WD), Menkes disease (MD), prion diseases, and multiple sclerosis (MS). This comprehensive review investigates the connection between the imbalance of copper homeostasis and neurodegenerative diseases, summarizing pertinent drugs and therapies that ameliorate neuropathological changes, motor deficits, and cognitive impairments in these conditions through the modulation of copper metabolism. These interventions include Metal-Protein Attenuating Compounds (MPACs), copper chelators, copper supplements, and zinc salts. Moreover, this review highlights the potential of active compounds derived from natural plant medicines to enhance neurodegenerative disease outcomes by regulating copper homeostasis. Among these compounds, polyphenols are particularly abundant. Consequently, this review holds significant implications for the future development of innovative drugs targeting the treatment of neurodegenerative diseases.}, } @article {pmid38036140, year = {2024}, author = {Karaśkiewicz, J and Wójcik, R}, title = {Modelling optimal water retention in hydrogenic habitats using LIDAR laser data.}, journal = {The Science of the total environment}, volume = {912}, number = {}, pages = {168983}, doi = {10.1016/j.scitotenv.2023.168983}, pmid = {38036140}, issn = {1879-1026}, abstract = {Degradation of hydrogenic habitats in climate change increased rapidly. It is important that we take actions to stop this process. Solution is to increase efficiency of water usage by ecosystems - especially water based ones. Building devices for delaying surface water runoff - like locks and dams - should improve hydrogenic habitats conditions and allow surrounding ecosystems use rainwater more efficient. Modelling of small retention in forests is an important aspect in decision making schema. Aim of this paper is to point optimal solutions for height and placement of devices which delay surface water runoff to set necessary water table level for renaturalization and maintenance of degrading natural habitats. Data used for analyses were acquired in the Polanów Forest Inspectorate in West Pomeranian voivodeship because of the topography diversification and the drainage infrastructure presence. There were three research plots selected based on decreased stability of habitats and historic data stated that there were natural water reservoirs, which were drained in past. Based on 2012 LiDAR (Light Detection and Ranging) point cloud the digital terrain model (DTM) was built. Water outflow points - melioration canals - were identified and analysed for optimal device localization. In following part of research specific data for each hydrogenic habitat were used to model height of devices which delay surface water runoff. Optimal level of device and area covered by water were set for each site separately. The results were handed over to the investor for implementation, then the compliance of the assumptions of the simulation of raising the water table with the as-built field measurements was checked. Study shows that it is possible to use laser technology to optimize location and height of devices which delay surface water runoff what allows to restore degraded hydrogenic habitats. Presented method supports small local retention what increases limited water resources in this region, decreases rapid runoff of surface water which causes frequent floods. Proposed method of modelling the location and height of the dams or locks is universal. Even though results are unique for each object the method is possible to be applied to every other situation.}, } @article {pmid38036035, year = {2024}, author = {Wang, X and Zhu, Z and Sun, J and Jia, L and Cai, L and Chen, Q and Yang, W and Wang, Y and Zhang, Y and Guo, S and Liu, W and Yang, Z and Zhao, P and Wang, Z and Lv, H}, title = {Changes in iron load in specific brain areas lead to neurodegenerative diseases of the central nervous system.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {129}, number = {}, pages = {110903}, doi = {10.1016/j.pnpbp.2023.110903}, pmid = {38036035}, issn = {1878-4216}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging/pathology ; Iron ; Genome-Wide Association Study ; Magnetic Resonance Imaging/methods ; Brain/diagnostic imaging/pathology ; *Alzheimer Disease/pathology ; *Parkinson Disease ; *Multiple Sclerosis ; }, abstract = {The causes of neurodegenerative diseases remain largely elusive, increasing their personal and societal impacts. To reveal the causal effects of iron load on Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis and multiple sclerosis, we used Mendelian randomisation and brain imaging data from a UK Biobank genome-wide association study of 39,691 brain imaging samples (predominantly of European origin). Using susceptibility-weighted images, which reflect iron load, we analysed genetically significant brain regions. Inverse variance weighting was used as the main estimate, while MR Egger and weighted median were used to detect heterogeneity and pleiotropy. Nine clear associations were obtained. For AD and PD, an increased iron load was causative: the right pallidum for AD and the right caudate, left caudate and right accumbens for PD. However, a reduced iron load was identified in the right and left caudate for multiple sclerosis, the bilateral hippocampus for mixed vascular dementia and the left thalamus and bilateral accumbens for subcortical vascular dementia. Thus, changes in iron load in different brain regions have causal effects on neurodegenerative diseases. Our results are crucial for understanding the pathogenesis and investigating the treatment of these diseases.}, } @article {pmid38035964, year = {2024}, author = {Khan, S and Upadhyay, S and Dave, U and Kumar, A and Gomes, J}, title = {Structural and mechanistic insights into ALS patient derived mutations in D-amino acid oxidase.}, journal = {International journal of biological macromolecules}, volume = {256}, number = {Pt 2}, pages = {128403}, doi = {10.1016/j.ijbiomac.2023.128403}, pmid = {38035964}, issn = {1879-0003}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Kinetics ; Mutation ; Serine/genetics ; }, abstract = {The D-amino acid oxidase protein modulates neurotransmission by controlling the levels of D-serine, a co-agonist of N-methyl-D-aspartate receptors. Mutations in the DAO gene have been associated with ALS, with some studies reporting pathogenic mechanisms of the R199W mutation. We have characterized two novel mutations R38H and Q201R found in ALS patients and report certain novel findings related to the R199W mutation. We report the first instance of crystal structure analysis of a patient-derived mutant of DAO, R38H, solved at 2.10 Å. The structure revealed significant perturbations and altered binding with the cofactor (FAD) and the inhibitor benzoate, supported by biochemical assays. Q201R-DAO also exhibited significantly lower ligand binding efficiency. Furthermore, kinetic analysis across all variants revealed reduced oxidase activity and substrate binding. Notably, R38H-DAO exhibited near-WT activity only at high substrate concentrations, while R199W-DAO and Q201R-DAO displayed drastic activity reduction. Additionally, structural perturbations were inferred for R199W-DAO and Q201R-DAO, evident by the higher oligomeric state in the holoenzyme form. We also observed thermal instability in case of R199W-DAO mutant. We hypothesize that the mutant enzymes may be rendered non-functional in a cellular context, potentially leading to NMDAR-associated excitotoxicity. The study provides novel insights into structural and functional aspects of DAO mutations in ALS.}, } @article {pmid38033869, year = {2023}, author = {Vukolova, MN and Yen, LY and Khmyz, MI and Sobolevsky, AI and Yelshanskaya, MV}, title = {Parkinson's disease, epilepsy, and amyotrophic lateral sclerosis-emerging role of AMPA and kainate subtypes of ionotropic glutamate receptors.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1252953}, pmid = {38033869}, issn = {2296-634X}, support = {R37 NS083660/NS/NINDS NIH HHS/United States ; R01 NS107253/NS/NINDS NIH HHS/United States ; R01 NS083660/NS/NINDS NIH HHS/United States ; R01 AR078814/AR/NIAMS NIH HHS/United States ; R01 CA206573/CA/NCI NIH HHS/United States ; }, abstract = {Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission and are implicated in various neurological disorders. In this review, we discuss the role of the two fastest iGluRs subtypes, namely, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, in the pathogenesis and treatment of Parkinson's disease, epilepsy, and amyotrophic lateral sclerosis. Although both AMPA and kainate receptors represent promising therapeutic targets for the treatment of these diseases, many of their antagonists show adverse side effects. Further studies of factors affecting the selective subunit expression and trafficking of AMPA and kainate receptors, and a reasonable approach to their regulation by the recently identified novel compounds remain promising directions for pharmacological research.}, } @article {pmid38033614, year = {2023}, author = {Nakken, O and Vaage, AM and Stigum, H and Heldal, E and Meyer, HE and Holmøy, T}, title = {Tuberculin responses after BCG vaccination predict amyotrophic lateral sclerosis risk.}, journal = {Brain, behavior, & immunity - health}, volume = {34}, number = {}, pages = {100704}, pmid = {38033614}, issn = {2666-3546}, abstract = {BACKGROUND: T cell infiltration around dying motor neurons is a hallmark of amyotrophic lateral sclerosis (ALS). It is not known if this immune response represents a cause or a consequence of the disease. We aimed to establish whether individual variation in regulation of a T cell driven immune response is associated with long-term ALS risk.

METHODS: Tuberculin skin test (TST) following BCG vaccination represents a standardized measure of a secondary T cell driven immune response. During a Norwegian tuberculosis screening program (1963-1975) Norwegian citizens born from 1910 to 1955 underwent TST. In those previously BCG vaccinated (median 7 years prior to TST), we related tuberculin skin tests to later ALS disease identified through validated Norwegian health registers. We fitted Cox proportional hazard models to investigate the association between tuberculin reactivity and ALS risk.

RESULTS: Among 324,629 participants (52 % women) with median age 22 (IQR 10) years at tuberculosis screening, 496 (50 % women) later developed ALS. Hazard ratio for ALS was 0.74 (95% CI 0.57-0.95) for those who remained TST negative compared to those who mounted a positive TST. The association was strongest when time between BCG immunization and TST was short. The associations observed persisted for more than four decades after TST measurement.

CONCLUSIONS: Negative TST responses after BCG vaccination is associated with decreased long-term risk for ALS development, supporting a primary role for adaptive immunity in ALS development.}, } @article {pmid38031465, year = {2024}, author = {Ghasemi, A and Sadedel, M and Moghaddam, MM}, title = {A wearable system to assist impaired-neck patients: Design and evaluation.}, journal = {Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine}, volume = {238}, number = {1}, pages = {63-77}, doi = {10.1177/09544119231211362}, pmid = {38031465}, issn = {2041-3033}, mesh = {Humans ; *Robotics ; Electromyography/methods ; *Stroke ; Movement ; *Wearable Electronic Devices ; }, abstract = {Patients with neurological disorders, such as amyotrophic lateral sclerosis, Parkinson's disease, and cerebral palsy, often face challenges due to head-neck immobility. The conventional treatment approach involves using a neck collar to maintain an upright head position, but this can be cumbersome and restricts head-neck movements over prolonged periods. This study introduces a wearable robot capable of providing three anatomical head motions for training and assistance. The primary contributions of this research include the design of an optimized structure and the incorporation of human-robot interaction. Based on human head motion data, our primary focus centered on developing a robot capable of accommodating a significant range of neutral head movements. To ensure safety, impedance control was employed to facilitate human-robot interaction. A human study was conducted involving 10 healthy subjects who participated in an experiment to assess the robot's assistance capabilities. Passive and active modes were used to evaluate the robot's effectiveness, taking into account head-neck movement error and muscle activity levels. Surface electromyography signals (sEMG) were collected from the splenius capitis muscles during the experiment. The results demonstrated that the robot covered nearly 85% of the overall range of head rotations. Importantly, using the robot during rehabilitation led to reduced muscle activation, highlighting its potential for assisting individuals with post-stroke movement impairments.}, } @article {pmid38030693, year = {2023}, author = {Vanbilsen, N and Kotz, SA and Rosso, M and Leman, M and Triccas, LT and Feys, P and Moumdjian, L}, title = {Auditory attention measured by EEG in neurological populations: systematic review of literature and meta-analysis.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {21064}, pmid = {38030693}, issn = {2045-2322}, support = {G082021N//Fonds Wetenschappelijk Onderzoek/ ; 1295923N//Fonds Wetenschappelijk Onderzoek/ ; }, mesh = {Humans ; Cross-Sectional Studies ; *Attention ; *Parkinson Disease ; Gait ; Electroencephalography ; }, abstract = {Sensorimotor synchronization strategies have been frequently used for gait rehabilitation in different neurological populations. Despite these positive effects on gait, attentional processes required to dynamically attend to the auditory stimuli needs elaboration. Here, we investigate auditory attention in neurological populations compared to healthy controls quantified by EEG recordings. Literature was systematically searched in databases PubMed and Web of Science. Inclusion criteria were investigation of auditory attention quantified by EEG recordings in neurological populations in cross-sectional studies. In total, 35 studies were included, including participants with Parkinson's disease (PD), stroke, Traumatic Brain Injury (TBI), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS). A meta-analysis was performed on P3 amplitude and latency separately to look at the differences between neurological populations and healthy controls in terms of P3 amplitude and latency. Overall, neurological populations showed impairments in auditory processing in terms of magnitude and delay compared to healthy controls. Consideration of individual auditory processes and thereafter selecting and/or designing the auditory structure during sensorimotor synchronization paradigms in neurological physical rehabilitation is recommended.}, } @article {pmid38030509, year = {2024}, author = {Jacobs, MT and San Gil, R and Walker, AK}, title = {UndERACting ion channels in neurodegeneration.}, journal = {Trends in neurosciences}, volume = {47}, number = {2}, pages = {87-89}, doi = {10.1016/j.tins.2023.11.002}, pmid = {38030509}, issn = {1878-108X}, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Endoplasmic Reticulum ; Ion Channels/genetics/metabolism ; Chloride Channels/metabolism ; }, abstract = {In a recent study, Guo and colleagues characterised the function of an elusive endoplasmic reticulum (ER) anion channel protein, Chloride Channel CLiC Like 1 (CLCC1), and identified rare CLCC1 variants in people with amyotrophic lateral sclerosis (ALS). CLCC1 mutants disrupted ER function in vitro and promoted ALS-like pathology and neurodegeneration in mice. This work reveals a previously uncharacterised pathway involved in ER calcium release and highlights new pathogenic mechanisms underlying neurodegeneration.}, } @article {pmid38029395, year = {2024}, author = {Song, J}, title = {Molecular Mechanisms of Phase Separation and Amyloidosis of ALS/FTD-linked FUS and TDP-43.}, journal = {Aging and disease}, volume = {15}, number = {5}, pages = {2084-2112}, pmid = {38029395}, issn = {2152-5250}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *RNA-Binding Protein FUS/metabolism/chemistry/genetics ; *DNA-Binding Proteins/metabolism/chemistry/genetics ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Amyloidosis/metabolism/pathology/genetics ; Phase Separation ; }, abstract = {FUS and TDP-43, two RNA-binding proteins from the heterogeneous nuclear ribonucleoprotein family, have gained significant attention in the field of neurodegenerative diseases due to their association with amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). They possess folded domains for binding ATP and various nucleic acids including DNA and RNA, as well as substantial intrinsically disordered regions (IDRs) including prion-like domains (PLDs) and RG-/RGG-rich regions. They play vital roles in various cellular processes, including transcription, splicing, microRNA maturation, RNA stability and transport and DNA repair. In particular, they are key components for forming ribonucleoprotein granules and stress granules (SGs) through homotypic or heterotypic liquid-liquid phase separation (LLPS). Strikingly, liquid-like droplets formed by FUS and TDP-43 may undergo aging to transform into less dynamic assemblies such as hydrogels, inclusions, and amyloid fibrils, which are the pathological hallmarks of ALS and FTD. This review aims to synthesize and consolidate the biophysical knowledge of the sequences, structures, stability, dynamics, and inter-domain interactions of FUS and TDP-43 domains, so as to shed light on the molecular mechanisms underlying their liquid-liquid phase separation (LLPS) and amyloidosis. The review further delves into the mechanisms through which ALS-causing mutants of the well-folded hPFN1 disrupt the dynamics of LLPS of FUS prion-like domain, providing key insights into a potential mechanism for misfolding/aggregation-prone proteins to cause neurodegenerative diseases and aging by gain of functions. With better understanding of different biophysical aspects of FUS and TDP-43, the ultimate goal is to develop drugs targeting LLPS and amyloidosis, which could mediate protein homeostasis within cells and lead to new treatments for currently intractable diseases, particularly neurodegenerative diseases such as ALS, FTD and aging. However, the study of membrane-less organelles and condensates is still in its infancy and therefore the review also highlights key questions that require future investigation.}, } @article {pmid38028604, year = {2023}, author = {Kumar, R and Madhavan, T and Ponnusamy, K and Sohn, H and Haider, S}, title = {Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators.}, journal = {Frontiers in genetics}, volume = {14}, number = {}, pages = {1282234}, pmid = {38028604}, issn = {1664-8021}, abstract = {Introduction: Kinesin family member 5A (KIF5A) is a motor neuron protein expressed in neurons and involved in anterograde transportation of organelles, proteins, and RNA. Variations in the KIF5A gene that interfere with axonal transport have emerged as a distinguishing feature in several neurodegenerative disorders, including hereditary spastic paraplegia (HSP10), Charcot-Marie-Tooth disease type 2 (CMT2), and Amyotrophic Lateral Sclerosis (ALS). Methods: In this study, we implemented a computational structural and systems biology approach to uncover the role of KIF5A in ALS. Using the computational structural biology method, we explored the role of non-synonymous Single Nucleotide Polymorphism (nsSNPs) in KIF5A. Further, to identify the potential inhibitory molecule against the highly destabilizing structure variant, we docked 24 plant-derived phytochemicals involved in ALS. Results: We found KIF5A[S291F] variant showed the most structure destabilizing behavior and the phytocompound "epigallocatechin gallate" showed the highest binding affinity (-9.0 Kcal/mol) as compared to wild KIF5A (-8.4 Kcal/mol). Further, with the systems biology approach, we constructed the KIF5A protein-protein interaction (PPI) network to identify the associated Kinesin Families (KIFs) proteins, modules, and their function. We also constructed a transcriptional and post-transcriptional regulatory network of KIF5A. With the network topological parameters of PPIN (Degree, Bottleneck, Closeness, and MNC) using CytoHubba and computational knock-out experiment using Network Analyzer, we found KIF1A, 5B, and 5C were the significant proteins. The functional modules were highly enriched with microtubule motor activity, chemical synaptic transmission in neurons, GTP binding, and GABA receptor activity. In regulatory network analysis, we found KIF5A post-transcriptionally down-regulated by miR-107 which is further transcriptionally up-regulated by four TFs (HIF1A, PPARA, SREBF1, and TP53) and down-regulated by three TFs (ZEB1, ZEB2, and LIN28A). Discussion: We concluded our study by finding a crucial variant of KIF5A and its potential therapeutic target (epigallocatechin gallate) and KIF5A associated significant genes with important regulators which could decrypt the novel therapeutics in ALS and other neurodegenerative diseases.}, } @article {pmid38026702, year = {2023}, author = {Pisciottani, A and Croci, L and Lauria, F and Marullo, C and Savino, E and Ambrosi, A and Podini, P and Marchioretto, M and Casoni, F and Cremona, O and Taverna, S and Quattrini, A and Cioni, JM and Viero, G and Codazzi, F and Consalez, GG}, title = {Neuronal models of TDP-43 proteinopathy display reduced axonal translation, increased oxidative stress, and defective exocytosis.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1253543}, pmid = {38026702}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, lethal neurodegenerative disease mostly affecting people around 50-60 years of age. TDP-43, an RNA-binding protein involved in pre-mRNA splicing and controlling mRNA stability and translation, forms neuronal cytoplasmic inclusions in an overwhelming majority of ALS patients, a phenomenon referred to as TDP-43 proteinopathy. These cytoplasmic aggregates disrupt mRNA transport and localization. The axon, like dendrites, is a site of mRNA translation, permitting the local synthesis of selected proteins. This is especially relevant in upper and lower motor neurons, whose axon spans long distances, likely accentuating their susceptibility to ALS-related noxae. In this work we have generated and characterized two cellular models, consisting of virtually pure populations of primary mouse cortical neurons expressing a human TDP-43 fusion protein, wt or carrying an ALS mutation. Both forms facilitate cytoplasmic aggregate formation, unlike the corresponding native proteins, giving rise to bona fide primary culture models of TDP-43 proteinopathy. Neurons expressing TDP-43 fusion proteins exhibit a global impairment in axonal protein synthesis, an increase in oxidative stress, and defects in presynaptic function and electrical activity. These changes correlate with deregulation of axonal levels of polysome-engaged mRNAs playing relevant roles in the same processes. Our data support the emerging notion that deregulation of mRNA metabolism and of axonal mRNA transport may trigger the dying-back neuropathy that initiates motor neuron degeneration in ALS.}, } @article {pmid38026695, year = {2023}, author = {Donison, N and Hintermayer, M and Subramaniam, M and Santandrea, E and Volkening, K and Strong, MJ}, title = {Upregulation of LRRK2 following traumatic brain injury does not directly phosphorylate Thr[175] tau.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1272899}, pmid = {38026695}, issn = {1662-5102}, abstract = {Phosphorylated microtubule-associated protein tau (tau) aggregates are a pathological hallmark of various neurodegenerative diseases, including chronic traumatic encephalopathy and amyotrophic lateral sclerosis with cognitive impairment. While there are many residues phosphorylated on tau, phosphorylation of threonine 175 (pThr[175] tau) has been shown to initiate fibril formation in vitro and is present in pathological tau aggregates in vivo. Given this, preventing Thr[175] tau phosphorylation presents a potential approach to reduce fibril formation; however, the kinase(s) acting on Thr[175] are not yet fully defined. Using a single controlled cortical impact rodent model of traumatic brain injury (TBI), which rapidly induces Thr[175] tau phosphorylation, we observed an upregulation and alteration in subcellular localization of leucine-rich repeat kinase 2 (LRRK2), a kinase that has been implicated in tau phosphorylation. LRRK2 upregulation was evident by one-day post-injury and persisted to day 10. The most notable changes were observed in microglia at the site of injury in the cortex. To determine if the appearance of pThr[175] tau was causally related to the upregulation of LRRK2 expression, we examined the ability of LRRK2 to phosphorylate Thr[175]in vitro by co-transfecting 2N4R human WT-tau with either LRRK2-WT, constitutively-active LRRK2-G2019S or inactive LRRK2-3XKD. We found no significant difference in the level of pThr[175] tau between the overexpression of LRRK2-WT, -G2019S or -3XKD, suggesting LRRK2 does not phosphorylate tau at Thr[175]. Further, downstream events known to follow Thr[175] phosphorylation and known to be associated with pathological tau fibril formation (pSer[9]-GSK3β and pThr[231] tau induction) also remained unchanged. We conclude that while LRRK2 expression is altered in TBI, it does not contribute directly to pThr[175] tau generation.}, } @article {pmid38025370, year = {2023}, author = {Narayan, MS and Sameer, M and Viburajah, V}, title = {Hip Fracture in a Patient with Overlap Syndrome - Conundrums Involved in the Management - A Case Report.}, journal = {Journal of orthopaedic case reports}, volume = {13}, number = {11}, pages = {106-111}, pmid = {38025370}, issn = {2250-0685}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition producing symptoms of varying severity depending on the extent and progression of the disease pathology most importantly respiratory insufficiency and pulmonary complications. Myasthenia gravis (MG) on the other hand is an autoimmune condition due to the pathology involving failure of neuromuscular transmission causing muscle weakness exacerbated by activity and involvement of the respiratory muscles leading to respiratory failure. Overlap syndrome is a condition wherein both motor neuron disease (MND) and MG are present in the same patient. The safety of using muscle-relaxing agents in patients with MG undergoing major surgical procedures has so far been assessed as insufficient. There have been many concerns regarding anesthetic management in relation to complications with respiratory function in patients with ALS, with regional anesthesia being considered slightly safer.

CASE REPORT: An 81-year-old female presented with a closed injury to her left hip, and she was diagnosed to have a left neck of femur fracture. She was also a known case of bulbar MND with an overlap syndrome of MG. She was hypertensive and controlled with regular medication. She was planned for a left hip bipolar arthroplasty. Anesthetic requirements and management of these patients require a high degree of expertise and anesthesia in patients undergoing surgery is prone to more complications and mortality. In addition, as the patient had an overlap of both MG and MND, more meticulous assessment and management strategies were necessary.

CONCLUSION: The importance and purpose of this study are to highlight a case of overlap syndrome of MND and MG patients who sustained a left neck femur fracture and underwent bipolar arthroplasty highlighting the anesthetic considerations in the patient for the procedure. We concluded that the choice of mode of anesthesia needs to be individualized based on each patient's requirements after careful analysis of the risk-benefit ratio of general versus regional. Regional anesthesia was successfully administered for this patient.}, } @article {pmid38025276, year = {2023}, author = {Audrain, M and Egesipe, AL and Tentillier, N and Font, L and Ratnam, M and Mottier, L and Clavel, M and Le Roux-Bourdieu, M and Fenyi, A and Ollier, R and Chevalier, E and Guilhot, F and Fuchs, A and Piorkowska, K and Carlyle, B and Arnold, SE and Berry, JD and Luthi-Carter, R and Adolfsson, O and Pfeifer, A and Kosco-Vilbois, M and Seredenina, T and Afroz, T}, title = {Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in CSF.}, journal = {Brain communications}, volume = {5}, number = {6}, pages = {fcad306}, pmid = {38025276}, issn = {2632-1297}, abstract = {In amyotrophic lateral sclerosis, a disease driven by abnormal transactive response DNA-binding protein of 43 kDa aggregation, CSF may contain pathological species of transactive response DNA-binding protein of 43 kDa contributing to the propagation of pathology and neuronal toxicity. These species, released in part by degenerating neurons, would act as a template for the aggregation of physiological protein contributing to the spread of pathology in the brain and spinal cord. In this study, a robust seed amplification assay was established to assess the presence of seeding-competent transactive response DNA-binding protein of 43 kDa species in CSF of apparently sporadic amyotrophic lateral sclerosis patients. These samples resulted in a significant acceleration of substrate aggregation differentiating the kinetics from healthy controls. In parallel, a second assay was developed to determine the level of target engagement that would be necessary to neutralize such species in human CSF by a therapeutic monoclonal antibody targeting transactive response DNA-binding protein of 43 kDa. For this, evaluation of the pharmacokinetic/pharmacodynamic effect for the monoclonal antibody, ACI-5891.9, in vivo and in vitro confirmed that a CSF concentration of ≍1100 ng/mL would be sufficient for sustained target saturation. Using this concentration in the seed amplification assay, ACI-5891.9 was able to neutralize the transactive response DNA-binding protein of 43 kDa pathogenic seeds derived from amyotrophic lateral sclerosis patient CSF. This translational work adds to the evidence of transmission of transactive response DNA-binding protein of 43 kDa pathology via CSF that could contribute to the non-contiguous pattern of clinical manifestations observed in amyotrophic lateral sclerosis and demonstrates the ability of a therapeutic monoclonal antibody to neutralize the toxic, extracellular seeding-competent transactive response DNA-binding protein of 43 kDa species in the CSF of apparently sporadic amyotrophic lateral sclerosis patients.}, } @article {pmid38022694, year = {2023}, author = {Maselli, F and D'Antona, S and Utichi, M and Arnaudi, M and Castiglioni, I and Porro, D and Papaleo, E and Gandellini, P and Cava, C}, title = {Computational analysis of five neurodegenerative diseases reveals shared and specific genetic loci.}, journal = {Computational and structural biotechnology journal}, volume = {21}, number = {}, pages = {5395-5407}, pmid = {38022694}, issn = {2001-0370}, abstract = {Neurodegenerative diseases (ND) are heterogeneous disorders of the central nervous system that share a chronic and selective process of neuronal cell death. A computational approach to investigate shared genetic and specific loci was applied to 5 different ND: Amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), and Lewy body dementia (LBD). The datasets were analyzed separately, and then we compared the obtained results. For this purpose, we applied a genetic correlation analysis to genome-wide association datasets and revealed different genetic correlations with several human traits and diseases. In addition, a clumping analysis was carried out to identify SNPs genetically associated with each disease. We found 27 SNPs in AD, 6 SNPs in ALS, 10 SNPs in PD, 17 SNPs in MS, and 3 SNPs in LBD. Most of them are located in non-coding regions, with the exception of 5 SNPs on which a protein structure and stability prediction was performed to verify their impact on disease. Furthermore, an analysis of the differentially expressed miRNAs of the 5 examined pathologies was performed to reveal regulatory mechanisms that could involve genes associated with selected SNPs. In conclusion, the results obtained constitute an important step toward the discovery of diagnostic biomarkers and a better understanding of the diseases.}, } @article {pmid38022487, year = {2023}, author = {Li, X and Liu, Q and Niu, T and Jia, H and Liu, T and Xin, Z and Li, Z and Zhou, X and Li, R and Liu, Y and Dong, H}, title = {Sleep Disturbances as a Potential Risk Factor for Deterioration of Respiratory Function in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Annals of Indian Academy of Neurology}, volume = {26}, number = {5}, pages = {754-760}, pmid = {38022487}, issn = {0972-2327}, abstract = {OBJECTIVES: Sleep disturbances are common in amyotrophic lateral sclerosis (ALS). However, previous studies have explored sleep quality at the cross-sectional level and the longitudinal variability characteristics are currently unknown. Our study aimed to longitudinally explore the effect of sleep quality on disease progression in patients with ALS.

METHODS: All enrolled patients with ALS were first diagnosed and completed the 6- and 12-month follow-ups. Subjective sleep disturbance was assessed using the Pittsburgh Sleep Quality Index (PSQI). Based on the PSQI score at baseline, patients with ALS were classified as poor sleepers (PSQI >5) and good sleepers (PSQI ≤5). Disease progression was assessed using the rate of disease progression, the absolute change from baseline forced vital capacity (ΔFVC) and the percentage change from baseline FVC (ΔFVC%) over the follow-up period.

RESULTS: Sixty-three patients were included in the study, 24 (38.1%) were poor sleepers and 39 were good sleepers. The percentage of patients with poor sleep quality was 38.1% at baseline, increasing to 60.3% and 74.6% at 6- and 12-month, respectively. Compared to good sleepers, ΔFVC and ΔFVC% values were greater in poor sleepers (P < 0.001 and P = 0.001, respectively). Poor sleep quality at diagnosis is associated with rapid deterioration of respiratory function during disease progression.

CONCLUSIONS: Sleep disturbances maybe a potential risk factor for deterioration of respiratory function in patients with ALS. The role of sleep disturbances in disease progression deserves attention, and early assessment and intervention may slow disease progression and improve life quality of patients with ALS.}, } @article {pmid38022476, year = {2023}, author = {Chawla, T and Goyal, V}, title = {Tofersen: Silver Lining or Hyperbole??.}, journal = {Annals of Indian Academy of Neurology}, volume = {26}, number = {5}, pages = {638-640}, pmid = {38022476}, issn = {0972-2327}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of anterior horn cells with a dismal prognosis. Over a century since its description, we still do not have a cure for this disorder. Edaravone, Riluzole, and combination of phenylbutyrate and taurursodiol are a handful of FDA-approved drugs that only delay the progression of the disease by a few months. Tofersen, an antisense oligonucleotide, in SOD1 related ALS, has joined the bandwagon of FDA-approved drugs for ALS recently. It is a gene therapy that has been found to lower SOD1 concentrations and neurofilament light chain concentrations in blood and CSF, a known biomarker of ALS, leading to the accelerated approval of the drug. Although it did not show any statistically significant clinical improvement. In this article, we discuss the development and approval process of the first gene-based therapy, Tofersen, for ALS.}, } @article {pmid38022431, year = {2023}, author = {Hiew, FL}, title = {Sleep and Survival in Amyotrophic Lateral Sclerosis (ALS): The Parallelism in Motor and Non-Motor Progression.}, journal = {Annals of Indian Academy of Neurology}, volume = {26}, number = {5}, pages = {628}, pmid = {38022431}, issn = {0972-2327}, } @article {pmid38022117, year = {2023}, author = {Jain, A and Madkan, S and Patil, P}, title = {The Role of Gut Microbiota in Neurodegenerative Diseases: Current Insights and Therapeutic Implications.}, journal = {Cureus}, volume = {15}, number = {10}, pages = {e47861}, pmid = {38022117}, issn = {2168-8184}, abstract = {Small microscopic entities known as microbes, having a population of hundreds of billions or perhaps even in trillions, reside in our gastrointestinal tract. A healthy immune system, digestion, and creation of vitamins and enzymes are all thanks to these microbes. However, new research has shown a hitherto unrecognized connection between the microbiota of the intestines and the genesis of neurodegenerative diseases. Neurons in the CNS gradually deteriorate in neurodegenerative illnesses like multiple sclerosis and Parkinson's disease (PD). This deterioration impairs cognitive and physical function. Amyotrophic lateral sclerosis (ALS), PD, and Alzheimer's disease (AD) are just a few examples of neurodegenerative illnesses that pose a serious threat to world health and have few effective treatments. Recent research suggests that the gut microbiota, a diverse microbial population found in the gastrointestinal system, may substantially impact the cause and development of various diseases. The discovery of altered gut microbiota composition in people with these illnesses is one of the most critical lines of evidence connecting gut microbiota dysbiosis to neurodegenerative diseases. AD patients have a distinct characteristic of having a particular microbiota profile. In addition, an excess population of a specific microbe data profile is seen as compared to a healthy individual. Similar changes in the gut microbiota composition have been noted in people with multiple sclerosis and PD. The latest study indicates the potential that dysbiosis, a condition characterized by alteration in the intestinal microbiota's makeup and functioning, may have an effect on the onset and progression of neurodegenerative diseases, including PD and multiple sclerosis. In order to emphasize any potential underlying mechanisms and examine potential treatment repercussions, the review article's goal is to summarize current knowledge about the connection between gut microbiota and neurodegenerative disorders. The review article aims to summarize current knowledge about the connection between gut microbiota and neurodegenerative disorders, highlighting potential underlying mechanisms and examining potential treatment repercussions.}, } @article {pmid38021968, year = {2023}, author = {Munoz, NR and Agwuegbo, CC and Ghorbani, A and Vincent Coralde, JM and Abdelmalik, R}, title = {Takotsubo Cardiomyopathy Induced by Stress From Amyotrophic Lateral Sclerosis and a Mechanical Fall.}, journal = {Cureus}, volume = {15}, number = {10}, pages = {e47068}, pmid = {38021968}, issn = {2168-8184}, abstract = {Named after the Japanese octopus trap, Takotsubo cardiomyopathy is an acute myocardial condition characterized by a reversible ventricular dysfunction with ballooning of the left ventricle (LV) during systole. A catecholamine surge is likely the primary mechanism responsible for myocardial damage in this condition. The association between amyotrophic lateral sclerosis (ALS) and Takotsubo cardiomyopathy has not been well established. We present a unique case of Takotsubo cardiomyopathy diagnosed in a patient with ALS who presented after a fall with shortness of breath, generalized weakness, and hypotension. She was found to have troponinemia, elevated brain natriuretic peptide, and Osborn waves without ST-segment changes noted on electrocardiography (EKG). The diagnosis of Takotsubo cardiomyopathy was confirmed via transthoracic echocardiography (TTE), which revealed reduced left ventricular ejection fraction, apical ballooning of the LV, akinesis of the ventricular apex, and hyperkinesis of the base of the heart. Coronary angiography revealed no coronary artery disease. She was managed medically and was hemodynamically stable at the time of discharge.}, } @article {pmid38020614, year = {2023}, author = {Xu, D and Chu, M and Chen, Y and Fang, Y and Wang, J and Zhang, X and Xu, F}, title = {Identification and verification of ferroptosis-related genes in the pathology of epilepsy: insights from CIBERSORT algorithm analysis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1275606}, pmid = {38020614}, issn = {1664-2295}, abstract = {BACKGROUND: Epilepsy is a neurological disorder characterized by recurrent seizures. A mechanism of cell death regulation, known as ferroptosis, which involves iron-dependent lipid peroxidation, has been implicated in various diseases, including epilepsy.

OBJECTIVE: This study aimed to provide a comprehensive understanding of the relationship between ferroptosis and epilepsy through bioinformatics analysis. By identifying key genes, pathways, and potential therapeutic targets, we aimed to shed light on the underlying mechanisms involved in the pathogenesis of epilepsy.

MATERIALS AND METHODS: We conducted a comprehensive analysis by screening gene expression data from the Gene Expression Omnibus (GEO) database and identified the differentially expressed genes (DEGs) related to ferroptosis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to gain insights into the biological processes and pathways involved. Moreover, we constructed a protein-protein interaction (PPI) network to identify hub genes, which was further validated using the receiver operating characteristic (ROC) curve analysis. To explore the relationship between immune infiltration and genes, we employed the CIBERSORT algorithm. Furthermore, we visualized four distinct interaction networks-mRNA-miRNA, mRNA-transcription factor, mRNA-drug, and mRNA-compound-to investigate potential regulatory mechanisms.

RESULTS: In this study, we identified a total of 33 differentially expressed genes (FDEGs) associated with epilepsy and presented them using a Venn diagram. Enrichment analysis revealed significant enrichment in the pathways related to reactive oxygen species, secondary lysosomes, and ubiquitin protein ligase binding. Furthermore, GSVA enrichment analysis highlighted significant differences between epilepsy and control groups in terms of the generation of precursor metabolites and energy, chaperone complex, and antioxidant activity in Gene Ontology (GO) analysis. Furthermore, during the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we observed differential expression in pathways associated with amyotrophic lateral sclerosis (ALS) and acute myeloid leukemia (AML) between the two groups. To identify hub genes, we constructed a protein-protein interaction (PPI) network using 30 FDEGs and utilized algorithms. This analysis led to the identification of three hub genes, namely, HIF1A, TLR4, and CASP8. The application of the CIBERSORT algorithm allowed us to explore the immune infiltration patterns between epilepsy and control groups. We found that CD4-naïve T cells, gamma delta T cells, M1 macrophages, and neutrophils exhibited higher expression in the control group than in the epilepsy group.

CONCLUSION: This study identified three FDEGs and analyzed the immune cells in epilepsy. These findings pave the way for future research and the development of innovative therapeutic strategies for epilepsy.}, } @article {pmid38020597, year = {2023}, author = {Nakamura, R and Kurihara, M and Kobashi, S and Tamaki, Y and Ogawa, N and Kitamura, A and Yamakawa, I and Bamba, S and Terashima, T and Urushitani, M}, title = {Ideal body weight-based determination of minimum oral calories beneficial to function and survival in ALS.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1286153}, pmid = {38020597}, issn = {1664-2295}, abstract = {INTRODUCTION: This study sought to identify the optimal caloric intake to improve function and survival in ALS patients by comparing oral intake per ideal body weight (IBW) and its discrepancy with total energy expenditure (TEE) using the Shimizu formula.

METHODS: A retrospective analysis of 104 ALS patients was conducted, categorizing them based on their average intake during the first week after admission using two primary intake cutoffs: 25 kcal/kgIBW and 30 kcal/kgIBW. The variance between oral intake and TEE was also evaluated using -300 kcal and 0 kcal as reference points.

RESULTS: Oral caloric intake per IBW and functional decline rate (rs = -0.35, p < 0.001), but the variance from TEE was not significantly correlated (-0.11, p = 0.27). Survival data showed that patients consuming less than 25 kcal/kgIBW had a median survival of 24 months, increasing to 38 months for those consuming between 25-30 kcal/kgIBW and 63 months for those consuming 30 kcal/kgIBW or more. Deviations from the TEE did not significantly affect survival (p = 0.36). Among patients consuming less than their TEE, those consuming less than 25 kcal/kgIBW had a shorter median survival (24 months) compared to their counterparts (46 months) (p = 0.022). Consumption of less than 25 kcal/kgBW emerged as a significant negative predictor of patient outcome, independent of factors such as age, gender or disease progression.

DISCUSSION: Intakes of 25 kcal/kgIBW or more are correlated with improved ALS outcomes, and larger, multi-regional studies are recommended for deeper insights.}, } @article {pmid38020546, year = {2023}, author = {de Brito Siqueira, ALG and Cremasco, PVV and Bahú, JO and Pioli da Silva, A and Melo de Andrade, LR and González, PGA and Crivellin, S and Cárdenas Concha, VO and Krambeck, K and Lodi, L and Severino, P and Souto, EB}, title = {Phytocannabinoids: Pharmacological effects, biomedical applications, and worldwide prospection.}, journal = {Journal of traditional and complementary medicine}, volume = {13}, number = {6}, pages = {575-587}, pmid = {38020546}, issn = {2225-4110}, abstract = {Scientific evidence exists about the association between neurological diseases (i.e., Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, depression, and memory loss) and oxidative damage. The increasing worldwide incidence of such diseases is attracting the attention of researchers to find palliative medications to reduce the symptoms and promote quality of life, in particular, in developing countries, e.g., South America and Africa. Among potential alternatives, extracts of Cannabis Sativa L. are suitable for people who have neurological disorders, spasticity, and pain, nausea, resulting from diseases such as cancer and arthritis. In this review, we discuss the latest developments in the use of Cannabis, its subtypes and constituents, extraction methods, and relevant pharmacological effects. Biomedical applications, marketed products, and prospects for the worldwide use of Cannabis Sativa L. extracts are also discussed, providing the bibliometric maps of scientific literature published in representative countries from South America (i.e., Brazil) and Africa (i.e., South Africa). A lack of evidence on the effectiveness and safety of Cannabis, besides the concerns about addiction and other adverse events, has led many countries to act with caution before changing Cannabis-related regulations. Recent findings are expected to increase the social acceptance of Cannabis, while new technologies seem to boost the global cannabis market because the benefits of (-)-trans-delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) use have been proven in several studies in addition to the potential to general new employment.}, } @article {pmid38020004, year = {2023}, author = {Du, W and Yan, M and Yin, C and Zhang, Z}, title = {A novel modified nano-alumina composite sol for potential application in forest firefighting.}, journal = {RSC advances}, volume = {13}, number = {48}, pages = {33820-33825}, pmid = {38020004}, issn = {2046-2069}, abstract = {Herein, modified ammonium polyphosphate wrapped nano-alumina (mAPP@Als) was first synthesized and then dispersed in traditional fire extinguishing solution (FES) to fabricate a FES-mAPP@Als composite sol. It was found that the phosphorus-silica containing units were attached onto the nano-alumina surface, and the mAPP@Als particles showed excellent dispersion level in FES with a single-domain particle size distribution range. Due to the synergistic effects of the phosphorus-nitrogen and silica-alumina flame retardant components, FES-mAPP@Als (5% concentration) coated wood exhibited improved limiting oxygen index (33.2%) and carbonization ability, and depressed heat release (41.9%) and smoke production (10.7%), as compared to the pristine wood. In addition, the FES-mAPP@Als composite sol showed enhanced fire-extinguishing and anti-reignition capacities compared to the FES. This research offers a novel composite sol fire extinguishing agent for fighting forest fires.}, } @article {pmid38019651, year = {2023}, author = {Harley, P and Kerins, C and Gatt, A and Neves, G and Riccio, F and Machado, CB and Cheesbrough, A and R'Bibo, L and Burrone, J and Lieberam, I}, title = {Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons.}, journal = {Cell reports}, volume = {42}, number = {12}, pages = {113509}, doi = {10.1016/j.celrep.2023.113509}, pmid = {38019651}, issn = {2211-1247}, support = {MR/N025865/1/MRC_/Medical Research Council/United Kingdom ; MR/N026063/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Axon Initial Segment/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; Action Potentials/physiology ; }, abstract = {Dysregulated neuronal excitability is a hallmark of amyotrophic lateral sclerosis (ALS). We sought to investigate how functional changes to the axon initial segment (AIS), the site of action potential generation, could impact neuronal excitability in ALS human induced pluripotent stem cell (hiPSC) motor neurons. We find that early TDP-43 and C9orf72 hiPSC motor neurons show an increase in the length of the AIS and impaired activity-dependent AIS plasticity that is linked to abnormal homeostatic regulation of neuronal activity and intrinsic hyperexcitability. In turn, these hyperactive neurons drive increased spontaneous myofiber contractions of in vitro hiPSC motor units. In contrast, late hiPSC and postmortem ALS motor neurons show AIS shortening, and hiPSC motor neurons progress to hypoexcitability. At a molecular level, aberrant expression of the AIS master scaffolding protein ankyrin-G and AIS-specific voltage-gated sodium channels mirror these dynamic changes in AIS function and excitability. Our results point toward the AIS as an important site of dysfunction in ALS motor neurons.}, } @article {pmid38019415, year = {2024}, author = {Zhu, Y and Li, M and Wang, H and Yang, F and Du, R and Pang, X and Bai, J and Huang, X}, title = {Mendelian Randomization Identifies Genetically Supported Drug Targets for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Molecular neurobiology}, volume = {61}, number = {7}, pages = {3809-3818}, pmid = {38019415}, issn = {1559-1182}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Frontotemporal Dementia/genetics/drug therapy ; Humans ; *Mendelian Randomization Analysis/methods ; Genome-Wide Association Study ; Quantitative Trait Loci ; Drug Repositioning/methods ; }, abstract = {Currently, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have no effective treatments. Drug repurposing offers a rapid method to meet therapeutic need for ALS and FTD. To identify therapeutic targets associated with ALS and FTD, Mendelian randomization (MR) analysis and colocalization were performed. Genetic instruments were based on transcriptomic and proteomic data for 422 actionable proteins targeted by approved drugs or clinical drug candidates. The publicly available ALS GWAS summary data (including a total of 20,806 ALS cases and 59,804 controls) and FTD GWAS summary data (including a total of 2154 patients with FTD and 4308 controls) were used. Using cis-expression quantitative trait loci and cis-protein quantitative trait loci genetic instruments, we identified several drug targets for repurposing (ALS: MARK3, false-discovery rate (FDR) = 0.043; LTBR, FDR = 0.068) (FTD: HLA-DRB1, FDR = 0.083; ADH5, FDR = 0.056). Our MR study analyzed the actionable druggable proteins and provided potential therapeutic targets for ALS and FTD. Future studies should further elucidate the underlying mechanism of corresponding drug targets in the pathogenesis of ALS and FTD.}, } @article {pmid38019311, year = {2023}, author = {Rothstein, JD and Baskerville, V and Rapuri, S and Mehlhop, E and Jafar-Nejad, P and Rigo, F and Bennett, F and Mizielinska, S and Isaacs, A and Coyne, AN}, title = {G2C4 targeting antisense oligonucleotides potently mitigate TDP-43 dysfunction in human C9orf72 ALS/FTD induced pluripotent stem cell derived neurons.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {1}, pmid = {38019311}, issn = {1432-0533}, support = {R00 NS123242/NS/NINDS NIH HHS/United States ; R01 NS132836/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Oligonucleotides, Antisense/pharmacology ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; *Induced Pluripotent Stem Cells ; DNA-Binding Proteins/genetics ; RNA, Antisense ; Dipeptides ; Neurons ; }, abstract = {The G4C2 repeat expansion in the C9orf72 gene is the most common genetic cause of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Many studies suggest that dipeptide repeat proteins produced from this repeat are toxic, yet, the contribution of repeat RNA toxicity is under investigated and even less is known regarding the pathogenicity of antisense repeat RNA. Recently, two clinical trials targeting G4C2 (sense) repeat RNA via antisense oligonucleotide failed despite a robust decrease in sense-encoded dipeptide repeat proteins demonstrating target engagement. Here, in this brief report, we show that G2C4 antisense, but not G4C2 sense, repeat RNA is sufficient to induce TDP-43 dysfunction in induced pluripotent stem cell (iPSC) derived neurons (iPSNs). Unexpectedly, only G2C4, but not G4C2 sense strand targeting, ASOs mitigate deficits in TDP-43 function in authentic C9orf72 ALS/FTD patient iPSNs. Collectively, our data suggest that the G2C4 antisense repeat RNA may be an important therapeutic target and provide insights into a possible explanation for the recent G4C2 ASO clinical trial failure.}, } @article {pmid38018433, year = {2023}, author = {Naylor, K and Chrzanowska-Wąsik, M and Okońska, P and Kucmin, T and Al-Wathinani, AM and Goniewicz, K}, title = {Adapting to a Pandemic: Web-Based Residency Training and Script Concordance Testing in Emergency Medicine During COVID-19.}, journal = {Disaster medicine and public health preparedness}, volume = {17}, number = {}, pages = {e541}, doi = {10.1017/dmp.2023.195}, pmid = {38018433}, issn = {1938-744X}, mesh = {Humans ; Child ; *Internship and Residency ; Educational Measurement/methods ; Pandemics ; *COVID-19/epidemiology ; Education, Medical, Continuing/methods ; *Emergency Medicine/education ; Clinical Competence ; Internet ; }, abstract = {OBJECTIVE: The coronavirus disease (COVID-19) pandemic necessitated alternative methods to ensure the continuity of medical education. Our study explores the efficacy and acceptability of a digital continuous medical education initiative for medical residents during this challenging period.

METHODS: From September to December 2020, 47 out of 60 enrolled trainee doctors participated in this innovative digital Continuous Medical Education (CME) approach. We utilized the Script Concordance Test to bolster clinical reasoning skills. Three simulation scenarios, namely Advanced Trauma Life Support (ATLS), Advanced Life Support (ALS), and European Paediatric Life Support (EPLS), were transformed into interactive online sessions via Zoom™. Participant feedback was also collected through a survey.

RESULTS: Consistent Script Concordance Testing (SCT) scores among participants indicated the effectiveness of the online training module. Feedback suggested a broad acceptance of this novel training approach. However, discrepancies observed between formative SCT scores, and summative Multiple-Choice Questions (MCQ) assessments highlighted areas for potential refinement.

CONCLUSIONS: Our findings showcase the resilience and adaptability of medical education amidst challenges like the global pandemic. The success of methodologies such as SCT, endorsed by prestigious bodies like the European Resuscitation Council and the American Heart Association, suggests their potential in preparing health care professionals for emergent situations. This research offers valuable insights for shaping future online CME strategies.}, } @article {pmid38018200, year = {2024}, author = {Monteiro, KLC and de Aquino, TM and da Silva-Júnior, EF}, title = {Natural Compounds as Inhibitors of Aβ Peptide and Tau Aggregation.}, journal = {CNS & neurological disorders drug targets}, volume = {23}, number = {10}, pages = {1234-1250}, pmid = {38018200}, issn = {1996-3181}, mesh = {Humans ; *tau Proteins/metabolism/antagonists & inhibitors ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Biological Products/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Plaque, Amyloid/drug therapy/metabolism ; Protein Aggregation, Pathological/drug therapy ; Neurofibrillary Tangles/drug effects/metabolism ; }, abstract = {Neurodegenerative conditions like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) encompass disorders characterized by the degeneration of neurons in specific circumstances. The quest for novel agents to influence these diseases, particularly AD, has unearthed various natural compounds displaying multifaceted activities and diverse pharmacological mechanisms. Given the ongoing extensive study of pathways associated with the accumulation of neurofibrillary aggregates and amyloid plaques, this paper aims to comprehensively review around 130 studies exploring natural products. These studies focus on inhibiting the formation of amyloid plaques and tau protein tangles, with the objective of potentially alleviating or delaying AD.}, } @article {pmid38018119, year = {2024}, author = {Brown, A and Armon, C and Barkhaus, P and Beauchamp, M and Bertorini, T and Bromberg, M and Cadavid, JM and Carter, GT and Crayle, J and Feldman, EL and Heiman-Patterson, T and Jhooty, S and Linares, A and Li, X and Mallon, E and Mcdermott, C and Mushannen, T and Nathaniel, G and Pattee, G and Pierce, K and Ratner, D and Slactova, L and Wicks, P and Bedlack, R}, title = {ALSUntangled #72: Insulin.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {416-419}, doi = {10.1080/21678421.2023.2288110}, pmid = {38018119}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Insulin/adverse effects ; }, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review insulin, which has at least one plausible mechanism for slowing ALS progression. However, pre-clinical studies are limited and there have been no trials in PALS yet. Insulin use in patients without a metabolic need may cause very serious and potentially lethal side effects. While further studies to evaluate potential benefits may be warranted, at this time we cannot endorse insulin treatment to slow ALS progression.}, } @article {pmid38017952, year = {2023}, author = {Li, Y and Chen, M and Qi, J and Deng, C and Du, L and Bo, Z and Han, C and Mao, Z and He, Y and Shao, X and Han, S}, title = {Underwater ghost imaging with detection distance up to 9.3 attenuation lengths.}, journal = {Optics express}, volume = {31}, number = {23}, pages = {38457-38474}, doi = {10.1364/OE.499186}, pmid = {38017952}, issn = {1094-4087}, abstract = {Underwater ghost imaging LiDAR is an effective method of underwater detection. In this research, theoretical and experimental investigations were conducted on underwater ghost imaging, combining the underwater optical field transmission model with the inherent optical parameters of a water body. In addition, the Wells model and the approximate Sahu-Shanmugam scattering phase function were used to create a model for underwater optical transmission. The second-order Glauber function of the optical field was then employed to analyze the scattering field degradation during the transmission process. The simulation and experimental results verified that the proposed underwater model could better reveal the degrading effect of a water body on ghost imaging. A further series of experiments comparing underwater ghost imaging at different detection distances was also conducted. In the experimental system, gated photomultiplier tube (PMT) was used to filter out the peak of backscattering, allowing a larger gain to be set for longer-range detection of the target. The laser with a central wavelength of 532 nm was operated at a frequency of 2 KHz, with a single pulse energy of 2 mJ, a pulse width of 10 ns. High-reflective targets were imaged up to 65.2 m (9.3 attenuation lengths (ALs), attenuation coefficient c = 0.1426 m[-1], and scattering coefficient b = 0.052 m[-1]) and diffuse-reflection targets up to 41.2 m (6.4 ALs, c = 0.1569 m[-1], and b = 0.081 m[-1]). For the Jerlov-I (c = 0.048 m[-1] and b = 0.002 m[-1]) water body, the experimentally obtained maximum detection distance of 9.3 ALs can be equivalent to 193.7 m under the same optical system conditions.}, } @article {pmid38015828, year = {2023}, author = {Iyer, AK and Schoch, KM and Verbeck, A and Galasso, G and Chen, H and Smith, S and Oldenborg, A and Miller, TM and Karch, CM and Bonni, A}, title = {Targeted ASO-mediated Atp1a2 knockdown in astrocytes reduces SOD1 aggregation and accelerates disease onset in mutant SOD1 mice.}, journal = {PloS one}, volume = {18}, number = {11}, pages = {e0294731}, pmid = {38015828}, issn = {1932-6203}, support = {R01 NS078398/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; Astrocytes/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Motor Neurons/metabolism ; Sodium-Potassium-Exchanging ATPase/metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Astrocyte-specific ion pump α2-Na+/K+-ATPase plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Here, we test the effect of Atp1a2 mRNA-specific antisense oligonucleotides (ASOs) to induce α2-Na+/K+-ATPase knockdown in the widely used ALS animal model, SOD1*G93A mice. Two ASOs led to efficient Atp1a2 knockdown and significantly reduced SOD1 aggregation in vivo. Although Atp1a2 ASO-treated mice displayed no off-target or systemic toxicity, the ASO-treated mice exhibited an accelerated disease onset and shorter lifespan than control mice. Transcriptomics studies reveal downregulation of genes involved in oxidative response, metabolic pathways, trans-synaptic signaling, and upregulation of genes involved in glutamate receptor signaling and complement activation, suggesting a potential role for these molecular pathways in de-coupling SOD1 aggregation from survival in Atp1a2 ASO-treated mice. Together, these results reveal a role for α2-Na+/K+-ATPase in SOD1 aggregation and highlight the critical effect of temporal modulation of genetically validated therapeutic targets in neurodegenerative diseases.}, } @article {pmid38014926, year = {2024}, author = {Giometto, S and Finocchietti, M and Paoletti, O and Lombardi, N and Celani, MG and Sciancalepore, F and Lucenteforte, E and Kirchmayer, U and , }, title = {Adherence to riluzole therapy in patients with amyotrophic lateral sclerosis in three Italian regions-The CAESAR study.}, journal = {Pharmacoepidemiology and drug safety}, volume = {33}, number = {1}, pages = {e5736}, doi = {10.1002/pds.5736}, pmid = {38014926}, issn = {1099-1557}, support = {//Agenzia Italiana del Farmaco, Ministero della Salute/ ; }, mesh = {Male ; Humans ; Aged ; Riluzole/adverse effects ; *Amyotrophic Lateral Sclerosis/drug therapy/epidemiology/chemically induced ; Retrospective Studies ; *Neurodegenerative Diseases/chemically induced/drug therapy ; *Neuroprotective Agents/therapeutic use ; Italy/epidemiology ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease. Riluzole may increase survival and delay the need for mechanical ventilation. The CAESAR project ('Comparative evaluation of the efficacy and safety of drugs used in rare neuromuscular and neurodegenerative diseases', FV AIFA project 2012-2013-2014) involves evaluating prescribing patterns, and analysing effectiveness and comparative safety of drugs, in patients with neurodegenerative diseases. The aim of this study is to evaluate adherence to riluzole in patients with ALS during the first year of use, identifying adherence clusters.

METHODS: A retrospective cohort study was conducted using administrative data from Latium, Tuscany, and Umbria. We identified subjects with a new diagnosis of ALS between 2014 and 2019, with the first dispensation of riluzole within 180 days of diagnosis. We considered a two-year look-back period for the characterization of patients, and we followed them from the date of first dispensing of riluzole for 1 year. We calculated 12 monthly adherence measures, through a modified version of the Medication Possession Ratio, estimating drug coverage with Defined Daily Dose. Adherence trajectories were identified using a three-step method: (1) calculation of statistical measures; (2) principal component analysis; (3) cluster analysis. Patient characteristics at baseline and during follow-up were described and compared between adherence groups identified.

RESULTS: We included 264 ALS patients as new users of riluzole in Latium, 344 in Tuscany, and 63 in Umbria. We observed a higher frequency of males (56.2%) and a mean age of 67.4 (standard deviation, SD, 10.4) in the overall population. We identified two clusters in all regions: one more numerous, including adherent patients (60%, 74%, 88%, respectively), and another one including patients who discontinued therapy (40%, 26%, 12%, respectively). In Tuscany patients discontinuing riluzole more frequently died (28.6% vs. 15.4%, p-value <0.01). Additionally, low-adherers had a higher frequency of central nervous system disorders (69.0% vs. 52.5%, p-value 0.01), and a greater use of non-pharmacological treatments (p-values ≤0.01 for invasive ventilation and tracheostomy). We did not observe any differences in Lazio, whereas in Umbria we observed a higher use of drugs for dementia-related psychiatric problems among low-adherers (57.1% vs. 7.8%, respectively, p-value <0.01), although with small numbers.

CONCLUSION: Most ALS patients who start riluzole adhere to therapy during the first year. Patients who discontinue therapy early show greater fragility and mortality.}, } @article {pmid38014869, year = {2024}, author = {Li, X and Pura, J and Allen, A and Owzar, K and Lu, J and Harms, M and Xie, J}, title = {DYNATE: Localizing rare-variant association regions via multiple testing embedded in an aggregation tree.}, journal = {Genetic epidemiology}, volume = {48}, number = {1}, pages = {42-55}, pmid = {38014869}, issn = {1098-2272}, support = {R01 HG012555/HG/NHGRI NIH HHS/United States ; 1R01HG012555-01/GF/NIH HHS/United States ; }, mesh = {Humans ; *Genetic Variation ; *Trees ; Models, Genetic ; Genetic Association Studies ; Mutation ; Genome-Wide Association Study/methods ; Autophagy-Related Proteins ; Vesicular Transport Proteins ; }, abstract = {Rare-variants (RVs) genetic association studies enable researchers to uncover the variation in phenotypic traits left unexplained by common variation. Traditional single-variant analysis lacks power; thus, researchers have developed various methods to aggregate the effects of RVs across genomic regions to study their collective impact. Some existing methods utilize a static delineation of genomic regions, often resulting in suboptimal effect aggregation, as neutral subregions within the test region will result in an attenuation of signal. Other methods use varying windows to search for signals but often result in long regions containing many neutral RVs. To pinpoint short genomic regions enriched for disease-associated RVs, we developed a novel method, DYNamic Aggregation TEsting (DYNATE). DYNATE dynamically and hierarchically aggregates smaller genomic regions into larger ones and performs multiple testing for disease associations with a controlled weighted false discovery rate. DYNATE's main advantage lies in its strong ability to identify short genomic regions highly enriched for disease-associated RVs. Extensive numerical simulations demonstrate the superior performance of DYNATE under various scenarios compared with existing methods. We applied DYNATE to an amyotrophic lateral sclerosis study and identified a new gene, EPG5, harboring possibly pathogenic mutations.}, } @article {pmid38014622, year = {2023}, author = {Yamashita, T and Nakano, Y and Sasaki, R and Tadokoro, K and Omote, Y and Yunoki, T and Kawahara, Y and Matsumoto, N and Taira, Y and Matsuoka, C and Morihara, R and Abe, K}, title = {Safety and Clinical Effects of a Muse Cell-Based Product in Patients With Amyotrophic Lateral Sclerosis: Results of a Phase 2 Clinical Trial.}, journal = {Cell transplantation}, volume = {32}, number = {}, pages = {9636897231214370}, pmid = {38014622}, issn = {1555-3892}, mesh = {Animals ; Mice ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Alprostadil/therapeutic use ; Interleukin-6 ; Tumor Necrosis Factor-alpha ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons. Multilineage-differentiating stress-enduring (Muse) cells are unique endogenous stem cells that show therapeutic effects on motor function in ALS mouse models. We conducted a single-center open phase II clinical trial to evaluate the safety and clinical effects of repeated intravenous injections of an allogenic Muse cell-based product, CL2020, in patients with ALS. Five patients with ALS received CL2020 intravenously once a month for a total of six doses. The primary endpoints were safety and tolerability, and the secondary endpoint was the rate of change in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score. In addition, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), sphingosine-1-phosphate (S1P), cerebrospinal fluid chitotriosidase-1 (CHIT-1), and neurofilament light chain (NfL) levels were evaluated. The CL2020 treatment was highly tolerated without serious side effects. The ALSFRS-R score change trended upward at 12 months post-CL2020 treatment compared with that at 3 months pre-administration, but the difference was not statistically significant. Among five patients diagnosed with ALS, three exhibited a decrease in the rate of ALSFRS-R score change, one demonstrated an increase, and another showed no change. In addition, the patients' serum IL-6 and TNF-α levels and cerebrospinal fluid CHIT-1 and NfL levels increased for up to 6 months post-treatment; however, their serum S1P levels continuously decreased over 12 months. These findings indicate a favorable safety profile of CL2020 therapy. In the near future, a double-blind study of a larger number of ALS patients should be conducted to confirm the efficacy of ALS treatment with CL2020.}, } @article {pmid38014545, year = {2023}, author = {Pestelacci, S and Hofer-Inteeworn, N and Dennler, M and Glaus, T}, title = {Balloon dilation and transient stenting of unilateral membranous choanal atresia in a British Shorthair cat with chronic purulent rhinitis and ascending meningoencephalitis.}, journal = {Schweizer Archiv fur Tierheilkunde}, volume = {165}, number = {12}, pages = {793-800}, doi = {10.17236/sat00414}, pmid = {38014545}, issn = {1664-2848}, mesh = {Humans ; Animals ; Cats ; *Rhinitis/surgery/veterinary ; *Choanal Atresia/surgery/veterinary ; Constriction, Pathologic/surgery/veterinary ; Dilatation/veterinary ; *Cat Diseases/surgery ; }, abstract = {Choanal atresia is a rare congenital anomaly in humans and animals, characterized by the absence of communication of one or both nasal cavities with the nasopharynx. The severity of clinical signs depends on the presence of unilateral versus bilateral stenosis as well as comorbidities. With bilateral atresia, respiration may be severely compromised particularly during sleep, as airflow can only occur when breathing through the open mouth. Various therapeutic modalities have been described in people and adopted for animals. All treatments may be associated with complications, the most important being post-therapeutic scar formation with re-stenosis. This report describes a 10-month-old British Shorthair cat with chronic unilateral serosal nasal discharge that changed to mucopurulent discharge. When acute neurological signs developed, the cat was presented to the veterinary hospital. A diagnosis of primary, membranous right sided choanal atresia was achieved via computed tomography (CT) and nasopharyngeal (posterior) rhinoscopy. Secondary changes included destructive rhinitis with progression to the CNS with a subdural empyema and meningoencephalitis. Retinal changes and aspiration bronchopneumonia were suspected additional complications. After recovery from the secondary infections, the membranous obstruction was perforated and dilated using a valvuloplasty balloon by an orthograde transnasal approach under endoscopic guidance from a retroflexed nasopharyngeal view. To prevent re-stenosis, a foley catheter was placed as a transient stent for 6 days. The cat recovered uneventfully and was asymptomatic after the stent removal. Endoscopic re-examination after 5 months confirmed a persistent opening and patency of the generated right choanal passage. The cat remains asymptomatic 10 months after the procedure. Transnasal endoscopic balloon dilation and transient stenting of choanal atresia is a minimally invasive and relatively simple procedure with potentially sustained success.}, } @article {pmid38014237, year = {2023}, author = {Alvarado, CX and Weller, CA and Johnson, N and Leonard, HL and Singleton, AB and Reed, X and Blauewendraat, C and Nalls, MA}, title = {Human brain single nucleus cell type enrichments in neurodegenerative diseases.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38014237}, issn = {2693-5015}, support = {Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; ZIA AG000534/ImNIH/Intramural NIH HHS/United States ; ZIA NS003154/ImNIH/Intramural NIH HHS/United States ; }, abstract = {BACKGROUND: Single-cell RNA sequencing has opened a window into clarifying the complex underpinnings of disease, particularly in quantifying the relevance of tissue- and cell-type-specific gene expression.

METHODS: To identify the cell types and genes important to therapeutic target development across the neurodegenerative disease spectrum, we leveraged genome-wide association studies, recent single-cell sequencing data, and bulk expression studies in a diverse series of brain region tissues.

RESULTS: We were able to identify significant immune-related cell types in the brain across three major neurodegenerative diseases: Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. Subsequently, putative roles of 30 fine-mapped loci implicating seven genes in multiple neurodegenerative diseases and their pathogenesis were identified.

CONCLUSIONS: We have helped refine the genetic regions and cell types effected across multiple neurodegenerative diseases, helping focus future translational research efforts.}, } @article {pmid38014203, year = {2023}, author = {Wilkins, OG and Chien, MZYJ and Wlaschin, JJ and Pisliakova, M and Thompson, D and Digby, H and Simkin, RL and Diaz, JA and Mehta, PR and Keuss, MJ and Zanovello, M and Brown, AL and Harley, P and Darbey, A and Karda, R and Fisher, EMC and Cunningham, TJ and Le Pichon, CE and Ule, J and Fratta, P}, title = {Creation of de novo cryptic splicing for ALS/FTD precision medicine.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38014203}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/S006508/1/MRC_/Medical Research Council/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; ZIA HD008966/ImNIH/Intramural NIH HHS/United States ; }, abstract = {A system enabling the expression of therapeutic proteins specifically in diseased cells would be transformative, providing greatly increased safety and the possibility of pre-emptive treatment. Here we describe "TDP-REG", a precision medicine approach primarily for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which exploits the cryptic splicing events that occur in cells with TDP-43 loss-of-function (TDP-LOF) in order to drive expression specifically in diseased cells. In addition to modifying existing cryptic exons for this purpose, we develop a deep-learning-powered algorithm for generating customisable cryptic splicing events, which can be embedded within virtually any coding sequence. By placing part of a coding sequence within a novel cryptic exon, we tightly couple protein expression to TDP-LOF. Protein expression is activated by TDP-LOF in vitro and in vivo, including TDP-LOF induced by cytoplasmic TDP-43 aggregation. In addition to generating a variety of fluorescent and luminescent reporters, we use this system to perform TDP-LOF-dependent genomic prime editing to ablate the UNC13A cryptic donor splice site. Furthermore, we design a panel of tightly gated, autoregulating vectors encoding a TDP-43/Raver1 fusion protein, which rescue key pathological cryptic splicing events. In summary, we combine deep-learning and rational design to create sophisticated splicing sensors, resulting in a platform that provides far safer therapeutics for neurodegeneration, potentially even enabling preemptive treatment of at-risk individuals.}, } @article {pmid38014069, year = {2023}, author = {Yang, S and Wijegunawardana, D and Sheth, U and Veire, AM and Salgado, JMS and Agrawal, M and Zhou, J and Pereira, JD and Gendron, TF and Guo, JU}, title = {Aberrant splicing exonizes C9ORF72 repeat expansion in ALS/FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38014069}, issn = {2692-8205}, support = {DP2 GM132930/GM/NIGMS NIH HHS/United States ; R35 GM152208/GM/NIGMS NIH HHS/United States ; }, abstract = {A nucleotide repeat expansion (NRE) in the first annotated intron of the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While C9 NRE-containing RNAs can be translated into several toxic dipeptide repeat proteins, how an intronic NRE can assess the translation machinery in the cytoplasm remains unclear. By capturing and sequencing NRE-containing RNAs from patient-derived cells, we found that C9 NRE was exonized by the usage of downstream 5' splice sites and exported from the nucleus in a variety of spliced mRNA isoforms. C9ORF72 aberrant splicing was substantially elevated in both C9 NRE[+] motor neurons and human brain tissues. Furthermore, NREs above the pathological threshold were sufficient to activate cryptic splice sites in reporter mRNAs. In summary, our results revealed a crucial and potentially widespread role of repeat-induced aberrant splicing in the biogenesis, localization, and translation of NRE-containing RNAs.}, } @article {pmid38013452, year = {2024}, author = {Smith, EN and Lee, J and Prilutsky, D and Zicha, S and Wang, Z and Han, S and Zach, N}, title = {Plasma neurofilament light levels show elevation two years prior to diagnosis of amyotrophic lateral sclerosis in the UK Biobank.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {170-176}, doi = {10.1080/21678421.2023.2285428}, pmid = {38013452}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Cohort Studies ; Biomarkers ; Biological Specimen Banks ; Intermediate Filaments ; *Neurodegenerative Diseases ; UK Biobank ; Neurofilament Proteins ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease with profound unmet need. In patients carrying genetic mutations, elevations in neurofilament light (NfL) have been shown to precede symptom onset, however, the natural history of NfL in general ALS patients is less characterized.

METHODS: We performed a secondary analysis of the UK Biobank Pharma Proteomics Project (UKB-PPP), a subset of the UK Biobank, a population-based cohort study in the United Kingdom, to examine plasma NfL levels in 237 participants subsequently diagnosed with ALS. We applied logistic and Cox proportional hazards regression to compare cases to 42,752 population-based and 948 age and sex-matched controls. Genetic information was obtained from exome and genotype array data.Results and Conclusions: We observed that NfL was 1.42-fold higher in cases vs population-based controls. At two to three years pre-diagnosis, NfL levels in patients exceeded the 95[th] percentile of age and sex-matched controls. A time-to-diagnosis analysis showed that a 2-fold increase in NfL levels was associated with a 3.4-fold risk of diagnosis per year, with NfL being most predictive of case status at two years (AUC = 0.96). Participants with genetic variation that might put them at risk for familial disease (N = 46) did not show a different pattern of association than those without (N = 191).

DISCUSSION: Our findings show that NfL is elevated and discriminative of future ALS diagnosis up to two years prior to diagnosis in patients with and without genetic risk variants.}, } @article {pmid38013317, year = {2023}, author = {Wang, Z and Yang, H and Han, Y and Teng, J and Kong, X and Qi, X}, title = {Screening and identification of key biomarkers associated with amyotrophic lateral sclerosis and depression using bioinformatics.}, journal = {Medicine}, volume = {102}, number = {47}, pages = {e36265}, pmid = {38013317}, issn = {1536-5964}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Depression/diagnosis/genetics ; Gene Expression Profiling ; *MicroRNAs/genetics ; Biomarkers ; Gene Regulatory Networks ; Computational Biology/methods ; }, abstract = {This study aims to identify common molecular biomarkers between amyotrophic lateral sclerosis (ALS) and depression using bioinformatics methods, in order to provide potential targets and new ideas and methods for the diagnosis and treatment of these diseases. Microarray datasets GSE139384, GSE35978 and GSE87610 were obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) between ALS and depression were identified. After screening for overlapping DEGs, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Furthermore, a protein-protein interaction (PPI) network was constructed using the STRING database and Cytoscape software, and hub genes were identified. Finally, a network between miRNAs and hub genes was constructed using the NetworkAnalyst tool, and possible key miRNAs were predicted. A total of 357 genes have been identified as common DEGs between ALS and depression. GO and KEGG enrichment analyses of the 357 DEGs showed that they were mainly involved in cytoplasmic translation. Further analysis of the PPI network using Cytoscape and MCODE plugins identified 6 hub genes, including mitochondrial ribosomal protein S12 (MRPS12), poly(rC) binding protein 1 (PARP1), SNRNP200, PCBP1, small G protein signaling modulator 1 (SGSM1), and DNA methyltransferase 1 (DNMT1). Five possible target miRNAs, including miR-221-5p, miR-21-5p, miR-100-5p, miR-30b-5p, and miR-615-3p, were predicted by constructing a miRNA-gene network. This study used bioinformatics techniques to explore the potential association between ALS and depression, and identified potential biomarkers. These biomarkers may provide new ideas and methods for the early diagnosis, treatment, and monitoring of ALS and depression.}, } @article {pmid38011840, year = {2024}, author = {Asawadethmetakul, P and Xie, F and Xie, C and Ma, J and You, Y and Yao, F}, title = {Effect of Tuina Combined with Chinese Herbal Compress on Primary Dysmenorrhea with Cold Coagulation and Blood Stasis Syndrome: A Study Protocol for a Randomized Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {20-29}, doi = {10.1159/000534335}, pmid = {38011840}, issn = {2504-2106}, mesh = {Female ; Humans ; *Dysmenorrhea/drug therapy ; China ; *Pain Threshold ; Randomized Controlled Trials as Topic ; Observational Studies as Topic ; }, abstract = {INDRODUCTION: Primary dysmenorrhea (PD) is a very common issue in young women that reduces the quality of women's lives. Both Western medicine and traditional Chinese medicine (TCM) provide several ways to treat PD; however, TCM treatment exhibits fewer side effects for the patient. Tuina massage and Chinese herbal compresses are considered forms of external TCM therapy that have been widely used to treat PD, especially in China. Therefore, to provide the most effective and safe treatment for PD, we combined Tuina and Chinese herbal compresses together in this observational study.

METHODS: A randomized controlled trial (RCT) consisting of 114 participants from the Shanghai University of Traditional Chinese Medicine who meet inclusion criteria will be divided into two groups in a 1:1 allocation ratio. The intervention group will receive Tuina combined with Chinese herbal compress therapy, while the control group will only receive Chinese herbal compress therapy. The treatment will be given 3 days before menstruation (once per day, 3 times per menstrual cycle). The primary outcome will be measured with the Visual Analog Scale (VAS). The secondary outcomes will be measured by the Dysmenorrhea Symptom Score, the Chinese Medical Dysmenorrhea Symptom Score, the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), and the pain threshold at Guanyuan (CV4).

CONCLUSION: This study will be the first RCT that will entail the combination of Tuina and Chinese herbal compresses to treat PD in the category of cold coagulation and blood stasis syndrome. If the results demonstrate that Tuina combined with a Chinese herbal compress is effective, we posit that this study will provide evidence-based references for a potential alternative treatment to treat PD in the future.

UNLABELLED: EinleitungDie primäre Dysmenorrhoe (PD) ist ein Problem, das bei jungen Frauen sehr häufig auftritt und ihre Lebensqualität beeinträchtigt. Sowohl die westliche Medizin als auch die traditionelle chinesische Medizin (TCM) bieten verschiedene Therapiemöglichkeiten zur Behandlung der PD, allerdings ist die TCM mit weniger Nebenwirkungen für die Patientin verbunden. Tuina-Massage und chinesische Kräuterkompressen gelten als Formen der äußerlichen TCM-Therapie, die besonders in China zur Behandlung der PD weit verbreitet sind. Daher haben wir in dieser Beobachtungsstudie Tuina und chinesische Kräuterkompressen kombiniert, um eine möglichst wirksame und sichere Behandlung der PD bereitzustellen.MethodenEs handelt sich um eine randomisierte kontrollierte Studie (randomized controlled trial, RCT), bei der 114 Teilnehmerinnen der Shanghai University of Traditional Chinese Medicine, die die Einschlusskriterien erfüllen, im Verhältnis 1:1 in zwei Gruppen aufgeteilt werden. Die Interventionsgruppe erhält Tuina in Kombination mit chinesischen Kräuterkompressen, während die Kontrollgruppe nur eine Behandlung mit chinesischen Kräuterkompressen erhält. Die Behandlung erfolgt drei Tage vor der Menstruation (einmal täglich, dreimal pro Menstruationszyklus). Das primäre Zielkriterium wird anhand der visuellen Analogskala (VAS) gemessen. Die sekundären Zielkriterien werden mithilfe des Dysmenorrhoe-Symptom-Scores, des chinesischen medizinischen Dysmenorrhoe-Symptom-Scores, der Self-rating Anxiety Scale (SAS), der Self-rating Depression Scale (SDS) und der Schmerzschwelle am Guanyuan-Akupunkturpunkt (CV4) ermittelt.SchlussfolgerungDiese Studie ist die erste randomisierte kontrollierte Studie, die die Kombination von Tuina und chinesischen Kräuterkompressen zur Behandlung von PD in der Kategorie Kältekoagulation und Blutstauungssyndrom untersucht. Sollten die Ergebnisse zeigen, dass Tuina in Kombination mit chinesischen Kräuterkompressen wirksam ist, erwarten wir, dass diese Studie evidenzbasierte Belege für eine mögliche alternative Behandlung von PD in der Zukunft liefern wird.}, } @article {pmid38010626, year = {2024}, author = {Zhong, R and Rua, MT and Wei-LaPierre, L}, title = {Targeting mitochondrial Ca[2+] uptake for the treatment of amyotrophic lateral sclerosis.}, journal = {The Journal of physiology}, volume = {602}, number = {8}, pages = {1519-1549}, pmid = {38010626}, issn = {1469-7793}, support = {R01 NS127858/NS/NINDS NIH HHS/United States ; R21 NS099545/NS/NINDS NIH HHS/United States ; R56 NS117429/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Calcium/metabolism ; *Neurodegenerative Diseases ; Motor Neurons/physiology ; Mitochondria/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare adult-onset neurodegenerative disease characterized by progressive motor neuron (MN) loss, muscle denervation and paralysis. Over the past several decades, researchers have made tremendous efforts to understand the pathogenic mechanisms underpinning ALS, with much yet to be resolved. ALS is described as a non-cell autonomous condition with pathology detected in both MNs and non-neuronal cells, such as glial cells and skeletal muscle. Studies in ALS patient and animal models reveal ubiquitous abnormalities in mitochondrial structure and function, and disturbance of intracellular calcium homeostasis in various tissue types, suggesting a pivotal role of aberrant mitochondrial calcium uptake and dysfunctional calcium signalling cascades in ALS pathogenesis. Calcium signalling and mitochondrial dysfunction are intricately related to the manifestation of cell death contributing to MN loss and skeletal muscle dysfunction. In this review, we discuss the potential contribution of intracellular calcium signalling, particularly mitochondrial calcium uptake, in ALS pathogenesis. Functional consequences of excessive mitochondrial calcium uptake and possible therapeutic strategies targeting mitochondrial calcium uptake or the mitochondrial calcium uniporter, the main channel mediating mitochondrial calcium influx, are also discussed.}, } @article {pmid38010108, year = {2024}, author = {Hincelin-Mery, A and Nicolas, X and Cantalloube, C and Pomponio, R and Lewanczyk, P and Benamor, M and Ofengeim, D and Krupka, E and Hsiao-Nakamoto, J and Eastenson, A and Atassi, N}, title = {Safety, pharmacokinetics, and target engagement of a brain penetrant RIPK1 inhibitor, SAR443820 (DNL788), in healthy adult participants.}, journal = {Clinical and translational science}, volume = {17}, number = {1}, pages = {e13690}, pmid = {38010108}, issn = {1752-8062}, mesh = {Adult ; Humans ; Healthy Volunteers ; Dose-Response Relationship, Drug ; Area Under Curve ; Half-Life ; Double-Blind Method ; *Brain ; *Receptor-Interacting Protein Serine-Threonine Kinases ; }, abstract = {SAR443820 (DNL788) is a selective, orally bioavailable, brain penetrant inhibitor of receptor-interacting serine/threonine protein kinase 1 (RIPK1). This phase I first-in-human healthy participant study (NCT05795907) was comprised of three parts: randomized, double-blind, placebo-controlled single ascending dose (SAD; part 1a); 14-day multiple ascending dose (MAD; part 2) parts that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of SAR443820; and a separate open-label, single-dose part 1b (PK-cerebrospinal fluid [CSF]) to assess SAR443820 levels in CSF. SAR443820 was well-tolerated in healthy participants, and no treatment discontinuation related to an adverse event (AE) occurred. Most common AEs were dizziness and headache. No clinically meaningful changes were noted in laboratory values, vital signs, or electrocardiogram parameters. SAR443820 had a favorable PK profile, with plasma half-lives (geometric mean) ranged between 5.7-8.0 h and 7.2-8.9 h after single and repeated doses, respectively. There were no major deviations from dose proportionality for maximum concentration and area under the curve across SAR443820 doses. Mean CSF-to-unbound plasma concentration ratio ranged from 0.8 to 1.3 over time (assessed up to 10 h postdose), indicating high brain penetrance. High levels of inhibition of activated RIPK1, as measured by decrease in pS166-RIPK1, were achieved in both SAD and MAD parts, with a maximum median inhibition from baseline close to 90% at predose (Ctrough) after multiple dosing in MAD, reflecting a marked RIPK1 target engagement at the peripheral level. These results support further development of SAR443820 in phase II trials in amyotrophic lateral sclerosis (NCT05237284) and multiple sclerosis (NCT05630547).}, } @article {pmid38009843, year = {2024}, author = {Cykowski, MD and Arumanayagam, AS and Powell, SZ and Appel, SH}, title = {Primary visual cortex pathology in ALS patients with C9ORF72 expansion.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {5}, pages = {e13229}, pmid = {38009843}, issn = {1750-3639}, support = {RF1 NS118584/NS/NINDS NIH HHS/United States ; RF1NS118584/NS/NINDS NIH HHS/United States ; 19-IIA-465//ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *C9orf72 Protein/genetics ; Middle Aged ; Female ; Male ; DNA Repeat Expansion ; Primary Visual Cortex/pathology ; Aged ; Proteins/genetics/metabolism ; }, abstract = {Poly-GA and poly-GP immunofluorescence studies show conspicuous dipeptide repeat pathology in layers IV and II of primary visual cortex in C9ALS patients.}, } @article {pmid38008627, year = {2024}, author = {Zhang, J and Wang, C and Zhou, M and Wang, Z}, title = {Comprehensive treatment of amyotrophic lateral sclerosis combined with colon cancer: A case report.}, journal = {Asian journal of surgery}, volume = {47}, number = {2}, pages = {1274-1275}, doi = {10.1016/j.asjsur.2023.11.063}, pmid = {38008627}, issn = {0219-3108}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Colonic Neoplasms ; }, } @article {pmid38008074, year = {2024}, author = {Saha, S and Singh, R and Mani, I and Chakraborty, K and Sarkar, P and Saha, S and Rana, A and Chattopadhyay, R}, title = {Individualized Homeopathic Medicines in the Treatment of Post-COVID-19 Fatigue in Adults: Single-Blind, Randomized, Placebo-Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {1-9}, doi = {10.1159/000535279}, pmid = {38008074}, issn = {2504-2106}, mesh = {Adult ; Humans ; *COVID-19/therapy ; India ; *Materia Medica ; Quality of Life ; Single-Blind Method ; Sulfur ; }, abstract = {INTRODUCTION: The coronavirus disease 2019 (COVID-19) is leading to unknown and unusual health conditions that are challenging to manage. Post-COVID-19 fatigue is one of those challenges, becoming increasingly common as the pandemic evolves, as it impairs the quality of life of an individual. This trial attempts to identify the preliminary evidence of the efficacy of individualized homeopathic medicines (IHMs) against placebos in the treatment of post-COVID-19 fatigue in adults.

METHODS: A 3-month, single-blind, randomized, placebo-controlled, parallel-arm trial was conducted at the outpatient department of The Calcutta Homoeopathic Medical College and Hospital, India. Sixty participants were randomized in a 1:1 ratio to receive either IHMs (n = 30) or identical-looking placebos (n = 30). The primary and secondary outcome measures were the Fatigue Assessment Scale (FAS) and Outcome in Relation to Impact on Daily Living (ORIDL), respectively, measured every month, for up to 3 months. Comparative analysis was carried out on the intention-to-treat sample to detect group differences.

RESULTS: Group differences in both the primary (FAS total: F1, 58 = 14.356, p < 0.001) and secondary outcomes (ORIDL: F1, 58 = 210.986, p < 0.001) after 3 months favored IHMs against placebos. Lycopodium clavatum (11.7%), sulfur (11.7%), Arsenicum album (10%), and Thuja occidentalis (10%) were the most frequently indicated medicines. No harm, unintended effects, homeopathic aggravations, or any serious adverse events were reported from either of the groups.

CONCLUSION: IHMs produced significantly better effects than placebos in the treatment of post-COVID-19 fatigue in adults. Definitive robust trials may be undertaken to confirm the findings.

UNLABELLED: EinleitungDie Coronainfektion (COVID-19) zieht unbekannte und ungewöhnliche gesundheitliche Probleme nach sich, deren Management oft eine Herausforderung darstellt. Das gilt unter anderem für Ermüdung nach einer COVID-19-Erkrankung, die mit zunehmender Dauer der Pandemie immer häufiger auftritt und die Lebensqualität der Betroffenen beeinträchtigt. In dieser Studie wird versucht, vorläufige Belege für die Wirksamkeit individualisierter homöopathischer Mittel (IHM) im Vergleich zu Placebo zur Behandlung von Ermüdung nach COVID-19 bei Erwachsenen zu identifizieren.MethodenEine einfach verblindete, randomisierte, placebokontrollierte Parallelgruppenstudie von 3 Monaten Dauer wurde im ambulanten Bereich des Calcutta Homoeopathic Medical College and Hospital in Indien durchgeführt. 60 Teilnehmer erhielten nach Randomisierung im Verhältnis 1:1 entweder IHM (n = 30) oder identisch aussehendes Placebo (n = 30). Die primäre und die sekundäre Zielgröße waren die Fatigue Assessment Scale (FAS) und das Outcome in Relation to Impact on Daily Living (ORIDL) für bis zu 3 Monate, jeweils monatlich gemessen. Vergleichende Analysen wurden an der Intent-to-treat-Population durchgeführt, um Unterschiede zwischen den Gruppen zu erkennen.ErgebnisseGruppenunterschiede bei der primären (FAS gesamt: F1, 58 = 14,356; p < 0.001) sowie der sekundären Zielgröße (ORIDL: F1, 58 = 210,986; p < 0.001) nach 3 Monaten sprachen für die IHM gegenüber Placebo. Lycopodium clavatum (11.7%), sulfur (11.7%), Arsenicum album (10%) und Thuja occidentalis (10%) waren die am häufigsten indizierten Mittel. In beiden Gruppen wurden keine Schädigungen, unbeabsichtigten Wirkungen, homöopathischen Verschlechterungen oder jegliche schwerwiegenden unerwünschten Ereignisse beobachtet.SchlussfolgerungDie IHM erzielten signifikant bessere Effekte als Placebo in der Behandlung von Post-COVID-Ermüdung bei Erwachsenen. Definitive, belastbare Studien können eingeleitet werden, um diese Befunde zu bestätigen.}, } @article {pmid38008065, year = {2024}, author = {Maier, GS and Rosar, G and Dietz, G and Hemken, N and Kafchitsas, K and Seeger, JB and Horas, K}, title = {Effectiveness of Mud-Pack Therapy and Mud-Bath Therapy in Osteoarthritis: A Systematic Review.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {30-39}, doi = {10.1159/000535437}, pmid = {38008065}, issn = {2504-2106}, mesh = {Humans ; *Mud Therapy ; *Osteoarthritis, Knee ; *Osteoarthritis, Hip ; Quality of Life ; *Low Back Pain ; }, abstract = {OBJECTIVES: Osteoarthritis has a tremendous socioeconomic impact in terms of drug spending, hospital admissions, work productivity, and temporary or permanent incapacity. Mud therapy has been discussed as potential conservative treatment options for osteoarthritis. However, findings from several trials still remain controversial. For this reason, we aimed to systematically review the highest evidence provided by published trials to estimate the clinical effect of mud-pack and mud-bath therapy for the treatment of osteoarthritis.

METHODS: We searched PubMed, PEDro, and the Cochrane CENTRAL Register for Controlled Trials for articles published between 2000 and 2020 using the terms "orthopedics," "orthopaedics," "musculoskeletal," "osteoarthritis," and "mud bath," "mud pack."

RESULTS: Of the 19 studies included, 15 examined the effects of mud-bath therapy in knee osteoarthritis treatment. One study focused on the treatment effect of mud bath on hand osteoarthritis, another study examined treatment effects in hip and knee osteoarthritis, and two studies enrolled patients with chronic low back pain caused by lumbar spine osteoarthritis. We systematically reviewed the data obtained from the literature and summarized the results on the basis of the main outcomes. The results show significant improvements in function, quality of life, and perceived pain for patients with osteoarthritis.

CONCLUSION: Results of randomized controlled trials suggest that mud therapy is part of a promising integrated and synergistic multidisciplinary approach in combination with other treatment forms like pharmacotherapy or physiotherapy.

UNLABELLED: ZieleDie sozio-ökonomischen Auswirkungen der Arthrose sind immens. Heiltorfbehandlungen sind seit einiger Zeit als mögliche Ergänzung der konservativen Therapieoptionen dieser Erkrankung Gegenstand wissenschaftlicher Untersuchungen. Ziel dieser Studie war es, die aktuellen Erkenntnisse zur Heiltorftherapie bei Arthrose zusammenzufassen.MethodenWir führten eine systematische Literaturrecherche der Datenbanken Pubmed, PEDro und Cochrane CENTRAL Register of Controlled Trials durch. Hierbei wurden Artikel, die zwischen 2000 und 2020 publiziert wurden und mit den Schlagwörtern “orthopedics”, “orthopaedics”, “musculoskeletal”, “osteoarthritis” und “mud-bath”, “mud-pack” assoziiert waren, erfasst.ErgebnisseVon den 19 näher untersuchten Studien beschäftigten sich 15 mit den Effekten der Heiltorftherapie bei Patienten mit Kniearthrose, eine Studie untersuchte Patienten mit Arthrose der Hand, eine weitere Studie untersuchte die Auswirkung der Therapie bei Arthrose der Hüfte. 2 Studien untersuchten den Effekt der Moorbäder bei Patienten mit chronischen Rückenschmerzen. Insgesamt zeigten sich signifikante Verbesserungen der Funktion, Lebensqualität und Schmerzlinderung bei den Patienten unter Heiltorftherapie.ZusammenfassungDie Ergebnisse der randomisierten, kontrollierten Studien zeigen, dass die Heiltorftherapie eine vielversprechende Ergänzung in einem multidisziplinären Ansatz der Arthrosetherapie ist.}, } @article {pmid38007795, year = {2023}, author = {Feng, T}, title = {Applications of Artificial Intelligence to Diagnosis of Neurodegenerative Diseases.}, journal = {Studies in health technology and informatics}, volume = {308}, number = {}, pages = {648-655}, doi = {10.3233/SHTI230896}, pmid = {38007795}, issn = {1879-8365}, mesh = {Humans ; Artificial Intelligence ; *Neurodegenerative Diseases/diagnostic imaging ; *Alzheimer Disease/diagnostic imaging ; Machine Learning ; Natural Language Processing ; }, abstract = {Artificial Intelligence (AI) is an umbrella term that represents a new technology for simulating and expanding human intelligence by using machines and computer systems. It consists of methods such as machine learning (ML), deep learning (DL), and natural language processing (NLP). In the era of big data, AI has emerged as an essential tool for improving the detection of neurodegenerative diseases, such as Alzheimer's diseases (AD), Parkinson's diseases, amyotrophic lateral sclerosis, etc. AI with its ability to extract critical information from the mass of data has enabled scientists to deal with various types of large-volume data, including genetic data, imaging data, and clinical data, rapidly generated in the course of neurodegenerative disease research. This review provides a comprehensive overview of the literature on current AI applications in the diagnosis of neurodegenerative diseases. Firstly, bioinformatics and AI approaches to identify potential biomarkers for neurodegenerative diseases such as AD are reviewed. Secondly, the use of ML and DL methods to analyze Magnetic Resonance Imaging (MRI) data for a better understanding of disease progression and predicting patient outcomes is discussed. Finally, the use of AI methods including NLP for Electronic Health Record (EHR) data analysis to extract meaningful information and identify patterns that may contribute to early diagnosis and treatment planning are reviewed. The potential benefits of AI-based approaches in improving patient outcomes and the challenges associated with their implementations are also discussed. Overall, this paper highlights the promise of AI in transforming the diagnosis and management of neurodegenerative diseases.}, } @article {pmid38007141, year = {2024}, author = {Wong, CH and Rahat, A and Chang, HC}, title = {Fused in sarcoma regulates glutamate signaling and oxidative stress response.}, journal = {Free radical biology & medicine}, volume = {210}, number = {}, pages = {172-182}, pmid = {38007141}, issn = {1873-4596}, support = {P40 OD010440/OD/NIH HHS/United States ; R01 GM131156/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Caenorhabditis elegans/metabolism ; Glutamates/metabolism ; Mutation ; Oxidation-Reduction ; Oxidative Stress/genetics ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics ; Disease Models, Animal ; *RNA-Binding Protein FUS/genetics/metabolism ; Caenorhabditis elegans Proteins/genetics/metabolism ; }, abstract = {Mutations in fused in sarcoma (fust-1) are linked to ALS. However, how these ALS causative mutations alter physiological processes and lead to the onset of ALS remains largely unknown. By obtaining humanized fust-1 ALS mutations via CRISPR-CAS9, we generated a C. elegans ALS model. Homozygous fust-1 ALS mutant and fust-1 deletion animals are viable in C. elegans. This allows us to better characterize the molecular mechanisms of fust-1-dependent responses. We found FUST-1 plays a role in regulating superoxide dismutase, glutamate signaling, and oxidative stress. FUST-1 suppresses SOD-1 and VGLUT/EAT-4 in the nervous system. FUST-1 also regulates synaptic AMPA-type glutamate receptor GLR-1. We found that fust-1 ALS mutations act as loss-of-function in SOD-1 and VGLUT/EAT-4 phenotypes, whereas the fust-1 ALS mutations act as gain-of-function in redox homeostasis and the microbe-induced oxidative stress response. We hypothesized that FUST-1 is a link between glutamate signaling and SOD-1. Our results may provide new insights into the human ALS alleles and their roles in pathological mechanisms that lead to ALS.}, } @article {pmid38006254, year = {2024}, author = {Kabir, V and Ombelet, F and Hobin, F and Lamaire, N and De Vocht, J and Van Damme, P}, title = {Prognostic value of motor and extramotor involvement in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {67-74}, doi = {10.1080/21678421.2023.2284899}, pmid = {38006254}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; *Frontotemporal Dementia/complications/diagnosis/psychology ; Cohort Studies ; Prognosis ; Retrospective Studies ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder resulting in upper and lower motor neuron loss. ALS often has a focal onset of weakness, which subsequently spreads to other body regions. Survival is limited to two to five years after disease onset, often due to respiratory failure. Cognitive impairment is present in approximately 30% to 50% of patients and in 10%-15% of patients, the clinical criteria of frontotemporal dementia (FTD) are met.

METHODS: In this retrospective single-center ALS cohort study, we examined the occurrence of cognitive and behavioral impairment in relation to motor impairment at disease presentation and studied its impact on survival.

RESULTS: The degree of lower motor neuron involvement was associated with a worse survival, but there was no effect for upper motor neuron involvement. Patients who were cognitively normal had a significantly better survival compared to patients with cognitive or behavioral impairment and to patients with comorbid FTD. There was no significant difference regarding survival between patients with FTD and patients with cognitive or behavioral impairment.

CONCLUSIONS: The extent of motor and extramotor involvement in patients with ALS at disease presentation holds complementary prognostic information.}, } @article {pmid38005489, year = {2023}, author = {Li, J and Liang, W and Yin, X and Li, J and Guan, W}, title = {Multimodal Gait Abnormality Recognition Using a Convolutional Neural Network-Bidirectional Long Short-Term Memory (CNN-BiLSTM) Network Based on Multi-Sensor Data Fusion.}, journal = {Sensors (Basel, Switzerland)}, volume = {23}, number = {22}, pages = {}, pmid = {38005489}, issn = {1424-8220}, support = {No. 2021AAA007//Department of Science and Technology of Hubei Province/ ; }, mesh = {Humans ; *Parkinson Disease/diagnosis ; *Amyotrophic Lateral Sclerosis ; Neural Networks, Computer ; Gait ; *Huntington Disease ; }, abstract = {Global aging leads to a surge in neurological diseases. Quantitative gait analysis for the early detection of neurological diseases can effectively reduce the impact of the diseases. Recently, extensive research has focused on gait-abnormality-recognition algorithms using a single type of portable sensor. However, these studies are limited by the sensor's type and the task specificity, constraining the widespread application of quantitative gait recognition. In this study, we propose a multimodal gait-abnormality-recognition framework based on a Convolutional Neural Network-Bidirectional Long Short-Term Memory (CNN-BiLSTM) network. The as-established framework effectively addresses the challenges arising from smooth data interference and lengthy time series by employing an adaptive sliding window technique. Then, we convert the time series into time-frequency plots to capture the characteristic variations in different abnormality gaits and achieve a unified representation of the multiple data types. This makes our signal processing method adaptable to several types of sensors. Additionally, we use a pre-trained Deep Convolutional Neural Network (DCNN) for feature extraction, and the consequently established CNN-BiLSTM network can achieve high-accuracy recognition by fusing and classifying the multi-sensor input data. To validate the proposed method, we conducted diversified experiments to recognize the gait abnormalities caused by different neuropathic diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Huntington's disease (HD). In the PDgait dataset, the framework achieved an accuracy of 98.89% in the classification of Parkinson's disease severity, surpassing DCLSTM's 96.71%. Moreover, the recognition accuracy of ALS, PD, and HD on the PDgait dataset was 100%, 96.97%, and 95.43% respectively, surpassing the majority of previously reported methods. These experimental results strongly demonstrate the potential of the proposed multimodal framework for gait abnormality identification. Due to the advantages of the framework, such as its suitability for different types of sensors and fewer training parameters, it is more suitable for gait monitoring in daily life and the customization of medical rehabilitation schedules, which will help more patients alleviate the harm caused by their diseases.}, } @article {pmid38005288, year = {2023}, author = {Lapshina, MA and Shevtsova, EF and Grigoriev, VV and Aksinenko, AY and Ustyugov, AA and Steinberg, DA and Maleev, GV and Dubrovskaya, ES and Goreva, TV and Epishina, TA and Zamoyski, VL and Makhaeva, GF and Fisenko, VP and Veselov, IM and Vinogradova, DV and Bachurin, SO}, title = {New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {22}, pages = {}, pmid = {38005288}, issn = {1420-3049}, support = {19-13-00378-P//Russian Science Foundation/ ; }, mesh = {Humans ; Edaravone/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Adamantane ; Riluzole ; Amantadine/therapeutic use ; }, abstract = {Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs-edaravone and riluzole-have been approved, but they have very limited efficacy. The aim of this work was to modify the structural core of the Edaravone-phenylpyrazolone moiety and combine it with aminoadamantane pharmacophore in order to expand the spectrum of its action to a number of processes involved in the pathogenesis of ALS. New conjugates of edaravone derivatives with 1-aminoadamantanes combined with alkylene or hydroxypropylene spacers were synthesized, and their biological activity was investigated. Compounds were found that could inhibit lipid peroxidation and calcium-related mitochondrial permeability, block fast sodium currents of CNS neurons, and reduce aggregation of the mutated form of the FUS-protein typical to ALS. So, the proposed modification of the edaravone molecule has allowed the obtaining of new original structures that combine some prospective therapeutic mechanisms against key chains of the pathogenesis of ALS. The identified lead compounds can be used for further optimization and development of new promising drugs on this basis for the treatment of ALS.}, } @article {pmid38004577, year = {2023}, author = {Niazi, SK}, title = {Non-Invasive Drug Delivery across the Blood-Brain Barrier: A Prospective Analysis.}, journal = {Pharmaceutics}, volume = {15}, number = {11}, pages = {}, pmid = {38004577}, issn = {1999-4923}, abstract = {Non-invasive drug delivery across the blood-brain barrier (BBB) represents a significant advancement in treating neurological diseases. The BBB is a tightly packed layer of endothelial cells that shields the brain from harmful substances in the blood, allowing necessary nutrients to pass through. It is a highly selective barrier, which poses a challenge to delivering therapeutic agents into the brain. Several non-invasive procedures and devices have been developed or are currently being investigated to enhance drug delivery across the BBB. This paper presents a review and a prospective analysis of the art and science that address pharmacology, technology, delivery systems, regulatory approval, ethical concerns, and future possibilities.}, } @article {pmid38003404, year = {2023}, author = {Huang, B and Liu, X and Zhang, T and Wu, Q and Huang, C and Xia, XG and Zhou, H}, title = {Increase in hnRNPA1 Expression Suffices to Kill Motor Neurons in Transgenic Rats.}, journal = {International journal of molecular sciences}, volume = {24}, number = {22}, pages = {}, pmid = {38003404}, issn = {1422-0067}, support = {R01 NS089701/NS/NINDS NIH HHS/United States ; R01 NS095962/NS/NINDS NIH HHS/United States ; R01 NS110455/NS/NINDS NIH HHS/United States ; NS089701, NS095962, NS110455/NS/NINDS NIH HHS/United States ; }, mesh = {Rats ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Rats, Transgenic ; Motor Neurons/metabolism ; Phenotype ; Mutation ; Mice, Transgenic ; Disease Models, Animal ; Superoxide Dismutase-1/genetics ; }, abstract = {A dominant mutation in hnRNPA1 causes amyotrophic lateral sclerosis (ALS), but it is not known whether this mutation leads to motor neuron death through increased or decreased function. To elucidate the relationship between pathogenic hnRNPA1 mutation and its native function, we created novel transgenic rats that overexpressed wildtype rat hnRNPA1 exclusively in motor neurons. This targeted expression of wildtype hnRNPA1 caused severe motor neuron loss and subsequent denervation muscle atrophy in transgenic rats that recapitulated the characteristics of ALS. These findings demonstrate that the augmentation of hnRNPA1 expression suffices to trigger motor neuron degeneration and the manifestation of ALS-like phenotypes. It is reasonable to infer that an amplification of an as-yet undetermined hnRNPA1 function plays a pivotal role in the pathogenesis of familial ALS caused by pathogenic hnRNPA1 mutation.}, } @article {pmid38003309, year = {2023}, author = {Toader, C and Dobrin, N and Brehar, FM and Popa, C and Covache-Busuioc, RA and Glavan, LA and Costin, HP and Bratu, BG and Corlatescu, AD and Popa, AA and Ciurea, AV}, title = {From Recognition to Remedy: The Significance of Biomarkers in Neurodegenerative Disease Pathology.}, journal = {International journal of molecular sciences}, volume = {24}, number = {22}, pages = {}, pmid = {38003309}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Amyotrophic Lateral Sclerosis ; *Parkinson Disease/diagnosis/metabolism ; *Alzheimer Disease/diagnosis ; Biomarkers/metabolism ; }, abstract = {With the inexorable aging of the global populace, neurodegenerative diseases (NDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose escalating challenges, which are underscored by their socioeconomic repercussions. A pivotal aspect in addressing these challenges lies in the elucidation and application of biomarkers for timely diagnosis, vigilant monitoring, and effective treatment modalities. This review delineates the quintessence of biomarkers in the realm of NDs, elucidating various classifications and their indispensable roles. Particularly, the quest for novel biomarkers in AD, transcending traditional markers in PD, and the frontier of biomarker research in ALS are scrutinized. Emergent susceptibility and trait markers herald a new era of personalized medicine, promising enhanced treatment initiation especially in cases of SOD1-ALS. The discourse extends to diagnostic and state markers, revolutionizing early detection and monitoring, alongside progression markers that unveil the trajectory of NDs, propelling forward the potential for tailored interventions. The synergy between burgeoning technologies and innovative techniques like -omics, histologic assessments, and imaging is spotlighted, underscoring their pivotal roles in biomarker discovery. Reflecting on the progress hitherto, the review underscores the exigent need for multidisciplinary collaborations to surmount the challenges ahead, accelerate biomarker discovery, and herald a new epoch of understanding and managing NDs. Through a panoramic lens, this article endeavors to provide a comprehensive insight into the burgeoning field of biomarkers in NDs, spotlighting the promise they hold in transforming the diagnostic landscape, enhancing disease management, and illuminating the pathway toward efficacious therapeutic interventions.}, } @article {pmid38003212, year = {2023}, author = {Lovatto, M and Gonçalves-Vidigal, MC and Vaz Bisneta, M and Calvi, AC and Mazucheli, J and Vidigal Filho, PS and Miranda, EGR and Melotto, M}, title = {Responsiveness of Candidate Genes on CoPv01[CDRK]/PhgPv01[CD][RK] Loci in Common Bean Challenged by Anthracnose and Angular Leaf Spot Pathogens.}, journal = {International journal of molecular sciences}, volume = {24}, number = {22}, pages = {}, pmid = {38003212}, issn = {1422-0067}, support = {408472/2018-9//National Council for Scientific and Technological Development/ ; BEX 88881.170662//2018-01//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; }, mesh = {Chromosome Mapping ; *Colletotrichum/genetics ; Disease Resistance/genetics ; Genetic Linkage ; Genetic Markers ; Kidney ; *Phaseolus/genetics ; Plant Diseases/genetics ; }, abstract = {Anthracnose (ANT) and angular leaf spot (ALS) are significant diseases in common bean, leading to considerable yield losses under specific environmental conditions. The California Dark Red Kidney (CDRK) bean cultivar is known for its resistance to multiple races of both pathogens. Previous studies have identified the CoPv01[CDRK]/PhgPv01[CDRK] resistance loci on chromosome Pv01. Here, we evaluated the expression levels of ten candidate genes near the CoPv01[CDRK]/PhgPv01[CDRK] loci and plant defense genes using quantitative real-time PCR in CDRK cultivar inoculated with races 73 of Colletotrichum lindemuthianum and 63-39 of Pseudocercospora griseola. Gene expression analysis revealed that the Phvul.001G246300 gene exhibited the most elevated levels, showing remarkable 7.8-fold and 8.5-fold increases for ANT and ALS, respectively. The Phvul.001G246300 gene encodes an abscisic acid (ABA) receptor with pyrabactin resistance, PYR1-like (PYL) protein, which plays a central role in the crosstalk between ABA and jasmonic acid responses. Interestingly, our results also showed that the other defense genes were initially activated. These findings provide critical insights into the molecular mechanisms underlying plant defense against these diseases and could contribute to the development of more effective disease management strategies in the future.}, } @article {pmid38002982, year = {2023}, author = {Lombardi, M and Corrado, L and Piola, B and Comi, C and Cantello, R and D'Alfonso, S and Mazzini, L and De Marchi, F}, title = {Variability in Clinical Phenotype in TARDBP Mutations: Amyotrophic Lateral Sclerosis Case Description and Literature Review.}, journal = {Genes}, volume = {14}, number = {11}, pages = {}, pmid = {38002982}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Italy ; Mutation ; Phenotype ; }, abstract = {Mutations in the 43 kDa transactive-response (TAR)-DNA-binding protein (TARDBP) are associated with 2-5% of familial Amyotrophic Lateral Sclerosis (ALS) cases. TAR DNA-Binding Protein 43 (TDP-43) is an RNA/DNA-binding protein involved in several cellular mechanisms (e.g., transcription, pre-mRNA processing, and splicing). Many ALS-linked TARDBP mutations have been described in the literature, but few phenotypic data on monogenic TARDBP-mutated ALS are available. In this paper, (1) we describe the clinical features of ALS patients carrying mutations in the TARDBP gene evaluated at the Tertiary ALS Center at Maggiore della Carità University Hospital, Novara, Italy, from 2010 to 2020 and (2) present the results of our review of the literature on this topic, analyzing data obtained for 267 patients and highlighting their main clinical and demographic features.}, } @article {pmid38002967, year = {2023}, author = {Tourtourikov, I and Dabchev, K and Todorov, T and Angelov, T and Chamova, T and Tournev, I and Kadiyska, T and Mitev, V and Todorova, A}, title = {Navigating the ALS Genetic Labyrinth: The Role of MAPT Haplotypes.}, journal = {Genes}, volume = {14}, number = {11}, pages = {}, pmid = {38002967}, issn = {2073-4425}, support = {D-186/ 14.06.2022//Medical University Sofia/ ; }, mesh = {Humans ; Haplotypes ; *Amyotrophic Lateral Sclerosis/genetics ; tau Proteins/genetics ; *Neurodegenerative Diseases ; Genetic Predisposition to Disease ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by wide clinical and biological heterogeneity, with a large proportion of ALS patients also exhibiting frontotemporal dementia (FTD) spectrum symptoms. This project aimed to characterize risk subtypes of the H1 haplotype within the MAPT (microtubule-associated protein tau) gene, according to their possible effect as a risk factor and as a modifying factor in relation to the age of disease onset. One hundred patients from Bulgaria with sporadic ALS were genotyped for the variants rs1467967, rs242557, rs1800547, rs3785883, rs2471738, and rs7521. Haploview 4.2 and SHEsisPlus were used to reconstruct haplotype frequencies using genotyping data from the 1000 Genomes project as controls. Genotype-phenotype correlation was investigated in the context of age of disease onset and risk of disease development. While the individual variants of the subtypes do not influence the age of onset of the disease, a correlation was found between the specific haplotype GGAGCA (H1b) and the risk of developing sALS, with results showing that individuals harboring this haplotype have a nearly two-fold increased risk of developing sALS compared to other H1 subtypes. The results from this study suggest that fine transcriptional regulation at the MAPT locus can influence the risk of ALS.}, } @article {pmid38002924, year = {2023}, author = {Genin, EC and Abou-Ali, M and Paquis-Flucklinger, V}, title = {Mitochondria, a Key Target in Amyotrophic Lateral Sclerosis Pathogenesis.}, journal = {Genes}, volume = {14}, number = {11}, pages = {}, pmid = {38002924}, issn = {2073-4425}, support = {ANR-16-CE16-0024-01//Agence Nationale de la Recherche/ ; MND202004011475//Fondation pour la Recherche Médicale/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Mitochondria/metabolism ; Motor Neurons/metabolism ; Cell Death/genetics ; Mitochondrial Proteins/genetics/metabolism ; }, abstract = {Mitochondrial dysfunction occurs in numerous neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS), where it contributes to motor neuron (MN) death. Of all the factors involved in ALS, mitochondria have been considered as a major player, as secondary mitochondrial dysfunction has been found in various models and patients. Abnormal mitochondrial morphology, defects in mitochondrial dynamics, altered activities of respiratory chain enzymes and increased production of reactive oxygen species have been described. Moreover, the identification of CHCHD10 variants in ALS patients was the first genetic evidence that a mitochondrial defect may be a primary cause of MN damage and directly links mitochondrial dysfunction to the pathogenesis of ALS. In this review, we focus on the role of mitochondria in ALS and highlight the pathogenic variants of ALS genes associated with impaired mitochondrial functions. The multiple pathways demonstrated in ALS pathogenesis suggest that all converge to a common endpoint leading to MN loss. This may explain the disappointing results obtained with treatments targeting a single pathological process. Fighting against mitochondrial dysfunction appears to be a promising avenue for developing combined therapies in the future.}, } @article {pmid38002659, year = {2023}, author = {O'Day, DH}, title = {Protein Biomarkers Shared by Multiple Neurodegenerative Diseases Are Calmodulin-Binding Proteins Offering Novel and Potentially Universal Therapeutic Targets.}, journal = {Journal of clinical medicine}, volume = {12}, number = {22}, pages = {}, pmid = {38002659}, issn = {2077-0383}, abstract = {Seven major neurodegenerative diseases and their variants share many overlapping biomarkers that are calmodulin-binding proteins: Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTD), Huntington's disease (HD), Lewy body disease (LBD), multiple sclerosis (MS), and Parkinson's disease (PD). Calcium dysregulation is an early and persistent event in each of these diseases, with calmodulin serving as an initial and primary target of increased cytosolic calcium. Considering the central role of calcium dysregulation and its downstream impact on calcium signaling, calmodulin has gained interest as a major regulator of neurodegenerative events. Here, we show that calmodulin serves a critical role in neurodegenerative diseases via binding to and regulating an abundance of biomarkers, many of which are involved in multiple neurodegenerative diseases. Of special interest are the shared functions of calmodulin in the generation of protein biomarker aggregates in AD, HD, LBD, and PD, where calmodulin not only binds to amyloid beta, pTau, alpha-synuclein, and mutant huntingtin but also, via its regulation of transglutaminase 2, converts them into toxic protein aggregates. It is suggested that several calmodulin binding proteins could immediately serve as primary drug targets, while combinations of calmodulin binding proteins could provide simultaneous insight into the onset and progression of multiple neurodegenerative diseases.}, } @article {pmid38002573, year = {2023}, author = {Goto, S and Maeda, N and Uehara, K and Ogawa, K and Matsumaru, M and Sugiyama, S and Ohnuma, K and Lawu, T and Noda, T}, title = {Effect of Segmented Optical Axial Length on the Performance of New-Generation Intraocular Lens Power Calculation Formulas in Extremely Long Eyes.}, journal = {Journal of clinical medicine}, volume = {12}, number = {22}, pages = {}, pmid = {38002573}, issn = {2077-0383}, abstract = {PURPOSE: To evaluate the performance of traditional vergence formulas with segmented axial length (AL) compared to traditional composite AL in extremely long eyes, and to determine whether the segmented AL can be extended to the new-generation formulas, including the Barrett Universal II, Emmetropia Verifying Optical 2.0 (EVO2), Hill-RBF 3.0 (Hill3), Kane, and Ladas Super formula (LSF) formulas in extremely long eyes.

SETTING: National Hospital. Organization, Tokyo Medical Center, Japan.

DESIGN: Retrospective case series.

METHODS: Consecutive patients who underwent uncomplicated cataract surgery implanted with a three-piece intraocular lens between December 2015 and March 2021 were retrospectively reviewed. The composite AL was measured with a swept-source optical coherence tomography (SS-OCT) biometer using a mean refractive index. The segmented AL was calculated by summing the geometric lengths of the ocular segments (cornea, aqueous, lens, and vitreous) using multiple specific refractive indices based on the data obtained by the SS-OCT-based biometer. When refraction was measured at three months postoperatively, the median absolute errors (MedAEs) were calculated with two ALs for each formula.

RESULTS: The study included 31 eyes of 22 patients. The segmented AL (30.45 ± 1.23 mm) was significantly shorter than the composite AL (30.71 ± 1.28 mm, p < 0.001). The MedAEs were significantly reduced when using segmented AL for SRK/T, Haigis, Hill3, and LSF, compared to those obtained using composite AL (0.38 vs. 0.62, 0.48 vs. 0.79, 0.50 vs. 0.90, 0.34 vs. 0.61, p < 0.001 for all formulas, respectively). On the contrary, the MedAE obtained by Kane with segmented AL was significantly worse compared to the one with composite AL (0.35 vs. 0.27, p = 0.03).

CONCLUSION: In extremely high myopic eyes, the segmented AL improves the performance of SRK/T, Haigis, Hill3, and LSF formulas compared to the composite AL, while the segmented AL worsens the prediction accuracy of the Kane formula.}, } @article {pmid38002490, year = {2023}, author = {Yang, J and Xin, C and Huo, J and Li, X and Dong, H and Liu, Q and Li, R and Liu, Y}, title = {Rab Geranylgeranyltransferase Subunit Beta as a Potential Indicator to Assess the Progression of Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {13}, number = {11}, pages = {}, pmid = {38002490}, issn = {2076-3425}, support = {H2021206310//Natural Science Foundation of Hebei Province/ ; }, abstract = {BACKGROUND: Currently, there is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder. Many biomarkers have been proposed, but because ALS is a clinically heterogeneous disease with an unclear etiology, biomarker discovery for ALS has been challenging due to the lack of specificity of these biomarkers. In recent years, the role of autophagy in the development and treatment of ALS has become a research hotspot. In our previous studies, we found that the expression of RabGGTase (low RABGGTB expression and no change in RABGGTA) is lower in the lumbar and thoracic regions of spinal cord motoneurons in SOD1G93A mice compared with WT (wild-type) mice groups, and upregulation of RABGGTB promoted prenylation modification of Rab7, which promoted autophagy to protect neurons by degrading SOD1. Given that RabGGTase is associated with autophagy and autophagy is associated with inflammation, and based on the above findings, since peripheral blood mononuclear cells are readily available from patients with ALS, we proposed to investigate the expression of RabGGTase in peripheral inflammatory cells.

METHODS: Information and venous blood were collected from 86 patients diagnosed with ALS between January 2021 and August 2023. Flow cytometry was used to detect the expression of RABGGTB in monocytes from peripheral blood samples collected from patients with ALS and healthy controls. Extracted peripheral blood mononuclear cells (PBMCs) were differentiated in vitro into macrophages, and then the expression of RABGGTB was detected by immunofluorescence. RABGGTB levels in patients with ALS were analyzed to determine their impact on disease progression.

RESULTS: Using flow cytometry in monocytes and immunofluorescence in macrophages, we found that RABGGTB expression in the ALS group was significantly higher than in the control group. Age, sex, original location, disease course, C-reactive protein (CRP), and interleukin-6 (IL-6) did not correlate with the ALS functional rating scale-revised (ALSFRS-R), whereas the RABGGTB level was significantly correlated with the ALSFRS-R. In addition, multivariate analysis revealed a significant correlation between RABGGTB and ALSFRS-R score. Further analysis revealed a significant correlation between RABGGTB expression levels and disease progression levels (ΔFS).

CONCLUSIONS: The RABGGTB level was significantly increased in patients with ALS compared with healthy controls. An elevated RABGGTB level in patients with ALS is associated with the rate of progression in ALS, suggesting that elevated RABGGTB levels in patients with ALS may serve as an indicator for tracking ALS progression.}, } @article {pmid38002405, year = {2023}, author = {Wu, CM and Chen, YJ and Chen, SC and Zheng, SF}, title = {Creating an AI-Enhanced Morse Code Translation System Based on Images for People with Severe Disabilities.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {10}, number = {11}, pages = {}, pmid = {38002405}, issn = {2306-5354}, support = {NSTC 111-2221-E-167-039 and MOST 111-2221-E-218-023//the National Science and Technology Council (NSTC), Taiwan/ ; }, abstract = {(1) Background: Patients with severe physical impairments (spinal cord injury, cerebral palsy, amyotrophic lateral sclerosis) often have limited mobility due to physical limitations, and may even be bedridden all day long, losing the ability to take care of themselves. In more severe cases, the ability to speak may even be lost, making even basic communication very difficult. (2) Methods: This research will design a set of image-assistive communication equipment based on artificial intelligence to solve communication problems of daily needs. Using artificial intelligence for facial positioning, and facial-motion-recognition-generated Morse code, and then translating it into readable characters or commands, it allows users to control computer software by themselves and communicate through wireless networks or a Bluetooth protocol to control environment peripherals. (3) Results: In this study, 23 human-typed data sets were subjected to recognition using fuzzy algorithms. The average recognition rates for expert-generated data and data input by individuals with disabilities were 99.83% and 98.6%, respectively. (4) Conclusions: Through this system, users can express their thoughts and needs through their facial movements, thereby improving their quality of life and having an independent living space. Moreover, the system can be used without touching external switches, greatly improving convenience and safety.}, } @article {pmid38002264, year = {2023}, author = {Duranti, E and Villa, C}, title = {Muscle Involvement in Amyotrophic Lateral Sclerosis: Understanding the Pathogenesis and Advancing Therapeutics.}, journal = {Biomolecules}, volume = {13}, number = {11}, pages = {}, pmid = {38002264}, issn = {2218-273X}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/therapy/pathology ; Motor Neurons/metabolism ; Muscle, Skeletal/pathology ; Muscular Atrophy/metabolism ; Paralysis/complications/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal condition characterized by the selective loss of motor neurons in the motor cortex, brainstem, and spinal cord. Muscle involvement, muscle atrophy, and subsequent paralysis are among the main features of this disease, which is defined as a neuromuscular disorder. ALS is a persistently progressive disease, and as motor neurons continue to degenerate, individuals with ALS experience a gradual decline in their ability to perform daily activities. Ultimately, muscle function loss may result in paralysis, presenting significant challenges in mobility, communication, and self-care. While the majority of ALS research has traditionally focused on pathogenic pathways in the central nervous system, there has been a great interest in muscle research. These studies were carried out on patients and animal models in order to better understand the molecular mechanisms involved and to develop therapies aimed at improving muscle function. This review summarizes the features of ALS and discusses the role of muscle, as well as examines recent studies in the development of treatments.}, } @article {pmid38001994, year = {2023}, author = {Jauregui, C and Blanco-Luquin, I and Macías, M and Roldan, M and Caballero, C and Pagola, I and Mendioroz, M and Jericó, I}, title = {Exploring the Disease-Associated Microglia State in Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {11}, number = {11}, pages = {}, pmid = {38001994}, issn = {2227-9059}, abstract = {BACKGROUND: Neuroinflammation, and specifically microglia, plays an important but not-yet well-understood role in the pathophysiology of amyotrophic lateral sclerosis (ALS), constituting a potential therapeutic target for the disease. Recent studies have described the involvement of different microglial transcriptional patterns throughout neurodegenerative processes, identifying a new state of microglia: disease-associated microglia (DAM). The aim of this study is to investigate expression patterns of microglial-related genes in ALS spinal cord.

METHODS: We analyzed mRNA expression levels via RT-qPCR of several microglia-related genes in their homeostatic and DAM state in postmortem tissue (anterior horn of the spinal cord) from 20 subjects with ALS-TDP43 and 19 controls donors from the Navarrabiomed Biobank.

RESULTS: The expression levels of TREM2, MS4A, CD33, APOE and TYROBP were found to be elevated in the spinal cord from ALS subjects versus controls (p-value < 0.05). However, no statistically significant gene expression differences were observed for TMEM119, SPP1 and LPL.

CONCLUSIONS: This study suggests that a DAM-mediated inflammatory response is present in ALS, and TREM2 plays a significant role in immune function of microglia. It also supports the role of C33 and MS4A in the physiopathology of ALS.}, } @article {pmid38001967, year = {2023}, author = {Seki, S and Kitaoka, Y and Kawata, S and Nishiura, A and Uchihashi, T and Hiraoka, SI and Yokota, Y and Isomura, ET and Kogo, M and Tanaka, S}, title = {Characteristics of Sensory Neuron Dysfunction in Amyotrophic Lateral Sclerosis (ALS): Potential for ALS Therapy.}, journal = {Biomedicines}, volume = {11}, number = {11}, pages = {}, pmid = {38001967}, issn = {2227-9059}, support = {21K17088//JSPS KAKENHI/ ; 20H03887//JSPS KAKENHI/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by the progressive degeneration of motor neurons, resulting in muscle weakness, paralysis, and, ultimately, death. Presently, no effective treatment for ALS has been established. Although motor neuron dysfunction is a hallmark of ALS, emerging evidence suggests that sensory neurons are also involved in the disease. In clinical research, 30% of patients with ALS had sensory symptoms and abnormal sensory nerve conduction studies in the lower extremities. Peroneal nerve biopsies show histological abnormalities in 90% of the patients. Preclinical research has reported several genetic abnormalities in the sensory neurons of animal models of ALS, as well as in motor neurons. Furthermore, the aggregation of misfolded proteins like TAR DNA-binding protein 43 has been reported in sensory neurons. This review aims to provide a comprehensive description of ALS-related sensory neuron dysfunction, focusing on its clinical changes and underlying mechanisms. Sensory neuron abnormalities in ALS are not limited to somatosensory issues; proprioceptive sensory neurons, such as MesV and DRG neurons, have been reported to form networks with motor neurons and may be involved in motor control. Despite receiving limited attention, sensory neuron abnormalities in ALS hold potential for new therapies targeting proprioceptive sensory neurons.}, } @article {pmid38001926, year = {2023}, author = {Reddy, VP}, title = {Oxidative Stress in Health and Disease.}, journal = {Biomedicines}, volume = {11}, number = {11}, pages = {}, pmid = {38001926}, issn = {2227-9059}, abstract = {Oxidative stress, resulting from the excessive intracellular accumulation of reactive oxygen species (ROS), reactive nitrogen species (RNS), and other free radical species, contributes to the onset and progression of various diseases, including diabetes, obesity, diabetic nephropathy, diabetic neuropathy, and neurological diseases, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Oxidative stress is also implicated in cardiovascular disease and cancer. Exacerbated oxidative stress leads to the accelerated formation of advanced glycation end products (AGEs), a complex mixture of crosslinked proteins and protein modifications. Relatively high levels of AGEs are generated in diabetes, obesity, AD, and other I neurological diseases. AGEs such as N[e]-carboxymethyllysine (CML) serve as markers for disease progression. AGEs, through interaction with receptors for advanced glycation end products (RAGE), initiate a cascade of deleterious signaling events to form inflammatory cytokines, and thereby further exacerbate oxidative stress in a vicious cycle. AGE inhibitors, AGE breakers, and RAGE inhibitors are therefore potential therapeutic agents for multiple diseases, including diabetes and AD. The complexity of the AGEs and the lack of well-established mechanisms for AGE formation are largely responsible for the lack of effective therapeutics targeting oxidative stress and AGE-related diseases. This review addresses the role of oxidative stress in the pathogenesis of AGE-related chronic diseases, including diabetes and neurological disorders, and recent progress in the development of therapeutics based on antioxidants, AGE breakers and RAGE inhibitors. Furthermore, this review outlines therapeutic strategies based on single-atom nanozymes that attenuate oxidative stress through the sequestering of reactive oxygen species (ROS) and reactive nitrogen species (RNS).}, } @article {pmid38001861, year = {2023}, author = {Fu, RH}, title = {Pectolinarigenin Improves Oxidative Stress and Apoptosis in Mouse NSC-34 Motor Neuron Cell Lines Induced by C9-ALS-Associated Proline-Arginine Dipeptide Repeat Proteins by Enhancing Mitochondrial Fusion Mediated via the SIRT3/OPA1 Axis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {11}, pages = {}, pmid = {38001861}, issn = {2076-3921}, support = {MOST 105-2314-B-039-017-MY3//The Ministry of Science and Technology (Taiwan)/ ; DMR112-122//China Medical University Hospital (Taiwan)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is considered a fatal progressive degeneration of motor neurons (MN) caused by oxidative stress and mitochondrial dysfunction. There are currently no treatments available. The most common inherited form of ALS is the C9orf72 mutation (C9-ALS). The proline-arginine dipeptide repeat protein (PR-DPR) produced by C9-ALS has been confirmed to be a functionally acquired pathogenic factor that can cause increased ROS, mitochondrial defects, and apoptosis in motor neurons. Pectolinarigenin (PLG) from the traditional medicinal herb Linaria vulgaris has antioxidant and anti-apoptotic properties. I established a mouse NSC-34 motor neuron cell line model expressing PR-DPR and confirmed the neuroprotective effect of PLG. The results showed that ROS production and apoptosis caused by PR-DPR could be improved by PLG treatment. In terms of mechanism research, PR-DPR inhibited the activity of the mitochondrial fusion proteins OPA1 and mitofusin 2. Conversely, the expression of fission protein fission 1 and dynamin-related protein 1 (DRP1) increased. However, PLG treatment reversed these effects. Furthermore, I found that PLG increased the expression and deacetylation of OPA1. Deacetylation of OPA1 enhances mitochondrial fusion and resistance to apoptosis. Finally, transfection with Sirt3 small interfering RNA abolished the neuroprotective effects of PLG. In summary, the mechanism by which PLG alleviates PR-DPR toxicity is mainly achieved by activating the SIRT3/OPA1 axis to regulate the balance of mitochondrial dynamics. Taken together, the potential of PLG in preclinical studies for C9-ALS drug development deserves further evaluation.}, } @article {pmid38001860, year = {2023}, author = {Martinez, A and Lamaizon, CM and Valls, C and Llambi, F and Leal, N and Fitzgerald, P and Guy, C and Kamiński, MM and Inestrosa, NC and van Zundert, B and Cancino, GI and Dulcey, AE and Zanlungo, S and Marugan, JJ and Hetz, C and Green, DR and Alvarez, AR}, title = {c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {11}, pages = {}, pmid = {38001860}, issn = {2076-3921}, support = {R35 CA231620/CA/NCI NIH HHS/United States ; R35CA23160/BC/NCI NIH HHS/United States ; Intramural funding/TR/NCATS NIH HHS/United States ; }, abstract = {The endoplasmic reticulum is a subcellular organelle key in the control of synthesis, folding, and sorting of proteins. Under endoplasmic reticulum stress, an adaptative unfolded protein response is activated; however, if this activation is prolonged, cells can undergo cell death, in part due to oxidative stress and mitochondrial fragmentation. Here, we report that endoplasmic reticulum stress activates c-Abl tyrosine kinase, inducing its translocation to mitochondria. We found that endoplasmic reticulum stress-activated c-Abl interacts with and phosphorylates the mitochondrial fusion protein MFN2, resulting in mitochondrial fragmentation and apoptosis. Moreover, the pharmacological or genetic inhibition of c-Abl prevents MFN2 phosphorylation, mitochondrial fragmentation, and apoptosis in cells under endoplasmic reticulum stress. Finally, in the amyotrophic lateral sclerosis mouse model, where endoplasmic reticulum and oxidative stress has been linked to neuronal cell death, we demonstrated that the administration of c-Abl inhibitor neurotinib delays the onset of symptoms. Our results uncovered a function of c-Abl in the crosstalk between endoplasmic reticulum stress and mitochondrial dynamics via MFN2 phosphorylation.}, } @article {pmid38001563, year = {2023}, author = {Fröhlich, A and Pfaff, AL and Bubb, VJ and Quinn, JP and Koks, S}, title = {Transcriptomic profiling of cerebrospinal fluid identifies ALS pathway enrichment and RNA biomarkers in MND individuals.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {248}, number = {23}, pages = {2325-2331}, pmid = {38001563}, issn = {1535-3699}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/complications/metabolism ; *Motor Neuron Disease/cerebrospinal fluid/complications ; Gene Expression Profiling ; Biomarkers/metabolism ; RNA ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder and the most common form of motor neurone disease (MND) which is characterized by the damage and death of motor neurons in the brain and spinal cord of affected individuals. Due to the heterogeneity of the disease, a better understanding of the interaction between genetics and biochemistry with the identification of biomarkers is crucial for therapy development. In this study, we used cerebrospinal fluid (CSF) RNA-sequencing data from the New York Genome Center (NYGC) ALS Consortium and analyzed differential gene expression between 47 MND individuals and 29 healthy controls. Pathway analysis showed that the affected genes are enriched in many pathways associated with ALS, including nucleocytoplasmic transport, autophagy, and apoptosis. Moreover, we assessed differential expression on both gene- and transcript-based levels and demonstrate that the expression of previously identified potential biomarkers, including CAPG, CCL3, and MAP2, was significantly higher in MND individuals. Ultimately, this study highlights the transcriptomic composition of CSF which enables insights into changes in the brain in ALS and therefore increases the confidence in the use of CSF for biomarker development.}, } @article {pmid38001557, year = {2024}, author = {Genge, A and Wainwright, S and Vande Velde, C}, title = {Amyotrophic lateral sclerosis: exploring pathophysiology in the context of treatment.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {225-236}, doi = {10.1080/21678421.2023.2278503}, pmid = {38001557}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex, neurodegenerative disorder in which alterations in structural, physiological, and metabolic parameters act synergistically. Over the last decade there has been a considerable focus on developing drugs to slow the progression of the disease. Despite this, only four disease-modifying therapies are approved in North America. Although additional research is required for a thorough understanding of ALS, we have accumulated a large amount of knowledge that could be better integrated into future clinical trials to accelerate drug development and provide patients with improved treatment options. It is likely that future, successful ALS treatments will take a multi-pronged therapeutic approach, targeting different pathways, akin to personalized medicine in oncology. In this review, we discuss the link between ALS pathophysiology and treatments, looking at the therapeutic failures as learning opportunities that can help us refine and optimize drug development.}, } @article {pmid38001260, year = {2023}, author = {Kuan, LH and Parnianpour, P and Kushol, R and Kumar, N and Anand, T and Kalra, S and Greiner, R}, title = {Accurate personalized survival prediction for amyotrophic lateral sclerosis patients.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {20713}, pmid = {38001260}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Neurodegenerative Diseases ; Probability ; Brain ; Learning ; Disease Progression ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disease. Accurately predicting the survival time for ALS patients can help patients and clinicians to plan for future treatment and care. We describe the application of a machine-learned tool that incorporates clinical features and cortical thickness from brain magnetic resonance (MR) images to estimate the time until a composite respiratory failure event for ALS patients, and presents the prediction as individual survival distributions (ISDs). These ISDs provide the probability of survival (none of the respiratory failures) at multiple future time points, for each individual patient. Our learner considers several survival prediction models, and selects the best model to provide predictions. We evaluate our learned model using the mean absolute error margin (MAE-margin), a modified version of mean absolute error that handles data with censored outcomes. We show that our tool can provide helpful information for patients and clinicians in planning future treatment.}, } @article {pmid38000932, year = {2024}, author = {Abel, EJ and Master, VA and Spiess, PE and Raman, JD and Shapiro, DD and Sexton, WJ and Zemp, L and Patil, D and Lauer, K and Allen, GO and Matin, SF and Karam, JA}, title = {Reply to Eduard Roussel, Riccardo Bertolo, Chiara Ciccarese, et al's Letter to the Editor re: E. Jason Abel, Viraj A. Master, Philippe E. Spiess, et al. The Selection for Cytoreductive Nephrectomy (SCREEN) Score: Improving Surgical Risk Stratification by Integrating Common Radiographic Features. Eur Urol Oncol. 2023;6:266-274.}, journal = {European urology oncology}, volume = {7}, number = {2}, pages = {302-303}, doi = {10.1016/j.euo.2023.10.025}, pmid = {38000932}, issn = {2588-9311}, mesh = {Humans ; *Cytoreduction Surgical Procedures ; *Kidney Neoplasms/surgery ; Nephrectomy ; Risk Assessment ; }, } @article {pmid37999738, year = {2024}, author = {Ovsepian, SV and O'Leary, VB and Martinez, S}, title = {Selective vulnerability of motor neuron types and functional groups to degeneration in amyotrophic lateral sclerosis: review of the neurobiological mechanisms and functional correlates.}, journal = {Brain structure & function}, volume = {229}, number = {1}, pages = {1-14}, pmid = {37999738}, issn = {1863-2661}, support = {Innovation Fund Award 2022//University of Greenwich/ ; COOPERATIO-207036//VBO, Charles University/ ; SAF2017-83702-R//Una manera de hacer Europa/ ; }, mesh = {Humans ; Animals ; *Amyotrophic Lateral Sclerosis ; Motor Neurons ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterised by a progressive loss of motor neurons controlling voluntary muscle activity. The disease manifests through a variety of motor dysfunctions related to the extent of damage and loss of neurons at different anatomical locations. Despite extensive research, it remains unclear why some motor neurons are especially susceptible to the disease, while others are affected less or even spared. In this article, we review the neurobiological mechanisms, neurochemical profiles, and morpho-functional characteristics of various motor neuron groups and types of motor units implicated in their differential exposure to degeneration. We discuss specific cell-autonomous (intrinsic) and extrinsic factors influencing the vulnerability gradient of motor units and motor neuron types to ALS, with their impact on disease manifestation, course, and prognosis, as revealed in preclinical and clinical studies. We consider the outstanding challenges and emerging opportunities for interpreting the phenotypic and mechanistic variability of the disease to identify targets for clinical interventions.}, } @article {pmid37999522, year = {2023}, author = {Metcalf, JS and Banack, SA and Cox, PA}, title = {Cyanotoxin Analysis of Air Samples from the Great Salt Lake.}, journal = {Toxins}, volume = {15}, number = {11}, pages = {}, pmid = {37999522}, issn = {2072-6651}, mesh = {Humans ; *Lakes/microbiology ; *Cyanobacteria ; Water ; Utah ; Cyanobacteria Toxins ; }, abstract = {The Great Salt Lake in Utah is the largest saline lake in the Western hemisphere and one of the largest terminal lakes in the world. Situated at the eastern edge of the Great Basin, it is a remnant of the freshwater Lake Bonneville whose water level precipitously lowered about 12,000 years ago due to a natural break in Red Rock pass to the north. It contains a diverse assemblage of cyanobacteria which vary spatially dependent on salinity. In 1984, the waters of the Great Salt Lake occupied 8500 km[2]. Nearly four decades later, the waters occupy 2500 km[2]-a reduction in surface area of 71%. With predominantly westerly winds, there is a potential for the adjacent metropolitan residents to the east to be exposed to airborne cyanobacteria- and cyanotoxin-containing dust. During the summer and fall months of 2022, air and dried sediment samples were collected and assessed for the presence of BMAA which has been identified as a risk factor for ALS. Collection of air samples equivalent to a person breathing for 1 h resulted in BMAA and isomers being found in some air samples, along with their presence in exposed lakebed samples. There was no clear relationship between the presence of these toxins in airborne and adjacent lakebed samples, suggesting that airborne toxins may originate from diffuse rather than point sources. These findings confirm that continued low water levels in the Great Salt Lake may constitute an increasing health hazard for the 2.5 million inhabitants of communities along the Wasatch Front.}, } @article {pmid37999510, year = {2023}, author = {Violi, JP and Pu, L and Pravadali-Cekic, S and Bishop, DP and Phillips, CR and Rodgers, KJ}, title = {Effects of the Toxic Non-Protein Amino Acid β-Methylamino-L-Alanine (BMAA) on Intracellular Amino Acid Levels in Neuroblastoma Cells.}, journal = {Toxins}, volume = {15}, number = {11}, pages = {}, pmid = {37999510}, issn = {2072-6651}, mesh = {Animals ; Humans ; Amino Acids ; *Amino Acids, Diamino/toxicity/metabolism ; Serine/pharmacology ; Neurotoxins/toxicity ; *Neuroblastoma ; }, abstract = {The cyanobacterial non-protein amino acid (AA) β-Methylamino-L-alanine (BMAA) is considered to be a neurotoxin. BMAA caused histopathological changes in brains and spinal cords of primates consistent with some of those seen in early motor neuron disease; however, supplementation with L-serine protected against some of those changes. We examined the impact of BMAA on AA concentrations in human neuroblastoma cells in vitro. Cells were treated with 1000 µM BMAA and intracellular free AA concentrations in treated and control cells were compared at six time-points over a 48 h culture period. BMAA had a profound effect on intracellular AA levels at specific time points but in most cases, AA homeostasis was re-established in the cell. The most heavily impacted amino acid was serine which was depleted in BMAA-treated cells from 9 h onwards. Correction of serine depletion could be a factor in the observation that supplementation with L-serine protects against BMAA toxicity in vitro and in vivo. AAs that could potentially be involved in protection against BMAA-induced oxidation such as histidine, tyrosine, and phenylalanine were depleted in cells at later time points.}, } @article {pmid37999501, year = {2023}, author = {Metcalf, JS and Banack, SA and Wyatt, PB and Nunn, PB and Cox, PA}, title = {A Direct Analysis of β-N-methylamino-l-alanine Enantiomers and Isomers and Its Application to Cyanobacteria and Marine Mollusks.}, journal = {Toxins}, volume = {15}, number = {11}, pages = {}, pmid = {37999501}, issn = {2072-6651}, mesh = {Animals ; Humans ; Chromatography, Liquid/methods ; Tandem Mass Spectrometry ; *Amino Acids, Diamino/toxicity ; Amino Acids/analysis ; *Bivalvia/chemistry ; *Cyanobacteria/metabolism ; Neurotoxins/toxicity ; }, abstract = {Of the wide variety of toxic compounds produced by cyanobacteria, the neurotoxic amino acid β-N-methylamino-l-alanine (BMAA) has attracted attention as a result of its association with chronic human neurodegenerative diseases such as ALS and Alzheimer's. Consequently, specific detection methods are required to assess the presence of BMAA and its isomers in environmental and clinical materials, including cyanobacteria and mollusks. Although the separation of isomers such as β-amino-N-methylalanine (BAMA), N-(2-aminoethyl)glycine (AEG) and 2,4-diaminobutyric acid (DAB) from BMAA has been demonstrated during routine analysis, a further compounding factor is the potential presence of enantiomers for some of these isomers. Current analytical methods for BMAA mostly do not discriminate between enantiomers, and the chiral configuration of BMAA in cyanobacteria is still largely unexplored. To understand the potential for the occurrence of D-BMAA in cyanobacteria, a chiral UPLC-MS/MS method was developed to separate BMAA enantiomers and isomers and to determine the enantiomeric configuration of endogenous free BMAA in a marine Lyngbya mat and two mussel reference materials. After extraction, purification and derivatization with N-(4-nitrophenoxycarbonyl)-l-phenylalanine 2-methoxyethyl ester ((S)-NIFE), both L- and D-BMAA were identified as free amino acids in cyanobacterial materials, whereas only L-BMAA was identified in mussel tissues. The finding of D-BMAA in biological environmental materials raises questions concerning the source and role of BMAA enantiomers in neurological disease.}, } @article {pmid37997256, year = {2024}, author = {Barker, MS and Ceslis, A and Argall, R and McCombe, P and Henderson, RD and Robinson, GA}, title = {Verbal and nonverbal fluency in amyotrophic lateral sclerosis.}, journal = {Journal of neuropsychology}, volume = {18}, number = {2}, pages = {265-285}, doi = {10.1111/jnp.12354}, pmid = {37997256}, issn = {1748-6653}, support = {//Brazil Family Program for Neurology/ ; //Motor Neurone Disease Research Institute of Australia/ ; APP1135769//National Health and Medical Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; Female ; Middle Aged ; Aged ; *Neuropsychological Tests ; *Gestures ; Verbal Behavior/physiology ; Apathy/physiology ; Adult ; Semantics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multi-system disorder that commonly affects cognition and behaviour. Verbal fluency impairments are consistently reported in ALS patients, and we aimed to investigate whether this deficit extends beyond the verbal domain. We further aimed to determine whether deficits are underpinned by a primary intrinsic response generation impairment (i.e., a global reduction across tasks), potentially related to apathy, or an inability to maintain responding over time (i.e., a 'drop off' pattern). Twenty-two ALS patients and 21 demographically-matched controls completed verbal and nonverbal fluency tasks (phonemic/semantic word fluency, design fluency, gesture fluency and ideational fluency), requiring the generation of responses over a specified time period. Fluency performance was analysed in terms of the overall number of novel items produced, as well as the number of items produced in the first 'initiation' and the remaining 'maintenance' time periods. ALS patients' overall performance was not globally reduced across tasks. Patients were impaired only on meaningful gesture fluency, which requires the generation of gestures that communicate meaning (e.g., waving). On phonemic fluency, ALS patients showed a 'drop off' pattern of performance, where they had difficulty maintaining responding over time, but this pattern was not evident on the other fluency tasks. Apathy did not appear to be related to fluency performance. The selective meaningful gesture fluency deficit, in the context of preserved meaningless gesture fluency, highlights that the retrieval of action knowledge may be weakened in early ALS.}, } @article {pmid37996528, year = {2024}, author = {López-Erauskin, J and Bravo-Hernandez, M and Presa, M and Baughn, MW and Melamed, Z and Beccari, MS and Agra de Almeida Quadros, AR and Arnold-Garcia, O and Zuberi, A and Ling, K and Platoshyn, O and Niño-Jara, E and Ndayambaje, IS and McAlonis-Downes, M and Cabrera, L and Artates, JW and Ryan, J and Hermann, A and Ravits, J and Bennett, CF and Jafar-Nejad, P and Rigo, F and Marsala, M and Lutz, CM and Cleveland, DW and Lagier-Tourenne, C}, title = {Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation.}, journal = {Nature neuroscience}, volume = {27}, number = {1}, pages = {34-47}, pmid = {37996528}, issn = {1546-1726}, support = {RF1 NS124203/NS/NINDS NIH HHS/United States ; R01 NS124203/NS/NINDS NIH HHS/United States ; T32 AG066596/AG/NIA NIH HHS/United States ; P30 NS047101/NS/NINDS NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; T32 GM008666/GM/NIGMS NIH HHS/United States ; R01 NS112503/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Axons/physiology ; Denervation ; DNA-Binding Proteins/genetics ; Intermediate Filaments/metabolism/pathology ; Motor Neurons/metabolism ; Stathmin/genetics/metabolism ; Disease Models, Animal ; }, abstract = {The mRNA transcript of the human STMN2 gene, encoding for stathmin-2 protein (also called SCG10), is profoundly impacted by TAR DNA-binding protein 43 (TDP-43) loss of function. The latter is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Using a combination of approaches, including transient antisense oligonucleotide-mediated suppression, sustained shRNA-induced depletion in aging mice, and germline deletion, we show that stathmin-2 has an important role in the establishment and maintenance of neurofilament-dependent axoplasmic organization that is critical for preserving the caliber and conduction velocity of myelinated large-diameter axons. Persistent stathmin-2 loss in adult mice results in pathologies found in ALS, including reduced interneurofilament spacing, axonal caliber collapse that drives tearing within outer myelin layers, diminished conduction velocity, progressive motor and sensory deficits, and muscle denervation. These findings reinforce restoration of stathmin-2 as an attractive therapeutic approach for ALS and other TDP-43-dependent neurodegenerative diseases.}, } @article {pmid37996229, year = {2023}, author = {Del Pozo Vegas, C and Zalama-Sánchez, D and Sanz-Garcia, A and López-Izquierdo, R and Sáez-Belloso, S and Mazas Perez Oleaga, C and Domínguez Azpíroz, I and Elío Pascual, I and Martín-Rodríguez, F}, title = {Prehospital acute life-threatening cardiovascular disease in elderly: an observational, prospective, multicentre, ambulance-based cohort study.}, journal = {BMJ open}, volume = {13}, number = {11}, pages = {e078815}, pmid = {37996229}, issn = {2044-6055}, mesh = {Adult ; Aged ; Humans ; Ambulances ; *Cardiovascular Diseases/therapy ; Cohort Studies ; *Emergency Medical Services/methods ; Prospective Studies ; }, abstract = {OBJECTIVE: The aim was to explore the association of demographic and prehospital parameters with short-term and long-term mortality in acute life-threatening cardiovascular disease by using a hazard model, focusing on elderly individuals, by comparing patients under 75 years versus patients over 75 years of age.

DESIGN: Prospective, multicentre, observational study.

SETTING: Emergency medical services (EMS) delivery study gathering data from two back-to-back studies between 1 October 2019 and 30 November 2021. Six advanced life support (ALS), 43 basic life support and five hospitals in Spain were considered.

PARTICIPANTS: Adult patients suffering from acute life-threatening cardiovascular disease attended by the EMS.

The primary outcome was in-hospital mortality from any cause within the first to the 365 days following EMS attendance. The main measures included prehospital demographics, biochemical variables, prehospital ALS techniques used and syndromic suspected conditions.

RESULTS: A total of 1744 patients fulfilled the inclusion criteria. The 365-day cumulative mortality in the elderly amounted to 26.1% (229 cases) versus 11.6% (11.6%) in patients under 75 years old. Elderly patients (≥75 years) presented a twofold risk of mortality compared with patients ≤74 years. Life-threatening interventions (mechanical ventilation, cardioversion and defibrillation) were also related to a twofold increased risk of mortality. Importantly, patients suffering from acute heart failure presented a more than twofold increased risk of mortality.

CONCLUSIONS: This study revealed the prehospital variables associated with the long-term mortality of patients suffering from acute cardiovascular disease. Our results provide important insights for the development of specific codes or scores for cardiovascular diseases to facilitate the risk of mortality characterisation.}, } @article {pmid37995198, year = {2023}, author = {Ayoubi, R and Ryan, J and Biddle, MS and Alshafie, W and Fotouhi, M and Bolivar, SG and Ruiz Moleon, V and Eckmann, P and Worrall, D and McDowell, I and Southern, K and Reintsch, W and Durcan, TM and Brown, C and Bandrowski, A and Virk, H and Edwards, AM and McPherson, P and Laflamme, C}, title = {Scaling of an antibody validation procedure enables quantification of antibody performance in major research applications.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {37995198}, issn = {2050-084X}, support = {U54 AG065187/AG/NIA NIH HHS/United States ; RF1AG057443/AG/NIA NIH HHS/United States ; R24 GM144308/GM/NIGMS NIH HHS/United States ; FDN154305/CAPMC/CIHR/Canada ; SGC/JAN18/988-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; RF1 AG057443/AG/NIA NIH HHS/United States ; U54AG065187/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Proteome ; *Antibodies/chemistry ; }, abstract = {Antibodies are critical reagents to detect and characterize proteins. It is commonly understood that many commercial antibodies do not recognize their intended targets, but information on the scope of the problem remains largely anecdotal, and as such, feasibility of the goal of at least one potent and specific antibody targeting each protein in a proteome cannot be assessed. Focusing on antibodies for human proteins, we have scaled a standardized characterization approach using parental and knockout cell lines (Laflamme et al., 2019) to assess the performance of 614 commercial antibodies for 65 neuroscience-related proteins. Side-by-side comparisons of all antibodies against each target, obtained from multiple commercial partners, have demonstrated that: (i) more than 50% of all antibodies failed in one or more applications, (ii) yet, ~50-75% of the protein set was covered by at least one high-performing antibody, depending on application, suggesting that coverage of human proteins by commercial antibodies is significant; and (iii) recombinant antibodies performed better than monoclonal or polyclonal antibodies. The hundreds of underperforming antibodies identified in this study were found to have been used in a large number of published articles, which should raise alarm. Encouragingly, more than half of the underperforming commercial antibodies were reassessed by the manufacturers, and many had alterations to their recommended usage or were removed from the market. This first study helps demonstrate the scale of the antibody specificity problem but also suggests an efficient strategy toward achieving coverage of the human proteome; mine the existing commercial antibody repertoire, and use the data to focus new renewable antibody generation efforts.}, } @article {pmid37993492, year = {2023}, author = {Ragagnin, AMG and Sundaramoorthy, V and Farzana, F and Gautam, S and Saravanabavan, S and Takalloo, Z and Mehta, P and Do-Ha, D and Parakh, S and Shadfar, S and Hunter, J and Vidal, M and Jagaraj, CJ and Brocardo, M and Konopka, A and Yang, S and Rayner, SL and Williams, KL and Blair, IP and Chung, RS and Lee, A and Ooi, L and Atkin, JD}, title = {ALS/FTD-associated mutation in cyclin F inhibits ER-Golgi trafficking, inducing ER stress, ERAD and Golgi fragmentation.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {20467}, pmid = {37993492}, issn = {2045-2322}, support = {10305133//National Health and Medical Research Council of Australia (NHMRC)/ ; 1086887//National Health and Medical Research Council of Australia (NHMRC)/ ; 1095215//National Health and Medical Research Council of Australia (NHMRC)/ ; 10305133//National Health and Medical Research Council of Australia (NHMRC)/ ; 1086887//National Health and Medical Research Council of Australia (NHMRC)/ ; 1095215//National Health and Medical Research Council of Australia (NHMRC)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Endoplasmic Reticulum-Associated Degradation ; Endoplasmic Reticulum/metabolism ; Golgi Apparatus/metabolism ; Mutation ; Cyclins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severely debilitating neurodegenerative condition that is part of the same disease spectrum as frontotemporal dementia (FTD). Mutations in the CCNF gene, encoding cyclin F, are present in both sporadic and familial ALS and FTD. However, the pathophysiological mechanisms underlying neurodegeneration remain unclear. Proper functioning of the endoplasmic reticulum (ER) and Golgi apparatus compartments is essential for normal physiological activities and to maintain cellular viability. Here, we demonstrate that ALS/FTD-associated variant cyclin F[S621G] inhibits secretory protein transport from the ER to Golgi apparatus, by a mechanism involving dysregulation of COPII vesicles at ER exit sites. Consistent with this finding, cyclin F[S621G] also induces fragmentation of the Golgi apparatus and activates ER stress, ER-associated degradation, and apoptosis. Induction of Golgi fragmentation and ER stress were confirmed with a second ALS/FTD variant cyclin F[S195R], and in cortical primary neurons. Hence, this study provides novel insights into pathogenic mechanisms associated with ALS/FTD-variant cyclin F, involving perturbations to both secretory protein trafficking and ER-Golgi homeostasis.}, } @article {pmid37993052, year = {2024}, author = {Wu, F and Malek, AM and Buchanich, JM and Arena, VC and Rager, JR and Sharma, RK and Vena, JE and Bear, T and Talbott, EO}, title = {Exposure to ambient air toxicants and the risk of amyotrophic lateral sclerosis (ALS): A matched case control study.}, journal = {Environmental research}, volume = {242}, number = {}, pages = {117719}, doi = {10.1016/j.envres.2023.117719}, pmid = {37993052}, issn = {1096-0953}, mesh = {Humans ; United States/epidemiology ; Case-Control Studies ; *Amyotrophic Lateral Sclerosis/chemically induced/epidemiology ; *Vinyl Chloride ; Bayes Theorem ; Risk Factors ; Solvents ; Cyanides ; *Dinitrobenzenes ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with few risk factors identified and no known cure. Gene-environment interaction is hypothesized especially for sporadic ALS cases (90-95%) which are of unknown etiology. We aimed to investigate risk factors for ALS including exposure to ambient air toxics.

METHODS: This population-based case-control study included 267 ALS cases (from the United States [U.S.] Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry National ALS Registry and Biorepository) and 267 age, sex, and county-matched controls identified via a commercial database. Exposure assessment for 34 ambient air toxicants was performed by assigning census tract-level U.S. Environmental Protection Agency (EPA) 2011 National Air Toxics Assessment (NATA) data to participants' residential ZIP codes. Conditional logistic regression was used to compute adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for individual compounds, chemical classes, and overall exposure. Sensitivity analyses using both conditional logistic regression and Bayesian grouped weighted quartile sum (GWQS) models were performed to assess the integrity of findings.

RESULTS: Using the 2011 NATA, the highest exposure quartile (Q4) compared to the lowest (Q1) of vinyl chloride (aOR = 6.00, 95% CI: 1.87-19.25), 2,4-dinitrotoluene (aOR = 5.45, 95% CI: 1.53-19.36), cyanide (aOR = 4.34, 95% CI: 1.52-12.43), cadmium (aOR = 3.30, 95% CI: 1.11-9.77), and carbon disulfide (aOR = 2.98, 95% CI: 1.00-8.91) was associated with increased odds of ALS. Residential air selenium showed an inverse association with ALS (second quartile [Q2] vs. Q1: aOR = 0.38, 95% CI: 0.18-0.79). Additionally, residential exposure to organic/chlorinated solvents (Q4 vs Q1: aOR = 2.62, 95% CI: 1.003-6.85) was associated with ALS.

CONCLUSIONS: Our findings using the 2011 NATA linked by census tract to residential area provide evidence of increased ALS risk in cases compared to controls for 2,4-dinitrotoluene, vinyl chloride, cyanide, and the organic/chlorinated solvents class. This underscores the importance of ongoing surveillance of potential exposures for at-risk populations.}, } @article {pmid37992921, year = {2024}, author = {Li, L and Lei, T and Xing, C and Du, H}, title = {Advances in microfluidic chips targeting toxic aggregation proteins for neurodegenerative diseases.}, journal = {International journal of biological macromolecules}, volume = {256}, number = {Pt 2}, pages = {128308}, doi = {10.1016/j.ijbiomac.2023.128308}, pmid = {37992921}, issn = {1879-0003}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Microfluidics ; *Alzheimer Disease ; Amyloid beta-Peptides ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by nervous system damage, often influenced by genetic and aging factors. Pathological analysis frequently reveals the presence of aggregated toxic proteins. The intricate and poorly understood origins of these diseases have hindered progress in early diagnosis and drug development. The development of novel in-vitro and in-vivo models could enhance our comprehension of ND mechanisms and facilitate clinical treatment advancements. Microfluidic chips are employed to establish three-dimensional culture conditions, replicating the human ecological niche and creating a microenvironment conducive to neuronal cell survival. The incorporation of mechatronic controls unifies the chip, cells, and culture medium optimizing living conditions for the cells. This study provides a comprehensive overview of microfluidic chip applications in drug and biomarker screening for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Our Lab-on-a-Chip system releases toxic proteins to simulate the pathological characteristics of neurodegenerative diseases, encompassing β-amyloid, α-synuclein, huntingtin, TAR DNA-binding protein 43, and Myelin Basic Protein. Investigating molecular and cellular interactions in vitro can enhance our understanding of disease mechanisms while minimizing harmful protein levels and can aid in screening potential therapeutic agents. We anticipate that our research will promote the utilization of microfluidic chips in both fundamental research and clinical applications for neurodegenerative diseases.}, } @article {pmid37992159, year = {2023}, author = {Shimizu, M and Shiraishi, N and Tada, S and Sasaki, T and Beck, G and Nagano, S and Kinoshita, M and Sumi, H and Sugimoto, T and Ishida, Y and Koda, T and Ishikura, T and Sugiyama, Y and Kihara, K and Kanakura, M and Nakajima, T and Takeda, S and Takahashi, MP and Yamashita, T and Okuno, T and Mochizuki, H}, title = {RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS.}, journal = {Science advances}, volume = {9}, number = {47}, pages = {eadg3193}, pmid = {37992159}, issn = {2375-2548}, mesh = {Animals ; Humans ; Mice ; Actins ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Antibodies ; Mice, Transgenic ; Motor Neurons/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone-collapsing factor. Previous reports have demonstrated the multifunctional roles of RGMa mediated by neogenin1. However, the pathogenic involvement of RGMa in amyotrophic lateral sclerosis (ALS) remains unclear. Here, we demonstrated that RGMa concentration was elevated in the cerebrospinal fluid of both patients with ALS and transgenic mice overexpressing the mutant human superoxide dismutase1 (mSOD1 mice). Treatment with humanized anti-RGMa monoclonal antibody ameliorated the clinical symptoms in mSOD1 mice. Histochemical analysis revealed that the anti-RGMa antibody significantly decreased mutant SOD1 protein accumulation in the motor neurons of mSOD1 mice via inhibition of actin depolymerization. In vitro analysis revealed that the anti-RGMa antibody inhibited the cellular uptake of the mutant SOD1 protein, presumably by reinforcing the neuronal actin barrier. Collectively, these data suggest that RGMa leads to the collapse of the neuronal actin barrier and promotes aberrant protein deposition, resulting in exacerbation of the ALS pathology.}, } @article {pmid37991691, year = {2024}, author = {Yu, L and Xu, G and Zhou, Q and Ouyang, M and Gao, L and Zeng, S}, title = {Biomechanical properties of the ascending aorta in patients with arterial hypertension by velocity vector imaging.}, journal = {The international journal of cardiovascular imaging}, volume = {40}, number = {2}, pages = {397-405}, pmid = {37991691}, issn = {1875-8312}, support = {81801721//the State Natural Sciences Foundation of China/ ; 81871372//the State Natural Sciences Foundation of China/ ; 2019JJ50880//the Natural Science Foundation of Hunan Province/ ; 2019JJ40425//the Natural Science Foundation of Hunan Province/ ; }, mesh = {Humans ; Aorta, Thoracic ; Predictive Value of Tests ; *Hypertension/complications/diagnosis/epidemiology ; Aorta/diagnostic imaging ; Echocardiography/methods ; *Aortic Diseases ; *Ventricular Dysfunction, Left ; }, abstract = {Aortic stiffness is an important risk factor for cardiovascular events and morbidity. Increased aortic stiffness is associated with an increase in cardiac and vascular hypertension-related organ damage. To evaluate the biomechanical properties of the ascending aorta (AA) in patients with arterial hypertension (AH) by velocity vector imaging (VVI). Ninety-five patients with AH and 53 normal healthy control participants were prospectively enrolled. AA biomechanical properties, i.e., ascending aortic global longitudinal strain (ALS), ascending aortic global circumferential strain (ACS), and fractional area change (FAC), were evaluated by VVI. Relative wall thickness (RWT) and left ventricular mass (LVM) were calculated. Pulsed Doppler early transmitral peak flow velocity (E), early diastolic mitral annular velocity (e'), left ventricular global longitudinal strain (GLS), distensibility (D) and stiffness index (SI) of AA were also obtained. The ALS, ACS and FAC were significantly lower in the AH patients, especially in those with ascending aorta dilatation (AAD), than in the normal healthy control subjects. The patients with AAD had a higher E/e' ratio, RWT, LVM and SI and a lower GLS and D than patients without AAD and normal healthy volunteers (p < 0.05). There were significant associations between biomechanical properties and D, SI, E/e' and GLS (ALS and D: r = 0.606, ALS and SI: r = - 0.645, ALS and E/e': r = - 0.489, ALS and GLS: r = 0.466, ACS and D: r = 0.564, ACS and SI: r = - 0.567, ACS and E/e': r = - 0.313, ACS and GLS: r = 0.320, FAC and D: r = 0.649, FAC and SI: r = - 0.601, FAC and E/e': r = - 0.504, FAC and GLS: r = 0.524, respectively, p < 0.05). The biomechanical properties of AA were impaired in patients with AH, especially patients with ascending aorta dilatation. Hypertension is associated with a high prevalence of diastolic and systolic dysfunction and increased arterial stiffness. Further study is needed to evaluate the clinical application of AA biomechanical properties by VVI.}, } @article {pmid37990637, year = {2024}, author = {Ng, SC and McCombie, A and Frizelle, F and Eglinton, T}, title = {Influence of the type of anatomic resection on anastomotic leak after surgery for colon cancer.}, journal = {ANZ journal of surgery}, volume = {94}, number = {3}, pages = {424-428}, doi = {10.1111/ans.18782}, pmid = {37990637}, issn = {1445-2197}, mesh = {Humans ; Male ; *Anastomotic Leak/epidemiology/etiology ; Retrospective Studies ; Risk Factors ; *Colonic Neoplasms/pathology ; Colectomy/adverse effects/methods ; Anastomosis, Surgical/adverse effects/methods ; }, abstract = {INTRODUCTION: Anastomotic leak (AL) after colon cancer resection is feared by surgeons because of its associated morbidity and mortality. Considerable research has been directed at predictive factors for AL, but not the anatomic type of colonic resection. Anecdotally, certain types of resection are associated with higher leak rates although there remains a paucity of data on this. This study aimed to determine the AL rate for different types of colon cancer resection to inform decisions regarding the choice of operation.

METHODOLOGY: Retrospective analysis of Bowel Cancer Outcome Registry (BCOR) for all colonic cancer resections with anastomosis between January 2007 and December 2020. Demographic, patient, tumour and outcome data were analysed. AL rates were compared among the different colonic procedures with both univariate and multivariate analysis.

RESULTS: 20 191 patients who underwent resection with anastomosis for cancer were included in this study. Of these 535 (2.6%) suffered ALs. While the univariate analysis found male sex, procedure type, symptomatic cancers, emergency surgery, unsupervised registrars, conversion to open surgery, medical complications and higher TNM staging were associated with AL, multivariate analysis, found only procedure type remained a significant predictor of AL (total colectomy (OR 4.049, P<0.001), subtotal colectomy (OR 2.477, P<0.001) and extended right hemicolectomy (OR 2.171, P < 0.001)).

CONCLUSION: AL is more common in extended colonic resections. With growing evidence of similar oncological outcomes between subtotal colectomy and left hemicolectomy for splenic flexure cancers, more limited resections should be considered. The type of colonic resection should be integrated into prediction tools for AL.}, } @article {pmid37988788, year = {2024}, author = {Basith, S and Manavalan, B and Lee, G}, title = {Unveiling local and global conformational changes and allosteric communications in SOD1 systems using molecular dynamics simulation and network analyses.}, journal = {Computers in biology and medicine}, volume = {168}, number = {}, pages = {107688}, doi = {10.1016/j.compbiomed.2023.107688}, pmid = {37988788}, issn = {1879-0534}, mesh = {Humans ; Superoxide Dismutase-1/genetics/metabolism ; *Molecular Dynamics Simulation ; Superoxide Dismutase/chemistry/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics ; Mutation ; Protein Folding ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a serious neurodegenerative disorder affecting nerve cells in the brain and spinal cord that is caused by mutations in the superoxide dismutase 1 (SOD1) enzyme. ALS-related mutations cause misfolding, dimerisation instability, and increased formation of aggregates. The underlying allosteric mechanisms, however, remain obscure as far as details of their fundamental atomistic structure are concerned. Hence, this gap in knowledge limits the development of novel SOD1 inhibitors and the understanding of how disease-associated mutations in distal sites affect enzyme activity.

METHODS: We combined microsecond-scale based unbiased molecular dynamics (MD) simulation with network analysis to elucidate the local and global conformational changes and allosteric communications in SOD1 Apo (unmetallated form), Holo, Apo_CallA (mutant and unmetallated form), and Holo_CallA (mutant form) systems. To identify hotspot residues involved in SOD1 signalling and allosteric communications, we performed network centrality, community network, and path analyses.

RESULTS: Structural analyses showed that unmetallated SOD1 systems and cysteine mutations displayed large structural variations in the catalytic sites, affecting structural stability. Inter- and intra H-bond analyses identified several important residues crucial for maintaining interfacial stability, structural stability, and enzyme catalysis. Dynamic motion analysis demonstrated more balanced atomic displacement and highly correlated motions in the Holo system. The rationale for structural disparity observed in the disulfide bond formation and R143 configuration in Apo and Holo systems were elucidated using distance and dihedral probability distribution analyses.

CONCLUSION: Our study highlights the efficiency of combining extensive MD simulations with network analyses to unravel the features of protein allostery.}, } @article {pmid37988653, year = {2024}, author = {Teplansky, KJ and Wisler, A and Goffman, L and Wang, J}, title = {The Impact of Stimulus Length in Tongue and Lip Movement Pattern Stability in Amyotrophic Lateral Sclerosis.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {67}, number = {10S}, pages = {4002-4014}, pmid = {37988653}, issn = {1558-9102}, support = {R01 DC013547/DC/NIDCD NIH HHS/United States ; R01 DC016621/DC/NIDCD NIH HHS/United States ; R03 DC013990/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Lip/physiopathology/physiology ; *Tongue/physiopathology/physiology ; Male ; Female ; Middle Aged ; Aged ; *Movement/physiology ; Speech/physiology ; Adult ; Speech Production Measurement ; Biomechanical Phenomena ; Case-Control Studies ; }, abstract = {PURPOSE: This study aimed to investigate the effect of stimulus signal length on tongue and lip motion pattern stability in speakers diagnosed with amyotrophic lateral sclerosis (ALS) compared to healthy controls.

METHOD: Electromagnetic articulography was used to derive articulatory motion patterns from individuals with mild (n = 27) and severe (n = 16) ALS and healthy controls (n = 25). The spatiotemporal index (STI) was used as a measure of articulatory stability. Two experiments were conducted to evaluate signal length effects on the STI: (a) the effect of the number of syllables on STI values and (b) increasing lengths of subcomponents of a single phrase. Two-way mixed analyses of variance were conducted to assess the effects of syllable length and group on the STI for the tongue tip (TT), tongue back (TB), and lower lip (LL).

RESULTS: Experiment 1 showed a significant main effect of syllable length (TT, p < .001; TB, p < .001; and LL, p < .001) and group (TT, p = .037; TB, p = .007; and LL, p = .017). TB and LL stability was generally higher with speech stimuli that included a greater number of syllables. Articulatory variability was significantly higher in speakers diagnosed with ALS compared to healthy controls. Experiment 2 showed a significant main effect of length (TT, p < .001; TB, p = .015; and LL, p < .001), providing additional support that STI values tend to be greater when calculated on longer speech signals.

CONCLUSIONS: Articulatory stability is influenced by the length of speech signals and manifests similarly in both healthy speakers and persons with ALS. TT stability may be significantly impacted by phonemic content due to greater movement flexibility. Compared to healthy controls, there was an increase in articulatory variability in those with ALS, which likely reflects deviations in speech motor control.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24463924.}, } @article {pmid37988405, year = {2024}, author = {Nusrath, S and Kalluru, P and Shukla, S and Dharanikota, A and Basude, M and Jonnada, P and Abualjadayel, M and Alabbad, S and Mir, TA and Broering, DC and Raju, K and Rao, TS and Vashist, YK}, title = {Current status of indocyanine green fluorescent angiography in assessing perfusion of gastric conduit and oesophago-gastric anastomosis.}, journal = {International journal of surgery (London, England)}, volume = {110}, number = {2}, pages = {1079-1089}, pmid = {37988405}, issn = {1743-9159}, mesh = {Humans ; *Indocyanine Green ; *Coloring Agents ; Angiography/adverse effects ; Anastomotic Leak/diagnostic imaging/etiology ; Anastomosis, Surgical/adverse effects/methods ; Esophagectomy/adverse effects/methods ; Perfusion ; }, abstract = {Anastomotic leak (AL) remains a significant complication after esophagectomy. Indocyanine green fluorescent angiography (ICG-FA) is a promising and safe technique for assessing gastric conduit (GC) perfusion intraoperatively. It provides detailed visualization of tissue perfusion and has demonstrated usefulness in oesophageal surgery. GC perfusion analysis by ICG-FA is crucial in constructing the conduit and selecting the anastomotic site and enables surgeons to make necessary adjustments during surgery to potentially reduce ALs. However, anastomotic integrity involves multiple factors, and ICG-FA must be combined with optimization of patient and procedural factors to decrease AL rates. This review summarizes ICG-FA's current applications in assessing esophago-gastric anastomosis perfusion, including qualitative and quantitative analysis and different imaging systems. It also explores how fluorescent imaging could decrease ALs and aid clinicians in utilizing ICG-FA to improve esophagectomy outcomes.}, } @article {pmid37986827, year = {2023}, author = {Simmonds, E and Levine, KS and Han, J and Iwaki, H and Koretsky, MJ and Kuznetsov, N and Faghri, F and Solsberg, CW and Schuh, A and Jones, L and Bandres-Ciga, S and Blauwendraat, C and Singleton, A and Escott-Price, V and Leonard, HL and Nalls, MA}, title = {Sleep disturbances as risk factors for neurodegeneration later in life.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {37986827}, abstract = {The relationship between sleep disorders and neurodegeneration is complex and multi-faceted. Using over one million electronic health records (EHRs) from Wales, UK, and Finland, we mined biobank data to identify the relationships between sleep disorders and the subsequent manifestation of neurodegenerative diseases (NDDs) later in life. We then examined how these sleep disorders' severity impacts neurodegeneration risk. Additionally, we investigated how sleep attributed risk may compensate for the lack of genetic risk factors (i.e. a lower polygenic risk score) in NDD manifestation. We found that sleep disorders such as sleep apnea were associated with the risk of Alzheimer's disease (AD), amyotrophic lateral sclerosis, dementia, Parkinson's disease (PD), and vascular dementia in three national scale biobanks, with hazard ratios (HRs) ranging from 1.31 for PD to 5.11 for dementia. These sleep disorders imparted significant risk up to 15 years before the onset of an NDD. Cumulative number of sleep disorders in the EHRs were associated with a higher risk of neurodegeneration for dementia and vascular dementia. Sleep related risk factors were independent of genetic risk for Alzheimer's and Parkinson's, potentially compensating for low genetic risk in overall disease etiology. There is a significant multiplicative interaction regarding the combined risk of sleep disorders and Parkinson's disease. Poor sleep hygiene and sleep apnea are relatively modifiable risk factors with several treatment options, including CPAP and surgery, that could potentially reduce the risk of neurodegeneration. This is particularly interesting in how sleep related risk factors are significantly and independently enriched in manifesting NDD patients with low levels of genetic risk factors for these diseases.}, } @article {pmid37986813, year = {2023}, author = {Glineburg, MR and Yildirim, E and Gomez, N and Li, X and Pak, J and Altheim, C and Waksmacki, J and McInerney, G and Barmada, SJ and Todd, PK}, title = {Stress granule formation helps to mitigate neurodegeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37986813}, issn = {2692-8205}, support = {R01 NS086810/NS/NINDS NIH HHS/United States ; P50 HD104463/HD/NICHD NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; }, abstract = {Cellular stress pathways that inhibit translation initiation lead to transient formation of cytoplasmic RNA/protein complexes known as stress granules. Many of the proteins found within stress granules and the dynamics of stress granule formation and dissolution are implicated in neurodegenerative disease. Whether stress granule formation is protective or harmful in neurodegenerative conditions is not known. To address this, we took advantage of the alphavirus protein nsP3, which selectively binds dimers of the central stress granule nucleator protein G3BP (rin in Drosophila) and markedly reduces stress granule formation without directly impacting the protein translational inhibitory pathways that trigger stress granule formation. In Drosophila and rodent neurons, reducing stress granule formation with nsP3 had modest impacts on lifespan even in the setting of serial stress pathway induction. In contrast, reducing stress granule formation in models of ataxia, amyotrophic lateral sclerosis and frontotemporal dementia largely exacerbated disease phenotypes. These data support a model whereby stress granules mitigate, rather than promote, neurodegenerative cascades.}, } @article {pmid37986728, year = {2023}, author = {Fan, C and Hahn, N and Kamdar, F and Avansino, D and Wilson, GH and Hochberg, L and Shenoy, KV and Henderson, JM and Willett, FR}, title = {Plug-and-Play Stability for Intracortical Brain-Computer Interfaces: A One-Year Demonstration of Seamless Brain-to-Text Communication.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {37986728}, issn = {2331-8422}, abstract = {Intracortical brain-computer interfaces (iBCIs) have shown promise for restoring rapid communication to people with neurological disorders such as amyotrophic lateral sclerosis (ALS). However, to maintain high performance over time, iBCIs typically need frequent recalibration to combat changes in the neural recordings that accrue over days. This requires iBCI users to stop using the iBCI and engage in supervised data collection, making the iBCI system hard to use. In this paper, we propose a method that enables self-recalibration of communication iBCIs without interrupting the user. Our method leverages large language models (LMs) to automatically correct errors in iBCI outputs. The self-recalibration process uses these corrected outputs ("pseudo-labels") to continually update the iBCI decoder online. Over a period of more than one year (403 days), we evaluated our Continual Online Recalibration with Pseudo-labels (CORP) framework with one clinical trial participant. CORP achieved a stable decoding accuracy of 93.84% in an online handwriting iBCI task, significantly outperforming other baseline methods. Notably, this is the longest-running iBCI stability demonstration involving a human participant. Our results provide the first evidence for long-term stabilization of a plug-and-play, high-performance communication iBCI, addressing a major barrier for the clinical translation of iBCIs.}, } @article {pmid37984338, year = {2023}, author = {Topaloğlu Ören, ED and Dorukoğlu, S and Ertem, G}, title = {The Use of Complementary and Alternative Medicine and Coping with Stress by Patients with Gynecological Cancer: A Cross-Sectional Study in Türkiye.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {502-516}, doi = {10.1159/000534707}, pmid = {37984338}, issn = {2504-2106}, mesh = {Humans ; Female ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; Cross-Sectional Studies ; Turkey ; *Neoplasms ; *Complementary Therapies ; Adaptation, Psychological ; }, abstract = {INTRODUCTION: Gynecological cancers are long-term, challenging, and stressful diseases. In Türkiye, the majority of patients with gynecological cancer use complementary and alternative medicine (CAM). Considering the stress that gynecological cancer patients are exposed to, patients need to know how to cope with stress.

OBJECTIVE: This study aimed to determine the use of CAM and coping with stress by patients with gynecological cancer and the relationships between them and the factors that predict the approaches to coping with stress in women with gynecological cancer in Türkiye.

METHODS: This is a descriptive and cross-sectional study. The study was conducted with 204 patients between April and August 2022. The data of the study were collected by face-to-face interview and filled out by the patients using the Descriptive Information Form and the Stress Coping Styles Scale (SCSS). Number, percentage, mean, χ2, one-way ANOVA, t test, and the Spearman correlation analysis were used in the data analysis. To analyze the multivariate independent associations between variables, a multivariate ordinal logistic regression model was used, with the SCSS domains as dependent variables. A 95% confidence interval was calculated, and all statistical tests had an alpha level of 0.05.

RESULTS: The mean age of the patients was 58.38 ± 12.64 years (32-80). The prevalence of CAM use by patients was 39.2%, and the most common types of CAM were herbal products (43.8%) and supplication (42.5%). The reasons for using CAM were relaxation (symptomatic)-feeling healthy (63.8%) and treating cancer (36.2%). No statistically significant difference was found between the use of CAM and their approaches to coping with stress (p > 0.05). As a result of multivariate ordinal logistic regression analysis, education level under high school, having ovary, cervix, and endometrium cancer, being in the first stage of cancer, receiving chemotherapy, receiving surgical treatment, having another cancer patient in the social environment and increased interest in a partner after the diagnosis of cancer was associated with an effective coping with stress (p < 0.05, adjusted R2 = 0.27, 0.79, and 0.32, respectively). Not working, experiencing an abortion, having another cancer patient in their social environment, being in the third stage of cancer, having an extended family, and living in a rural area of residence were associated with ineffective coping with stress (p < 0.05, adjusted R2 = 0.20 and 0.24, respectively).

CONCLUSIONS: The prevalence of CAM use by patients was low. While determining the approaches of the patients to cope with stress, their education level, place of residence, family type, diagnosis of cancer, stage of cancer, treatment, partner support, and stressful life events should be considered. As nurses, we need to be more knowledgeable about the use of CAM to provide correct guidance to our patients for access to accurate and effective information. We need to determine our patients' stressors and how our patients cope with stress.

UNLABELLED: EinleitungGynäkologische Krebserkrankungen sind langfristige, herausfordernde und belastende Krankheiten. In der Türkei nehmen die meisten Patientinnen mit gynäkologischen Krebserkrankungen Komplementär- und Alternativmedizin in Anspruch. Angesichts der großen Belastungen, denen Patientinnen mit gynäkologischen Krebserkrankungen ausgesetzt sind, müssen sie wissen, wie sie mit Stress umgehen können.ZielMit dieser Studie sollen die Inanspruchnahme von Komplementär- und Alternativmedizin und die Stressbewältigung von Patientinnen mit gynäkologischer Krebserkrankung ermittelt werden und es sollen die Zusammenhänge zwischen diesen beiden Aspekten und den prädiktiven Faktoren für die Ansätze zur Stressbewältigung bei Frauen mit gynäkologischer Krebserkrankung untersucht werden.MethodenEs handelt sich um eine deskriptive Querschnittsstudie. Die Studie wurde mit 204 Patientinnen zwischen April und August 2022 durchgeführt. Die Erhebung der Studiendaten erfolgte durch persönliche Befragung und mithilfe des deskriptiven Informationsformulars sowie der Stress Coping Styles-Skala, die die Patientinnen ausfüllten. Für die Datenanalyse wurden Anzahl, Prozentanteil, Mittelwert, Chi-Quadrat-Test, einfaktorielle ANOVA, t Test und die Spearman-Korrelationsanalyse verwendet. Zur Analyse der multivariaten unabhängigen Zusammenhänge zwischen den Variablen wurde ein multivariates ordinales logistisches Regressionsmodell verwendet mit den SCSS (Stress Coping Styles-Skala)-Domänen als abhängigen Variablen. Es wurde ein 95%-Konfidenzintervall berechnet, und das Signifikanzniveau betrug für alle statistischen Tests α = 0.05.ErgebnisseDas Durchschnittsalter der Patientinnen betrug 58.38 ± 12.64 Jahre (32–80 Jahre). Die Prävalenz der Inanspruchnahme von Komplementär- und Alternativmedizin (CAM) durch die Patientinnen lag bei 39.2%, und die häufigsten CAM-Arten waren pflanzliche Produkte (43.8%) und Bittgebete (42.5%). Die Gründe für die Inanspruchnahme von Komplementär- und Alternativmedizin waren Entspannung (symptomatisch), das Gefühl von Gesundheit (63.8%) und die Behandlung der Krebserkrankung (36.2%). Es fand sich kein statistisch signifikanter Unterschied zwischen der Inanspruchnahme von Komplementär- und Alternativmedizin und ihren Ansätzen zur Stressbewältigung (p > 0.05). Die multivariate ordinale logistische Regressionsanalyse zeigte, dass ein Bildungsniveau unterhalb der Oberstufe sowie Ovarial-, Zervix- und Endometriumkarzinom, Krebs im Anfangsstadium, Chemotherapie, operative Behandlung, eine andere Krebspatientin im sozialen Umfeld und ein gesteigertes Interesse an einem Partner nach der Krebsdiagnose mit effektiver Stressbewältigung assoziiert waren (p < 0.05, adjustiertes R2 = 0.27, 0.79 bzw. 0.32). Fehlende Berufstätigkeit, Fehlgeburt/Schwangerschaftsabbruch, eine andere Krebspatientin im sozialen Umfeld, eine Krebserkrankung im dritten Stadium, eine Großfamilie zu haben und in einer ländlichen Gegend zu leben waren mit ineffektiver Stressbewältigung verbunden (p < 0.05, adjustiertes R2 = 0.20 bzw. 0.24).SchlussfolgerungenDie Prävalenz der Inanspruchnahme von Komplementär- und Alternativmedizin durch die Patientinnen war gering. Bei der Ermittlung der Ansätze der Patientinnen zur Stressbewältigung sollten ihr Bildungsniveau, ihr Wohnort, ihr Familientyp, die Krebsdiagnose, das Krebsstadium, die Behandlung, die Unterstützung durch den Partner und belastende Lebensereignisse berücksichtigt werden. Als Pflegekräfte müssen wir mehr über die Inanspruchnahme von Komplementär- und Alternativmedizin wissen, um unsere Patientinnen in Hinblick auf den Zugang zu genauen und wirksamen Informationen die richtige Orientierungshilfe zu geben. Wir müssen die Stressfaktoren unserer Patientinnen ermitteln und herausfinden, wie unsere Patientinnen mit Stress umgehen.}, } @article {pmid37983967, year = {2024}, author = {Slyne, AD and Ó Murchú, SC}, title = {Persistent inward currents: PICking apart the temporal changes in intrinsic motor neuron excitability in amyotrophic lateral sclerosis.}, journal = {The Journal of physiology}, volume = {602}, number = {1}, pages = {13-14}, doi = {10.1113/JP285776}, pmid = {37983967}, issn = {1469-7793}, support = {//Lilly Research Scholarship/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Motor Neurons/physiology ; Action Potentials/physiology ; }, } @article {pmid37983951, year = {2024}, author = {Turhan, SA and Karlsson, P and Ozun, Y and Gunes, H and Surucu, S and Toker, E and Isak, B}, title = {Identification of corneal and intra-epidermal axonal swellings in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {69}, number = {1}, pages = {78-86}, doi = {10.1002/mus.27995}, pmid = {37983951}, issn = {1097-4598}, support = {//Novo Nordisk/ ; NNF18OC0052301//PK (Pall Karlsson) is funded by a grant from the Novo Nordisk Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Axons/pathology ; Cornea/innervation ; Skin/pathology ; Nerve Fibers, Unmyelinated/pathology ; Microscopy, Confocal ; }, abstract = {INTRODUCTION/AIMS: In patients with amyotrophic lateral sclerosis (ALS), axonal spheroids in motor axons have been identified in post-mortem studies. In this study, axonal spheroids and swellings on C-fibers of ALS patients were investigated using corneal confocal microscopy (CCM) and skin biopsy, respectively.

METHODS: Thirty-one ALS patients and 20 healthy subjects were evaluated with CCM to assess corneal nerve-fiber length (CNFL), -fiber density (CNFD), -branch density (CNBD), dendritic cell (DC) density, and axonal spheroids originating from C-fibers (>100 μm[2]). In addition, intraepidermal nerve fiber density (IENFD) and axonal swellings (>1.5 μm) were assessed in skin biopsies obtained from the arms and legs of 22 patients and 17 controls.

RESULTS: In ALS patients, IENFD, CNFD, CNFL, and CNBD were not different from controls. The density of DCs and the number of patients with increased DC density were higher in ALS patients than controls (p = .0005 and p = .008). The number of patients with axonal spheroids was higher than controls (p = .03).

DISCUSSION: Evaluation of DCs and axonal bulbs in C-fibers of ALS patients could provide insights into pathophysiology or potentially serve as biomarkers in ALS.}, } @article {pmid37983563, year = {2024}, author = {Wen, D and Ji, Y and Li, Y and Duan, W and Wang, Y and Li, Z and Tao, M and Liu, Y}, title = {OPTN gene therapy increases autophagy and protects mitochondria in SOD1-G93A-expressing transgenic mice and cells.}, journal = {The FEBS journal}, volume = {291}, number = {4}, pages = {795-813}, doi = {10.1111/febs.17009}, pmid = {37983563}, issn = {1742-4658}, support = {H2021206048//Hebei Natural Science Foundation/ ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; Superoxide Dismutase/genetics/metabolism ; Autophagy/genetics ; Mitochondria/genetics/metabolism ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron (MN) death. Mutation of the superoxide dismutase 1 (SOD1) gene, which results in abnormal protein aggregation, is one of the causes of familial ALS. Autophagic dysfunction occurs in SOD1-G93A mutant mice as the disease progresses, but the etiology of this disease is still unclear. Optineurin (OPTN) is an adaptor that is involved in autophagy and participates in aggrephagy and mitophagy. Previous studies have established that OPTN mutations contribute to diseases such as glaucoma and ALS. However, the function of OPTN in autophagy and mitophagy has not been intensively investigated in models of ALS. In this study, we assessed the beneficial effect of OPTN on autophagy and mitochondrial function by intrathecally injecting adeno-associated virus 9 (AAV9)-OPTN into SOD1-G93A transgenic mice and by administering lentivirus (LV)-OPTN to cells expressing the SOD1-G93A mutant protein. The expression of voltage-dependent anion channel 1 (VDAC1) was increased and autophagy was elevated after OPTN gene therapy, as shown by a lower level of p62 and a higher level of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II. Moreover, using electron microscopy, we observed a hyperpolarized mitochondrial transmembrane potential and reversal of mitochondrial morphological abnormalities. Furthermore, the protein level of TANK-binding kinase 1 (TBK1) was increased, suggesting that mitophagy was increased. Our findings from both animal and cell line studies strongly suggest that OPTN gene therapy is a powerful strategy to increase autophagy and protect mitochondria to prevent the progression of ALS and could be effective in the treatment of ALS.}, } @article {pmid37982993, year = {2023}, author = {Tsui, A and Kouznetsova, VL and Kesari, S and Fiala, M and Tsigelny, IF}, title = {Role of Senataxin in Amyotrophic Lateral Sclerosis.}, journal = {Journal of molecular neuroscience : MN}, volume = {73}, number = {11-12}, pages = {996-1009}, pmid = {37982993}, issn = {1559-1166}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Motor Neurons/metabolism ; Gene Expression Regulation ; Mutation ; DNA Helicases/genetics ; RNA Helicases/genetics/metabolism ; Multifunctional Enzymes/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, uncurable neurodegenerative disorder characterized by the degradation of motor neurons leading to muscle impairment, failure, and death. Senataxin, encoded by the SETX gene, is a human helicase protein whose mutations have been linked with ALS onset, particularly in its juvenile ALS4 form. Using senataxin's yeast homolog Sen1 as a model for study, it is suggested that senataxin's N-terminus interacts with RNA polymerase II, whilst its C-terminus engages in helicase activity. Senataxin is heavily involved in transcription regulation, termination, and R-loop resolution, enabled by recruitment and interactions with enzymes such as ubiquitin protein ligase SAN1 and ribonuclease H (RNase H). Senataxin also engages in DNA damage response (DDR), primarily interacting with the exosome subunit Rrp45. The Sen1 mutation E1597K, alongside the L389S and R2136H gain-of-function mutations to senataxin, is shown to cause negative structural and thus functional effects to the protein, thus contributing to a disruption in WT functions, motor neuron (MN) degeneration, and the manifestation of ALS clinical symptoms. This review corroborates and summarizes published papers concerning the structure and function of senataxin as well as the effects of their mutations in ALS pathology in order to compile current knowledge and provide a reference for future research. The findings compiled in this review are indicative of the experimental and therapeutic potential of senataxin and its mutations as a target in future ALS treatment/cure discovery, with some potential therapeutic routes also being discussed in the review.}, } @article {pmid37982655, year = {2024}, author = {Mossa, A and Mayahara, M and Emezue, C and Paun, O}, title = {The Impact of Rapidly Progressing Neurodegenerative Disorders on Caregivers: An Integrative Literature Review.}, journal = {Journal of hospice and palliative nursing : JHPN : the official journal of the Hospice and Palliative Nurses Association}, volume = {26}, number = {2}, pages = {E62-E73}, pmid = {37982655}, issn = {1539-0705}, mesh = {Humans ; *Quality of Life ; Caregivers ; *Amyotrophic Lateral Sclerosis ; Disease Progression ; Death ; }, abstract = {Neurodegenerative disorders affect over 6 million people in the United States. A subset of these patients experiences symptoms that progress rapidly, along with a 5- to 10-year life expectancy (amyotrophic lateral sclerosis). This subgroup often becomes dependent on family caregivers. Managing care demands at the end of life that are brought on by rapid disease progression has a negative impact on caregiver quality of life. The purpose of this integrative review is to highlight the gaps in the existing body of research on the effect of neuropalliative care on quality of life of this caregiver population. A total of 13 articles met inclusion criteria and were selected for review. The most frequently occurring themes and findings in the literature shed light on neuropalliative care and provided some insight into both caregivers and patients' perspective at the end of life. What sets this population apart from caregivers and patients of other terminal diseases is the nature of disease progression and the rapid life adjustments that come along with it. Integration of neuropalliative has shown to provide additional support for caregivers and patients; however, it remains underused. To promote equitable access to these services, it is necessary to address several structural barriers.}, } @article {pmid37981575, year = {2024}, author = {Shojaie, A and Al Khleifat, A and Sarraf, P and Al-Chalabi, A}, title = {Analysis of non-motor symptoms in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {237-241}, pmid = {37981575}, issn = {2167-9223}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; Surveys and Questionnaires ; Pain/epidemiology/etiology ; }, abstract = {OBJECTIVE: We investigated non-motor symptoms in ALS using sequential questionnaires; here we report the findings of the second questionnaire.

METHODS: A social media platform (Twitter, now known as X) was used to publicize the questionnaires. Data were downloaded from SurveyMonkey and analyzed by descriptive statistics, comparison of means, and regression models.

RESULTS: There were 182 people with ALS and 57 controls. The most important non-motor symptoms were cold limbs (60.4% cases, 14% controls, p = 9.67 x 10[-10]) and appetite loss (29.7% cases, 5.3% controls, p = 1.6 x 10[-4]). The weaker limb was most likely to feel cold (p = 9.67 x 10[-10]), and symptoms were more apparent in the evening and night. Appetite loss was reported as due to feeling full and the time taken to eat. People with ALS experienced medium-intensity pain, more usually shock-like pain than burning or cold-like pain, although the most prevalent type of pain was non-differentiated.

CONCLUSIONS: Non-motor symptoms are an important feature of ALS. Further investigation is needed to understand their physiological basis and whether they represent phenotypic differences useful for subtyping ALS.}, } @article {pmid37981468, year = {2024}, author = {Sutter, PA and Lavoie, ER and Lombardo, ET and Pinter, MK and Crocker, SJ}, title = {Emerging Role of Astrocyte-Derived Extracellular Vesicles as Active Participants in CNS Neuroimmune Responses.}, journal = {Immunological investigations}, volume = {53}, number = {1}, pages = {26-39}, pmid = {37981468}, issn = {1532-4311}, support = {F30 NS129238/NS/NINDS NIH HHS/United States ; R01 NS131327/NS/NINDS NIH HHS/United States ; R21 NS125332/NS/NINDS NIH HHS/United States ; R56 NS099359/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Astrocytes ; *Extracellular Vesicles ; Cell Communication ; Biomarkers ; }, abstract = {Astrocyte-derived extracellular vesicles (ADEVs) have garnered attention as a fundamental mechanism of intercellular communication in health and disease. In the context of neurological diseases, for which prodromal diagnosis would be advantageous, ADEVs are also being explored for their potential utility as biomarkers. In this review, we provide the current state of data supporting our understanding on the manifold roles of ADEVs in several common neurological disorders. We also discuss these findings from a unique emerging perspective that ADEVs represent a means by which the central nervous system may broadcast influence over other systems in the body to affect neuroinflammatory processes, with both dual potential to either propagate illness or restore health and homeostasis.}, } @article {pmid37981210, year = {2024}, author = {Kim, Y and Lee, Y and Choo, M and Yun, N and Cho, JW and Oh, YJ}, title = {A surge of cytosolic calcium dysregulates lysosomal function and impairs autophagy flux during cupric chloride-induced neuronal death.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {1}, pages = {105479}, pmid = {37981210}, issn = {1083-351X}, mesh = {*Autophagy/drug effects/genetics ; *Calcium/metabolism ; *Copper/pharmacology ; *Dopaminergic Neurons/cytology/drug effects/metabolism/ultrastructure ; *Lysosomes/metabolism ; Animals ; Mice ; Cell Line ; Cell Survival/drug effects ; Cytosol/metabolism ; }, abstract = {Autophagy is a degradative pathway that plays an important role in maintaining cellular homeostasis. Dysfunction of autophagy is associated with the progression of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although one of the typical features of brain aging is an accumulation of redox-active metals that eventually lead to neurodegeneration, a plausible link between trace metal-induced neurodegeneration and dysregulated autophagy has not been clearly determined. Here, we used a cupric chloride-induced neurodegeneration model in MN9D dopaminergic neuronal cells along with ultrastructural and biochemical analyses to demonstrate impaired autophagic flux with accompanying lysosomal dysfunction. We found that a surge of cytosolic calcium was involved in cupric chloride-induced dysregulated autophagy. Consequently, buffering of cytosolic calcium by calbindin-D28K overexpression or co-treatment with the calcium chelator BAPTA attenuated the cupric chloride-induced impairment in autophagic flux by ameliorating dysregulation of lysosomal function. Thus, these events allowed the rescue of cells from cupric chloride-induced neuronal death. These phenomena were largely confirmed in cupric chloride-treated primary cultures of cortical neurons. Taken together, these results suggest that abnormal accumulation of trace metal elements and a resultant surge of cytosolic calcium leads to neuronal death by impairing autophagic flux at the lysosomal level.}, } @article {pmid37981175, year = {2023}, author = {Wang, C and Cui, Y and Xu, T and Zhou, Y and Yang, R and Wang, T}, title = {New insights into glycogen synthase kinase-3: A common target for neurodegenerative diseases.}, journal = {Biochemical pharmacology}, volume = {218}, number = {}, pages = {115923}, doi = {10.1016/j.bcp.2023.115923}, pmid = {37981175}, issn = {1873-2968}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Glycogen Synthase Kinase 3 ; *Parkinson Disease ; *Alzheimer Disease ; *Diabetes Mellitus/drug therapy ; Glycogen Synthase Kinase 3 beta ; }, abstract = {Glycogen synthase kinase 3 (GSK-3) is a highly conserved protein serine/threonine kinase that plays a central role in a wide variety of cellular processes to coordinate catabolic and anabolic pathways and regulate cell growth and fate. There is increasing evidence showing that abnormal glycogen synthase kinase 3 (GSK-3) is associated with the pathogenesis and progression of many disorders, such as cancer, diabetes, psychiatric diseases, and neurodegenerative diseases. In this review, we summarize recent findings about the regulatory role of GSK-3 in the occurrence and development of multiple neurodegenerative diseases, mainly focusing on Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The aim of this study is to provide new insight into the shared working mechanism of GSK-3 as a therapeutic target of multiple neurodegenerative diseases.}, } @article {pmid37980296, year = {2024}, author = {He, D and Liu, Y and Dong, S and Shen, D and Yang, X and Hao, M and Yin, X and He, X and Li, Y and Wang, Y and Liu, M and Wang, J and Chen, X and Cui, L}, title = {The prognostic value of systematic genetic screening in amyotrophic lateral sclerosis patients.}, journal = {Journal of neurology}, volume = {271}, number = {3}, pages = {1385-1396}, pmid = {37980296}, issn = {1432-1459}, support = {XDB39040000//Strategic Priority Research Program (Pilot study) "Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Prognosis ; *Neurodegenerative Diseases/genetics ; Genetic Association Studies ; Genetic Testing ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with complex genetic architecture. Emerging evidence has indicated comorbidity between ALS and autoimmune conditions, suggesting a potential shared genetic basis. The objective of this study is to assess the prognostic value of systematic screening for rare deleterious mutations in genes associated with ALS and aberrant inflammatory responses.

METHODS: A discovery cohort of 494 patients and a validation cohort of 69 patients were analyzed in this study, with population-matched healthy subjects (n = 4961) served as controls. Whole exome sequencing (WES) was performed to identify rare deleterious variants in 50 ALS genes and 1177 genes associated with abnormal inflammatory responses. Genotype-phenotype correlation was assessed, and an integrative prognostic model incorporating genetic and clinical factors was constructed.

RESULTS: In the discovery cohort, 8.1% of patients carried confirmed ALS variants, and an additional 15.2% of patients carried novel ALS variants. Gene burden analysis revealed 303 immune-implicated genes with enriched rare variants, and 13.4% of patients harbored rare deleterious variants in these genes. Patients with ALS variants exhibited a more rapid disease progression (HR 2.87 [95% CI 2.03-4.07], p < 0.0001), while no significant effect was observed for immune-implicated variants. The nomogram model incorporating genetic and clinical information demonstrated improved accuracy in predicting disease outcomes (C-index, 0.749).

CONCLUSION: Our findings enhance the comprehension of the genetic basis of ALS within the Chinese population. It also appears that rare deleterious mutations occurring in immune-implicated genes exert minimal influence on the clinical trajectories of ALS patients.}, } @article {pmid37979250, year = {2024}, author = {Chen, K and Gao, T and Liu, Y and Zhu, K and Wang, T and Zeng, P}, title = {Identifying risk loci for FTD and shared genetic component with ALS: A large-scale multitrait association analysis.}, journal = {Neurobiology of aging}, volume = {134}, number = {}, pages = {28-39}, doi = {10.1016/j.neurobiolaging.2023.09.017}, pmid = {37979250}, issn = {1558-1497}, mesh = {Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Genome-Wide Association Study ; Mutation ; *Pick Disease of the Brain ; Proteins/genetics ; Nuclear Proteins/genetics ; }, abstract = {Current genome-wide association studies of frontotemporal dementia (FTD) are underpowered due to limited samples. Further, common genetic etiologies between FTD and amyotrophic lateral sclerosis (ALS) remain unknown. Using the largest summary statistics of FTD (3526 cases and 9402 controls) and ALS (27,205 cases and 110,881 controls), we found a significant genetic correlation between them (rˆg = 0.637, P = 0.032) and identified 190 FTD-related variants within 5 loci (3p22.1, 5q35.1, 9p21.2, 19p13.11, and 20q13.13). Among these, ALS and FTD had causal variants in 9p21.2 and 19p13.11. Moreover, MOBP (3p22.1), C9orf72 (9p21.2), MOB3B (9p21.2), UNC13A (19p13.11), SLC9A8 (20q13.13), SNAI1 (20q13.13), and SPATA2 (20q13.13) were discovered by both SNP- and gene-level analyses, which together discovered 15 FTD-associated genes, with 10 not detected before (IFNK, RNF114, SLC9A8, SPATA2, SNAI1, SCFD1, POLDIP2, TMEM97, G2E3, and PIGW). Functional analyses showed these genes were enriched in heart left ventricle, kidney cortex, and some brain regions. Overall, this study provides insights into genetic determinants of FTD and shared genetic etiology underlying FTD and ALS.}, } @article {pmid37977335, year = {2023}, author = {Benussi, A and Cantoni, V and Grassi, M and Libri, I and Cotelli, MS and Tarantino, B and Datta, A and Thomas, C and Huber, N and Kärkkäinen, S and Herukka, SK and Haapasalo, A and Filosto, M and Padovani, A and Borroni, B}, title = {Cortico-spinal tDCS in amyotrophic lateral sclerosis: A randomized, double-blind, sham-controlled trial followed by an open-label phase.}, journal = {Brain stimulation}, volume = {16}, number = {6}, pages = {1666-1676}, doi = {10.1016/j.brs.2023.11.008}, pmid = {37977335}, issn = {1876-4754}, mesh = {Humans ; *Transcranial Direct Current Stimulation ; *Amyotrophic Lateral Sclerosis/therapy ; Quality of Life ; Transcranial Magnetic Stimulation ; Double-Blind Method ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive disease for which no curative treatment is currently available.

OBJECTIVE: This study aimed to investigate whether cortico-spinal transcranial direct current stimulation (tDCS) could mitigate symptoms in ALS patients via a randomized, double-blind, sham-controlled trial, followed by an open-label phase.

METHODS: Thirty-one participants were randomized into two groups for the initial controlled phase. At baseline (T0), Group 1 received placebo stimulation (sham tDCS), while Group 2 received cortico-spinal stimulation (real tDCS) for five days/week for two weeks (T1), with an 8-week (T2) follow-up (randomized, double-blind, sham-controlled phase). At the 24-week follow-up (T3), all participants (Groups 1 and 2) received a second treatment of anodal bilateral motor cortex and cathodal spinal stimulation (real tDCS) for five days/week for two weeks (T4). Follow-up evaluations were performed at 32-weeks (T5) and 48-weeks (T6) (open-label phase). At each time point, clinical assessment, blood sampling, and intracortical connectivity measures using transcranial magnetic stimulation (TMS) were evaluated. Additionally, we evaluated survival rates.

RESULTS: Compared to sham stimulation, cortico-spinal tDCS significantly improved global strength, caregiver burden, and quality of life scores, which correlated with the restoration of intracortical connectivity measures. Serum neurofilament light levels decreased among patients who underwent real tDCS but not in those receiving sham tDCS. The number of completed 2-week tDCS treatments significantly influenced patient survival.

CONCLUSIONS: Cortico-spinal tDCS may represent a promising therapeutic and rehabilitative approach for patients with ALS. Further larger-scale studies are necessary to evaluate whether tDCS could potentially impact patient survival.

CLINICAL TRIAL REGISTRATION: NCT04293484.}, } @article {pmid37976792, year = {2023}, author = {Larsson, BJ and Nordin, K and Nygren, I}, title = {Symptoms of anxiety and depression in patients with amyotrophic lateral sclerosis and their relatives during the disease trajectory.}, journal = {Journal of the neurological sciences}, volume = {455}, number = {}, pages = {122780}, doi = {10.1016/j.jns.2023.122780}, pmid = {37976792}, issn = {1878-5883}, mesh = {Humans ; *Depression/epidemiology/diagnosis ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; Longitudinal Studies ; Prospective Studies ; Anxiety/epidemiology ; }, abstract = {OBJECTS: The aim of this study was to describe the presence of anxiety and depression among patients with Amyotrophic Lateral Sclerosis (ALS) and their relatives from diagnosis and during the disease progression. An additional aim was to explore if the patient's physical function correlated with the patients' or relatives' anxiety and depression.

METHODS: A prospective and longitudinal study, including 33 patients with ALS and their relatives who filled out the Hospital Anxiety and Depression Scale (HADS) at the time of diagnosis and over a period of two years. The patient's physical function was measured with the revised Amyotrophic Lateral Sclerosis Functional and Rating Scale (ALS FRS-R).

RESULTS: The results showed that many patients (45%) and relatives (58%) had symptoms of anxiety and that 13% of the patients and 29% of the relatives had symptoms of depression soon after the patient had been diagnosed with ALS. The prevalence of anxiety decreased over time in the group of patients but remained stable in the group of relatives. Relatives had more symptoms of anxiety compared to patients. There was a correlation between the patient's physical function and HADS in the group of relatives; however, no correlation was found in the group of patients.

CONCLUSION: The results showed that many patients and relatives suffered from symptoms of anxiety quite soon after their diagnosis, and that many relatives had symptoms of anxiety during the disease trajectory. This highlights the need to continuously measure patients' anxiety/depression level but also to pay attention to symptoms among relatives.}, } @article {pmid37975798, year = {2024}, author = {Saini, A and Chawla, PA}, title = {Breaking barriers with tofersen: Enhancing therapeutic opportunities in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {2}, pages = {e16140}, pmid = {37975798}, issn = {1468-1331}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase-1/genetics ; *Neurodegenerative Diseases ; Oligonucleotides/therapeutic use ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects adults, characterized by muscle weakness resulting from the specific death of motor neurons in the spinal cord and brain. The pathogenesis of ALS is associated with the accumulation of mutant superoxide dismutase 1 (SOD1) proteins and neurofilaments in motor neurons, highlighting the critical need for disease-modifying treatments. Current therapies, such as riluzole and edaravone, provide only symptomatic relief. Recently, tofersen gained approval from the US FDA under the brand name Qalsody as the first and only gene therapy for ALS, addressing a significant pathological aspect of the disease.

METHODS: We carried out a literature survey using PubMed, Scopus, National Institutes of Health, and Biogen for articles published in the English language concerned with "amyotrophic lateral sclerosis", pathophysiology, current treatment, treatment under clinical trial, and the newly approved drug "tofersen" and its detailed summary.

RESULTS: A comprehensive review of the literature on the pathophysiology, available treatment, and newly approved drug for this condition revealed convincing evidence that we are now able to better monitor and treat ALS.

CONCLUSIONS: Although treatment of ALS is difficult, the newly approved drug tofersen has emerged as a potential therapy to slow down the progression of ALS by targeting SOD1 mRNA, representing a significant advancement in the treatment of ALS.}, } @article {pmid37975796, year = {2024}, author = {Witzel, S and Statland, JM and Steinacker, P and Otto, M and Dorst, J and Schuster, J and Barohn, RJ and Ludolph, AC}, title = {Longitudinal course of neurofilament light chain levels in amyotrophic lateral sclerosis-insights from a completed randomized controlled trial with rasagiline.}, journal = {European journal of neurology}, volume = {31}, number = {3}, pages = {e16154}, pmid = {37975796}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Intermediate Filaments ; Biomarkers ; Neurofilament Proteins ; Disease Progression ; *Indans ; }, abstract = {BACKGROUND AND PURPOSE: Rasagiline might be disease modifying in patients with amyotrophic lateral sclerosis (ALS). The aim was to evaluate the effect of rasagiline 2 mg/day on neurofilament light chain (NfL), a prognostic biomarker in ALS.

METHODS: In 65 patients with ALS randomized in a 3:1 ratio to rasagiline 2 mg/day (n = 48) or placebo (n = 17) in a completed randomized controlled multicentre trial, NfL levels in plasma were measured at baseline, month 6 and month 12. Longitudinal changes in NfL levels were evaluated regarding treatment and clinical parameters.

RESULTS: Baseline NfL levels did not differ between the study arms and correlated with disease progression rates both pre-baseline (r = 0.64, p < 0.001) and during the study (r = 0.61, p < 0.001). NfL measured at months 6 and 12 did not change significantly from baseline in both arms, with a median individual NfL change of +1.4 pg/mL (interquartile range [IQR] -5.6, 14.2) across all follow-up time points. However, a significant difference in NfL change at month 12 was observed between patients with high and low NfL baseline levels treated with rasagiline (high [n = 13], -6.9 pg/mL, IQR -20.4, 6.0; low [n = 18], +5.9 pg/mL, IQR -1.4, 19.7; p = 0.025). Additionally, generally higher longitudinal NfL variability was observed in patients with high baseline levels, whereas disease progression rates and disease duration at baseline had no impact on the longitudinal NfL course.

CONCLUSION: Post hoc NfL measurements in completed clinical trials are helpful in interpreting NfL data from ongoing and future interventional trials and could provide hypothesis-generating complementary insights. Further studies are warranted to ultimately differentiate NfL response to treatment from other factors.}, } @article {pmid37975632, year = {2024}, author = {Fornage, LB and O'Neil, C and Dowker, SR and Wanta, ER and Lewis, RS and Brown, LH}, title = {Prehospital Intervention Improves Outcomes for Patients Presenting in Atrial Fibrillation with Rapid Ventricular Response.}, journal = {Prehospital emergency care}, volume = {28}, number = {7}, pages = {910-919}, doi = {10.1080/10903127.2023.2283885}, pmid = {37975632}, issn = {1545-0066}, mesh = {Humans ; Retrospective Studies ; Male ; Female ; *Atrial Fibrillation/therapy/drug therapy ; Aged ; *Emergency Medical Services/methods ; Middle Aged ; Adult ; Aged, 80 and over ; Adolescent ; Cohort Studies ; Advanced Cardiac Life Support/methods ; Propensity Score ; Out-of-Hospital Cardiac Arrest/therapy/mortality ; Young Adult ; }, abstract = {OBJECTIVE: To compare outcomes of patients presenting to emergency medical services (EMS) with atrial fibrillation with rapid ventricular response (AF-RVR) who did and did not receive prehospital advanced life support (ALS) rate or rhythm control intervention(s).

METHODS: This retrospective cohort study used the 2021 ESO Data Collaborative (Austin, TX) dataset. We identified 9-1-1 scene responses for patients aged 16 to 100 years old presenting with AF and an initial heart rate ≥ 110 beats per minute (bpm). Prehospital ALS interventions for AF-RVR included medications (e.g., calcium channel blockers, beta blockers, etc.) or electrical cardioversion. Outcome measures included prehospital rate control (i.e., final prehospital heart rate < 110 bpm), emergency department (ED) discharge to home, ED and hospital length of stay, and mortality. We also evaluated prehospital adverse events-specifically bradycardia, hypotension, and cardiac arrest. We used propensity score matching to compare outcomes among treated and untreated patients with similar demographic and clinical characteristics. We determined the average treatment effect on the treated (ATET) with 95% confidence intervals (CI) and the number needed to treat (NNT).

RESULTS: After propensity score matching, prehospital outcomes were available for 4,859 treated patients matched with 4,859 similar untreated patients. Prehospital rate control was more frequent for treated than for untreated patients (41.0% vs. 18.2%, ATET +22.8%, CI: +21.1%; +24.6%, NNT = 5). Hospital outcomes were available for 1,347 treated patients matched with 1,347 similar untreated patients. Treated patients were more likely to be discharged from the ED (37.9% vs. 34.0%, ATET +3.9%, CI: +0.2%; +7.5%, NNT = 26) and less likely to die (4.3% vs. 6.7%, ATET -2.5%, CI: -4.2%; -0.8%, NNT = 40) compared to untreated patients. Hypotension occurred more often in treated patients (ATET +2.6%, CI: +1.5%; +3.7%), but resolved before ED arrival in 73% of affected patients. Otherwise, adverse event rates did not significantly differ for the two groups.

CONCLUSIONS: In this propensity score matched study of patients presenting to EMS with AF-RVR, prehospital ALS interventions were associated with more frequent prehospital rate control, more frequent discharge to home from the ED, and lower mortality.}, } @article {pmid37975411, year = {2025}, author = {Noorbakhsh Varnosfaderani, SM and Sadat Haeri, M and Arian, AS and Yousefi Rad, A and Yazdanpour, M and Mojahedian, F and Yaghoubzad-Maleki, M and Zalpoor, H and Baziyar, P and Nabi-Afjadi, M}, title = {Fighting against amyotrophic lateral sclerosis (ALS) with flavonoids: a computational approach to inhibit superoxide dismutase (SOD1) mutant aggregation.}, journal = {Journal of biomolecular structure & dynamics}, volume = {43}, number = {1}, pages = {419-436}, doi = {10.1080/07391102.2023.2281641}, pmid = {37975411}, issn = {1538-0254}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Flavonoids/pharmacology/chemistry ; Humans ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; *Molecular Dynamics Simulation ; *Mutation ; Protein Aggregates/drug effects ; Molecular Docking Simulation ; Protein Binding ; Hydrogen Bonding ; Protein Aggregation, Pathological/drug therapy/genetics ; Hydrophobic and Hydrophilic Interactions ; Thermodynamics ; }, abstract = {Protein aggregation is a biological process that occurs when proteins misfold. Misfolding and aggregation of human superoxide dismutase (hSOD1) cause a neurodegenerative disease called amyotrophic lateral sclerosis (ALS). Among the mutations occurring, targeting the E21K mutation could be a good choice to understand the pathological mechanism of SOD1 in ALS, whereof it significantly reduces life hopefulness in patients. Naturally occurring polyphenolic flavonoids have been suggested as a way to alleviate the amyloidogenic behavior of proteins. In this study, computational tools were used to identify promising flavonoid compounds that effectively inhibit the pathogenic behavior of the E21K mutant. Initial screening identified Pelargonidin, Curcumin, and Silybin as promising leads. Molecular dynamics (MD) simulations showed that the binding of flavonoids to the mutated SOD1 caused changes in the protein stability, hydrophobicity, flexibility, and restoration of lost hydrogen bonds. Secondary structure analysis indicated that the protein destabilization and the increased propensity of β-sheet caused by the mutation were restored to the wild-type state upon binding of flavonoids. Free energy landscape (FEL) analysis was also used to differentiate aggregation, and results showed that Silybin followed by Pelargonidin had the most therapeutic efficacy against the E21K mutant SOD1. Therefore, these flavonoids hold great potential as highly effective inhibitors in mitigating ALS's fatal and insuperable effects.Communicated by Ramaswamy H. Sarma.}, } @article {pmid37975189, year = {2024}, author = {Lee, I and Mitsumoto, H and Lee, S and Kasarskis, E and Rosenbaum, M and Factor-Litvak, P and Nieves, JW}, title = {Higher Glycemic Index and Glycemic Load Diet Is Associated with Slower Disease Progression in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {95}, number = {2}, pages = {217-229}, pmid = {37975189}, issn = {1531-8249}, support = {K23 NS131586/NS/NINDS NIH HHS/United States ; K23NS131586/NS/NINDS NIH HHS/United States ; R01ES016348/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Cohort Studies ; Glycemic Index ; Prospective Studies ; *Glycemic Load ; Diet ; Disease Progression ; }, abstract = {OBJECTIVE: High-caloric diets may slow the progression of amyotrophic lateral sclerosis; however, key macronutrients have not been identified. We examined whether dietary macronutrients are associated with the rate of progression and length of survival among the prospective cohort study participants.

METHODS: Participants with a confirmed diagnosis of sporadic amyotrophic lateral sclerosis enrolled in the Multicenter Cohort Study of Oxidative Stress were included (n = 304). We evaluated baseline macronutrient intake assessed by food frequency questionnaire in relation to change in revised amyotrophic lateral sclerosis functional rating scale total-score, and tracheostomy-free survival using linear regression and Cox proportional hazard models. Baseline age, sex, disease duration, diagnostic certainty, body mass index, bulbar onset, revised amyotrophic lateral sclerosis functional rating scale total-score, and forced vital capacity were included as covariates.

RESULTS: Baseline higher glycemic index and load were associated with less decline of revised amyotrophic lateral sclerosis functional rating scale total score at 3-month follow-up (β = -0.13, 95% CI -0.2, -0.01, p = 0.03) and (β = -0.01, 95% CI -0.03, -0.0007, p = 0.04), respectively. Glycemic index second-quartile, third-quartile, and fourth-quartile groups were associated with less decline at 3 months by 1.9 (95% CI -3.3, -0.5, p = 0.008), 2.0 (95% CI -3.3, -0.6, p = 0.006), and 1.6 (95% CI -3.0, -0.2, p = 0.03) points compared with the first-quartile group; the glycemic load fourth-quartile group had 1.4 points less decline compared with the first-quartile group (95% CI -2.8, 0.1, p = 0.07). Higher glycemic index was associated with a trend toward longer tracheostomy-free survival (HR 0.97, 95% CI 0.93, 1.00, p = 0.07).

INTERPRETATION: Higher dietary glycemic index and load are associated with slower disease progression in amyotrophic lateral sclerosis. ANN NEUROL 2024;95:217-229.}, } @article {pmid37974959, year = {2023}, author = {Bhargava, S and Kulkarni, R and Dewangan, B and Kulkarni, N and Jiaswar, C and Kumar, K and Kumar, A and Bodhe, PR and Kumar, H and Sahu, B}, title = {Microtubule stabilising peptides: new paradigm towards management of neuronal disorders.}, journal = {RSC medicinal chemistry}, volume = {14}, number = {11}, pages = {2192-2205}, pmid = {37974959}, issn = {2632-8682}, abstract = {Neuronal cells made of soma, axon, and dendrites are highly compartmentalized and possess a specialized transport system that can convey long-distance electrical signals for the cross-talk. The transport system is made up of microtubule (MT) polymers and MT-binding proteins. MTs play vital and diverse roles in various cellular processes. Therefore, defects and dysregulation of MTs and their binding proteins lead to many neurological disorders as exemplified by Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and many others. MT-stabilising agents (MSAs) altering the MT-associated protein connections have shown great potential for several neurodegenerative disorders. Peptides are an important class of molecules with high specificity, biocompatibility and are devoid of side effects. In the past, peptides have been explored in various neuronal disorders as therapeutics. Davunetide, a MT-stabilising octapeptide, has entered into phase II clinical trials for schizophrenia. Numerous examples of peptides emerging as MSAs reflect the emergence of a new paradigm for peptides which can be explored further as drug candidates for neuronal disorders. Although small molecule-based MSAs have been reviewed in the past, there is no systematic review in recent years focusing on peptides as MSAs apart from davunetide in 2013. Therefore, a systematic updated review on MT stabilising peptides may shed light on many hidden aspects and enable researchers to develop new therapies for diseases related to the CNS. In this review we have summarised the recent examples of peptides as MSAs.}, } @article {pmid37974279, year = {2023}, author = {Pelaez, MC and Desmeules, A and Gelon, PA and Glasson, B and Marcadet, L and Rodgers, A and Phaneuf, D and Pozzi, S and Dutchak, PA and Julien, JP and Sephton, CF}, title = {Neuronal dysfunction caused by FUSR521G promotes ALS-associated phenotypes that are attenuated by NF-κB inhibition.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {182}, pmid = {37974279}, issn = {2051-5960}, support = {RGPIN-2020-06376//Natural Sciences and Engineering Research Council of Canada/ ; DGECR-2020-00060//Natural Sciences and Engineering Research Council of Canada/ ; RGPIN-2018-06227//Natural Sciences and Engineering Research Council of Canada/ ; DGECR-2018-00093//Natural Sciences and Engineering Research Council of Canada/ ; Junior 1//Fonds de Recherche du Québec - Santé/ ; }, mesh = {Aged ; Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; Disease Progression ; *Frontotemporal Dementia/pathology ; Mice, Transgenic ; Motor Neurons/metabolism ; Mutation ; NF-kappa B/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative diseases that belong to a common disease spectrum based on overlapping clinical, pathological and genetic evidence. Early pathological changes to the morphology and synapses of affected neuron populations in ALS/FTD suggest a common underlying mechanism of disease that requires further investigation. Fused in sarcoma (FUS) is a DNA/RNA-binding protein with known genetic and pathological links to ALS/FTD. Expression of ALS-linked FUS mutants in mice causes cognitive and motor defects, which correlate with loss of motor neuron dendritic branching and synapses, in addition to other pathological features of ALS/FTD. The role of ALS-linked FUS mutants in causing ALS/FTD-associated disease phenotypes is well established, but there are significant gaps in our understanding of the cell-autonomous role of FUS in promoting structural changes to motor neurons, and how these changes relate to disease progression. Here we generated a neuron-specific FUS-transgenic mouse model expressing the ALS-linked human FUSR521G variant, hFUS[R521G/Syn1], to investigate the cell-autonomous role of FUSR521G in causing loss of dendritic branching and synapses of motor neurons, and to understand how these changes relate to ALS-associated phenotypes. Longitudinal analysis of mice revealed that cognitive impairments in juvenile hFUS[R521G/Syn1] mice coincide with reduced dendritic branching of cortical motor neurons in the absence of motor impairments or changes in the neuromorphology of spinal motor neurons. Motor impairments and dendritic attrition of spinal motor neurons developed later in aged hFUS[R521G/Syn1] mice, along with FUS cytoplasmic mislocalisation, mitochondrial abnormalities and glial activation. Neuroinflammation promotes neuronal dysfunction and drives disease progression in ALS/FTD. The therapeutic effects of inhibiting the pro-inflammatory nuclear factor kappa B (NF-κB) pathway with an analog of Withaferin A, IMS-088, were assessed in symptomatic hFUS[R521G/Syn1] mice and were found to improve cognitive and motor function, increase dendritic branches and synapses of motor neurons, and attenuate other ALS/FTD-associated pathological features. Treatment of primary cortical neurons expressing FUSR521G with IMS-088 promoted the restoration of dendritic mitochondrial numbers and mitochondrial activity to wild-type levels, suggesting that inhibition of NF-κB permits the restoration of mitochondrial stasis in our models. Collectively, this work demonstrates that FUSR521G has a cell-autonomous role in causing early pathological changes to dendritic and synaptic structures of motor neurons, and that these changes precede motor defects and other well-known pathological features of ALS/FTD. Finally, these findings provide further support that modulation of the NF-κB pathway in ALS/FTD is an important therapeutic approach to attenuate disease.}, } @article {pmid37974227, year = {2023}, author = {Awuah, WA and Ahluwalia, A and Ghosh, S and Roy, S and Tan, JK and Adebusoye, FT and Ferreira, T and Bharadwaj, HR and Shet, V and Kundu, M and Yee, ALW and Abdul-Rahman, T and Atallah, O}, title = {The molecular landscape of neurological disorders: insights from single-cell RNA sequencing in neurology and neurosurgery.}, journal = {European journal of medical research}, volume = {28}, number = {1}, pages = {529}, pmid = {37974227}, issn = {2047-783X}, mesh = {Humans ; *Neurosurgery ; Neurosurgical Procedures ; *Neurology ; *Brain Neoplasms/genetics ; Sequence Analysis, RNA ; Tumor Microenvironment ; }, abstract = {Single-cell ribonucleic acid sequencing (scRNA-seq) has emerged as a transformative technology in neurological and neurosurgical research, revolutionising our comprehension of complex neurological disorders. In brain tumours, scRNA-seq has provided valuable insights into cancer heterogeneity, the tumour microenvironment, treatment resistance, and invasion patterns. It has also elucidated the brain tri-lineage cancer hierarchy and addressed limitations of current models. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis have been molecularly subtyped, dysregulated pathways have been identified, and potential therapeutic targets have been revealed using scRNA-seq. In epilepsy, scRNA-seq has explored the cellular and molecular heterogeneity underlying the condition, uncovering unique glial subpopulations and dysregulation of the immune system. ScRNA-seq has characterised distinct cellular constituents and responses to spinal cord injury in spinal cord diseases, as well as provided molecular signatures of various cell types and identified interactions involved in vascular remodelling. Furthermore, scRNA-seq has shed light on the molecular complexities of cerebrovascular diseases, such as stroke, providing insights into specific genes, cell-specific expression patterns, and potential therapeutic interventions. This review highlights the potential of scRNA-seq in guiding precision medicine approaches, identifying clinical biomarkers, and facilitating therapeutic discovery. However, challenges related to data analysis, standardisation, sample acquisition, scalability, and cost-effectiveness need to be addressed. Despite these challenges, scRNA-seq has the potential to transform clinical practice in neurological and neurosurgical research by providing personalised insights and improving patient outcomes.}, } @article {pmid37973672, year = {2023}, author = {Lo Giudice, M and Cocco, A and Reggiardo, G and Lalli, S and Albanese, A}, title = {Tauro-Urso-Deoxycholic Acid Trials in Amyotrophic Lateral Sclerosis: What is Achieved and What to Expect.}, journal = {Clinical drug investigation}, volume = {43}, number = {12}, pages = {893-903}, pmid = {37973672}, issn = {1179-1918}, support = {755094//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Phenylbutyrates ; Taurochenodeoxycholic Acid/adverse effects ; }, abstract = {Phase II studies on tauro-urso-deoxycholic acid (TUDCA) raised the promise of safety and efficacy in patients with amyotrophic lateral sclerosis, a currently incurable and devastating disease. We review the available evidence on the efficacy and safety of TUDCA, administered alone or in combination, by analyzing and comparing published and ongoing studies on amyotrophic lateral sclerosis. Two independent phase II studies (using TUDCA solo or combined with sodium phenylbutyrate) showed similar efficacy in slowing disease progression measured by functional scales. One open-label follow-up TUDCA+sodium phenylbutyrate study suggested a benefit on survival. Two subsequent phase III studies with TUDCA (solo or combined with sodium phenylbutyrate) have been initiated and are currently ongoing. Their completion is expected by the end of 2023 and beginning of 2024. Evidence collected by phase II studies indicates that there are no safety concerns in patients with amyotrophic lateral sclerosis. The efficacy shown in phase II studies was considered sufficient to grant approval in some countries but not in others, owing to discrepant views on the strength of evidence. It will be necessary to wait for the results of ongoing phase III studies to attain a full appreciation of these data.}, } @article {pmid37973064, year = {2024}, author = {Lisi, E and Abellan, JJ}, title = {Statistical analysis of actigraphy data with generalised additive models.}, journal = {Pharmaceutical statistics}, volume = {23}, number = {3}, pages = {308-324}, doi = {10.1002/pst.2350}, pmid = {37973064}, issn = {1539-1612}, support = {//GlaxoSmithKline/ ; }, mesh = {Humans ; *Actigraphy/statistics & numerical data/methods ; *Models, Statistical ; Exercise/physiology ; Data Interpretation, Statistical ; Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Pulmonary Disease, Chronic Obstructive/physiopathology/diagnosis ; Time Factors ; }, abstract = {There is a growing interest in the use of physical activity data in clinical studies, particularly in diseases that limit mobility in patients. High-frequency data collected with digital sensors are typically summarised into actigraphy features aggregated at epoch level (e.g., by minute). The statistical analysis of such volume of data is not straightforward. The general trend is to derive metrics, capturing specific aspects of physical activity, that condense (say) a week worth of data into a single numerical value. Here we propose to analyse the entire time-series data using Generalised Additive Models (GAMs). GAMs are semi-parametric models that allow inclusion of both parametric and non-parametric terms in the linear predictor. The latter are smooth terms (e.g., splines) and, in the context of actigraphy minute-by-minute data analysis, they can be used to assess daily patterns of physical activity. This in turn can be used to better understand changes over time in longitudinal studies as well as to compare treatment groups. We illustrate the application of GAMs in two clinical studies where actigraphy data was collected: a non-drug, single-arm study in patients with amyotrophic lateral sclerosis, and a physical-activity sub-study included in a phase 2b clinical trial in patients with chronic obstructive pulmonary disease.}, } @article {pmid37972988, year = {2024}, author = {Ando, T and Riku, Y and Akagi, A and Miyahara, H and Uematsu, T and Aiba, I and Sone, J and Katsuno, M and Yoshida, M and Iwasaki, Y}, title = {Degeneration of olivospinal tract in the upper cervical spinal cord of multiple system atrophy patients: Reappraisal of Helweg's triangular tract.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {3}, pages = {e13226}, pmid = {37972988}, issn = {1750-3639}, support = {//Health, Labor, and Welfare Sciences Research Grants/ ; 30-8//Intramural Research Grant for Neurological and Psychiatric Disorders from the NCNP/ ; JP22wm0425019//Japan Agency for Medical Research and Development/ ; JP23K06935//JSPS KAKENHI/ ; //The HORI Science and Arts Foundation/ ; NFRCH 23-0002//The Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital Research Grant/ ; //The Ministry of Health, Labor, and Welfare, Japan/ ; //The Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases/ ; }, mesh = {Adult ; Humans ; *Multiple System Atrophy/metabolism ; alpha-Synuclein/metabolism ; *Cervical Cord/metabolism ; *Olivopontocerebellar Atrophies ; }, abstract = {Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder that presents with variable combinations of autonomic dysfunction, cerebellar ataxia, parkinsonism, and pyramidal signs. The inferior olivary nucleus is targeted in MSA, with a phenotype of olivopontocerebellar atrophy in particular, and involvement of the olivocerebellar tract is well known. However, degeneration of the olivospinal tract has not been studied in MSA. We examined 97 spinal cords from consecutively autopsied patients with MSA. Myelin staining revealed that 22 cords (22.7%) had small, bilateral, triangular-shaped tract degeneration in the boundary of the anterior and lateral funiculi, which appeared continuously from C1 to C5. The anatomical pathway of the degenerated tract was consistent with the description of the olivospinal tract provided by Helweg in 1888. The MSA patients showing degeneration of this tract were younger at disease onset (average: 56.4 ± 8.7 years, range: 42-74), and had longer disease duration (average: 10.1 ± 4.8 years, range: 2-25) and more severe olivopontocerebellar changes compared to other MSA patients. Quantitative analyses revealed that patients with olivospinal tract degeneration had a lower neuronal density in the inferior olivary nucleus compared to other patients. Microglial density in this tract was negatively correlated with the neuronal density in the inferior olivary nucleus. The densities of glial cytoplasmic inclusions in the inferior olivary nucleus and in the olivospinal tract were strongly correlated with each other. Neurologically healthy controls (n = 22) and disease controls with Lewy body disease (n = 30), amyotrophic lateral sclerosis (n = 30), and progressive supranuclear palsy (n = 30) did not present the olivospinal tract degeneration. Our results indicate an impairment of the neural connection between the inferior olivary nucleus and the spinal cord in MSA patients, which may develop in a descending manner.}, } @article {pmid37972860, year = {2023}, author = {Rizzuti, M and Sali, L and Melzi, V and Scarcella, S and Costamagna, G and Ottoboni, L and Quetti, L and Brambilla, L and Papadimitriou, D and Verde, F and Ratti, A and Ticozzi, N and Comi, GP and Corti, S and Gagliardi, D}, title = {Genomic and transcriptomic advances in amyotrophic lateral sclerosis.}, journal = {Ageing research reviews}, volume = {92}, number = {}, pages = {102126}, doi = {10.1016/j.arr.2023.102126}, pmid = {37972860}, issn = {1872-9649}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Transcriptome/genetics ; Gene Expression Profiling/methods ; *MicroRNAs/genetics/metabolism ; Biomarkers ; Epigenomics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. ALS shows substantial clinical and molecular heterogeneity. In vitro and in vivo models coupled with multiomic techniques have provided important contributions to unraveling the pathomechanisms underlying ALS. To date, despite promising results and accumulating knowledge, an effective treatment is still lacking. Here, we provide an overview of the literature on the use of genomics, epigenomics, transcriptomics and microRNAs to deeply investigate the molecular mechanisms developing and sustaining ALS. We report the most relevant genes implicated in ALS pathogenesis, discussing the use of different high-throughput sequencing techniques and the role of epigenomic modifications. Furthermore, we present transcriptomic studies discussing the most recent advances, from microarrays to bulk and single-cell RNA sequencing. Finally, we discuss the use of microRNAs as potential biomarkers and promising tools for molecular intervention. The integration of data from multiple omic approaches may provide new insights into pathogenic pathways in ALS by shedding light on diagnostic and prognostic biomarkers, helping to stratify patients into clinically relevant subgroups, revealing novel therapeutic targets and supporting the development of new effective therapies.}, } @article {pmid37971544, year = {2024}, author = {Fergany, A and Zong, C and Ekuban, FA and Wu, B and Ueha, S and Shichino, S and Matsushima, K and Iwakura, Y and Ichihara, S and Ichihara, G}, title = {Transcriptome analysis of the cerebral cortex of acrylamide-exposed wild-type and IL-1β-knockout mice.}, journal = {Archives of toxicology}, volume = {98}, number = {1}, pages = {181-205}, pmid = {37971544}, issn = {1432-0738}, support = {17H06396//Japan Society for the Promotion of Science London/ ; 19H04279//Japan Society for the Promotion of Science London/ ; }, mesh = {Animals ; Mice ; *Acrylamide/toxicity ; Brain ; Cerebral Cortex ; Gene Expression Profiling ; Mice, Inbred C57BL ; *Neurotoxicity Syndromes/genetics ; }, abstract = {Acrylamide is an environmental electrophile that has been produced in large amounts for many years. There is concern about the adverse health effects of acrylamide exposure due to its widespread industrial use and also presence in commonly consumed foods and others. IL-1β is a key cytokine that protects the brain from inflammatory insults, but its role in acrylamide-induced neurotoxicity remains unknown. We reported recently that deletion of IL-1β gene exacerbates ACR-induced neurotoxicity in mice. The aim of this study was to identify genes or signaling pathway(s) involved in enhancement of ACR-induced neurotoxicity by IL-1β gene deletion or ACR-induced neurotoxicity to generate a hypothesis mechanism explaining ACR-induced neurotoxicity. C57BL/6 J wild-type and IL-1β KO mice were exposed to ACR at 0, 12.5, 25 mg/kg by oral gavage for 7 days/week for 4 weeks, followed by extraction of mRNA from mice cerebral cortex for RNA sequence analysis. IL-1β deletion altered the expression of genes involved in extracellular region, including upregulation of PFN1 gene related to amyotrophic lateral sclerosis and increased the expression of the opposite strand of IL-1β. Acrylamide exposure enhanced mitochondria oxidative phosphorylation, synapse and ribosome pathways, and activated various pathways of different neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, Huntington disease, and prion disease. Protein network analysis suggested the involvement of different proteins in related to learning and cognitive function, such as Egr1, Egr2, Fos, Nr4a1, and Btg2. Our results identified possible pathways involved in IL-1β deletion-potentiated and ACR-induced neurotoxicity in mice.}, } @article {pmid37968433, year = {2024}, author = {Quattrocchi, S and Bonan, L and Cirillo, L and Avoni, P and Di Stasi, V and Rizzo, G and Liguori, R and Vacchiano, V}, title = {Bibrachial amyotrophy as a rare manifestation of intraspinal fluid collection: a case report and systematic review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {5}, pages = {2279-2288}, pmid = {37968433}, issn = {1590-3478}, mesh = {Humans ; Male ; Middle Aged ; *Magnetic Resonance Imaging ; Electromyography ; Motor Neuron Disease/diagnosis/complications ; }, abstract = {INTRODUCTION: Intraspinal cerebrospinal fluid (CSF) collection has been reported as a rare cause of lower motor neuron (LMN) disorder. We report a case of bibrachial diplegia associated with intraspinal CSF collection and perform a systematic literature review.

PATIENT AND METHODS: A 52-year-old man developed a bibrachial amyotrophy over 6 years, confirmed by the presence of cervical subacute neurogenic changes at electromyography (EMG). Brain magnetic resonance imaging (MRI) revealed cerebral siderosis, while spine MRI showed a ventral longitudinal intraspinal fluid collection (VLISFC) from C2 to L2. No CSF leakage was localized at myelography; a conservative treatment was chosen. We searched for all published cases until 30th April 2023 and extrapolated data of 44 patients reported in 27 publications.

RESULTS: We observed a male predominance, a younger disease onset compared to amyotrophic lateral sclerosis, and a quite long disease duration, highlighting a slow disease progression. LMN signs were more frequently bilateral, mostly involving C5-C6 myotomes. Around 61% of patients presented additional symptoms, but only three referred to a history of headache. Accordingly, CSF opening pressure was mostly normal. Spinal MRI revealed the presence of VLISFC and in some cases myelomalacia. EMG patterns displayed both chronic and subacute neurogenic change in the cervical region. The disease course mainly depended on the treatment choice, which was mostly represented by a surgical approach when a specific dural defect was detected by imaging.

CONCLUSION: Bibrachial diplegia due to VLISFC can be a treatable cause of focal amyotrophy and presents some clinical and radiological "red flags" which cannot be missed by a clinical neurologist.}, } @article {pmid37968324, year = {2023}, author = {Beni, T and Borselli, D and Bonechi, L and Lombardi, L and Gonzi, S and Melelli, L and Turchetti, MA and Fanò, L and D'Alessandro, R and Gigli, G and Casagli, N}, title = {Laser scanner and UAV digital photogrammetry as support tools for cosmic-ray muon radiography applications: an archaeological case study from Italy.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {19983}, pmid = {37968324}, issn = {2045-2322}, abstract = {The use of light detection and ranging technologies, i.e. terrestrial laser scanner (TLS), airborne laser scanner (ALS) and mobile laser scanner (MLS), together with the unmanned aerial vehicles digital photogrammetry (UAV-DP) and satellite data are proving to be fundamental tools to carry out reliable muographic measurement campaigns. The main purpose of this paper is to propose a workflow to correctly plan and exploit these types of data for muon radiography aims. To this end, a real case study is presented: searching for hidden tombs in the Etruscan necropolis of Palazzone (Umbria, Italy). A high-resolution digital elevation model (DEM) and three-dimensional models of the ground surface/sub-surface of the study area were created by merging data obtained using different survey methods to achieve the most accurate three-dimensional environment. Indeed, the simulated muon flux transmission used to infer relative transmission values, and the estimated density distribution, depends on the reliability of the three-dimensional reconstructed ground surface model. The aim of this study is to provide knowledge on the use of TLS and UAV-DP data and GPS-acquired points within the transmission-based muography process and how these data could improve or worsen the muon imaging results. Moreover, this study confirmed that muography applications require a multidisciplinary approach.}, } @article {pmid37967540, year = {2023}, author = {Jalal Jumaah, T and Faal Siahkal, S and Behboodi Moghadam, Z and Ebrahimi, E}, title = {The Effect of Yoga on Maternal Anxiety in Women with Excessive Gestational Weight Gain: A Randomized Controlled Trial.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {517-524}, doi = {10.1159/000534776}, pmid = {37967540}, issn = {2504-2106}, mesh = {Pregnancy ; Infant, Newborn ; Humans ; Female ; *Yoga ; *Gestational Weight Gain ; Anxiety/therapy ; Iran ; }, abstract = {BACKGROUND: Excessive gestational weight gain (EGWG) and anxiety are comorbid conditions that increase the risk of adverse maternal and neonatal outcomes. This study was conducted to investigate the effect of yoga on the anxiety of women with EGWG.

MATERIALS AND METHODS: This randomized controlled trial was performed on EGWG pregnant women referring to comprehensive health centers in Qom city, Iran, between October 2021 and August 2022. Eighty-eight participants were assigned to the intervention (N = 44) and control (N = 44) groups. The experimental group participated in six sessions of 90-min yoga classes, and the control group only received routine care. Two questionnaires including a demographic information questionnaire and the State-Trait Anxiety Inventory (STAI) questionnaire were used for data collection. Data were analyzed using SPSS software version 22.

RESULTS: The results of this study showed a statistically significant difference between the two groups in terms of trait anxiety (25.84 ± 3.45 vs. 57.38 ± 8.07; p < 0.05) and state anxiety (27.93 ± 3.72 vs. 60.13 ± 8.13; p < 0.05) after intervention. On the other hand, the trait and state anxiety rates were stable in the experimental group before and after intervention, while they increased to the severe form of anxiety in the control group (effect size = -21.84 ± 10.66 vs. -19.43 ± 8.44).

CONCLUSION: The result of this study showed that yoga has a positive effect on the anxiety of pregnant women with EGWG and can be used as a preventive or complementary solution to control the anxiety of these mothers.

UNLABELLED: HintergrundExzessive Gewichtszunahme in der Schwangerschaft (EGWG) und Angst sind Komorbiditäten, die das Risiko für einen ungünstigen Verlauf für Mutter und Kind erhöhen. Diese Studie wurde durchgeführt, um die Auswirkung von Yoga auf Angst bei Frauen mit exzessiver Gewichtszunahme in der Schwangerschaft zu untersuchen.Material und MethodenDiese randomisierte, kontrollierte Studie wurde bei Schwangeren mit EGWG durchgeführt, die sich zwischen Oktober 2021 und August 2022 an Zentren für ganzheitliche Gesundheit in der Stadt Ghom im Iran vorstellten. 88 Teilnehmerinnen wurden einer Interventions- (N = 44) und einer Kontrollgruppe (N = 44) zugeteilt. Die experimentelle Gruppe nahm an einem Yogakurs von sechsmal 90 minuten Dauer teil, die Kontrollgruppe erhielt lediglich die Standardversorgung. Die Datenerhebung erfolgte mit zwei Fragebögen: einem Fragebogen zu demografischen Angaben und dem State-Trait-Angstinventar (STAI). Die Auswertung der Daten erfolgte mit SPSS-Software, Version 22.ErgebnisseDie Ergebnisse dieser Studie zeigten einen statistisch signifikanten Unterschied zwischen beiden Gruppen im Hinblick auf Eigenschaftsangst (25.84 ± 3.45 vs. 57.38 ± 8.07; p < 0.05) und Zustandsangst (27.93 ± 3.72 vs. 60.13 ± 8.13; p < 0.05) nach der Intervention. Auf der anderen Seite waren die Raten von Eigenschafts- und Zustandsangst in der experimentellen Gruppe vor und nach der Intervention stabil, während sie in der Kontrollgruppe zur schweren Form von Angst anstiegen (Effektstärke = −21.84 ± 10.66 vs. −19.43 ± 8.44).SchlussfolgerungDie Ergebnisse dieser Studie zeigen, dass Yoga sich bei Schwangeren mit EGWG positive auf Angst auswirkt und als präventive oder komplementäre Lösung zur Beherrschung von Angst bei diesen Müttern eingesetzt werden kann.}, } @article {pmid37967511, year = {2023}, author = {Pavey, N and Hannaford, A and Higashihara, M and van den Bos, M and Kiernan, MC and Menon, P and Vucic, S}, title = {Utility of split hand index with different motor unit number estimation techniques in ALS.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {156}, number = {}, pages = {175-182}, doi = {10.1016/j.clinph.2023.09.018}, pmid = {37967511}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Muscle, Skeletal ; Hand ; Area Under Curve ; Action Potentials/physiology ; Electromyography/methods ; }, abstract = {OBJECTIVE: Utility of the split hand index (SI) in amyotrophic lateral sclerosis (ALS) has been reported when using the compound muscle action potential (CMAP) amplitude method (SICMAP amp). A motor unit number index (MUNIX) based SI method (SIMUNIX) was purported to exhibit higher sensitivity. The present study assessed the clinical utility of SI, derived by CMAP amplitude, MUNIX and MScan-MUNE (SIMScanFit-MUNE) methods, in ALS.

METHODS: Sixty-two consecutive patients with neuromuscular symptoms (36 ALS and 26 ALS-mimics) were prospectively recruited. The SI was derived by dividing the product of the CMAP amplitude, MUNIX and MScan-MUNE values recorded over first dorsal interosseous and abductor pollicis brevis by values recorded over abductor digit minimi.

RESULTS: SICMAP amp, SIMUNIX and SIMScanFit-MUNE were significantly reduced in ALS, with SICMAP amp (area under curve (AUC) = 0.801) and SIMScanFit-MUNE (AUC = 0.805) exhibiting greater diagnostic utility than SIMUNIX (AUC = 0.713). SICMAP amp and SIMScanFit-MUNE exhibited significant correlations with clinical measures of functional disability and weakness of intrinsic hand muscles.

CONCLUSIONS: SI differentiated ALS from mimic disorders, with SICMAP amp and SIMScanFit-MUNE exhibiting greater utility.

SIGNIFICANCE: The split hand index represents could serve as a potential diagnostic biomarker in ALS.}, } @article {pmid37967220, year = {2023}, author = {Watanabe, S and Murata, Y and Oka, Y and Oiwa, K and Horiuchi, M and Iguchi, Y and Komine, O and Sobue, A and Katsuno, M and Ogi, T and Yamanaka, K}, title = {Mitochondria-associated membrane collapse impairs TBK1-mediated proteostatic stress response in ALS.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {47}, pages = {e2315347120}, pmid = {37967220}, issn = {1091-6490}, support = {17H04986 23K06826//Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; 18H02740 18H04860 19KK0214 22H00467//Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; JP21ek0109426 JP23wm0425014//Japan Agency for Medical Research and Development (AMED)/ ; //Uehara Memorial Foundation (UMF)/ ; //Public Foundation of Chubu Science and Technology Center (CSTC)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; Endoplasmic Reticulum/metabolism ; Protein Serine-Threonine Kinases/genetics/metabolism ; }, abstract = {The organelle contact site of the endoplasmic reticulum and mitochondria, known as the mitochondria-associated membrane (MAM), is a multifunctional microdomain in cellular homeostasis. We previously reported that MAM disruption is a common pathological feature in amyotrophic lateral sclerosis (ALS); however, the precise role of MAM in ALS was uncovered. Here, we show that the MAM is essential for TANK-binding kinase 1 (TBK1) activation under proteostatic stress conditions. A MAM-specific E3 ubiquitin ligase, autocrine motility factor receptor, ubiquitinated nascent proteins to activate TBK1 at the MAM, which results in ribosomal protein degradation. MAM or TBK1 deficiency under proteostatic stress conditions resulted in increased cellular vulnerability in vitro and motor impairment in vivo. Thus, MAM disruption exacerbates proteostatic stress via TBK1 inactivation in ALS. Our study has revealed a proteostatic mechanism mediated by the MAM-TBK1 axis, highlighting the physiological importance of the organelle contact sites.}, } @article {pmid37966863, year = {2024}, author = {Babcock, CD and Volk, VL and Zeng, W and Hamilton, LD and Shelburne, KB and Fitzpatrick, CK}, title = {Neural-driven activation of 3D muscle within a finite element framework: exploring applications in healthy and neurodegenerative simulations.}, journal = {Computer methods in biomechanics and biomedical engineering}, volume = {27}, number = {16}, pages = {2389-2399}, pmid = {37966863}, issn = {1476-8259}, support = {U01 AR072989/AR/NIAMS NIH HHS/United States ; }, mesh = {Humans ; *Finite Element Analysis ; *Amyotrophic Lateral Sclerosis/physiopathology ; Muscle, Skeletal/physiopathology/physiology ; Computer Simulation ; Models, Biological ; Motor Neurons/physiology ; }, abstract = {This paper presents a novel computational framework for neural-driven finite element muscle models, with an application to amyotrophic lateral sclerosis (ALS). The multiscale neuromusculoskeletal (NMS) model incorporates physiologically accurate motor neurons, 3D muscle geometry, and muscle fiber recruitment. It successfully predicts healthy muscle force and tendon elongation and demonstrates a progressive decline in muscle force due to ALS, dropping from 203 N (healthy) to 155 N (120 days after ALS onset). This approach represents a preliminary step towards developing integrated neural and musculoskeletal simulations to enhance our understanding of neurodegenerative and neurodevelopmental conditions through predictive NMS models.}, } @article {pmid37966813, year = {2024}, author = {Fang, M and Liu, Y and Huang, C and Fan, S}, title = {Targeting stress granules in neurodegenerative diseases: A focus on biological function and dynamics disorders.}, journal = {BioFactors (Oxford, England)}, volume = {50}, number = {3}, pages = {422-438}, doi = {10.1002/biof.2017}, pmid = {37966813}, issn = {1872-8081}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Stress Granules/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Alzheimer Disease/metabolism/pathology/genetics ; Huntington Disease/metabolism/genetics/pathology ; Parkinson Disease/metabolism/pathology/genetics ; Animals ; Frontotemporal Dementia/metabolism/pathology/genetics ; Neurons/metabolism/pathology ; }, abstract = {Stress granules (SGs) are membraneless organelles formed by eukaryotic cells in response to stress to promote cell survival through their pleiotropic cytoprotective effects. SGs recruit a variety of components to enhance their physiological function, and play a critical role in the propagation of pathological proteins, a key factor in neurodegeneration. Recent advances indicate that SG dynamic disorders exacerbate neuronal susceptibility to stress in neurodegenerative diseases (NDs) including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington's disease (HD) and Parkinson's disease (PD). Here, we outline the biological functions of SGs, highlight SG dynamic disorders in NDs, and emphasize therapeutic approaches for enhancing SG dynamics to provide new insights into ND intervention.}, } @article {pmid37966683, year = {2024}, author = {Ansari, MA and Tripathi, T and Venkidasamy, B and Monziani, A and Rajakumar, G and Alomary, MN and Alyahya, SA and Onimus, O and D'souza, N and Barkat, MA and Al-Suhaimi, EA and Samynathan, R and Thiruvengadam, M}, title = {Multifunctional Nanocarriers for Alzheimer's Disease: Befriending the Barriers.}, journal = {Molecular neurobiology}, volume = {61}, number = {5}, pages = {3042-3089}, pmid = {37966683}, issn = {1559-1182}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Animals ; *Drug Carriers/chemistry ; Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism/drug effects ; Nanoparticles/chemistry ; Multifunctional Nanoparticles/chemistry ; }, abstract = {Neurodegenerative diseases (NDDs) have been increasing in incidence in recent years and are now widespread worldwide. Neuronal death is defined as the progressive loss of neuronal structure or function which is closely associated with NDDs and represents the intrinsic features of such disorders. Amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's, Parkinson's, and Huntington's diseases (AD, PD, and HD, respectively) are considered neurodegenerative diseases that affect a large number of people worldwide. Despite the testing of various drugs, there is currently no available therapy that can remedy or effectively slow the progression of these diseases. Nanomedicine has the potential to revolutionize drug delivery for the management of NDDs. The use of nanoparticles (NPs) has recently been developed to improve drug delivery efficiency and is currently subjected to extensive studies. Nanoengineered particles, known as nanodrugs, can cross the blood-brain barrier while also being less invasive compared to the most treatment strategies in use. Polymeric, magnetic, carbonic, and inorganic NPs are examples of NPs that have been developed to improve drug delivery efficiency. Primary research studies using NPs to cure AD are promising, but thorough research is needed to introduce these approaches to clinical use. In the present review, we discussed the role of metal-based NPs, polymeric nanogels, nanocarrier systems such as liposomes, solid lipid NPs, polymeric NPs, exosomes, quantum dots, dendrimers, polymersomes, carbon nanotubes, and nanofibers and surfactant-based systems for the therapy of neurodegenerative diseases. In addition, we highlighted nanoformulations such as N-butyl cyanoacrylate, poly(butyl cyanoacrylate), D-penicillamine, citrate-coated peptide, magnetic iron oxide, chitosan (CS), lipoprotein, ceria, silica, metallic nanoparticles, cholinesterase inhibitors, an acetylcholinesterase inhibitors, metal chelators, anti-amyloid, protein, and peptide-loaded NPs for the treatment of AD.}, } @article {pmid37965583, year = {2023}, author = {Oh, Y}, title = {Editorial: Cell-based neurodegenerative disease modeling.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1323954}, doi = {10.3389/fcell.2023.1323954}, pmid = {37965583}, issn = {2296-634X}, } @article {pmid37964005, year = {2023}, author = {Lim, L and Kang, J and Song, J}, title = {Extreme diversity of 12 cations in folding ALS-linked hSOD1 unveils novel hSOD1-dependent mechanisms for Fe[2+]/Cu[2+]-induced cytotoxicity.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {19868}, pmid = {37964005}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Cations/chemistry/metabolism ; Copper ; Disulfides/chemistry/metabolism ; *Superoxide Dismutase-1/chemistry/genetics/metabolism ; Zinc ; Protein Folding ; }, abstract = {153-Residue copper-zinc superoxide dismutase 1 (hSOD1) is the first gene whose mutation was linked to FALS. To date, > 180 ALS-causing mutations have been identified within hSOD1, yet the underlying mechanism still remains mysterious. Mature hSOD1 is exceptionally stable constrained by a disulfide bridge to adopt a Greek-key β-barrel fold that accommodates copper/zinc cofactors. Conversely, nascent hSOD1 is unfolded and susceptible to aggregation and amyloid formation, requiring Zn[2+] to initiate folding to a coexistence of folded and unfolded states. Recent studies demonstrate mutations that disrupt Zn[2+]-binding correlate with their ability to form toxic aggregates. Therefore, to decode the role of cations in hSOD1 folding provides not only mechanistic insights, but may bear therapeutic implications for hSOD1-linked ALS. Here by NMR, we visualized the effect of 12 cations: 8 essential for humans (Na[+], K[+], Ca[2+], Zn[2+], Mg[2+], Mn[2+], Cu[2+], Fe[2+]), 3 mimicking zinc (Ni[2+], Cd[2+], Co[2+]), and environmentally abundant Al[3+]. Surprisingly, most cations, including Zn[2+]-mimics, showed negligible binding or induction for folding of nascent hSOD1. Cu[2+] exhibited extensive binding to the unfolded state but led to severe aggregation. Unexpectedly, for the first time Fe[2+] was deciphered to have Zn[2+]-like folding-inducing capacity. Zn[2+] was unable to induce folding of H80S/D83S-hSOD1, while Fe[2+] could. In contrast, Zn[2+] could trigger folding of G93A-hSOD1, but Fe[2+] failed. Notably, pre-existing Fe[2+] disrupted the Zn[2+]-induced folding of G93A-hSOD1. Comparing with the ATP-induced folded state, our findings delineate that hSOD1 maturation requires: (1) intrinsic folding capacity encoded by the sequence; (2) specific Zn[2+]-coordination; (3) disulfide formation and Cu-load catalyzed by hCCS. This study unveils a previously-unknown interplay of cations in governing the initial folding of hSOD1, emphasizing the pivotal role of Zn[2+] in hSOD1-related ALS and implying new hSOD1-dependent mechanisms for Cu[2+]/Fe[2+]-induced cytotoxicity, likely relevant to aging and other diseases.}, } @article {pmid37962258, year = {2024}, author = {Nowakowska-Kotas, M and Korbecki, A and Budrewicz, S and Bladowska, J}, title = {Investigation of cerebellar damage in adult amyotrophic lateral sclerosis patients using magnetic resonance imaging and diffusion tensor imaging.}, journal = {Advances in clinical and experimental medicine : official organ Wroclaw Medical University}, volume = {33}, number = {9}, pages = {1023-1028}, doi = {10.17219/acem/172698}, pmid = {37962258}, issn = {1899-5276}, mesh = {Humans ; Female ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *Diffusion Tensor Imaging/methods ; Retrospective Studies ; Aged ; *Cerebellum/diagnostic imaging/pathology ; Adult ; Magnetic Resonance Imaging/methods ; }, abstract = {BACKGROUND: Research on amyotrophic lateral sclerosis (ALS) reveals that the disorder is not restricted to motor neurons.

OBJECTIVES: This neuroimaging study aimed to investigate the presence of cerebellar damage in adult ALS patients.

MATERIAL AND METHODS: The study retrospectively analyzed magnetic resonance imaging (MRI) examinations performed on a 1.5T MR unit of 33 patients (17 men and 16 women with a mean age of 59.3 years) diagnosed with ALS. Cerebellar and posterior fossa dimensions were calculated using plain MR images. In addition, diffusion tensor imaging (DTI) was used to obtain white matter integrity measurements, represented as fractional anisotropy (FA) values, in the posterior limbs of internal capsules (PLIC) and middle cerebellar peduncles (MCPs). These measurements were compared to 36 healthy volunteers (11 men and 25 women with a mean age of 55.3 years). The study also assessed clinical data for correlations with cerebellar imaging findings.

RESULTS: The linear measurements of the cerebellum did not differ between groups. However, the transverse cerebellar dimension (TCD) ratio to the maximum length of the posterior fossa (0.973 compared to 0.982, t = -2.76, p < 0.01) and FA value in both MCPs (0.67 compared to 0.65 and 0.69 compared to 0.67, p < 0.05) were significantly lower in ALS patients. No significant differences were found in FA value in the PLIC, and no significant correlations were observed between patient clinical characteristics and cerebellar damage.

CONCLUSION: This study provides evidence of cerebellar damage in adult ALS patients. These findings contribute to ALS understanding and highlight the importance of considering cerebellar involvement in the disease process. The results suggest that measuring the TCD ratio and FA value in both MCPs could be potential biomarkers for cerebellar damage in ALS patients.}, } @article {pmid37961916, year = {2023}, author = {Joilin, G and Hafezparast, M}, title = {A case for non-coding RNA as a suitable biomarker of amyotrophic lateral sclerosis.}, journal = {Expert review of molecular diagnostics}, volume = {23}, number = {12}, pages = {1049-1051}, doi = {10.1080/14737159.2023.2283522}, pmid = {37961916}, issn = {1744-8352}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Biomarkers ; RNA, Untranslated ; }, } @article {pmid37961424, year = {2023}, author = {Johnson, CN and Sojitra, KA and Sohn, EJ and Moreno-Romero, AK and Baudin, A and Xu, X and Mittal, J and Libich, DS}, title = {Insights into Molecular Diversity within the FET Family: Unraveling Phase Separation of the N-Terminal Low Complexity Domain from RNA-Binding Protein EWS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37961424}, issn = {2692-8205}, support = {R01 GM136917/GM/NIGMS NIH HHS/United States ; R01 GM140127/GM/NIGMS NIH HHS/United States ; }, abstract = {The FET family proteins, which includes FUS, EWS, and TAF15, are RNA chaperones instrumental in processes such as mRNA maturation, transcriptional regulation, and the DNA damage response. These proteins have clinical significance: chromosomal rearrangements in FET proteins are implicated in Ewing family tumors and related sarcomas. Furthermore, point mutations in FUS and TAF15 are associated with neurodegenerative conditions like amyotrophic lateral sclerosis and frontotemporal lobar dementia. The fusion protein EWS::FLI1, the causative mutation of Ewing sarcoma, arises from a genomic translocation that fuses the low-complexity domain (LCD) of EWS (EWS[LCD]) with the DNA binding domain of the ETS transcription factor FLI1. This fusion not only alters transcriptional programs but also hinders native EWS functions like splicing. However, the precise function of the intrinsically disordered EWS[LCD] is still a topic of active investigation. Due to its flexible nature, EWS[LCD] can form transient interactions with itself and other biomolecules, leading to the formation of biomolecular condensates through phase separation - a mechanism thought to be central to the oncogenicity of EWS::FLI1. In our study, we used paramagnetic relaxation enhancement NMR, analytical ultracentrifugation, light microscopy, and all-atom molecular dynamics (MD) simulations to better understand the self-association and phase separation tendencies of EWS[LCD]. Our aim was to elucidate the molecular events that underpin EWS[LCD]-mediated biomolecular condensation. Our NMR data suggest tyrosine residues primarily drive the interactions vital for EWS[LCD] phase separation. Moreover, a higher density and proximity of tyrosine residues amplify the likelihood of condensate formation. Atomistic MD simulations and hydrodynamic experiments revealed that the tyrosine-rich N and C-termini tend to populate compact conformations, establishing unique contact networks, that are connected by a predominantly extended, tyrosine-depleted, linker region. MD simulations provide critical input on the relationship between contacts formed within a single molecule (intramolecular) and inside the condensed phase (intermolecular), and changes in protein conformations upon condensation. These results offer deeper insights into the condensate-forming abilities of the FET proteins and highlights unique structural and functional nuances between EWS and its counterparts, FUS and TAF15.}, } @article {pmid37961353, year = {2023}, author = {Salaikumaran, MR and Gopal, PP}, title = {Rational Design of TDP-43 Derived α-Helical Peptide Inhibitors: an In-Silico Strategy to Prevent TDP-43 Aggregation in Neurodegenerative Disorders.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.10.26.564235}, pmid = {37961353}, issn = {2692-8205}, support = {R01 NS122907/NS/NINDS NIH HHS/United States ; }, abstract = {TDP-43, an essential RNA/DNA-binding protein, is central to the pathology of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Pathological mislocalization and aggregation of TDP-43 disrupts RNA splicing, mRNA stability, and mRNA transport, thereby impairing neuronal function and survival. The formation of amyloid-like TDP-43 filaments is largely facilitated by the destabilization of an α-helical segment within the disordered C-terminal region. In this study, we hypothesized that preventing the destabilization of the α-helical domain could potentially halt the growth of these pathological filaments. To explore this, we utilized a range of in-silico techniques to design and evaluate peptide-based therapeutics. Various pathological TDP-43 amyloid-like filament crystal structures were selected for their potential to inhibit the binding of additional TDP-43 monomers to the growing filaments. Our computational approaches included biophysical and secondary structure property prediction, molecular docking, 3D structure prediction, and molecular dynamics simulations. Through these techniques, we were able to assess the structure, stability, and binding affinity of these peptides in relation to pathological TDP-43 filaments. The results of our in-silico analyses identified a selection of promising peptides, which displayed a stable α-helical structure, exhibited an increased number of intramolecular hydrogen bonds within the helical domain, and demonstrated high binding affinities for pathological TDP-43 amyloid-like filaments. Additionally, molecular dynamics simulations provided further support for the stability of these peptides, as they exhibited lower root mean square deviations in their helical propensity over 100ns. These findings establish α-helical propensity peptides as potential lead molecules for the development of novel therapeutics against TDP-43 aggregation. This structure-based computational approach for rational design of peptide inhibitors opens a new direction in the search for effective interventions for ALS, FTD, and other related neurodegenerative diseases. The peptides identified as the most promising candidates in this study are currently subject to further testing and validation through both in vitro and in vivo experiments.}, } @article {pmid37960974, year = {2023}, author = {Li, M and Liao, Y and Luo, Z and Song, H and Yang, Z}, title = {Work-related factors and risk of amyotrophic lateral sclerosis: A multivariable Mendelian randomization study.}, journal = {Brain and behavior}, volume = {13}, number = {12}, pages = {e3317}, pmid = {37960974}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Smoking ; Tobacco Smoking ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: The causal relationship between work-related factors and amyotrophic lateral sclerosis (ALS) is unclear. We used a Mendelian randomization (MR) analysis to investigate the unconfounded association between work-related factors and ALS.

METHODS: Univariable MR analyses were conducted to evaluate the causal effects of work-related factors on ALS. Instrumental variables from the UK Biobank on work-related factors (n = 263,615) were used as proxies. The outcome dataset used ALS (n case = 20,806, n control = 59,804) summary-level data from a large-scale genome-wide association study based on European ancestry. MR analysis used inverse variance weighted (IVW), MR-Egger, and weighted median (WM) to assess causal effects and other methods of MR for sensitivity analysis. Further multivariable MR analyses were performed to explore potential mediating effects.

RESULTS: In univariable MR, IVW methods support evidence that genetically determined job involves heavy manual or physical work (OR = 2.04, 95% CI: 1.26-3.31; p = .004) was associated with an increased risk of ALS, and the WM methods also confirm this result (OR = 2.36, 95% CI: 1.30-4.28; p = .005). No evidence of heterogeneity or horizontal pleiotropy was found in the results. In multivariable MR, the association was absent after adjusting for smoking and blood pressure.

CONCLUSIONS: Our MR analysis results demonstrate the potential causal relationship between jobs that involve heavy manual or physical work and ALS, which might be mediated by smoking and high systolic blood pressure.}, } @article {pmid37960542, year = {2023}, author = {Zhao, D and Ji, L and Yang, F}, title = {Land Cover Classification Based on Airborne Lidar Point Cloud with Possibility Method and Multi-Classifier.}, journal = {Sensors (Basel, Switzerland)}, volume = {23}, number = {21}, pages = {}, pmid = {37960542}, issn = {1424-8220}, support = {61972363//National Natural Science Foundation of China/ ; YDZJSX2021C008//Central Government Leading Local Science and Technology Development Fund Project/ ; 20221832//Postgraduate Science and Technology Project of North University of China/ ; }, abstract = {As important geospatial data, point cloud collected from an aerial laser scanner (ALS) provides three-dimensional (3D) information for the study of the distribution of typical urban land cover, which is critical in the construction of a "digital city". However, existing point cloud classification methods usually use a single machine learning classifier that experiences uncertainty in making decisions for fuzzy samples in confusing areas. This limits the improvement of classification accuracy. To take full advantage of different classifiers and reduce uncertainty, we propose a classification method based on possibility theory and multi-classifier fusion. Firstly, the feature importance measure was performed by the XGBoost algorithm to construct a feature space, and two commonly used support vector machines (SVMs) were the chosen base classifiers. Then, classification results from the two base classifiers were quantitatively evaluated to define the confusing areas in classification. Finally, the confidence degree of each classifier for different categories was calculated by the confusion matrix and normalized to obtain the weights. Then, we synthesize different classifiers based on possibility theory to achieve more accurate classification in the confusion areas. DALES datasets were utilized to assess the proposed method. The results reveal that the proposed method can significantly improve classification accuracy in confusing areas.}, } @article {pmid37960284, year = {2023}, author = {Zheng, Y and Bonfili, L and Wei, T and Eleuteri, AM}, title = {Understanding the Gut-Brain Axis and Its Therapeutic Implications for Neurodegenerative Disorders.}, journal = {Nutrients}, volume = {15}, number = {21}, pages = {}, pmid = {37960284}, issn = {2072-6643}, support = {Fondi Studenti PhD//University of Camerino/ ; }, mesh = {Humans ; Brain-Gut Axis ; *Neurodegenerative Diseases/therapy ; *Gastrointestinal Microbiome ; *Alzheimer Disease/therapy ; *Parkinson Disease/therapy ; Brain ; Dysbiosis/therapy ; }, abstract = {The gut-brain axis (GBA) is a complex bidirectional communication network connecting the gut and brain. It involves neural, immune, and endocrine communication pathways between the gastrointestinal (GI) tract and the central nervous system (CNS). Perturbations of the GBA have been reported in many neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), among others, suggesting a possible role in disease pathogenesis. The gut microbiota is a pivotal component of the GBA, and alterations in its composition, known as gut dysbiosis, have been associated with GBA dysfunction and neurodegeneration. The gut microbiota might influence the homeostasis of the CNS by modulating the immune system and, more directly, regulating the production of molecules and metabolites that influence the nervous and endocrine systems, making it a potential therapeutic target. Preclinical trials manipulating microbial composition through dietary intervention, probiotic and prebiotic supplementation, and fecal microbial transplantation (FMT) have provided promising outcomes. However, its clear mechanism is not well understood, and the results are not always consistent. Here, we provide an overview of the major components and communication pathways of the GBA, as well as therapeutic approaches targeting the GBA to ameliorate NDDs.}, } @article {pmid37959385, year = {2023}, author = {Azcarate, I and Urigüen, JA and Leturiondo, M and Sandoval, CL and Redondo, K and Gutiérrez, JJ and Russell, JK and Wallmüller, P and Sterz, F and Daya, MR and Ruiz de Gauna, S}, title = {The Role of Chest Compressions on Ventilation during Advanced Cardiopulmonary Resuscitation.}, journal = {Journal of clinical medicine}, volume = {12}, number = {21}, pages = {}, pmid = {37959385}, issn = {2077-0383}, abstract = {Background: There is growing interest in the quality of manual ventilation during cardiopulmonary resuscitation (CPR), but accurate assessment of ventilation parameters remains a challenge. Waveform capnography is currently the reference for monitoring ventilation rate in intubated patients, but fails to provide information on tidal volumes and inspiration-expiration timing. Moreover, the capnogram is often distorted when chest compressions (CCs) are performed during ventilation compromising its reliability during CPR. Our main purpose was to characterize manual ventilation during CPR and to assess how CCs may impact on ventilation quality. Methods: Retrospective analysis were performed of CPR recordings fromtwo databases of adult patients in cardiac arrest including capnogram, compression depth, and airway flow, pressure and volume signals. Using automated signal processing techniques followed by manual revision, individual ventilations were identified and ventilation parameters were measured. Oscillations on the capnogram plateau during CCs were characterized, and its correlation with compression depth and airway volume was assessed. Finally, we identified events of reversed airflow caused by CCs and their effect on volume and capnogram waveform. Results: Ventilation rates were higher than the recommended 10 breaths/min in 66.7% of the cases. Variability in ventilation rates correlated with the variability in tidal volumes and other ventilatory parameters. Oscillations caused by CCs on capnograms were of high amplitude (median above 74%) and were associated with low pseudo-volumes (median 26 mL). Correlation between the amplitude of those oscillations with either the CCs depth or the generated passive volumes was low, with correlation coefficients of -0.24 and 0.40, respectively. During inspiration and expiration, reversed airflow events caused opposed movement of gases in 80% of ventilations. Conclusions: Our study confirmed lack of adherence between measured ventilation rates and the guideline recommendations, and a substantial dispersion in manual ventilation parameters during CPR. Oscillations on the capnogram plateau caused by CCs did not correlate with compression depth or associated small tidal volumes. CCs caused reversed flow during inspiration, expiration and in the interval between ventilations, sufficient to generate volume changes and causing oscillations on capnogram. Further research is warranted to assess the impact of these findings on ventilation quality during CPR.}, } @article {pmid37958929, year = {2023}, author = {Boylan, MA and Pincetic, A and Romano, G and Tatton, N and Kenkare-Mitra, S and Rosenthal, A}, title = {Targeting Progranulin as an Immuno-Neurology Therapeutic Approach.}, journal = {International journal of molecular sciences}, volume = {24}, number = {21}, pages = {}, pmid = {37958929}, issn = {1422-0067}, mesh = {Humans ; Progranulins/genetics ; Intercellular Signaling Peptides and Proteins/genetics ; *Frontotemporal Dementia/genetics ; Neurons/pathology ; *Amyotrophic Lateral Sclerosis ; }, abstract = {Immuno-neurology is an emerging therapeutic strategy for dementia and neurodegeneration designed to address immune surveillance failure in the brain. Microglia, as central nervous system (CNS)-resident myeloid cells, routinely perform surveillance of the brain and support neuronal function. Loss-of-function (LOF) mutations causing decreased levels of progranulin (PGRN), an immune regulatory protein, lead to dysfunctional microglia and are associated with multiple neurodegenerative diseases, including frontotemporal dementia caused by the progranulin gene (GRN) mutation (FTD-GRN), Alzheimer's disease (AD), Parkinson's disease (PD), limbic-predominant age-related transactivation response deoxyribonucleic acid binding protein 43 (TDP-43) encephalopathy (LATE), and amyotrophic lateral sclerosis (ALS). Immuno-neurology targets immune checkpoint-like proteins, offering the potential to convert aging and dysfunctional microglia into disease-fighting cells that counteract multiple disease pathologies, clear misfolded proteins and debris, promote myelin and synapse repair, optimize neuronal function, support astrocytes and oligodendrocytes, and maintain brain vasculature. Several clinical trials are underway to elevate PGRN levels as one strategy to modulate the function of microglia and counteract neurodegenerative changes associated with various disease states. If successful, these and other immuno-neurology drugs have the potential to revolutionize the treatment of neurodegenerative disorders by harnessing the brain's immune system and shifting it from an inflammatory/pathological state to an enhanced physiological/homeostatic state.}, } @article {pmid37958767, year = {2023}, author = {Gonzalo-Gobernado, R and Moreno-Martínez, L and González, P and Dopazo, XM and Calvo, AC and Pidal-Ladrón de Guevara, I and Seisdedos, E and Díaz-Muñoz, R and Mellström, B and Osta, R and Naranjo, JR}, title = {Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice.}, journal = {International journal of molecular sciences}, volume = {24}, number = {21}, pages = {}, pmid = {37958767}, issn = {1422-0067}, support = {PI21/00372//Instituto de Salud Carlos III/ ; 307//Biomedical Research Networking Center on Neurodegenerative Diseases/ ; }, mesh = {Mice ; Animals ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Activating Transcription Factor 6/genetics/metabolism ; Neuroprotection ; Motor Neurons/metabolism ; Kv Channel-Interacting Proteins/metabolism ; Superoxide Dismutase/genetics/metabolism ; Disease Models, Animal ; }, abstract = {The interaction of the activating transcription factor 6 (ATF6), a key effector of the unfolded protein response (UPR) in the endoplasmic reticulum, with the neuronal calcium sensor Downstream Regulatory Element Antagonist Modulator (DREAM) is a potential therapeutic target in neurodegeneration. Modulation of the ATF6-DREAM interaction with repaglinide (RP) induced neuroprotection in a model of Huntington's disease. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no cure, characterized by the progressive loss of motoneurons resulting in muscle denervation, atrophy, paralysis, and death. The aim of this work was to investigate the potential therapeutic significance of DREAM as a target for intervention in ALS. We found that the expression of the DREAM protein was reduced in the spinal cord of SOD1G93A mice compared to wild-type littermates. RP treatment improved motor strength and reduced the expression of the ALS progression marker collagen type XIXα1 (Col19α1 mRNA) in the quadriceps muscle in SOD1G93A mice. Moreover, treated SOD1G93A mice showed reduced motoneuron loss and glial activation and increased ATF6 processing in the spinal cord. These results indicate that the modulation of the DREAM-ATF6 interaction ameliorates ALS symptoms in SOD1G93A mice.}, } @article {pmid37958596, year = {2023}, author = {Stoka, V and Vasiljeva, O and Nakanishi, H and Turk, V}, title = {The Role of Cysteine Protease Cathepsins B, H, C, and X/Z in Neurodegenerative Diseases and Cancer.}, journal = {International journal of molecular sciences}, volume = {24}, number = {21}, pages = {}, pmid = {37958596}, issn = {1422-0067}, support = {J1-2473, P1-0140//Slovenian Research Agency/ ; }, mesh = {Humans ; *Cysteine Proteases ; *Neurodegenerative Diseases ; Cysteine/metabolism ; Cathepsin B ; *Neoplasms ; Lysosomes/metabolism ; }, abstract = {Papain-like cysteine proteases are composed of 11 human cysteine cathepsins, originally located in the lysosomes. They exhibit broad specificity and act as endopeptidases and/or exopeptidases. Among them, only cathepsins B, H, C, and X/Z exhibit exopeptidase activity. Recently, cysteine cathepsins have been found to be present outside the lysosomes and often participate in various pathological processes. Hence, they have been considered key signalling molecules. Their potentially hazardous proteolytic activities are tightly regulated. This review aims to discuss recent advances in understanding the structural aspects of these four cathepsins, mechanisms of their zymogen activation, regulation of their activities, and functional aspects of these enzymes in neurodegeneration and cancer. Neurodegenerative effects have been evaluated, particularly in Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and neuropsychiatric disorders. Cysteine cathepsins also participate in tumour progression and metastasis through the overexpression and secretion of proteases, which trigger extracellular matrix degradation. To our knowledge, this is the first review to provide an in-depth analysis regarding the roles of cysteine cathepsins B, H, C, and X in neurodegenerative diseases and cancer. Further advances in understanding the functions of cysteine cathepsins in these conditions will result in the development of novel, targeted therapeutic strategies.}, } @article {pmid37957721, year = {2023}, author = {Tan, RH and McCann, H and Shepherd, CE and Pinkerton, M and Mazumder, S and Devenney, EM and Adler, GL and Rowe, DB and Kril, J and Halliday, GM and Kiernan, MC}, title = {Heterogeneity of cortical pTDP-43 inclusion morphologies in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {180}, pmid = {37957721}, issn = {2051-5960}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Frontotemporal Dementia/pathology ; DNA-Binding Proteins/genetics ; Neurons/pathology ; Phenotype ; }, abstract = {BACKGROUND: Despite the presence of significant cortical pTDP-43 inclusions of heterogeneous morphologies in patients diagnosed with amyotrophic lateral sclerosis (ALS), pathological subclassification is routinely performed in the minority of patients with concomitant frontotemporal dementia (FTD).

OBJECTIVE: In order to improve current understanding of the presence and relevance of pathological pTDP-43 subtypes in ALS, the present study examined the pattern of cortical pTDP-43 aggregates in 61 ALS cases without FTD.

RESULTS: Based on the presence, morphology and composition of pTDP-43 pathology, three distinct ALS-TDP subtypes were delineated: (1) A predominant pattern of pTDP-43 granulofilamentous neuronal inclusions (GFNIs) and grains that were immuno-negative for p62 was identified in 18% of cases designated ALS-TDP type E; (2) neuronal cytoplasmic inclusions (NCIs) that were immuno-positive for both pTDP-43 and p62 were observed in 67% of cases assigned ALS-TDP type B; and (3) scarce cortical pTDP-43 and p62 aggregates were identified in 15% of cases coined ALS-TDP type SC (scarce cortical). Quantitative analyses revealed a significantly greater burden of pTDP-43 GFNI and grains in ALS-TDP type E. Principal component analysis demonstrated significant relationships between GFNIs, grains and ALS-TDP subtypes to support the distinction of subtypes E and B. No significant difference in age at death or disease duration was found between ALS-TDP subgroups to suggest that these subtypes represent earlier or later stages of the same disease process. Instead, a significantly higher ALS-TDP stage, indicating greater topographical spread of pTDP-43, was identified in ALS-TDP type E. Alzheimer's disease neuropathological change (ABC score ≥ intermediate) and Lewy body disease (Braak stage ≥ IV) was more prevalent in the ALS-TDP type SC cohort, which also demonstrated a significantly lower overall cognitive score.

CONCLUSION: In summary, the present study demonstrates that ALS-TDP does not represent a single homogenous neuropathology. We propose the subclassification of ALS-TDP into three distinct subtypes using standard immuno-stains for pTDP-43 and p62 in the motor cortex, which is routinely sampled and evaluated for diagnostic neuropathological characterisation of ALS. We propose that future studies specify both clinicopathological group and pTDP-43 subtype to advance current understanding of the pathogenesis of clinical phenotypes in pTDP-43 proteinopathies, which will have significant relevance to the development of targeted therapies for this heterogeneous disorder.}, } @article {pmid37955773, year = {2023}, author = {Colasuonno, F and Price, R and Moreno, S}, title = {Upper and Lower Motor Neurons and the Skeletal Muscle: Implication for Amyotrophic Lateral Sclerosis (ALS).}, journal = {Advances in anatomy, embryology, and cell biology}, volume = {236}, number = {}, pages = {111-129}, pmid = {37955773}, issn = {0301-5556}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis ; Motor Neurons ; Muscle, Skeletal ; Neurons, Efferent ; *Nerve Tissue ; }, abstract = {The relationships between motor neurons and the skeletal muscle during development and in pathologic contexts are addressed in this Chapter.We discuss the developmental interplay of muscle and nervous tissue, through neurotrophins and the activation of differentiation and survival pathways. After a brief overview on muscular regulatory factors, we focus on the contribution of muscle to early and late neurodevelopment. Such a role seems especially intriguing in relation to the epigenetic shaping of developing motor neuron fate choices. In this context, emphasis is attributed to factors regulating energy metabolism, which may concomitantly act in muscle and neural cells, being involved in common pathways.We then review the main features of motor neuron diseases, addressing the cellular processes underlying clinical symptoms. The involvement of different muscle-associated neurotrophic factors for survival of lateral motor column neurons, innervating MyoD-dependent limb muscles, and of medial motor column neurons, innervating Myf5-dependent back musculature is discussed. Among the pathogenic mechanisms, we focus on oxidative stress, that represents a common and early trait in several neurodegenerative disorders. The role of organelles primarily involved in reactive oxygen species scavenging and, more generally, in energy metabolism-namely mitochondria and peroxisomes-is discussed in the frame of motor neuron degeneration.We finally address muscular involvement in amyotrophic lateral sclerosis (ALS), a multifactorial degenerative disorder, hallmarked by severe weight loss, caused by imbalanced lipid metabolism. Even though multiple mechanisms have been recognized to play a role in the disease, current literature generally assumes that the primum movens is neuronal degeneration and that muscle atrophy is only a consequence of such pathogenic event. However, several lines of evidence point to the muscle as primarily involved in the disease, mainly through its role in energy homeostasis. Data from different ALS mouse models strongly argue for an early mitochondrial dysfunction in muscle tissue, possibly leading to motor neuron disturbances. Detailed understanding of skeletal muscle contribution to ALS pathogenesis will likely lead to the identification of novel therapeutic strategies.}, } @article {pmid37955564, year = {2024}, author = {Pinto, S and Oliveira Santos, M and Gromicho, M and Swash, M and de Carvalho, M}, title = {Impact of diabetes mellitus on the respiratory function of amyotrophic lateral sclerosis patients.}, journal = {European journal of neurology}, volume = {31}, number = {2}, pages = {e16129}, pmid = {37955564}, issn = {1468-1331}, support = {GA101017598//European Union's Horizon 2020 research and innovation program/ ; }, mesh = {Male ; Humans ; Middle Aged ; Aged ; *Amyotrophic Lateral Sclerosis ; Retrospective Studies ; *Respiratory Insufficiency/complications ; Respiratory Function Tests/adverse effects ; *Diabetes Mellitus ; }, abstract = {BACKGROUND AND PURPOSE: Respiratory insufficiency and its complications are the main cause of death in amyotrophic lateral sclerosis (ALS). The impact of diabetes mellitus (DM) on respiratory function of ALS patients is uncertain.

METHODS: A retrospective cohort study was carried out. From the 1710 patients with motor neuron disease followed in our unit, ALS and progressive muscular atrophy patients were included. We recorded demographic characteristics, functional ALS rating scale (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R]) and its subscores at first visit, respiratory function tests, arterial blood gases, phrenic nerve amplitude (PhrenAmpl), and mean nocturnal oxygen saturation (SpO2 mean). We excluded patients with other relevant diseases. Two subgroups were analysed: DIAB (patients with DM) and noDIAB (patients without DM). Independent t-test, χ[2] , or Fisher exact test was applied. Binomial logistic regression analyses assessed DM effects. Kaplan-Meier analysis assessed survival. p < 0.05 was considered significant.

RESULTS: We included 1639 patients (922 men, mean onset age = 62.5 ± 12.6 years, mean disease duration = 18.1 ± 22.0 months). Mean survival was 43.3 ± 40.7 months. More men had DM (p = 0.021). Disease duration was similar between groups (p = 0.063). Time to noninvasive ventilation (NIV) was shorter in DIAB (p = 0.004); total survival was similar. No differences were seen for ALSFRS-R or its decay rate. At entry, DIAB patients were older (p < 0.001), with lower forced vital capacity (p = 0.001), arterial oxygen pressure (p = 0.01), PhrenAmpl (p < 0.001), and SpO2 mean (p = 0.014).

CONCLUSIONS: ALS patients with DM had increased risk of respiratory impairment and should be closely monitored. Early NIV allowed for similar survival rate between groups.}, } @article {pmid37955299, year = {2023}, author = {Yuan, YH and Mao, ND and Duan, JL and Zhang, H and Garrido, C and Lirussi, F and Gao, Y and Xie, T and Ye, XY}, title = {Recent progress in discovery of novel AAK1 inhibitors: from pain therapy to potential anti-viral agents.}, journal = {Journal of enzyme inhibition and medicinal chemistry}, volume = {38}, number = {1}, pages = {2279906}, pmid = {37955299}, issn = {1475-6374}, mesh = {Humans ; *Protein Serine-Threonine Kinases ; *Antiviral Agents/pharmacology ; Phosphorylation ; Pain ; }, abstract = {Adaptor associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of Ser/Thr kinases, is a specific key kinase regulating Thr156 phosphorylation at the μ2 subunit of the adapter complex-2 (AP-2) protein. Due to their important biological functions, AAK1 systems have been validated in clinics for neuropathic pain therapy, and are being explored as potential therapeutic targets for diseases caused by various viruses such as Hepatitis C (HCV), Dengue, Ebola, and COVID-19 viruses and for amyotrophic lateral sclerosis (ALS). Centreing on the advances of drug discovery programs in this field up to 2023, AAK1 inhibitors are discussed from the aspects of the structure-based rational molecular design, pharmacology, toxicology and synthetic routes for the compounds of interest in this review. The aim is to provide the medicinal chemistry community with up-to-date information and to accelerate the drug discovery programs in the field of AAK1 small molecule inhibitors.}, } @article {pmid37955056, year = {2024}, author = {Spörndly-Nees, S and Jakobsson Larsson, B and Zetterberg, L and Åkerblom, Y and Nyholm, D and Åsenlöf, P}, title = {Pain in patients with motor neuron disease: Variation of pain and association with disease severity, health-related quality of life and depression - A longitudinal study.}, journal = {Palliative & supportive care}, volume = {22}, number = {5}, pages = {1150-1157}, doi = {10.1017/S1478951523001347}, pmid = {37955056}, issn = {1478-9523}, mesh = {Humans ; Female ; Male ; *Quality of Life/psychology ; Middle Aged ; Longitudinal Studies ; *Depression/psychology/etiology/complications ; Aged ; *Motor Neuron Disease/complications/psychology ; Prospective Studies ; *Pain/psychology/etiology/complications ; Severity of Illness Index ; Surveys and Questionnaires ; Pain Measurement/methods ; Adult ; Cohort Studies ; Disease Progression ; Psychometrics/methods/instrumentation ; }, abstract = {OBJECTIVES: To describe levels of pain over time during disease progression in individual patients and for a total sample of patients with motor neuron disease (MND), respectively, and to examine associations between pain, disease severity, health-related quality of life (HRQOL), and depression.

METHODS: A prospective cohort study was conducted on 68 patients with MND, including data collected on five occasions over a period of 2 years. Pain was assessed using the Brief Pain Inventory - Short Form. Depression was assessed using the Amyotrophic Lateral Sclerosis (ALS)-Depression-Inventory (ADI-12). Disability progression was measured using the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Version (ALSFRS-R). HRQOL was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5).

RESULTS: Participants reported great individual variation over time. The median level of pain was 4 (min 0 and max 10). Higher levels of pain during the last 24 h were associated with higher depression scores (ADI-12), poorer quality of life (ALSAQ-5), and lower reporting of fine and gross motor skills (ALSFRS-R). Baseline pain levels did not predict future values of depression and function. Individuals reporting average pain >3 experienced more hopelessness toward the future and reported higher depression scores compared with participants reporting average pain <3.

SIGNIFICANCE OF RESULTS: Great within-individual variation of pain intensity was reported. Pain intensity was associated with depression, function and HRQOL cross-sectionally, but it did not have a strong prognostic value for future depression, function, or HRQOL. Patients with MND should be offered frequent assessment of pain and depressive symptoms in person-centered care, allowing for individualization of treatment.}, } @article {pmid37954904, year = {2023}, author = {Zhao, K and Chen, P and Alexander-Bloch, A and Wei, Y and Dyrba, M and Yang, F and Kang, X and Wang, D and Fan, D and Ye, S and Tang, Y and Yao, H and Zhou, B and Lu, J and Yu, C and Wang, P and Liao, Z and Chen, Y and Huang, L and Zhang, X and Han, Y and Li, S and Liu, Y}, title = {A neuroimaging biomarker for Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN): a cross-sectional study.}, journal = {EClinicalMedicine}, volume = {65}, number = {}, pages = {102276}, pmid = {37954904}, issn = {2589-5370}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that poses a worldwide public health challenge. A neuroimaging biomarker would significantly improve early diagnosis and intervention, ultimately enhancing the quality of life for affected individuals and reducing the burden on healthcare systems.

METHODS: Cross-sectional and longitudinal data (10,099 participants with 13,380 scans) from 12 independent datasets were used in the present study (this study was performed between September 1, 2021 and February 15, 2023). The Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN) score was developed via integrated regional- and network-based measures under an ensemble machine learning model based on structural MRI data. We systematically assessed whether IBRAIN could be a neuroimaging biomarker for AD.

FINDINGS: IBRAIN accurately differentiated individuals with AD from NCs (AUC = 0.92) and other neurodegenerative diseases, including Frontotemporal dementia (FTD), Parkinson's disease (PD), Vascular dementia (VaD) and Amyotrophic Lateral Sclerosis (ALS) (AUC = 0.92). IBRAIN was significantly correlated to clinical measures and gene expression, enriched in immune process and protein metabolism. The IBRAIN score exhibited a significant ability to reveal the distinct progression of prodromal AD (i.e., Mild cognitive impairment, MCI) (Hazard Ratio (HR) = 6.52 [95% CI: 4.42∼9.62], p < 1 × 10[-16]), which offers similar powerful performance with Cerebrospinal Fluid (CSF) Aβ (HR = 3.78 [95% CI: 2.63∼5.43], p = 2.13 × 10[-14]) and CSF Tau (HR = 3.77 [95% CI: 2.64∼5.39], p = 9.53 × 10[-15]) based on the COX and Log-rank test. Notably, the IBRAIN shows comparable sensitivity (beta = -0.70, p < 1 × 10[-16]) in capturing longitudinal changes in individuals with conversion to AD than CSF Aβ (beta = -0.26, p = 4.40 × 10[-9]) and CSF Tau (beta = 0.12, p = 1.02 × 10[-5]).

INTERPRETATION: Our findings suggested that IBRAIN is a biologically relevant, specific, and sensitive neuroimaging biomarker that can serve as a clinical measure to uncover prodromal AD progression. It has strong potential for application in future clinical practice and treatment trials.

FUNDING: Science and Technology Innovation 2030 Major Projects, the National Natural Science Foundation of China, Beijing Natural Science Funds, the Fundamental Research Funds for the CentralUniversity, and the Startup Funds for Talents at Beijing Normal University.}, } @article {pmid37954145, year = {2023}, author = {Kalia, M and Miotto, M and Ness, D and Opie-Martin, S and Spargo, TP and Di Rienzo, L and Biagini, T and Petrizzelli, F and Al Khleifat, A and Kabiljo, R and , and , and Mazza, T and Ruocco, G and Milanetti, E and Dobson, RJ and Al-Chalabi, A and Iacoangeli, A}, title = {Molecular dynamics analysis of superoxide dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression.}, journal = {Computational and structural biotechnology journal}, volume = {21}, number = {}, pages = {5296-5308}, pmid = {37954145}, issn = {2001-0370}, abstract = {Mutations in the superoxide dismutase 1 (SOD1) gene are the second most common known cause of ALS. SOD1 variants express high phenotypic variability and over 200 have been reported in people with ALS. It was previously proposed that variants can be broadly classified in two groups, 'wild-type like' (WTL) and 'metal binding region' (MBR) variants, based on their structural location and biophysical properties. MBR variants, but not WTL variants, were associated with a reduction of SOD1 enzymatic activity. In this study we used molecular dynamics and large clinical datasets to characterise the differences in the structural and dynamic behaviour of WTL and MBR variants with respect to the wild-type SOD1, and how such differences influence the ALS clinical phenotype. Our study identified marked structural differences, some of which are observed in both variant groups, while others are group specific. Moreover, collecting clinical data of approximately 500 SOD1 ALS patients carrying variants, we showed that the survival time of patients carrying an MBR variant is generally longer (∼6 years median difference, p < 0.001) with respect to patients with a WTL variant. In conclusion, our study highlighted key differences in the dynamic behaviour between WTL and MBR SOD1 variants, and between variants and wild-type SOD1 at an atomic and molecular level, that could be further investigated to explain the associated phenotypic variability. Our results support the hypothesis of a decoupling between mechanisms of onset and progression of SOD1 ALS, and an involvement of loss-of-function of SOD1 with the disease progression.}, } @article {pmid37953591, year = {2023}, author = {Benlefki, S and Younes, R and Challuau, D and Bernard-Marissal, N and Hilaire, C and Scamps, F and Bowerman, M and Kothary, R and Schneider, BL and Raoul, C}, title = {Differential effect of Fas activation on spinal muscular atrophy motoneuron death and induction of axonal growth.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {69}, number = {10}, pages = {1-8}, doi = {10.14715/cmb/2023.69.10.1}, pmid = {37953591}, issn = {1165-158X}, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; *Muscular Atrophy, Spinal/genetics/metabolism/pathology ; Axons/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most common motoneuron diseases affecting adults and infants, respectively. ALS and SMA are both characterized by the selective degeneration of motoneurons. Although different in their genetic etiology, growing evidence indicates that they share molecular and cellular pathogenic signatures that constitute potential common therapeutic targets. We previously described a motoneuron-specific death pathway elicited by the Fas death receptor, whereby vulnerable ALS motoneurons show an exacerbated sensitivity to Fas activation. However, the mechanisms that drive the loss of SMA motoneurons remains poorly understood. Here, we describe an in vitro model of SMA-associated degeneration using primary motoneurons derived from Smn2B/- SMA mice and show that Fas activation selectively triggers death of the proximal motoneurons. Fas-induced death of SMA motoneurons has the molecular signature of the motoneuron-selective Fas death pathway that requires activation of p38 kinase, caspase-8, -9 and -3 as well as upregulation of collapsin response mediator protein 4 (CRMP4). In addition, Rho-associated Kinase (ROCK) is required for Fas recruitment. Remarkably, we found that exogenous activation of Fas also promotes axonal elongation in both wildtype and SMA motoneurons. Axon outgrowth of motoneurons promoted by Fas requires the activity of ERK, ROCK and caspases. This work defines a dual role of Fas signaling in motoneurons that can elicit distinct responses from cell death to axonal growth.}, } @article {pmid37953075, year = {2023}, author = {Shimizu, H and Nishimura, Y and Shiide, Y and Akimoto, M and Yashiro, M and Ueda, M and Hirai, M and Yoshino, H and Mizutani, T and Kanai, K and Kano, O and Kimura, H and Sekino, H and Ito, K}, title = {Pharmacokinetics of Edaravone Oral Suspension in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Clinical therapeutics}, volume = {45}, number = {12}, pages = {1251-1258}, doi = {10.1016/j.clinthera.2023.09.025}, pmid = {37953075}, issn = {1879-114X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/pharmacokinetics ; Glucuronides/therapeutic use ; *Neuroprotective Agents/pharmacokinetics ; Sulfates/therapeutic use ; }, abstract = {PURPOSE: Edaravone is a neuroprotective agent approved as an intravenous treatment for amyotrophic lateral sclerosis (ALS). The intravenous administration of edaravone places a burden on patients and there is a clinical need for oral agents for the treatment of ALS. This report aimed to assess the pharmacokinetics and safety of an edaravone oral suspension in patients with ALS after oral and percutaneous endoscopic gastrostomy (PEG) tube administration.

METHODS: Two single-dose, open-label phase 1 clinical studies were conducted. Edaravone oral suspension (105 mg of edaravone in 5 mL aqueous suspension) was administered orally and via PEG tube to 9 and 6 Japanese patients with ALS, respectively. Plasma and urinary pharmacokinetics of unchanged edaravone and its metabolites (sulfate and glucuronide conjugates) were determined. Safety was also evaluated.

FINDINGS: After reaching maximum plasma concentration, the mean plasma concentration-time of unchanged edaravone showed a triphasic elimination. Mean plasma concentration-time profiles of the metabolites were higher than those of unchanged edaravone. The mean urinary excretion ratios were higher for the glucuronide conjugate than for either unchanged edaravone or the sulfate conjugate. In patients administered edaravone orally, a single adverse event occurred (blood urine present), which was mild and improved without medical intervention. No adverse drug reactions or serious adverse events were reported. In patients administered edaravone via PEG tube, 5 treatment-emergent adverse events were reported in 3 patients; none were related to the study drug. No adverse drug reactions were reported.

IMPLICATIONS: In patients with ALS, a single dose of edaravone oral suspension was well absorbed and mainly eliminated in urine as the glucuronide conjugate. No safety concerns emerged. Pharmacokinetics were similar to those previously reported in healthy participants following oral administration. This indicates that effective drug concentrations were achieved and edaravone can be successfully administered both orally and via a PEG tube in patients with ALS.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04176224 (oral administration) and NCT04254913 (PEG tube administration), www.

CLINICALTRIALS: gov.}, } @article {pmid37952981, year = {2023}, author = {Okano, H and Morimoto, S and Kato, C and Nakahara, J and Takahashi, S}, title = {Induced pluripotent stem cells-based disease modeling, drug screening, clinical trials, and reverse translational research for amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {167}, number = {5}, pages = {603-614}, doi = {10.1111/jnc.16005}, pmid = {37952981}, issn = {1471-4159}, support = {JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP20H00485//Japan Society for the Promotion of Science/ ; JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Drug Evaluation, Preclinical ; *Neurodegenerative Diseases/metabolism ; Translational Research, Biomedical ; Randomized Controlled Trials as Topic ; }, abstract = {It has been more than 10 years since the hopes for disease modeling and drug discovery using induced pluripotent stem cell (iPSC) technology boomed. Recently, clinical trials have been conducted with drugs identified using this technology, and some promising results have been reported. For amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, several groups have identified candidate drugs, ezogabine (retigabine), bosutinib, and ropinirole, using iPSCs-based drug discovery, and clinical trials using these drugs have been conducted, yielding interesting results. In our previous study, an iPSCs-based drug repurposing approach was utilized to show the potential of ropinirole hydrochloride (ROPI) in reducing ALS-specific pathological phenotypes. Recently, a phase 1/2a trial was conducted to investigate the effects of ropinirole on ALS further. This double-blind, randomized, placebo-controlled study confirmed the safety and tolerability of and provided evidence of its ability to delay disease progression and prolong the time to respiratory failure in ALS patients. Furthermore, in the reverse translational research, in vitro characterization of patient-derived iPSCs-motor neurons (MNs) mimicked the therapeutic effects of ROPI in vivo, suggesting the potential application of this technology to the precision medicine of ALS. Interestingly, RNA-seq data showed that ROPI treatment suppressed the sterol regulatory element-binding protein 2-dependent cholesterol biosynthesis pathway. Therefore, this pathway may be involved in the therapeutic effect of ROPI on ALS. The possibility that this pathway may be involved in the therapeutic effect of ALS was demonstrated. Finally, new future strategies for ALS using iPSCs technology will be discussed in this paper.}, } @article {pmid37952517, year = {2024}, author = {Zürcher, BF}, title = {The Tibetan Formula Cong zhi 6 in the ORL (ENT) Practice: Experiences with Laryngopharyngeal Reflux.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {84-88}, doi = {10.1159/000534212}, pmid = {37952517}, issn = {2504-2106}, mesh = {Humans ; *Laryngopharyngeal Reflux/drug therapy ; Retrospective Studies ; Pepsin A ; Tibet ; Europe ; }, abstract = {BACKGROUND: Laryngopharyngeal reflux (LPR) is a frequent condition; in European countries, the prevalence can be estimated as 10-30% of the general population. Treatment includes lifestyle measures and highly dosed proton pump inhibitors (PPIs) over at least 4 weeks. However, PPIs are not unproblematic due to their potential side effects and the known phenomenon of rebound acid hypersecretion. Cong zhi 6 is a multi-herbal Tibetan formula additionally containing calcium carbonate and is available in several European countries as a food supplement Padma Aciben/Padma AciTib.

CASE REPORT: Ten patients with LPR took Cong zhi 6. The course of the complaints was documented, and the data were retrospectively analysed. Clinical symptoms as assessed with the Reflux Symptom Index (RSI) questionnaire and the findings in laryngoscopy with the Reflux Finding Score (RFS) both showed marked improvement of several symptoms. The number of patients with pathological LPR sum score was significantly reduced from 8 to 2 patients and from 10 to 1 patient in RSI and RFS, respectively. The mean sum scores were reduced from 18.1 to 8.4 (RSI) and from 12.9 to 4.4 (RFS), respectively. Also, other gastrointestinal symptoms, such as abdominal pain, bloating, feeling of fullness, and nausea, which are usually associated with functional dyspepsia and irritable bowel syndrome, were markedly improved (reduction of mean score of the 3 most frequent symptoms by 77-87%).

CONCLUSION: Standard medical treatment for LPR consists in high dosed PPI for at least 4 weeks, which is known for several side effects and does not treat reliable the nonacid component of LPR of pepsin or other gastric enzymes. Therefore, other medical treatment options are urgently needed. The promising data of this case series suggest that the Tibetan herbal formula Cong zhi 6 may be a treatment option in LPR and related gastrointestinal symptoms and warrant further research.

UNLABELLED: HintergrundDer laryngopharyngeale Reflux (LPR) ist eine häufige Erkrankung. In europäischen Ländern wird die Prävalenz in der Gesamtbevölkerung auf 10–30% geschätzt. Die Behandlung beinhaltet Ernährungs- und Verhaltensänderung sowie die Gabe hochdosierter Protonen-Pumpen-Hemmer (PPI) über mindestens 4 Wochen. PPI sind jedoch aufgrund ihrer hohen potenziellen Nebenwirkungen und des bekannten Rebound-Phänomens der sauren Magensafthypersekretion nicht unproblematisch. Cong zhi 6 ist eine tibetische Rezeptur aus einem Vielpflanzengemisch sowie zusätzlich Calciumcarbonat und ist in einigen europäischen Ländern als Nahrungsergänzungsmittel Padma Aciben/Padma AciTib erhältlich.Case ReportZehn Patienten mit laryngo-pharyngealem Reflux (LPR) nahmen Cong zhi 6 ein. Der Beschwerdeverlauf wurde dokumentiert und die Daten retrospektiv analysiert. Die klinischen Symptome, die mithilfe des Reflux Symptom Index (RSI) Fragebogens erfasst wurden und die mittels des Reflux Finding Score (RFS) beurteilten laryngoskopischen Befunde zeigten beide eine deutliche Verbesserung verschiedener Symptome. Die Zahl der Patienten mit pathologischen LPR-Summenscore reduzierte sich signifikant, im RSI von 8 auf 2 und im RFS von 10 auf 1 Patienten. Der mittlere Summenwert sank von 18.1 auf 8.4 (RSI) und von 12.9 auf 4.4 (RFS). Des Weiteren zeigte sich auch bei anderen gastrointestinalen Beschwerden, wie Bauchschmerzen, Blähungen, Völlegefühl und Übelkeit, die normalerweise mit funktioneller Dyspepsie oder Reizdarm zusammenhängen, eine deutliche Verbesserung (durchschnittliche Verringerung des Scores der drei häufigsten Symptome um 77–87%).ZusammenfassungDie medikamentöse Standardbehandlung bei LPR besteht aus der hochdosierten PPI-Gabe über mindestens 4 Wochen, die jedoch für verschiedene Nebenwirkungen bekannt ist und die nicht-saure Komponente von LPR, wie Pepsin oder andere digestive Enzyme, nicht mitbehandelt. Daher sind andere medikamentöse Behandlungsmöglichkeiten dringend erforderlich. Die vielversprechenden Daten dieser Fallserie deuten darauf hin, dass die tibetische Pflanzenrezeptur Cong zhi 6 eine Behandlungsoption bei LPR sowie deren gastrointestinalen Symptome darstellt und rechtfertigen weitere Studien.}, } @article {pmid37952511, year = {2023}, author = {Zhang, X and Qu, X and Zou, Y}, title = {The Effect of Astragalus on Humoral and Cellular Immune Response: A Systematic Review and Meta-Analysis of Human Studies.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {535-543}, doi = {10.1159/000534826}, pmid = {37952511}, issn = {2504-2106}, mesh = {Humans ; *Interleukin-10 ; *Interleukin-2 ; Interleukin-4 ; Interleukin-6 ; Tumor Necrosis Factor-alpha ; Biomarkers ; }, abstract = {INTRODUCTION: Astragalus is used in traditional Chinese medicine for immune system disorders. Its effect on immune system function is evaluated in multiple studies. The objective of this systematic review and meta-analysis was to evaluate the effect of Astragalus on humoral and cellular immune response in human studies.

METHODS: A comprehensive search of electronic databases was conducted to identify relevant studies published up to April 2023. Studies that assessed the impact of Astragalus on humoral and cellular immune markers were included. The data were extracted, and a random-effects meta-analysis was performed to determine the overall effect size. Subgroup analyses were conducted based on outcome measures.

RESULTS: A total of 19 studies, including 1,094 human participants, were included in the meta-analysis. The analysis of humoral immune markers revealed a significant reduction in proinflammatory cytokines, including IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ, following Astragalus intervention (SMD -2.8765, 95% CI: -3.2385 to -2.5145, p < 0.0001). In the cellular immunity domain, Astragalus was found to significantly increase CD3 levels and the CD4/CD8 ratio (SMD 2.4629, 95% CI: 1.9598; 2.9661). Subgroup analyses based on outcome measures supported these findings. However, substantial heterogeneity was observed among the included studies.

CONCLUSION: This systematic review and meta-analysis provide evidence supporting the immunomodulatory effects of Astragalus on humoral and cellular response. Astragalus demonstrated a significant reduction in proinflammatory cytokines and an enhancement of cellular immune markers, suggesting its potential as a therapeutic agent for immune-related disorders.

UNLABELLED: EinleitungAstragalus wird in der traditionellen chinesischen Medizin bei Erkrankungen des Immunsystems eingesetzt. Seine Wirkung auf das Immunsystem ist in mehreren Studien untersucht worden. Das Ziel dieser systematischen Übersichtsarbeit und Metaanalyse ist es, die Wirkung von Astragalus auf die humorale und zelluläre Immunantwort in Studien am Menschen zu untersuchen.MethodenEine umfassende Suche in elektronischen Datenbanken wurde durchgeführt, um einschlägige Studien zu finden, die bis April 2023 veröffentlicht wurden. Eingeschlossen wurden Studien, die die Auswirkung von Astragalus auf Marker der humoralen und zellulären Immunantwort untersuchten. Die Daten wurden extrahiert und eine Random-Effects-Metaanalyse durchgeführt, um die Gesamt-Effektstärke zu ermitteln. Subgruppenanalysen wurden basierend auf Zielgrößen durchgeführt.ErgebnisseInsgesamt 19 Studien mit 1’094 menschlichen Teilnehmern wurden in die Metaanalyse eingeschlossen. Die Analyse der humoralen Immunmarker ergab eine signifikante Abnahme proinflammatorischer Zytokine, darunter IL-2, IL-4, IL-6, IL-10, TNF-α und IFN-γ, nach Anwendung von Astragalus (SMD –2.8765; 95%-KI: −3.2385, −2.5145; p < 0.0001). Bei der zellulären Immunität zeigte Astralagus eine signifikante Erhöhung der CD3-Konzentration und des CD4/CD8-Quotienten (SMD 2.4629; 95%-KI: 1.9598, 2.9661). Die Subgruppenanalysen nach Zielgrößen bestätigten diese Ergebnisse. Zwischen den eingeschlossenen Studien bestand jedoch erhebliche Heterogenität.SchlussfolgerungDiese systematische Übersichtsarbeit und Metaanalyse liefert Belege für die immunmodulatorischen Effekte von Astragalus auf die humorale und zelluläre Immunantwort. Astragalus zeigte eine signifikante Abnahme proinflammatorischer Zytokine und eine Verbesserung von Markern der zellulären Immunität, was auf sein Potenzial als Therapeutikum bei immunvermittelten Störungen hindeutet.}, } @article {pmid37952009, year = {2024}, author = {Hu, N and Zhang, L and Shen, D and Yang, X and Liu, M and Cui, L}, title = {Incidence of amyotrophic lateral sclerosis-associated genetic variants: a clinic-based study.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {4}, pages = {1515-1522}, pmid = {37952009}, issn = {1590-3478}, support = {XDB39040000//The Strategic Priority Research Program (Pilot study)"Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; CIFMS 2021-I2M-1-003//CAMS Innovation Fund for Medical Sciences/ ; 2022-PUMCH-B-017//National High Level Hospital Clinical Research Funding/ ; 7202158//Natural Science Foundation of Beijing Municipality/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Incidence ; *Cerebellar Ataxia ; Mutation ; }, abstract = {OBJECTIVE: This study is to determine the incidence of genetic forms of amyotrophic lateral sclerosis (ALS) in clinic-based population.

METHODS: Next-generation sequencing (NGS) of whole exome sequencing (WES) was conducted among a total of 374 patients with definite or probable ALS to identify ALS-associated genes based on ALSoD database (https://alsod.ac.uk) [2023-07-01].

RESULTS: Variants of ALS-associated genes were detected in 54.01% (202/374) ALS patients, among which 8.29% (31/374) were pathogenic/likely pathogenic (P/LP). The detection rates of P/LP variants were significantly higher in familial ALS than sporadic ALS (42.31% vs 5.75%, p < 0.001), while VUS mutations were more commonly detected in sporadic ALS (23.07% vs 47.13%, p = 0.018). There is no significant difference in detection rate between patients with and without early onset (8.93% vs 7.77%), rapid progression (9.30% vs 8.91%), cognitive decline (15.00% vs 7.93%), and cerebellar ataxia (20.00% vs 8.15%) (p > 0.05).

CONCLUSION: Over half of our ALS patients carried variants of ALS-related genes, most of which were variants of uncertain significance (VUS). Family history of ALS could work as strong evidence for carrying P/LP variants regarding ALS. There was no additionally suggestive effect of indicators including early onset, progression rate, cognitive decline, or cerebellar ataxia on the recommendation of genetic testing in clinical practice.}, } @article {pmid37951279, year = {2024}, author = {Vu Trung, K and Heise, C and Abou-Ali, E and Auriemma, F and Karam, E and van der Wiel, SE and Bruno, MJ and Caillol, F and Giovannini, M and Masaryk, V and Will, U and Anderloni, A and Pérez-Cuadrado-Robles, E and Dugic, A and Meier, B and Paik, WH and Petrone, MC and Wichmann, D and Dinis-Ribeiro, M and Gonçalves, TC and Wedi, E and Schmidt, A and Gulla, A and Hoffmeister, A and Rosendahl, J and Ratone, JP and Saadeh, R and Repici, A and Deprez, P and Sauvanet, A and Souche, FR and Fabre, JM and Muehldorfer, S and Caca, K and Löhr, M and Michl, P and Krug, S and Regner, S and Gaujoux, S and Hollenbach, M}, title = {Endoscopic papillectomy for ampullary lesions of minor papilla.}, journal = {Gastrointestinal endoscopy}, volume = {99}, number = {4}, pages = {587-595.e1}, doi = {10.1016/j.gie.2023.10.040}, pmid = {37951279}, issn = {1097-6779}, mesh = {Humans ; Treatment Outcome ; *Ampulla of Vater/surgery/pathology ; Endoscopy, Gastrointestinal ; Pancreatic Ducts/pathology ; *Pancreatic Neoplasms/pathology ; *Duodenal Neoplasms/pathology ; *Common Bile Duct Neoplasms/surgery/pathology ; Retrospective Studies ; }, abstract = {BACKGROUND AND AIMS: Ampullary lesions (ALs) of the minor duodenal papilla are extremely rare. Endoscopic papillectomy (EP) is a routinely used treatment for AL of the major duodenal papilla, but the role of EP for minor AL has not been accurately studied.

METHODS: We identified 20 patients with ALs of minor duodenal papilla in the multicentric database from the Endoscopic Papillectomy vs Surgical Ampullectomy vs Pancreatitcoduodenectomy for Ampullary Neoplasm study, which included 1422 EPs. We used propensity score matching (nearest-neighbor method) to match these cases with ALs of the major duodenal papilla based on age, sex, histologic subtype, and size of the lesion in a 1:2 ratio. Cohorts were compared by means of chi-square or Fisher exact test as well as Mann-Whitney U test.

RESULTS: Propensity score-based matching identified a cohort of 60 (minor papilla 20, major papilla 40) patients with similar baseline characteristics. The most common histologic subtype of lesions of minor papilla was an ampullary adenoma in 12 patients (3 low-grade dysplasia and 9 high-grade dysplasia). Five patients revealed nonneoplastic lesions. Invasive cancer (T1a), adenomyoma, and neuroendocrine neoplasia were each found in 1 case. The rate of complete resection, en-bloc resection, and recurrences were similar between the groups. There were no severe adverse events after EP of lesions of minor papilla. One patient had delayed bleeding that could be treated by endoscopic hemostasis, and 2 patients showed a recurrence in surveillance endoscopy after a median follow-up of 21 months (interquartile range, 12-50 months).

CONCLUSIONS: EP is safe and effective in ALs of the minor duodenal papilla. Such lesions could be managed according to guidelines for EP of major duodenal papilla.}, } @article {pmid37950760, year = {2024}, author = {Beloribi-Djefaflia, S and Morales, RJ and Fatehi, F and Isapof, A and Servais, L and Leonard-Louis, S and Michaud, M and Verdure, P and Gidaro, T and Pouget, J and Poinsignon, V and Bonello-Palot, N and Attarian, S}, title = {Clinical and genetic features of patients suffering from CMT4J.}, journal = {Journal of neurology}, volume = {271}, number = {3}, pages = {1355-1365}, pmid = {37950760}, issn = {1432-1459}, mesh = {Adolescent ; Humans ; *Amyotrophic Lateral Sclerosis ; *Charcot-Marie-Tooth Disease/diagnosis/genetics ; *Flavoproteins/genetics ; Heterozygote ; Mutation/genetics ; Phenotype ; *Phosphoric Monoester Hydrolases/genetics ; }, abstract = {Mutations in the FIG4 gene have been identified in various diseases, including amyotrophic lateral sclerosis, Parkinson's disease, and Charcot-Marie-Tooth 4 J (CMT4J), with a wide range of phenotypic manifestations. We present eight cases of CMT4J patients carrying the p.Ile41Thr mutation of FIG4. The patients were categorized according to their phenotype. Six patients had a pure CMT; whereas, two patients had a CMT associated with parkinsonism. Three patients had an early onset and exhibited more severe forms of the disease. Three others experienced symptoms in their teenage years and had milder forms. Two patients had a late onset in adulthood. Four patients showed electrophysiological evidence of conduction blocks, typically associated with acquired neuropathies. Consequently, two of them received intravenous immunoglobulin treatment without a significant objective response. Interestingly, two heterozygous patients with the same mutations exhibited contrasting phenotypes, one having a severe early-onset form and the other experiencing a slow disease progression starting at the age of 49. Notably, although 7 out of 8 patients in this study were compound heterozygous for the p.Ile41Thr mutation, only one individual was found to be homozygous for this genetic variant and exhibited an early-onset, severe form of the disease. Additionally, one patient who developed the disease in his youth was also diagnosed with hereditary neuropathy with pressure palsies. Our findings provide insights into the CMT4J subtype by reporting on eight heterogeneous patient cases and highlight the potential for misdiagnosis when conduction blocks or asymmetrical nerve conduction study results are observed in patients with FIG4 mutations.}, } @article {pmid37950613, year = {2024}, author = {Gray, D and Lesley, R and Mayberry, EJ and Williams, L and McHutchison, C and Newton, J and Pal, S and Chandran, S and MacPherson, SE and Abrahams, S and , }, title = {Development, reliability, validity, and acceptability of the remote administration of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {96-103}, doi = {10.1080/21678421.2023.2278512}, pmid = {37950613}, issn = {2167-9223}, mesh = {Humans ; *Cognition Disorders/diagnosis/etiology/psychology ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Reproducibility of Results ; Pandemics ; Neuropsychological Tests ; Cognition ; }, abstract = {BACKGROUND: ALS clinical care and research has changed dramatically since the COVID-19 pandemic, accelerating the need for cognitive assessments to be adapted for remote use.

OBJECTIVES: To develop the remote administration method of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), and determine its reliability and validity. Methods: The validation process consisted of: (1) Two versions of the ECAS (A and B) were administered, one in-person and one remotely via video call in a randomized order to 27 people without ALS; (2) The ECAS was administered remotely to 24 pwALS, with a second rater independently scoring performance; and (3) Acceptability was assessed by gathering feedback from 17 pwALS and 19 clinicians and researchers about their experience of using the ECAS remotely.

RESULTS: In the group without ALS, the remote and in-person ECAS total scores were found to be equivalent, and a Bland-Altman plot showed good agreement between the two administration methods. In pwALS, there was excellent agreement between two raters (ICC = 0.99). Positive feedback was gained from pwALS, researchers and clinicians with regards to ease of process, convenience, time, and the environment.

CONCLUSIONS: These findings provide evidence of the reliability and validity of the remote administration of the ECAS for pwALS, with clinicians, researchers and pwALS viewing it as a good alternative to face-to-face administration.}, } @article {pmid37949994, year = {2023}, author = {McMackin, R and Bede, P and Ingre, C and Malaspina, A and Hardiman, O}, title = {Biomarkers in amyotrophic lateral sclerosis: current status and future prospects.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {12}, pages = {754-768}, pmid = {37949994}, issn = {1759-4766}, support = {MALASPINA/APR13/817-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Biomarkers ; Prognosis ; Disease Progression ; Drug Development ; }, abstract = {Disease heterogeneity in amyotrophic lateral sclerosis poses a substantial challenge in drug development. Categorization based on clinical features alone can help us predict the disease course and survival, but quantitative measures are also needed that can enhance the sensitivity of the clinical categorization. In this Review, we describe the emerging landscape of diagnostic, categorical and pharmacodynamic biomarkers in amyotrophic lateral sclerosis and their place in the rapidly evolving landscape of new therapeutics. Fluid-based markers from cerebrospinal fluid, blood and urine are emerging as useful diagnostic, pharmacodynamic and predictive biomarkers. Combinations of imaging measures have the potential to provide important diagnostic and prognostic information, and neurophysiological methods, including various electromyography-based measures and quantitative EEG-magnetoencephalography-evoked responses and corticomuscular coherence, are generating useful diagnostic, categorical and prognostic markers. Although none of these biomarker technologies has been fully incorporated into clinical practice or clinical trials as a primary outcome measure, strong evidence is accumulating to support their clinical utility.}, } @article {pmid37949878, year = {2023}, author = {Nagel, G and Kurz, D and Peter, RS and Rosenbohm, A and Koenig, W and Dupuis, L and Bäzner, H and Börtlein, A and Dempewolf, S and Schabet, M and Hecht, M and Kohler, A and Opherk, C and Naegele, A and Sommer, N and Lindner, A and Tumani, H and Ludolph, AC and Rothenbacher, D}, title = {Cystatin C based estimation of chronic kidney disease and amyotrophic lateral sclerosis in the ALS registry Swabia: associated risk and prognostic value.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {19594}, pmid = {37949878}, issn = {2045-2322}, mesh = {Male ; Humans ; Aged ; Female ; Prognosis ; *Amyotrophic Lateral Sclerosis ; Case-Control Studies ; Prospective Studies ; Cystatin C ; *Renal Insufficiency, Chronic/complications ; Glomerular Filtration Rate ; Registries ; Creatinine ; Biomarkers ; }, abstract = {Kidney function as part of metabolic changes could be associated with amyotrophic lateral-sclerosis (ALS). We investigated the associations between estimated chronic kidney disease (CKD), based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin C equation, and the risk at onset and prognostic value of CKD for ALS. Between October 2010 and June 2014, 362 ALS cases (59.4% men, mean age 65.7 years) and 681 controls (59.5% men, means age 66.3 years) were included in a population-based case-control study based on the ALS registry Swabia in Southern Germany. All ALS cases were followed-up (median 89.7 months), 317 died. Serum samples were measured for cystatin C to estimate the glomerular filtration rate (eGFR) according to the CKD-EPI equation. Information on covariates were assessed by an interview-based standardized questionnaire. Conditional logistic regression models were applied to calculate odds ratios (OR) for risk of ALS associated with eGFR/CKD stages. Time-to-death associated with renal parameters at baseline was assessed in ALS cases only. ALS cases were characterized by lower body mass index, slightly lower smoking prevalence, more intense occupational work and lower education than controls. Median serum cystatin-C based eGFR concentrations were lower in ALS cases than in controls (54.0 vs. 59.5 mL/min pro 1.73 m[2]). The prevalence of CKD stage ≥ 3 was slightly higher in ALS cases than in controls (14.1 vs. 11.0%). In the adjusted models, CKD stage 2 (OR 1.82, 95% CI 1.32, 2.52) and stage 3 (OR 2.34, 95% CI 1.38, 3.96) were associated with increased ALS risk. In this cohort of ALS cases, eGFR and CKD stage ≥ 3 (HR 0.94; 95% CI 0.64, 1.38) were not associated with prognosis. In this case-control study, higher CKD stages were associated with increased ALS risk, while in the prospective cohort of ALS cases, no indication of an association of CysC-based CKD on mortality was seen. In addition, our work strengthens the importance to evaluate renal function using a marker independent of muscle mass in ALS patients.}, } @article {pmid37949836, year = {2024}, author = {Yang, L and Jasiqi, Y and Zettor, A and Vadas, O and Chiaravalli, J and Agou, F and Lashuel, HA}, title = {Effective Inhibition of TDP-43 Aggregation by Native State Stabilization.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {63}, number = {3}, pages = {e202314587}, doi = {10.1002/anie.202314587}, pmid = {37949836}, issn = {1521-3773}, support = {1398//École Polytechnique Fédérale de Lausanne/ ; }, mesh = {Humans ; *TDP-43 Proteinopathies/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases ; DNA-Binding Proteins/chemistry ; }, abstract = {Preventing the misfolding or aggregation of transactive response DNA binding protein with 43 kDa (TDP-43) is the most actively pursued disease-modifying strategy to treat amyotrophic lateral sclerosis and other neurodegenerative diseases. In this work, we provide proof of concept that native state stabilization of TDP-43 is a viable and effective strategy for treating TDP-43 proteinopathies. Firstly, we leveraged the Cryo-EM structures of TDP-43 fibrils to design C-terminal substitutions that disrupt TDP-43 aggregation. Secondly, we showed that these substitutions (S333D/S342D) stabilize monomeric TDP-43 without altering its physiological properties. Thirdly, we demonstrated that binding native oligonucleotide ligands stabilized monomeric TDP-43 and prevented its fibrillization and phase separation in the absence of direct binding to the aggregation-prone C-terminal domain. Fourthly, we showed that the monomeric TDP-43 variant could be induced to aggregate in a controlled manner, which enabled the design and implementation of a high-throughput screening assay to identify native state stabilizers of TDP-43. Altogether, our findings demonstrate that different structural domains in TDP-43 could be exploited and targeted to develop drugs that stabilize the native state of TDP-43 and provide a platform to discover novel drugs to treat TDP-43 proteinopathies.}, } @article {pmid37948743, year = {2024}, author = {Wang, SW and Igarashi-Yokoi, T and Mochida, S and Fujinami, K and Ohno-Matsui, K}, title = {PREVALENCE AND CLINICAL FEATURES OF RADIAL FUNDUS AUTOFLUORESCENCE IN HIGH MYOPIC WOMEN.}, journal = {Retina (Philadelphia, Pa.)}, volume = {44}, number = {3}, pages = {446-454}, doi = {10.1097/IAE.0000000000003981}, pmid = {37948743}, issn = {1539-2864}, mesh = {Humans ; Female ; Child ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Prevalence ; Fundus Oculi ; *Retinitis Pigmentosa/diagnosis ; *Myopia/diagnosis/epidemiology ; Electroretinography ; Retrospective Studies ; Fluorescein Angiography ; Tomography, Optical Coherence ; Eye Proteins ; }, abstract = {PURPOSE: To determine the prevalence and characteristics of radial fundus autofluorescence (FAF) in highly myopic women.

METHODS: This was a retrospective, observational case study to determine the prevalence of radial FAF in the ultra-widefield FAF images in women. The clinical characteristics of these patients were evaluated.

RESULTS: Fifteen of 1,935 (0.78%) highly myopic women were found to have radial FAF. Their mean age was 36.6 ± 25.6 years, and their mean best-corrected visual acuity was 0.3 ± 0.42 logMAR units. The mean axial length (AL) was 28.8 ± 2.8 mm. Among the 15 cases, eight did not have pigmentary changes and seven had pigmentary changes in the ultra-widefield FAF images. The women with the pigmentary changes were significantly older (P = 0.021), had poorer BCVA (P = 0.001), and had longer ALs (P = 0.002). The visual fields and electroretinograms were worse in the eyes with pigmentary changes.

CONCLUSION: The prevalence of radial FAF was 0.78% in women with high myopia. These patients might have mutations in the RPGR or RP2 genes and can develop high myopia and retinitis pigmentosa. Ultra-widefield FAF images should be examined in all highly myopic patients for early detection of radial FAF, and myopia prevention and genetic counseling for possible genetic therapy are recommended.}, } @article {pmid37948524, year = {2023}, author = {Ortega, JA and Sasselli, IR and Boccitto, M and Fleming, AC and Fortuna, TR and Li, Y and Sato, K and Clemons, TD and Mckenna, ED and Nguyen, TP and Anderson, EN and Asin, J and Ichida, JK and Pandey, UB and Wolin, SL and Stupp, SI and Kiskinis, E}, title = {CLIP-Seq analysis enables the design of protective ribosomal RNA bait oligonucleotides against C9ORF72 ALS/FTD poly-GR pathophysiology.}, journal = {Science advances}, volume = {9}, number = {45}, pages = {eadf7997}, pmid = {37948524}, issn = {2375-2548}, support = {R01 NS097850/NS/NINDS NIH HHS/United States ; R01 NS104219/NS/NINDS NIH HHS/United States ; R01 NS131409/NS/NINDS NIH HHS/United States ; R21 NS107761/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics/metabolism ; RNA, Ribosomal/genetics ; Chromatin Immunoprecipitation Sequencing ; RNA/genetics ; Drosophila/genetics/metabolism ; DNA Repeat Expansion ; }, abstract = {Amyotrophic lateral sclerosis and frontotemporal dementia patients with a hexanucleotide repeat expansion in C9ORF72 (C9-HRE) accumulate poly-GR and poly-PR aggregates. The pathogenicity of these arginine-rich dipeptide repeats (R-DPRs) is thought to be driven by their propensity to bind low-complexity domains of multivalent proteins. However, the ability of R-DPRs to bind native RNA and the significance of this interaction remain unclear. Here, we used computational and experimental approaches to characterize the physicochemical properties of R-DPRs and their interaction with RNA. We find that poly-GR predominantly binds ribosomal RNA (rRNA) in cells and exhibits an interaction that is predicted to be energetically stronger than that for associated ribosomal proteins. Critically, modified rRNA "bait" oligonucleotides restore poly-GR-associated ribosomal deficits and ameliorate poly-GR toxicity in patient neurons and Drosophila models. Our work strengthens the hypothesis that ribosomal function is impaired by R-DPRs, highlights a role for direct rRNA binding in mediating ribosomal dysfunction, and presents a strategy for protecting against C9-HRE pathophysiological mechanisms.}, } @article {pmid37948306, year = {2023}, author = {Lai, Q and Mason, AH and Agarwal, A and Edenfield, WC and Zhang, X and Kobayashi, T and Kratish, Y and Marks, TJ}, title = {Rapid Polyolefin Hydrogenolysis by a Single-Site Organo-Tantalum Catalyst on a Super-Acidic Support: Structure and Mechanism.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {62}, number = {50}, pages = {e202312546}, doi = {10.1002/anie.202312546}, pmid = {37948306}, issn = {1521-3773}, support = {DE-FG02-03ER15457//Office of Science/ ; ECCS-2025633//National Science Foundation/ ; NNA04CC36G//Ames Research Center/ ; DE-SC0001329//U.S. Department of Energy/ ; DE-AC02-06CH11357//U.S. Department of Energy/ ; DE-AC02-07CH11358//U.S. Department of Energy/ ; DE-SC0014664//Oak Ridge Institute for Science and Education/ ; }, abstract = {The novel electrophilic organo-tantalum catalyst AlS/TaNpx (1) (Np=neopentyl) is prepared by chemisorption of the alkylidene Np3 Ta=CH[t] Bu onto highly Brønsted acidic sulfated alumina (AlS). The proposed catalyst structure is supported by EXAFS, XANES, ICP, DRIFTS, elemental analysis, and SSNMR measurements and is in good agreement with DFT analysis. Catalyst 1 is highly effective for the hydrogenolysis of diverse linear and branched hydrocarbons, ranging from C2 to polyolefins. To the best of our knowledge, 1 exhibits one of the highest polyolefin hydrogenolysis activities (9,800 (CH2 units) ⋅ mol(Ta)[-1] ⋅ h[-1] at 200 °C/17 atm H2) reported to date in the peer-reviewed literature. Unlike the AlS/ZrNp2 analog, the Ta catalyst is more thermally stable and offers multiple potential C-C bond activation pathways. For hydrogenolysis, AlS/TaNpx is effective for a wide variety of pre- and post-consumer polyolefin plastics and is not significantly deactivated by standard polyolefin additives at typical industrial concentrations.}, } @article {pmid37947306, year = {2024}, author = {Ackrivo, J}, title = {Response to: "Pulmonary care for ALS: There is more to the story": We agree more than we disagree.}, journal = {Muscle & nerve}, volume = {69}, number = {1}, pages = {117-118}, pmid = {37947306}, issn = {1097-4598}, support = {K23 HL151879/HL/NHLBI NIH HHS/United States ; HL-151879/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Respiratory Insufficiency ; *Noninvasive Ventilation ; }, } @article {pmid37946793, year = {2023}, author = {Rogers, ML and Schultz, DW and Karnaros, V and Shepheard, SR}, title = {Urinary biomarkers for amyotrophic lateral sclerosis: candidates, opportunities and considerations.}, journal = {Brain communications}, volume = {5}, number = {6}, pages = {fcad287}, pmid = {37946793}, issn = {2632-1297}, support = {U01 NS107027/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis is a relentless neurodegenerative disease that is mostly fatal within 3-5 years and is diagnosed on evidence of progressive upper and lower motor neuron degeneration. Around 15% of those with amyotrophic lateral sclerosis also have frontotemporal degeneration, and gene mutations account for ∼10%. Amyotrophic lateral sclerosis is a variable heterogeneous disease, and it is becoming increasingly clear that numerous different disease processes culminate in the final degeneration of motor neurons. There is a profound need to clearly articulate and measure pathological process that occurs. Such information is needed to tailor treatments to individuals with amyotrophic lateral sclerosis according to an individual's pathological fingerprint. For new candidate therapies, there is also a need for methods to select patients according to expected treatment outcomes and measure the success, or not, of treatments. Biomarkers are essential tools to fulfil these needs, and urine is a rich source for candidate biofluid biomarkers. This review will describe promising candidate urinary biomarkers of amyotrophic lateral sclerosis and other possible urinary candidates in future areas of investigation as well as the limitations of urinary biomarkers.}, } @article {pmid37946741, year = {2023}, author = {Ebrahimi, A and Kamyab, A and Hosseini, S and Ebrahimi, S and Ashkani-Esfahani, S}, title = {Involvement of Coenzyme Q10 in Various Neurodegenerative and Psychiatric Diseases.}, journal = {Biochemistry research international}, volume = {2023}, number = {}, pages = {5510874}, pmid = {37946741}, issn = {2090-2247}, abstract = {Coenzyme Q10 (CoQ10), commonly known as ubiquinone, is a vitamin-like component generated in mitochondrial inner membranes. This molecule is detected broadly in different parts of the human body in various quantities. This molecule can be absorbed by the digestive system from various nutritional sources as supplements. CoQ10 exists in three states: in a of reduced form (ubiquinol), in a semiquinone radical form, and in oxidized ubiquinone form in different organs of the body, playing a crucial role in electron transportation and contributing to energy metabolism and oxygen utilization, especially in the musculoskeletal and nervous systems. Since the early 1980s, research about CoQ10 has become the interest for two reasons. First, CoQ10 deficiency has been found to have a link with cardiovascular, neurologic, and cancer disorders. Second, this molecule has an antioxidant and free-radical scavenger nature. Since then, several investigations have indicated that the drug may benefit patients with cardiovascular, neuromuscular, and neurodegenerative illnesses. CoQ10 may protect the neurological system from degeneration and degradation due to its antioxidant and energy-regulating activity in mitochondria. This agent has shown its efficacy in preventing and treating neurological diseases such as migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and Friedreich's ataxia. This study reviews the literature to highlight this agent's potential therapeutic effects in the mentioned neurological disorders.}, } @article {pmid37946655, year = {2023}, author = {Lochbaum, R and Hoffmann, TK and Greve, J and Hahn, J}, title = {[Medikamente als Auslöser Bradykinin-vermittelter Angioödeme - mehr als ACE-Hemmer].}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {21}, number = {11}, pages = {1283-1290}, doi = {10.1111/ddg.15154_g}, pmid = {37946655}, issn = {1610-0387}, } @article {pmid37945695, year = {2023}, author = {Faria Assoni, A and Giove Mitsugi, T and Wardenaar, R and Oliveira Ferreira, R and Farias Jandrey, EH and Machado Novaes, G and Fonseca de Oliveira Granha, I and Bakker, P and Kaid, C and Zatz, M and Foijer, F and Keith Okamoto, O}, title = {Neurodegeneration-associated protein VAPB regulates proliferation in medulloblastoma.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {19481}, pmid = {37945695}, issn = {2045-2322}, mesh = {Child ; Humans ; *Medulloblastoma/genetics ; *Cerebellar Neoplasms/genetics ; Cell Proliferation/genetics ; Vesicular Transport Proteins ; }, abstract = {VAMP (Vesicle-associated membrane protein)-associated protein B and C (VAPB) has been widely studied in neurodegenerative diseases such as ALS, but little is known about its role in cancer. Medulloblastoma is a common brain malignancy in children and arises from undifferentiated cells during neuronal development. Therefore, medulloblastoma is an interesting model to investigate the possible relationship between VAPB and tumorigenesis. Here we demonstrate that high VAPB expression in medulloblastoma correlates with decreased overall patient survival. Consistent with this clinical correlation, we find that VAPB is required for normal proliferation rates of medulloblastoma cells in vitro and in vivo. Knockout of VAPB (VAPB[KO]) delayed cell cycle progression. Furthermore, transcript levels of WNT-related proteins were decreased in the VAPB[KO]. We conclude that VAPB is required for proliferation of medulloblastoma cells, thus revealing VAPB as a potential therapeutic target for medulloblastoma treatment.}, } @article {pmid37945618, year = {2023}, author = {Ramon-Gonen, R and Dori, A and Shelly, S}, title = {Towards a practical use of text mining approaches in electrodiagnostic data.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {19483}, pmid = {37945618}, issn = {2045-2322}, mesh = {Humans ; Male ; Female ; Retrospective Studies ; Data Mining/methods ; *Brachial Plexus Neuropathies ; *Myasthenia Gravis ; *Polyneuropathies ; }, abstract = {Healthcare professionals produce abounding textual data in their daily clinical practice. Text mining can yield valuable insights from unstructured data. Extracting insights from multiple information sources is a major challenge in computational medicine. In this study, our objective was to illustrate how combining text mining techniques with statistical methodologies can yield new insights and contribute to the development of neurological and neuromuscular-related health information. We demonstrate how to utilize and derive knowledge from medical text, identify patient groups with similar diagnostic attributes, and examine differences between groups using demographical data and past medical history (PMH). We conducted a retrospective study for all patients who underwent electrodiagnostic (EDX) evaluation in Israel's Sheba Medical Center between May 2016 and February 2022. The data extracted for each patient included demographic data, test results, and unstructured summary reports. We conducted several analyses, including topic modeling that targeted clinical impressions and topic analysis to reveal age- and sex-related differences. The use of suspected clinical condition text enriched the data and generated additional attributes used to find associations between patients' PMH and the emerging diagnosis topics. We identified 6096 abnormal EMG results, of which 58% (n = 3512) were males. Based on the latent Dirichlet allocation algorithm we identified 25 topics that represent different diagnoses. Sex-related differences emerged in 7 topics, 3 male-associated and 4 female-associated. Brachial plexopathy, myasthenia gravis, and NMJ Disorders showed statistically significant age and sex differences. We extracted keywords related to past medical history (n = 37) and tested them for association with the different topics. Several topics revealed a close association with past medical history, for example, length-dependent symmetric axonal polyneuropathy with diabetes mellitus (DM), length-dependent sensory polyneuropathy with chemotherapy treatments and DM, brachial plexopathy with motor vehicle accidents, myasthenia gravis and NMJ disorders with botulin treatments, and amyotrophic lateral sclerosis with swallowing difficulty. Summarizing visualizations were created to easily grasp the results and facilitate focusing on the main insights. In this study, we demonstrate the efficacy of utilizing advanced computational methods in a corpus of textual data to accelerate clinical research. Additionally, using these methods allows for generating clinical insights, which may aid in the development of a decision-making process in real-life clinical practice.}, } @article {pmid37944939, year = {2024}, author = {Kalantari, F and Rendl, G and Hecht, S and Pirich, C and Beheshti, M}, title = {[Atypisches lokales Larynxkarzinom-Rezidiv imitiert als entzündlicher thyreoidaler Uptake in der 18F-FDG PET/CT].}, journal = {RoFo : Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin}, volume = {196}, number = {2}, pages = {195-196}, doi = {10.1055/a-2123-3867}, pmid = {37944939}, issn = {1438-9010}, mesh = {*Fluorodeoxyglucose F18 ; *Positron Emission Tomography Computed Tomography ; Positron-Emission Tomography ; Tomography, X-Ray Computed ; Radiopharmaceuticals ; }, } @article {pmid37944521, year = {2024}, author = {Yang, K and Tang, Z and Xing, C and Yan, N}, title = {STING signaling in the brain: Molecular threats, signaling activities, and therapeutic challenges.}, journal = {Neuron}, volume = {112}, number = {4}, pages = {539-557}, pmid = {37944521}, issn = {1097-4199}, support = {R01 AI151708/AI/NIAID NIH HHS/United States ; R01 NS117424/NS/NINDS NIH HHS/United States ; R01 NS122825/NS/NINDS NIH HHS/United States ; R56 AI151708/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Brain/pathology ; *Nervous System Diseases ; Signal Transduction ; }, abstract = {Stimulator of interferon genes (STING) is an innate immune signaling protein critical to infections, autoimmunity, and cancer. STING signaling is also emerging as an exciting and integral part of many neurological diseases. Here, we discuss recent advances in STING signaling in the brain. We summarize how molecular threats activate STING signaling in the diseased brain and how STING signaling activities in glial and neuronal cells cause neuropathology. We also review human studies of STING neurobiology and consider therapeutic challenges in targeting STING to treat neurological diseases.}, } @article {pmid37944503, year = {2023}, author = {Sun, HJ and Zhang, J and Lu, JP and Wu, MT}, title = {The Improvement in Function of Poststroke Spasticity by Vibrational and Heated Stone-Needle Therapy and Meridian Dredging Exercise: A Randomized, Controlled, Preliminary Trial.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {492-501}, doi = {10.1159/000534993}, pmid = {37944503}, issn = {2504-2106}, mesh = {Humans ; Animals ; Mice ; *Quality of Life ; *Meridians ; Physical Therapy Modalities ; }, abstract = {BACKGROUND: Poststroke spasticity (PSS) is a common complication of stroke. Current PSS treatments have been linked to high costs, lack of long-term effectiveness, and undesirable side effects. Vibrational and heated stone-needle therapy (VHS) has not been utilized to treat PSS, and its safety and effectiveness have yet to be proven by high-quality clinical research.

OBJECTIVE: The aim of this study was to determine the effectiveness of VHS combined with meridian dredging exercise (MDE) in patients with PSS.

METHODS: One hundred participants with stroke were included and randomly assigned to a treatment group (VHS plus MDEs) and a control group (MDEs alone). Patients in both groups were treated for 4 weeks. The primary outcome measures were the Modified Ashworth Scale (MAS) and Fugl-Meyer Assessment (FMA), while the secondary outcome measures were the Activity of Daily Living (ADL) Scale and Stroke-Specific Quality of Life Scale (SS-QOL). The evaluations were at baseline (T0) at 4 weeks of treatment (T1) and at 12 weeks of follow-up without treatment (T2).

RESULTS: At T1 and T2, there were significant differences in MAS between the two groups (p = 0.001). From the perspective of distribution, the VHS plus MDE group had significant changes, and the group-time interactions of upper and lower extremities in FMA, ADL, and SS-QOL were statistically significant (p < 0.001), indicating that patients' symptoms improved after treatment. But the overall effect size is small, especially the effect size of improvement in SS-QOL at T1.

CONCLUSION: VHS in combination with MDE can consistently alleviate PSS, enhance limb function, and improve the quality of life of patients with PSS. But we need to optimize the device further and observe the improvement of patients for a more extended period.

UNLABELLED: HintergrundSpastik nach Schlaganfall (PSS; post-stroke spasticity) ist eine häufige Komplikation des Schlaganfalls. Gegenwärtige PSS-Behandlungen sind mit hohen Kosten, mangelnder langfristiger Wirksamkeit und unerwünschten Nebenwirkungen in Verbindung gebracht worden. Vibrierende und erhitzte Steinnadeln (VHS) sind bisher nicht zur Behandlung des PSS eingesetzt worden, und der Nachweis ihrer Sicherheit und Wirksamkeit durch hochwertige klinische Forschung steht noch aus.ZielBeurteilung der Wirksamkeit von vibrierenden und erhitzten Steinnadeln (VHS) in Kombination mit Meridian-Ausbagger-Übungen (MDE) bei Patienten mit PSS.Methoden100 Patienten mit Schlaganfall wurden eingeschlossen und per Randomisierung auf eine Behandlungsgruppe (VHS plus MDEs) und eine Kontrollgruppe (nur MDE) aufgeteilt. In beiden Gruppen wurden die Patienten 4 Wochen lang behandelt. Die primären Messinstrumente waren die Modified Ashworth Scale (MAS) und das Fugl-Meyer Assessment (FMA), als sekundäre Messinstrumente wurden die Activity of Daily Living Scale (ADL) und die Stroke-Specific Quality of Life Scale (SS-QOL) erhoben. Die Beurteilungszeitpunkte waren bei Baseline (T0) nach 4 Wochen Behandlung (T1) und nach 12 Wochen Nachbeobachtung ohne Behandlung (T2).ErgebnisseBei T1 und T2 bestanden signifikante Unterschiede bei der MAS zwischen den Gruppen (p = 0.001). Aus der Perspektive der Distribution zeigte die “VHS plus MDE”-Gruppe signifikante Veränderungen, und die Gruppe*Zeit-Interaktionen der oberen and unteren Extremitäten bei FMA, ADL und SS-QOL waren statistisch signifikant (p < 0.001), was darauf hindeutet, dass die Beschwerden der Patienten sich nach der Behandlung besserten. Die Effektstärke ist allerdings gering, insbesondere die der SS-QOL-Verbesserung bei T1.SchlussfolgerungDie Anwendung von vibrierenden und erhitzten Steinnadeln in Kombination mit Meridian-Ausbagger-Übungen kann PSS durchgängig lindern, die Funktion der Extremitäten verbessern und die Lebensqualität der Patienten mit PSS erhöhen. Jedoch muss das Produkt weiter optimiert werden, und die Verbesserungen bei den Patienten müssen über einen längeren Zeitraum beobachtet werden.}, } @article {pmid37942848, year = {2024}, author = {Soreq, H}, title = {Novel single-nucleus transcriptomics unravels developmental and functionally controlled principles of mammalian neuromuscular junctions.}, journal = {Journal of neurochemistry}, volume = {168}, number = {4}, pages = {339-341}, doi = {10.1111/jnc.15986}, pmid = {37942848}, issn = {1471-4159}, mesh = {Animals ; Humans ; Neuromuscular Junction/metabolism ; *Receptors, Nicotinic/genetics/metabolism ; Synaptic Transmission ; *Amyotrophic Lateral Sclerosis/metabolism ; Gene Expression Profiling ; Mammals/metabolism ; }, abstract = {Prof Ohno's team (Ohkawara et al. 2023, current issue) underscored the dynamic and functional features that co-shape the embryonic and early post-natal development of mammalian neuromuscular junctions (NMJs) using single-nucleus transcriptomics which provides specific insights into the activities of individually studied nuclei and their functional characteristics. Unlike other single-nucleus transcriptomics studies, which tend to be limited to single developmental time points, this article provides novel views of the complex developmental and regulatory dynamics and embryonic cell type origins underscoring the formation of functioning mammalian NMJs by combining this transcriptomic approach with interference tests in cultured C2C12 myotubes. This reveals intriguing novel links between the particular nicotinic acetylcholine receptor genes (nAChR) and regulator transcripts thereof and enables outlining the sequential development of functioning NMJs along embryogenesis and soon after delivery. Specifically, the timewise and cell type origins of the studied nuclei emerged as essential for NMJ neurogenesis and inter-cellular transfer of specific regulators has been indicated. Breaking the barriers between distinct research subdisciplines, this study opens new neurochemistry research directions that recombine developmental, regulatory, and functional transcriptomics in NMJ-including tissues. Moreover, these findings may facilitate tests of diverse pharmaceutical and therapeutic modulators of neuromuscular functioning in health and disease, assisting the translational research progress in treating devastating neuromuscular states such as in amyotrophic lateral sclerosis, myasthenia gravis or individuals poisoned occupationally or otherwise with anticholinesterase inhibitors.}, } @article {pmid37942236, year = {2023}, author = {Itou, J and Munakata, Y and Kuramitsu, Y and Madarame, H and Okazaki, K}, title = {Incidence and Distribution of Deep Vein Thrombosis Following Total Hip Arthroplasty Using an Anterolateral Supine Approach.}, journal = {Orthopedic research and reviews}, volume = {15}, number = {}, pages = {199-205}, pmid = {37942236}, issn = {1179-1462}, abstract = {PURPOSE: Venous thromboembolism (VTE) is a potential major complication in patients undergoing total hip arthroplasty (THA). However, the incidence of VTE following THA using anterolateral supine approach (ALS) has not been reported. The purpose of this study was to investigate the incidence of perioperative VTE and the distribution and characteristics of deep vein thrombosis (DVT) following ALS THA.

PATIENTS AND METHODS: This retrospective single-arm study analyzed the 182 consecutive hips of 164 patients who underwent primary ALS THA. Pharmacological prophylaxis consisted of enoxaparin 20 mg twice daily for approximately 6 days starting 24 h postoperatively until duplex ultrasonography was performed to determine whether postoperative DVT was present. DVT was assessed by whole-leg Doppler ultrasound, and the location and characteristics of any thrombus were recorded. If pulmonary thromboembolism was suspected, contrast-enhanced computed tomography was performed.

RESULTS: The overall incidence of VTE was 9.9% for DVT (18/182 hips) and 0.5% for pulmonary thromboembolism (1/182 hips). Most DVTs were in the soleal vein on the affected side and showed isoechoic or hypoechoic echogenicity. All thrombi were non-floating.

CONCLUSION: Following ALS THA with standard pharmacological prophylaxis and an early weight-bearing protocol, the incidence of perioperative DVT was approximately 10%, mostly occurring in the lower leg.}, } @article {pmid37942135, year = {2023}, author = {Shi, Y and Zhu, R}, title = {Analysis of damage-associated molecular patterns in amyotrophic lateral sclerosis based on ScRNA-seq and bulk RNA-seq data.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1259742}, pmid = {37942135}, issn = {1662-4548}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons. Despite extensive research, the exact etiology of ALS remains elusive. Emerging evidence highlights the critical role of the immune system in ALS pathogenesis and progression. Damage-Associated Molecular Patterns (DAMPs) are endogenous molecules released by stressed or damaged cells, acting as danger signals and activating immune responses. However, their specific involvement in ALS remains unclear.

METHODS: We obtained single-cell RNA sequencing (scRNA-seq) data of ALS from the primary motor cortex in the Gene Expression Omnibus (GEO) database. To better understand genes associated with DAMPs, we performed analyses on cell-cell communication and trajectory. The abundance of immune-infiltrating cells was assessed using the single-sample Gene Set Enrichment Analysis (ssGSEA) method. We performed univariate Cox analysis to construct the risk model and utilized the least absolute shrinkage and selection operator (LASSO) analysis. Finally, we identified potential small molecule drugs targeting ALS by screening the Connectivity Map database (CMap) and confirmed their potential through molecular docking analysis.

RESULTS: Our study annotated 10 cell types, with the expression of genes related to DAMPs predominantly observed in microglia. Analysis of intercellular communication revealed 12 ligand-receptor pairs in the pathways associated with DAMPs, where microglial cells acted as ligands. Among these pairs, the SPP1-CD44 pair demonstrated the greatest contribution. Furthermore, trajectory analysis demonstrated distinct differentiation fates of different microglial states. Additionally, we constructed a risk model incorporating four genes (TRPM2, ROCK1, HSP90AA1, and HSPA4). The validity of the risk model was supported by multivariate analysis. Moreover, external validation from dataset GSE112681 confirmed the predictive power of the model, which yielded consistent results with datasets GSE112676 and GSE112680. Lastly, the molecular docking analysis suggested that five compounds, namely mead-acid, nifedipine, nifekalant, androstenol, and hydrastine, hold promise as potential candidates for the treatment of ALS.

CONCLUSION: Taken together, our study demonstrated that DAMP entities were predominantly observed in microglial cells within the context of ALS. The utilization of a prognostic risk model can accurately predict ALS patient survival. Additionally, genes related to DAMPs may present viable drug targets for ALS therapy.}, } @article {pmid37942130, year = {2023}, author = {Piñeros-Fernández, MC}, title = {Artificial Intelligence Applications in the Diagnosis of Neuromuscular Diseases: A Narrative Review.}, journal = {Cureus}, volume = {15}, number = {11}, pages = {e48458}, pmid = {37942130}, issn = {2168-8184}, abstract = {The accurate diagnosis of neuromuscular diseases (NMD) is in many cases difficult; the starting point is the clinical approach based on the course of the disease and a careful physical examination of the patient. Electrodiagnostic tests, imaging, muscle biopsy, and genetics are fundamental complementary studies for the diagnosis of NMD. The large volume of data obtained from such studies makes it necessary to look for efficient solutions, such as artificial intelligence (AI) applications, which can help classify, synthesize, and organize the information of patients with NMD to facilitate their accurate and timely diagnosis. The objective of this study was to describe the usefulness of AI applications in the diagnosis of patients with neuromuscular diseases. A narrative review was done, including publications on artificial intelligence applied to the diagnostic methods of NMD currently existing. Twelve studies were included. Two of the studies focused on muscle ultrasound, five of the studies on muscle MRI, two studies on electromyography, two studies on amyotrophic lateral sclerosis (ALS) biomarkers, and one study on genes related to myopathies. The accuracy of classification using different classification algorithms used in each of the studies included in this narrative review was already 90% in most studies. In conclusion, the future design of more accurate algorithms applied to NMD with greater precision will have an impact on the earlier diagnosis of this group of diseases.}, } @article {pmid37941924, year = {2023}, author = {Zaita, BM and Ghosh, A and Lee, S and Raymond, A and Agnihotri, T and Akhter, NM}, title = {Radiologically inserted gastrostomy tube in neurological disease: A retrospective study.}, journal = {Journal of clinical imaging science}, volume = {13}, number = {}, pages = {35}, pmid = {37941924}, issn = {2156-7514}, abstract = {OBJECTIVES: This study aimed to compare the safety and efficacy of balloon and non-balloon (or dilator) gastrostomy devices in radiologically inserted gastrostomy (RIG) for patients with neurological disease.

MATERIAL AND METHODS: A retrospective analysis of 152 patients was conducted at a tertiary care hospital from July 2017 to September 2020. 104 and 48 patients were included in the balloon and non-balloon groups, respectively. The frequency of complications per specific neurological indication as well as the breakdown of the different complications pertaining to each indication was recorded for analysis. The recovery time, fluoroscopy time, contrast volume, peak radiation, and pain management dosages for each procedure were all reviewed to evaluate for statistical differences between the balloon and non-balloon groups. An adjusted model odds ratio (OR) was conducted to evaluate how each of the variables (type of gastrostomy tube, body mass index [BMI], age, and gender) affected the frequency of complications within our cohort.

RESULTS: This study included 152 patients, with an average age of 65.17 years (interquartile range [IQR] = 12.66) and an average BMI of 26.97 (IQR = 7.19). The majority of patients were male (71.1%). The most common indication for the procedure was stroke (24.3%), followed by post-intubation dysphagia (16.4%) and intracranial hemorrhage (11.8%). Amyotrophic lateral sclerosis (ALS) and altered mental status had a similar prevalence at 9.9%. The overall complication rate was 33.8%, overall mortality rate 3.3%, 30-day mortality rate of 2.6%, and no other major complications according to CIRSE criteria. Notably, patients with neurodegenerative disorders exhibited comparable rates of minor complications: 33.3% in ALS (5/15 patients), 50% in myasthenia gravis (1/2 patients), and 100% in muscular dystrophy (1/1 patient). The study compared two groups: the balloon group (104 patients) and the dilator group (48 patients). The balloon group received significantly lower preoperative sedation in the form of fentanyl (Avg = 4.46 min vs. 6.54 min, P = 0.287). The balloon group had shorter fluoroscopy time, lower radiation exposure dose, and shorter operating time compared to the dilator group, though not statistically significant. In the logistic regression model, there was no statistical difference in complication rates between the dilator and balloon groups. BMI, age, and gender did not significantly affect minor complication rates.

CONCLUSION: RIG tube insertions may serve as a valuable, alternative approach in providing enteral support in patients with neurological disease.}, } @article {pmid37941604, year = {2023}, author = {Dyer, MS and Odierna, GL and Clark, RM and Woodhouse, A and Blizzard, CA}, title = {Synaptic remodeling follows upper motor neuron hyperexcitability in a rodent model of TDP-43.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1274979}, pmid = {37941604}, issn = {1662-5102}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is an incurable disease characterized by relentlessly progressive degeneration of the corticomotor system. Cortical hyperexcitability has been identified as an early pre-symptomatic biomarker of ALS. This suggests that hyperexcitability occurs upstream in the ALS pathological cascade and may even be part of the mechanism that drives development of symptoms or loss of motor neurons in the spinal cord. However, many studies also indicate a loss to the synaptic machinery that mediates synaptic input which raises the question of which is the driver of disease, and which is a homeostatic response. Herein, we used an inducible mouse model of TDP-43 mediated ALS that permits for the construction of detailed phenotypic timelines. Our work comprehensively describes the relationship between intrinsic hyperexcitability and altered synaptic input onto motor cortical layer 5 pyramidal neurons over time. As a result, we have constructed the most complete timeline of electrophysiological changes following induction of TDP-43 dysfunction in the motor cortex. We report that intrinsic hyperexcitability of layer 5 pyramidal neurons precedes changes to excitatory synaptic connections, which manifest as an overall loss of inputs onto layer 5 pyramidal neurons. This finding highlights the importance of hyperexcitability as a primary mechanism of ALS and re-contextualizes synaptic changes as possibly representing secondary adaptive responses. Recognition of the relationship between intrinsic hyperexcitability and reduced excitatory synaptic input has important implications for the development of useful therapies against ALS. Novel strategies will need to be developed that target neuronal output by managing excitability against synapses separately.}, } @article {pmid37941227, year = {2023}, author = {Young, H and Gerez, L and Cole, T and Inirio, B and Proietti, T and Closs, B and Paganoni, S and Walsh, C}, title = {Air Efficient Soft Wearable Robot for High-Torque Elbow Flexion Assistance.}, journal = {IEEE ... International Conference on Rehabilitation Robotics : [proceedings]}, volume = {2023}, number = {}, pages = {1-6}, doi = {10.1109/ICORR58425.2023.10304679}, pmid = {37941227}, issn = {1945-7901}, mesh = {Humans ; Elbow/physiology ; *Robotics ; *Elbow Joint ; Torque ; *Amyotrophic Lateral Sclerosis ; *Wearable Electronic Devices ; }, abstract = {Recent developments in soft wearable robots have shown promise for assistive and rehabilitative use-cases. For inflatable approaches, a major challenge in developing portable systems is finding a balance between portability, performance, and usability. In this paper, we present a textile-based robotic sleeve that can provide functional elbow flexion assistance and is compatible with a portable actuation unit (PAU). Flexion is driven by a curved textile actuator with internal pneumatic supports (IPS). We show that the addition of IPS improves torque generation and increases battery-powered actuations by 60%. We demonstrate that the device can provide enough torque throughout the ROM of the elbow joint for daily life assistance. Specifically, the device generates 13.5 Nm of torque at 90°. Experimental testing in five healthy individuals and two individuals with Amyotrophic Lateral Sclerosis (ALS) demonstrates its impact on wearer muscle activity and kinematics. The results with healthy subjects show that the device was able to reduce the bicep muscle activity by an average of 49.1±13.3% during static and dynamic exercises, 43.6±11.1% during simulated ADLs, and provided an assisted ROM of 134°±13°. Both ALS participants reported a reduced rate of perceived exertion during both static and dynamic tasks while wearing the device and had an average ROM of 115°±8°. Future work will explore other applications of the IPS and extend the approach to assisting multiple joints.}, } @article {pmid37941028, year = {2023}, author = {Huang, Y and Liu, B and Sinha, SC and Amin, S and Gan, L}, title = {Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {79}, pmid = {37941028}, issn = {1750-1326}, support = {R01 AG074541/AG/NIA NIH HHS/United States ; R01AG072758/AG/NIA NIH HHS/United States ; R01AG074541/AG/NIA NIH HHS/United States ; R01AG054214/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Signal Transduction/physiology ; Nucleotidyltransferases/genetics/metabolism ; DNA/metabolism ; *Interferon Type I/genetics/metabolism ; *Nervous System Diseases ; }, abstract = {DNA sensing is a pivotal component of the innate immune system that is responsible for detecting mislocalized DNA and triggering downstream inflammatory pathways. Among the DNA sensors, cyclic GMP-AMP synthase (cGAS) is a primary player in detecting cytosolic DNA, including foreign DNA from pathogens and self-DNA released during cellular damage, culminating in a type I interferon (IFN-I) response through stimulator of interferon genes (STING) activation. IFN-I cytokines are essential in mediating neuroinflammation, which is widely observed in CNS injury, neurodegeneration, and aging, suggesting an upstream role for the cGAS DNA sensing pathway. In this review, we summarize the latest developments on the cGAS-STING DNA-driven immune response in various neurological diseases and conditions. Our review covers the current understanding of the molecular mechanisms of cGAS activation and highlights cGAS-STING signaling in various cell types of central and peripheral nervous systems, such as resident brain immune cells, neurons, and glial cells. We then discuss the role of cGAS-STING signaling in different neurodegenerative conditions, including tauopathies, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as aging and senescence. Finally, we lay out the current advancements in research and development of cGAS inhibitors and assess the prospects of targeting cGAS and STING as therapeutic strategies for a wide spectrum of neurological diseases.}, } @article {pmid37939393, year = {2023}, author = {Lualdi, M and Casale, F and Rizzone, MG and Zibetti, M and Monti, C and Colugnat, I and Calvo, A and De Marco, G and Moglia, C and Fuda, G and Comi, C and Chiò, A and Lopiano, L and Fasano, M and Alberio, T}, title = {Shared and Unique Disease Pathways in Amyotrophic Lateral Sclerosis and Parkinson's Disease Unveiled in Peripheral Blood Mononuclear Cells.}, journal = {ACS chemical neuroscience}, volume = {14}, number = {23}, pages = {4240-4251}, pmid = {37939393}, issn = {1948-7193}, mesh = {Humans ; *Parkinson Disease/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Prospective Studies ; Leukocytes, Mononuclear/metabolism ; Proteomics ; }, abstract = {Recent evidence supports an association between amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Indeed, prospective population-based studies demonstrated that about one-third of ALS patients develop parkinsonian (PK) signs, even though different neuronal circuitries are involved. In this context, proteomics represents a valuable tool to identify unique and shared pathological pathways. Here, we used two-dimensional electrophoresis to obtain the proteomic profile of peripheral blood mononuclear cells (PBMCs) from PD and ALS patients including a small cohort of ALS patients with parkinsonian signs (ALS-PK). After the removal of protein spots correlating with confounding factors, we applied a sparse partial least square discriminant analysis followed by recursive feature elimination to obtain two protein classifiers able to discriminate (i) PD and ALS patients (30 spots) and (ii) ALS-PK patients among all ALS subjects (20 spots). Functionally, the glycolysis pathway was significantly overrepresented in the first signature, while extracellular interactions and intracellular signaling were enriched in the second signature. These results represent molecular evidence at the periphery for the classification of ALS-PK as ALS patients that manifest parkinsonian signs, rather than comorbid patients suffering from both ALS and PD. Moreover, we confirmed that low levels of fibrinogen in PBMCs is a characteristic feature of PD, also when compared with another movement disorder. Collectively, we provide evidence that peripheral protein signatures are a tool to differentially investigate neurodegenerative diseases and highlight altered biochemical pathways.}, } @article {pmid37939160, year = {2023}, author = {Gendron, TF and Petrucelli, L}, title = {Immunological drivers of amyotrophic lateral sclerosis.}, journal = {Science translational medicine}, volume = {15}, number = {721}, pages = {eadj9332}, doi = {10.1126/scitranslmed.adj9332}, pmid = {37939160}, issn = {1946-6242}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease involving complex genetic and environmental factors, is associated with neuroinflammation. Preclinical and clinical studies support immune system involvement in ALS pathogenesis, thereby spurring investigations into potential pathogenic mechanisms, immune response biomarkers, and ALS therapeutics.}, } @article {pmid37938192, year = {2023}, author = {Maharaj, D and Kaur, K and Saltese, A and Gouvea, J}, title = {Personalized Precision Immunotherapy for Amyotrophic Lateral Sclerosis (ALS).}, journal = {Critical reviews in immunology}, volume = {43}, number = {2}, pages = {1-11}, doi = {10.1615/CritRevImmunol.2023048372}, pmid = {37938192}, issn = {1040-8401}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Immunotherapy ; Brain ; Cytokines ; Inflammation ; }, abstract = {Neurological syndrome amyotrophic lateral sclerosis (ALS) affects motor neurons and is characterized by progressive motor neuron loss in the brain and spinal cord. ALS starts with mainly focal onset but when the disease progresses, it spreads to different parts of the body, with survival limits of 2-5 years after disease initiation. To date, only supportive care is provided for ALS patients, and no effective treatment or cure has been discovered. This review is focused on clinical and immunological aspects of ALS patients, based on our case studies, and we discuss the treatment we have provided to those patients based on a detailed evaluation of their peripheral blood immune cells and blood-derived serum secreted factors, cytokines, chemokines and growth factors. We show that using a personalized approach of low dose immunotherapy there is an improvement in the effects on inflammation and immunological dysfunction.}, } @article {pmid37935449, year = {2024}, author = {Darke, AC}, title = {Can I Be Honest With My Neurologist? A Problem of Health Technology Assessment in Canada.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {51}, number = {5}, pages = {603-605}, doi = {10.1017/cjn.2023.307}, pmid = {37935449}, issn = {0317-1671}, } @article {pmid37934576, year = {2023}, author = {Gao, H and Yu, J and Chen, J and Wang, H and Liang, S and Feng, Z and Gu, Y and Dong, L}, title = {Target-Site and Metabolic Resistance Mechanisms to Penoxsulam in Late Watergrass (Echinochloa phyllopogon) in China.}, journal = {Journal of agricultural and food chemistry}, volume = {71}, number = {46}, pages = {17742-17751}, doi = {10.1021/acs.jafc.3c05921}, pmid = {37934576}, issn = {1520-5118}, mesh = {*Echinochloa/genetics/metabolism ; Herbicide Resistance/genetics ; Tandem Mass Spectrometry ; *Herbicides/pharmacology/metabolism ; *Acetolactate Synthase/genetics/metabolism ; }, abstract = {Echinochloa phyllopogon, a malignant weed in Northeast China's paddy fields, is currently presenting escalating resistance concerns. Our study centered on the HJHL-715 E. phyllopogon population, which showed heightened resistance to penoxsulam, through a whole-plant bioassay. Pretreatment with a P450 inhibitor malathion significantly increased penoxsulam sensitivity in resistant plants. In order to determine the resistance mechanism of the resistant population, we purified the resistant population from individual plants and isolated target-site resistance (TSR) and nontarget-site resistance (NTSR) materials. Pro-197-Thr and Trp-574-Leu mutations in acetolactate synthase (ALS) 1 and ALS2 of the resistant population drove reduced sensitivity of penoxsulam to the target-site ALS, the primary resistance mechanisms. To fully understand the NTSR mechanism, NTSR materials were investigated by using RNA-sequencing (RNA-seq) combined with a reference genome. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis further supported the enhanced penoxsulam metabolism in NTSR materials. Gene expression data and quantitative reverse transcription polymerase chain reaction (qRT-PCR) validation confirmed 29 overexpressed genes under penoxsulam treatment, with 16 genes concurrently upregulated with quinclorac and metamifop treatment. Overall, our study confirmed coexisting TSR and NTSR mechanisms in E. phyllopogon's resistance to ALS inhibitors.}, } @article {pmid37934011, year = {2024}, author = {Palmieri, JL and Bach, JR}, title = {Pulmonary care for ALS: There is more to the story.}, journal = {Muscle & nerve}, volume = {69}, number = {1}, pages = {115-116}, doi = {10.1002/mus.27996}, pmid = {37934011}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; }, } @article {pmid37933884, year = {2024}, author = {Walter, U and Sobiella, G and Prudlo, J and Batchakaschvili, M and Böhmert, J and Storch, A and Hermann, A}, title = {Ultrasonic detection of vagus, accessory, and phrenic nerve atrophy in amyotrophic lateral sclerosis: Relation to impairment and mortality.}, journal = {European journal of neurology}, volume = {31}, number = {2}, pages = {e16127}, pmid = {37933884}, issn = {1468-1331}, support = {GHS-15-0017//European Regional Development Fund/ ; //Hermann und Lilly Schilling-Stiftung für Medizinische Forschung/ ; }, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging ; Atrophy ; Phrenic Nerve/diagnostic imaging ; Ultrasonics ; Vagus Nerve ; Male ; Female ; }, abstract = {BACKGROUND AND PURPOSE: In amyotrophic lateral sclerosis (ALS), phrenic nerve (PN) atrophy has been found, whereas there is controversy regarding vagus nerve (VN) atrophy. Here, we aimed to find out whether PN atrophy is related to respiratory function and 12-month survival. Moreover, we investigated the relevance of VN and spinal accessory nerve (AN) atrophy in ALS.

METHODS: This prospective observational monocentric study included 80 adult participants (40 ALS patients, 40 age- and sex-matched controls). The cross-sectional area (CSA) of bilateral cervical VN, AN, and PN was measured on high-resolution ultrasonography. Clinical assessments included the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), the Non-Motor Symptoms Questionnaire, and handheld spirometry of forced vital capacity (FVC). One-year survival was documented.

RESULTS: The CSA of each nerve, VN, AN, and PN, was smaller in ALS patients compared to controls. VN atrophy was unrelated to nonmotor symptom scores. PN CSA correlated with the respiratory subscore of the ALSFRS-R (Spearman test, r = 0.59, p < 0.001), the supine FVC (r = 0.71, p < 0.001), and the relative change of sitting-supine FVC (r = -0.64, p = 0.001). Respiratory impairment was predicted by bilateral mean PN CSA (p = 0.046, optimum cutoff value of ≤0.37 mm[2] , sensitivity = 92%, specificity = 56%) and by the sum of PN and AN CSA (p = 0.036). The combination of ALSFRS-R score with PN and AN CSA measures predicted 1-year survival with similar accuracy as the combination of ALSFRS-R score and FVC.

CONCLUSIONS: Ultrasonography detects degeneration of cranial nerve motor fibers. PN and AN calibers are tightly related to respiratory function and 1-year survival in ALS.}, } @article {pmid37931706, year = {2024}, author = {Xuan, X and Zheng, G and Zhu, W and Sun, Q and Zeng, Y and Du, J and Huang, X}, title = {Alterations in regional homogeneity and functional connectivity in the cerebellum of patients with sporadic amyotrophic lateral sclerosis.}, journal = {Behavioural brain research}, volume = {458}, number = {}, pages = {114749}, doi = {10.1016/j.bbr.2023.114749}, pmid = {37931706}, issn = {1872-7549}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Magnetic Resonance Imaging/methods ; Brain ; Cerebellum/pathology ; }, abstract = {OBJECTIVE: The purpose of this study was to examine the cerebellum's local and global functional characteristics in individuals with sporadic amyotrophic lateral sclerosis (sALS) and their correlation with clinical data.

METHODS: Resting-state functional magnetic resonance imaging was performed on 39 patients with sALS and on 23 healthy controls. Regional homogeneity (ReHo) in the cerebellum of all participants was analyzed, and the cerebellar regions with differences in ReHo were considered regions of interest (ROIs). In addition, the functional connectivity between the ROIs and other brain regions was analyzed.

RESULTS: In patients with sALS, ReHo increased in parts of the posterior cerebellar lobe. Then, the two regions with increased ReHo of the cerebellum were used as seeds, and further analysis revealed that the connectivity of the right cerebellum to the right medial superior frontal gyrus, left lingual gyrus (calcarine sulcus), left precentral gyrus, left supplementary motor area, and right Crus II was significantly increased.

CONCLUSION: The results demonstrate that resting-state functional connectivity changes in both motor and extra-motor regions of the cerebellum in patients with sALS, and that the cerebellum plays a pathophysiological role in sALS.}, } @article {pmid37931648, year = {2024}, author = {Aust, E and Günther, R and Hermann, A and Linse, K}, title = {[Psychologically guided group meetings for family caregivers of ALS patients].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {92}, number = {3}, pages = {81-89}, doi = {10.1055/a-2156-9013}, pmid = {37931648}, issn = {1439-3522}, mesh = {Humans ; *Caregivers/psychology ; Adaptation, Psychological ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Emotions ; Palliative Care ; Quality of Life/psychology ; }, abstract = {BACKGROUND: The course of amyotrophic lateral sclerosis (ALS,) associated with progressive physical limitations, is a challenge to the patients themselves and also to their family caregivers, who have to deal with psychosocial, socio-medical and organizational issues. Caregivers are often closely involved and heavily burdened themselves, which is why specific support is recommended. The aim of this study was to investigate the feasibility and acceptance of psychologically guided supportive group meetings for family caregivers in a specialist ALS outpatient clinic.

METHODS: Over a period of two years, data were collected from a total of 26 caregivers of ALS patients in order to evaluate the relevance, usefulness and criticisms of open-topic meetings that took place every three months.

RESULTS: Topics discussed in the meetings included mainly psychosocial issues such as self-care, dealing with emotions or with conflicts with the patients and third parties, as well as practical and organizational matters. The meetings were predominantly rated as helpful, well understandable and personally relevant and the exchange in a "community of destiny" was perceived as emotionally relieving.

DISCUSSION: The ALS caregiver group meetings in the described format were easy to carry out and well accepted. Supportive interventions, such as the one reported here, might be a valuable component of ALS care, to relieve the highly burdened caregivers of ALS-patients by providing them with social, emotional and practical support. However, the quantitative verification of the intervention's effectiveness is challenging - both methodologically and due to the caregivers' complex life situation. Psychosocial support services for ALS caregivers are feasible with little effort and should be an integral part of the standard ALS care based on a multi-dimensional, palliative care concept.}, } @article {pmid37930717, year = {2023}, author = {Lam, K and Cenzer, I and Levy, CR and Matlock, DD and Smith, AK and Covinsky, KE}, title = {The Natural History of Disability and Caregiving Before and After Long-Term Care Entry.}, journal = {JAMA internal medicine}, volume = {183}, number = {12}, pages = {1295-1303}, pmid = {37930717}, issn = {2168-6114}, support = {P01 AG066605/AG/NIA NIH HHS/United States ; P30 AG044281/AG/NIA NIH HHS/United States ; R03 AG074038/AG/NIA NIH HHS/United States ; KL2 TR001870/TR/NCATS NIH HHS/United States ; K24 AG068312/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Humans ; Female ; United States/epidemiology ; Aged, 80 and over ; Male ; *Long-Term Care ; *Activities of Daily Living ; Longitudinal Studies ; Medicare ; Caregivers/statistics & numerical data ; }, abstract = {IMPORTANCE: Many older persons move into long-term care facilities (LTCFs) due to disability and insufficient home caregiving options. However, the extent of disability and caregiving provided around the time of entry is unknown.

OBJECTIVE: To quantitatively describe disability and caregiving before and after LTCF entry, comparing nursing home (NH), assisted living (AL), and independent living (IL) entrants.

A longitudinal cohort study using prospectively collected annual data from the National Health and Aging Trends Study from 2011 to 2020 including participants in the continental US. Overall, 932 community-dwelling Medicare beneficiaries entering LTCF from 2011 to 2019 were included. Entry into LTCF was set as t = 0, and participant interviews from 4 years before and 2 years after were used.

MAIN OUTCOMES AND MEASURES: Prevalence of severe disability (severe difficulty or dependence in ≥3 activities of daily living), prevalence of caregivers, and median weekly caregiving hours per entrant, using weighted mixed-effects regression against time as linear spline.

RESULTS: At entry, mean (SD) age was 84 (8.4) years, 609 (64%, all percentages survey weighted) were women, 143 (6%) were Black, 29 (3%) were Hispanic, 30 (4%) were other (other race and ethnicity included American Indian, Asian, Native Hawaiian, and other), and 497 (49%) had dementia. 349 (34%) entered NH, 426 (45%) entered AL, and 157 (21%) entered IL. Overall, NH and AL entry were preceded by months of severe disability and escalating caregiving. Before entry, 49% (95% CI, 29%-68%) of NH entrants and 10% (95% CI, 3%-24%) of AL entrants had severe disability. Most (>97%) had at least a caregiver, but only one-third (NH, 33%; 95% CI, 20%-50%; AL, 33%; 95% CI, 24%-44%) had a paid caregiver. Median care was 27 hours weekly (95% CI, 18-40) in NH entrants and 18 (95% CI, 14-24) in AL entrants. On NH and AL entry, severe disability rose to 89% (95% CI, 82%-94%) and 28% (95% CI, 16%-44%) on NH and AL entry and was 66% (95% CI, 55%-75%) 2 years after entry in AL residents. Few IL entrants (<2%) had severe disability and their median care remained less than 7 hours weekly before and after entry.

CONCLUSIONS: This study found that persons often enter NHs and ALs after months of severe disability and substantial help at home, usually from unpaid caregivers. Assisted living residents move when less disabled, but approach levels of disability similar to NH entrants within 2 years. Data may help clinicians understand when home supports approach a breaking point.}, } @article {pmid37930481, year = {2024}, author = {Domi, T and Schito, P and Sferruzza, G and Russo, T and Pozzi, L and Agosta, F and Carrera, P and Riva, N and Filippi, M and Quattrini, A and Falzone, YM}, title = {Unveiling the SOD1-mediated ALS phenotype: insights from a comprehensive meta-analysis.}, journal = {Journal of neurology}, volume = {271}, number = {3}, pages = {1342-1354}, pmid = {37930481}, issn = {1432-1459}, mesh = {Humans ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Phenotype ; Genetic Testing ; Mutation ; C9orf72 Protein/genetics ; RNA-Binding Protein FUS/genetics ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis associated with mutations in SOD1 (SOD1-ALS) might be susceptible to specific treatment. The aim of the study is to outline the clinical features of SOD1-ALS patients by comparing them to patients without ALS major gene variants and patients with variants in other major ALS genes. Defining SOD1-ALS phenotype may assist clinicians in identifying patients who should be prioritized for genetic testing.

METHODS: We performed an extensive literature research including original studies which reported the clinical features of SOD1-ALS and at least one of the following patient groups: C9ORF72 hexanucleotide repeat expansion (C9-ALS), TARDBP (TARDBP-ALS), FUS (FUS-ALS) or patients without a positive test for a major-ALS gene (N-ALS). A random effects meta-analytic model was applied to clinical data extracted encompassing sex, site and age of onset. To reconstruct individual patient survival data, the published Kaplan-Meier curves were digitized. Data were measured as odds ratio (OR) or standardized mean difference (SMD) as appropriate. Median survival was compared between groups.

RESULTS: Twenty studies met the inclusion criteria. We identified 721 SOD1-ALS, 470 C9-ALS, 183 TARDBP-ALS, 113 FUS-ALS and 2824 N-ALS. SOD1-ALS showed a higher rate of spinal onset compared with N-ALS and C9-ALS (OR = 4.85, 95% CI = 3.04-7.76; OR = 10.47, 95% CI = 4.32-27.87) and an earlier onset compared with N-ALS (SMD = - 0.45, 95% CI = - 0.72 to - 0.18). SOD1-ALS had a similar survival compared with N-ALS (p = 0.14), a longer survival compared with C9-ALS (p < 0.01) and FUS-ALS (p = 0.019) and a shorter survival compared with TARDBP-ALS (p < 0.01).

DISCUSSION: This study indicates the presence of a specific SOD1-ALS phenotype. Insights in SOD1-ALS clinical features are important in genetic counseling, disease prognosis and support patients' stratification in clinical trials.}, } @article {pmid37930016, year = {2023}, author = {Ahn, JJ and Miller, RH and Islam, Y}, title = {Isolation of Pure Astrocytes and Microglia from the Adult Mouse Spinal Cord For In Vitro Assays and Transcriptomic Studies.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {200}, pages = {}, doi = {10.3791/65893}, pmid = {37930016}, issn = {1940-087X}, support = {F31 NS117085/NS/NINDS NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Microglia ; Astrocytes ; Transcriptome ; Proteomics ; Spinal Cord ; *Spinal Cord Injuries/pathology ; }, abstract = {Astrocytes and microglia play pivotal roles in central nervous system development, injury responses, and neurodegenerative diseases. These highly dynamic cells exhibit rapid responses to environmental changes and display significant heterogeneity in terms of morphology, transcriptional profiles, and functions. While our understanding of the functions of glial cells in health and disease has advanced substantially, there remains a need for in vitro, cell-specific analyses conducted in the context of insults or injuries to comprehensively characterize distinct cell populations. Isolating cells from the adult mouse offers several advantages over cell lines or neonatal animals, as it allows for the analysis of cells under pathological conditions and at specific time points. Furthermore, focusing on spinal cord-specific isolation, excluding brain involvement, enables research into spinal cord pathologies, including experimental autoimmune encephalomyelitis, spinal cord injury, and amyotrophic lateral sclerosis. This protocol presents an efficient method for isolating astrocytes and microglia from the adult mouse spinal cord, facilitating immediate or future analysis with potential applications in functional, molecular, or proteomic downstream studies.}, } @article {pmid37929431, year = {2023}, author = {Nagappa, M and Sharma, S and Govindaraj, P and Chickabasaviah, YT and Siram, R and Shroti, A and Seshagiri, DV and Debnath, M and Sinha, S and Bindu, PS and Taly, AB}, title = {Characterisation of Patients with SH3TC2 Associated Neuropathy in an Indian Cohort.}, journal = {Neurology India}, volume = {71}, number = {5}, pages = {940-945}, doi = {10.4103/0028-3886.388101}, pmid = {37929431}, issn = {1998-4022}, mesh = {Humans ; Female ; Male ; *Intracellular Signaling Peptides and Proteins/genetics ; Mutation ; Phenotype ; *Charcot-Marie-Tooth Disease/genetics ; Electrophysiological Phenomena ; }, abstract = {BACKGROUND: SH3TC2 variations lead to demyelinating recessive Charcot-Marie-Tooth (CMT) disease, which is commonly associated with early-onset scoliosis and cranial neuropathy. Data from Indian ethnicity is limited.

OBJECTIVE: We aim to report the characteristics of patients with SH3TC2-associated neuropathy from an Indian cohort.

PATIENTS AND METHODS: Data of five unrelated subjects with SH3TC2 variations were analyzed.

RESULTS: Clinical features included female predominance (n = 4), early-onset neuropathy (n = 2), pes cavus and hammer toes (n = 4), kyphoscoliosis (n = 1), impaired vision and hearing (n = 1), facial muscle weakness (n = 1), impaired kinaesthetic sense (n = 3), tremor (n = 2), and ataxia (n = 1). Four patients had the "CMT" phenotype, while one patient had Roussy-Levy syndrome. All had demyelinating electrophysiology with conduction velocities being "very slow" in one, "slow" in one, "mildly slow" in two, and "intermediate" in one patient. Brain stem auditory evoked potentials were universally abnormal though only one patient had symptomatic deafness. Seven variants were identified in SH3TC2 [homozygous = 3 (c.1412del, c.69del, c.3152G>A), heterozygous = 4 (c.1105C>T, c.3511C>T, c.2028G>C, c.254A>T)]. Except for c.3511C>T variant, the rest were novel. Three patients had additional variations in genes having pathobiological relevance in other CMTs or amyotrophic lateral sclerosis.

CONCLUSION: We provide data on a cohort of patients of Indian origin with SH3TC2 variations and highlight differences from other cohorts. Though the majority were not symptomatic for hearing impairment, evoked potentials disclosed abnormalities in all. Further studies are required to establish the functional consequences of novel variants and their interacting molecular partners identified in the present study to strengthen their association with the phenotype.}, } @article {pmid37928737, year = {2023}, author = {Johnson, GA and Krishnamoorthy, RR and Stankowska, DL}, title = {Modulating mitochondrial calcium channels (TRPM2/MCU/NCX) as a therapeutic strategy for neurodegenerative disorders.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1202167}, pmid = {37928737}, issn = {1662-4548}, support = {T32 AG020494/AG/NIA NIH HHS/United States ; }, abstract = {Efficient cellular communication is essential for the brain to regulate diverse functions like muscle contractions, memory formation and recall, decision-making, and task execution. This communication is facilitated by rapid signaling through electrical and chemical messengers, including voltage-gated ion channels and neurotransmitters. These messengers elicit broad responses by propagating action potentials and mediating synaptic transmission. Calcium influx and efflux are essential for releasing neurotransmitters and regulating synaptic transmission. Mitochondria, which are involved in oxidative phosphorylation, and the energy generation process, also interact with the endoplasmic reticulum to store and regulate cytoplasmic calcium levels. The number, morphology, and distribution of mitochondria in different cell types vary based on energy demands. Mitochondrial damage can cause excess reactive oxygen species (ROS) generation. Mitophagy is a selective process that targets and degrades damaged mitochondria via autophagosome-lysosome fusion. Defects in mitophagy can lead to a buildup of ROS and cell death. Numerous studies have attempted to characterize the relationship between mitochondrial dysfunction and calcium dysregulation in neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic lateral sclerosis, spinocerebellar ataxia, and aging. Interventional strategies to reduce mitochondrial damage and accumulation could serve as a therapeutic target, but further research is needed to unravel this potential. This review offers an overview of calcium signaling related to mitochondria in various neuronal cells. It critically examines recent findings, exploring the potential roles that mitochondrial dysfunction might play in multiple neurodegenerative diseases and aging. Furthermore, the review identifies existing gaps in knowledge to guide the direction of future research.}, } @article {pmid37928442, year = {2023}, author = {Chen, SK and Hawley, ZCE and Zavodszky, MI and Hana, S and Ferretti, D and Grubor, B and Hawes, M and Xu, S and Hamann, S and Marsh, G and Cullen, P and Challa, R and Carlile, TM and Zhang, H and Lee, WH and Peralta, A and Clarner, P and Wei, C and Koszka, K and Gao, F and Lo, SC}, title = {Efficacy and safety of a SOD1-targeting artificial miRNA delivered by AAV9 in mice are impacted by miRNA scaffold selection.}, journal = {Molecular therapy. Nucleic acids}, volume = {34}, number = {}, pages = {102057}, pmid = {37928442}, issn = {2162-2531}, abstract = {Toxic gain-of-function mutations in superoxide dismutase 1 (SOD1) contribute to approximately 2%-3% of all amyotrophic lateral sclerosis (ALS) cases. Artificial microRNAs (amiRs) delivered by adeno-associated virus (AAV) have been proposed as a potential treatment option to silence SOD1 expression and mitigate disease progression. Primary microRNA (pri-miRNA) scaffolds are used in amiRs to shuttle a hairpin RNA into the endogenous miRNA pathway, but it is unclear whether different primary miRNA (pri-miRNA) scaffolds impact the potency and safety profile of the expressed amiR in vivo. In our process to develop an AAV amiR targeting SOD1, we performed a preclinical characterization of two pri-miRNA scaffolds, miR155 and miR30a, sharing the same guide strand sequence. We report that, while the miR155-based vector, compared with the miR30a-based vector, leads to a higher level of the amiR and more robust suppression of SOD1 in vitro and in vivo, it also presents significantly greater risks for CNS-related toxicities in vivo. Despite miR30a-based vector showing relatively lower potency, it can significantly delay the development of ALS-like phenotypes in SOD1-G93A mice and increase survival in a dose-dependent manner. These data highlight the importance of scaffold selection in the pursuit of highly efficacious and safe amiRs for RNA interference gene therapy.}, } @article {pmid37926865, year = {2024}, author = {Xiao, X and Li, M and Ye, Z and He, X and Wei, J and Zha, Y}, title = {FUS gene mutation in amyotrophic lateral sclerosis: a new case report and systematic review.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {1-15}, doi = {10.1080/21678421.2023.2272170}, pmid = {37926865}, issn = {2167-9223}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Mutation/genetics ; Mutation, Missense ; *Neurodegenerative Diseases ; Retrospective Studies ; RNA-Binding Protein FUS/genetics ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with upper and lower motor neuron degeneration and necrosis, characterized by progressive muscle weakness, atrophy, and paralysis. The FUS mutation-associated ALS has been classified as ALS6. We reported a case of ALS6 with de novo mutation and investigated retrospectively the characteristics of cases with FUS mutation.

METHODS: We reported a male patient with a new heterozygous variant of the FUS gene and comprehensively reviewed 173 ALS cases with FUS mutation. The literature was reviewed from the PubMed MEDLINE electronic database (https://www.ncbi.nlm.nih.gov/pubmed) using "Amyotrophic Lateral Sclerosis and Fus mutation" or "Fus mutation" as key words from 1 January 2009 to 1 January 2022.

RESULTS: We report a case of ALS6 with a new mutation point (c.1225-1227delGGA) and comprehensively review 173 ALS cases with FUS mutation. Though ALS6 is all with FUS mutation, it is still a highly heterogenous subtype. The average onset age of ALS6 is 35.2 ± 1.3 years, which is much lower than the average onset age of ALS (60 years old). Juvenile FUS mutations have an aggressive progression of disease, with an average time from onset to death or tracheostomy of 18.2 ± 0.5 months. FUS gene has the characteristics of early onset, faster progress, and shorter survival, especially in deletion mutation p.G504Wfs *12 and missense mutation of p.P525L.

CONCLUSIONS: ALS6 is a highly heterogenous subtype. Our study could allow clinicians to better understand the non-ALS typical symptoms, phenotypes, and pathophysiology of ALS6.}, } @article {pmid37924056, year = {2023}, author = {Sun, J and Chen, J and Xie, Q and Sun, M and Zhang, W and Wang, H and Liu, N and Wang, Q and Wang, M}, title = {Sodium butyrate alleviates R97-116 peptide-induced myasthenia gravis in mice by improving the gut microbiota and modulating immune response.}, journal = {Journal of inflammation (London, England)}, volume = {20}, number = {1}, pages = {37}, pmid = {37924056}, issn = {1476-9255}, abstract = {Fermented butyrate exhibits an anti-inflammatory response to maintain immune homeostasis within the gut. However, the effect and underlying mechanism of butyrate on myasthenia gravis (MG) remain unclear. The changes in the gut microbiota and fecal contents of SCFAs in MG patients were examined. R97-116 peptide was used to induce the experimental autoimmune myasthenia gravis (EAMG) mice and sodium butyrate (NaB) was gavaged to the EAMG mice. Gut microbiota, the frequency of Th1, Th17, Treg, Tfh, and B cells, the levels of IFN-γ, IL-17 A, IL-10, IL-21, and anti-R97-116 IgG, RNA-seq of total B cells in the spleen were explored by metagenomics, flow cytometry, ELISA, and transcriptomics. A significant reduction in SCFA-producing bacteria including Butyricimonas synergistica and functional modules including butyrate synthesis/production II was observed in MG patients and fecal SCFAs detection confirmed the increase. The EAMG mice were successfully constructed and NaB supplementation has changed the composition and function of the gut microbiota. The numbers of Th1, Th17, Tfh, and B cells were significantly increased while that of Treg cells was obviously decreased in EAMG mice compared with controls. Interestingly, NaB treatment has reduced the amounts of Th17, Tfh, and B cells but increased that of Treg cells. Accordingly, the levels of IL-17 A, IL-21, and IgG were increased while IL-10 was decreased in EAMG mice. However, NaB treatment reduced IL-17 A and IL-21 but increased that of IL-10. RNA-seq of B cells has revealed 4577 deferentially expressed genes (DEGs), in which 1218 DEGs were up-regulated while 3359 DEGs were down-regulated in NaB-treated EAMG mice. GO enrichment and KEGG pathway analysis unveiled that the function of these DEGs was mainly focused on immunoglobulin production, mitochondrial respiratory chain complex, ribosome, oxidative phosphorylation, and CNS diseases including amyotrophic lateral sclerosis. We have found that butyrate was significantly reduced in MG patients and NaB gavage could evidently improve MG symptoms in EAMG mice by changing the gut microbiota, regulating the immune response, and altering the gene expression and function of B cells, suggesting NaB might be a potential immunomodulatory supplement for MG drugs.}, } @article {pmid37922093, year = {2024}, author = {Jellinger, KA}, title = {Understanding depression with amyotrophic lateral sclerosis: a short assessment of facts and perceptions.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {131}, number = {2}, pages = {107-115}, pmid = {37922093}, issn = {1435-1463}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/diagnosis ; Depression/complications ; Quality of Life ; Affect ; *Neurodegenerative Diseases/complications ; }, abstract = {Depression with an average prevalence of 25-40% is a serious condition in amyotrophic lateral sclerosis (ALS) that can impact quality of life and survival of patients and caregiver burden, yet the underlying neurobiology is poorly understood. Preexisting depression has been associated with a higher risk of developing ALS, while people with ALS have a significantly higher risk of developing depression that can cause multiple complications. Depression may be a prodromal or subclinical symptom prior to motor involvement, although its relations with disease progression and impairment of quality of life are under discussion. Unfortunately, there are no studies existing that explore the pathogenic mechanisms of depression associated with the basic neurodegenerative process, and no specific neuroimaging data or postmortem findings for the combination of ALS and depression are currently available. Experience from other neurodegenerative processes suggests that depressive symptoms in ALS may be the consequence of cortical thinning in prefrontal regions and other cortex areas, disruption of mood-related brain networks, dysfunction of neurotransmitter systems, changing cortisol levels and other, hitherto unknown mechanisms. Treatment of both ALS and depression is a multidisciplinary task, depression generally being treated with a combination of antidepressant medication, physiotherapy, psychological and other interventions, while electroconvulsive therapy and deep brain stimulation might not be indicated in the majority of patients in view of their poor prognosis. Since compared to depression in other neurodegenerative diseases, our knowledge of its molecular basis in ALS is missing, multidisciplinary clinicopathological studies to elucidate the pathomechanism of depression in motor system disorders including ALS are urgently warranted.}, } @article {pmid37920668, year = {2023}, author = {Ho, WY and Chak, LL and Hor, JH and Liu, F and Diaz-Garcia, S and Chang, JC and Sanford, E and Rodriguez, MJ and Alagappan, D and Lim, SM and Cho, YL and Shimizu, Y and Sun, AX and Tyan, SH and Koo, E and Kim, SH and Ravits, J and Ng, SY and Okamura, K and Ling, SC}, title = {FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons.}, journal = {iScience}, volume = {26}, number = {11}, pages = {108152}, pmid = {37920668}, issn = {2589-0042}, abstract = {MicroRNAs (miRNAs) modulate mRNA expression, and their deregulation contributes to various diseases including amyotrophic lateral sclerosis (ALS). As fused in sarcoma (FUS) is a causal gene for ALS and regulates biogenesis of miRNAs, we systematically analyzed the miRNA repertoires in spinal cords and hippocampi from ALS-FUS mice to understand how FUS-dependent miRNA deregulation contributes to ALS. miRNA profiling identified differentially expressed miRNAs between different central nervous system (CNS) regions as well as disease states. Among the up-regulated miRNAs, miR-1197 targets the pro-survival pseudokinase Trib2. A reduced TRIB2 expression was observed in iPSC-derived motor neurons from ALS patients. Pharmacological stabilization of TRIB2 protein with a clinically approved cancer drug rescues the survival of iPSC-derived human motor neurons, including those from a sporadic ALS patient. Collectively, our data indicate that miRNA profiling can be used to probe the molecular mechanisms underlying selective vulnerability, and TRIB2 is a potential therapeutic target for ALS.}, } @article {pmid37920473, year = {2023}, author = {Lemos, JP and Tenório, LPG and Mouly, V and Butler-Browne, G and Mendes-da-Cruz, DA and Savino, W and Smeriglio, P}, title = {T cell biology in neuromuscular disorders: a focus on Duchenne Muscular Dystrophy and Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1202834}, pmid = {37920473}, issn = {1664-3224}, mesh = {Humans ; *Muscular Dystrophy, Duchenne/therapy ; *Amyotrophic Lateral Sclerosis/therapy/genetics ; *Neuromuscular Diseases ; Muscles ; Genetic Therapy/methods ; }, abstract = {Growing evidence demonstrates a continuous interaction between the immune system, the nerve and the muscle in neuromuscular disorders of different pathogenetic origins, such as Duchenne Muscular Dystrophy (DMD) and Amyotrophic Lateral Sclerosis (ALS), the focus of this review. Herein we highlight the complexity of the cellular and molecular interactions involving the immune system in neuromuscular disorders, as exemplified by DMD and ALS. We describe the distinct types of cell-mediated interactions, such as cytokine/chemokine production as well as cell-matrix and cell-cell interactions between T lymphocytes and other immune cells, which target cells of the muscular or nervous tissues. Most of these interactions occur independently of exogenous pathogens, through ligand-receptor binding and subsequent signal transduction cascades, at distinct levels of specificity. Although this issue reveals the complexity of the system, it can also be envisioned as a window of opportunity to design therapeutic strategies (including synthetic moieties, cell and gene therapy, as well as immunotherapy) by acting upon one or more targets. In this respect, we discuss ongoing clinical trials using VLA-4 inhibition in DMD, and in ALS, with a focus on regulatory T cells, both revealing promising results.}, } @article {pmid37920145, year = {2024}, author = {Stamatelatou, A and Bertinetto, CG and Jansen, JJ and Postma, G and Selnaes, KM and Bathen, TF and Heerschap, A and Scheenen, TWJ and , }, title = {A multivariate curve resolution analysis of multicenter proton spectroscopic imaging of the prostate for cancer localization and assessment of aggressiveness.}, journal = {NMR in biomedicine}, volume = {37}, number = {3}, pages = {e5062}, doi = {10.1002/nbm.5062}, pmid = {37920145}, issn = {1099-1492}, support = {813120//European Union's Horizon 2020 research and innovation program/ ; }, mesh = {Male ; Humans ; *Prostate/diagnostic imaging/pathology ; Protons ; *Prostatic Neoplasms/diagnostic imaging ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy/methods ; Least-Squares Analysis ; }, abstract = {In this study, we investigated the potential of the multivariate curve resolution alternating least squares (MCR-ALS) algorithm for analyzing three-dimensional (3D) [1] H-MRSI data of the prostate in prostate cancer (PCa) patients. MCR-ALS generates relative intensities of components representing spectral profiles derived from a large training set of patients, providing an interpretable model. Our objectives were to classify magnetic resonance (MR) spectra, differentiating tumor lesions from benign tissue, and to assess PCa aggressiveness. We included multicenter 3D [1] H-MRSI data from 106 PCa patients across eight centers. The patient cohort was divided into a training set (N = 63) and an independent test set (N = 43). Singular value decomposition determined that MR spectra were optimally represented by five components. The profiles of these components were extracted from the training set by MCR-ALS and assigned to specific tissue types. Using these components, MCR-ALS was applied to the test set for a quantitative analysis to discriminate tumor lesions from benign tissue and to assess tumor aggressiveness. Relative intensity maps of the components were reconstructed and compared with histopathology reports. The quantitative analysis demonstrated a significant separation between tumor and benign voxels (t-test, p < 0.001). This result was achieved including voxels with low-quality MR spectra. A receiver operating characteristic analysis of the relative intensity of the tumor component revealed that low- and high-risk tumor lesions could be distinguished with an area under the curve of 0.88. Maps of this component properly identified the extent of tumor lesions. Our study demonstrated that MCR-ALS analysis of [1] H-MRSI of the prostate can reliably identify tumor lesions and assess their aggressiveness. It handled multicenter data with minimal preprocessing and without using prior knowledge or quality control. These findings indicate that MCR-ALS can serve as an automated tool to assess the presence, extent, and aggressiveness of tumor lesions in the prostate, enhancing diagnostic capabilities and treatment planning of PCa patients.}, } @article {pmid37919089, year = {2023}, author = {Moda, F and Ciullini, A and Dellarole, IL and Lombardo, A and Campanella, N and Bufano, G and Cazzaniga, FA and Giaccone, G}, title = {Secondary Protein Aggregates in Neurodegenerative Diseases: Almost the Rule Rather than the Exception.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {28}, number = {10}, pages = {255}, doi = {10.31083/j.fbl2810255}, pmid = {37919089}, issn = {2768-6698}, mesh = {Humans ; Aged ; *Neurodegenerative Diseases/pathology ; Protein Aggregates ; *Lewy Body Disease/metabolism/pathology ; *Synucleinopathies ; *Alzheimer Disease/metabolism ; *Parkinson Disease/metabolism ; tau Proteins/metabolism ; *Prion Diseases ; Amyloid beta-Peptides ; *Frontotemporal Lobar Degeneration ; }, abstract = {The presence of protein aggregates is a hallmark of many neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD). Traditionally, each disease has been associated with the aggregation of specific proteins, which serve as disease-specific biomarkers. For example, aggregates of α-synuclein (α-syn) are found in α-synucleinopathies such as PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Similarly, AD is characterized by aggregates of amyloid-beta (Aβ) and tau proteins. However, it has been observed that these protein aggregates can also occur in other neurodegenerative diseases, contributing to disease progression. For instance, α-syn aggregates have been detected in AD, Down syndrome, Huntington's disease, prion diseases, and various forms of FTLD. Similarly, Aβ aggregates have been found in conditions like DLB and PD. Tau aggregates, in addition to being present in primary tauopathies, have been identified in prion diseases, α-synucleinopathies, and cognitively healthy aged subjects. Finally, aggregates of TDP-43, typically associated with FTLD and amyotrophic lateral sclerosis (ALS), have been observed in AD, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), MSA, DLB, and other neurodegenerative diseases. These findings highlight the complexity of protein aggregation in neurodegeneration and suggest potential interactions and common mechanisms underlying different diseases. A deeper understating of this complex scenario may eventually lead to the identification of a better elucidation of the pathogenetic mechanisms of these devastating conditions and hopefully new therapeutic stragegies.}, } @article {pmid37918554, year = {2023}, author = {Mishra, D and Narain, P and Dave, U and Gomes, J}, title = {Role of ALS-associated OPTN-K489E mutation in neuronal cell-death regulation.}, journal = {Molecular and cellular neurosciences}, volume = {127}, number = {}, pages = {103904}, doi = {10.1016/j.mcn.2023.103904}, pmid = {37918554}, issn = {1095-9327}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neuroblastoma ; Mutation ; Cell Death ; Apoptosis/genetics ; }, abstract = {Optineurin (OPTN) gene is a marker of amyotrophic lateral sclerosis (ALS). However, the role of optineurin protein (OPTN) in ALS pathology is unclear, even though it is known to regulate autophagy, apoptosis, and other survival-death cellular processes. Genetic analysis of Indian ALS patients by our group ascertained a novel mutation K489E in the OPTN gene. To identify the molecular mechanism associated with OPTN and its mutation, we developed an in-vitro cell model using SH-SY5Y cells harbouring OPTN and OPTN-K489E mutation along with its control vector. Since we observed a significant decrease in cell viability in the mutant, we measured the expressions of genes and proteins mediating apoptosis, necroptosis, and autophagy, to establish the role of OPTN in cell death regulation. Our results show that OPTN-K489E mutation changes the relative gene expressions of miRNA-9, REST, CoREST and BDNF, and causes apoptosis. We also observed an up-regulation in the expressions of necroptosis mediated genes RIPK1, RIPK3, and MLKL and autophagy mediated genes TBK1, P62, and LC3II. The results of FACS analyses revealed that this mutation promotes apoptotic and necroptotic processes confirming the pathogenicity of OPTN-K489E.}, } @article {pmid37916886, year = {2024}, author = {Tang, L and Tang, X and Zhao, Q and Li, Y and Bu, Y and Liu, Z and Li, J and Guo, J and Shen, L and Jiang, H and Tang, B and Xu, R and Cao, W and Yuan, Y and Wang, J}, title = {Mutation and clinical analysis of the CLCC1 gene in amyotrophic lateral sclerosis patients from Central South China.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {1}, pages = {79-88}, pmid = {37916886}, issn = {2328-9503}, support = {2021YFA0805202//National Key Research and Development Program of China/ ; 81300981//National Natural Science Foundation of China/ ; 81671120//National Natural Science Foundation of China/ ; 82171431//National Natural Science Foundation of China/ ; 2020LNJJ13//the Project Program of National Clinical Research Center for Geriatric Disorders at Xiangya Hospital/ ; STI2030 Major Projects 2021ZD0201803//the Science and Technology Innovation 2030/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Mutation ; Mutation, Missense ; Genetic Association Studies ; China ; Chloride Channels/genetics ; }, abstract = {INTRODUCTION: Recently, chloride channel CLIC-like 1 (CLCC1) was reported to be a novel ALS-related gene. We aimed to screen CLCC1 variants in our ALS cohort and further explore the genotype-phenotype correlation of CLCC1-related ALS.

METHODS: We screened rare damaging variants in CLCC1 from our cohorts of 1005 ALS patients and 1224 healthy controls with whole-exome sequencing in Central South China. Fisher's exact test was conducted for association analysis at the entire gene level and single variant level.

RESULTS: In total, four heterozygous missense variants in CLCC1 were identified from four unrelated sporadic ALS patients and predicted to be putative pathogenic by in silico tools and protein model prediction, accounting for 0.40% of all patients (4/1005). The four variants were c.A275C (p.Q92P), c.G1139A (p.R380K), c.C1244T (p.T415M), and c.G1328A (p.R443Q), respectively, which had not been reported in ALS patients previously. Three of four variants were located in exon 10. Patients harboring CLCC1 variants seemed to share a group of similar clinical features, including earlier age at onset, rapid progression, spinal onset, and vulnerable cognitive status. Statistically, we did not find CLCC1 to be associated with the risk of ALS at the entire gene level or single variant level.

CONCLUSION: Our findings further expanded the genetic and clinical spectrum of CLCC1-related ALS and provided more genetic evidence for anion channel involvement in the pathogenesis of ALS, but further investigations are needed to verify our findings.}, } @article {pmid37915644, year = {2023}, author = {Kassahun Bekele, B and Kwizera, L and Abdul Razzak, R and Alfadul, ESA and Anand, A and Wojtara, M and Nazir, A and Uwishema, O}, title = {ALS in Africa: current knowledge and exciting opportunities for future study - short communication.}, journal = {Annals of medicine and surgery (2012)}, volume = {85}, number = {11}, pages = {5827-5830}, pmid = {37915644}, issn = {2049-0801}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that can present with motor and extra-motor manifestations. Its global prevalence is 4.42 per 1 000 000, and it has a high mortality rate. In sub-Saharan Africa alone, 15 per 100 000 develop ALS mainly between their 40s and 60s and only one-fourth of them have access to treatment. ALS was found to be not only affected by genetic variation but also by the patient's mood and lifestyle. In Africa, males and younger people tend to be affected with ALS and rarely present with bulbar onset. ALS diagnosis is very challenging due to the lack of ALS-specific biomarkers and the sharing of some clinical features with other syndromes. ALS treatment is mainly riluzole and supportive treatment via nasogastric tube and ventilatory support. The access to treatment in Africa is very limited, thus a very bad prognosis with a median survival time of 14 months post-diagnosis. Further research is needed to assess the real situation in Africa and to try to closely monitor patients suffering from ALS.}, } @article {pmid37915239, year = {2024}, author = {Lee, J and Yoon, D and Sung, KW and Bae, EJ and Park, DH and Suh, YH and Kwon, YT}, title = {Targeted degradation of SNCA/α-synuclein aggregates in neurodegeneration using the AUTOTAC chemical platform.}, journal = {Autophagy}, volume = {20}, number = {2}, pages = {463-465}, pmid = {37915239}, issn = {1554-8635}, mesh = {Mice ; Animals ; *alpha-Synuclein/metabolism ; Autophagy/physiology ; Ligands ; *Parkinson Disease/metabolism ; Brain/metabolism ; }, abstract = {Parkinson disease (PD) characterized by dopaminergic neuronal loss is caused by aggregation of misfolded SNCA/α-synuclein. We recently developed autophagy-targeting chimera (AUTOTAC), a targeted protein degradation (TPD) technology based on the macroautophagy/autophagy-lysosome pathway (ALP). In this study, we employed AUTOTAC to synthesize ATC161, a chimeric compound that adopts Anle138b as target-binding ligand (TBL) for SNCA aggregates. The autophagy-targeting ligand (ATL) of ATC161 was designed to allosterically activate the autophagy receptor SQSTSM1/p62 (sequestosome 1), a key step for targeting SNCA aggregates to the phagophore. The lysosomal degradation of SNCA aggregates by ATC161 acutely occurs at DC50 of 100-500 nM with no significant off-target degradation of monomeric SNCA. ATC161 protects cells from DNA and mitochondrial damage by SNCA aggregates. In PD model mice, oral administration of ATC161 decreases the level of SNCA aggregates and their propagation across brain regions, which mitigates glial inflammatory responses and improves muscle strength and locomotive activity. An Investigational New Drug (IND) was approved by the Korean Food and Drug Administration for a phase 1 clinical trial to treat PD, Alzheimer disease (AD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). We suggest that AUTOTAC provides a platform for drug discovery in proteinopathies and other diseases.}, } @article {pmid37914747, year = {2023}, author = {Sung, W and Kim, JA and Kim, YS and Park, J and Oh, KW and Sung, JJ and Ki, CS and Kim, YE and Kim, SH}, title = {An analysis of variants in TARDBP in the Korean population with amyotrophic lateral sclerosis: comparison with previous data.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {18805}, pmid = {37914747}, issn = {2045-2322}, mesh = {Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics/pathology ; Cohort Studies ; Genetic Testing ; Mutation ; Mutation, Missense ; Republic of Korea/epidemiology ; }, abstract = {The TARDBP gene variant is a known major cause of amyotrophic lateral sclerosis (ALS), with limited reports of Korean patients with ALS harboring the variants in TARDBP. This large cohort study introduces four ALS patients who share the p.M337V variant of the TARDBP, allowing for an investigation of clinical characteristics and prognosis by analyzing previously reported cases with the same variant. From November 2014 to August 2022, participants were recruited from two tertiary hospitals in Seoul, Korea. Clinical characteristics of patients diagnosed with ALS carrying the variant in TARDBP were evaluated. Previous articles demonstrating subjects' characteristics were reviewed. Four patients were identified with the pathogenic missense variant (c.1009A>G; p.M337V) in the TARDBP. The mean age of onset was 55 years old, and none of the patients showed severe cognitive impairment. Sixty-three patients carrying the p.M337V variant in TARDBP from this study and previous reports delineated young age of onset (51.6 years), high frequency of bulbar onset patients (61.9%), and low comorbidity of frontotemporal dementia. This study reveals the presence of pathogenic variant of TARDBP in Korea and emphasizes the importance of genetic screening of the TARDBP gene, in diagnosing ALS and evaluating prognosis among familial and simplex ALS patients in Korea.}, } @article {pmid37913752, year = {2023}, author = {Chou, PY and Chen, CM and Wang, CC and Tai, CJ and Lin, YK and Tang, YJ}, title = {Characteristics and Effects of Chinese Herbal Medicine in the Management of Female Infertility: A Hospital-Based Study.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {481-491}, doi = {10.1159/000534590}, pmid = {37913752}, issn = {2504-2106}, mesh = {Humans ; Female ; Retrospective Studies ; *Drugs, Chinese Herbal/therapeutic use ; *Infertility, Female/therapy ; Treatment Outcome ; Hospitals ; }, abstract = {BACKGROUND: In Taiwan, Chinese herbal medicine (CHM) is used to treat female infertility. Evidence indicates that the absence of monotherapy efficacy assessment and comparison with mainstream interventions may lead to the improper use of CHM for female infertility.

METHODS: A retrospective cohort study enrolled female patients at a hospital undergoing CHM intervention to treat infertility from 2012 to 2020 in order to determine the outcomes of CHM monotherapy for female infertility. Kaplan-Meier analysis under strict assumptions was used to estimate the cumulative probability of pregnancy and live births after CHM. Cox hazard regression analysis was used to estimate the hazard ratios of prognostic variables, namely, the woman's age and diagnostic category.

RESULTS: 694 women met the inclusion criteria and accounted for 2,145 cycles. A total of 190 pregnancies resulted in 125 live births, all of which were singleton births of babies with 16 perinatal complications requiring hospitalization. The real cumulative pregnancy rate and cumulative live birth rate (CLBR) for the total population after 10 cycles were between 27.4% and 35.2% and between 18% and 22.1%, respectively. Compared with the live birth rate corresponding to patients aged under 35 years, that of older patients, particularly those aged 38-39 years, was significantly lower (hazard ratio: 0.19, 95% confidence interval: 0.11-0.33). Women with other diagnoses, namely, uterine problems or endometriosis, had a greater probability of a live birth than did women with tubal pathology (hazard ratio: 6.31, 95% confidence interval: 1.99-20.07).

CONCLUSION: To the best of our knowledge, this is the first retrospective study to employ life table analysis to determine the CHM treatment outcomes in terms of female infertility. The study established a basis to compare in vitro fertilization (IVF) with CHM and identified the advantages and disadvantages of CHM for treating female infertility. Although the CLBR of present study is lower than those reported in IVF studies, CHM in treating female infertility can still be beneficial to women aged younger than 38 years or with diagnoses other than tubal pathology and worth recommendation by reproductive specialists according to the promising results gained from the strict criteria. However, in order to determine the optimal timing, possible mechanism, corresponding side effects, and the efficacy of CHM combined with IVF for treating female infertility, rigorous research is required.

UNLABELLED: HintergrundIn Taiwan wird die chinesische Heilpflanzenmedizin (CHM) zur Behandlung weiblicher Infertilität angewendet. Es liegen Hinweise vor, nach denen fehlende Wirksamkeitsbeurteilungen der Monotherapien und Vergleiche mit herkömmlichen Interventionen zu einer unsachgemäßen Anwendung von CHM bei weiblicher Infertilität führen können.MethodenEine retrospektive Kohortenstudie schloss Patientinnen eines Krankenhauses ein, die von 2012 bis 2020 wegen Infertilität mit CHM behandelt wurden, um die Behandlungsergebnisse der CHM-Monotherapie bei weiblicher Infertilität zu ermitteln. Zur Schätzung der kumulativen Wahrscheinlichkeit von Schwangerschaften und Lebendgeburten nach einer CHM-Behandlung wurde die Kaplan-Meier-Analyse unter strengen Annahmen verwendet. Mit Hilfe der Cox-Hazard-Regressionsanalyse wurden die Risikoverhältnisse der prognostischen Variablen Alter der Frau und Diagnosekategorie geschätzt.Ergebnisse694 Frauen erfüllten die Einschlusskriterien und die Zahl der Zyklen betrug 2,145. Insgesamt 190 Schwangerschaften führten zu 125 Lebendgeburten, allesamt Einlingsgeburten, mit 16 perinatalen Komplikationen, die eine Hospitalisierung erforderten. Die reale kumulative Schwangerschaftsrate und die kumulative Lebendgeburtenrate (cumulative live birth rate, CLBR) für die Gesamtpopulation nach 10 Zyklen lagen zwischen 27.4% und 35.2% bzw. zwischen 18% und 22.1%. Die Lebendgeburtenrate bei älteren Patientinnen, insbesondere im Alter von 38 bis 39 Jahren, war deutlich niedriger als bei Patientinnen unter 35 Jahren (Hazard Ratio: 0.19, 95%-Konfidenzintervall: 0.11–0.33). Bei Frauen mit anderen Diagnosen wie Gebärmutterproblemen oder Endometriose war die Wahrscheinlichkeit einer Lebendgeburt höher als bei Frauen mit Eileitererkrankungen (Hazard Ratio: 6.31, 95%-Konfidenzintervall: 1.99–20.07).SchlussfolgerungUnseres Wissens ist dies die erste retrospektive Studie, in der die Ergebnisse der CHM-Behandlung bei weiblicher Infertilität mittels Sterbetafelanalyse ermittelt wurden. Die Studie bildet eine Grundlage für den Vergleich von In-vitro-Fertilisation (IVF) mit CHM und zeigt die Vor- und Nachteile der CHM zur Behandlung weiblicher Infertilität auf. Zwar fällt die kumulative Lebendgeburtenrate in der vorliegenden Studie niedriger aus als in IVF-Studien, doch kann die CHM bei der Behandlung weiblicher Infertilität für Frauen unter 38 Jahren oder Frauen, die eine andere Diagnose als eine Eileitererkrankung haben, von Nutzen sein und angesichts der vielversprechenden Ergebnisse, die aus den strengen Kriterien gewonnen wurden, ist sie eine Empfehlung durch Reproduktionsspezialisten wert. Allerdings sind rigorose Forschungsarbeiten erforderlich, um die optimale Zeitplanung, den möglichen Mechanismus, die entsprechenden Nebenwirkungen und die Wirksamkeit der CHM in Kombination mit IVF zur Behandlung der weiblichen Infertilität zu ermitteln.}, } @article {pmid37910649, year = {2025}, author = {Franklin, JE}, title = {Palliative hypnosis approaches in the symptomatic treatment of amyotrophic lateral sclerosis (ALS).}, journal = {The American journal of clinical hypnosis}, volume = {67}, number = {1}, pages = {54-68}, doi = {10.1080/00029157.2023.2252875}, pmid = {37910649}, issn = {2160-0562}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Hypnosis/methods ; *Palliative Care/methods ; Male ; Middle Aged ; Aged ; Female ; Veterans/psychology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, incurable, and ultimately fatal, devastating, progressive degenerative neurologic disease. It causes upheaval in the lives of patients and family caregivers alike. Palliative care can play an important supportive role in the care of patients and families dealing with the devastation of this illness. Clinical hypnosis has demonstrated benefits in treating the symptoms associated with severe chronic illness. There are, however, few studies looking at the benefits of clinical hypnosis in treating the symptom burden of ALS. This article describes palliative care and how it can provide an additional layer of support to seriously ill patients. A brief review of previous studies of hypnosis in the supportive, symptomatic treatment of ALS is provided, followed by a description of a case series of 30 Veterans who received clinical hypnosis and self-hypnosis training as a complementary treatment for the symptoms of ALS. Details of three case histories are included to highlight and discuss specific strategies and emblematic clinical responses. There is evidence that clinical hypnosis can benefit ALS patients and family caregivers struggling with this devastating illness.}, } @article {pmid37910562, year = {2023}, author = {Lugg, A and Schindle, M and Sivak, A and Tankisi, H and Jones, KE}, title = {Nerve excitability measured with the TROND protocol in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neurophysiology}, volume = {130}, number = {6}, pages = {1480-1491}, doi = {10.1152/jn.00174.2023}, pmid = {37910562}, issn = {1522-1598}, support = {RGPIN-2017-05624//Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; }, mesh = {Humans ; Action Potentials/physiology ; *Amyotrophic Lateral Sclerosis ; Axons/physiology ; Biomarkers ; Prospective Studies ; Clinical Protocols ; }, abstract = {This meta-analysis assessed the 30+ nerve excitability indices generated by the TROND protocol to identify potential biomarkers for amyotrophic lateral sclerosis (ALS). A comprehensive search was conducted in multiple databases to identify human studies that tested median motor axons. Forest plot analyses were performed using a random-effects model to determine the pooled effect (Z-score), heterogeneity (I[2]), and Cohen's d for potential biomarker identification. Out of 2,866 studies, 23 studies met the inclusion criteria, incorporating data from 719 controls and 942 patients with ALS. Seven indices emerged as potential biomarkers: depolarizing threshold electrotonus (TEd) 90-100 ms, strength-duration time constant (SDTC), superexcitability, TEd 40-60 ms, resting I/V slope, 50% depolarizing I/V, and subexcitability (ranked by the magnitude of the difference between patients and controls from largest to smallest). In a sensitivity analysis focusing on patients with larger compound muscle action potentials (CMAPs), only four indices were potential biomarkers: TEd 10-20 ms, TEd 90-100 ms, superexcitability, and SDTC. Among the extensive range of 30+ excitability indices generated by the TROND protocol, we have identified seven indices that effectively differentiate patients with ALS from healthy controls. Furthermore, a smaller subset of four indices shows promise as potential biomarkers when the CMAP remains relatively large. However, most studies were considered to be at moderate risk of bias due to case-control designs and absence of sensitivity and specificity calculations, underscoring the need for more prospective diagnostic test-accuracy studies with appropriate disease controls.NEW & NOTEWORTHY This meta-analysis uncovers seven potential axonal excitability biomarkers for lower motor neuron pathology in ALS, shedding light on ion channel dysfunction. The identified dysfunction aligns with the primary pathology-protein homeostasis disruption. These biomarkers could fill a gap to detect presymptomatic spread of the disease in the spinal cord and monitor treatments targeting protein homeostasis and limiting spread, toward enhancing patient care.}, } @article {pmid37910250, year = {2024}, author = {Khamaysa, M and Lefort, M and Pélégrini-Issac, M and Lackmy-Vallée, A and Mendili, MME and Preuilh, A and Devos, D and Bruneteau, G and Salachas, F and Lenglet, T and Amador, MM and Le Forestier, N and Hesters, A and Gonzalez, J and Rolland, AS and Desnuelle, C and Chupin, M and Querin, G and Georges, M and Morelot-Panzini, C and Marchand-Pauvert, V and Pradat, PF and , }, title = {Quantitative brainstem and spinal MRI in amyotrophic lateral sclerosis: implications for predicting noninvasive ventilation needs.}, journal = {Journal of neurology}, volume = {271}, number = {3}, pages = {1235-1246}, pmid = {37910250}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/therapy/complications ; *Noninvasive Ventilation/methods ; Disease Progression ; Magnetic Resonance Imaging/methods ; Brain Stem/diagnostic imaging ; }, abstract = {BACKGROUND: Respiratory complications resulting from motor neurons degeneration are the primary cause of death in amyotrophic lateral sclerosis (ALS). Predicting the need for non-invasive ventilation (NIV) in ALS is important for advance care planning and clinical trial design. The aim of this study was to assess the potential of quantitative MRI at the brainstem and spinal cord levels to predict the need for NIV during the first six months after diagnosis.

METHODS: Forty-one ALS patients underwent MRI and spirometry shortly after diagnosis. The need for NIV was monitored according to French health guidelines for 6 months. The performance of four regression models based on: clinical variables, brainstem structures volumes, cervical spinal measurements, and combined variables were compared to predict the need for NIV within this period.

RESULTS: Both the clinical model (R[2] = 0.28, AUC = 0.85, AICc = 42.67, BIC = 49.8) and the brainstem structures' volumes model (R[2] = 0.30, AUC = 0.85, AICc = 40.13, BIC = 46.99) demonstrated good predictive performance. In addition, cervical spinal cord measurements model similar performance (R[2] = 0.338, AUC = 0.87, AICc = 37.99, BIC = 44.49). Notably, the combined model incorporating predictors from all three models yielded the best performance (R[2] = 0.60, AUC = 0.959, AICc = 36.38, BIC = 44.8). These findings are supported by observed positive correlations between brainstem volumes, cervical (C4/C7) cross-sectional area, and spirometry-measured lung volumes.

CONCLUSIONS: Our study shows that brainstem volumes and spinal cord area are promising measures to predict respiratory intervention needs in ALS.}, } @article {pmid37909610, year = {2023}, author = {Reis, AHO and Figalo, LB and Orsini, M and Lemos, B}, title = {The implications of DNA methylation for amyotrophic lateral sclerosis.}, journal = {Anais da Academia Brasileira de Ciencias}, volume = {95}, number = {suppl 2}, pages = {e20230277}, doi = {10.1590/0001-3765202320230277}, pmid = {37909610}, issn = {1678-2690}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; DNA Methylation/genetics ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex and serious neurodegenerative disorder that develops in consequence of the progressive loss of the upper and lower motor neurons. Cases of ALS are classified as sporadic (sALS), or familial (fALS). Over 90% of cases are sALS, while roughly 10% are related to inherited genetic mutations (fALS). Approximately 70% of the genetic mutations that contribute to fALS have been identified. On the other hand, the majority of the sALS cases have an undetermined genetic contributor and few mutations have been described, despite the advanced genetic analysis methods. Also, several factors contribute to the onset and progression of ALS. Numerous lines of evidence indicate that epigenetic changes are linked to aging, as well as neurodegenerative disorders, such as ALS. In most cases, they act as the heritable regulation of transcription by DNA methylation, histone modification and expression of noncoding RNAs. Mechanisms involving aberrant DNA methylation could be relevant to human ALS pathobiology and therapeutic targeting. Despite advances in research to find factors associated with ALS and more effective treatments, this disease remains complex and has low patient survival. Here, we provide a narrative review of the role of DNA methylation for this complex neurodegenerative disorder.}, } @article {pmid37909302, year = {2024}, author = {Chen, S and Carter, D and Brockenbrough, PB and Cox, S and Gwathmey, K}, title = {Racial disparities in ALS diagnostic delay: a single center's experience and review of potential contributing factors.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {112-118}, doi = {10.1080/21678421.2023.2273361}, pmid = {37909302}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Delayed Diagnosis ; Retrospective Studies ; Vital Capacity ; }, abstract = {OBJECTIVE: Outcomes for amyotrophic lateral sclerosis (ALS) patients are improved with prompt diagnosis, earlier initiation of disease-modifying treatments, and participation in a multidisciplinary clinic. We studied diagnostic delay and disease severity at time of clinic presentation between Black and non-Hispanic Caucasian ALS patients.

METHODS: We performed a retrospective analysis of non-Hispanic Caucasian and Black ALS patients seen in the Virginia Commonwealth University Health System multidisciplinary ALS clinic between 2017 and 2023. Diagnostic delay, ALS Functional Rating Scale-Revised (ALSFRS-R) and upright forced vital capacity (FVC) scores at baseline appointment were collected. Patient's distance from clinic and affluency of residential neighborhood were evaluated.

RESULTS: We analyzed 172 non-Hispanic Caucasian and 33 Black ALS patients. Black patients had a 64% increase in diagnostic delay compared to non-Hispanic Caucasian patients. Black patients had a lower performance on ALSFRS-R (5.3 points, p < 0.001) and FVC (17.9 percentage points p < 0.001) at time of first clinic visit. Black patients lived closer to clinic, with higher proportion living in the city of Richmond, but in less affluent areas with lower median house income ($55,300 ± 22,600 vs $69,900 ± 23,700).

DISCUSSION: Our findings demonstrate a large racial difference in ALS diagnostic delay, and greater disease severity and lower respiratory function at time of diagnosis for Black ALS patients. Delay in diagnosis prolongs access to disease-modifying therapies, multidisciplinary care, durable medical equipment, and respiratory and nutritional support. Potential sources of these racial disparities include providers' implicit bias and structural racism.}, } @article {pmid37908143, year = {2024}, author = {Azad, A and Gökmen, ÜR and Uysal, H and Köksoy, S and Bilge, U and Manguoğlu, AE}, title = {Autophagy dysregulation plays a crucial role in regulatory T-cell loss and neuroinflammation in amyotrophic lateral sclerosis (ALS).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {336-344}, doi = {10.1080/21678421.2023.2273365}, pmid = {37908143}, issn = {2167-9223}, mesh = {Humans ; *T-Lymphocytes, Regulatory/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Neuroinflammatory Diseases ; Autophagy ; Forkhead Transcription Factors/metabolism ; }, abstract = {OBJECTIVE: Neuroinflammation is the hallmark of amyotrophic lateral sclerosis (ALS) disease. Regulatory T cells (Tregs) are essential in immune tolerance and neuroinflammation prevention. It has been shown that a significant decrease in Treg and FoxP3 protein expression is observed in ALS patients. The main reason for the FoxP3[+] Treg loss in ALS is unknown. In this study, the role of autophagy dysregulation in FoxP3[+] Tregs in ALS was investigated.

METHODS: Twenty-three ALS patients and 24 healthy controls were recruited for the study. Mononuclear cells (MNCs) were obtained from peripheral blood, and then Tregs were isolated. Isolated Tregs were stained with FoxP3 and LC3 antibodies and analyzed in flow cytometry to determine autophagy levels in FoxP3[+] Tregs in patients and controls.

RESULTS: The mean of FoxP3[+] LC3[+] cells, were 0.47 and 0.45 in patients and controls, respectively. The mean of FoxP3[+] LC3- cells was 0.15 in patients and 0.20 in controls, p = 0.030 (p < 0.05). There is no significant correlation between ALSFRS-R decay rate and autophagy level in patients. Also, there is no significant difference between autophagy levels in FoxP3[+] Tregs in patients with rapidly progressing ALS and slow-progressing ALS.

CONCLUSION: Excessive autophagy levels in FoxP3[+] Tregs in ALS patients can potentially be an explanation for an increased cell death and result in worsened neuroinflammation and disease onset. However, the disease progress is not attributable to autophagy levels in FoxP3[+] Tregs.}, } @article {pmid37907717, year = {2024}, author = {Yamamoto, K and Itoi, T and Matsunami, Y and Sofuni, A and Tsuchiya, T and Mukai, S and Kojima, H and Minami, H and Nakatsubo, R and Tonozuka, R}, title = {Early and late effects of endoscopic interventions in patients with malignant afferent loop syndrome: A single-center experience and literature review.}, journal = {Journal of hepato-biliary-pancreatic sciences}, volume = {31}, number = {2}, pages = {120-132}, doi = {10.1002/jhbp.1380}, pmid = {37907717}, issn = {1868-6982}, mesh = {Humans ; *Afferent Loop Syndrome/diagnostic imaging/etiology/surgery ; *Cholestasis/etiology ; Drainage ; Endoscopy ; Endosonography ; Liver/pathology ; Retrospective Studies ; Stents/adverse effects ; Treatment Outcome ; }, abstract = {BACKGROUND/PURPOSE: Afferent loop syndrome (ALS) is a rare adverse event after gastrointestinal surgery requiring appropriate early decompression treatment. Several endoscopic interventions have been attempted for treatment, including endoscopic enteral metal stent placement (EMSP), endoscopic ultrasound (EUS)-guided entero-enterostomy (EUS-EE), and EUS-guided hepaticogastrostomy (EUS-HGS). However, there are limited data on outcomes, including duration of stent patency. In this study, we evaluated the usefulness of each endoscopic intervention for malignant ALS.

METHODS: We retrospectively investigated nine patients with malignant ALS who underwent EMSP, EUS-EE, or EUS-HGS. Information on technical success, clinical efficacy, adverse events, stent dysfunction, and overall survival was collected and analyzed.

RESULTS: The most common symptoms were abdominal pain and cholangitis. ALS was treated by EMSP in three patients, EUS-EE in three patients, and EUS-HGS in three patients. Stent placement was successful and clinically effective in all patients with no adverse events. During follow-up, stent dysfunction occurred in two patients treated by EUS-HGS. Eight patients died of primary disease during a median follow-up of 157 days.

CONCLUSIONS: Each of the available endoscopic interventions for malignant ALS can be expected to produce similar outcomes, including duration of stent patency. The choice of endoscopic intervention should be made based on the characteristics of each treatment.}, } @article {pmid37907134, year = {2023}, author = {Birajdar, SV and Mazahir, F and Alam, MI and Kumar, A and Yadav, AK}, title = {Repurposing and clinical attributes of antidiabetic drugs for the treatment of neurodegenerative disorders.}, journal = {European journal of pharmacology}, volume = {961}, number = {}, pages = {176117}, doi = {10.1016/j.ejphar.2023.176117}, pmid = {37907134}, issn = {1879-0712}, mesh = {Humans ; Mice ; Animals ; Hypoglycemic Agents/pharmacology/therapeutic use ; Amyloid beta-Peptides/metabolism ; *Diabetes Mellitus, Type 2/drug therapy ; Drug Repositioning ; Neuroinflammatory Diseases ; *Alzheimer Disease/drug therapy ; Insulin/metabolism ; *Metformin/pharmacology ; }, abstract = {The risk of neurodegeneration was found to be increased among people with type 2 diabetes mellitus (T2DM). Brain disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and others are considered neurodegenerative diseases and can be characterized by progressive loss of neurons. The deficiency of insulin, impaired signaling, and its resistance lead to alteration in the neuronal functioning of the brain. Insulin degrading enzyme (IDE) plays a significant role in the amyloid β metabolism, aggregation, and deposition of misfolded proteins in the brain's hippocampal and cortical neuronal regions. The insulin signaling via IP3 activation upregulates the IDE and could be a promising approach to regulate neurodegeneration. The repurposing of existing antidiabetic drugs such as Metformin, DPP-4 inhibitors, thiazolidinediones, glucagon-like peptides (GLP-1), sodium-glucose co-transport-2 (SGCT-2) inhibitors, and insulin could be an alternative and effective strategy to treat neurodegeneration via modulating insulin signaling, insulin resistance, IDE activity, oxidative stress, mitochondrial dysfunction, serum lipid profile and neuroinflammation in the brain. Antidiabetic medications reduce the risk of neuroinflammation, oxidative stress, and Aβ deposition by enhancing their clearance rate. The downregulation of IDE alters the degradation of Aβ monomers in the Tg2576 APP mice. Also, the treatment with metformin activated the AMPK pathway and suppressed mTOR and BACE-1 protein expression in the APP/PS1-induced mice model. Thus, the primary intention of this review is to explore the link between T2DM and neurodegenerative disorders, and the possible role of various antidiabetic drugs in the management of neurodegenerative disorders.}, } @article {pmid37906991, year = {2023}, author = {Prohaska, S and Matthias, K}, title = {Effectiveness of Mindfulness-Based Stress Reduction as a Nondrug Preventive Intervention in Patients with Migraine: A Systematic Review with Meta-Analyses.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {525-534}, doi = {10.1159/000534653}, pmid = {37906991}, issn = {2504-2106}, mesh = {Adult ; Humans ; *Mindfulness ; Treatment Outcome ; *Migraine Disorders/prevention & control ; Headache ; Stress, Psychological ; }, abstract = {INTRODUCTION: Migraine is a neurological disorder characterized by recurrent, severe headaches that are often accompanied by other symptoms. There are various factors that can trigger a migraine in sufferers. Stress can be such a trigger. Drug and nondrug treatments are available for the preventive treatment of migraine. According to a German guideline, mindfulness can be recommended for the prophylaxis of migraine. Therefore, the aim was to investigate the effectiveness of mindfulness-based stress reduction (MBSR) in relation to patient-relevant outcomes in adult patients with migraine. Patient-relevant outcomes in this context are migraine frequency, headache intensity during a migraine attack, depressive symptoms, and quality of life.

MATERIAL AND METHODS: The conduct of this study was guided by the PRISMA 2020 statement. A systematic literature search for randomized controlled trials (RCTs) of the effectiveness of MBSR in adult migraine patients was conducted in December 2021 in three databases: MEDLINE via PubMed, the Cochrane Library, and Web of Science. In addition, a review of reference lists and a search of study registries were performed. The last search was conducted on October 7, 2022. In a two-step process, studies were selected based on predefined inclusion and exclusion criteria. The potential for bias was assessed using the Cochrane Risk of Bias Tool 2. The results were summarized descriptively and by means of quantitative synthesis.

RESULTS: Four RCTs with a total of 275 patients and the follow-up publication of one of these studies were included. The risk of bias in one study each was judged to be low or of some concern and high in two studies. Four studies were included in the quantitative analysis. For the endpoint migraine frequency, the meta-analytic summary of three studies failed to show a statistically significant benefit for MBSR (SMD: -0.23; 95% CI: -0.79 to 0.32). For the endpoint depressive symptoms, a meta-analytic summary of three studies showed a statistically significant benefit for MBSR (SMD: -0.59; 95% CI: -0.93 to -0.25). No study had examined the severity of headaches during a migraine episode.

CONCLUSION: Some results suggest that migraine patients may benefit from MBSR. However, the evidence base is currently insufficient for recommendations on the use of MBSR as a nondrug treatment option. Further adequately powered, high-quality RCTs are needed.

UNLABELLED: EinleitungMigräne ist eine neurologische Erkrankung, die durch wiederkehrende, starke Kopfschmerzen gekennzeichnet ist, die häufig von anderen Symptomen einhergehen. Es gibt verschiedene Faktoren, die bei den Betroffenen eine Migräne auslösen können. Ein solcher Auslöser kann Stress sein. Für die präventive Behandlung der Migräne stehen medikamentöse und nichtmedikamentöse Verfahren zur Verfügung. Laut einer deutschen Leitlinie kann Achtsamkeit zur Prophylaxe von Migräne empfohlen werden. Ziel der Studie war es daher, die Wirksamkeit von achtsamkeitsbasierter Stressreduktion (MBSR) in Bezug auf patientenrelevante Outcomes bei erwachsenen Migränepatienten zu untersuchen. Patientenrelevante Outcomes in diesem Zusammenhang sind Migränehäufigkeit, Kopfschmerzintensität während einer Migräneattacke, depressive Symptome und Lebensqualität.MethodenDie Durchführung dieser Studie orientierte sich am PRISMA-Statement. Eine systematische Literatursuche nach randomisierten kontrollierten Studien zur Wirksamkeit von MBSR bei erwachsenen Migränepatienten wurde im Dezember 2021 in drei Datenbanken durchgeführt: MEDLINE über PubMed, die Cochrane Library und Web of Science. Darüber hinaus wurden Referenzlisten und Studienregister durchsucht. Die letzte Suche erfolgte am 7. Oktober 2022. In einem zweistufigen Verfahren wurden die Studien anhand von vordefinierten Ein- und Ausschlusskriterien ausgewählt. Das Verzerrungspotential der Studien wurde mit dem Cochrane Risk of Bias Tool 2 bewertet. Die Ergebnisse wurden deskriptiv und mit Hilfe einer quantitativen Synthese zusammengefasst.ErgebnisseEs wurden vier randomisiert-kontrollierte Studien mit insgesamt 275 Patienten und die Nachfolgepublikation einer dieser Studien eingeschlossen. Das Verzerrungspotential wurde bei je einer Studie als gering oder bedenklich und bei zwei Studien als hoch eingestuft. Vier Studien wurden in die quantitative Analyse einbezogen. Für den Endpunkt Migränehäufigkeit ergab die metaanalytische Zusammenfassung von drei Studien keinen statistisch signifikanten Vorteil für MBSR (SMD −0.23; 95% CI −0.79 bis 0.32). Für den Endpunkt depressive Symptome zeigte eine metaanalytische Zusammenfassung von drei Studien einen statistisch signifikanten Vorteil für MBSR (SMD −0.59; 95% CI −0.93 bis −0.25). Keine Studie hatte die Schwere der Kopfschmerzen während einer Migräneepisode untersucht.SchlussfolgerungEinige Ergebnisse deuten darauf hin, dass Migränepatienten von MBSR profitieren können. Allerdings ist die Evidenzbasis derzeit nicht ausreichend, um Empfehlungen für den Einsatz von MBSR als nichtmedikamentöse Behandlungsoption abzuleiten. Es werden daher weitere qualitativ hochwertige randomisiert-kontrollierte Studien mit ausreichender statistischer Power benötigt.}, } @article {pmid37906785, year = {2022}, author = {Matamala, JM and Moreno-Roco, J and Acosta, I and Hughes, R and Lillo, P and Casar, JC and Earle, N}, title = {[Multidisciplinary care and therapeutic advances in amyotrophic lateral sclerosis].}, journal = {Revista medica de Chile}, volume = {150}, number = {12}, pages = {1633-1646}, doi = {10.4067/s0034-98872022001201633}, pmid = {37906785}, issn = {0717-6163}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/psychology ; *Neurodegenerative Diseases ; Quality of Life ; Palliative Care ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that mainly affects the motor system, resulting in progressive weakness and muscle wasting. Despite the tremendous advances in physiopathological and clinical characterization, we do not have a curative treatment yet. The progressive and fatal course of ALS makes its management particularly complex and challenging given the diversity of symptoms presenting during the disease progression. The main goal in the treatment of ALS patients is to minimize morbidity and maximize the quality of life. Currently, a series of therapeutic interventions improve the quality of life and prolong survival, including multidisciplinary care, respiratory management, and disease-modifying therapy. Within the supportive interventions, weight maintenance through nutritional and metabolic support is critical. In addition, the management of neuropsychiatric manifestations and preservation of communicative capacity before speech loss are also crucial. Lastly, early palliative care intervention is essential to optimize symptomatic management. Anticipatory guidelines to face the inevitable patient deterioration should be devised. This article updates the main therapeutic strategies used in these patients, including evolving clinical trials with promising novel therapies.}, } @article {pmid37906538, year = {2023}, author = {Dong, H and Zhang, H and Jalin, J and He, Z and Wang, R and Huang, L and Liu, Z and Zhang, S and Dai, B and Li, D}, title = {Nucleocapsid proteins from human coronaviruses possess phase separation capabilities and promote FUS pathological aggregation.}, journal = {Protein science : a publication of the Protein Society}, volume = {32}, number = {12}, pages = {e4826}, pmid = {37906538}, issn = {1469-896X}, support = {32170683//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Nucleocapsid Proteins/genetics/metabolism ; Amyloid/metabolism ; Amyloidogenic Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; SARS-CoV-2/genetics/metabolism ; RNA-Binding Protein FUS/chemistry ; }, abstract = {The nucleocapsid (N) protein is an essential structural component necessary for genomic packaging and replication in various human coronaviruses (HCoVs), such as SARS-CoV-2 and MERS-CoV. Recent studies have revealed that the SARS-CoV-2 N protein exhibits a high capacity for liquid-liquid phase separation (LLPS), which plays multiple roles in viral infection and replication. In this study, we systematically investigate the LLPS capabilities of seven homologous N proteins from different HCoVs using a high-throughput protein phase separation assay. We found that LLPS is a shared intrinsic property among these N proteins. However, the phase separation profiles of the various N protein homologs differ, and they undergo phase separation under distinct in vitro conditions. Moreover, we demonstrate that N protein homologs can co-phase separate with FUS, a SG-containing protein, and accelerate its liquid-to-solid phase transition and amyloid aggregation, which is closely related to amyotrophic lateral sclerosis. Further study shows that N protein homologs can directly bind to the low complexity domain of FUS. Together, our work demonstrates that N proteins of different HCoVs possess phase separation capabilities, which may contribute to promoting pathological aggregation of host proteins and disrupting SG homeostasis during the infection and replication of various HCoVs.}, } @article {pmid37905874, year = {2024}, author = {Abyadeh, M and Gupta, V and Paulo, JA and Mahmoudabad, AG and Shadfar, S and Mirshahvaladi, S and Gupta, V and Nguyen, CTO and Finkelstein, DI and You, Y and Haynes, PA and Salekdeh, GH and Graham, SL and Mirzaei, M}, title = {Amyloid-beta and tau protein beyond Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {19}, number = {6}, pages = {1262-1276}, pmid = {37905874}, issn = {1673-5374}, support = {R01 GM132129/GM/NIGMS NIH HHS/United States ; }, abstract = {The aggregation of amyloid-beta peptide and tau protein dysregulation are implicated to play key roles in Alzheimer's disease pathogenesis and are considered the main pathological hallmarks of this devastating disease. Physiologically, these two proteins are produced and expressed within the normal human body. However, under pathological conditions, abnormal expression, post-translational modifications, conformational changes, and truncation can make these proteins prone to aggregation, triggering specific disease-related cascades. Recent studies have indicated associations between aberrant behavior of amyloid-beta and tau proteins and various neurological diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as retinal neurodegenerative diseases like Glaucoma and age-related macular degeneration. Additionally, these proteins have been linked to cardiovascular disease, cancer, traumatic brain injury, and diabetes, which are all leading causes of morbidity and mortality. In this comprehensive review, we provide an overview of the connections between amyloid-beta and tau proteins and a spectrum of disorders.}, } @article {pmid37905867, year = {2024}, author = {Xiong, W and Lu, L and Li, J}, title = {Long non-coding RNAs with essential roles in neurodegenerative disorders.}, journal = {Neural regeneration research}, volume = {19}, number = {6}, pages = {1212-1220}, pmid = {37905867}, issn = {1673-5374}, abstract = {Recently, with the advent of high-resolution and high-throughput sequencing technologies, an increasing number of long non-coding RNAs (lncRNAs) have been found to be involved in the regulation of neuronal function in the central nervous system with specific spatiotemporal patterns, across different neurodegenerative diseases. However, the underlying mechanisms of lncRNAs during neurodegeneration remain poorly understood. This review provides an overview of the current knowledge of the biology of lncRNAs and focuses on introducing the latest identified roles, regulatory mechanisms, and research status of lncRNAs in Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Finally, this review discusses the potential values of lncRNAs as diagnostic biomarkers and therapeutic targets for neurodegenerative diseases, hoping to provide broader implications for developing effective treatments.}, } @article {pmid37905864, year = {2024}, author = {Cauchi, RJ}, title = {SCFD1 in amyotrophic lateral sclerosis: reconciling a genetic association with in vivo functional analysis.}, journal = {Neural regeneration research}, volume = {19}, number = {6}, pages = {1201-1202}, pmid = {37905864}, issn = {1673-5374}, } @article {pmid37905855, year = {2024}, author = {Claud, K and Sun, J}, title = {Metabolites and micronutrition in modulating amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {6}, pages = {1183-1184}, pmid = {37905855}, issn = {1673-5374}, } @article {pmid37904275, year = {2024}, author = {Kacem, I and Sghaier, I and Peverelli, S and Abida, Y and Ben Brahim, H and Ratti, A and Nasri, A and Ticozzi, N and Silani, V and Gouider, R}, title = {Optineurin in patients with Amyotrophic Lateral Sclerosis associated to atypical Parkinsonism in Tunisian population.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {128-134}, doi = {10.1080/21678421.2023.2273961}, pmid = {37904275}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Family ; *Frontotemporal Dementia/genetics ; Mutation/genetics ; *Parkinson Disease ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous disorder and the phenotypic variability goes far beyond the used clinical stratification parameter. Evidence has emerged that ALS may coexist with distinct neurodegenerative diseases in single cases. We aim to study the clinical features of two familial cases of ALS carriers of two distinct variants harbored in the Optineurin (OPTN) gene. We included definite familial ALS followed up in the Department of Neurology of Razi University Hospital, Tunisia, and selected according to Byrne criteria. Preliminary screening for the four main ALS genes (SOD1, C9ORF72, TARDBP, FUS) was conducted. Given the negative results, we proceeded to NGS target-re-sequencing with a custom panel including genes associated with ALS-FTD, Alzheimer's, and Parkinson's diseases. Both families are carriers of two different OPTN variants and they present very different ALS clinical features. The first family comprises two siblings diagnosed with ALS and Corticobasal syndrome (ALS-CBS) at an early age of onset and carriers of OPTN p.E135X in the homozygous state. The proband for the second family was diagnosed with ALS at an early age of onset presenting as progressive muscular atrophy with rapid progression. Genetic analysis revealed the presence of the homozygous variant p.R520H. Our findings highlight the peculiarity of genetic Tunisian drift. Indeed, genes with a recessive mode of inheritance may explain part of ALS diversity in clinical features. Therefore, the screening of the OPTN gene is highly recommended among inbreeding populations such as the Tunisian one.}, } @article {pmid37904013, year = {2024}, author = {Chen, X and Luo, J and Zheng, W and Huang, Q and Du, C and Yuan, H and Xiao, F}, title = {Hyperhidrosis as the initial symptom in FUS mutation-associated amyotrophic lateral sclerosis: a case report and comprehensive literature review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {4}, pages = {1523-1527}, pmid = {37904013}, issn = {1590-3478}, mesh = {Female ; Humans ; Young Adult ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/genetics ; *Hyperhidrosis/genetics ; Mutation ; *Neurodegenerative Diseases ; Quality of Life ; RNA-Binding Protein FUS/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is now recognized to involve autonomic dysfunction. The burden of autonomic dysfunction is an important factor in the quality of life and prognosis of ALS patients. This article presents the clinical characteristics of a young female ALS patient with a fused in sarcoma (FUS) gene mutation and notable hyperhidrosis.

METHOD: Detailed clinical characteristics of the patients were collected, and comprehensive examinations such as electrophysiological assessment, neuro-ultrasound, genetic testing, and relevant blood tests were conducted.

RESULT: A 24-year-old female experienced progressive weakness in both lower limbs for over 5 months, along with excessive sweating on both palms and feet. A positive skin iodine-starch test was observed. Electromyography revealed extensive neurogenic damage and prolonged sympathetic skin response (SSR) latency in both lower limbs. Full exon gene sequencing showed a heterozygous mutation c.1574C>T (p.Pro525Leu) in the FUS gene.

CONCLUSION: The pathogenesis of ALS remains unclear at present. This case underscores the presence of autonomic nervous symptoms in ALS associated with FUS mutation and highlights the importance of early diagnosis and timely treatment intervention to enhance patient prognosis.}, } @article {pmid37902807, year = {2024}, author = {Sampson, CS and Maberry, MD and Stilley, JA}, title = {Football Saturday: are collegiate football stadiums adequately prepared to handle spectator emergencies?.}, journal = {The Journal of sports medicine and physical fitness}, volume = {64}, number = {1}, pages = {73-77}, doi = {10.23736/S0022-4707.23.15428-4}, pmid = {37902807}, issn = {1827-1928}, mesh = {Humans ; Emergencies ; *Emergency Medical Services/organization & administration ; *Football ; *Sports and Recreational Facilities/organization & administration ; }, abstract = {BACKGROUND: Mass gatherings are a commonly occurring event, especially on college campuses. Any mass gathering gives rise to possible small- or large-scale emergencies. Mass gathering medicine is an integral part of emergency medical services (EMS). An assessment was performed to see if collegiate stadiums possess capabilities for advanced medical care when emergencies arise among attendees.

METHODS: A standardized survey was sent by a single researcher to all National Collegiate Athletic Association (NCAA) Division I programs regarding medical services they currently have in place at their stadiums during Saturday football games. A follow-up inquiry was made at each local community office of emergency management (OEM) to confirm responses or obtain missing data.

RESULTS: Only 21.5% (N.=17) of stadium facilities reported having physicians solely dedicated to the care of fans and other support staff. Most stadiums (N.=70, 88.6%) offered ALS services for their fans, with the remaining ALS services provided by paramedics (N.=46, 58.2%) or registered nurses (N.=7, 8.9%). The remaining stadiums only offered BLS services (N.=6, 7.6%) or basic first aid (N.=3, 3.8%). One stadium offered athletic trainer services to its fan in addition to the ALS care.

CONCLUSIONS: Given the potential for a large influx of patients at sporting events, almost all stadiums have some degree of prehospital emergency care on site. More than a 10% of stadiums lacked ALS services and very few stadiums have physicians on site. Many stadiums were unaware of the resources available during these events. The ability to have ALS services on site who can provide rapid, advanced care to spectators is important due to likely delays in 911 response. At a minimum ALS services should be available within the stadium with consideration of physician coverage as well.}, } @article {pmid37901127, year = {2023}, author = {Aslam, A and Sarmad, E and Nawaz, A and Numan, A and Ahmad, A and Hassan, MA}, title = {Brait-Fahn-Schwartz Disease: A Unique Co-Occurrence of Parkinson's Disease and Amyotrophic Lateral Sclerosis.}, journal = {Case reports in neurology}, volume = {15}, number = {1}, pages = {207-214}, pmid = {37901127}, issn = {1662-680X}, abstract = {The Parkinson's disease-amyotrophic lateral sclerosis (ALS) complex typically manifests as levodopa-responsive parkinsonism, followed by ALS. It is extremely rare for Parkinson's disease and ALS to coexist without other neurological disorders. Named after the scientists who first described this overlap of two neurodegenerative conditions, it is referred to as Brait-Fahn-Schwartz disease. Given its variable presentation, increasing rarity, and lack of any diagnostic test, it poses a diagnostic challenge for physicians. We present a case of a 55-year-old Pakistani male experiencing progressive quadriparesis with spastic lower limbs and flaccid upper limbs, in addition to the cardinal features of idiopathic Parkinson's disease. Since there is currently no cure available for either Parkinson's disease or ALS, all available treatment focuses on improving quality of life, which we achieved in our patient. This case is unique in being the first incidence of Parkinson's disease-ALS complex in a novel geographic region such as Pakistan, where genetic testing and cost constraints limit the diagnosis of rare disorders. The coexistence of extrapyramidal symptoms and pyramidal symptoms is uncommon. In such situations, physicians may overlook one group of symptoms, potentially leading to a misdiagnosis. This case highlights the value of a thorough physical examination and electrodiagnostic studies and suggests the association between Parkinson's disease and ALS. This case demonstrates the significance of understanding when Parkinson's disease symptoms start to appear in patients with ALS and the need to start dopaminergic therapy in those who had Parkinson's disease features before ALS to alleviate the suffering of an individual and enhance quality of life.}, } @article {pmid37898010, year = {2023}, author = {Halkiadakis, Y and Davidson, N and Morgan, KD}, title = {Time series modeling characterizes stride time variability to identify individuals with neurodegenerative disorders.}, journal = {Human movement science}, volume = {92}, number = {}, pages = {103152}, doi = {10.1016/j.humov.2023.103152}, pmid = {37898010}, issn = {1872-7646}, mesh = {Humans ; Time Factors ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases/diagnosis ; Gait/physiology ; Walking/physiology ; *Huntington Disease ; }, abstract = {The progressive death and dysfunction of neurons causes altered stride-to-stride variability in individuals with Amyotrophic Lateral Sclerosis (ALS) and Huntington's Disease (HD). Yet these altered gait dynamics can manifest differently in these populations based on how and where these neurodegenerative disorders attack the central nervous system. Time series analyses can quantify differences in stride time variability which can help contribute to the detection and identification of these disorders. Here, autoregressive modeling time series analysis was utilized to quantify differences in stride time variability amongst the Controls, the individuals with ALS, and the individuals with HD. For this study, fifteen Controls, 12 individuals with ALS and 15 individuals with HD walked up and down a hallway continuously for 5-min. Participants wore force sensitive resistors in their shoes to collect stride time data. A second order autoregressive (AR) model was fit to the time series created from the stride time data. The mean stride time and two AR model coefficients served as metrics to identify differences in stride time variability amongst the three groups. The individuals with HD walked with significantly greater stride time variability indicating a more chaotic gait while the individuals with ALS adopted more ordered, less variable stride time dynamics (p < 0.001). A plot of the stride time metrics illustrated how each group exhibited significantly different stride time dynamics. The stride time metrics successfully quantified differences in stride time variability amongst individuals with neurodegenerative disorders. This work provided valuable insight about how these neuromuscular disorders disrupt motor coordination leading to the adoption of new gait dynamics.}, } @article {pmid37897436, year = {2024}, author = {Connolly, A and Bailey, S and Lamont, R and Tu, A}, title = {Factors associated with assistive technology prescription and acceptance in motor neurone disease.}, journal = {Disability and rehabilitation. Assistive technology}, volume = {19}, number = {6}, pages = {2229-2238}, doi = {10.1080/17483107.2023.2272858}, pmid = {37897436}, issn = {1748-3115}, mesh = {Humans ; *Motor Neuron Disease/rehabilitation ; *Self-Help Devices ; Male ; Female ; Middle Aged ; *Focus Groups ; *Qualitative Research ; Adult ; Quality of Life ; Aged ; Attitude of Health Personnel ; Interviews as Topic ; Patient Acceptance of Health Care ; }, abstract = {PURPOSE: The risk of delaying assistive technology (AT) prescription and implementation has significant implications on the safety and quality of life of people with Motor Neurone Disease (PwMND). This study aims to explore the barriers and enablers of AT prescription and implementation identified by PwMND and clinicians.

METHODS: A qualitative study using semi-structured focus groups with clinicians and in-depth interviews with PwMND. Sixteen clinicians and ten PwMND were recruited. Thematic analysis was completed and results were compared and discussed to reach an agreement on the final themes.

RESULTS: Three main factors were identified - PwMND, Clinician and Extrapersonal. For PwMND, personal characteristics, such as mindset, was the strongest enabler and inability to accept diagnosis and AT was the key barrier. For Clinician, communication approach was both the most identified enabler and barrier. For Extrapersonal, the availability of interactive education of AT was the strongest enabler and long wait time was a significant barrier.

CONCLUSION: Our study identified themes that clinicians could have an impact on, such as, providing interactive education, engaging PwMND and their support network, and ongoing upskilling of clinicians working in this field. Themes identified that were beyond the control of clinicians were personal characteristics, acceptance and support networks. It highlights the importance for clinicians to be flexible with their communication approach to accommodate the needs of PwMND in the acceptance of AT.}, } @article {pmid37895110, year = {2023}, author = {Provenzano, F and Torazza, C and Bonifacino, T and Bonanno, G and Milanese, M}, title = {The Key Role of Astrocytes in Amyotrophic Lateral Sclerosis and Their Commitment to Glutamate Excitotoxicity.}, journal = {International journal of molecular sciences}, volume = {24}, number = {20}, pages = {}, pmid = {37895110}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Glutamic Acid/metabolism ; Astrocytes/metabolism ; Neuroglia/metabolism ; Neurons/metabolism ; }, abstract = {In the last two decades, there has been increasing evidence supporting non-neuronal cells as active contributors to neurodegenerative disorders. Among glial cells, astrocytes play a pivotal role in driving amyotrophic lateral sclerosis (ALS) progression, leading the scientific community to focus on the "astrocytic signature" in ALS. Here, we summarized the main pathological mechanisms characterizing astrocyte contribution to MN damage and ALS progression, such as neuroinflammation, mitochondrial dysfunction, oxidative stress, energy metabolism impairment, miRNAs and extracellular vesicles contribution, autophagy dysfunction, protein misfolding, and altered neurotrophic factor release. Since glutamate excitotoxicity is one of the most relevant ALS features, we focused on the specific contribution of ALS astrocytes in this aspect, highlighting the known or potential molecular mechanisms by which astrocytes participate in increasing the extracellular glutamate level in ALS and, conversely, undergo the toxic effect of the excessive glutamate. In this scenario, astrocytes can behave as "producers" and "targets" of the high extracellular glutamate levels, going through changes that can affect themselves and, in turn, the neuronal and non-neuronal surrounding cells, thus actively impacting the ALS course. Moreover, this review aims to point out knowledge gaps that deserve further investigation.}, } @article {pmid37895020, year = {2023}, author = {Davis, SE and Cirincione, AB and Jimenez-Torres, AC and Zhu, J}, title = {The Impact of Neurotransmitters on the Neurobiology of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {20}, pages = {}, pmid = {37895020}, issn = {1422-0067}, support = {R01 DA057866/DA/NIDA NIH HHS/United States ; F31 DA057163/DA/NIDA NIH HHS/United States ; R01 DA047924/DA/NIDA NIH HHS/United States ; R01 DA035714/DA/NIDA NIH HHS/United States ; DA047924/NH/NIH HHS/United States ; DA035714/NH/NIH HHS/United States ; DA057866/NH/NIH HHS/United States ; DA057163/NH/NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Alzheimer Disease/pathology ; Brain/pathology ; *Huntington Disease/pathology ; *HIV Infections/pathology ; }, abstract = {Neurodegenerative diseases affect millions of people worldwide. Neurodegenerative diseases result from progressive damage to nerve cells in the brain or peripheral nervous system connections that are essential for cognition, coordination, strength, sensation, and mobility. Dysfunction of these brain and nerve functions is associated with Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and motor neuron disease. In addition to these, 50% of people living with HIV develop a spectrum of cognitive, motor, and/or mood problems collectively referred to as HIV-Associated Neurocognitive Disorders (HAND) despite the widespread use of a combination of antiretroviral therapies. Neuroinflammation and neurotransmitter systems have a pathological correlation and play a critical role in developing neurodegenerative diseases. Each of these diseases has a unique pattern of dysregulation of the neurotransmitter system, which has been attributed to different forms of cell-specific neuronal loss. In this review, we will focus on a discussion of the regulation of dopaminergic and cholinergic systems, which are more commonly disturbed in neurodegenerative disorders. Additionally, we will provide evidence for the hypothesis that disturbances in neurotransmission contribute to the neuronal loss observed in neurodegenerative disorders. Further, we will highlight the critical role of dopamine as a mediator of neuronal injury and loss in the context of NeuroHIV. This review will highlight the need to further investigate neurotransmission systems for their role in the etiology of neurodegenerative disorders.}, } @article {pmid37894774, year = {2023}, author = {Moțățăianu, A and Șerban, G and Andone, S}, title = {The Role of Short-Chain Fatty Acids in Microbiota-Gut-Brain Cross-Talk with a Focus on Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {24}, number = {20}, pages = {}, pmid = {37894774}, issn = {1422-0067}, support = {PN-III-P1-1.1-TE-2021-0960//Ministry of Research, Innovation and Digitization, CNCS - UEFISCDI/ ; }, mesh = {Humans ; Aged ; *Gastrointestinal Microbiome/physiology ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; Brain/metabolism ; Fatty Acids, Volatile/metabolism ; Fatty Acids/metabolism ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by the gradual loss of motor neurons in the brain and spinal cord, leading to progressive motor function decline. Unfortunately, there is no effective treatment, and its increasing prevalence is linked to an aging population, improved diagnostics, heightened awareness, and changing lifestyles. In the gastrointestinal system, the gut microbiota plays a vital role in producing metabolites, neurotransmitters, and immune molecules. Short-chain fatty acids, of interest for their potential health benefits, are influenced by a fiber- and plant-based diet, promoting a diverse and balanced gut microbiome. These fatty acids impact the body by binding to receptors on enteroendocrine cells, influencing hormones like glucagon-like peptide-1 and peptide YY, which regulate appetite and insulin sensitivity. Furthermore, these fatty acids impact the blood-brain barrier, neurotransmitter levels, and neurotrophic factors, and directly stimulate vagal afferent nerves, affecting gut-brain communication. The vagus nerve is a crucial link between the gut and the brain, transmitting signals related to appetite, inflammation, and various processes. Dysregulation of this pathway can contribute to conditions like obesity and irritable bowel syndrome. Emerging evidence suggests the complex interplay among these fatty acids, the gut microbiota, and environmental factors influences neurodegenerative processes via interconnected pathways, including immune function, anti-inflammation, gut barrier, and energy metabolism. Embracing a balanced, fiber-rich diet may foster a diverse gut microbiome, potentially impacting neurodegenerative disease risk. Comprehensive understanding requires further research into interventions targeting the gut microbiome and fatty acid production and their potential therapeutic role in neurodegeneration.}, } @article {pmid37893463, year = {2023}, author = {Laucius, O and Drūteika, J and Balnytė, R and Petrikonis, K and Ališauskienė, M and Vaitkus, A}, title = {Sonographic Phrenic Nerve Changes in Amyotrophic Lateral Sclerosis.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {59}, number = {10}, pages = {}, pmid = {37893463}, issn = {1648-9144}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging ; Phrenic Nerve/physiology ; *Neurodegenerative Diseases ; Prognosis ; Muscle Weakness/complications ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects both the upper and lower motor neurons in the nervous system, causing muscle weakness and severe disability. The progressive course of the disease reduces the functional capacity of the affected patients, limits daily activities, and leads to complete dependence on caregivers, ultimately resulting in a fatal outcome. Respiratory dysfunction mostly occurs later in the disease and is associated with a worse prognosis. Forty-six participants were included in our study, with 23 patients in the ALS group and 23 individuals in the control group. The ultrasound examination of the phrenic nerve (PN) was performed by two authors using a high-resolution "Philips EPIQ 7" ultrasound machine with a linear 4-18 MHz transducer. Our study revealed that the phrenic nerve is significantly smaller on both sides in ALS patients compared to the control group (p < 0.001). Only one significant study on PN ultrasound in ALS, conducted in Japan, also showed significant results (p < 0.00001). These small studies are particularly promising, as they suggest that ultrasound findings could serve as an additional diagnostic tool for ALS.}, } @article {pmid37893165, year = {2023}, author = {De Marchi, F and Munitic, I and Vidatic, L and Papić, E and Rački, V and Nimac, J and Jurak, I and Novotni, G and Rogelj, B and Vuletic, V and Liscic, RM and Cannon, JR and Buratti, E and Mazzini, L and Hecimovic, S}, title = {Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders.}, journal = {Biomedicines}, volume = {11}, number = {10}, pages = {}, pmid = {37893165}, issn = {2227-9059}, abstract = {Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann-Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation.}, } @article {pmid37893003, year = {2023}, author = {Wu, YS and Taniar, D and Adhinugraha, K and Tsai, LK and Pai, TW}, title = {Detection of Amyotrophic Lateral Sclerosis (ALS) Comorbidity Trajectories Based on Principal Tree Model Analytics.}, journal = {Biomedicines}, volume = {11}, number = {10}, pages = {}, pmid = {37893003}, issn = {2227-9059}, support = {MOST 111-2221-E-027 -113 -MY2//National Science and Technology Council/ ; }, abstract = {The multifaceted nature and swift progression of Amyotrophic Lateral Sclerosis (ALS) pose considerable challenges to our understanding of its evolution and interplay with comorbid conditions. This study seeks to elucidate the temporal dynamics of ALS progression and its interaction with associated diseases. We employed a principal tree-based model to decipher patterns within clinical data derived from a population-based database in Taiwan. The disease progression was portrayed as branched trajectories, each path representing a series of distinct stages. Each stage embodied the cumulative occurrence of co-existing diseases, depicted as nodes on the tree, with edges symbolizing potential transitions between these linked nodes. Our model identified eight distinct ALS patient trajectories, unveiling unique patterns of disease associations at various stages of progression. These patterns may suggest underlying disease mechanisms or risk factors. This research re-conceptualizes ALS progression as a migration through diverse stages, instead of the perspective of a sequence of isolated events. This new approach illuminates patterns of disease association across different progression phases. The insights obtained from this study hold the potential to inform doctors regarding the development of personalized treatment strategies, ultimately enhancing patient prognosis and quality of life.}, } @article {pmid37892126, year = {2023}, author = {Ramos, V and Reis, M and Ferreira, L and Silva, AM and Ferraz, R and Vieira, M and Vasconcelos, V and Martins, R}, title = {Stalling the Course of Neurodegenerative Diseases: Could Cyanobacteria Constitute a New Approach toward Therapy?.}, journal = {Biomolecules}, volume = {13}, number = {10}, pages = {}, pmid = {37892126}, issn = {2218-273X}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Oxidative Stress ; *Parkinson Disease/drug therapy ; Antioxidants/pharmacology ; *Cyanobacteria/metabolism ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by progressive and irreversible neuronal loss, accompanied by a range of pathological pathways, including aberrant protein aggregation, altered energy metabolism, excitotoxicity, inflammation, and oxidative stress. Some of the most common NDs include Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD). There are currently no available cures; there are only therapeutic approaches that ameliorate the progression of symptoms, which makes the search for new drugs and therapeutic targets a constant battle. Cyanobacteria are ancient prokaryotic oxygenic phototrophs whose long evolutionary history has resulted in the production of a plethora of biomedically relevant compounds with anti-inflammatory, antioxidant, immunomodulatory, and neuroprotective properties, that can be valuable in this field. This review summarizes the major NDs and their pathophysiology, with a focus on the anti-neurodegenerative properties of cyanobacterial compounds and their main effects.}, } @article {pmid37891975, year = {2023}, author = {Fu, RH and Chen, HJ and Hong, SY}, title = {Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {10}, pages = {}, pmid = {37891975}, issn = {2076-3921}, support = {MOST 105-2314-B-039-017-MY3//the Ministry of Science and Technology (Taiwan)/ ; DMR-111-140//China Medical University Hospital (Taiwan)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal rare disease of progressive degeneration of motor neurons. The most common genetic mutation in ALS is the hexanucleotide repeat expansion (HRE) located in the first intron of the C9orf72 gene (C9-ALS). HRE can produce dipeptide repeat proteins (DPRs) such as poly glycine-alanine (GA) in a repeat-associated non-ATG (RAN) translation. GA-DPR has been shown to be toxic to motor neurons in various biological models. However, its effects on microglia involved in C9-ALS have not been reported. Here, we show that GA-DPR (GA50) activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome in a human HMC3 microglia model. MCC950 (specific inhibitor of the NLRP3) treatment can abrogate this activity. Next, using yeast two-hybrid screening, we identified sulfide quinone oxidoreductase (SQOR) as a GA50 interacting protein. SQOR knockdown in HMC3 cells can significantly induce the activity of the NLRP3 inflammasome by upregulating the level of intracellular reactive oxygen species and the cytoplasmic escape of mitochondrial DNA. Furthermore, we obtained irisflorentin as an effective blocker of the interaction between SQOR and GA50, thus inhibiting NLRP3 inflammasome activity in GA50-expressing HMC3 cells. These results imply the association of GA-DPR, SQOR, and NLRP3 inflammasomes in microglia and establish a treatment strategy for C9-ALS with irisflorentin.}, } @article {pmid37891966, year = {2023}, author = {Grossini, E and De Marchi, F and Venkatesan, S and Mele, A and Ferrante, D and Mazzini, L}, title = {Effects of Acetyl-L-Carnitine on Oxidative Stress in Amyotrophic Lateral Sclerosis Patients: Evaluation on Plasma Markers and Members of the Neurovascular Unit.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {10}, pages = {}, pmid = {37891966}, issn = {2076-3921}, abstract = {Oxidative stress, the alteration of mitochondrial function, and the neurovascular unit (NVU), play a role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. We aimed to demonstrate the changes in the plasma redox system and nitric oxide (NO) in 32 new ALS-diagnosed patients in treatment with Acetyl-L-Carnitine (ALCAR) compared to healthy controls. We also evaluated the effects of plasma on human umbilical cord-derived endothelial vascular cells (HUVEC) and astrocytes. The analyses were performed at the baseline (T0), after three months (T1), and after six months (T2). In ALS patients at T0/T1, the plasma markers of lipid peroxidation, thiobarbituric acid reactive substances (TBARS) and 4-hydroxy nonenal (4-HNE) were higher, whereas the antioxidants, glutathione (GSH) and the glutathione peroxidase (GPx) activity were lower than in healthy controls. At T2, plasma TBARS and 4-HNE decreased, whereas plasma GSH and the GPx activity increased in ALS patients. As regards NO, the plasma levels were firmly lower at T0-T2 than those of healthy controls. Cell viability, and mitochondrial membrane potential in HUVEC/astrocytes treated with the plasma of ALS patients at T0-T2 were reduced, while the oxidant release increased. Those results, which confirmed the fundamental role of oxidative stress, mitochondrial function, and of the NVU in ALS pathogenesis, can have a double meaning, acting as disease markers at baseline and potential markers of drug effects in clinical practice and during clinical trials.}, } @article {pmid37891890, year = {2023}, author = {Korczowska-Łącka, I and Słowikowski, B and Piekut, T and Hurła, M and Banaszek, N and Szymanowicz, O and Jagodziński, PP and Kozubski, W and Permoda-Pachuta, A and Dorszewska, J}, title = {Disorders of Endogenous and Exogenous Antioxidants in Neurological Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {10}, pages = {}, pmid = {37891890}, issn = {2076-3921}, abstract = {In diseases of the central nervous system, such as Alzheimer's disease (AD), Parkinson's disease (PD), stroke, amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and even epilepsy and migraine, oxidative stress load commonly surpasses endogenous antioxidative capacity. While oxidative processes have been robustly implicated in the pathogenesis of these diseases, the significance of particular antioxidants, both endogenous and especially exogenous, in maintaining redox homeostasis requires further research. Among endogenous antioxidants, enzymes such as catalase, superoxide dismutase, and glutathione peroxidase are central to disabling free radicals, thereby preventing oxidative damage to cellular lipids, proteins, and nucleic acids. Whether supplementation with endogenously occurring antioxidant compounds such as melatonin and glutathione carries any benefit, however, remains equivocal. Similarly, while the health benefits of certain exogenous antioxidants, including ascorbic acid (vitamin C), carotenoids, polyphenols, sulforaphanes, and anthocyanins are commonly touted, their clinical efficacy and effectiveness in particular neurological disease contexts need to be more robustly defined. Here, we review the current literature on the cellular mechanisms mitigating oxidative stress and comment on the possible benefit of the most common exogenous antioxidants in diseases such as AD, PD, ALS, HD, stroke, epilepsy, and migraine. We selected common neurological diseases of a basically neurodegenerative nature.}, } @article {pmid37891753, year = {2023}, author = {Rostás, R and Fekete, I and Horváth, L and Fekete, K}, title = {Blink Reflex Examination in Patients with Amyotrophic Lateral Sclerosis Compared to Diseases Affecting the Peripheral Nervous System and Healthy Controls.}, journal = {Brain sciences}, volume = {13}, number = {10}, pages = {}, pmid = {37891753}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal form of neuromuscular disease. The aim of this study was to assess changes in the blink reflex (BR) parameters as a valid and easy-to-use tool in ALS patients. We assessed the BR test in patients with a definitive diagnosis of ALS, healthy volunteers, and patients with diseases affecting the peripheral nervous system. The BR was studied in 29 patients who met the Awaji criteria. Latencies were compared with our healthy controls (N = 50) and other diseases of the peripheral nervous system (N = 61). The ALS Functional Rating Scale-Revised (ALSFRS-R) was used to evaluate functional status. Significantly prolonged R2i and R2c latencies were found in the ALS group compared with the healthy control group (p < 0.001). The latencies of R1, R2i, R2c were all increased in the bulbar subtype compared to the limb-onset subtype (p < 0.05). According to our results, BR examination might be a promising tool to monitor the course of the disease or serve as a prognostic biomarker in patients with ALS, but it should be assessed in further studies. The abnormalities detected through BR might help perform earlier interventions in ALS patients and might be useful in other diseases affecting the peripheral nervous system.}, } @article {pmid37891396, year = {2023}, author = {Carey, LB and Bambling, M and Hodgson, TJ and Jamieson, N and Bakhurst, MG and Koenig, HG}, title = {Pastoral Narrative Disclosure: The Development and Evaluation of an Australian Chaplaincy Intervention Strategy for Addressing Moral Injury.}, journal = {Journal of religion and health}, volume = {62}, number = {6}, pages = {4032-4071}, pmid = {37891396}, issn = {1573-6571}, mesh = {Humans ; *Stress Disorders, Post-Traumatic ; Australia ; *Veterans ; Morals ; Narration ; *Pastoral Care/methods ; Clergy ; *Chaplaincy Service, Hospital ; Spirituality ; }, abstract = {This paper describes the development and initial chaplaincy user evaluation of 'Pastoral Narrative Disclosure' (PND) as a rehabilitation strategy developed for chaplains to address moral injury among veterans. PND is an empirically informed and integrated intervention comprising eight stages of pastoral counselling, guidance and education that was developed by combining two previously existing therapeutic techniques, namely Litz et al's (2017) 'Adaptive Disclosure' and 'Confessional Practice' (Joob & Kettunen, 2013). The development and results of PND can be categorized into five phases. Phase 1: PND Strategy Formation-based upon extensive international research demonstrating that MI is a complex bio-psycho-social-spiritual syndrome with symptoms sufficiently distinct from post-traumatic stress disorder. The review also provided evidence of the importance of chaplains being involved in moral injury rehabilitation. Phase II: Development and Implementation of 'Moral Injury Skills Training' (MIST)-which involved the majority of available Australian Defence Force (ADF) Chaplains (n = 242/255: 94.9%) completing a basic 'Introduction to Moral Injury' (MIST-1) as well as an 'Introduction to PND' (MIST-2). Phase III: MIST-3-PND-Pilot evaluation-involved a representative chaplaincy cohort (n = 13) undergoing the PND eight-stage strategy to ensure the integrity and quality of PND from a chaplaincy perspective prior to wider implementation. The pilot PND evaluation indicated a favourable satisfaction rating (n = 11/13: 84.6%; M = 4.73/5.0 satisfaction). Phase IV: MIST-3-PND Implementation-involved a larger cohort of ADF Chaplaincy participants (n = 210) completing a revised and finalized PND strategy which was regarded favourably by the majority of ADF Chaplains (n = 201/210: 95.7%; M = 4.73/5.0 satisfaction). Phase V: Summation. In conclusion the positive satisfaction ratings by a significant number of ADF chaplaincy personnel completing MIST-3-PND, provided evidence that chaplains evaluated PND as a suitable counselling, guidance and education strategy, which affirmed its utilisation and justifies further research for using PND to address MI among veterans, that may also prove valuable for other chaplains working in community health and first responder contexts.}, } @article {pmid37890889, year = {2023}, author = {Ilieva, H and Vullaganti, M and Kwan, J}, title = {Advances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis.}, journal = {BMJ (Clinical research ed.)}, volume = {383}, number = {}, pages = {e075037}, pmid = {37890889}, issn = {1756-1833}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Pathology, Molecular ; Disease Progression ; }, abstract = {Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an effective therapy remains slow. This review summarizes the critical discoveries and outlines the advances in disease characterization, diagnosis, imaging, and biomarkers, along with the current status of approaches to ALS care and treatment. Additional knowledge of the factors driving disease progression and heterogeneity will hopefully soon transform the care for patients with ALS into an individualized, multi-prong approach able to prevent disease progression sufficiently to allow for a dignified life with limited disability.}, } @article {pmid37889424, year = {2024}, author = {Yan, Z and Xu, Y and Li, K and Liu, L}, title = {Association between genetically proxied lipid-lowering drug targets, lipid traits, and amyotrophic lateral sclerosis: a mendelian randomization study.}, journal = {Acta neurologica Belgica}, volume = {124}, number = {2}, pages = {485-494}, pmid = {37889424}, issn = {2240-2993}, support = {No. 81860826//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Cholesterol, LDL/genetics ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; *Amyotrophic Lateral Sclerosis/genetics ; Mendelian Randomization Analysis ; Apolipoproteins B/genetics ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: The use of circulating lipid traits as biomarkers to predict the risk of amyotrophic lateral sclerosis (ALS) is currently controversial, and the evidence-based medical evidence for the use of lipid-lowering agents, especially statins, on ALS risk remains insufficient. Our aim was to apply a Mendelian randomization (MR) approach to assess the causal impact of lipid-lowering agents and circulating lipid traits on ALS risk.

MATERIALS AND METHODS: Our study included primary and secondary analyses, in which the risk associations of lipid-lowering gene inhibitors, lipid traits, and ALS were assessed by the inverse variance weighting method as the primary approach. The robustness of the results was assessed using LDSC assessment, conventional MR sensitivity analysis, and used Mediating MR to explore potential mechanisms of occurrence. In the secondary analysis, the association of lipid-lowering genes with ALS was validated using the Summary data-based Mendelian Randomization (SMR) method.

RESULTS: Our results showed strong evidence between genetic proxies for Apolipoprotein B (ApoB) inhibitor (OR = 0.76, 95% CI = 0.68 - 0.86; P = 5.58 × 10[-6]) and reduced risk of ALS. Additionally, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor (OR = 1.06, 95% CI = 0. 85-1.33) was not found to increase ALS risk. SMR results suggested that ApoB expression was associated with increased ALS risk, and colocalization analysis did not support a significant common genetic variation between ApoB and ALS. Mediator MR analysis suggested a possible mediating role for interleukin-6 and low-density lipoprotein cholesterol (LDL-C). While elevated LDL-C was significantly associated with increased risk of ALS among lipid traits, total cholesterol (TC) and ApoB were weakly associated with ALS. LDSC results suggested a potential genetic correlation between these lipid traits and ALS.

CONCLUSIONS: Using ApoB inhibitor can lower the risk of ALS, statins do not trigger ALS, and LDL-C, TC, and ApoB levels can predict the risk of ALS.}, } @article {pmid37889099, year = {2023}, author = {Liddell, JR and Hilton, JBW and Crouch, PJ}, title = {Cu[II](atsm) significantly decreases microglial reactivity in patients with sporadic amyotrophic lateral sclerosis.}, journal = {Neuropathology and applied neurobiology}, volume = {49}, number = {5}, pages = {e12938}, doi = {10.1111/nan.12938}, pmid = {37889099}, issn = {1365-2990}, support = {//National Health and Medical Research Council/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis ; Microglia ; Copper ; Mice, Transgenic ; }, } @article {pmid37887472, year = {2023}, author = {Palazzo, L and Pizzolato, L and Rigo, M and Bondì, G}, title = {Amyotrophic Lateral Sclerosis and Its Management during the COVID-19 Pandemic: A Qualitative Study with Thematic Analysis of Patients and Caregivers Who Participated in Self-Help Groups.}, journal = {Behavioral sciences (Basel, Switzerland)}, volume = {13}, number = {10}, pages = {}, pmid = {37887472}, issn = {2076-328X}, abstract = {This study employs a qualitative methodology to explore the effects of the pandemic on the lives of ALS patients and their caregivers. It aims to understand whether and how online self-help groups have assisted families dealing with amyotrophic lateral sclerosis (ALS) patients. ALS is a neurodegenerative disease with both physical and psychosocial implications. Consequently, it significantly affects the lives of patients' caregivers. In 2020, the COVID-19 pandemic exacerbated this situation. The results show that the pandemic has had a negative impact on the well-being of ALS caregivers and patients. Furthermore, bereavement and death were dealt with in different ways by the families involved. The pandemic aggravated the health of ALS patients and increased the workload of their caregivers; however, online psychological support was appreciated for its role in providing emotional help and diminishing social isolation.}, } @article {pmid37887320, year = {2023}, author = {Fu, RH and Chen, HJ and Hong, SY}, title = {Interaction of the C9orf72-Amyotrophic Lateral Sclerosis-Related Proline-Arginine Dipeptide Repeat Protein with the RNA-Binding Protein NOVA1 Causes Decreased Expression of UNC13A Due to Enhanced Inclusion of Cryptic Exons, Which Is Reversed by Betulin Treatment.}, journal = {Cells}, volume = {12}, number = {20}, pages = {}, pmid = {37887320}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Arginine/metabolism ; C9orf72 Protein/genetics/metabolism ; Dipeptides/metabolism ; Motor Neurons/pathology ; Neuro-Oncological Ventral Antigen ; Proline/metabolism ; RNA, Messenger/genetics/metabolism ; RNA-Binding Proteins/genetics/metabolism ; }, abstract = {C9orf72 mutations are the most common form of familial amyotrophic lateral sclerosis (C9-ALS). It causes the production of proline-arginine dipeptide repeat proteins (PR-DPRs) in motor neurons (MNs), leading to the molecular pathology characteristic of ALS. UNC13A is critical for maintaining the synaptic function of MNs. Most ALS patients have nuclear deletion of the splicing repressor TDP-43 in MNs, which causes inclusion of the cryptic exon (CE) of UNC13A mRNA, resulting in nonsense-mediated mRNA decay and reduced protein expression. Therefore, in this study, we explored the role of PR-DPR in CE inclusion of UNC13A mRNA. Our results showed that PR-DPR (PR50) induced CE inclusion and decreased the protein expression of UNC13A in human neuronal cell lines. We also identified an interaction between the RNA-binding protein NOVA1 and PR50 by yeast two-hybrid screening. NOVA1 expression is known to be reduced in patients with ALS. We found that knockdown of NOVA1 enhanced CE inclusion of UNC13A mRNA. Furthermore, the naturally occurring triterpene betulin can inhibit the interaction between NOVA1 and PR50, thus preventing CE inclusion of UNC13A mRNA and protein reduction in human neuronal cell lines. This study linked PR-DPR with CE inclusion of UNC13A mRNA and developed candidate therapeutic strategies for C9-ALS using betulin.}, } @article {pmid37887305, year = {2023}, author = {Provasek, VE and Kodavati, M and Guo, W and Wang, H and Boldogh, I and Van Den Bosch, L and Britz, G and Hegde, ML}, title = {lncRNA Sequencing Reveals Neurodegeneration-Associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists in Motor Neurons.}, journal = {Cells}, volume = {12}, number = {20}, pages = {}, pmid = {37887305}, issn = {2073-4409}, support = {RF1NS112719/NS/NINDS NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; R03AG064266/NH/NIH HHS/United States ; R01NS094535/NH/NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; R01NS088645/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; Motor Neurons/metabolism ; Mutation/genetics ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Fused-in sarcoma (FUS) gene mutations have been implicated in amyotrophic lateral sclerosis (ALS). This study aimed to investigate the impact of FUS mutations (R521H and P525L) on the transcriptome of induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs). Using RNA sequencing (RNA Seq), we characterized differentially expressed genes (DEGs) and differentially expressed lncRNAs (DELs) and subsequently predicted lncRNA-mRNA target pairs (TAR pairs). Our results show that FUS mutations significantly altered the expression profiles of mRNAs and lncRNAs in iPSCs. Using this large dataset, we identified and verified six key differentially regulated TAR pairs in iPSCs that were also altered in iMNs. These target transcripts included: GPR149, NR4A, LMO3, SLC15A4, ZNF404, and CRACD. These findings indicated that selected mutant FUS-induced transcriptional alterations persist from iPSCs into differentiated iMNs. Functional enrichment analyses of DEGs indicated pathways associated with neuronal development and carcinogenesis as likely altered by these FUS mutations. Furthermore, ingenuity pathway analysis (IPA) and GO network analysis of lncRNA-targeted mRNAs indicated associations between RNA metabolism, lncRNA regulation, and DNA damage repair. Our findings provide insights into potential molecular mechanisms underlying the pathophysiology of ALS-associated FUS mutations and suggest potential therapeutic targets for the treatment of ALS.}, } @article {pmid37887017, year = {2023}, author = {You, J and Youssef, MMM and Santos, JR and Lee, J and Park, J}, title = {Microglia and Astrocytes in Amyotrophic Lateral Sclerosis: Disease-Associated States, Pathological Roles, and Therapeutic Potential.}, journal = {Biology}, volume = {12}, number = {10}, pages = {}, pmid = {37887017}, issn = {2079-7737}, abstract = {Microglial and astrocytic reactivity is a prominent feature of amyotrophic lateral sclerosis (ALS). Microglia and astrocytes have been increasingly appreciated to play pivotal roles in disease pathogenesis. These cells can adopt distinct states characterized by a specific molecular profile or function depending on the different contexts of development, health, aging, and disease. Accumulating evidence from ALS rodent and cell models has demonstrated neuroprotective and neurotoxic functions from microglia and astrocytes. In this review, we focused on the recent advancements of knowledge in microglial and astrocytic states and nomenclature, the landmark discoveries demonstrating a clear contribution of microglia and astrocytes to ALS pathogenesis, and novel therapeutic candidates leveraging these cells that are currently undergoing clinical trials.}, } @article {pmid37886540, year = {2023}, author = {Snyder, A and Ryan, VH and Hawrot, J and Lawton, S and Ramos, DM and Qi, YA and Johnson, K and Reed, X and Johnson, NL and Kollasch, AW and Duffy, M and VandeVrede, L and Cochran, JN and Miller, BL and Toro, C and Bielekova, B and Yokoyama, JS and Marks, DS and Kwan, JY and Cookson, MR and Ward, ME}, title = {An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37886540}, issn = {2693-5015}, support = {P50 AG023501/AG/NIA NIH HHS/United States ; K01 AG049152/AG/NIA NIH HHS/United States ; R01 AG062588/AG/NIA NIH HHS/United States ; FI2 GM142475/GM/NIGMS NIH HHS/United States ; U19 AG079774/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; ZIA AG000539/ImNIH/Intramural NIH HHS/United States ; ZIA AG000534/ImNIH/Intramural NIH HHS/United States ; R00 AG068271/AG/NIA NIH HHS/United States ; K23 AG073514/AG/NIA NIH HHS/United States ; 75N95022C00031/DA/NIDA NIH HHS/United States ; U54 NS123985/NS/NINDS NIH HHS/United States ; }, abstract = {As genetic testing has become more accessible and affordable, variants of uncertain significance (VUS) are increasingly identified, and determining whether these variants play causal roles in disease is a major challenge. The known disease-associated Annexin A11 (ANXA11) mutations result in ANXA11 aggregation, alterations in lysosomal-RNA granule co-trafficking, and TDP-43 mis-localization and present as amyotrophic lateral sclerosis or frontotemporal dementia. We identified a novel VUS in ANXA11 (P93S) in a kindred with corticobasal syndrome and unique radiographic features that segregated with disease. We then queried neurodegenerative disorder clinic databases to identify the phenotypic spread of ANXA11 mutations. Multi-modal computational analysis of this variant was performed and the effect of this VUS on ANXA11 function and TDP-43 biology was characterized in iPSC-derived neurons. Single-cell sequencing and proteomic analysis of iPSC-derived neurons and microglia were used to determine the multiomic signature of this VUS. Mutations in ANXA11 were found in association with clinically diagnosed corticobasal syndrome, thereby establishing corticobasal syndrome as part of ANXA11 clinical spectrum. In iPSC-derived neurons expressing mutant ANXA11, we found decreased colocalization of lysosomes and decreased neuritic RNA as well as decreased nuclear TDP-43 and increased formation of cryptic exons compared to controls. Multiomic assessment of the P93S variant in iPSC-derived neurons and microglia indicates that the pathogenic omic signature in neurons is modest compared to microglia. Additionally, omic studies reveal that immune dysregulation and interferon signaling pathways in microglia are central to disease. Collectively, these findings identify a new pathogenic variant in ANXA11, expand the range of clinical syndromes caused by ANXA11 mutations, and implicate both neuronal and microglia dysfunction in ANXA11 pathophysiology. This work illustrates the potential for iPSC-derived cellular models to revolutionize the variant annotation process and provides a generalizable approach to determining causality of novel variants across genes.}, } @article {pmid37885757, year = {2023}, author = {Krannich, T and Sarrias, MH and Ben Aribi, H and Shokrof, M and Iacoangeli, A and Al-Chalabi, A and Sedlazeck, FJ and Busby, B and Al Khleifat, A}, title = {VariantSurvival: a tool to identify genotype-treatment response.}, journal = {Frontiers in bioinformatics}, volume = {3}, number = {}, pages = {1277923}, pmid = {37885757}, issn = {2673-7647}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Motivation: For a number of neurological diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, and many others, certain genes are known to be involved in the disease mechanism. A common question is whether a structural variant in any such gene may be related to drug response in clinical trials and how this relationship can contribute to the lifecycle of drug development. Results: To this end, we introduce VariantSurvival, a tool that identifies changes in survival relative to structural variants within target genes. VariantSurvival matches annotated structural variants with genes that are clinically relevant to neurological diseases. A Cox regression model determines the change in survival between the placebo and clinical trial groups with respect to the number of structural variants in the drug target genes. We demonstrate the functionality of our approach with the exemplary case of the SETX gene. VariantSurvival has a user-friendly and lightweight graphical user interface built on the shiny web application package.}, } @article {pmid37885418, year = {2023}, author = {Biebelberg, B and Klompas, M and Rhee, C}, title = {The authors' reply to Schaffzin et al's Letter to the Editor.}, journal = {Infection control and hospital epidemiology}, volume = {44}, number = {12}, pages = {2098}, doi = {10.1017/ice.2023.222}, pmid = {37885418}, issn = {1559-6834}, } @article {pmid37885330, year = {2023}, author = {Lunghi, G and Di Biase, E and Carsana, EV and Henriques, A and Callizot, N and Mauri, L and Ciampa, MG and Mari, L and Loberto, N and Aureli, M and Sonnino, S and Spedding, M and Chiricozzi, E and Fazzari, M}, title = {GM1 ganglioside exerts protective effects against glutamate-excitotoxicity via its oligosaccharide in wild-type and amyotrophic lateral sclerosis motor neurons.}, journal = {FEBS open bio}, volume = {13}, number = {12}, pages = {2324-2341}, pmid = {37885330}, issn = {2211-5463}, support = {//Banca d'Italia/ ; 200045//Mizutani Foundation for Glycoscience/ ; //APC central fund of the University of Milan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; G(M1) Ganglioside/pharmacology/metabolism ; Glutamic Acid ; *Neurodegenerative Diseases/metabolism ; Superoxide Dismutase/metabolism ; Motor Neurons/metabolism ; }, abstract = {Alterations in glycosphingolipid metabolism have been linked to the pathophysiological mechanisms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. Accordingly, administration of GM1, a sialic acid-containing glycosphingolipid, is protective against neuronal damage and supports neuronal homeostasis, with these effects mediated by its bioactive component, the oligosaccharide head (GM1-OS). Here, we add new evidence to the therapeutic efficacy of GM1 in ALS: Its administration to WT and SOD1[G93A] motor neurons affected by glutamate-induced excitotoxicity significantly increased neuronal survival and preserved neurite networks, counteracting intracellular protein accumulation and mitochondria impairment. Importantly, the GM1-OS faithfully replicates GM1 activity, emphasizing that even in ALS the protective function of GM1 strictly depends on its pentasaccharide.}, } @article {pmid37882882, year = {2023}, author = {Wang, Y and Sun, S and Zhai, J and Liu, Y and Song, C and Sun, C and Li, Q and Liu, J and Jiang, H and Liu, Y}, title = {scAAV9-VEGF alleviates symptoms of amyotrophic lateral sclerosis (ALS) mice through regulating aromatase.}, journal = {Experimental brain research}, volume = {241}, number = {11-12}, pages = {2817-2827}, pmid = {37882882}, issn = {1432-1106}, support = {ZR2020QH126//Natural Science Foundation of Shandong Province Youth Fund/ ; ZR2020QH124//Natural Science Foundation of Shandong Province Youth Fund/ ; 2019ZC010137//Zibo city key research and development plan/ ; 2021Q048//TCM science and technology Project of Shandong Province/ ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Motor Neurons/physiology ; Vascular Endothelial Growth Factor A/metabolism/pharmacology ; *Neurodegenerative Diseases/metabolism ; Aromatase/genetics/metabolism/pharmacology ; Superoxide Dismutase/genetics/metabolism/pharmacology ; Mice, Transgenic ; Disease Models, Animal ; Estrogens/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset, chronic, progressive, and fatal neurodegenerative disease that leads to progressive atrophy and weakness of the muscles throughout the body. Herein, we found that the intrathecal injection of adeno-associated virus (AAV)-delivered VEGF in SOD1-G93A transgenic mice, as well as ALS mice, could significantly delay disease onset and preserve motor functions and neurological functions, thus prolonging the survival of mice models. Moreover, we found that VEGF treatment could induce the elevated expression of aromatase, which is a key enzyme in estrogen synthesis, in neurons but not in astrocytes. On the other hand, the changes in the expression of oxidative stress-related factors HO-1 and GCLM and autophagy-related proteins p62 and LC3II upon the administration of VEGF revealed the involvement of oxidative stress and autophagy underlying the downstream of the VEGF-induced mitigation of ALS. In conclusion, this study proved the protective effects of VEGF in the onset and development of ALS and revealed the involvement of estrogen, oxidative stress and autophagy in the VEGF-induced alleviation of ALS. Our results highlighted the potential of VEGF as a promising therapeutic agent in the treatment of ALS.}, } @article {pmid37882537, year = {2024}, author = {Hung, C and Patani, R}, title = {Elevated 4R tau contributes to endolysosomal dysfunction and neurodegeneration in VCP-related frontotemporal dementia.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {3}, pages = {970-979}, pmid = {37882537}, issn = {1460-2156}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; /CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; *Induced Pluripotent Stem Cells ; Lysosomes ; *Valosin Containing Protein/genetics ; }, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two incurable neurodegenerative diseases that exist on a clinical, genetic and pathological spectrum. The VCP gene is highly relevant, being directly implicated in both FTD and ALS. Here, we investigate the effects of VCP mutations on the cellular homoeostasis of human induced pluripotent stem cell-derived cortical neurons, focusing on endolysosomal biology and tau pathology. We found that VCP mutations cause abnormal accumulation of enlarged endolysosomes accompanied by impaired interaction between two nuclear RNA binding proteins: fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) in human cortical neurons. The spatial dissociation of intranuclear FUS and SFPQ correlates with alternative splicing of the MAPT pre-mRNA and increased tau phosphorylation. Importantly, we show that inducing 4R tau expression using antisense oligonucleotide technology is sufficient to drive neurodegeneration in control human neurons, which phenocopies VCP-mutant neurons. In summary, our findings demonstrate that tau hyperphosphorylation, endolysosomal dysfunction, lysosomal membrane rupture, endoplasmic reticulum stress and apoptosis are driven by a pathogenic increase in 4R tau.}, } @article {pmid37882288, year = {2023}, author = {Barco-Antoñanzas, M and Font-Farre, M and Eceiza, MV and Gil-Monreal, M and van der Hoorn, RAL and Royuela, M and Zabalza, A}, title = {Cysteine proteases are activated in sensitive Amaranthus palmeri populations upon treatment with herbicides inhibiting amino acid biosynthesis.}, journal = {Physiologia plantarum}, volume = {175}, number = {5}, pages = {e13993}, doi = {10.1111/ppl.13993}, pmid = {37882288}, issn = {1399-3054}, support = {//Eusko Jaurlaritza/ ; 2020 117723-RB-100//Ministerio de Ciencia e Innovación/ ; AGL2016-77531-R//Ministerio de Economía y Competitividad/ ; }, mesh = {Herbicide Resistance ; *Amaranthus/metabolism ; *Herbicides/pharmacology/metabolism ; *Cysteine Proteases/metabolism/pharmacology ; }, abstract = {The herbicides glyphosate and pyrithiobac inhibit the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) in the aromatic amino acid biosynthetic pathway and acetolactate synthase (ALS) in the branched-chain amino acid biosynthetic pathway, respectively. Here we characterise the protease activity profiles of a sensitive (S), a glyphosate-resistant (GR) and a multiple-resistant (MR) population of Amaranthus palmeri in response to glyphosate and pyrithiobac. Amino acid accumulation and cysteine protease activities were induced with both herbicides in the S population and with pyrithiobac in the GR population, suggesting that the increase in cysteine proteases is responsible for the increased degradation of the available proteins and the observed increase in free amino acids. Herbicides did not induce any changes in the proteolytic activities in the populations with target-site resistance, indicating that this effect was only induced in sensitive plants.}, } @article {pmid37881503, year = {2023}, author = {Petrashen, AP and Lin, Y and Kun, B and Kreiling, JA}, title = {A cluster of X-linked miRNAs are de-repressed with age in mouse liver and target growth hormone signaling.}, journal = {Frontiers in aging}, volume = {4}, number = {}, pages = {1261121}, pmid = {37881503}, issn = {2673-6217}, support = {P20 GM119943/GM/NIGMS NIH HHS/United States ; T32 AG041688/AG/NIA NIH HHS/United States ; T32 GM136566/GM/NIGMS NIH HHS/United States ; }, abstract = {Growth hormone (GH) signaling influences lifespan in a wide variety of mammalian species. We previously reported that a cluster of miRNAs located on the X-chromosome are de-repressed with age in male mouse liver, and a subset, the mir-465 family, can directly attenuate expression of the growth hormone receptor (GHR) in vitro leading to a reduction in GH signaling. Here we show that this cluster of miRNAs is also upregulated in the liver with age in females, and that calorie restriction and the Ames dwarf genotype, both known to delay aging, attenuate the upregulation of the miRNA cluster. Upregulation of mir-465 in vivo leads to a reduction in GHR mRNA in the liver and an attenuation of GH signaling, indicated by a reduction in GHR, IGF-1, IGFBP3, and ALS mRNA expression. There is a corresponding reduction in IGF-1 protein levels in the liver and plasma. These results suggest that the age-associated upregulation of the X-chromosomal cluster of miRNAs could influence lifespan.}, } @article {pmid37881309, year = {2023}, author = {Li, T and Ye, M and Yang, G and Diao, S and Zhou, Y and Qin, Y and Ding, D and Zhu, M and Fang, Q}, title = {Regional white matter hyperintensity volume predicts persistent cognitive impairment in acute lacunar infarct patients.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1265743}, pmid = {37881309}, issn = {1664-2295}, abstract = {BACKGROUND: White matter hyperintensity (WMH) is often described in acute lacunar stroke (ALS) patients. However, the specific relationship between regional WMH volume and persistent cognitive impairment remains unclear.

METHODS: We enrolled patients with ALS who were hospitalized at the First Affiliated Hospital of Soochow University between January 2020 and November 2022. All patients were assessed for global cognitive function using the Montreal Cognitive Assessment (MoCA) scale at 14 ± 2 days and 6 months after the onset of ALS. Manifestations of chronic cerebral small vessel disease (CSVD) were assessed via MRI scan. The distributions of regional WMH were segmented, and their relationship with cognitive impairment was evaluated.

RESULTS: A total of 129 patients were enrolled. Baseline frontal WMH volume (OR = 1.18, P = 0.04) was an independent risk factor for long-term cognitive impairment after ALS. Furthermore, the presence of WMH at the genu of the corpus callosum (GCC) at baseline (OR = 3.1, P = 0.033) was strongly associated with persistent cognitive decline. Multivariable logistic regression analysis showed that depression (OR = 6.252, P = 0.029), NIHSS score (OR = 1.24, P = 0.011), and albumin at admission (OR = 0.841, P = 0.032) were also important determinants of long-term cognitive impairment after ALS.

CONCLUSIONS: Our study found that WMH, especially frontal WMH volume and the presence of WMH at the GCC at baseline, independently contributed to long-term cognitive decline in ALS patients. This study provides new evidence of the clinical relationship between regional WMH volume and cognitive impairment in ALS patients.}, } @article {pmid37880984, year = {2024}, author = {Menon, D and Nashi, S and Mohanty, M and Dubbal, R and Mk, F and Vengalil, S and Thomas, A and Kumar, V and Baskar, D and Arunachal, G and Nalini, A}, title = {A novel DHTKD1 gene mutation with ALS like presentation: a case report.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {3-4}, pages = {413-415}, doi = {10.1080/21678421.2023.2273366}, pmid = {37880984}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism ; Ketoglutarate Dehydrogenase Complex/genetics/metabolism ; *Ketone Oxidoreductases/genetics/metabolism ; Mitochondria ; Mutation/genetics ; Aged ; }, abstract = {DHTKD1 is a nuclear gene that encodes "dehydrogenase E1 and transketolase domain-containing 1", essential in mitochondrial metabolism. First identified in the patients of 2-amino-apidic and 2 oxoapidic aciduria, mutation in this gene has recently been implicated in CMT2Q and ALS. Here we report the case of a septuagenarian who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical exome sequencing revealed a heterozygous nonsense variant in exon 8 of the DHTKD1 gene, which was previously described in CMT2Q. This report highlights the pleotropic phenotypic presentation of DHTKD1 mutation and the need for genetic testing even in sporadic cases of ALS presenting at a later age.}, } @article {pmid37880536, year = {2024}, author = {Iazzolino, B and Grassano, M and Moglia, C and Canosa, A and Manera, U and Vasta, R and Cabras, S and Callegaro, S and Matteoni, E and Di Pede, F and Palumbo, F and Mora, G and Calvo, A and Chiò, A}, title = {High serum uric acid levels are protective against cognitive impairment in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {2}, pages = {955-961}, pmid = {37880536}, issn = {1432-1459}, support = {RF-2016-02362405//Ministero della Salute/ ; 2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 259867//Seventh Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Frontotemporal Dementia/complications/diagnosis ; Uric Acid ; *Cognitive Dysfunction/diagnosis ; *Cognition Disorders/complications ; }, abstract = {BACKGROUND: Uric acid (UA) has emerged as a factor that can modify cognitive function both in the general population and in people with neurodegenerative disorders. Since very few data are available concerning amyotrophic lateral sclerosis (ALS), we explored the correlation of UA levels and cognitive impairment in a large cohort of ALS patients.

METHODS: We enrolled ALS patients consecutively seen at the Turin ALS expert center in the 2007-2018 period who underwent both cognitive/behavioral and UA evaluation at diagnosis. Patients were classified in 5 categories: normal cognition (ALS-CN), isolated cognitive impairment (ALSci), isolated behavioural impairment (ALSbi), cognitive and behavioural impairment (ALScbi), frontotemporal dementia (ALS-FTD). For this study, ALSci, ALSbi and ALScbi were merged as ALS with intermediate cognitive impairment (ALS-INT).

RESULTS: Out of the 841 ALS patients, 422 had ALS-CN, 271 ALS-INT and 148 ALS-FTD. The mean values of UA were significantly different among the cognitive subgroups of patients, with the lowest values in the ALS-FTD (ALS-CN, 288.5 ± 78.0 (μmol/L; ALS-INT, 289.7 ± 75.5 μmol/L; ALS-FTD, 271.8 ± 74.9 μmol/L; p = 0.046). The frequency of ALS-FTD was significantly higher in the 1st tertile of UA. Lower UA levels were independently associated with FTD (OR 1.32, 95% c.i. 1.01-1.43; p = 0.038) in binary logistic regression.

CONCLUSIONS: We found that in ALS lower UA serum levels are correlated with reduced frequency of co-morbid FTD. Patients with intermediate cognitive impairment showed UA levels similar to ALS-CN but higher than ALS-FTD, implying that higher UA levels can prevent or delay cognitive function deterioration.}, } @article {pmid37879951, year = {2023}, author = {Liu, JY and Lu, YR and Guo, J and Li, H and Wang, Y and Zhao, YQ and Li, J and Wang, Q}, title = {Effect of electroacupuncture intervention on the spinal cord PPIA/NF-κB signaling pathway in mice with amyotrophic lateral sclerosis.}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {48}, number = {10}, pages = {1009-1016}, doi = {10.13702/j.1000-0607.20230251}, pmid = {37879951}, issn = {1000-0607}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; DNA-Binding Proteins/metabolism ; *Electroacupuncture ; Motor Neurons/metabolism ; NF-kappa B/genetics/metabolism ; Riluzole ; Signal Transduction ; Spinal Cord ; Superoxide Dismutase-1/genetics/metabolism ; Peptidylprolyl Isomerase/metabolism ; }, abstract = {OBJECTIVES: To observe the effects of electroacupuncture (EA) on motor function, expression of extracellular cyclophile A(PPIA) and PPIA/nuclear factor-κB (NF-κB) signaling pathway in spinal cord of amyotrophic la-teral sclerosis (ALS) mice, so as to explore the mechanism of EA intervention in regulating extracellular PPIA on neuroinflammation in ALS mice.

METHODS: Thirty ALS-SOD1[G93A] mice with hSOD1-G93A gene were randomly divided into model, EA and Riluzole groups , with 10 mice in each group, and other 10 ALS-SOD1[G93A] negative mice were used as the blank group. EA was applied to bilateral "Yanglingquan"(GB34) and "Zusanli"(ST36) for 20 min once daily, 5 days a week for 2 weeks. In the Riluzole group, riluzole solution (30 mg·kg[-1]·d[-1]) was administrated intragastrically, and the treatment time was the same as that in the EA group.Rotating rod experiment and open field experiment were used to evaluate the changes in motor function of mice .The morphology of motor neurons in the anterior horn of spinal cord was observed by HE staining.The relative protein expression levels of PPIA, TDP-43 and NF-κB in the spinal cord were detected by Western blot.The positive expression level of TDP-43 in the spinal cord was detected by immunohistochemistry. The positive expression level of PPIA in spinal cord was marked by immunofluorescence. Serum PPIA content was determined by ELISA.

RESULTS: Compared with the blank group, the time of rod dropping and the total distance of open field movement in the model group were shortened (P<0.01), the number of motor neurons in the anterior horn of the spinal cord was reduced, the cell morphology was incomplete, the cell body was atrophied, the protein expression and positive expression of TDP-43 were increased (P<0.01), the protein expressions of PPIA and NF-κB in the spinal cord were increased(P<0.01), the serum content of PPIA and immunofluorescence expression of PPIA in spinal cord were increased (P<0.01). Compared with the model group, the time of rod dropping and the total distance of open field movement of mice in the EA group and the Riluzole group were prolonged (P<0.05, P<0.01), and the injury of motor neuron in the anterior horn of the spinal cord was decreased, the protein expression and positive expression of TDP-43 in the spinal cord were decreased (P<0.05, P<0.01)；the relative expression levels of PPIA and NF-κB proteins were decreased (P<0.05, P<0.01), and the content of PPIA in serum and the immunofluorescence expression of PPIA in the spinal cord were decreased (P<0.05, P<0.01) in the EA group；the relative protein expression of NF-κB and fluorescence expression of PPIA in spinal cord of mice in the Riluzole group were decreased (P<0.05).

CONCLUSIONS: EA intervention can improve motor function in ALS mice, and its mechanism may be related to the inhibition of PPIA/NF-κB signaling pathway by EA to alleviating neuroinflammatory response.}, } @article {pmid37877583, year = {2024}, author = {Haldar, S and Khan, AH and De, A and Reichmayr, F and Morag, A and Yu, M and Schneemann, A and Kaskel, S}, title = {Fluorinated Benzimidazole-Linked Highly Conjugated Polymer Enabling Covalent Polysulfide Anchoring for Stable Sulfur Batteries.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {30}, number = {2}, pages = {e202302779}, doi = {10.1002/chem.202302779}, pmid = {37877583}, issn = {1521-3765}, support = {SPP2248//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Sulfur is one of the most abundant and economical elements in the p-block family and highly redox active, potentially utilizable as a charge-storing electrode with high theoretical capacities. However, its inherent good solubility in many electrolytes inhibits its accessibility as an electrode material in typical metal-sulfur batteries. In this work, the synthetically designed fluorinated porous polymer, when treated with elemental sulfur through a well-known nucleophilic aromatic substitution mechanism (SN Ar), allows for the covalent integration of polysulfides into a highly conjugated benzimidazole polymer by replacing the fluorine atoms. Chemically robust benzimidazole linkages allow such harsh post-synthetic treatment and facilitate the electronic activation of the anchored polysulfides for redox reactions under applied potential. The electrode amalgamated with sulfurized polymer mitigates the so-called polysulfide shuttle effect in the lithium-sulfur (Li-S) battery and also enables a reversible, more environmentally friendly, and more economical aluminum-sulfur (Al-S) battery that is configured with mostly p-block elements as cathode, anode, and electrolytes. The improved cycling stabilities and reduction of the overpotential in both cases pave the way for future sustainable energy storage solutions.}, } @article {pmid38344317, year = {2022}, author = {Baziyar, P and Seyedalipour, B and Hosseinkhani, S and Nazifi, E}, title = {Development of In Silico Analysis and Molecular Dynamics Simulation on L67P and D76Y Mutants of the Human Superoxide Dismutase 1(hSOD1) Related to Amyotrophic Lateral Sclerosis.}, journal = {Iranian journal of biotechnology}, volume = {20}, number = {4}, pages = {e3178}, pmid = {38344317}, issn = {1728-3043}, abstract = {BACKGROUND: One neurodegenerative disorder that is caused by a mutation in the hSOD1 gene is Amyotrophic lateral sclerosis (ALS).

OBJECTIVES: The current study was developed in order to evaluate the effect exerted by two ALS-associated point mutations, L67P and D76Y are located in the metal-binding loop, on structural characterization of hSOD1 protein using molecular dynamics (MD) simulations and computational predictions.

MATERIALS AND METHODS: In this study, GROMACS was utilized to perform molecular dynamics simulations along with 9 different algorithms such as Predict SNP, PhD-SNP, MAPP, PolyPhen-1, Polyphen-2, SNP, SIFT, SNP&GO, and PMUT for predicting and also evaluating the mutational effect on the structural and conformational characterization of hSOD1.

RESULTS: Our study was done by several programs predicting the destabilizing and harmful effect exerted by mutant hSOD1. The deleterious effect of L67P mutation was predicted by MAPP and PhD-SNP algorithms, and D76Y mutation was predicted by 9 algorithms. Comparative studies that were conducted on mutants and wild-type indicated the altar in flexibility and protein conformational stability influenced the metal-binding loop's conformation. The outcomes of the MD exhibited an increase and decrease of flexibility for D76Y and L67P mutants compared to the wild type, respectively. On the other hand, analysis of the gyration radius indicated lower and higher compactness for D76Y and L67P, respectively, suggesting that replacing amino acid at the metal-binding loop can alter the protein compactness compared with the protein the wild type.

CONCLUSIONS: Overall, these findings provided insight into the effect of mutations on the hSOD1, which leads to neurodegeneration disorders in humans. The results show that the mutations of L67P and D76Y influence the stability of protein conformational and flexibility associated with ALS disease. Thus, results of such mutations are can be a prerequisite to achieve a thorough understanding of ALS pathogenicity.}, } @article {pmid38177466, year = {2022}, author = {Ramamoorthy, D and Severson, K and Ghosh, S and Sachs, K and , and Glass, JD and Fournier, CN and , and , and Herrington, TM and Berry, JD and Ng, K and Fraenkel, E}, title = {Identifying patterns in amyotrophic lateral sclerosis progression from sparse longitudinal data.}, journal = {Nature computational science}, volume = {2}, number = {9}, pages = {605-616}, pmid = {38177466}, issn = {2662-8457}, support = {IK2 CX001595/CX/CSRD VA/United States ; K23 NS099380/NS/NINDS NIH HHS/United States ; U54 NS091046/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Disease Progression ; *Neurodegenerative Diseases ; *Parkinson Disease/diagnosis ; }, abstract = {The clinical presentation of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, varies widely across patients, making it challenging to determine if potential therapeutics slow progression. We sought to determine whether there were common patterns of disease progression that could aid in the design and analysis of clinical trials. We developed an approach based on a mixture of Gaussian processes to identify clusters of patients sharing similar disease progression patterns, modeling their average trajectories and the variability in each cluster. We show that ALS progression is frequently nonlinear, with periods of stable disease preceded or followed by rapid decline. We also show that our approach can be extended to Alzheimer's and Parkinson's diseases. Our results advance the characterization of disease progression of ALS and provide a flexible modeling approach that can be applied to other progressive diseases.}, } @article {pmid38011426, year = {2022}, author = {Fateh, HR and Askary-Kachoosangy, R and Shirzad, N and Akbarzadeh-Baghban, A and Fatehi, F}, title = {The effect of energy conservation strategies on fatigue, function, and quality of life in adults with motor neuron disease: Randomized controlled trial.}, journal = {Current journal of neurology}, volume = {21}, number = {2}, pages = {83-90}, pmid = {38011426}, issn = {2717-011X}, abstract = {Background: Fatigue is one of the most frequent complaints in patients with motor neuron diseases (MNDs), with a significant impact on the quality of life (QOL). There is lack of enough evidence for current pharmacological or non-pharmacological treatments of fatigue in this population to be applied in clinical setting. Energy conservation strategies are one of the key interventions for fatigue management in chronic diseases. We aimed to investigate the effect of applying these techniques in the fatigue management of patients with MND. Methods: This randomized controlled trial (RCT) study was carried out on 28 patients with MND. Participants were randomly assigned to either the intervention or control group. In addition to routine treatment, patients in the intervention group participated in 3 weekly 1-hour energy conservation programs provided by an experienced occupational therapist. The Fatigue Severity Scale (FSS) score, 36-Item Short Form Survey (SF-36), and Canadian Occupational Performance Measure (COPM) were measured at baseline, immediately after the last intervention session, and one month later. Results: FSS and COPM significantly changed after the course in the intervention group (P < 0.001 and P = 0.001, respectively). Both FSS and COPM improved significantly toward the final assessment only in the intervention group. The SF-36 changes were not significant in each of the groups. Conclusion: According to the findings of the present study, using energy conservation strategies could lead to better mid-term fatigue management and occupational performance improvement, but it did not improve QOL in patients with MND.}, } @article {pmid38283317, year = {2022}, author = {Cheung, K and Mitsumoto, H}, title = {Evaluating Personalized (N-of-1) Trials in Rare Diseases: How Much Experimentation Is Enough?.}, journal = {Harvard data science review}, volume = {2022}, number = {Spec Iss 3}, pages = {}, pmid = {38283317}, issn = {2644-2353}, support = {P30 AG063786/AG/NIA NIH HHS/United States ; R01 LM012836/LM/NLM NIH HHS/United States ; R01 MH109496/MH/NIMH NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; }, abstract = {For rare diseases, conducting large, randomized trials of new treatments can be infeasible due to limited sample size, and it may answer the wrong scientific questions due to heterogeneity of treatment effects. Personalized (N-of-1) trials are multi-period crossover studies that aim to estimate individual treatment effects, thereby identifying the optimal treatments for individuals. This article examines the statistical design issues of evaluating a personalized (N-of-1) treatment program in people with amyotrophic lateral sclerosis (ALS). We propose an evaluation framework based on an analytical model for longitudinal data observed in a personalized trial. Under this framework, we address two design parameters: length of experimentation in each trial and number of trials needed. For the former, we consider patient-centric design criteria that aim to maximize the benefits of enrolled patients. Using theoretical investigation and numerical studies, we demonstrate that, from a patient's perspective, the duration of an experimentation period should be no longer than one-third of the entire follow-up period of the trial. For the latter, we provide analytical formulae to calculate the power for testing quality improvement due to personalized trials in a randomized evaluation program and hence determine the required number of trials needed for the program. We apply our theoretical results to design an evaluation program for ALS treatments informed by pilot data and show that the length of experimentation has a small impact on power relative to other factors such as the degree of heterogeneity of treatment effects.}, } @article {pmid37994346, year = {2022}, author = {Yang, C and Qian, C and Singh, N and Xiao, C and Westover, MB and Solomonik, E and Sun, J}, title = {ATD: Augmenting CP Tensor Decomposition by Self Supervision.}, journal = {Advances in neural information processing systems}, volume = {35}, number = {}, pages = {32039-32052}, pmid = {37994346}, issn = {1049-5258}, support = {R01 NS102190/NS/NINDS NIH HHS/United States ; RF1 NS120947/NS/NINDS NIH HHS/United States ; R01 HL161253/HL/NHLBI NIH HHS/United States ; R01 NS126282/NS/NINDS NIH HHS/United States ; R01 NS107291/NS/NINDS NIH HHS/United States ; }, abstract = {Tensor decompositions are powerful tools for dimensionality reduction and feature interpretation of multidimensional data such as signals. Existing tensor decomposition objectives (e.g., Frobenius norm) are designed for fitting raw data under statistical assumptions, which may not align with downstream classification tasks. In practice, raw input tensor can contain irrelevant information while data augmentation techniques may be used to smooth out class-irrelevant noise in samples. This paper addresses the above challenges by proposing augmented tensor decomposition (ATD), which effectively incorporates data augmentations and self-supervised learning (SSL) to boost downstream classification. To address the non-convexity of the new augmented objective, we develop an iterative method that enables the optimization to follow an alternating least squares (ALS) fashion. We evaluate our proposed ATD on multiple datasets. It can achieve 0.8% ~ 2.5% accuracy gain over tensor-based baselines. Also, our ATD model shows comparable or better performance (e.g., up to 15% in accuracy) over self-supervised and autoencoder baselines while using less than 5% of learnable parameters of these baseline models.}, } @article {pmid38011420, year = {2021}, author = {Eishi-Oskouei, A and Basiri, K}, title = {Safety and efficacy of edaravone in well-defined Iranian patients with amyotrophic lateral sclerosis: A parallel-group single-blind trial.}, journal = {Current journal of neurology}, volume = {20}, number = {1}, pages = {1-7}, pmid = {38011420}, issn = {2717-011X}, abstract = {Background: This parallel-group single-blind trial evaluates the safety and efficacy of Edaravone, as a free radical scavenger, in a highly selective subgroup of Iranian patients with amyotrophic lateral sclerosis (ALS). Methods: The study was registered in ClinicalTrials.gov (registration number: NCT03272802) and Iranian Registry of Clinical Trials (registration number: IRCT20190324043105N). Patients were included into the study, who were diagnosed as probable or definite ALS (according to revised El Escorial criteria), mildly to moderately affected by the disease [according to Amyotrophic Lateral Sclerosis Health State Scale (ALS/HSS)], scored ≥ 2 points on all items of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and had forced vital capacity (FVC) of at least 80%. 20 patients (10 cases, 10 controls) were observed for 12 cycles (each cycle lasted four weeks). Cases received Edaravone for the first 14 days in the first cycle and for the first 10 days in the next cycles. In addition, all patients received Riluzole. The 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40), ALSFRS-R, and Manual Muscle Testing (MMT) scores were measured every 3 cycles to evaluate the physical and functional status of the patients. Besides, injection reactions, adverse events (AEs), and serious adverse events (SAEs) were measured during the study. Results: ALSAQ-40, ALSFRS-R, and MMT scores were not significantly different between cases and controls in 5 different time points. During the study, no injection reactions were observed. AEs and SAEs were not significantly different between cases and controls. Conclusion: Our data did not demonstrate efficacy of Edaravone in ALS treatment, but showed its safety for use in patients with ALS. Further studies are necessary to investigate Edaravone efficacy in patients with ALS before prescribing this new drug outside Japan.}, } @article {pmid38011400, year = {2021}, author = {Afrakhteh, M and Esmaeili, S and Shati, M and Shojaei, SF and Bahadori, M and Zamani, B and Almasi-Doghaee, M and Haghi-Ashtiani, B}, title = {Validating the Persian version of the amyotrophic lateral sclerosis-specific quality of life-revised instrument.}, journal = {Current journal of neurology}, volume = {20}, number = {1}, pages = {37-42}, pmid = {38011400}, issn = {2717-011X}, abstract = {Background: Amyotrophic Lateral Sclerosis-Specific Quality of Life-Revised (ALSSQOL-R) encompasses 50 items which assess quality of life (QOL) in patients with amyotrophic lateral sclerosis (ALS) in six major domains. This study aims to translate the ALSSQOL-R into Persian and evaluate its reliability and validity among Iranian patients. Methods: ALSSQOL-R was translated by the standard multi-step forward-backward method. Content validity was calculated using item content validity index (I-CVI). Three items in the "intimacy" domain were deleted considering Iranian culture. Cronbach's alpha was used for all 6 dimensions to calculate the internal consistency reliability. Test-retest reliability was evaluated using intraclass correlation coefficient (ICC) with one-month interval. Concurrent validity was measured by the validated version of 36-Item Short Form Health Survey (SF-36) questionnaire. Results: Sixty-three patients with ALS were enrolled in the study. I-CVI was 70%, promoted to 85% after modifications (acceptable). Regarding internal consistency reliability, Cronbach's alpha in all six domains was 0.70 and total Cronbach's alpha was 0.89 which is assumed as good. In terms of test-retest reliability, ICC [95% confidence interval (CI)] was 0.91 (91%) and Pearson correlation coefficient (r) was 0.90 (P < 0.001), all indicating an excellent reliability. The concurrent validity was established based on a strong correlation with SF-36 (r = 0.744, P < 0.001). Conclusion: The findings show that the modified Persian version of ALSSQOL-R is a valid and reliable QOL questionnaire which can be used for Iranian patients with ALS in both clinical and research settings.}, } @article {pmid38011396, year = {2020}, author = {Okhovat, AA and Fatehi, F and Rafiemehr, M and Moradi, K and Kiani-Mehr, G and Nafissi, S}, title = {Evaluation of quality of life and mood disorders in caregivers of patients with amyotrophic lateral sclerosis: A single-center cross-sectional study.}, journal = {Current journal of neurology}, volume = {19}, number = {4}, pages = {190-195}, pmid = {38011396}, issn = {2717-011X}, abstract = {Background: Caregivers of patients with amyotrophic lateral sclerosis (ALS) may suffer from anxiety, depression, and reduced quality of life (QoL). Our goal was to evaluate the QoL and mood disorders in caregivers and their correlation with the patients' demographic, physical, and mental conditions. Methods: We analyzed data from 39 patients with ALS and their caregivers. Patients completed questionnaires of anxiety assessed by Generalised Anxiety Disorder Assessment (GAD-7), depression using the Beck Depression Inventory-II (BDI-II), and QoL via 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40). Physical impairment was also measured in the patients using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Caregivers were also assessed by BDI-II, GAD-7, and 36-item Short-Form Health Survey questionnaire (SF-36). Results: The prevalence of depression and anxiety in the patients was 82.1% and 71.8%, respectively. Caregivers also had higher rates of anxiety and depression and lower levels of QoL in comparison with the general population (anxiety: 66.7%, depression: 43.6%). Depression and anxiety were considerably associated with worsened QoL in the caregivers. None of the demographic, physical, or mental characteristics of patients with ALS were related to either mood status or QoL of the caregiver population. Conclusion: Caregivers experience higher rates of anxiety and depression and lower QoL in comparison with the general population. The severity of mood disorders is inversely associated with the physical and mental domains of caregivers' QoL. Nonetheless, QoL in the caregivers is not affected by the physical or mental disability of the patients.}, } @article {pmid38396386, year = {2016}, author = {Aimo, J and Promancio, E and Damiani, PC}, title = {Determination of reducing sugars in foodstuff applying multivariate second-order calibration.}, journal = {Analytical methods : advancing methods and applications}, volume = {8}, number = {23}, pages = {4617-4631}, doi = {10.1039/c6ay00964f}, pmid = {38396386}, issn = {1759-9679}, abstract = {In the present report, a chemometrics-assisted second-order kinetic-spectrophotometric method has been developed for determining reducing sugars, glucose, fructose and lactose, in food samples, based on the reaction with hexacyanoferrate, HCF, at 70 °C in alkaline medium. A suitable experimental design helped us to establish the conditions (pH, temperature, and HCF concentration) for optimal sensitivity and selectivity among analytes. Second order data were recorded by measuring the absorbance of unreacted HCF in the spectral range of 370 to 470 nm for five minutes using a diode array. A calibration set of samples was prepared according to a central composite design containing the three sugars for training the algorithms. Validation samples containing only the analytes were prepared for checking the reliability of the algorithms. In this particular system, identical profiles for sample components are obtained in the spèctral dimension corresponding to unreacted HCF. Moreover, two kinds of interferents may be present: sample components active in the spectral region at which HCF absorbs as well as potential reducing interferents, causing linear dependence, since they provide identical profiles in spectral dimension to those of the analytes of interest. In the present work, MCR-ALS in the spectral augmentation mode was the only algorithm that could successfully resolve linear dependence. Satisfactory results were obtained by applying MCR-ALS in the spectral augmentation mode in order to achieve a second order advantage for the determination of fructose and glucose in validation samples, in test samples containing the two kinds of interferents and in real food samples, providing LODs of 4.0 and 5.0 mg L[-1], respectively. However, bad results were obtained for lactose which may be due to its low sensitivity in the augmented dimension. Good results were also obtained by applying U-PLS/RBL and N-PLS/RBL for determining simultaneously the three sugars in validation samples and in test samples containing only active spectral interferents. Finally, lactose and also, glucose and fructose, were successfully quantified in real milk samples, with LODmin = 1.0 mg L[-1], 1.0 mg L[-1] and 0.1 mg L[-1] and LODmax = 3.5, 3.8 and 4.4 mg L[-1], respectively, using UPLS/RBL, and LODmin of 1.3, 1.1 and 0.1 mg L[-1] and LODmax of 4.0, 4.3 and 4.9 mg L[-1] for lactose, glucose and fructose, respectively, for NPLS/RBL. Results for real samples in all cases were statistically comparable to those obtained by applying a reference method based on HPLC (High Performance Liquid Chromatography).}, } @article {pmid37877361, year = {2023}, author = {Heyming, TW and Knudsen-Robbins, C and Shelton, SK and Pham, PK and Brukman, S and Wickens, M and Valdez, B and Bacon, K and Thorpe, J and Kwon, KT and Schultz, C}, title = {9-1-1 Activations from Ambulatory Care Centers: A Sicker Pediatric Population.}, journal = {Prehospital and disaster medicine}, volume = {38}, number = {6}, pages = {749-756}, pmid = {37877361}, issn = {1945-1938}, mesh = {Child ; Child, Preschool ; Female ; Humans ; Male ; Ambulatory Care/statistics & numerical data ; *Emergency Medical Services/statistics & numerical data ; Emergency Service, Hospital ; Retrospective Studies ; Life Support Care/statistics & numerical data ; }, abstract = {BACKGROUND: Pediatric patients transferred by Emergency Medical Services (EMS) from urgent care (UC) and office-based physician practices to the emergency department (ED) following activation of the 9-1-1 EMS system are an under-studied population with scarce literature regarding outcomes for these children. The objectives of this study were to describe this population, explore EMS level-of-care transport decisions, and examine ED outcomes.

METHODS: This was a retrospective review of patients zero to <15 years of age transported by EMS from UC and office-based physician practices to the ED of two pediatric receiving centers from January 2017 through December 2019. Variables included reason for transfer, level of transport, EMS interventions and medications, ED medications/labs/imaging ordered in the first hour, ED procedures, ED disposition, and demographics. Data were analyzed with descriptive statistics, X test, point biserial correlation, two-sample z test, Mann-Whitney U test, and 2-way ANOVA.

RESULTS: A total of 450 EMS transports were included in this study: 382 Advanced Life Support (ALS) runs and 68 Basic Life Support (BLS) runs. The median patient age was 2.66 years, 60.9% were male, and 60.7% had private insurance. Overall, 48.9% of patients were transported from an office-based physician practice and 25.1% were transported from UC. Almost one-half (48.7%) of ALS patients received an EMS intervention or medication, as did 4.41% of BLS patients. Respiratory distress was the most common reason for transport (46.9%). Supplemental oxygen was the most common EMS intervention and albuterol was the most administered EMS medication. There was no significant association between level of transport and ED disposition (P = .23). The in-patient admission rate for transported patients was significantly higher than the general ED admission rate (P <.001).

CONCLUSION: This study demonstrates that pediatric patients transferred via EMS after activation of the 9-1-1 system from UC and medical offices are more acutely ill than the general pediatric ED population and are likely sicker than the general pediatric EMS population. Paramedics appear to be making appropriate level-of-care transport decisions.}, } @article {pmid37877320, year = {2024}, author = {Yom-Tov, E and Navar, I and Fraenkel, E and Berry, JD}, title = {Identifying amyotrophic lateral sclerosis through interactions with an internet search engine.}, journal = {Muscle & nerve}, volume = {69}, number = {1}, pages = {40-47}, doi = {10.1002/mus.27991}, pmid = {37877320}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Search Engine ; Delayed Diagnosis ; *Motor Neuron Disease ; *Cognitive Dysfunction ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS), a motor neuron disease, remains a clinical diagnosis with an average time from onset of symptoms to diagnosis of about 1 year. Herein we examine the possibility that interactions with an internet search engine can identify people with ALS.

METHODS: We identified 285 anonymous Bing users whose queries indicated that they had been diagnosed with ALS and matched them to: (1) 3276 control users; and (2) 1814 users whose searches indicated they had ALS disease mimics. We tested whether the ALS group could be distinguished from controls and disease mimics based on search engine query data. Finally, we conducted a prospective validation from participants who provided access to their Bing search data.

RESULTS: The model distinguished between the ALS group and controls with an area under the curve (AUC) of 0.81. Model scores for the ALS group differed from the disease mimics group (rank sum test, p < .05 with Bonferroni correction). Mild cognitive impairment could not be distinguished from ALS (p > .05). In the prospective analysis, the model reached an AUC of 0.74.

DISCUSSION: Our results suggest that interactions with search engines should be further studied to understand the potential to act as a tool to assist in screening for ALS and to reduce diagnostic delay.}, } @article {pmid37877256, year = {2024}, author = {Gariscsak, PJ and Appireddy, R and Vyas, A and Ritsma, BR}, title = {Virtual Multidisciplinary ALS Clinic Care During the COVID-19 Pandemic: A Canadian Cohort.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {51}, number = {5}, pages = {719-722}, doi = {10.1017/cjn.2023.302}, pmid = {37877256}, issn = {0317-1671}, } @article {pmid37877011, year = {2023}, author = {Ghaderi, S and Batouli, SAH and Mohammadi, S and Fatehi, F}, title = {Iron quantification in basal ganglia using quantitative susceptibility mapping in a patient with ALS: a case report and literature review.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1229082}, pmid = {37877011}, issn = {1662-4548}, abstract = {BACKGROUND: Quantitative susceptibility mapping (QSM) is a magnetic resonance imaging (MRI) technique that can measure the magnetic susceptibility of tissues, which can reflect their iron content. QSM has been used to detect iron accumulation in cortical and subcortical brain regions. However, its application in subcortical regions such as the basal ganglia, particularly the putamen, is rare in patients with amyotrophic lateral sclerosis (ALS).

We present the case of a 40-year-old male patient with ALS who underwent an MRI for QSM. We compared his QSM images with those of a control subject and performed a quantitative analysis of the magnetic susceptibility values in the putamen regions. We also reviewed the literature on previous QSM studies in ALS and summarized their methods and findings. Our QSM analysis revealed increased magnetic susceptibility values in the bilateral putamen of the ALS patient compared to controls, indicating iron overload. This finding is consistent with previous studies reporting iron dysregulation in subcortical nuclei in ALS. We also discussed the QSM processing techniques used in our study and in the literature, highlighting their advantages and limitations.

CONCLUSION: This case report demonstrates the potential of QSM as a sensitive MRI biomarker for evaluating iron levels in subcortical regions of ALS patients. QSM can provide quantitative information on iron deposition patterns in both motor and extra-motor areas of ALS patients, which may help understand the pathophysiology of ALS and monitor disease progression. Further studies with larger samples are needed to validate these results and explore the clinical implications of QSM in ALS.}, } @article {pmid37875807, year = {2023}, author = {Loubet, I and Meyer, L and Michel, S and Pernin, F and Carrère, S and Barrès, B and Le Corre, V and Délye, C}, title = {A high diversity of non-target site resistance mechanisms to acetolactate-synthase (ALS) inhibiting herbicides has evolved within and among field populations of common ragweed (Ambrosia artemisiifolia L.).}, journal = {BMC plant biology}, volume = {23}, number = {1}, pages = {510}, pmid = {37875807}, issn = {1471-2229}, support = {DRAGON 29001099-1944//Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement/ ; DRAGON 29001099-1944//ACTA - Les instituts techniques agricoles/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; 2018-CRD-02 PPV18//Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail/ ; }, mesh = {Humans ; Ambrosia/genetics ; *Herbicides/pharmacology ; *Acetolactate Synthase ; Transcriptome ; Herbicide Resistance/genetics ; }, abstract = {BACKGROUND: Non-target site resistance (NTSR) to herbicides is a polygenic trait that threatens the chemical control of agricultural weeds. NTSR involves differential regulation of plant secondary metabolism pathways, but its precise genetic determinisms remain fairly unclear. Full-transcriptome sequencing had previously been implemented to identify NTSR genes. However, this approach had generally been applied to a single weed population, limiting our insight into the diversity of NTSR mechanisms. Here, we sought to explore the diversity of NTSR mechanisms in common ragweed (Ambrosia artemisiifolia L.) by investigating six field populations from different French regions where NTSR to acetolactate-synthase-inhibiting herbicides had evolved.

RESULTS: A de novo transcriptome assembly (51,242 contigs, 80.2% completeness) was generated as a reference to seek genes differentially expressed between sensitive and resistant plants from the six populations. Overall, 4,609 constitutively differentially expressed genes were identified, of which none were common to all populations, and only 197 were shared by several populations. Similarly, population-specific transcriptomic response was observed when investigating early herbicide response. Gene ontology enrichment analysis highlighted the involvement of stress response and regulatory pathways, before and after treatment. The expression of 121 candidate constitutive NTSR genes including CYP71, CYP72, CYP94, oxidoreductase, ABC transporters, gluco and glycosyltransferases was measured in 220 phenotyped plants. Differential expression was validated in at least one ragweed population for 28 candidate genes. We investigated whether expression patterns at some combinations of candidate genes could predict phenotype. Within populations, prediction accuracy decreased when applied to an additional, independent plant sampling. Overall, a wide variety of genes linked to NTSR was identified within and among ragweed populations, of which only a subset was captured in our experiments.

CONCLUSION: Our results highlight the complexity and the diversity of NTSR mechanisms that can evolve in a weed species in response to herbicide selective pressure. They strongly point to a non-redundant, population-specific evolution of NTSR to ALS inhibitors in ragweed. It also alerts on the potential of common ragweed for rapid adaptation to drastic environmental or human-driven selective pressures.}, } @article {pmid37875404, year = {2023}, author = {Luo, S and Angrick, M and Coogan, C and Candrea, DN and Wyse-Sookoo, K and Shah, S and Rabbani, Q and Milsap, GW and Weiss, AR and Anderson, WS and Tippett, DC and Maragakis, NJ and Clawson, LL and Vansteensel, MJ and Wester, BA and Tenore, FV and Hermansky, H and Fifer, MS and Ramsey, NF and Crone, NE}, title = {Stable Decoding from a Speech BCI Enables Control for an Individual with ALS without Recalibration for 3 Months.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {10}, number = {35}, pages = {e2304853}, pmid = {37875404}, issn = {2198-3844}, support = {U01 DC016686/DC/NIDCD NIH HHS/United States ; UH3 NS114439/NS/NINDS NIH HHS/United States ; U01DC016686/DC/NIDCD NIH HHS/United States ; UH3NS114439/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Speech ; *Brain-Computer Interfaces ; *Amyotrophic Lateral Sclerosis/complications ; Electrocorticography ; }, abstract = {Brain-computer interfaces (BCIs) can be used to control assistive devices by patients with neurological disorders like amyotrophic lateral sclerosis (ALS) that limit speech and movement. For assistive control, it is desirable for BCI systems to be accurate and reliable, preferably with minimal setup time. In this study, a participant with severe dysarthria due to ALS operates computer applications with six intuitive speech commands via a chronic electrocorticographic (ECoG) implant over the ventral sensorimotor cortex. Speech commands are accurately detected and decoded (median accuracy: 90.59%) throughout a 3-month study period without model retraining or recalibration. Use of the BCI does not require exogenous timing cues, enabling the participant to issue self-paced commands at will. These results demonstrate that a chronically implanted ECoG-based speech BCI can reliably control assistive devices over long time periods with only initial model training and calibration, supporting the feasibility of unassisted home use.}, } @article {pmid37875101, year = {2024}, author = {Karacaoglu, C and Ersoy, S and Pala, E and Engin, VS}, title = {Evaluation of the Effectiveness of Wet Cupping Therapy in Fibromyalgia Patients: A Randomized Controlled Trial.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {10-19}, doi = {10.1159/000534637}, pmid = {37875101}, issn = {2504-2106}, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; *Cupping Therapy ; *Fibromyalgia/therapy ; Quality of Life ; Treatment Outcome ; Adolescent ; Young Adult ; Aged ; }, abstract = {INTRODUCTION: The aim of this study was to investigate the efficacy of wet cupping therapy (WCT) in patients diagnosed with fibromyalgia syndrome (FMS) as a complementary method in fibromyalgia treatment.

MATERIALS AND METHODS: A total of 120 participants between 18 and 65 years who were diagnosed with FMS were included in the study. They were randomized into two groups: 60 patients as the intervention and 60 patients as the control group. Each participant in the intervention group received 3 sessions of WCT once a month in addition to their ongoing treatment whereas the control group received only routine medical treatment. The evaluation was conducted in both groups based on the fibromyalgia impact questionnaire (FIQ), visual analog scale (VAS), and quality of life scale (QoL) parameters initially (at 0th week) and 1 week after the WCT sessions (at the 10th week). For the comparison of quantitative variables showing a normal distribution between the two groups, the Student's t test was used, while the Mann-Whitney U test was employed for variables not showing a normal distribution. The χ2 test and Continuity (Yates) Correction were used for the comparison of qualitative data. The significance level was set at p < 0.05.

RESULTS: The study included 107 female and 13 male participants, with a mean age of 45.79 ± 8.49 years. When comparing the pretreatment FIQ, VAS, and QoL scores with the scores obtained after three sessions of WCT, it was observed that in the WCT group, the FIQ and VAS values significantly decreased compared to the control group while the QoL significantly increased compared to the control group (p < 0.001 in all).

CONCLUSION: The findings obtained from this study indicate that WCT can be an effective treatment option for patients with FMS.

UNLABELLED: EinleitungMit dieser Studie soll die Wirksamkeit der blutigen Schröpftherapie (wet cupping therapy, WCT) bei Patienten mit diagnostiziertem Fibromyalgie-Syndrom (FMS) als komplementäre Methode in der Fibromyalgie-Behandlung untersucht werden.Material und MethodenInsgesamt wurden 120 Teilnehmer mit diagnostiziertem FMS zwischen 18 und 65 Jahren in die Studie aufgenommen. Diese wurden randomisiert zwei Gruppen zugeordnet: 60 Patienten wurden der Interventionsgruppe zugewiesen und 60 Patienten der Kontrollgruppe. Alle Teilnehmer der Interventionsgruppe erhielten einmal im Monat drei Sitzungen WCT zusätzlich zu ihrer laufenden Therapie, während die Kontrollgruppe lediglich die Standardbehandlung erhielt. Die Bewertung erfolgte in beiden Gruppen anhand des Fibromyalgia Impact Questionnaire (FIQ), der Visuellen Analogskala (VAS) und der Parameter der Quality of Life (QoL) Scale zu Beginn (in Woche 0) und eine Woche nach den WCT-Sitzungen (in Woche 10). Für den Vergleich von quantitativen Variablen, die eine Normalverteilung zwischen den beiden Gruppen aufwiesen, wurde der Student’s t-Test verwendet, während bei Variablen ohne Normalverteilung der Mann-Whitney-U-Test zur Anwendung kam. Qualitative Daten wurden mit dem Chi-Quadrat-Test und der Kontinuitätskorrektur (Yates) verglichen. Das Signifikanzniveau wurde auf p < 0,05 festgelegt.ErgebnisseIn die Studie wurden 107 Frauen und 13 Männer mit einem Durchschnittsalter von 45,79 ± 8,49 Jahren aufgenommen. Beim Vergleich der FIQ-, VAS- und QoL-Werte vor der Behandlung mit den nach drei WCT-Sitzungen erhobenen Werten zeigte sich in der WCT-Gruppe ein signifikanter Rückgang der FIQ- und VAS-Werte im Vergleich zur Kontrollgruppe, wohingegen bei der QoL ein signifikanter Anstieg gegenüber der Kontrollgruppe zu beobachten war (p < 0,001 in allen Fällen).SchlussfolgerungDie Ergebnisse dieser Studie deuten darauf hin, dass die WCT eine wirksame therapeutische Option für Patienten mit FMS sein kann.}, } @article {pmid37874905, year = {2023}, author = {Harrison, D and Billinton, A and Bock, MG and Doedens, JR and Gabel, CA and Holloway, MK and Porter, RA and Reader, V and Scanlon, J and Schooley, K and Watt, AP}, title = {Discovery of Clinical Candidate NT-0796, a Brain-Penetrant and Highly Potent NLRP3 Inflammasome Inhibitor for Neuroinflammatory Disorders.}, journal = {Journal of medicinal chemistry}, volume = {66}, number = {21}, pages = {14897-14911}, doi = {10.1021/acs.jmedchem.3c01398}, pmid = {37874905}, issn = {1520-4804}, mesh = {Humans ; *Inflammasomes/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/physiology ; Neuroinflammatory Diseases ; Brain/metabolism ; Esters ; }, abstract = {The NLRP3 inflammasome is a component of the innate immune system involved in the production of proinflammatory cytokines. Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, have been shown to have a component driven by NLRP3 inflammasome activation. Diseases such as these with large unmet medical needs have resulted in an interest in inhibiting the NLRP3 inflammasome as a potential pharmacological treatment, but to date, no marketed drugs specifically targeting NLRP3 have been approved. Furthermore, the requirement for CNS-penetrant molecules adds additional complexity to the search for NLRP3 inflammasome inhibitors suitable for clinical investigation of neuroinflammatory disorders. We designed a series of ester-substituted carbamate compounds as selective NLRP3 inflammasome inhibitors, leading to NT-0796, an isopropyl ester that undergoes intracellular conversion to NDT-19795, the carboxylic acid active species. NT-0796 was shown to be a potent and selective NLRP3 inflammasome inhibitor with demonstrated in vivo brain penetration.}, } @article {pmid37874476, year = {2024}, author = {Liu, Y and He, X and Yuan, Y and Li, B and Liu, Z and Li, W and Li, K and Tan, S and Zhu, Q and Tang, Z and Han, F and Wu, Z and Shen, L and Jiang, H and Tang, B and Qiu, J and Hu, Z and Wang, J}, title = {Association of TRMT2B gene variants with juvenile amyotrophic lateral sclerosis.}, journal = {Frontiers of medicine}, volume = {18}, number = {1}, pages = {68-80}, pmid = {37874476}, issn = {2095-0225}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Neurodegenerative Diseases ; HEK293 Cells ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons, and it demonstrates high clinical heterogeneity and complex genetic architecture. A variation within TRMT2B (c.1356G>T; p.K452N) was identified to be associated with ALS in a family comprising two patients with juvenile ALS (JALS). Two missense variations and one splicing variation were identified in 10 patients with ALS in a cohort with 910 patients with ALS, and three more variants were identified in a public ALS database including 3317 patients with ALS. A decreased number of mitochondria, swollen mitochondria, lower expression of ND1, decreased mitochondrial complex I activities, lower mitochondrial aerobic respiration, and a high level of ROS were observed functionally in patient-originated lymphoblastoid cell lines and TRMT2B interfering HEK293 cells. Further, TRMT2B variations overexpression cells also displayed decreased ND1. In conclusion, a novel JALS-associated gene called TRMT2B was identified, thus broadening the clinical and genetic spectrum of ALS.}, } @article {pmid37873269, year = {2023}, author = {Pottinger, TD and Motelow, JE and Povysil, G and Moreno, CAM and Ren, Z and Phatnani, H and , and Aitman, TJ and Santoyo-Lopez, J and , and Mitsumoto, H and , and , and , and Goldstein, DB and Harms, MB}, title = {Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {37873269}, support = {K01 MH098126/MH/NIMH NIH HHS/United States ; RC2 MH089915/MH/NIMH NIH HHS/United States ; P01 HD080642/HD/NICHD NIH HHS/United States ; R01 MH097971/MH/NIMH NIH HHS/United States ; RC2 NS070344/NS/NINDS NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UM1 AI100645/AI/NIAID NIH HHS/United States ; P30 AG028377/AG/NIA NIH HHS/United States ; U54 NS078059/NS/NINDS NIH HHS/United States ; P01 AG007232/AG/NIA NIH HHS/United States ; RF1 AG054023/AG/NIA NIH HHS/United States ; R01 HD048805/HD/NICHD NIH HHS/United States ; U01 HG007672/HG/NHGRI NIH HHS/United States ; U01 NS053998/NS/NINDS NIH HHS/United States ; U01 NS077303/NS/NINDS NIH HHS/United States ; U19 AI067854/AI/NIAID NIH HHS/United States ; R01 AG037212/AG/NIA NIH HHS/United States ; R01 ES016348/ES/NIEHS NIH HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 30,000 people in the United States. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms, such as antisense oligonucleotides, continue to develop, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.

METHODS: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger cohort of 6,970 ALS patients from a large multi-ethnic cohort as well as 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.

RESULTS: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR=19.18, p = 3.67 × 10[-39]; OR=4.73, p = 2 × 10[-10]; OR=2.3, p = 7.49 × 10[-9], respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10[-7]), was protective for ALS in this model. An intolerant domain based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR=10.08, p = 3.62 × 10[-16]). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p=8.38 × 10[-6]).

CONCLUSIONS: In a large multi-ethnic cohort of 6,970 ALS patients, rare variant burden testing validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.}, } @article {pmid37873158, year = {2024}, author = {Alecki, C and Rizwan, J and Le, P and Jacob-Tomas, S and Fernandez-Comaduran, M and Verbrugghe, M and Xu, JSM and Minotti, S and Lynch, J and Biswas, J and Wu, T and Durham, H and Yeo, GW and Vera, M}, title = {Localized synthesis of molecular chaperones sustains neuronal proteostasis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.10.03.560761}, pmid = {37873158}, issn = {2692-8205}, abstract = {Neurons are challenged to maintain proteostasis in neuronal projections, particularly with the physiological stress at synapses to support intercellular communication underlying important functions such as memory and movement control. Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. Using high-resolution fluorescent microscopy, we discovered that neurons localize a subset of chaperone mRNAs to their dendrites, particularly more proximal regions, and increase this asymmetric localization following proteotoxic stress through microtubule-based transport from the soma. The most abundant chaperone mRNA in dendrites encodes the constitutive heat shock protein 70, HSPA8. Proteotoxic stress in cultured neurons, induced by inhibiting proteasome activity or inducing oxidative stress, enhanced transport of Hspa8 mRNAs to dendrites and the percentage of mRNAs engaged in translation on mono and polyribosomes. Knocking down the ALS-related protein Fused in Sarcoma (FUS) and a dominant mutation in the heterogenous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) impaired stress-mediated localization of Hspa8 mRNA to dendrites in cultured murine motor neurons and human iPSC-derived neurons, respectively, revealing the importance of these RNA-binding proteins in maintaining proteostasis. These results reveal the increased dendritic localization and translation of the constitutive HSP70 Hspa8 mRNA as a crucial neuronal stress response to uphold proteostasis and prevent neurodegeneration.}, } @article {pmid37873064, year = {2023}, author = {Mann, N and Hill, J and Wang, K and Hughes, RM}, title = {OptoProfilin: A Single Component Biosensor of Applied Cellular Stress.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37873064}, issn = {2692-8205}, support = {R15 NS125564/NS/NINDS NIH HHS/United States ; }, abstract = {The actin cytoskeleton is a biosensor of cellular stress and a potential prognosticator of human disease. In particular, aberrant cytoskeletal structures such as cofilin-actin rods and stress granules formed in response to energetic and oxidative stress are closely linked to neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. Whether these cytoskeletal phenomena can be harnessed for the development of biosensors for cytoskeletal dysfunction and, by extension, neurodegenerative disease progression, remains an open question. In this work, we describe the design and development of an optogenetic iteration of profilin, an actin monomer binding protein with critical functions in cytoskeletal dynamics. We demonstrate that this optically activated profilin ('OptoProfilin') can act as an optically triggered biosensor of applied cellular stress in select immortalized cell lines. Notably, OptoProfilin is a single component biosensor, likely increasing its utility for experimentalists. While a large body of preexisting work closely links profilin activity with cellular stress and neurodegenerative disease, this, to our knowledge, is the first example of profilin as an optogenetic biosensor of stress-induced changes in the cytoskeleton.}, } @article {pmid37872794, year = {2023}, author = {You, FL and Xia, GF and Cai, J}, title = {Behavioural Variant Frontotemporal Dementia due to CCNF Gene Mutation: A Case Report.}, journal = {Current Alzheimer research}, volume = {20}, number = {5}, pages = {371-378}, doi = {10.2174/1567205020666230811092906}, pmid = {37872794}, issn = {1875-5828}, mesh = {Male ; Humans ; Aged ; *Frontotemporal Dementia/diagnosis/genetics ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Neurodegenerative Diseases ; Memantine/therapeutic use ; Mutation/genetics ; Neuropsychological Tests ; Sodium ; Cyclins/genetics ; }, abstract = {BACKGROUND: Frontal, temporal lobe dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative diseases. Studies have found that CCNF mutations have been found in patients with familial and sporadic ALS and FTD. Behavioural variant frontotemporal dementia (bvFTD) is a clinical syndrome characterized by progressive deterioration of personality, social behaviour, and cognitive function, which is most closely related to genetic factors. As the early symptoms of bvFTD are highly heterogeneous, the condition is often misdiagnosed as Alzheimer's disease or psychiatric disorders. In this study, a bvFTD patient had a CCNF gene mutation, which led to ubiquitinated protein accumulation and ultimately caused neurodegenerative disease. Genetic detection should be improved urgently for bvFTD patients and family members to provide a clinical reference for early diagnosis of frontotemporal dementia.

CASE PRESENTATION: In this case, the patient was 65 years old with an insidious onset, early-onset memory loss, a significant decline in the episodic memory, an early AD diagnosis, and oral treatment with donepezil hydrochloride for 3 years with poor efficacy, followed by a change to oral memantine hydrochloride tablets, which controlled the condition for several months. His medication was switched to sodium oligomannate capsules, and his condition was gradually controlled, but no significant improvement was observed. After spontaneous drug withdrawal, the patient's condition progressed rapidly; therefore, he visited our hospital and underwent neuropsychological tests for moderate to severe cognitive impairment. AD cerebrospinal fluid markers showed no significant abnormalities, and cranial MRI revealed frontotemporal lobe atrophy and decreased hippocampal volume. Genetic testing for the presence of the CCNF gene revealed a c.1532C > A (p. T511N) heterozygous variant, which might be a diagnostic criterion for bvFTD. Therefore, the patient's symptoms recurred after transient improvement with the combination of donepezil, oral memantine hydrochloride tablets, and sodium oligomannate, but his overall condition was improved compared to that before, and this treatment regimen was continued to observe changes during the follow-up.

CONCLUSION: The early clinical manifestations of bvFTD are complex and variable, and the condition is easily misdiagnosed, thus delaying treatment. Therefore, for patients with a high clinical suspicion of FTD, in addition to a detailed understanding of their medical history and family history and improvement of relevant examinations, genetic testing should be performed as early as possible to help confirm the diagnosis. For diseases closely related to genes, genetic testing of other family members should be optimised as much as possible to allow early diagnosis and intervention and guide fertility in the next generation.}, } @article {pmid37872607, year = {2023}, author = {Falker-Gieske, C}, title = {Transcriptome driven discovery of novel candidate genes for human neurological disorders in the telomer-to-telomer genome assembly era.}, journal = {Human genomics}, volume = {17}, number = {1}, pages = {94}, pmid = {37872607}, issn = {1479-7364}, support = {R01 GM129325/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Transcriptome/genetics ; Genomics ; *Nervous System Diseases/genetics ; Sequence Analysis, RNA ; Telomere ; }, abstract = {BACKGROUND: With the first complete draft of a human genome, the Telomere-to-Telomere Consortium unlocked previously concealed genomic regions for genetic analyses. These regions harbour nearly 2000 potential novel genes with unknown function. In order to uncover candidate genes associated with human neurological pathologies, a comparative transcriptome study using the T2T-CHM13 and the GRCh38 genome assemblies was conducted on previously published datasets for eight distinct human neurological disorders.

RESULTS: The analysis of differential expression in RNA sequencing data led to the identification of 336 novel candidate genes linked to human neurological disorders. Additionally, it was revealed that, on average, 3.6% of the differentially expressed genes detected with the GRCh38 assembly may represent potential false positives. Among the noteworthy findings, two novel genes were discovered, one encoding a pore-structured protein and the other a highly ordered β-strand-rich protein. These genes exhibited upregulation in multiple epilepsy datasets and hold promise as candidate genes potentially modulating the progression of the disease. Furthermore, an analysis of RNA derived from white matter lesions in multiple sclerosis patients indicated significant upregulation of 26 rRNA encoding genes. Additionally, putative pathology related genes were identified for Alzheimer's disease, amyotrophic lateral sclerosis, glioblastoma, glioma, and conditions resulting from the m.3242 A > G mtDNA mutation.

CONCLUSION: The results presented here underline the potential of the T2T-CHM13 assembly in facilitating the discovery of candidate genes from transcriptome data in the context of human disorders. Moreover, the results demonstrate the value of remapping sequencing data to a superior genome assembly. Numerous potential pathology related genes, either as causative factors or related elements, have been unveiled, warranting further experimental validation.}, } @article {pmid37872558, year = {2023}, author = {Schmitz, J and Liebold, F and Hinkelbein, J and Nöhl, S and Thal, SC and Sellmann, T}, title = {Cardiopulmonary resuscitation during hyperbaric oxygen therapy: a comprehensive review and recommendations for practice.}, journal = {Scandinavian journal of trauma, resuscitation and emergency medicine}, volume = {31}, number = {1}, pages = {57}, pmid = {37872558}, issn = {1757-7241}, mesh = {Humans ; *Cardiopulmonary Resuscitation ; *Heart Arrest/therapy ; Heart Massage ; *Hyperbaric Oxygenation ; Ventricular Fibrillation ; Practice Guidelines as Topic ; }, abstract = {BACKGROUND: Cardiopulmonary resuscitation (CPR) during hyperbaric oxygen therapy (HBOT) presents unique challenges due to limited access to patients in cardiac arrest (CA) and the distinct physiological conditions present during hyperbaric therapy. Despite these challenges, guidelines specifically addressing CPR during HBOT are lacking. This review aims to consolidate the available evidence and offer recommendations for clinical practice in this context.

MATERIALS AND METHODS: A comprehensive literature search was conducted in PubMed, EMBASE, Cochrane Library, and CINAHL using the search string: "(pressure chamber OR decompression OR hyperbaric) AND (cardiac arrest OR cardiopulmonary resuscitation OR advanced life support OR ALS OR life support OR chest compression OR ventricular fibrillation OR heart arrest OR heart massage OR resuscitation)". Additionally, relevant publications and book chapters not identified through this search were included.

RESULTS: The search yielded 10,223 publications, with 41 deemed relevant to the topic. Among these, 18 articles (primarily case reports) described CPR or defibrillation in 22 patients undergoing HBOT. The remaining 23 articles provided information or recommendations pertaining to CPR during HBOT. Given the unique physiological factors during HBOT, the limitations of current resuscitation guidelines are discussed.

CONCLUSIONS: CPR in the context of HBOT is a rare, yet critical event requiring special considerations. Existing guidelines should be adapted to address these unique circumstances and integrated into regular training for HBOT practitioners. This review serves as a valuable contribution to the literature on "CPR under special circumstances".}, } @article {pmid37872557, year = {2023}, author = {Li, C and Wei, Q and Hou, Y and Lin, J and Ou, R and Zhang, L and Jiang, Q and Xiao, Y and Liu, K and Chen, X and Yang, T and Song, W and Zhao, B and Wu, Y and Shang, H}, title = {Genome-wide analyses identify NEAT1 as genetic modifier of age at onset of amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {77}, pmid = {37872557}, issn = {1750-1326}, mesh = {Humans ; Age of Onset ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Asian People ; Genome-Wide Association Study/methods ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) demonstrate great heterogeneity in the age at onset (AAO), which is closely related to the course of disease. However, most genetic studies focused on the risk of ALS, while the genetic background underlying AAO of ALS is still unknown.

METHODS: To identify genetic determinants influencing AAO of ALS, we performed genome-wide association analysis using a Cox proportional hazards model in 2,841 patients with ALS (Ndiscovery = 2,272, Nreplication = 569) in the Chinese population. We further conducted colocalization analysis using public cis-eQTL dataset, and Mendelian randomization analysis to identify risk factors for AAO of ALS. Finally, functional experiments including dual-luciferase reporter assay and RT-qPCR were performed to explore the regulatory effect of the target variant.

RESULTS: The total heritability of AAO of ALS was ~ 0.24. One novel locus rs10128627 (FRMD8) was significantly associated with earlier AAO by ~ 3.15 years (P = 1.54E-08, beta = 0.31, SE = 0.05). This locus was cis-eQTL of NEAT1 in multiple brain tissues and blood. Colocalization analysis detected association signals at this locus between AAO of ALS and expression of NEAT1. Furthermore, functional exploration supported the variant rs10128627 was associated with upregulated expression of NEAT1 in cell models and patients with ALS. Causal inference suggested higher total cholesterol, low-density lipoprotein, and eosinophil were nominally associated with earlier AAO of ALS, while monocyte might delay the AAO.

CONCLUSIONS: Collective evidence from genetic, bioinformatic, and functional results suggested NEAT1 as a key player in the disease progression of ALS. These findings improve the current understanding of the genetic role in AAO of ALS, and provide a novel target for further research on the pathogenesis and therapeutic options to delay the disease onset.}, } @article {pmid37871782, year = {2024}, author = {Burns, B and Marschner, I and Eggins, R and Buscher, H and Morton, RL and Bendall, J and Keech, A and Dennis, M and , }, title = {A randomized trial of expedited intra-arrest transfer versus more extended on-scene resuscitation for refractory out of hospital cardiac arrest: Rationale and design of the EVIDENCE trial.}, journal = {American heart journal}, volume = {267}, number = {}, pages = {22-32}, doi = {10.1016/j.ahj.2023.10.003}, pmid = {37871782}, issn = {1097-6744}, mesh = {Adolescent ; Adult ; Aged ; Humans ; Middle Aged ; Young Adult ; *Cardiopulmonary Resuscitation ; *Emergency Medical Services ; *Out-of-Hospital Cardiac Arrest/therapy ; Prospective Studies ; Quality of Life ; *Tachycardia, Ventricular ; }, abstract = {BACKGROUND: Refractory Out of Hospital Cardiac Arrest (r-OHCA) is common and the benefit versus harm of intra-arrest transport of patients to hospital is not clear.

OBJECTIVE: To assess the rate of survival to hospital discharge in adult patients with r-OHCA, initial rhythm pulseless ventricular tachycardia (VT)/ventricular fibrillation (VF) or Pulseless Electrical Activity (PEA) treated with 1 of 2 locally accepted standards of care:[1] expedited transport from scene; or[2] ongoing advanced life support (ALS) resuscitation on-scene.

HYPOTHESIS: We hypothesize that expedited transport from scene in r-OHCA improves survival with favorable neurological status/outcome.

METHODS/DESIGN: Phase III, multi-center, partially blinded, prospective, intention-to-treat, safety and efficacy clinical trial with contemporaneous registry of patient ineligible for the clinical trial. Eligible patients for inclusion are adults with witnessed r-OHCA; estimated age 18 to 70, assumed medical cause with immediate bystander cardiopulmonary resuscitation (CPR); initial rhythm of VF/pulseless VT, or PEA; no return of spontaneous circulation following 3 shocks and/or 15 minutes of professional on-scene resuscitation; with mechanical CPR available. Two hundred patients will be randomized in a 1:1 ratio to either expedited transport from scene or ongoing ALS at the scene of cardiac arrest.

SETTING: Two urban regions in NSW Australia.

OUTCOMES: Primary: survival to hospital discharge with cerebral performance category (CPC) 1 or 2. Secondary: safety, survival, prognostic factors, use of ECMO supported CPR and functional assessment at hospital discharge and 4 weeks and 6 months, quality of life, healthcare use and cost-effectiveness.

CONCLUSIONS: The EVIDENCE trial will determine the potential risks and benefits of an expedited transport from scene of cardiac arrest.}, } @article {pmid37870685, year = {2023}, author = {Zhou, L and Chen, W and Jiang, S and Xu, R}, title = {In Vitro Models of Amyotrophic Lateral Sclerosis.}, journal = {Cellular and molecular neurobiology}, volume = {43}, number = {8}, pages = {3783-3799}, pmid = {37870685}, issn = {1573-6830}, support = {30560042//National Natural Science Foundation of China/ ; 81160161//National Natural Science Foundation of China/ ; 81360198//National Natural Science Foundation of China/ ; 82160255//National Natural Science Foundation of China/ ; GJJ13198//Education Department of Jiangxi Province/ ; GJJ170021//Education Department of Jiangxi Province/ ; 20192BAB205043//Jiangxi Provincial Department of Science and Technology/ ; 20181019//Health and Family Planning Commission of Jiangxi Province/ ; 202210002//Health and Family Planning Commission of Jiangxi Province/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Disease Models, Animal ; Motor Neurons/metabolism ; Mutation/genetics ; Superoxide Dismutase/metabolism ; Mice, Transgenic ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is one of the commonest neurodegenerative diseases of adult-onset, which is characterized by the progressive death of motor neurons in the cerebral cortex, brain stem and spinal cord. The dysfunction and death of motor neurons lead to the progressive muscle weakness, atrophy, fasciculations, spasticity and ultimately the whole paralysis of body. Despite the identification of several genetic mutations associated with the pathogenesis of ALS, including mutations in chromosome 9 open reading frame 72 leading to the abnormal expansion of GGGGCC repeat sequence, TAR DNA-binding protein 43, fused in sarcoma/translocated in liposarcoma, copper/zinc superoxide dismutase 1 (SOD1) and TANK-binding kinase 1, the exact mechanisms underlying the specific degeneration of motor neurons that causes ALS remain incompletely understood. At present, since the transgenic model expressed SOD1 mutants was established, multiple in vitro models of ALS have been developed for studying the pathology, pathophysiology and pathogenesis of ALS as well as searching the effective neurotherapeutics. This review reviewed the details of present established in vitro models used in studying the pathology, pathophysiology and pathogenesis of ALS. Meanwhile, we also discussed the advantages, disadvantages, cost and availability of each models.}, } @article {pmid37870677, year = {2024}, author = {Wang, S and Zheng, X and Wei, Q and Lin, J and Yang, T and Xiao, Y and Jiang, Q and Li, C and Shang, H}, title = {Rare DNAJC7 Variants May Play a Minor Role in Chinese Patients with ALS.}, journal = {Molecular neurobiology}, volume = {61}, number = {4}, pages = {2265-2269}, pmid = {37870677}, issn = {1559-1182}, support = {2022ZDZX0023//Sichuan Science and Technology Program/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Genetic Association Studies ; Mutation, Missense ; Gene Frequency ; China ; Heat-Shock Proteins/genetics ; Molecular Chaperones ; }, abstract = {DnaJ heat shock protein family member C7 gene (DNAJC7) has been identified as a genetic risk factor for amyotrophic lateral sclerosis (ALS). In our study, we aimed to screen for rare variants in DNAJC7 in a large cohort of Chinese ALS patients, and investigate the genotype-phenotype correlation of DNAJC7 in ALS. Four (0.19%) variants of DNAJC7 with minor allele frequency (MAF) < 0.1% among 2124 patients were identified, including 1 protein-truncating variant and 3 missense variants, all of which were predicted to be damaging. The patients carrying variants of DNAJC7 in our cohort tented to have a limb onset and a relatively slow disease progression. However, burden analysis did not show an enrichment of rare damaging variants in ALS patients compared to controls. Further analysis involving diverse regions and larger sample size is necessary to elucidate the role of DNAJC7 in the pathogenicity of ALS.}, } @article {pmid37870566, year = {2023}, author = {Miller, CCJ and Gomez-Suaga, P}, title = {Poor communication between ER and mitochondria: a signature of ALS/FTD?.}, journal = {Aging}, volume = {15}, number = {20}, pages = {10814-10816}, pmid = {37870566}, issn = {1945-4589}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; DNA Repeat Expansion ; Mitochondria ; }, } @article {pmid37868386, year = {2023}, author = {Hoxhaj, P and Hastings, N and Kachhadia, MP and Gupta, R and Sindhu, U and Durve, SA and Azam, A and Auz Vinueza, MJ and Bhuvan, and Win, SH and Rathod, DC and Afsar, AP}, title = {Exploring Advancements in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review of Current Modalities and Future Prospects.}, journal = {Cureus}, volume = {15}, number = {9}, pages = {e45489}, pmid = {37868386}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and incurable disease requiring a multidisciplinary treatment approach and a collaborative therapeutic effort. A combination of both upper and lower motor neuron degeneration ultimately leads to respiratory failure, similar to other dementia-type neurodegenerative diseases. The aim of this paper is to pioneer current ALS research by carrying out a narrative literature review of the current treatment modalities of the disease. Through these efforts, we hope to condense the most pertinent information regarding current treatments and enhance the management of ALS patients as a whole, giving these patients a better quality of life as the search for a cure continues. We used a Pubmed search strategy and specific MeSH terms for the selection of the literature articles using the keywords "ALS," "new treatment," "treatment," and "symptomatic treatment." A combination of pharmaceutical interventions, psychological support, and physical rehabilitation has been most effective in enhancing the quality of life of patients with ALS (PALS). Among potential pharmacological therapies, only a few have been approved by the US Food and Drug Administration(FDA) to be used to treat ALS and its symptoms. Other treatment modalities being considered include gene therapy, cellular therapy, psychological therapy, physical therapy, and speech therapy, alongside robotics, alternative feeding methods, and communication devices.}, } @article {pmid37865869, year = {2024}, author = {Vélez-GóMEZ, B and Perna, A and Vazquez, C and Ketzoian, C and Lillo, P and Godoy-Reyes, G and Sáez, D and Zaldivar Vaillant, T and Gutiérrez Gil, JV and Lara-Fernández, GE and Povedano, M and Heverin, M and McFarlane, R and Logroscino, G and Hardiman, O}, title = {LAENALS: epidemiological and clinical features of amyotrophic lateral sclerosis in Latin America.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {119-127}, doi = {10.1080/21678421.2023.2271517}, pmid = {37865869}, issn = {2167-9223}, mesh = {Male ; Humans ; Female ; Latin America/epidemiology ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Cuba/epidemiology ; Uruguay/epidemiology ; Prevalence ; }, abstract = {OBJECTIVE: The Latin American Epidemiologic study of ALS (LAENALS) aims to gather data on ALS epidemiology, phenotype, and risk factors in Cuba, Chile, and Uruguay, to understand the impact of genetic and environmental factors on ALS.

METHODS: A harmonized data collection protocol was generated, and a Latin-American Spanish language Register was constructed. Patient data were collected in Uruguay in 2018, in Chile from 2017 to 2019, and in Cuba between 2017 and 2018. Statistical analysis was performed using SPSS 25.0.0 software. Crude cumulative incidence, standardized incidence, and prevalence were calculated in the population aged 15 years and older.

RESULTS: During 2017-2019, 90 people with ALS from Uruguay (55.6% men), 219 from Chile (54.6% men), and 49 from Cuba (55.1% men) were included. The cumulative crude incidence in 2018 was 1.73/100,000 persons in Uruguay, 1.08 in Chile and 0.195 in Cuba. Crude prevalence in 2018 was 2.19 per 100,000 persons in Uruguay, 1.39 in Chile and 0.55 in Cuba. Mean age at onset was 61.8 ± 11.96 SD years in Uruguay, 61.9 ± 10.4 SD years in Chile, and 60.21 ± 12.45 SD years in Cuba (p = 0.75). Median survival from onset was 32.43 months (21.93 - 42.36) in Uruguay, 24 months (13.5 - 33.5) in Chile, and 29 months (15 - 42.5) in Cuba (p = 0.006).

CONCLUSIONS: These preliminary data from LAENALS confirm the lower incidence and prevalence of ALS in counties with admixed populations. The LAENALS database is now open to other Latin American countries for harmonized prospective data collection.}, } @article {pmid37865833, year = {2023}, author = {Wu, YK and Wecht, JM and Bloom, OE and Panza, GS and Harel, NY}, title = {Remote Ischemic conditioning as an emerging tool to improve corticospinal transmission in individuals with chronic spinal cord injury.}, journal = {Current opinion in neurology}, volume = {36}, number = {6}, pages = {523-530}, doi = {10.1097/WCO.0000000000001216}, pmid = {37865833}, issn = {1473-6551}, support = {R03 HD097709/HD/NICHD NIH HHS/United States ; }, mesh = {Adult ; Humans ; *Myocardial Infarction ; *Stroke ; *Spinal Cord Injuries ; Hypoxia ; }, abstract = {PURPOSE OF REVIEW: Remote ischemic conditioning (RIC) involves transient blood flow restriction to one limb leading to systemic tissue-protective effects. RIC shares some potential underlying mechanisms with intermittent hypoxia (IH), in which brief bouts of systemic hypoxia trigger increases in growth factor expression and neural plasticity. RIC has shown promise in acute myocardial infarction and stroke but may be applicable toward chronic neuropathology as well. Consequently, this review discusses similarities and differences between RIC and IH and presents preliminary and ongoing research findings regarding RIC.

RECENT FINDINGS: Several publications demonstrated that combining RIC with motor training may enhance motor learning in adults with intact nervous systems, though the precise mechanisms were unclear. Our own preliminary data has found that RIC, in conjunction with task specific exercise, can increase corticospinal excitability in a subset of people without neurological injury and in those with chronic cervical spinal cord injury or amyotrophic lateral sclerosis.

SUMMARY: RIC is a low-cost intervention easy to deliver in a clinical or home setting. Its potential application to facilitate neural plasticity and motor learning during rehabilitation training for individuals with chronic neurological disorders is a novel concept requiring further investigation to characterize mechanisms, safety, and efficacy.}, } @article {pmid37864389, year = {2024}, author = {Xiao, F and He, Z and Wang, S and Li, J and Fan, X and Yan, T and Yang, M and Yang, D}, title = {Regulatory mechanism of circular RNAs in neurodegenerative diseases.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {4}, pages = {e14499}, pmid = {37864389}, issn = {1755-5949}, support = {//China Scholarship Council/ ; //National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/genetics ; RNA, Circular/metabolism ; *MicroRNAs/genetics ; *Alzheimer Disease/genetics ; *Parkinson Disease ; Biomarkers ; }, abstract = {BACKGROUND: Neurodegenerative disease is a collective term for a category of diseases that are caused by neuronal dysfunction, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Circular RNAs (circRNAs) are a class of non-coding RNAs without the 3' cap and 5' poly(A) and are linked by covalent bonds. CircRNAs are highly expressed in brain neurons and can regulate the pathological process of neurodegenerative diseases by affecting the levels of various deposition proteins.

AIMS: This review is aiming to suggest that the majority of circRNAs influence neurodegenerative pathologies mainly by affecting the abnormal deposition of proteins in neurodegenerative diseases.

METHODS: We systematically summarized the pathological features of neurodegenerative diseases and the regulatory mechanisms of circRNAs in various types of neurodegenerative diseases.

RESULTS: Neurodegenerative disease main features include intercellular ubiquitin-proteasome system abnormalities, changes in cytoskeletal proteins, and the continuous deposition of insoluble protein fragments and inclusion bodies in the cytoplasm or nucleus, resulting in impairment of the normal physiological processes of the neuronal system. CircRNAs have multiple mechanisms, such as acting as microRNA sponges, binding to proteins, and regulating transcription. CircRNAs, which are highly stable molecules, are expected to be potential biomarkers for the pathological detection of neurodegenerative diseases such as AD and PD.

CONCLUSIONS: In this review, we describe the regulatory roles and mechanisms of circRNAs in neurodegenerative diseases and aim to employ circRNAs as biomarkers for the diagnosis and treatment of neurodegenerative diseases.}, } @article {pmid37864255, year = {2023}, author = {Godfrey, RK and Alsop, E and Bjork, RT and Chauhan, BS and Ruvalcaba, HC and Antone, J and Gittings, LM and Michael, AF and Williams, C and Hala'ufia, G and Blythe, AD and Hall, M and Sattler, R and Van Keuren-Jensen, K and Zarnescu, DC}, title = {Modelling TDP-43 proteinopathy in Drosophila uncovers shared and neuron-specific targets across ALS and FTD relevant circuits.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {168}, pmid = {37864255}, issn = {2051-5960}, support = {RF1 NS091299/NS/NINDS NIH HHS/United States ; T34 GM008718/GM/NIGMS NIH HHS/United States ; R01 NS091299/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; DNA-Binding Proteins/genetics/metabolism ; Drosophila/metabolism ; *Frontotemporal Dementia/genetics/pathology ; Motor Neurons/metabolism ; *Pick Disease of the Brain/pathology ; RNA, Messenger ; *TDP-43 Proteinopathies/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comprise a spectrum of neurodegenerative diseases linked to TDP-43 proteinopathy, which at the cellular level, is characterized by loss of nuclear TDP-43 and accumulation of cytoplasmic TDP-43 inclusions that ultimately cause RNA processing defects including dysregulation of splicing, mRNA transport and translation. Complementing our previous work in motor neurons, here we report a novel model of TDP-43 proteinopathy based on overexpression of TDP-43 in a subset of Drosophila Kenyon cells of the mushroom body (MB), a circuit with structural characteristics reminiscent of vertebrate cortical networks. This model recapitulates several aspects of dementia-relevant pathological features including age-dependent neuronal loss, nuclear depletion and cytoplasmic accumulation of TDP-43, and behavioral deficits in working memory and sleep that occur prior to axonal degeneration. RNA immunoprecipitations identify several candidate mRNA targets of TDP-43 in MBs, some of which are unique to the MB circuit and others that are shared with motor neurons. Among the latter is the glypican Dally-like-protein (Dlp), which exhibits significant TDP-43 associated reduction in expression during aging. Using genetic interactions we show that overexpression of Dlp in MBs mitigates TDP-43 dependent working memory deficits, conistent with Dlp acting as a mediator of TDP-43 toxicity. Substantiating our findings in the fly model, we find that the expression of GPC6 mRNA, a human ortholog of dlp, is specifically altered in neurons exhibiting the molecular signature of TDP-43 pathology in FTD patient brains. These findings suggest that circuit-specific Drosophila models provide a platform for uncovering shared or disease-specific molecular mechanisms and vulnerabilities across the spectrum of TDP-43 proteinopathies.}, } @article {pmid37863900, year = {2023}, author = {Hutter, N and Hendricks, S and Jutila, A and Ricker, R and von Albedyll, L and Birnbaum, G and Haas, C}, title = {Digital elevation models of the sea-ice surface from airborne laser scanning during MOSAiC.}, journal = {Scientific data}, volume = {10}, number = {1}, pages = {729}, pmid = {37863900}, issn = {2052-4463}, support = {03F0866A//Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)/ ; 03F0866A//Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)/ ; NA20OAR4320271 - 2023-1311//United States Department of Commerce | National Oceanic and Atmospheric Administration (NOAA)/ ; }, abstract = {Airborne laser scanners (ALS) are used to map the sea-ice surface at sub-meter resolution. We conducted 64 flights over the Arctic sea ice between September 2019 and September 2020 during the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition to measure sea-ice surface elevation. The flights ranged from repeated, local-scale 5 × 5 km[2] floe grid surveys to regional-scale transects more than 100 km long. We provide data at different processing levels: geolocated elevation point clouds and gridded segments of elevation and freeboard with a spatial resolution of 0.5 m. The latter product is corrected for atmospheric backscatter, sea-ice drift, and offset in elevation due to degraded INS/GNSS solutions > 85° N. For floe grid surveys, all data are combined to merged two-dimensional elevation maps. Other provided parameters include laser reflectance and echo width. The presented data offer a unique possibility to study the temporal evolution, spatial distribution, and variability of the snow and sea-ice surface and their properties in addition to validating satellite products.}, } @article {pmid37863594, year = {2023}, author = {The Lancet Neurology, }, title = {Speeding up research to improve the lives of people with ALS.}, journal = {The Lancet. Neurology}, volume = {22}, number = {11}, pages = {971}, doi = {10.1016/S1474-4422(23)00380-0}, pmid = {37863594}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; }, } @article {pmid37862967, year = {2023}, author = {Rabeh, N and Hajjar, B and Maraka, JO and Sammanasunathan, AF and Khan, M and Alkhaaldi, SMI and Mansour, S and Almheiri, RT and Hamdan, H and Abd-Elrahman, KS}, title = {Targeting mGluR group III for the treatment of neurodegenerative diseases.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {168}, number = {}, pages = {115733}, doi = {10.1016/j.biopha.2023.115733}, pmid = {37862967}, issn = {1950-6007}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Signal Transduction/physiology ; Glutamic Acid ; Neurotransmitter Agents ; Neurons ; *Receptors, Metabotropic Glutamate/physiology ; }, abstract = {Glutamate, an excitatory neurotransmitter, is essential for neuronal function, and it acts on ionotropic or metabotropic glutamate receptors (mGluRs). A disturbance in glutamatergic signaling is a hallmark of many neurodegenerative diseases. Developing disease-modifying treatments for neurodegenerative diseases targeting glutamate receptors is a promising avenue. The understudied group III mGluR 4, 6-8 are commonly found in the presynaptic membrane, and their activation inhibits glutamate release. Thus, targeted mGluRs therapies could aid in treating neurodegenerative diseases. This review describes group III mGluRs and their pharmacological ligands in the context of amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's diseases. Attempts to evaluate the efficacy of these drugs in clinical trials are also discussed. Despite a growing list of group III mGluR-specific pharmacological ligands, research on the use of these drugs in neurodegenerative diseases is limited, except for Parkinson's disease. Future efforts should focus on delineating the contribution of group III mGluR to neurodegeneration and developing novel ligands with superior efficacy and a favorable side effect profile for the treatment of neurodegenerative diseases.}, } @article {pmid37862206, year = {2024}, author = {Hu, Y and Chen, W and Wei, C and Jiang, S and Li, S and Wang, X and Xu, R}, title = {Pathological mechanisms of amyotrophic lateral Sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {5}, pages = {1036-1044}, pmid = {37862206}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis refers to a neurodegenerative disease involving the motor system, the cause of which remains unexplained despite several years of research. Thus, the journey to understanding or treating amyotrophic lateral sclerosis is still a long one. According to current research, amyotrophic lateral sclerosis is likely not due to a single factor but rather to a combination of mechanisms mediated by complex interactions between molecular and genetic pathways. The progression of the disease involves multiple cellular processes and the interaction between different complex mechanisms makes it difficult to identify the causative factors of amyotrophic lateral sclerosis. Here, we review the most common amyotrophic lateral sclerosis-associated pathogenic genes and the pathways involved in amyotrophic lateral sclerosis, as well as summarize currently proposed potential mechanisms responsible for amyotrophic lateral sclerosis disease and their evidence for involvement in amyotrophic lateral sclerosis. In addition, we discuss current emerging strategies for the treatment of amyotrophic lateral sclerosis. Studying the emergence of these new therapies may help to further our understanding of the pathogenic mechanisms of the disease.}, } @article {pmid37862205, year = {2024}, author = {Romano, R and Bucci, C}, title = {Antisense therapy: a potential breakthrough in the treatment of neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {19}, number = {5}, pages = {1027-1035}, pmid = {37862205}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system. Currently, there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide. Therefore, it is necessary to find new therapeutic approaches, and antisense therapies offer this possibility, having the great advantage of not modifying cellular genome and potentially being safer. Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases. The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases, with a focus on those antisense therapies that have already received the approval of the U.S. Food and Drug Administration.}, } @article {pmid37862202, year = {2024}, author = {Tarot, P and Lasbleiz, C and Liévens, JC}, title = {NRF2 signaling cascade in amyotrophic lateral sclerosis: bridging the gap between promise and reality.}, journal = {Neural regeneration research}, volume = {19}, number = {5}, pages = {1006-1012}, pmid = {37862202}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons. Symptoms include muscle weakness and atrophy, spasticity, and progressive paralysis. Currently, there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis. The only two treatments actually approved, riluzole and edaravone, have shown mitigated beneficial effects. The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis. Among mechanisms, abnormal RNA metabolism, nucleocytoplasmic transport defects, accumulation of unfolded protein, and mitochondrial dysfunction would in fine induce oxidative damage and vice versa. A potent therapeutic strategy will be to find molecules that break this vicious circle. Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense, mitochondrial functioning, and inflammation. We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis.}, } @article {pmid37862201, year = {2024}, author = {Yang, K and Yan, Y and Yu, A and Zhang, R and Zhang, Y and Qiu, Z and Li, Z and Zhang, Q and Wu, S and Li, F}, title = {Mitophagy in neurodegenerative disease pathogenesis.}, journal = {Neural regeneration research}, volume = {19}, number = {5}, pages = {998-1005}, pmid = {37862201}, issn = {1673-5374}, abstract = {Mitochondria are critical cellular energy resources and are central to the life of the neuron. Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis. Mature neurons are postmitotic and consume substantial energy, thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria. Recent evidence indicates that mitophagy is pivotal to the pathogenesis of neurological diseases. However, more work is needed to study mitophagy pathway components as potential therapeutic targets. In this review, we briefly discuss the characteristics of nonselective autophagy and selective autophagy, including ERphagy, aggrephagy, and mitophagy. We then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological conditions. Next, we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate mitophagy. Importantly, we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Last, we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative diseases. Together, our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.}, } @article {pmid37861203, year = {2024}, author = {Van Wijk, IF and Van Eijk, RPA and Van Boxmeer, L and Westeneng, HJ and Van Es, MA and Van Rheenen, W and Van Den Berg, LH and Eijkemans, MJC and Veldink, JH}, title = {Assessment of risk of ALS conferred by the GGGGCC hexanucleotide repeat expansion in C9orf72 among first-degree relatives of patients with ALS carrying the repeat expansion.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {188-196}, doi = {10.1080/21678421.2023.2272187}, pmid = {37861203}, issn = {2167-9223}, mesh = {Humans ; Aged, 80 and over ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; C9orf72 Protein/genetics ; DNA Repeat Expansion/genetics ; Proteins/genetics ; }, abstract = {OBJECTIVES: We aimed to estimate the age-related risk of ALS in first-degree relatives of patients with ALS carrying the C9orf72 repeat expansion.

METHODS: We included all patients with ALS carrying a C9orf72 repeat expansion in The Netherlands. Using structured questionnaires, we determined the number of first-degree relatives, their age at death due to ALS or another cause, or age at time of questionnaire. The cumulative incidence of ALS among first-degree relatives was estimated, while accounting for death from other causes. Variability in ALS risk between families was evaluated using a random effects hazards model. We used a second, distinct approach to estimate the risk of ALS and FTD in the general population, using previously published data.

RESULTS: In total, 214 of the 2,486 (9.2%) patients with ALS carried the C9orf72 repeat expansion. The mean risk of ALS at age 80 for first-degree relatives carrying the repeat expansion was 24.1%, but ranged between individual families from 16.0 to 60.6%. Using the second approach, we found the risk of ALS and FTD combined was 28.7% (95% CI 17.8%-54.3%) for carriers in the general population.

CONCLUSIONS: On average, our estimated risk of ALS in the C9orf72 repeat expansion was lower compared to historical estimates. We showed, however, that the risk of ALS likely varies between families and one overall penetrance estimate may not be sufficient to describe ALS risk. This warrants a tailor-made, patient-specific approach in testing. Further studies are needed to assess the risk of FTD in the C9orf72 repeat expansion.}, } @article {pmid37860934, year = {2024}, author = {Recasens, BB and Balañá Corberó, A and Llorens, JMM and Guillen-Sola, A and Moreno, MV and Escobar, GG and Umayahara, Y and Soh, Z and Tsuji, T and Rubio, MÁ}, title = {Sound-based cough peak flow estimation in patients with neuromuscular disorders.}, journal = {Muscle & nerve}, volume = {69}, number = {2}, pages = {213-217}, doi = {10.1002/mus.27987}, pmid = {37860934}, issn = {1097-4598}, mesh = {Humans ; Reproducibility of Results ; *Neuromuscular Diseases/complications ; Peak Expiratory Flow Rate ; *Nervous System Diseases ; Cough ; }, abstract = {INTRODUCTION/AIMS: Cough impairment is common in individuals with neuromuscular disorders and is associated with respiratory infections and shorter survival. Cough strength is assessed by measuring cough peak flow (CPF) using a flow meter, but this method requires a complex device setup and trained staff. The aim of the study is to evaluate the reliability of a smartphone app to estimate CPF based on cough sounds in a cohort of individuals with neuromuscular disorders.

METHODS: Individuals with neuromuscular disorders underwent CPF measurement with a flow meter and a smartphone app. A CPF <270 L/min was considered abnormal.

RESULTS: Of the 50 patients studied, 26 had amyotrophic lateral sclerosis (52%), 15 had hereditary myopathies (30%), and 9 had myasthenia gravis (18%). The intraclass correlation coefficient (ICC) between the CPF measured with a flow meter and CPF estimated with cough sounds was 0.774 (p < .001) even if the patients had orofacial weakness (ICC = 0.806, p < .001). The smartphone app had 94.4% sensitivity and 100% specificity to detect patients with CPF of less than 270 L/min.

DISCUSSION: Our findings suggest that sounds measured with a smartphone app provide a reliable estimate of CPF in patients with neuromuscular disorders, even in the presence of with orofacial weakness. This may be a convenient way to monitor respiratory involvement in patients with neuromuscular disorders, but larger studies of more diverse patient cohorts are needed.}, } @article {pmid37860271, year = {2023}, author = {Ayoubi, R and Alshafie, W and You, Z and Southern, K and McPherson, PS and Laflamme, C}, title = {Identification of high-performing antibodies for Superoxide dismutase [Cu-Zn] 1 (SOD1) for use in Western blot, immunoprecipitation, and immunofluorescence.}, journal = {F1000Research}, volume = {12}, number = {}, pages = {391}, pmid = {37860271}, issn = {2046-1402}, support = {FDN154305//CIHR/Canada ; }, mesh = {Superoxide Dismutase-1/genetics/metabolism ; Reproducibility of Results ; *Superoxide Dismutase/genetics/metabolism ; Blotting, Western ; *Antibodies ; Immunoprecipitation ; Fluorescent Antibody Technique ; Zinc ; }, abstract = {Superoxide dismutase [Cu-Zn] 1 (SOD1), is an antioxidant enzyme encoded by the gene SOD1, responsible for regulating oxidative stress levels by sequestering free radicals. Identified as the first gene with mutations in Amyotrophic lateral sclerosis (ALS), SOD1 is a determinant for studying diseases of aging and neurodegeneration. With guidance on well-characterized anti-SOD1 antibodies, the reproducibility of SOD1 research would be enhanced. In this study, we characterized eleven SOD1 commercial antibodies for Western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.}, } @article {pmid37859765, year = {2023}, author = {Vinceti, G and Carbone, C and Gallingani, C and Fiondella, L and Salemme, S and Zucchi, E and Martinelli, I and Gianferrari, G and Tondelli, M and Mandrioli, J and Chiari, A and Zamboni, G}, title = {The association between lifelong personality and clinical phenotype in the FTD-ALS spectrum.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1248622}, pmid = {37859765}, issn = {1662-4548}, abstract = {INTRODUCTION: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two phenotypes of the same neurodegenerative disease, the FTD-ALS spectrum. What determines the development of one rather than the other phenotype is still unknown. Based on the clinical observation that patients' personality seems to differ between the two phenotypes, i.e., ALS patients tend to display kind, prosocial behaviors whereas FTD patients tend to present anti-social behaviors, and that these traits are often reported as pre-existing the disease onset by caregivers, we set up to study experimentally patients' personality in their premorbid life.

METHODS: We first tested for differences between groups, then tested the association between premorbid personality and current functional organization of the brain. Premorbid personality of a cohort of forty patients, 27 FTD and 13 ALS, was explored through the NEO Personality Inventory 3 (NEO-PI-3), which analyses the five main personality factors, completed by the caregiver with reference to patient's personality 20 years before symptoms onset (premorbid). A subgroup of patients underwent a brain MRI including structural and resting-state functional MRI (rsfMRI).

RESULTS: A significant difference between FTD and ALS in premorbid personality emerged in the Openness (133.92 FTD vs. 149.84 ALS, p = 0.01) and Extraversion (136.55 FTD vs. 150.53 ALS, p = 0.04) factors. This suggests that ALS patients had been, in their premorbid life, more open to new experiences, more sociable and optimistic than FTD patients. They also showed greater functional connectivity than both FTD and a control group in the Salience resting state network, over and above differences in gray matter atrophy. Finally, there was a positive correlation between premorbid Openness and functional connectivity in the Salience network across all patients, suggesting a possible association between premorbid personality and current functional organization of the brain, irrespective of the degree of atrophy.

DISCUSSION: Our proof-of-concept results suggest that premorbid personality may eventually predispose to the development of one, rather than the other, phenotype in the FTD-ALS spectrum.}, } @article {pmid37858681, year = {2023}, author = {Wang, Y and Liang, W and Wang, T and Zhang, C and Yang, Y and Cong, C and Wang, X and Wang, S and Wang, D and Huo, D and Wang, H and Su, X and Tan, X and Feng, H}, title = {Researches of calcium-activated chloride channel ANO1 intervening amyotrophic lateral sclerosis progression by activating EGFR and CaMKII signaling.}, journal = {Brain research bulletin}, volume = {204}, number = {}, pages = {110792}, doi = {10.1016/j.brainresbull.2023.110792}, pmid = {37858681}, issn = {1873-2747}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Anoctamin-1 ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Chloride Channels ; Disease Models, Animal ; ErbB Receptors/metabolism ; Mice, Transgenic ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/metabolism ; }, abstract = {BACKGROUND: ANO1 is closely correlated with the activation of EGFR and CaMKII, while EGFR and CaMKII show low activation in amyotrophic lateral sclerosis (ALS) models. Therefore, we designed experiments to verify that ANO1 may play a protective role on motor neurons in ALS by activating EGFR and CaMKII.

METHODS: The expression changes of ANO1, EGFR, CaMKII, pEGFR, and pCaMKII, cell survival status, and apoptosis were studied by western blot, real-time quantitative PCR, immunofluorescence, immunohistochemistry, CCK-8, and flow cytometry. The role of ANO1 in the ALS model by activating EGFR and CaMKII was studied by applying corresponding activators, inhibitors, gene silencing, and overexpression.

RESULTS: In hSOD1[G93A] transgenic animals and cell lines, low expression of ANO1 and low activation of EGFR and CaMKII were identified. ANO1 expression decreased gradually with the progression of ALS. Overexpression of ANO1 in the hSOD1[G93A] cell line and primary neurons of hSOD1[G93A] transgenic mice increased cell viability and decreased cell apoptosis. After the application of ANO1 inhibitor CaCC-inhA01 in hSOD1[G93A] cell line and primary neurons of hSOD1[G93A] transgenic mice, EGFR activator EGF and CaMKII activator Carbachol, increased cell viability and reduced cell apoptosis. After ANO1 was overexpressed in the hSOD1[G93A] cell line and primary neurons of hSOD1[G93A] transgenic mice, EGFR inhibitor AEE788 and CaMKII inhibitor KN93 decreased cell viability and increased cell apoptosis.

CONCLUSIONS: Our results suggest that ANO1 plays an important role in the survival of ALS motor neurons. ANO1 can increase cell activity and reduce apoptosis by activating EGFR and CaMKII signals.}, } @article {pmid37858624, year = {2024}, author = {Lauck, KC and Malick, H and Tolkachjov, SN}, title = {Response to Joshi et al's "Considerations for perioperative antibiotic prophylaxis in Mohs micrographic surgery".}, journal = {Journal of the American Academy of Dermatology}, volume = {90}, number = {3}, pages = {e103-e104}, doi = {10.1016/j.jaad.2023.10.019}, pmid = {37858624}, issn = {1097-6787}, mesh = {Humans ; *Mohs Surgery/adverse effects ; Antibiotic Prophylaxis ; *Skin Neoplasms/surgery ; Surgical Wound Infection/prevention & control ; }, } @article {pmid37858563, year = {2023}, author = {Ezenarro, J and García-Pizarro, Á and Busto, O and de Juan, A and Boqué, R}, title = {Analysing olive ripening with digital image RGB histograms.}, journal = {Analytica chimica acta}, volume = {1280}, number = {}, pages = {341884}, doi = {10.1016/j.aca.2023.341884}, pmid = {37858563}, issn = {1873-4324}, mesh = {*Olea/chemistry ; Olive Oil/analysis ; Fruit/chemistry ; }, abstract = {Digital images are commonly used to monitor processes that are based on colour changes due to their simplicity and easy capture. Colour information in these images can be analysed objectively and accurately using colour histograms. One such process is olive ripening, which is characterized by changes in chemical composition, sensory properties and can be followed by changes in physical appearance, mainly colour. The reference method to quantify the ripeness of olives is the Maturity Index (MI), which is determined by trained experts assigning individual olives into a colour scale through visual inspection. Instead, this study proposes a methodology based on Chemometrics Assisted Colour Histogram-based Analytical Systems (CACHAS) to automatically assess the MI of olives based on R, G, and B colour histograms derived from digital images. The methodology was shown to be easily transferable for routine analysis and capable of controlling the ripening of olives. The study also confirms the high potential of digital images to understand the ripening process of olives (and potentially other fruits) and to predict the MI with satisfactory accuracy, providing an objective and reproducible alternative to visual inspection of trained experts.}, } @article {pmid37858176, year = {2023}, author = {Xie, M and Pallegar, PN and Parusel, S and Nguyen, AT and Wu, LJ}, title = {Regulation of cortical hyperexcitability in amyotrophic lateral sclerosis: focusing on glial mechanisms.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {75}, pmid = {37858176}, issn = {1750-1326}, support = {R35 NS132326/NS/NINDS NIH HHS/United States ; RF1AG082314/AG/NIA NIH HHS/United States ; RF1 AG082314/AG/NIA NIH HHS/United States ; U19AG 069701/AG/NIA NIH HHS/United States ; R35NS132326/NS/NINDS NIH HHS/United States ; U19 AG069701/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Motor Neurons/pathology ; Neuroglia/pathology ; Microglia/pathology ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, resulting in muscle weakness, atrophy, paralysis, and eventually death. Motor cortical hyperexcitability is a common phenomenon observed at the presymptomatic stage of ALS. Both cell-autonomous (the intrinsic properties of motor neurons) and non-cell-autonomous mechanisms (cells other than motor neurons) are believed to contribute to cortical hyperexcitability. Decoding the pathological relevance of these dynamic changes in motor neurons and glial cells has remained a major challenge. This review summarizes the evidence of cortical hyperexcitability from both clinical and preclinical research, as well as the underlying mechanisms. We discuss the potential role of glial cells, particularly microglia, in regulating abnormal neuronal activity during the disease progression. Identifying early changes such as neuronal hyperexcitability in the motor system may provide new insights for earlier diagnosis of ALS and reveal novel targets to halt the disease progression.}, } @article {pmid37857264, year = {2024}, author = {Kiene, H and Hamre, HJ}, title = {A Fundamental Question for Complementary Medicine: Are There Other Forces in the Natural World Besides the Physical Forces?.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {71-77}, doi = {10.1159/000534592}, pmid = {37857264}, issn = {2504-2106}, mesh = {*Complementary Therapies ; *Homeopathy ; DNA ; RNA ; }, abstract = {BACKGROUND: The integration of conventional and complementary medicine reflects the pluralism in science. Still, a critical issue is the conception of the natural world. Many complementary therapy systems seem to contradict the reductionist-atomistic paradigm that all of natural reality is essentially based on the physical interactions of atoms and molecules. Thus, a fundamental question about the natural world is: Do other than the physical forces exist?

SUMMARY: The assumption that no other than physical forces exist and work in the natural world is not tenable. For example, the formation and maintenance of the functional Gestalt of organisms cannot possibly be explained by molecular processes (e.g., from DNA to RNA and further to amino acids and proteins). The processes on each structural level - from molecules, organelles, cells, organs up to the whole organism - are regulated in regard to the formation of the next higher level. Specific Gestalt-forming forces exist and can be systematically investigated. Their existence implies an extended conception of matter. The Gestalt-forming forces and the extended concept of matter may be relevant for the scientific assessment of complementary therapies.

KEY MESSAGES: (i) In the natural world, specific Gestalt-forming forces exist in addition to the physical forces, and can be systematically investigated. (ii) The existence of these forces implies an extended conception of matter. (iii) These forces and this extended concept of matter may be relevant for the scientific assessment of complementary therapies, e.g., homeopathy.

UNLABELLED: HintergrundIn der Integration von konventioneller und komplementärer Medizin spiegelt sich der Methodenpluralismus der Wissenschaft. Die Ontologien vieler komplementärmedizinisches Systeme liegen allerdings außerhalb der Erklärbarkeit durch die Kräfte der Physik. Eine zentrale Frage ist deshalb: Gibt es Kräfte in der Natur, die eine materielle Wirkung haben, deren Ursprung aber nicht in Atomen oder Molekülen und in diesem Sinne nicht in der Materie liegt?ZusammenfassungDie Annahme, dass in der Natur keine anderen als die mit Atomen und Molekülen assoziierten physikalischen Kräfte existent und wirksam seien, ist wissenschaftlich nicht begründet. Beispielsweise ist die Bildung und Erhaltung der funktionsfähigen Gestalt von Organismen nicht durch molekulare Prozesse (z.B. von der DNA zur RNA und weiter zu Aminosäuren und Proteinen) erklärbar. Die Prozesse auf jeder strukturellen Ebene – von den Molekülen, Organellen, Zellen, Organen bis hinauf zum Gesamtorganismus – sind in Hinblick auf die Bildung der funktionsfähigen Gestalt der jeweils nächsthöheren Ebene gesteuert. Für diese Gestaltbildung gibt es spezifische Kräfte, die systematisch erforscht werden können. Ihre Existenz impliziert eine erweiterte Konzeption von Materie. Diese Gestalt-bildenden Kräfte und dieses erweiterte Konzept von Materie sind relevant für die wissenschaftliche Erfassung komplementärmedizinischer Systeme.Zentrale Aussagen(i) In der Natur sind außer den physikalischen Kräften noch weitere spezifische Kräfte wirksam, beispielsweise bei der Bildung und Erhaltung der funktionsfähigen Gestalt von Organismen. Diese Kräfte können systematisch erforscht werden. (ii) Die Existenz dieser Kräfte impliziert eine erweitere Konzeption von Materie. (iii) Diese Kräfte und das erweiterte Materiekonzept sind relevant für die wissenschaftliche Erfassung komplementärmedizinischer Systeme, beispielsweise der Homöopathie.}, } @article {pmid37856900, year = {2023}, author = {Magrì, B and D'Amico, AG and Maugeri, G and Morello, G and La Cognata, V and Saccone, S and Federico, C and Cavallaro, S and D'Agata, V}, title = {Neuroprotective effect of the PACAP-ADNP axis on SOD1G93A mutant motor neuron death induced by trophic factors deprivation.}, journal = {Neuropeptides}, volume = {102}, number = {}, pages = {102386}, doi = {10.1016/j.npep.2023.102386}, pmid = {37856900}, issn = {1532-2785}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Pituitary Adenylate Cyclase-Activating Polypeptide/pharmacology/metabolism ; *Neuroprotective Agents/pharmacology/metabolism ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; *Neurodegenerative Diseases ; Motor Neurons/metabolism/pathology ; Superoxide Dismutase/genetics/metabolism ; Nerve Degeneration/metabolism/pathology ; Mutation ; Nerve Tissue Proteins/metabolism ; Homeodomain Proteins/genetics/metabolism/pharmacology ; }, abstract = {Amyotrophic lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motor neurons in the central nervous system. Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) account for approximately in 20% of familial ALS cases. The pathological mechanisms underlying the toxicity induced by mutated SOD1 are still unknown. However, it has been hypothesized that oxidative stress (OS) has a crucial role in motor neuron degeneration in ALS patients. Moreover, it has been described that SOD1 mutation interferes expression of nuclear factor erythroid 2-related factor 2 (Nrf2), a protective key modulator against OS and reactive oxygen species (ROS) formation. The protective effect of pituitary adenylate cyclase-activating peptide (PACAP) has been demonstrated in various neurological disorders, including ALS. Some of its effects are mediated by the stimulation of an intracellular factor known as activity-dependent protein (ADNP). The role of PACAP-ADNP axis on mutated SOD1 motor neuron degeneration has not been explored, yet. The present study aimed to investigate whether PACAP prevented apoptotic cell death induced by growth factor deprivation through ADNP activation and whether the peptidergic axis can counteract the OS insult. By using an in vitro model of ALS, we demonstrated that PACAP by binding to PAC1 receptor (PAC1R) prevented motor neuron death induced by serum deprivation through induction of the ADNP expression via PKC stimulation. Furthermore, we have also demonstrated that the PACAP/ADNP axis counteracted ROS formation by inducing translocation of the Nfr2 from the cytoplasm to the nucleus. In conclusion, our study provides new insights regarding the protective role of PACAP-ADNP in ALS.}, } @article {pmid37855949, year = {2023}, author = {Suh, A and Ong, J and Kamran, SA and Waisberg, E and Paladugu, P and Zaman, N and Sarker, P and Tavakkoli, A and Lee, AG}, title = {Retina Oculomics in Neurodegenerative Disease.}, journal = {Annals of biomedical engineering}, volume = {51}, number = {12}, pages = {2708-2721}, pmid = {37855949}, issn = {1573-9686}, support = {80NSSC20K183//NASA Grant/ ; }, mesh = {Humans ; *Artificial Intelligence ; *Neurodegenerative Diseases/diagnostic imaging ; Quality of Life ; Retina/diagnostic imaging ; Tomography, Optical Coherence/methods ; Biomarkers ; }, abstract = {Ophthalmic biomarkers have long played a critical role in diagnosing and managing ocular diseases. Oculomics has emerged as a field that utilizes ocular imaging biomarkers to provide insights into systemic diseases. Advances in diagnostic and imaging technologies including electroretinography, optical coherence tomography (OCT), confocal scanning laser ophthalmoscopy, fluorescence lifetime imaging ophthalmoscopy, and OCT angiography have revolutionized the ability to understand systemic diseases and even detect them earlier than clinical manifestations for earlier intervention. With the advent of increasingly large ophthalmic imaging datasets, machine learning models can be integrated into these ocular imaging biomarkers to provide further insights and prognostic predictions of neurodegenerative disease. In this manuscript, we review the use of ophthalmic imaging to provide insights into neurodegenerative diseases including Alzheimer Disease, Parkinson Disease, Amyotrophic Lateral Sclerosis, and Huntington Disease. We discuss recent advances in ophthalmic technology including eye-tracking technology and integration of artificial intelligence techniques to further provide insights into these neurodegenerative diseases. Ultimately, oculomics opens the opportunity to detect and monitor systemic diseases at a higher acuity. Thus, earlier detection of systemic diseases may allow for timely intervention for improving the quality of life in patients with neurodegenerative disease.}, } @article {pmid37855870, year = {2024}, author = {Borghero, G and Pili, F and Muroni, A and Ercoli, T and Pateri, MI and Pilotto, S and Maccabeo, A and Defazio, G}, title = {Disease survival and progression in TARDBP ALS patients from Sardinia, Italy.}, journal = {Journal of neurology}, volume = {271}, number = {2}, pages = {929-934}, pmid = {37855870}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics ; C9orf72 Protein/genetics ; Delayed Diagnosis ; Disease Progression ; Italy/epidemiology ; Mutation/genetics ; Phenotype ; }, abstract = {BACKGROUND: Common genes implicated in amyotrophic lateral sclerosis (ALS) development may also influence its progression rate. The C9orf72 mutations featured a faster progression rate while the European SOD1 mutations were associated with a slower progression. In this study, we assessed the relationship between TARDBP and ALS progression/survival.

METHODS: ALS incident patients (2010-2019) were diagnosed by El Escorial revised criteria and staged over the disease course by the King's staging system. Disease progression was analysed by Kaplan-Meier survival curves and Cox regression models, with survival measured from symptom onset to death/tracheostomy or censor date.

RESULTS: The study population included 76 patients carrying TARDBP mutations (A382T/G295S), 28 patients carrying the C9orf72 GGGGCC expansion, and 158 patients who had no evidence of causative genetic mutations (nmALS group). TARDBP patients reached death/tracheostomy later than C9orf72 and nmALS patients, independently of possible prognostic indicators (sex, age at ALS onset, diagnostic delay, phenotype at onset, and family history of ALS). On King's staging, the time elapsed between disease onset (King's stage 1) and involvement of the second body region (King's stage 2B) was similar in TARDBP and nmALS patients but longer in TARDBP than in C9orf72 patients. TARDBP patients reached King's stages 3 and 4 later than C9orf72 and nmALS patients.

CONCLUSIONS: TARDBP patients have a better survival/prognosis than C9orf72-positive and nmALS patients. King's staging also suggested that the higher survival rate and the slower progression associated with the TARDBP mutation could mainly be attributed to the longer time elapsed between King's stages 2B to 3.}, } @article {pmid37855859, year = {2024}, author = {Vieira, TCRG and Barros, CA and Domingues, R and Outeiro, TF}, title = {PrP meets alpha-synuclein: Molecular mechanisms and implications for disease.}, journal = {Journal of neurochemistry}, volume = {168}, number = {8}, pages = {1625-1639}, doi = {10.1111/jnc.15992}, pmid = {37855859}, issn = {1471-4159}, support = {SFB1286 (B8)//Deutsche Forschungsgemeinschaft/ ; EXC 2067/1-390729940//Deutsche Forschungsgemeinschaft/ ; //Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)/ ; //Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; }, mesh = {Humans ; *alpha-Synuclein/metabolism ; Animals ; Synucleinopathies/metabolism/pathology ; Prion Proteins/metabolism ; }, abstract = {The discovery of prions has challenged dogmas and has revolutionized our understanding of protein-misfolding diseases. The concept of self-propagation via protein conformational changes, originally discovered for the prion protein (PrP), also applies to other proteins that exhibit similar behavior, such as alpha-synuclein (aSyn), a central player in Parkinson's disease and in other synucleinopathies. aSyn pathology appears to spread from one cell to another during disease progression, and involves the misfolding and aggregation of aSyn. How the transfer of aSyn between cells occurs is still being studied, but one important hypothesis involves receptor-mediated transport. Interestingly, recent studies indicate that the cellular prion protein (PrP[C]) may play a crucial role in this process. PrP[C] has been shown to act as a receptor/sensor for protein aggregates in different neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. Here, we provide a comprehensive overview of the current state of knowledge regarding the interaction between aSyn and PrP[C] and discuss its role in synucleinopathies. We examine the properties of PrP and aSyn, including their structure, function, and aggregation. Additionally, we discuss the current understanding of PrP[C]'s role as a receptor/sensor for aSyn aggregates and identify remaining unanswered questions in this area of research. Ultimately, we posit that exploring the interaction between aSyn and PrP[C] may offer potential treatment options for synucleinopathies.}, } @article {pmid37855109, year = {2024}, author = {Jia, H and Li, Z and Liu, H and Ren, M and Liu, T and Zhou, X and Li, X and Li, R and Liu, Q and Liu, Y and Dong, H}, title = {The Beaumont behavioral intervention in a Chinese amyotrophic lateral sclerosis cohort.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {88-95}, doi = {10.1080/21678421.2023.2271518}, pmid = {37855109}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/complications ; *Frontotemporal Dementia/diagnosis ; Cross-Sectional Studies ; Sensitivity and Specificity ; *Pick Disease of the Brain ; Neuropsychological Tests ; }, abstract = {OBJECTIVE: The prevalence of behavior impairment (27.38%) in the Chinese amyotrophic lateral sclerosis (ALS) cohort is lower. We hypothesize that the screening scales used among studies might not be appropriate to diagnose behavioral disorders in ALS patients. So, we urgently need to find a behavior scale with a high detection rate designed specifically for ALS. This study aims to verify the Chinese translation of the Beaumont Behavioral Inventory (BBI) as an effective assessment in a Chinese ALS cohort.

METHODS: Ninety-eighty ALS patients and ninety-three healthy controls were included in this cross-sectional study. All participants took emotional state, overall cognitive, sleep quality and gastroenteric function, and behavioral evaluation.

RESULTS: The BBI scores showed a strong association with the amyotrophic lateral sclerosis-Frontotemporal Dementia-Questionnaire (ALS-FTD-Q) (rs = 0.71, p < 0.001) as well as a moderate correlation with the Frontal Behavioral Inventory (FBI) (rs = 0.55, p < 0.001). High internal consistency was demonstrated in patients using BBI-after items (Cronbach's a = 0.89). When tested against clinical diagnoses, the optimal cutoff of total BBI score was identified at 5.5 (AUC = 0.95; SE = 0.02; 95% CI [0.91, 0.99]), the BBI reached optimal sensitivity and specificity values (91.5% and 87.2%). The BBI turned out to be more precise than the FBI (AUC = 0.76; SE = 0.05; 95% CI [0.66, 0.86]) and the ALS-FTD-Q (AUC = 0.84; SE = 0.04; 95% CI [0.77, 0.92]).

CONCLUSION: The Chinese version of BBI is a quicker and more efficient instrument for assessing behavioral impairment in the ALS population in China.}, } @article {pmid37853696, year = {2023}, author = {Ingólfsson, HI and Rizuan, A and Liu, X and Mohanty, P and Souza, PCT and Marrink, SJ and Bowers, MT and Mittal, J and Berry, J}, title = {Multiscale simulations reveal TDP-43 molecular-level interactions driving condensation.}, journal = {Biophysical journal}, volume = {122}, number = {22}, pages = {4370-4381}, pmid = {37853696}, issn = {1542-0086}, support = {R01 NS116176/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Protein Domains ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/metabolism ; Molecular Dynamics Simulation ; Amyloid ; }, abstract = {The RNA-binding protein TDP-43 is associated with mRNA processing and transport from the nucleus to the cytoplasm. TDP-43 localizes in the nucleus as well as accumulating in cytoplasmic condensates such as stress granules. Aggregation and formation of amyloid-like fibrils of cytoplasmic TDP-43 are hallmarks of numerous neurodegenerative diseases, most strikingly present in >90% of amyotrophic lateral sclerosis (ALS) patients. If excessive accumulation of cytoplasmic TDP-43 causes, or is caused by, neurodegeneration is presently not known. In this work, we use molecular dynamics simulations at multiple resolutions to explore TDP-43 self- and cross-interaction dynamics. A full-length molecular model of TDP-43, all 414 amino acids, was constructed from select structures of the protein functional domains (N-terminal domain, and two RNA recognition motifs, RRM1 and RRM2) and modeling of disordered connecting loops and the low complexity glycine-rich C-terminus domain. All-atom CHARMM36m simulations of single TDP-43 proteins served as guides to construct a coarse-grained Martini 3 model of TDP-43. The Martini model and a coarser implicit solvent C⍺ model, optimized for disordered proteins, were subsequently used to probe TDP-43 interactions; self-interactions from single-chain full-length TDP-43 simulations, cross-interactions from simulations with two proteins and simulations with assemblies of dozens to hundreds of proteins. Our findings illustrate the utility of different modeling scales for accessing TDP-43 molecular-level interactions and suggest that TDP-43 has numerous interaction preferences or patterns, exhibiting an overall strong, but dynamic, association and driving the formation of biomolecular condensates.}, } @article {pmid37852234, year = {2023}, author = {Sueda, T and Tei, M and Mori, S and Nishida, K and Yasuyama, A and Nomura, M and Yoshikawa, Y and Tsujie, M}, title = {Clinical Impact of Transanal Drainage Tube on Anastomosis Leakage Following Minimally Invasive Resection Without Diverting Stoma in Patients With Rectal Cancer: A Propensity Score-matched Analysis.}, journal = {Surgical laparoscopy, endoscopy & percutaneous techniques}, volume = {33}, number = {6}, pages = {608-616}, doi = {10.1097/SLE.0000000000001237}, pmid = {37852234}, issn = {1534-4908}, mesh = {Humans ; *Anastomotic Leak/etiology/prevention & control/surgery ; Anastomosis, Surgical/adverse effects/methods ; Retrospective Studies ; Propensity Score ; *Rectal Neoplasms/surgery/complications ; Drainage/methods ; }, abstract = {OBJECTIVES: As one of the most serious complications of rectal cancer (RC) surgery, preventing anastomotic leakage (AL) is crucial. Several studies have suggested a positive role of the transanal drainage tube (TaDT) in AL prevention. However, whether TaDT is beneficial for AL in patients with RC remains controversial. The present study aimed to evaluate the clinical impact of TaDT on AL following minimally invasive resection without diverting stoma (DS) in patients with RC.

MATERIALS AND METHODS: We retrospectively analyzed 392 consecutive patients with RC who had undergone minimally invasive resection without DS between 2010 and 2021. Propensity score matching (PSM) was performed to reduce selection bias. AL was classified as grade A, B, or C.

RESULTS: A TaDT was used in 214 patients overall. After PSM, we enrolled 316 patients (n=158 in each group). Before PSM, significant group-dependent differences were observed in terms of age, American Society of Anesthesiologists physical status, and the use of antiplatelet/anticoagulant agents. The frequency of AL was 7.3% in the overall cohort and was significantly lower in the TaDT group (3.7%) than in the non-TaDT group (11.8%). The rate of grade B AL was significantly lower in the TaDT group than in the non-TaDT group (before PSM, P <0.01; after PSM, P =0.02). However, no significant differences between groups were found for grade C AL. Moreover, multivariate analysis identified the lack of a TaDT as an independent risk factor for AL in the overall and matched cohorts [before PSM, odds ratio, 3.64, P <0.01; after PSM, odds ratio, 2.91, P =0.02].

CONCLUSION: These results indicated that TaDT may play a beneficial role in preventing AL, particularly of grade B, for patients with RC undergoing minimally invasive resection without DS. However, further randomized controlled trials, including patient-reported outcomes, are still needed to understand better the role of TaDT in preventing ALs in patients with RC undergoing minimally invasive resection without DS.}, } @article {pmid37851044, year = {2023}, author = {Gwathmey, K and Heiman-Patterson, TD}, title = {Multidisciplinary Clinics in Neuromuscular Medicine.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {29}, number = {5}, pages = {1585-1594}, pmid = {37851044}, issn = {1538-6899}, mesh = {Humans ; Quality of Life ; *Telemedicine ; *Amyotrophic Lateral Sclerosis/diagnosis ; Ambulatory Care ; *Neuromuscular Diseases/diagnosis/therapy ; }, abstract = {Multidisciplinary care is comprehensive, coordinated clinical care across medical disciplines and allied health professions. Neuromuscular disorders, such as amyotrophic lateral sclerosis and muscular dystrophies, are often associated with disabling weakness and extramuscular symptoms and may benefit from care in a model that consolidates numerous clinic visits into a single more efficient multidisciplinary clinic visit. The goal of the neuromuscular multidisciplinary care model is to improve patient outcomes, patient satisfaction, quality of life, access to medications and equipment, and survival. Although the costs of running a multidisciplinary clinic are high, they are likely associated with cost savings from the patient's perspective. Several barriers to acceptance of multidisciplinary clinics include the distance needed to travel to the clinic and the duration of the clinic visit. Telehealth multidisciplinary clinic visits may address some of these concerns. Further study is needed to understand the value of multidisciplinary clinics and is a necessary step toward creating a sustainable model.}, } @article {pmid37851042, year = {2023}, author = {Izenberg, A}, title = {Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {29}, number = {5}, pages = {1538-1563}, pmid = {37851042}, issn = {1538-6899}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; *Motor Neuron Disease/diagnosis/genetics/therapy ; Biomarkers ; }, abstract = {OBJECTIVE: This article reviews the clinical spectrum of amyotrophic lateral sclerosis (ALS), its variant presentations, and the approach to diagnosis and management. This review includes a detailed discussion of current and emerging disease-modifying therapies and the management of respiratory and bulbar manifestations of disease. An updated review of ALS genetics and pathophysiology is also provided. This article also touches on several other important motor neuron diseases.

LATEST DEVELOPMENTS: A new set of simplified diagnostic criteria may help identify patients at earlier stages of the disease. A coformulation of sodium phenylbutyrate and tauroursodeoxycholic acid has been shown to have a significant benefit on disease progression and survival, leading to approval by regulatory authorities in the United States and Canada. An oral formulation of edaravone and an antisense oligonucleotide to a SOD1 gene variation (tofersen) have also recently been approved by the US Food and Drug Administration (FDA). Phase 3 trials of intrathecal mesenchymal stem cells failed to meet primary end points for efficacy. Updated American Academy of Neurology quality measures for the care of patients with ALS were published in 2023.

ESSENTIAL POINTS: There has been continued progress in ALS genetics, diagnosis, and disease-modifying therapies. However, we still lack a definitive biomarker or a treatment that can halt the progression or reverse the course of disease. The evolving understanding of the genetic and pathophysiologic underpinnings of disease offers promise for more effective and clinically meaningful treatments in the future.}, } @article {pmid37850654, year = {2024}, author = {Chen, S and Huan, X and Xu, CZ and Luo, SS and Zhao, CB and Zhong, HH and Zheng, XY and Qiao, K and Dong, Y and Wang, Y and Liu, CY and Huang, HP and Chen, Y and Zou, ZY}, title = {Eomesodermin expression in CD4[+]T-cells associated with disease progression in amyotrophic lateral sclerosis.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {4}, pages = {e14503}, pmid = {37850654}, issn = {1755-5949}, support = {81901286, 81974199, 82271458//National Natural Science Foundation of China/ ; 2018Y9026, 2021Y9065//The Joint Funds for the innovation of science and Technology, Fujian province/ ; 2018QH1032//The Startup Fund for scientific research, Fujian Medical University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/immunology ; Biomarkers ; Disease Progression ; Longitudinal Studies ; Prognosis ; T-Lymphocytes ; *T-Box Domain Proteins/metabolism ; *CD4-Positive T-Lymphocytes/immunology/metabolism ; }, abstract = {AIM: To clarify the role of Eomesodermin (EOMES) to serve as a disease-relevant biomarker and the intracellular molecules underlying the immunophenotype shifting of CD4[+]T subsets in amyotrophic lateral sclerosis (ALS).

METHODS: The derivation and validation cohorts included a total of 148 ALS patients and 101 healthy controls (HCs). Clinical data and peripheral blood were collected. T-cell subsets and the EOMES expression were quantified using multicolor flow cytometry. Serum neurofilament light chain (NFL) was measured. In 1-year longitudinal follow-ups, the ALSFRS-R scores and primary endpoint events were further recorded in the ALS patients of the validation cohort.

RESULTS: In the derivation cohort, the CD4[+]EOMES[+]T-cell subsets were significantly increased (p < 0.001). EOMES[+] subset was positively correlated with increased serum NFL levels in patients with onset longer than 12 months. In the validation cohort, the elevated CD4[+]EOMES[+]T-cell proportions and their association with NFL levels were also identified. The longitudinal study revealed that ALS patients with higher EOMES expression were associated with higher progression rates (p = .010) and worse prognosis (p = .003).

CONCLUSIONS: We demonstrated that increased CD4[+]EOMES[+]T-cell subsets in ALS were associated with disease progression and poor prognosis. Identifying these associations may contribute to a better understanding of the immunopathological mechanism of ALS.}, } @article {pmid37849894, year = {2023}, author = {Fang, M and Deibler, SK and Nana, AL and Vatsavayai, SC and Banday, S and Zhou, Y and Almeida, S and Weiss, A and Brown, RH and Seeley, WW and Gao, FB and Green, MR}, title = {Loss of TDP-43 function contributes to genomic instability in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1251228}, pmid = {37849894}, issn = {1662-4548}, support = {R01 NS104437/NS/NINDS NIH HHS/United States ; RF1 NS101986/NS/NINDS NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; R01 GM035490/GM/NIGMS NIH HHS/United States ; R21 NS119952/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; R21 NS112766/NS/NINDS NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; }, abstract = {A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the cytoplasmic mislocalization and aggregation of the DNA/RNA-binding protein TDP-43, but how loss of nuclear TDP-43 function contributes to ALS and FTD pathogenesis remains largely unknown. Here, using large-scale RNAi screening, we identify TARDBP, which encodes TDP-43, as a gene whose loss-of-function results in elevated DNA mutation rate and genomic instability. Consistent with this finding, we observe increased DNA damage in induced pluripotent stem cells (iPSCs) and iPSC-derived post-mitotic neurons generated from ALS patients harboring TARDBP mutations. We find that the increase in DNA damage in ALS iPSC-derived neurons is due to defects in two major pathways for DNA double-strand break repair: non-homologous end joining and homologous recombination. Cells with defects in DNA repair are sensitive to DNA damaging agents and, accordingly, we find that ALS iPSC-derived neurons show a marked reduction in survival following treatment with a DNA damaging agent. Importantly, we find that increased DNA damage is also observed in neurons with nuclear TDP-43 depletion from ALS/FTD patient brain tissues. Collectively, our results demonstrate that ALS neurons with loss of nuclear TDP-43 function have elevated levels of DNA damage and contribute to the idea that genomic instability is a defining pathological feature of ALS/FTD patients with TDP-43 pathology.}, } @article {pmid37849367, year = {2023}, author = {Takagi, S and Daimon, S and Inoue, K and Umeda, M and Kobayashi, Z}, title = {[A Case of Amyotrophic Lateral Sclerosis with Semantic Variant Primary Progressive Aphasia: A Study of Language Symptoms and Agraphia].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {75}, number = {10}, pages = {1155-1161}, doi = {10.11477/mf.1416202493}, pmid = {37849367}, issn = {1881-6096}, mesh = {Male ; Humans ; Aged ; *Agraphia/etiology ; Semantics ; *Amyotrophic Lateral Sclerosis/complications ; Language ; Magnetic Resonance Imaging/adverse effects ; *Aphasia, Primary Progressive/diagnostic imaging/complications ; Atrophy/complications ; }, abstract = {The patient was a 66-year-old man brought to the emergency room with impaired consciousness due to hypercarbonemia, managed on a respirator, and diagnosed with amyotrophic lateral sclerosis (ALS). MRI showed atrophy of the anterior and medial surfaces of the bilateral temporal lobes that was more severe in the right side. The patient had dysgraphia in both kana and kanji. Detailed examinations of the language function revealed impaired single-word comprehension, impaired naming, and surface dysgraphia, leading to the diagnosis of semantic variant primary progressive aphasia (svPPA). ALS patients with atrophy of the anterior temporal lobe and surface dysgraphia of kanji may have svPPA as a complication. (Received April 14, 2023; Accepted June 21, 2023; Published October 1, 2023).}, } @article {pmid37849306, year = {2024}, author = {Olsen, CG and Busk, ØL and Holla, ØL and Tveten, K and Holmøy, T and Tysnes, OB and Høyer, H}, title = {Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {177-187}, doi = {10.1080/21678421.2023.2270705}, pmid = {37849306}, issn = {2167-9223}, mesh = {Humans ; Genetic Predisposition to Disease/genetics ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Genetic Association Studies ; Family ; *Neurodegenerative Diseases/epidemiology/genetics ; ATPases Associated with Diverse Cellular Activities/genetics ; ATP-Dependent Proteases/genetics ; LDL-Receptor Related Proteins/genetics ; Membrane Transport Proteins/genetics ; Kinesins/genetics ; Cytoskeletal Proteins/genetics ; *Cell Cycle Proteins ; }, abstract = {OBJECTIVE: In Norway, 89% of patients with Amyotrophic lateral sclerosis (ALS) lacks a genetic diagnose. ALS genes and genes that cause other neuromuscular or neurodegenerative disorders extensively overlap. This population-based study examined whether patients with ALS have a family history of neurological disorders and explored the occurrence of rare genetic variants associated with other neurodegenerative or neuromuscular disorders.

METHODS: During a two-year period, blood samples and clinical data from patients with ALS were collected from all 17 neurological departments in Norway. Our genetic analysis involved exome sequencing and bioinformatics filtering of 510 genes associated with neurodegenerative and neuromuscular disorders. The variants were interpreted using genotype-phenotype correlations and bioinformatics tools.

RESULTS: A total of 279 patients from a Norwegian population-based ALS cohort participated in this study. Thirty-one percent of the patients had first- or second-degree relatives with other neurodegenerative disorders, most commonly dementia and Parkinson's disease. The genetic analysis identified 20 possible pathogenic variants, in ATL3, AFG3L2, ATP7A, BICD2, HARS1, KIF1A, LRRK2, MSTO1, NEK1, NEFH, and SORL1, in 25 patients. NEK1 risk variants were present in 2.5% of this ALS cohort. Only four of the 25 patients reported relatives with other neurodegenerative or neuromuscular disorders.

CONCLUSION: Gene variants known to cause other neurodegenerative or neuromuscular disorders, most frequently in NEK1, were identified in 9% of the patients with ALS. Most of these patients had no family history of other neurodegenerative or neuromuscular disorders. Our findings indicated that AFG3L2, ATP7A, BICD2, KIF1A, and MSTO1 should be further explored as potential ALS-causing genes.}, } @article {pmid37847372, year = {2023}, author = {Sattler, R and Traynor, BJ and Robertson, J and Van Den Bosch, L and Barmada, SJ and Svendsen, CN and Disney, MD and Gendron, TF and Wong, PC and Turner, MR and Boxer, A and Babu, S and Benatar, M and Kurnellas, M and Rohrer, JD and Donnelly, CJ and Bustos, LM and Van Keuren-Jensen, K and Dacks, PA and Sabbagh, MN and , }, title = {Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit.}, journal = {Neurology and therapy}, volume = {12}, number = {6}, pages = {1821-1843}, pmid = {37847372}, issn = {2193-8253}, support = {RF1 NS114128/NS/NINDS NIH HHS/United States ; ZIAAG000933-15/AG/NIA NIH HHS/United States ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; MR/T046015/1/MRC_/Medical Research Council/United Kingdom ; ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; R35 NS116846/NS/NINDS NIH HHS/United States ; }, abstract = {A summit held March 2023 in Scottsdale, Arizona (USA) focused on the intronic hexanucleotide expansion in the C9ORF72 gene and its relevance in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS; C9ORF72-FTD/ALS). The goal of this summit was to connect basic scientists, clinical researchers, drug developers, and individuals affected by C9ORF72-FTD/ALS to evaluate how collaborative efforts across the FTD-ALS disease spectrum might break down existing disease silos. Presentations and discussions covered recent discoveries in C9ORF72-FTD/ALS disease mechanisms, availability of disease biomarkers and recent advances in therapeutic development, and clinical trial design for prevention and treatment for individuals affected by C9ORF72-FTD/ALS and asymptomatic pathological expansion carriers. The C9ORF72-associated hexanucleotide repeat expansion is an important locus for both ALS and FTD. C9ORF72-FTD/ALS may be characterized by loss of function of the C9ORF72 protein and toxic gain of functions caused by both dipeptide repeat (DPR) proteins and hexanucleotide repeat RNA. C9ORF72-FTD/ALS therapeutic strategies discussed at the summit included the use of antisense oligonucleotides, adeno-associated virus (AAV)-mediated gene silencing and gene delivery, and engineered small molecules targeting RNA structures associated with the C9ORF72 expansion. Neurofilament light chain, DPR proteins, and transactive response (TAR) DNA-binding protein 43 (TDP-43)-associated molecular changes were presented as biomarker candidates. Similarly, brain imaging modalities (i.e., magnetic resonance imaging [MRI] and positron emission tomography [PET]) measuring structural, functional, and metabolic changes were discussed as important tools to monitor individuals affected with C9ORF72-FTD/ALS, at both pre-symptomatic and symptomatic disease stages. Finally, summit attendees evaluated current clinical trial designs available for FTD or ALS patients and concluded that therapeutics relevant to FTD/ALS patients, such as those specifically targeting C9ORF72, may need to be tested with composite endpoints covering clinical symptoms of both FTD and ALS. The latter will require novel clinical trial designs to be inclusive of all patient subgroups spanning the FTD/ALS spectrum.}, } @article {pmid37845811, year = {2024}, author = {Holt, MW and Robinson, EC and Shlobin, NA and Hanson, JT and Bozkurt, I}, title = {Intracortical brain-computer interfaces for improved motor function: a systematic review.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {2}, pages = {213-223}, pmid = {37845811}, issn = {2191-0200}, mesh = {Humans ; *Brain-Computer Interfaces ; *Motor Cortex/physiology/physiopathology ; }, abstract = {In this systematic review, we address the status of intracortical brain-computer interfaces (iBCIs) applied to the motor cortex to improve function in patients with impaired motor ability. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Guidelines for Systematic Reviews. Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) and the Effective Public Health Practice Project (EPHPP) were used to assess bias and quality. Advances in iBCIs in the last two decades demonstrated the use of iBCI to activate limbs for functional tasks, achieve neural typing for communication, and other applications. However, the inconsistency of performance metrics employed by these studies suggests the need for standardization. Each study was a pilot clinical trial consisting of 1-4, majority male (64.28 %) participants, with most trials featuring participants treated for more than 12 months (55.55 %). The systems treated patients with various conditions: amyotrophic lateral sclerosis, stroke, spinocerebellar degeneration without cerebellar involvement, and spinal cord injury. All participants presented with tetraplegia at implantation and were implanted with microelectrode arrays via pneumatic insertion, with nearly all electrode locations solely at the precentral gyrus of the motor cortex (88.88 %). The development of iBCI devices using neural signals from the motor cortex to improve motor-impaired patients has enhanced the ability of these systems to return ability to their users. However, many milestones remain before these devices can prove their feasibility for recovery. This review summarizes the achievements and shortfalls of these systems and their respective trials.}, } @article {pmid37845749, year = {2023}, author = {Bennett, CL and Dastidar, S and Arnold, FJ and McKinstry, SU and Stockford, C and Freibaum, BD and Sopher, BL and Wu, M and Seidner, G and Joiner, W and Taylor, JP and West, RJH and La Spada, AR}, title = {Senataxin helicase, the causal gene defect in ALS4, is a significant modifier of C9orf72 ALS G4C2 and arginine-containing dipeptide repeat toxicity.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {164}, pmid = {37845749}, issn = {2051-5960}, support = {R01 GM125080/GM/NIGMS NIH HHS/United States ; R35 NS122140/NS/NINDS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Dipeptides/genetics ; C9orf72 Protein/genetics/metabolism ; Arginine/genetics/metabolism ; HEK293 Cells ; Motor Neurons/metabolism ; Drosophila/metabolism ; RNA/metabolism ; *Frontotemporal Dementia/genetics ; DNA Repeat Expansion/genetics ; DNA Helicases/genetics ; RNA Helicases/genetics ; Multifunctional Enzymes/genetics ; }, abstract = {Identifying genetic modifiers of familial amyotrophic lateral sclerosis (ALS) may reveal targets for therapeutic modulation with potential application to sporadic ALS. GGGGCC (G4C2) repeat expansions in the C9orf72 gene underlie the most common form of familial ALS, and generate toxic arginine-containing dipeptide repeats (DPRs), which interfere with membraneless organelles, such as the nucleolus. Here we considered senataxin (SETX), the genetic cause of ALS4, as a modifier of C9orf72 ALS, because SETX is a nuclear helicase that may regulate RNA-protein interactions involved in ALS dysfunction. After documenting that decreased SETX expression enhances arginine-containing DPR toxicity and C9orf72 repeat expansion toxicity in HEK293 cells and primary neurons, we generated SETX fly lines and evaluated the effect of SETX in flies expressing either (G4C2)58 repeats or glycine-arginine-50 [GR(50)] DPRs. We observed dramatic suppression of disease phenotypes in (G4C2)58 and GR(50) Drosophila models, and detected a striking relocalization of GR(50) out of the nucleolus in flies co-expressing SETX. Next-generation GR(1000) fly models, that show age-related motor deficits in climbing and movement assays, were similarly rescued with SETX co-expression. We noted that the physical interaction between SETX and arginine-containing DPRs is partially RNA-dependent. Finally, we directly assessed the nucleolus in cells expressing GR-DPRs, confirmed reduced mobility of proteins trafficking to the nucleolus upon GR-DPR expression, and found that SETX dosage modulated nucleolus liquidity in GR-DPR-expressing cells and motor neurons. These findings reveal a hitherto unknown connection between SETX function and cellular processes contributing to neuron demise in the most common form of familial ALS.}, } @article {pmid37845449, year = {2023}, author = {Shin, J and Kang, H and Kim, S}, title = {Primo Vessels Inside Lymphatic Vessels Are Absent in an ALS Mouse Model.}, journal = {Advances in experimental medicine and biology}, volume = {1438}, number = {}, pages = {113-117}, pmid = {37845449}, issn = {0065-2598}, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases ; *Lymphatic Vessels ; Lymph Nodes ; Oxygen/analysis ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the central nervous system. It is also a representative rare disease among degenerative diseases of the nervous system. Although many drugs for the treatment of degenerative brain diseases are being developed, they are not delivered correctly to the target due to the blood-brain barrier. The present study aimed to analyze changes in the primo vascular system (PVS) in ALS mice with symptoms and the partial oxygen pressure (pO2) in normal mice. In normal mice, we consistently observed primo vessels in lymphatic vessels (L-PVS). However, in ALS mice with symptoms, L-PVS were mostly lost, rendering them difficult to observe. The pO2 of the L-PVS in normal mice was significantly higher than that of normal dermis and lymph nodes.In conclusion, the relatively higher oxygen levels measured in the L-PVS than in normal dermis and lymph nodes suggest a role for the PVS in oxygen transport and enable a hypothesis that the L-PVS can function as a drug delivery pathway.}, } @article {pmid37845420, year = {2024}, author = {Zhang, J and Liu, Y and Xu, G and Cao, X and Wang, W and Zhang, D and Zhu, M}, title = {Causal relationship between coffee intake and neurological diseases: a Mendelian randomization study.}, journal = {European journal of clinical nutrition}, volume = {78}, number = {2}, pages = {114-119}, pmid = {37845420}, issn = {1476-5640}, support = {82260225//National Natural Science Foundation of China (National Science Foundation of China)/ ; 20202BAB216043//Natural Science Foundation of Jiangxi Province (Jiangxi Province Natural Science Foundation)/ ; }, mesh = {Humans ; Coffee/adverse effects ; Mendelian Randomization Analysis ; *Nervous System Diseases/etiology/genetics ; *Migraine Disorders/genetics ; Causality ; }, abstract = {BACKGROUND: Previous observational studies focused on the association of coffee consumption and neurological disease. However, it is not known whether these associations are causal.

METHODS: We used Mendelian randomization (MR) study to assess the causal relationship of coffee intake with the risk of neurological diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, stroke, and migraine. Single-nucleotide polymorphisms (SNPs) which had genetic statistical significance with coffee intake were used as instrumental variable (IV). Genetic instruments were stretched from the MRC-IEU (MRC Integrative Epidemiology Unit) analysis on the UK Biobank. We performed MR analyses using the inverse variance weighted (IVW) method as the main approach. Sensitivity analyses were further performed using MR-Egger and MR-PRESSO to assess the robustness.

RESULTS: In the MR analysis, 40 SNPs were selected as IV, the F statistics for all SNPs ranged from 16 to 359. In IVW approach, our results provide genetic evidence supporting a potential causal association between coffee intake and a lower risk of migraine (OR = 0.528, 95% CI = 0.342-0.817, P = 0.004) and migraine with aura (OR = 0.374, 95% CI = 0.208-0.672, P = 0.001). However, we found no significant association between coffee intake and other neurological diseases along with their subtypes in this MR study.

CONCLUSION: Using genetic data, our MR study found significant evidence supporting a causal association between coffee intake and migraine. This suggests that coffee consumption is likely a trigger or a prevention strategy for migraine.}, } @article {pmid37845101, year = {2023}, author = {Ugawa, Y}, title = {Somatosensory cortex/tracts involvement in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {156}, number = {}, pages = {249-250}, doi = {10.1016/j.clinph.2023.09.009}, pmid = {37845101}, issn = {1872-8952}, } @article {pmid37844546, year = {2023}, author = {Polverino, M and Sampaolo, S and Capuozzo, A and Fasolino, M and Aliberti, M and Satta, E and Santoriello, C and Orengo, JP and Polverino, F}, title = {Respiratory Function Changes as Early Signs of Amyotrophic Lateral Sclerosis.}, journal = {Respiration; international review of thoracic diseases}, volume = {102}, number = {11}, pages = {919-923}, pmid = {37844546}, issn = {1423-0356}, support = {R01 HL149744/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Respiration ; Respiratory Function Tests ; Lung ; Exhalation ; }, abstract = {BACKGROUND: The current diagnostic criteria for amyotrophic lateral sclerosis (ALS) may remain unsatisfactory for months or years in the early disease. Pulmonary assessment has never been considered useful in the early diagnosis of ALS, and studies of pulmonary function in this patient category are lacking.

OBJECTIVES: The objective of this study was to assess the pulmonary function in subjects with unspecific symptoms of ALS in whom an ALS diagnosis cannot be reached based on the current available guidelines.

METHODS: We performed pulmonary function tests, arterial gas analysis, maximal inspiratory (MIP) and expiratory (MEP) pressure, and respiratory drive (P0.1) assessment in 35 patients with unspecific neurological symptoms at the time of the visit and those were subsequently diagnosed with ALS 2 years after the initial visit ("pre-ALS"); we compared these patients with 29 patients with established ALS and with 28 control subjects.

RESULTS: Spirometric parameters were not different between the three groups. However, MIP was significantly lower and P0.1 was significantly increased (with the ratio P0.1/MIP significantly higher) in both established and pre-ALS patients compared to controls, while both MIP and P0.1 were similar between established ALS and pre-ALS.

CONCLUSIONS: Changes in MIP, P0.1, and P0.1/MIP ratio are highly suggestive of preclinical ALS when the spirometry and neurodiagnostic tests are still inconclusive. MIP and P0.1 are noninvasive measurements that can be easily assessed in an ambulatory setting. Future studies on larger cohorts are needed to validate the use of these parameters in the preclinical diagnosis of ALS as well as in other neuromuscular diseases.}, } @article {pmid37844376, year = {2023}, author = {Qassim, HM and Seyedalipour, B and Baziyar, P and Ahamady-Asbchin, S}, title = {Polyphenolic flavonoid compounds act as the inhibitory potential of aggregation process: Implications for the prevention and therapeutics against FALS-associated D101G SOD1 mutant.}, journal = {Computational biology and chemistry}, volume = {107}, number = {}, pages = {107967}, doi = {10.1016/j.compbiolchem.2023.107967}, pmid = {37844376}, issn = {1476-928X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Superoxide Dismutase-1/genetics/chemistry/metabolism ; *Hesperidin/pharmacology ; Superoxide Dismutase/chemistry/genetics/metabolism ; Mutation ; }, abstract = {Aggregation of proteins is a biological phenomenon caused by misfolded proteins. Human superoxide dismutase (hSOD1) misfolding and aggregation underlie the neurological illness amyotrophic lateral sclerosis (ALS). The most significant contributing factor to ALS is genetic point mutations in SOD1. particularly, D101G mutant is the most harmful because it significantly reduces the life expectancy of patients. Subsequently, the use of natural polyphenolic flavonoids is strongly recommended to reduce the amyloidogenic behavior of protopathic proteins. In this study, using computational parameters such as protein-ligand interaction and molecular dynamics (MD) simulation analyses, we are trying to identify a pharmacodynamically promising flavonoid compound that can effectively inhibit the pathogenic behavior of the D101G mutant. Epigallocatechin-gallate (EGCG), Hesperidin, Isorhamnetin, and Diosmetin were identified as potential leads in a preliminary screening of flavonoids to anti-amyloid action. The results of MD showed that the binding of flavonoids to D101G mutant caused changes in stability, hydrophobicity of protein, and flexibility, as well as significantly led to the restoration of lost hydrogen bonds. Secondary structure analysis showed that protein destabilization and the increased propensity of β-sheet caused by the mutation were restored to the wild-type state upon binding of flavonoids. Besides, to differentiate aggregation, we elucidated alterations in the free energy landscape (FEL) and dynamic cross-correlation matrix (DCCM) of WT-SOD1 and mutant (unbound /bound) states. Among flavonoids, Epigallocatechin-gallate and Hesperidin had the most therapeutic efficacy against the D101G mutant. Therefore, Epigallocatechin-gallate and Hesperidin promise considerable therapeutic potential to develop highly effective inhibitors in reducing fatal and irreversible ALS.}, } @article {pmid37843219, year = {2024}, author = {Liu, X and Liu, Y and Liu, J and Zhang, H and Shan, C and Guo, Y and Gong, X and Cui, M and Li, X and Tang, M}, title = {Correlation between the gut microbiome and neurodegenerative diseases: a review of metagenomics evidence.}, journal = {Neural regeneration research}, volume = {19}, number = {4}, pages = {833-845}, pmid = {37843219}, issn = {1673-5374}, abstract = {A growing body of evidence suggests that the gut microbiota contributes to the development of neurodegenerative diseases via the microbiota-gut-brain axis. As a contributing factor, microbiota dysbiosis always occurs in pathological changes of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. High-throughput sequencing technology has helped to reveal that the bidirectional communication between the central nervous system and the enteric nervous system is facilitated by the microbiota's diverse microorganisms, and for both neuroimmune and neuroendocrine systems. Here, we summarize the bioinformatics analysis and wet-biology validation for the gut metagenomics in neurodegenerative diseases, with an emphasis on multi-omics studies and the gut virome. The pathogen-associated signaling biomarkers for identifying brain disorders and potential therapeutic targets are also elucidated. Finally, we discuss the role of diet, prebiotics, probiotics, postbiotics and exercise interventions in remodeling the microbiome and reducing the symptoms of neurodegenerative diseases.}, } @article {pmid37843214, year = {2024}, author = {Wang, X and Hu, Y and Xu, R}, title = {The pathogenic mechanism of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {4}, pages = {800-806}, pmid = {37843214}, issn = {1673-5374}, abstract = {The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex, basal ganglia, brainstem, and spinal cord, and commonly involves the muscles of the upper and/or lower extremities, and the muscles of the bulbar and/or respiratory regions. However, as the disease progresses, it affects the adjacent body regions, leading to generalized muscle weakness, occasionally along with memory, cognitive, behavioral, and language impairments; respiratory dysfunction occurs at the final stage of the disease. The disease has a complicated pathophysiology and currently, only riluzole, edaravone, and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries. The TAR DNA-binding protein 43 inclusions are observed in 97% of those diagnosed with amyotrophic lateral sclerosis. This review provides a preliminary overview of the potential effects of TAR DNA-binding protein 43 in the pathogenesis of amyotrophic lateral sclerosis, including the abnormalities in nucleoplasmic transport, RNA function, post-translational modification, liquid-liquid phase separation, stress granules, mitochondrial dysfunction, oxidative stress, axonal transport, protein quality control system, and non-cellular autonomous functions (e.g., glial cell functions and prion-like propagation).}, } @article {pmid37843208, year = {2024}, author = {King, PH}, title = {Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis: a narrative review.}, journal = {Neural regeneration research}, volume = {19}, number = {4}, pages = {747-753}, pmid = {37843208}, issn = {1673-5374}, support = {I01 BX001148/BX/BLRD VA/United States ; I01 BX005899/BX/BLRD VA/United States ; R01 NS092651/NS/NINDS NIH HHS/United States ; R21 NS111275/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target. Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis, there is considerable heterogeneity, including clinical presentation, progression, and the underlying triggers for disease initiation. Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations, it has become apparent that overt disease is preceded by a prodromal phase, possibly in years, where compensatory mechanisms delay symptom onset. Since 85-90% of amyotrophic lateral sclerosis is sporadic, there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration. Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease. Skeletal muscle, including the neuromuscular junction, manifests abnormalities at the earliest stages of the disease, before motor neuron loss, making it a promising source for identifying biomarkers of the prodromal phase. The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time. The advent of "omics" technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle, ranging from coding and non-coding RNAs to proteins and metabolites. This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms. A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease. There are two major goals of this review. The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity, evidence of a similar dysregulation in the SOD1[G93A] mouse during presymptomatic stages, and evidence of progressive change during disease progression. The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression, and as such, their potential as therapeutic targets in amyotrophic lateral sclerosis.}, } @article {pmid37842553, year = {2023}, author = {Zucchi, E and Musazzi, UM and Fedele, G and Martinelli, I and Gianferrari, G and Simonini, C and Fini, N and Ghezzi, A and Caputo, M and Sette, E and Vacchiano, V and Zinno, L and Anceschi, P and Canali, E and Vinceti, M and Ferro, S and Mandrioli, J and , }, title = {Effect of tauroursodeoxycholic acid on survival and safety in amyotrophic lateral sclerosis: a retrospective population-based cohort study.}, journal = {EClinicalMedicine}, volume = {65}, number = {}, pages = {102256}, pmid = {37842553}, issn = {2589-5370}, abstract = {BACKGROUND: Oral tauroursodeoxycholic acid (TUDCA) is a commercial drug currently tested in patients with amyotrophic lateral sclerosis (ALS) both singly and combined with sodium phenylbutyrate. This retrospective study aimed to investigate, in a real-world setting, whether TUDCA had an impact on the overall survival of patients with ALS who were treated with this drug compared to those patients who received standard care only.

METHODS: This propensity score-matched study was conducted in the Emilia Romagna Region (Italy), which has had an ALS regional registry since 2009. Out of 627 patients with ALS diagnosed from January 1st, 2015 to June 30th, 2021 and recorded in the registry with available information on death/tracheostomy, 86 patients took TUDCA and were matched in a 1:2 ratio with patients who received only usual care according to age at onset, sex, phenotype, diagnostic latency, ALS Functional Rating Scale-Revised (ALSFRS-R) at first visit, disease progression rate at first visit, and BMI at diagnosis. The primary outcome was survival difference (time from onset of symptoms to tracheostomy/death) between TUDCA exposed and unexposed patients.

FINDINGS: A total of 86 patients treated with TUDCA were matched to 172 patients who did not receive treatment. TUDCA-exposed patients were stratified based on dosage (less than or equal to 1000 mg/day or greater) and duration (less than or equal to 12 months or longer) of treatment. The median overall survival was 49.6 months (95% CI 41.7-93.5) among those treated with TUDCA and 36.2 months (95% CI 32.7-41.6) in the control group, with a reduced risk of death observed in patients exposed to a higher dosage (defined as ≥ 1000 mg/day) of TUDCA (HR 0.56; 95% CI 0.38-0.83; p = 0.0042) compared to both the control group and those with lower TUDCA dosages (defined as < 1000 mg/day). TUDCA was generally well-tolerated, except for a minority of patients (n = 7, 8.1%) who discontinued treatment due to side effects, primarily gastrointestinal and mild in severity; only 2 adverse events required hospital access but resolved without sequelae.

INTERPRETATION: In this population-based exploratory study, patients with ALS who were treated with TUDCA may have prolonged survival compared to patients receiving standard care only. Additional prospective randomized studies are needed to confirm the efficacy and safety of this drug.

FUNDING: Emilia-Romagna Region.}, } @article {pmid37841873, year = {2023}, author = {Crone, N and Candrea, D and Shah, S and Luo, S and Angrick, M and Rabbani, Q and Coogan, C and Milsap, G and Nathan, K and Wester, B and Anderson, W and Rosenblatt, K and Clawson, L and Maragakis, N and Vansteensel, M and Tenore, F and Ramsey, N and Fifer, M and Uchil, A}, title = {A click-based electrocorticographic brain-computer interface enables long-term high-performance switch-scan spelling.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37841873}, issn = {2693-5015}, support = {T32 HD007414/HD/NICHD NIH HHS/United States ; UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Brain-computer interfaces (BCIs) can restore communication in movement- and/or speech-impaired individuals by enabling neural control of computer typing applications. Single command "click" decoders provide a basic yet highly functional capability.

METHODS: We sought to test the performance and long-term stability of click-decoding using a chronically implanted high density electrocorticographic (ECoG) BCI with coverage of the sensorimotor cortex in a human clinical trial participant (ClinicalTrials.gov, NCT03567213) with amyotrophic lateral sclerosis (ALS). We trained the participant's click decoder using a small amount of training data (< 44 minutes across four days) collected up to 21 days prior to BCI use, and then tested it over a period of 90 days without any retraining or updating.

RESULTS: Using this click decoder to navigate a switch-scanning spelling interface, the study participant was able to maintain a median spelling rate of 10.2 characters per min. Though a transient reduction in signal power modulation interrupted testing with this fixed model, a new click decoder achieved comparable performance despite being trained with even less data (< 15 min, within one day).

CONCLUSION: These results demonstrate that a click decoder can be trained with a small ECoG dataset while retaining robust performance for extended periods, providing functional text-based communication to BCI users.}, } @article {pmid37841575, year = {2023}, author = {Ayala, YM}, title = {Uncovering Critical Roles for RNA in Neurodegeneration.}, journal = {Missouri medicine}, volume = {120}, number = {5}, pages = {374-380}, pmid = {37841575}, issn = {0026-6620}, mesh = {Humans ; RNA/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; }, abstract = {RNA-binding proteins, in particular TDP-43, are key players in neurodegenerative disorders, mainly amyotrophic lateral sclerosis and frontotemporal dementia. We aim to elucidate how TDP-43 dysfunction alters cell metabolism and to identify mechanisms linked to aberrant behavior. We find that RNA binding plays a key role in maintaining TDP-43 homeostasis and in controlling cellular organization, two processes of essential importance to TDP-43 pathology. This research will provide insight into pathogenesis and help develop therapeutic interventions.}, } @article {pmid37840177, year = {2023}, author = {Li, XG and Liu, MS and Cui, LY}, title = {[Attention should be paid to the importance of genetic testing in clinical practice of amyotrophic lateral sclerosis].}, journal = {Zhonghua yi xue za zhi}, volume = {103}, number = {39}, pages = {3071-3076}, doi = {10.3760/cma.j.cn112137-20230516-00796}, pmid = {37840177}, issn = {0376-2491}, support = {81750002//National Natural Science Foundation of China/ ; 320675017092//the WJP Medical Foundation/ ; 2021I2MC&TA003//CAMS Innovation Fund for Medical Sciences (CIFMS)/ ; YJXJJZ2021001406//Beijing Yicheng Cooperative Development Foundation Research Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Neurodegenerative Diseases/genetics/pathology ; Motor Neurons/pathology ; Superoxide Dismutase-1/genetics ; Genetic Testing ; Mutation ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis(ALS) is a progressive and fatal neurodegenerative disease that mainly involves upper and lower motor neurons. It lacks clear biomarkers and can be clearly diagnosed only one and a half years after the onset. Gene test is of great significance for diagnosis, prognosis and genetic counseling. In recent years, several gene therapy studies have entered the clinical trial stage of ALS, among which the antisense oligonucleotide therapy targeting the pathogenic variation of the superoxide dismutase 1 (SOD1) gene has been launched, and it is urgent to carry out routine gene test in clinical practice. On the basis of progress of ALS gene research in recent years, family history, age of onset and typical clinical manifestations of patients are no longer considered as the basis for genetic testing. However, the target genes of clinical gene testing needs to be further clarified according to the diagnostic purpose, the testing method and scheme need to be standardized, and the genetic consultation before testing should be paid attention to, and the informed consent should be fully achieved.}, } @article {pmid37839397, year = {2023}, author = {Helwa, N and Sharma, M and Vanama, MS and Helwa, Y and El-Falou, A}, title = {Colonic Anastomotic Leak Model in Swine.}, journal = {European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes}, volume = {64}, number = {4}, pages = {406-411}, doi = {10.1159/000534580}, pmid = {37839397}, issn = {1421-9921}, mesh = {Swine ; Animals ; *Anastomotic Leak/etiology ; *Colon/surgery ; Anastomosis, Surgical/adverse effects ; Postoperative Complications/etiology ; Models, Animal ; }, abstract = {INTRODUCTION: Anastomotic leaks (ALs) are serious postoperative complications. Current experimental studies designed to investigate leaks are based on acute intraoperative dehiscence of the anastomosis. Clinically, however, AL usually happens later in the postoperative course. Presented here is a clinically relevant colonic AL model in swine.

METHODS: Seventeen Yorkshire pigs were divided into 2 groups: the control group (n = 6) and the experimental group (n = 11). An enterotomy was performed on the descending colon and an end-to-end handsewn anastomosis was created in the groups. The proximal and distal ends of the suture were exteriorized and tied to a plastic tube. Subsequently, the suture was cut and pulled to induce breakdown of the anastomosis in the experimental group 3-4 h postoperatively. Study endpoints included behavioral changes, clinical assessment, laboratory indicators, and macroscopic indicators of leakage.

RESULTS: Leaks were successfully created in 8/11 of the experimental group animals and confirmed through exploratory relaparotomy. Seven of the experimental pigs showed complete anastomotic breakdown and one showed partial rupture. Fecal peritonitis and enteric spillage were observed macroscopically within the abdomen of the experimental pigs, confirming the presence of a leak. The remaining (3/11) experimental pigs did not experience those findings due to either a tamponade/containment by the abdominal wall or surrounding organs. Statistical significance (p < 0.05) was achieved between the experimental and control cohorts for laboratory and clinical indicators including fever, leukocytosis, and decreased blood potassium.

CONCLUSION: This animal model generated postoperative induced leak in approximately three-quarters (8/11) of experimental pigs, allowing control over the time of leak onset to simulate clinical settings.}, } @article {pmid37839080, year = {2024}, author = {Gaynor, LS and Yadollahikhales, G and Tsoy, E and Hall, M and Boxer, AL and Miller, BL and Grinberg, LT}, title = {C9orf72 Repeat Expansion Initially Presenting as Late-Onset Bipolar Disorder With Psychosis.}, journal = {The neurologist}, volume = {29}, number = {2}, pages = {109-112}, pmid = {37839080}, issn = {2331-2637}, support = {P50 AG023501/AG/NIA NIH HHS/United States ; K24 AG045333/AG/NIA NIH HHS/United States ; K24 AG053435/AG/NIA NIH HHS/United States ; R01 AG038791/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; U54 NS092089/NS/NINDS NIH HHS/United States ; T32 AG023481/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; }, mesh = {Female ; Humans ; Adult ; Middle Aged ; *Bipolar Disorder/diagnosis/genetics ; C9orf72 Protein/genetics ; *Frontotemporal Dementia/diagnosis/genetics ; *Psychotic Disorders/diagnosis/genetics ; *Apraxias ; }, abstract = {INTRODUCTION: C9orf72 expansion is the most common genetic abnormality in behavioral variant frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis. Although psychiatric prodromes are common in C9orf72 expansion carriers, there are only scattered reported cases of primary psychiatric disorders, such as bipolar disorder, diagnosed at disease onset. Moreover, C9orf72 carrier status is rarely identified in bipolar disorder genetic studies.

CASE REPORT: A 51-year-old, right-handed woman with 16 years of education presented for evaluation of long-standing cognitive and behavioral change. She initially displayed symptoms of mania and florid, multimodal psychotic symptoms at age 39. Her bipolar disorder symptoms were initially responsive to medication; however, she later developed executive dysfunction and behavioral symptoms consistent with bvFTD. She became progressively nonverbal, and her limited speech was notable for speech apraxia. At the time of presentation, she demonstrated cortical sensory deficit, ideomotor and oral-buccal apraxia, and unstable gait. Neuroimaging revealed diffuse brain atrophy. Postmortem histopathological evaluation revealed frontotemporal lobar degeneration with TDP-43 inclusions, type B, and genetic study identified C9orf72 expansion. A detailed review of family history found a strong paternal history of bipolar disorder and substance use disorder.

CONCLUSIONS: We describe a rare case of C9orf72 expansion initially characterized by late-onset bipolar disorder and florid, multimodal psychotic symptoms, followed years later by bvFTD diagnosis. This report emphasizes the importance of completing a neurological examination, obtaining a detailed family history, and pursuing genetic screening to distinguish between primary psychiatric disorder and bvFTD in individuals who meet the criteria for late-onset bipolar disorder.}, } @article {pmid37838979, year = {2024}, author = {Jagadish, A and Shankaranarayana, AM and Natarajan, M and Solomon, JM}, title = {Transcranial direct current stimulation for fatigue in neurological conditions: A systematic scoping review.}, journal = {Physiotherapy research international : the journal for researchers and clinicians in physical therapy}, volume = {29}, number = {1}, pages = {e2054}, doi = {10.1002/pri.2054}, pmid = {37838979}, issn = {1471-2865}, mesh = {Humans ; *Brain Injuries, Traumatic ; Fatigue/therapy/etiology ; *Multiple Sclerosis/complications/therapy ; *Parkinson Disease ; Quality of Life ; *Stroke ; *Transcranial Direct Current Stimulation/adverse effects ; }, abstract = {BACKGROUND AND PURPOSE: Fatigue following neurological conditions negatively impacts daily activities, reducing overall quality of life. Transcranial direct current stimulation (tDCS) for fatigue management is still underexplored. This scoping review explores its use in managing fatigue among various neurological conditions.

METHODS: A thorough literature search was carried out using PubMed, Scopus, CINAHL, Web of Science, Embase, ProQuest, and the Cochrane Library. Google Scholar and clinicaltrials.gov were manually searched for gray literature and ongoing trials, respectively. Regardless of the study design, all studies utilizing tDCS for the management of fatigue in various neurological conditions were considered. Two reviewers independently screened all the studies, following which the data were retrieved.

RESULTS: Studies employing tDCS for fatigue management across neurological conditions is as follows: Multiple sclerosis (MS) (n = 28, 66%), stroke (n = 5, 12%), Parkinson's disease (PD) (n = 4, 10%), post-polio syndrome (PPS) (n = 2, 5%), traumatic brain injury (TBI) (n = 2, 5%), and amyotrophic lateral sclerosis (n = 1, 2%). All the studies used anodal stimulation, with the common stimulation site being the left dorsolateral prefrontal cortex for MS, stroke, and PD. A stimulation intensity of 1.0-4.0 mA with a duration ranging from 15 to 30 min in 1 to 24 sessions were commonly reported. The Fatigue Severity Scale (n = 21) and Modified Fatigue Impact Scale (n = 17) were frequently implemented outcome measures. Regardless of the study design, 36/42 (85.7%) studies reported an improvement in fatigue scores in the tDCS group. The common adverse events noted were tingling (n = 8, 35%), headache (n = 6, 26%), and itching (n = 6, 26%).

DISCUSSION: Application of tDCS for fatigue was explored in individuals with stroke, PD, PPS, and TBI after MS. Even though a wide range of treatment parameters and outcome measures were adopted to assess and target fatigue, tDCS proves to have a promising role in alleviating this symptom.}, } @article {pmid37838698, year = {2023}, author = {Zeballos C, MA and Moore, HJ and Smith, TJ and Powell, JE and Ahsan, NS and Zhang, S and Gaj, T}, title = {Mitigating a TDP-43 proteinopathy by targeting ataxin-2 using RNA-targeting CRISPR effector proteins.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {6492}, pmid = {37838698}, issn = {2041-1723}, support = {R01 GM141296/GM/NIGMS NIH HHS/United States ; T32 EB019944/EB/NIBIB NIH HHS/United States ; U01 NS122102/NS/NINDS NIH HHS/United States ; R01 NS123556/NS/NINDS NIH HHS/United States ; }, mesh = {Mice ; Animals ; Ataxin-2/genetics ; RNA/metabolism ; *TDP-43 Proteinopathies/genetics/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics ; DNA-Binding Proteins/genetics/metabolism ; }, abstract = {The TDP-43 proteinopathies, which include amyotrophic lateral sclerosis and frontotemporal dementia, are a devastating group of neurodegenerative disorders that are characterized by the mislocalization and aggregation of TDP-43. Here we demonstrate that RNA-targeting CRISPR effector proteins, a programmable class of gene silencing agents that includes the Cas13 family of enzymes and Cas7-11, can be used to mitigate TDP-43 pathology when programmed to target ataxin-2, a modifier of TDP-43-associated toxicity. In addition to inhibiting the aggregation and transit of TDP-43 to stress granules, we find that the in vivo delivery of an ataxin-2-targeting Cas13 system to a mouse model of TDP-43 proteinopathy improved functional deficits, extended survival, and reduced the severity of neuropathological hallmarks. Further, we benchmark RNA-targeting CRISPR platforms against ataxin-2 and find that high-fidelity forms of Cas13 possess improved transcriptome-wide specificity compared to Cas7-11 and a first-generation effector. Our results demonstrate the potential of CRISPR technology for TDP-43 proteinopathies.}, } @article {pmid37838538, year = {2024}, author = {Wang, SA and Lee, HW and Ko, YC and Sun, JT and Matsuyama, T and Lin, CH and Hsieh, MJ and Chiang, WC and Ma, MH}, title = {Effect of crew ratio of advanced life support-trained personnel on patients with out-of-hospital cardiac arrest: A systematic review and meta-analysis.}, journal = {Journal of the Formosan Medical Association = Taiwan yi zhi}, volume = {123}, number = {5}, pages = {561-570}, doi = {10.1016/j.jfma.2023.10.008}, pmid = {37838538}, issn = {0929-6646}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; *Emergency Medical Services ; *Advanced Cardiac Life Support ; Cardiopulmonary Resuscitation ; Taiwan ; Return of Spontaneous Circulation ; Japan ; }, abstract = {BACKGROUND/PURPOSE: This review aimed to investigate the effect of crew ratios of on-scene advanced life support (ALS)-trained personnel on patients with out-of-hospital cardiac arrest (OHCA).

METHODS: We systematically searched PubMed, Ovid EMBASE, and the Cochrane Central Register of Controlled Trials databases from the inception date until September 30, 2022, for eligible studies. Two reviewers independently screened the studies for relevance, extracted data, and quality. We compared the effect of the ratio of on-scene ALS-trained personnel >50 % to those with a ratio ≤50 % among prehospital personnel on the clinical outcomes of OHCA patients. The primary outcome was survival-to-discharge and secondary outcomes were any return of spontaneous circulation (ROSC), sustained ROSC (≥2 h), and favourable neurological outcome at discharge (cerebral performance category scores: 1 or 2). Pooled odds ratios (ORs) were calculated, and the certainty of evidence was assessed.

RESULTS: From 10,864 references, we identified four non-randomised studies, including 16,475 patients. Two studies were performed in Japan and two in Taiwan. There were significant differences in survival-to-discharge (OR: 1.24, 95 % confidence interval [CI]: 1.07-1.44, I[2]: 7 %), any ROSC (OR:1.22, 95 % CI: 1.04-1.43, I[2]: 74 %) and sustained ROSC (OR: 1.39, 95 % CI: 1.16-1.65, I[2]: 40 %), but insignificant differences in favourable neurological outcome at discharge. The overall certainty of evidence was rated as very low for all outcomes.

CONCLUSION: Prehospital ALS care with a ratio of on-scene ALS-trained personnel >50 % could improve OHCA patient outcomes than crew ratios ≤50 %. Further studies are required to reach a robust conclusion.}, } @article {pmid37838312, year = {2023}, author = {Kumar, R and Malik, MZ and Thanaraj, TA and Bagabir, SA and Haque, S and Tambuwala, M and Haider, S}, title = {A computational biology approach to identify potential protein biomarkers and drug targets for sporadic amyotrophic lateral sclerosis.}, journal = {Cellular signalling}, volume = {112}, number = {}, pages = {110915}, doi = {10.1016/j.cellsig.2023.110915}, pmid = {37838312}, issn = {1873-3913}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Neurodegenerative Diseases ; Molecular Docking Simulation ; Proteins ; Computational Biology ; Biomarkers ; *Cyclosporins/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the loss of upper and lower motor neurons. The sporadic ALS (sALS) is a multigenic disorder and the complex mechanisms underlying its onset are still not fully delineated. Despite the recent scientific advancements, certain aspects of ALS pathogenic targets need to be yet clarified. The aim of the presented study is to identify potential genetic biomarkers and drug targets for sALS, by analysing gene expression profiles, presented in the publicly available GSE68605 dataset, of motor neurons cells obtained from sALS patients. We used different computational approaches including differential expression analysis, protein network mapping, candidate protein biomarker (CPB) identification, elucidation of the role of functional modules, and molecular docking analysis. The resultant top ten up- and downregulated genes were further used to construct protein-protein interaction network (PPIN). The PPIN analysis resulted in identifying four CPBs (namely RIOK2, AKT1, CTNNB1, and TNF) that commonly overlapped with one another in network parameters (degree, bottleneck and maximum neighbourhood component). The RIOK2 protein emerged as a potential mediator of top five functional modules that are associated with RNA binding, lipoprotein particle receptor binding in pre-ribosome, and interferon, cytokine-mediated signaling pathway. Furthermore, molecular docking analysis revealed that cyclosporine exhibited the highest binding affinity (-8.6 kJ/mol) with RIOK2, and surpassed the FDA-approved ALS drugs, such as riluzole and edaravone. This suggested that cyclosporine may serve as a promising candidate for targeting RIOK2 downregulation observed in sALS patients. In order to validate our computational results, it is suggested that in vitro and in vivo studies may be conducted in future to provide a more detailed understanding of ALS diagnosis, prognosis, and therapeutic intervention.}, } @article {pmid37837871, year = {2023}, author = {Nakamori, M and Shimizu, Y and Takahashi, T and Toko, M and Yamada, H and Hayashi, Y and Ushio, K and Yoshikawa, K and Hiraoka, A and Yoshikawa, M and Nagasaki, T and Mikami, Y and Maruyama, H}, title = {Swallowing sound index analysis using electronic stethoscope and artificial intelligence for patients with Parkinson's disease.}, journal = {Journal of the neurological sciences}, volume = {454}, number = {}, pages = {120831}, doi = {10.1016/j.jns.2023.120831}, pmid = {37837871}, issn = {1878-5883}, mesh = {Humans ; Deglutition/physiology ; *Parkinson Disease/diagnosis/diagnostic imaging ; *Deglutition Disorders/diagnostic imaging/etiology ; Artificial Intelligence ; *Stethoscopes ; Electronics ; }, abstract = {BACKGROUND AND PURPOSE: Several noninvasive tools assess swallowing disorders, including electronic stethoscope artificial intelligence (AI) analysis for remote diagnosis, with the potential for telemedicine. This study investigated the swallowing sound index in patients with Parkinson's disease (PD).

METHODS: This single-arm, open-label trial assessed the impact of cervical percutaneous interferential current stimulation on swallowing in patients with PD classified as Hoehn-Yahr stages 2-4. Stimulation was conducted for 8 weeks. Baseline data were used to examine the link between the swallowing sound index and indicators such as videofluoroscopy (VF). Furthermore, we examined changes in the swallowing sound index after the intervention.

RESULTS: Twenty-five patients were included. The swallowing sound index in patients with PD was higher than that in those with amyotrophic lateral sclerosis but considerably lower than that in healthy controls. The number of patients with normal EAT-10 scores positively correlated with the swallowing sound index, whereas elevated C-reactive protein levels were negatively correlated with the swallowing sound index. However, the index displayed no correlation with other indicators, including the VF results. Despite the intervention, the index remained unchanged throughout the study.

CONCLUSION: In patients with PD, a decrease in the swallowing sound index suggests a potential association between swallowing disorders and the risk of aspiration pneumonia.

TRIAL REGISTRATION NUMBER: jRCTs062220013.}, } @article {pmid37837507, year = {2024}, author = {Hamad, AA and Amer, BE and Abbas, NB and Alnajjar, AZ and Meshref, M}, title = {Prevalence and correlates of fatigue in amyotrophic lateral sclerosis: A systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {2}, pages = {485-493}, pmid = {37837507}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/epidemiology ; Prevalence ; Quality of Life ; Fatigue/etiology/complications ; }, abstract = {OBJECTIVES: This systematic review and meta-analysis aimed to determine the frequency and correlates of fatigue in patients with amyotrophic lateral sclerosis (ALS).

METHODS: Three databases were searched up to 2nd May 2023 to identify studies reporting fatigue frequency in ALS. Studies included had to identify ALS patients through one of ALS diagnostic criteria and measure fatigue by a validated tool with a specific cut-off value. Meta-analysis was conducted using RStudio's "meta" package with a random-effects model. Subgroup analyses and meta-regression explored the relationship between fatigue frequency in ALS and different covariates.

RESULTS: Eleven studies, compromising 1072 patients, met the inclusion criteria and were included in our analysis. The pooled frequency of fatigue across all studies was 48% (95% CI = 40% to 57%). Our subgroup analysis based on the ALSFRS-R revealed a higher frequency of fatigue in studies with lower scores (< 30) compared to those with higher scores (≥ 30), with a pooled frequency of 62% (95% CI = 43% to 79%) and 43% (95% CI = 37% to 49%), respectively. Also, the meta-regression analysis showed a significant negative association between fatigue and ALSFRS-R mean (P = 0.02). The included studies reported an association between fatigue and lower functional status and poorer quality of life in patients with ALS.

CONCLUSION: Our findings suggest that fatigue is prevalent in almost half of ALS patients and is associated with lower functional status and poorer quality of life, highlighting the importance of assessing and managing fatigue in ALS patients.}, } @article {pmid37836771, year = {2023}, author = {Colombo, E and Olla, S and Minnelli, C and Formato, A and Veroni, C and Corbisiero, S and Pericolo, M and Siguri, C and Mobbili, G and Agresti, C and Seneci, P}, title = {Synthesis and Characterization of Edaravone Analogues as Remyelinating Agents and Putative Mechanistic Probes.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {19}, pages = {}, pmid = {37836771}, issn = {1420-3049}, support = {2017/R/2//Fondazione Italiana Sclerosi Multipla/ ; }, mesh = {Humans ; Edaravone/pharmacology/therapeutic use ; *Antioxidants/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Oxidative Stress ; Esters/pharmacology ; }, abstract = {Edaravone (EDA), an antioxidant drug approved for the treatment of ischemic stroke and amyotrophic lateral sclerosis, was recently proposed as a remyelinating candidate for the treatment of multiple sclerosis. Here, we synthesized twelve EDA analogues 2b-4c showing three substitution patterns A-C, searching for improved remyelinating agents and putative molecular targets responsible for their regenerative activity. We profiled them in three primary assays to determine their stimulation of oligodendrocyte progenitor cell metabolism (tetrazolium MTT assay), their antioxidant potential (2,2-diphenyl-1-picrylhydrazyl-DPPH assay) and to predict their bioavailability (virtual ADME profile). Active 4'-carboxylate 2b, 4'-ester 2c and N[1]-carbamate-4'-ester 4a were further characterized, justifying their in vitro effects and selecting 4a as a putative EDA 1 prodrug suitable for in vivo testing.}, } @article {pmid37834458, year = {2023}, author = {Shvetcov, A and Thomson, S and Spathos, J and Cho, AN and Wilkins, HM and Andrews, SJ and Delerue, F and Couttas, TA and Issar, JK and Isik, F and Kaur, S and Drummond, E and Dobson-Stone, C and Duffy, SL and Rogers, NM and Catchpoole, D and Gold, WA and Swerdlow, RH and Brown, DA and Finney, CA}, title = {Blood-Based Transcriptomic Biomarkers Are Predictive of Neurodegeneration Rather Than Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {24}, number = {19}, pages = {}, pmid = {37834458}, issn = {1422-0067}, support = {P01 AG060882/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/diagnosis/genetics/metabolism ; *Neurodegenerative Diseases ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism ; Transcriptome ; *Parkinson Disease/diagnosis/genetics/metabolism ; Biomarkers/metabolism ; }, abstract = {Alzheimer's disease (AD) is a growing global health crisis affecting millions and incurring substantial economic costs. However, clinical diagnosis remains challenging, with misdiagnoses and underdiagnoses being prevalent. There is an increased focus on putative, blood-based biomarkers that may be useful for the diagnosis as well as early detection of AD. In the present study, we used an unbiased combination of machine learning and functional network analyses to identify blood gene biomarker candidates in AD. Using supervised machine learning, we also determined whether these candidates were indeed unique to AD or whether they were indicative of other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Our analyses showed that genes involved in spliceosome assembly, RNA binding, transcription, protein synthesis, mitoribosomes, and NADH dehydrogenase were the best-performing genes for identifying AD patients relative to cognitively healthy controls. This transcriptomic signature, however, was not unique to AD, and subsequent machine learning showed that this signature could also predict PD and ALS relative to controls without neurodegenerative disease. Combined, our results suggest that mRNA from whole blood can indeed be used to screen for patients with neurodegeneration but may be less effective in diagnosing the specific neurodegenerative disease.}, } @article {pmid37834407, year = {2023}, author = {Baj, J and Flieger, W and Barbachowska, A and Kowalska, B and Flieger, M and Forma, A and Teresiński, G and Portincasa, P and Buszewicz, G and Radzikowska-Büchner, E and Flieger, J}, title = {Consequences of Disturbing Manganese Homeostasis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {19}, pages = {}, pmid = {37834407}, issn = {1422-0067}, mesh = {Humans ; Manganese/toxicity/metabolism ; *Diabetes Mellitus, Type 2 ; *Manganese Poisoning/metabolism ; Homeostasis ; *Neurodegenerative Diseases ; }, abstract = {Manganese (Mn) is an essential trace element with unique functions in the body; it acts as a cofactor for many enzymes involved in energy metabolism, the endogenous antioxidant enzyme systems, neurotransmitter production, and the regulation of reproductive hormones. However, overexposure to Mn is toxic, particularly to the central nervous system (CNS) due to it causing the progressive destruction of nerve cells. Exposure to manganese is widespread and occurs by inhalation, ingestion, or dermal contact. Associations have been observed between Mn accumulation and neurodegenerative diseases such as manganism, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. People with genetic diseases associated with a mutation in the gene associated with impaired Mn excretion, kidney disease, iron deficiency, or a vegetarian diet are at particular risk of excessive exposure to Mn. This review has collected data on the current knowledge of the source of Mn exposure, the experimental data supporting the dispersive accumulation of Mn in the brain, the controversies surrounding the reference values of biomarkers related to Mn status in different matrices, and the competitiveness of Mn with other metals, such as iron (Fe), magnesium (Mg), zinc (Zn), copper (Cu), lead (Pb), calcium (Ca). The disturbed homeostasis of Mn in the body has been connected with susceptibility to neurodegenerative diseases, fertility, and infectious diseases. The current evidence on the involvement of Mn in metabolic diseases, such as type 2 diabetes mellitus/insulin resistance, osteoporosis, obesity, atherosclerosis, and non-alcoholic fatty liver disease, was collected and discussed.}, } @article {pmid37834374, year = {2023}, author = {Oprisan, AL and Popescu, BO}, title = {Dysautonomia in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {19}, pages = {}, pmid = {37834374}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Neurodegenerative Diseases/pathology ; Motor Neurons/pathology ; *Primary Dysautonomias/etiology/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, characterized in its typical presentation by a combination of lower and upper motor neuron symptoms, with a progressive course and fatal outcome. Due to increased recognition of the non-motor symptoms, it is currently considered a multisystem disorder with great heterogeneity, regarding genetical, clinical, and neuropathological features. Often underestimated, autonomic signs and symptoms have been described in patients with ALS, and various method analyses have been used to assess autonomic nervous system involvement. The aim of this paper is to offer a narrative literature review on autonomic disturbances in ALS, based on the scarce data available to date.}, } @article {pmid37834128, year = {2023}, author = {Huber, K and Szerenos, E and Lewandowski, D and Toczylowski, K and Sulik, A}, title = {The Role of Adipokines in the Pathologies of the Central Nervous System.}, journal = {International journal of molecular sciences}, volume = {24}, number = {19}, pages = {}, pmid = {37834128}, issn = {1422-0067}, mesh = {Humans ; Adipokines/metabolism ; Central Nervous System/metabolism ; *Alzheimer Disease/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Adipose Tissue/metabolism ; }, abstract = {Adipokines are protein hormones secreted by adipose tissue in response to disruptions in physiological homeostasis within the body's systems. The regulatory functions of adipokines within the central nervous system (CNS) are multifaceted and intricate, and they have been identified in a number of pathologies. Therefore, specific adipokines have the potential to be used as biomarkers for screening purposes in neurological dysfunctions. The systematic review presented herein focuses on the analysis of the functions of various adipokines in the pathogenesis of CNS diseases. Thirteen proteins were selected for analysis through scientific databases. It was found that these proteins can be identified within the cerebrospinal fluid either by their ability to modify their molecular complex and cross the blood-brain barrier or by being endogenously produced within the CNS itself. As a result, this can correlate with their measurability during pathological processes, including Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, depression, or brain tumors.}, } @article {pmid37834094, year = {2023}, author = {Jellinger, KA}, title = {The Spectrum of Cognitive Dysfunction in Amyotrophic Lateral Sclerosis: An Update.}, journal = {International journal of molecular sciences}, volume = {24}, number = {19}, pages = {}, pmid = {37834094}, issn = {1422-0067}, support = {000//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; Brain/pathology ; *Cognition Disorders/pathology ; *Cognitive Dysfunction/pathology ; *Neurodegenerative Diseases/pathology ; *Pick Disease of the Brain/pathology ; }, abstract = {Cognitive dysfunction is an important non-motor symptom in amyotrophic lateral sclerosis (ALS) that has a negative impact on survival and caregiver burden. It shows a wide spectrum ranging from subjective cognitive decline to frontotemporal dementia (FTD) and covers various cognitive domains, mainly executive/attention, language and verbal memory deficits. The frequency of cognitive impairment across the different ALS phenotypes ranges from 30% to 75%, with up to 45% fulfilling the criteria of FTD. Significant genetic, clinical, and pathological heterogeneity reflects deficits in various cognitive domains. Modern neuroimaging studies revealed frontotemporal degeneration and widespread involvement of limbic and white matter systems, with hypometabolism of the relevant areas. Morphological substrates are frontotemporal and hippocampal atrophy with synaptic loss, associated with TDP-43 and other co-pathologies, including tau deposition. Widespread functional disruptions of motor and extramotor networks, as well as of frontoparietal, frontostriatal and other connectivities, are markers for cognitive deficits in ALS. Cognitive reserve may moderate the effect of brain damage but is not protective against cognitive decline. The natural history of cognitive dysfunction in ALS and its relationship to FTD are not fully understood, although there is an overlap between the ALS variants and ALS-related frontotemporal syndromes, suggesting a differential vulnerability of motor and non-motor networks. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of cognitive impairment in ALS, which might even serve as novel targets for effective disease-modifying therapies.}, } @article {pmid37833071, year = {2023}, author = {}, title = {Erratum: Huh et al., "Time Course of Alterations in Adult Spinal Motoneuron Properties in the SOD1(G93A) Mouse Model of ALS".}, journal = {eNeuro}, volume = {10}, number = {10}, pages = {}, doi = {10.1523/ENEURO.0370-23.2023}, pmid = {37833071}, issn = {2373-2822}, } @article {pmid37833013, year = {2023}, author = {Bryukhovetskiy, AS and Grivtsova, LY and Bogachev, SS and Ustyugov, AA and Nebogatikov, VO and Shurdov, MA}, title = {Technology of genomic balancing of chromatin of autologous hematopoietic stem cells for gene therapy of fatal immune-mediated diseases of civilization, extended life expectancy and sudden human death prevention.}, journal = {International review of neurobiology}, volume = {172}, number = {}, pages = {237-284}, doi = {10.1016/bs.irn.2023.07.005}, pmid = {37833013}, issn = {2162-5514}, mesh = {Rats ; Humans ; Animals ; Mice ; *Chromatin/metabolism ; *Quality of Life ; Rats, Wistar ; Hematopoietic Stem Cells/metabolism ; Genetic Therapy ; Life Expectancy ; Genomics ; DNA/metabolism ; Technology ; Death, Sudden ; Civilization ; }, abstract = {A biotechnology for personalized ex vivo gene therapy based on molecular genomic balancing of hematopoietic stem cell (HSC) chromatin with nucleosome monomers of human genomic DNA (hDNA[nmr]) has been developed and implemented in the clinic to change (to "correct") mutant chromosome loci genomes of dominant HSC clones that form mono- and oligoclonal hematopoiesis during aging and major (oncological, cardiovascular, neurodegenerative and autoimmune) fatal immune-mediated diseases of civilization. A fundamentally new biotechnological approach has been applied to the delivery of genetic material into eukaryotic stem and progenitor cells by establishing an artificial "recombinogenic situation" in them to induce homologous recombination (equivalent replacement) of mutant DNA regions with healthy hDNA[nmr]. In experimental preclinical trials, the effectiveness of genomic balancing technology has been proven to reduce the risk of sudden death in old animals and to increase the lifespan of outbred mice by 30% and Wistar rats by 57%. The improvement in their quality of life, compared with the control, is explained by an increase in the telomeric regions of the HSCs and HPCs chromosomes by 1.5-2 times. The potential of the technology to slow down the hereditary neurodegenerative diseases on the model of amyotrophic lateral sclerosis is shown. The effectiveness of this technology in clinical practice is presented on the example of a terminal patient with stage 4 neuroendocrine cancer. This technology used in the treatment of a number of oncological, neurodegenerative, autoimmune and hereditary diseases with clonal hematopoiesis is able to arrest the progression of the disease, prevent its recurrence, prolong the active life of a person, increase the average life expectancy and prevent sudden death.}, } @article {pmid37832609, year = {2023}, author = {Rezaee, D and Saadatpour, F and Akbari, N and Zoghi, A and Najafi, S and Beyranvand, P and Zamani-Rarani, F and Rashidi, MA and Bagheri-Mohammadi, S and Bakhtiari, M}, title = {The role of microRNAs in the pathophysiology of human central nervous system: A focus on neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {92}, number = {}, pages = {102090}, doi = {10.1016/j.arr.2023.102090}, pmid = {37832609}, issn = {1872-9649}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Amyloid beta-Peptides ; *Alzheimer Disease/genetics/metabolism ; Central Nervous System/metabolism ; *Neoplasms ; }, abstract = {microRNAs (miRNAs) are suggested to play substantial roles in regulating the development and various physiologic functions of the central nervous system (CNS). These include neurogenesis, cell fate and differentiation, morphogenesis, formation of dendrites, and targeting non-neural mRNAs. Notably, deregulation of an increasing number of miRNAs is associated with several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and CNS tumors. They are particularly known to affect the amyloid β (Aβ) cleavage and accumulation, tau protein homeostasis, and expression of alpha-synuclein (α-syn), Parkin, PINK1, and brain-derived neurotrophic factor (BDNF) that play pivotal roles in the pathogenesis of neurodegenerative diseases. These include miR-16, miR-17-5p, miR-20a, miR-106a, miR-106b, miR-15a, miR-15b, miR-103, miR-107, miR-298, miR-328, miR-195, miR-485, and miR-29. In CNS tumors, several miRNAs, including miR-31, miR-16, and miR-21 have been identified to modulate tumorigenesis through impacting tumor invasion and apoptosis. In this review article, we have a look at the recent advances on our knowledge about the role of miRNAs in human brain development and functions, neurodegenerative diseases, and their clinical potentials.}, } @article {pmid37832429, year = {2023}, author = {Migliorelli, L and Scoppolini Massini, L and Coccia, M and Villani, L and Frontoni, E and Squartini, S}, title = {A deep learning-based telemonitoring application to automatically assess oral diadochokinesis in patients with bulbar amyotrophic lateral sclerosis.}, journal = {Computer methods and programs in biomedicine}, volume = {242}, number = {}, pages = {107840}, doi = {10.1016/j.cmpb.2023.107840}, pmid = {37832429}, issn = {1872-7565}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Deep Learning ; Software ; }, abstract = {BACKGROUND AND OBJECTIVES: Timely identification of dysarthria progression in patients with bulbar-onset amyotrophic lateral sclerosis (ALS) is relevant to have a comprehensive assessment of the disease evolution. To this goal literature recognized the utmost importance of the assessment of the number of syllables uttered by a subject during the oral diadochokinesis (DDK) test.

METHODS: To support clinicians, this work proposes a remote deep learning-based system, which consists (i) of a web application to acquire audio tracks of bulbar-onset ALS patients and healthy control subjects while performing the oral DDK test (i.e., repeating the /pa/, /pa-ta-ka/ and /oo-ee/ syllables) and (ii) a DDK-AID network designed to process the acquired audio signals which have different duration and to output the number of per-task syllables repeated by the subject.

RESULTS: The DDK-AID network overcomes the comparative method achieving a mean Accuracy of 90.23 in counting syllables repeated by the eleven bulbar-onset ALS-patients while performing the oral DDK test.

CONCLUSIONS: The proposed remote monitoring system, in the light of the achieved performance, represents an important step towards the implementation of self-service telemedicine systems which may ensure customised care plans.}, } @article {pmid37832380, year = {2023}, author = {Kwon, S and Kim, B and Han, KD and Jung, W and Cho, EB and Yang, JH and Shin, DW and Min, JH}, title = {Increased risk of myocardial infarction in amyotrophic lateral sclerosis: A nationwide cohort study in South Korea.}, journal = {Journal of the neurological sciences}, volume = {454}, number = {}, pages = {120829}, doi = {10.1016/j.jns.2023.120829}, pmid = {37832380}, issn = {1878-5883}, mesh = {Humans ; Male ; Female ; Cohort Studies ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Myocardial Infarction/epidemiology ; Obesity ; Incidence ; }, abstract = {BACKGROUND: The risk of myocardial infarction (MI), the major form of CVD, in amyotrophic lateral sclerosis (ALS) is currently unknown. We investigated the risk of MI in ALS and analyzed the effect of ALS-related physical disability on the risk of MI using the Korean National Health Insurance Service database.

METHODS: A total of 659 ALS patients and 10,927 non-ALS participants were finally selected between January 1, 2011, and December 31, 2015. A Cox hazard regression model was used to examine the hazard ratios (HRs) for MI in ALS after adjustment for potential confounders.

RESULTS: The incidence rate of MI was 26.2 per 1000 person-years, and the adjusted HR (aHR) for MI in ALS patients was 10.6 (95% confidence interval [CI] 7.2-15.4) compared with the controls. ALS patients who developed physical disability had an even higher risk of MI (aHR 18.6, 95% CI 11.5-30.0) compared with those who did not develop disability (aHR 7.4, 95% CI 4.6-11.9). The increased risk of MI was more prominent in female subjects than in male subjects (aHR 17.8, 95% CI 10.8-29.4 vs. aHR 6.9, 95% CI 4.1-11.6, P for interaction 0.006) and in obese subjects than in non-obese subjects (aHR 17.8, 95% CI 10.5-30.1 vs. aHR 7.9, 95% CI 4.9-12.8, P for interaction 0.018).

CONCLUSIONS: Our findings suggest that the risk of MI is high in ALS patients compared with a control population, and the risk is more prominent in those who develop physical disability, or who are female or obese.}, } @article {pmid37831677, year = {2023}, author = {Kim, JA and Jang, H and Choi, Y and Min, YG and Hong, YH and Sung, JJ and Choi, SJ}, title = {Subclinical articulatory changes of vowel parameters in Korean amyotrophic lateral sclerosis patients with perceptually normal voices.}, journal = {PloS one}, volume = {18}, number = {10}, pages = {e0292460}, pmid = {37831677}, issn = {1932-6203}, mesh = {Humans ; *Dysarthria/diagnosis/etiology ; *Amyotrophic Lateral Sclerosis ; Speech Intelligibility ; Phonetics ; Republic of Korea ; Speech Acoustics ; }, abstract = {The available quantitative methods for evaluating bulbar dysfunction in patients with amyotrophic lateral sclerosis (ALS) are limited. We aimed to characterize vowel properties in Korean ALS patients, investigate associations between vowel parameters and clinical features of ALS, and analyze subclinical articulatory changes of vowel parameters in those with perceptually normal voices. Forty-three patients with ALS (27 with dysarthria and 16 without dysarthria) and 20 healthy controls were prospectively collected in the study. Dysarthria was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R) speech subscores, with any loss of 4 points indicating the presence of dysarthria. The structured speech samples were recorded and analyzed using Praat software. For three corner vowels (/a/, /i/, and /u/), data on the vowel duration, fundamental frequency, frequencies of the first two formants (F1 and F2), harmonics-to-noise ratio, vowel space area (VSA), and vowel articulation index (VAI) were extracted from the speech samples. Corner vowel durations were significantly longer in ALS patients with dysarthria than in healthy controls. The F1 frequency of /a/, F2 frequencies of /i/ and /u/, the VSA, and the VAI showed significant differences between ALS patients with dysarthria and healthy controls. The area under the curve (AUC) was 0.912. The F1 frequency of /a/ and the VSA were the major determinants for differentiating ALS patients who had not yet developed apparent dysarthria from healthy controls (AUC 0.887). In linear regression analyses, as the ALSFRS-R speech subscore decreased, both the VSA and VAI were reduced. In contrast, vowel durations were found to be rather prolonged. The analyses of vowel parameters provided a useful metric correlated with disease severity for detecting subclinical bulbar dysfunction in ALS patients.}, } @article {pmid37831552, year = {2023}, author = {Trabelsi, T and Esposito, VJ and Francisco, JS}, title = {Spectroscopy and Photochemistry of Aluminum-Bearing Species in the Universe.}, journal = {Accounts of chemical research}, volume = {56}, number = {21}, pages = {3045-3052}, doi = {10.1021/acs.accounts.3c00481}, pmid = {37831552}, issn = {1520-4898}, abstract = {ConspectusMetal-bearing molecules impact the chemical and physical environment of many astronomical sources such as the circumstellar envelopes of large asymptotic giant branch and red supergiant stars, the interstellar medium, and planetary atmospheres (e.g., ablation of ∼20 tons per day into the Earth's upper atmosphere). In recent decades, the number of successfully detected metal-containing molecules has increased via rotational spectroscopic observations, which are driven by theoretical and experimental investigations. Following formation, the ultimate fate of each species (stabilization, dissociation, etc.) is determined by its electronic structure and electronic spectroscopic properties as it encounters the pervasive radiation fields in the vacuum of space. Studying these properties can evince the possibility of detection and predict the impact each molecule has on its surrounding environment. Aluminum, one of the most abundant elements and metals, is distributed throughout the universe as a constituent of gas-phase molecules (e.g., AlO, AlOH, AlCl, etc.) as well as condensed onto solid dust grains such as Al2O3. Free gas-phase aluminum-bearing molecules are synthesized by nonthermal equilibrium processes such as shocks and pulsations near the stellar photosphere or via the reaction of molecules on the surface of dust grains. Recent investigations in our research group utilizing quantum chemical methods, such as coupled cluster (CCSD(T) and CCSD(T)-F12) and multireference configuration interaction (MRCI) with large basis sets, have explored a wide breadth of spectroscopy and photochemistry of small (triatomic and tetratomic) aluminum-bearing molecules, including Al-H, Al-C, Al-N, Al-O, Al-Si, Al-P, and Al-S bonds, among others. The ground-state spectroscopy (rotational and vibrational) of various aluminum-bearing molecules is discussed in the context of experimental and observational detection potentials. These detection potentials depend on various factors, such as the magnitude of the permanent dipole moment (PDM) and the population of states yielding transition frequencies in detectable ranges. Many aluminum-bearing molecules possess large PDMs and may be prime candidates for astronomical and laboratory detection. Within this discussion, interesting aspects of the ground-state molecular orbital configuration of OAlNO are shown to lead to an uncommon triplet ground state. Additionally, the electronic absorption spectrum of the quasi-isoenergetic ground-state isomers of AlOSO is discussed as a sensitive method for detecting this species and differentiating between the two isomers. Finally, photochemical mechanisms key to the production of AlO and AlOH in low-density regions and the destruction of AlCO and AlOC are also discussed in order to understand the radiation-induced formation and destruction of these molecules.}, } @article {pmid37831200, year = {2023}, author = {Latorre-Rodríguez, AR and Huang, J and Schaheen, L and Smith, MA and Hashimi, S and Bremner, RM and Mittal, SK}, title = {Diagnosis and management of anastomotic leaks after Ivor Lewis esophagectomy: a single-center experience.}, journal = {Langenbeck's archives of surgery}, volume = {408}, number = {1}, pages = {397}, pmid = {37831200}, issn = {1435-2451}, mesh = {Humans ; *Anastomotic Leak/diagnosis/etiology/therapy ; Esophagectomy/adverse effects ; *Esophageal Neoplasms/surgery ; Endoscopy, Gastrointestinal/adverse effects ; Retrospective Studies ; Postoperative Complications/diagnosis/epidemiology/etiology ; Anastomosis, Surgical/adverse effects ; Treatment Outcome ; }, abstract = {PURPOSE: Esophageal anastomotic leaks (ALs) after esophagectomy are a common and serious complication. The incidence, diagnostic approach, and management have changed over time. We described the diagnosis and management of patients who developed an esophageal AL after an Ivor Lewis esophagectomy at our center.

METHODS: After IRB approval, we queried our prospectively maintained database for patients who developed an esophageal AL after esophagectomy from August 2016 through July 2022. Data pertaining to demographics, comorbidities, surgical and oncological characteristics, and clinical course were extracted and analyzed.

RESULTS: During the study period, 145 patients underwent an Ivor Lewis esophagectomy; 10 (6.9%) developed an AL, diagnosed a median of 7.5 days after surgery, and detected by enteric contents in wound drains (n = 3), endoscopy (n = 3), CT (n = 2), and contrast esophagogram (n = 2). Nine patients (90%) had an increasing white blood cell count and additional signs of sepsis. One asymptomatic patient was identified by contrast esophagography. All patients received enteral nutritional support, intravenous antibiotics, and antifungals. Primary treatment of ALs included endoscopic placement of a self-expanding metal stent (SEMS; n = 6), surgery (n = 2), and SEMS with endoluminal vacuum therapy (n = 2). One patient required surgery after SEMS placement. The median length of ICU and total hospital stays were 11.5 and 22.5 days, respectively. There was no 30-day mortality.

CONCLUSION: The incidence of esophageal ALs at our center is similar to that of other high-volume centers. Most ALs can be managed without surgery; however, ALs remain a significant source of postoperative morbidity despite clinical advancements that have improved mortality.}, } @article {pmid37830099, year = {2023}, author = {Berlowitz, DJ and Mathers, S and Hutchinson, K and Hogden, A and Carey, KA and Graco, M and Whelan, BM and Charania, S and Steyn, F and Allcroft, P and Crook, A and Sheers, NL}, title = {The complexity of multidisciplinary respiratory care in amyotrophic lateral sclerosis.}, journal = {Breathe (Sheffield, England)}, volume = {19}, number = {3}, pages = {220269}, pmid = {37830099}, issn = {1810-6838}, abstract = {UNLABELLED: Motor neurone disease/amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with no known cure, where death is usually secondary to progressive respiratory failure. Assisting people with ALS through their disease journey is complex and supported by clinics that provide comprehensive multidisciplinary care (MDC). This review aims to apply both a respiratory and a complexity lens to the key roles and areas of practice within the MDC model in ALS. Models of noninvasive ventilation care, and considerations in the provision of palliative therapy, respiratory support, and speech and language therapy are discussed. The impact on people living with ALS of both inequitable funding models and the complexity of clinical care decisions are illustrated using case vignettes. Considerations of the impact of emerging antisense and gene modifying therapies on MDC challenges are also highlighted. The review seeks to illustrate how MDC members contribute to collective decision-making in ALS, how the sum of the parts is greater than any individual care component or health professional, and that the MDC per se adds value to the person living with ALS. Through this approach we hope to support clinicians to navigate the space between what are minimum, guideline-driven, standards of care and what excellent, person-centred ALS care that fully embraces complexity could be.

EDUCATIONAL AIMS: To highlight the complexities surrounding respiratory care in ALS.To alert clinicians to the risk that complexity of ALS care may modify the effectiveness of any specific, evidence-based therapy for ALS.To describe the importance of person-centred care and shared decision-making in optimising care in ALS.}, } @article {pmid37828541, year = {2023}, author = {Richardson, PJ and Smith, DP and de Giorgio, A and Snetkov, X and Almond-Thynne, J and Cronin, S and Mead, RJ and McDermott, CJ and Shaw, PJ}, title = {Janus kinase inhibitors are potential therapeutics for amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {12}, number = {1}, pages = {47}, pmid = {37828541}, issn = {2047-9158}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Janus Kinase Inhibitors/therapeutic use ; *Neurodegenerative Diseases ; Central Nervous System/metabolism ; Janus Kinases/metabolism/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles. As with other multifactorial diseases, it is likely that drugs will need to target multiple disease processes and cell types to be effective. We review here the role of Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) signalling in ALS, confirm the association of this signalling with fundamental ALS disease processes using the BenevolentAI Knowledge Graph, and demonstrate that inhibitors of this pathway could reduce the ALS pathophysiology in neurons, glia, muscle fibres, and blood cells. Specifically, we suggest that inhibition of the JAK enzymes by approved inhibitors known as Jakinibs could reduce STAT3 activation and modify the progress of this disease. Analysis of the Jakinibs highlights baricitinib as a suitable candidate due to its ability to penetrate the central nervous system and exert beneficial effects on the immune system. Therefore, we recommend that this drug be tested in appropriately designed clinical trials for ALS.}, } @article {pmid37828358, year = {2023}, author = {Abrahams, S}, title = {Neuropsychological impairment in amyotrophic lateral sclerosis-frontotemporal spectrum disorder.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {11}, pages = {655-667}, pmid = {37828358}, issn = {1759-4766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; *Frontotemporal Dementia/complications ; *Neurodegenerative Diseases ; *Cognitive Dysfunction ; *Cognition Disorders/diagnosis/etiology ; Neuropsychological Tests ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a rapid course, characterized by motor neuron dysfunction, leading to progressive disability and death. This Review, which is aimed at neurologists, psychologists and other health professionals who follow evidence-based practice relating to ALS and frontotemporal dementia (FTD), examines the neuropsychological evidence that has driven the reconceptualization of ALS as a spectrum disorder ranging from a pure motor phenotype to ALS-FTD. It focuses on changes in cognition and behaviour, which vary in severity across the spectrum: around 50% individuals with ALS are within the normal range, 15% meet the criteria for ALS-FTD, and the remaining 35% are in the mid-spectrum range with milder and more focal impairments. The cognitive impairments include deficits in verbal fluency, executive functions, social cognition and language, and apathy is the most prevalent behavioural change. The pattern and severity of cognitive and behavioural change predicts underlying regional cerebral dysfunction from brain imaging and post-mortem pathology. Our increased recognition of cognition and behaviour as part of the ALS phenotype has led to the development and standardization of assessment tools, which have been incorporated into research and clinical care. Measuring change over the course of the disease is vital for clinical trials, and neuropsychology is proving to be a biomarker for the earliest preclinical changes.}, } @article {pmid37827960, year = {2023}, author = {Todd, TW and Shao, W and Zhang, YJ and Petrucelli, L}, title = {The endolysosomal pathway and ALS/FTD.}, journal = {Trends in neurosciences}, volume = {46}, number = {12}, pages = {1025-1041}, pmid = {37827960}, issn = {1878-108X}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; RF1 AG062171/AG/NIA NIH HHS/United States ; RF1 AG062077/AG/NIA NIH HHS/United States ; R21 NS127331/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R01 NS117461/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Frontotemporal Dementia/genetics ; Mutation ; Autophagy ; C9orf72 Protein/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are considered to be part of a disease spectrum that is associated with causative mutations and risk variants in a wide range of genes. Mounting evidence indicates that several of these genes are linked to the endolysosomal system, highlighting the importance of this pathway in ALS/FTD. Although many studies have focused on how disruption of this pathway impacts on autophagy, recent findings reveal that this may not be the whole picture: specifically, disrupting autophagy may not be sufficient to induce disease, whereas disrupting the endolysosomal system could represent a crucial pathogenic driver. In this review we discuss the connections between ALS/FTD and the endolysosomal system, including a breakdown of how disease-associated genes are implicated in this pathway. We also explore the potential downstream consequences of disrupting endolysosomal activity in the brain, outside of an effect on autophagy.}, } @article {pmid37827930, year = {2023}, author = {Cassereau, J and Bernard, E and Genestet, S and Chebbah, M and Le Clanche, S and Verschueren, A and Couratier, P}, title = {Management of amyotrophic lateral sclerosis in clinical practice: Results of the expert consensus using the Delphi methodology.}, journal = {Revue neurologique}, volume = {179}, number = {10}, pages = {1134-1144}, doi = {10.1016/j.neurol.2023.07.011}, pmid = {37827930}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Riluzole/therapeutic use ; Motor Neurons ; Diagnosis, Differential ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare disease characterized by a progressive and irreversible degeneration of upper and lower motor neurons leading to death. In France, limited data exist describing the criteria used in clinical practice for diagnosis and follow-up, and how novel therapies may fit in. The objective of this Delphi panel was to obtain an overview of current French practices in ALS diagnosis, management, and follow-up by determining the scales and criteria used in clinical practice outside of clinical trials, as well as the place of a future treatment like AMX0035, acting on endoplasmic reticulum (ER) stress and mitochondrial dysfunction, in the current therapeutic strategies. A questionnaire was administered to 24 ALS healthcare providers practicing in ALS centers in France. Two rounds of remote voting were organized, before proposition of final consensus statements. Consensus was considered reached when at least 66% of the voters agreed. Consensus were obtained to define the new Gold Coast criteria as the ones used in clinical practice to establish the diagnosis of ALS, thus replacing the revised El Escorial criteria, considered too complex and now mainly used to characterize the patient populations to be included in clinical trials. The clinical factors considered to establish ALS diagnosis are mainly the demonstration of progression of the motor deficit and elimination of differential diagnoses. The ALSFRS-R scale is used in daily clinical practice to assess patient's functional impairment in terms of number of points lost, with the bulbar, respiratory, and fine motor subscores being the most important to evaluate independently. A critical medical need was identified regarding the provision of new therapeutic alternatives in ALS. The panel members would support the earliest management of patients. In this landscape, based on data from a very encouraging phase II (Centaur trial), AMX0035 represents a new tool of choice in current treatment strategies for all patients for whom experts are confident in the diagnosis of ALS, in combination with riluzole. These results will need to be confirmed by the ongoing phase III trial (Phoenix trial).}, } @article {pmid37827904, year = {2023}, author = {Santiago, JA and Karthikeyan, M and Lackey, M and Villavicencio, D and Potashkin, JA}, title = {Diabetes: a tipping point in neurodegenerative diseases.}, journal = {Trends in molecular medicine}, volume = {29}, number = {12}, pages = {1029-1044}, pmid = {37827904}, issn = {1471-499X}, support = {R01 AG062176/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Brain/metabolism ; *Diabetes Mellitus/metabolism ; }, abstract = {Diabetes is associated with an increased risk and progression of Alzheimer's (AD) and Parkinson's (PD) diseases. Conversely, diabetes may confer neuroprotection against amyotrophic lateral sclerosis (ALS). It has been posited that perturbations in glucose and insulin regulation, cholesterol metabolism, and mitochondrial bioenergetics defects may underlie the molecular underpinnings of diabetes effects on the brain. Nevertheless, the precise molecular mechanisms remain elusive. Here, we discuss the evidence from molecular, epidemiological, and clinical studies investigating the impact of diabetes on neurodegeneration and highlight shared dysregulated pathways between these complex comorbidities. We also discuss promising antidiabetic drugs, molecular diagnostics currently in clinical trials, and outstanding questions and challenges for future pursuit.}, } @article {pmid37827876, year = {2023}, author = {Shimizu, T and Nakayama, Y and Hayashi, K and Mochizuki, Y and Matsuda, C and Haraguchi, M and Bokuda, K and Komori, T and Takahashi, K}, title = {Somatosensory pathway dysfunction in patients with amyotrophic lateral sclerosis in a completely locked-in state.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {156}, number = {}, pages = {253-261}, doi = {10.1016/j.clinph.2023.09.004}, pmid = {37827876}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Superoxide Dismutase-1 ; Evoked Potentials, Somatosensory/physiology ; Median Nerve ; }, abstract = {OBJECTIVE: To investigate somatosensory pathway function in patients with amyotrophic lateral sclerosis (ALS) dependent on invasive ventilation and in a completely locked-in state (CLIS).

METHODS: We examined median nerve somatosensory evoked potentials (SEPs) in 17 ALS patients in a CLIS, including 11 patients with sporadic ALS, one with familial ALS with genes not examined, four with a Cu/Zn superoxide-dismutase-1 (SOD1) gene variant (Val118Leu, Gly93Ser, Cys146Arg), and one with a fused-in-sarcoma gene variant (P525L). We evaluated N9, N13, N20 and P25, and central conduction time (CCT); the data were compared with those of 73 healthy controls.

RESULTS: N20 and N13 were abolished in 12 and 10 patients, and their latencies was prolonged in four and three patients, respectively. The CCT was prolonged in five patients with measurable N13 and N20. Two patients with SOD1 gene mutations had absent or slightly visible N9. Compared to the CCT and latencies and amplitudes of N13 and N20 in the controls, those in the patient cohort were significantly abnormal.

CONCLUSIONS: The central somatosensory pathway is severely involved in patients with ALS in a CLIS.

SIGNIFICANCE: Our findings suggest that median nerve SEP cannot be utilized for communication in patients with ALS in a CLIS.}, } @article {pmid37827570, year = {2024}, author = {McHutchison, CA and Wuu, J and McMillan, CT and Rademakers, R and Statland, J and Wu, G and Rampersaud, E and Myers, J and Hernandez, JP and Abrahams, S and Benatar, M and , }, title = {Temporal course of cognitive and behavioural changes in motor neuron diseases.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {4}, pages = {316-324}, pmid = {37827570}, issn = {1468-330X}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Male ; Middle Aged ; Female ; *Amyotrophic Lateral Sclerosis/diagnosis ; C9orf72 Protein/genetics ; *Motor Neuron Disease/genetics/complications ; *Cognitive Dysfunction/genetics/complications ; Cognition/physiology ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Cognitive and behavioural dysfunction may occur in people with motor neuron disease (MND), with some studies suggesting an association with the C9ORF72 repeat expansion. Their onset and progression, however, is poorly understood. We explored how cognition and behaviour change over time, and whether demographic, clinical and genetic factors impact these changes.

METHODS: Participants with MND were recruited through the Phenotype-Genotype-Biomarker study. Every 3-6 months, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was used to assess amyotrophic lateral sclerosis (ALS) specific (executive functioning, verbal fluency, language) and ALS non-specific (memory, visuospatial) functions. Informants reported on behaviour symptoms via semi-structured interview.

RESULTS: Participants with neuropsychological data at ≥3 visits were included (n=237, mean age=59, 60% male), of which 18 (8%) were C9ORF72 positive. Baseline cognitive impairment was apparent in 18 (8%), typically in ALS specific domains, and associated with lower education, but not C9ORF72 status. Cognition, on average, remained stable over time, with two exceptions: (1) C9ORF72 carriers declined in all ECAS domains, (2) 8%-9% of participants with baseline cognitive impairment further declined, primarily in the ALS non-specific domain, which was associated with less education. Behavioural symptoms were uncommon.

CONCLUSIONS: In this study, cognitive dysfunction was less common than previously reported and remained stable over time for most. However, cognition declines longitudinally in a small subset, which is not entirely related to C9ORF72 status. Our findings raise questions about the timing of cognitive impairment in MND, and whether it arises during early clinically manifest disease or even prior to motor manifestations.}, } @article {pmid37827425, year = {2024}, author = {Jia, H and Li, Z and Guo, F and Hua, Z and Zhou, X and Li, X and Li, R and Liu, Q and Liu, Y and Dong, H}, title = {Cortical structure and the risk of amyotrophic lateral sclerosis: A bidirectional Mendelian randomization study.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {129}, number = {}, pages = {110872}, doi = {10.1016/j.pnpbp.2023.110872}, pmid = {37827425}, issn = {1878-4216}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Reproducibility of Results ; Magnetic Resonance Imaging/methods ; }, abstract = {BACKGROUND: Current observational studies indicate progressive brain atrophy is closely associated with the clinical feature of amyotrophic lateral sclerosis. However, it is unclear whether the changes in cortical structure are the cause or result of ALS. Our study aimed to investigate the causal relationship between cortical structure and ALS risk using a bidirectional two-sample MR study.

METHODS: We collected publicly available genome-wide association studies' summary statistics for cortical structure from UK Biobank and ENIGMA consortium (n = 33,992) and ALS from the Project MinE (n = 138,086). We used the inverse variance weighted method (IVW) as primary analysis in order to evaluate the causal effects. In addition, the weighted median and MR Egger methods were performed to ensure the robustness and reliability of the IVW results.

RESULTS: We found the decreased surface of the paracentral lobule and thickness of the frontal pole and middle temporal lobe were suggestively associated with an increased risk of ALS as well as the increased surface of medial orbitofrontal and middle temporal lobe. In another aspect, the causalities between the susceptibility to ALS and the volume of the transverse temporal gyrus and superior temporal gyrus were negative. Besides, the susceptibility to ALS might also contribute to an increased thickness of the postcentral gyrus and superior parietal gyrus.

CONCLUSION: In this two-sample MR analysis, we observed that multiple cortical brain regions are associated with a higher ALS risk. Further research into the underlying mechanisms is required to back up our findings.}, } @article {pmid37827137, year = {2024}, author = {Heckmann, JG and Kiem, M and Immich, G}, title = {Forest Therapy as a Nature-Based Intervention: An Option for Neurological Rehabilitation?.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {56-63}, doi = {10.1159/000534533}, pmid = {37827137}, issn = {2504-2106}, mesh = {Humans ; *Medicine ; *Neurological Rehabilitation ; *Sleep Wake Disorders ; *Stroke/therapy ; *Dementia ; Observational Studies as Topic ; }, abstract = {BACKGROUND: Forest therapy demonstrates positive effects on mood, immune system, stress levels, and general well-being. Studies on depression, stress-related illnesses, sleep disorders, and arterial hypertension have provided evidence-based proof of this.

SUMMARY: The aim of this review was to examine the possible effects of forest therapy with regard to its evidence in the treatment of chronic neurological diseases such as stroke in the rehabilitation phase, Parkinson's disease, dementia, and multiple sclerosis. Therefore, the electronic databases Medline, Scopus, and Cochrane were searched for such clinical trials for the years 1970 to mid-2023 without language restriction. The literature search revealed only few studies with positive indications but too few cases to be able to make generalizable evidence-based statements. In terms of improvement in the Hamilton Depression Scale analysis of two studies in stroke patients showed slight benefits in the forest therapy group (standard mean difference -0.43; 95% CI: -0.76 to -0.10; p < 0.01). One observational study revealed a higher rate of stroke survival in patients living in marked greenness. Few nature-based interventions in dementia patients showed certain benefits in particular details.

KEY MESSAGES: There are no evidence-based results on the benefit of forest therapy for chronic neurological diseases. However, there are hints that forest therapy could have a positive benefit. Therefore, a proposal for forest therapy as a component of multimodal neurological rehabilitation is presented.

UNLABELLED: HintergrundDie Waldtherapie zeigt positive Auswirkungen auf die Stimmung, das Immunsystem, das Stressniveau und das allgemeine Wohlbefinden. Studien zu Depressionen, stressbedingten Erkrankungen, Schlafstörungen und arteriellem Bluthochdruck haben dies evidenzbasiert belegt.ZusammenfassungZiel dieser Übersichtsarbeit war es, die möglichen Wirkungen der Waldtherapie im Hinblick auf ihre Evidenz bei der Behandlung chronischer neurologischer Erkrankungen wie Schlaganfall in der Rehabilitationsphase, Morbus Parkinson, Demenz und Multiple Sklerose zu untersuchen. Dazu wurden die elektronischen Datenbanken Medline, Scopus und Cochrane für die Jahre 1970 bis Mitte 2023 ohne sprachliche Einschränkung nach solchen klinischen Studien durchsucht. Die Literaturrecherche ergab nur wenige Studien mit positiven Indikationen, aber zu wenigen Fällen, um verallgemeinerbare evidenzbasierte Aussagen machen zu können. Im Hinblick auf Verbesserung in der Hamilton Depressionsskala zeigte die Analyse von 2 Studien bei Schlaganfallpatienten leichte Vorteile der Waldtherapiegruppen (Standard Mean Difference −0.43; 95% CI: -0.76- -0,10; p < 0.01). Eine Beobachtungsstudie ergab eine höhere Schlaganfall-Überlebensrate bei Patienten, die in ausgeprägtem Grün leben. Einige naturbasierte Interventionen bei Demenzpatienten zeigten in einzelnen Parametern gewisse Vorteile.FazitEs gibt bis dato keine verallgemeinerbaren evidenzbasierten Ergebnisse zum Nutzen der Waldtherapie bei chronischen neurologischen Erkrankungen. Es gibt jedoch Hinweise, dass die Waldtherapie einen positiven Nutzen haben könnte. Es wird daher ein Vorschlag für eine Waldtherapie als Bestandteil einer multimodalen neurologischen Rehabilitation vorgestellt.}, } @article {pmid37823684, year = {2024}, author = {Marlin, E and Valencia, M and Peregrín, N and Ferrero, R and Nicolás, MJ and Vinueza-Gavilanes, R and Pineda-Lucena, A and Artieda, J and Arrasate, M and Aragón, T}, title = {Pharmacological inhibition of the integrated stress response accelerates disease progression in an amyotrophic lateral sclerosis mouse model.}, journal = {British journal of pharmacology}, volume = {181}, number = {3}, pages = {495-508}, doi = {10.1111/bph.16260}, pmid = {37823684}, issn = {1476-5381}, support = {Predoctoral Fellowship//AC-CIMA/ ; Proyectos I+D 2017//Fundación para la Investigación Médica Aplicada/ ; 0011-0537-2018-000006 Predoctoral fellowship//Gobierno de Navarra, Departamento de Universidad, Innovación y Transformación Digital/ ; Intramural IdiSNA 2022//Instituto de Investigación Sanitaria de Navarra (IdiSNA)/ ; BFU2017-90043-P MICINN/ AEI/10.13039/501100011033//Ministerio de Ciencia e Innovación/ ; PID2020-120497RB-I00 MICINN/ AEI /10.13039/501100011//Ministerio de Ciencia e Innovación/ ; //Proyecto Intramural IdisNa 2022/ ; //Fundación para la Investigación Médica Aplicada (FIMA)/ ; 0011-0537-2018-000006//Departamento de Educación, Gobierno de Navarra/ ; //Asociación de Amigos (ADA)/ ; }, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Superoxide Dismutase-1/genetics ; Eukaryotic Initiation Factor-2B ; Superoxide Dismutase/metabolism ; Mice, Transgenic ; Disease Progression ; Disease Models, Animal ; }, abstract = {BACKGROUND AND PURPOSE: The integrated stress response (ISR) regulates translation in response to diverse stresses. ISR activation has been documented in amyotrophic lateral sclerosis (ALS) patients and ALS experimental models. In experimental models, both ISR stimulation and inhibition prevented ALS neurodegeneration; however, which mode of ISR regulation would work in patients is still debated. We previously demonstrated that the ISR modulator ISRIB (Integrated Stress Response InhiBitor, an eIF2B activator) enhances survival of neurons expressing the ALS neurotoxic allele SOD1 G93A. Here, we tested the effect of two ISRIB-like eIF2B activators (2BAct and PRXS571) in the disease progression of transgenic SOD1[G93A] mice.

EXPERIMENTAL APPROACH: After biochemical characterization in primary neurons, SOD1[G93A] mice were treated with 2BAct and PRXS571. Muscle denervation of vulnerable motor units was monitored with a longitudinal electromyographic test. We used a clinical score to document disease onset and progression; force loss was determined with the hanging wire motor test. Motor neuronal survival was assessed by immunohistochemistry.

KEY RESULTS: In primary neurons, 2BAct and PRXS571 relieve the ISR-imposed translational inhibition while maintaining high ATF4 levels. Electromyographic recordings evidenced an earlier and more dramatic muscle denervation in treated SOD1[G93A] mice that correlated with a decrease in motor neuron survival. Both compounds anticipated disease onset and shortened survival time.

CONCLUSION AND IMPLICATIONS: 2BAct and PRXS571 anticipate disease onset, aggravating muscle denervation and motor neuronal death of SOD1[G93A] mice. This study reveals that the ISR works as a neuroprotective pathway in ALS motor neurons and reveals the toxicity that eIF2B activators may display in ALS patients.}, } @article {pmid37823580, year = {2023}, author = {Mehta, AK and Sarmet, M and Maiser, S and Meyer, JA and Kolodziejczak, S and Washington, K and Simmons, Z}, title = {Quality-of-life assessment instruments used across ALS clinics.}, journal = {Muscle & nerve}, volume = {68}, number = {6}, pages = {865-872}, doi = {10.1002/mus.27985}, pmid = {37823580}, issn = {1097-4598}, mesh = {Humans ; *Quality of Life ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Palliative Care ; Surveys and Questionnaires ; Ambulatory Care ; }, abstract = {INTRODUCTION/AIMS: Instruments have been developed to assess quality of life (QoL) among people with amyotrophic lateral sclerosis (ALS). It is unclear whether these are utilized regularly in the clinical setting to guide individual patient care. In this study we aimed to understand the current use of instruments and existing barriers to assessing QoL in clinical ALS care.

METHODS: An anonymous survey developed by Northeast ALS (NEALS) Consortium Palliative Committee members was distributed to all multidisciplinary NEALS members. Data were summarized via calculation of descriptive statistics. ALS Center characteristics were compared using chi-square and Fisher exact tests for categorical variables.

RESULTS: Seventy-three (6.4%) of the 1132 NEALS members responded to the survey, representing 148 clinics, 49.3% of whom reported assessing QoL during clinic visits. The most used ALS-specific instruments were the ALS Assessment Questionnaire (19.4%) and Amyotrophic Lateral Sclerosis Specific Quality of Life scale (16.6%). Barriers reported were uncertainty regarding which instrument to use and length of visits. QoL assessment was not significantly correlated with length of clinic visit but with access to specialty palliative care.

DISCUSSION: QoL assessments are performed by some, but not all, ALS centers during clinical visits. Although this study did have a low number of responding centers, the percentage, the proportion is similar to that seen in earlier studies, which limits the findings' generalizability. The value of QoL assessments' impact on outcomes should be further investigated and, if warranted, creative ways sought to increase the frequency of their use, including patient self-assessments before clinic and/or the use of teleheath to reduce the length of clinic visits.}, } @article {pmid37822527, year = {2023}, author = {Colombo, E and Gentile, F and Maranzano, A and Doretti, A and Verde, F and Olivero, M and Gagliardi, D and Faré, M and Meneri, M and Poletti, B and Maderna, L and Corti, S and Corbo, M and Morelli, C and Silani, V and Ticozzi, N}, title = {The impact of upper motor neuron involvement on clinical features, disease progression and prognosis in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1249429}, pmid = {37822527}, issn = {1664-2295}, } @article {pmid37821950, year = {2023}, author = {Košir, M and Možina, H and Podbregar, M}, title = {Skeletal muscle oxygenation during cardiopulmonary resuscitation as a predictor of return of spontaneous circulation: a pilot study.}, journal = {European journal of medical research}, volume = {28}, number = {1}, pages = {418}, pmid = {37821950}, issn = {2047-783X}, mesh = {Adult ; Humans ; Male ; Aged ; Female ; *Cardiopulmonary Resuscitation/methods ; Pilot Projects ; Return of Spontaneous Circulation ; Cerebrovascular Circulation/physiology ; *Out-of-Hospital Cardiac Arrest/therapy ; }, abstract = {BACKGROUND: Near-infrared spectroscopy (NIRS) provides regional tissue oxygenation (rSO2) even in pulseless states, such as out-of-hospital cardiac arrest (OHCA). Brain rSO2 seems to be important predictor of return of spontaneous circulation (ROSC) during cardiopulmonary resuscitation (CPR). Aim of our study was to explore feasibility for monitoring and detecting changes of skeletal muscle rSO2 during resuscitation.

METHODS: Skeletal muscle and brain rSO2 were measured by NIRS (SenSmart Model X-100, Nonin, USA) during CPR in adult patient with OHCA. Start (basal) rSO2, maximal during CPR (maximal) and difference between maximal-minimal rSO2 (delta-rSO2), were recorded. Patients were divided into ROSC and NO-ROSC group.

RESULTS: 20 patients [age: 66.0ys (60.5-79.5), 65% male] with OHCA [50% witnessed, 70% BLS, time to ALS 13.5 min (11.0-19.0)] were finally analyzed. ROSC was confirmed in 5 (25%) patients. Basal and maximal skeletal muscle rSO2 were higher in ROSC compared to NO-ROSC group [49.0% (39.7-53.7) vs. 15.0% (12.0-25.2), P =  0.006; 76.0% (52.7-80.5) vs. 34.0% (18.0-49.5), P =  0.005, respectively]. There was non-linear cubic relationship between time of collapse and basal skeletal muscle rSO2 in witnessed OHCA and without BLS (F-ratio = 9.7713, P =  0.0261). There was correlation between maximal skeletal muscle and brain rSO2 (n = 18, rho: 0.578, P =   0.0121).

CONCLUSIONS: Recording of skeletal muscle rSO2 during CPR in patients with OHCA is feasible. Basal and maximal skeletal muscle rSO2 were higher in ROSC compared to NO-ROSC group. Clinical trial registration number ClinicalTrials.gov, NCT04058925, registered on: 16th August 2019. URL of trial registry record: https://www.

CLINICALTRIALS: gov/ct2/show/NCT04058925?titles=Tissue+Oxygenation+During+Cardiopulmonary+Resuscitation+as+a+Predictor+of+Return+of+Spontaneous+Circulation&draw=2&rank=1 .}, } @article {pmid37821429, year = {2023}, author = {Zhang, S and Tong, M and Zheng, D and Huang, H and Li, L and Ungermann, C and Pan, Y and Luo, H and Lei, M and Tang, Z and Fu, W and Chen, S and Liu, X and Zhong, Q}, title = {C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediated membrane tethering and fusion in mammalian autophagy.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {6360}, pmid = {37821429}, issn = {2041-1723}, mesh = {Animals ; Autophagy ; C9orf72 Protein/genetics/metabolism ; Catalysis ; Guanosine Triphosphate/metabolism ; Mammals/metabolism ; *Membrane Fusion/physiology ; Vacuoles/metabolism ; }, abstract = {The multi-subunit homotypic fusion and vacuole protein sorting (HOPS) membrane-tethering complex is required for autophagosome-lysosome fusion in mammals, yet reconstituting the mammalian HOPS complex remains a challenge. Here we propose a "hook-up" model for mammalian HOPS complex assembly, which requires two HOPS sub-complexes docking on membranes via membrane-associated Rabs. We identify Rab39A as a key small GTPase that recruits HOPS onto autophagic vesicles. Proper pairing with Rab2 and Rab39A enables HOPS complex assembly between proteoliposomes for its tethering function, facilitating efficient membrane fusion. GTP loading of Rab39A is important for the recruitment of HOPS to autophagic membranes. Activation of Rab39A is catalyzed by C9orf72, a guanine exchange factor associated with amyotrophic lateral sclerosis and familial frontotemporal dementia. Constitutive activation of Rab39A can rescue autophagy defects caused by C9orf72 depletion. These results therefore reveal a crucial role for the C9orf72-Rab39A-HOPS axis in autophagosome-lysosome fusion.}, } @article {pmid37819987, year = {2023}, author = {Zhang, Z and Sun, S}, title = {Linking ALS mutations to the disruption of the MHC-II pathway.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {43}, pages = {e2315240120}, pmid = {37819987}, issn = {1091-6490}, support = {R01 AG078948/AG/NIA NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; }, mesh = {*Antigen Presentation ; *Histocompatibility Antigens Class II/immunology ; Genes, MHC Class II ; Mutation ; }, } @article {pmid37819399, year = {2023}, author = {Feng, CY and Han, JR and Lu, CY and Gu, L and Li, S and Lian, WH and Dong, L and Li, WJ}, title = {Telluribacter roseus sp. nov., Isolated from the Kumtag Desert Soil.}, journal = {Current microbiology}, volume = {80}, number = {12}, pages = {365}, pmid = {37819399}, issn = {1432-0991}, support = {32061143043//National Natural Science Foundation of China/ ; 32270076//National Natural Science Foundation of China/ ; 32000005//National Natural Science Foundation of China/ ; 2022xjkk1204//the Third Xinjiang Scientific Expedition Program/ ; 2023A1515012020//Guangdong Basic and Applied Basic Research Foundation, China/ ; MB2020KF05//Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases/ ; }, mesh = {*Soil ; Phylogeny ; RNA, Ribosomal, 16S/genetics ; Bacterial Typing Techniques ; DNA, Bacterial/genetics ; *Phospholipids/chemistry ; Fatty Acids/chemistry ; Sequence Analysis, DNA ; }, abstract = {A pink-pigmented bacterium, designated as strain SYSU D00476[T], was isolated from sandy soil collected from the Kumtag Desert in China. Colonies were opaque, smooth and of a slight convexity with a clearly defined border. Cells were rod-shaped, Gram-stain-negative, catalase- and oxidase-positive. Growth occurred at 4-45 ℃ (optimum at 28-30 ℃), pH 6.0-8.0 (optimum at 7.0), and with 0-3.0% NaCl (w/v, optimum at 0-2.0%). Major fatty acids (> 10%) were C16:0, summed feature 3 (C16:1 ω7c and/or C16:1 ω6c), iso-C17:0 3-OH and iso-C15:0. Polar lipids comprised of three unidentified polar aminolipids (ALs), two unidentified aminophosphoglycolipids (APLs), one unidentified glycolipid (GL) and three unidentified phospholipids (PLs). The predominant respiratory quinone was MK-7. The genomic DNA G + C content was 50.5%. The low digital DNA-DNA hybridization (dDDH, 27.4%) and average nucleotide identity (ANI, 85%) values between strain SYSU D00476[T] and Telluribacter humicola KCTC 42819[T] indicated that SYSU D00476[T] represent a distinct species. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain SYSU D00476[T] belonged to the genus Telluribacter, showing 97.5% similarity with T. humicola KCTC 42819[T]. All these data support that strain SYSU D00476[T] represent a novel species of the genus Telluribacter within the family Spirosomataceae, named as Telluribacter roseus sp. nov. The type strain is SYSU D00476[T] (= KCTC 82285[T] = CGMCC 1.18647[T] = MCCC 1K04983[T]).}, } @article {pmid37819053, year = {2023}, author = {Necarsulmer, JC and Simon, JM and Evangelista, BA and Chen, Y and Tian, X and Nafees, S and Marquez, AB and Jiang, H and Wang, P and Ajit, D and Nikolova, VD and Harper, KM and Ezzell, JA and Lin, FC and Beltran, AS and Moy, SS and Cohen, TJ}, title = {RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {37819053}, issn = {2050-084X}, support = {F31 NS122242/NS/NINDS NIH HHS/United States ; R01 NS105981/NS/NINDS NIH HHS/United States ; P50 HD103573/HD/NICHD NIH HHS/United States ; P30NS045892/NS/NINDS NIH HHS/United States ; P30 NS045892/NS/NINDS NIH HHS/United States ; T32 GM133364/GM/NIGMS NIH HHS/United States ; F30 AG072786/AG/NIA NIH HHS/United States ; R01NS105981/NS/NINDS NIH HHS/United States ; UM1TR004406/TR/NCATS NIH HHS/United States ; T32 GM008719/GM/NIGMS NIH HHS/United States ; UM1 TR004406/TR/NCATS NIH HHS/United States ; F31NS122242/NS/NINDS NIH HHS/United States ; U54 HD079124/HD/NICHD NIH HHS/United States ; F30AG072786/AG/NIA NIH HHS/United States ; 1T32GM133364-01A1/GM/NIGMS NIH HHS/United States ; 5T32GM008719-19/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Animals ; Mice ; *TDP-43 Proteinopathies/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Lobar Degeneration/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; Disease Models, Animal ; *Cognitive Dysfunction ; RNA ; }, abstract = {TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic acid-binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed endogenous models of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of acetylation-mimic TDP-43[K145Q] resulted in stress-induced nuclear TDP-43 foci and loss of TDP-43 function in primary mouse and human-induced pluripotent stem cell (hiPSC)-derived cortical neurons. Mice harboring the TDP-43[K145Q] mutation recapitulated key hallmarks of FTLD, including progressive TDP-43 phosphorylation and insolubility, TDP-43 mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes that regulate synaptic plasticity and stress response signaling. The neurodegenerative cascade initiated by TDP-43 acetylation recapitulates many aspects of human FTLD and provides a new paradigm to further interrogate TDP-43 proteinopathies.}, } @article {pmid37818935, year = {2024}, author = {Rehmann, R}, title = {Editorial for: "Quantitative MRI Analysis of Brachial Plexus and Limb-Girdle Muscles in Upper Extremity Onset Amyotrophic Lateral Sclerosis".}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {60}, number = {1}, pages = {302-303}, doi = {10.1002/jmri.29051}, pmid = {37818935}, issn = {1522-2586}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; *Brachial Plexus/diagnostic imaging ; *Muscle, Skeletal/diagnostic imaging ; Upper Extremity/diagnostic imaging ; }, } @article {pmid37818590, year = {2023}, author = {Grima, N and Liu, S and Southwood, D and Henden, L and Smith, A and Lee, A and Rowe, DB and D'Silva, S and Blair, IP and Williams, KL}, title = {RNA sequencing of peripheral blood in amyotrophic lateral sclerosis reveals distinct molecular subtypes: Considerations for biomarker discovery.}, journal = {Neuropathology and applied neurobiology}, volume = {49}, number = {6}, pages = {e12943}, pmid = {37818590}, issn = {1365-2990}, support = {//Motor Neurone Disease Research Australia/ ; //National Health and Medical Research Council/ ; 2011120//NHMRC/ ; //FightMND/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Neurodegenerative Diseases ; Australia ; Biomarkers ; Sequence Analysis, RNA ; }, abstract = {AIM: Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease with limited therapeutic options. A key factor limiting the development of effective therapeutics is the lack of disease biomarkers. We sought to assess whether biomarkers for diagnosis, prognosis or cohort stratification could be identified by RNA sequencing (RNA-seq) of ALS patient peripheral blood.

METHODS: Whole blood RNA-seq data were generated for 96 Australian sporadic ALS (sALS) cases and 48 healthy controls (NCBI GEO accession GSE234297). Differences in sALS-control gene expression, transcript usage and predicted leukocyte proportions were assessed, with pathway analysis used to predict the activity state of biological processes. Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning algorithms were applied to search for diagnostic and prognostic gene expression patterns. Unsupervised clustering analysis was employed to determine whether sALS patient subgroups could be detected.

RESULTS: Two hundred and forty-five differentially expressed genes were identified in sALS patients relative to controls, with enrichment of immune, metabolic and stress-related pathways. sALS patients also demonstrated switches in transcript usage across a small set of genes. We established a classification model that distinguished sALS patients from controls with an accuracy of 78% (sensitivity: 79%, specificity: 75%) using the expression of 20 genes. Clustering analysis identified four patient subgroups with gene expression signatures and immune cell proportions reflective of distinct peripheral effects.

CONCLUSIONS: Our findings suggest that peripheral blood RNA-seq can identify diagnostic biomarkers and distinguish molecular subtypes of sALS patients however, its prognostic value requires further investigation.}, } @article {pmid37817804, year = {2023}, author = {Cui, S and Zhang, T and Xiong, X and Zhao, J and Cao, Q and Zhou, H and Xia, XG}, title = {Detergent-insoluble PFN1 inoculation expedites disease onset and progression in PFN1 transgenic rats.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1279259}, pmid = {37817804}, issn = {1662-4548}, support = {R01 NS089701/NS/NINDS NIH HHS/United States ; R01 NS099635/NS/NINDS NIH HHS/United States ; R01 NS110455/NS/NINDS NIH HHS/United States ; RF1 AG064822/AG/NIA NIH HHS/United States ; }, abstract = {Accumulating evidence suggests a gain of elusive toxicity in pathogenically mutated PFN1. The prominence of PFN1 aggregates as a pivotal pathological hallmark in PFN1 transgenic rats underscores the crucial involvement of protein aggregation in the initiation and progression of neurodegeneration. Detergent-insoluble materials were extracted from the spinal cords of paralyzed rats afflicted with ALS and were intramuscularly administered to asymptomatic recipient rats expressing mutant PFN1, resulting in an accelerated development of PFN1 inclusions and ALS-like phenotypes. This effect diminished when the extracts derived from wildtype PFN1 transgenic rats were employed, as detergent-insoluble PFN1 was detected exclusively in mutant PFN1 transgenic rats. Consequently, the factor influencing the progression of ALS pathology in recipient rats is likely associated with the presence of detergent-insoluble PFN1 within the extracted materials. Noteworthy is the absence of disease course modification upon administering detergent-insoluble extracts to rats that already displayed PFN1 inclusions, suggesting a seeding rather than augmenting role of such extracts in initiating neuropathological changes. Remarkably, pathogenic PFN1 exhibited an enhanced affinity for the molecular chaperone DNAJB6, leading to the sequestration of DNAJB6 within protein inclusions, thereby depleting its availability for cellular functions. These findings shed light on a novel mechanism that underscores the prion-like characteristics of pathogenic PFN1 in driving neurodegeneration in the context of PFN1-related ALS.}, } @article {pmid37816542, year = {2024}, author = {McHenry, KL}, title = {Airway Clearance Strategies and Secretion Management in Amyotrophic Lateral Sclerosis.}, journal = {Respiratory care}, volume = {69}, number = {2}, pages = {227-237}, pmid = {37816542}, issn = {1943-3654}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Respiratory Therapy/methods ; *Chest Wall Oscillation ; Bodily Secretions ; *Insufflation/methods ; Cough/etiology ; *Respiratory Insufficiency/therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative motor neuron disease that affects voluntary muscle movement. Often, difficulty in coughing, breathing, and swallowing are sequela associated with the condition, and the presence of bulbar muscle predominant weakness results in deleterious effects on airway clearance and secretion management. This narrative review will provide practical guidance for clinicians treating this population. Cough insufficiency in this population typically manifests as a prolonged, slow, weak cough effort that impedes the clearability of secretions and airway protection. Dystussia and dysphagia frequently occur simultaneously in bulbar dysfunction, subsequently impacting respiratory health. Measures of respiratory strength should be obtained and monitored every 3-6 months, preferably in a multidisciplinary clinic setting. Cough augmentation, whether manual or mechanical techniques, should be sought as early in the disease progression as possible to adequately control secretions in the proximal airways. This airway clearance strategy can aid in the prevention and treatment of respiratory tract infections (RTIs), which can pose a significant clinical hurdle to those with ALS. The use of mechanical insufflation-exsufflation may be complicated by severe bulbar dysfunction rendering this technique ineffective. Though peripheral airway clearance strategies, such as high-frequency chest-wall compression, have the advantage of being less impacted by bulbar dysfunction, it is only recommended this modality be used in conjunction with, versus in lieu of, proximal strategies. Salivary secretion management includes the use of anticholinergics, botulinum toxin, and radiation therapy depending on severity and desire for relief.}, } @article {pmid37815936, year = {2023}, author = {Shammas, MK and Nie, Y and Gilsrud, A and Huang, X and Narendra, DP and Chinnery, PF}, title = {CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature.}, journal = {Human molecular genetics}, volume = {33}, number = {1}, pages = {91-101}, pmid = {37815936}, issn = {1460-2083}, support = {MR/S035699/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; MR/S005021/1/MRC_/Medical Research Council/United Kingdom ; 212219/Z/18/Z/WT_/Wellcome Trust/United Kingdom ; 224486/Z/21/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; DNA, Mitochondrial/genetics/metabolism ; *Frontotemporal Dementia/genetics ; Mitochondria/metabolism ; *Mitochondrial Proteins/genetics/metabolism ; Mutation ; }, abstract = {Mutations affecting the mitochondrial intermembrane space protein CHCHD10 cause human disease, but it is not known why different amino acid substitutions cause markedly different clinical phenotypes, including amyotrophic lateral sclerosis-frontotemporal dementia, spinal muscular atrophy Jokela-type, isolated autosomal dominant mitochondrial myopathy and cardiomyopathy. CHCHD10 mutations have been associated with deletions of mitochondrial DNA (mtDNA deletions), raising the possibility that these explain the clinical variability. Here, we sequenced mtDNA obtained from hearts, skeletal muscle, livers and spinal cords of WT and Chchd10 G58R or S59L knockin mice to characterise the mtDNA deletion signatures of the two mutant lines. We found that the deletion levels were higher in G58R and S59L mice than in WT mice in some tissues depending on the Chchd10 genotype, and the deletion burden increased with age. Furthermore, we observed that the spinal cord was less prone to the development of mtDNA deletions than the other tissues examined. Finally, in addition to accelerating the rate of naturally occurring deletions, Chchd10 mutations also led to the accumulation of a novel set of deletions characterised by shorter direct repeats flanking the deletion breakpoints. Our results indicate that Chchd10 mutations in mice induce tissue-specific deletions which may also contribute to the clinical phenotype associated with these mutations in humans.}, } @article {pmid37815307, year = {2024}, author = {Liu, KF and Ramachandran, S and Chang, CW and Chen, RF and Huang, CH and Huang, HT and Lee, CC and Li, YT and Kuo, YR}, title = {The Synergistic Effect of Full-Spectrum Light Therapy and Transient Immunosuppressants Prolonged Allotransplant Survival.}, journal = {Plastic and reconstructive surgery}, volume = {154}, number = {4}, pages = {775-783}, doi = {10.1097/PRS.0000000000011135}, pmid = {37815307}, issn = {1529-4242}, support = {SH11003//Kaohsiung Medical University Hospital, Taiwan./ ; }, mesh = {Animals ; *Immunosuppressive Agents/therapeutic use ; *Graft Survival/drug effects/immunology ; *Rats, Inbred Lew ; Rats ; *Vascularized Composite Allotransplantation/methods ; *Hindlimb/transplantation ; Male ; Combined Modality Therapy ; Cyclosporine ; Graft Rejection/prevention & control/immunology ; Phototherapy/methods ; Rats, Inbred BN ; Antilymphocyte Serum ; }, abstract = {BACKGROUND: The lifelong administration of immunosuppressants remains the largest drawback in vascularized composite allotransplantation (VCA). Therefore, developing alternative strategies to minimize the long-term use of immunosuppressive agents is crucial. This study investigated whether full-spectrum bright light therapy (FBLT) combined with short-term immunosuppressant therapy could prolong VCA survival in a rodent hindlimb model.

METHODS: Hindlimb allotransplantation was conducted from Brown-Norway to Lewis rats, and the rats were divided into 4 groups. Group 1 did not receive treatment as a rejection control. Group 2 received FBLT alone. Group 3 was treated with short-term antilymphocyte serum (ALS) and cyclosporine A (CsA). Group 4 was administered short-term ALS/CsA combined with FBLT for 8 weeks. Peripheral blood and transplanted tissues were collected for analysis.

RESULTS: The results revealed median survival time of FBLT alone (group 2) did not increase allograft survival compared with the control (group 1). However, in group 4, FBLT combined with short-term ALS/CsA, median composite tissue allograft survival time (266 days) was significantly prolonged compared with groups 1 (11 days), 2 (10 days), and 3 (41 days) (P < 0.01). Group 4 also showed a significant increase in regulatory T cells (P = 0.04) and transforming growth factor-β1 levels (P = 0.02), and a trend toward a decrease in interleukin-1β levels (P = 0.03) at 16 weeks after transplantation as compared with control (group 1).

CONCLUSIONS: FBLT combined with short-term immunosuppressants prolonged allotransplant survival by modulating T-cell regulatory functions and antiinflammatory cytokine expression. This approach could be a potential strategy to increase VCA survival.

CLINICAL RELEVANCE STATEMENT: Full-spectrum light therapy could be a potential strategy to increase vascularized composite allotransplant survival.}, } @article {pmid37815224, year = {2024}, author = {Northall, A and Doehler, J and Weber, M and Tellez, I and Petri, S and Prudlo, J and Vielhaber, S and Schreiber, S and Kuehn, E}, title = {Multimodal layer modelling reveals in vivo pathology in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {3}, pages = {1087-1099}, pmid = {37815224}, issn = {1460-2156}, support = {2019-A03//Else Kröner Fresenius Stiftung/ ; KU 3711/2-1//Deutsche Forschungsgemeinschaft/ ; 501214112//SCHR/ ; }, mesh = {Humans ; Calcium ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Neurodegenerative Diseases ; *Dermatitis ; Iron ; *Demyelinating Diseases ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by the loss of motor control. Current understanding of ALS pathology is largely based on post-mortem investigations at advanced disease stages. A systematic in vivo description of the microstructural changes that characterize early stage ALS, and their subsequent development, is so far lacking. Recent advances in ultra-high field (7 T) MRI data modelling allow us to investigate cortical layers in vivo. Given the layer-specific and topographic signature of ALS pathology, we combined submillimetre structural 7 T MRI data (qT1, QSM), functional localizers of body parts (upper limb, lower limb, face) and layer modelling to systematically describe pathology in the primary motor cortex (M1), in 12 living ALS patients with reference to 12 matched controls. Longitudinal sampling was performed for a subset of patients. We calculated multimodal pathology maps for each layer (superficial layer, layer 5a, layer 5b, layer 6) of M1 to identify hot spots of demyelination, iron and calcium accumulation in different cortical fields. We show preserved mean cortical thickness and layer architecture of M1, despite significantly increased iron in layer 6 and significantly increased calcium in layer 5a and superficial layer, in patients compared to controls. The behaviourally first-affected cortical field shows significantly increased iron in L6 compared to other fields, while calcium accumulation is atopographic and significantly increased in the low myelin borders between cortical fields compared to the fields themselves. A subset of patients with longitudinal data shows that the low myelin borders are particularly disrupted and that calcium hot spots, but to a lesser extent iron hot spots, precede demyelination. Finally, we highlight that a very slow progressing patient (Patient P4) shows a distinct pathology profile compared to the other patients. Our data show that layer-specific markers of in vivo pathology can be identified in ALS patients with a single 7 T MRI measurement after first diagnosis, and that such data provide critical insights into the individual disease state. Our data highlight the non-topographic architecture of ALS disease spread and the role of calcium, rather than iron accumulation, in predicting future demyelination. We also highlight a potentially important role of low myelin borders, that are known to connect to multiple areas within the M1 architecture, in disease spread. Finally, the distinct pathology profile of a very-slow progressing patient (Patient P4) highlights a distinction between disease duration and progression. Our findings demonstrate the importance of in vivo histology imaging for the diagnosis and prognosis of neurodegenerative diseases such as ALS.}, } @article {pmid37815061, year = {2024}, author = {Zhang, X and Dai, L and Long, Y and Chen, X and Alhafi, MAK}, title = {Healthcare costs for patients with rare diseases: Evidence from China.}, journal = {The International journal of health planning and management}, volume = {39}, number = {1}, pages = {48-61}, doi = {10.1002/hpm.3713}, pmid = {37815061}, issn = {1099-1751}, support = {21Y012//Hubei Provincial Department of Education Project/ ; }, mesh = {Humans ; *Insurance, Health ; Rare Diseases/therapy ; *Amyotrophic Lateral Sclerosis ; Health Care Costs ; Health Expenditures ; China ; }, abstract = {OBJECTIVE: Rare diseases cause a huge financial burden to countless patients and families. It is an important public health issue that requires widespread attention. This study analyzes medical expenses composition and the change in trends of out-of-pocket (OOP) expenses for patients with Amyotrophic lateral sclerosis (ALS) and explores the factors influencing these changes.

METHODS: Data were obtained from the Chinese Medical Insurance Department database from 2018 to 2020, including 857 patients with ALS in 60 cities across 30 provinces. We used descriptive methods to analyse the baseline characteristics and medical expenses of outpatients and inpatients with ALS. And we used quantile regression to analyse the differences in patient OOP ratio and the factors influencing them.

RESULTS: In China, 80.3% of ALS patients chose tertiary hospitals, with an annual direct medical cost of 11,339.7 RMB per patient and an OOP ratio of 41.6%. The annual medical cost for outpatients was 345.1 RMB per patient, with an OOP ratio of 36.7%. The annual medical cost for inpatients was 28,139.8 RMB per patient, with an OOP ratio of 41.7%. Compared to outpatients, inpatients had higher medical costs but lower actual reimbursement rates. The OOP ratio of ALS patients decreased, then increased over time. And the OOP ratio was influenced by medical institution, medical insurance, and age (p < 0.05). Patients who chose tertiary hospitals, those who were covered by the urban resident basic medical insurance and younger patients had relatively higher OOP ratio.

CONCLUSION: In recent years, although China has begun to pay attention to the rights and interests of patients with rare diseases, the government has provided some healthcare security to patients with rare diseases. However, the level of medical insurance coverage was still low, the equity of protection was still insufficient and the financial burden on patients was high. Therefore, the government should further improve the healthcare system to provide full life-cycle and affordable healthcare services to patients with rare diseases.}, } @article {pmid37814924, year = {2023}, author = {Spiliopoulos, KC and Lykouras, D and Veltsista, D and Skaramagkas, V and Karkoulias, K and Tzouvelekis, A and Chroni, E}, title = {The utility of diaphragm ultrasound thickening indices for assessing respiratory decompensation in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {68}, number = {6}, pages = {850-856}, doi = {10.1002/mus.27980}, pmid = {37814924}, issn = {1097-4598}, mesh = {Humans ; Diaphragm/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging ; *Noninvasive Ventilation ; *Respiratory Insufficiency/diagnostic imaging/etiology ; Ultrasonography ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) leads to diaphragmatic weakness at some point during its course, which is a major cause of respiratory insufficiency. The aim of this study was to evaluate ultrasound-based measures for assessing the diaphragmatic competency and the need for ventilatory support.

METHODS: Twenty-six subjects with ALS and 12 healthy controls were enrolled. All participants underwent B-mode diaphragm ultrasound (DUS). Diaphragm thickness and thickening indices were recorded. In the subjects with ALS, further assessments included functional scales and spirometry. We investigated the diagnostic accuracy of DUS thickening indices in predicting diaphragmatic dysfunction and the correlation between clinical, spirometric, and DUS data.

RESULTS: Significant relationships were found between forced vital capacity and all diaphragmatic thickening indices. Similarly, all diaphragmatic thickening indices correlated with both Milano Torino staging and disease progression rate. Only thickening fraction (TFdi) correlated with score on the revised ALS Functional Rating Scale (r = 0.459, P = .024). TFdi had better accuracy in predicting diaphragmatic dysfunction (area under the curve [AUC] = 0.839, 95% confidence interval [CI] 0.643 to 0.953) and the need for initiation of noninvasive ventilation (NIV) (AUC = 0.989, 95% CI 0.847 to 1.000) compared with the other indices. A TFdi cut-off point of 0.50 was a sensitive threshold to consider NIV.

DISCUSSION: DUS successfully identifies diaphragmatic dysfunction in ALS, being a valuable accessory modality for investigating respiratory symptoms. TFdi was found to be the most useful DUS index, which encourages further investigation.}, } @article {pmid37814618, year = {2023}, author = {Li, B and Zhang, W and Zhong, S and Pan, J and Wang, X and Zou, H and Dou, X}, title = {Short-term outcome of plasma adsorption therapy in amyotrophic lateral sclerosis.}, journal = {Journal of medical biochemistry}, volume = {42}, number = {3}, pages = {401-406}, pmid = {37814618}, issn = {1452-8258}, abstract = {BACKGROUND: To observe the short-term outcome of plasma adsorption PA therapy in amyotrophic lateral sclerosis (ALS).

METHODS: 28 cases of als patients were recruited in this study, of which 20 were male and 8 were female with a mean age of 53.21±9.07 years and the average course of 33±23.35 months. The clinical manifestations were limb weakness (N=27), muscular atrophy (N=27), muscular tremor (N=5), dysphagia (N=12) and dysarthria (N=12). The clinical data of the patients recruited were graded by Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRSR) : <10 (N=1), 11-20 (N=4), 21-30 (N=6), 31-40 (N=12), >40 (N=5). All patients received PA therapy once a week for three successive times after examining the conditions of blood coagulation and virus infection. PA therapy was supplemented with neurotrophic therapy meanwhile. All patients' clinical manifestations and scores of ALSFRSR before treatment and one week after treatment were evaluated and compared. The levels of serum superoxide dismutase (SOD), interleukin-10 (IL-10), serum creatine kinase (CK) and lactate dehydrogenase (LDH) before and after treatment were compared.

RESULTS: After PA therapy, 14 patients have improved obviously in muscle strength, 4 patients in hypermyotonia partially, 3 patients in muscular tremor, 5 patients in dysarthria, 3 patients in salivation to some extent and 2 patients in swallowing function. The score of ALSFRSR after PA treatment (31.89±10.36) was remarkably higher than that before PA treatment (30.68±10.52) (P<0.01). The levels of SOD (155.10±21.87 IU/L) and IL-10 (138.06±185.88 pg/mL) after PA treatment were significantly higher than the levels before PA treatment (143.08.3±19.16 IU/L and 46.34±75.31 pg/mL, respectively) (P<0.05). The levels of CK (168.86±113.50 IU/L) and LDH (152.07±32.65 IU/L) after PA treatment were significantly lower than the levels before PA treatment (356.68±250.30 IU/L and 181.36±33.74 IU/L respectively) (P<0.01). At the end of follow-up period (November, 2019), five patients died of respiratory failure 16-21 months after PA treatment and two patents died of respiratory infection 15-20 months after PA treatment. 7 patients were still alive. The score of ALSFRS-R of these patients who survived at the end of follow-up (13.00±13.37) were significantly lower than before PA treatment (36.71±8.56) (P<0.05) and after PA treatment (38.14±8.82) (P<0.05).

CONCLUSIONS: Plasma adsorption (PA) therapy has shortterm therapeutic effects on als. The effects might be attributed to the anti-oxygen free radical effect by increasing SOD level and the anti-inflammation effect by increasing IL-10 level. As the efficacy of PA therapy was obtained in a small sample size and short follow-up period, the longterm observation of PA efficacy in treating als should be further investigated.}, } @article {pmid37814465, year = {2023}, author = {Fan, J and Li, Y and Niu, JW and Hu, N and Guan, YZ and Cui, LY and Liu, MS}, title = {Differentiation Between Amyotrophic Lateral Sclerosis and Mimics Using Quantitative Analysis of Fsciculation with Muscle Ultrasound.}, journal = {Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih}, volume = {38}, number = {4}, pages = {265-272}, doi = {10.24920/004282}, pmid = {37814465}, issn = {1001-9294}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Fasciculation/diagnostic imaging ; *Radiculopathy ; Muscle, Skeletal/diagnostic imaging ; Ultrasonography/methods ; }, abstract = {Objective To determine the diagnostic accuracy of the intensity of fasciculation evaluated by muscle ultrasound in the differential diagnosis of amyotrophic lateral sclerosis (ALS). Methods We prospectively recruited patients who had ALS and neuropathy-radiculopathy attending Peking Union Medical College Hospital from 2017 to 2020. Healthy adults from a community were recruited as healthy controls. Muscle strength was assessed using the Medical Research Council (MRC) scale. At the first visit to the hospital, patients were assessed for maximal grade of fasciculations, total fasciculation score, and fasciculation grade in 16 muscle groups of bilateral upper and lower limbs using ultrasonography. The sensitivity and specificity of maximal grade of fasciculations, total fasciculation score, and fasciculation grade for the diagnosis of ALS were assessed by receiver operating characteristic analyses. Results The percentage of limb muscles with a maximal fasciculation grade higher than grade 2 in ALS patients and neuropathy-radiculopathy patients was 84.9% and 9.8%, respectively (χ[2] = 172.436, P < 0.01). Of the 16 limb muscles detected, the total fasciculation score [median (interquartile range)] was 29 (15, 41) in ALS patients and 3 (0, 8) in neuropathy-radiculopathy patients (Z = 9.642, P < 0.001). Remarkable fasciculations were seen in ALS patients whose muscles with a MRC score ranging from 2 to 4, followed by patients with MRC score 5, and then in those with MRC score 0 and 1. The sensitivity and specificity of total fasciculation score for diagnosis of ALS were 80.6% and 93.4%, respectively (cut-off value 14). In patients with ALS, for muscles with MRC score 4 and 5, the percentage of muscles with fasciculation grades ≥ 3 was 42.3% and 24.1% respectively, while in neuropathy-radiculopathy patients, the percentage for muscles with MRC score 4 and 5 was only 1.7% and 0, respectively. Conclusion A combined analysis of fasciculation intensity and MRC score of the limb muscles may be helpful for differential diagnosis of ALS.}, } @article {pmid37813308, year = {2023}, author = {Babazadeh, A and Rayner, SL and Lee, A and Chung, RS}, title = {TDP-43 as a therapeutic target in neurodegenerative diseases: Focusing on motor neuron disease and frontotemporal dementia.}, journal = {Ageing research reviews}, volume = {92}, number = {}, pages = {102085}, doi = {10.1016/j.arr.2023.102085}, pmid = {37813308}, issn = {1872-9649}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/therapy ; DNA-Binding Proteins/metabolism ; *Frontotemporal Dementia/therapy ; *Motor Neuron Disease/therapy/pathology ; *Neurodegenerative Diseases/therapy ; }, abstract = {A common feature of adult-onset neurodegenerative diseases is the presence of characteristic pathological accumulations of specific proteins. These pathological protein depositions can vary in their protein composition, cell-type distribution, and intracellular (or extracellular) location. For example, abnormal cytoplasmic protein deposits which consist of the TDP-43 protein are found within motor neurons in patients with amyotrophic lateral sclerosis (ALS, a common form of motor neuron disease) and frontotemporal dementia (FTD). The presence of these insoluble intracellular TDP-43 inclusions suggests that restoring TDP-43 homeostasis represents a potential therapeutical strategy, which has been demonstrated in alleviating neurodegenerative symptoms in cell and animal models of ALS/FTD. We have reviewed the mechanisms that lead to disrupted TDP-43 homeostasis and discussed how small molecule-based therapies could be applied in modulating these mechanisms. This review covers recent advancements and challenges in small molecule-based therapies that could be used to clear pathological forms of TDP-43 through various protein homeostasis mechanisms and advance the way towards finding effective therapeutical drug discoveries for neurodegenerative diseases characterized by TDP-43 proteinopathies, especially ALS and FTD. We also consider the wider insight of these therapeutic strategies for other neurodegenerative diseases.}, } @article {pmid37813148, year = {2023}, author = {Heidet, M and Benjamin Leung, KH and Bougouin, W and Alam, R and Frattini, B and Liang, D and Jost, D and Canon, V and Deakin, J and Hubert, H and Christenson, J and Vivien, B and Chan, T and Cariou, A and Dumas, F and Jouven, X and Marijon, E and Bennington, S and Travers, S and Souihi, S and Mermet, E and Freyssenge, J and Arrouy, L and Lecarpentier, E and Derkenne, C and Grunau, B}, title = {Improving EMS response times for out-of-hospital cardiac arrest in urban areas using drone-like vertical take-off and landing air ambulances: An international, simulation-based cohort study.}, journal = {Resuscitation}, volume = {193}, number = {}, pages = {109995}, doi = {10.1016/j.resuscitation.2023.109995}, pmid = {37813148}, issn = {1873-1570}, mesh = {Adult ; Humans ; *Cardiopulmonary Resuscitation ; Cohort Studies ; *Air Ambulances ; *Out-of-Hospital Cardiac Arrest/therapy ; Reaction Time ; Unmanned Aerial Devices ; *Emergency Medical Services ; }, abstract = {BACKGROUND: Advances in vertical take-off and landing (VTOL) technologies may enable drone-like crewed air ambulances to rapidly respond to out-of-hospital cardiac arrest (OHCA) in urban areas. We estimated the impact of incorporating VTOL air ambulances on OHCA response intervals in two large urban centres in France and Canada.

METHODS: We included adult OHCAs occurring between Jan. 2017-Dec. 2018 within Greater Paris in France and Metro Vancouver in Canada. Both regions utilize tiered OHCA response with basic (BLS)- and advanced life support (ALS)-capable units. We simulated incorporating 1-2 ALS-capable VTOL air ambulances dedicated to OHCA response in each study region, and computed time intervals from call reception by emergency medical services (EMS) to arrival of the: (1) first ALS unit ("call-to-ALS arrival interval"); and (2) first EMS unit ("call-to-first EMS arrival interval").

RESULTS: There were 6,217 OHCAs included during the study period (3,760 in Greater Paris and 2,457 in Metro Vancouver). Historical median call-to-ALS arrival intervals were 21 min [IQR 16-29] in Greater Paris and 12 min [IQR 9-17] in Metro Vancouver, while median call-to-first EMS arrival intervals were 11 min [IQR 8-14] and 7 min [IQR 5-8] respectively. Incorporating 1-2 VTOL air ambulances improved median call-to-ALS arrival intervals to 7-9 min and call-to-first EMS arrival intervals to 6-8 min in both study regions (all P < 0.001).

CONCLUSION: VTOL air ambulances dedicated to OHCA response may improve EMS response intervals, with substantial improvements in ALS response metrics.}, } @article {pmid37812352, year = {2023}, author = {Salemi, M and Mandarà, LGM and Salluzzo, MG and Schillaci, FA and Castiglione, R and Cordella, A and Iorio, R and Perrotta, CS and Ferri, R and Romano, C}, title = {NGS study in a sicilian case series with a genetic diagnosis for Gerstmann-Sträussler-Scheinker syndrome (PRNP, p.P102L).}, journal = {Molecular biology reports}, volume = {50}, number = {11}, pages = {9715-9720}, pmid = {37812352}, issn = {1573-4978}, support = {(RC 2773804)//Ministero della Salute/ ; }, mesh = {Animals ; Humans ; *Gerstmann-Straussler-Scheinker Disease/diagnosis/genetics/metabolism ; *Prions/genetics ; Prion Proteins/genetics ; Mutation/genetics ; High-Throughput Nucleotide Sequencing ; }, abstract = {BACKGROUND: Gerstmann Sträussler Scheinker (GSS) is an inherited, invariably fatal prion disease. Like other human prion diseases, GSS is caused by missense mutations in the prion protein (PrP) gene (PRNP), and by the formation and overtime accumulation of the misfolded, pathogenic scrapie PrP (PrPSc). The first mutation identified in the PRNP gene, and the one blamed as the main cause of the disease, is c.C305T:p.P102L.

METHODS AND RESULTS: The Sanger sequencing method was performed on the PRNP gene for the detection of c.C305T:p.P102L mutations in a cohort of 10 subjects; moreover, a study was carried out, using Next Generation Sequencing (NGS), by sequencing a group of genes related to amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), movement disorders and dementia which show a phenotypic profile similar to that of GSS. The results obtained from the study using NGS indicate the potential role of other genetic variants which could contribute to the various GSS phenotypes.

CONCLUSIONS: In conclusion, we highlight the large clinical variability in subjects presenting with GSS and p.P102L, as well as the hypothesis that the mutation in PrP codon 102 alone is not sufficient to trigger the cardinal clinical signs of the disease; furthermore, we do not exclude the possibility that further genetic variants play a decisive role in the aspects of the various phenotypes with which GSS manifests itself.}, } @article {pmid37811740, year = {2023}, author = {Grossschaedl, K and Vallant, C and Dernoscheg, MT and Richtig, M and Öllinger, A and Balakirski, G and Wilsmann-Theis, D and Nguyen, VA and Weinlich, G and Tsiogka, A and Koelblinger, P and Scheffel, J and Richtig, E and Richtig, G}, title = {[Verwendung und Nutzen des Internets als Informationsquelle für Erkrankungen und Therapien in der Dermatologie: Usage and benefit of the Internet as a source of information on disease and therapy in dermatology].}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {21}, number = {11}, pages = {1383-1386}, doi = {10.1111/ddg.15199_g}, pmid = {37811740}, issn = {1610-0387}, } @article {pmid37810917, year = {2023}, author = {Carrera-Juliá, S and Estrela, JM and Zacarés, M and Navarro, MÁ and Vega-Bello, MJ and de la Rubia Ortí, JE and Moreno, ML and Drehmer, E}, title = {Effect of the Mediterranean diet supplemented with nicotinamide riboside and pterostilbene and/or coconut oil on anthropometric variables in amyotrophic lateral sclerosis. A pilot study.}, journal = {Frontiers in nutrition}, volume = {10}, number = {}, pages = {1232184}, pmid = {37810917}, issn = {2296-861X}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a chronic and progressive neurodegenerative disease that causes the death of motor neurons and alters patients' body composition. Supplementation with the antioxidants nicotinamide riboside (NR) and pterostilbene (PTER) can combat associated oxidative stress. Additionally, coconut oil is an alternative energy substrate that can address mitochondrial dysfunction. The aim of the present study is to assess the impact of a Mediterranean Diet supplemented with NR and PTER and/or with coconut oil on the anthropometric variables of patients with ALS. A prospective, mixed, randomized, analytical and experimental pilot study in humans was performed through a clinical trial (registered with ClinicalTrials.gov under number NCT03489200) with pre- and post-intervention assessments. The sample was made up of 40 subjects categorized into four study groups (Control, Antioxidants, Coconut oil, and Antioxidants + Coconut oil). Pre- and post-intervention anthropometric assessments were carried out to determine the following data: weight, percentage of fat and muscle mass, skinfolds, body perimeters, Body Mass Index (BMI), Waste-to-Hip Index (WHI) and Waist-Height Ratio (WHR). Compared to the Control group, GAx significantly increased muscle mass percentage and decreased fat mass percentage, triceps, iliac crest, and abdominal skinfolds. GCoco significantly increased muscle mass percentage and decreased fat mass percentage, subscapular skinfolds, and abdominal skinfolds. GAx + coco significantly increased muscle mass percentage and decreased abdominal skinfolds. Therefore, our results suggest that the Mediterranean Diet supplemented with NR and PTER and the Mediterranean Diet supplemented with coconut oil (ketogenic diet) are the two nutritional interventions that have reported the greatest benefits, at anthropometric level.}, } @article {pmid37809062, year = {2023}, author = {Akhtar, M and Basher, SR and Nizam, NN and Hossain, L and Bhuiyan, TR and Qadri, F and Lundgren, A}, title = {T helper cell responses in adult diarrheal patients following natural infection with enterotoxigenic Escherichia coli are primarily of the Th17 type.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1220130}, pmid = {37809062}, issn = {1664-3224}, mesh = {Adult ; Humans ; Antibodies, Bacterial ; *Bacterial Toxins ; Diarrhea ; *Enterotoxigenic Escherichia coli ; Enterotoxins ; Immunoglobulin A ; Interleukin-17 ; Leukocytes, Mononuclear/chemistry ; Th17 Cells ; }, abstract = {BACKGROUND: Infection with enterotoxigenic Escherichia coli (ETEC) gives rise to IgA antibodies against both the heat labile toxin (LT) and colonization factors (CFs), which are considered to synergistically protect against ETEC diarrhea. Since the development of ETEC-specific long lived plasma cells and memory B cells is likely to be dependent on T helper (Th) cells, we investigated if natural ETEC diarrhea elicits ETEC-specific Th cells and their relation to IgA responses.

METHODS: Th cell subsets were analyzed in adult Bangladeshi patients hospitalized due to ETEC diarrhea by flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) isolated from blood collected day 2, 7, 30 and 90 after hospitalization as well as in healthy controls. The LT- and CF-specific Th responses were determined by analysis of IL-17A and IFN-γ in antigen stimulated PBMC cultures using ELISA. ETEC-specific IgA secreted by circulating antibody secreting cells (plasmablasts) were analyzed by using the antibodies in lymphocyte supernatants (ALS) ELISA-based method and plasma IgA was also measured by ELISA.

RESULTS: ETEC patients mounted significant ALS and plasma IgA responses against LTB and CFs on day 7 after hospitalization. ETEC patients had significantly elevated proportions of memory Th cells with a Th17 phenotype (CCR6+CXCR3-) in blood compared to controls, while frequencies of Th1 (CCR6-CXCR3+) or Th2 (CCR6-CXCR3-) cells were not increased. Antigen stimulation of PBMCs revealed IL-17A responses to LT, most clearly observed after stimulation with double mutant heat labile toxin (dmLT), but also with LT B subunit (LTB), and to CS6 in samples from patients with LT+ or CS6+ ETEC bacteria. Some individuals also mounted IFN-γ responses to dmLT and LTB. Levels of LTB specific IgA antibodies in ALS, but not plasma samples correlated with both IL-17A (r=0.5, p=0.02) and IFN-γ (r=0.6, p=0.01) responses to dmLT.

CONCLUSIONS: Our results show that ETEC diarrhea induces T cell responses, which are predominantly of the Th17 type. The correlations between IL-17A and IFN-g and intestine-derived plasmablast responses support that Th responses may contribute to the development of protective IgA responses against ETEC infection. These observations provide important insights into T cell responses that need to be considered in the evaluation of advanced ETEC vaccine candidates.}, } @article {pmid37808871, year = {2024}, author = {Okekenwa, S and Tsai, M and Dooley, P and Wang, B and Comassio, P and Moreira, J and Kriefall, N and Martin, S and Morfini, G and Brady, S and Song, Y}, title = {Divergent Molecular Pathways for Toxicity of Selected Mutant C9ORF72-derived Dipeptide Repeats.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.09.28.558663}, pmid = {37808871}, issn = {2692-8205}, abstract = {Expansion of a hexanucleotide repeat in a noncoding region of the C9ORF72 gene is responsible for a significant fraction of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) cases, but mechanisms linking mutant gene products to neuronal toxicity remain debatable. Pathogenesis was proposed to involve the production of toxic RNA species and/or accumulation of toxic dipeptide repeats (DPRs) but distinguishing between these mechanisms has been challenging. In this study, we first use complementary model systems for analyzing pathogenesis in adult-onset neurodegenerative diseases to characterize the pathogenicity of DPRs produced by Repeat Associated Non-ATG translation of C9ORF72 in specific cellular compartments: isolated axoplasm and giant synapse from the squid. Results showed selective axonal and presynaptic toxicity of GP-DPRs, independent of associated RNA. These effects involved a MAPK signaling pathway that affects fast axonal transport and synaptic function, a pathogenic mechanism shared with other mutant proteins associated with familial ALS, like SOD1 and FUS. In primary cultured neurons, GP but not other DPRs promote the "dying-back" axonopathy seen in ALS. Interestingly, GR- and PR-DPRs, which had no effect on axonal transport or synaptic transmission, were found to disrupt the nuclear membrane, promoting "dying-forward" neuropathy. All C9-DPR-mediated toxic effects observed in these studies are independent of whether the corresponding mRNAs contained hexanucleotide repeats or alternative codons. Finally, C9ORF72 human tissues confirmed a close association between GP and active P38 in degenerating motor neurons as well as GR-associated nuclear damage in the cortex. Collectively, our studies establish compartment-specific toxic effects of C9-DPRs associated with degeneration, suggesting that two independent pathogenic mechanisms may contribute to disease heterogeneity and/or synergize on disease progression in C9ORF72 patients with ALS and/or FTD symptoms.}, } @article {pmid37807882, year = {2023}, author = {Pereira-Elizeu, AV and de Ávila-Panisset, J and Rodrigues-da Silva, ML and da Silva-Paz, LP and da Costa-Cunha, K and da Silva, ML and Monsores, N}, title = {Factors associated with the time taken for diagnosis of amyotrophic lateral sclerosis (ALS) in Brazil. An online population-based inquiry.}, journal = {Revista de neurologia}, volume = {77}, number = {8}, pages = {177-183}, pmid = {37807882}, issn = {1576-6578}, mesh = {Male ; Humans ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis ; Brazil ; }, abstract = {OBJECTIVE: This study evaluated factors associated with the time, in months, between the onset of symptoms and the diagnosis (time taken for diagnosis) of ALS for patients in Brazil, in the year 2014.

PATIENTS AND METHODS: An electronic questionnaire composed of 38 questions was developed and applied through internet-based social networks of patients. From the 210 replies, 194 were considered (86 from women, 108 from men). Most respondents were 51 to 60 years old. The Mann-Whitney test was used to compare the time taken for diagnosis between the strata of the sample.

RESULTS: The mean time taken for diagnosis was 14.21 (±16.87) months. There was a statistically significant difference only for higher education conditions (p = 0.009) and low education status (p = 0.042). There was no statistically significant difference between sexes, bulbar onset, age groups, and the presence of spouse, or 'partnership with ALS patients associations or exchange of experiences'.

CONCLUSION: These data suggest that the time taken for diagnosis of ALS is influenced by socioeconomic conditions that promote access to information and/or health services.}, } @article {pmid37807839, year = {2023}, author = {Paganoni, S and Quintana, M and Sherman, AV and Vestrucci, M and Wu, Y and Timmons, J and Cudkowicz, M and , }, title = {Analysis of sodium phenylbutyrate and taurursodiol survival effect in ALS using external controls.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {12}, pages = {2297-2304}, pmid = {37807839}, issn = {2328-9503}, support = {//ALS Association/ ; //ALS Finding a Cure®/ ; //Amylyx Pharmaceuticals, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Phenylbutyrates/pharmacology/therapeutic use ; Survival Analysis ; Proportional Hazards Models ; }, abstract = {OBJECTIVE: Sodium phenylbutyrate and taurursodiol (PB and TURSO) was evaluated in amyotrophic lateral sclerosis (ALS) in the CENTAUR trial encompassing randomized placebo-controlled and open-label extension phases. On intent-to-treat (ITT) survival analysis, median overall survival (OS) was 4.8 months longer and risk of death 36% lower in those originally randomized to an initial 6-month double-blind period of PB and TURSO versus placebo. To estimate PB and TURSO treatment effect without placebo-to-active crossover, we performed a post hoc survival analysis comparing PB and TURSO-randomized participants from CENTAUR and a propensity score-matched, PB and TURSO-naïve external control cohort from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.

METHODS: Clinical trial control participants from the PRO-ACT database who met prespecified eligibility criteria were propensity score matched 1:1 with PB and TURSO-randomized CENTAUR participants using prognostically significant covariates in ALS.

RESULTS: Baseline characteristics including propensity score-matched covariates were generally well balanced between CENTAUR PB and TURSO (n = 89) and PRO-ACT external control (n = 85) groups. Estimated median (IQR) OS was 23.54 (14.56-39.32) months in the CENTAUR PB and TURSO group and 13.15 (9.83-19.20) months in the PRO-ACT external control group; hazard of death was 52% lower in the former group (hazard ratio, 0.48; 95% CI, 0.31-0.72; p = 0.00048).

INTERPRETATION: This analysis suggests potentially greater survival benefit with PB and TURSO in ALS without placebo-to-active crossover than seen on ITT analysis in CENTAUR. Analyses using well-matched external controls may provide additional context for evaluating survival effects in future ALS trials.}, } @article {pmid37807784, year = {2023}, author = {Barba, L and Otto, M and Abu-Rumeileh, S}, title = {The Underestimated Relevance of Alzheimer's Disease Copathology in Amyotrophic Lateral Sclerosis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {95}, number = {4}, pages = {1401-1404}, doi = {10.3233/JAD-230900}, pmid = {37807784}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Amyotrophic Lateral Sclerosis/diagnosis ; tau Proteins/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; *Cognitive Dysfunction ; Amyloid beta-Peptides/cerebrospinal fluid ; }, abstract = {Concomitant Alzheimer's disease (AD) pathology can be observed in approximately 10-15% of cases with amyotrophic lateral sclerosis (ALS). ALS-AD patients have a higher prevalence of amnestic cognitive disturbances, which may often precede motor symptoms. Cerebrospinal fluid (CSF) AD core biomarkers usually show no or slightly significant changes in ALS, whereas blood phosphorylated tau protein might be increased independently from AD copathology. Neurofilament proteins are consistently elevated in CSF and blood of ALS, but have been poorly investigated in ALS-AD. All these issues should be taken into account when using fluid biomarkers as inclusion criteria or secondary endpoints in clinical trials.}, } @article {pmid37807406, year = {2023}, author = {Anderson, G}, title = {Gut Microbiome and Circadian Interactions with Platelets Across Human Diseases, including Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Cancer.}, journal = {Current topics in medicinal chemistry}, volume = {23}, number = {28}, pages = {2699-2719}, doi = {10.2174/0115680266253465230920114223}, pmid = {37807406}, issn = {1873-4294}, mesh = {Humans ; *Melatonin/metabolism ; *Alzheimer Disease ; *Gastrointestinal Microbiome ; *Amyotrophic Lateral Sclerosis ; *Neoplasms ; Tumor Microenvironment ; }, abstract = {Platelets have traditionally been investigated for their role in clot formation in the course of cardiovascular diseases and strokes. However, recent work indicates platelets to be an integral aspect of wider systemic processes, with relevance to the pathophysiology of a host of diverse medical conditions, including neurodegenerative disorders and cancer. This article reviews platelet function and interactions with the gut microbiome and circadian systems, highlighting the role of the platelet mitochondrial melatonergic pathway in determining platelet activation, fluxes and plasticity. This provides a number of novel conceptualizations of platelet function and mode of interaction with other cell types, including in the pathoetiology and pathophysiology of diverse medical conditions, such as cancer, Alzheimer's disease, and amyotrophic lateral sclerosis. It is proposed that a platelet-gut axis allows platelets to contribute to many of the pathophysiological processes linked to gut dysbiosis and gut permeability. This is at least partly via platelet sphingosine- 1-phosphate release, which regulates enteric glial cells and lymphocyte chemotaxis, indicating an etiological role for platelets in a wide array of medical conditions linked to alterations in the gut microbiome. Platelets are also an important regulator of the various microenvironments that underpin most human medical conditions, including the tumor microenvironment, neurodegenerative diseases, and autoimmune disorders. Platelet serotonin release regulates the availability of the mitochondrial melatonergic pathway systemically, thereby being an important determinant of the dynamic metabolic interactions occurring across cell types that underpin the pathoetiology of many medical conditions. In addition, a number of novel and diverse future research directions and treatment implications are proposed.}, } @article {pmid37806880, year = {2024}, author = {Wang, L and Cao, W and Xi, MH and Li, Y}, title = {Appendectomy and the risk of neurodegenerative diseases: A two-sample Mendelian randomization study.}, journal = {Asian journal of surgery}, volume = {47}, number = {1}, pages = {673-674}, doi = {10.1016/j.asjsur.2023.09.170}, pmid = {37806880}, issn = {0219-3108}, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; Mendelian Randomization Analysis ; Appendectomy ; Genetic Predisposition to Disease ; }, } @article {pmid37804508, year = {2023}, author = {Mamontova, EM and Clément, MJ and Sukhanova, MV and Joshi, V and Bouhss, A and Rengifo-Gonzalez, JC and Desforges, B and Hamon, L and Lavrik, OI and Pastré, D}, title = {FUS RRM regulates poly(ADP-ribose) levels after transcriptional arrest and PARP-1 activation on DNA damage.}, journal = {Cell reports}, volume = {42}, number = {10}, pages = {113199}, doi = {10.1016/j.celrep.2023.113199}, pmid = {37804508}, issn = {2211-1247}, mesh = {Humans ; *DNA Damage ; DNA Repair ; HeLa Cells ; Poly (ADP-Ribose) Polymerase-1/genetics/metabolism ; *Poly Adenosine Diphosphate Ribose/metabolism ; Poly(ADP-ribose) Polymerase Inhibitors ; *Poly(ADP-ribose) Polymerases/genetics/metabolism ; RNA Recognition Motif ; *RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {PARP-1 activation at DNA damage sites leads to the synthesis of long poly(ADP-ribose) (PAR) chains, which serve as a signal for DNA repair. Here we show that FUS, an RNA-binding protein, is specifically directed to PAR through its RNA recognition motif (RRM) to increase PAR synthesis by PARP-1 in HeLa cells after genotoxic stress. Using a structural approach, we also identify specific residues located in the FUS RRM, which can be PARylated by PARP-1 to control the level of PAR synthesis. Based on the results of this work, we propose a model in which, following a transcriptional arrest that releases FUS from nascent mRNA, FUS can be recruited by PARP-1 activated by DNA damage to stimulate PAR synthesis. We anticipate that this model offers new perspectives to understand the role of FET proteins in cancers and in certain neurodegenerative diseases such as amyotrophic lateral sclerosis.}, } @article {pmid37804412, year = {2024}, author = {Kusama-Eguchi, K and Tokui, Y and Minoura, A and Yanai, Y and Hirose, D and Furukawa, M and Kosuge, Y and Miura, M and Ohkoshi, E and Makino, M and Minagawa, K and Matsuzaki, K and Ogawa, Y and Watanabe, K and Ohsaki, A}, title = {2(3H)-Dihydrofranolactone metabolites from Pleosporales sp. NUH322 as anti-amyotrophic lateral sclerosis drugs.}, journal = {Journal of natural medicines}, volume = {78}, number = {1}, pages = {146-159}, pmid = {37804412}, issn = {1861-0293}, support = {12-021//A Grant from the Ministry of Education, Culture, Sports, Science, and Technology to promote 2001-multidisciplinary research projects/ ; 13-023//A Grant from the Ministry of Education, Culture, Sports, Science, and Technology to promote 2001-multidisciplinary research projects/ ; 22590088//Grant-in-Aid for Scientific Research/ ; }, mesh = {Mice ; Male ; Female ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Motor Neurons/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Superoxide Dismutase/metabolism ; Spinal Cord/metabolism ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor disease with limited treatment options. A domestic fungal extract library was screened using three assays related to the pathophysiology of ALS with the aim of developing a novel ALS drug. 2(3H)-dihydrofuranolactones 1 and 2, and five known compounds 3-7 were isolated from Pleosporales sp. NUH322 culture media, and their protective activity against the excitotoxicity of β-N-oxalyl-L-α,β-diaminopropionic acid (ODAP), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamatergic agonist, was evaluated under low mitochondrial glutathione levels induced by ethacrynic acid (EA) and low sulfur amino acids using our developed ODAP-EA assay. Additional assays evaluated the recovery from cytotoxicity caused by transfected SOD1-G93A, an ALS-causal gene, and the inhibitory effect against reactive oxygen species (ROS) elevation. The structures of 1 and 2 were elucidated using various spectroscopic methods. We synthesized 1 from D-ribose, and confirmed the absolute structure. Isolated and synthesized 1 displayed higher ODAP-EA activities than the extract and represented its activity. Furthermore, 1 exhibited protective activity against SOD1-G93A-induced toxicity. An ALS mouse model, SOD1-G93A, of both sexes, was treated orally with 1 at pre- and post-symptomatic stages. The latter treatment significantly extended their lifespan (p = 0.03) and delayed motor deterioration (p = 0.001-0.01). Our result suggests that 1 is a promising lead compound for the development of ALS drugs with a new spectrum of action targeting both SOD1-G93A proteopathy and excitotoxicity through its action on the AMPA-type glutamatergic receptor.}, } @article {pmid37803257, year = {2023}, author = {Genuis, SK and Luth, W and Weber, G and Bubela, T and Johnston, WS}, title = {Asynchronous online focus groups for research with people living with amyotrophic lateral sclerosis and family caregivers: usefulness, acceptability and lessons learned.}, journal = {BMC medical research methodology}, volume = {23}, number = {1}, pages = {222}, pmid = {37803257}, issn = {1471-2288}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Caregivers ; Focus Groups ; Travel ; Travel-Related Illness ; }, abstract = {BACKGROUND: People with amyotrophic lateral sclerosis (ALS) face disability- and travel-related barriers to research participation. We investigate the usefulness and acceptability of asynchronous, online focus groups (AOFGs) for research involving people affected by ALS (patients and family caregivers) and outline lessons learned.

METHODS: The ALS Talk Project, consisting of seven AOFGs and 100 participants affected by ALS, provided context for this investigation. Hosted on the secure itracks Board™ platform, participants interacted in a threaded web forum structure. Moderators posted weekly discussion questions and facilitated discussion. Data pertaining to methodology, participant interaction and experience, and moderator technique were analyzed using itracks and NVivo 12 analytics (quantitative) and conventional content analysis and the constant-comparative approach (qualitative).

RESULTS: There was active engagement within groups, with post lengths averaging 111.48 words and a complex network of branching interactions between participants. One third of participant responses included individual reflections without further interaction. Participants affirmed their co-group members, offered practical advice, and discussed shared and differing perspectives. Moderators responded to all posts, indicating presence and probing answers. AOFGs facilitated qualitative and quantitative data-gathering and flexible response to unanticipated events. Although total participation fell below 50% after 10-12 weeks, participants valued interacting with peers in an inclusive, confidential forum. Participants used a variety of personal devices, browsers, and operating systems when interacting on the online platform.

CONCLUSIONS: This methodological examination of AOFGs for patient-centred investigations involving people affected by ALS demonstrates their usefulness and acceptability, and advances knowledge of online research methodologies. Lessons learned include: early identification of research goals and participant needs is critical to selecting an AOFG platform; although duration longer than 10-12 weeks may be burdensome in this population, participants were positive about AOFGs; AOFGs offer real world flexibility enabling response to research challenges and opportunities; and, AOGFs can effectively foster safe spaces for sharing personal perspectives and discussing sensitive topics. With moderators playing an important role in fostering engagement, AOFGs facilitated rich data gathering and promoted reciprocity by fostering the exchange of ideas and interaction between peers. Findings may have implications for research involving other neurologically impaired and/or medically vulnerable populations.}, } @article {pmid37802187, year = {2024}, author = {Weiss, BD}, title = {Role of health literacy screening in clinical practice-Response to Reddy et al's JAAD paper titled "Health literacy screening tools to identify patients at risk of misunderstanding wound care instructions after dermatologic surgery".}, journal = {Journal of the American Academy of Dermatology}, volume = {90}, number = {1}, pages = {e39}, doi = {10.1016/j.jaad.2023.07.1046}, pmid = {37802187}, issn = {1097-6787}, mesh = {Humans ; *Health Literacy ; Dermatologic Surgical Procedures/adverse effects ; }, } @article {pmid37801095, year = {2024}, author = {Gentile, F and Maranzano, A and Verde, F and Bettoni, V and Colombo, E and Doretti, A and Olivero, M and Scheveger, F and Colombrita, C and Bulgarelli, I and Spinelli, EG and Torresani, E and Messina, S and Maderna, L and Agosta, F and Morelli, C and Filippi, M and Silani, V and Ticozzi, N}, title = {The value of routine blood work-up in clinical stratification and prognosis of patients with amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {2}, pages = {794-803}, pmid = {37801095}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Creatinine ; Chlorides ; Disease Progression ; Prognosis ; Biomarkers ; }, abstract = {BACKGROUND: There is an unmet need in amyotrophic lateral sclerosis (ALS) to provide specific biomarkers for the disease. Due to their easy availability, we aimed to investigate whether routine blood parameters provide useful clues for phenotypic classification and disease prognosis.

METHODS: We analyzed a large inpatient cohort of 836 ALS patients who underwent deep phenotyping with evaluation of the clinical and neurophysiological burden of upper (UMN) and lower (LMN) motor neuron signs. Disability and progression rate were measured through the revised ALS Functional Rating Scale (ALSFRS-R) and its changes during time. Cox regression analysis was performed to assess survival associations.

RESULTS: Creatinine significantly correlated with LMN damage (r = 0.38), active (r = 0.18) and chronic (r = 0.24) denervation and baseline ALSFRS-R (r = 0.33). Creatine kinase (CK), alanine (ALT) and aspartate (AST) transaminases correlated with active (r = 0.35, r = 0.27, r = 0.24) and chronic (r = 0.37, r = 0.20, r = 0.19) denervation, while albumin and C-reactive protein significantly correlated with LMN score (r = 0.20 and r = 0.17). Disease progression rate showed correlations with chloride (r = -0.19) and potassium levels (r = -0.16). After adjustment for known prognostic factors, total protein [HR 0.70 (95% CI 0.57-0.86)], creatinine [HR 0.86 (95% CI 0.81-0.92)], chloride [HR 0.95 (95% CI 0.92-0.99)], lactate dehydrogenase [HR 0.99 (95% CI 0.99-0.99)], and AST [HR 1.02 (95% CI 1.01-1.02)] were independently associated with survival.

CONCLUSIONS: Creatinine is a reliable biomarker for ALS, associated with clinical features, disability and survival. Markers of nutrition/inflammation may offer additional prognostic information and partially correlate with clinical features. AST and chloride could further assist in predicting progression rate and survival.}, } @article {pmid37800716, year = {2023}, author = {Shipley, PZ and Falkenstern, SK}, title = {Life Patterns of Family Caregivers of Patients With Amyotrophic Lateral Sclerosis.}, journal = {Nursing science quarterly}, volume = {36}, number = {4}, pages = {356-368}, doi = {10.1177/08943184231187903}, pmid = {37800716}, issn = {1552-7409}, mesh = {Humans ; Caregivers/psychology ; *Amyotrophic Lateral Sclerosis/psychology ; Adaptation, Psychological ; *Nursing Research ; Surveys and Questionnaires ; Family/psychology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a terminal disease that greatly affects patients and the family caregivers who provide most of their care. Despite the psychological, physical, and financial strain placed on ALS caregivers, few research efforts have been directed to this caregiving phenomenon. The purpose of this research study, utilizing Newman's health as expanding consciousness as the theoretical framework and research method, was to advance understanding of the experience of ALS family caregivers for the advancement of nursing science. Nine patterns of the whole across all family caregivers emerged from the data, showing important implications for nursing research and practice.}, } @article {pmid37800457, year = {2023}, author = {Billings, JL and Hilton, JBW and Liddell, JR and Hare, DJ and Crouch, PJ}, title = {Fundamental Neurochemistry Review: Copper availability as a potential therapeutic target in progressive supranuclear palsy: Insight from other neurodegenerative diseases.}, journal = {Journal of neurochemistry}, volume = {167}, number = {3}, pages = {337-346}, doi = {10.1111/jnc.15978}, pmid = {37800457}, issn = {1471-4159}, mesh = {Humans ; *Supranuclear Palsy, Progressive/diagnosis/pathology ; Copper ; *Neurodegenerative Diseases/therapy ; Superoxide Dismutase-1 ; *Neurochemistry ; *Parkinson Disease/pathology ; }, abstract = {Since the first description of Parkinson's disease (PD) over two centuries ago, the recognition of rare types of atypical parkinsonism has introduced a spectrum of related PD-like diseases. Among these is progressive supranuclear palsy (PSP), a neurodegenerative condition that clinically differentiates through the presence of additional symptoms uncommon in PD. As with PD, the initial symptoms of PSP generally present in the sixth decade of life when the underpinning neurodegeneration is already significantly advanced. The causal trigger of neuronal cell loss in PSP is unknown and treatment options are consequently limited. However, converging lines of evidence from the distinct neurodegenerative conditions of PD and amyotrophic lateral sclerosis (ALS) are beginning to provide insights into potential commonalities in PSP pathology and opportunity for novel therapeutic intervention. These include accumulation of the high abundance cuproenzyme superoxide dismutase 1 (SOD1) in an aberrant copper-deficient state, associated evidence for altered availability of the essential micronutrient copper, and evidence for neuroprotection using compounds that can deliver available copper to the central nervous system. Herein, we discuss the existing evidence for SOD1 pathology and copper imbalance in PSP and speculate that treatments able to provide neuroprotection through manipulation of copper availability could be applicable to the treatment of PSP.}, } @article {pmid37798838, year = {2024}, author = {Shojaie, A and Al Khleifat, A and Opie-Martin, S and Sarraf, P and Al-Chalabi, A}, title = {Non-motor symptoms in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {61-66}, pmid = {37798838}, issn = {2167-9223}, support = {/WT_/Wellcome Trust/United Kingdom ; P30 AG066509/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Quality of Life ; Pain/etiology ; Disease Progression ; }, abstract = {OBJECTIVE: While motor symptoms are well-known in ALS, non-motor symptoms are often under-reported and may have a significant impact on quality of life. In this study, we aimed to examine the nature and extent of non-motor symptoms in ALS.

METHODS: A 20-item questionnaire was developed covering the domains of autonomic function, sleep, pain, gastrointestinal disturbance, and emotional lability, posted online and shared on social media platforms to target people with ALS and controls.

RESULTS: A total of 1018 responses were received, of which 927 were complete from 506 people with ALS and 421 unaffected individuals. Cold limbs (p 1.66 × 10[-36)], painful limbs (p 6.14 × 10[-28]), and urinary urgency (p 4.70 × 10[-23]) were associated with ALS. People with ALS were more likely to report autonomic symptoms, pain, and psychiatric symptoms than controls (autonomic symptoms B = 0.043, p 6.10 × 10[-5], pain domain B = 0.18, p 3.72 × 10[-11] and psychiatric domain B = 0.173, p 1.32 × 10[-4]).

CONCLUSIONS: Non-motor symptoms in ALS are common. The identification and management of non-motor symptoms should be integrated into routine clinical care for people with ALS. Further research is warranted to investigate the relationship between non-motor symptoms and disease progression, as well as to develop targeted interventions to improve the quality of life for people with ALS.}, } @article {pmid37797839, year = {2024}, author = {Hooper, MJ and Veon, FL and Enriquez, GL and Nguyen, M and Grimes, CB and LeWitt, TM and Pang, Y and Case, S and Choi, J and Guitart, J and Burns, MB and Zhou, XA}, title = {Reply to Wu et al's US SEER analysis of sepsis in Black patients with CTCL.}, journal = {Journal of the American Academy of Dermatology}, volume = {90}, number = {2}, pages = {e79}, pmid = {37797839}, issn = {1097-6787}, support = {KL2 TR001424/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Lymphoma, T-Cell, Cutaneous ; SEER Program ; Black People ; *Sepsis/diagnosis/epidemiology ; *Skin Neoplasms/epidemiology ; }, } @article {pmid37797620, year = {2023}, author = {Yonekura, K and Maki-Yonekura, S and Takaba, K}, title = {Applications and limitations of electron 3D crystallography.}, journal = {Structure (London, England : 1993)}, volume = {31}, number = {11}, pages = {1328-1334}, doi = {10.1016/j.str.2023.09.007}, pmid = {37797620}, issn = {1878-4186}, mesh = {Crystallography/methods ; *Electrons ; Crystallography, X-Ray ; *Proteins/chemistry ; Microscopy, Electron, Transmission ; Peptides ; }, abstract = {Three-dimensional electron diffraction (3D ED) is a measurement and analysis technique in transmission electron microscopy that is used for determining atomic structures from small crystals. Diverse targets such as proteins, polypeptides, and organic compounds, whose crystals exist in aqueous solutions and organic solvents, or as dried powders, can be studied with 3D ED. We have been involved in the development of this technique, which can now rapidly process a large number of data collected through AI control, enabling efficient structure determination. Here, we introduce this method and describe our recent results. These include the structures and pathogenic mechanisms of wild-type and mutant polypeptides associated with the debilitating disease amyotrophic lateral sclerosis (ALS), the double helical structure of nanographene promoting nanofiber formation, and the structural properties of an organic semiconductor containing disordered regions. We also discuss the limitations and prospects of 3D ED compared to microcrystallography with X-ray free electron lasers.}, } @article {pmid37796272, year = {2023}, author = {Weber, S and Corcia, P and Viader, F}, title = {[Genetics of amyotrophic lateral sclerosis].}, journal = {La Revue du praticien}, volume = {73}, number = {7}, pages = {783-787}, pmid = {37796272}, issn = {2101-017X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Mutation ; }, abstract = {GENETICS OF AMYOTROPHIC LATERAL SCLEROSIS. Approximately 10 to 15% of people with amyotrophic lateral sclerosis (ALS) have a family history of the disease. In 2/3 of them, but also in 10% of subjects without any family history of ALS, a pathogenic genetic variant can be identified. Many genes are involved, the four main ones being C9orf72 (which can also be responsible for dementia), SOD1, TARDBP and FUS. ALS of genetic origin is almost always inherited in an autosomal dominant pattern. The progress made in recent years in the knowledge of the genetic forms of ALS has led to a better understanding of the pathophysiology of the disease and has opened up new therapeutic avenues, some of which are already being explored. For all these reasons, it is now recommended that all patients with ALS, whether familial or not, undergo a genetic investigation, with analyses appropriate to their age and family history. When a pathogenic variant is found, it can then be sought in at-risk relatives who so desire. These tests must follow legally mandated procedures and can only be conducted in a specialized ALS center under the supervision of a geneticist after a thorough discussion of the personal and family implications of the result and written consent from the patient.}, } @article {pmid37796077, year = {2023}, author = {Belenky, VV and Plakhotina, NA and Skoromets, AA and Dugaev, PP and Komantsev, VN and Leontiev, OV}, title = {[Diagnostic capabilities of spinal MR angiography and spinal MR tractography in a patient with motor neuron disease].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {123}, number = {9}, pages = {111-115}, doi = {10.17116/jnevro2023123091111}, pmid = {37796077}, issn = {1997-7298}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Magnetic Resonance Angiography ; *Motor Neuron Disease/diagnostic imaging ; Motor Neurons/pathology ; *Muscular Atrophy, Spinal ; Spinal Cord/diagnostic imaging ; }, abstract = {Motor neuron diseases (MND) include two main forms - amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). A certain part of these diseases is hereditary, while etiology of sporadic cases remains unknown. Both entities are known to develop because of motoneurons damage. Difference between them lies in the state of the descending pyramidal pathways. The pyramidal pathways in SMA are intact, as brain pyramidal neurons are not affected, thus pathology of SMA is restricted to anterior horns of spinal cord. Meanwhile, most forms of ALS arise due to loss of both cerebral and spinal motoneurons, which, in addition to anterior horn lesion, leads to pyramidal descending pathways damage either in brain or in spinal cord. While pathological distinction between these two entities is clear and definite, the clinical difference remains obscure. We present the case of 41-year old patient with MND, in whom spinal MR tractography has revealed lateral columns to be intact that proves the utility of spinal MR tractography in differential diagnosis between ALS and SMA. Given that ischemic diseases of the spinal cord often occur with a clinical picture of MND, we also examined this patient using spinal MRI angiography, revealing a pronounced narrowing and tortuosity of the spinal arteries, complicated by occlusion of the right twelve intercostal artery.}, } @article {pmid37795580, year = {2024}, author = {Rodriguez, P and Blakely, RD}, title = {Sink or swim: Does a worm paralysis phenotype hold clues to neurodegenerative disease?.}, journal = {Journal of cellular physiology}, volume = {239}, number = {6}, pages = {e31125}, doi = {10.1002/jcp.31125}, pmid = {37795580}, issn = {1097-4652}, support = {22A01//Florida Department of Health Ed/ ; }, mesh = {Animals ; *Caenorhabditis elegans/genetics ; *Neurodegenerative Diseases/genetics ; *Phenotype ; Humans ; *Disease Models, Animal ; Caenorhabditis elegans Proteins/genetics/metabolism ; Paralysis/genetics ; Swimming ; Signal Transduction/genetics ; Dopamine/metabolism ; }, abstract = {Receiving a neurodegenerative disease (NDD) diagnosis, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis, is devastating, particularly given the limited options for treatment. Advances in genetic technologies have allowed for efficient modeling of NDDs in animals and brought hope for new disease-modifying medications. The complexity of the mammalian brain and the costs and time needed to identify and develop therapeutic leads limits progress. Modeling NDDs in invertebrates, such as the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, offers orders of magnitude increases in speed of genetic analysis and manipulation, and can be pursued at substantially reduced cost, providing an important, platform complement and inform research with mammalian NDD models. In this review, we describe how our efforts to exploit C. elegans for the study of neural signaling and health led to the discovery of a paralytic phenotype (swimming-induced paralysis) associated with altered dopamine signaling and, surprisingly, to the discovery of a novel gene and pathway whose dysfunction in glial cells triggers neurodegeneration. Research to date on swip-10 and its putative mammalian ortholog MBLAC1, suggests that a tandem analysis will offer insights into NDD mechanisms and insights into novel, disease-modifying therapeutics.}, } @article {pmid37795273, year = {2023}, author = {Venediktov, AA and Bushueva, OY and Kudryavtseva, VA and Kuzmin, EA and Moiseeva, AV and Baldycheva, A and Meglinski, I and Piavchenko, GA}, title = {Closest horizons of Hsp70 engagement to manage neurodegeneration.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1230436}, pmid = {37795273}, issn = {1662-5099}, abstract = {Our review seeks to elucidate the current state-of-the-art in studies of 70-kilodalton-weighed heat shock proteins (Hsp70) in neurodegenerative diseases (NDs). The family has already been shown to play a crucial role in pathological aggregation for a wide spectrum of brain pathologies. However, a slender boundary between a big body of fundamental data and its implementation has only recently been crossed. Currently, we are witnessing an anticipated advancement in the domain with dozens of studies published every month. In this review, we briefly summarize scattered results regarding the role of Hsp70 in the most common NDs including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We also bridge translational studies and clinical trials to portray the output for medical practice. Available options to regulate Hsp70 activity in NDs are outlined, too.}, } @article {pmid37795262, year = {2023}, author = {Lin, TJ and Cheng, KC and Wu, LY and Lai, WY and Ling, TY and Kuo, YC and Huang, YH}, title = {Corrigendum: Potential of cellular therapy for ALS: current strategies and future prospects.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1292681}, doi = {10.3389/fcell.2023.1292681}, pmid = {37795262}, issn = {2296-634X}, abstract = {[This corrects the article DOI: 10.3389/fcell.2022.851613.].}, } @article {pmid37794802, year = {2024}, author = {Din Abdul Jabbar, MA and Guo, L and Guo, Y and Simmons, Z and Pioro, EP and Ramasamy, S and Yeo, CJJ}, title = {Describing and characterising variability in ALS disease progression.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {34-45}, doi = {10.1080/21678421.2023.2260838}, pmid = {37794802}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Disease Progression ; }, abstract = {BACKGROUND, OBJECTIVES: Decrease in the revised ALS Functional Rating Scale (ALSFRS-R) score is currently the most widely used measure of disease progression. However, it does not sufficiently encompass the heterogeneity of ALS. We describe a measure of variability in ALSFRS-R scores and demonstrate its utility in disease characterization.

METHODS: We used 5030 ALS clinical trial patients from the Pooled Resource Open-Access ALS Clinical Trials database to calculate variability in disease progression employing a novel measure and correlated variability with disease span. We characterized the more and less variable populations and designed a machine learning model that used clinical, laboratory and demographic data to predict class of variability. The model was validated with a holdout clinical trial dataset of 84 ALS patients (NCT00818389).

RESULTS: Greater variability in disease progression was indicative of longer disease span on the patient-level. The machine learning model was able to predict class of variability with accuracy of 60.1-72.7% across different time periods and yielded a set of predictors based on clinical, laboratory and demographic data. A reduced set of 16 predictors and the holdout dataset yielded similar accuracy.

DISCUSSION: This measure of variability is a significant determinant of disease span for fast-progressing patients. The predictors identified may shed light on pathophysiology of variability, with greater variability in fast-progressing patients possibly indicative of greater compensatory reinnervation and longer disease span. Increasing variability alongside decreasing rate of disease progression could be a future aim of trials for faster-progressing patients.}, } @article {pmid37794794, year = {2024}, author = {Goyal, NA and Bonar, K and Savic, N and Beau Lejdstrom, R and Wright, J and Mellor, J and McDermott, C}, title = {Misdiagnosis of amyotrophic lateral sclerosis in clinical practice in Europe and the USA: a patient chart review and physician survey.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {16-25}, doi = {10.1080/21678421.2023.2260808}, pmid = {37794794}, issn = {2167-9223}, mesh = {Humans ; Adolescent ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/therapy ; Cross-Sectional Studies ; Europe/epidemiology ; *Physicians ; Diagnostic Errors ; }, abstract = {OBJECTIVE: Delays in amyotrophic lateral sclerosis (ALS) diagnosis can result in compromised disease management and unnecessary costs. We examined the extent of ALS misdiagnosis in the US and Europe.

METHODS: Data were collected via the Adelphi ALS Disease Specific Programme™, a cross-sectional survey of physicians and a medical chart review of their consulting patients with ALS in France, Germany, Italy, Spain, the UK (EU5), and the US. Between July 2020 and March 2021, eligible physicians (primary speciality neurology, active involvement in managing patients with ALS) abstracted data from patients (≥18 years old) with confirmed ALS.

RESULTS: Overall, 138 physicians completed the survey (EU5 107, US 31), with data reviewed from 795 patient medical charts (EU5 568, US 227); 278 (35.0%) patients (EU5 183 [32.2%], US 95 [41.9%]) had received ≥1 initial misdiagnosis based on symptoms later attributed to ALS. Mean (SD) time from symptom onset to first healthcare professional consultation was 3.8 (5.2) months (EU5 4.3 [4.8] months, US 2.6 [5.8] months). Mean (SD) time from symptom onset to ALS diagnosis was 8.2 (12.5) months (EU5 9.6 [14.0] months, US 5.0 [6.8] months) and increased to 10.4 (17.9) for patients with a misdiagnosis (compared with 6.9 [7.2] for patients with no misdiagnosis). Physician-identified barriers to timely ALS diagnosis included the similarity of symptoms to other conditions and delayed referral to neurologists.

CONCLUSIONS: Misdiagnosis of ALS is frequent, with a protracted diagnostic pathway. Targeted education of patients and physicians about signs and symptoms and benefits of prompt referral to multidisciplinary care are needed.}, } @article {pmid37793650, year = {2024}, author = {Mori, F and Yasui, H and Miki, Y and Kon, T and Arai, A and Kurotaki, H and Tomiyama, M and Wakabayashi, K}, title = {Colocalization of TDP-43 and stress granules at the early stage of TDP-43 aggregation in amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {2}, pages = {e13215}, pmid = {37793650}, issn = {1750-3639}, support = {21K07452//Japan Society for the Promotion of Science/ ; 22H02948//Japan Society for the Promotion of Science/ ; 23K06802//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Anterior Horn Cells/pathology ; Cytoplasm ; DNA-Binding Proteins ; Stress Granules ; }, abstract = {TDP-43 aggregates (skeins and round inclusions [RIs]) are frequent histopathological features of amyotrophic lateral sclerosis (ALS). We have shown that diffuse punctate cytoplasmic staining (DPCS) is the earliest pathologic manifestation of TDP-43 in ALS, corresponding to nonfibrillar TDP-43 located in the rough endoplasmic reticulum. Previous in vitro studies have suggested that TDP-43 inclusions may be derived from stress granules (SGs). Therefore, we investigated the involvement of SGs in the formation of TDP-43 inclusions. Formalin-fixed spinal cords of six ALS patients with a disease duration of less than 1 year (short duration), eight patients with a disease duration of 2-5 years (standard duration), and five normal controls were subjected to histopathological examination using antibodies against an SG marker, HuR. In normal controls, the cytoplasm of anterior horn cells was diffusely HuR-positive. In short-duration and standard-duration ALS, the number of HuR-positive anterior horn cells was significantly decreased relative to the controls. DPCS and RIs were more frequent in short-duration ALS than in standard-duration ALS. The majority of DPCS areas and a small proportion of RIs, but not skeins, were positive for HuR. Immunoelectron microscopy showed that ribosome-like granular structures in DPCS areas and RIs were labeled with anti-HuR, whereas skeins were not. These findings suggest that colocalization of TDP-43 and SGs occurs at the early stage of TDP-43 aggregation.}, } @article {pmid37791873, year = {2023}, author = {Kour, S and Fortuna, T and Anderson, EN and Mawrie, D and Bilstein, J and Sivasubramanian, R and Ward, C and Roy, R and Rajasundaram, D and Sterneckert, J and Pandey, UB}, title = {Drosha-dependent microRNAs modulate FUS-mediated neurodegeneration in vivo.}, journal = {Nucleic acids research}, volume = {51}, number = {20}, pages = {11258-11276}, pmid = {37791873}, issn = {1362-4962}, support = {R01 NS081303/NS/NINDS NIH HHS/United States ; S10 OD028483/OD/NIH HHS/United States ; }, mesh = {Animals ; Amyotrophic Lateral Sclerosis/metabolism ; Drosophila/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; Mutation ; Neurons/metabolism ; RNA-Binding Proteins/genetics/metabolism ; Neurodegenerative Diseases/metabolism ; *Heterogeneous-Nuclear Ribonucleoprotein Group F-H/metabolism ; Humans ; *Ribonuclease III/metabolism ; *Drosophila Proteins/metabolism ; }, abstract = {Mutations in the Fused in Sarcoma (FUS) gene cause the familial and progressive form of amyotrophic lateral sclerosis (ALS). FUS is a nuclear RNA-binding protein involved in RNA processing and the biogenesis of a specific set of microRNAs. Here we report that Drosha and two previously uncharacterized Drosha-dependent miRNAs are strong modulators of FUS expression and prevent the cytoplasmic segregation of insoluble mutant FUS in vivo. We demonstrate that depletion of Drosha mitigates FUS-mediated degeneration, survival and motor defects in Drosophila. Mutant FUS strongly interacts with Drosha and causes its cytoplasmic mis-localization into the insoluble FUS inclusions. Reduction in Drosha levels increases the solubility of mutant FUS. Interestingly, we found two Drosha dependent microRNAs, miR-378i and miR-6832-5p, which differentially regulate the expression, solubility and cytoplasmic aggregation of mutant FUS in iPSC neurons and mammalian cells. More importantly, we report different modes of action of these miRNAs against mutant FUS. Whereas miR-378i may regulate mutant FUS inclusions by preventing G3BP-mediated stress granule formation, miR-6832-5p may affect FUS expression via other proteins or pathways. Overall, our research reveals a possible association between ALS-linked FUS mutations and the Drosha-dependent miRNA regulatory circuit, as well as a useful perspective on potential ALS treatment via microRNAs.}, } @article {pmid37791834, year = {2024}, author = {Hyppa-Martin, J and Lilley, J and Chen, M and Friese, J and Schmidt, C and Bunnell, HT}, title = {A large-scale comparison of two voice synthesis techniques on intelligibility, naturalness, preferences, and attitudes toward voices banked by individuals with amyotrophic lateral sclerosis.}, journal = {Augmentative and alternative communication (Baltimore, Md. : 1985)}, volume = {40}, number = {1}, pages = {31-45}, doi = {10.1080/07434618.2023.2262032}, pmid = {37791834}, issn = {1477-3848}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis ; *Communication Devices for People with Disabilities ; *Communication Disorders/complications ; *Voice ; Dysarthria ; Speech Intelligibility ; }, abstract = {Amyotrophic lateral sclerosis (ALS) commonly results in the inability to produce natural speech, making speech-generating devices (SGDs) important. Historically, synthetic voices generated by SGDs were neither unique, nor age- or dialect-appropriate, which depersonalized SGD use. Voices generated by SGDs can now be customized via voice banking and should ideally sound uniquely like the individual's natural speech, be intelligible, and elicit positive reactions from communication partners. This large-scale 2 x 2 mixed between- and within-participants design examined perceptions of 831 adult listeners regarding custom synthetic voices created for two individuals diagnosed with ALS via two synthesis systems in common clinical use (waveform concatenation and statistical parametric synthesis). The study explored relationships among synthesis system, dysarthria severity, synthetic speech intelligibility, naturalness, and preferences, and also provided a preliminary examination of attitudes regarding the custom synthetic voices. Synthetic voices generated via statistical parametric synthesis trained on deep neural networks were more intelligible, natural, and preferred than voices produced via waveform concatenation, and were associated with more positive attitudes. The custom synthetic voice created from moderately dysarthric speech was more intelligible than the voice created from mildly dysarthric speech. Clinical implications and factors that may have contributed to the relative intelligibilities are discussed.}, } @article {pmid37791757, year = {2023}, author = {Rønne, ME and Tandrup, T and Madsen, M and Hunt, CJ and Myers, PN and Moll, JM and Holck, J and Brix, S and Strube, ML and Aachmann, FL and Wilkens, C and Svensson, B}, title = {Three alginate lyases provide a new gut Bacteroides ovatus isolate with the ability to grow on alginate.}, journal = {Applied and environmental microbiology}, volume = {89}, number = {10}, pages = {e0118523}, pmid = {37791757}, issn = {1098-5336}, mesh = {Polysaccharide-Lyases/metabolism ; Bacteroides ; Oligosaccharides/metabolism ; *Bacteria/metabolism ; *Alginates/metabolism ; Humans ; Substrate Specificity ; }, abstract = {Humans consume alginate in the form of seaweed, food hydrocolloids, and encapsulations, making the digestion of this mannuronic acid (M) and guluronic acid (G) polymer of key interest for human health. To increase knowledge on alginate degradation in the gut, a gene catalog from human feces was mined for potential alginate lyases (ALs). The predicted ALs were present in nine species of the Bacteroidetes phylum, of which two required supplementation of an endo-acting AL, expected to mimic cross-feeding in the gut. However, only a new isolate grew on alginate. Whole-genome sequencing of this alginate-utilizing isolate suggested that it is a new Bacteroides ovatus strain harboring a polysaccharide utilization locus (PUL) containing three ALs of families: PL6, PL17, and PL38. The BoPL6 degraded polyG to oligosaccharides of DP 1-3, and BoPL17 released 4,5-unsaturated monouronate from polyM. BoPL38 degraded both alginates, polyM, polyG, and polyMG, in endo-mode; hence, it was assumed to deliver oligosaccharide substrates for BoPL6 and BoPL17, corresponding well with synergistic action on alginate. BoPL17 and BoPL38 crystal structures, determined at 1.61 and 2.11 Å, respectively, showed (α/α)6-barrel + anti-parallel β-sheet and (α/α)7-barrel folds, distinctive for these PL families. BoPL17 had a more open active site than the two homologous structures. BoPL38 was very similar to the structure of an uncharacterized PL38, albeit with a different triad of residues possibly interacting with substrate in the presumed active site tunnel. Altogether, the study provides unique functional and structural insights into alginate-degrading lyases of a PUL in a human gut bacterium.IMPORTANCEHuman ingestion of sustainable biopolymers calls for insight into their utilization in our gut. Seaweed is one such resource with alginate, a major cell wall component, used as a food hydrocolloid and for encapsulation of pharmaceuticals and probiotics. Knowledge is sparse on the molecular basis for alginate utilization in the gut. We identified a new Bacteroides ovatus strain from human feces that grew on alginate and encoded three alginate lyases in a gene cluster. BoPL6 and BoPL17 show complementary specificity toward guluronate (G) and mannuronate (M) residues, releasing unsaturated oligosaccharides and monouronic acids. BoPL38 produces oligosaccharides degraded by BoPL6 and BoPL17 from both alginates, G-, M-, and MG-substrates. Enzymatic and structural characterization discloses the mode of action and synergistic degradation of alginate by these alginate lyases. Other bacteria were cross-feeding on alginate oligosaccharides produced by an endo-acting alginate lyase. Hence, there is an interdependent community in our guts that can utilize alginate.}, } @article {pmid37791472, year = {2023}, author = {Zhang, Y and Nelson, SCK and Viera Ortiz, AP and Lee, EB and Fairman, R}, title = {C9orf72 proline-arginine dipeptide repeats disrupt the proteasome and perturb proteolytic activities.}, journal = {Journal of neuropathology and experimental neurology}, volume = {82}, number = {11}, pages = {901-910}, pmid = {37791472}, issn = {1554-6578}, support = {P40 OD018537/OD/NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; R01 NS095793/NS/NINDS NIH HHS/United States ; P30AG072979/NH/NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Drosophila melanogaster/genetics/metabolism ; Proteasome Endopeptidase Complex/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; Arginine/genetics/metabolism ; Proteolysis ; Dipeptides/genetics/metabolism ; Proline/genetics/metabolism ; *Frontotemporal Dementia/genetics ; DNA Repeat Expansion ; }, abstract = {The hexanucleotide G4C2 repeat expansion in C9orf72 is the most frequent genetic cause of familial amyotrophic lateral sclerosis (ALS). Aberrant translation of this hexanucleotide sequence leads to production of 5 dipeptide repeats (DPRs). One of these DPRs is proline-arginine (polyPR), which is found in C9orf72-expanded ALS (C9ALS) patient brain tissue and is neurotoxic across multiple model systems. PolyPR was previously reported to bind and impair proteasomes in vitro. Nevertheless, the clinical relevance of the polyPR-proteasome interaction and its functional consequences in vivo are yet to be established. Here, we aim to confirm and functionally characterize polyPR-induced impairment of proteolysis in C9ALS patient tissue and an in vivo model system. Confocal microscopy and immunofluorescence studies on both human and Drosophila melanogaster brain tissues revealed sequestration of proteasomes by polyPR into inclusion-like bodies. Co-immunoprecipitation in D. melanogaster showed that polyPR strongly binds to the proteasome. In vivo, functional evidence for proteasome impairment is further shown by the accumulation of ubiquitinated proteins along with lysosomal accumulation and hyper-acidification, which can be rescued by a small-molecule proteasomal enhancer. Together, we provide the first clinical report of polyPR-proteasome interactions and offer in vivo evidence proposing polyPR-induced proteolytic dysfunction as a pathogenic mechanism in C9ALS.}, } @article {pmid37791043, year = {2023}, author = {Richter, V and Neumann, M and Green, JR and Richburg, B and Roesler, O and Kothare, H and Ramanarayanan, V}, title = {Remote Assessment for ALS using Multimodal Dialog Agents: Data Quality, Feasibility and Task Compliance.}, journal = {Interspeech}, volume = {2023}, number = {}, pages = {5441-5445}, pmid = {37791043}, issn = {2308-457X}, support = {K24 DC016312/DC/NIDCD NIH HHS/United States ; R42 DC019877/DC/NIDCD NIH HHS/United States ; }, abstract = {We investigate the feasibility, task compliance and audiovisual data quality of a multimodal dialog-based solution for remote assessment of Amyotrophic Lateral Sclerosis (ALS). 53 people with ALS and 52 healthy controls interacted with Tina, a cloud-based conversational agent, in performing speech tasks designed to probe various aspects of motor speech function while their audio and video was recorded. We rated a total of 250 recordings for audio/video quality and participant task compliance, along with the relative frequency of different issues observed. We observed excellent compliance (98%) and audio (95.2%) and visual quality rates (84.8%), resulting in an overall yield of 80.8% recordings that were both compliant and of high quality. Furthermore, recording quality and compliance were not affected by level of speech severity and did not differ significantly across end devices. These findings support the utility of dialog systems for remote monitoring of speech in ALS.}, } @article {pmid37790622, year = {2023}, author = {Renz, M and Müller, L and Herbst, M and Riedel, J and Mohnke, K and Ziebart, A and Ruemmler, R}, title = {Analysis of cerebral Interleukin-6 and tumor necrosis factor alpha patterns following different ventilation strategies during cardiac arrest in pigs.}, journal = {PeerJ}, volume = {11}, number = {}, pages = {e16062}, pmid = {37790622}, issn = {2167-8359}, mesh = {Animals ; *Cardiopulmonary Resuscitation/methods ; Cytokines ; *Heart Arrest/therapy ; Interleukin-6/genetics ; Prospective Studies ; RNA, Messenger ; Swine ; Tumor Necrosis Factor-alpha/genetics ; }, abstract = {Hypoxia-induced neuroinflammation after cardiac arrest has been shown to be mitigated by different ventilation methods. In this prospective randomized animal trial, 35 landrace pigs were randomly divided into four groups: intermittent positive pressure ventilation (IPPV), synchronized ventilation 20 mbar (SV 20 mbar), chest compression synchronized ventilation 40 mbar (CCSV 40 mbar) and a control group (Sham). After inducing ventricular fibrillation, basic life support (BLS) and advanced life support (ALS) were performed, followed by post-resuscitation monitoring. After 6 hours, the animals were euthanized, and direct postmortem brain tissue samples were taken from the hippocampus (HC) and cortex (Cor) for molecular biological investigation of cytokine mRNA levels of Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα). The data analysis showed that CCSV 40 mbar displayed low TNFα mRNA-levels, especially in the HC, while the highest TNFα mRNA-levels were detected in SV 20 mbar. The results indicate that chest compression synchronized ventilation may have a potential positive impact on the cytokine expression levels post-resuscitation. Further studies are needed to derive potential therapeutic algorithms from these findings.}, } @article {pmid37789566, year = {2024}, author = {Raymond, J and Berry, J and Kasarskis, EJ and Larson, T and Horton, DK and Mehta, P}, title = {A brief report on juvenile amyotrophic lateral sclerosis cases in the United States National ALS Registry: 2010-2018.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {211-213}, pmid = {37789566}, issn = {2167-9223}, support = {CC999999/ImCDC/Intramural CDC HHS/United States ; }, mesh = {Adult ; Humans ; Male ; United States/epidemiology ; Young Adult ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Risk Factors ; Registries ; Databases, Factual ; }, abstract = {Juvenile ALS (jALS) is a rare form of ALS, defined as symptom onset before age 25. This report describes the demographic characteristics of confirmed and likely jALS cases in a large cohort of ALS patients ascertained in the National ALS Registry (Registry) from 2010 to 2018. Patients in the Registry must be at least 18 years of age. Of the 44 identified patients, 37.8% were diagnosed at age 24, were more likely to be nonwhite (54.5%), male (79.5%), and live in the Midwest or Northeast regions (54.5%) of the US. Some 68.9% of the jALS cases were received from federal administrative databases, and 16% came from the web portal only. Demographic characteristics for jALS cases in the Registry differed from previous publications examining ALS cases for all adults. More research is needed to better understand risk factors contributing to jALS, which could lead to earlier diagnosis and therapeutic interventions.}, } @article {pmid37789557, year = {2024}, author = {Kläppe, U and Sennfält, S and Lovik, A and Finn, A and Bofaisal, U and Zetterberg, H and Blennow, K and Piehl, F and Kmezic, I and Press, R and Samuelsson, K and Månberg, A and Fang, F and Ingre, C}, title = {Neurodegenerative biomarkers outperform neuroinflammatory biomarkers in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {150-161}, doi = {10.1080/21678421.2023.2263874}, pmid = {37789557}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Neuroinflammatory Diseases ; Case-Control Studies ; Biomarkers ; Prognosis ; Neurofilament Proteins/cerebrospinal fluid ; }, abstract = {OBJECTIVE: To describe the diagnostic and prognostic performance, and longitudinal trajectories, of potential biomarkers of neuroaxonal degeneration and neuroinflammation in amyotrophic lateral sclerosis (ALS).

METHODS: This case-control study included 192 incident ALS patients, 42 ALS mimics, 114 neurological controls, and 117 healthy controls from Stockholm, Sweden. Forty-four ALS patients provided repeated measurements. We assessed biomarkers of (1)neuroaxonal degeneration: neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in cerebrospinal fluid (CSF) and NfL in serum, and (2)neuroinflammation: chitotriosidase-1 (CHIT1) and monocyte chemoattractant protein 1 (MCP-1) in CSF. To evaluate diagnostic performance, we calculated the area under the curve (AUC). To estimate prognostic performance, we applied quantile regression and Cox regression. We used linear regression models with robust standard errors to assess temporal changes over time.

RESULTS: Neurofilaments performed better at differentiating ALS patients from mimics (AUC: pNfH 0.92, CSF NfL 0.86, serum NfL 0.91) than neuroinflammatory biomarkers (AUC: CHIT1 0.71, MCP-1 0.56). Combining biomarkers did not improve diagnostic performance. Similarly, neurofilaments performed better than neuroinflammatory biomarkers at predicting functional decline and survival. The stratified analysis revealed differences according to the site of onset: in bulbar patients, neurofilaments and CHIT1 performed worse at predicting survival and correlations were lower between biomarkers. Finally, in bulbar patients, neurofilaments and CHIT1 increased longitudinally but were stable in spinal patients.

CONCLUSIONS: Biomarkers of neuroaxonal degeneration displayed better diagnostic and prognostic value compared with neuroinflammatory biomarkers. However, in contrast to spinal patients, in bulbar patients neurofilaments and CHIT1 performed worse at predicting survival and seemed to increase over time.}, } @article {pmid37787835, year = {2024}, author = {Li, S and Zhao, L and Xiao, J and Guo, Y and Fu, R and Zhang, Y and Xu, S}, title = {The gut microbiome: an important role in neurodegenerative diseases and their therapeutic advances.}, journal = {Molecular and cellular biochemistry}, volume = {479}, number = {9}, pages = {2217-2243}, pmid = {37787835}, issn = {1573-4919}, support = {No. 81973626, No. 81774059//National Natural Science Foundation of China/ ; No. 21JCYBJC01620//Tianjin Municipal Science and Technology Commission of China/ ; No. 2021099//Tianjin Health Committee/ ; No. 2021KJ146//Tianjin Education Committee/ ; }, mesh = {Humans ; *Gastrointestinal Microbiome ; *Neurodegenerative Diseases/therapy/microbiology ; *Fecal Microbiota Transplantation ; *Probiotics/therapeutic use ; Animals ; Parkinson Disease/therapy/microbiology ; Alzheimer Disease/therapy/microbiology ; }, abstract = {There are complex interactions between the gut and the brain. With increasing research on the relationship between gut microbiota and brain function, accumulated clinical and preclinical evidence suggests that gut microbiota is intimately involved in the pathogenesis of neurodegenerative diseases (NDs). Increasingly studies are beginning to focus on the association between gut microbiota and central nervous system (CNS) degenerative pathologies to find potential therapies for these refractory diseases. In this review, we summarize the changes in the gut microbiota in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis and contribute to our understanding of the function of the gut microbiota in NDs and its possible involvement in the pathogenesis. We subsequently discuss therapeutic approaches targeting gut microbial abnormalities in these diseases, including antibiotics, diet, probiotics, and fecal microbiota transplantation (FMT). Furthermore, we summarize some completed and ongoing clinical trials of interventions with gut microbes for NDs, which may provide new ideas for studying NDs.}, } @article {pmid37787812, year = {2024}, author = {Beswick, E and Johnson, M and Newton, J and Dakin, R and Stenson, A and Abrahams, S and Carson, A and Chandran, S and Pal, S}, title = {Factors impacting trial participation in people with motor neuron disease.}, journal = {Journal of neurology}, volume = {271}, number = {1}, pages = {543-552}, pmid = {37787812}, issn = {1432-1459}, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/therapy ; *Motor Neuron Disease/therapy ; Probability ; Prospective Studies ; Randomized Controlled Trials as Topic ; Adaptive Clinical Trials as Topic ; }, abstract = {Motor neuron disease (MND) is a rapidly progressive neurodegenerative disorder with limited treatment options. Historically, neurological trials have been plagued by suboptimal recruitment and high rates of attrition. The Motor Neuron Disease-Systematic Multi-Arm Randomised Adaptive Trial (MND-SMART) seeks to identify effective disease modifying drugs. This study investigates person-specific factors affecting recruitment and retention. Improved understanding of these factors may improve trial protocol design, optimise recruitment and retention. Participants with MND completed questionnaires and this was supplemented with clinical data. 12 months after completing the questionnaires we used MND-SMART recruitment data to establish if members of our cohort engaged with the trial. 120 people with MND completed questionnaires for this study. Mean age at participation was 66 (SD = 9), 14% (n = 17) were categorised as long survivors, with 68% (n = 81) of participants male and 60% (n = 73) had the ALS sub-type. Of the 120 study participants, 50% (n = 60) were randomised into MND-SMART and 78% (n = 94) expressed interest an in participating. After the 1-year follow-up period 65% (n = 39) of the 60 randomised participants remained in MND-SMART. Older age was significantly associated with reduced likelihood of participation (OR = 0.92, 95% CI = 0.88-0.96, p = 0.000488). The findings show that people with MND are highly motivated to engage in research, but older individuals remain significantly less likely to participate. We recommend the inclusion of studies to explore characteristics of prospective and current participants alongside trials.}, } @article {pmid37787459, year = {2023}, author = {Wei, S and Yang, Y and Wang, Y}, title = {Proximity Proteomics Revealed Aberrant mRNA Splicing Elicited by ALS-Linked Profilin-1 Mutants.}, journal = {Analytical chemistry}, volume = {95}, number = {41}, pages = {15141-15145}, pmid = {37787459}, issn = {1520-6882}, support = {R35 ES031707/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Profilins/genetics/metabolism ; Actins/metabolism ; Proteomics ; Mutation ; Basic Helix-Loop-Helix Transcription Factors/genetics ; }, abstract = {Profilin 1 (PFN1) is a cytoskeleton protein that modulates actin dynamics through binding to monomeric actin and polyproline-containing proteins. Mutations in PFN1 have been linked to the pathogenesis of familial amyotrophic lateral sclerosis (ALS). Here, we employed an unbiased proximity labeling strategy in combination with proteomic analysis for proteome-wide profiling of proteins that differentially interact with mutant and wild-type (WT) PFN1 proteins in human cells. We uncovered 11 mRNA splicing proteins that are preferentially enriched in the proximity proteomes of the two ALS-linked PFN1 variants, C71G and M114T, over that of wild-type PFN1. We validated the preferential interactions of the ALS-linked PFN1 variants with two mRNA splicing factors, hnRNPC and U2AF2, by immunoprecipitation, followed with immunoblotting. We also found that the two ALS-linked PFN1 variants promoted the exonization of Alu elements in the mRNAs of MTO1, TCFL5, WRN and POLE genes in human cells. Together, we showed that the two ALS-linked PFN1 variants interacted preferentially with mRNA splicing proteins, which elicited aberrant exonization of the Alu elements in mRNAs. Thus, our work provided pivotal insights into the perturbations of ALS-linked PFN1 variants in RNA biology and their potential contributions to ALS pathology.}, } @article {pmid37786726, year = {2023}, author = {Bell, AM and Utting, C and Dickie, AC and Kucharczyk, MW and Quillet, R and Gutierrez-Mecinas, M and Razlan, ANB and Cooper, AH and Lan, Y and Hachisuka, J and Weir, GA and Bannister, K and Watanabe, M and Kania, A and Hoon, MA and Macaulay, IC and Denk, F and Todd, AJ}, title = {Deep sequencing of Phox2a nuclei reveals five classes of anterolateral system neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37786726}, issn = {2692-8205}, support = {MR/T01072X/1/MRC_/Medical Research Council/United Kingdom ; MR/W004739/1/MRC_/Medical Research Council/United Kingdom ; MRF_MRF-160-0015-ELP-DENK-C0844/MRF/MRF/United Kingdom ; MR/V033638/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; 26815/CRUK_/Cancer Research UK/United Kingdom ; }, abstract = {The anterolateral system (ALS) is a major ascending pathway from the spinal cord that projects to multiple brain areas and underlies the perception of pain, itch and skin temperature. Despite its importance, our understanding of this system has been hampered by the considerable functional and molecular diversity of its constituent cells. Here we use fluorescence-activated cell sorting to isolate ALS neurons belonging to the Phox2a-lineage for single-nucleus RNA sequencing. We reveal five distinct clusters of ALS neurons (ALS1-5) and document their laminar distribution in the spinal cord using in situ hybridization. We identify 3 clusters of neurons located predominantly in laminae I-III of the dorsal horn (ALS1-3) and two clusters with cell bodies located in deeper laminae (ALS4 & ALS5). Our findings reveal the transcriptional logic that underlies ALS neuronal diversity in the adult mouse and uncover the molecular identity of two previously identified classes of projection neurons. We also show that these molecular signatures can be used to target groups of ALS neurons using retrograde viral tracing. Overall, our findings provide a valuable resource for studying somatosensory biology and targeting subclasses of ALS neurons.}, } @article {pmid37783557, year = {2023}, author = {Chen, D and Huang, H and Saberi, H and Sharma, HS}, title = {Positive and negative cell therapy in randomized control trials for central nervous system diseases.}, journal = {International review of neurobiology}, volume = {171}, number = {}, pages = {241-254}, doi = {10.1016/bs.irn.2023.05.017}, pmid = {37783557}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Quality of Life ; *Central Nervous System Diseases/therapy ; Cell- and Tissue-Based Therapy ; *Parkinson Disease/therapy ; Brain Damage, Chronic ; }, abstract = {Neurorestorative cell therapies have been tested to treat patients with nervous system diseases for over 20 years. Now it is still hard to answer which kinds of cells can really play a role on improving these patients' quality of life. Non-randomized clinical trials or studies could not provide strong evidences in answering this critical question. In this review, we summarized randomized clinical trials of cell therapies for central nervous diseases, such as stroke, spinal cord injury, cerebral palsy (CP), Parkinson's disease (PD), multiple sclerosis (MS), brain trauma, amyotrophic lateral sclerosis (ALS), etc. Most kinds of cell therapies demonstrated negative results for stoke, brain trauma and amyotrophic lateral sclerosis. A few kinds of cell therapies showed neurorestorative effects in this level of evidence-based medicine, such as olfactory ensheating cells for chronic ischemic stroke. Some kinds of cells showed positive or negative effects from different teams in the same or different diseases. We analyzed the possible failed reasons of negative results and the cellular bio-propriety basis of positive results. Based on therapeutic results of randomized control trials and reasonable analysis, we recommend: (1) to further conduct trials for successful cell therapies with positive results to increase neurorestorative effects; (2) to avoid in repeating failed cell therapies with negative results in same diseases because it is nonsense for them to be done with similar treatment methods, such as cell dosage, transplanting way, time of window, etc. Furthermore, we strongly suggest not to do non-randomized clinical trials for cells that had shown negative results in randomized clinical trials.}, } @article {pmid37782813, year = {2023}, author = {Pennisi, F and Lo Presti, T and Ricciardi, GE and Dalla Valle, Z and Minerva, M and Privitera, G and Signorelli, C}, title = {Training and career opportunities for residencies in Hygiene and Preventive Medicine: results of a survey on 39 Italian schools.}, journal = {Igiene e sanita pubblica}, volume = {80}, number = {4}, pages = {94-100}, pmid = {37782813}, issn = {0019-1639}, mesh = {Humans ; *Internship and Residency ; State Medicine ; Public Health/education ; Hygiene/education ; Universities ; Preventive Medicine/education ; }, abstract = {INTRODUCTION: The Italian National Health Service (SSN) is currently grappling. with a complex situation, characterized by a persistent shortage of medical personnel and the divergent aspirations of young medical graduates. Additionally, recent regulatory developments concerning specialist training further contribute to the intricacies of the landscape, calling for a comprehensive analysis of the challenges and opportunities within the sector. This study aims to provide an updated overview of the current placement of medical graduates, residents and specialists in the specific hygiene and preventive medicine (Public Health) field.

METHODS: Data on admissions, withdrawals and resignations were obtained from the Ministries of Universities and Health and from the archives of the "Associazione Liberi Specializzandi" (ALS). Information regarding the professional prospects for specialists and residents in the field of Public Health was gathered through a tailored survey conducted by the "Consulta dei Medici in Formazione Specialistica" (Council of Medical Residents) of the Italian Society of Hygiene (SItI).

RESULTS: In 2022, a total of 483 specialization contracts were granted, indicating a decrease of 37% compared to the previous year. Notably, 85 positions (17.6%) remained unallocated or resulted in dropouts. Six months after completing their residency, 1.5% of hygiene residents were still actively seeking employment. On a positive note, 75.4% of fourth-year residents secured contracts under the "Decreto Calabria". Career opportunities within the Italian SSN have witnessed growth, with a significant proportion of placements in territorial services and hospital medical directorates.

DISCUSSION AND CONCLUSIONS: The updating of training programs provided by residency schools and the exploration of innovative approaches are of paramount importance to address the urgent need for high-quality training and to cater to the requirements of the national health system.}, } @article {pmid37782796, year = {2023}, author = {Huang, J and Fan, X and Jin, X and Teng, L and Yan, N}, title = {Dual-pocket inhibition of Nav channels by the antiepileptic drug lamotrigine.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {41}, pages = {e2309773120}, pmid = {37782796}, issn = {1091-6490}, mesh = {Humans ; Anticonvulsants/pharmacology ; Lamotrigine/pharmacology ; *Cannabidiol ; Sodium/metabolism ; *Voltage-Gated Sodium Channels/chemistry ; }, abstract = {Voltage-gated sodium (Nav) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Nav channels serve as the primary targets for several classes of widely used and investigational drugs, including local anesthetics, antiepileptic drugs, antiarrhythmics, and analgesics. In this study, we present cryogenic electron microscopy (cryo-EM) structures of human Nav1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 Å and 2.7 Å, respectively. A 3D EM reconstruction of ligand-free Nav1.7 was also obtained at 2.1 Å resolution. RLZ resides in the central cavity of the pore domain and is coordinated by residues from repeats III and IV. Whereas one LTG molecule also binds to the central cavity, the other is found beneath the intracellular gate, known as site BIG. Therefore, LTG, similar to lacosamide and cannabidiol, blocks Nav channels via a dual-pocket mechanism. These structures, complemented with docking and mutational analyses, also explain the structure-activity relationships of the LTG-related linear 6,6 series that have been developed for improved efficacy and subtype specificity on different Nav channels. Our findings reveal the molecular basis for these drugs' mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs.}, } @article {pmid37782409, year = {2023}, author = {Lee, SY and Cho, HY and Oh, JP and Park, J and Bae, SH and Park, H and Kim, EJ and Lee, JH}, title = {Therapeutic Effects of Combination of Nebivolol and Donepezil: Targeting Multifactorial Mechanisms in ALS.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {20}, number = {6}, pages = {1779-1795}, pmid = {37782409}, issn = {1878-7479}, support = {S3030175//Korea Technology and Information Promotion Agency for SMEs/ ; }, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Donepezil/therapeutic use ; Nebivolol/therapeutic use/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; HeLa Cells ; Quality of Life ; Spinal Cord/metabolism ; Disease Progression ; Disease Models, Animal ; Mice, Transgenic ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons in the spinal cord. Although the disease's pathophysiological mechanism remains poorly understood, multifactorial mechanisms affecting motor neuron loss converge to worsen the disease. Although two FDA-approved drugs, riluzole and edaravone, targeting excitotoxicity and oxidative stress, respectively, are available, their efficacies are limited to extending survival by only a few months. Here, we developed combinatorial drugs targeting multifactorial mechanisms underlying key components in ALS disease progression. Using data analysis based on the genetic information of patients with ALS-derived cells and pharmacogenomic data of the drugs, a combination of nebivolol and donepezil (nebivolol-donepezil) was identified for ALS therapy. Here, nebivolol-donepezil markedly reduced the levels of cytokines in the microglial cell line, inhibited nuclear factor-κB (NF-κB) nucleus translocation in the HeLa cell and substantially protected against excitotoxicity-induced neuronal loss by regulating the PI3K-Akt pathway. Nebivolol-donepezil significantly promoted the differentiation of neural progenitor cells (NPC) into motor neurons. Furthermore, we verified the low dose efficacy of nebivolol-donepezil on multiple indices corresponding to the quality of life of patients with ALS in vivo using SOD1[G93A] mice. Nebivolol-donepezil delayed motor function deterioration and halted motor neuronal loss in the spinal cord. Drug administration effectively suppressed muscle atrophy by mitigating the proportion of smaller myofibers and substantially reducing phospho-neurofilament heavy chain (pNF-H) levels in the serum, a promising ALS biomarker. High-dose nebivolol-donepezil significantly prolonged survival and delayed disease onset compared with vehicle-treated mice. These results indicate that the combination of nebivolol-donepezil efficiently prevents ALS disease progression, benefiting the patients' quality of life and life expectancy.}, } @article {pmid37782260, year = {2023}, author = {Bchara, L and Eritja, R and Gargallo, R and Benavente, F}, title = {Rapid and Highly Efficient Separation of i-Motif DNA Species by CE-UV and Multivariate Curve Resolution.}, journal = {Analytical chemistry}, volume = {95}, number = {41}, pages = {15189-15198}, pmid = {37782260}, issn = {1520-6882}, mesh = {*DNA ; Spectrophotometry ; Spectrophotometry, Ultraviolet/methods ; Temperature ; *Electrophoresis, Capillary/methods ; }, abstract = {The i-motif is a class of nonstandard DNA structure with potential biological implications. A novel capillary electrophoresis with an ultraviolet absorption spectrophotometric detection (CE-UV) method has been developed for the rapid analysis of the i-motif folding equilibrium as a function of pH and temperature. The electrophoretic analyses are performed in reverse polarity of the separation voltage with 32 cm long fused silica capillaries permanently coated with hydroxypropyl cellulose (HPC), after an appropriate conditioning procedure was used to achieve good repeatability. However, the electrophoretic separation between the folded and unfolded conformers of the studied cytosine-rich i-motif sequences (i.e., TT, Py39WT, and nmy01) is compromised, especially for Py39WT and nmy01, which result in completely overlapped peaks. Therefore, deconvolution with multivariate curve resolution-alternating least-squares (MCR-ALS) has been required for the efficient separation of the folded and unfolded species found at different concentration levels at pH 6.5 and between 12 and 40 °C, taking advantage of the small dissimilarities in the electrophoretic mobilities and UV spectra levels. MCR-ALS has also provided quantitative information that has been used to estimate melting temperatures (Tm), which are similar to those determined by UV and circular dichroism (CD) spectroscopies. The obtained results demonstrate that CE-UV assisted by MCR-ALS may become a very useful tool to get novel insight into the folding of i-motifs and other complex DNA structures.}, } @article {pmid37782142, year = {2023}, author = {Rahman, A and Saikia, B and Baruah, A}, title = {In silico analysis of SOD1 aggregation inhibition modes of tertiary amine pyrazolone and pyrano coumarin ferulate as ALS drug candidates.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {25}, number = {39}, pages = {26833-26846}, doi = {10.1039/d3cp03978a}, pmid = {37782142}, issn = {1463-9084}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Mutation ; *Neurodegenerative Diseases ; Protein Folding ; Superoxide Dismutase-1/chemistry/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, the familial form (fALS) of which is often cognate to mutations in the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD1) leading to misfolding and aggregation. Two small molecules, a tertiary amine pyrazolone (TAP) and a pyrano coumarin ferulate (PCF) were suggested to be ALS drug candidates following experimental observation of their ability to inhibit SOD1 protein misfolding and aggregation. The present work aims at computational investigation of these experimentally proposed drug candidates to gain insight into their mechanism of SOD1 misfolding and aggregation inhibition. On the basis of molecular docking, molecular dynamics simulation, MM-PBSA and per-residue energy decomposition analysis, we examined the specific interactions of TAP and PCF with three probable binding sites of SOD1, namely, dimeric interface cavity, W32 and, UMP binding sites. Results suggest that the binding of TAP at W32 and at UMP sites are least probable due to absence of any favorable interaction. The binding of TAP to dimeric cavity is also unstable due to strong unfavorable interactions. In case of PCF, binding at the UMP site is least probable while binding at dimeric cavity is accompanied by unfavorable interactions. PCF, however, exhibits stable binding with the W32 binding site of SOD1 by stabilizing the solvent accessible hydrophobic residues, which otherwise would have acted as contact points for aggregation. Thus the results imply that compound PCF functions as an inhibitior of SOD1 misfolding/aggregation through direct interaction with the protein SOD1 at the W32 binding site. However, TAP is likely to act as an inhibitor through a different mechanism rather than direct interaction with the protein SOD1. These results apart from reinforcing previous experimental findings, shed light on the probable mechanism of action of the proposed drug candidates.}, } @article {pmid37781884, year = {2023}, author = {Erdag, E and Haskologlu, IC and Mercan, M and Abacioglu, N and Sehirli, AO}, title = {An in silico investigation: Can melatonin serve as an adjuvant in NR1D1-linked chronotherapy for amyotrophic lateral sclerosis?.}, journal = {Chronobiology international}, volume = {40}, number = {10}, pages = {1395-1403}, doi = {10.1080/07420528.2023.2265476}, pmid = {37781884}, issn = {1525-6073}, mesh = {Animals ; Humans ; *Melatonin/pharmacology ; Circadian Rhythm/physiology ; *Amyotrophic Lateral Sclerosis/drug therapy ; Molecular Docking Simulation ; Chronotherapy/methods ; Nuclear Receptor Subfamily 1, Group D, Member 1/genetics ; }, abstract = {Chronobiology, which studies biological rhythms and their impacts on health, presents a potential avenue for treating amyotrophic lateral sclerosis. Clock gene-related therapies, focusing on genes responsible for regulating biological rhythms, may hold promise in the treatment. Among these clock genes, nuclear receptor subfamily 1 Group D member 1 (NR1D1) plays a vital role in neurodegenerative diseases. In this particular study, it was aimed to investigate the potential of FDA-approved drugs commonly used in amyotrophic lateral sclerosis treatment and melatonin, a hormone known for its role in regulating sleep-wake cycles, as ligands for clock gene-related therapy. The ligands were subjected to molecular docking and molecular dynamics simulation methods against the NR1D1 clock gene. These results suggested that combining melatonin with FDA-approved medications commonly used in the treatment might yield positive outcomes. This study provides preliminary data and lays the groundwork for future investigations involving in vitro (laboratory-based) and in vivo (animal or human-based) research on chronotherapy. In summary, this research highlights the potential of clock gene-related therapy utilizing melatonin in conjunction with FDA-approved drugs for amyotrophic lateral sclerosis treatment, offering insights into novel treatment strategies. The findings underscore the need for further studies to explore the effectiveness of this hypothetical approach in experimental and clinical settings.}, } @article {pmid37781096, year = {2023}, author = {Yu, H and Xiong, M and Zhang, Z}, title = {The role of glycogen synthase kinase 3 beta in neurodegenerative diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1209703}, pmid = {37781096}, issn = {1662-5099}, abstract = {Neurodegenerative diseases (NDDs) pose an increasingly prevalent threat to the well-being and survival of elderly individuals worldwide. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and so on. They are characterized by progressive loss or dysfunction of neurons in the central or peripheral nervous system and share several cellular and molecular mechanisms, including protein aggregation, mitochondrial dysfunction, gene mutations, and chronic neuroinflammation. Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase that is believed to play a pivotal role in the pathogenesis of NDDs. Here we summarize the structure and physiological functions of GSK3β and explore its involvement in NDDs. We also discussed its potential as a therapeutic target.}, } @article {pmid37780700, year = {2023}, author = {Li, H and Xuan, T and Xu, T and Yang, J and Cheng, J and Wang, Z}, title = {SIGMAR1 variants in ALS-PD complex cases: a case report of a novel mutation and literature review.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1242472}, pmid = {37780700}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons, with occasional involvement of the extrapyramidal system. Mutations in the sigma non-opioid intracellular receptor 1 (SIGMAR1) gene have been identified as one of the causes of ALS. Here, we present a case of a 49-year-old man diagnosed with ALS-Parkinson's disease (PD) complex. The patient exhibited bradykinesia and tremor, and whole-exome sequencing revealed homozygous mutations in the SIGMAR1 gene (c.446-2A > T). In addition, we conducted an investigation into the clinical and molecular phenotype of previously reported variants of SIGMAR1 associated with ALS. This case report aims to raise awareness among physicians regarding atypical phenotypes of amyotrophic lateral sclerosis and to encourage further research on the factors leading to SIGMAR1 mutations in patients.}, } @article {pmid37780560, year = {2023}, author = {Zwicker, J and Smith, IC and Rice, J and Murphy, R and Breiner, A and McNeely, S and Duff, M and Buenger, U and Zehrt, B and Nogo, D and Watt, CL}, title = {Palliative care at any stage of amyotrophic lateral sclerosis: a prospective feasibility study.}, journal = {Frontiers in medicine}, volume = {10}, number = {}, pages = {1204816}, pmid = {37780560}, issn = {2296-858X}, abstract = {INTRODUCTION: Many patients with amyotrophic lateral sclerosis (ALS) receive palliative care (PC) very late or not at all. The impact of PC on patients with ALS and caregivers has not been quantified. Study goals included (1) measuring the impact of early PC on quality of life and mood of patients/caregivers and (2) describing patient/caregiver satisfaction with PC.

METHODS: The study was a non-randomized, prospective feasibility study of patients with ALS being treated at The Ottawa Hospital ALS Clinic and their caregivers. Exclusion criteria were age < 18 years, inability to complete questionnaires, and prior receipt of PC. The ALS Specific Quality of Life-Revised (ALSSQOL-R) questionnaire (patients only) and Hospital Anxiety and Depression Scale (HADS) were completed at regular intervals for up to 2 years. Patients accepting a PC consultation completed a post-PC satisfaction survey. Primary outcome measures included ALSSQOL-R and HADS scores compared before and after PC consultation, and between groups receiving and not receiving a PC consultation. Secondary outcome measures included responses on the post-PC satisfaction survey (1 = strongly disagree, 5 = strongly agree).

RESULTS: 39 patients with ALS (age 66 ± 10 years, median time from diagnosis = 6 months) and 22 caregivers were enrolled. 32 patients had a PC consultation (30 were virtual). Patients and caregivers agreed with statements that the PC consult was helpful (mean ± SD = 4.54 ± 0.60, range = 3-5) and they would recommend PC to others with ALS (4.59 ± 0.59, range = 3-5). Participants disagreed with statements that the consult would have been better later in disease course (1.87 ± 0.80, range = 1-4) and that it took too much time/energy (1.44 ± 0.85, range = 1-4). Average ALSSQOL-R scores worsened significantly over time. HADS and ALSSQOL-R scores did not significantly differ between groups receiving and not receiving PC.

CONCLUSION: Patients with ALS and their caregivers found virtual PC consultations beneficial irrespective of disease duration or severity. Offering routine PC to all patients with ALS is feasible and should be considered as part of standard care.

CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT04257760, identifier NCT04257760.}, } @article {pmid37779364, year = {2024}, author = {Matveeva, A and Watters, O and Rukhadze, A and Khemka, N and Gentile, D and Perez, IF and Llorente-Folch, I and Farrell, C and Lo Cacciato, E and Jackson, J and Piazzesi, A and Wischhof, L and Woods, I and Halang, L and Hogg, M and Muñoz, AG and Dillon, ET and Matallanas, D and Arijs, I and Lambrechts, D and Bano, D and Connolly, NMC and Prehn, JHM}, title = {Integrated analysis of transcriptomic and proteomic alterations in mouse models of ALS/FTD identify early metabolic adaptions with similarities to mitochondrial dysfunction disorders.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {135-149}, doi = {10.1080/21678421.2023.2261979}, pmid = {37779364}, issn = {2167-9223}, mesh = {Mice ; Animals ; Humans ; *Frontotemporal Dementia/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Proteomics ; *Neurodegenerative Diseases ; *Pick Disease of the Brain ; Mice, Transgenic ; *Mitochondrial Diseases ; Gene Expression Profiling ; RNA, Messenger ; }, abstract = {OBJECTIVE: Sporadic and familial amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that results in loss of motor neurons and, in some patients, associates with frontotemporal dementia (FTD). Apart from the accumulation of proteinaceous deposits, emerging literature indicates that aberrant mitochondrial bioenergetics may contribute to the onset and progression of ALS/FTD. Here we sought to investigate the pathophysiological signatures of mitochondrial dysfunction associated with ALS/FTD.

METHODS: By means of label-free mass spectrometry (MS) and mRNA sequencing (mRNA-seq), we report pre-symptomatic changes in the cortices of TDP-43 and FUS mutant mouse models. Using tissues from transgenic mouse models of mitochondrial diseases as a reference, we performed comparative analyses and extracted unique and common mitochondrial signatures that revealed neuroprotective compensatory mechanisms in response to early damage.

RESULTS: In this regard, upregulation of both Acyl-CoA Synthetase Long-Chain Family Member 3 (ACSL3) and mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) were the most representative change in pre-symptomatic ALS/FTD tissues, suggesting that fatty acid beta-oxidation and mitochondrial protein translation are mechanisms of adaptation in response to ALS/FTD pathology.

CONCLUSIONS: Together, our unbiased integrative analyses unveil novel molecular components that may influence mitochondrial homeostasis in the earliest phase of ALS.}, } @article {pmid37777552, year = {2023}, author = {Ometto, JP and Gorgens, EB and de Souza Pereira, FR and Sato, L and de Assis, MLR and Cantinho, R and Longo, M and Jacon, AD and Keller, M}, title = {A biomass map of the Brazilian Amazon from multisource remote sensing.}, journal = {Scientific data}, volume = {10}, number = {1}, pages = {668}, pmid = {37777552}, issn = {2052-4463}, mesh = {*Biomass ; Brazil ; Carbon/analysis ; *Forests ; *Remote Sensing Technology/methods ; Tropical Climate ; }, abstract = {The Amazon Forest, the largest contiguous tropical forest in the world, stores a significant fraction of the carbon on land. Changes in climate and land use affect total carbon stocks, making it critical to continuously update and revise the best estimates for the region, particularly considering changes in forest dynamics. Forest inventory data cover only a tiny fraction of the Amazon region, and the coverage is not sufficient to ensure reliable data interpolation and validation. This paper presents a new forest above-ground biomass map for the Brazilian Amazon and the associated uncertainty both with a resolution of 250 meters and baseline for the satellite dataset the year of 2016 (i.e., the year of the satellite observation). A significant increase in data availability from forest inventories and remote sensing has enabled progress towards high-resolution biomass estimates. This work uses the largest airborne LiDAR database ever collected in the Amazon, mapping 360,000 km[2] through transects distributed in all vegetation categories in the region. The map uses airborne laser scanning (ALS) data calibrated by field forest inventories that are extrapolated to the region using a machine learning approach with inputs from Synthetic Aperture Radar (PALSAR), vegetation indices obtained from the Moderate-Resolution Imaging Spectroradiometer (MODIS) satellite, and precipitation information from the Tropical Rainfall Measuring Mission (TRMM). A total of 174 field inventories geolocated using a Differential Global Positioning System (DGPS) were used to validate the biomass estimations. The experimental design allowed for a comprehensive representation of several vegetation types, producing an above-ground biomass map varying from a maximum value of 518 Mg ha[-1], a mean of 174 Mg ha[-1], and a standard deviation of 102 Mg ha[-1]. This unique dataset enabled a better representation of the regional distribution of the forest biomass and structure, providing further studies and critical information for decision-making concerning forest conservation, planning, carbon emissions estimate, and mechanisms for supporting carbon emissions reductions.}, } @article {pmid37776851, year = {2023}, author = {Tsioras, K and Smith, KC and Edassery, SL and Garjani, M and Li, Y and Williams, C and McKenna, ED and Guo, W and Wilen, AP and Hark, TJ and Marklund, SL and Ostrow, LW and Gilthorpe, JD and Ichida, JK and Kalb, RG and Savas, JN and Kiskinis, E}, title = {Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis.}, journal = {Cell reports}, volume = {42}, number = {10}, pages = {113160}, pmid = {37776851}, issn = {2211-1247}, support = {S10 OD032464/OD/NIH HHS/United States ; R01 AG078796/AG/NIA NIH HHS/United States ; R01 NS134166/NS/NINDS NIH HHS/United States ; R21 NS107761/NS/NINDS NIH HHS/United States ; R01 NS097850/NS/NINDS NIH HHS/United States ; R01 NS124802/NS/NINDS NIH HHS/United States ; R01 NS104219/NS/NINDS NIH HHS/United States ; R01 NS122908/NS/NINDS NIH HHS/United States ; R01 NS096746/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Proteome/metabolism ; Valosin Containing Protein/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Caenorhabditis elegans/metabolism ; Motor Neurons/metabolism ; Homeostasis ; Mutation ; }, abstract = {Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS) through gain-of-function effects, yet the mechanisms by which misfolded mutant SOD1 (mutSOD1) protein impairs human motor neurons (MNs) remain unclear. Here, we use induced-pluripotent-stem-cell-derived MNs coupled to metabolic stable isotope labeling and mass spectrometry to investigate proteome-wide degradation dynamics. We find several proteins, including the ALS-causal valosin-containing protein (VCP), which predominantly acts in proteasome degradation and autophagy, that degrade slower in mutSOD1 relative to isogenic control MNs. The interactome of VCP is altered in mutSOD1 MNs in vitro, while VCP selectively accumulates in the affected motor cortex of ALS-SOD1 patients. Overexpression of VCP rescues mutSOD1 toxicity in MNs in vitro and in a C. elegans model in vivo, in part due to its ability to modulate the degradation of insoluble mutSOD1. Our results demonstrate that VCP contributes to mutSOD1-dependent degeneration, link two distinct ALS-causal genes, and highlight selective protein degradation impairment in ALS pathophysiology.}, } @article {pmid37776476, year = {2023}, author = {Ocharán-Mercado, A and Loaeza-Loaeza, J and Castro-Coronel, Y and Acosta-Saavedra, LC and Hernández-Kelly, LC and Hernández-Sotelo, D and Ortega, A}, title = {RNA-Binding Proteins: A Role in Neurotoxicity?.}, journal = {Neurotoxicity research}, volume = {41}, number = {6}, pages = {681-697}, pmid = {37776476}, issn = {1476-3524}, mesh = {Humans ; Aged ; *Neurodegenerative Diseases/metabolism ; RNA-Binding Proteins/metabolism ; Neurons/metabolism ; *Frontotemporal Dementia ; *Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Despite sustained efforts to treat neurodegenerative diseases, little is known at the molecular level to understand and generate novel therapeutic approaches for these malignancies. Therefore, it is not surprising that neurogenerative diseases are among the leading causes of death in the aged population. Neurons require sophisticated cellular mechanisms to maintain proper protein homeostasis. These cells are generally sensitive to loss of gene expression control at the post-transcriptional level. Post-translational control responds to signals that can arise from intracellular processes or environmental factors that can be regulated through RNA-binding proteins. These proteins recognize RNA through one or more RNA-binding domains and form ribonucleoproteins that are critically involved in the regulation of post-transcriptional processes from splicing to the regulation of association of the translation machinery allowing a relatively rapid and precise modulation of the transcriptome. Neurotoxicity is the result of the biological, chemical, or physical interaction of agents with an adverse effect on the structure and function of the central nervous system. The disruption of the proper levels or function of RBPs in neurons and glial cells triggers neurotoxic events that are linked to neurodegenerative diseases such as spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), fragile X syndrome (FXS), and frontotemporal dementia (FTD) among many others. The connection between RBPs and neurodegenerative diseases opens a new landscape for potentially novel therapeutic targets for the intervention of these neurodegenerative pathologies. In this contribution, a summary of the recent findings of the molecular mechanisms involved in the plausible role of RBPs in RNA processing in neurodegenerative disease is discussed.}, } @article {pmid37774774, year = {2023}, author = {Gschwendtberger, T and Thau-Habermann, N and von der Ohe, J and Luo, T and Hass, R and Petri, S}, title = {Protective effects of EVs/exosomes derived from permanently growing human MSC on primary murine ALS motor neurons.}, journal = {Neuroscience letters}, volume = {816}, number = {}, pages = {137493}, doi = {10.1016/j.neulet.2023.137493}, pmid = {37774774}, issn = {1872-7972}, mesh = {Mice ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Exosomes/metabolism ; Antioxidants/pharmacology ; Motor Neurons/metabolism ; *Mesenchymal Stem Cells/metabolism ; }, abstract = {In recent years, the neuroprotective potential of mesenchymal stroma-/stem-like cells (MSC) as well as of MSC-derived extracellular vesicles (EVs) like exosomes has been intensively explored. This included preclinical evaluation regarding treatment of neurodegenerative disorders such as the fatal motor neuron disease amyotrophic Lateral Sclerosis (ALS). Several studies have reported that MSC-derived exosomes can stimulate tissue regeneration and reduce inflammation. MSC release EVs and trophic factors and thereby modify cell-to-cell communication. These cell-free products may protect degenerating motor neurons (MNs) and represent a potential therapeutic approach for ALS. In the present study we investigated the effects of exosomes derived from a permanently growing MSC line on both, wild type and ALS (SOD1[G93A] transgenic) primary motor neurons. Following application in a normal and stressed environment we could demonstrate beneficial effects of MSC exosomes on neurite growth and morphology indicating the potential for further preclinical evaluation and clinical therapeutic development. Investigation of gene expression profiles detected transcripts of several antioxidant and anti-inflammatory genes in MSC exosomes. Characterization of their microRNA (miRNA) content revealed miRNAs capable of regulating antioxidant and anti-apoptotic pathways.}, } @article {pmid37774738, year = {2023}, author = {Stipancic, KL and Golzy, M and Zhao, Y and Pinkerton, L and Rohl, A and Kuruvilla-Dugdale, M}, title = {Improving Perceptual Speech Ratings: The Effects of Auditory Training on Judgments of Dysarthric Speech.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {66}, number = {11}, pages = {4236-4258}, pmid = {37774738}, issn = {1558-9102}, support = {R15 DC016383/DC/NIDCD NIH HHS/United States ; R21 DC019952/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; Dysarthria/therapy ; *Speech Perception ; Judgment ; Reproducibility of Results ; *Amyotrophic Lateral Sclerosis ; Speech Intelligibility ; Speech Production Measurement ; *Parkinson Disease/complications ; }, abstract = {PURPOSE: Auditory training has been shown to reduce rater variability in perceptual voice assessment. Because rater variability is also a central issue in the auditory-perceptual assessment of dysarthria, this study sought to determine if training produces a meaningful change in rater reliability, criterion validity, and scaling magnitude of four features: overall speech impairment, articulatory imprecision, monotony, and slow rate.

METHOD: Forty-four nonexperts randomized to training and nontraining listener groups completed a pretest and posttest. Only the former group underwent auditory training between pre- and posttests. For both testing and training, listeners rated samples from speakers with amyotrophic lateral sclerosis (ALS), speakers with Parkinson's disease (PD), and neurologically healthy control speakers using separate visual analog scales (VASs) for each of the four features. Intraclass correlation coefficients were used to compare inter- and intrarater reliability between pre- and posttest for both listener groups. For criterion validity, severity ratings from the two nonexpert listener groups were compared to those of two experienced listeners for all four features. To determine changes in scaling magnitude, raw VAS scores for each feature were compared from pre- to posttest within the two nonexpert listener groups. Scaling changes were also compared between the two listener groups for the pre- and posttest conditions.

RESULTS AND CONCLUSIONS: In the training group, a meaningful improvement in interrater reliability was observed for some features in all three speaker groups, but not in the nontraining group. In contrast, for intrarater reliability, in the nontraining group, a meaningful improvement was observed for many features in all three speaker groups, but only for PD monotony and slow rate in the training group. All ratings from the nonexpert listeners were valid except for monotony. Raw VAS scores did not meaningfully change from pre- to posttest for any of the features, but there was a trend toward lower scores posttraining, mainly for the ALS samples. Modifications to the auditory training paradigm to further improve reliability and validity, along with future goals for optimizing training, are discussed.}, } @article {pmid37773576, year = {2024}, author = {Aiello, EN and Solca, F and Torre, S and Gentile, F and Scheveger, F and Olivero, M and Colombo, E and Maranzano, A and Manzoni, M and Morelli, C and Doretti, A and Verde, F and Silani, V and Ticozzi, N and Poletti, B}, title = {Frontotemporal-spectrum disorders and functional independence in non-demented ALS patients.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {3}, pages = {1087-1095}, pmid = {37773576}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Activities of Daily Living ; Functional Status ; Neuropsychological Tests ; *Frontotemporal Dementia ; Cognition ; }, abstract = {BACKGROUND: The present study aimed at determining whether, net of motor confounders, neuropsychological features affect functional independence (FI) in activities of daily living (ADLs) in non-demented amyotrophic lateral sclerosis (ALS) patients.

METHODS: N = 88 ALS patients without frontotemporal dementia were assessed for FI-Katz's Basic ADL Scale (BADL) and Lawton-Brody's Instrumental ADL Scale (IADL)-, cognition-Edinburgh Cognitive and Behavioural ALS Screen (ECAS)-and behaviour-Beaumont Behavioural Inventory and Dimensional Apathy Scale. The association between cognitive and behavioural measures and BADL/IADL scores was assessed by covarying for demographics, anxiety and depression levels, disease duration and motor confounders-i.e. ALS Functional Rating Scale-Revised (ALSFRS-R) scores, progression rate and both King's and Milano-Torino stages.

RESULTS: Higher scores on the ECAS-Language were associated with higher IADL scores (p = 0.005), whilst higher apathetic features-as measured by the Dimensional Apathy Scale (DAS)-were inversely related to the BADL (p = 0.003). Whilst IADL scores were related to all ECAS-Language tasks, the DAS-Initiation was the only subscale associated with BADL scores. Patients with abnormal ECAS-Language (p = 0.023) and DAS (p = 0.008) scores were more functionally dependent than those without.

DISCUSSION: Among non-motor features, language changes and apathetic features detrimentally affect FI in non-demented ALS patients.}, } @article {pmid37773166, year = {2023}, author = {Aguilar-Vázquez, CA and Gallardo-González, LI and Raymundo-Carrillo, AD and Reyes-Sosa, LC and Martínez-Romo, ES}, title = {[Parkinson-dementia and amyotrophic lateral sclerosis association (complex of Guam). Diagnostic challenge, Mexican patient].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {61}, number = {5}, pages = {677-684}, pmid = {37773166}, issn = {2448-5667}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; *Parkinson Disease/complications/pathology ; *Dementia/complications/epidemiology/pathology ; *Neurodegenerative Diseases ; Guam/epidemiology ; *Parkinsonian Disorders/etiology/complications ; }, abstract = {BACKGROUND: The Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Complex (ALS-PDC) was first described in the islands of Guam. This pathology presented its peak incidence in the 1950s. Due to the rarity of the association, we report a clinical case with this complex. The objective was to describe the nosological and pathogenic implications of these neurodegenerative disorder, since they are not frequent to find in our population.

CLINICAL CASE: We present a case of Latinoamerican origin who initially manifested systemic symptoms of more than 6 years of evolution, with subsequent cognitive alterations. Later, patient began with gait disturbances and motor symptoms suggestive of parkinsonism with atypical data and data of motor neurone disease (MND). More studies were carried out and confirmed findings compatible with upper and lower motor neuron involvement. A mutation in the POLG gene was observed, related to mitochondrial depletion syndrome.

CONCLUSION: Despite the knowledge of this association, it is an entity whose clinical diagnosis could be very difficult to achieve. In addition, molecular mechanisms have not been fully identified, the most common genes related to Parkinsonism and ALS have been excluded, and even attempts to locate the locus were made, without achieving accurate results. Unfortunately, being a neurodegenerative disease, the prognosis is fatal, with no disease-modifying treatment.}, } @article {pmid37772684, year = {2023}, author = {Ali, Z and Godoy-Corchuelo, JM and Martins-Bach, AB and Garcia-Toledo, I and Fernández-Beltrán, LC and Nair, RR and Spring, S and Nieman, BJ and Jimenez-Coca, I and Bains, RS and Forrest, H and Lerch, JP and Miller, KL and Fisher, EMC and Cunningham, TJ and Corrochano, S}, title = {Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations.}, journal = {Disease models & mechanisms}, volume = {16}, number = {10}, pages = {}, pmid = {37772684}, issn = {1754-8411}, support = {FISHER/APR14/874-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0801110/MRC_/Medical Research Council/United Kingdom ; MR/L021056/1/MRC_/Medical Research Council/United Kingdom ; MC_EX_MR/N501931/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/pathology ; Nuclear Localization Signals/genetics/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; Mutation/genetics ; Neurons/metabolism ; }, abstract = {Variants in the ubiquitously expressed DNA/RNA-binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). Most FUS mutation studies have focused on motor neuron degeneration; little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity. RNA sequencing of multiple organs aimed to identify pathways altered by the mutant protein in the systemic transcriptome, including metabolic tissues, given the link between ALS-frontotemporal dementia and altered metabolism. Few genes were commonly altered across all tissues, and most genes and pathways affected were generally tissue specific. Phenotypic assessment of mice revealed systemic metabolic alterations related to the pathway changes identified. Magnetic resonance imaging brain scans and histological characterisation revealed that homozygous FUSDelta14 brains were smaller than heterozygous and wild-type brains and displayed significant morphological alterations, including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with early cognitive impairment and fatal seizures. These findings show that the disease aetiology of FUS variants can include both neurodevelopmental and systemic alterations.}, } @article {pmid37770379, year = {2023}, author = {Souza, INO and Roychaudhuri, R and de Belleroche, J and Mothet, JP}, title = {d-Amino acids: new clinical pathways for brain diseases.}, journal = {Trends in molecular medicine}, volume = {29}, number = {12}, pages = {1014-1028}, doi = {10.1016/j.molmed.2023.09.001}, pmid = {37770379}, issn = {1471-499X}, mesh = {Humans ; *Amino Acids/metabolism ; Critical Pathways ; Central Nervous System/metabolism ; Brain/metabolism ; *Alzheimer Disease/metabolism ; }, abstract = {Free d-amino acids (d-AAs) are emerging as a novel and important class of signaling molecules in many organs, including the brain and endocrine systems. There has been considerable progress in our understanding of the fundamental roles of these atypical messengers, with increasingly recognized implications in a wide range of neuropathologies, including schizophrenia (SCZ), epilepsy, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), substance abuse, and chronic pain, among others. Research has enabled the discovery that d-serine, d-aspartate and more recently d-cysteine are essential for the healthy development and function of the central nervous system (CNS). We discuss recent progress that has profoundly transformed our vision of numerous physiological processes but has also shown how d-AAs are now offering therapeutic promise in clinical settings for several human diseases.}, } @article {pmid37770137, year = {2023}, author = {Bivehed, E and Hellman, B and Fan, Y and Haglöf, J and Buratovic, S}, title = {DNA integrity under alkaline conditions: An investigation of factors affecting the comet assay.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {891}, number = {}, pages = {503680}, doi = {10.1016/j.mrgentox.2023.503680}, pmid = {37770137}, issn = {1879-3592}, mesh = {Humans ; *Comet Assay/methods ; DNA ; DNA Damage ; DNA Repair ; Hydrogen-Ion Concentration ; }, abstract = {The effect of pH on DNA integrity was assessed using a three-step approach. The comet assay was used on a whole genome level, with three different protocols: neutral (no alkaline unwinding), flash (pH 12.5 with 2.5 min unwinding), and the conventional alkaline protocol (pH>13 with 40 min unwinding). Real-time quantitative PCR (RT-qPCR) was then used to study the isolated DNA, revealing that gene amplification decreased with increasing pH, indicating DNA degradation. Specially designed molecular beacons were used to examine DNA at the molecular level, with or without alkali-labile site (ALS) insertions. At pH 12.5, fluorescence in the hairpins with ALS started to increase after 30 min, while at pH> 13, this increase was already observed after 5 min, indicating a significant increase in DNA strand breaks. Liquid chromatography analysis was also used, demonstrating that the hairpins remained intact up to pH 10, even after 1 h exposure, whereas, at pH 12.5, partial conversion into strand breaks occurred after 30 min. At pH> 13, the hairpins were almost completely degraded after 30 min. The flash protocol effectively detects DNA single- and double-strand breaks and identified these damages after 2.5 min of alkaline treatment at pH 12.5. When the hairpins were exposed to pH 12.5 for 60 min, ALS were converted to strand breaks, demonstrating the sensitivity of this approach to detect changes in DNA structure. These findings indicate that pH poses a substantial risk to DNA integrity, leading to significantly higher background levels of DNA damage compared to conditions closer to neutrality. Our study demonstrates the importance of understanding the influence of pH on DNA stability and provides insights into risks associated with alkaline environments, especially at pH> 13.}, } @article {pmid37769591, year = {2023}, author = {Pazian Martins, M and González-Salazar, C and de Lima, FD and Bernardes Leoni, T and R M Martinez, A and Nunes Gonçalves, JP and Nucci, A and Cavalcante França, M}, title = {Autonomic function in sporadic and familial ALS type 8.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {155}, number = {}, pages = {68-74}, doi = {10.1016/j.clinph.2023.08.006}, pmid = {37769591}, issn = {1872-8952}, abstract = {OBJECTIVE: To characterize and compare autonomic function in patients with sporadic (sALS) and familial ALS type 8 (fALS8).

METHODS: We selected 11 patients with sALS (7 men), 14 with fALS8 (8 men) and 26 controls (15 men). All groups were gender and age-matched. For each subject, Scale for Outcomes in Parkinson's Disease for Autonomic Symptoms (SCOPA-AUT) was applied and data from heart rate variability, Quantitative Sudomotor Axon Reflex Test (QSART) and skin sympathetic response (SSR) were collected. These data were compared across groups using nonparametric tests. P-values < 0.05 were considered significant.

RESULTS: SCOPA-AUT revealed predominant clinical complaints in thermoregulatory, pupillomotor and sexual domains in fALS8 relative to sALS as well as controls. Neurophysiological tests demonstrated significant differences in Valsalva ratio, Expiratory:Inspiratory index and RR minimum values in both ALS groups relative to controls. Sudomotor dysfunction was also observed in sALS and fALS8 groups, as shown by reduced medial forearm and foot QSART volumes and absence of SSR in lower limbs.

CONCLUSIONS: Dysautonomia - cardiac and sudomotor - is part of the phenotype in sALS and fALS8. The profile of autonomic symptoms, however, is different in each group.

SIGNIFICANCE: Patients with fALS8 and sALS have autonomic dysfunction involving both sympathetic and parasympathetic divisions.}, } @article {pmid37768998, year = {2023}, author = {Abraham, A and Fainmesser, Y and Drory, VE and Bril, V}, title = {Quantitative sonographic assessment of muscle thickness and fasciculations distribution is a sensitive tool for neuromuscular disorders.}, journal = {PloS one}, volume = {18}, number = {9}, pages = {e0292123}, pmid = {37768998}, issn = {1932-6203}, mesh = {Humans ; Fasciculation/diagnostic imaging ; Muscle, Skeletal/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Electromyography ; *Neuromuscular Diseases/diagnostic imaging ; *Muscular Diseases ; Ultrasonography ; *Polyneuropathies/diagnostic imaging ; }, abstract = {INTRODUCTION: Loss of muscle thickness can be demonstrated in a wide spectrum of neuromuscular disorders, while fasciculations are more frequent in amyotrophic lateral sclerosis (ALS). In the current study, we aimed to determine the sensitivity and specificity of quantitative sonographic assessment of muscle thickness and the presence of fasciculations for diagnosing various neuromuscular disorders.

METHODS: The thickness and the presence of fasciculations in eight muscles were determined by sonography in patients with myopathy (22), polyneuropathy (36), ALS (91), and spinal muscular atrophy (SMA) (31) and compared to normative values determined in 65 heathy control subjects.

RESULTS: Reduced muscle thickness in at least one relaxed muscle showed 92-100% sensitivity for diagnosing a neuromuscular disease, with a specificity of 85% for differentiating patients from heathy controls (AUC = 0.90). Subtracting distal from proximal muscle thickness may differentiate between myopathy and polyneuropathy. Fasciculations in ≥1 proximal muscle showed good diagnostic accuracy (AUC = 0.87) for diagnosing ALS.

DISCUSSION: Sonographic assessment of muscle thickness is a sensitive tool for diagnosing a wide spectrum of neuromuscular diseases, and may facilitate diagnosis even in patients with normal strength on neurological examination, while the presence of fasciculations in proximal muscles may facilitate ALS diagnosis.}, } @article {pmid37768719, year = {2023}, author = {Aksoy, ME and Özkan, AE and Kitapcioglu, D and Usseli, T}, title = {Comparing the Outcomes of Virtual Reality-Based Serious Gaming and Lecture-Based Training for Advanced Life Support Training: Randomized Controlled Trial.}, journal = {JMIR serious games}, volume = {11}, number = {}, pages = {e46964}, pmid = {37768719}, issn = {2291-9279}, abstract = {BACKGROUND: Simulation-based Advanced Cardiac Life Support (ACLS) or Advanced Life Support (ALS) training for health care professionals is important worldwide for saving lives. Virtual reality (VR)-based serious gaming can be an alternative modality to be used as a part of simulation-based ALS training.

OBJECTIVE: The aim of this study is to investigate whether a VR-based ALS serious game module can replace classroom-based ALS lectures, the latter being part of existing conventional ALS training protocols in addition to skills training.

METHODS: Participants were students from Acibadem Mehmet Ali Aydinlar University's Vocational School for Anesthesiology (N=29) randomly divided into 2 groups with 15 (conventional training group) and 14 (VR-based training group) participants each. Participants in the conventional training group had to complete the pretest consisting of multiple-choice questions at the beginning of the study. Afterward, they took part in an interactive classroom-based ALS lecture. The next step involved skills training with task trainers to teach them compression skills. Following this, the conventional training group was divided into Code Blue teams, each consisting of 5 participants for the simulation session. Two independent instructors evaluated video recordings in terms of technical and nontechnical skills. The score acquired from the manikin-based simulation session was considered the main performance indicator in this study to measure the learning outcome. A similar workflow was used for the VR-based training group, but this group was trained with the VR-based ALS serious game module instead of the theoretical lecture. The final stage of the study involved completing the posttest consisting of multiple-choice questions. A preference survey was conducted among the study participants. Mann-Whitney U and Wilcoxon signed-rank tests were used to analyze the 2 groups' performances in this study.

RESULTS: The improvement in posttest results compared with pretest results was significant in the conventional training group (P=.002). Hands-on technical scores of the conventional training group were higher than those of the VR-based training group during manikin-based simulation, but total scores, including those for technical and crisis resource management skills, acquired from the manikin-based simulation session did not reveal any significant difference between the 2 groups. The results of the VR preference survey revealed that the majority of the participants prefer VR-based serious game-based training instead of classroom lectures.

CONCLUSIONS: Although hands-on technical scores of the conventional training group during the manikin-based simulation session were higher than those of the VR-based training group, both groups' total performance scores, including those for technical and crisis resource management skills, did not differ significantly. The preference survey reveals that the majority of the participants would prefer a VR-based ALS serious gaming module instead of lecture-based training. Further studies are required to reveal the learning outcome of VR-based ALS serious gaming.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05798910; https://clinicaltrials.gov/study/NCT05798910.}, } @article {pmid37768183, year = {2023}, author = {Trajano, GS and Orssatto, LBR and McCombe, PA and Rivlin, W and Tang, L and Henderson, RD}, title = {Longitudinal changes in intrinsic motoneuron excitability in amyotrophic lateral sclerosis are dependent on disease progression.}, journal = {The Journal of physiology}, volume = {601}, number = {21}, pages = {4723-4735}, doi = {10.1113/JP285181}, pmid = {37768183}, issn = {1469-7793}, mesh = {Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis ; Cross-Sectional Studies ; Superoxide Dismutase-1/genetics ; Motor Neurons/physiology ; Muscle, Skeletal ; Muscle Weakness ; Paresis ; Disease Progression ; }, abstract = {Increased amplitude of persistent inward currents (PICs) is observed in pre-symptomatic genetically modified SOD1 mice models of amyotrophic lateral sclerosis (ALS). However, at the symptomatic stage this reverses and there is a large reduction in PIC amplitude. It remains unclear whether these changes in PICs can be observed in humans, with cross-sectional studies in humans reporting contradictory findings. In people with ALS, we estimated the PIC contribution to self-sustained firing of motoneurons, using the paired-motor unit analysis to calculate the Δfrequency (ΔF), to compare the weaker and stronger muscles during the course of disease. We hypothesised that, with disease progression, ΔFs would relatively increase in the stronger muscles; and decline in the weaker muscles. Forty-three individuals with ALS were assessed in two occasions on average 17 weeks apart. Tibialis anterior high-density electromyograms were recorded during dorsiflexion (40% of maximal capacity) ramped contractions, followed by clinical tests. ∆F increased from 3.14 (2.57, 3.71) peaks per second (pps) to 3.55 (2.94, 4.17) pps on the stronger muscles (0.41 (0.041, 0.781) pps, standardised difference (d) = 0.287 (0.023, 0.552), P = 0.030). ∆F reduced from 3.38 (95% CI 2.92, 3.84) pps to 2.88 (2.40, 3.36) pps on the weaker muscles (-0.50 (-0.80, -0.21) pps, d = 0.353 (0.138, 0.567), P = 0.001). The ALSFRS-R score reduced 3.9 (2.3, 5.5) points. These data indicate that the contribution of PICs to motoneuron self-sustained firing increases over time in early stages of the disease when there is little weakness before decreasing as the disease progresses and muscle weakness exacerbates, in alignment with the findings from studies using SOD1 mice. KEY POINTS: Research on mouse model of amyotrophic lateral sclerosis (ALS) suggests that the amplitude of persistent inward currents (PICs) is increased in early stages before decreasing as the disease progresses. Cross-sectional studies in humans have reported contradictory findings with both higher and lower PIC contributions to motoneuron self-sustained firing. In this longitudinal (∼17 weeks) study we tracked changes in PIC contribution to motoneuron self-sustained firing, using the ΔF calculation (i.e. onset-offset hysteresis of motor unit pairs), in tibialis anterior muscles with normal strength and with clinical signs of weakness in people with ALS. ΔFs decreased over time in muscles with clinical signs of weakness. The PIC contribution to motoneuron self-sustained firing increases before the onset of muscle weakness, and subsequently decreases when muscle weakness progresses.}, } @article {pmid37767949, year = {2024}, author = {Liang, W and Liu, Y and Zhao, Y and Chen, Y and Yin, Y and Zhai, L and Li, Z and Gong, Z and Zhang, J and Zhang, M}, title = {Quantitative MRI Analysis of Brachial Plexus and Limb-Girdle Muscles in Upper Extremity Onset Amyotrophic Lateral Sclerosis.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {60}, number = {1}, pages = {291-301}, doi = {10.1002/jmri.29027}, pmid = {37767949}, issn = {1522-2586}, support = {82271478//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Female ; Male ; Middle Aged ; *Magnetic Resonance Imaging/methods ; *Brachial Plexus/diagnostic imaging ; *Upper Extremity/diagnostic imaging ; Retrospective Studies ; Aged ; Adult ; Muscle, Skeletal/diagnostic imaging ; }, abstract = {BACKGROUND: Recent evidence highlights the potential of axonal degeneration as a biomarker for amyotrophic lateral sclerosis (ALS) detection. However, the diagnostic potential of peripheral nerve axon changes in ALS remains unclear.

PURPOSE: To evaluate the diagnostic performance of quantitative MRI of the brachial plexus and limb-girdle muscles (LGMs) in patients with upper extremity onset of ALS.

STUDY TYPE: Retrospective.

POPULATION: 47 patients with upper extremity onset of ALS and 20 healthy volunteers.

FIELD STRENGTH/SEQUENCE: 3-T, three-dimensional sampling perfection with application-optimized contrasts using different flip angle evolutions with short-tau inversion recovery sequences, T2-weighted turbo spin-echo Dixon sequence.

ASSESSMENT: The cross-sectional area (CSA) and nerve-muscle T2 signal intensity ratio (nT2) of the bilateral brachial plexus as well as the CSA and fat fraction (FF) of the bilateral LGMs were assessed by two radiologists. Disease severity and clinical stage of ALS patients were assessed by two neurologists.

STATISTICAL TESTS: Student's t-test, Wilcoxon rank-sum test, binary logistic regression, interclass correlation coefficient, receiver operating characteristic analysis, and correlation analysis were performed for MRI quantitative metrics and clinical variables. Significance level: P < 0.05.

RESULTS: In the affected limbs of patients with ALS, the CSA of the brachial plexus roots, trunks, and cords and the nT2 values of the brachial plexus trunks were significantly smaller than in the healthy controls. In the LGMs, the affected limbs of ALS showed significantly smaller CSA and higher FF than controls. The model containing parameters such as brachial plexus trunk CSA, subscapularis CSA, infraspinatus CSA, and subscapularis FF had excellent diagnostic efficacy for ALS. Additionally, increased subscapularis FF and supraspinatus FF were correlated with disease severity, and subscapularis CSA was negatively correlated with the clinical stage.

DATA CONCLUSION: Brachial plexus thinning, LGM atrophy, and fatty infiltration might serve as MRI-derived biomarkers for ALS with upper extremity onset.

LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.}, } @article {pmid37767237, year = {2023}, author = {Trofimov, A and Pavlov, D and Goswami, A and Gorlova, A and Chaprov, K and Umriukhin, A and Kalueff, A and Deykin, A and Lesch, KP and Anthony, DC and Strekalova, T}, title = {Lipopolysaccharide triggers exacerbated microglial activation, excessive cytokine release and behavioural disturbances in mice with truncated Fused-in-Sarcoma Protein (FUS).}, journal = {Brain, behavior, & immunity - health}, volume = {33}, number = {}, pages = {100686}, pmid = {37767237}, issn = {2666-3546}, abstract = {CNS inflammation, including microglial activation, in response to peripheral infections are known to contribute to the pathology of both familial and sporadic neurodegenerative disease. The relationship between Fused-in-Sarcoma Protein (FUS)-mediated disease in the transgenic FUS[1-359] animals and the systemic inflammatory response have not been explored. Here, we investigated microglial activation, inflammatory gene expression and the behavioural responses to lipopolysaccharide-induced (LPS; 0.1 mg/kg) systemic inflammation in the FUS[1-359] transgenic mice. The pathology of these mice recapitulates the key features of mutant FUS-associated familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Here, pre-symptomatic 8-week-old mutant or wild type controls were challenged with LPS or with saline and sucrose intake, novel cage exploration, marble burying and swimming behaviours were analyzed. The level of pro-inflammatory gene expression was also determined, and microglial activation was evaluated. In chronic experiments, to discover whether the LPS challenge would affect the onset of ALS-like paralysis, animals were evaluated for clinical signs from 5 to 7 weeks post-injection. Compared to controls, acutely challenged FUS[1-359]-tg mice exhibited decreased sucrose intake and increased floating behaviours. The FUS[1-359]-tg mice exhibited an increase in immunoreactivity for Iba1-positive cells in the prefrontal cortex and ventral horn of the spinal cord, which was accompanied by increased expression of interleukin-1β, tumour necrosis factor, cyclooxygenase-(COX)-1 and COX-2. However, the single LPS challenge did not alter the time to development of paralysis in the FUS[1-359]-tg mice. Thus, while the acute inflammatory response was enhanced in the FUS mutant animals, it did not have a lasting impact on disease progression.}, } @article {pmid37767023, year = {2023}, author = {Ayoubi, R and Alshafie, W and Southern, K and McPherson, PS and Laflamme, C and , }, title = {The identification of high-performing antibodies for Coiled-coil-helix-coiled-coil-helix domain containing protein 10 (CHCHD10) for use in Western Blot, immunoprecipitation and immunofluorescence.}, journal = {F1000Research}, volume = {12}, number = {}, pages = {403}, pmid = {37767023}, issn = {2046-1402}, mesh = {Humans ; *Fluorescent Antibody Technique/methods ; *Immunoprecipitation/methods ; *Mitochondrial Proteins/immunology ; *Blotting, Western ; *Antibodies/immunology ; HEK293 Cells ; }, abstract = {CHCHD10 is a mitochondrial protein, implicated in the regulation of mitochondrial morphology and cristae structure, as well as the maintenance of mitochondrial DNA integrity. Recently discovered to be associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in its mutant form, the scientific community would benefit from the availability of validated anti-CHCHD10 antibodies. In this study, we characterized four CHCHD10 commercial antibodies for Western Blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. As this study highlights high-performing antibodies for CHCHD10, we encourage readers to use it as a guide to select the most appropriate antibody for their specific needs.}, } @article {pmid37766843, year = {2023}, author = {Olukoya, AO and Stires, H and Bahnassy, S and Persaud, S and Guerra, Y and Ranjit, S and Ma, S and Cruz, MI and Benitez, C and Rozeboom, AM and Ceuleers, H and Berry, DL and Jacobsen, BM and Raj, GV and Riggins, RB}, title = {Riluzole Suppresses Growth and Enhances Response to Endocrine Therapy in ER+ Breast Cancer.}, journal = {Journal of the Endocrine Society}, volume = {7}, number = {10}, pages = {bvad117}, pmid = {37766843}, issn = {2472-1972}, support = {T32 CA009686/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a significant clinical problem. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis. A benzothiazole-based glutamate release inhibitor with several context-dependent mechanism(s) of action, riluzole has shown antitumor activity in multiple malignancies, including melanoma, glioblastoma, and breast cancer. We previously reported that the acquisition of tamoxifen resistance in a cellular model of invasive lobular breast cancer is accompanied by the upregulation of GRM mRNA expression and growth inhibition by riluzole.

METHODS: We tested the ability of riluzole to reduce cell growth, alone and in combination with endocrine therapy, in a diverse set of ER+ invasive ductal and lobular breast cancer-derived cell lines, primary breast tumor explant cultures, and the estrogen-independent, ESR1-mutated invasive lobular breast cancer patient-derived xenograft model HCI-013EI.

RESULTS: Single-agent riluzole suppressed the growth of ER+ invasive ductal and lobular breast cancer cell lines in vitro, inducing a histologic subtype-associated cell cycle arrest (G0-G1 for ductal, G2-M for lobular). Riluzole induced apoptosis and ferroptosis and reduced phosphorylation of multiple prosurvival signaling molecules, including Akt/mTOR, CREB, and Fak/Src family kinases. Riluzole, in combination with either fulvestrant or 4-hydroxytamoxifen, additively suppressed ER+ breast cancer cell growth in vitro. Single-agent riluzole significantly inhibited HCI-013EI patient-derived xenograft growth in vivo, and the combination of riluzole plus fulvestrant significantly reduced proliferation in ex vivo primary breast tumor explant cultures.

CONCLUSION: Riluzole may offer therapeutic benefits in diverse ER+ breast cancers, including lobular breast cancer.}, } @article {pmid37766430, year = {2023}, author = {Cheng, W and Huang, J and Fu, XQ and Tian, WY and Zeng, PM and Li, Y and Luo, ZG}, title = {Intrathecal delivery of AAV-NDNF ameliorates disease progression of ALS mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {31}, number = {11}, pages = {3277-3289}, pmid = {37766430}, issn = {1525-0024}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Dependovirus/genetics ; Disease Models, Animal ; Disease Progression ; Mice, Transgenic ; Motor Neurons/metabolism ; Nerve Growth Factors/metabolism ; *Neurodegenerative Diseases/metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a uniformly lethal neurodegenerative disease characterized by progressive deterioration of motor neurons and neuromuscular denervation. Adeno-associated virus (AAV)-mediated delivery of trophic factors is being considered as a potential disease-modifying therapeutic avenue. Here we show a marked effect of AAV-mediated over-expression of neuron-derived neurotrophic factor (NDNF) on SOD1[G93A] ALS model mice. First, we adopt AAV-PHP.eB capsid to enable widespread expression of target proteins in the brain and spinal cord when delivered intrathecally. Then we tested the effects of AAV-NDNF on SOD1[G93A] mice at different stages of disease. Interestingly, AAV-NDNF markedly improved motor performance and alleviated weight loss when delivered at early post-symptomatic stage. Injection in the middle post-symptomatic stages still improved the locomotion ability, although it did not alleviate the loss of body weight. Injection in the late stage also extended the life span of SOD1[G93A] mice. Furthermore, NDNF expression promoted the survival of spinal motoneurons, reduced abnormal protein aggregation, and preserved the innervated neuromuscular functions. We further analyzed the signaling pathways of NDNF expression and found that it activates cell survival and growth-associated mammalian target of rapamycin signaling pathway and downregulates apoptosis-related pathways. Thus, intrathecally AAV-NDNF delivery has provided a potential strategy for the treatment of ALS.}, } @article {pmid37766226, year = {2023}, author = {Ayers, JI and Xu, G and Lu, Q and Dillon, K and Fromholt, S and Borchelt, DR}, title = {Multiple Factors Influence the Incubation Period of ALS Prion-like Transmission in SOD1 Transgenic Mice.}, journal = {Viruses}, volume = {15}, number = {9}, pages = {}, pmid = {37766226}, issn = {1999-4915}, support = {R01 NS092788/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; Young Adult ; *Amyotrophic Lateral Sclerosis/genetics ; Mice, Transgenic ; Paralysis ; *Prions ; Superoxide Dismutase-1/genetics ; }, abstract = {Mutations in superoxide dismutase 1 (SOD1) that are associated with amyotrophic lateral sclerosis (ALS) cause its misfolding and aggregation. Prior studies have demonstrated that the misfolded conformation of ALS-SOD1 can template with naïve SOD1 "host proteins" to propagate, spread, and induce paralysis in SOD1 transgenic mice. These observations have advanced the argument that SOD1 is a host protein for an ALS conformer that is prion-like and experimentally transmissible. Here, we investigated the propagation of different isolates of G93A-SOD1 ALS conformers using a paradigm involving transmission to mice expressing human G85R-SOD1 fused to yellow fluorescent protein (G85R-SOD1:YFP). In these studies, we also utilized a newly developed line of mice in which the G85R-SOD1:YFP construct was flanked by loxp sites, allowing its temporal and spatial regulation. We used methods in which the G93A ALS conformers were injected into the sciatic nerve or hindlimb muscle of adult transgenic mice. We observed that the incubation period to paralysis varied significantly depending upon the source of inoculum containing misfolded G93A SOD1. Serial passage and selection produced stable isolates of G93A ALS conformers that exhibited a defined minimum incubation period of ~2.5 months when injected into the sciatic nerve of young adult mice. As expected, neuronal excision of the transgene in loxpG85R-SOD1:YFP mice blocked induction of paralysis by transmission of G93A ALS conformers. Our findings indicate that G93A ALS conformers capable of inducing disease require neuronal expression of a receptive host SOD1 protein for propagation, with a defined incubation period to paralysis.}, } @article {pmid37763163, year = {2023}, author = {Kortazar-Zubizarreta, I and Manero-Azua, A and Afonso-Agüera, J and Perez de Nanclares, G}, title = {C9ORF72 Gene GGGGCC Hexanucleotide Expansion: A High Clinical Variability from Amyotrophic Lateral Sclerosis to Frontotemporal Dementia.}, journal = {Journal of personalized medicine}, volume = {13}, number = {9}, pages = {}, pmid = {37763163}, issn = {2075-4426}, abstract = {The expanded GGGGCC hexanucleotide repeat (HRE) in the non-coding region of the C9ORF72 gene (C9ORF72-HRE) is the most common genetic cause of familial forms of amyotrophic lateral sclerosis (ALS), FTD, and concurrent ALS and FTD (ALS-FTD), in addition to contributing to the sporadic forms of these diseases. Both syndromes overlap not only genetically, but also sharing similar clinical and neuropathological findings, being considered as a spectrum. In this paper we describe the clinical-genetic findings in a Basque family with different manifestations within the spectrum, our difficulties in reaching the diagnosis, and a narrative review, carried out as a consequence, of the main features associated with C9ORF72-HRE. Family members underwent a detailed clinical assessment, neurological examination, and genetic analysis by repeat-primed PCR. We studied 10 relatives of a symptomatic carrier of the C9ORF72-HRE expansion. Two of them presented the expansion in the pathological range, one of them was symptomatic whereas the other one remained asymptomatic at 72 years. Given the great intrafamilial clinical variability of C9ORF72-HRE, the characterization of patients and family members with particular clinical and genetic subgroups within ALS and FTD becomes a bottleneck for medication development, in particular for genetically focused medicines for ALS and FTD.}, } @article {pmid37762807, year = {2023}, author = {Annunziata, A and Calabrese, C and Simioli, F and Coppola, A and Pierucci, P and Mariniello, DF and Fiorentino, G}, title = {Psychological Factors Influencing Adherence to NIV in Neuromuscular Patients Dependent on Non Invasive Mechanical Ventilation: Preliminary Results.}, journal = {Journal of clinical medicine}, volume = {12}, number = {18}, pages = {}, pmid = {37762807}, issn = {2077-0383}, abstract = {BACKGROUND: Non-invasive ventilation (NIV) is associated with improvement of both morbility and mortality in patients affected by neuromuscular diseases with chronic respiratory failure. Several studies have also shown that long-term NIV positively impacts the patient's quality of life and perception of disease status. Its effectiveness is likely related to the adherence to NIV. Several factors, patient- and not patient-related, may compromise adherence to NIV, such as physical, behavioral, familiar, and social issues. Few data are currently available on the role of psychological factors in influencing NIV adherence.

MATERIALS AND METHODS: In this pilot study, we evaluated the adherence to NIV in a group of 15 adult patients with neuromuscular diseases (Duchenne muscular dystrophy, myotonic dystrophy, and amyotrophic lateral sclerosis) in relation to their grade of depression assessed by the Beck Depression Inventory (BDI) questionnaire. Other data were collected, such as clinical features (age and sex), use of anxiolytic drugs, the presence of a family or professional caregiver, the quality of patient-physician relationship, the beginning of psychological support after BDI screening, and the family acceptance of NIV. NIV adherence was definied as the use of NIV for at least 4 h per night on 70% of nights in a month.

RESULTS: The overall rate of NIV adherence was 60%. Based on the BDI questionnaire, patients who were non-adherent to NIV had a higher rate of depression, mainly observed in the oldest patients. The acceptance of NIV by the family and positive physician-patient interaction seem to favor NIV adherence.

CONCLUSION: Depression can interfere with NIV adherence in patients with neuromuscolar diseases.}, } @article {pmid37762599, year = {2023}, author = {Taneva, SG and Todinova, S and Andreeva, T}, title = {Morphometric and Nanomechanical Screening of Peripheral Blood Cells with Atomic Force Microscopy for Label-Free Assessment of Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {18}, pages = {}, pmid = {37762599}, issn = {1422-0067}, support = {KP-06-H31/8//Bulgarian Science Fund/ ; funding programme Open Access Publishing//Baden-Württemberg Ministry of Science, Research and Culture/ ; }, mesh = {Humans ; *Parkinson Disease/diagnosis ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Alzheimer Disease/diagnosis ; Microscopy, Atomic Force ; Blood Cells ; }, abstract = {Neurodegenerative disorders (NDDs) are complex, multifactorial disorders with significant social and economic impact in today's society. NDDs are predicted to become the second-most common cause of death in the next few decades due to an increase in life expectancy but also to a lack of early diagnosis and mainly symptomatic treatment. Despite recent advances in diagnostic and therapeutic methods, there are yet no reliable biomarkers identifying the complex pathways contributing to these pathologies. The development of new approaches for early diagnosis and new therapies, together with the identification of non-invasive and more cost-effective diagnostic biomarkers, is one of the main trends in NDD biomedical research. Here we summarize data on peripheral biomarkers, biofluids (cerebrospinal fluid and blood plasma), and peripheral blood cells (platelets (PLTs) and red blood cells (RBCs)), reported so far for the three most common NDDs-Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). PLTs and RBCs, beyond their primary physiological functions, are increasingly recognized as valuable sources of biomarkers for NDDs. Special attention is given to the morphological and nanomechanical signatures of PLTs and RBCs as biophysical markers for the three pathologies. Modifications of the surface nanostructure and morphometric and nanomechanical signatures of PLTs and RBCs from patients with AD, PD, and ALS have been revealed by atomic force microscopy (AFM). AFM is currently experiencing rapid and widespread adoption in biomedicine and clinical medicine, in particular for early diagnostics of various medical conditions. AFM is a unique instrument without an analog, allowing the generation of three-dimensional cell images with extremely high spatial resolution at near-atomic scale, which are complemented by insights into the mechanical properties of cells and subcellular structures. Data demonstrate that AFM can distinguish between the three pathologies and the normal, healthy state. The specific PLT and RBC signatures can serve as biomarkers in combination with the currently used diagnostic tools. We highlight the strong correlation of the morphological and nanomechanical signatures between RBCs and PLTs in PD, ALS, and AD.}, } @article {pmid37762278, year = {2023}, author = {Mastrangelo, A and Vacchiano, V and Zenesini, C and Ruggeri, E and Baiardi, S and Cherici, A and Avoni, P and Polischi, B and Santoro, F and Capellari, S and Liguori, R and Parchi, P}, title = {Amyloid-Beta Co-Pathology Is a Major Determinant of the Elevated Plasma GFAP Values in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {18}, pages = {}, pmid = {37762278}, issn = {1422-0067}, support = {Ricerca Corrente//Ministero della Salute/ ; PE0000006//#NextGenerationEU/ ; }, abstract = {Recent studies reported increased plasma glial acidic fibrillary protein (GFAP) levels in amyotrophic lateral sclerosis (ALS) patients compared to controls. We expanded these findings in a larger cohort, including 156 ALS patients and 48 controls, and investigated the associations of plasma GFAP with clinical variables and other biofluid biomarkers. Plasma GFAP and Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers were assessed by the single molecule array and the Lumipulse platforms, respectively. In ALS patients, plasma GFAP was higher than in controls (p < 0.001) and associated with measures of cognitive decline. Twenty ALS patients (12.8%) showed a positive amyloid status (A+), of which nine also exhibited tau pathology (A+T+, namely ALS-AD). ALS-AD patients showed higher plasma GFAP than A- ALS participants (p < 0.001) and controls (p < 0.001), whereas the comparison between A- ALS and controls missed statistical significance (p = 0.07). Plasma GFAP distinguished ALS-AD subjects more accurately (area under the curve (AUC) 0.932 ± 0.027) than plasma p-tau181 (AUC 0.692 ± 0.058, p < 0.0001) and plasma neurofilament light chain protein (AUC, 0.548 ± 0.088, p < 0.0001). Cognitive measures differed between ALS-AD and other ALS patients. AD co-pathology deeply affects plasma GFAP values in ALS patients. Plasma GFAP is an accurate biomarker for identifying AD co-pathology in ALS, which can influence the cognitive phenotype.}, } @article {pmid37762112, year = {2023}, author = {Gimenez, J and Spalloni, A and Cappelli, S and Ciaiola, F and Orlando, V and Buratti, E and Longone, P}, title = {TDP-43 Epigenetic Facets and Their Neurodegenerative Implications.}, journal = {International journal of molecular sciences}, volume = {24}, number = {18}, pages = {}, pmid = {37762112}, issn = {1422-0067}, support = {PathensTDP//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; JPND2020-568-078//EU Joint Programme - Neurodegenerative Disease Research/ ; }, mesh = {Humans ; *Chromatin ; Cytoplasm ; *DNA-Binding Proteins/genetics ; Epigenesis, Genetic ; Epigenomics ; }, abstract = {Since its initial involvement in numerous neurodegenerative pathologies in 2006, either as a principal actor or as a cofactor, new pathologies implicating transactive response (TAR) DNA-binding protein 43 (TDP-43) are regularly emerging also beyond the neuronal system. This reflects the fact that TDP-43 functions are particularly complex and broad in a great variety of human cells. In neurodegenerative diseases, this protein is often pathologically delocalized to the cytoplasm, where it irreversibly aggregates and is subjected to various post-translational modifications such as phosphorylation, polyubiquitination, and cleavage. Until a few years ago, the research emphasis has been focused particularly on the impacts of this aggregation and/or on its widely described role in complex RNA splicing, whether related to loss- or gain-of-function mechanisms. Interestingly, recent studies have strengthened the knowledge of TDP-43 activity at the chromatin level and its implication in the regulation of DNA transcription and stability. These discoveries have highlighted new features regarding its own transcriptional regulation and suggested additional mechanistic and disease models for the effects of TPD-43. In this review, we aim to give a comprehensive view of the potential epigenetic (de)regulations driven by (and driving) this multitask DNA/RNA-binding protein.}, } @article {pmid37762010, year = {2023}, author = {Tsuruta, K and Shidara, T and Miyagishi, H and Nango, H and Nakatani, Y and Suzuki, N and Amano, T and Suzuki, T and Kosuge, Y}, title = {Anti-Inflammatory Effects of Miyako Bidens pilosa in a Mouse Model of Amyotrophic Lateral Sclerosis and Lipopolysaccharide-Stimulated BV-2 Microglia.}, journal = {International journal of molecular sciences}, volume = {24}, number = {18}, pages = {}, pmid = {37762010}, issn = {1422-0067}, support = {22K06654 (Y.K.) and 21K06620 (H.M. and Y.K.)//JSPS KAKENHI/ ; 2211//a Nihon University Research Grant for 2022-2023/ ; 2019//Shorei Foundation for Science and Technology/ ; 2020//The Research Foundation for Pharmaceutical Sciences/ ; }, mesh = {Humans ; Animals ; Mice ; Microglia ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Bidens ; Interleukin-6 ; Lipopolysaccharides/toxicity ; Cytokines ; Disease Models, Animal ; }, abstract = {Neuroinflammation is a fundamental feature in the pathogenesis of amyotrophic lateral sclerosis (ALS) and arises from the activation of astrocytes and microglial cells. Previously, we reported that Miyako Bidens pilosa extract (MBP) inhibited microglial activation and prolonged the life span in a human ALS-linked mutant superoxide dismutase-1 (SOD1[G93A]) transgenic mouse model of ALS (G93A mice). Herein, we evaluated the effect of MBP on microglial activation in the spinal cord of G93A mice and lipopolysaccharide-stimulated BV-2 microglial cells. The administration of MBP inhibited the upregulation of the M1-microglia/macrophage marker (interferon-γ receptor (IFN-γR)) and pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6) in G93A mice. However, MBP did not affect the increase in the M2-microglia/macrophage marker (IL-13R) and anti-inflammatory cytokines (transforming growth factor (TGF)-β and IL-10) in G93A mice. BV-2 cell exposure to MBP resulted in a decrease in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) reduction activity and bromodeoxyuridine incorporation, without an increase in the number of ethidium homodimer-1-stained dead cells. Moreover, MBP suppressed the production of lipopolysaccharide-induced pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in BV-2 cells. These results suggest that the selective suppression of M1-related pro-inflammatory cytokines is involved in the therapeutic potential of MBP in ALS model mice.}, } @article {pmid37761265, year = {2023}, author = {Anghel, L and Ciubară, A and Nechita, A and Nechita, L and Manole, C and Baroiu, L and Ciubară, AB and Mușat, CL}, title = {Sleep Disorders Associated with Neurodegenerative Diseases.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {13}, number = {18}, pages = {}, pmid = {37761265}, issn = {2075-4418}, abstract = {Sleep disturbances are common in various neurological pathologies, including amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), hereditary ataxias, Huntington's disease (HD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). This article reviews the prevalence and characteristics of sleep disorders in these conditions, highlighting their impact on patients' quality of life and disease progression. Sleep-related breathing disorders, insomnia, restless legs syndrome (RLS), periodic limb movement syndrome (PLMS), and rapid eye movement sleep behavior disorder (RBD) are among the common sleep disturbances reported. Both pharmacological and non-pharmacological interventions play crucial roles in managing sleep disturbances and enhancing overall patient care.}, } @article {pmid37760880, year = {2023}, author = {Milella, G and Sciancalepore, D and Cavallaro, G and Piccirilli, G and Nanni, AG and Fraddosio, A and D'Errico, E and Paolicelli, D and Fiorella, ML and Simone, IL}, title = {Acoustic Voice Analysis as a Useful Tool to Discriminate Different ALS Phenotypes.}, journal = {Biomedicines}, volume = {11}, number = {9}, pages = {}, pmid = {37760880}, issn = {2227-9059}, abstract = {Approximately 80-96% of people with amyotrophic lateral sclerosis (ALS) become unable to speak during the disease progression. Assessing upper and lower motor neuron impairment in bulbar regions of ALS patients remains challenging, particularly in distinguishing spastic and flaccid dysarthria. This study aimed to evaluate acoustic voice parameters as useful biomarkers to discriminate ALS clinical phenotypes. Triangular vowel space area (tVSA), alternating motion rates (AMRs), and sequential motion rates (SMRs) were analyzed in 36 ALS patients and 20 sex/age-matched healthy controls (HCs). tVSA, AMR, and SMR values significantly differed between ALS and HCs, and between ALS with prevalent upper (pUMN) and lower motor neuron (pLMN) impairment. tVSA showed higher accuracy in discriminating pUMN from pLMN patients. AMR and SMR were significantly lower in patients with bulbar onset than those with spinal onset, both with and without bulbar symptoms. Furthermore, these values were also lower in patients with spinal onset associated with bulbar symptoms than in those with spinal onset alone. Additionally, AMR and SMR values correlated with the degree of dysphagia. Acoustic voice analysis may be considered a useful prognostic tool to differentiate spastic and flaccid dysarthria and to assess the degree of bulbar involvement in ALS.}, } @article {pmid37760050, year = {2023}, author = {Rubino, V and La Rosa, G and Pipicelli, L and Carriero, F and Damiano, S and Santillo, M and Terrazzano, G and Ruggiero, G and Mondola, P}, title = {Insights on the Multifaceted Roles of Wild-Type and Mutated Superoxide Dismutase 1 in Amyotrophic Lateral Sclerosis Pathogenesis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {9}, pages = {}, pmid = {37760050}, issn = {2076-3921}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neurodegenerative disease. Cell damage in ALS is the result of many different, largely unknown, pathogenetic mechanisms. Astrocytes and microglial cells play a critical role also for their ability to enhance a deranged inflammatory response. Excitotoxicity, due to excessive glutamate levels and increased intracellular Ca[2+] concentration, has also been proposed to play a key role in ALS pathogenesis/progression. Reactive Oxygen Species (ROS) behave as key second messengers for multiple receptor/ligand interactions. ROS-dependent regulatory networks are usually mediated by peroxides. Superoxide Dismutase 1 (SOD1) physiologically mediates intracellular peroxide generation. About 10% of ALS subjects show a familial disease associated with different gain-of-function SOD1 mutations. The occurrence of sporadic ALS, not clearly associated with SOD1 defects, has been also described. SOD1-dependent pathways have been involved in neuron functional network as well as in immune-response regulation. Both, neuron depolarization and antigen-dependent T-cell activation mediate SOD1 exocytosis, inducing increased interaction of the enzyme with a complex molecular network involved in the regulation of neuron functional activity and immune response. Here, alteration of SOD1-dependent pathways mediating increased intracellular Ca[2+] levels, altered mitochondria functions and defective inflammatory process regulation have been proposed to be relevant for ALS pathogenesis/progression.}, } @article {pmid37759926, year = {2023}, author = {Shimizu, T and Nakayama, Y and Bokuda, K and Takahashi, K}, title = {Sensory Gating during Voluntary Finger Movement in Amyotrophic Lateral Sclerosis with Sensory Cortex Hyperexcitability.}, journal = {Brain sciences}, volume = {13}, number = {9}, pages = {}, pmid = {37759926}, issn = {2076-3425}, support = {16H05583//Japan Society for the Promotion of Science/ ; 19H03939//Japan Society for the Promotion of Science/ ; 22H03398//Japan Society for the Promotion of Science/ ; }, abstract = {Cortical responses in somatosensory evoked potentials (SEP) are enhanced in patients with amyotrophic lateral sclerosis (ALS). This study investigated whether sensory gating is involved in the pathophysiology of sensory cortical hyperactivity in ALS patients. The median nerve SEP was recorded at rest and during voluntary finger movements in 14 ALS patients and 13 healthy control subjects. The parietal N20, P25, and frontal N30 were analyzed, and sensory gating was assessed by measuring the amplitude of each component during finger movement. The amplitudes of the N20 onset-peak, N20 peak-P25 peak, and N30 onset-peak were higher in ALS patients than in controls. Nonetheless, there were no significant differences in the amplitude reduction ratio of SEPs between patients and controls. There was a significant correlation between the baseline amplitudes of the N20 onset-peak or N20 peak-P25 peak and their gating ratios in patients with ALS. Our findings indicate that the excitability of the primary sensory cortex and secondary motor cortex is enhanced in ALS, while sensory gating is preserved in the early stages of ALS. This result suggests that enhanced SEP is caused by the hyperexcitability of the primary sensory and secondary motor cortices but not by the dysfunction of inhibitory mechanisms during voluntary movements.}, } @article {pmid37759773, year = {2023}, author = {Goto, S and Zhang, Y and Vyas, SA and Zhu, Q and Wildsoet, CF}, title = {Changes in Expression in BMP2 and Two Closely Related Genes in Guinea Pig Retinal Pigment Epithelium during Induction and Recovery from Myopia.}, journal = {Biomolecules}, volume = {13}, number = {9}, pages = {}, pmid = {37759773}, issn = {2218-273X}, support = {R01 EY012392/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Guinea Pigs ; Bone Morphogenetic Protein 2/genetics ; Choroid ; *Myopia/genetics ; *Retinal Pigment Epithelium ; }, abstract = {PURPOSE: We previously reported differential gene expression of the bone morphogenetic protein 2 (Bmp2) in guinea pig retinal pigment epithelium (RPE) after 1 day of hyperopic defocus, imposed with a negative contact lens (CLs). The study reported here sought to obtain insights into the temporal profiles of gene expression changes in Bmp2, as well as those of two closely related genes, the inhibitor of DNA binding 3 (Id3) and Noggin (Nog), both during myopia induction and when the CL treatment was terminated to allow recovery from induced myopia.

METHODS: To induce myopia, 2-week-old pigmented guinea pigs (New Zealand strain, n = 8) wore monocular -10 diopter (D) rigid gas-permeable (RGP) CLs for one week, while the other eye served as a control. Ocular measurements were made at baseline, 3 days, and 7 days after the initiation of CL wear, with treatment then being terminated and additional measurements being made after a further 3 days, 1 week, and 2 weeks. Spherical equivalent refractive errors (SERs), axial length (AL), choroidal thickness (ChT), and scleral thickness (ScT) data were collected using retinoscopy, optical biometry (Lenstar), and spectral domain optical coherence tomography (SD-OCT), respectively. RPE samples were collected from both eyes of the guinea pigs after either 1 day or 1 week of CL wear or 1 day or 2 weeks after its termination, and RNA was subsequently isolated and subjected to quantitative real-time PCR (qRT-PCR) analyses, targeting the Bmp2, Id3, and Nog genes.

RESULTS: Mean interocular differences (treated-control) in AL and SER were significantly different from baseline after 3 and 7 days of CL wear, consistent with induced myopia (p < 0.001 for all cases). Termination of CL wear resulted in the normalization (i.e., recovery) of the ALs and SERs of the treated eyes within 7 days, and the earlier significant ChT thinning with CL wear (p = 0004, day 7) was replaced by rapid thickening, which remained significant on day 7 (p = 0.009) but had normalized by day 14. The ChT changes were much smaller in magnitude than the AL changes in both phases. Interocular differences in the ScT showed no significant changes. The Bmp2 and Id3 genes were both significantly downregulated with CL wear, after 1 day (p = 0.012 and 0.016) and 7 days (p = 0.002 and 0.005), while Bmp2 gene expression increased and Nog gene expression decreased after the termination of CL wear, albeit transiently, which was significant on 1 day (p = 0.004 and 0.04) but not 2 weeks later. No change in Id3 gene expression was observed over the latter period. Conclusions: The above patterns of myopia induction and recovery validate this negative RGP-CL model as an alternative to traditional spectacle lens models for guinea pigs. The defocus-driven, sign-dependent changes in the expression of the Bmp2 gene in guinea pig RPE are consistent with observations in chicks and demonstrate the important role of BMP2 in eye growth regulation.}, } @article {pmid37759656, year = {2023}, author = {Angelopoulou, E and Pyrgelis, ES and Ahire, C and Suman, P and Mishra, A and Piperi, C}, title = {Functional Implications of Protein Arginine Methyltransferases (PRMTs) in Neurodegenerative Diseases.}, journal = {Biology}, volume = {12}, number = {9}, pages = {}, pmid = {37759656}, issn = {2079-7737}, abstract = {During the aging of the global population, the prevalence of neurodegenerative diseases will be continuously growing. Although each disorder is characterized by disease-specific protein accumulations, several common pathophysiological mechanisms encompassing both genetic and environmental factors have been detected. Among them, protein arginine methyltransferases (PRMTs), which catalyze the methylation of arginine of various substrates, have been revealed to regulate several cellular mechanisms, including neuronal cell survival and excitability, axonal transport, synaptic maturation, and myelination. Emerging evidence highlights their critical involvement in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) spectrum, Huntington's disease (HD), spinal muscular atrophy (SMA) and spinal and bulbar muscular atrophy (SBMA). Underlying mechanisms include the regulation of gene transcription and RNA splicing, as well as their implication in various signaling pathways related to oxidative stress responses, apoptosis, neuroinflammation, vacuole degeneration, abnormal protein accumulation and neurotransmission. The targeting of PRMTs is a therapeutic approach initially developed against various forms of cancer but currently presents a novel potential strategy for neurodegenerative diseases. In this review, we discuss the accumulating evidence on the role of PRMTs in the pathophysiology of neurodegenerative diseases, enlightening their pathogenesis and stimulating future research.}, } @article {pmid37759591, year = {2023}, author = {Wang, X and Hu, W and Li, Y and Jiang, M and Zhao, N and Cao, H and Liao, M}, title = {Cytochrome P450s-Involved Enhanced Metabolism Contributes to the High Level of Nicosulfuron Resistance in Digitaria sanguinalis from China.}, journal = {Biology}, volume = {12}, number = {9}, pages = {}, pmid = {37759591}, issn = {2079-7737}, support = {202203a06020016//the Science and Technology Major Project of Anhui Province/ ; rc342004//the Talent Research Project of Anhui Agricultural University/ ; X202310364519//the College Students' Innovation Training Project in Anhui Agricultural University/ ; }, abstract = {Large crabgrass (Digitaria sanguinalis (L.) Scop.) is one of the major malignant grass weeds in Chinese maize (Zea mays L.) fields, and it has recently developed resistance to the acetolactate synthase (ALS)-inhibiting herbicide nicosulfuron. This study focused on a suspected nicosulfuron-resistant (R) population (LJ-01) of D. sanguinalis, collected from Lujiang County in Anhui Province, China, to explore the resistance level and potential resistance mechanism. Whole-plant dose-response testing confirmed that the LJ-01 population evolved a high level of resistance to nicosulfuron (11.5-fold) compared to the susceptible (S) population, DY-02. The ALS gene sequencing and relative expression assay of the R plants indicated that target gene mutation and overexpression were not responsible for the resistance phenotype. However, pretreatment with malathion, a known cytochrome P450 monooxygenase (P450) inhibitor, alleviated the resistance of the R population to nicosulfuron by approximately 36%. High-performance liquid chromatography (HPLC) analysis revealed that the R plants metabolized nicosulfuron faster than the S plants. Moreover, cross-resistance testing suggested that the R population exhibited low levels of resistance to thifensulfuron-methyl and pyrazosulfuron-ethyl, but it remained susceptible to rimsulfuron. Multiple resistance patterns showed that the R population evolved low resistance to the photosystem inhibitors bromoxynil octanoate and atrazine and sensitivity to the acetyl-CoA carboxylase (ACCase) inhibitor cyhalofop-butyl and the 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors tembotrione, mesotrione, and topramezone. This study reports, for the first time, the simultaneous resistance to ALS and different photosystem inhibitors in D. sanguinalis. The nicosulfuron resistance observed in the R population could primarily be attributed to an enhanced metabolism involving P450 enzymes.}, } @article {pmid37759540, year = {2023}, author = {Sanghai, N and Tranmer, GK}, title = {Biochemical and Molecular Pathways in Neurodegenerative Diseases: An Integrated View.}, journal = {Cells}, volume = {12}, number = {18}, pages = {}, pmid = {37759540}, issn = {2073-4409}, abstract = {Neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are defined by a myriad of complex aetiologies. Understanding the common biochemical molecular pathologies among NDDs gives an opportunity to decipher the overlapping and numerous cross-talk mechanisms of neurodegeneration. Numerous interrelated pathways lead to the progression of neurodegeneration. We present evidence from the past pieces of literature for the most usual global convergent hallmarks like ageing, oxidative stress, excitotoxicity-induced calcium butterfly effect, defective proteostasis including chaperones, autophagy, mitophagy, and proteosome networks, and neuroinflammation. Herein, we applied a holistic approach to identify and represent the shared mechanism across NDDs. Further, we believe that this approach could be helpful in identifying key modulators across NDDs, with a particular focus on AD, PD, and ALS. Moreover, these concepts could be applied to the development and diagnosis of novel strategies for diverse NDDs.}, } @article {pmid37759469, year = {2023}, author = {Castillo Bautista, CM and Eismann, K and Gentzel, M and Pelucchi, S and Mertens, J and Walters, HE and Yun, MH and Sterneckert, J}, title = {Obatoclax Rescues FUS-ALS Phenotypes in iPSC-Derived Neurons by Inducing Autophagy.}, journal = {Cells}, volume = {12}, number = {18}, pages = {}, pmid = {37759469}, issn = {2073-4409}, support = {R01 AG056306/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; ERC-STG-2019-852086/ERC_/European Research Council/International ; AG056306/AG/NIA NIH HHS/United States ; RF1 AG056306/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Motor Neurons/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Mutation ; Autophagy/physiology ; Phenotype ; Proto-Oncogene Proteins c-bcl-2/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Aging is associated with the disruption of protein homeostasis and causally contributes to multiple diseases, including amyotrophic lateral sclerosis (ALS). One strategy for restoring protein homeostasis and protecting neurons against age-dependent diseases such as ALS is to de-repress autophagy. BECN1 is a master regulator of autophagy; however, is repressed by BCL2 via a BH3 domain-mediated interaction. We used an induced pluripotent stem cell model of ALS caused by mutant FUS to identify a small molecule BH3 mimetic that disrupts the BECN1-BCL2 interaction. We identified obatoclax as a brain-penetrant drug candidate that rescued neurons at nanomolar concentrations by reducing cytoplasmic FUS levels, restoring protein homeostasis, and reducing degeneration. Proteomics data suggest that obatoclax protects neurons via multiple mechanisms. Thus, obatoclax is a candidate for repurposing as a possible ALS therapeutic and, potentially, for other age-associated disorders linked to defects in protein homeostasis.}, } @article {pmid37759179, year = {2023}, author = {Garcia-Vaquero, ML and Heim, M and Flix, B and Pereira, M and Palin, L and Marques, TM and Pinto, FR and de Las Rivas, J and Voigt, A and Besse, F and Gama-Carvalho, M}, title = {Analysis of asymptomatic Drosophila models for ALS and SMA reveals convergent impact on functional protein complexes linked to neuro-muscular degeneration.}, journal = {BMC genomics}, volume = {24}, number = {1}, pages = {576}, pmid = {37759179}, issn = {1471-2164}, mesh = {Adult ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Drosophila/genetics ; *Muscular Atrophy, Spinal ; Motor Neurons ; RNA ; DNA-Binding Proteins ; *Drosophila Proteins/genetics ; }, abstract = {BACKGROUND: Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS) share phenotypic and molecular commonalities, including the fact that they can be caused by mutations in ubiquitous proteins involved in RNA metabolism, namely SMN, TDP-43 and FUS. Although this suggests the existence of common disease mechanisms, there is currently no model to explain the resulting motor neuron dysfunction. In this work we generated a parallel set of Drosophila models for adult-onset RNAi and tagged neuronal expression of the fly orthologues of the three human proteins, named Smn, TBPH and Caz, respectively. We profiled nuclear and cytoplasmic bound mRNAs using a RIP-seq approach and characterized the transcriptome of the RNAi models by RNA-seq. To unravel the mechanisms underlying the common functional impact of these proteins on neuronal cells, we devised a computational approach based on the construction of a tissue-specific library of protein functional modules, selected by an overall impact score measuring the estimated extent of perturbation caused by each gene knockdown.

RESULTS: Transcriptome analysis revealed that the three proteins do not bind to the same RNA molecules and that only a limited set of functionally unrelated transcripts is commonly affected by their knock-down. However, through our integrative approach we were able to identify a concerted effect on protein functional modules, albeit acting through distinct targets. Most strikingly, functional annotation revealed that these modules are involved in critical cellular pathways for motor neurons, including neuromuscular junction function. Furthermore, selected modules were found to be significantly enriched in orthologues of human neuronal disease genes.

CONCLUSIONS: The results presented here show that SMA and ALS disease-associated genes linked to RNA metabolism functionally converge on neuronal protein complexes, providing a new hypothesis to explain the common motor neuron phenotype. The functional modules identified represent promising biomarkers and therapeutic targets, namely given their alteration in asymptomatic settings.}, } @article {pmid37759084, year = {2024}, author = {Tan, EL and Tahedl, M and Lope, J and Hengeveld, JC and Doherty, MA and McLaughlin, RL and Hardiman, O and Chang, KM and Finegan, E and Bede, P}, title = {Language deficits in primary lateral sclerosis: cortical atrophy, white matter degeneration and functional disconnection between cerebral regions.}, journal = {Journal of neurology}, volume = {271}, number = {1}, pages = {431-445}, pmid = {37759084}, issn = {1432-1459}, mesh = {Humans ; *White Matter/diagnostic imaging/pathology ; Diffusion Tensor Imaging/methods ; Prospective Studies ; *Motor Neuron Disease/pathology ; Atrophy/pathology ; Magnetic Resonance Imaging ; }, abstract = {BACKGROUND: Primary lateral sclerosis (PLS) is traditionally regarded as a pure upper motor neuron disorder, but recent cases series have highlighted cognitive deficits in executive and language domains.

METHODS: A single-centre, prospective neuroimaging study was conducted with comprehensive clinical and genetic profiling. The structural and functional integrity of language-associated brain regions and networks were systematically evaluated in 40 patients with PLS in comparison to 111 healthy controls. The structural integrity of the arcuate fascicle, frontal aslant tract, inferior occipito-frontal fascicle, inferior longitudinal fascicle, superior longitudinal fascicle and uncinate fascicle was evaluated. Functional connectivity between the supplementary motor region and the inferior frontal gyrus and connectivity between Wernicke's and Broca's areas was also assessed.

RESULTS: Cortical thickness reductions were observed in both Wernicke's and Broca's areas. Fractional anisotropy reduction was noted in the aslant tract and increased radical diffusivity (RD) identified in the aslant tract, arcuate fascicle and superior longitudinal fascicle in the left hemisphere. Functional connectivity was reduced along the aslant track, i.e. between the supplementary motor region and the inferior frontal gyrus, but unaffected between Wernicke's and Broca's areas. Cortical thickness alterations, structural and functional connectivity changes were also noted in the right hemisphere.

CONCLUSIONS: Disease-burden in PLS is not confined to motor regions, but there is also a marked involvement of language-associated tracts, networks and cortical regions. Given the considerably longer survival in PLS compared to ALS, the impact of language impairment on the management of PLS needs to be carefully considered.}, } @article {pmid37758732, year = {2023}, author = {Marzullo, M and Romano, G and Pellacani, C and Riccardi, F and Ciapponi, L and Feiguin, F}, title = {Su(var)3-9 mediates age-dependent increase in H3K9 methylation on TDP-43 promoter triggering neurodegeneration.}, journal = {Cell death discovery}, volume = {9}, number = {1}, pages = {357}, pmid = {37758732}, issn = {2058-7716}, abstract = {Aging progressively modifies the physiological balance of the organism increasing susceptibility to both genetic and sporadic neurodegenerative diseases. These changes include epigenetic chromatin remodeling events that may modify the transcription levels of disease-causing genes affecting neuronal survival. However, how these events interconnect is not well understood. Here, we found that Su(var)3-9 causes increased methylation of histone H3K9 in the promoter region of TDP-43, the most frequently altered factor in amyotrophic lateral sclerosis (ALS), affecting the mRNA and protein expression levels of this gene through epigenetic modifications that appear to be conserved in aged Drosophila brains, mouse, and human cells. Remarkably, augmented Su(var)3-9 activity causes a decrease in TDP-43 expression followed by early defects in locomotor activities. In contrast, decreasing Su(var)3-9 action promotes higher levels of TDP-43 expression, improving motility parameters in old flies. The data uncover a novel role of this enzyme in regulating TDP-43 expression and locomotor senescence and indicate conserved epigenetic mechanisms that may play a role in the pathogenesis of ALS.}, } @article {pmid37758454, year = {2024}, author = {Goutman, SA and Boss, J and Jang, DG and Mukherjee, B and Richardson, RJ and Batterman, S and Feldman, EL}, title = {Environmental risk scores of persistent organic pollutants associate with higher ALS risk and shorter survival in a new Michigan case/control cohort.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {3}, pages = {241-248}, pmid = {37758454}, issn = {1468-330X}, support = {R01 TS000289/TS/ATSDR CDC HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; UL1 TR002240/TR/NCATS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Persistent Organic Pollutants ; Michigan/epidemiology ; *Amyotrophic Lateral Sclerosis ; *Environmental Pollutants/adverse effects ; Risk Factors ; *Hydrocarbons, Chlorinated ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurogenerative disease caused by combined genetic susceptibilities and environmental exposures. Identifying and validating these exposures are of paramount importance to modify disease risk. We previously reported that persistent organic pollutants (POPs) associate with ALS risk and survival and aimed to replicate these findings in a new cohort.

METHOD: Participants with and without ALS recruited in Michigan provided plasma samples for POPs analysis by isotope dilution with triple quadrupole mass spectrometry. ORs for risk models and hazard ratios for survival models were calculated for individual POPs. POP mixtures were represented by environmental risk scores (ERS), a summation of total exposures, to evaluate the association with risk (ERS[risk]) and survival (ERS[survival]).

RESULTS: Samples from 164 ALS and 105 control participants were analysed. Several individual POPs significantly associated with ALS, including 8 of 22 polychlorinated biphenyls and 7 of 10 organochlorine pesticides (OCPs). ALS risk was most strongly represented by the mixture effects of OCPs alpha-hexachlorocyclohexane, hexachlorobenzene, trans-nonachlor and cis-nonachlor and an interquartile increase in ERS[risk] enhanced ALS risk 2.58 times (p<0.001). ALS survival was represented by the combined mixture of all POPs and an interquartile increase in ERS[survival] enhanced ALS mortality rate 1.65 times (p=0.008).

CONCLUSIONS: These data continue to support POPs as important factors for ALS risk and progression and replicate findings in a new cohort. The assessments of POPs in non-Michigan ALS cohorts are encouraged to better understand the global effect and the need for targeted disease risk reduction strategies.}, } @article {pmid37758263, year = {2024}, author = {Crumbley, C and Cepni, AB and Taylor, A and Thompson, D and Moran, NE and Olvera, N and O'Connor, DP and Johnston, CA and Ledoux, TA}, title = {Exploring Factors Associated With Accelerometer Validity Among Ethnically Diverse Toddlers.}, journal = {Pediatric exercise science}, volume = {36}, number = {2}, pages = {66-74}, doi = {10.1123/pes.2022-0114}, pmid = {37758263}, issn = {1543-2920}, mesh = {Humans ; Male ; Female ; Child, Preschool ; Adult ; *Exercise ; *Sedentary Behavior ; Parents ; Patient Compliance ; Accelerometry ; }, abstract = {PURPOSE: Studying physical activity in toddlers using accelerometers is challenging due to noncompliance with wear time (WT) and activity log (AL) instructions. The aims of this study are to examine relationships between WT and AL completion and (1) demographic and socioeconomic variables, (2) parenting style, and (3) whether sedentary time differs by AL completion.

METHODS: Secondary analysis was performed using baseline data from a community wellness program randomized controlled trial for parents with toddlers (12-35 mo). Parents had toddlers wear ActiGraph wGT3x accelerometers and completed ALs. Valid days included ≥600-minute WT. Analysis of variance and chi-square analyses were used.

RESULTS: The sample (n = 50) comprised racial and ethnically diverse toddlers (mean age = 27 mo, 58% male) and parents (mean age = 31.7 y, 84% female). Twenty-eight families (56%) returned valid accelerometer data with ALs. Participants in relationships were more likely to complete ALs (P < .05). Toddler sedentary time did not differ between those with ALs and those without.

CONCLUSIONS: We found varied compliance with WT instructions and AL completion. Returned AL quality was poor, presenting challenges in correctly characterizing low-activity counts to improve internal validity of WT and physical activity measures. Support from marital partners may be important for adherence to study protocols.}, } @article {pmid37756636, year = {2023}, author = {Wang, Y and Liu, L and Chen, H and Yang, Y and Mu, C and Ren, H and Liu, Y and Yu, L and Fang, Q and Wang, G and Hao, Z}, title = {Disrupted phase behavior of FUS underlies poly-PR-induced DNA damage in amyotrophic lateral sclerosis.}, journal = {Human molecular genetics}, volume = {33}, number = {1}, pages = {64-77}, doi = {10.1093/hmg/ddad163}, pmid = {37756636}, issn = {1460-2083}, support = {//National Natural Science Foundation of China/ ; //Priority Academic Program Development of Jiangsu Higher Education Institutions/ ; 2020M671572//China Postdoctoral Science Foundation/ ; 21KJA180003//Key Project of Natural Science Foundation of Jiangsu Provincial Higher Education Institutions/ ; 32271039//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; DNA Repeat Expansion ; *Frontotemporal Dementia/genetics/metabolism ; Proteins/genetics ; DNA Damage/genetics ; Arginine/genetics ; C9orf72 Protein/genetics/metabolism ; Dipeptides/genetics ; }, abstract = {GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the first intron of the chromosome 9 open reading frame 72 (C9ORF72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Among the five dipeptide repeat proteins translated from G4C2 HRE, arginine-rich poly-PR (proline:arginine) is extremely toxic. However, the molecular mechanism responsible for poly-PR-induced cell toxicity remains incompletely understood. Here, we found that poly-PR overexpression triggers severe DNA damage in cultured cells, primary cortical neurons, and the motor cortex of a poly-PR transgenic mouse model. Interestingly, we identified a linkage between poly-PR and RNA-binding protein fused in sarcoma (FUS), another ALS-related gene product associated with DNA repair. Poly-PR interacts with FUS both in vitro and in vivo, phase separates with FUS in a poly-PR concentration-dependent manner, and impairs the fluidity of FUS droplets in vitro and in cells. Moreover, poly-PR impedes the recruitment of FUS and its downstream protein XRCC1 to DNA damage foci after microirradiation. Importantly, overexpression of FUS significantly decreased the level of DNA damage and dramatically reduced poly-PR-induced cell death. Our data suggest the severe DNA damage caused by poly-PR and highlight the interconnection between poly-PR and FUS, enlightening the potential therapeutic role of FUS in alleviating poly-PR-induced cell toxicity.}, } @article {pmid37756598, year = {2023}, author = {Prior-González, M and Lazo-Gómez, R and Tapia, R}, title = {Sodium butyrate does not protect spinal motor neurons from AMPA-induced excitotoxic degeneration in vivo.}, journal = {Disease models & mechanisms}, volume = {16}, number = {10}, pages = {}, pmid = {37756598}, issn = {1754-8411}, mesh = {Humans ; Animals ; *Amyotrophic Lateral Sclerosis/pathology ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism ; Butyric Acid/pharmacology/metabolism ; Motor Neurons/pathology ; Spinal Cord/pathology ; }, abstract = {Motor neuron (MN) loss is the primary pathological hallmark of amyotrophic lateral sclerosis (ALS). Histone deacetylase 4 (HDAC4) is one of several factors involved in nerve-muscle communication during MN loss, hindering muscle reinnervation, as shown in humans and in animal models of ALS, and may explain the differential progression observed in patients with ALS - rapid versus slow progression. In this work, we inhibited HDAC4 activity through the administration of a pan-histone deacetylase inhibitor, sodium butyrate, in an in vivo model of chronic spinal MN death induced by AMPA-mediated excitotoxicity. We infused AMPA into the spinal cord at low and high doses, which mimic the rapid and slow progression observed in humans, respectively. We found that muscle HDAC4 expression was increased by high-dose infusion of AMPA. Treatment of animals with sodium butyrate further decreased expression of muscle HDAC4, although non-significantly, and did not prevent the paralysis or the MN loss induced by AMPA infusion. These results inform on the role of muscle HDAC4 in MN degeneration in vivo and provide insights for the search for more suitable therapeutic strategies.}, } @article {pmid37755677, year = {2024}, author = {Hu, C and Yan, Y and Jin, Y and Yang, J and Xi, Y and Zhong, Z}, title = {Decoding the Cellular Trafficking of Prion-like Proteins in Neurodegenerative Diseases.}, journal = {Neuroscience bulletin}, volume = {40}, number = {2}, pages = {241-254}, pmid = {37755677}, issn = {1995-8218}, mesh = {Humans ; *Prions ; *Neurodegenerative Diseases/pathology ; Amyloid beta-Peptides ; *Alzheimer Disease ; alpha-Synuclein ; tau Proteins ; *Parkinson Disease ; }, abstract = {The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, or Amyotrophic Lateral Sclerosis. In a process known as 'seeding', prion-like proteins such as amyloid beta, microtubule-associated protein tau, α-synuclein, silence superoxide dismutase 1, or transactive response DNA-binding protein 43 kDa, propagate their misfolded conformations by transforming their respective soluble monomers into fibrils. Cellular and molecular evidence of prion-like propagation in NDs, the clinical relevance of their 'seeding' capacities, and their levels of contribution towards disease progression have been intensively studied over recent years. This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization, endo-lysosomal leaking, aggregate degradation, and secretion. Debates on the importance of the role of prion-like protein aggregates in NDs, whether causal or consequent, are also discussed. Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.}, } @article {pmid37753578, year = {2023}, author = {Yang, X and Hayes, LR}, title = {Order from chaos: Using CSF proteomics to predict ALS progression.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {12}, pages = {2176-2178}, pmid = {37753578}, issn = {2328-9503}, support = {R03 NS127011/NS/NINDS NIH HHS/United States ; R01 NS123538/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Biomarkers ; Disease Progression ; *Proteomics ; *Cerebrospinal Fluid Proteins/analysis ; }, } @article {pmid37753280, year = {2023}, author = {Orr, JE and Chen, K and Vaida, F and Schmickl, CN and Laverty, CG and Ravits, J and Lesser, D and Bhattacharjee, R and Malhotra, A and Owens, RL}, title = {Effectiveness of long-term noninvasive ventilation measured by remote monitoring in neuromuscular disease.}, journal = {ERJ open research}, volume = {9}, number = {5}, pages = {}, pmid = {37753280}, issn = {2312-0541}, support = {K23 HL151880/HL/NHLBI NIH HHS/United States ; K23 HL161336/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVE: Patients with neuromuscular disease are often treated with home noninvasive ventilation (NIV) with devices capable of remote patient monitoring. We sought to determine whether long-term NIV data could provide insight into the effectiveness of ventilation over time.

METHODS: We abstracted available longitudinal data for adults with neuromuscular disease in monthly increments from first available to most recent. Generalised linear mixed-effects modelling with subject-level random effects was used to evaluate trajectories over time.

RESULTS: 1799 months of data across 85 individuals (median age 61, interquartile range (IQR) 46-71 years; 44% female; 49% amyotrophic lateral sclerosis (ALS)) were analysed, with a median (IQR) of 17 (8-35) months per individual. Over time, tidal volume increased and respiratory rate decreased. Dynamic respiratory system compliance decreased, accompanied by increased pressure support. Compared to volume-assured mode, fixed-pressure modes were associated with lower initial tidal volume, higher respiratory rate and lower pressures, which did not fully equalise with volume-assured mode over time. Compared with non-ALS patients, those with ALS had lower initial pressure support, but faster increases in pressure support over time, and ALS was associated wtih a more robust increase in respiratory rate in response to low tidal volume. Nonsurvivors did not differ from survivors in ventilatory trajectories over time, but did exhibit decreasing NIV use prior to death, in contrast with stable use in survivors.

CONCLUSION: NIV keeps breathing patterns stable over time, but support needs are dynamic and influenced by diagnosis and ventilation mode. Mortality is preceded by decreased NIV use rather than inadequate support during use.}, } @article {pmid37753182, year = {2023}, author = {Marciante, AB and Seven, YB and Kelly, MN and Perim, RR and Mitchell, GS}, title = {Magnitude and Mechanism of Phrenic Long-term Facilitation Shift Between Daily Rest Versus Active Phase.}, journal = {Function (Oxford, England)}, volume = {4}, number = {6}, pages = {zqad041}, pmid = {37753182}, issn = {2633-8823}, support = {T32 HL134621/HL/NHLBI NIH HHS/United States ; }, mesh = {Rats ; Animals ; Humans ; Rats, Sprague-Dawley ; *Serotonin ; *Hypoxia ; Signal Transduction ; Adenosine ; }, abstract = {Plasticity is a fundamental property of the neural system controlling breathing. One key example of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a persistent increase in phrenic nerve activity elicited by acute intermittent hypoxia (AIH). pLTF can arise from distinct cell signaling cascades initiated by serotonin versus adenosine receptor activation, respectively, and interact via powerful cross-talk inhibition. Here, we demonstrate that the daily rest/active phase and the duration of hypoxic episodes within an AIH protocol have profound impact on the magnitude and mechanism of pLTF due to shifts in serotonin/adenosine balance. Using the historical "standard" AIH protocol (3, 5-min moderate hypoxic episodes), we demonstrate that pLTF magnitude is unaffected by exposure in the midactive versus midrest phase, yet the mechanism driving pLTF shifts from serotonin-dominant (midrest) to adenosine-dominant (midactive). This mechanistic "flip" results from combined influences of hypoxia-evoked adenosine release and daily fluctuations in basal spinal adenosine. Since AIH evokes less adenosine with shorter (15, 1-min) hypoxic episodes, midrest pLTF is amplified due to diminished adenosine constraint on serotonin-driven plasticity; in contrast, elevated background adenosine during the midactive phase suppresses serotonin-dominant pLTF. These findings demonstrate the importance of the serotonin/adenosine balance in regulating the amplitude and mechanism of AIH-induced pLTF. Since AIH is emerging as a promising therapeutic modality to restore respiratory and nonrespiratory movements in people with spinal cord injury or ALS, knowledge of how time-of-day and hypoxic episode duration impact the serotonin/adenosine balance and the magnitude and mechanism of pLTF has profound biological, experimental, and translational implications.}, } @article {pmid37752364, year = {2023}, author = {Guan, T and Zhou, T and Zhang, X and Guo, Y and Yang, C and Lin, J and Zhang, JV and Cheng, Y and Marzban, H and Wang, YT and Kong, J}, title = {Selective removal of misfolded SOD1 delays disease onset in a mouse model of amyotrophic lateral sclerosis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {80}, number = {10}, pages = {304}, pmid = {37752364}, issn = {1420-9071}, mesh = {Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; Superoxide Dismutase-1/genetics ; *Neurodegenerative Diseases ; Disease Models, Animal ; Motor Neurons ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. There is no cure currently. The discovery that mutations in the gene SOD1 are a cause of ALS marks a breakthrough in the search for effective treatments for ALS. SOD1 is an antioxidant that is highly expressed in motor neurons. Human SOD1 is prone to aberrant modifications. Familial ALS-linked SOD1 variants are particularly susceptible to aberrant modifications. Once modified, SOD1 undergoes conformational changes and becomes misfolded. This study aims to determine the effect of selective removal of misfolded SOD1 on the pathogenesis of ALS.

METHODS: Based on the chaperone-mediated protein degradation pathway, we designed a fusion peptide named CT4 and tested its efficiency in knocking down intracellularly misfolded SOD1 and its efficacy in modifying the pathogenesis of ALS.

RESULTS: Expression of the plasmid carrying the CT4 sequence in human HEK cells resulted in robust removal of misfolded SOD1 induced by serum deprivation. Co-transfection of the CT4 and the G93A-hSOD1 plasmids at various ratios demonstrated a dose-dependent knockdown efficiency on G93A-hSOD1, which could be further increased when misfolding of SOD1 was enhanced by serum deprivation. Application of the full-length CT4 peptide to primary cultures of neurons expressing the G93A variant of human SOD1 revealed a time course of the degradation of misfolded SOD1; misfolded SOD1 started to decrease by 2 h after the application of CT4 and disappeared by 7 h. Intravenous administration of the CT4 peptide at 10 mg/kg to the G93A-hSOD1 reduced human SOD1 in spinal cord tissue by 68% in 24 h and 54% in 48 h in presymptomatic ALS mice. Intraperitoneal administration of the CT4 peptide starting from 60 days of age significantly delayed the onset of ALS and prolonged the lifespan of the G93A-hSOD1 mice.

CONCLUSIONS: The CT4 peptide directs the degradation of misfolded SOD1 in high efficiency and specificity. Selective removal of misfolded SOD1 significantly delays the onset of ALS, demonstrating that misfolded SOD1 is the toxic form of SOD1 that causes motor neuron death. The study proves that selective removal of misfolded SOD1 is a promising treatment for ALS.}, } @article {pmid37752346, year = {2024}, author = {Cabrera, GT and Meijboom, KE and Abdallah, A and Tran, H and Foster, Z and Weiss, A and Wightman, N and Stock, R and Gendron, T and Gruntman, A and Giampetruzzi, A and Petrucelli, L and Brown, RH and Mueller, C}, title = {Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo.}, journal = {Gene therapy}, volume = {31}, number = {3-4}, pages = {105-118}, pmid = {37752346}, issn = {1476-5462}, support = {NS088689//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS088689/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; C9orf72 Protein/genetics/metabolism ; Dipeptides/genetics/metabolism ; DNA Repeat Expansion/genetics ; Mice, Transgenic ; *MicroRNAs/genetics ; *Neurodegenerative Diseases ; Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons, causing progressive muscle weakness and respiratory failure. The presence of an expanded hexanucleotide repeat in chromosome 9 open reading frame 72 (C9ORF72) is the most frequent mutation causing familial ALS and frontotemporal dementia (FTD). To determine if suppressing expression of C9ORF72 gene products can reduce toxicity, we designed a set of artificial microRNAs (amiRNA) targeting the human C9ORF72 gene. Here we report that an AAV9-mediated amiRNA significantly suppresses expression of the C9ORF72 mRNA, protein, and toxic dipeptide repeat proteins generated by the expanded repeat in the brain and spinal cord of C9ORF72 transgenic mice.}, } @article {pmid37752099, year = {2024}, author = {Koreki, A and Michel, S and Lebeaux, C and Trouilh, L and Délye, C}, title = {Prevalence, spatial structure and evolution of resistance to acetolactate-synthase (ALS) inhibitors and 2,4-D in the major weed Papaver rhoeas (L.) assessed using a massive, country-wide sampling.}, journal = {Pest management science}, volume = {80}, number = {2}, pages = {637-647}, doi = {10.1002/ps.7791}, pmid = {37752099}, issn = {1526-4998}, support = {//Corteva Agriscience/ ; }, mesh = {2,4-Dichlorophenoxyacetic Acid/pharmacology ; *Acetolactate Synthase/antagonists & inhibitors/genetics ; Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Lactates ; Mutation ; Nucleotides ; *Papaver/drug effects/genetics ; }, abstract = {BACKGROUND: Corn poppy (Papaver rhoeas) is the most damaging broadleaf weed in France. Massively parallel amplicon sequencing was used to investigate the prevalence, mode of evolution and spread of resistance-endowing ALS alleles in 422 populations randomly sampled throughout poppy's range in France. Bioassays were used to detect resistance to the synthetic auxin 2,4-D in 43 of these populations.

RESULTS: A total of 21 100 plants were analysed and 24 mutant ALS alleles carrying an amino-acid substitution involved or potentially involved in resistance were identified. The vast majority (97.6%) of the substitutions occurred at codon Pro197, where all six possible single-nucleotide non-synonymous substitutions plus four double-nucleotide substitutions were identified. Changes observed in the enzymatic properties of the mutant ALS isoforms could not explain the differences in prevalence among the corresponding alleles. Sequence read analysis showed that mutant ALS alleles had multiple, independent evolutionary origins, and could have evolved several times independently within an area of a few kilometres. Finally, 2,4-D resistance was associated with mutant ALS alleles in individual plants in one third of the populations assayed.

CONCLUSION: The intricate geographical mosaic of mutant ALS alleles observed is the likely result of the combination of huge population sizes, multiple independent mutation events and human-mediated spread of resistance. Our work highlights the ability of poppy populations and individual plants to accumulate different ALS alleles and as yet unknown mechanisms conferring resistance to synthetic auxins. This does not bode well for the continued use of chemical herbicides to control poppy. © 2023 Society of Chemical Industry.}, } @article {pmid37751856, year = {2023}, author = {Martin Schaff, C and Kurent, JE and Kolodziejczak, S and Milic, M and Foster, LA and Mehta, AK}, title = {Neuroprognostication for Patients with Amyotrophic Lateral Sclerosis: An Updated, Evidence-Based Review.}, journal = {Seminars in neurology}, volume = {43}, number = {5}, pages = {776-790}, doi = {10.1055/s-0043-1775595}, pmid = {37751856}, issn = {1098-9021}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Quality of Life ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder that presents and progresses in various ways, making prognostication difficult. Several paradigms exist for providers to elucidate prognosis in a way that addresses not only the amount of time a patient has to live, but also a patient's quality of their life moving forward. Prognostication, with regard to both survivability and quality of life, is impacted by several features that include, but are not limited to, patient demographics, clinical features on presentation, and over time, access to therapy, and access to multidisciplinary clinics. An understanding of the impact that these features have on the life of a patient with ALS can help providers to develop a better and more personalized approach for patients related to their clinical prognosis after a diagnosis is made. The ultimate goal of prognostication is to empower patients with ALS to take control and make decisions with their care teams to ensure that their goals are addressed and met.}, } @article {pmid37751804, year = {2023}, author = {Wang, Z and Zhang, C and Fan, C and Liu, Y}, title = {Post-translational modifications in stress granule and their implications in neurodegenerative diseases.}, journal = {Biochimica et biophysica acta. Gene regulatory mechanisms}, volume = {1866}, number = {4}, pages = {194989}, doi = {10.1016/j.bbagrm.2023.194989}, pmid = {37751804}, issn = {1876-4320}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism ; Stress Granules ; Protein Processing, Post-Translational ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; RNA, Messenger/metabolism ; }, abstract = {Stress granules (SGs) arise as formations of mRNAs and proteins in response to translation initiation inhibition during stress. These dynamic compartments adopt a fluidic nature through liquid-liquid phase separation (LLPS), exhibiting a composition subject to constant change within cellular contexts. Research has unveiled an array of post-translational modifications (PTMs) occurring on SG proteins, intricately orchestrating SG dynamics. In the realm of neurodegenerative diseases, pathological mutant proteins congregate into insoluble aggregates alongside numerous SG proteins, manifesting resilience against disassembly. Specific PTMs conspicuously label these aggregates, designating them for subsequent degradation. The strategic manipulation of aberrant SGs via PTMs emerges as a promising avenue for therapeutic intervention. This review discerns recent strides in comprehending the impact of PTMs on LLPS behavior and the assembly/disassembly kinetics of SGs. By delving into the roles of PTMs in governing SG dynamics, we augment our cognizance of the molecular underpinnings of neurodegeneration. Furthermore, we offer invaluable insights into potential targets for therapeutic intervention in neurodegenerative afflictions, encompassing conditions like amyotrophic lateral sclerosis and frontotemporal dementia.}, } @article {pmid37749234, year = {2023}, author = {Linsenmeier, M and Faltova, L and Morelli, C and Capasso Palmiero, U and Seiffert, C and Küffner, AM and Pinotsi, D and Zhou, J and Mezzenga, R and Arosio, P}, title = {The interface of condensates of the hnRNPA1 low-complexity domain promotes formation of amyloid fibrils.}, journal = {Nature chemistry}, volume = {15}, number = {10}, pages = {1340-1349}, pmid = {37749234}, issn = {1755-4349}, support = {101002094//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; }, abstract = {The maturation of liquid-like protein condensates into amyloid fibrils has been associated with several neurodegenerative diseases. However, the molecular mechanisms underlying this liquid-to-solid transition have remained largely unclear. Here we analyse the amyloid formation mediated by condensation of the low-complexity domain of hnRNPA1, a protein involved in amyotrophic lateral sclerosis. We show that phase separation and fibrillization are connected but distinct processes that are modulated by different regions of the protein sequence. By monitoring the spatial and temporal evolution of amyloid formation we demonstrate that the formation of fibrils does not occur homogeneously inside the droplets but is promoted at the interface of the condensates. We further show that coating the interface of the droplets with surfactant molecules inhibits fibril formation. Our results reveal that the interface of biomolecular condensates of hnRNPA1 promotes fibril formation, therefore suggesting interfaces as a potential novel therapeutic target against the formation of aberrant amyloids mediated by condensation.}, } @article {pmid37748881, year = {2023}, author = {McFarlane, R and Peelo, C and Galvin, M and Heverin, M and Hardiman, O}, title = {Epidemiologic Trends of Amyotrophic Lateral Sclerosis in Ireland, 1996-2021.}, journal = {Neurology}, volume = {101}, number = {19}, pages = {e1905-e1912}, pmid = {37748881}, issn = {1526-632X}, mesh = {Male ; Humans ; Female ; Middle Aged ; Aged ; *Amyotrophic Lateral Sclerosis/diagnosis ; Ireland/epidemiology ; Delayed Diagnosis ; Riluzole ; Proportional Hazards Models ; }, abstract = {BACKGROUND AND OBJECTIVES: The objective of this study was to examine changes to the incidence, prevalence, age at onset, and survival of patients diagnosed with amyotrophic lateral sclerosis (ALS) in the Republic of Ireland over 25 years.

METHODS: Incident and prevalent cases of ALS were estimated using the Irish population-based ALS Register, which has been in continuous operation since 1994. Incident cases were age standardized using the direct method and applied to 3 standard populations (Irish, European, and American). Survival was determined using Kaplan-Meier curves and Cox regression models. Non-normally distributed groups were compared using the Kruskal-Wallis test with a Bonferroni correction.

RESULTS: A total of 2,771 patients with ALS were identified in the Republic of Ireland over 25 years. Incidence per 100,000 was determined for the population older than 15 years. Crude incidence increased from 2.64 to 5.46 per 100,000. Standardized incidence increased from 2.64 to 3.1 per 100,000. Prevalence increased from 5.83 to 8.10 per 100,000. The median age at onset increased from 64 to 67 years. The peak age of incidence increased from those between 70 and 74 years to those between 75 and 79 years. Overall, women had a consistently later median age at onset of 67 years compared with men at 65 years (p < 0.001). No significant difference in survival was noted between those captured across 3 different epochs (1996-2003, 2004-2012, 2013-2021). Older age at onset (hazard ratio [HR] 1.03, CI 1.02-1.04, p < 0.001) was a negative predictive factor of survival in multivariate Cox regression analysis. Riluzole use (HR 0.67, CI 0.50-0.90, p = 0.033) and diagnostic delay (HR 0.98, CI 0.98-0.99, p < 0.001) were positive predictive factors.

DISCUSSION: Within the Republic of Ireland, the age-standardized overall incidence, peak incidence, prevalence, and age at onset of ALS have all increased over 25 years. Despite the widespread use of noninvasive ventilation, aggressive secretion management, and changes in ALS care, the mean survival within the Irish population has not changed.}, } @article {pmid37748861, year = {2023}, author = {Soustelle, L and Aimond, F and López-Andrés, C and Brugioti, V and Raoul, C and Layalle, S}, title = {ALS-Associated KIF5A Mutation Causes Locomotor Deficits Associated with Cytoplasmic Inclusions, Alterations of Neuromuscular Junctions, and Motor Neuron Loss.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {43}, number = {47}, pages = {8058-8072}, pmid = {37748861}, issn = {1529-2401}, mesh = {Male ; Animals ; Female ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Kinesins/genetics/metabolism ; Genome-Wide Association Study ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Neuromuscular Junction/metabolism ; Mutation/genetics ; Drosophila/metabolism ; Inclusion Bodies/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Recently, genome-wide association studies identified KIF5A as a new ALS-causing gene. KIF5A encodes a protein of the kinesin-1 family, allowing the anterograde transport of cargos along the microtubule rails in neurons. In ALS patients, mutations in the KIF5A gene induce exon 27 skipping, resulting in a mutated protein with a new C-terminal region (KIF5A Δ27). To understand how KIF5A Δ27 underpins the disease, we developed an ALS-associated KIF5A Drosophila model. When selectively expressed in motor neurons, KIF5A Δ27 alters larval locomotion as well as morphology and synaptic transmission at neuromuscular junctions in both males and females. We show that the distribution of mitochondria and synaptic vesicles is profoundly disturbed by KIF5A Δ27 expression. That is consistent with the numerous KIF5A Δ27-containing inclusions observed in motor neuron soma and axons. Moreover, KIF5A Δ27 expression leads to motor neuron death and reduces life expectancy. Our in vivo model reveals that a toxic gain of function underlies the pathogenicity of ALS-linked KIF5A mutant.SIGNIFICANCE STATEMENT Understanding how a mutation identified in patients with amyotrophic lateral sclerosis (ALS) causes the disease and the loss of motor neurons is crucial to fight against this disease. To this end, we have created a Drosophila model based on the motor neuron expression of the KIF5A mutant gene, recently identified in ALS patients. KIF5A encodes a kinesin that allows the anterograde transport of cargos. This model recapitulates the main features of ALS, including alterations of locomotion, synaptic neurotransmission, and morphology at neuromuscular junctions, as well as motor neuron death. KIF5A mutant is found in cytoplasmic inclusions, and its pathogenicity is because of a toxic gain of function.}, } @article {pmid37748443, year = {2024}, author = {Jütte, R}, title = {Involving Voters and Consumers in Decision-Making about the Health Care System - The Swiss Case: A Review.}, journal = {Complementary medicine research}, volume = {31}, number = {1}, pages = {78-83}, doi = {10.1159/000534268}, pmid = {37748443}, issn = {2504-2106}, mesh = {Humans ; Switzerland ; *Voting ; *Complementary Therapies ; Evidence-Based Medicine ; }, abstract = {BACKGROUND: Behind the principle of involving users and voters directly in decision-making about the health care system are ideas relating to empowerment. This implies a challenge to the traditional view that scientific knowledge is generally believed to be of higher value than empirical knowledge, as it is the case with CAM. The objectives of this review are (a) to show that this assumption disregards the fact that CAM is as scientific as conventional medicine but has different basic assumptions what the world is being made of and consequently uses different/adapted scientific methods; (b) to demonstrate how a perspective of the history of medicine and science as well as direct democracy mechanisms such as stipulated in the Swiss constitution can be used to achieve the acceptance of CAM in a modern medical health care system. A public health care system financed by levies from the population should also reflect the widely documented desire in the population for medical pluralism (provided that therapeutical alternatives are not risky). Otherwise, the problem of social inequality arises because only people with a good financial background can afford this medicine.

SUMMARY: From the perspective of scientific theory and the history of science, the answer to the question of whether complementary medicine and conventional medical procedures must provide proof of efficacy according to a uniform scientific is quite controversial according to epistemologically oriented studies on this issue.

KEY MESSAGES: This review found strong evidence for involving voters and consumers directly in decision-making about the provision of CAM in the health care system. It also seems necessary to step back in the debate on evidence-based medicine, taking a history of medicine and science perspective, as the role which the proper method occupies and plays in medicine is defined by the scientific nature of the world view.

UNLABELLED: Hinter dem Grundsatz, Nutzer und Wähler direkt in die Entscheidungsfindung über das Gesundheitssystem einzubeziehen, stehen Vorstellungen von Empowerment. Dies impliziert eine Infragestellung der traditionellen Ansicht, dass wissenschaftliches Wissen im Allgemeinen als wertvoller angesehen wird als empirisches Wissen und erprobte Erfahrung, wie es bei der Komplementärmedizin der Fall ist. Die Ziele dieser Übersichtsarbeit sind: (a) zu zeigen, dass diese Annahme die Tatsache außer Acht lässt, dass die Komplementärmedizin ebenso wissenschaftlich ist wie die Schulmedizin, aber von anderen Grundannahmen ausgeht, wie die Welt beschaffen ist, und folglich andere/angepasste wissenschaftliche Methoden anwendet; (b) aufzuzeigen, wie eine medizin- und wissenschaftsgeschichtliche Perspektive sowie Mechanismen der direkten Demokratie, wie sie in der Schweizer Verfassung vorgesehen sind, genutzt werden können, um die Akzeptanz der Komplementärmedizin in einem modernen medizinischen Gesundheitssystem zu erreichen. Ein öffentliches, durch Abgaben der Bevölkerung finanziertes Gesundheitssystem sollte auch dem vielfach dokumentierten Wunsch der Bevölkerung nach medizinischem Pluralismus Rechnung tragen (sofern die therapeutischen Alternativen nicht riskant sind). Andernfalls stellt sich das Problem der sozialen Ungleichheit, weil sich nur Menschen mit einem guten finanziellen Hintergrund diese Medizin leisten können.}, } @article {pmid37747929, year = {2023}, author = {Krupp, S and Hubbard, I and Tam, O and Hammell, GM and Dubnau, J}, title = {TDP-43 pathology in Drosophila induces glial-cell type specific toxicity that can be ameliorated by knock-down of SF2/SRSF1.}, journal = {PLoS genetics}, volume = {19}, number = {9}, pages = {e1010973}, pmid = {37747929}, issn = {1553-7404}, support = {R01 AG078788/AG/NIA NIH HHS/United States ; RF1 AG057338/AG/NIA NIH HHS/United States ; RF1 AG076493/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Astrocytes/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Drosophila/genetics/metabolism ; *Drosophila Proteins/genetics/metabolism ; *Frontotemporal Dementia ; Neurons/metabolism ; RNA Splicing Factors/metabolism ; }, abstract = {Accumulation of cytoplasmic inclusions of TAR-DNA binding protein 43 (TDP-43) is seen in both neurons and glia in a range of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). Disease progression involves non-cell autonomous interactions among multiple cell types, including neurons, microglia and astrocytes. We investigated the effects in Drosophila of inducible, glial cell type-specific TDP-43 overexpression, a model that causes TDP-43 protein pathology including loss of nuclear TDP-43 and accumulation of cytoplasmic inclusions. We report that TDP-43 pathology in Drosophila is sufficient to cause progressive loss of each of the 5 glial sub-types. But the effects on organismal survival were most pronounced when TDP-43 pathology was induced in the perineural glia (PNG) or astrocytes. In the case of PNG, this effect is not attributable to loss of the glial population, because ablation of these glia by expression of pro-apoptotic reaper expression has relatively little impact on survival. To uncover underlying mechanisms, we used cell-type-specific nuclear RNA sequencing to characterize the transcriptional changes induced by pathological TDP-43 expression. We identified numerous glial cell-type specific transcriptional changes. Notably, SF2/SRSF1 levels were found to be decreased in both PNG and in astrocytes. We found that further knockdown of SF2/SRSF1 in either PNG or astrocytes lessens the detrimental effects of TDP-43 pathology on lifespan, but extends survival of the glial cells. Thus TDP-43 pathology in astrocytes or PNG causes systemic effects that shorten lifespan and SF2/SRSF1 knockdown rescues the loss of these glia, and also reduces their systemic toxicity to the organism.}, } @article {pmid37747630, year = {2023}, author = {Oh, JE and Oh, JA and Demopoulos, M and Clark, KM and Phillips, MC}, title = {Impact of the metabolic syndrome on prevalence and survival in motor neuron disease: a retrospective case series.}, journal = {Metabolic brain disease}, volume = {38}, number = {8}, pages = {2583-2589}, pmid = {37747630}, issn = {1573-7365}, support = {Waikato Hospital Neurology Research Fund//Waikato Hospital Neurology Research Fund/ ; }, mesh = {Prevalence ; Retrospective Studies ; *Amyotrophic Lateral Sclerosis ; *Motor Neuron Disease/epidemiology/complications/diagnosis ; *Metabolic Syndrome/epidemiology/complications ; Humans ; Australasian People ; Maori People ; }, abstract = {Metabolic dysfunction is an important factor in the pathogenesis of motor neuron disease, but its prevalence and association with survival in this disorder is unknown. We hypothesized that patients with motor neuron disease would show a higher prevalence of metabolic syndrome compared to the general New Zealand population, and that metabolic syndrome would be associated with worsened survival. We undertook a retrospective analysis in 109 motor neuron disease patients diagnosed and treated at Waikato Hospital from 2013 to 2020. Demographic, clinical, and laboratory data were collected. Survival was defined as the date of initial symptom onset to the date of death. Of 104 eligible patients, 34 patients (33%) had metabolic syndrome (33% of Europeans, 46% of Māori). Mean survival in motor neuron disease patients with metabolic syndrome was significantly reduced compared to patients without metabolic syndrome (38 vs. 61 months, P = 0.044), with a 5-year survival rate of 21% for the former and 38% for the latter (P = 0.012). Compared with the general New Zealand population, metabolic syndrome is highly prevalent amongst motor neuron disease patients in the Waikato region and it is associated with worsened survival. Metabolic dysfunction may be a key factor underlying the pathogenesis of motor neuron disease.}, } @article {pmid37747451, year = {2023}, author = {Brisley, A and Lambert, H and Rodrigues, C}, title = {Antibiotics in Catalan Primary Care: Prescription, Use and Remedies for a Crisis of Care.}, journal = {Medical anthropology}, volume = {42}, number = {7}, pages = {682-696}, pmid = {37747451}, issn = {1545-5882}, support = {/WT_/Wellcome Trust/United Kingdom ; 210359/Z/18/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Anti-Bacterial Agents/therapeutic use ; Anthropology, Medical ; *Prescriptions ; Primary Health Care ; Europe ; }, abstract = {Antimicrobial resistance is one of the twenty-first century's major health challenges. Linked to the extensive use of antibiotics and other antimicrobials, resistance occurs when microbes stop responding to medications. Rates of antibiotic consumption in Spain are among the highest in Europe. Drawing on research conducted in Catalonia, in this article we present findings from ethnographic fieldwork and semi-structured interviews with general practitioners, residents of Barcelona, and professionals who have worked in antibiotic stewardship. We argue that the circulation of antibiotics should be understood in relation to broader historical processes and the deficient systems of health and social care provision they have produced.}, } @article {pmid37746849, year = {2023}, author = {Martino, J and Liu, Q and Vukojevic, K and Ke, J and Lim, TY and Khan, A and Gupta, Y and Perez, A and Yan, Z and Milo Rasouly, H and Vena, N and Lippa, N and Giordano, JL and Saraga, M and Saraga-Babic, M and Westland, R and Bodria, M and Piaggio, G and Bendapudi, PK and Iglesias, AD and Wapner, RJ and Tasic, V and Wang, F and Ionita-Laza, I and Ghiggeri, GM and Kiryluk, K and Sampogna, RV and Mendelsohn, CL and D'Agati, VD and Gharavi, AG and Sanna-Cherchi, S}, title = {Mouse and human studies support DSTYK loss of function as a low-penetrance and variable expressivity risk factor for congenital urinary tract anomalies.}, journal = {Genetics in medicine : official journal of the American College of Medical Genetics}, volume = {25}, number = {12}, pages = {100983}, doi = {10.1016/j.gim.2023.100983}, pmid = {37746849}, issn = {1530-0366}, support = {P20 DK116191/DK/NIDDK NIH HHS/United States ; R01 DK103184/DK/NIDDK NIH HHS/United States ; R01 DK115574/DK/NIDDK NIH HHS/United States ; T35 DK093430/DK/NIDDK NIH HHS/United States ; R01 DK080099/DK/NIDDK NIH HHS/United States ; U54 DK104309/DK/NIDDK NIH HHS/United States ; }, mesh = {*Urogenital Abnormalities/genetics ; Vesico-Ureteral Reflux ; Mice, Inbred C3H ; Mice, Inbred C57BL ; *Urinary Tract ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics ; Risk Factors ; Penetrance ; Humans ; Mice ; Animals ; *Epilepsy/genetics ; Kidney/abnormalities ; }, abstract = {PURPOSE: Previous work identified rare variants in DSTYK associated with human congenital anomalies of the kidney and urinary tract (CAKUT). Here, we present a series of mouse and human studies to clarify the association, penetrance, and expressivity of DSTYK variants.

METHODS: We phenotypically characterized Dstyk knockout mice of 3 separate inbred backgrounds and re-analyzed the original family segregating the DSTYK c.654+1G>A splice-site variant (referred to as "SSV" below). DSTYK loss of function (LOF) and SSVs were annotated in individuals with CAKUT, epilepsy, or amyotrophic lateral sclerosis vs controls. A phenome-wide association study analysis was also performed using United Kingdom Biobank (UKBB) data.

RESULTS: Results demonstrate ∼20% to 25% penetrance of obstructive uropathy, at least, in C57BL/6J and FVB/NJ Dstyk[-/-] mice. Phenotypic penetrance increased to ∼40% in C3H/HeJ mutants, with mild-to-moderate severity. Re-analysis of the original family segregating the rare SSV showed low penetrance (43.8%) and no alternative genetic causes for CAKUT. LOF DSTYK variants burden showed significant excess for CAKUT and epilepsy vs controls and an exploratory phenome-wide association study supported association with neurological disorders.

CONCLUSION: These data support causality for DSTYK LOF variants and highlights the need for large-scale sequencing studies (here >200,000 cases) to accurately assess causality for genes and variants to lowly penetrant traits with common population prevalence.}, } @article {pmid37746513, year = {2023}, author = {Singh, A and Arora, S and Chavan, M and Shahbaz, S and Jabeen, H}, title = {An Overview of the Neurotrophic and Neuroprotective Properties of the Psychoactive Drug Lithium as an Autophagy Modulator in Neurodegenerative Conditions.}, journal = {Cureus}, volume = {15}, number = {8}, pages = {e44051}, pmid = {37746513}, issn = {2168-8184}, abstract = {For both short-term and long-term treatment of bipolar disorder, lithium is a prototypical mood stabilizer. Lithium's neuroprotective properties were revealed by cumulative translational research, which opened the door to reforming the chemical as a treatment for neurodegenerative illnesses. The control of homeostatic systems such as oxidative stress, autophagy, apoptosis, mitochondrial function, and inflammation underlies lithium's neuroprotective characteristics. The fact that lithium inhibits the enzymes inositol monophosphatase (IMPase) and glycogen synthase kinase (GSK)-3 may be the cause of the various intracellular reactions. In this article, we review lithium's neurobiological properties, as demonstrated by its neurotrophic and neuroprotective capabilities, as well as translational studies in cells in culture and in animal models of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Prion disease, amyotrophic lateral sclerosis (ALS), ischemic stroke, and neuronal ceroid lipofuscinosis (NCL), discussing the justification for the drug's use in the treatment of these neurodegenerative disorders.}, } @article {pmid37746061, year = {2023}, author = {Bennett, SA and Cobos, SN and Son, E and Segal, R and Mathew, S and Yousuf, H and Torrente, MP}, title = {Impaired RNA Binding Does Not Prevent Histone Modification Changes in a FUS ALS/FTD Yeast Model.}, journal = {microPublication biology}, volume = {2023}, number = {}, pages = {}, pmid = {37746061}, issn = {2578-9430}, support = {R15 NS125394/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in the RNA-binding protein FUS are linked to amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). FUS mutants mislocalize and aggregate in dying neurons. We previously established that FUS proteinopathy is linked to changes in the histone modification landscape in a yeast ALS/FTD model. Here, we examine whether FUS' RNA binding is necessary for this connection. We find that overexpression of a FUS mutant unable to bind RNA is still associated with reduced levels of H3S10ph, H3K14ac and H3K56ac. Hence, FUS' ability to bind RNA is not required in the mechanism connecting FUS proteinopathy to altered histone post-translational modifications.}, } @article {pmid37745492, year = {2024}, author = {Hwang, RD and Lu, Y and Tang, Q and Periz, G and Park, G and Li, X and Xiang, Q and Liu, Y and Zhang, T and Wang, J}, title = {DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.09.12.556394}, pmid = {37745492}, issn = {2692-8205}, abstract = {Proteotoxic stress impairs cellular homeostasis and underlies the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The proteasomal and autophagic degradation of proteins are two major pathways for protein quality control in the cell. Here, we report a genome-wide CRISPR screen uncovering a major regulator of cytotoxicity resulting from the inhibition of the proteasome. Dihydrolipoamide branched chain transacylase E2 (DBT) was found to be a robust suppressor, the loss of which protects against proteasome inhibition-associated cell death through promoting clearance of ubiquitinated proteins. Loss of DBT altered the metabolic and energetic status of the cell and resulted in activation of autophagy in an AMP-activated protein kinase (AMPK)-dependent mechanism in the presence of proteasomal inhibition. Loss of DBT protected against proteotoxicity induced by ALS-linked mutant TDP-43 in Drosophila and mammalian neurons. DBT is upregulated in the tissues from ALS patients. These results demonstrate that DBT is a master switch in the metabolic control of protein quality control with implications in neurodegenerative diseases.}, } @article {pmid37745304, year = {2023}, author = {Yokota, M and Yoshino, Y and Hosoi, M and Hashimoto, R and Kakuta, S and Shiga, T and Ishikawa, KI and Okano, H and Hattori, N and Akamatsu, W and Koike, M}, title = {Reduced ER-mitochondrial contact sites and mitochondrial Ca[2+] flux in PRKN-mutant patient tyrosine hydroxylase reporter iPSC lines.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1171440}, pmid = {37745304}, issn = {2296-634X}, abstract = {Endoplasmic reticulum-mitochondrial contact sites (ERMCS) play an important role in mitochondrial dynamics, calcium signaling, and autophagy. Disruption of the ERMCS has been linked to several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, the etiological role of ERMCS in these diseases remains unclear. We previously established tyrosine hydroxylase reporter (TH-GFP) iPSC lines from a PD patient with a PRKN mutation to perform correlative light-electron microscopy (CLEM) analysis and live cell imaging in GFP-expressing dopaminergic neurons. Here, we analyzed ERMCS in GFP-expressing PRKN-mutant dopaminergic neurons from patients using CLEM and a proximity ligation assay (PLA). The PLA showed that the ERMCS were significantly reduced in PRKN-mutant patient dopaminergic neurons compared to the control under normal conditions. The reduction of the ERMCS in PRKN-mutant patient dopaminergic neurons was further enhanced by treatment with a mitochondrial uncoupler. In addition, mitochondrial calcium imaging showed that mitochondrial Ca[2+] flux was significantly reduced in PRKN-mutant patient dopaminergic neurons compared to the control. These results suggest a defect in calcium flux from ER to mitochondria is due to the decreased ERMCS in PRKN-mutant patient dopaminergic neurons. Our study of ERMCS using TH-GFP iPSC lines would contribute to further understanding of the mechanisms of dopaminergic neuron degeneration in patients with PRKN mutations.}, } @article {pmid37744877, year = {2023}, author = {Wilkins, JM and Gakh, O and Guo, Y and Popescu, B and Staff, NP and Lucchinetti, CF}, title = {Biomolecular alterations detected in multiple sclerosis skin fibroblasts using Fourier transform infrared spectroscopy.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1223912}, pmid = {37744877}, issn = {1662-5102}, abstract = {Multiple sclerosis (MS) is the leading cause of non-traumatic disability in young adults. New avenues are needed to help predict individuals at risk for developing MS and aid in diagnosis, prognosis, and outcome of therapeutic treatments. Previously, we showed that skin fibroblasts derived from patients with MS have altered signatures of cell stress and bioenergetics, which likely reflects changes in their protein, lipid, and biochemical profiles. Here, we used Fourier transform infrared (FTIR) spectroscopy to determine if the biochemical landscape of MS skin fibroblasts were altered when compared to age- and sex-matched controls (CTRL). More so, we sought to determine if FTIR spectroscopic signatures detected in MS skin fibroblasts are disease specific by comparing them to amyotrophic lateral sclerosis (ALS) skin fibroblasts. Spectral profiling of skin fibroblasts from MS individuals suggests significant alterations in lipid and protein organization and homeostasis, which may be affecting metabolic processes, cellular organization, and oxidation status. Sparse partial least squares-discriminant analysis of spectral profiles show that CTRL skin fibroblasts segregate well from diseased cells and that changes in MS and ALS may be unique. Differential changes in the spectral profile of CTRL, MS, and ALS cells support the development of FTIR spectroscopy to detect biomolecular modifications in patient-derived skin fibroblasts, which may eventually help establish novel peripheral biomarkers.}, } @article {pmid37741764, year = {2024}, author = {Ducharme, S and Pijnenburg, Y and Rohrer, JD and Huey, E and Finger, E and Tatton, N}, title = {Identifying and Diagnosing TDP-43 Neurodegenerative Diseases in Psychiatry.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {32}, number = {1}, pages = {98-113}, pmid = {37741764}, issn = {1545-7214}, support = {U01 AG079850/AG/NIA NIH HHS/United States ; MR/M008525/1/MRC_/Medical Research Council/United Kingdom ; R01 MH120794/MH/NIMH NIH HHS/United States ; MR/T046015/1/MRC_/Medical Research Council/United Kingdom ; R01 AG062268/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; DNA-Binding Proteins/genetics ; *Frontotemporal Dementia/diagnosis/genetics ; *Neurodegenerative Diseases/diagnosis/genetics ; *Psychiatry ; }, abstract = {Neuropsychiatric symptoms (NPS) are common manifestations of neurodegenerative disorders and are often early signs of those diseases. Among those neurodegenerative diseases, TDP-43 proteinopathies are an increasingly recognized cause of early neuropsychiatric manifestations. TDP-43-related diseases include frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE). The majority of TDP-43-related diseases are sporadic, but a significant proportion is hereditary, with progranulin (GRN) mutations and C9orf72 repeat expansions as the most common genetic etiologies. Studies reveal that NPS can be the initial manifestation of those diseases or can complicate disease course, but there is a lack of awareness among clinicians about TDP-43-related diseases, which leads to common diagnostic mistakes or delays. There is also emerging evidence that TDP-43 accumulations could play a role in late-onset primary psychiatric disorders. In the absence of robust biomarkers for TDP-43, the diagnosis remains primarily based on clinical assessment and neuroimaging. Given the association with psychiatric symptoms, clinical psychiatrists have a key role in the early identification of patients with TDP-43-related diseases. This narrative review provides a comprehensive overview of the pathobiology of TDP-43, resulting clinical presentations, and associated neuropsychiatric manifestations to help guide clinical practice.}, } @article {pmid37741265, year = {2024}, author = {Li, M and Zhang, L and Jiang, LL and Zhao, ZB and Long, YH and Chen, DM and Bin, J and Kang, C and Liu, YJ}, title = {Label-free Raman microspectroscopic imaging with chemometrics for cellular investigation of apple ring rot and nondestructive early recognition using near-infrared reflection spectroscopy with machine learning.}, journal = {Talanta}, volume = {267}, number = {}, pages = {125212}, doi = {10.1016/j.talanta.2023.125212}, pmid = {37741265}, issn = {1873-3573}, mesh = {Machine Learning ; *Malus ; Chemometrics ; Spectroscopy, Near-Infrared/methods ; Ascomycota ; Pectins ; }, abstract = {Apple ring rot caused by Botryosphaeria dothidea can cause fruit decay during the growth and storage stages of apple fruit. Understanding the infection process and cellular defense response at the cellular micro-level holds immense importance in the field of prevention and control. Consequently, there is a pressing need to develop suitable chemical imaging analysis methods. Here we proposed a label-free, high-throughput imaging method for cellular investigation of apple fruit ring rot infected by Botryosphaeria dothidea, based on confocal Raman microspectroscopic imaging technology combined with multivariate curve resolution-alternating least squares algorithm (MCR-ALS). We conducted Raman measurements on every apple fruit and obtain an image cube. This cube was then unfolded into an augmented matrix in a column-wise manner. We proceeded with simultaneous MCR-ALS analysis, resolving the single-substance spectrum and concentration profile from the mixed signals. Lastly, the accurate and pure molecular imaging of low methoxyl pectin, high methoxyl pectin, cellulose, lignin, and phenols were realized by refolding the resolved concentration data to construct the composition image. Thereafter, we realized the study of the spatial-temporal changes distribution of the above substances in the cuticle and cell wall of green and red apples at different stages of infection. The imaging method proposed in this paper is expected to provide a chemical imaging strategy for studying pathogen infection process and fruit defense response at the cellular level. In addition, by utilizing a fiber-optic probe near-infrared reflection spectrometer in conjunction with machine learning, we developed a rapid and non-destructive classification method. This method allows for the timely identification of apples exhibiting early infection by Botryosphaeria dothidea. Notably, both principal component analysis-quadratic discriminant analysis and support vector machine achieved a classification accuracy of 100%.}, } @article {pmid37741154, year = {2023}, author = {Wabwile, JM and Angeyo, HK and Massop, AD}, title = {Exploring band-free Raman microspectrometry combined with PCA and MCR-ALS for size-resolved forensic analysis of uranium in aerosols in a model nuclear atmosphere.}, journal = {Journal of environmental radioactivity}, volume = {270}, number = {}, pages = {107295}, doi = {10.1016/j.jenvrad.2023.107295}, pmid = {37741154}, issn = {1879-1700}, mesh = {*Radiation Monitoring ; *Uranium/analysis ; Least-Squares Analysis ; Principal Component Analysis ; Aerosols/analysis ; Atmosphere ; }, abstract = {Achieving non-destructive micrometer-scale molecular and structural analysis of uranic materials in atmospheric aerosols with traditional methodologies is a challenge. Spatially resolved analysis of uranium in actinide-bearing aerosols is critical for nuclear forensics. Although laser Raman microspectrometry enables this, for the normally low uranium concentrations in the aerosols the spectra are indiscernible (band-free) against pronounced background: trace analysis requires a push in analytical strategy. We combined laser Raman microspectrometry (utilizing two lasers (λ = 532 nm, λ = 785 nm)) with principal component analysis (PCA) and multivariate curve resolution-alternate least squares (MCR-ALS) to perform size-resolved analysis of uranium in aerosols. Uranium-specific Raman scatter bands corresponding to uranyl nitrate (860 cm[-1]), uranium sulphate (868 cm[-1]), uranyl chloride (816 cm[-1]) and uranium trioxide (839 cm[-1]) were detected. The 816 cm[-1], 854 cm[-1], 868 cm[-1] bands were resolved by MCR-ALS and used to identify and map uranium in PM4.5 size aerosols. Based on spectral feature selection of the signature bands, PCA identified two sources of aerosol particles in model nuclear atmosphere - Sea spray for PM4.5 and re-suspension of 'nuclear' dust from a rare earth element (REE) mine for PM2.5. The MCR-ALS-resolved uranium bands showed the potential for attributive nuclear forensic analysis.}, } @article {pmid37740686, year = {2023}, author = {Vucic, S and Kiernan, MC}, title = {Nanocrystalline gold (CNM-Au8): a novel bioenergetic treatment for ALS.}, journal = {Expert opinion on investigational drugs}, volume = {32}, number = {9}, pages = {783-785}, doi = {10.1080/13543784.2023.2263368}, pmid = {37740686}, issn = {1744-7658}, } @article {pmid37739217, year = {2023}, author = {Chakraborty, J and Chakraborty, S and Chakraborty, S and Narayan, MN}, title = {Entanglement of MAPK pathways with gene expression and its omnipresence in the etiology for cancer and neurodegenerative disorders.}, journal = {Biochimica et biophysica acta. Gene regulatory mechanisms}, volume = {1866}, number = {4}, pages = {194988}, doi = {10.1016/j.bbagrm.2023.194988}, pmid = {37739217}, issn = {1876-4320}, mesh = {Humans ; Mitogen-Activated Protein Kinases ; MAP Kinase Signaling System/genetics ; *Neoplasms/genetics/drug therapy ; *Neurodegenerative Diseases/genetics ; Gene Expression ; }, abstract = {Mitogen Activated Protein Kinase (MAPK) is one of the most well characterized cellular signaling pathways that controls fundamental cellular processes including proliferation, differentiation, and apoptosis. These cellular functions are consequences of transcription of regulatory genes that are influenced and regulated by the MAP-Kinase signaling cascade. MAP kinase components such as Receptor Tyrosine Kinases (RTKs) sense external cues or ligands and transmit these signals via multiple protein complexes such as RAS-RAF, MEK, and ERKs and eventually modulate the transcription factors inside the nucleus to induce transcription and other regulatory functions. Aberrant activation, dysregulation of this signaling pathway, and genetic alterations in any of these components results in the developmental disorders, cancer, and neurodegenerative disorders. Over the years, the MAPK pathway has been a prime pharmacological target, to treat complex human disorders that are genetically linked such as cancer, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The current review re-visits the mechanism of MAPK pathways in gene expression regulation. Further, a current update on the progress of the mechanistic understanding of MAPK components is discussed from a disease perspective.}, } @article {pmid37739207, year = {2023}, author = {Verdile, V and Palombo, R and Ferrante, G and Ferri, A and Amadio, S and Volonté, C and Paronetto, MP}, title = {Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis.}, journal = {Progress in neurobiology}, volume = {231}, number = {}, pages = {102529}, doi = {10.1016/j.pneurobio.2023.102529}, pmid = {37739207}, issn = {1873-5118}, mesh = {Humans ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Alternative Splicing/genetics ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Superoxide Dismutase-1/genetics ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles. A hallmark of ALS is the frequent nuclear loss and cytoplasmic accumulation of RNA binding proteins (RBPs) in motor neurons (MN), which leads to aberrant alternative splicing regulation. However, whether altered splicing patterns are also present in familial models of ALS without mutations in RBP-encoding genes has not been investigated yet. Herein, we found that altered splicing of synaptic genes is a common trait of familial ALS MNs. Similar deregulation was also observed in hSOD1[G93A] MN-like cells. In silico analysis identified the potential regulators of these pre-mRNAs, including the RBP Sam68. Immunofluorescence analysis and biochemical fractionation experiments revealed that Sam68 accumulates in the cytoplasmic insoluble ribonucleoprotein fraction of MN. Remarkably, the synaptic splicing events deregulated in ALS MNs were also affected in Sam68[-/-] spinal cords. Recombinant expression of Sam68 protein was sufficient to rescue these splicing changes in ALS hSOD1[G93A] MN-like cells. Hence, our study highlights an aberrant function of Sam68, which leads to splicing changes in synaptic genes and may contribute to the MN phenotype that characterizes ALS.}, } @article {pmid37739033, year = {2023}, author = {Tanaka, Y and Ito, SI and Honma, Y and Hasegawa, M and Kametani, F and Suzuki, G and Kozuma, L and Takeya, K and Eto, M}, title = {Dysregulation of the progranulin-driven autophagy-lysosomal pathway mediates secretion of the nuclear protein TDP-43.}, journal = {The Journal of biological chemistry}, volume = {299}, number = {11}, pages = {105272}, pmid = {37739033}, issn = {1083-351X}, mesh = {Humans ; *Autophagy/drug effects/genetics ; *DNA-Binding Proteins/genetics/metabolism ; HeLa Cells ; Intercellular Signaling Peptides and Proteins/genetics/metabolism ; *Lysosomes/metabolism ; *Progranulins/genetics/metabolism ; Microtubule-Associated Proteins/genetics/metabolism ; Gene Expression Regulation/drug effects ; Extracellular Vesicles/metabolism ; Enzyme Inhibitors/pharmacology ; Autophagosomes/drug effects/metabolism ; Autophagy-Related Proteins/genetics/metabolism ; }, abstract = {The cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 kDa (TDP-43) has been linked to the progression of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 secreted into the extracellular space has been suggested to contribute to the cell-to-cell spread of the cytoplasmic accumulation of TDP-43 throughout the brain; however, the underlying mechanisms remain unknown. We herein demonstrated that the secretion of TDP-43 was stimulated by the inhibition of the autophagy-lysosomal pathway driven by progranulin (PGRN), a causal protein of frontotemporal lobar degeneration. Among modulators of autophagy, only vacuolar-ATPase inhibitors, such as bafilomycin A1 (Baf), increased the levels of the full-length and cleaved forms of TDP-43 and the autophagosome marker LC3-II (microtubule-associated proteins 1A/1B light chain 3B) in extracellular vesicle fractions prepared from the culture media of HeLa, SH-SY5Y, or NSC-34 cells, whereas vacuolin-1, MG132, chloroquine, rapamycin, and serum starvation did not. The C-terminal fragment of TDP-43 was required for Baf-induced TDP-43 secretion. The Baf treatment induced the translocation of the aggregate-prone GFP-tagged C-terminal fragment of TDP-43 and mCherry-tagged LC3 to the plasma membrane. The Baf-induced secretion of TDP-43 was attenuated in autophagy-deficient ATG16L1 knockout HeLa cells. The knockdown of PGRN induced the secretion of cleaved TDP-43 in an autophagy-dependent manner in HeLa cells. The KO of PGRN in mouse embryonic fibroblasts increased the secretion of the cleaved forms of TDP-43 and LC3-II. The treatment inducing TDP-43 secretion increased the nuclear translocation of GFP-tagged transcription factor EB, a master regulator of the autophagy-lysosomal pathway in SH-SY5Y cells. These results suggest that the secretion of TDP-43 is promoted by dysregulation of the PGRN-driven autophagy-lysosomal pathway.}, } @article {pmid37738797, year = {2023}, author = {Dong, W and Peng, Q and Liu, Z and Xie, Z and Guo, X and Li, Y and Chen, C}, title = {Estrogen plays an important role by influencing the NLRP3 inflammasome.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {167}, number = {}, pages = {115554}, doi = {10.1016/j.biopha.2023.115554}, pmid = {37738797}, issn = {1950-6007}, abstract = {The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is an important part of the natural immune system that plays an important role in many diseases. Estrogen is a sex hormone that plays an important role in controlling reproduction and regulates many physiological and pathological processes. Recent studies have indicated that estrogen is associated with disease progression. Estrogen can ameliorate some diseases (e. g, sepsis, mood disturbances, cerebral ischemia, some hepatopathy, Parkinson's disease, amyotrophic lateral sclerosis, inflammatory bowel disease, spinal cord injury, multiple sclerosis, myocardial ischemia/reperfusion injury, osteoarthritis, and renal fibrosis) by inhibiting the NLRP3 inflammasome. Estrogen can also promote the development of diseases (e.g., ovarian endometriosis, dry eye disease, and systemic lupus erythematosus) by upregulating the NLRP3 inflammasome. In addition, estrogen has a dual effect on the development of cancers and asthma. However, the mechanism of these effects is not summarized. This article reviewed the progress in understanding the effects of estrogen on the NLRP3 inflammasome and its mechanisms in recent years to provide a theoretical basis for an in-depth study.}, } @article {pmid37737151, year = {2024}, author = {Cabona, C and Ferraro, PM and Scialò, C and Bandettini Di Poggio, M and Novi, G and Gemelli, C and Vignolo, M and Rao, F and Capovilla, M and Marogna, M and Mandich, P and Origone, P and Schenone, A and Caponnetto, C}, title = {Clinical epidemiology of amyotrophic lateral sclerosis in Liguria, Italy: a ten year follow up study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {104-111}, doi = {10.1080/21678421.2023.2260842}, pmid = {37737151}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/therapy ; Follow-Up Studies ; Prospective Studies ; Delayed Diagnosis ; Italy/epidemiology ; }, abstract = {OBJECTIVE: This article presents an updated analysis of the LIGALS register, a prospective study conducted over a ten-year period (2009-2018) in Liguria, Italy, aimed at evaluating the incidence, prevalence, clinical presentation, and management of amyotrophic lateral sclerosis (ALS).

METHODS: We calculated the mean annual crude incidence rate of ALS, assessed the point prevalence of ALS on January 1, 2018, and analyzed demographic factors, clinical characteristics, and clinical management strategies. Data analysis included Cox regression analysis to identify predictors of survival.

RESULTS: The mean annual crude incidence rate of ALS was 3.16/100,000 per year (CI 95%) while the point prevalence of ALS on January 1, 2018, was 9.31/100,000 population (CI 95%). Among the patients, 6.5% were familial ALS, while 93.5% were sporadic cases. Clinical management strategies, including percutaneous endoscopic gastrostomy (PEG) and noninvasive ventilation (NIV), were employed. The study observed a stable frequency of NIV initiation and PEG placement over time, with a growing trend toward earlier PEG positioning. The mean survival from symptom onset was 39 months, whereas from diagnosis, it was 26 months. Cox regression analysis identified several predictors of survival, including gender, age at onset and diagnosis, site of onset, diagnostic category, phenotype, and diagnostic delay.

CONCLUSIONS: This comprehensive analysis provides valuable insights into the long-term trends in ALS epidemiology and clinical management in Liguria, Italy. It underscores the importance of continued research efforts in understanding and addressing the challenges posed by ALS, particularly in terms of early diagnosis and optimizing clinical interventions to improve patient outcomes.}, } @article {pmid37736795, year = {2024}, author = {Liu, WS and Zhang, YR and Ge, YJ and Wang, HF and Cheng, W and Yu, JT}, title = {Inflammation and Brain Structure in Alzheimer's Disease and Other Neurodegenerative Disorders: a Mendelian Randomization Study.}, journal = {Molecular neurobiology}, volume = {61}, number = {3}, pages = {1593-1604}, pmid = {37736795}, issn = {1559-1182}, mesh = {Humans ; *Alzheimer Disease/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics ; *Parkinson Disease/genetics ; Brain/metabolism ; Inflammation/genetics ; Cytokines/genetics/metabolism ; *Encephalitis ; }, abstract = {Previous in vitro and post-mortem studies have reported the role of inflammation in neurodegenerative disorders. However, the association between inflammation and brain structure in vivo and the transcriptome-driven functional basis with relevance to neurodegenerative disorders remains elusive. The aim of the present study is to identify the association among inflammation, brain structure, and neurodegenerative disorders at genetic and transcriptomic levels. Genetic variants associated with inflammatory cytokines were selected from the latest and largest genome-wide association studies of European ancestry. Neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and dementia with Lewy bodies (DLB) and brain structure imaging measures were selected as the outcomes. Two-sample Mendelian randomization analyses were conducted to identify the causal associations. Single-nucleus transcriptome data of the occipitotemporal cortex was further analyzed to identify the differential expressed genes in AD, which were tested for biological processes and protein interaction network. MR analysis indicated that genetically predicted TREM2 and sTREM2 were significantly associated with AD (TREM2: z-score = -9.088, p-value = 1.02 × 10[-19]; sTREM2: z-score = -7.495, p-value = 6.61 × 10[-14]). The present study found no evidence to support the causal associations between other inflammatory cytokines and the risks of AD, PD, ALS, or DLB. Genetically predicted TREM2 was significantly associated with the cortical thickness of inferior temporal (z-score = -4.238, p-value = 2.26 × 10[-5]) and pole temporal (z-score = -4.549, p-value = 5.40 × 10[-6]). In the occipitotemporal cortex samples, microglia were the main source of TREM2 gene and showed increasing expression of genes associated with inflammation and immunity. The present study has leveraged genetic and transcriptomic data to identify the association among TREM2, temporal lobe, and AD and the underlying cellular and molecular basis, thus providing a new perspective on the role of TREM2 in AD and insights into the complex associations among inflammation, brain structure, and neurodegenerative disorders, particularly AD.}, } @article {pmid37736756, year = {2023}, author = {Vahsen, BF and Nalluru, S and Morgan, GR and Farrimond, L and Carroll, E and Xu, Y and Cramb, KML and Amein, B and Scaber, J and Katsikoudi, A and Candalija, A and Carcolé, M and Dafinca, R and Isaacs, AM and Wade-Martins, R and Gray, E and Turner, MR and Cowley, SA and Talbot, K}, title = {C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {5898}, pmid = {37736756}, issn = {2041-1723}, support = {MR/M024962/1/MRC_/Medical Research Council/United Kingdom ; 102176/Z/13/Z/WT_/Wellcome Trust/United Kingdom ; MR/N013468/1/MRC_/Medical Research Council/United Kingdom ; WADE-MARTINS/OCT13/867-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; /DH_/Department of Health/United Kingdom ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; 203141/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Matrix Metalloproteinase 9/genetics ; C9orf72 Protein/genetics ; Microglia ; Coculture Techniques ; *Induced Pluripotent Stem Cells ; Lipopolysaccharides ; *Neurodegenerative Diseases ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, with additional pathophysiological involvement of non-neuronal cells such as microglia. The commonest ALS-associated genetic variant is a hexanucleotide repeat expansion (HRE) mutation in C9orf72. Here, we study its consequences for microglial function using human iPSC-derived microglia. By RNA-sequencing, we identify enrichment of pathways associated with immune cell activation and cyto-/chemokines in C9orf72 HRE mutant microglia versus healthy controls, most prominently after LPS priming. Specifically, LPS-primed C9orf72 HRE mutant microglia show consistently increased expression and release of matrix metalloproteinase-9 (MMP9). LPS-primed C9orf72 HRE mutant microglia are toxic to co-cultured healthy motor neurons, which is ameliorated by concomitant application of an MMP9 inhibitor. Finally, we identify release of dipeptidyl peptidase-4 (DPP4) as a marker for MMP9-dependent microglial dysregulation in co-culture. These results demonstrate cellular dysfunction of C9orf72 HRE mutant microglia, and a non-cell-autonomous role in driving C9orf72-ALS pathophysiology in motor neurons through MMP9 signaling.}, } @article {pmid37736625, year = {2023}, author = {Kvande, K and Garetto, B and Deplano, G and Signorile, M and Solemsli, BG and Prodinger, S and Olsbye, U and Beato, P and Bordiga, S and Svelle, S and Borfecchia, E}, title = {Understanding C-H activation in light alkanes over Cu-MOR zeolites by coupling advanced spectroscopy and temperature-programmed reduction experiments.}, journal = {Chemical science}, volume = {14}, number = {36}, pages = {9704-9723}, pmid = {37736625}, issn = {2041-6520}, abstract = {The direct activation of methane to methanol (MTM) proceeds through a chemical-looping process over Cu-oxo sites in zeolites. Herein, we extend the overall understanding of oxidation reactions over metal-oxo sites and C-H activation reactions by pinpointing the evolution of Cu species during reduction. To do so, a set of temperature-programmed reduction experiments were performed with CH4, C2H6, and CO. With a temperature ramp, the Cu reduction could be accelerated to detect changes in Cu speciation that are normally not detected due to the slow CH4 adsorption/interaction during MTM (∼200 °C). To follow the Cu-speciation with the three reductants, X-ray absorption spectroscopy (XAS), UV-vis and FT-IR spectroscopy were applied. Multivariate curve resolution alternating least-square (MCR-ALS) analysis was used to resolve the time-dependent concentration profiles of pure Cu components in the X-ray absorption near edge structure (XANES) spectra. Within the large datasets, as many as six different Cu[II] and Cu[I] components were found. Close correlations were found between the XANES-derived Cu[II] to Cu[I] reduction, CH4 consumption, and CO2 production. A reducibility-activity relationship was also observed for the Cu-MOR zeolites. Extended X-ray absorption fine structure (EXAFS) spectra for the pure Cu components were furthermore obtained with MCR-ALS analysis. With wavelet transform (WT) analysis of the EXAFS spectra, we were able to resolve the atomic speciation at different radial distances from Cu (up to about 4 Å). These results indicate that all the Cu[II] components consist of multimeric Cu[II]-oxo sites, albeit with different Cu-Cu distances.}, } @article {pmid37736067, year = {2023}, author = {Chambers, C and Lichten, L and Crook, A and Uhlmann, WR and Dratch, L}, title = {Incorporating Genetic Testing Into the Care of Patients With Amyotrophic Lateral Sclerosis/Frontotemporal Degeneration Spectrum Disorders.}, journal = {Neurology. Clinical practice}, volume = {13}, number = {5}, pages = {e200201}, pmid = {37736067}, issn = {2163-0402}, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorders have a strong genetic component. Genetic counselors are a limited resource, and therefore, other providers must be prepared to integrate genetic testing into their practice.

RECENT FINDINGS: Recent ALS/FTD studies have demonstrated that lack of family history does not preclude a genetic etiology. The benefits of a genetic diagnosis have expanded to include the potential to treat; thus, genetic testing is increasingly recommended to be offered to all persons with ALS/FTD.

SUMMARY: Offering genetic testing to persons with ALS/FTD spectrum disorders should be part of routine clinical neurologic care. All genetic testing should include discussion about the medical and psychosocial implications of testing for the patient and family members. Neurologists should be prepared to facilitate this process and recognize when referral to a genetic counselor is indicated.}, } @article {pmid37735909, year = {2023}, author = {Irie, T and Sawa, M}, title = {CDC7 kinase inhibitors: a survey of recent patent literature (2017-2022).}, journal = {Expert opinion on therapeutic patents}, volume = {33}, number = {7-8}, pages = {493-501}, doi = {10.1080/13543776.2023.2262138}, pmid = {37735909}, issn = {1744-7674}, mesh = {Humans ; *Cell Cycle Proteins/metabolism ; Patents as Topic ; Protein Serine-Threonine Kinases ; DNA Replication ; *Neoplasms ; }, abstract = {INTRODUCTION: CDC7 is a serine/threonine kinase which plays an important role in DNA replication. Inhibition of CDC7 in cancer cells causes lethal S phase or M phase progression, whereas inhibition of CDC7 in normal cells does not cause cell death and only leads to cell cycle arrest at the DNA replication checkpoint. Therefore, CDC7 has been recognized as a potential target for novel therapeutic interventions in cancers.

AREAS COVERED: Patent literature claiming novel small molecule compounds inhibiting CDC7 disclosed from 2017 to 2022.

EXPERT OPINION: Despite the indisputable positive impact of CDC7 as a drug target, there have been reported only a handful of chemical scaffolds as CDC7 inhibitors. Several CDC7 inhibitors have been progressed into clinical trials for cancer treatments, but they did not result in satisfactory efficacies in those trials. One possible reason for the failure might be due to the dose-limiting toxicities, and some of the observed toxicities were thought to be not related to CDC7 inhibition, suggesting it should be important to identify novel chemical scaffolds to eliminate unwanted toxicities. Another important factor is the patient stratification that would enable greater response, and the identification of such predictive biomarkers should be the key to success for the development of CDC7 inhibitors.}, } @article {pmid37735683, year = {2023}, author = {Sołek, P and Czechowska, E and Sowa-Kućma, M and Stachowicz, K and Kaczka, P and Tabęcka-Łonczyńska, A}, title = {Elucidating the molecular mechanisms underlying the induction of autophagy by antidepressant-like substances in C57BL/6J mouse testis model upon LPS challenge.}, journal = {Cell communication and signaling : CCS}, volume = {21}, number = {1}, pages = {251}, pmid = {37735683}, issn = {1478-811X}, mesh = {Animals ; Male ; Mice ; Antidepressive Agents/pharmacology ; Autophagy ; *Lipopolysaccharides/pharmacology ; Mice, Inbred C57BL ; Testis ; }, abstract = {The treatment of depression with pharmaceuticals is associated with many adverse side effects, including male fertility problems. The precise mechanisms by which these agents affect testicular cells remain largely unknown, but they are believed to induce cellular stress, which is sensed by the endoplasmic reticulum (ER) and the Golgi apparatus. These organelles are responsible for maintaining cellular homeostasis and regulating signal pathways that lead to autophagy or apoptosis. Therefore, in this study, we aimed to investigate the autophagy, ER, and Golgi stress-related pathways in mouse testis following treatment with antidepressant-like substances (ALS) and ALS combined with lipopolysaccharide (LPS). We found that most ALS and activated proteins are associated with the induction of apoptosis. However, when imipramine (IMI) was combined with NS-398 (a cyclooxygenase-2 inhibitor) after LPS administration, we observed a marked increase in the BECLIN1, Bcl-2, ATG16L, and LC3 expression, which are marker proteins of autophagosome formation. The expression of the BECN1 and ATG16L genes was also high compared to the control, indicating the induction of autophagy processes that may potentially protect mouse testicular cells from death and regulate metabolism in the testis. Our findings may provide a better understanding of the stress-related effects of specific ALS on the testis. Video Abstract.}, } @article {pmid37735622, year = {2023}, author = {Sarkar, S and Elliott, EC and Henry, HR and Ludovico, ID and Melchior, JT and Frazer-Abel, A and Webb-Robertson, BJ and Davidson, WS and Holers, VM and Rewers, MJ and Metz, TO and Nakayasu, ES}, title = {Systematic review of type 1 diabetes biomarkers reveals regulation in circulating proteins related to complement, lipid metabolism, and immune response.}, journal = {Clinical proteomics}, volume = {20}, number = {1}, pages = {38}, pmid = {37735622}, issn = {1542-6416}, support = {P30 DK116073/DK/NIDDK NIH HHS/United States ; R01 DK032493/DK/NIDDK NIH HHS/United States ; U01 DK127505/DK/NIDDK NIH HHS/United States ; U01 DK127786/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND: Type 1 diabetes (T1D) results from an autoimmune attack of the pancreatic β cells that progresses to dysglycemia and symptomatic hyperglycemia. Current biomarkers to track this evolution are limited, with development of islet autoantibodies marking the onset of autoimmunity and metabolic tests used to detect dysglycemia. Therefore, additional biomarkers are needed to better track disease initiation and progression. Multiple clinical studies have used proteomics to identify biomarker candidates. However, most of the studies were limited to the initial candidate identification, which needs to be further validated and have assays developed for clinical use. Here we curate these studies to help prioritize biomarker candidates for validation studies and to obtain a broader view of processes regulated during disease development.

METHODS: This systematic review was registered with Open Science Framework (https://doi.org/10.17605/OSF.IO/N8TSA). Using PRISMA guidelines, we conducted a systematic search of proteomics studies of T1D in the PubMed to identify putative protein biomarkers of the disease. Studies that performed mass spectrometry-based untargeted/targeted proteomic analysis of human serum/plasma of control, pre-seroconversion, post-seroconversion, and/or T1D-diagnosed subjects were included. For unbiased screening, 3 reviewers screened all the articles independently using the pre-determined criteria.

RESULTS: A total of 13 studies met our inclusion criteria, resulting in the identification of 266 unique proteins, with 31 (11.6%) being identified across 3 or more studies. The circulating protein biomarkers were found to be enriched in complement, lipid metabolism, and immune response pathways, all of which are found to be dysregulated in different phases of T1D development. We found 2 subsets: 17 proteins (C3, C1R, C8G, C4B, IBP2, IBP3, ITIH1, ITIH2, BTD, APOE, TETN, C1S, C6A3, SAA4, ALS, SEPP1 and PI16) and 3 proteins (C3, CLUS and C4A) have consistent regulation in at least 2 independent studies at post-seroconversion and post-diagnosis compared to controls, respectively, making them strong candidates for clinical assay development.

CONCLUSIONS: Biomarkers analyzed in this systematic review highlight alterations in specific biological processes in T1D, including complement, lipid metabolism, and immune response pathways, and may have potential for further use in the clinic as prognostic or diagnostic assays.}, } @article {pmid37735487, year = {2023}, author = {Gao, C and Jiang, J and Tan, Y and Chen, S}, title = {Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets.}, journal = {Signal transduction and targeted therapy}, volume = {8}, number = {1}, pages = {359}, pmid = {37735487}, issn = {2059-3635}, mesh = {Animals ; *Neurodegenerative Diseases/genetics ; Microglia ; Neuroinflammatory Diseases ; Protein Aggregates ; *Alzheimer Disease/genetics ; }, abstract = {Microglia activation is observed in various neurodegenerative diseases. Recent advances in single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified microglia in specific states correlate with pathological hallmarks and are associated with specific functions. Microglia both exert protective function by phagocytosing and clearing pathological protein aggregates and play detrimental roles due to excessive uptake of protein aggregates, which would lead to microglial phagocytic ability impairment, neuroinflammation, and eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression. Microglia also act as a mobile vehicle to propagate protein aggregates. Extracellular vesicles released from microglia and autophagy impairment in microglia all contribute to pathological progression and neurodegeneration. Thus, enhancing microglial phagocytosis, reducing microglial-mediated neuroinflammation, inhibiting microglial exosome synthesis and secretion, and promoting microglial conversion into a protective phenotype are considered to be promising strategies for the therapy of neurodegenerative diseases. Here we comprehensively review the biology of microglia and the roles of microglia in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies and Huntington's disease. We also summarize the possible microglia-targeted interventions and treatments against neurodegenerative diseases with preclinical and clinical evidence in cell experiments, animal studies, and clinical trials.}, } @article {pmid37735229, year = {2023}, author = {He, X and Yang, J and Feng, J and Huang, H and Dong, X and Zhao, Q and Shen, Q and Hu, C and Xu, Y}, title = {Venous blood parameters in determination of respiratory impairment in amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {15695}, pmid = {37735229}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Respiratory Insufficiency ; Leukocyte Count ; Cholesterol, HDL ; Cholesterol, LDL ; Creatinine ; }, abstract = {This study aimed to investigate the relationship between venous blood parameters and respiratory functions in patients with amyotrophic lateral sclerosis (ALS) and develop a model to predict respiratory impairment for individual patients with ALS. A total of 416 ALS patients were included in the study, and various hematologic and biochemical laboratory parameters as well as demographic and clinical factors were collected and compared. A multivariable logistic regression model was constructed to assess the association between FVC and venous blood biomarkers and clinical factors. The results showed that along with onset age, bulbar-onset, disease duration, BMI, eosinophil count (EO#), basophil count (BASO#), creatinine (CREA), uric acid (URCI) and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL/HDL) ratio were associated with reduced FVC. The area under the ROC curve is 0.735 for the test set and 0.721 for the validation set. The study also developed a relatively acceptable model for predicting respiratory impairment in ALS patients. These findings suggest that EO#, BASO#, CREA, URIC and LDL/HDL ratio can be useful in assessing FVC in ALS and can be easily accessible, accurate, and low-cost parameters.}, } @article {pmid37735015, year = {2023}, author = {Corcia, P and Vourc'h, P and Bernard, E and Cassereau, J and Codron, P and Fleury, MC and Guy, N and Mouzat, K and Pradat, PF and Soriani, MH and Couratier, P}, title = {French National Protocol for genetic of amyotrophic lateral sclerosis.}, journal = {Revue neurologique}, volume = {179}, number = {9}, pages = {1020-1029}, doi = {10.1016/j.neurol.2023.05.005}, pmid = {37735015}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics ; Mutation ; }, abstract = {Relationships between genes and amyotrophic lateral sclerosis (ALS) have been widely accepted since the first studies highlighting pathogenic mutations in the SOD1 gene 30years ago. Over the last three decades, scientific literature has clearly highlighted the central role played by genetic factors in the disease, in both clinics and pathophysiology, as well as in therapeutics. This implies that health professionals who care for patients with ALS are increasingly faced with patients and relatives eager to have answers to questions related to the role of genetic factors in the occurrence of the disease and the risk for their relatives to develop ALS. In order to address these public health issues, the French ALS network FILSLAN proposed to the Haute Autorité de santé (HAS) the drafting of a French National Protocol (PNDS) on ALS genetics. This PNDS was developed according to the "method for developing a national diagnosis and care protocol for rare diseases" published by the HAS in 2012 (methodological guide for PNDS available on the HAS website: http://www.has-sante.fr/). This document aims to provide the most recent data on the role of genes in ALS and to detail the implications for diagnosis and care.}, } @article {pmid37734916, year = {2023}, author = {Kredentser, MS and Mackenzie, CS and McClement, SE and Enns, MW and Hiebert-Murphy, D and Murphy, DJ and Chochinov, HM}, title = {Neuroticism as a moderator of symptom-related distress and depression in 4 noncancer end-of-life populations.}, journal = {Palliative & supportive care}, volume = {}, number = {}, pages = {1-9}, doi = {10.1017/S147895152300127X}, pmid = {37734916}, issn = {1478-9523}, abstract = {OBJECTIVES: Neuroticism is a significant predictor of adverse psychological outcomes in patients with cancer. Less is known about how this relationship manifests in those with noncancer illness at the end-of-life (EOL). The objective of this study was to examine the impact of neuroticism as a moderator of physical symptoms and development of depression in patients with amyotrophic lateral sclerosis (ALS), chronic obstructive pulmonary disease (COPD), end-stage renal disease (ESRD), and frailty in the last 6 months of life.

METHODS: We met this objective using secondary data collected in the Dignity and Distress across End-of-Life Populations study. The data included N = 404 patients with ALS (N = 101), COPD (N = 100), ESRD (N = 101), and frailty (N = 102) in the estimated last 6 months of life, with a range of illness-related symptoms, assessed longitudinally at 2 time points. We examined neuroticism as a moderator of illness-related symptoms at Time 1 (∼6 months before death) and depression at Time 2 (∼3 months before death) using ordinary least squares regression.

RESULTS: Results revealed that neuroticism significantly moderated the relationship between the following symptoms and depression measured 3 months later: drowsiness, fatigue, shortness of breath, wellbeing (ALS); drowsiness, trouble sleeping, will to live, activity (COPD); constipation (ESRD); and weakness and will to live (frailty).

SIGNIFICANCE OF RESULTS: These findings suggest that neuroticism represents a vulnerability factor that either attenuates or amplifies the relationship of specific illness and depressive symptoms in these noncancer illness groups at the EOL. Identifying those high in neuroticism may provide insight into patient populations that require special care at the EOL.}, } @article {pmid37734449, year = {2023}, author = {Hayashi, K and Sasaki, K}, title = {Number of kinesins engaged in axonal cargo transport: A novel biomarker for neurological disorders.}, journal = {Neuroscience research}, volume = {197}, number = {}, pages = {25-30}, doi = {10.1016/j.neures.2023.09.004}, pmid = {37734449}, issn = {1872-8111}, mesh = {Humans ; *Kinesins/metabolism ; Axonal Transport/physiology ; Axons/metabolism ; Dyneins/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Kinesin motor proteins play crucial roles in anterograde transport of cargo vesicles in neurons, moving them along axons from the cell body towards the synaptic region. Not only the transport force and velocity of single motor protein, but also the number of kinesin molecules involved in transporting a specific cargo, is pivotal for synapse formation. This collective transport by multiple kinesins ensures stable and efficient cargo transport in neurons. Abnormal increases or decreases in the number of engaged kinesin molecules per cargo could potentially act as biomarkers for neurodegenerative diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), spastic paraplegia, polydactyly syndrome, and virus transport disorders. We review here a model constructed using physical measurements to quantify the number of kinesin molecules associated with their cargo, which could shed light on the molecular mechanisms of neurodegenerative diseases related to axonal transport.}, } @article {pmid37734132, year = {2023}, author = {Cengiz, B and Koçak, ÖK and Erdoğan, T and Yanık, E and Pek, G and Savrun, Y and Evren Boran, H and Reha Kuruoğlu, H}, title = {Excitability of somatosensory cortex is increased in ALS: A SEP recovery function study.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {155}, number = {}, pages = {58-64}, doi = {10.1016/j.clinph.2023.08.013}, pmid = {37734132}, issn = {1872-8952}, abstract = {OBJECTIVE: Neuronal loss in the somatosensory, as well as the motor cortex in amyotrophic lateral sclerosis (ALS), indicative of a structural abnormality has been reported. Previously we have shown that afferent inhibition was impaired in ALS, suggestive of sensory involvement. In this study, we aimed to evaluate excitability changes in the somatosensory cortex of ALS patients.

METHODS: ALS patients underwent a paired pulse somatosensory evoked potential (SEP) paradigm at various interstimulus intervals (ISI). The amplitude ratio obtained by dividing the amplitude of paired pulse SEP stimulation S2 (paired pulse stimulation) to S1 (the single pulse stimulation) was considered the somatosensory cortex excitability parameter. Findings were compared to the results obtained from healthy controls. Resting motor threshold (RMT) was also assessed in the ALS group.

RESULTS: An increased S2/S1 ratio was found in the ALS group in every ISI examined. Additionally, the reduced inhibition correlated negatively with forced vital capacity, Medical Research Council sum score, median nerve compound muscle action potential amplitude, while there was a positive association with Penn upper motor neuron score and sural nerve conduction velocity. No correlation existed with RMT.

CONCLUSIONS: Our findings demonstrated increased somatosensory cortical excitability in ALS, which was associated with clinical parameters such as reduced pulmonary function and motor strength.

SIGNIFICANCE: Somatosensory cortical excitability is impaired in ALS. Whether this is associated with increased motor cortical excitability requires further studies.}, } @article {pmid37733208, year = {2023}, author = {Hernández, S and Salvany, S and Casanovas, A and Piedrafita, L and Soto-Bernardini, MC and Tarabal, O and Blasco, A and Gras, S and Gatius, A and Schwab, MH and Calderó, J and Esquerda, JE}, title = {Persistent NRG1 Type III Overexpression in Spinal Motor Neurons Has No Therapeutic Effect on ALS-Related Pathology in SOD1[G93A] Mice.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {20}, number = {6}, pages = {1820-1834}, pmid = {37733208}, issn = {1878-7479}, support = {PID2021-122785OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; 202005-30//Fundació la Marató de TV3/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Mice, Transgenic ; Motor Neurons/pathology ; Neuregulin-1/genetics ; *Neurodegenerative Diseases/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons (MNs). Neuregulin-1 (NRG1) is a pleiotropic growth factor that has been shown to be potentially valuable for ALS when supplemented by means of viral-mediated gene therapy. However, these results are inconsistent with other reports. An alternative approach for investigating the therapeutic impact of NRG1 on ALS is the use of transgenic mouse lines with genetically defined NRG1 overexpression. Here, we took advantage of a mouse line with NRG1 type III overexpression in spinal cord α motor neurons (MN) to determine the impact of steadily enhanced NRG1 signalling on mutant superoxide dismutase 1 (SOD1)-induced disease. The phenotype of SOD1[G93A]-NRG1 double transgenic mice was analysed in detail, including neuropathology and extensive behavioural testing. At least 3 animals per condition and sex were histopathologically assessed, and a minimum of 10 mice per condition and sex were clinically evaluated. The accumulation of misfolded SOD1 (mfSOD1), MN degeneration, and a glia-mediated neuroinflammatory response are pathological hallmarks of ALS progression in SOD1[G93A] mice. None of these aspects was significantly improved when examined in double transgenic NRG1-SOD1[G93A] mice. In addition, behavioural testing revealed that NRG1 type III overexpression did not affect the survival of SOD1[G93A] mice but accelerated disease onset and worsened the motor phenotype.}, } @article {pmid37732211, year = {2023}, author = {Guo, L and Mann, JR and Mauna, JC and Copley, KE and Wang, H and Rubien, JD and Odeh, HM and Lin, J and Lee, BL and Ganser, L and Robinson, E and Kim, KM and Murthy, AC and Paul, T and Portz, B and Gleixner, AM and Diaz, Z and Carey, JL and Smirnov, A and Padilla, G and Lavorando, E and Espy, C and Shang, Y and Huang, EJ and Chesi, A and Fawzi, NL and Myong, S and Donnelly, CJ and Shorter, J}, title = {Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.09.04.555754}, pmid = {37732211}, issn = {2692-8205}, support = {F31 NS129101/NS/NINDS NIH HHS/United States ; R01 NS121143/NS/NINDS NIH HHS/United States ; R35 GM138109/GM/NIGMS NIH HHS/United States ; RF1 NS121143/NS/NINDS NIH HHS/United States ; }, abstract = {RNA-binding proteins with prion-like domains, such as FUS and TDP-43, condense into functional liquids, which can transform into pathological fibrils that underpin fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Here, we define short RNAs (24-48 nucleotides) that prevent FUS fibrillization by promoting liquid phases, and distinct short RNAs that prevent and, remarkably, reverse FUS condensation and fibrillization. These activities require interactions with multiple RNA-binding domains of FUS and are encoded by RNA sequence, length, and structure. Importantly, we define a short RNA that dissolves aberrant cytoplasmic FUS condensates, restores nuclear FUS, and mitigates FUS proteotoxicity in optogenetic models and human motor neurons. Another short RNA dissolves aberrant cytoplasmic TDP-43 condensates, restores nuclear TDP-43, and mitigates TDP-43 proteotoxicity. Since short RNAs can be effectively delivered to the human brain, these oligonucleotides could have therapeutic utility for ALS/FTD and related disorders.}, } @article {pmid37730935, year = {2024}, author = {Ferrari, C and Ingannato, A and Matà, S and Ramat, S and Caremani, L and Bagnoli, S and Bessi, V and Sorbi, S and Nacmias, B}, title = {Parkinson-ALS with a novel MAPT variant.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {3}, pages = {1051-1055}, pmid = {37730935}, issn = {1590-3478}, mesh = {Female ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics/pathology ; tau Proteins/genetics ; *Parkinson Disease/genetics ; Mutation/genetics ; *Parkinsonian Disorders/genetics ; }, abstract = {The mutations on microtubule associated protein tau (MAPT) gene manifest clinically with behavioural frontotemporal dementia (FTD), parkinsonism, such as progressive supranuclear palsy and corticobasal degeneration, and rarely with amyotrophic lateral sclerosis (ALS). FTD-parkinsonism and FTD-ALS are clinical overlaps included in the spectrum of MAPT mutation's phenotypes. The mutations on MAPT gene cause the dysfunction of tau protein determining its accumulation in neurofibrillary tangles. Recent data describe frequently the co-occurrence of the aggregation of tau protein and α-synuclein in patients with parkinsonism and Parkinson disease (PD), suggesting an interaction of the two proteins in determining neurodegenerative process. The sporadic description of PD-ALS clinical complex, known as Brait-Fahn-Schwarz disease, supports the hypothesis of common neuropathological pathways between different disorders. Here we report the case of a 54-year-old Italian woman with idiopathic PD later complicated by ALS carrying a novel MAPT variant (Pro494Leu). The variant is characterized by an amino acid substitution and is classified as damaging for MAPT functions. The case supports the hypothesis of tau dysfunction as the basis of multiple neurodegenerative disorders.}, } @article {pmid37730668, year = {2023}, author = {Zhu, L and Li, S and Li, XJ and Yin, P}, title = {Pathological insights from amyotrophic lateral sclerosis animal models: comparisons, limitations, and challenges.}, journal = {Translational neurodegeneration}, volume = {12}, number = {1}, pages = {46}, pmid = {37730668}, issn = {2047-9158}, mesh = {Humans ; Animals ; Swine ; *Amyotrophic Lateral Sclerosis/genetics ; *Neurodegenerative Diseases ; Brain ; }, abstract = {In order to dissect amyotrophic lateral sclerosis (ALS), a multigenic, multifactorial, and progressive neurodegenerative disease with heterogeneous clinical presentations, researchers have generated numerous animal models to mimic the genetic defects. Concurrent and comparative analysis of these various models allows identification of the causes and mechanisms of ALS in order to finally obtain effective therapeutics. However, most genetically modified rodent models lack overt pathological features, imposing challenges and limitations in utilizing them to rigorously test the potential mechanisms. Recent studies using large animals, including pigs and non-human primates, have uncovered important events that resemble neurodegeneration in patients' brains but could not be produced in small animals. Here we describe common features as well as discrepancies among these models, highlighting new insights from these models. Furthermore, we will discuss how to make rodent models more capable of recapitulating important pathological features based on the important pathogenic insights from large animal models.}, } @article {pmid37729728, year = {2023}, author = {Anzilotti, S and Valente, V and Brancaccio, P and Franco, C and Casamassa, A and Lombardi, G and Palazzi, A and Conte, A and Paladino, S and Canzoniero, LMT and Annunziato, L and Pierantoni, GM and Pignataro, G}, title = {Chronic exposure to l-BMAA cyanotoxin induces cytoplasmic TDP-43 accumulation and glial activation, reproducing an amyotrophic lateral sclerosis-like phenotype in mice.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {167}, number = {}, pages = {115503}, doi = {10.1016/j.biopha.2023.115503}, pmid = {37729728}, issn = {1950-6007}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and often fatal neurodegenerative disease characterized by the loss of Motor Neurons (MNs) in spinal cord, motor cortex and brainstem. Despite significant efforts in the field, the exact pathogenetic mechanisms underlying both familial and sporadic forms of ALS have not been fully elucidated, and the therapeutic possibilities are still very limited. Here we investigate the molecular mechanisms of neurodegeneration induced by chronic exposure to the environmental cyanotoxin L-BMAA, which causes a form of ALS/Parkinson's disease (PD) in several populations consuming food and/or water containing high amounts of this compound.

METHODS: In this effort, mice were chronically exposed to L-BMAA and analyzed at different time points to evaluate cellular and molecular alterations and behavioral deficits, performing MTT assay, immunoblot, immunofluorescence and immunohistochemistry analysis, and behavioral tests.

RESULTS: We found that cyanotoxin L-BMAA determines apoptotic cell death and a marked astrogliosis in spinal cord and motor cortex, and induces neurotoxicity by favoring TDP-43 cytoplasmic accumulation.

CONCLUSIONS: Overall, our results characterize a new versatile neurotoxic animal model of ALS that may be useful for the identification of new druggable targets to develop innovative therapeutic strategies for this disease.}, } @article {pmid37728482, year = {2023}, author = {Keun, CH and Choi, SJ and Kim, YJ and Kim, SM and Hong, YH and Sung, JJ}, title = {Suicide Attempts in Patients With Amyotrophic Lateral Sclerosis: An Analysis of the Korean National Health Insurance Database.}, journal = {The Journal of clinical psychiatry}, volume = {84}, number = {6}, pages = {}, doi = {10.4088/JCP.22m14754}, pmid = {37728482}, issn = {1555-2101}, mesh = {Humans ; *Suicide, Attempted ; *Amyotrophic Lateral Sclerosis/epidemiology ; Cohort Studies ; National Health Programs ; Republic of Korea/epidemiology ; }, abstract = {Objective: The knowledge of the common risk factors for suicide attempts may not be simply applicable to patients with amyotrophic lateral sclerosis (ALS). We aimed to identify risk factors associated with suicide attempts in patients with ALS and to determine the annual prevalence and periods of vulnerability associated with attempts. Methods: This nationwide cohort study was performed using the Korean National Health Insurance Database. All patients with ALS concomitantly registered for the Exempted Calculation of Health Insurance for rare, incurable diseases between 2011 and 2017 were identified. We used the Cox proportional hazards regression model and competing risk model to identify the risk factors for suicide attempts. The multivariable models were adjusted for potential risk factors from the univariate analysis. Results: Among 2,955 incident patients, 47 attempted suicide. After adjusting for sex, previous attempts, and previous psychiatric disorders, the hazard ratios for psychiatric hospitalization before ALS diagnosis were 3.17 (95% confidence interval [CI], 1.31-7.70; P = .01) and 3.02 (95% CI, 1.32-6.90; P = .01) in the Cox regression model and the competing risk model, respectively. The annual prevalence of suicide attempts was 0.29%-1.12%. Twenty (42.6%) and 9 (19.1%) attempts occurred within 3 months and 12-18 months after diagnosis, respectively. Conclusions: Psychiatric hospitalization increased the risk of suicide attempts, which clustered at the early stage or on losing autonomy. Those with a history of psychiatric hospitalization should receive an in-depth evaluation and be cautiously monitored.}, } @article {pmid37728307, year = {2024}, author = {Shefner, JM and Bunte, T and Kittle, G and Genge, A and van den Berg, LH}, title = {Harmonized standard operating procedures for administering the ALS functional rating scale-revised.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {26-33}, doi = {10.1080/21678421.2023.2260832}, pmid = {37728307}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Outcome Assessment, Health Care ; Europe ; }, abstract = {The ALS Functional Rating Scale-Revised is the most commonly used primary outcome measure in current ALS clinical trials. While rigorous training and certification is generally recognized as critical to reliable performance, differences have existed between training in the two groups responsible for most training in ALS outcome measures. We present a harmonized standard operating procedure which is intended to further reduce response variability by the use of identical training in North America and Europe.}, } @article {pmid37725936, year = {2024}, author = {Giannakopoulos, A and Papanastasiou, AD and Zarkadis, IK and Andrew, SF and Rosenfeld, RG and Efthymiadou, A and Chrysis, D and Hwa, V}, title = {A Novel, Heterozygous, de novo Splicing Variant Affecting the Intracellular Domain of the Growth Hormone Receptor, and Causing a Mild Short Stature.}, journal = {Hormone research in paediatrics}, volume = {97}, number = {4}, pages = {397-403}, doi = {10.1159/000534183}, pmid = {37725936}, issn = {1663-2826}, mesh = {Humans ; Male ; Adolescent ; *Receptors, Somatotropin/genetics ; Heterozygote ; RNA Splicing ; Laron Syndrome/genetics ; Protein Domains ; Dwarfism/genetics ; Mutation ; Body Height/genetics ; }, abstract = {INTRODUCTION: Although the majority of growth hormone insensitivity syndrome (GHIS) cases are classical, the spectrum of clinical phenotypes has expanded to include "atypical" GHIS subjects with milder phenotypes due to very rare heterozygous growth hormone receptor (GHR) mutations with dominant negative effects.

CASE PRESENTATION: A 13-year-old pubertal boy presented with short stature (-1.7 SDS) and delayed bone age (11.5 years). His serum IGF-1 was low (16 ng/mL; reference range: 179-540). IGFBP-3 (1.3 mg/L; 3.1-9.5) and ALS (565 mU/mL; 1,500-3,500) were also low. GH stimulation test was normal, and GHBP was markedly elevated (6,300 pmol/L; 240-3,000). Additionally, the boy had insulin resistance and liver steatosis. His final height reached -1.8 SDS, which was 3.0 SDS below his mid-parental height. GHR gene from genomic DNA and established primary fibroblast culture was analyzed and a synonymous heterozygous GHR: c.945G>A variant, in the last nucleotide of exon 9 (encoding intracellular domain of GHR) was identified. In vitro analysis of the GHR cDNA demonstrated a splicing defect, leading to the heterozygous excision of exon 9. The final predicted product was a truncated GHR protein which explained the elevated GHBP levels.

CONCLUSION: We describe the first synonymous heterozygous GHR splicing variant in the exon 9-encoding part of the intracellular domain of GHR identified in a patient with mild short stature, thus supporting the continuum of genotype-phenotype of GHIS.}, } @article {pmid37725878, year = {2023}, author = {Singh, N and Vishwas, S and Kaur, A and Kaur, H and Kakoty, V and Khursheed, R and Chaitanya, MVNL and Babu, MR and Awasthi, A and Corrie, L and Harish, V and Yanadaiah, P and Gupta, S and Sayed, AA and El-Sayed, A and Ali, I and Kensara, OA and Ghaboura, N and Gupta, G and Dou, AM and Algahtani, M and El-Kott, AF and Dua, K and Singh, SK and Abdel-Daim, MM}, title = {Harnessing role of sesamol and its nanoformulations against neurodegenerative diseases.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {167}, number = {}, pages = {115512}, doi = {10.1016/j.biopha.2023.115512}, pmid = {37725878}, issn = {1950-6007}, abstract = {Sesamol is a lignan of sesame seeds and a natural phenolic molecule that has emerged as a useful medical agent. Sesamol is a non-toxic phytoconstituent, which exerts certain valuable effects in the management of cancer, diabetes, cardiovascular diseases, neurodegenerative diseases (NDs), etc. Sesamol is known to depict its neuroprotective role by various mechanisms, such as metabolic regulators, action on oxidative stress, neuroinflammation, etc. However, its poor oral bioavailability, rapid excretion (as conjugates), and susceptibility to gastric irritation/toxicity (particularly in rats' forestomach) may restrict its effectiveness. To overcome the associated limitations, novel drug delivery system-based formulations of sesamol are emerging and being researched extensively. These can conjugate with sesamol and enhance the bioavailability and solubility of free sesamol, along with delivery at the target site. In this review, we have summarized various research works highlighting the role of sesamol on various NDs, including Alzheimer's disease, Huntington's disease, Amyotrophic lateral sclerosis, and Parkinson's disease. Moreover, the formulation strategies and neuroprotective role of sesamol-based nano-formulations have also been discussed.}, } @article {pmid37725216, year = {2024}, author = {Dar, NJ and John, U and Bano, N and Khan, S and Bhat, SA}, title = {Oxytosis/Ferroptosis in Neurodegeneration: the Underlying Role of Master Regulator Glutathione Peroxidase 4 (GPX4).}, journal = {Molecular neurobiology}, volume = {61}, number = {3}, pages = {1507-1526}, pmid = {37725216}, issn = {1559-1182}, mesh = {Humans ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; *Ferroptosis ; Cell Death ; Oxidation-Reduction ; *Neurodegenerative Diseases ; Glutathione Peroxidase/metabolism ; Glutathione/metabolism ; Lipid Peroxidation ; }, abstract = {Oxytosis/ferroptosis is an iron-dependent oxidative form of cell death triggered by lethal accumulation of phospholipid hydroperoxides (PLOOHs) in membranes. Failure of the intricate PLOOH repair system is a principle cause of ferroptotic cell death. Glutathione peroxidase 4 (GPX4) is distinctly vital for converting PLOOHs in membranes to non-toxic alcohols. As such, GPX4 is known as the master regulator of oxytosis/ferroptosis. Ferroptosis has been implicated in a number of disorders such as neurodegenerative diseases (amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), etc.), ischemia/reperfusion injury, and kidney degeneration. Reduced function of GPX4 is frequently observed in degenerative disorders. In this study, we examine how diminished GPX4 function may be a critical event in triggering oxytosis/ferroptosis to perpetuate or initiate the neurodegenerative diseases and assess the possible therapeutic importance of oxytosis/ferroptosis in neurodegenerative disorders. These discoveries are important for advancing our understanding of neurodegenerative diseases because oxytosis/ferroptosis may provide a new target to slow the course of the disease.}, } @article {pmid37723585, year = {2023}, author = {Beckers, J and Tharkeshwar, AK and Fumagalli, L and Contardo, M and Van Schoor, E and Fazal, R and Thal, DR and Chandran, S and Mancuso, R and Van Den Bosch, L and Van Damme, P}, title = {A toxic gain-of-function mechanism in C9orf72 ALS impairs the autophagy-lysosome pathway in neurons.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {151}, pmid = {37723585}, issn = {2051-5960}, support = {MR/N013255/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; Gain of Function Mutation ; Lysosomes ; Motor Neurons ; Autophagy ; }, abstract = {BACKGROUND: Motor neurons (MNs), which are primarily affected in amyotrophic lateral sclerosis (ALS), are a specialized type of neurons that are long and non-dividing. Given their unique structure, these cells heavily rely on transport of organelles along their axons and the process of autophagy to maintain their cellular homeostasis. It has been shown that disruption of the autophagy pathway is sufficient to cause progressive neurodegeneration and defects in autophagy have been associated with various subtypes of ALS, including those caused by hexanucleotide repeat expansions in the C9orf72 gene. A more comprehensive understanding of the dysfunctional cellular mechanisms will help rationalize the design of potent and selective therapies for C9orf72-ALS.

METHODS: In this study, we used induced pluripotent stem cell (iPSC)-derived MNs from C9orf72-ALS patients and isogenic control lines to identify the underlying mechanisms causing dysregulations of the autophagy-lysosome pathway. Additionally, to ascertain the potential impact of C9orf72 loss-of-function on autophagic defects, we characterized the observed phenotypes in a C9orf72 knockout iPSC line (C9-KO).

RESULTS: Despite the evident presence of dysfunctions in several aspects of the autophagy-lysosome pathway, such as disrupted lysosomal homeostasis, abnormal lysosome morphology, inhibition of autophagic flux, and accumulation of p62 in C9orf72-ALS MNs, we were surprised to find that C9orf72 loss-of-function had minimal influence on these phenotypes. Instead, we primarily observed impairment in endosome maturation as a result of C9orf72 loss-of-function. Additionally, our study shed light on the pathological mechanisms underlying C9orf72-ALS, as we detected an increased TBK1 phosphorylation at S172 in MNs derived from C9orf72 ALS patients.

CONCLUSIONS: Our data provides further insight into the involvement of defects in the autophagy-lysosome pathway in C9orf72-ALS and strongly indicate that those defects are mainly due to the toxic gain-of-function mechanisms underlying C9orf72-ALS.}, } @article {pmid37723203, year = {2023}, author = {Huang, X and Jia, H and Xu, J and Wang, Y and Wen, J and Wang, N}, title = {Transgene-free genome editing of vegetatively propagated and perennial plant species in the T0 generation via a co-editing strategy.}, journal = {Nature plants}, volume = {9}, number = {10}, pages = {1591-1597}, pmid = {37723203}, issn = {2055-0278}, support = {2022-70029-38471//US Department of Agriculture/ ; 2021-67013-34588//US Department of Agriculture/ ; 2018-70016-27412//US Department of Agriculture/ ; 2016-70016-24833//US Department of Agriculture/ ; FLA-CRC-005979//Florida Department of Agriculture and Consumer Services/ ; }, mesh = {*Gene Editing ; CRISPR-Cas Systems ; Transgenes ; Plants, Genetically Modified/genetics ; *Herbicides ; Genome, Plant ; }, abstract = {Transgene-free plant genome editing in the T0 generation is highly desirable but challenging[1,2]. Here we achieved such a goal using a co-editing strategy via Agrobacterium-mediated transient expression of cytosine base editor to edit ALS encoding acetolactate synthase to confer herbicide chlorsulfuron resistance as a selection marker, Cas12a/CRISPR RNA for editing gene(s) of interest, and green fluorescent protein for selecting transgene-free transformants. The biallelic/homozygous transgene-free mutation rates for target genes among herbicide-resistant transformants ranged from 1.9% to 42.1% in tomato, tobacco, potato and citrus. This co-editing strategy is particularly useful for transgene-free genome editing of vegetatively propagated and perennial plant species in the T0 generation.}, } @article {pmid37722062, year = {2023}, author = {Chi, B and Öztürk, MM and Paraggio, CL and Leonard, CE and Sanita, ME and Dastpak, M and O'Connell, JD and Coady, JA and Zhang, J and Gygi, SP and Lopez-Gonzalez, R and Yin, S and Reed, R}, title = {Causal ALS genes impact the MHC class II antigen presentation pathway.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {39}, pages = {e2305756120}, pmid = {37722062}, issn = {1091-6490}, support = {R01 GM067945/GM/NIGMS NIH HHS/United States ; R35 GM122524/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Antigen Presentation/genetics ; Genes, MHC Class II ; Major Histocompatibility Complex ; Motor Neurons ; RNA-Binding Proteins/genetics ; Nuclear Matrix-Associated Proteins ; }, abstract = {Mutations in RNA/DNA-binding proteins cause amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain unclear. Here, we report that a set of ALS-associated proteins, namely FUS, EWSR1, TAF15, and MATR3, impact the expression of genes encoding the major histocompatibility complex II (MHC II) antigen presentation pathway. Both subunits of the MHC II heterodimer, HLA-DR, are down-regulated in ALS gene knockouts/knockdown in HeLa and human microglial cells, due to loss of the MHC II transcription factor CIITA. Importantly, hematopoietic progenitor cells (HPCs) derived from human embryonic stem cells bearing the FUS[R495X] mutation and HPCs derived from C9ORF72 ALS patient induced pluripotent stem cells also exhibit disrupted MHC II expression. Given that HPCs give rise to numerous immune cells, our data raise the possibility that loss of the MHC II pathway results in global failure of the immune system to protect motor neurons from damage that leads to ALS.}, } @article {pmid37721281, year = {2024}, author = {Jourdi, G and Fleury, S and Boukhatem, I and Lordkipanidzé, M}, title = {Soluble p75 neurotrophic receptor as a reliable biomarker in neurodegenerative diseases: what is the evidence?.}, journal = {Neural regeneration research}, volume = {19}, number = {3}, pages = {536-541}, pmid = {37721281}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are often misdiagnosed, especially when the diagnosis is based solely on clinical symptoms. The p75 neurotrophic receptor (p75[NTR]) has been studied as an index of sensory and motor nerve development and maturation. Its cleavable extracellular domain (ECD) is readily detectable in various biological fluids including plasma, serum and urine. There is evidence for increased p75[NTR] ECD levels in neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, age-related dementia, schizophrenia, and diabetic neuropathy. Whether p75[NTR] ECD could be used as a biomarker for diagnosis and/or prognosis in these disorders, and whether it could potentially lead to the development of targeted therapies, remains an open question. In this review, we present and discuss published studies that have evaluated the relevance of this emerging biomarker in the context of various neurodegenerative diseases. We also highlight areas that require further investigation to better understand the role of p75[NTR] ECD in the clinical diagnosis and management of neurodegenerative disorders.}, } @article {pmid37721161, year = {2024}, author = {Guo, K and Figueroa-Romero, C and Noureldein, MH and Murdock, BJ and Savelieff, MG and Hur, J and Goutman, SA and Feldman, EL}, title = {Gut microbiome correlates with plasma lipids in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {2}, pages = {665-679}, pmid = {37721161}, issn = {1460-2156}, support = {R01 TS000289/TS/ATSDR CDC HHS/United States ; UL1TR002240/NH/NIH HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01TS000339/ACL/ACL HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; UL1 TR002240/TR/NCATS NIH HHS/United States ; R01 TS000339/TS/ATSDR CDC HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; /CC/CDC HHS/United States ; UL1 TR000433/TR/NCATS NIH HHS/United States ; UM1 TR004404/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Gastrointestinal Microbiome/genetics ; *Neurodegenerative Diseases ; Biomarkers ; Lipids ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex, fatal neurodegenerative disease. Disease pathophysiology is incompletely understood but evidence suggests gut dysbiosis occurs in ALS, linked to impaired gastrointestinal integrity, immune system dysregulation and altered metabolism. Gut microbiome and plasma metabolome have been separately investigated in ALS, but little is known about gut microbe-plasma metabolite correlations, which could identify robust disease biomarkers and potentially shed mechanistic insight. Here, gut microbiome changes were longitudinally profiled in ALS and correlated to plasma metabolome. Gut microbial structure at the phylum level differed in ALS versus control participants, with differential abundance of several distinct genera. Unsupervised clustering of microbe and metabolite levels identified modules, which differed significantly in ALS versus control participants. Network analysis found several prominent amplicon sequence variants strongly linked to a group of metabolites, primarily lipids. Similarly, identifying the features that contributed most to case versus control separation pinpointed several bacteria correlated to metabolites, predominantly lipids. Mendelian randomization indicated possible causality from specific lipids related to fatty acid and acylcarnitine metabolism. Overall, the results suggest ALS cases and controls differ in their gut microbiome, which correlates with plasma metabolites, particularly lipids, through specific genera. These findings have the potential to identify robust disease biomarkers and shed mechanistic insight into ALS.}, } @article {pmid37721118, year = {2024}, author = {Gao, J and Jiang, M and Erricolo, D and Magin, RL and Morfini, G and Royston, T and Larson, AC and Li, W}, title = {Identifying potential imaging markers for diffusion property changes in a mouse model of amyotrophic lateral sclerosis: Application of the continuous time random walk model to ultrahigh b-value diffusion-weighted MR images of spinal cord tissue.}, journal = {NMR in biomedicine}, volume = {37}, number = {1}, pages = {e5037}, doi = {10.1002/nbm.5037}, pmid = {37721118}, issn = {1099-1492}, support = {RO1CA181658/GF/NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Superoxide Dismutase-1 ; Spinal Cord/diagnostic imaging/pathology ; Mice, Transgenic ; Diffusion Magnetic Resonance Imaging ; Disease Models, Animal ; }, abstract = {Diffusion MRI (dMRI) explores tissue microstructures by analyzing diffusion-weighted signal decay measured at different b-values. While relatively low b-values are used for most dMRI models, high b-value diffusion-weighted imaging (DWI) techniques have gained interest given that the non-Gaussian water diffusion behavior observed at high b-values can yield potentially valuable information. In this study, we investigated anomalous diffusion behaviors associated with degeneration of spinal cord tissue using a continuous time random walk (CTRW) model for DWI data acquired across an extensive range of ultrahigh b-values. The diffusion data were acquired in situ from the lumbar level of spinal cords of wild-type and age-matched transgenic SOD1[G93A] mice, a well-established animal model of amyotrophic lateral sclerosis (ALS) featuring progressive degeneration of axonal tracts in this tissue. Based on the diffusion decay behaviors at low and ultrahigh b-values, we applied the CTRW model using various combinations of b-values and compared diffusion metrics calculated from the CTRW model between the experimental groups. We found that diffusion-weighted signal decay curves measured with ultrahigh b-values (up to 858,022 s/mm[2] in this study) were well represented by the CTRW model. The anomalous diffusion coefficient obtained from lumbar spinal cords was significantly higher in SOD1[G93A] mice compared with control mice (14.7 × 10[-5] ± 5.54 × 10[-5] vs. 7.87 × 10[-5] ± 2.48 × 10[-5] mm[2] /s, p = 0.01). We believe this is the first study to illustrate the efficacy of the CTRW model for analyzing anomalous diffusion regimes at ultrahigh b-values. The CTRW modeling of ultrahigh b-value dMRI can potentially present a novel approach for noninvasively evaluating alterations in spinal cord tissue associated with ALS pathology.}, } @article {pmid37720931, year = {2023}, author = {Martínez-Camarena, Á and Sour, A and Faller, P}, title = {Impact of human serum albumin on Cu[II] and Zn[II] complexation by ATSM (diacetyl-bis(N4-methylthiosemicarbazone)) and a water soluble analogue.}, journal = {Dalton transactions (Cambridge, England : 2003)}, volume = {52}, number = {38}, pages = {13758-13768}, doi = {10.1039/d3dt02380j}, pmid = {37720931}, issn = {1477-9234}, mesh = {Humans ; *Coordination Complexes ; *Organometallic Compounds/chemistry ; Diacetyl ; Serum Albumin, Human ; Ligands ; Zinc ; *Thiosemicarbazones/chemistry ; Copper Radioisotopes ; Radiopharmaceuticals ; }, abstract = {The chelator diacetyl-bis(N4-methylthiosemicarbazone) (ATSM) and its complexes with Cu[II] and Zn[II] are becoming increasingly investigated for medical applications such as PET imaging for anti-tumour therapy and the treatment of amyotrophic lateral sclerosis. However, the solubility in water of both the ligand and the complexes presents certain limitations for in vitro studies. Moreover, the stability of the Cu[II] and Zn[II] complexes and their metal exchange reaction against the potential biological competitor human serum albumin (HSA) has not been studied in depth. In this work it was observed that the ATSM with an added carboxylic group into the structure increases its solubility in aqueous solutions without altering the coordination mode and the conjugated system of the ligand. The poorly water-soluble Cu[II]- and Zn[II]-ATSM complexes were prevented from precipitating due to the binding to HSA. Both HSA and ATSM show a similar thermodynamic affinity for Zn[II]. Finally, the Cu[II]-competition experiments with EDTA and the water-soluble ATSM ligands yielded an apparent log Kd at pH 7.4 of about -19. When ATSM was added to Cu[II]- and Zn[II]-loaded HSA, withdrawing of Zn[II] was kinetically favoured, but this metal is slowly substituted by the Cu[II] afterwards taken from HSA so that this protein could be considered as a source of Cu[II] for ATSM.}, } @article {pmid37720552, year = {2023}, author = {Naskar, A and Nayak, A and Salaikumaran, MR and Vishal, SS and Gopal, PP}, title = {Phase separation and pathologic transitions of RNP condensates in neurons: implications for amyotrophic lateral sclerosis, frontotemporal dementia and other neurodegenerative disorders.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1242925}, pmid = {37720552}, issn = {1662-5099}, support = {R01 NS122907/NS/NINDS NIH HHS/United States ; }, abstract = {Liquid-liquid phase separation results in the formation of dynamic biomolecular condensates, also known as membrane-less organelles, that allow for the assembly of functional compartments and higher order structures within cells. Multivalent, reversible interactions between RNA-binding proteins (RBPs), including FUS, TDP-43, and hnRNPA1, and/or RNA (e.g., RBP-RBP, RBP-RNA, RNA-RNA), result in the formation of ribonucleoprotein (RNP) condensates, which are critical for RNA processing, mRNA transport, stability, stress granule assembly, and translation. Stress granules, neuronal transport granules, and processing bodies are examples of cytoplasmic RNP condensates, while the nucleolus and Cajal bodies are representative nuclear RNP condensates. In neurons, RNP condensates promote long-range mRNA transport and local translation in the dendrites and axon, and are essential for spatiotemporal regulation of gene expression, axonal integrity and synaptic function. Mutations of RBPs and/or pathologic mislocalization and aggregation of RBPs are hallmarks of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease. ALS/FTD-linked mutations of RBPs alter the strength and reversibility of multivalent interactions with other RBPs and RNAs, resulting in aberrant phase transitions. These aberrant RNP condensates have detrimental functional consequences on mRNA stability, localization, and translation, and ultimately lead to compromised axonal integrity and synaptic function in disease. Pathogenic protein aggregation is dependent on various factors, and aberrant dynamically arrested RNP condensates may serve as an initial nucleation step for pathologic aggregate formation. Recent studies have focused on identifying mechanisms by which neurons resolve phase transitioned condensates to prevent the formation of pathogenic inclusions/aggregates. The present review focuses on the phase separation of neurodegenerative disease-linked RBPs, physiological functions of RNP condensates, and the pathologic role of aberrant phase transitions in neurodegenerative disease, particularly ALS/FTD. We also examine cellular mechanisms that contribute to the resolution of aberrant condensates in neurons, and potential therapeutic approaches to resolve aberrantly phase transitioned condensates at a molecular level.}, } @article {pmid37720544, year = {2023}, author = {McGoldrick, P and Robertson, J}, title = {Unraveling the impact of disrupted nucleocytoplasmic transport systems in C9orf72-associated ALS.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1247297}, pmid = {37720544}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two adult-onset neurodegenerative diseases that are part of a common disease spectrum due to clinical, genetic, and pathological overlap. A prominent genetic factor contributing to both diseases is a hexanucleotide repeat expansion in a non-coding region of the C9orf72 gene. This mutation in C9orf72 leads to nuclear depletion and cytoplasmic aggregation of Tar DNA-RNA binding protein 43 (TDP-43). TDP-43 pathology is characteristic of the majority of ALS cases, irrespective of disease causation, and is present in ~50% of FTD cases. Defects in nucleocytoplasmic transport involving the nuclear pore complex, the Ran-GTPase cycle, and nuclear transport factors have been linked with the mislocalization of TDP-43. Here, we will explore and discuss the implications of these system abnormalities of nucleocytoplasmic transport in C9orf72-ALS/FTD, as well as in other forms of familial and sporadic ALS.}, } @article {pmid37720012, year = {2023}, author = {Simmatis, L and Robin, J and Spilka, M and Yunusova, Y}, title = {Detecting bulbar amyotrophic lateral sclerosis (ALS) using automatic acoustic analysis.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37720012}, issn = {2693-5015}, support = {R01 DC013547/DC/NIDCD NIH HHS/United States ; }, abstract = {Home-based speech assessments have the potential to dramatically improve ALS clinical practice and facilitate patient stratification for ALS clinical trials. Acoustic speech analysis has demonstrated the ability to capture a variety of relevant speech motor impairments, but implementation has been hindered by both the nature of lab-based assessments (requiring travel and time for patients) and also by the opacity of some acoustic feature analysis methods. Furthermore, these challenges and others have obscured the ability to distinguish different ALS disease stages/severities. Validation of remote-capable acoustic analysis tools could enable detection of early signs of ALS, and these tools could be deployed to screen and monitor patients without requiring clinic visits. Here, we sought to determine whether acoustic features gathered using a remote-capable assessment app could detect ALS as well as different levels of speech impairment severity resulting from ALS. Speech samples (readings of a standardized, 99-word passage) from 119 ALS patients with varying degrees of disease severity as well as 22 neurologically healthy participants were analyzed, and 53 acoustic features were extracted. Patients were stratified into early and late stages of disease (ALS-early/ALS-E and ALS-late/ALS-L) based on the ALS Functional Ratings Scale - Revised bulbar score (FRS-bulb). Data were analyzed using a sparse Bayesian logistic regression classifier. It was determined that the current relatively small set of acoustic features could distinguish between ALS and controls well (area under receiver operating characteristic curve/AUROC = 0.85), that the ALS-E patients could be separated well from control participants (AUROC = 0.78), and that ALS-E and ALS-L patients could be reasonably separated (AUROC = 0.70). These results highlight the potential for remote acoustic analyses to detect and stratify ALS.}, } @article {pmid37717009, year = {2023}, author = {Malnar Črnigoj, M and Čerček, U and Yin, X and Ho, MT and Repic Lampret, B and Neumann, M and Hermann, A and Rouleau, G and Suter, B and Mayr, M and Rogelj, B}, title = {Phenylalanine-tRNA aminoacylation is compromised by ALS/FTD-associated C9orf72 C4G2 repeat RNA.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {5764}, pmid = {37717009}, issn = {2041-1723}, mesh = {Humans ; Transfer RNA Aminoacylation ; Aminoacylation ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; C9orf72 Protein/genetics ; Phenylalanine/genetics ; RNA, Transfer, Phe ; RNA, Antisense ; }, abstract = {The expanded hexanucleotide GGGGCC repeat mutation in the C9orf72 gene is the main genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Under one disease mechanism, sense and antisense transcripts of the repeat are predicted to bind various RNA-binding proteins, compromise their function and cause cytotoxicity. Here we identify phenylalanine-tRNA synthetase (FARS) subunit alpha (FARSA) as the main interactor of the CCCCGG antisense repeat RNA in cytosol. The aminoacylation of tRNA[Phe] by FARS is inhibited by antisense RNA, leading to decreased levels of charged tRNA[Phe]. Remarkably, this is associated with global reduction of phenylalanine incorporation in the proteome and decrease in expression of phenylalanine-rich proteins in cellular models and patient tissues. In conclusion, this study reveals functional inhibition of FARSA in the presence of antisense RNA repeats. Compromised aminoacylation of tRNA could lead to impairments in protein synthesis and further contribute to C9orf72 mutation-associated pathology.}, } @article {pmid37714849, year = {2023}, author = {Li, J and Jaiswal, MK and Chien, JF and Kozlenkov, A and Jung, J and Zhou, P and Gardashli, M and Pregent, LJ and Engelberg-Cook, E and Dickson, DW and Belzil, VV and Mukamel, EA and Dracheva, S}, title = {Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {5714}, pmid = {37714849}, issn = {2041-1723}, support = {R01 MH122590/MH/NIMH NIH HHS/United States ; I01 BX005585/BX/BLRD VA/United States ; R01 MH122592/MH/NIMH NIH HHS/United States ; I01 BX003625/BX/BLRD VA/United States ; U01 MH122590/MH/NIMH NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; U01 MH122592/MH/NIMH NIH HHS/United States ; R01 AG067151/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; Transcriptome/genetics ; Epigenome ; Mutation ; }, abstract = {A repeat expansion in the C9orf72 (C9) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we investigate single nucleus transcriptomics (snRNA-seq) and epigenomics (snATAC-seq) in postmortem motor and frontal cortices from C9-ALS, C9-FTD, and control donors. C9-ALS donors present pervasive alterations of gene expression with concordant changes in chromatin accessibility and histone modifications. The greatest alterations occur in upper and deep layer excitatory neurons, as well as in astrocytes. In neurons, the changes imply an increase in proteostasis, metabolism, and protein expression pathways, alongside a decrease in neuronal function. In astrocytes, the alterations suggest activation and structural remodeling. Conversely, C9-FTD donors have fewer high-quality neuronal nuclei in the frontal cortex and numerous gene expression changes in glial cells. These findings highlight a context-dependent molecular disruption in C9-ALS and C9-FTD, indicating unique effects across cell types, brain regions, and diseases.}, } @article {pmid37714236, year = {2023}, author = {Santhanam, V and Modi, P and Mishra, UK and Jahan, I and Ramesh, NG and Deep, S}, title = {Rational design and synthesis of novel triazole- and tetrazole-fused iminosugars as potential inhibitors of amyotrophic lateral sclerosis (ALS) linked SOD1 aggregation.}, journal = {International journal of biological macromolecules}, volume = {253}, number = {Pt 4}, pages = {126900}, doi = {10.1016/j.ijbiomac.2023.126900}, pmid = {37714236}, issn = {1879-0003}, mesh = {Humans ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis ; Superoxide Dismutase/genetics ; Mutation ; }, abstract = {In this manuscript we report the first example of an iminosugar that inhibits superoxide dismutase fibrillation associated with the amyotrophic lateral sclerosis (ALS). The present work involves synthesis of novel triazole and tetrazole embedded iminosugars, synthesized in 11-13 high yielding steps starting from readily available tri-O-benzyl-D-glucal and proceeding through a concomitant azidation - thermal intramolecular [3 + 2] cycloaddition reaction as the key step. One of these pre-designed iminosugars was found to inhibit fibrillation of SOD1 and also has shown propensity to break pre-formed fibrils. Docking and MD simulation studies suggest that the most probable interaction of this compound is a hydrogen bonding with Arg69, a loop IV residue of SOD1, which has a crucial role in stabilizing the native conformation of SOD1.}, } @article {pmid37713127, year = {2024}, author = {Aust, E and Graupner, ST and Günther, R and Linse, K and Joos, M and Grosskreutz, J and Prudlo, J and Pannasch, S and Hermann, A}, title = {Impairment of oculomotor functions in patients with early to advanced amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {1}, pages = {325-339}, pmid = {37713127}, issn = {1432-1459}, support = {01VSF16026//Gemeinsame Bundesausschuss/ ; 13GW0482//Bundesministerium für Bildung und Forschung/ ; }, mesh = {Humans ; *Saccades ; *Amyotrophic Lateral Sclerosis ; Eye Movements ; Pursuit, Smooth ; }, abstract = {Amyotrophic lateral sclerosis (ALS) can result into an incomplete locked in state (iLIS), in which communication depends on eye tracking computer devices. Oculomotor function impairments in ALS have been reported, but there is little research, particularly with respect to patients in iLIS. In the present study, we compared reflexive and executive oculomotor function by means of an eye tracking test battery between three groups: advanced ALS patients in iLIS (n = 22), patients in early to middle ALS stages (n = 44) and healthy subjects (n = 32). Patients with ALS showed significant deteriorations in oculomotor functions, with stronger impairments in iLIS. More specifically, ALS patients produced visually guided prosaccades with longer latencies and more frequent hypometria compared to healthy subjects. Longest latencies were obtained in iLIS patients, with a stronger prolongation for vertical than for horizontal prosaccades. ALS patients made more antisaccade errors and generated antisaccades with longer latencies. Smooth pursuit was also impaired in ALS. In the earlier ALS stages, bulbar onset patients presented stronger antisaccade and smooth pursuit deficits than spinal onset patients. Our findings reveal a relevant deterioration of important oculomotor functions in ALS, which increases in iLIS. It includes impairments of reflexive eye movements to loss of executive inhibitory control, indicating a progressing pathological involvement of prefrontal, midbrain and brainstem areas. The assessment of oculomotor functions may therefore provide clinically relevant bio- and progression marker, particularly in advanced ALS.}, } @article {pmid37712858, year = {2024}, author = {Al-Kuraishy, HM and Jabir, MS and Al-Gareeb, AI and Saad, HM and Batiha, GE and Klionsky, DJ}, title = {The beneficial role of autophagy in multiple sclerosis: Yes or No?.}, journal = {Autophagy}, volume = {20}, number = {2}, pages = {259-274}, pmid = {37712858}, issn = {1554-8635}, support = {R35 GM131919/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Multiple Sclerosis/metabolism ; Leukocytes, Mononuclear/metabolism ; Autophagy ; Central Nervous System ; *Encephalomyelitis, Autoimmune, Experimental ; Mice, Inbred C57BL ; }, abstract = {Multiple sclerosis (MS) is a chronic progressive demyelinating disease of the central nervous system (CNS) due to an increase of abnormal peripherally auto-reactive T lymphocytes which elicit autoimmunity. The main pathophysiology of MS is myelin sheath damage by immune cells and a defect in the generation of myelin by oligodendrocytes. Macroautophagy/autophagy is a critical degradation process that eliminates dysfunctional or superfluous cellular components. Autophagy has the property of a double-edged sword in MS in that it may have both beneficial and detrimental effects on MS neuropathology. Therefore, this review illustrates the protective and harmful effects of autophagy with regard to this disease. Autophagy prevents the progression of MS by reducing oxidative stress and inflammatory disorders. In contrast, over-activated autophagy is associated with the progression of MS neuropathology and in this case the use of autophagy inhibitors may alleviate the pathogenesis of MS. Furthermore, autophagy provokes the activation of different immune and supporting cells that play an intricate role in the pathogenesis of MS. Autophagy functions in the modulation of MS neuropathology by regulating cell proliferation related to demyelination and remyelination. Autophagy enhances remyelination by increasing the activity of oligodendrocytes, and astrocytes. However, autophagy induces demyelination by activating microglia and T cells. In conclusion, specific autophagic activators of oligodendrocytes, and astrocytes, and specific autophagic inhibitors of dendritic cells (DCs), microglia and T cells induce protective effects against the pathogenesis of MS.Abbreviations: ALS: amyotrophic lateral sclerosis; APCs: antigen-presenting cells; BBB: blood-brain barrier; CSF: cerebrospinal fluid; CNS: central nervous system; DCs: dendritic cells; EAE: experimental autoimmune encephalomyelitis; ER: endoplasmic reticulum; LAP: LC3-associated phagocytosis; MS: multiple sclerosis; NCA: non-canonical autophagy; OCBs: oligoclonal bands; PBMCs: peripheral blood mononuclear cells; PD: Parkinson disease; ROS: reactive oxygen species; UPR: unfolded protein response.}, } @article {pmid37712540, year = {2023}, author = {Zhao, R and Huang, QW and Yu, ZY and Han, Z and Fan, K and Zhao, ZH and Nie, DX}, title = {[Simultaneous determination of 36 mycotoxins in fruits by QuEChERS coupled with ultra performance liquid chromatography-tandem mass spectrometry].}, journal = {Se pu = Chinese journal of chromatography}, volume = {41}, number = {9}, pages = {760-770}, pmid = {37712540}, issn = {1872-2059}, mesh = {Animals ; Humans ; Chromatography, Liquid ; *Fruit ; Tandem Mass Spectrometry ; *Patulin ; Acetonitriles ; }, abstract = {Mycotoxins are secondary metabolites produced by toxigenic fungi under specific environmental conditions. Fruits, owing to their high moisture content, rich nutrition, and improper harvest or storage conditions, are highly susceptible to various mycotoxins, such as ochratoxin A (OTA), zearalenone (ZEN), patulin (PAT), Alternaria toxins, etc. These mycotoxins can cause acute and chronic toxic effects (teratogenicity, mutagenicity, and carcinogenicity, etc) in animals and humans. Given the high toxicity and wide prevalence of mycotoxins, establishing an efficient analytical method to detect multiple mycotoxins simultaneously in different types of fruits is of great importance. Conventional mycotoxin detection methods rely on high performance liquid chromatography (HPLC) coupled with mass spectrometry (MS). However, fruit sample matrices contain large amounts of pigments, cellulose, and minerals, all of which dramatically impede the detection of trace mycotoxins in fruits. Therefore, the efficient enrichment and purification of multiple mycotoxins in fruit samples is crucial before instrumental analysis. In this study, a reliable method based on a QuEChERs sample preparation approach coupled with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was established to determine 36 mycotoxins in fruits. In the optimal extraction method, 2.0 g of a sample was extracted with 10 mL of acetic acid-acetonitrile-water (1∶79∶20, v/v/v) in a 50 mL centrifuge tube, vortexed for 30 s, and ultrasonicated for 40 min. The mixture was then salted out with 2.0 g of anhydrous MgSO4 and 0.5 g of NaCl and centrifuged for 5 min. Next, 6 mL of the supernatant was purified using 85 mg of octadecylsilane-bonded silica gel (C18) and 15 mg of N-propylethylenediamine (PSA). After vigorous shaking and centrifugation, the supernatant was collected and dried with nitrogen at 40 ℃. Finally, the residues were redissolved in 1 mL of 5 mmol/L ammonium acetate aqueous solution-acetonitrile (50∶50, v/v) and passed through a 0.22 μm nylon filter before analysis. The mycotoxins were separated on a Waters XBridge BEH C18 column using a binary gradient mixture of ammonium acetate aqueous solution and methanol. The injection volume was 3 μL. The mycotoxins were analyzed in multiple reaction monitoring (MRM) mode under both positive and negative electrospray ionization. Quantitative analysis was performed using an external standard method with matrix-matched calibration curves. Under optimal conditions, good linear relationships were obtained in the respective linear ranges, with correlation coefficients (R[2]) no less than 0.990. The limits of detection (LODs) and quantification (LOQs) were 0.02-5 and 0.1-10 μg/kg, respectively. The recoveries of the 36 mycotoxins in fruits ranged from 77.0% to 118.9% at low, medium, and high spiked levels, with intra- and inter-day precisions in the range of 1.3%-14.9% and 0.2%-17.3%, respectively. The validated approach was employed to investigate mycotoxin contamination in actual fruit samples, including strawberry, grape, pear, and peach (15 samples of each type). Eleven mycotoxins, namely, altenuene (ALT), altenusin (ALS), alternariol-methyl ether (AME), tenuazonic acid (TeA), tentoxin (Ten), OTA, beauvericin (BEA), PAT, zearalanone (ZAN), T-2 toxin (T2), and mycophenolic acid (MPA), were found in the samples; three samples were contaminated with multiple mycotoxins. The incidence rates of mycotoxins in strawberry, grape, pear, and peach were 27%, 40%, 40%, and 33%, respectively. In particular, Alternaria toxins were the most frequently found mycotoxins in these fruits, with an incidence of 15%. The proposed method is simple, rapid, accurate, sensitive, reproducible, and stable; thus, it is suitable for the simultaneous detection of the 36 mycotoxins in different fruits.}, } @article {pmid37711512, year = {2023}, author = {Tomiyama, ALMR and Cartarozzi, LP and de Oliveira Coser, L and Chiarotto, GB and Oliveira, ALR}, title = {Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1[G93A] mice.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1211486}, pmid = {37711512}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that progressively affects motoneurons, causing muscle atrophy and evolving to death. Astrocytes inhibit the expression of MHC-I by neurons, contributing to a degenerative outcome. The present study verified the influence of interferon β (IFN β) treatment, a proinflammatory cytokine that upregulates MHC-I expression, in SOD1[G93A] transgenic mice. For that, 17 days old presymptomatic female mice were subjected to subcutaneous application of IFN β (250, 1,000, and 10,000 IU) every other day for 20 days. Rotarod motor test, clinical score, and body weight assessment were conducted every third day throughout the treatment period. No significant intergroup variations were observed in such parameters during the pre-symptomatic phase. All mice were then euthanized, and the spinal cords collected for comparative analysis of motoneuron survival, reactive gliosis, synapse coverage, microglia morphology classification, cytokine analysis by flow cytometry, and RT-qPCR quantification of gene transcripts. Additionally, mice underwent Rotarod motor assessment, weight monitoring, and neurological scoring. The results show that IFN β treatment led to an increase in the expression of MHC-I, which, even at the lowest dose (250 IU), resulted in a significant increase in neuronal survival in the ALS presymptomatic period which lasted until the onset of the disease. The treatment also influenced synaptic preservation by decreasing excitatory inputs and upregulating the expression of AMPA receptors by astrocytes. Microglial reactivity quantified by the integrated density of pixels did not decrease with treatment but showed a less activated morphology, coupled with polarization to an M1 profile. Disease progression upregulated gene transcripts for pro- and anti-inflammatory cytokines, and IFN β treatment significantly decreased mRNA expression for IL4. Overall, the present results demonstrate that a low dosage of IFN β shows therapeutic potential by increasing MHC-I expression, resulting in neuroprotection and immunomodulation.}, } @article {pmid37711501, year = {2023}, author = {Zare, H and Najand, B and Fugal, A and Assari, S}, title = {Allostatic load in the US general population: Race and educational intersection.}, journal = {Public health in practice (Oxford, England)}, volume = {6}, number = {}, pages = {100425}, pmid = {37711501}, issn = {2666-5352}, abstract = {OBJECTIVES: Educational attainment is a protective factor against poor health, but high educational attainment has a weaker effect on black people than on white people; this pattern has been called marginalization-related diminished returns (MDRs). Using a national sample of white people and black people 25 years and above, this study estimates the association between high educational attainment and allostatic load between black people and white people, and within each group.

STUDY DESIGN: This cross-sectional study uses data from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2016, including 2761 black people and 7058 white people. The outcome variable of interest was the Allostatic Load Scale (AL). We created the allostatic load scale by using 8 biomarkers, then created a binary variable (if ALS≥4 as 1 and ALS<4 as 0) to present elevated AL.

METHODS: We used several weighted modified Poisson regression models controlling for educational attainment (a predictor) and race (a moderator variable), age, sex, and marital status. We also controlled the models for smoking and drinking status as health behavior variables. As a sensitivity analysis, we ran several sets of regression analysis using the AL scale as a continuous outcome variable.

RESULTS: We found an inverse association between AL and educational attainment. The interaction between race and education has resulted in an inverse association between AL and educational attainment, with a weaker association in black people than in white people. We found similar findings by running regression models with AL as a continuous variable.

CONCLUSIONS: We observed a weaker association between educational attainment and AL in black people than in white people, suggesting that educational attainment has more robust protection against allostatic load for white people than black people.}, } @article {pmid37711011, year = {2023}, author = {Rodrigues, RB and Orsini, M and Neves, SV and de Rezende Pinto, WBV and da Silva Catarino, AM and Pereira, DA and Oliveira, ASB}, title = {Differential Diagnosis or Etiology: A Case Report on Amyotrophic Lateral Sclerosis-like Neuropathy Associated with HIV Infection.}, journal = {Current HIV research}, volume = {21}, number = {5}, pages = {323-329}, doi = {10.2174/1570162X21666230914104220}, pmid = {37711011}, issn = {1873-4251}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/drug therapy ; *HIV Infections/complications/drug therapy ; Diagnosis, Differential ; }, abstract = {BACKGROUND: Retroviruses are described as a risk factor for chronic neuropathy. However, it is still unknown if they can work as amyotrophic lateral sclerosis triggers. Over the years, some cases of this association have been described with heterogenous disclosures.

CASE REPRESENTATION: This study aimed to report a case of HIV and ALS-like neuropathy and briefly discuss peculiarities of clinical aspects, such as physiopathology and treatment options. The patient underwent neurological examination associated with blood tests, electromyography, analysis of cerebrospinal fluid, and imaging studies.

DISCUSSION: A non-systematic review was performed in major databases regarding the topic. The case presented mixed upper and lower motor neuron signs and was framed as a probable case of ALS following the present criteria.

CONCLUSION: After a short follow-up and viral load cleansing, neurological stabilization was achieved.}, } @article {pmid37710422, year = {2024}, author = {Thomas, A and Garg, D and Srivastava, AK and Kumar, A and Pandit, AK and Vibha, D and Vivekanandhan, S and Shukla, G and Prasad, K}, title = {Clinical factors and vascular endothelial growth factor as determinants of disease progression in Indian patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {46-52}, doi = {10.1080/21678421.2023.2256362}, pmid = {37710422}, issn = {2167-9223}, mesh = {Humans ; Male ; Adult ; Middle Aged ; Female ; *Amyotrophic Lateral Sclerosis/diagnosis ; Vascular Endothelial Growth Factor A ; Cross-Sectional Studies ; Biomarkers ; Disease Progression ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder. Prognostication remains sub-optimally defined. We aimed to assess clinical determinants of disease progression rates in Indian patients with ALS and to assess the role of vascular endothelial growth factor (VEGF) in disease progression.

METHODS: In this cross-sectional study, consecutive patients with clinically definite/probable ALS according to the revised El Escorial criteria and controls were included. Patients were classified into fast or slow progressors based on disease progression rate (DPR). Serum and CSF VEGF level was assessed for patients and controls.

RESULTS: Of 142 patients recruited, 93 (65.5%) were male. Mean age at enrollment was 49.37 ± 12.65 years. Mean duration of symptoms was 20.53 ± 20.88 months. Mean DPR was 1.14 ± 0.94. Based on DPR, 81 (57%) patients were slow progressors and 61 (43%) were fast progressors. Univariate analysis demonstrated a statistically significant association of DPR with age at onset, symptom duration, time to spread, wasting of small muscles of the hand, frontal release signs, and neurophysiologic bulbar abnormalities. On multivariate analysis, age at onset and symptom duration had a significant association with disease progression. The CSF VEGF levels of ALS patients (46.18 ± 27.8) were significantly elevated compared to controls (25.95 ± 25.64 pg/ml) (p = 0.001), but not serum VEGF.

CONCLUSION: Age at symptom onset and duration of disease had a significant impact on disease progression in Indian patients with ALS. CSF VEGF levels were significantly elevated in ALS compared to controls, indicating the role of CSF VEGF as a potential biomarker.}, } @article {pmid37710261, year = {2023}, author = {Zeng, Q and Wang, K and Liu, WX and Zeng, JZ and Li, XL and Zhang, QF and Ren, SQ and Xu, WM}, title = {Efficacy of high-fidelity simulation in advanced life support training: a systematic review and meta-analysis of randomized controlled trials.}, journal = {BMC medical education}, volume = {23}, number = {1}, pages = {664}, pmid = {37710261}, issn = {1472-6920}, support = {2023NSFSC1475//Sichuan Province Science and Technology Support Program/ ; 2023-207//Health Commission of Sichuan Province/ ; 2021ZX01//Sichuan Provincial People's Hospital/ ; KLET-202104//Ministry of Education Hainan Medical University/ ; R2021012//Peking Union Medical Foundation/ ; }, mesh = {Humans ; Computer Simulation ; Educational Status ; *High Fidelity Simulation Training ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Simulation is an increasingly used novel method for the education of medical professionals. This study aimed to systematically review the efficacy of high-fidelity (HF) simulation compared with low-fidelity (LF) simulation or no simulation in advanced life support (ALS) training.

METHODS: A comprehensive search of the PubMed, Chinese Biomedicine Database, Embase, CENTRAL, ISI, and China Knowledge Resource Integrated Database was performed to identify randomized controlled trials (RCTs) that evaluated the use of HF simulation in ALS training. Quality assessment was based on the Cochrane Handbook for Systematic Reviews of Interventions version 5.0.1. The primary outcome was the improvement of knowledge and skill performance. The secondary outcomes included the participants' confidence and satisfaction at the course conclusion, skill performance at one year, skill performance in actual resuscitation, and patient outcomes. Data were synthesized using the RevMan 5.4 software.

RESULTS: Altogether, 25 RCTs with a total of 1,987 trainees were included in the meta-analysis. In the intervention group, 998 participants used HF manikins, whereas 989 participants received LF simulation-based or traditional training (classical training without simulation). Pooled data from the RCTs demonstrated a benefit in improvement of knowledge [standardized mean difference (SMD) = 0.38; 95% confidence interval (CI): 0.18-0.59, P = 0.0003, I[2] = 70%] and skill performance (SMD = 0.63; 95% CI: 0.21-1.04, P = 0.003, I[2] = 92%) for HF simulation when compared with LF simulation and traditional training. The subgroup analysis revealed a greater benefit in knowledge with HF simulation compared with traditional training at the course conclusion (SMD = 0.51; 95% CI: 0.20-0.83, P = 0.003, I[2] = 61%). Studies measuring knowledge at three months, skill performance at one year, teamwork behaviors, participants' satisfaction and confidence demonstrated no significant benefit for HF simulation.

CONCLUSIONS: Learners using HF simulation more significantly benefited from the ALS training in terms of knowledge and skill performance at the course conclusion. However, further research is necessary to enhance long-term retention of knowledge and skill in actual resuscitation and patient's outcomes.}, } @article {pmid37709948, year = {2023}, author = {Goutman, SA and Savelieff, MG and Jang, DG and Hur, J and Feldman, EL}, title = {The amyotrophic lateral sclerosis exposome: recent advances and future directions.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {10}, pages = {617-634}, pmid = {37709948}, issn = {1759-4766}, support = {R01 TS000289/TS/ATSDR CDC HHS/United States ; R01 TS000327/TS/ATSDR CDC HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/etiology/genetics ; *Exposome ; Environmental Exposure/adverse effects ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration with typical survival of only 2-5 years from diagnosis. The causes of ALS are multifactorial: known genetic mutations account for only around 70% of cases of familial ALS and 15% of sporadic cases, and heritability estimates range from 8% to 61%, indicating additional causes beyond genetics. Consequently, interest has grown in environmental contributions to ALS risk and progression. The gene-time-environment hypothesis posits that ALS onset occurs through an interaction of genes with environmental exposures during ageing. An alternative hypothesis, the multistep model of ALS, suggests that several hits, at least some of which could be environmental, are required to trigger disease onset, even in the presence of highly penetrant ALS-associated mutations. Studies have sought to characterize the ALS exposome - the lifetime accumulation of environmental exposures that increase disease risk and affect progression. Identifying the full scope of environmental toxicants that enhance ALS risk raises the prospect of preventing disease by eliminating or mitigating exposures. In this Review, we summarize the evidence for an ALS exposome, discussing the strengths and limitations of epidemiological studies that have identified contributions from various sources. We also consider potential mechanisms of exposure-mediated toxicity and suggest future directions for ALS exposome research.}, } @article {pmid37709589, year = {2023}, author = {Jin, J and Zhong, XB}, title = {ASO drug Qalsody (tofersen) targets amyotrophic lateral sclerosis.}, journal = {Trends in pharmacological sciences}, volume = {44}, number = {12}, pages = {1043-1044}, pmid = {37709589}, issn = {1873-3735}, support = {R35 GM140862/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Oligonucleotides ; }, } @article {pmid37709437, year = {2023}, author = {Cavallini, N and Strani, L and Becchi, PP and Pizzamiglio, V and Michelini, S and Savorani, F and Cocchi, M and Durante, C}, title = {Tracing the identity of Parmigiano Reggiano "Prodotto di Montagna - Progetto Territorio" cheese using NMR spectroscopy and multivariate data analysis.}, journal = {Analytica chimica acta}, volume = {1278}, number = {}, pages = {341761}, doi = {10.1016/j.aca.2023.341761}, pmid = {37709437}, issn = {1873-4324}, mesh = {*Cheese ; Data Analysis ; Gene Library ; Metabolomics ; Multivariate Analysis ; }, abstract = {BACKGROUND: Nuclear magnetic resonance (NMR) spectroscopy is one of the well-established tools for food metabolomic analysis, as it proved to be very effective in authenticity and quality control of dairy products, as well as to follow product evolution during processing and storage. The analytical assessment of the EU mountain denomination label, specifically for Parmigiano Reggiano "Prodotto di Montagna - Progetto Territorio" (Mountain-CQ) cheese, has received limited attention. Although it was established in 2012 the EU mountain denomination label has not been much studied from an analytical point of view. Nonetheless, tracing a specific profile for the mountain products is essential to support the value chain of this specialty.

RESULTS: The aim of the study was to produce an identity profile for Parmigiano Reggiano "Prodotto di Montagna - Progetto Territorio" (Mountain-CQ) cheese, and to differentiate it from Parmigiano Reggiano PDO samples (conventional-PDO) using [1]H NMR spectroscopy coupled with multivariate data analysis. Three different approaches were applied and compared. First, the spectra-as-such were analysed after proper preprocessing. For the other two approaches, Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) was used for signals resolution and features extraction, either individually on manually-defined spectral intervals or by reapplying MCR-ALS on the whole spectra with selectivity constraints using the reconstructed "pure profiles" as initial estimates and targets. All approaches provided comparable information regarding the samples' distribution, as in all three cases the separation between the two product categories conventional-PDO and Mountain-CQ could be highlighted. Moreover, a novel MATLAB toolbox for features extraction via MCR-ALS was developed and used in synergy with the Chenomx library, allowing for a putative identification of the selected features.

SIGNIFICANCE: A first identity profile for Parmigiano Reggiano "Prodotto di Montagna - Progetto Territorio" obtained by interpreting the metabolites signals in NMR spectroscopy was obtained. Our workflow and toolbox for generating the features dataset allows a more straightforward interpretation of the results, to overcome the limitations due to dimensionality and to peaks overlapping, but also to include the signals assignment and matching since the early stages of the data processing and analysis.}, } @article {pmid37708975, year = {2024}, author = {Isaq, NA and Link, JL}, title = {Response to Papp et al's "Long-term safety and disease control with ruxolitinib cream in atopic dermatitis: Results from two phase 3 studies".}, journal = {Journal of the American Academy of Dermatology}, volume = {90}, number = {1}, pages = {e19-e20}, doi = {10.1016/j.jaad.2023.04.076}, pmid = {37708975}, issn = {1097-6787}, mesh = {Humans ; *Dermatitis, Atopic/drug therapy ; Nitriles ; Pyrimidines/adverse effects ; Pyrazoles/adverse effects ; }, } @article {pmid37707250, year = {2023}, author = {Guo, Y and Jin, W and Wang, W and He, Y and Qiu, S}, title = {Baseline correction for Raman spectra using a spectral estimation-based asymmetrically reweighted penalized least squares method.}, journal = {Applied optics}, volume = {62}, number = {18}, pages = {4766-4776}, doi = {10.1364/AO.489478}, pmid = {37707250}, issn = {1539-4522}, abstract = {Baseline correction is necessary for the qualitative and quantitative analysis of samples because of the existence of background fluorescence interference in Raman spectra. The asymmetric least squares (ALS) method is an adaptive and automated algorithm that avoids peak detection operations along with other user interactions. However, current ALS-based improved algorithms only consider the smoothness configuration of regions where the signals are greater than the fitted baseline, which results in smoothing distortion. In this paper, an asymmetrically reweighted penalized least squares method based on spectral estimation (SEALS) is proposed. SEALS considers not only the uniform distribution of additive noise along the baseline but also the energy distribution of the signal above and below the fitted baseline. The energy distribution is estimated using inverse Fourier and autoregressive models to create a spectral estimation kernel. This kernel effectively optimizes and balances the asymmetric weight assigned to each data point. By doing so, it resolves the issue of local oversmoothing that is typically encountered in the asymmetrically reweighted penalized least squares method. This oversmoothing problem can negatively impact the iteration depth and accuracy of baseline fitting. In comparative experiments on simulated spectra, SEALS demonstrated a better baseline fitting performance compared to several other advanced baseline correction methods, both under moderate and strong fluorescence backgrounds. It has also been proven to be highly resistant to noise interference. When applied to real Raman spectra, the algorithm correctly restored the weak peaks and removed the fluorescence peaks, demonstrating the effectiveness of this method. The computation time of the proposed method was approximately 0.05 s, which satisfies the real-time baseline correction requirements of practical spectroscopy acquisition.}, } @article {pmid37706096, year = {2023}, author = {Stipa, G and Ancidoni, A and Vanacore, N and Bellomo, G}, title = {Raw Water and ALS: A Unifying Hypothesis for the Environmental Agents Involved in ALS.}, journal = {Annals of neurosciences}, volume = {30}, number = {2}, pages = {124-132}, pmid = {37706096}, issn = {0972-7531}, abstract = {Different studies identified the presence of several altered genes in familial and sporadic amyotrophic lateral sclerosis (ALS) forms. The experimental data, together with the epidemiological data, would seem to suggest the existence of molecular mechanisms (e.g., axonal transport) related to these genes, together with a susceptibility of the same genes to certain environmental factors that would therefore suggest an impact of the environment on the etiopathogenesis of ALS. In our review, we considered the most relevant environmental clusters around the world, collecting different hypotheses and underlining common environmental factors among the different clusters. Moreover, further epidemiological data identified a higher risk of ALS in professional athletes and, in particular, in soccer and football players. Despite this increased risk of ALS highlighted by the epidemiological evidence in aforementioned sports, the mechanisms remain unclear. At last, the use of raw water has been associated with ALS risk. The aim of the present review is to characterize a possible relationship between these clusters, to be explored in the context of the interaction between genetic and environmental factors on the etiopathogenesis of ALS.}, } @article {pmid37705092, year = {2023}, author = {Gerovska, D and Noer, JB and Qin, Y and Ain, Q and Januzi, D and Schwab, M and Witte, OW and Araúzo-Bravo, MJ and Kretz, A}, title = {A distinct circular DNA profile intersects with proteome changes in the genotoxic stress-related hSOD1[G93A] model of ALS.}, journal = {Cell & bioscience}, volume = {13}, number = {1}, pages = {170}, pmid = {37705092}, issn = {2045-3701}, support = {EKFS//Else Kröner-Fresenius-Stiftung/ ; WI 830/12-1//Deutsche Forschungsgemeinschaft/ ; RegenerAging-52-5581-413-FSU-I-03/14//TMWWDG/ ; FF01//Center for Clinical and Translational Research/ ; 899417//HORIZON EUROPE European Innovation Council/ ; PID2020-119715GB-I00/AEI/10.13039/501100011033//Ministerio de Ciencia e Innovación/ ; iDATA-MP//Instituto de Salud Carlos III/ ; iDATA-MP//Instituto de Salud Carlos III/ ; 8088-00049B//Innovationsfonden/ ; CF21-0167//Carlsbergfondet/ ; NNF21OC0072023//Novo Nordisk Fonden/ ; }, abstract = {BACKGROUND: Numerous genes, including SOD1, mutated in familial and sporadic amyotrophic lateral sclerosis (f/sALS) share a role in DNA damage and repair, emphasizing genome disintegration in ALS. One possible outcome of chromosomal instability and repair processes is extrachromosomal circular DNA (eccDNA) formation. Therefore, eccDNA might accumulate in f/sALS with yet unknown function.

METHODS: We combined rolling circle amplification with linear DNA digestion to purify eccDNA from the cervical spinal cord of 9 co-isogenic symptomatic hSOD1[G93A] mutants and 10 controls, followed by deep short-read sequencing. We mapped the eccDNAs and performed differential analysis based on the split read signal of the eccDNAs, referred as DifCir, between the ALS and control specimens, to find differentially produced per gene circles (DPpGC) in the two groups. Compared were eccDNA abundances, length distributions and genic profiles. We further assessed proteome alterations in ALS by mass spectrometry, and matched the DPpGCs with differentially expressed proteins (DEPs) in ALS. Additionally, we aligned the ALS-specific DPpGCs to ALS risk gene databases.

RESULTS: We found a six-fold enrichment in the number of unique eccDNAs in the genotoxic ALS-model relative to controls. We uncovered a distinct genic circulome profile characterized by 225 up-DPpGCs, i.e., genes that produced more eccDNAs from distinct gene sequences in ALS than under control conditions. The inter-sample recurrence rate was at least 89% for the top 6 up-DPpGCs. ALS proteome analyses revealed 42 corresponding DEPs, of which 19 underlying genes were itemized for an ALS risk in GWAS databases. The up-DPpGCs and their DEP tandems mainly impart neuron-specific functions, and gene set enrichment analyses indicated an overrepresentation of the adenylate cyclase modulating G protein pathway.

CONCLUSIONS: We prove, for the first time, a significant enrichment of eccDNA in the ALS-affected spinal cord. Our triple circulome, proteome and genome approach provide indication for a potential importance of certain eccDNAs in ALS neurodegeneration and a yet unconsidered role as ALS biomarkers. The related functional pathways might open up new targets for therapeutic intervention.}, } @article {pmid37704403, year = {2023}, author = {Lin, CC and Hill, CE and Kerber, KA and Burke, JF and Skolarus, LE and Esper, GJ and de Havenon, A and De Lott, LB and Callaghan, BC}, title = {Patient Travel Distance to Neurologist Visits.}, journal = {Neurology}, volume = {101}, number = {18}, pages = {e1807-e1820}, pmid = {37704403}, issn = {1526-632X}, support = {K23 NS126495/NS/NINDS NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; United States/epidemiology ; Aged ; *Neurologists ; Medicare ; Cross-Sectional Studies ; *Amyotrophic Lateral Sclerosis ; Travel ; Health Services Accessibility ; }, abstract = {BACKGROUND AND OBJECTIVES: The density of neurologists within a given geographic region varies greatly across the United States. We aimed to measure patient travel distance and travel time to neurologist visits, across neurologic conditions and subspecialties. Our secondary goal was to identify factors associated with long-distance travel for neurologic care.

METHODS: We performed a cross-sectional analysis using a 2018 Medicare sample of patients with at least 1 outpatient neurologist visit. Long-distance travel was defined as driving distance ≥50 miles 1-way to the visit. Travel time was measured as driving time in minutes. Multilevel generalized linear mixed models with logistic link function, which accounted for clustering of patients within hospital referral region and allowed modeling of region-specific random effects, were used to determine the association of patient and regional characteristics with long-distance travel.

RESULTS: We identified 563,216 Medicare beneficiaries with a neurologist visit in 2018. Of them, 96,213 (17%) traveled long distance for care. The median driving distance and time were 81.3 (interquartile range [IQR]: 59.9-144.2) miles and 90 (IQR: 69-149) minutes for patients with long-distance travel compared with 13.2 (IQR: 6.5-23) miles and 22 (IQR: 14-33) minutes for patients without long-distance travel. Comparing across neurologic conditions, long-distance travel was most common for nervous system cancer care (39.6%), amyotrophic lateral sclerosis [ALS] (32.1%), and MS (22.8%). Many factors were associated with long-distance travel, most notably low neurologist density (first quintile: OR 3.04 [95% CI 2.41-3.83] vs fifth quintile), rural setting (4.89 [4.79-4.99]), long-distance travel to primary care physician visit (3.6 [3.51-3.69]), and visits for ALS and nervous system cancer care (3.41 [3.14-3.69] and 5.27 [4.72-5.89], respectively). Nearly one-third of patients bypassed the nearest neurologist by 20+ miles, and 7.3% of patients crossed state lines for neurologist care.

DISCUSSION: We found that nearly 1 in 5 Medicare beneficiaries who saw a neurologist traveled ≥50 miles 1-way for care, and travel burden was most common for lower-prevalence neurologic conditions that required coordinated multidisciplinary care. Important potentially addressable predictors of long-distance travel were low neurologist density and rural location, suggesting interventions to improve access to care such as telemedicine or neurologic subspecialist support to local neurologists. Future work should evaluate differences in clinical outcomes between patients with long-distance travel and those without.}, } @article {pmid37704056, year = {2023}, author = {Tang, J and Kang, Y and Zhou, Y and Chen, Q and Lan, J and Liu, X and Peng, Y}, title = {Umbilical cord mesenchymal stem cell-conditioned medium inhibits microglial activation to ameliorate neuroinflammation in amyotrophic lateral sclerosis mice and cell models.}, journal = {Brain research bulletin}, volume = {202}, number = {}, pages = {110760}, doi = {10.1016/j.brainresbull.2023.110760}, pmid = {37704056}, issn = {1873-2747}, mesh = {Mice ; Animals ; Microglia ; Neuroinflammatory Diseases ; *Amyotrophic Lateral Sclerosis ; Culture Media, Conditioned/pharmacology ; *Neurodegenerative Diseases ; Superoxide Dismutase-1 ; *Mesenchymal Stem Cells ; Mice, Transgenic ; Cytokines ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease for which few effective therapeutic strategies are available. Increasing evidence indicates that neuroinflammation plays a significant role in ALS pathogenesis. Mesenchymal stem cell (MSC)-based therapy has been proposed for the treatment of neurodegenerative diseases, including ALS. In this study, we first demonstrated that systemic administration of conditioned medium derived from umbilical cord MSCs (UCMSC-CM) extends the lifespan of transgenic SOD1-G93A mice, a well-characterized model of familial ALS. Moreover, UCMSC-CM inhibits microglial activation and astrogliosis and alleviates the inflammatory milieu by reducing the release of proinflammatory cytokines and the expression of iNOS in the spinal cord. Using BV-2 cells overexpressing the SOD1-G93A mutant as an ALS cellular model, we uncovered that UCMSC-CM also suppresses the lipopolysaccharide (LPS)-induced inflammatory response, including reduced expression of proinflammatory cytokines and iNOS. Importantly, by culturing astrocytes alone in microglia-conditioned medium (MCM) or together with microglia in a transwell coculture system, we found that UCMSC-CM modulates the secretome of microglia exposed to inflammatory stimuli, thereby preventing the conversion of astrocytes to the A1 neurotoxic phenotype. This study revealed the anti-inflammatory properties of UCMSC-CM and its regulatory effect on glial activation in the treatment of neuroinflammation in ALS, providing strong evidence for the clinical application of UCMSC-CM.}, } @article {pmid37703175, year = {2023}, author = {Runfola, V and Giambruno, R and Caronni, C and Pannese, M and Andolfo, A and Gabellini, D}, title = {MATR3 is an endogenous inhibitor of DUX4 in FSHD muscular dystrophy.}, journal = {Cell reports}, volume = {42}, number = {9}, pages = {113120}, pmid = {37703175}, issn = {2211-1247}, support = {R21 CA249378/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Amyotrophic Lateral Sclerosis/genetics ; Gene Expression Regulation ; Genes, Homeobox ; *Homeodomain Proteins/genetics/metabolism ; Muscle, Skeletal/metabolism ; *Muscular Dystrophy, Facioscapulohumeral/genetics/metabolism ; Neurodegenerative Diseases/genetics ; Nuclear Matrix-Associated Proteins/metabolism ; RNA-Binding Proteins/metabolism ; }, abstract = {Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders and has no cure. Due to an unknown molecular mechanism, FSHD displays overlapping manifestations with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). FSHD is caused by aberrant gain of expression of the transcription factor double homeobox 4 (DUX4), which triggers a pro-apoptotic transcriptional program resulting in inhibition of myogenic differentiation and muscle wasting. Regulation of DUX4 activity is poorly known. We identify Matrin 3 (MATR3), whose mutation causes ALS and dominant distal myopathy, as a cellular factor controlling DUX4 expression and activity. MATR3 binds to the DUX4 DNA-binding domain and blocks DUX4-mediated gene expression, rescuing cell viability and myogenic differentiation of FSHD muscle cells, without affecting healthy muscle cells. Finally, we characterize a shorter MATR3 fragment that is necessary and sufficient to directly block DUX4-induced toxicity to the same extent as the full-length protein. Collectively, our data suggest MATR3 as a candidate for developing a treatment for FSHD.}, } @article {pmid37700955, year = {2023}, author = {Cardenas, J and Cardenas, JM and Garber, M and Irazuzta, J}, title = {Incidence of Air Leak Syndrome in Pediatric Patients With SARS-COV-2 Pneumonia and Respiratory Failure: A Single-Center Retrospective Study.}, journal = {Cureus}, volume = {15}, number = {8}, pages = {e43329}, pmid = {37700955}, issn = {2168-8184}, abstract = {Air leak syndrome (ALS) is defined as the extrusion of air from an aerated compartment into an unaerated compartment with associated symptoms of respiratory distress. This syndrome can occur as a consequence of trauma, iatrogenic causes, or spontaneously. Retrospective investigations conducted in the adult population have demonstrated an elevated risk of spontaneous ALS development in patients with coronavirus disease 2019 (COVID-19) pneumonia, along with its correlation with mortality. However, no studies have yet explored this phenomenon within the pediatric population. In light of this knowledge gap, we conducted a retrospective chart review comprising 128 pediatric patients ranging in age from one month to 18 years. The primary objective was to assess the incidence of ALS in two distinct groups: patients diagnosed with COVID-19 pneumonia and those with non-COVID-19 viral pneumonia. The groups were compared using Fisher's exact test for sex, the presence of ALS, the requirement of extracorporeal membrane oxygenation (ECMO), and death. The modified Wald method was used to calculate the 95% confidence interval for the mortality rate in patients with COVID-19 pneumonia in the presence of ALS. Our findings revealed a higher prevalence of ALS in patients with COVID-19 pneumonia compared to the non-COVID-19 viral pneumonia group, with a statistically significant P-value of 0.02 and an odds ratio (OR) of 6.72. In terms of mortality rates, there was a statistically significant difference between the two groups (P = 0.025, OR = 1.083). In addition, in patients with ALS in the presence of COVID-19 pneumonia, the mortality rate was 37.5%. However, the requirement of ECMO was not statistically significant (P = 0.16, OR = 1.04). These results suggest that patients with COVID-19 pneumonia have an increased mortality rate and a heightened risk of developing ALS compared to individuals with other viral pneumonias. Furthermore, the presence of ALS was associated with a high mortality rate in COVID-19 pneumonia patients. However, it is crucial to note that obtaining a larger patient sample and involving multiple institutions would be necessary to obtain more consistent and robust data.}, } @article {pmid37700418, year = {2023}, author = {Madanchi, M and Brenner, M and Navarini, AA and Juratli, HA}, title = {[Ageusie als Symptom bei Affenpockeninfektion].}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {21}, number = {9}, pages = {1035-1037}, doi = {10.1111/ddg.15118_g}, pmid = {37700418}, issn = {1610-0387}, } @article {pmid37698628, year = {2023}, author = {Aly, A and Laszlo, ZI and Rajkumar, S and Demir, T and Hindley, N and Lamont, DJ and Lehmann, J and Seidel, M and Sommer, D and Franz-Wachtel, M and Barletta, F and Heumos, S and Czemmel, S and Kabashi, E and Ludolph, A and Boeckers, TM and Henstridge, CM and Catanese, A}, title = {Correction to: Integrative proteomics highlight presynaptic alterations and c-Jun misactivation as convergent pathomechanisms in ALS.}, journal = {Acta neuropathologica}, volume = {146}, number = {5}, pages = {783}, doi = {10.1007/s00401-023-02630-9}, pmid = {37698628}, issn = {1432-0533}, } @article {pmid37698313, year = {2023}, author = {Abraham, A and Abramovich, B and Banon, T and Weil, C and Chodick, G and Birman, N and Fainmesser, Y and Drory, VE}, title = {Pre-morbid Laboratory Tests, Diseases, and Medications in Amyotrophic Lateral Sclerosis in Israel.}, journal = {The Israel Medical Association journal : IMAJ}, volume = {25}, number = {9}, pages = {617-621}, pmid = {37698313}, issn = {1565-1088}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy/epidemiology ; Israel/epidemiology ; *Cardiovascular Diseases ; Morbidity ; Antiviral Agents ; }, abstract = {BACKGROUND: There is an unmet need for real-world data regarding laboratory results, co-morbidities, and medication use prior to the first symptoms of amyotrophic lateral sclerosis (ALS). Researchers must identify specific subpopulations at risk for developing ALS and understand pathogenic mechanisms preceding the clinical presentation of ALS as well as possible subclinical disease manifestations.

OBJECTIVES: To valuate the role of laboratory results, co-morbidities, and medication use prior to the first symptoms of patients with ALS in Israel so that specific subpopulations at risk for developing ALS can be identified and for possible subclinical disease manifestations. To understand pathogenic mechanisms preceding the clinical presentation of ALS.

METHODS: At the ALS clinic at Tel Aviv Sourasky Medical Center, 259 ALS patients insured by Maccabi Healthcare Services and seen between January 1998 and December 2017 were included. Comparisons of demographics, co-morbidities, medications taken, history of trauma, and laboratory tests prior to disease onset were performed between patients and 1295 matched controls.

RESULTS: Prior to disease presentation, ALS patients had a higher frequency of hypertension and cardiovascular disease; presented more frequently with trauma and viral infections; more frequently used analgesics, non-steroidal anti-inflammatory drugs, narcotics, antibiotics, and antiviral medications; and had higher creatine kinase levels.

CONCLUSIONS: ALS patients showed higher frequency of cardiovascular disease prior to diagnosis, as well as higher frequency of trauma, infections, and pain medication usage.}, } @article {pmid37697342, year = {2023}, author = {Li, Z and Wang, X and Wang, X and Yi, X and Wong, YK and Wu, J and Xie, F and Hu, D and Wang, Q and Wang, J and Zhong, T}, title = {Research progress on the role of extracellular vesicles in neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {12}, number = {1}, pages = {43}, pmid = {37697342}, issn = {2047-9158}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/therapy ; *Extracellular Vesicles ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, affect millions of people worldwide. Tremendous efforts have been put into disease-related research, but few breakthroughs have been made in diagnostic and therapeutic approaches. Extracellular vesicles (EVs) are heterogeneous cell-derived membrane structures that arise from the endosomal system or are directly separated from the plasma membrane. EVs contain many biomolecules, including proteins, nucleic acids, and lipids, which can be transferred between different cells, tissues, or organs, thereby regulating cross-organ communication between cells during normal and pathological processes. Recently, EVs have been shown to participate in various aspects of neurodegenerative diseases. Abnormal secretion and levels of EVs are closely related to the pathogenesis of neurodegenerative diseases and contribute to disease progression. Numerous studies have proposed EVs as therapeutic targets or biomarkers for neurodegenerative diseases. In this review, we summarize and discuss the advanced research progress on EVs in the pathological processes of several neurodegenerative diseases. Moreover, we outline the latest research on the roles of EVs in neurodegenerative diseases and their therapeutic potential for the diseases.}, } @article {pmid37696852, year = {2023}, author = {Latallo, MJ and Wang, S and Dong, D and Nelson, B and Livingston, NM and Wu, R and Zhao, N and Stasevich, TJ and Bassik, MC and Sun, S and Wu, B}, title = {Single-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {5581}, pmid = {37696852}, issn = {2041-1723}, support = {R01 GM136897/GM/NIGMS NIH HHS/United States ; R21 AG072078/AG/NIA NIH HHS/United States ; T32 GM007445/GM/NIGMS NIH HHS/United States ; T32 GM008403/GM/NIGMS NIH HHS/United States ; R01 NS107347/NS/NINDS NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; T32 GM135131/GM/NIGMS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; RNA/genetics ; Single Molecule Imaging ; Dipeptides ; Carrier Proteins ; }, abstract = {C9ORF72 hexanucleotide repeat expansion is the most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One pathogenic mechanism is the accumulation of toxic dipeptide repeat (DPR) proteins like poly-GA, GP and GR, produced by the noncanonical translation of the expanded RNA repeats. However, how different DPRs are synthesized remains elusive. Here, we use single-molecule imaging techniques to directly measure the translation dynamics of different DPRs. Besides initiation, translation elongation rates vary drastically between different frames, with GP slower than GA and GR the slowest. We directly visualize frameshift events using a two-color single-molecule translation assay. The repeat expansion enhances frameshifting, but the overall frequency is low. There is a higher chance of GR-to-GA shift than in the reversed direction. Finally, the ribosome-associated protein quality control (RQC) factors ZNF598 and Pelota modulate the translation dynamics, and the repeat RNA sequence is important for invoking the RQC pathway. This study reveals that multiple translation steps modulate the final DPR production. Understanding repeat RNA translation is critically important to decipher the DPR-mediated pathogenesis and identify potential therapeutic targets in C9ORF72-ALS/FTD.}, } @article {pmid37696099, year = {2023}, author = {Wiesenfarth, M and Huppertz, HJ and Dorst, J and Lulé, D and Ludolph, AC and Müller, HP and Kassubek, J}, title = {Structural and microstructural neuroimaging signature of C9orf72-associated ALS: A multiparametric MRI study.}, journal = {NeuroImage. Clinical}, volume = {39}, number = {}, pages = {103505}, pmid = {37696099}, issn = {2213-1582}, mesh = {Humans ; *Multiparametric Magnetic Resonance Imaging ; Diffusion Tensor Imaging ; C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics ; Neuroimaging ; }, abstract = {BACKGROUND: ALS patients with hexanucleotide expansion in C9orf72 are characterized by a specific clinical phenotype, including more aggressive disease course and cognitive decline. Computerized multiparametric MRI with gray matter volumetry and diffusion tensor imaging (DTI) to analyze white matter structural connectivity is a potential in vivo biomarker.

OBJECTIVE: The objective of this study was to develop a multiparametric MRI signature in a large cohort of ALS patients with C9orf72 mutations. The aim was to investigate how morphological features of C9orf72-associated ALS differ in structural MRI and DTI compared to healthy controls and ALS patients without C9orf72 mutations.

METHODS: Atlas-based volumetry (ABV) and whole brain-based DTI-based analyses were performed in a cohort of n = 51 ALS patients with C9orf72 mutations and compared with both n = 51 matched healthy controls and n = 51 C9orf72 negative ALS patients, respectively. Subsequently, Spearman correlation analysis of C9orf72 ALS patients' data with clinical parameters (age of onset, sex, ALS-FRS-R, progression rate, survival) as well as ECAS and p-NfH in CSF was performed.

RESULTS: The whole brain voxel-by-voxel comparison of fractional anisotropy (FA) maps between C9orf72 ALS patients and controls showed significant bilateral alterations in axonal structures of the white matter at group level, primarily along the corticospinal tracts and in fibers projecting to the frontal lobes. For the frontal lobes, these alterations were also significant between C9orf72 positive and C9orf72 negative ALS patients. In ABV, patients with C9orf72 mutations showed lower volumes of the frontal, temporal, and parietal lobe, with the lowest values in the gray matter of the superior frontal and the precentral gyrus, but also in hippocampi and amygdala. Compared to C9orf72 negative ALS, the differences were shown to be significant for cerebral gray matter (p = 0.04), especially in the frontal (p = 0.01) and parietal lobe (p = 0.01), and in the thalamus (p = 0.004). A correlation analysis between ECAS and averaged regional FA values revealed significant correlations between cognitive performance in ECAS and frontal association fibers. Lower FA values in the frontal lobes were associated with worse performance in all cognitive domains measured (language, verbal fluency, executive functions, memory and spatial perception). In addition, there were significant negative correlations between age of onset and atlas-based volumetry results for gray matter.

CONCLUSIONS: This study demonstrates a distinct pattern of DTI alterations of the white matter and ubiquitous volume reductions of the gray matter early in the disease course of C9orf72-associated ALS. Alterations were closely linked to a more aggressive cognitive phenotype. These results are in line with an expected pTDP43 propagation pattern of cortical affection and thus strengthen the hypothesis that an underlying developmental disorder is present in ALS with C9orf72 expansions. Thus, multiparametric MRI could contribute to the assessment of the disease as an in vivo biomarker even in the early phase of the disease.}, } @article {pmid37695947, year = {2024}, author = {Sanson, G and Antonaglia, V and Buttignon, G and Caggegi, GD and Pegani, C and Peratoner, A}, title = {Dynamic Course of Clinical State Transitions in Patients Undergoing Advanced Life Support after Out-of-Hospital Cardiac Arrest.}, journal = {Prehospital emergency care}, volume = {28}, number = {3}, pages = {461-469}, doi = {10.1080/10903127.2023.2258192}, pmid = {37695947}, issn = {1545-0066}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/complications ; *Cardiopulmonary Resuscitation ; Retrospective Studies ; *Emergency Medical Services ; Ventricular Fibrillation/therapy/complications ; *Tachycardia, Ventricular/complications ; Arrhythmias, Cardiac ; }, abstract = {OBJECTIVES: Studies of out-of-hospital cardiac arrest generally document the presenting (pulseless electrical activity [PEA], ventricular fibrillation/tachycardia (VF/VT), asystole), and the final states (resuming stable spontaneous circulation [s-ROSC], being declared dead). Only a few studies described the transitions between clinical states during advanced life support (ALS). The aim of this study was to describe and analyze the dynamics of state transitions during ALS.

METHODS: A retrospective analysis of 464 OHCA events was conducted. Any observed state and its corresponding changing time were documented through continuous electrocardiographic and trans-thoracic impedance recording.

RESULTS: When achieved, most s-ROSCs were obtained by 30 min, regardless of the presenting state. After this time point, the persistence of any transient state was associated with a great probability of being declared dead. The most probable change for VF/VT or PEA at any time was the transition to asystole (36.4% and 34.4%, respectively); patients in asystole at any time had a 70% probability of death. Patients achieving s-ROSC mostly came from a VF/VT state.In most cases, the presenting rhythm tended to persist over time during ALS. Asystole was the most stable state; a higher degree of instability was observed when the presenting rhythms were VF/VT or PEA. Transient ROSC episodes occurred mainly as the first transition after the presenting state, especially for initial PEA.

CONCLUSIONS: An understanding of the dynamic course of clinical state transitions during ALS may allow treatment strategies to be tailored in patients affected by OHCA.}, } @article {pmid37695732, year = {2023}, author = {Barasa, L and Chaudhuri, S and Zhou, JY and Jiang, Z and Choudhary, S and Green, RM and Wiggin, E and Cameron, M and Humphries, F and Fitzgerald, KA and Thompson, PR}, title = {Development of LB244, an Irreversible STING Antagonist.}, journal = {Journal of the American Chemical Society}, volume = {145}, number = {37}, pages = {20273-20288}, pmid = {37695732}, issn = {1520-5126}, support = {R35 GM118112/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Proteome ; *Amyotrophic Lateral Sclerosis ; *Autoimmune Diseases of the Nervous System ; Cyclic GMP ; Nucleotidyltransferases ; }, abstract = {The cGMP-AMP Synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway plays a critical role in sensing dsDNA localized to the cytosol, resulting in the activation of a robust inflammatory response. While cGAS-STING signaling is essential for antiviral immunity, aberrant STING activation is observed in amyotrophic lateral sclerosis (ALS), lupus, and autoinflammatory diseases such as Aicardi-Goutières syndrome (AGS) and STING associated vasculopathy with onset in infancy (SAVI). Significant efforts have therefore focused on the development of STING inhibitors. In a concurrent submission, we reported that BB-Cl-amidine inhibits STING-dependent signaling in the nanomolar range, both in vitro and in vivo. Considering this discovery, we sought to generate analogs with higher potency and proteome-wide selectivity. Herein, we report the development of LB244, which displays nanomolar potency and inhibits STING signaling with markedly enhanced proteome-wide selectivity. Moreover, LB244 mirrored the efficacy of BB-Cl-amidine in vivo. In summary, our data identify novel chemical entities that inhibit STING signaling and provide a scaffold for the development of therapeutics for treating STING-dependent inflammatory diseases.}, } @article {pmid37695623, year = {2023}, author = {Genge, A and van den Berg, LH and Frick, G and Han, S and Abikoff, C and Simmons, A and Lin, Q and Patra, K and Kupperman, E and Berry, JD}, title = {Efficacy and Safety of Ravulizumab, a Complement C5 Inhibitor, in Adults With Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {80}, number = {10}, pages = {1089-1097}, pmid = {37695623}, issn = {2168-6157}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects/administration & dosage ; Middle Aged ; Double-Blind Method ; Aged ; Adult ; Complement Inactivating Agents/therapeutic use/adverse effects/administration & dosage ; Treatment Outcome ; Complement C5/antagonists & inhibitors ; }, abstract = {IMPORTANCE: Additional therapies for amyotrophic lateral sclerosis (ALS) are urgently needed. Immune-mediated complement activation may be involved in ALS pathogenesis as evidenced by the upregulation of terminal components; thus, complement inhibition could potentially slow progression.

OBJECTIVE: To evaluate the safety and efficacy of the terminal complement C5 inhibitor ravulizumab in adults with ALS.

This double-blind, placebo-controlled, parallel-group, multinational, randomized, phase 3 clinical trial was conducted from March 30, 2020, to October 17, 2021, in 81 ALS specialty centers across 17 countries. A preplanned, unmasked, nonbinding interim futility analysis was conducted when 33% of participants had completed week 26, wherein a conditional power of less than 10% would halt the trial. A total of 478 individuals were screened, and 96 were excluded. Inclusion criteria were weight of 40 kg or more, fulfillment of the El Escorial diagnostic criteria, and a minimal prestudy Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) progression score of -0.3 points per month.

INTERVENTIONS: Study treatment consisted of placebo or a weight-based dose of intravenous ravulizumab every 8 weeks until week 42. Participants could continue standard-of-care treatment.

MAIN OUTCOMES AND MEASURES: The primary end point was change from baseline in ALSFRS-R score at week 50 based on the Combined Assessment of Function and Survival (CAFS).

RESULTS: A total of 382 participants were randomly assigned 2:1 to receive ravulizumab (n = 255; mean [SD] age, 58.6 [10.6] years; 94 female [36.9%] and 161 male [63.1%]) or placebo (n = 127; mean [SD] age, 58.0 [11.0] years; 58 female [45.7%] and 69 male [54.3%]). The interim analysis showed that the observed mean change from baseline in ALSFRS-R at week 50 was -14.67 points (SE, 0.89 points; 95% CI, -16.42 to -12.91 points) for ravulizumab and -13.33 points (SE, 1.22 points; 95% CI, -15.72 to -10.93 points) for placebo, with no significant difference between the groups (mean [SE] difference, -1.34 [1.46] points; 95% CI, -4.21 to 1.53 points). Based on these data, the trial was terminated for futility. The primary analysis at week 50 showed no significant difference in CAFS between groups (mean [SE], 5.5 [10.8] points; 95% CI, -15.7 to 26.6 points; P = .61). Overall incidence rates for treatment-emergent adverse events were similar for ravulizumab (204 participants [80.0%]) and placebo (108 participants [85.0%]).

CONCLUSIONS AND RELEVANCE: This trial rapidly showed that terminal complement C5 inhibition with ravulizumab did not slow functional decline in participants with ALS and that the safety profiles of ravulizumab and placebo were similar. Highly effective, novel treatments are critically needed to slow functional decline and extend survival in patients with ALS.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04248465.}, } @article {pmid37695446, year = {2024}, author = {Yang, EJ}, title = {Combined Treatment with Bojungikgi-tang (Buzhong Yiqi Decoction) and Riluzole Attenuates Cell Death in TDP-43-Expressing Cells.}, journal = {Chinese journal of integrative medicine}, volume = {30}, number = {7}, pages = {616-622}, pmid = {37695446}, issn = {1993-0402}, mesh = {*Drugs, Chinese Herbal/pharmacology ; *DNA-Binding Proteins/metabolism ; *Cell Death/drug effects ; *Riluzole/pharmacology ; Cell Line ; Autophagy/drug effects ; Animals ; Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; Cell Survival/drug effects ; Drug Therapy, Combination ; Humans ; }, abstract = {OBJECTIVE: To examine the effect of combined treatment with Bojungikgi-tang (BJIGT, Buzhong Yiqi Decoction) and riluzole (RZ) in transactive response DNA-binding protein 43 (TDP-43) stress granule (SG) cells, a amyotrophic lateral sclerosis (ALS) cell line using transcriptomic and molecular techniques.

METHODS: TDP-43 SG cells were pretreated with BJIGT (100 µg/mL), RZ (50 µmol/L), and combined BJIGT (100 µg/mL)/RZ (50 µmol/L) for 6 h before treatment with lipopolysaccharide (LPS, 200 µmol/L). Cell viability assay was performed to elucidate cell toxicity in TDP-43 SC cells using a cell-counting kit-8 (CCK8) assay kit. The expression levels of cell death-related proteins, including Bax, caspase 1, cleaved caspase 3 and DJ1 in TDP-43 SG cells were examined by Western blot analysis. The autophagy-related proteins, including pmTOR/mTOR, LC3b, P62, ATG7 and Bcl-2-associated athanogene 3 (Bag3) were investigated using immunofluorescence and immunoblotting assays.

RESULTS: Cell viability assay and Western blot analysis showed that combined treatment with BJIGT and RZ suppressed LPS-induced cell death and expression of cell death-related proteins, including Bax, caspase 1, and DJ1 (P<0.05 or P<0.01). Immunofluorescence and immunoblotting assays showed that combined treatment with BJIGT and RZ reduced LPS-induced formation of TDP-43 aggregates and regulated autophagy-related protein levels, including p62, light chain 3b, Bag3, and ATG7, in TDP-43-expressing cells (P<0.05 or P<0.01).

CONCLUSION: The combined treatment of BJIGT and RZ might reduce inflammation and regulate autophagy dysfunction in TDP-43-induced ALS.}, } @article {pmid37694825, year = {2023}, author = {Tahedl, M and Tan, EL and Chipika, RH and Lope, J and Hengeveld, JC and Doherty, MA and McLaughlin, RL and Hardiman, O and Hutchinson, S and McKenna, MC and Bede, P}, title = {The involvement of language-associated networks, tracts, and cortical regions in frontotemporal dementia and amyotrophic lateral sclerosis: Structural and functional alterations.}, journal = {Brain and behavior}, volume = {13}, number = {11}, pages = {e3250}, pmid = {37694825}, issn = {2162-3279}, mesh = {Humans ; *Frontotemporal Dementia/diagnostic imaging/genetics/pathology ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/genetics ; C9orf72 Protein/genetics ; Brain/pathology ; Language ; }, abstract = {BACKGROUND: Language deficits are cardinal manifestations of some frontotemporal dementia (FTD) phenotypes and also increasingly recognized in sporadic and familial amyotrophic lateral sclerosis (ALS). They have considerable social and quality-of-life implications, and adaptive strategies are challenging to implement. While the neuropsychological profiles of ALS-FTD phenotypes are well characterized, the neuronal underpinnings of language deficits are less well studied.

METHODS: A multiparametric, quantitative neuroimaging study was conducted to characterize the involvement of language-associated networks, tracts, and cortical regions with a panel of structural, diffusivity, and functional magnetic resonance imaging (MRI) metrics. Seven study groups were evaluated along the ALS-FTD spectrum: healthy controls (HC), individuals with ALS without cognitive impairment (ALSnci), C9orf72-negative ALS-FTD, C9orf72-positive ALS-FTD, behavioral-variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA). The integrity of the Broca's area, Wernicke's area, frontal aslant tract (FAT), arcuate fascicle (AF), inferior occipitofrontal fascicle (IFO), inferior longitudinal fascicle (ILF), superior longitudinal fascicle (SLF), and uncinate fascicle (UF) was quantitatively evaluated. The functional connectivity (FC) between Broca's and Wernicke' areas and FC along the FAT was also specifically assessed.

RESULTS: Patients with nfvPPA and svPPA exhibit distinctive patterns of gray and white matter degeneration in language-associated brain regions. Individuals with bvFTD exhibit Broca's area, right FAT, right IFO, and UF degeneration. The ALSnci group exhibits Broca's area atrophy and decreased FC along the FAT. Both ALS-FTD cohorts, irrespective of C9orf72 status, show bilateral FAT, AF, and IFO pathology. Interestingly, only C9orf72-negative ALS-FTD patients exhibit bilateral uncinate and right ILF involvement, while C9orf72-positive ALS-FTD patients do not.

CONCLUSIONS: Language-associated tracts and networks are not only affected in language-variant FTD phenotypes but also in ALS and bvFTD. Language domains should be routinely assessed in ALS irrespective of the genotype.}, } @article {pmid37694369, year = {2023}, author = {Verde, F and Aiello, EN and Adobbati, L and Poletti, B and Solca, F and Tiloca, C and Sangalli, D and Maranzano, A and Muscio, C and Ratti, A and Zago, S and Ticozzi, N and Frisoni, GB and Silani, V}, title = {Coexistence of Amyotrophic Lateral Sclerosis and Alzheimer's Disease: Case Report and Review of the Literature.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {95}, number = {4}, pages = {1383-1399}, doi = {10.3233/JAD-230562}, pmid = {37694369}, issn = {1875-8908}, mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/genetics ; *Alzheimer Disease/diagnosis/diagnostic imaging ; *Cognitive Dysfunction/complications ; Brain/diagnostic imaging ; *Frontotemporal Dementia/complications/diagnostic imaging/genetics ; }, abstract = {We describe a case of amyotrophic lateral sclerosis (ALS) associated with Alzheimer's disease (AD) and review the literature about the coexistence of the two entities, highlighting the following: mean age at onset is 63.8 years, with slight female predominance; ALS tends to manifest after cognitive impairment and often begins in the bulbar region; average disease duration is 3 years; cognitive phenotype is mostly amnestic; the pattern of brain involvement is, in most cases, consistent with AD. Our case and the reviewed ones suggest that patients with ALS and dementia lacking unequivocal features of FTD should undergo additional examinations in order to recognize AD.}, } @article {pmid37694126, year = {2023}, author = {Liguori, F and Pandey, UB and Digilio, FA}, title = {Editorial: Drosophila as a model to study neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1275253}, pmid = {37694126}, issn = {1662-4548}, } @article {pmid37693725, year = {2023}, author = {Barbalho, IMP and Fonseca, ALA and Fernandes, F and Henriques, J and Gil, P and Nagem, D and Lindquist, R and Lima, T and Dos Santos, JPQ and Paiva, J and Morais, AHF and Dourado Júnior, MET and Valentim, RAM}, title = {Digital health solution for monitoring and surveillance of Amyotrophic Lateral Sclerosis in Brazil.}, journal = {Frontiers in public health}, volume = {11}, number = {}, pages = {1209633}, pmid = {37693725}, issn = {2296-2565}, mesh = {Humans ; Brazil/epidemiology ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Neurodegenerative Diseases ; Databases, Factual ; Health Personnel ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex and rare neurodegenerative disease given its heterogeneity. Despite being known for many years, few countries have accurate information about the characteristics of people diagnosed with ALS, such as data regarding diagnosis and clinical features of the disease. In Brazil, the lack of information about ALS limits data for the research progress and public policy development that benefits people affected by this health condition. In this context, this article aims to show a digital health solution development and application for research, intervention, and strengthening of the response to ALS in the Brazilian Health System. The proposed solution is composed of two platforms: the Brazilian National ALS Registry, responsible for the data collection in a structured way from ALS patients all over Brazil; and the Brazilian National ALS Observatory, responsible for processing the data collected in the National Registry and for providing a monitoring room with indicators on people diagnosed with ALS in Brazil. The development of this solution was supported by the Brazilian Ministry of Health (MoH) and was carried out by a multidisciplinary team with expertise in ALS. This solution represents a tool with great potential for strengthening public policies and stands out for being the only public database on the disease, besides containing innovations that allow data collection by health professionals and/or patients. By using both platforms, it is believed that it will be possible to understand the demographic and epidemiological data of ALS in Brazil, since the data will be able to be analyzed by care teams and also by public health managers, both in the individual and collective monitoring of people living with ALS in Brazil.}, } @article {pmid37693322, year = {2023}, author = {Bayraktar, E and Çiftçi, V and Uysal, H and Başak, AN}, title = {Another de novo mutation in the SOD1 gene: the first Turkish patient with SOD1-His47Arg, a case report.}, journal = {Frontiers in genetics}, volume = {14}, number = {}, pages = {1208673}, pmid = {37693322}, issn = {1664-8021}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease of motor neurons. Most ALS cases are considered sporadic due to the presence of a combination of environmental and complex genetic risk factors, while approximately 10% of cases have a family history. Pathogenic variants in the SOD1 gene are the second most frequent causative factor of genetics-based ALS worldwide, after C9ORF72 hexanucleotide repeat expansion. The De novo occurrence of pathogenic mutations in ALS-associated genes and its effect on disease progression have been studied previously, especially in the FUS gene. Recent studies have shown that a very small portion of SOD1 cases occurred de novo. Here, we present the first de novo case of the SOD1 His47Arg mutation in a young female patient with mild symptoms and, currently, a slow progression for 7 years.}, } @article {pmid37692101, year = {2023}, author = {Stansberry, WM and Pierchala, BA}, title = {Neurotrophic factors in the physiology of motor neurons and their role in the pathobiology and therapeutic approach to amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1238453}, pmid = {37692101}, issn = {1662-5099}, support = {R01 NS089585/NS/NINDS NIH HHS/United States ; }, abstract = {The discovery of the neurotrophins and their potent survival and trophic effects led to great enthusiasm about their therapeutic potential to rescue dying neurons in neurodegenerative diseases. The further discovery that brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF) had potent survival-promoting activity on motor neurons led to the proposal for their use in motor neuron diseases such as amyotrophic lateral sclerosis (ALS). In this review we synthesize the literature pertaining to the role of NGF, BDNF, CNTF and GDNF on the development and physiology of spinal motor neurons, as well as the preclinical studies that evaluated their potential for the treatment of ALS. Results from the clinical trials of these molecules will also be described and, with the aid of decades of hindsight, we will discuss what can reasonably be concluded and how this information can inform future clinical development of neurotrophic factors for ALS.}, } @article {pmid37691335, year = {2023}, author = {Corcoran, J and Kluger, BM}, title = {Prognosis in chronic progressive neurologic disease: a narrative review.}, journal = {Annals of palliative medicine}, volume = {12}, number = {5}, pages = {952-962}, doi = {10.21037/apm-22-1338}, pmid = {37691335}, issn = {2224-5839}, mesh = {Humans ; *Parkinson Disease/diagnosis/therapy ; *Nervous System Diseases ; Prognosis ; Palliative Care ; Chronic Disease ; *Dementia ; }, abstract = {BACKGROUND AND OBJECTIVE: Prognostication is the process of predicting a patient's likely outcome from their medical condition, and consists of determining both how well and how long a patient may live. There are few disease-specific prognostic tools to estimate a patient's individualized prognosis in terms of symptom burden and mortality. Here we summarize relevant literature on prognosis in four progressive neurologic diseases-dementia, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis-as well as on best practices on communicating prognosis with patients and care partners.

METHODS: We conducted a PubMed search for terms including "prognosis", "mortality" and "prognostic indicators" in addition to specific diseases, and for terms including "prognosis AND communication". Only English-language papers were included in this review. The time frame of our literature search was 1965 through March 1, 2023.

KEY CONTENT AND FINDINGS: There is some literature to help clinicians in predicting disease progression and survival. These include both general factors (e.g., age, medical co-morbidities) and disease-specific factors (e.g., postural instability in Parkinson's disease). There is also literature on communication of prognosis in neurologic and non-neurologic disease which demonstrates that many patients and care partners prefer to hear prognosis early after diagnosis and to have prognosis discussed as a roadmap of disease.

CONCLUSIONS: More work is needed to develop tools for individualized prognostication and communication for patients with neurologic disease. While there is limited literature on disease-specific prognostic models, existing literature combined with palliative care approaches may improve prognostic guidance for patients.}, } @article {pmid37691292, year = {2023}, author = {Roggenbuck, J and Eubank, BHF and Wright, J and Harms, MB and Kolb, SJ and , }, title = {Evidence-based consensus guidelines for ALS genetic testing and counseling.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {11}, pages = {2074-2091}, pmid = {37691292}, issn = {2328-9503}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; C9orf72 Protein/genetics ; Systematic Reviews as Topic ; Meta-Analysis as Topic ; Genetic Testing ; Counseling ; }, abstract = {OBJECTIVE: Advances in amyotrophic lateral sclerosis (ALS) gene discovery, ongoing gene therapy trials, and patient demand have driven increased use of ALS genetic testing. Despite this progress, the offer of genetic testing to persons with ALS is not yet "standard of care." Our primary goal is to develop clinical ALS genetic counseling and testing guidelines to improve and standardize genetic counseling and testing practice among neurologists, genetic counselors or any provider caring for persons with ALS.

METHODS: Core clinical questions were identified and a rapid review performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) 2015 method. Guideline recommendations were drafted and the strength of evidence for each recommendation was assessed by combining two systems: the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) System and the Evaluation of Genomic Applications in Practice and Prevention (EGAPP). A modified Delphi approach was used to reach consensus among a group of content experts for each guideline statement.

RESULTS: A total of 35 guideline statements were developed. In summary, all persons with ALS should be offered single-step genetic testing, consisting of a C9orf72 assay, along with sequencing of SOD1, FUS, and TARDBP, at a minimum. The key education and genetic risk assessments that should be provided before and after testing are delineated. Specific guidance regarding testing methods and reporting for C9orf72 and other genes is provided for commercial laboratories.

INTERPRETATION: These evidence-based, consensus guidelines will support all stakeholders in the ALS community in navigating benefits and challenges of genetic testing.}, } @article {pmid37691199, year = {2024}, author = {Bhat, MA and Dhaneshwar, S}, title = {Neurodegenerative Diseases: New Hopes and Perspectives.}, journal = {Current molecular medicine}, volume = {24}, number = {8}, pages = {1004-1032}, pmid = {37691199}, issn = {1875-5666}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/pathology ; Animals ; }, abstract = {Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and Friedrich ataxia are all incurable neurodegenerative diseases defined by the continuous progressive loss of distinct neuronal subtypes. Despite their rising prevalence among the world's ageing population, fewer advances have been made in the concurrent massive efforts to develop newer drugs. Recently, there has been a shift in research focus towards the discovery of new therapeutic agents for neurodegenerative diseases. In this review, we have summarized the recently developed therapies and their status in the management of neurodegenerative diseases.}, } @article {pmid37689642, year = {2023}, author = {Bustamante-Barrientos, FA and Luque-Campos, N and Araya, MJ and Lara-Barba, E and de Solminihac, J and Pradenas, C and Molina, L and Herrera-Luna, Y and Utreras-Mendoza, Y and Elizondo-Vega, R and Vega-Letter, AM and Luz-Crawford, P}, title = {Mitochondrial dysfunction in neurodegenerative disorders: Potential therapeutic application of mitochondrial transfer to central nervous system-residing cells.}, journal = {Journal of translational medicine}, volume = {21}, number = {1}, pages = {613}, pmid = {37689642}, issn = {1479-5876}, mesh = {Humans ; Mitochondria ; *Neurodegenerative Diseases/therapy ; *Alzheimer Disease ; *Parkinson Disease ; Central Nervous System ; }, abstract = {Mitochondrial dysfunction is reiteratively involved in the pathogenesis of diverse neurodegenerative diseases. Current in vitro and in vivo approaches support that mitochondrial dysfunction is branded by several molecular and cellular defects, whose impact at different levels including the calcium and iron homeostasis, energetic balance and/or oxidative stress, makes it difficult to resolve them collectively given their multifactorial nature. Mitochondrial transfer offers an overall solution since it contains the replacement of damage mitochondria by healthy units. Therefore, this review provides an introducing view on the structure and energy-related functions of mitochondria as well as their dynamics. In turn, we summarize current knowledge on how these features are deregulated in different neurodegenerative diseases, including frontotemporal dementia, multiple sclerosis, amyotrophic lateral sclerosis, Friedreich ataxia, Alzheimer´s disease, Parkinson´s disease, and Huntington's disease. Finally, we analyzed current advances in mitochondrial transfer between diverse cell types that actively participate in neurodegenerative processes, and how they might be projected toward developing novel therapeutic strategies.}, } @article {pmid37689321, year = {2023}, author = {Donini, L and Tanel, R and Zuccarino, R and Basso, M}, title = {Protein biomarkers for the diagnosis and prognosis of Amyotrophic Lateral Sclerosis.}, journal = {Neuroscience research}, volume = {197}, number = {}, pages = {31-41}, doi = {10.1016/j.neures.2023.09.002}, pmid = {37689321}, issn = {1872-8111}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Prognosis ; Biomarkers ; Disease Progression ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease, still incurable. The disease is highly heterogenous both genetically and phenotypically. Therefore, developing efficacious treatments is challenging in many aspects because it is difficult to predict the rate of disease progression and stratify the patients to minimize statistical variability in clinical studies. Moreover, there is a lack of sensitive measures of therapeutic effect to assess whether a pharmacological intervention ameliorates the disease. There is also urgency of markers that reflect a molecular mechanism dysregulated by ALS pathology and can be rescued when a treatment relieves the condition. Here, we summarize and discuss biomarkers tested in multicentered studies and across different laboratories like neurofilaments, the most used marker in ALS clinical studies, neuroinflammatory-related proteins, p75[ECD], p-Tau/t-Tau, and UCHL1. We also explore the applicability of muscle proteins and extracellular vesicles as potential biomarkers.}, } @article {pmid37688751, year = {2023}, author = {Khakha, N and Khan, H and Kaur, A and Singh, TG}, title = {Therapeutic implications of phosphorylation- and dephosphorylation-dependent factors of cAMP-response element-binding protein (CREB) in neurodegeneration.}, journal = {Pharmacological reports : PR}, volume = {75}, number = {5}, pages = {1152-1165}, pmid = {37688751}, issn = {2299-5684}, mesh = {Animals ; *Alzheimer Disease/drug therapy ; Cyclic AMP Response Element-Binding Protein/metabolism ; *Neurodegenerative Diseases/drug therapy/genetics ; Phosphorylation ; Response Elements ; Humans ; }, abstract = {Neurodegeneration is a condition of the central nervous system (CNS) characterized by loss of neural structures and function. The most common neurodegenerative disorders (NDDs) include Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), motor neuron disorders, psychological disorders, dementia with vascular dementia (VaD), Lewy body dementia (DLB), epilepsy, cerebral ischemia, mental illness, and behavioral disorders. CREB (cAMP-response element-binding protein) represent a nuclear protein that regulates gene transcriptional activity. The primary focus of the review pertains to the exploration of CREB expression and activation within the context of neurodegenerative diseases, specifically in relation to the phosphorylation and dephosphorylation events that occur within the CREB signaling pathway under normal physiological conditions. The findings mentioned have contributed to the elucidation of the regulatory mechanisms governing CREB activity. Additionally, they have provided valuable insights into the potential mediation of diverse biological processes, such as memory consolidation and neuroprotective effects, by various related studies. The promotion of synaptic plasticity and neurodevelopment in the central nervous system through the targeting of CREB proteins has the potential to contribute to the prevention or delay of the onset of neurodegenerative disorders. Multiple drugs have been found to initiate downstream signaling pathways, leading to neuroprotective advantages in both animal model studies and clinical trials. The clinical importance of the cAMP-response element-binding protein (CREB) is examined in this article, encompassing its utility as both a predictive/prognostic marker and a target for therapeutic interventions.}, } @article {pmid37688660, year = {2023}, author = {Yue, W and Tang, CW and Fang, Y}, title = {PIKFYVE Inhibition, A Neuronal "Emetic" for Treating ALS?.}, journal = {Neuroscience bulletin}, volume = {39}, number = {11}, pages = {1738-1740}, pmid = {37688660}, issn = {1995-8218}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Neurons ; Phosphatidylinositol 3-Kinases ; *Phosphoinositide-3 Kinase Inhibitors/therapeutic use ; }, } @article {pmid37688479, year = {2024}, author = {Li, Z and Tian, M and Jia, H and Li, X and Liu, Q and Zhou, X and Li, R and Dong, H and Liu, Y}, title = {Genetic variation in targets of lipid-lowering drugs and amyotrophic lateral sclerosis risk: a Mendelian randomization study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {197-206}, doi = {10.1080/21678421.2023.2255622}, pmid = {37688479}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/epidemiology/genetics ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; Cholesterol, LDL ; Apolipoproteins B/genetics ; Genetic Variation ; Polymorphism, Single Nucleotide/genetics ; }, abstract = {BACKGROUND: The use of lipid-lowering drugs is still highly controversial in patients with amyotrophic lateral sclerosis (ALS). We performed a drug-target Mendelian randomization (MR) analysis to investigate the effect of targeted lipid-lowering drugs on the risk of ALS.

METHODS: First, we evaluated the causal relationship between HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase (HMGCR) inhibitors-taking trait and ALS using a bidirectional two-sample MR study. Second, we investigated the causal relationship between lipid-lowering drugs and ALS through a drug-target MR approach. The summary data for HMGCR inhibitors-taking traits were extracted from a genome-wide association study (GWAS) of medication use and associated disease in the UK Biobank. The summary data for low-density lipoprotein cholesterol and apolipoprotein B (apoB) were extracted from a meta-analysis of GWAS in individuals of European ancestry in the UKB. The GWAS summary data of ALS were obtained from the Project MinE.

RESULTS: Our bidirectional two-sample MR showed that genetically determined increased HMGCR inhibitors-taking trait was an independent risk factor for ALS (odds ratio [OR] = 1.090, 95% confidence interval [CI] = 1.035-1.150, p = 0.001). The results of drug-target MR showed that the increased expression of the HMGCR gene in blood with the higher risk of ALS (OR = 1.21, 95% CI = 1.01-1.46; p = 0.042) through SMR method and the apoB level mediated by the APOB gene increased the risk of ALS (OR = 1.15; 95% CI =1.05-1.25; p = 0.001) through inverse-variance weighted MR method.

CONCLUSION: This present study provides genetic support for a positive causal effect of HMGCR inhibitors-taking trait and ALS. The reason for this may be due to the underlying disease condition behind the medication, rather than the medication itself. Our findings also suggested that HMGCR and apoB inhibitors may have potential protective effects on ALS.}, } @article {pmid37687832, year = {2023}, author = {Pavelka, K and Matoušková, E and Pavelka, K}, title = {Remarks on Geomatics Measurement Methods Focused on Forestry Inventory.}, journal = {Sensors (Basel, Switzerland)}, volume = {23}, number = {17}, pages = {}, pmid = {37687832}, issn = {1424-8220}, abstract = {This contribution focuses on a comparison of modern geomatics technologies for the derivation of growth parameters in forest management. The present text summarizes the results of our measurements over the last five years. As a case project, a mountain spruce forest with planned forest logging was selected. In this locality, terrestrial laser scanning (TLS) and terrestrial and drone close-range photogrammetry were experimentally used, as was the use of PLS mobile technology (personal laser scanning) and ALS (aerial laser scanning). Results from the data joining, usability, and economics of all technologies for forest management and ecology were discussed. ALS is expensive for small areas and the results were not suitable for a detailed parameter derivation. The RPAS (remotely piloted aircraft systems, known as "drones") method of data acquisition combines the benefits of close-range and aerial photogrammetry. If the approximate height and number of the trees are known, one can approximately calculate the extracted cubage of wood mass before forest logging. The use of conventional terrestrial close-range photogrammetry and TLS proved to be inappropriate and practically unusable in our case, and also in standard forestry practice after consultation with forestry workers. On the other hand, the use of PLS is very simple and allows you to quickly define ordered parameters and further calculate, for example, the cubic volume of wood stockpiles. The results from our research into forestry show that drones can be used to estimate quantities (wood cubature) and inspect the health status of spruce forests, However, PLS seems, nowadays, to be the best solution in forest management for deriving forest parameters. Our results are mainly oriented to practice and in no way diminish the general research in this area.}, } @article {pmid37686737, year = {2023}, author = {Zhou, J and Zhang, W and Cao, Z and Lian, S and Li, J and Nie, J and Huang, Y and Zhao, K and He, J and Liu, C}, title = {Association of Selenium Levels with Neurodegenerative Disease: A Systemic Review and Meta-Analysis.}, journal = {Nutrients}, volume = {15}, number = {17}, pages = {}, pmid = {37686737}, issn = {2072-6643}, support = {81903294//National Natural Science Foundation of China/ ; 202102020120//Guangzhou Basic and Applied Basic Research Foundation/ ; A2022080//Medical Scientific Research Foundation of Guangdong Province of China/ ; }, mesh = {Humans ; *Selenium ; *Neurodegenerative Diseases ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; Databases, Factual ; }, abstract = {BACKGROUND: Neurodegenerative diseases (NDs) have posed significant challenges to public health, and it is crucial to understand their mechanisms in order to develop effective therapeutic strategies. Recent studies have highlighted the potential role of selenium in ND pathogenesis, as it plays a vital role in maintaining cellular homeostasis and preventing oxidative damage. However, a comprehensive analysis of the association between selenium and NDs is still lacking.

METHOD: Five public databases, namely PubMed, Web of Science, EMBASE, Cochrane and Clinical Trials, were searched in our research. Random model effects were chosen, and Higgins inconsistency analyses (I[2]), Cochrane's Q test and Tau2 were calculated to evaluate the heterogeneity.

RESULT: The association of selenium in ND patients with Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) was studied. A statistically significant relationship was only found for AD patients (SMD = -0.41, 95% CI (-0.64, -0.17), p < 0.001), especially for erythrocytes. However, no significant relationship was observed in the analysis of the other four diseases.

CONCLUSION: Generally, this meta-analysis indicated that AD patients are strongly associated with lower selenium concentrations compared with healthy people, which may provide a clinical reference in the future. However, more studies are urgently needed for further study and treatment of neurodegenerative diseases.}, } @article {pmid37686322, year = {2023}, author = {Badu-Mensah, A and Guo, X and Mendez, R and Parsaud, H and Hickman, JJ}, title = {The Effect of Skeletal Muscle-Specific Creatine Treatment on ALS NMJ Integrity and Function.}, journal = {International journal of molecular sciences}, volume = {24}, number = {17}, pages = {}, pmid = {37686322}, issn = {1422-0067}, support = {R01 NS050452/NS/NINDS NIH HHS/United States ; R01NS050452/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Creatine/pharmacology/therapeutic use ; Muscle Fatigue ; Muscle, Skeletal ; Neuromuscular Junction ; }, abstract = {Although skeletal muscle (hSKM) has been proven to be actively involved in Amyotrophic Lateral Sclerosis (ALS) neuromuscular junction (NMJ) dysfunction, it is rarely considered as a pharmacological target in preclinical drug discovery. This project investigated how improving ALS hSKM viability and function effects NMJ integrity. Phenotypic ALS NMJ human-on-a-chip models developed from patient-derived induced pluripotent stem cells (iPSCs) were used to study the effect of hSKM-specific creatine treatment on clinically relevant functional ALS NMJ parameters, such as NMJ numbers, fidelity, stability, and fatigue index. Results indicated comparatively enhanced NMJ numbers, fidelity, and stability, as well as reduced fatigue index, across all hSKM-specific creatine-treated systems. Immunocytochemical analysis of the NMJs also revealed improved post-synaptic nicotinic Acetylcholine receptor (AChR) clustering and cluster size in systems supplemented with creatine relative to the un-dosed control. This work strongly suggests hSKM as a therapeutic target in ALS drug discovery. It also demonstrates the need to consider all tissues involved in multi-systemic diseases, such as ALS, in drug discovery efforts. Finally, this work further establishes the BioMEMs NMJ platform as an effective means of performing mutation-specific drug screening, which is a step towards personalized medicine for rare diseases.}, } @article {pmid37686239, year = {2023}, author = {Zalar, M and Wang, B and Plavec, J and Šket, P}, title = {Insight into Tetramolecular DNA G-Quadruplexes Associated with ALS and FTLD: Cation Interactions and Formation of Higher-Ordered Structure.}, journal = {International journal of molecular sciences}, volume = {24}, number = {17}, pages = {}, pmid = {37686239}, issn = {1422-0067}, support = {P1-0242//Slovenian Research Agency/ ; J1-1704//Slovenian Research Agency/ ; J1-7108//Slovenian Research Agency/ ; }, mesh = {Humans ; *G-Quadruplexes ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia ; *Frontotemporal Lobar Degeneration ; Cations ; Potassium ; }, abstract = {The G4C2 hexanucleotide repeat expansion in the c9orf72 gene is a major genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), with the formation of G-quadruplexes directly linked to the development of these diseases. Cations play a crucial role in the formation and structure of G-quadruplexes. In this study, we investigated the impact of biologically relevant potassium ions on G-quadruplex structures and utilized [15]N-labeled ammonium cations as a substitute for K[+] ions to gain further insights into cation binding and exchange dynamics. Through nuclear magnetic resonance spectroscopy and molecular dynamics simulations, we demonstrate that the single d(G4C2) repeat, in the presence of [15]NH4[+] ions, adopts a tetramolecular G-quadruplex with an all-syn quartet at the 5'-end. The movement of [15]NH4[+] ions through the central channel of the G-quadruplex, as well as to the bulk solution, is governed by the vacant cation binding site, in addition to the all-syn quartet at the 5'-end. Furthermore, the addition of K[+] ions to G-quadruplexes folded in the presence of [15]NH4[+] ions induces stacking of G-quadruplexes via their 5'-end G-quartets, leading to the formation of stable higher-ordered species.}, } @article {pmid37683919, year = {2023}, author = {Yu, Z and Zhang, H and Wang, Y}, title = {Cervical Spondylotic Amyotrophy Initially Misdiagnosed as Amyotrophic Lateral Sclerosis.}, journal = {World neurosurgery}, volume = {180}, number = {}, pages = {3-5}, doi = {10.1016/j.wneu.2023.08.130}, pmid = {37683919}, issn = {1878-8769}, mesh = {Male ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis ; Muscular Atrophy/diagnosis/surgery ; Muscle, Skeletal ; Muscle Weakness/etiology ; *Spondylosis/diagnostic imaging/surgery ; Diagnostic Errors ; Cervical Vertebrae/diagnostic imaging/surgery ; }, abstract = {A 63-year-old man diagnosed with mixed-type cervical spondylotic amyotrophy exhibited severe atrophy in the right biceps brachii, teres major, and intrinsic hand muscles, resulting in level 3 muscle weakness. Magnetic resonance imaging showed symmetrical high signal, also referred to as the snake eye sign. Previously, he was erroneously diagnosed with amyotrophic lateral sclerosis. He had undergone anterior cervical surgery 7 years prior. At present, his right upper limb muscles display minimal atrophy compared with the left, with muscle strength nearing level 4, which is considered normal. We believe that prompt surgical intervention on diagnosis of cervical spondylotic amyotrophy, along with comprehensive postsurgery rehabilitation, can halt further deterioration of the condition and accelerate recovery.}, } @article {pmid37683611, year = {2023}, author = {Harding, O and Holzer, E and Riley, JF and Martens, S and Holzbaur, ELF}, title = {Damaged mitochondria recruit the effector NEMO to activate NF-κB signaling.}, journal = {Molecular cell}, volume = {83}, number = {17}, pages = {3188-3204.e7}, pmid = {37683611}, issn = {1097-4164}, support = {R01 NS060698/NS/NINDS NIH HHS/United States ; R37 NS060698/NS/NINDS NIH HHS/United States ; W 1261/FWF_/Austrian Science Fund FWF/Austria ; }, mesh = {*NF-kappa B/genetics ; *Signal Transduction ; I-kappa B Kinase/genetics ; Protein Serine-Threonine Kinases/genetics ; Mitochondria/genetics ; }, abstract = {Failure to clear damaged mitochondria via mitophagy disrupts physiological function and may initiate damage signaling via inflammatory cascades, although how these pathways intersect remains unclear. We discovered that nuclear factor kappa B (NF-κB) essential regulator NF-κB effector molecule (NEMO) is recruited to damaged mitochondria in a Parkin-dependent manner in a time course similar to recruitment of the structurally related mitophagy adaptor, optineurin (OPTN). Upon recruitment, NEMO partitions into phase-separated condensates distinct from OPTN but colocalizing with p62/SQSTM1. NEMO recruitment, in turn, recruits the active catalytic inhibitor of kappa B kinase (IKK) component phospho-IKKβ, initiating NF-κB signaling and the upregulation of inflammatory cytokines. Consistent with a potential neuroinflammatory role, NEMO is recruited to mitochondria in primary astrocytes upon oxidative stress. These findings suggest that damaged, ubiquitinated mitochondria serve as an intracellular platform to initiate innate immune signaling, promoting the formation of activated IKK complexes sufficient to activate NF-κB signaling. We propose that mitophagy and NF-κB signaling are initiated as parallel pathways in response to mitochondrial stress.}, } @article {pmid37682899, year = {2023}, author = {van Eenennaam, RM and Rave, N and Kruithof, WJ and Kruitwagen-van Reenen, ET and van den Berg, LH and Visser-Meily, JA and Beelen, A}, title = {Control in the absence of choice: A qualitative study on decision-making about gastrostomy in people with amyotrophic lateral sclerosis, caregivers, and healthcare professionals.}, journal = {PloS one}, volume = {18}, number = {9}, pages = {e0290508}, pmid = {37682899}, issn = {1932-6203}, mesh = {Humans ; *Caregivers ; Gastrostomy ; *Amyotrophic Lateral Sclerosis/therapy ; Health Personnel ; Delivery of Health Care ; }, abstract = {BACKGROUND: Gastrostomy is recommended in amyotrophic lateral sclerosis for long-term nutritional support, however, people with amyotrophic lateral sclerosis and healthcare professionals perceive decision-making as complex.

METHOD: To explore their perspectives on decision-making regarding gastrostomy, we used semi-structured interviews with people with amyotrophic lateral sclerosis, who had made a decision, and their caregivers; healthcare professionals were interviewed separately. Interviews were transcribed and analyzed thematically.

RESULTS: In 14 cases, 13 people with amyotrophic lateral sclerosis and 12 caregivers were interviewed; and in 10 of these cases, 5 healthcare professionals. Participants described decision-making on gastrostomy as a continuous process of weighing (future) clinical need against their values and beliefs in coming to a decision to accept or reject gastrostomy, or to postpone decision-making, while being supported by loved ones and healthcare professionals. Participants described gastrostomy as inevitable, but retained agency through control over the timing of decision-making. They said physical necessity, experiences of loss and identity, and expectations about gastrostomy placement were important factors in decision-making. Decision-making was described as a family affair, with caregivers supporting patient choice. healthcare professionals supported people with amyotrophic lateral sclerosis during the decision-making process and respected their autonomy and values. People with amyotrophic lateral sclerosis stressed the importance of adequate information on the procedure and the benefits.

CONCLUSION: People with amyotrophic lateral sclerosis feel in control of decision-making on gastrostomy if they are able to make their own choice at their own pace, supported by loved ones and healthcare professionals. Person-centered decision-making on gastrostomy requires early information exchange and repeated discussions with people with amyotrophic lateral sclerosis and their caregivers, incorporating their values and respecting patient choice.}, } @article {pmid37682317, year = {2023}, author = {Sassi, S and Bianchi, E and Diamanti, L and Tornabene, D and Sette, E and Medici, D and Matà, S and Leccese, D and Sperti, M and Martinelli, I and Ghezzi, A and Mandrioli, J and Iuzzolino, VV and Dubbioso, R and Trojsi, F and Passaniti, C and D'Alvano, G and Filosto, M and Padovani, A and Mazzini, L and De Marchi, F and Zinno, L and Nuredini, A and Bongioanni, P and Dolciotti, C and Canali, E and Toschi, G and Petrucci, A and Perna, A and Riso, V and Inghilleri, M and Libonati, L and Cambieri, C and Pupillo, E}, title = {Correction to: Retrospective observational study on the use of acetyl-L-carnitine in ALS.}, journal = {Journal of neurology}, volume = {270}, number = {11}, pages = {5358-5359}, doi = {10.1007/s00415-023-11960-3}, pmid = {37682317}, issn = {1432-1459}, } @article {pmid37682161, year = {2023}, author = {Tang, X and Zhan, Y and Yang, B and Du, B and Huang, J}, title = {Exploring the mechanism of Semen Strychni in treating amyotrophic lateral sclerosis based on network pharmacology.}, journal = {Medicine}, volume = {102}, number = {36}, pages = {e35101}, pmid = {37682161}, issn = {1536-5964}, mesh = {Humans ; *Semen ; *Amyotrophic Lateral Sclerosis/drug therapy ; Network Pharmacology ; Molecular Docking Simulation ; Phosphatidylinositol 3-Kinases ; }, abstract = {Semen Strychni (SS), known as an agonist of central nervous system, is a traditional herb widely used in treating amyotrophic lateral sclerosis (ALS) in small doses to relieve muscle weakness and improve muscle strength. However, the potential mechanisms and the main components of SS in treating ALS remain unclear. To explore the underlying mechanism of SS in treating ALS based on network pharmacology and molecular docking. The active components of SS were obtained using TCMSP, Herb, ETCM, and BATMAN-TCM. The targets of SS were gained from PharmMapper. The targets of ALS were searched on Genecards, Drugbank, DisGeNET, OMIM, TTD and GEO database. After obtaining the coincidence targets, we submitted them to the STRING database to build a protein-protein interaction network. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed subsequently. The active components and targets were further investigated using molecular docking technology. 395 targets of SS and 1925 targets of ALS were obtained with 125 common targets. The protein-protein interaction analysis indicated that SRC, AKT1, MAPK1, EGFR, and HSP90AA1 received the higher degree value and were considered the central genes. The Ras, PI3K-Akt, and MAPK signaling pathway could be involved in the treatment of ALS. Brucine-N-oxide obtained the lowest binding energy in molecular docking. This study explored the mechanism of SS in the treatment of ALS and provides a new perspective for future study. However, further experimental studies are needed to validate the therapeutic effect.}, } @article {pmid37681895, year = {2023}, author = {Dunn, E and Steinert, JR and Stone, A and Sahota, V and Williams, RSB and Snowden, S and Augustin, H}, title = {Medium-Chain Fatty Acids Rescue Motor Function and Neuromuscular Junction Degeneration in a Drosophila Model of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {12}, number = {17}, pages = {}, pmid = {37681895}, issn = {2073-4409}, support = {/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Drosophila ; *Frontotemporal Dementia ; Drosophila melanogaster ; *Neurodegenerative Diseases ; Fatty Acids ; Neuromuscular Junction ; Larva ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterised by progressive degeneration of the motor neurones. An expanded GGGGCC (G4C2) hexanucleotide repeat in C9orf72 is the most common genetic cause of ALS and frontotemporal dementia (FTD); therefore, the resulting disease is known as C9ALS/FTD. Here, we employ a Drosophila melanogaster model of C9ALS/FTD (C9 model) to investigate a role for specific medium-chain fatty acids (MCFAs) in reversing pathogenic outcomes. Drosophila larvae overexpressing the ALS-associated dipeptide repeats (DPRs) in the nervous system exhibit reduced motor function and neuromuscular junction (NMJ) defects. We show that two MCFAs, nonanoic acid (NA) and 4-methyloctanoic acid (4-MOA), can ameliorate impaired motor function in C9 larvae and improve NMJ degeneration, although their mechanisms of action are not identical. NA modified postsynaptic glutamate receptor density, whereas 4-MOA restored defects in the presynaptic vesicular release. We also demonstrate the effects of NA and 4-MOA on metabolism in C9 larvae and implicate various metabolic pathways as dysregulated in our ALS model. Our findings pave the way to identifying novel therapeutic targets and potential treatments for ALS.}, } @article {pmid37681887, year = {2023}, author = {Vasconcelos, CFM and Ribas, VT and Petrs-Silva, H}, title = {Shared Molecular Pathways in Glaucoma and Other Neurodegenerative Diseases: Insights from RNA-Seq Analysis and miRNA Regulation for Promising Therapeutic Avenues.}, journal = {Cells}, volume = {12}, number = {17}, pages = {}, pmid = {37681887}, issn = {2073-4409}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/therapy ; RNA-Seq ; Homeostasis ; *Glaucoma/genetics/therapy ; *MicroRNAs/genetics ; }, abstract = {Advances in RNA-sequencing technologies have led to the identification of molecular biomarkers for several diseases, including neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's diseases and Amyotrophic Lateral Sclerosis. Despite the nature of glaucoma as a neurodegenerative disorder with several similarities with the other above-mentioned diseases, transcriptional data about this disease are still scarce. microRNAs are small molecules (~17-25 nucleotides) that have been found to be specifically expressed in the CNS as major components of the system regulating the development signatures of neurodegenerative diseases and the homeostasis of the brain. In this review, we sought to identify similarities between the functional mechanisms and the activated pathways of the most common neurodegenerative diseases, as well as to discuss how those mechanisms are regulated by miRNAs, using RNA-Seq as an approach to compare them. We also discuss therapeutically suitable applications for these disease hallmarks in clinical future studies.}, } @article {pmid37680659, year = {2023}, author = {Choayb, S and Harras, YE and Fikri, M and Kettani, NEE and Jiddane, M and Touarsa, F}, title = {Brain MRI abnormalities associated with amyotrophic lateral sclerosis: A case illustration.}, journal = {Radiology case reports}, volume = {18}, number = {11}, pages = {3972-3974}, pmid = {37680659}, issn = {1930-0433}, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative pathology. It involves both upper and lower motor neurons, leading to their degeneration. Lower motor neurons can be detected with an electromyogram, but the detection of upper motor neuron dysfunction may be more accurate using MRI. We present the case of a 64-year-old woman with amyotrophic lateral sclerosis, presenting the motor band sign and the bright tongue sign on MRI.}, } @article {pmid37680538, year = {2023}, author = {Dunn, E and Zhang, B and Sahota, VK and Augustin, H}, title = {Potential benefits of medium chain fatty acids in aging and neurodegenerative disease.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1230467}, pmid = {37680538}, issn = {1663-4365}, abstract = {Neurodegenerative diseases are a large class of neurological disorders characterized by progressive dysfunction and death of neurones. Examples include Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Aging is the primary risk factor for neurodegeneration; individuals over 65 are more likely to suffer from a neurodegenerative disease, with prevalence increasing with age. As the population ages, the social and economic burden caused by these diseases will increase. Therefore, new therapies that address both aging and neurodegeneration are imperative. Ketogenic diets (KDs) are low carbohydrate, high-fat diets developed initially as an alternative treatment for epilepsy. The classic ketogenic diet provides energy via long-chain fatty acids (LCFAs); naturally occurring medium chain fatty acids (MCFAs), on the other hand, are the main components of the medium-chain triglyceride (MCT) ketogenic diet. MCT-based diets are more efficient at generating the ketone bodies that are used as a secondary energy source for neurones and astrocytes. However, ketone levels alone do not closely correlate with improved clinical symptoms. Recent findings suggest an alternative mode of action for the MCFAs, e.g., via improving mitochondrial biogenesis and glutamate receptor inhibition. MCFAs have been linked to the treatment of both aging and neurodegenerative disease via their effects on metabolism. Through action on multiple disease-related pathways, MCFAs are emerging as compounds with notable potential to promote healthy aging and ameliorate neurodegeneration. MCFAs have been shown to stimulate autophagy and restore mitochondrial function, which are found to be disrupted in aging and neurodegeneration. This review aims to provide insight into the metabolic benefits of MCFAs in neurodegenerative disease and healthy aging. We will discuss the use of MCFAs to combat dysregulation of autophagy and mitochondrial function in the context of "normal" aging, Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease.}, } @article {pmid37679883, year = {2024}, author = {de Boer, EMJ and Demaegd, KC and de Bie, CI and Veldink, JH and van den Berg, LH and van Es, MA}, title = {Familial motor neuron disease: co-occurrence of PLS and ALS (-FTD).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {53-60}, doi = {10.1080/21678421.2023.2255621}, pmid = {37679883}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics ; *Frontotemporal Dementia/genetics ; Prospective Studies ; *Motor Neuron Disease/epidemiology/genetics/pathology ; *Muscular Atrophy, Spinal/epidemiology/genetics ; }, abstract = {OBJECTIVE: To report the frequency and characteristics of patients diagnosed with primary lateral sclerosis (PLS) with a positive family history for motor neuron diseases (MND) in the Netherlands and to compare our findings to the literature.

METHODS: Patients were identified through our ongoing, prospective population-based study on MND in The Netherlands, which also includes a standardized collection of patient characteristics, genetic testing, and family history. Only patients meeting the latest consensus criteria for definite PLS were included. The family history was considered positive for MND if any family members had been diagnosed with PLS, amyotrophic lateral sclerosis (ALS)(-FTD), or progressive muscular atrophy (PMA). Additionally, the literature was reviewed on PLS cases in which MND co-occurred within the same family.

RESULTS: We identified 392 definite PLS cases, resulting in 9 families with a PLS patient and a positive family history for MND (2.3%). In only one of these pedigrees, a pathogenic variant (C9orf72 repeat expansion) was found. Our literature review revealed 23 families with a co-occurrence of PLS and MND, with 12 of them having a potentially pathogenic genetic variant.

CONCLUSIONS: The consistent observation of PLS patients with a positive family history for MND, evident in both our study and the literature, implies the presence of shared underlying genetic factors between PLS and ALS. However, these factors are yet to be elucidated.}, } @article {pmid37679868, year = {2024}, author = {Martinelli, I and Zucchi, E and Simonini, C and Gianferrari, G and Bedin, R and Biral, C and Ghezzi, A and Fini, N and Carra, S and Mandrioli, J}, title = {SerpinA1 levels in amyotrophic lateral sclerosis patients: An exploratory study.}, journal = {European journal of neurology}, volume = {31}, number = {1}, pages = {e16054}, pmid = {37679868}, issn = {1468-1331}, support = {bando per la ricerca clinica 2015//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; grant number 2016-02364678//Agenzia Italiana del Farmaco, Ministero della Salute/ ; Neurobiobanca di Modena//Fondazione Cassa di Risparmio di Modena/ ; bando per la ricerca finalizzata 2016, grant number RF-2016-02361616//Ministero della Salute/ ; bando FAR 2021, Progetti di ricerca Interdisciplinari Mission Oriented, NEURALS project//Università Degli Studi di Modena e Reggio Emila/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Disease Progression ; Neurofilament Proteins/cerebrospinal fluid ; Prognosis ; Biomarkers ; }, abstract = {BACKGROUND: SerpinA1, a serine protease inhibitor, is involved in the modulation of microglial-mediated inflammation in neurodegenerative diseases. We explored SerpinA1 levels in cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients to understand its potential role in the pathogenesis of the disease.

METHODS: SerpinA1, neurofilament light (NfL) and heavy (NfH) chain, and chitinase-3-like protein-1 (CHI3L1) were determined in CSF and serum of ALS patients (n = 110) and healthy controls (n = 10) (automated next-generation ELISA), and correlated with clinical parameters, after identifying three classes of progressors (fast, intermediate, slow). Biomarker levels were analyzed for diagnostic power and association with progression and survival.

RESULTS: SerpinA1serum was significantly decreased in ALS (median: 1032 μg/mL) compared with controls (1343 μg/mL) (p = 0.02). SerpinA1CSF was elevated only in fast progressors (8.6 μg/mL) compared with slow (4.43 μg/mL, p = 0.01) and intermediate (4.42 μg/mL, p = 0.03) progressors. Moreover, SerpinA1CSF correlated with neurofilament and CHI3L1 levels in CSF. Contrarily to SerpinA1CSF , neurofilament and CHI3L1 concentrations in CSF correlated with measures of disease progression in ALS, while SerpinA1serum mildly related with time to generalization (rho = 0.20, p = 0.04). In multivariate analysis, the ratio between serum and CSF SerpinA1 (SerpinA1 ratio) and NfHCSF were independently associated with survival.

CONCLUSIONS: Higher SerpinA1CSF levels are found in fast progressors, suggesting SerpinA1 is a component of the neuroinflammatory mechanisms acting upon fast-progressing forms of ALS. Both neurofilaments or CHI3L1CSF levels outperformed SerpinA1 at predicting disease progression rate in our cohort, and so the prognostic value of SerpinA1 alone as a measure remains inconclusive.}, } @article {pmid37678221, year = {2024}, author = {Huynh, A and Adams, K and Barnett-Tapia, C and Kalra, S and Zinman, L and Yunusova, Y}, title = {Accessing and Receiving Speech-Language Pathology Services at the Multidisciplinary Amyotrophic Lateral Sclerosis Clinic: An Exploratory Qualitative Study of Patient Experiences and Needs.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {67}, number = {10S}, pages = {4025-4037}, pmid = {37678221}, issn = {1558-9102}, support = {R01 DC017291/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy/complications ; *Speech-Language Pathology ; Male ; Female ; *Qualitative Research ; Middle Aged ; Aged ; *Caregivers/psychology ; *Health Services Accessibility ; Canada ; Health Services Needs and Demand ; Adult ; }, abstract = {PURPOSE: This study sought to explore how patients with amyotrophic lateral sclerosis (ALS) presenting with coexisting bulbar and cognitive impairments and their caregivers experienced the speech-language pathologist (SLP) services provided in multidisciplinary ALS clinics in Canada and identified their perceived needs for bulbar symptom management.

METHOD: This qualitative study was informed by interpretive description. Seven interviews were conducted with patients with severe bulbar dysfunction or severe bulbar and cognitive dysfunction due to ALS or ALS-frontotemporal dementia, respectively, and/or their caregivers. Purposive sampling was used to recruit individuals with severe bulbar or bulbar and cognitive disease. Thematic analysis was used to analyze interview data.

RESULTS: Patients and caregivers reported difficulties with accessing and receiving SLP services at the multidisciplinary ALS clinic. These difficulties were further exacerbated in those with severe cognitive disease. Participants expressed a need for more specific (i.e., disease and service-related) information and personalized care to address their changing needs and preferences. Engaging caregivers earlier in SLP appointments was perceived as vital to support care planning and provide in-time caregiver education.

CONCLUSIONS: This study highlighted the challenges experienced by patients and caregivers in accessing and receiving SLP services. There is a pressing need for a more person-centered approach to ALS care and a continuing need for education of SLPs on care provision in cases of complex multisymptom diseases within a multidisciplinary ALS clinic.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24069222.}, } @article {pmid37675986, year = {2023}, author = {Sonobe, Y and Lee, S and Krishnan, G and Gu, Y and Kwon, DY and Gao, FB and Roos, RP and Kratsios, P}, title = {Translation of dipeptide repeat proteins in C9ORF72 ALS/FTD through unique and redundant AUG initiation codons.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {37675986}, issn = {2050-084X}, support = {R01 NS101986/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; RF1 NS101986/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *C9orf72 Protein/genetics/metabolism ; Codon, Initiator/genetics ; Dipeptides/genetics/metabolism ; *Frontotemporal Dementia/pathology ; *Pick Disease of the Brain ; Proteins/genetics ; }, abstract = {A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A hallmark of ALS/FTD pathology is the presence of dipeptide repeat (DPR) proteins, produced from both sense GGGGCC (poly-GA, poly-GP, poly-GR) and antisense CCCCGG (poly-PR, poly-PG, poly-PA) transcripts. Translation of sense DPRs, such as poly-GA and poly-GR, depends on non-canonical (non-AUG) initiation codons. Here, we provide evidence for canonical AUG-dependent translation of two antisense DPRs, poly-PR and poly-PG. A single AUG is required for synthesis of poly-PR, one of the most toxic DPRs. Unexpectedly, we found redundancy between three AUG codons necessary for poly-PG translation. Further, the eukaryotic translation initiation factor 2D (EIF2D), which was previously implicated in sense DPR synthesis, is not required for AUG-dependent poly-PR or poly-PG translation, suggesting that distinct translation initiation factors control DPR synthesis from sense and antisense transcripts. Our findings on DPR synthesis from the C9ORF72 locus may be broadly applicable to many other nucleotide repeat expansion disorders.}, } @article {pmid37674720, year = {2023}, author = {Chen, S and Puri, A and Bell, B and Fritsche, J and Palacios, H and Balch, M and Sprunger, M and Howard, M and Patterson, J and Patti, G and Davis, A and Jackrel, M}, title = {HtrA1 prevents and reverses α-synuclein aggregation, rendering it non-toxic and seeding incompetent.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37674720}, issn = {2693-5015}, support = {K08 NS101118/NS/NINDS NIH HHS/United States ; R35 GM128772/GM/NIGMS NIH HHS/United States ; }, abstract = {Parkinson disease (PD) is closely linked to the misfolding and accumulation of α-synuclein (α-syn) into Lewy bodies. HtrA1 is a PDZ serine protease that degrades fibrillar tau, which is associated with Alzheimer disease (AD). Further, inactivating mutations to mitochondrial HtrA2 have been implicated in PD. Here, we establish that HtrA1 inhibits the aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We demonstrate that the protease domain of HtrA1 is necessary and sufficient for inhibition of aggregation, yet this activity is independent of HtrA1 proteolytic activity. Further, we find that HtrA1 also disaggregates preformed α-syn fibrils, which may promote their clearance. Treatment of α-syn fibrils with HtrA1 renders α-syn incapable of seeding the aggregation of endogenous α-syn in mammalian biosensor cells. We find that HtrA1 remodels α-syn by specifically targeting the NAC domain, which is the key domain that catalyzes α-syn oligomerization and fibrillization. Finally, in a primary neuron model of α-syn aggregation, we show that HtrA1 and its proteolytically inactive form both detoxify α-syn and prevent the formation of hyperphosphorylated α-syn accumulations. Our findings suggest that HtrA1 prevents aggregation and promotes disaggregation of multiple disease-associated proteins, and may be a therapeutic target for treating a range of neurodegenerative disorders.}, } @article {pmid37674380, year = {2024}, author = {Volpato, E and Banfi, P and Poletti, V and Pagnini, F}, title = {Living beyond loss: a qualitative investigation of caregivers' experiences after the death of their relatives with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {75-87}, doi = {10.1080/21678421.2023.2255628}, pmid = {37674380}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/psychology ; Caregivers/psychology ; Social Support ; Coping Skills ; Qualitative Research ; }, abstract = {BACKGROUND: Caregivers of Amyotrophic Lateral Sclerosis (ALS) patients experience varying psychological responses following the patient's death, including sadness, loneliness, guilt, and a loss of purpose.

OBJECTIVES: This research aims to investigate the caregiver journey experienced from the time of diagnosis to the loss of a care recipient, with a specific focus on understanding the factors that contribute to improved coping with bereavement.

METHODS: The present study used the Interpretative Phenomenological Approach (IPA) to qualitatively explore the accounts of 41 Italian bereaved caregivers of people affected by ALS (Mean Age = 59.78; Female: 60.98%; Male: 39.02%).

RESULTS: Results revealed 5 overarching themes representing 5 macro areas that emerged from the analysis of the interviews ("Caregiver's perception of his/her life", "Caregiver's feelings", "Caregiver's life after patient's death", "Caregiver's disease description", "Caregiver's help resources"), these were further defined based on 12 main themes, which were, in turn, articulated into 30 subthemes. The transition from life before ALS ("a peaceful landscape") to caregiver life (compared to the color "black") was a "shock", during which caregivers had to change their needs. However, life after the person living with ALS' death was both characterized by a sense of "re-birth" and "emptiness", and a general need for "psychological assistance" and "social support".

CONCLUSIONS: Results emphasize the need to improve the psychological support offered to caregivers of person living with ALS after the patient's death, tailoring it to the specificity of the condition, to meet their emotional needs, reduce isolation and help them cope with practical challenges and plans.}, } @article {pmid37674309, year = {2024}, author = {Yamamoto, M and Tsukasaki, K and Kyota, K}, title = {Relationship Between Resilience Factors and Caregiving Status of Families of Patients with Amyotrophic Lateral Sclerosis (ALS) in Japan.}, journal = {Journal of community health nursing}, volume = {41}, number = {1}, pages = {44-56}, doi = {10.1080/07370016.2023.2254771}, pmid = {37674309}, issn = {1532-7655}, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/therapy ; Adaptation, Psychological ; *Resilience, Psychological ; Cross-Sectional Studies ; Japan ; Quality of Life ; Caregivers ; }, abstract = {PURPOSE: To identify innate and acquired factors leading to amyotrophic lateral sclerosis (ALS) caregivers' resilience, the relationships among these factors, and caregiving situations.

DESIGN: Cross-sectional study.

METHODS: Questionnaires measuring resilience, caregiver burden, and family functioning were mailed to caregivers of ALS patients in Japan.

FINDINGS: The 370 responses showed that increases in both innate and acquired factors were related to having an ALS association membership, while decreases were associated with reduced family function. Increases in innate factors were related to employment and those consenting to ventilators, while decreases were associated with being male and having a sense of the care burden. Decreases in acquired factors were related to the presence of an alternative caregiver.

CONCLUSIONS: By identifying the caregiving situation based on innate and acquired factors, we were able to identify the significance and direction of specific caregiving support.

CLINICAL EVIDENCE: Community health nurses should focus on improving family function and creating a supportive environment. Further, support for male and non-working caregivers should be strengthened and consultation on the use of respiratory equipment promoted to reduce the caregiving burden.}, } @article {pmid37672915, year = {2023}, author = {Rajagopalan, V and Pioro, EP}, title = {Graph network measures reveal distinct white matter abnormalities in motor and extra-motor brain regions of two UMN-predominant ALS subtypes.}, journal = {Journal of the neurological sciences}, volume = {452}, number = {}, pages = {120765}, doi = {10.1016/j.jns.2023.120765}, pmid = {37672915}, issn = {1878-5883}, mesh = {Humans ; *White Matter/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Cerebellum ; Echo-Planar Imaging ; *Leukoaraiosis ; Motor Neurons ; }, abstract = {BACKGROUND: Routine clinical magnetic resonance imaging (MRI) shows bilateral corticospinal tract (CST) hyperintensity in some patients with upper motor neuron (UMN)-predominant ALS (ALS-CST+) but not in others (ALS-CST-). Although, similar in their UMN features, the ALS-CST+ patient group is significantly younger in age, has faster disease progression and shorter survival than the ALS-CST- patient group. Reasons for the differences are unclear.

METHOD: In order to evaluate more objective MRI measures of these ALS subgroups, we used diffusion tensor images (DTI) obtained using single shot echo planar imaging sequence from 1.5 T Siemens MRI Scanner. We performed an exploratory whole brain white matter (WM) network analysis using graph theory approach on 45 ALS patients (ALS-CST+) (n = 21), and (ALS-CST-) (n = 24) and neurological controls (n = 14).

RESULTS: Significant (p < 0.05) differences in nodal degree measure between ALS patients and controls were observed in motor and extra motor regions, supplementary motor area, subcortical WM regions, cerebellum and vermis. Importantly, WM network abnormalities were significantly (p < 0.05) different between ALS-CST+ and ALS-CST- subgroups. Compared to neurologic controls, both ALS subgroups showed hubs in the right superior occipital gyrus and cuneus as well as significantly (p < 0.05) reduced small worldness supportive of WM network damage.

CONCLUSIONS: Significant differences between ALS-CST+ and ALS-CST- subgroups of WM network abnormalities, age of onset, symptom duration prior to MRI, and progression rate suggest these patients represent distinct clinical phenotypes and possibly pathophysiologic mechanisms of ALS.}, } @article {pmid37672770, year = {2023}, author = {Naveed, M and Aqib Shabbir, M and Aziz, T and Hurraira, HM and Fatima Zaidi, S and Athar, R and Chattha, HA and Alharbi, M and Alshammari, A and Alasmari, AF}, title = {CRISPR-Cas9 guided rna based model for the treatment of Amyotrophic Lateral Sclerosis: A progressive neurodegenerative disorder.}, journal = {Acta biochimica Polonica}, volume = {70}, number = {3}, pages = {643-653}, doi = {10.18388/abp.2020_6789}, pmid = {37672770}, issn = {1734-154X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; CRISPR-Cas Systems/genetics ; Gene Editing ; Muscles ; RNA, Guide, CRISPR-Cas Systems ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that leads to the degeneration of motor neurons and the weakening of muscles. Despite extensive research efforts, there is currently no cure for ALS and existing treatments only address its symptoms. To address this unmet medical need, genome editing technologies, such as CRISPR-Cas9, have emerged as a promising solution for the development of new treatments for ALS. Studies have shown that CRISPR-Cas9-guided RNAs have the potential to provide accurate and effective silencing in the genetic disease of ALS. Results have demonstrated a 67% on-target score and a 98% off-target score with GC content within the range of 40-60%. This is further validated by the correlation between the gRNA's structural accuracy and the minimum free energy. The use of CRISPR-Cas9 provides a unique opportunity to target this disease at the molecular level, offering hope for the development of a more effective treatment. In silico and computational therapeutic approaches for ALS suggest that the CRISPR-Cas9 protein holds promise as a future treatment candidate. The CRISPR mechanism and the specificity of gRNA provide a novel therapeutic approach for this genetic disease, offering new hope to those affected by ALS. This study highlights the potential of CRISPR-Cas9 as a promising solution for the development of new treatments for ALS. Further research is required to validate these findings in preclinical and clinical trials and to establish the safety and efficacy of this approach in the treatment of ALS.}, } @article {pmid37671427, year = {2023}, author = {Gastelum, S and Michael, AF and Bolger, TA}, title = {Saccharomyces cerevisiae as a research tool for RNA-mediated human disease.}, journal = {Wiley interdisciplinary reviews. RNA}, volume = {}, number = {}, pages = {e1814}, doi = {10.1002/wrna.1814}, pmid = {37671427}, issn = {1757-7012}, support = {R01 GM136827/GM/NIGMS NIH HHS/United States ; GM136827/GM/NIGMS NIH HHS/United States ; }, abstract = {The budding yeast, Saccharomyces cerevisiae, has been used for decades as a powerful genetic tool to study a broad spectrum of biological topics. With its ease of use, economic utility, well-studied genome, and a highly conserved proteome across eukaryotes, it has become one of the most used model organisms. Due to these advantages, it has been used to study an array of complex human diseases. From broad, complex pathological conditions such as aging and neurodegenerative disease to newer uses such as SARS-CoV-2, yeast continues to offer new insights into how cellular processes are affected by disease and how affected pathways might be targeted in therapeutic settings. At the same time, the roles of RNA and RNA-based processes have become increasingly prominent in the pathology of many of these same human diseases, and yeast has been utilized to investigate these mechanisms, from aberrant RNA-binding proteins in amyotrophic lateral sclerosis to translation regulation in cancer. Here we review some of the important insights that yeast models have yielded into the molecular pathology of complex, RNA-based human diseases. This article is categorized under: RNA in Disease and Development > RNA in Disease.}, } @article {pmid37671079, year = {2023}, author = {Alothmani, OS and Siddiqui, AY}, title = {Accuracy of Root ZX Electronic Apex Locator in Relation to Two Different Employment Protocols: An In Vitro Study.}, journal = {Cureus}, volume = {15}, number = {9}, pages = {e44659}, pmid = {37671079}, issn = {2168-8184}, abstract = {Objective The aim of this study is to determine the apical level of the root canal, whether it is the apical foramen or a level coronal to it, that Root ZX (J. Morita Co., Kyoto, Japan) targets and to identify its employment protocol that provides better accuracy. Methods Actual lengths (ALs) of 75 extracted single-rooted teeth were obtained by inserting a K-file size 8 until its tip was in level with the most coronal border of the apical foramen. Reference length (RL) was calculated by deducting 0.5 mm from AL. Roots were placed in porous sponge block soaked with Ringer's solution, and canals were irrigated with 2 mL of 5% sodium hypochlorite. The blinded operator used Root ZX to measure lengths with K-file size 8. In the first tested employment protocol, the file was advanced to the "APEX mark" of the digital display, and the length was obtained. The second employment protocol followed the manufacturer's recommendations by inserting the file until the "APEX mark" followed by its withdrawal to the "0.5 mark." Stability of the digital meter for 5 seconds was mandatory before recording the lengths. All measurements were repeated one week later and then both measurements were averaged to represent "APEX mark" and "0.5 mark," respectively. Data were analyzed using t-test, with significance set at 0.05. Results Regardless of the employment protocol, most registered lengths were longer than targeted. The mean "APEX mark" was significantly longer than the mean AL (P=0.000), and the mean "0.5 mark" was significantly longer than the mean RL (P=0.000). Although the mean "0.5 mark" was longer than the mean AL, the difference was not significant (P=0.07). Conclusion The apical level of the root canal targeted by the Root ZX was the apical foramen. The most accurate employment protocol to achieve that is to use the Root ZX according to the manufacturer's recommendations.}, } @article {pmid37671010, year = {2023}, author = {Broadhead, MJ and Ayvazian-Hancock, A and Doucet, K and Kantelberg, O and Motherwell, L and Zhu, F and Grant, SGN and Horrocks, MH and Miles, GB}, title = {Synaptic expression of TAR-DNA-binding protein 43 in the mouse spinal cord determined using super-resolution microscopy.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1027898}, pmid = {37671010}, issn = {1662-5099}, support = {MILES/APR18/863-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is characterised by a loss of motor neurons in the brain and spinal cord that is preceded by early-stage changes in synapses that may be associated with TAR-DNA-Binding Protein 43 (TDP-43) pathology. Cellular inclusions of hyperphosphorylated TDP-43 (pTDP-43) are a key hallmark of neurodegenerative diseases such ALS. However, there has been little characterisation of the synaptic expression of TDP-43 inside subpopulations of spinal cord synapses. This study utilises a range of high-resolution and super-resolution microscopy techniques with immunolabelling, as well as an aptamer-based TDP-43 labelling strategy visualised with single-molecule localisation microscopy, to characterise and quantify the presence of pTDP-43 in populations of excitatory synapses near where motor neurons reside in the lateral ventral horn of the mouse lumbar spinal cord. We observe that TDP-43 is expressed in approximately half of spinal cord synapses as nanoscale clusters. Synaptic TDP-43 clusters are found most abundantly at synapses associated with VGLUT1-positive presynaptic terminals, compared to VGLUT2-associated synapses. Our nanoscopy techniques showed no difference in the subsynaptic expression of pTDP-43 in the ALS mouse model, SOD1[G93a], compared to healthy controls, despite prominent structural deficits in VGLUT1-associated synapses in SOD1[G93a] mice. This research characterises the basic synaptic expression of TDP-43 with nanoscale precision and provides a framework with which to investigate the potential relationship between TDP-43 pathology and synaptic pathology in neurodegenerative diseases.}, } @article {pmid37670160, year = {2023}, author = {Devalckeneer, A and Bourgeois, P and Caudron, Y and Estrade, L and Obled, L and Leclerc, X and Assaker, R and Lejeune, JP and Aboukais, R}, title = {Surgical evolution in spinal dural arteriovenous fistula treatment-a 7 years monocentric experience.}, journal = {Neurosurgical review}, volume = {46}, number = {1}, pages = {225}, pmid = {37670160}, issn = {1437-2320}, mesh = {Adult ; Humans ; *Central Nervous System Vascular Malformations ; Cerebrospinal Fluid Leak ; Laminectomy ; Retrospective Studies ; *Spinal Cord Diseases ; }, abstract = {Accounting for 70% of all spinal vascular malformations, spinal dural arteriovenous fistulas (SDAVF) are the most common type of malformation. Interruption of the fistulous arterialized vein point is the goal of surgical treatment. The aim of the study was to compare open surgery (laminectomy) versus minimal invasive surgery (MIS) in SDAVF treatment. Between March 2013 and March 2020, we retrospectively collected 21 consecutive adult patients with SDAVF. Since March 2017, MIS has been routinely used for surgical treatment. Pre- and post-operative clinical evaluations used Aminoff-Logue score (ALS). Complication rate was noted. Post-operative occlusion of the malformation was confirmed by digital subtraction angiography (DSA) in all patients. MIS was compared to open surgery in terms of efficacy and complications with statistical evaluation. Standard laminectomy was performed in 12 patients and MIS technique in 9 patients. No difference was noted on pre-operative parameters. ALS and MRI signs of myelopathy were improved in all cases except for 1 patient in each group. All SDAVFs were excluded based on post-operative DSA. Significant differences were noted between the 2 groups in terms of perioperative blood loss (p<0.001), post-operative pain visual analog scale values (p<0.001), and first time out of bed (p<0.001). Wrong level surgery occurred in one patient in each group; patients were re-operated using the same technique. No infection or cerebrospinal fluid (CSF) leak was noted. In our experience, MIS is a safe alternative to open laminectomy for SDAVF treatment. MIS contributes to patient comfort and minimizes blood loss without increasing complication rate.}, } @article {pmid37670116, year = {2023}, author = {Kang, J and Lim, L and Song, J}, title = {ATP induces folding of ALS-causing C71G-hPFN1 and nascent hSOD1.}, journal = {Communications chemistry}, volume = {6}, number = {1}, pages = {186}, pmid = {37670116}, issn = {2399-3669}, abstract = {ALS-causing C71G-hPFN1 coexists in both folded and unfolded states, while nascent hSOD1 is unfolded. So far, the mechanisms underlying their ALS-triggering potential remain enigmatic. Here we show by NMR that ATP completely converts C71G-hPFN1 into the folded state at a 1:2 ratio, while inducing nascent hSOD1 into two co-existing states at a 1:8 ratio. Surprisingly, the inducing capacity of ATP comes from its triphosphate, but free triphosphate triggers aggregation. The inducing capacity ranks as: ATP = ATPP = PPP > ADP = AMP-PNP = AMP-PCP = PP, while AMP, adenosine, P, and NaCl show no conversion. Mechanistically, ATP and triphosphate appear to enhance the intrinsic folding capacity encoded in the sequences, as unveiled by comparing conformations and dynamics of ATP- and Zn[2+]-induced hSOD1 folded states. Our study provides a mechanism for the finding that some single-cell organisms employ polyphosphates as primordial chaperones, and sheds light on the enigma of age-related onset of familial ALS and risk increase of neurodegenerative diseases.}, } @article {pmid37669876, year = {2023}, author = {Quinn, L and Bird, P and Remsing, S and Reeves, K and Lilford, R}, title = {Unintended consequences of the 18-week referral to treatment standard in NHS England: a threshold analysis.}, journal = {BMJ quality & safety}, volume = {32}, number = {12}, pages = {712-720}, pmid = {37669876}, issn = {2044-5423}, mesh = {Humans ; *State Medicine ; *Hospitals ; Patients ; England ; Referral and Consultation ; }, abstract = {OBJECTIVE: In 2012, an '18-week referral to treatment standard' was introduced in England. Among people on the list of those waiting for hospital treatment at a point in time, the standard states that at least '92% of patients should have been waiting for less than 18 weeks'. Targets can have unintended consequences, where patients are prioritised based on the target rather than clinical need. Such an effect will be evident as a spike in the number of hospital trusts at the target threshold, referred to as a threshold effect. This study examines for threshold effects across all non-specialist acute NHS England hospital trusts by financial year.

METHODS: A retrospective observational study of publicly available data examined waiting times for patients on the waiting list. We examined trust performance against the 92% target by financial year, from 2015/16 to 2021/22, using Cattaneo et al's manipulation density test (test for discontinuity/spike in data around target threshold) for all patients and by type of treatment.

RESULTS: The proportion of NHS hospital trusts meeting the 92% target deteriorated over time. From 2015/16 to 2019/20, there was strong evidence of a threshold effect at the 92% target (p<0.001). There was no evidence of a threshold effect in 2020/21 (p=0.063) or 2021/22 (p=0.090). Threshold effects were present across most types of treatment in 2016/17 and fewer types from 2017/18 onwards.

CONCLUSION: We observed striking evidence of a threshold effect suggesting that while targets change behaviour, they do so in a selective way, focusing on the threshold rather than a pervasive improvement in practice. However, at the height of the pandemic, as almost no trusts could reach the target, the threshold effect disappeared.}, } @article {pmid37669872, year = {2023}, author = {}, title = {Dextromethorphan-Quinidine (Nuedexta) Improves Swallowing in Bulbar Onset ALS Patients With Pseudobulbar Affect - Pre-Post Observational Study in 86 ALS Patients (P4.4-019).}, journal = {Neurology}, volume = {101}, number = {16}, pages = {730}, doi = {10.1212/WNL.0000000000207886}, pmid = {37669872}, issn = {1526-632X}, } @article {pmid37668918, year = {2024}, author = {Asakawa, K and Handa, H and Kawakami, K}, title = {In Vivo Optogenetic Phase Transition of an Intrinsically Disordered Protein.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2707}, number = {}, pages = {257-264}, pmid = {37668918}, issn = {1940-6029}, mesh = {Animals ; *Intrinsically Disordered Proteins/genetics ; Optogenetics ; Zebrafish ; DNA-Binding Proteins ; Motor Neurons ; }, abstract = {Proteins containing intrinsically disordered regions (IDRs) control a wide variety of cellular processes by assembly of membrane-less organelles via IDR-mediated liquid-liquid phase separation. Dysregulated IDR-mediated phase transition has been implicated in the pathogenesis of diseases characterized by deposition of abnormal protein aggregates. Here, we describe a method to enhance interactions between the IDRs of the RNA/DNA-binding protein and TAR DNA-binding protein 43 (TDP-43) by light to drive its phase transition in the motor neurons of zebrafish. The optically controlled TDP-43 phase transition in motor neurons, in vivo, provides a unique opportunity to evaluate the impact of dysregulated TDP-43 phase transition on the physiology of motor neurons. This will help to address the etiology of neurodegenerative diseases associated with abnormal TDP-43 phase transition and aggregation, including amyotrophic lateral sclerosis (ALS).}, } @article {pmid37668704, year = {2023}, author = {Martinelli, I and Ghezzi, A and Zucchi, E and Gianferrari, G and Ferri, L and Moglia, C and Manera, U and Solero, L and Vasta, R and Canosa, A and Grassano, M and Brunetti, M and Mazzini, L and De Marchi, F and Simonini, C and Fini, N and Vinceti, M and Pinti, M and Chiò, A and Calvo, A and Mandrioli, J}, title = {Predictors for progression in amyotrophic lateral sclerosis associated to SOD1 mutation: insight from two population-based registries.}, journal = {Journal of neurology}, volume = {270}, number = {12}, pages = {6081-6092}, pmid = {37668704}, issn = {1432-1459}, support = {RF-2016-02362405//Ministero della Salute/ ; 259867//Seventh Framework Programme/ ; 2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 101017598//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Superoxide Dismutase-1/genetics ; Mutation ; Registries ; *Neoplasms ; Superoxide Dismutase/genetics ; }, abstract = {BACKGROUND: Uncovering distinct features and trajectories of amyotrophic lateral sclerosis (ALS) associated with SOD1 mutations (SOD1-ALS) can provide valuable insights for patient' counseling and stratification for trials, and interventions timing. Our study aims to pinpoint distinct clinical characteristics of SOD1-ALS by delving into genotype-phenotype correlations and factors that potentially impact disease progression.

METHODS: This is a retrospective observational study of a SOD1-ALS cohort from two Italian registers situated in the regions of Emilia-Romagna, Piedmont and Valle d'Aosta.

RESULTS: Out of 2204 genotyped ALS patients, 2.5% carried SOD1 mutations, with a M:F ratio of 0.83. SOD1-ALS patients were younger, and more frequently reported a family history of ALS and/or FTD. SOD1-ALS had a longer survival compared to patients without ALS-associated gene mutations. However, here was considerable variability in survival across distinct SOD1 mutations, with an average survival of less than a year for the L39V, G42S, G73S, D91N mutations. Among SOD1-ALS, multivariate analysis showed that, alongside established clinical prognostic factors such as advanced age at onset and high progression rate at diagnosis, mutations located in exon 2 or within highly conserved gene positions predicted worse survival. Conversely, among comorbidities, cancer history was independently associated with longer survival.

INTERPRETATION: Within the context of an overall slower disease, SOD1-ALS exhibits some degree of heterogeneity linked to the considerable genetic diversity arising from the multitude of potential mutations sites and specific clinical prognostic factors, including cancer history. Revealing the factors that modulate the phenotypic heterogeneity of SOD1-ALS could prove advantageous in improving the efficacy of upcoming therapeutic approaches.}, } @article {pmid37666761, year = {2023}, author = {Li, Q and Zhang, T and Song, Y and Liu, Y and Sun, M}, title = {[A design and evaluation of wearable p300 brain-computer interface system based on Hololens2].}, journal = {Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi}, volume = {40}, number = {4}, pages = {709-717}, pmid = {37666761}, issn = {1001-5515}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Brain-Computer Interfaces ; Quality of Life ; Event-Related Potentials, P300 ; *Wearable Electronic Devices ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) often have difficulty in expressing their intentions through language and behavior, which prevents them from communicating properly with the outside world and seriously affects their quality of life. The brain-computer interface (BCI) has received much attention as an aid for ALS patients to communicate with the outside world, but the heavy device causes inconvenience to patients in the application process. To improve the portability of the BCI system, this paper proposed a wearable P300-speller brain-computer interface system based on the augmented reality (MR-BCI). This system used Hololens2 augmented reality device to present the paradigm, an OpenBCI device to capture EEG signals, and Jetson Nano embedded computer to process the data. Meanwhile, to optimize the system's performance for character recognition, this paper proposed a convolutional neural network classification method with low computational complexity applied to the embedded system for real-time classification. The results showed that compared with the P300-speller brain-computer interface system based on the computer screen (CS-BCI), MR-BCI induced an increase in the amplitude of the P300 component, an increase in accuracy of 1.7% and 1.4% in offline and online experiments, respectively, and an increase in the information transfer rate of 0.7 bit/min. The MR-BCI proposed in this paper achieves a wearable BCI system based on guaranteed system performance. It has a positive effect on the realization of the clinical application of BCI.}, } @article {pmid37666695, year = {2023}, author = {Duplessis, C and Clarkson, KA and Ross Turbyfill, K and Alcala, AN and Gutierrez, R and Riddle, MS and Lee, T and Paolino, K and Weerts, HP and Lynen, A and Oaks, EV and Porter, CK and Kaminski, R}, title = {GMP manufacture of Shigella flexneri 2a Artificial Invaplex (InvaplexAR) and evaluation in a Phase 1 Open-label, dose escalating study administered intranasally to healthy, adult volunteers.}, journal = {Vaccine}, volume = {41}, number = {42}, pages = {6261-6271}, doi = {10.1016/j.vaccine.2023.08.051}, pmid = {37666695}, issn = {1873-2518}, abstract = {Shigella species cause severe disease among travelers to, and children living in, endemic countries. Although significant efforts have been made to improve sanitation, increased antibiotic resistance and other factors suggest an effective vaccine is a critical need. Artificial Invaplex (InvaplexAR) is a subunit vaccine approach complexing Shigella LPS with invasion plasmid antigens. In pre-clinical studies, the InvaplexAR vaccine demonstrated increased immunogenicity as compared to the first generation product and was subsequently manufactured under cGMP for clinical testing in a first-in-human Phase 1 study. The primary objective of this study was the safety of S. flexneri 2a InvaplexAR given by intranasal (IN) immunization (without adjuvant) in a single-center, open-label, dose-escalating Phase 1 trial and secondarily to assess immunogenicity to identify a dose of InvaplexAR for subsequent clinical evaluations. Subjects received three IN immunizations of InvaplexAR, two weeks apart, in increasing dose cohorts (10 µg, 50 µg, 250 µg, and 500 μg). Adverse events were monitored using symptom surveillance, memory aids, and targeted physical exams. Samples were collected throughout the study to investigate vaccine-induced systemic and mucosal immune responses. There were no adverse events that met vaccination-stopping criteria. The majority (96%) of vaccine-related adverse events were mild in severity (most commonly nasal congestion, rhinorrhea, and post-nasal drip). Vaccination with InvaplexAR induced anti-LPS serum IgG responses and anti-Invaplex IgA and IgG antibody secreting cell (ASC) responses at vaccine doses ≥250 µg. Additionally, mucosal immune responses and functional antibody responses were seen from the serum bactericidal assay measurements. Notably, the responder rates and the kinetics of ASCs and antibody lymphocyte secretion (ALS) were similar, suggesting that either assay may be employed to identify IgG and IgA secreting cells. Further studies with InvaplexAR will evaluate alternative immunization routes, vaccination schedules and formulations to further optimize immunogenicity. (Clinical Trial Registry Number NCT02445963).}, } @article {pmid37666602, year = {2023}, author = {Chen, X and Ma, Y and Huang, M and Li, W and Zeng, D and Li, J and Wang, Y}, title = {Multiple herbicide resistance in a Cyperus difformis population in rice field from China.}, journal = {Pesticide biochemistry and physiology}, volume = {195}, number = {}, pages = {105576}, doi = {10.1016/j.pestbp.2023.105576}, pmid = {37666602}, issn = {1095-9939}, mesh = {*Oryza/genetics ; *2-Methyl-4-chlorophenoxyacetic Acid ; *Cyperus ; Herbicide Resistance/genetics ; China ; ATP-Binding Cassette Transporters ; *Acetolactate Synthase/genetics ; *Herbicides/pharmacology ; Indoleacetic Acids ; }, abstract = {Herbicide resistance is rapidly emerging in Cyperus difformis in rice fields across China. The response of a C. difformis population GX-35 was tested against five acetolactate synthase (ALS)-inhibiting herbicides, auxin herbicide MCPA and photosynthesis II (PSII)-inhibitor bentazone. Population GX-35 evolved multiple resistance to ALS-inhibiting herbicides (penoxsulam, bispyribac‑sodium, pyrazosulfuron-ethyl, halosulfuron-methly and imazapic) and auxin herbicide MCPA, with resistance levels of 140-, 1253-, 578-, 18-, 13-, and 21-fold, respectively, compared to the susceptible population. In this population, ALS gene expression was similar to that of the susceptible population. However, an Asp376Glu mutation in ALS gene was observed, leading to reduced inhibition of in-vitro ALS activities by five ALS-inhibiting herbicides. Furthermore, CYP71D8, CYP77A3, CYP78A5 and three ABC transporter genes (cluster-14412.23067, cluster-14412.25321, and cluster-14412.24716) over-expressed in absence of penoxsulam. On the other hand, an UGT73C1 and an ABC transporter (cluster-14412.25038) were induced by penoxsulam. Additionally, both over-expression and induction were observed for CYP74, CYP71A1, UGT88A1 and an ABC transporter (cluster-14412.21723). The GX-35 population has indeed evolved multiple herbicide resistance in China. Therefore, a diverse range of weed control tactics should be implemented in rice field.}, } @article {pmid37666564, year = {2023}, author = {Odland, ML and Abdul-Latif, AM and Ignatowicz, A and Bekele, A and Chu, K and Howard, A and Tabiri, S and Byiringiro, JC and Davies, J and , }, title = {Governance for injury care systems in Ghana, South Africa and Rwanda: development and pilot testing of an assessment tool.}, journal = {BMJ open}, volume = {13}, number = {9}, pages = {e074088}, pmid = {37666564}, issn = {2044-6055}, support = {130036/DH_/Department of Health/United Kingdom ; }, mesh = {Humans ; Ghana ; Rwanda ; South Africa ; Africa, Northern ; *Consensus ; }, abstract = {OBJECTIVES: This study aims to evaluate health systems governance for injury care in three sub-Saharan countries from policymakers' and injury care providers' perspectives.

SETTING: Ghana, Rwanda and South Africa.

DESIGN: Based on Siddiqi et al's framework for governance, we developed an online assessment tool for health system governance for injury with 37 questions covering health policy and implementation under 10 overarching principles of strategic vision, participation and consensus orientation, rule of law, transparency, responsiveness of institutions, equity, effectiveness or efficiency, accountability, ethics and intelligence and information. A literature review was also done to support the scoring. We derived scores using two methods-investigator scores and respondent scores.

PARTICIPANTS: The tool was sent out to purposively selected stakeholders, including policymakers and injury care providers in Ghana, Rwanda and South Africa. Data were collected between October 2020 and February 2021.

Investigator-weighted and respondent percentage scores for health system governance for injury care. This was calculated for each country in total and per principle.

RESULTS: Rwanda had the highest overall investigator-weighted percentage score (70%), followed by South Africa (59%). Ghana had the lowest overall investigator score (48%). The overall results were similar for the respondent scores. Some areas, such as participation and consensus, scored high in all three countries, while other areas, such as transparency, scored very low.

CONCLUSION: In this multicountry governance survey, we provide insight into and evaluation of health system governance for trauma in three low- and middle-income countries (LMICs) in sub-Saharan Africa. It highlights areas of improvement that need to be prioritised, such as transparency, to meet the high burden of trauma and injuries in LMICs.}, } @article {pmid37666395, year = {2023}, author = {Atiya, A and Muhsinah, AB and Alrouji, M and Alhumaydhi, FA and Al Abdulmonem, W and Aljasir, MA and Sharaf, SE and Furkan, M and Khan, RH and Shahwan, M and Shamsi, A}, title = {Unveiling promising inhibitors of superoxide dismutase 1 (SOD1) for therapeutic interventions.}, journal = {International journal of biological macromolecules}, volume = {253}, number = {Pt 2}, pages = {126684}, doi = {10.1016/j.ijbiomac.2023.126684}, pmid = {37666395}, issn = {1879-0003}, mesh = {Humans ; Superoxide Dismutase-1/genetics ; Molecular Docking Simulation ; *Amyotrophic Lateral Sclerosis/metabolism ; Oxidation-Reduction ; *Neoplasms ; Superoxide Dismutase/metabolism ; Mutation ; }, abstract = {Superoxide dismutase 1 (SOD1) is a vital enzyme responsible for controlling cellular oxidative stress. Any dysregulation of SOD1 activity is linked with cancer pathogenesis and neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS). Among the inhibitors known to be effective against SOD1, LCS-1 stands out; however, its efficacy, specificity, and safety profiles are somewhat restricted. In this study, we used PubChem library to retrieve compounds that exhibited a structural similarity of at least 90 % with LCS-1. These compounds underwent molecular docking analyses to examine their interaction patterns and binding affinities with SOD1. Further, we applied filters based on physicochemical and ADMET properties, refining the selection process. Our analysis revealed that selected compounds interact with crucial residues of SOD1 active site. To gain further insights into conformational stability and dynamics of the SOD1-ligand complexes, we conducted all-atom molecular dynamics (MD) simulations for 100 ns. We identified two compounds, CID:133306073 and CID:133446715, as potential scaffolds with promising inhibitory properties against SOD1. Both compounds hold significant potential for further exploration as therapeutic SOD1 inhibitors. Further studies are warranted to fully harness their therapeutic potential in targeting SOD1 for cancer and ALS treatment, offering new avenues for improved patient outcomes and disease management.}, } @article {pmid37664610, year = {2023}, author = {Cicardi, ME and Hallgren, JH and Mawrie, D and Krishnamurthy, K and Markandaiah, SS and Nelson, AT and Kankate, V and Anderson, EN and Pasinelli, P and Pandey, UB and Eischen, CM and Trotti, D}, title = {C9orf72 poly(PR) mediated neurodegeneration is associated with nucleolar stress.}, journal = {iScience}, volume = {26}, number = {9}, pages = {107505}, pmid = {37664610}, issn = {2589-0042}, support = {R01 NS109150/NS/NINDS NIH HHS/United States ; R21 NS090912/NS/NINDS NIH HHS/United States ; RF1 AG057882/AG/NIA NIH HHS/United States ; }, abstract = {The ALS/FTD-linked intronic hexanucleotide repeat expansion in the C9orf72 gene is aberrantly translated in the sense and antisense directions into dipeptide repeat proteins, among which poly proline-arginine (PR) displays the most aggressive neurotoxicity in-vitro and in-vivo. PR partitions to the nucleus when heterologously expressed in neurons and other cell types. We show that by lessening the nuclear accumulation of PR, we can drastically reduce its neurotoxicity. PR strongly accumulates in the nucleolus, a nuclear structure critical in regulating the cell stress response. We determined that, in neurons, PR caused nucleolar stress and increased levels of the transcription factor p53. Downregulating p53 levels also prevented PR-mediated neurotoxicity both in in-vitro and in-vivo models. We investigated if PR could induce the senescence phenotype in neurons. However, we did not observe any indications of such an effect. Instead, we found evidence for the induction of programmed cell death via caspase-3 activation.}, } @article {pmid37664457, year = {2023}, author = {Horánszky, A and Shashikadze, B and Elkhateib, R and Lombardo, SD and Lamberto, F and Zana, M and Menche, J and Fröhlich, T and Dinnyés, A}, title = {Proteomics and disease network associations evaluation of environmentally relevant Bisphenol A concentrations in a human 3D neural stem cell model.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1236243}, pmid = {37664457}, issn = {2296-634X}, abstract = {Bisphenol A (BPA) exposure is associated with a plethora of neurodevelopmental abnormalities and brain disorders. Previous studies have demonstrated BPA-induced perturbations to critical neural stem cell (NSC) characteristics, such as proliferation and differentiation, although the underlying molecular mechanisms remain under debate. The present study evaluated the effects of a repeated-dose exposure of environmentally relevant BPA concentrations during the in vitro 3D neural induction of human induced pluripotent stem cells (hiPSCs), emulating a chronic exposure scenario. Firstly, we demonstrated that our model is suitable for NSC differentiation during the early stages of embryonic brain development. Our morphological image analysis showed that BPA exposure at 0.01, 0.1 and 1 µM decreased the average spheroid size by day 21 (D21) of the neural induction, while no effect on cell viability was detected. No alteration to the rate of the neural induction was observed based on the expression of key neural lineage and neuroectodermal transcripts. Quantitative proteomics at D21 revealed several differentially abundant proteins across all BPA-treated groups with important functions in NSC proliferation and maintenance (e.g., FABP7, GPC4, GAP43, Wnt-8B, TPPP3). Additionally, a network analysis demonstrated alterations to the glycolytic pathway, potentially implicating BPA-induced changes to glycolytic signalling in NSC proliferation impairments, as well as the pathophysiology of brain disorders including intellectual disability, autism spectrum disorders, and amyotrophic lateral sclerosis (ALS). This study enhances the current understanding of BPA-related NSC aberrations based mostly on acute, often high dose exposures of rodent in vivo and in vitro models and human GWAS data in a novel human 3D cell-based model with real-life scenario relevant prolonged and low-level exposures, offering further mechanistic insights into the ramifications of BPA exposure on the developing human brain and consequently, later life neurological disorders.}, } @article {pmid37664456, year = {2023}, author = {Garodia, P and Hegde, M and Kunnumakkara, AB and Aggarwal, BB}, title = {Curcumin, inflammation, and neurological disorders: How are they linked?.}, journal = {Integrative medicine research}, volume = {12}, number = {3}, pages = {100968}, pmid = {37664456}, issn = {2213-4220}, abstract = {BACKGROUND: Despite the extensive research in recent years, the current treatment modalities for neurological disorders are suboptimal. Curcumin, a polyphenol found in Curcuma genus, has been shown to mitigate the pathophysiology and clinical sequalae involved in neuroinflammation and neurodegenerative diseases.

METHODS: We searched PubMed database for relevant publications on curcumin and its uses in treating neurological diseases. We also reviewed relevant clinical trials which appeared on searching PubMed database using 'Curcumin and clinical trials'.

RESULTS: This review details the pleiotropic immunomodulatory functions and neuroprotective properties of curcumin, its derivatives and formulations in various preclinical and clinical investigations. The effects of curcumin on neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), brain tumors, epilepsy, Huntington's disorder (HD), ischemia, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI) with a major focus on associated signalling pathways have been thoroughly discussed.

CONCLUSION: This review demonstrates curcumin can suppress spinal neuroinflammation by modulating diverse astroglia mediated cascades, ensuring the treatment of neurological disorders.}, } @article {pmid37663359, year = {2023}, author = {Gomes de Souza E Silva, EM and Tomaz da Silva, S and Januário de Holanda, L and Tezoni Borges, D and Mendonça Fernandes, AP and Evangelista Rodrigues da Silva, K and Souza Ribeiro, T and Protásio de Melo, L and de Medeiros Valentim, RA and Alves Pinto Nagem, D and Rodrigues Lindquist, AR}, title = {Effects of a self-care educational program via telerehabilitation on quality of life and caregiver burden in amyotrophic lateral sclerosis: a single-blinded randomized clinical trial protocol.}, journal = {Frontiers in psychology}, volume = {14}, number = {}, pages = {1164370}, pmid = {37663359}, issn = {1664-1078}, abstract = {INTRODUCTION: The implementation of a telerehabilitation protocol for self-care in the routine of caregivers of individuals with amyotrophic lateral sclerosis (ALS) has been associated with reduced levels of stress and improved quality of life. Moreover, it may reduce the difficulty of traveling to perform physical or other self-care activities. Thus, this study designed a clinical trial protocol to investigate the effects of a self-care education program via telerehabilitation on the burden and quality of life of caregivers of individuals with ALS.

METHODS: This single-blinded randomized clinical trial will recruit 26 caregivers and randomly allocate them to the experimental (EG = 13) or control group (CG = 13). The EG will receive an informative booklet and participate in a 6-week synchronous telerehabilitation program with a neuropsychologist, nutritionist, and physiotherapist to discuss physical and mental health. The CG will receive an informative booklet on self-care and physical activity and weekly phone calls for 6 weeks to solve questions about the booklet. Outcomes will include the caregiver burden (Zarit scale), quality of life (World Health Organization Quality of Life BREF), pain (McGill Pain Questionnaire), stress (Perceived Stress Scale), and depression (Beck Depression Inventory), which will be evaluated at the baseline after the six-week program and 30 days after the program. Additionally, we will assess daily the nocturnal awakenings, sleep patterns, level of physical activity, and heart rate variability.

DISCUSSION: This study aimed to investigate the effectiveness of telerehabilitation for caregivers of individuals with ALS. If effective, this program could be disseminated among health professionals, increasing the possibility of remotely monitoring individuals with difficulty performing physical activities.

TRIAL REGISTRATION NUMBER: NCT05884034 (clinicaltrials.gov).}, } @article {pmid37662922, year = {2023}, author = {Cao, W and Fan, D}, title = {Neutrophils: a subgroup of neglected immune cells in ALS.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1246768}, pmid = {37662922}, issn = {1664-3224}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Neutrophils ; *Neurodegenerative Diseases ; Motor Neurons ; Immunity, Innate ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic, progressive neurodegenerative disease characterized by the loss of motor neurons. Dysregulated peripheral immunity has been identified as a hallmark of ALS. Neutrophils, as the front-line responders of innate immunity, contribute to host defense through pathogen clearance. However, they can concurrently play a detrimental role in chronic inflammation. With the unveiling of novel functions of neutrophils in neurodegenerative diseases, it becomes essential to review our current understanding of neutrophils and to recognize the gap in our knowledge about their role in ALS. Thus, a detailed comprehension of the biological processes underlying neutrophil-induced pathogenesis in ALS may assist in identifying potential cell-based therapeutic strategies to delay disease progression.}, } @article {pmid37662623, year = {2023}, author = {Shoji, H and Sakamoto, R and Saito, C and Akino, K and Taniguchi, M}, title = {Re-survey of 16 Japanese patients with advanced-stage hereditary motor sensory neuropathy with proximal dominant involvement (HMSN-P): Painful muscle cramps for early diagnosis.}, journal = {Intractable & rare diseases research}, volume = {12}, number = {3}, pages = {198-201}, pmid = {37662623}, issn = {2186-3644}, abstract = {Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is an intractable neurological disease with autosomal dominant inheritance, four-limb weakness, sensory impairment, and a slowly progressive course. HMSN-P patients develop four-limb paralysis at the advanced-stage, as in amyotrophic lateral sclerosis (ALS). There is a natural 20- to 30-year course from initial painful muscle cramps and four-limb paralysis to respiratory dysfunction. A delay in the diagnosis of HMSN-P occurs due to the 20- to 30-year span from the initial symptom(s) to typical quadriplegia. Its early diagnosis is important, but the involvement of painful muscle cramps as an early symptom has not been clear. Following our earlier survey, we conducted a re-survey focusing on painful muscle cramps, assistive-device use, and hope for specific therapies in 16 Japanese patients with advanced-stage HMSN-P. Fifteen patients presented painful muscle cramps as the initial symptom, and muscle cramps in the lower abdomen including the flank were described by 10 of the patients. The presence of painful muscle cramps including those in the abdominal region may be a clue for the early diagnosis of HMSN-P. Painful abdominal cramps have not described in related diseases, e.g., ALS, spinal muscular atrophy, and Charcot-Marie-Tooth disease. Recent patient-welfare improvements and advances in assistive devices including robot-suit assistive limbs are delaying the terminal state of HMSN-P. Regarding specific therapies for HMSN-P, many patients choose both nucleic acid medicine and the application of induced pluripotent stem cells as a specific therapy for HMSN-P.}, } @article {pmid37662046, year = {2023}, author = {Zhu, Y and Bai, J and Li, M and Wang, H and Wang, J and Huang, X}, title = {Repetitive nerve stimulation on survival in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1244385}, pmid = {37662046}, issn = {1664-2295}, abstract = {OBJECTIVE: No previous studies investigated the association between decrement of low-frequency repetitive nerve stimulation (LF-RNS) and amyotrophic lateral sclerosis (ALS) survival. We aim to study the relationship between decrement and survival in ALS.

METHODS: Sporadic ALS patients diagnosed at the Department of Neurology, the First Medical Center, Chinese PLA General Hospital from January 2018 to December 2019 were enrolled in this study. Experienced neurologists followed up the participants regularly every 6 months until January 2022. A decremental response of 10% or greater at least in one muscle was considered positive. According to the decrement, the participants were divided into LF-RNS (+) and LF-RNS (-) groups.

RESULTS: One hundred and eighty-one sporadic ALS patients were recruited in our study, including 100 males and 81 females. Among them, 10 cases (5.5%) were lost to follow-up, 99 cases (54.7%) died, and 72 patients (39.8%) were still alive at the last follow-up. The median survival time of all ALS patients in this study was 42.0 months. There was no significant difference of median survival in LF-RNS(+) group and LF-RNS(-) group (p = 0.159, Kaplan-Meier method). In multivariate Cox regression analysis, age of onset, diagnostic delay, and ALS Functional Rating Scale-Revised (ALSFRS-R) score were associated with ALS survival, but the decrement was not correlated with ALS survival (p = 0.238).

CONCLUSION: The decrement in accessory and ulnar nerves was not associated with the survival of ALS. The decrement of LF-RNS could not be an electrophysiological marker to predict ALS survival.}, } @article {pmid37661426, year = {2023}, author = {Conroy, E and Vélez-Gómez, B and O'Brien, D and Heverin, M and Hardiman, O and Mcdermott, C and Galvin, M}, title = {IMPACT-ALS: summary of results from a European survey of people living with ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2023.2249515}, pmid = {37661426}, issn = {2167-9223}, abstract = {OBJECTIVE: The IMPACT-ALS survey collected the experiences of people living with ALS (plwALS) across nine European countries. We aimed to better understand the functional burden of ALS to ensure the experiences of plwALS inform the development of person-centered therapies.

METHODS: The content was informed by the US IMPACT-ALS survey, with adjustments relevant to the European population. Questionnaires consisted of four modules, each of which was pilot tested in advance of distribution. Data were captured using the Qualtrics software and were analyzed in SPSS.

RESULTS: 857 respondents completed the survey, with a participation rate ranging from 0.2% to 6.3% across the nine participating countries. The majority were male and aged 55-74 years old. In the previous 2 weeks, symptoms experienced included weakness (81%), fatigue (61%), speech impairment (38%), pain (27%), and depression and other mood changes (23%). Eighty-two percent of respondents reported fears, of which the most common were leaving family too soon (68%) and death from respiratory failure (50%). Lifestyle changes since diagnosis were reported by 89% of respondents, with less time spent doing most daily activities but more time on the internet (81%), reading (56%) and communicating with family and friends (55%). Stopping progression of ALS was the most desired impact for a new therapy for 68% respondents.

CONCLUSIONS: The European IMPACT-ALS survey has generated insights into the complex experiences of plwALS. The data provide unique patient perspectives on common symptoms, fears, functional limitations, lifestyle changes, and wishes for future therapies that will enhance patient-centric care in ALS.}, } @article {pmid37660686, year = {2023}, author = {Bhakta, P and Dutta, A}, title = {Homeopathic Treatment of Ramsay Hunt Syndrome: A Case Report.}, journal = {Complementary medicine research}, volume = {30}, number = {6}, pages = {544-552}, doi = {10.1159/000533849}, pmid = {37660686}, issn = {2504-2106}, mesh = {Female ; Humans ; Young Adult ; Adult ; *Facial Paralysis ; *Homeopathy ; *Herpes Zoster Oticus/therapy ; *Deglutition Disorders ; Quality of Life ; Ulcer ; }, abstract = {INTRODUCTION: Ramsay Hunt syndrome (RHS) is an uncommon neurological complication resulting from the reactivation of latent herpes zoster virus. The condition often presents with facial paralysis, palatal ulcers, dysphagia, and altered taste sensation, leading to reduced quality of life. Standard therapeutic options for RHS have limitations, prompting the exploration of alternative treatments with improved prognostic outcomes. This case report aims to present a noteworthy clinical observation of RHS managed with individualized homeopathic treatment, emphasizing its potential therapeutic effect.

CASE DESCRIPTION: A 24-year-old female patient exhibited left-sided facial weakness, along with palatal ulcers, dysphagia, and ageusia, prompting the diagnosis of RHS. Following the principles of homeopathy, a personalized therapeutic regimen was formulated, consisting tailored administration of Rhus toxicodendron, Spigelia anthelmia, and Sulfur. The House-Brackmann scale was employed to objectively assess the severity of facial palsy, while photographic documentation tracked the progression of palatal ulcers and facial paralysis. Over a carefully monitored observation period of 14 days, the patient demonstrated notable therapeutic response. There was a significant reduction in the extent of palatal ulceration and left-sided facial palsy exhibited marked improvement. Subsequent days of follow-up witnessed a consistent amelioration of the patient's condition, substantiating the effect of the individualized homeopathic treatment.

CONCLUSION: This case report highlights an exceptional instance of RHS recovery within a relatively short timeframe, achieved through the administration of individualized homeopathic therapy. The favorable outcomes observed in this case underscore the potential of homeopathy as a promising intervention for RHS management. Nevertheless, further systematic investigations are imperative to comprehensively evaluate the scope and applicability of homeopathy in the treatment of RHS.

UNLABELLED: EinleitungDas Ramsay‐Hunt‐Syndrom (RHS) ist eine seltene neurologische Komplikation, die durch die Reaktivierung einer latenten Herpes‐Zoster‐Virusinfektion verursacht wird. Die Krankheit manifestiert sich häufig mit Gesichtslähmung, Ulcerationen am Gaumen, Dysphagie und verändertem Geschmacksempfinden und ist mit einer Einschränkung der Lebensqualität verbunden. Die Standardtherapieoptionen für RHS sind begrenzt, weshalb nach alternativen Behandlungsmöglichkeiten mit besseren prognostischen Ergebnissen gesucht wird. Im vorliegenden Fallbericht wird eine interessante klinische Beobachtung bei RHS vorgestellt, das mit individualisierter Homöopathie behandelt wurde, und deren potenzielle therapeutische Wirksamkeit wird hervorgehoben.Der FallEine 24-jährige Patientin zeigte eine linksseitige Gesichtsschwäche in Verbindung mit Ulcerationen am Gaumen, Dysphagie und Ageusie, so dass die Diagnose RHS gestellt wurde. Gemäß den Prinzipien der Homöopathie wurde ein personalisiertes Therapieschema formuliert, das die individuell zugeschnittene Gabe von Rhus toxicodendron, Spigelia anthelmia, und Sulphur umfasste. Die objektive Bewertung des Schweregrads der Gesichtslähmung erfolgte mithilfe der House-Brackmann-Skala, wohingegen das Fortschreiten der Gaumenulcerationen und der Gesichtslähmung fotografisch dokumentiert wurde. Während eines sorgfältig überwachten Beobachtungszeitraums von 14 Tagen zeigte die Patientin ein deutliches therapeutisches Ansprechen. Das Ausmaß der Gaumenulcerationen ging signifikant zurück, und die linksseitige Gesichtslähmung besserte sich deutlich. In den folgenden Tagen besserte sich der Zustand der Patientin kontinuierlich, was die Wirkung der individualisierten homöopathischen Behandlung untermauert.SchlussfolgerungDieser Fallbericht beleuchtet einen ungewöhnlichen Fall von Genesung nach einem RHS innerhalb relativ kurzer Zeit, die durch Verabreichung einer individualisierten homöopathischen Therapie erreicht wurde. Die im vorliegenden Fall beobachteten günstigen Ergebnisse unterstreichen das Potenzial der Homöopathie als vielversprechende Intervention zur Behandlung von RHS. Allerdings sind weitere systematische Untersuchungen unabdingbar, um den Umfang und die Anwendbarkeit der Homöopathie bei der Behandlung von RHS umfassend zu beurteilen.}, } @article {pmid37658972, year = {2023}, author = {Singh, S and Shukla, R}, title = {Nanovesicular-Mediated Intranasal Drug Therapy for Neurodegenerative Disease.}, journal = {AAPS PharmSciTech}, volume = {24}, number = {7}, pages = {179}, pmid = {37658972}, issn = {1530-9932}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Nose ; Drug Delivery Systems ; Brain ; *Glioblastoma ; }, abstract = {Numerous neurodegenerative conditions, such as Alzheimer's, Huntington's, Parkinson's, amyotrophic lateral sclerosis, and glioblastoma multiform are now becoming significant concerns of global health. Formulation-related issues, physiological and anatomical barriers, post-administration obstacles, physical challenges, regulatory limitations, environmental hurdles, and health and safety issues have all hindered successful delivery and effective outcomes despite a variety of treatment options. In the current review, we covered the intranasal route, an alternative strategic route targeting brain for improved delivery across the BBB. The trans-nasal pathway is non-invasive, directing therapeutics directly towards brain, circumventing the barrier and reducing peripheral exposure. The delivery of nanosized vesicles loaded with drugs was also covered in the review. Nanovesicle systems are organised in concentric bilayered lipid membranes separated with aqueous layers. These carriers surmount the disadvantages posed by intranasal delivery of rapid mucociliary clearance and enzymatic degradation, and enhance retention of drug to reach the site of target. In conclusion, the review covers in-depth conclusions on numerous aspects of formulation of drug-loaded vesicular system delivery across BBB, current marketed nasal devices, significant jeopardies, potential therapeutic aids, and current advancements followed by future perspectives.}, } @article {pmid37660155, year = {2023}, author = {Chandhok, S and Pereira, L and Momchilova, EA and Marijan, D and Zapf, R and Lacroix, E and Kaur, A and Keymanesh, S and Krieger, C and Audas, TE}, title = {Stress-mediated aggregation of disease-associated proteins in amyloid bodies.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {14471}, pmid = {37660155}, issn = {2045-2322}, support = {PJT-162364//CIHR/Canada ; }, mesh = {Humans ; Diclofenac/pharmacology ; Amyloidogenic Proteins ; *Amyloidosis ; Prostaglandin-Endoperoxide Synthases ; *Immunoglobulin Light-chain Amyloidosis ; }, abstract = {The formation of protein aggregates is a hallmark of many neurodegenerative diseases and systemic amyloidoses. These disorders are associated with the fibrillation of a variety of proteins/peptides, which ultimately leads to cell toxicity and tissue damage. Understanding how amyloid aggregation occurs and developing compounds that impair this process is a major challenge in the health science community. Here, we demonstrate that pathogenic proteins associated with Alzheimer's disease, diabetes, AL/AA amyloidosis, and amyotrophic lateral sclerosis can aggregate within stress-inducible physiological amyloid-based structures, termed amyloid bodies (A-bodies). Using a limited collection of small molecule inhibitors, we found that diclofenac could repress amyloid aggregation of the β-amyloid (1-42) in a cellular setting, despite having no effect in the classic Thioflavin T (ThT) in vitro fibrillation assay. Mapping the mechanism of the diclofenac-mediated repression indicated that dysregulation of cyclooxygenases and the prostaglandin synthesis pathway was potentially responsible for this effect. Together, this work suggests that the A-body machinery may be linked to a subset of pathological amyloidosis, and highlights the utility of this model system in the identification of new small molecules that could treat these debilitating diseases.}, } @article {pmid37659835, year = {2023}, author = {Bermudo Fuenmayor, S and Serrano Castro, PJ and Quiroga Subirana, P and López Palmero, S and Requena Mullor, M and Parrón Carreño, T}, title = {Environmental exposure to pesticides and Amyotrophic Lateral Sclerosis in the South of Spain.}, journal = {Neurologia}, volume = {38}, number = {7}, pages = {447-452}, doi = {10.1016/j.nrleng.2021.01.004}, pmid = {37659835}, issn = {2173-5808}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/chemically induced/epidemiology ; *Pesticides/adverse effects ; Spain/epidemiology ; Case-Control Studies ; Environmental Exposure/adverse effects ; }, abstract = {OBJECTIVE: To determine if there is a relationship between environmental exposure to pesticides and the prevalence of Amyotrophic Lateral Sclerosis (ALS) in Andalusia.

METHOD: We carried out a case-control study using the logistic regression method to verify the relationship between the prevalence of ALS in the area exposed to pesticides versus the unexposed area, through the Odds Ratio statistical test.

RESULTS: The study population consisted of 519 individuals diagnosed with ALS between January 2016 and December 2018 according to the CMBD (Minimum Basic Data Set) as cases. In the control group, we have 8,384,083 individuals obtained from data from the National Institute of Statistics (INE). The Odds Ratio (OR) was used as a measure of association between cases and controls, obtaining an OR between 0.76 and 1.08 for the confidence interval of the CI (95%).

CONCLUSIONS: Despite the existence of various studies that suggest a possible association between environmental exposure to pesticides and the risk of Amyotrophic Lateral Sclerosis, our analysis of the Andalusian population did not find significant evidence of this association.}, } @article {pmid37659173, year = {2023}, author = {Hirayama, T and Shibukawa, M and Morioka, H and Hozumi, M and Tsuda, H and Atsuta, N and Izumi, Y and Nakayama, Y and Shimizu, T and Inoue, H and Urushitani, M and Yamanaka, K and Aoki, M and Ebihara, S and Takeda, A and Kano, O}, title = {The necessity to improve disaster preparedness among patients with amyotrophic lateral sclerosis and their families.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {116}, number = {}, pages = {87-92}, doi = {10.1016/j.jocn.2023.08.002}, pmid = {37659173}, issn = {1532-2653}, mesh = {Humans ; Male ; Middle Aged ; Aged ; *Amyotrophic Lateral Sclerosis/therapy ; Communication ; *Disasters ; Educational Status ; Japan ; }, abstract = {Disaster preparation is an important issue for patients with amyotrophic lateral sclerosis (ALS). However, to the best of our knowledge, no studies have investigated disaster preparedness among patients with ALS. In this study, we aimed to investigate disaster preparation in patients with ALS and their caregivers, including their families, in Japan. We conducted a nationwide webinar in September 2022 titled "ALS Café" and distributed a self-report questionnaire to participants with questions about awareness of disaster preparedness, social countermeasures, stockpiles, and electricity demand. Forty-eight patients with ALS (27 male; average age 60.0 ± 9.3 years) and 23 caregivers (8 male; 55.7 ± 9.9 years) responded. The median revised ALS Functional Rating Scale score was 30.5, and 25% of the patients with ALS were on a ventilator. More than 70% of the respondents answered that they were not prepared for disasters, increasing to 89% in patients not using ventilators. In the event of their phones being down, 86% of the respondents had no plans for alternative means of communication. <30% of the respondents, including ventilator users, had secured human resources for transportation. Twenty-five percent of the respondents did not stockpile food and beverages, and 12% of the ventilator users had no government-recommended ventilator preparation equipment. Thus, although patients with ALS and their families with ventilators have a high awareness of disaster preparedness, their awareness remains insufficient. Furthermore, patients with ALS and their families without ventilators have a low awareness of disaster preparedness. Therefore, better education regarding disaster preparedness is necessary for these groups.}, } @article {pmid37658515, year = {2024}, author = {Howe, SL and Holdom, CJ and McCombe, PA and Henderson, RD and Zigman, JM and Ngo, ST and Steyn, FJ}, title = {Associations of postprandial ghrelin, liver-expressed antimicrobial peptide 2 and leptin levels with body composition, disease progression and survival in patients with amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {1}, pages = {e16052}, pmid = {37658515}, issn = {1468-1331}, support = {R01 DK103884/DK/NIDDK NIH HHS/United States ; /NH/NIH HHS/United States ; }, mesh = {Humans ; *Leptin/metabolism ; Ghrelin/metabolism ; *Amyotrophic Lateral Sclerosis ; Hepcidins/metabolism ; Prospective Studies ; Delayed Diagnosis ; Body Weight ; Disease Progression ; Body Composition ; }, abstract = {BACKGROUND AND PURPOSE: Loss of appetite contributes to weight loss and faster disease progression in amyotrophic lateral sclerosis (ALS). Impairment of appetite control in ALS may include altered production or action of orexigenic (i.e., ghrelin) and anorexigenic (i.e., liver-expressed antimicrobial peptide 2 [LEAP2] and leptin) hormones. We aimed to determine if postprandial circulating ghrelin levels, LEAP2 levels, LEAP2:ghrelin molar ratio and leptin levels differ in ALS patients compared to non-neurodegenerative disease controls, and whether they are associated with disease progression and body composition.

METHODS: In this prospective natural history study, we assessed postprandial plasma levels of ghrelin, LEAP2 and leptin in patients with ALS (cases; n = 46) and controls (controls; n = 43). For cases, measures were compared to changes in body weight, body composition and clinical outcomes.

RESULTS: Postprandial ghrelin level was decreased by 52% in cases compared to controls (p = 0.013). LEAP2:ghrelin molar ratio was increased by 249% (p = 0.009), suggesting greater ghrelin resistance. Patients with lower LEAP2:ghrelin tended to have better functional capacity at assessment, as inferred by the ALS Functional Rating Scale-Revised (τ = -0.179, p = 0.086). Furthermore, ghrelin and LEAP2:ghrelin molar ratio correlated with diagnostic delay (ghrelin, τ = 0.223, p = 0.029; LEAP2:ghrelin, τ = -0.213, p = 0.037). Baseline ghrelin level, LEAP2 level, LEAP2:ghrelin ratio and leptin level were, however, not predictive of change in functional capacity during follow-up. Also, patients with higher postprandial ghrelin levels (hazard ratio [HR] 1.375, p = 0.048), and lower LEAP2:ghelin ratios (HR 0.828, p = 0.051) had an increased risk of earlier death.

CONCLUSIONS: Reduced postprandial ghrelin levels, coupled with increased LEAP2:ghrelin molar ratios, suggests a loss of ghrelin action in patients with ALS. Given ghrelin's actions on appetite, metabolism and neuroprotection, reduced ghrelin and greater ghrelin resistance could contribute to impaired capacity to tolerate the physiological impact of disease. Comprehensive studies are needed to explain how ghrelin and LEAP2 contribute to body weight regulation and disease progression in ALS.}, } @article {pmid37657967, year = {2023}, author = {Ryan, SK and Ugalde, CL and Rolland, AS and Skidmore, J and Devos, D and Hammond, TR}, title = {Therapeutic inhibition of ferroptosis in neurodegenerative disease.}, journal = {Trends in pharmacological sciences}, volume = {44}, number = {10}, pages = {674-688}, doi = {10.1016/j.tips.2023.07.007}, pmid = {37657967}, issn = {1873-3735}, support = {MC_PC_19032/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Ferroptosis ; *Neurodegenerative Diseases/drug therapy ; Iron ; }, abstract = {Iron accumulation has been associated with the etiology and progression of multiple neurodegenerative diseases (NDDs). The exact role of iron in these diseases is not fully understood, but an iron-dependent form of regulated cell death called ferroptosis could be key. Although there is substantial preclinical and clinical evidence that ferroptosis plays a role in NDD, there are still questions regarding how to target ferroptosis therapeutically, including which proteins to target, identification of clinically relevant biomarkers, and which patients might benefit most. Clinical trials of iron- and ferroptosis-targeted therapies are beginning to provide some answers, but there is growing interest in developing new ferroptosis inhibitors. We describe newly identified ferroptosis targets, opportunities, and challenges in NDD, as well as key considerations for progressing new therapeutics to the clinic.}, } @article {pmid37657945, year = {2023}, author = {Cristi, AC and Rapuri, S and Coyne, AN}, title = {Nuclear pore complex and nucleocytoplasmic transport disruption in neurodegeneration.}, journal = {FEBS letters}, volume = {597}, number = {20}, pages = {2546-2566}, pmid = {37657945}, issn = {1873-3468}, support = {R00 NS123242/NS/NINDS NIH HHS/United States ; R01 NS132836/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Nuclear Pore/metabolism ; Active Transport, Cell Nucleus/physiology ; Nuclear Envelope ; Nuclear Pore Complex Proteins/genetics/metabolism ; Endosomal Sorting Complexes Required for Transport/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Nuclear pore complexes (NPCs) play a critical role in maintaining the equilibrium between the nucleus and cytoplasm, enabling bidirectional transport across the nuclear envelope, and are essential for proper nuclear organization and gene regulation. Perturbations in the regulatory mechanisms governing NPCs and nuclear envelope homeostasis have been implicated in the pathogenesis of several neurodegenerative diseases. The ESCRT-III pathway emerges as a critical player in the surveillance and preservation of well-assembled, functional NPCs, as well as nuclear envelope sealing. Recent studies have provided insights into the involvement of nuclear ESCRT-III in the selective reduction of specific nucleoporins associated with neurodegenerative pathologies. Thus, maintaining quality control of the nuclear envelope and NPCs represents a pivotal element in the pathological cascade leading to neurodegenerative diseases. This review describes the constituents of the nuclear-cytoplasmic transport machinery, encompassing the nuclear envelope, NPC, and ESCRT proteins, and how their structural and functional alterations contribute to the development of neurodegenerative diseases.}, } @article {pmid37657764, year = {2023}, author = {Zhou, S and Zhou, Y and Zhong, W and Su, Z and Qin, Z}, title = {Involvement of protein L-isoaspartyl methyltransferase in the physiopathology of neurodegenerative diseases: Possible substrates associated with synaptic function.}, journal = {Neurochemistry international}, volume = {170}, number = {}, pages = {105606}, doi = {10.1016/j.neuint.2023.105606}, pmid = {37657764}, issn = {1872-9754}, mesh = {Humans ; *Protein D-Aspartate-L-Isoaspartate Methyltransferase/metabolism ; *Neurodegenerative Diseases/metabolism ; Proteins/metabolism ; Isoaspartic Acid/metabolism ; Aspartic Acid/metabolism ; }, abstract = {Synaptic dysfunction is a typical pathophysiologic change in neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Hintington's disease (HD) and amyotrophic lateral sclerosis (ALS), which involves protein post-translational modifications (PTMs) including L-isoaspartate (L-isoAsp) formed by isomerization of aspartate or deamidation of asparagine. The formation of L-isoAsp could be repaired by protein L-isoaspartyl methyltransferase (PIMT). Some synaptic proteins have been identified as PIMT potential substrates and play an essential role in ensuring synaptic function. In this review, we discuss the role of certain synaptic proteins as PIMT substrates in neurodegenerative disease, thus providing therapeutic synapse-centered targets for the treatment of NDs.}, } @article {pmid37654673, year = {2023}, author = {Fischetti, F and Poli, L and De Tommaso, M and Paolicelli, D and Greco, G and Cataldi, S}, title = {The role of exercise parameters on small extracellular vesicles and microRNAs cargo in preventing neurodegenerative diseases.}, journal = {Frontiers in physiology}, volume = {14}, number = {}, pages = {1241010}, pmid = {37654673}, issn = {1664-042X}, abstract = {Physical activity (PA), which includes exercise, can reduce the risk of developing various non-communicable diseases, including neurodegenerative diseases (NDs), and mitigate their adverse effects. However, the mechanisms underlying this ability are not yet fully understood. Among several possible mechanisms proposed, such as the stimulation of brain-derived neurotrophic factor (BDNF), endothelial nitric oxide synthase (eNOS), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and nerve growth factor (NGF), the possible involvement of particular vesicular structures enclosed in lipid membranes known as extracellular vesicles (EVs) has recently been investigated. These EVs would appear to exert a paracrine and systemic action through their ability to carry various molecules, particularly so-called microRNAs (miRNAs), performing a function as mediators of intercellular communication. Interestingly, EVs and miRNAs are differentially expressed following PA, but evidence on how different exercise parameters may differentially affect EVs and the miRNAs they carry is still scarce. In this review we summarized the current human findings on the effects of PA and different exercise parameters exerted on EVs and their cargo, focusing on miRNAs molecules, and discussing how this may represent one of the biological mechanisms through which exercise contributes to preventing and slowing NDs.}, } @article {pmid37653823, year = {2023}, author = {Oh, SH and Jin, HS and Park, CH}, title = {Risk factors and neonatal outcomes of pulmonary air leak syndrome in extremely preterm infants: A nationwide descriptive cohort study.}, journal = {Medicine}, volume = {102}, number = {34}, pages = {e34759}, pmid = {37653823}, issn = {1536-5964}, mesh = {Female ; Humans ; Infant, Newborn ; Pregnancy ; Cohort Studies ; *Infant, Extremely Premature ; Prospective Studies ; Risk Factors ; Salts ; Sodium Chloride ; Sodium Chloride, Dietary ; *Lung Diseases ; Syndrome ; }, abstract = {Most extremely preterm infants (EPIs), who were born before 28 weeks of gestation, with pulmonary air leak syndrome (ALS) are symptomatic, often severe, and require drainage. EPIs with severe air leak syndrome (sALS) that require tube drainage or needle aspiration are at high risk of morbidities and mortality. This study aimed to investigate perinatal characteristics, morbidities, and mortality in EPIs with sALS, and to estimate the risk of mortality according to gestational age (GA). A prospective cohort study conducted from 2013 to 2020 compiled the Korean Neonatal Network database to evaluate the incidence, perinatal characteristics, and outcomes of sALS in EPIs born before 28 weeks of gestation. Among 5666 EPIs, the incidence of sALS was 9.4% and inversely related to GA. From this cohort, we compared 532 EPIs with sALS to 1064 EPIs without sALS as controls, matching the subjects by GA and birth weight. Preterm premature rupture of membranes, oligohydramnios, resuscitation after birth, low Apgar scores, repeated surfactant administration, persistent pulmonary hypertension of the newborn, and pulmonary hemorrhage were associated with the development of pneumothorax. The sALS group required a higher fraction of inspired oxygen and more invasive respiratory support at both 28 days of life and 36 weeks of postmenstrual age. The sALS group had a higher incidence of bronchopulmonary dysplasia and major brain injury. The mortality rate was higher in the sALS group than in the control group (55.3% vs 32.5%, P < .001), and the ALS group had a 1.7 times risk of mortality than the control group. More attention should be paid to sALS in EPIs because the frequency of sALS increased as GA decreased, and the risk of mortality was more significant at lower GA.}, } @article {pmid37651908, year = {2024}, author = {Câmara, ABF and da Silva, WJO and Neves, ACO and Moura, HOMA and de Lima, KMG and de Carvalho, LS}, title = {Excitation-emission fluorescence spectroscopy coupled with PARAFAC and MCR-ALS with area correlation for investigation of jet fuel contamination.}, journal = {Talanta}, volume = {266}, number = {Pt 2}, pages = {125126}, doi = {10.1016/j.talanta.2023.125126}, pmid = {37651908}, issn = {1873-3573}, abstract = {The contamination of jet fuel has gained attention in the past years as a notable factor in aircraft accidents. Identifying the contamination sources is still a challenge, especially when they have a similar composition to the fuel, such as kerosene solvent (KS). A novel analytical methodology was developed by combining a set of excitation-emission matrix (EEM) fluorescence to area constrained multivariate curve resolution with alternating least-squares (MCR-ALS) and PARAllel FACtor (PARAFAC) analysis, in order to identify KS in blends with JET-A1. For this purpose, a dataset with 50 samples (KS and JET-A1 blends, 2.0-100% v/v) was used to build the multivariate models. Both PARAFAC and MCR-ALS allowed fuel quantification with 4.64% and 3.46% RMSEP, respectively; both models (PARAFAC and MCR-ALS) could quantify KS with high accuracy (RMSEP <5.36%). In addition, MCR-ALS model was able to recover the pure spectral profiles of KS, JET-A1 and interferers. GC-MS data of the samples proved the composition similarities between both petroleum distillates, thus being inefficient for identifying the contamination. These results indicate that the development of multivariate models using EEM was the key for contributing with a new low-cost and accurate method for on-line screening of jet fuel contamination.}, } @article {pmid37651612, year = {2023}, author = {Sadžak, A and Eraković, M and Šegota, S}, title = {Kinetics of Flavonoid Degradation and Controlled Release from Functionalized Magnetic Nanoparticles.}, journal = {Molecular pharmaceutics}, volume = {20}, number = {10}, pages = {5148-5159}, doi = {10.1021/acs.molpharmaceut.3c00478}, pmid = {37651612}, issn = {1543-8392}, abstract = {Flavonoids are naturally occurring antioxidants that have been shown to protect cell membranes from oxidative stress and have a potential use in photodynamic cancer treatment. However, they degrade at physiological pH values, which is often neglected in drug release studies. Kinetic study of flavonoid oxidation can help to understand the mechanism of degradation and to correctly analyze flavonoid release data. Additionally, the incorporation of flavonoids into magnetic nanocarriers can be utilized to mitigate degradation and overcome their low solubility, while the release can be controlled using magnetic fields (MFs). An approach that combines alternating least squares (ALS) and multilinear regression to consider flavonoid autoxidation in release studies is presented. This approach can be used in general cases to account for the degradation of unstable drugs released from nanoparticles. The oxidation of quercetin, myricetin (MCE), and myricitrin (MCI) was studied in PBS buffer (pH = 7.4) using UV-vis spectrophotometry. ALS was used to determine the kinetic profiles and characteristic spectra, which were used to analyze UV-vis data of release from functionalized magnetic nanoparticles (MNPs). MNPs were selected for their unique magnetic properties, which can be exploited for both targeted drug delivery and control over the drug release. MNPs were prepared and characterized by X-ray diffraction, infrared spectroscopy, scanning electron microscopy, superconducting quantum interference device magnetometer, and electrophoretic mobility measurements. Autoxidation of all three flavonoids follows a two-step first-order kinetic model. MCE showed the fastest degradation, while the oxidation of MCI was the slowest. The flavonoids were successfully loaded into the prepared MNPs, and the drug release was described by the first-order and Korsmeyer-Peppas models. External MFs were utilized to control the release mechanism and the cumulative mass of the flavonoids released.}, } @article {pmid37651420, year = {2023}, author = {Williams, W and Theron, E and Khan, W and Stassen, W}, title = {Developing a South African curriculum for education in neonatal critical care retrieval: An initial exploration.}, journal = {PloS one}, volume = {18}, number = {8}, pages = {e0290972}, pmid = {37651420}, issn = {1932-6203}, mesh = {Infant, Newborn ; Humans ; South Africa ; Retrospective Studies ; Educational Status ; *Curriculum ; *Critical Care ; }, abstract = {BACKGROUND: Owing to limited or centralised neonatal critical care resources, the interfacility transfer of neonates is inevitable. In many high-income settings, dedicated Critical Care Retrieval Services (CCRS) with additional education and training undertake neonatal critical care retrieval (CCR). In South Africa, however, these transfers are mostly conducted by advanced paramedics with limited education in neonatal care, and this may lead to high adverse event rates. In SA, a shortage of skilled neonatal interfacility transport services has been identified as one of the top ten avoidable causes of under-5 mortality. In order to address this gap in neonatal transfer education for paramedics in South Africa, the aim of this study is to develop a curriculum for neonatal critical care retrieval in South Africa.

METHODS: Using Kern's approach to curriculum development, a general and targeted needs assessment was conducted through semi-structured interviews with experts in the field and a focus group discussion with a prospective student group. Interviews were preceded and informed by a literature review and retrospective chart review of neonates who underwent CCR in SA over a one-year period. Audio recordings of interviews were transcribed verbatim and subjected to inductive-dominant content analysis. Finally, qualitative codes were expanded into course outcome and a curriculum map was developed.

RESULTS: Six experts in neonatal critical care and retrieval participated in semi-structured interviews with a mean duration of 59 minutes. Following transcription and analysis, 372 codes were developed. Seven prehospital providers (prospective students) who are involved in neonatal transfers in South Africa participated in a focus group discussion with a duration of 91 minutes. The audio recording was transcribed and analysed with 97 codes extracted. The main categories were: Current status of neonatal CCR in South Africa; learning and education in neonatal CCR; and proposed curriculum structure. The proposed curriculum structure described 13 broad course outcomes to be delivered as a blended postgraduate programme. Participants noted that funding, employer buy-in and internet resources would be required. The targeted prospective student group should be all Advanced Life Support (ALS) providers with a change in their scope of practice on completion.

CONCLUSION: This study described the need for additional education in neonatal critical care retrieval due to the limitations in the current and past education systems. This study provides a curriculum structure with course outcomes that can be used as a basis for the development of a complete curriculum for education in neonatal CCR, with the potential to greatly reduce adverse event rates.}, } @article {pmid37651231, year = {2023}, author = {Held, A and Adler, M and Marques, C and Reyes, CJ and Kavuturu, AS and Quadros, ARAA and Ndayambaje, IS and Lara, E and Ward, M and Lagier-Tourenne, C and Wainger, BJ}, title = {iPSC motor neurons, but not other derived cell types, capture gene expression changes in postmortem sporadic ALS motor neurons.}, journal = {Cell reports}, volume = {42}, number = {9}, pages = {113046}, pmid = {37651231}, issn = {2211-1247}, support = {RF1 NS127407/NS/NINDS NIH HHS/United States ; RF1 NS124203/NS/NINDS NIH HHS/United States ; DP2 NS106664/NS/NINDS NIH HHS/United States ; R01 NS112503/NS/NINDS NIH HHS/United States ; F32 NS114319/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; Gene Expression ; DNA-Binding Proteins/metabolism ; }, abstract = {Motor neuron degeneration, the defining feature of amyotrophic lateral sclerosis (ALS), is a primary example of cell-type specificity in neurodegenerative diseases. Using isogenic pairs of induced pluripotent stem cells (iPSCs) harboring different familial ALS mutations, we assess the capacity of iPSC-derived lower motor neurons, sensory neurons, astrocytes, and superficial cortical neurons to capture disease features including transcriptional and splicing dysregulation observed in human postmortem neurons. At early time points, differentially regulated genes in iPSC-derived lower motor neurons, but not other cell types, overlap with one-third of the differentially regulated genes in laser-dissected motor neurons from ALS compared with control postmortem spinal cords. For genes altered in both the iPSC model and bona fide human lower motor neurons, expression changes correlate between the two populations. In iPSC-derived lower motor neurons, but not other derived cell types, we detect the downregulation of genes affected by TDP-43-dependent splicing. This reduction takes place exclusively within genotypes known to involve TDP-43 pathology.}, } @article {pmid37650499, year = {2023}, author = {Morichon, L and Hirtz, C and Tiers, L and Mezghrani, A and Raoul, C and Esselin, F and La Cruz, E and Julien, JP and Camu, W and Lehmann, S}, title = {Ultrasensitive digital immunoassays for SOD1 conformation in amyotrophic lateral sclerosis.}, journal = {Bioanalysis}, volume = {15}, number = {15}, pages = {927-936}, doi = {10.4155/bio-2023-0103}, pmid = {37650499}, issn = {1757-6199}, support = {misSOD1//ARSLA: Association pour la recherche sur la SLA/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Superoxide Dismutase-1 ; Biological Assay ; Immunoassay ; Molecular Conformation ; }, abstract = {Aim: The aim of this study was to detect misfolded Cu/Zn SOD1 as a potential biomarker for amyotrophic lateral sclerosis (ALS). Materials & methods: Two ultrasensitive immunodetection assays were developed for the quantification of total and misfolded SOD1. Results: The detection of total and misfolded SOD1 was possible in human serum and cerebrospinal fluid. Total SOD1 was increased in cerebrospinal fluid from ALS patients. Misfolded SOD1 had low and variable expression in both control and ALS patient samples. Conclusion: These assays hold promise for improving our understanding of ALS and its detection, and could lead to more effective treatment options in the future. Further studies in larger cohorts are now required.}, } @article {pmid37650100, year = {2023}, author = {De Marchi, F and Ferraro, PM and Introna, A and Spinelli, EG}, title = {Editorial: What's next? Innovative translational markers across the ALS-FTD continuum.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1250127}, pmid = {37650100}, issn = {1662-4548}, } @article {pmid37649875, year = {2023}, author = {Shrestha, R and Indrasena, BSH and Subedi, P and Lamsal, D and Moulton, C and Aylott, J}, title = {Evaluation of junior doctors' retention of knowledge and skills after simulation training in shockable rhythm cardiac arrest in a low-resource setting in Nepal.}, journal = {Resuscitation plus}, volume = {15}, number = {}, pages = {100448}, pmid = {37649875}, issn = {2666-5204}, abstract = {AIMS: To test junior doctors' abilities to retain advanced life support psychomotor skills and theoretical knowledge in management of shockable rhythm cardiac arrest.

METHODS: A repeated measure pre-post study design was used with 43 junior doctors, recruited after notifying them with robust method of attraction through flyers, brochures, email and phone calls. Written and performance tests, initial pre-test, immediate post-training, 30-days post-training and 60-days post-training, using simulation-based scenarios with a low-fidelity manikin were used with recording performance of ALS.

INSTRUMENTATION: Resuscitation Council UK ALS algorithms and guidelines[1] were used in a simulated testing environment.

RESULTS: There was a highly significant improvement in knowledge immediately after training (p < 0.00), with a net gain of marks from a mean value of 63.2% before training to 87.7% after training by 24.5% (95% CI 19.4, 29.6).There was a gradual decline of retained knowledge with time from immediate post-training over, 30-days and 60-days post-training (p < 0.00). The simulation pre-training assessments and immediate post-training assessments results were statistically significant (p < .00). The mean difference was 44.1% (95% CI 50.11, 38.10). There was a statistically significant decline of the competency with time (p < .00). Unlike for the knowledge test, the drop was significant on the 30th day (p < .00) with a mean difference of -10.5% (95% CI -13.55, -7.40).

CONCLUSION: The training of junior doctors in shockable rhythm cardiac arrest in a low resource setting, improved knowledge and skills in the participants after training. However, retention of knowledge declined at 30 days and more significantly after 60 days and retention of skill was declined more significantly at 30 days.}, } @article {pmid37648703, year = {2023}, author = {Chan-Yao-Chong, M and Chan, J and Kono, H}, title = {Benchmarking of force fields to characterize the intrinsically disordered R2-FUS-LC region.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {14226}, pmid = {37648703}, issn = {2045-2322}, mesh = {Humans ; Amyotrophic Lateral Sclerosis ; *Intrinsically Disordered Proteins ; RNA-Binding Protein FUS ; Water ; }, abstract = {Intrinsically Disordered Proteins (IDPs) play crucial roles in numerous diseases like Alzheimer's and ALS by forming irreversible amyloid fibrils. The effectiveness of force fields (FFs) developed for globular proteins and their modified versions for IDPs varies depending on the specific protein. This study assesses 13 FFs, including AMBER and CHARMM, by simulating the R2 region of the FUS-LC domain (R2-FUS-LC region), an IDP implicated in ALS. Due to the flexibility of the region, we show that utilizing multiple measures, which evaluate the local and global conformations, and combining them together into a final score are important for a comprehensive evaluation of force fields. The results suggest c36m2021s3p with mTIP3p water model is the most balanced FF, capable of generating various conformations compatible with known ones. In addition, the mTIP3P water model is computationally more efficient than those of top-ranked AMBER FFs with four-site water models. The evaluation also reveals that AMBER FFs tend to generate more compact conformations compared to CHARMM FFs but also more non-native contacts. The top-ranking AMBER and CHARMM FFs can reproduce intra-peptide contacts but underperform for inter-peptide contacts, indicating there is room for improvement.}, } @article {pmid37648532, year = {2023}, author = {Kim, YS and Kim, YE and Choung, YH and Kim, H and Kim, HJ and Jung, NY and Lee, SM and Kim, EJ and Moon, SY}, title = {Pearls & Oy-sters: Familial Verbal Auditory Agnosia Due to C9orf72 Repeat Expansion.}, journal = {Neurology}, volume = {101}, number = {20}, pages = {e2046-e2050}, pmid = {37648532}, issn = {1526-632X}, mesh = {Humans ; Male ; Middle Aged ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; C9orf72 Protein/genetics ; Proteins/genetics ; DNA Repeat Expansion/genetics ; *Pick Disease of the Brain/genetics ; }, abstract = {Chromosome 9 open reading frame 72 (C9orf72) gene pathogenic variants have been typically associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), but recent studies suggest their involvement in other disorders. This report describes a family with an autosomal dominant pattern of inheritance of progressive verbal auditory agnosia due to GGGGCC repeat expansion in C9orf72. A 60-year-old right-handed male truck driver presented with slowly progressive poor speech perception for 8 years, which became most troublesome when receiving verbal orders over the phone. He had difficulty recognizing single-syllable spoken words beyond his hearing loss but had no problem understanding complex written language. He had a heterozygous pathogenic variant carrying 160 hexanucleotide repeats in the C9orf72 gene. His family history included his deceased mother with similar symptoms that had progressed over 30 years, as well as his older brother and youngest sister who experienced speech perception difficulty beginning in their early fifties. His asymptomatic younger brother had a heterozygous 2 repeat in the C9orf72 gene, while his symptomatic youngest sister had a heterozygous 159 repeat. The patient and his sister exhibited more pronounced cortical thinning in the frontotemporoparietal areas. The discrepancy observed between the distribution of atrophy and the presentation of symptoms in patients with C9orf72 pathogenic repeat expansion may be attributable to the slow progression of their clinical course over time. The variable symptom presentation of C9orf72 pathogenic repeat expansion highlights the importance of considering this pathogenic variant as a potential cause of autosomal dominant degenerative brain diseases beyond FTD and ALS.}, } @article {pmid37648527, year = {2023}, author = {Kastner, S}, title = {A Marxist Exegesis of ALS.}, journal = {Neurology}, volume = {101}, number = {21}, pages = {966-967}, doi = {10.1212/WNL.0000000000207760}, pmid = {37648527}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; }, } @article {pmid37647907, year = {2023}, author = {Gondim, FAA and Pinto, WBVR and Chieia, MAT and Correia, CDC and Cunha, FMB and Dourado, MET and França Júnior, MC and Marques Júnior, W and Oliveira, ASB and Rodrigues, CL and Silva, DJD and Dias-Tosta, E}, title = {Definitions, phenomenology, diagnosis, and management of the disorders of laughter and crying in amyotrophic lateral sclerosis (ALS): Consensus from ALS and Motor Neuron Disease Scientific Department of the Brazilian Academy of Neurology.}, journal = {Arquivos de neuro-psiquiatria}, volume = {81}, number = {8}, pages = {764-775}, pmid = {37647907}, issn = {1678-4227}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Brazil ; *Laughter ; Consensus ; Crying ; *Motor Neuron Disease ; *Neurology ; }, abstract = {The spectrum of neuropsychiatric phenomena observed in amyotrophic lateral sclerosis (ALS) is wide and not fully understood. Disorders of laughter and crying stand among the most common manifestations. The aim of this study is to report the results of an educational consensus organized by the Brazilian Academy of Neurology to evaluate the definitions, phenomenology, diagnosis, and management of the disorders of laughter and crying in ALS patients. Twelve members of the Brazilian Academy of Neurology - considered to be experts in the field - were recruited to answer 12 questions about the subject. After exchanging revisions, a first draft was prepared. A face-to-face meeting was held in Fortaleza, Brazil on 9.23.22 to discuss it. The revised version was subsequently emailed to all members of the ALS Scientific Department from the Brazilian Academy of Neurology and the final revised version submitted for publication. The prevalence of pseudobulbar affect/pathological laughter and crying (PBA/PLC) in ALS patients from 15 combined studies and 3906 patients was 27.4% (N = 1070), ranging from 11.4% to 71%. Bulbar onset is a risk factor but there are limited studies evaluating the differences in prevalence among the different motor neuron diseases subtypes, including patients with and without frontotemporal dementia. Antidepressants and a combination of dextromethorphan and quinidine (not available in Brazil) are possible therapeutic options. This group of panelists acknowledge the multiple gaps in the current literature and reinforces the need for further studies.}, } @article {pmid37647208, year = {2024}, author = {Vázquez-Costa, JF}, title = {Do we really need to calculate a minimal important difference for ALSFRS-R?: A letter in response to 'Clinically meaningful change: evaluation of the Rasch-built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) and the ALSFRS-R' published in Vol. 24(3-4), pp. 311-316.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {214-215}, doi = {10.1080/21678421.2023.2248199}, pmid = {37647208}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Surveys and Questionnaires ; *Persons with Disabilities ; Disease Progression ; }, } @article {pmid37646130, year = {2023}, author = {Pattee, GL and Genge, A and Couratier, P and Lunetta, C and Sobue, G and Aoki, M and Yoshino, H and Jackson, CE and Wymer, J and Salah, A and Nelson, S}, title = {Oral Edaravone - Introducing a Flexible Treatment Option for Amyotrophic Lateral Sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {23}, number = {10}, pages = {859-866}, doi = {10.1080/14737175.2023.2251687}, pmid = {37646130}, issn = {1744-8360}, mesh = {Humans ; Edaravone/pharmacokinetics ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neurodegenerative Diseases/drug therapy ; Free Radical Scavengers/pharmacology ; Administration, Intravenous ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease. While pharmacotherapy options remain limited, the Food and Drug Administration (FDA) approved intravenous (IV) and oral edaravone for the treatment of ALS in 2017 and 2022, respectively. With the addition of oral edaravone, patients with ALS may exclusively use oral medications.

AREAS COVERED: The authors performed a review of the published literature using the United States (US) National Library of Medicine's PubMed.gov resource to describe the pharmacokinetics, pharmacodynamics, safety, and efficacy of oral edaravone, as well as pertinent completed and ongoing clinical trials, including the oral edaravone clinical trial development program. The clinical profile of oral edaravone is also discussed.

EXPERT OPINION: Edaravone has been shown to slow the rate of motor function deterioration experienced by patients with ALS. As the oral formulation has been approved, patients with ALS may use it alone or in combination with other approved therapeutics. Additional clinical trials and real-world evidence are ongoing to gain further understanding of the clinical profile of oral edaravone.}, } @article {pmid37646115, year = {2023}, author = {Vu, L and Garcia-Mansfield, K and Pompeiano, A and An, J and David-Dirgo, V and Sharma, R and Venugopal, V and Halait, H and Marcucci, G and Kuo, YH and Uechi, L and Rockne, RC and Pirrotte, P and Bowser, R}, title = {Proteomics and mathematical modeling of longitudinal CSF differentiates fast versus slow ALS progression.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {11}, pages = {2025-2042}, pmid = {37646115}, issn = {2328-9503}, support = {R56 NS061867/NS/NINDS NIH HHS/United States ; R01 NS061867/NS/NINDS NIH HHS/United States ; P30 CA033572/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Proteome/metabolism ; Proteomics/methods ; Biomarkers/cerebrospinal fluid ; Disease Progression ; Retinol-Binding Proteins, Plasma ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease with a complex etiology that lacks biomarkers predicting disease progression. The objective of this study was to use longitudinal cerebrospinal fluid (CSF) samples to identify biomarkers that distinguish fast progression (FP) from slow progression (SP) and assess their temporal response.

METHODS: We utilized mass spectrometry (MS)-based proteomics to identify candidate biomarkers using longitudinal CSF from a discovery cohort of SP and FP ALS patients. Immunoassays were used to quantify and validate levels of the top biomarkers. A state-transition mathematical model was created using the longitudinal MS data that also predicted FP versus SP.

RESULTS: We identified a total of 1148 proteins in the CSF of all ALS patients. Pathway analysis determined enrichment of pathways related to complement and coagulation cascades in FPs and synaptogenesis and glucose metabolism in SPs. Longitudinal analysis revealed a panel of 59 candidate markers that could segregate FP and SP ALS. Based on multivariate analysis, we identified three biomarkers (F12, RBP4, and SERPINA4) as top candidates that segregate ALS based on rate of disease progression. These proteins were validated in the discovery and a separate validation cohort. Our state-transition model determined that the overall variance of the proteome over time was predictive of the disease progression rate.

INTERPRETATION: We identified pathways and protein biomarkers that distinguish rate of ALS disease progression. A mathematical model of the CSF proteome determined that the change in entropy of the proteome over time was predictive of FP versus SP.}, } @article {pmid37645951, year = {2023}, author = {Bridges, LR}, title = {Replicating RNA as a component of scrapie fibrils.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37645951}, issn = {2692-8205}, support = {P41 GM103311/GM/NIGMS NIH HHS/United States ; R01 GM129325/GM/NIGMS NIH HHS/United States ; }, abstract = {Recently, electron cryo-microscopy (cryo-EM) maps of fibrils from the brains of mice and hamsters with five infectious scrapie strains have been published[1-5] and deposited in the electron microscopy data bank (EMDB)[6]. This represents long-awaited near-atomic level structural evidence, widely expected to confirm the protein-only prion hypothesis[7,8]. Instead, the maps reveal a second component, other than protein. The aim of the present study was to identify the nature of this second component, in the published maps[1-5], using an in silico approach. Extra densities (EDs) containing this component were continuous, straight, axial, at right angles to protein rungs and within hydrogen-bonding distance of protein, consistent with a role as guide and support in fibril construction. EDs co-located with strips of basic residues, notably lysines, and formed a conspicuous cladding over parts of the N-terminal lobe of the protein. In one ED, there was evidence of a Y-shaped polymer forming two antiparallel chains, consistent with replicating RNA. Although the protein-only prion hypothesis[7] is still popular, convincing counter-evidence for an essential role of RNA as a cofactor has amassed in the last 20 years[8]. The present findings go beyond this in providing evidence for RNA as the genetic element of scrapie. To reflect the monotonous nature of the protein interface, it is suggested that the RNA may be a tandem repeat. This is against the protein-only prion hypothesis and in favour of a more orthodox agent, more akin to a virus. Fibrils from brains of patients with Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and other neurodegenerations also contain EDs[9] and may be of a similar aetiology.}, } @article {pmid37645251, year = {2023}, author = {Rojas, F and Aguilar, R and Almeida, S and Fritz, E and Corvalán, D and Ampuero, E and Abarzúa, S and Garcés, P and Amaro, A and Diaz, I and Arredondo, C and Cortes, N and Sanchez, M and Mercado, C and Varela-Nallar, L and Gao, FB and Montecino, M and van Zundert, B}, title = {Mature iPSC-derived astrocytes of an ALS/FTD patient carrying the TDP43[A90V] mutation display a mild reactive state and release polyP toxic to motoneurons.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1226604}, pmid = {37645251}, issn = {2296-634X}, support = {R01 NS101986/NS/NINDS NIH HHS/United States ; R21 NS119952/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; RF1 NS101986/NS/NINDS NIH HHS/United States ; }, abstract = {Astrocytes play a critical role in the maintenance of a healthy central nervous system and astrocyte dysfunction has been implicated in various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). There is compelling evidence that mouse and human ALS and ALS/FTD astrocytes can reduce the number of healthy wild-type motoneurons (MNs) in co-cultures or after treatment with astrocyte conditioned media (ACM), independently of their genotype. A growing number of studies have shown that soluble toxic factor(s) in the ACM cause non-cell autonomous MN death, including our recent identification of inorganic polyphosphate (polyP) that is excessively released from mouse primary astrocytes (SOD1, TARDBP, and C9ORF72) and human induced pluripotent stem cells (iPSC)-derived astrocytes (TARDBP) to kill MNs. However, others have reported that astrocytes carrying mutant TDP43 do not produce detectable MN toxicity. This controversy is likely to arise from the findings that human iPSC-derived astrocytes exhibit a rather immature and/or reactive phenotype in a number of studies. Here, we have succeeded in generating a highly homogenous population of functional quiescent mature astrocytes from control subject iPSCs. Using identical conditions, we also generated mature astrocytes from an ALS/FTD patient carrying the TDP43[A90V] mutation. These mutant TDP43 patient-derived astrocytes exhibit key pathological hallmarks, including enhanced cytoplasmic TDP-43 and polyP levels. Additionally, mutant TDP43 astrocytes displayed a mild reactive signature and an aberrant function as they were unable to promote synaptogenesis of hippocampal neurons. The polyP-dependent neurotoxic nature of the TDP43[A90V] mutation was further confirmed as neutralization of polyP in ACM derived from mutant TDP43 astrocytes prevented MN death. Our results establish that human astrocytes carrying the TDP43[A90V] mutation exhibit a cell-autonomous pathological signature, hence providing an experimental model to decipher the molecular mechanisms underlying the generation of the neurotoxic phenotype.}, } @article {pmid37645021, year = {2023}, author = {Littleton, SW and Laghi, F}, title = {Pearls and pitfalls of respiratory testing in a patient with amyotrophic lateral sclerosis and COPD.}, journal = {Breathe (Sheffield, England)}, volume = {19}, number = {2}, pages = {230043}, pmid = {37645021}, issn = {1810-6838}, abstract = {Interpretation of pulmonary function testing in patients with amyotrophic lateral sclerosis must account for coexisting lung diseases, when making patient care decisions. https://bit.ly/3Co2yR0.}, } @article {pmid37644984, year = {2023}, author = {Raghavendran, HRB and Kumaramanickavel, G and Iwata, T}, title = {Editorial: Personalized medicine-Where do we stand regarding bench to bedside translation?.}, journal = {Frontiers in medicine}, volume = {10}, number = {}, pages = {1243896}, pmid = {37644984}, issn = {2296-858X}, } @article {pmid37644868, year = {2023}, author = {Marton, S and Miquel, E and Acosta-Rodríguez, J and Fontenla, S and Libisch, G and Cassina, P}, title = {SOD1[G93A] Astrocyte-Derived Extracellular Vesicles Induce Motor Neuron Death by a miRNA-155-5p-Mediated Mechanism.}, journal = {ASN neuro}, volume = {15}, number = {}, pages = {17590914231197527}, pmid = {37644868}, issn = {1759-0914}, mesh = {Mice ; Animals ; Superoxide Dismutase-1/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Astrocytes/metabolism ; *Neurodegenerative Diseases/metabolism ; Mice, Transgenic ; Motor Neurons ; *MicroRNAs/genetics ; *Extracellular Vesicles/metabolism ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by upper and lower motor neuron (MN) degeneration. Astrocytes surrounding MNs are known to modulate ALS progression. When cocultured with astrocytes overexpressing the ALS-linked mutant Cu/Zn superoxide dismutase (SOD1[G93A]) or when cultured with conditioned medium from SOD1[G93A] astrocytes, MN survival is reduced. The exact mechanism of this neurotoxic effect is unknown. Astrocytes secrete extracellular vesicles (EVs) that transport protein, mRNA, and microRNA species from one cell to another. The size and protein markers characteristic of exosomes were observed in the EVs obtained from cultured astrocytes, indicating their abundance in exosomes. Here, we analyzed the microRNA content of the exosomes derived from SOD1[G93A] astrocytes and evaluated their role in MN survival. Purified MNs exposed to SOD1[G93A] astrocyte-derived exosomes showed reduced survival and neurite length compared to those exposed to exosomes derived from non-transgenic (non-Tg) astrocytes. Analysis of the miRNA content of the exosomes revealed that miR-155-5p and miR-582-3p are differentially expressed in SOD1[G93A] exosomes compared with exosomes from non-Tg astrocytes. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicates that miR-155-5p and miR-582-3p predicted targets are enriched in the neurotrophin signaling pathway. Importantly, when levels of miR-155-5p were reduced by incubation with a specific antagomir, SOD1[G93A] exosomes did not affect MN survival or neurite length. These results demonstrate that SOD1[G93A]-derived exosomes are sufficient to induce MN death, and miRNA-155-5p contributes to this effect. miRNA-155-5p may offer a new therapeutic target to modulate disease progression in ALS.}, } @article {pmid37644692, year = {2023}, author = {Clark, RM and Clark, CM and Lewis, KEA and Dyer, MS and Chuckowree, JA and Hoyle, JA and Blizzard, CA and Dickson, TC}, title = {Intranasal neuropeptide Y1 receptor antagonism improves motor deficits in symptomatic SOD1 ALS mice.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {11}, pages = {1985-1999}, pmid = {37644692}, issn = {2328-9503}, mesh = {Mice ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Superoxide Dismutase-1/genetics ; Motor Neurons ; Mice, Transgenic ; Superoxide Dismutase/genetics ; Peptides/pharmacology ; *Neuropeptides/metabolism ; }, abstract = {OBJECTIVE: Neuropeptide Y (NPY) is a 36 amino acid peptide widely considered to provide neuroprotection in a range of neurodegenerative diseases. In the fatal motor neuron disease amyotrophic lateral sclerosis (ALS), recent evidence supports a link between NPY and ALS disease processes. The goal of this study was to determine the therapeutic potential and role of NPY in ALS, harnessing the brain-targeted intranasal delivery of the peptide, previously utilised to correct motor and cognitive phenotypes in other neurological conditions.

METHODS: To confirm the association with clinical disease characteristics, NPY expression was quantified in post-mortem motor cortex tissue of ALS patients and age-matched controls. The effect of NPY on ALS cortical pathophysiology was investigated using slice electrophysiology and multi-electrode array recordings of SOD1[G93A] cortical cultures in vitro. The impact of NPY on ALS disease trajectory was investigated by treating SOD1[G93A] mice intranasally with NPY and selective NPY receptor agonists and antagonists from pre-symptomatic and symptomatic phases of disease.

RESULTS: In the human post-mortem ALS motor cortex, we observe a significant increase in NPY expression, which is not present in the somatosensory cortex. In vitro, we demonstrate that NPY can ameliorate ALS hyperexcitability, while brain-targeted nasal delivery of NPY and a selective NPY Y1 receptor antagonist modified survival and motor deficits specifically within the symptomatic phase of the disease in the ALS SOD1[G93A] mouse.

INTERPRETATION: Taken together, these findings highlight the capacity for non-invasive brain-targeted interventions in ALS and support antagonism of NPY Y1Rs as a novel strategy to improve ALS motor function.}, } @article {pmid37644512, year = {2023}, author = {Morón-Oset, J and Fischer, LKS and Jauré, N and Zhang, P and Jahn, AJ and Supèr, T and Pahl, A and Isaacs, AM and Grönke, S and Partridge, L}, title = {Repeat length of C9orf72-associated glycine-alanine polypeptides affects their toxicity.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {140}, pmid = {37644512}, issn = {2051-5960}, support = {/WT_/Wellcome Trust/United Kingdom ; P40 OD018537/OD/NIH HHS/United States ; WT098565/Z/12/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; *Frontotemporal Dementia ; Peptides ; Dipeptides/toxicity ; Insulin ; Alanine ; Drosophila ; }, abstract = {G4C2 hexanucleotide repeat expansions in a non-coding region of the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). G4C2 insertion length is variable, and patients can carry up to several thousand repeats. Dipeptide repeat proteins (DPRs) translated from G4C2 transcripts are thought to be a main driver of toxicity. Experiments in model organisms with relatively short DPRs have shown that arginine-rich DPRs are most toxic, while polyGlycine-Alanine (GA) DPRs cause only mild toxicity. However, GA is the most abundant DPR in patient brains, and experimental work in animals has generally relied on the use of low numbers of repeats, with DPRs often tagged for in vivo tracking. Whether repeat length or tagging affect the toxicity of GA has not been systematically assessed. Therefore, we generated Drosophila fly lines expressing GA100, GA200 or GA400 specifically in adult neurons. Consistent with previous studies, expression of GA100 and GA200 caused only mild toxicity. In contrast, neuronal expression of GA400 drastically reduced climbing ability and survival of flies, indicating that long GA DPRs can be highly toxic in vivo. This toxicity could be abolished by tagging GA400. Proteomics analysis of fly brains showed a repeat-length-dependent modulation of the brain proteome, with GA400 causing earlier and stronger changes than shorter GA proteins. PolyGA expression up-regulated proteins involved in ER to Golgi trafficking, and down-regulated proteins involved in insulin signalling. Experimental down-regulation of Tango1, a highly conserved regulator of ER-to Golgi transport, partially rescued GA400 toxicity, suggesting that misregulation of this process contributes to polyGA toxicity. Experimentally increasing insulin signaling also rescued GA toxicity. In summary, our data show that long polyGA proteins can be highly toxic in vivo, and that they may therefore contribute to ALS/FTD pathogenesis in patients.}, } @article {pmid37642362, year = {2023}, author = {Bireley, JD and Morren, JA}, title = {CNM-Au8: an experimental agent for the treatment of amyotrophic lateral sclerosis (ALS).}, journal = {Expert opinion on investigational drugs}, volume = {32}, number = {8}, pages = {677-683}, doi = {10.1080/13543784.2023.2252738}, pmid = {37642362}, issn = {1744-7658}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Edaravone/pharmacokinetics/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Quality of Life ; Drugs, Investigational/therapeutic use ; }, abstract = {INTRODUCTION: Two established disease-specific therapies for the treatment of amyotrophic lateral sclerosis (ALS) are riluzole and edaravone. Limitations of these medications include minimal progression slowing or survival benefit, and effectiveness only in selected populations, particularly for edaravone. AMX0035 and tofersen received US FDA approval in September 2022 and April 2023, respectively. However, phase 3 trials, further examining both medications' efficacy, are ongoing. CNM-Au8 is an efficient catalyst of energy metabolism and is therefore a potential disease-modifying treatment for ALS, a neurodegenerative condition in which there is bioenergetics impairment.

AREAS COVERED: In this review, we provide an overview of the current ALS treatment market, followed by a description of the pharmacodynamics and pharmacokinetics of CNM-Au8. The main preclinical and available early clinical evidence of CNM-Au8 is then described, as well as its potential as an ALS treatment.

EXPERT OPINION: Oral treatment with CNM-Au8 failed to meet primary clinical and electrodiagnostic endpoints in phase 2/3 clinical trials. Despite this failure, a number of exploratory endpoints included in phase 2/3 trials suggest CNM-Au8 has the potential to significantly slow clinical worsening, improve quality of life, and prolong survival in ALS. Further study of CNM-Au8 in a phase 3 clinical trial is currently underway.}, } @article {pmid37642179, year = {2023}, author = {Tucker, H and Duncan, T and Craven, PA and Goode, C and Scheidler, J}, title = {A Retrospective Application of the Arbon and Hartman Models to the Union Cycliste International Mountain Bike World Cup.}, journal = {Prehospital and disaster medicine}, volume = {38}, number = {5}, pages = {612-616}, pmid = {37642179}, issn = {1945-1938}, mesh = {Humans ; *Emergency Medical Services/methods ; Retrospective Studies ; Bicycling ; Mass Behavior ; Mass Gatherings ; }, abstract = {INTRODUCTION: Outdoor activities have accelerated in the past several years. The authors were tasked with providing medical care for the Union Cycliste International (UCI) mountain biking World Cup in Snowshoe, West Virginia (USA) in September 2021. The Hartman and Arbon models were designed to predict patient presentation and hospital transport rates as well as needed medical resources at urban mass-gathering events. However, there is a lack of standardized methods to predict injury, illness, and insult severity at rural mass gatherings.

STUDY OBJECTIVE: This study aimed to determine whether the Arbon model would predict, within 10%, the number of patient presentations to be expected and to determine if the event classification provided by the Hartman model would adequately predict resources needed during the event.

METHODS: Race data were collected from UCI event officials and injury data were collected from participants at time of presentation for medical care. Predicted presentation and transport rates were calculated using the Arbon model, which was then compared to the actual observed presentation rates. Furthermore, the event classification provided by the Hartman model was compared to the resources utilized during the event.

RESULTS: During the event, 34 patients presented for medical care and eight patients required some level of transport to a medical facility. The Arbon predictive model for the 2021 event yielded 30.3 expected patient presentations. There were 34 total patient presentations during the 2021 race, approximately 11% more than predicted. The Hartman model yielded a score of four. Based on this score, this race would be classified as an "intermediate" event, requiring multiple Advanced Life Support (ALS) and Basic Life Support (BLS) personnel and transport units.

CONCLUSION: The Arbon model provided a predicted patient presentation rate within reasonable error to allow for effective pre-event planning and resource allocation with only a four patient presentation difference from the actual data. While the Arbon model under-predicted patient presentations, the Hartman model under-estimated resources needed due to the high-risk nature of downhill cycling. The events staffed required physician skills and air medical services to safely care for patients. Further evaluation of rural events will be needed to determine if there is a generalized need for physician presence at smaller events with inherently risky activities, or if this recurring cycling event is an outlier.}, } @article {pmid37642165, year = {2023}, author = {Shelash Al-Hawary, SI and Yahya Ali, A and Mustafa, YF and Margiana, R and Maksuda Ilyasovna, S and Ramadan, MF and Almalki, SG and Alwave, M and Alkhayyat, S and Alsalamy, A}, title = {The microRNAs (miRs) overexpressing mesenchymal stem cells (MSCs) therapy in neurological disorders; hope or hype.}, journal = {Biotechnology progress}, volume = {39}, number = {6}, pages = {e3383}, doi = {10.1002/btpr.3383}, pmid = {37642165}, issn = {1520-6033}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Nervous System Diseases/genetics/therapy/metabolism ; *Mesenchymal Stem Cells/metabolism ; *Parkinson Disease/therapy ; Neurogenesis ; }, abstract = {Altered expression of multiple miRNAs was found to be extensively involved in the pathogenesis of different neurological disorders including Alzheimer's disease, Parkinson's disease, stroke, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. One of the biggest concerns within gene-based therapy is the delivery of the therapeutic microRNAs to the intended place, which is obligated to surpass the biological barriers without undergoing degradation in the bloodstream or renal excretion. Hence, the delivery of modified and unmodified miRNA molecules using excellent vehicles is required. In this light, mesenchymal stem cells (MSCs) have attracted increasing attention. The MSCs can be genetically modified to express or overexpress a particular microRNA aimed with promote neurogenesis and neuroprotection. The current review has focused on the therapeutic capabilities of microRNAs-overexpressing MSCs to ameliorate functional deficits in neurological conditions.}, } @article {pmid37641631, year = {2023}, author = {Fetit, R}, title = {Celebrating the life and research of BNA Past-President Colin Blakemore.}, journal = {Brain and neuroscience advances}, volume = {7}, number = {}, pages = {23982128231195514}, pmid = {37641631}, issn = {2398-2128}, abstract = {Professor Sir Colin Blakemore was a remarkable neuroscientist, persuasive communicator, and brave advocate for animal research who, sadly, passed away in June 2022 from amyotrophic lateral sclerosis. His work helped establish the concept of neuronal plasticity, which was fundamental to our understanding of the postnatal brain and continues to impact our outlook on neurodegenerative disorders. The BNA2023 Festival of Neuroscience dedicated its last plenary session in his honour, bringing together five prominent neuroscientists whose careers were shaped by Professor Blakemore. Here, we summarise the speakers' reflections on how Colin's support, generosity, and foresight influenced their academic paths, inspired their research, and changed their outlook on life.}, } @article {pmid37641579, year = {2024}, author = {Shefner, JM and Jacobsen, B and Kupfer, S and Malik, FI and Meng, L and Wei, J and Wolff, AA and Rudnicki, SA}, title = {Relationship between quantitative strength and functional outcomes in the phase 2 FORTITUDE-ALS trial.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {162-169}, doi = {10.1080/21678421.2023.2252468}, pmid = {37641579}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Hand Strength ; Quality of Life ; Surveys and Questionnaires ; Muscle Strength ; Disease Progression ; }, abstract = {OBJECTIVE: To assess the relationship among measurements of strength, function, and quality of life in an amyotrophic lateral sclerosis (ALS) clinical trial.

METHODS: In the FORTITUDE-ALS clinical trial (NCT03160898), 456 participants in the full-analysis set were treated with either reldesemtiv or placebo for 12 weeks; this post hoc analysis included all participants regardless of treatment assignments. Assessments included slow vital capacity (SVC), the ALS Functional Rating Scale-Revised (ALSFRS-R), and the 5-item ALS Assessment Questionnaire (ALSAQ-5). Muscle strength was measured quantitatively with hand-held dynamometry, and grip strength with a dedicated dynamometer. The relationship between strength and ALSFRS-R fine and gross motor domain scores, or responses to ALSAQ-5 questions on hand function and walking, was assessed with Spearman's rank correlation. The relationship between mean upper- or lower-extremity muscle strength and specific ALSFRS-R domains was modeled using principal-components analysis.

RESULTS: Upper-extremity muscle strength and hand grip were highly correlated with ALSFRS-R fine motor scores and the ALSAQ-5 hand function question. Similarly, lower-extremity strength correlated well with ALSFRS-R gross motor domain and the ALSAQ-5 walking question. For SVC, correlation was poor with the ALSFRS-R respiratory domain, but stronger with the total score, potentially reflecting the insensitivity of the respiratory questions in the scale. Upper- and lower-extremity strength were both strong predictors of ALSFRS-R domain scores.

CONCLUSIONS: In this analysis of data from an ALS clinical trial, muscle strength quantified by dynamometry was strongly correlated with functional capacity. These results suggest that muscle strength directly relates to specific functions of importance to people with ALS.}, } @article {pmid37641443, year = {2023}, author = {Maragakis, NJ and de Carvalho, M and Weiss, MD}, title = {Therapeutic targeting of ALS pathways: Refocusing an incomplete picture.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {11}, pages = {1948-1971}, pmid = {37641443}, issn = {2328-9503}, support = {R01 NS117604/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Neurodegenerative Diseases ; Biomarkers ; }, abstract = {Numerous potential amyotrophic lateral sclerosis (ALS)-relevant pathways have been hypothesized and studied preclinically, with subsequent translation to clinical trial. However, few successes have been observed with only modest effects. Along with an improved but incomplete understanding of ALS as a neurodegenerative disease is the evolution of more sophisticated and diverse in vitro and in vivo preclinical modeling platforms, as well as clinical trial designs. We highlight proposed pathological pathways that have been major therapeutic targets for investigational compounds. It is likely that the failures of so many of these therapeutic compounds may not have occurred because of lack of efficacy but rather because of a lack of preclinical modeling that would help define an appropriate disease pathway, as well as a failure to establish target engagement. These challenges are compounded by shortcomings in clinical trial design, including lack of biomarkers that could predict clinical success and studies that are underpowered. Although research investments have provided abundant insights into new ALS-relevant pathways, most have not yet been developed more fully to result in clinical study. In this review, we detail some of the important, well-established pathways, the therapeutics targeting them, and the subsequent clinical design. With an understanding of some of the shortcomings in translational efforts over the last three decades of ALS investigation, we propose that scientists and clinicians may choose to revisit some of these therapeutic pathways reviewed here with an eye toward improving preclinical modeling, biomarker development, and the investment in more sophisticated clinical trial designs.}, } @article {pmid37640472, year = {2023}, author = {Yamamuro-Tanabe, A and Kosuge, Y and Ishimaru, Y and Yoshioka, Y}, title = {Schwann cell derived-peroxiredoxin protects motor neurons against hydrogen peroxide-induced cell death in mouse motor neuron cell line NSC-34.}, journal = {Journal of pharmacological sciences}, volume = {153}, number = {2}, pages = {73-83}, doi = {10.1016/j.jphs.2023.07.006}, pmid = {37640472}, issn = {1347-8648}, mesh = {Animals ; Mice ; *Hydrogen Peroxide/toxicity ; *Amyotrophic Lateral Sclerosis/genetics ; Reactive Oxygen Species ; Superoxide Dismutase-1/genetics ; Motor Neurons ; Cell Death ; Schwann Cells ; Cell Line ; Peroxiredoxins/genetics ; }, abstract = {Schwann cells and oligodendrocytes secrete proteins that promote neuron survival, but their role in amyotrophic lateral sclerosis (ALS) is unclear. To address this question, we evaluated the effect of molecules secreted by Schwann cells on reactive oxygen species (ROS)-induced motor neuronal cell death. We observed that in motor neuron cell line NSC-34 cultures, the conditioned medium (CM) from Schwann cell line YST-1 (YST-1 CM) cultures had a protective effect against hydrogen peroxide-induced cell death. However, this protective effect of YST-1 CM was abolished by removing peroxiredoxin 1-4 (PRDX1-4) from the CM. We found that the expression of PRDX1 mRNA was markedly downregulated in the lumbar spinal cord of the superoxide dismutase 1 (SOD1)[G93A] mouse model of ALS. We also found that transient transfection of YST-1 cells with G93A SOD1 resulted in reduced PRDX1 mRNA expression. Additionally, in the mutant transfected cells, YST-1 CM showed decreased neuroprotective effect against hydrogen peroxide-induced NSC-34 cell death compared to those transfected with WT SOD1. Our results suggest that Schwann cells protect motor neurons from oxidative stress by secreting PRDX1 and that the reduction of PRDX secreted from Schwann cells contributes to increased ROS and associated motor neuronal death in ALS.}, } @article {pmid37640438, year = {2023}, author = {Hong Tuan Ha, V and Jost, D and Bougouin, W and Joly, G and Jouffroy, R and Jabre, P and Beganton, F and Derkenne, C and Lemoine, S and Frédéric, L and Lamhaut, L and Loeb, T and Revaux, F and Dumas, F and Trichereau, J and Stibbe, O and Deye, N and Marijon, E and Cariou, A and Jouven, X and Travers, S}, title = {Trends in survival from out-of-hospital cardiac arrest with a shockable rhythm and its association with bystander resuscitation: a retrospective study.}, journal = {Emergency medicine journal : EMJ}, volume = {40}, number = {11}, pages = {761-767}, doi = {10.1136/emermed-2023-213220}, pmid = {37640438}, issn = {1472-0213}, mesh = {Humans ; *Cardiopulmonary Resuscitation ; Retrospective Studies ; *Out-of-Hospital Cardiac Arrest ; Defibrillators ; Arrhythmias, Cardiac ; *Emergency Medical Services ; }, abstract = {OBJECTIVE: Over 300 000 cases of out-of-hospital cardiac arrests (OHCAs) occur each year in the USA and Europe. Despite decades of investment and research, survival remains disappointingly low. We report the trends in survival after a ventricular fibrillation/pulseless ventricular tachycardia OHCA, over a 13-year period, in a French urban region, and describe the simultaneous evolution of the rescue system.

METHODS: We investigated four 18-month periods between 2005 and 2018. The first period was considered baseline and included patients from the randomised controlled trial 'DEFI 2005'. The three following periods were based on the Paris Sudden Death Expertise Center Registry (France). Inclusion criteria were non-traumatic cardiac arrests treated with at least one external electric shock with an automated external defibrillator from the basic life support team and resuscitated by a physician-staffed ALS team. Primary outcome was survival at hospital discharge with a good neurological outcome.

RESULTS: Of 21 781 patients under consideration, 3476 (16%) met the inclusion criteria. Over all study periods, survival at hospital discharge increased from 12% in 2005 to 25% in 2018 (p<0.001), and return of spontaneous circulation at hospital admission increased from 43% to 58% (p=0.004).Lay-rescuer cardiopulmonary resuscitation (CPR) and telephone CPR (T-CPR) rates increased significantly, but public defibrillator use remained limited.

CONCLUSION: In a two-tiered rescue system, survival from OHCA at hospital discharge doubled over a 13-year study period. Concomitantly, the system implemented an OHCA patient registry and increased T-CPR frequency, despite a consistently low rate of public defibrillator use.}, } @article {pmid37639764, year = {2023}, author = {Stenson, K and O'Callaghan, L and Mellor, J and Wright, J and Gibson, G and Earl, L and Barlow, S and Fournier, CN}, title = {Healthcare resource utilization at different stages of amyotrophic lateral sclerosis: Results from a real-world survey.}, journal = {Journal of the neurological sciences}, volume = {452}, number = {}, pages = {120764}, doi = {10.1016/j.jns.2023.120764}, pmid = {37639764}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/therapy ; Patient Acceptance of Health Care ; France ; *General Practitioners ; Germany ; }, abstract = {People with amyotrophic lateral sclerosis (pALS) require complex, multi-disciplinary care, resulting in extensive healthcare resource utilization (HCRU). To investigate the relationship between HCRU and ALS progression, the study objectives were (i) to characterize HCRU in pALS and (ii) to establish whether this varied according to disease stage, as defined using three different methodologies: neurologist-defined early/mid/late stage, the King's clinical staging system for ALS, and the Milan Torino Staging system for ALS (MiToS). Real-world data were drawn from the Adelphi ALS Disease-Specific Programme™, a point-in-time survey of neurologists in France, Germany, Italy, Spain, the UK, and the USA conducted July 2020-March 2021. The analysis included survey responses from 142 physicians with respect to 880 pALS. With advancing ALS stage, significant differences were observed in the number of healthcare professional consultations and X-rays per person (both p < 0.05 for all staging systems), and the proportion of pALS with emergency room admissions, intensive care unit admissions, and assisted ventilation (all p < 0.05 for all staging systems). Across stages, >55% of pALS received care from a general neurologist and a general/primary care practitioner. With increasing stage, there was a significant difference in the proportion receiving care from a physical therapist, pulmonologist/respiratory care practitioner, respiratory therapist, speech/language therapist, and palliative care team, and in the proportion receiving care only from professional caregivers (all p < 0.05 for all staging systems). This study confirmed the substantial HCRU required to support pALS through all stages of ALS and highlighted an increasing need for healthcare resources as the disease progresses.}, } @article {pmid37639327, year = {2024}, author = {Baskerville, V and Rapuri, S and Mehlhop, E and Coyne, AN}, title = {SUN1 facilitates CHMP7 nuclear influx and injury cascades in sporadic amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {1}, pages = {109-121}, pmid = {37639327}, issn = {1460-2156}, support = {R00 NS123242/NS/NINDS NIH HHS/United States ; R01 NS132836/NS/NINDS NIH HHS/United States ; R00NS123242/GF/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia/pathology ; *Pick Disease of the Brain ; C9orf72 Protein/genetics/metabolism ; Neurons/metabolism ; Membrane Proteins ; Microtubule-Associated Proteins ; Nuclear Proteins ; Endosomal Sorting Complexes Required for Transport ; }, abstract = {We have recently identified the aberrant nuclear accumulation of the ESCRT-III protein CHMP7 as an initiating event that leads to a significant injury to the nuclear pore complex (NPC) characterized by the reduction of specific nucleoporins from the neuronal NPC in sporadic amyotrophic lateral sclerosis (sALS) and C9orf72 ALS/frontotemporal dementia (FTD)-induced pluripotent stem cell-derived neurons (iPSNs), a phenomenon also observed in post-mortem patient tissues. Importantly, this NPC injury is sufficient to contribute to TDP-43 dysfunction and mislocalization, a common pathological hallmark of neurodegenerative diseases. However, the molecular mechanisms and events that give rise to increased nuclear translocation and/or retention of CHMP7 to initiate this pathophysiological cascade remain largely unknown. Here, using an iPSN model of sALS, we demonstrate that impaired NPC permeability barrier integrity and interactions with the LINC complex protein SUN1 facilitate CHMP7 nuclear localization and the subsequent 'activation' of NPC injury cascades. Collectively, our data provide mechanistic insights in the pathophysiological underpinnings of ALS/FTD and highlight SUN1 as a potent contributor to and modifier of CHMP7-mediated toxicity in sALS pathogenesis.}, } @article {pmid37639066, year = {2024}, author = {Ma, Y and Jia, T and Qin, F and He, Y and Han, F and Zhang, C}, title = {Abnormal Brain Protein Abundance and Cross-tissue mRNA Expression in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {61}, number = {1}, pages = {510-518}, pmid = {37639066}, issn = {1559-1182}, support = {2021YFS0248//Key R & D Projects of Science and Technology Department of Sichuan Province/ ; 2020HXBH163//Postdoctoral Foundation of West China Hospital/ ; 20221174L//College Students' innovation and entrepreneurship training program/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Genome-Wide Association Study ; Bayes Theorem ; Brain/metabolism ; Proteome/metabolism ; RNA, Messenger/genetics ; ATPases Associated with Diverse Cellular Activities/genetics/metabolism ; Electron Transport Complex III/metabolism ; 17-Hydroxysteroid Dehydrogenases/metabolism ; }, abstract = {Due to the limitations of the present risk genes in understanding the etiology of amyotrophic lateral sclerosis (ALS), it is necessary to find additional causative genes utilizing novel approaches. In this study, we conducted a two-stage proteome-wide association study (PWAS) using ALS genome-wide association study (GWAS) data (N = 152,268) and two distinct human brain protein quantitative trait loci (pQTL) datasets (ROSMAP N = 376 and Banner N = 152) to identify ALS risk genes and prioritized candidate genes with Mendelian randomization (MR) and Bayesian colocalization analysis. Next, we verified the aberrant expression of risk genes in multiple tissues, including lower motor neurons, skeletal muscle, and whole blood. Six ALS risk genes (SCFD1, SARM1, TMEM175, BCS1L, WIPI2, and DHRS11) were found during the PWAS discovery phase, and SARM1 and BCS1L were confirmed during the validation phase. The following MR (p = 2.10 × 10[-7]) and Bayesian colocalization analysis (ROSMAP PP4 = 0.999, Banner PP4 = 0.999) confirmed the causal association between SARM1 and ALS. Further differential expression analysis revealed that SARM1 was markedly downregulated in lower motor neurons (p = 7.64 × 10[-3]), skeletal muscle (p = 9.34 × 10[-3]), and whole blood (p = 1.94 × 10[-3]). Our findings identified some promising protein candidates for future investigation as therapeutic targets. The dysregulation of SARM1 in multiple tissues provides a new way to explain ALS pathology.}, } @article {pmid37638500, year = {2024}, author = {Ross, JP and Akçimen, F and Liao, C and Kwan, K and Phillips, DE and Schmilovich, Z and Spiegelman, D and Genge, A and Dupré, N and Dion, PA and Farhan, SMK and Rouleau, GA}, title = {Rare-variant and polygenic analyses of amyotrophic lateral sclerosis in the French-Canadian genome.}, journal = {Genetics in medicine : official journal of the American College of Medical Genetics}, volume = {26}, number = {1}, pages = {100967}, doi = {10.1016/j.gim.2023.100967}, pmid = {37638500}, issn = {1530-0366}, mesh = {Humans ; Genetic Association Studies ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Genome-Wide Association Study ; Canada ; Genome ; Genetic Predisposition to Disease ; }, abstract = {PURPOSE: The genetic etiology of amyotrophic lateral sclerosis (ALS) includes few rare, large-effect variants and potentially many common, small-effect variants per case. The genetic risk liability for ALS might require a threshold comprised of a certain amount of variants. Here, we tested the degree to which risk for ALS was affected by rare variants in ALS genes, polygenic risk score, or both.

METHODS: 335 ALS cases and 356 controls from Québec, Canada were concurrently tested by microarray genotyping and targeted sequencing of ALS genes known at the time of study inception. ALS genome-wide association studies summary statistics were used to estimate an ALS polygenic risk score (PRS). Cases and controls were subdivided into rare-variant heterozygotes and non-heterozygotes.

RESULTS: Risk for ALS was significantly associated with PRS and rare variants independently in a logistic regression model. Although ALS PRS predicted a small amount of ALS risk overall, the effect was most pronounced between ALS cases and controls that were not heterozygous for a rare variant in the ALS genes surveyed.

CONCLUSION: Both PRS and rare variants in ALS genes impact risk for ALS. PRS for ALS is most informative when rare variants are not observed in ALS genes.}, } @article {pmid37638449, year = {2023}, author = {McCann, EP and Grima, N and Fifita, JA and Chan Moi Fat, S and Lehnert, K and Henden, L and Blair, IP and Williams, KL}, title = {Characterising the Genetic Landscape of Amyotrophic Lateral Sclerosis: A Catalogue and Assessment of Over 1,000 Published Genetic Variants.}, journal = {Journal of neuromuscular diseases}, volume = {10}, number = {6}, pages = {1127-1141}, pmid = {37638449}, issn = {2214-3602}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Neurodegenerative Diseases ; Gene Frequency ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with genetic and phenotypic heterogeneity. Pathogenic genetic variants remain the only validated cause of disease, the majority of which were discovered in familial ALS patients. While causal gene variants are a lesser contributor to sporadic ALS, an increasing number of risk alleles (low penetrance genetic variants associated with a small increase in disease risk) and variants of uncertain significance have been reported.

OBJECTIVE: To examine the pathogenic potential of genetic variation in ALS, we sought to characterise variant- and gene-level attributes of previously reported ALS-implicated variants.

METHODS: A list of 1,087 genetic variants reported in ALS to March 2021 was compiled through comprehensive literature review. Individual variants were annotated using in silico tools and databases across variant features including pathogenicity scores, localisation to protein domains, evolutionary conservation, and minor allele frequencies. Gene level attributes of genic tolerance, gene expression in ALS-relevant tissues and gene ontology terms were assessed for 33 ALS genes. Statistical analysis was performed for each characteristic, and we compared the most penetrant variants found in familial cases with risk alleles exclusive to sporadic cases, to explore genetic variant features that associate with disease penetrance.

RESULTS: We provide spreadsheet (hg19 and GRCh38) and variant call format (GRCh38) resources for all 1,087 reported ALS-implicated variants, including detailed summaries for each attribute. We demonstrate that the characteristics of variants found exclusively in sporadic ALS cases are less severe than those observed in familial ALS.

CONCLUSIONS: We provide a comprehensive, literature-derived catalogue of genetic variation in ALS thus far and reveal crucial attributes that contribute to ALS pathogenicity. Our variant- and gene-level observations highlight the complexity of genetic variation in ALS, and we discuss important implications and considerations for novel variant interpretation.}, } @article {pmid37638324, year = {2023}, author = {Zhou, W and Xu, R}, title = {Current insights in the molecular genetic pathogenesis of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1189470}, pmid = {37638324}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that leads to the massive loss of motor neurons in cerebrum, brain stem and spinal cord. It affects not only motor neurons but also other neurons and glial cells, resulting in the progressive muscle atrophy, the severe disability and the eventual death due to the respiratory failure. The pathogenesis of ALS is not fully understood. Currently, several factors are considered to be involved in the pathogenesis of ALS, such as genetic factors, imbalances in protein homeostasis, RNA metabolism disorders, mitochondrial dysfunctions, glutamate-mediated excitatory toxicities and intra-neuronal material transport disorders in neurons. The study of genetic mutations related to ALS pathogenesis will link the molecular and cellular mechanisms of the disease, thus enhancing the understanding of its occurrence and progression, thereby providing new insights for the pathogenesis of ALS. This review summarizes the current insights in the molecular genetic pathogenesis of ALS.}, } @article {pmid37636591, year = {2023}, author = {Jamali, AM and Kethamreddy, M and Burkett, BJ and Port, JD and Pandey, MK}, title = {PET and SPECT Imaging of ALS: An Educational Review.}, journal = {Molecular imaging}, volume = {2023}, number = {}, pages = {5864391}, pmid = {37636591}, issn = {1536-0121}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Positron-Emission Tomography ; Tomography, Emission-Computed, Single-Photon ; Brain/diagnostic imaging ; Fluorodeoxyglucose F18 ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disease leading to progressive motor degeneration and ultimately death. It is a complex disease that can take a significantly long time to be diagnosed, as other similar pathological conditions must be ruled out for a definite diagnosis of ALS. Noninvasive imaging of ALS has shed light on disease pathology and altered biochemistry in the ALS brain. Other than magnetic resonance imaging (MRI), two types of functional imaging, positron emission tomography (PET) and single photon emission computed tomography (SPECT), have provided valuable data about what happens in the brain of ALS patients compared to healthy controls. PET imaging has revealed a specific pattern of brain metabolism through [[18]F]FDG, while other radiotracers have uncovered neuroinflammation, changes in neuronal density, and protein aggregation. SPECT imaging has shown a general decrease in regional cerebral blood flow (rCBF) in ALS patients. This educational review summarizes the current state of ALS imaging with various PET and SPECT radiopharmaceuticals to better understand the pathophysiology of ALS.}, } @article {pmid37636024, year = {2023}, author = {Nouri Nojadeh, J and Bildiren Eryilmaz, NS and Ergüder, BI}, title = {CRISPR/Cas9 genome editing for neurodegenerative diseases.}, journal = {EXCLI journal}, volume = {22}, number = {}, pages = {567-582}, pmid = {37636024}, issn = {1611-2156}, abstract = {Gene therapy has emerged as a promising therapeutic strategy for various conditions, including blood disorders, ocular disease, cancer, and nervous system disorders. The advent of gene editing techniques has facilitated the ability of researchers to specifically target and modify the eukaryotic cell genome, making it a valuable tool for gene therapy. This can be performed through either in vivo or ex vivo approaches. Gene editing tools, such as zinc finger nucleases, transcription activator-like effector nucleases, and CRISPR-Cas-associated nucleases, can be employed for gene therapy purposes. Among these tools, CRISPR-Cas-based gene editing stands out because of its ability to introduce heritable genome changes by designing short guide RNAs. This review aims to provide an overview of CRISPR-Cas technology and summarizes the latest research on the application of CRISPR/Cas9 genome editing technology for the treatment of the most prevalent neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and Spinocerebellar ataxia.}, } @article {pmid37635943, year = {2023}, author = {Alshafie, W and Fotouhi, M and Ayoubi, R and Shlaifer, I and Southern, K and McPherson, PS and Laflamme, C and , }, title = {The identification of high-performing antibodies for Charged multivesicular body protein 2b for use in Western Blot, immunoprecipitation and immunofluorescence.}, journal = {F1000Research}, volume = {12}, number = {}, pages = {884}, pmid = {37635943}, issn = {2046-1402}, support = {SGC/JAN18/988-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Frontotemporal Dementia ; Multivesicular Bodies ; Reproducibility of Results ; Blotting, Western ; Fluorescent Antibody Technique ; Immunoprecipitation ; Antibodies ; }, abstract = {Charged multivesicular body protein 2B is a subunit of the endosomal sorting complex required for transport III (ESRCT-III), a complex implicated in the lysosomal degradation pathway and formation of multivesicular bodies. Mutations to the CHMP2B gene can result in abnormal protein aggregates in neurons and is therefore predicted to be associated in neurodegenerative diseases, including across the ALS-FTD spectrum. Through our standardized experimental protocol which compares read-outs in knockout cell lines and isogenic parental controls, this study aims to enhance the reproducibility of research on this target by characterizing eight commercial antibodies against charged multivesicular body protein 2b using Western Blot, immunoprecipitation, and immunofluorescence. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.}, } @article {pmid37635508, year = {2023}, author = {Djordjevic, G and Milosevic, V and Ljubisavljevic, S and Stojanovic, I and Stojanov, A}, title = {Values of Nitric Oxide and Superoxide Dismutase in Cerebrospinal Fluid of Patients with Sporadic Amyotrophic Lateral Sclerosis.}, journal = {Neurology India}, volume = {71}, number = {4}, pages = {742-747}, doi = {10.4103/0028-3886.383853}, pmid = {37635508}, issn = {1998-4022}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Nitric Oxide/cerebrospinal fluid ; Superoxide Dismutase/cerebrospinal fluid ; Disease Progression ; }, abstract = {INTRODUCTION: Neurons are highly energy-dependent and highly specialized cells, showing great sensitivity to oxidative stress (OS). Nitric oxide (NO) and its oxidation products play a central role in neurodegeneration. This study aimed to contribute to the further elucidation of the role of OS in the pathogenesis of amyotrophic lateral sclerosis (ALS).

METHODS: We assessed NO and superoxide dismutase (SOD) levels in cerebrospinal fluid (CSF) of 24 sporadic ALS (sALS) patients (13 of them presented with spinal form while 11 patients had bulbar form) and 20 controls (CG).

RESULTS: The obtained SOD levels in sALS patients were lower than those in CG (p < 0.001), while NO showed higher levels compared to CG (p < 0.001). Observed separately, there were no significant differences in the levels of NO and SOD in CSF between patients about their clinical presentations (p > 0.05). There were significant negative correlations between SOD and NO levels in all sALS patients (r = 0.31, P = 0.025). Significant correlation between SOD and functional rating scale as well as disease progression index was recorded in patients with sALS (r = 0.618. r = 0.425, P < 0.01), while NO levels were significantly associated with disease progression only (r = 0.348, P < 0.01).

CONCLUSION: The data presented clearly support the role of impaired oxidant/antioxidant balance in the pathogenesis of ALS, where NO overproduction and decreased SOD defense activity seem to be particularly involved. The CSF SOD and NO level might serve as useful biomarkers for functional disorder and progression of the disease.}, } @article {pmid37633753, year = {2023}, author = {Singh, J and Habean, ML and Panicker, N}, title = {Inflammasome assembly in neurodegenerative diseases.}, journal = {Trends in neurosciences}, volume = {46}, number = {10}, pages = {814-831}, pmid = {37633753}, issn = {1878-108X}, support = {R00 AG066862/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases ; Inflammasomes ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis ; }, abstract = {Neurodegenerative disorders are characterized by the progressive dysfunction and death of selectively vulnerable neuronal populations, often associated with the accumulation of aggregated host proteins. Sustained brain inflammation and hyperactivation of inflammasome complexes have been increasingly demonstrated to contribute to neurodegenerative disease progression. Here, we review molecular mechanisms leading to inflammasome assembly in neurodegeneration. We focus primarily on four degenerative brain disorders in which inflammasome hyperactivation has been well documented: Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and the spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We discuss shared and divergent principles of inflammasome assembly across these disorders, and underscore the differences between neurodegeneration-associated inflammasome activation pathways and their peripheral-immune counterparts. We examine how aberrant assembly of inflammasome complexes may amplify pathology in neurodegeneration, including misfolded protein aggregation, and highlight prospects for neurotherapeutic interventions based on targeting inflammasome pathways.}, } @article {pmid37632964, year = {2023}, author = {Wang, T and Yang, X and Du, R and Zheng, S and Cui, H}, title = {Acupuncture in the Treatment of Amyotrophic Lateral Sclerosis: A Research Progress in Clinical Trials.}, journal = {Alternative therapies in health and medicine}, volume = {29}, number = {7}, pages = {114-118}, pmid = {37632964}, issn = {1078-6791}, abstract = {BACKGROUND: Acupuncture, a complementary and alternative medicine (CAM) modality, shows promise as an integrative therapy for Amyotrophic Lateral Sclerosis (ALS) due to the chronic nature of the disease and its persistent symptoms. Many patients turn to CAM for ALS treatment.

OBJECTIVE: This review assesses acupuncture's efficacy in treating Amyotrophic Lateral Sclerosis.

METHODS: We searched China National Knowledge Network (CNKI) and PubMed databases for Chinese and English articles, including clinical trials, case studies, cohorts, and randomized controlled trials. The search, performed on March 31, 2023, encompassed literature published up to that date. Keywords used in titles and abstracts were (acupuncture) OR (electro-acupuncture)) AND (Amyotrophic Lateral Sclerosis).

RESULTS: Among the 45 articles studied, 34 were included in this research. Acupuncture's benefits primarily lie in neuro-immune system regulation, enhanced quality of life, reduced fatigue, disease progression delay, and fewer relapses.

CONCLUSIONS: Recent clinical trials highlight the potential of traditional Chinese acupuncture in improving Amyotrophic Lateral Sclerosis symptoms (e.g., fatigue, neural functional deficits) and curtailing relapses. Consequently, acupuncture holds promise as an integrative therapy for ALS patients.}, } @article {pmid37631001, year = {2023}, author = {Yan, J and Bading, H}, title = {The Disruption of NMDAR/TRPM4 Death Signaling with TwinF Interface Inhibitors: A New Pharmacological Principle for Neuroprotection.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {16}, number = {8}, pages = {}, pmid = {37631001}, issn = {1424-8247}, abstract = {With the discovery that the acquisition of toxic features by extrasynaptic NMDA receptors (NMDARs) involves their physical interaction with the non-selective cation channel, TRPM4, it has become possible to develop a new pharmacological principle for neuroprotection, namely the disruption of the NMDAR/TRPM4 death signaling complex. This can be accomplished through the expression of the TwinF domain, a 57-amino-acid-long stretch of TRPM4 that mediates its interaction with NMDARs, but also using small molecule TwinF interface (TI) inhibitors, also known as NMDAR/TRPM4 interaction interface inhibitors. Both TwinF and small molecule TI inhibitors detoxify extrasynaptic NMDARs without interfering with synaptic NMDARs, which serve important physiological functions in the brain. As the toxic signaling of extrasynaptic NMDARs contributes to a wide range of neurodegenerative conditions, TI inhibitors may offer therapeutic options for currently untreatable human neurodegenerative diseases including Amyotrophic Lateral Sclerosis, Alzheimer's disease, and Huntington's disease.}, } @article {pmid37629277, year = {2023}, author = {Fernandes, F and Barbalho, I and Bispo Júnior, A and Alves, L and Nagem, D and Lins, H and Arrais Júnior, E and Coutinho, KD and Morais, AHF and Santos, JPQ and Machado, GM and Henriques, J and Teixeira, C and Dourado Júnior, MET and Lindquist, ARR and Valentim, RAM}, title = {Digital Alternative Communication for Individuals with Amyotrophic Lateral Sclerosis: What We Have.}, journal = {Journal of clinical medicine}, volume = {12}, number = {16}, pages = {}, pmid = {37629277}, issn = {2077-0383}, support = {132/2018//Brazilian Ministry of Health/ ; 132/2018//Norte-Grandense Foundation for Research and Culture and the Federal University of Rio Grande do Norte (FUNPEC)/ ; }, abstract = {Amyotrophic Lateral Sclerosis is a disease that compromises the motor system and the functional abilities of the person in an irreversible way, causing the progressive loss of the ability to communicate. Tools based on Augmentative and Alternative Communication are essential for promoting autonomy and improving communication, life quality, and survival. This Systematic Literature Review aimed to provide evidence on eye-image-based Human-Computer Interaction approaches for the Augmentative and Alternative Communication of people with Amyotrophic Lateral Sclerosis. The Systematic Literature Review was conducted and guided following a protocol consisting of search questions, inclusion and exclusion criteria, and quality assessment, to select primary studies published between 2010 and 2021 in six repositories: Science Direct, Web of Science, Springer, IEEE Xplore, ACM Digital Library, and PubMed. After the screening, 25 primary studies were evaluated. These studies showcased four low-cost, non-invasive Human-Computer Interaction strategies employed for Augmentative and Alternative Communication in people with Amyotrophic Lateral Sclerosis. The strategies included Eye-Gaze, which featured in 36% of the studies; Eye-Blink and Eye-Tracking, each accounting for 28% of the approaches; and the Hybrid strategy, employed in 8% of the studies. For these approaches, several computational techniques were identified. For a better understanding, a workflow containing the development phases and the respective methods used by each strategy was generated. The results indicate the possibility and feasibility of developing Human-Computer Interaction resources based on eye images for Augmentative and Alternative Communication in a control group. The absence of experimental testing in people with Amyotrophic Lateral Sclerosis reiterates the challenges related to the scalability, efficiency, and usability of these technologies for people with the disease. Although challenges still exist, the findings represent important advances in the fields of health sciences and technology, promoting a promising future with possibilities for better life quality.}, } @article {pmid37629005, year = {2023}, author = {La Cognata, V and D'Amico, AG and Maugeri, G and Morello, G and Guarnaccia, M and Magrì, B and Aronica, E and Alkon, DL and D'Agata, V and Cavallaro, S}, title = {The ε-Isozyme of Protein Kinase C (PKCε) Is Impaired in ALS Motor Cortex and Its Pulse Activation by Bryostatin-1 Produces Long Term Survival in Degenerating SOD1-G93A Motor Neuron-like Cells.}, journal = {International journal of molecular sciences}, volume = {24}, number = {16}, pages = {}, pmid = {37629005}, issn = {1422-0067}, support = {DSB.AD007.304//IRIB-CNR/ ; }, mesh = {Humans ; Protein Kinase C-epsilon/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Isoenzymes/genetics ; Superoxide Dismutase-1/genetics ; *Motor Cortex ; Bryostatins/pharmacology ; *Neurodegenerative Diseases ; Motor Neurons ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease, characterized by a progressive depletion of upper and lower motor neurons (MNs) in the brain and spinal cord. The aberrant regulation of several PKC-mediated signal transduction pathways in ALS has been characterized so far, describing either impaired expression or altered activity of single PKC isozymes (α, β, ζ and δ). Here, we detailed the distribution and cellular localization of the ε-isozyme of protein kinase C (PKCε) in human postmortem motor cortex specimens and reported a significant decrease in both PKCε mRNA (PRKCE) and protein immunoreactivity in a subset of sporadic ALS patients. We furthermore investigated the steady-state levels of both pan and phosphorylated PKCε in doxycycline-activated NSC-34 cell lines carrying the human wild-type (WT) or mutant G93A SOD1 and the biological long-term effect of its transient agonism by Bryostatin-1. The G93A-SOD1 cells showed a significant reduction of the phosphoPKCε/panPKCε ratio compared to the WT. Moreover, a brief pulse activation of PKCε by Bryostatin-1 produced long-term survival in activated G93A-SOD1 degenerating cells in two different cell death paradigms (serum starvation and chemokines-induced toxicity). Altogether, the data support the implication of PKCε in ALS pathophysiology and suggests its pharmacological modulation as a potential neuroprotective strategy, at least in a subgroup of sporadic ALS patients.}, } @article {pmid37628709, year = {2023}, author = {De Marchi, F and Tondo, G and Corrado, L and Menegon, F and Aprile, D and Anselmi, M and D'Alfonso, S and Comi, C and Mazzini, L}, title = {Neuroinflammatory Pathways in the ALS-FTD Continuum: A Focus on Genetic Variants.}, journal = {Genes}, volume = {14}, number = {8}, pages = {}, pmid = {37628709}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; Neuroinflammatory Diseases ; Oxidative Stress ; Astrocytes ; Mitochondrial Proteins ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FDT) are progressive neurodegenerative disorders that, in several cases, overlap in clinical presentation, and genetic and pathological disease mechanisms. About 10-15% of ALS cases and up to 40% of FTD are familial, usually with dominant traits. ALS and FTD, in several cases, share common gene mutations, such as in C9ORF72, TARDBP, SQSTM-1, FUS, VCP, CHCHD10, and TBK-1. Also, several mechanisms are involved in ALS and FTD pathogenesis, such as protein misfolding, oxidative stress, and impaired axonal transport. In addition, neuroinflammation and neuroinflammatory cells, such as astrocytes, oligodendrocytes, microglia, and lymphocytes and, overall, the cellular microenvironment, have been proposed as pivotal players in the pathogenesis the ALS-FTD spectrum disorders. This review overviews the current evidence regarding neuroinflammatory markers in the ALS/FTD continuum, focusing on the neuroinflammatory pathways involved in the genetic cases, moving from post-mortem reports to in vivo biofluid and neuroimaging data. We further discuss the potential link between genetic and autoimmune disorders and potential therapeutic implications.}, } @article {pmid37627588, year = {2023}, author = {Giménez-Bejarano, A and Alegre-Cortés, E and Yakhine-Diop, SMS and Gómez-Suaga, P and Fuentes, JM}, title = {Mitochondrial Dysfunction in Repeat Expansion Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {8}, pages = {}, pmid = {37627588}, issn = {2076-3921}, support = {CIBERNED CB06/05/0041//Instituto de Salud Carlos III/ ; }, abstract = {Repeat expansion diseases are a group of neuromuscular and neurodegenerative disorders characterized by expansions of several successive repeated DNA sequences. Currently, more than 50 repeat expansion diseases have been described. These disorders involve diverse pathogenic mechanisms, including loss-of-function mechanisms, toxicity associated with repeat RNA, or repeat-associated non-ATG (RAN) products, resulting in impairments of cellular processes and damaged organelles. Mitochondria, double membrane organelles, play a crucial role in cell energy production, metabolic processes, calcium regulation, redox balance, and apoptosis regulation. Its dysfunction has been implicated in the pathogenesis of repeat expansion diseases. In this review, we provide an overview of the signaling pathways or proteins involved in mitochondrial functioning described in these disorders. The focus of this review will be on the analysis of published data related to three representative repeat expansion diseases: Huntington's disease, C9orf72-frontotemporal dementia/amyotrophic lateral sclerosis, and myotonic dystrophy type 1. We will discuss the common effects observed in all three repeat expansion disorders and their differences. Additionally, we will address the current gaps in knowledge and propose possible new lines of research. Importantly, this group of disorders exhibit alterations in mitochondrial dynamics and biogenesis, with specific proteins involved in these processes having been identified. Understanding the underlying mechanisms of mitochondrial alterations in these disorders can potentially lead to the development of neuroprotective strategies.}, } @article {pmid37627315, year = {2023}, author = {Kandeel, M and Morsy, MA and Alkhodair, KM and Alhojaily, S}, title = {Mesenchymal Stem Cell-Derived Extracellular Vesicles: An Emerging Diagnostic and Therapeutic Biomolecules for Neurodegenerative Disabilities.}, journal = {Biomolecules}, volume = {13}, number = {8}, pages = {}, pmid = {37627315}, issn = {2218-273X}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis ; *Mesenchymal Stem Cells ; *Adult Stem Cells ; *Alzheimer Disease ; *Extracellular Vesicles ; *Huntington Disease ; *Multiple Sclerosis ; *Parkinson Disease/diagnosis/therapy ; }, abstract = {Mesenchymal stem cells (MSCs) are a type of versatile adult stem cells present in various organs. These cells give rise to extracellular vesicles (EVs) containing a diverse array of biologically active elements, making them a promising approach for therapeutics and diagnostics. This article examines the potential therapeutic applications of MSC-derived EVs in addressing neurodegenerative disorders such as Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Furthermore, the present state-of-the-art for MSC-EV-based therapy in AD, HD, PD, ALS, and MS is discussed. Significant progress has been made in understanding the etiology and potential treatments for a range of neurodegenerative diseases (NDs) over the last few decades. The contents of EVs are carried across cells for intercellular contact, which often results in the control of the recipient cell's homeostasis. Since EVs represent the therapeutically beneficial cargo of parent cells and are devoid of many ethical problems connected with cell-based treatments, they offer a viable cell-free therapy alternative for tissue regeneration and repair. Developing innovative EV-dependent medicines has proven difficult due to the lack of standardized procedures in EV extraction processes as well as their pharmacological characteristics and mechanisms of action. However, recent biotechnology and engineering research has greatly enhanced the content and applicability of MSC-EVs.}, } @article {pmid37627263, year = {2023}, author = {Rühmkorf, A and Harbauer, AB}, title = {Role of Mitochondria-ER Contact Sites in Mitophagy.}, journal = {Biomolecules}, volume = {13}, number = {8}, pages = {}, pmid = {37627263}, issn = {2218-273X}, mesh = {Humans ; *Mitophagy ; Mitochondria ; Mitochondrial Membranes ; *Amyotrophic Lateral Sclerosis ; Apoptosis ; Mitochondrial Proteins ; Receptors, Estrogen ; }, abstract = {Mitochondria are often referred to as the "powerhouse" of the cell. However, this organelle has many more functions than simply satisfying the cells' metabolic needs. Mitochondria are involved in calcium homeostasis and lipid metabolism, and they also regulate apoptotic processes. Many of these functions require contact with the ER, which is mediated by several tether proteins located on the respective organellar surfaces, enabling the formation of mitochondria-ER contact sites (MERCS). Upon damage, mitochondria produce reactive oxygen species (ROS) that can harm the surrounding cell. To circumvent toxicity and to maintain a functional pool of healthy organelles, damaged and excess mitochondria can be targeted for degradation via mitophagy, a form of selective autophagy. Defects in mitochondria-ER tethers and the accumulation of damaged mitochondria are found in several neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, which argues that the interplay between the two organelles is vital for neuronal health. This review provides an overview of the different mechanisms of mitochondrial quality control that are implicated with the different mitochondria-ER tether proteins, and also provides a novel perspective on how MERCS are involved in mediating mitophagy upon mitochondrial damage.}, } @article {pmid37627248, year = {2023}, author = {Belo do Nascimento, I and Ates, G and Desmet, N and Beckers, P and Massie, A and Hermans, E}, title = {AMPKα1 Deficiency in Astrocytes from a Rat Model of ALS Is Associated with an Altered Metabolic Resilience.}, journal = {Biomolecules}, volume = {13}, number = {8}, pages = {}, pmid = {37627248}, issn = {2218-273X}, mesh = {Rats ; Animals ; *Amyotrophic Lateral Sclerosis/genetics ; Astrocytes ; AMP-Activated Protein Kinases ; Motor Neurons ; Glutamic Acid ; Superoxide Dismutase-1/genetics ; Adenosine Triphosphate ; }, abstract = {Alterations in the activity of the regulator of cell metabolism AMP-activated protein kinase (AMPK) have been reported in motor neurons from patients and animal models of amyotrophic lateral sclerosis (ALS). Considering the key role played by astrocytes in modulating energy metabolism in the nervous system and their compromised support towards neurons in ALS, we examined whether a putative alteration in AMPK expression/activity impacted astrocytic functions such as their metabolic plasticity and glutamate handling capacity. We found a reduced expression of AMPK mRNA in primary cultures of astrocytes derived from transgenic rats carrying an ALS-associated mutated superoxide dismutase (hSOD1[G93A]). The activation of AMPK after glucose deprivation was reduced in hSOD1[G93A] astrocytes compared to non-transgenic. This was accompanied by a lower increase in ATP levels and increased vulnerability to this insult, although the ATP production rate did not differ between the two cell types. Furthermore, soliciting the activity of glutamate transporters was found to induce similar AMPK activity in these cells. However, manipulation of AMPK activity did not influence glutamate transport. Together, these results suggest that the altered AMPK responsiveness in ALS might be context dependent and may compromise the metabolic adaptation of astrocytes in response to specific cellular stress.}, } @article {pmid37626868, year = {2023}, author = {Guerra, M and Meola, L and Lattante, S and Conte, A and Sabatelli, M and Sette, C and Bernardini, C}, title = {Characterization of SOD1-DT, a Divergent Long Non-Coding RNA in the Locus of the SOD1 Human Gene.}, journal = {Cells}, volume = {12}, number = {16}, pages = {}, pmid = {37626868}, issn = {2073-4409}, mesh = {Humans ; *RNA, Long Noncoding/genetics ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; *Neuroblastoma ; Alleles ; }, abstract = {Researchers studying Amyotrophic Lateral Sclerosis (ALS) have made significant efforts to find a unique mechanism to explain the etiopathology of the different forms of the disease. However, despite several mutations associated with ALS having been discovered in recent years, the link between the mutated genes and its onset has not yet been fully elucidated. Among the genes associated with ALS, superoxide dismutase 1 (SOD1) was the first to be identified, but its role in the etiopathogenesis of the disease is still unclear. In recent years, research has been focused on the non-coding part of the genome to fully understand the mechanisms underlying gene regulation. Non-coding RNAs are conserved molecules and are not usually translated in protein. A total of 98% of the human genome is composed of non-protein coding sequences with roles in the transcriptional and post-transcriptional regulation of gene expression. In this study, we characterized a divergent nuclear lncRNA (SOD1-DT) transcribed in the antisense direction from the 5' region of the SOD1 coding gene in both the SH-SY5Y cell line and fibroblasts derived from ALS patients. Interestingly, this lncRNA seems to regulate gene expression, since its inhibition leads to the upregulation of surrounding genes including SOD1. SOD1-DT represents a very complex molecule, displaying allelic and transcriptional variability concerning transposable elements (TEs) included in its sequence, widening the scenario of gene expression regulation in ALS disease.}, } @article {pmid37626649, year = {2023}, author = {Younes, R and Issa, Y and Jdaa, N and Chouaib, B and Brugioti, V and Challuau, D and Raoul, C and Scamps, F and Cuisinier, F and Hilaire, C}, title = {The Secretome of Human Dental Pulp Stem Cells and Its Components GDF15 and HB-EGF Protect Amyotrophic Lateral Sclerosis Motoneurons against Death.}, journal = {Biomedicines}, volume = {11}, number = {8}, pages = {}, pmid = {37626649}, issn = {2227-9059}, support = {R20071FF//ARSLA/ ; 0000//Délégation Régionale Occitanie Méditerranée/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and incurable paralytic disorder caused by the progressive death of upper and lower motoneurons. Although numerous strategies have been developed to slow disease progression and improve life quality, to date only a few therapeutic treatments are available with still unsatisfactory therapeutic benefits. The secretome of dental pulp stem cells (DPSCs) contains numerous neurotrophic factors that could promote motoneuron survival. Accordingly, DPSCs confer neuroprotective benefits to the SOD1[G93A] mouse model of ALS. However, the mode of action of DPSC secretome on motoneurons remains largely unknown. Here, we used conditioned medium of human DPSCs (DPSCs-CM) and assessed its effect on survival, axonal length, and electrical activity of cultured wildtype and SOD1[G93A] motoneurons. To further understand the role of individual factors secreted by DPSCs and to circumvent the secretome variability bias, we focused on GDF15 and HB-EGF whose neuroprotective properties remain elusive in the ALS pathogenic context. DPSCs-CM rescues motoneurons from trophic factor deprivation-induced death, promotes axon outgrowth of wildtype but not SOD1[G93A] mutant motoneurons, and has no impact on the spontaneous electrical activity of wildtype or mutant motoneurons. Both GDF15 and HB-EGF protect SOD1[G93A] motoneurons against nitric oxide-induced death, but not against death induced by trophic factor deprivation. GDF15 and HB-EGF receptors were found to be expressed in the spinal cord, with a two-fold increase in expression for the GDF15 low-affinity receptor in SOD1[G93A] mice. Therefore, the secretome of DPSCs appears as a new potential therapeutic candidate for ALS.}, } @article {pmid37626421, year = {2023}, author = {Wang, S and Sun, S}, title = {Translation dysregulation in neurodegenerative diseases: a focus on ALS.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {58}, pmid = {37626421}, issn = {1750-1326}, support = {R21 AG072078/AG/NIA NIH HHS/United States ; R01 NS107347/NS/NINDS NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; R01 AG078948/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Nerve Degeneration ; Homeostasis ; RNA ; }, abstract = {RNA translation is tightly controlled in eukaryotic cells to regulate gene expression and maintain proteome homeostasis. RNA binding proteins, translation factors, and cell signaling pathways all modulate the translation process. Defective translation is involved in multiple neurological diseases including amyotrophic lateral sclerosis (ALS). ALS is a progressive neurodegenerative disorder and poses a major public health challenge worldwide. Over the past few years, tremendous advances have been made in the understanding of the genetics and pathogenesis of ALS. Dysfunction of RNA metabolisms, including RNA translation, has been closely associated with ALS. Here, we first introduce the general mechanisms of translational regulation under physiological and stress conditions and review well-known examples of translation defects in neurodegenerative diseases. We then focus on ALS-linked genes and discuss the recent progress on how translation is affected by various mutant genes and the repeat expansion-mediated non-canonical translation in ALS.}, } @article {pmid37622689, year = {2024}, author = {Dey, B and Kumar, A and Patel, AB}, title = {Pathomechanistic Networks of Motor System Injury in Amyotrophic Lateral Sclerosis.}, journal = {Current neuropharmacology}, volume = {22}, number = {11}, pages = {1778-1806}, pmid = {37622689}, issn = {1875-6190}, support = {DST/CSRI/2017/258//Department of Science and Technology (DST), Govt. of India/ ; DBT/JRF/BET-17/1/2017/AL/400//Department of Biotechnology (DBT), Govt. of India/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Animals ; Gene-Environment Interaction ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is the most common, adult-onset, progressive motor neurodegenerative disorder that results in death within 3 years of the clinical diagnosis. Due to the clinicopathological heterogeneity, any reliable biomarkers for diagnosis or prognosis of ALS have not been identified till date. Moreover, the only three clinically approved treatments are not uniformly effective in slowing the disease progression. Over the last 15 years, there has been a rapid advancement in research on the complex pathomechanistic landscape of ALS that has opened up new avenues for successful clinical translation of targeted therapeutics. Multiple studies suggest that the age-dependent interaction of risk-associated genes with environmental factors and endogenous modifiers is critical to the multi-step process of ALS pathogenesis. In this review, we provide an updated discussion on the dysregulated cross-talk between intracellular homeostasis processes, the unique molecular networks across selectively vulnerable cell types, and the multisystemic nature of ALS pathomechanisms. Importantly, this work highlights the alteration in epigenetic and epitranscriptomic landscape due to gene-environment interactions, which have been largely overlooked in the context of ALS pathology. Finally, we suggest that precision medicine research in ALS will be largely benefitted from the stratification of patient groups based on the clinical phenotype, onset and progression, genome, exposome, and metabolic identities.}, } @article {pmid37621312, year = {2023}, author = {Sun, Z and Liu, X and Zuo, W and Fu, Q and Xu, T and Cui, L and Zhang, B and Peng, Y}, title = {Development of a robust UPLC-MS/MS method for the quantification of riluzole in human plasma and its application in pharmacokinetics.}, journal = {Frontiers in pharmacology}, volume = {14}, number = {}, pages = {1227354}, pmid = {37621312}, issn = {1663-9812}, abstract = {Introduction: The aim of the present study was to establish a simple method for the determination of riluzole in human plasma by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and apply it for the determination of riluzole in amyotrophic lateral sclerosis (ALS) patients. Methods: Samples were prepared by protein precipitation and were then gradient-eluted on a column of ACQUITY UPLC[®] HSS T3 by using 0.1% formic acid acetonitrile and 0.1% formic acid water as the mobile phase. Detection was performed on a Xevo TQ-S tandem mass spectrometer in the multiple-reaction monitoring mode using positive electrospray ionization. Validation was performed in the range of 5-800 ng/mL. Results and discussion: Three batches of precision accuracy, selectivity, matrix effects, extraction recovery, and stability were also verified and met the requirements. The results showed that the method was reliable and successfully applied to the pharmacokinetics study of riluzole in Chinese amyotrophic lateral sclerosis patients. Meanwhile, in comparison with other prior published methods, our method has the advantages of simple sample preparation, relatively short running time, and small plasma sample consumption, which represented a high-throughput sample determination potential.}, } @article {pmid37620418, year = {2023}, author = {Artuğ, NT}, title = {Fully automated F-wave corridor extraction and analysis algorithm for F-wave analyses and MUNE studies.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {13822}, pmid = {37620418}, issn = {2045-2322}, mesh = {Humans ; *Algorithms ; Software ; Foot ; *Poliomyelitis/diagnosis ; Thumb ; }, abstract = {F-waves are used in motor unit number estimation (MUNE) studies, which require rapid dedicated software to perform calculations. The aim of this study is to define a mathematical method for a fully automated F-wave extraction algorithm to perform F-wave and MUNE studies while performing baseline corrections without distorting traces. Ten recordings from each class, such as healthy controls, polio patients and ALS patients, were included. Submaximal stimuli were applied to the median and ulnar nerves to record 300 traces from the abductor pollicis brevis and abductor digiti minimi muscles. The autocorrelation function and the signal of sum of all traces were used to find the location for the maximum amplitude of the F-waves. F-waves were revealed by using a cutting window. Linear line estimation was preferred for baseline corrections because it did not cause any distortion in the traces. The algorithm automatically revealed F-waves from all 30 recordings in accordance with the locations marked by a neurophysiologist. The execution of the algorithm was less than 2 (usually < 1) minutes when 300 traces were analyzed. Mean sMUP amplitudes and MUNE values are important for differentiating healthy controls from patients. Moreover, F-wave parameters belonging to polio patients on whom there was a relatively low number of studies conducted were also evaluated.}, } @article {pmid37620323, year = {2023}, author = {Krebs, AS and Liu, HF and Zhou, Y and Rey, JS and Levintov, L and Shen, J and Howe, A and Perilla, JR and Bartesaghi, A and Zhang, P}, title = {Molecular architecture and conservation of an immature human endogenous retrovirus.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {5149}, pmid = {37620323}, issn = {2041-1723}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 AI157843/AI/NIAID NIH HHS/United States ; R01 GM141223/GM/NIGMS NIH HHS/United States ; U54 AI170791/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Endogenous Retroviruses/genetics ; *Amyotrophic Lateral Sclerosis ; Biological Evolution ; Capsid ; Capsid Proteins/genetics ; }, abstract = {The human endogenous retrovirus K (HERV-K) is the most recently acquired endogenous retrovirus in the human genome and is activated and expressed in many cancers and amyotrophic lateral sclerosis. We present the immature HERV-K capsid structure at 3.2 Å resolution determined from native virus-like particles using cryo-electron tomography and subtomogram averaging. The structure shows a hexamer unit oligomerized through a 6-helix bundle, which is stabilized by a small molecule analogous to IP6 in immature HIV-1 capsid. The HERV-K immature lattice is assembled via highly conserved dimer and trimer interfaces, as detailed through all-atom molecular dynamics simulations and supported by mutational studies. A large conformational change mediated by the linker between the N-terminal and the C-terminal domains of CA occurs during HERV-K maturation. Comparison between HERV-K and other retroviral immature capsid structures reveals a highly conserved mechanism for the assembly and maturation of retroviruses across genera and evolutionary time.}, } @article {pmid37620293, year = {2023}, author = {Kuiper, EFE and Prophet, SM and Schlieker, C}, title = {Coordinating nucleoporin condensation and nuclear pore complex assembly.}, journal = {FEBS letters}, volume = {597}, number = {20}, pages = {2534-2545}, doi = {10.1002/1873-3468.14725}, pmid = {37620293}, issn = {1873-3468}, support = {//Dystonia Medical Research Foundation/ ; ALTF 910-2022//European Molecular Biology Organization/ ; 019.222EN.007//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; PR200788//U.S. Department of Defense/ ; }, abstract = {The nuclear pore complex (NPC) is among the most elaborate protein complexes in eukaryotes. While ribosomes and proteasomes are known to require dedicated assembly machinery, our understanding of NPC assembly is at a relatively early stage. Defects in NPC assembly or homeostasis are tied to movement disorders, including dystonia and amyotrophic lateral sclerosis (ALS), as well as aging, requiring a better understanding of these processes to enable therapeutic intervention. Here, we discuss recent progress in the understanding of NPC assembly and highlight how related defects in human disorders can shed light on NPC biogenesis. We propose that the condensation of phenylalanine-glycine repeat nucleoporins needs to be carefully controlled during NPC assembly to prevent aberrant condensation, aggregation, or amyloid formation.}, } @article {pmid37620092, year = {2023}, author = {Fink, JK}, title = {The hereditary spastic paraplegias.}, journal = {Handbook of clinical neurology}, volume = {196}, number = {}, pages = {59-88}, doi = {10.1016/B978-0-323-98817-9.00022-3}, pmid = {37620092}, issn = {0072-9752}, mesh = {Child, Preschool ; Humans ; *Spastic Paraplegia, Hereditary/genetics ; Biological Transport ; *Cerebral Palsy ; Exercise ; Family ; }, abstract = {The hereditary spastic paraplegias (HSPs) are a group of more than 90 genetic disorders in which lower extremity spasticity and weakness are either the primary neurologic impairments ("uncomplicated HSP") or when accompanied by other neurologic deficits ("complicated HSP"), important features of the clinical syndrome. Various genetic types of HSP are inherited such as autosomal dominant, autosomal recessive, X-linked, and maternal (mitochondrial) traits. Symptoms that begin in early childhood may be nonprogressive and resemble spastic diplegic cerebral palsy. Symptoms that begin later, typically progress insidiously over a number of years. Genetic testing is able to confirm the diagnosis for many subjects. Insights from gene discovery indicate that abnormalities in diverse molecular processes underlie various forms of HSP, including disturbance in axon transport, endoplasmic reticulum morphogenesis, vesicle transport, lipid metabolism, and mitochondrial function. Pathologic studies in "uncomplicated" HSP have shown axon degeneration particularly involving the distal ends of corticospinal tracts and dorsal column fibers. Treatment is limited to symptom reduction including amelioration of spasticity, reducing urinary urgency, proactive physical therapy including strengthening, stretching, balance, and agility exercise.}, } @article {pmid37620088, year = {2023}, author = {Muzio, L and Ghirelli, A and Agosta, F and Martino, G}, title = {Novel therapeutic approaches for motor neuron disease.}, journal = {Handbook of clinical neurology}, volume = {196}, number = {}, pages = {523-537}, doi = {10.1016/B978-0-323-98817-9.00027-2}, pmid = {37620088}, issn = {0072-9752}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases ; *Motor Neuron Disease/therapy ; *Amyotrophic Lateral Sclerosis/therapy ; Motor Neurons ; Cognition ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to the neurodegeneration and death of upper and lower motor neurons (MNs). Although MNs are the main cells involved in the process of neurodegeneration, a growing body of evidence points toward other cell types as concurrent to disease initiation and propagation. Given the current absence of effective therapies, the quest for other therapeutic targets remains open and still challenges the scientific community. Both neuronal and extra-neuronal mechanisms of cellular stress and damage have been studied and have posed the basis for the development of novel therapies that have been investigated on both animal models and humans. In this chapter, a thorough review of the main mechanisms of cellular damage and the respective therapeutic attempts targeting them is reported. The main areas covered include neuroinflammation, protein aggregation, RNA metabolism, and oxidative stress.}, } @article {pmid37620070, year = {2023}, author = {Younger, DS and Brown, RH}, title = {Amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {196}, number = {}, pages = {203-229}, doi = {10.1016/B978-0-323-98817-9.00031-4}, pmid = {37620070}, issn = {0072-9752}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Motor Neurons ; Syndrome ; }, abstract = {The scientific landscape surrounding amyotrophic lateral sclerosis has shifted immensely with a number of well-defined ALS disease-causing genes, each with related phenotypical and cellular motor neuron processes that have come to light. Yet in spite of decades of research and clinical investigation, there is still no etiology for sporadic amyotrophic lateral sclerosis, and treatment options even for those with well-defined familial syndromes are still limited. This chapter provides a comprehensive review of the genetic basis of amyotrophic lateral sclerosis, highlighting factors that contribute to its heritability and phenotypic manifestations, and an overview of past, present, and upcoming therapeutic strategies.}, } @article {pmid37619957, year = {2023}, author = {Chaves-Filho, AB and Diniz, LS and Santos, RS and Lima, RS and Oreliana, H and Pinto, IFD and Dantas, LS and Inague, A and Faria, RL and Medeiros, MHG and Glezer, I and Festuccia, WT and Yoshinaga, MY and Miyamoto, S}, title = {Plasma oxylipin profiling by high resolution mass spectrometry reveal signatures of inflammation and hypermetabolism in amyotrophic lateral sclerosis.}, journal = {Free radical biology & medicine}, volume = {208}, number = {}, pages = {285-298}, doi = {10.1016/j.freeradbiomed.2023.08.019}, pmid = {37619957}, issn = {1873-4596}, mesh = {Rats ; Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Oxylipins ; *Neurodegenerative Diseases ; Mass Spectrometry ; Superoxide Dismutase-1/genetics/metabolism ; Inflammation ; Disease Models, Animal ; Mice, Transgenic ; Superoxide Dismutase/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons, systemic hypermetabolism, and inflammation. In this context, oxylipins have been investigated as signaling molecules linked to neurodegeneration, although their specific role in ALS remains unclear. Importantly, most methods focused on oxylipin analysis are based on low-resolution mass spectrometry, which usually confers high sensitivity, but not great accuracy for molecular characterization, as provided by high-resolution MS (HRMS). Here, we established an ultra-high performance liquid chromatography HRMS (LC-HRMS) method for simultaneous analysis of 126 oxylipins in plasma. Intra- and inter-day method validation showed high sensitivity (0.3-25 pg), accuracy and precision for more than 90% of quality controls. This method was applied in plasma of ALS rats overexpressing the mutant human Cu/Zn-superoxide dismutase gene (SOD1-G93A) at asymptomatic (ALS 70 days old) and symptomatic stages (ALS 120 days old), and their respective age-matched wild type controls. From the 56 oxylipins identified in plasma, 17 species were significantly altered. Remarkably, most of oxylipins linked to inflammation and oxidative stress derived from arachidonic acid (AA), like prostaglandins and mono-hydroxides, were increased in ALS 120 d rats. In addition, ketones derived from AA and linoleic acid (LA) were increased in both WT 120 d and ALS 120 d groups, supporting that age also modulates oxylipin metabolism in plasma. Interestingly, the LA-derived diols involved in fatty acid uptake and β-oxidation, 9(10)-DiHOME and 12(13)-DiHOME, were decreased in ALS 120 d rats and showed significant synergic effects between age and disease factors. In summary, we validated a high-throughput LC-HRMS method for oxylipin analysis and provided a comprehensive overview of plasma oxylipins involved in ALS disease progression. Noteworthy, the oxylipins altered in plasma have potential to be investigated as biomarkers for inflammation and hypermetabolism in ALS.}, } @article {pmid37619619, year = {2023}, author = {Wang, Y and Lv, MN and Zhao, WJ}, title = {Research on ferroptosis as a therapeutic target for the treatment of neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {91}, number = {}, pages = {102035}, doi = {10.1016/j.arr.2023.102035}, pmid = {37619619}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Ferroptosis ; *Alzheimer Disease/drug therapy ; *Parkinson Disease/drug therapy ; *Huntington Disease ; }, abstract = {Ferroptosis is an iron- and lipid peroxidation (LPO)-mediated programmed cell death type. Recently, mounting evidence has indicated the involvement of ferroptosis in neurodegenerative diseases, especially in Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and so on. Treating ferroptosis presents opportunities as well as challenges for neurodegenerative diseases. This review provides a comprehensive overview of typical features of ferroptosis and the underlying mechanisms that contribute to its occurrence, as well as their implications in the pathogenesis and advancement of major neurodegenerative disorders. Meanwhile, we summarize the utilization of ferroptosis inhibition in both experimental and clinical approaches for the treatment of major neurodegenerative disorders. In addition, we specifically summarize recent advances in developing therapeutic means targeting ferroptosis in these diseases, which may guide future approaches for the effective management of these devastating medical conditions.}, } @article {pmid37619554, year = {2023}, author = {Cheesbrough, A and Harley, P and Riccio, F and Wu, L and Song, W and Lieberam, I}, title = {A scalable human iPSC-based neuromuscular disease model on suspended biobased elastomer nanofiber scaffolds.}, journal = {Biofabrication}, volume = {15}, number = {4}, pages = {}, pmid = {37619554}, issn = {1758-5090}, support = {/DH_/Department of Health/United Kingdom ; MR/W006251/1/MRC_/Medical Research Council/United Kingdom ; MR/N026063/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; BB/M009513/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MR/N025865/1/MRC_/Medical Research Council/United Kingdom ; 108874/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; WT098503/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Induced Pluripotent Stem Cells ; *Nanofibers ; Elastomers ; *Neuromuscular Diseases ; }, abstract = {Many devastating neuromuscular diseases currently lack effective treatments. This is in part due to a lack of drug discovery platforms capable of assessing complex human neuromuscular disease phenotypes in a scalable manner. A major obstacle has been generating scaffolds to stabilise mature contractile myofibers in a multi-well assay format amenable to high content image (HCI) analysis. This study describes the development of a scalable human induced pluripotent stem cell (iPSC)-neuromuscular disease model, whereby suspended elastomer nanofibers support long-term stability, alignment, maturation, and repeated contractions of iPSC-myofibers, innervated by iPSC-motor neurons in 96-well assay plates. In this platform, optogenetic stimulation of the motor neurons elicits robust myofiber-contractions, providing a functional readout of neuromuscular transmission. Additionally, HCI analysis provides rapid and automated quantification of axonal outgrowth, myofiber morphology, and neuromuscular synapse number and morphology. By incorporating amyotrophic lateral sclerosis (ALS)-related TDP-43[G298S]mutant motor neurons and CRISPR-corrected controls, key neuromuscular disease phenotypes are recapitulated, including weaker myofiber contractions, reduced axonal outgrowth, and reduced number of neuromuscular synapses. Treatment with a candidate ALS drug, the receptor-interacting protein kinase-1 (RIPK1)-inhibitor necrostatin-1, rescues these phenotypes in a dose-dependent manner, highlighting the potential of this platform to screen novel treatments for neuromuscular diseases.}, } @article {pmid37615876, year = {2023}, author = {Kobayashi, H and Ueda, K and Morimoto, S and Ishikawa, M and Leventoux, N and Sasaki, R and Hirokawa, Y and Kokubo, Y and Okano, H}, title = {Protein profiling of extracellular vesicles from iPSC-derived astrocytes of patients with ALS/PDC in Kii peninsula.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {12}, pages = {4511-4516}, pmid = {37615876}, issn = {1590-3478}, support = {JP15J03921//Japan Society for the Promotion of Science/ ; JP18K07368//Japan Society for the Promotion of Science/ ; JP18KK0239//Japan Society for the Promotion of Science/ ; JP19K17002//Japan Society for the Promotion of Science/ ; JP19K08002//Japan Society for the Promotion of Science/ ; JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP25305030//Japan Society for the Promotion of Science/ ; JP15K09364//Japan Society for the Promotion of Science/ ; JP17H01689//Japan Society for the Promotion of Science/ ; JP18K07514//Japan Society for the Promotion of Science/ ; JP20H00485//Japan Society for the Promotion of Science/ ; JP21F21410//Japan Society for the Promotion of Science/ ; JP21H05273//Japan Society for the Promotion of Science/ ; JP22KF0333//Japan Society for the Promotion of Science/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; 17ek0109139h0003//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP20ek0109395//Japan Agency for Medical Research and Development/ ; JP20ek0109329//Japan Agency for Medical Research and Development/ ; JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; 21210301//Ministry of Health, Labour and Welfare/ ; H29-Nanchi- Ippan-085//Ministry of Health, Labour and Welfare/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Induced Pluripotent Stem Cells/metabolism/pathology ; *Neurodegenerative Diseases ; Astrocytes/pathology ; Proteome ; Japan/epidemiology ; *Extracellular Vesicles/metabolism/pathology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis/Parkinsonism-dementia complex in Kii peninsula, Japan (Kii ALS/PDC), is an endemic neurodegenerative disease whose causes and pathogenesis remain unknown. However, astrocytes in autopsied cases of Kii ALS/PDC show characteristic lesions. In addition, relationships between extracellular vesicles (EVs) and neurodegenerative diseases are increasingly apparent. Therefore, we focused on proteins in EVs derived from Kii ALS/PDC astrocytes in the present study.

METHODS: Induced pluripotent stem cells (iPSCs) derived from three healthy controls (HCs) and three patients with Kii ALS/PDC were differentiated into astrocytes. EVs in the culture medium of astrocytes were collected and subjected to quantitative proteome analysis.

RESULTS: Our proteome analysis reveals that EV-containing proteins derived from astrocytes of patients with Kii ALS/PDC show distinctive patterns compared with those of HCs. Moreover, EVs derived from Kii ALS/PDC astrocytes display increased proteins related to proteostasis and decreased proteins related to anti-inflammation.

DISCUSSION: Proteins contained in EVs from astrocytes unveil protective support to neurons and may reflect the molecular pathomechanism of Kii ALS/PDC; accordingly, they may be potential biomarker candidates of Kii ALS/PDC.}, } @article {pmid37615751, year = {2023}, author = {Ortholand, J and Pradat, PF and Tezenas du Montcel, S and Durrleman, S}, title = {Interaction of sex and onset site on the disease trajectory of amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {270}, number = {12}, pages = {5903-5912}, pmid = {37615751}, issn = {1432-1459}, support = {826421 (TVB-Cloud)//H2020 program/ ; ANR-10-IAIHU-06 (IHU ICM)//Agence Nationale de la Recherche/ ; ANR-19-P3IA-0001 (PRAIRIE 3IA Institute)//Agence Nationale de la Recherche/ ; ANR-19-JPW2-000 (E- DADS)//Agence Nationale de la Recherche/ ; }, mesh = {Male ; Humans ; Female ; *Amyotrophic Lateral Sclerosis ; Cross-Sectional Studies ; Disease Progression ; Survival Analysis ; Body Mass Index ; }, abstract = {BACKGROUND: Studies showed the impact of sex and onset site (spinal or bulbar) on disease onset and survival in ALS. However, they mainly result from cross-sectional or survival analysis, and the interaction of sex and onset site on the different proxies of disease trajectory has not been fully investigated.

METHODS: We selected all patients with repeated observations in the PRO-ACT database. We divided them into four groups depending on their sex and onset site. We estimated a multivariate disease progression model, named ALS Course Map, to investigate the combined temporal changes of the four sub-scores of the revised ALS functional rating scale (ALSFRSr), the forced vital capacity (FVC), and the body mass index (BMI). We then compared the progression rate, the estimated age at onset, and the relative progression of the outcomes across each group.

RESULTS: We included 1438 patients from the PRO-ACT database. They were 51% men with spinal onset, 12% men with bulbar onset, 26% women with spinal onset, and 11% women with bulbar onset. We showed a significant influence of both sex and onset site on the ALSFRSr progression. The BMI decreased 8.9 months earlier (95% CI [3.9, 13.8]) in women than men, after correction for the onset site. Among patients with bulbar onset, FVC was impaired 2.6 months earlier (95% CI [0.6, 4.6]) in women.

CONCLUSION: Using a multivariable disease modelling approach, we showed that sex and onset site are important drivers of the progression of motor function, BMI, and FVC decline.}, } @article {pmid37615238, year = {2023}, author = {Merriam, AB and Malone, JM and Hereward, JP and Gill, G and Preston, C}, title = {Point mutations including a novel Pro-197-Phe mutation confer cross-resistance to acetolactate synthase (ALS) inhibiting herbicides in Lactuca serriola in Australia.}, journal = {Pest management science}, volume = {79}, number = {12}, pages = {5333-5340}, doi = {10.1002/ps.7743}, pmid = {37615238}, issn = {1526-4998}, support = {//Grains Research and Development Corporation/ ; //Australian Government Research Training Program Scholarship/ ; }, mesh = {Humans ; Point Mutation ; *Acetolactate Synthase/genetics/metabolism ; *Herbicides/pharmacology ; Mutation ; Herbicide Resistance/genetics ; Phenylalanine/genetics ; Australia ; Proline/genetics ; Plant Proteins/genetics/metabolism ; }, abstract = {BACKGROUND: Control of prickly lettuce has become increasingly difficult for lentil growers in southern Australia because of widespread resistance to common herbicides, a lack of alternative herbicide options and the prolific production of highly mobile seed. This study aimed to quantify acetolactate synthase (ALS)-inhibiting herbicide resistance in the Mid North (MN) and Yorke Peninsula (YP) of South Australia, characterize the resistance mutations present and investigate population structure and gene flow in this species.

RESULTS: Resistance was identified in all populations tested, with average survival of 92% to chlorsulfuron and 95% to imazamox + imazapyr. Five different amino acid substitutions were identified at proline 197 of the ALS gene. There was no significant difference in the median lethal dose (LD50) between plants with these five different substitutions when treated with metsulfuron-methyl; however, the imidazolinone resistance level was higher in plants with a phenylalanine substitution and lower in plants with a serine. Population structure based on 701 single nucleotide polymorphisms and 271 individuals provided evidence for both independent evolution of the same mutation in different populations, as well as frequent short- to medium-distance dispersal accompanied by occasional long-distance dispersal events. The overall inbreeding coefficient (FIS) was calculated at 0.5174, indicating an intermediate level of outcrossing despite the cross-pollination experiment showing only low outcrossing. In the structure analyses, most individuals from YP were assigned to a single cluster, whereas most individuals from MN were assigned 50% to each of two clusters, indicating some genetic differences between these two regions, but also evidence for dispersal between them.

CONCLUSIONS: Use of imidazolinone herbicides has selected for mutations conferring higher levels of resistance, such as the Pro-197-Phe mutation, and resulted in further spread of resistance in this species. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid37614471, year = {2023}, author = {Bhattacharya, MRC}, title = {A nerve-wracking buzz: lessons from Drosophila models of peripheral neuropathy and axon degeneration.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1166146}, pmid = {37614471}, issn = {1663-4365}, support = {R01 NS105680/NS/NINDS NIH HHS/United States ; }, abstract = {The degeneration of axons and their terminals occurs following traumatic, toxic, or genetically-induced insults. Common molecular mechanisms unite these disparate triggers to execute a conserved nerve degeneration cascade. In this review, we will discuss how models of peripheral nerve injury and neuropathy in Drosophila have led the way in advancing molecular understanding of axon degeneration and nerve injury pathways. Both neuron-intrinsic as well as glial responses to injury will be highlighted. Finally, we will offer perspective on what additional questions should be answered to advance these discoveries toward clinical interventions for patients with neuropathy.}, } @article {pmid37614251, year = {2023}, author = {Hussein, S and Pingili, S and Makkena, VK and Jaramillo, AP and Awosusi, BL and Ayyub, J and Dabhi, KN and Gohil, NV and Tanveer, N and Hamid, P}, title = {The Impact of Serum Uric Acid on the Progression of Amyotrophic Lateral Sclerosis in Adults Aged 18 and Older: A Systematic Review.}, journal = {Cureus}, volume = {15}, number = {7}, pages = {e42312}, pmid = {37614251}, issn = {2168-8184}, abstract = {We have conducted this review to see if serum uric acid (UA) is associated with slowing amyotrophic lateral sclerosis (ALS) progression in adult patients who are at least 18 years old. Understanding the effects of this biomarker for future use is critical because of its easy accessibility. This systematic review paper examined five previous years of recent studies and reports, published in English and limited to human investigations from the Cochrane, PubMed, and Google Scholar databases. Using instruments for assessing the eligibility and quality of systematic and narrative reviews, we narrowed our search to 11 reports that show evidence of a positive association between high blood uric acid and the progression of ALS. However, this claim still needs confirmation by future studies to confirm that possibility. The results of this systematic review may provide a strong foundation for future studies on this biomarker, demonstrating the significance of blood uric acid levels in ALS and highlighting the necessity of using that biomarker to track the disease's progression.}, } @article {pmid37614226, year = {2023}, author = {Pickles, S and Zanetti Alepuz, D and Koike, Y and Yue, M and Tong, J and Liu, P and Zhou, Y and Jansen-West, K and Daughrity, LM and Song, Y and DeTure, M and Oskarsson, B and Graff-Radford, NR and Boeve, BF and Petersen, RC and Josephs, KA and Dickson, DW and Ward, ME and Dong, L and Prudencio, M and Cook, CN and Petrucelli, L}, title = {CRISPR interference to evaluate modifiers of C9ORF72-mediated toxicity in FTD.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1251551}, pmid = {37614226}, issn = {2296-634X}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; R01 AG065219/AG/NIA NIH HHS/United States ; R01 AG063780/AG/NIA NIH HHS/United States ; RF1 AG062077/AG/NIA NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R01 AG037491/AG/NIA NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; RF1 NS120992/NS/NINDS NIH HHS/United States ; }, abstract = {Treatments for neurodegenerative disease, including Frontotemporal dementia (FTD) and Amyotrophic lateral sclerosis (ALS), remain rather limited, underscoring the need for greater mechanistic insight and disease-relevant models. Our ability to develop novel disease models of genetic risk factors, disease modifiers, and other FTD/ALS-relevant targets is impeded by the significant amount of time and capital required to develop conventional knockout and transgenic mice. To overcome these limitations, we have generated a novel CRISPRi interference (CRISPRi) knockin mouse. CRISPRi uses a catalytically dead form of Cas9, fused to a transcriptional repressor to knockdown protein expression, following the introduction of single guide RNA against the gene of interest. To validate the utility of this model we have selected the TAR DNA binding protein (TDP-43) splicing target, stathmin-2 (STMN2). STMN2 RNA is downregulated in FTD/ALS due to loss of TDP-43 activity and STMN2 loss is suggested to play a role in ALS pathogenesis. The involvement of STMN2 loss of function in FTD has yet to be determined. We find that STMN2 protein levels in familial FTD cases are significantly reduced compared to controls, supporting that STMN2 depletion may be involved in the pathogenesis of FTD. Here, we provide proof-of-concept that we can simultaneously knock down Stmn2 and express the expanded repeat in the Chromosome 9 open reading frame 72 (C9ORF72) gene, successfully replicating features of C9-associated pathology. Of interest, depletion of Stmn2 had no effect on expression or deposition of dipeptide repeat proteins (DPRs), but significantly decreased the number of phosphorylated Tdp-43 (pTdp-43) inclusions. We submit that our novel CRISPRi mouse provides a versatile and rapid method to silence gene expression in vivo and propose this model will be useful to understand gene function in isolation or in the context of other neurodegenerative disease models.}, } @article {pmid37614106, year = {2023}, author = {Golini, E and Marinelli, S and Pisu, S and De Angelis, F and Vacca, V and Rava, A and Casola, I and Laurenzi, G and Rizzuto, E and Giuliani, A and Musarò, A and Dobrowolny, G and Mandillo, S}, title = {Wheel Running Adversely Affects Disease Onset and Neuromuscular Interplay in Amyotrophic Lateral Sclerosis Slow Progression Mouse Model.}, journal = {Current neurovascular research}, volume = {20}, number = {3}, pages = {362-376}, doi = {10.2174/1567202620666230823095922}, pmid = {37614106}, issn = {1875-5739}, mesh = {Male ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis ; Motor Activity ; Disease Models, Animal ; Disease Progression ; }, abstract = {BACKGROUND: Physical activity in Amyotrophic Lateral Sclerosis (ALS) plays a controversial role. In some epidemiological studies, both recreational or professional sport exercise has been associated to an increased risk for ALS but the mechanisms underlying the effects of exercise have not been fully elucidated in either patients or animal models.

METHODS: To better reproduce the influence of this environmental factor in the pathogenesis of ALS, we exposed SOD1[G93A] low-copy male mice to multiple exercise sessions at asymptomatic and pre-symptomatic disease stages in an automated home-cage running-wheel system for about 3 months.

RESULTS: Repeated voluntary running negatively influenced disease progression by anticipating disease onset, impairing neuromuscular transmission, worsening neuromuscular decline, and exacerbating muscle atrophy. Muscle fibers and neuromuscular junctions (NMJ) as well as key molecular players of the nerve-muscle circuit were similarly affected.

CONCLUSION: It thus appears that excessive physical activity can be detrimental in predisposed individuals and these findings could model the increased risk of developing ALS in predisposed and specific professional athletes.}, } @article {pmid37614052, year = {2023}, author = {Oleinik, N and Albayram, O and Kassir, MF and Atilgan, FC and Walton, C and Karakaya, E and Kurtz, J and Alekseyenko, A and Alsudani, H and Sheridan, M and Szulc, ZM and Ogretmen, B}, title = {Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects.}, journal = {Aging cell}, volume = {22}, number = {10}, pages = {e13954}, pmid = {37614052}, issn = {1474-9726}, support = {I01 BX002466/BX/BLRD VA/United States ; R01 DE016572/DE/NIDCR NIH HHS/United States ; P20 GM148302/GM/NIGMS NIH HHS/United States ; CA203628/CA/NCI NIH HHS/United States ; R56 AG069769/AG/NIA NIH HHS/United States ; R01 CA214461/CA/NCI NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Mitophagy ; *Malates ; Ceramides/metabolism ; Motor Neurons/metabolism ; Fumarates ; Ubiquitin-Protein Ligases ; }, abstract = {The metabolic consequences of mitophagy alterations due to age-related stress in healthy aging brains versus neurodegeneration remain unknown. Here, we demonstrate that ceramide synthase 1 (CerS1) is transported to the outer mitochondrial membrane by the p17/PERMIT transporter that recognizes mislocalized mitochondrial ribosomes (mitoribosomes) via 39-FLRN-42 residues, inducing ceramide-mediated mitophagy. P17/PERMIT-CerS1-mediated mitophagy attenuated the argininosuccinate/fumarate/malate axis and induced d-glucose and fructose accumulation in neurons in culture and brain tissues (primarily in the cerebellum) of wild-type mice in vivo. These metabolic changes in response to sodium-selenite were nullified in the cerebellum of CerS1to/to (catalytically inactive for C18-ceramide production CerS1 mutant), PARKIN-/- or p17/PERMIT-/- mice that have dysfunctional mitophagy. Whereas sodium selenite induced mitophagy in the cerebellum and improved motor-neuron deficits in aged wild-type mice, exogenous fumarate or malate prevented mitophagy. Attenuating ceramide-mediated mitophagy enhanced damaged mitochondria accumulation and age-dependent sensorimotor abnormalities in p17/PERMIT-/- mice. Reinstituting mitophagy using a ceramide analog drug with selenium conjugate, LCL768, restored mitophagy and reduced malate/fumarate metabolism, improving sensorimotor deficits in old p17/PERMIT-/- mice. Thus, these data describe the metabolic consequences of alterations to p17/PERMIT/ceramide-mediated mitophagy associated with the loss of mitochondrial quality control in neurons and provide therapeutic options to overcome age-dependent sensorimotor deficits and related disorders like amyotrophic lateral sclerosis (ALS).}, } @article {pmid37614020, year = {2024}, author = {Rotshild, V and Matok, I}, title = {Authors Reply to Comment on Rotshild et al's "The Risk for Prostate Cancer With Calcium Channel Blockers".}, journal = {The Annals of pharmacotherapy}, volume = {58}, number = {4}, pages = {443}, doi = {10.1177/10600280231185784}, pmid = {37614020}, issn = {1542-6270}, mesh = {Male ; Humans ; *Calcium Channel Blockers/adverse effects ; *Prostatic Neoplasms/drug therapy ; }, } @article {pmid37614019, year = {2024}, author = {Liao, KF and Hwang, BF and Liu, CS and Lai, SW}, title = {Comment on Rotshild et al's "The Risk for Prostate Cancer With Calcium Channel Blockers".}, journal = {The Annals of pharmacotherapy}, volume = {58}, number = {4}, pages = {441-442}, doi = {10.1177/10600280231185781}, pmid = {37614019}, issn = {1542-6270}, mesh = {Male ; Humans ; *Calcium Channel Blockers/adverse effects ; *Prostatic Neoplasms/drug therapy ; }, } @article {pmid37612833, year = {2023}, author = {Choi, SJ and Yoon, SH and Sung, JJ and Lee, JH}, title = {Association Between Fat Depletion and Prognosis of Amyotrophic Lateral Sclerosis: CT-Based Body Composition Analysis.}, journal = {Annals of neurology}, volume = {94}, number = {6}, pages = {1116-1125}, doi = {10.1002/ana.26775}, pmid = {37612833}, issn = {1531-8249}, support = {04-2021-2280//Seoul National University Hospital Research Fund/ ; }, mesh = {Male ; Female ; Humans ; Child, Preschool ; *Sarcopenia/diagnostic imaging/complications ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging/pathology ; Retrospective Studies ; Creatinine ; Prognosis ; Muscle, Skeletal/pathology ; Body Composition ; Tomography, X-Ray Computed ; }, abstract = {OBJECTIVE: The purpose of this study was to present the results of our investigation of the prognostic value of adipopenia and sarcopenia in patients with amyotrophic lateral sclerosis (ALS).

METHODS: Consecutive patients with ALS with abdominal computed tomography (CT) were retrospectively identified at a single tertiary hospital between January 2010 and July 2021. Deep learning-based volumetric CT body composition analysis software was used to obtain abdominal waist fat volume, fat attenuation, and skeletal muscle area at the L3 level, then normalized to the fat volume index (FVI) and skeletal muscle index (SMI). Adipopenia and sarcopenia were defined as the sex-specific lowest quartile and SMI reference values, respectively. The associations of CT-derived body composition parameters with clinical variables, such as body mass index (BMI) and creatinine, were evaluated by Pearson correlation analyses, and associations with survival were assessed using the multivariable Cox regression analysis.

RESULTS: Eighty subjects (40 men, 65.5 ± 9.4 years of age) were investigated (median interval between disease onset and CT examination = 25 months). The mean BMI at the CT examination was 20.3 ± 4.3 kg/m[2] . The BMI showed a positive correlation with both FVI (R = 0.70, p < 0.001) and SMI (R = 0.63, p < 0.001), and the serum creatinine level was associated with SMI (R = 0.68, p < 0.001). After adjusting for sex, age, King's stage, BMI, creatinine, progression rate, and sarcopenia, adipopenia was associated with shorter survival (hazard ratio [HR] = 5.94, 95% confidence interval [CI] = 1.01, 35.0, p = 0.049). In a subgroup analysis for subjects with nutritional failure (stage 4a), the HR of adipopenia was 15.1 (95% CI = 2.45, 93.4, p = 0.003).

INTERPRETATION: Deep learning-based CT-derived adipopenia in patients with ALS is an independent poor prognostic factor for survival. ANN NEUROL 2023;94:1116-1125.}, } @article {pmid37612500, year = {2023}, author = {Willett, FR and Kunz, EM and Fan, C and Avansino, DT and Wilson, GH and Choi, EY and Kamdar, F and Glasser, MF and Hochberg, LR and Druckmann, S and Shenoy, KV and Henderson, JM}, title = {A high-performance speech neuroprosthesis.}, journal = {Nature}, volume = {620}, number = {7976}, pages = {1031-1036}, pmid = {37612500}, issn = {1476-4687}, support = {R01 MH060974/MH/NIMH NIH HHS/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; U01 DC019430/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation ; *Brain-Computer Interfaces ; Cerebral Cortex/physiology ; Microelectrodes ; *Paralysis/physiopathology/rehabilitation ; *Speech ; Vocabulary ; *Neural Prostheses ; }, abstract = {Speech brain-computer interfaces (BCIs) have the potential to restore rapid communication to people with paralysis by decoding neural activity evoked by attempted speech into text[1,2] or sound[3,4]. Early demonstrations, although promising, have not yet achieved accuracies sufficiently high for communication of unconstrained sentences from a large vocabulary[1-7]. Here we demonstrate a speech-to-text BCI that records spiking activity from intracortical microelectrode arrays. Enabled by these high-resolution recordings, our study participant-who can no longer speak intelligibly owing to amyotrophic lateral sclerosis-achieved a 9.1% word error rate on a 50-word vocabulary (2.7 times fewer errors than the previous state-of-the-art speech BCI[2]) and a 23.8% word error rate on a 125,000-word vocabulary (the first successful demonstration, to our knowledge, of large-vocabulary decoding). Our participant's attempted speech was decoded at 62 words per minute, which is 3.4 times as fast as the previous record[8] and begins to approach the speed of natural conversation (160 words per minute[9]). Finally, we highlight two aspects of the neural code for speech that are encouraging for speech BCIs: spatially intermixed tuning to speech articulators that makes accurate decoding possible from only a small region of cortex, and a detailed articulatory representation of phonemes that persists years after paralysis. These results show a feasible path forward for restoring rapid communication to people with paralysis who can no longer speak.}, } @article {pmid37612427, year = {2023}, author = {Cheng, J and Ho, WK and Wu, BT and Liu, HP and Lin, WY}, title = {miRNA profiling as a complementary diagnostic tool for amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {13805}, pmid = {37612427}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; *MicroRNAs/analysis/genetics ; Gene Expression Profiling ; Machine Learning ; }, abstract = {Amyotrophic lateral sclerosis (ALS), the most prevalent motor neuron disease characterized by its complex genetic structure, lacks a single diagnostic test capable of providing a conclusive diagnosis. In order to demonstrate the potential for genetic diagnosis and shed light on the pathogenic role of miRNAs in ALS, we developed an ALS diagnostic rule by training the model using 80% of a miRNA profiling dataset consisting of 253 ALS samples and 103 control samples. Subsequently, we validated the diagnostic rule using the remaining 20% of unseen samples. The diagnostic rule we developed includes miR-205-5p, miR-206, miR-376a-5p, miR-412-5p, miR-3927-3p, miR-4701-3p, miR-6763-5p, and miR-6801-3p. Remarkably, the rule achieved an 82% true positive rate and a 73% true negative rate when predicting the unseen samples. Furthermore, the identified miRNAs target 21 genes in the PI3K-Akt pathway and 27 genes in the ALS pathway, including notable genes such as BCL2, NEFH, and OPTN. We propose that miRNA profiling may serve as a complementary diagnostic tool to supplement the clinical presentation and aid in the early recognition of ALS.}, } @article {pmid37612295, year = {2023}, author = {Kokalj, Ž and Džeroski, S and Šprajc, I and Štajdohar, J and Draksler, A and Somrak, M}, title = {Machine learning-ready remote sensing data for Maya archaeology.}, journal = {Scientific data}, volume = {10}, number = {1}, pages = {558}, pmid = {37612295}, issn = {2052-4463}, support = {4000130508/20/I-NB//European Space Agency (ESA)/ ; P2-0406//Javna Agencija za Raziskovalno Dejavnost RS (Slovenian Research Agency)/ ; J6-7085//Javna Agencija za Raziskovalno Dejavnost RS (Slovenian Research Agency)/ ; P6-0079//Javna Agencija za Raziskovalno Dejavnost RS (Slovenian Research Agency)/ ; J6-7085//Javna Agencija za Raziskovalno Dejavnost RS (Slovenian Research Agency)/ ; J6-7085//Javna Agencija za Raziskovalno Dejavnost RS (Slovenian Research Agency)/ ; J6-7085//Javna Agencija za Raziskovalno Dejavnost RS (Slovenian Research Agency)/ ; P2-0406//Javna Agencija za Raziskovalno Dejavnost RS (Slovenian Research Agency)/ ; }, abstract = {In our study, we set out to collect a multimodal annotated dataset for remote sensing of Maya archaeology, that is suitable for deep learning. The dataset covers the area around Chactún, one of the largest ancient Maya urban centres in the central Yucatán Peninsula. The dataset includes five types of data records: raster visualisations and canopy height model from airborne laser scanning (ALS) data, Sentinel-1 and Sentinel-2 satellite data, and manual data annotations. The manual annotations (used as binary masks) represent three different types of ancient Maya structures (class labels: buildings, platforms, and aguadas - artificial reservoirs) within the study area, their exact locations, and boundaries. The dataset is ready for use with machine learning, including convolutional neural networks (CNNs) for object recognition, object localization (detection), and semantic segmentation. We would like to provide this dataset to help more research teams develop their own computer vision models for investigations of Maya archaeology or improve existing ones.}, } @article {pmid37611905, year = {2024}, author = {Huang, Q and Wang, Y and Chen, S and Liang, F}, title = {Glycometabolic Reprogramming of Microglia in Neurodegenerative Diseases: Insights from Neuroinflammation.}, journal = {Aging and disease}, volume = {15}, number = {3}, pages = {1155-1175}, pmid = {37611905}, issn = {2152-5250}, mesh = {*Microglia/metabolism ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Glucose/metabolism ; Neuroinflammatory Diseases/metabolism/immunology ; Animals ; }, abstract = {Neurodegenerative diseases (ND) are conditions defined by progressive deterioration of the structure and function of the nervous system. Some major examples include Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). These diseases lead to various dysfunctions, like impaired cognition, memory, and movement. Chronic neuroinflammation may underlie numerous neurodegenerative disorders. Microglia, an important immunocell in the brain, plays a vital role in defending against neuroinflammation. When exposed to different stimuli, microglia are activated and assume different phenotypes, participating in immune regulation of the nervous system and maintaining tissue homeostasis. The immunological activity of activated microglia is affected by glucose metabolic alterations. However, in the context of chronic neuroinflammation, specific alterations of microglial glucose metabolism and their mechanisms of action remain unclear. Thus, in this paper, we review the glycometabolic reprogramming of microglia in ND. The key molecular targets and main metabolic pathways are the focus of this research. Additionally, this study explores the mechanisms underlying microglial glucose metabolism reprogramming in ND and offers an analysis of the most recent therapeutic advancements. The ultimate aim is to provide insights into the development of potential treatments for ND.}, } @article {pmid37611832, year = {2023}, author = {González-Torralva, F and Norsworthy, JK}, title = {Quizalofop resistance in weedy rice (Oryza sativa L.) is mainly conferred by an Ile1781Leu mutation.}, journal = {Plant science : an international journal of experimental plant biology}, volume = {336}, number = {}, pages = {111838}, doi = {10.1016/j.plantsci.2023.111838}, pmid = {37611832}, issn = {1873-2259}, mesh = {*Oryza/genetics ; Herbicide Resistance/genetics ; Mutation ; Plant Weeds/genetics ; *Herbicides/pharmacology ; }, abstract = {Weedy rice (Oryza sativa L.) is an economically important weed species in rice (Oryza sativa L.) cropping systems. Two weedy rice samples (acc7 and acc8) suspected to be resistant to quizalofop-ethyl (quizalofop) were collected in Arkansas. In this research, susceptibility to quizalofop and resistance mechanisms have been explored. Dose-response assays displayed a resistance index of 42- and 58-fold for the acc7 and acc8, respectively. Experiments with metabolism inhibitors demonstrated that NBD-Cl (4-chloro-7-nitrobenzofurazan) increased quizalofop efficacy slightly in acc8, whereas malathion did not improve effectiveness in resistant samples. Sequencing of the ACCase gene displayed an Ile1781Leu substitution in the resistant samples, like the mutation present in Provisia™ rice. In addition, an allele-specific PCR was developed to genotype the Ile1781Leu mutation. The gene copy number of ACCase showed similar values among samples. In the resistant plants, a KASP (Kompetitive Allele Specific PCR) assay to detect the ALS[S653D] (acetolactate synthase) and HIS1 (HPPD Inhibitor Sensitive 1) traits revealed that 37.5% of plants carried the ALS[S653D] trait, whereas 25% showed the HIS1 allele. In summary, a target-site mutation is the main resistance mechanism to quizalofop in weedy rice. Results also suggest the presence of herbicide metabolism (a non-target site resistance mechanism) mediated by glutathione-S-transferases (GSTs) in one resistant sample.}, } @article {pmid37610866, year = {2023}, author = {Kołodziej, D and Sobczak, Ł and Łączkowski, KZ}, title = {New opportunities for treatment and prevention of neurodegenerative diseases with PTP1B inhibitors.}, journal = {Future medicinal chemistry}, volume = {15}, number = {16}, pages = {1443-1447}, doi = {10.4155/fmc-2023-0187}, pmid = {37610866}, issn = {1756-8927}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/prevention & control ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis ; }, } @article {pmid37610446, year = {2023}, author = {Bombaci, A and Lupica, A and Pozzi, FE and Remoli, G and Manera, U and Di Stefano, V}, title = {Sensory neuropathy in amyotrophic lateral sclerosis: a systematic review.}, journal = {Journal of neurology}, volume = {270}, number = {12}, pages = {5677-5691}, pmid = {37610446}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/epidemiology ; *Neurodegenerative Diseases ; Quality of Life ; Motor Neurons/physiology ; Electromyography ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of both upper and lower motoneurons, leading to motor and non-motor symptoms. Recent evidence suggests that ALS is indeed a multisystem disorder, associated with cognitive impairment, dysautonomia, pain and fatigue, excess of secretions, and sensory symptoms. To evaluate whether sensory neuropathy could broaden its spectrum, we systematically reviewed its presence and characteristics in ALS, extracting data on epidemiological, clinical, neurophysiological, neuropathological, and genetic features. Sensory neuropathy can be found in up to 20% of ALS patients, affecting both large and small fibers, although there is a great heterogeneity related to different techniques used for its detection (electromyography vs skin biopsy vs nerve biopsy). Moreover, the association between CIDP-like neuropathy and ALS needs to be better explored, although it could be interpreted as part of the neuroinflammatory process in the latter disease. Sensory neuropathy in ALS may be associated with a spinal onset and might be more frequent in SOD1 patients. Moreover, it seems mutually exclusive with cognitive impairment. No associations with sex and other genetic mutation were observed. All these data in the literature reveal the importance of actively looking for sensory neuropathy in ALS patients, and suggest including sensory neuropathy among ALS non-motor features, as it may explain sensory symptoms frequently reported throughout the course of the disease. Its early identification could help avoid diagnostic delays and improve patients' treatment and quality of life.}, } @article {pmid37609280, year = {2023}, author = {Read, TA and Cisterna, BA and Skruber, K and Ahmadieh, S and Lindamood, HL and Vitriol, JA and Shi, Y and Lefebvre, AEYT and Black, JB and Butler, MT and Bear, JE and Cherezova, A and Ilatovskaya, DV and Weintraub, NL and Vitriol, EA}, title = {The actin binding protein profilin 1 is critical for mitochondria function.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37609280}, issn = {2692-8205}, support = {R35 GM137959/GM/NIGMS NIH HHS/United States ; }, abstract = {Profilin 1 (PFN1) is an actin binding protein that is vital for the polymerization of monomeric actin into filaments. Here we screened knockout cells for novel functions of PFN1 and discovered that mitophagy, a type of selective autophagy that removes defective or damaged mitochondria from the cell, was significantly upregulated in the absence of PFN1. Despite successful autophagosome formation and fusion with the lysosome, and activation of additional mitochondrial quality control pathways, PFN1 knockout cells still accumulate damaged, dysfunctional mitochondria. Subsequent imaging and functional assays showed that loss of PFN1 significantly affects mitochondria morphology, dynamics, and respiration. Further experiments revealed that PFN1 is located to the mitochondria matrix and is likely regulating mitochondria function from within rather than through polymerizing actin at the mitochondria surface. Finally, PFN1 mutants associated with amyotrophic lateral sclerosis (ALS) fail to rescue PFN1 knockout mitochondrial phenotypes and form aggregates within mitochondria, further perturbing them. Together, these results suggest a novel function for PFN1 in regulating mitochondria and identify a potential pathogenic mechanism of ALS-linked PFN1 variants.}, } @article {pmid37609205, year = {2023}, author = {Shen, T and Vogel, JW and Duda, J and Phillips, JS and Cook, PA and Gee, J and Elman, L and Quinn, C and Amado, DA and Baer, M and Massimo, L and Grossman, M and Irwin, DJ and McMillan, CT}, title = {Novel data-driven subtypes and stages of brain atrophy in the ALS-FTD spectrum.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37609205}, issn = {2693-5015}, support = {T32 MH019112/MH/NIMH NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 AG054519/AG/NIA NIH HHS/United States ; K01 AG061277/AG/NIA NIH HHS/United States ; R01 NS109260/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: TDP-43 proteinopathies represents a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS-FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS-FTD spectrum.

METHODS: We used a data-driven procedure to identify 13 anatomic clusters of brain volumes for 57 behavioral variant FTD (bvFTD; with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants), 103 ALS, and 47 ALS-FTD patients with likely TDP-43. A Subtype and Stage Inference (SuStaIn) model was trained to identify subtypes of individuals along the ALS-FTD spectrum with distinct brain atrophy patterns, and we related subtypes and stages to clinical, genetic, and neuropathological features of disease.

RESULTS: SuStaIn identified three novel subtypes: two disease subtypes with predominant brain atrophy either in prefrontal/somatomotor regions or limbic-related regions, and a normal-appearing group without obvious brain atrophy. The Limbic-predominant subtype tended to present with more impaired cognition, higher frequencies of pathogenic variants in TBK1 and TARDBP genes, and a higher proportion of TDP-43 type B, E and C. In contrast, the Prefrontal/Somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A. The normal-appearing brain group showed higher frequency of ALS relative to ALS-FTD and bvFTD patients, higher cognitive capacity, higher proportion of lower motor neuron onset, milder motor symptoms, and lower frequencies of genetic pathogenic variants. Overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration, higher King's stage, and cognitive decline. Additionally, SuStaIn stages differed across clinical phenotypes, genotypes and types of TDP-43 pathology.

CONCLUSIONS: Our findings suggest distinct neurodegenerative subtypes of disease along the ALS-FTD spectrum that can be identified in vivo, each with distinct brain atrophy, clinical, genetic and pathological patterns.}, } @article {pmid37608584, year = {2023}, author = {Solovyev, N and Lucio, M and Mandrioli, J and Forcisi, S and Kanawati, B and Uhl, J and Vinceti, M and Schmitt-Kopplin, P and Michalke, B}, title = {Interplay of Metallome and Metabolome in Amyotrophic Lateral Sclerosis: A Study on Cerebrospinal Fluid of Patients Carrying Disease-Related Gene Mutations.}, journal = {ACS chemical neuroscience}, volume = {14}, number = {17}, pages = {3035-3046}, pmid = {37608584}, issn = {1948-7193}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Copper ; Manganese ; *Neurodegenerative Diseases ; Metabolome ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal progressive neurodegenerative disease, characterized by a loss of function of upper and lower motor neurons. This study aimed to explore probable pathological alterations occurring in individuals with ALS compared to neurologically healthy controls through the analysis of cerebrospinal fluid (CSF), a medium, which directly interacts with brain parenchyma. A total of 7 ALS patients with disease-associated mutations (ATXN2, C9ORF72, FUS, SOD1, and TARDBP) and 13 controls were included in the study. Multiple analytical approaches were employed, including metabolomic and metallomics profiling, as well as genetic screening, using CSF samples obtained from the brain compartment. Data analysis involved the application of multivariate statistical methods. Advanced hyphenated selenium and redox metal (iron, copper, and manganese) speciation techniques and nontargeted Fourier transform ion cyclotron resonance mass spectrometry-based metabolomics were used for data acquisition. Nontargeted metabolomics showed reduced steroids, including sex hormones; additionally, copper and manganese species were found to be the most relevant features for ALS patients. This indicates a potential alteration of sex hormone pathways in the ALS-affected brain, as reflected in the CSF.}, } @article {pmid37608352, year = {2023}, author = {Bjorklund, GR and Wong, J and Brafman, D and Bowser, R and Stabenfeldt, SE}, title = {Traumatic brain injury induces TDP-43 mislocalization and neurodegenerative effects in tissue distal to the primary injury site in a non-transgenic mouse.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {137}, pmid = {37608352}, issn = {2051-5960}, support = {R01 NS116657/NS/NINDS NIH HHS/United States ; R03 NS122018/NS/NINDS NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis ; *Frontotemporal Dementia ; *Brain Injuries, Traumatic/complications ; Brain ; *Alzheimer Disease ; DNA-Binding Proteins/genetics ; *Pick Disease of the Brain ; }, abstract = {Traumatic brain injury (TBI) initiates tissue and cellular damage to the brain that is immediately followed by secondary injury sequalae with delayed and continual damage. This secondary damage includes pathological processes that may contribute to chronic neurodegeneration and permanent functional and cognitive deficits. TBI is also associated with an increased risk of developing neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) as indicated by shared pathological features. For example, abnormalities in the TAR DNA-binding Protein 43 (TDP-43) that includes cytoplasmic mislocalization, cytosolic aggregation, and an increase in phosphorylation and ubiquitination are seen in up to 50% of FTD cases, up to 70% of AD cases, and is considered a hallmark pathology of ALS occurring in > 97% of cases. Yet the prevalence of TDP-43 pathology post-TBI has yet to be fully characterized. Here, we employed a non-transgenic murine controlled cortical injury model of TBI and observed injury-induced hallmark TDP-43 pathologies in brain and spinal cord tissue distal to the primary injury site and did not include the focally damaged tissue within the primary cortical injury site. Analysis revealed a temporal-dependent and significant increase in neuronal TDP-43 mislocalization in the cortical forebrain rostral to and distant from the primary injury site up to 180 days post injury (DPI). TDP-43 mislocalization was also detected in neurons located in the ventral horns of the cervical spinal cord following a TBI. Moreover, a cortical layer-dependent affect was identified, increasing from superficial to deeper cortical layers over time from 7 DPI up to 180 DPI. Lastly, RNAseq analysis confirmed an injury-induced misregulation of several key biological processes implicated in neurons that increased over time. Collectively, this study demonstrates a connection between a single moderate TBI event and chronic neurodegenerative processes that are not limited to the primary injury site and broadly distributed throughout the cortex and corticospinal tract.}, } @article {pmid37608094, year = {2023}, author = {Mlynárik, V}, title = {Amyotrophic lateral sclerosis and the upper motor neurons: we do need more than meets the eye.}, journal = {European radiology}, volume = {33}, number = {11}, pages = {7675-7676}, pmid = {37608094}, issn = {1432-1084}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Motor Cortex ; Motor Neurons ; }, } @article {pmid37608081, year = {2023}, author = {Chattopadhyay, S and Do, NP and Flower, DR and Chattopadhyay, AK}, title = {Extracting prime protein targets as possible drug candidates: machine learning evaluation.}, journal = {Medical & biological engineering & computing}, volume = {61}, number = {11}, pages = {3035-3048}, pmid = {37608081}, issn = {1741-0444}, support = {76/QD-BGDDT//National Foundation for Science and Technology Development/ ; }, mesh = {Molecular Docking Simulation ; *Drug Design ; *Proteins ; Algorithms ; Machine Learning ; }, abstract = {Extracting "high ranking" or "prime protein targets" (PPTs) as potent MRSA drug candidates from a given set of ligands is a key challenge in efficient molecular docking. This study combines protein-versus-ligand matching molecular docking (MD) data extracted from 10 independent molecular docking (MD) evaluations - ADFR, DOCK, Gemdock, Ledock, Plants, Psovina, Quickvina2, smina, vina, and vinaxb to identify top MRSA drug candidates. Twenty-nine active protein targets (APT) from the enhanced DUD-E repository (http://DUD-E.decoys.org) are matched against 1040 ligands using "forward modeling" machine learning for initial "data mining and modeling" (DDM) to extract PPTs and the corresponding high affinity ligands (HALs). K-means clustering (KMC) is then performed on 400 ligands matched against 29 PTs, with each cluster accommodating HALs, and the corresponding PPTs. Performance of KMC is then validated against randomly chosen head, tail, and middle active ligands (ALs). KMC outcomes have been validated against two other clustering methods, namely, Gaussian mixture model (GMM) and density based spatial clustering of applications with noise (DBSCAN). While GMM shows similar results as with KMC, DBSCAN has failed to yield more than one cluster and handle the noise (outliers), thus affirming the choice of KMC or GMM. Databases obtained from ADFR to mine PPTs are then ranked according to the number of the corresponding HAL-PPT combinations (HPC) inside the derived clusters, an approach called "reverse modeling" (RM). From the set of 29 PTs studied, RM predicts high fidelity of 5 PPTs (17%) that bind with 76 out of 400, i.e., 19% ligands leading to a prediction of next-generation MRSA drug candidates: PPT2 (average HPC is 41.1%) is the top choice, followed by PPT14 (average HPC 25.46%), and then PPT15 (average HPC 23.12%). This algorithm can be generically implemented irrespective of pathogenic forms and is particularly effective for sparse data.}, } @article {pmid37607754, year = {2023}, author = {Cluse, F and Hermier, M and Demarquay, G and Rogemond, V and Mallaret, M and Svahn, J and Pegat, A and Honnorat, J and Bernard, E}, title = {Trigeminal Nerve Involvement in Bulbar-Onset Anti-IgLON5 Disease.}, journal = {Neurology(R) neuroimmunology & neuroinflammation}, volume = {10}, number = {6}, pages = {}, pmid = {37607754}, issn = {2332-7812}, mesh = {*Amyotrophic Lateral Sclerosis ; *Trigeminal Nerve Diseases ; Gadolinium ; Trigeminal Nerve ; Humans ; Contrast Media ; Hashimoto Disease ; Encephalitis ; }, abstract = {OBJECTIVES: Anti-IgLON5 disease (IgLON5-D) may present with a bulbar-onset motor neuron disease-like phenotype, mimicking bulbar-onset amyotrophic lateral sclerosis. Recognition of their distinctive clinical and paraclinical features may help for differential diagnosis. We report 2 cases of atypical trigeminal neuropathy in bulbar-onset IgLON5-D.

METHODS: Trigeminal nerve involvement was assessed using comprehensive clinical, laboratory, electrophysiologic, and MRI workup.

RESULTS: Both patients were referred for progressive dysphagia, sialorrhea, and hoarseness. They were treated with bilevel positive airway pressure for nocturnal hypoventilation. Patient 1 complained of continuous facial burning pain with allodynia, exacerbated by mastication and prolonged speech. Patient 2 reported no facial pain. Anti-IgLON5 autoantibodies (IgLON5-Abs) were positive in serum for both patients and CSF for patient 1. Cerebral MRI revealed bilateral T2 fluid-attenuated inversion recovery (FLAIR) hyperintensity and enlargement of trigeminal nerves without gadolinium enhancement in both patients. Needle myography showed fasciculations in masseter muscles. Blink-reflex study confirmed bilateral trigeminal neuropathy only in patient 2. Cortical laser-evoked potentials showed a bilateral small-fiber dysfunction in the trigeminal nerve ophthalmic branch in patient 1.

DISCUSSION: In case of progressive atypical bulbar symptoms, the presence of a trigeminal neuropathy or trigeminal nerve abnormalities on MRI should encourage the testing of IgLON5-Abs in serum and CSF.}, } @article {pmid37607386, year = {2023}, author = {Rong, P and Taylor, A}, title = {A Vowel-Centric View Toward Characterizing Temporal Organization of Motor Speech Activities in Neurologically Impaired and Healthy Speakers.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {66}, number = {10}, pages = {3697-3720}, doi = {10.1044/2023_JSLHR-23-00129}, pmid = {37607386}, issn = {1558-9102}, mesh = {Humans ; *Speech ; *Amyotrophic Lateral Sclerosis/complications ; Speech Acoustics ; Speech Disorders ; Speech Production Measurement ; Speech Intelligibility ; }, abstract = {PURPOSE: This study tested the hypotheses that (a) motor speech activities are temporally organized around the nuclei into vowel-centric units that hold both stability and flexibility and (b) such temporal organization is impacted by motor speech impairment.

METHOD: Thirteen individuals with amyotrophic lateral sclerosis and 10 healthy controls read a sentence 3 times at each of the following rates: habitual, fast, and slow. Articulatory gestures and phonatory event were assessed in two vowel-centric units, as operationally defined within and across the boundaries of two target words-cat and must-to accommodate common coda omission and coarticulation. Twelve absolute and relative timing measures centering on the nucleus were derived to characterize the temporal organization of each unit. These measures were evaluated in terms of (a) their relations with global duration across rate conditions and (b) between-groups differences for the habitual rate condition.

RESULTS: Both vowel-centric units remained stable in relative timing between the articulatory gestures approaching and moving away from the nucleus across rate conditions. Relative timing between the articulatory gestures and phonatory event at smaller temporal granularities varied with global duration, but in different ways for neurologically impaired and healthy speakers. Disease impacts on relative timing were only detected across word boundaries. All absolute timing measures revealed consistent temporal scaling effects and disease-related prolongations.

CONCLUSIONS: The findings provide preliminary support for vowel-centric temporal organization of motor speech activities. Such temporal organization holds some extent of both stability and flexibility, which may facilitate the parsing of syllabic events during auditory processing, while accommodating task-specific suprasegmental variations. The timing impairments in amyotrophic lateral sclerosis are likely attributed to the disease-imposed dynamic constraints, reducing the entrainment of the related motor speech activities to the underlying linguistic elements. These findings have potential implications in guiding the assessment and management of temporal speech deficits in ALS.}, } @article {pmid37607205, year = {2023}, author = {Keifer, OP and Gutierrez, J and Butt, MT and Cramer, SD and Bartus, R and Tansey, M and Deaver, D and Betourne, A and Boulis, NM}, title = {Spinal cord and brain concentrations of riluzole after oral and intrathecal administration: A potential new treatment route for amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {18}, number = {8}, pages = {e0277718}, pmid = {37607205}, issn = {1932-6203}, mesh = {Humans ; Animals ; Dogs ; *Amyotrophic Lateral Sclerosis/drug therapy ; Riluzole/therapeutic use ; Brain ; Administration, Oral ; *Drug-Related Side Effects and Adverse Reactions ; }, abstract = {Riluzole is the only treatment known to improve survival in patients with Amyotrophic Lateral Sclerosis (ALS). However, oral riluzole efficacy is modest at best, further it is known to have large inter-individual variability of serum concentration and clearance, is formulated as an oral drug in a patient population plagued with dysphagia, and has known systemic side-effects like asthenia (limiting patient compliance) and elevated liver enzymes. In this context, we postulated that continuous intrathecal (IT) infusion of low doses of riluzole could provide consistent elevations of the drug spinal cord (SC) concentrations at or above those achieved with oral dosing, without increasing the risk for adverse events associated with systemic drug exposure or off-target side effects in the brain. We developed a formulation of riluzole for IT delivery and conducted our studies in purpose-bred hound dogs. Our non-GLP studies revealed that IT infusion alone was able to increase SC concentrations above those provided by oral administration, without increasing plasma concentrations. We then conducted two GLP studies that combined IT infusion with oral administration at human equivalent dose, to evaluate SC and brain concentrations of riluzole along with assessments of safety and tolerability. In the 6-week study, the highest IT dose (0.2 mg/hr) was well tolerated by the animals and increased SC concentrations above those achieved with oral riluzole alone, without increasing brain concentrations. In the 6-month study, the highest dose tested (0.4 mg/hr) was not tolerated and yielded SC significantly above those achieved in all previous studies. Our data show the feasibility and safety profile of continuous IT riluzole delivery to the spinal cord, without concurrent elevated liver enzymes, and minimal brain concentrations creating another potential therapeutic route of delivery to be used in isolation or in combination with other therapeutics."}, } @article {pmid37606662, year = {2023}, author = {Lo Russo, F and Contarino, VE and Conte, G and Morelli, C and Trogu, F and Casale, S and Sbaraini, S and Caschera, L and Genovese, V and Liu, C and Cinnante, CM and Silani, V and Triulzi, FM}, title = {Amyotrophic lateral sclerosis with upper motor neuron predominance: diagnostic accuracy of qualitative and quantitative susceptibility metrics in the precentral gyrus.}, journal = {European radiology}, volume = {33}, number = {11}, pages = {7677-7685}, pmid = {37606662}, issn = {1432-1084}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Motor Cortex/diagnostic imaging ; Retrospective Studies ; Motor Neurons ; *Motor Neuron Disease/diagnostic imaging ; Magnetic Resonance Imaging/methods ; }, abstract = {OBJECTIVE: The study aims at comparing the diagnostic accuracy of qualitative and quantitative assessment of the susceptibility in the precentral gyrus in detecting amyotrophic lateral sclerosis (ALS) with predominance of upper motor neuron (UMN) impairment.

METHODS: We retrospectively collected clinical and 3T MRI data of 47 ALS patients, of whom 12 with UMN predominance (UMN-ALS). We further enrolled 23 healthy controls (HC) and 15 ALS Mimics (ALS-Mim). The Motor Cortex Susceptibility (MCS) score was qualitatively assessed on the susceptibility-weighted images (SWI) and automatic metrics were extracted from the quantitative susceptibility mapping (QSM) in the precentral gyrus. MCS scores and QSM-based metrics were tested for correlation, and ROC analyses.

RESULTS: The correlation of MCS score and susceptibility skewness was significant (Rho = 0.55, p < 0.001). The susceptibility SD showed an AUC of 0.809 with a specificity and positive predictive value of 100% in differentiating ALS and ALS Mim versus HC, significantly higher than MCS (Z = -3.384, p-value = 0.00071). The susceptibility skewness value of -0.017 showed specificity of 92.3% and predictive positive value of 91.7% in differentiating UMN-ALS versus ALS mimics, even if the performance was not significantly better than MCS (Z = 0.81, p = 0.21).

CONCLUSION: The MCS and susceptibility skewness of the precentral gyrus show high diagnostic accuracy in differentiating UMN-ALS from ALS-mimics subjects. The quantitative assessment might be preferred being an automatic measure unbiased by the reader.

CLINICAL RELEVANCE STATEMENT: The clinical diagnostic evaluation of ALS patients might benefit from the qualitative and/or quantitative assessment of the susceptibility in the precentral gyrus as imaging marker of upper motor neuron predominance.

KEY POINTS: • Amyotrophic lateral sclerosis diagnostic work-up lacks biomarkers able to identify upper motor neuron involvement. • Susceptibility-weighted imaging/quantitative susceptibility mapping-based measures showed good diagnostic accuracy in discriminating amyotrophic lateral sclerosis with predominant upper motor neuron impairment from patients with suspected motor neuron disorder. • Susceptibility-weighted imaging/quantitative susceptibility mapping-based assessment of the magnetic susceptibility provides a diagnostic marker for amyotrophic lateral sclerosis with upper motor neuron predominance.}, } @article {pmid37606396, year = {2023}, author = {Shirai, R and Cho, M and Isogai, M and Fukatsu, S and Okabe, M and Okawa, M and Miyamoto, Y and Torii, T and Yamauchi, J}, title = {FTD/ALS Type 7-Associated Thr104Asn Mutation of CHMP2B Blunts Neuronal Process Elongation, and Is Recovered by Knockdown of Arf4, the Golgi Stress Regulator.}, journal = {Neurology international}, volume = {15}, number = {3}, pages = {980-993}, pmid = {37606396}, issn = {2035-8385}, abstract = {Frontotemporal dementia and/or amyotrophic lateral sclerosis type 7 (FTD/ALS7) is an autosomal dominant neurodegenerative disorder characterized by the onset of FTD and/or ALS, mainly in adulthood. Patients with some types of mutations, including the Thr104Asn (T104N) mutation of charged multivesicular body protein 2B (CHMP2B), have predominantly ALS phenotypes, whereas patients with other mutations have predominantly FTD phenotypes. A few mutations result in patients having both phenotypes approximately equally; however, the reason why phenotypes differ depending on the position of the mutation is unknown. CHMP2B comprises one part of the endosomal sorting complexes required for transport (ESCRT), specifically ESCRT-III, in the cytoplasm. We describe here, for the first time, that CHMP2B with the T104N mutation inhibits neuronal process elongation in the N1E-115 cell line, a model line undergoing neuronal differentiation. This inhibitory phenotype was accompanied by changes in marker protein expression. Of note, CHMP2B with the T104N mutation, but not the wild-type form, was preferentially accumulated in the Golgi body. Of the four major Golgi stress signaling pathways currently known, the pathway through Arf4, the small GTPase, was specifically upregulated in cells expressing CHMP2B with the T104N mutation. Conversely, knockdown of Arf4 with the cognate small interfering (si)RNA recovered the neuronal process elongation inhibited by the T104N mutation. These results suggest that the T104N mutation of CHMP2B inhibits morphological differentiation by triggering Golgi stress signaling, revealing a possible therapeutic molecular target for recovering potential molecular and cellular phenotypes underlying FTD/ALS7.}, } @article {pmid37606360, year = {2023}, author = {Bouché, TV and Coates, JR and Moore, SA and Faissler, D and Rishniw, M and Olby, NJ}, title = {Diagnosis and management of dogs with degenerative myelopathy: A survey of neurologists and rehabilitation professionals.}, journal = {Journal of veterinary internal medicine}, volume = {37}, number = {5}, pages = {1815-1820}, pmid = {37606360}, issn = {1939-1676}, mesh = {Humans ; Dogs ; Animals ; *Spinal Cord Diseases/diagnosis/therapy/veterinary ; *Amyotrophic Lateral Sclerosis/genetics/pathology/veterinary ; Neurologists ; Superoxide Dismutase-1/genetics ; Mutation ; *Dog Diseases/diagnosis/therapy/genetics ; }, abstract = {BACKGROUND: Antemortem diagnosis of degenerative myelopathy (DM) in dogs is presumptive and there are no accepted guidelines for the management of this condition.

HYPOTHESIS/OBJECTIVES: Describe current practices of neurology clinicians and physical rehabilitation professionals in the diagnosis and management of DM.

ANIMALS: None.

METHODS: Online surveys examining diagnosis and management of DM were constructed and distributed via neurology and rehabilitation listservs.

RESULTS: One hundred ninety neurology and 79 rehabilitation professionals from 20 countries participated. Most neurology (142/189) and rehabilitation (23/39) respondents required genetic testing for the superoxide dismutase 1 (SOD1) mutation and 82/189 neurologists also required spinal magnetic resonance imaging (MRI) for presumptive DM diagnosis. Most neurology respondents recommended exercise (187/190) and physical rehabilitation (184/190). Over 50% (102/190) of neurology respondents perform rechecks on dogs diagnosed with DM. Rehabilitation respondents reported preservation or improvement of strength (78/79) and coordination (77/79) as therapeutic goals. At-home exercises (75/79), underwater treadmill (64/79), gait training (55/79), and strength building exercises (65/79) were used to maintain strength (58/79), coordination (56/79), muscle mass (56/79), and improve overall wellbeing (54/79). Neurology respondents reported that owners elect euthanasia when dogs become nonambulatory paraparetic whereas rehabilitation respondents report euthanasia when paraplegia and incontinence develop.

The majority of dogs diagnosed with DM have not undergone advanced imaging, the combination of history, neurological findings, and genetic testing is heavily relied upon. Whereas the diagnosis of DM is frequently made by veterinary neurologists, continued care is often performed by rehabilitation professionals or primary veterinarians.}, } @article {pmid37605404, year = {2024}, author = {De, SK}, title = {New Pyrrolopyrimidines as LRRK2 Inhibitors for Treating Parkinson's Disease.}, journal = {Current medicinal chemistry}, volume = {31}, number = {33}, pages = {5477-5480}, pmid = {37605404}, issn = {1875-533X}, mesh = {Humans ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors/metabolism ; *Parkinson Disease/drug therapy/metabolism ; *Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use ; *Pyrimidines/chemistry/pharmacology/therapeutic use ; *Pyrroles/chemistry/pharmacology/therapeutic use ; Patents as Topic ; }, abstract = {This patent describes the novel pyrroloppyrimidine compounds as LRRK2 kinase inhibitors. The patent includes the synthesis of compounds, compositions containing them and their use in the treatment of or prevention of diseases associated with LRRK2 kinase activity, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).}, } @article {pmid37605276, year = {2023}, author = {Estades Ayuso, V and Pickles, S and Todd, T and Yue, M and Jansen-West, K and Song, Y and González Bejarano, J and Rawlinson, B and DeTure, M and Graff-Radford, NR and Boeve, BF and Knopman, DS and Petersen, RC and Dickson, DW and Josephs, KA and Petrucelli, L and Prudencio, M}, title = {TDP-43-regulated cryptic RNAs accumulate in Alzheimer's disease brains.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {57}, pmid = {37605276}, issn = {1750-1326}, support = {RF1 NS120992/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R01 AG037491/AG/NIA NIH HHS/United States ; R35 NS097273/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis ; Brain ; *DNA-Binding Proteins/metabolism ; Frontotemporal Dementia ; }, abstract = {BACKGROUND: Inclusions of TAR DNA-binding protein 43 kDa (TDP-43) has been designated limbic-predominant, age-related TDP-43 encephalopathy (LATE), with or without co-occurrence of Alzheimer's disease (AD). Approximately, 30-70% AD cases present TDP-43 proteinopathy (AD-TDP), and a greater disease severity compared to AD patients without TDP-43 pathology. However, it remains unclear to what extent TDP-43 dysfunction is involved in AD pathogenesis.

METHODS: To investigate whether TDP-43 dysfunction is a prominent feature in AD-TDP cases, we evaluated whether non-conserved cryptic exons, which serve as a marker of TDP-43 dysfunction in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), accumulate in AD-TDP brains. We assessed a cohort of 192 post-mortem brains from three different brain regions: amygdala, hippocampus, and frontal cortex. Following RNA and protein extraction, qRT-PCR and immunoassays were performed to quantify the accumulation of cryptic RNA targets and phosphorylated TDP-43 pathology, respectively.

RESULTS: We detected the accumulation of misspliced cryptic or skiptic RNAs of STMN2, KCNQ2, UNC13A, CAMK2B, and SYT7 in the amygdala and hippocampus of AD-TDP cases. The topographic distribution of cryptic RNA accumulation mimicked that of phosphorylated TDP-43, regardless of TDP-43 subtype classification. Further, cryptic RNAs efficiently discriminated AD-TDP cases from controls.

CONCLUSIONS: Overall, our results indicate that cryptic RNAs may represent an intriguing new therapeutic and diagnostic target in AD, and that methods aimed at detecting and measuring these species in patient biofluids could be used as a reliable tool to assess TDP-43 pathology in AD. Our work also raises the possibility that TDP-43 dysfunction and related changes in cryptic splicing could represent a common molecular mechanism shared between AD-TDP and FTLD-TDP.}, } @article {pmid37604821, year = {2023}, author = {Gupta, AS and Patel, S and Premasiri, A and Vieira, F}, title = {At-home wearables and machine learning sensitively capture disease progression in amyotrophic lateral sclerosis.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {5080}, pmid = {37604821}, issn = {2041-1723}, support = {R01 NS117826/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Disease Progression ; Machine Learning ; Motor Neurons ; *Wearable Electronic Devices ; }, abstract = {Amyotrophic lateral sclerosis causes degeneration of motor neurons, resulting in progressive muscle weakness and impairment in motor function. Promising drug development efforts have accelerated in amyotrophic lateral sclerosis, but are constrained by a lack of objective, sensitive, and accessible outcome measures. Here we investigate the use of wearable sensors, worn on four limbs at home during natural behavior, to quantify motor function and disease progression in 376 individuals with amyotrophic lateral sclerosis. We use an analysis approach that automatically detects and characterizes submovements from passively collected accelerometer data and produces a machine-learned severity score for each limb that is independent of clinical ratings. We show that this approach produces scores that progress faster than the gold standard Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (-0.86 ± 0.70 SD/year versus -0.73 ± 0.74 SD/year), resulting in smaller clinical trial sample size estimates (N = 76 versus N = 121). This method offers an ecologically valid and scalable measure for potential use in amyotrophic lateral sclerosis trials and clinical care.}, } @article {pmid37604596, year = {2023}, author = {Bhaumik, S and Zwi, AB and Norton, R and Jagnoor, J}, title = {How and why snakebite became a global health priority: a policy analysis.}, journal = {BMJ global health}, volume = {8}, number = {8}, pages = {}, pmid = {37604596}, issn = {2059-7908}, mesh = {Humans ; Antivenins ; *Global Health ; *Health Priorities ; Policy Making ; *Snake Bites/epidemiology ; Animals ; }, abstract = {BACKGROUND: Snakebite was added to the WHO neglected tropical disease (NTD) list in 2017, followed by a World Health Assembly resolution in 2018, and an explicit global target being set to reduce the burden in 2019. We aimed to understand how and why snakebite became a global health priority.

METHODS: We conducted a policy case study, using in-depth interviews, and documents (peer-reviewed and grey literature) as data sources. We drew on Shiffman et al's framework on global health network to guide the analysis.

RESULTS: We conducted 20 interviews and examined 91 documents. The prioritisation of snakebite occurred in four phases: pre-crescendo, crescendo, de-crescendo and re-crescendo. The core snakebite network consisted of academics, which expanded during the re-crescendo phase to include civil society organisations and state actors. The involvement of diverse stakeholders led to better understanding of WHO processes. The use of intersecting and layered issue framing, framing solutions around snake antivenoms, in a background of cross-cultural fascination and fear of snakes enabled prioritisation in the re-crescendo phase. Ebbs and flows in legitimacy of the network and reluctant acceptance of snakebite within the NTD community are challenges.

CONCLUSION: Our analyses imply a fragile placement of snakebite in the global agenda. We identify two challenges, which needs to be overcome. The study highlights the need to review the WHO criteria for classifying diseases as NTD. We propose that future prioritisation analysis should consider identifying temporal patterns, as well as integrating legitimacy dimensions, as in our study.}, } @article {pmid37604125, year = {2023}, author = {Lee, SW and Lyu, YR and Yang, WK and Kim, SH and Kim, SY and Kang, W and Jung, IC and Lee, BJ and Choi, JY and Lee, MY and Park, YC}, title = {Efficacy and Safety of Yukmijihwang-Tang in the Treatment of Cough-Variant Asthma: Study Protocol for a Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial.}, journal = {Complementary medicine research}, volume = {30}, number = {5}, pages = {424-430}, doi = {10.1159/000533252}, pmid = {37604125}, issn = {2504-2106}, mesh = {Humans ; *Cough/drug therapy ; *Asthma/drug therapy ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; Clinical Trials, Phase II as Topic ; }, abstract = {BACKGROUND: Cough-variant asthma (CVA), a precursor of typical asthma, is the main cause of chronic cough. We hypothesize that yukmijihwang-tang (YJT), which has been used for chronic cough in traditional medicine and has been reported to have an anti-inflammatory effect, could be an adjuvant to asthma treatment.

METHODS: We plan a randomized, double-blind, placebo-controlled, multicenter, phase 2 trial to investigate the efficacy and safety of YJT in CVA patients. A total of 60 patients with CVA will be recruited and randomly assigned to either a high-dose YJT group, standard-dose YJT group, or control group (placebo) in a 1:1:1 allocation ratio after a 2-week run-in period. For the run-in period, only inhaled corticosteroids (ICSs) will be used, and the investigational drug will be administered once a day with concomitant ICS for 6 weeks. Data will be collected at baseline, week 3, and week 6, and the primary outcome measure will be the mean cough symptom score (CSS) change before and after medication. The secondary outcome measures will include the Leicester cough questionnaire-Korean version (LCQ-K) score, eosinophil count and eosinophil cationic protein level, pulmonary function test, and the number of uses of rescue medication, and so on.

CONCLUSION: This study aimed to evaluate the efficacy and safety of YJT in concomitant treatment with ICS in patients with CVA and to determine the optimal dosage of YJT. The results are expected to provide evidence for the use of YJT as an adjuvant treatment for CVA.

UNLABELLED: HintergrundCough-Variant-Asthma (CVA), eine Frühform von typischem Asthma, ist die Hauptursache von chronischem Husten. Unserer Vermutung nach könnte Yukmijihwang-Tang (YJT), das in der traditionellen Medizin zur Behandlung von chronischem Husten eingesetzt wird und das Berichten zufolge einen entzündungshemmenden Effekt hat, unterstützend in der Asthma-Therapie wirken.Methoden: Wir planen eine randomisierte, doppelblinde, placebokontrollierte, multizentrische Phase-2-Studie, um die Wirksamkeit und Sicherheit von YJT bei Patienten mit CVA zu untersuchen. Insgesamt werden 60 CVA-Patienten für die Studie rekrutiert und nach einer zweiwöchigen Run-in-Phase randomisiert im Verhältnis 1:1:1 einer Gruppe mit hochdosiertem YJT, einer Gruppe, die YJT in der Standarddosierung erhält oder einer Kontrollgruppe (Placebo) zugewiesen. Während der Run-in-Phase werden nur inhalative Corticosteroide (ICS) verwendet, und das Prüfpräparat wird über 6 Wochen einmal täglich gleichzeitig mit den ICS angewendet. Die Datenerhebung erfolgt bei Studienbeginn, in Woche 3 sowie in Woche 6, und das primäre Zielkriterium ist die Änderung des mittleren Hustenscores (cough symptom score, CSS) vor und nach der Anwendung der Medikamente. Zu den sekundären Zielkriterien gehören der Score des Leicester Hustenfragebogens - koreanische Version (LCQ-K), die Eosinophilenzahl und der Spiegel an eosinophilem kationischen Protein, Lungenfunktionstests sowie die Anzahl der Anwendungen von Bedarfsmedikation usw.SchlussfolgerungZiel dieser Studie ist es, die Wirksamkeit und Sicherheit von YJT bei gleichzeitiger Behandlung mit ICS bei Patienten mit CVA zu bewerten und die optimale YJT-Dosis zu ermitteln. Es wird erwartet, dass die Ergebnisse Belege für die Anwendung von YJT als adjuvante Therapie bei CVA liefern werden.Registrierung der StudieWHO International Clinical Trials Registry Platform, Clinical Research Information Service (CRIS), KCT0006994, registriert am 10. Februar 2022, https://cris.nih.go.kr/cris/search/detailSearch.do/21743.}, } @article {pmid37602847, year = {2023}, author = {Klingl, YE and Da Cruz, S and Van Den Bosch, L}, title = {Current Methods In ALS Research.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {193}, pages = {}, doi = {10.3791/65016}, pmid = {37602847}, issn = {1940-087X}, mesh = {Adult ; Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis ; Caenorhabditis elegans ; Zebrafish ; Motor Neurons ; Drosophila ; }, abstract = {Asakawa, K., Handa, H., Kawakami, K. Optogenetic phase transition of TDP-43 in spinal motor neurons of zebrafish larvae. Journal of Visualized Experiments. (180), e62932 (2022). Coyne, A. N., Rothstein, J. D. Nuclei isolation and super-resolution structured illumination microscopy for examining nucleoporin alterations in human neurodegeneration. (175), e62789 (2021). Currey, H. N., Liachko, N. F. Evaluation of motor impairment in C. elegans models of amyotrophic lateral sclerosis. (175), e62699 (2021). Hayes, L. R., Duan, L., Vidensky, S., Kalab, P. Nuclear transport assays in permeabilized mouse cortical neurons. (173), e62710 (2021). Krishnamurthy, K., Trotti, D., Pasinelli, P., Jensen, B. Real-time fluorescent measurements of synaptic functions in models of amyotrophic lateral sclerosis. (173), e62813 (2021). Loganathan, S., Ball H. E., Manzo, E., Zarnescu, D. C. Measuring glucose uptake in Drosophila models of TDP-43 proteinopathy. (174), e62936 (2021). Stilwell, G., Agudelo, A. Dissection and immunohistochemistry of the Drosophila adult leg to detect changes at the neuromuscular junction for an identified motor neuron. (180), e62844 (2022) Taga, A. et al. Establishment of an electrophysiological platform for modeling ALS with regionally-specific human pluripotent stem cell-derived astrocytes and neurons. (174), e62726 (2021). Stoklund Dittlau, K. et al., Generation of human motor units with functional neuromuscular junctions in microfluidic devices. (175), e62959 (2021).}, } @article {pmid37602649, year = {2023}, author = {Mehta, P and Raymond, J and Zhang, Y and Punjani, R and Han, M and Larson, T and Muravov, O and Lyles, RH and Horton, DK}, title = {Prevalence of amyotrophic lateral sclerosis in the United States, 2018.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2023.2245858}, pmid = {37602649}, issn = {2167-9223}, abstract = {OBJECTIVE: To estimate prevalent ALS cases in the United States for calendar year 2018.

METHODS: The National ALS Registry (Registry) compiled data from national administrative databases (from the Centers for Medicare and Medicaid Services, the Veterans Health Administration, and the Veterans Benefits Administration) and enrollment data voluntarily submitted through a web portal (www.cdc.gov/als). We used log-linear capture-recapture (CRC) model-based methodology to estimate the number of cases not ascertained by the Registry.

RESULTS: The Registry identified 21,655 cases of ALS in 2018, with an age-adjusted prevalence of 6.6 per 100,000 U.S. population. When CRC methods were used, an estimated 29,824 cases were identified, for an adjusted prevalence of 9.1 per 100,000 U.S. population. The demographics of cases of ALS did not change from previous year's reports. ALS continues to impact Whites, males, and persons over 50 years of age more so than other comparison groups. The results from the present report suggest case ascertainment for the Registry has improved, with the estimate of missing prevalent cases decreasing from 44% in 2017 to 27% in in 2018.

DISCUSSION: Consistent with previous estimates that used CRC, ALS prevalence in the United States is about 29,824 cases per year.}, } @article {pmid37602388, year = {2023}, author = {Sharma, S and Tomar, VR and Deep, S}, title = {Mechanism of the interaction of toxic SOD1 fibrils with two potent polyphenols: curcumin and quercetin.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {25}, number = {34}, pages = {23081-23091}, doi = {10.1039/d3cp02120c}, pmid = {37602388}, issn = {1463-9084}, mesh = {Humans ; *Curcumin/pharmacology ; Quercetin/pharmacology ; Superoxide Dismutase-1 ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases ; Polyphenols ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease commonly caused due to the aggregation of superoxide dismutase 1 (SOD1) protein. Finding inhibitors of SOD1 aggregation is of prime concern, but understanding the mechanistic action of inhibitors is equally important. Recent experiments found that two polyphenols, curcumin, and quercetin, have the ability to inhibit SOD1 aggregation. Quercetin was experimentally proven to break pre-formed fibrils into shorter segments, while curcumin did not significantly affect the pre-formed species. Here, we delve deeper into understanding the mechanism of action of quercetin and curcumin on pre-formed octameric fibrils of SOD1 ([28]PVKVWGSIKGL[38]: chains A-H) with the help of molecular dynamics (MD) simulations of a fibril docked polyphenol complex. Our results suggest that quercetin shows π-π stacking interaction with one of the key residues for toxic amyloid formation, Trp 32 of chains D, E, and F, and breaks the peptide chains G, and H from the rest of the fibril. On the other hand, curcumin binds to the hydrophobic amino acids of almost all the chains B-H and stabilizes the fibril rather than destabilizing it. Binding free energy calculations using MM/PBSA showed that curcumin binds more strongly to the SOD1 fibril due to greater van der Waals interactions compared to quercetin. These findings provide insights for the development of potential ALS treatments.}, } @article {pmid37602264, year = {2023}, author = {Nakamori, M and Ishikawa, R and Watanabe, T and Toko, M and Naito, H and Takahashi, T and Simizu, Y and Yamazaki, Y and Maruyama, H}, title = {Swallowing sound evaluation using an electronic stethoscope and artificial intelligence analysis for patients with amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1212024}, pmid = {37602264}, issn = {1664-2295}, abstract = {BACKGROUND AND PURPOSE: Non-invasive, simple, and repetitive swallowing evaluation is required to prevent aspiration pneumonia in neurological care. We investigated the usefulness of swallowing sound evaluation in patients with amyotrophic lateral sclerosis (ALS) using our new electronic stethoscope artificial intelligence (AI) analysis tool.

METHODS: We studied patients with ALS who provided written informed consent. We used an electronic stethoscope, placed a Bluetooth-enabled electronic stethoscope on the upper end of the sternum, performed a 3-mL water swallow three times, and remotely identified the intermittent sound components of the water flow caused at that time by AI, with the maximum value as the swallowing sound index. We examined the correlation between the swallowing sound index and patient background, including swallowing-related parameters.

RESULTS: We evaluated 24 patients with ALS (age 64.0 ± 11.8 years, 13 women, median duration of illness 17.5 months). The median ALS Functional Rating Scale-Revised (ALSFRS-R) score was 41 (minimum 18, maximum 47). In all cases, the mean swallowing sound index was 0.209 ± 0.088. A multivariate analysis showed that a decrease in the swallowing sound index was significantly associated with a low ALSFRS-R score, an ALSFRS-R bulbar symptom score, % vital capacity, tongue pressure, a Mann Assessment of Swallowing Ability (MASA) score, and a MASA pharyngeal phase-related score.

CONCLUSION: Swallowing sound evaluation using an electronic stethoscope AI analysis showed a correlation with existing indicators in swallowing evaluation in ALS and suggested its usefulness as a new method. This is expected to be a useful examination method in home and remote medical care.}, } @article {pmid37602234, year = {2023}, author = {Luzzi, A and Wang, F and Li, S and Iacovino, M and Chou, TF}, title = {Skeletal muscle cell protein dysregulation highlights the pathogenesis mechanism of myopathy-associated p97/VCP R155H mutations.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1211635}, pmid = {37602234}, issn = {1664-2295}, support = {R01 NS102279/NS/NINDS NIH HHS/United States ; }, abstract = {p97/VCP, a hexametric member of the AAA-ATPase superfamily, has been associated with a wide range of cellular protein pathways, such as proteasomal degradation, the unfolding of polyubiquitinated proteins, and autophagosome maturation. Autosomal dominant p97/VCP mutations cause a rare hereditary multisystem disorder called IBMPFD/ALS (Inclusion Body Myopathy with Paget's Disease and Frontotemporal Dementia/Amyotrophic Lateral Sclerosis), characterized by progressive weakness and subsequent atrophy of skeletal muscles, and impacting bones and brains, such as Parkinson's disease, Lewy body disease, Huntington's disease, and amyotrophic lateral ALS. Among all disease-causing mutations, Arginine 155 to Histidine (R155H/+) was reported to be the most common one, affecting over 50% of IBMPFD patients, resulting in disabling muscle weakness, which might eventually be life-threatening due to cardiac and respiratory muscle involvement. Induced pluripotent stem cells (iPSCs) offer an unlimited resource of cells to study pathology's underlying molecular mechanism, perform drug screening, and investigate regeneration. Using R155H/+ patients' fibroblasts, we generated IPS cells and corrected the mutation (Histidine to Arginine, H155R) to generate isogenic control cells before differentiating them into myotubes. The further proteomic analysis allowed us to identify differentially expressed proteins associated with the R155H mutation. Our results showed that R155H/+ cells were associated with dysregulated expression of several proteins involved in skeletal muscle function, cytoskeleton organization, cell signaling, intracellular organelles organization and function, cell junction, and cell adhesion. Our findings provide molecular evidence of dysfunctional protein expression in R155H/+ myotubes and offer new therapeutic targets for treating IBMPFD/ALS.}, } @article {pmid37601533, year = {2023}, author = {Guareschi, S and Ravasi, M and Baldessari, D and Pozzi, S and Zaffino, T and Melazzini, M and Ambrosini, A}, title = {The positive impact on translational research of Fondazione italiana di ricerca per la Sclerosi Laterale Amiotrofica (AriSLA), a non-profit foundation focused on amyotrophic lateral sclerosis. Convergence of ex-ante evaluation and ex-post outcomes when goals are set upfront.}, journal = {Frontiers in research metrics and analytics}, volume = {8}, number = {}, pages = {1067981}, pmid = {37601533}, issn = {2504-0537}, abstract = {Charities investing on rare disease research greatly contribute to generate ground-breaking knowledge with the clear goal of finding a cure for their condition of interest. Although the amount of their investments may be relatively small compared to major funders, the advocacy groups' clear mission promotes innovative research and aggregates highly motivated and mission-oriented scientists. Here, we illustrate the case of Fondazione italiana di ricerca per la Sclerosi Laterale Amiotrofica (AriSLA), the main Italian funding agency entirely dedicated to amyotrophic lateral sclerosis research. An international benchmark analysis of publications derived from AriSLA-funded projects indicated that their mean relative citation ratio values (iCite dashboard, National Institutes of Health, U.S.) were very high, suggesting a strong influence on the referring international scientific community. An interesting trend of research toward translation based on the "triangle of biomedicine" and paper citations (iCite) was also observed. Qualitative analysis on researchers' accomplishments was convergent with the bibliometric data, indicating a high level of performance of several working groups, lines of research that speak of progression toward clinical translation, and one study that has progressed from the investigation of cellular mechanisms to a Phase 2 international clinical trial. The key elements of the success of the AriSLA investment lie in: (i) the clear definition of the objectives (research with potential impact on patients, no matter how far), (ii) a rigorous peer-review process entrusted to an international panel of experts, (iii) diversification of the portfolio with ad hoc selection criteria, which also contributed to bringing new experts and younger scientists to the field, and (iv) a close interaction of AriSLA stakeholders with scientists, who developed a strong sense of belonging. Periodic review of the portfolio of investments is a vital practice for funding agencies. Sharing information between funding agencies about their own policies and research assessment methods and outcomes help guide the international debate on funding strategies and research directions to be undertaken, particularly in the field of rare diseases, where synergy is a relevant enabling factor.}, } @article {pmid37600819, year = {2023}, author = {Räuber, S and Nelke, C and Schroeter, CB and Barman, S and Pawlitzki, M and Ingwersen, J and Akgün, K and Günther, R and Garza, AP and Marggraf, M and Dunay, IR and Schreiber, S and Vielhaber, S and Ziemssen, T and Melzer, N and Ruck, T and Meuth, SG and Herty, M}, title = {Classifying flow cytometry data using Bayesian analysis helps to distinguish ALS patients from healthy controls.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1198860}, pmid = {37600819}, issn = {1664-3224}, mesh = {*Flow Cytometry/classification/methods ; Bayes Theorem ; Algorithms ; *Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; Models, Theoretical ; Male ; Female ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; }, abstract = {INTRODUCTION: Given its wide availability and cost-effectiveness, multidimensional flow cytometry (mFC) became a core method in the field of immunology allowing for the analysis of a broad range of individual cells providing insights into cell subset composition, cellular behavior, and cell-to-cell interactions. Formerly, the analysis of mFC data solely relied on manual gating strategies. With the advent of novel computational approaches, (semi-)automated gating strategies and analysis tools complemented manual approaches.

METHODS: Using Bayesian network analysis, we developed a mathematical model for the dependencies of different obtained mFC markers. The algorithm creates a Bayesian network that is a HC tree when including raw, ungated mFC data of a randomly selected healthy control cohort (HC). The HC tree is used to classify whether the observed marker distribution (either patients with amyotrophic lateral sclerosis (ALS) or HC) is predicted. The relative number of cells where the probability q is equal to zero is calculated reflecting the similarity in the marker distribution between a randomly chosen mFC file (ALS or HC) and the HC tree.

RESULTS: Including peripheral blood mFC data from 68 ALS and 35 HC, the algorithm could correctly identify 64/68 ALS cases. Tuning of parameters revealed that the combination of 7 markers, 200 bins, and 20 patients achieved the highest AUC on a significance level of p < 0.0001. The markers CD4 and CD38 showed the highest zero probability. We successfully validated our approach by including a second, independent ALS and HC cohort (55 ALS and 30 HC). In this case, all ALS were correctly identified and side scatter and CD20 yielded the highest zero probability. Finally, both datasets were analyzed by the commercially available algorithm 'Citrus', which indicated superior ability of Bayesian network analysis when including raw, ungated mFC data.

DISCUSSION: Bayesian network analysis might present a novel approach for classifying mFC data, which does not rely on reduction techniques, thus, allowing to retain information on the entire dataset. Future studies will have to assess the performance when discriminating clinically relevant differential diagnoses to evaluate the complementary diagnostic benefit of Bayesian network analysis to the clinical routine workup.}, } @article {pmid37600635, year = {2023}, author = {Fathi, M and Sedaghat, M and Ahadi, H}, title = {Quality of Life of Amyotrophic Lateral Sclerosis Patients in Iran.}, journal = {Medical journal of the Islamic Republic of Iran}, volume = {37}, number = {}, pages = {76}, pmid = {37600635}, issn = {1016-1430}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rare disease that can bring different emotional, physical, and psychological burdens. This study aimed to investigate the quality of life in patients with ALS.

METHODS: This is a cross-sectional study. Fifty-two patients contributed in this study. The setting was an ALS clinic in Iran. A mixed method was used in this study. We applied a short form of the WHO Quality of Life questionnaire (WHOQOL) to measure the quality of life of patients. Also, all participants were interviewed through the semi-structured interview guide. To measure physical strength and functioning the Appel ALS Rating Scale (AALS) was employed in this study. To analyze the data, a two-tailed t-test and x2 test were used.

RESULTS: 42.3% of the participants were female. The age of the participants ranged between 28 to 81 (mean=57.6). The disease duration ranged from 0.07 to 14 years (mean=1.8). The overall mean QOL was 58.7 (±8.1). The overall mean of the AALS score was 74.4 (±24.2). The results of the qualitative part of the study showed four psychosocial themes: (1) internal personality traits, communicating with friends and family; (2) religion and spirituality; (3) stress, mood changes, and difficult relationship; and (4) changes in lifestyle, work, leisure time and financial situation.

CONCLUSION: Despite recent advances, ALS is still one of the diseases for which there is no effective treatment. Paying attention to psychosocial issues in patients with ALS can play a very important role in increasing the quality of life of patients.}, } @article {pmid37599994, year = {2023}, author = {Baker, BH and Zhang, S and Simon, JM and McLarnan, SM and Chung, WK and Pearson, BL}, title = {Environmental carcinogens disproportionally mutate genes implicated in neurodevelopmental disorders.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1106573}, pmid = {37599994}, issn = {1662-4548}, support = {P50 HD103573/HD/NICHD NIH HHS/United States ; }, abstract = {INTRODUCTION: De novo mutations contribute to a large proportion of sporadic psychiatric and developmental disorders, yet the potential role of environmental carcinogens as drivers of causal de novo mutations in neurodevelopmental disorders is poorly studied.

METHODS: To explore environmental mutation vulnerability of disease-associated gene sets, we analyzed publicly available whole genome sequencing datasets of mutations in human induced pluripotent stem cell clonal lines exposed to 12 classes of environmental carcinogens, and human lung cancers from individuals living in highly polluted regions. We compared observed rates of exposure-induced mutations in disease-related gene sets with the expected rates of mutations based on control genes randomly sampled from the genome using exact binomial tests. To explore the role of sequence characteristics in mutation vulnerability, we modeled the effects of sequence length, gene expression, and percent GC content on mutation rates of entire genes and gene coding sequences using multivariate Quasi-Poisson regressions.

RESULTS: We demonstrate that several mutagens, including radiation and polycyclic aromatic hydrocarbons, disproportionately mutate genes related to neurodevelopmental disorders including autism spectrum disorders, schizophrenia, and attention deficit hyperactivity disorder. Other disease genes including amyotrophic lateral sclerosis, Alzheimer's disease, congenital heart disease, orofacial clefts, and coronary artery disease were generally not mutated more than expected. Longer sequence length was more strongly associated with elevated mutations in entire genes compared with mutations in coding sequences. Increased expression was associated with decreased coding sequence mutation rate, but not with the mutability of entire genes. Increased GC content was associated with increased coding sequence mutation rates but decreased mutation rates in entire genes.

DISCUSSION: Our findings support the possibility that neurodevelopmental disorder genetic etiology is partially driven by a contribution of environment-induced germ line and somatic mutations.}, } @article {pmid37599467, year = {2024}, author = {Sung, H and Lloyd, TE}, title = {Disrupted endoplasmic reticulum-mediated autophagosomal biogenesis in a Drosophila model of C9-ALS-FTD.}, journal = {Autophagy}, volume = {20}, number = {1}, pages = {94-113}, pmid = {37599467}, issn = {1554-8635}, support = {P30 NS050274/NS/NINDS NIH HHS/United States ; R01 NS094239/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Frontotemporal Dementia/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Drosophila ; DNA Repeat Expansion ; Autophagy/genetics ; Transcription Factors ; }, abstract = {3R: UAS construct expressing 3 G4C2 repeats (used as control); 3WJ: three-way junction; 12R: UAS construct expressing leader sequence and 12 G4C2 repeats; 30R: UAS construct expressing 30 G4C2 repeats; 36R: UAS construct expressing 36 G4C2 repeats; 44R: UAS construct expressing leader sequence and 44 G4C2 repeats; ALS: amyotrophic lateral sclerosis; Atg: autophagy related; atl: atlastin; C9-ALS-FTD: ALS or FTD caused by hexanuleotide repeat expansion in C9orf72; ER: endoplasmic reticulum; FTD: frontotemporal dementia; HRE: GGGGCC hexanucleotide repeat expansion; HSP: hereditary spastic paraplegia; Lamp1: lysosomal associated membrane protein 1; MT: microtubule; NMJ: neuromuscular junction; Rab: Ras-associated binding GTPase; RAN: repeat associated non-AUG (RAN) translation; RO-36: UAS construct expression "RNA-only" version of 36 G4C2 repeats in which stop codons in all six reading frames are inserted.; Rtnl1: Reticulon-like 1; SN: segmental nerve; TFEB/Mitf: transcription factor EB/microphthalmia associated transcription factor (Drosophila ortholog of TFEB); TrpA1: transient receptor potential cation channel A1; VAPB: VAMP associated protein B and C; VNC: ventral nerve cord (spinal cord in Drosophila larvae).}, } @article {pmid37598759, year = {2023}, author = {Rani, N and Alam, MM and Jamal, A and Bin Ghaffar, U and Parvez, S}, title = {Caenorhabditis elegans: A transgenic model for studying age-associated neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {91}, number = {}, pages = {102036}, doi = {10.1016/j.arr.2023.102036}, pmid = {37598759}, issn = {1872-9649}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/genetics ; Caenorhabditis elegans/metabolism ; *Alzheimer Disease/genetics ; *Parkinson Disease ; *Huntington Disease/genetics ; }, abstract = {Neurodegenerative diseases (NDs) are a heterogeneous group of aging-associated ailments characterized by interrupting cellular proteostasic machinery and the misfolding of distinct proteins to form toxic aggregates in neurons. Neurodegenerative diseases, which include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and others, are becoming an increasing threat to human health worldwide. The degeneration and death of certain specific groups of neurons are the hallmarks of these diseases. Over the past decades, Caenorhabditis eleganshas beenwidely used as a transgenic model to investigate biological processes related to health and disease. The nematode Caenorhabditis elegans (C. elegans) has developed as a powerful tool for studying disease mechanisms due to its ease of genetic handling and instant cultivation while providing a whole-animal system amendable to several molecular and biochemical techniques. In this review, we elucidate the potential of C. elegans as a versatile platform for systematic dissection of the molecular basis of human disease, focusing on neurodegenerative disorders, and may help better our understanding of the disease mechanisms and search for new therapeutics for these devastating diseases.}, } @article {pmid37597354, year = {2023}, author = {Alaoui Mansouri, M and Kharbach, M and El Maouardi, M and Barra, I and Bouklouze, A}, title = {Quantification of ciprofloxacin in pharmaceutical products from various brands using FT-NIR: A comparative investigation of PLS and MCR-ALS.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {303}, number = {}, pages = {123268}, doi = {10.1016/j.saa.2023.123268}, pmid = {37597354}, issn = {1873-3557}, mesh = {*Excipients ; Least-Squares Analysis ; *Chemometrics ; Ciprofloxacin ; Spectroscopy, Fourier Transform Infrared ; }, abstract = {This study aims to quantify ciprofloxacin in commercial tablets with varying excipient compositions using Fourier Transform Near-Infrared Spectroscopy (FT-NIR) and chemometric models: Partial Least Squares (PLS) and Multivariate Curve Resolution - Alternating Least Squares (MCR-ALS). Matrix variation, arising from differences in excipient compositions among the tablets, can impact quantification accuracy. We discuss this phenomenon, emphasizing potential issues introduced by varying certain excipients and its importance in reliable ciprofloxacin quantification. We evaluated the performance of PLS and MCR-ALS models independently on two sets of tablets, each containing the same drug substance but different excipients. The statistical results revealed promising results with PLS prediction error of 0.38% w/w of the first set and 0.47% w/w of the second set, while MCR-ALS achieved prediction errors of 0.67% w/w of the first set and 1.76% w/w of the second set. To address the challenge of matrix variation, we developed single models for PLS and MCR-ALS using a dataset combining both first and second sets. The PLS single model demonstrated a prediction error of 4.3% w/w and a relative error of 6.41% w/w, while the MCR-ALS single model showed a prediction error of 1.88% w/w and a relative error of 1.29% w/w. We then assessed the performance of the single PLS and MCR-ALS models developed based on the combination of the first and the second set in quantifying ciprofloxacin in various commercial tablet brands containing new excipients. The PLS model achieved a prediction error ranging between 6.2% w/w and 8.39% w/w, with relative errors varied between 8.53% w/w and 12.82% w/w. On the other hand, the MCR-ALS model had a prediction error between 1.11% w/w and 2.66% w/w, and the relative errors ranging from 0.8% to 1.74% w/w.}, } @article {pmid37596282, year = {2023}, author = {Liu, S and Heumüller, SE and Hossinger, A and Müller, SA and Buravlova, O and Lichtenthaler, SF and Denner, P and Vorberg, IM}, title = {Reactivated endogenous retroviruses promote protein aggregate spreading.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {5034}, pmid = {37596282}, issn = {2041-1723}, mesh = {Humans ; *Endogenous Retroviruses/genetics ; Protein Aggregates ; *Amyotrophic Lateral Sclerosis ; Antiviral Agents ; *Prions ; }, abstract = {Prion-like spreading of protein misfolding is a characteristic of neurodegenerative diseases, but the exact mechanisms of intercellular protein aggregate dissemination remain unresolved. Evidence accumulates that endogenous retroviruses, remnants of viral germline infections that are normally epigenetically silenced, become upregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis and tauopathies. Here we uncover that activation of endogenous retroviruses affects prion-like spreading of proteopathic seeds. We show that upregulation of endogenous retroviruses drastically increases the dissemination of protein aggregates between cells in culture, a process that can be inhibited by targeting the viral envelope protein or viral protein processing. Human endogenous retrovirus envelopes of four different clades also elevate intercellular spreading of proteopathic seeds, including pathological Tau. Our data support a role of endogenous retroviruses in protein misfolding diseases and suggest that antiviral drugs could represent promising candidates for inhibiting protein aggregate spreading.}, } @article {pmid37595581, year = {2023}, author = {Yang, M and Liu, M and Sánchez, YF and Avazzadeh, S and Quinlan, LR and Liu, G and Lu, Y and Yang, G and O'Brien, T and Henshall, DC and Hardiman, O and Shen, S}, title = {A novel protocol to derive cervical motor neurons from induced pluripotent stem cells for amyotrophic lateral sclerosis.}, journal = {Stem cell reports}, volume = {18}, number = {9}, pages = {1870-1883}, pmid = {37595581}, issn = {2213-6711}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Induced Pluripotent Stem Cells ; Motor Neurons ; Autophagy ; Cell Differentiation ; *Osteochondrodysplasias ; }, abstract = {Sporadic amyotrophic lateral sclerosis (sALS) is the majority of ALS, and the lack of appropriate disease models has hindered its research. Induced pluripotent stem cell (iPSC) technology now permits derivation of iPSCs from somatic cells of sALS patients to investigate disease phenotypes and mechanisms. Most existing differentiation protocols are time-consuming or low efficient in generating motor neurons (MNs). Here we report a rapid and simple protocol to differentiate MNs in monolayer culture using small molecules, which led to nearly pure neural stem cells in 6 days, robust OLIG2[+] pMNs (73%-91%) in 12 days, enriched CHAT[+] cervical spinal MNs (sMNs) (88%-97%) in 18 days, and functionally mature sMNs in 28 days. This simple and reproducible protocol permitted the identification of hyperexcitability phenotypes in our sALS iPSC-derived sMNs, and its application in neurodegenerative diseases should facilitate in vitro disease modeling, drug screening, and the development of cell therapy.}, } @article {pmid37593923, year = {2023}, author = {Pino, MG and Rich, KA and Hall, NJ and Jones, ML and Fox, A and Musier-Forsyth, K and Kolb, SJ}, title = {Heterogeneous splicing patterns resulting from KIF5A variants associated with amyotrophic lateral sclerosis.}, journal = {Human molecular genetics}, volume = {32}, number = {22}, pages = {3166-3180}, doi = {10.1093/hmg/ddad134}, pmid = {37593923}, issn = {1460-2083}, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/genetics ; *Neurodegenerative Diseases/genetics ; RNA Splicing/genetics ; RNA, Messenger/genetics ; Exons/genetics ; Kinesins/genetics/metabolism ; }, abstract = {Single-nucleotide variants (SNVs) in the gene encoding Kinesin Family Member 5A (KIF5A), a neuronal motor protein involved in anterograde transport along microtubules, have been associated with amyotrophic lateral sclerosis (ALS). ALS is a rapidly progressive and fatal neurodegenerative disease that primarily affects the motor neurons. Numerous ALS-associated KIF5A SNVs are clustered near the splice-site junctions of the penultimate exon 27 and are predicted to alter the carboxy-terminal (C-term) cargo-binding domain of KIF5A. Mis-splicing of exon 27, resulting in exon exclusion, is proposed to be the mechanism by which these SNVs cause ALS. Whether all SNVs proximal to exon 27 result in exon exclusion is unclear. To address this question, we designed an in vitro minigene splicing assay in human embryonic kidney 293 cells, which revealed heterogeneous site-specific effects on splicing: only 5' splice-site (5'ss) SNVs resulted in exon skipping. We also quantified splicing in select clustered, regularly interspaced, short palindromic repeats-edited human stem cells, differentiated to motor neurons, and in neuronal tissues from a 5'ss SNV knock-in mouse, which showed the same result. Moreover, the survival of representative 3' splice site, 5'ss, and truncated C-term variant KIF5A (v-KIF5A) motor neurons was severely reduced compared with wild-type motor neurons, and overt morphological changes were apparent. While the total KIF5A mRNA levels were comparable across the cell lines, the total KIF5A protein levels were decreased for v-KIF5A lines, suggesting an impairment of protein synthesis or stability. Thus, despite the heterogeneous effect on ribonucleic acid splicing, KIF5A SNVs similarly reduce the availability of the KIF5A protein, leading to axonal transport defects and motor neuron pathology.}, } @article {pmid37592793, year = {2024}, author = {Manera, U and Matteoni, E and Canosa, A and Callegaro, S and Casale, F and Marchis, D and Vasta, R and Moglia, C and Chiò, A and Calvo, A}, title = {Mycotoxins and Amyotrophic Lateral Sclerosis: Food Exposure, Nutritional Implications and Dietary Solutions.}, journal = {CNS & neurological disorders drug targets}, volume = {23}, number = {5}, pages = {562-572}, pmid = {37592793}, issn = {1996-3181}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Mycotoxins/toxicity ; Animals ; Environmental Exposure/adverse effects ; Food Contamination ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder determined by a combination of both genetic and environmental factors. Despite wide investigations, the role of chronic exposure to environmental pollutants is still rather unknown. Among natural toxins, the mycotoxins have received major attention only in the last few years, due to both technical and scientific achievements that allowed to disentangle many important features of the complex fungal biology. Whereas the effects of acute and high-dose mycotoxin exposure are well known, the potential effects of chronic and low-dose exposure on neurodegeneration have not been broadly elucidated. In this review, we have summarized all the studies concerning environmental exposure to unknown substances that caused ALS outbreaks all over the world, reinterpreting in light of the new scientific acquisitions and highlighting the potential and neglected role of mycotoxins. Then, we focused on recent papers about food exposure to mycotoxin, mycobiome and fungal infections in ALS and other neurodegenerative diseases. We analyzed the gaps of current literature that lead to an undervaluation of mycotoxins as detrimental molecules. By listing all the most important mycotoxins and analyzing all the biological pathways that they can affect, we explained the reasons why they need to be considered in the next epidemiological studies on ALS and other neurodegenerative and neuroinflammatory diseases. In conclusion, after suggesting some possible solutions to mitigate mycotoxin exposure risk, we affirm that future collaborations between scientists and policymakers are important to develop sustainable interventions and promote health through dietary diversity.}, } @article {pmid37591957, year = {2023}, author = {Mandrioli, J and D'Amico, R and Zucchi, E and De Biasi, S and Banchelli, F and Martinelli, I and Simonini, C and Lo Tartaro, D and Vicini, R and Fini, N and Gianferrari, G and Pinti, M and Lunetta, C and Gerardi, F and Tarlarini, C and Mazzini, L and De Marchi, F and Scognamiglio, A and Sorarù, G and Fortuna, A and Lauria, G and Bella, ED and Caponnetto, C and Meo, G and Chio, A and Calvo, A and Cossarizza, A}, title = {Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {4970}, pmid = {37591957}, issn = {2041-1723}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Interleukin-18 ; Quality of Life ; Ribosomal Proteins ; Autophagy ; }, abstract = {In preclinical studies rapamycin was found to target neuroinflammation, by expanding regulatory T cells, and affecting autophagy, two pillars of amyotrophic lateral sclerosis (ALS) pathogenesis. Herein we report a multicenter, randomized, double-blind trial, in 63 ALS patients who were randomly assigned in a 1:1:1 ratio to receive rapamycin 2 mg/m[2]/day,1 mg/m[2]/day or placebo (EUDRACT 2016-002399-28; NCT03359538). The primary outcome, the number of patients exhibiting an increase >30% in regulatory T cells from baseline to treatment end, was not attained. Secondary outcomes were changes from baseline of T, B, NK cell subpopulations, inflammasome mRNA expression and activation status, S6-ribosomal protein phosphorylation, neurofilaments; clinical outcome measures of disease progression; survival; safety and quality of life. Of the secondary outcomes, rapamycin decreased mRNA relative expression of the pro-inflammatory cytokine IL-18, reduced plasmatic IL-18 protein, and increased the percentage of classical monocytes and memory switched B cells, although no corrections were applied for multiple tests. In conclusion, we show that rapamycin treatment is well tolerated and provides reassuring safety findings in ALS patients, but further trials are necessary to understand the biological and clinical effects of this drug in ALS.}, } @article {pmid37591233, year = {2023}, author = {Donohue, C and Robison, R and Steele, CM and Wymer, JP and Plowman, EK}, title = {Profiling Number of Swallows per Bolus and Residue in Individuals With Amyotrophic Lateral Sclerosis.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {66}, number = {10}, pages = {3763-3772}, pmid = {37591233}, issn = {1558-9102}, support = {K00 AG076123/AG/NIA NIH HHS/United States ; R01 AG077481/AG/NIA NIH HHS/United States ; R01 DC011020/DC/NIDCD NIH HHS/United States ; R01 NS100859/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Deglutition Disorders/etiology ; *Amyotrophic Lateral Sclerosis/complications ; Deglutition ; Fluoroscopy/methods ; Food ; Pharynx ; }, abstract = {PURPOSE: Swallowing efficiency impairments are the most prevalent and earliest manifestation of dysphagia in people with amyotrophic lateral sclerosis (pALS). We aimed to profile number of swallows elicited in pALS across thin liquid, moderately thick liquid, extremely thick liquid, and crackers compared to expected healthy reference data and to determine relationships between degree of pharyngeal residue, number of elicited swallows, and swallowing safety.

METHOD: pALS underwent standardized videofluoroscopic swallowing studies of 10 bolus trials. Trained raters performed duplicate, independent, and blinded ratings to derive Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) efficiency and safety grades and Analysis of Swallowing Physiology: Events, Kinematics, and Timing (ASPEKT) percent total pharyngeal residue. Number of swallows per bolus was quantified (1 = typical, 2 = atypically high, 3 = extremely high). Kruskal-Wallis, Pearson chi-square, and odds ratio analyses were performed at bolus and participant levels.

KEY RESULTS: At the bolus level (N = 2,523), number of swallows per bolus was observed to be, in rank order, as follows: atypically high (49.1%), extremely high (28.5%), and typical (22.4%). Mean number of swallows significantly differed by International Dysphagia Diet Standardisation Initiative level (p < .0001), with a higher number of swallows elicited in pALS for moderately thick versus thin liquids, extremely thick liquids, and crackers, p < .0001. Number of swallows per bolus increased with increasing DIGEST efficiency grades (p < .0001). Positive correlations were observed between ASPEKT percent residue and number of swallows for thin (r = .24) and moderately thick (r = .16) liquids, p < .05. DIGEST efficiency and safety grades were not significantly associated (p > .05).

CONCLUSION AND INFERENCES: pALS demonstrated a higher number of swallows per bolus compared to healthy reference data that may represent a compensation for reductions in swallowing efficiency to clear pharyngeal residue.}, } @article {pmid37590965, year = {2023}, author = {Rani, A and Saini, V and Patra, P and Prashar, T and Pandey, RK and Mishra, A and Jha, HC}, title = {Epigallocatechin Gallate: A Multifaceted Molecule for Neurological Disorders and Neurotropic Viral Infections.}, journal = {ACS chemical neuroscience}, volume = {14}, number = {17}, pages = {2968-2980}, doi = {10.1021/acschemneuro.3c00368}, pmid = {37590965}, issn = {1948-7193}, mesh = {Humans ; *Alzheimer Disease ; *Epstein-Barr Virus Infections ; Glycogen Synthase Kinase 3 ; Phosphatidylinositol 3-Kinases ; *Zika Virus Infection ; Herpesvirus 4, Human ; *Zika Virus ; *Nervous System Diseases ; }, abstract = {Epigallocatechin-3-gallate (EGCG), a polyphenolic moiety found in green tea extracts, exhibits pleiotropic bioactivities to combat many diseases including neurological ailments. These neurological diseases include Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. For instance, in the case of Alzheimer's disease, the formation of a β-sheet in the region of the 10th-21st amino acids was significantly reduced in EGCG-induced oligomeric samples of Aβ40. Its interference induces the formation of Aβ structures with an increase in intercenter-of-mass distances, reduction in interchain/intrachain contacts, reduction in β-sheet propensity, and increase in α-helix. Besides, numerous neurotropic viruses are known to instigate or aggravate neurological ailments. It exerts an effect on the oxidative damage caused in neurodegenerative disorders by acting on GSK3-β, PI3K/Akt, and downstream signaling pathways via caspase-3 and cytochrome-c. EGCG also diminishes these viral-mediated effects, such as EGCG delayed HSV-1 infection by blocking the entry for virions, inhibitory effects on NS3/4A protease or NS5B polymerase of HCV and potent inhibitor of ZIKV NS2B-NS3pro/NS3 serine protease (NS3-SP). It showed a reduction in the neurotoxic properties of HIV-gp120 and Tat in the presence of IFN-γ. EGCG also involves numerous viral-mediated inflammatory cascades, such as JAK/STAT. Nonetheless, it also inhibits the Epstein-Barr virus replication protein (Zta and Rta). Moreover, it also impedes certain viruses (influenza A and B strains) by hijacking the endosomal and lysosomal compartments. Therefore, the current article aims to describe the importance of EGCG in numerous neurological diseases and its inhibitory effect against neurotropic viruses.}, } @article {pmid37590829, year = {2023}, author = {Lee-Iannotti, JK}, title = {Sleep Disorders in Patients with Neurologic Disease.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {29}, number = {4}, pages = {1188-1204}, pmid = {37590829}, issn = {1538-6899}, mesh = {Humans ; *Neurodegenerative Diseases ; *Sleep Wake Disorders/complications/diagnosis ; *Parkinson Disease ; *Multiple Sclerosis ; *Stroke ; }, abstract = {OBJECTIVE: This article provides an overview of the growing body of evidence showing bidirectional relationships between sleep and various neurologic disorders.

LATEST DEVELOPMENTS: Mounting evidence demonstrates that disrupted sleep can negatively impact various neurologic disease processes, including stroke, multiple sclerosis, epilepsy, neuromuscular disorders including amyotrophic lateral sclerosis, and headache syndromes. Abnormal sleep can also be a precursor to Alzheimer disease and neurodegenerative disease states such as Parkinson disease and dementia with Lewy bodies. Interventions to improve sleep and treat obstructive sleep apnea may play a vital role in preventing neurologic disease development and progression.

ESSENTIAL POINTS: Sleep disorders are common among patients with neurologic disorders. To provide comprehensive care to patients with neurologic conditions, neurologists must ask patients about sleep issues that may warrant further diagnostic testing, treatment, and sleep medicine referral when indicated.}, } @article {pmid37590144, year = {2023}, author = {Hendricks, E and Quihuis, AM and Hung, ST and Chang, J and Dorjsuren, N and Der, B and Staats, KA and Shi, Y and Sta Maria, NS and Jacobs, RE and Ichida, JK}, title = {The C9ORF72 repeat expansion alters neurodevelopment.}, journal = {Cell reports}, volume = {42}, number = {8}, pages = {112983}, pmid = {37590144}, issn = {2211-1247}, support = {R00 NS077435/NS/NINDS NIH HHS/United States ; R01 NS097850/NS/NINDS NIH HHS/United States ; R44 NS097094/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; *C9orf72 Protein/genetics ; Dipeptides ; *Frontotemporal Dementia/genetics ; Mutation ; Disease Models, Animal ; }, abstract = {Genetic mutations that cause adult-onset neurodegenerative diseases are often expressed during embryonic stages, but it is unclear whether they alter neurodevelopment and how this might influence disease onset. Here, we show that the most common cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), a repeat expansion in C9ORF72, restricts neural stem cell proliferation and reduces cortical and thalamic size in utero. Surprisingly, a repeat expansion-derived dipeptide repeat protein (DPR) not known to reduce neuronal viability plays a key role in impairing neurodevelopment. Pharmacologically mimicking the effects of the repeat expansion on neurodevelopment increases susceptibility of C9ORF72 mice to motor defects. Thus, the C9ORF72 repeat expansion stunts development of the brain regions prominently affected in C9ORF72 FTD/ALS patients.}, } @article {pmid37589710, year = {2023}, author = {Shu, L and Du, C and Zuo, Y}, title = {Abnormal phosphorylation of protein tyrosine in neurodegenerative diseases.}, journal = {Journal of neuropathology and experimental neurology}, volume = {82}, number = {10}, pages = {826-835}, doi = {10.1093/jnen/nlad066}, pmid = {37589710}, issn = {1554-6578}, mesh = {Humans ; Phosphorylation ; *Neurodegenerative Diseases/pathology ; Tyrosine/metabolism ; Signal Transduction ; Protein-Tyrosine Kinases ; Protein Tyrosine Phosphatases/metabolism ; }, abstract = {Neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis, are chronic disorders of the CNS that are characterized by progressive neuronal dysfunction. These diseases have diverse clinical and pathological features and their pathogenetic mechanisms are not yet fully understood. Currently, widely accepted hypotheses include the accumulation of misfolded proteins, oxidative stress from reactive oxygen species, mitochondrial dysfunction, DNA damage, neurotrophin dysfunction, and neuroinflammatory processes. In the CNS of patients with neurodegenerative diseases, a variety of abnormally phosphorylated proteins play important roles in pathological processes such as neuroinflammation and intracellular accumulation of β-amyloid plaques and tau. In recent years, the roles of abnormal tyrosine phosphorylation of intracellular signaling molecules regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) in neurodegenerative diseases have attracted increasing attention. Here, we summarize the roles of signaling pathways related to protein tyrosine phosphorylation in the pathogenesis of neurodegenerative diseases and the progress of therapeutic studies targeting PTKs and PTPs that provide theoretical support for future studies on therapeutic strategies for these devastating and important neurodegenerative diseases.}, } @article {pmid37587694, year = {2023}, author = {Taylor, M and Marx, O and Norris, A}, title = {TDP-1 and FUST-1 co-inhibit exon inclusion and control fertility together with transcriptional regulation.}, journal = {Nucleic acids research}, volume = {51}, number = {18}, pages = {9610-9628}, pmid = {37587694}, issn = {1362-4962}, support = {R01 NS111055/NS/NINDS NIH HHS/United States ; R35GM133461/GM/NIGMS NIH HHS/United States ; R35 GM133461/GM/NIGMS NIH HHS/United States ; R01NS111055/NS/NINDS NIH HHS/United States ; /NH/NIH HHS/United States ; }, abstract = {Gene expression is a multistep process and crosstalk among regulatory layers plays an important role in coordinating gene expression. To identify functionally relevant gene expression coordination, we performed a systematic reverse-genetic interaction screen in C. elegans, combining RNA binding protein (RBP) and transcription factor (TF) mutants to generate over 100 RBP;TF double mutants. We identified many unexpected double mutant phenotypes, including two strong genetic interactions between the ALS-related RBPs, fust-1 and tdp-1, and the homeodomain TF ceh-14. Losing any one of these genes alone has no effect on the health of the organism. However, fust-1;ceh-14 and tdp-1;ceh-14 double mutants both exhibit strong temperature-sensitive fertility defects. Both double mutants exhibit defects in gonad morphology, sperm function, and oocyte function. RNA-Seq analysis of double mutants identifies ceh-14 as the main controller of transcript levels, while fust-1 and tdp-1 control splicing through a shared role in exon inhibition. A skipped exon in the polyglutamine-repeat protein pqn-41 is aberrantly included in tdp-1 mutants, and genetically forcing this exon to be skipped in tdp-1;ceh-14 double mutants rescues their fertility. Together our findings identify a novel shared physiological role for fust-1 and tdp-1 in promoting C. elegans fertility and a shared molecular role in exon inhibition.}, } @article {pmid37587387, year = {2023}, author = {Hamad, AA and Amer, BE and Al Mawla, AM and Goufa, E and Abdelwahab, MM and Serag, I}, title = {Clinical characteristics, course, and outcomes of amyotrophic lateral sclerosis overlapping with pregnancy: a systematic review of 38 published cases.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {12}, pages = {4219-4231}, pmid = {37587387}, issn = {1590-3478}, mesh = {Female ; Infant, Newborn ; Humans ; Pregnancy ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; *Neurodegenerative Diseases/complications ; Prognosis ; Health Status ; Databases, Factual ; }, abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disease that can overlap with pregnancy, but little is known about its clinical characteristics, course, and outcomes in this context. This systematic review aimed to synthesize the current evidence on ALS overlapping with pregnancy.

METHODS: We comprehensively searched four databases on February 2, 2023, to identify case studies reporting cases of ALS overlapping with pregnancy. Joanna Brigs Institute tool was followed to assess the quality of the included studies.

RESULTS: Twenty-six articles reporting 38 cases were identified and included in our study. Out of the 38 cases, 18 were aged < 30 years. The onset of ALS was before pregnancy in 18 cases, during pregnancy in 16 cases, and directly after pregnancy in 4 cases. ALS progression course was rapid or severe in 55% of the cases during pregnancy, and this percentage reached 61% in cases with an onset of ALS before pregnancy. While ALS progression course after pregnancy was rapid or severe in 63% and stable in 37% of the cases. Most cases (95%) were able to complete the pregnancy and gave live birth. However, preterm delivery was common. For neonates, 86% were healthy without any complications.

CONCLUSION: While pregnancy with ALS is likely to survive and result in giving birth to healthy infants, it could be associated with rapid or severe progression of ALS and result in a worse prognosis, highlighting the importance of close monitoring and counselling for patients and healthcare providers.}, } @article {pmid37586842, year = {2024}, author = {Honda, H and Yagita, K and Arahata, H and Hamasaki, H and Noguchi, H and Koyama, S and Sasagasako, N}, title = {Increased expression of human antiviral protein MxA in FUS proteinopathy in amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {2}, pages = {e13191}, pmid = {37586842}, issn = {1750-3639}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Antiviral Agents/metabolism ; Mutation ; Neurons/pathology ; RNA-Binding Protein FUS/genetics ; }, abstract = {FUS mutations are one of the major mutations in familial amyotrophic lateral sclerosis (ALS). The pathological hallmark is FUS-positive neuronal cytoplasmic inclusions (FUS-NCI), known as FUS proteinopathy. Human myxovirus resistance protein 1 (MxA) is an IFN-induced dynamin-like GTPase that acts as antiviral factor. In this study, we examined the expression of MxA in neurons bearing FUS-NCI. We performed immunohistochemistry for FUS and MxA to examine the expression of MxA in two autopsy cases with different FUS gene mutations localized at the nuclear localization signal site (Case 1, H517P; Case 2, R521C). MxA. Most neurons bearing FUS-NCI have increased cytoplasmic MxA expression. Increased cytoplasmic MxA showed several distribution patterns in relation to FUS-NCIs such as the following: colocalization with NCI, distribution more widely than NCI, and different distribution peaks from NCI. Our results suggested that antiviral signaling IFNs are involved upstream in the formation of FUS-NCI in ALS-FUS patients.}, } @article {pmid37585529, year = {2023}, author = {Mann, JR and McKenna, ED and Mawrie, D and Papakis, V and Alessandrini, F and Anderson, EN and Mayers, R and Ball, HE and Kaspi, E and Lubinski, K and Baron, DM and Tellez, L and Landers, JE and Pandey, UB and Kiskinis, E}, title = {Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import.}, journal = {Science advances}, volume = {9}, number = {33}, pages = {eadi5548}, pmid = {37585529}, issn = {2375-2548}, support = {R01 NS134166/NS/NINDS NIH HHS/United States ; R56 NS073873/NS/NINDS NIH HHS/United States ; I01 BX002466/BX/BLRD VA/United States ; P41 GM108569/GM/NIGMS NIH HHS/United States ; R01 NS073873/NS/NINDS NIH HHS/United States ; T32 AG020506/AG/NIA NIH HHS/United States ; P30 CA060553/CA/NCI NIH HHS/United States ; F31 NS117084/NS/NINDS NIH HHS/United States ; S10 OD025194/OD/NIH HHS/United States ; R01 NS104219/NS/NINDS NIH HHS/United States ; T32 NS041234/NS/NINDS NIH HHS/United States ; R21 NS107761/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Active Transport, Cell Nucleus ; NIMA-Related Kinase 1/genetics ; Proteins ; Motor Neurons ; Microtubules ; Homeostasis ; }, abstract = {Loss-of-function variants in NIMA-related kinase 1 (NEK1) constitute a major genetic cause of amyotrophic lateral sclerosis (ALS), accounting for 2 to 3% of all cases. However, how NEK1 mutations cause motor neuron (MN) dysfunction is unknown. Using mass spectrometry analyses for NEK1 interactors and NEK1-dependent expression changes, we find functional enrichment for proteins involved in the microtubule cytoskeleton and nucleocytoplasmic transport. We show that α-tubulin and importin-β1, two key proteins involved in these processes, are phosphorylated by NEK1 in vitro. NEK1 is essential for motor control and survival in Drosophila models in vivo, while using several induced pluripotent stem cell (iPSC)-MN models, including NEK1 knockdown, kinase inhibition, and a patient mutation, we find evidence for disruptions in microtubule homeostasis and nuclear import. Notably, stabilizing microtubules with two distinct classes of drugs restored NEK1-dependent deficits in both pathways. The capacity of NEK1 to modulate these processes that are critically involved in ALS pathophysiology renders this kinase a formidable therapeutic candidate.}, } @article {pmid37584401, year = {2023}, author = {Casiraghi, A and Gentile, A and Marjanovic, I and Chiò, A}, title = {Crushing riluzole tablets: evaluation of loss of powder and active principle in a home-simulation experiment.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2023.2245860}, pmid = {37584401}, issn = {2167-9223}, abstract = {Objective: Swallowing difficulties cause patients with amyotrophic lateral sclerosis (ALS) to crush oral medications, falling outside the labeling instructions and entailing some risks. To date, there is no evidence about consequences of crushing riluzole tablets in a home setting. This simulation experiment evaluated the loss of powder and active principle ingredient (API) mimicking the home setting with two alternative crushing methods (A and B). Methods: The tests were carried out by 15 volunteers without experience in the preparation of medication. Each volunteer manually crushed 5 tablets with a meat tenderizer (method A) or two spoons pressed against each other (method B). Riluzole was weighed before (W1) and after crushing (W2). Then, a subsample of crushed tablets was analyzed by HPLC to measure API content. The loss of powder was calculated as a percentage of the intact tablet weight, and the loss of API as a percentage of the labeled API content. Results: The quantitative analysis showed a mean percentage loss of 6.27% corresponding to a mean (SD) loss of powder of 13(±13) mg. The API loss was directly related to the powder loss: overall the mean percentage of API loss was 8.53% (corresponding to a mean API loss of 4.27 ± 4.50 mg). The difference in powder and API loss was highly statistically significant. Conclusion: Crushing riluzole tablets in a simulated home setting determined a significant loss of powder and API. These results support neurologists to evaluate formulations that minimize the need to alter the product and can improve ALS patient journey.}, } @article {pmid37584389, year = {2024}, author = {Liu, S and Sun, X and Ren, Q and Chen, Y and Dai, T and Yang, Y and Gong, G and Li, W and Zhao, Y and Meng, X and Lin, P and Yan, C}, title = {Glymphatic dysfunction in patients with early-stage amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {1}, pages = {100-108}, doi = {10.1093/brain/awad274}, pmid = {37584389}, issn = {1460-2156}, support = {2020M672067//China Postdoctoral Science Foundation/ ; NSFC82001354//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/complications ; Diffusion Tensor Imaging ; *Neurodegenerative Diseases ; Retrospective Studies ; Aquaporin 4 ; }, abstract = {Recently, an astrocytic aquaporin 4-dependent drainage system, that is, the glymphatic system, has been identified in the live murine and human brain. Growing evidence suggests that glymphatic function is impaired in patients with several neurodegenerative diseases, including Alzheimer's and Parkinson's disease. As the third most common neurodegenerative disease, although animal studies have indicated that early glymphatic dysfunction is likely an important pathological mechanism underpinning amyotrophic lateral sclerosis (ALS), no available study has been conducted to thoroughly assess glymphatic function in vivo in ALS patients to date, particularly in patients with early-stage ALS. Thus, using diffusion tensor imaging analysis along the perivascular space (ALPS) index, an approximate measure of glymphatic function in vivo, we aimed to explore whether glymphatic function is impaired in patients with patients with early-stage ALS, and the diagnostic performance of the ALPS index in distinguishing between patients with early-stage ALS and healthy subjects. We also aimed to identify the relationships between glymphatic dysfunction and clinical disabilities and sleep problems in patients with early-stage ALS. In this retrospective study, King's Stage 1 ALS patients were defined as patients with early-stage ALS. We enrolled 56 patients with early-stage ALS and 32 age- and sex-matched healthy control subjects. All participants completed clinical screening, sleep assessment and ALPS index analysis. For the sleep assessment, the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and polysomnography were used. Compared with healthy control subjects, patients with early-stage ALS had a significantly lower ALPS index after family-wise error correction (P < 0.05). Moreover, receiver operating characteristic analysis showed that the area under the curve for the ALPS index was 0.792 (95% confidence interval 0.700-0.884). Partial correlation analyses showed that the ALPS index was significantly correlated with clinical disability and sleep disturbances in patients with early-stage ALS. Multivariate analysis showed that sleep efficiency (r = 0.419, P = 0.002) and periodic limb movements in sleep index (r = -0.294, P = 0.017) were significant predictive factors of the ALPS index in patients with early-stage ALS. In conclusion, our study continues to support an important role for glymphatic dysfunction in ALS pathology, and we provide additional insights into the early diagnostic value of glymphatic dysfunction and its correlation with sleep disturbances in vivo in patients with early-stage ALS. Moreover, we suggest that early improvement of glymphatic function may be a promising strategy for slowing the neurodegenerative process in ALS. Future studies are needed to explore the diagnostic and therapeutic value of glymphatic dysfunction in individuals with presymptomatic-stage neurodegenerative diseases.}, } @article {pmid37582053, year = {2024}, author = {Assoni, AF and Guerrero, EN and Wardenaar, R and Oliveira, D and Bakker, PL and Alves, LM and Carvalho, VM and Okamoto, OK and Zatz, M and Foijer, F}, title = {IFNγ protects motor neurons from oxidative stress via enhanced global protein synthesis in FUS-associated amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {1}, pages = {e13206}, pmid = {37582053}, issn = {1750-3639}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Motor Neurons/metabolism ; Mutation ; Oxidative Stress ; RNA-Binding Protein FUS/genetics ; }, abstract = {Amyotrophic lateral sclerosis type 6 (ALS6) is a familial subtype of ALS linked to Fused in Sarcoma (FUS) gene mutation. FUS mutations lead to decreased global protein synthesis, but the mechanism that drives this has not been established. Here, we used ALS6 patient-derived induced pluripotent stem cells (hIPSCs) to study the effect of the ALS6 FUS[R521H] mutation on the translation machinery in motor neurons (MNs). We find, in agreement with findings of others, that protein synthesis is decreased in FUS[R521H] MNs. Furthermore, FUS[R521H] MNs are more sensitive to oxidative stress and display reduced expression of TGF-β and mTORC gene pathways when stressed. Finally, we show that IFNγ treatment reduces apoptosis of FUS[R521H] MNs exposed to oxidative stress and partially restores the translation rates in FUS[R521H] MNs. Overall, these findings suggest that a functional IFNγ response is important for FUS-mediated protein synthesis, possibly by FUS nuclear translocation in ALS6.}, } @article {pmid37581600, year = {2023}, author = {Mehdipour, A and Teshler, L and Dal Bello-Haas, V and Richardson, J and Beauchamp, M and Turnbull, J and Chum, M and Johnston, W and O'Connell, C and Luth, W and Kuspinar, A}, title = {Assessing the Measurement Properties of the Self-Administered Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R): A Rasch Analysis.}, journal = {Physical therapy}, volume = {103}, number = {11}, pages = {}, doi = {10.1093/ptj/pzad109}, pmid = {37581600}, issn = {1538-6724}, support = {//ALS Society of Canada Project/ ; }, mesh = {Male ; Humans ; Middle Aged ; Female ; *Amyotrophic Lateral Sclerosis ; Reproducibility of Results ; Language ; Psychometrics ; Disease Progression ; }, abstract = {OBJECTIVE: The self-administered version of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is used to monitor function and disease progression in individuals with amyotrophic lateral sclerosis (ALS). However, the performance of the self-administered ALSFRS-R has not been assessed using Rasch Measurement Theory. Therefore, the purpose of this study was to examine the psychometric properties of the self-administered ALSFRS-R using Rasch analysis.

METHODS: Rasch analysis was performed on self-administered ALSFRS-R data from individuals with ALS across Canada. The following 6 aspects of Rasch analysis were examined using RUMM2030: fit via residuals and chi-square statistics, targeting via person-item threshold maps, dependency via item residual correlations, unidimensionality through principal components analysis of residuals, reliability via person separation index, and stability through differential item functioning analyses for sex, age, and language.

RESULTS: Analysis was performed on 122 participants (mean age: 52.9 years; 62.8% men). The overall scale demonstrated good fit, reliability, and stability; however, multidimensionality was found. To address this issue, items were divided into 3 subscales (bulbar, motor, and respiratory function), and Rasch analysis was performed for each subscale. The subscales demonstrated good fit, reliability, stability, and unidimensionality. However, there were still issues with item dependency for all subscale and targeting for bulbar and respiratory subscales.

CONCLUSIONS: The self-administered ALSFRS-R is reliable, internally valid, and stable across sex, age, and language subgroups; however, it is recommended that the ALSFRS-R be scored by subscale. Future studies can look at revising and/or adding items to tackle misfit, redundancy, and ceiling effects.

IMPACT: Self-administered measures are simple to administer and inexpensive. The self-administered ALSFRS-R was found to be psychometrically sound and can be used as a tool to monitor disease progression and function in ALS.}, } @article {pmid37581487, year = {2023}, author = {van Roon-Mom, W and Ferguson, C and Aartsma-Rus, A}, title = {From Failure to Meet the Clinical Endpoint to U.S. Food and Drug Administration Approval: 15th Antisense Oligonucleotide Therapy Approved Qalsody (Tofersen) for Treatment of SOD1 Mutated Amyotrophic Lateral Sclerosis.}, journal = {Nucleic acid therapeutics}, volume = {33}, number = {4}, pages = {234-237}, doi = {10.1089/nat.2023.0027}, pmid = {37581487}, issn = {2159-3345}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Mutation ; *Oligonucleotides, Antisense/therapeutic use ; Superoxide Dismutase-1/genetics ; United States ; United States Food and Drug Administration ; Drug Approval ; Endpoint Determination ; }, } @article {pmid37581144, year = {2023}, author = {Risavi, BL and Carlson, J and Reese, EM and Raleigh, A and Wallis, J}, title = {Prehospital Surgical Airway Management Skills in a Rural Emergency Medical Service System.}, journal = {Cureus}, volume = {15}, number = {7}, pages = {e41864}, pmid = {37581144}, issn = {2168-8184}, abstract = {BACKGROUND: The objective of this study is to describe the education, training, and use of prehospital surgical airways in a rural Emergency Medical Service (EMS) system.

MATERIALS AND METHODS: We conducted an internet-based survey instrument of all advanced life support (ALS) EMS agencies in a seven-county rural EMS system in Pennsylvania. ALS agencies were queried regarding basic demographic information as well as the number of surgical airways performed in the previous 10 years as well as the education and training of EMS providers in surgical airways.

RESULTS: The survey was completed by 11 of 20 ALS EMS agencies in our region (55% rate of return). The content and frequency of training varied considerably among EMS agencies. Only four prehospital surgical airways were performed during the study period. One patient survived to hospital discharge to home.

CONCLUSION: Surgical airways are an infrequently performed procedure in the rural prehospital setting. There is no universally accepted standard for teaching or evaluating the competency of this potentially life-saving procedure. Further efforts to establish a core educational curriculum appear warranted.}, } @article {pmid37579999, year = {2023}, author = {Lin, S and Zhang, H and Qi, M and Cooper, DN and Yang, Y and Yang, Y and Zhao, H}, title = {Inferring the genetic relationship between brain imaging-derived phenotypes and risk of complex diseases by Mendelian randomization and genome-wide colocalization.}, journal = {NeuroImage}, volume = {279}, number = {}, pages = {120325}, doi = {10.1016/j.neuroimage.2023.120325}, pmid = {37579999}, issn = {1095-9572}, mesh = {Humans ; *Depressive Disorder, Major/diagnostic imaging/genetics ; *Cardiovascular Diseases/diagnostic imaging/genetics ; Genome-Wide Association Study/methods ; *Autism Spectrum Disorder/diagnostic imaging/genetics ; *Amyotrophic Lateral Sclerosis ; Mendelian Randomization Analysis/methods ; Phenotype ; *Brain Diseases/diagnostic imaging/genetics ; *Hypertension ; Neuroimaging ; }, abstract = {Observational studies consistently disclose brain imaging-derived phenotypes (IDPs) as critical markers for early diagnosis of both brain disorders and cardiovascular diseases. However, it remains unclear about the shared genetic landscape between brain IDPs and the risk of brain disorders and cardiovascular diseases, restricting the applications of potential diagnostic techniques through brain IDPs. Here, we reported genetic correlations and putative causal relationships between 921 brain IDPs, 20 brain disorders and six cardiovascular diseases by leveraging their large-scale genome-wide association study (GWAS) summary statistics. Applications of Mendelian randomization (MR) identified significant putative causal effects of multiple region-specific brain IDPs in relation to the increased risks for amyotrophic lateral sclerosis (ALS), major depressive disorder (MDD), autism spectrum disorder (ASD) and schizophrenia (SCZ). We also found brain IDPs specifically from temporal lobe as a putatively causal consequence of hypertension. The genome-wide colocalization analysis identified three genomic regions in which MDD, ASD and SCZ colocalized with the brain IDPs, and two novel SNPs to be associated with ASD, SCZ, and multiple brain IDPs. Furthermore, we identified a list of candidate genes involved in the shared genetics underlying pairs of brain IDPs and MDD, ASD, SCZ, ALS and hypertension. Our results provide novel insights into the genetic relationships between brain disorders and cardiovascular diseases and brain IDP, which may server as clues for using brain IDPs to predict risks of diseases.}, } @article {pmid37579835, year = {2023}, author = {Yadav, H and Jaldhi, and Bhardwaj, R and Anamika, and Bakshi, A and Gupta, S and Maurya, SK}, title = {Unveiling the role of gut-brain axis in regulating neurodegenerative diseases: A comprehensive review.}, journal = {Life sciences}, volume = {330}, number = {}, pages = {122022}, doi = {10.1016/j.lfs.2023.122022}, pmid = {37579835}, issn = {1879-0631}, mesh = {Humans ; *Neurodegenerative Diseases ; Brain-Gut Axis ; *Parkinson Disease/therapy ; *Gastrointestinal Microbiome/physiology ; *Probiotics/therapeutic use ; Brain ; }, abstract = {Emerging evidence have shown the importance of gut microbiota in regulating brain functions. The diverse molecular mechanisms involved in cross-talk between gut and brain provide insight into importance of this communication in maintenance of brain homeostasis. It has also been observed that disturbed gut microbiota contributes to neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and aging. Recently, gut microbiome-derived exosomes have also been reported to play an essential role in the development and progression of neurodegenerative diseases and could thereby act as a therapeutic target. Further, pharmacological interventions including antibiotics, prebiotics and probiotics can influence gut microbiome-mediated management of neurological diseases. However, extensive research is warranted to better comprehend this interconnection in maintenance of brain homeostasis and its implication in neurological diseases. Thus, the present review is aimed to provide a detailed understanding of gut-brain axis followed by possibilities to target the gut microbiome for improving neurological health.}, } @article {pmid37579155, year = {2023}, author = {Mohanty, P and Shenoy, J and Rizuan, A and Mercado-Ortiz, JF and Fawzi, NL and Mittal, J}, title = {A synergy between site-specific and transient interactions drives the phase separation of a disordered, low-complexity domain.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {34}, pages = {e2305625120}, pmid = {37579155}, issn = {1091-6490}, support = {R01 NS116176/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Protein Domains ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Frontotemporal Dementia/genetics ; DNA-Binding Proteins/metabolism ; Methionine ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is involved in key processes in RNA metabolism and is frequently implicated in many neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia. The prion-like, disordered C-terminal domain (CTD) of TDP-43 is aggregation-prone, can undergo liquid-liquid phase separation (LLPS) in isolation, and is critical for phase separation (PS) of the full-length protein under physiological conditions. While a short conserved helical region (CR, spanning residues 319-341) promotes oligomerization and is essential for LLPS, aromatic residues in the flanking disordered regions (QN-rich, IDR1/2) are also found to play a critical role in PS and aggregation. Compared with other phase-separating proteins, TDP-43 CTD has a notably distinct sequence composition including many aliphatic residues such as methionine and leucine. Aliphatic residues were previously suggested to modulate the apparent viscosity of the resulting phases, but their direct contribution toward CTD phase separation has been relatively ignored. Using multiscale simulations coupled with in vitro saturation concentration (csat) measurements, we identified the importance of aromatic residues while also suggesting an essential role for aliphatic methionine residues in promoting single-chain compaction and LLPS. Surprisingly, NMR experiments showed that transient interactions involving phenylalanine and methionine residues in the disordered flanking regions can directly enhance site-specific, CR-mediated intermolecular association. Overall, our work highlights an underappreciated mode of biomolecular recognition, wherein both transient and site-specific hydrophobic interactions act synergistically to drive the oligomerization and phase separation of a disordered, low-complexity domain.}, } @article {pmid37579081, year = {2023}, author = {Sulistyo, A and Abrahao, A and Freitas, ME and Ritsma, B and Zinman, L}, title = {Enteral tube feeding for amyotrophic lateral sclerosis/motor neuron disease.}, journal = {The Cochrane database of systematic reviews}, volume = {8}, number = {8}, pages = {CD004030}, pmid = {37579081}, issn = {1469-493X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Deglutition Disorders/therapy/complications ; Enteral Nutrition/methods ; Intubation, Gastrointestinal ; *Motor Neuron Disease/complications ; }, abstract = {BACKGROUND: Maintaining adequate nutrition is critical for people with amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND). Enteral tube feeding is offered to people experiencing difficulty swallowing (dysphagia) to prevent weight loss and aspiration pneumonia. Among the types of enteral tube feeding, percutaneous endoscopic gastrostomy (PEG) is the typical procedure offered to people with ALS and will be mainly discussed here.

OBJECTIVES: To examine the effectiveness of percutaneous endoscopic gastrostomy or other enteral tube feeding in people with ALS, compared to oral feeds without enteral tube feeding on: 1. survival; 2. nutritional status; 3. quality of life. To examine the incidence of minor and major complications of percutaneous endoscopic gastrostomy (PEG) and other enteral tube feeding procedures in people with ALS.

SEARCH METHODS: On 3 January 2020 and 6 February 2021, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE. Embase, ClinicalTrials.gov and WHO ICTRP. We screened the results to identify randomized controlled studies on enteral tube feeding in ALS. We reviewed all references from the search in published articles to identify any additional references.

SELECTION CRITERIA: We included randomized controlled trials (RCTs), quasi-RCTs, and cross-over trials evaluating the effectiveness and complications of PEG or other enteral tube feeding placement in ALS.

DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane.

MAIN RESULTS: We found no RCTs or quasi-RCTs comparing the effectiveness of enteral tube feeding versus oral feeds without enteral tube feeding.

AUTHORS' CONCLUSIONS: There are no RCTs or quasi-RCTs to indicate whether enteral tube feeding is effective compared to continuation of oral feeding for any of the outcome measures. Such RCTs are very unlikely to be performed for ethical reasons. RCTs evaluating the effect of different enteral tube insertion techniques and timings of tube placement on survival and quality of life of people with ALS dysphagia are feasible and warranted.}, } @article {pmid37578398, year = {2024}, author = {Baskar, D and Veeramani-Kumar, P and Polavarapu, K and Nashi, S and Vengalil, S and Menon, D and Thomas, A and Bhargava Sanka, S and Muddasu Suhasini, K and Huddar, A and Unnikrishnan, G and Bardhan, M and Thomas, PT and Manjunath, N and Atchayaram, N}, title = {Clinical spectrum, biochemical profile and disease progression of Kennedy disease in an Indian cohort.}, journal = {Internal medicine journal}, volume = {54}, number = {3}, pages = {455-460}, doi = {10.1111/imj.16205}, pmid = {37578398}, issn = {1445-5994}, mesh = {Humans ; *Bulbo-Spinal Atrophy, X-Linked ; Retrospective Studies ; Disease Progression ; }, abstract = {BACKGROUND: Kennedy disease (KD) is a slowly progressive lower motor neuron degenerative disease. The prevalence of KD is unknown in India.

AIM: To describe the phenotypic and laboratory features of an Indian cohort of KD patients.

METHODS: A retrospective study was done on seven genetically confirmed KD patients based on demographic, clinical and laboratory details.

RESULTS: Mean age at onset and presentation was 37 ± 11.9 and 44.6 ± 13.5 years respectively. Progressive asymmetric proximal and distal limb weakness was the commonest symptom (57.1%). All patients had motor symptoms along with non-specific symptoms such as cramps from the onset. Easy fatigability, decremental response along with ptosis were noted in two patients, which was a novel finding. Gynaecomastia and tongue wasting with fasciculations were universal findings. All five patients with nerve conduction studies showed sensorimotor neuropathy. Magnetic resonance imaging muscle done in two patients showed a prominent moth-eaten appearance in the thigh and posterior leg compartment in one patient. The mean cytosine-adenine-guanine repeats were 44 ± 3.7, and there was no association between age of onset or severity with repeat length. Only one patient required an assistive device for ambulation after 15 years of symptom onset.

CONCLUSIONS: This study showed phenotypic heterogeneity in the Indian cohort. The age of onset was earlier with a slowly progressive indolent course as compared with other ethnic cohorts. This highlights the importance of considering the KD diagnosis in patients with the indolent course and suspected ALS diagnosis even with ptosis and fatigability in an appropriate clinical context.}, } @article {pmid37577689, year = {2023}, author = {Alvarado, CX and Weller, CA and Johnson, N and Leonard, HL and Singleton, AB and Reed, X and Blauewendraat, C and Nalls, M}, title = {Human brain single nucleus cell type enrichments in neurodegenerative diseases.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {37577689}, abstract = {Single cell RNA sequencing has opened a window into clarifying the complex underpinnings of disease, particularly in quantifying the relevance of tissue- and cell-type-specific gene expression. To identify the cell types and genes important to therapeutic target development across the neurodegenerative disease spectrum, we leveraged genome-wide association studies, recent single cell sequencing data, and bulk expression studies in a diverse series of brain region tissues. We were able to identify significant immune-related cell types in the brain across three major neurodegenerative diseases: Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Parkinson's Diseases. Subsequently, we identified the major role of 30 fine-mapped loci implicating seven genes in multiple neurodegenerative diseases and their pathogenesis.}, } @article {pmid37577533, year = {2023}, author = {Duffy, MF and Ding, J and Langston, RG and Shah, SI and Nalls, MA and Scholz, SW and Whitaker, DT and Auluck, PK and Marenco, S and Gibbs, JR and Cookson, MR}, title = {Divergent patterns of healthy aging across human brain regions at single-cell resolution reveal links to neurodegenerative disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37577533}, issn = {2692-8205}, support = {P30 AG050911/AG/NIA NIH HHS/United States ; ZIA AG000539/ImNIH/Intramural NIH HHS/United States ; ZIA NS003154/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Age is a major common risk factor underlying neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Previous studies reported that chronological age correlates with differential gene expression across different brain regions. However, prior datasets have not disambiguated whether expression associations with age are due to changes in cell numbers and/or gene expression per cell. In this study, we leveraged single nucleus RNA-sequencing (snRNAseq) to examine changes in cell proportions and transcriptomes in four different brain regions, each from 12 donors aged 20-30 years (young) or 60-85 years (old). We sampled 155,192 nuclei from two cortical regions (entorhinal cortex and middle temporal gyrus) and two subcortical regions (putamen and subventricular zone) relevant to neurodegenerative diseases or the proliferative niche. We found no changes in cellular composition of different brain regions with healthy aging. Surprisingly, we did find that each brain region has a distinct aging signature, with only minor overlap in differentially associated genes across regions. Moreover, each cell type shows distinct age-associated expression changes, including loss of protein synthesis genes in cortical inhibitory neurons, axonogenesis genes in excitatory neurons and oligodendrocyte precursor cells, enhanced gliosis markers in astrocytes and disease-associated markers in microglia, and genes critical for neuron-glia communication. Importantly, we find cell type-specific enrichments of age associations with genes nominated by Alzheimer's disease and Parkinson's disease genome-wide association studies (GWAS), such as apolipoprotein E (APOE), and leucine-rich repeat kinase 2 (LRRK2) in microglia that are independent of overall expression levels across cell types. We present this data as a new resource which highlights, first, region- and cell type-specific transcriptomic changes in healthy aging that may contribute to selective vulnerability and, second, provide context for testing GWAS-nominated disease risk genes in relevant subtypes and developing more targeted therapeutic strategies. The data is readily accessible without requirement for extensive computational support in a public website, https://brainexp-hykyffa56a-uc.a.run.app/.}, } @article {pmid37577380, year = {2023}, author = {Thompson, AG and Marsden, R and Talbot, K and Turner, MR}, title = {Primary care blood tests show lipid profile changes in pre-symptomatic amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {5}, number = {4}, pages = {fcad211}, pmid = {37577380}, issn = {2632-1297}, support = {MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {Multiple sources of evidence suggest that changes in metabolism may precede the onset of motor symptoms in amyotrophic lateral sclerosis. This study aimed to seek evidence for alterations in the levels of blood indices collected routinely in the primary care setting prior to the onset of motor symptoms in amyotrophic lateral sclerosis. Premorbid data, measured as part of routine health screening, for total cholesterol, high-density and low-density lipoprotein cholesterol, triglyceride, glycated haemoglobin A1c and creatinine were collected retrospectively from (i) a cohort of amyotrophic lateral sclerosis patients attending a specialist clinic (n = 143) and (ii) from primary care-linked data within UK Biobank. Data were fitted using linear mixed effects models with linear b-splines to identify inflection points, controlling for age and sex. In specialist amyotrophic lateral sclerosis clinic cases, models indicated decreasing levels of total and low-density lipoprotein cholesterol prior to an inflection point in the years before symptom onset (total cholesterol 3.25 years, low-density lipoprotein cholesterol 1.25 years), after which they stabilized or rose. A similar pattern was observed in amyotrophic lateral sclerosis cases within UK Biobank, occurring several years prior to diagnosis (total cholesterol 7 years, low-density lipoprotein cholesterol 7.25 years), differing significantly from matched controls. High-density lipoprotein cholesterol followed a similar pattern but was less robust to sensitivity analyses. Levels of triglyceride remained stable throughout. Glycated haemoglobin temporal profiles were not consistent between the clinic and biobank cohorts. Creatinine level trajectories prior to amyotrophic lateral sclerosis did not differ significantly from controls but decreased significantly in the symptomatic period after an inflection point of 0.25 years after symptom onset (clinic cohort) or 0.5 years before diagnosis (UK Biobank). These data provide further evidence for a pre-symptomatic period of dynamic metabolic change in amyotrophic lateral sclerosis, consistently associated with alterations in blood cholesterols. Such changes may ultimately contribute to biomarkers applicable to population screening and for pathways guiding the targeting of preventative therapy.}, } @article {pmid37576491, year = {2023}, author = {Seidel, M and Rajkumar, S and Steffke, C and Noeth, V and Agarwal, S and Roger, K and Lipecka, J and Ludolph, A and Guerrera, CI and Boeckers, T and Catanese, A}, title = {Propranolol reduces the accumulation of cytotoxic aggregates in C9orf72-ALS/FTD in vitro models.}, journal = {Current research in neurobiology}, volume = {5}, number = {}, pages = {100105}, pmid = {37576491}, issn = {2665-945X}, abstract = {Mutations in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The pathogenetic mechanisms linked to this gene are a direct consequence of an aberrant intronic expansion of a GGGGCC hexanucleotide located between the 1a and 1b non-coding exons, which can be transcribed to form cytotoxic RNA foci or even translated into aggregation-prone dipeptide repeat proteins. Importantly, the abnormal length of these repeats affects also the expression levels of C9orf72 itself, which suggests haploinsufficiency as additional pathomechanism. Thus, it appears that both toxic gain of function and loss of function are distinct but still coexistent features contributing to the insurgence of the disease in case of C9orf72 mutations. In this study, we aimed at identifying a strategy to address both aspects of the C9orf72-related pathobiochemistry and provide proof-of-principle information for a better understanding of the mechanisms leading to neuronal loss. By using primary neurons overexpressing toxic poly(GA), the most abundant protein product of the GGGGCC repeats, we found that the antiarrhythmic drug propranolol could efficiently reduce the accumulation of aberrant aggregates and increase the survival of C9orf72-related cultures. Interestingly, the improved catabolism appeared to not depend on major degradative pathways such as autophagy and the proteasome. By analyzing the proteome of poly(GA)-expressing neurons after exposure to propranolol, we found that the drug increased lysosomal degradation through a mechanism directly involving C9orf72 protein, whose levels were increased after treatment. Further confirmation of the beneficial effect of the beta blocker on aggregates' accumulation and survival of hiPSC-derived C9orf72-mutant motoneurons strengthened the finding that addressing both facets of C9orf72 pathology might represent a valid strategy for the treatment of these ALS/FTD cases.}, } @article {pmid37576467, year = {2023}, author = {Yang, D and Wheeler, M and Karanth, SD and Aduse-Poku, L and Leeuwenburgh, C and Anton, S and Guo, Y and Bian, J and Liang, M and Yoon, HS and Akinyemiju, T and Braithwaite, D and Zhang, D}, title = {Allostatic load and risk of all-cause, cancer-specific, and cardiovascular mortality in older cancer survivors: an analysis of the National Health and Nutrition Examination Survey 1999-2010.}, journal = {Aging and cancer}, volume = {4}, number = {2}, pages = {74-84}, pmid = {37576467}, issn = {2643-8909}, support = {R01 CA249506/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Allostatic load has been linked to an increased risk of death in various populations. However, to date, there is no research specifically investigating the effect of allostatic load on mortality in older cancer survivors.

AIMS: To investigate the association between allostatic load (AL) and mortality in older cancer survivors.

METHOD: A total of 1,291 adults aged 60 years or older who survived for ≥1 year since cancer diagnoses were identified from the 1999-2010 National Health and Nutrition Examination Survey. AL was the exposure of interest incorporating 9 clinical measures/biomarkers; one point was added to AL if any of the measures/biomarkers exceeded the normal level. The sum of points was categorized as an ordinal variable to reflect low, moderate, and high AL. Our outcomes of interest were all-cause, cancer-specific, and cardiovascular disease (CVD)-specific mortality. Death was identified by linkage to the National Death Index. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratio (aHR) and 95% confidence intervals (CI) of mortality by AL category.

RESULTS: Overall, 53.6% of participants were male and 78.4% were white. The mean age of study participants at interview was 72.8 years (SD=7.1). A total of 546 participants died during the follow-up (median follow-up time: 8.0 years). Among them, 158 died of cancer and 106 died of cardiovascular events. Results from multivariable Cox proportional hazards models showed that higher ALS was positively associated with higher all-cause mortality (ALS=4-9 vs. ALS =0-1: aHR=1.52, 95% CI =1.17-1.98, p-trend<0.01) and higher cancer-specific mortality (ALS=4-9 vs. ALS =0-1: aHR=1.80, 95% CI =1.12-2.90, p-trend=0.01). The association between ALS and cardiovascular mortality was positive but non-significant (ALS=4-9 vs. ALS =0-1: aHR=1.59, 95% CI =0.86-2.94, p-trend=0.11).

CONCLUSIONS: Our study suggests that older cancer survivors can have a higher risk of death if they have a high burden of AL.}, } @article {pmid37575992, year = {2023}, author = {Mohammadi, M and Yarmohammadi, A and Salehi-Abargouei, A and Ghasemirad, H and Shirvani, M and Ghoshouni, H}, title = {Uric acid and glaucoma: a systematic review and meta-analysis.}, journal = {Frontiers in medicine}, volume = {10}, number = {}, pages = {1159316}, pmid = {37575992}, issn = {2296-858X}, abstract = {BACKGROUND: Glaucoma, the leading cause of irreversible blindness, is a common disorder that contributes to gradual optic nerve degeneration. The beneficial impacts of uric acid (UA) have been reported in some neurodegenerative conditions such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. But the results of current studies about the association between serum UA level and glaucoma are conflicting. The present meta-analysis was conducted to provide a better understanding of the association between serum UA level and glaucoma.

METHODS: We searched the databases of PubMed, Scopus, Web of Science, and Google Scholar systematically until November 20, 2022 to identify case-control studies, comparing the serum UA concentrations of the patients with glaucoma and controls. The mean ± standard division difference was used to assess the difference in serum UA concentrations between the glaucoma patients and controls.

RESULTS: Six studies involving 1,221 glaucoma patients and 1,342 control group were included in the present meta-analysis. This meta-analysis using a random effect model indicated that the mean UA level in glaucoma patients was 0.13 (I[2] = 91.92%, 95% CI = -0.42 to 0.68) higher than the controls; however, it was not statistically significant.

CONCLUSIONS: Our findings provide evidence that glaucoma patients have a higher serum UA level compared to the controls, but this difference is not statistically significant. Prospective studies are needed to determine the possible association between increased UA and glaucoma pathogenesis.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022364055, identifier: CRD42022364055.}, } @article {pmid37575265, year = {2023}, author = {Clénet, ML and Keaney, J and Gillet, G and Valadas, JS and Langlois, J and Cardenas, A and Gasser, J and Kadiu, I}, title = {Divergent functional outcomes of NLRP3 blockade downstream of multi-inflammasome activation: therapeutic implications for ALS.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1190219}, pmid = {37575265}, issn = {1664-3224}, mesh = {Mice ; Animals ; Humans ; Inflammasomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Neurodegenerative Diseases ; NLR Proteins ; }, abstract = {NOD-Like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome modulation has emerged as a potential therapeutic approach targeting inflammation amplified by pyroptotic innate immune cell death. In diseases characterized by non-cell autonomous neurodegeneration including amyotrophic lateral sclerosis (ALS), the activation of several inflammasomes has been reported. Since functional redundancy can exist among inflammasome pathways, here we investigate the effects of NLRP3 inhibition on NLRP3, NLR family CARD Domain Containing 4 (NLRC4) and non-canonical pathways to understand whether NLRP3 blockade alone can mitigate pro-inflammatory cytokine release and pyroptotic cell death in contexts where single or multiple inflammasome pathways independent of NLRP3 are activated. In this study we do not limit our insights into inflammasome biology by solely relying on the THP-1 monocytic line under the LPS/nigericin-mediated NLRP3 pathway activation paradigm. We assess therapeutic potential and limitations of NLRP3 inhibition in multi-inflammasome activation contexts utilizing various human cellular systems including cell lines expressing gain of function (GoF) mutations for several inflammasomes, primary human monocytes, macrophages, healthy and Amyotrophic Lateral Sclerosis (ALS) patient induced pluripotent stem cells (iPSC)-derived microglia (iMGL) stimulated for canonical and non-canonical inflammasome pathways. We demonstrate that NLRP3 inhibition can modulate the NLRC4 and non-canonical inflammasome pathways; however, these effects differ between immortalized, human primary innate immune cells, and iMGL. We extend our investigation in more complex systems characterized by activation of multiple inflammasomes such as the SOD1[G93A] mouse model. Through deep immune phenotyping by single-cell mass cytometry we demonstrate that acute NLRP3 inhibition does not ameliorate spinal cord inflammation in this model. Taken together, our data suggests that NLRP3 inhibition alone may not be sufficient to address dynamic and complex neuroinflammatory pathobiological mechanisms including dysregulation of multiple inflammasome pathways in neurodegenerative disease such as ALS.}, } @article {pmid37575227, year = {2023}, author = {Terrabuio, E and Zenaro, E and Constantin, G}, title = {The role of the CD8+ T cell compartment in ageing and neurodegenerative disorders.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1233870}, pmid = {37575227}, issn = {1664-3224}, mesh = {Humans ; *CD8-Positive T-Lymphocytes ; Cytokines ; Central Nervous System ; *Amyotrophic Lateral Sclerosis ; }, abstract = {CD8+ lymphocytes are adaptive immunity cells with the particular function to directly kill the target cell following antigen recognition in the context of MHC class I. In addition, CD8+ T cells may release pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), and a plethora of other cytokines and chemoattractants modulating immune and inflammatory responses. A role for CD8+ T cells has been suggested in aging and several diseases of the central nervous system (CNS), including Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, limbic encephalitis-induced temporal lobe epilepsy and Susac syndrome. Here we discuss the phenotypic and functional alterations of CD8+ T cell compartment during these conditions, highlighting similarities and differences between CNS disorders. Particularly, we describe the pathological changes in CD8+ T cell memory phenotypes emphasizing the role of senescence and exhaustion in promoting neuroinflammation and neurodegeneration. We also discuss the relevance of trafficking molecules such as selectins, mucins and integrins controlling the extravasation of CD8+ T cells into the CNS and promoting disease development. Finally, we discuss how CD8+ T cells may induce CNS tissue damage leading to neurodegeneration and suggest that targeting detrimental CD8+ T cells functions may have therapeutic effect in CNS disorders.}, } @article {pmid37573779, year = {2023}, author = {Zhang, Z and Zhu, Y and Zhu, C and Li, S and Zhao, Y and Yang, J and Qin, Y and Hou, J and Zhang, J and Han, C}, title = {Effects of Dihuang Yinzi Decoction on Alzheimer's Disease: A Systematic Review and Meta-Analysis.}, journal = {Complementary medicine research}, volume = {30}, number = {5}, pages = {440-452}, doi = {10.1159/000531931}, pmid = {37573779}, issn = {2504-2106}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Treatment Outcome ; *Medicine ; Medicine, Chinese Traditional ; China ; }, abstract = {OBJECTIVE: The aim of this study was to systematically evaluate the therapeutic effects of Dihuang Yinzi decoction on Alzheimer's disease (AD) and provide a medical evidence-based clinical application of traditional Chinese medicine (TCM).

METHODS: A comprehensive search was conducted across multiple databases, including PubMed, Embase, Cochrane Library, China National Journals Full-text Database, VIP Database for Chinese Technical Periodicals, Wan Fang database, and SinoMed database, to collect clinical randomized controlled trials of Dihuang Yinzi decoction in the treatment of AD. Strict literature screening was performed based on predefined inclusion and exclusion criteria. The Cochrane Collaboration risk of bias assessment tool and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system recommendation-level method was used to assess the quality of the included studies. Review Manager 5.4 and Stata 17 software were used for data synthesis and processing, while GRADE Profiler 3.6 software was used to evaluate the quality of evidence for outcome indicators (risk ratio, standardized mean difference, and weighted mean difference).

RESULTS: A total of 11 studies involving 798 patients met the inclusion criteria. Dihuang Yinzi decoction, whether used alone or in combination with conventional Western medicine, demonstrated superior efficacy compared to conventional Western medicine alone in improving the clinical effective rate, TCM syndrome score, activity of daily living score, Mini-Mental State Examination score, and Hasegawa Dementia Scale score in AD treatment. Furthermore, it exhibited a favorable safety profile. However, the GRADE evidence quality rating for the included studies was low.

CONCLUSIONS: Dihuang Yinzi decoction, either used alone or in combination with conventional Western medicine, shows promising results in enhancing cognitive and memory functions as well as the self-care ability of patients with AD. However, the low GRADE evidence quality rating highlights the need for focused advancements in the planning and execution of clinical randomized controlled trials during future research attempts.

UNLABELLED: ZIELZiel dieser Studie ist es, die therapeutischen Effekte von Dihuang Yinzi-Dekokt auf die Alzheimer-Krankheit systematisch zu bewerten und eine evidenzbasierte klinische Anwendung der traditionellen chinesischen Medizin (TCM) bereitzustellen.MethodenEs wurde eine umfassende Suche in mehreren Datenbanken, darunter PubMed, Embase, Cochrane Library, China National Journals Volltext-Datenbank, VIP Database for Chinese Technical Periodicals, Wan Fang Datenbank und SinoMed-Datenbank durchgeführt, um randomisierte, kontrollierte klinische Studien zu Dihuang Yinzi-Dekokt in der Behandlung der Alzheimer-Krankheit zu erfassen. Die strenge Literatursuche erfolgte auf Grundlage von vordefinierten Ein-und Ausschlusskriterien. Zur Bewertung der Qualität der eingeschlossenen Studien wurden das Risk-of-Bias-Tool von Cochrane und das GRADE (Grading of Recommendations Assessment, Development, and Evaluation)-System zur Beurteilung der Empfehlungsgrade herangezogen. Die Datensynthese und -verarbeitung erfolgten mithilfe der Review Manager 5.4- und der Stata 17-Software, während für die Bewertung der Evidenzqualität der Outcome-Indikatoren (Risikoverhältnis, standardisierte Mittelwertdifferenz und gewichtete Mittelwertdifferenz) die Software GRADE Profiler 3.6 verwendet wurde.ErgebnisseInsgesamt erfüllten 11 Studien, an denen 798 Patienten teilnahmen, die Einschlusskriterien. Dihuang Yinzi-Dekokt zeigte allein oder in Kombination mit konventioneller westlicher Medizin eine überlegene Wirksamkeit gegenüber der alleinigen Verwendung von konventioneller westlicher Medizin in Bezug auf die klinische Gesamtwirksamkeitsrate, den TCM-Syndrom-Score, den Score für die Alltagsaktivitäten, den Mini-Mental State Examination-Score und den Score der Hasegawa-Demenz-Skala in der Behandlung der Alzheimer-Krankheit. Darüber hinaus wies es ein günstiges Sicherheitsprofil auf. Die Evidenzqualität der eingeschlossenen Studien gemäß GRADE wurde jedoch als gering eingestuft.SchlussfolgerungenDihuang Yinzi-Dekokt zeigt allein oder in Kombination mit konventioneller westlicher Medizin vielversprechende Ergebnisse in Bezug auf die Verbesserung der kognitiven und Gedächtnisfunktionen sowie die Selbstversorgungsfähigkeit von Alzheimer-Patienten. Die niedrige Bewertung der Evidenzqualität gemäß GRADE unterstreicht jedoch die Notwendigkeit von zielgerichteten Weiterentwicklungen bei der Planung und Durchführung von randomisierten, kontrollierten klinischen Studien in zukünftigen Forschungsunternehmungen.}, } @article {pmid37573646, year = {2023}, author = {Kushol, R and Luk, CC and Dey, A and Benatar, M and Briemberg, H and Dionne, A and Dupré, N and Frayne, R and Genge, A and Gibson, S and Graham, SJ and Korngut, L and Seres, P and Welsh, RC and Wilman, AH and Zinman, L and Kalra, S and Yang, YH}, title = {SF2Former: Amyotrophic lateral sclerosis identification from multi-center MRI data using spatial and frequency fusion transformer.}, journal = {Computerized medical imaging and graphics : the official journal of the Computerized Medical Imaging Society}, volume = {108}, number = {}, pages = {102279}, doi = {10.1016/j.compmedimag.2023.102279}, pmid = {37573646}, issn = {1879-0771}, support = {//CIHR/Canada ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Canada ; Magnetic Resonance Imaging/methods ; Neuroimaging ; Brain/diagnostic imaging/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by motor neuron degeneration. Significant research has begun to establish brain magnetic resonance imaging (MRI) as a potential biomarker to diagnose and monitor the state of the disease. Deep learning has emerged as a prominent class of machine learning algorithms in computer vision and has shown successful applications in various medical image analysis tasks. However, deep learning methods applied to neuroimaging have not achieved superior performance in classifying ALS patients from healthy controls due to insignificant structural changes correlated with pathological features. Thus, a critical challenge in deep models is to identify discriminative features from limited training data. To address this challenge, this study introduces a framework called SF[2]Former, which leverages the power of the vision transformer architecture to distinguish ALS subjects from the control group by exploiting the long-range relationships among image features. Additionally, spatial and frequency domain information is combined to enhance the network's performance, as MRI scans are initially captured in the frequency domain and then converted to the spatial domain. The proposed framework is trained using a series of consecutive coronal slices and utilizes pre-trained weights from ImageNet through transfer learning. Finally, a majority voting scheme is employed on the coronal slices of each subject to generate the final classification decision. The proposed architecture is extensively evaluated with multi-modal neuroimaging data (i.e., T1-weighted, R2*, FLAIR) using two well-organized versions of the Canadian ALS Neuroimaging Consortium (CALSNIC) multi-center datasets. The experimental results demonstrate the superiority of the proposed strategy in terms of classification accuracy compared to several popular deep learning-based techniques.}, } @article {pmid37573553, year = {2023}, author = {Ling, YTT and Korneva, A and Quigley, HA and Nguyen, TD}, title = {Computational study of the mechanical behavior of the astrocyte network and axonal compartments in the mouse optic nerve head.}, journal = {Biomechanics and modeling in mechanobiology}, volume = {22}, number = {5}, pages = {1751-1772}, pmid = {37573553}, issn = {1617-7940}, support = {P30 EY001765/EY/NEI NIH HHS/United States ; R01 EY002120/EY/NEI NIH HHS/United States ; R56 EY002120/EY/NEI NIH HHS/United States ; EY 01765/NH/NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Optic Disk ; Astrocytes ; *Glaucoma ; Intraocular Pressure ; Axons ; }, abstract = {Glaucoma is a blinding disease characterized by the degeneration of the retinal ganglion cell (RGC) axons at the optic nerve head (ONH). A major risk factor for glaucoma is the intraocular pressure (IOP). However, it is currently impossible to measure the IOP-induced mechanical response of the axons of the ONH. The objective of this study was to develop a computational modeling method to estimate the IOP-induced strains and stresses in the axonal compartments in the mouse astrocytic lamina (AL) of the ONH, and to investigate the effect of the structural features on the mechanical behavior. We developed experimentally informed finite element (FE) models of six mouse ALs to investigate the effect of structure on the strain responses of the astrocyte network and axonal compartments to pressure elevation. The specimen-specific geometries of the FE models were reconstructed from confocal fluorescent images of cryosections of the mouse AL acquired in a previous study that measured the structural features of the astrocytic processes and axonal compartments. The displacement fields obtained from digital volume correlation in prior inflation tests of the mouse AL were used to determine the displacement boundary conditions of the FE models. We then applied Gaussian process regression to analyze the effects of the structural features on the strain outcomes simulated for the axonal compartments. The axonal compartments experienced, on average, 6 times higher maximum principal strain but 1800 times lower maximum principal stress compared to those experienced by the astrocyte processes. The strains experienced by the axonal compartments were most sensitive to variations in the area of the axonal compartments. Larger axonal compartments that were more vertically aligned, closer to the AL center, and with lower local actin area fraction had higher strains. Understanding the factors affecting the deformation in the axonal compartments will provide insights into mechanisms of glaucomatous axonal damage.}, } @article {pmid37573101, year = {2023}, author = {Queral-Beltran, A and Marín-García, M and Lacorte, S and Tauler, R}, title = {UV-Vis absorption spectrophotometry and LC-DAD-MS-ESI(+)-ESI(-) coupled to chemometrics analysis of the monitoring of sulfamethoxazole degradation by chlorination, photodegradation, and chlorination/photodegradation.}, journal = {Analytica chimica acta}, volume = {1276}, number = {}, pages = {341563}, doi = {10.1016/j.aca.2023.341563}, pmid = {37573101}, issn = {1873-4324}, mesh = {*Sulfamethoxazole ; *Chemometrics ; Halogenation ; Photolysis ; Chlorine ; Spectrophotometry/methods ; Mass Spectrometry/methods ; Chromatography, Liquid ; }, abstract = {Sulfamethoxazole (SMX) is one of the most widely used antibiotics worldwide and has been detected at high concentrations in wastewater treatment plant effluents and river waters. In this study, the SMX degradation process combining the simultaneous chlorine oxidation and UV photodegradation is assessed and compared with both photodegradation and chlorine oxidation processes individually. Photodegradation and Chlorine/UV tests were performed using Suntest CPS equipment. Different experimental techniques, including UV-Visible spectrophotometry and liquid chromatography coupled to a diode array detector and positive and negative ionization mass spectrometry (LC-DAD-MS-ESI(+)-ESI(-)), were used to evaluate the degradation reaction of SMX. All the analytical data generated have been processed with the Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) method to monitor, resolve, and identify the several transformation products generated during the studied degradation processes. A new data fusion analysis strategy is proposed to examine the three processes simultaneously (with only photodegradation, only chlorination, and simultaneous chlorination+photodegradation). Combined with the analysis of different analytical techniques individually (spectrophotometry, LC-DAD, and LC-MS), the fusion of all generated data improved the description of the degradation processes. Detection using DAD allowed a better correspondence among the species monitored spectrophotometrically (UV-Vis) with those analyzed chromatographically. On the other side, detection using MS in both positive and negative acquisition modes allowed resolving a larger number of chemical compounds (specially SMX degradation subproducts) that could not be detected by UV-Vis spectrometry. The results obtained permitted the comparison of the effects produced by the three different degradation processes.}, } @article {pmid37572163, year = {2023}, author = {Teli, P and Kale, V and Vaidya, A}, title = {Beyond animal models: revolutionizing neurodegenerative disease modeling using 3D in vitro organoids, microfluidic chips, and bioprinting.}, journal = {Cell and tissue research}, volume = {394}, number = {1}, pages = {75-91}, pmid = {37572163}, issn = {1432-0878}, abstract = {Neurodegenerative diseases (NDs) are characterized by uncontrolled loss of neuronal cells leading to a progressive deterioration of brain functions. The transition rate of numerous neuroprotective drugs against Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, leading to FDA approval, is only 8-14% in the last two decades. Thus, in spite of encouraging preclinical results, these drugs have failed in human clinical trials, demonstrating that traditional cell cultures and animal models cannot accurately replicate human pathophysiology. Hence, in vitro three-dimensional (3D) models have been developed to bridge the gap between human and animal studies. Such technological advancements in 3D culture systems, such as human-induced pluripotent stem cell (iPSC)-derived cells/organoids, organ-on-a-chip technique, and 3D bioprinting, have aided our understanding of the pathophysiology and underlying mechanisms of human NDs. Despite these recent advances, we still lack a 3D model that recapitulates all the key aspects of NDs, thus making it difficult to study the ND's etiology in-depth. Hence in this review, we propose developing a combinatorial approach that allows the integration of patient-derived iPSCs/organoids with 3D bioprinting and organ-on-a-chip technique as it would encompass the neuronal cells along with their niche. Such a 3D combinatorial approach would characterize pathological processes thoroughly, making them better suited for high-throughput drug screening and developing effective novel therapeutics targeting NDs.}, } @article {pmid37570984, year = {2023}, author = {Jin, R and Wang, J and Guo, B and Yang, T and Hu, J and Wang, B and Yu, Q}, title = {Identification and Expression Analysis of the Alfin-like Gene Family in Tomato and the Role of SlAL3 in Salt and Drought Stresses.}, journal = {Plants (Basel, Switzerland)}, volume = {12}, number = {15}, pages = {}, pmid = {37570984}, issn = {2223-7747}, support = {2022D01A269//Natural Science Foundation of Xinjiang Uygur Autonomous Region/ ; xjnkywdzc-2022001-8//Key Programs for Crop Important Traits Formation and Cutting-edge Technologies in Biological Breeding/ ; 2022B02002//Key Research and Development Task Special Project of Xinjiang Uygur Autonomous Region/ ; }, abstract = {Alfin-like (AL) transcription factors are a family of plant-specific genes with a PHD-finger-like structural domain at the C-terminus and a DUF3594 structural domain at the N-terminus that play important roles in plant development and stress response. In the present study, genome-wide identification and analysis were performed of the AL protein family in cultivated tomato (Solanum lycopersicum) and three wild relatives (S. pennellii, S. pimpinellifolium, and S. lycopersicoides) to evaluate their response to different abiotic stresses. A total of 39 ALs were identified and classified into four groups and based on phylogenetic tree and evolutionary analysis were shown to have formed prior to the differentiation of monocotyledons and dicots. Moreover, cis-acting element analysis revealed that various phytohormone response and abiotic stress response elements were highly existed in tomato. In addition, further analysis of the SlAL3 gene revealed that its expression was induced by drought and salt stresses and localized to the nucleus. In conclusion, our findings concerning AL genes provide useful information for further studies on their functions and regulatory mechanisms and provide theoretical references for studying AL gene response to abiotic stresses in plants.}, } @article {pmid37570771, year = {2023}, author = {Liu, X and Zhao, X and He, J and Wang, S and Shen, X and Liu, Q and Wang, S}, title = {Advances in the Structure of GGGGCC Repeat RNA Sequence and Its Interaction with Small Molecules and Protein Partners.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {15}, pages = {}, pmid = {37570771}, issn = {1420-3049}, support = {22274050//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia/genetics ; Base Sequence ; DNA Repeat Expansion ; RNA/genetics/chemistry ; RNA-Binding Proteins/genetics/metabolism ; }, abstract = {The aberrant expansion of GGGGCC hexanucleotide repeats within the first intron of the C9orf72 gene represent the predominant genetic etiology underlying amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). The transcribed r(GGGGCC)n RNA repeats form RNA foci, which recruit RNA binding proteins and impede their normal cellular functions, ultimately resulting in fatal neurodegenerative disorders. Furthermore, the non-canonical translation of the r(GGGGCC)n sequence can generate dipeptide repeats, which have been postulated as pathological causes. Comprehensive structural analyses of r(GGGGCC)n have unveiled its polymorphic nature, exhibiting the propensity to adopt dimeric, hairpin, or G-quadruplex conformations, all of which possess the capacity to interact with RNA binding proteins. Small molecules capable of binding to r(GGGGCC)n have been discovered and proposed as potential lead compounds for the treatment of ALS and FTD. Some of these molecules function in preventing RNA-protein interactions or impeding the phase transition of r(GGGGCC)n. In this review, we present a comprehensive summary of the recent advancements in the structural characterization of r(GGGGCC)n, its propensity to form RNA foci, and its interactions with small molecules and proteins. Specifically, we emphasize the structural diversity of r(GGGGCC)n and its influence on partner binding. Given the crucial role of r(GGGGCC)n in the pathogenesis of ALS and FTD, the primary objective of this review is to facilitate the development of therapeutic interventions targeting r(GGGGCC)n RNA.}, } @article {pmid37569549, year = {2023}, author = {Yabata, H and Riku, Y and Miyahara, H and Akagi, A and Sone, J and Urushitani, M and Yoshida, M and Iwasaki, Y}, title = {Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {15}, pages = {}, pmid = {37569549}, issn = {1422-0067}, support = {JP20K16586, JP22K07359, JP23K06935//JSPS KAKENHI/ ; JP20ek0109392, JP20ek0109391//AMED/ ; (30-8)//Intramural Research Grant for Neurological and Psychiatric Disorders of NCNP/ ; not applicable//Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour, and Welfare Sciences Research Grants, the Ministry of Health, Labour, and Welfare, Japan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/metabolism ; Motor Neurons/metabolism ; Ubiquitination ; }, abstract = {The transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological protein of amyotrophic lateral sclerosis (ALS). TDP-43 pathology is characterized by a combination of the cytoplasmic aggregation and nuclear clearance of this protein. However, the mechanisms underlying TDP-43 pathology have not been fully clarified. The aim of this study was to evaluate the relationships between the expression level of nuclear TDP-43 and the pathological properties of cytoplasmic aggregates in autopsied ALS cases. We included 22 consecutively autopsied cases with sporadic TDP-43-related ALS. The motor neuron systems were neuropathologically assessed. We identified 790 neurons with cytoplasmic TDP-43 inclusions from the lower motor neuron system of included cases. Nuclear TDP-43 disappeared in 84% (n = 660) and expressed in 16% (n = 130) of neurons with cytoplasmic inclusions; the former was defined as TDP-43 cytoplasmic immunoreactivity (c-ir), and the latter was defined as nuclear and cytoplasmic immunoreactivity (n/c-ir). Morphologically, diffuse cytoplasmic inclusions were significantly more prevalent in TDP-43 n/c-ir neurons than in c-ir neurons, while skein-like and round inclusions were less prevalent in n/c-ir neurons. The cytoplasmic inclusions of TDP-43 n/c-ir neurons were phosphorylated but poorly ubiquitylated when compared with those of c-ir neurons. TDP-43 n/c-ir neurons became less dominant than the c-ir neurons among cases with a prolonged disease duration. The expression level of nuclear TDP-43 was significantly lower in n/c-ir neurons than in normal neurons without cytoplasmic inclusions. Our results indicate that the maturation of cytoplasmic TDP-43 inclusions correlates with the depletion of nuclear TDP-43 in each affected neuron. This finding supports the view that an imbalance between nuclear and cytoplasmic TDP-43 may be an essential pathway to TDP-43 pathology.}, } @article {pmid37569475, year = {2023}, author = {Napoli, G and Rubin, M and Cutillo, G and Schito, P and Russo, T and Quattrini, A and Filippi, M and Riva, N}, title = {Tako-Tsubo Syndrome in Amyotrophic Lateral Sclerosis: Single-Center Case Series and Brief Literature Review.}, journal = {International journal of molecular sciences}, volume = {24}, number = {15}, pages = {}, pmid = {37569475}, issn = {1422-0067}, support = {Percorso Marazzina//Giovanni Marazzina Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; *Takotsubo Cardiomyopathy/complications ; *Neurodegenerative Diseases/complications ; Retrospective Studies ; *Primary Dysautonomias ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with variable phenotypic expressions which has been associated with autonomic dysfunction. The cardiovascular system seems to be affected especially in the context of bulbar involvement. We describe four new cases of Tako-Tsubo syndrome (TTS) in ALS patients with an appraisal of the literature. We present a late-stage ALS patient with prominent bulbar involvement that presented TTS during hospitalization. We then retrospectively identify three additional ALS-TTS cases reporting relevant clinical findings. TTS cardiomyopathy has been observed in different acute neurological conditions, and the co-occurrence of ALS and TTS has already been reported. Cardiovascular autonomic dysfunctions have been described in ALS, especially in the context of an advanced diseases and with bulbar involvement. Noradrenergic hyperfunction linked to sympathetic denervation and ventilatory deficits coupled in different instances with a trigger event could play a synergistic role in the development of TTS in ALS. Sympathetic hyperfunctioning and ventilatory deficits in conjunction with cardiac autonomic nerves impairment may play a role in the development of TTS in a context of ALS.}, } @article {pmid37568457, year = {2023}, author = {Boentert, M and Hermann, A and Großkreutz, J}, title = {Amyotrophic Lateral Sclerosis: Advances and Prospects.}, journal = {Journal of clinical medicine}, volume = {12}, number = {15}, pages = {}, pmid = {37568457}, issn = {2077-0383}, abstract = {The JCM Topical Collection "Amyotrophic Lateral Sclerosis: Latest Advances and Prospects" started in 2020 and currently includes 11 publications reflecting a broad range of clinical research areas in the ALS field [...].}, } @article {pmid37568439, year = {2023}, author = {Risi, B and Cotti Piccinelli, S and Gazzina, S and Labella, B and Caria, F and Damioli, S and Poli, L and Padovani, A and Filosto, M}, title = {Prognostic Usefulness of Motor Unit Number Index (MUNIX) in Patients Newly Diagnosed with Amyotrophic Lateral Sclerosis.}, journal = {Journal of clinical medicine}, volume = {12}, number = {15}, pages = {}, pmid = {37568439}, issn = {2077-0383}, abstract = {UNLABELLED: The MUNIX technique allows us to estimate the number and size of surviving motor units (MUs). Previous studies on ALS found correlations between MUNIX and several clinical measures, but its potential role as a predictor of disease progression rate (DPR) has not been thoroughly evaluated to date. We aimed to investigate MUNIX's ability to predict DPR at a six-month follow up.

METHODS: 24 ALS patients with short disease duration (<24 months from symptoms' onset) were enrolled and divided according to their baseline DPR into two groups (normal [DPR-N] and fast [DPR-F] progressors). MUNIX values were obtained from five muscles (TA, APB, ADM, FDI, Trapezius) and averaged for each subject.

RESULTS: MUNIX was found to predict DPR at follow up in a multivariable linear regression model; namely, patients with lower MUNIX values were at risk of showing greater DPR scores at follow up. The result was replicated in a simple logistic regression analysis, with the dichotomic category "MUNIX-Low" as the independent variable and the outcome "DPR-F" as the dependent variable.

CONCLUSIONS: our results pave the way for the use of the MUNIX method as a prognostic tool in early ALS, enabling patients' stratification according to their rates of future decline.}, } @article {pmid37567819, year = {2024}, author = {Marrie, RA and Maxwell, CJ and Rotstein, DL and Tsai, CC and Tremlett, H}, title = {Prodromes in demyelinating disorders, amyotrophic lateral sclerosis, Parkinson disease, and Alzheimer's dementia.}, journal = {Revue neurologique}, volume = {180}, number = {3}, pages = {125-140}, doi = {10.1016/j.neurol.2023.07.002}, pmid = {37567819}, issn = {0035-3787}, mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Parkinson Disease/complications/diagnosis ; *Amyotrophic Lateral Sclerosis/diagnosis ; Biomarkers ; *Multiple Sclerosis ; Prodromal Symptoms ; }, abstract = {A prodrome is an early set of symptoms, which indicates the onset of a disease; these symptoms are often non-specific. Prodromal phases are now recognized in multiple central nervous system diseases. The depth of understanding of the prodromal phase varies across diseases, being more nascent for multiple sclerosis for example, than for Parkinson disease or Alzheimer's disease. Key challenges when identifying the prodromal phase of a disease include the lack of specificity of prodromal symptoms, and consequent need for accessible and informative biomarkers. Further, heterogeneity of the prodromal phase may be influenced by age, sex, genetics and other poorly understood factors. Nonetheless, recognition that an individual is in the prodromal phase of disease offers the opportunity for earlier diagnosis and with it the opportunity for earlier intervention.}, } @article {pmid37567224, year = {2023}, author = {Takano, HK and Benko, ZL and Zielinski, MM and Hamza, A and Kalnmals, CA and Roth, JJ and Bravo-Altamirano, K and Siddall, T and Satchivi, N and Church, JB and Riar, DS}, title = {Discovery and Mode-of-Action Characterization of a New Class of Acetolactate Synthase-Inhibiting Herbicides.}, journal = {Journal of agricultural and food chemistry}, volume = {71}, number = {47}, pages = {18227-18238}, doi = {10.1021/acs.jafc.3c03858}, pmid = {37567224}, issn = {1520-5118}, mesh = {*Herbicides/pharmacology/chemistry ; *Acetolactate Synthase/chemistry ; Herbicide Resistance ; Ethers ; }, abstract = {Herbicides are effective tools to manage weeds and enable food production and sustainable agriculture. Corteva Agriscience R&D has recently discovered new diphenyl-ether compounds displaying excellent postemergent efficacy on important weed species along with corn safety. Here, we describe the chemistry, biology, biochemistry, and computational modeling research that led to the discovery and elucidation of the primary mode of action for these compounds. The target protein was found to be acetolactate synthase (ALS), a key enzyme in the biosynthesis of branched chain amino acids (valine, leucine, and isoleucine). While weed resistance evolution to ALS herbicides is widespread, the molecular interaction of the diphenyl-ether compounds at the active site of the ALS enzyme differs significantly from that of some commercial ALS inhibitors. The unique biochemical profile of these molecules along with their excellent herbicidal activity and corn selectivity make them a noteworthy development in the pursuit of novel, safe, and sustainable weed control solutions.}, } @article {pmid37566385, year = {2023}, author = {Kreple, CJ and Gajagowni, S and Jockel-Balsaratti, J and Bucelli, RC and Miller, TM}, title = {Lumbar punctures are safe in patients with ALS and have a risk profile similar to that in the non-ALS population.}, journal = {Muscle & nerve}, volume = {68}, number = {5}, pages = {771-775}, doi = {10.1002/mus.27956}, pmid = {37566385}, issn = {1097-4598}, support = {R01NS097816/NH/NIH HHS/United States ; R01NS078398/NH/NIH HHS/United States ; R01NS097816/NH/NIH HHS/United States ; R01NS078398/NH/NIH HHS/United States ; }, abstract = {INTRODUCTION/AIMS: Analysis of biofluids, especially cerebrospinal fluid (CSF), is critically important for amyotrophic lateral sclerosis (ALS) research. Collection of CSF is typically performed by lumbar puncture (LP). Previous studies have demonstrated the safety of LPs in patients with other neurodegenerative diseases, such as Alzheimer's disease, although there are no published studies of the safety of LPs in patients with ALS. We performed a retrospective analysis of complications resulting from LPs.

METHODS: This is a retrospective study of LPs performed between 2015 and 2021 on a total of 233 participants (healthy controls [n = 63], ALS [n = 154], and disease controls [n = 16]) as part of clinical research studies at the Washington University ALS Center. We used bivariate logistical analyses looking for associations between participant characteristics and adverse events (AEs), and likelihood ratio tests were used for significance testing.

RESULTS: We found an overall AE rate of 21.03%. AEs included headache, back pain, vasovagal syncope, and severe headache requiring epidural blood patch. Participants with ALS were not more likely to experience post-LP AEs compared to controls (odds ratio [OR] 0.61 [0.32-1.18]). Post-LP headaches were significantly less likely in participants with ALS (OR 0.36 [0.15-0.83]).

DISCUSSION: Our findings demonstrate that LP is a safe procedure for participants with ALS, with a similar or lower rate of AEs than in participants without ALS.}, } @article {pmid37566177, year = {2024}, author = {Meyer, M and Meijer, O and Hunt, H and Belanoff, J and Lima, A and de Kloet, ER and Gonzalez Deniselle, MC and De Nicola, AF}, title = {Stress-induced Neuroinflammation of the Spinal Cord is Restrained by Cort113176 (Dazucorilant), A Specific Glucocorticoid Receptor Modulator.}, journal = {Molecular neurobiology}, volume = {61}, number = {1}, pages = {1-14}, pmid = {37566177}, issn = {1559-1182}, support = {PIP 11220170100002CO//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; PIP 11220210100091CO//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; PICT 2021 00389//Ministerio de Ciencia, Tecnología e Innovación Productiva/ ; Ubacyt 20020170100224BA//Secretaria de Ciencia y Tecnica, Universidad de Buenos Aires/ ; }, mesh = {Male ; Mice ; Humans ; Animals ; Receptors, Glucocorticoid/metabolism ; Corticosterone ; *HMGB1 Protein/metabolism ; Neuroinflammatory Diseases ; Gliosis/metabolism ; Toll-Like Receptor 4/metabolism ; Glucocorticoids/pharmacology ; Spinal Cord/metabolism ; *Neurodegenerative Diseases/metabolism ; *Isoquinolines ; *Pyrazoles ; }, abstract = {Glucocorticoids exert antiinflammatory, antiproliferative and immunosupressive effects. Paradoxically they may also enhance inflammation particularly in the nervous system, as shown in Cushing´ syndrome and neurodegenerative disorders of humans and models of human diseases. ."The Wobbler mouse model of amyotrophic lateral sclerosis shows hypercorticoidism and neuroinflammation which subsided by treatment with the glucocorticoid receptor (GR) modulator Dazucorilant (CORT113176). This effect suggests that GR mediates the chronic glucocorticoid unwanted effects. We now tested this hypothesis using a chronic stress model resembling the condition of the Wobbler mouse Male NFR/NFR mice remained as controls or were subjected to a restraining / rotation stress protocol for 3 weeks, with a group of stressed mice receiving CORT113176 also for 3 weeks. We determined the mRNAS or reactive protein for the proinflamatory factors HMGB1, TLR4, NFkB, TNFα, markers of astrogliosis (GFAP, SOX9 and acquaporin 4), of microgliosis (Iba, CD11b, P2RY12 purinergic receptor) as well as serum IL1β and corticosterone. We showed that chronic stress produced high levels of serum corticosterone and IL1β, decreased body and spleen weight, produced microgliosis and astrogliosis and increased proinflammatory mediators. In stressed mice, modulation of the GR with CORT113176 reduced Iba + microgliosis, CD11b and P2RY12 mRNAs, immunoreactive HMGB1 + cells, GFAP + astrogliosis, SOX9 and acquaporin expression and TLR4 and NFkB mRNAs vs. stress-only mice. The effects of CORT113176 indicate that glucocorticoids are probably involved in neuroinflammation. Thus, modulation of the GR would become useful to dampen the inflammatory component of neurodegenerative disorders.}, } @article {pmid37566088, year = {2023}, author = {Rossi, S and Di Salvio, M and Balì, M and De Simone, A and Apolloni, S and D'Ambrosi, N and Arisi, I and Cipressa, F and Cozzolino, M and Cestra, G}, title = {C9orf72 Toxic Species Affect ArfGAP-1 Function.}, journal = {Cells}, volume = {12}, number = {15}, pages = {}, pmid = {37566088}, issn = {2073-4409}, mesh = {Animals ; Humans ; Mice ; ADP-Ribosylation Factor 1/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; *C9orf72 Protein/genetics/metabolism ; Drosophila/genetics/metabolism ; RNA/metabolism ; RNA, Messenger/genetics ; *GTPase-Activating Proteins/genetics/metabolism ; }, abstract = {Compelling evidence indicates that defects in nucleocytoplasmic transport contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). In particular, hexanucleotide (G4C2) repeat expansions in C9orf72, the most common cause of genetic ALS, have a widespread impact on the transport machinery that regulates the nucleocytoplasmic distribution of proteins and RNAs. We previously reported that the expression of G4C2 hexanucleotide repeats in cultured human and mouse cells caused a marked accumulation of poly(A) mRNAs in the cell nuclei. To further characterize the process, we set out to systematically identify the specific mRNAs that are altered in their nucleocytoplasmic distribution in the presence of C9orf72-ALS RNA repeats. Interestingly, pathway analysis showed that the mRNAs involved in membrane trafficking are particularly enriched among the identified mRNAs. Most importantly, functional studies in cultured cells and Drosophila indicated that C9orf72 toxic species affect the membrane trafficking route regulated by ADP-Ribosylation Factor 1 GTPase Activating Protein (ArfGAP-1), which exerts its GTPase-activating function on the small GTPase ADP-ribosylation factor 1 to dissociate coat proteins from Golgi-derived vesicles. We demonstrate that the function of ArfGAP-1 is specifically affected by expanded C9orf72 RNA repeats, as well as by C9orf72-related dipeptide repeat proteins (C9-DPRs), indicating the retrograde Golgi-to-ER vesicle-mediated transport as a target of C9orf72 toxicity.}, } @article {pmid37566031, year = {2023}, author = {Torazza, C and Provenzano, F and Gallia, E and Cerminara, M and Balbi, M and Bonifacino, T and Tessitore, S and Ravera, S and Usai, C and Musante, I and Puliti, A and Van Den Bosch, L and Jafar-Nejad, P and Rigo, F and Milanese, M and Bonanno, G}, title = {Genetic Downregulation of the Metabotropic Glutamate Receptor Type 5 Dampens the Reactive and Neurotoxic Phenotype of Adult ALS Astrocytes.}, journal = {Cells}, volume = {12}, number = {15}, pages = {}, pmid = {37566031}, issn = {2073-4409}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Astrocytes/metabolism ; Down-Regulation/genetics ; Glutamic Acid/metabolism ; Mice, Transgenic ; *Neurodegenerative Diseases/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; *Receptor, Metabotropic Glutamate 5/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons (MNs). Astrocytes display a toxic phenotype in ALS, which results in MN damage. Glutamate (Glu)-mediated excitotoxicity and group I metabotropic glutamate receptors (mGluRs) play a pathological role in the disease progression. We previously demonstrated that in vivo genetic ablation or pharmacological modulation of mGluR5 reduced astrocyte activation and MN death, prolonged survival and ameliorated the clinical progression in the SOD1[G93A] mouse model of ALS. This study aimed to investigate in vitro the effects of mGluR5 downregulation on the reactive spinal cord astrocytes cultured from adult late symptomatic SOD1[G93A] mice. We observed that mGluR5 downregulation in SOD1[G93A] astrocytes diminished the cytosolic Ca[2+] overload under resting conditions and after mGluR5 simulation and reduced the expression of the reactive glial markers GFAP, S100β and vimentin. In vitro exposure to an anti-mGluR5 antisense oligonucleotide or to the negative allosteric modulator CTEP also ameliorated the altered reactive astrocyte phenotype. Downregulating mGluR5 in SOD1[G93A] mice reduced the synthesis and release of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α and ameliorated the cellular bioenergetic profile by improving the diminished oxygen consumption and ATP synthesis and by lowering the excessive lactate dehydrogenase activity. Most relevantly, mGluR5 downregulation hampered the neurotoxicity of SOD1[G93A] astrocytes co-cultured with spinal cord MNs. We conclude that selective reduction in mGluR5 expression in SOD1[G93A] astrocytes positively modulates the astrocyte reactive phenotype and neurotoxicity towards MNs, further supporting mGluR5 as a promising therapeutic target in ALS.}, } @article {pmid37566027, year = {2023}, author = {Bagyinszky, E and Hulme, J and An, SSA}, title = {Studies of Genetic and Proteomic Risk Factors of Amyotrophic Lateral Sclerosis Inspire Biomarker Development and Gene Therapy.}, journal = {Cells}, volume = {12}, number = {15}, pages = {}, pmid = {37566027}, issn = {2073-4409}, mesh = {Humans ; Child ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; *Neurodegenerative Diseases ; Proteomics ; DNA-Binding Proteins/metabolism ; Superoxide Dismutase-1 ; Biomarkers ; Risk Factors ; DNA Helicases ; RNA Helicases ; Multifunctional Enzymes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease affecting the upper and lower motor neurons, leading to muscle weakness, motor impairments, disabilities and death. Approximately 5-10% of ALS cases are associated with positive family history (familial ALS or fALS), whilst the remainder are sporadic (sporadic ALS, sALS). At least 50 genes have been identified as causative or risk factors for ALS. Established pathogenic variants include superoxide dismutase type 1 (SOD1), chromosome 9 open reading frame 72 (c9orf72), TAR DNA Binding Protein (TARDBP), and Fused In Sarcoma (FUS); additional ALS-related genes including Charged Multivesicular Body Protein 2B (CHMP2B), Senataxin (SETX), Sequestosome 1 (SQSTM1), TANK Binding Kinase 1 (TBK1) and NIMA Related Kinase 1 (NEK1), have been identified. Mutations in these genes could impair different mechanisms, including vesicle transport, autophagy, and cytoskeletal or mitochondrial functions. So far, there is no effective therapy against ALS. Thus, early diagnosis and disease risk predictions remain one of the best options against ALS symptomologies. Proteomic biomarkers, microRNAs, and extracellular vehicles (EVs) serve as promising tools for disease diagnosis or progression assessment. These markers are relatively easy to obtain from blood or cerebrospinal fluids and can be used to identify potential genetic causative and risk factors even in the preclinical stage before symptoms appear. In addition, antisense oligonucleotides and RNA gene therapies have successfully been employed against other diseases, such as childhood-onset spinal muscular atrophy (SMA), which could also give hope to ALS patients. Therefore, an effective gene and biomarker panel should be generated for potentially "at risk" individuals to provide timely interventions and better treatment outcomes for ALS patients as soon as possible.}, } @article {pmid37565992, year = {2023}, author = {Cheng, JY and Deng, YT and Yu, JT}, title = {The causal role of circulating amino acids on neurodegenerative disorders: A two-sample Mendelian randomization study.}, journal = {Journal of neurochemistry}, volume = {166}, number = {6}, pages = {972-981}, doi = {10.1111/jnc.15937}, pmid = {37565992}, issn = {1471-4159}, mesh = {Humans ; Amino Acids/genetics ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics ; Glutamine ; *Parkinson Disease ; *Alzheimer Disease ; *Lewy Body Disease ; Causality ; }, abstract = {Potential associations between the risk of neurodegenerative diseases and circulating levels of amino acids have been implied in both experimental research and observational studies. However, because of the confounding and reverse causality, the findings could be biased. We aimed to determine whether circulating amino acid levels have potential effects on the risk of neurodegenerative diseases through a more robust analysis. So, we performed a total of two MR analyses, a discovery two-sample MR analysis, and a replication test, using summary-level genome-wide association study (GWAS) data, both with circulating levels of amino acids as exposure and risk of neurodegenerative diseases as an outcome. The potential causalities between nine amino acids (Glutamine [Glu], Leucine [Leu], Isoleucine [Ile], Phenylalanine [Phe], Valine [Val], Alanine [Ala], Tyrosine [Tyr], Histidine [His], and Glycine [Gly]) and six neurodegenerative disorders (Alzheimer's disease [AD], Parkinson's disease [PD], Multiple sclerosis [MS], Frontotemporal dementia [FTD], Lewy body dementia [DLB], Amyotrophic lateral sclerosis [ALS]) were explored in this study. According to the discovery MR analysis, 1 SD. increase in circulating levels of Gln was genetically determined to result in a 13% lower risk of AD (IVW ORSD [95% CI] = 0.872 [0.822, 0.926]; FDR = 7.46 × 10[-5]) while PD risk was decreased to 63% per SD. increase of circulating Leu levels (IVW ORSD [95% CI] = 0.628 [0.467, 0.843]; FDR = 0.021). Results from the replication test provide further evidence of the potential association between circulating Gln levels and AD risk (IVW ORSD [95% CI] = 0.094 [0.028, 0.311]; FDR = 9.98 × 10[-4]). Meanwhile, sensitivity analysis demonstrated that the significant relationships revealed by our two-sample MR outcomes were reliable. Our analyses provided robust evidence of causal associations between circulating levels of Gln and AD risk as well as circulating Leu levels and risk of PD. However, the underlying mechanisms remain to be further investigated.}, } @article {pmid37565261, year = {2023}, author = {Murphy, S and Schmitt-John, T and Dowling, P and Henry, M and Meleady, P and Swandulla, D and Ohlendieck, K}, title = {Proteomic profiling of the brain from the wobbler mouse model of amyotrophic lateral sclerosis reveals elevated levels of the astrogliosis marker glial fibrillary acidic protein.}, journal = {European journal of translational myology}, volume = {33}, number = {3}, pages = {}, pmid = {37565261}, issn = {2037-7452}, abstract = {The wobbler mouse is a widely used model system of amyotrophic lateral sclerosis and exhibits progressive neurodegeneration and neuroinflammation in association with skeletal muscle wasting. This study has used wobbler brain preparations for the systematic and mass spectrometric determination of proteome-wide changes. The proteomic characterization of total protein extracts from wobbler specimens was carried out with the help of an Orbitrap mass spectrometer and revealed elevated levels of glia cell marker proteins, i.e., glial fibrillary acidic protein and the actin-binding protein coronin. In contrast, the abundance of the actin-binding protein neurabin and the scaffolding protein named piccolo of the presynaptic cytomatrix were shown to be reduced. The increased abundance of glial fibrillary acidic protein, which is frequently used in neuropathological studies as a marker protein of glial scar formation, was confirmed by immunoblotting. In analogy, the proteomic profiling of the brain from another established murine model of motor neuron disease, the SOD1mouse, also showed increased levels of this intermediate filament protein. This suggests that neurodegenerative processes are associated with astrogliosis in both the wobbler and SOD1 brain.}, } @article {pmid37565183, year = {2023}, author = {Sheers, NL and O'Sullivan, R and Howard, ME and Berlowitz, DJ}, title = {The role of lung volume recruitment therapy in neuromuscular disease: a narrative review.}, journal = {Frontiers in rehabilitation sciences}, volume = {4}, number = {}, pages = {1164628}, pmid = {37565183}, issn = {2673-6861}, abstract = {Respiratory muscle weakness results in substantial discomfort, disability, and ultimately death in many neuromuscular diseases. Respiratory system impairment manifests as shallow breathing, poor cough and associated difficulty clearing mucus, respiratory tract infections, hypoventilation, sleep-disordered breathing, and chronic ventilatory failure. Ventilatory support (i.e., non-invasive ventilation) is an established and key treatment for the latter. As survival outcomes improve for people living with many neuromuscular diseases, there is a shift towards more proactive and preventative chronic disease multidisciplinary care models that aim to manage symptoms, improve morbidity, and reduce mortality. Clinical care guidelines typically recommend therapies to improve cough effectiveness and mobilise mucus, with the aim of averting acute respiratory compromise or respiratory tract infections. Moreover, preventing recurrent infective episodes may prevent secondary parenchymal pathology and further lung function decline. Regular use of techniques that augment lung volume has similarly been recommended (volume recruitment). It has been speculated that enhancing lung inflation in people with respiratory muscle weakness when well may improve respiratory system "flexibility", mitigate restrictive chest wall disease, and slow lung volume decline. Unfortunately, clinical care guidelines are based largely on clinical rationale and consensus opinion rather than level A evidence. This narrative review outlines the physiological changes that occur in people with neuromuscular disease and how these changes impact on breathing, cough, and respiratory tract infections. The biological rationale for lung volume recruitment is provided, and the clinical trials that examine the immediate, short-term, and longer-term outcomes of lung volume recruitment in paediatric and adult neuromuscular diseases are presented and the results synthesised.}, } @article {pmid37564731, year = {2023}, author = {Kudritzki, V and Howard, IM}, title = {Telehealth-based exercise in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1238916}, pmid = {37564731}, issn = {1664-2295}, abstract = {The Veterans Health Administration (VHA) has served as a leader in the implementation of telerehabilitation technologies and continues to expand utilization of non-traditional patient encounters to better serve a geographically and demographically diverse population. Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease impacting Veterans at a higher rate than the civilian population and associated with high levels of disability and limited access to subspecialized care. There is growing evidence supporting exercise-based interventions as an independent or adjunctive treatment to maintain or restore function for this patient population; many of these interventions can be delivered remotely by telehealth. The recent advancements in disease-modifying therapies for neuromuscular disorders will likely increase the importance of rehabilitation interventions to maximize functional outcomes. Here, we review the evidence for specific exercise interventions in ALS and the evidence for telehealth-based exercise in neuromuscular disorders. We then use this existing literature to propose a framework for telehealth delivery of these treatments, including feasible exercise interventions and remote outcome measures, recommended peripheral devices, and an example of a current remote group exercise program offered through VHA.}, } @article {pmid37564648, year = {2023}, author = {Calafatti, M and Cocozza, G and Limatola, C and Garofalo, S}, title = {Microglial crosstalk with astrocytes and immune cells in amyotrophic lateral sclerosis.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1223096}, pmid = {37564648}, issn = {1664-3224}, mesh = {Mice ; Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Microglia/pathology ; Astrocytes/pathology ; Motor Neurons/pathology ; }, abstract = {In recent years, biomedical research efforts aimed to unravel the mechanisms involved in motor neuron death that occurs in amyotrophic lateral sclerosis (ALS). While the main causes of disease progression were first sought in the motor neurons, more recent studies highlight the gliocentric theory demonstrating the pivotal role of microglia and astrocyte, but also of infiltrating immune cells, in the pathological processes that take place in the central nervous system microenvironment. From this point of view, microglia-astrocytes-lymphocytes crosstalk is fundamental to shape the microenvironment toward a pro-inflammatory one, enhancing neuronal damage. In this review, we dissect the current state-of-the-art knowledge of the microglial dialogue with other cell populations as one of the principal hallmarks of ALS progression. Particularly, we deeply investigate the microglia crosstalk with astrocytes and immune cells reporting in vitro and in vivo studies related to ALS mouse models and human patients. At last, we highlight the current experimental therapeutic approaches that aim to modulate microglial phenotype to revert the microenvironment, thus counteracting ALS progression.}, } @article {pmid37563264, year = {2023}, author = {Nag, S and Schneider, JA}, title = {Limbic-predominant age-related TDP43 encephalopathy (LATE) neuropathological change in neurodegenerative diseases.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {9}, pages = {525-541}, pmid = {37563264}, issn = {1759-4766}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; R01 AG042210/AG/NIA NIH HHS/United States ; R01 AG067482/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; RF1 AG022018/AG/NIA NIH HHS/United States ; }, mesh = {*Frontotemporal Lobar Degeneration/diagnosis ; *Alzheimer Disease/pathology ; *Neurodegenerative Diseases ; Dementia ; TDP-43 Proteinopathies ; Humans ; *Amyotrophic Lateral Sclerosis/complications ; Adult ; *Frontotemporal Dementia/pathology ; Aged, 80 and over ; DNA-Binding Proteins ; }, abstract = {TAR DNA-binding protein 43 (TDP43) is a focus of research in late-onset dementias. TDP43 pathology in the brain was initially identified in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and later in Alzheimer disease (AD), other neurodegenerative diseases and ageing. Limbic-predominant age-related TDP43 encephalopathy (LATE), recognized as a clinical entity in 2019, is characterized by amnestic dementia resembling AD dementia and occurring most commonly in adults over 80 years of age. Neuropathological findings in LATE, referred to as LATE neuropathological change (LATE-NC), consist of neuronal and glial cytoplasmic TDP43 localized predominantly in limbic areas with or without coexisting hippocampal sclerosis and/or AD neuropathological change and without frontotemporal lobar degeneration or amyotrophic lateral sclerosis pathology. LATE-NC is frequently associated with one or more coexisting pathologies, mainly AD neuropathological change. The focus of this Review is the pathology, genetic risk factors and nature of the cognitive impairments and dementia in pure LATE-NC and in LATE-NC associated with coexisting pathologies. As the clinical and cognitive profile of LATE is currently not easily distinguishable from AD dementia, it is important to develop biomarkers to aid in the diagnosis of this condition in the clinic. The pathogenesis of LATE-NC should be a focus of future research to form the basis for the development of preventive and therapeutic strategies.}, } @article {pmid37562878, year = {2023}, author = {Weil, EL and Nakawah, MO and Masdeu, JC}, title = {Advances in the neuroimaging of motor disorders.}, journal = {Handbook of clinical neurology}, volume = {195}, number = {}, pages = {359-381}, doi = {10.1016/B978-0-323-98818-6.00039-X}, pmid = {37562878}, issn = {0072-9752}, mesh = {Humans ; Diffusion Tensor Imaging ; *Motor Disorders ; Neuroimaging/methods ; Magnetic Resonance Imaging/methods ; *Amyotrophic Lateral Sclerosis ; *Motor Neuron Disease/diagnostic imaging ; }, abstract = {Neuroimaging is a valuable adjunct to the history and examination in the evaluation of motor system disorders. Conventional imaging with computed tomography or magnetic resonance imaging depicts important anatomic information and helps to identify imaging patterns which may support diagnosis of a specific motor disorder. Advanced imaging techniques can provide further detail regarding volume, functional, or metabolic changes occurring in nervous system pathology. This chapter is an overview of the advances in neuroimaging with particular emphasis on both standard and less well-known advanced imaging techniques and findings, such as diffusion tensor imaging or volumetric studies, and their application to specific motor disorders. In addition, it provides reference to emerging imaging biomarkers in motor system disorders such as Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease, and briefly reviews the neuroimaging findings in different causes of myelopathy and peripheral nerve disorders.}, } @article {pmid37562867, year = {2023}, author = {Mahjoub, Y and Martino, D}, title = {Immunology and microbiome: Implications for motor systems.}, journal = {Handbook of clinical neurology}, volume = {195}, number = {}, pages = {135-157}, doi = {10.1016/B978-0-323-98818-6.00001-7}, pmid = {37562867}, issn = {0072-9752}, mesh = {Animals ; Humans ; *Gastrointestinal Microbiome/physiology ; Dysbiosis ; *Tourette Syndrome ; *Microbiota ; *Parkinson Disease ; }, abstract = {Immune-inflammatory mechanisms seem to play a relevant role in neurodegenerative disorders affecting motor systems, particularly Parkinson's disease, where activity changes in inflammatory cells and evidence of neuroinflammation in experimental models and patients is available. Amyotrophic lateral sclerosis is also characterized by neuroinflammatory changes that involve primarily glial cells, both microglia and astrocytes, as well as systemic immune dysregulation associated with more rapid progression. Similarly, the exploration of gut dysbiosis in these two prototypical neurodegenerative motor disorders is advancing rapidly. Altered composition of gut microbial constituents and related metabolic and putative functional pathways is supporting a pathophysiological link that is currently explored in preclinical, germ-free animal models. Less compelling, but still intriguing, evidence suggests that motor neurodevelopmental disorders, e.g., Tourette syndrome, are associated with abnormal trajectories of maturation that include also immune system development. Microglia has a key role also in these disorders, and new therapeutic avenues aiming at its modulation are exciting prospects. Preclinical and clinical research on the role of gut dysbiosis in Tourette syndrome and related behavioral disorders is still in its infancy, but early findings support the rationale to delve deeper into its contribution to neural and immune maturation abnormalities in its spectrum.}, } @article {pmid37562449, year = {2023}, author = {Blackmer-Raynolds, L and Sampson, TR}, title = {Overview of the Gut Microbiome.}, journal = {Seminars in neurology}, volume = {43}, number = {4}, pages = {518-529}, doi = {10.1055/s-0043-1771463}, pmid = {37562449}, issn = {1098-9021}, mesh = {Animals ; Humans ; *Gastrointestinal Microbiome/physiology ; Quality of Life ; *Nervous System Diseases ; Brain ; *Parkinson Disease ; }, abstract = {The human gastrointestinal tract is home to trillions of microorganisms-collectively referred to as the gut microbiome-that maintain a symbiotic relationship with their host. This diverse community of microbes grows and changes as we do, with developmental, lifestyle, and environmental factors all shaping microbiome community structure. Increasing evidence suggests this relationship is bidirectional, with the microbiome also influencing host physiological processes. For example, changes in the gut microbiome have been shown to alter neurodevelopment and have lifelong effects on the brain and behavior. Age-related changes in gut microbiome composition have also been linked to inflammatory changes in the brain, perhaps increasing susceptibility to neurological disease. Indeed, associations between gut dysbiosis and many age-related neurological diseases-including Parkinson's disease, Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis-have been reported. Further, microbiome manipulation in animal models of disease highlights a potential role for the gut microbiome in disease development and progression. Although much remains unknown, these associations open up an exciting new world of therapeutic targets, potentially allowing for improved quality of life for a wide range of patient populations.}, } @article {pmid37560029, year = {2023}, author = {Meng, J and Li, R and Huang, Q and Guo, D and Fan, K and Zhang, J and Zhu, X and Wang, M and Chen, X and Nie, D and Cao, C and Zhao, Z and Han, Z}, title = {Survey and toxigenic abilities of Aspergillus, Fusarium, and Alternaria fungi from wheat and paddy grains in Shanghai, China.}, journal = {Frontiers in plant science}, volume = {14}, number = {}, pages = {1202738}, pmid = {37560029}, issn = {1664-462X}, abstract = {A systematic study was carried out on 638 wheat and paddy grains (including fresh and stored samples) collected in 2021 from Shanghai, China, to identify the major mycobiota and their toxigenic abilities. A total of 349 fungi, namely, 252 Fusarium, 53 Aspergillus, and 44 Alternaria, were characterized by morphological and molecular identification. Fusarium and Aspergillus were more frequently isolated in paddy with Fusarium sambucinum species complex and Aspergillus section flavi as the predominant species, respectively. The genus Alternaria was the most frequently isolated fungal species in wheat. The toxin-producing potentials of the identified fungi were further evaluated in vitro. Deoxynevalenol (DON) was produced by 34.5% of Fusarium isolates and zearalenone (ZEN) was produced by 47.6% of them, and one isolate also processed the abilities for fumonisin B1 (FB1), B2 (FB2), and B3 (FB3) productions. Aflatoxin B1 (AFB1), B2 (AFB2), and G1 (AFG1) were only generated by Aspergillus section flavi, with the production rate of 65.5%, 27.6%, and 13.8%, respectively. Alternariol (AOH) was the most prevalent Alternaria toxin, which could be produced by 95.5% of the isolates, followed by alternariol monomethyl ether (AME) (72.7%), altenuene (ALT) (52.3%), tenuazonic acid (TeA) (45.5%), tentoxin (TEN) (29.5%), and altenusin (ALS) (4.5%). A combinational analysis of mycobiota and toxigenic ability allowed us to provide comprehensive information about the production mechanisms of mycotoxins in wheat and paddy in a specific geographic area, and will be helpful for developing efficient prevention and control programs.}, } @article {pmid37559423, year = {2023}, author = {Kim, S and An, S and Lee, J and Jeong, Y and You, CL and Kim, H and Bae, JH and Yun, CE and Ryu, D and Bae, GU and Kang, JS}, title = {Cdon ablation in motor neurons causes age-related motor neuron degeneration and impaired sciatic nerve repair.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {14}, number = {5}, pages = {2239-2252}, pmid = {37559423}, issn = {2190-6009}, support = {NRF-2016R1A5A2945889//National Research Foundation Grant funded by the Korean Government (MSIP)/ ; NRF-2022R1A2B5B02001482//National Research Foundation Grant funded by the Korean Government (MSIP)/ ; }, abstract = {BACKGROUND: The functional deterioration and loss of motor neurons are tightly associated with degenerative motor neuron diseases and aging-related muscle wasting. Motor neuron diseases or aging-related muscle wasting in turn contribute to increased risk of adverse health outcomes in the elderly. Cdon (cell adhesion molecule-downregulated oncogene) belongs to the immunoglobulin superfamily of cell adhesion molecule and plays essential roles in multiple signalling pathways, including sonic hedgehog (Shh), netrin, and cadherin-mediated signalling. Cdon as a Shh coreceptor plays a critical role in motor neuron specification during embryonic development. However, its role in adult motor neuron function is unknown.

METHODS: Hb9-Cre recombinase-driven motor neuron-specific Cdon deficient mice (mnKO) and a compound mutant mice (mnKO::SOD1[G93A]) were generated to investigate the role of Cdon in motor neuron degeneration. Motor neuron regeneration was examined by using a sciatic nerve crush injury model. To investigate the phenotype, physical activity, compound muscle action potential, immunostaining, and transmission electron microscopy were carried out. In the mechanism study, RNA sequencing and RNA/protein analyses were employed.

RESULTS: Mice lacking Cdon in motor neurons exhibited middle age onset lethality and aging-related decline in motor function. In the sciatic nerve crush injury model, mnKO mice exhibited an impairment in motor function recovery evident by prolonged compound muscle action potential duration (4.63 ± 0.35 vs. 3.93 ± 0.22 s for f/f, P < 0.01) and physical activity. Consistently, neuromuscular junctions of mnKO muscles were incompletely occupied (49.79 ± 5.74 vs. 79.39 ± 3.77% fully occupied neuromuscular junctions for f/f, P < 0.0001), suggesting an impaired reinnervation. The transmission electron microscopy analysis revealed that mnKO sciatic nerves had smaller axon diameter (0.88 ± 0.13 vs. 1.43 ± 0.48 μm for f/f, P < 0.0001) and myelination defects. RNA sequencing of mnKO lumbar spinal cords showed alteration in genes related to neurogenesis, inflammation and cell death. Among the altered genes, ErbB4 and FgfR expressions were significantly altered in mnKO as well as in Cdon-depleted NSC34 motor neuron cells. Consistently, Cdon-depleted NSC34 cells exhibited elevated levels of cleaved Caspase3 and γH2AX proteins, as well as Bax transcription. Cdon-depleted NSC34 cells also exhibited impaired activation of Akt in response to neuregulin-1 (NRG1) treatment.

CONCLUSIONS: Our current data demonstrate the functional importance of Cdon in motor neuron function and nerve repair. Cdon ablation causes alterations in neurotrophin signalling that leads to motor neuron degeneration.}, } @article {pmid37558576, year = {2023}, author = {Prado, MB and Pedro, KM and Adiao, KJB}, title = {Efficacy, safety and tolerability of high caloric diet in amyotrophic lateral sclerosis patients: A systematic review and meta-analysis.}, journal = {Revue neurologique}, volume = {179}, number = {9}, pages = {1008-1019}, doi = {10.1016/j.neurol.2023.01.731}, pmid = {37558576}, issn = {0035-3787}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Prospective Studies ; *Motor Neuron Disease ; Diet ; Carbohydrates/therapeutic use ; }, abstract = {BACKGROUND: Several randomized clinical trials were done to determine whether supplementation with a high caloric diet, either through carbohydrate or lipid supplementation, is safe, tolerable and improves survival. However, most of these trials are small and the results are conflicting.

METHODS: Randomized prospective trials utilizing high caloric supplementation among patients with amyotrophic lateral sclerosis (ALS) were searched using the terms [("amyotrophic lateral sclerosis" or "motor neuron disease" or "ALS" or "MND") and ("high calorie" or "high fat" or "high protein" or "high carbohydrate" or "supplementation")] in Medline, Cochrane, Embase, Scopus, Prospero and Herdin by two independent neurologists. Journal articles deemed relevant were assessed for eligibility.

MAIN RESULTS: There were 57 articles obtained from databases, 49 of which were excluded. Four articles were further excluded since all of them had different interventions. Overall, there were 311 ALS patients included in the study, 176 of them were from the intervention group while 135 were used as controls. Overall, high caloric supplementation in ALS was deemed safe and tolerable, and also when adverse events, tolerability and mortality are combined using meta-analysis. Although in most publications the efficacy of giving high caloric supplementation has been generally beneficial, some of the outcome parameters are not statistically different from controls when studies are combined using meta-analysis.

CONCLUSIONS: Current evidence suggests that high calorie supplementation is generally safe and tolerable for patients with ALS. However, it has not been shown to be efficacious in improving weight and functional disability.}, } @article {pmid37558109, year = {2023}, author = {Dave, U and Khan, S and Gomes, J}, title = {Characterization of E121K mutation of D-amino acid oxidase - Insights into mechanisms leading to amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta. Proteins and proteomics}, volume = {1871}, number = {6}, pages = {140947}, doi = {10.1016/j.bbapap.2023.140947}, pmid = {37558109}, issn = {1878-1454}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Mutation ; Amino Acids/genetics ; Oxidoreductases/genetics ; India ; }, abstract = {D-amino acid oxidase (DAO) maintains the intracellular d-serine level which modulates the activity of the N-methyl-d-aspartate receptor and its dysfunction has been linked to several neurodegenerative disorders. In targeted next-generation sequencing study by our group, E121K mutation in DAO was associated with amyotrophic lateral sclerosis (ALS) in patients from India. However, variations in molecular mechanisms caused by this mutation which leads to ALS have not been studied. Hence, we carried out comparative biophysical characterization and assay studies of the wildtype- and mutant E121K-DAO. We observed that the purified E121K-DAO was inactive and exhibited a lower affinity for the FAD cofactor and benzoate inhibitor. Structural studies revealed that the E121K mutant has higher beta-sheet content, melting temperature, and oligomeric states compared to the wildtype. Kinetic study of aggregation of the variants using thioflavin-T confirmed that the E121K-DAO was more prone to aggregation. Microscopic visualization showed that the aggregation proceeds through an intermediate step involving the formation of fibrillar structures in the E121K mutant. Our results give insights into the underlying mechanisms leading to ALS pathogenesis.}, } @article {pmid37558082, year = {2024}, author = {Giannini, M and Porrua, O}, title = {Senataxin: A key actor in RNA metabolism, genome integrity and neurodegeneration.}, journal = {Biochimie}, volume = {217}, number = {}, pages = {10-19}, doi = {10.1016/j.biochi.2023.08.001}, pmid = {37558082}, issn = {1638-6183}, mesh = {Humans ; RNA Helicases/genetics/metabolism ; DNA Helicases/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Neurodegenerative Diseases/genetics ; Transcription, Genetic ; Mutation ; Multifunctional Enzymes/genetics/metabolism ; RNA ; }, abstract = {The RNA/DNA helicase senataxin (SETX) has been involved in multiple crucial processes related to genome expression and integrity such us transcription termination, the regulation of transcription-replication conflicts and the resolution of R-loops. SETX has been the focus of numerous studies since the discovery that mutations in its coding gene are the root cause of two different neurodegenerative diseases: Ataxia with Oculomotor Apraxia type 2 (AOA2) and a juvenile form of Amyotrophic Lateral Sclerosis (ALS4). A plethora of cellular phenotypes have been described as the result of SETX deficiency, yet the precise molecular function of SETX as well as the molecular pathways leading from SETX mutations to AOA2 and ALS4 pathologies have remained unclear. However, recent data have shed light onto the biochemical activities and biological roles of SETX, thus providing new clues to understand the molecular consequences of SETX mutation. In this review we summarize near two decades of scientific effort to elucidate SETX function, we discuss strengths and limitations of the approaches and models used thus far to investigate SETX-associated diseases and suggest new possible research avenues for the study of AOA2 and ALS4 pathogenesis.}, } @article {pmid37558009, year = {2023}, author = {Monteiro Neto, JR and Ribeiro, GD and Magalhães, RSS and Follmer, C and Outeiro, TF and Eleutherio, ECA}, title = {Glycation modulates superoxide dismutase 1 aggregation and toxicity in models of sporadic amyotrophic lateral sclerosis.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1869}, number = {8}, pages = {166835}, doi = {10.1016/j.bbadis.2023.166835}, pmid = {37558009}, issn = {1879-260X}, mesh = {Humans ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/pathology ; Superoxide Dismutase/metabolism ; Maillard Reaction ; Magnesium Oxide ; Motor Neurons/metabolism ; DNA-Binding Proteins/metabolism ; }, abstract = {Different SOD1 proteoforms are implicated## in both familial and sporadic cases of Amyotrophic Lateral Sclerosis (ALS), an aging-associated disease that affects motor neurons. SOD1 is crucial to neuronal metabolism and health, regulating the oxidative stress response and the shift between oxidative-fermentative metabolism, which is important for astrocyte-neuron metabolic cooperation. Neurons have a limited capacity to metabolize methylglyoxal (MGO), a potentially toxic side product of glycolysis. MGO is highly reactive and can readily posttranslationally modify proteins, in a reaction known as glycation, impacting their normal biology. Here, we aimed to investigate the effect of glycation on the aggregation and toxicity of human SOD1WT (hSOD1WT). Cells with deficiency in MGO metabolism showed increased levels of hSOD1WT inclusions, displaying also reduced hSOD1WT activity and viability. Strikingly, we also found that the presence of hSOD1WT in stress granules increased upon MGO treatment. The treatment of recombinant hSOD1WT with MGO resulted in the formation of SDS-stable oligomers, specially trimers, and thioflavin-T positive aggregates, which can promote cell toxicity and TDP-43 pathology. Together, our results suggest that glycation may play a still underappreciated role on hSOD1WT and TDP-43 pathologies in sporadic ALS, which could open novel perspectives for therapeutic intervention.}, } @article {pmid37556308, year = {2023}, author = {Kadambi, P and Stegmann, GM and Liss, J and Berisha, V and Hahn, S}, title = {Wav2DDK: Analytical and Clinical Validation of an Automated Diadochokinetic Rate Estimation Algorithm on Remotely Collected Speech.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {66}, number = {8S}, pages = {3166-3181}, pmid = {37556308}, issn = {1558-9102}, support = {R01 DC006859/DC/NIDCD NIH HHS/United States ; R21 DC019475/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Speech ; *Amyotrophic Lateral Sclerosis ; Reproducibility of Results ; Speech Articulation Tests ; Algorithms ; }, abstract = {PURPOSE: Oral diadochokinesis is a useful task in assessment of speech motor function in the context of neurological disease. Remote collection of speech tasks provides a convenient alternative to in-clinic visits, but scoring these assessments can be a laborious process for clinicians. This work describes Wav2DDK, an automated algorithm for estimating the diadochokinetic (DDK) rate on remotely collected audio from healthy participants and participants with amyotrophic lateral sclerosis (ALS).

METHOD: Wav2DDK was developed using a corpus of 970 DDK assessments from healthy and ALS speakers where ground truth DDK rates were provided manually by trained annotators. The clinical utility of the algorithm was demonstrated on a corpus of 7,919 assessments collected longitudinally from 26 healthy controls and 82 ALS speakers. Corpora were collected via the participants' own mobile device, and instructions for speech elicitation were provided via a mobile app. DDK rate was estimated by parsing the character transcript from a deep neural network transformer acoustic model trained on healthy and ALS speech.

RESULTS: Algorithm estimated DDK rates are highly accurate, achieving .98 correlation with manual annotation, and an average error of only 0.071 syllables per second. The rate exactly matched ground truth for 83% of files and was within 0.5 syllables per second for 95% of files. Estimated rates achieve a high test-retest reliability (r = .95) and show good correlation with the revised ALS functional rating scale speech subscore (r = .67).

CONCLUSION: We demonstrate a system for automated DDK estimation that increases efficiency of calculation beyond manual annotation. Thorough analytical and clinical validation demonstrates that the algorithm is not only highly accurate, but also provides a convenient, clinically relevant metric for tracking longitudinal decline in ALS, serving to promote participation and diversity of participants in clinical research.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.23787033.}, } @article {pmid37556038, year = {2023}, author = {Yamamuro-Tanabe, A and Mukai, Y and Kojima, W and Zheng, S and Matsumoto, N and Takada, S and Mizuhara, M and Kosuge, Y and Ishimaru, Y and Yoshioka, Y}, title = {An Increase in Peroxiredoxin 6 Expression Induces Neurotoxic A1 Astrocytes in the Lumbar Spinal Cord of Amyotrophic Lateral Sclerosis Mice Model.}, journal = {Neurochemical research}, volume = {48}, number = {12}, pages = {3571-3584}, pmid = {37556038}, issn = {1573-6903}, mesh = {Mice ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Astrocytes/metabolism ; Peroxiredoxin VI/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Mice, Transgenic ; Spinal Cord/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; *Neurotoxicity Syndromes/metabolism ; RNA, Messenger/metabolism ; Superoxide Dismutase-1/genetics ; Superoxide Dismutase/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with selective degeneration of motor neurons. It has been reported that an increase in the levels of inflammatory cytokines and glial cells such as reactive astrocytes is closely involved in the pathological progression of ALS. Recently, the levels of neuropathic cytotoxic (A1) astrocytes among reactive astrocytes have reportedly increased in the central nervous system of ALS mice, which induce motor neuron degeneration through the production of inflammatory cytokines and secretion of neuropathic factors. Hence, elucidating the induction mechanism of A1 astrocytes in ALS is important to understand the mechanism of disease progression in ALS. In this study, we observed that the expression of peroxiredoxin 6 (PRDX6), a member of the peroxiredoxin family, was markedly upregulated in astrocytes of the lumbar spinal cord of SOD1[G93A] mice model for ALS. Additionally, when PRDX6 was transiently transfected into the mouse astrocyte cell line C8-D1A and human astrocytoma cell line U-251 MG, the mRNA expression of complement C3 (a marker for A1 astrocyte phenotype) and inflammatory cytokines was increased. Furthermore, the mRNA expression of C3 and inflammatory cytokine was increased in C8-D1A and U-251 MG cells stably expressing PRDX6, and the increased mRNA expression was significantly suppressed by MJ33 (lithium[1-hexadecoxy-3-(2,2,2-trifluoroethoxy) propan-2-yl] methyl phosphate), an inhibitor of the phospholipase A2 activity of PRDX6. Our results suggest that the expression of PRDX6 in astrocytes plays an important role in the induction of A1 astrocytes and expression of inflammatory cytokines in the ALS mice model.}, } @article {pmid37555859, year = {2023}, author = {Tsuboguchi, S and Nakamura, Y and Ishihara, T and Kato, T and Sato, T and Koyama, A and Mori, H and Koike, Y and Onodera, O and Ueno, M}, title = {TDP-43 differentially propagates to induce antero- and retrograde degeneration in the corticospinal circuits in mouse focal ALS models.}, journal = {Acta neuropathologica}, volume = {146}, number = {4}, pages = {611-629}, pmid = {37555859}, issn = {1432-0533}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; DNA-Binding Proteins/genetics/metabolism ; Motor Neurons/metabolism ; *Retrograde Degeneration/metabolism/pathology ; Spinal Cord/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by TDP-43 inclusions in the cortical and spinal motor neurons. It remains unknown whether and how pathogenic TDP-43 spreads across neural connections to progress degenerative processes in the cortico-spinal motor circuitry. Here we established novel mouse ALS models that initially induced mutant TDP-43 inclusions in specific neuronal or cell types in the motor circuits, and investigated whether TDP-43 and relevant pathological processes spread across neuronal or cellular connections. We first developed ALS models that primarily induced TDP-43 inclusions in the corticospinal neurons, spinal motor neurons, or forelimb skeletal muscle, by using adeno-associated virus (AAV) expressing mutant TDP-43. We found that TDP-43 induced in the corticospinal neurons was transported along the axons anterogradely and transferred to the oligodendrocytes along the corticospinal tract (CST), coinciding with mild axon degeneration. In contrast, TDP-43 introduced in the spinal motor neurons did not spread retrogradely to the cortical or spinal neurons; however, it induced an extreme loss of spinal motor neurons and subsequent degeneration of neighboring spinal neurons, suggesting a degenerative propagation in a retrograde manner in the spinal cord. The intraspinal degeneration further led to severe muscle atrophy. Finally, TDP-43 induced in the skeletal muscle did not propagate pathological events to spinal neurons retrogradely. Our data revealed that mutant TDP-43 spread across neuro-glial connections anterogradely in the corticospinal pathway, whereas it exhibited different retrograde degenerative properties in the spinal circuits. This suggests that pathogenic TDP-43 may induce distinct antero- and retrograde mechanisms of degeneration in the motor system in ALS.}, } @article {pmid37555725, year = {2024}, author = {Wei, F and Liang, X and Shi, JC and Luo, JN and Qiu, LJ and Li, XX and Lu, LJ and Wen, YQ and Feng, JY}, title = {Pan-Genomic Analysis Identifies the Chinese Strain as a New Subspecies of Xanthomonas fragariae.}, journal = {Plant disease}, volume = {108}, number = {1}, pages = {45-49}, doi = {10.1094/PDIS-05-23-0933-SC}, pmid = {37555725}, issn = {0191-2917}, mesh = {*Genomics ; Multilocus Sequence Typing ; *Xanthomonas/genetics ; }, abstract = {Xanthomonas fragariae is classified as a quarantine pathogen by the European and Mediterranean Plant Protection Organization. It commonly induces typical angular leaf spot (ALS) symptoms in strawberry leaves. X. fragariae strains from China (YL19, SHAQP01, and YLX21) exhibit ALS symptoms in leaves and more severe symptoms of dry cavity rot in strawberry crowns. Conversely, strains from other countries do not cause severe dry cavity rot symptoms in strawberries. After employing multilocus sequence analysis (MLSA), average nucleotide identity (ANI), and amino acid identity (AAI), we determined that Chinese strains of X. fragariae are genetically distinct from other strains and can be considered a new subspecies. Subsequent analysis of 63 X. fragariae genomes published at NCBI using IPGA and EDGAR3.0 revealed the pan-genomic profile, with 1,680 shared genes present in all 63 strains, including 71 virulence-related genes. Additionally, we identified 123 genes exclusive to all the Chinese strains, encompassing 12 virulence-related genes. The qRT-PCR analysis demonstrated that the expression of XopD, XopG1, CE8, GT2, and GH121 out of 12 virulence-related genes of Chinese strains (YL19) exhibited a constant increase in the early stages (6, 24, 54, and 96 hours postinoculation [hpi]) of strawberry leaf infected by YL19. So, the presence of XopD, XopG1, CE8, GT2, and GH121 in Chinese strains may play important roles in the early infection process of Chinese strains. These findings offer novel insights into comprehending the population structure and variation in the pathogenic capacity of X. fragariae.}, } @article {pmid37555646, year = {2023}, author = {Ribeiro, SS and Gnutt, D and Azoulay-Ginsburg, S and Fetahaj, Z and Spurlock, E and Lindner, F and Kuz, D and Cohen-Erez, Y and Rapaport, H and Israelson, A and Gruzman, AL and Ebbinghaus, S}, title = {Intracellular spatially-targeted chemical chaperones increase native state stability of mutant SOD1 barrel.}, journal = {Biological chemistry}, volume = {404}, number = {10}, pages = {909-930}, pmid = {37555646}, issn = {1437-4315}, mesh = {Humans ; Superoxide Dismutase-1/genetics/chemistry/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy ; Protein Folding ; Mutation ; Molecular Chaperones ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder with currently no cure. Central to the cellular dysfunction associated with this fatal proteinopathy is the accumulation of unfolded/misfolded superoxide dismutase 1 (SOD1) in various subcellular locations. The molecular mechanism driving the formation of SOD1 aggregates is not fully understood but numerous studies suggest that aberrant aggregation escalates with folding instability of mutant apoSOD1. Recent advances on combining organelle-targeting therapies with the anti-aggregation capacity of chemical chaperones have successfully reduce the subcellular load of misfolded/aggregated SOD1 as well as their downstream anomalous cellular processes at low concentrations (micromolar range). Nevertheless, if such local aggregate reduction directly correlates with increased folding stability remains to be explored. To fill this gap, we synthesized and tested here the effect of 9 ER-, mitochondria- and lysosome-targeted chemical chaperones on the folding stability of truncated monomeric SOD1 (SOD1bar) mutants directed to those organelles. We found that compound ER-15 specifically increased the native state stability of ER-SOD1bar-A4V, while scaffold compound FDA-approved 4-phenylbutyric acid (PBA) decreased it. Furthermore, our results suggested that ER15 mechanism of action is distinct from that of PBA, opening new therapeutic perspectives of this novel chemical chaperone on ALS treatment.}, } @article {pmid37555559, year = {2023}, author = {Reimer, RJ and Goncalves, A and Soper, B and Cadena, J and Wilson, JL and Gryshuk, AL and Suarez, P and Osborne, TF and Grimes, KV and Ray, P}, title = {An electronic health record cohort of Veterans with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2023.2239300}, pmid = {37555559}, issn = {2167-9223}, abstract = {Objective: To assemble and characterize an electronic health record (EHR) dataset for a large cohort of US military Veterans diagnosed with ALS (Amyotrophic Lateral Sclerosis). Methods: An EHR dataset for 19,662 Veterans diagnosed with ALS between January 1, 2000 to December 31, 2020 was compiled from the Veterans Health Administration (VHA) EHR database by a query for ICD9 diagnosis (335.20) or ICD10 diagnosis (G12.21) for Amyotrophic Lateral Sclerosis. Results: The cohort is predominantly male (98.94%) and white (72.37%) with a median age at disease onset of 68 years and median survival from the date of diagnosis of 590 days. With the designation of ALS as a compensable illness in 2009, there was a subsequent increase in the number of Veterans diagnosed per year in the VHA, but no change in median survival. The cohort included a greater-than-expected proportion of individuals whose branch of service at the time of separation was the Army. Conclusions: The composition of the cohort reflects the VHA population who are at greatest risk for ALS. The greater than expected proportion of individuals whose branch of service at the time of separation was the Army suggests the possibility of a branch-specific risk factor for ALS.}, } @article {pmid37554051, year = {2023}, author = {Cao, W and Cao, Z and Tian, Y and Zhang, L and Wang, W and Tang, L and Xu, C and Fan, D}, title = {Neutrophils Are Associated with Higher Risk of Incident Amyotrophic Lateral Sclerosis in a BMI- and Age-Dependent Manner.}, journal = {Annals of neurology}, volume = {94}, number = {5}, pages = {942-954}, doi = {10.1002/ana.26760}, pmid = {37554051}, issn = {1531-8249}, mesh = {Humans ; Aged ; *Neutrophils ; *Amyotrophic Lateral Sclerosis/epidemiology ; Body Mass Index ; Lymphocytes ; Prognosis ; Biomarkers ; Retrospective Studies ; Inflammation ; }, abstract = {OBJECTIVE: Peripheral immune markers have been associated with the progression and prognosis of amyotrophic lateral sclerosis (ALS). However, whether dysregulation of peripheral immunity is a risk factor for ALS or a consequence of motor neuron degeneration has not yet been clarified. We aimed to identify longitudinal associations between prediagnostic peripheral immunity and the risk of incident ALS.

METHODS: A total of 345,000 individuals from the UK Biobank between 2006 and 2010 were included at the baseline. The counts of peripheral immune markers (neutrophils, lymphocytes, monocytes, platelets, and CRP) and its derived metrics (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], lymphocyte-to-monocyte ratio [LMR], and systemic immune-inflammation index [SII]) were analyzed in relation to the following incident ALS by Cox proportional hazard models. Subgroup and interaction analyses were performed to explore the covariates of these relationships further.

RESULTS: After adjusting for all covariates, the multivariate analysis showed that high neutrophil counts and their derived metrics (NLR and SII) were associated with an increased risk of ALS incidence (per SD increment hazard ratio [HR] = 1.15, 95% confidence interval [CI] = 1.02-1.29 for neutrophils; HR = 1.15, 95% CI = 1.03-1.28 for NLR; and HR = 1.17, 95% CI = 1.05-1.30 for SII). Subgroup and interaction analyses revealed that body mass index (BMI) and age had specific effects on this association. In participants with BMI ≥ 25 or age < 65 years, higher neutrophil counts, and their metrics increased the risk of incident ALS; however, in participants with BMI < 25 or age ≥ 65 years, neutrophils had no effect on incident ALS.

INTERPRETATION: Our study provides evidence that increased neutrophil levels and neutrophil-derived metrics (NLR and SII) are associated with an increased risk of developing ALS. ANN NEUROL 2023;94:942-954.}, } @article {pmid37552461, year = {2023}, author = {Weeks, RD and Banack, SA and Howell, S and Thunga, P and Metcalf, JS and Green, AJ and Cox, PA and Planchart, A}, title = {The Effects of Long-term, Low-dose β-N-methylamino-L-alanine (BMAA) Exposures in Adult SOD[G93R] Transgenic Zebrafish.}, journal = {Neurotoxicity research}, volume = {41}, number = {5}, pages = {481-495}, pmid = {37552461}, issn = {1476-3524}, support = {P30 ES025128/ES/NIEHS NIH HHS/United States ; T32 ES007046/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Zebrafish ; *Neurodegenerative Diseases/etiology ; *Amyotrophic Lateral Sclerosis/chemically induced/genetics/complications ; *Amino Acids, Diamino/toxicity ; Animals, Genetically Modified ; Neurotoxins/toxicity ; Superoxide Dismutase ; }, abstract = {β-N-Methylamino-L-alanine (BMAA) is a non-proteinogenic amino acid produced by cyanobacteria, which has been implicated in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). It is postulated that chronic exposure to BMAA can lead to formation of protein aggregates, oxidative stress, and/or excitotoxicity, which are mechanisms involved in the etiology of ALS. While specific genetic mutations are identified in some instances of ALS, it is likely that a combination of genetic and environmental factors, such as exposure to the neurotoxin BMAA, contributes to disease. We used a transgenic zebrafish with an ALS-associated mutation, compared with wild-type fish to explore the potential neurotoxic effects of BMAA through chronic long-term exposures. While our results revealed low concentrations of BMAA in the brains of exposed fish, we found no evidence of decreased swim performance or behavioral differences that might be reflective of neurodegenerative disease. Further research is needed to determine if chronic BMAA exposure in adult zebrafish is a suitable model to study neurodegenerative disease initiation and/or progression.}, } @article {pmid37550954, year = {2023}, author = {Weemering, DN and Midei, M and Milner, P and Gopalakrishnan, V and Kumar, A and Dannenberg, AJ and Bunte, TM and Foucher, J and Ingre, C and Ķēniņa, V and Rallmann, K and van den Berg, LH and van Eijk, RPA}, title = {A randomized, double-blind, placebo-controlled phase 2 study to assess safety, tolerability, and efficacy of RT001 in patients with amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {30}, number = {12}, pages = {3722-3731}, doi = {10.1111/ene.16020}, pmid = {37550954}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Linoleic Acids/therapeutic use ; Double-Blind Method ; Treatment Outcome ; }, abstract = {BACKGROUND AND PURPOSE: RT001 is a deuterated synthetic homologue of linoleic acid, which makes membrane polyunsaturated fatty acids resistant to lipid peroxidation, a process involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS).

METHODS: We conducted a randomized, multicenter, placebo-controlled clinical trial. Patients with ALS were randomly allocated to receive either RT001 or placebo for 24 weeks. After the double-blind period, all patients received RT001 during an open-label phase for 24 weeks. The primary outcome measures were safety and tolerability. Key efficacy outcomes included the ALS Functional Rating Scale (ALSFRS-R), percent predicted slow vital capacity, and plasma neurofilament light chain concentration.

RESULTS: In total, 43 patients (RT001 = 21; placebo = 22) were randomized. RT001 was well tolerated; one patient required dose reduction due to adverse events (AEs). Numerically, there were more AEs in the RT001 group compared to the placebo group (71% versus 55%, p = 0.35), with gastrointestinal symptoms being the most common (43% in RT001, 27% in placebo, p = 0.35). Two patients in the RT001 group experienced a serious AE, though unrelated to treatment. The least-squares mean difference in ALSFRS-R total score at week 24 of treatment was 1.90 (95% confidence interval = -1.39 to 5.19) in favor of RT001 (p = 0.25). The directions of other efficacy outcomes favored RT001 compared to placebo, although no inferential statistics were performed.

CONCLUSIONS: Initial data indicate that RT001 is safe and well tolerated. Given the exploratory nature of the study, a larger clinical trial is required to evaluate its efficacy.}, } @article {pmid37550578, year = {2024}, author = {Maksymowicz, S and Siwek, T}, title = {Diagnostic odyssey in amyotrophic lateral sclerosis: diagnostic criteria and reality.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {1}, pages = {191-196}, pmid = {37550578}, issn = {1590-3478}, mesh = {Male ; Female ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Quality of Life ; *Physicians ; Rare Diseases ; }, abstract = {BACKGROUND: Diagnosing a rare disease, such as amyotrophic lateral sclerosis, is a major challenge for physicians and patients. Despite detailed diagnostic criteria, this process often does not proceed as it should, exacerbating the problems of patients. In the following study, we show how the process, which in medical sciences has been called the "diagnostic odyssey", proceeds and how it affects patients.

MATERIALS AND METHODS: Participants were recruited via a neurology clinic. Twenty-four patients with the diagnosed disease were interviewed using in-depth interviews and an author questionnaire: 9 females and 15 males ages ranging from 30-39 to 60-69.

RESULTS: The median time from 1st symptoms to diagnosis was almost 12 months and mean almost 20 months (min. 3, max 106). Only 5 patients waited less than 6 months for being diagnosed. Over 80% of patients received an alternative diagnosis on the first attempt.

CONCLUSION: ALS is a fast-paced fatal disease, which requires immediate action to slow down the course of the disease and improve patients' quality of life. However, in many cases, the disease is diagnosed too late. It also happens that a wrong diagnosis causes inaccurate treatment, which accelerates the development of ALS. For this reason, it is necessary to expand the clinical and communication competences of medical personnel already at the stage of medical studies. In addition, the diagnostic criteria should highlight the common problem with diagnosing ALS.}, } @article {pmid37550499, year = {2023}, author = {Wang, XH and Peng, BB and Zhang, L and Zhao, J and Zhang, L and Ren, H and Hu, P and Li, H and Zhong, S}, title = {Mixed mode of artificial liver support in patients with acute-on-chronic liver failure: a retrospective cohort study.}, journal = {Hepatology international}, volume = {17}, number = {5}, pages = {1241-1250}, pmid = {37550499}, issn = {1936-0541}, support = {82173237//National Natural Science Foundation of China/ ; 81902068//National Natural Science Foundation of China/ ; No. [2022]15//Senior Medical Talents Program of Chongqing for Young and Middle-aged/ ; W0082//Program for Youth Innovation in Future Medicine, Chongqing Medical University/ ; Shan Zhong//Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University/ ; Hu Li//Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University/ ; }, mesh = {Female ; Humans ; Male ; *Acute-On-Chronic Liver Failure/mortality ; Liver Cirrhosis/complications ; *Liver, Artificial/adverse effects ; Prognosis ; Retrospective Studies ; }, abstract = {BACKGROUND AND AIMS: Different modes of artificial liver support (ALS) therapy can improve the survival of patients with acute-on-chronic liver failure (ACLF). This study aimed to compare the effects of mixed using different modes of ALS (MALS) and single using one mode of ALS (SALS) on 28- and 90-day survival rates of ACLF.

METHODS: Clinical data and survival times of patients with ACLF treated for ALS between January 1, 2018 and December 30, 2021 were retrospectively collected. Cox regression analysis was performed to identify risk factors of 28- and 90-day mortalities.

RESULTS: Of the 462 eligible ACLF patients, 388 belonged to the SALS group (76.3% male, 74.2% cirrhosis) and 74 to the MALS group (86.5% male, 71.6% cirrhosis). Comparison of 28-day and 90-day crude mortality between the SALS and MALS groups showed no significant differences (28-day: 20.4% vs. 14.9%, p = 0.27; 90-day: 44.6% vs. 52.7%, p = 0.20). After adjusting for confounders, the 28-day mortality (adjusted hazard ratio [aHR]: 0.32, 95% confidence interval [CI] 0.16-0.65) and 90-day mortality (aHR: 0.65, 95% CI 0.44-0.95) in the MALS group were significantly lower than those in the SALS group. These associations were consistently observed across pre-specified subgroups according to age, sex, etiology, and Child-Pugh grade. However, positive interactions between MALS and 90-day mortality were found between MALS and 90-day mortality in those with MELD score ≥ 22 and international normalized ratio ≥ 1.9 (p for interaction < 0.05).

CONCLUSION: MALS therapy significantly decreased 28- and 90-day mortalities of ACLF than SALS did, especially in advanced stages.}, } @article {pmid37549725, year = {2023}, author = {Fan, H and Bai, Q and Yang, Y and Shi, X and Du, G and Yan, J and Shi, J and Wang, D}, title = {The key roles of reactive oxygen species in microglial inflammatory activation: Regulation by endogenous antioxidant system and exogenous sulfur-containing compounds.}, journal = {European journal of pharmacology}, volume = {956}, number = {}, pages = {175966}, doi = {10.1016/j.ejphar.2023.175966}, pmid = {37549725}, issn = {1879-0712}, mesh = {Humans ; *Antioxidants/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; *Microglia ; Sulfur Compounds/metabolism/pharmacology ; Neuroinflammatory Diseases ; Cysteine/pharmacology ; Sulfur/metabolism/pharmacology ; }, abstract = {Aberrant innate immunity in the brain has been implicated in the pathogenesis of several central nervous system (CNS) disorders, including Alzheimer's disease, Huntington's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and depression. Except for extraparenchymal CNS-associated macrophages, which predominantly afford protection against peripheral invading pathogens, it has been reported that microglia, a population of macrophage-like cells governing CNS immune defense in nearly all neurological diseases, are the main CNS resident immune cells. Although microglia have been recognized as the most important source of reactive oxygen species (ROS) in the CNS, ROS also may underlie microglial functions, especially M1 polarization, by modulating redox-sensitive signaling pathways. Recently, endogenous antioxidant systems, including glutathione, hydrogen sulfide, superoxide dismutase, and methionine sulfoxide reductase A, were found to be involved in regulating microglia-mediated neuroinflammation. A series of natural sulfur-containing compounds, including S-adenosyl methionine, S-methyl-L-cysteine, sulforaphane, DMS, and S-alk(enyl)-l-cysteine sulfoxide, modulating endogenous antioxidant systems have been discovered. We have summarized the current knowledge on the involvement of endogenous antioxidant systems in regulating microglial inflammatory activation and the effects of sulfur-containing compounds on endogenous antioxidant systems. Finally, we discuss the possibilities associated with compounds targeting the endogenous antioxidant system to treat neuroinflammation-associated diseases.}, } @article {pmid37548757, year = {2024}, author = {Zhu, Y and Huo, Y and Bai, J and Li, M and Wang, H and Wang, J and Huang, X}, title = {Serum Cystatin C is a potential biomarker for predicting amyotrophic lateral sclerosis survival.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {1}, pages = {197-201}, pmid = {37548757}, issn = {1590-3478}, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis ; Biomarkers ; Cystatin C ; Delayed Diagnosis ; Disease Progression ; Prognosis ; }, abstract = {OBJECTIVE: Currently, it is unclear whether serum Cystatin C can be used to evaluate the prognosis of ALS. We aim to study the relationship between serum Cystatin C and survival in ALS.

METHODS: Sporadic ALS patients diagnosed at the Department of Neurology, the First Medical Center, and the Chinese PLA General Hospital from January 2016 to December 2019 were enrolled in this study. Experienced neurologists followed up the participants regularly every 6 months until January 2022. According to the levels of serum Cystatin C, the participants were divided into high and low Cystatin C levels groups. The comparison between groups was performed with parametric or non-parametric test. Kaplan-Meier method and Cox regression model were used to calculate survival analysis.

RESULTS: Three hundred fifty-six sporadic ALS patients were enrolled in this study, including 203 males and 153 females. Among all ALS patients, 26 cases (7.3%) were lost to follow-up, 226 cases (63.5%) died, and 104 cases (29.2%) were still alive at the last follow-up. The median survival time of all ALS patients was 42.0 months. Patients with high Cystatin C levels had shorter median survival than those with lower Cystatin C levels (38.0 months vs. 48.0 months, P = 2.58 × 10[-4]). In multivariate Cox regression analysis, onset form, age of onset, diagnostic delay, disease progression rate, creatinine, and serum Cystatin C levels were associated with ALS survival.

CONCLUSIONS: Our study found that serum Cystatin C was associated with ALS survival, and serum Cystatin C level might be an independent predictor of ALS survival.}, } @article {pmid37548234, year = {2023}, author = {Notarstefano, V and Belloni, A and Mariani, P and Orilisi, G and Orsini, G and Giorgini, E and Byrne, HJ}, title = {Multivariate curve Resolution-Alternating least squares coupled with Raman microspectroscopy: new insights into the kinetic response of primary oral squamous carcinoma cells to cisplatin.}, journal = {The Analyst}, volume = {148}, number = {18}, pages = {4365-4372}, doi = {10.1039/d3an01182h}, pmid = {37548234}, issn = {1364-5528}, mesh = {Humans ; *Cisplatin/pharmacology ; Least-Squares Analysis ; Spectrum Analysis, Raman/methods ; *Carcinoma, Squamous Cell/drug therapy ; Multivariate Analysis ; }, abstract = {Raman MicroSpectroscopy (RMS) is a powerful label-free tool to probe the effects of drugs at a cellular/subcellular level. It is important, however, to be able to extract relevant biochemical and kinetic spectroscopic signatures of the specific cellular responses. In the present study, a combination of Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and Principal Component Analysis (PCA) is used to analyse the RMS data for the example of exposure of primary Oral Squamous Carcinoma Cells (OSCC) to the chemotherapeutic agent cisplatin. Dosing regimens were established by cytotoxicity assays, and the effects of the drug on cellular spectral profiles were monitored from 16 to 72 hours post-exposure using an apoptosis assay, to establish the relative populations of viable (V), early (EA) and late apoptotic/dead (LA/D) cells after the drug treatment. Based on a kinetic model of the progression from V > EA > D, MCR-ALS regression analysis of the RMS responses was able to extract spectral profiles associated with each stage of the cellular responses, enabling a quantitative comparison of the response rates for the respective drug treatments. Moreover, PCA was used to compare the spectral profiles of the viable cells exposed to the drug. Spectral differences were highlighted in the early stages (16 hours exposure), indicative of the initial cellular response to the drug treatment, and also in the late stages (48-72 hours exposure), representing the cell death pathway. The study demonstrates that RMS coupled with multivariate analysis can be used to quantitatively monitor the progression of cellular responses to different drugs, towards future applications for label-free, in vitro, pre-clinical screening.}, } @article {pmid37548032, year = {2024}, author = {LeBlanc, MA and Gough, A and Rideout, AL and Dyack, S and Singh, K and MacNeil, M}, title = {Atypical Neuropsychiatric Presentation of FTD-ALS Caused by a Pathogenic Repeat Expansion in C9orf72: A Case Report.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {37}, number = {2}, pages = {157-162}, pmid = {37548032}, issn = {1552-5708}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; C9orf72 Protein/genetics ; DNA Repeat Expansion ; *Frontotemporal Dementia/diagnosis/genetics ; Mutation ; Adult ; }, abstract = {The case report describes the presentation of a 42-year-old male ultimately diagnosed with FTD-ALS caused by a genetic mutation, who initially presented with atypical psychiatric symptoms. Given that the initial clinical manifestations of FTD-ALS can be quite variable, the diagnosis is often challenging; the case report aims to highlight several key considerations in the diagnostic assessment, including genetic testing in order to guide clinicians in more timely diagnosis and ultimately improve patient care.}, } @article {pmid37547740, year = {2023}, author = {Aiello, EN and Solca, F and Torre, S and Patisso, V and De Lorenzo, A and Treddenti, M and Colombo, E and Maranzano, A and Morelli, C and Doretti, A and Verde, F and Silani, V and Ticozzi, N and Poletti, B}, title = {Bulbar involvement and cognitive features in amyotrophic lateral sclerosis: a retrospective study on 347 patients.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1217080}, pmid = {37547740}, issn = {1663-4365}, abstract = {BACKGROUND: This study aimed at clarifying the role of bulbar involvement (BI) as a risk factor for cognitive impairment (CI) in non-demented amyotrophic lateral sclerosis (ALS) patients.

METHODS: Data on N = 347 patients were retrospectively collected. Cognition was assessed via the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). On the basis of clinical records and ALS Functional Rating Scale-Revised (ALSFRS-R) scores, BI was characterized as follows: (1) BI at onset-from medical history; (2) BI at testing (an ALSFRS-R-Bulbar score ≤11); (3) dysarthria (a score ≤3 on item 1 of the ALSFRS-R); (4) severity of BI (the total score on the ALSFRS-R-Bulbar); and (5) progression rate of BI (computed as 12-ALSFRS-R-Bulbar/disease duration in months). Logistic regressions were run to predict a below- vs. above-cutoff performance on each ECAS measure based on BI-related features while accounting for sex, disease duration, severity and progression rate of respiratory and spinal involvement and ECAS response modality.

RESULTS: No predictors yielded significance either on the ECAS-Total and -ALS-non-specific or on ECAS-Language/-Fluency or -Visuospatial subscales. BI at testing predicted a higher probability of an abnormal performance on the ECAS-ALS-specific (p = 0.035) and ECAS-Executive Functioning (p = 0.018). Lower ALSFRS-R-Bulbar scores were associated with a defective performance on the ECAS-Memory (p = 0.025). No other BI-related features affected other ECAS performances.

DISCUSSION: In ALS, the occurrence of BI itself, while neither its specific features nor its presence at onset, might selectively represent a risk factor for executive impairment, whilst its severity might be associated with memory deficits.}, } @article {pmid37547466, year = {2023}, author = {Vinciguerra, C and Di Fonzo, A and Monfrini, E and Ronchi, D and Cuoco, S and Piscosquito, G and Barone, P and Pellecchia, MT}, title = {Case report: Asp194Ala variant in MFN2 is associated with ALS-FTD in an Italian family.}, journal = {Frontiers in genetics}, volume = {14}, number = {}, pages = {1235887}, pmid = {37547466}, issn = {1664-8021}, abstract = {Background: MFN2 gene encodes the protein Mitofusin 2, involved in essential mitochondrial functions such as fusion, trafficking, turnover, and cellular interactions. We describe a family carrying a novel MFN2 mutation associated with ALS-frontotemporal dementia (FTD) clinical phenotype in the mother and Charcot-Marie-Tooth disease type 2A (CMT2A) in her son. Case presentation: The mother, a 67-year-old woman, referred to us for a three year-history of mood disturbance and gait impairment, and a more recent hypophonia, dysarthria, dysphagia, and diffuse muscle wasting. Family history was positive for psychiatric disorders and gait disturbances. Brain 18F-FDG PET showed severe hypometabolism in the fronto-temporal brain cortex bilaterally. Electrodiagnostic studies (EDX) showed severe motor axonopathy in the bulbar, cervical and lumbosacral districts. Her 41-year-old son had a history of mood depression and sensory disturbances in the limbs, along with mild muscle wasting, weakness, and reduced reflexes. Nerve conduction studies revealed a moderate sensory-motor polyneuropathy, while brain MRI was normal. Whole exome sequencing of the patients' DNA identified the novel MFN2 (NM_014874.4) variant c.581A>C p.(Asp194Ala). Conclusion: Our findings provide evidence of heterogenous clinical manifestations in family members sharing the same MFN2 molecular defect. Additionally, we present the first documented case of ASL-FTD associated with an MFN2 mutation, thereby expanding the range of MFN-related disorders. Further research involving larger cohorts of patients will be needed to better understand the role of MFN2 as a contributing gene in the development of ALS-FTD.}, } @article {pmid37546945, year = {2023}, author = {Syed, SA and Singh, J and Elkholy, H and Palavra, IR and Tomicevic, M and Eric, AP and da Costa, MP and Guloksuz, S and Radhakrishnan, R}, title = {International perspective on physician knowledge, attitude and practices related to medical cannabis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {37546945}, support = {R01 DA054314/DA/NIDA NIH HHS/United States ; R21 AT010763/AT/NCCIH NIH HHS/United States ; R21 DA054491/DA/NIDA NIH HHS/United States ; }, abstract = {BACKGROUND: The trends of recreational use of cannabis and use of cannabis for medical indications (i.e. "medical cannabis") have grown in recent years. Despite that, there is still limited scientific evidence to guide clinical decision-making and the strength of evidence for the medical use of cannabis is currently considered to be low. In contrast, there's growing evidence for negative health outcomes related to use of cannabis. In this rapidly shifting landscape, the role of physician's attitudes regarding the therapeutic value of cannabis has become essential. This study aimed to characterize knowledge/experience, attitudes, and potential predictors of clinical practice regarding medical cannabis.

METHODS: We conducted a cross-sectional survey of physicians from 17 countries between 2016-2018. The survey comprised of 28 questions designed to explore physician knowledge, attitude, and practices regarding the use of medical cannabis. Descriptive statistics were used to examine willingness to recommend medical cannabis for medical and psychiatric indications, followed by regression analysis to identify predictors of physician willingness to recommend medical cannabis.

RESULTS: A total of 323 physicians responded to the survey. Mean age was 35.4± 9.5 years, with 10.04 ±8.6 years of clinical experience. 53 percent of physicians were women. Clinical experience with medical cannabis was overall limited (51.4% noted never having recommended medical cannabis; 33% noted inadequate knowledge regarding medical cannabis). Overall willingness to recommend medical cannabis was highest for chemotherapy-induced nausea, refractory chronic neuropathic pain, and spasticity in amyotropic lateral sclerosis (ALS).

CONCLUSION: This international study examining knowledge, attitudes and practices related to medical cannabis among physicians revealed that there are significant gaps in domain-specific knowledge related to medical cannabis. There is wide variability in willingness to recommend medical cannabis that is not consistent with the current strength of evidence. This study thus highlights the need for greater education related to domain-specific knowledge about medical cannabis.}, } @article {pmid37545643, year = {2023}, author = {Brunette, S and Sharma, A and Bell, R and Puente, L and Megeney, LA}, title = {Caspase 3 exhibits a yeast metacaspase proteostasis function that protects mitochondria from toxic TDP43 aggregates.}, journal = {Microbial cell (Graz, Austria)}, volume = {10}, number = {8}, pages = {157-169}, pmid = {37545643}, issn = {2311-2638}, abstract = {Caspase 3 activation is a hallmark of cell death and there is a strong correlation between elevated protease activity and evolving pathology in neurodegenerative disease, such as amyotrophic lateral sclerosis (ALS). At the cellular level, ALS is characterized by protein aggregates and inclusions, comprising the RNA binding protein TDP-43, which are hypothesized to trigger pathogenic activation of caspase 3. However, a growing body of evidence indicates this protease is essential for ensuring cell viability during growth, differentiation and adaptation to stress. Here, we explored whether caspase 3 acts to disperse toxic protein aggregates, a proteostasis activity first ascribed to the distantly related yeast metacaspase ScMCA1. We demonstrate that human caspase 3 can functionally substitute for the ScMCA1 and limit protein aggregation in yeast, including TDP-43 inclusions. Proteomic analysis revealed that disrupting caspase 3 in the same yeast substitution model resulted in detrimental TDP-43/mitochondrial protein associations. Similarly, suppression of caspase 3, in either murine or human skeletal muscle cells, led to accumulation of TDP-43 aggregates and impaired mitochondrial function. These results suggest that caspase 3 is not inherently pathogenic, but may act as a compensatory proteostasis factor, to limit TDP-43 protein inclusions and protect organelle function in aggregation related degenerative disease.}, } @article {pmid37545536, year = {2023}, author = {Ramachandran, S and Grozdanov, V and Leins, B and Kandler, K and Witzel, S and Mulaw, M and Ludolph, AC and Weishaupt, JH and Danzer, KM}, title = {Low T-cell reactivity to TDP-43 peptides in ALS.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1193507}, pmid = {37545536}, issn = {1664-3224}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; CD8-Positive T-Lymphocytes/metabolism ; DNA-Binding Proteins/metabolism ; Interleukin-2 ; }, abstract = {BACKGROUND: Dysregulation of the immune system in amyotrophic lateral sclerosis (ALS) includes changes in T-cells composition and infiltration of T cells in the brain and spinal cord. Recent studies have shown that cytotoxic T cells can directly induce motor neuron death in a mouse model of ALS and that T cells from ALS patients are cytotoxic to iPSC-derived motor neurons from ALS patients. Furthermore, a clonal expansion to unknown epitope(s) was recently found in familial ALS and increased peripheral and intrathecal activation of cytotoxic CD8[+] T cells in sporadic ALS.

RESULTS: Here, we show an increased activation of peripheral T cells from patients with sporadic ALS by IL-2 treatment, suggesting an increase of antigen-experienced T cells in ALS blood. However, a putative antigen for T-cell activation in ALS has not yet been identified. Therefore, we investigated if peptides derived from TDP-43, a key protein in ALS pathogenesis, can act as epitopes for antigen-mediated activation of human T cells by ELISPOT and flow cytometry. We found that TDP-43 peptides induced only a weak MHCI or MHCII-restricted activation of both naïve and antigen-experienced T cells from healthy controls and ALS patients. Interestingly, we found less activation in T cells from ALS patients to TDP-43 and control stimuli. Furthermore, we found no change in the levels of naturally occurring auto-antibodies against full-length TDP-43 in ALS.

CONCLUSION: Our data suggests a general increase in antigen-experienced T cells in ALS blood, measured by in-vitro culture with IL-2 for 14 days. Furthermore, it suggests that TDP-43 is a weak autoantigen.}, } @article {pmid37545133, year = {2023}, author = {Correa-Arrieta, C and Ortiz-Corredor, F and Castellar-Leones, S and Sánchez-Peñarete, D}, title = {Slowly progressive late-onset spinal muscular atrophy Finkel-type related to p.Pro56Ser VABP mutation in Colombia.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2023.2241881}, pmid = {37545133}, issn = {2167-9223}, abstract = {Late-onset spinal muscular atrophy associated with the VAPB gene is a slowly progressing, adult-onset, lower motor neuron disease with an autosomal dominant inheritance pattern. We present a male with progressive weakness beginning at age 44, predominantly in the proximal legs, fasciculations, and gait disturbance, with similar clinical syndrome in his mother. On physical examination, he presented weakness in 4 extremities, predominantly proximal, with atrophy and areflexia. The genetic study identified the c.166C > T mutation in the VAPB gene. The P56S mutation of the VAPB gene is associated with adult-onset spinal muscular atrophy and amyotrophic lateral sclerosis; It has been reported in different countries, although the prevalence is higher in Brazil, related to Portuguese migration. Clinically, the patients present with late-onset ALS or SMA. The disease usually onset in the fifth decade of life as progressive weakness, predominantly proximal in the lower extremities, without bulbar or respiratory involvement.}, } @article {pmid37545108, year = {2023}, author = {Portley, M and Sherer, C and Wu, T and Farren, J and Danielian, LE and Scholz, SW and Traynor, BJ and Ward, ME and Haselhuhn, T and Snyder, A and Kwan, JY}, title = {Cognitive determinants of decisional capacity in neurodegenerative disorders.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {10}, pages = {1816-1823}, pmid = {37545108}, issn = {2328-9503}, support = {K24 AG000949/AG/NIA NIH HHS/United States ; Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; }, mesh = {United States ; Humans ; *Mental Competency/psychology ; Informed Consent/psychology ; Cross-Sectional Studies ; *Frontotemporal Dementia/diagnosis ; Cognition ; }, abstract = {OBJECTIVE: Cognitive contributions to decisional capacity are complex and not well understood. Capacity to consent for research has been linked to executive function, but executive function assessment tools are imperfect. In this study, we examine the relationship between decisional capacity and a newly developed executive function composite score and determine whether cognitive performance can predict impaired decisional capacity.

METHODS: This is a cross sectional study of participants at the National Institutes of Health with frontotemporal dementia-amyotrophic lateral sclerosis spectrum disorders enrolled between 2017 and 2022. A structured interview tool was used to ascertain research decisional capacity. Study participant Uniform Data Set (v3.0) executive function (UDS3-EF) composite score, Clinical Dementia Rating Scale©, and Neuropsychiatric Inventory was determined.

RESULTS: A decrease in UDS3-EF composite score significantly increased the odds of impaired decisional capacity (OR = 2.92, 95% CI [1.66-5.13], p = 0.0002). Executive function was most impaired in frontotemporal dementia (-2.86, SD = 1.26) and least impaired in amyotrophic lateral sclerosis (-0.52, SD = 1.25) participants. The UDS3-EF composite score was also strongly correlated to the Clinical Dementia Rating Scale©.

INTERPRETATION: Decisional capacity is intrinsically related to executive function in neurodegenerative disorders, and executive dysfunction may predict a lack of decisional capacity alerting investigators of the need for additional scrutiny during the informed consent process.}, } @article {pmid37543533, year = {2024}, author = {Morishima, R and Shimizu, T and Kimura, H and Bokuda, K and Saotome, T and Nakayama, Y and Takahashi, K}, title = {High doses of opioids usage for amyotrophic lateral sclerosis patients with non-invasive ventilation.}, journal = {Acta neurologica Belgica}, volume = {124}, number = {1}, pages = {101-107}, pmid = {37543533}, issn = {2240-2993}, mesh = {Humans ; *Noninvasive Ventilation ; Respiration, Artificial ; *Amyotrophic Lateral Sclerosis/drug therapy/diagnosis ; Analgesics, Opioid/therapeutic use ; Retrospective Studies ; Morphine Derivatives ; }, abstract = {INTRODUCTION: While opioids have been found to be useful in relieving suffering in amyotrophic lateral sclerosis (ALS), there is a lack of evidence concerning how and how much to use them in practice. This study was conducted to clarify how opioids were used for patients with ALS.

METHODS: We performed a retrospective case-based analysis at a single tertiary neurology center in Tokyo from 2010 to 2018. We enrolled patients with ALS who had died before the end of 2018. We examined the opioid dosage equivalent of morphine hydrochloride and patients' clinical backgrounds, focusing on ventilatory support.

RESULTS: Morphine was administered in 110 patients with ALS, and 84 were followed up until their death. Of these 84 patients, 57 (69.9%) did not use mechanical ventilation until death (no-MV group), and 21 (22.9%) utilized only non-invasive ventilation (NIV group). Final morphine dosage in the NIV group was significantly higher (mean 65.7 mg [SD 54.6], range 10-200 mg) than in the no-MV group (mean 31.7 mg [SD 26.9], range 0-120 mg; p = 0.015, Welch's t-test). The NIV group needed psychotropic drugs more frequently than the no-MV group (62% [n = 13] vs. 35% [n = 20]).

CONCLUSION: Patients in the NIV group used opioids for a statistically significantly longer time and at a higher dose than those in the no-MV group. Symptom control with opioids alone may be difficult, and the development of multifaceted evaluation and care is desirable.}, } @article {pmid37543480, year = {2023}, author = {Petrić Howe, M and Patani, R}, title = {Nonsense-mediated mRNA decay in neuronal physiology and neurodegeneration.}, journal = {Trends in neurosciences}, volume = {46}, number = {10}, pages = {879-892}, doi = {10.1016/j.tins.2023.07.001}, pmid = {37543480}, issn = {1878-108X}, support = {/CRUK_/Cancer Research UK/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Nonsense Mediated mRNA Decay ; *Protein Biosynthesis ; Neurons ; }, abstract = {The processes of mRNA export from the nucleus and subsequent mRNA translation in the cytoplasm are of particular relevance in eukaryotic cells. In highly polarised cells such as neurons, finely-tuned molecular regulation of these processes serves to safeguard the spatiotemporal fidelity of gene expression. Nonsense-mediated mRNA decay (NMD) is a cytoplasmic translation-dependent quality control process that regulates gene expression in a wide range of scenarios in the nervous system, including neurodevelopment, learning, and memory formation. Moreover, NMD dysregulation has been implicated in a broad range of neurodevelopmental and neurodegenerative disorders. We discuss how NMD and related aspects of mRNA translation regulate key neuronal functions and, in particular, we focus on evidence implicating these processes in the molecular pathogenesis of neurodegeneration. Finally, we discuss the therapeutic potential and challenges of targeting mRNA translation and NMD across the spectrum of largely untreatable neurological diseases.}, } @article {pmid37543426, year = {2023}, author = {Kruithof, WJ and Kruitwagen-van Reenen, E and van Eenennaam, RM and Ronda, MCM and Lamers, MJ and Visser-Meily, JMA and Beelen, A and van den Berg, LH}, title = {Multidisciplinary end-of-life care for a patient with amyotrophic lateral sclerosis requesting euthanasia.}, journal = {Lancet (London, England)}, volume = {402}, number = {10400}, pages = {484}, doi = {10.1016/S0140-6736(23)01286-2}, pmid = {37543426}, issn = {1474-547X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Terminal Care ; *Euthanasia ; }, } @article {pmid37543304, year = {2023}, author = {Kwon, S and Lee, E and Choi, EK and Lee, SR and Oh, S and Choi, YS}, title = {Long-term outcomes of abandoned leads of cardiac implantable electronic devices.}, journal = {Heart rhythm}, volume = {20}, number = {12}, pages = {1639-1646}, doi = {10.1016/j.hrthm.2023.07.068}, pmid = {37543304}, issn = {1556-3871}, mesh = {Humans ; *Defibrillators, Implantable/adverse effects ; Retrospective Studies ; Constriction, Pathologic/etiology ; *Vascular Diseases/etiology ; *Thrombosis/etiology ; *Venous Thrombosis/etiology ; *Pacemaker, Artificial/adverse effects ; *Prosthesis-Related Infections/diagnosis/epidemiology/etiology ; }, abstract = {BACKGROUND: Evidence of the long-term outcomes of abandoned leads (ALs) in patients with cardiac implantable electronic devices (CIEDs) is scarce.

OBJECTIVE: This study aimed to investigate the long-term outcomes of ALs.

METHODS: This retrospective cohort study reviewed a single-center CIED registry of 2962 procedures performed from 1984-2018 and identified 130 patients with AL (AL group). We matched 2 controls without AL (by age, sex, device type, and device revision/removal date) to each patient with AL (n = 260) and compared CIED-related infection, venous thrombosis/stenosis, and all-cause mortality between groups using a Cox proportional hazard model analysis.

RESULTS: For a mean follow-up period of 11.2 ± 8.2 years, 14 (3.6%), 7 (1.8%), and 143 (36.7%) patients had a CIED-related infection, venous thrombosis/stenosis, or experienced all-cause mortality, respectively. The AL group had more comorbidities than the control group. Lead malfunction was the most common cause of abandonment (64.6%). After adjustment for covariates, no significant intergroup differences were noted in the risks of infection, venous thrombosis/stenosis, or all-cause mortality (adjusted hazard ratio [aHR] 2.52; 95% confidence interval [CI] 0.77-8.25; aHR 1.18; 95% CI 0.25-5.64; aHR 1.26; 95% CI 0.89-1.80, respectively). Patients with multiple ALs had increased risks of infection and all-cause mortality vs controls (aHR 8.61; 95% CI 2.13-34.84; aHR 2.42; 95% CI 1.17-5.00, respectively).

CONCLUSION: Patients with a single AL showed similar risks of CIED-related infections, venous thrombosis/stenosis, and all-cause mortality as those without ALs, whereas those with multiple ALs showed increased risks of infection and all-cause mortality.}, } @article {pmid37543248, year = {2023}, author = {Batty, GD and Kivimäki, M and Frank, P and Gale, CR and Wright, L}, title = {Systemic inflammation and subsequent risk of amyotrophic lateral sclerosis: Prospective cohort study.}, journal = {Brain, behavior, and immunity}, volume = {114}, number = {}, pages = {46-51}, pmid = {37543248}, issn = {1090-2139}, support = {MR/P023444/1/MRC_/Medical Research Council/United Kingdom ; MR/S011676/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/epidemiology ; Prospective Studies ; Biomarkers ; C-Reactive Protein/metabolism ; Inflammation/complications ; }, abstract = {BACKGROUND: While systemic inflammation has been implicated in the etiology of selected neurodegenerative disorders, its role in the development of amyotrophic lateral sclerosis (ALS), a condition with high case-fatality, is untested. Accordingly, we quantified the relationship of C-reactive protein (CRP), an acute-phase reactant and marker of systemic inflammation, with subsequent ALS occurrence.

METHODS: We used data from UK Biobank, a prospective cohort study of 502,649 participants who were aged 37 to 73 years when examined at research centers between 2006 and 2010. Venous blood was collected at baseline in the full cohort and assayed for CRP, and repeat measurement was made 3-7 years later in a representative subgroup (N = 14,514) enabling correction for regression dilution. ALS was ascertained via national hospitalization and mortality registries until 2021. We computed multivariable hazard ratios with accompanying 95% confidence intervals for log-transformed CRP expressed as standard deviation and tertiles.

RESULTS: In an analytical sample of 400,884 initially ALS-free individuals (218,203 women), a mean follow-up of 12 years gave rise to 231 hospitalizations and 223 deaths ascribed to ALS. After adjustment for covariates which included health behaviors, comorbidity, and socio-economic status, a one standard deviation higher log-CRP was associated with elevated rates of both ALS mortality (hazard ratios; 95% confidence intervals: 1.32; 1.13, 1.53) and hospitalizations (1.20; 1.00, 1.39). There was evidence of dose-response effects across tertiles of CRP for both outcomes (p for trend ≤ 0.05). Correction for regression dilution led to a strengthening of the relationship with CRP for both mortality (1.62; 1.27, 2.08) and hospitalizations (1.37; 1.05, 1.76).

CONCLUSIONS: Higher levels of CRP, a blood-based biomarker widely captured in clinical practice, is associated with moderately increased future risk of amyotrophic lateral sclerosis.}, } @article {pmid37542825, year = {2023}, author = {Lee, A and Henderson, R and Arachchige, BJ and Robertson, T and McCombe, PA}, title = {Proteomic investigation of ALS motor cortex identifies known and novel pathogenetic mechanisms.}, journal = {Journal of the neurological sciences}, volume = {452}, number = {}, pages = {120753}, doi = {10.1016/j.jns.2023.120753}, pmid = {37542825}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Motor Cortex/pathology ; Proteomics ; Motor Neurons/pathology ; Spinal Cord/pathology ; }, abstract = {The key pathological feature in ALS is death of motor neurones from the brain and spinal cord, but the molecular mechanisms underlying this degeneration remain unknown. Quantifying the motor cortex proteome in autopsy brain and comparing tissues from ALS cases and non-ALS controls is critical to understanding these mechanisms. We used Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) to characterize the proteomes of the motor cortex from ALS cases (n = 8) and control subjects (n = 8). A total of 1427 proteins were identified at a critical local false discovery rate < 5%; 187 of these exhibited significant expression differences between ALS cases and controls. Of these, 91 proteins were significantly upregulated and 96 proteins were significantly downregulated. Bioinformatics analysis revealed that these proteins are involved in molecular transport, protein trafficking, free radical scavenging, lipid metabolism, cell death and survival, nucleic acid metabolism, inflammatory response or amino acid metabolism and carbohydrate metabolism. Differentially expressed proteins were subjected to pathway analysis. This revealed abnormalities in pathways involving mitochondrial function, sirtuin signaling, oxidative phosphorylation, glycolysis, phagosome maturation, SNARE signaling, redox regulation and several others. Core analysis revealed mitochondrial dysfunction to be the top canonical pathway. The top-enriched networks involved JNK activation and inhibition of AKT signaling, suggesting that disruption of these signaling pathways could lead to demise of motor neurons in the ALS motor cortex.}, } @article {pmid37541304, year = {2023}, author = {Zhou, Q and Zhang, X and Wu, Y and Jiang, X and Li, T and Chen, M and Ni, L and Diao, G}, title = {Polyoxometalates@Metal-Organic Frameworks Derived Bimetallic Co/Mo2 C Nanoparticles Embedded in Carbon Nanotube-Interwoven Hierarchically Porous Carbon Polyhedron Composite as a High-Efficiency Electrocatalyst for Al-S Batteries.}, journal = {Small (Weinheim an der Bergstrasse, Germany)}, volume = {19}, number = {48}, pages = {e2304515}, doi = {10.1002/smll.202304515}, pmid = {37541304}, issn = {1613-6829}, support = {21971221//National Natural Science Foundation of China/ ; 21401162//National Natural Science Foundation of China/ ; 21773203//National Natural Science Foundation of China/ ; KYCX22_3467//Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; yzuxk202010//Yangzhou University Interdisciplinary Research Foundation for Chemistry Discipline/ ; //High-Level Entrepreneurial and Innovative Talents Program of Jiangsu/ ; //"Qing Lan Project" in Colleges and Universities of Jiangsu Province/ ; //Lvyangjinfeng Talent Program of Yangzhou/ ; }, abstract = {Al-S battery (ASB) is a promising energy storage device, notable for its safety, crustal abundance, and high theoretical energy density. However, its development faces challenges due to slow reaction kinetics and poor reversibility. The creation of a multifunctional cathode material that can both adsorb polysulfides and accelerate their conversion is key to advancing ASB. Herein, a composite composed of polyoxometalate nanohybridization-derived Mo2 C and N-doped carbon nanotube-interwoven polyhedrons (Co/Mo2 C@NCNHP) is proposed for the first time as an electrochemical catalyst in the sulfur cathode. This composite improves the utilization and conductivity of sulfur within the cathode. DFT calculations and experimental results indicate that Co enables the chemisorption of polysulfides while Mo2 C catalyzes the reduction reaction of long-chain polysulfides. X-ray photoelectron spectroscopy (XPS) and in situ UV analysis reveal the different intermediates of Al polysulfide species in Co/Mo2 C@NCNHP during discharging/charging. As a cathode material for ASB, Co/Mo2 C@NCNHP@S composite can deliver a discharge-charge voltage hysteresis of 0.75 V with a specific capacity of 370 mAh g[-1] after 200 cycles at 1A g[-1] .}, } @article {pmid37540751, year = {2023}, author = {Oiwa, K and Watanabe, S and Onodera, K and Iguchi, Y and Kinoshita, Y and Komine, O and Sobue, A and Okada, Y and Katsuno, M and Yamanaka, K}, title = {Monomerization of TDP-43 is a key determinant for inducing TDP-43 pathology in amyotrophic lateral sclerosis.}, journal = {Science advances}, volume = {9}, number = {31}, pages = {eadf6895}, pmid = {37540751}, issn = {2375-2548}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; DNA-Binding Proteins/genetics/metabolism ; Inclusion Bodies/metabolism ; Motor Neurons/metabolism ; }, abstract = {The cytoplasmic aggregation of TAR DNA binding protein-43 (TDP-43), also known as TDP-43 pathology, is the pathological hallmark of amyotrophic lateral sclerosis (ALS). However, the mechanism underlying TDP-43 cytoplasmic mislocalization and subsequent aggregation remains unclear. Here, we show that TDP-43 dimerization/multimerization is impaired in the postmortem brains and spinal cords of patients with sporadic ALS and that N-terminal dimerization-deficient TDP-43 consists of pathological inclusion bodies in ALS motor neurons. Expression of N-terminal dimerization-deficient mutant TDP-43 in Neuro2a cells and induced pluripotent stem cell-derived motor neurons recapitulates TDP-43 pathology, such as Nxf1-dependent cytoplasmic mislocalization and aggregate formation, which induces seeding effects. Furthermore, TDP-DiLuc, a bimolecular luminescence complementation reporter assay, could detect decreased N-terminal dimerization of TDP-43 before TDP-43 pathological changes caused by the transcription inhibition linked to aberrant RNA metabolism in ALS. These findings identified TDP-43 monomerization as a critical determinant inducing TDP-43 pathology in ALS.}, } @article {pmid37540049, year = {2023}, author = {Ko, JI and Choi, SJ and Yoo, SH and Cho, B and Kim, MS and Kim, KH and Lee, SY}, title = {Epidemiology and characteristics of emergency department utilization by patients with amyotrophic lateral sclerosis in Korea from 2016 to 2020: A nationwide study.}, journal = {Muscle & nerve}, volume = {68}, number = {4}, pages = {451-459}, doi = {10.1002/mus.27952}, pmid = {37540049}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/therapy ; Cross-Sectional Studies ; Emergency Service, Hospital ; *Respiratory Insufficiency/epidemiology/etiology/therapy ; Dyspnea ; Republic of Korea/epidemiology ; Retrospective Studies ; }, abstract = {INTRODUCTION/AIMS: Patients with amyotrophic lateral sclerosis (ALS) inevitably visit the emergency department (ED) due to their increased risk of respiratory failure and mobility limitations. However, nationwide data on ED visits by patients with ALS are limited. This study investigated the characteristics of patients with ALS-related ED visits.

METHODS: We conducted a cross-sectional study from 2016 to 2020, utilizing a nationwide ED database. The total number of patients with ALS who visited the ED and their primary reasons for visiting/diagnoses were analyzed.

RESULTS: In total, 6036 visits to the ED were made by patients with ALS. Of these, 41.8% arrived by ambulance and 27.7% spent >9 h in the ED. Following ED treatment, 57.4% were hospitalized, including 19.3% admitted to the intensive care unit (ICU) and 5.4% who died in the hospital. The primary reasons for ALS-related ED visits were dyspnea (35.2%), feeding tube problems (10.1%), fever (7.8%), and mental status changes (3.6%). The most common diagnoses were pneumonia (14.5%), respiratory failure (5.7%), dyspnea (5.5%), aspiration pneumonia (4.3%), and tracheostomy complications (3.4%).

DISCUSSION: Reasons for ED visits for patients with ALS include acute respiratory distress, as well as concerns related to tube feeding and tracheostomy. To reduce the risk of patients with ALS requiring ED visits, it is essential to ensure the provision of timely respiratory support and high-quality home-based medical care teams that can support and address patients before their condition deteriorates.}, } @article {pmid37539949, year = {2023}, author = {Raymond, J and Punjani, R and Larson, T and Berry, JD and Horton, DK and Mehta, P}, title = {Comparing Amyotrophic lateral sclerosis (ALS) patient characteristics from the National ALS Registry and the Massachusetts ALS Registry, data through 2015.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, pmid = {37539949}, issn = {2167-9223}, support = {CC999999/ImCDC/Intramural CDC HHS/United States ; }, abstract = {OBJECTIVE: To compare, for completeness, ALS patients identified in the National ALS Registry (National Registry) from MA to those in the Massachusetts ALS Registry (MA Registry) through 2015.

METHODS: Sensitivity analyses were conducted to determine the completeness among patients reported in both registries. Patients were matched on first and last name, month and year of birth, sex, as well as Soundex name matching. Demographics for matching and nonmatching ALS patients were also examined using bivariate analyses and logistic regression.

RESULTS: There were 1,042 ALS patients in the MA Registry, and 642 patients matched (61.6%) in the National Registry. Sensitivity analyses found the National Registry had a sensitivity of 87.7% and specificity of 60%. For these matched patients, 522 (81.2%) came from Medicare. Of the 400 patients in the MA Registry not matched to the National Registry, 11.1% were nonwhite, compared to 6.0% in the matched group) (p = 0.0091) and 59.2% were diagnosed before age 60, compared to 28.6% in the matched group (p < 0.0001). Multivariate logistic regression analysis showed being an ALS case (p < 0.0001) and having an ALS diagnosis at age 60 or later (p < 0.0001) were associated with being more likely to match between the two registries.

CONCLUSIONS: These findings show that ALS's non-notifiable condition status at the national level continues to pose a challenge in identifying all ALS patients. This analysis also showed missing cases at the state level even with a reporting statute. Additional strategies are needed for better patient-ascertainment to quantify all ALS patients in the U.S.}, } @article {pmid37537908, year = {2023}, author = {Tandan, R and Howard, D and Matthews, DE}, title = {Increased total daily energy expenditure in mild to moderate ALS: greater contribution from physical activity energy expenditure than hyper-metabolism.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2023.2240377}, pmid = {37537908}, issn = {2167-9223}, abstract = {Objective: It is unknown whether the relative contribution to energy imbalance in amyotrophic lateral sclerosis (ALS) is due to decreased energy intake, or increased energy expenditure from hyper-metabolism and/or physical activity, or both. Methods: We studied 10 free-living sporadic ALS subjects with mild to moderate disease and 10 matched healthy controls to address this question. We estimated energy intake by 24-h recall in ALS subjects and three-day food diary in all. We estimated body composition by dual energy X-ray absorptiometry and resting metabolic rate by indirect calorimetry; and measured total daily energy expenditure (TEE) and physical activity-energy expenditure using doubly labeled water. Results: Daily energy intake was no different between ALS subjects and controls. Despite lower fat-free mass, unadjusted TEE was higher in ALS subjects than controls (2844 ± 319 vs. 2505 ± 261 kcal/d, p = 0.005 by paired t-test). Compared to controls, hyper-metabolism occurred in 80% of ALS subjects. Physical activity-energy expenditure was higher in ALS subjects than controls (718 ± 262 kcal/d vs. 487 ± 196 kcal/d, p = 0.04). In controls, energy intake matched TEE; in ALS subjects TEE was higher than energy intake. Conclusions: We found higher TEE in ALS subjects than controls, with larger contribution to difference from physical activity-energy expenditure than hyper-metabolism. Although daily energy intake in ALS subjects was similar to that in controls, they were unable to compensate for increased energy needs. To accurately determine energy balance and optimize nutrition in ALS, future studies should consider measuring energy intake, energy expenditure, and physical activity.}, } @article {pmid37536971, year = {2023}, author = {Crook-Rumsey, M and Daniels, SJC and Abulikemu, S and Lai, H and Rapeaux, A and Hadjipanayi, C and Soreq, E and Li, LM and Bashford, J and Jeyasingh-Jacob, J and Gruia, DC and Lambert, D and Weil, R and Hampshire, A and Sharp, DJ and Haar, S}, title = {Multicohort cross-sectional study of cognitive and behavioural digital biomarkers in neurodegeneration: the Living Lab Study protocol.}, journal = {BMJ open}, volume = {13}, number = {8}, pages = {e072094}, pmid = {37536971}, issn = {2044-6055}, support = {/WT_/Wellcome Trust/United Kingdom ; UKDRI-7004/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; Cross-Sectional Studies ; Activities of Daily Living ; *Neurodegenerative Diseases/diagnosis ; *Cognitive Dysfunction/psychology ; Cognition ; Biomarkers ; Observational Studies as Topic ; }, abstract = {INTRODUCTION AND AIMS: Digital biomarkers can provide a cost-effective, objective and robust measure for neurological disease progression, changes in care needs and the effect of interventions. Motor function, physiology and behaviour can provide informative measures of neurological conditions and neurodegenerative decline. New digital technologies present an opportunity to provide remote, high-frequency monitoring of patients from within their homes. The purpose of the living lab study is to develop novel digital biomarkers of functional impairment in those living with neurodegenerative disease (NDD) and neurological conditions.

METHODS AND ANALYSIS: The Living Lab study is a cross-sectional observational study of cognition and behaviour in people living with NDDs and other, non-degenerative neurological conditions. Patients (n≥25 for each patient group) with dementia, Parkinson's disease, amyotrophic lateral sclerosis, mild cognitive impairment, traumatic brain injury and stroke along with controls (n≥60) will be pragmatically recruited. Patients will carry out activities of daily living and functional assessments within the Living Lab. The Living Lab is an apartment-laboratory containing a functional kitchen, bathroom, bed and living area to provide a controlled environment to develop novel digital biomarkers. The Living Lab provides an important intermediary stage between the conventional laboratory and the home. Multiple passive environmental sensors, internet-enabled medical devices, wearables and electroencephalography (EEG) will be used to characterise functional impairments of NDDs and non-NDD conditions. We will also relate these digital technology measures to clinical and cognitive outcomes.

ETHICS AND DISSEMINATION: Ethical approvals have been granted by the Imperial College Research Ethics Committee (reference number: 21IC6992). Results from the study will be disseminated at conferences and within peer-reviewed journals.}, } @article {pmid37535076, year = {2023}, author = {Yang, X and Zhang, Y and Luo, JX and Zhu, T and Ran, Z and Mu, BR and Lu, MH}, title = {Targeting mitophagy for neurological disorders treatment: advances in drugs and non-drug approaches.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {396}, number = {12}, pages = {3503-3528}, pmid = {37535076}, issn = {1432-1912}, mesh = {Animals ; Humans ; Mitophagy/physiology ; Mitochondria/metabolism ; *Parkinson Disease/metabolism ; *Alzheimer Disease/metabolism ; }, abstract = {Mitochondria serve as a vital energy source for nerve cells. The mitochondrial network also acts as a defense mechanism against external stressors that can threaten the stability of the nervous system. However, excessive accumulation of damaged mitochondria can lead to neuronal death. Mitophagy is an essential pathway in the mitochondrial quality control system and can protect neurons by selectively removing damaged mitochondria. In most neurological disorders, dysfunctional mitochondria are a common feature, and drugs that target mitophagy can improve symptoms. Here, we reviewed the role of mitophagy in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, stroke, and traumatic brain injuries. We also summarized drug and non-drug approaches to promote mitophagy and described their therapeutic role in neurological disorders in order to provide valuable insight into the potential therapeutic agents available for neurological disease treatment. However, most studies on mitophagy regulation are based on preclinical research using cell and animal models, which may not accurately reflect the effects in humans. This poses a challenge to the clinical application of drugs targeting mitophagy. Additionally, these drugs may carry the risk of intolerable side effects and toxicity. Future research should focus on the development of safer and more targeted drugs for mitophagy.}, } @article {pmid37534756, year = {2023}, author = {Spargo, TP and Opie-Martin, S and Hunt, GP and Kalia, M and Al Khleifat, A and Topp, SD and Shaw, CE and Al-Chalabi, A and Iacoangeli, A and , }, title = {SOD1-ALS-Browser: a web-utility for investigating the clinical phenotype in SOD1 amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2023.2236650}, pmid = {37534756}, issn = {2167-9223}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Objective: Variants in the superoxide dismutase (SOD1) gene are among the most common genetic causes of amyotrophic lateral sclerosis. Reflecting the wide spectrum of putatively deleterious variants that have been reported to date, it has become clear that SOD1-linked ALS presents a highly variable age at symptom onset and disease duration.Methods: Here we describe an open access web tool for comparative phenotype analysis in ALS: https://sod1-als-browser.rosalind.kcl.ac.uk/. The tool contains a built-in dataset of clinical information from 1383 people with ALS harboring a SOD1 variant resulting in one of 162 unique amino acid sequence alterations and from a non-SOD1 comparator ALS cohort of 13,469 individuals. We present two examples of analyses possible with this tool, testing how the ALS phenotype relates to SOD1 variants that alter amino acid residue hydrophobicity and to distinct variants at the 94[th] residue of SOD1, where six are sampled.Results and conclusions: The tool provides immediate access to the datasets and enables bespoke analysis of phenotypic trends associated with different protein variants, including the option for users to upload their own datasets for integration with the server data. The tool can be used to study SOD1-ALS and provides an analytical framework to study the differences between other user-uploaded ALS groups and our large reference database of SOD1 and non-SOD1 ALS. The tool is designed to be useful for clinicians and researchers, including those without programming expertise, and is highly flexible in the analyses that can be conducted.}, } @article {pmid37534731, year = {2023}, author = {Tian, Y and Ma, G and Li, H and Zeng, Y and Zhou, S and Wang, X and Shan, S and Xu, Y and Xiong, J and Cheng, G}, title = {Shared Genetics and Comorbid Genes of Amyotrophic Lateral Sclerosis and Parkinson's Disease.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {38}, number = {10}, pages = {1813-1821}, doi = {10.1002/mds.29572}, pmid = {37534731}, issn = {1531-8257}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Parkinson Disease/genetics ; Genome-Wide Association Study ; Genetic Predisposition to Disease/genetics ; Comorbidity ; Polymorphism, Single Nucleotide/genetics ; Mendelian Randomization Analysis ; Membrane Proteins/genetics ; ADAM Proteins/genetics ; Transcription Factors/genetics ; DNA Repair Enzymes/genetics ; }, abstract = {BACKGROUND: Comorbidity exists between amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), but the role of genetic factors is unclear.

OBJECTIVE: We aim to investigate genetic correlation, causal relationship, and comorbid genes between ALS and PD.

METHODS: Leveraging the largest genome-wide association study data (ALS: 27,205 cases, 110,881 controls; PDG: 33,674 cases, 449,056 controls), we used linkage disequilibrium score regression and Mendelian randomization analysis for genetic correlation and causal inference. We performed genome-wide cross-trait analysis via Multi-Trait Analysis of Genome-Wide Association Studies and Cross-Phenotype Association to identify specific single-nucleotide polymorphisms, followed by functional mapping and annotation. Integrating expression quantitative trait loci data from 13 brain regions, we conducted a transcriptome-wide association study via functional summary-based imputation and joint-tissue imputation to explore comorbid genes, followed by pathway enrichment analysis.

RESULTS: We found that PD positively correlates with ALS (rg  = 0.144, P = 0.026) and confers a causal effect (odds ratio = 1.09, 95% confidence interval: 1.03-1.15, P = 3.00 × 10[-3]). We identified nine single-nucleotide polymorphisms (eight new), associating with three risk loci (chromosomes 4, 10, and 17) and seven genes (TMEM175, MAPT, NSF, LRRC37A2, ARHGAP27, GAK, and FGFRL1). In transcriptome-wide association study analysis, we showed six previously unreported pleiotropic genes (KANSL1, ARL17B, EFNA1, WNT3, ERCC8, and ADAM15), and we found these candidate genes are mainly enriched in negative regulation of neuron projection development (GO:0010977).

CONCLUSIONS: Our work demonstrates shared genetic architecture between ALS and PD, reports new pleiotropic genes, and sheds light on the comorbid mechanism. © 2023 International Parkinson and Movement Disorder Society.}, } @article {pmid37534581, year = {2023}, author = {Lebœuf, M and Vargas-Abonce, SE and Pezé-Hedsieck, E and Dupont, E and Jimenez-Alonso, L and Moya, KL and Prochiantz, A}, title = {ENGRAILED-1 transcription factor has a paracrine neurotrophic activity on adult spinal α-motoneurons.}, journal = {EMBO reports}, volume = {24}, number = {8}, pages = {e56525}, pmid = {37534581}, issn = {1469-3178}, support = {339379/ERC_/European Research Council/International ; }, mesh = {Mice ; Animals ; *Transcription Factors/genetics/metabolism ; *Motor Neurons/metabolism ; Spinal Cord/metabolism ; Homeodomain Proteins/genetics/metabolism ; Interneurons/metabolism ; }, abstract = {Several homeoprotein transcription factors transfer between cells and regulate gene expression, protein translation, and chromatin organization in recipient cells. ENGRAILED-1 is one such homeoprotein expressed in spinal V1 interneurons that synapse on α-motoneurons. Neutralizing extracellular ENGRAILED-1 by expressing a secreted single-chain antibody blocks its capture by spinal motoneurons resulting in α-motoneuron loss and limb weakness. A similar but stronger phenotype is observed in the Engrailed-1 heterozygote mouse, confirming that ENGRAILED-1 exerts a paracrine neurotrophic activity on spinal cord α-motoneurons. Intrathecal injection of ENGRAILED-1 leads to its specific internalization by spinal motoneurons and has long-lasting protective effects against neurodegeneration and weakness. Midbrain dopaminergic neurons express Engrailed-1 and, similarly to spinal cord α-motoneurons, degenerate in the heterozygote. We identify genes expressed in spinal cord motoneurons whose expression changes in mouse Engrailed-1 heterozygote midbrain neurons. Among these, p62/SQSTM1 shows increased expression during aging in spinal cord motoneurons in the Engrailed-1 heterozygote and upon extracellular ENGRAILED-1 neutralization. We conclude that ENGRAILED-1 might regulate motoneuron aging and has non-cell-autonomous neurotrophic activity.}, } @article {pmid37533065, year = {2023}, author = {Jones, BD and Wilkins, JLM and Schram, ÁB and Gladman, T and Kenwright, D and A Lucio-Ramírez, C}, title = {Validating a measure of motivational climate in health science courses.}, journal = {BMC medical education}, volume = {23}, number = {1}, pages = {548}, pmid = {37533065}, issn = {1472-6920}, mesh = {Humans ; *Motivation ; Schools ; *Students, Medical ; Achievement ; Surveys and Questionnaires ; }, abstract = {PURPOSE: The aim of the study was to examine the validity evidence for the 19-item form of the MUSIC Model of Academic Motivation Inventory (College Student version) within health science schools in three different countries. The MUSIC Inventory includes five scales that assess the motivational climate by measuring students' perceptions related to five separate constructs: empowerment, usefulness, success, interest, and caring.

BACKGROUND: The 26-item form of the MUSIC Inventory has been validated for use with undergraduate students and with students in professional schools, including students at a veterinary medicine school, a pharmacy school, and a medical school. A 19-item form of the MUSIC Inventory has also been validated for use with undergraduate students, but it has not yet been validated for use with medical school students. The purpose of this study was to provide validity evidence for the use of the 19-item form in heath science schools in three different countries to determine if this version is acceptable for use in different cultures. If validated, this shorter form of the MUSIC Inventory would provide more differentiation between the Interest and Usefulness scales and could reduce respondent fatigue.

METHODOLOGY: Cook et al's [1] practical guidelines were followed to implement Kane's [2] validity framework as a means to examine the evidence of validity through scoring inferences, generalization inferences, and extrapolation inferences. Students (n = 667) in health science schools within three countries were surveyed.

RESULTS: The results produced evidence to support all five hypotheses related to scoring, generalization, and extrapolation inferences.

CONCLUSIONS: Scores from the 19-item form of the MUSIC Inventory are valid for use in health science courses within professional schools in different countries. Therefore, the MUSIC Inventory can be used in these schools to assess students' perceptions of the motivational climate.}, } @article {pmid37532939, year = {2023}, author = {Arseni, D and Chen, R and Murzin, AG and Peak-Chew, SY and Garringer, HJ and Newell, KL and Kametani, F and Robinson, AC and Vidal, R and Ghetti, B and Hasegawa, M and Ryskeldi-Falcon, B}, title = {TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP.}, journal = {Nature}, volume = {620}, number = {7975}, pages = {898-903}, pmid = {37532939}, issn = {1476-4687}, support = {P30 AG010133/AG/NIA NIH HHS/United States ; RF1 AG071177/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; U01 NS110437/NS/NINDS NIH HHS/United States ; MC_UP_1201/25/MRC_/Medical Research Council/United Kingdom ; R01 AG071177/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Citrullination ; Cryoelectron Microscopy ; *DNA-Binding Proteins/chemistry/metabolism/ultrastructure ; *Frontotemporal Dementia/metabolism/pathology ; *Frontotemporal Lobar Degeneration/classification/metabolism/pathology ; Methylation ; }, abstract = {The abnormal assembly of TAR DNA-binding protein 43 (TDP-43) in neuronal and glial cells characterizes nearly all cases of amyotrophic lateral sclerosis (ALS) and around half of cases of frontotemporal lobar degeneration (FTLD)[1,2]. A causal role for TDP-43 assembly in neurodegeneration is evidenced by dominantly inherited missense mutations in TARDBP, the gene encoding TDP-43, that promote assembly and give rise to ALS and FTLD[3-7]. At least four types (A-D) of FTLD with TDP-43 pathology (FTLD-TDP) are defined by distinct brain distributions of assembled TDP-43 and are associated with different clinical presentations of frontotemporal dementia[8]. We previously showed, using cryo-electron microscopy, that TDP-43 assembles into amyloid filaments in ALS and type B FTLD-TDP[9]. However, the structures of assembled TDP-43 in FTLD without ALS remained unknown. Here we report the cryo-electron microscopy structures of assembled TDP-43 from the brains of three individuals with the most common type of FTLD-TDP, type A. TDP-43 formed amyloid filaments with a new fold that was the same across individuals, indicating that this fold may characterize type A FTLD-TDP. The fold resembles a chevron badge and is unlike the double-spiral-shaped fold of ALS and type B FTLD-TDP, establishing that distinct filament folds of TDP-43 characterize different neurodegenerative conditions. The structures, in combination with mass spectrometry, led to the identification of two new post-translational modifications of assembled TDP-43, citrullination and monomethylation of R293, and indicate that they may facilitate filament formation and observed structural variation in individual filaments. The structures of TDP-43 filaments from type A FTLD-TDP will guide mechanistic studies of TDP-43 assembly, as well as the development of diagnostic and therapeutic compounds for TDP-43 proteinopathies.}, } @article {pmid37532350, year = {2023}, author = {Zhao, B and Xu, X and Li, B and Qi, Z and Huang, J and Hu, A and Wang, G and Liu, X}, title = {Target-site mutation and enhanced metabolism endow resistance to nicosulfuron in a Digitaria sanguinalis population.}, journal = {Pesticide biochemistry and physiology}, volume = {194}, number = {}, pages = {105488}, doi = {10.1016/j.pestbp.2023.105488}, pmid = {37532350}, issn = {1095-9939}, mesh = {Digitaria/genetics ; Sulfonylurea Compounds/pharmacology ; Pyridines ; Mutation ; *Acetolactate Synthase/metabolism ; Enzyme Inhibitors/pharmacology ; *Herbicides/pharmacology ; Herbicide Resistance/genetics ; }, abstract = {Digitaria sanguinalis is a competitive and annual grass weed that commonly infests crops across the world. In recent years, the control of D. sanguinalis by nicosulfuron has declined in Hebei Province, China. To determine the resistance mechanisms of D. sanguinalis to nicosulfuron, a population of D. sanguinalis where nicosulfuron had failed was collected from a maize field of Hebei Province, China. Whole-plant dose-response experiments demonstrated that the resistant population (HBMT-15) displayed 6.9-fold resistance to nicosulfuron compared with the susceptible population (HBMT-5). Addition of the glutathione S-transferase (GSTs) inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) significantly reduced the resistance level of the HBMT-15 population to nicosulfuron, and the GSTs activity of the HBMT-15 population was higher than the HBMT-5 population after nicosulfuron treatment. In vitro acetolactate synthase (ALS) enzyme experiments revealed that the nicosulfuron I50 value for the HBMT-15 population was 41 times higher than that of the HBMT-5 population. An Asp376 to Glu substitution in the ALS gene was identified in the HBMT-15 population. The HBMT-15 population had a moderate (2- to 4-fold) level of cross-resistance to three other ALS inhibitors (imazethapyr, pyroxsulam, and flucarbazone‑sodium), but was susceptible to pyrithiobac‑sodium. This study demonstrated that both an Asp376 to Glu substitution in the ALS gene and GSTs-involved metabolic resistance to ALS inhibitors coexisted in a D. sanguinalis population.}, } @article {pmid37532339, year = {2023}, author = {Deng, W and Li, Y and Yao, S and Duan, Z and Yang, Q and Yuan, S}, title = {ACCase gene mutations and P450-mediated metabolism contribute to cyhalofop-butyl resistance in Eleusine indica biotypes from direct-seeding paddy fields.}, journal = {Pesticide biochemistry and physiology}, volume = {194}, number = {}, pages = {105530}, doi = {10.1016/j.pestbp.2023.105530}, pmid = {37532339}, issn = {1095-9939}, mesh = {*Eleusine/genetics ; Acetyl-CoA Carboxylase/metabolism ; Herbicide Resistance/genetics ; *Oryza/genetics/metabolism ; Mutation ; *Herbicides/pharmacology ; }, abstract = {Eleusine indica causes problems in direct-seeding rice fields across Jiangsu Province in China. Long-term application of chemical herbicides has led to the widespread evolution of resistance in E. indica. In this study, we surveyed the resistance level of cyhalofop-butyl (CyB) in 19 field-collected E. indica biotypes, and characterized its underlying resistance mechanisms. All 19 biotypes evolved moderate- to high-level resistance to CyB (from 5.8- to 171.1-fold). 18 biotypes had a target-site mechanism with Trp-1999-Ser, Trp-2027-Cys, or Asp-2078-Gly mutations, respectively. One biotype (JSSQ-1) was identified to have metabolic resistance, in which malathion pretreatment significantly reduced the CyB resistance, and cyhalofop acid was degraded 1.7- to 2.5-times faster in this biotype compared with a susceptible control. Furthermore, the JSSQ-1 biotype showed multiple resistance to acetyl-CoA carboxylase (ACCase) inhibitor metamifop (RI = 4.6) and fenoxaprop-p-ethyl (RI = 5.1), acetolactate synthase (ALS) inhibitor imazethapyr (RI = 4.1), and hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor mesotrione (RI = 3.5). In addition, 11 out of 19 E. indica biotypes exhibited multiple resistance to glyphosate. This research has identified the widespread occurrence of CyB resistance in E. indica, attributed to target-site mutations or enhanced metabolism. Moreover, certain biotypes have exhibited resistance to multiple herbicides or even cross-resistance. Consequently, there is an urgent need to implement diverse weed management practices to effectively combat the proliferation of this weed in rice fields.}, } @article {pmid37532326, year = {2023}, author = {Guan, Y and Cao, S and Zou, Y and Liu, L and Yang, C and Ji, M}, title = {Enhanced metabolic ability enabled wild panicgrass (Panicum miliaceum L. var. ruderale kit.) resistance to ALS inhibitor herbicide.}, journal = {Pesticide biochemistry and physiology}, volume = {194}, number = {}, pages = {105510}, doi = {10.1016/j.pestbp.2023.105510}, pmid = {37532326}, issn = {1095-9939}, mesh = {*Panicum/metabolism ; *Herbicides/pharmacology ; Sulfonylurea Compounds/pharmacology ; Pyridines/pharmacology ; Zea mays ; Herbicide Resistance/genetics ; *Acetolactate Synthase/metabolism ; Plant Proteins/genetics ; }, abstract = {Wild panicgrass (Panicum miliaceum L. var. ruderale kit.) is an annual grass weed that primarily occurs in maize fields. Nicosulfuron is a widely used selective herbicide that effectively controls gramineous weeds in maize fields. However, owing to its long-term and extensive application, the control of P. miliaceum has been substantially reduced. The objective of this study was to determine the resistance pattern to ALS inhibitors in P. miliaceum and investigate the underlying resistance mechanisms. These are important for guiding the prevention and eradication of resistant weeds. Whole plant bioassays showed P. miliaceum had evolved high levels of resistance to nicosulfuron and multiple resistance to atrazine and mesotrione. The ALS gene sequence results indicated the absence of mutations in the resistant population. Additionally, there was no significant difference found in the inhibition rate of the ALS enzyme activity (I50) between the resistant and sensitive populations. Following the application of malathion the resistant P. miliaceum population became more sensitive to nicosulfuron. At 96 h after application of nicosulfuron, glutathione-S-transferase activity in the resistant population was significantly higher than that in the susceptible population. The study reveals that the main cause of resistance to ALS inhibitor herbicide in P. miliaceum is likely increased metabolism of herbicides. These findings may assist in devising effective strategies for preventing and eliminating resistant P. miliaceum.}, } @article {pmid37531027, year = {2023}, author = {Gomes, BC and Peixinho, N and Pisco, R and Gromicho, M and Pronto-Laborinho, AC and Rueff, J and de Carvalho, M and Rodrigues, AS}, title = {Differential Expression of miRNAs in Amyotrophic Lateral Sclerosis Patients.}, journal = {Molecular neurobiology}, volume = {60}, number = {12}, pages = {7104-7117}, pmid = {37531027}, issn = {1559-1182}, mesh = {Humans ; *MicroRNAs/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Delayed Diagnosis ; Brain ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control, muscle atrophy and in later stages, death. Diagnosis has an average delay of 1 year after symptoms onset, which impairs early management. The identification of a specific disease biomarker could help decrease the diagnostic delay. MicroRNA (miRNA) expression levels have been proposed as ALS biomarkers, and altered function has been reported in ALS pathogenesis. The aim of this study was to assess the differential expression of plasma miRNAs in ALS patients and two control populations (healthy controls and ALS-mimic disorders). For that, 16 samples from each group were pooled, and then 1008 miRNAs were assessed through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). From these, ten candidate miRNAs were selected and validated in 35 ALS patients, 16 ALS-mimic disorders controls and 15 healthy controls. We also assessed the same miRNAs in two different time points of disease progression. Although we were unable to determine a miRNA signature to use as disease or condition marker, we found that miR-7-2-3p, miR-26a-1-3p, miR-224-5p and miR-206 are good study candidates to understand the pathophysiology of ALS.}, } @article {pmid37529232, year = {2023}, author = {Wen, T and Zhang, Z}, title = {Cellular mechanisms of fibrin (ogen): insight from neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1197094}, pmid = {37529232}, issn = {1662-4548}, abstract = {Neurodegenerative diseases are prevalent and currently incurable conditions that progressively impair cognitive, behavioral, and psychiatric functions of the central or peripheral nervous system. Fibrinogen, a macromolecular glycoprotein, plays a crucial role in the inflammatory response and tissue repair in the human body and interacts with various nervous system cells due to its unique molecular structure. Accumulating evidence suggests that fibrinogen deposits in the brains of patients with neurodegenerative diseases. By regulating pathophysiological mechanisms and signaling pathways, fibrinogen can exacerbate the neuro-pathological features of neurodegenerative diseases, while depletion of fibrinogen contributes to the amelioration of cognitive function impairment in patients. This review comprehensively summarizes the molecular mechanisms and biological functions of fibrinogen in central nervous system cells and neurodegenerative diseases, including Alzheimer's disease, Multiple Sclerosis, Parkinson's disease, Vascular dementia, Huntington's disease, and Amyotrophic Lateral Sclerosis. Additionally, we discuss the potential of fibrinogen-related treatments in the management of neurodegenerative disorders.}, } @article {pmid37528809, year = {2023}, author = {Lee, YY and Caron-Roy, S and Turko, B and Shearer, J and Campbell, DJ and Elliott, C and Barker, D and Raine, KD and Tyminski, S and Olstad, DL}, title = {Experiences and perceived outcomes of a grocery gift card programme for households at risk of food insecurity.}, journal = {Public health nutrition}, volume = {26}, number = {11}, pages = {2460-2469}, pmid = {37528809}, issn = {1475-2727}, mesh = {Child ; Humans ; *Food Supply ; Cognition ; Family Characteristics ; Alberta ; Food Insecurity ; *Food Assistance ; }, abstract = {OBJECTIVE: This study explored programme recipients' and deliverers' experiences and perceived outcomes of accessing or facilitating a grocery gift card (GGC) programme from I Can for Kids (iCAN), a community-based programme that provides GGC to low-income families with children.

DESIGN: This qualitative descriptive study used Freedman et al's framework of nutritious food access to guide data generation and analysis. Semi-structured interviews were conducted between August and November 2020. Data were analysed using directed content analysis with a deductive-inductive approach.

PARTICIPANTS: Fifty-four participants were purposively recruited, including thirty-seven programme recipients who accessed iCAN's GGC programme and seventeen programme deliverers who facilitated it.

SETTING: Calgary, Alberta, Canada.

RESULTS: Three themes were generated from the data. First, iCAN's GGC programme promoted a sense of autonomy and dignity among programme recipients as they appreciated receiving financial support, the flexibility and convenience of using GGC, and the freedom to select foods they desired. Recipients perceived these benefits improved their social and emotional well-being. Second, recipients reported that the use of GGC improved their households' dietary patterns and food skills. Third, both participant groups identified programmatic strengths and limitations.

CONCLUSION: Programme recipients reported that iCAN's GGC programme provided them with dignified access to nutritious food and improved their households' finances, dietary patterns, and social and emotional well-being. Increasing the number of GGC provided to households on each occasion, establishing clear and consistent criteria for distributing GGC to recipients, and increasing potential donors' awareness of iCAN's GGC programme may augment the amount of support iCAN could provide to households.}, } @article {pmid37528491, year = {2023}, author = {Li, C and Lin, J and Jiang, Q and Yang, T and Xiao, Y and Huang, J and Hou, Y and Wei, Q and Cui, Y and Wang, S and Zheng, X and Ou, R and Liu, K and Chen, X and Song, W and Zhao, B and Shang, H}, title = {Genetic Modifiers of Age at Onset for Amyotrophic Lateral Sclerosis: A Genome-Wide Association Study.}, journal = {Annals of neurology}, volume = {94}, number = {5}, pages = {933-941}, doi = {10.1002/ana.26752}, pmid = {37528491}, issn = {1531-8249}, mesh = {Humans ; *Genome-Wide Association Study ; Age of Onset ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Polymorphism, Single Nucleotide/genetics ; Risk Factors ; }, abstract = {OBJECTIVE: Age at onset (AAO) is an essential clinical feature associated with disease progression and mortality in amyotrophic lateral sclerosis (ALS). Identification of genetic variants and environmental risk factors influencing AAO of ALS could help better understand the disease's biological mechanism and provide clinical guidance. However, most genetic studies focused on the risk of ALS, while the genetic background of AAO is less explored. This study aimed to identify genetic and environmental determinants for AAO of ALS.

METHODS: We performed a genome-wide association analysis using a Cox proportional hazards model on AAO of ALS in 10,068 patients. We further conducted colocalization analysis and in-vitro functional exploration for the target variants, as well as Mendelian randomization analysis to identify risk factors influencing AAO of ALS.

RESULTS: The total heritability of AAO of ALS was ~0.16 (standard error [SE] = 0.03). One novel locus rs2046243 (CTIF) was significantly associated with earlier AAO by ~1.29 years (p = 1.68E-08, beta = 0.10, SE = 0.02). Functional exploration suggested this variant was associated with increased expression of CTIF in multiple tissues including the brain. Colocalization analysis detected a colocalization signal at the locus between AAO of ALS and expression of CTIF. Causal inference indicated higher education level was associated with later AAO.

INTERPRETATION: These findings improve the current knowledge of the genetic and environmental etiology of AAO of ALS, and provide a novel target CTIF for further research on ALS pathogenesis and potential therapeutic options to delay the disease onset. ANN NEUROL 2023;94:933-941.}, } @article {pmid37528084, year = {2023}, author = {Gao, XK and Sheng, ZK and Lu, YH and Sun, YT and Rao, XS and Shi, LJ and Cong, XX and Chen, X and Wu, HB and Huang, M and Zheng, Q and Guo, JS and Jiang, LJ and Zheng, LL and Zhou, YT}, title = {VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling.}, journal = {Cell discovery}, volume = {9}, number = {1}, pages = {83}, pmid = {37528084}, issn = {2056-5968}, support = {32270720//National Natural Science Foundation of China (National Science Foundation of China)/ ; 91954121//National Natural Science Foundation of China (National Science Foundation of China)/ ; T2121004//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32100671//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82072201//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2021M702848//China Postdoctoral Science Foundation/ ; }, abstract = {The scaffold protein IRS-1 is an essential node in insulin/IGF signaling. It has long been recognized that the stability of IRS-1 is dependent on its endomembrane targeting. However, how IRS-1 targets the intracellular membrane, and what type of intracellular membrane is actually targeted, remains poorly understood. Here, we found that the phase separation-mediated IRS-1 puncta attached to endoplasmic reticulum (ER). VAPB, an ER-anchored protein that mediates tethers between ER and membranes of other organelles, was identified as a direct interacting partner of IRS-1. VAPB mainly binds active IRS-1 because IGF-1 enhanced the VAPB-IRS-1 association and replacing of the nine tyrosine residues of YXXM motifs disrupted the VAPB-IRS-1 association. We further delineated that the Y745 and Y746 residues in the FFAT-like motif of IRS-1 mediated the association with VAPB. Notably, VAPB targeted IRS-1 to the ER and subsequently maintained its stability. Consistently, ablation of VAPB in mice led to downregulation of IRS-1, suppression of insulin signaling, and glucose intolerance. The amyotrophic lateral sclerosis (ALS)-derived VAPB P56S mutant also impaired IRS-1 stability by interfering with the ER-tethering of IRS-1. Our findings thus revealed a previously unappreciated condensate-membrane contact (CMC), by which VAPB stabilizes the membraneless IRS-1 signalosome through targeting it to ER membrane.}, } @article {pmid37527763, year = {2023}, author = {Cao, MC and Ryan, B and Wu, J and Curtis, MA and Faull, RLM and Dragunow, M and Scotter, EL}, title = {A panel of TDP-43-regulated splicing events verifies loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue.}, journal = {Neurobiology of disease}, volume = {185}, number = {}, pages = {106245}, doi = {10.1016/j.nbd.2023.106245}, pmid = {37527763}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Brain/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics ; RNA ; RNA Splicing ; }, abstract = {TDP-43 dysfunction is a molecular hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major hypothesis of TDP-43 dysfunction in disease is the loss of normal nuclear function, resulting in impaired RNA regulation and the emergence of cryptic exons. Cryptic exons and differential exon usage are emerging as promising markers of lost TDP-43 function in addition to revealing biological pathways involved in neurodegeneration in ALS/FTD. In this brief report, we identified markers of TDP-43 loss of function by depleting TARDBP from post-mortem human brain pericytes, a manipulable in vitro primary human brain cell model, and identifying differential exon usage events with bulk RNA-sequencing analysis. We present these data in an interactive database (https://www.scotterlab.auckland.ac.nz/research-themes/tdp43-lof-db-v2/) together with seven other TDP-43-depletion datasets we meta-analysed previously, for user analysis of differential expression and splicing signatures. Differential exon usage events that were validated by qPCR were then compiled into a 'differential exon usage panel' with other well-established TDP-43 loss-of-function exon markers. This differential exon usage panel was investigated in ALS and control motor cortex tissue to verify whether, and to what extent, TDP-43 loss of function occurs in ALS. We find that profiles of TDP-43-regulated cryptic exons, changed exon usage and changed 3' UTR usage discriminate ALS brain tissue from controls, verifying that TDP-43 loss of function occurs in ALS. We propose that TDP-43-regulated splicing events that occur in brain tissue will have promise as predictors of disease.}, } @article {pmid37527465, year = {2023}, author = {Kahriman, A and Bouley, J and Tuncali, I and Dogan, EO and Pereira, M and Luu, T and Bosco, DA and Jaber, S and Peters, OM and Brown, RH and Henninger, N}, title = {Repeated mild traumatic brain injury triggers pathology in asymptomatic C9ORF72 transgenic mice.}, journal = {Brain : a journal of neurology}, volume = {146}, number = {12}, pages = {5139-5152}, pmid = {37527465}, issn = {1460-2156}, support = {R01 NS111990/NS/NINDS NIH HHS/United States ; R01 NS088689/NS/NINDS NIH HHS/United States ; K08 NS091499/NS/NINDS NIH HHS/United States ; MC_PC_16030/2/MRC_/Medical Research Council/United Kingdom ; R01 NS104022/NS/NINDS NIH HHS/United States ; MR/W004879/1/MRC_/Medical Research Council/United Kingdom ; R21 NS131756/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Female ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; *Brain Concussion/pathology ; *C9orf72 Protein/genetics/metabolism ; DNA Repeat Expansion ; *Frontotemporal Dementia/genetics/pathology ; Mice, Transgenic ; *Pick Disease of the Brain ; }, abstract = {Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative diseases that represent ends of the spectrum of a single disease. The most common genetic cause of FTD and ALS is a hexanucleotide repeat expansion in the C9orf72 gene. Although epidemiological data suggest that traumatic brain injury (TBI) represents a risk factor for FTD and ALS, its role in exacerbating disease onset and course remains unclear. To explore the interplay between traumatic brain injury and genetic risk in the induction of FTD/ALS pathology we combined a mild repetitive traumatic brain injury paradigm with an established bacterial artificial chromosome transgenic C9orf72 (C9BAC) mouse model without an overt motor phenotype or neurodegeneration. We assessed 8-10 week-old littermate C9BACtg/tg (n = 21), C9BACtg/- (n = 20) and non-transgenic (n = 21) mice of both sexes for the presence of behavioural deficits and cerebral histopathology at 12 months after repetitive TBI. Repetitive TBI did not affect body weight gain, general neurological deficit severity, nor survival over the 12-month observation period and there was no difference in rotarod performance, object recognition, social interaction and acoustic characteristics of ultrasonic vocalizations of C9BAC mice subjected to repetitive TBI versus sham injury. However, we found that repetitive TBI increased the time to the return of the righting reflex, reduced grip force, altered sociability behaviours and attenuated ultrasonic call emissions during social interactions in C9BAC mice. Strikingly, we found that repetitive TBI caused widespread microglial activation and reduced neuronal density that was associated with loss of histological markers of axonal and synaptic integrity as well as profound neuronal transactive response DNA binding protein 43 kDa mislocalization in the cerebral cortex of C9BAC mice at 12 months; this was not observed in non-transgenic repetitive TBI and C9BAC sham mice. Our data indicate that repetitive TBI can be an environmental risk factor that is sufficient to trigger FTD/ALS-associated neuropathology and behavioural deficits, but not paralysis, in mice carrying a C9orf72 hexanucleotide repeat expansion.}, } @article {pmid37527390, year = {2023}, author = {Firnberg, MT and Lerner, EB and Nan, N and Ma, CX and Shah, MI and Mann, NC and Dayan, PS}, title = {National Variation in EMS Response and Antiepileptic Medication Administration for Children with Seizures in the Prehospital Setting.}, journal = {The western journal of emergency medicine}, volume = {24}, number = {4}, pages = {805-813}, pmid = {37527390}, issn = {1936-9018}, mesh = {Male ; Female ; Humans ; Child ; United States/epidemiology ; Anticonvulsants/therapeutic use ; Midazolam/therapeutic use ; *Emergency Medical Services ; *Emergency Medical Technicians ; Seizures/drug therapy ; Retrospective Studies ; }, abstract = {BACKGROUND AND OBJECTIVES: Prehospital Advanced Life Support (ALS) is important to improve patient outcomes in children with seizures, yet data is limited regarding national prehospital variation in ALS response for these children. We aimed to determine the variation in ALS response and prehospital administration of antiepileptic medication for children with seizures across the United States.

METHODS: We analyzed children <19 years with 9-1-1 dispatch codes for seizure in the 2019 National Emergency Medical Services Information System dataset. We defined ALS response as ALS-paramedic, ALS-Advanced Emergency Medical Technician, or ALS-intermediate responses. We conducted regression analyses to identify associations between ALS response (primary outcome), antiepileptic administration (secondary outcome) and age, gender, location, and US census regions.

RESULTS: Of 147,821 pediatric calls for seizures, 88% received ALS responses. Receipt of ALS response was associated with urbanicity, with wilderness (adjusted odds ratio [aOR] 0.44, 0.39-0.49) and rural (aOR 0.80, 0.75-0.84) locations less likely to have ALS responses than urban areas. Of 129,733 emergency medical service (EMS) activations with an ALS responder's impression of seizure, antiepileptic medications were administered in 9%. Medication administration was independently associated with age (aOR 1.008, 95% confidence interval [CI] 1.005-1.010) and gender (aOR 1.22, 95% CI 1.18-1.27), with females receiving medications more than males. Of the 11,698 children who received antiepileptic medications, midazolam was the most commonly used (83%).

CONCLUSION: The majority of children in the US receive ALS responses for seizures. Although medications are infrequently administered, the majority who received medications had midazolam given, which is the current standard of care. Further research should determine the proportion of children who are continuing to seize upon EMS arrival and would most benefit from immediate treatment.}, } @article {pmid37526799, year = {2024}, author = {Brylev, L and Demeshonok, VS and Ataulina, AI and Kovalchuk, MO and Druzhinin, DS and Guekht, AB}, title = {Validity and reliability of the Russian version of the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {1}, pages = {187-189}, pmid = {37526799}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Reproducibility of Results ; Activities of Daily Living ; Russia ; }, abstract = {OBJECTIVE: The aim of this study is to elaborate a valid and reliable Russian version of the ALSFRS-R.

METHODS: Russian adaptation of the ALSFRS-R was applied twice in 50 ALS patients followed by the test-retest analysis with a 7-day interval between applications and internal consistency analysis.

RESULTS: Test-retest analysis showed very strong correlation for all of the ALSFRS-R variables. The intra-class correlation coefficient was 0.83.

CONCLUSION: The elaborated Russian version of the ALSFRS-R has shown to be comparable with the original English version of the scale.}, } @article {pmid37525592, year = {2023}, author = {Brooks, BR and Pioro, EP and Sakata, T and Takahashi, F and Hagan, M and Apple, S}, title = {The effects of intervention with intravenous edaravone in Study 19 on hospitalization, tracheostomy, ventilation, and death in patients with amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {68}, number = {4}, pages = {397-403}, doi = {10.1002/mus.27946}, pmid = {37525592}, issn = {1097-4598}, mesh = {Humans ; Edaravone/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Tracheostomy ; Proportional Hazards Models ; Survival Analysis ; }, abstract = {INTRODUCTION/AIMS: Intravenous (IV) edaravone is a US Food and Drug Administration-approved treatment for amyotrophic lateral sclerosis (ALS), shown in clinical trials to slow physical functional decline. In this study we compared the effect of IV edaravone (edaravone-first group) versus placebo followed by IV edaravone (placebo-first group) on survival and additional milestone events.

METHODS: This work is a post hoc analysis of Study 19/MCI186-19, which was a randomized, placebo-controlled, phase 3 study investigating IV edaravone versus placebo. Study 19 and its 24-week extension have been described previously (NCT01492686). Edaravone-first versus placebo-first group time to events for specific milestone(s) were analyzed post hoc. Time-to-event composite endpoints were time to death; time to death, tracheostomy, or permanent assisted ventilation (PAV); and time to death, tracheostomy, PAV, or hospitalization.

RESULTS: The risk for death, tracheostomy, PAV, or hospitalization was 53% lower among patients in the edaravone-first vs placebo-first groups (hazard ratio = 0.47 [95% confidence interval 0.25 to 0.88], P = .02). The overall effect of IV edaravone on ALS progression could be seen in the significant separation of time-to-event curves for time to death, tracheostomy, PAV, or hospitalization. ALS survival composite endpoint analyses (ALS/SURV) suggested a treatment benefit (least-squares mean difference) for the edaravone-first versus the placebo-first group at week 24 (0.15 ± 0.05 [95% confidence interval 0.06 to 0.25], P < .01) and week 48 (0.11 ± 0.05 [95% confidence interval 0.02 to 0.21], P = .02).

DISCUSSION: These analyses illustrate the value of timely and continued IV edaravone treatment, as earlier initiation was associated with a lower risk of death, tracheostomy, PAV, or hospitalization in patients with ALS.}, } @article {pmid37525497, year = {2024}, author = {Chong, ZZ and Menkes, DL and Souayah, N}, title = {Pathogenesis underlying hexanucleotide repeat expansions in C9orf72 gene in amyotrophic lateral sclerosis.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {1}, pages = {85-97}, pmid = {37525497}, issn = {2191-0200}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; C9orf72 Protein/genetics/metabolism ; Proteins/genetics/metabolism ; Dipeptides/genetics/metabolism ; RNA ; Arginine ; Alanine ; Glycine ; Proline ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder. Mutations in C9orf72 and the resulting hexanucleotide repeat (GGGGCC) expansion (HRE) has been identified as a major cause of familial ALS, accounting for about 40 % of familial and 6 % of sporadic cases of ALS in Western patients. The pathological outcomes of HRE expansion in ALS have been recognized as the results of two mechanisms that include both the toxic gain-of-function and loss-of-function of C9ORF72. The gain of toxicity results from RNA and dipeptide repeats (DPRs). The HRE can be bidirectionally transcribed into RNA foci, which can bind to and disrupt RNA splicing, transport, and translation. The DPRs that include poly-glycine-alanine, poly-glycine-proline, poly-glycine- arginine, poly-proline-alanine, and poly-proline-arginine can induce toxicity by direct binding and sequestrating other proteins to interfere rRNA synthesis, ribosome biogenesis, translation, and nucleocytoplasmic transport. The C9ORF72 functions through binding to its partners-Smith-Magenis chromosome regions 8 (SMCR8) and WD repeat-containing protein (WDR41). Loss of C9ORF72 function results in impairment of autophagy, deregulation of autoimmunity, increased stress, and disruption of nucleocytoplasmic transport. Further insight into the mechanism in C9ORF72 HRE pathogenesis will facilitate identifying novel and effective therapeutic targets for ALS.}, } @article {pmid37525032, year = {2023}, author = {Papageorgiou, L and Mangana, E and Papakonstantinou, E and Diakou, I and Pierouli, K and Dragoumani, K and Bacopoulou, F and Chrousos, GP and Exarchos, TP and Vlamos, P and Eliopoulos, E and Vlachakis, D}, title = {An Updated Evolutionary and Structural Study of TBK1 Reveals Highly Conserved Motifs as Potential Pharmacological Targets in Neurodegenerative Diseases.}, journal = {Advances in experimental medicine and biology}, volume = {1423}, number = {}, pages = {41-57}, pmid = {37525032}, issn = {0065-2598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Phylogeny ; *Neurodegenerative Diseases/drug therapy/genetics ; Phosphorylation ; NF-kappa B/metabolism ; Protein Serine-Threonine Kinases/genetics/metabolism ; }, abstract = {TANK-binding kinase 1 protein (TBK1) is a kinase that belongs to the IκB (IKK) family. TBK1, also known as T2K, FTDALS4, NAK, IIAE8, and NF-κB, is responsible for the phosphorylation of the amino acid residues, serine and threonine. This enzyme is involved in various key biological processes, including interferon activation and production, homeostasis, cell growth, autophagy, insulin production, and the regulation of TNF-α, IFN-β, and IL-6. Mutations in the TBK1 gene alter the protein's normal function and may lead to an array of pathological conditions, including disorders of the central nervous system. The present study sought to elucidate the role of the TBK1 protein in amyotrophic lateral sclerosis (ALS), a human neurodegenerative disorder. A broad evolutionary and phylogenetic analysis of TBK1 was performed across numerous organisms to distinguish conserved regions important for the protein's function. Subsequently, mutations and SNPs were explored, and their potential effect on the enzyme's function was investigated. These analytical steps, in combination with the study of the secondary, tertiary, and quaternary structure of TBK1, enabled the identification of conserved motifs, which can function as novel pharmacological targets and inform therapeutic strategies for amyotrophic lateral sclerosis.}, } @article {pmid37524961, year = {2023}, author = {Ferraro, PM and Ponzano, M and Cillerai, M and Signori, A and Caponnetto, C}, title = {Reply to "Cognition and motor phenotypes in ALS: a retrospective study".}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {12}, pages = {4531-4533}, pmid = {37524961}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Retrospective Studies ; Cognition ; *Motor Cortex ; Phenotype ; }, } @article {pmid37524863, year = {2023}, author = {Verdile, V and Riccioni, V and Guerra, M and Ferrante, G and Sette, C and Valle, C and Ferri, A and Paronetto, MP}, title = {An impaired splicing program underlies differentiation defects in hSOD1[G93A] neural progenitor cells.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {80}, number = {8}, pages = {236}, pmid = {37524863}, issn = {1420-9071}, support = {IG21877//Associazione Italiana per la Ricerca sul Cancro/ ; }, mesh = {Animals ; *Neural Stem Cells/metabolism/cytology ; Mice ; *Cell Differentiation/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Neurogenesis/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Motor Neurons/metabolism/pathology ; Disease Models, Animal ; RNA Splicing/genetics ; Humans ; Mice, Transgenic ; Alternative Splicing/genetics ; Cell Proliferation/genetics ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult devastating neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), resulting in progressive paralysis and death. Genetic animal models of ALS have highlighted dysregulation of synaptic structure and function as a pathogenic feature of ALS-onset and progression. Alternative pre-mRNA splicing (AS), which allows expansion of the coding power of genomes by generating multiple transcript isoforms from each gene, is widely associated with synapse formation and functional specification. Deciphering the link between aberrant splicing regulation and pathogenic features of ALS could pave the ground for novel therapeutic opportunities. Herein, we found that neural progenitor cells (NPCs) derived from the hSOD1[G93A] mouse model of ALS displayed increased proliferation and propensity to differentiate into neurons. In parallel, hSOD1[G93A] NPCs showed impaired splicing patterns in synaptic genes, which could contribute to the observed phenotype. Remarkably, master splicing regulators of the switch from stemness to neural differentiation are de-regulated in hSOD1[G93A] NPCs, thus impacting the differentiation program. Our data indicate that hSOD1[G93A] mutation impacts on neurogenesis by increasing the NPC pool in the developing mouse cortex and affecting their intrinsic properties, through the establishment of a specific splicing program.}, } @article {pmid37524529, year = {2023}, author = {Kvam, KA and Benatar, M and Brownlee, A and Caller, T and Das, RR and Green, P and Kolodziejczak, S and Russo, J and Sanders, D and Sethi, N and Stavros, K and Stierwalt, J and Giles Walters, N and Bennett, A and Wessels, SR and Brooks, BR}, title = {Amyotrophic Lateral Sclerosis Quality Measurement Set 2022 Update: Quality Improvement in Neurology.}, journal = {Neurology}, volume = {101}, number = {5}, pages = {223-232}, pmid = {37524529}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Quality Improvement ; *Neurology ; }, } @article {pmid37524128, year = {2023}, author = {Bernstein, HG and Smalla, KH and Keilhoff, G and Dobrowolny, H and Kreutz, MR and Steiner, J}, title = {The many "Neurofaces" of Prohibitins 1 and 2: Crucial for the healthy brain, dysregulated in numerous brain disorders.}, journal = {Journal of chemical neuroanatomy}, volume = {132}, number = {}, pages = {102321}, doi = {10.1016/j.jchemneu.2023.102321}, pmid = {37524128}, issn = {1873-6300}, mesh = {Humans ; *Prohibitins ; Endothelial Cells/metabolism ; Mitochondria/metabolism ; Brain/metabolism ; *Brain Diseases/metabolism ; }, abstract = {Prohibitin 1 (PHB1) and prohibitin 2 (PHB2) are proteins that are nearly ubiquitously expressed. They are localized in mitochondria, cytosol and cell nuclei. In the healthy CNS, they occur in neurons and non-neuronal cells (oligodendrocytes, astrocytes, microglia, and endothelial cells) and fulfill pivotal functions in brain development and aging, the regulation of brain metabolism, maintenance of structural integrity, synapse formation, aminoacidergic neurotransmission and, probably, regulation of brain action of certain hypothalamic-pituitary hormones.With regard to the diseased brain there is increasing evidence that prohibitins are prominently involved in numerous major diseases of the CNS, which are summarized and discussed in the present review (brain tumors, neurotropic viruses, Alzheimer disease, Down syndrome, Fronto-temporal and vascular dementia, dementia with Lewy bodies, Parkinson disease, Huntington disease, Multiple sclerosis, Amyotrophic lateral sclerosis, stroke, alcohol use disorder, schizophrenia and autism). Unfortunately, there is no PHB-targeted therapy available for any of these diseases.}, } @article {pmid37523555, year = {2023}, author = {Chiot, A and Roemer, SF and Ryner, L and Bogachuk, A and Emberley, K and Brownell, D and Jimenez, GA and Leviten, M and Woltjer, R and Dickson, DW and Steinman, L and Ajami, B}, title = {Elevated α5 integrin expression on myeloid cells in motor areas in amyotrophic lateral sclerosis is a therapeutic target.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {32}, pages = {e2306731120}, pmid = {37523555}, issn = {1091-6490}, support = {P01 NS084974/NS/NINDS NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; }, mesh = {Mice ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Integrin alpha5/metabolism ; *Motor Cortex ; Mice, Transgenic ; Superoxide Dismutase/metabolism ; Macrophages/metabolism ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease affecting upper and lower motor neurons. Microglia directly interact with motor neurons and participate in the progression of ALS. Single-cell mass cytometry (CyTOF) analysis revealed prominent expression of α5 integrin in microglia and macrophages in a superoxide dismutase-1 G93A mouse model of ALS (SOD1[G93A]). In postmortem tissues from ALS patients with various clinical ALS phenotypes and disease duration, α5 integrin is prominent in motor pathways of the central and peripheral nervous system and in perivascular zones associated with the blood-brain barrier. In SOD1[G93A] mice, administration of a monoclonal antibody against α5 integrin increased survival compared to an isotype control and improved motor function on behavioral testing. Together, these findings in mice and in humans suggest that α5 integrin is a potential therapeutic target in ALS.}, } @article {pmid37522762, year = {2023}, author = {Webber, CJ and Murphy, CN and Rondón-Ortiz, AN and van der Spek, SJF and Kelly, EX and Lampl, NM and Chiesa, G and Khalil, AS and Emili, A and Wolozin, B}, title = {Human herpesvirus 8 ORF57 protein is able to reduce TDP-43 pathology: network analysis identifies interacting pathways.}, journal = {Human molecular genetics}, volume = {32}, number = {20}, pages = {2966-2980}, pmid = {37522762}, issn = {1460-2083}, support = {R01 EB029483/EB/NIBIB NIH HHS/United States ; AG080810/NH/NIH HHS/United States ; }, mesh = {Humans ; *Herpesvirus 8, Human/metabolism ; Proteomics ; *Neuroblastoma ; DNA-Binding Proteins/genetics/metabolism ; Cell Line ; *Amyotrophic Lateral Sclerosis/metabolism ; Viral Regulatory and Accessory Proteins/metabolism ; }, abstract = {Aggregation of TAR DNA-binding protein 43 kDa (TDP-43) is thought to drive the pathophysiology of amyotrophic lateral sclerosis and some frontotemporal dementias. TDP-43 is normally a nuclear protein that in neurons translocates to the cytoplasm and can form insoluble aggregates upon activation of the integrated stress response (ISR). Viruses evolved to control the ISR. In the case of Herpesvirus 8, the protein ORF57 acts to bind protein kinase R, inhibit phosphorylation of eIF2α and reduce activation of the ISR. We hypothesized that ORF57 might also possess the ability to inhibit aggregation of TDP-43. ORF57 was expressed in the neuronal SH-SY5Y line and its effects on TDP-43 aggregation characterized. We report that ORF57 inhibits TDP-43 aggregation by 55% and elicits a 2.45-fold increase in the rate of dispersion of existing TDP-43 granules. These changes were associated with a 50% decrease in cell death. Proteomic studies were carried out to identify the protein interaction network of ORF57. We observed that ORF57 directly binds to TDP-43 as well as interacts with many components of the ISR, including elements of the proteostasis machinery known to reduce TDP-43 aggregation. We propose that viral proteins designed to inhibit a chronic ISR can be engineered to remove aggregated proteins and dampen a chronic ISR.}, } @article {pmid37522559, year = {2023}, author = {Kaur, K and Chen, PC and Ko, MW and Huerta-Yepez, S and Maharaj, D and Jewett, A}, title = {The Potential Role of Cytotoxic Immune Effectors in Amyotrophic Lateral Sclerosis (ALS); A Longitudinal Case Study Comparing Patients with Genetically Identical Healthy Twin.}, journal = {Critical reviews in immunology}, volume = {43}, number = {1}, pages = {27-39}, doi = {10.1615/CritRevImmunol.2023047233}, pmid = {37522559}, issn = {1040-8401}, abstract = {Amyotrophic lateral sclerosis (ALS) is an auto-immune neurodegenerative disorder affecting the motor-neurons. The causes of ALS are heterogeneous, and are only partially understood to date. We studied percentage and function of immune cell subsets in particular natural killer (NK) and CD8+ T cells in an ALS patient and compared the results to those obtained from his genetically identical healthy twin in a longitudinal study. We found several basic mechanisms which were potentially involved in the disease induction and progression. Our findings demonstrate that ALS patient's peripheral blood contained higher NK and B cells and, lower T cell percentages compared with the healthy twin brother's peripheral blood. Significantly increased interferon-gamma secretion by anti-CD3/28 monoclonal antibody-treated peripheral blood mononuclear cells, and sorted CD8+ T cells were observed in the ALS patient, suggesting that hyper-responsiveness of T cell compartment could be a potential mechanism of ALS progression. Significant increase in NK cell function due to genetic mutations in ALS associated genes may partly be responsible for the increase expansion and function of CD8+ T cells with effector/memory phenotype, in addition to direct activation and expansion of antigen specific T cells by such mutations. Weekly N-acetyl cysteine infusion to block cell death in patient in addition to a number of other therapies listed in this paper were not effective, and even though the treatments might have extended the patient's life, it was not curative. Therefore, activated CD8+ T and NK cells are likely cells targeting motor neurons in the patient, and strategies should be designed to decrease the aggressive nature of these cells to achieve longer lasting therapeutic benefits.}, } @article {pmid37522558, year = {2023}, author = {Chen, PC and Kaur, K and Ko, MW and Huerta-Yepez, S and Jain, Y and Jewett, A}, title = {Regulation of Cytotoxic Immune Effector Function by AJ3 Probiotic Bacteria in Amyotrophic Lateral Sclerosis (ALS).}, journal = {Critical reviews in immunology}, volume = {43}, number = {1}, pages = {13-26}, doi = {10.1615/CritRevImmunol.2023047231}, pmid = {37522558}, issn = {1040-8401}, mesh = {Humans ; Interleukin-10/pharmacology ; *Amyotrophic Lateral Sclerosis/therapy ; Leukocytes, Mononuclear ; Interleukin-2 ; Cytokines ; Interferon-gamma ; *Antineoplastic Agents/pharmacology ; Antibodies, Monoclonal ; }, abstract = {Our recent studies indicated that amyotrophic lateral sclerosis (ALS) patients suffer from significantly elevated levels of interferon-gamma (IFN-γ) secretion by natural killer (NK) and CD8+ T cells, which may be responsible for the immune-pathologies seen in central nervous system and in peripheral organs of the patients. In order to counter such elevated induction of IFN-γ in patients we designed a treatment strategy to increase anti-inflammatory cytokine interleukin-10 (IL-10) by the use of probiotic strains which significantly increase the levels of IL-10. Therefore, in this paper we demonstrate disease specific functions of Al-Pro (AJ3) formulated for the adjunct treatment of auto-immune diseases including ALS, and compared the function with CA/I-Pro (AJ4) for the treatment of cancer and viral diseases, and NK-CLK (AJ2) for maintenance of immune balance and promotion of disease prevention. The three different formulations of probiotic bacteria have distinct profiles of activation of peripheral blood mononuclear cells (PBMCs), NK, and CD8+ T cells, and their induced activation is different from those mediated by either IL-2 or IL-2 + anti-CD16 monoclonal antibodies (mAbs) or IL-2 + anti-CD3/CD28 mAbs. IL-2 + anti-CD16 mAb activation of PBMCs and NK cells had the highest IFN-γ/IL-10 ratio, whereas IL-2 combination with sAJ4 had the next highest followed by IL-2 + sAJ2 and the lowest was seen with IL-2 + sAJ3. Accordingly, the highest secretion of IFN-γ was seen when the PBMCs and NK cells were treated with IL-2 + sAJ4, intermediate for IL-2 + sAJ2 and the lowest with IL-2 + sAJ3. The levels of IFN-γ induction and the ratio of IFN-γ to IL-10 induced by different probiotic bacteria formulation in the absence of IL-2 treatment remained much lower when compared to those treated in the presence of IL-2. Of note is the difference between NK cells and CD8+ T cells in which synergistic induction of IFN-y by IL-2 + sAJ4 was significantly higher in NK cells than those seen by CD8+ T cells. Based on these results, sAJ3 should be effective in alleviating auto-immunity seen in ALS since it will greatly regulate the levels and function of IFN-γ negatively, decreasing overactivation of cytotoxic immune effectors and prevention of death in motor neurons.}, } @article {pmid37522557, year = {2023}, author = {Kaur, K and Chen, PC and Ko, MW and Mei, A and Huerta-Yepez, S and Maharaj, D and Malarkannan, S and Jewett, A}, title = {Successes and Challenges in Taming the Beast: Cytotoxic Immune Effectors in Amyotrophic Lateral Sclerosis.}, journal = {Critical reviews in immunology}, volume = {43}, number = {1}, pages = {1-11}, doi = {10.1615/CritRevImmunol.2023047235}, pmid = {37522557}, issn = {1040-8401}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Motor Neurons/metabolism/pathology ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; Cytokines/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of motor neurons in the brain and spinal cord. No effective therapeutic strategies have been established thus far, and therefore there is a significant unmet need for effective therapeutics to arrest the disease and reverse the pathologies induced by it. Although the cause of ALS is not well-defined, it appears to be heterogenous. Currently over 20 genes have been found to be associated with ALS. Family history can only be found in 10% of ALS patients, but in the remaining 90% no association with family history is found. The most common genetic causes are expansion in the C9orf72 gene and mutations in superoxide dismutase 1, TDP-43, and FUS. In our recent study, we also found mutations in TDP43 and FUS in ALS patients. To understand the pathogenesis of the disease, we set ourselves the task of analyzing the phenotype and function of all key immune effectors in ALS patients, comparing them with either a genetically healthy twin or healthy individuals. Our study demonstrated a significant increase in functional activation of NK and CD8+ T cytotoxic immune effectors and release of significant IFN-γ not only by the effector cells but also in the serum of ALS patients. Longitudinal analysis of CD8+ T cell-mediated IFN-γ secretion from ALS patients demonstrated continued and sustained increase in IFN-γ secretion with periods of decrease which coincided with certain treatments; however, the effects were largely short-lived. N-acetyl cysteine (NAC), one of the treatments used, is known to block cell death; however, even though such treatment was able to block most of the proinflammatory cytokines, chemokines, and growth factor release, it was not able to block IFN-γ and TNF-α, the two cytokines we had demonstrated previously to induce differentiation of the cells. In this review, we discuss the contribution of cytotoxic effector cells, especially primary NK cells, supercharged NK cells (sNK), and the contribution of sNK cells in expansion and functional activation of CD8+ T cells to memory/effector T cells in the pathogenesis of ALS. Potential new targeted therapeutic strategies are also discussed.}, } @article {pmid37521204, year = {2023}, author = {Dou, J and Bakulski, K and Guo, K and Hur, J and Zhao, L and Saez-Atienzar, S and Stark, A and Chia, R and García-Redondo, A and Rojas-Garcia, R and Vázquez Costa, JF and Santiago, RF and Bandres-Ciga, S and Gómez-Garre, P and Periñán, MT and Mir, P and Pérez-Tur, J and Cardona, F and Menendez-Gonzalez, M and Riancho, J and Borrego-Hernández, D and Galán-Dávila, L and Ceberio, JI and Pastor, P and Paradas, C and Dols-Icardo, O and , and Traynor, BJ and Feldman, EL and Goutman, SA}, title = {Erratum: Cumulative Genetic Score and C9orf72 Repeat Status Independently Contribute to Amyotrophic Lateral Sclerosis Risk in 2 Case-Control Studies.}, journal = {Neurology. Genetics}, volume = {9}, number = {5}, pages = {e200095}, pmid = {37521204}, issn = {2376-7839}, abstract = {[This corrects the article DOI: 10.1212/NXG.0000000000200079.].}, } @article {pmid37520962, year = {2023}, author = {Souayah, N and Pahwa, A and Jaffry, M and Patel, T and Nasar, A and Chong, ZZ and Sander, HW}, title = {Electrodiagnostic profile of conduction slowing in amyotrophic lateral sclerosis.}, journal = {Heliyon}, volume = {9}, number = {8}, pages = {e18400}, pmid = {37520962}, issn = {2405-8440}, abstract = {OBJECTIVE: Since motor nerve conduction slowing can occur due to loss of large axons, we investigate the conduction slowing profile in amyotrophic lateral sclerosis (ALS) and identify the limits beyond which the diagnosis of exclusive axonal loss is unlikely.

METHODS: First, using linear regression analysis, we established the range of motor conduction slowing in 76 chronic inflammatory demyelinating polyneuropathy (CIDP) patients. Demyelinating range confidence intervals were defined by assessing conduction velocity (CV), distal latency (DML), and F-wave latency (F) in relation to distal compound muscle action potential (CMAP) amplitude of median, ulnar, fibular, and tibial nerves. Results were subsequently validated in 38 additional CIDP patients. Then, the newly established demyelination confidence intervals were used to investigate the profile of conduction slowing in 95 ALS patients.

RESULTS: CV slowing, prolonged DML, and abnormal F were observed in 22.2%, 19.6%, and 47.1% of the studied nerves respectively in ALS patients. When slowing occurred, it affected more than one segment of the motor nerve, suggesting that CMAP amplitude dependent conduction slowing caused by an exclusive loss of large axons is the main mechanism of slowing. No ALS patient had more than 2 nerves with CV slowing in the confidence interval defined by the regression equations or the American Academy of Neurology (AAN) research criteria for CIDP diagnosis.

CONCLUSIONS: The presence of more than two motor nerves with CV slowing in the demyelinating range defined by the regression analysis or AAN criteria in ALS patients suggests the contribution of acquired demyelination or other additional mechanisms exist in the electrodiagnostic profile of ALS.}, } @article {pmid37520009, year = {2023}, author = {Gouveia, D and Correia, J and Cardoso, A and Carvalho, C and Oliveira, AC and Almeida, A and Gamboa, Ó and Ribeiro, L and Branquinho, M and Sousa, A and Lopes, B and Sousa, P and Moreira, A and Coelho, A and Rêma, A and Alvites, R and Ferreira, A and Maurício, AC and Martins, Â}, title = {Intensive neurorehabilitation and allogeneic stem cells transplantation in canine degenerative myelopathy.}, journal = {Frontiers in veterinary science}, volume = {10}, number = {}, pages = {1192744}, pmid = {37520009}, issn = {2297-1769}, abstract = {INTRODUCTION: Degenerative myelopathy (DM) is a neurodegenerative spinal cord disease with upper motor neurons, with progressive and chronic clinical signs, similar to amyotrophic lateral sclerosis (ALS). DM has a complex etiology mainly associated with SOD1 gene mutation and its toxic role, with no specific treatment. Daily intensive rehabilitation showed survival time near 8 months but most animals are euthanized 6-12 months after clinical signs onset.

METHODS: This prospective controlled blinded cohort clinical study aims to evaluate the neural regeneration response ability of DM dogs subjected to an intensive neurorehabilitation protocol with mesenchymal stem cells (MSCs) transplantation. In total, 13 non-ambulatory (OFS 6 or 8) dogs with homozygous genotype DM/DM and diagnosed by exclusion were included. All were allocated to the intensive neurorehabilitation with MSCs protocol (INSCP) group (n = 8) or to the ambulatory rehabilitation protocol (ARP) group (n = 5), which differ in regard to training intensity, modalities frequency, and MSCs transplantation. The INSCP group was hospitalized for 1 month (T0 to T1), followed by MSCs transplantation (T1) and a second month (T2), whereas the ARP group was under ambulatory treatment for the same 2 months.

RESULTS: Survival mean time of total population was 375 days, with 438 days for the INSCP group and 274 for the ARP group, with a marked difference on the Kaplan-Meier survival analysis. When comparing the literature's results, there was also a clear difference in the one-sample t-test (p = 0.013) with an increase in time of approximately 70%. OFS classifications between groups at each time point were significantly different (p = 0.008) by the one-way ANOVA and the independent sample t-test.

DISCUSSION: This INSCP showed to be safe, feasible, and a possibility for a long progression of DM dogs with quality of life and functional improvement. This study should be continued.}, } @article {pmid37519899, year = {2023}, author = {Feng, T and Minevich, G and Liu, P and Qin, HX and Wozniak, G and Pham, J and Pham, K and Korgaonkar, A and Kurnellas, M and Defranoux, NA and Long, H and Mitra, A and Hu, F}, title = {AAV-GRN partially corrects motor deficits and ALS/FTLD-related pathology in Tmem106b[-/-]Grn[-/-] mice.}, journal = {iScience}, volume = {26}, number = {7}, pages = {107247}, pmid = {37519899}, issn = {2589-0042}, support = {R01 NS088448/NS/NINDS NIH HHS/United States ; R01 NS095954/NS/NINDS NIH HHS/United States ; }, abstract = {Loss of function of progranulin (PGRN), encoded by the granulin (GRN) gene, is implicated in several neurodegenerative diseases. Several therapeutics to boost PGRN levels are currently in clinical trials. However, it is difficult to test the efficacy of PGRN-enhancing drugs in mouse models due to the mild phenotypes of Grn[-/-] mice. Recently, mice deficient in both PGRN and TMEM106B were shown to develop severe motor deficits and pathology. Here, we show that intracerebral ventricle injection of PGRN-expressing AAV1/9 viruses partially rescues motor deficits, neuronal loss, glial activation, and lysosomal abnormalities in Tmem106b[-/-]Grn[-/-] mice. Widespread expression of PGRN is detected in both the brain and spinal cord for both AAV subtypes. However, AAV9 but not AAV1-mediated expression of PGRN results in high levels of PGRN in the serum. Together, these data support using the Tmem106b[-/-]Grn[-/-] mouse strain as a robust mouse model to determine the efficacy of PGRN-elevating therapeutics.}, } @article {pmid37519724, year = {2023}, author = {Khosla, R and Bhagat, H and Lal, P and Anand, A}, title = {ALS plasma reduces the viability of NSC34 cells via altering mRNA expression of VEGF: A short report.}, journal = {Heliyon}, volume = {9}, number = {7}, pages = {e18287}, pmid = {37519724}, issn = {2405-8440}, abstract = {INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder that progressively leads to motor neuron degeneration at the neuromuscular junctions, resulting in paralysis in the patients. The clinical diagnosis of ALS is time taking and further delays the therapeutics that can be helpful if the disease is diagnosed at an early stage. Changes in plasma composition can be reflected upon CSF composition and hence, can be used to study the diagnosis and prognosis markers for the disease.

AIM: To develop a simple model system using motor neuron like cell line after plasma induction.

METHOD: Neuroblastoma × Spinal Cord hybridoma cell line (NSC34) was cultured under appropriate conditions. 10% ALS patients' plasma was added to the media, and cells were conditioned for 12 h. Cell survival analysis and differential gene expression of a panel of molecules (published previously, VEGF, VEGFR2, ANG, OPTN, TDP43, and MCP-1) were done.

RESULTS: ALS patients' plasma impacted the life of the cells and reduced survival to nearly 50% after induction. VEGF was found to be significantly down-regulated in the cells, which can be explained as a reason for reduced cell survival.

CONCLUSION: ALS plasma altered the expression of an essential neuroprotective and growth factor VEGF in NSC34 cells leading to reduced viability.}, } @article {pmid37519256, year = {2023}, author = {Foucher, J and Winroth, I and Lovik, A and Sennfält, S and Pereira, JB and Fang, F and Lule, D and Andersen, PM and Ingre, C}, title = {Validity and reliability measures of the Swedish Karolinska version of the Edinburgh Cognitive and Behavioral ALS Screen (SK-ECAS).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/21678421.2023.2239857}, pmid = {37519256}, issn = {2167-9223}, abstract = {OBJECTIVE: Cognitive and behavioral impairment is observed in up to 50% of patients with amyotrophic lateral sclerosis (ALS). The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is a 5-domain screening tool customized for quick cognitive screening in patients with ALS. Although the ECAS is available in Swedish at the Karolinska University Hospital (SK-ECAS), it has not yet been validated in Sweden stressing the need to assess validity and reliability of the SK-ECAS Version A.

METHODS: The study included 176 patients with ALS or other motor neuron disease diagnosed between September 2017 and October 2021 at the Karolinska ALS Clinical Research Center in Stockholm, Sweden, and 35 age-matched healthy control subjects. SK-ECAS was validated against the Montreal Cognitive Assessment (MoCA) and optimal cutoffs, receiver operating characteristic (ROC) curve and area under the curve (AUC) were calculated.

RESULTS: We identified an optimal cutoff of 108 for the SK-ECAS total score and 82 for the SK-ECAS ALS-specific score to detect cognitive impairment. The SK-ECAS showed good performance in indicating abnormal cognition with an AUC of 0.73 for SK-ECAS ALS-specific score and 0.77 for SK-ECAS total score. There was good internal consistency with a Cronbach's alpha of 0.79.

CONCLUSIONS: This study demonstrates good validity and reliability indices for SK-ECAS Version A for the detection of cognitive impairment in newly diagnosed ALS patients.}, } @article {pmid37519183, year = {2023}, author = {Siokas, V and Liampas, I and Aloizou, AM and Bakirtzis, C and Tsouris, Z and Nousia, A and Nasios, G and Papadimitriou, D and Lavdas, E and Liakos, P and Bogdanos, DP and Hadjigeorgiou, GM and Dardiotis, E}, title = {Lack of Association between CD33 rs3865444 and Amyotrophic Lateral Sclerosis: A Case-Control Study.}, journal = {Journal of integrative neuroscience}, volume = {22}, number = {4}, pages = {106}, doi = {10.31083/j.jin2204106}, pmid = {37519183}, issn = {0219-6352}, support = {5287//Research Committee of the University of Thessaly/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Case-Control Studies ; Sialic Acid Binding Ig-like Lectin 3 ; }, abstract = {BACKGROUND: Microglial activation is considered to assume a role in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). To date, the relationship between ALS and the rs3865444 polymorphism of the cluster of differentiation 33 (CD33) has not been explored. The current report aimed to investigate the potential connection between CD33 rs3865444 and ALS.

METHODS: Patients diagnosed with sporadic ALS according to the revised El Escorial criteria, as well as age and sex matched community controls, were enrolled. Two evenly numbered, age and sex matched groups of 155 participants each were genotyped.

RESULTS: No association was found between rs3865444 and ALS [log-additive odds ratio (OR) = 0.83 (0.57, 1.22), over-dominant OR = 0.86 (0.55, 1.36), recessive OR = 0.73 (0.25, 2.17), dominant OR = 0.82 (0.52, 1.29), co-dominant OR1 = 0.68 (0.23, 2.05) and co-dominant OR2 = 0.84 (0.53, 1.33)]. Moreover, no relationship was established between rs3865444 and the age of ALS onset based on both unadjusted and sex adjusted Cox-proportional hazards models. Finally, no association between rs3865444 and ALS was found in subgroup analyses based on the site of ALS onset (bulbar or spinal) and sex.

CONCLUSIONS: The current analysis is the first to report that rs3865444 is not linked to ALS. Larger multi-racial studies are required to confirm these findings.}, } @article {pmid37519177, year = {2023}, author = {Blagov, A and Borisov, E and Grechko, A and Popov, M and Sukhorukov, V and Orekhov, A}, title = {The Role of Impaired Mitochondrial Transport in the Development of Neurodegenerative Diseases.}, journal = {Journal of integrative neuroscience}, volume = {22}, number = {4}, pages = {86}, doi = {10.31083/j.jin2204086}, pmid = {37519177}, issn = {0219-6352}, support = {23-25-00237//Russian Science Foundation/ ; }, mesh = {Humans ; *Neurodegenerative Diseases ; Mitochondria ; *Alzheimer Disease ; *Parkinson Disease ; *Huntington Disease ; }, abstract = {The fight against neurodegenerative diseases is one of the key direction of modern medicine. Unfortunately, the difficulties in understanding the factors underlying the development of neurodegeneration hinder the development of breakthrough therapeutics that can stop or at least greatly slow down the progression of these diseases. In this review, it is considered the disruption of mitochondrial transport as one of the pathogenesis factors contributing to neurodegeneration using the examples of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Here, the mechanism of mitochondrial transport under normal conditions and the mechanisms of disturbances for the indicated diseases will be considered.}, } @article {pmid37517821, year = {2023}, author = {Huang, Y and Yang, H and Yang, B and Zheng, Y and Hou, X and Chen, G and Zhang, W and Zeng, X and DU, B}, title = {Ginsenoside-Rg1 combined with a conditioned medium from induced neuron-like hUCMSCs alleviated the apoptosis in a cell model of ALS through regulating the NF-κB/Bcl-2 pathway.}, journal = {Chinese journal of natural medicines}, volume = {21}, number = {7}, pages = {540-550}, doi = {10.1016/S1875-5364(23)60445-5}, pmid = {37517821}, issn = {1875-5364}, mesh = {Humans ; NF-kappa B/genetics/metabolism ; *Ginsenosides/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Culture Media, Conditioned/pharmacology ; Superoxide Dismutase-1 ; *Neurodegenerative Diseases ; Neurons/metabolism ; Apoptosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons in the brain and spinal cord. One important aspect of ALS pathogenesis is superoxide dismutase 1 (SOD1) mutant-mediated mitochondrial toxicity, leading to apoptosis in neurons. This study aimed to evaluate the neural protective synergistic effects of ginsenosides Rg1 (G-Rg1) and conditioned medium (CM) on a mutational SOD1 cell model, and to explore the underlying mechanisms. We found that the contents of nerve growth factor, glial cell line-derived neurotrophic factor, and brain-derived neurotrophic factor significantly increased in CM after human umbilical cord mesenchymal stem cells (hUCMSCs) were exposed to neuron differentiation reagents for seven days. CM or G-Rg1 decreased the apoptotic rate of SOD1[G93A]-NSC34 cells to a certain extent, but their combination brought about the least apoptosis, compared with CM or G-Rg1 alone. Further research showed that the anti-apoptotic protein Bcl-2 was upregulated in all the treatment groups. Proteins associated with mitochondrial apoptotic pathways, such as Bax, caspase 9 (Cas-9), and cytochrome c (Cyt c), were downregulated. Furthermore, CM or G-Rg1 also inhibited the activation of the nuclear factor-kappa B (NF-κB) signaling pathway by reducing the phosphorylation of p65 and IκBα. CM/G-Rg1 or their combination also reduced the apoptotic rate induced by betulinic acid (BetA), an agonist of the NF-κB signaling pathway. In summary, the combination of CM and G-Rg1 effectively reduced the apoptosis of SOD1[G93A]-NSC34 cells through suppressing the NF-κB/Bcl-2 signaling pathway (Fig. 1 is a graphical representation of the abstract).}, } @article {pmid37517401, year = {2023}, author = {Gerlach, K}, title = {Improvement of Spinocerebellar Ataxia 3 Symptoms Treated with Eurythmy Therapy: A Case Vignette.}, journal = {Complementary medicine research}, volume = {30}, number = {5}, pages = {460-465}, doi = {10.1159/000532120}, pmid = {37517401}, issn = {2504-2106}, mesh = {Male ; Humans ; Middle Aged ; *Machado-Joseph Disease ; *Sleep Wake Disorders ; Ataxia ; Exercise Therapy ; Spasm ; }, abstract = {A 58-year-old male with genetically confirmed spinocerebellar ataxia 3 was treated with 10 sessions of eurythmy therapy. He was rated 9 on the "Scale for Assessment and Rating of Ataxia" before therapy started. Among movement and mental symptoms, he complained about sleep disturbances, insensitivity in the feet, and spasms in the legs. The patient was asked to build strong inner images as a basis for the eurythmy therapy movement exercises. After 10 sessions, he reported improvement in sleep disturbances, insensitivity in the feet, and spasms in the legs. He improved to 7.5 points on the "Scale for Assessment and Rating of Ataxia". In the 3 months, before starting and during eurythmy therapy, the patient did not alter the only medication taken (Bryophyllum 50% powder) and did not undergo any other therapy. Ein 58-jähriger Mann mit genetisch bestätigter spinozerebellärer Ataxie 3 wurde mit 10 Sitzungen Heileurythmie behandelt. Vor Beginn der Therapie wurde er auf der “Scale for Assessment and Rating of Ataxia” mit 9 bewertet. Neben Bewegungs- und psychischen Symptomen klagte er über Schlafstörungen, Unempfindlichkeit in den Füßen und Spasmen in den Beinen. Der Patient wurde aufgefordert, starke innere Bilder als Grundlage für die heileurythmischen Bewegungsübungen aufzubauen. Nach 10 Sitzungen berichtete er über eine Verbesserung der Schlafstörungen, der Unempfindlichkeit in den Füßen und der Spasmen in den Beinen. Er verbesserte sich auf 7.5 Punkte auf der “Scale for Assessment and Rating of Ataxia”. Während der drei Monate vor Beginn und während der Eurythmie Therapie änderte der Patient seine Medikation nicht (Bryophyllum 50% Pulver) und unterzog sich keiner weiteren Therapie.}, } @article {pmid37516990, year = {2023}, author = {Tröger, J and Baltes, J and Baykara, E and Kasper, E and Kring, M and Linz, N and Robin, J and Schäfer, S and Schneider, A and Hermann, A}, title = {PROSA-a multicenter prospective observational study to develop low-burden digital speech biomarkers in ALS and FTD.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2023.2239312}, pmid = {37516990}, issn = {2167-9223}, abstract = {Objective: There is a need for novel biomarkers that can indicate disease state, project disease progression, or assess response to treatment for amyotrophic lateral sclerosis (ALS) and associated neurodegenerative diseases such as frontotemporal dementia (FTD). Digital biomarkers are especially promising as they can be collected non-invasively and at low burden for patients. Speech biomarkers have the potential to objectively measure cognitive, motor as well as respiratory symptoms at low-cost and in a remote fashion using widely available technology such as telephone calls. Methods: The PROSA study aims to develop and evaluate low-burden frequent prognostic digital speech biomarkers. The main goal is to create a single, easy-to-perform battery that serves as a valid and reliable proxy for cognitive, respiratory, and motor domains in ALS and FTD. The study will be a multicenter 12-months observational study aiming to include 75 ALS and 75 FTD patients as well as 50 healthy controls and build on three established longitudinal cohorts: DANCER, DESCRIBE-ALS and DESCRIBE-FTD. In addition to the extensive clinical phenotyping in DESCRIBE, PROSA collects a comprehensive speech protocol in fully remote and automated fashion over the telephone at four time points. This longitudinal speech data, together with gold standard measures, will allow advanced speech analysis using artificial intelligence for the development of speech-based phenotypes of ALS and FTD patients measuring cognitive, motor and respiratory symptoms. Conclusion: Speech-based phenotypes can be used to develop diagnostic and prognostic models predicting clinical change. Results are expected to have implications for future clinical trial stratification as well as supporting innovative trial designs in ALS and FTD.}, } @article {pmid37516812, year = {2023}, author = {Yin, Z and Chen, J and Xia, M and Zhang, X and Li, Y and Chen, Z and Bao, Q and Zhong, W and Yao, J and Wu, K and Zhao, L and Liang, F}, title = {Assessing causal relationship between circulating cytokines and age-related neurodegenerative diseases: a bidirectional two-sample Mendelian randomization analysis.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {12325}, pmid = {37516812}, issn = {2045-2322}, mesh = {Humans ; Cytokines/genetics ; *Neurodegenerative Diseases/genetics ; Mendelian Randomization Analysis ; *Amyotrophic Lateral Sclerosis/genetics ; Fibroblast Growth Factor 2 ; Genome-Wide Association Study ; *Alzheimer Disease ; *Parkinson Disease/genetics ; }, abstract = {Numerous studies have reported that circulating cytokines (CCs) are linked to age-related neurodegenerative diseases (ANDDs); however, there is a lack of systematic investigation for the causal association. A two-sample bidirectional Mendelian Randomisation (MR) method was utilized to evaluate the causal effect. We applied genetic variants correlated with concentrations of CCs from a genome-wide association study meta-analysis (n = 8293) as instrumental variables. Summary data of three major ANDDs [Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS)] were identified from the IEU OpenGWAS platform (n = 627, 266). Inverse-variance weighted method is the main approach to analyse causal effect, and MR results are verified by several sensitivity and pleiotropy analyses. In directional MR, it suggested that several CCs were nominally correlated with the risk of ANDDs, with a causal odds ratio (OR) of Interleukin (IL)-5 of 0.909 for AD; OR of IL-2 of 1.169 for PD; and OR of Beta nerve growth factor of 1.142 for ALS). In reverse MR, there were some suggestively causal effects of ANDDs on CCs (AD on increased Basic fibroblast growth factor and IL-12 and decreased Stem cell growth factor beta; PD on decreased Monokine induced by interferon-gamma; ALS on decreased Basic fibroblast growth factor and IL-17). The findings were stable across sensitivity and pleiotropy analyses. However, after Bonferroni correction, there is no statistically significant association between CCs and ANDDs. Through the genetic epidemiological approach, our study assessed the role and presented possible causal associations between CCs and ANDDs. Further studies are warranted to verify the causal associations.}, } @article {pmid37516663, year = {2023}, author = {Ahmed, M and Spicer, C and Harley, J and Taylor, JP and Hanna, M and Patani, R and Greensmith, L}, title = {Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models.}, journal = {Molecular neurobiology}, volume = {60}, number = {12}, pages = {6896-6915}, pmid = {37516663}, issn = {1559-1182}, support = {MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; Animals ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Frontotemporal Dementia/drug therapy/genetics/pathology ; Hydroxylamines/therapeutic use ; Heat-Shock Response ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are now known as parts of a disease spectrum with common pathological features and genetic causes. However, as both conditions are clinically heterogeneous, patient groups may be phenotypically similar but pathogenically and genetically variable. Despite numerous clinical trials, there remains no effective therapy for these conditions, which, in part, may be due to challenges of therapy development in a heterogeneous patient population. Disruption to protein homeostasis is a key feature of different forms of ALS and FTD. Targeting the endogenous protein chaperone system, the heat shock response (HSR) may, therefore, be a potential therapeutic approach. We conducted a preclinical study of a known pharmacological amplifier of the HSR, called arimoclomol, in mice with a mutation in valosin-containing protein (VCP) which causes both ALS and FTD in patients. We demonstrate that amplification of the HSR ameliorates the ALS/FTD-like phenotype in the spinal cord and brain of mutant VCP mice and prevents neuronal loss, replicating our earlier findings in the SOD1 mouse model of ALS. Moreover, in human cell models, we demonstrate improvements in pathology upon arimoclomol treatment in mutant VCP patient fibroblasts and iPSC-derived motor neurons. Our findings suggest that targeting of the HSR may have therapeutic potential, not only in non-SOD1 ALS, but also for the treatment of FTD.}, } @article {pmid37516410, year = {2023}, author = {Ying, Z and Ye, N and Ma, Q and Chen, F and Li, N and Zhen, X}, title = {Targeted to neuronal organelles for CNS drug development.}, journal = {Advanced drug delivery reviews}, volume = {200}, number = {}, pages = {115025}, doi = {10.1016/j.addr.2023.115025}, pmid = {37516410}, issn = {1872-8294}, mesh = {Humans ; Mitochondria/metabolism/pathology ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Parkinson Disease ; Central Nervous System/metabolism/pathology ; Drug Development ; Central Nervous System Agents/pharmacology ; }, abstract = {Significant evidences indicate that sub-cellular organelle dynamics is critical for both physiological and pathological events and therefore may be attractive drug targets displaying great therapeutic potential. Although the basic biological mechanism underlying the dynamics of intracellular organelles has been extensively studied, relative drug development is still limited. In the present review, we show that due to the development of technical advanced imaging tools, especially live cell imaging methods, intracellular organelle dynamics (including mitochondrial dynamics and membrane contact sites) can be dissected at the molecular level. Based on these identified molecular targets, we review and discuss the potential of drug development to target organelle dynamics, especially mitochondria dynamics and ER-organelle membrane contact dynamics, in the central nervous system for treating human diseases, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.}, } @article {pmid37515753, year = {2023}, author = {Manicardi, A and Scarabel, L and Llenes, JM and Montull, JM and Osuna, MD and Torra Farré, J and Milani, A}, title = {Genetic basis and origin of resistance to acetolactate synthase inhibitors in Amaranthus palmeri from Spain and Italy.}, journal = {Pest management science}, volume = {79}, number = {12}, pages = {4886-4896}, doi = {10.1002/ps.7690}, pmid = {37515753}, issn = {1526-4998}, support = {//Agencia Estatal de Investigación/ ; //European Regional Development Fund/ ; //Horizon 2020 Framework Programme/ ; //Ministerio de Ciencia e Innovación/ ; }, mesh = {*Herbicides/pharmacology ; *Amaranthus/genetics ; *Acetolactate Synthase/genetics ; Herbicide Resistance/genetics ; Spain ; Italy ; }, abstract = {BACKGROUND: Amaranthus palmeri is an aggressive annual weed native to the United States, which has become invasive in some European countries. Populations resistant to acetolactate synthase (ALS) inhibitors have been recorded in Spain and Italy, but the evolutionary origin of the resistance traits remains unknown. Bioassays were conducted to identify cross-resistance to ALS inhibitors and a haplotype-based genetic approach was used to elucidate the origin and distribution of resistance in both countries.

RESULTS: Amaranthus palmeri populations were resistant to thifensulfuron-methyl and imazamox, and the 574-Leu mutant ALS allele was found to be the main cause of resistance among them. In two Spanish populations, 376-Glu and 197-Thr mutant ALS alleles were also found. The haplotype analyses revealed the presence of two and four distinct 574-Leu mutant haplotypes in the Italian and Spanish populations, respectively. None was common to both countries, but some mutant haplotypes were shared between geographically close populations or between populations more than 100 km apart. Wide genetic diversity was found in two very close Spanish populations.

CONCLUSION: ALS-resistant A. palmeri populations were introduced to Italy and Spain from outside Europe. Populations from both countries have different evolutionary histories and originate from independent introduction events. ALS resistance then spread over short and long distances by seed dispersal. The higher number and genetic diversity among mutant haplotypes from the Spanish populations indicated recurrent invasions. The implementation of control tactics to limit seed dispersal and the establishment of A. palmeri is recommended in both countries. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid37514344, year = {2023}, author = {Lu, H and Liu, Y and Bu, D and Yang, F and Zhang, Z and Qiang, S}, title = {A Double Mutation in the ALS Gene Confers a High Level of Resistance to Mesosulfuron-Methyl in Shepherd's-Purse.}, journal = {Plants (Basel, Switzerland)}, volume = {12}, number = {14}, pages = {}, pmid = {37514344}, issn = {2223-7747}, support = {32102238//National Natural Science Foundation of China/ ; 2021YFD1700102//National Key R&D Program of China/ ; }, abstract = {Shepherd's-purse (Capsella bursa-pastoris), a globally distributed noxious weed species often found in wheat, has evolved resistance to ALS-inhibiting herbicides mainly due to single mutations in the ALS gene. In the present study, dose-response bioassays showed that a shepherd's-purse population (R), collected from Xinghua, Jiangsu Province, China, had high level of resistance to the ALS-inhibiting herbicide, mesosulfuron-methyl (800-fold), and even much higher resistance levels to other reported ALS-inhibiting herbicides, tribenuron-methyl (1313-fold), bensulfuron-methyl (969-fold) and penoxsulam (613-fold). Sequencing of the open reading frame of the ALS gene revealed a double ALS gene mutation (Pro197-Ser plus Trp574-Leu) conferring the high resistance in the R plants. Docking analysis of the ALS protein and mesosulfuron-methyl predicts that the two amino acid substitutions in the R samples reduces the binding energy to the herbicide by decreasing the hydrogen bonds (H-bonds) and other interactions, thus endowing resistance to ALS-inhibiting herbicides. These results demonstrate that the double ALS mutation confers high resistance levels to ALS-inhibiting herbicides. To our knowledge, this is the first evidence of the double ALS mutation in shepherd's-purse endowing ALS-inhibiting herbicide resistance.}, } @article {pmid37513359, year = {2023}, author = {Pecheu, CN and Tchieda, VK and Tajeu, KY and Jiokeng, SLZ and Lesch, A and Tonle, IK and Ngameni, E and Janiak, C}, title = {Electrochemical Determination of Epinephrine in Pharmaceutical Preparation Using Laponite Clay-Modified Graphene Inkjet-Printed Electrode.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {14}, pages = {}, pmid = {37513359}, issn = {1420-3049}, mesh = {*Graphite/chemistry ; Carbon/chemistry ; Clay ; Electrochemical Techniques/methods ; Epinephrine/chemistry ; Electrodes ; Pharmaceutical Preparations ; }, abstract = {Epinephrine (EP, also called adrenaline) is a compound belonging to the catecholamine neurotransmitter family. It can cause neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. This work describes an amperometric sensor for the electroanalytical detection of EP by using an inkjet-printed graphene electrode (IPGE) that has been chemically modified by a thin layer of a laponite (La) clay mineral. The ion exchange properties and permeability of the chemically modified electrode (denoted La/IPGE) were evaluated using multi-sweep cyclic voltammetry, while its charge transfer resistance was determined by electrochemical impedance spectroscopy. The results showed that La/IPGE exhibited higher sensitivity to EP compared to the bare IPGE. The developed sensor was directly applied for the determination of EP in aqueous solution using differential pulse voltammetry. Under optimized conditions, a linear calibration graph was obtained in the concentration range between 0.8 µM and 10 μM. The anodic peak current of EP was directly proportional to its concentration, leading to detection limits of 0.34 μM and 0.26 μM with bare IPGE and La/IPGE, respectively. The sensor was successfully applied for the determination of EP in pharmaceutical preparations. Recovery rates and the effects of interfering species on the detection of EP were evaluated to highlight the selectivity of the elaborated sensor.}, } @article {pmid37512004, year = {2023}, author = {Hildebrand, A and Schreiber, F and Weber, L and Arndt, P and Garz, C and Petri, S and Prudlo, J and Meuth, SG and Waerzeggers, Y and Henneicke, S and Vielhaber, S and Schreiber, S}, title = {Peripheral Nerve Ultrasound for the Differentiation between ALS, Inflammatory, and Hereditary Polyneuropathies.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {59}, number = {7}, pages = {}, pmid = {37512004}, issn = {1648-9144}, support = {02728/STV//Stiftung für Medizinische Wissenschaft/ ; }, mesh = {Humans ; *Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Peripheral Nerves/diagnostic imaging ; *Polyneuropathies/diagnostic imaging ; Ultrasonography/methods ; }, abstract = {Background and Objectives: Ultrasound (US) is a non-invasive tool for the in vivo detection of peripheral nerve alterations. Materials and Methods: In this study, we applied nerve US to assist the discrimination between the spectrum of amyotrophic lateral sclerosis (ALS, n = 11), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 5), and genetically confirmed Charcot-Marie-Tooth disease (CMT, n = 5). All participants and n = 15 controls without neurological diseases underwent high-resolution US of the bilateral tibial nerve. The nerve cross-sectional area (CSA) and nerve microvascular blood flow were compared between the groups and related to cerebrospinal fluid (CSF) measures, clinical symptoms, and nerve conduction studies. The analyses are part of a larger multimodal study on the comparison between US and 7 Tesla (7T) magnetic resonance neurography (MRN). Results: The patients and controls were matched with respect to their demographical data. CMT had the longest disease duration, followed by CIDP and ALS. CSA was related to age, weight, and disease duration. CSA was larger in CMT and CIDP compared to ALS and controls. The blood flow was greatest in CIDP, and higher than in CMT, ALS, and controls. In ALS, greater CSA was correlated with greater CSF total protein and higher albumin quotient. The US measures did not correlate with clinical scores or nerve conduction studies in any of the subgroups. Conclusion: Our results point towards the feasibility of CSA and blood flow to discriminate between ALS, CIDP, and CMT, even in groups of small sample size. In ALS, larger CSA could indicate an inflammatory disease subtype characterized by reduced blood-nerve barrier integrity. Our upcoming analysis will focus on the additive value of 7T MRN in combination with US to disentangle the spectrum between more inflammatory or more degenerative disease variants among the disease groups.}, } @article {pmid37511491, year = {2023}, author = {Antonioni, A and Raho, EM and Lopriore, P and Pace, AP and Latino, RR and Assogna, M and Mancuso, M and Gragnaniello, D and Granieri, E and Pugliatti, M and Di Lorenzo, F and Koch, G}, title = {Frontotemporal Dementia, Where Do We Stand? A Narrative Review.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37511491}, issn = {1422-0067}, mesh = {Middle Aged ; Humans ; *Frontotemporal Dementia/diagnosis/therapy/pathology ; *Neurodegenerative Diseases ; *Pick Disease of the Brain ; *Amyotrophic Lateral Sclerosis/pathology ; Temporal Lobe/pathology ; }, abstract = {Frontotemporal dementia (FTD) is a neurodegenerative disease of growing interest, since it accounts for up to 10% of middle-age-onset dementias and entails a social, economic, and emotional burden for the patients and caregivers. It is characterised by a (at least initially) selective degeneration of the frontal and/or temporal lobe, generally leading to behavioural alterations, speech disorders, and psychiatric symptoms. Despite the recent advances, given its extreme heterogeneity, an overview that can bring together all the data currently available is still lacking. Here, we aim to provide a state of the art on the pathogenesis of this disease, starting with established findings and integrating them with more recent ones. In particular, advances in the genetics field will be examined, assessing them in relation to both the clinical manifestations and histopathological findings, as well as considering the link with other diseases, such as amyotrophic lateral sclerosis (ALS). Furthermore, the current diagnostic criteria will be explored, including neuroimaging methods, nuclear medicine investigations, and biomarkers on biological fluids. Of note, the promising information provided by neurophysiological investigations, i.e., electroencephalography and non-invasive brain stimulation techniques, concerning the alterations in brain networks and neurotransmitter systems will be reviewed. Finally, current and experimental therapies will be considered.}, } @article {pmid37511443, year = {2023}, author = {Kittipeerapat, N and Fabian, R and Bernsen, S and Weydt, P and Castro-Gomez, S}, title = {Creatine Kinase MB Isoenzyme Is a Complementary Biomarker in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37511443}, issn = {1422-0067}, support = {390873048//Deutsche Forschungsgemeinschaft/ ; 21060//Alzheimer Forschung Initiative/ ; 0001//Alle-Lieben-Schmidt e.V/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Isoenzymes ; *Neurodegenerative Diseases ; Creatine Kinase, MB Form ; Creatine Kinase ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an invariably fatal neurodegenerative disease with limited therapeutic options. There is an urgent need for novel biomarkers to be used as surrogates for new therapeutic trials and disease monitoring. In this study, we sought to systematically study creatine kinase isoenzyme MB (CK-MB) in a real-world cohort of ALS patients, assess the diagnostic performance, and evaluate its association with other laboratory and clinical parameters. We reviewed data from 194 consecutive patients that included 130 ALS patients and 64 disease control patients (primary lateral sclerosis [PLS], benign fasciculations syndrome [BFS], Huntington's disease [HD] and Alzheimer's disease [AD]). CK-MB was elevated in the sera of more than half of all patients with ALS. In patients with spinal-onset ALS, CK-MB levels were significantly higher than in patients with other neurodegenerative diseases. Patients with slower rates of functional decline had a significantly higher baseline CK-MB. Furthermore, CK-MB elevations correlated with cardiac troponin T (cTnT) and with revised ALS Functional Rating Scale (ALSFRS-R) bulbar subcategory. We posit that measuring CK-MB in ALS patients in a complimentary fashion could potentially aid in the diagnostic workup of ALS and help discriminate the disease from some ALS mimics and other neurodegenerative diseases. CK-MB levels also may provide valuable prognostic information regarding disease aggressiveness as well as correlations with specific phenotypic presentations.}, } @article {pmid37511314, year = {2023}, author = {Pfaff, AL and Bubb, VJ and Quinn, JP and Koks, S}, title = {A Genome-Wide Screen for the Exonisation of Reference SINE-VNTR-Alus and Their Expression in CNS Tissues of Individuals with Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37511314}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Minisatellite Repeats ; Short Interspersed Nucleotide Elements ; Alu Elements ; RNA, Messenger/genetics ; }, abstract = {The hominid-specific retrotransposon SINE-VNTR-Alu (SVA) is a composite element that has contributed to the genetic variation between individuals and influenced genomic structure and function. SVAs are involved in modulating gene expression and splicing patterns, altering mRNA levels and sequences, and have been associated with the development of disease. We evaluated the genome-wide effects of SVAs present in the reference genome on transcript sequence and expression in the CNS of individuals with and without the neurodegenerative disorder Amyotrophic Lateral Sclerosis (ALS). This study identified SVAs in the exons of 179 known transcripts, several of which were expressed in a tissue-specific manner, as well as 92 novel exonisation events occurring in the motor cortex. An analysis of 65 reference genome SVAs polymorphic for their presence/absence in the ALS consortium cohort did not identify any elements that were significantly associated with disease status, age at onset, and survival. However, there were transcripts, such as transferrin and HLA-A, that were differentially expressed between those with or without disease, and expression levels were associated with the genotype of proximal SVAs. This study demonstrates the functional consequences of several SVA elements altering mRNA splicing patterns and expression levels in tissues of the CNS.}, } @article {pmid37511056, year = {2023}, author = {Bettendorff, L}, title = {Synthetic Thioesters of Thiamine: Promising Tools for Slowing Progression of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37511056}, issn = {1422-0067}, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/drug therapy ; Thiamine/pharmacology/therapeutic use ; Thiamine Pyrophosphate ; Coenzymes ; }, abstract = {Thiamine (vitamin B1) is essential for the brain. This is attributed to the coenzyme role of thiamine diphosphate (ThDP) in glucose and energy metabolism. The synthetic thiamine prodrug, the thioester benfotiamine (BFT), has been extensively studied and has beneficial effects both in rodent models of neurodegeneration and in human clinical studies. BFT has no known adverse effects and improves cognitive outcomes in patients with mild Alzheimer's disease. In cell culture and animal models, BFT has antioxidant and anti-inflammatory properties that seem to be mediated by a mechanism independent of the coenzyme function of ThDP. Recent in vitro studies show that another thiamine thioester, O,S-dibenzoylthiamine (DBT), is even more efficient than BFT, especially with respect to its anti-inflammatory potency, and is effective at lower concentrations. Thiamine thioesters have pleiotropic properties linked to an increase in circulating thiamine concentrations and possibly in hitherto unidentified open thiazole ring derivatives. The identification of the active neuroprotective metabolites and the clarification of their mechanism of action open extremely promising perspectives in the field of neurodegenerative, neurodevelopmental, and psychiatric conditions. The present review aims to summarize existing data on the neuroprotective effects of thiamine thioesters and give a comprehensive account.}, } @article {pmid37511037, year = {2023}, author = {Xiang, L and Wang, Y and Liu, S and Liu, B and Jin, X and Cao, X}, title = {Targeting Protein Aggregates with Natural Products: An Optional Strategy for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37511037}, issn = {1422-0067}, support = {32000387//National Natural Science Foundation of China/ ; LY23C060001//Zhejiang Provincial Natural Science Foundation/ ; 2021LFR053//Scientific Research Foundation of Zhejiang A&F University/ ; 19 0069//Swedish Cancer Society/ ; VR 2019-03604//Swedish Research Council/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Protein Aggregates ; *Biological Products/pharmacology/therapeutic use ; *Parkinson Disease ; *Alzheimer Disease ; }, abstract = {Protein aggregation is one of the hallmarks of aging and aging-related diseases, especially for the neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and others. In these diseases, many pathogenic proteins, such as amyloid-β, tau, α-Syn, Htt, and FUS, form aggregates that disrupt the normal physiological function of cells and lead to associated neuronal lesions. Protein aggregates in NDs are widely recognized as one of the important targets for the treatment of these diseases. Natural products, with their diverse biological activities and rich medical history, represent a great treasure trove for the development of therapeutic strategies to combat disease. A number of in vitro and in vivo studies have shown that natural products, by virtue of their complex molecular scaffolds that specifically bind to pathogenic proteins and their aggregates, can inhibit the formation of aggregates, disrupt the structure of aggregates and destabilize them, thereby alleviating conditions associated with NDs. Here, we systematically reviewed studies using natural products to improve disease-related symptoms by reducing or inhibiting the formation of five pathogenic protein aggregates associated with NDs. This information should provide valuable insights into new directions and ideas for the treatment of neurodegenerative diseases.}, } @article {pmid37511010, year = {2023}, author = {Carata, E and Muci, M and Di Giulio, S and Mariano, S and Panzarini, E}, title = {Looking to the Future of the Role of Macrophages and Extracellular Vesicles in Neuroinflammation in ALS.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37511010}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Neuroinflammatory Diseases ; Macrophages/metabolism ; Inflammation/metabolism ; *Extracellular Vesicles/metabolism ; }, abstract = {Neuroinflammation is a common pathological feature of amyotrophic lateral sclerosis (ALS). Although scientific evidence to date does not allow defining neuroinflammation as an ALS trigger, its role in exacerbating motor neuron (MNs) degeneration and disease progression is attracting research interest. Activated CNS (Central Nervous System) glial cells, proinflammatory peripheral and infiltrated T lymphocytes and monocytes/macrophages, as well as the immunoreactive molecules they release, represent the active players for the role of immune dysregulation enhancing neuroinflammation. The crosstalk between the peripheral and CNS immune cells significantly correlates with the survival of ALS patients since the modification of peripheral macrophages can downregulate inflammation at the periphery along the nerves and in the CNS. As putative vehicles for misfolded protein and inflammatory mediators between cells, extracellular vesicles (EVs) have also drawn particular attention in the field of ALS. Both CNS and peripheral immune cells release EVs, which are able to modulate the behavior of neighboring recipient cells; unfortunately, the mechanisms involved in EVs-mediated communication in neuroinflammation remain unclear. This review aims to synthesize the current literature regarding EV-mediated cell-to-cell communication in the brain under ALS, with a particular point of view on the role of peripheral macrophages in responding to inflammation to understand the biological process and exploit it for ALS management.}, } @article {pmid37510999, year = {2023}, author = {Halder, SK and Milner, R}, title = {Spinal Cord Blood Vessels in Aged Mice Show Greater Levels of Hypoxia-Induced Vascular Disruption and Microglial Activation.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37510999}, issn = {1422-0067}, support = {RF1 NS119477/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/pathology ; Hypoxia ; Microglia/pathology ; *Spinal Cord/pathology ; *White Matter/pathology ; *Aging/pathology ; }, abstract = {In response to chronic mild hypoxia (CMH, 8% O2), spinal cord blood vessels launch a robust angiogenic response that is associated with transient disruption of the blood-spinal cord barrier (BSCB) which, in turn, triggers a microglial vasculo-protective response. Because hypoxia occurs in many age-related conditions, the goal of this study was to define how aging influences these responses by comparing events in young (8-10 weeks) and aged (20 months) mice. This revealed that aged mice had much greater (3-4-fold) levels of hypoxic-induced BSCB disruption than young mice and that, while the early stage of the angiogenic response in aged mice was no different to young mice, the maturation of newly formed vessels was significantly delayed. Interestingly, microglia in the spinal cords of aged mice were much more activated than young mice, even under normoxic conditions, and this was further enhanced by CMH, though, surprisingly, this resulted in reduced microglial clustering around leaky blood vessels and diminished vasculo-protection. Vascular disruption was associated with loss of myelin in spinal cord white matter (WM) in both young and aged mice. Furthermore, it was notable that the spinal cord of aged mice contained a lower density of Olig2+ oligodendroglial cells even under normoxic conditions and that CMH significantly reduced the density of Olig2+ cells in spinal cord WM of the aged, but not the young, mice. These results demonstrate that spinal cord blood vessels of aged mice are much more vulnerable to the damaging effects of hypoxia than young mice, in part due to the reduced vasculo-protection conferred by chronically activated microglial cells. These observations may have implications for the pathogenesis and/or treatment of spinal cord diseases such as amyotrophic lateral sclerosis (ALS) and suggest that an improvement in microglial function could offer therapeutic potential for treating these age-related conditions.}, } @article {pmid37509677, year = {2023}, author = {Zoccolella, S and Giugno, A and Milella, G and Filardi, M and Introna, A and Fraddosio, A and D'Errico, E and Gnoni, V and Tamburrino, L and Urso, D and Caputo, F and Misceo, S and Logroscino, G}, title = {A Clinical Scale for Rating the Severity of Bulbar Lower Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {11}, number = {7}, pages = {}, pmid = {37509677}, issn = {2227-9059}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper (UMN) and lower motor neurons (LMN) in four different body regions (bulbar, cervical, thoracic, and lumbosacral). Over the past decades, several clinical scoring systems have been developed to assess the UMN and LMN burden in ALS. However, concerning the bulbar LMN burden, the available scoring systems solely assess the presence/absence of bulbar LMN signs without providing a degree of impairment. Therefore, in this study, we proposed a novel scale to stratify subjects with ALS according to the bulbar LMN involvement and assessed its prognostic value.

METHODS: We developed a four-item scale based on the LMN signs according to the El Escorial criteria. Ten raters, specializing in ALS or neurocognitive disorders, retrospectively applied the scale to the first evaluation of 195 patients with ALS. Cohen's kappa (Cohen's k) and an intra-class correlation coefficient (ICC) were used to assess the inter-rater reliability. The Kaplan-Mayer estimator was used to estimate survival distribution according to the bulbar scale scores.

RESULTS: The raters showed a substantial to excellent agreement with Cohen's k, ranging from 0.834 to 0.975, with an overall ICC of 0.922 (95% CI = 0.906-0.936). The survival distribution was statistically different across the three bulbar scale scores (χ[2](2) = 9.50, p < 0.01).

CONCLUSIONS: Our bulbar LMN scale represents a reliable measure of the bulbar LMN signs in ALS. This easy-to-administer clinical scale could provide unique information in phenotyping and predicting survival in ALS.}, } @article {pmid37509570, year = {2023}, author = {Wang, W and Zhang, L and Cao, W and Xia, K and Huo, J and Huang, T and Fan, D}, title = {Systematic Screening of Associations between Medication Use and Risk of Neurodegenerative Diseases Using a Mendelian Randomization Approach.}, journal = {Biomedicines}, volume = {11}, number = {7}, pages = {}, pmid = {37509570}, issn = {2227-9059}, support = {82101489, 81873784, 82071426//National Natural Science Foundation of China/ ; 2021M690255//China Postdoctoral Science Foundation/ ; BYESS2023317//Young Elite Scientists Sponsorship Program by BAST/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; }, abstract = {BACKGROUND: Systematically assessing the causal associations between medications and neurodegenerative diseases is significant in identifying disease etiology and novel therapies. Here, we investigated the putative causal associations between 23 existing medication categories and major neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

METHODS: A two-sample mendelian randomization (MR) approach was conducted. Estimates were calculated using the inverse-variance weighted (IVW) method as the main model. A sensitivity analysis and a pleiotropy analysis were performed to identify potential violations.

RESULTS: Genetically predisposition to antihypertensives (OR = 0.809, 95% CI = 0.668-0.981, p = 0.031), thyroid preparations (OR = 0.948, 95% CI = 0.909-0.988, p = 0.011), and immunosuppressants (OR = 0.879, 95% CI = 0.789-0.979, p = 0.018) was associated with a decreased risk of AD. Genetic proxies for thyroid preparations (OR = 0.934, 95% CI = 0.884-0.988, p = 0.017), immunosuppressants (OR = 0.825, 95% CI = 0.699-0.973, p = 0.022), and glucocorticoids (OR = 0.862, 95% CI = 0.756-0.983, p = 0.027) were causally associated with a decreased risk of PD. Genetically determined antithrombotic agents (OR = 1.234, 95% CI = 1.042-1.461, p = 0.015), HMG CoA reductase inhibitors (OR = 1.085, 95% CI = 1.025-1.148, p = 0.005), and salicylic acid and derivatives (OR = 1.294, 95% CI = 1.078-1.553, p = 0.006) were associated with an increased risk of ALS.

CONCLUSIONS: We presented a systematic view concerning the causal associations between medications and NDs, which will promote the etiology discovery, drug repositioning and patient management for NDs.}, } @article {pmid37509427, year = {2023}, author = {Badini, S and Regondi, S and Lammi, C and Bollati, C and Donvito, G and Pugliese, R}, title = {Computational Mechanics of Form-Fitting 3D-Printed Lattice-Based Wrist-Hand Orthosis for Motor Neuron Disease.}, journal = {Biomedicines}, volume = {11}, number = {7}, pages = {}, pmid = {37509427}, issn = {2227-9059}, support = {F45C22000230003//Regione Lombardia and Unioncamere Lombardia/ ; }, abstract = {Motor neuron disease (MND) patients often experience hand-wrist muscle atrophy resulting in severe social consequences and hampering their daily activities. Although hand-wrist orthosis is commonly used to assist weakened muscles, its effectiveness is limited due to the rapid progression of the disease and the need for customization to suit individual patient requirements. To address these challenges, this study investigates the application of three-dimensional (3D) printing technology to design and fabricate two lattice structures inspired by silkworm cocoons, using poly-ε-caprolactone as feedstock material. Finite element method (FEM) analysis is employed to study the mechanical behavior, enabling control over the geometric configuration incorporated into the hand-wrist orthosis. Through tensile displacement and three-point bending simulations, the stress distribution is examined for both lattice geometries. Geometry-1 demonstrates anisotropic behavior, while geometry-2 exhibits no strict directional dependence due to its symmetry and uniform node positioning. Moreover, the biocompatibility of lattices with human skin fibroblasts is investigated, confirming excellent biocompatibility. Lastly, the study involves semi-structured interviews with MND patients to gather feedback and develop prototypes of form-fitting 3D-printed lattice-based hand-wrist orthosis. By utilizing 3D printing technology, this study aims to provide customized orthosis that can effectively support weakened muscles and reposition the hand for individuals with MND.}, } @article {pmid37509182, year = {2023}, author = {Stump, AL and Rioux, DJ and Albright, R and Melki, GL and Prosser, DC}, title = {Yeast Models of Amyotrophic Lateral Sclerosis Type 8 Mimic Phenotypes Seen in Mammalian Cells Expressing Mutant VAPB[P56S].}, journal = {Biomolecules}, volume = {13}, number = {7}, pages = {}, pmid = {37509182}, issn = {2218-273X}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Vesicular Transport Proteins/genetics/metabolism ; *Neurodegenerative Diseases ; Mutation ; Mammals/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease that results in the loss of motor neurons and can occur sporadically or due to genetic mutations. Among the 30 genes linked to familial ALS, a P56S mutation in VAPB, an ER-resident protein that functions at membrane contact sites, causes ALS type 8. Mammalian cells expressing VAPB[P56S] have distinctive phenotypes, including ER collapse, protein and/or membrane-containing inclusions, and sensitivity to ER stress. VAPB is conserved through evolution and has two homologs in budding yeast, SCS2 and SCS22. Previously, a humanized version of SCS2 bearing disease-linked mutations was described, and it caused Scs2-containing inclusions when overexpressed in yeast. Here, we describe a yeast model for ALS8 in which the two SCS genes are deleted and replaced with a single chromosomal copy of either wild-type or mutant yeast SCS2 or human VAPB expressed from the SCS2 promoter. These cells display ER collapse, the formation of inclusion-like structures, and sensitivity to tunicamycin, an ER stress-inducing drug. Based on the phenotypic similarity to mammalian cells expressing VAPB[P56S], we propose that these models can be used to study the molecular basis of cell death or dysfunction in ALS8. Moreover, other conserved ALS-linked genes may create opportunities for the generation of yeast models of disease.}, } @article {pmid37508574, year = {2023}, author = {Malhotra, S and Miras, MCM and Pappolla, A and Montalban, X and Comabella, M}, title = {Liquid Biopsy in Neurological Diseases.}, journal = {Cells}, volume = {12}, number = {14}, pages = {}, pmid = {37508574}, issn = {2073-4409}, mesh = {Humans ; Liquid Biopsy/methods ; *Cell-Free Nucleic Acids ; *MicroRNAs ; *Central Nervous System Neoplasms ; Biomarkers ; }, abstract = {The most recent and non-invasive approach for studying early-stage biomarkers is liquid biopsy. This implies the extraction and analysis of non-solid biological tissues (serum, plasma, saliva, urine, and cerebrospinal fluid) without undergoing invasive procedures to determine disease prognosis. Liquid biopsy can be used for the screening of several components, such as extracellular vesicles, microRNAs, cell-free DNA, cell-free mitochondrial and nuclear DNA, circulating tumour cells, circulating tumour DNA, transfer RNA, and circular DNA or RNA derived from body fluids. Its application includes early disease diagnosis, the surveillance of disease activity, and treatment response monitoring, with growing evidence for validating this methodology in cancer, liver disease, and central nervous system (CNS) disorders. This review will provide an overview of mentioned liquid biopsy components, which could serve as valuable biomarkers for the evaluation of complex neurological conditions, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, stroke, traumatic brain injury, CNS tumours, and neuroinfectious diseases. Furthermore, this review highlights the future directions and potential limitations associated with liquid biopsy.}, } @article {pmid37508558, year = {2023}, author = {Wu, LY and Song, YJ and Zhang, CL and Liu, J}, title = {KV Channel-Interacting Proteins in the Neurological and Cardiovascular Systems: An Updated Review.}, journal = {Cells}, volume = {12}, number = {14}, pages = {}, pmid = {37508558}, issn = {2073-4409}, mesh = {*Neurons/metabolism ; Carrier Proteins/metabolism ; Kv Channel-Interacting Proteins/genetics/metabolism ; Cell Membrane/metabolism ; *Cardiovascular System/metabolism ; }, abstract = {KV channel-interacting proteins (KChIP1-4) belong to a family of Ca[2+]-binding EF-hand proteins that are able to bind to the N-terminus of the KV4 channel α-subunits. KChIPs are predominantly expressed in the brain and heart, where they contribute to the maintenance of the excitability of neurons and cardiomyocytes by modulating the fast inactivating-KV4 currents. As the auxiliary subunit, KChIPs are critically involved in regulating the surface protein expression and gating properties of KV4 channels. Mechanistically, KChIP1, KChIP2, and KChIP3 promote the translocation of KV4 channels to the cell membrane, accelerate voltage-dependent activation, and slow the recovery rate of inactivation, which increases KV4 currents. By contrast, KChIP4 suppresses KV4 trafficking and eliminates the fast inactivation of KV4 currents. In the heart, IKs, ICa,L, and INa can also be regulated by KChIPs. ICa,L and INa are positively regulated by KChIP2, whereas IKs is negatively regulated by KChIP2. Interestingly, KChIP3 is also known as downstream regulatory element antagonist modulator (DREAM) because it can bind directly to the downstream regulatory element (DRE) on the promoters of target genes that are implicated in the regulation of pain, memory, endocrine, immune, and inflammatory reactions. In addition, all the KChIPs can act as transcription factors to repress the expression of genes involved in circadian regulation. Altered expression of KChIPs has been implicated in the pathogenesis of several neurological and cardiovascular diseases. For example, KChIP2 is decreased in failing hearts, while loss of KChIP2 leads to increased susceptibility to arrhythmias. KChIP3 is increased in Alzheimer's disease and amyotrophic lateral sclerosis, but decreased in epilepsy and Huntington's disease. In the present review, we summarize the progress of recent studies regarding the structural properties, physiological functions, and pathological roles of KChIPs in both health and disease. We also summarize the small-molecule compounds that regulate the function of KChIPs. This review will provide an overview and update of the regulatory mechanism of the KChIP family and the progress of targeted drug research as a reference for researchers in related fields.}, } @article {pmid37508548, year = {2023}, author = {Morello, G and La Cognata, V and Guarnaccia, M and La Bella, V and Conforti, FL and Cavallaro, S}, title = {A Diagnostic Gene-Expression Signature in Fibroblasts of Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {12}, number = {14}, pages = {}, pmid = {37508548}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/metabolism ; Transcriptome/genetics ; *Neurodegenerative Diseases/metabolism ; Gene Expression Profiling/methods ; Fibroblasts/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease with limited treatment options. Diagnosis can be difficult due to the heterogeneity and non-specific nature of the initial symptoms, resulting in delays that compromise prompt access to effective therapeutic strategies. Transcriptome profiling of patient-derived peripheral cells represents a valuable benchmark in overcoming such challenges, providing the opportunity to identify molecular diagnostic signatures. In this study, we characterized transcriptome changes in skin fibroblasts of sporadic ALS patients (sALS) and controls and evaluated their utility as a molecular classifier for ALS diagnosis. Our analysis identified 277 differentially expressed transcripts predominantly involved in transcriptional regulation, synaptic transmission, and the inflammatory response. A support vector machine classifier based on this 277-gene signature was developed to discriminate patients with sALS from controls, showing significant predictive power in both the discovery dataset and in six independent publicly available gene expression datasets obtained from different sALS tissue/cell samples. Taken together, our findings support the utility of transcriptional signatures in peripheral cells as valuable biomarkers for the diagnosis of ALS.}, } @article {pmid37508478, year = {2023}, author = {La Cognata, V and D'Amico, AG and Maugeri, G and Morello, G and Guarnaccia, M and Magrì, B and Aronica, E and D'Agata, V and Cavallaro, S}, title = {CXCR2 Is Deregulated in ALS Spinal Cord and Its Activation Triggers Apoptosis in Motor Neuron-Like Cells Overexpressing hSOD1-G93A.}, journal = {Cells}, volume = {12}, number = {14}, pages = {}, pmid = {37508478}, issn = {2073-4409}, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Apoptosis ; Chemokine CXCL2/metabolism ; Ligands ; Mice, Transgenic ; Motor Neurons/pathology ; *Neurodegenerative Diseases/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by progressive depletion of motor neurons (MNs). Recent evidence suggests a role in ALS pathology for the C-X-C motif chemokine receptor 2 (CXCR2), whose expression was found increased at both mRNA and protein level in cortical neurons of sporadic ALS patients. Previous findings also showed that the receptor inhibition is able to prevent iPSC-derived MNs degeneration in vitro and improve neuromuscular function in SOD1-G93A mice. Here, by performing transcriptional analysis and immunofluorescence studies, we detailed the increased expression and localization of CXCR2 and its main ligand CXCL8 in the human lumbar spinal cord of sporadic ALS patients. We further investigated the functional role of CXCR2/ligands axis in NSC-34 motor neuron-like cells expressing human wild-type (WT) or mutant (G93A) SOD1. A significant expression of CXCR2 was found in doxycycline-induced G93A-SOD1-expressing cells, but not in WT cells. In vitro assays showed CXCR2 activation by GROα and MIP2α, two murine endogenous ligands and functional homologs of CXCL8, reduces cellular viability and triggers apoptosis in a dose dependent manner, while treatment with reparixin, a non-competitive allosteric CXCR2 inhibitor, effectively counteracts GROα and MIP2α toxicity, significantly inhibiting the chemokine-induced cell death. Altogether, data further support a role of CXCR2 axis in ALS etiopathogenesis and confirm its pharmacological modulation as a candidate therapeutic strategy.}, } @article {pmid37507754, year = {2023}, author = {Brockmann, SJ and Buck, E and Casoli, T and Meirelles, JL and Ruf, WP and Fabbietti, P and Holzmann, K and Weishaupt, JH and Ludolph, AC and Conti, F and Danzer, KM}, title = {Mitochondrial genome study in blood of maternally inherited ALS cases.}, journal = {Human genomics}, volume = {17}, number = {1}, pages = {70}, pmid = {37507754}, issn = {1479-7364}, mesh = {Humans ; *Genome, Mitochondrial/genetics ; Maternal Inheritance/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; DNA, Mitochondrial/genetics ; Mitochondria/genetics ; Mutation ; }, abstract = {BACKGROUND: ALS is a heterogeneous disease in which different factors such as mitochondrial phenotypes act in combination with a genetic predisposition. This study addresses the question of whether homoplasmic (total mitochondrial genome of a sample is affected) and/or heteroplasmic mutations (wildtype and mutant mitochondrial DNA molecules coexist) might play a role in familial ALS. Blood was drawn from familial ALS patients with a possible maternal pattern of inheritance according to their pedigrees, which was compared to blood of ALS patients without maternal association as well as age-matched controls. In two cohorts, we analyzed the mitochondrial genome from whole blood or isolated white blood cells and platelets using a resequencing microarray (Affymetrix MitoChip v2.0) that is able to detect homoplasmic and heteroplasmic mitochondrial DNA mutations and allows the assessment of low-level heteroplasmy.

RESULTS: We identified an increase in homoplasmic ND5 mutations, a subunit of respiratory chain complex I, in whole blood of ALS patients that allowed maternal inheritance. This effect was more pronounced in patients with bulbar onset. Heteroplasmic mutations were significantly increased in different mitochondrial genes in platelets of patients with possible maternal inheritance. No increase of low-level heteroplasmy was found in maternal ALS patients.

CONCLUSION: Our results indicate a contribution of homoplasmic ND5 mutations to maternally associated ALS with bulbar onset. Therefore, it might be conceivable that specific maternally transmitted rather than randomly acquired mitochondrial DNA mutations might contribute to the disease process. This stands in contrast with observations from Alzheimer's and Parkinson's diseases showing an age-dependent accumulation of unspecific mutations in mitochondrial DNA.}, } @article {pmid37507019, year = {2023}, author = {Clark, NE and Katolik, A and Gallant, P and Welch, A and Murphy, E and Buerer, L and Schorl, C and Naik, N and Naik, MT and Holloway, SP and Cano, K and Weintraub, ST and Howard, KM and Hart, PJ and Jogl, G and Damha, MJ and Fairbrother, WG}, title = {Activation of human RNA lariat debranching enzyme Dbr1 by binding protein TTDN1 occurs though an intrinsically disordered C-terminal domain.}, journal = {The Journal of biological chemistry}, volume = {299}, number = {9}, pages = {105100}, pmid = {37507019}, issn = {1083-351X}, support = {R01 GM094157/GM/NIGMS NIH HHS/United States ; R01 GM095612/GM/NIGMS NIH HHS/United States ; R01 GM105681/GM/NIGMS NIH HHS/United States ; R01 GM127472/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Introns ; *RNA Nucleotidyltransferases/genetics/metabolism ; RNA Splicing ; *Adaptor Proteins, Signal Transducing/metabolism ; Enzyme Activation/genetics ; Protein Domains ; Protein Binding ; Intrinsically Disordered Proteins/genetics/metabolism ; Entamoeba histolytica/enzymology/genetics ; Metals, Heavy/metabolism ; }, abstract = {In eukaryotic cells, the introns are excised from pre-mRNA by the spliceosome. These introns typically have a lariat configuration due to the 2'-5' phosphodiester bond between an internal branched residue and the 5' terminus of the RNA. The only enzyme known to selectively hydrolyze the 2'-5' linkage of these lariats is the RNA lariat debranching enzyme Dbr1. In humans, Dbr1 is involved in processes such as class-switch recombination of immunoglobulin genes, and its dysfunction is implicated in viral encephalitis, HIV, ALS, and cancer. However, mechanistic details of precisely how Dbr1 affects these processes are missing. Here we show that human Dbr1 contains a disordered C-terminal domain through sequence analysis and nuclear magnetic resonance. This domain stabilizes Dbr1 in vitro by reducing aggregation but is dispensable for debranching activity. We establish that Dbr1 requires Fe[2+] for efficient catalysis and demonstrate that the noncatalytic protein Drn1 and the uncharacterized protein trichothiodystrophy nonphotosensitive 1 directly bind to Dbr1. We demonstrate addition of trichothiodystrophy nonphotosensitive 1 to in vitro debranching reactions increases the catalytic efficiency of human Dbr1 19-fold but has no effect on the activity of Dbr1 from the amoeba Entamoeba histolytica, which lacks a disordered C-terminal domain. Finally, we systematically examine how the identity of the branchpoint nucleotide affects debranching rates. These findings describe new aspects of Dbr1 function in humans and further clarify how Dbr1 contributes to human health and disease.}, } @article {pmid37505455, year = {2023}, author = {Dos Santos, MM and Ishida, K}, title = {We need to talk about Candida tropicalis: Virulence factors and survival mechanisms.}, journal = {Medical mycology}, volume = {61}, number = {8}, pages = {}, doi = {10.1093/mmy/myad075}, pmid = {37505455}, issn = {1460-2709}, support = {2022/08516-5//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 001 - 88887.663125/2022-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 306041/2022-7//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, mesh = {Animals ; *Candida tropicalis/genetics ; *Antifungal Agents/therapeutic use ; Virulence Factors/genetics/metabolism ; Candida ; Candida albicans ; Drug Resistance, Fungal ; Microbial Sensitivity Tests/veterinary ; }, abstract = {Candida tropicalis is a notable species of the Candida genus representing an impressive epidemiology in tropical regions, especially in South America and Asia, where India already presents the species as the first in Candida epidemiology. Candida tropicalis has also shown a worrying antifungal resistance profile in recent years. It is essential to highlight that each pathogenic species of the Candida genus has a particular biology; however, Candida virulence factors are almost entirely based on studies with C. albicans. The intrinsic resistance of C. krusei to some azoles, the intrinsic osmotolerance of C. tropicalis, and the multidrug resistance of C. auris are just a few examples of how the biology of each Candida species is unique. Despite being a phylogenetically close species, C. tropicalis can support 15% NaCl, antagonistically metabolize and signal N-acetylglucosamine, encode 16 reported ALS genes, and other specificities discussed here compared to C. albicans. It is essential to clarify the details of the C. tropicalis infectious process, including identifying the participating secreted enzyme(s), the factors responsible for tissue damage, and the mechanisms underlying the morphogenesis and tolerance signaling pathways. In this review, we thoroughly assembled what is known about the main virulence factors of C. tropicalis, highlighting the missing pieces to stimulate further research with C. tropicalis and other non-Candida albicans species.}, } @article {pmid37503230, year = {2023}, author = {Broce, IJ and Sirkis, DW and Nillo, RM and Bonham, LW and Lee, SE and Miller, B and Castruita, P and Sturm, VE and Sugrue, LS and Desikan, RS and Yokoyama, JS}, title = {C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37503230}, issn = {2692-8205}, support = {R01 AG062588/AG/NIA NIH HHS/United States ; R01 AG052496/AG/NIA NIH HHS/United States ; T32 AG058529/AG/NIA NIH HHS/United States ; R25 NS117367/NS/NINDS NIH HHS/United States ; R01 AG058233/AG/NIA NIH HHS/United States ; K01 AG070376/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: A hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis.

METHODS: We leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, cerebellum) with average gene expression values for 15,633 protein-coding genes, including 50 genes known to be associated with ALS, FTD, or ALS-FTD. We then evaluated whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n=19). Lastly, we explored whether genes with significant C9orf72 radiogenomic correlations (i.e., 'C9orf72 gene network') were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways.

RESULTS: A total of 1,748 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 gene network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic motor neurons in the spinal cord, and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with multiple neurotransmitter systems, protein ubiquitination, autophagy, and MAPK signaling, among others.

CONCLUSIONS: Considered together, we identified a network of C9orf72-associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.}, } @article {pmid37503131, year = {2023}, author = {Hobson, R and Levy, SHS and Flaherty, D and Xiao, H and Ciener, B and Reddy, H and Singal, C and Teich, AF and Shneider, NA and Bradshaw, EM and Elyaman, W}, title = {Clonal CD8 T cells in the leptomeninges are locally controlled and influence microglia in human neurodegeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.07.13.548931}, pmid = {37503131}, issn = {2692-8205}, support = {R01 AG067581/AG/NIA NIH HHS/United States ; }, abstract = {Recent murine studies have highlighted a crucial role for the meninges in surveilling the central nervous system (CNS) and influencing CNS inflammation. However, how meningeal immunity is altered in human neurodegeneration and its potential effects on neuroinflammation is understudied. In the present study, we performed single-cell analysis of the transcriptomes and T cell receptor repertoire of 72,576 immune cells from 36 postmortem human brain and leptomeninges tissues from donors with neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. We identified the meninges as an important site of antigen presentation and CD8 T cell activation and clonal expansion and found that T cell activation in the meninges is a requirement for infiltration into the CNS. We further found that natural killer cells have the potential to negatively regulate T cell activation locally in the meninges through direct killing and are one of many regulatory mechanisms that work to control excessive neuroinflammation.}, } @article {pmid37502965, year = {2023}, author = {Kodavati, M and Wang, H and Guo, W and Mitra, J and Hegde, PM and Provasek, V and Maloji Rao, VH and Vedula, I and Zhang, A and Mitra, S and Tomkinson, AE and Hamilton, DJ and Bosch, LVD and Hegde, ML}, title = {FUS Unveiled in Mitochondrial DNA Repair and Targeted Ligase-1 Expression Rescues Repair-Defects in FUS-Linked Neurodegeneration.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37502965}, issn = {2693-5015}, support = {R01 NS094535/NS/NINDS NIH HHS/United States ; R01 ES012512/ES/NIEHS NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {This study establishes the physiological role of Fused in Sarcoma (FUS) in mitochondrial DNA (mtDNA) repair and highlights its implications to the pathogenesis of FUS-associated neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS). Endogenous FUS interacts with and recruits mtDNA Ligase IIIα (mtLig3) to DNA damage sites within mitochondria, a relationship essential for maintaining mtDNA repair and integrity in healthy cells. Using ALS patient-derived FUS mutant cell lines, a transgenic mouse model, and human autopsy samples, we discovered that compromised FUS functionality hinders mtLig3's repair role, resulting in increased mtDNA damage and mutations. These alterations cause various manifestations of mitochondrial dysfunction, particularly under stress conditions relevant to disease pathology. Importantly, rectifying FUS mutations in patient-derived induced pluripotent cells (iPSCs) preserves mtDNA integrity. Similarly, targeted introduction of human DNA Ligase 1 restores repair mechanisms and mitochondrial activity in FUS mutant cells, suggesting a potential therapeutic approach. Our findings unveil FUS's critical role in mitochondrial health and mtDNA repair, offering valuable insights into the mechanisms underlying mitochondrial dysfunction in FUS-associated neurodegeneration.}, } @article {pmid37502200, year = {2023}, author = {Syam, V and Safal, S and Bhutia, O and Singh, AK and Giri, D and Bhandari, SS and Panigrahi, R}, title = {A non-invasive method for prediction of neurodegenerative diseases using gait signal features.}, journal = {Procedia computer science}, volume = {218}, number = {}, pages = {1529-1541}, pmid = {37502200}, issn = {1877-0509}, support = {D43 TW009120/TW/FIC NIH HHS/United States ; }, abstract = {The steady degeneration of neurons is the hallmark of neurodegenerative illnesses, which are, by definition, incurable. Corticobasal Syndrome (CS), Huntington's Disease (HD), Dementia, Amyotrophic Lateral Sclerosis (ALS), Progressive supranuclear palsy (PSP) and Parkinson's Disease (PD) are some of the common neurodegenerative diseases which has impacted millions of people, predominantly among the older population. Various computational techniques, including but not limited to machine learning, are emerging as discrimination and detection of neuro-related diseases. This research proposed a machine learning-based framework to correctly detect PD, HD, and ALS from the gait signals of subjects both in binary and multi-class detection environment. The detection approach proposed here combines the classification power of Naïve Bayes and Logistic Regression jointly in a modern UltraBoost ensemble framework. The proposed method is unique in its ability to detect neuro diseases with a small number of gait features. The proposed approach ascertains most essential gait features through three state-of-the-art feature selection schemes, infinite feature selection, infinite latent feature selection and Sigmis feature selection. It has been observed that the gait signal features of the subjects are identified through Infinite Feature Selection manifests better detection results than the features obtained through Infinite Latent Feature and Sigmis feature selection while detecting Parkinson's and Huntington's Disease in a multi-class environment. So far as the binary detection environment is concern, the Amyotrophic lateral sclerosis is detected with 99.1% detection accuracy using 18 Sigmis gait features, with 99.1% sensitivity and 98.9% specificity, respectively. Similarly, Huntington's disease was detected with 94.2% detection accuracy, 94.2% sensitivity, and 94.5% specificity using 5 Sigmis gait features. Finally, Parkinson's disease was detected with 98.4% sensitivity, specificity, and detection accuracy.}, } @article {pmid37501540, year = {2023}, author = {Ma, Q and Xin, J and Peng, Q and Li, N and Sun, S and Hou, H and Ma, G and Wang, N and Zhang, L and Tam, KY and Dussmann, H and Prehn, JH and Wang, H and Ying, Z}, title = {UBQLN2 and HSP70 participate in Parkin-mediated mitophagy by facilitating outer mitochondrial membrane rupture.}, journal = {EMBO reports}, volume = {24}, number = {9}, pages = {e55859}, pmid = {37501540}, issn = {1469-3178}, mesh = {Humans ; Mitochondrial Membranes/metabolism ; *Amyotrophic Lateral Sclerosis/genetics ; Mitophagy ; *Frontotemporal Dementia/genetics ; Adaptor Proteins, Signal Transducing/genetics ; Autophagy-Related Proteins/genetics ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitin/metabolism ; *Neurodegenerative Diseases/metabolism ; Transcription Factors/metabolism ; Ubiquitin-Protein Ligases/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two aging-related neurodegenerative diseases that share common key features, including aggregation of pathogenic proteins, dysfunction of mitochondria, and impairment of autophagy. Mutations in ubiquilin 2 (UBQLN2), a shuttle protein in the ubiquitin-proteasome system (UPS), can cause ALS/FTD, but the mechanism underlying UBQLN2-mediated pathogenesis is still uncertain. Recent studies indicate that mitophagy, a selective form of autophagy which is crucial for mitochondrial quality control, is tightly associated with neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and ALS. In this study, we show that after Parkin-dependent ubiquitination of damaged mitochondria, UBQLN2 is recruited to poly-ubiquitinated mitochondria through the UBA domain. UBQLN2 cooperates with the chaperone HSP70 to promote UPS-driven degradation of outer mitochondrial membrane (OMM) proteins. The resulting rupture of the OMM triggers the autophagosomal recognition of the inner mitochondrial membrane receptor PHB2. UBQLN2 is required for Parkin-mediated mitophagy and neuronal survival upon mitochondrial damage, and the ALS/FTD pathogenic mutations in UBQLN2 impair mitophagy in primary cultured neurons. Taken together, our findings link dysfunctional mitophagy to UBQLN2-mediated neurodegeneration.}, } @article {pmid37500993, year = {2023}, author = {Ludolph, A and Dupuis, L and Kasarskis, E and Steyn, F and Ngo, S and McDermott, C}, title = {Nutritional and metabolic factors in amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {9}, pages = {511-524}, pmid = {37500993}, issn = {1759-4766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases ; Energy Metabolism ; Prognosis ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease that is classically thought to impact the motor system. Over the past 20 years, research has started to consider the contribution of non-motor symptoms and features of the disease, and how they might affect ALS prognosis. Of the non-motor features of the disease, nutritional status (for example, malnutrition) and metabolic balance (for example, weight loss and hypermetabolism) have been consistently shown to contribute to more rapid disease progression and/or earlier death. Several complex cellular changes observed in ALS, including mitochondrial dysfunction, are also starting to be shown to contribute to bioenergetic failure. The resulting energy depletion in high energy demanding neurons makes them sensitive to apoptosis. Given that nutritional and metabolic stressors at the whole-body and cellular level can impact the capacity to maintain optimal function, these factors present avenues through which we can identify novel targets for treatment in ALS. Several clinical trials are now underway evaluating the effectiveness of modifying energy balance in ALS, making this article timely in reviewing the evidence base for metabolic and nutritional interventions.}, } @article {pmid37499984, year = {2023}, author = {Azoulay, L and St-Jean, A and Platt, RW}, title = {Response to Magnaterra et al's unveiling hydrochlorothiazide: Skin cancer risk and hidden interactions.}, journal = {Journal of the American Academy of Dermatology}, volume = {89}, number = {5}, pages = {e247-e248}, doi = {10.1016/j.jaad.2023.07.1012}, pmid = {37499984}, issn = {1097-6787}, } @article {pmid37499137, year = {2023}, author = {Illner, V and Tykalova, T and Skrabal, D and Klempir, J and Rusz, J}, title = {Automated Vowel Articulation Analysis in Connected Speech Among Progressive Neurological Diseases, Dysarthria Types, and Dysarthria Severities.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {66}, number = {8}, pages = {2600-2621}, doi = {10.1044/2023_JSLHR-22-00526}, pmid = {37499137}, issn = {1558-9102}, mesh = {Humans ; Dysarthria/etiology ; Speech/physiology ; *Cerebellar Ataxia ; *Parkinson Disease/complications ; Articulation Disorders ; Atrophy ; Speech Acoustics ; Speech Intelligibility ; }, abstract = {PURPOSE: Although articulatory impairment represents distinct speech characteristics in most neurological diseases affecting movement, methods allowing automated assessments of articulation deficits from the connected speech are scarce. This study aimed to design a fully automated method for analyzing dysarthria-related vowel articulation impairment and estimate its sensitivity in a broad range of neurological diseases and various types and severities of dysarthria.

METHOD: Unconstrained monologue and reading passages were acquired from 459 speakers, including 306 healthy controls and 153 neurological patients. The algorithm utilized a formant tracker in combination with a phoneme recognizer and subsequent signal processing analysis.

RESULTS: Articulatory undershoot of vowels was presented in a broad spectrum of progressive neurodegenerative diseases, including Parkinson's disease, progressive supranuclear palsy, multiple-system atrophy, Huntington's disease, essential tremor, cerebellar ataxia, multiple sclerosis, and amyotrophic lateral sclerosis, as well as in related dysarthria subtypes including hypokinetic, hyperkinetic, ataxic, spastic, flaccid, and their mixed variants. Formant ratios showed a higher sensitivity to vowel deficits than vowel space area. First formants of corner vowels were significantly lower for multiple-system atrophy than cerebellar ataxia. Second formants of vowels /a/ and /i/ were lower in ataxic compared to spastic dysarthria. Discriminant analysis showed a classification score of up to 41.0% for disease type, 39.3% for dysarthria type, and 49.2% for dysarthria severity. Algorithm accuracy reached an F-score of 0.77.

CONCLUSIONS: Distinctive vowel articulation alterations reflect underlying pathophysiology in neurological diseases. Objective acoustic analysis of vowel articulation has the potential to provide a universal method to screen motor speech disorders.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.23681529.}, } @article {pmid37498094, year = {2023}, author = {Christoforidou, E and Simoes, FA and Gordon, D and Talbot, K and Hafezparast, M}, title = {Aberrant dynein function promotes TDP-43 aggregation and upregulation of p62 in male mice harboring transgenic human TDP-43.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2023.2239276}, pmid = {37498094}, issn = {2167-9223}, abstract = {OBJECTIVE: Most TDP-43 mouse models of ALS do not display cytoplasmic mislocalisation or protein aggregation of TDP-43 in spinal motor neurons in vivo. Thus, we investigated whether a combination of defective dynein with a TDP-43 mutation could trigger TDP-43 pathology.

METHODS: Using immunohistochemical methods we examined the intracellular motor neuron pathology of the offspring of TDP-43[WT] and TDP-43[M337V] transgenic mice bred to heterozygous Loa mice, which carry an autosomal dominant mutation in dynein cytoplasmic 1 heavy chain 1 (Dync1h1).

RESULTS: These mice did not exhibit TDP-43 mislocalisation in spinal motor neurons, but the expression of mutant dynein in combination with wildtype human TDP-43 resulted in p62 upregulation and TDP-43 aggregation, thus partially recapitulating the human disease.

CONCLUSIONS: These findings provide new insights into the possible relationship between dynein and TDP-43 and could prove useful in future studies looking to elucidate the mechanism behind the TDP-43 pathology observed in ALS.}, } @article {pmid37497262, year = {2023}, author = {Ajjarapu, A and Feely, SME and Shy, ME and Trout, C and Zuchner, S and Moore, SA and Mathews, KD}, title = {Thirty-Year Follow-Up of Early Onset Amyotrophic Lateral Sclerosis with a Pathogenic Variant in SPTLC1.}, journal = {Case reports in neurology}, volume = {15}, number = {1}, pages = {146-152}, pmid = {37497262}, issn = {1662-680X}, support = {P50 NS053672/NS/NINDS NIH HHS/United States ; U54 NS065712/NS/NINDS NIH HHS/United States ; }, abstract = {Dominant mutations in serine palmitoyltransferase long chain base subunit 1 (SPTLC1), a known cause of hereditary sensory autonomic neuropathy type 1 (HSAN1), are a recently identified cause of juvenile amyotrophic lateral sclerosis (JALS) with slow progression. We present a case of SPTLC1-associated JALS followed for 30 years. She was initially evaluated at age 22 years for upper extremity weakness. She experienced gradual decline in muscle strength with development of weakness and hyperreflexia in lower extremities and diffuse fasciculations in the upper extremities at 26 years. She lost independent ambulation at age 45 years. Pulmonary function declined from a forced vital capacity of 94% predicted at 27 years to 49% predicted at 47 years, and she was hospitalized twice for respiratory failure. To our knowledge, this is the longest documented follow-up period of JALS caused by a de novo pathogenic variant in SPTLC1.}, } @article {pmid37496277, year = {2023}, author = {Melka, D and Demisse, H and Assefa, H and Zenebe, Y and A Ayele, B and Awraris, M and Gelan, Y and Kifelew, S and Fedlu, M and Tsehayneh, F and Zebenigus, M and Alemayehu, S and Tesfaye, H and Gulelat, H and Guta, T and Tafesse, A and Bekele, N and Saez, M and Veldink, JH and Al-Chalabi, A and Povedano, M and Al Khleifat, A}, title = {Epidemiological and clinical profile of amyotrophic lateral sclerosis in Ethiopia: a 5-year multicenter retrospective study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2023.2238016}, pmid = {37496277}, issn = {2167-9223}, support = {MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in progressive weakness of skeletal muscles including respiratory muscles. Epidemiological and clinical aspects of ALS are derived from a few world regions with very little representation of low- and middle-income countries. We therefore set out to determine the epidemiological and clinical phenotype of individuals with ALS in Ethiopia. Methods: Multicenter retrospective analysis was conducted using clinical records from ALS patients seen in Ethiopia at Tikur Anbessa Specialized Hospital and Yehuleshet specialty clinic between January 2016 and August 2021. The data collected included clinical characteristics, disease-related symptoms, a revised ALS functional rating scale, and medications. Results: Patients in Ethiopia had a younger age of onset with a mean age of disease onset of 51.9 years. 2.9% of patients had juvenile ALS, and the male-to-female ratio was almost 2:1. 4.9% had a positive family history of the disease. 68% of patients had spinal region involvement at onset, while 32% had bulbar region involvement at onset. Riluzole was used by 31% of ALS patients. 20.6% of patients had some respiratory symptoms, but none received a standard respiratory function assessment. 33.3% of patients were wheelchair-bound. Conclusion: In this retrospective study spanning 5 years, we examined the clinical phenotype of ALS in Ethiopian patients. Our findings suggest that most patients had clinically definite ALS with spinal region involvement. Further research, including genetic and epigenetic information, is necessary to understand the early onset of the disease in Ethiopia.}, } @article {pmid37496071, year = {2023}, author = {Onda-Ohto, A and Hasegawa-Ogawa, M and Matsuno, H and Shiraishi, T and Bono, K and Hiraki, H and Kanegae, Y and Iguchi, Y and Okano, HJ}, title = {Specific vulnerability of iPSC-derived motor neurons with TDP-43 gene mutation to oxidative stress.}, journal = {Molecular brain}, volume = {16}, number = {1}, pages = {62}, pmid = {37496071}, issn = {1756-6606}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; DNA-Binding Proteins/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/pathology ; Mutation/genetics ; Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disease that affects motor neurons and has a poor prognosis. We focused on TAR DNA-binding protein 43 kDa (TDP-43), which is a common component of neuronal inclusions in many ALS patients. To analyze the contribution of TDP-43 mutations to ALS in human cells, we first introduced TDP-43 mutations into healthy human iPSCs using CRISPR/Cas9 gene editing technology, induced the differentiation of these cells into motor and sensory neurons, and analyzed factors that are assumed to be altered in or associated with ALS (cell morphology, TDP-43 localization and aggregate formation, cell death, TDP-43 splicing function, etc.). We aimed to clarify the pathological alterations caused solely by TDP-43 mutation, i.e., the changes in human iPSC-derived neurons with TDP-43 mutation compared with those with the same genetic background except TDP-43 mutation. Oxidative stress induced by hydrogen peroxide administration caused the death of TDP-43 mutant-expressing motor neurons but not in sensory neurons, indicating the specific vulnerability of human iPSC-derived motor neurons with TDP-43 mutation to oxidative stress. In our model, we observed aggregate formation in a small fraction of TDP-43 mutant-expressing motor neurons, suggesting that aggregate formation seems to be related to ALS pathology but not the direct cause of cell death. This study provides basic knowledge for elucidating the pathogenesis of ALS and developing treatments for the disease.}, } @article {pmid37495641, year = {2023}, author = {Caballero-Eraso, C and Carrera-Cueva, C and de Benito Zorrero, E and Lopez-Ramirez, C and Marin-Romero, S and Asensio-Cruz, MI and Barrot-Cortes, E and Jara-Palomares, L}, title = {Prospective study to evaluate quality of life in amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {12074}, pmid = {37495641}, issn = {2045-2322}, mesh = {Humans ; Female ; Middle Aged ; Aged ; Male ; *Quality of Life ; Prospective Studies ; *Amyotrophic Lateral Sclerosis ; Surveys and Questionnaires ; Patients ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative rare disease characterized by symptoms and signs in the upper and lower motor neurons, leading to progressive neuro-degeneration and muscle atrophy. Our objective was to analyse the quality of life (QoL) in patients with ALS and compare with general population and with patients with cancer. Prospective study from consecutive ALS patients in one center. In order to assess quality of life, during the first visit three questionnaires were administered: Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), Short Form-36 (SF-36) and EuroQoL 5D (EQ-5D). We compared SF-36 of ALS patients with a reference population (n = 9151), and we compared the EQ-5D index score of ALS patients versus patients with cancer in the same area and in the same period (2015-2018). Between June 2015 and September 2017, 23 were included. The mean age was 65.1 ± 12.6 years and 56.5% were women. Compared with the general population, patients with ALS showed lowest QoL (p < 0.05) in all the dimensions, with a very important impairment in physical function (median: 0; p25-75: 0-10) and physical role (median: 0; p25-75: 0-6.25). In EQ-5D questionnaire, patients with ALS presented an EQ-5D index score of 0.21 ± 0.39 (mean ± standard deviation) with a visual analog scale (VAS) score of 0.32 ± 0.24. Compared with an oncological population, patients with ALS had a worse EQ-5D index score both clinically and statistically (0.21 ± 0.39 vs. 0.77 ± 0.27; p < 0.05). We demonstrate a poorer quality of life in patients with ALS is poor, and clinically and statistically worse than in patients with cancer or general population. New studies need to evaluate the impact of strategies in this population to improve the quality of life.}, } @article {pmid37495165, year = {2023}, author = {Sammeta, SS and Banarase, TA and Rahangdale, SR and Wankhede, NL and Aglawe, MM and Taksande, BG and Mangrulkar, SV and Upaganlawar, AB and Koppula, S and Kopalli, SR and Umekar, MJ and Kale, MB}, title = {Molecular understanding of ER-MT communication dysfunction during neurodegeneration.}, journal = {Mitochondrion}, volume = {72}, number = {}, pages = {59-71}, doi = {10.1016/j.mito.2023.07.005}, pmid = {37495165}, issn = {1872-8278}, mesh = {Humans ; Endoplasmic Reticulum/metabolism ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; *Neurodegenerative Diseases/metabolism ; *Parkinson Disease/pathology ; }, abstract = {Biological researchers are seeing organelles in a new light. These cellular entities have been believed to be singular and distinctive structures that performed specialized purposes for a very long time. But in recentpast years, scientists have learned that organelles become dynamic and make physical contact. Additionally, Biological processes are regulated by organelles interactions and its alteration play an important role in cell malfunctioning and several pathologies, including neurodegenerative diseases. Mitochondrial-ER contact sites (MERCS) have received considerable attention in the domain of cell homeostasis and dysfunction, specifically in the area of neurodegeneration. This is largely due to the significant role of this subcellular compartment in a diverse array of vital cellular functions, including Ca[2+] homeostasis, transport, bioenergetics and turnover, mitochondrial dynamics, apoptotic signaling, ER stress, and inflammation. A significant number of disease-associated proteins were found to physically interact with the ER-Mitochondria (ER-MT) interface, causing structural and/or functional alterations in this compartment. In this review, we summarize current knowledge about the structure and functions of the ER-MT contact sites, as well as the possible repercussions of their alteration in notable neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and fronto-temporal dementia. The constraints and complexities in defining the nature and origin of the highlighted defects in ER-MT communication, as well as their concise contribution to the neurodegenerative process, are illustrated in particular. The possibility of using MERCS as a potential drug target to prevent neuronal damage and ultimately neurodegeneration is the topic of our final discussion.}, } @article {pmid37494887, year = {2023}, author = {Bouvier, L and Green, JR and Tapia, CB and Tilton-Bolowsky, V and Maffei, MF and Fless, Z and Seaver, K and Huynh, A and Gutz, SE and Martino, R and Abrahao, A and Berry, J and Zinman, L and Yunusova, Y}, title = {Amyotrophic Lateral Sclerosis-Bulbar Dysfunction Index-Remote: Test-Retest and Interrater Reliability of Candidate Items.}, journal = {American journal of speech-language pathology}, volume = {32}, number = {4S}, pages = {1884-1900}, pmid = {37494887}, issn = {1558-9110}, support = {R01 DC017291/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Reproducibility of Results ; Neurologic Examination ; Deglutition ; Severity of Illness Index ; }, abstract = {PURPOSE: The primary aim of this study was to establish the reliability of candidate items as a step in the development of the Amyotrophic Lateral Sclerosis-Bulbar Dysfunction Index-Remote (ALS-BDI-Remote), a novel tool being developed for the detection and monitoring of bulbar signs and symptoms in remote settings.

METHOD: The set of candidate items included 40 items covering three domains: cranial nerve examination, auditory-perceptual evaluation, and functional assessment. Forty-eight participants diagnosed with ALS and exhibiting a range of bulbar disease severity were included. Data collection for each participant took place on Zoom over three sessions. During Session 1, the participants were instructed to adjust their Zoom settings and to optimize their recording environment (e.g., lighting, background noise). Their cognition and eating were screened to determine their ability to follow instructions and their eligibility to perform the swallowing and chewing tasks. During Session 2, two speech-language pathologists (SLPs) administered the tool consecutively to determine the items' interrater reliability. During Session 3, one of the SLPs readministered the tool within 2 weeks of Session 1 to assess test-retest reliability. The reliability of each item was estimated using weighted kappa and the percentage of agreement. To be considered reliable, the items had to reach a threshold of 0.5 weighted kappa or 80% percentage agreement (if skewed distribution of the scores) for both interrater and test-retest reliability.

RESULTS: In total, 33 of the 40 candidate items reached the reliability cutoff for both reliability analyses. All assessment domains included reliable items. Items requiring very good visualization of structures or movements were generally less reliable.

CONCLUSIONS: This study resulted in the selection of reliable items to be included in the next version of the ALS-BDI-Remote, which will undergo psychometric evaluation (reliability, validity, and responsiveness analyses). Additionally, the results contributed to our understanding of the remote administration of SLP assessments for telehealth applications.}, } @article {pmid37494873, year = {2023}, author = {Ramya, L and Helina Hilda, S}, title = {Structural dynamics of moonlighting intrinsically disordered proteins - A black box in multiple sclerosis.}, journal = {Journal of molecular graphics & modelling}, volume = {124}, number = {}, pages = {108572}, doi = {10.1016/j.jmgm.2023.108572}, pmid = {37494873}, issn = {1873-4243}, mesh = {Humans ; *Multiple Sclerosis ; *Intrinsically Disordered Proteins ; Myelin Proteins ; Membrane Proteins ; }, abstract = {Multiple Sclerosis (MS) is a demyelinating disease of the central nervous system that disturbs the flow of brain signals to other parts of the body. The actual cause of the disease is still not apparent. The intrinsically disordered proteins (IDP) play a crucial role in neurodegenerative diseases like Alzheimer's, Lewy bodies, Parkinson's, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, etc. In MS, it was known that the immune system attacks the proteins like Myelin Basic Protein (MBP), Myelin-associated Oligodendrocyte Basic protein (MOBP), Myelin-Associated Protein (MAG), and Myelin Proteolipid Protein (PLP) and this leads to demyelination causing MS. Here the proteins MBP and MOBP are both moonlighting intrinsically disordered proteins and exist between the myelin sheath, unlike MAG which is a transmembrane protein. The main focus of the article was to examine the significant role of proteins intrinsically disordered regions (IDR) in maintaining their function. Molecular dynamics simulation studies were performed to study the conformational dynamics of these protein IDRs both in water and near the myelin sheath. The results suggest that the IDR dominates the structural dynamics of these proteins and IDR in both proteins was responsible for their interaction with the myelin sheath. Interestingly, it was noted that the known epitopes MBP83-96 and MOBP65-87 in the IDR have no interaction with the myelin sheath. Thus when the protein remains intrinsically disordered it maintains the proper function and myelin integrity and if it adopts folds the region was identified as an epitope by the immune system leading to demyelination causing MS.}, } @article {pmid37494786, year = {2023}, author = {Jin, S and Zhang, L and Wang, L}, title = {Kaempferol, a potential neuroprotective agent in neurodegenerative diseases: From chemistry to medicine.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {165}, number = {}, pages = {115215}, doi = {10.1016/j.biopha.2023.115215}, pmid = {37494786}, issn = {1950-6007}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/pathology ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; *Amyotrophic Lateral Sclerosis/drug therapy ; Kaempferols/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy ; *Parkinson Disease/drug therapy ; *Huntington Disease/drug therapy ; }, abstract = {Neurodegenerative diseases (NDDs) encompass a range of conditions that involve progressive deterioration and dysfunction of the nervous system. Some of the common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Although significant progress has been made in understanding the pathological mechanisms of NDDs in recent years, the development of targeted and effective drugs for their treatment remains challenging. Kaempferol is a flavonoid whose derivatives include kaempferol-O-rhamnoside, 3-O-β-rutinoside/6-hydroxykaempferol 3,6-di-O-β-d-glucoside, and kaempferide. Emerging studies have suggested that kaempferol and its derivatives possess neuroprotective properties and may have potential therapeutic benefits in NDDs. Here, we aimed to provide a theoretical basis for the use of kaempferol and its derivatives in the clinical treatment of NDDs. We systematically reviewed the literature in the PubMed, Web of Science, and Science Direct databases until June 2022 using the search terms "kaempferol," "kaempferol derivatives," "NDDs," "pharmacokinetics," and "biosynthesis" according to the reporting items for systematic review (PRISMA) standard. Based on combined results of in vivo and in vitro studies, we summarize the basic mechanisms and targets of kaempferol and its derivatives in the management of AD, PD, HD, and ALS. Kaempferol and its derivatives exert a neuroprotective role mainly by preventing the deposition of amyloid fibrils (such as Aβ, tau, and α-synuclein), inhibiting microglia activation, reducing the release of inflammatory factors, restoring the mitochondrial membrane to prevent oxidative stress, protecting the blood-brain barrier, and inhibiting specific enzyme activities (such as cholinesterase). Kaempferol and its derivatives are promising natural neuroprotective agents. By determining their pharmacological mechanism, kaempferol and its derivatives may be new candidate drugs for the treatment of NDDs.}, } @article {pmid37493896, year = {2023}, author = {Lo Piccolo, L and Umegawachi, T and Yeewa, R and Potikanond, S and Nimlamool, W and Prachayasittikul, V and Gotoh, Y and Yoshida, H and Yamaguchi, M and Jantrapirom, S}, title = {A Novel Drosophila-based Drug Repurposing Platform Identified Fingolimod As a Potential Therapeutic for TDP-43 Proteinopathy.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {20}, number = {5}, pages = {1330-1346}, pmid = {37493896}, issn = {1878-7479}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics ; DNA-Binding Proteins/genetics ; Drosophila/metabolism ; Drug Repositioning ; Fingolimod Hydrochloride/therapeutic use ; *TDP-43 Proteinopathies/pathology ; }, abstract = {Pathogenic changes to TAR DNA-binding protein 43 (TDP-43) leading to alteration of its homeostasis are a common feature shared by several progressive neurodegenerative diseases for which there is no effective therapy. Here, we developed Drosophila lines expressing either wild type TDP-43 (WT) or that carrying an Amyotrophic Lateral Sclerosis /Frontotemporal Lobar Degeneration-associating G384C mutation that recapitulate several aspects of the TDP-43 pathology. To identify potential therapeutics for TDP-43-related diseases, we implemented a drug repurposing strategy that involved three consecutive steps. Firstly, we evaluated the improvement of eclosion rate, followed by the assessment of locomotive functions at early and late developmental stages. Through this approach, we successfully identified fingolimod, as a promising candidate for modulating TDP-43 toxicity. Fingolimod exhibited several beneficial effects in both WT and mutant models of TDP-43 pathology, including post-transcriptional reduction of TDP-43 levels, rescue of pupal lethality, and improvement of locomotor dysfunctions. These findings provide compelling evidence for the therapeutic potential of fingolimod in addressing TDP-43 pathology, thereby strengthening the rationale for further investigation and consideration of clinical trials. Furthermore, our study demonstrates the utility of our Drosophila-based screening pipeline in identifying novel therapeutics for TDP-43-related diseases. These findings encourage further scale-up screening endeavors using this platform to discover additional compounds with therapeutic potential for TDP-43 pathology.}, } @article {pmid37493444, year = {2023}, author = {Gonzalez Deniselle, MC and Bettini, M and Garrido, RM and Meyer, M and Lara, A and Garay, LI and Casas, S and Fulgenzi, E and Nuñez, M and Rugiero, MF and De Nicola, AF and Gargiulo-Monachelli, G}, title = {Exposure to endogenous and exogenous sex hormones and reproductive history influence prognosis in women with ALS.}, journal = {Muscle & nerve}, volume = {68}, number = {4}, pages = {414-421}, doi = {10.1002/mus.27942}, pmid = {37493444}, issn = {1097-4598}, mesh = {Male ; Humans ; Female ; *Amyotrophic Lateral Sclerosis ; Reproductive History ; *Neurodegenerative Diseases/complications ; Gonadal Steroid Hormones ; Prognosis ; Risk Factors ; Steroids ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a higher incidence in men suggesting an influence of sex steroids. Our objective was to investigate past exposure to endogenous and synthetic steroids in female ALS patients and controls.

METHODS: We administered a questionnaire to 158 postmenopausal women (75 ALS patients and 83 controls). We calculated reproductive time span (RTS), lifetime endogenous estrogen (LEE) and progesterone exposures (LPE), oral contraceptive pill (OCP) use, and reproductive history.

RESULTS: ALS patients showed shorter LEE and LPE, a lower proportion of breast cancer, and 11% showed no history of pregnancies vs. 4% of controls. Odds ratios (ORs) showed that <17 y of LEE and a delayed menarche (>13 y) constitute risk factors for ALS [OR = 2.1 (95% confidence interval {CI}, 1.08-4.2); and OR = 2.4 (95% CI, 1.1-5.1) respectively]. According to Cox survival analysis, for each year the LEE increased over 17 y, it was independently associated with longer survival [hazard ratio (HR) = 0.37 (95% CI, 0.16-0.85)] after adjusting for smoking, age and site of onset. Multivariate regression analysis demonstrated that for each month using OCP for longer than 40 mo increased the risk of ALS [adjusted OR = 4.1 (95% CI, 1.2-13.8)].

DISCUSSION: Thus, longer exposure to endogenous female sex steroids increased survival and reduced ALS susceptibility. In contrast, longer exposure to synthetic sex steroids showed a negative impact by reducing the production of endogenous female sex steroids or due to crossover with other steroid receptors. Given the neuroprotective effects of sex steroids, we suggest that abnormalities of neuroendocrine components may alter motor function in women with ALS.}, } @article {pmid37493197, year = {2024}, author = {Sun, Y and Benatar, M and Mascías Cadavid, J and Ennist, D and Wicks, P and Staats, K and Beauchamp, M and Jhooty, S and Pattee, G and Brown, A and Bertorini, T and Barkhaus, P and Bromberg, M and Carter, G and Bedlack, R and Li, X}, title = {ALSUntangled #71: Nuedexta.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {1-2}, pages = {218-222}, doi = {10.1080/21678421.2023.2239292}, pmid = {37493197}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Dextromethorphan/therapeutic use ; Drug Combinations ; *Quinidine/therapeutic use ; }, abstract = {Nuedexta is a combination of dextromethorphan hydrobromide and quinidine sulfate and was approved by the Food and Drug Administration (FDA) in 2010 to treat pseudobulbar affect (PBA). There have since been anecdotal case reports of bulbar function improvements after Nuedexta treatment. Here, we review the off-label use of Nuedexta for improving bulbar function in people with ALS. Nuedexta has plausible mechanisms for protecting brain stem motor neurons via its effects on S1R and glutamate excitotoxicity. Recent clinical trials support that Nuedexta can improve bulbar function in PALS, with or without PBA. Nuedexta causes mild to moderate side effects. Based on this information, we support considering Nuedexta treatment for bulbar dysfunction in ALS patients with or without PBA.}, } @article {pmid37491680, year = {2023}, author = {Vasta, R and Callegaro, S and Sgambetterra, S and Cabras, S and Di Pede, F and De Mattei, F and Matteoni, E and Grassano, M and Bombaci, A and De Marco, G and Fuda, G and Marchese, G and Palumbo, F and Canosa, A and Mazzini, L and De Marchi, F and Moglia, C and Manera, U and Chiò, A and Calvo, A}, title = {Presymptomatic geographical distribution of ALS patients suggests the involvement of environmental factors in the disease pathogenesis.}, journal = {Journal of neurology}, volume = {270}, number = {11}, pages = {5475-5482}, pmid = {37491680}, issn = {1432-1459}, support = {grant RF-2016-02362405//Ministero della Salute/ ; FP7/2007-2013 under grant agreement 259867//Seventh Framework Programme/ ; PRIN//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; grant 2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; Brainteaser Project//European Union's Horizon 2020 research and innovation programme/ ; grant GA101017598//European Union's Horizon 2020 research and innovation programme/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/etiology ; Risk ; Incidence ; Cluster Analysis ; }, abstract = {BACKGROUND: Given that the pathogenetic process of ALS begins many years prior to its clinical onset, examining patients' residential histories may offer insights on the disease risk factors. Here, we analyzed the spatial distribution of a large ALS cohort in the 50 years preceding the disease onset.

METHODS: Data from the PARALS register were used. A spatial cluster analysis was performed at the time of disease onset and at 1-year intervals up to 50 years prior to that.

RESULTS: A total of 1124 patients were included. The analysis revealed a higher-incidence cluster in a large area (435,000 inhabitants) west of Turin. From 9 to 2 years before their onset, 105 cases were expected and 150 were observed, resulting in a relative risk of 1.49 (P = 0.04). We also found a surprising high number of patients pairs (51) and trios (3) who lived in the same dwelling while not being related. Noticeably, these occurrences were not observed in large dwellings as we would have expected. The probability of this occurring in smaller buildings only by chance was very low (P = 0.01 and P = 0.04 for pairs and trios, respectively).

CONCLUSIONS: We identified a higher-incidence ALS cluster in the years preceding the disease onset. The cluster area being densely populated, many exposures could have contributed to the high incidence ALS cluster, while we could not find a shared exposure among the dwellings where multiple patients had lived. However, these findings support that exogenous factors are likely involved in the ALS pathogenesis.}, } @article {pmid37491426, year = {2023}, author = {Yazar, V and Kühlwein, JK and Knehr, A and Grozdanov, V and Ekici, AB and Ludolph, AC and Danzer, KM}, title = {Impaired ATF3 signaling involves SNAP25 in SOD1 mutant ALS patients.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {12019}, pmid = {37491426}, issn = {2045-2322}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Leukocytes, Mononuclear/metabolism ; Mice, Transgenic ; Mutation ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {Epigenetic remodeling is emerging as a critical process for several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Genetics alone fails to explain the etiology of ALS, the investigation of the epigenome might therefore provide novel insights into the molecular mechanisms of the disease. In this study, we interrogated the epigenetic landscape in peripheral blood mononuclear cells (PBMCs) of familial ALS (fALS) patients with either chromosome 9 open reading frame 72 (C9orf72) or superoxide dismutase 1 (SOD1) mutation and aimed to identify key epigenetic footprints of the disease. To this end, we used an integrative approach that combines chromatin immunoprecipitation targeting H3K27me3 (ChIP-Seq) with the matching gene expression data to gain new insights into the likely impact of blood-specific chromatin remodeling on ALS-related molecular mechanisms. We demonstrated that one of the hub molecules that modulates changes in PBMC transcriptome in SOD1-mutant ALS patients is ATF3, which has been previously reported in an SOD1[G93A] mouse model. We also identified potential suppression of SNAP25, with impaired ATF3 signaling in SOD1-mutant ALS blood. Together, our study shed light on the mechanistic underpinnings of SOD1 mutations in ALS.}, } @article {pmid37491361, year = {2023}, author = {Aousji, O and Feldengut, S and Antonucci, S and Schön, M and Boeckers, TM and Matschke, J and Mawrin, C and Ludolph, AC and Del Tredici, K and Roselli, F and Braak, H}, title = {Patterns of synaptic loss in human amyotrophic lateral sclerosis spinal cord: a clinicopathological study.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {120}, pmid = {37491361}, issn = {2051-5960}, mesh = {Humans ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/pathology ; Retrospective Studies ; Motor Neurons/metabolism ; Spinal Cord/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is mainly characterized by the degeneration of corticospinal neurons and spinal α-motoneurons; vulnerable cells display prominent pTDP-43 inclusions. Evidence gathered from genetics, murine models, and iPSC-derived neurons point to the early involvement of synapses in the disease course and their crucial role in the pathogenic cascade. However, pathology studies, with specimens from large post-mortem cohorts, mapping the pattern of synaptic disturbances over clinical and neuropathological hallmarks of disease progression, are currently not available. Thus, the appearance and progression of synaptic degeneration in human ALS patients are currently not known, preventing a full validation of the murine and in vitro models. Here, we investigated the loss of synaptophysin-positive terminals in cervical, thoracic, and lumbar spinal cord samples from a retrospective cohort of n = 33 ALS patients and n = 8 healthy controls, and we correlated the loss of synapses against clinicodemographic features and neuropathological ALS stage. We found that, although dorsal and intermediate spinal cord laminae do not lose synapses, ALS patients displayed a substantial but variable loss of synapses in the ventral horn of lumbar and cervical spinal cord. The amount of synaptic loss was predicted by disease duration, by the clinical site of onset, and by the loss of α-motoneurons, although not by the fraction of pTDP-43-immunopositive α-motoneurons. Taken together, our findings validate the synaptic pathology observed in other models and suggest that pathogenic pathways unfolding in the spinal microenvironment are critical to the progressive disassembly of local synaptic connectivity.}, } @article {pmid37490673, year = {2023}, author = {Kovrazhkina, EA and Serdyuk, AV and Razinskaya, OD and Shurdumova, MH and Vyatkina, NV and Baranova, EA}, title = {[Myasthenic syndrome in a patient with end-stage amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {123}, number = {7}, pages = {102-107}, doi = {10.17116/jnevro2023123071102}, pmid = {37490673}, issn = {1997-7298}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/therapy ; *Myasthenia Gravis/complications/diagnosis ; *Lambert-Eaton Myasthenic Syndrome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and myasthenia gravis are diseases with similar clinical features but different prognosis and approach to treatment. It is possible as an extremely rare combination of these diseases, as well as myasthenia gravis with signs of ALS (MuSK-positive), as well as ALS, accompanied by myasthenic syndrome. Latter option is the most common. Myasthenic syndrome accompanying the ALS characterized by pathological muscle fatigue signs, symptoms variability during the day, partial sensitivity to neostigmine, M-wave decrements detection during electromyographyc study. We present a case of a patient with terminal ALS and myasthenic syndrome. The main pathogenesis theories of this condition and the differential diagnosis of ALS and myasthenia gravis are discussed.}, } @article {pmid37490576, year = {2023}, author = {Beyermann, A and Asp, M and Godskesen, T and Söderman, M}, title = {Nurses' challenges when supporting the family of patients with ALS in specialized palliative home care: A qualitative study.}, journal = {International journal of qualitative studies on health and well-being}, volume = {18}, number = {1}, pages = {2238984}, pmid = {37490576}, issn = {1748-2631}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Palliative Care/psychology ; *Home Care Services ; Family/psychology ; Qualitative Research ; *Nurses ; }, abstract = {PURPOSE: Being a family member to someone who has amyotrophic lateral sclerosis (ALS) is demanding and often requires sacrificing a lot. Family members can experience fatigue, anxiety, guilt and need support. The aim was to explore registered nurses' (RNs') experiences of providing support to the families of patients with ALS within specialized palliative home care (SPHC).

METHODS: A qualitative explorative design. Interviews were conducted with RNs (n = 11) from five SPHCs in Sweden and analysed using qualitative content analysis.

RESULTS: The results emerged in the following categories:"To support in an increasingly difficult everyday life", based on the sub-categories: "Creating a trusting relationship", "Balancing between the needs of patients and their families", and "Sharing knowledge about dying to the families";"To support in emotionally challenging situations", based on the sub-categories: "Harbouring family members' difficult feelings", "Providing support even though the situation is unpleasant" and "Being able to give support by receiving confirmation and support from others".

CONCLUSIONS: RNs working in SPHC have an important role in providing support in several ways to the families of patients with ALS, through facilitating their everyday life and giving emotional support when needed, based on the needs of both patients and the families.}, } @article {pmid37489926, year = {2023}, author = {Greensmith, L and Bryson, JB}, title = {The cholesterol depleting agent, (2-Hydroxypropyl)-ß-cyclodextrin, does not affect disease progression in SOD1[G93A] mice.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2023.2239867}, pmid = {37489926}, issn = {2167-9223}, abstract = {Objective: Previously, we demonstrated that Amyloid Precursor Protein (APP) contributes to pathology in the SOD1[G93A] mouse model of ALS and that genetic ablation of APP in SOD1[G93A] mice significantly improved multiple disease parameters, including muscle innervation and motor neuron survival. We also observed elevated levels of potentially neurotoxic Aß peptides that have been implicated in Alzheimer's Disease (AD) pathogenesis, within motor neurons and astrocytes in SOD1[G93A] mice. More recently, it has been shown that blocking Aß production improves outcome measures in SOD1[G93A] mice. The cyclodextrin, (2-Hydroxypropyl)-ß-cyclodextrin (HP-β-CD), has previously been shown to deplete intraneuronal unesterified cholesterol, resulting in effective reduction of Aß production and amelioration of disease progression in mouse models of AD and Niemann Pick Type C (NPC) disease. Here, we tested whether HP-β-CD could also improve phenotypic progression in SOD1[G93A] mice. Methods: Pre-symptomatic male SOD1[G93A] mice were randomly assigned to the following treatment groups: HP-β-CD (4000mg/kg, n = 9) or vehicle (saline; n = 10), delivered by weekly subcutaneous injection, commencing at 67 days of age. Longitudinal grip-strength and body mass analysis was performed until late-stage disease (120 days of age), followed by in vivo bilateral isometric muscle tension analysis of tibialis anterior (TA) and extensor digitorum longus (EDL) muscles. Results: HP-β-CD administration had no effect on body mass or grip-strength compared to vehicle treated SOD1[G93A] mice. Similarly, HP-β-CD treatment had no effect on muscle force, contractile properties or motor unit number estimates (MUNE) at late-stage disease in SOD1[G93A] mice. Conclusion: This study shows that HP-β-CD does not confer any therapeutic benefit in SOD1[G93A] mice. However, the absence of detrimental effects is informative, given the common use of cyclodextrins as complexing agents for other pharmaceutical products, their standalone therapeutic potential and the emerging association between dyslipidaemia and ALS progression.}, } @article {pmid37489441, year = {2023}, author = {Ramakrishna, K and Nalla, LV and Naresh, D and Venkateswarlu, K and Viswanadh, MK and Nalluri, BN and Chakravarthy, G and Duguluri, S and Singh, P and Rai, SN and Kumar, A and Singh, V and Singh, SK}, title = {WNT-β Catenin Signaling as a Potential Therapeutic Target for Neurodegenerative Diseases: Current Status and Future Perspective.}, journal = {Diseases (Basel, Switzerland)}, volume = {11}, number = {3}, pages = {}, pmid = {37489441}, issn = {2079-9721}, abstract = {Wnt/β-catenin (WβC) signaling pathway is an important signaling pathway for the maintenance of cellular homeostasis from the embryonic developmental stages to adulthood. The canonical pathway of WβC signaling is essential for neurogenesis, cell proliferation, and neurogenesis, whereas the noncanonical pathway (WNT/Ca[2+] and WNT/PCP) is responsible for cell polarity, calcium maintenance, and cell migration. Abnormal regulation of WβC signaling is involved in the pathogenesis of several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and spinal muscular atrophy (SMA). Hence, the alteration of WβC signaling is considered a potential therapeutic target for the treatment of neurodegenerative disease. In the present review, we have used the bibliographical information from PubMed, Google Scholar, and Scopus to address the current prospects of WβC signaling role in the abovementioned neurodegenerative diseases.}, } @article {pmid37489031, year = {2023}, author = {Rahimzadeh Goradel, R and Sattarpour, R and Hooshyari, Z and Taebi, M and Ghavampour, A and Jazani, MR and Sarraf, P}, title = {Examining the validity and reliability of the Persian version of the MiND-B questionnaire in ALS patients.}, journal = {Brain and behavior}, volume = {13}, number = {9}, pages = {e3167}, pmid = {37489031}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Reproducibility of Results ; *Cognition Disorders ; Cognition/physiology ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: In addition to affecting the nerves and muscles, amyotrophic lateral sclerosis (ALS) disease also affects the behavior and cognition of patients. In this study, we examine the validity and reliability of the Persian version of Motor Neuron Disease Behavioral instrument (MiND-B) questionnaire to investigate behavioral changes in Persian-speaking ALS patients.

METHODS: Forty-six Persian-speaking patients with ALS filled out the MiND-B questionnaire. Then, the overall scores and each of the domains of this questionnaire were statistically analyzed.

RESULTS: Cronbach's alpha coefficient was calculated .70 for the whole questionnaire. To check the validity of the questionnaire, the correlation of its scores with the Edinburgh Cognitive and Behavioral ALS screen (ECAS-A) questionnaire was taken, and this correlation was significant (p = .038).

CONCLUSION: The findings of this study show that the Persian version of the MiND-B questionnaire has the necessary validity and reliability to investigate behavioral changes in Persian-speaking patients with ALS.}, } @article {pmid37488957, year = {2023}, author = {Lee, J and Kim, A and Choi, SJ and Cho, E and Seo, J and Oh, SI and Jung, J and Kim, JS and Sung, JJ and Abrahams, S and Hong, YH}, title = {Development and Validation of the Korean Version of the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS-K).}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {19}, number = {5}, pages = {454-459}, pmid = {37488957}, issn = {1738-6586}, support = {2020R1F1A1072153/NRF/National Research Foundation of Korea/Korea ; }, abstract = {BACKGROUND AND PURPOSE: Cognitive and behavioral changes are common in amyotrophic lateral sclerosis (ALS), with about 15% of patients presenting with overt frontotemporal dementia and 30%-50% with varying degrees of impairments. We aimed to develop and validate the Korean version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS-K), a brief multidomain assessment tool developed for ALS patients with physical disability.

METHODS: We developed the ECAS-K according to the translation guidelines, and administered it to 38 patients with ALS and 26 age- and education-level-matched controls. We also administered the Montreal Cognitive Assessment (MoCA) and Frontal Assessment Battery (FAB) to investigate convergent validity, and the Center for Neurologic Study-Liability Scale to assess the association between pseudobulbar affect and cognitive/behavioral changes.

RESULTS: Internal consistency among the ECAS-K test items was found to be high, with a Cronbach's alpha of 0.87. Significant differences were found between patients with ALS and the controls in language, fluency, and memory functions (p<0.05). Abnormal performance based on the ECAS total score was noted in 39.4% of patients, and 66.6% presented behavioral changes in at least one domain. Significant correlations were observed between the scores of the ECAS-K and those of other cognitive screening tools (MoCA and FAB, with correlation coefficients of 0.69 and 0.55, respectively; p<0.01).

CONCLUSIONS: We developed and validated the ECAS-K which could be used as an effective tool to screen the cognitive and behavioral impairments in Korean patients with ALS.}, } @article {pmid37488888, year = {2024}, author = {Zhou, M and Li, S and Huang, C}, title = {Physiological and pathological functions of circular RNAs in the nervous system.}, journal = {Neural regeneration research}, volume = {19}, number = {2}, pages = {342-349}, pmid = {37488888}, issn = {1673-5374}, abstract = {Circular RNAs (circRNAs) are a class of covalently closed single-stranded RNAs that are expressed during the development of specific cells and tissues. CircRNAs play crucial roles in physiological and pathological processes by sponging microRNAs, modulating gene transcription, controlling the activity of certain RNA-binding proteins, and producing functional peptides. A key focus of research at present is the functionality of circRNAs in the nervous system and several advances have emerged over the last 2 years. However, the precise role of circRNAs in the nervous system has yet to be comprehensively reviewed. In this review, we first summarize the recently described roles of circRNAs in brain development, maturity, and aging. Then, we focus on the involvement of circRNAs in various diseases of the central nervous system, such as brain cancer, chronic neurodegenerative diseases, acute injuries of the nervous system, and neuropathic pain. A better understanding of the functionality of circRNAs will help us to develop potential diagnostic, prognostic, and therapeutic strategies to treat diseases of the nervous system.}, } @article {pmid37488879, year = {2024}, author = {Yu, Z and Teng, Y and Yang, J and Yang, L}, title = {The role of exosomes in adult neurogenesis: implications for neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {19}, number = {2}, pages = {282-288}, pmid = {37488879}, issn = {1673-5374}, abstract = {Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness. Exosomes are widely distributed in a range of body fluids, including urine, blood, milk, and saliva. Exosomes exert biological function by transporting factors between different cells and by regulating biological pathways in recipient cells. As an important form of intercellular communication, exosomes are increasingly being investigated due to their ability to transfer bioactive molecules such as lipids, proteins, mRNAs, and microRNAs between cells, and because they can regulate physiological and pathological processes in the central nervous system. Adult neurogenesis is a multistage process by which new neurons are generated and migrate to be integrated into existing neuronal circuits. In the adult brain, neurogenesis is mainly localized in two specialized niches: the subventricular zone adjacent to the lateral ventricles and the subgranular zone of the dentate gyrus. An increasing body of evidence indicates that adult neurogenesis is tightly controlled by environmental conditions with the niches. In recent studies, exosomes released from different sources of cells were shown to play an active role in regulating neurogenesis both in vitro and in vivo, thereby participating in the progression of neurodegenerative disorders in patients and in various disease models. Here, we provide a state-of-the-art synopsis of existing research that aimed to identify the diverse components of exosome cargoes and elucidate the therapeutic potential of exosomal contents in the regulation of neurogenesis in several neurodegenerative diseases. We emphasize that exosomal cargoes could serve as a potential biomarker to monitor functional neurogenesis in adults. In addition, exosomes can also be considered as a novel therapeutic approach to treat various neurodegenerative disorders by improving endogenous neurogenesis to mitigate neuronal loss in the central nervous system.}, } @article {pmid37488847, year = {2024}, author = {Huber, CC and Wang, H}, title = {Pathogenic and therapeutic role of exosomes in neurodegenerative disorders.}, journal = {Neural regeneration research}, volume = {19}, number = {1}, pages = {75-79}, pmid = {37488847}, issn = {1673-5374}, support = {P20 GM103443/GM/NIGMS NIH HHS/United States ; P20 RR016479/RR/NCRR NIH HHS/United States ; RF1 AG072510/AG/NIA NIH HHS/United States ; T32 GM136503/GM/NIGMS NIH HHS/United States ; }, abstract = {Neurodegenerative disorders affect millions of people worldwide, and the prevalence of these disorders is only projected to rise as the number of people over 65 will drastically increase in the coming years. While therapies exist to aid in symptomatic relief, effective treatments that can stop or reverse the progress of each neurodegenerative disease are lacking. Recently, research on the role of extracellular vesicles as disease markers and therapeutics has been intensively studied. Exosomes, 30-150 nm in diameter, are one type of extracellular vesicles facilitating cell-to-cell communication. Exosomes are thought to play a role in disease propagation in a variety of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Accordingly, the exosomes derived from the patients are an invaluable source of disease biomarkers. On the other hand, exosomes, especially those derived from stem cells, could serve as a therapeutic for these disorders, as seen by a rapid increase in clinical trials investigating the therapeutic efficacy of exosomes in different neurological diseases. This review summarizes the pathological burden and therapeutic approach of exosomes in neurodegenerative disorders. We also highlight how heat shock increases the yield of exosomes while still maintaining their therapeutic efficacy. Finally, this review concludes with outstanding questions that remain to be addressed in exosomal research.}, } @article {pmid37488208, year = {2023}, author = {Aly, A and Laszlo, ZI and Rajkumar, S and Demir, T and Hindley, N and Lamont, DJ and Lehmann, J and Seidel, M and Sommer, D and Franz-Wachtel, M and Barletta, F and Heumos, S and Czemmel, S and Kabashi, E and Ludolph, A and Boeckers, TM and Henstridge, CM and Catanese, A}, title = {Integrative proteomics highlight presynaptic alterations and c-Jun misactivation as convergent pathomechanisms in ALS.}, journal = {Acta neuropathologica}, volume = {146}, number = {3}, pages = {451-475}, pmid = {37488208}, issn = {1432-0533}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Neurodegenerative Diseases/pathology ; Proteomics ; Superoxide Dismutase-1/genetics ; Motor Neurons/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease mainly affecting upper and lower motoneurons. Several functionally heterogeneous genes have been associated with the familial form of this disorder (fALS), depicting an extremely complex pathogenic landscape. This heterogeneity has limited the identification of an effective therapy, and this bleak prognosis will only improve with a greater understanding of convergent disease mechanisms. Recent evidence from human post-mortem material and diverse model systems has highlighted the synapse as a crucial structure actively involved in disease progression, suggesting that synaptic aberrations might represent a shared pathological feature across the ALS spectrum. To test this hypothesis, we performed the first comprehensive analysis of the synaptic proteome from post-mortem spinal cord and human iPSC-derived motoneurons carrying mutations in the major ALS genes. This integrated approach highlighted perturbations in the molecular machinery controlling vesicle release as a shared pathomechanism in ALS. Mechanistically, phosphoproteomic analysis linked the presynaptic vesicular phenotype to an accumulation of cytotoxic protein aggregates and to the pro-apoptotic activation of the transcription factor c-Jun, providing detailed insights into the shared pathobiochemistry in ALS. Notably, sub-chronic treatment of our iPSC-derived motoneurons with the fatty acid docosahexaenoic acid exerted a neuroprotective effect by efficiently rescuing the alterations revealed by our multidisciplinary approach. Together, this study provides strong evidence for the central and convergent role played by the synaptic microenvironment within the ALS spinal cord and highlights a potential therapeutic target that counteracts degeneration in a heterogeneous cohort of human motoneuron cultures.}, } @article {pmid37488110, year = {2023}, author = {Huang, LY and Ou, YN and Yang, YX and Wang, ZT and Tan, L and Yu, JT}, title = {Associations of cardiovascular risk factors and lifestyle behaviors with neurodegenerative disease: a Mendelian randomization study.}, journal = {Translational psychiatry}, volume = {13}, number = {1}, pages = {267}, pmid = {37488110}, issn = {2158-3188}, mesh = {Humans ; Risk Factors ; *Neurodegenerative Diseases/epidemiology/genetics ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; *Amyotrophic Lateral Sclerosis/genetics ; *Cardiovascular Diseases/epidemiology/genetics ; Heart Disease Risk Factors ; Polymorphism, Single Nucleotide ; Life Style ; }, abstract = {Previous observational studies reported that midlife clustering of cardiovascular risk factors and lifestyle behaviors were associated with neurodegenerative disease; however, these findings might be biased by confounding and reverse causality. This study aimed to investigate the causal associations of cardiovascular risk factors and lifestyle behaviors with neurodegenerative disease, using the two-sample Mendelian randomization design. Genetic variants for the modifiable risk factors and neurodegenerative disease were extracted from large-scale genome-wide association studies. The inverse-variance weighted method was used as the main analysis method, and MR-Egger regression and leave-one-out analyses were performed to identify potential violations. Genetically predicted diastolic blood pressure (DBP: OR per 1 mmHg, 0.990 [0.979-1.000]), body mass index (BMI: OR per 1 SD, 0.880 [0.825-0.939]), and educational level (OR per 1 SD, 0.698 [0.602-0.810]) were associated with lower risk of late-onset Alzheimer's disease (LOAD), while genetically predicted low-density lipoprotein (LDL: OR per 1 SD, 1.302 [1.066-1.590]) might increase LOAD risk. Genetically predicted exposures (including LDL and BMI) applied to familial AD showed the same effect. The association of LDL was also found with Amyotrophic lateral sclerosis (ALS) (LDL: OR per 1 SD, 1.180 [1.080-1.289]). This MR analysis showed that LDL, BMI, BP, and educational level were causally related to AD; a significant association between LDL and ALS risk, as well as the potential effect of sleep duration on PD risk, were also revealed. Targeting these modifiable factors was a promising strategy of neurodegenerative disease prevention.}, } @article {pmid37488055, year = {2023}, author = {Letko, A and Brülisauer, F and Häfliger, IM and Corr, E and Scholes, S and Drögemüller, C}, title = {Loss-of-function variant in the ovine TMCO6 gene in North Country Cheviot sheep with motor neuron disease.}, journal = {Genomics}, volume = {115}, number = {5}, pages = {110689}, doi = {10.1016/j.ygeno.2023.110689}, pmid = {37488055}, issn = {1089-8646}, abstract = {In North Country Cheviot lambs with early-onset progressive ataxia and motor neuron degeneration, whole-genome sequencing identified a homozygous loss-of-function variant in the ovine transmembrane and coiled-coil domains (TMCO6) gene. The familial recessive form of motor neuron disease in sheep is due to a pathogenic 4 bp deletion leading to a 50% protein truncation that is assumed to result in the absence of a functional TMCO6. This uncharacterised protein is proposed to interact with ubiquilin 1 which is associated with Alzheimer's disease, whereas sporadic forms of amyotrophic lateral sclerosis are caused by variants in UBQLN2. Our findings provide a first spontaneous animal model for TMCO6, which could have implications in the studies of other comparative neurodegenerative diseases. In addition, these results will allow the design of a genetic test to prevent the occurrence of this fatal disease in the affected sheep population.}, } @article {pmid37486495, year = {2023}, author = {Papikinos, T and Krokidis, MG and Vrahatis, A and Vlamos, P and Exarchos, TP}, title = {Signature-Based Computational Drug Repurposing for Amyotrophic Lateral Sclerosis.}, journal = {Advances in experimental medicine and biology}, volume = {1424}, number = {}, pages = {201-211}, pmid = {37486495}, issn = {0065-2598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; Drug Repositioning ; *Neurodegenerative Diseases ; Transcriptome ; Motor Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. There are currently limited approved drugs for the disorder, and for this reason the strategy of repositioning already approved therapeutics could exhibit a successful outcome. Herein, we used CMAP and L1000CDS[2] databases which include gene expression profiles datasets (genomic signatures) to identify potent compounds and classes of compounds which reverse disease's signature which could in turn reverse its phenotype. ALS signature was obtained by comparing gene expression of muscle biopsy specimens between diseased and healthy individuals. Statistical analysis was conducted to explore differentially transcripts in patients' samples. Then, the list of upregulated and downregulated genes was used to query both databases in order to determine molecules which downregulate the genes which are upregulated by ALS and vice versa. These compounds, based on their chemical structure along with known treatments, were clustered to reveal drugs with novel and potentially more effective mode of action with most of them predicted to affect pathways heavily involved in ALS. This evidence suggests that these compounds are strong candidates for moving to the next phase of the drug repurposing pipeline which is in vitro and in vivo experimental evaluation.}, } @article {pmid37486108, year = {2023}, author = {Malmström, N and Jakobsson Larsson, B and Nilsson, S and Öhlén, J and Nygren, I and Andersen, PM and Ozanne, A}, title = {Living with a parent with ALS - adolescents' need for professional support from the adolescents' and the parents' perspectives.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2023.2228348}, pmid = {37486108}, issn = {2167-9223}, abstract = {AIM: The aim of the study was to qualitatively investigate the adolescents' need for professional support when a parent has amyotrophic lateral sclerosis (ALS) - from the adolescents' and the parents' perspectives.

METHODS: A total of 37 individual semi-structured single interviews with 18 families were conducted, including 11 adolescents aged 8-25 and 26 parents, 13 with ALS and 13 co-parents. Data was analysed using qualitative content analysis.

RESULTS: Both adolescents and parents described the adolescents as needing professional support but found it difficult to articulate this need. However, the results indicate that the adolescents needed help in bringing manageability into their lives due to the uncertainty of living with the illness in the family. It was therefore essential to ensure that the adolescents were not forgotten in the disease context and that their needs for being involved as well as for obtaining information and understanding, was addressed. The importance of offering the adolescents support early was emphasized, but also of actively helping the families to master challenges in their everyday life. Support adapted to each family's unique situation and preferences was desired, as the adolescents' need for support seemed to be individual, disease-dependent and varied during different phases.

CONCLUSION: Given the adolescents' need for information and understanding, healthcare professionals must actively work to reach the adolescents as early as possible. It is crucial to ensure that the adolescents are given the opportunity to be involved based on their own conditions, as well as to support the families to strengthen their communication.}, } @article {pmid37485983, year = {2023}, author = {van Kessel, CS and Waller, J and Steffens, D and Lee, PJ and Austin, KKS and Stalley, PD and Solomon, MJ}, title = {Improving Surgical Outcomes in Pelvic Exenteration Surgery: Comparison of Prone Sacrectomy With Anterior Cortical Sacrectomy Techniques.}, journal = {Annals of surgery}, volume = {278}, number = {6}, pages = {945-953}, doi = {10.1097/SLA.0000000000006040}, pmid = {37485983}, issn = {1528-1140}, mesh = {Humans ; *Pelvic Exenteration/methods ; *Rectal Neoplasms/surgery/pathology ; Retrospective Studies ; Sacrum/surgery/pathology ; Treatment Outcome ; }, abstract = {OBJECTIVE: To assess the effect of changing our sacrectomy approach from prone to anterior on surgical and oncological outcomes.

BACKGROUND: In patients with advanced pelvic malignancy involving the sacrum, pelvic exenteration (PE) with en-bloc sacrectomy is the only potential curative option but morbidity is high. Over time sacrectomy techniques have evolved from prone sacrectomy (PS) to abdominolithotomy sacrectomy (ALS, ≤S3) and high anterior cortical sacrectomy (HACS, >S3) to optimize surgical outcomes.

METHODS: A retrospective, single institution analysis of prospectively collected data for patients undergoing PE with en-bloc sacrectomy between 1994 and 2021 was performed.

RESULTS: A total of 363 patients were identified and divided into PS (n=77, 21.2%), ALS (n=247, 68.0%), and HACS (n=39, 10.7%). Indications were: locally advanced (n=92) or recurrent (n=177) rectal cancer, primary other (n=31), recurrent other (n=60), and benign disease (n=3). PS resulted in longer operating time (P <0.01) and more blood loss (P <0.01). Patients with HACS had more major nerve (87.2%) and vascular (25.6%) resections (P <0.01). Vertical rectus abdominis myocutaneous flap repair was less common following HACS (7.7%) than ALS (25.5%) and PS (27.3%) (P =0.040). R0 rate was 80.8%, 65.8%, and 76.9% following ALS, PS, and HACS, respectively (P =0.024). Wound-related complications and re-operations were significantly reduced following ALS and HACS compared with PS.

CONCLUSIONS: Changing our practice from PS to an anterior approach with ALS or HAS has been safe and improved overall surgical and perioperative outcomes, while maintaining good oncological outcomes. Given the improved perioperative and surgical outcomes, it would be important for surgeons to learn and adopt the anterior sacrectomy approaches.}, } @article {pmid37484758, year = {2023}, author = {Chen, TY and Hsu, CW and Chang, YP and Wang, MT and Wu, YJ and Wang, CH and Wang, KY and Chu, TH and Lee, YK}, title = {Percutaneous transhepatic duodenal drainage is good option for afferent loop syndrome for obstructive colorectal cancer patient with history of Billroth's operation II: A case report of a rare postoperative complication.}, journal = {Clinical case reports}, volume = {11}, number = {7}, pages = {e7725}, pmid = {37484758}, issn = {2050-0904}, abstract = {KEY CLINICAL MESSAGE: Temporal percutaneous transhepatic duodenum drainage (PTDD) seems to be effective in the treatment of postoperative afferent loop syndrome (ALS) following transverse loop colostomy for obstructive colorectal cancer.

ABSTRACT: Management of obstructive colorectal cancer still remains a challenge. There are various options with different risks of mortality and mobility for obstructive colorectal cancer. A rare unexpected postoperative ALS following a low anterior resection and transverse loop colostomy for obstructive colorectal cancer is presented in this report. A 64-year-old man had the acute ALS had been noted 10 days after transverse loop colostomy. An option was temporal PTDD treatment in the patient with history of Billroth's operation II for upper gastrointestinal bleeding 30 years ago. Acute ALS was treated by temporal PTDD. The drainage tube for PTDD was not removed until closure of the transverse colostomy 2 months later. The patient recovered uneventfully. Acute ALS after transverse loop colostomy for obstructive colorectal cancer is rare and has never been reported in the literature. The mechanism of acute ALS after construction of a loop colostomy and the treatment strategy of PTDD for acute ALS is presented.}, } @article {pmid37484552, year = {2023}, author = {}, title = {Correction to: Bulbar onset amyotrophic lateral sclerosis with more evident symptoms in the left hemibody: a case report.}, journal = {Oxford medical case reports}, volume = {2023}, number = {7}, pages = {omad077}, doi = {10.1093/omcr/omad077}, pmid = {37484552}, issn = {2053-8855}, abstract = {[This corrects the article DOI: 10.1093/omcr/omad045.].}, } @article {pmid37483353, year = {2023}, author = {Shi, Y and Zhao, Y and Lu, L and Gao, Q and Yu, D and Sun, M}, title = {CRISPR/Cas9: implication for modeling and therapy of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1223777}, pmid = {37483353}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a deadly neurological disease with a complicated and variable pathophysiology yet to be fully understood. There is currently no effective treatment available to either slow or terminate it. However, recent advances in ALS genomics have linked genes to phenotypes, encouraging the creation of novel therapeutic approaches and giving researchers more tools to create efficient animal models. Genetically engineered rodent models replicating ALS disease pathology have a high predictive value for translational research. This review addresses the history of the evolution of gene editing tools, the most recent ALS disease models, and the application of CRISPR/Cas9 against ALS disease.}, } @article {pmid37482930, year = {2023}, author = {Grassano, M and Manera, U and De Marchi, F and Cugnasco, P and Matteoni, E and Daviddi, M and Solero, L and Bombaci, A and Palumbo, F and Vasta, R and Canosa, A and Salamone, P and Fuda, G and Casale, F and Mazzini, L and Calvo, A and Moglia, C and Chiò, A}, title = {The role of peripheral immunity in ALS: a population-based study.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {9}, pages = {1623-1632}, pmid = {37482930}, issn = {2328-9503}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis ; Lymphocytes ; Blood Cell Count ; Leukocytes ; Inflammation ; }, abstract = {BACKGROUND: Systemic inflammation has been proposed as a relevant mechanism in amyotrophic lateral sclerosis (ALS). Still, comprehensive data on ALS patients' innate and adaptive immune responses and their effect on the clinical phenotype are lacking. Here, we investigate systemic immunity in a population-based ALS cohort using readily available hematological indexes.

METHODS: We collected clinical data and the complete blood count (CBC) at diagnosis in ALS patients from the Piemonte and Valle d'Aosta Register for ALS (PARALS) from 2007 to 2019. Leukocytes populations, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic-immune-inflammation index (SII), and lymphocyte-to-monocyte ratio (LMR) were derived from CBC. All variables were analyzed for association with clinical features in the entire cohort and then in sex- and age-based subgroups.

RESULTS: Neutrophils (P = 0.001) and markers of increased innate immunity (NLR, P = 0.008 and SII, P = 0.006) were associated with a faster disease progression. Similarly, elevated innate immunity correlated with worse pulmonary function and shorter survival. The prognosis in women also correlated with low lymphocytes (P = 0.045) and a decreased LMR (P = 0.013). ALS patients with cognitive impairment exhibited lower monocytes (P = 0.0415).

CONCLUSIONS AND RELEVANCE: The dysregulation of the systemic immune system plays a multifaceted role in ALS. More specifically, an elevated innate immune response is associated with faster progression and reduced survival. Conversely, ALS patients with cognitive impairment showed a reduction in monocyte count. Additionally, immune response varied according to sex and age, thus suggesting that involved immune pathways are patient specific. Further studies will help translate those findings into clinical practice or targeted treatments.}, } @article {pmid37482646, year = {2024}, author = {Liu, K and Guo, Q and Ding, Y and Luo, L and Huang, J and Zhang, Q}, title = {Alterations in nasal microbiota of patients with amyotrophic lateral sclerosis.}, journal = {Chinese medical journal}, volume = {137}, number = {2}, pages = {162-171}, pmid = {37482646}, issn = {2542-5641}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/microbiology ; Feces/microbiology ; *Microbiota/genetics ; *Gastrointestinal Microbiome/genetics ; Bacteria/genetics ; RNA, Ribosomal, 16S/genetics ; }, abstract = {BACKGROUND: Links between alterations in gut microbiota composition and amyotrophic lateral sclerosis (ALS) have previously been reported. This study aimed to examine the microbiota in the nasal cavity of ALS.

METHODS: Sixty-six ALS patients and 40 healthy caregivers who live in close proximity with patients were enrolled. High throughput metagenomic sequencing of the 16S ribosomal deoxyribonucleic acid (rDNA) gene V3-V4 region of nasal microbiota was used to characterize the alpha and beta diversity and relative abundance of bacterial taxa, predict function, and conduct correlation analysis between specific taxa and clinical features.

RESULTS: The nasal microbiome of ALS patients showed lower alpha diversity than that of corresponding healthy family members. Genera Gaiella , Sphingomonas , Polaribacter _1, Lachnospiraceae _NK4A136_group, Klebsiella , and Alistipes were differentially enriched in ALS patients compared to controls. Nasal microbiota composition in ALS patients significantly differed from that in healthy subjects (unweighted UniFrac P = 0.001), while Linear discriminant analysis Effect Size (LEfSe) analysis indicated that Bacteroidetes and Firmicutes dominated healthy nasal communities at the phylum level, whereas Actinobacteria was the predominant phylum and Thermoleophilia was the predominant class in ALS patients. Genus Faecalibacterium and Alistipes were positively correlated with ALS functional rating scale revised (ALSFRS-R; rs = 0.349, P = 0.020 and rs = 0.393, P = 0.008), while Prevotella -9 and Bacteroides operational taxonomic units (OTUs) were positively associated with lung function (FVC) in ALS patients (rs = 0.304, P = 0.045, and rs = 0.300, P = 0.048, respectively). Prevotella -1 was positively correlated with white blood cell counts (WBC, rs = 0.347, P = 0.021), neutrophil percentage (Neu%, rs = 0.428, P = 0.004), and neutrophil-to-lymphocyte ratio (NLR, rs = 0.411, P = 0.006), but negatively correlated with lymphocyte percentage (Lym%, rs = -0.408, P = 0.006). In contrast, Streptococcus was negatively associated with Neu% (rs = -0.445, P = 0.003) and NLR (rs = -0.436, P = 0.003), while positively associated with Lym% (rs = 0.437, P = 0.003). No significant differences in nasal microbiota richness and evenness were detected among the severe and mild ALS patients.

CONCLUSIONS: ALS is accompanied by altered nasal microbial community composition and diversity. The findings presented here highlight the need to understand how dysbiosis of nasal microbiota may contribute to the development of ALS.}, } @article {pmid37481656, year = {2023}, author = {Mohovic, N and Peradinovic, J and Markovinovic, A and Cimbro, R and Minic, Z and Dominovic, M and Jakovac, H and Nimac, J and Rogelj, B and Munitic, I}, title = {Neuroimmune characterization of optineurin insufficiency mouse model during ageing.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {11840}, pmid = {37481656}, issn = {2045-2322}, mesh = {Male ; Mice ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Dementia ; Polyubiquitin/genetics ; Cell Cycle Proteins/metabolism ; Signal Transduction ; Mutation ; Aging ; }, abstract = {Optineurin is a multifunctional polyubiquitin-binding protein implicated in inflammatory signalling. Optineurin mutations are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), neurodegenerative diseases characterised by neuronal loss, neuroinflammation, and peripheral immune disbalance. However, the pathogenic role of optineurin mutations is unclear. We previously observed no phenotype in the unmanipulated young optineurin insufficiency mice (Optn[470T]), designed to mimic ALS/FTD-linked truncations deficient in polyubiquitin binding. The purpose of this study was to investigate whether ageing would trigger neurodegeneration. We performed a neurological, neuropathological, and immunological characterization of ageing wild-type (WT) and Optn[470T] mice. No motor or cognitive differences were detected between the genotypes. Neuropathological analyses demonstrated signs of ageing including lipofuscin accumulation and microglial activation in WT mice. However, this was not worsened in Optn[470T] mice, and they did not exhibit TAR DNA-binding protein 43 (TDP-43) aggregation or neuronal loss. Spleen immunophenotyping uncovered T cell immunosenescence at two years but without notable differences between the WT and Optn[470T] mice. Conventional dendritic cells (cDC) and macrophages exhibited increased expression of activation markers in two-year-old Optn[470T] males but not females, although the numbers of innate immune cells were similar between genotypes. Altogether, a combination of optineurin insufficiency and ageing did not induce ALS/FTD-like immune imbalance and neuropathology in mice.}, } @article {pmid37481642, year = {2023}, author = {Yang, R and Yang, B and Liu, W and Tan, C and Chen, H and Wang, X}, title = {Emerging role of non-coding RNAs in neuroinflammation mediated by microglia and astrocytes.}, journal = {Journal of neuroinflammation}, volume = {20}, number = {1}, pages = {173}, pmid = {37481642}, issn = {1742-2094}, support = {32102749//National Natural Science Foundation of China/ ; 32122086//National Natural Science Foundation of China/ ; 2022M721277//China Postdoctoral Science Foundation/ ; 2021YFD1800800//National Key Research and Development Program of China/ ; 2021CFA016//Natural Science Foundation of Hubei Province/ ; 2662023PY005//Fundamental Research Funds for the Central Universities/ ; }, mesh = {Humans ; Astrocytes ; Microglia ; Neuroinflammatory Diseases ; *RNA, Long Noncoding/genetics ; *MicroRNAs ; }, abstract = {Neuroinflammation has been implicated in the initiation and progression of several central nervous system (CNS) disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, ischemic stroke, traumatic brain injury, spinal cord injury, viral encephalitis, and bacterial encephalitis. Microglia and astrocytes are essential in neural development, maintenance of synaptic connections, and homeostasis in a healthy brain. The activation of astrocytes and microglia is a defense mechanism of the brain against damaged tissues and harmful pathogens. However, their activation triggers neuroinflammation, which can exacerbate or induce CNS injury. Non-coding RNAs (ncRNAs) are functional RNA molecules that lack coding capabilities but can actively regulate mRNA expression and function through various mechanisms. ncRNAs are highly expressed in astrocytes and microglia and are potential mediators of neuroinflammation. We reviewed the recent research progress on the role of miRNAs, lncRNAs, and circRNAs in regulating neuroinflammation in various CNS diseases. Understanding how these ncRNAs affect neuroinflammation will provide important therapeutic insights for preventing and managing CNS dysfunction.}, } @article {pmid37481159, year = {2023}, author = {Sharma, K and Banerjee, S and Savran, D and Rajes, C and Wiese, S and Girdhar, A and Schwierz, N and Lee, C and Shorter, J and Schmidt, M and Guo, L and Fändrich, M}, title = {Cryo-EM Structure of the Full-length hnRNPA1 Amyloid Fibril.}, journal = {Journal of molecular biology}, volume = {435}, number = {18}, pages = {168211}, pmid = {37481159}, issn = {1089-8638}, support = {R01 GM099836/GM/NIGMS NIH HHS/United States ; R35 GM138109/GM/NIGMS NIH HHS/United States ; /CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {*Amyloid/chemistry ; Cryoelectron Microscopy/methods ; *Heterogeneous Nuclear Ribonucleoprotein A1/chemistry ; Mutation ; Prions/chemistry ; Protein Domains ; }, abstract = {Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is a multifunctional RNA-binding protein that is associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis and multisystem proteinopathy. In this study, we have used cryo-electron microscopy to investigate the three-dimensional structure of amyloid fibrils from full-length hnRNPA1 protein. We find that the fibril core is formed by a 45-residue segment of the prion-like low-complexity domain of the protein, whereas the remaining parts of the protein (275 residues) form a fuzzy coat around the fibril core. The fibril consists of two fibril protein stacks that are arranged into a pseudo-21 screw symmetry. The ordered core harbors several of the positions that are known to be affected by disease-associated mutations, but does not encompass the most aggregation-prone segments of the protein. These data indicate that the structures of amyloid fibrils from full-length proteins may be more complex than anticipated by current theories on protein misfolding.}, } @article {pmid37480846, year = {2023}, author = {Ziff, OJ and Harley, J and Wang, Y and Neeves, J and Tyzack, G and Ibrahim, F and Skehel, M and Chakrabarti, AM and Kelly, G and Patani, R}, title = {Nucleocytoplasmic mRNA redistribution accompanies RNA binding protein mislocalization in ALS motor neurons and is restored by VCP ATPase inhibition.}, journal = {Neuron}, volume = {111}, number = {19}, pages = {3011-3027.e7}, doi = {10.1016/j.neuron.2023.06.019}, pmid = {37480846}, issn = {1097-4199}, support = {FC010110/WT_/Wellcome Trust/United Kingdom ; FC010110/CRUK_/Cancer Research UK/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; FC010110/MRC_/Medical Research Council/United Kingdom ; MC_PC_19038/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Adenosine Triphosphatases/genetics/metabolism ; RNA, Messenger/metabolism ; Motor Neurons/metabolism ; RNA-Binding Proteins/metabolism ; Valosin Containing Protein/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by nucleocytoplasmic mislocalization of the RNA-binding protein (RBP) TDP-43. However, emerging evidence suggests more widespread mRNA and protein mislocalization. Here, we employed nucleocytoplasmic fractionation, RNA sequencing, and mass spectrometry to investigate the localization of mRNA and protein in induced pluripotent stem cell-derived motor neurons (iPSMNs) from ALS patients with TARDBP and VCP mutations. ALS mutant iPSMNs exhibited extensive nucleocytoplasmic mRNA redistribution, RBP mislocalization, and splicing alterations. Mislocalized proteins exhibited a greater affinity for redistributed transcripts, suggesting a link between RBP mislocalization and mRNA redistribution. Notably, treatment with ML240, a VCP ATPase inhibitor, partially restored mRNA and protein localization in ALS mutant iPSMNs. ML240 induced changes in the VCP interactome and lysosomal localization and reduced oxidative stress and DNA damage. These findings emphasize the link between RBP mislocalization and mRNA redistribution in ALS motor neurons and highlight the therapeutic potential of VCP inhibition.}, } @article {pmid37480213, year = {2023}, author = {Suddull, HJ and Rosa-Fernandes, L and Lee, A}, title = {How can proteomics help solve the lack of biomarkers to aid in the early diagnosis of motor neuron disease (MND)?.}, journal = {Expert review of proteomics}, volume = {20}, number = {7-9}, pages = {121-123}, doi = {10.1080/14789450.2023.2240513}, pmid = {37480213}, issn = {1744-8387}, } @article {pmid37478793, year = {2023}, author = {Fournier, JE and Mak, G and Gordon, K and Glogauer, J and Fareez, F and Provias, J and Tarnopolsky, MA and Lu, JQ}, title = {Cylindrical spirals and other concentric structures of skeletal muscle in patients with neurological diseases.}, journal = {Journal of the neurological sciences}, volume = {451}, number = {}, pages = {120734}, doi = {10.1016/j.jns.2023.120734}, pmid = {37478793}, issn = {1878-5883}, mesh = {Adult ; Humans ; Infant ; Muscle, Skeletal/pathology ; *Muscular Diseases/pathology ; *Neuromuscular Diseases ; *Huntington Disease/pathology ; Muscular Atrophy/pathology ; }, abstract = {Cylindrical spirals (CSs) are ultrastructurally distinct, intracytoplasmic inclusions characterized by concentrically wrapped lamellae, which are rarely found in skeletal muscle biopsies on electron microscopy (EM). CSs are often confused with other EM concentric structures including concentric laminated bodies and mitochondrial concentric cristae (MCC), due to similarities in these ultrastructures. In this study, we found CSs in 9 muscle biopsies from 9 patients, accounting for 0.5% of the biopsies examined routinely by EM. The frequency of CSs in these muscles varied from sparse and segregated to focally frequent and aggregated. CS-associated features included muscle fiber denervation atrophy in all 9 cases, fiber type grouping in 7/8 cases, tubular aggregates in 3/9 cases, and MCC in 2/9 cases. We also compared the concentric structures and highlighted their differences to distinguish CSs from other similar structures. Clinically, 8 out of 9 patients were adults aged 41-74 years and only one patient was 17 month-old. CSs were associated with several neurological diseases including Huntington's disease, amyotrophic lateral sclerosis, Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes, and other complex neurological disorders with neuropathy/encephalopathy, as well as anti-MDA5+ dermatomyositis. Eight of nine patients had genetic findings such as trinucleotide repeat expansion of huntingtin gene, ALS2 variant, MT-TL1 m.3243A > G mutation, and PMP 22 gene deletion. These results suggest that CSs may be highly variable in frequency and likely are under-reported/under-detected; they may be associated with neurogenic myopathy or central/peripheral nervous system disorders including some genetic neurological/neuromuscular diseases. Our findings of more CS-associated neurological diseases and an association of CSs with muscle neurogenic features may contribute to a better understanding of the clinico-pathological significance of CSs.}, } @article {pmid37477391, year = {2023}, author = {Alix, JJP and Plesia, M and Shaw, PJ and Mead, RJ and Day, JCC}, title = {Combining electromyography and Raman spectroscopy: optical EMG.}, journal = {Muscle & nerve}, volume = {68}, number = {4}, pages = {464-470}, pmid = {37477391}, issn = {1097-4598}, support = {MC_PC_15034/MRC_/Medical Research Council/United Kingdom ; NF-SI-0617-10077/DH_/Department of Health/United Kingdom ; IS-BRC-1215-20017/DH_/Department of Health/United Kingdom ; }, mesh = {Mice ; Animals ; Electromyography ; Superoxide Dismutase-1/genetics ; *Spectrum Analysis, Raman ; Muscle, Skeletal ; Mice, Transgenic ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Disease Models, Animal ; Superoxide Dismutase ; }, abstract = {INTRODUCTION/AIMS: Electromyography (EMG) remains a key component of the diagnostic work-up for suspected neuromuscular disease, but it does not provide insight into the molecular composition of muscle which can provide diagnostic information. Raman spectroscopy is an emerging neuromuscular biomarker capable of generating highly specific, molecular fingerprints of tissue. Here, we present "optical EMG," a combination of EMG and Raman spectroscopy, achieved using a single needle.

METHODS: An optical EMG needle was created to collect electrophysiological and Raman spectroscopic data during a single insertion. We tested functionality with in vivo recordings in the SOD1[G93A] mouse model of amyotrophic lateral sclerosis (ALS), using both transgenic (n = 10) and non-transgenic (NTg, n = 7) mice. Under anesthesia, compound muscle action potentials (CMAPs), spontaneous EMG activity and Raman spectra were recorded from both gastrocnemius muscles with the optical EMG needle. Standard concentric EMG needle recordings were also undertaken. Electrophysiological data were analyzed with standard univariate statistics, Raman data with both univariate and multivariate analyses.

RESULTS: A significant difference in CMAP amplitude was observed between SOD1[G93A] and NTg mice with optical EMG and standard concentric needles (p = .015 and p = .011, respectively). Spontaneous EMG activity (positive sharp waves) was detected in transgenic SOD1[G93A] mice only. Raman spectra demonstrated peaks associated with key muscle components. Significant differences in molecular composition between SOD1[G93A] and NTg muscle were identified through the Raman spectra.

DISCUSSION: Optical EMG can provide standard electrophysiological data and molecular Raman data during a single needle insertion and represents a potential biomarker for neuromuscular disease.}, } @article {pmid37476298, year = {2023}, author = {Nitu, NS and Sultana, SZ and Haq, A and Sumi, SA and Bose, SK and Sinha, S and Kumar, S and Haque, M}, title = {Histological Study on the Thickness of Gray Matter at the Summit and Bottom of Folium in Different Age Groups of Bangladeshi People.}, journal = {Cureus}, volume = {15}, number = {7}, pages = {e42103}, pmid = {37476298}, issn = {2168-8184}, abstract = {Context The cerebellum is a part of the hindbrain and consists of cortical gray matter (GM) at the surface and a medullary core of white matter (WM). The GM contains a cell body of neurons that helps process and transmit any command type through nerve fibers found in the WM. The main functions of GM in the central nervous system empower persons to control motor activity, recollection, and passion. So, this research aims to assess the thickness of GM at the summit and bottom of folia by histologically studying the cerebellum cortex. Methods The collection of data was a descriptive type of cross-sectional study. The method was the purposive type. This study was conducted from August 2016 to March 2017, and the research was carried out at Mymensingh Medical College's Department of Anatomy, Bangladesh. Specimens containing cerebellum were preserved from Bangladeshi cadavers according to sexes and ages ranging in years. We chose fresh specimens from people who died within the last 12 hours and preserved them in 10% formol saline. The size of the tissue that was collected for the histological study was not more than 2 cm[2] and not more than 4-5 mm thick. Then the tissue was placed in 10% formol saline. This fluid was used for quick fixation and partial dehydration of the tissue. After dehydration, each tissue segment is processed for infiltration and embedding separately. Every section was stained with hematoxylin and eosin stain (H&E) before being coated with dibutyl phthalate polystyrene xylene (DPX) coverslips on slides. Result The mean (±SD) thickness of GM at the summit of folium was 886.2±29.7µm in Group A, 925.2±25.9µm in Group B, 912.7±22.3µm in Group C, and 839.9±40.7µm in Group D. Mean (±SD) GM thickness at the bottom of the fissure was 395.6±12.2 µm, 403.9±26.0µm, 380.4±23.4 µm, and 375.8±28.8 µm in Groups A, B, C, and D respectively. Conclusion The thickness of the cortex is an essential factor in the normal development process, and it was similar in the current study. Normal aging, Alzheimer's disease, and other dementias cause reduced GM which makes the cortical sheet thin. Huntington's disease, corticobasal degeneration, amyotrophic lateral sclerosis, and schizophrenia are all examples of neurological disorders. Cortical thinning is typically locally localized, and the progression of atrophy can thus disclose much about a disease's history and causal variables. The present study correspondingly found that GM was reduced after the age of 50 years onward. Furthermore, longitudinal investigations of cortical atrophy have the potential to be extremely useful in measuring the efficacy of a wide range of treatments.}, } @article {pmid37475885, year = {2023}, author = {Acosta-Galeana, I and Hernández-Martínez, R and Reyes-Cruz, T and Chiquete, E and Aceves-Buendia, JJ}, title = {RNA-binding proteins as a common ground for neurodegeneration and inflammation in amyotrophic lateral sclerosis and multiple sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1193636}, pmid = {37475885}, issn = {1662-5099}, abstract = {The neurodegenerative and inflammatory illnesses of amyotrophic lateral sclerosis and multiple sclerosis were once thought to be completely distinct entities that did not share any remarkable features, but new research is beginning to reveal more information about their similarities and differences. Here, we review some of the pathophysiological features of both diseases and their experimental models: RNA-binding proteins, energy balance, protein transportation, and protein degradation at the molecular level. We make a thorough analysis on TDP-43 and hnRNP A1 dysfunction, as a possible common ground in both pathologies, establishing a potential link between neurodegeneration and pathological immunity. Furthermore, we highlight the putative variations that diverge from a common ground in an atemporal course that proposes three phases for all relevant molecular events.}, } @article {pmid37475056, year = {2023}, author = {Yang, S and Park, JH and Lu, HC}, title = {Axonal energy metabolism, and the effects in aging and neurodegenerative diseases.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {49}, pmid = {37475056}, issn = {1750-1326}, support = {R01 NS086794/NS/NINDS NIH HHS/United States ; NS086794/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Neurodegenerative Diseases/metabolism ; NAD/metabolism ; Aging/metabolism ; Axons/metabolism ; Energy Metabolism ; Glucose/metabolism ; }, abstract = {Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of aging (NDAs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. Glucose is the major brain fuel and glucose hypometabolism has been observed in brain regions vulnerable to aging and NDAs. Many neurodegenerative susceptible regions are in the topological central hub of the brain connectome, linked by densely interconnected long-range axons. Axons, key components of the connectome, have high metabolic needs to support neurotransmission and other essential activities. Long-range axons are particularly vulnerable to injury, neurotoxin exposure, protein stress, lysosomal dysfunction, etc. Axonopathy is often an early sign of neurodegeneration. Recent studies ascribe axonal maintenance failures to local bioenergetic dysregulation. With this review, we aim to stimulate research in exploring metabolically oriented neuroprotection strategies to enhance or normalize bioenergetics in NDA models. Here we start by summarizing evidence from human patients and animal models to reveal the correlation between glucose hypometabolism and connectomic disintegration upon aging/NDAs. To encourage mechanistic investigations on how axonal bioenergetic dysregulation occurs during aging/NDAs, we first review the current literature on axonal bioenergetics in distinct axonal subdomains: axon initial segments, myelinated axonal segments, and axonal arbors harboring pre-synaptic boutons. In each subdomain, we focus on the organization, activity-dependent regulation of the bioenergetic system, and external glial support. Second, we review the mechanisms regulating axonal nicotinamide adenine dinucleotide (NAD[+]) homeostasis, an essential molecule for energy metabolism processes, including NAD[+] biosynthetic, recycling, and consuming pathways. Third, we highlight the innate metabolic vulnerability of the brain connectome and discuss its perturbation during aging and NDAs. As axonal bioenergetic deficits are developing into NDAs, especially in asymptomatic phase, they are likely exaggerated further by impaired NAD[+] homeostasis, the high energetic cost of neural network hyperactivity, and glial pathology. Future research in interrogating the causal relationship between metabolic vulnerability, axonopathy, amyloid/tau pathology, and cognitive decline will provide fundamental knowledge for developing therapeutic interventions.}, } @article {pmid37474791, year = {2023}, author = {Li, D and Johmura, Y and Morimoto, S and Doi, M and Nakanishi, K and Ozawa, M and Tsunekawa, Y and Inoue-Yamauchi, A and Naruse, H and Matsukawa, T and Takeshita, Y and Suzuki, N and Aoki, M and Nishiyama, A and Zeng, X and Konishi, C and Suzuki, N and Nishiyama, A and Harris, AS and Morita, M and Yamaguchi, K and Furukawa, Y and Nakai, K and Tsuji, S and Yamazaki, S and Yamanashi, Y and Shimada, S and Okada, T and Okano, H and Toda, T and Nakanishi, M}, title = {LONRF2 is a protein quality control ubiquitin ligase whose deficiency causes late-onset neurological deficits.}, journal = {Nature aging}, volume = {3}, number = {8}, pages = {1001-1019}, pmid = {37474791}, issn = {2662-8465}, mesh = {Animals ; Mice ; DNA Helicases/metabolism ; DNA-Binding Proteins/genetics ; Ligases/metabolism ; *Motor Neurons/metabolism ; Poly-ADP-Ribose Binding Proteins/metabolism ; RNA Helicases/metabolism ; RNA Recognition Motif Proteins/metabolism ; *Ubiquitin/metabolism ; *Ubiquitin-Protein Ligases/genetics/metabolism ; }, abstract = {Protein misfolding is a major factor of neurodegenerative diseases. Post-mitotic neurons are highly susceptible to protein aggregates that are not diluted by mitosis. Therefore, post-mitotic cells may have a specific protein quality control system. Here, we show that LONRF2 is a bona fide protein quality control ubiquitin ligase induced in post-mitotic senescent cells. Under unperturbed conditions, LONRF2 is predominantly expressed in neurons. LONRF2 binds and ubiquitylates abnormally structured TDP-43 and hnRNP M1 and artificially misfolded proteins. Lonrf2[-/-] mice exhibit age-dependent TDP-43-mediated motor neuron (MN) degeneration and cerebellar ataxia. Mouse induced pluripotent stem cell-derived MNs lacking LONRF2 showed reduced survival, shortening of neurites and accumulation of pTDP-43 and G3BP1 after long-term culture. The shortening of neurites in MNs from patients with amyotrophic lateral sclerosis is rescued by ectopic expression of LONRF2. Our findings reveal that LONRF2 is a protein quality control ligase whose loss may contribute to MN degeneration and motor deficits.}, } @article {pmid37474587, year = {2023}, author = {Zilio, F and Gomez-Pilar, J and Chaudhary, U and Fogel, S and Fomina, T and Synofzik, M and Schöls, L and Cao, S and Zhang, J and Huang, Z and Birbaumer, N and Northoff, G}, title = {Altered brain dynamics index levels of arousal in complete locked-in syndrome.}, journal = {Communications biology}, volume = {6}, number = {1}, pages = {757}, pmid = {37474587}, issn = {2399-3642}, support = {//CIHR/Canada ; }, mesh = {Humans ; *Locked-In Syndrome ; Electroencephalography/methods ; Brain/physiology ; Wakefulness ; Biomarkers ; }, abstract = {Complete locked-in syndrome (CLIS) resulting from late-stage amyotrophic lateral sclerosis (ALS) is characterised by loss of motor function and eye movements. The absence of behavioural indicators of consciousness makes the search for neuronal correlates as possible biomarkers clinically and ethically urgent. EEG-based measures of brain dynamics such as power-law exponent (PLE) and Lempel-Ziv complexity (LZC) have been shown to have explanatory power for consciousness and may provide such neuronal indices for patients with CLIS. Here, we validated PLE and LZC (calculated in a dynamic way) as benchmarks of a wide range of arousal states across different reference states of consciousness (e.g., awake, sleep stages, ketamine, sevoflurane). We show a tendency toward high PLE and low LZC, with high intra-subject fluctuations and inter-subject variability in a cohort of CLIS patients with values graded along different arousal states as in our reference data sets. In conclusion, changes in brain dynamics indicate altered arousal in CLIS. Specifically, PLE and LZC are potentially relevant biomarkers to identify or diagnose the arousal level in CLIS and to determine the optimal time point for treatment, including communication attempts.}, } @article {pmid37473705, year = {2023}, author = {Chen, W and Li, S and Bai, D and Li, Z and Liu, H and Bai, L and Pan, L}, title = {Detoxification mechanism of herbicide in Polypogon fugax and its influence on rhizosphere enzyme activities.}, journal = {Ecotoxicology and environmental safety}, volume = {263}, number = {}, pages = {115263}, doi = {10.1016/j.ecoenv.2023.115263}, pmid = {37473705}, issn = {1090-2414}, mesh = {*Herbicides/toxicity ; Molecular Docking Simulation ; Rhizosphere ; Poaceae/metabolism ; Herbicide Resistance/genetics ; Plant Proteins/metabolism ; }, abstract = {The excessive use of chemical herbicides has resulted in evolution of herbicide-resistant weeds. Cytochrome P450 monooxygenases (P450s) are vital detoxification enzymes for herbicide-resistant weeds. Herein, we confirmed a resistant (R) Polypogon fugax population showing resistance to quizalofop-p-ethyl, acetolactate synthase (ALS)-inhibiting herbicide pyroxsulam, and several other ACCase (acetyl-CoA carboxylase)-inhibiting herbicides. Molecular analysis revealed no target-site gene mutations in the R population. Foliar spraying with malathion clearly reversed the quizalofop-p-ethyl phytotoxicity. Higher level of quizalofop-p-ethyl degradation was confirmed in the R population using HPLC analysis. Subsequently, RNA-Seq transcriptome analysis indicated that the overexpression of CYP89A2 gene appeared to be responsible for reducing quizalofop-p-ethyl phytotoxicity. The molecular docking results supported a metabolic effect of CYP89A2 protein on most herbicides tested. Furthermore, we found that low doses of herbicides stimulated the rhizosphere enzyme activities in P. fugax and the increase of rhizosphere dehydrogenase of R population may be related to its resistance mechanism. In summary, our research has shown that metabolic herbicide resistance mediated by CYP89A2, contributes to quizalofop-p-ethyl resistance in P. fugax.}, } @article {pmid37473581, year = {2023}, author = {Woo, E and Bredvik, K and Liu, B and Fuchs, TJ and Manfredi, G and Konrad, C}, title = {Machine learning approaches based on fibroblast morphometry do not predict ALS.}, journal = {Neurobiology of aging}, volume = {130}, number = {}, pages = {80-83}, doi = {10.1016/j.neurobiolaging.2023.06.010}, pmid = {37473581}, issn = {1558-1497}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Biomarkers ; Endoplasmic Reticulum/metabolism ; Machine Learning ; Fibroblasts/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease with limited therapeutic options. Biomarkers are needed for early disease detection, clinical trial design, and personalized medicine. Early evidence suggests that specific morphometric features in ALS primary skin fibroblasts may be used as biomarkers; however, this hypothesis has not been rigorously tested in conclusively large fibroblast populations. Here, we imaged ALS-relevant organelles (mitochondria, endoplasmic reticulum, lysosomes) and proteins (TAR DNA-binding protein 43, Ras GTPase-activating protein-binding protein 1, heat-shock protein 60) at baseline and under stress perturbations and tested their predictive power on a total set of 443 human fibroblast lines from ALS and healthy individuals. Machine learning approaches were able to confidently predict stress perturbation states (ROC-AUC ∼0.99) but not disease groups or clinical features (ROC-AUC 0.58-0.64). Our findings indicate that multivariate models using patient-derived fibroblast morphometry can accurately predict different stressors but are insufficient to develop viable ALS biomarkers.}, } @article {pmid37471224, year = {2023}, author = {Park, J and Wu, Y and Shao, W and Gendron, TF and van der Spek, SJF and Sultanakhmetov, G and Basu, A and Castellanos Otero, P and Jones, CJ and Jansen-West, K and Daughrity, LM and Phanse, S and Del Rosso, G and Tong, J and Castanedes-Casey, M and Jiang, L and Libera, J and Oskarsson, B and Dickson, DW and Sanders, DW and Brangwynne, CP and Emili, A and Wolozin, B and Petrucelli, L and Zhang, YJ}, title = {Poly(GR) interacts with key stress granule factors promoting its assembly into cytoplasmic inclusions.}, journal = {Cell reports}, volume = {42}, number = {8}, pages = {112822}, pmid = {37471224}, issn = {2211-1247}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; RF1 AG062171/AG/NIA NIH HHS/United States ; U01 AG072577/AG/NIA NIH HHS/United States ; RF1 AG062077/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R21 NS127331/NS/NINDS NIH HHS/United States ; R01 NS117461/NS/NINDS NIH HHS/United States ; RF1 AG061706/AG/NIA NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; R01 AG080810/AG/NIA NIH HHS/United States ; P01 NS099114/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; DNA Helicases/metabolism ; Stress Granules ; DNA Repeat Expansion ; Poly-ADP-Ribose Binding Proteins/genetics/metabolism ; RNA Helicases/genetics/metabolism ; RNA Recognition Motif Proteins/metabolism ; *Frontotemporal Dementia/metabolism ; Inclusion Bodies/metabolism ; Heat-Shock Proteins/metabolism ; RNA/metabolism ; C9orf72 Protein/genetics/metabolism ; }, abstract = {C9orf72 repeat expansions are the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Poly(GR) proteins are toxic to neurons by forming cytoplasmic inclusions that sequester RNA-binding proteins including stress granule (SG) proteins. However, little is known of the factors governing poly(GR) inclusion formation. Here, we show that poly(GR) infiltrates a finely tuned network of protein-RNA interactions underpinning SG formation. It interacts with G3BP1, the key driver of SG assembly and a protein we found is critical for poly(GR) inclusion formation. Moreover, we discovered that N[6]-methyladenosine (m6A)-modified mRNAs and m6A-binding YTHDF proteins not only co-localize with poly(GR) inclusions in brains of c9FTD/ALS mouse models and patients with c9FTD, they promote poly(GR) inclusion formation via the incorporation of RNA into the inclusions. Our findings thus suggest that interrupting interactions between poly(GR) and G3BP1 or YTHDF1 proteins or decreasing poly(GR) altogether represent promising therapeutic strategies to combat c9FTD/ALS pathogenesis.}, } @article {pmid37470509, year = {2023}, author = {Strnad, P and San Martin, J}, title = {RNAi therapeutics for diseases involving protein aggregation: fazirsiran for alpha-1 antitrypsin deficiency-associated liver disease.}, journal = {Expert opinion on investigational drugs}, volume = {32}, number = {7}, pages = {571-581}, doi = {10.1080/13543784.2023.2239707}, pmid = {37470509}, issn = {1744-7658}, mesh = {Humans ; *Protein Aggregates ; RNA Interference ; RNAi Therapeutics ; *alpha 1-Antitrypsin Deficiency/complications/genetics/therapy ; RNA, Small Interfering ; }, abstract = {INTRODUCTION: Therapeutic agents that prevent protein misfolding or promote protein clearance are being studied to treat proteotoxic diseases. Among them, alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the alpha-1 antitrypsin (SERPINA1) gene. Fazirsiran is a small interfering RNA (siRNA) that is intended to address the underlying cause of liver disease associated with AATD through the RNA interference (RNAi) mechanism.

AREAS COVERED: This article describes the role of misfolded proteins and protein aggregates in disease and options for therapeutic approaches. The RNAi mechanism is discussed, along with how the siRNA therapeutic fazirsiran for the treatment of AATD was developed. We also describe the implications of siRNA therapeutics in extrahepatic diseases.

EXPERT OPINION: Using RNAi as a therapeutic approach is well suited to treat disease in conditions where an excess of a protein or the effect of an abnormal mutated protein causes disease. The results observed for the first few siRNA therapeutics that were approved or are in development provide an important promise for the development of future drugs that can address such conditions in a specific and targeted way. Current developments should enable the use of RNAi therapeutics outside the liver, where there are many more possible diseases to address.}, } @article {pmid37470197, year = {2023}, author = {Zhan, Z and Fu, J and Chen, H and Pan, H and Weng, S and He, J and Guo, C}, title = {Development and characterization of a spleen cell line from yellowfin seabream Acanthopagrus latus and its susceptibility to Mandarinfish ranavirus.}, journal = {Journal of fish diseases}, volume = {46}, number = {11}, pages = {1173-1181}, doi = {10.1111/jfd.13837}, pmid = {37470197}, issn = {1365-2761}, support = {//Agriculture Research System of China/ ; //Guangdong Basic and Applied Basic Research Foundation/ ; //Guangdong Key Research and Development Program/ ; //Guangdong Laboratory for Lingnan Modern Agriculture/ ; //Guangdong Provincial Special Fund for Modern Agriculture Industry Technology Innovation Teams/ ; //Innovation Group Project of Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai)/ ; //National Key Research and Development Program of China/ ; }, abstract = {Yellowfin seabream (Acanthopagrus latus) is one of the most commercially important marine fish in China. In this study, a new continuous cell line, named ALS cells, was developed from the spleen tissue of A. latus. The cell line was maintained in Dulbecco's modified Eagle medium/Nutrient Mixture F-12 Ham (DMEM/F-12) supplemented with 10% fetal bovine serum (FBS) and successfully cultured up to 50 passages. The cell line was authenticated by amplifying and sequencing mitochondrial cytochrome C oxidase subunit-I (coi-I) gene. The ALS cell line had the maximum growth rate in DMEM/F-12 medium containing 20% FBS at 27°C. Chromosome number analysis showed that the ALS cells have a modal diploid chromosome number of 34. The ALS cell line was transfected with the pEGFP-N1 plasmid, and green fluorescence was observed. The ALS cell line was used for testing Mandarinfish ranavirus (MRV) susceptibility, and the cytopathic effects in the cell line were observed at 4 days post-infection (dpi). Furthermore, the susceptibility of the ALS cell line to MRV and the levels of MRV mRNA and viral loads were found to be significantly increased at 1-7 dpi. This study revealed that the ALS cell line could be useful for molecular, virological, and biotechnological studies on yellowfin seabream.}, } @article {pmid37469832, year = {2023}, author = {Mora, S and Allodi, I}, title = {Neural circuit and synaptic dysfunctions in ALS-FTD pathology.}, journal = {Frontiers in neural circuits}, volume = {17}, number = {}, pages = {1208876}, pmid = {37469832}, issn = {1662-5110}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Frontotemporal Dementia/complications/genetics/pathology ; Brain ; Cognition ; }, abstract = {Action selection is a capital feature of cognition that guides behavior in processes that range from motor patterns to executive functions. Here, the ongoing actions need to be monitored and adjusted in response to sensory stimuli to increase the chances of reaching the goal. As higher hierarchical processes, these functions rely on complex neural circuits, and connective loops found within the brain and the spinal cord. Successful execution of motor behaviors depends, first, on proper selection of actions, and second, on implementation of motor commands. Thus, pathological conditions crucially affecting the integrity and preservation of these circuits and their connectivity will heavily impact goal-oriented motor behaviors. Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurodegenerative disorders known to share disease etiology and pathophysiology. New evidence in the field of ALS-FTD has shown degeneration of specific neural circuits and alterations in synaptic connectivity, contributing to neuronal degeneration, which leads to the impairment of motor commands and executive functions. This evidence is based on studies performed on animal models of disease, post-mortem tissue, and patient derived stem cells. In the present work, we review the existing evidence supporting pathological loss of connectivity and selective impairment of neural circuits in ALS and FTD, two diseases which share strong genetic causes and impairment in motor and executive functions.}, } @article {pmid37469125, year = {2023}, author = {Ghaderi, S and Fatehi, F and Kalra, S and Batouli, SAH}, title = {MRI biomarkers for memory-related impairment in amyotrophic lateral sclerosis: a systematic review.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/21678421.2023.2236651}, pmid = {37469125}, issn = {2167-9223}, abstract = {Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with cognitive and behavioral impairments and motor symptoms. Magnetic resonance imaging (MRI) biomarkers have been investigated as potential tools for detecting and monitoring memory-related impairment in ALS. Our objective was to examine the importance of identifying MRI biomarkers for memory-related impairment in ALS, motor neuron disease (MND), and ALS frontotemporal dementia (FTD) (ALS-FTD) patients. Methods: PubMed and Scopus databases were searched. Keywords covering magnetic resonance imaging, ALS, MND, and memory impairments were searched. There were a total of 25 studies included in our work here. Results: The structural MRI (sMRI) studies reported gray matter (GM) atrophy in the regions associated with memory processing, such as the hippocampus and parahippocampal gyrus (PhG), in ALS patients. The diffusion tensor imaging (DTI) studies showed white matter (WM) alterations in the corticospinal tract (CST) and other tracts that are related to motor and extra-motor functions, and these alterations were associated with memory and executive function impairments in ALS. The functional MRI (fMRI) studies also demonstrated an altered activation in the prefrontal cortex, limbic system, and other brain regions involved in memory and emotional processing in ALS patients. Conclusion: MRI biomarkers show promise in uncovering the neural mechanisms of memory-related impairment in ALS. Nonetheless, addressing challenges such as sample sizes, imaging protocols, and longitudinal studies is crucial for future research. Ultimately, MRI biomarkers have the potential to be a tool for detecting and monitoring memory-related impairments in ALS.}, } @article {pmid37467887, year = {2023}, author = {Troxell, DA and Bach, JR and Nilsestuen, JO}, title = {Mechanical Insufflation-Exsufflation Implementation and Management, Aided by Graphics Analysis.}, journal = {Chest}, volume = {164}, number = {6}, pages = {1505-1511}, doi = {10.1016/j.chest.2023.07.007}, pmid = {37467887}, issn = {1931-3543}, mesh = {Humans ; *Insufflation ; Respiration, Artificial ; Lung ; *Respiratory Insufficiency/therapy ; Cough ; }, abstract = {Mechanical insufflation-exsufflation (MIE) facilitates airway clearance to mitigate respiratory infection, decompensation, and ultimately the need for intubation and placement of a tracheostomy tube. Despite widespread adoption as a respiratory support intervention for motor neuron disease, muscular dystrophy, spinal cord injury, and other diseases associated with ventilatory pump failure and ineffective cough peak flow, there is debate in the clinical community about how to optimize settings when MIE is implemented. This article will demonstrate the clinical utility of MIE graphics in titrating the initial MIE settings, guiding upper airway and lung protective strategies and providing insight to clinicians for ongoing clinical management.}, } @article {pmid37467213, year = {2023}, author = {Oey, A and McClure, M and Symons, JA and Chanda, S and Fry, J and Smith, PF and Luciani, K and Fayon, M and Chokephaibulkit, K and Uppala, R and Bernatoniene, J and Furuno, K and Stanley, T and Huntjens, D and Witek, J and , }, title = {Lumicitabine, an orally administered nucleoside analog, in infants hospitalized with respiratory syncytial virus (RSV) infection: Safety, efficacy, and pharmacokinetic results.}, journal = {PloS one}, volume = {18}, number = {7}, pages = {e0288271}, pmid = {37467213}, issn = {1932-6203}, mesh = {Adult ; Child ; Humans ; Infant ; Infant, Newborn ; Antiviral Agents/adverse effects ; *Neutropenia/complications ; Nucleosides/therapeutic use ; *Respiratory Syncytial Virus Infections ; *Respiratory Syncytial Virus, Human ; }, abstract = {Respiratory syncytial virus (RSV) infection is the leading cause of infant hospitalizations and mortality. Lumicitabine, an oral nucleoside analog was studied for the treatment of RSV. The phase 1b and phase 2b studies reported here assessed the safety, pharmacokinetics, and pharmacodynamics of lumicitabine in infants/neonates hospitalized with RSV. In the phase 1b study, infants (≥1 to ≤12 months) and neonates (<28 days) received a single-ascending or multiple-ascending doses (single loading dose [LD] then 9 maintenance doses [MD] of lumicitabine, or placebo [3:1]). In the phase 2b study, infants/children (28 days to ≤36 months old) received lumicitabine 40/20 mg/kg, 60/40 mg/kg LD/MD twice-daily or placebo (1:1:1) for 5 days. Safety, pharmacokinetics, and efficacy parameters were assessed over 28 days. Lumicitabine was associated with a dose-related increase in the incidence and severity of reversible neutropenia. Plasma levels of ALS-008112, the active nucleoside analog, were dose-proportional with comparable mean exposure levels at the highest doses in both studies. There were no significant differences between the lumicitabine groups and placebo in reducing viral load, time to viral non-detectability, and symptom resolution. No emergent resistance-associated substitutions were observed at the RSV L-gene positions of interest. In summary, lumicitabine was associated with a dose-related increase in the incidence and severity of reversible neutropenia and failed to demonstrate antiviral activity in RSV-infected hospitalized infants. This contrasts with the findings of the previous RSV-A adult challenge study where significant antiviral activity was noted, without incidence of neutropenia. Trial registration ClinicalTrials.gov Identifier: NCT02202356 (phase 1b); NCT03333317 (phase 2b).}, } @article {pmid37466825, year = {2024}, author = {Poppe, C and Elger, BS}, title = {Brain-Computer Interfaces, Completely Locked-In State in Neurodegenerative Diseases, and End-of-Life Decisions.}, journal = {Journal of bioethical inquiry}, volume = {21}, number = {1}, pages = {19-27}, pmid = {37466825}, issn = {1872-4353}, mesh = {Humans ; *Brain-Computer Interfaces/ethics ; *Terminal Care/ethics ; *Neurodegenerative Diseases ; *Quality of Life ; *Decision Making/ethics ; Suicide, Assisted/ethics ; Locked-In Syndrome ; Mental Competency ; }, abstract = {In the future, policies surrounding end-of-life decisions will be faced with the question of whether competent people in a completely locked-in state should be enabled to make end-of-life decisions via brain-computer interfaces (BCI). This article raises ethical issues with acting through BCIs in the context of these decisions, specifically self-administration requirements within assisted suicide policies. We argue that enabling patients to end their life even once they have entered completely locked-in state might, paradoxically, prolong and uphold their quality of life.}, } @article {pmid37466726, year = {2023}, author = {Gittings, LM and Alsop, EB and Antone, J and Singer, M and Whitsett, TG and Sattler, R and Van Keuren-Jensen, K}, title = {Cryptic exon detection and transcriptomic changes revealed in single-nuclei RNA sequencing of C9ORF72 patients spanning the ALS-FTD spectrum.}, journal = {Acta neuropathologica}, volume = {146}, number = {3}, pages = {433-450}, pmid = {37466726}, issn = {1432-0533}, support = {P30 AG019610/AG/NIA NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Frontotemporal Dementia/genetics/pathology ; C9orf72 Protein/genetics/metabolism ; Transcriptome ; *Pick Disease of the Brain/genetics ; DNA-Binding Proteins/genetics/metabolism ; Exons ; Sequence Analysis, RNA ; }, abstract = {The C9ORF72-linked diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by the nuclear depletion and cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43). Recent studies have shown that the loss of TDP-43 function leads to the inclusion of cryptic exons (CE) in several RNA transcript targets of TDP-43. Here, we show for the first time the detection of CEs in a single-nuclei RNA sequencing (snRNA-seq) dataset obtained from frontal and occipital cortices of C9ORF72 patients that phenotypically span the ALS-FTD disease spectrum. We assessed each cellular cluster for detection of recently described TDP-43-induced CEs. Transcripts containing CEs in the genes STMN2 and KALRN were detected in the frontal cortex of all C9ORF72 disease groups with the highest frequency in excitatory neurons in the C9ORF72-FTD group. Within the excitatory neurons, the cluster with the highest proportion of cells containing a CE had transcriptomic similarities to von Economo neurons, which are known to be vulnerable to TDP-43 pathology and selectively lost in C9ORF72-FTD. Differential gene expression and pathway analysis of CE-containing neurons revealed multiple dysregulated metabolic processes. Our findings reveal novel insights into the transcriptomic changes of neurons vulnerable to TDP-43 pathology.}, } @article {pmid37466098, year = {2023}, author = {Borghero, G and Sechi, MM and Vasta, R and Pierri, V and Pili, F and Pateri, I and Pilotto, S and Ercoli, T and Muroni, A and Chiò, A and Defazio, G}, title = {Spatial clustering of amyotrophic lateral sclerosis in Sardinia, Italy: The contribution of age, sex, and genetic factors.}, journal = {Muscle & nerve}, volume = {68}, number = {3}, pages = {323-328}, doi = {10.1002/mus.27939}, pmid = {37466098}, issn = {1097-4598}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Mutation/genetics ; Incidence ; Risk Factors ; Cluster Analysis ; Italy/epidemiology ; }, abstract = {INTRODUCTION/AIMS: Several microgeographic clusters of higher/lower incidence of amyotrophic lateral sclerosis (ALS) have been identified worldwide. Differences in the distribution of local factors were proposed to explain the excess ALS risk, whereas the contribution of known genetic/epigenetic factors remains unclear. The aim is to identify restricted areas of higher risk in Sardinia and to assess whether age, sex, and the most common causative genetic mutations in Sardinia (C9orf72 and TARDBP mutations) contributed to the variation in the ALS risk.

METHODS: We performed an ad hoc analysis of the 10-y population-based incident cohort of ALS cases from a recent study of a large Sardinian area. Cluster analysis was performed by age- and sex-adjusted Kulldorff's spatial scan statistic.

RESULTS: We identified a statistically significant cluster of higher ALS incidence in a relatively large area including 34 municipalities and >100,000 individuals. The investigated genetic mutations were more frequent in the cluster area than outside. Regardless of the genetic mutations, the excess of ALS risk was significantly associated with either sex or with age ≥ 65 y. Finally, an additive interaction between older age and male sex contributed to the excess of ALS risk in the cluster area but not outside.

DISCUSSION: Our analysis demonstrated that known genetic factors, age, and sex may contribute to microgeographic variation in ALS incidence. The significant additive interaction between older age and male sex we found in the high-incidence cluster could suggest the presence of a third factor connecting the analyzed risk factors.}, } @article {pmid37465879, year = {2023}, author = {Alhindi, A and Shand, M and Smith, HL and Leite, AS and Huang, YT and van der Hoorn, D and Ridgway, Z and Faller, KME and Jones, RA and Gillingwater, TH and Chaytow, H}, title = {Neuromuscular junction denervation and terminal Schwann cell loss in the hTDP-43 overexpression mouse model of amyotrophic lateral sclerosis.}, journal = {Neuropathology and applied neurobiology}, volume = {49}, number = {4}, pages = {e12925}, doi = {10.1111/nan.12925}, pmid = {37465879}, issn = {1365-2990}, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/pathology ; *Neurodegenerative Diseases/pathology ; Neuromuscular Junction/pathology ; Motor Neurons/pathology ; Schwann Cells/metabolism/pathology ; Denervation ; DNA-Binding Proteins/metabolism ; Mice, Transgenic ; Disease Models, Animal ; }, abstract = {AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with complex aetiology. Despite evidence of neuromuscular junction (NMJ) denervation and 'dying-back' pathology in models of SOD1-dependent ALS, evidence in other genetic forms of ALS is limited by a lack of suitable animal models. TDP-43, a key mediator protein in ALS, is overexpressed in neurons in Thy1-hTDP-43[WT] mice. We therefore aimed to comprehensively analyse NMJ pathology in this model of ALS.

METHODS: Expression of TDP-43 was assessed via western blotting. Immunohistochemistry techniques, alongside NMJ-morph quantification, were used to analyse motor neuron number, NMJ denervation status and terminal Schwann cell morphology.

RESULTS: We present a time course of progressive, region-specific motor neuron pathology in Thy1-hTDP-43[WT] mice. Thy1-driven hTDP-43 expression increased steadily, correlating with developing hindlimb motor weakness and associated motor neuron loss in the spinal cord with a median survival of 21 days. Pronounced NMJ denervation was observed in hindlimb muscles, mild denervation in cranial muscles but no evidence of denervation in either forelimb or trunk muscles. NMJ pathology was restricted to motor nerve terminals, with denervation following the same time course as motor neuron loss. Terminal Schwann cells were lost from NMJs in hindlimb muscles, directly correlating with denervation status.

CONCLUSIONS: Thy1-hTDP-43[WT] mice represent a severe model of ALS, with NMJ pathology/denervation of distal muscles and motor neuron loss, as observed in ALS patients. This model therefore provides an ideal platform to investigate mechanisms of dying-back pathology, as well as NMJ-targeting disease-modifying therapies in ALS.}, } @article {pmid37465321, year = {2023}, author = {Gnoni, V and Zoccolella, S and Giugno, A and Urso, D and Tamburrino, L and Filardi, M and Logroscino, G}, title = {Hypothalamus and amyotrophic lateral sclerosis: potential implications in sleep disorders.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1193483}, pmid = {37465321}, issn = {1663-4365}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects both motor and non-motor functions, including sleep regulation. Emerging evidence suggests that the hypothalamus, a brain region that plays a critical role in sleep-wake regulation, may be involved in the pathogenesis of ALS-related sleep disturbances. In this review, we have summarized results of studies on sleep disorders in ALS published between 2000 and 2023. Thereafter, we examined possible mechanisms by which hypothalamic dysfunctions may contribute to ALS-related sleep disturbances. Achieving a deeper understanding of the relationship between hypothalamic dysfunction and sleep disturbances in ALS can help improve the overall management of ALS and reduce the burden on patients and their families.}, } @article {pmid37465304, year = {2023}, author = {Kargbo, RB}, title = {Microbiome-Gut-Brain Axis Modulation: New Approaches in Treatment of Parkinson's Disease and Amyotrophic Lateral Sclerosis.}, journal = {ACS medicinal chemistry letters}, volume = {14}, number = {7}, pages = {886-888}, pmid = {37465304}, issn = {1948-5875}, abstract = {Parkinson's Disease (PD) is a neurodegenerative movement disorder characterized by symptoms like resting tremor, rigidity, bradykinesia, and postural instability, mainly due to dopamine depletion and degeneration of dopaminergic neurons. Mitochondrial dysfunction plays a critical role in the disease's progression, while amyotrophic Lateral Sclerosis (ALS), or Lou Gehrig's disease, is a fatal progressive neurodegenerative disease characterized by significant motor neuron loss in the primary motor cortex, brainstem, and spinal cord. This loss results in impaired movements such as breathing, leading to death within 2-5 years of diagnosis. Patients experience muscle weakness in the hands, arms, legs, and swallowing muscles and may require breathing aids. This Patent Highlight describes blends, such as microbiome compositions, that can be used to treat various diseases or conditions, particularly those affecting the nervous system, like neurodegenerative diseases (PD and ALS).}, } @article {pmid37463628, year = {2023}, author = {Soumya, BS and Shreenidhi, VP and Agarwal, A and Gandhirajan, RK and Dharmarajan, A and Warrier, S}, title = {Unwinding the role of Wnt signaling cascade and molecular triggers of motor neuron degeneration in amyotrophic lateral sclerosis (ALS).}, journal = {Cellular signalling}, volume = {110}, number = {}, pages = {110807}, doi = {10.1016/j.cellsig.2023.110807}, pmid = {37463628}, issn = {1873-3913}, mesh = {Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; Wnt Signaling Pathway ; Motor Neurons/metabolism ; Oxidative Stress ; Nerve Degeneration/metabolism/pathology ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative condition, triggered by various factors causing the degeneration of upper and lower motor neurons, resulting in progressive muscle wasting, paralysis, and death. Multiple in vivo and in vitro models have been established to unravel the molecular events leading to the deterioration of motor neurons in ALS. The canonical and non-canonical Wnt signaling pathway has been implicated to play a crucial role in the progression of neurodegenerative disorders. This review discusses the role of Wnt signaling in the reported causes of ALS such as oxidative stress, mitochondrial dysfunction, autophagy, and apoptosis. Mutations in ALS-associated genes such as SOD1, C9orf72, TDP43, FUS, and OPTN cause an imbalance in neuronal integrity and homeostasis leading to motor neuron demise. Wnt signaling is also observed to play a crucial role in the muscle sparing of oculomotor neurons. The non-canonical Wnt/Ca[2+] pathway which regulates intrinsic electrophysiological properties and mobilizes calcium ions to maintain neuronal integrity has been found to be altered in the stem cell-derived ALS model. Thus, the interplay of dysregulated canonical and non-canonical Wnt pathways in multiple motor neuron disease models has shown that Wnt contributes to disease progression indicating it to be utilized as a potential target for ALS.}, } @article {pmid37462337, year = {2023}, author = {Genuis, SK and Luth, W and Bubela, T and Johnston, WS}, title = {What do people affected by amyotrophic lateral sclerosis want from health communications? Evidence from the ALS Talk Project.}, journal = {Muscle & nerve}, volume = {68}, number = {3}, pages = {286-295}, doi = {10.1002/mus.27935}, pmid = {37462337}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Health Communication ; Quality of Life ; Caregivers ; Health Personnel ; }, abstract = {INTRODUCTION/AIMS: Health communication is central to effective, supportive amyotrophic lateral sclerosis (ALS) clinical care. Guidance for ALS communication is limited, focuses on diagnosis disclosure, and frequently relies on expert consensus and/or reviews. Patient-based evidence is needed to guide ALS health communication. We investigated how the experiences of ALS patients and family caregivers can inform effective communication practices from diagnosis to end-of-life.

METHODS: Data were drawn from the ALS Talk Project, an asynchronous, online focus group study. Seven focus groups and five interviews (105 participants) were conducted. Data were qualitatively analyzed using directed content analysis and the constant-comparative approach.

RESULTS: We found four primary themes: communication content, communication circumstances, information sufficiency, and communication manner. Data indicate participants relied on clinicians for medical information but also wanted practical information; health communication should attend to the circumstances within which conversations occur; information must be sufficient for individual needs, without overwhelming; and an empathetic, direct, and honest manner facilitated trust. Participants identified communication challenges and strategies to improve communication across major themes, including stepwise approaches and conversations tailored to individuals and their heterogeneous disease experiences.

DISCUSSION: Healthcare professionals should discuss patient/caregiver communication preferences early in the therapeutic relationship, co-develop a communication agreement, and update the agreement in response to changing needs and disease progression. This will foster regular discussion of information needs and promote timely discussions of challenging topics, including advance care, while giving patients and families a sense of control. Findings may have implications for other neuromuscular disease and/or seriously ill populations.}, } @article {pmid37461717, year = {2023}, author = {Provasek, VE and Kodavati, M and Guo, W and Wang, H and Boldogh, I and Van Den Bosch, L and Britz, G and Hegde, M}, title = {lncRNA Sequencing Reveals Neurodegeneration-associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists In Motor Neurons.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37461717}, issn = {2693-5015}, support = {R01 NS088645/NS/NINDS NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {Fused-in Sarcoma (FUS) gene mutations have been implicated in amyotrophic lateral sclerosis (ALS). This study aimed to investigate the impact of FUS mutations (R521H and P525L) on the transcriptome of induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs). Using RNA sequencing (RNA Seq), we characterized differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs), and subsequently predicted lncRNA-mRNA target pairs (TAR pairs). Our results show that FUS mutations significantly altered expression profiles of mRNAs and lncRNAs in iPSCs. We identified key differentially regulated TAR pairs, including LMO3, TMEM132D, ERMN, GPR149, CRACD, and ZNF404 in mutant FUS iPSCs. We performed reverse transcription PCR (RT-PCR) validation in iPSCs and iMNs. Validation confirmed RNA-Seq findings and suggested that mutant FUS-induced transcriptional alterations persisted from iPSCs into differentiated iMNs. Functional enrichment analyses of DEGs indicated pathways associated with neuronal development and carcinogenesis that were likely altered by FUS mutations. Ingenuity Pathway Analysis (IPA) and GO network analysis of lncRNA-targeted mRNAs indicated associations related to RNA metabolism, lncRNA regulation, and DNA damage repair. Our findings provide insights into the molecular mechanisms underlying the pathophysiology of ALS-associated FUS mutations and suggest potential therapeutic targets for the treatment of ALS.}, } @article {pmid37461319, year = {2023}, author = {Fujino, Y and Ueyama, M and Ishiguro, T and Ozawa, D and Ito, H and Sugiki, T and Murata, A and Ishiguro, A and Gendron, T and Mori, K and Tokuda, E and Taminato, T and Konno, T and Koyama, A and Kawabe, Y and Takeuchi, T and Furukawa, Y and Fujiwara, T and Ikeda, M and Mizuno, T and Mochizuki, H and Mizusawa, H and Wada, K and Ishikawa, K and Onodera, O and Nakatani, K and Petrucelli, L and Taguchi, H and Nagai, Y}, title = {FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA in C9orf72-linked ALS/FTD.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {37461319}, issn = {2050-084X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/pathology ; RNA/metabolism ; RNA-Binding Protein FUS/genetics ; RNA-Binding Proteins/genetics ; Drosophila/genetics ; }, abstract = {Abnormal expansions of GGGGCC repeat sequence in the noncoding region of the C9orf72 gene is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). The expanded repeat sequence is translated into dipeptide repeat proteins (DPRs) by noncanonical repeat-associated non-AUG (RAN) translation. Since DPRs play central roles in the pathogenesis of C9-ALS/FTD, we here investigate the regulatory mechanisms of RAN translation, focusing on the effects of RNA-binding proteins (RBPs) targeting GGGGCC repeat RNAs. Using C9-ALS/FTD model flies, we demonstrated that the ALS/FTD-linked RBP FUS suppresses RAN translation and neurodegeneration in an RNA-binding activity-dependent manner. Moreover, we found that FUS directly binds to and modulates the G-quadruplex structure of GGGGCC repeat RNA as an RNA chaperone, resulting in the suppression of RAN translation in vitro. These results reveal a previously unrecognized regulatory mechanism of RAN translation by G-quadruplex-targeting RBPs, providing therapeutic insights for C9-ALS/FTD and other repeat expansion diseases.}, } @article {pmid37461167, year = {2023}, author = {Berger, A and Locatelli, M and Arcila-Londono, X and Hayat, G and Olney, N and Wymer, J and Gwathmey, K and Lunetta, C and Heiman-Patterson, T and Ajroud-Driss, S and Macklin, EA and Bind, MA and Goslin, K and Stuchiner, T and Brown, L and Bazan, T and Regan, T and Adamo, A and Ferment, V and Schroeder, C and Somers, M and Manousakis, G and Faulconer, K and Sinani, E and Mirochnick, J and Yu, H and Sherman, AV and Walk, D and , }, title = {The natural history of ALS: Baseline characteristics from a multicenter clinical cohort.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2023.2232812}, pmid = {37461167}, issn = {2167-9223}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare disease with urgent need for improved treatment. Despite the acceleration of research in recent years, there is a need to understand the full natural history of the disease. As only 40% of people living with ALS are eligible for typical clinical trials, clinical trial datasets may not generalize to the full ALS population. While biomarker and cohort studies have more generous inclusion criteria, these too may not represent the full range of phenotypes, particularly if the burden for participation is high. To permit a complete understanding of the heterogeneity of ALS, comprehensive data on the full range of people with ALS is needed.

METHODS: The ALS Natural History Consortium (ALS NHC) consists of nine ALS clinics and was created to build a comprehensive dataset reflective of the ALS population. At each clinic, most patients are asked to participate and about 95% do. After obtaining consent, a minimum dataset is abstracted from each participant's electronic health record. Participant burden is therefore minimal.

RESULTS: Data on 1925 ALS patients were submitted as of 9 December 2022. ALS NHC participants were more heterogeneous relative to anonymized clinical trial data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The ALS NHC includes ALS patients of older age of onset and a broader distribution of El Escorial categories, than the PRO-ACT database.

CONCLUSIONS: ALS NHC participants had a higher diversity of diagnostic and demographic data compared to ALS clinical trial participants.Key MessagesWhat is already known on this topic: Current knowledge of the natural history of ALS derives largely from regional and national registries that have broad representation of the population of people living with ALS but do not always collect covariates and clinical outcomes. Clinical studies with rich datasets of participant characteristics and validated clinical outcomes have stricter inclusion and exclusion criteria that may not be generalizable to the full ALS population.What this study adds: To bridge this gap, we collected baseline characteristics for a sample of the population of people living with ALS seen at a consortium of ALS clinics that collect extensive, pre-specified participant-level data, including validated outcome measures.How this study might affect research, practice, or policy: A clinic-based longitudinal dataset can improve our understanding of the natural history of ALS and can be used to inform the design and analysis of clinical trials and health economics studies, to help the prediction of clinical course, to find matched controls for open label extension trials and expanded access protocols, and to document real-world evidence of the impact of novel treatments and changes in care practice.}, } @article {pmid37460793, year = {2023}, author = {Gawlik-Dziki, U and Wrzesińska-Krupa, B and Nowak, R and Pietrzak, W and Zyprych-Walczak, J and Obrępalska-Stęplowska, A}, title = {Herbicide resistance status impacts the profile of non-anthocyanin polyphenolics and some phytomedical properties of edible cornflower (Centaurea cyanus L.) flowers.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {11538}, pmid = {37460793}, issn = {2045-2322}, mesh = {*Herbicide Resistance ; *Herbicides/pharmacology ; Flowers ; Centaurea ; Plant Weeds ; }, abstract = {To ensure sufficient food supply worldwide, plants are treated with pesticides to provide protection against pathogens and pests. Herbicides are the most commonly utilised pesticides, used to reduce the growth of weeds. However, their long-term use has resulted in the emergence of herbicide-resistant biotypes in many weed species. Cornflower (Centaurea cyanus L., Asteraceae) is one of these plants, whose biotypes resistant to herbicides from the group of acetolactate synthase (ALS) inhibitors have begun to emerge in recent years. Some plants, although undesirable in crops and considered as weeds, are of great importance in phytomedicine and food production, and characterised by a high content of health-promoting substances, including antioxidants. Our study aimed to investigate how the acquisition of herbicide resistance affects the health-promoting properties of plants on the example of cornflower, as well as how they are affected by herbicide treatment. To this end, we analysed non-anthocyanin polyphenols and antioxidant capacity in flowers of C. cyanus from herbicide-resistant and susceptible biotypes. Our results indicated significant compositional changes associated with an increase in the content of substances and activities that have health-promoting properties. High antioxidant activity and higher total phenolic and flavonoid compounds as well as reducing power were observed in resistant biotypes. The latter one increased additionally after herbicide treatment which might also suggest their role in the resistance acquisition mechanism. Overall, these results show that the herbicide resistance development, although unfavourable to crop production, may paradoxically have very positive effects for medicinal plants such as cornflower.}, } @article {pmid37460332, year = {2023}, author = {Lacroix, C and Guilhaumou, R and Micallef, J and Bruneteau, G and Desnuelle, C and Blin, O}, title = {Cannabis for the treatment of amyotrophic lateral sclerosis: What is the patients' view?.}, journal = {Revue neurologique}, volume = {179}, number = {9}, pages = {967-974}, doi = {10.1016/j.neurol.2023.03.018}, pmid = {37460332}, issn = {0035-3787}, mesh = {Humans ; *Cannabis/adverse effects ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; Quality of Life ; *Cannabinoids/adverse effects ; Pain ; }, abstract = {Cannabis may have therapeutic benefits to relieve symptoms of amyotrophic lateral sclerosis (ALS) thanks to its pleiotropic pharmacological activity. This study is the first to present a large questionnaire-based survey about the "real-life" situation regarding cannabis use in the medical context in ALS patients in France. There were 129 respondents and 28 reported the use of cannabis (21.7%) to relieve symptoms of ALS. Participants mostly reported the use of cannabidiol (CBD) oil and cannabis weed and declared benefits both on motor (rigidity, cramps, fasciculations) and non-motor (sleep quality, pain, emotional state, quality of life, depression) symptoms and only eight reported minor adverse reactions (drowsiness, euphoria and dry mouth). Even if cannabis is mostly used outside medical pathways and could expose patients to complications (street and uncontrolled drugs, drug-drug interactions, adverse effects…), most of the participants reported "rational" consumption (legal cannabinoids, with only few combustion and adverse reactions). Despite some limitations, this study highlights the need for further research on the potential benefits of cannabis use for the management of ALS motor and non-motor symptoms. Indeed, there is an urgent need and call for and from patients to know more about cannabis and secure its use in a medical context.}, } @article {pmid37460258, year = {2023}, author = {Pedron, S and Herbert-Maul, A and Sauter, A and Linder, S and Sommer, R and Vomhof, M and Gontscharuk, V and Abu-Omar, K and Thiel, A and Ziemainz, H and Holle, R and Laxy, M}, title = {Preferences of women in difficult life situations for a physical activity programme: protocol of a discrete choice experiment in the German NU-BIG project.}, journal = {BMJ open}, volume = {13}, number = {7}, pages = {e067235}, pmid = {37460258}, issn = {2044-6055}, mesh = {Humans ; Female ; *Choice Behavior ; *Exercise ; Socioeconomic Factors ; Surveys and Questionnaires ; Patient Preference ; }, abstract = {INTRODUCTION: The BIG project ('Bewegung als Investition in die Gesundheit', ie, 'Movement as Investment in Health') was developed in 2005 as a community-based participatory research programme to offer accessible opportunities for physical activity to women in difficult life situations. Since then, the programme has been expanded to eight sites in Germany. A systematic evaluation of BIG is currently being conducted. As part of this effort, we strive to understand the preferences of participating women for different aspects of the programme, and to analyse their willingness to pay.

METHODS AND ANALYSIS: In this protocol, we describe the development and analysis plan of a discrete choice experiment (DCE) to investigate participants' preferences for a physical activity programme for women in difficult life situations. The experiment will be embedded in a questionnaire covering several aspects of participation in the programme (eg, reach, efficacy and further effects) and the socioeconomic characteristics of all active participants. After a thorough search of the literature, BIG documents review and expert interviews, we identified five important attributes of the programme: course times, travel time to the course venue, additional social activities organised by BIG, consideration of wishes and interests for the further planning of courses and costs per course unit. Thereafter, we piloted the experiment with a sample of participants from the target group. After data collection, the experiment will be analysed using a conditional logit model and a latent class analysis to assess eventual heterogeneity in preferences.

ETHICS AND DISSEMINATION: Understanding women's preferences will provide useful insights for the further development of the programme and ultimately increase participation and retention. The questionnaire, the included DCE and the pretest on participants received ethical approval (application no. 20-247_1-B). We plan to disseminate the results of the DCE in peer-reviewed journals, national conferences and among participants and programme coordinators and organisers.}, } @article {pmid37460141, year = {2023}, author = {}, title = {Tofersen (Qalsody) for ALS.}, journal = {The Medical letter on drugs and therapeutics}, volume = {65}, number = {1681}, pages = {113-114}, doi = {10.58347/tml.2023.1681a}, pmid = {37460141}, issn = {1523-2859}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Edaravone ; Oligonucleotides ; }, } @article {pmid37459708, year = {2023}, author = {Li, X and Liu, Q and Niu, T and Liu, T and Xin, Z and Zhou, X and Li, R and Li, Z and Jia, L and Liu, Y and Dong, H}, title = {Sleep disorders and white matter integrity in patients with sporadic amyotrophic lateral sclerosis.}, journal = {Sleep medicine}, volume = {109}, number = {}, pages = {170-180}, doi = {10.1016/j.sleep.2023.07.003}, pmid = {37459708}, issn = {1878-5506}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *White Matter/diagnostic imaging ; Diffusion Tensor Imaging/methods ; Extremities ; *Sleep Initiation and Maintenance Disorders/complications ; }, abstract = {This study aimed to explore the characteristics of sleep disorders and their relationship with abnormal white-matter integrity in patients with sporadic amyotrophic lateral sclerosis. One hundred and thirty-six patients and 80 healthy controls were screened consecutively, and 56 patients and 43 healthy controls were ultimately analyzed. Sleep disorders were confirmed using the Pittsburgh sleep quality index, the Epworth sleepiness scale, and polysomnography; patients were classified into those with poor and good sleep quality. White-matter integrity was assessed using diffusion tensor imaging and compared between groups to identify the white-matter tracts associated with sleep disorders. The relationship between scores on the Pittsburgh sleep quality index and impaired white-matter tracts was analyzed using multiple regression. Poor sleep quality was more common in patients (adjusted odds ratio, 4.26; p = 0.005). Compared to patients with good sleep quality (n = 30), patients with poor sleep quality (n = 26; 46.4%) showed decreased fractional anisotropy, increased mean diffusivity, and increased radial diffusivity of projection and commissural fibers, and increased radial diffusivity of the right thalamus. The Pittsburgh score showed the best fit with the mean fractional anisotropy of the right anterior limb of the internal capsule (r = - 0.355, p = 0.011) and the mean radial diffusivity of the right thalamus (r = 0.309, p = 0.028). We conclude that sleep disorders are common in patients with sporadic amyotrophic lateral sclerosis and are associated with reduced white-matter integrity. The pathophysiology of amyotrophic lateral sclerosis may contribute directly to sleep disorders.}, } @article {pmid37459678, year = {2023}, author = {Fuentes, CA and Öztop, MH and Rojas-Rioseco, M and Bravo, M and Göksu, AÖ and Manley, M and Castillo, RDP}, title = {Application of segmented analysis via multivariate curve resolution with alternating least squares to [1]H-nuclear magnetic resonance spectroscopy to identify different sugar sources.}, journal = {Food chemistry}, volume = {428}, number = {}, pages = {136817}, doi = {10.1016/j.foodchem.2023.136817}, pmid = {37459678}, issn = {1873-7072}, mesh = {*Sugars ; Multivariate Analysis ; Least-Squares Analysis ; *Carbohydrates ; Magnetic Resonance Spectroscopy ; }, abstract = {The different types of sugar employed in the food industry exhibit chemical similarity and are mostly dominated by sucrose. Owing to the sugar origin of and differences in production, the presence of certain minor organic compounds differs. To differentiate between sugars based on their botanical source, geographical origin, or storage conditions, commercial brown sugars and sugar beet extracts were analyzed by [1]H NMR spectroscopy applying a segmented analysis by means of multivariate curve resolution-alternating least squares (MCR-ALS). Principal component analysis and partial least squares-discriminant analysis yielded excellent differentiation between sugars from different sources after the application of this preprocessing strategy; without loss of chemical information and with direct interpretation of the results. By applying a segmented analysis via MCR-ALS to [1]H NMR sugar data, similar spectroscopic profiles could be differentiated. This improved the selectivity of [1]H NMR spectroscopy for sugar source differentiation which can be useful for industrial sugar authentication purposes.}, } @article {pmid37458987, year = {2023}, author = {Gupta, R and Advani, D and Yadav, D and Ambasta, RK and Kumar, P}, title = {Dissecting the Relationship Between Neuropsychiatric and Neurodegenerative Disorders.}, journal = {Molecular neurobiology}, volume = {60}, number = {11}, pages = {6476-6529}, pmid = {37458987}, issn = {1559-1182}, mesh = {Humans ; Aged ; *Alzheimer Disease/genetics ; *Parkinson Disease ; *Huntington Disease ; *Amyotrophic Lateral Sclerosis ; *Depressive Disorder, Major ; *Autism Spectrum Disorder ; *Neurodegenerative Diseases/metabolism ; }, abstract = {Neurodegenerative diseases (NDDs) and neuropsychiatric disorders (NPDs) are two common causes of death in elderly people, which includes progressive neuronal cell death and behavioral changes. NDDs include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and motor neuron disease, characterized by cognitive defects and memory impairment, whereas NPDs include depression, seizures, migraine headaches, eating disorders, addictions, palsies, major depressive disorders, anxiety, and schizophrenia, characterized by behavioral changes. Mounting evidence demonstrated that NDDs and NPDs share an overlapping mechanism, which includes post-translational modifications, the microbiota-gut-brain axis, and signaling events. Mounting evidence demonstrated that various drug molecules, namely, natural compounds, repurposed drugs, multitarget directed ligands, and RNAs, have been potentially implemented as therapeutic agents against NDDs and NPDs. Herein, we highlighted the overlapping mechanism, the role of anxiety/stress-releasing factors, cytosol-to-nucleus signaling, and the microbiota-gut-brain axis in the pathophysiology of NDDs and NPDs. We summarize the therapeutic application of natural compounds, repurposed drugs, and multitarget-directed ligands as therapeutic agents. Lastly, we briefly described the application of RNA interferences as therapeutic agents in the pathogenesis of NDDs and NPDs. Neurodegenerative diseases and neuropsychiatric diseases both share a common signaling molecule and molecular phenomenon, namely, pro-inflammatory cytokines, γCaMKII and MAPK/ERK, chemokine receptors, BBB permeability, and the gut-microbiota-brain axis. Studies have demonstrated that any alterations in the signaling mentioned above molecules and molecular phenomena lead to the pathophysiology of neurodegenerative diseases, namely, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, and neuropsychiatric disorders, such as bipolar disorder, schizophrenia, depression, anxiety, autism spectrum disorder, and post-traumatic stress disorder.}, } @article {pmid37458842, year = {2023}, author = {Vigano', M and Mantero, V and Basilico, P and Pirro, F and Ronchi, D and Di Fonzo, A and Salmaggi, A}, title = {Don't forget Allgrove syndrome in adult patients as a bulbar-ALS mimicker.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {10}, pages = {3703-3705}, pmid = {37458842}, issn = {1590-3478}, mesh = {Humans ; Adult ; *Esophageal Achalasia/diagnosis/genetics ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Adrenal Insufficiency/diagnosis/genetics ; *Lacrimal Apparatus Diseases/diagnosis ; }, abstract = {INTRODUCTION: Allgrove syndrome is a genetic disorder characterized by a multisystem involvement manifesting mainly in childhood with esophageal achalasia, adrenal insufficiency, and alacrima. Associated neurological manifestations are frequent in patients with late-onset forms and include peripheral, central, and autonomic dysfunction. The definitive diagnosis remains genetic, but neurological symptoms/signs could be a relevant clue for the diagnosis.

DISCUSSION: This syndrome is rare, but it is not impossible for it to occur in adults, so all neurologists must be alert. Moreover, in this regard, neurological symptoms can sometimes be very similar to those of motor neuron disease patients, so that, although rare, Allgrove syndrome may also enter into the differential diagnosis with the bulbar variant of amyotrophic lateral sclerosis. Nevertheless, attention to extra-neurological symptoms must remain high as these play an equally important role in reaching the diagnosis.

CASE REPORT: Here we present the case of a patient with some peculiarities that are onset at an advanced age, genetic confirmation of the diagnosis, and prominent neurological involvement, which also opens the differential diagnosis to amyotrophic lateral sclerosis.}, } @article {pmid37458788, year = {2023}, author = {El Mendili, MM and Verschueren, A and Ranjeva, JP and Guye, M and Attarian, S and Zaaraoui, W and Grapperon, AM}, title = {Association between brain and upper cervical spinal cord atrophy assessed by MRI and disease aggressiveness in amyotrophic lateral sclerosis.}, journal = {Neuroradiology}, volume = {65}, number = {9}, pages = {1395-1403}, pmid = {37458788}, issn = {1432-1920}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *Cervical Cord/diagnostic imaging ; Magnetic Resonance Imaging ; *White Matter ; Atrophy/pathology ; }, abstract = {PURPOSE: To study the relative contributions of brain and upper cervical spinal cord compartmental atrophy to disease aggressiveness in amyotrophic lateral sclerosis (ALS).

METHODS: Twenty-nine ALS patients and 24 age- and gender-matched healthy controls (HC) were recruited. Disease duration and the Revised-ALS Functional Rating Scale (ALSFRS-R) at baseline, 3- and 6-months follow-up were assessed. Patients were clinically differentiated into fast (n=13) and slow (n=16) progressors according to their ALSFRS-R progression rate. Brain grey (GM) and white matter, brainstem sub-structures volumes and spinal cord cross-sectional area (SC-CSA) at C1-C2 vertebral levels were measured from a 3D-T1-weighted MRI.

RESULTS: Fast progressors showed significant GM, medulla oblongata and SC atrophy compared to HC (p<0.001, p=0.013 and p=0.008) and significant GM atrophy compared to slow progressors (p=0.008). GM volume correlated with the ALSFRS-R progression rate (Rho/p=-0.487/0.007), the ALSFRS-R at 3-months (Rho/p=0.622/0.002), and ALSFRS-R at 6-months (Rho/p=0.407/0.039). Medulla oblongata volume and SC-CSA correlated with the ALSFRS-R at 3-months (Rho/p=0.510/0.015 and Rho/p=0.479/0.024). MRI measures showed high performance to discriminate between fast and slow progressors.

CONCLUSION: Our study suggests an association between compartmental atrophy and disease aggressiveness. This result is consistent with the combination of upper and lower motor neuron degeneration as the main driver of disease worsening and severity in ALS. Our study highlights the potential of brain and spinal cord atrophy measured by MRI as biomarker of disease aggressiveness signature.}, } @article {pmid37458559, year = {2023}, author = {Desnuelle, C}, title = {[Living with… amyotrophic lateral].}, journal = {La Revue du praticien}, volume = {73}, number = {6}, pages = {659-660}, pmid = {37458559}, issn = {2101-017X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; }, } @article {pmid37457842, year = {2023}, author = {Mavridis, IN and Pyrgelis, ES}, title = {Nucleus accumbens changes in amyotrophic lateral sclerosis.}, journal = {American journal of neurodegenerative disease}, volume = {12}, number = {3}, pages = {85-88}, pmid = {37457842}, issn = {2165-591X}, abstract = {Amyotrophic lateral sclerosis (ALS), a representative example of motor neuron disease, is a progressive and fatal neurodegenerative disorder. The nucleus accumbens (NA) is the ventral striatum's main part and is considered as a modulator of the human brain's reward network. The purpose of this article is to review the current knowledge regarding NA changes in ALS patients. The NA involvement in ALS includes volumetric, cellular and molecular changes. There are recent imaging and pathological studies revealing NA atrophy in ALS, a finding which seems to be related to neuronal loss and protein deposition in this area. The clinical significance of NA atrophy in these patients is not currently fully understood. Perhaps it could be correlated with apathy, behavioral disturbances and cognitive impairment that ALS patients sometimes manifest.}, } @article {pmid37456581, year = {2023}, author = {Giovannelli, L and Bari, E and Jommi, C and Tartara, F and Armocida, D and Garbossa, D and Cofano, F and Torre, ML and Segale, L}, title = {Mesenchymal stem cell secretome and extracellular vesicles for neurodegenerative diseases: Risk-benefit profile and next steps for the market access.}, journal = {Bioactive materials}, volume = {29}, number = {}, pages = {16-35}, pmid = {37456581}, issn = {2452-199X}, abstract = {Neurodegenerative diseases represent a growing burden on healthcare systems worldwide. Mesenchymal stem cells (MSCs) have shown promise as a potential therapy due to their neuroregenerative, neuroprotective, and immunomodulatory properties, which are, however, linked to the bioactive substances they release, collectively known as secretome. This paper provides an overview of the most recent research on the safety and efficacy of MSC-derived secretome and extracellular vesicles (EVs) in clinical (if available) and preclinical models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, acute ischemic stroke, and spinal cord injury. The article explores the biologically active substances within MSC-secretome/EVs, the mechanisms responsible for the observed therapeutic effects, and the strategies that may be used to optimize MSC-secretome/EVs production based on specific therapeutic needs. The review concludes with a critical discussion of current clinical trials and a perspective on potential future directions in translating MSC-secretome and EVs into the clinic, specifically regarding how to address the challenges associated with their pharmaceutical manufacturing, including scalability, batch-to-batch consistency, adherence to Good Manufacturing Practices (GMP) guidelines, formulation, and storage, along with quality controls, access to the market and relative costs, value for money and impact on total expenditure.}, } @article {pmid37456074, year = {2023}, author = {Li, Y and Xie, D and Wang, Y and Jin, S and Zhou, K and Zhang, Z and Li, W and Zhang, W and Mu, X and Yan, G}, title = {Individual tree segmentation of airborne and UAV LiDAR point clouds based on the watershed and optimized connection center evolution clustering.}, journal = {Ecology and evolution}, volume = {13}, number = {7}, pages = {e10297}, pmid = {37456074}, issn = {2045-7758}, abstract = {Light detection and ranging (LiDAR) data can provide 3D structural information of objects and are ideal for extracting individual tree parameters, and individual tree segmentation (ITS) is a vital step for this purpose. Various ITS methods have been emerging from airborne LiDAR scanning (ALS) or unmanned aerial vehicle LiDAR scanning (ULS) data. Here, we propose a new individual tree segmentation method, which couples the classical and efficient watershed algorithm (WS) and the newly developed connection center evolution (CCE) clustering algorithm in pattern recognition. The CCE is first used in ITS and comprehensively optimized by considering tree structure and point cloud characteristics. Firstly, the amount of data is greatly reduced by mean shift voxelization. Then, the optimal clustering scale is automatically determined by the shapes in the projection of three different directions. We select five forest plots in Saihanba, China and 14 public plots in Alpine region, Europe with ULS or ALS point cloud densities from 11 to 3295 pts/m[2]. Eleven ITS methods were used for comparison. The accuracy of tree top detection and tree height extraction is estimated by five and two metrics, respectively. The results show that the matching rate (R match) of tree tops is up to 0.92, the coefficient of determination (R [2]) of tree height estimation is up to .94, and the minimum root mean square error (RMSE) is 0.6 m. Our method outperforms the other methods especially in the broadleaf forests plot on slopes, where the five evaluation metrics for tree top detection outperformed the other algorithms by at least 11% on average. Our ITS method is both robust and efficient and has the potential to be used especially in coniferous forests to extract the structural parameters of individual trees for forest management, carbon stock estimation, and habitat mapping.}, } @article {pmid37454169, year = {2023}, author = {Antoniani, F and Cimino, M and Mediani, L and Vinet, J and Verde, EM and Secco, V and Yamoah, A and Tripathi, P and Aronica, E and Cicardi, ME and Trotti, D and Sterneckert, J and Goswami, A and Carra, S}, title = {Loss of PML nuclear bodies in familial amyotrophic lateral sclerosis-frontotemporal dementia.}, journal = {Cell death discovery}, volume = {9}, number = {1}, pages = {248}, pmid = {37454169}, issn = {2058-7716}, support = {DFG FZT 111 and DFG EXC 168//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; WE 1406/16-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurodegenerative disorders that share genetic causes and pathogenic mechanisms. The critical genetic players of ALS and FTD are the TARDBP, FUS and C9orf72 genes, whose protein products, TDP-43, FUS and the C9orf72-dipeptide repeat proteins, accumulate in form of cytoplasmic inclusions. The majority of the studies focus on the understanding of how cells control TDP-43 and FUS aggregation in the cytoplasm, overlooking how dysfunctions occurring at the nuclear level may influence the maintenance of protein solubility outside of the nucleus. However, protein quality control (PQC) systems that maintain protein homeostasis comprise a cytoplasmic and a nuclear arm that are interconnected and share key players. It is thus conceivable that impairment of the nuclear arm of the PQC may have a negative impact on the cytoplasmic arm of the PQC, contributing to the formation of the cytoplasmic pathological inclusions. Here we focused on two stress-inducible condensates that act as transient deposition sites for misfolding-prone proteins: Promyelocytic leukemia protein (PML) nuclear bodies (PML-NBs) and cytoplasmic stress granules (SGs). Upon stress, PML-NBs compartmentalize misfolded proteins, including defective ribosomal products (DRiPs), and recruit chaperones and proteasomes to promote their nuclear clearance. SGs transiently sequester aggregation-prone RNA-binding proteins linked to ALS-FTD and mRNAs to attenuate their translation. We report that PML assembly is impaired in the human brain and spinal cord of familial C9orf72 and FUS ALS-FTD cases. We also show that defective PML-NB assembly impairs the compartmentalization of DRiPs in the nucleus, leading to their accumulation inside cytoplasmic SGs, negatively influencing SG dynamics. Although it is currently unclear what causes the decrease of PML-NBs in ALS-FTD, our data highlight the existence of a cross-talk between the cytoplasmic and nuclear PQC systems, whose alteration can contribute to SG accumulation and cytoplasmic protein aggregation in ALS-FTD.}, } @article {pmid37452624, year = {2023}, author = {Asakawa, K and Handa, H and Kawakami, K}, title = {Dysregulated TDP-43 proteostasis perturbs excitability of spinal motor neurons during brainstem-mediated fictive locomotion in zebrafish.}, journal = {Development, growth & differentiation}, volume = {65}, number = {8}, pages = {446-452}, pmid = {37452624}, issn = {1440-169X}, support = {//Daiichi-Sankyo Foundation of Life Science/ ; JP23gm6410011h0003//Japan Agency for Medical Research and Development/ ; JP16K07045//Japan Society for the Promotion of Science/ ; JP19K06933//Japan Society for the Promotion of Science/ ; JP21H02463//Japan Society for the Promotion of Science/ ; JP22H02958//Japan Society for the Promotion of Science/ ; JP23H04266//Japan Society for the Promotion of Science/ ; //Nakabayashi Trust For ALS Research/ ; //National BioResource Project (NBRP)/ ; //Takeda Science Foundation/ ; //The Kato Memorial Trust For Nambyo Research/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Zebrafish/metabolism ; Calcium/metabolism ; Proteostasis ; Motor Neurons/metabolism/pathology ; Spinal Cord ; DNA-Binding Proteins/genetics/metabolism ; }, abstract = {Spinal motor neurons (SMNs) are the primary target of degeneration in amyotrophic lateral sclerosis (ALS). Degenerating motor neurons accumulate cytoplasmic TAR DNA-binding protein 43 (TDP-43) aggregates in most ALS cases. This SMN pathology can occur without mutation in the coding sequence of the TDP-43-encoding gene, TARDBP. Whether and how wild-type TDP-43 drives pathological changes in SMNs in vivo remains largely unexplored. In this study, we develop a two-photon calcium imaging setup in which tactile-evoked neural responses of motor neurons in the brainstem and spinal cord can be monitored using the calcium indicator GCaMP. We devise a piezo-assisted tactile stimulator that reproducibly evokes a brainstem descending neuron upon tactile stimulation of the head. A direct comparison between caudal primary motor neurons (CaPs) with or without TDP-43 overexpression in contiguous spinal segments demonstrates that CaPs overexpressing TDP-43 display attenuated Ca[2+] transients during fictive escape locomotion evoked by the tactile stimulation. These results show that excessive amounts of TDP-43 protein reduce the neuronal excitability of SMNs and potentially contribute to asymptomatic pathological lesions of SMNs and movement disorders in patients with ALS.}, } @article {pmid37452450, year = {2023}, author = {Boyle, J and Wheeler, DC and Naum, R and Burke Brockenbrough, P and Gebhardt, M and Smith, L and Harrell, T and Stewart, D and Gwathmey, K}, title = {Analysis of the spatial distribution of amyotrophic lateral sclerosis in Virginia.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2023.2236653}, pmid = {37452450}, issn = {2167-9223}, abstract = {Objective: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that is usually fatal. Environmental exposures have been posited in the etiology of ALS, but few studies have modeled the spatial risk of ALS over large geographic areas. In this paper, our goal was to analyze the spatial distribution of ALS in Virginia and identify any areas with significantly elevated risk using Virginia ALS Association administrative data. Methods: We used Bayesian hierarchical spatial regression models to estimate the relative risk for ALS in Virginia census tracts, adjusting for several covariates posited to be associated with the disease. We used an intrinsic conditional autoregressive prior to allow for spatial correlation in the risk estimates and stabilize estimates over space. Results: Considerable variation in ALS risk existed across Virginia, with greater relative risk found in the central and western parts of the state. We identified significantly elevated relative risk in a number of census tracts. In particular, Henrico, Albemarle, and Botetourt counties all contained at least four census tracts with significantly elevated risk. Conclusions: We identified several areas with significantly elevated ALS risk across Virginia census tracts. These results can inform future studies of potential environmental triggers for the disease, whose etiology is still being understood.}, } @article {pmid37451615, year = {2023}, author = {Yen, H and Yen, H and Huang, CH and Huang, IH and Hung, WK and Su, HJ and Tai, CC and Haw, WWY and Flohr, C and Yiu, ZZN and Chi, CC}, title = {Systematic Review and Critical Appraisal of Urticaria Clinical Practice Guidelines: A Global Guidelines in Dermatology Mapping Project (GUIDEMAP).}, journal = {The journal of allergy and clinical immunology. In practice}, volume = {11}, number = {10}, pages = {3213-3220.e11}, doi = {10.1016/j.jaip.2023.07.002}, pmid = {37451615}, issn = {2213-2201}, mesh = {Humans ; Australia ; Databases, Factual ; *Dermatology ; Stakeholder Participation ; *Urticaria/diagnosis/therapy ; Practice Guidelines as Topic ; }, abstract = {BACKGROUND: Management of urticaria can be optimized with clinical practice guidelines (CPGs). However, the quality of recent urticaria CPGs remains unclear.

OBJECTIVE: To identify and appraise urticaria CPGs worldwide published in the last 5 years.

METHODS: A search for relevant urticaria CPGs was conducted between January 1, 2017, and May 31, 2022, using the following databases: MEDLINE, Embase, National Institute for Health and Care Excellence (NICE) Evidence Search, Guidelines International Network, ECRI Guidelines Trust, Australian Clinical Practice Guidelines, Trip Medical Database, and DynaMed. The included CPGs were critically appraised using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, Lenzer et al's red flags, and the Institute of Medicine (IOM) criteria of trustworthiness.

RESULTS: We included 21 urticaria CPGs. Most guidelines reviewed treatment recommendations of chronic spontaneous urticaria. The majority of guidelines were from European and Asian countries with high and high-middle sociodemographic index, written in English, and openly accessible. Seventeen guidelines (81%) had at least 1 AGREE II domain rated poor quality. Applicability, rigor of development, and stakeholder involvement were the 3 AGREE II domains that scored the lowest across guidelines. Appraisal with Lenzer et al's red flags showed that 18 guidelines (86%) raised at least 1 red flag indicating potential bias. The top 3 domains raising red flags were: no inclusion of nonphysician experts/patient representative/community stakeholders, no or limited involvement of a methodologist in the evaluation of evidence, and lack of external review. Based on IOM's criteria of trustworthiness, 20 guidelines (95%) had 1 or more criteria that did not meet best practice standards. The 3 domains with the highest number of best practice standards not met were updating procedures, rating strength of recommendations, and external review. Guidelines scored highest for the AGREE II domains of defining scope and purpose and clarity of presentation, and had the most fully met IOM's best practice standard for articulation of recommendations. However, only 1 urticaria CPG by NICE was identified as rigorously developed across all 3 appraisal tools.

CONCLUSIONS: The quality of urticaria CPGs in the last 5 years varied widely. Only the NICE urticaria guideline consistently demonstrated excellent quality, high trustworthiness, and low risk of bias. Use of a rigorous framework to rate certainty of evidence and grade strength of recommendation, involvement of methodologists, stakeholder engagement with external review, and clear guidance for updating can help improve the quality of future CPGs.}, } @article {pmid37451236, year = {2023}, author = {Koike, Y and Pickles, S and Ayuso, VE and Jansen-West, K and Qi, YA and Li, Z and Daughrity, LM and Yue, M and Zhang, YJ and Cook, CN and Dickson, DW and Ward, M and Petrucelli, L and Prudencio, M}, title = {Correction: TDP-43 and other hnRNPs regulate cryptic exon inclusion of a key ALS/FTD risk gene, UNC13A.}, journal = {PLoS biology}, volume = {21}, number = {7}, pages = {e3002228}, pmid = {37451236}, issn = {1545-7885}, abstract = {[This corrects the article DOI: 10.1371/journal.pbio.3002028.].}, } @article {pmid37450673, year = {2023}, author = {Mushtaq, U}, title = {EP1 receptor: Devil in emperors coat.}, journal = {Journal of cellular biochemistry}, volume = {124}, number = {8}, pages = {1105-1114}, doi = {10.1002/jcb.30436}, pmid = {37450673}, issn = {1097-4644}, mesh = {Receptors, Prostaglandin E, EP1 Subtype/genetics ; *Signal Transduction/physiology ; *Protein Kinase C/metabolism ; }, abstract = {EP1 receptor belongs to prostanoid receptors and is activated by prostaglandin E2. The receptor performs contrasting functions in central nervous system (CNS) and other tissues. Although the receptor is neurotoxic and proapoptotic in CNS, it has also been reported to act in an antiapoptotic manner by modulating cell survival, proliferation, invasion, and migration in different types of cancers. The receptor mediates its neurotoxic effects by increasing cytosolic Ca[2+] levels, leading to the activation of its downstream target, protein kinase C, in different neurological disorders including Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and epilepsy. Antagonists ONO-8713, SC51089, and SC51322 against EP1 receptor ameliorate the neurotoxic effect by attenuating the neuroinflammation. The receptor also shows increased expression in different types of cancers and has been found to activate different signaling pathways, which lead to the development, progression, and metastasis of different cancers. The receptor stimulates the cell survival pathway by phosphorylating the AKT and PTEN (phosphatase and tensin homolog deleted on chromosome 10) signaling pathways. Although there are limited studies about this receptor and not a single clinical trial has been targeting the EP1 receptor for different neurological disorders or cancer, the receptor is appearing as a potential candidate for therapeutic targets. The aim of this article is to review the recent progress in understanding the pathogenic roles of EP1 receptors in different pathological conditions.}, } @article {pmid37450615, year = {2024}, author = {Karasz, A and Nemiroff, S and Joo, P and Blanco, I and Fishman, AY and Kelly, MS and Henick, SM and Lambros, M and Burton, WB}, title = {A Sense of Belonging: Perceptions of the Medical School Learning Environment among URM and Non-URM Students.}, journal = {Teaching and learning in medicine}, volume = {36}, number = {5}, pages = {566-576}, doi = {10.1080/10401334.2023.2232347}, pmid = {37450615}, issn = {1532-8015}, mesh = {Humans ; *Students, Medical/psychology/statistics & numerical data ; New York City ; Female ; *Schools, Medical ; Male ; Minority Groups/psychology/statistics & numerical data ; Education, Medical, Undergraduate ; Perception ; Adult ; }, abstract = {Approach: Using Gruppen et al's model, this study investigated experiences of the LE from the perspectives of both URM and non-URM students at a medical school in New York City. In examining experiences of the organizational, social, and physical domains of the LE, we sought to explore the symbolic and experiential links across domains and identify concrete needs for improvement. Findings: Institutional structures and policies, features of the built environment, and social relationships that put learning first and generated a sense of community were highly valued. Although both URM and non-URM students shared many perceptions and experiences, URM students expressed heightened vulnerability to the experiences of devaluation and exclusion. Insights: All participants in the study greatly appreciated aspects of the LE that made them feel like valued members of the community. Medical schools should approach the task of improving the LE for URM students using a comprehensive, multi-dimensional approach.}, } @article {pmid37450566, year = {2023}, author = {Rifai, OM and O'Shaughnessy, J and Dando, OR and Munro, AF and Sewell, MDE and Abrahams, S and Waldron, FM and Sibley, CR and Gregory, JM}, title = {Distinct neuroinflammatory signatures exist across genetic and sporadic amyotrophic lateral sclerosis cohorts.}, journal = {Brain : a journal of neurology}, volume = {146}, number = {12}, pages = {5124-5138}, pmid = {37450566}, issn = {1460-2156}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 NS127186/NS/NINDS NIH HHS/United States ; 5-R01-NS127186-02/GF/NIH HHS/United States ; 108890/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; Brain-Derived Neurotrophic Factor/genetics ; NF-kappa B ; *Neurodegenerative Diseases/genetics ; Dystonic Disorders ; Humans ; DNA Repeat Expansion ; C9orf72 Protein/genetics ; *Frontotemporal Dementia/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. ALS is on a pathogenetic disease spectrum with frontotemporal dementia, referred to as ALS-frontotemporal spectrum disorder (ALS-FTSD). For mutations associated with ALS-FTSD, such as the C9orf72 hexanucleotide repeat expansion, the molecular factors associated with heterogeneity along this spectrum require further characterization. Here, using a targeted NanoString molecular barcoding approach, we interrogate neuroinflammatory dysregulation and heterogeneity at the level of gene expression in post-mortem motor cortex tissue from a cohort of clinically heterogeneous C9-ALS-FTSD cases. We identified 20 dysregulated genes in C9-ALS-FTSD, with enrichment of microglial and inflammatory response gene sets. Two genes with significant correlations to available clinical metrics were selected for validation: FKBP5, a correlate of cognitive function, and brain-derived neurotrophic factor (BDNF), a correlate of disease duration. FKBP5 and its signalling partner, NF-κB, appeared to have a cell type-specific staining distribution, with activated (i.e. nuclear) NF-κB immunoreactivity in C9-ALS-FTSD. Expression of BDNF, a correlate of disease duration, was confirmed to be higher in individuals with long compared to short disease duration using BaseScope™ in situ hybridization. Our analyses also revealed two distinct neuroinflammatory panel signatures (NPS), NPS1 and NPS2, delineated by the direction of expression of proinflammatory, axonal transport and synaptic signalling pathways. We compared NPS between C9-ALS-FTSD cases and those from sporadic ALS and SOD1-ALS cohorts and identified NPS1 and NPS2 across all cohorts. Moreover, a subset of NPS was also able to separate publicly available RNA sequencing data from independent C9-ALS and sporadic ALS cohorts into two inflammatory subgroups. Importantly, NPS subgroups did not clearly segregate with available demographic, genetic, clinical or pathological features, highlighting the value of molecular stratification in clinical trials for inflammatory subgroup identification. Our findings thus underscore the importance of tailoring therapeutic approaches based on distinct molecular signatures that exist between and within ALS-FTSD cohorts.}, } @article {pmid37450246, year = {2023}, author = {Candelise, N and Caissutti, D and Zenuni, H and Nesci, V and Scaricamazza, S and Salvatori, I and Spinello, Z and Mattei, V and Garofalo, T and Ferri, A and Valle, C and Misasi, R}, title = {Different Chronic Stress Paradigms Converge on Endogenous TDP43 Cleavage and Aggregation.}, journal = {Molecular neurobiology}, volume = {60}, number = {11}, pages = {6346-6361}, pmid = {37450246}, issn = {1559-1182}, support = {Post-doctoral Fellowship 2021 - anno 2021//Fondazione Umberto Veronesi/ ; CUP B89J22001910007//Fondazione Cassa di Risparmio di Pistoia e Pescia/ ; PRIN 20109MXHNR//Ministero dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Cell Line ; Cytoplasm/metabolism ; *DNA-Binding Proteins/metabolism ; Neuroblastoma/metabolism ; TDP-43 Proteinopathies/metabolism ; }, abstract = {The TAR-DNA binding protein (TDP43) is a nuclear protein whose cytoplasmic inclusions are hallmarks of Amyotrophic Lateral Sclerosis (ALS). Acute stress in cells causes TDP43 mobilization to the cytoplasm and its aggregation through different routes. Although acute stress elicits a strong phenotype, is far from recapitulating the years-long aggregation process. We applied different chronic stress protocols and described TDP43 aggregation in a human neuroblastoma cell line by combining solubility assays, thioflavin-based microscopy and flow cytometry. This approach allowed us to detect, for the first time to our knowledge in vitro, the formation of 25 kDa C-terminal fragment of TDP43, a pathogenic hallmark of ALS. Our results indicate that chronic stress, compared to the more common acute stress paradigm, better recapitulates the cell biology of TDP43 proteinopathies. Moreover, we optimized a protocol for the detection of bona fide prions in living cells, suggesting that TDP43 may form amyloids as a stress response.}, } @article {pmid37450244, year = {2023}, author = {Dubowsky, M and Theunissen, F and Carr, JM and Rogers, ML}, title = {The Molecular Link Between TDP-43, Endogenous Retroviruses and Inflammatory Neurodegeneration in Amyotrophic Lateral Sclerosis: a Potential Target for Triumeq, an Antiretroviral Therapy.}, journal = {Molecular neurobiology}, volume = {60}, number = {11}, pages = {6330-6345}, pmid = {37450244}, issn = {1559-1182}, support = {1950//Motor Neurone Disease Australia/ ; 1950//Andrew Butcher Grant/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Endogenous Retroviruses ; *Motor Neuron Disease/pathology ; Motor Neurons/metabolism ; DNA-Binding Proteins/metabolism ; *HIV Infections/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurological disorder, characterised by the death of upper and lower motor neurons. The aetiology of ALS remains unknown, and treatment options are limited. Endogenous retroviruses (ERVs), specifically human endogenous retrovirus type K (HERV-K), have been proposed to be involved in the propagation of neurodegeneration in ALS. ERVs are genomic remnants of ancient viral infection events, with most being inactive and not retaining the capacity to encode a fully infectious virus. However, some ERVs retain the ability to be activated and transcribed, and ERV transcripts have been found to be elevated within the brain tissue of MND patients. A hallmark of ALS pathology is altered localisation of the transactive response (TAR) DNA binding protein 43 kDa (TDP-43), which is normally found within the nucleus of neuronal and glial cells and is involved in RNA regulation. In ALS, TDP-43 aggregates within the cytoplasm and facilitates neurodegeneration. The involvement of ERVs in ALS pathology is thought to occur through TDP-43 and neuroinflammatory mediators. In this review, the proposed involvement of TDP-43, HERV-K and immune regulators on the onset and progression of ALS will be discussed. Furthermore, the evidence supporting a therapy based on targeting ERVs in ALS will be reviewed.}, } @article {pmid37449847, year = {2023}, author = {Wang, J and Mao, Y and McGarry, B and Cai, S and Temkin-Greener, H}, title = {Assisted living or nursing home: Who is moving in?.}, journal = {Journal of the American Geriatrics Society}, volume = {71}, number = {11}, pages = {3480-3488}, pmid = {37449847}, issn = {1532-5415}, support = {R01 HS026893/HS/AHRQ HHS/United States ; 1R01HS026893/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; Aged ; United States ; *Skilled Nursing Facilities ; Retrospective Studies ; *Medicare ; Nursing Homes ; Hospitalization ; Patient Discharge ; }, abstract = {BACKGROUND: Despite the rapid growth of assisted living (AL) communities and the increasing similarity between AL and nursing home (NH) populations, little is known about the characteristics of older adults at the time of AL admission and how these characteristics compare to individuals newly admitted to NH from the community. This study examined the individual, facility, and geographic factors associated with new AL admission.

METHODS: This retrospective descriptive study used data from the national Medicare enrollment and claims datasets, the Minimum Data Set, and the Medicare Provider Analysis and Review. The study cohort included 158,124 Medicare beneficiaries newly admitted to ALs and 715,261 newly admitted to NHs during 10/2017-10/2019. Multinomial logistic regression analysis and logistic regression analysis were conducted to examine factors associated with new admissions.

RESULTS: Demographic, socioeconomic, and health service use characteristics were associated with new admission to long-term care. Specifically, Medicare fee-for-service beneficiaries, those age 75 years and older, male, having one skilled nursing facility (SNF) stay or any hospital stay in the past 6 months are more likely to be newly admitted to AL, whereas those who are dually eligible, racial/ethnic minorities, and having two or more SNF stays in the past 6 months are more likely to be admitted to an NH.

CONCLUSION: There are substantial differences between individuals who are newly admitted from the community to AL versus those to NH.}, } @article {pmid37448088, year = {2023}, author = {Xu, J and Huang, Z and Liu, L and Li, X and Wei, K}, title = {Eye-Gaze Controlled Wheelchair Based on Deep Learning.}, journal = {Sensors (Basel, Switzerland)}, volume = {23}, number = {13}, pages = {}, pmid = {37448088}, issn = {1424-8220}, mesh = {Humans ; *Deep Learning ; *Wheelchairs ; Fixation, Ocular ; Movement ; Motion ; }, abstract = {In this paper, we design a technologically intelligent wheelchair with eye-movement control for patients with ALS in a natural environment. The system consists of an electric wheelchair, a vision system, a two-dimensional robotic arm, and a main control system. The smart wheelchair obtains the eye image of the controller through a monocular camera and uses deep learning and an attention mechanism to calculate the eye-movement direction. In addition, starting from the relationship between the trajectory of the joystick and the wheelchair speed, we establish a motion acceleration model of the smart wheelchair, which reduces the sudden acceleration of the smart wheelchair during rapid motion and improves the smoothness of the motion of the smart wheelchair. The lightweight eye-movement recognition model is transplanted into an embedded AI controller. The test results show that the accuracy of eye-movement direction recognition is 98.49%, the wheelchair movement speed is up to 1 m/s, and the movement trajectory is smooth, without sudden changes.}, } @article {pmid37446372, year = {2023}, author = {Alarcan, H and Vourc'h, P and Berton, L and Benz-De Bretagne, I and Piver, E and Andres, CR and Corcia, P and Veyrat-Durebex, C and Blasco, H}, title = {Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients.}, journal = {International journal of molecular sciences}, volume = {24}, number = {13}, pages = {}, pmid = {37446372}, issn = {1422-0067}, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics ; Retrospective Studies ; Sex Factors ; Delayed Diagnosis ; Central Nervous System ; }, abstract = {Central nervous system (CNS) barrier impairment has been reported in amyotrophic lateral sclerosis (ALS), highlighting its potential significance in the disease. In this context, we aim to shed light on its involvement in the disease, by determining albumin quotient (QAlb) at the time of diagnosis of ALS in a large cohort of patients. Patients from the university hospital of Tours (n = 307) were included in this monocentric, retrospective study. In total, 92 patients (30%) had elevated QAlb levels. This percentage was higher in males (43%) than in females (15%). Interestingly, QAlb was not associated with age of onset, age at sampling or diagnostic delay. However, we found an association with ALS functional rating scale-revised (ALSFRS-r) at diagnosis but this was significant only in males. The QAlb levels were not linked to the presence of a pathogenic mutation. Finally, we performed a multivariate survival analysis and found that QAlb was significantly associated with survival in male patients (HR = 2.3, 95% CI = 1.2-4.3, p = 0.009). A longitudinal evaluation of markers of barrier impairment, in combination with inflammatory biomarkers, could give insight into the involvement of CNS barrier impairment in the pathogenesis of the disease. The gender difference might guide the development of new drugs and help personalise the treatment of ALS.}, } @article {pmid37445986, year = {2023}, author = {Ciurea, AV and Mohan, AG and Covache-Busuioc, RA and Costin, HP and Glavan, LA and Corlatescu, AD and Saceleanu, VM}, title = {Unraveling Molecular and Genetic Insights into Neurodegenerative Diseases: Advances in Understanding Alzheimer's, Parkinson's, and Huntington's Diseases and Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {13}, pages = {}, pmid = {37445986}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Huntington Disease/genetics ; *Alzheimer Disease/genetics ; *Parkinson Disease/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Neurodegenerative diseases are, according to recent studies, one of the main causes of disability and death worldwide. Interest in molecular genetics has started to experience exponential growth thanks to numerous advancements in technology, shifts in the understanding of the disease as a phenomenon, and the change in the perspective regarding gene editing and the advantages of this action. The aim of this paper is to analyze the newest approaches in genetics and molecular sciences regarding four of the most important neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We intend through this review to focus on the newest treatment, diagnosis, and predictions regarding this large group of diseases, in order to obtain a more accurate analysis and to identify the emerging signs that could lead to a better outcome in order to increase both the quality and the life span of the patient. Moreover, this review could provide evidence of future possible novel therapies that target the specific genes and that could be useful to be taken into consideration when the classical approaches fail to shed light.}, } @article {pmid37445890, year = {2023}, author = {Kousparou, C and Fyrilla, M and Stephanou, A and Patrikios, I}, title = {DHA/EPA (Omega-3) and LA/GLA (Omega-6) as Bioactive Molecules in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {13}, pages = {}, pmid = {37445890}, issn = {1422-0067}, mesh = {Humans ; Eicosapentaenoic Acid/pharmacology ; Docosahexaenoic Acids/therapeutic use/metabolism ; *Neurodegenerative Diseases/drug therapy ; *Fatty Acids, Omega-3/therapeutic use ; Fatty Acids, Unsaturated/metabolism ; Arachidonic Acid/metabolism ; Linoleic Acids ; Inflammation/drug therapy ; }, abstract = {Neurodegenerative diseases are characterized by neuroinflammation, neuronal depletion and oxidative stress. They coincide with subtle chronic or flaring inflammation, sometimes escalating with infiltrations of the immune system cells in the inflamed parts causing mild to severe or even lethal damage. Thus, neurodegenerative diseases show all features of autoimmune diseases. Prevalence of neurodegenerative diseases has dramatically increased in recent decades and unfortunately, the therapeutic efficacy and safety profile of available drugs is moderate. The beneficial effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) polyunsaturated fatty acids (omega-3 PUFAs) are nowadays highlighted by a plethora of studies. They play a role in suppression of inflammation, gene expression, cellular membrane fluidity/permeability, immune functionality and intracellular/exocellular signaling. The role of omega-6 polyunsaturated fatty acids, such as linoleic acid (LA), gamma linolenic acid (GLA), and arachidonic acid (AA), on neuroprotection is controversial, as some of these agents, specifically AA, are proinflammatory, whilst current data suggest that they may have neuroprotective properties as well. This review provides an overview of the existing recent clinical studies with respect to the role of omega-3 and omega-6 PUFAs as therapeutic agents in chronic, inflammatory, autoimmune neurodegenerative diseases as well as the dosages and the period used for testing.}, } @article {pmid37443797, year = {2023}, author = {Afonso, GJM and Cavaleiro, C and Valero, J and Mota, SI and Ferreiro, E}, title = {Recent Advances in Extracellular Vesicles in Amyotrophic Lateral Sclerosis and Emergent Perspectives.}, journal = {Cells}, volume = {12}, number = {13}, pages = {}, pmid = {37443797}, issn = {2073-4409}, support = {PTDC/BTM-ORG/0055/2021, UIDB/04539/2020, UIDP/04539/2020, LA/P/0058/2020, 2022.13281.BD, DL57/2016/CP1448/CT0027, CEECIND/00322/2017, 2022.00011.CEECIND.//Fundação para a Ciência e Tecnologia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases ; *Extracellular Vesicles ; Motor Neurons ; *Exosomes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe and incurable neurodegenerative disease characterized by the progressive death of motor neurons, leading to paralysis and death. It is a rare disease characterized by high patient-to-patient heterogeneity, which makes its study arduous and complex. Extracellular vesicles (EVs) have emerged as important players in the development of ALS. Thus, ALS phenotype-expressing cells can spread their abnormal bioactive cargo through the secretion of EVs, even in distant tissues. Importantly, owing to their nature and composition, EVs' formation and cargo can be exploited for better comprehension of this elusive disease and identification of novel biomarkers, as well as for potential therapeutic applications, such as those based on stem cell-derived exosomes. This review highlights recent advances in the identification of the role of EVs in ALS etiopathology and how EVs can be promising new therapeutic strategies.}, } @article {pmid37443723, year = {2023}, author = {Spalloni, A and de Stefano, S and Gimenez, J and Greco, V and Mercuri, NB and Chiurchiù, V and Longone, P}, title = {The Ying and Yang of Hydrogen Sulfide as a Paracrine/Autocrine Agent in Neurodegeneration: Focus on Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {12}, number = {13}, pages = {}, pmid = {37443723}, issn = {2073-4409}, support = {RF-2018-12365509//Italian Ministry of Health/ ; Ricerca Corrente (Linea di Ricerca 2)//Governo Italiano/ ; }, mesh = {Humans ; *Hydrogen Sulfide ; *Neurodegenerative Diseases ; *Amyotrophic Lateral Sclerosis ; Central Nervous System ; Nitric Oxide ; }, abstract = {Ever since its presence was reported in the brain, the nature and role of hydrogen sulfide (H2S) in the Central Nervous System (CNS) have changed. Consequently, H2S has been elected as the third gas transmitter, along with carbon monoxide and nitric oxide, and a number of studies have focused on its neuromodulatory and protectant functions in physiological conditions. The research on H2S has highlighted its many facets in the periphery and in the CNS, and its role as a double-faced compound, switching from protective to toxic depending on its concentration. In this review, we will focus on the bell-shaped nature of H2S as an angiogenic factor and as a molecule released by glial cells (mainly astrocytes) and non-neuronal cells acting on the surrounding environment (paracrine) or on the releasing cells themselves (autocrine). Finally, we will discuss its role in Amyotrophic Lateral Sclerosis, a paradigm of a neurodegenerative disease.}, } @article {pmid37442650, year = {2024}, author = {Lopez-Garcia, YK and Valdez-Carrizales, M and Nuñez-Zuno, JA and Apodaca-Chávez, E and Rangel-Patiño, J and Demichelis-Gómez, R}, title = {Are delays in diagnosis and treatment of acute leukemia in a middle-income country associated with poor outcomes? A retrospective cohort study.}, journal = {Hematology, transfusion and cell therapy}, volume = {46}, number = {4}, pages = {366-373}, pmid = {37442650}, issn = {2531-1387}, abstract = {INTRODUCTION: Acute leukemias (ALs) are aggressive diseases that lead to death without medical attention. We evaluated the association between delays in diagnosis and poor outcomes in AL by evaluating the symptom onset to treatment intervals in adults with newly diagnosed AL and their effect on an early death (ED).

METHODS: We assessed adults diagnosed with AL between 2015 and 2020 and evaluated baseline characteristics, the patient interval (PI), diagnostic interval (DI), treatment interval (TI) and the total time interval (TTI) to determine ED-associated factors.

MAIN RESULTS: We assessed 102 patients with acute lymphoblastic leukemia (ALL), 57 with acute myeloblastic leukemia (AML) and 29 with acute promyelocytic leukemia (APL). Median interval days were PI 14, DI 10, TI 4 and TTI 31.5. The TI and TTI intervals were lower in APL than in ALL and AML; TI 1 vs. 4 and 3 (p = 0.001) and TTI 21 vs. 31 and 35 (p = 0.016). The 30-day and 60-day EDs were 13.8% and 20.7%, mainly infections. ECOG > 2 (OR = 15.0) and PI < 7 days (OR = 4.06) were associated with 30-day ED; AML (OR = 2.69), high-risk (OR = 3.34), albumin < 3.5 g/dl (OR = 5) and platelets < 20 × 10[3]/uL (OR = 2.71) with a 60-day ED.

CONCLUSION: None of the interval-delays were associated with an ED. Intervals seemed to be longer in patients without an ED, except for the TI, probably because of "the waiting time paradox." Aggressive manifestations of disease may lead to shorter diagnostic intervals, but increased mortality.}, } @article {pmid37440197, year = {2023}, author = {Yang, J and Li, H and Zhao, Y}, title = {Dessert or Poison? The Roles of Glycosylation in Alzheimer's, Parkinson's, Huntington's Disease, and Amyotrophic Lateral Sclerosis.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {24}, number = {16}, pages = {e202300017}, doi = {10.1002/cbic.202300017}, pmid = {37440197}, issn = {1439-7633}, mesh = {Humans ; Aged ; *Huntington Disease ; *Neurodegenerative Diseases ; *Alzheimer Disease ; *Amyotrophic Lateral Sclerosis ; *Parkinson Disease ; Glycosylation ; *Poisons ; Quality of Life ; }, abstract = {Ministry of Education and Key Laboratory of Neurons and glial cells of the central nervous system (CNS) are modified by glycosylation and rely on glycosylation to achieve normal neural function. Neurodegenerative disease is a common disease of the elderly, affecting their healthy life span and quality of life, and no effective treatment is currently available. Recent research implies that various glycosylation traits are altered during neurodegenerative diseases, suggesting a potential implication of glycosylation in disease pathology. Herein, we summarized the current knowledge about glycosylation associated with Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS) pathogenesis, focusing on their promising functional avenues. Moreover, we collected research aimed at highlighting the need for such studies to provide a wealth of disease-related glycosylation information that will help us better understand the pathophysiological mechanisms and hopefully specific glycosylation information to provide further diagnostic and therapeutic directions for neurodegenerative diseases.}, } @article {pmid37439013, year = {2023}, author = {Zhou, Q and Kang, Q and Chen, W and Xu, R}, title = {Potential effects of brain lipid binding protein in the pathogenesis of amyotrophic lateral sclerosis.}, journal = {Science progress}, volume = {106}, number = {3}, pages = {368504231184320}, pmid = {37439013}, issn = {2047-7163}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; *Fatty Acid-Binding Protein 7/genetics ; *Neural Stem Cells ; Superoxide Dismutase-1 ; Disease Models, Animal ; }, abstract = {Current studies suggest that the abnormal alteration of brain lipid binding protein (BLBP) might participate in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, the detailed understanding of ALS pathogenesis been yet to be elucidated. Therefore, this research intended to explore the potential effects of BLBP in ALS. The observation and analysis of BLBP-altered features in various anatomical areas and different spinal segments was conducted at the pre-onset, onset, and progression stages of Tg(SOD1*G93A)1Gur (TG) mice and the same periods of age-matched SOD1 wild-type (WT) mice by fluorescence immunohistochemistry and western blotting. BLBP-positive cells were comprehensively distributed in various spinal anatomical areas, especially in both the anterior and posterior horn, around the central canal and in anterior, lateral, and posterior funiculi. Overall, BLBP expression tended to increase from the pre-onset to the onset to the progression stages of the same periods of age-matched WT mice. Furthermore, in TG mice, BLBP expression in the entire spinal cord significantly increased from onset to the progression stage. BLBP was expressed in neurons, astrocytes, and radial glial cells, and at the early and late stages of neural precursor cells (NPCs) and was predominantly distributed outside the cell nucleus. The increase of BLBP-positive cells was closely related to neural cell reduction in TG mice. The distribution and increased expression of BLBP among the cervical, thoracic, and lumbar segments of the spinal cord might participate in the development of ALS and exert potential effects in the pathogenesis of ALS by regulating NPCs.}, } @article {pmid37438565, year = {2023}, author = {da Silveira Estevão, PL and Lemes, LFR and Soares, FLF and Nagata, N}, title = {Raman mapping for determination of TiO2 in different solid food samples by multivariate curve resolution with alternating least squares.}, journal = {Analytical and bioanalytical chemistry}, volume = {415}, number = {21}, pages = {5235-5245}, pmid = {37438565}, issn = {1618-2650}, support = {3080/20112011//Financiadora de Estudos e Projetos/ ; }, mesh = {Least-Squares Analysis ; *Titanium/analysis ; *Food ; Food Additives ; Multivariate Analysis ; }, abstract = {Titanium dioxide is a food additive commonly used as a white food coloring (E171). Its wide use by the food industry associated with the nanometric size distribution of the particles of this pigment has shown high genotoxicity associated with recurrent exposure by ingestion. Therefore, the use of E171 in food products has already been banned by some industries and in the European Union. Such banishment should soon be extended to other countries around the world, making it important to establish techniques for the efficient determination of TiO2 in different food products. The association between hyperspectral images and chemometric tools can be useful in this sense, aiming to enable the use of a single method for sample preparation and analysis of different types of food. Thus, the present work aims to evaluate the use of Raman mapping associated with the resolution of multivariate curves with alternating least squares (MCR-ALS) for the determination of titanium dioxide in solid food samples with different compositions, without the need to introduce specific sample preparation. The proposed method allowed for the first-time quantification of TiO2 in different food matrices without specific sample preparation, with a simple, rapid, accurate (93% of recovery), low detection limits (0.0111% m/m) and quantification (0.0370% m/m) and adequate linearity (r = 0.9990) and precise (standard deviation around 0.020-0.030% w/w) methodology. Such results highlight the potential use of Raman mapping associated with the MCR-ALS for quantification of the nano-TiO2 in commercial samples.}, } @article {pmid37438085, year = {2023}, author = {Balendra, R and Ruiz de Los Mozos, I and Odeh, HM and Glaria, I and Milioto, C and Wilson, KM and Ule, AM and Hallegger, M and Masino, L and Martin, S and Patani, R and Shorter, J and Ule, J and Isaacs, AM}, title = {Transcriptome-wide RNA binding analysis of C9orf72 poly(PR) dipeptides.}, journal = {Life science alliance}, volume = {6}, number = {9}, pages = {}, pmid = {37438085}, issn = {2575-1077}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; 107196/Z/14/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Transcriptome/genetics ; C9orf72 Protein/genetics ; *Gene Expression Profiling ; Poly A ; Dipeptides ; RNA/genetics ; }, abstract = {An intronic GGGGCC repeat expansion in C9orf72 is a common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The repeats are transcribed in both sense and antisense directions to generate distinct dipeptide repeat proteins, of which poly(GA), poly(GR), and poly(PR) have been implicated in contributing to neurodegeneration. Poly(PR) binding to RNA may contribute to toxicity, but analysis of poly(PR)-RNA binding on a transcriptome-wide scale has not yet been carried out. We therefore performed crosslinking and immunoprecipitation (CLIP) analysis in human cells to identify the RNA binding sites of poly(PR). We found that poly(PR) binds to nearly 600 RNAs, with the sequence GAAGA enriched at the binding sites. In vitro experiments showed that poly(GAAGA) RNA binds poly(PR) with higher affinity than control RNA and induces the phase separation of poly(PR) into condensates. These data indicate that poly(PR) preferentially binds to poly(GAAGA)-containing RNAs, which may have physiological consequences.}, } @article {pmid37437982, year = {2023}, author = {Sharma, K and Sarkar, J and Trisal, A and Ghosh, R and Dixit, A and Singh, AK}, title = {Targeting mitochondrial dysfunction to salvage cellular senescence for managing neurodegeneration.}, journal = {Advances in protein chemistry and structural biology}, volume = {136}, number = {}, pages = {309-337}, doi = {10.1016/bs.apcsb.2023.02.016}, pmid = {37437982}, issn = {1876-1631}, mesh = {Humans ; *Cellular Senescence ; Mitochondria ; *Alzheimer Disease ; Cyclin-Dependent Kinase Inhibitor Proteins ; }, abstract = {Aging is an inevitable phenomenon that causes a decline in bodily functions over time. One of the most important processes that play a role in aging is senescence. Senescence is characterized by accumulation of cells that are no longer functional but elude the apoptotic pathway. These cells secrete inflammatory molecules that comprise the senescence associated secretory phenotype (SASP). Several essential molecules such as p53, Rb, and p16INK4a regulate the senescence process. Mitochondrial regulation has been found to play an important role in senescence. Reactive oxygen species (ROS) generated from mitochondria can affect cellular senescence by inducing the persistent DNA damage response, thus stabilizing the senescence. Evidently, senescence plays a major contributory role to the development of age-related neurological disorders. In this chapter, we discuss the role of senescence in the progression and onset of several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Moreover, we also discuss the efficacy of certain molecules like MitoQ, SkQ1, and Latrepirdine that could be proven therapeutics with respect to these disorders by regulating mitochondrial activity.}, } @article {pmid37436778, year = {2023}, author = {Zamiri, K and Kesari, S and Paul, K and Hwang, SH and Hammock, B and Kaczor-Urbanowicz, KE and Urbanowicz, A and Gao, L and Whitelegge, J and Fiala, M}, title = {Therapy of autoimmune inflammation in sporadic amyotrophic lateral sclerosis: Dimethyl fumarate and H-151 downregulate inflammatory cytokines in the cGAS-STING pathway.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {37}, number = {8}, pages = {e23068}, pmid = {37436778}, issn = {1530-6860}, support = {R01 NS078410/NS/NINDS NIH HHS/United States ; R35 ES030443/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Cytokines/metabolism ; Interleukin-17 ; Dimethyl Fumarate ; Leukocytes, Mononuclear/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy ; Granzymes ; Inflammation/drug therapy ; Nucleotidyltransferases ; }, abstract = {In sporadic amyotrophic lateral sclerosis (sALS), IL-17A- and granzyme-positive cytotoxic T lymphocytes (CTL), IL-17A-positive mast cells, and inflammatory macrophages invade the brain and spinal cord. In some patients, the disease starts following a trauma or a severe infection. We examined cytokines and cytokine regulators over the disease course and found that, since the early stages, peripheral blood mononuclear cells (PBMC) exhibit increased expression of inflammatory cytokines IL-12A, IFN-γ, and TNF-α, as well as granzymes and the transcription factors STAT3 and STAT4. In later stages, PBMCs upregulated the autoimmunity-associated cytokines IL-23A and IL-17B, and the chemokines CXCL9 and CXCL10, which attract CTL and monocytes into the central nervous system. The inflammation is fueled by the downregulation of IL-10, TGFβ, and the inhibitory T-cell co-receptors CTLA4, LAG3, and PD-1, and, in vitro, by stimulation with the ligand PD-L1. We investigated in two sALS patients the regulation of the macrophage transcriptome by dimethyl fumarate (DMF), a drug approved against multiple sclerosis and psoriasis, and the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway inhibitor H-151. Both DMF and H-151 downregulated the expression of granzymes and the pro-inflammatory cytokines IL-1β, IL-6, IL-15, IL-23A, and IFN-γ, and induced a pro-resolution macrophage phenotype. The eicosanoid epoxyeicosatrienoic acids (EET) from arachidonic acid was anti-inflammatory in synergy with DMF. H-151 and DMF are thus candidate drugs targeting the inflammation and autoimmunity in sALS via modulation of the NFκB and cGAS/STING pathways.}, } @article {pmid37436254, year = {2023}, author = {Cunha-Correia, CD and Gama, MDP and Fontana, PN and Fantini, FGMM and Prado, GF and Dourado Júnior, MET and Schwingel, PA}, title = {Noninvasive mechanical ventilation assistance in amyotrophic lateral sclerosis: a systematic review.}, journal = {Sao Paulo medical journal = Revista paulista de medicina}, volume = {142}, number = {1}, pages = {e2022470}, pmid = {37436254}, issn = {1806-9460}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications ; *Noninvasive Ventilation/methods ; Quality of Life ; Respiration, Artificial/adverse effects ; *Respiratory Insufficiency/therapy/complications ; }, abstract = {BACKGROUND: Respiratory failure is the most common cause of death in patients with amyotrophic lateral sclerosis (ALS), and morbidity is related to poor quality of life (QOL). Non-invasive ventilation (NIV) may be associated with prolonged survival and QOL in patients with ALS.

OBJECTIVES: To assess whether NIV is effective and safe for patients with ALS in terms of survival and QOL, alerting the health system.

DESIGN AND SETTING: Systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting standards using population, intervention, comparison, and outcome strategies.

METHODS: The Cochrane Library, CENTRAL, MEDLINE, LILACS, EMBASE, and CRD databases were searched based on the eligibility criteria for all types of studies on NIV use in patients with ALS published up to January 2022. Data were extracted from the included studies, and the findings were presented using a narrative synthesis.

RESULTS: Of the 120 papers identified, only 14 were related to systematic reviews. After thorough reading, only one meta-analysis was considered eligible. In the second stage, 248 studies were included; however, only one systematic review was included. The results demonstrated that NIV provided relief from the symptoms of chronic hypoventilation, increased survival, and improved QOL compared to standard care. These results varied according to clinical phenotype.

CONCLUSIONS: NIV in patients with ALS improves the outcome and can delay the indication for tracheostomy, reducing expenditure on hospitalization and occupancy of intensive care unit beds.

PROSPERO database: CRD42021279910 - https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=279910.}, } @article {pmid37435576, year = {2023}, author = {Titus, MB and Chang, AW and Popitsch, N and Ebmeier, CC and Bono, JM and Olesnicky, EC}, title = {The identification of protein and RNA interactors of the splicing factor Caper in the adult Drosophila nervous system.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1114857}, pmid = {37435576}, issn = {1662-5099}, support = {R15 NS104976/NS/NINDS NIH HHS/United States ; }, abstract = {Post-transcriptional gene regulation is a fundamental mechanism that helps regulate the development and healthy aging of the nervous system. Mutations that disrupt the function of RNA-binding proteins (RBPs), which regulate post-transcriptional gene regulation, have increasingly been implicated in neurological disorders including amyotrophic lateral sclerosis, Fragile X Syndrome, and spinal muscular atrophy. Interestingly, although the majority of RBPs are expressed widely within diverse tissue types, the nervous system is often particularly sensitive to their dysfunction. It is therefore critical to elucidate how aberrant RNA regulation that results from the dysfunction of ubiquitously expressed RBPs leads to tissue specific pathologies that underlie neurological diseases. The highly conserved RBP and alternative splicing factor Caper is widely expressed throughout development and is required for the development of Drosophila sensory and motor neurons. Furthermore, caper dysfunction results in larval and adult locomotor deficits. Nonetheless, little is known about which proteins interact with Caper, and which RNAs are regulated by Caper. Here we identify proteins that interact with Caper in both neural and muscle tissue, along with neural specific Caper target RNAs. Furthermore, we show that a subset of these Caper-interacting proteins and RNAs genetically interact with caper to regulate Drosophila gravitaxis behavior.}, } @article {pmid37434215, year = {2023}, author = {Riemenschneider, H and Simonetti, F and Sheth, U and Katona, E and Roth, S and Hutten, S and Farny, D and Michaelsen, M and Nuscher, B and Schmidt, MK and Flatley, A and Schepers, A and Gruijs da Silva, LA and Zhou, Q and Klopstock, T and Liesz, A and Arzberger, T and Herms, J and Feederle, R and Gendron, TF and Dormann, D and Edbauer, D}, title = {Targeting the glycine-rich domain of TDP-43 with antibodies prevents its aggregation in vitro and reduces neurofilament levels in vivo.}, journal = {Acta neuropathologica communications}, volume = {11}, number = {1}, pages = {112}, pmid = {37434215}, issn = {2051-5960}, mesh = {Animals ; Mice ; *Antibodies, Monoclonal ; Epitopes ; Immunization ; *Intermediate Filaments ; NF-kappa B ; }, abstract = {Cytoplasmic aggregation and concomitant nuclear clearance of the RNA-binding protein TDP-43 are found in ~ 90% of cases of amyotrophic lateral sclerosis and ~ 45% of patients living with frontotemporal lobar degeneration, but no disease-modifying therapy is available. Antibody therapy targeting other aggregating proteins associated with neurodegenerative disorders has shown beneficial effects in animal models and clinical trials. The most effective epitopes for safe antibody therapy targeting TDP-43 are unknown. Here, we identified safe and effective epitopes in TDP-43 for active and potential future passive immunotherapy. We prescreened 15 peptide antigens covering all regions of TDP-43 to identify the most immunogenic epitopes and to raise novel monoclonal antibodies in wild-type mice. Most peptides induced a considerable antibody response and no antigen triggered obvious side effects. Thus, we immunized mice with rapidly progressing TDP-43 proteinopathy ("rNLS8" model) with the nine most immunogenic peptides in five pools prior to TDP-43ΔNLS transgene induction. Strikingly, combined administration of two N-terminal peptides induced genetic background-specific sudden lethality in several mice and was therefore discontinued. Despite a strong antibody response, no TDP-43 peptide prevented the rapid body weight loss or reduced phospho-TDP-43 levels as well as the profound astrogliosis and microgliosis in rNLS8 mice. However, immunization with a C-terminal peptide containing the disease-associated phospho-serines 409/410 significantly lowered serum neurofilament light chain levels, indicative of reduced neuroaxonal damage. Transcriptomic profiling showed a pronounced neuroinflammatory signature (IL-1β, TNF-α, NfκB) in rNLS8 mice and suggested modest benefits of immunization targeting the glycine-rich region. Several novel monoclonal antibodies targeting the glycine-rich domain potently reduced phase separation and aggregation of TDP-43 in vitro and prevented cellular uptake of preformed aggregates. Our unbiased screen suggests that targeting the RRM2 domain and the C-terminal region of TDP-43 by active or passive immunization may be beneficial in TDP-43 proteinopathies by inhibiting cardinal processes of disease progression.}, } @article {pmid37433768, year = {2023}, author = {Zhang, W and Xiao, D and Mao, Q and Xia, H}, title = {Role of neuroinflammation in neurodegeneration development.}, journal = {Signal transduction and targeted therapy}, volume = {8}, number = {1}, pages = {267}, pmid = {37433768}, issn = {2059-3635}, support = {UL1 TR002538/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Inflammation/genetics ; Neuroinflammatory Diseases ; *Parkinson Disease/genetics ; Protein Aggregates ; Humans ; Clinical Trials as Topic ; Disease Models, Animal ; }, abstract = {Studies in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis, Huntington's disease, and so on, have suggested that inflammation is not only a result of neurodegeneration but also a crucial player in this process. Protein aggregates which are very common pathological phenomenon in neurodegeneration can induce neuroinflammation which further aggravates protein aggregation and neurodegeneration. Actually, inflammation even happens earlier than protein aggregation. Neuroinflammation induced by genetic variations in CNS cells or by peripheral immune cells may induce protein deposition in some susceptible population. Numerous signaling pathways and a range of CNS cells have been suggested to be involved in the pathogenesis of neurodegeneration, although they are still far from being completely understood. Due to the limited success of traditional treatment methods, blocking or enhancing inflammatory signaling pathways involved in neurodegeneration are considered to be promising strategies for the therapy of neurodegenerative diseases, and many of them have got exciting results in animal models or clinical trials. Some of them, although very few, have been approved by FDA for clinical usage. Here we comprehensively review the factors affecting neuroinflammation and the major inflammatory signaling pathways involved in the pathogenicity of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. We also summarize the current strategies, both in animal models and in the clinic, for the treatment of neurodegenerative diseases.}, } @article {pmid37433222, year = {2023}, author = {Shihora, A and Elias, RD and Hammond, JA and Ghirlando, R and Deshmukh, L}, title = {ALS Variants of Annexin A11's Proline-Rich Domain Impair Its S100A6-Mediated Fibril Dissolution.}, journal = {ACS chemical neuroscience}, volume = {14}, number = {15}, pages = {2583-2589}, pmid = {37433222}, issn = {1948-7193}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Annexins/genetics ; *Neurodegenerative Diseases ; Solubility ; Amyloid/metabolism ; Proline/genetics ; S100 Calcium Binding Protein A6 ; Cell Cycle Proteins/chemistry/metabolism ; }, abstract = {Mutations in the proline-rich domain (PRD) of annexin A11 are linked to amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, and generate abundant neuronal A11 inclusions by an unknown mechanism. Here, we demonstrate that recombinant A11-PRD and its ALS-associated variants form liquidlike condensates that transform into β-sheet-rich amyloid fibrils. Surprisingly, these fibrils dissolved in the presence of S100A6, an A11 binding partner overexpressed in ALS. The ALS variants of A11-PRD showed longer fibrillization half-times and slower dissolution, even though their binding affinities for S100A6 were not significantly affected. These findings indicate a slower fibril-to-monomer exchange for these ALS variants, resulting in a decreased level of S100A6-mediated fibril dissolution. These ALS-A11 variants are thus more likely to remain aggregated despite their slower fibrillization.}, } @article {pmid37433093, year = {2023}, author = {Wong, W}, title = {Managed care considerations to improve health care utilization for patients with ALS.}, journal = {The American journal of managed care}, volume = {29}, number = {7 Suppl}, pages = {S120-S126}, doi = {10.37765/ajmc.2023.89388}, pmid = {37433093}, issn = {1936-2692}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Edaravone ; Activities of Daily Living ; Quality of Life ; Patient Acceptance of Health Care ; Managed Care Programs ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatally progressive degenerative disease, with many patients succumbing to the condition within 3 to 5 years after diagnosis. It is a rare, orphan disease with an estimated US prevalence of 25,000 patients. Patients with ALS and their caregivers are faced with a substantial financial burden as a result of the condition, as ALS has an estimated national financial burden of $1.03 billion. A significant driver of the patient financial burden includes the continued need for caregiver support as the weakening of muscles progresses to dysphagia and dyspnea, making it difficult to complete activities of daily living as the disease progresses. Caregivers also experience financial burdens, as well as feelings of anxiety, depression, and decreased quality of life. In addition to needed caregiver support, patients with ALS and their families also incur substantial nonmedical costs including travel expenses, home modifications such as ramps, and indirect costs such as productivity loss. Due to the wide range of clinical symptoms that patients may exhibit when first presenting with ALS symptoms, diagnosis is often delayed, which negatively affects patient outcomes and impacts missed opportunity for clinical trial recruitment aimed at developing new disease-modifying therapies. Additionally, delay in diagnosis and referral to ALS treatment centers results in increased overall health care costs. Telemedicine may be a tool used to promote timely care from an ALS treatment center in addition to clinical trial participation for those patients who cannot overcome mobility barriers for care. Currently, 4 therapies are approved for the treatment of ALS. Riluzole has demonstrated modest improvement in survival. Other recently approved therapies include oral edaravone, a combination therapy of sodium phenylbutyrate and taurursodiol (PB/TURSO), and tofersen, which is administered intrathecally and approved under an accelerated approval. Long-term studies have shown PB/TURSO to have a dual benefit on survival and function. The Institute for Clinical and Economic Review (ICER) 2022 Evidence Report for ALS does not value the high price points of edaravone and PB/TURSO as cost-effective based on the current evidence, despite valuing the need for new treatment options for this patient population.}, } @article {pmid37433092, year = {2023}, author = {Lynch, K}, title = {Optimizing pharmacologic treatment for ALS to improve outcomes and quality of life.}, journal = {The American journal of managed care}, volume = {29}, number = {7 Suppl}, pages = {S112-S119}, doi = {10.37765/ajmc.2023.89389}, pmid = {37433092}, issn = {1936-2692}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Quality of Life ; Riluzole ; Edaravone ; }, abstract = {Just 3 disease-modifying treatments-edaravone, riluzole, and sodium phenylbutyrate and taurursodiol (PB/TURSO)-are currently FDA approved to slow progression of amyotrophic lateral sclerosis (ALS). A fourth therapy has been recently approved under accelerated approval and is contingent upon verification of clinical benefit in confirmatory trials(s). Therapy selection is based largely upon patient characteristics, as guidelines have not been updated since the recent approval of PB/TURSO or accelerated approval of tofersen. Managing ALS symptomatically is important to improve patients' quality of life. Although evidence is lacking for many pharmacologic therapies, providers use symptomatic treatments to address common symptoms including anxiety, depression, emotional lability (pseudobulbar affect), fasciculations, fatigue, insomnia, muscle cramps or spasms, musculoskeletal pain due to immobility, neuropathic type pain, excessive salivation (sialorrhea), spasticity, constipation, and urinary urgency. Emerging agents offer some hope for patients with ALS. Among the drugs, biologics, and interventions under investigation for ALS are an oral tyrosine kinase inhibitor, RIPK1 inhibition, the use of mesenchymal stem cells, antisense oligonucleotides, sequential administration of all experimental treatments in a new study design, and modification of the patient's own mesenchymal stem cells.}, } @article {pmid37433091, year = {2023}, author = {Lynch, K}, title = {Pathogenesis and presentation of ALS: examining reasons for delayed diagnosis and identifying opportunities for improvement.}, journal = {The American journal of managed care}, volume = {29}, number = {7 Suppl}, pages = {S104-S111}, doi = {10.37765/ajmc.2023.89390}, pmid = {37433091}, issn = {1936-2692}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Delayed Diagnosis ; Quality of Life ; Brain ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS), or Lou Gehrig disease, is a progressive, always-fatal neuromuscular disease characterized by motor neuron degeneration in the brain and spinal cord. As upper and lower motor neurons fail, inability to transmit messages to the muscles causes muscle stiffness, atrophy, and wasting. The incidence of this incurable disease is increasing in the United States, and its prognosis is grim. On average, patients survive about 3 to 5 years from symptom onset. Until recently, few risk factors were known, but some are newly emerging. About 10% of cases are related to genetic variants. Patients who develop ALS often experience diagnostic delays (10-16 months on average), and its heterogeneity contributes to that delay. Diagnosis is based primarily on clinical signs and symptoms and exclusion of other causes of motor neuron dysfunction. Reliable, accessible biomarkers are needed to aid early ALS diagnosis, differentiate from ALS-mimicking diseases, predict survival, and monitor disease progression and treatment response. Misdiagnosing ALS can have devastating consequences, including unnecessary emotional burden, delayed and/or inappropriate treatment, and undue financial burden. The grim prognosis and sure progression to death creates considerable burden and reduces quality of life for patients and caregivers.}, } @article {pmid37432640, year = {2024}, author = {Maurya, S and Gaur, M and Yadav, AB}, title = {Staphylococcus aureus Biofilm Destabilization by Tween-80 and Lung Surfactants to Overcome Biofilm-Imposed Drug Resistance.}, journal = {Applied biochemistry and biotechnology}, volume = {196}, number = {3}, pages = {1558-1569}, pmid = {37432640}, issn = {1559-0291}, mesh = {Animals ; *Staphylococcus aureus ; Anti-Bacterial Agents/pharmacology ; Polysorbates/pharmacology ; Biofilms ; *Staphylococcal Infections/microbiology ; Surface-Active Agents/pharmacology ; Drug Resistance ; Lung ; }, abstract = {This study is aimed to evaluating the potential of tween-80 and artificial lung surfactant (ALS) to destabilize S. aureus biofilm. The biofilm destabilization was studied by crystal violet staining, bright field microscopy, and scanning electron microscopy (SEM). During the study, S. aureus biofilm was exposed with tween-80 along various concentrations (1%, 0.1%, and 0.05%) or LS (lung surfactant) at (2.5%, 5%, and 15%) for 2 hrs. It was observed that 0.1% of tween-80 destabilized 63.83 ± 4.35% and 15% ALS 77 ± 1.7% biofilm in comparison to without treatment. The combination of tween-80 and ALS was used and showed a synergistic effect to destabilize 83.4 ± 1.46% biofilm. These results showed the potential of tween-80 and ALS as biofilm disruptors, which further needs to explore in an in-vivo animal model to access the actual potential of biofilm disruption in natural conditions. This study could play a pivotal role to overcome the problem of antibiotic resistance imposed due to biofilm formation to combat antibiotic resistance imposed by bacteria.}, } @article {pmid37432384, year = {2023}, author = {Renke, G and Almeida, VBP and Souza, EA and Lessa, S and Teixeira, RL and Rocha, L and Sousa, PL and Starling-Soares, B}, title = {Clinical Outcomes of the Deleterious Effects of Aluminum on Neuro-Cognition, Inflammation, and Health: A Review.}, journal = {Nutrients}, volume = {15}, number = {9}, pages = {}, pmid = {37432384}, issn = {2072-6643}, mesh = {Humans ; *Aluminum/toxicity ; *Inflammation ; Adjuvants, Immunologic ; Chelating Agents ; Cognition ; Food Additives ; }, abstract = {Introduction: In the scenario of metal toxicity, aluminum (Al) stands out as a ubiquitous type of metal that can be combined with other elements and form different compounds. Al is widely used daily as an adjuvant in vaccines, antacids, food additives (as components of AI-containing food additives), skin care products, cosmetics, and kitchenware, and can be an element or contaminant present in our daily life. Objective: To present a review of the main deleterious effects of Al on human health. Methods: The search was carried out from September 2022 to February 2023 in the Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases, using scientific articles from 2012 to 2023. The quality of the studies was based on the GRADE instrument, and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusions: A total of 115 files were search returned. Further, 95 articles were evaluated, and 44 were included in this review. Based on the results, measuring Al's relevance to health is essential in medicine. Several studies have demonstrated clinical outcomes and metabolic alterations with Al exposure. The tolerable weekly intake established by the European Food Safety Authority (EFSA) of 1 mg Al/kg body weight can be achieved through dietary exposure alone. Proven neurotoxicity in humans is the critical adverse effect of Al. A carcinogenic effect of Al has not been proven so far. Preventive medicine advocates that exposure to Al should be kept as low as possible. Chelating agents, such as calcium disodium ethylene diamine tetraacetic acid and deferoxamine, are options for acute poisoning, and monomethysilanetriol supplementation may be a long-term strategy with chelation potential. Further studies are needed to assess the impacts of Al on human health.}, } @article {pmid37431963, year = {2023}, author = {Pérez-Berlanga, M and Wiersma, VI and Zbinden, A and De Vos, L and Wagner, U and Foglieni, C and Mallona, I and Betz, KM and Cléry, A and Weber, J and Guo, Z and Rigort, R and de Rossi, P and Manglunia, R and Tantardini, E and Sahadevan, S and Stach, O and Hruska-Plochan, M and Allain, FH and Paganetti, P and Polymenidou, M}, title = {Loss of TDP-43 oligomerization or RNA binding elicits distinct aggregation patterns.}, journal = {The EMBO journal}, volume = {42}, number = {17}, pages = {e111719}, pmid = {37431963}, issn = {1460-2075}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Frontotemporal Lobar Degeneration/metabolism ; DNA-Binding Proteins/metabolism ; Neurons/metabolism ; RNA/genetics ; }, abstract = {Aggregation of the RNA-binding protein TAR DNA-binding protein 43 (TDP-43) is the key neuropathological feature of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). In physiological conditions, TDP-43 is predominantly nuclear, forms oligomers, and is contained in biomolecular condensates assembled by liquid-liquid phase separation (LLPS). In disease, TDP-43 forms cytoplasmic or intranuclear inclusions. How TDP-43 transitions from physiological to pathological states remains poorly understood. Using a variety of cellular systems to express structure-based TDP-43 variants, including human neurons and cell lines with near-physiological expression levels, we show that oligomerization and RNA binding govern TDP-43 stability, splicing functionality, LLPS, and subcellular localization. Importantly, our data reveal that TDP-43 oligomerization is modulated by RNA binding. By mimicking the impaired proteasomal activity observed in ALS/FTLD patients, we found that monomeric TDP-43 forms inclusions in the cytoplasm, whereas its RNA binding-deficient counterpart aggregated in the nucleus. These differentially localized aggregates emerged via distinct pathways: LLPS-driven aggregation in the nucleus and aggresome-dependent inclusion formation in the cytoplasm. Therefore, our work unravels the origins of heterogeneous pathological species reminiscent of those occurring in TDP-43 proteinopathy patients.}, } @article {pmid37431079, year = {2023}, author = {Kurashige, T}, title = {[Histopathological Diagnostic Marker for ALS: Phosphorylated Transacting Response DNA-Binding Protein of 43kDa in Intramuscular Nerve Bundles].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {75}, number = {7}, pages = {877-887}, doi = {10.11477/mf.1416202436}, pmid = {37431079}, issn = {1881-6096}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Retrospective Studies ; Autopsy ; DNA-Binding Proteins ; }, abstract = {The discovery of transacting response DNA-binding protein of 43 kDa (TDP-43) led to a deeper understanding of the pathogenesis of amyotrophic lateral sclerosis (ALS). Since this discovery, blood and cerebrospinal fluid biomarkers of ALS have been reported. However, these biomarkers do not exhibit sufficient specificity for ALS. Our case-control postmortem and retrospective muscle biopsy cohort studies revealed phosphorylated TDP-43 in intramuscular nerve bundles, which precedes the clinical fulfillment of the Gold Coast criteria. We attempted to establish a histopathological biomarker for ALS and identify molecular targets for the treatment of lower motor dysfunction in patients with ALS.}, } @article {pmid37430314, year = {2023}, author = {Mitsumoto, H and Cheung, K and Oskarsson, B and Andrews, HF and Jang, GE and Andrews, JA and Shah, JS and Fernandes, JA and McElhiney, M and Santella, RM}, title = {Randomized double-blind personalized N-of-1 clinical trial to test the safety and potential efficacy of TJ-68 for treating muscle cramps in amyotrophic lateral sclerosis (ALS): study protocol for a TJ-68 trial.}, journal = {Trials}, volume = {24}, number = {1}, pages = {449}, pmid = {37430314}, issn = {1745-6215}, support = {no number//Tsumura and Company/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/drug therapy ; Drug Combinations ; *Drugs, Chinese Herbal ; Muscle Cramp/diagnosis/drug therapy/etiology ; Quality of Life ; Randomized Controlled Trials as Topic ; }, abstract = {INTRODUCTION/AIMS: Muscle cramps are a common and often disabling symptom in amyotrophic lateral sclerosis (ALS), a devastating and incurable neurodegenerative disorder. To date, there are no medications specifically approved for the treatment of muscle cramps. Ameliorating muscle cramps in ALS may improve and sustain quality of life. A widely prescribed traditional Japanese (Kampo) medicine against muscle cramps, shakuyakukanzoto (TJ-68), has been studied in advanced liver disease, spinal stenosis, kidney failure, and diabetic neuropathy. The Japanese ALS Management Guideline mentions TJ-68 for difficult muscle cramps in ALS. Therefore, the rationale of our trial is to investigate the safety and effectiveness of TJ-68 in treating painful and disabling muscle cramps in people with ALS outside of Japan. Accordingly, we are conducting a randomized clinical trial to test the safety and efficacy of TJ-68 in participants with ALS reporting frequent muscle cramps using an innovative, personalized N-of-1 design. If successful, TJ-68 may be used for muscle cramps in a broader population of people with ALS.

METHODS: This is a two-site, double-blind, randomized personalized N-of-1 early clinical trial with TJ-68. At least 22 participants with ALS and daily muscle cramps will receive drug or placebo for 2 weeks (one treatment period) followed by a 1-week washout in a four-period cross-over design. While the primary objective is to evaluate the safety of TJ-68, the study has 85% power to detect a one-point shift on the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity of the Columbia Muscle Cramp Scale (MCS). Secondary outcomes include the full MCS score, a Cramp Diary, Clinical Global Impression of Changes, Goal Attainment Scale, quality of life scale and ALS functional rating scale-revised (ALSFRS-R).

DISCUSSION: The study is underway. A personalized N-of-1 trial design is an efficient approach to testing medications that alleviate muscle cramps in rare disorders. If TJ-68 proves safe and efficacious then it may be used to treat cramps in ALS, and help to improve and sustain quality of life.

TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov (NCT04998305), 8/9/2021.}, } @article {pmid37430221, year = {2023}, author = {Miyake, N and Igarashi, Y and Nakae, R and Mizobuchi, T and Masuno, T and Yokobori, S}, title = {Ventilator management and risk of air leak syndrome in patients with SARS-CoV-2 pneumonia: a single-center, retrospective, observational study.}, journal = {BMC pulmonary medicine}, volume = {23}, number = {1}, pages = {251}, pmid = {37430221}, issn = {1471-2466}, mesh = {Adult ; Humans ; SARS-CoV-2 ; Retrospective Studies ; *COVID-19/therapy ; *Pneumonia ; Ventilators, Mechanical ; Syndrome ; }, abstract = {BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia is reportedly associated with air leak syndrome (ALS), including mediastinal emphysema and pneumothorax, and has a high mortality rate. In this study, we compared values obtained every minute from ventilators to clarify the relationship between ventilator management and risk of developing ALS.

METHODS: This single-center, retrospective, observational study was conducted at a tertiary care hospital in Tokyo, Japan, over a 21-month period. Information on patient background, ventilator data, and outcomes was collected from adult patients with SARS-CoV-2 pneumonia on ventilator management. Patients who developed ALS within 30 days of ventilator management initiation (ALS group) were compared with those who did not (non-ALS group).

RESULTS: Of the 105 patients, 14 (13%) developed ALS. The median positive-end expiratory pressure (PEEP) difference was 0.20 cmH2O (95% confidence interval [CI], 0.20-0.20) and it was higher in the ALS group than in the non-ALS group (9.6 [7.8-20.2] vs. 9.3 [7.3-10.2], respectively). For peak pressure, the median difference was -0.30 cmH2O (95% CI, -0.30 - -0.20) (20.4 [17.0-24.4] in the ALS group vs. 20.9 [16.7-24.6] in the non-ALS group). The mean pressure difference of 0.0 cmH2O (95% CI, 0.0-0.0) (12.7 [10.9-14.6] vs. 13.0 [10.3-15.0], respectively) was also higher in the non-ALS group than in the ALS group. The difference in single ventilation volume per ideal body weight was 0.71 mL/kg (95% CI, 0.70-0.72) (8.17 [6.79-9.54] vs. 7.43 [6.03-8.81], respectively), and the difference in dynamic lung compliance was 8.27 mL/cmH2O (95% CI, 12.76-21.95) (43.8 [28.2-68.8] vs. 35.7 [26.5-41.5], respectively); both were higher in the ALS group than in the non-ALS group.

CONCLUSIONS: There was no association between higher ventilator pressures and the development of ALS. The ALS group had higher dynamic lung compliance and tidal volumes than the non-ALS group, which may indicate a pulmonary contribution to ALS. Ventilator management that limits tidal volume may prevent ALS development.}, } @article {pmid37429415, year = {2023}, author = {Asveda, T and Talwar, P and Ravanan, P}, title = {Exploring microglia and their phenomenal concatenation of stress responses in neurodegenerative disorders.}, journal = {Life sciences}, volume = {328}, number = {}, pages = {121920}, doi = {10.1016/j.lfs.2023.121920}, pmid = {37429415}, issn = {1879-0631}, mesh = {Humans ; Microglia/metabolism ; *Neurodegenerative Diseases/metabolism ; Central Nervous System/metabolism ; *Alzheimer Disease/metabolism ; *Parkinson Disease/metabolism ; }, abstract = {Neuronal cells are highly functioning but also extremely stress-sensitive cells. By defending the neuronal cells against pathogenic insults, microglial cells, a unique cell type, act as the frontline cavalry in the central nervous system (CNS). Their remarkable and unique ability to self-renew independently after their creation is crucial for maintaining normal brain function and neuroprotection. They have a wide range of molecular sensors that help maintain CNS homeostasis during development and adulthood. Despite being the protector of the CNS, studies have revealed that persistent microglial activation may be the root cause of innumerable neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS). From our vigorous review, we state that there is a possible interlinking between pathways of Endoplasmic reticulum (ER) stress response, inflammation, and oxidative stress resulting in dysregulation of the microglial population, directly influencing the accumulation of pro-inflammatory cytokines, complement factors, free radicals, and nitric oxides leading to cell death via apoptosis. Recent research uses the suppression of these three pathways as a therapeutic approach to prevent neuronal death. Hence, in this review, we have spotlighted the advancement in microglial studies, which focus on their molecular defenses against multiple stresses, and current therapeutic strategies indirectly targeting glial cells for neurodevelopmental diseases.}, } @article {pmid37427714, year = {2023}, author = {Van Unnik, JWJ and Bakers, JNE and Kokx, S and Van Den Berg, LH and Visser-Meily, JMA and Beelen, A and Van Eijk, RPA}, title = {Portable fixed dynamometry enables home-based, reliable assessment of muscle strength in patients with amyotrophic lateral sclerosis: a pilot study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2023.2231494}, pmid = {37427714}, issn = {2167-9223}, abstract = {OBJECTIVE: To determine the feasibility, reliability, and sensitivity of remotely monitoring muscle strength loss of knee extensors using a novel portable fixed dynamometer (PFD) in patients with amyotrophic lateral sclerosis (ALS).

METHODS: We conducted a pilot study with a newly developed device to measure knee extension strength. Patients performed unsupervised PFD measurements, biweekly, for 6 months at home. We evaluated feasibility using adherence and a device-specific questionnaire. Reliability was assessed by (1) comparing unsupervised and supervised measurements to identify systematic bias, and (2) comparing consecutive unsupervised measurements to determine test-retest reliability expressed as intraclass correlation coefficient (ICC) and standard error of measurement (SEM). Sensitivity to detect longitudinal change was described using linear mixed-effects models.

RESULTS: We enrolled 18 patients with ALS. Adherence was 86%, where all patients found that the device suitable to measure muscle strength at home; 4 patients (24%) found the measurements burdensome. The correlation between (un)supervised measurements was excellent (Pearson's r 0.97, 95%CI; 0.94 - 0.99) and no systematic bias was present (mean difference 0.13, 95%CI; -2.22 - 2.48, p = 0.91). Unsupervised measurements had excellent test-retest reliability with an average ICC of 0.97 (95%CI: 0.94 - 0.99) and SEM of 5.8% (95%CI: 4.8 - 7.0). Muscle strength declined monthly by 1.9 %predicted points (95%CI; -3.0 to -0.9, p = 0.001).

CONCLUSIONS: Using the PFD, it proved feasible to perform knee extension strength measurements at home which were reliable and sensitive for detecting muscle strength loss. Larger studies are warranted to compare the device with conventional outcomes.}, } @article {pmid37427570, year = {2023}, author = {Diaz Villanueva, L and Lada Colunga, B and Villanueva Ordóñez, MJ and Cuartas Álvarez, T and Cernuda Martinez, JA and Castro Delgado, R}, title = {Impact of the COVID-19 Pandemic on the Profile of Patients in SAMU-Asturias EMS (Spain): A Two-Year Retrospective Analysis of Advanced Life Support Unit Data.}, journal = {Prehospital and disaster medicine}, volume = {38}, number = {4}, pages = {430-435}, doi = {10.1017/S1049023X23006015}, pmid = {37427570}, issn = {1945-1938}, mesh = {Humans ; *COVID-19/epidemiology/prevention & control ; Cross-Sectional Studies ; *Emergency Medical Services/methods/statistics & numerical data ; Pandemics/prevention & control ; Retrospective Studies ; Spain/epidemiology ; *Advanced Cardiac Life Support/statistics & numerical data ; }, abstract = {INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic had important consequences on the health system. Emergency Medical Services (EMS) were a key element in the response and were forced to modify their daily procedures. The main objective of this study was to find out if there were differences in response times and in the profile of patients treated by the Advanced Life Support (ALS) units of Servicio de Asistencia Médica Urgente (SAMU)-Asturias, the EMS of the Principality of Asturias, between the pre-pandemic period and the pandemic period.

METHODOLOGY: This was a descriptive, cross-sectional, observational, and retrospective study that included all patients treated by SAMU-Asturias ALS from January 1, 2019 through December 31, 2020.

RESULTS: The pandemic has had an impact on daily activity of SAMU-Asturias, with a 9.2% decrease in daily ALS services during the pandemic, longer prehospital times during the pandemic period (mean = 54'35"; SD = 0'48"; P = 0.00) mainly due to an increase in scene time (mean = 28'01"; SD = 12'57"; P = 0.00), and a slight increase in the average age of patients during the pandemic in relation to the pre-pandemic period. No differences were found between the types of incidents for ALS or between the resolution of the patients.

CONCLUSIONS: The COVID-19 pandemic mainly affects prehospital times in an emergency service, with no differences being observed in types of incidents; in EMS future pandemic planning, this should be taken into consideration.}, } @article {pmid37427325, year = {2023}, author = {Najafi, S and Najafi, P and Kaffash Farkhad, N and Hosseini Torshizi, G and Assaran Darban, R and Boroumand, AR and Sahab-Negah, S and Khodadoust, MA and Tavakol-Afshari, J}, title = {Mesenchymal stem cell therapy in amyotrophic lateral sclerosis (ALS) patients: A comprehensive review of disease information and future perspectives.}, journal = {Iranian journal of basic medical sciences}, volume = {26}, number = {8}, pages = {872-881}, pmid = {37427325}, issn = {2008-3866}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare deadly progressive neurological disease that primarily affects the upper and lower motor neurons with an annual incidence rate of 0.6 to 3.8 per 100,000 people. Weakening and gradual atrophy of the voluntary muscles are the first signs of the disease onset affecting all aspects of patients' lives, including eating, speaking, moving, and even breathing. Only 5-10% of patients have a familial type of the disease and show an autosomal dominant pattern, but the cause of the disease is unknown in the remaining 90% of patients (Sporadic ALS). However, in both types of disease, the patient's survival is 2 to 5 years from the disease onset. Some clinical and molecular biomarkers, magnetic resonance imaging (MRI), blood or urine test, muscle biopsy, and genetic testing are complementary methods for disease diagnosis. Unfortunately, with the exception of Riluzole, the only medically approved drug for the management of this disease, there is still no definitive cure for it. In this regard, the use of mesenchymal stem cells (MSCs) for the treatment or management of the disease has been common in preclinical and clinical studies for many years. MSCs are multipotent cells having immunoregulatory, anti-inflammatory, and differentiation ability that makes them a good candidate for this purpose. This review article aims to discuss multiple aspects of ALS disease and focus on MSCs' role in disease management based on performed clinical trials.}, } @article {pmid37427180, year = {2023}, author = {Chapagain, S and Khati, N and Lama, R and Karki, R and Aryal, R and Pangyani, B and Koirala, A}, title = {Amyotrophic lateral sclerosis with respiratory failure and dysautonomia: a case report.}, journal = {Annals of medicine and surgery (2012)}, volume = {85}, number = {7}, pages = {3623-3625}, pmid = {37427180}, issn = {2049-0801}, abstract = {UNLABELLED: Amyotrophic lateral sclerosis (ALS) is a disease that affects both upper and lower motor neurons, causing a range of symptoms beyond the motor system. Recent research has shown that the autonomic nervous system can also be affected, with symptoms such as orthostatic hypotension, fluctuations in blood pressure, and dizziness being reported.

CASE PRESENTATION: A 58-year-old male presented with left lower limb limping, difficulty climbing stairs, and left foot weakness, followed by right upper limb weakness and was diagnosed with ALS and received edaravone and riluzole treatment. He presented again with right lower limb weakness, shortness of breath, and wide fluctuations in blood pressure, leading to ICU admission with new diagnosis of ALS with dysautonomia with respiratory failure and was managed with non-invasive ventilation, physiotherapy, and gait training exercises.

CLINICAL DISCUSSION: ALS is a progressive neurodegenerative disease affecting motor neurons but non-motor symptoms can also occur, including dysautonomia, which can result in blood pressure fluctuations. Dysautonomia in ALS is caused by several mechanisms such as severe muscle atrophy, prolonged ventilatory support, and upper and lower motor neuron lesions. Management of ALS involves giving a definitive diagnosis, providing nutritional support, using disease-modifying drugs such as riluzole and non-invasive ventilation to improve survival and quality of life. Early diagnosis is essential for effective management of the disease.

CONCLUSION: Early diagnosis, use of disease-modifying drugs, non-invasive ventilation, and maintaining the patient's nutritional status are crucial for managing ALS which can have non-motor symptoms as well.}, } @article {pmid37427010, year = {2023}, author = {Mballa Yene, BV and Lee, SY and Park, KS and Kang, YJ and Seo, SH and Yoo, JI}, title = {Prevalence of Sarcopenia in Africa: A Systematic Review.}, journal = {Clinical interventions in aging}, volume = {18}, number = {}, pages = {1021-1035}, pmid = {37427010}, issn = {1178-1998}, mesh = {Male ; Female ; Humans ; *Sarcopenia/epidemiology/diagnosis ; Prevalence ; Africa/epidemiology ; }, abstract = {OBJECTIVE: The world population gradually getting older, age-related sarcopenia is becoming more frequent. Known to be highly prevalent in high income countries, relative data in Africa are still scarce. This review aims to estimate the prevalence of sarcopenia in Africa and its characteristics.

STUDY DESIGN AND SETTING: A literature search in PubMed, Web of Science, Google Scholar, and Scopus was conducted in October 2022. All studies reporting the prevalence of sarcopenia in Africa within 15 years were included, and we did an assessment of bias with Hoy et al's risk bias assessment tool. The estimated prevalence of sarcopenia was the outcome and we performed secondary analyses by age, gender, and diagnostic criteria. The random effect model was used for the prevalence estimation. The prevalence of sarcopenia and 95% confidence interval (95% CI) were calculated using the inverse-variance method.

RESULTS: A total of 17 studies met our eligibility criteria, for a study population of 12,690 participants with 44.3% males and 55.7% females. The overall prevalence of sarcopenia was 25% (95% CI: 19-30%). The prevalence of sarcopenia among 50 years old and older was 23% (95% CI: 17-29%). We had a higher prevalence of sarcopenia among males (30%, %95 IC: 20-39%) than females (29%, %95 IC: 21-36%). The prevalence of sarcopenia was different depending on the diagnosis criteria used.

CONCLUSION: The prevalence of sarcopenia in Africa was relatively high. However, the fact that the majority of included studies were hospital-based studies shows the necessity of further community-based studies in order to have a more accurate representation of the situation in the general population.}, } @article {pmid37426441, year = {2023}, author = {Pamphlett, R and Bishop, DP}, title = {The toxic metal hypothesis for neurological disorders.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1173779}, pmid = {37426441}, issn = {1664-2295}, abstract = {Multiple sclerosis and the major sporadic neurogenerative disorders, amyotrophic lateral sclerosis, Parkinson disease, and Alzheimer disease are considered to have both genetic and environmental components. Advances have been made in finding genetic predispositions to these disorders, but it has been difficult to pin down environmental agents that trigger them. Environmental toxic metals have been implicated in neurological disorders, since human exposure to toxic metals is common from anthropogenic and natural sources, and toxic metals have damaging properties that are suspected to underlie many of these disorders. Questions remain, however, as to how toxic metals enter the nervous system, if one or combinations of metals are sufficient to precipitate disease, and how toxic metal exposure results in different patterns of neuronal and white matter loss. The hypothesis presented here is that damage to selective locus ceruleus neurons from toxic metals causes dysfunction of the blood-brain barrier. This allows circulating toxicants to enter astrocytes, from where they are transferred to, and damage, oligodendrocytes, and neurons. The type of neurological disorder that arises depends on (i) which locus ceruleus neurons are damaged, (ii) genetic variants that give rise to susceptibility to toxic metal uptake, cytotoxicity, or clearance, (iii) the age, frequency, and duration of toxicant exposure, and (iv) the uptake of various mixtures of toxic metals. Evidence supporting this hypothesis is presented, concentrating on studies that have examined the distribution of toxic metals in the human nervous system. Clinicopathological features shared between neurological disorders are listed that can be linked to toxic metals. Details are provided on how the hypothesis applies to multiple sclerosis and the major neurodegenerative disorders. Further avenues to explore the toxic metal hypothesis for neurological disorders are suggested. In conclusion, environmental toxic metals may play a part in several common neurological disorders. While further evidence to support this hypothesis is needed, to protect the nervous system it would be prudent to take steps to reduce environmental toxic metal pollution from industrial, mining, and manufacturing sources, and from the burning of fossil fuels.}, } @article {pmid37425721, year = {2023}, author = {Angrick, M and Luo, S and Rabbani, Q and Candrea, DN and Shah, S and Milsap, GW and Anderson, WS and Gordon, CR and Rosenblatt, KR and Clawson, L and Maragakis, N and Tenore, FV and Fifer, MS and Hermansky, H and Ramsey, NF and Crone, NE}, title = {Online speech synthesis using a chronically implanted brain-computer interface in an individual with ALS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {37425721}, support = {UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {Recent studies have shown that speech can be reconstructed and synthesized using only brain activity recorded with intracranial electrodes, but until now this has only been done using retrospective analyses of recordings from able-bodied patients temporarily implanted with electrodes for epilepsy surgery. Here, we report online synthesis of intelligible words using a chronically implanted brain-computer interface (BCI) in a clinical trial participant (ClinicalTrials.gov, NCT03567213) with dysarthria due to amyotrophic lateral sclerosis (ALS). We demonstrate a reliable BCI that synthesizes commands freely chosen and spoken by the user from a vocabulary of 6 keywords originally designed to allow intuitive selection of items on a communication board. Our results show for the first time that a speech-impaired individual with ALS can use a chronically implanted BCI to reliably produce synthesized words that are intelligible to human listeners while preserving the participants voice profile.}, } @article {pmid37425709, year = {2023}, author = {Rhodes, E and Alfa, S and Jin, H and Massimo, L and Elman, L and Amado, D and Baer, M and Quinn, C and McMillan, CT}, title = {Cognitive reserve in ALS: The role of occupational skills and requirements.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.06.21.23291677}, pmid = {37425709}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative condition featuring variable degrees of motor decline and cognitive impairment. We test the hypothesis that cognitive reserve (CR), defined by occupational histories involving more complex cognitive demands, may protect against cognitive decline, while motor reserve (MR), defined by working jobs requiring complex motor skills, may protect against motor dysfunction.

METHODS: Individuals with ALS (n=150) were recruited from the University of Pennsylvania's Comprehensive ALS Clinic. Cognitive performance was evaluated using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), and motor functioning was measured using Penn Upper Motor Neuron (PUMNS) scale and ALS Functional Rating Scales (ALSFRS-R). The Occupational Information Network (O*NET) Database was used to derive 17 factors representing distinct worker characteristics, occupational requirements, and worker requirements, which were related to ECAS, PUMNS, and ALSFRS-R scores using multiple linear regression.

RESULTS: A history of working jobs involving greater reasoning ability (β=2.12, p<.05), social ability (β=1.73, p<.05), analytic skills, (β=3.12, p<.01) and humanities knowledge (β=1.83, p<.01) was associated with better performance on the ECAS, while jobs involving more exposure to environmental hazards (β=-2.57, p<.01) and technical skills (β=-2.16, p<.01) were associated with lower ECAS Total Scores. Jobs involving greater precision skills (β=1.91, p<.05) were associated with greater disease severity on the PUMNS. Findings for the ALSFRS-R did not survive correction for multiple comparisons.

DISCUSSION: Jobs requiring greater reasoning abilities, social skills, and humanities knowledge were related to preserved cognitive functioning consistent with CR, while jobs with greater exposure to environmental hazards and technical demands were linked to poorer cognitive functioning. We did not find evidence of MR as no protective effects of occupational skills and requirements were found for motor symptoms, and jobs involving greater precision skills and reasoning abilities were associated with worse motor functioning. Occupational history provides insight into protective and risk factors for variable degrees of cognitive and motor dysfunction in ALS.}, } @article {pmid37424512, year = {2023}, author = {de Alcântara, C and Cruzeiro, MM and França, MC and Alencar, MA and Jaeger, A and de Araújo, CM and da Gama, NAS and Camargos, ST and de Souza, LC}, title = {A comparative study of cognitive and behavioral profiles between sporadic and type 8 amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {68}, number = {3}, pages = {316-322}, doi = {10.1002/mus.27927}, pmid = {37424512}, issn = {1097-4598}, mesh = {Male ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis ; Executive Function ; *Apathy ; Cognition ; Neuropsychological Tests ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) type 8 (ALS8) is caused by VAPB gene mutations. The differences between neuropsychological and behavioral profiles of patients with sporadic ALS (sALS) and those with ALS8 are unclear. We aimed to compare cognitive performance and behavioral aspects between sALS and ALS8 patients.

METHODS: Our study included 29 symptomatic ALS8 patients (17 men; median age 49 years), 20 sALS patients (12 men; median age 55 years), and 30 healthy controls (16 men; median age 50 years), matched for sex, age, and education. Participants underwent neuropsychological assessments focused on executive functions, visual memory, and facial emotion recognition. Behavioral and psychiatric symptoms were evaluated using the Hospital Anxiety and Depression Scale and the Cambridge Behavioral Inventory.

RESULTS: Clinical groups (sALS and ALS8) exhibited lower global cognitive efficiency and impaired cognitive flexibility, processing speed, and inhibitory control compared with controls. ALS8 and sALS showed similar performance in most executive tests, except for poorer verbal (lexical) fluency in those with sALS. Apathy, anxiety, and stereotypical behaviors were frequent in both clinical groups.

DISCUSSION: sALS and ALS8 patients demonstrated similar deficits in most cognitive domains and had comparable behavioral profiles. These findings should be considered in the care of patients.}, } @article {pmid37424394, year = {2024}, author = {Dratch, L and Owczarzak, J and Mu, W and Cousins, KAQ and Massimo, L and Grossman, M and Erby, L}, title = {The lived experience of reconstructing identity in response to genetic risk of frontotemporal degeneration and amyotrophic lateral sclerosis.}, journal = {Journal of genetic counseling}, volume = {33}, number = {3}, pages = {515-527}, pmid = {37424394}, issn = {1573-3599}, support = {P01 AG066597/AG/NIA NIH HHS/United States ; ZIE HG200353/ImNIH/Intramural NIH HHS/United States ; /HG/NHGRI NIH HHS/United States ; AG066597/AG/NIA NIH HHS/United States ; /HG/NHGRI NIH HHS/United States ; AG066597/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/psychology ; Female ; Male ; Middle Aged ; Adult ; Genetic Predisposition to Disease ; Aged ; Frontotemporal Lobar Degeneration/genetics/psychology ; }, abstract = {With the increasing availability of predictive genetic testing for adult-onset neurodegenerative conditions, it is imperative that we better understand the impact of learning one's risk status. Frontotemporal degeneration (FTD) is the second most prevalent cause of early-onset dementia. About one-third of patients have an identifiable genetic etiology, and some genetic variants that cause FTD can also cause amyotrophic lateral sclerosis (ALS). To understand individuals' risk perception and broader experience of living at risk, we completed semi-structured telephone interviews with 14 asymptomatic adults who tested positive for a variant known to cause risk for FTD and/or ALS. We conducted a thematic analysis, and within the core topic of identity, we derived three themes: conceptualization of FTD and ALS as a threat to identity, enduring uncertainty and dread, and varying centrality of risk status to identity. FTD and ALS risk raised fundamental issues for participants related to the essence of personhood, challenged them to confront Cartesian dualism (the philosophy of mind-body separation), and exposed how time, relationships, and social roles have affected their understanding of the nature of the self. Our findings provide important insight into how being at genetic risk shapes an individual's identity. We conclude that genetic counseling interventions that allow for identity exploration, anticipatory guidance, and uncertainty management should be utilized when supporting persons at risk.}, } @article {pmid37423671, year = {2023}, author = {Gómez-Sánchez, A and Vitale, R and Devos, O and de Juan, A and Ruckebusch, C}, title = {Kernelizing: A way to increase accuracy in trilinear decomposition analysis of multiexponential signals.}, journal = {Analytica chimica acta}, volume = {1273}, number = {}, pages = {341545}, doi = {10.1016/j.aca.2023.341545}, pmid = {37423671}, issn = {1873-4324}, abstract = {The unmixing of multiexponential decay signals into monoexponential components using soft modelling approaches is a challenging task due to the strong correlation and complete window overlap of the profiles. To solve this problem, slicing methodologies, such as PowerSlicing, tensorize the original data matrix into a three-way data array that can be decomposed based on trilinear models providing unique solutions. Satisfactory results have been reported for different types of data, e.g., nuclear magnetic resonance or time-resolved fluorescence spectra. However, when decay signals are described by only a few sampling (time) points, a significant degradation of the results can be observed in terms of accuracy and precision of the recovered profiles. In this work, we propose a methodology called Kernelizing that provides a more efficient way to tensorize data matrices of multiexponential decays. Kernelizing relies on the invariance of exponential decays, i.e., when convolving a monoexponential decaying function with any positive function of finite width (hereafter called "kernel"), the shape of the decay (determined by the characteristic decay constant) remains unchanged and only the preexponential factor varies. The way preexponential factors are affected across the sample and time modes is linear, and it only depends on the kernel used. Thus, using kernels of different shapes, a set of convolved curves can be obtained for every sample, and a three-way data array generated, for which the modes are sample, time and kernelizing effect. This three-way array can be afterwards analyzed by a trilinear decomposition method, such as PARAFAC-ALS, to resolve the underlying monoexponential profiles. To validate this new approach and assess its performance, we applied Kernelizing to simulated datasets, real time-resolved fluorescence spectra collected on mixtures of fluorophores and fluorescence-lifetime imaging microscopy data. When the measured multiexponential decays feature few sampling points (down to fifteen), more accurate trilinear model estimates are obtained than when using slicing methodologies.}, } @article {pmid37422901, year = {2023}, author = {Zhao, B and Jiang, Q and Lin, J and Wei, Q and Li, C and Hou, Y and Cao, B and Zhang, L and Ou, R and Liu, K and Yang, T and Xiao, Y and Shang, H}, title = {TBK1 variants in Chinese patients with amyotrophic lateral sclerosis: Genetic analysis and clinical features.}, journal = {European journal of neurology}, volume = {30}, number = {10}, pages = {3079-3089}, doi = {10.1111/ene.15973}, pmid = {37422901}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; East Asian People ; Mutation, Missense ; Asian People/genetics ; Mutation ; Protein Serine-Threonine Kinases/genetics ; }, abstract = {BACKGROUND AND PURPOSE: Haploinsufficiency of TANK-binding kinase 1 (TBK1) loss-of-function (LoF) variants has been shown to be pathogenic in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the genetic spectrum of TBK1 and clinical features of ALS patients with TBK1 variants remain largely unknown in Asians.

METHODS: Genetic analysis was performed on 2011 Chinese ALS patients. Software was used to predict the deleteriousness of missense variants in TBK1. In addition, PubMed, Embase and Web of Science were searched for related literature.

RESULTS: Twenty-six TBK1 variants were identified in 33 of 2011 ALS patients, including six novel LoF variants (0.3%) and 20 rare missense variants, 12 of which were predicted to be deleterious (0.6%). In addition to TBK1 variants, 11 patients had other ALS-related gene variants. Forty-two previous studies found that the frequency of TBK1 variants was 1.81% in ALS/FTD patients. The frequency of TBK1 LoF variants in ALS was 0.5% (Asians 0.4%; Caucasian 0.6%) and that of missense variants was 0.8% (Asians 1.0%; Caucasian 0.8%). ALS patients with TBK1 LoF variants affecting the kinase domain had a significantly younger age of onset than patients carrying LoF variants affecting the coiled coil domains CCD1 and CCD2. FTD has a frequency of 10% in Caucasian ALS patients with TBK1 LoF variants, which was not found in our cohort.

CONCLUSION: Our study expanded the genotypic spectrum of ALS patients with TBK1 variants and found that the clinical manifestations of TBK1 carriers are diverse.}, } @article {pmid37422655, year = {2023}, author = {van Eijk, RPA and van den Berg, LH and Roes, KCB and Tian, L and Lai, TL and Nelson, LM and Li, C and Scowcroft, A and Garcia-Segovia, J and Lu, Y}, title = {Hybrid Controlled Clinical Trials Using Concurrent Registries in Amyotrophic Lateral Sclerosis: A Feasibility Study.}, journal = {Clinical pharmacology and therapeutics}, volume = {114}, number = {4}, pages = {883-892}, doi = {10.1002/cpt.2994}, pmid = {37422655}, issn = {1532-6535}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Feasibility Studies ; Research Design ; }, abstract = {Hybrid designs with both randomized arms and an external control cohort preserve key features of randomization and utilize external information to augment clinical trials. In this study, we propose to leverage high-quality, patient-level concurrent registries to enhance clinical trials and illustrate the impact on trial design for amyotrophic lateral sclerosis. The proposed methodology was evaluated in a randomized, placebo-controlled clinical trial. We used patient-level information from a well-defined, population-based registry, that was running parallel to the randomized clinical trial, to identify concurrently nonparticipating, eligible patients who could be matched with trial participants, and integrate them into the statistical analysis. We assessed the impact of the addition of the external controls on the treatment effect estimate, precision, and time to reach a conclusion. During the runtime of the trial, a total of 1,141 registry patients were alive; 473 (41.5%) of them fulfilled the eligibility criteria and 133 (11.7%) were enrolled in the study. A matched control population could be identified among the nonparticipating patients. Augmenting the randomized controls with matched external controls could have avoided unnecessary randomization of 17 patients (-12.8%) as well as reducing the study duration from 30.1 months to 22.6 months (-25.0%). Matching eligible external controls from a different calendar period led to bias in the treatment effect estimate. Hybrid trial designs utilizing a concurrent registry with rigorous matching can minimize bias due to a mismatch in calendar time and differences in standard of care, and may accelerate the development of new treatments.}, } @article {pmid37422580, year = {2024}, author = {Naito, H and Sugimoto, T and Kimoto, K and Abe, T and Ohno, N and Giga, M and Kono, T and Ueno, H and Nomura, E and Maruyama, H}, title = {Detection of episodic nocturnal hypercapnia in patients with neurodegenerative disorders.}, journal = {Sleep & breathing = Schlaf & Atmung}, volume = {28}, number = {1}, pages = {393-399}, pmid = {37422580}, issn = {1522-1709}, mesh = {Humans ; Hypercapnia/diagnosis/epidemiology ; Hypoventilation/diagnosis ; Carbon Dioxide ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; *Neurodegenerative Diseases/diagnosis/epidemiology ; Biomarkers ; }, abstract = {PURPOSE: Episodic nocturnal hypercapnia (eNH) in transcutaneous carbon dioxide pressure (PtcCO2) corresponding to rapid eye movement sleep hypoventilation is a useful biomarker for detecting nocturnal hypoventilation. However, the relationship between eNH and neurodegenerative diseases with sleep-related breathing disorders (SRBDs) is unknown. The aim of this study was to evaluate the relationship between eNH and nocturnal hypoventilation in neurodegenerative diseases.

METHODS: Patients with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Parkinson's disease, progressive supranuclear palsy, corticobasal syndrome, and idiopathic normal pressure hydrocephalus, were enrolled and received overnight PtcCO2 monitoring. The patients were divided into groups for eNH and sleep-associated hypoventilation (SH) prevalence analysis: A (ALS), B (MSA), and C (others).

RESULTS: Among 110 patients, twenty-three (21%) and 10 (9%) of the patients met eNH and SH criteria, respectively. eNH and SH were significantly more frequent in groups A and B than in C. The prevalence of SH in the patients with eNH was 39% whereas most of patients with SH (90%) presented with eNH. Among patients with daytime carbon dioxide pressure in arterial blood ≤ 45 mmHg, eNH frequency was 13%, whereas none of the patients met SH criteria. The frequency of noninvasive positive pressure ventilation after PtcCO2 monitoring was significantly higher in those with than without eNH.

CONCLUSIONS: eNH is common in patients with MSA and ALS who present with SRBD. eNH with overnight PtcCO2 monitoring is a useful biomarker to detect hypoventilation among neurodegenerative diseases with different SRBD mechanisms.}, } @article {pmid37421736, year = {2023}, author = {Migliorelli, L and Berardini, D and Cela, K and Coccia, M and Villani, L and Frontoni, E and Moccia, S}, title = {A store-and-forward cloud-based telemonitoring system for automatic assessing dysarthria evolution in neurological diseases from video-recording analysis.}, journal = {Computers in biology and medicine}, volume = {163}, number = {}, pages = {107194}, doi = {10.1016/j.compbiomed.2023.107194}, pmid = {37421736}, issn = {1879-0534}, mesh = {Humans ; *Dysarthria/diagnosis ; *Amyotrophic Lateral Sclerosis ; Cloud Computing ; Speech ; Video Recording ; }, abstract = {BACKGROUND AND OBJECTIVES: Patients suffering from neurological diseases may develop dysarthria, a motor speech disorder affecting the execution of speech. Close and quantitative monitoring of dysarthria evolution is crucial for enabling clinicians to promptly implement patients' management strategies and maximizing effectiveness and efficiency of communication functions in term of restoring, compensating or adjusting. In the clinical assessment of orofacial structures and functions, at rest condition or during speech and non-speech movements, a qualitative evaluation is usually performed, throughout visual observation.

METHODS: To overcome limitations posed by qualitative assessments, this work presents a store-and-forward self-service telemonitoring system that integrates, within its cloud architecture, a convolutional neural network (CNN) for analyzing video recordings acquired by individuals with dysarthria. This architecture - called facial landmark Mask RCNN - aims at locating facial landmarks as a prior for assessing the orofacial functions related to speech and examining dysarthria evolution in neurological diseases.

RESULTS: When tested on the Toronto NeuroFace dataset, a publicly available annotated dataset of video recordings from patients with amyotrophic lateral sclerosis (ALS) and stroke, the proposed CNN achieved a normalized mean error equal to 1.79 on localizing the facial landmarks. We also tested our system in a real-life scenario on 11 bulbar-onset ALS subjects, obtaining promising outcomes in terms of facial landmark position estimation.

DISCUSSION AND CONCLUSIONS: This preliminary study represents a relevant step towards the use of remote tools to support clinicians in monitoring the evolution of dysarthria.}, } @article {pmid37421418, year = {2023}, author = {Kim, H and Choi, M and Han, S and Park, SY and Jeong, M and Kim, SR and Hwang, EM and Lee, SG}, title = {Expression patterns of AEG-1 in the normal brain.}, journal = {Brain structure & function}, volume = {228}, number = {7}, pages = {1629-1641}, pmid = {37421418}, issn = {1863-2661}, support = {NRF-2020R1F1A1071525//National Research Foundation of Korea/ ; NRF-2017R1D1A1B03032218//National Research Foundation of Korea/ ; }, mesh = {Animals ; Humans ; Mice ; *Brain/metabolism ; Brain Neoplasms/pathology ; Cell Adhesion Molecules/metabolism ; *Membrane Proteins/genetics/metabolism ; }, abstract = {Astrocyte elevated gene-1 (AEG-1) is a well-known oncogene implicated in various types of human cancers, including brain tumors. Recently, AEG-1 has also been reported to play pivotal roles in glioma-associated neurodegeneration and neurodegenerative diseases like Parkinson's disease and amyotrophic lateral sclerosis. However, the normal physiological functions and expression patterns of AEG-1 in the brain are not well understood. In this study, we investigated the expression patterns of AEG-1 in the normal mouse brain and found that AEG-1 is widely expressed in neurons and neuronal precursor cells, but little in glial cells. We observed differential expression levels of AEG-1 in various brain regions, and its expression was mainly localized in the cell body of neurons rather than the nucleus. Additionally, AEG-1 was expressed in the cytoplasm of Purkinje cells in both the mouse and human cerebellum, suggesting its potential role in this brain region. These findings suggest that AEG-1 may have important functions in normal brain physiology and warrant further investigation. Our results may also shed light on the differential expression patterns of AEG-1 in normal and pathological brains, providing insights into its roles in various neurological disorders.}, } @article {pmid37420383, year = {2022}, author = {Park, S and Simeone, O}, title = {Speeding up Training of Linear Predictors for Multi-Antenna Frequency-Selective Channels via Meta-Learning.}, journal = {Entropy (Basel, Switzerland)}, volume = {24}, number = {10}, pages = {}, pmid = {37420383}, issn = {1099-4300}, support = {725731/ERC_/European Research Council/International ; }, abstract = {An efficient data-driven prediction strategy for multi-antenna frequency-selective channels must operate based on a small number of pilot symbols. This paper proposes novel channel-prediction algorithms that address this goal by integrating transfer and meta-learning with a reduced-rank parametrization of the channel. The proposed methods optimize linear predictors by utilizing data from previous frames, which are generally characterized by distinct propagation characteristics, in order to enable fast training on the time slots of the current frame. The proposed predictors rely on a novel long short-term decomposition (LSTD) of the linear prediction model that leverages the disaggregation of the channel into long-term space-time signatures and fading amplitudes. We first develop predictors for single-antenna frequency-flat channels based on transfer/meta-learned quadratic regularization. Then, we introduce transfer and meta-learning algorithms for LSTD-based prediction models that build on equilibrium propagation (EP) and alternating least squares (ALS). Numerical results under the 3GPP 5G standard channel model demonstrate the impact of transfer and meta-learning on reducing the number of pilots for channel prediction, as well as the merits of the proposed LSTD parametrization.}, } @article {pmid37418099, year = {2023}, author = {Moglia, C and Palumbo, F and Veronese, S and , and Calvo, A}, title = {Withdrawal of mechanical ventilation in amyotrophic lateral sclerosis patients: a multicenter Italian survey.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {12}, pages = {4349-4357}, pmid = {37418099}, issn = {1590-3478}, support = {RF-2016-02362405//Ministero della Salute/ ; 2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; FP7/2007-2013//Seventh Framework Programme/ ; 101017598//Horizon 2020/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Respiration, Artificial ; *Terminal Care/methods ; Delivery of Health Care ; *Neurology ; }, abstract = {BACKGROUND: Law 219/2017 was approved in Italy in December 2017, after a years-long debate on the autonomy of healthcare choices. This Law, for the first time in Italian legislation, guarantees the patient's right to request for withdrawal of life-sustaining treatments, including mechanical ventilation (MV).

OBJECTIVE: To investigate the current status of MV withdrawal in amyotrophic lateral sclerosis (ALS) patients in Italy and to assess the impact of Law 219/2017 on this practice.

METHODS: We conducted a Web-based survey, addressed to Italian neurologists with expertise in ALS care, and members of the Motor Neuron Disease Study Group of the Italian Society of Neurology.

RESULTS: Out of 40 ALS Italian centers, 34 (85.0%) responded to the survey. Law 219/2017 was followed by an increasing trend in MV withdrawals, and a significant increase of neurologists involved in this procedure (p 0.004). However, variations across Italian ALS centers were observed, regarding the inconsistent involvement of community health services and palliative care (PC) services, and the intervention and composition of the multidisciplinary team.

CONCLUSIONS: Law 219/2017 has had a positive impact on the practice of MV withdrawal in ALS patients in Italy. The recent growing public attention on end-of-life care choices, along with the cultural and social changes in Italy, requires further regulatory frameworks that strengthen tools for self-determination, increased investment of resources in community and PC health services, and practical recommendations and guidelines for health workers involved.}, } @article {pmid37414530, year = {2023}, author = {Pinkerton, M and Lourenco, G and Pacheco, MT and Halliday, GM and Kiernan, MC and Tan, RH}, title = {Survival in sporadic ALS is associated with lower p62 burden in the spinal cord.}, journal = {Journal of neuropathology and experimental neurology}, volume = {82}, number = {9}, pages = {769-773}, pmid = {37414530}, issn = {1554-6578}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Motor Neurons/pathology ; Spinal Cord/pathology ; Inclusion Bodies/pathology ; }, abstract = {The autophagy marker p62 appears as a consistent component of pathological aggregates in amyotrophic lateral sclerosis (ALS) and its modulation to facilitate protein degradation has been proposed as a potential therapeutic target. Importantly, recent studies have implicated diffuse phosphorylated TDP-43 inclusions that are immuno-negative for p62 in more rapid disease, highlighting the need for better understanding of p62 involvement in ALS pathogenesis. The present study set out to assess p62 pathology in the motor neurons of 31 patients with sporadic ALS that had either a short (<2 years) or longer (4-7 years) disease duration to determine its association with pTDP-43 pathology, motor neuron loss, and survival in sporadic disease. Our results identified significantly more cytoplasmic p62 aggregates in the spinal cord of patients with a shorter survival. Disease duration demonstrated a negative association with p62 burden and density of remaining motor neurons in the spinal cord, suggesting that survival in sporadic ALS is associated with the successful clearance of lower motor neurons with p62 aggregates. These findings implicate the autophagy pathway in ALS survival and provide support for further study of p62 as a potential prognostic biomarker in ALS.}, } @article {pmid37410912, year = {2023}, author = {Bodin, A and Greibill, L and Gouju, J and Letournel, F and Pozzi, S and Julien, JP and Renaud, L and Bohl, D and Millecamps, S and Verny, C and Cassereau, J and Lenaers, G and Chevrollier, A and Tassin, AM and Codron, P}, title = {Transactive response DNA-binding protein 43 is enriched at the centrosome in human cells.}, journal = {Brain : a journal of neurology}, volume = {146}, number = {9}, pages = {3624-3633}, pmid = {37410912}, issn = {1460-2156}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/genetics/metabolism ; *TDP-43 Proteinopathies/pathology ; *Frontotemporal Lobar Degeneration/pathology ; Centrosome/metabolism/pathology ; }, abstract = {The centrosome, as the main microtubule organizing centre, plays key roles in cell polarity, genome stability and ciliogenesis. The recent identification of ribosomes, RNA-binding proteins and transcripts at the centrosome suggests local protein synthesis. In this context, we hypothesized that TDP-43, a highly conserved RNA binding protein involved in the pathophysiology of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, could be enriched at this organelle. Using dedicated high magnification sub-diffraction microscopy on human cells, we discovered a novel localization of TDP-43 at the centrosome during all phases of the cell cycle. These results were confirmed on purified centrosomes by western blot and immunofluorescence microscopy. In addition, the co-localization of TDP-43 and pericentrin suggested a pericentriolar enrichment of the protein, leading us to hypothesize that TDP-43 might interact with local mRNAs and proteins. Supporting this hypothesis, we found four conserved centrosomal mRNAs and 16 centrosomal proteins identified as direct TDP-43 interactors. More strikingly, all the 16 proteins are implicated in the pathophysiology of TDP-43 proteinopathies, suggesting that TDP-43 dysfunction in this organelle contributes to neurodegeneration. This first description of TDP-43 centrosomal enrichment paves the way for a more comprehensive understanding of TDP-43 physiology and pathology.}, } @article {pmid37408276, year = {2023}, author = {Hosaka, T and Tsuji, H and Kwak, S}, title = {Roles of Aging, Circular RNAs, and RNA Editing in the Pathogenesis of Amyotrophic Lateral Sclerosis: Potential Biomarkers and Therapeutic Targets.}, journal = {Cells}, volume = {12}, number = {10}, pages = {}, pmid = {37408276}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; RNA, Circular/genetics/metabolism ; RNA Editing/genetics ; RNA/genetics/metabolism ; Aging/genetics ; Biomarkers/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease caused by upper and lower motor neuron death. Despite advances in our understanding of ALS pathogenesis, effective treatment for this fatal disease remains elusive. As aging is a major risk factor for ALS, age-related molecular changes may provide clues for the development of new therapeutic strategies. Dysregulation of age-dependent RNA metabolism plays a pivotal role in the pathogenesis of ALS. In addition, failure of RNA editing at the glutamine/arginine (Q/R) site of GluA2 mRNA causes excitotoxicity due to excessive Ca[2+] influx through Ca[2+]-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, which is recognized as an underlying mechanism of motor neuron death in ALS. Circular RNAs (circRNAs), a circular form of cognate RNA generated by back-splicing, are abundant in the brain and accumulate with age. Hence, they are assumed to play a role in neurodegeneration. Emerging evidence has demonstrated that age-related dysregulation of RNA editing and changes in circRNA expression are involved in ALS pathogenesis. Herein, we review the potential associations between age-dependent changes in circRNAs and RNA editing, and discuss the possibility of developing new therapies and biomarkers for ALS based on age-related changes in circRNAs and dysregulation of RNA editing.}, } @article {pmid37408187, year = {2023}, author = {Zimyanin, VL and Pielka, AM and Glaß, H and Japtok, J and Großmann, D and Martin, M and Deussen, A and Szewczyk, B and Deppmann, C and Zunder, E and Andersen, PM and Boeckers, TM and Sterneckert, J and Redemann, S and Storch, A and Hermann, A}, title = {Live Cell Imaging of ATP Levels Reveals Metabolic Compartmentalization within Motoneurons and Early Metabolic Changes in FUS ALS Motoneurons.}, journal = {Cells}, volume = {12}, number = {10}, pages = {}, pmid = {37408187}, issn = {2073-4409}, support = {S10 OD025156/OD/NIH HHS/United States ; R01 NS111220/NS/NINDS NIH HHS/United States ; R01 NS091617/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Motor Neurons/metabolism ; Mutation ; Mitochondria/metabolism ; Adenosine Triphosphate/metabolism ; RNA-Binding Protein FUS/genetics/metabolism/pharmacology ; }, abstract = {Motoneurons are one of the most energy-demanding cell types and a primary target in Amyotrophic lateral sclerosis (ALS), a debilitating and lethal neurodegenerative disorder without currently available effective treatments. Disruption of mitochondrial ultrastructure, transport, and metabolism is a commonly reported phenotype in ALS models and can critically affect survival and the proper function of motor neurons. However, how changes in metabolic rates contribute to ALS progression is not fully understood yet. Here, we utilize hiPCS-derived motoneuron cultures and live imaging quantitative techniques to evaluate metabolic rates in fused in sarcoma (FUS)-ALS model cells. We show that differentiation and maturation of motoneurons are accompanied by an overall upregulation of mitochondrial components and a significant increase in metabolic rates that correspond to their high energy-demanding state. Detailed compartment-specific live measurements using a fluorescent ATP sensor and FLIM imaging show significantly lower levels of ATP in the somas of cells carrying FUS-ALS mutations. These changes lead to the increased vulnerability of diseased motoneurons to further metabolic challenges with mitochondrial inhibitors and could be due to the disruption of mitochondrial inner membrane integrity and an increase in its proton leakage. Furthermore, our measurements demonstrate heterogeneity between axonal and somatic compartments, with lower relative levels of ATP in axons. Our observations strongly support the hypothesis that mutated FUS impacts the metabolic states of motoneurons and makes them more susceptible to further neurodegenerative mechanisms.}, } @article {pmid37408045, year = {2023}, author = {Morris, JL and Chalkley, AE and Helme, ZE and Timms, O and Young, E and McLoughlin, GM and Bartholomew, JB and Daly-Smith, A}, title = {Initial insights into the impact and implementation of Creating Active Schools in Bradford, UK.}, journal = {The international journal of behavioral nutrition and physical activity}, volume = {20}, number = {1}, pages = {80}, pmid = {37408045}, issn = {1479-5868}, mesh = {Humans ; *School Health Services ; *Schools ; Exercise ; Focus Groups ; United Kingdom ; }, abstract = {BACKGROUND: Few whole-school physical activity programmes integrate implementation science frameworks within the design, delivery, and evaluation. As a result, knowledge of the key factors that support implementation at scale is lacking. The Creating Active Schools (CAS) programme was co-designed and is underpinned by the Capability, Opportunity, Motivation and Behaviour (COM-B) model and the Consolidated Framework for Implementation Research (CFIR). The study aims to understand the initial impact and implementation of CAS in Bradford over 9 months using McKay's et al.'s (2019) implementation evaluation roadmap.

METHODS: Focus groups and interviews were conducted with school staff (n = 30, schools = 25), CAS Champions (n = 9), and the CAS strategic lead (n = 1). Qualitative data were analysed both inductively and deductively. The deductive analysis involved coding data into a priori themes based on McKay et al's implementation evaluation roadmap, using a codebook approach to thematic analysis. The inductive analysis included producing initial codes and reviewing themes before finalising.

RESULTS: Identified themes aligned into three categories: (i) key ingredients for successful adoption and implementation of CAS, (ii) CAS implementation: challenges and solutions, and (iv) the perceived effectiveness of CAS at the school level. This included the willingness of schools to adopt and implement whole-school approaches when they are perceived as high quality and aligned with current school values. The programme implementation processes were seen as supportive; schools identified and valued the step-change approach to implementing CAS long-term. Formal and informal communities of practice provided "safe spaces" for cross-school support. Conversely, challenges persisted with gaining broader reach within schools, school staff's self-competence and shifting school culture around physical activity. This resulted in varied uptake between and within schools.

CONCLUSIONS: This study provides novel insights into the implementation of CAS, with outcomes aligning to the adoption, reach, and sustainability. Successful implementation of CAS was underpinned by determinants including acceptability, intervention complexity, school culture and school stakeholders' perceived self-efficacy. The combination of McKay's evaluation roadmap and CFIR establishes a rigorous approach for evaluating activity promotion programmes underpinned by behavioural and implementation science. Resultantly this study offers originality and progression in understanding the implementation and effectiveness of whole-school approaches to physical activity.}, } @article {pmid37407098, year = {2023}, author = {Kious, BM}, title = {Medical Assistance in Dying in Neurology.}, journal = {Neurologic clinics}, volume = {41}, number = {3}, pages = {443-454}, doi = {10.1016/j.ncl.2023.03.002}, pmid = {37407098}, issn = {1557-9875}, mesh = {Humans ; *Suicide, Assisted/psychology ; *Alzheimer Disease ; Medical Assistance ; *Neurology ; }, abstract = {An increasing number of jurisdictions have legalized medical assistance in dying (MAID) with significant variation in the procedures and eligibility criteria used. In the United States, MAID is available for persons with terminal illnesses but is frequently sought by persons with neurologic conditions. Persons with conditions that cause cognitive impairment, such as Alzheimer dementia, are often ineligible for MAID, as their illness is not considered terminal in its early stages, whereas in later stages, they may have impaired decision-making capacity.}, } @article {pmid37402805, year = {2023}, author = {Kiani, L}, title = {Electrophysiology test for early ALS diagnosis.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {8}, pages = {459}, pmid = {37402805}, issn = {1759-4766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Motor Neurons ; Electrophysiology ; }, } @article {pmid37402803, year = {2023}, author = {Kiani, L}, title = {Fatty acids might slow ALS progression.}, journal = {Nature reviews. Neurology}, volume = {19}, number = {8}, pages = {459}, pmid = {37402803}, issn = {1759-4766}, mesh = {Humans ; *Fatty Acids ; *Amyotrophic Lateral Sclerosis/genetics ; Disease Progression ; }, } @article {pmid37401984, year = {2023}, author = {Gomes, BPFA and Berber, VB and Chiarelli-Neto, VM and Aveiro, E and Chapola, RC and Passini, MRZ and Lopes, EM and Chen, T and Paster, BJ}, title = {Microbiota present in combined endodontic-periodontal diseases and its risks for endocarditis.}, journal = {Clinical oral investigations}, volume = {27}, number = {8}, pages = {4757-4771}, pmid = {37401984}, issn = {1436-3771}, mesh = {Humans ; *Periodontal Diseases ; *Endocarditis ; Bacteria ; Periodontal Pocket/microbiology ; *Microbiota ; }, abstract = {INTRODUCTION: Infective endocarditis (IE) is an inflammatory disease usually caused by bacteria that enter the bloodstream and establish infections in the inner linings or valves of the heart, including blood vessels. Despite the availability of modern antimicrobial and surgical treatments, IE continues to cause substantial morbidity and mortality. Oral microbiota is considered one of the most significant risk factors for IE. The objective of this study was to evaluate the microbiota present in root canal (RC) and periodontal pocket (PP) clinical samples in cases with combined endo-periodontal lesions (EPL) to detect species related to IE using NGS.

METHODS: Microbial samples were collected from 15 RCs and their associated PPs, also from 05 RCs with vital pulp tissues (negative control, NC). Genomic studies associated with bioinformatics, combined with structuring of a database (genetic sequences of bacteria reported for infective endocarditis), allowed for the assessment of the microbial community at both sites. Functional prediction was conducted using PICRUSt2.

RESULTS: Parvimonas, Streptococcus, and Enterococcus were the major genera detected in the RCs and PPs. A total of 79, 96, and 11 species were identified in the RCs, PPs, and NCs, respectively. From them, a total of 34 species from RCs, 53 from PPs, and 2 from NCs were related to IE. Functional inference demonstrated that CR and PP microbiological profiles may not be the only risk factors for IE but may also be associated with systemic diseases, including myocarditis, human cytomegalovirus infection, bacterial invasion of epithelial cells, Huntington's disease, amyotrophic lateral sclerosis, and hypertrophic cardiomyopathy. Additionally, it was possible to predict antimicrobial resistance variants for broad-spectrum drugs, including ampicillin, tetracycline, and macrolides.

CONCLUSION: Microorganisms present in the combined EPL may not be the only risk factor for IE but also for systemic diseases. Antimicrobial resistance variants for broad-spectrum drugs were inferred based on PICRUSt-2. State-of-the-art sequencing combined with bioinformatics has proven to be a powerful tool for conducting studies on microbial communities and could considerably assist in the diagnosis of serious infections.

CLINICAL RELEVANCE: Few studies have investigated the microbiota in teeth compromised by combined endo-periodontal lesions (EPL), but none have correlated the microbiological findings to any systemic condition, particularly IE, using NGS techniques. In such cases, the presence of apical periodontitis and periodontal disease can increase IE risk in susceptible patients.}, } @article {pmid37401737, year = {2024}, author = {Brewer, MK and Torres, P and Ayala, V and Portero-Otin, M and Pamplona, R and Andrés-Benito, P and Ferrer, I and Gentry, MS and Guinovart, JJ and Duran, J}, title = {Glycogen accumulation modulates life span in a mouse model of amyotrophic lateral sclerosis.}, journal = {Journal of neurochemistry}, volume = {168}, number = {5}, pages = {744-759}, pmid = {37401737}, issn = {1471-4159}, support = {P01 NS097197/NS/NINDS NIH HHS/United States ; R35 NS116824/NS/NINDS NIH HHS/United States ; 754510//H2020 Marie Skłodowska-Curie Actions/ ; //Ministerio de Ciencia e Innovación/ ; PI20/00155//Ministerio de Ciencia, Innovación y Universidades/ ; BFU2017-84345-P//Ministerio de Ciencia, Innovación y Universidades/ ; PID2020-118699GB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; //Ministerio de Economía y Competitividad/ ; //Ministerio de Universidades/ ; P01 NS097197/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Glycogen/metabolism ; Mice ; *Mice, Transgenic ; *Disease Models, Animal ; *Longevity ; *Spinal Cord/metabolism/pathology ; *Astrocytes/metabolism ; Male ; Mice, Inbred C57BL ; Humans ; Superoxide Dismutase-1/genetics/metabolism ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord. Glial cells, including astrocytes and microglia, have been shown to contribute to neurodegeneration in ALS, and metabolic dysfunction plays an important role in the progression of the disease. Glycogen is a soluble polymer of glucose found at low levels in the central nervous system that plays an important role in memory formation, synaptic plasticity, and the prevention of seizures. However, its accumulation in astrocytes and/or neurons is associated with pathological conditions and aging. Importantly, glycogen accumulation has been reported in the spinal cord of human ALS patients and mouse models. In the present work, using the SOD1[G93A] mouse model of ALS, we show that glycogen accumulates in the spinal cord and brainstem during symptomatic and end stages of the disease and that the accumulated glycogen is associated with reactive astrocytes. To study the contribution of glycogen to ALS progression, we generated SOD1[G93A] mice with reduced glycogen synthesis (SOD1[G93A] GS[het] mice). SOD1[G93A] GS[het] mice had a significantly longer life span than SOD1[G93A] mice and showed lower levels of the astrocytic pro-inflammatory cytokine Cxcl10, suggesting that the accumulation of glycogen is associated with an inflammatory response. Supporting this, inducing an increase in glycogen synthesis reduced life span in SOD1[G93A] mice. Altogether, these results suggest that glycogen in reactive astrocytes contributes to neurotoxicity and disease progression in ALS.}, } @article {pmid37399804, year = {2023}, author = {Hanhisuanto, M and Solje, E and Jokela, M and Sipilä, JOT}, title = {Amyotrophic Lateral Sclerosis in Southwestern and Eastern Finland.}, journal = {Neuroepidemiology}, volume = {57}, number = {4}, pages = {238-245}, doi = {10.1159/000531238}, pmid = {37399804}, issn = {1423-0208}, mesh = {Male ; Humans ; Female ; Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/genetics ; Riluzole ; Finland/epidemiology ; C9orf72 Protein/genetics ; Phenotype ; }, abstract = {INTRODUCTION: The incidence of amyotrophic lateral sclerosis (ALS) worldwide is approximately 1-2.6/1,000,000 and prevalence is 5-6/100,000. ALS has been suggested to be relatively common in Finland, but epidemiological information on the subject is scarce and outdated.

MATERIAL AND METHODS: Patients with ALS diagnostic codes were identified from mandatory administrative registries in the provinces of Southwestern Finland (population circa 430,000) and North Karelia (population circa 170,000), together comprising 11.7% of the total population of Finland. The diagnoses were verified, and data were extracted by reviewing the patient records. Incidence period was 2010-2018, and the prevalence date was December 31, 2018. Age-standardization was performed using the European Standard Population 2013 (ESP2013).

RESULTS: Overall crude incidence of ALS was 4.2/100,000 person-years in Southwestern Finland (ESP2013: 4.0/100,000) and 5.6/100,000 person-years in North Karelia (ESP2013: 4.8/100,000), while crude prevalences were 11.9/100,000 (ESP2013: 10.5/100,000) and 10.9/100,000 (ESP2013: 9.3/100,000), respectively. Mean age at diagnosis was 65.5-71.6 years in women (higher in Southwestern Finland compared to North Karelia, p = 0.003) and 64.7-67.3 years in men (no difference between provinces, p = 0.39). The diagnosis had been made in 50% before the age of 70 years in Southwestern Finland and before the age of 65 years in 51% in North Karelia. Genetic testing had been conducted in 28% of all patients with the most common findings being SOD1 and C9orf72. After the diagnosis, mean survival was 2.0-2.7 and median survival 1.3-1.4 years. Onset phenotype (p < 0.001), age at diagnosis (p < 0.001), and genotype (p = 0.001) predicted survival. Riluzole had been used by 25% of patients and tracheostomy and invasive ventilation (TIV) had been performed in <1%.

CONCLUSIONS: Both incidence and prevalence of ALS in Finland are among the highest in the world but with some notable differences between the eastern and southwestern parts of the country. Low median life expectancy may be related to the advanced age of patients and the high prevalence of C9orf72 repeat expansion in Finland as well infrequent use of TIV and riluzole.}, } @article {pmid37399802, year = {2023}, author = {Pannek, J and Mahler, J and Wöllner, J and Krebs, J}, title = {Satisfaction with Homeopathic Service and Care for Persons with Spinal Cord Injury.}, journal = {Complementary medicine research}, volume = {30}, number = {5}, pages = {408-414}, doi = {10.1159/000531658}, pmid = {37399802}, issn = {2504-2106}, mesh = {Humans ; Cross-Sectional Studies ; *Homeopathy ; Surveys and Questionnaires ; Switzerland ; }, abstract = {BACKGROUND: The aim of the study was to investigate the satisfaction of individuals with spinal cord injury (SCI) with a homeopathic service at an SCI rehabilitation center.

PATIENTS AND METHODS: A cross-sectional questionnaire study was performed at an SCI rehabilitation center in Switzerland. It included patients with chronic SCI who presented themselves to a homeopathic service offered by the hospital in a 12-months period. The participants filled in standardized questionnaires in German: "Measure Yourself Medical Outcome Profile" (MYMOP), Treatment Satisfaction Questionnaire for Medication (TSQM-9), the European Project on Patient Evaluation of General Practice Care (EUROPEP) questionnaire, and a self-administered questionnaire.

RESULTS: The data of 14 patients were analyzed. Symptom severity as well as bother by the symptoms that led to homeopathic treatment decreased under homeopathic treatment (severity: from 4.3 to 3.3; bother: from 4.2 to 2.9) and remained lower over time (severity: 2.6; bother: 2.7), suggesting a sustained effect. Irrespective of the test instrument used, satisfaction rates were higher for homeopathic service than for homeopathic medication, which was rated as successful by 50% of the participants.

CONCLUSION: Persons with SCI suffering from secondary complications of SCI who accessed homeopathic care reported high satisfaction rates with the service. Therefore, homeopathic service can be considered as an additive measure in persons with SCI suffering from recurrent symptoms.

UNLABELLED: HintergrundEvaluierung der Zufriedenheit von Personen mit Querschnittlähmung (QSL) mit einer homöopathischen Betreuung an einem Rehabilitationszentrum für QSL.Patient*innen und MethodikAn einem Rehabilitationszentrum für QSL in der Schweiz wurde eine Querschnittserhebung mittels Fragebögen durchgeführt. Eingeschlossen wurden Personen mit chronischer QSL, die sich in einer von der Klinik angebotenen homöopathischen Sprechstunde in einem 12-Monats-Intervall vorstellten. Die Teilnehmenden füllten standardisierte Fragebogen in deutscher Sprache aus: "Measure Yourself Medical Outcome Profile" (MYMOP), Treatment Satisfaction Questionnaire for Medication (TSQM-9), den "European Project on Patient Evaluation of General Practice Care (EUROPEP)" Fragebogen sowie einen selbst-erstellten Fragebogen.ErgebnisseDie Daten von 14 Teilnehmenden wurden ausgewertet. Der Schweregrad der Symptome sowie die Belastung durch die Symptome die zur homöopathischen Behandlung geführt haben, wurden unter der homöopathischen Therapie geringer (Schweregrad: von 4.3 auf 3.3; Belastung: von 4.2 auf 2.9) und blieben über den Untersuchungszeitraum geringer (Schweregrad: 2.6; Belastung 2.7), was einen anhaltenden Effekt nahelegt. Unabhängig von dem verwendeten Testinstrument waren die Zufriedenheitsraten für die homöopathische Betreuung höher als diejenigen für die homöopathische Medikation, die von 50% der Teilnehmenden als erfolgreich bewertet wurde.SchlussfolgerungPersonen mit QSL, die wegen Sekundärkomplikationen eine homöopathische Sprechstunde aufsuchten, berichteten eine hohe Zufriedenheit mit dieser Betreuung. Daher kann eine homöopathische Betreuung als zusätzliche Massnahme bei Personen mit QSL mit persistierender Symptomatik in Betracht gezogen werden.}, } @article {pmid37399380, year = {2023}, author = {Pérez-Cabello, JA and Silvera-Carrasco, L and Franco, JM and Capilla-González, V and Armaos, A and Gómez-Lima, M and García-García, R and Yap, XW and Leal-Lasarte, M and Lall, D and Baloh, RH and Martínez, S and Miyata, Y and Tartaglia, GG and Sawarkar, R and García-Domínguez, M and Pozo, D and Roodveldt, C}, title = {MAPK/MAK/MRK overlapping kinase (MOK) controls microglial inflammatory/type-I IFN responses via Brd4 and is involved in ALS.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {28}, pages = {e2302143120}, pmid = {37399380}, issn = {1091-6490}, support = {MC_UU_00025/8/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Disease Models, Animal ; Microglia/metabolism ; *Neurodegenerative Diseases/metabolism ; Nuclear Proteins/metabolism ; Transcription Factors/genetics/metabolism ; *Bromodomain Containing Proteins/genetics/metabolism ; *Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease affecting motor neurons and characterized by microglia-mediated neurotoxic inflammation whose underlying mechanisms remain incompletely understood. In this work, we reveal that MAPK/MAK/MRK overlapping kinase (MOK), with an unknown physiological substrate, displays an immune function by controlling inflammatory and type-I interferon (IFN) responses in microglia which are detrimental to primary motor neurons. Moreover, we uncover the epigenetic reader bromodomain-containing protein 4 (Brd4) as an effector protein regulated by MOK, by promoting Ser[492]-phospho-Brd4 levels. We further demonstrate that MOK regulates Brd4 functions by supporting its binding to cytokine gene promoters, therefore enabling innate immune responses. Remarkably, we show that MOK levels are increased in the ALS spinal cord, particularly in microglial cells, and that administration of a chemical MOK inhibitor to ALS model mice can modulate Ser[492]-phospho-Brd4 levels, suppress microglial activation, and modify the disease course, indicating a pathophysiological role of MOK kinase in ALS and neuroinflammation.}, } @article {pmid37399127, year = {2023}, author = {Shi, L and Li, X and Xue, L and Zhang, J and Huang, B and Sun, Z and Zhang, Z and Dai, X and Han, S and Dong, W and Zhang, X}, title = {Creation of herbicide-resistance in allotetraploid peanut using CRISPR/Cas9-meditated cytosine base-editing.}, journal = {Plant biotechnology journal}, volume = {21}, number = {10}, pages = {1923-1925}, pmid = {37399127}, issn = {1467-7652}, mesh = {Arachis/genetics ; CRISPR-Cas Systems/genetics ; Cytosine ; *Fabaceae ; *Herbicides ; Gene Editing ; }, } @article {pmid37399044, year = {2023}, author = {Hokkoku, K and Tsukamoto, H and Uchida, Y and Gatto, DM and Sonoo, M}, title = {Different Tendencies in Muscle Ultrasound Characteristic in Amyotrophic Lateral Sclerosis and Chronic Inflammatory Demyelinating Polyradiculoneuropathy.}, journal = {Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society}, volume = {40}, number = {5}, pages = {450-455}, doi = {10.1097/WNP.0000000000000898}, pmid = {37399044}, issn = {1537-1603}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnostic imaging ; Action Potentials/physiology ; Muscle, Skeletal/innervation ; Arm ; Neural Conduction/physiology ; }, abstract = {INTRODUCTION: The difference in muscle ultrasound (MUS) characteristics in primary axonal degeneration and demyelination has not been well established. The authors aimed to investigate the subject based on the correlation between MUS findings (echo intensity and muscle thickness) and compound muscle action potential (CMAP) amplitude in amyotrophic lateral sclerosis (ALS) and chronic inflammatory demyelinating polyradiculoneuropathy.

METHODS: Fifteen patients with ALS and 16 patients with chronic inflammatory demyelinating polyradiculoneuropathy were examined. For each patient, echo intensity and muscle thickness of the abductor pollicis brevis, abductor digiti minimi, and first dorsal interosseous muscles were investigated. Compound muscle action potential amplitudes were measured by median and ulnar nerve conduction studies.

RESULTS: In total, 45 muscles were evaluated in each group. The ALS group showed a linear correlation between the MUS finding and CMAP amplitude (rs = -0.70 and 0.59 for echo intensity and muscle thickness, respectively), whereas the chronic inflammatory demyelinating polyradiculoneuropathy group showed a weaker correlation than the ALS group (rs = -0.32 for echo intensity and rs = 0.34 for muscle thickness).

CONCLUSIONS: The relationship between MUS abnormalities and CMAP amplitude showed different tendencies in ALS and chronic inflammatory demyelinating polyradiculoneuropathy. The results suggested that MUS abnormalities substantially reflect the muscle function in primary axonal degeneration, whereas a discrepancy between MUS findings and muscle function can be frequently seen in demyelination; specifically, MUS findings tend to be normal even though CMAP showed a reduction. These tendencies originating from underlying pathophysiology should be considered when MUS findings are used as biomarkers of disease severity.}, } @article {pmid37398206, year = {2023}, author = {Acharya, A and Ambikan, AT and Thurman, M and Malik, MR and Dyavar, SR and Végvári, Á and Neogi, U and Byrareddy, SN}, title = {Proteomic landscape of astrocytes and pericytes infected with HIV/SARS-CoV-2 mono/co-infection, impacting on neurological complications.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37398206}, issn = {2693-5015}, support = {R01 DA052845/DA/NIDA NIH HHS/United States ; }, abstract = {BACKGROUND: Although most individuals recover from coronavirus disease 2019 (COVID-19) within a few weeks, some people continue to experience a wide range of symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. Majority of patients with PASC develop neurological disorders like brain fog, fatigue, mood swings, sleep disorders, loss of smell and test among others collectively called neuro-PASC. While the people living with HIV (PWH) do not have a higher risk of developing severe disease and mortality/morbidity due to COVID-19. As a large section of PWH suffered from HIV-associated neurocognitive disorders (HAND), it is essential to understand the impact of neuro-PASC on people with HAND. In pursuit of this, we infected HIV/SARS-CoV-2 alone or together in primary human astrocytes and pericytes and performed proteomics to understand the impact of co-infection in the central nervous system.

METHODS: Primary human astrocytes and pericytes were infected with SARS-CoV-2 or HIV or HIV + SARS-CoV-2. The concentration of HIV and SARS-CoV-2 genomic RNA in the culture supernatant was quantified using reverse transcriptase quantitative real time polymerase chain reaction (RT-qPCR). This was followed by a quantitative proteomics analysis of mock, HIV, SARS-CoV-2, and HIV + SARS-CoV-2 infected astrocytes and pericytes to understand the impact of the virus in CNS cell types.

RESULTS: Both healthy and HIV-infected astrocytes and pericytes support abortive/low level of SARS-CoV-2 replication. In both mono-infected and co-infected cells, we observe a modest increase in the expression of SARS-CoV-2 host cell entry factors (ACE2, TMPRSS2, NRP1, and TRIM28) and inflammatory mediators (IL-6, TNF-α, IL-1β and IL-18). Quantitative proteomic analysis has identified uniquely regulated pathways in mock vs SARS-CoV-2, mock vs HIV + SARS-CoV-2, and HIV vs HIV + SARS-CoV-2 infected astrocytes and pericytes. The gene set enrichment analysis revealed that the top ten enriched pathways are linked to several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.

CONCLUSIONS: Our study emphasizes the significance of long-term monitoring of patients co-infected with HIV and SARS-CoV-2 to detect and understand the development of neurological abnormalities. By unraveling the molecular mechanisms involved, we can identify potential targets for future therapeutic interventions.}, } @article {pmid37398081, year = {2023}, author = {Funes, S and Gadd, DH and Mosqueda, M and Zhong, J and Jung, J and Shankaracharya, and Unger, M and Cameron, D and Dawes, P and Keagle, PJ and McDonough, JA and Boopathy, S and Sena-Esteves, M and Lutz, C and Skarnes, WC and Lim, ET and Schafer, DP and Massi, F and Landers, JE and Bosco, DA}, title = {Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.06.01.541136}, pmid = {37398081}, issn = {2692-8205}, abstract = {Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be fully elucidated. To investigate the effect of neurodegenerative disease-linked genes on the intrinsic properties of microglia, we studied microglia-like cells derived from human induced pluripotent stem cells (iPSCs), termed iMGs, harboring mutations in profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs exhibited lipid dysmetabolism and deficits in phagocytosis, a critical microglia function. Our cumulative data implicate an effect of ALS-linked PFN1 on the autophagy pathway, including enhanced binding of mutant PFN1 to the autophagy signaling molecule PI3P, as an underlying cause of defective phagocytosis in ALS-PFN1 iMGs. Indeed, phagocytic processing was restored in ALS-PFN1 iMGs with Rapamycin, an inducer of autophagic flux. These outcomes demonstrate the utility of iMGs for neurodegenerative disease research and highlight microglia vesicular degradation pathways as potential therapeutic targets for these disorders.}, } @article {pmid37397495, year = {2023}, author = {Boldin, R and Zychar, BC and Gonçalves, LRC and Sciani, JM}, title = {Design, in silico and pharmacological evaluation of a peptide inhibitor of BACE-1.}, journal = {Frontiers in pharmacology}, volume = {14}, number = {}, pages = {1184006}, pmid = {37397495}, issn = {1663-9812}, abstract = {Introduction: Alzheimer's disease (AD) is the main type of dementia, caused by the accumulation of amyloid plaques, formed by amyloid peptides after being processed from amyloid precursor protein (APP) by γ- and ß-secretases (BACE-1). Although amyloid peptides have been well established for AD, they have been found in other neurodegenerative diseases, such as Parkinson's disease, Lewy body dementia, and amyotrophic lateral sclerosis. Inhibitors of BACE-1 have been searched and developed, but clinical trials failed due to lack of efficacy or toxicity. Nevertheless, it is still considered a good therapeutic target, as it was proven to remove amyloid peptides and improve memory. Methods: In this work, we designed a peptide based on a sequence obtained from the marine fish Merluccius productus and evaluated it by molecular docking to verify its binding to BACE-1, which was tested experimentally by enzymatic kinetics and cell culture assays. The peptide was injected in healthy mice to study its pharmacokinetics and toxicity. Results: We could obtain a new sequence in which the first N-terminal amino acids and the last one bound to the catalytic site of BACE-1 and showed high stability and hydrophobicity. The synthetic peptide showed a competitive inhibition of BACE-1 and Ki = 94 nM, and when injected in differentiated neurons, it could reduce Aβ42o production. In plasma, its half-life is ∼1 h, clearance is 0.0015 μg/L/h, and Vss is 0.0015 μg/L/h. The peptide was found in the spleen and liver 30 min after injection and reduced its level after that, when it was quantified in the kidneys, indicating its fast distribution and urinary excretion. Interestingly, the peptide was found in the brain 2 h after its administration. Histological analysis showed no morphological alteration in any organ, as well as the absence of inflammatory cells, indicating a lack of toxicity. Discussion: We obtained a new BACE-1 inhibitor peptide with fast distribution to the tissues, without accumulation in any organ, but found in the brain, with the possibility to reach its molecular target, BACE-1, contributing to the reduction in the amyloid peptide, which causes amyloid-linked neurodegenerative diseases.}, } @article {pmid37396808, year = {2023}, author = {Vucic, S and Menon, P and Huynh, W and Mahoney, C and Ho, KS and Hartford, A and Rynders, A and Evan, J and Evan, J and Ligozio, S and Glanzman, R and Hotchkin, MT and Kiernan, MC}, title = {Efficacy and safety of CNM-Au8 in amyotrophic lateral sclerosis (RESCUE-ALS study): a phase 2, randomised, double-blind, placebo-controlled trial and open label extension.}, journal = {EClinicalMedicine}, volume = {60}, number = {}, pages = {102036}, pmid = {37396808}, issn = {2589-5370}, abstract = {BACKGROUND: CNM-Au8® is a catalytically-active gold nanocrystal neuroprotective agent that enhances intracellular energy metabolism and reduces oxidative stress. The phase 2, randomised, double-blind, placebo-controlled trial and open label extension RESCUE-ALS trial evaluated the efficacy and safety of CNM-Au8 for treatment of amyotrophic lateral sclerosis (ALS).

METHODS: RESCUE-ALS and its long-term open label extension (OLE) were conducted at two multidisciplinary ALS clinics located in Sydney, Australia: (i) the Brain and Mind Centre and (ii) Westmead Hospital. The double-blind portion of RESCUE-ALS was conducted from January 16, 2020 (baseline visit, first-patient first-visit (FPFV)) through July 13, 2021 (double-blind period, last-patient last-visit (LPLV)). Participants (N = 45) were randomised 1:1 to receive 30 mg of CNM-Au8 or matching placebo daily over 36 weeks in addition to background standard of care, riluzole. The primary outcome was mean percent change in summed motor unit number index (MUNIX), a sensitive neurophysiological biomarker of lower motor neuron function. Change in total (or summated) MUNIX score and change in forced vital capacity (FVC) were secondary outcome measures. ALS disease progression events, ALS Functional Rating Scale (ALSFRS-R) change, change in quality of life (ALSSQOL-SF) were assessed as exploratory outcome measures. Long-term survival evaluated vital status of original active versus placebo randomisation for all participants through at least 12 months following last-patient last-visit (LPLV) of the double-blind period. RESCUE-ALS and the open label study are registered in clinicaltrials.gov with registration numbers NCT04098406 and NCT05299658, respectively.

FINDINGS: In the intention-to-treat (ITT) population, there was no significant difference in the summated MUNIX score percent change (LS mean difference: 7.7%, 95% CI: -11.9 to 27.3%, p = 0.43), total MUNIX score change (18.8, 95% CI: -56.4 to 94.0), or FVC change (LS mean difference: 3.6, 95% CI: -12.4 to 19.7) between the active and placebo treated groups at week 36. In contrast, survival analyses through 12-month LPLV demonstrated a 60% reduction in all-cause mortality with CNM-Au8 treatment [hazard ratio = 0.408 (95% Wald CI: 0.166 to 1.001, log-rank p = 0.0429). 36 participants entered the open label extension (OLE), and those initially randomised to CNM-Au8 exhibited a slower rate of disease progression, as measured by time to the occurrence of death, tracheostomy, initiation of non-invasive ventilatory support, or gastrostomy tube placement. CNM-Au8 was well-tolerated, and no safety signals were observed.

INTERPRETATION: CNM-Au8, in combination with riluzole, was well-tolerated in ALS with no identified safety signals. While the primary and secondary outcomes of this trial were not significant, the clinically meaningful exploratory results support further investigation of CNM-Au8 in ALS.

FUNDING: The RESCUE-ALS was substantially funded by a grant from FightMND. Additional funding was provided by Clene Australia Pty Ltd.}, } @article {pmid37395323, year = {2023}, author = {Stevenson, R and Samokhina, E and Mangat, A and Rossetti, I and Purushotham, SS and Malladi, CS and Morley, JW and Buskila, Y}, title = {Astrocytic K[+] clearance during disease progression in amyotrophic lateral sclerosis.}, journal = {Glia}, volume = {71}, number = {10}, pages = {2456-2472}, doi = {10.1002/glia.24435}, pmid = {37395323}, issn = {1098-1136}, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis ; Astrocytes ; Superoxide Dismutase-1 ; Motor Neurons/physiology ; Spinal Cord ; Disease Models, Animal ; Disease Progression ; Mice, Transgenic ; Superoxide Dismutase ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder in which patients lose motor functions due to progressive loss of motor neurons in the cortex, brainstem, and spinal cord. Whilst the loss of neurons is central to the disease, it is becoming clear that glia, specifically astrocytes, contribute to the onset and progression of neurodegeneration. Astrocytes play an important role in maintaining ion homeostasis in the extracellular milieu and regulate multiple brain functions by altering their extracellular concentrations. In this study, we have investigated the ability of astrocytes to maintain K[+] homeostasis in the brain via direct measurement of the astrocytic K[+] clearance rate in the motor and somatosensory cortices of an ALS mouse model (SOD1[G93A]). Using electrophysiological recordings from acute brain slices, we show region-specific alterations in the K[+] clearance rate, which was significantly reduced in the primary motor cortex but not the somatosensory cortex. This decrease was accompanied by significant changes in astrocytic morphology, impaired conductivity via Kir4.1 channels and low coupling ratio in astrocytic networks in the motor cortex, which affected their ability to form the K[+] gradient needed to disperse K[+] through the astrocytic syncytium. These findings indicate that the supportive function astrocytes typically provide to motoneurons is diminished during disease progression and provides a potential explanation for the increased vulnerability of motoneurons in ALS.}, } @article {pmid37395272, year = {2023}, author = {Hurtle, BT and Xie, L and Donnelly, CJ}, title = {Disrupting pathologic phase transitions in neurodegeneration.}, journal = {The Journal of clinical investigation}, volume = {133}, number = {13}, pages = {}, pmid = {37395272}, issn = {1558-8238}, support = {R01 NS127187/NS/NINDS NIH HHS/United States ; L30 AG048607/AG/NIA NIH HHS/United States ; R01 NS105756/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Aged ; *TDP-43 Proteinopathies/pathology ; *Neurodegenerative Diseases/pathology ; *Frontotemporal Lobar Degeneration/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Proteins ; }, abstract = {Solid-like protein deposits found in aged and diseased human brains have revealed a relationship between insoluble protein accumulations and the resulting deficits in neurologic function. Clinically diverse neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis, exhibit unique and disease-specific biochemical protein signatures and abnormal protein depositions that often correlate with disease pathogenesis. Recent evidence indicates that many pathologic proteins assemble into liquid-like protein phases through the highly coordinated process of liquid-liquid phase separation. Over the last decade, biomolecular phase transitions have emerged as a fundamental mechanism of cellular organization. Liquid-like condensates organize functionally related biomolecules within the cell, and many neuropathology-associated proteins reside within these dynamic structures. Thus, examining biomolecular phase transitions enhances our understanding of the molecular mechanisms mediating toxicity across diverse neurodegenerative diseases. This Review explores the known mechanisms contributing to aberrant protein phase transitions in neurodegenerative diseases, focusing on tau and TDP-43 proteinopathies and outlining potential therapeutic strategies to regulate these pathologic events.}, } @article {pmid37394908, year = {2023}, author = {Bakavayev, S and Stavsky, A and Argueti-Ostrovsky, S and Yehezkel, G and Fridmann-Sirkis, Y and Barak, Z and Gitler, D and Israelson, A and Engel, S}, title = {Blocking an epitope of misfolded SOD1 ameliorates disease phenotype in a model of amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {146}, number = {11}, pages = {4594-4607}, doi = {10.1093/brain/awad222}, pmid = {37394908}, issn = {1460-2156}, mesh = {Mice ; Animals ; Superoxide Dismutase-1/genetics ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase/genetics/metabolism ; Epitopes ; Phenotype ; Protein Folding ; Disease Models, Animal ; Mice, Transgenic ; }, abstract = {The current strategies to mitigate the toxicity of misfolded superoxide dismutase 1 (SOD1) in familial amyotrophic lateral sclerosis via blocking SOD1 expression in the CNS are indiscriminative for misfolded and intact proteins, and as such, entail a risk of depriving CNS cells of their essential antioxidant potential. As an alternative approach to neutralize misfolded and spare unaffected SOD1 species, we developed scFv-SE21 antibody that blocks the β6/β7 loop epitope exposed exclusively in misfolded SOD1. The β6/β7 loop epitope has previously been proposed to initiate amyloid-like aggregation of misfolded SOD1 and mediate its prion-like activity. The adeno-associated virus-mediated expression of scFv-SE21 in the CNS of hSOD1G37R mice rescued spinal motor neurons, reduced the accumulation of misfolded SOD1, decreased gliosis and thus delayed disease onset and extended survival by 90 days. The results provide evidence for the role of the exposed β6/β7 loop epitope in the mechanism of neurotoxic gain-of-function of misfolded SOD1 and open avenues for the development of mechanism-based anti-SOD1 therapeutics, whose selective targeting of misfolded SOD1 species may entail a reduced risk of collateral oxidative damage to the CNS.}, } @article {pmid37394881, year = {2023}, author = {Dilliott, AA and Kwon, S and Rouleau, GA and Iqbal, S and Farhan, SMK}, title = {Characterizing proteomic and transcriptomic features of missense variants in amyotrophic lateral sclerosis genes.}, journal = {Brain : a journal of neurology}, volume = {146}, number = {11}, pages = {4608-4621}, pmid = {37394881}, issn = {1460-2156}, support = {//CIHR/Canada ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Transcriptome/genetics ; Proteomics ; Mutation, Missense/genetics ; Genetic Testing ; }, abstract = {Within recent years, there has been a growing number of genes associated with amyotrophic lateral sclerosis (ALS), resulting in an increasing number of novel variants, particularly missense variants, many of which are of unknown clinical significance. Here, we leverage the sequencing efforts of the ALS Knowledge Portal (3864 individuals with ALS and 7839 controls) and Project MinE ALS Sequencing Consortium (4366 individuals with ALS and 1832 controls) to perform proteomic and transcriptomic characterization of missense variants in 24 ALS-associated genes. The two sequencing datasets were interrogated for missense variants in the 24 genes, and variants were annotated with gnomAD minor allele frequencies, ClinVar pathogenicity classifications, protein sequence features including Uniprot functional site annotations, and PhosphoSitePlus post-translational modification site annotations, structural features from AlphaFold predicted monomeric 3D structures, and transcriptomic expression levels from Genotype-Tissue Expression. We then applied missense variant enrichment and gene-burden testing following binning of variation based on the selected proteomic and transcriptomic features to identify those most relevant to pathogenicity in ALS-associated genes. Using predicted human protein structures from AlphaFold, we determined that missense variants carried by individuals with ALS were significantly enriched in β-sheets and α-helices, as well as in core, buried or moderately buried regions. At the same time, we identified that hydrophobic amino acid residues, compositionally biased protein regions and regions of interest are predominantly enriched in missense variants carried by individuals with ALS. Assessment of expression level based on transcriptomics also revealed enrichment of variants of high and medium expression across all tissues and within the brain. We further explored enriched features of interest using burden analyses and identified individual genes were indeed driving certain enrichment signals. A case study is presented for SOD1 to demonstrate proof-of-concept of how enriched features may aid in defining variant pathogenicity. Our results present proteomic and transcriptomic features that are important indicators of missense variant pathogenicity in ALS and are distinct from features associated with neurodevelopmental disorders.}, } @article {pmid37394863, year = {2023}, author = {Zhao, YN and Fu, JY and He, J and Fan, DS}, title = {[Progress in the application of uric acid-lowering treatments in amyotrophic lateral sclerosis].}, journal = {Zhonghua nei ke za zhi}, volume = {62}, number = {7}, pages = {885-890}, doi = {10.3760/cma.j.cn112138-20220708-00498}, pmid = {37394863}, issn = {0578-1426}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Uric Acid ; }, } @article {pmid37394036, year = {2023}, author = {Arnold, FJ and Nguyen, AD and Bedlack, RS and Bennett, CL and La Spada, AR}, title = {Intercellular transmission of pathogenic proteins in ALS: Exploring the pathogenic wave.}, journal = {Neurobiology of disease}, volume = {184}, number = {}, pages = {106218}, doi = {10.1016/j.nbd.2023.106218}, pmid = {37394036}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase-1/metabolism ; Protein Aggregates ; C9orf72 Protein/genetics ; DNA-Binding Proteins/genetics/metabolism ; }, abstract = {In patients with amyotrophic lateral sclerosis (ALS), disease symptoms and pathology typically spread in a predictable spatiotemporal pattern beginning at a focal site of onset and progressing along defined neuroanatomical tracts. Like other neurodegenerative diseases, ALS is characterized by the presence of protein aggregates in postmortem patient tissue. Cytoplasmic, ubiquitin-positive aggregates of TDP-43 are observed in approximately 97% of sporadic and familial ALS patients, while SOD1 inclusions are likely specific to cases of SOD1-ALS. Additionally, the most common subtype of familial ALS, caused by a hexanucleotide repeat expansion in the first intron of the C9orf72 gene (C9-ALS), is further characterized by the presence of aggregated dipeptide repeat proteins (DPRs). As we will describe, cell-to-cell propagation of these pathological proteins tightly correlates with the contiguous spread of disease. While TDP-43 and SOD1 are capable of seeding protein misfolding and aggregation in a prion-like manner, C9orf72 DPRs appear to induce (and transmit) a 'disease state' more generally. Multiple mechanisms of intercellular transport have been described for all of these proteins, including anterograde and retrograde axonal transport, extracellular vesicle secretion, and macropinocytosis. In addition to neuron-to-neuron transmission, transmission of pathological proteins occurs between neurons and glia. Given that the spread of ALS disease pathology corresponds with the spread of symptoms in patients, the various mechanisms by which ALS-associated protein aggregates propagate through the central nervous system should be closely examined.}, } @article {pmid37393503, year = {2023}, author = {Vítor, J and Saracino, D and Ströer, S and Camuzat, A and Dorgham, K and Clot, F and Martin-Hardy, P and Pasquier, F and , and Le Ber, I}, title = {Atypical White Matter Hyperintensities Markedly Impact Plasma Neurofilament Light Chain Variability in GRN Patients.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {94}, number = {4}, pages = {1351-1360}, doi = {10.3233/JAD-230315}, pmid = {37393503}, issn = {1875-8908}, mesh = {Humans ; Biomarkers ; *Frontotemporal Dementia/genetics ; Intermediate Filaments ; Mutation ; Neurofilament Proteins ; Progranulins/genetics ; *White Matter/diagnostic imaging ; }, abstract = {GRN mutations, causing frontotemporal dementia, can be associated with atypical white matter hyperintensities (WMH). We hypothesized that the presence of WMH may impact neurofilament light chain (NfL) levels, markers of neuroaxonal damage. We analyzed plasma NfL in 20 GRN patients and studied their association to visually-scored WMH burden. The 12 patients displaying atypical WMH had significantly higher NfL levels (98.4±34.9 pg/mL) than those without WMH (47.2±29.4 pg/mL, p = 0.003), independently from age, disease duration and Fazekas-Schmidt grade. NfL correlated with WMH burden (rho = 0.55, p = 0.01). This study prompts considering WMH burden as a variability factor when evaluating NfL levels in GRN patients.}, } @article {pmid37392160, year = {2023}, author = {Hivare, P and Mujmer, K and Swarup, G and Gupta, S and Bhatia, D}, title = {Endocytic pathways of pathogenic protein aggregates in neurodegenerative diseases.}, journal = {Traffic (Copenhagen, Denmark)}, volume = {24}, number = {10}, pages = {434-452}, doi = {10.1111/tra.12906}, pmid = {37392160}, issn = {1600-0854}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; Protein Aggregates ; *Alzheimer Disease/metabolism ; *Parkinson Disease/metabolism ; alpha-Synuclein/metabolism ; }, abstract = {Endocytosis is the fundamental uptake process through which cells internalize extracellular materials and species. Neurodegenerative diseases (NDs) are characterized by a progressive accumulation of intrinsically disordered protein species, leading to neuronal death. Misfolding in many proteins leads to various NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and other disorders. Despite the significance of disordered protein species in neurodegeneration, their spread between cells and the cellular uptake of extracellular species is not entirely understood. This review discusses the major internalization mechanisms of the different conformer species of these proteins and their endocytic mechanisms. We briefly introduce the broad types of endocytic mechanisms found in cells and then summarize what is known about the endocytosis of monomeric, oligomeric and aggregated conformations of tau, Aβ, α-Syn, Huntingtin, Prions, SOD1, TDP-43 and other proteins associated with neurodegeneration. We also highlight the key players involved in internalizing these disordered proteins and the several techniques and approaches to identify their endocytic mechanisms. Finally, we discuss the obstacles involved in studying the endocytosis of these protein species and the need to develop better techniques to elucidate the uptake mechanisms of a particular disordered protein species.}, } @article {pmid37391647, year = {2023}, author = {Karati, D and Mukherjee, S and Roy, S}, title = {Molecular and Structural Insight into Adenosine A2A Receptor in Neurodegenerative Disorders: A Significant Target for Efficient Treatment Approach.}, journal = {Molecular neurobiology}, volume = {60}, number = {10}, pages = {5987-6000}, pmid = {37391647}, issn = {1559-1182}, mesh = {Humans ; *Adenosine/pharmacology ; Receptor, Adenosine A2A/metabolism ; Ligands ; *Neurodegenerative Diseases/drug therapy ; Purinergic P1 Receptor Antagonists/therapeutic use ; Receptors, Purinergic P1 ; }, abstract = {All biological tissues and bodily fluids include the autacoid adenosine. The P1 class of purinergic receptors includes adenosine receptors. Four distinct G-protein-coupled receptors on the cellular membrane mediate the effects of adenosine, whose cytoplasmic content is regulated by producing/degrading enzymes and nucleoside transporters. A2A receptor has received a great deal of attention in recent years because it has a wide range of potential therapeutic uses. A2B and, more significantly, A2A receptors regulate numerous physiological mechanisms in the central nervous system (CNS). The inferior targetability of A2B receptors towards adenosine points that they might portray a promising medicinal target since they are triggered only under pharmacological circumstances (when adenosine levels rise up to micromolar concentrations). The accessibility of specific ligands for A2B receptors would permit the exploration of such a theory. A2A receptors mediate both potentially neurotoxic and neuroprotective actions. Hence, it is debatable to what extent they play a role in neurodegenerative illnesses. However, A2A receptor blockers have demonstrated clear antiparkinsonian consequences, and a significant attraction exists in the role of A2A receptors in other neurodegenerative disorders. Amyloid peptide extracellular accumulation and tau hyperphosphorylation are the pathogenic components of AD that lead to neuronal cell death, cognitive impairment, and memory loss. Interestingly, in vitro and in vivo research has shown that A2A adenosine receptor antagonists may block each of these clinical symptoms, offering a crucial new approach to combat a condition for which, regrettably, only symptomatic medications are currently available. At least two requirements must be met to determine whether such receptors are a target for diseases of the CNS: a complete understanding of the mechanisms governing A2A-dependent processes and the availability of ligands that can distinguish between the various receptor populations. This review concisely summarises the biological effects mediated by A2A adenosine receptors in neurodegenerative disorders and discusses the chemical characteristics of A2A adenosine receptor antagonists undergoing clinical trials. Selective A2A receptor blocker against neurodegenerative disorders.}, } @article {pmid37391243, year = {2023}, author = {Gerecht, RB and Nable, JV}, title = {Out-of-Hospital Cardiac Arrest.}, journal = {Emergency medicine clinics of North America}, volume = {41}, number = {3}, pages = {433-453}, doi = {10.1016/j.emc.2023.03.002}, pmid = {37391243}, issn = {1558-0539}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/diagnosis/therapy ; *Emergency Medical Services ; }, abstract = {Survival from out-of-hospital cardiac arrest (OHCA) is predicated on a community and system-wide approach that includes rapid recognition of cardiac arrest, capable bystander CPR, effective basic and advanced life support (BLS and ALS) by EMS providers, and coordinated postresuscitation care. Management of these critically ill patients continues to evolve. This article focuses on the management of OHCA by EMS providers.}, } @article {pmid37390744, year = {2023}, author = {Eskandari, S and Rezayof, A and Asghari, SM and Hashemizadeh, S}, title = {Neurobiochemical characteristics of arginine-rich peptides explain their potential therapeutic efficacy in neurodegenerative diseases.}, journal = {Neuropeptides}, volume = {101}, number = {}, pages = {102356}, doi = {10.1016/j.npep.2023.102356}, pmid = {37390744}, issn = {1532-2785}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Arginine ; Oxidative Stress ; Peptides/metabolism ; *Nucleic Acids/metabolism/therapeutic use ; *Alzheimer Disease/metabolism ; }, abstract = {Neurodegenerative diseases, including Alzheimer̕ s disease (AD), Parkinson̕ s disease (PD), Huntington̕ s disease (HD), and Amyotrophic Lateral Sclerosis (ALS) require special attention to find new potential treatment methods. This review aims to summarize the current knowledge of the relationship between the biochemical properties of arginine-rich peptides (ARPs) and their neuroprotective effects to deal with the harmful effects of risk factors. It seems that ARPs have portrayed a promising and fantastic landscape for treating neurodegeneration-associated disorders. With multimodal mechanisms of action, ARPs play various unprecedented roles, including as the novel delivery platforms for entering the central nervous system (CNS), the potent antagonists for calcium influx, the invader molecules for targeting mitochondria, and the protein stabilizers. Interestingly, these peptides inhibit the proteolytic enzymes and block protein aggregation to induce pro-survival signaling pathways. ARPs also serve as the scavengers of toxic molecules and the reducers of oxidative stress agents. They also have anti-inflammatory, antimicrobial, and anti-cancer properties. Moreover, by providing an efficient nucleic acid delivery system, ARPs can play an essential role in developing various fields, including gene vaccines, gene therapy, gene editing, and imaging. ARP agents and ARP/cargo therapeutics can be raised as an emergent class of neurotherapeutics for neurodegeneration. Part of the aim of this review is to present recent advances in treating neurodegenerative diseases using ARPs as an emerging and powerful therapeutic tool. The applications and progress of ARPs-based nucleic acid delivery systems have also been discussed to highlight their usefulness as a broad-acting class of drugs.}, } @article {pmid37390359, year = {2023}, author = {Sheers, NL and Howard, ME and Rochford, PD and Rautela, L and Chao, C and McKim, DA and Berlowitz, DJ}, title = {A Randomized Controlled Clinical Trial of Lung Volume Recruitment in Adults with Neuromuscular Disease.}, journal = {Annals of the American Thoracic Society}, volume = {20}, number = {10}, pages = {1445-1455}, pmid = {37390359}, issn = {2325-6621}, mesh = {Female ; Humans ; Adult ; Middle Aged ; Adolescent ; *Quality of Life ; Prospective Studies ; Lung Volume Measurements ; Lung ; *Neuromuscular Diseases/complications ; }, abstract = {Rationale: Clinical care guidelines advise that lung volume recruitment (LVR) be performed routinely by people with neuromuscular disease (NMD) to maintain lung and chest wall flexibility and slow lung function decline. However, the evidence base is limited, and no randomized controlled trials of regular LVR in adults have been published. Objectives: To evaluate the effect of regular LVR on respiratory function and quality of life in adults with NMD. Methods: A randomized controlled trial with assessor blinding was conducted between September 2015 and May 2019. People (>14 years old) with NMD and vital capacity <80% predicted were eligible, stratified by disease subgroup (amyotrophic lateral sclerosis/motor neuron disease or other NMDs), and randomized to 3 months of twice-daily LVR or breathing exercises. The primary outcome was change in maximum insufflation capacity (MIC) from baseline to 3 months, analyzed using a linear mixed model approach. Results: Seventy-six participants (47% woman; median age, 57 [31-68] years; mean baseline vital capacity, 40 ± 18% predicted) were randomized (LVR, n = 37). Seventy-three participants completed the study. There was a statistically significant difference in MIC between groups (linear model interaction effect P = 0.002, observed mean difference, 0.19 [0.00-0.39] L). MIC increased by 0.13 (0.01-0.25) L in the LVR group, predominantly within the first month. No interaction or treatment effects were observed in secondary outcomes of lung volumes, respiratory system compliance, and quality of life. No adverse events were reported. Conclusions: Regular LVR increased MIC in a sample of LVR-naive participants with NMD. We found no direct evidence that regular LVR modifies respiratory mechanics or slows the rate of lung volume decline. The implications of increasing MIC are unclear, and the change in MIC may represent practice. Prospective long-term clinical cohorts with comprehensive follow-up, objective LVR use, and clinically meaningful outcome data are needed. Clinical trial registered with anzctr.org.au (ACTRN12615000565549).}, } @article {pmid37388914, year = {2023}, author = {Kaivola, K and Chia, R and Ding, J and Rasheed, M and Fujita, M and Menon, V and Walton, RL and Collins, RL and Billingsley, K and Brand, H and Talkowski, M and Zhao, X and Dewan, R and Stark, A and Ray, A and Solaiman, S and Alvarez Jerez, P and Malik, L and Dawson, TM and Rosenthal, LS and Albert, MS and Pletnikova, O and Troncoso, JC and Masellis, M and Keith, J and Black, SE and Ferrucci, L and Resnick, SM and Tanaka, T and , and , and , and , and Topol, E and Torkamani, A and Tienari, P and Foroud, TM and Ghetti, B and Landers, JE and Ryten, M and Morris, HR and Hardy, JA and Mazzini, L and D'Alfonso, S and Moglia, C and Calvo, A and Serrano, GE and Beach, TG and Ferman, T and Graff-Radford, NR and Boeve, BF and Wszolek, ZK and Dickson, DW and Chiò, A and Bennett, DA and De Jager, PL and Ross, OA and Dalgard, CL and Gibbs, JR and Traynor, BJ and Scholz, SW}, title = {Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias.}, journal = {Cell genomics}, volume = {3}, number = {6}, pages = {100316}, pmid = {37388914}, issn = {2666-979X}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; K08 AG065463/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; T32 HG002295/HG/NHGRI NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; ZIA AG000935/ImNIH/Intramural NIH HHS/United States ; ZIA NS003154/ImNIH/Intramural NIH HHS/United States ; P50 NS038377/NS/NINDS NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; R35 NS127253/NS/NINDS NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; RF1 AG057473/AG/NIA NIH HHS/United States ; }, abstract = {We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer's dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.}, } @article {pmid37388502, year = {2023}, author = {Mohamed, W and Kumar, J and Alghamdi, BS and Soliman, AH and Toshihide, Y}, title = {Neurodegeneration and inflammation crosstalk: Therapeutic targets and perspectives.}, journal = {IBRO neuroscience reports}, volume = {14}, number = {}, pages = {95-110}, pmid = {37388502}, issn = {2667-2421}, abstract = {Glia, which was formerly considered to exist just to connect neurons, now plays a key function in a wide range of physiological events, including formation of memory, learning, neuroplasticity, synaptic plasticity, energy consumption, and homeostasis of ions. Glial cells regulate the brain's immune responses and confers nutritional and structural aid to neurons, making them an important player in a broad range of neurological disorders. Alzheimer's, ALS, Parkinson's, frontotemporal dementia (FTD), and epilepsy are a few of the neurodegenerative diseases that have been linked to microglia and astroglia cells, in particular. Synapse growth is aided by glial cell activity, and this activity has an effect on neuronal signalling. Each glial malfunction in diverse neurodegenerative diseases is distinct, and we will discuss its significance in the progression of the illness, as well as its potential for future treatment.}, } @article {pmid37387467, year = {2023}, author = {Timmins, HC and Vucic, S and Kiernan, MC}, title = {Cortical hyperexcitability in amyotrophic lateral sclerosis: from pathogenesis to diagnosis.}, journal = {Current opinion in neurology}, volume = {36}, number = {4}, pages = {353-359}, doi = {10.1097/WCO.0000000000001162}, pmid = {37387467}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; Motor Neurons ; Transcranial Magnetic Stimulation/methods ; *Frontotemporal Dementia/diagnosis/genetics ; Biomarkers ; }, abstract = {PURPOSE OF REVIEW: Identification of upper motor neuron involvement remains a critical component of a diagnosis of amyotrophic lateral sclerosis (ALS), although supportive clinical signs are often not easily appreciated, particularly in the early symptomatic stages of the disease. Although diagnostic criteria have been developed to facilitate improved detection of lower motor neuron impairment through electrophysiological features that have improved diagnostic sensitivity, assessment of upper motor neuron involvement remains problematic.

RECENT FINDINGS: Recent evidence has emerged about pathophysiological processes, particularly glutamate-mediated excitotoxicity, which has resulted in the development of novel diagnostic investigations and uncovered potential therapeutic targets. Advances in genetics, including the C9orf72 gene, have changed concepts of ALS, from being classified as a neuromuscular disease to a disease that forms a continuum with other primary neurodegenerative disorders, particularly frontotemporal dementia. Transcranial magnetic stimulation has been utilized to provide pathophysiological insights, leading to the development of diagnostic and therapeutic biomarkers, which are now being introduced into the clinical setting.

SUMMARY: Specifically, the advent of cortical hyperexcitability has been consistently identified as an early and intrinsic feature of ALS. With greater accessibility of TMS techniques promoting clinical utilization, TMS measures of cortical function may develop as a diagnostic biomarker, with further potential utility in the clinical trial setting for monitoring of neuroprotective and genetic-based therapies.}, } @article {pmid37386798, year = {2023}, author = {Hirsch-Reinshagen, V and Hercher, C and Vila-Rodriguez, F and Neumann, M and Rademakers, R and Honer, WG and Hsiung, GR and Mackenzie, IR}, title = {Psychotic symptoms in frontotemporal dementia with TDP-43 tend to be associated with type B pathology.}, journal = {Neuropathology and applied neurobiology}, volume = {49}, number = {4}, pages = {e12921}, pmid = {37386798}, issn = {1365-2990}, support = {P01 AG019724/AG/NIA NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; C9orf72 Protein/genetics ; DNA-Binding Proteins/genetics ; *Frontotemporal Dementia/genetics/pathology ; *Frontotemporal Lobar Degeneration/pathology ; *Psychotic Disorders/complications ; Retrospective Studies ; }, abstract = {AIMS: Psychotic symptoms are increasingly recognized as a distinguishing clinical feature in patients with dementia due to frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Within this group, carriers of the C9orf72 repeat expansion are particularly prone to develop delusions and hallucinations.

METHODS: The present retrospective study sought to provide novel details about the relationship between FTLD-TDP pathology and the presence of psychotic symptoms during life.

RESULTS: We found that FTLD-TDP subtype B was more frequent in patients with psychotic symptoms than in those without. This relationship was present even when corrected for the presence of C9orf72 mutation, suggesting that pathophysiological processes leading to the development of subtype B pathology may increase the risk of psychotic symptoms. Within the group of FTLD-TDP cases with subtype B pathology, psychotic symptoms tended to be associated with a greater burden of TDP-43 pathology in the white matter and a lower burden in lower motor neurons. When present, pathological involvement of motor neurons was more likely to be asymptomatic in patients with psychosis.

CONCLUSIONS: This work suggests that psychotic symptoms in patients with FTLD-TDP tend to be associated with subtype B pathology. This relationship is not completely explained by the effects of the C9orf72 mutation and raises the possibility of a direct link between psychotic symptoms and this particular pattern of TDP-43 pathology.}, } @article {pmid37386297, year = {2023}, author = {Sheridan, C}, title = {Unprecedented blood biomarker enables ALS drug approval.}, journal = {Nature biotechnology}, volume = {41}, number = {7}, pages = {886-888}, doi = {10.1038/s41587-023-01862-0}, pmid = {37386297}, issn = {1546-1696}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/drug therapy ; Biomarkers/blood ; Drug Approval ; }, } @article {pmid37386082, year = {2023}, author = {Szebényi, K and Barrio-Hernandez, I and Gibbons, GM and Biasetti, L and Troakes, C and Beltrao, P and Lakatos, A}, title = {A human proteogenomic-cellular framework identifies KIF5A as a modulator of astrocyte process integrity with relevance to ALS.}, journal = {Communications biology}, volume = {6}, number = {1}, pages = {678}, pmid = {37386082}, issn = {2399-3642}, support = {MR/P008658/1/MRC_/Medical Research Council/United Kingdom ; MR/X006867/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Astrocytes ; Genome-Wide Association Study ; Kinesins/genetics ; *Proteogenomics ; }, abstract = {Genome-wide association studies identified several disease-causing mutations in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the contribution of genetic variants to pathway disturbances and their cell type-specific variations, especially in glia, is poorly understood. We integrated ALS GWAS-linked gene networks with human astrocyte-specific multi-omics datasets to elucidate pathognomonic signatures. It predicts that KIF5A, a motor protein kinesin-1 heavy-chain isoform, previously detected only in neurons, can also potentiate disease pathways in astrocytes. Using postmortem tissue and super-resolution structured illumination microscopy in cell-based perturbation platforms, we provide evidence that KIF5A is present in astrocyte processes and its deficiency disrupts structural integrity and mitochondrial transport. We show that this may underly cytoskeletal and trafficking changes in SOD1 ALS astrocytes characterised by low KIF5A levels, which can be rescued by c-Jun N-terminal Kinase-1 (JNK1), a kinesin transport regulator. Altogether, our pipeline reveals a mechanism controlling astrocyte process integrity, a pre-requisite for synapse maintenance and suggests a targetable loss-of-function in ALS.}, } @article {pmid37385457, year = {2023}, author = {DuMont, M and Agostinis, A and Singh, K and Swan, E and Buttle, Y and Tropea, D}, title = {Sex representation in neurodegenerative and psychiatric disorders' preclinical and clinical studies.}, journal = {Neurobiology of disease}, volume = {184}, number = {}, pages = {106214}, doi = {10.1016/j.nbd.2023.106214}, pmid = {37385457}, issn = {1095-953X}, mesh = {Humans ; Male ; Female ; *Alzheimer Disease ; *Parkinson Disease ; *Amyotrophic Lateral Sclerosis/epidemiology/therapy ; *Attention Deficit Disorder with Hyperactivity ; }, abstract = {Many studies show the importance of biological sex for the onset, progression, and response to treatment in brain disorders. In line with these reports, health agencies have requested that all trials, both at the clinical and preclinical level, use a similar number of male and female subjects to correctly interpret the results. Despite these guidelines, many studies still tend to be unbalanced in the use of male and female subjects. In this review we consider three neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and three psychiatric disorders: Depression, Attention Deficit Hyperactivity Disorder, and Schizophrenia. These disorders were chosen because of their prevalence and their recognized sex-specific differences in onset, progression, and response to treatment. Alzheimer's disease and Depression demonstrate higher prevalence in females, whereas Parkinson's Disease, Amyotrophic lateral sclerosis, Attention Deficit Hyperactivity Disorder, and schizophrenia show higher prevalence in males. Results from preclinical and clinical studies examining each of these disorders revealed sex-specific differences in risk factors, diagnostic biomarkers, and treatment response and efficacy, suggesting a role for sex-specific therapies in neurodegenerative and neuropsychiatric disorders. However, the qualitative analysis of the percentage of males and females enrolled in clinical trials in the last two decades shows that for most of the disorders, there is still a sex bias in the patients' enrolment.}, } @article {pmid37384409, year = {2023}, author = {Tejwani, L and Jung, Y and Kokubu, H and Sowmithra, S and Ni, L and Lee, C and Sanders, B and Lee, PJ and Xiang, Y and Luttik, K and Soriano, A and Yoon, J and Park, J and Ro, HH and Ju, H and Liao, C and Tieze, SM and Rigo, F and Jafar-Nejad, P and Lim, J}, title = {Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration.}, journal = {The Journal of clinical investigation}, volume = {133}, number = {16}, pages = {}, pmid = {37384409}, issn = {1558-8238}, support = {R21 MH119803/MH/NIMH NIH HHS/United States ; R01 NS083706/NS/NINDS NIH HHS/United States ; R01 NS088321/NS/NINDS NIH HHS/United States ; R01 AG076154/AG/NIA NIH HHS/United States ; R01 AG066447/AG/NIA NIH HHS/United States ; R01 AG074609/AG/NIA NIH HHS/United States ; T32 NS007224/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Lysosomes/metabolism ; *Neurodegenerative Diseases/genetics ; Humans ; }, abstract = {Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding transactive response DNA-binding protein 43 kDa (TDP-43), account for less than 1% of all ALS cases, TDP-43-positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS-causing (fALS-causing) mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimer's disease, and Parkinson's disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a function of nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and life span deficits in 2 distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared through the autophagy/lysosome pathway, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.}, } @article {pmid37384248, year = {2023}, author = {Hipke, K and Pitter, B and Hruscha, A and van Bebber, F and Modic, M and Bansal, V and Lewandowski, SA and Orozco, D and Edbauer, D and Bonn, S and Haass, C and Pohl, U and Montanez, E and Schmid, B}, title = {Loss of TDP-43 causes ectopic endothelial sprouting and migration defects through increased fibronectin, vcam 1 and integrin α4/β1.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1169962}, pmid = {37384248}, issn = {2296-634X}, abstract = {Aggregation of the Tar DNA-binding protein of 43 kDa (TDP-43) is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia and likely contributes to disease by loss of nuclear function. Analysis of TDP-43 function in knockout zebrafish identified an endothelial directional migration and hypersprouting phenotype during development prior lethality. In human umbilical vein cells (HUVEC) the loss of TDP-43 leads to hyperbranching. We identified elevated expression of FIBRONECTIN 1 (FN1), the VASCULAR CELL ADHESION MOLECULE 1 (VCAM1), as well as their receptor INTEGRIN α4β1 (ITGA4B1) in HUVEC cells. Importantly, reducing the levels of ITGA4, FN1, and VCAM1 homologues in the TDP-43 loss-of-function zebrafish rescues the angiogenic defects indicating the conservation of human and zebrafish TDP-43 function during angiogenesis. Our study identifies a novel pathway regulated by TDP-43 important for angiogenesis during development.}, } @article {pmid37383106, year = {2023}, author = {Wu, C and Feng, Y}, title = {Exploring the potential of mindfulness-based therapy in the prevention and treatment of neurodegenerative diseases based on molecular mechanism studies.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1097067}, pmid = {37383106}, issn = {1662-4548}, abstract = {Neurodegenerative diseases (ND) have received increasing attention due to their irreversibility, but there is still no means to completely cure ND in clinical practice. Mindfulness therapy (MT), including Qigong, Tai Chi, meditation, and yoga, etc., has become an effective complementary treatment modality in solving clinical and subclinical problems due to its advantages of low side effects, less pain, and easy acceptance by patients. MT is primarily used to treat mental and emotional disorders. In recent years, evidence has shown that MT has a certain therapeutic effect on ND with a potential molecular basis. In this review, we summarize the pathogenesis and risk factors of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), relating to telomerase activity, epigenetics, stress, and the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB) mediated inflammatory response, and analyze the molecular mechanism basis of MT to prevent and treat ND, to provide possible explanations for the potential of MT treatments for ND.}, } @article {pmid37382103, year = {2023}, author = {Benatar, M and Turner, MR and Wuu, J}, title = {Presymptomatic amyotrophic lateral sclerosis: from characterization to prevention.}, journal = {Current opinion in neurology}, volume = {36}, number = {4}, pages = {360-364}, pmid = {37382103}, issn = {1473-6551}, support = {R01 NS105479/NS/NINDS NIH HHS/United States ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/prevention & control ; *Frontotemporal Dementia/genetics ; Longitudinal Studies ; Biomarkers ; Asymptomatic Diseases ; }, abstract = {PURPOSE OF REVIEW: Significant progress in characterizing presymptomatic amyotrophic lateral sclerosis (ALS) is ushering in an era of potential disease prevention. Although these advances have largely been based on cohorts of deep-phenotyped mutation carriers at an elevated risk for ALS, there are increasing opportunities to apply principles and insights gleaned, to the broader population at risk for ALS [and frontotemporal dementia (FTD)].

RECENT FINDINGS: The discovery that blood neurofilament light chain (NfL) level increases presymptomatically and may serve as a susceptibility biomarker, predicting timing of phenoconversion in some mutation carriers, has empowered the first-ever prevention trial in SOD1 -ALS. Moreover, there is emerging evidence that presymptomatic disease is not uniformly clinically silent, with mild motor impairment (MMI), mild cognitive impairment (MCI), and/or mild behavioral impairment (MBI) representing a prodromal stage of disease. Structural and functional brain abnormalities, as well as systemic markers of metabolic dysfunction, have emerged as potentially even earlier markers of presymptomatic disease. Ongoing longitudinal studies will determine the extent to which these reflect an endophenotype of genetic risk.

SUMMARY: The discovery of presymptomatic biomarkers and the delineation of prodromal states is yielding unprecedented opportunities for earlier diagnosis, treatment, and perhaps even prevention of genetic and apparently sporadic forms of disease.}, } @article {pmid37381832, year = {2023}, author = {Zhang, Y and Cao, X and Gao, Z and Ma, X and Wang, Q and Xu, X and Cai, X and Zhang, Y and Zhang, Z and Wei, G and Wen, B}, title = {MATR3-antisense LINE1 RNA meshwork scaffolds higher-order chromatin organization.}, journal = {EMBO reports}, volume = {24}, number = {8}, pages = {e57550}, pmid = {37381832}, issn = {1469-3178}, mesh = {Humans ; *RNA, Antisense ; Histones/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Chromatin/genetics ; Cell Nucleus/genetics/metabolism ; RNA-Binding Proteins/genetics ; Nuclear Matrix-Associated Proteins/genetics/metabolism ; }, abstract = {Long interspersed nuclear elements (LINEs) play essential roles in shaping chromatin states, while the factors that cooperate with LINEs and their roles in higher-order chromatin organization remain poorly understood. Here, we show that MATR3, a nuclear matrix protein, interplays with antisense LINE1 (AS L1) RNAs to form a meshwork via phase separation, providing a dynamic platform for chromatin spatial organization. MATR3 and AS L1 RNAs affect the nuclear localization of each other. After MATR3 depletion, the chromatin, particularly H3K27me3-modified chromatin, redistributes in the cell nuclei. Topologically associating domains (TADs) that highly transcribe MATR3-associated AS L1 RNAs show decreased intra-TAD interactions in both AML12 and ES cells. MATR3 depletion increases the accessibility of H3K27me3 domains adjacent to MATR3-associated AS L1, without affecting H3K27me3 modifications. Furthermore, amyotrophic lateral sclerosis (ALS)-associated MATR3 mutants alter biophysical features of the MATR3-AS L1 RNA meshwork and cause an abnormal H3K27me3 staining. Collectively, we reveal a role of the meshwork formed by MATR3 and AS L1 RNAs in gathering chromatin in the nucleus.}, } @article {pmid37380145, year = {2023}, author = {Mercadante, S and Al-Husinat, L}, title = {Palliative Care in Amyotrophic Lateral Sclerosis.}, journal = {Journal of pain and symptom management}, volume = {66}, number = {4}, pages = {e485-e499}, doi = {10.1016/j.jpainsymman.2023.06.029}, pmid = {37380145}, issn = {1873-6513}, mesh = {Humans ; Palliative Care ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis ; Quality of Life ; *Neurodegenerative Diseases ; *Hospice and Palliative Care Nursing ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease of the motor neurons. Given the evolutive characteristics of this disease, palliative care principles should be a foundation of ALS care. A multidisciplinary medical intervention is of paramount importance in the different phases of disease. The involvement of the palliative care team improves quality of life and symptoms, and prognosis. Early initiation is of paramount importance to ensuring patient-centered care, when the patient has still the capability to communicate effectively and participate in his medical care. Advance care planning supports patients and family members in understanding and sharing their preferences according to their personal values and life goals regarding future medical treatment. The principal problems which require intensive supportive care include cognitive disturbances, psychological distress, pain, sialorrhrea, nutrition, and ventilatory support. Communication skills of health-care professionals are mandatory to manage the inevitability of death. Palliative sedation has peculiar aspects in this population, particularly with the decision of withdrawing ventilatory support.}, } @article {pmid37379901, year = {2023}, author = {Rypka, KJ and Goldfarb, N and Mansh, M}, title = {Response to the feasibility of Kreher et al's "Risk of melanoma and nonmelanoma skin cancer with immunosuppressants, part II: methotrexate, alkylating agents, biologics, and small molecule inhibitors".}, journal = {Journal of the American Academy of Dermatology}, volume = {89}, number = {4}, pages = {e181-e185}, doi = {10.1016/j.jaad.2023.05.095}, pmid = {37379901}, issn = {1097-6787}, mesh = {Humans ; Methotrexate/therapeutic use ; Immunosuppressive Agents ; *Biological Products ; Alkylating Agents ; Feasibility Studies ; *Skin Neoplasms/drug therapy/epidemiology ; *Melanoma/drug therapy ; }, } @article {pmid37379726, year = {2023}, author = {Floudiotis, N and Modi, G and Mochan, A}, title = {Motor neuron disease in black African patients at a tertiary care hospital in Soweto, South Africa.}, journal = {Journal of the neurological sciences}, volume = {451}, number = {}, pages = {120710}, doi = {10.1016/j.jns.2023.120710}, pmid = {37379726}, issn = {1878-5883}, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis ; Cross-Sectional Studies ; Delayed Diagnosis ; *Motor Neuron Disease ; South Africa/epidemiology ; Tertiary Care Centers ; Adult ; Middle Aged ; }, abstract = {INTRODUCTION: In this brief report, we describe the nature of ALS in a South African cohort of patients of Black African ancestry - a population which has been historically understudied.

METHODS: We performed a chart review of all patients attending the ALS/MND clinic at the Chris Hani Baragwanath Academic Hospital in Soweto, Johannesburg, South Africa, during the period 1 January 2015 to 30 June 2020. Cross-sectional demographic and clinical data captured at the time of diagnosis was collected.

RESULTS: Seventy-one patients were included in the study. Males constituted 66% (n = 47), with a male to female sex ratio of 2:1. The median age at onset of symptoms was 46 years (IQR 40-57) with a median disease duration at diagnosis (diagnostic delay) of 2 years (IQR 1-3). The onset was spinal in 76% and bulbar in 23%. The median ALSFRS-R score at time of presentation was 29 (IQR 23-38.5). The median ALSFRS-R slope (unit/month) was 0.80 (IQR 0.43-1.39). Sixty five patients (92%) were diagnosed with the classic ALS phenotype. Fourteen patients were known to be HIV positive, and of those, 12 were on antiretroviral treatment (ART). None of the patients had familial ALS.

CONCLUSION: Our findings of an earlier age at symptom onset and seemingly advanced disease at presentation in patients with Black African ancestry support the existing literature on the African population.}, } @article {pmid37379724, year = {2023}, author = {Paucar, M and Laffita-Mesa, J and Niemelä, V and Malmgren, H and Nennesmo, I and Lagerstedt-Robinson, K and Nordenskjöld, M and Svenningsson, P}, title = {Genetic screening for Huntington disease phenocopies in Sweden: A tertiary center case series focused on short tandem repeat (STR) disorders.}, journal = {Journal of the neurological sciences}, volume = {451}, number = {}, pages = {120707}, doi = {10.1016/j.jns.2023.120707}, pmid = {37379724}, issn = {1878-5883}, mesh = {*Huntington Disease/diagnosis/genetics ; Spinocerebellar Ataxias ; Sweden ; Humans ; C9orf72 Protein/genetics ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Genetic Testing ; *Prion Diseases ; Microsatellite Repeats ; Ubiquitin-Protein Ligases/genetics ; DNA Repeat Expansion ; *Prions ; }, abstract = {OBJECTIVE: To perform a screening for Huntington disease (HD) phenocopies in a Swedish cohort.

METHODS: Seventy-three DNA samples negative for HD were assessed at a tertiary center in Stockholm. The screening included analyses for C9orf72-frontotemporal dementia/amyotrophic lateral sclerosis (C9orf72-FTD/ALS), octapeptide repeat insertions (OPRIs) in PRNP associated with inherited prion diseases (IPD), Huntington's disease-like 2 (HDL2), spinocerebellar ataxia-2 (SCA2), spinocerebellar ataxia 3 (SCA3) and spinocerebellar ataxia-17 (SCA17). Targeted genetic analysis was carried out in two cases based on the salient phenotypic features.

RESULTS: The screening identified two patients with SCA17, one patient with IPD associated with 5-OPRI but none with nucleotide expansions in C9orf72 or for HDL2, SCA2 or SCA3. Furthermore, SGCE-myoclonic-dystonia 11 (SGCE-M-D) and benign hereditary chorea (BHC) was diagnosed in two sporadic cases. WES identified VUS in STUB1 in two patients with predominant cerebellar ataxia.

CONCLUSIONS: Our results are in keeping with previous screenings and suggest that other genes yet to be discovered are involved in the etiology of HD phenocopies.}, } @article {pmid37378756, year = {2023}, author = {Sassi, S and Bianchi, E and Diamanti, L and Tornabene, D and Sette, E and Medici, D and Matà, S and Leccese, D and Sperti, M and Martinelli, I and Ghezzi, A and Mandrioli, J and Iuzzolino, VV and Dubbioso, R and Trojsi, F and Passaniti, C and D'Alvano, G and Filosto, M and Padovani, A and Mazzini, L and De Marchi, F and Zinno, L and Nuredini, A and Bongioanni, P and Dolciotti, C and Canali, E and Toschi, G and Petrucci, A and Perna, A and Riso, V and Inghilleri, M and Libonati, L and Cambieri, C and Pupillo, E}, title = {Retrospective observational study on the use of acetyl-L-carnitine in ALS.}, journal = {Journal of neurology}, volume = {270}, number = {11}, pages = {5344-5357}, pmid = {37378756}, issn = {1432-1459}, mesh = {Humans ; *Acetylcarnitine/therapeutic use ; *Amyotrophic Lateral Sclerosis/diagnosis ; Retrospective Studies ; Case-Control Studies ; Double-Blind Method ; }, abstract = {ALCAR (Acetyl-L-carnitine) is a donor of acetyl groups and increases the intracellular levels of carnitine, the primary transporter of fatty acids across the mitochondrial membranes. In vivo studies showed that ALCAR decrease oxidative stress markers and pro-inflammatory cytokines. In a previous double-blind placebo-controlled phase II trial showed positive effects on self-sufficiency (defined as a score of 3+ on the ALSFRS-R items for swallowing, cutting food and handling utensils, and walking) ALSFRS-R total score and FVC. We conducted an observational, retrospective, multicentre, case-control study to provide additional data on the effects of ALCAR in subjects with ALS in Italy. Subjects treated with ALCAR 1.5 g/day or 3 g/day were included and matched with not treated subjects by sex, age at diagnosis, site of onset, and time from diagnosis to baseline, (45 subjects per group). ALCAR 3 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 23 (51.1%) treated subjects (adj. OR 1.18, 95% CI 0.46-3.02). No statistically significant differences were detected in ALSFRS nor FVC nor self-sufficiency. ALCAR 1.5 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 32 (71.1%) treated subjects (adj. OR 0.27, 95% CI 0.10-0.71). For ALSFRS-R, a mean slope of - 1.0 was observed in treated subjects compared to - 1.4 in those not treated (p = 0.0575). No statistically significant difference was detected in the FVC nor self-sufficiency. Additional evidence should be provided to confirm the efficacy of the drug and provide a rationale for the dosage.}, } @article {pmid37378058, year = {2023}, author = {Sancho, J and Ferrer, S}, title = {How to increase noninvasive ventilation effectiveness in bulbar amyotrophic lateral sclerosis patients.}, journal = {Breathe (Sheffield, England)}, volume = {19}, number = {1}, pages = {220266}, pmid = {37378058}, issn = {1810-6838}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease in which the respiratory muscles are also affected, leading to respiratory failure. Bulbar impairment develops in almost all cases during the course of the disease, becoming severe in the late stages of disease. Noninvasive ventilation (NIV) has been shown to increase survival in ALS; however, severe bulbar dysfunction has a negative impact on NIV tolerance and effectiveness. Therefore, certain steps should be taken to improve NIV outcomes in these patients including optimal ventilatory parameters, adequate interface selection, effective respiratory secretion management and control of bulbar symptoms.}, } @article {pmid37375224, year = {2023}, author = {Zhang, Y and Huang, J and Yu, K and Cui, X}, title = {G-Quadruplexes Formation by the C9orf72 Nucleotide Repeat Expansion d(GGGGCC)n and Conformation Regulation by Fangchinoline.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {12}, pages = {}, pmid = {37375224}, issn = {1420-3049}, support = {KLEEMA202201//Key Laboratory of Ecology and Environment in 458 Minority Areas (Minzu University of China), National Ethnic Affairs Commission/ ; }, mesh = {Humans ; *Frontotemporal Dementia ; *G-Quadruplexes ; C9orf72 Protein/genetics ; Nucleotides ; *Amyotrophic Lateral Sclerosis/genetics ; RNA/chemistry ; DNA/genetics ; }, abstract = {The G-quadruplex (GQ)-forming hexanucleotide repeat expansion (HRE) in the C9orf72 (C9) gene has been found to be the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (collectively, C9ALS/FTD), implying the great significance of modulating C9-HRE GQ structures in C9ALS/FTD therapeutic treatment strategies. In this study, we investigated the GQ structures formed by varied lengths of C9-HRE DNA sequences d(GGGGCC)4 (C9-24mer) and d(GGGGCC)8 (C9-48mer), and found that the C9-24mer forms anti-parallel GQ (AP-GQ) in the presence of potassium ions, while the long C9-48mer bearing eight guanine tracts forms unstacked tandem GQ consisting of two C9-24mer unimolecular AP-GQs. Moreover, the natural small molecule Fangchinoline was screened out in order to be able to stabilize and alter the C9-HRE DNA to parallel GQ topology. Further study of the interaction of Fangchinoline with the C9-HRE RNA GQ unit r(GGGGCC)4 (C9-RNA) revealed that it can also recognize and improve the thermal stability of C9-HRE RNA GQ. Finally, use of AutoDock simulation results indicated that Fangchinoline binds to the groove regions of the parallel C9-HRE GQs. These findings pave the way for further studies of GQ structures formed by pathologically related long C9-HRE sequences, and also provide a natural small-molecule ligand that modulates the structure and stability of C9-HRE GQ, both in DNA and RNA levels. Altogether, this work may contribute to therapeutic approaches of C9ALS/FTD which take the upstream C9-HRE DNA region, as well as the toxic C9-HRE RNA, as targets.}, } @article {pmid37375216, year = {2023}, author = {De Luca, M and Ioele, G and Grande, F and Occhiuzzi, MA and Chieffallo, M and Garofalo, A and Ragno, G}, title = {Multivariate Curve Resolution Methodology Applied to the ATR-FTIR Data for Adulteration Assessment of Virgin Coconut Oil.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {12}, pages = {}, pmid = {37375216}, issn = {1420-3049}, support = {PON R&I 2014-2020 - ARS01_00568//PON R&I 2014-2020 - ARS01_00568 - SI.F.I.PA.CRO.DE. - Sviluppo e industrializzazione farmaci innovativi per terapia molecolare personalizzata PA.CRO.DE/ ; }, mesh = {Coconut Oil ; Spectroscopy, Fourier Transform Infrared/methods ; Fourier Analysis ; *Food Contamination/analysis ; *Plant Oils/analysis ; Least-Squares Analysis ; Olive Oil/analysis ; }, abstract = {Virgin coconut oil (VCO) is a functional food with important health benefits. Its economic interest encourages fraudsters to deliberately adulterate VCO with cheap and low-quality vegetable oils for financial gain, causing health and safety problems for consumers. In this context, there is an urgent need for rapid, accurate, and precise analytical techniques to detect VCO adulteration. In this study, the use of Fourier transform infrared (FTIR) spectroscopy combined with multivariate curve resolution-alternating least squares (MCR-ALS) methodology was evaluated to verify the purity or adulteration of VCO with reference to low-cost commercial oils such as sunflower (SO), maize (MO) and peanut (PO) oils. A two-step analytical procedure was developed, where an initial control chart approach was designed to assess the purity of oil samples using the MCR-ALS score values calculated on a data set of pure and adulterated oils. The pre-treatment of the spectral data by derivatization with the Savitzky-Golay algorithm allowed to obtain the classification limits able to distinguish the pure samples with 100% of correct classifications in the external validation. In the next step, three calibration models were developed using MCR-ALS with correlation constraints for analysis of adulterated coconut oil samples in order to assess the blend composition. Different data pre-treatment strategies were tested to best extract the information contained in the sample fingerprints. The best results were achieved by derivative and standard normal variate procedures obtaining RMSEP and RE% values in the ranges of 1.79-2.66 and 6.48-8.35%, respectively. The models were optimized using a genetic algorithm (GA) to select the most important variables and the final models in the external validations gave satisfactory results in quantifying adulterants, with absolute errors and RMSEP of less than 4.6% and 1.470, respectively.}, } @article {pmid37375110, year = {2023}, author = {Xu, E and Park, S and Calderon, J and Cao, D and Liang, B}, title = {In Silico Identification and In Vitro Validation of Repurposed Compounds Targeting the RSV Polymerase.}, journal = {Microorganisms}, volume = {11}, number = {6}, pages = {}, pmid = {37375110}, issn = {2076-2607}, support = {R01 GM130950/GM/NIGMS NIH HHS/United States ; R01GM130950/NH/NIH HHS/United States ; }, abstract = {Respiratory Syncytial Virus (RSV) is the top cause of infant hospitalization globally, with no effective treatments available. Researchers have sought small molecules to target the RNA-dependent RNA Polymerase (RdRP) of RSV, which is essential for replication and transcription. Based on the cryo-EM structure of the RSV polymerase, in silico computational analysis including molecular docking and the protein-ligand simulation of a database, including 6554 molecules, is currently undergoing phases 1-4 of clinical trials and has resulted in the top ten repurposed compound candidates against the RSV polymerase, including Micafungin, Totrombopag, and Verubecestat. We performed the same procedure to evaluate 18 small molecules from previous studies and chose the top four compounds for comparison. Among the top identified repurposed compounds, Micafungin, an antifungal medication, showed significant inhibition and binding affinity improvements over current inhibitors such as ALS-8112 and Ribavirin. We also validated Micafungin's inhibition of the RSV RdRP using an in vitro transcription assay. These findings contribute to RSV drug development and hold promise for broad-spectrum antivirals targeting the non-segmented negative-sense (NNS) RNA viral polymerases, including those of rabies (RABV) and Ebola (EBOV).}, } @article {pmid37374084, year = {2023}, author = {McCluskey, G and Morrison, KE and Donaghy, C and McConville, J and McCarron, MO and McVerry, F and Duddy, W and Duguez, S}, title = {Serum Neurofilaments in Motor Neuron Disease and Their Utility in Differentiating ALS, PMA and PLS.}, journal = {Life (Basel, Switzerland)}, volume = {13}, number = {6}, pages = {}, pmid = {37374084}, issn = {2075-1729}, support = {Clinical research fellowship//Guarantors of Brain/ ; Clinical Research Fellowship//Association of British Neurologists/ ; Research Grant//Irish Institute of Clinical Neuroscience/ ; }, abstract = {Neurofilament levels are elevated in many neurodegenerative diseases and have shown promise as diagnostic and prognostic biomarkers in Amyotrophic Lateral Sclerosis (ALS), the most common form of Motor Neuron Disease (MND). This study assesses serum neurofilament light (NFL) and neurofilament heavy (NFH) chain concentrations in patients with ALS, other variants of motor neuron disease such as Progressive Muscular Atrophy (PMA) and Primary Lateral Sclerosis (PLS), and a range of other neurological diseases. It aims to evaluate the use of NFL and NFH to differentiate these conditions and for the prognosis of MND disease progression. NFL and NFH levels were quantified using electrochemiluminescence immunoassays (ECLIA). Both were elevated in 47 patients with MND compared to 34 patients with other neurological diseases and 33 healthy controls. NFL was able to differentiate patients with MND from the other groups with a Receiver Operating Characteristic (ROC) curve area under the curve (AUC) of 0.90 (p < 0.001). NFL correlated with the rate of disease progression in MND (rho 0.758, p < 0.001) and with the ALS Functional Rating Scale (rho -0.335, p = 0.021). NFL levels were higher in patients with ALS compared to both PMA (p = 0.032) and PLS (p = 0.012) and were able to distinguish ALS from both PMA and PLS with a ROC curve AUC of 0.767 (p = 0.005). These findings support the use of serum NFL to help diagnose and differentiate types of MND, in addition to providing prognostic information to patients and their families.}, } @article {pmid37373667, year = {2023}, author = {Sipilä, JOT}, title = {Adult-Onset Neuroepidemiology in Finland: Lessons to Learn and Work to Do.}, journal = {Journal of clinical medicine}, volume = {12}, number = {12}, pages = {}, pmid = {37373667}, issn = {2077-0383}, abstract = {Finland is a relatively small genetic isolate with a genetically non-homogenous population. Available Finnish data on neuroepidemiology of adult-onset disorders are limited, and this paper describes the conclusions that can be drawn and their implications. Apparently, Finnish people have a (relatively) high risk of developing Unverricht-Lundborg disease (EPM1), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), Spinal muscular atrophy, Jokela type (SMAJ) and adult-onset dystonia. On the other hand, some disorders, such as Friedreich's ataxia (FRDA) and Wilson's disease (WD), are almost absent or completely absent in the population. Valid and timely data concerning even many common disorders, such as stroke, migraine, neuropathy, Alzheimer's disease and Parkinson's disease, are unavailable, and there are virtually no data on many less-common neurological disorders, such as neurosarcoidosis or autoimmune encephalitides. There also appear to be marked regional differences in the incidence and prevalence of many diseases, suggesting that non-granular nationwide data may be misleading in many cases. Concentrated efforts to advance neuroepidemiological research in the country would be of clinical, administrative and scientific benefit, but currently, all progress is blocked by administrative and financial obstacles.}, } @article {pmid37371694, year = {2023}, author = {De Marchi, F and Franjkic, T and Schito, P and Russo, T and Nimac, J and Chami, AA and Mele, A and Vidatic, L and Kriz, J and Julien, JP and Apic, G and Russell, RB and Rogelj, B and Cannon, JR and Baralle, M and Agosta, F and Hecimovic, S and Mazzini, L and Buratti, E and Munitic, I}, title = {Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder.}, journal = {Biomedicines}, volume = {11}, number = {6}, pages = {}, pmid = {37371694}, issn = {2227-9059}, abstract = {Proteinopathy and neuroinflammation are two main hallmarks of neurodegenerative diseases. They also represent rare common events in an exceptionally broad landscape of genetic, environmental, neuropathologic, and clinical heterogeneity present in patients. Here, we aim to recount the emerging trends in amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorder. Our review will predominantly focus on neuroinflammation and systemic immune imbalance in ALS and FTD, which have recently been highlighted as novel therapeutic targets. A common mechanism of most ALS and ~50% of FTD patients is dysregulation of TAR DNA-binding protein 43 (TDP-43), an RNA/DNA-binding protein, which becomes depleted from the nucleus and forms cytoplasmic aggregates in neurons and glia. This, in turn, via both gain and loss of function events, alters a variety of TDP-43-mediated cellular events. Experimental attempts to target TDP-43 aggregates or manipulate crosstalk in the context of inflammation will be discussed. Targeting inflammation, and the immune system in general, is of particular interest because of the high plasticity of immune cells compared to neurons.}, } @article {pmid37371389, year = {2023}, author = {Górska, A and Markiewicz-Gospodarek, A and Markiewicz, R and Chilimoniuk, Z and Borowski, B and Trubalski, M and Czarnek, K}, title = {Distribution of Iron, Copper, Zinc and Cadmium in Glia, Their Influence on Glial Cells and Relationship with Neurodegenerative Diseases.}, journal = {Brain sciences}, volume = {13}, number = {6}, pages = {}, pmid = {37371389}, issn = {2076-3425}, abstract = {Recent data on the distribution and influence of copper, zinc and cadmium in glial cells are summarized. This review also examines the relationship between those metals and their role in neurodegenerative diseases like Alzheimer disease, multiple sclerosis, Parkinson disease and Amyotrophic lateral sclerosis, which have become a great challenge for today's physicians. The studies suggest that among glial cells, iron has the highest concentration in oligodendrocytes, copper in astrocytes and zinc in the glia of hippocampus and cortex. Previous studies have shown neurotoxic effects of copper, iron and manganese, while zinc can have a bidirectional effect, i.e., neurotoxic but also neuroprotective effects depending on the dose and disease state. Recent data point to the association of metals with neurodegeneration through their role in the modulation of protein aggregation. Metals can accumulate in the brain with aging and may be associated with age-related diseases.}, } @article {pmid37369876, year = {2023}, author = {Verde, F and Milone, I and Colombo, E and Maranzano, A and Dubini, A and Colombrita, C and Gentile, F and Doretti, A and Torre, S and Messina, S and Morelli, C and Torresani, E and Poletti, B and Priori, A and Maderna, L and Ratti, A and Silani, V and Ticozzi, N}, title = {Phosphorylated tau in plasma could be a biomarker of lower motor neuron impairment in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {10}, pages = {3697-3702}, pmid = {37369876}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Motor Neurons ; Biomarkers/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; }, abstract = {INTRODUCTION: Plasma levels of phosphorylated tau (P-tau181) have been recently reported to be increased in amyotrophic lateral sclerosis (ALS) and associated with lower motor neuron (LMN) impairment.

PATIENTS AND METHODS: We quantified plasma P-tau181 (pP-tau181) in a cohort of 29 deeply phenotyped ALS patients using the new fully automated Lumipulse assay and analysed phenotype-biomarker correlations.

RESULTS: pP-tau181 levels correlated positively with a clinical LMN score (r = 0.3803) and negatively, albeit not significantly, with a composite index of muscle strength (r =  - 0.3416; p = 0.0811), but not with Penn Upper Motor Neuron (UMN) Score. Accordingly, pP-tau181 correlated with electromyographic indices of spinal active and chronic denervation (r = 0.4507 and r = 0.3864, respectively) but not with transcranial magnetic stimulation parameters of UMN dysfunction. pP-tau181 levels did not correlate with those in the cerebrospinal fluid (CSF), serum NFL, serum GFAP, CSF/serum albumin ratio, or estimated glomerular filtration rate, but correlated with plasma creatine kinase levels (r = 0.4661). Finally, while not being associated with neuropsychological phenotype, pP-tau181 correlated negatively with pH (r =  - 0.5632) and positively with partial pressure of carbon dioxide (PaCO2; r = 0.7092), bicarbonate (sHCO3[-]; r = 0.6667) and base excess (r = 0.6611) on arterial blood gas analysis.

DISCUSSION: pP-tau181 has potential as ALS biomarker and could be associated with LMN impairment. Its raised levels might reflect pathophysiological processes (tau hyperphosphorylation and/or release) occurring in the axons of LMNs distantly from the CNS and the CSF. pP-tau181 could also be associated with respiratory dysfunction.}, } @article {pmid37369861, year = {2023}, author = {Zhu, Q and Xu, D and Huang, H and Li, D and Yang, D and Zhou, J and Zhao, Y}, title = {The safety and effectiveness of high-calorie therapy for treating amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of neurology}, volume = {270}, number = {10}, pages = {4729-4743}, pmid = {37369861}, issn = {1432-1459}, support = {2022BCA055//Department of Science and Technology, Hubei Provincial People's Government/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Lipids/therapeutic use ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting the upper and lower motor neurons, which can lead to death from respiratory failure within 3-5 years after the onset of this disease. Nowadays, no drug can effectively slow down the progression of this disease. High-calorie therapy, an emerging complementary alternative treatment, has been reported in studies to prolong the survival time of patients, prevent muscle atrophy and provide a better prognosis. However, no systematic review and meta-analysis were performed to summarize the evidence of this therapy. This meta-analysis comprehensively evaluates the effectiveness and safety of high-calorie therapy for treating ALS.

METHODS: We searched the electronic databases from inception to 1 April 2023: PubMed, Embase, Web of Science, Cochrane Library, Scopus, Ovid/Medline, and ProQuest. Randomized controlled trials (RCTs) that met the inclusion criteria were performed by meta-analysis. All statistical analyses were performed in STATA software.

RESULTS: A total of six eligible RCTs were included in this meta-analysis, involving 370 ALS patients. The meta-analyses showed that high-calorie therapy had superiority in improving body weight (SMD = 1, 95% CI 0.36, 1.65) and BMI (SMD = 0.83, 95% CI 0.02, 1.63). With respect to safety, there was no difference between the high-calorie therapy and the control group regarding the number of adverse events (RR = 3.61, 95% CI 0.08, 162.49). However, ALSFRS-R scores (SMD = 0.34, 95% CI - 0.4, 1.08), survival rate (RR = 1.23, 95% CI 0.98, 1.55), and lipid profile (LDL: SMD = 0.21, 95% CI - 0.33, 0.75; HDL: SMD = 0.17, 95% CI - 0.37, 0.71; TC: SMD = 0.21, 95% CI - 0.33, 0.75), CRP (SMD = 0.85, 95% CI - 1.37, 3.06) showed no significant difference compared to the control groups.

CONCLUSIONS: High-calorie therapy is effective in gaining weight and BMI with few side effects. However, no significant superiority was detected in ALSFRS-R scores, survival time, lipid profile, and CRP indicator. The overall quality of the included studies is high, and the results have some credibility, but future corroboration by high-quality RCTs is also expected.}, } @article {pmid37368631, year = {2023}, author = {Barney, RE and Huang, G and Gallagher, TL and Tischbein, M and DeWitt, J and Martindale, R and LaRochelle, EMP and Tsongalis, GJ and Stommel, EW}, title = {Validation of a Droplet Digital PCR (ddPCR) Assay to Detect Cyanobacterial 16S rDNA in Human Lung Tissue.}, journal = {Toxics}, volume = {11}, number = {6}, pages = {}, pmid = {37368631}, issn = {2305-6304}, abstract = {Cyanobacteria produce a variety of secondary metabolites, including toxins that may contribute to the development of disease. Previous work was able to detect the presence of a cyanobacterial marker in human nasal and broncoalveolar lavage samples; however, it was not able to determine the quantification of the marker. To further research the relationship between cyanobacteria and human health, we validated a droplet digital polymerase chain reaction (ddPCR) assay to simultaneously detect the cyanobacterial 16S marker and a human housekeeping gene in human lung tissue samples. The ability to detect cyanobacteria in human samples will allow further research into the role cyanobacteria plays in human health and disease.}, } @article {pmid37368071, year = {2023}, author = {Xia, X and Zhang, W and Guo, J and Chang, X and Zhao, R and Wang, J and Pang, X and Zhang, J}, title = {Diagnostic utility of different dysphagia screening tools to detect dysphagia in individuals with amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {11}, pages = {3919-3927}, pmid = {37368071}, issn = {1590-3478}, abstract = {OBJECTIVE: Dysphagia is a common and serious clinical symptom of amyotrophic lateral sclerosis (ALS). The study aimed to evaluate the diagnostic utility of four dysphagia screening tools in ALS, including the ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subscale, water-swallowing test (WST), Eating Assessment Tool-10 (EAT-10) and Sydney Swallow Questionnaire (SSQ).

METHODS: A total of 68 individuals from First Hospital, Shanxi medical university, were recruited in the study. The ALSFRS-R, WST, EAT-10, SSQ and the gold standard video fluoroscopic swallowing study (VFSS) were performed. The Penetration Aspiration Scale (PAS) during VFSS was assessed to identify unsafe swallowing (PAS ≥ 3) and aspiration (PAS ≥ 6). Receiver operator characteristic curve (ROC) analyses were performed to evaluate the accuracy of the 4 tools. Youden index was used to determine the ideal cut-off value for each tool.

RESULTS: Of the patients, 20.59% (14/68) presented unsafety swallowing and 16.18% (11/68) had aspiration. The four tools could effectively identify patients with unsafe swallowing and aspiration. The EAT-10 had the maximum AUC (0.873 and 0.963, respectively) among the tools in the diagnosis of unsafe swallowing and aspiration. To detect unsafe swallowing and aspiration, an EAT-10 score of 6 (sensitivity: 78.6%, specificity: 87.0%) and an EAT-10 score of 8 (sensitivity: 90.9%, specificity: 91.2%), were the most appropriate cut-off points, respectively.

CONCLUSIONS: The ALSFRS-R bulbar subscale, WST, EAT-10, and SSQ could effectively identify unsafe swallowing and aspiration in patients with ALS. Of the four tools, the EAT-10 was relatively accurate, safe, and convenient. Further studies including more patients should be conducted to verify the conclusions.}, } @article {pmid37367854, year = {2023}, author = {Barros, ANAB and Felipe, MLDN and Barbosa, IR and Leite-Lais, L and Pedrosa, LFC}, title = {Dietary Intake of Micronutrients and Disease Severity in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Metabolites}, volume = {13}, number = {6}, pages = {}, pmid = {37367854}, issn = {2218-1989}, support = {001//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; }, abstract = {Vitamins and essential metals have been studied as potential risk and prognostic factors in amyotrophic lateral sclerosis (ALS). This study aimed to evaluate the prevalence of inadequate micronutrient intake in ALS patients, comparing subgroups according to the disease severity. Data were obtained from the medical records of 69 individuals. Assessment of disease severity was determined by the revised ALS Functional Scale (ALSFRS-R), using the median as the cutoff. The prevalence of inadequate micronutrient intake was estimated using the Estimated Average Requirements (EAR) cut-point method. The prevalence of inadequate vitamin D, E, riboflavin, pyridoxine, folate, cobalamin, calcium, zinc, and magnesium intake was considered severe. Patients with lower ALSFRS-R scores had lower intakes of vitamin E (p < 0.001), niacin (p = 0.033), pantothenic acid (p = 0.037), pyridoxin (p = 0.008), folate (p = 0.009) and selenium (p = 0.001). Therefore, ALS patients should be monitored regarding dietary intake of micronutrients essential in neurological processes.}, } @article {pmid37366506, year = {2022}, author = {Erustes, AG and Guarache, GC and Guedes, EDC and Leão, AHFF and Pereira, GJDS and Smaili, SS}, title = {α-Synuclein Interactions in Mitochondria-ER Contacts: A Possible Role in Parkinson's Disease.}, journal = {Contact (Thousand Oaks (Ventura County, Calif.))}, volume = {5}, number = {}, pages = {25152564221119347}, pmid = {37366506}, issn = {2515-2564}, abstract = {Endoplasmic reticulum-mitochondria contact sites regulate various biological processes, such as mitochondrial dynamics, calcium homeostasis, autophagy and lipid metabolism. Notably, dysfunctions in these contact sites are closely related to neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. However, details about the role of endoplasmic reticulum-mitochondria contact sites in neurodegenerative diseases remain unknown. In Parkinson's disease, interactions between α-synuclein in the contact sites and components of tether complexes that connect organelles can lead to various dysfunctions, especially with regards to calcium homeostasis. This review will summarize the main tether complexes present in endoplasmic reticulum-mitochondria contact sites, and their roles in calcium homeostasis and trafficking. We will discuss the impact of α-synuclein accumulation, its interaction with tethering complex components and the implications in Parkinson's disease pathology.}, } @article {pmid37365312, year = {2023}, author = {Li, Y and Dou, X and Liu, J and Xiao, Y and Zhang, Z and Hayes, L and Wu, R and Fu, X and Ye, Y and Yang, B and Ostrow, LW and He, C and Sun, S}, title = {Globally reduced N[6]-methyladenosine (m[6]A) in C9ORF72-ALS/FTD dysregulates RNA metabolism and contributes to neurodegeneration.}, journal = {Nature neuroscience}, volume = {26}, number = {8}, pages = {1328-1338}, pmid = {37365312}, issn = {1546-1726}, support = {RM1 HG008935/HG/NHGRI NIH HHS/United States ; R21 AG072078/AG/NIA NIH HHS/United States ; R01 NS123538/NS/NINDS NIH HHS/United States ; R01 NS107347/NS/NINDS NIH HHS/United States ; R01 ES030546/ES/NIEHS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; K08 NS104273/NS/NINDS NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; Dipeptides/genetics/metabolism ; DNA Repeat Expansion/genetics ; *Frontotemporal Dementia/genetics/metabolism ; RNA ; RNA, Messenger ; }, abstract = {Repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we show that N[6]-methyladenosine (m[6]A), the most prevalent internal mRNA modification, is downregulated in C9ORF72-ALS/FTD patient-derived induced pluripotent stem cell (iPSC)-differentiated neurons and postmortem brain tissues. The global m[6]A hypomethylation leads to transcriptome-wide mRNA stabilization and upregulated gene expression, particularly for genes involved in synaptic activity and neuronal function. Moreover, the m[6]A modification in the C9ORF72 intron sequence upstream of the expanded repeats enhances RNA decay via the nuclear reader YTHDC1, and the antisense RNA repeats can also be regulated through m[6]A modification. The m[6]A reduction increases the accumulation of repeat RNAs and the encoded poly-dipeptides, contributing to disease pathogenesis. We further demonstrate that, by elevating m[6]A methylation, we could significantly reduce repeat RNA levels from both strands and the derived poly-dipeptides, rescue global mRNA homeostasis and improve survival of C9ORF72-ALS/FTD patient iPSC-derived neurons.}, } @article {pmid37364449, year = {2023}, author = {Fan, J and Li, Y and Niu, J and Liu, J and Guan, Y and Cui, L and Liu, M}, title = {The cross-sectional area of peripheral nerve in amyotrophic lateral sclerosis: A case-control study.}, journal = {Clinical neurology and neurosurgery}, volume = {231}, number = {}, pages = {107847}, doi = {10.1016/j.clineuro.2023.107847}, pmid = {37364449}, issn = {1872-6968}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Case-Control Studies ; Peripheral Nerves/diagnostic imaging ; Median Nerve/diagnostic imaging ; Spinal Nerve Roots ; }, abstract = {OBJECTIVE: A growing body of literature recognises the importance of peripheral nerve ultrasound in neuromuscular disorders. Several attempts have been made to differentiate amyotrophic lateral sclerosis (ALS) from multifocal motor neuropathy (MMN) using peripheral nerve ultrasound. A much-debated question is whether the cross-sectional area (CSA) of peripheral nerve in ALS patients is significantly smaller compared to healthy controls. This study aims to determine the CSA of peripheral nerves in patients with ALS.

METHODS: One hundred and thirty-nine patients with ALS and 75 healthy controls were recruited. Ultrasound of the median, ulnar, and trunks of the brachial plexus and cervical nerve roots was undertaken in ALS patients and controls.

RESULTS: Compared to controls, ALS patients had mild reductions of the median nerve, most sites of the ulnar nerve, trunks of the brachial plexus and cervical nerve roots. Another important finding of this study is that the median nerve tends to have a more significant reduction than the ulnar nerve in ALS patients, especially at the proximal.

CONCLUSIONS: Ultrasound could be sensitive to nerve motor fibre loss in patients with ALS. CSA at the proximal Median nerve may be a promising biomarker in patients with ALS.}, } @article {pmid37363576, year = {2023}, author = {Aderinto, N and Muili AbdulBasit, O and Afolayan, O and Jolayemi, MM}, title = {Current status and future directions of amyotrophic lateral sclerosis research in Africa: a perspective.}, journal = {Annals of medicine and surgery (2012)}, volume = {85}, number = {6}, pages = {3204-3208}, pmid = {37363576}, issn = {2049-0801}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with a global burden. Despite significant strides in ALS research, challenges facing ALS research in Africa are substantial. This paper discusses the current status and future directions of ALS research in Africa. Challenges and opportunities for ALS research in the region are highlighted, including limited funding and resources, the need for collaboration, and capacity building. Emerging technologies in ALS research in Africa are described, including telemedicine, neuroimaging, and genetic studies. Priorities for future ALS research in Africa are identified, including epidemiological studies, developing culturally appropriate diagnostic and management tools, and clinical trials of emerging treatments. Addressing these priorities will be critical to advancing ALS research and improving patient outcomes in Africa.}, } @article {pmid37363428, year = {2022}, author = {Sienes Bailo, P and Llorente Martín, E and Calmarza, P and Montolio Breva, S and Bravo Gómez, A and Pozo Giráldez, A and Sánchez-Pascuala Callau, JJ and Vaquer Santamaría, JM and Dayaldasani Khialani, A and Cerdá Micó, C and Camps Andreu, J and Sáez Tormo, G and Fort Gallifa, I}, title = {The role of oxidative stress in neurodegenerative diseases and potential antioxidant therapies.}, journal = {Advances in laboratory medicine}, volume = {3}, number = {4}, pages = {342-360}, pmid = {37363428}, issn = {2628-491X}, abstract = {OBJECTIVES: The central nervous system (CNS) is essential for homeostasis and controls the physiological functions of the body. However, the biochemical characteristics of the CNS make it especially vulnerable to oxidative damage (OS). This phenomenon compromises correct CNS functioning, leading to neurodegeneration and neuronal death.

CONTENTS: OS plays a crucial role in the physiopathology of neurodegenerative diseases. It is involved in multiple mechanisms of nucleic acid, protein, and lipid oxidation, thereby contributing to progressive brain damage. These mechanisms include mitochondrial dysfunction; excessive production of reactive oxygen and nitrogen species; deficiency of antioxidant defenses; protein oligomerization; cytokine production and inflammatory response; blood-brain barrier abnormalities; and proteasome dysfunction. All these dysfunctions are involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, or amyotrophic lateral sclerosis.

SUMMARY AND OUTLOOK: A curative treatment is currently not available. Research is focused on the search for therapies that reduce oxidative damage and delay disease progression. In the recent years, researchers have focused their attention on the effects of antioxidant therapies.}, } @article {pmid37360345, year = {2023}, author = {Iijima, K and Watanabe, H and Nakashiro, Y and Iida, Y and Nonaka, M and Moriwaka, F and Hamada, S}, title = {Long-term effects of the gait treatment using a wearable cyborg hybrid assistive limb in a patient with spinal and bulbar muscular atrophy: a case report with 5 years of follow-up.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1143820}, pmid = {37360345}, issn = {1664-2295}, abstract = {BACKGROUND: Spinal and bulbar muscular atrophy (SBMA) is a progressive neuromuscular degenerative disease characterized by the degeneration of lower motor neurons in the spinal cord and brainstem and neurogenic atrophy of the skeletal muscle. Although the short-term effectiveness of gait treatment using a wearable cyborg hybrid assistive limb (HAL) has been demonstrated for the rehabilitation of patients with SBMA, the long-term effects of this treatment are unclear. Thus, this study aimed to investigate the long-term effects of the continued gait treatment with HAL in a patient with SBMA.

RESULTS: A 68-year-old man with SBMA had lower limb muscle weakness and atrophy, gait asymmetry, and decreased walking endurance. The patient performed nine courses of HAL gait treatment (as one course three times per week for 3 weeks, totaling nine times) for ~5 years. The patient performed HAL gait treatment to improve gait symmetry and endurance. A physical therapist adjusted HAL based on the gait analysis and physical function of the patient. Outcome measurements, such as 2-min walking distance (2MWD), 10-meter walking test (maximal walking speed, step length, cadence, and gait symmetry), muscle strength, Revised Amyotrophic Lateral Sclerosis Functional Assessment Scale (ALSFRS-R), and patient-reported outcomes, were evaluated immediately before and after gait treatment with HAL for each course. 2MWD improved from 94 m to 101.8 m, and the ALSFRS-R gait items remained unchanged (score 3) for approximately 5 years. The patient could maintain walking ability in terms of gait symmetry, walking endurance, and independence walking despite disease progression during HAL treatment.

CONCLUSION: The long-term gait treatment with HAL in a patient with SBMA may contribute to the maintenance and improvement of the gait endurance and ability to perform activities of daily living. The cybernics treatment using HAL may enable patients to relearn correct gait movements. The gait analysis and physical function assessment by a physical therapist might be important to maximize the benefits of HAL treatment.}, } @article {pmid37360176, year = {2023}, author = {Borg, R and Herrera, P and Purkiss, A and Cacciottolo, R and Cauchi, RJ}, title = {Reduced levels of ALS gene DCTN1 induce motor defects in Drosophila.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1164251}, pmid = {37360176}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neuromuscular disease that has a strong genetic component. Deleterious variants in the DCTN1 gene are known to be a cause of ALS in diverse populations. DCTN1 encodes the p150 subunit of the molecular motor dynactin which is a key player in the bidirectional transport of cargos within cells. Whether DCTN1 mutations lead to the disease through either a gain or loss of function mechanism remains unresolved. Moreover, the contribution of non-neuronal cell types, especially muscle tissue, to ALS phenotypes in DCTN1 carriers is unknown. Here we show that gene silencing of Dctn1, the Drosophila main orthologue of DCTN1, either in neurons or muscles is sufficient to cause climbing and flight defects in adult flies. We also identify Dred, a protein with high homology to Drosophila Dctn1 and human DCTN1, that on loss of function also leads to motoric impairments. A global reduction of Dctn1 induced a significant reduction in the mobility of larvae and neuromuscular junction (NMJ) deficits prior to death at the pupal stage. RNA-seq and transcriptome profiling revealed splicing alterations in genes required for synapse organisation and function, which may explain the observed motor dysfunction and synaptic defects downstream of Dctn1 ablation. Our findings support the possibility that loss of DCTN1 function can lead to ALS and underscore an important requirement for DCTN1 in muscle in addition to neurons.}, } @article {pmid37358634, year = {2023}, author = {Dubbioso, R and Provitera, V and Pacella, D and Santoro, L and Manganelli, F and Nolano, M}, title = {Autonomic dysfunction is associated with disease progression and survival in amyotrophic lateral sclerosis: a prospective longitudinal cohort study.}, journal = {Journal of neurology}, volume = {270}, number = {10}, pages = {4968-4977}, pmid = {37358634}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Longitudinal Studies ; Prospective Studies ; Disease Progression ; *Primary Dysautonomias ; }, abstract = {BACKGROUND: Among non-motor symptoms, autonomic disturbances have been described in amyotrophic lateral sclerosis (ALS) and reported as mild to moderate in up to 75% of patients. However, no study has systematically investigated autonomic symptoms as prognostic factors.

OBJECTIVES: The main aim of this longitudinal study was to examine the association of autonomic dysfunction with disease progression and survival in ALS.

METHODS: We enrolled newly diagnosed ALS patients and a healthy control group (HC). Time from disease onset to disease milestone (King's stage 4) and death were calculated to assess disease progression and survival. Autonomic symptoms were assessed by a dedicated questionnaire. Longitudinal evaluation of parasympathetic cardiovascular activity was performed by the heart rate variability (HRV). Multivariable Cox proportional hazards regression models on the risk of the disease milestone and death were used. A mixed-effect linear regression model was used to compare autonomic dysfunction with a HC group as well as its impairment over time.

RESULTS: A total of 102 patients and 41 HC were studied. ALS patients, compared with HC, complained of more autonomic symptoms, especially in bulbar onset patients. Autonomic symptoms occurred in 69 (68%) patients at diagnosis and progressed over time (post-6: p = 0.015 and post-12: p < 0.001). A higher autonomic symptom burden was an independent marker of faster development of King's stage 4 (HR 1.05; 95% CI 1.00-1.11; p = 0.022); whereas, urinary complaints were independent factors of a shorter survival (HR 3.12; 95% CI 1.22-7.97; p = 0.018). Moreover, HRV in ALS patients was lower than in HC (p = 0.018) and further decreased over time (p = 0.003), implying a parasympathetic hypofunction that progressed over time.

CONCLUSION: Autonomic symptoms occur in most of the ALS patients at diagnosis and progress over time, implying that autonomic dysfunction represents an intrinsic non-motor feature of the disease. A higher autonomic burden is a poor prognostic factor, associated with a more rapid development of disease milestones and shorter survival.}, } @article {pmid37358003, year = {2024}, author = {Canever, JB and Queiroz, LY and Soares, ES and de Avelar, NCP and Cimarosti, HI}, title = {Circadian rhythm alterations affecting the pathology of neurodegenerative diseases.}, journal = {Journal of neurochemistry}, volume = {168}, number = {8}, pages = {1475-1489}, doi = {10.1111/jnc.15883}, pmid = {37358003}, issn = {1471-4159}, support = {//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology/pathology/metabolism ; *Circadian Rhythm/physiology ; Animals ; }, abstract = {The circadian rhythm is a nearly 24-h oscillation found in various physiological processes in the human brain and body that is regulated by environmental and genetic factors. It is responsible for maintaining body homeostasis and it is critical for essential functions, such as metabolic regulation and memory consolidation. Dysregulation in the circadian rhythm can negatively impact human health, resulting in cardiovascular and metabolic diseases, psychiatric disorders, and premature death. Emerging evidence points to a relationship between the dysregulation circadian rhythm and neurodegenerative diseases, suggesting that the alterations in circadian function might play crucial roles in the pathogenesis and progression of neurodegenerative diseases. Better understanding this association is of paramount importance to expand the knowledge on the pathophysiology of neurodegenerative diseases, as well as, to provide potential targets for the development of new interventions based on the dysregulation of circadian rhythm. Here we review the latest findings on dysregulation of circadian rhythm alterations in Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, spinocerebellar ataxia and multiple-system atrophy, focusing on research published in the last 3 years.}, } @article {pmid37356043, year = {2023}, author = {Nguyen, QT and Thanh, LN and Hoang, VT and Phan, TTK and Heke, M and Hoang, DM}, title = {Bone Marrow-Derived Mononuclear Cells in the Treatment of Neurological Diseases: Knowns and Unknowns.}, journal = {Cellular and molecular neurobiology}, volume = {43}, number = {7}, pages = {3211-3250}, pmid = {37356043}, issn = {1573-6830}, mesh = {Humans ; *Autism Spectrum Disorder ; Bone Marrow ; *Stroke/therapy ; Bone Marrow Cells ; }, abstract = {Bone marrow-derived mononuclear cells (BMMNCs) have been used for decades in preclinical and clinical studies to treat various neurological diseases. However, there is still a knowledge gap in the understanding of the underlying mechanisms of BMMNCs in the treatment of neurological diseases. In addition, prerequisite factors for the efficacy of BMMNC administration, such as the optimal route, dose, and number of administrations, remain unclear. In this review, we discuss known and unknown aspects of BMMNCs, including the cell harvesting, administration route and dose; mechanisms of action; and their applications in neurological diseases, including stroke, cerebral palsy, spinal cord injury, traumatic brain injury, amyotrophic lateral sclerosis, autism spectrum disorder, and epilepsy. Furthermore, recommendations on indications for BMMNC administration and the advantages and limitations of BMMNC applications for neurological diseases are discussed. BMMNCs in the treatment of neurological diseases. BMMNCs have been applied in several neurological diseases. Proposed mechanisms for the action of BMMNCs include homing, differentiation and paracrine effects (angiogenesis, neuroprotection, and anti-inflammation). Further studies should be performed to determine the optimal cell dose and administration route, the roles of BMMNC subtypes, and the indications for the use of BMMNCs in neurological conditions with and without genetic abnormalities.}, } @article {pmid37356024, year = {2023}, author = {Heinrich, F and Cordts, I and Günther, R and Stolte, B and Zeller, D and Schröter, C and Weyen, U and Regensburger, M and Wolf, J and Schneider, I and Hermann, A and Metelmann, M and Kohl, Z and Linker, RA and Koch, JC and Radelfahr, F and Schönfelder, E and Gardt, P and Mohajer-Peseschkian, T and Osmanovic, A and Klopstock, T and Dorst, J and Ludolph, AC and Schöffski, O and Boentert, M and Hagenacker, T and Deschauer, M and Lingor, P and Petri, S and Schreiber-Katz, O}, title = {Economic evaluation of Motor Neuron Diseases: a nationwide cross-sectional analysis in Germany.}, journal = {Journal of neurology}, volume = {270}, number = {10}, pages = {4922-4938}, pmid = {37356024}, issn = {1432-1459}, mesh = {Humans ; Quality of Life ; Cost of Illness ; Cross-Sectional Studies ; *Amyotrophic Lateral Sclerosis ; Cost-Benefit Analysis ; Surveys and Questionnaires ; Health Care Costs ; Germany/epidemiology ; *Muscular Atrophy, Spinal ; }, abstract = {BACKGROUND AND OBJECTIVES: Motor Neuron Diseases (MND) are rare diseases but have a high impact on affected individuals and society. This study aims to perform an economic evaluation of MND in Germany.

METHODS: Primary patient-reported data were collected including individual impairment, the use of medical and non-medical resources, and self-rated Health-Related Quality of Life (HRQoL). Annual socio-economic costs per year as well as Quality-Adjusted Life Years (QALYs) were calculated.

RESULTS: 404 patients with a diagnosis of Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA) or Hereditary Spastic Paraplegia (HSP) were enrolled. Total annual costs per patient were estimated at 83,060€ in ALS, 206,856€ in SMA and 27,074€ in HSP. The main cost drivers were informal care (all MND) and disease-modifying treatments (SMA). Self-reported HRQoL was best in patients with HSP (mean EuroQoL Five Dimension Five Level (EQ-5D-5L) index value 0.67) and lowest in SMA patients (mean EQ-5D-5L index value 0.39). QALYs for patients with ALS were estimated to be 1.89 QALYs, 23.08 for patients with HSP and 14.97 for patients with SMA, respectively. Cost-utilities were estimated as follows: 138,960€/QALY for ALS, 525,033€/QALY for SMA, and 49,573€/QALY for HSP. The main predictors of the high cost of illness and low HRQoL were disease progression and loss of individual autonomy.

CONCLUSION: As loss of individual autonomy was the main cost predictor, therapeutic and supportive measures to maintain this autonomy may contribute to reducing high personal burden and also long-term costs, e.g., care dependency and absenteeism from work.}, } @article {pmid37355220, year = {2023}, author = {Balog, BM and Sonti, A and Zigmond, RE}, title = {Neutrophil biology in injuries and diseases of the central and peripheral nervous systems.}, journal = {Progress in neurobiology}, volume = {228}, number = {}, pages = {102488}, pmid = {37355220}, issn = {1873-5118}, support = {F32 NS122918/NS/NINDS NIH HHS/United States ; R01 NS114891/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Neutrophils ; *Axons/physiology ; Nerve Regeneration/physiology ; Peripheral Nervous System ; Biology ; }, abstract = {The role of inflammation in nervous system injury and disease is attracting increased attention. Much of that research has focused on microglia in the central nervous system (CNS) and macrophages in the peripheral nervous system (PNS). Much less attention has been paid to the roles played by neutrophils. Neutrophils are part of the granulocyte subtype of myeloid cells. These cells, like macrophages, originate and differentiate in the bone marrow from which they enter the circulation. After tissue damage or infection, neutrophils are the first immune cells to infiltrate into tissues and are directed there by specific chemokines, which act on chemokine receptors on neutrophils. We have reviewed here the basic biology of these cells, including their differentiation, the types of granules they contain, the chemokines that act on them, the subpopulations of neutrophils that exist, and their functions. We also discuss tools available for identification and further study of neutrophils. We then turn to a review of what is known about the role of neutrophils in CNS and PNS diseases and injury, including stroke, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinal cord and traumatic brain injuries, CNS and PNS axon regeneration, and neuropathic pain. While in the past studies have focused on neutrophils deleterious effects, we will highlight new findings about their benefits. Studies on their actions should lead to identification of ways to modify neutrophil effects to improve health.}, } @article {pmid37354387, year = {2023}, author = {Garbuzova-Davis, S and Borlongan, CV}, title = {Transplanted Human Bone Marrow Endothelial Progenitor Cells Prolong Functional Benefits and Extend Survival of ALS Mice Likely via Blood-Spinal Cord Barrier Repair.}, journal = {Stem cell reviews and reports}, volume = {19}, number = {7}, pages = {2284-2291}, pmid = {37354387}, issn = {2629-3277}, support = {1R01NS090962/NH/NIH HHS/United States ; 1R01NS090962/NH/NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial disease with one of these factors being an impaired blood-spinal cord barrier (BSCB). In order to block harmful components in systemic circulation from accessing the CNS, barrier damage needs alleviation. Recently, we found that symptomatic ALS animals treated with intravenously delivered human bone marrow-derived CD34+ (hBM34+) cells or endothelial progenitor cells (hBMEPCs) showed delayed disease progression for 4 weeks post-transplant via BSCB repair. However, despite noted benefits from transplanted human bone marrow-derived stem cells, long-term effects of transplanted cells in ALS mice remain undetermined. This study aimed to determine prolonged effects of single equal doses of hBM34[+] cells and hBMEPCs systemically transplanted into symptomatic G93A SOD1 mice on behavioral disease outcomes and mouse lifespan. Results showed that transplanted hBMEPCs better ameliorated disease behavioral outcomes than hBM34 + cells until near end-stage disease and significantly increased lifespan vs. media-treated mice. These results provide important evidence that transplanted hBMEPCs prolonged functional benefits and extended survival of ALS mice, potentially by repairing the damaged BSCB. However, due to modestly increased lifespan of hBMEPC-treated mice, repeated cell transplants into symptomatic ALS mice may more effectively delay motor function deficit and extend lifespan by continuous reparative processes via replacement of damaged endothelial cells during disease progression.}, } @article {pmid37354059, year = {2023}, author = {Stikvoort García, DJL and Sleutjes, BTHM and van Schelven, LJ and Goedee, HS and van den Berg, LH}, title = {Diagnostic accuracy of nerve excitability and compound muscle action potential scan derived biomarkers in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {30}, number = {10}, pages = {3068-3078}, doi = {10.1111/ene.15954}, pmid = {37354059}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Action Potentials/physiology ; *Motor Neuron Disease ; Muscle, Skeletal ; Gold ; }, abstract = {BACKGROUND AND PURPOSE: The lack of reliable early biomarkers still causes substantial diagnostic delays in amyotrophic lateral sclerosis (ALS). The aim was to assess the diagnostic accuracy of a novel electrophysiological protocol in patients with suspected motor neuron disease (MND).

METHODS: Consecutive patients with suspected MND were prospectively recruited at our tertiary referral centre for MND in Utrecht, The Netherlands. Procedures were performed in accordance with the Standards for Reporting of Diagnostic Accuracy. In addition to the standard diagnostic workup, an electrophysiological protocol of compound muscle action potential (CMAP) scans and nerve excitability tests was performed on patients' thenar muscles. The combined diagnostic yield of nerve excitability and CMAP scan based motor unit number estimation was compared to the Awaji and Gold Coast criteria and their added value was determined.

RESULTS: In all, 153 ALS or progressive muscular atrophy patients, 63 disease controls and 43 healthy controls were included. Our electrophysiological protocol had high diagnostic accuracy (area under the curve [AUC] 0.85, 95% confidence interval [95% CI] 0.80-0.90), even in muscles with undetectable axon loss (AUC 0.78, 95% CI 0.70-0.85) and in bulbar-onset patients (AUC 0.85, 95% CI 0.73-0.95). Twenty-four of 33 (73%) ALS patients who could not be diagnosed during the same visit were correctly identified, as well as 8/13 (62%) ALS patients not meeting the Gold Coast criteria and 49/59 (83%) ALS patients not meeting the Awaji criteria during this first visit.

CONCLUSIONS: Our practical and non-invasive electrophysiological protocol may improve early diagnosis in clinically challenging patients with suspected ALS. Routine incorporation may boost early diagnosis, enhance patient selection and generate baseline measures for clinical trials.}, } @article {pmid37353279, year = {2023}, author = {van Eenennaam, RM and Kruithof, W and Beelen, A and Bakker, LA and van Eijk, RPA and Maessen, M and Baardman, JF and Visser-Meily, JMA and Veldink, JH and van den Berg, LH}, title = {Frequency of euthanasia, factors associated with end-of-life practices, and quality of end-of-life care in patients with amyotrophic lateral sclerosis in the Netherlands: a population-based cohort study.}, journal = {The Lancet. Neurology}, volume = {22}, number = {7}, pages = {591-601}, doi = {10.1016/S1474-4422(23)00155-2}, pmid = {37353279}, issn = {1474-4465}, mesh = {Male ; Female ; Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Netherlands/epidemiology ; Cohort Studies ; Quality of Life ; *Neurodegenerative Diseases/complications ; *Terminal Care ; *Suicide, Assisted ; Death ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis is a progressive and lethal neurodegenerative disease that is at the forefront of debates on regulation of assisted dying. Since 2002, when euthanasia was legally regulated in the Netherlands, the frequency of this end-of-life practice has increased substantially from 1·7% of all deaths in 1990 and 2005 to 4·5% in 2015. We aimed to investigate whether the frequency of euthanasia in patients with amyotrophic lateral sclerosis had similarly increased since 2002, and to assess the factors associated with end-of-life practices and the quality of end-of-life care in patients with this disease.

METHODS: Using data from the Netherlands ALS registry, we did a population-based cohort study of clinicians and informal caregivers of patients with amyotrophic lateral sclerosis to assess factors associated with end-of-life decision making and the quality of end-of-life care. We included individuals who were diagnosed with amyotrophic lateral sclerosis according to the revised El-Escorial criteria, and who died between Jan 1, 2014, and Dec 31, 2016. We calculated the frequency of euthanasia in patients with amyotrophic lateral sclerosis from reports made to euthanasia review committees (ERCs) between 2012 and 2020. Results were compared with clinic-based survey studies conducted in 1994-2005. End-of-life practices were end-of-life decisions by a clinician when hastening of death was considered as the potential, probable, or definite effect comprising euthanasia, physician-assisted suicide, ending of life without explicit request, forgoing life-prolonging treatment, and intensified alleviation of symptoms.

FINDINGS: Between Jan 1, 2012, and Dec 31, 2020, 4130 reports of death from amyotrophic lateral sclerosis were made to ERCs, of which 1014 were from euthanasia or physician-assisted suicide (mean frequency 25% [SD 3] per year). Sex and gender data were unavailable from the ERC registry. Of 884 patients with amyotrophic lateral sclerosis who died between Jan 1, 2014, and Dec 31, 2016, their treating clinician was identified for 731 and a caregiver was identified for 741, of whom 356 (49%) and 450 (61%), respectively, agreed to participate in the population-based survey study. According to clinicians, end-of-life practices were chosen by 280 (79%) of 356 patients with amyotrophic lateral sclerosis who died. The frequency of euthanasia in patients with amyotrophic lateral sclerosis in 2014-16 (141 [40%] of 356 deaths in patients with amyotrophic lateral sclerosis) was higher than in 1994-98 (35 [17%] of 203) and 2000-05 (33 [16%] of 209). Median survival of patients with amyotrophic lateral sclerosis from diagnosis was 15·9 months (95% CI 12·6-17·6) for those who chose euthanasia and 16·1 months (13·4-19·1) for those who did not choose euthanasia (hazard ratio 1·07, 95% CI 0·85-1·34; p=0·58). According to caregivers, compared with other end-of-life practices, patients with amyotrophic lateral sclerosis choosing euthanasia commonly reported reasons to hasten death as no chance of improvement (53 [56%] of 94 patients who chose euthanasia vs 28 [39%] of 72 patients who chose other end-of-life practices), loss of dignity (47 [50%] vs 15 [21%]), dependency (34 [36%] vs five [7%]), and fatigue or extreme weakness (41 [44%] vs 14 [20%]). According to caregivers, people with amyotrophic lateral sclerosis-whether they chose euthanasia or did not-were satisfied with the general quality (83 [93%] of 89 patients who chose euthanasia vs 73 [86%] of 85 patients who did not) and availability (85 [97%] of 88 vs 81 [91%] of 90) of end-of-life care.

INTERPRETATION: The proportion of patients with amyotrophic lateral sclerosis who chose euthanasia in the Netherlands has increased since 2002. The choice of euthanasia was not associated with disease or patient characteristics, depression or hopelessness, or the availability or quality of end-of-life care. The choice of euthanasia had no effect on overall survival. Future studies could focus on the effect of discussing end-of-life options on quality of life as part of multidisciplinary care throughout the course of the disease, to reduce feelings of loss of autonomy and dignity in patients living with amyotrophic lateral sclerosis.

FUNDING: Netherlands ALS Foundation.}, } @article {pmid37353271, year = {2023}, author = {Hardiman, O}, title = {End-of-life decision making in amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {22}, number = {7}, pages = {547-548}, doi = {10.1016/S1474-4422(23)00193-X}, pmid = {37353271}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Death ; Quality of Life ; Decision Making ; }, } @article {pmid37352984, year = {2023}, author = {Yang, B and Pan, J and Zhang, XN and Wang, H and He, L and Rong, X and Li, X and Peng, Y}, title = {NRF2 activation suppresses motor neuron ferroptosis induced by the SOD1[G93A] mutation and exerts neuroprotection in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {184}, number = {}, pages = {106210}, doi = {10.1016/j.nbd.2023.106210}, pmid = {37352984}, issn = {1095-953X}, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism ; Disease Models, Animal ; *Ferroptosis ; Mice, Transgenic ; Motor Neurons/metabolism ; Mutation/genetics ; *Neurodegenerative Diseases/metabolism ; Neuroprotection ; NF-E2-Related Factor 2/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {The progressive neurodegenerative disease amyotrophic lateral sclerosis (ALS) is caused by a decline in motor neuron function, resulting in worsened motor impairments, malnutrition, respiratory failure and mortality, and there is a lack of effective clinical treatments. The exact mechanism of motor neuronal degeneration remains unclear. Previously, we reported that ferroptosis, which is characterized by the accumulation of lipid peroxide and glutathione depletion in an iron-dependent manner, contributed to motor neuronal death in ALS cell models with the hSOD1[G93A] (human Cu/Zn-superoxide dismutase) gene mutation. In this study, we further explored the role of ferroptosis in motor neurons and its regulation in mutant hSOD1[G93A] cell and mouse models. Our results showed that ferroptosis was activated in hSOD1[G93A] NSC-34 cells and mouse models, which was accompanied by decreased nuclear retention of nuclear factor erythroid 2-related factor 2 (NRF2) and downregulation of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) levels. Moreover, RTA-408, an NRF2 activator, inhibited ferroptosis in hSOD1[G93A] NSC-34 cells by upregulating the protein expression of SLC7A11 and GPX4. Moreover, hSOD1[G93A] mice treated with RTA-408 showed obvious improvements in body weight and motor function. Our study demonstrated that ferroptosis contributed to the toxicity of motor neurons and that activating NRF2 could alleviate neuronal degeneration in ALS with the hSOD1[G93A] mutation.}, } @article {pmid37352136, year = {2023}, author = {Fukushi, M and Ohsawa, R and Okinaka, Y and Oikawa, D and Kiyono, T and Moriwaki, M and Irie, T and Oda, K and Kamei, Y and Tokunaga, F and Sotomaru, Y and Maruyama, H and Kawakami, H and Sakaguchi, T}, title = {Optineurin deficiency impairs autophagy to cause interferon beta overproduction and increased survival of mice following viral infection.}, journal = {PloS one}, volume = {18}, number = {6}, pages = {e0287545}, pmid = {37352136}, issn = {1932-6203}, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; Autophagy/genetics ; *Cell Cycle Proteins/genetics ; Immunity, Innate ; Interferon-beta/genetics ; Transcription Factor TFIIIA/genetics/metabolism ; *Virus Diseases ; *Membrane Transport Proteins/genetics ; Mice, Knockout ; }, abstract = {BACKGROUND: Optineurin (OPTN) is associated with several human diseases, including amyotrophic lateral sclerosis (ALS), and is involved in various cellular processes, including autophagy. Optineurin regulates the expression of interferon beta (IFNβ), which plays a central role in the innate immune response to viral infection. However, the role of optineurin in response to viral infection has not been fully clarified. It is known that optineurin-deficient cells produce more IFNβ than wild-type cells following viral infection. In this study, we investigate the reasons for, and effects of, IFNβ overproduction during optineurin deficiency both in vitro and in vivo.

METHODS: To investigate the mechanism of IFNβ overproduction, viral nucleic acids in infected cells were quantified by RT-qPCR and the autophagic activity of optineurin-deficient cells was determined to understand the basis for the intracellular accumulation of viral nucleic acids. Moreover, viral infection experiments using optineurin-disrupted (Optn-KO) animals were performed with several viruses.

RESULTS: IFNβ overproduction following viral infection was observed not only in several types of optineurin-deficient cell lines but also in Optn-KO mice and human ALS patient cells carrying mutations in OPTN. IFNβ overproduction in Optn-KO cells was revealed to be caused by excessive accumulation of viral nucleic acids, which was a consequence of reduced autophagic activity caused by the loss of optineurin. Additionally, IFNβ overproduction in Optn-KO mice suppressed viral proliferation, resulting in increased mouse survival following viral challenge.

CONCLUSION: Our findings indicate that the combination of optineurin deficiency and viral infection leads to IFNβ overproduction in vitro and in vivo. The effects of optineurin deficiency are elicited by viral infection, therefore, viral infection may be implicated in the development of optineurin-related diseases.}, } @article {pmid37351379, year = {2023}, author = {, }, title = {Erratum: Autophagy and neurodegeneration: unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1225439}, doi = {10.3389/fncel.2023.1225439}, pmid = {37351379}, issn = {1662-5102}, abstract = {[This corrects the article DOI: 10.3389/fncel.2023.1086895.].}, } @article {pmid37351305, year = {2023}, author = {Lins, J and Brock, TJ and Hopkins, CE and Hart, AC}, title = {Generation of a C. elegans tdp-1 null allele and humanized TARDBP containing human disease-variants.}, journal = {microPublication biology}, volume = {2023}, number = {}, pages = {}, pmid = {37351305}, issn = {2578-9430}, support = {R43 AG061978/AG/NIA NIH HHS/United States ; }, abstract = {Clinical variants of TARDBP are associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and other degenerative diseases. The predicted C. elegans ortholog of TARDBP is encoded by tdp-1 , but functional orthology has not been demonstrated in vivo. We undertook CRISPR/Cas9-based genome editing of the tdp-1 locus to create a complete loss of function allele; all tdp-1 exons and introns were deleted, creating tdp-1(tgx58) , which resulted in neurodegeneration after oxidative stress. Next, we undertook CRISPR-based genome editing to replace tdp-1 exons with human TARDBP coding sequences, creating humanized (hTARDBP) C. elegans expressing TDP-43 . Based on the efficiency of this genome editing, we suggest that iterative genome editing of the tdp-1 target locus using linked coCRISPR markers, like dpy-10 , would be a more efficient strategy for sequential assembly of the large engineered transgenes. hTARDBP decreased the neurodegeneration defect of tdp-1(tgx58) , demonstrating functional cross-species orthology. To develop C. elegans models of FTD and ALS, we inserted five different patient TARDBP variants in the C. elegans hTARDBP locus. Only one clinical variant increased stress-induced neurodegeneration; other variants caused inconsistent or negligible defects under these conditions. Combined, this work yielded an unambiguous null allele for tdp-1 , a validated, humanized hTARDBP, and multiple ALS/FTD patient-associated variant models that can be used for future studies.}, } @article {pmid37350671, year = {2023}, author = {Kalnmals, CA and Benko, ZL and Hamza, A and Bravo-Altamirano, K and Siddall, TL and Zielinski, M and Takano, HK and Riar, DS and Satchivi, NM and Roth, JJ and Church, JB}, title = {A New Class of Diaryl Ether Herbicides: Structure-Activity Relationship Studies Enabled by a Rapid Scaffold Hopping Approach.}, journal = {Journal of agricultural and food chemistry}, volume = {71}, number = {47}, pages = {18171-18187}, doi = {10.1021/acs.jafc.3c01285}, pmid = {37350671}, issn = {1520-5118}, mesh = {*Herbicides/pharmacology ; Ether ; Structure-Activity Relationship ; Ethers/pharmacology ; Plant Weeds/metabolism ; Ethyl Ethers ; *Acetolactate Synthase/metabolism ; Herbicide Resistance ; }, abstract = {We report on the development of a novel class of diaryl ether herbicides. After the discovery of a phenoxybenzoic acid with modest herbicidal activity, optimization led to several molecules with improved control of broadleaf and grass weeds. To facilitate this process, we first employed a three-step combinatorial approach, then pivoted to a one-step Ullmann-type coupling that provided faster access to new analogs. After determining that the primary target site of our benchmark diaryl ethers was acetolactate synthase (ALS), we further leveraged this copper-catalyzed methodology to conduct a scaffold hopping campaign in the hope of uncovering an additional mode of action with fewer documented cases of resistance. Our comprehensive and systematic investigation revealed that while the herbicidal activity of this area seems to be exclusively linked to ALS inhibition, our molecules represent a structurally distinct class of Group 2 herbicides. The structure-activity relationships that led us to this conclusion are described herein.}, } @article {pmid37350306, year = {2023}, author = {Zhou, J and Zeng, Q and Liao, Q and Niu, Q and Gu, W and Su, D and Li, S and Xiao, B and Bi, F}, title = {Biomarkers in cerebrospinal fluid for amyotrophic lateral sclerosis phenotypes.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {8}, pages = {1467-1480}, pmid = {37350306}, issn = {2328-9503}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/cerebrospinal fluid ; Proteomics ; HLA-DR alpha-Chains ; *Neurodegenerative Diseases ; Biomarkers/cerebrospinal fluid ; Phenotype ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper and lower motor neurons. The motor phenotypes of ALS are highly clinically heterogeneous, and the underlying mechanisms are poorly understood.

METHODS: A comparative proteomic analysis was performed in the cerebrospinal fluid (CSF) of bulbar-onset (BO) and spinal-onset (SO) ALS patients and controls (n = 14). Five biomarker candidates were selected from a differentially regulated protein pool, and further validation was performed in a larger independent cohort (n = 92) using enzyme-linked immunosorbent assay (ELISA).

RESULTS: A total of 1732 CSF proteins were identified, and 78 differentially expressed proteins were found among BO-ALS patients, SO-ALS patients, and controls. Five promising biomarker candidates were selected for further validation, and lipopolysaccharide-binding protein (LBP) and HLA class II histocompatibility antigen, DR alpha chain (HLA-DRA) were validated. CSF LBP levels were increased in ALS patients compared with controls and higher in BO-ALS versus SO-ALS. The increased CSF LBP levels were correlated with the revised ALS Functional Scale (ALSFRS-R) score. CSF HLA-DRA levels were specifically elevated in BO-ALS patients, and there was no significant difference between SO-ALS patients and controls. Increased HLA-DRA expression was correlated with decreased survival.

INTERPRETATION: Our data shows that elevated CSF LBP is a good biomarker for ALS and correlates with clinical severity, and increased HLA-DRA is a specific biomarker for BO-ALS and may predict short survival. It also suggests that the microglial pathway and HLA-II-related adaptive immunity may be differentially involved in ALS phenotypes and may be new therapeutic targets for ALS.}, } @article {pmid37349911, year = {2023}, author = {Trojsi, F and Di Nardo, F and D'Alvano, G and Passaniti, C and Sharbafshaaer, M and Canale, F and Russo, A and Silvestro, M and Lavorgna, L and Cirillo, M and Esposito, F and Tedeschi, G and Siciliano, M}, title = {Cognitive, behavioral, and brain functional connectivity correlates of fatigue in amyotrophic lateral sclerosis.}, journal = {Brain and behavior}, volume = {13}, number = {7}, pages = {e2931}, pmid = {37349911}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging ; *Persons with Disabilities ; *Motor Disorders ; Brain ; Magnetic Resonance Imaging/methods ; Mental Fatigue/diagnostic imaging/etiology ; Cognition ; }, abstract = {INTRODUCTION: Fatigue is defined as a symptom of exhaustion unexplained by drug effects or psychiatric disorders and comprises two main components (i.e., central or "mental" and peripheral or "physical" components), both influencing global disability in amyotrophic lateral sclerosis (ALS). We aim at investigating the clinical correlations between "physical" and "mental" components of fatigue, measured by the Multidimensional Fatigue Inventory scale, and motor and cognitive/behavioral disability in a large sample of patients with ALS. We also investigated the correlations between these measures of fatigue and resting-state functional connectivity of brain functional magnetic resonance imaging (RS-fMRI) large-scale networks in a subset of patients.

METHODS: One hundred and thirty ALS patients were assessed for motor disability, cognitive and behavioral dysfunctions, fatigue, anxiety, apathy, and daytime sleepiness. Moreover, the collected clinical parameters were correlated with RS-fMRI functional connectivity changes in the large-scale brain networks of 30 ALS patients who underwent MRI.

RESULTS: Multivariate correlation analysis revealed that "physical" fatigue was related to anxiety and respiratory dysfunction, while "mental" fatigue was related to memory impairment and apathy. Moreover, the mental fatigue score was directly related to functional connectivity in the right and left insula (within the salience network), and inversely related to functional connectivity in the left middle temporal gyrus (within the default mode network).

CONCLUSIONS: Although the "physical" component of fatigue may be influenced by the disease itself, in ALS the "mental" component of fatigue correlates with cognitive and behavioral impairment, as well as with alterations of functional connectivity in extra-motor networks.}, } @article {pmid37349906, year = {2023}, author = {Shojaie, A and Rota, S and Al Khleifat, A and Ray Chaudhuri, K and Al-Chalabi, A}, title = {Non-motor symptoms in amyotrophic lateral sclerosis: lessons from Parkinson's disease.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2023.2220748}, pmid = {37349906}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis and Parkinson's disease are neurodegenerative diseases of the motor system which are now recognized also to affect non-motor pathways. Non-motor symptoms have been acknowledged as important determinants of quality of life in Parkinson's disease, and there is increasing interest in understanding the extent and role of non-motor symptoms in amyotrophic lateral sclerosis. We therefore reviewed what is known about non-motor symptoms in amyotrophic lateral sclerosis, using lessons from Parkinson's disease.}, } @article {pmid37348646, year = {2023}, author = {Lone, MA and Zeng, S and Bourquin, F and Wang, M and Huang, S and Lin, Z and Tang, B and Zhang, R and Hornemann, T}, title = {SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS.}, journal = {Biochimica et biophysica acta. Molecular and cell biology of lipids}, volume = {1868}, number = {9}, pages = {159359}, doi = {10.1016/j.bbalip.2023.159359}, pmid = {37348646}, issn = {1879-2618}, mesh = {Female ; Humans ; Child ; *Amyotrophic Lateral Sclerosis/genetics ; HEK293 Cells ; Sphingolipids/metabolism ; Mutation ; Serine C-Palmitoyltransferase/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease. Recently, several gain-of-function mutations in SPTLC1 were associated with juvenile ALS. SPTLC1 encodes for a subunit of the serine-palmitoyltransferase (SPT) - the rate-limiting enzyme in the de novo synthesis of sphingolipids (SL). SPT activity, and thus SL de novo synthesis, is tightly controlled by a homeostatic feedback mechanism mediated by ORMDL proteins. Here we report a novel SPTLC1p.L38R mutation in a young Chinese girl with a signature of juvenile ALS. The patient presented with muscular weakness and atrophy, tongue tremor and fasciculation, breathing problems and positive pyramidal signs. All SPTLC1-ALS mutations including the SPTLC1 p.L38R are located within a single membrane-spanning domain of the protein and impede the interaction with the regulatory ORMDL subunit of SPT. Pertinent to the altered homeostatic control, lipid analysis showed overall increased SL levels in the patient plasma. An increased SPT activity and SL de novo synthesis was confirmed in p.L38R expressing HEK293 cells. Particularily dihydro-sphingolipids (dhSL) were signficantly increased in patient plasma and p.L38R mutant expressing cells. Increased dhSL formation has been previously linked to neurotoxicity and may be involved in the pathomechanism of SPTLC1-ALS mutations.}, } @article {pmid37346932, year = {2023}, author = {Monnakgotla, NR and Mahungu, AC and Heckmann, JM and Botha, G and Mulder, NJ and Wu, G and Rampersaud, E and Myers, J and Van Blitterswijk, M and Rademakers, R and Taylor, JP and Wuu, J and Benatar, M and Nel, M}, title = {Analysis of Structural Variants Previously Associated With ALS in Europeans Highlights Genomic Architectural Differences in Africans.}, journal = {Neurology. Genetics}, volume = {9}, number = {4}, pages = {e200077}, pmid = {37346932}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a degenerative condition of the brain and spinal cord in which protein-coding variants in known ALS disease genes explain a minority of sporadic cases. There is a growing interest in the role of noncoding structural variants (SVs) as ALS risk variants or genetic modifiers of ALS phenotype. In small European samples, specific short SV alleles in noncoding regulatory regions of SCAF4, SQSTM1, and STMN2 have been reported to be associated with ALS, and several groups have investigated the possible role of SMN1/SMN2 gene copy numbers in ALS susceptibility and clinical severity.

METHODS: Using short-read whole genome sequencing (WGS) data, we investigated putative ALS-susceptibility SCAF4 (3'UTR poly-T repeat), SQSTM1 (intron 5 AAAC insertion), and STMN2 (intron 3 CA repeat) alleles in African ancestry patients with ALS and described the architecture of the SMN1/SMN2 gene region. South African cases with ALS (n = 114) were compared with ancestry-matched controls (n = 150), 1000 Genomes Project samples (n = 2,336), and H3Africa Genotyping Chip Project samples (n = 347).

RESULTS: There was no association with previously reported SCAF4 poly-T repeat, SQSTM1 AAAC insertion, and long STMN2 CA alleles with ALS risk in South Africans (p > 0.2). Similarly, SMN1 and SMN2 gene copy numbers did not differ between South Africans with ALS and matched population controls (p > 0.9). Notably, 20% of the African samples in this study had no SMN2 gene copies, which is a higher frequency than that reported in Europeans (approximately 7%).

DISCUSSION: We did not replicate the reported association of SCAF4, SQSTM1, and STMN2 short SVs with ALS in a small South African sample. In addition, we found no link between SMN1 and SMN2 copy numbers and susceptibility to ALS in this South African sample, which is similar to the conclusion of a recent meta-analysis of European studies. However, the SMN gene region findings in Africans replicate previous results from East and West Africa and highlight the importance of including diverse population groups in disease gene discovery efforts. The clinically relevant differences in the SMN gene architecture between African and non-African populations may affect the effectiveness of targeted SMN2 gene therapy for related diseases such as spinal muscular atrophy.}, } @article {pmid37346371, year = {2023}, author = {Lorenzini, I and Alsop, E and Levy, J and Gittings, LM and Lall, D and Rabichow, BE and Moore, S and Pevey, R and Bustos, LM and Burciu, C and Bhatia, D and Singer, M and Saul, J and McQuade, A and Tzioras, M and Mota, TA and Logemann, A and Rose, J and Almeida, S and Gao, FB and Marks, M and Donnelly, CJ and Hutchins, E and Hung, ST and Ichida, J and Bowser, R and Spires-Jones, T and Blurton-Jones, M and Gendron, TF and Baloh, RH and Van Keuren-Jensen, K and Sattler, R}, title = {Moderate intrinsic phenotypic alterations in C9orf72 ALS/FTD iPSC-microglia despite the presence of C9orf72 pathological features.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1179796}, pmid = {37346371}, issn = {1662-5102}, support = {RF1 NS101986/NS/NINDS NIH HHS/United States ; R01 NS097545/NS/NINDS NIH HHS/United States ; R21 NS119952/NS/NINDS NIH HHS/United States ; I01 BX003625/BX/BLRD VA/United States ; T32 NS007433/NS/NINDS NIH HHS/United States ; T32 NS082174/NS/NINDS NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; R01 NS120331/NS/NINDS NIH HHS/United States ; }, abstract = {While motor and cortical neurons are affected in C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), it remains largely unknown if and how non-neuronal cells induce or exacerbate neuronal damage. We differentiated C9orf72 ALS/FTD patient-derived induced pluripotent stem cells into microglia (iPSC-MG) and examined their intrinsic phenotypes. Similar to iPSC motor neurons, C9orf72 ALS/FTD iPSC-MG mono-cultures form G4C2 repeat RNA foci, exhibit reduced C9orf72 protein levels, and generate dipeptide repeat proteins. Healthy control and C9orf72 ALS/FTD iPSC-MG equally express microglial specific genes and perform microglial functions, including inflammatory cytokine release and phagocytosis of extracellular cargos, such as synthetic amyloid beta peptides and healthy human brain synaptoneurosomes. RNA sequencing analysis revealed select transcriptional changes of genes associated with neuroinflammation or neurodegeneration in diseased microglia yet no significant differentially expressed microglial-enriched genes. Moderate molecular and functional differences were observed in C9orf72 iPSC-MG mono-cultures despite the presence of C9orf72 pathological features suggesting that a diseased microenvironment may be required to induce phenotypic changes in microglial cells and the associated neuronal dysfunction seen in C9orf72 ALS/FTD neurodegeneration.}, } @article {pmid37345437, year = {2023}, author = {Rush, CL and Lester, EG and Manglani, H and Woodworth, E and Vitolo, O and Fava, M and Berry, JD and Brizzi, K and Babu, S and Lindenberger, EC and Curtis, JR and Vranceanu, AM}, title = {Resilient together-ALS: leveraging the NDD transdiagnostic framework to develop an early dyadic intervention for people with amyotrophic lateral sclerosis and their informal care-partners.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2023.2224400}, pmid = {37345437}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive weakness and eventual death, usually within 3-5 years. An ALS diagnosis is associated with substantial emotional distress for both the affected person and their family care-partners which impairs the ability to engage in important conversations about long term care planning, negatively impacts ALS symptoms for the patient, and quality of life for both patient and care-partner. Here we 1) discuss published works identified by the authors about psychosocial interventions for the ALS population, 2) identify a lack of early, dyadic interventions to support psychosocial needs of people with ALS and care-partners; 3) describe the Neurodegenerative Diseases (NDD) framework for early dyadic intervention development and 4) propose an adaptation of an evidence-based early dyadic psychosocial intervention, Recovering Together, for the unique needs of people with ALS and their care-partners (Resilient Together-ALS; RT-ALS) using the NDD framework. Future work will use stakeholder feedback to optimize the intervention for subsequent efficacy testing.}, } @article {pmid37345346, year = {2023}, author = {Donohue, C and Chapin, JL and Anderson, A and DiBiase, L and Gray, LT and Wymer, JP and Plowman, EK}, title = {Sensitivity and specificity of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised to detect dysarthria in individuals with amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {68}, number = {3}, pages = {296-302}, pmid = {37345346}, issn = {1097-4598}, support = {R01 NS100859/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Dysarthria/diagnosis/etiology ; Severity of Illness Index ; Sensitivity and Specificity ; ROC Curve ; }, abstract = {INTRODUCTION/AIMS: Given the widespread use of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) to measure disease progression in ALS and recent reports demonstrating its poor sensitivity, we aimed to determine the sensitivity and specificity of the ALSFRS-R bulbar subscale and speech item to detect validated clinical ratings of dysarthria in individuals with ALS.

METHODS: Paired ALSFRS-R and validated Speech Intelligibility Test (SIT) data from individuals with ALS were analyzed. Trained raters completed duplicate, independent, and blinded ratings of audio recordings to obtain speech intelligibility (%) and speaking rate (words per minute, WPM). Binary dysarthria profiles were derived (dysarthria ≤96% intelligible and/or <150 WPM). Data were obtained using the Kruskal-Wallis test, receiver-operating characteristic (ROC) curve, area under the curve (AUC), sensitivity and specificity percentages, and positive/negative predictive values (PPV/NPV).

RESULTS: A total of 250 paired SIT and ALSFRS-R data points were analyzed. Dysarthria was confirmed in 72.4% (n = 181). Dysarthric speakers demonstrated lower ALSFRS-R bulbar subscale (8.9 vs. 11.2) and speech item (2.7 vs. 3.7) scores (P < .0001). The ALSFRS-R bulbar subscale score had an AUC of 0.81 (95% confidence interval [CI] 0.75 to 0.86). A subscale score of ≤11 yielded a sensitivity of 86%, specificity of 57%, PPV of 84%, and NPV of 60% to correctly identify dysarthria status. The ALSFRS-R speech item score demonstrated an AUC of 0.81 to detect dysarthria (95% CI 0.76 to 0.85), with sensitivity of 79%, specificity of 75%, PPV of 89%, and NPV of 58% for a speech item cutpoint of ≤3.

DISCUSSION: The ALSFRS-R bulbar and speech item subscale scores may be useful, inexpensive, and quick tools for monitoring dysarthria status in ALS.}, } @article {pmid37345246, year = {2023}, author = {Li, X and Tian, Y and Wu, H and Wang, T}, title = {Network Pharmacology and Molecular Docking to Unveil the Mechanism of Shudihuang against Amyotrophic Lateral Sclerosis.}, journal = {Current pharmaceutical design}, volume = {29}, number = {19}, pages = {1535-1545}, doi = {10.2174/1381612829666230621105552}, pmid = {37345246}, issn = {1873-4286}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Molecular Docking Simulation ; Network Pharmacology ; Sitosterols ; Cyclooxygenase 2 ; PPAR gamma ; Stigmasterol ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Medicine, Chinese Traditional ; }, abstract = {BACKGROUND: Shudihuang has been clinically proven to be an effective Chinese medicine compatible with the treatment of amyotrophic lateral sclerosis. However, the underlying mechanism of Shudihuang against amyotrophic lateral sclerosis remains unclear.

OBJECTIVES: The present study aims to elucidate the possible mechanism of Shudihuang in treating ALS using network pharmacology and molecular docking.

METHODS: The primary active components of Shudihuang and their relevant targets were identified by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the Swiss Target Prediction database, respectively. The ALS-related targets were obtained from the Disgenet and OMIM databases. The shared targets were derived by the intersection of disease-associated and component-associated targets and then introduced into the Cytoscape software to construct a network of drug-component-target. In addition, protein interaction relationships among the shared targets were analyzed by the STRING and Cytoscape software. Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) functional enrichment analysis were conducted by the Metascape platform. The binding activities between the hub targets and the active components were assessed with molecular docking.

RESULTS: Stigmasterol and sitosterol were identified as the core components of Shudihuang, and the hub targets of ALS are PTGS2, PPARG, ESR1, IGF-1R, and MAPK3, with the highest degrees in the PPI network. The finding that stigmasterol and sitosterol had a good affinity with PTGS2, PPARG, ESR1, IGF-1R, and MAPK3 also supported this. Finally, it was revealed that Shudihuang treatment of ALS predominantly involves estrogen- related pathways such as nuclear receptor activity and steroid binding.

CONCLUSION: In summary, this study suggested that the main active components of Shudihuang (stigmasterol and sitosterol) may exert a critical effect in ALS treatment by binding to hub targets (PTGS2, PPARG, ESR1, IGF-1R, and MAPK3) and then modulating estrogen receptor-related pathways to attenuate glutamate excitotoxicity, inhibit oxidative stress and antagonize inflammation.}, } @article {pmid37344897, year = {2023}, author = {Dweikat, IM and Gelli, M and Bernards, M and Martin, A and Jhala, A}, title = {Mutations in the acetolactate synthase (ALS) enzyme affect shattercane (Sorghum bicolor) response to ALS-inhibiting herbicides.}, journal = {Hereditas}, volume = {160}, number = {1}, pages = {28}, pmid = {37344897}, issn = {1601-5223}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Sorghum ; *Herbicides/pharmacology ; Herbicide Resistance/genetics ; Mutation ; Plant Proteins/genetics ; }, abstract = {BACKGROUND: Shattercane [Sorghum bicolor (L.) Moench ssp. Arundinaceum (Desv.)] is a competitive weed in North America's corn, soybean, sorghum, and other agronomic crops. Control of shattercane with POST herbicides in corn became possible with the introduction of acetolactate synthase (ALS)-inhibiting herbicides in the 1980s, and their extensive use resulted in the evolution of ALS-inhibitors resistant shattercane.

RESULTS: Shattercane seeds were collected from 16 south-eastern and south-central Nebraska fields that were treated with primisulfuron for three consecutive years. Three resistant plants were found in greenhouse evaluations of more than 30,000 plants. Results from a greenhouse bioassay conducted to assess the response of each shattercane biotype to ALS-inhibiting herbicides showed a differential response to ALS inhibitors within and between chemical classes. Biotype P8-30 was resistant or partially resistant to all ALS-inhibiting herbicides applied and displayed a unique amino acid sequence substitution (Trp574 to Leu) relative to the other two resistant biotypes, P2-205 and P9-102. Whole plant dose-response studies confirmed a 4- to the 12-fold level of primisulfuron resistance in three shattercane biotypes compared with the known primisulfuron-susceptible shattercane biotype. The ALS gene was sequenced using primers designed from the corn ALS sequence to identify mutations in the ALS gene that confer resistance. A total of seven nucleotide substitutions were detected in the three herbicide-resistant biotypes P2-205, P8-30, and P9-102. These biotypes are being crossed to adapted sorghum lines (grain, sweet, and forage) to broaden germplasm with resistance to ALS-inhibiting herbicides.

CONCLUSION: The discovery of these mutants should accelerate the development of sorghum genotypes that tolerate ALS-based herbicides, which provide additional choices for sorghum farmers to control weeds, especially grasses, in their fields.}, } @article {pmid37344230, year = {2023}, author = {Bjornevik, K and Cortese, M and Furtado, JD and Paganoni, S and Schwarzschild, MA and Cudkowicz, ME and Ascherio, A}, title = {Association of Polyunsaturated Fatty Acids and Clinical Progression in Patients With ALS: Post Hoc Analysis of the EMPOWER Trial.}, journal = {Neurology}, volume = {101}, number = {7}, pages = {e690-e698}, pmid = {37344230}, issn = {1526-632X}, mesh = {Male ; Humans ; Middle Aged ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy ; Fatty Acids, Unsaturated ; *Fatty Acids, Omega-3 ; Fatty Acids, Omega-6 ; Disease Progression ; Fatty Acids ; }, abstract = {BACKGROUND AND OBJECTIVES: Polyunsaturated fatty acids (PUFAs) have neuroprotective and anti-inflammatory effects and could be beneficial in amyotrophic lateral sclerosis (ALS). Higher dietary intake and plasma levels of PUFAs, in particular alpha-linolenic acid (ALA), have been associated with a lower risk of ALS in large epidemiologic cohort studies, but data on disease progression in patients with ALS are sparse. We examined whether plasma levels of ALA and other PUFAs contributed to predicting survival time and functional decline in patients with ALS.

METHODS: We conducted a study among participants in the EMPOWER clinical trial who had plasma samples collected at the time of randomization that were available for fatty acid analyses. Plasma fatty acids were measured using gas chromatography. We used Cox proportional hazards models and linear regression to evaluate the association of individual fatty acids with risk of death and joint rank test score of functional decline and survival.

RESULTS: Fatty acid analyses were conducted in 449 participants. The mean (SD) age of these participants at baseline was 57.5 (10.7) years, and 293 (65.3%) were men; 126 (28.1%) died during follow-up. Higher ALA levels were associated with lower risk of death (age-adjusted and sex-adjusted hazard ratio comparing highest vs lowest quartile 0.50, 95% CI 0.29-0.86, p-trend = 0.041) and higher joint rank test score (difference in score according to 1 SD increase 10.7, 95% CI 0.2-21.1, p = 0.045), consistent with a slower functional decline. The estimates remained similar in analyses adjusted for body mass index, race/ethnicity, symptom duration, site of onset, riluzole use, family history of ALS, predicted upright slow vital capacity, and treatment group. Higher levels of the n-3 fatty acid eicosapentaenoic acid and the n-6 fatty acid linoleic acid were associated with a lower risk of death during follow-up.

DISCUSSION: Higher levels of ALA were associated with longer survival and slower functional decline in patients with ALS. These results suggest that ALA may have a favorable effect on disease progression in patients with ALS.}, } @article {pmid37343857, year = {2023}, author = {Mauri, L and Tarolli, P}, title = {Modeling windthrow effects on water runoff and hillslope stability in a mountain catchment affected by the VAIA storm.}, journal = {The Science of the total environment}, volume = {895}, number = {}, pages = {164831}, doi = {10.1016/j.scitotenv.2023.164831}, pmid = {37343857}, issn = {1879-1026}, abstract = {Windthrows seriously affect forest landscapes, causing several issues in hydrological and geomorphological terms. In this regard, Airborne Laser Scanning (ALS) topographic data recently increased the opportunity to investigate in detail physical processes at the catchment scale. Moreover, topographically based hydrological and geomorphological models allow quantifying runoff alteration due to windthrows-driven land cover changes and detect the occurrence of land degradative processes at the sub-catchment scale. In this connection, accurate investigations about windthrows role in varying local runoff regimes over time are still obscure, as well as the possibility of predicting terrain instabilities due to windstorm occurrence. This research aims to investigate the interaction between windthrows, runoff alterations and hillslope failures affecting a landslide-prone mountain catchment (northern Italy). Hydrological HEC-HMS and geomorphological RESS models were applied. Windthrows' role in altering runoff regimes and hillslope stability was investigated starting from the elaboration of ALS-derived points clouds acquired before and after the occurrence of the Vaia storm. Digital Terrain Models (DTMs) were elaborated for the two scenarios to compare daily runoff variations and predict the activation of terrain instabilities by looking at land cover changes driven by the blowdown event at the sub-catchment detail. Results attested the key role of windstorms in altering local runoff, with a maximum relative runoff increment equal to 2.56 % and a maximum runoff difference equal to 3.12 mmh[-1], as well as in encouraging the activation of the observed shallow landslide. The correlation between windthrows occurrence and runoff alterations was validated by performing regression analysis (R[2] = 0.76), while the accuracy of instabilities predictions was tested through the Distance to Perfect Classification (D2PC) index and True Skill Statistic (TSS) score, respectively resulted equal to 0.076 and 0.898. This research represents a valid tool for investigating similar issues at a wider scale, also providing suggestions for promoting interventions in wind-disturbed forest areas.}, } @article {pmid37343835, year = {2023}, author = {Lilly, E and Hamilton, HK and Dover, JS}, title = {Response to Richey et al's "Psychiatric comorbidity and pharmacology in a cosmetic dermatology setting: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {89}, number = {4}, pages = {e187}, doi = {10.1016/j.jaad.2023.02.068}, pmid = {37343835}, issn = {1097-6787}, mesh = {Humans ; *Dermatology ; Retrospective Studies ; Comorbidity ; }, } @article {pmid37343522, year = {2023}, author = {Zhou, ZD and Yi, LX and Tan, EK}, title = {Targeting gasdermin E in neurodegenerative diseases.}, journal = {Cell reports. Medicine}, volume = {4}, number = {6}, pages = {101075}, pmid = {37343522}, issn = {2666-3791}, mesh = {Humans ; Gasdermins ; *Neurodegenerative Diseases ; *Frontotemporal Dementia ; *Amyotrophic Lateral Sclerosis ; }, abstract = {Neel et al. identified pathophysiologic clues linking gasdermin-E (GSDME) with frontotemporal dementia and amyotrophic lateral sclerosis.[1] Therapeutic studies targeting GSDME may provide a viable approach for neurodegenerative diseases.}, } @article {pmid37342380, year = {2023}, author = {Shamsaei, G and Houshmand, F and Ahmadzadeh Deylami, A and Valizadeh, A and Rafie, S and Moradi, M}, title = {The Efficacy and Safety of Intrathecal Autologous Bone Marrow-Derived Mesenchymal Stromal Cells in Amyotrophic Lateral Sclerosis: A Pilot Study.}, journal = {Advanced pharmaceutical bulletin}, volume = {13}, number = {2}, pages = {361-367}, pmid = {37342380}, issn = {2228-5881}, abstract = {Purpose: Amyotrophic lateral sclerosis (ALS) is an uncommon and aggressive neurodegenerative disorder that influences the lower and upper motor neurons. There are low eligible drugs for ALS treatment; in this regard, supplemental and replacement treatments are essential. There are relative studies in the field of mesenchymal stromal cells (MSCs) therapy in ALS, but the different methods, differently used medium, and difference in follow-up periods affect the outcome treatment. Methods: The current survey is a single-center, phase I clinical trial to evaluating the efficacy and safety of autologous bone marrow (BM)-derived MSCs through intrathecal administration in ALS patients. MNCs were isolated from BM specimens and cultured. The clinical outcome was evaluated based Revised Amyotrophic Lateral Sclerosis Functional Rating (ALSFRS-R) Scale. Results: Each patient received 15±3×10[6] cells through subarachnoid space. No adverse events (AEs) were detected. Just one patient experienced a mild headache after injection. Following injection, no new intradural cerebrospinal pathology transplant-related was observed. None of the patients' pathologic disruptions following transplantation were detected by magnetic resonance imaging (MRI). The additional analyses have shown the average rate of ALSFRS-R score and forced vital capacity (FVC) reduction have decreased during 10 months following MSCs transplantation versus the pretreatment period, from -5.4±2.3 to -2±3.08 ALSFRS-R points/period (P=0.014) and -12.6±5.22% to -4.8±14.72%/period (P<0.001), respectively. Conclusion: These results have shown that autologous MSCs transplantation reduces the disease's progression and has favorable safety. Trial Registration: This study performed as a phase I clinical trial (code IRCT20200828048551N1).}, } @article {pmid37341302, year = {2023}, author = {Wang, Y and Wu, S and Li, Q and Sun, H and Wang, H}, title = {Pharmacological Inhibition of Ferroptosis as a Therapeutic Target for Neurodegenerative Diseases and Strokes.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {10}, number = {24}, pages = {e2300325}, pmid = {37341302}, issn = {2198-3844}, support = {81260196//National Natural Science Foundation of China/ ; 81450036//National Natural Science Foundation of China/ ; 2020YK02//Science Foundation of AMHT/ ; 2021YK05//Science Foundation of AMHT/ ; 2022YK01//Science Foundation of AMHT/ ; YN202104//Science Foundation of ASCH/ ; YN202305//Science Foundation of ASCH/ ; 2020MS08175//Natural Science Foundation of Inner Mongolia Autonomous Region/ ; 2021LHMS08024//Natural Science Foundation of Inner Mongolia Autonomous Region/ ; 2022MS08046//Natural Science Foundation of Inner Mongolia Autonomous Region/ ; YC202305//Science Foundation of Inner Mongolia Key Laboratory of human genetic diseases/ ; YC202304//Science Foundation of Inner Mongolia Key Laboratory of human genetic diseases/ ; }, mesh = {Humans ; *Ferroptosis ; *Neurodegenerative Diseases/drug therapy ; *Stroke/drug therapy ; Cell Death ; }, abstract = {Emerging evidence suggests that ferroptosis, a unique regulated cell death modality that is morphologically and mechanistically different from other forms of cell death, plays a vital role in the pathophysiological process of neurodegenerative diseases, and strokes. Accumulating evidence supports ferroptosis as a critical factor of neurodegenerative diseases and strokes, and pharmacological inhibition of ferroptosis as a therapeutic target for these diseases. In this review article, the core mechanisms of ferroptosis are overviewed and the roles of ferroptosis in neurodegenerative diseases and strokes are described. Finally, the emerging findings in treating neurodegenerative diseases and strokes through pharmacological inhibition of ferroptosis are described. This review demonstrates that pharmacological inhibition of ferroptosis by bioactive small-molecule compounds (ferroptosis inhibitors) could be effective for treatments of these diseases, and highlights a potential promising therapeutic avenue that could be used to prevent neurodegenerative diseases and strokes. This review article will shed light on developing novel therapeutic regimens by pharmacological inhibition of ferroptosis to slow down the progression of these diseases in the future.}, } @article {pmid37340732, year = {2023}, author = {Hsueh, SJ and Chao, CC and Chen, TF and Chen, YF and Hsueh, HW and Tsai, LK and Wu, WC and Hsieh, ST}, title = {Brain imaging signatures in amyotrophic lateral sclerosis: Correlation with peripheral motor degeneration.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {8}, pages = {1456-1466}, pmid = {37340732}, issn = {2328-9503}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Diffusion Tensor Imaging/methods ; Brain/diagnostic imaging ; Magnetic Resonance Imaging ; Neuroimaging ; }, abstract = {OBJECTIVE: This study aimed to explore the clinical significance of brain imaging signatures in the context of clinical neurological deficits in association with upper and lower motor neuron degeneration in amyotrophic lateral sclerosis (ALS).

METHODS: We performed brain MRI examinations to quantitatively evaluate (1) gray matter volume and (2) white matter tract fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). Image-derived indices were correlated with (1) global neurological deficits of MRC muscle strength sum score, revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R), and forced vital capacity (FVC), and (2) focal scores of University of Pennsylvania Upper motor neuron score (Penn score) and the summation of compound muscle action potential Z scores (CMAP Z sum score).

RESULTS: There were 39 ALS patients and 32 control subjects matched for age and gender. Compared to controls, ALS patients had a lower gray matter volume in the precentral gyrus of the primary motor cortex, which was correlated with FA of corticofugal tracts. The gray matter volume of the precentral gyrus was correlated with FVC, MRC sum score, and CMAP Z sum score, while the FA of the corticospinal tract was linearly associated with CMAP Z sum score and Penn score on multivariate linear regression model.

INTERPRETATION: This study indicated that clinical assessment of muscle strength and routine measurements on nerve conduction studies provided surrogate markers of brain structural changes for ALS. Furthermore, these findings suggested parallel involvement of both upper and lower motor neurons in ALS.}, } @article {pmid37340319, year = {2023}, author = {Ozzoude, M and Varriano, B and Beaton, D and Ramirez, J and Adamo, S and Holmes, MF and Scott, CJM and Gao, F and Sunderland, KM and McLaughlin, P and Goubran, M and Kwan, D and Roberts, A and Bartha, R and Symons, S and Tan, B and Swartz, RH and Abrahao, A and Saposnik, G and Masellis, M and Lang, AE and Marras, C and Zinman, L and Shoesmith, C and Borrie, M and Fischer, CE and Frank, A and Freedman, M and Montero-Odasso, M and Kumar, S and Pasternak, S and Strother, SC and Pollock, BG and Rajji, TK and Seitz, D and Tang-Wai, DF and Turnbull, J and Dowlatshahi, D and Hassan, A and Casaubon, L and Mandzia, J and Sahlas, D and Breen, DP and Grimes, D and Jog, M and Steeves, TDL and Arnott, SR and Black, SE and Finger, E and Rabin, J and , and Tartaglia, MC}, title = {White matter hyperintensities and smaller cortical thickness are associated with neuropsychiatric symptoms in neurodegenerative and cerebrovascular diseases.}, journal = {Alzheimer's research & therapy}, volume = {15}, number = {1}, pages = {114}, pmid = {37340319}, issn = {1758-9193}, mesh = {Humans ; Female ; *White Matter/diagnostic imaging ; *Frontotemporal Dementia ; *Parkinson Disease ; *Cognitive Dysfunction/psychology ; *Cerebrovascular Disorders/complications/diagnostic imaging ; Magnetic Resonance Imaging ; }, abstract = {BACKGROUND: Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical thickness to NPS in participants across neurodegenerative and cerebrovascular diseases.

METHODS: Five hundred thirteen participants with one of these conditions, i.e. Alzheimer's Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson's Disease, or Cerebrovascular Disease, were included in the study. NPS were assessed using the Neuropsychiatric Inventory - Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter loss.

RESULTS: Although NPS were frequent across the five disease groups, participants with frontotemporal dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both frontotemporal dementia and Parkinson's disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities.

CONCLUSIONS: In participants with neurodegenerative and cerebrovascular diseases, our results suggest that smaller cortical thickness and white matter hyperintensity burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed.}, } @article {pmid37340309, year = {2023}, author = {Yue, W and Deng, X and Wang, Z and Jiang, M and Hu, R and Duan, Y and Wang, Q and Cui, J and Fang, Y}, title = {Inhibition of the MEK/ERK pathway suppresses immune overactivation and mitigates TDP-43 toxicity in a Drosophila model of ALS.}, journal = {Immunity & ageing : I & A}, volume = {20}, number = {1}, pages = {27}, pmid = {37340309}, issn = {1742-4933}, support = {31970697//National Natural Science Foundation of China/ ; 201409003300//Science and Technology Commission of Shanghai Municipality/ ; }, abstract = {TDP-43 is an important DNA/RNA-binding protein that is associated with age-related neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); however, its pathomechanism is not fully understood. In a transgenic RNAi screen using Drosophila as a model, we uncovered that knockdown (KD) of Dsor1 (the Drosophila MAPK kinase dMEK) suppressed TDP-43 toxicity without altering TDP-43 phosphorylation or protein levels. Further investigation revealed that the Dsor1 downstream gene rl (dERK) was abnormally upregulated in TDP-43 flies, and neuronal overexpression of dERK induced profound upregulation of antimicrobial peptides (AMPs). We also detected a robust immune overactivation in TDP-43 flies, which could be suppressed by downregulation of the MEK/ERK pathway in TDP-43 fly neurons. Furthermore, neuronal KD of abnormally increased AMPs improved the motor function of TDP-43 flies. On the other hand, neuronal KD of Dnr1, a negative regulator of the Drosophila immune deficiency (IMD) pathway, activated the innate immunity and boosted AMP expression independent of the regulation by the MEK/ERK pathway, which diminished the mitigating effect of RNAi-dMEK on TDP-43 toxicity. Finally, we showed that an FDA-approved MEK inhibitor trametinib markedly suppressed immune overactivation, alleviated motor deficits and prolonged the lifespan of TDP-43 flies, but did not exhibit a lifespan-extending effect in Alzheimer disease (AD) or spinocerebellar ataxia type 3 (SCA3) fly models. Together, our findings suggest an important role of abnormal elevation of the MEK/ERK signaling and innate immunity in TDP-43 pathogenesis and propose trametinib as a potential therapeutic agent for ALS and other TDP-43-related diseases.}, } @article {pmid37339631, year = {2023}, author = {Kume, K and Kurashige, T and Muguruma, K and Morino, H and Tada, Y and Kikumoto, M and Miyamoto, T and Akutsu, SN and Matsuda, Y and Matsuura, S and Nakamori, M and Nishiyama, A and Izumi, R and Niihori, T and Ogasawara, M and Eura, N and Kato, T and Yokomura, M and Nakayama, Y and Ito, H and Nakamura, M and Saito, K and Riku, Y and Iwasaki, Y and Maruyama, H and Aoki, Y and Nishino, I and Izumi, Y and Aoki, M and Kawakami, H}, title = {CGG repeat expansion in LRP12 in amyotrophic lateral sclerosis.}, journal = {American journal of human genetics}, volume = {110}, number = {7}, pages = {1086-1097}, pmid = {37339631}, issn = {1537-6605}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Motor Neurons/pathology ; *Muscular Dystrophies/genetics ; *Neurodegenerative Diseases/genetics ; C9orf72 Protein/genetics ; DNA Repeat Expansion ; Low Density Lipoprotein Receptor-Related Protein-1/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons. Although repeat expansion in C9orf72 is its most common cause, the pathogenesis of ALS isn't fully clear. In this study, we show that repeat expansion in LRP12, a causative variant of oculopharyngodistal myopathy type 1 (OPDM1), is a cause of ALS. We identify CGG repeat expansion in LRP12 in five families and two simplex individuals. These ALS individuals (LRP12-ALS) have 61-100 repeats, which contrasts with most OPDM individuals with repeat expansion in LRP12 (LRP12-OPDM), who have 100-200 repeats. Phosphorylated TDP-43 is present in the cytoplasm of iPS cell-derived motor neurons (iPSMNs) in LRP12-ALS, a finding that reproduces the pathological hallmark of ALS. RNA foci are more prominent in muscle and iPSMNs in LRP12-ALS than in LRP12-OPDM. Muscleblind-like 1 aggregates are observed only in OPDM muscle. In conclusion, CGG repeat expansions in LRP12 cause ALS and OPDM, depending on the length of the repeat. Our findings provide insight into the repeat length-dependent switching of phenotypes.}, } @article {pmid37339001, year = {2023}, author = {Song, J and Dikwella, N and Sinske, D and Roselli, F and Knöll, B}, title = {SRF deletion results in earlier disease onset in a mouse model of amyotrophic lateral sclerosis.}, journal = {JCI insight}, volume = {8}, number = {15}, pages = {}, pmid = {37339001}, issn = {2379-3708}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; Etoposide ; Gene Expression Regulation ; Motor Neurons/physiology ; Serum Response Factor/genetics ; }, abstract = {Changes in neuronal activity modulate the vulnerability of motoneurons (MNs) in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). So far, the molecular basis of neuronal activity's impact in ALS is poorly understood. Herein, we investigated the impact of deleting the neuronal activity-stimulated transcription factor (TF) serum response factor (SRF) in MNs of SOD1G93A mice. SRF was present in vulnerable MMP9+ MNs. Ablation of SRF in MNs induced an earlier disease onset starting around 7-8 weeks after birth, as revealed by enhanced weight loss and decreased motor ability. This earlier disease onset in SRF-depleted MNs was accompanied by a mild elevation of neuroinflammation and neuromuscular synapse degeneration, whereas overall MN numbers and mortality were unaffected. In SRF-deficient mice, MNs showed impaired induction of autophagy-encoding genes, suggesting a potentially new SRF function in transcriptional regulation of autophagy. Complementary, constitutively active SRF-VP16 enhanced autophagy-encoding gene transcription and autophagy progression in cells. Furthermore, SRF-VP16 decreased ALS-associated aggregate induction. Chemogenetic modulation of neuronal activity uncovered SRF as having important TF-mediating activity-dependent effects, which might be beneficial to reduce ALS disease burden. Thus, our data identify SRF as a gene regulator connecting neuronal activity with the cellular autophagy program initiated in degenerating MNs.}, } @article {pmid37338894, year = {2023}, author = {Burg, T and Van Den Bosch, L}, title = {Abnormal energy metabolism in ALS: a key player?.}, journal = {Current opinion in neurology}, volume = {36}, number = {4}, pages = {338-345}, pmid = {37338894}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/pathology ; Motor Neurons/pathology ; Energy Metabolism ; Precision Medicine ; }, abstract = {PURPOSE OF THE REVIEW: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease of the motor system due to the selective and progressive degeneration of both upper and lower motor neurons. Disturbances in energy homeostasis were repeatedly associated with the ALS pathogenesis and appear early during the disease process. In this review, we highlight recent work demonstrating the crucial role of energy metabolism in ALS and discuss its potential clinical relevance.

RECENT FINDINGS: The alteration of various metabolic pathways contributes to the heterogeneity of the clinical phenotype of ALS. Recent work showed that different ALS mutations selectively impact these pathways and translate to the disease phenotypes in patients and disease models. Strikingly, a growing number of studies point towards an early, even presymptomatic, contribution of abnormal energy homeostasis to the ALS pathogenesis. Advances in metabolomics generated valuable tools to study altered metabolic pathways, to test their therapeutic potential, and to develop personalized medicine. Importantly, recent preclinical studies and clinical trials demonstrated that targeting energy metabolism is a promising therapeutic approach.

SUMMARY: Abnormal energy metabolism is a key player in ALS pathogenesis, emerging as a source of potential disease biomarkers and therapeutic targets.}, } @article {pmid37338836, year = {2023}, author = {Seefeldt, T and Aitzetmüller-Klietz, ML and Kückelhaus, M and Wiebringhaus, P and Hirsch, T and Harati, K and Aitzetmüller-Klietz, MM}, title = {[Liposuktion beim Lipödem - Doch besser als ihr Ruf?].}, journal = {Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG}, volume = {21}, number = {6}, pages = {601-610}, doi = {10.1111/ddg.15064_g}, pmid = {37338836}, issn = {1610-0387}, } @article {pmid37338820, year = {2023}, author = {Willemse, SW and van Es, MA}, title = {Susceptibility and disease modifier genes in amyotrophic lateral sclerosis: from genetic associations to therapeutic implications.}, journal = {Current opinion in neurology}, volume = {36}, number = {4}, pages = {365-370}, pmid = {37338820}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; Genes, Modifier ; Superoxide Dismutase-1/genetics/therapeutic use ; Motor Neurons ; Mutation ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a severe disease characterized by the degeneration of motor neurons. Large-scale genetic studies have now identified over 60 genes that are associated with ALS, which in large part have also been functionally characterized. The purpose of this review is to outline how these advances are being translated into novel therapeutic strategies.

RECENT FINDINGS: The emergence of techniques that allow the specific therapeutic targeting of a (mutant) gene, in particular antisense oligonucleotide therapy (ASOs), have led to the first successful gene therapy for SOD1-ALS and multiple other gene-targeted trials are underway. This includes genetic variants that modify the disease phenotype as well as causal mutations.

SUMMARY: Technological and methodological advances are enabling researchers to unravel the genetics of ALS. Both causal mutations and genetic modifiers are viable therapeutic targets. By performing natural history studies, the phenotype-genotype correlations can be characterized. In conjunction with biomarkers for target engagement and international collaboration, this makes performing gene-targeted trials ALS feasible. The first effective treatment has now been developed for SOD1-ALS and, with multiple studies underway, it seems realistic that more therapies will follow.}, } @article {pmid37338613, year = {2023}, author = {Milella, G and Zoccolella, S and Giugno, A and Filardi, M and Urso, D and Nigro, S and Tafuri, B and Tamburrino, L and Gnoni, V and Logroscino, G}, title = {The impact of upper and lower motor neuron burden on diagnostic certainty, and clinical course of spinal-onset amyotrophic lateral sclerosis: a cluster-based approach.}, journal = {Journal of neurology}, volume = {270}, number = {10}, pages = {4868-4875}, pmid = {37338613}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/complications ; Bayes Theorem ; Motor Neurons/physiology ; Prognosis ; Disease Progression ; }, abstract = {BACKGROUND: Upper motor neuron (UMN) and lower motor neuron (LMN) involvement represent the core clinical features of amyotrophic lateral sclerosis (ALS). Several studies divided patients into prevalent UMN and LMN impairment phenotypes to investigate the association between motor systems impairments and ALS clinical course. However, this distinction was somehow heterogeneous and significantly affected the comparability across studies.

AIMS: This study aimed to investigate whether patients spontaneously segregate based on the extent of UMN and LMN involvement without a-priori categorization and to identify potential clinical and prognostic features of different clusters.

METHODS: Eighty-eight consecutive spinal-onset ALS patients were referred to an ALS tertiary center between 2015 and 2022. UMN and LMN burden was assessed with the Penn Upper Motor Neuron scale (PUMNS) and the Devine score, respectively. PUMNS and LMN scores were normalized into 0-1 and analyzed using a two-step cluster analysis and the Euclidean distance measure. The Bayesian Information Criterion was used to determine the cluster number. Demographic and clinical variables were tested for differences among the clusters.

RESULTS: Three distinct clusters emerged at cluster analysis. Patients in "cluster-1" showed moderate UMN and severe LMN involvement, corresponding to the typical ALS phenotype. Patients in "cluster-2" showed mild LMN and severe UMN damage, corresponding to a predominant UMN phenotype, while "cluster-3" patients showed mild UMN and moderate LMN damage, corresponding to a predominant LMN phenotype. Patients in "cluster-1" and "cluster-2" showed a higher prevalence of definite ALS than those in "cluster-3" (61% and 46 vs 9%, p < 0.001). "Cluster-1" patients had a lower median ALSFRS-r score compared to both "cluster-2" and 3 patients (27 vs 40 and 35, < 0.001). "Cluster-1" (HR: 8.5; 95% CI 2.1-35.1 and p = 0.003) and 3 (HR: 3.2; 95% CI 1.1-9.1; p = 0.03) were associated with shorter survival than those in "cluster-2".

CONCLUSIONS: Spinal-onset ALS can be categorized into three groups according to LMN and UMN burden. The UMN burden is related to higher diagnostic certainty and broader disease spread, while LMN involvement is associated with higher disease severity and shorter survival.}, } @article {pmid37338307, year = {2023}, author = {Tripathi, SJ and Chakraborty, S and Miller, E and Pieper, AA and Paul, BD}, title = {Hydrogen sulfide signalling in neurodegenerative diseases.}, journal = {British journal of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {37338307}, issn = {1476-5381}, support = {P30 AG062428/AG/NIA NIH HHS/United States ; R01 AG071512/AG/NIA NIH HHS/United States ; RO1AG066707/AG/NIA NIH HHS/United States ; 1 U01 AG073323/AG/NIA NIH HHS/United States ; RM1 GM142002/GM/NIGMS NIH HHS/United States ; U01 AG073323/AG/NIA NIH HHS/United States ; R01 AG066707/AG/NIA NIH HHS/United States ; T32 AG071474/AG/NIA NIH HHS/United States ; P50 DA044123/DA/NIDA NIH HHS/United States ; 1 P30 AGO62428-01/AG/NIA NIH HHS/United States ; R01AG071512/AG/NIA NIH HHS/United States ; I01 BX005976/BX/BLRD VA/United States ; 1R21AG073684-01/AG/NIA NIH HHS/United States ; DA044123/DA/NIDA NIH HHS/United States ; R21 AG073684/AG/NIA NIH HHS/United States ; }, abstract = {The gaseous neurotransmitter hydrogen sulfide (H2 S) exerts neuroprotective efficacy in the brain via post-translational modification of cysteine residues by sulfhydration, also known as persulfidation. This process is comparable in biological impact to phosphorylation and mediates a variety of signalling events. Unlike conventional neurotransmitters, H2 S cannot be stored in vesicles due to its gaseous nature. Instead, it is either locally synthesized or released from endogenous stores. Sulfhydration affords both specific and general neuroprotective effects and is critically diminished in several neurodegenerative disorders. Conversely, some forms of neurodegenerative disease are linked to excessive cellular H2 S. Here, we review the signalling roles of H2 S across the spectrum of neurodegenerative diseases, including Huntington's disease, Parkinson's disease, Alzheimer's disease, Down syndrome, traumatic brain injury, the ataxias, and amyotrophic lateral sclerosis, as well as neurodegeneration generally associated with ageing.}, } @article {pmid37337289, year = {2023}, author = {Nango, H and Tsuruta, K and Miyagishi, H and Aono, Y and Saigusa, T and Kosuge, Y}, title = {Update on the pathological roles of prostaglandin E2 in neurodegeneration in amyotrophic lateral sclerosis.}, journal = {Translational neurodegeneration}, volume = {12}, number = {1}, pages = {32}, pmid = {37337289}, issn = {2047-9158}, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/pathology ; Mice, Transgenic ; Dinoprostone/metabolism/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. The pathogenesis of ALS remains largely unknown; however, inflammation of the spinal cord is a focus of ALS research and an important pathogenic process in ALS. Prostaglandin E2 (PGE2) is a major lipid mediator generated by the arachidonic-acid cascade and is abundant at inflammatory sites. PGE2 levels are increased in the postmortem spinal cords of ALS patients and in ALS model mice. Beneficial therapeutic effects have been obtained in ALS model mice using cyclooxygenase-2 inhibitors to inhibit the biosynthesis of PGE2, but the usefulness of this inhibitor has not yet been proven in clinical trials. In this review, we present current evidence on the involvement of PGE2 in the progression of ALS and discuss the potential of microsomal prostaglandin E synthase (mPGES) and the prostaglandin receptor E-prostanoid (EP) 2 as therapeutic targets for ALS. Signaling pathways involving prostaglandin receptors mediate toxic effects in the central nervous system. In some situations, however, the receptors mediate neuroprotective effects. Our recent studies demonstrated that levels of mPGES-1, which catalyzes the final step of PGE2 biosynthesis, are increased at the early-symptomatic stage in the spinal cords of transgenic ALS model mice carrying the G93A variant of superoxide dismutase-1. In addition, in an experimental motor-neuron model used in studies of ALS, PGE2 induces the production of reactive oxygen species and subsequent caspase-3-dependent cytotoxicity through activation of the EP2 receptor. Moreover, this PGE2-induced EP2 up-regulation in motor neurons plays a role in the death of motor neurons in ALS model mice. Further understanding of the pathophysiological role of PGE2 in neurodegeneration may provide new insights to guide the development of novel therapies for ALS.}, } @article {pmid37336982, year = {2023}, author = {Nikom, D and Zheng, S}, title = {Alternative splicing in neurodegenerative disease and the promise of RNA therapies.}, journal = {Nature reviews. Neuroscience}, volume = {24}, number = {8}, pages = {457-473}, pmid = {37336982}, issn = {1471-0048}, support = {R01 NS125276/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Alternative Splicing/genetics ; RNA/genetics/metabolism ; *Neurodegenerative Diseases/genetics/therapy/metabolism ; RNA Splicing ; Protein Isoforms/genetics/metabolism ; *Amyotrophic Lateral Sclerosis ; *Frontotemporal Dementia/genetics ; }, abstract = {Alternative splicing generates a myriad of RNA products and protein isoforms of different functions from a single gene. Dysregulated alternative splicing has emerged as a new mechanism broadly implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson disease and repeat expansion diseases. Understanding the mechanisms and functional outcomes of abnormal splicing in neurological disorders is vital in developing effective therapies to treat mis-splicing pathology. In this Review, we discuss emerging research and evidence of the roles of alternative splicing defects in major neurodegenerative diseases and summarize the latest advances in RNA-based therapeutic strategies to target these disorders.}, } @article {pmid37336364, year = {2023}, author = {Di Maio, A and Nuzzo, T and Gilio, L and Serra, M and Buttari, F and Errico, F and De Rosa, A and Bassi, MS and Morelli, M and Sasabe, J and Sulzer, D and Carta, M and Centonze, D and Usiello, A}, title = {Homeostasis of serine enantiomers is disrupted in the post-mortem caudate putamen and cerebrospinal fluid of living Parkinson's disease patients.}, journal = {Neurobiology of disease}, volume = {184}, number = {}, pages = {106203}, doi = {10.1016/j.nbd.2023.106203}, pmid = {37336364}, issn = {1095-953X}, support = {R01 NS095435/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Parkinson Disease/metabolism ; Serine/metabolism ; Putamen/metabolism ; *Amyotrophic Lateral Sclerosis ; *Alzheimer Disease/metabolism ; Amino Acids ; Receptors, N-Methyl-D-Aspartate/metabolism ; N-Methylaspartate ; Homeostasis ; }, abstract = {L-serine generated in astrocytes plays a pivotal role in modulating essential neurometabolic processes, while its enantiomer, D-serine, specifically regulates NMDA receptor (NMDAR) signalling. Despite their physiological relevance in modulating cerebral activity, serine enantiomers metabolism in Parkinson's disease (PD) remains elusive. Using High-Performance Liquid Chromatography (HPLC), we measured D- and L-serine levels along with other amino acids known to modulate NMDAR function, such as L-glutamate, L-aspartate, D-aspartate, and glycine, in the post-mortem caudate putamen (CPu) and superior frontal gyrus (SFG) of PD patients. Moreover, we examined these amino acids in the cerebrospinal fluid (CSF) of de novo living PD, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) patients versus subjects with other neurological disorders (OND), used as control. We found higher D-serine and L-serine levels in the CPu of PD patients but not in the SFG, a cerebral region that, in contrast to the CPu, is not innervated by nigral dopaminergic terminals. We also highlighted a significant elevation of both serine enantiomers in the CSF samples from PD but not in those of AD and ALS patients, compared with control subjects. By contrast, none or only minor changes were found in the amount of other NMDAR modulating amino acids. Our findings identify D-serine and L-serine level upregulation as a biochemical signature associated with nigrostriatal dopaminergic degeneration in PD.}, } @article {pmid37335771, year = {2023}, author = {Peters, B and Wiedrick, J and Baylor, C}, title = {Effects of Aided Communication on Communicative Participation for People With Amyotrophic Lateral Sclerosis.}, journal = {American journal of speech-language pathology}, volume = {32}, number = {4}, pages = {1450-1465}, pmid = {37335771}, issn = {1558-9110}, support = {R01 DC009834/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Communication ; Speech ; Speech Disorders ; Dysarthria/diagnosis/etiology ; }, abstract = {PURPOSE: Many people with amyotrophic lateral sclerosis (PALS) experience speech changes, which may interfere with participation in communication situations. This study was designed to investigate the effects of aided communication on self-rated communicative participation among PALS and the relationship between speech function and communicative participation for PALS at various stages of speech impairment and communication aid use.

METHOD: Participants with amyotrophic lateral sclerosis completed an online questionnaire in which they identified their current communication methods, rated their speech function, and rated their communicative participation in various situations on a modified version of the Communicative Participation Item Bank short form. PALS who reported using aided communication rated their communicative participation under two conditions: with unaided communication only and with access to all of their communication methods.

RESULTS: Communication aids appeared to support communicative participation for many participants with dysarthria. Across all levels of speech function, PALS who use aided communication reported better participation under the all-methods condition than the unaided-only condition, with the largest benefits for participants with anarthria (Revised ALS Functional Rating Scale [ALSFRS-R] speech rating = 0). Communicative participation ratings worsened with more severe speech impairment under both conditions for most levels of speech function, but PALS with anarthria (ALSFRS-R speech rating = 0) reported better participation under the all-methods condition than those who used residual speech in combination with non speech methods (ALSFRS-R speech rating = 1).

CONCLUSIONS: Aided communication can help PALS continue to participate in various communication situations as their speech function deteriorates. Variability in self-rated communicative participation, even for PALS at the same level of speech function, highlights the need for an individualized approach and consideration of personal and environmental factors in augmentative and alternative communication intervention.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.22782986.}, } @article {pmid37335396, year = {2023}, author = {Dubbioso, R and Spisto, M and Hausdorff, JM and Aceto, G and Iuzzolino, VV and Senerchia, G and De Marco, S and Marcuccio, L and Femiano, C and Iodice, R and Salvatore, E and Santangelo, G and Trojano, L and Moretta, P}, title = {Cognitive impairment is associated with gait variability and fall risk in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {30}, number = {10}, pages = {3056-3067}, doi = {10.1111/ene.15936}, pmid = {37335396}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; *Cognitive Dysfunction/complications ; Gait ; Walking ; Cognition ; }, abstract = {BACKGROUND: In amyotrophic lateral sclerosis (ALS), gait abnormalities contribute to poor mobility and represent a relevant risk for falls. To date, gait studies in ALS patients have focused on the motor dimension of the disease, underestimating the cognitive aspects.

METHODS: Using a wearable gait analysis device, we compared gait patterns in ambulatory ALS patients with mild cognitive impairment (ALS MCI+; n = 18), and without MCI (ALS MCI-; n = 24), and healthy subjects (HS; n = 16) under two conditions: (1) normal gait (single task) and (2) walking while counting backward (dual task). Finally, we examined if the occurrence and number of falls in the 3 months following the baseline test were related to cognition.

RESULTS: In the single task condition, ALS patients, regardless of cognition, displayed higher gait variability than HS, especially for stance and swing time (p < 0.001). The dual task condition revealed additional differences in gait variability parameters between ALS MCI+ and ALS MCI- for cadence (p = 0.005), stance time (p = 0.04), swing time (p = 0.04) and stability index (p = 0.02). Moreover, ALS MCI+ showed a higher occurrence (p = 0.001) and number of falls (p < 0.001) at the follow-up. Regression analyses demonstrated that MCI condition predicted the occurrence of future falls (β = 3.649; p = 0.01) and, together with executive dysfunction, was associated with the number of falls (cognitive impairment: β = 0.63; p < 0.001; executive dysfunction: β = 0.39; p = 0.03), regardless of motor impairment at clinical examination.

CONCLUSION: In ALS, MCI is associated with exaggerated gait variability and predicts the occurrence and number of short-term falls.}, } @article {pmid37334341, year = {2023}, author = {Galeazzi, L and Holzman, J and Mondoloni, M and Rochefort, J}, title = {Lingual fasciculation: A point of call for the diagnosis of amyotrophic lateral sclerosis.}, journal = {Clinical case reports}, volume = {11}, number = {6}, pages = {e7560}, pmid = {37334341}, issn = {2050-0904}, abstract = {A 60-year-old female patient, with no notable medical history, was referred by the internal medicine department for a dry mouth workup. The clinical examination revealed an absence of dryness, and the presence of lingual fasciculations, associated with difficulties in mastication and phonation. These symptoms appeared spontaneously 9 months before the consultation, after leaving confinement. Given the presence of lingual fasciculations, the diagnostic hypothesis of a neurological pathology, in particular amyotrophic lateral sclerosis (ALS), was suspected. After performing an electromyogram (EMG), the diagnosis of ALS was retained. Riluzole treatment was then started, and physical therapy sessions were scheduled. Riluzole allows an average gain of 4 to 6 months of life expectancy. Speech therapy and physical therapy allow to maintain the functions as long as possible and to improve the end-of-life conditions. The interest of early detection of ALS allows delaying the progression of the disease.}, } @article {pmid37334257, year = {2023}, author = {Sennfält, S and Aspegren, O and Engvall, M and Granberg, T and Piehl, F}, title = {Systemic Capillary Leak Syndrome With Cerebral Involvement in a C9orf72 Expansion Carrier: Case Report and Review of the Literature.}, journal = {Neurology. Genetics}, volume = {9}, number = {4}, pages = {e200081}, pmid = {37334257}, issn = {2376-7839}, abstract = {OBJECTIVE: Systemic capillary leak syndrome (SCLS) is a rare condition associated with episodes of hypotension, hemoconcentration, hypoalbuminemia, and rhabdomyolysis. We describe a middle-aged man presenting with several distinct SCLS-like episodes, the last being fatal. In addition, in the year before the final event, he developed rapid cognitive decline with contrast-enhancing lesions on MRI and highly elevated neurofilament light protein levels in CSF.

METHODS: Data and imaging were obtained from patient medical records.

RESULTS: At the time, the SCLS-like episodes were interpreted as myositis secondary to viral infection. A thorough workup for other causes, including genetic testing, was negative. As for the rapid cognitive decline, despite an extensive workup for infectious and inflammatory causes, no definitive diagnosis was made. Whole genome sequencing however identified a C9orf72 hexanucleotide expansion.

DISCUSSION: The C9orf72 expansion is associated with frontotemporal dementia and amyotrophic lateral sclerosis but has also been shown to increase susceptibility to neuroinflammation. Recent findings also suggest C9orf72 to exert functions in the immune system, in particular regulation of type I interferon responses, in turn shown to be associated with SCLS. This case suggests a possible link between SCLS, cerebral inflammation, dysregulated type I interferon signaling, and expansions in C9orf72.}, } @article {pmid37334170, year = {2023}, author = {Zhao, D and Ma, Y and Meng, J and Hu, Y and Hong, M and Zhang, J and Zuo, G and Lv, X and Liu, Y and Shi, C}, title = {MCR-ALS-based muscle synergy extraction method combined with LSTM neural network for motion intention detection.}, journal = {Frontiers in neurorobotics}, volume = {17}, number = {}, pages = {1174710}, pmid = {37334170}, issn = {1662-5218}, abstract = {INTRODUCTION: The time-varying and individual variability of surface electromyographic signals (sEMG) can lead to poorer motor intention detection results from different subjects and longer temporal intervals between training and testing datasets. The consistency of using muscle synergy between the same tasks may be beneficial to improve the detection accuracy over long time ranges. However, the conventional muscle synergy extraction methods, such as non-negative matrix factorization (NMF) and principal component analysis (PCA) have some limitations in the field of motor intention detection, especially in the continuous estimation of upper limb joint angles.

METHODS: In this study, we proposed a reliable multivariate curve-resolved-alternating least squares (MCR-ALS) muscle synergy extraction method combined with long-short term memory neural network (LSTM) to estimate continuous elbow joint motion by using the sEMG datasets from different subjects and different days. The pre-processed sEMG signals were then decomposed into muscle synergies by MCR-ALS, NMF and PCA methods, and the decomposed muscle activation matrices were used as sEMG features. The sEMG features and elbow joint angular signals were input to LSTM to establish a neural network model. Finally, the established neural network models were tested by using sEMG dataset from different subjects and different days, and the detection accuracy was measured by correlation coefficient.

RESULTS: The detection accuracy of elbow joint angle was more than 85% by using the proposed method. This result was significantly higher than the detection accuracies obtained by using NMF and PCA methods. The results showed that the proposed method can improve the accuracy of motor intention detection results from different subjects and different acquisition timepoints.

DISCUSSION: This study successfully improves the robustness of sEMG signals in neural network applications using an innovative muscle synergy extraction method. It contributes to the application of human physiological signals in human-machine interaction.}, } @article {pmid37333922, year = {2023}, author = {Vaccarino, AL and Black, SE and Gilbert Evans, S and Frey, BN and Javadi, M and Kennedy, SH and Lam, B and Lam, RW and Lasalandra, B and Martens, E and Masellis, M and Milev, R and Mitchell, S and Munoz, DP and Sparks, A and Swartz, RH and Tan, B and Uher, R and Evans, KR}, title = {Rasch analyses of the Quick Inventory of Depressive Symptomatology Self-Report in neurodegenerative and major depressive disorders.}, journal = {Frontiers in psychiatry}, volume = {14}, number = {}, pages = {1154519}, pmid = {37333922}, issn = {1664-0640}, abstract = {BACKGROUND: Symptoms of depression are present in neurodegenerative disorders (ND). It is important that depression-related symptoms be adequately screened and monitored in persons living with ND. The Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) is a widely-used self-report measure to assess and monitor depressive severity across different patient populations. However, the measurement properties of the QIDS-SR have not been assessed in ND.

AIM: To use Rasch Measurement Theory to assess the measurement properties of the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) in ND and in comparison to major depressive disorder (MDD).

METHODS: De-identified data from the Ontario Neurodegenerative Disease Research Initiative (NCT04104373) and Canadian Biomarker Integration Network in Depression (NCT01655706) were used in the analyses. Five hundred and twenty participants with ND (Alzheimer's disease or mild cognitive impairment, amyotrophic lateral sclerosis, cerebrovascular disease, frontotemporal dementia and Parkinson's disease) and 117 participants with major depressive disorder (MDD) were administered the QIDS-SR. Rasch Measurement Theory was used to assess measurement properties of the QIDS-SR, including unidimensionality and item-level fit, category ordering, item targeting, person separation index and reliability and differential item functioning.

RESULTS: The QIDS-SR fit well to the Rasch model in ND and MDD, including unidimensionality, satisfactory category ordering and goodness-of-fit. Item-person measures (Wright maps) showed gaps in item difficulties, suggesting poor precision for persons falling between those severity levels. Differences between mean person and item measures in the ND cohort logits suggest that QIDS-SR items target more severe depression than experienced by the ND cohort. Some items showed differential item functioning between cohorts.

CONCLUSION: The present study supports the use of the QIDS-SR in MDD and suggest that the QIDS-SR can be also used to screen for depressive symptoms in persons with ND. However, gaps in item targeting were noted that suggests that the QIDS-SR cannot differentiate participants falling within certain severity levels. Future studies would benefit from examination in a more severely depressed ND cohort, including those with diagnosed clinical depression.}, } @article {pmid37333274, year = {2023}, author = {Tseng, YJ and Malik, I and Deng, X and Krans, A and Jansen-West, K and Tank, EMH and Gomez, NB and Sher, R and Petrucelli, L and Barmada, SJ and Todd, PK}, title = {Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37333274}, issn = {2692-8205}, support = {RF1 AG062171/AG/NIA NIH HHS/United States ; R01 NS086810/NS/NINDS NIH HHS/United States ; P50 HD104463/HD/NICHD NIH HHS/United States ; RF1 AG062077/AG/NIA NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R35 NS097273/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; }, abstract = {A GGGGCC (G4C2) hexanucleotide repeat expansion in C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), while a CGG trinucleotide repeat expansion in FMR1 leads to the neurodegenerative disorder Fragile X-associated tremor/ataxia syndrome (FXTAS). These GC-rich repeats form RNA secondary structures that support repeat-associated non-AUG (RAN) translation of toxic proteins that contribute to disease pathogenesis. Here we assessed whether these same repeats might trigger stalling and interfere with translational elongation. We find that depletion of ribosome-associated quality control (RQC) factors NEMF, LTN1, and ANKZF1 markedly boost RAN translation product accumulation from both G4C2 and CGG repeats while overexpression of these factors reduces RAN production in both reporter cell lines and C9ALS/FTD patient iPSC-derived neurons. We also detected partially made products from both G4C2 and CGG repeats whose abundance increased with RQC factor depletion. Repeat RNA sequence, rather than amino acid content, is central to the impact of RQC factor depletion on RAN translation - suggesting a role for RNA secondary structure in these processes. Together, these findings suggest that ribosomal stalling and RQC pathway activation during RAN translation elongation inhibits the generation of toxic RAN products. We propose augmenting RQC activity as a therapeutic strategy in GC-rich repeat expansion disorders.}, } @article {pmid37333227, year = {2023}, author = {Krebs, AS and Liu, HF and Zhou, Y and Rey, JS and Levintov, L and Shen, J and Howe, A and Perilla, JR and Bartesaghi, A and Zhang, P}, title = {Molecular architecture and conservation of an immature human endogenous retrovirus.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37333227}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 AI157843/AI/NIAID NIH HHS/United States ; R01 GM141223/GM/NIGMS NIH HHS/United States ; }, abstract = {A significant part of the human genome consists of endogenous retroviruses sequences. Human endogenous retrovirus K (HERV-K) is the most recently acquired endogenous retrovirus, is activated and expressed in many cancers and amyotrophic lateral sclerosis and possibly contributes to the aging process. To understand the molecular architecture of endogenous retroviruses, we determined the structure of immature HERV-K from native virus-like particles (VLPs) using cryo-electron tomography and subtomogram averaging (cryoET STA). The HERV-K VLPs show a greater distance between the viral membrane and immature capsid lattice, correlating with the presence of additional peptides, SP1 and p15, between the capsid (CA) and matrix (MA) proteins compared to the other retroviruses. The resulting cryoET STA map of the immature HERV-K capsid at 3.2 Å resolution shows a hexamer unit oligomerized through a 6-helix bundle which is further stabilized by a small molecule in the same way as the IP6 in immature HIV-1 capsid. The HERV-K immature CA hexamer assembles into the immature lattice via highly conserved dimmer and trimer interfaces, whose interactions were further detailed through all-atom molecular dynamics simulations and supported by mutational studies. A large conformational change mediated by the flexible linker between the N-terminal and the C-terminal domains of CA occurs between the immature and the mature HERV-K capsid protein, analogous to HIV-1. Comparison between HERV-K and other retroviral immature capsid structures reveals a highly conserved mechanism for the assembly and maturation of retroviruses across genera and evolutionary time.}, } @article {pmid37333144, year = {2023}, author = {Nelson, AT and Cicardi, ME and Markandaiah, SS and Han, J and Philp, N and Welebob, E and Haeusler, AR and Pasinelli, P and Manfredi, G and Kawamata, H and Trotti, D}, title = {Glucose Hypometabolism Prompts RAN Translation and Exacerbates C9orf72-related ALS/FTD Phenotypes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37333144}, issn = {2692-8205}, support = {RF1 NS114128/NS/NINDS NIH HHS/United States ; R21 NS090912/NS/NINDS NIH HHS/United States ; R01 NS109150/NS/NINDS NIH HHS/United States ; R35 NS122209/NS/NINDS NIH HHS/United States ; F31 NS118838/NS/NINDS NIH HHS/United States ; RF1 AG057882/AG/NIA NIH HHS/United States ; }, abstract = {The most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC)n nucleotide repeat expansion (NRE) occurring in the first intron of the C9orf72 gene (C9). Brain glucose hypometabolism is consistently observed in C9-NRE carriers, even at pre-symptomatic stages, although its potential role in disease pathogenesis is unknown. Here, we identified alterations in glucose metabolic pathways and ATP levels in the brain of asymptomatic C9-BAC mice. We found that, through activation of the GCN2 kinase, glucose hypometabolism drives the production of dipeptide repeat proteins (DPRs), impairs the survival of C9 patient-derived neurons, and triggers motor dysfunction in C9-BAC mice. We also found that one of the arginine-rich DPRs (PR) can directly contribute to glucose metabolism and metabolic stress. These findings provide a mechanistic link between energy imbalances and C9-ALS/FTD pathogenesis and support a feedforward loop model that opens several opportunities for therapeutic intervention.}, } @article {pmid37333094, year = {2023}, author = {Guise, AJ and Misal, SA and Carson, R and Boekweg, H and Watt, DV and Truong, T and Liang, Y and Chu, JH and Welsh, NC and Gagnon, J and Payne, SH and Plowey, ED and Kelly, RT}, title = {TDP-43-stratified single-cell proteomic profiling of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37333094}, issn = {2692-8205}, support = {R01 GM138931/GM/NIGMS NIH HHS/United States ; R33 CA225248/CA/NCI NIH HHS/United States ; }, abstract = {Unbiased proteomics has been employed to interrogate central nervous system (CNS) tissues (brain, spinal cord) and fluid matrices (CSF, plasma) from amyotrophic lateral sclerosis (ALS) patients; yet, a limitation of conventional bulk tissue studies is that motor neuron (MN) proteome signals may be confounded by admixed non-MN proteins. Recent advances in trace sample proteomics have enabled quantitative protein abundance datasets from single human MNs (Cong et al., 2020b). In this study, we leveraged laser capture microdissection (LCM) and nanoPOTS (Zhu et al., 2018c) single-cell mass spectrometry (MS)-based proteomics to query changes in protein expression in single MNs from postmortem ALS and control donor spinal cord tissues, leading to the identification of 2515 proteins across MNs samples (>900 per single MN) and quantitative comparison of 1870 proteins between disease groups. Furthermore, we studied the impact of enriching/stratifying MN proteome samples based on the presence and extent of immunoreactive, cytoplasmic TDP-43 inclusions, allowing identification of 3368 proteins across MNs samples and profiling of 2238 proteins across TDP-43 strata. We found extensive overlap in differential protein abundance profiles between MNs with or without obvious TDP-43 cytoplasmic inclusions that together point to early and sustained dysregulation of oxidative phosphorylation, mRNA splicing and translation, and retromer-mediated vesicular transport in ALS. Our data are the first unbiased quantification of single MN protein abundance changes associated with TDP-43 proteinopathy and begin to demonstrate the utility of pathology-stratified trace sample proteomics for understanding single-cell protein abundance changes in human neurologic diseases.}, } @article {pmid37333039, year = {2023}, author = {Mann, RH}, title = {Impaired Thiamine Metabolism in Amyotrophic Lateral Sclerosis and Its Potential Treatment With Benfotiamine: A Case Report and a Review of the Literature.}, journal = {Cureus}, volume = {15}, number = {6}, pages = {e40511}, pmid = {37333039}, issn = {2168-8184}, abstract = {Homogenates of brain tissue from the frontal cortex at autopsy in patients with amyotrophic lateral sclerosis (ALS) showed dramatically reduced levels of the enzyme thiamine pyrophosphatase (TPPase), the enzyme responsible for the conversion of thiamine pyrophosphate (TPP) to thiamine monophosphate (TMP). Additionally, free thiamine (vitamin B1) and TMP levels have been shown to be significantly reduced in the plasma and cerebral spinal fluid (CSF) of patients with ALS. These findings suggest that there is impaired thiamine metabolism in patients with ALS. Impaired thiamine metabolism decreases adenosine triphosphate (ATP) production and is a well-established cause of neurodegeneration. Decreased levels of TPPase, resulting in decreased levels of TMP in the cells of the frontal cortex, might account for the focal neurodegenerative changes observed in motor neurons in ALS. Benfotiamine, a safe, lipid-soluble, highly absorbable thiamine analogue, significantly raises free thiamine, TMP, and TPP levels in the blood. A case in which benfotiamine may have positively impacted the symptoms of a patient with ALS is presented. The use of benfotiamine in patients with ALS appears to be a promising therapeutic option. Considering the severity and the lack of satisfactory treatment options associated with this disease, more research on the effects of benfotiamine on the course of ALS is urgently needed.}, } @article {pmid37333000, year = {2023}, author = {Boostani, R and Olfati, N and Shamshiri, H and Salimi, Z and Fatehi, F and Hedjazi, SA and Fakharian, A and Ghasemi, M and Okhovat, AA and Basiri, K and Haghi Ashtiani, B and Ansari, B and Raissi, GR and Khatoonabadi, SA and Sarraf, P and Movahed, S and Panahi, A and Ziaadini, B and Yazdchi, M and Bakhtiyari, J and Nafissi, S}, title = {Iranian clinical practice guideline for amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1154579}, pmid = {37333000}, issn = {1664-2295}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegeneration involving motor neurons. The 3-5 years that patients have to live is marked by day-to-day loss of motor and sometimes cognitive abilities. Enormous amounts of healthcare services and resources are necessary to support patients and their caregivers during this relatively short but burdensome journey. Organization and management of these resources need to best meet patients' expectations and health system efficiency mandates. This can only occur in the setting of multidisciplinary ALS clinics which are known as the gold standard of ALS care worldwide. To introduce this standard to the care of Iranian ALS patients, which is an inevitable quality milestone, a national ALS clinical practice guideline is the necessary first step. The National ALS guideline will serve as the knowledge base for the development of local clinical pathways to guide patient journeys in multidisciplinary ALS clinics. To this end, we gathered a team of national neuromuscular experts as well as experts in related specialties necessary for delivering multidisciplinary care to ALS patients to develop the Iranian ALS clinical practice guideline. Clinical questions were prepared in the Patient, Intervention, Comparison, and Outcome (PICO) format to serve as a guide for the literature search. Considering the lack of adequate national/local studies at this time, a consensus-based approach was taken to evaluate the quality of the retrieved evidence and summarize recommendations.}, } @article {pmid37332910, year = {2023}, author = {Rather, MA and Khan, A and Wang, L and Jahan, S and Rehman, MU and Makeen, HA and Mohan, S}, title = {TRP channels: Role in neurodegenerative diseases and therapeutic targets.}, journal = {Heliyon}, volume = {9}, number = {6}, pages = {e16910}, pmid = {37332910}, issn = {2405-8440}, abstract = {TRP (Transient receptor potential) channels are integral membrane proteins consisting of a superfamily of cation channels that allow permeability of both monovalent and divalent cations. TRP channels are subdivided into six subfamilies: TRPC, TRPV, TRPM, TRPP, TRPML, and TRPA, and are expressed in almost every cell and tissue. TRPs play an instrumental role in the regulation of various physiological processes. TRP channels are extensively represented in brain tissues and are present in both prokaryotes and eukaryotes, exhibiting responses to several mechanisms, including physical, chemical, and thermal stimuli. TRP channels are involved in the perturbation of Ca[2+] homeostasis in intracellular calcium stores, both in neuronal and non-neuronal cells, and its discrepancy leads to several neuronal disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). TRPs participate in neurite outgrowth, receptor signaling, and excitotoxic cell death in the central nervous system. Understanding the mechanism of TRP channels in neurodegenerative diseases may extend to developing novel therapies. Thus, this review articulates TRP channels' physiological and pathological role in exploring new therapeutic interventions in neurodegenerative diseases.}, } @article {pmid37332610, year = {2023}, author = {Ghaffari, LT and Trotti, D and Haeusler, AR}, title = {Differential response of C9orf72 transcripts following neuronal depolarization.}, journal = {iScience}, volume = {26}, number = {6}, pages = {106959}, pmid = {37332610}, issn = {2589-0042}, support = {R21 NS090912/NS/NINDS NIH HHS/United States ; R21 NS116761/NS/NINDS NIH HHS/United States ; RF1 AG057882/AG/NIA NIH HHS/United States ; RF1 NS114128/NS/NINDS NIH HHS/United States ; }, abstract = {The (G4C2)n nucleotide repeat expansion (NRE) mutation in C9orf72 is the most common genetic cause of ALS and FTD. The biological functions of C9orf72 are becoming understood, but it is unclear if this gene is regulated in a neural-specific manner. Neuronal activity is a crucial modifier of biological processes in health and neurodegenerative disease contexts. Here, we show that prolonged membrane depolarization in healthy human iPSC-cortical neurons leads to a significant downregulation of a transcript variant 3 (V3) of C9orf72, with a concomitant increase in variant 2 (V2), which leads to total C9orf72 RNA transcript levels remaining unchanged. However, the same response is not observed in cortical neurons derived from patients with the C9-NRE mutation. These findings reveal the impact of depolarization on C9orf72 transcripts, and how this response diverges in C9-NRE-carriers, which may have important implications in the underlying unique clinical associations of C9-NRE transcripts and disease pathogenesis.}, } @article {pmid37332605, year = {2023}, author = {Miyagi, T and Ueda, K and Sugimoto, M and Yagi, T and Ito, D and Yamazaki, R and Narumi, S and Hayamizu, Y and Uji-I, H and Kuroda, M and Kanekura, K}, title = {Differential toxicity and localization of arginine-rich C9ORF72 dipeptide repeat proteins depend on de-clustering of positive charges.}, journal = {iScience}, volume = {26}, number = {6}, pages = {106957}, pmid = {37332605}, issn = {2589-0042}, abstract = {Arginine-rich dipeptide repeat proteins (R-DPRs), poly(PR) and poly(GR), translated from the hexanucleotide repeat expansion in the amyotrophic lateral sclerosis (ALS)-causative C9ORF72 gene, contribute significantly to pathogenesis of ALS. Although both R-DPRs share many similarities, there are critical differences in their subcellular localization, phase separation, and toxicity mechanisms. We analyzed localization, protein-protein interactions, and phase separation of R-DPR variants and found that sufficient segregation of arginine charges is necessary for nucleolar distribution. Proline not only efficiently separated the charges, but also allowed for weak, but highly multivalent binding. In contrast, because of its high flexibility, glycine cannot fully separate the charges, and poly(GR) behaves similarly to the contiguous arginines, being trapped in the cytoplasm. We conclude that the amino acid that spaces the arginine charges determines the strength and multivalency of the binding, leading to differences in localization and toxicity mechanisms.}, } @article {pmid37331748, year = {2023}, author = {Ma, Y and Ye, S and Zhao, D and Liu, X and Cao, L and Zhou, H and Zuo, G and Shi, C}, title = {Using different matrix factorization approaches to identify muscle synergy in stroke survivors.}, journal = {Medical engineering & physics}, volume = {117}, number = {}, pages = {103993}, doi = {10.1016/j.medengphy.2023.103993}, pmid = {37331748}, issn = {1873-4030}, mesh = {Humans ; *Muscle, Skeletal/physiology ; Electromyography ; *Stroke/complications ; Algorithms ; }, abstract = {Over the past several decades, many scholars have investigated muscle synergy as a promising tool for evaluating motor function. However, it is challenging to obtain favorable robustness using the general muscle synergy identification algorithms, namely non-negative matrix factorization (NMF), independent component analysis (ICA), and factor analysis (FA). Some scholars have proposed improved muscle synergy identification algorithms to overcome the shortcomings of these approaches, such as singular value decomposition NMF (SVD-NMF), sparse NMF (S-NMF), and multivariate curve resolution-alternating least squares (MCR-ALS). However, performance comparisons of these algorithms are seldom conducted. In this study, experimental electromyography (EMG) data collected from healthy individuals and stroke survivors were applied to assess the repeatability and intra-subject consistency of NMF, SVD-NMF, S-NMF, ICA, FA, and MCR-ALS. MCR-ALS presented higher repeatability and intra-subject consistencies than the other algorithms. More synergies and lower intra-subject consistencies were observed in stroke survivors than in healthy individuals. Thus, MCR-ALS is considered a favorable muscle synergy identification algorithm for patients with neural system disorders.}, } @article {pmid37331636, year = {2023}, author = {Zhang, H and Qi, G and Wang, K and Yang, J and Shen, Y and Yang, X and Chen, X and Yao, X and Gu, X and Qi, L and Zhou, C and Sun, H}, title = {Oxidative stress: Roles in skeletal muscle atrophy.}, journal = {Biochemical pharmacology}, volume = {214}, number = {}, pages = {115664}, doi = {10.1016/j.bcp.2023.115664}, pmid = {37331636}, issn = {1873-2968}, mesh = {Humans ; *Muscular Atrophy/metabolism ; Oxidative Stress ; Muscle, Skeletal/metabolism ; *Sarcopenia/drug therapy/metabolism/pathology ; Antioxidants/metabolism ; Chronic Disease ; }, abstract = {Oxidative stress, inflammation, mitochondrial dysfunction, reduced protein synthesis, and increased proteolysis are all critical factors in the process of muscle atrophy. In particular, oxidative stress is the key factor that triggers skeletal muscle atrophy. It is activated in the early stages of muscle atrophy and can be regulated by various factors. The mechanisms of oxidative stress in the development of muscle atrophy have not been completely elucidated. This review provides an overview of the sources of oxidative stress in skeletal muscle and the correlation of oxidative stress with inflammation, mitochondrial dysfunction, autophagy, protein synthesis, proteolysis, and muscle regeneration in muscle atrophy. Additionally, the role of oxidative stress in skeletal muscle atrophy caused by several pathological conditions, including denervation, unloading, chronic inflammatory diseases (diabetes mellitus, chronic kidney disease, chronic heart failure, and chronic obstructive pulmonary disease), sarcopenia, hereditary neuromuscular diseases (spinal muscular atrophy, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy), and cancer cachexia, have been discussed. Finally, this review proposes the alleviation oxidative stress using antioxidants, Chinese herbal extracts, stem cell and extracellular vesicles as a promising therapeutic strategy for muscle atrophy. This review will aid in the development of novel therapeutic strategies and drugs for muscle atrophy.}, } @article {pmid37328865, year = {2023}, author = {Wainberg, M and Andrews, SJ and Tripathy, SJ}, title = {Shared genetic risk loci between Alzheimer's disease and related dementias, Parkinson's disease, and amyotrophic lateral sclerosis.}, journal = {Alzheimer's research & therapy}, volume = {15}, number = {1}, pages = {113}, pmid = {37328865}, issn = {1758-9193}, support = {R00 AG070109/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics ; *Parkinson Disease/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Genome-Wide Association Study ; Genetic Predisposition to Disease/genetics ; *Neurodegenerative Diseases/genetics ; Polymorphism, Single Nucleotide/genetics ; }, abstract = {BACKGROUND: Genome-wide association studies (GWAS) have indicated moderate genetic overlap between Alzheimer's disease (AD) and related dementias (ADRD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), neurodegenerative disorders traditionally considered etiologically distinct. However, the specific genetic variants and loci underlying this overlap remain almost entirely unknown.

METHODS: We leveraged state-of-the-art GWAS for ADRD, PD, and ALS. For each pair of disorders, we examined each of the GWAS hits for one disorder and tested whether they were also significant for the other disorder, applying Bonferroni correction for the number of variants tested. This approach rigorously controls the family-wise error rate for both disorders, analogously to genome-wide significance.

RESULTS: Eleven loci with GWAS hits for one disorder were also associated with one or both of the other disorders: one with all three disorders (the MAPT/KANSL1 locus), five with ADRD and PD (near LCORL, CLU, SETD1A/KAT8, WWOX, and GRN), three with ADRD and ALS (near GPX3, HS3ST5/HDAC2/MARCKS, and TSPOAP1), and two with PD and ALS (near GAK/TMEM175 and NEK1). Two of these loci (LCORL and NEK1) were associated with an increased risk of one disorder but decreased risk of another. Colocalization analysis supported a shared causal variant between ADRD and PD at the CLU, WWOX, and LCORL loci, between ADRD and ALS at the TSPOAP1 locus, and between PD and ALS at the NEK1 and GAK/TMEM175 loci. To address the concern that ADRD is an imperfect proxy for AD and that the ADRD and PD GWAS have overlapping participants (nearly all of which are from the UK Biobank), we confirmed that all our ADRD associations had nearly identical odds ratios in an AD GWAS that excluded the UK Biobank, and all but one remained nominally significant (p < 0.05) for AD.

CONCLUSIONS: In one of the most comprehensive investigations to date of pleiotropy between neurodegenerative disorders, we identify eleven genetic risk loci shared among ADRD, PD, and ALS. These loci support lysosomal/autophagic dysfunction (GAK/TMEM175, GRN, KANSL1), neuroinflammation/immunity (TSPOAP1), oxidative stress (GPX3, KANSL1), and the DNA damage response (NEK1) as transdiagnostic processes underlying multiple neurodegenerative disorders.}, } @article {pmid37328685, year = {2023}, author = {Pisharady, PK and Eberly, LE and Adanyeguh, IM and Manousakis, G and Guliani, G and Walk, D and Lenglet, C}, title = {Multimodal MRI improves diagnostic accuracy and sensitivity to longitudinal change in amyotrophic lateral sclerosis.}, journal = {Communications medicine}, volume = {3}, number = {1}, pages = {84}, pmid = {37328685}, issn = {2730-664X}, support = {P41 EB015894/EB/NIBIB NIH HHS/United States ; }, abstract = {BACKGROUND: Recent advances in MRI acquisitions and image analysis have increased the utility of neuroimaging in understanding disease-related changes. In this work, we aim to demonstrate increased sensitivity to disease progression as well as improved diagnostic accuracy in Amyotrophic lateral sclerosis (ALS) with multimodal MRI of the brain and cervical spinal cord.

METHODS: We acquired diffusion MRI data from the brain and cervical cord, and T1 data from the brain, of 20 participants with ALS and 20 healthy control participants. Ten ALS and 14 control participants, and 11 ALS and 13 control participants were re-scanned at 6-month and 12-month follow-ups respectively. We estimated cross-sectional differences and longitudinal changes in diffusion metrics, cortical thickness, and fixel-based microstructure measures, i.e. fiber density and fiber cross-section.

RESULTS: We demonstrate improved disease diagnostic accuracy and sensitivity through multimodal analysis of brain and spinal cord metrics. The brain metrics also distinguished lower motor neuron-predominant ALS participants from control participants. Fiber density and cross-section provided the greatest sensitivity to longitudinal change. We demonstrate evidence of progression in a cohort of 11 participants with slowly progressive ALS, including in participants with very slow change in ALSFRS-R. More importantly, we demonstrate that longitudinal change is detectable at a six-month follow-up visit. We also report correlations between ALSFRS-R and the fiber density and cross-section metrics.

CONCLUSIONS: Our findings suggest that multimodal MRI is useful in improving disease diagnosis, and fixel-based measures may serve as potential biomarkers of disease progression in ALS clinical trials.}, } @article {pmid37328037, year = {2023}, author = {Xu, L and Wang, D and Zhao, L and Yang, Z and Liu, X and Li, X and Yuan, T and Wang, Y and Huang, T and Bian, N and He, Y and Chen, X and Tian, B and Liu, Z and Luo, F and Si, W and Gao, G and Ji, W and Niu, Y and Wei, J}, title = {C9orf72 poly(PR) aggregation in nucleus induces ALS/FTD-related neurodegeneration in cynomolgus monkeys.}, journal = {Neurobiology of disease}, volume = {184}, number = {}, pages = {106197}, doi = {10.1016/j.nbd.2023.106197}, pmid = {37328037}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; C9orf72 Protein/genetics/metabolism ; Dipeptides/genetics ; DNA Repeat Expansion ; *Frontotemporal Dementia/genetics/pathology ; Macaca fascicularis/genetics/metabolism ; Proteins/genetics ; Proteomics ; Disease Models, Animal ; }, abstract = {Poly(PR) is a dipeptide repeat protein comprising proline and arginine residues. It is one of the translational product of expanded G4C2 repeats in the C9orf72 gene, and its accumulation is contributing to the neuropathogenesis of C9orf72-associated amyotrophic lateral sclerosis and/or frontotemporal dementia (C9-ALS/FTD). In this study, we demonstrate that poly(PR) protein alone is sufficient to induce neurodegeneration related to ALS/FTD in cynomolgus monkeys. By delivering poly(PR) via AAV, we observed that the PR proteins were located within the nucleus of infected cells. The expression of (PR)50 protein, consisting of 50 PR repeats, led to increased loss of cortical neurons, cytoplasmic lipofuscin, and gliosis in the brain, as well as demyelination and loss of ChAT positive neurons in the spinal cord of monkeys. While, these pathologies were not observed in monkeys expressing (PR)5, a protein comprising only 5 PR repeats. Furthermore, the (PR)50-expressing monkeys exhibited progressive motor deficits, cognitive impairment, muscle atrophy, and abnormal electromyography (EMG) potentials, which closely resemble clinical symptoms seen in C9-ALS/FTD patients. By longitudinally tracking these monkeys, we found that changes in cystatin C and chitinase-1 (CHIT1) levels in the cerebrospinal fluid (CSF) corresponded to the phenotypic progression of (PR)50-induced disease. Proteomic analysis revealed that the major clusters of dysregulated proteins were nuclear-localized, and downregulation of the MECP2 protein was implicated in the toxic process of poly(PR). This research indicates that poly(PR) expression alone induces neurodegeneration and core phenotypes associated with C9-ALS/FTD in monkeys, which may provide insights into the mechanisms of disease pathogenesis.}, } @article {pmid37327984, year = {2023}, author = {Tzeplaeff, L and Seguin, J and Le Gras, S and Megat, S and Cosquer, B and Plassard, D and Dieterlé, S and Paiva, I and Picchiarelli, G and Decraene, C and Alcala-Vida, R and Cassel, JC and Merienne, K and Dupuis, L and Boutillier, AL}, title = {Mutant FUS induces chromatin reorganization in the hippocampus and alters memory processes.}, journal = {Progress in neurobiology}, volume = {227}, number = {}, pages = {102483}, doi = {10.1016/j.pneurobio.2023.102483}, pmid = {37327984}, issn = {1873-5118}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; Chromatin/metabolism ; Epigenesis, Genetic ; *Frontotemporal Dementia/genetics ; Hippocampus/metabolism ; Mutation ; RNA-Binding Protein FUS/genetics/metabolism ; Disease Models, Animal ; }, abstract = {Cytoplasmic mislocalization of the nuclear Fused in Sarcoma (FUS) protein is associated to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS accumulation is recapitulated in the frontal cortex and spinal cord of heterozygous Fus[∆NLS/+] mice. Yet, the mechanisms linking FUS mislocalization to hippocampal function and memory formation are still not characterized. Herein, we show that in these mice, the hippocampus paradoxically displays nuclear FUS accumulation. Multi-omic analyses showed that FUS binds to a set of genes characterized by the presence of an ETS/ELK-binding motifs, and involved in RNA metabolism, transcription, ribosome/mitochondria and chromatin organization. Importantly, hippocampal nuclei showed a decompaction of the neuronal chromatin at highly expressed genes and an inappropriate transcriptomic response was observed after spatial training of Fus[∆NLS/+] mice. Furthermore, these mice lacked precision in a hippocampal-dependent spatial memory task and displayed decreased dendritic spine density. These studies shows that mutated FUS affects epigenetic regulation of the chromatin landscape in hippocampal neurons, which could participate in FTD/ALS pathogenic events. These data call for further investigation in the neurological phenotype of FUS-related diseases and open therapeutic strategies towards epigenetic drugs.}, } @article {pmid37327376, year = {2023}, author = {Shefner, JM and Musaro, A and Ngo, ST and Lunetta, C and Steyn, FJ and Robitaille, R and De Carvalho, M and Rutkove, S and Ludolph, AC and Dupuis, L}, title = {Skeletal muscle in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {146}, number = {11}, pages = {4425-4436}, pmid = {37327376}, issn = {1460-2156}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/pathology ; Motor Neurons/pathology ; Muscle, Skeletal/pathology ; Neuromuscular Junction/pathology ; Muscle Weakness ; }, abstract = {Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with muscle changes interpreted as a consequence of the progressive loss of motor neurons and neuromuscular junctions. This has led to the prevailing view that the involvement of muscle in ALS is only secondary to motor neuron loss. Skeletal muscle and motor neurons reciprocally influence their respective development and constitute a single functional unit. In ALS, multiple studies indicate that skeletal muscle dysfunction might contribute to progressive muscle weakness, as well as to the final demise of neuromuscular junctions and motor neurons. Furthermore, skeletal muscle has been shown to participate in disease pathogenesis of several monogenic diseases closely related to ALS. Here, we move the narrative towards a better appreciation of muscle as a contributor of disease in ALS. We review the various potential roles of skeletal muscle cells in ALS, from passive bystanders to active players in ALS pathophysiology. We also compare ALS to other motor neuron diseases and draw perspectives for future research and treatment.}, } @article {pmid37326935, year = {2023}, author = {Cantisani, TA}, title = {Is there a treatment effective and safe for sialorrhea in people with amyotrophic lateral sclerosis (ALS)? Summary of a Cochrane Systematic Review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {9}, pages = {3083-3085}, pmid = {37326935}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; *Botulinum Toxins/therapeutic use ; *Sialorrhea/therapy/drug therapy ; Treatment Outcome ; Systematic Reviews as Topic ; }, } @article {pmid37326908, year = {2023}, author = {Zheng, C and Li, W and Ali, T and Peng, Z and Liu, J and Pan, Z and Feng, J and Li, S}, title = {Ibrutinib Delays ALS Installation and Increases Survival of SOD1[G93A] Mice by Modulating PI3K/mTOR/Akt Signaling.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {18}, number = {3}, pages = {383-396}, pmid = {37326908}, issn = {1557-1904}, support = {NCT03721302//International Cooperation Project（NCT03721302）of Shenzhen Children's Hospital/ ; 2019SHIBS0004//Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions/ ; JCYJ20220530155611026//Basic research of Shenzhen Science and Technology Plan Project（General Program/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal multisystem degenerative disorder with minimal available therapeutic. However, some recent studies showed promising results of immunological-based treatment. Here, we aimed to evaluate the efficacy of ibrutinib against ALS-associated abnormalities by targeting inflammation and muscular atrophy. Ibrutinib was administrated orally to SOD1 [G93A] mice from 6 to 19 weeks for prophylactic administration and 13 to 19 weeks for therapeutic administration. Our results demonstrated that ibrutinib treatment significantly delayed ALS-like symptom onset in the SOD1 [G93A] mice, as shown by improved survival time and reduced behavioral impairments. Ibrutinib treatment significantly reduced muscular atrophy by increasing muscle/body weight and decreasing muscular necrosis. The ibrutinib treatment also considerably reduced pro-inflammatory cytokine production, IBA-1, and GFAP expression, possibly mediated by mTOR/Akt/Pi3k signaling in the medulla, motor cortex and spinal cord of the ALS mice. In conclusion, our study demonstrated that ibrutinib could delay ALS onset, increase survival time, and reduce ALS progression by targeting inflammation and muscular atrophy via mTOR/Akt/PI3K modulation.}, } @article {pmid37323141, year = {2023}, author = {Khatoon, S and Kalam, N and Rashid, S and Bano, G}, title = {Effects of gut microbiota on neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1145241}, pmid = {37323141}, issn = {1663-4365}, abstract = {A progressive degradation of the brain's structure and function, which results in a reduction in cognitive and motor skills, characterizes neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The morbidity linked to NDs is growing, which poses a severe threat to human being's mental and physical ability to live well. The gut-brain axis (GBA) is now known to have a crucial role in the emergence of NDs. The gut microbiota is a conduit for the GBA, a two-way communication system between the gut and the brain. The myriad microorganisms that make up the gut microbiota can affect brain physiology by transmitting numerous microbial chemicals from the gut to the brain via the GBA or neurological system. The synthesis of neurotransmitters, the immunological response, and the metabolism of lipids and glucose have all been demonstrated to be impacted by alterations in the gut microbiota, such as an imbalance of helpful and harmful bacteria. In order to develop innovative interventions and clinical therapies for NDs, it is crucial to comprehend the participation of the gut microbiota in these conditions. In addition to using antibiotics and other drugs to target particular bacterial species that may be a factor in NDs, this also includes using probiotics and other fecal microbiota transplantation to maintain a healthy gut microbiota. In conclusion, the examination of the GBA can aid in understanding the etiology and development of NDs, which may benefit the improvement of clinical treatments for these disorders and ND interventions. This review indicates existing knowledge about the involvement of microbiota present in the gut in NDs and potential treatment options.}, } @article {pmid37323039, year = {2023}, author = {Baeken, C}, title = {[Haalt rTMS ECT in als behandeling voor depressie? Waarschijnlijk niet in Europa].}, journal = {Tijdschrift voor psychiatrie}, volume = {65}, number = {4}, pages = {219-221}, pmid = {37323039}, issn = {0303-7339}, mesh = {Humans ; *Depressive Disorder, Major ; Transcranial Magnetic Stimulation ; }, } @article {pmid37322338, year = {2023}, author = {Maxwell, MN and Marullo, AL and Slyne, AD and Lucking, EF and O'Halloran, KD}, title = {Ventilatory Effects of Acute Intermittent Hypoxia in Conscious Dystrophic Mice.}, journal = {Advances in experimental medicine and biology}, volume = {1427}, number = {}, pages = {83-88}, doi = {10.1007/978-3-031-32371-3_9}, pmid = {37322338}, issn = {0065-2598}, mesh = {Mice ; Male ; Animals ; Mice, Inbred mdx ; *Hypoxia ; *Respiration ; Hypercapnia ; }, abstract = {Exposure to acute intermittent hypoxia (AIH) elicits a form of respiratory plasticity known as long-term facilitation (LTF). Interest has grown in developing AIH interventions to treat ventilatory insufficiency, with promising results in spinal cord injury and amyotrophic lateral sclerosis. Therapeutic AIH may have application in neuromuscular disorders including muscular dystrophies. We sought to establish hypoxic ventilatory responsiveness and the expression of ventilatory LTF in X-linked muscular dystrophy (mdx) mice.Experiments were performed in 15 male wild-type (BL10) and 15 male mdx mice at 4 months of age. Ventilation was assessed using whole-body plethysmography. Baseline measures of ventilation and metabolism were established. Mice were exposed to 10 successive bouts of hypoxia, each lasting 5 min, interspersed with 5-min bouts of normoxia. Measurements were taken for 60 min following termination of AIH.In mdx mice, ventilation was significantly increased 60 min post-AIH compared to baseline. However, metabolic CO2 production was also increased. Therefore, ventilatory equivalent was unaffected by AIH exposure, i.e., no ventilatory LTF manifestation. In wild-type mice, ventilation and metabolism were not affected by AIH.Eliciting ventilatory LTF is dependent on many factors and may require concomitant isocapnia or hypercapnia during AIH exposures and/or repeated daily AIH exposures, which is worthy of further pursuit.}, } @article {pmid37319115, year = {2023}, author = {Yang, F and Mahaman, YAR and Zhang, B and Wang, JZ and Liu, R and Liu, F and Wang, X}, title = {C9orf72 poly-PR helps p53 escape from the ubiquitin-proteasome system and promotes its stability.}, journal = {Journal of neurochemistry}, volume = {166}, number = {2}, pages = {389-402}, doi = {10.1111/jnc.15872}, pmid = {37319115}, issn = {1471-4159}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Proteasome Endopeptidase Complex/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Ubiquitin/metabolism ; C9orf72 Protein/genetics/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; Cytoplasm/metabolism ; Dipeptides/genetics ; DNA Repeat Expansion ; }, abstract = {C9orf72-derived dipeptide repeats (DPRs) proteins have been regarded as the pathogenic cause of neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). As the most toxic DPRs in C9-ALS/FTD, poly-proline-arginine (poly-PR) is associated with the stability and accumulation of p53, which consequently induces neurodegeneration. However, the exact molecular mechanism via which C9orf72 poly-PR stabilizes p53 remains unclear. In this study, we showed that C9orf72 poly-PR induces not only neuronal damage but also p53 accumulation and p53 downstream gene activation in primary neurons. C9orf72 (PR)50 also slows down p53 protein turnover without affecting the p53 transcription level and thus promotes its stability in N2a cells. Interestingly, the ubiquitin-proteasome system but not the autophagy function was impaired in (PR)50 transfected N2a cells, resulting in defective p53 degradation. Moreover, we found that (PR)50 induces mdm2 mistranslocation from the nucleus to the cytoplasm and competitively binds to p53, reducing mdm2-p53 interactions in the nucleus in two different (PR)50 transfected cells. Our data strongly indicate that (PR)50 reduces mdm2-p53 interactions and causes p53 to escape from the ubiquitin-proteasome system, promoting its stability and accumulation. Inhibiting or at least downregulating (PR)50 binding with p53 may be therapeutically exploited for the treatment of C9-ALS/FTD.}, } @article {pmid37318330, year = {2023}, author = {Docherty, SR and Safonova, OV and Copéret, C}, title = {Surface Redox Dynamics in Gold-Zinc CO2 Hydrogenation Catalysts.}, journal = {Journal of the American Chemical Society}, volume = {145}, number = {25}, pages = {13526-13530}, doi = {10.1021/jacs.3c03522}, pmid = {37318330}, issn = {1520-5126}, abstract = {Au-Zn catalysts have previously been shown to promote the hydrogenation of CO2 to methanol, but their active state is poorly understood. Here, silica-supported bimetallic Au-Zn alloys, prepared by surface organometallic chemistry (SOMC), are shown to be proficient catalysts for hydrogenation of CO2 to methanol. In situ X-ray absorption spectroscopy (XAS), in conjunction with gas-switching experiments, is used to amplify subtle changes occurring at the surface of this tailored catalyst during reaction. Consequently, an Au-Zn alloy is identified and is shown to undergo subsequent reversible redox changes under reaction conditions according to multivariate curve resolution alternating least-squares (MCR-ALS) analysis. These results highlight the role of alloying and dealloying in Au-based CO2 hydrogenation catalysts and illustrate the role of these reversible processes in driving reactivity.}, } @article {pmid37317656, year = {2023}, author = {Jülg, J and Edbauer, D and Behrends, C}, title = {C9orf72 protein quality control by UBR5-mediated heterotypic ubiquitin chains.}, journal = {EMBO reports}, volume = {24}, number = {8}, pages = {e55895}, pmid = {37317656}, issn = {1469-3178}, mesh = {Humans ; C9orf72 Protein/genetics/metabolism ; Ubiquitin/metabolism ; Carrier Proteins/metabolism ; Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Ubiquitin-Protein Ligases/genetics/metabolism ; Molecular Chaperones/metabolism ; }, abstract = {Hexanucleotide repeat expansions within C9orf72 are a frequent cause of amyotrophic lateral sclerosis and frontotemporal dementia. Haploinsufficiency leading to reduced C9orf72 protein contributes to disease pathogenesis. C9orf72 binds SMCR8 to form a robust complex that regulates small GTPases, lysosomal integrity, and autophagy. In contrast to this functional understanding, we know far less about the assembly and turnover of the C9orf72-SMCR8 complex. Loss of either subunit causes the concurrent ablation of the respective partner. However, the molecular mechanism underlying this interdependence remains elusive. Here, we identify C9orf72 as a substrate of branched ubiquitin chain-dependent protein quality control. We find that SMCR8 prevents C9orf72 from rapid degradation by the proteasome. Mass spectrometry and biochemical analyses reveal the E3 ligase UBR5 and the BAG6 chaperone complex as C9orf72-interacting proteins, which are components of the machinery that modifies proteins with K11/K48-linked heterotypic ubiquitin chains. Depletion of UBR5 results in reduced K11/K48 ubiquitination and increased C9orf72 when SMCR8 is absent. Our data provide novel insights into C9orf72 regulation with potential implication for strategies to antagonize C9orf72 loss during disease progression.}, } @article {pmid37317638, year = {2023}, author = {Yang, Y and Rowe, D and McCann, H and Shepherd, CE and Kril, JJ and Kiernan, MC and Halliday, GM and Tan, RH}, title = {Treatment with the copper compound CuATSM has no significant effect on motor neuronal pathology in patients with ALS.}, journal = {Neuropathology and applied neurobiology}, volume = {49}, number = {4}, pages = {e12919}, pmid = {37317638}, issn = {1365-2990}, support = {R28 AA012725/AA/NIAAA NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology ; Copper ; Superoxide Dismutase-1 ; Riluzole ; Superoxide Dismutase ; Motor Neurons/pathology ; Spinal Cord/pathology ; DNA-Binding Proteins ; Mice, Transgenic ; }, abstract = {AIMS: Although the orally available brain-penetrant copper compound CuATSM has demonstrated promising effects in SOD1-linked mouse models, the impact of CuATSM on disease pathology in patients with amyotrophic lateral sclerosis (ALS) remains unknown.

METHODS: The present study set out to address this deficit by performing the first pilot comparative analysis of ALS pathology in patients that had been administered CuATSM and riluzole [N = 6 cases composed of ALS-TDP (n = 5) and ALS-SOD1 (n = 1)] versus riluzole only [N = 6 cases composed of ALS-TDP (n = 4) and ALS-SOD1 (n = 2)].

RESULTS: Our results revealed no significant difference in neuron density or TDP-43 burden in the motor cortex and spinal cord of patients that had received CuATSM compared with patients that had not. In patients that had received CuATSM, p62-immunoreactive astrocytes were observed in the motor cortex and reduced Iba1 density was found in the spinal cord. However, no significant difference in measures of astrocytic activity and SOD1 immunoreactivity was found with CuATSM treatment.

DISCUSSION: These findings, in this first postmortem investigation of patients with ALS in CuATSM trials, demonstrate that in contrast to that seen in preclinical models of disease, CuATSM does not significantly alleviate neuronal pathology or astrogliosis in patients with ALS.}, } @article {pmid37316950, year = {2023}, author = {Petri, S and Grehl, T and Grosskreutz, J and Hecht, M and Hermann, A and Jesse, S and Lingor, P and Löscher, W and Maier, A and Schoser, B and Weber, M and Ludolph, AC}, title = {Guideline "Motor neuron diseases" of the German Society of Neurology (Deutsche Gesellschaft für Neurologie).}, journal = {Neurological research and practice}, volume = {5}, number = {1}, pages = {25}, pmid = {37316950}, issn = {2524-3489}, abstract = {INTRODUCTION: In 2021, the Deutsche Gesellschaft für Neurology published a new guideline on diagnosis and therapy of motor neuron disorders. Motor neuron disorders affect upper motor neurons in the primary motor cortex and/or lower motor neurons in the brain stem and spinal cord. The most frequent motor neuron disease amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease with an average life expectancy of 2-4 years with a yearly incidence of 3.1/100,000 in Central Europe (Rosenbohm et al. in J Neurol 264(4):749-757, 2017. https://doi.org/10.1007/s00415-017-8413-3). It is considered a rare disease mainly due to its low prevalence as a consequence of short disease duration.

RECOMMENDATIONS: These guidelines comprise recommendations regarding differential diagnosis, neuroprotective therapies and multidisciplinary palliative care including management of respiration and nutrition as well as provision of assistive devices and end-of-life situations.

CONCLUSION: Diagnostic and therapeutic guidelines are necessary due the comparatively high number of cases and the aggressive disease course. Given the low prevalence and the severe impairment of patients, it is often impossible to generate evidence-based data so that ALS guidelines are partially dependent on expert opinion.}, } @article {pmid37316681, year = {2023}, author = {Blair, HA}, title = {Tofersen: First Approval.}, journal = {Drugs}, volume = {83}, number = {11}, pages = {1039-1043}, pmid = {37316681}, issn = {1179-1950}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Superoxide Dismutase/genetics ; Oligonucleotides/pharmacology/therapeutic use ; Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Tofersen (Qalsody[™]) is an antisense oligonucleotide being developed by Biogen for the treatment of amyotrophic lateral sclerosis (ALS). On 25 April 2023, tofersen was approved in the USA for the treatment of ALS in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This article summarizes the milestones in the development of tofersen leading to this first approval for ALS.}, } @article {pmid37316187, year = {2023}, author = {Iverson, GL and Castellani, RJ and Cassidy, JD and Schneider, GM and Schneider, KJ and Echemendia, RJ and Bailes, JE and Hayden, KA and Koerte, IK and Manley, GT and McNamee, M and Patricios, JS and Tator, CH and Cantu, RC and Dvorak, J}, title = {Examining later-in-life health risks associated with sport-related concussion and repetitive head impacts: a systematic review of case-control and cohort studies.}, journal = {British journal of sports medicine}, volume = {57}, number = {12}, pages = {810-821}, doi = {10.1136/bjsports-2023-106890}, pmid = {37316187}, issn = {1473-0480}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Sports ; *Brain Concussion/epidemiology/etiology ; Cohort Studies ; Case-Control Studies ; *Dementia ; }, abstract = {OBJECTIVE: Concern exists about possible problems with later-in-life brain health, such as cognitive impairment, mental health problems and neurological diseases, in former athletes. We examined the future risk for adverse health effects associated with sport-related concussion, or exposure to repetitive head impacts, in former athletes.

DESIGN: Systematic review.

DATA SOURCES: Search of MEDLINE, Embase, Cochrane, CINAHL Plus and SPORTDiscus in October 2019 and updated in March 2022.

ELIGIBILITY CRITERIA: Studies measuring future risk (cohort studies) or approximating that risk (case-control studies).

RESULTS: Ten studies of former amateur athletes and 18 studies of former professional athletes were included. No postmortem neuropathology studies or neuroimaging studies met criteria for inclusion. Depression was examined in five studies in former amateur athletes, none identifying an increased risk. Nine studies examined suicidality or suicide as a manner of death, and none found an association with increased risk. Some studies comparing professional athletes with the general population reported associations between sports participation and dementia or amyotrophic lateral sclerosis (ALS) as a cause of death. Most did not control for potential confounding factors (eg, genetic, demographic, health-related or environmental), were ecological in design and had high risk of bias.

CONCLUSION: Evidence does not support an increased risk of mental health or neurological diseases in former amateur athletes with exposure to repetitive head impacts. Some studies in former professional athletes suggest an increased risk of neurological disorders such as ALS and dementia; these findings need to be confirmed in higher quality studies with better control of confounding factors.

PROSPERO REGISTRATION NUMBER: CRD42022159486.}, } @article {pmid37316165, year = {2023}, author = {Ziegler, A and Öner, A and Quadflieg, G and Betschart, RO and Thiéry, A and Babel, H and Mwambi, HG and Neumeyer, H and Mackschin, S and Hintz, S and Mann, M and Dittrich, H and Schmidt, C}, title = {Cost-effectiveness of a telemonitoring programme in patients with cardiovascular diseases compared with standard of care.}, journal = {Heart (British Cardiac Society)}, volume = {109}, number = {21}, pages = {1617-1623}, pmid = {37316165}, issn = {1468-201X}, mesh = {Humans ; *Cardiovascular Diseases/therapy ; Cost-Benefit Analysis ; Quality of Life ; Standard of Care ; *Hypertension/diagnosis/therapy ; Quality-Adjusted Life Years ; }, abstract = {OBJECTIVES: The main aim of this work was to analyse the cost-effectiveness of an integrated care concept (NICC) that combines telemonitoring with the support of a care centre in addition to guideline therapy for patients. Secondary aims were to compare health utility and health-related quality of life (QoL) between NICC and standard of care (SoC).

METHODS: The randomised controlled CardioCare MV Trial compared NICC and SoC in patients from Mecklenburg-West Pomerania (Germany) with atrial fibrillation, heart failure or treatment-resistant hypertension. QoL was measured using the EQ-5D-5L at baseline, 6 months and 1 year follow-up. Quality-adjusted life years (QALYs), EQ5D utility scores, Visual Analogue Scale (VAS) Scores and VAS adjusted life years (VAS-AL) were calculated. Cost data were obtained from health insurance companies, and the payer perspective was taken in health economic analyses. Quantile regression was used with adjustments for stratification variables.

RESULTS: The net benefit of NICC (QALY) was 0.031 (95% CI 0.012 to 0.050; p=0.001) in this trial involving 957 patients. EQ5D Index values, VAS-ALs and VAS were larger for NICC compared with SoC at 1 year follow-up (all p≤0.004). Direct cost per patient and year were €323 (CI €157 to €489) lower in the NICC group. When 2000 patients are served by the care centre, NICC is cost-effective if one is willing to pay €10 652 per QALY per year.

CONCLUSION: NICC was associated with higher QoL and health utility. The programme is cost-effective if one is willing to pay approximately €11 000 per QALY per year.}, } @article {pmid37316101, year = {2023}, author = {Tavazzi, E and Longato, E and Vettoretti, M and Aidos, H and Trescato, I and Roversi, C and Martins, AS and Castanho, EN and Branco, R and Soares, DF and Guazzo, A and Birolo, G and Pala, D and Bosoni, P and Chiò, A and Manera, U and de Carvalho, M and Miranda, B and Gromicho, M and Alves, I and Bellazzi, R and Dagliati, A and Fariselli, P and Madeira, SC and Di Camillo, B}, title = {Artificial intelligence and statistical methods for stratification and prediction of progression in amyotrophic lateral sclerosis: A systematic review.}, journal = {Artificial intelligence in medicine}, volume = {142}, number = {}, pages = {102588}, doi = {10.1016/j.artmed.2023.102588}, pmid = {37316101}, issn = {1873-2860}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Artificial Intelligence ; Brain ; Cluster Analysis ; Databases, Factual ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterised by the progressive loss of motor neurons in the brain and spinal cord. The fact that ALS's disease course is highly heterogeneous, and its determinants not fully known, combined with ALS's relatively low prevalence, renders the successful application of artificial intelligence (AI) techniques particularly arduous.

OBJECTIVE: This systematic review aims at identifying areas of agreement and unanswered questions regarding two notable applications of AI in ALS, namely the automatic, data-driven stratification of patients according to their phenotype, and the prediction of ALS progression. Differently from previous works, this review is focused on the methodological landscape of AI in ALS.

METHODS: We conducted a systematic search of the Scopus and PubMed databases, looking for studies on data-driven stratification methods based on unsupervised techniques resulting in (A) automatic group discovery or (B) a transformation of the feature space allowing patient subgroups to be identified; and for studies on internally or externally validated methods for the prediction of ALS progression. We described the selected studies according to the following characteristics, when applicable: variables used, methodology, splitting criteria and number of groups, prediction outcomes, validation schemes, and metrics.

RESULTS: Of the starting 1604 unique reports (2837 combined hits between Scopus and PubMed), 239 were selected for thorough screening, leading to the inclusion of 15 studies on patient stratification, 28 on prediction of ALS progression, and 6 on both stratification and prediction. In terms of variables used, most stratification and prediction studies included demographics and features derived from the ALSFRS or ALSFRS-R scores, which were also the main prediction targets. The most represented stratification methods were K-means, and hierarchical and expectation-maximisation clustering; while random forests, logistic regression, the Cox proportional hazard model, and various flavours of deep learning were the most widely used prediction methods. Predictive model validation was, albeit unexpectedly, quite rarely performed in absolute terms (leading to the exclusion of 78 eligible studies), with the overwhelming majority of included studies resorting to internal validation only.

CONCLUSION: This systematic review highlighted a general agreement in terms of input variable selection for both stratification and prediction of ALS progression, and in terms of prediction targets. A striking lack of validated models emerged, as well as a general difficulty in reproducing many published studies, mainly due to the absence of the corresponding parameter lists. While deep learning seems promising for prediction applications, its superiority with respect to traditional methods has not been established; there is, instead, ample room for its application in the subfield of patient stratification. Finally, an open question remains on the role of new environmental and behavioural variables collected via novel, real-time sensors.}, } @article {pmid37315804, year = {2023}, author = {Helm, M and Helm, T and Helm, K and Foulke, G}, title = {Response to Jerjen et al's "Systemic sclerosis in adults. Part I: clinical features and pathogenesis".}, journal = {Journal of the American Academy of Dermatology}, volume = {89}, number = {4}, pages = {e171}, doi = {10.1016/j.jaad.2023.04.074}, pmid = {37315804}, issn = {1097-6787}, mesh = {Humans ; Adult ; *Scleroderma, Systemic/diagnosis ; *Scleroderma, Localized ; }, } @article {pmid37315803, year = {2023}, author = {Barry, R and Murray, G and Hazel, K and Ryan, J and Watchorn, RE}, title = {Response to Pan et al's "Non-melanoma skin cancer in patients with hereditary hemochromatosis: A case-control study".}, journal = {Journal of the American Academy of Dermatology}, volume = {89}, number = {4}, pages = {e167-e168}, doi = {10.1016/j.jaad.2023.05.078}, pmid = {37315803}, issn = {1097-6787}, mesh = {Humans ; Case-Control Studies ; *Hemochromatosis/complications/epidemiology/genetics ; *Skin Neoplasms/epidemiology ; *Carcinoma, Basal Cell ; }, } @article {pmid37315438, year = {2023}, author = {Yang, HC and Park, SM and Lee, KJ and Jo, YH and Kim, YJ and Lee, DK and Jang, DH}, title = {Delayed arrival of advanced life support adversely affects the neurological outcome in a multi-tier emergency response system.}, journal = {The American journal of emergency medicine}, volume = {71}, number = {}, pages = {1-6}, doi = {10.1016/j.ajem.2023.06.001}, pmid = {37315438}, issn = {1532-8171}, mesh = {Adult ; Humans ; Electric Countershock ; *Emergency Medical Services ; *Out-of-Hospital Cardiac Arrest/therapy ; Retrospective Studies ; *Advanced Cardiac Life Support ; }, abstract = {AIM: Prehospital management of out-of-hospital cardiac arrest (OHCA) is based on basic life support, with the addition of advanced life support (ALS) if possible. This study aimed to investigate the effect of delayed arrival of ALS on neurological outcomes of patients with OHCA at hospital discharge.

METHODS: This was a retrospective study of a registry of patients with OHCA. A multi-tier emergency response system was established in the study area. ALS was initiated when the second-arrival team arrived at the scene. A restricted cubic spline curve was used to investigate the relationship between the response time interval of the second-arrival team and neurological outcomes at hospital discharge. Multivariable logistic regression analysis was performed to assess the independent association between the response time interval of the second-arrival team and neurological outcomes of patients at hospital discharge.

RESULTS: A total of 3186 adult OHCA patients who received ALS at the scene were included in the final analysis. A restricted cubic spline curve showed that a long response time interval of the second-arrival team was correlated with a high likelihood of poor neurological outcomes. Meanwhile, multivariable logistic regression analysis showed that a long response time interval of the second-arrival team was independently associated with poor neurological outcomes (odds ratio, 1.10; 95% confidence interval, 1.03-1.17).

CONCLUSION: In a multi-tiered prehospital emergency response system, the delayed arrival of ALS was associated with poor neurological outcomes at hospital discharge.}, } @article {pmid37315423, year = {2023}, author = {Tracey, TJ and Jiang, L and Gill, MK and Ranie, SN and Ovchinnikov, DA and Wolvetang, EJ and Ngo, ST}, title = {Generation of a human induced pluripotent stem cell line (UQi001-A-1) edited with the CRISPR-Cas9 system to carry the heterozygous TARDBP c.1144G > A (p.A382T) missense mutation.}, journal = {Stem cell research}, volume = {70}, number = {}, pages = {103137}, doi = {10.1016/j.scr.2023.103137}, pmid = {37315423}, issn = {1876-7753}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; CRISPR-Cas Systems/genetics ; DNA-Binding Proteins/genetics ; *Induced Pluripotent Stem Cells/cytology ; Mutation ; Mutation, Missense ; *Neurodegenerative Diseases/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease in which the TDP-43 protein is believed to play a central role in disease pathophysiology. Using the CRISPR-Cas9 system, we introduced the heterozygous c.1144G > A (p.A382T) missense mutation in exon 6 of the TARDBP gene into an iPSC line derived from a healthy individual. These edited iPSCs displayed normal cellular morphology, expressed major pluripotency markers, were capable of tri-lineage differentiation, and possessed a normal karyotype.}, } @article {pmid37315349, year = {2023}, author = {Ustun, R and Chalmers, G and Tehrani, D and Uzun, B}, title = {Computational molecular explanation of Soybean AHAS resistance from P197S mutation.}, journal = {Plant physiology and biochemistry : PPB}, volume = {201}, number = {}, pages = {107782}, doi = {10.1016/j.plaphy.2023.107782}, pmid = {37315349}, issn = {1873-2690}, mesh = {Glycine max/genetics/metabolism ; Sulfonamides ; *Herbicides/pharmacology/chemistry ; Mutation/genetics ; Amino Acids ; *Acetolactate Synthase/genetics ; Herbicide Resistance/genetics ; }, abstract = {The first enzyme in the pathway involving branched-chain amino is acetohydroxyacid synthase (AHAS, E.C. 2.2.1.6), which is inhibited by five commercial herbicide families. In this work a computational study of a point mutation of Proline-197-Serine of the Soybean AHAS enzyme, which was obtained by mutagenesis, explains the latter's S197 resistance to the commonly used Chlorsulfuron. Using protein-ligand docking and large-scale sampling and distributions from AlphaFold-generated the resistant and susceptible soybean AHAS protein structure. The computational approach here is scaled to screen for mutation probabilities of protein binding sites, similar to screening compounds for potential hits in therapeutic design using the docking software. P197 and S197 AHAS structures were found to be different even if only one amino acid was changed. The non-specific distribution of bindings in the S197 cavity after the P197S change has been rigorously calculated by RMSD analysis that it would require x20 more concentrations to fill the P197 site by the same amount. There is no previously performed detailed chlorsulfuron soybean P197S AHAS binding calculation. In the herbicide site of AHAS, several amino acids interact - a computational study could elucidate the optimal choice of point mutations for herbicidal resistance either individually or collectively by mutations one at a time and analyzing the effects with a set of herbicides individually. With a computational approach, enzymes involved in crop research and development could be analyzed more quickly, enabling faster discovery and development of herbicides.}, } @article {pmid37315259, year = {2023}, author = {Kutlubaev, MA and Areprintseva, DK and Pervushina, EV}, title = {[The influence of uric acid on the course of amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {123}, number = {5}, pages = {177-180}, doi = {10.17116/jnevro2023123051177}, pmid = {37315259}, issn = {1997-7298}, mesh = {Male ; Humans ; Uric Acid ; *Amyotrophic Lateral Sclerosis ; *Gout/complications/drug therapy ; Antioxidants/therapeutic use ; Neuroprotection ; }, abstract = {Uric acid has antioxidant and neuroprotective properties. A number of studies show that high levels of uric acid may have a positive influence on the course of amyotrophic lateral sclerosis (ALS), especially in males. The frequency of ALS is lower in patients with gout than in the general population. We present a case of a patient with gout and slowly progressive ALS. More research is needed on the potential role of uric acid in ALS and other neurodegenerative disorders.}, } @article {pmid37314311, year = {2023}, author = {Sharma, S and Tomar, VR and Deep, S}, title = {Myricetin: A Potent Anti-Amyloidogenic Polyphenol against Superoxide Dismutase 1 Aggregation.}, journal = {ACS chemical neuroscience}, volume = {14}, number = {13}, pages = {2461-2475}, doi = {10.1021/acschemneuro.3c00276}, pmid = {37314311}, issn = {1948-7193}, mesh = {Humans ; Superoxide Dismutase-1/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Polyphenols/pharmacology ; Flavonoids/pharmacology ; Superoxide Dismutase/metabolism ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is believed to be caused by the aggregation of misfolded or mutated superoxide dismutase 1 (SOD1). As there is currently no treatment, research into aggregation inhibitors continues. Based on docking, molecular dynamics (MD) simulations, and experimental observations, we propose that myricetin, a plant flavonoid, can act as a potent anti-amyloidogenic polyphenol against SOD1 aggregation. Our MD simulation results showed that myricetin stabilizes the protein interface, destabilizes the preformed fibril, and decreases the rate of fibril elongation. Myricetin inhibits the aggregation of SOD1 in a dose-dependent manner as shown by the ThT aggregation kinetics curves. Our transmission electron microscopy, dynamic light scattering, and circular dichroism experiments indicate that fewer shorter fibrils have formed. Fluorescence spectroscopy results predict the involvement of a static quenching mechanism characterized by a strong binding between protein and myricetin. Importantly, size exclusion chromatography revealed the potential of myricetin for fibril destabilization and depolymerization. These experimental observations complement the MD results. Thus, myricetin is a potent SOD1 aggregation inhibitor that can reduce the fibril load. Using the structure of myricetin as a reference, it is possible to design more effective therapeutic inhibitors against ALS that prevent the disease and reverse its effects.}, } @article {pmid37313936, year = {2023}, author = {Negi, R and Srivastava, A and Srivastava, AK and Pandeya, A and Vatsa, P and Ansari, UA and Pant, AB}, title = {Proteome architecture of human-induced pluripotent stem cell-derived three-dimensional organoids as a tool for early diagnosis of neuronal disorders.}, journal = {Indian journal of pharmacology}, volume = {55}, number = {2}, pages = {108-118}, pmid = {37313936}, issn = {1998-3751}, mesh = {Humans ; Proteome ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics ; *Induced Pluripotent Stem Cells ; Proteomics ; Early Diagnosis ; DNA-Binding Proteins ; Organoids ; }, abstract = {BACKGROUND AND OBJECTIVES: Induced pluripotent stem cells (iPSCs) derived three-dimensional (3D) model for rare neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) is emerging as a novel alternative to human diseased tissue to explore the disease etiology and potential drug discovery. In the interest of the same, we have generated a TDP-43-mutated human iPSCs (hiPSCs) derived 3D organoid model of ALS disease. The high-resolution mass spectrometry (MS)-based proteomic approach is used to explore the differential mechanism under disease conditions and the suitability of a 3D model to study the disease.

MATERIALS AND METHODS: The hiPSCs cell line was procured from a commercial source, grown, and characterized following standard protocols. The mutation in hiPSCs was accomplished using CRISPR/Cas-9 technology and predesigned gRNA. The two groups of organoids were produced by normal and mutated hiPSCs and subjected to the whole proteomic profiling by high-resolution MS in two biological replicates with three technical replicas of each.

RESULTS: The proteomic analysis of normal and mutated organoids revealed the proteins associated with pathways of neurodegenerative disorders, proteasomes, autophagy, and hypoxia-inducible factor-1 signaling. Differential proteomic analysis revealed that the mutation in TDP-43 gene caused proteomic deregulation, which impaired protein quality mechanisms. Furthermore, this impairment may contribute to the generation of stress conditions that may ultimately lead to the development of ALS pathology.

CONCLUSION: The developed 3D model represents the majority of candidate proteins and associated biological mechanisms altered in ALS disease. The study also offers novel protein targets that may uncloud the precise disease pathological mechanism and be considered for future diagnostic and therapeutic purposes for various neurodegenerative disorders.}, } @article {pmid37312655, year = {2023}, author = {Stevens-Jones, O and Malmeström, C and Constantinescu, C and Dalla, K and Nellgård, B and Zelano, J and Constantinescu, R and Axelsson, M}, title = {Presence of neural surface and onconeural autoantibodies in cerebrospinal fluid and serum in neurological diseases presents a potential risk for misdiagnosis.}, journal = {European journal of neurology}, volume = {30}, number = {9}, pages = {2602-2610}, doi = {10.1111/ene.15926}, pmid = {37312655}, issn = {1468-1331}, mesh = {*Multiple Sclerosis/diagnosis ; Diagnostic Errors ; *Parkinson Disease/diagnosis ; Hashimoto Disease ; Encephalitis ; Humans ; Autoantibodies ; }, abstract = {BACKGROUND AND PURPOSE: Autoantibodies have been found to contribute to pathology and are used in the diagnosis of some neurological diseases. We examined the prevalence of autoantibodies in patients with various neurological diseases and whether patients who had autoantibodies differed in age, sex, or disability from those who did not.

METHODS: We examined the prevalence of neural surface and onconeural autoantibodies in cerebrospinal fluid (CSF) and serum from patients with multiple sclerosis (n = 64), Parkinson disease plus atypical parkinsonism (n = 150), amyotrophic lateral sclerosis (n = 43), or autoimmune encephalitis (positive control; n = 7) and a healthy control group (n = 37). A total of 12 onconeural autoantibodies and six neural surface autoantibodies were tested in all participants.

RESULTS: Autoantibodies were present in all cohorts. The prevalence of autoantibodies was high (>80%) in the autoimmune encephalitis cohort but low (<20%) in all other cohorts. When comparing patients within cohorts who were positive for autoantibodies to patients who were not, there was no difference in age, sex, and disability. This was apart from the multiple sclerosis and Parkinson disease plus atypical parkinsonism cohorts, where those with positivity for autoantibodies in the CSF were significantly older.

CONCLUSIONS: The presence of the autoantibodies examined does not appear to have a substantial clinical impact within the diseases examined in this study. The presence of autoantibodies in all cohorts presents a risk for misdiagnosis when the method is used incorrectly on patients with atypical clinical presentation.}, } @article {pmid37312136, year = {2023}, author = {Ciećwierska, K and Lulé, D and Bielecki, M and Helczyk, O and Maksymowicz-Śliwińska, A and Finsel, J and Nieporęcki, K and Andersen, PM and Ludolph, AC and Kuźma-Kozakiewicz, M}, title = {Quality of life and depression in patients with amyotrophic lateral sclerosis - does the country of origin matter?.}, journal = {BMC palliative care}, volume = {22}, number = {1}, pages = {72}, pmid = {37312136}, issn = {1472-684X}, support = {JPND; 01ED1405//EU Joint Program - Neurodegenerative Disease Research project/ ; JPND; 01ED1405//EU Joint Program - Neurodegenerative Disease Research project/ ; JPND; 01ED1405//EU Joint Program - Neurodegenerative Disease Research project/ ; LU 336/13-2 BI 195/54-2//Deutsche Forschungsgemeinschaft/ ; LU 336/13-2 BI 195/54-2//Deutsche Forschungsgemeinschaft/ ; LU 336/13-2 BI 195/54-2//Deutsche Forschungsgemeinschaft/ ; 3/IV/MAXOMOD/11.2020//ERA-NET-E Rare/ ; 3/IV/MAXOMOD/11.2020//ERA-NET-E Rare/ ; KAW #2014.0305//the Knut and Alice Wallenberg Foundation/ ; }, mesh = {Humans ; Male ; *Quality of Life ; *Amyotrophic Lateral Sclerosis/complications ; Depression/etiology ; Health Status ; Germany ; }, abstract = {BACKGROUND: Given the inevitable relentless progressing nature of amyotrophic lateral sclerosis (ALS), it is essential to identify factors influencing patients' wellbeing. The study aimed to prospectively assess factors influencing the quality of life (QoL) and depression in ALS patients compared to healthy controls (HCs) from Poland, Germany and Sweden and their relationship to socio-demographic and clinical factors.

METHODS: 314 ALS patients (120 from Poland, 140 from Germany, 54 from Sweden) and 311 age-, sex- and education-level-matched HCs underwent standardized interviews for quality of life, depression, functional status and pain.

RESULTS: Patients from all three countries showed similar levels of functional impairment (ALSFRS-R). Overall, ALS patients assessed their quality of life as lower compared to HCs (p < 0.001 for the anamnestic comparative self-assessment (ACSA), p = 0.002 for the Schedule for the evaluation of the subjective quality of life - SEIQoL- direct weighting (SEIQoL-DW). Also, the German and Swedish patients, but not the Polish, reported higher depression levels than the corresponding HCs (p < 0.001). Analysis of ALS groups revealed that functional impairment was related to a lower quality of life (ACSA) and higher depression levels among German ALS patients. Longer time since diagnosis predicted lower depression and (in male subjects) higher quality of life.

CONCLUSIONS: ALS patients assess their quality of life and mood lower than healthy individuals within the studied countries. The relationships between clinical and demographic factors are moderated by country of provenance, which bears implications for the design and interpretation of scientific and clinical studies, which should reflect the complexity and heterogeneity of mechanisms determining QoL.}, } @article {pmid37311649, year = {2023}, author = {de Jongh, AD and van Eijk, RPA and Bakker, LA and Bunte, TM and Beelen, A and van der Meijden, C and van Es, MA and Visser-Meily, JMA and Kruitwagen, ET and Veldink, JH and van den Berg, LH}, title = {Development of a Rasch-Built Amyotrophic Lateral Sclerosis Impairment Multidomain Scale to Measure Disease Progression in ALS.}, journal = {Neurology}, volume = {101}, number = {6}, pages = {e602-e612}, pmid = {37311649}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Reproducibility of Results ; Prognosis ; Probability ; Disease Progression ; }, abstract = {BACKGROUND AND OBJECTIVES: Current scales used in amyotrophic lateral sclerosis (ALS) attempt to summarize different functional domains or "dimensions" into 1 overall score, which may not accurately characterize the individual patient's disease severity or prognosis. The use of composite score risks declaring treatments ineffective if not all dimensions of ALS disease progression are affected equally. We aimed to develop the ALS Impairment Multidomain Scale (AIMS) to comprehensively characterize disease progression and increase the likelihood of identifying effective treatments.

METHODS: The Revised ALS Functional Rating Scale (ALSFRS-R) and a preliminary questionnaire, based on literature review and patient input, were completed online by patients from the Netherlands ALS registry at bimonthly intervals over a period of 12 months. A 2-week test-retest, factor analysis, Rasch analysis, and a signal-to-noise optimization strategy were performed to create a multidomain scale. Reliability, longitudinal decline, and associations with survival were evaluated. The sample size required to detect a 35% reduction in progression rate over 6 or 12 months was assessed for a clinical trial that defines the ALSFRS-R or AIMS subscales as a primary endpoint family.

RESULTS: The preliminary questionnaire, consisting of 110 questions, was completed by 367 patients. Three unidimensional subscales were identified, and a multidomain scale was constructed with 7 bulbar, 11 motor, and 5 respiratory questions. Subscales fulfilled Rasch model requirements, with excellent test-retest reliability of 0.91-0.94 and a strong relationship with survival (p < 0.001). Compared with the ALSFRS-R, signal-to-noise ratios were higher as patients declined more uniformly per subscale. Consequently, the estimated sample size reductions achieved with the AIMS compared with those achieved with the ALSFRS-R were 16.3% and 25.9% for 6-month and 12-month clinical trials, respectively.

DISCUSSION: We developed the AIMS, consisting of unidimensional bulbar, motor, and respiratory subscales, which may characterize disease severity better than a total score. AIMS subscales have high test-retest reliability, are optimized to measure disease progression, and are strongly related to survival time. The AIMS can be easily administered and may increase the likelihood of identifying effective treatments in ALS clinical trials.}, } @article {pmid37310359, year = {2023}, author = {Fang, J and Huang, Y and Wu, J and Shen, B and Yang, Y and Ju, M}, title = {Fluorogenic methodology for visualization of phase separation in chemical biology.}, journal = {Organic & biomolecular chemistry}, volume = {21}, number = {25}, pages = {5140-5149}, doi = {10.1039/d3ob00660c}, pmid = {37310359}, issn = {1477-0539}, mesh = {Humans ; *Alzheimer Disease ; Biology ; }, abstract = {Phase separation is a common biological phenomenon in the liquid environment of organisms. Phase separation has been shown to be a key cause of many existing incurable diseases, such as the protein aggregates formed by phase separation of Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, etc. Tracking the occurrence of phase separation in vivo is critical to many disease detection methods and solving many treatment problems. Its physicochemical properties and visual detection methods have flourished in the last few years in chemical biology, among which the fluorogenic toolbox has great application potential compared to the traditional detection methods that cannot visualize the phase separation process intuitively, but just show some parameters indirectly. This paper reviews the mechanism and disease correlation proven in recent years for phase separation and analyzes the detection methods for phase separation, including functional microscope imaging techniques, turbidity monitoring, macromolecule congestion sensing, in silico analysis, etc. It is worth mentioning that the qualitative and quantitative analysis of aggregates formed by phase separation using in vitro parameters has successfully provided basic physical and chemical properties for phase separation aggregates, and is an important cornerstone for researchers to carry forward the past and break through the existing technical shackles to create new in vivo monitoring methods such as fluorescence methodology. Crucially, fluorescence methods for cell microenvironment imaging based on different mechanisms are discussed, such as AIE-based probes, TICT-based probes and FRET-based probes, etc.}, } @article {pmid37310119, year = {2023}, author = {Jackson, IM and Carlson, ML and Beinat, C and Malik, N and Kalita, M and Reyes, S and Azevedo, EC and Nagy, SC and Alam, IS and Sharma, R and La Rosa, SA and Moradi, F and Cleland, J and Shen, B and James, ML}, title = {Clinical Radiosynthesis and Translation of [[18]F]OP-801: A Novel Radiotracer for Imaging Reactive Microglia and Macrophages.}, journal = {ACS chemical neuroscience}, volume = {14}, number = {13}, pages = {2416-2424}, pmid = {37310119}, issn = {1948-7193}, support = {T32 GM007365/GM/NIGMS NIH HHS/United States ; T32 GM145402/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; Brain ; Fluorine Radioisotopes/chemistry ; Macrophages ; *Microglia ; *Positron-Emission Tomography/methods ; Radiopharmaceuticals/chemistry ; Clinical Trials, Phase I as Topic ; Clinical Trials, Phase II as Topic ; }, abstract = {Positron emission tomography (PET) is a powerful tool for studying neuroinflammatory diseases; however, current PET biomarkers of neuroinflammation possess significant limitations. We recently reported a promising dendrimer PET tracer ([[18]F]OP-801), which is selectively taken up by reactive microglia and macrophages. Here, we describe further important characterization of [[18]F]OP-801 in addition to optimization and validation of a two-step clinical radiosynthesis. [[18]F]OP-801 was found to be stable in human plasma for 90 min post incubation, and human dose estimates were calculated for 24 organs of interest; kidneys and urinary bladder wall without bladder voiding were identified as receiving the highest absorbed dose. Following optimization detailed herein, automated radiosynthesis and quality control (QC) analyses of [[18]F]OP-801 were performed in triplicate in suitable radiochemical yield (6.89 ± 2.23% decay corrected), specific activity (37.49 ± 15.49 GBq/mg), and radiochemical purity for clinical imaging. Importantly, imaging mice with tracer (prepared using optimized methods) 24 h following the intraperitoneal injection of liposaccharide resulted in the robust brain PET signal. Cumulatively, these data enable clinical translation of [[18]F]OP-801 for imaging reactive microglia and macrophages in humans. Data from three validation runs of the clinical manufacturing and QC were submitted to the Food and Drug Administration (FDA) as part of a Drug Master File (DMF). Subsequent FDA approval to proceed was obtained, and a phase 1/2 clinical trial (NCT05395624) for first-in-human imaging in healthy controls and patients with amyotrophic lateral sclerosis is underway.}, } @article {pmid37309712, year = {2023}, author = {Ribeiro, VHV and Brunharo, CA and Mallory-Smith, C and Walenta, DL and Barroso, J}, title = {First report of target-site resistance to ACCase-inhibiting herbicides in Bromus tectorum L.}, journal = {Pest management science}, volume = {79}, number = {10}, pages = {4025-4033}, doi = {10.1002/ps.7607}, pmid = {37309712}, issn = {1526-4998}, support = {//Oregon Fine Fescue Comission/ ; }, mesh = {*Bromus ; *Herbicides/pharmacology ; Herbicide Resistance/genetics ; Mutation ; Acetyl-CoA Carboxylase/genetics ; Enzyme Inhibitors/pharmacology ; }, abstract = {BACKGROUND: The prevalent and repeated use of acetyl-coenzyme A carboxylase (ACCase)-inhibiting herbicides for Bromus tectorum L. control in fine fescue (Festuca L. spp) grown for seed has selected ACCase-resistant B. tectorum populations. The objectives of this study were to (1) evaluate the response of nine B. tectorum populations to the ACCase inhibitors clethodim, sethoxydim, fluazifop-P-butyl, and quizalofop-P-ethyl and the acetolactate synthase (ALS) inhibitor sulfosulfuron and (2) characterize the resistance mechanisms.

RESULTS: Bromus tectorum populations were confirmed to be resistant to the ACCase-inhibiting herbicides tested. The levels of resistance varied among the populations for clethodim (resistance ratio, RR = 5.1-14.5), sethoxydim (RR = 18.7-44.7), fluazifop-P-butyl (RR = 3.1-40.3), and quizalofop-P-ethyl (RR = 14.5-36). Molecular investigations revealed that the mutations Ile2041Thr and Gly2096Ala were the molecular basis of resistance to the ACCase-inhibiting herbicides. The Gly2096Ala mutation resulted in cross-resistance to the aryloxyphenoxypropionate (APP) herbicides fluazifop-P-butyl and quizalofop-P-ethyl, and the cyclohexanedione (CHD) herbicides clethodim, and sethoxydim, whereas Ile2041Thr mutation resulted in resistance only to the two APP herbicides. All B. tectorum populations were susceptible to sulfosulfuron (RR = 0.3-1.7).

CONCLUSIONS: This is the first report of target-site mutations conferring resistance to ACCase-inhibiting herbicides in B. tectorum. The results of this study suggest multiple evolutionary origins of resistance and contribute to understanding the patterns of cross-resistance to ACCase inhibitors associated with different mutations in B. tectorum. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid37309077, year = {2023}, author = {Stegmann, G and Charles, S and Liss, J and Shefner, J and Rutkove, S and Berisha, V}, title = {A speech-based prognostic model for dysarthria progression in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-6}, pmid = {37309077}, issn = {2167-9223}, support = {R01 DC006859/DC/NIDCD NIH HHS/United States ; R43 DC017625/DC/NIDCD NIH HHS/United States ; }, abstract = {Objective: We demonstrated that it was possible to predict ALS patients' degree of future speech impairment based on past data. We used longitudinal data from two ALS studies where participants recorded their speech on a daily or weekly basis and provided ALSFRS-R speech subscores on a weekly or quarterly basis (quarter-annually). Methods: Using their speech recordings, we measured articulatory precision (a measure of the crispness of pronunciation) using an algorithm that analyzed the acoustic signal of each phoneme in the words produced. First, we established the analytical and clinical validity of the measure of articulatory precision, showing that the measure correlated with perceptual ratings of articulatory precision (r = .9). Second, using articulatory precision from speech samples from each participant collected over a 45-90 day model calibration period, we showed it was possible to predict articulatory precision 30-90 days after the last day of the model calibration period. Finally, we showed that the predicted articulatory precision scores mapped onto ALSFRS-R speech subscores. Results: the mean absolute error was as low as 4% for articulatory precision and 14% for ALSFRS-R speech subscores relative to the total range of their respective scales. Conclusion: Our results demonstrated that a subject-specific prognostic model for speech predicts future articulatory precision and ALSFRS-R speech values accurately.}, } @article {pmid37308477, year = {2023}, author = {Xie, T and Liu, P and Wu, X and Dong, F and Zhang, Z and Yue, J and Mahawar, U and Farooq, F and Vohra, H and Fang, Q and Liu, W and Wattenberg, BW and Gong, X}, title = {Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {3475}, pmid = {37308477}, issn = {2041-1723}, support = {R21 NS120128/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Child ; *Ceramides ; Sphingolipids ; *Amyotrophic Lateral Sclerosis ; Binding Sites ; Homeostasis ; }, abstract = {The ORM/ORMDL family proteins function as regulatory subunits of the serine palmitoyltransferase (SPT) complex, which is the initiating and rate-limiting enzyme in sphingolipid biosynthesis. This complex is tightly regulated by cellular sphingolipid levels, but the sphingolipid sensing mechanism is unknown. Here we show that purified human SPT-ORMDL complexes are inhibited by the central sphingolipid metabolite ceramide. We have solved the cryo-EM structure of the SPT-ORMDL3 complex in a ceramide-bound state. Structure-guided mutational analyses reveal the essential function of this ceramide binding site for the suppression of SPT activity. Structural studies indicate that ceramide can induce and lock the N-terminus of ORMDL3 into an inhibitory conformation. Furthermore, we demonstrate that childhood amyotrophic lateral sclerosis (ALS) variants in the SPTLC1 subunit cause impaired ceramide sensing in the SPT-ORMDL3 mutants. Our work elucidates the molecular basis of ceramide sensing by the SPT-ORMDL complex for establishing sphingolipid homeostasis and indicates an important role of impaired ceramide sensing in disease development.}, } @article {pmid37308302, year = {2023}, author = {Wolfson, C and Gauvin, DE and Ishola, F and Oskoui, M}, title = {Global Prevalence and Incidence of Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Neurology}, volume = {101}, number = {6}, pages = {e613-e623}, pmid = {37308302}, issn = {1526-632X}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology ; Incidence ; Prevalence ; Humans ; Africa/epidemiology ; Asia/epidemiology ; Europe/epidemiology ; North America/epidemiology ; South America/epidemiology ; Oceania/epidemiology ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder affecting upper and lower motor neurons. Due to its rarity and rapidly progressive nature, studying the epidemiology of ALS is challenging, and a comprehensive picture of the global burden of this disease is lacking. The objective of this systematic review was to describe the global incidence and prevalence of ALS.

METHODS: We searched MEDLINE, Embase, Global Health, PsycInfo, Cochrane Library, and CINAHL to identify articles published between January 1, 2010, and May 6, 2021. Studies that were population based and reported estimates of prevalence, incidence, and/or mortality of ALS were eligible for inclusion. This study focuses on the incidence and prevalence. Quality assessment was performed using a tool developed to evaluate methodology relevant to prevalence and incidence studies. This review was registered with PROSPERO, CRD42021250559.

RESULTS: This search generated 6,238 articles, of which 140 were selected for data extraction and quality assessment. Of these, 85 articles reported on the incidence and 61 on the prevalence of ALS. Incidence ranged from 0.26 per 100,000 person-years in Ecuador to 23.46 per 100,000 person-years in Japan. Point prevalence ranged from 1.57 per 100,000 in Iran to 11.80 per 100,000 in the United States. Many articles identified cases with ALS from multiple data sources.

DISCUSSION: There is variation in reported incidence and prevalence estimates of ALS across the world. While registries are an important and powerful tool to quantify disease burden, such resources are not available everywhere. This results in gaps in reporting of the global epidemiology of ALS, as highlighted by the degree of variation (and quality) in estimates of incidence and prevalence reported in this review.}, } @article {pmid37308278, year = {2023}, author = {Morón-Oset, J and Fischer, LK and Carcolé, M and Giblin, A and Zhang, P and Isaacs, AM and Grönke, S and Partridge, L}, title = {Toxicity of C9orf72-associated dipeptide repeat peptides is modified by commonly used protein tags.}, journal = {Life science alliance}, volume = {6}, number = {9}, pages = {}, pmid = {37308278}, issn = {2575-1077}, support = {WT098565/Z/12/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Dipeptides ; C9orf72 Protein ; Peptides ; Genes, Regulator ; *Amyotrophic Lateral Sclerosis ; Drosophila ; *Skin Neoplasms ; }, abstract = {Hexanucleotide repeat expansions in the C9orf72 gene are the most prevalent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Transcripts of the expansions are translated into toxic dipeptide repeat (DPR) proteins. Most preclinical studies in cell and animal models have used protein-tagged polyDPR constructs to investigate DPR toxicity but the effects of tags on DPR toxicity have not been systematically explored. Here, we used Drosophila to assess the influence of protein tags on DPR toxicity. Tagging of 36 but not 100 arginine-rich DPRs with mCherry increased toxicity, whereas adding mCherry or GFP to GA100 completely abolished toxicity. FLAG tagging also reduced GA100 toxicity but less than the longer fluorescent tags. Expression of untagged but not GFP- or mCherry-tagged GA100 caused DNA damage and increased p62 levels. Fluorescent tags also affected GA100 stability and degradation. In summary, protein tags affect DPR toxicity in a tag- and DPR-dependent manner, and GA toxicity might be underestimated in studies using tagged GA proteins. Thus, including untagged DPRs as controls is important when assessing DPR toxicity in preclinical models.}, } @article {pmid37308108, year = {2023}, author = {Kögel, A and Lauerer, M and Zank, D}, title = {[Income of physicians in private practice in Germany: Results of a micro census].}, journal = {Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany))}, volume = {85}, number = {12}, pages = {1205-1212}, doi = {10.1055/a-2075-7696}, pmid = {37308108}, issn = {1439-4421}, mesh = {Male ; Humans ; Female ; *Censuses ; Germany ; *General Practitioners ; Private Practice ; }, abstract = {EINLEITUNG: Daten zum Einkommen von Ärzt:innen in Deutschland sind bisher nur teilweise verfügbar. Die Einkommen der niedergelassenen Ärzteschaft werden vor allem aus den Praxiserträgen abgeleitet, was aber große Interpretationsspielräume eröffnet. Ziel des Artikels ist es, diese Lücke zu schließen.

METHODIK: Hierfür werden die Einkommensangaben aus dem Mikrozensus 2017 ausgewertet - mit besonderem Fokus auf niedergelassene Ärzt:innen. Neben dem persönlichen Einkommen erfolgt eine Darstellung der Einkommenssituation auf Haushaltsebene. Die Einkommensziffern werden nach Tätigkeitsumfang, Tätigkeitsgruppe (Allgemein-/Fach-/Zahnärzte), Geschlecht und Stadt/Land differenziert.

Das verfügbare persönliche Nettoeinkommen niedergelassener Ärzt:innen beträgt bei Vollzeittätigkeit im Mittel knapp 7.900 € pro Monat. Fachärzt:innen liegen bei 8.250 €, Allgemein- und Zahnärzt:innen bei ca. 7.700 €. Eine finanzielle Benachteiligung von Landärzt:innen lässt sich nicht feststellen, Allgemeinärzt:innen aus Gemeinden<5.000 Einwohnerinnen und Einwohner haben mit 8.700 € sogar das höchste Durchschnittseinkommen - bei einer mittleren Arbeitszeit von 51 Stunden pro Woche. Ärztinnen arbeiten häufiger in Teilzeit als Ärzte. Ein niedrigeres Einkommen resultiert überwiegend aus einem geringeren Tätigkeitsumfang.

INTRODUCTION: Data on the income of physicians in Germany are only partially available to date. The income of physicians in private practice is derived primarily from practice income, but this opens up considerable scope for interpretation. The aim of this article is to close this gap.

METHODOLOGY: For this purpose, the income data from the 2017 micro census were evaluated, with a special focus on physicians in private practice. In addition to personal income, the income situation was presented at the household level. The income figures were differentiated according to the scope of activity, activity group (general practitioners/specialists/dentists), gender and city/country.

RESULTS AND CONCLUSION: The disposable personal income of physicians in private practice was just under € 7,900 per month on average for full-time employment. Specialists earned € 8,250, while general practitioners and dentists earned about € 7,700. Rural physicians were not found to suffer from financial disadvantages; general practitioners from municipalities with<5,000 inhabitants even had the highest average income of € 8,700, with an average working time of 51 hours per week. Female physicians worked part-time more often than did male physicians. A lower income resulted primarily from a lower scope of activity.}, } @article {pmid37307969, year = {2023}, author = {Mavadat, E and Seyedalipour, B and Hosseinkhani, S and Colagar, AH}, title = {Role of charged residues of the "electrostatic loop" of hSOD1 in promotion of aggregation: Implications for the mechanism of ALS-associated mutations under amyloidogenic conditions.}, journal = {International journal of biological macromolecules}, volume = {244}, number = {}, pages = {125289}, doi = {10.1016/j.ijbiomac.2023.125289}, pmid = {37307969}, issn = {1879-0003}, mesh = {Humans ; Superoxide Dismutase-1/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Superoxide Dismutase/metabolism ; Static Electricity ; Mutation ; Amyloid/chemistry ; }, abstract = {Protein misfolding and amyloid formation are hallmarks of numerous diseases, including amyotrophic lateral sclerosis (ALS), in which hSOD1 aggregation is involved in pathogenesis. We used two point mutations in the electrostatic loop, G138E and T137R, to analyze charge distribution under destabilizing circumstances to gain more about how ALS-linked mutations affect SOD1 protein stability or net repulsive charge. We show that protein charge is important in the ALS disease process using bioinformatics and experiments. The MD simulation findings demonstrate that the mutant protein differs significantly from WT SOD1, which is consistent with the experimental evidence. The specific activity of the wild type was 1.61 and 1.48 times higher than that of the G138E and T137R mutants, respectively. Under amyloid induction conditions, the intensity of intrinsic and ANS fluorescence in both mutants reduced. Increasing the content of β-sheet structures in mutants can be attributed to aggregation propensity, which was confirmed using CD polarimetry and FTIR spectroscopy. Our findings show that two ALS-related mutations promote the formation of amyloid-like aggregates at near physiological pH under destabilizing conditions, which were detected using spectroscopic probes such as Congo red and ThT fluorescence, and also further confirmation of amyloid-like species by TEM. Overall, our results provide evidence supporting the notion that negative charge changes combined with other destabilizing factors play an important role in increasing protein aggregation by reducing repulsive negative charges.}, } @article {pmid37307822, year = {2024}, author = {Chen, S and Cai, X and Lao, L and Wang, Y and Su, H and Sun, H}, title = {Brain-Gut-Microbiota Axis in Amyotrophic Lateral Sclerosis: A Historical Overview and Future Directions.}, journal = {Aging and disease}, volume = {15}, number = {1}, pages = {74-95}, pmid = {37307822}, issn = {2152-5250}, mesh = {Humans ; Aged ; Child, Preschool ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Neurodegenerative Diseases/complications ; *Gastrointestinal Microbiome/physiology ; Brain-Gut Axis ; Brain ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease which is strongly associated with age. The incidence of ALS increases from the age of 40 and peaks between the ages of 65 and 70. Most patients die of respiratory muscle paralysis or lung infections within three to five years of the appearance of symptoms, dealing a huge blow to patients and their families. With aging populations, improved diagnostic methods and changes in reporting criteria, the incidence of ALS is likely to show an upward trend in the coming decades. Despite extensive researches have been done, the cause and pathogenesis of ALS remains unclear. In recent decades, large quantities of studies focusing on gut microbiota have shown that gut microbiota and its metabolites seem to change the evolvement of ALS through the brain-gut-microbiota axis, and in turn, the progression of ALS will exacerbate the imbalance of gut microbiota, thereby forming a vicious cycle. This suggests that further exploration and identification of the function of gut microbiota in ALS may be crucial to break the bottleneck in the diagnosis and treatment of this disease. Hence, the current review summarizes and discusses the latest research advancement and future directions of ALS and brain-gut-microbiota axis, so as to help relevant researchers gain correlative information instantly.}, } @article {pmid37307819, year = {2024}, author = {He, D and Xu, Y and Liu, M and Cui, L}, title = {The Inflammatory Puzzle: Piecing together the Links between Neuroinflammation and Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {15}, number = {1}, pages = {96-114}, pmid = {37307819}, issn = {2152-5250}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Neuroinflammatory Diseases ; *Neurodegenerative Diseases/complications ; Central Nervous System ; Signal Transduction/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that has a complex genetic basis. Through advancements in genetic screening, researchers have identified more than 40 mutant genes associated with ALS, some of which impact immune function. Neuroinflammation, with abnormal activation of immune cells and excessive production of inflammatory cytokines in the central nervous system, significantly contributes to the pathophysiology of ALS. In this review, we examine recent evidence on the involvement of ALS-associated mutant genes in immune dysregulation, with a specific focus on the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway and N6-methyladenosine (m[6]A)-mediated immune regulation in the context of neurodegeneration. We also discuss the perturbation of immune cell homeostasis in both the central nervous system and peripheral tissues in ALS. Furthermore, we explore the advancements made in the emerging genetic and cell-based therapies for ALS. This review underscores the complex relationship between ALS and neuroinflammation, highlighting the potential to identify modifiable factors for therapeutic intervention. A deeper understanding of the connection between neuroinflammation and the risk of ALS is crucial for advancing effective treatments for this debilitating disorder.}, } @article {pmid37307637, year = {2023}, author = {Tamai, Y and Noda, A and Yamamoto, E}, title = {Estimation of confidence intervals for quantitation of coeluted peaks in liquid chromatography-Photodiode array detection through a combination of multivariate curve resolution-alternating least-square and Bayesian inference techniques.}, journal = {Journal of chromatography. A}, volume = {1704}, number = {}, pages = {464136}, doi = {10.1016/j.chroma.2023.464136}, pmid = {37307637}, issn = {1873-3778}, mesh = {*Confidence Intervals ; Bayes Theorem ; Reproducibility of Results ; Chromatography, Liquid ; Chromatography, High Pressure Liquid/methods ; }, abstract = {There is a dramatic increase in drug candidates that exhibit complex structures and do not comply with Lipinski's rule of five. One of the most critical and complex technical challenges in the quality control of such drug candidates is the control of analogous substances contained in active pharmaceutical ingredients and related formulations. Although the development of ultrahigh-performance liquid chromatography and high-performance columns has improved efficiency per unit time, the difficulty of peak separation to quantify impurities with similar structures and physicochemical properties continues to rise, and so does the probability of failure to achieve the necessary separation. Coeluting peaks observed in the case of high-performance liquid chromatography (HPLC) with photodiode array detection can be separated using the multivariate curve resolution-alternating least-square (MCR-ALS) method exploiting differences in analyte UV spectra. However, relatively large quantitation errors have been observed for coeluting analogous substances, and the reliability of the corresponding quantitative data requires improvement. Herein, Bayesian inference is applied to separation by the MCR-ALS method to develop an algorithm assigning a confidence interval to the quantitative data of each analogous substance. The usefulness and limitations of this approach are tested using two analogs of telmisartan as models. For this test, a simulated two-component HPLC-UV dataset with an intensity ratio (relative to the main peak) of 0.1-1.0 and a resolution of 0.5-1.0 is used. The developed algorithm allows the prediction confidence interval, including the true value, to be assigned to the peak area in almost all cases, even when the intensity ratio, resolution, and signal-to-noise ratio are changed. Finally, the developed algorithm is also evaluated on a real HPLC-UV dataset to confirm that reasonable prediction confidence intervals including true values are assigned to peak areas. In addition to allowing the separation and quantitation of substances such as impurities challenging to separate by HPLC in a scientifically valid manner, which is impossible for conventional HPLC-UV detection, our method can assign confidence intervals to quantitative data. Therefore, the adopted approach is expected to resolve the issues associated with assessing impurities in the quality control of pharmaceuticals.}, } @article {pmid37307220, year = {2023}, author = {Lai, SW}, title = {Comment on Parameswaran et al's "Increased Stroke Risk Following Herpes Zoster Infection and Protection With Zoster Vaccine".}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {77}, number = {5}, pages = {801-802}, doi = {10.1093/cid/ciad352}, pmid = {37307220}, issn = {1537-6591}, mesh = {Humans ; *Herpes Zoster Vaccine ; *Herpes Zoster/complications/epidemiology/prevention & control ; *Stroke/prevention & control ; }, } @article {pmid37306196, year = {2023}, author = {Lloyd, EM and Pinniger, GJ and Murphy, RM and Grounds, MD}, title = {Slow or fast: Implications of myofibre type and associated differences for manifestation of neuromuscular disorders.}, journal = {Acta physiologica (Oxford, England)}, volume = {238}, number = {4}, pages = {e14012}, doi = {10.1111/apha.14012}, pmid = {37306196}, issn = {1748-1716}, mesh = {Male ; Animals ; Female ; *Muscle Fibers, Fast-Twitch ; *Muscle Fibers, Slow-Twitch ; Muscle, Skeletal/physiology ; Muscle Contraction/physiology ; Aging ; Mammals ; }, abstract = {Many neuromuscular disorders can have a differential impact on a specific myofibre type, forming the central premise of this review. The many different skeletal muscles in mammals contain a spectrum of slow- to fast-twitch myofibres with varying levels of protein isoforms that determine their distinctive contractile, metabolic, and other properties. The variations in functional properties across the range of classic 'slow' to 'fast' myofibres are outlined, combined with exemplars of the predominantly slow-twitch soleus and fast-twitch extensor digitorum longus muscles, species comparisons, and techniques used to study these properties. Other intrinsic and extrinsic differences are discussed in the context of slow and fast myofibres. These include inherent susceptibility to damage, myonecrosis, and regeneration, plus extrinsic nerves, extracellular matrix, and vasculature, examined in the context of growth, ageing, metabolic syndrome, and sexual dimorphism. These many differences emphasise the importance of carefully considering the influence of myofibre-type composition on manifestation of various neuromuscular disorders across the lifespan for both sexes. Equally, understanding the different responses of slow and fast myofibres due to intrinsic and extrinsic factors can provide deep insight into the precise molecular mechanisms that initiate and exacerbate various neuromuscular disorders. This focus on the influence of different myofibre types is of fundamental importance to enhance translation for clinical management and therapies for many skeletal muscle disorders.}, } @article {pmid37304072, year = {2023}, author = {Santiago, JA and Potashkin, JA}, title = {Physical activity and lifestyle modifications in the treatment of neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1185671}, pmid = {37304072}, issn = {1663-4365}, support = {R01 AG062176/AG/NIA NIH HHS/United States ; }, abstract = {Neurodegenerative diseases have reached alarming numbers in the past decade. Unfortunately, clinical trials testing potential therapeutics have proven futile. In the absence of disease-modifying therapies, physical activity has emerged as the single most accessible lifestyle modification with the potential to fight off cognitive decline and neurodegeneration. In this review, we discuss findings from epidemiological, clinical, and molecular studies investigating the potential of lifestyle modifications in promoting brain health. We propose an evidence-based multidomain approach that includes physical activity, diet, cognitive training, and sleep hygiene to treat and prevent neurodegenerative diseases.}, } @article {pmid37303947, year = {2023}, author = {Miura, S and Hiruki, S and Okada, T and Takei, SI and Senzaki, K and Okada, Y and Ochi, M and Tanabe, Y and Ochi, H and Igase, M and Ohyagi, Y and Shibata, H}, title = {Case report: Frontotemporal dementia and amyotrophic lateral sclerosis caused by a missense variant (p.Arg89Trp) in the valosin-containing protein gene.}, journal = {Frontiers in genetics}, volume = {14}, number = {}, pages = {1155998}, pmid = {37303947}, issn = {1664-8021}, abstract = {Frontotemporal dementia and/or amyotrophic lateral sclerosis 6, also known as amyotrophic lateral sclerosis 14, is an autosomal dominant, progressive neurodegenerative disorder caused by various mutations in the valosin-containing protein gene. In this report, we examined a 51-year-old female Japanese patient with frontotemporal dementia and amyotrophic lateral sclerosis. The patient began noticing gait disturbances at the age of 45 years. Neurological examination at the age of 46 years met the Awaji criteria for clinically probable amyotrophic lateral sclerosis. At the age of 49 years, she tended to have poor mood and an aversion to activity. Her symptoms gradually worsened. She required a wheelchair for transport and had difficulty communicating with others because of poor comprehension. She then began to frequently exhibit irritability. Eventually, she was admitted to the psychiatric hospital because uncontrollable violent behavior throughout the day. Longitudinal brain magnetic resonance imaging revealed progressive brain atrophy with temporal dominance, non-progressive cerebellar atrophy, and some non-specific white matter intensities. Brain single photon emission computed tomography showed hypoperfusion in the bilateral temporal lobes and cerebellar hemispheres. Clinical exome sequencing revealed the presence of a heterozygous nonsynonymous variant (NM_007126.5, c.265C>T; p.Arg89Trp) in the valosin-containing protein gene, which was absent in the 1000 Genomes Project, the Exome Aggregation Consortium Database, and the Genome Aggregation Database, and was predicted to be "damaging" by PolyPhen-2 and "deleterious" using SIFT with a Combined Annotation Dependent Depletion score of 35. We also confirmed the absence of this variant in 505 Japanese control subjects. Therefore, we concluded that the variant in the valosin-containing protein gene was responsible for the symptoms of this patient.}, } @article {pmid37303816, year = {2023}, author = {Maurer, L and Brown, M and Saggi, T and Cardiges, A and Kolarcik, CL}, title = {Hindlimb muscle representations in mouse motor cortex defined by viral tracing.}, journal = {Frontiers in neuroanatomy}, volume = {17}, number = {}, pages = {965318}, pmid = {37303816}, issn = {1662-5129}, support = {P40 OD010996/OD/NIH HHS/United States ; }, abstract = {INTRODUCTION: Descending pathways from the cortex to the spinal cord are involved in the control of natural movement. Although mice are widely used to study the neurobiology of movement and as models of neurodegenerative disease, an understanding of motor cortical organization is lacking, particularly for hindlimb muscles.

METHODS: In this study, we used the retrograde transneuronal transport of rabies virus to compare the organization of descending cortical projections to fast- and slow-twitch hindlimb muscles surrounding the ankle joint in mice.

RESULTS: Although the initial stage of virus transport from the soleus muscle (predominantly slow-twitch) appeared to be more rapid than that associated with the tibialis anterior muscle (predominantly fast-twitch), the rate of further transport of virus to cortical projection neurons in layer V was equivalent for the two injected muscles. After appropriate survival times, dense concentrations of layer V projection neurons were identified in three cortical areas: the primary motor cortex (M1), secondary motor cortex (M2), and primary somatosensory cortex (S1).

DISCUSSION: The origin of the cortical projections to each of the two injected muscles overlapped almost entirely within these cortical areas. This organization suggests that cortical projection neurons maintain a high degree of specificity; that is, even when cortical projection neurons are closely located, each neuron could have a distinct functional role (controlling fast- versus slow-twitch and/or extensor versus flexor muscles). Our results represent an important addition to the understanding of the mouse motor system and lay the foundation for future studies investigating the mechanisms underlying motor system dysfunction and degeneration in diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy.}, } @article {pmid37303084, year = {2023}, author = {Liu, Q and Huang, Y and Yang, Q and Peng, H and Wang, J}, title = {An Attention-Aware Long Short-Term Memory-Like Spiking Neural Model for Sentiment Analysis.}, journal = {International journal of neural systems}, volume = {33}, number = {8}, pages = {2350037}, doi = {10.1142/S0129065723500375}, pmid = {37303084}, issn = {1793-6462}, mesh = {Humans ; *Neural Networks, Computer ; Sentiment Analysis ; }, abstract = {LSTM-SNP model is a recently developed long short-term memory (LSTM) network, which is inspired from the mechanisms of spiking neural P (SNP) systems. In this paper, LSTM-SNP is utilized to propose a novel model for aspect-level sentiment analysis, termed as ALS model. The LSTM-SNP model has three gates: reset gate, consumption gate and generation gate. Moreover, attention mechanism is integrated with LSTM-SNP model. The ALS model can better capture the sentiment features in the text to compute the correlation between context and aspect words. To validate the effectiveness of the ALS model for aspect-level sentiment analysis, comparison experiments with 17 baseline models are conducted on three real-life data sets. The experimental results demonstrate that the ALS model has a simpler structure and can achieve better performance compared to these baseline models.}, } @article {pmid37302030, year = {2023}, author = {Rudge, JD}, title = {The Lipid Invasion Model: Growing Evidence for This New Explanation of Alzheimer's Disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {94}, number = {2}, pages = {457-470}, pmid = {37302030}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Brain/pathology ; Blood-Brain Barrier/metabolism ; Cholesterol ; }, abstract = {The Lipid Invasion Model (LIM) is a new hypothesis for Alzheimer's disease (AD) which argues that AD is a result of external lipid invasion to the brain, following damage to the blood-brain barrier (BBB). The LIM provides a comprehensive explanation of the observed neuropathologies associated with the disease, including the lipid irregularities first described by Alois Alzheimer himself, and accounts for the wide range of risk factors now identified with AD, all of which are also associated with damage to the BBB. This article summarizes the main arguments of the LIM, and new evidence and arguments in support of it. The LIM incorporates and extends the amyloid hypothesis, the current main explanation of the disease, but argues that the greatest cause of late-onset AD is not amyloid-β (Aβ) but bad cholesterol and free fatty acids, let into the brain by a damaged BBB. It suggests that the focus on Aβ is the reason why we have made so little progress in treating the disease in the last 30 years. As well as offering new perspectives for further research into the diagnosis, prevention, and treatment of AD, based on protecting and repairing the BBB, the LIM provides potential new insights into other neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis/motor neuron disease.}, } @article {pmid37300059, year = {2023}, author = {Stateczny, A and Halicki, A and Specht, M and Specht, C and Lewicka, O}, title = {Review of Shoreline Extraction Methods from Aerial Laser Scanning.}, journal = {Sensors (Basel, Switzerland)}, volume = {23}, number = {11}, pages = {}, pmid = {37300059}, issn = {1424-8220}, support = {LIDER/10/0030/L-11/19/NCBR/2020//National Centre for Research and Development in Poland/ ; WN/2023/PZ/05//Gdynia Maritime University/ ; }, abstract = {Autonomous technologies are increasingly used in various areas of science. The use of unmanned vehicles for hydrographic surveys in shallow coastal areas requires accurate estimation of shoreline position. This is a nontrivial task, which can be performed using a wide range of sensors and methods. The aim of the publication is to review shoreline extraction methods based solely on data from aerial laser scanning (ALS). This narrative review discusses and critically analyses seven publications drawn up in the last ten years. The discussed papers employed nine different shoreline extraction methods based on aerial light detection and ranging (LiDAR) data. It should be noted that unambiguous evaluation of shoreline extraction methods is difficult or impossible. This is because not all of the methods reported achieved accuracy, the methods were assessed on different datasets, the measurements were conducted using different devices, the water areas differed in geometrical and optical properties, the shorelines had different geometries, and the extent of anthropogenic transformation. The methods proposed by the authors were compared with a wide range of reference methods.}, } @article {pmid37299139, year = {2023}, author = {Zhang, J and Zhang, L and Wang, Q and Liu, J and Sun, Y}, title = {Diurnal Regulation of Leaf Photosynthesis Is Related to Leaf-Age-Dependent Changes in Assimilate Accumulation in Camellia oleifera.}, journal = {Plants (Basel, Switzerland)}, volume = {12}, number = {11}, pages = {}, pmid = {37299139}, issn = {2223-7747}, support = {32001348//the National Natural Science Foundation Project/ ; }, abstract = {In order to clarify the mechanism of diurnal changes in photosynthesis of leaves of different leaf ages in Camellia oleifera, current-year leaves (CLs) and annual leaves (ALs) were used as the test materials to analyze the diurnal changes in photosynthetic parameters, assimilate contents and enzyme activities, as well as structural differences and expression levels of sugar transport regulating genes. The rate of net photosynthesis in CLs and ALs was highest in the morning. During the day, there was a decrease in the CO2 assimilation rate, and this decrease was greater in ALs than in CLs at midday. The maximal efficiency of photosystem II (PSII) photochemistry (Fv/Fm) showed a decreasing trend as the sunlight intensity increased, but no significant difference between CLs and ALs was found. Compared with CLs, ALs showed a greater decrease in the carbon export rate at midday and the levels of sugars and starch increased significantly in ALs, accompanied by higher enzyme activity of sucrose synthetase and ADP-glucose pyrophosphorylase. In addition, compared with CLs, ALs had a larger leaf vein area and higher leaf vein density, as well as higher expression levels of sugar transport regulating genes during the day. It is concluded that the excessive accumulation of assimilate is an important factor contributing to the midday depression of photosynthesis in Camellia oleifera annual leaves on a sunny day. Sugar transporters may play an important regulatory role in excessive accumulation of assimilate in leaves.}, } @article {pmid37299097, year = {2023}, author = {Dominguez-Valenzuela, JA and Palma-Bautista, C and Vazquez-Garcia, JG and Yanniccari, M and Gigón, R and Alcántara-de la Cruz, R and De Prado, R and Portugal, J}, title = {Convergent Adaptation of Multiple Herbicide Resistance to Auxin Mimics and ALS- and EPSPS-Inhibitors in Brassica rapa from North and South America.}, journal = {Plants (Basel, Switzerland)}, volume = {12}, number = {11}, pages = {}, pmid = {37299097}, issn = {2223-7747}, abstract = {Herbicide-resistant weeds have been identified and recorded on every continent where croplands are available. Despite the diversity of weed communities, it is of interest how selection has led to the same consequences in distant regions. Brassica rapa is a widespread naturalized weed that is found throughout temperate North and South America, and it is a frequent weed among winter cereal crops in Argentina and in Mexico. Broadleaf weed control is based on glyphosate that is used prior to sowing and sulfonylureas or mimic auxin herbicides that are used once the weeds have already emerged. This study was aimed at determining whether a convergent phenotypic adaptation to multiple herbicides had occurred in B. rapa populations from Mexico and Argentina by comparing the herbicide sensitivity to inhibitors of the acetolactate synthase (ALS), 5-enolpyruvylshikimate-3-phosphate (EPSPS), and auxin mimics. Five B. rapa populations were analyzed from seeds collected in wheat fields in Argentina (Ar1 and Ar2) and barley fields in Mexico (Mx1, Mx2 and MxS). Mx1, Mx2, and Ar1 populations presented multiple resistance to ALS- and EPSPS-inhibitors and to auxin mimics (2,4-D, MCPA, and fluroxypyr), while the Ar2 population showed resistance only to ALS-inhibitors and glyphosate. Resistance factors ranged from 947 to 4069 for tribenuron-methyl, from 1.5 to 9.4 for 2,4-D, and from 2.7 to 42 for glyphosate. These were consistent with ALS activity, ethylene production, and shikimate accumulation analyses in response to tribenuron-methyl, 2,4-D, and glyphosate, respectively. These results fully support the evolution of the multiple- and cross-herbicide resistance to glyphosate, ALS-inhibitors, and auxinic herbicides in B. rapa populations from Mexico and Argentina.}, } @article {pmid37298586, year = {2023}, author = {Cerasuolo, M and Di Meo, I and Auriemma, MC and Trojsi, F and Maiorino, MI and Cirillo, M and Esposito, F and Polito, R and Colangelo, AM and Paolisso, G and Papa, M and Rizzo, MR}, title = {Iron and Ferroptosis More than a Suspect: Beyond the Most Common Mechanisms of Neurodegeneration for New Therapeutic Approaches to Cognitive Decline and Dementia.}, journal = {International journal of molecular sciences}, volume = {24}, number = {11}, pages = {}, pmid = {37298586}, issn = {1422-0067}, mesh = {Humans ; Iron/metabolism ; *Alzheimer Disease/metabolism ; *Ferroptosis ; *Neurodegenerative Diseases/metabolism ; *Cognitive Dysfunction/drug therapy/etiology/metabolism ; }, abstract = {Neurodegeneration is a multifactorial process that involves multiple mechanisms. Examples of neurodegenerative diseases are Parkinson's disease, multiple sclerosis, Alzheimer's disease, prion diseases such as Creutzfeldt-Jakob's disease, and amyotrophic lateral sclerosis. These are progressive and irreversible pathologies, characterized by neuron vulnerability, loss of structure or function of neurons, and even neuron demise in the brain, leading to clinical, functional, and cognitive dysfunction and movement disorders. However, iron overload can cause neurodegeneration. Dysregulation of iron metabolism associated with cellular damage and oxidative stress is reported as a common event in several neurodegenerative diseases. Uncontrolled oxidation of membrane fatty acids triggers a programmed cell death involving iron, ROS, and ferroptosis, promoting cell death. In Alzheimer's disease, the iron content in the brain is significantly increased in vulnerable regions, resulting in a lack of antioxidant defenses and mitochondrial alterations. Iron interacts with glucose metabolism reciprocally. Overall, iron metabolism and accumulation and ferroptosis play a significant role, particularly in the context of diabetes-induced cognitive decline. Iron chelators improve cognitive performance, meaning that brain iron metabolism control reduces neuronal ferroptosis, promising a novel therapeutic approach to cognitive impairment.}, } @article {pmid37298554, year = {2023}, author = {Michetti, F and Clementi, ME and Di Liddo, R and Valeriani, F and Ria, F and Rende, M and Di Sante, G and Romano Spica, V}, title = {The S100B Protein: A Multifaceted Pathogenic Factor More Than a Biomarker.}, journal = {International journal of molecular sciences}, volume = {24}, number = {11}, pages = {}, pmid = {37298554}, issn = {1422-0067}, mesh = {Humans ; Biomarkers/metabolism ; *Nervous System Diseases ; *Parkinson Disease/metabolism ; *S100 Calcium Binding Protein beta Subunit ; }, abstract = {S100B is a calcium-binding protein mainly concentrated in astrocytes in the nervous system. Its levels in biological fluids are recognized as a reliable biomarker of active neural distress, and more recently, mounting evidence points to S100B as a Damage-Associated Molecular Pattern molecule, which, at high concentration, triggers tissue reactions to damage. S100B levels and/or distribution in the nervous tissue of patients and/or experimental models of different neural disorders, for which the protein is used as a biomarker, are directly related to the progress of the disease. In addition, in experimental models of diseases such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic and vascular acute neural injury, epilepsy, and inflammatory bowel disease, alteration of S100B levels correlates with the occurrence of clinical and/or toxic parameters. In general, overexpression/administration of S100B worsens the clinical presentation, whereas deletion/inactivation of the protein contributes to the amelioration of the symptoms. Thus, the S100B protein may be proposed as a common pathogenic factor in different disorders, sharing different symptoms and etiologies but appearing to share some common pathogenic processes reasonably attributable to neuroinflammation.}, } @article {pmid37298512, year = {2023}, author = {Guo, Z}, title = {Ganglioside GM1 and the Central Nervous System.}, journal = {International journal of molecular sciences}, volume = {24}, number = {11}, pages = {}, pmid = {37298512}, issn = {1422-0067}, support = {R35 GM131686/GM/NIGMS NIH HHS/United States ; R35GM131686/NH/NIH HHS/United States ; }, mesh = {Humans ; *G(M1) Ganglioside/metabolism ; *Gangliosidosis, GM1 ; Central Nervous System/metabolism ; Brain/metabolism ; Glycosphingolipids/metabolism ; }, abstract = {GM1 is one of the major glycosphingolipids (GSLs) on the cell surface in the central nervous system (CNS). Its expression level, distribution pattern, and lipid composition are dependent upon cell and tissue type, developmental stage, and disease state, which suggests a potentially broad spectrum of functions of GM1 in various neurological and neuropathological processes. The major focus of this review is the roles that GM1 plays in the development and activities of brains, such as cell differentiation, neuritogenesis, neuroregeneration, signal transducing, memory, and cognition, as well as the molecular basis and mechanisms for these functions. Overall, GM1 is protective for the CNS. Additionally, this review has also examined the relationships between GM1 and neurological disorders, such as Alzheimer's disease, Parkinson's disease, GM1 gangliosidosis, Huntington's disease, epilepsy and seizure, amyotrophic lateral sclerosis, depression, alcohol dependence, etc., and the functional roles and therapeutic applications of GM1 in these disorders. Finally, current obstacles that hinder more in-depth investigations and understanding of GM1 and the future directions in this field are discussed.}, } @article {pmid37298129, year = {2023}, author = {Molinaro, P and Sanguigno, L and Casamassa, A and Valsecchi, V and Sirabella, R and Pignataro, G and Annunziato, L and Formisano, L}, title = {Emerging Role of DREAM in Healthy Brain and Neurological Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {11}, pages = {}, pmid = {37298129}, issn = {1422-0067}, support = {PE0000006//Ministry of Education, Universities and Research/ ; PE0000012//Ministry of Education, Universities and Research/ ; CN00000041//Ministry of Education, Universities and Research/ ; 2017JL8SRX//Ministry of Education, Universities and Research/ ; 20173EAZ2Z//Ministry of Education, Universities and Research/ ; 2017WJZ9W9//Ministry of Education, Universities and Research/ ; }, mesh = {*Kv Channel-Interacting Proteins/metabolism ; *Repressor Proteins/genetics ; Brain/metabolism ; Dynorphins/metabolism ; Cell Nucleus/metabolism ; }, abstract = {The downstream regulatory element antagonist modulator (DREAM) is a multifunctional Ca[2+]-sensitive protein exerting a dual mechanism of action to regulate several Ca[2+]-dependent processes. Upon sumoylation, DREAM enters in nucleus where it downregulates the expression of several genes provided with a consensus sequence named dream regulatory element (DRE). On the other hand, DREAM could also directly modulate the activity or the localization of several cytosolic and plasma membrane proteins. In this review, we summarize recent advances in the knowledge of DREAM dysregulation and DREAM-dependent epigenetic remodeling as a central mechanism in the progression of several diseases affecting central nervous system, including stroke, Alzheimer's and Huntington's diseases, amyotrophic lateral sclerosis, and neuropathic pain. Interestingly, DREAM seems to exert a common detrimental role in these diseases by inhibiting the transcription of several neuroprotective genes, including the sodium/calcium exchanger isoform 3 (NCX3), brain-derived neurotrophic factor (BDNF), pro-dynorphin, and c-fos. These findings lead to the concept that DREAM might represent a pharmacological target to ameliorate symptoms and reduce neurodegenerative processes in several pathological conditions affecting central nervous system.}, } @article {pmid37297781, year = {2023}, author = {Gentili, D and Deiana, G and Chessa, V and Calabretta, A and Marras, E and Solinas, C and Gugliotta, C and Azara, A}, title = {Quality of Life in Amyotrophic Lateral Sclerosis Patients and Care Burden of Caregivers in Sardinia during COVID-19 Pandemic.}, journal = {Healthcare (Basel, Switzerland)}, volume = {11}, number = {11}, pages = {}, pmid = {37297781}, issn = {2227-9032}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rare neurogenerative disorder whose median survival ranges from 2 to 4 years after symptomatic onset. Therefore, the global Quality of Life (QoL) assessment in these patients should be carefully evaluated to guarantee an adequate care level, particularly during the COVID-19 pandemic period, given the increased social isolation and the pressure on healthcare services. Caregiving has been recognized as an important source of physical and psychological burden, with a possible QoL impairment. The purpose of this study was to evaluate the QoL of ALS patients and the burden of their caregivers across Sardinia, Italy. The ALS Specific QoL Instrument-Short Form (ALSSQOL-SF) and the Zarit Burden Inventory (ZBI) tools were used to assess patient's QoL and the burden on their caregivers, respectively. The questionnaires were supplemented with items specific for the COVID-19 period. Sixty-six family units of patients with advanced ALS were interviewed between June and August 2021 across Sardinia. Patients' psychological and social well-being were found to significantly affect the patients' QoL, regardless of their physical condition. In addition, the caregiver burden resulted as being inversely proportional to the patient's perceived QoL. Lack of adequate psychological support was reported among the caregivers during the emergency period. Providing adequate psychological and social support might be useful to improve QoL in middle and late stages of ALS patients and to decrease caregivers' perceived home care burden.}, } @article {pmid37296644, year = {2023}, author = {Tzeplaeff, L and Wilfling, S and Requardt, MV and Herdick, M}, title = {Current State and Future Directions in the Therapy of ALS.}, journal = {Cells}, volume = {12}, number = {11}, pages = {}, pmid = {37296644}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Riluzole/therapeutic use ; Motor Neurons/pathology ; Biomarkers ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from respiratory failure three to five years after symptom onset. As the exact underlying causative pathological pathway is unclear and potentially diverse, finding a suitable therapy to slow down or possibly stop disease progression remains challenging. Varying by country Riluzole, Edaravone, and Sodium phenylbutyrate/Taurursodiol are the only drugs currently approved in ALS treatment for their moderate effect on disease progression. Even though curative treatment options, able to prevent or stop disease progression, are still unknown, recent breakthroughs, especially in the field of targeting genetic disease forms, raise hope for improved care and therapy for ALS patients. In this review, we aim to summarize the current state of ALS therapy, including medication as well as supportive therapy, and discuss the ongoing developments and prospects in the field. Furthermore, we highlight the rationale behind the intense research on biomarkers and genetic testing as a feasible way to improve the classification of ALS patients towards personalized medicine.}, } @article {pmid37296623, year = {2023}, author = {Kandhavivorn, W and Glaß, H and Herrmannsdörfer, T and Böckers, TM and Uhlarz, M and Gronemann, J and Funk, RHW and Pietzsch, J and Pal, A and Hermann, A}, title = {Restoring Axonal Organelle Motility and Regeneration in Cultured FUS-ALS Motoneurons through Magnetic Field Stimulation Suggests an Alternative Therapeutic Approach.}, journal = {Cells}, volume = {12}, number = {11}, pages = {}, pmid = {37296623}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Motor Neurons/pathology ; Axons/metabolism ; Organelles/metabolism ; Magnetic Fields ; RNA-Binding Protein FUS/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motoneuron disease characterized by sustained loss of neuromuscular junctions, degenerating corticospinal motoneurons and rapidly progressing muscle paralysis. Motoneurons have unique features, essentially a highly polarized, lengthy architecture of axons, posing a considerable challenge for maintaining long-range trafficking routes for organelles, cargo, mRNA and secretion with a high energy effort to serve crucial neuronal functions. Impaired intracellular pathways implicated in ALS pathology comprise RNA metabolism, cytoplasmic protein aggregation, cytoskeletal integrity for organelle trafficking and maintenance of mitochondrial morphology and function, cumulatively leading to neurodegeneration. Current drug treatments only have marginal effects on survival, thereby calling for alternative ALS therapies. Exposure to magnetic fields, e.g., transcranial magnetic stimulations (TMS) on the central nervous system (CNS), has been broadly explored over the past 20 years to investigate and improve physical and mental activities through stimulated excitability as well as neuronal plasticity. However, studies of magnetic treatments on the peripheral nervous system are still scarce. Thus, we investigated the therapeutic potential of low frequency alternating current magnetic fields on cultured spinal motoneurons derived from induced pluripotent stem cells of FUS-ALS patients and healthy persons. We report a remarkable restoration induced by magnetic stimulation on axonal trafficking of mitochondria and lysosomes and axonal regenerative sprouting after axotomy in FUS-ALS in vitro without obvious harmful effects on diseased and healthy neurons. These beneficial effects seem to derive from improved microtubule integrity. Thus, our study suggests the therapeutic potential of magnetic stimulations in ALS, which awaits further exploration and validation in future long-term in vivo studies.}, } @article {pmid37296572, year = {2023}, author = {Dučić, T and Koch, JC}, title = {Synchrotron-Based Fourier-Transform Infrared Micro-Spectroscopy of Cerebrospinal Fluid from Amyotrophic Lateral Sclerosis Patients Reveals a Unique Biomolecular Profile.}, journal = {Cells}, volume = {12}, number = {11}, pages = {}, pmid = {37296572}, issn = {2073-4409}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Spectroscopy, Fourier Transform Infrared ; *Neurodegenerative Diseases ; Synchrotrons ; Lipids ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, with the most common adult-onset neurodegenerative disorder affecting motoneurons. Although disruptions in macromolecular conformation and homeostasis have been described in association with ALS, the underlying pathological mechanisms are still not completely understood, and unambiguous biomarkers are lacking. Fourier Transform Infrared Spectroscopy (FTIR) of cerebrospinal fluid (CSF) is appealing to extensive interest due to its potential to resolve biomolecular conformation and content, as this approach offers a non-invasive, label-free identification of specific biologically relevant molecules in a few microliters of CSF sample. Here, we analyzed the CSF of 33 ALS patients compared to 32 matched controls using FTIR spectroscopy and multivariate analysis and demonstrated major differences in the molecular contents. A significant change in the conformation and concentration of RNA is demonstrated. Moreover, significantly increased glutamate and carbohydrates are found in ALS. Moreover, key markers of lipid metabolism are strongly altered; specifically, we find a decrease in unsaturated lipids and an increase in peroxidation of lipids in ALS, whereas the total amount of lipids compared to proteins is reduced. Our study demonstrates that FTIR characterization of CSF could represent a powerful tool for ALS diagnosis and reveals central features of ALS pathophysiology.}, } @article {pmid37296571, year = {2023}, author = {Valori, CF and Sulmona, C and Brambilla, L and Rossi, D}, title = {Astrocytes: Dissecting Their Diverse Roles in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.}, journal = {Cells}, volume = {12}, number = {11}, pages = {}, pmid = {37296571}, issn = {2073-4409}, mesh = {Animals ; *Astrocytes ; *Frontotemporal Dementia ; *Amyotrophic Lateral Sclerosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders often co-occurring in the same patient, a feature that suggests a common origin of the two diseases. Consistently, pathological inclusions of the same proteins as well as mutations in the same genes can be identified in both ALS/FTD. Although many studies have described several disrupted pathways within neurons, glial cells are also regarded as crucial pathogenetic contributors in ALS/FTD. Here, we focus our attention on astrocytes, a heterogenous population of glial cells that perform several functions for optimal central nervous system homeostasis. Firstly, we discuss how post-mortem material from ALS/FTD patients supports astrocyte dysfunction around three pillars: neuroinflammation, abnormal protein aggregation, and atrophy/degeneration. Furthermore, we summarize current attempts at monitoring astrocyte functions in living patients using either novel imaging strategies or soluble biomarkers. We then address how astrocyte pathology is recapitulated in animal and cellular models of ALS/FTD and how we used these models both to understand the molecular mechanisms driving glial dysfunction and as platforms for pre-clinical testing of therapeutics. Finally, we present the current clinical trials for ALS/FTD, restricting our discussion to treatments that modulate astrocyte functions, directly or indirectly.}, } @article {pmid37296379, year = {2023}, author = {Piccoli, T and Castro, F and La Bella, V and Meraviglia, S and Di Simone, M and Salemi, G and Dieli, F and Spataro, R}, title = {Role of the immune system in amyotrophic lateral sclerosis. Analysis of the natural killer cells and other circulating lymphocytes in a cohort of ALS patients.}, journal = {BMC neurology}, volume = {23}, number = {1}, pages = {222}, pmid = {37296379}, issn = {1471-2377}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/complications ; Disease Progression ; Killer Cells, Natural ; }, abstract = {AIMS: Neuroinflammation might be involved in the degeneration and progression of Amyotrophic Lateral Sclerosis (ALS). Here, we studied the role of the circulating lymphocytes in ALS, in particular the NK cells. We focused on the relationship between blood lymphocytes, ALS clinical subtype and disease severity.

SUBJECTS AND METHODS: Blood samples were collected from 92 patients with sporadic ALS, 21 patients with Primary Lateral Sclerosis (PLS) and 37 patients affected by primary progressive multiple sclerosis (PPMS) with inactive plaques. Blood was taken from ALS and controls at the time of diagnosis/referral. Circulating lymphocytes were analyzed by flow cytometry with specific antibodies. Values were expressed as absolute number (n°/µl) of viable lymphocytes subpopulations in ALS were compared with controls. Multivariable analysis was made using site of onset, gender changes in ALSFRS-R and disease progression rate (calculated as ΔFS score).

RESULTS: Age at onset was 65y (58-71) in ALS (spinal 67.4%; bulbar, 32.6%), 57y (48-78) in PLS and 56y (44-68) PPMS. Absolute blood levels of the lymphocytes in the different cohorts were within normal range. Furthermore, while levels of lymphocytes T and B were not different between disease groups, NK cells were increased in the ALS cohort (ALS = 236 [158-360] vs. Controls = 174[113-240], p < 0.001). In ALS, blood levels of NK cells were not related with the main clinical-demographic variables, including the rate of disease progression. Multivariable analysis suggested that male gender and bulbar onset were independently associated with a risk of high blood NK cells levels.

CONCLUSIONS: We show that blood NK cells are selectively increased in ALS, though their level appear unaffected in patients with an estimated rapidly progressing disease. Being of a male gender and with a bulbar onset seems to confer higher susceptibility to have increased NK lymphocytes levels at diagnosis/referral. Our experiments provides a further clear-cut evidence of the role of the NK lymphocytes as a significant player in ALS pathogenesis.}, } @article {pmid37295966, year = {2023}, author = {Alves, I and Gromicho, M and Oliveira Santos, M and Pinto, S and Pronto-Laborinho, A and Swash, M and de Carvalho, M}, title = {Demographic changes in a large motor neuron disease cohort in Portugal: a 27 year experience.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2023.2220747}, pmid = {37295966}, issn = {2167-9223}, abstract = {Objective: Motor Neuron Diseases (MND) have a large clinical spectrum, being the most common amyotrophic lateral sclerosis (ALS) but there is significant clinical heterogeneity. Our goal was to investigate this heterogeneity and any potential changes during a long period. Methods: We performed a retrospective cohort study among a large Portuguese cohort of MND patients (n = 1550) and investigated changing patterns in clinical and demographic characteristics over the 27-year period of our database. With that aim, patients were divided into three 9-year groups according to the date of their first visit to our unit: P1, 1994-2002; P2, 2003-2011; P3, 2012-2020. Results: The overall cohort's clinical and demographic characteristics are consistent with clinical experience, but our findings point to gradual changes over time. Time pattern analysis revealed statistically significant differences in the distribution of clinical phenotypes, the average age of onset, diagnostic delay, the proportin of patients using respiratory support with noninvasive ventilation (NIV), time to NIV, and survival. Across time, in the overall cohort, we found an increasing age at onset (p = 0.029), a decrease of two months in diagnostic delay (p < 0.001) and a higher relative frequency of progressive muscular atrophy patients. For ALS patients with spinal onset, from P1 to P2, there was a more widespread (54.8% vs 69.4%, p = 0.005) and earlier (36.9 vs 27.2 months, p = 0.05) use of NIV and a noteworthy 13-month increase in median survival (p = 0.041). Conclusions: Our results probably reflect better comprehensive care, and they are relevant for future studies exploring the impact of new treatments on ALS patients.}, } @article {pmid37295429, year = {2023}, author = {Boeynaems, S and Dorone, Y and Zhuang, Y and Shabardina, V and Huang, G and Marian, A and Kim, G and Sanyal, A and Şen, NE and Griffith, D and Docampo, R and Lasker, K and Ruiz-Trillo, I and Auburger, G and Holehouse, AS and Kabashi, E and Lin, Y and Gitler, AD}, title = {Poly(A)-binding protein is an ataxin-2 chaperone that regulates biomolecular condensates.}, journal = {Molecular cell}, volume = {83}, number = {12}, pages = {2020-2034.e6}, pmid = {37295429}, issn = {1097-4164}, support = {P30 NS069375/NS/NINDS NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R21 AI140421/AI/NIAID NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R35 NS097263/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Ataxin-2/genetics ; Poly(A)-Binding Protein I ; *Neurodegenerative Diseases/metabolism ; Biomolecular Condensates ; }, abstract = {Biomolecular condensation underlies the biogenesis of an expanding array of membraneless assemblies, including stress granules (SGs), which form under a variety of cellular stresses. Advances have been made in understanding the molecular grammar of a few scaffold proteins that make up these phases, but how the partitioning of hundreds of SG proteins is regulated remains largely unresolved. While investigating the rules that govern the condensation of ataxin-2, an SG protein implicated in neurodegenerative disease, we unexpectedly identified a short 14 aa sequence that acts as a condensation switch and is conserved across the eukaryote lineage. We identify poly(A)-binding proteins as unconventional RNA-dependent chaperones that control this regulatory switch. Our results uncover a hierarchy of cis and trans interactions that fine-tune ataxin-2 condensation and reveal an unexpected molecular function for ancient poly(A)-binding proteins as regulators of biomolecular condensate proteins. These findings may inspire approaches to therapeutically target aberrant phases in disease.}, } @article {pmid37323688, year = {2021}, author = {Zhang, Y and Yang, H and Wei, D and Zhang, X and Wang, J and Wu, X and Chang, J}, title = {Mitochondria-targeted nanoparticles in treatment of neurodegenerative diseases.}, journal = {Exploration (Beijing, China)}, volume = {1}, number = {3}, pages = {20210115}, pmid = {37323688}, issn = {2766-2098}, abstract = {Neurodegenerative diseases (NDs) are a class of heterogeneous diseases that includes Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Mitochondria play an important role in oxidative balance and metabolic activity of neurons; therefore, mitochondrial dysfunction is associated with NDs and mitochondria are considered a potential treatment target for NDs. Several obstacles, including the blood-brain barrier (BBB) and cell/mitochondrial membranes, reduce the efficiency of drug entry into the target lesions. Therefore, a variety of neuron mitochondrial targeting strategies has been developed. Among them, nanotechnology-based treatments show especially promising results. Owing to their adjustable size, appropriate charge, and lipophilic surface, nanoparticles (NPs) are the ideal theranostic system for crossing the BBB and targeting the neuronal mitochondria. In this review, we discussed the role of dysfunctional mitochondria in ND pathogenesis as well as the physiological barriers to various treatment strategies. We also reviewed the use and advantages of various NPs (including organic, inorganic, and biological membrane-coated NPs) for the treatment and diagnosis of NDs. Finally, we summarized the evidence and possible use for the promising role of NP-based theranostic systems in the treatment of mitochondrial dysfunction-related NDs.}, } @article {pmid37786905, year = {2021}, author = {Huang, ZQ and Ba, ZS and Huang, NQ and Li, YY and Luo, Y}, title = {Aberrant TDP-43 phosphorylation: a key wind gap from TDP-43 to TDP-43 proteinopathy.}, journal = {Ibrain}, volume = {7}, number = {2}, pages = {119-131}, pmid = {37786905}, issn = {2769-2795}, abstract = {TDP-43 proteinopathy is a kind of neurodegenerative diseases related to the TAR DNA-binding protein of 43-kDa molecular weight (TDP-43). The typical neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), Parkinson's disease (PD) and so on. As the disease process cannot be blocked or slowed down, these patients have poor quality of life and poor prognosis, and bring a huge burden to the family and society. So far, the specific pathogenesis of TDP-43 proteinopathy is not clear, and there is no effective preventive measure and treatment program for this kind of disease. TDP-43 plays an important role in triggering or promoting the occurrence and progression of TDP-43 proteinopathy. The hyperphosphorylation of TDP-43 is undoubtedly an important factor in triggering or promoting the process of TDP-43 proteinopathy. Hyperphosphorylation of TDP-43 can inhibit the degradation of TDP-43, aggravate the aggregation of TDP-43 protein, increase the wrong localization of TDP-43 in cells, and enhance the cytotoxicity of TDP-43. More and more evidences show that the hyperphosphorylation of TDP-43 plays an important role in the pathogenesis of TDP-43 proteinopathy. Inhibition of TDP-43 hyperphosphorylation may be one of the important strategies for the treatment of TDP-43 proteinopathy. Therefore, this article reviews the role of TDP-43 phosphorylation in TDP-43 proteinopathy and the related mechanisms.}, } @article {pmid37427003, year = {2021}, author = {Horowitz, AJ and Guger, C and Korostenskaja, M}, title = {What Internal Variables Affect Sensorimotor Rhythm Brain-Computer Interface (SMR-BCI) Performance?.}, journal = {HCA healthcare journal of medicine}, volume = {2}, number = {3}, pages = {163-179}, pmid = {37427003}, issn = {2689-0216}, abstract = {Description In this review article, we aimed to create a summary of the effects of internal variables on the performance of sensorimotor rhythm-based brain computer interfaces (SMR-BCIs). SMR-BCIs can be potentially used for interfacing between the brain and devices, bypassing usual central nervous system output, such as muscle activity. The careful consideration of internal factors, affecting SMR-BCI performance, can maximize BCI application in both healthy and disabled people. Internal variables may be generalized as descriptors of the processes mainly dependent on the BCI user and/or originating within the user. The current review aimed to critically evaluate and summarize the currently accumulated body of knowledge regarding the effect of internal variables on SMR-BCI performance. The examples of such internal variables include motor imagery, hand coordination, attention, motivation, quality of life, mood and neurophysiological signals other than SMR. We will conclude our review with the discussion about the future developments regarding the research on the effects of internal variables on SMR-BCI performance. The end-goal of this review paper is to provide current BCI users and researchers with the reference guide that can help them optimize the SMR-BCI performance by accounting for possible influences of various internal factors.}, } @article {pmid37366377, year = {2021}, author = {Borgese, N and Navone, F and Nukina, N and Yamanaka, T}, title = {Mutant VAPB: Culprit or Innocent Bystander of Amyotrophic Lateral Sclerosis?.}, journal = {Contact (Thousand Oaks (Ventura County, Calif.))}, volume = {4}, number = {}, pages = {25152564211022515}, pmid = {37366377}, issn = {2515-2564}, abstract = {Nearly twenty years ago a mutation in the VAPB gene, resulting in a proline to serine substitution (p.P56S), was identified as the cause of a rare, slowly progressing, familial form of the motor neuron degenerative disease Amyotrophic Lateral Sclerosis (ALS). Since then, progress in unravelling the mechanistic basis of this mutation has proceeded in parallel with research on the VAP proteins and on their role in establishing membrane contact sites between the ER and other organelles. Analysis of the literature on cellular and animal models reviewed here supports the conclusion that P56S-VAPB, which is aggregation-prone, non-functional and unstable, is expressed at levels that are insufficient to support toxic gain-of-function or dominant negative effects within motor neurons. Instead, insufficient levels of the product of the single wild-type allele appear to be required for pathological effects, and may be the main driver of the disease. In light of the multiple interactions of the VAP proteins, we address the consequences of specific VAPB depletion and highlight various affected processes that could contribute to motor neuron degeneration. In the future, distinction of specific roles of each of the two VAP paralogues should help to further elucidate the basis of p.P56S familial ALS, as well as of other more common forms of the disease.}, } @article {pmid37387779, year = {2021}, author = {Huang, H and Chen, L and Chopp, M and Young, W and Robert Bach, J and He, X and Sarnowaska, A and Xue, M and Chunhua Zhao, R and Shetty, A and Siniscalco, D and Guo, X and Khoshnevisan, A and Hawamdeh, Z}, title = {The 2020 Yearbook of Neurorestoratology.}, journal = {Journal of neurorestoratology}, volume = {9}, number = {1}, pages = {1-12}, pmid = {37387779}, issn = {2324-2426}, abstract = {COVID-19 has been an emerging and rapidly evolving risk to people of the world in 2020. Facing this dangerous situation, many colleagues in Neurorestoratology did their best to avoid infection if themselves and their patients, and continued their work in the research areas described in the 2020 Yearbook of Neurorestoratology. Neurorestorative achievements and progress during 2020 includes recent findings on the pathogenesis of neurological diseases, neurorestorative mechanisms and clinical therapeutic achievements. Therapeutic progress during this year included advances in cell therapies, neurostimulation/neuromodulation, brain-computer interface (BCI), and pharmaceutical neurorestorative therapies, which improved neurological functions and quality of life for patients. Four clinical guidelines or standards of Neurorestoratology were published in 2020. Milestone examples include: 1) a multicenter randomized, double-blind, placebo-controlled study of olfactory ensheathing cell treatment of chronic stroke showed functional improvements; 2) patients after transhumeral amputation experienced increased sensory acuity and had improved effectiveness in work and other activities of daily life using a prosthesis; 3) a patient with amyotrophic lateral sclerosis used a steady-state visual evoked potential (SSVEP)-based BCI to achieve accurate and speedy computer input; 4) a patient with complete chronic spinal cord injury recovered both motor function and touch sensation with a BCI and restored ability to detect objects by touch and several sensorimotor functions. We hope these achievements motivate and encourage other scientists and physicians to increase neurorestorative research and its therapeutic applications.}, } @article {pmid37465403, year = {2020}, author = {Au, C and Myatt, T}, title = {Loose PEG Tube Leading to Peristomal Leakage and Peritonitis, a Case Report.}, journal = {Journal of education & teaching in emergency medicine}, volume = {5}, number = {2}, pages = {V7-V10}, pmid = {37465403}, issn = {2474-1949}, abstract = {UNLABELLED: We present the case of a 37-year-old male with history of amyotrophic lateral sclerosis (ALS) and recent percutaneous endoscopic gastrostomy (PEG) tube placement presented with abdominal pain, nausea, vomiting, abdominal distention, tenderness and guarding. Given the concern for peritonitis, upright/decubitus chest X-ray was obtained and showed bilateral free peritoneal air suggesting possible perforation or peristomal leakage after PEG tube placement. While PEG complication rates are relatively low, clinicians should consider them and remember that chest X-ray can be a very efficient and accurate method of evaluation for possible gastrointestinal perforation, especially in acute emergencies.

TOPICS: Abdominal/gastrointestinal, peritonitis, perforation, surgical complication.}, } @article {pmid37577056, year = {2020}, author = {Fogarty, MJ and Brown, AD and Sieck, GC}, title = {MOTOR NEURON LOSS IN AGING AND AMYOTROPHIC LATERAL SCLEROSIS: DIFFERENT FUSE LENGTHS, SAME EXPLOSION.}, journal = {Physiological mini-reviews}, volume = {13}, number = {1}, pages = {1-11}, pmid = {37577056}, issn = {1669-5410}, support = {R01 AG044615/AG/NIA NIH HHS/United States ; R01 AG057052/AG/NIA NIH HHS/United States ; R01 HL146114/HL/NHLBI NIH HHS/United States ; T32 HL105355/HL/NHLBI NIH HHS/United States ; }, abstract = {Advanced age and amyotrophic lateral sclerosis (ALS) are both associated with a loss of motor neurons resulting in muscle fiber atrophy and muscle weakness. Aging associated muscle fiber atrophy and weakening is termed sarcopenia, but the association with motor neuron loss is not as clearly established as in ALS, probably related to the prolonged time course of aging-related changes. Although aging and ALS effects on limb muscle strength and neuromotor performance are serious, such effects on the diaphragm muscle can be life threatening. Converging evidence indicates that larger phrenic motor neurons, innervating more fatigable type IIx and/or IIb diaphragm muscle fibers (fast fatigue intermediate, FInt and fast fatigable, FF motor units) are more susceptible to degeneration with both aging and ALS compared to smaller phrenic motor neurons innervating type I and IIa diaphragm muscle fibers (slow and fast fatigue resistant motor units, respectively). The etiology of ALS and age-related loss of motor neurons appears to involve mitochondrial function and neuroinflammation, both chronic and acute exacerbation. How mitochondrial dysfunction, neuroinflammation and motor neuron size intersect is the focus of continuing investigation.}, } @article {pmid37295193, year = {2023}, author = {Yamashita, S and Tawara, N and Hara, K and Ueda, M}, title = {Gender differences in clinical features at the initial examination of late-onset amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {451}, number = {}, pages = {120697}, doi = {10.1016/j.jns.2023.120697}, pmid = {37295193}, issn = {1878-5883}, mesh = {Male ; Female ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/epidemiology ; Retrospective Studies ; *Neurodegenerative Diseases ; Sex Factors ; Motor Neurons ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that mainly affects motor neurons in the brain and spinal cord. With the advent of aging societies, the proportion of elderly patients with ALS is expected to increase.

METHODS: We retrospectively compared the clinical characteristics at the initial examination of patients with onset of ALS at age 74 years or younger (early onset) and those aged 75 years or older at onset (late-onset) at a single regional ALS diagnostic center in Japan.

RESULTS: The phenotype of late-onset ALS differed between males and females, with late-onset females having more bulbar-onset ALS and significantly lower body mass index, late-onset males having more frequent bulbar and respiratory symptoms at the initial examination, and significantly lower forced vital capacity at the initial examination in both groups compared to early onset patients.

CONCLUSION: For late-onset patients, maintenance of skeletal muscle mass by early intervention for bulbar and respiratory symptoms may be useful for prolonging survival; however, a prospective analysis is warranted.}, } @article {pmid37294668, year = {2023}, author = {Sato, K and Farquhar, CE and Rodriguez, J and Pentelute, BL}, title = {Automated Fast-Flow Synthesis of Chromosome 9 Open Reading Frame 72 Dipeptide Repeat Proteins.}, journal = {Journal of the American Chemical Society}, volume = {145}, number = {24}, pages = {12992-12997}, doi = {10.1021/jacs.3c02285}, pmid = {37294668}, issn = {1520-5126}, mesh = {Humans ; *Dipeptides/chemistry ; C9orf72 Protein/genetics/metabolism ; Open Reading Frames ; *Proteins/chemistry ; Glycine ; Alanine ; Proline ; Arginine/genetics ; Chromosomes, Human, Pair 9/metabolism ; }, abstract = {An expansion of the hexanucleotide (GGGGCC) repeat sequence in chromosome 9 open frame 72 (c9orf72) is the most common genetic mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mutation leads to the production of toxic dipeptide repeat proteins (DPRs) that induce neurodegeneration. However, the fundamental physicochemical properties of DPRs remain largely unknown due to their limited availability. Here, we synthesized the c9orf72 DPRs poly-glycine-arginine (poly-GR), poly-proline-arginine (poly-PR), poly-glycine-proline (poly-GP), poly-proline-alanine (poly-PA), and poly-glycine-alanine (poly-GA) using automated fast-flow peptide synthesis (AFPS) and achieved single-domain chemical synthesis of proteins with up to 200 amino acids. Circular dichroism spectroscopy of the synthetic DPRs revealed that proline-containing poly-PR, poly-GP, and poly-PA could adopt polyproline II-like helical secondary structures. In addition, structural analysis by size-exclusion chromatography indicated that longer poly-GP and poly-PA might aggregate. Furthermore, cell viability assays showed that human neuroblastoma cells cultured with poly-GR and poly-PR with longer repeat lengths resulted in reduced cell viability, while poly-GP and poly-PA did not, thereby reproducing the cytotoxic property of endogenous DPRs. This research demonstrates the potential of AFPS to synthesize low-complexity peptides and proteins necessary for studying their pathogenic mechanisms and constructing disease models.}, } @article {pmid37294189, year = {2023}, author = {Pegat, A and Bernard, E}, title = {Immunoglobulin light-chain amyloidosis mimicking bulbar amyotrophic lateral sclerosis.}, journal = {Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis}, volume = {30}, number = {3}, pages = {346-347}, doi = {10.1080/13506129.2022.2163891}, pmid = {37294189}, issn = {1744-2818}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Immunoglobulin Light-chain Amyloidosis/diagnosis ; Tongue Diseases/diagnosis ; }, } @article {pmid37293667, year = {2023}, author = {Manera, U and Grassano, M and Matteoni, E and Bombaci, A and Vasta, R and Palumbo, F and Torrieri, MC and Cugnasco, P and Moglia, C and Canosa, A and Chiò, A and Calvo, A}, title = {Serum chloride as a respiratory failure marker in amyotrophic lateral sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1188827}, pmid = {37293667}, issn = {1663-4365}, abstract = {Respiratory failure is the most common cause of death in patients with amyotrophic lateral sclerosis (ALS) and occurs with great variability among patients according to different phenotypic features. Early predictors of respiratory failure in ALS are important to start non-invasive ventilation (NIV). Venous serum chloride values correlate with carbonate (HCO3-) blood levels and reflect metabolic compensation of respiratory acidosis. Despite its wide availability and low cost, few data on serum chloride as a prognostic marker exist in ALS literature. In the present study, we evaluated serum chloride values at diagnosis as prognostic biomarkers for overall survival and NIV adaptation in a retrospective center-based cohort of ALS patients. We collected all ALS patients with serum chloride assessment at diagnosis, identified through the Piemonte and Valle d'Aosta Register for ALS, evaluating the correlations among serum chloride, clinical features, and other serum biomarkers. Thereafter, time-to-event analysis was modeled to predict overall survival and NIV start. We found a significant correlation between serum chloride and inflammatory status markers, serum sodium, forced vital capacity (FVC), ALS functional rating scale-revised (ALSFRS-R) item 10 and 11, age at diagnosis, and weight loss. Time-to-event analysis confirmed both in univariate analysis and after multiple confounders' adjustment that serum chloride value at diagnosis significantly influenced survival and time to NIV start. According to our analysis, based on a large ALS cohort, we found that serum chloride analyzed at diagnosis is a low-cost marker of impending respiratory decompensation. In our opinion, it should be added among the serum prognostic biomarkers that are able to stratify patients into different prognostic categories even when performed in the early phases of the disease.}, } @article {pmid37293291, year = {2023}, author = {Dou, J and Bakulski, K and Guo, K and Hur, J and Zhao, L and Saez-Atienzar, S and Stark, A and Chia, R and García-Redondo, A and Rojas-Garcia, R and Vázquez Costa, JF and Fernandez Santiago, R and Bandres-Ciga, S and Gómez-Garre, P and Periñán, MT and Mir, P and Pérez-Tur, J and Cardona, F and Menendez-Gonzalez, M and Riancho, J and Borrego-Hernández, D and Galán-Dávila, L and Infante Ceberio, J and Pastor, P and Paradas, C and Dols-Icardo, O and Traynor, BJ and Feldman, EL and Goutman, SA and , }, title = {Cumulative Genetic Score and C9orf72 Repeat Status Independently Contribute to Amyotrophic Lateral Sclerosis Risk in 2 Case-Control Studies.}, journal = {Neurology. Genetics}, volume = {9}, number = {4}, pages = {e200079}, pmid = {37293291}, issn = {2376-7839}, support = {P30 ES017885/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000289/TS/ATSDR CDC HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Most patients with amyotrophic lateral sclerosis (ALS) lack a monogenic mutation. This study evaluates ALS cumulative genetic risk in an independent Michigan and Spanish replication cohort using polygenic scores.

METHODS: Participant samples from University of Michigan were genotyped and assayed for the chromosome 9 open reading frame 72 hexanucleotide expansion. Final cohort size was 219 ALS and 223 healthy controls after genotyping and participant filtering. Polygenic scores excluding the C9 region were generated using an independent ALS genome-wide association study (20,806 cases, 59,804 controls). Adjusted logistic regression and receiver operating characteristic curves evaluated the association and classification between polygenic scores and ALS status, respectively. Population attributable fractions and pathway analyses were conducted. An independent Spanish study sample (548 cases, 2,756 controls) was used for replication.

RESULTS: Polygenic scores constructed from 275 single-nucleotide variation (SNV) had the best model fit in the Michigan cohort. An SD increase in ALS polygenic score associated with 1.28 (95% CI 1.04-1.57) times higher odds of ALS with area under the curve of 0.663 vs a model without the ALS polygenic score (p value = 1 × 10[-6]). The population attributable fraction of the highest 20th percentile of ALS polygenic scores, relative to the lowest 80th percentile, was 4.1% of ALS cases. Genes annotated to this polygenic score enriched for important ALS pathomechanisms. Meta-analysis with the Spanish study, using a harmonized 132 single nucleotide variation polygenic score, yielded similar logistic regression findings (odds ratio: 1.13, 95% CI 1.04-1.23).

DISCUSSION: ALS polygenic scores can account for cumulative genetic risk in populations and reflect disease-relevant pathways. If further validated, this polygenic score will inform future ALS risk models.}, } @article {pmid37292457, year = {2023}, author = {Davies, JC and Dharmadasa, T and Thompson, AG and Edmond, EC and Yoganathan, K and Gao, J and Talbot, K and Turner, MR}, title = {Limited value of serum neurofilament light chain in diagnosing amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {5}, number = {3}, pages = {fcad163}, pmid = {37292457}, issn = {2632-1297}, support = {MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; TURNER/OCT18/989-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {A biomarker specific for the diagnosis of amyotrophic lateral sclerosis must be sensitive across a spectrum of clinical heterogeneity. Neurofilament light chain levels in amyotrophic lateral sclerosis correlate with the rate of disability progression. Previous attempts to establish a diagnostic role for neurofilament light chain have been limited to comparison with healthy individuals or controls with alternative diagnoses unlikely to be confused with amyotrophic lateral sclerosis in real-world clinical practice. In a tertiary amyotrophic lateral sclerosis referral clinic, at first visit, serum was taken for neurofilament light chain measurement after prospectively recording the clinical diagnosis as 'amyotrophic lateral sclerosis', 'primary lateral sclerosis', 'alternative' or 'currently uncertain'. Of 133 referrals, 93 patients were diagnosed with amyotrophic lateral sclerosis (median neurofilament light chain 218.1 pg/ml, interquartile range 130.7-311.9), three primary lateral sclerosis (65.6, 51.5-106.9) and 19 alternative diagnoses (45.2, 13.5-71.9) at first visit. Of 18 initially uncertain diagnoses, eight were subsequently diagnosed with amyotrophic lateral sclerosis (98.5, 45.3-300.1). Neurofilament light chain ≥110.9 pg/ml had a positive predictive value of 0.92 for amyotrophic lateral sclerosis; <110.9 pg/ml had a negative predictive value of 0.48. In a specialized clinic, neurofilament light chain is largely confirmatory to clinical judgement in diagnosing amyotrophic lateral sclerosis and has limited ability to exclude alternative diagnoses. The current, important, value of neurofilament light chain is its potential to stratify patients with amyotrophic lateral sclerosis by disease activity and as a biomarker in therapeutic trials.}, } @article {pmid37292026, year = {2023}, author = {Poletti, B and Aiello, EN and La Tona, A and Solca, F and Torre, S and Colombo, E and Maranzano, A and Morelli, C and Doretti, A and Verde, F and Monti, A and Brugnera, A and Compare, A and Ferrucci, R and Barbieri, S and Mameli, F and Priori, A and Pravettoni, G and Silani, V and Ticozzi, N}, title = {Single task-level, 2SD-based cutoffs for the Italian version of the Edinburgh Cognitive and Behavioral ALS screen (ECAS).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2023.2220746}, pmid = {37292026}, issn = {2167-9223}, abstract = {The present study aimed at deriving, by means of a traditional "2 standard deviation-based" (2SD) approach, single task-level cutoffs for the Italian version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Cutoffs were derived - as M-2*SD - from the sample of healthy participants (HPs) included within 2016 Poletti et al.'s normative study - N = 248; 104 males; age: 57.8 ± 10.6; education: 14.1 ± 4.6 - separately for the four, original demographic classes: 1) education <14 years and age ≤60 years; 2) education <14 years and age >60 years; 3) education ≥14 years and age ≤60 years; 4) education ≥14 years and age >60 years. The prevalence of deficits on each task was then estimated within a cohort of N = 377 amyotrophic lateral sclerosis (ALS) patients without dementia. The distribution of abnormal performance prevalences was overall consistent with the cognitive phenotype of ALS. In conclusion, the single task-level cutoffs herewith provided for the Italian version of the ECAS, which complement those already available within Poletti et al.'s normative framework, will help better profile Italian ALS patients' cognitive phenotype within both clinical and research settings.}, } @article {pmid37291830, year = {2023}, author = {Ibrahim, NM and Jagota, P and Pal, PK and Bhidayasiri, R and Lim, SY and Ugawa, Y and Aldaajani, Z and Jeon, B and Fujioka, S and Lee, JY and Kukkle, PL and Shang, H and Phokaewvarangkul, O and Diesta, C and Shambetova, C and Lin, CH}, title = {Historical and More Common Nongenetic Movement Disorders From Asia.}, journal = {Journal of movement disorders}, volume = {16}, number = {3}, pages = {248-260}, pmid = {37291830}, issn = {2005-940X}, abstract = {Nongenetic movement disorders are common throughout the world. The movement disorders encountered may vary depending on the prevalence of certain disorders across various geographical regions. In this paper, we review historical and more common nongenetic movement disorders in Asia. The underlying causes of these movement disorders are diverse and include, among others, nutritional deficiencies, toxic and metabolic causes, and cultural Latah syndrome, contributed by geographical, economic, and cultural differences across Asia. The industrial revolution in Japan and Korea has led to diseases related to environmental toxin poisoning, such as Minamata disease and β-fluoroethyl acetate-associated cerebellar degeneration, respectively, while religious dietary restriction in the Indian subcontinent has led to infantile tremor syndrome related to vitamin B12 deficiency. In this review, we identify the salient features and key contributing factors in the development of these disorders.}, } @article {pmid37291782, year = {2024}, author = {Dai, S and Qiu, L and Veeraraghavan, VP and Sheu, CL and Mony, U}, title = {Advances in iPSC Technology in Neural Disease Modeling, Drug Screening, and Therapy.}, journal = {Current stem cell research & therapy}, volume = {19}, number = {6}, pages = {809-819}, doi = {10.2174/1574888X18666230608105703}, pmid = {37291782}, issn = {2212-3946}, mesh = {Humans ; *Induced Pluripotent Stem Cells/cytology ; *Drug Evaluation, Preclinical/methods ; Animals ; *Neurodegenerative Diseases/therapy ; Cell- and Tissue-Based Therapy/methods ; Cell Differentiation ; Disease Models, Animal ; }, abstract = {Neurodegenerative disorders (NDs) including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease are all incurable and can only be managed with drugs for the associated symptoms. Animal models of human illnesses help to advance our understanding of the pathogenic processes of diseases. Understanding the pathogenesis as well as drug screening using appropriate disease models of neurodegenerative diseases (NDs) are vital for identifying novel therapies. Human-derived induced pluripotent stem cell (iPSC) models can be an efficient model to create disease in a dish and thereby can proceed with drug screening and identifying appropriate drugs. This technology has many benefits, including efficient reprogramming and regeneration potential, multidirectional differentiation, and the lack of ethical concerns, which open up new avenues for studying neurological illnesses in greater depth. The review mainly focuses on the use of iPSC technology in neuronal disease modeling, drug screening, and cell therapy.}, } @article {pmid37290723, year = {2023}, author = {Lu, Y and Wang, JT and Li, N and Zhu, X and Li, Y and Bansal, S and Wang, Y and Al-Jamal, KT}, title = {Intranasal administration of edaravone nanoparticles improves its stability and brain bioavailability.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {359}, number = {}, pages = {257-267}, doi = {10.1016/j.jconrel.2023.06.001}, pmid = {37290723}, issn = {1873-4995}, mesh = {Animals ; Mice ; Administration, Intranasal ; *Amyotrophic Lateral Sclerosis/drug therapy ; Biological Availability ; Brain/metabolism ; Chromatography, Liquid ; Drug Carriers/chemistry ; Drug Delivery Systems ; *Edaravone/administration & dosage/pharmacokinetics ; Hydrogen Peroxide/metabolism ; *Nanoparticles/administration & dosage ; Particle Size ; Polylactic Acid-Polyglycolic Acid Copolymer/metabolism ; Tandem Mass Spectrometry ; Tissue Distribution ; Cell Line ; }, abstract = {The clinical application of EDV, a potent antioxidant drug approved for amyotrophic lateral sclerosis (ALS), is limited by its short biological half-life and poor water solubility necessitating hospitalization during intravenous infusion. Nanotechnology-based drug delivery constitutes a powerful tool through inferring drug stability and targeted drug delivery improving drug bioavailability at the diseased site. Nose-to-brain drug delivery offers direct access to the brain bypassing the blood brain barrier and reducing systemic biodistribution. In this study, we designed EDV-loaded poly(lactic-co-glycolic acid) (PLGA)-based polymeric nanoparticles (NP-EDV) for intranasal administration. NPs were formulated by the nanoprecipitation method. Morphology, EDV loading, physicochemical properties, shelf-life stability, in vitro release and pharmacokinetic assessment in mice were conducted. EDV was efficiently loaded into ∼90 nm NPs, stable up to 30 days of storage, at ∼3% drug loading. NP-EDV reduced H2O2-induced oxidative stress toxicity in mouse microglial cell line BV-2. Optical imaging and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) showed that intranasal delivery of NP-EDV offered higher and more sustained brain uptake of EDV compared to intravenous administration. This study is the first of its kind to develop an ALS drug in a nanoparticulate formulation for nose-to-brain delivery raising hope to ALS patients where currently treatment options are limited to two clinically approved drugs only.}, } @article {pmid37290686, year = {2023}, author = {Liu, Y and Ding, M and Pan, S and Zhou, R and Yao, J and Fu, R and Yu, H and Lu, Z}, title = {MicroRNA-23a-3p Is Upregulated in Plasma Exosomes of Bulbar-onset ALS Patients and Targets ERBB4.}, journal = {Neuroscience}, volume = {524}, number = {}, pages = {65-78}, doi = {10.1016/j.neuroscience.2023.05.030}, pmid = {37290686}, issn = {1873-7544}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Exosomes/metabolism ; *Neurodegenerative Diseases/metabolism ; *MicroRNAs/metabolism ; Apoptosis ; Receptor, ErbB-4/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease related to the progressive death of motor neurons. Understanding the pathogenesis of ALS continues to provide considerable challenges. Bulbar-onset ALS involves faster functional loss and shorter survival time than spinal cord-onset ALS. However, debate is ongoing regarding typical plasma miRNA changes in ALS patients with bulbar onset. Exosomal miRNAs have not yet been described as a tool for bulbar-onset ALS diagnosis or prognosis prediction. In this study, candidate exosomal miRNAs were identified by small RNA sequencing using samples from patients with bulbar-onset ALS and healthy controls. Potential pathogenic mechanisms were identified through enrichment analysis of target genes for differential miRNAs. Expression of miR-16-5p, miR-23a-3p, miR-22-3p, and miR-93-5p was significantly up-regulated in plasma exosomes from bulbar-onset ALS patients compared with healthy control subjects. Among them, miR-16-5p and miR-23a-3p were significantly lower in spinal-onset ALS patients than those with bulbar-onset. Furthermore, up-regulation of miR-23a-3p in motor neuron-like NSC-34 cells promoted apoptosis and inhibited cell viability. This miRNA was found to directly target ERBB4 and regulate the AKT/GSK3β pathway. Collectively, the above miRNAs and their targets are related to the development of bulbar-onset ALS. Our research indicates that miR-23a-3p might have an effect on motor neuron loss observed in bulbar-onset ALS and may be a novel target for the therapy of ALS in the future.}, } @article {pmid37290609, year = {2023}, author = {Bai, J and Zhang, X and Wang, H and Yu, W and He, Z and Wang, J and Feng, F and Li, M and Wang, H and Yang, F and Huang, X}, title = {Gender-specific association of uric acid and survival in sporadic amyotrophic lateral sclerosis patients.}, journal = {Brain research}, volume = {1815}, number = {}, pages = {148445}, doi = {10.1016/j.brainres.2023.148445}, pmid = {37290609}, issn = {1872-6240}, mesh = {Humans ; Male ; Female ; *Uric Acid ; *Amyotrophic Lateral Sclerosis ; Creatinine ; }, abstract = {OBJECTIVE: To investigate the relationship between serum uric acid (UA) and survival in sporadic amyotrophic lateral sclerosis (sALS) patients.

METHOD: A total of 801 sporadic amyotrophic lateral sclerosis (sALS) patients fulfilled the revised El Escorial criteria were enrolled and followed up in the study. Baseline clinical data and laboratory variables including gender, age, age of onset, site of onset, disease duration, body mass index (BMI), uric acid (UA), creatinine (Cr), and creatine kinase (CK) were collected during enrollment. Multivariate Cox regression models were used to evaluate the survival-related factors after adjustment for confounders.

RESULTS: The serum UA level was significantly lower in female patients than that in male patients (243.5 vs 314.9 μmol/L, p < 0.001). Gender, BMI, Cr, CK were significantly associated with the level of uric acid according to the linear regression analysis. In the multivariate Cox regression analysis, higher serum UA level (>268.0 μmol/L) was an independent protective factor for prolonged survival among female patients (HR = 0.69, P = 0.042) after adjustment for confounders.

CONCLUSION: The present study provided further support that higher UA was a protective factor for survival in sALS patients, especially in female.}, } @article {pmid37289771, year = {2023}, author = {Ahn, JY and Ryoo, HW and Jung, H and Ro, YS and Park, JH}, title = {Impact of emergency medical service with advanced life support training for adults with out-of-hospital cardiac arrest in the Republic of Korea: A retrospective multicenter study.}, journal = {PloS one}, volume = {18}, number = {6}, pages = {e0286047}, pmid = {37289771}, issn = {1932-6203}, mesh = {Adult ; Humans ; *Cardiopulmonary Resuscitation/methods ; *Emergency Medical Services/methods ; *Out-of-Hospital Cardiac Arrest/therapy ; Pilot Projects ; Registries ; Republic of Korea ; Retrospective Studies ; }, abstract = {Prehospital advanced life support (ALS) has been offered in many countries for patients experiencing out-of-hospital cardiac arrest (OHCA); however, its effectiveness remains unclear. This study aimed to determine the impact of emergency medical service (EMS) with ALS training as a nationwide pilot project for adults with OHCA in the Republic of Korea. This retrospective multicenter observational study was conducted between July 2019 and December 2020 using the Korean Cardiac Arrest Research Consortium registry. The patients were categorized into an intervention group that received EMS with ALS training and a control group that did not receive EMS with ALS training. Conditional logistic regression analysis was performed using matched data to compare clinical outcomes between the two groups. Compared with the control group, the intervention group had a lower rate of supraglottic airway usage (60.5% vs. 75.6%) and a higher rate of undergoing endotracheal intubation (21.7% vs. 6.1%, P < 0.001). In addition, the intervention group was administered more intravenous epinephrine (59.8% vs. 14.2%, P < 0.001) and used mechanical chest compression devices more frequently in prehospital settings than the control group (59.0% vs. 23.8%, P < 0.001). Based on the results of multivariable conditional logistic regression analysis, survival to hospital discharge (odds ratio: 0.48, 95% confidence interval: 0.27-0.87) of the intervention group was significantly lower than that of the control group; however, good neurological outcome was not significantly different between the two groups. In this study, survival to hospital discharge was worse in patients with OHCA who received EMS with ALS training than in those who did not.}, } @article {pmid37289322, year = {2023}, author = {Miscioscia, A and Puthenparampil, M and Blasi, L and Rinaldi, F and Perini, P and Sorarù, G and Gallo, P}, title = {Neurodegeneration in the retina of motoneuron diseases: a longitudinal study in amyotrophic lateral sclerosis and Kennedy's disease.}, journal = {Journal of neurology}, volume = {270}, number = {9}, pages = {4478-4486}, pmid = {37289322}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging/pathology ; Longitudinal Studies ; *Bulbo-Spinal Atrophy, X-Linked ; Retina/diagnostic imaging/pathology ; *Motor Neuron Disease/pathology ; *Retinal Degeneration/diagnostic imaging/etiology/pathology ; Tomography, Optical Coherence/methods ; Atrophy/pathology ; Motor Neurons/pathology ; }, abstract = {BACKGROUND: To what extent retinal atrophy in neurodegenerative diseases reflects the severity and/or the chronicity of brain pathology or is a local independent phenomenon remains to be clarified. Moreover, whether retinal atrophy has a clinical (diagnostic and prognostic) value in these diseases remains unclear.

OBJECTIVE: To add light on the pathological significance and clinical value of retinal atrophy in patients with amyotrophic lateral sclerosis (ALS) and Kennedy's disease (KD).

METHODS: Thirty-five ALS, thirty-seven KD, and forty-nine age-matched healthy controls (HC) were included in a one-year longitudinal study. Spectrum-domain optical coherence tomography (OCT) was performed at study entry (T0) and after 12 months (T1). Disease duration and functional rating scale (FRS) for ALS and KD patients were correlated to retinal thicknesses.

RESULTS: Compared to HC, peripapillary retinal nerve fiber layer (pRNFL) thickness was significantly thinner in both ALS (p = 0.034) and KD (p = 0.003). pRNFL was thinner in KD compared to ALS, but the difference was not significant. In KD, pRNFL atrophy significantly correlated with both disease severity (r = 0.296, p = 0.035) and disease duration (r = - 0.308, p = 0.013) while no significant correlation was found in ALS (disease severity: r = 0.147, p = 0.238; disease duration: r = - 0.093, p = 0.459). During the follow-up, pRNFL thickness remained stable in KD while significantly decreased in ALS (p = 0.043).

CONCLUSIONS: Our study provides evidence of retinal atrophy in both ALS and KD and suggests that retinal thinning is a primary local phenomenon in motoneuron diseases. The clinical value of pRNFL atrophy in KD is worthy of further investigation.}, } @article {pmid37288776, year = {2023}, author = {Hatch, J and Barkhaus, P and Barnes, B and Beauchamp, M and Benatar, M and Bertorini, T and Bowser, R and Bromberg, M and Brown, A and Mascias Cadavid, J and Carter, GT and Cole, N and Crayle, J and Dimachkie, M and Ennist, D and Feldman, E and Fullam, T and Heiman-Patterson, T and Jhooty, S and Levine, T and Li, X and Lund, I and Mallon, E and Maragakis, N and McDermott, C and Pattee, G and Pierce, K and Ratner, D and Staats, K and Wicks, P and Wiedau, M and Bedlack, R}, title = {ALSUntangled #70: caffeine.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/21678421.2023.2220742}, pmid = {37288776}, issn = {2167-9223}, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here, we review caffeine which has plausible mechanisms for slowing ALS progression. However, pre-clinical studies are contradictory, and a large case series showed no relationship between caffeine intake and ALS progression rate. While low doses of caffeine are safe and inexpensive, higher doses can cause serious side effects. At this time, we cannot endorse caffeine as a treatment to slow ALS progression.}, } @article {pmid37288312, year = {2023}, author = {Costello, E and Ryan, M and Donohoe, B and Kavanagh, C and Pinto-Grau, M and Doherty, M and McLaughlin, RL and McHutchison, C and Abrahams, S and Heverin, M and Hardiman, O and Pender, N}, title = {Cognitive and neuropsychiatric endophenotypes in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {5}, number = {3}, pages = {fcad166}, pmid = {37288312}, issn = {2632-1297}, abstract = {First- and second-degree relatives of people with amyotrophic lateral sclerosis report higher rates of neuropsychiatric disorders, indicating that risk genes may be pleiotropic, causing multiple phenotypes within kindreds. Such phenotypes may constitute a disease endophenotype that associates with disease liability. We have directly investigated cognitive functioning and neuropsychiatric traits among relatives of people with amyotrophic lateral sclerosis to identify potential endophenotypes of the disease. In a family-based, cross-sectional study design, first- and second-degree relatives of people with amyotrophic lateral sclerosis (n = 149) were compared to controls (n = 60) using an in-depth neuropsychological and neuropsychiatric assessment. Subgroup analyses examined the effect of family history and C9orf72 repeat expansion status (n = 16 positive carriers). Relatives of people with amyotrophic lateral sclerosis had lower scores on executive functioning, language and memory tasks compared to controls, with large effect sizes observed on object naming (d = 0.91, P = 0.00001) and phonemic verbal fluency (d = 0.81, P = 0.0003). Relatives also had higher autism quotient attention to detail traits (d = -0.52, P = 0.005), lower conscientiousness (d = 0.57, P = 0.003) and lower openness to experience personality traits (d = 0.54, P = 0.01) than controls. These effects were typically larger in relatives of people with familial, rather than sporadic, amyotrophic lateral sclerosis and were present in both gene carrier and non-carrier relatives of probands with a C9orf72 repeat expansion. Poorer phonemic fluency and object naming, along with autism and personality traits, are more frequent in relatives of people with amyotrophic lateral sclerosis. Among kindreds carrying the C9orf72 repeat expansion, these traits were identified in relatives regardless of their carrier status, suggesting the presence of a disease-associated endophenotype that is not exclusively mediated by the C9orf72 expansion.}, } @article {pmid37288069, year = {2023}, author = {Corrigan, F and Wee, IC and Collins-Praino, LE}, title = {Chronic motor performance following different traumatic brain injury severity-A systematic review.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1180353}, pmid = {37288069}, issn = {1664-2295}, abstract = {INTRODUCTION: Traumatic brain injury (TBI) is now known to be a chronic disease, causing ongoing neurodegeneration and linked to increased risk of neurodegenerative motor diseases, such as Parkinson's disease and amyotrophic lateral sclerosis. While the presentation of motor deficits acutely following traumatic brain injury is well-documented, however, less is known about how these evolve in the long-term post-injury, or how the initial severity of injury affects these outcomes. The purpose of this review, therefore, was to examine objective assessment of chronic motor impairment across the spectrum of TBI in both preclinical and clinical models.

METHODS: PubMed, Embase, Scopus, and PsycINFO databases were searched with a search strategy containing key search terms for TBI and motor function. Original research articles reporting chronic motor outcomes with a clearly defined TBI severity (mild, repeated mild, moderate, moderate-severe, and severe) in an adult population were included.

RESULTS: A total of 97 studies met the inclusion criteria, incorporating 62 preclinical and 35 clinical studies. Motor domains examined included neuroscore, gait, fine-motor, balance, and locomotion for preclinical studies and neuroscore, fine-motor, posture, and gait for clinical studies. There was little consensus among the articles presented, with extensive differences both in assessment methodology of the tests and parameters reported. In general, an effect of severity was seen, with more severe injury leading to persistent motor deficits, although subtle fine motor deficits were also seen clinically following repeated injury. Only six clinical studies investigated motor outcomes beyond 10 years post-injury and two preclinical studies to 18-24 months post-injury, and, as such, the interaction between a previous TBI and aging on motor performance is yet to be comprehensively examined.

CONCLUSION: Further research is required to establish standardized motor assessment procedures to fully characterize chronic motor impairment across the spectrum of TBI with comprehensive outcomes and consistent protocols. Longitudinal studies investigating the same cohort over time are also a key for understanding the interaction between TBI and aging. This is particularly critical, given the risk of neurodegenerative motor disease development following TBI.}, } @article {pmid37287555, year = {2023}, author = {Işık, K and Morkavuk, G and Odabaşı, Z}, title = {Dropped Head Syndrome As a Presenting Sign of Different Diseases: Report of Three Cases.}, journal = {Noro psikiyatri arsivi}, volume = {60}, number = {2}, pages = {185-187}, pmid = {37287555}, issn = {1300-0667}, abstract = {Dropped head is an abnormal forward flexion of the cervical spine. Patients can straighten their heads with support. This condition, which is seen as neck extensor muscle weakness, is defined as 'head ptosis' or 'dropped head syndrome' and is seen in various central and neuromuscular diseases. Myasthenia gravis, inflammatory myopathy, amyotrophic lateral sclerosis, facio-scapulo-humeral dystrophy, nemaline myopathy, carnitine deficiency and spinal muscular atrophy are some of the neuromuscular diseases seen in dropped head cases. We aimed to present 3 different cases with a diagnosis of myasthenia gravis, inflammatory myopathy, and amyotrophic lateral sclerosis presenting with dropped head.}, } @article {pmid37285737, year = {2023}, author = {Taheri, M and Askari, A and Hussen, BM and Eghbali, A and Ghafouri-Fard, S}, title = {A review on the role of MYC-induced long non-coding RNA in human disorders.}, journal = {Pathology, research and practice}, volume = {248}, number = {}, pages = {154568}, doi = {10.1016/j.prp.2023.154568}, pmid = {37285737}, issn = {1618-0631}, mesh = {Humans ; *Carcinoma, Hepatocellular/pathology ; Gene Expression Regulation, Neoplastic ; *Liver Neoplasms/pathology ; *MicroRNAs/genetics/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; }, abstract = {MINCR (MYC-Induced Long Non-Coding RNA) is classified as an lncRNA. It has a significant correlation with MYC gene. MINCR has important roles in the carcinogenesis. It has been approved that this lncRNA can act as molecular sponge for miR-28-5p, miR-708-5p, miR-876-5p and miR-146a-5p. Dysregulated levels of MINCR has been observed in different types of cancer, especially hepatocellular carcinoma. In addition to malignant conditions, schizophrenia and neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis are associated with dysregulation of expression patterns of MINCR. This review outlines MINCR molecular mechanisms of action in different disorders.}, } @article {pmid37284659, year = {2023}, author = {Zhu, Q and Zhou, J and Zhang, Y and Huang, H and Han, J and Cao, B and Xu, D and Zhao, Y and Chen, G}, title = {Risk factors associated with amyotrophic lateral sclerosis based on the observational study: a systematic review and meta-analysis.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1196722}, pmid = {37284659}, issn = {1662-4548}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting the upper and lower motor neurons. Though the pathogenesis of ALS is still unclear, exploring the associations between risk factors and ALS can provide reliable evidence to find the pathogenesis. This meta-analysis aims to synthesize all related risk factors of ALS to understand this disease comprehensively.

METHODS: We searched the following databases: PubMed, EMBASE, Cochrane library, Web of Science, and Scopus. Moreover, observational studies, including cohort studies, and case-control studies, were included in this meta-analysis.

RESULTS: A total of 36 eligible observational studies were included, and 10 of them were cohort studies and the rest were case-control studies. We found six factors exacerbated the progression of disease: head trauma (OR = 1.26, 95% CI = 1.13, 1.40), physical activity (OR = 1.06, 95% CI = 1.04, 1.09), electric shock (OR = 2.72, 95% CI = 1.62, 4.56), military service (OR = 1.34, 95% CI = 1.11, 1.61), pesticides (OR = 1.96, 95% CI = 1.7, 2.26), and lead exposure (OR = 2.31, 95% CI = 1.44, 3.71). Of note, type 2 diabetes mellitus was a protective factor for ALS. However, cerebrovascular disease (OR = 0.99, 95% CI = 0.75, 1.29), agriculture (OR = 1.22, 95% CI = 0.74, 1.99), industry (OR = 1.24, 95% CI = 0.81, 1.91), service (OR = 0.47, 95% CI = 0.19, 1.17), smoking (OR = 1.25, 95% CI = 0.5, 3.09), chemicals (OR = 2.45, 95% CI = 0.89, 6.77), and heavy metal (OR = 1.5, 95% CI = 0.47, 4.84) were not risk factors for ALS based on meta-analyses.

CONCLUSIONS: Head trauma, physical activity, electric shock, military service, pesticides, and lead were risk factors for ALS onset and progression. But DM was a protective factor. This finding provides a better understanding of ALS risk factors with strong evidence for clinicians to rationalize clinical intervention strategies.

INPLSY REGISTRATION NUMBER: https://inplasy.com/inplasy-2022-9-0118/, INPLASY202290118.}, } @article {pmid37284147, year = {2022}, author = {}, title = {66th Annual Meeting of the German Society of Neuropathology and Neuroanatomy (DGNN) - Meeting Abstracts: Berlin, November 1-5, 2022.}, journal = {Free neuropathology}, volume = {3}, number = {}, pages = {20}, doi = {10.17879/freeneuropathology-2022-4366}, pmid = {37284147}, issn = {2699-4445}, abstract = {Liebe Kolleginnen und Kollegen, zur 66. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie im Rahmen der Neurowoche vom 1. bis zum 5. November 2022 begrüße ich Sie herzlich in Berlin. Die letzten Jahre haben eine enorme Erweiterung der analytischen Methodik mit Schwerpunkt auf molekularen Untersuchungen gebracht. Ein großer Teil dieser Untersuchungen wurde in unseren Einrichtungen entwickelt und wird dort erbracht. In der Tat hat sich die Neuropathologie zu einem Motor der neuroonkologischen und neurowissenschaftlichen Forschung entwickelt und deutschsprachige neuropathologische Institutionen haben wesentlich dazu beigetragen. Ganz neue Therapien bauen auf diese Erkenntnisse auf. Dadurch sind wir für die Versorgung unserer Patienten wichtiger denn jeher. Deswegen sehe ich einen großen und zunehmenden Bedarf dem wir Neuropathologen nachkommen müssen. Alle Schwerpunkte unseres Faches sind hiervon betroffen, die Gehirntumordiagnostik, die neurodegenerativen Erkrankungen, Entzündung und Erkrankungen der Muskeln und der Nerven. Wir arbeiten eng mit unseren Kollegen aus der Neuroonkologie, Neuropädiatrie, Neurologie Neurochirurgie und Neuroradiologie zusammen. Der interdisziplinäre Austausch hat einen hohen Stellenwert und wir freuen uns deshalb besonders, dass unsere Jahrestagung in diesem Jahr wieder im Rahmen der Neurowoche stattfindet, was die Kommunikation und den Wissenstransfer über die Fächergrenzen beflügelt. Dieses Jahr wollen wir besonders die jungen Neuropathologen und Neuropathologinnen in den Vordergrund stellen. Sie sollen unser Fach als lebendig und besonders zukunftsfähig erleben. Von ihnen erwarten wir die Dynamik, den Einsatz und den Ideenreichtum, der die Neuropathologie in den nächsten Jahren noch weiter zu einer zentralen Querschnittsplattform für die Neurofächer machen wird. Wir haben einen Kongressstrang mit wissenschaftlichen Sitzungen am Donnerstag, Freitag und Samstag ausgerichtet. Sie dürfen Vorträge mit jungen neuropathologischen Expertinnen und Experten sowie von jungen Nachwuchswissenschaftlerinnen und Nachwuchswissenschaftlern erwarten. Ich freue mich auf lebhafte Diskussionen und spannende interdisziplinäre Debatten! Ihr Prof. Dr. Andreas von Deimling Universitätsklinikum Heidelberg Neuropathologie.}, } @article {pmid37283936, year = {2023}, author = {Margeta, M}, title = {Neuromuscular disease: 2023 update.}, journal = {Free neuropathology}, volume = {4}, number = {}, pages = {2}, pmid = {37283936}, issn = {2699-4445}, abstract = {This review highlights ten important advances in the neuromuscular disease field that were reported in 2022. As with prior updates in this article series, the overarching topics include (i) advances in understanding of fundamental neuromuscular biology; (ii) new / emerging diseases; (iii) advances in understanding of disease etiology and pathogenesis; (iv) diagnostic advances; and (v) therapeutic advances. Within this general framework, the individual disease entities that are discussed in more detail include neuromuscular complications of COVID-19 (another look at the topic first covered in the 2021 and 2022 reviews), DNAJB4-associated myopathy, NMNAT2-deficient hereditary axonal neuropathy, Guillain-Barré syndrome, sporadic inclusion body myositis, and amyotrophic lateral sclerosis. In addition, the review highlights a few other advances (including new insights into mechanisms of fiber maturation during muscle regeneration and fiber rebuilding following reinnervation, improved genetic testing methods for facioscapulohumeral and myotonic muscular dystrophies, and the use of SARM1 inhibitors to block Wallerian degeneration) that will be of significant interest for clinicians and researchers who specialize in neuromuscular disease.}, } @article {pmid37282469, year = {2023}, author = {Dash, BP and Hermann, A}, title = {Combination of novel RNA sequencing and sophisticated network modeling to reveal a common denominator in amyotrophic lateral sclerosis?.}, journal = {Neural regeneration research}, volume = {18}, number = {11}, pages = {2403-2405}, pmid = {37282469}, issn = {1673-5374}, } @article {pmid37280513, year = {2023}, author = {Vidovic, M and Freigang, M and Aust, E and Linse, K and Petzold, D and Günther, R}, title = {Cognitive performance of adult patients with SMA before and after treatment initiation with nusinersen.}, journal = {BMC neurology}, volume = {23}, number = {1}, pages = {216}, pmid = {37280513}, issn = {1471-2377}, mesh = {Humans ; Adult ; Longitudinal Studies ; *Muscular Atrophy, Spinal/drug therapy ; *Spinal Muscular Atrophies of Childhood ; Cognition ; }, abstract = {BACKGROUND: Spinal muscular atrophy (SMA) is a genetic neuromuscular disease caused by mutations of the SMN1 gene. Deficient SMN protein causes irreversible degeneration of alpha motor neurons characterized by progressive muscle weakness and atrophy. Considering that SMA is a multi-systemic disorder and SMN protein was found to be expressed in cortical structures, the cognitive profile of adult patients with SMA has recently been of particular interest. With nusinersen, a novel, disease-modifying drug has been established, but its effects on neuropsychological functions have not been validated yet. Aim of this study was to investigate the cognitive profile of adult patients with SMA during treatment initiation with nusinersen and to reveal improvement or deterioration in cognitive performance.

METHODS: This monocentric longitudinal study included 23 patients with SMA type 2 and 3. All patients were assessed with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) before and after 14 months of treatment initiation with nusinersen. Additionally, motor function was evaluated by Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM) and Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R).

RESULTS: Of the treatment-naive patients, only three were below the age- and education-matched cut-off for cognitive impairment in the ECAS total score. Significant differences between SMA type 2 and 3 were only detected in the domain of Language. After 14 months of treatment, patients showed significant improvement of absolute scores in all three ALS-specific domains, in the non-ALS-specific domain of Memory, in both subscores and in the ECAS total score. No associations were detected between cognitive and functional outcome measures.

CONCLUSIONS: In some adult patients with SMA abnormal cognitive performance in ALS-specific functions of the ECAS was evident. However, the presented results suggest no clinically significant cognitive changes during the observed treatment period with nusinersen.}, } @article {pmid37280477, year = {2023}, author = {Nakamagoe, K and Matsumoto, S and Touno, N and Tateno, I and Koganezawa, T}, title = {Correction to: Saccadic oscillations as a biomarker of clinical symptoms in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {10}, pages = {3767}, doi = {10.1007/s10072-023-06889-4}, pmid = {37280477}, issn = {1590-3478}, } @article {pmid37280445, year = {2023}, author = {Ohgaki, Y and Ishibashi, Y and Hatao, F and Furuta, R and Saito, N and Inayoshi, R and Morita, Y}, title = {Laparoscopically assisted percutaneous endoscopic gastrostomy performed for remnant stomach in patient with amyotrophic lateral sclerosis: a case report.}, journal = {Surgical case reports}, volume = {9}, number = {1}, pages = {98}, pmid = {37280445}, issn = {2198-7793}, abstract = {BACKGROUND: Although percutaneous endoscopic gastrostomy (PEG) offers better access to the gastrointestinal system, in patients with previous abdominal surgery, PEG can be unsuccessful. Laparoscopically assisted percutaneous endoscopic gastrostomy (LAPEG) is indicated for such patients. However, patients with amyotrophic lateral sclerosis (ALS) may be more susceptible to anesthesia-related complications than other patients, requiring the indications for LAPEG, along with perioperative management, to be considered carefully.

CASE PRESENTATION: A 70-year-old, male patient with ALS was referred to our hospital for a gastrostomy for progressive dysphagia. He had undergone an open distal gastrectomy for gastric ulcer perforation in his twenties. Upper gastrointestinal endoscopy denied the transillumination sign and focal finger invagination. Because the risk of respiratory complications caused by general anesthesia was not considered serious, the decision was made to perform a LAPEG. Under careful, intraoperative airway management and neuromuscular monitoring, adhesiolysis was performed to increase mobility of the remnant stomach. A gastrostomy tube was inserted through the abdominal wall and into the remnant stomach under laparoscopic and endoscopic guidance. The patient was discharged in stable condition on postoperative day 3 without any respiratory complications.

CONCLUSIONS: LAPEG was able to be performed in a patient with ALS with a previous gastrectomy. A perioperative team comprised of neurologists, endoscopists, surgeons, anesthesiologists, and nurses who are fully conversant with ALS must be assembled to deal with potentially complex medical issues related to the procedure and anesthetic and perioperative management.}, } @article {pmid37280161, year = {2023}, author = {Nakamura, M and Nishii, M and Kume, K and Kawakami, H and Yakushiji, Y}, title = {An autopsy case of sporadic, adult-onset amyotrophic lateral sclerosis with heterozygous p.N1935S SETX gene variant.}, journal = {Journal of neuropathology and experimental neurology}, volume = {82}, number = {8}, pages = {734-738}, doi = {10.1093/jnen/nlad041}, pmid = {37280161}, issn = {1554-6578}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Autopsy ; DNA Helicases/genetics ; Heterozygote ; Multifunctional Enzymes/genetics ; Mutation/genetics ; RNA Helicases/genetics ; }, } @article {pmid37279716, year = {2023}, author = {Clair, S and Kirk, R and Coulter, ID and Saller, R}, title = {A Pragmatic Historical Assessment Tool: A New Systematic Framework for the Collation and Evaluation of Documented Empirical Effectiveness and Safety of Traditional Plant Medicines in the European Materia Medica.}, journal = {Complementary medicine research}, volume = {30}, number = {4}, pages = {340-353}, doi = {10.1159/000531021}, pmid = {37279716}, issn = {2504-2106}, mesh = {Humans ; *Materia Medica ; Medicine, Traditional/methods ; Phytotherapy ; Plant Extracts ; Plant Oils ; *Plants, Medicinal ; }, abstract = {INTRODUCTION: Traditional plant medicines (TPMs) are plant-derived therapeutic products prepared and applied according to longstanding medical customs. Around the world they are widely used in primary and preventative health care. The World Health Organization (WHO) calls in its Traditional Medicine Strategy 2014-2023 for Member States to provide a regulatory framework so that the formal contribution of traditional therapeutics can be advanced in national systems of health care. Evidence of effectiveness and safety is paramount for the regulatory integration of TPMs; however, a presumed lack of such "evidence" is one obstacle for full integration. The consequential health policy question is how to systematically evaluate therapeutic claims relating to herbal remedies when the extant evidence is predominantly based on historical and contemporary clinical usage, i.e., is empiricist in nature. This paper introduces a new method along with several illustrative examples.

METHOD: Our research design employs a longitudinal, comparative textual analysis of standard textbooks of the professional European medical literature from the early modern period (1588/1664) onwards to today. It then triangulated these intergenerationally documented clinical observations on two exemplars (Arnica and St. John's Wort) with corresponding listings in multiple qualitative and quantitative sources. A Pragmatic Historical Assessment (PHA) tool was developed and tested as a method to systematically collate the large amount of pharmacological data recorded in these judiciously selected sources. The evidential validity of longstanding professional clinical knowledge could thus be compared with therapeutic indications approved in official and authoritative sources (pharmacopoeias, monographs) and with those supported by contemporary scientific research (randomised-controlled trials [RCTs], experimental research).

RESULTS: There was high congruency between therapeutic indications that are based on repeated empirical observations from professional patient care (empirical evidence), those approved in pharmacopoeias and monographs, and modern scientific evidence based on RCTs. The extensive herbal triangulation confirmed parallel records of all main therapeutic indications of the exemplars across all qualitative and quantitative sources over the past 400 years.

CONCLUSIONS: Historical clinical medical textbooks and contemporary phytotherapeutic equivalents are the key repository of repeatedly evaluated therapeutic plant knowledge. The professional clinical literature proved to be a reliable and verifiable body of empirical evidence that harmonised with contemporary scientific assessments. The newly developed PHA tool provides a coding framework for the systematic collation and evaluation of empirical data on the effectiveness and safety of TPMs. It is suggested as a feasible and efficient tool to extend evidence typologies that substantiate therapeutic claims for TPMs as part of an evidence-based regulatory framework that formally integrates these medically and culturally important therapeutics.

UNLABELLED: EinleitungTraditionelle pflanzliche Arzneimittel sind aus Pflanzen gewonnene Heilmittel, die gemäß langjähriger medizinischer Praxis zubereitet und angewendet werden. Weltweit sind sie in der primären und präventiven Gesundheitsversorgung weit verbreitet. Die Weltgesundheitsorganisation (WHO) ruft in ihrer Traditional Medicine Strategy 2014–2023 die Mitgliedstaaten dazu auf, regulatorische Rahmenbedingungen zu schaffen, welche den formellen Beitrag traditioneller Therapeutika in den nationalen Gesundheitssystemen fördern. Der Nachweis von Wirksamkeit und Sicherheit ist von zentraler Bedeutung für die regulatorische Integration traditioneller pflanzlicher Arzneimittel, doch das angebliche Fehlen solcher “Nachweise“ ist eine der Hürden für die vollständige Integration. Daraus ergibt sich die gesundheitspolitische Frage, wie man therapeutische Anwendungsgebiete pflanzlicher Heilmittel systematisch evaluieren kann, wenn die vorliegende Evidenz überwiegend auf deren historischer und aktueller klinischen Verwendung beruht, also empirischer Natur ist. In dieser Arbeit wird eine neue Methode mitsamt veranschaulichenden Beispielen vorgestellt.MethodenUnser Forschungsansatz beruhte auf einer longitudinalen, vergleichenden Textanalyse von Standard-Lehrwerken der europäischen medizinischen Fachliteratur ausgehend von der frühen Neuzeit (1588/1664) bis heute. Die über Generationen dokumentierten klinischen Beobachtungen wurden anhand von zwei Beispielen (Arnika and Johanniskraut) mit den diesbezüglichen Angaben in unterschiedlichen qualitativen und quantitativen Quellen trianguliert. Ein Pragmatisch‐Historisches Auswertungstool (PHA) wurde als Methode entwickelt und getestet, um die großen Mengen der in diesen kritisch ausgewählten Quellen enthaltenen pharmakologischen Daten systematisch zu erfassen. Die Evidenzvalidität des langjährigen klinischen Fachwissens konnte so mit den therapeutischen Anwendungsgebieten verglichen werden, die in offiziellen und autoritativen Quellen (Pharmakopöen, Monografien) zugelassen sind, sowie mit denjenigen, die durch zeitgenössische wissenschaftliche Forschung gestützt werden (randomisierte kontrollierte Studien [RCTs], experimentelle Forschung).ErgebnisseEs bestand ein hohes Maß an Kongruenz zwischen den therapeutischen Anwendungsgebieten, welche auf wiederholte empirische Beobachtung aus der professionellen Patientenversorgung beruhen (empirische Evidenz), den zugelassenen Indikationen in Pharmakopöen und Monographien sowie der aktuellen wissenschaftlichen Evidenz basierend auf klinischen Studien. Die umfassende pflanzenbezogene Triangulation bestätigte parallele Aufzeichnungen aller wesentlichen Anwendungsgebiete der untersuchten Beispiele in allen qualitativen und quantitativen Quellen über die letzten 400 Jahre hinweg.SchlussfolgerungenHistorische Lehrbücher für klinische Medizin und zeitgenössische phytotherapeutische Äquivalente sind die wichtigsten Quellen von wiederholt evaluiertem therapeutischem Wissen zu Heilpflanzen. Die klinische Fachliteratur erwies sich als zuverlässiger und verifizierbarer Korpus empirischer Evidenz, der mit aktuellen wissenschaftlichen Untersuchungen übereinstimmte. Das neu entwickelte PHA-Verfahren bietet ein Kodierungs‐Instrument für das systematische Erfassen und Auswerten empirischer Daten zur Wirksamkeit und Sicherheit von traditionellen pflanzlichen Arzneimitteln. Das PHA‐Verfahren wird als praktikables und effizientes Instrument zur Erweiterung der Evidenz‐Typologien empfohlen, indem es therapeutische Indikationen für traditionelle pflanzliche Arzneimittel untermauern kann, so dass diese medizinisch und kulturell wichtigen Therapeutika in einen evidenz-basierten regulatorischen Rahmen integriert werden können.}, } @article {pmid37279497, year = {2023}, author = {van Selms, MKA and Henselijn, JCR and Schaminée, ACM and van der Meijden, C and van der Linden, MW}, title = {[Oral care in patients with ALS: an exploratory study].}, journal = {Nederlands tijdschrift voor tandheelkunde}, volume = {130}, number = {6}, pages = {287-294}, doi = {10.5177/ntvt.2023.06.23013}, pmid = {37279497}, issn = {0028-2200}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Toothbrushing ; Emotions ; Gagging ; }, abstract = {For this exploratory study, ALS patients and their partners/caregivers were interviewed to find out what problems they encounter when performing oral care. In addition, the tooth brushing procedure was recorded on video. Most mentioned by the six patients was that the performance of oral care is hampered by the loss of motor skills and by the gag reflex. They also mentioned various adjustments that would ease dental visits. Three of the four partners indicated that an instructional video would have additional value, and two partners said they sometimes felt insecure whether they were performing oral care properly. The five videos showed that there are major differences regarding tooth brushing duration, which surfaces are being brushed, and the brushing technique. This study shows that there are several ways in which oral care is performed in ALS patients. Furthermore, not all caregivers are aware of how oral care should be performed.}, } @article {pmid37279301, year = {2023}, author = {Fehlings, MG and Moghaddamjou, A and Harrop, JS and Stanford, R and Ball, J and Aarabi, B and Freeman, BJC and Arnold, PM and Guest, JD and Kurpad, SN and Schuster, JM and Nassr, A and Schmitt, KM and Wilson, JR and Brodke, DS and Ahmad, FU and Yee, A and Ray, WZ and Brooks, NP and Wilson, J and Chow, DS and Toups, EG and Kopjar, B}, title = {Safety and Efficacy of Riluzole in Acute Spinal Cord Injury Study (RISCIS): A Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Trial.}, journal = {Journal of neurotrauma}, volume = {40}, number = {17-18}, pages = {1878-1888}, pmid = {37279301}, issn = {1557-9042}, mesh = {Humans ; Riluzole/adverse effects ; *Neuroprotective Agents/adverse effects ; Pandemics ; Prospective Studies ; Treatment Outcome ; Double-Blind Method ; *COVID-19 ; *Spinal Cord Injuries/drug therapy/chemically induced ; }, abstract = {Riluzole is a sodium-glutamate antagonist that attenuates neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favorable results in promoting recovery in pre-clinical models of traumatic spinal cord injury (tSCI) and in early phase clinical trials. This study aimed to evaluate the efficacy and safety of riluzole in acute cervical tSCI. An international, multi-center, prospective, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial (NCT01597518) was undertaken. Patients with American Spinal Injury Association Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 h from injury were randomized to receive either riluzole, at an oral dose of 100 mg twice per day (BID) for the first 24 h followed by 50 mg BID for the following 13 days, or placebo. The primary efficacy end-point was change in Upper Extremity Motor (UEM) scores at 180 days. The primary efficacy analyses were conducted on an intention to treat (ITT) and completed cases (CC) basis. The study was powered at a planned enrolment of 351 patients. The trial began in October 2013 and was halted by the sponsor on May 2020 (and terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the pre-planned enrolment) were randomized with a follow-up rate of 82.7% at 180 days. At 180 days, in the CC population the riluzole-treated patients compared with placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor scores (CI: -6.79-12.52). No drug-related serious adverse events were associated with the use of riluzole. Additional pre-planned sensitivity analyses revealed that in the AIS C population, riluzole was associated with significant improvement in total motor scores (estimate: standard error [SE] 8.0; CI 1.5-14.4) and upper extremity motor scores (SE 13.8; CI 3.1-24.5) at 6 months. AIS B patients had higher reported independence, measured by the Spinal Cord Independence Measure score (45.3 vs. 27.3; d: 18.0 CI: -1.7-38.0) and change in mental health scores, measured by the Short Form 36 mental health domain (2.01 vs. -11.58; d: 13.2 CI: 1.2-24.8) at 180 days. AIS A patients who received riluzole had a higher average gain in neurological levels at 6 months compared with placebo (mean 0.50 levels gained vs. 0.12 in placebo; d: 0.38, CI: -0.2-0.9). The primary analysis did not achieve the predetermined end-point of efficacy for riluzole, likely related to insufficient power. However, on pre-planned secondary analyses, all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with riluzole showed significant gains in functional recovery. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.}, } @article {pmid37279290, year = {2023}, author = {Schwartzenburg, JB and Cruise, SC and Reed, RE and Hutchinson, CM and Mirzalieva, OS and Edwards, KN and Edwards, S and Gilpin, NW and Molina, PE and Desai, SD}, title = {Neuropathological Outcomes of Traumatic Brain Injury and Alcohol Use in Males and Females: Studies Using Pre-Clinical Rodent and Clinical Human Specimens.}, journal = {Journal of neurotrauma}, volume = {40}, number = {21-22}, pages = {2410-2426}, pmid = {37279290}, issn = {1557-9042}, support = {R01 AA025792/AA/NIAAA NIH HHS/United States ; T32 AA007577/AA/NIAAA NIH HHS/United States ; R21 NS060960/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Animals ; Rats ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Rodentia/metabolism ; *Brain Injuries, Traumatic/metabolism ; DNA-Binding Proteins/genetics ; *Chronic Traumatic Encephalopathy ; Alcohol Drinking ; }, abstract = {Traumatic brain injury (TBI) and alcohol misuse are inextricably linked and can increase the risk for development of neurodegenerative diseases, particularly in military veterans and contact sport athletes. Proteinopathy (defects in protein degradation) is considered an underlying factor in neurodegenerative diseases. Whether it contributes to TBI/alcohol-mediated neurodegeneration is unexplored, however. Our recent studies have identified ISGylation, a conjugated form of ISG15 (Interferon-Stimulated Gene 15) and inducer of proteinopathy, as a potential mechanistic link underlying TBI-mediated neurodegeneration and proteinopathy in veterans. In the current study, a rat model of combined TBI and alcohol use was utilized to investigate the same relationship. Here, we report sustained induction of Interferon β (IFNβ), changes in TAR DNA Binding 43 (TDP-43) ISGylation levels, TDP-43 proteinopathy (C-terminal fragmentation [CTF]), and neurodegeneration in the ventral horns of the lumbar spinal cords (LSCs) and/or motor cortices (MCs) of female rats post-TBI in a time-dependent manner. In males, these findings mostly remained non-significant, although moderate alcohol use appears to decrease neurodegeneration in males (but not females) post-TBI. We, however, do not claim that moderate alcohol consumption is beneficial for preventing TBI-mediated neurodegeneration. We have previously demonstrated that ISGylation is increased in the LSCs of veterans with TBI/ALS (amyotrophic lateral sclerosis). Here, we show increased ISGylation of TDP-43 in the LSCs of TBI/ALS-afflicted female veterans compared with male veterans. Knowing that ISGylation induces proteinopathy, we suggest targeting ISGylation may prevent proteinopathy-mediated neurodegeneration post-TBI, particularly in women; however, causal studies are required to confirm this claim.}, } @article {pmid37279166, year = {2023}, author = {Anand, T and Ishaque, A and Ta, D and Khan, MU and Bharti, K and Wu, A and Krebs, D and Beaulieu, C and Seres, P and Kalra, S}, title = {Characterization of white matter alterations using diffusion kurtosis imaging in patients with amyotrophic lateral sclerosis.}, journal = {Brain and behavior}, volume = {13}, number = {7}, pages = {e3102}, pmid = {37279166}, issn = {2162-3279}, support = {//CIHR/Canada ; }, mesh = {Humans ; Diffusion Tensor Imaging/methods ; *White Matter/diagnostic imaging/pathology ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Brain/diagnostic imaging/pathology ; *Brain Diseases/pathology ; }, abstract = {BACKGROUND: To evaluate the degeneration of the corticospinal tract (CST) and corpus callosum (CC) in patients with motor neuron disease and upper motor neuron (UMN) dysfunction using diffusion kurtosis imaging (DKI).

METHODS: Twenty-seven patients and 33 healthy controls underwent magnetic resonance imaging along with clinical and neuropsychological testing. Tractography of diffusion tensor images was performed to extract tracts of the bilateral CST and CC. Group mean differences both across the entire averaged tract and along each tract were assessed, including correlations between diffusion metrics and clinical measures. Tract-based spatial statistics (TBSS) was performed to evaluate the spatial distribution of whole-brain microstructural abnormalities in patients.

RESULTS: In comparison to controls, patients had significantly higher mean and radial diffusivity and lower fractional anisotropy (FA), kurtosis anisotropy, mean kurtosis (MK), and radial kurtosis (RK) in the CST and CC (p < .017). Along-the-tract analysis revealed changes concentrated in the posterior limb of the internal capsule, corona radiata, and primary motor cortex (false-discovery rate p < .05). FA of the left CST correlated with disease progression rate, whereas MK of the bilateral CST correlated with UMN burden (p < .01). TBSS results corroborated along-tract analysis findings and additionally revealed reduced RK and MK in the fornix, where diffusion tensor imaging (DTI) changes were absent.

CONCLUSION: DKI abnormalities in the CST and CC are present in patients with UMN dysfunction, potentially revealing complementary information to DTI regarding the pathology and microstructural alterations occurring in such patients. DKI shows promise as a potential in vivo biomarker for cerebral degeneration in amyotrophic lateral sclerosis.}, } @article {pmid37277972, year = {2023}, author = {Mori, K and Gotoh, S and Ikeda, M}, title = {Aspects of degradation and translation of the expanded C9orf72 hexanucleotide repeat RNA.}, journal = {Journal of neurochemistry}, volume = {166}, number = {2}, pages = {156-171}, doi = {10.1111/jnc.15847}, pmid = {37277972}, issn = {1471-4159}, mesh = {Humans ; C9orf72 Protein/genetics ; Proteins/genetics/metabolism ; RNA/genetics/metabolism ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; DNA Repeat Expansion/genetics ; }, abstract = {An hexanucleotide repeat expansion mutation in the non-coding region of C9orf72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis. This mutation is estimated to be the most frequent genetic cause of these currently incurable diseases. Since the mutation causes autosomal dominantly inherited diseases, disease cascade essentially starts from the expanded DNA repeats. However, molecular disease mechanism is inevitably complex because possible toxic entity for the disease is not just functional loss of translated C9ORF72 protein, if any, but potentially includes bidirectionally transcribed expanded repeat containing RNA and their unconventional repeat-associated non-AUG translation products in all possible reading frames. Although the field learned so much about the disease since the identification of the mutation in 2011, how the expanded repeat causes a particular type of fronto-temporal lobe dominant neurodegeneration and/or motor neuron degeneration is not yet clear. In this review, we summarize and discuss the current understandings of molecular mechanism of this repeat expansion mutation with focuses on the degradation and translation of the repeat containing RNA transcripts.}, } @article {pmid37276151, year = {2024}, author = {Peters, GA and Cash, RE and Goldberg, SA and Kolb, LM and Ordoobadi, AJ and Camargo, CA}, title = {Emergency Medical Services Management of Bronchospasm in the United States: A Cross-Sectional Analysis and Nationwide Quality Assessment.}, journal = {Prehospital emergency care}, volume = {28}, number = {2}, pages = {231-242}, doi = {10.1080/10903127.2023.2220021}, pmid = {37276151}, issn = {1545-0066}, mesh = {Adult ; Aged ; Child ; Female ; Humans ; Male ; Adrenal Cortex Hormones ; *Bronchial Spasm/drug therapy ; Cross-Sectional Studies ; *Emergency Medical Services ; Oxygen ; United States ; Child, Preschool ; Adolescent ; Middle Aged ; }, abstract = {Background/Objective: Bronchospasm, caused by asthma and other related conditions, is a significant cause of morbidity and mortality commonly managed by emergency medical services (EMS). We aimed to evaluate the quality of prehospital management of bronchospasm by EMS in the US.Methods: The National EMS Information System Public Release Research dataset, a nationwide convenience sample of prehospital patient care report data from 2018 to 2019, was used to capture 9-1-1 activations where patients aged ≥2 years were treated and transported by EMS for suspected bronchospasm. First, we described the extent to which EMS care met eight quality measures identified from available statewide EMS protocols, existing quality measures, and national guidelines. Second, we quantified the extent of risk-standardized agency-level variation in administration of inhaled beta agonists and systemic corticosteroids using logistic regression models, accounting for patient characteristics, severity, and clustering by agencies. Third, we compared rates of completed prehospital interventions between pediatric (age <18 years) versus adult patients using two-sample t-tests.Results: A total of 1,336,988 EMS encounters for suspected bronchospasm met inclusion criteria. Median age of patients was 66 years, with only 4% pediatric; 55% were female. Advanced life support (ALS) units managed 94% of suspected bronchospasm. Respiratory rate (98%) and pulse oximetry (96%) were documented in nearly all cases. Supplemental oxygen was administered to hypoxic patients by 65% of basic life support (BLS) and 73% of ALS units. BLS administered inhaled beta-agonist therapy less than half the time (48%), compared to 77% by ALS. ALS administered inhaled anticholinergic therapy in 38% of cases, and systemic corticosteroids in 19% of cases. Pediatric patients were significantly less likely to receive supplemental oxygen when hypoxic, inhaled beta-agonists, inhaled anticholinergics, or systemic corticosteroids.Conclusions: We found important gaps in recent EMS practice for prehospital care of suspected bronchospasm. We highlight three targets for improvement: inhaled beta-agonist administration by BLS, systemic corticosteroid administration by ALS, and increased interventions for pediatric patients. These findings indicate important areas for research, protocol modification, and quality improvement efforts to improve EMS management of bronchospasm.}, } @article {pmid37274187, year = {2023}, author = {Santarelli, S and Londero, C and Soldano, A and Candelaresi, C and Todeschini, L and Vernizzi, L and Bellosta, P}, title = {Drosophila melanogaster as a model to study autophagy in neurodegenerative diseases induced by proteinopathies.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1082047}, pmid = {37274187}, issn = {1662-4548}, abstract = {Proteinopathies are a large group of neurodegenerative diseases caused by both genetic and sporadic mutations in particular genes which can lead to alterations of the protein structure and to the formation of aggregates, especially toxic for neurons. Autophagy is a key mechanism for clearing those aggregates and its function has been strongly associated with the ubiquitin-proteasome system (UPS), hence mutations in both pathways have been associated with the onset of neurodegenerative diseases, particularly those induced by protein misfolding and accumulation of aggregates. Many crucial discoveries regarding the molecular and cellular events underlying the role of autophagy in these diseases have come from studies using Drosophila models. Indeed, despite the physiological and morphological differences between the fly and the human brain, most of the biochemical and molecular aspects regulating protein homeostasis, including autophagy, are conserved between the two species.In this review, we will provide an overview of the most common neurodegenerative proteinopathies, which include PolyQ diseases (Huntington's disease, Spinocerebellar ataxia 1, 2, and 3), Amyotrophic Lateral Sclerosis (C9orf72, SOD1, TDP-43, FUS), Alzheimer's disease (APP, Tau) Parkinson's disease (a-syn, parkin and PINK1, LRRK2) and prion diseases, highlighting the studies using Drosophila that have contributed to understanding the conserved mechanisms and elucidating the role of autophagy in these diseases.}, } @article {pmid37274121, year = {2023}, author = {Keukeleire, P and Makrodimitris, S and Reinders, M}, title = {Cell type deconvolution of methylated cell-free DNA at the resolution of individual reads.}, journal = {NAR genomics and bioinformatics}, volume = {5}, number = {2}, pages = {lqad048}, pmid = {37274121}, issn = {2631-9268}, abstract = {Cell-free DNA (cfDNA) are DNA fragments originating from dying cells that are detectable in bodily fluids, such as the plasma. Accelerated cell death, for example caused by disease, induces an elevated concentration of cfDNA. As a result, determining the cell type origins of cfDNA molecules can provide information about an individual's health. In this work, we aim to increase the sensitivity of methylation-based cell type deconvolution by adapting an existing method, CelFiE, which uses the methylation beta values of individual CpG sites to estimate cell type proportions. Our new method, CelFEER, instead differentiates cell types by the average methylation values within individual reads. We additionally improved the originally reported performance of CelFiE by using a new approach for finding marker regions that are differentially methylated between cell types. We show that CelFEER estimates cell type proportions with a higher correlation (r = 0.94 ± 0.04) than CelFiE (r = 0.86 ± 0.09) on simulated mixtures of cell types. Moreover, we show that the cell type proportion estimated by CelFEER can differentiate between ALS patients and healthy controls, between pregnant women in their first and third trimester, and between pregnant women with and without gestational diabetes.}, } @article {pmid37273905, year = {2023}, author = {McIntosh, J and Mekrouda, I and Dashti, M and Giuraniuc, CV and Banks, RW and Miles, GB and Bewick, GS}, title = {Development of abnormalities at the neuromuscular junction in the SOD1-G93A mouse model of ALS: dysfunction then disruption of postsynaptic structure precede overt motor symptoms.}, journal = {Frontiers in molecular neuroscience}, volume = {16}, number = {}, pages = {1169075}, pmid = {37273905}, issn = {1662-5099}, abstract = {INTRODUCTION: The ultimate deficit in amyotrophic lateral sclerosis (ALS) is neuromuscular junction (NMJ) loss, producing permanent paralysis, ultimately in respiratory muscles. However, understanding the functional and structural deficits at NMJs prior to this loss is crucial for therapeutic strategy design. Should early interventions focus on reversing denervation, or supporting largely intact NMJs that are functionally impaired? We therefore determined when functional and structural deficits appeared in diaphragmatic NMJs relative to the onset of hindlimb tremor (the first overt motor symptoms) in vivo in the SOD1-G93A mouse model of ALS.

MATERIALS AND METHODS: We employed electrophysiological recording of NMJ postsynaptic potentials for spontaneous and nerve stimulation-evoked responses. This was correlated with fluorescent imaging microscopy of the postsynaptic acetylcholine receptor (AChR) distribution throughout the postnatal developmental timecourse from 2 weeks to early symptomatic ages.

RESULTS: Significant reduction in the amplitudes of spontaneous miniature endplate potentials (mEPPs) and evoked EPPs emerged only at early symptomatic ages (in our colony, 18-22 weeks). Reductions in mEPP frequency, number of vesicles per EPP, and EPP rise time were seen earlier, at 16weeks, but this reversed by early symptomatic ages. However, the earliest and most striking impairment was an inability to maintain EPP amplitude during a 20 Hz stimulus train, which appeared 6 weeks before overt in vivo motor symptoms. Despite this, fluorescent α-bungarotoxin labelling revealed no systematic, progressive changes in 11 comprehensive NMJ morphological parameters (area, shape, compactness, number of acetylcholine receptor, AChR, regions, etc.) with disease progression. Rather, while NMJs were largely normally-shaped, from 16 weeks there was a progressive and substantial disruption in AChR concentration and distribution within the NMJ footprint.

DISCUSSION: Thus, NMJ functional deficits appear at least 6 weeks before motor symptoms in vivo, while structural deficits occur 4 weeks later, and predominantly within NMJs. These data suggest initial therapies focused on rectifying suboptimal NMJ function could produce effective relief of symptoms of weakness.}, } @article {pmid37273142, year = {2023}, author = {Iida, S and Kanouchi, T and Hattori, T and Kanai, K and Nakazato, T and Hattori, N and Yokota, T}, title = {Verification of propagation hypothesis in patients with sporadic hand onset amyotrophic lateral sclerosis.}, journal = {Acta neurologica Belgica}, volume = {123}, number = {4}, pages = {1511-1517}, pmid = {37273142}, issn = {2240-2993}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Retrospective Studies ; Hand ; }, abstract = {OBJECTIVE: If lesions in sporadic amyotrophic lateral sclerosis (ALS) originate from a single focal onset site and spread contiguously by prion-like cell-to-cell propagation at a constant speed, the lesion spread time should be proportional to the anatomical distance. We verify this model in the patients.

METHODS: In 29 sporadic ALS patients with hand onset followed by spread to shoulder and leg, we retrospectively evaluated the inter/intra-regional spread time ratio: time interval of symptoms from hand-to-leg divided by that from hand-to-shoulder. We also obtained the corresponding inter-/intra-regional distance ratios of spinal cord from magnetic resonance imaging of 12 patients, and those of primary motor cortex from coordinates using neuroimaging software.

RESULTS: Inter-/intra-regional spread time ratios ranged from 0.29 to 6.00 (median 1.20). Distance ratios ranged from 1.85 to 2.86 in primary motor cortex and from 5.79 to 8.67 in spinal cord. Taken together with clinical manifestations, of 27 patients with the requisite information available, lesion spreading was consistent with the model in primary motor cortex in 4 (14.8%) patients, and in spinal cord in only 1 (3.7%) patient. However, in more patients (12 of 29 patients: 41.4%), the inter-regional spread times in a long anatomical distance of hand-to-leg were shorter than or equal to the intra-regional spread times in a short anatomical distance of hand-to-shoulder.

CONCLUSION: Contiguous cell-to-cell propagation at a constant speed might not play a major role at least in distant lesion spreading of ALS. Several mechanisms can be responsible for progression in ALS.}, } @article {pmid37272384, year = {2023}, author = {Enriquez de Salamanca Gambara, R and Sanz-García, A and Martín-Conty, JL and Polonio-López, B and Del Pozo Vegas, C and Martín-Rodríguez, F and López-Izquierdo, R}, title = {Long-Term Mortality in Patients Transferred by Emergency Medical Services: Prospective Cohort Study.}, journal = {Prehospital and disaster medicine}, volume = {38}, number = {3}, pages = {352-359}, doi = {10.1017/S1049023X23005800}, pmid = {37272384}, issn = {1945-1938}, mesh = {Adult ; Humans ; Prospective Studies ; *Emergency Medical Services ; Emergency Service, Hospital ; Ambulances ; Risk Factors ; }, abstract = {OBJECTIVE: This study aimed to determine the long-term mortality (one-year follow-up) associated with patients transferred by Emergency Medical Services (EMS), and to reveal the determinants (causes and risk factors).

METHODS: This was a multicenter, prospective, observational, controlled, ambulance-based study of adult patients transferred by ambulance to emergency departments (EDs) from October 2019 through July 2021 for any cause. A total of six Advanced Life Support (ALS) units, 38 Basic Life Support (BLS) units, and five hospitals from Spain were included. Physiological, biochemical, demographic, and reasons for transfer variables were collected. A longitudinal analysis was performed to determine the factors associated to long-term mortality (any cause).

RESULTS: The final cohort included 1,406 patients. The one-year mortality rate was 21.6% (n = 304). Mortality over the first two days reached 5.2% of all the patients; between Day 2 and Day 30, reached 5.3%; and between Day 31 and Day 365, reached 11.1%. Low Glasgow values, elevated lactate levels, elevated blood urea nitrogen (BUN) levels, low oxygen saturation, high respiratory rate, as well as being old and suffering from circulatory diseases and neurological diseases were risk factors for long-term mortality.

CONCLUSION: The quick identification of patients at risk of long-term worsening could provide an opportunity to customize care through specific follow-up.}, } @article {pmid37272348, year = {2024}, author = {Bouvier, L and McKinlay, S and Truong, J and Genge, A and Dupré, N and Dionne, A and Kalra, S and Yunusova, Y}, title = {Speech timing and monosyllabic diadochokinesis measures in the assessment of amyotrophic lateral sclerosis in Canadian French.}, journal = {International journal of speech-language pathology}, volume = {26}, number = {2}, pages = {267-277}, pmid = {37272348}, issn = {1754-9515}, support = {R01 DC017291/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Speech ; *Amyotrophic Lateral Sclerosis/complications ; Canada ; Speech Production Measurement/methods ; Language ; }, abstract = {PURPOSE: The primary objective of this study was to determine if speech and pause measures obtained using a passage reading task and timing measures from a monosyllabic diadochokinesis (DDK) task differ across speakers of Canadian French diagnosed with amyotrophic lateral sclerosis (ALS) presenting with and without bulbar symptoms, and healthy controls. The secondary objective was to determine if these measures can reflect the severity of bulbar symptoms.

METHOD: A total of 29 Canadian French speakers with ALS (classified as bulbar symptomatic [n = 14] or pre-symptomatic [n = 15]) and 17 age-matched healthy controls completed a passage reading task and a monosyllabic DDK task (/pa/ and /ta/), for up to three follow-up visits. Measures of speaking rate, total duration, speech duration, and pause events were extracted from the passage reading recordings using a semi-automated speech and pause analysis procedure. Manual analysis of DDK recordings provided measures of DDK rate and variability.

RESULT: Group comparisons revealed significant differences (p = < .05) between the symptomatic group and the pre-symptomatic and control groups for all passage measures and DDK rates. Only the DDK rate in /ta/ differentiated the pre-symptomatic and control groups. Repeated measures correlations revealed moderate correlations (rrm = > 0.40; p = < 0.05) between passage measures of total duration, speaking rate, speech duration, and number of pauses, and ALSFRS-R total and bulbar scores, as well as between DDK rate and ALSFRS-R total score.

CONCLUSION: Speech and pause measures in passage and timing measures in monosyllabic DDK tasks might be suitable for monitoring bulbar functional symptoms in French speakers with ALS, but more work is required to identify which measures are sensitive to the earliest stages of the disease.}, } @article {pmid37270090, year = {2023}, author = {Shibahashi, K and Kato, T and Hikone, M and Sugiyama, K}, title = {Identifying individuals satisfying the termination of resuscitation rule but having potential to achieve favourable neurological outcome following out-of-hospital cardiac arrest.}, journal = {Resuscitation}, volume = {190}, number = {}, pages = {109860}, doi = {10.1016/j.resuscitation.2023.109860}, pmid = {37270090}, issn = {1873-1570}, mesh = {Adolescent ; Aged, 80 and over ; Humans ; *Cardiopulmonary Resuscitation ; Decision Support Techniques ; *Emergency Medical Services ; *Out-of-Hospital Cardiac Arrest/therapy ; Registries ; Resuscitation Orders ; Life Support Care ; }, abstract = {AIM: To develop a simple scoring model that identifies individuals satisfying the termination of resuscitation (TOR) rule but having potential to achieve favourable neurological outcome following out-of-hospital cardiac arrest (OHCA).

METHODS: This study analysed the All-Japan Utstein Registry from 1 January 2010 to 31 December 2019. We identified patients satisfying basic life support (BLS) and advanced life support (ALS) TOR rules and determined factors associated with favourable neurological outcome (cerebral performance category scale of 1 or 2) for each cohort using multivariable logistic regression analysis. Scoring models were derived and validated to identify patient subgroups that might benefit from continued resuscitation efforts.

RESULTS: Among 1,695,005 eligible patients, 1,086,092 (64.1%) and 409,498 (24.2%) satisfied BLS and ALS TOR rules, respectively. One month post-arrest, 2038 (0.2%) and 590 (0.1%) patients in the BLS and ALS cohorts, respectively, achieved favourable neurological outcome. A scoring model derived for the BLS cohort (2 points for age <17 years or ventricular fibrillation/ventricular tachycardia rhythm; 1 point for age <80 years, pulseless electrical activity rhythm, or transport time <25 min) effectively stratified the probability of achieving 1-month favourable neurological outcome, with patients scoring <4 having a probability of <1%, whereas those scoring 4, 5, and 6 having probabilities of 1.1%, 7.1%, and 11.1%, respectively. In the ALS cohort, the probability increased with scores; however, it remained <1%.

CONCLUSION: A simple scoring model comprising age, first documented cardiac rhythm, and transport time effectively stratified the likelihood of achieving favourable neurological outcome in patients satisfying the BLS TOR rule.}, } @article {pmid37269968, year = {2023}, author = {Alqahtani, T and Deore, SL and Kide, AA and Shende, BA and Sharma, R and Dadarao Chakole, R and Nemade, LS and Kishor Kale, N and Borah, S and Shrikant Deokar, S and Behera, A and Dhawal Bhandari, D and Gaikwad, N and Kalam Azad, A and Ghosh, A}, title = {Mitochondrial dysfunction and oxidative stress in Alzheimer's disease, and Parkinson's disease, Huntington's disease and Amyotrophic Lateral Sclerosis -An updated review.}, journal = {Mitochondrion}, volume = {71}, number = {}, pages = {83-92}, doi = {10.1016/j.mito.2023.05.007}, pmid = {37269968}, issn = {1872-8278}, mesh = {Humans ; *Parkinson Disease/pathology ; *Alzheimer Disease/pathology ; *Huntington Disease/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Oxidative Stress/physiology ; *Neurodegenerative Diseases/metabolism ; Mitochondria/metabolism ; }, abstract = {Misfolded proteins in the central nervous system can induce oxidative damage, which can contribute to neurodegenerative diseases in the mitochondria. Neurodegenerative patients face early mitochondrial dysfunction, impacting energy utilization. Amyloid-ß and tau problems both have an effect on mitochondria, which leads to mitochondrial malfunction and, ultimately, the onset of Alzheimer's disease. Cellular oxygen interaction yields reactive oxygen species within mitochondria, initiating oxidative damage to mitochondrial constituents. Parkinson's disease, linked to oxidative stress, α-synuclein aggregation, and inflammation, results from reduced brain mitochondria activity. Mitochondrial dynamics profoundly influence cellular apoptosis via distinct causative mechanisms. The condition known as Huntington's disease is characterized by an expansion of polyglutamine, primarily impactingthe cerebral cortex and striatum. Research has identified mitochondrial failure as an early pathogenic mechanism contributing to HD's selective neurodegeneration. The mitochondria are organelles that exhibit dynamism by undergoing fragmentation and fusion processes to attain optimal bioenergetic efficiency. They can also be transported along microtubules and regulateintracellular calcium homeostasis through their interaction with the endoplasmic reticulum. Additionally, the mitochondria produce free radicals. The functions of eukaryotic cells, particularly in neurons, have significantly deviated from the traditionally assigned role of cellular energy production. Most of them areimpaired in HD, which may lead to neuronal dysfunction before symptoms manifest. This article summarizes the most important changes in mitochondrial dynamics that come from neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's and Amyotrophic Lateral Sclerosis. Finally, we discussed about novel techniques that can potentially treat mitochondrial malfunction and oxidative stress in four most dominating neuro disorders.}, } @article {pmid37269231, year = {2024}, author = {Alqallaf, A and Cates, DW and Render, KP and Patel, KA}, title = {Sodium Phenylbutyrate and Taurursodiol: A New Therapeutic Option for the Treatment of Amyotrophic Lateral Sclerosis.}, journal = {The Annals of pharmacotherapy}, volume = {58}, number = {2}, pages = {165-173}, doi = {10.1177/10600280231172802}, pmid = {37269231}, issn = {1542-6270}, mesh = {United States ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Phenylbutyrates/adverse effects ; }, abstract = {OBJECTIVE: To review the safety and efficacy of sodium phenylbutyrate and taurursodiol (SP + T) in slowing progression of amyotrophic lateral sclerosis (ALS) compared with pre-existing therapies.

DATA SOURCES: A PubMed (from January 1, 2009, to April 13, 2023) and ClinicalTrials.gov search conducted using sodium phenylbutyrate, taurursodiol, AMX0035, riluzole, and edaravone. Additional articles were identified by hand from references.

This included English-language articles evaluating SP + T efficacy or safety in humans for decreasing neuronal death and slowing the progression of ALS.

DATA SYNTHESIS: In one phase II clinical trial that encompassed an open-label extension phase, disease severity, assessed by the rate of decline in overall score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised with higher scores indicating more functional ability, was -1.24 points per month with active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03-0.81; P = 0.03). Post hoc analysis found survival benefit of median 4.8 months with active medication compared with placebo.

SP + T is a new US Food and Drug Administration-approved oral suspension for the treatment of ALS. Patients who received active medication through the phase II trial showed decreased rates of disease progression. Overall, SP + T could be considered a potential agent for the treatment of ALS which has a high unmet need.

CONCLUSION: SP + T is an option for the treatment of ALS; however, additional data regarding efficacy in phase III trials with long-term safety profile considerations, as well as trials to compare current therapy with SP + T, are needed.}, } @article {pmid37269166, year = {2023}, author = {Vucic, S}, title = {Clinical utility of far field motor potentials in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {68}, number = {3}, pages = {237-239}, doi = {10.1002/mus.27852}, pmid = {37269166}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Evoked Potentials ; }, } @article {pmid37268555, year = {2024}, author = {Fakim, H and Vande Velde, C}, title = {The implications of physiological biomolecular condensates in amyotrophic lateral sclerosis.}, journal = {Seminars in cell & developmental biology}, volume = {156}, number = {}, pages = {176-189}, doi = {10.1016/j.semcdb.2023.05.006}, pmid = {37268555}, issn = {1096-3634}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Biomolecular Condensates ; DNA-Binding Proteins/genetics/metabolism ; *Neurodegenerative Diseases/metabolism ; Mutation/genetics ; RNA ; }, abstract = {In recent years, there has been an emphasis on the role of phase-separated biomolecular condensates, especially stress granules, in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). This is largely due to several ALS-associated mutations occurring in genes involved in stress granule assembly and observations that pathological inclusions detected in ALS patient neurons contain stress granule proteins, including the ALS-linked proteins TDP-43 and FUS. However, protein components of stress granules are also found in numerous other phase-separated biomolecular condensates under physiological conditions which are inadequately discussed in the context of ALS. In this review, we look beyond stress granules and describe the roles of TDP-43 and FUS in physiological condensates occurring in the nucleus and neurites, such as the nucleolus, Cajal bodies, paraspeckles and neuronal RNA transport granules. We also discuss the consequences of ALS-linked mutations in TDP-43 and FUS on their ability to phase separate into these stress-independent biomolecular condensates and perform their respective functions. Importantly, biomolecular condensates sequester multiple overlapping protein and RNA components, and their dysregulation could contribute to the observed pleiotropic effects of both sporadic and familial ALS on RNA metabolism.}, } @article {pmid37268333, year = {2023}, author = {Chen, X and Zhou, L and Cui, C and Sun, J}, title = {Evolving markers in amyotrophic lateral sclerosis.}, journal = {Advances in clinical chemistry}, volume = {114}, number = {}, pages = {225-246}, doi = {10.1016/bs.acc.2023.02.002}, pmid = {37268333}, issn = {2162-9471}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; *Neurodegenerative Diseases ; Motor Neurons/physiology ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relatively rare but fatal neurodegenerative disease with the progressive loss of both upper and lower motor neurons. Although electromyography, imaging and multi-omics technologies have suggested numerous functional, structural, circulating and microbiota markers for ALS, no clinically validated markers have, as yet, been identified. Here we summarize the advances to characterize markers underlying ALS pathophysiology as well as their potential use in diagnosis, prognosis and therapy.}, } @article {pmid37267913, year = {2023}, author = {Morimoto, S and Takahashi, S and Ito, D and Daté, Y and Okada, K and Kato, C and Nakamura, S and Ozawa, F and Chyi, CM and Nishiyama, A and Suzuki, N and Fujimori, K and Kondo, T and Takao, M and Hirai, M and Kabe, Y and Suematsu, M and Jinzaki, M and Aoki, M and Fujiki, Y and Sato, Y and Suzuki, N and Nakahara, J and , and Okano, H}, title = {Phase 1/2a clinical trial in ALS with ropinirole, a drug candidate identified by iPSC drug discovery.}, journal = {Cell stem cell}, volume = {30}, number = {6}, pages = {766-780.e9}, doi = {10.1016/j.stem.2023.04.017}, pmid = {37267913}, issn = {1875-9777}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Indoles/adverse effects/pharmacology ; *Induced Pluripotent Stem Cells ; Motor Neurons ; }, abstract = {iPSC-based drug discovery led to a phase 1/2a trial of ropinirole in ALS. 20 participants with sporadic ALS received ropinirole or placebo for 24 weeks in the double-blind period to evaluate safety, tolerability, and therapeutic effects. Adverse events were similar in both groups. During the double-blind period, muscle strength and daily activity were maintained, but a decline in the ALSFRS-R, which assesses the functional status of ALS patients, was not different from that in the placebo group. However, in the open-label extension period, the ropinirole group showed significant suppression of ALSFRS-R decline and an additional 27.9 weeks of disease-progression-free survival. iPSC-derived motor neurons from participants showed dopamine D2 receptor expression and a potential involvement of the SREBP2-cholesterol pathway in therapeutic effects. Lipid peroxide represents a clinical surrogate marker to assess disease progression and drug efficacy. Limitations include small sample sizes and high attrition rates in the open-label extension period, requiring further validation.}, } @article {pmid37267911, year = {2023}, author = {Mazzini, L and De Marchi, F}, title = {iPSC-based research in ALS precision medicine.}, journal = {Cell stem cell}, volume = {30}, number = {6}, pages = {748-749}, doi = {10.1016/j.stem.2023.05.008}, pmid = {37267911}, issn = {1875-9777}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Induced Pluripotent Stem Cells/physiology ; Precision Medicine ; Motor Neurons ; }, abstract = {Clinical trials in amyotrophic lateral sclerosis (ALS) are challenged by the lack of pre-clinical models and biomarkers of disease onset and progression. In this issue, Morimoto et al. use induced pluripotent stem cell (iPSC)-derived motor neurons from patients with ALS to study therapeutic mechanisms of ropinirole in a clinical trial and identify treatment responders.}, } @article {pmid37266922, year = {2024}, author = {Parra-Cantu, C and Martinez-Thompson, JM and Linch, FB and Welch, TL and Chou, CZ and Pattinson, AK and Staff, NP and Neisen, M}, title = {Radiologically Inserted Gastrostomy Tube Placement Guided by the Assessment and Primary Palliative Care Provided by an Amyotrophic Lateral Sclerosis Multidisciplinary Clinic: A Single-Arm Retrospective Clinical Study.}, journal = {The American journal of hospice & palliative care}, volume = {41}, number = {5}, pages = {516-526}, doi = {10.1177/10499091231180553}, pmid = {37266922}, issn = {1938-2715}, mesh = {Humans ; Gastrostomy/methods ; Retrospective Studies ; *Amyotrophic Lateral Sclerosis/therapy ; Palliative Care ; *Neurodegenerative Diseases ; Quality of Life ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a median survival of about 3 years. An ALS multidisciplinary team can provide primary palliative care and improve outcomes and quality of life for patients. Feeding tube insertion may be considered for patients with significant weight loss, or respiratory insufficiency. While radiologically inserted gastrostomy (RIG) tube placement may be an option, further studies are required to determine its best timing and appropriateness. This study's objectives were to evaluate the feasibility and outcomes of RIG tube placement in ALS patients over a 90-day follow-up period through the assessment and primary palliative care provided by the multidisciplinary team. This retrospective study reviewed the placement of 16 or 18 French RIG-tube without intubation or endoscopy for 36 ALS patients at a single center between April 2019 and December 2021. Measures included ALS Functional Rating Scale-Revised (ALSFRS-R) scores to determine the ALS stage. Demographic, clinical, procedural, and follow-up data were reviewed. Results showed that the RIG tube placement had a low rate of minor adverse events (11%) and no major procedure-related adverse events. The mean ALSFRS-R score at the time of procedure in subjects who died within 90 days was lower than of those alive beyond 90 days (P = .04). This study found that RIG-tube placement is a safe and effective way to manage dysphagia in ALS patients and highlights the importance of educating members of the multidisciplinary clinic in palliative care principles to determine the appropriateness of RIG tube placement.}, } @article {pmid37266849, year = {2024}, author = {Ugale, V and Deshmukh, R and Lokwani, D and Narayana Reddy, P and Khadse, S and Chaudhari, P and Kulkarni, PP}, title = {GluN2B subunit selective N-methyl-D-aspartate receptor ligands: Democratizing recent progress to assist the development of novel neurotherapeutics.}, journal = {Molecular diversity}, volume = {28}, number = {3}, pages = {1765-1792}, pmid = {37266849}, issn = {1573-501X}, mesh = {*Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors ; Humans ; Ligands ; Animals ; Structure-Activity Relationship ; Protein Subunits/metabolism/chemistry ; }, abstract = {N-methyl-D-aspartate receptors (NMDARs) play essential roles in vital aspects of brain functions. NMDARs mediate clinical features of neurological diseases and thus, represent a potential therapeutic target for their treatments. Many findings implicated the GluN2B subunit of NMDARs in various neurological disorders including epilepsy, ischemic brain damage, and neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's chorea, and amyotrophic lateral sclerosis. Although a large amount of information is growing consistently on the importance of GluN2B subunit, however, limited recent data is available on how subunit-selective ligands impact NMDAR functions, which blunts the ability to render the diagnosis or craft novel treatments tailored to patients. To bridge this gap, we have focused on and summarized recently reported GluN2B selective ligands as emerging subunit-selective antagonists and modulators of NMDAR. Herein, we have also presented an overview of the structure-function relationship for potential GluN2B/NMDAR ligands with their binding sites and connection to CNS functionalities. Understanding of design rules and roles of GluN2B selective compounds will provide the link to medicinal chemists and neuroscientists to explore novel neurotherapeutic strategies against dysfunctions of glutamatergic neurotransmission.}, } @article {pmid37266403, year = {2023}, author = {Petersen, RB and Walter, B}, title = {Editorial: Insights into Parkinson's disease and aging related movement disorders.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1193197}, pmid = {37266403}, issn = {1663-4365}, } @article {pmid37265463, year = {2023}, author = {Gagliardi, D and Ripellino, P and Meneri, M and Del Bo, R and Antognozzi, S and Comi, GP and Gobbi, C and Ratti, A and Ticozzi, N and Silani, V and Ronchi, D and Corti, S}, title = {Clinical and molecular features of patients with amyotrophic lateral sclerosis and SOD1 mutations: a monocentric study.}, journal = {Frontiers in neurology}, volume = {14}, number = {}, pages = {1169689}, pmid = {37265463}, issn = {1664-2295}, abstract = {INTRODUCTION: SOD1 was the first gene associated with both familial and sporadic forms of amyotrophic lateral sclerosis (ALS) and is the second most mutated gene in Caucasian ALS patients. Given their high clinical and molecular heterogeneity, a detailed characterization of SOD1-ALS patients could improve knowledge about the natural history of this disease. Here, the authors aimed to provide a clinical and molecular description of a monocentric cohort of SOD1-ALS patients.

METHODS: Amyotrophic lateral sclerosis (ALS) patients referring to the neurology unit of our center between 2008 and 2021 were clinically assessed and underwent molecular testing for SOD1. Segregation studies in available family members and in silico analysis were performed to sustain the pathogenicity of the identified SOD1 variants.

RESULTS: Among the 576 patients in our cohort, we identified 19 individuals harboring a mutation in SOD1 (3.3%), including 15 (78.9%) with a familial and four (21.1%) with a sporadic form. The spinal onset of the disease was observed in all patients, and survival was extremely variable, ranging from 8 months to over 30 years. Twelve different SOD1 missense variants were identified in our cohort, including one novel mutation (p.Pro67Leu).

DISCUSSION: In the present series, we provided the first description of an Italian monocentric cohort of SOD1-ALS patients, and we expanded the repertoire of SOD1 mutations. Our cohort presents several remarkable features, including variable expressivity in the same family, atypical presentation (ataxia, cognitive impairment, and other extra-motor symptoms), and different modes of inheritance of a given mutation in the same family. Given the recent authorization of SOD1-directed antisense oligonucleotide for use in SOD1-ALS patients, we recommend prompt screening for SOD1 mutations in novel ALS patients with familiar or sporadic presentations.}, } @article {pmid37265174, year = {2023}, author = {Tabor Gray, L and Locatelli, E and Vasilopoulos, T and Wymer, J and Plowman, EK}, title = {Dextromethorphan/quinidine for the treatment of bulbar impairment in amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {10}, number = {8}, pages = {1296-1304}, pmid = {37265174}, issn = {2328-9503}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/drug therapy ; Dextromethorphan/pharmacology/therapeutic use ; Quinidine/pharmacology/therapeutic use ; Deglutition ; Speech ; }, abstract = {OBJECTIVE: No efficacious treatments exist to improve or prolong bulbar functions of speech and swallowing in persons with amyotrophic lateral sclerosis (pALS). This study evaluated the short-term impact of dextromethorphan/quinidine (DMQ) treatment on speech and swallowing function in pALS.

METHODS: This was a cohort trial conducted between August 2019 to August 2021 in pALS with a confirmed diagnosis of probable-definite ALS (El-Escorial Criteria-revisited) and bulbar impairment (ALS Functional Rating Scale score ≤ 10 and speaking rate ≤ 140 words per minute) who were DMQ naïve. Efficacy of DMQ was assessed via pre-post change in the ALS Functional Rating Scale-Revised bulbar subscale and validated speech and swallowing outcomes. Paired t-tests, Fisher's exact, and χ[2] tests were conducted with alpha at 0.05.

RESULTS: Twenty-eight pALS enrolled, and 24 participants completed the 28-day trial of DMQ. A significant increase in ALSFRS-R bulbar subscale score pre- (7.47 ± 1.98) to post- (8.39 ± 1.79) treatment was observed (mean difference: 0.92, 95% CI: 0.46-1.36, p < 0.001). Functional swallowing outcomes improved, with a reduction in unsafe (75% vs. 44%, p = 0.003) and inefficient swallowing (67% vs. 58%, p = 0.002); the relative speech event duration in a standard reading passage increased, indicating a greater duration of uninterrupted speech (mean difference: 0.33 s, 95% CI: 0.02-0.65, p = 0.035). No differences in diadochokinetic rate or speech intelligibility were observed (p > 0.05).

INTERPRETATION: Results of this study provide preliminary evidence that DMQ pharmacologic intervention may have the potential to improve or maintain bulbar function in pALS.}, } @article {pmid37263460, year = {2023}, author = {Punessen, NC and Pena, C and Sandberg, A and Koza, LA and Linseman, DA}, title = {A novel anti-apoptotic role for Cdc42/ACK-1 signaling in neurons.}, journal = {Molecular and cellular neurosciences}, volume = {126}, number = {}, pages = {103865}, doi = {10.1016/j.mcn.2023.103865}, pmid = {37263460}, issn = {1095-9327}, mesh = {Rats ; Animals ; *Protein-Tyrosine Kinases/metabolism ; *rho GTP-Binding Proteins/metabolism/pharmacology ; Neurons/metabolism ; Apoptosis/physiology ; }, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's and Parkinson's disease are caused by a progressive and aberrant destruction of neurons in the brain and spinal cord. These disorders lack effective long-term treatments that impact the underlying mechanisms of pathogenesis and as a result, existing options focus primarily on alleviating symptomology. Dysregulated programmed cell death (i.e., apoptosis) is a significant contributor to neurodegeneration, and is controlled by a number of different factors. Rho family GTPases are molecular switches with recognized importance in proper neuronal development and migration that have more recently emerged as central regulators of apoptosis and neuronal survival. Here, we investigated a role for the Rho GTPase family member, Cdc42, and its downstream effectors, in neuronal survival and apoptosis. We initially induced apoptosis in primary cultures of rat cerebellar granule neurons (CGNs) by removing both growth factor-containing serum and depolarizing potassium from the cell medium. We then utilized both chemical inhibitors and adenoviral shRNA targeted to Cdc42 to block the function of Cdc42 or its downstream effectors under either control or apoptotic conditions. Our in vitro studies demonstrate that functional inhibition of Cdc42 or its downstream effector, activated Cdc42-associated tyrosine kinase-1 (ACK-1), had no adverse effects on CGN survival under control conditions, but significantly sensitized neurons to cell death under apoptotic conditions. In conclusion, our results suggest a key pro-survival role for Cdc42/ACK-1 signaling in neurons, particularly in regulating neuronal susceptibility to pro-apoptotic stress such as that observed in neurodegenerative disorders.}, } @article {pmid37263278, year = {2025}, author = {Guler, Y}, title = {Clinical and pathological risk factors for tumour recurrence and upstaging in second TURBT for patients with NMIBC: a systematic review and meta-analysis.}, journal = {Aktuelle Urologie}, volume = {56}, number = {1}, pages = {30-40}, doi = {10.1055/a-2063-3144}, pmid = {37263278}, issn = {1438-8820}, mesh = {Humans ; *Neoplasm Recurrence, Local/pathology ; Risk Factors ; *Neoplasm Staging ; *Urinary Bladder Neoplasms/pathology/surgery ; Cystectomy ; Reoperation ; Non-Muscle Invasive Bladder Neoplasms ; }, abstract = {UNLABELLED: ZIEL: Offenlegung signifikanter Risikofaktoren durch Identifizierung gepoolter Effektschätzungsstatistiken in einer systemischen Überprüfung und Metaanalyse klinischer und pathologischer Risikofaktoren, die ein Tumorrezidiv und ein Upstaging auf eine zweite TURBT bei Patienten mit hochgradigem NMIBC vorhersagen.

MATERIAL-METHODE: Alle Datenquellen wurden umfassend bis Oktober 2022 untersucht. Die Daten wurden aus den relevanten Studien extrahiert und mit der Software RevMan analysiert. In einem inversen Varianzmodell mit zufälligen und festen Effekten werden Odds Ratio (OR)-Werte mit 95%-Konfidenzintervallen [95%-KI] angegeben.

ERGEBNISSE: Der Review umfasste insgesamt 18 Studien und 4548 Patienten. Gemäß den gepoolten Effektschätzern waren Carcinoma in situ (CIS), Tumorgrad, Multiplizität und Chirurgenfaktoren signifikante Risikofaktoren. Die gepoolten Effektschätzungen für das Tumorstadium und die Tumormorphologie waren sehr nahe an der Signifikanz. Für CIS, Grad, Multiplizität und Chirurgenfaktor, OR, IVR oder IVF [95%-KI] waren die p- und I2-Werte 1,8 [1,1, 3,0], 0,03, 75%; 2 [1,1, 3,4], 0,02, 53%; 1,3 [1,2, 1,6], <0,01, 40%; und 2 [1,4, 3], <0,01, 66%.

SCHLUSSFOLGERUNGEN: Als Ergebnis der ersten TURBT; Eine zweite TURBT sollte in den 2-6 Wochen der postoperativen Phase für Patienten mit hochgradigem, begleitendem CIS, multipler, solider Morphologie, DM(-) im pathologischen Präparat und NMIBC, das von Trainern/Juniorchirurgen operiert wird, geplant werden.}, } @article {pmid37263249, year = {2023}, author = {Balamurugan, D and Nayak, C and Chattopadhyay, A and Karuppusamy, A and Ambrose, MM and Kumar, A and Singh, NK and Koley, M and Saha, S}, title = {Individualized Homeopathic Medicines in the Treatment of Psoriasis Vulgaris: Double-Blind, Randomized, Placebo-Controlled Trial.}, journal = {Complementary medicine research}, volume = {30}, number = {4}, pages = {317-331}, doi = {10.1159/000530180}, pmid = {37263249}, issn = {2504-2106}, mesh = {Humans ; *Psoriasis/drug therapy ; Double-Blind Method ; *Homeopathy ; India ; }, abstract = {INTRODUCTION: Psoriasis is a chronic inflammatory skin disorder, affecting the trunk and extensor surfaces of the limbs and scalp predominantly. Worldwide prevalence ranges between 0.1 and 11.4%, and in India between 0.4 and 2.8%; this creates a serious health burden. Psoriasis remains a frequently encountered condition in homeopathy practice, but there is a dearth of conclusive efficacy data supporting its use.

METHODS: This 6-month, double-blind, randomized trial was conducted on 51 patients suffering from psoriasis at the National Institute of Homoeopathy, India. Patients were randomized to receive either individualized homeopathic medicines (IHMs; n = 25) in LM potencies or identical-looking placebos (n = 26). Psoriasis area and severity index (PASI; primary), psoriasis disability index (PDI), and dermatological life quality index (DLQI; secondary) were measured at baseline and every 2 months, up to 6 months. The intention-to-treat sample was analyzed using a two-way repeated measure analysis of variance.

RESULTS: Although intragroup changes were significant in both groups in the outcome measures, improvements were significantly higher in the IHMs group than in placebos in PASI scores after 6 months of intervention (F1, 49 = 10.448, p = 0.002). DLQI daily activity subscale scores also yielded similar significant results favoring IHMs against placebos after 6 months (F1, 49 = 5.480, p = 0.023). Improvement in PDI total (F1, 49 = 0.063, p = 0.803), DLQI total (F1, 49 = 1.371, p = 0.247), and all remaining subscales were higher in the IHMs group than placebos after 6 months, but nonsignificant statistically. Calcarea carbonica, Mercurius solubilis, Arsenicum album, and Petroleum were the most frequently prescribed medicines.

CONCLUSIONS: IHMs exhibited better results than placebos in the treatment of psoriasis. Further research is warranted.

UNLABELLED: EinleitungPsoriasis ist eine chronisch entzündliche Hauterkrankung, die vor allem den Körperstamm und die Streckseiten der Extremitäten sowie die Kopfhaut betrifft. Die weltweite Prävalenz liegt zwischen 0,1 und 11,4% und in Indien zwischen 0,4 und 2,8%, was sie zu einer erheblichen Belastung für das Gesundheitssystem macht. In der homöopathischen Praxis ist die Psoriasis nach wie vor häufig anzutreffen, doch mangelt es an schlüssigen Wirksamkeitsdaten, die deren Anwendung stützen.MethodenDiese sechsmonatige, doppelblinde, randomisierte Studie wurde mit 51 Psoriasis-Patienten am National Institute of Homoeopathy in Indien durchgeführt. Die Patienten erhielten randomisiert entweder individualisierte homöopathische Arzneimittel (individualized homeopathic medicines, IHMs; n = 25) in LM-Potenzen oder identisch aussehende Placebos (n = 26). Der Psoriasis Area and Severity Index (PASI; primär), der Psoriasis Disability Index (PDI) und der Dermatological Life Quality Index (DLQI; sekundär) wurden bei Baseline und anschließend alle zwei Monate für bis zu sechs Monate gemessen. Die Analyse der Intention-to-Treat-Stichprobe erfolgte mittels zweifaktorieller Varianzanalyse mit wiederholten Messungen.ErgebnisseZwar waren in beiden Gruppen die gruppeninternen Veränderungen bei den Zielkriterien signifikant, doch fielen die Verbesserungen der PASI-Werte nach der sechsmonatigen Intervention in der IHM-Gruppe signifikant höher aus als in der Placebogruppe (F1, 49 = 10,448, p = 0,002), und die Werte der DLQI-Subskala für die tägliche Aktivität zeigten nach 6 Monaten ähnliche signifikante Ergebnisse zugunsten der IHMs gegenüber Placebo (F1, 49 = 5,480, p = 0,023). Die Verbesserungen beim PDI-Gesamt-Score (F1, 49 = 0,063, p = 0,803), beim DLQI-Gesamt-Score (F1, 49 = 1,371, p = 0,247) und bei den anderen Subskalen waren nach 6 Monaten in der IHM-Gruppe höher als in der Placebo-Gruppe, erreichten jedoch keine statistische Signifikanz. Calcarea carbonica, Mercurius solubilis, Arsenicum album und Petroleum waren die am häufigsten verordneten Arzneimittel.SchlussfolgerungenDie IHMs zeigten in der Behandlung der Psoriasis bessere Ergebnisse als Placebo. Weitere Untersuchungen sind erforderlich.}, } @article {pmid37261630, year = {2023}, author = {Zhu, Y and Li, M and He, Z and Pang, X and Du, R and Yu, W and Zhang, J and Bai, J and Wang, J and Huang, X}, title = {Evaluating the causal association between microRNAs and amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {10}, pages = {3567-3575}, pmid = {37261630}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics ; Genome-Wide Association Study ; *MicroRNAs/genetics/metabolism ; *Circulating MicroRNA/genetics ; Biomarkers ; }, abstract = {BACKGROUND: Currently, miRNAs are involved in the development of amyotrophic lateral sclerosis (ALS), and identifying circulating miRNAs that are causally associated with ALS risk as biomarkers is imperative.

METHODS: We performed a two-sample Mendelian randomization study to evaluate the causal relationship between miRNAs and ALS. Our analysis was conducted using summary statistics from miRNA expression quantitative loci (eQTL) data of the Framingham Heart Study and ALS genome-wide association studies data. Another independent miRNA data was used to further validate.

RESULTS: We identified eight unique miRNAs that were causally associated with ALS risk. Using expression data of miRNAs from an independent study, we validated three high-confidence miRNAs, namely hsa-miR-27b-3p, hsa-miR-139-5p, and hsa-miR-152-3p, which might have a potential causal effect on ALS risk.

CONCLUSION: We suggested that higher levels of hsa-miR-27b-3p and hsa-miR-139-5p had protective effects on ALS, whereas higher levels of hsa-miR-152-3p might act as a risk factor for ALS. The analytical framework presented in this study helps to understand the role of miRNAs in the development of ALS and to identify the biomarkers for ALS risk.}, } @article {pmid37260726, year = {2023}, author = {Chavan, M and Singh, A and Bathvar, PK and Mehta, ST and Qadree, AK and Dhakal, S}, title = {Bulbar onset amyotrophic lateral sclerosis with more evident symptoms in the left hemibody: a case report.}, journal = {Oxford medical case reports}, volume = {2023}, number = {5}, pages = {omad045}, pmid = {37260726}, issn = {2053-8855}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative neuromuscular condition. The procedure and difficulties involved in the clinical diagnosis of ALS have been the subject of numerous investigations. The understanding of the genetics and the epigenetics of the disease is still at infancy with several missing links. We present a case report of a 73-year-old woman suffering from bulbar onset ALS with a 4-month history of progressive dysphagia and dyspnea. She displayed tongue fasciculations and muscle atrophy. The bilateral palmomental reflexes, snout reflex, Hoffman, Babinski, diminished gag reflex, bilateral clonus and wild mood swings confirmed the neurodegenerative condition of the patient. The diagnosis of ALS can be challenging; therefore, the data presented may be useful to investigate its characteristics of the onset and to improve the understanding of the aspects of differentiation from other neurodegenerative disorders.}, } @article {pmid37260495, year = {2023}, author = {Garcia-Guerra, A and Ellerington, R and Gaitzsch, J and Bath, J and Kye, M and Varela, MA and Battaglia, G and Wood, MJA and Manzano, R and Rinaldi, C and Turberfield, AJ}, title = {A modular RNA delivery system comprising spherical nucleic acids built on endosome-escaping polymeric nanoparticles.}, journal = {Nanoscale advances}, volume = {5}, number = {11}, pages = {2941-2949}, pmid = {37260495}, issn = {2516-0230}, support = {205162/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; MC_PC_16056/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Nucleic acid therapeutics require delivery systems to reach their targets. Key challenges to be overcome include avoidance of accumulation in cells of the mononuclear phagocyte system and escape from the endosomal pathway. Spherical nucleic acids (SNAs), in which a gold nanoparticle supports a corona of oligonucleotides, are promising carriers for nucleic acids with valuable properties including nuclease resistance, sequence-specific loading and control of receptor-mediated endocytosis. However, SNAs accumulate in the endosomal pathway and are thus vulnerable to lysosomal degradation or recycling exocytosis. Here, an alternative SNA core based on diblock copolymer PMPC25-PDPA72 is investigated. This pH-sensitive polymer self-assembles into vesicles with an intrinsic ability to escape endosomes via osmotic shock triggered by acidification-induced disassembly. DNA oligos conjugated to PMPC25-PDPA72 molecules form vesicles, or polymersomes, with DNA coronae on luminal and external surfaces. Nucleic acid cargoes or nucleic acid-tagged targeting moieties can be attached by hybridization to the coronal DNA. These polymeric SNAs are used to deliver siRNA duplexes against C9orf72, a genetic target with therapeutic potential for amyotrophic lateral sclerosis, to motor neuron-like cells. By attaching a neuron-specific targeting peptide to the PSNA corona, effective knock-down is achieved at doses of 2 particles per cell.}, } @article {pmid37259916, year = {2023}, author = {Berth, SH and Lloyd, TE}, title = {Disruption of axonal transport in neurodegeneration.}, journal = {The Journal of clinical investigation}, volume = {133}, number = {11}, pages = {}, pmid = {37259916}, issn = {1558-8238}, support = {K08 NS118123/NS/NINDS NIH HHS/United States ; R01 NS082563/NS/NINDS NIH HHS/United States ; R01 NS094239/NS/NINDS NIH HHS/United States ; P30 NS050274/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Axonal Transport/physiology ; *Neurodegenerative Diseases/metabolism ; Neurons/metabolism ; *Alzheimer Disease/metabolism ; *Parkinson Disease/metabolism ; }, abstract = {Neurons are markedly compartmentalized, which makes them reliant on axonal transport to maintain their health. Axonal transport is important for anterograde delivery of newly synthesized macromolecules and organelles from the cell body to the synapse and for the retrograde delivery of signaling endosomes and autophagosomes for degradation. Dysregulation of axonal transport occurs early in neurodegenerative diseases and plays a key role in axonal degeneration. Here, we provide an overview of mechanisms for regulation of axonal transport; discuss how these mechanisms are disrupted in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, hereditary spastic paraplegia, amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease; and discuss therapeutic approaches targeting axonal transport.}, } @article {pmid37259156, year = {2023}, author = {Ionescu, A and Altman, T and Perlson, E}, title = {Looking for answers far away from the soma-the (un)known axonal functions of TDP-43, and their contribution to early NMJ disruption in ALS.}, journal = {Molecular neurodegeneration}, volume = {18}, number = {1}, pages = {35}, pmid = {37259156}, issn = {1750-1326}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; Axons/metabolism ; *DNA-Binding Proteins/metabolism ; *Neurodegenerative Diseases/metabolism ; Neuromuscular Junction ; }, abstract = {Axon degeneration and Neuromuscular Junction (NMJ) disruption are key pathologies in the fatal neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). Despite accumulating evidence that axons and NMJs are impacted at a very early stage of the disease, current knowledge about the mechanisms leading to their degeneration remains elusive. Cytoplasmic mislocalization and accumulation of the protein TDP-43 are considered key pathological hallmarks of ALS, as they occur in ~ 97% of ALS patients, both sporadic and familial. Recent studies have identified pathological accumulation of TDP-43 in intramuscular nerves of muscle biopsies collected from pre-diagnosed, early symptomatic ALS patients. These findings suggest a gain of function for TDP-43 in axons, which might facilitate early NMJ disruption. In this review, we dissect the process leading to axonal TDP-43 accumulation and phosphorylation, discuss the known and hypothesized roles TDP-43 plays in healthy axons, and review possible mechanisms that connect TDP-43 pathology to the axon and NMJ degeneration in ALS.}, } @article {pmid37258447, year = {2023}, author = {Liu, J and Duan, W and Deng, Y and Zhang, Q and Li, R and Long, J and Ahmed, W and Gu, C and Qiu, Y and Cai, H and Hu, Y and Chen, L}, title = {New Insights into Molecular Mechanisms Underlying Neurodegenerative Disorders.}, journal = {Journal of integrative neuroscience}, volume = {22}, number = {3}, pages = {58}, doi = {10.31083/j.jin2203058}, pmid = {37258447}, issn = {0219-6352}, support = {2022YFA1104900//National Key R&D Program of China/ ; 2022YFA1104904//National Key R&D Program of China/ ; 2021A1515010013//Natural Science Foundation of Guangdong Province/ ; 2021ZDZX2011//Department of Education of Guangdong Province/ ; 20221275//Traditional Chinese Medicine Bureau of Guangdong Province/ ; 202201011760//Guangzhou Municipal Science and Technology Project/ ; 1202101003//President Foundation of Integrated Hospital of Traditional Chinese Medicine of Southern Medical University/ ; 1202103007//President Foundation of Integrated Hospital of Traditional Chinese Medicine of Southern Medical University/ ; }, mesh = {Humans ; Quality of Life ; *Neurodegenerative Diseases/metabolism ; *Alzheimer Disease/metabolism ; *Parkinson Disease/etiology/therapy/metabolism ; Oxidative Stress ; }, abstract = {As a large and heterogeneous group of disorders, neurodegenerative diseases are characterized by the progressive loss of structure or function in neurons, finally leading to neuronal death. Neurodegenerative diseases cause serious threat to a patient's quality of life and the most common are Alzheimer's disease and Parkinson's disease. Currently, little is known of the detailed etiology of these disorders; as such, there are no effective treatments available. Furthermore, the lack of targeted, effective, and resolvable therapy for neurodegenerative diseases, represents an expanding research field for the discovery of new therapeutic strategies. Investigations of the potential pathogenesis of neurodegenerative diseases will become the basis of preventing the occurrence and development of neurodegenerative diseases and finding effective therapies. Existing theories and mechanisms, such as genetic and environmental factors, abnormal protein accumulation, and oxidative stress, are intricately associated with each other. However, there is no molecular theory that can entirely explain the pathological processes underlying neurodegenerative diseases. Due to the development of experimental technology and the support of multidisciplinary integration, it has been possible to perform more in-depth research on potential targets for neurodegenerative diseases and there have been many exciting discoveries in terms of original theories and underlying mechanisms. With this review, we intend to review the existing literature and provide new insights into the molecular mechanisms underlying neurodegenerative diseases.}, } @article {pmid37257946, year = {2023}, author = {Idera, A and Sharkey, LM and Kurauchi, Y and Kadoyama, K and Paulson, HL and Katsuki, H and Seki, T}, title = {Wild-type and pathogenic forms of ubiquilin 2 differentially modulate components of the autophagy-lysosome pathways.}, journal = {Journal of pharmacological sciences}, volume = {152}, number = {3}, pages = {182-192}, doi = {10.1016/j.jphs.2023.05.002}, pmid = {37257946}, issn = {1347-8648}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Adaptor Proteins, Signal Transducing/genetics ; Autophagy/genetics ; Mutation ; Autophagy-Related Proteins/genetics/metabolism ; Transcription Factors/metabolism ; Lysosomes/metabolism/pathology ; }, abstract = {Missense mutations of ubiquilin 2 (UBQLN2) have been identified to cause X-linked amyotrophic lateral sclerosis (ALS). Proteasome-mediated protein degradation is reported to be impaired by ALS-associated mutations of UBQLN2. However, it remains unknown how these mutations affect autophagy-lysosome protein degradation, which consists of macroautophagy (MA), microautophagy (mA), and chaperone-mediated autophagy (CMA). Using a CMA/mA fluorescence reporter we found that overexpression of wild-type UBQLN2 impairs CMA. Conversely, knockdown of endogenous UBQLN2 increases CMA activity, suggesting that normally UBQLN2 negatively regulates CMA. ALS-associated mutant forms of UBQLN2 exacerbate this impairment of CMA. Using cells stably transfected with wild-type or ALS-associated mutant UBQLN2, we further determined that wild-type UBQLN2 increased the ratio of LAMP2A (a CMA-related protein) to LAMP1 (a lysosomal protein). This could represent a compensatory reaction to the impairment of CMA by wild-type UBQLN2. However, ALS-associated mutant UBQLN2 failed to show this compensation, exacerbating the impairment of CMA by mutant UBQLN2. We further demonstrated that ALS-associated mutant forms of UBQLN2 also impair MA, but wild-type UBQLN2 does not. These results support the view that ALS-associated mutant forms of UBQLN2 impair both CMA and MA which may contribute to the neurodegeneration observed in patients with UBQLN2-mediated ALS.}, } @article {pmid37257710, year = {2023}, author = {Kim, S and Yang, M and Ku, B and Cha, E and Seo, W and Son, I and Kang, H and Kim, D and Song, B and Yang, CS and Kim, S}, title = {Efficacy of mecasin for treatment of amyotrophic lateral sclerosis: A phase IIa multicenter randomized double-blinded placebo-controlled trial.}, journal = {Journal of ethnopharmacology}, volume = {315}, number = {}, pages = {116670}, doi = {10.1016/j.jep.2023.116670}, pmid = {37257710}, issn = {1872-7573}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Double-Blind Method ; Vital Capacity ; Disease Progression ; Pain ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder characterized by progressive paralysis of voluntary muscles. Mecasin, the extract of modified jakyakgamchobuja-tang-a herbal preparation comprising of Radix Paeoniae Alba, Radix Glycyrrhizae, Radix Aconiti Lateralis Preparata, Radix Salviae Miltiorrhizae, Rhizoma Gastrodiae, Radix Polygalae, Curcuma Root, Fructus Chaenomelis, and Rhizoma Atractylodis Japonicae-shows neuroprotective and anti-neuroinflammatory effects and alleviates the symptoms in patients with ALS.

AIM OF THE STUDY: This trial aimed to evaluate the efficacy and safety of mecasin in these patients.

MATERIAL AND METHODS: Patients were randomized to receive mecasin 1.6 g daily, mecasin 2.4 g daily, or placebo for 12 weeks. The primary endpoint was the Korean version of ALS Functional Rating Scale-Revised (K-ALSFRS-R) score. The secondary endpoints were muscular atrophy measurements, pulmonary function test results, creatine kinase levels, body weight, safety, and scores of the Medical Research Council (MRC) scale for muscle strength; Visual Analog Scale for pain (VAS pain); Hamilton Rating Scale for Depression; and Fatigue Severity Scale.

RESULTS: Among the 30 patients randomized, 24 completed the follow-up. Significant between-group differences were detected in the primary endpoint using the omnibus F-test. The changes in the K-ALSFRS-R score between 12 weeks and baseline were -0·25, -1·32, and -2·78 in the mecasin 1.6 g, mecasin 2.4 g, and placebo groups, respectively. The difference in the K-ALSFRS-R score between the mecasin 1.6 g and placebo groups was 2·53 points (95% confidence interval [CI]: 0·61-4·45), and that between the 2.4 g and placebo groups was 1·46 points (95% CI: 0·48-3·40). However, no significant differences were detected in the secondary endpoints (MRC: dyspnea, p = 0·139; VAS pain, p = 0·916; forced vital capacity, p = 0·373). The incidence of adverse events was similar and low in all groups.

CONCLUSIONS: Mecasin may retard symptomatic progression without major adverse effects. A phase IIb study to evaluate its long-term effects in ALS is ongoing.}, } @article {pmid37257665, year = {2023}, author = {Lazo, PA and Morejón-García, P}, title = {VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases.}, journal = {Neurobiology of disease}, volume = {183}, number = {}, pages = {106172}, doi = {10.1016/j.nbd.2023.106172}, pmid = {37257665}, issn = {1095-953X}, mesh = {Humans ; Coiled Bodies/metabolism ; Syndrome ; Mutation ; *Motor Neuron Disease/metabolism ; Intracellular Signaling Peptides and Proteins/genetics ; *Charcot-Marie-Tooth Disease/genetics ; }, abstract = {Distal hereditary neuropathies and neuro motor diseases are complex neurological phenotypes associated with pathogenic variants in a large number of genes, but in some the origin is unknown. Recently, rare pathogenic variants of the human VRK1 gene have been associated with these neurological phenotypes. All VRK1 pathogenic variants are recessive, and their clinical presentation occurs in either homozygous or compound heterozygous patients. The pathogenic VRK1 gene pathogenic variants are located in three clusters within the protein sequence. The main, and initial, shared clinical phenotype among VRK1 pathogenic variants is a distal progressive loss of motor and/or sensory function, which includes diseases such as spinal muscular atrophy, Charcot-Marie-Tooth, amyotrophic lateral sclerosis and hereditary spastic paraplegia. In most cases, symptoms start early in infancy, or in utero, and are slowly progressive. Additional neurological symptoms vary among non-related patients, probably because of their different VRK1 variants and their genetic background. The underlying common pathogenic mechanism, by its functional impairment, is a likely consequence of the roles that the VRK1 protein plays in the regulation on the stability and assembly of Cajal bodies, which affect RNA maturation and processing, neuronal migration of RNPs along axons, and DNA-damage responses. Alterations of these processes are associated with several neuro sensory or motor syndromes. The clinical heterogeneity of the neurological phenotypes associated with VRK1 is a likely consequence of the protein complexes in which VRK1 is integrated, which include several proteins known to be associated with Cajal bodies and DNA damage responses. Several hereditary distal neurological diseases are a consequence of pathogenic variants in genes that alter these cellular functions. We conclude that VRK1-related distal hereditary neuropathies and motor neuron diseases represent a novel subgroup of Cajal body related neurological syndromes.}, } @article {pmid37257467, year = {2023}, author = {Fidelix, EC and Santana, GC and Barros, DMDS and Dourado Junior, MET}, title = {Telehealth for amyotrophic lateral sclerosis in a multidisciplinary service in a Brazilian reference center.}, journal = {Arquivos de neuro-psiquiatria}, volume = {81}, number = {5}, pages = {469-474}, pmid = {37257467}, issn = {1678-4227}, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/therapy ; Brazil ; Retrospective Studies ; *COVID-19 ; *Telemedicine ; }, abstract = {BACKGROUND: Telehealth has been used in the treatment of different diseases, and it has been shown to provide benefits for patients with amyotrophic lateral sclerosis (ALS). Due to the social distancing measures put into effect during the coronavirus disease 2019 (COVID-19) pandemic, there was an urgent need for telehealth to ensure the provision of healthcare.

OBJECTIVE: To evaluate the feasibility of telehealth for the provision of multidisciplinary ALS care, and to assess its acceptability among patients and caregivers.

METHODS: We conducted a retrospective cohort study in which multidisciplinary evaluations were performed using the Teleconsulta platform. The patients included had ALS and at least one in-person clinical evaluation. The patients and the caregivers answered satisfaction questionnaires.

RESULTS: The sample was composed of 46 patients, 32 male and 14 female subjects. The average distance from their residences to the reference services was of 115 km. Respiratory adjustment was the most addressed topic.

CONCLUSION: The strategy is viable and well accepted in terms of satisfaction. It was even more positive for patients in advanced stages of the disease or for those living far from the referral center.}, } @article {pmid37256664, year = {2023}, author = {Castillo Padrós, MR and Pastor, N and Altarriba Paracolls, J and Mosquera Peña, M and Pergolizzi, D and Salvador Vergès, À}, title = {A Smart System for Remote Monitoring of Patients in Palliative Care (HumanITcare Platform): Mixed Methods Study.}, journal = {JMIR formative research}, volume = {7}, number = {}, pages = {e45654}, pmid = {37256664}, issn = {2561-326X}, abstract = {BACKGROUND: Due to the complexities of advanced illnesses and their treatments, it can be difficult for patients in palliative care to maintain their quality of life. Telemedicine interventions in chronic disease management engage patients in their care, provide continuous follow-up by their health care providers, identify symptoms earlier, and allow a quick response to illness-related decline.

OBJECTIVE: We aimed to detail and reflect on the design of an app and evaluate its feasibility to monitor the clinical situation of patients with advanced illnesses.

METHODS: This study used a mixed methods design using qualitative methods to inform app development and design and quantitative methods for data collection and analysis of patient evaluations. Palliative care units in 2 Spanish university hospitals (Nuestra Señora de la Candelaria in Santa Cruz de Tenerife and University Hospital Complex of Ferrol in A Coruña) carried out a literature review, designed the study protocol, and obtained approval from the Ethics Committee from June to December 2020. In addition, focus group meetings were held, and the design and technical development of the app were elaborated on and subsequently presented in the participating palliative care units. From January to March 2021, the app was made public on the App Store and Play Store, and a pilot study with patients was carried out in April to September 2021.

RESULTS: Six focus group meetings were held that included doctors, nurses, app developers, technology consultants, and sponsors. In addition, the technology consultants presented their results 3 times in the participating palliative care units to obtain feedback. After the app's final design, it was possible to publish it on the usual servers and begin its evaluation in patients (n=60, median age 72 years). Sixty percent (n=36) of the participants were women and 40% (n=24) were men. The most prevalent advanced pathology was cancer (n=46, 76%), followed by other diseases (n=7, 12%) and amyotrophic lateral sclerosis (n=5, 8%). Seventy percent (n=42) of the patients were already in follow-up prior to the start of the study, while 30% (n=18) were included at the start of their follow-up. The information in the app was collected and entered by relatives or caregivers in 60% (n=36) of the cases. The median follow-up was 52 (IQR 14-104) days. In all, 69% (n=41) had a follow-up >30 days (10 were deceased and 9 were missing data). The use of the different sections of the app ranged from 37% (n=22) for the glycemic record to 90% (n=54) for the constipation scale). Patients and caregivers were delighted with its ease of use and usefulness.

CONCLUSIONS: Incorporating an intelligent remote patient monitoring system in clinical practice for patients in palliative care can improve access to health services and provide more information to professionals.}, } @article {pmid37256332, year = {2023}, author = {Tayebi, H and Azadnajafabad, S and Maroufi, SF and Pour-Rashidi, A and Khorasanizadeh, M and Faramarzi, S and Slavin, KV}, title = {Applications of brain-computer interfaces in neurodegenerative diseases.}, journal = {Neurosurgical review}, volume = {46}, number = {1}, pages = {131}, pmid = {37256332}, issn = {1437-2320}, mesh = {Humans ; *Brain-Computer Interfaces ; Electroencephalography/methods ; *Neurodegenerative Diseases/therapy ; Brain ; Central Nervous System ; }, abstract = {Brain-computer interfaces (BCIs) provide the central nervous system with channels of direct communication to the outside world, without having to go through the peripheral nervous system. Neurodegenerative diseases (NDs) are notoriously incurable and burdensome medical conditions that will result in progressive deterioration of the nervous system. The applications of BCIs in NDs have been studied for decades now through different approaches, resulting in a considerable amount of literature in all related areas. In this study, we begin by introducing BCIs and proceed by explaining the principles of BCI-based neurorehabilitation. Then, we go through four specific types of NDs, including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and spinal muscular atrophy, and review some of the applications of BCIs in the neural rehabilitation of these diseases. We conclude with a discussion of the characteristics, challenges, and future possibilities of research in the field. Going through the uses of BCIs in NDs, we can see that approaches and strategies employed to tackle the wide range of limitations caused by NDs are numerous and diverse. Furthermore, NDs can fall under different categories based on the target area of neurodegeneration and thus require different methods of BCI-based rehabilitation. In recent years, neurotechnology companies have substantially invested in research on BCIs, focusing on commercializing BCIs and bringing BCI-based technologies from bench to bedside. This can mean the beginning of a new era for BCI-based neurorehabilitation, with an anticipated spike in interest among researchers, practitioners, engineers, and entrepreneurs alike.}, } @article {pmid37255643, year = {2023}, author = {Saucedo, S and Katsuura, Y}, title = {Preventing Unnecessary Surgery in Patients Presenting for Orthopedic Spine Surgery: Literature Review and Case Series.}, journal = {Journal of orthopaedic case reports}, volume = {13}, number = {5}, pages = {76-81}, pmid = {37255643}, issn = {2250-0685}, abstract = {INTRODUCTION: Almost 40% of patients who have been diagnosed with amyotrophic lateral sclerosis (ALS) may have been misdiagnosed. Some of these patients may have undergone surgical procedures to address symptoms that could have actually be early indications of ALS.Up to 40% of patients diagnosed with amyotrophic lateral sclerosis (ALS) have received an incorrect diagnosis, a number undergo surgical treatment for signs and symptoms that can be attributed to early manifestations of ALS. Initial presentation of ALS is elusive and is often mistaken for other disorders originating from the cervical spine such as cervical radiculopathy or myelopathy. Such incorrect diagnoses often display symptoms that fall within the scope of an orthopedic spine surgeon, who can remedy said diagnoses. Given that a diagnosis of ALS is grave, it is crucial to establish a definitive diagnosis quickly, without unnecessary surgery. The objective of this series is to highlight patients who were referred by other physicians for spine surgery to remedy potential side effects of cervical myelopathy but were ultimately diagnosed with ALS.

CASE REPORT: Case 1: A 46-year-old Caucasian woman with carpal tunnel syndrome and cervical intervertebral disc degeneration. Case 2: A 77-year-old African American man with a history of arthritis, GERD, a herniated disc, claw hand, hypertension, prostate disease, and general weakness. Case 3: A 74-year-old Caucasian woman with a background history of hypertension, dyslipidemia, hypothyroidism, osteopenia, and foot drop.

CONCLUSION: In orthopedic spine surgery, ALS could be an easily misdiagnosed disease, which can be mistaken for cervical spondylosis, cervical radiculopathy, cervical myelopathy, lumbar radiculopathy, and lumbar myelopathy; it is of note to be aware of how ALS may initially present. It is imperative for the orthopedic spine surgeon to consider ALS with patients presenting with progressive unilateral/bilateral upper extremity weakness.}, } @article {pmid37254833, year = {2023}, author = {White, S and O'Cathain, A and Halliday, V and Croot, L and McDermott, CJ}, title = {Factors influencing decisions people with motor neuron disease make about gastrostomy placement and ventilation: A qualitative evidence synthesis.}, journal = {Health expectations : an international journal of public participation in health care and health policy}, volume = {26}, number = {4}, pages = {1418-1435}, pmid = {37254833}, issn = {1369-7625}, support = {NIHR301592//National Institute for Health and Care Research/ ; }, mesh = {Humans ; *Gastrostomy/psychology ; Quality of Life ; *Motor Neuron Disease/therapy/complications/psychology ; Health Personnel ; Caregivers/psychology ; }, abstract = {BACKGROUND: People with motor neuron disease (pwMND) are routinely offered gastrostomy feeding tube placement and (non-invasive and invasive) ventilation to manage the functional decline associated with the disease. This study aimed to synthesise the findings from the qualitative literature to understand how individual, clinical team and organisational factors influence pwMND decisions about these interventions.

METHODS: The study design was guided by the enhancing transparency in reporting the synthesis of qualitative research (ENTREC) statement. The search of five bibliography databases and an extensive supplementary search strategy identified 27 papers that included qualitative accounts of pwMND, caregivers and healthcare professionals' (HCPs) experiences of making decisions about gastrostomy and ventilation. The findings from each study were included in a thematic synthesis.

FINDINGS: Making decisions about interventions is an emotional rather than simply a functional issue for pwMND. The interventions can signal an end to normality, and increasing dependence, where pwMND consider the balance between quality of life and extending survival. Interactions with multiple HCPs and caregivers can influence the process of decision-making and the decisions made. These interactions contribute to the autonomy pwMND are able to exert during decision-making. HCPs can both promote and threaten pwMND perceived agency over decisions through how they approach discussions about these interventions. Though there is uncertainty over the timing of interventions, pwMND who agree to interventions report reaching a tipping point where they accept the need for change.

CONCLUSION: Discussion of gastrostomy and ventilation options generate an emotional response in pwMND. Decisions are the consequence of interactions with multiple external agents, including HCPs treading a complex ethical path when trying to improve health outcomes while respecting pwMND right to autonomy. Future decision support interventions that address the emotional response and seek to support autonomy have the potential to enable pwMND to make informed and timely decisions about gastrostomy placement and ventilation.

The lead author collaborated with several patient and participant involvement (PPI) groups with regards to the conceptualisation and design of this project. Decisions that have been influenced by discussions with multiple PPI panels include widening the scope of decisions about ventilation in addition to gastrostomy placement and the perceptions of all stakeholders involved (i.e., pwMND, caregivers and HCPs).}, } @article {pmid37254449, year = {2023}, author = {Shefner, JM and Al-Chalabi, A and Andrews, JA and Chio, A and De Carvalho, M and Cockroft, BM and Corcia, P and Couratier, P and Cudkowicz, ME and Genge, A and Hardiman, O and Heiman-Patterson, T and Henderson, RD and Ingre, C and Jackson, CE and Johnston, W and Lechtzin, N and Ludolph, A and Maragakis, NJ and Miller, TM and Mora Pardina, JS and Petri, S and Simmons, Z and Van Den Berg, LH and Zinman, L and Kupfer, S and Malik, FI and Meng, L and Simkins, TJ and Wei, J and Wolff, AA and Rudnicki, SA}, title = {COURAGE-ALS: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {24}, number = {5-6}, pages = {523-534}, doi = {10.1080/21678421.2023.2216223}, pmid = {37254449}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; *Courage ; Double-Blind Method ; Probability ; Disease Progression ; }, abstract = {Objective: To determine the target population and optimize the study design of the phase 3 clinical trial evaluating reldesemtiv in participants with amyotrophic lateral sclerosis (ALS).Methods: We evaluated the phase 2 study of reldesemtiv, FORTITUDE-ALS, to inform eligibility criteria and design features that would increase trial efficiency and reduce participant burden of the phase 3 trial.Results: In FORTITUDE-ALS, the effect of reldesemtiv was particularly evident among participants in the intermediate- and fast-progressing tertiles for pre-study disease progression. These participants most often had symptom onset ≤24 months and an ALS Functional Rating Scale-Revised (ALSFRS-R) total score ≤44 at baseline. Compared with the overall FORTITUDE-ALS population, the subgroup meeting these criteria declined by fewer ALSFRS-R points at 12 weeks (difference of least-squares mean [SE] versus placebo 1.84 [0.49] and 0.87 [0.35] for the overall population). These inclusion criteria will be used for the phase 3 clinical trial, COURAGE-ALS, in which the primary outcome is the change in ALSFRS-R total score at week 24. We also measure durable medical equipment use and evaluate strength in muscles expected to change rapidly. To reduce participant burden, study visits are often remote, and strength evaluation is simplified to reduce time and effort.Conclusions: In COURAGE-ALS, the phase 3 clinical trial to evaluate reldesemtiv, the sensitivity of detecting a potential treatment effect may be increased by defining eligibility criteria that limit the proportion of participants who have slower disease progression. Implementing remote visits and simplifying strength measurements will reduce both site and participant burden.ClinicalTrials.gov identifiers: NCT03160898 (FORTITUDE-ALS) and NCT04944784 (COURAGE-ALS).}, } @article {pmid37253318, year = {2023}, author = {Liu, W and Ma, R and Sun, C and Xu, Y and Liu, Y and Hu, J and Ma, Y and Wang, D and Wen, D and Yu, Y}, title = {Implications from proteomic studies investigating circadian rhythm disorder-regulated neurodegenerative disease pathology.}, journal = {Sleep medicine reviews}, volume = {70}, number = {}, pages = {101789}, doi = {10.1016/j.smrv.2023.101789}, pmid = {37253318}, issn = {1532-2955}, mesh = {Humans ; *Neurodegenerative Diseases ; Proteomics ; *Parkinson Disease/metabolism ; *Alzheimer Disease ; *Chronobiology Disorders ; Circadian Rhythm/genetics ; }, abstract = {Neurodegenerative diseases (NDs) affect 15% of the world's population and are becoming an increasingly common cause of morbidity and mortality worldwide. Circadian rhythm disorders (CRDs) have been reported to be involved in the pathogenic regulation of various neurologic diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis. Proteomic technology is helpful to explore treatment targets for CRDs in patients with NDs. Here, we review the key differentially expressed (DE) proteins identified in previous proteomic studies investigating NDs, CRDs and associated models and the related pathways identified by enrichment analysis. Furthermore, we summarize the advantages and disadvantages of the above studies and propose new proteomic technologies for the precise study of circadian disorder-mediated regulation of ND pathology. This review provides a theoretical and technical reference for the precise study of circadian disorder-mediated regulation of ND pathology.}, } @article {pmid37252342, year = {2023}, author = {Wajnberg, G and Allain, EP and Roy, JW and Srivastava, S and Saucier, D and Morin, P and Marrero, A and O'Connell, C and Ghosh, A and Lewis, SM and Ouellette, RJ and Crapoulet, N}, title = {Application of annotation-agnostic RNA sequencing data analysis tools for biomarker discovery in liquid biopsy.}, journal = {Frontiers in bioinformatics}, volume = {3}, number = {}, pages = {1127661}, pmid = {37252342}, issn = {2673-7647}, abstract = {RNA sequencing analysis is an important field in the study of extracellular vesicles (EVs), as these particles contain a variety of RNA species that may have diagnostic, prognostic and predictive value. Many of the bioinformatics tools currently used to analyze EV cargo rely on third-party annotations. Recently, analysis of unannotated expressed RNAs has become of interest, since these may provide complementary information to traditional annotated biomarkers or may help refine biological signatures used in machine learning by including unknown regions. Here we perform a comparative analysis of annotation-free and classical read-summarization tools for the analysis of RNA sequencing data generated for EVs isolated from persons with amyotrophic lateral sclerosis (ALS) and healthy donors. Differential expression analysis and digital-droplet PCR validation of unannotated RNAs also confirmed their existence and demonstrates the usefulness of including such potential biomarkers in transcriptome analysis. We show that find-then-annotate methods perform similarly to standard tools for the analysis of known features, and can also identify unannotated expressed RNAs, two of which were validated as overexpressed in ALS samples. We demonstrate that these tools can therefore be used for a stand-alone analysis or easily integrated into current workflows and may be useful for re-analysis as annotations can be integrated post hoc.}, } @article {pmid37252191, year = {2023}, author = {Maruyama, T and Tanabe, S and Uyeda, A and Suzuki, T and Muramatsu, R}, title = {Free fatty acids support oligodendrocyte survival in a mouse model of amyotrophic lateral sclerosis.}, journal = {Frontiers in cellular neuroscience}, volume = {17}, number = {}, pages = {1081190}, pmid = {37252191}, issn = {1662-5102}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the white matter degeneration. Although changes in blood lipids are involved in the pathogenesis of neurological diseases, the pathological role of blood lipids in ALS remains unclear.

METHODS AND RESULTS: We performed lipidome analysis on the plasma of ALS model mice, mutant superoxide dismutase 1 (SOD1[G93A]) mice, and found that the concentration of free fatty acids (FFAs), including oleic acid (OA) and linoleic acid (LA), decreased prior to disease onset. An in vitro study revealed that OA and LA directly inhibited glutamate-induced oligodendrocytes cell death via free fatty acid receptor 1 (FFAR1). A cocktail containing OA/LA suppressed oligodendrocyte cell death in the spinal cord of SOD1[G93A] mice.

DISCUSSION: These results suggested that the reduction of FFAs in the plasma is a pathogenic biomarker for ALS in the early stages, and supplying a deficiency in FFAs is a potential therapeutic approach for ALS by preventing oligodendrocyte cell death.}, } @article {pmid37251807, year = {2023}, author = {Allen, SP and Al Sultan, A and Kabucho Kibirige, E and Tonkiss, E and Hamer, KJ and Castelli, LM and Lin, YH and Roscoe, S and Stefanidis, N and Mead, RJ and Highley, JR and Cooper-Knock, J and Hautbergue, GM and Heath, PR and Kirby, J and Shaw, PJ}, title = {A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1151848}, pmid = {37251807}, issn = {1663-4365}, support = {/WT_/Wellcome Trust/United Kingdom ; ALLEN/OCT15/956-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {A p.Y374X truncation in TARDBP was recently shown to reduce expression of TDP43 in fibroblasts isolated from ALS cases. In this follow up study focused on assessing the downstream phenotypic consequences of loss of TDP43 in the context of the truncation, we have shown a striking effect on the fibroblast metabolic profile. Phenotypic metabolic screening uncovered a distinct metabolic profile in TDP43-Y374X fibroblasts compared to controls, which was driven by alterations in key metabolic checkpoint intermediates including pyruvate, alpha-ketoglutarate and succinate. These metabolic alterations were confirmed using transcriptomics and bioenergetic flux analysis. These data suggest that TDP43 truncation directly compromises glycolytic and mitochondrial function, identifying potential therapeutic targets for mitigating the effects of TDP43-Y374X truncation.}, } @article {pmid37250416, year = {2023}, author = {Wang, H and Guan, L and Deng, M}, title = {Recent progress of the genetics of amyotrophic lateral sclerosis and challenges of gene therapy.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1170996}, pmid = {37250416}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons in the brain and spinal cord. The causes of ALS are not fully understood. About 10% of ALS cases were associated with genetic factors. Since the discovery of the first familial ALS pathogenic gene SOD1 in 1993 and with the technology advancement, now over 40 ALS genes have been found. Recent studies have identified ALS related genes including ANXA11, ARPP21, CAV1, C21ORF2, CCNF, DNAJC7, GLT8D1, KIF5A, NEK1, SPTLC1, TIA1, and WDR7. These genetic discoveries contribute to a better understanding of ALS and show the potential to aid the development of better ALS treatments. Besides, several genes appear to be associated with other neurological disorders, such as CCNF and ANXA11 linked to FTD. With the deepening understanding of the classic ALS genes, rapid progress has been made in gene therapies. In this review, we summarize the latest progress on classical ALS genes and clinical trials for these gene therapies, as well as recent findings on newly discovered ALS genes.}, } @article {pmid37250330, year = {2023}, author = {Pang, W and Hu, F}, title = {C9ORF72 suppresses JAK-STAT mediated inflammation.}, journal = {iScience}, volume = {26}, number = {5}, pages = {106579}, pmid = {37250330}, issn = {2589-0042}, abstract = {Hexanucleotide repeat expansion in the gene C9ORF72 is a leading cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). C9ORF72 deficiency leads to severe inflammatory phenotypes in mice, but exactly how C9ORF72 regulates inflammation remains to be fully elucidated. Here, we report that loss of C9ORF72 leads to the hyperactivation of the JAK-STAT pathway and an increase in the protein levels of STING, a transmembrane adaptor protein involved in immune signaling in response to cytosolic DNA. Treatment with a JAK inhibitor rescues the enhanced inflammatory phenotypes caused by C9ORF72 deficiency in cell culture and mice. Furthermore, we showed that the ablation of C9ORF72 results in compromised lysosome integrity, which could contribute to the activation of the JAK/STAT-dependent inflammatory responses. In summary, our study identifies a mechanism by which C9ORF72 regulates inflammation, which might facilitate therapeutic development for ALS/FTLD with C9ORF72 mutations.}, } @article {pmid37250128, year = {2023}, author = {Mazzaro, A and Vita, V and Ronfini, M and Casola, I and Klein, A and Dobrowolny, G and Sorarù, G and Musarò, A and Mongillo, M and Zaglia, T}, title = {Sympathetic neuropathology is revealed in muscles affected by amyotrophic lateral sclerosis.}, journal = {Frontiers in physiology}, volume = {14}, number = {}, pages = {1165811}, pmid = {37250128}, issn = {1664-042X}, abstract = {Rationale: The anatomical substrate of skeletal muscle autonomic innervation has remained underappreciated since it was described many decades ago. As such, the structural and functional features of muscle sympathetic innervation are largely undetermined in both physiology and pathology, mainly due to methodological limitations in the histopathological analysis of small neuronal fibers in tissue samples. Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease which mainly targets motor neurons, and despite autonomic symptoms occurring in a significant fraction of patients, peripheral sympathetic neurons (SNs) are generally considered unaffected and, as such, poorly studied. Purpose: In this research, we compared sympathetic innervation of normal and ALS muscles, through structural analysis of the sympathetic network in human and murine tissue samples. Methods and Results: We first refined tissue processing to circumvent methodological limitations interfering with the detection of muscle sympathetic innervation. The optimized "Neuro Detection Protocol" (NDP) was validated in human muscle biopsies, demonstrating that SNs innervate, at high density, both blood vessels and skeletal myofibers, independent of the fiber metabolic type. Subsequently, NDP was exploited to analyze sympathetic innervation in muscles of SOD1[G93A] mice, a preclinical ALS model. Our data show that ALS murine muscles display SN denervation, which has already initiated at the early disease stage and worsened during aging. SN degeneration was also observed in muscles of MLC/SOD1[G93A] mice, with muscle specific expression of the SOD1[G93A] mutant gene. Notably, similar alterations in SNs were observed in muscle biopsies from an ALS patient, carrying the SOD1[G93A] mutation. Conclusion: We set up a protocol for the analysis of murine and, more importantly, human muscle sympathetic innervation. Our results indicate that SNs are additional cell types compromised in ALS and suggest that dysfunctional SOD1[G93A] muscles affect their sympathetic innervation.}, } @article {pmid37249795, year = {2023}, author = {Patel, RB and Bajpai, AK and Thirumurugan, K}, title = {Differential Expression of MicroRNAs and Predicted Drug Target in Amyotrophic Lateral Sclerosis.}, journal = {Journal of molecular neuroscience : MN}, volume = {73}, number = {6}, pages = {375-390}, pmid = {37249795}, issn = {1559-1166}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/diagnosis ; *Neurodegenerative Diseases ; *Curcumin ; Molecular Docking Simulation ; *MicroRNAs/genetics/metabolism ; Gene Expression Profiling ; }, abstract = {ALS (Amyotrophic Lateral Sclerosis) is a rare type of neurodegenerative disease. It shows progressive degradation of motor neurons in the brain and spinal cord. At present, there is no treatment available that can completely cure ALS. The available treatments can only increase a patient's life span by a few months. Recently, microRNAs (miRNAs), a sub-class of small non-coding RNAs have been shown to play an essential role in the diagnosis, prognosis, and therapy of ALS. Our study focuses on analyzing differential miRNA profiles and predicting drug targets in ALS using bioinformatics and computational approach. The study identifies eight highly differentially expressed miRNAs in ALS patients, four of which are novel. We identified 42 hub genes for these eight highly expressed miRNAs with Amyloid Precursor Protein (APP) as a candidate gene among them for highly expressed down-regulated miRNA, hsa-miR-455-3p using protein-protein interaction network and Cytoscape analysis. A novel association has been found between hsa-miR-455-3p/APP/serotonergic pathway using KEGG pathway analysis. Also, molecular docking studies have revealed curcumin as a potential drug target that may be used for the treatment of ALS. Thus, the present study has identified four novel miRNA biomarkers: hsa-miR-3613-5p, hsa-miR-24, hsa-miR-3064-5p, and hsa-miR-4455. There is a formation of a novel axis, hsa-miR-455-3p/APP/serotonergic pathway, and curcumin is predicted as a potential drug target for ALS.}, } @article {pmid37249667, year = {2023}, author = {Nourelden, AZ and Kamal, I and Hagrass, AI and Tawfik, AG and Elhady, MM and Fathallah, AH and Eshag, MME and Zaazouee, MS}, title = {Safety and efficacy of edaravone in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {10}, pages = {3429-3442}, pmid = {37249667}, issn = {1590-3478}, mesh = {United States ; Humans ; Edaravone/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/chemically induced ; Prospective Studies ; Quality of Life ; Severity of Illness Index ; }, abstract = {AIM: The study aims to increase understanding of edaravone's efficacy and safety as an amyotrophic lateral sclerosis (ALS) treatment and provide significant insights regarding this field's future research.

METHODS: We conducted a comprehensive search of the Embase, PubMed, Cochrane Library, Web of Science, and Scopus databases for randomized controlled trials and observational studies up until September 2022. We evaluated the studies' quality using the Cochrane risk of bias tool and the National Institutes of Health tool.

RESULTS: We included 11 studies with 2845 ALS patients. We found that edaravone improved the survival rate at 18, 24, and 30 months (risk ratio (RR) = 1.03, 95% confidence interval (CI) [1.02 to 1.24], P = 0.02), (RR = 1.22, 95% CI [1.06 to 1.41], P = 0.007), and (RR = 1.17, 95% CI [1.01 to 1.34], P = 0.03), respectively. However, the administration of edaravone did not result in any significant difference in adverse effects or efficacy outcomes between the two groups, as indicated by a P value greater than 0.05.

CONCLUSION: Edaravone improves survival rates of ALS patients at 18, 24, and 30 months with no adverse effects. However, edaravone does not affect functional outcomes. In order to ensure the validity of our findings and assess the results in accordance with the disease stage, it is essential to carry out additional prospective, rigorous, and high-quality clinical trials. The current study offers preliminary indications regarding the effectiveness and safety of edaravone. However, further comprehensive research is required to establish the generalizability and sustainability of the findings.}, } @article {pmid37248728, year = {2023}, author = {Young, HM and Kilaberia, TR and Whitney, R and Link, BM and Bell, JF and Tonkikh, O and Famula, J and Oskarsson, B}, title = {Needs of persons living with ALS at home and their family caregivers: A scoping review.}, journal = {Muscle & nerve}, volume = {68}, number = {3}, pages = {240-249}, doi = {10.1002/mus.27849}, pmid = {37248728}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Caregivers/psychology ; Cross-Sectional Studies ; *Home Care Services ; Emotions ; }, abstract = {INTRODUCTION/AIMS: Most persons with amyotrophic lateral sclerosis (ALS) live at home with support of family caregivers, with escalating complexity of care over the trajectory of the disease requiring resources and support to mitigate negative physical, social, and emotional outcomes.

METHODS: This scoping review identifies the home health/home care needs of persons with ALS and their caregivers as a basis for creating a home health medical standard. We used the PRISMA Extension for Scoping Reviews (PRISMA-ScR) to examine studies describing home care needs published between 2011 and 2021.

RESULTS: Our search yielded 481 articles, of which 44 were included with a total of 3592 (9-273) participants. Most studies used a cross-sectional design and 20 (45%) were rated as high quality. We grouped the needs identified as emotional/psychological, assistive devices and technology, information and education, and human resources and professional services. Most studies demonstrated persistent unmet needs and that available interventions were helpful while needs generally were not met proactively, despite the predictable trajectory.

DISCUSSION: This review describes biopsychosocial and equipment interventions over the trajectory of ALS with implications for anticipatory planning by clinicians, as well as policy for coverage of necessary services and supports. Interdisciplinary expert teams could develop consensus around needs across the trajectory and recommended services and supports. To make knowledge more accessible, encourage availability of services, and clarify the need for coverage of services, we aim to develop an expert consensus-based ALS home health medical standard guidance document in collaboration with the American Association of Neuromuscular and Electrodiagnostic Medicine.}, } @article {pmid37248338, year = {2023}, author = {Kumar, ST and Nazarov, S and Porta, S and Maharjan, N and Cendrowska, U and Kabani, M and Finamore, F and Xu, Y and Lee, VM and Lashuel, HA}, title = {Seeding the aggregation of TDP-43 requires post-fibrillization proteolytic cleavage.}, journal = {Nature neuroscience}, volume = {26}, number = {6}, pages = {983-996}, pmid = {37248338}, issn = {1546-1726}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *TDP-43 Proteinopathies/pathology ; *Frontotemporal Lobar Degeneration/metabolism ; *Frontotemporal Dementia ; DNA-Binding Proteins/genetics/metabolism ; }, abstract = {Despite the strong evidence linking the transactive response DNA-binding protein 43 (TDP-43) aggregation to the pathogenesis of frontotemporal lobar degeneration with TDP-43, amyotrophic lateral sclerosis and several neurodegenerative diseases, our knowledge of the sequence and structural determinants of its aggregation and neurotoxicity remains incomplete. Herein, we present a new method for producing recombinant full-length TDP-43 filaments that exhibit sequence and morphological features similar to those of brain-derived TDP-43 filaments. We show that TDP-43 filaments contain a β-sheet-rich helical amyloid core that is fully buried by the flanking structured domains of the protein. We demonstrate that the proteolytic cleavage of TDP-43 filaments and exposure of this amyloid core are necessary for propagating TDP-43 pathology and enhancing the seeding of brain-derived TDP-43 aggregates. Only TDP-43 filaments with exposed amyloid core efficiently seeded the aggregation of endogenous TDP-43 in cells. These findings suggest that inhibiting the enzymes mediating cleavage of TDP-43 aggregates represents a viable disease-modifying strategy to slow the progression of amyotrophic lateral sclerosis and other TDP-43 proteinopathies.}, } @article {pmid37248019, year = {2023}, author = {Zhang, L and Wang, W and Du, Y and Deng, Y and Bai, T and Ji, M}, title = {Multiple resistance of Echinochloa phyllopogon to synthetic auxin, ALS-, and ACCase-inhibiting herbicides in Northeast China.}, journal = {Pesticide biochemistry and physiology}, volume = {193}, number = {}, pages = {105450}, doi = {10.1016/j.pestbp.2023.105450}, pmid = {37248019}, issn = {1095-9939}, mesh = {Herbicide Resistance/genetics ; *Echinochloa/genetics ; Indoleacetic Acids ; *Herbicides/pharmacology ; Acetyl-CoA Carboxylase/genetics ; }, abstract = {Echinochloa phyllopogon is a self-pollinating allotetraploid weed and a serious threat to global rice production. One sensitive and three multiple-resistant populations collected from two provinces of Northeast China were used to analyze the mechanism of multiple resistance of E. phyllopogon to penoxsulam, metamifop, and quinclorac. Compared with the sensitive population LN12, LN1 showed higher resistance to these three herbicides; LN24 showed medium resistance to penoxsulam and metamifop and higher resistance to quinclorac (274-fold); HLJ4 showed low resistance to penoxsulam and high resistance to metamifop and quinclorac. Target sequence analysis showed no mutations in acetolactate synthase or acetyl-CoA carboxylase genes. In-vitro enzyme activity analysis showed that the activity of the target enzyme of multiple herbicide-resistant populations was similar to that of the sensitive population. The P450 inhibitor, malathion, noticeably increased the sensitivity of LN1, LN24, and HLJ4 to penoxsulam, LN1 to metamifop, and HLJ4 to quinclorac. Under all four treatments, the GSTs activities of resistant and sensitive populations showed an increasing trend from day 1 to day 5, but the sensitivity and activity of GSTs were higher in the multiple-resistant population than that in the sensitive population LN12. This study identified the development of multiple-resistant E. phyllopogon populations that pose a serious threat to rice production in rice fields in Northeast China, preliminarily confirming that multiple-resistance was likely due to non-target-site resistance mechanisms. These populations of E. phyllopogon are likely to be more difficult to control.}, } @article {pmid37247505, year = {2023}, author = {Moreno, R and Recio, J and Barber, S and Gil, C and Martinez, A}, title = {The emerging role of mixed lineage kinase 3 (MLK3) and its potential as a target for neurodegenerative diseases therapies.}, journal = {European journal of medicinal chemistry}, volume = {257}, number = {}, pages = {115511}, doi = {10.1016/j.ejmech.2023.115511}, pmid = {37247505}, issn = {1768-3254}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Parkinson Disease/drug therapy ; MAP Kinase Kinase Kinases ; Cell Death ; Mitogen-Activated Protein Kinase Kinase Kinase 11 ; }, abstract = {Selective and brain-permeable protein kinase inhibitors are in preclinical development for treating neurodegenerative diseases. Among them, MLK3 inhibitors, with a potent neuroprotective biological action have emerged as valuable agents for the treatment of pathologies such as Alzheimer's, Parkinson's disease and amyotrophic lateral sclerosis. In fact, one MLK3 inhibitor, CEP-1347, reached clinical trials for Parkinson's disease. Additionally, another compound called prostetin/12k, a potent and rather selective MLK3 inhibitor has started clinical development for ALS based on its motor neuron protection in both in vitro and in vivo models. In this review, we will focus on the role of MLK3 in neuron-related cell death processes, neurodegenerative diseases, and the potential advantages of targeting this kinase through pharmacological modulation for neuroprotective treatment.}, } @article {pmid37247026, year = {2023}, author = {Becker, W and Behler, A and Vintonyak, O and Kassubek, J}, title = {Patterns of small involuntary fixation saccades (SIFSs) in different neurodegenerative diseases: the role of noise.}, journal = {Experimental brain research}, volume = {241}, number = {7}, pages = {1821-1833}, pmid = {37247026}, issn = {1432-1106}, mesh = {Humans ; Saccades ; *Neurodegenerative Diseases ; *Amyotrophic Lateral Sclerosis ; Fixation, Ocular ; *Supranuclear Palsy, Progressive ; *Ocular Motility Disorders ; }, abstract = {During the attempt to steadily fixate at a single spot, sequences of small involuntary fixation saccades (SIFSs, known also as microsaccades οr intrusions) occur which form spatio-temporal patterns such as square wave jerks (SWJs), a pattern characterised by alternating centrifugal and centripetal movements of similar magnitude. In many neurodegenerative disorders, SIFSs exhibit elevated amplitudes and frequencies. Elevated SIFS amplitudes have been shown to favour the occurrence of SWJs ("SWJ coupling"). We analysed SIFSs in different subject groups comprising both healthy controls (CTR) and patients with amyotrophic lateral sclerosis (ALS) and progressive supranuclear palsy (PSP), i.e. two neurodegenerative diseases with completely different neuropathological basis and different clinical phenotypes. We show that, across these groups, the relations between SIFS amplitude and the relative frequency of SWJ-like patterns and other SIFS characteristics follow a common law. As an explanation, we propose that physiological and technical noise comprises a small, amplitude-independent component that has little effect on large SIFSs, but causes considerable deviations from the intended amplitude and direction of small ones. Therefore, in contrast to large SIFSs, successive small SIFSs have a lower chance to meet the SWJ similarity criteria. In principle, every measurement of SIFSs is affected by an amplitude-independent noise background. Therefore, the dependence of SWJ coupling on SIFS amplitude will probably be encountered in almost any group of subjects. In addition, we find a positive correlation between SIFS amplitude and frequency in ALS, but none in PSP, suggesting that the elevated amplitudes might arise at different sites in the two disorders.}, } @article {pmid37246507, year = {2023}, author = {Pillai, M and Das, A and Jha, SK}, title = {Electrostatic Modulation of Intramolecular and Intermolecular Interactions during the Formation of an Amyloid-like Assembly.}, journal = {Biochemistry}, volume = {62}, number = {12}, pages = {1890-1905}, doi = {10.1021/acs.biochem.3c00014}, pmid = {37246507}, issn = {1520-4995}, mesh = {Static Electricity ; *Protein Aggregates ; *Amyloid/chemistry ; Amyloidogenic Proteins ; DNA-Binding Proteins/chemistry ; Protein Folding ; }, abstract = {The mechanism of protein aggregation can be broadly viewed as a shift from the native-state stabilizing intramolecular to the aggregated-phase sustaining intermolecular interactions. Understanding the role of electrostatic forces on the extent of modulation of this switch has recently evolved as a topic of monumental significance as protein aggregation has lately been connected to charge modifications of an aging proteome. To decipher the distinctive role of electrostatic forces on the extremely complicated phase separation landscape, we opted for a combined in vitro-in silico approach to ascertain the structure-dynamics-stability-aggregability relationship of the functional tandem RRM domains of the ALS-related protein TDP-43 (TDP-43[tRRM]), under a bivariate solution condition in terms of pH and salt concentration. Under acidic pH conditions, the native TDP-43[tRRM] protein creates an aggregation-prone entropically favorable partially unfolded conformational landscape due to enthalpic destabilization caused by the protonation of the buried ionizable residues and consequent overwhelming fluctuations of selective segments of the sequence leading to anti-correlated movements of the two domains of the protein. The evolved fluffy ensemble with a comparatively exposed backbone then easily interacts with incoming protein molecules in the presence of salt via typical amyloid-aggregate-like intermolecular backbone hydrogen bonds with a considerable contribution originating from the dispersion forces. Subsequent exposure to excess salt at low pH conditions expedites the aggregation process via an electrostatic screening mechanism where salt shows preferential binding to the positively charged side chain. The applied target observable-specific approach complementarity unveils the hidden information landscape of an otherwise complex process with unquestionable conviction.}, } @article {pmid37245265, year = {2023}, author = {Biglari, N and Mehdizadeh, A and Vafaei Mastanabad, M and Gharaeikhezri, MH and Gol Mohammad Pour Afrakoti, L and Pourbala, H and Yousefi, M and Soltani-Zangbar, MS}, title = {Application of mesenchymal stem cells (MSCs) in neurodegenerative disorders: History, findings, and prospective challenges.}, journal = {Pathology, research and practice}, volume = {247}, number = {}, pages = {154541}, doi = {10.1016/j.prp.2023.154541}, pmid = {37245265}, issn = {1618-0631}, mesh = {Humans ; Prospective Studies ; *Neurodegenerative Diseases/metabolism/therapy ; *Mesenchymal Stem Cells/metabolism ; *Parkinson Disease ; *Alzheimer Disease/metabolism ; }, abstract = {Over the past few decades, the application of mesenchymal stem cells has captured the attention of researchers and practitioners worldwide. These cells can be obtained from practically every tissue in the body and are used to treat a broad variety of conditions, most notably neurological diseases such as Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Studies are still being conducted, and the results of these studies have led to the identification of several different molecular pathways involved in the neuroglial speciation process. These molecular systems are closely regulated and interconnected due to the coordinated efforts of many components that make up the machinery responsible for cell signaling. Within the scope of this study, we compared and contrasted the numerous mesenchymal cell sources and their cellular features. These many sources of mesenchymal cells included adipocyte cells, fetal umbilical cord tissue, and bone marrow. In addition, we investigated whether these cells can potentially treat and modify neurodegenerative illnesses.}, } @article {pmid37245191, year = {2023}, author = {Louapre, C and Rosenzwajg, M and Golse, M and Roux, A and Pitoiset, F and Adda, L and Tchitchek, N and Papeix, C and Maillart, E and Ungureanu, A and Charbonnier-Beaupel, F and Galanaud, D and Corvol, JC and Vicaut, E and Lubetzki, C and Klatzmann, D}, title = {A randomized double-blind placebo-controlled trial of low-dose interleukin-2 in relapsing-remitting multiple sclerosis.}, journal = {Journal of neurology}, volume = {270}, number = {9}, pages = {4403-4414}, pmid = {37245191}, issn = {1432-1459}, support = {ANR-16-RHUS-0001//ANR/ ; }, mesh = {Female ; Humans ; Double-Blind Method ; Interleukin-2/therapeutic use ; *Multiple Sclerosis ; *Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging/drug therapy ; Treatment Outcome ; Male ; Adult ; }, abstract = {BACKGROUND: Multiple sclerosis (MS) is associated with regulatory T cells (Tregs) insufficiency while low-dose interleukin-2 (IL2LD) activates Tregs and reduces disease activity in autoimmune diseases.

METHODS: We aimed at addressing whether IL2LD improved Tregs from MS patients. MS-IL2 was a single-center double-blind phase-2 study. Thirty patients (mean [SD] age 36.8 years [8.3], 16 female) with relapsing-remitting MS with new MRI lesions within 6 months before inclusion were randomly assigned in a 1:1 ratio to placebo or IL-2 at 1 million IU, daily for 5 days and then fortnightly for 6 months. The primary endpoint was change in Tregs at day-5.

RESULTS: Unlike previous trials of IL2LD in more than 20 different autoimmune diseases, Tregs were not expanded at day-5 in IL2LD group, but only at day-15 (median [IQR] fold change from baseline: 1.26 [1.21-1.33] in IL2LD group; 1.01 [0.95-1.05] in placebo group, p < 0.001). At day-5, however, Tregs had acquired an activated phenotype (fold change of CD25 expression in Tregs: 2.17 [1.70-3.55] in IL2LD versus 0.97 [0.86-1.28] in placebo group, p < 0.0001). Regulator/effector T cells ratio remained elevated throughout treatment period in the IL2LD group (p < 0.001). Number of new active brain lesions and of relapses tended to be reduced in IL2LD treated patients, but the difference did not reach significance in this trial not powered to detect clinical efficacy.

CONCLUSION: The effect of IL2LD on Tregs in MS patients was modest and delayed, compared to other auto-immune diseases. This, together with findings that Tregs improve remyelination in MS models and recent reports of IL2LD efficacy in amyotrophic lateral sclerosis, warrants larger studies of IL2LD in MS, notably with increased dosages and/or modified modalities of administration.

ClinicalTrials.gov: NCT02424396; EU Clinical trials Register: 2014-000088-42.}, } @article {pmid37245090, year = {2023}, author = {Quintana, M and Saville, BR and Vestrucci, M and Detry, MA and Chibnik, L and Shefner, J and Berry, JD and Chase, M and Andrews, J and Sherman, AV and Yu, H and Drake, K and Cudkowicz, M and Paganoni, S and Macklin, EA and , }, title = {Design and Statistical Innovations in a Platform Trial for Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {94}, number = {3}, pages = {547-560}, doi = {10.1002/ana.26714}, pmid = {37245090}, issn = {1531-8249}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Bayes Theorem ; Disease Progression ; Time Factors ; Clinical Trials as Topic ; Adaptive Clinical Trials as Topic ; }, abstract = {Platform trials allow efficient evaluation of multiple interventions for a specific disease. The HEALEY ALS Platform Trial is testing multiple investigational products in parallel and sequentially in persons with amyotrophic lateral sclerosis (ALS) with the goal of rapidly identifying novel treatments to slow disease progression. Platform trials have considerable operational and statistical efficiencies compared with typical randomized controlled trials due to their use of shared infrastructure and shared control data. We describe the statistical approaches required to achieve the objectives of a platform trial in the context of ALS. This includes following regulatory guidance for the disease area of interest and accounting for potential differences in outcomes of participants within the shared control (potentially due to differences in time of randomization, mode of administration, and eligibility criteria). Within the HEALEY ALS Platform Trial, the complex statistical objectives are met using a Bayesian shared parameter analysis of function and survival. This analysis serves to provide a common integrated estimate of treatment benefit, overall slowing in disease progression, as measured by function and survival while accounting for potential differences in the shared control group using Bayesian hierarchical modeling. Clinical trial simulation is used to provide a better understanding of this novel analysis method and complex design. ANN NEUROL 2023;94:547-560.}, } @article {pmid37244664, year = {2023}, author = {Carabajal, MD and Vidal, RP and Arancibia, JA and Olivieri, AC}, title = {A new constraint to model background signals when processing chromatographic-spectral second-order data with multivariate curve resolution.}, journal = {Analytica chimica acta}, volume = {1266}, number = {}, pages = {341354}, doi = {10.1016/j.aca.2023.341354}, pmid = {37244664}, issn = {1873-4324}, abstract = {BACKGROUND: the chemometric processing of second-order chromatographic-spectral data is usually carried out with the aid of multivariate curve resolution-alternating least-squares (MCR-ALS). When baseline contributions occur in the data, the background profile retrieved with MCR-ALS may show abnormal lumps or negative dips at the position of the remaining component peaks.

RESULTS: The phenomenon is shown to be due to remaining rotational ambiguity in the obtained profiles, as confirmed by the estimation of the boundaries of the range of feasible bilinear profiles. To avoid the abnormal features in the retrieved profile, a new background interpolation constraint is proposed and described in detail. Both simulated and experimental data are employed to support the need of the new MCR-ALS constraint. In the latter case, the estimated analyte concentrations agreed with those previously reported.

SIGNIFICANCE: The developed procedure helps to reduce the extent of rotational ambiguity in the solution and to better interpret the results on physicochemical grounds.}, } @article {pmid37243816, year = {2023}, author = {Davidson, JM and Wu, SSL and Rayner, SL and Cheng, F and Duncan, K and Russo, C and Newbery, M and Ding, K and Scherer, NM and Balez, R and García-Redondo, A and Rábano, A and Rosa-Fernandes, L and Ooi, L and Williams, KL and Morsch, M and Blair, IP and Di Ieva, A and Yang, S and Chung, RS and Lee, A}, title = {The E3 Ubiquitin Ligase SCF Cyclin F Promotes Sequestosome-1/p62 Insolubility and Foci Formation and is Dysregulated in ALS and FTD Pathogenesis.}, journal = {Molecular neurobiology}, volume = {60}, number = {9}, pages = {5034-5054}, pmid = {37243816}, issn = {1559-1182}, support = {IG1910//Motor Neurone Disease Research Australia/ ; IG2029//Motor Neurone Disease Research Australia/ ; IG2036//Motor Neurone Disease Research Australia/ ; IG2221//Motor Neurone Disease Research Australia/ ; Phyllis Diana Seman MND Research Grant//Motor Neurone Disease Research Australia/ ; BLP1901//Motor Neurone Disease Research Australia/ ; IG2308//Motor Neurone Disease Research Australia/ ; APP1095215//National Health and Medical Research Council/ ; APP1107644//National Health and Medical Research Council/ ; APP1176913//National Health and Medical Research Council/ ; APP2020035//National Health and Medical Research Council/ ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics/pathology ; *Amyotrophic Lateral Sclerosis/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Cyclins/metabolism ; Ubiquitination ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS)- and frontotemporal dementia (FTD)-linked mutations in CCNF have been shown to cause dysregulation to protein homeostasis. CCNF encodes for cyclin F, which is part of the cyclin F-E3 ligase complex SCF[cyclinF] known to ubiquitylate substrates for proteasomal degradation. In this study, we identified a function of cyclin F to regulate substrate solubility and show how cyclin F mechanistically underlies ALS and FTD disease pathogenesis. We demonstrated that ALS and FTD-associated protein sequestosome-1/p62 (p62) was a canonical substrate of cyclin F which was ubiquitylated by the SCF[cyclinF] complex. We found that SCF[cyclin F] ubiquitylated p62 at lysine(K)281, and that K281 regulated the propensity of p62 to aggregate. Further, cyclin F expression promoted the aggregation of p62 into the insoluble fraction, which corresponded to an increased number of p62 foci. Notably, ALS and FTD-linked mutant cyclin F p.S621G aberrantly ubiquitylated p62, dysregulated p62 solubility in neuronal-like cells, patient-derived fibroblasts and induced pluripotent stem cells and dysregulated p62 foci formation. Consistently, motor neurons from patient spinal cord tissue exhibited increased p62 ubiquitylation. We suggest that the p.S621G mutation impairs the functions of cyclin F to promote p62 foci formation and shift p62 into the insoluble fraction, which may be associated to aberrant mutant cyclin F-mediated ubiquitylation of p62. Given that p62 dysregulation is common across the ALS and FTD spectrum, our study provides insights into p62 regulation and demonstrates that ALS and FTD-linked cyclin F mutant p.S621G can drive p62 pathogenesis associated with ALS and FTD.}, } @article {pmid37243319, year = {2023}, author = {Elmansy, MF and Reidl, CT and Rahaman, M and Özdinler, PH and Silverman, RB}, title = {Small molecules targeting different cellular pathologies for the treatment of amyotrophic lateral sclerosis.}, journal = {Medicinal research reviews}, volume = {43}, number = {6}, pages = {2260-2302}, pmid = {37243319}, issn = {1098-1128}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Neurodegenerative Diseases/metabolism ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease in which the motor neuron circuitry displays progressive degeneration, affecting mostly the motor neurons in the brain and in the spinal cord. There are no effective cures, albeit three drugs, riluzole, edaravone, and AMX0035 (a combination of sodium phenylbutyrate and taurursodiol), have been approved by the Food and Drug Administration, with limited improvement in patients. There is an urgent need to build better and more effective treatment strategies for ALS. Since the disease is very heterogenous, numerous approaches have been explored, such as targeting genetic mutations, decreasing oxidative stress and excitotoxicity, enhancing mitochondrial function and protein degradation mechanisms, and inhibiting neuroinflammation. In addition, various chemical libraries or previously identified drugs have been screened for potential repurposing in the treatment of ALS. Here, we review previous drug discovery efforts targeting a variety of cellular pathologies that occur from genetic mutations that cause ALS, such as mutations in SOD1, C9orf72, FUS, and TARDP-43 genes. These mutations result in protein aggregation, which causes neuronal degeneration. Compounds used to target cellular pathologies that stem from these mutations are discussed and comparisons among different preclinical models are presented. Because the drug discovery landscape for ALS and other motor neuron diseases is changing rapidly, we also offer recommendations for a novel, more effective, direction in ALS drug discovery that could accelerate translation of effective compounds from animals to patients.}, } @article {pmid37240836, year = {2023}, author = {Barbieri, R and Nizzari, M and Zanardi, I and Pusch, M and Gavazzo, P}, title = {Voltage-Gated Sodium Channel Dysfunctions in Neurological Disorders.}, journal = {Life (Basel, Switzerland)}, volume = {13}, number = {5}, pages = {}, pmid = {37240836}, issn = {2075-1729}, abstract = {The pore-forming subunits (α subunits) of voltage-gated sodium channels (VGSC) are encoded in humans by a family of nine highly conserved genes. Among them, SCN1A, SCN2A, SCN3A, and SCN8A are primarily expressed in the central nervous system. The encoded proteins Nav1.1, Nav1.2, Nav1.3, and Nav1.6, respectively, are important players in the initiation and propagation of action potentials and in turn of the neural network activity. In the context of neurological diseases, mutations in the genes encoding Nav1.1, 1.2, 1.3 and 1.6 are responsible for many forms of genetic epilepsy and for Nav1.1 also of hemiplegic migraine. Several pharmacological therapeutic approaches targeting these channels are used or are under study. Mutations of genes encoding VGSCs are also involved in autism and in different types of even severe intellectual disability (ID). It is conceivable that in these conditions their dysfunction could indirectly cause a certain level of neurodegenerative processes; however, so far, these mechanisms have not been deeply investigated. Conversely, VGSCs seem to have a modulatory role in the most common neurodegenerative diseases such as Alzheimer's, where SCN8A expression has been shown to be negatively correlated with disease severity.}, } @article {pmid37240666, year = {2023}, author = {González-Mingot, C and Miana-Mena, FJ and Iñarrea, PJ and Iñiguez, C and Capablo, JL and Osta, R and Gil-Sánchez, A and Brieva, L and Larrodé, P}, title = {Mitochondrial Aconitase Enzymatic Activity: A Potential Long-Term Survival Biomarker in the Blood of ALS Patients.}, journal = {Journal of clinical medicine}, volume = {12}, number = {10}, pages = {}, pmid = {37240666}, issn = {2077-0383}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multisystemic, progressive, neurodegenerative disorder. Despite it being generally fatal within a period of 2-4 years, it is highly heterogeneous; as a result, survival periods may vary greatly among individual patients. Biomarkers can serve as tools for diagnosis, prognosis, indicators of therapeutic response, and future therapeutics. Free-radical-dependent mitochondrial damage is believed to play a crucial role in neurodegeneration in ALS. Mitochondrial aconitase, which is also known as aconitase 2 (Aco2), is a key Krebs cycle enzyme and is involved in the regulation of cellular metabolism and iron homeostasis. Aco2 is very sensitive to oxidative inactivation and can aggregate and accumulate in the mitochondrial matrix, causing mitochondrial dysfunction. Loss of Aco2 activity may therefore reflect increased levels of mitochondrial dysfunction due to oxidative damage and could be relevant to ALS pathogenesis. The aim of our study was to confirm changes in mitochondrial aconitase activity in peripheral blood and to determine whether such changes are dependent on, or independent of, the patient's condition and to propose the feasibility of using them as possible valid biomarkers to quantify the progression of the disease and as a predictor of individual prognosis in ALS.

METHODS: We measured the Aco2 enzymatic activity in the platelets of blood samples taken from 22 controls and 26 ALS patients at different stages of disease development. We then correlated antioxidant activity with clinical and prognostic variables.

RESULTS: Aco2 activity was significantly lower in the 26 ALS patients than in the 22 controls (p < 0.05). Patients with higher levels of Aco2 activity survived longer than those with lower levels (p < 0.05). Aco2 activity was also higher in patients with earlier onset (p < 0.05) and in those with predominantly upper motor neuron signs.

CONCLUSIONS: Aco2 activity seems to be an independent factor that could be used in the long-term survival prognosis of ALS. Our findings suggest that blood Aco2 could be a leading candidate for use as a biomarker to improve prognosis. More studies are needed to confirm these results.}, } @article {pmid37240459, year = {2023}, author = {Carlucci, A and Fusar Poli, B}, title = {Getting It Right in Restrictive Lung Disease.}, journal = {Journal of clinical medicine}, volume = {12}, number = {10}, pages = {}, pmid = {37240459}, issn = {2077-0383}, abstract = {Restrictive lung disease (predominantly in patients with neuromuscular disease (NMD) and ribcage deformity) may induce chronic hypercapnic respiratory failure, which represents an absolute indication to start home NIV (HNIV). However, in the early phases of NMD, patients may present only diurnal symptoms or orthopnoea and sleep disturbances with normal diurnal gas exchange. The evaluation of respiratory function decline may predict the presence of sleep disturbances (SD) and nocturnal hypoventilation that can be respectively diagnosed with polygraphy and PCO2 transcutaneous monitoring. If nocturnal hypoventilation and/or apnoea/hypopnea syndrome are detected, HNIV should be introduced. Once HNIV has been started, adequate follow-up is mandatory. The ventilator's built-in software provides important information about patient adherence and eventual leaks to correct. Detailed data about pressure and flow curves may suggest the presence of upper airway obstruction (UAO) during NIV that may occur with or without decrease in respiratory drive. Etiology and treatment of these two different forms of UAO are different. For this reason, in some circumstances, it might be useful to perform a polygraph. PtCO2 monitoring, together with pulse-oximetry, seem to be very important tools to optimize HNIV. The role of HNIV in neuromuscular disease is to correct diurnal and nocturnal hypoventilation with the consequence of improving quality of life, symptoms, and survival.}, } @article {pmid37240370, year = {2023}, author = {Mukhamedyarov, MA and Khabibrakhmanov, AN and Khuzakhmetova, VF and Giniatullin, AR and Zakirjanova, GF and Zhilyakov, NV and Mukhutdinova, KA and Samigullin, DV and Grigoryev, PN and Zakharov, AV and Zefirov, AL and Petrov, AM}, title = {Early Alterations in Structural and Functional Properties in the Neuromuscular Junctions of Mutant FUS Mice.}, journal = {International journal of molecular sciences}, volume = {24}, number = {10}, pages = {}, pmid = {37240370}, issn = {1422-0067}, support = {21-14-00044//Russian Science Foundation/ ; contract 1/22-3 dated July 13, 2022//Kazan State Medical University/ ; }, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics ; Neuromuscular Junction/metabolism ; Neurotransmitter Agents/metabolism ; RNA-Binding Protein FUS/genetics ; Synapsins/genetics/metabolism ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is manifested as skeletal muscle denervation, loss of motor neurons and finally severe respiratory failure. Mutations of RNA-binding protein FUS are one of the common genetic reasons of ALS accompanied by a 'dying back' type of degeneration. Using fluorescent approaches and microelectrode recordings, the early structural and functional alterations in diaphragm neuromuscular junctions (NMJs) were studied in mutant FUS mice at the pre-onset stage. Lipid peroxidation and decreased staining with a lipid raft marker were found in the mutant mice. Despite the preservation of the end-plate structure, immunolabeling revealed an increase in levels of presynaptic proteins, SNAP-25 and synapsin 1. The latter can restrain Ca[2+]-dependent synaptic vesicle mobilization. Indeed, neurotransmitter release upon intense nerve stimulation and its recovery after tetanus and compensatory synaptic vesicle endocytosis were markedly depressed in FUS mice. There was a trend to attenuation of axonal [Ca[2+]]in increase upon nerve stimulation at 20 Hz. However, no changes in neurotransmitter release and the intraterminal Ca[2+] transient in response to low frequency stimulation or in quantal content and the synchrony of neurotransmitter release at low levels of external Ca[2+] were detected. At a later stage, shrinking and fragmentation of end plates together with a decrease in presynaptic protein expression and disturbance of the neurotransmitter release timing occurred. Overall, suppression of synaptic vesicle exo-endocytosis upon intense activity probably due to alterations in membrane properties, synapsin 1 levels and Ca[2+] kinetics could be an early sign of nascent NMJ pathology, which leads to neuromuscular contact disorganization.}, } @article {pmid37240368, year = {2023}, author = {Singh, J and Goodman-Vincent, E and Santosh, P}, title = {Evidence Synthesis of Gene Therapy and Gene Editing from Different Disorders-Implications for Individuals with Rett Syndrome: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {24}, number = {10}, pages = {}, pmid = {37240368}, issn = {1422-0067}, support = {RE16403//Reverse Rett/ ; RE16403//Reverse Rett/ ; }, mesh = {Humans ; *Rett Syndrome/therapy/drug therapy ; Gene Editing ; Tissue Distribution ; Methyl-CpG-Binding Protein 2/genetics/metabolism ; Brain/metabolism ; Genetic Therapy ; }, abstract = {This systematic review and thematic analysis critically evaluated gene therapy trials in amyotrophic lateral sclerosis, haemoglobinopathies, immunodeficiencies, leukodystrophies, lysosomal storage disorders and retinal dystrophies and extrapolated the key clinical findings to individuals with Rett syndrome (RTT). The PRISMA guidelines were used to search six databases during the last decade, followed by a thematic analysis to identify the emerging themes. Thematic analysis across the different disorders revealed four themes: (I) Therapeutic time window of gene therapy; (II) Administration and dosing strategies for gene therapy; (III) Methods of gene therapeutics and (IV) Future areas of clinical interest. Our synthesis of information has further enriched the current clinical evidence base and can assist in optimising gene therapy and gene editing studies in individuals with RTT, but it would also benefit when applied to other disorders. The findings suggest that gene therapies have better outcomes when the brain is not the primary target. Across different disorders, early intervention appears to be more critical, and targeting the pre-symptomatic stage might prevent symptom pathology. Intervention at later stages of disease progression may benefit by helping to clinically stabilise patients and preventing disease-related symptoms from worsening. If gene therapy or editing has the desired outcome, older patients would need concerted rehabilitation efforts to reverse their impairments. The timing of intervention and the administration route would be critical parameters for successful outcomes of gene therapy/editing trials in individuals with RTT. Current approaches also need to overcome the challenges of MeCP2 dosing, genotoxicity, transduction efficiencies and biodistribution.}, } @article {pmid37240018, year = {2023}, author = {Pardo-Moreno, T and Mohamed-Mohamed, H and Suleiman-Martos, S and Ramos-Rodriguez, JJ and Rivas-Dominguez, A and Melguizo-Rodríguez, L and Gómez-Urquiza, JL and Bermudez-Pulgarin, B and Garcia-Morales, V}, title = {Amyotrophic Lateral Sclerosis and Serum Lipid Level Association: A Systematic Review and Meta-Analytic Study.}, journal = {International journal of molecular sciences}, volume = {24}, number = {10}, pages = {}, pmid = {37240018}, issn = {1422-0067}, support = {P18-RT-3324//Regional Government of Andalusia/ ; 20-01293 and PECART-0096-2020//Regional Government of Andalusia/ ; P20-01061//Regional Government of Andalusia/ ; PID2019-110960GB-I00//Ministry of Science and Innovation, Spain/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Neurodegenerative Diseases ; Triglycerides ; Cholesterol, HDL ; Cholesterol, LDL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown etiology. Many metabolic alterations occur during ALS progress and can be used as a method of pre-diagnostic and early diagnosis. Dyslipidemia is one of the physiological changes observed in numerous ALS patients. The aim of this study is to analyze the possible relationship between the rate of disease progression (functional rating scale (ALS-FRS)) and the plasma lipid levels at the early stage of ALS. A systematic review was carried out in July 2022. The search equation was "Triglycerides AND amyotrophic lateral sclerosis" and its variants. Four meta-analyses were performed. Four studies were included in the meta-analysis. No significant differences were observed between the lipid levels (total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol) and the ALS-FRS score at the onset of the disease. Although the number of studies included in this research was low, the results of this meta-analytic study suggest that there is no clear relationship between the symptoms observed in ALS patients and the plasma lipid levels. An increase in research, as well as an expansion of the geographical area, would be of interest.}, } @article {pmid37239468, year = {2023}, author = {Hedges, EC and Cocks, G and Shaw, CE and Nishimura, AL}, title = {Generation of an Open-Access Patient-Derived iPSC Biobank for Amyotrophic Lateral Sclerosis Disease Modelling.}, journal = {Genes}, volume = {14}, number = {5}, pages = {}, pmid = {37239468}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Neurodegenerative Diseases/metabolism ; Biological Specimen Banks ; Motor Neurons/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting the upper and lower motor neurons, causing patients to lose control over voluntary movement, and leading to gradual paralysis and death. There is no cure for ALS, and the development of viable therapeutics has proved challenging, demonstrated by a lack of positive results from clinical trials. One strategy to address this is to improve the tool kit available for pre-clinical research. Here, we describe the creation of an open-access ALS iPSC biobank generated from patients carrying mutations in the TARDBP, FUS, ANXA11, ARPP21, and C9ORF72 genes, alongside healthy controls. To demonstrate the utilisation of these lines for ALS disease modelling, a subset of FUS-ALS iPSCs were differentiated into functionally active motor neurons. Further characterisation revealed an increase in cytoplasmic FUS protein and reduced neurite outgrowth in FUS-ALS motor neurons compared to the control. This proof-of-principle study demonstrates that these novel patient-derived iPSC lines can recapitulate specific and early disease-related ALS phenotypes. This biobank provides a disease-relevant platform for discovery of ALS-associated cellular phenotypes to aid the development of novel treatment strategies.}, } @article {pmid37239275, year = {2023}, author = {Chen, H and Hu, Z and Ke, Z and Xu, Y and Bai, F and Liu, Z}, title = {Aberrant Multimodal Connectivity Pattern Involved in Default Mode Network and Limbic Network in Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {13}, number = {5}, pages = {}, pmid = {37239275}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that progressively affects bulbar and limb function. Despite increasing recognition of the disease as a multinetwork disorder characterized by aberrant structural and functional connectivity, its integrity agreement and its predictive value for disease diagnosis remain to be fully elucidated. In this study, we recruited 37 ALS patients and 25 healthy controls (HCs). High-resolution 3D T1-weighted imaging and resting-state functional magnetic resonance imaging were, respectively, applied to construct multimodal connectomes. Following strict neuroimaging selection criteria, 18 ALS and 25 HC patients were included. Network-based statistic (NBS) and the coupling of grey matter structural-functional connectivity (SC-FC coupling) were performed. Finally, the support vector machine (SVM) method was used to distinguish the ALS patients from HCs. Results showed that, compared with HCs, ALS individuals exhibited a significantly increased functional network, predominantly encompassing the connections between the default mode network (DMN) and the frontoparietal network (FPN). The increased structural connections predominantly involved the inter-regional connections between the limbic network (LN) and the DMN, the salience/ventral attention network (SVAN) and FPN, while the decreased structural connections mainly involved connections between the LN and the subcortical network (SN). We also found increased SC-FC coupling in DMN-related brain regions and decoupling in LN-related brain regions in ALS, which could differentiate ALS from HCs with promising capacity based on SVM. Our findings highlight that DMN and LN may play a vital role in the pathophysiological mechanism of ALS. Additionally, SC-FC coupling could be regarded as a promising neuroimaging biomarker for ALS and shows important clinical potential for early recognition of ALS individuals.}, } @article {pmid37239045, year = {2023}, author = {Ferecskó, AS and Smallwood, MJ and Moore, A and Liddle, C and Newcombe, J and Holley, J and Whatmore, J and Gutowski, NJ and Eggleton, P}, title = {STING-Triggered CNS Inflammation in Human Neurodegenerative Diseases.}, journal = {Biomedicines}, volume = {11}, number = {5}, pages = {}, pmid = {37239045}, issn = {2227-9059}, abstract = {BACKGROUND: Some neurodegenerative diseases have an element of neuroinflammation that is triggered by viral nucleic acids, resulting in the generation of type I interferons. In the cGAS-STING pathway, microbial and host-derived DNA bind and activate the DNA sensor cGAS, and the resulting cyclic dinucleotide, 2'3-cGAMP, binds to a critical adaptor protein, stimulator of interferon genes (STING), which leads to activation of downstream pathway components. However, there is limited work demonstrating the activation of the cGAS-STING pathway in human neurodegenerative diseases.

METHODS: Post-mortem CNS tissue from donors with multiple sclerosis (n = 4), Alzheimer's disease (n = 6), Parkinson's disease (n = 3), amyotrophic lateral sclerosis (n = 3) and non-neurodegenerative controls (n = 11) were screened by immunohistochemistry for STING and relevant protein aggregates (e.g., amyloid-β, α-synuclein, TDP-43). Human brain endothelial cells were cultured and stimulated with the STING agonist palmitic acid (1-400 μM) and assessed for mitochondrial stress (release of mitochondrial DNA into cytosol, increased oxygen consumption), downstream regulator factors, TBK-1/pIRF3 and inflammatory biomarker interferon-β release and changes in ICAM-1 integrin expression.

RESULTS: In neurodegenerative brain diseases, elevated STING protein was observed mainly in brain endothelial cells and neurons, compared to non-neurodegenerative control tissues where STING protein staining was weaker. Interestingly, a higher STING presence was associated with toxic protein aggregates (e.g., in neurons). Similarly high STING protein levels were observed within acute demyelinating lesions in multiple sclerosis subjects. To understand non-microbial/metabolic stress activation of the cGAS-STING pathway, brain endothelial cells were treated with palmitic acid. This evoked mitochondrial respiratory stress up to a ~2.5-fold increase in cellular oxygen consumption. Palmitic acid induced a statistically significant increase in cytosolic DNA leakage from endothelial cell mitochondria (Mander's coefficient; p < 0.05) and a significant increase in TBK-1, phosphorylated transcription factor IFN regulatory factor 3, cGAS and cell surface ICAM. In addition, a dose response in the secretion of interferon-β was observed, but it failed to reach statistical significance.

CONCLUSIONS: The histological evidence shows that the common cGAS-STING pathway appears to be activated in endothelial and neural cells in all four neurodegenerative diseases examined. Together with the in vitro data, this suggests that the STING pathway might be activated via perturbation of mitochondrial stress and DNA leakage, resulting in downstream neuroinflammation; hence, this pathway may be a target for future STING therapeutics.}, } @article {pmid37239030, year = {2023}, author = {Wang, W and Zhang, L and Xia, K and Huang, T and Fan, D}, title = {Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects.}, journal = {Biomedicines}, volume = {11}, number = {5}, pages = {}, pmid = {37239030}, issn = {2227-9059}, support = {82101489, 81873784, 82071426//National Natural Science Foundation of China/ ; 2021M690255//China Postdoctoral Science Foundation/ ; }, abstract = {BACKGROUND: Observational studies suggest that statins may affect amyotrophic lateral sclerosis (ALS). However, they are limited by confounding and reverse causality biases. Therefore, we aimed to investigate the potential causal associations between statins and ALS using a mendelian randomization (MR) approach.

METHODS: Two-sample MR and drug-target MR were performed. Exposure sources included GWAS summary statistics of statin use, low-density-lipoprotein cholesterol (LDL-C), HMGCR-mediated LDL-C and LDL-C response to statins.

RESULTS: Genetic predisposition to statin medication was associated with increased ALS risk (OR = 1.085, 95% CI = 1.025-1.148, p = 0.005). After removing SNPs significantly associated with statin use from the instrumental variables (IVs), LDL-C-related higher ALS risk was absent (before removing: OR = 1.075, 95% CI = 1.013-1.141, p = 0.017; after removing: OR = 1.036, 95% CI = 0.949-1.131, p = 0.432). HMGCR-mediated LDL-C (OR = 1.033, 95% CI = 0.823-1.296, p = 0.779) and blood LDL-C response to statins (OR = 0.998, 95% CI = 0.991-1.005, p = 0.538) had no association with ALS.

CONCLUSIONS: Here, we show that statins may be a risky exposure that increases ALS risk independent of the lowering effect of LDL-C in peripheral circulation. This provides insights into ALS development and prevention.}, } @article {pmid37238987, year = {2023}, author = {Ravnik Glavač, M and Mezzavilla, M and Dolinar, A and Koritnik, B and Glavač, D}, title = {Aberrantly Expressed Hsa_circ_0060762 and CSE1L as Potential Peripheral Blood Biomarkers for ALS.}, journal = {Biomedicines}, volume = {11}, number = {5}, pages = {}, pmid = {37238987}, issn = {2227-9059}, support = {P3-0054, P3-0338, P1-0170, AD PhD thesis grant//Slovenian Research Agency/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive adult-onset neurodegenerative disease that is often diagnosed with a delay due to initial non-specific symptoms. Therefore, reliable and easy-to-obtain biomarkers are an absolute necessity for earlier and more accurate diagnostics. Circular RNAs (circRNAs) have already been proposed as potential biomarkers for several neurodegenerative diseases. In this study, we further investigated the usefulness of circRNAs as potential biomarkers for ALS. We first performed a microarray analysis of circRNAs on peripheral blood mononuclear cells of a subset of ALS patients and controls. Among the differently expressed circRNA by microarray analysis, we selected only the ones with a host gene that harbors the highest level of conservation and genetic constraints. This selection was based on the hypothesis that genes under selective pressure and genetic constraints could have a major role in determining a trait or disease. Then we performed a linear regression between ALS cases and controls using each circRNA as a predictor variable. With a False Discovery Rate (FDR) threshold of 0.1, only six circRNAs passed the filtering and only one of them remained statistically significant after Bonferroni correction: hsa_circ_0060762 and its host gene CSE1L. Finally, we observed a significant difference in expression levels between larger sets of patients and healthy controls for both hsa_circ_0060762 and CSE1L. CSE1L is a member of the importin β family and mediates inhibition of TDP-43 aggregation; the central pathogenicity in ALS and hsa_circ_0060762 has binding sites for several miRNAs that have been already proposed as biomarkers for ALS. In addition, receiver operating characteristics curve analysis showed diagnostic potential for CSE1L and hsa_circ_0060762. Hsa_circ_0060762 and CSE1L thus represent novel potential peripheral blood biomarkers and therapeutic targets for ALS.}, } @article {pmid37238921, year = {2023}, author = {Oh, S and Jang, Y and Na, CH}, title = {Discovery of Biomarkers for Amyotrophic Lateral Sclerosis from Human Cerebrospinal Fluid Using Mass-Spectrometry-Based Proteomics.}, journal = {Biomedicines}, volume = {11}, number = {5}, pages = {}, pmid = {37238921}, issn = {2227-9059}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons, which eventually may lead to death. Critical to the mission of developing effective therapies for ALS is the discovery of biomarkers that can illuminate mechanisms of neurodegeneration and have diagnostic, prognostic, or pharmacodynamic value. Here, we merged unbiased discovery-based approaches and targeted quantitative comparative analyses to identify proteins that are altered in cerebrospinal fluid (CSF) from patients with ALS. Mass spectrometry (MS)-based proteomic approaches employing tandem mass tag (TMT) quantification methods from 40 CSF samples comprising 20 patients with ALS and 20 healthy control (HC) individuals identified 53 proteins that are differential between the two groups after CSF fractionation. Notably, these proteins included both previously identified ones, validating our approach, and novel ones that have the potential for expanding biomarker repertoire. The identified proteins were subsequently examined using parallel reaction monitoring (PRM) MS methods on 61 unfractionated CSF samples comprising 30 patients with ALS and 31 HC individuals. Fifteen proteins (APOB, APP, CAMK2A, CHI3L1, CHIT1, CLSTN3, ERAP2, FSTL4, GPNMB, JCHAIN, L1CAM, NPTX2, SERPINA1, SERPINA3, and UCHL1) showed significant differences between ALS and the control. Taken together, this study identified multiple novel proteins that are altered in ALS, providing the foundation for developing new biomarkers for ALS.}, } @article {pmid37238732, year = {2023}, author = {Maksimovic, K and Youssef, M and You, J and Sung, HK and Park, J}, title = {Evidence of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis (ALS) Patients and Animal Models.}, journal = {Biomolecules}, volume = {13}, number = {5}, pages = {}, pmid = {37238732}, issn = {2218-273X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Models, Animal ; Glucose/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventual death. Research from the past few decades has appreciated that ALS is not only a disease of the motor neurons but also a disease that involves systemic metabolic dysfunction. This review will examine the foundational research of understanding metabolic dysfunction in ALS and provide an overview of past and current studies in ALS patients and animal models, spanning from full systems to various metabolic organs. While ALS-affected muscle tissue exhibits elevated energy demand and a fuel preference switch from glycolysis to fatty acid oxidation, adipose tissue in ALS undergoes increased lipolysis. Dysfunctions in the liver and pancreas contribute to impaired glucose homeostasis and insulin secretion. The central nervous system (CNS) displays abnormal glucose regulation, mitochondrial dysfunction, and increased oxidative stress. Importantly, the hypothalamus, a brain region that controls whole-body metabolism, undergoes atrophy associated with pathological aggregates of TDP-43. This review will also cover past and present treatment options that target metabolic dysfunction in ALS and provide insights into the future of metabolism research in ALS.}, } @article {pmid37238605, year = {2023}, author = {Zhang, H and Dai, S and Yang, Y and Wei, J and Li, X and Luo, P and Jiang, X}, title = {Role of Sirtuin 3 in Degenerative Diseases of the Central Nervous System.}, journal = {Biomolecules}, volume = {13}, number = {5}, pages = {}, pmid = {37238605}, issn = {2218-273X}, mesh = {Humans ; Central Nervous System/metabolism ; Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism ; *Parkinson Disease/metabolism ; *Sirtuin 3/metabolism ; }, abstract = {An NAD[+]-dependent deacetylase called Sirtuin 3 (Sirt3) is involved in the metabolic processes of the mitochondria, including energy generation, the tricarboxylic acid cycle, and oxidative stress. Sirt3 activation can slow down or prevent mitochondrial dysfunction in response to neurodegenerative disorders, demonstrating a strong neuroprotective impact. The mechanism of Sirt3 in neurodegenerative illnesses has been elucidated over time; it is essential for neuron, astrocyte, and microglial function, and its primary regulatory factors include antiapoptosis, oxidative stress, and the maintenance of metabolic homeostasis. Neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), may benefit from a thorough and in-depth investigation of Sirt3. In this review, we primarily cover Sirt3's role and its regulation in the nerve cells and the connection between Sirt3 and neurodegenerative disorders.}, } @article {pmid37237880, year = {2023}, author = {Wunsch, FT and Metzler-Nolte, N and Theiss, C and Matschke, V}, title = {Defects in Glutathione System in an Animal Model of Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {37237880}, issn = {2076-3921}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progredient neurodegenerative disease characterized by a degeneration of the first and second motor neurons. Elevated levels of reactive oxygen species (ROS) and decreased levels of glutathione, which are important defense mechanisms against ROS, have been reported in the central nervous system (CNS) of ALS patients and animal models. The aim of this study was to determine the cause of decreased glutathione levels in the CNS of the ALS model wobbler mouse. We analyzed changes in glutathione metabolism in the spinal cord, hippocampus, cerebellum, liver, and blood samples of the ALS model, wobbler mouse, using qPCR, Western Blot, HPLC, and fluorometric assays. Here, we show for the first time a decreased expression of enzymes involved in glutathione synthesis in the cervical spinal cord of wobbler mice. We provide evidence for a deficient glutathione metabolism, which is not restricted to the nervous system, but can be seen in various tissues of the wobbler mouse. This deficient system is most likely the reason for an inefficient antioxidative system and, thus, for elevated ROS levels.}, } @article {pmid37236359, year = {2023}, author = {Thornburg-Suresh, EJC and Richardson, JE and Summers, DW}, title = {The Stathmin-2 membrane-targeting domain is required for axon protection and regulated degradation by DLK signaling.}, journal = {The Journal of biological chemistry}, volume = {299}, number = {7}, pages = {104861}, pmid = {37236359}, issn = {1083-351X}, support = {R01 NS126191/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Stathmin/genetics/metabolism ; Axons/metabolism ; Neurons/metabolism ; Signal Transduction ; *Amyotrophic Lateral Sclerosis/metabolism ; MAP Kinase Kinase Kinases/metabolism ; }, abstract = {Axon integrity is essential for functional connectivity in the nervous system. The degeneration of stressed or damaged axons is a common and sometimes initiating event in neurodegenerative disorders. Stathmin-2 (Stmn2) is an axon maintenance factor that is depleted in amyotrophic lateral sclerosis, and replenishment of Stmn2 can restore neurite outgrowth in diseased neurons. However, mechanisms responsible for Stmn2-mediated axon maintenance in injured neurons are not known. We used primary sensory neurons to interrogate the role of Stmn2 in the degeneration of severed axons. We discover that membrane association of Stmn2 is critical for its axon-protective activity. Structure-function studies revealed that axonal enrichment of Stmn2 is driven by palmitoylation as well as tubulin interaction. Using live imaging, we discover that another Stmn, Stmn3, comigrates with Stmn2-containing vesicles. We also demonstrate that Stmn3 undergoes regulated degradation through dual leucine zipper kinase (DLK)-c-Jun N-terminal kinase signaling. The Stmn2 membrane-targeting domain is both necessary and sufficient for localization to a specific vesicle population and confers sensitivity to DLK-dependent degradation. Our findings reveal a broader role for DLK in tuning the local abundance of palmitoylated Stmns in axon segments. Moreover, palmitoylation is a critical component of Stmn-mediated axon protection, and defining the Stmn2-containing vesicle population will provide important clues toward mechanisms of axon maintenance.}, } @article {pmid37233619, year = {2023}, author = {Hrafnkelsdottir, AE and Bjornsson, HM and Oskarsson, JP and Runolfsson, S}, title = {[Training of Icelandic rural doctors in managing trauma and acute illness].}, journal = {Laeknabladid}, volume = {109}, number = {6}, pages = {283-290}, doi = {10.17992/lbl.2023.06.747}, pmid = {37233619}, issn = {1670-4959}, mesh = {Humans ; Child ; Iceland ; Emergencies ; Cross-Sectional Studies ; Acute Disease ; *General Practitioners ; *Rural Health Services ; }, abstract = {INTRODUCTION: Rural medicine is in many ways different from urban primary care. In addition to providing primary care for a population, the rural doctor is tasked with the initial evaluation and stabilization of all emergencies usually managed by an Emergency Department in urban areas. The goal of this study was to assess rural doctors' in Iceland attendance of courses in Emergency Medicine (EM), how rural doctors grade their own ability to respond to emergencies and evaluate their Continuous Medical Education (CME) within the field of EM.

MATERIALS AND METHODS: In this descriptive cross-sectional study, all rural general practitioners (GP) in Iceland with at least two years of experience post foundation training and who practiced at least a quarter of every year outside the capital area were surveyed using an electronic questionnaire. T-test and qi-square test were used for analysis and significance determined if p<0.05.

RESULTS: The survey was sent to 84 doctors with 47 (56%) completing the survey. Over 90% of the participants reported having completed a course in Advanced Life Support (ALS) but only 18% had completed a course in prehospital EM specifically designed for this group of doctors. Over half of the participants considered themselves to have good training to perform 7 out of 11 surveyed emergency procedures. Over 40% of participants considered it necessary to improve their CME in 7 out of 10 categories of EM. The majority of rural GPs considered shortage of doctors in the rural environment a significant factor limiting their CME.

CONCLUSIONS: The majority of rural doctors in Iceland consider themselves to have a good training to provide initial EM care in their community. Efforts to improve their training in this field of medicine should focus on scene safety and working in the prehospital setting, pediatrics, labor and deliveries and gynecological emergencies. Rural doctors need to have access to appropriate EM training courses.}, } @article {pmid37231286, year = {2023}, author = {Goudarzi, A and Agah, E and Ghajarzadeh, M and Jazani, MR and Sarraf, P}, title = {Clinical determinants of sleep quality in patients with amyotrophic lateral sclerosis.}, journal = {Sleep & breathing = Schlaf & Atmung}, volume = {27}, number = {6}, pages = {2517-2522}, pmid = {37231286}, issn = {1522-1709}, mesh = {Humans ; Sleep Quality ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Severity of Illness Index ; Deglutition/physiology ; Patient Acuity ; *Sleep Wake Disorders/diagnosis/epidemiology/complications ; }, abstract = {OBJECTIVES: Poor sleep quality is more prevalent in patients with amyotrophic lateral sclerosis (ALS) than in healthy populations. The purpose of this study was to examine whether or not motor dysfunction at various distinct levels correlates with subjective sleep quality.

METHODS: Patients with ALS and controls were assessed using the Pittsburgh Sleep Quality Index (PSQI), ALS Functional Rating Scale Revised (ALSFRS-R), Beck Depression Inventory-II (BDI-II), and the Epworth Sleepiness Scale (ESS). The ALSFRS-R was used to obtain information on 12 different aspects of motor function in patients with ALS. We compared these data between the groups with poor and good sleep quality.

RESULTS: A total of 92 patients with ALS and 92 age- and sex-matched controls entered the study. The global PSQI score was significantly higher in patients with ALS than in healthy subjects (5.5 ± 4.2 vs. 4.0 ± 2.8) and 44% of the patients with ALS had poor sleep quality (PSQI score > 5). The sleep duration, sleep efficiency, and sleep disturbances components were significantly worse in patients with ALS. Sleep quality (PSQI) score correlated with ALSFRS-R score, BDI-II score, and ESS score. Of the 12 ALSFRS-R functions, swallowing significantly affected sleep quality. Orthopnea, speech, salivation, dyspnea, and walking had a medium effect. In addition, turning in bed, climbing stairs, and dressing and hygiene were found to have a small effect on sleep quality among patients with ALS.

CONCLUSIONS: Nearly half of our patients had poor sleep quality related to disease severity, depression, and daytime sleepiness. Bulbar muscle dysfunction may be associated with sleep disturbances in individuals with ALS, particularly when swallowing is impaired. In addition, patients suffering from axial or lower limb muscle disruptions are likely to have trouble sleeping.}, } @article {pmid37231108, year = {2023}, author = {Berriat, F and Lobsiger, CS and Boillée, S}, title = {The contribution of the peripheral immune system to neurodegeneration.}, journal = {Nature neuroscience}, volume = {26}, number = {6}, pages = {942-954}, pmid = {37231108}, issn = {1546-1726}, mesh = {Humans ; Central Nervous System ; *Alzheimer Disease/metabolism ; *Neurodegenerative Diseases/pathology ; *Amyotrophic Lateral Sclerosis/pathology ; Leukocytes/metabolism ; }, abstract = {Microglial cells are the major immune cells of the central nervous system (CNS), and directly react to neurodegeneration, but other immune cell types are also able to react to pathology and can modify the course of neurodegenerative processes. These mainly include monocytes/macrophages and lymphocytes. While these peripheral immune cells were initially considered to act only after infiltrating the CNS, recent evidence suggests that some of them can also act directly from the periphery. We will review the existing and emerging evidence for a role of peripheral immune cells in neurodegenerative diseases, both with and without CNS infiltration. Our focus will be on amyotrophic lateral sclerosis, but we will also compare to Alzheimer's disease and Parkinson's disease to highlight similarities or differences. Peripheral immune cells are easily accessible, and therefore may be an attractive therapeutic target for neurodegenerative diseases. Thus, understanding how these peripheral immune cells communicate with the CNS deserves deeper investigation.}, } @article {pmid37228467, year = {2022}, author = {Murphy, D}, title = {Invited discussant comments during the UCL-Penn Global COVID Study webinar 'Reflections, Resilience, and Recovery: A qualitative study of Covid-19's impact on an international adult population's mental health and priorities for support': part 3 of 3.}, journal = {UCL open. Environment}, volume = {4}, number = {}, pages = {e007}, pmid = {37228467}, issn = {2632-0886}, abstract = {This discussant commentary considers the findings presented from the UCL-Penn Global COVID Study webinar 'Let's Talk! What do you need to recover from Covid-19?' and published in Wong et al's article in this journal, Reflections, Resilience, and Recovery, drawing into focus the support required to recover from the changes in people's mental health, physical health and relationships brought on by the Covid-19 pandemic. Acknowledging the importance of not making broad generalisations about the effect of the lockdown allows us to see individuals in their own context and their own particular challenges. As we emerge from the Covid-19 pandemic, we need to use the lessons from this study as the foundations for building resilience against future pandemics.}, } @article {pmid37228252, year = {2023}, author = {Liu, X and Qin, T and Li, T and Shan, L and Lei, X and Xu, X and Wen, B and Feng, Y and Yin, P and Fan, D}, title = {"Huoling Shengji granule" for amyotrophic lateral sclerosis: protocol for a multicenter, randomized, double-blind, riluzole parallel controlled clinical trial.}, journal = {Frontiers in aging neuroscience}, volume = {15}, number = {}, pages = {1153973}, pmid = {37228252}, issn = {1663-4365}, abstract = {BACKGROUND: There is still a large demand for effective treatments to delay disease deterioration in amyotrophic lateral sclerosis (ALS). Typical symptoms of ALS are considered "flaccidity syndrome" in traditional Chinese medicine (TCM). Huoling Shengji Granule (HLSJ) is a TCM formula used to treat flaccidity syndrome. Results of preclinical tests and a previous clinical study support HLSJ as a novel drug for ALS patients. This trial proposed to examine whether a 48-week course of HLSJ is effective and safe for ALS patients diagnosed with the Chinese medicine syndrome of spleen qi insufficiency and kidney yang deficiency.

METHODS AND ANALYSIS: In this phase II, multicenter, randomized, double-blind, riluzole parallel-controlled, superiority-design study, eligible participants had the equal opportunity to be assigned to receive either HLSJ or riluzole randomly. Eleven specialized ALS centers in Mainland China will recruit 144 patients for this trial. The primary and secondary outcomes included the change in the ALSFRS-R score and the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) from baseline to Week 48.

DISCUSSION: Here, we endeavored to evaluate TCM for ALS using a standard evidence-based approach for the first time. In addition, the ROADS, a self-report linear-weighted questionnaire, was selected as a secondary outcome measure. We expect to offer a new reference for the outcome evaluation of ALS trials.Clinical trial registration:http://www.Chictr.org.cn, identifier ChiCTR2100044085.}, } @article {pmid37225489, year = {2024}, author = {Toyoshima, M and Suzuki, N and Mitsuzawa, S and Soga, T and Izumi, R and Mitsui, K and Miyagi, S and Aoki, M and Kato, M}, title = {Amyotrophic Lateral Sclerosis with a Priority Request for a Postmortem Kidney Donation to a Relative.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {63}, number = {2}, pages = {305-307}, pmid = {37225489}, issn = {1349-7235}, mesh = {Male ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/surgery ; *Tissue and Organ Procurement ; Autopsy ; Kidney ; }, abstract = {The patient was 57 years old when he was diagnosed with amyotrophic lateral sclerosis (ALS) at 1 year after developing bulbar symptoms. At 58 years old, he stated that he was considering donating his kidney to his son suffering from diabetic nephropathy. We confirmed the patient's intentions through repeated interviews before his death at 61 years old. Nephrectomy was performed 30 min after his cardiac death. Organ donation spontaneously proposed by an ALS patient should be considered in order to meet the requests of patients who want their families and other patients to live longer, thereby imparting a beneficial legacy through their deaths.}, } @article {pmid37225320, year = {2023}, author = {Shanker, OR and Kumar, S and Dixit, AB and Banerjee, J and Tripathi, M and Sarat Chandra, P}, title = {Epigenetics of neurological diseases.}, journal = {Progress in molecular biology and translational science}, volume = {198}, number = {}, pages = {165-184}, doi = {10.1016/bs.pmbts.2023.01.006}, pmid = {37225320}, issn = {1878-0814}, mesh = {Humans ; *Nervous System Diseases/genetics ; Epigenesis, Genetic ; *Parkinson Disease/genetics ; DNA Methylation/genetics ; Chromatin ; }, abstract = {Higher-order DNA structure and gene expression are governed by epigenetic processes like DNA methylation and histone modifications. Abnormal epigenetic mechanisms are known to contribute to the emergence of numerous diseases, including cancer. Historically, the chromatin abnormalities were only considered to be limited to discrete DNA sequences and were thought to be associated with rare genetic syndrome however, recent discoveries have pointed to genome-wide level changes in the epigenetic machinery which has contributed to a better knowledge of the mechanisms underlying developmental and degenerative neuronal problems associated with diseases such as Parkinson's disease, Huntington's disease, Epilepsy, Multiple sclerosis, etc. In the given chapter we describe the epigenetic alterations seen in various neurological disorders and further discuss the influence of these epigenetic changes on developing novel therapies.}, } @article {pmid37224600, year = {2023}, author = {Santos Silva, C and Swash, M and de Carvalho, M}, title = {Exploring the split hand phenomenon with the neurophysiological index.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {53}, number = {4}, pages = {102864}, doi = {10.1016/j.neucli.2023.102864}, pmid = {37224600}, issn = {1769-7131}, abstract = {In 164 subjects of different age groups, we studied the neurophysiological index (NI) ([CMAP amplitude/Distal motor latency] *[F-wave frequency]; CMAP=compound muscle action potential) for three hand muscles (APB= abductor pollicis brevis; FDI= first dorsal interosseous; ADM= abductor digiti minimi). A split hand index based on CMAP amplitude (SHI_CMAP) and NI (SHI_NI) were calculated ([APB CMAP amplitude or NI * FDI CMAP amplitude or NI]/[ADM CMAP amplitude or NI]). All these neurophysiological measurements differed between age groups (p<0.001). Hand muscle NIs, as well as SHI_NI and SHI_CMAP were age dependent. This may be relevant for diagnostic purposes in motor neuron diseases.}, } @article {pmid37223625, year = {2023}, author = {Mashriqi, F and Mishra, BB and Giliberto, L and Franceschi, AM}, title = {[18] F-FDG Brain PET/MRI in Amyotrophic Lateral Sclerosis- Frontotemporal Spectrum Disorder (ALS-FTSD).}, journal = {World journal of nuclear medicine}, volume = {22}, number = {2}, pages = {135-139}, pmid = {37223625}, issn = {1450-1147}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disorder involving both upper and lower motor neurons. Interestingly, 15 to 41% of patients with ALS have concomitant frontotemporal dementia (FTD). Approximately, 50% of patients with ALS can copresent with a broader set of neuropsychological pathologies that do not meet FTD diagnostic criteria. This association resulted in revised and expanded criteria establishing the ALS-frontotemporal spectrum disorder (FTSD). In this case report, we review background information, epidemiology, pathophysiology, and structural and molecular imaging features of ALS-FTSD.}, } @article {pmid37223565, year = {2023}, author = {Brotherton, JML and McDermott, T and Smith, MA and Machalek, DA and Shilling, H and Prang, KH and Jennett, C and Nightingale, C and Zammit, C and Pagotto, A and Rankin, NM and Kelaher, M}, title = {Implementation of Australia's primary human papillomavirus (HPV) cervical screening program: The STakeholders Opinions of Renewal Implementation and Experiences Study.}, journal = {Preventive medicine reports}, volume = {33}, number = {}, pages = {102213}, pmid = {37223565}, issn = {2211-3355}, abstract = {In this study, we aimed to document stakeholders' experiences of implementing Australia's renewed National Cervical Screening Program. In December 2017, the program changed from 2nd yearly cytology for 20-69 year olds to 5 yearly human papillomavirus (HPV) screening for women 25-74 years. We undertook semi-structured interviews with key stakeholders including government, program administrators, register staff, clinicians and health care workers, non-government organisations, professional bodies, and pathology laboratories from across Australia between Nov 2018 - Aug 2019. Response rate to emailed invitations was 49/85 (58%). We used Proctor et al's (2011) implementation outcomes framework to guide our questions and thematic analysis. We found that stakeholders were evenly divided over whether implementation was successful. There was strong support for change, but concern over aspects of the implementation. There was some frustration related to the delayed start, timeliness of communication and education, shortcomings in change management, lack of inclusion of Aboriginal and Torres Strait Islander people in planning and implementation, failure to make self-collection widely available, and delays in the National Cancer Screening Register. Barriers centred around a perceived failure to appreciate the enormity of the change and register build, and consequent failure to resource, project manage and communicate effectively. Facilitators included the good will and dedication of stakeholders, strong evidence base for change and the support of jurisdictions during the delay. We documented substantial implementation challenges, offering learnings for other countries transitioning to HPV screening. Sufficient planning, significant and transparent engagement and communication with stakeholders, and change management are critical.}, } @article {pmid37223542, year = {2023}, author = {Ciccarone, F and Castelli, S and Lazzarino, G and Scaricamazza, S and Mangione, R and Bernardini, S and Apolloni, S and D'Ambrosi, N and Ferri, A and Ciriolo, MR}, title = {Lipid catabolism and mitochondrial uncoupling are stimulated in brown adipose tissue of amyotrophic lateral sclerosis mouse models.}, journal = {Genes & diseases}, volume = {10}, number = {2}, pages = {321-324}, pmid = {37223542}, issn = {2352-3042}, } @article {pmid37223130, year = {2023}, author = {Ruf, WP and Boros, M and Freischmidt, A and Brenner, D and Grozdanov, V and de Meirelles, J and Meyer, T and Grehl, T and Petri, S and Grosskreutz, J and Weyen, U and Guenther, R and Regensburger, M and Hagenacker, T and Koch, JC and Emmer, A and Roediger, A and Steinbach, R and Wolf, J and Weishaupt, JH and Lingor, P and Deschauer, M and Cordts, I and Klopstock, T and Reilich, P and Schoeberl, F and Schrank, B and Zeller, D and Hermann, A and Knehr, A and Günther, K and Dorst, J and Schuster, J and Siebert, R and Ludolph, AC and Müller, K}, title = {Spectrum and frequency of genetic variants in sporadic amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {5}, number = {3}, pages = {fcad152}, pmid = {37223130}, issn = {2632-1297}, abstract = {Therapy of motoneuron diseases entered a new phase with the use of intrathecal antisense oligonucleotide therapies treating patients with specific gene mutations predominantly in the context of familial amyotrophic lateral sclerosis. With the majority of cases being sporadic, we conducted a cohort study to describe the mutational landscape of sporadic amyotrophic lateral sclerosis. We analysed genetic variants in amyotrophic lateral sclerosis-associated genes to assess and potentially increase the number of patients eligible for gene-specific therapies. We screened 2340 sporadic amyotrophic lateral sclerosis patients from the German Network for motor neuron diseases for variants in 36 amyotrophic lateral sclerosis-associated genes using targeted next-generation sequencing and for the C9orf72 hexanucleotide repeat expansion. The genetic analysis could be completed on 2267 patients. Clinical data included age at onset, disease progression rate and survival. In this study, we found 79 likely pathogenic Class 4 variants and 10 pathogenic Class 5 variants (without the C9orf72 hexanucleotide repeat expansion) according to the American College of Medical Genetics and Genomics guidelines, of which 31 variants are novel. Thus, including C9orf72 hexanucleotide repeat expansion, Class 4, and Class 5 variants, 296 patients, corresponding to ∼13% of our cohort, could be genetically resolved. We detected 437 variants of unknown significance of which 103 are novel. Corroborating the theory of oligogenic causation in amyotrophic lateral sclerosis, we found a co-occurrence of pathogenic variants in 10 patients (0.4%) with 7 being C9orf72 hexanucleotide repeat expansion carriers. In a gene-wise survival analysis, we found a higher hazard ratio of 1.47 (95% confidence interval 1.02-2.1) for death from any cause for patients with the C9orf72 hexanucleotide repeat expansion and a lower hazard ratio of 0.33 (95% confidence interval 0.12-0.9) for patients with pathogenic SOD1 variants than for patients without a causal gene mutation. In summary, the high yield of 296 patients (∼13%) harbouring a pathogenic variant and oncoming gene-specific therapies for SOD1/FUS/C9orf72, which would apply to 227 patients (∼10%) in this cohort, corroborates that genetic testing should be made available to all sporadic amyotrophic lateral sclerosis patients after respective counselling.}, }